An Imprint of Elsevier The Curtis Center 170 S Independence Mall W 300E Philadelphia, Pennsylvania 19106 Urologic Oncology
ISBN: 0-7216-0003-4
Copyright © 2005 by Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Health Sciences Rights Department in Philadelphia, PA, USA: phone: (+1) 215 238 7869, fax: (+1) 215 238 2239, e-mail:
[email protected]. You may also complete your request on-line via the Elsevier homepage (http://www.elsevier.com), by selecting “Customer Support” and then “Obtaining Permissions.”
NOTICE Urologic oncology is an ever-changing field. Standard safety precautions must be followed, but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product information provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the licensed prescriber, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the publisher nor the author assumes any liability for any injury and/or damage to persons or property arising from this publication.
Library of Congress Cataloging-in-Publication Data Urologic oncology / [edited by] Jerome P. Richie, Anthony D’Amico. p.; cm. Includes bibliographical references. ISBN 0-7216-0003-4 (alk. paper) 1. Genitourinary organs–Cancer. I. Richie, Jerome P. II. D’Amico, Anthony V. [DNLM: 1. Urologic Neoplasms–therapy. 2. Urologic Neoplasms–diagnosis. WJ 160 U7844 2005] RC280.U74U75 2005 616.99¢461–dc22 2004045390
Acquisitions Editor: Rebecca Schmidt Gaertner Editorial Assistant: Suzanne Flint Printed in the United States of America Last digit is the print number:
9
8
7
6
5
4
3
2
1
CONTRIBUTORS SIDNEY C. ABREU, MD
RICHARD BIHRLE, MD
Fellow, Section of Laparoscopic and Minimally Invasive Surgery Glickman Urological Institute Cleveland Clinic Foundation Cleveland, Ohio 13: Laparoscopic Radical and Partial Nephrectomy
Professor of Urology Indiana University School of Medicine Indianapolis, Indiana 38: Radical Orchiectomy and Retroperitoneal Lymph Node Dissection
ALEX F. ALTHAUSEN, MD
FIONA C. BURKHARD, MD
Associate Clinical Professor (Urology), Department of Surgery Harvard Medical School and Massachusetts General Hospital Cancer Center Boston, Massachusetts 22: Selective Bladder Preservation by Combined Modality Treatment
GERALD L. ANDRIOLE, MD Professor, Department of Surgery Chief, Division of Urologic Surgery Washington University School of Medicine; Director, Prostate Study Center at Barnes-Jewish Hospital St. Louis, Missouri 43: Superficial Carcinoma of the Penis: Management and Prognosis
DARIUS J. BÄGLI, MD, CM, FRCSC, FAAP Associate Professor of Surgery, Division of Urology The University of Toronto Faculty of Medicine Toronto, Ontario, Canada 49: Prepubertal Testicular Tumors
Department of Urology University of Bern Bern, Switzerland 24: Orthotopic Bladder Substitution in the Male and Female
MICHAEL C. CARR, MD, PhD Assistant Professor of Urology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 46: Neuroblastoma
PETER R. CARROLL, MD Professor and Chair, Department of Urology University of California, San Francisco San Francisco, California 23: Noncontinent and Continent Cutaneous Urinary Diversion 26A: Clinically Localized Adenocarcinoma of the Prostate: (Stage T1a-T2c): Surgical Management and Prognosis
GLEN W. BARRISFORD, MD Resident in Urology Brigham and Women’s Hospital Harvard Medical School Boston, Massachusetts 32: Complications of Surgical Treatment for Localized Prostatectomy Cancer
WILLIAM J. CATALONA, MD
JAY S. BELANI, MD
XAVIER CATHELINEAU, MD
Resident, Division of Urologic Surgery Washington University School of Medicine St. Louis, Missouri 43: Superficial Carcinoma of the Penis: Management and Prognosis
ARIE BELLDEGRUN, MD, FACS Professor of Urology; Chief, Division of Urologic Oncology David Geffen School of Medicine at UCLA Los Angeles, California 14: Treatment of Advanced Renal Cell Carcinoma
Professor of Urology Northwestern University Feinberg School of Medicine Chicago, Illinois 29: Anatomic Nerve-Sparing Radical Retropubic Prostatectomy
Professor, Department of Urology L’Institut Mutualiste Montsouris Paris, France 31: Laparoscopic Radical Prostatectomy
SAM S. CHANG, MD Assistant Professor, Department of Urologic Surgery Vanderbilt University School of Medicine Nashville, Tennessee 19: Prognosis and Management of Invasive Transitional Cell Carcinoma
v
vi Contributors
RICHARD CHILDS, MD
ANDREW J. DRESLIN, MD
Allogeneic Hematopoietic Cell Transplant Unit, Hematology Branch National Heart, Lung, and Blood Institute National Institutes of Health Bethesda, Maryland 5: Immunotherapy: Basic Guidelines
Resident in Urology Brigham and Women’s Hospital Boston, Massachusetts 16: Management of Upper Urinary Tract Transitional Cell Carcinoma
STEVEN J. CHMURA, MD, PhD
Professor of Urology Mount Sinai School of Medicine New York, New York 17: Diagnosis and Staging of Bladder Cancer
Resident, Department of Radiation and Cellular Oncology The University of Chicago Hospitals Chicago, Illinois 3: Principles and Applications of Radiation Oncology
MICHAEL J. DROLLER, MD
DONALD S. COFFEY, PhD
VICTOR FERLISE, MD
Professor, Oncology, Pharmacology and Molecular Sciences; Director, Research Laboratories James Buchanan Brady Urological Institution The Johns Hopkins Medical Institutions Baltimore, Maryland 1: The Molecular and Cellular Biology of Urologic Cancers
Instructor of Urology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 39: Retroperitoneal Tumors: Diagnosis, Staging, Surgery, Management, and Prognosis
MICHAEL S. COOKSON, MD
ROBERT A. FIGLIN, MD, FACP
Associate Professor, Department of Urologic Surgery Vanderbilt University School of Medicine Nashville, Tennessee 19: Prognosis and Management of Invasive Transitional Cell Carcinoma
Professor of Medicine and Urology David Geffen School of Medicine at UCLA Los Angeles, California 14: Treatment of Advanced Renal Cell Carcinoma
MAX J. COPPES, MD, PhD, MBA Head, Division of Paediatric Oncology; Professor, Departments of Oncology and Paediatrics University of Calgary Faculty of Medicine Calgary, Alberta, Canada 47: Wilms’ Tumor
PATRICK J. CREAVEN, MBBS, PhD Research Professor School of Medicine & Biomedical Sciences SUNY Buffalo; Senior Investigator Roswell Park Cancer Institute Buffalo, New York 4: Principles of Chemotherapy for Genitourinary Cancer
ANTHONY V. D’AMICO, MD, PhD
ROBERT C. FLANIGAN, MD Albert J. Speh, Jr, and Clair R. Speh Professor and Chairperson Department of Urology Stritch School of Medicine Loyola University Maywood, Illinois 40: Urethral Cancer
RICHARD S. FOSTER, MD Professor of Urology Indiana University School of Medicine Indianapolis, Indiana 38: Radical Orchiectomy and Retroperitoneal Lymph Node Dissection
Professor, Department of Radiation Oncology Harvard Medical School; Chief, Genitourinary Radiation Oncology Dana-Farber Cancer Institute Brigham and Women’s Hospital Boston, Massachusetts 25: Cancer of the Prostate: Detection and Staging
YVES FRADET, MD, FRCSC
PHILLIPP DAHM, MD
JUDSON R. GASH, MD
Associate Professor, Division of Urology Department of Surgery Duke University Medical Center Durham, North Carolina 30: Radical Perineal Prostatectomy
Associate Professor of Radiology University of Tennessee Knoxville, Tennessee 10: Diagnosis and Staging of Renal Cell Cancer
TRACY M. DOWNS, MD
INDERBIR S. GILL, MD, MCH
Assistant Professor, Division of Urology University of California, San Diego School of Medicine La Jolla, California 23: Noncontinent and Continent Cutaneous Urinary Diversion
Glickman Urological Institute Cleveland Clinic Foundation Cleveland, Ohio 13: Laparoscopic Radical and Partial Nephrectomy
Professor and Chairman, Department of Surgery Faculty of Medicine Université Laval Québec, Canada 20: Transurethral Surgery of Bladder Tumors
Contributors vii
MISOP HAN, MD
FREDERICK A. KLEIN, MD
Assistant Professor, Department of Urology Feinberg School of Medicine Northwestern University Chicago, Illinois 29: Anatomic Nerve-Sparing Radical Retropubic Prostatectomy
Professor and Chairman, Division of Urology University of Tennessee Medical Center Knoxville, Tennessee 10: Diagnosis and Staging of Renal Cell Cancer
J. MATTHEW HASSAN, MD
ERIC A. KLEIN, MD
Resident Vanderbilt University School of Medicine Nashville, Tennessee 19: Prognosis and Management of Invasive Transitional Cell Carcinoma
NIALL M. HENEY, MD, Clinical Assistant Professor of Surgery Harvard Medical School and Massachusetts General Hospital Boston, Massachusetts 22: Selective Bladder Preservation by Combined Modality Treatment
Glickman Urological Institute The Cleveland Clinic Foundation Cleveland, Ohio 37: Nongerm Cell Tumors of the Testis
BADRINATH R. KONETY, MD, MBA Assistant Professor, Department of Urology University of Iowa Iowa City, Iowa 15: Transitional Cell Carcinoma of the Renal Cell Pelvis and Ureter: Evaluation and Treatment
TRACEY KRUPSKI, MD WERNER W. HOCHREITER, MD Department of Urology University Hospital of Bern Bern, Switzerland 24: Orthotopic Bladder Substitution in the Male and Female
Clinical Instructor David Geffen School of Medicine at UCLA Los Angeles, California 14: Treatment of Advanced Renal Cell Carcinoma
SANJAYA KUMAR, MD
Urologist Lakeshore General Hospital Montreal, Québec, Canada 34: Testis Tumors: Diagnosis and Staging
Assistant Professor, Department of Surgery Harvard Medical School; Division of Urology Brigham & Women’s Hospital Boston, Massachusetts 41: Urethrectomy
MICHAEL A.S. JEWETT, MD, FRCSC, FACS
LOUIS LACOMBE, MD, FRCSC
Professor, Department of Surgery (Urology) University of Toronto Toronto, Ontario, Canada 35: Seminoma: Management and Prognosis
Assistant Professor of Urology, Department of Surgery Faculty of Medicine Université Laval Québec, Canada 20: Transurethral Surgery of Bladder Tumors
AVRUM JACOBSON, MD, CM
MICHAEL W. KATTAN, PhD, MD Associate Professor of Public Health and Biostatistics in Urology Cornell University New York, New York 25: Cancer of the Prostate: Detection and Staging
DONALD S. KAUFMAN, MD
PAUL H. LANGE, MD Professor and Chairman Department of Urology University of Washington Medical Center Seattle, Washington 34: Testis Tumors: Diagnosis and Staging
Clinical Professor of Medicine Harvard Medical School; Director, The Claire and John Bertucci Center for Genitourinary Cancers Massachusetts General Hospital Boston, Massachusetts 22: Selective Bladder Preservation by Combined Modality Treatment
W. ROBERT LEE, MD, MS
HYUNG KIM, MD
HOWARD S. LEVIN, MD
Assistant Professor, Department of Urology Roswell Park Cancer Center Buffalo, New York 14: Treatment of Advanced Renal Cell Carcinoma
Staff, Department of Anatomic Pathology The Cleveland Clinic Foundation Cleveland, Ohio 37: Nongerm Cell Tumors of the Testis
Associate Professor and Vice-Chairman Department of Radiation Oncology Wake Forest University School of Medicine Winston-Salem, North Carolina 26B: Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy
viii Contributors
W. MARSTON LINEHAN, MD
MAXWELL V. MENG, MD
Chief, Urologic Surgery National Institutes of Health National Cancer Institute/Urologic Oncology Branch Bethesda, Maryland 5: Immunotherapy: Basic Guidelines
Assistant Professor, Department of Urology University of California, San Francisco San Francisco, California 23: Noncontinent and Continent Cutaneous Urinary Diversion; 26A: Clinically Localized Adenocarcinoma of the Prostate: (Stage T1aT2c): Surgical Management and Prognosis
MARK S. LITWIN, MD, MPH Professor of Urology and Health Services David Geffen School of Medicine at UCLA Los Angeles, California 6: Health-Related Quality of Life Issues in Urologic Oncology
KEVIN R. LOUGHLIN, MD, MBA
PETER D. METCALFE, MD Resident in Urology Dalhousie University Halifax, Nova Scotia, Canada 49: Prepubertal Testicular Tumors
Professor of Surgery (Urology) Harvard Medical School; Senior Surgeon Brigham and Women’s Hospital Boston, Massachusetts 42: Squamous Cell Carcinoma of the Penis: Diagnosis and Staging
M. DROR MICHAELSON, MD, PhD
DONALD F. LYNCH, Jr, MD
AARON J. MILBANK, MD
Instructor in Medicine Harvard Medical School Boston, Massachusetts 22: Selective Bladder Preservation by Combined Modality Treatment
Professor and Chairman, Department of Urology Eastern Virginia Medical School and Jones Institute for Reproductive Medicine Norfolk, Virginia 45: Penectomy and Ilioinguinal Lymphadenectomy
Glickman Urological Institute The Cleveland Clinic Foundation Cleveland, Ohio 37: Nongerm Cell Tumors of the Testis
S. BRUCE MALKOWICZ, MD Professor of Urology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 39: Retroperitoneal Tumors: Diagnosis, Staging, Surgery, Management, and Prognosis
Professor of Urology University of Washington School of Medicine; Chief, Division of Pediatric Urology Children’s Hospital & Regional Medical Center Seattle, Washington 46: Neuroblastoma
MURUGESAN MANOHARAN, MD, FRCS
ASHRAF MOSHARAFA, MD
Assistant Professor, Department of Urology University of Miami School of Medicine Miami, Florida 18: Superficial Transitional Cell Carcinoma of the Bladder: Management and Prognosis
MICHAEL E. MITCHELL, MD
Fellow in Urology Indiana University School of Medicine Indianapolis, Indiana 38: Radical Orchiectomy and Retroperitoneal Lymph Node Dissection
ANDREW C. NOVICK, MD FRAY F. MARSHALL, MD Chairman of Urology Emory University School of Medicine Atlanta, Georgia 11: Renal Cell Carcinoma: Localized Disease
MARY FRANCES MCALEER, MD, PhD
Professor of Surgery Cleveland Clinic Lerner College of Medicine; Chairman, Glickman Urological Institute Cleveland Clinic Foundation Cleveland, Ohio 12: Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy
Resident, Department of Radiation Oncology Thomas Jefferson University Philadelphia, Pennsylvania 27: Regionally Advanced Adenocarcinoma of the Prostate: (T3-4N + M0): Management and Prognosis
WILLIAM K. OH, MD
W. SCOTT MCDOUGAL, MD
MICHAEL P. O’LEARY, MD
Walter S. Kerr, Jr. Professor of Urology Harvard Medical School; Chief, Urology Service Massachusetts General Hospital Boston, Massachusetts 44: Invasive Carcinoma of the Penis: Management and Prognosis
Assistant Professor, Department of Surgery Harvard Medical School; Division of Urology Brigham and Women’s Hospital Boston, Massachusetts 32: Management of Complications of Radical Prostatectomy Surgery
Assistant Professor of Medicine Harvard Medical School Boston, Massachusetts 28: Metastatic Adenocarcinoma of the Prostate
Contributors ix
KENNETH OGAN, MD
MARTIN G. SANDA, MD
Assistant Professor of Urology Emory University School of Medicine Atlanta, Georgia 11: Renal Cell Carcinoma: Localized Disease
Visiting Associate Professor at Harvard Medical School, Division of Urology; Beth Israel Deaconess Medical Center Boston, Massachusetts 2: Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations
RISHIKESH PANDYA, MCH, DNB, MS Fellow, Division of Urology University of Toronto Toronto, Ontario, Canada 35: Seminoma: Management and Prognosis
DAVID F. PAULSON, MD Professor of Urology Duke University Medical Center Durham, North Carolina 30: Radical Perineal Prostatectomy
DAVID F. PENSON, MD, MPH Associate Professor of Urology and Preventive Medicine Keck School of Medicine University of Southern California Los Angeles, California 6: Health-Related Quality of Life Issues in Urologic Oncology
WILLIAM U. SHIPLEY, MD Andres Soriano Professor of Radiation Oncology Harvard Medical School; Head, Genitourinary Oncology Unit Department of Radiation Oncology Massachusetts General Hospital Boston, Massachusetts 22: Selective Bladder Preservation by Combined Modality Treatment
WENDLA SILVERBERG, MD Resident, Department of Radiation and Cellular Oncology The University of Chicago Chicago, Illinois 3: Principles and Applications of Radiation Oncology
DONALD G. SKINNER, MD
Assistant Professor of Medicine Keck School of Medicine University of Southern California Los Angeles, California 4: Principles of Chemotherapy for Genitourinary Cancer
Professor and Chairman, Department of Urology Hanson-White Chair in Medical Research Keck School of Medicine University of Southern California Los Angeles, California 21: Partial and Radical Cystectomy
DEREK RAGHAVAN, MD, PhD
JOSEPH A. SMITH, Jr, MD
DAVID I. QUINN, MD
Professor, Lerner College of Medicine; Chairman and Director, Cleveland Clinic Taussig Cancer Center The Cleveland Clinic Foundation Cleveland, Ohio 4: Principles of Chemotherapy for Genitourinary Cancer
MICHAEL L. RITCHEY, MD Professor of Surgery and Pediatrics; Director, Division of Urology University of Texas Health Science Center Houston Medical Center Houston, Texas 47: Wilms’ Tumor
William L. Bray Professor and Chairman Department of Urologic Surgery Vanderbilt University School of Medicine Nashville, Tennessee 19: Prognosis and Management of Invasive Transitional Cell Carcinoma
HOWARD M. SNYDER, III, MD Professor of Urology University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 48: Rhabdomyosarcoma of the Pelvis and Paratesticular Structures
MARK S. SOLOWAY, MD
Assistant Professor, Department of Urology The Johns Hopkins University Baltimore, Maryland 2: Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations
Professor and Chairman Department of Urology University of Miami School of Medicine Miami, Florida 18: Superficial Transitional Cell Carcinoma of the Bladder: Management and Prognosis
RANDALL G. ROWLAND, MD, PHD
GRAEME S. STEELE, MD
Professor and Chief, Division of Urology University of Kentucky College of Medicine Lexington, Kentucky 36: Nonseminomatous Germ Cell Tumors: Management and Prognosis
Assistant Professor of Surgery Harvard Medical School and Brigham and Women’s Hospital Boston, Massachusetts 16: Management of Upper Urinary Tract Transitional Cell Carcinoma
RONALD RODRIGUEZ, MD, PhD
x Contributors
JOHN P. STEIN, MD
PAMELA UNGER, MD
Associate Professor of Urology Keck School of Medicine University of Southern California Los Angeles, California 21: Partial and Radial Cystectomy
Associate Professor of Pathology Mount Sinai School of Medicine New York, New York 33: Seminal Vesicles: Diagnosis, Staging, Surgery, Management, and Prognosis
RICHARD G. STOCK, MD
RICHARD K. VALICENTI, MD
Professor of Radiation Oncology Mount Sinai School of Medicine New York, New York 33: Seminal Vesicles: Diagnosis, Staging, Surgery, Management, and Prognosis
NELSON N. STONE, MD
Associate Professor of Radiation Oncology Thomas Jefferson University Philadelphia, Pennsylvania 27: Regionally Advanced Adenocarcinoma of the Prostate: (T3-4N + M0): Management and Prognosis
Professor of Urology and Radiation Oncology Mount Sinai School of Medicine New York, New York 33: Seminal Vesicles: Diagnosis, Staging, Surgery, Management, and Prognosis
GUY VALLANCIEN, MD
URS E. STUDER, MD
CELI VAROL, MD
Chairman University of Bern; Director, Department of Urology University Hospital of Bern Bern, Switzerland 24: Orthotopic Bladder Substitution in the Male and Female
AGNIESZKA SZOT BARNES, MD, MS Research Fellow in Prostate Image-Guided Therapy Program Department of Radiology Brigham and Women’s Hospital Boston, Massachusetts 7: Image-Guided Minimally Invasive Therapy
SHAHIN TABATABAEI, MD Instructor in Surgery Harvard Medical School Boston, Massachusetts 44: Invasive Carcinoma of the Penis: Management and Prognosis
MIAH-HIANG TAY, MBBS, MRCP National Cancer Centre of Singapore Singapore 28: Metastatic Adenocarcinoma of the Prostate
Head, Departments of Urology and Nephrology L’Institut Mutualiste Montsouris Paris, France 31: Laparoscopic Radical Prostatectomy
Department of Urology University Hospital of Bern Bern, Switzerland 24: Orthotopic Bladder Substitution in the Male and Female
E. DARRACOTT VAUGHAN, Jr, MD Professor Weill Medical College of Cornell University New York, New York 8: Adrenal Tumors
JOHANNES VIEWEG, MD Associate Professor of Urology and Immunology Duke University Medical Center Durham, North Carolina 30: Radical Perineal Prostatectomy
DONALD VINDIVICH, MD Senior Researcher, James Buchanan Brady Urological Institution The Johns Hopkins Medical Institutions Baltimore, Maryland 1: The Molecular and Cellular Biology of Urologic Cancers
CLARE M.C. TEMPANY, MB, BAO, BCh
DAVID S. WANG, MD
Professor, Department of Radiology Harvard Medical School; Director, Clinical Magnetic Resonance Imaging Brigham and Women’s Hospital Boston, Massachusetts 7: Image-Guided Minimally Invasive Therapy
PADRAIG WARDE, MB, BCh, BAO
RABI TIGUERT, MD Fellow, Urology–Oncology Université Laval Québec, Canada 20: Transurethral Surgery of Bladder Tumors
Assistant Professor of Urology Boston University School of Medicine Boston, Massachusetts 9: Open and Laparoscopic Surgery of Adrenal Tumors
Professor, Department of Radiation Oncology University of Toronto; Associate Director, Radiation Medicine Program Princess Margaret Hospital Toronto, Ontario, Canada 35: Seminoma: Management and Prognosis
Contributors xi
W. BEDFORD WATERS, MD
HSI-YANG WU, MD
Professor of Urology University of Tennessee Knoxville, Tennessee 10: Diagnosis and Staging of Renal Cell Cancer
Assistant Professor of Urology University of Pittsburgh Pittsburgh, Pennsylvania 48: Rhabdomyosarcoma of the Pelvis and Paratesticular Structures
RALPH R. WEICHSELBAUM, MD
JASON B. WYNBERG, MD, FRCSC
Chairman, Department of Radiation and Cellular Oncology The University of Chicago Chicago, Illinois 3: Principles and Applications of Radiation Oncology
Urologic Oncology Fellow National Cancer Institute Bethesda, Maryland 5: Immunotherapy: Basic Guidelines
RICHARD D. WILLIAMS, MD
ANTHONY L. ZIETMAN, MD
Professor and Head, Department of Urology Rubin H. Flocks Chair University of Iowa Iowa City, Iowa 15: Transitional Cell Carcinoma of the Renal Cell Pelvis and Ureter: Evaluation and Treatment
Professor of Radiation Oncology Harvard Medical School; Director of Residency Training for Radiation Oncology Massachusetts General Hospital Boston, Massachusetts 22: Selective Bladder Preservation by Combined Modality Treatment
HOWARD N. WINFIELD, MD Professor of Urology Director of Endourology and Minimally Invasive Surgery; University of Iowa Iowa City, Iowa 9: Open and Laparoscopic Surgery of Adrenal Tumors
PREFACE Urologic cancer has become a major public health problem in the United States: an estimated 42% of all new cancers in men and 16% of cancer deaths in men are a result of urologic cancers. Although less common in women, bladder and kidney cancer still rank among significant causes of morbidity and mortality. The impact of urologic cancers on the population and the far-reaching advances in urologic oncology have provided the impetus for this new textbook, which covers all aspects of urologic oncology in a concise yet focused fashion. Major strides have been accomplished in the field of urologic oncology, particularly in the area of prostate cancer, where an estimated 220,900 new cases were expected in 2003 and a significant but decreasing number of deaths totaling 31,800. Three sentinel factors have catalyzed the advances in the diagnosis and treatment of prostate cancer: the discovery and application of serum prostate specific antigen and its isoforms for early detection of prostate cancer, the development of effective surgical and radiotherapeutic approaches that increase efficacy and reduce morbidity from prostate cancer, and the utilization of an increasing number of transrectal ultrasound spring loaded needle guided biopsies to more efficiently diagnose prostate cancer in an ambulatory setting. Urologic oncology has matured from case studies to evidence-based medicine. Randomized prospective studies in many arenas of urologic oncology have aided the clinician in decision-making processes. The stratification of patients into various prognostic groups based on pretreatment factors has allowed accurate comparisons of cancer control outcome of different modalities of treatment. Urologic oncology has become a multidisciplinary specialty, with integration of medical oncology and radiation oncology specialists along with urologic oncologist to provide the most comprehensive treatment options for the patient with urologic malignancy. This textbook provides basic principles of medical and surgical urologic oncology. Each urologic cancer tumor type is reviewed with regard to incidence, etiology, clinical presentation, diagnosis and staging, treatment options, prognosis, and future directions. Common surgical procedures for genitourinary cancers are discussed in terms of indications, preoperative preparation, technique, efficacy, and side effects. Both adult and pediatric malignancies, including neuroblastoma, Wilms’ tumor, testis tumors, and rhabdomyosarcoma, are reviewed in detail. Leading authorities in the field have contributed their knowledge and expertise to this compendium of urologic oncology. The text is supplemented with tables and figures, as well as a bibliography containing classic references and recent papers published in the urologic and medical literature. We expect that this textbook will serve as a valuable resource to the oncologist in need of pertinent information in every aspect of urologic oncology, from basic principles to treatment to multidisciplinary approaches. Jerome P. Richie, MD Anthony V. D’Amico, MD, PhD
xiii
C H A P T E R
1 The Molecular and Cellular Biology of Urologic Cancers Donald S. Coffey, PhD, and Donald Vindivich, MD
The focus of this chapter is to provide an overview of some of the important concepts and discoveries that have recently revolutionized our understanding of cancer. This will be accomplished by giving simple schematics that show the complexity and elegance of the control mechanisms involved in controlling life and how these processes go astray when cancer develops. This will not be an extensive review with detailed references but rather an overview of the most important and complex medical problems. THE ENIGMAS OF GENITOURINARY CANCERS All of our present molecular concepts of the role of inherited genetics as the sole cause of cancers appear to be challenged by the tissue specificity of the genitourinary cancers. Each organ inherits the same genome, but only certain organs, such as the prostate, bladder and kidney, are highly prone to form cancers. In contrast, other organs in close anatomic proximity are essentially devoid of any historic presence of a reported cancer, such as the epididymis, vas deferens, and bulbourethral glands. All of these organs with vast differences in their cancer risk can reside within the same human; thus, they have the same inheritance, genome, environmental exposure, and have aged to exactly the same time (Figure 1-1). For example, the bulbourethral gland and the prostate are both derived from the same developmental anlagen, the urogenital sinus, and they both bud off as adjacent structures from the developing urethra. Both organs are androgen responsive and have a similar blood supply and nerve stimulation and reside within the same host, sharing a common diet, carcinogenic intake, hormonal environments, and identical aging. One would have
anticipated that whatever causes the multimillions of accumulated cases of prostate cancers in the history of the world should have produced at least a dozen bulbourethral cancers, but not one has ever been reported. The same is true for the epididymis. No simple comparative analysis of replication rates, DNA repair, acquired mutation, inherited gene, or lifestyle and environments seems appropriate to explain this paradox of such a marked tissue specificity for cancer risk. Something within the biologic and molecular contexts of the cell type and differentiation would appear to be involved; this nongenetic effect is termed an epigenetic event (Figure 1-2). EPIGENETIC EFFECTS Since the same DNA sequence in two different cell types can produce such drastic differences in cancer risk factors, it is apparent that other factors besides just the DNA sequence (genetics) may affect this carcinogenesis. This epigenetic process is usually thought to be related to the maturation of the stem cell to a specific cell type. What is the molecular basis of epigenetics? The same gene sequence can produce a different messenger RNA in different cell types due to alternative splicing of the RNA. DNA rearrangements can also alter the message. Recent attention has been focused on alterations in chromatin structure, which changes the way DNA is wrapped around the histone cores to form a nucleosome and alter gene expression. One hundred and forty-seven base pairs (bp) of DNA are coiled twice around each histone octamer that is made up of two copies each of H2A, H2B, H3, and H4. This tight interaction of the nucleosome with DNA can be loosened by acetylation of the histone through the action
3
4
Part I Principles of Urologic Oncology
Figure 1-1 Within a human the prostate and bulbourethral gland are similar, yet the risk of cancer is astronomically different. Understanding the molecular basis of this tissue specificity is one of the great riddles of cancer.
of histone acetyl transferases (HAT) or the DNA nucleosome can be tightened by histone deacetylation (HDAC). In addition, some of these histones can be methylated, which usually occurs on the lysine of histone H3. Histone hypoacetylation and H3 methylation both tend to tighten DNA and silent chromatin from being expressed. In addition, the DNA may be silenced by DNA methylation through methylation of the cytosine in the five positions (5 mC). These three types of regulations work closely in coordination, and can be transferred during propagation to the daughter cell, and, therefore, can act like pseudogenetic elements or as termed, an epigenetic event. A fourth element modifying chromatin structure is small molecular weight RNA, such as interference RNA (RNAi). These and other small RNA molecules are not read out into proteins but appear to have powerful regulatory abilities in directing chromatin structure, message availability, cell function, and gene function. One of these small RNAs that are not translated is termed DD3 and is overexpressed in prostate cancer and may be an important control factor or diagnostic agent. DNA topology involves the winding and unwinding of the double helix and can change the super helical density through the actions of topoisomerases and helices that can greatly alter chromatin structure. These factors are usually attached at the base of 60,000 molecular weight DNA loops that are attached to the fixed replication complex on the nuclear matrix. The nuclear matrix is tissue specific in its protein composition. This loop organization represents a much higher order structure of DNA and chromatin and is cell type specific and represents one of the frontiers of understanding epigenetic events. Five to ten percent of the total proteins made within the cell are transcription factors, and it is estimated that
Figure 1-2 An inherited gene that causes cancer is present in every cell, but it only produces cancer in a specific type of cell: this specificity is an epigenetic event dictated by the context of the cell.
there are about 3000 different types of these transcription factors within a human. It now appears that organism complexity, as well as cellular diversity, may arise from the diversity of these transcription complexes that form large cellular machinery in a tissue-specific manner of self-assembly.1 Once a protein is formed by translation of a specific gene, its turnover rate is regulated by a series of posttranslational modifications, such as ubiquination and proteosome interactions, clipping or glycosylation, etc. Certainly, folding of proteins into various dynamic structures is essential for their proper action. Many of these proteins are transported to specific cellular sites and can interact in heterodimers with thousands of other proteins to form complex networks. Understanding these self-assembling networks has now become a major frontier of cell biology.2 CARCINOGENS What causes genitourinary cancers? Is it mostly environment (nurture) or inheritance (nature)? Obviously it is both, but environment has been understudied. In China, prostate and breast cancer incidence is less than onetenth of the incidence rate in the U.S., and this is true of many other parts of Asia. When Asian populations, with low prostate cancer rates, migrate to the U.S., there is a dramatic increase in their incidence of prostate cancer that occurs by the second generation. This alteration risk is different with migration and would appear to involve a change in environmental exposure or a change in lifestyle risk factors that are beyond a simple Mendelian model of genetics. It now appears that genes and environment interact in a system we have not resolved, but it can still
Chapter 1 The Molecular and Cellular Biology of Urologic Cancers 5
only be an effective carcinogenic event when it occurs in a specific type of cell within the body. It is still unclear whether this migration to a higher cancer risk area removes a protective agent that was in the Asian environment or has added a carcinogenic agent in the United States’ environment. With few exceptions, it has been extremely difficult to induce prostate cancer in aging rats. However, if rats are fed with burnt meat, both prostate cancer and breast cancer appear.3 A polycyclic hydrocarbon has been identified from burnt meat and appears to make adducts to the DNA and thus produces mutations. DNA repair cuts out these aberrant bases, and they appear in the urine. The production of these carcinogens in burnt meat is related to the temperature and time of cooking and might easily explain many cultural variations in food processing that alter carcinogens. For example, the Chinese eat meat, but they do not burn it excessively in the same way as we do in the U.S. in our barbecuing and tendencies to sear to the point of burning in the preparation of many of our meats. Obviously, other cultural aspects of diet might also be involved, such as the absence of milk and cheese in the diet of Asia in contrast to its heavy use in the U.S. and Northern Europe, or the addition of tea and soy in the Asian diet. INFLAMMATION Chronic inflammation has recently received tremendous interest as an etiologic factor associated with many diseases appearing during aging, including arteriosclerosis, arthritis, and now cancer. It has long been recognized that schistosomiasis infections in Egypt were associated with a high incidence of bladder cancer. Now a new mechanism for inflammation in the formation of prostate cancer is becoming evident.4 This new mechanism may combine many aspects of genetics and epigenetics defined by lifestyle and risks. In the aging prostate, there appear to be many small foci of atrophy. Usually, atrophy indicates a dormant state or DNA synthesis that is often seen when androgens are withdrawn. Following androgen ablation the entire prostate becomes atrophied in relation to its epithelial cells and DNA synthesis and replication essentially cease.5 The paradox was that in some prostates in humans these small foci of atrophy could be seen in juxtaposition to acini with highly stimulated luminal epithelial cells that appeared to be under strong androgen stimulation. The paradox of atrophy next to stimulation was resolved in part when it was observed that these atrophied epithelial cells seen in the small foci were actually not dormant for DNA synthesis but were highly stimulated and were undergoing rapid DNA synthesis. This proliferative type of atrophy was often associated with areas of prostate inflammation. Prostate inflammation is
very common and is often not associated with any symptoms, and it must be distinguished from prostatitis, which frequently can be symptomatic. The cause of this hidden prostate inflammation is unknown. It may be related to pathogens, it could also be associated with autoimmunity. Nevertheless, this close proximity of highly replicating prostate cells in focal proliferative atrophy juxtaposition with inflammatory cells that could produce high levels of reactive oxygen species (ROS) could be highly detrimental to the DNA of the prostate epithelial cells unless they can protect themselves against this oxidative onslaught. One of the common mechanisms of protecting against this type of oxidative damage is to induce a stress response that up-regulates glutathione-S-transferase pi (GSTPi) that provides a strong protection against carcinogens and ROS. These prostate cells that are under stress near the inflammation have indeed induced their defenses by the induction of this GSTPi, however, a few isolated epithelial cells appear to be unable to produce this protective effect. These cells are highly prone to DNA damage, and when replicated would then accumulate and be the early events in prostatic interepithelial neoplasia (PIN), a precursor to prostate cancer. This model has been proposed and tested by Angelo De Marzo, and a recent review discusses details of the molecular mechanism.4 How is GSTPi regulated? As stated, the DNA promoter region of GSTPi is in a CpG-rich island domain located within the promoter region. This promoter is silenced by the methylation of the cytosine residues in these CpG islands, thus turning off the expression protective effect of GSTPi for the replicating cells located in the reactive oxygen environment of the inflammation. The final prostate cancer cells that form have a hypermethylated CpG island region in the promoter of GSTPi, and this is the most common molecular and genome change (>90%) that has been reported to be associated with all forms of prostate cancer. The cellular and molecular events that can be correlated with the early pathology pathway to prostate cancer have been defined and named proliferative inflammatory atrophy (PIA).4 It is also of interest that in animal models of prostate inflammation in the rat, that the inflammation can be suppressed by high levels of soy in the diet; a possible clue to a protective factor in the Asian diet.5 Two genes that have been implicated as candidates in familial human prostate cancer studies and by microarray studies are the macrophage scavenger receptor (MSR-1) and RNASEL6 (Table 1-1). These genes have been shown to increase infections in knock out animals devoid of these genes. Thus, the role of pathogens might be implicated in this process, but equal attention should be given at this time to the possibility that this type of inflammation may be produced by autoimmune reactions. Estrogen imprinting in the early neonate life of the rat can result in later
6
Part I Principles of Urologic Oncology
Table 1-1 Selected Genes Proposed to be Involved in Prostate Cancer Initiation or Progression, or in Modifying the Risk of Prostate Cancer Development Gene
Proposed Function
Mutations causing decreased activity MS (MSR-1) RNASEL ELAC2
Antiinfectious, macrophage scavenger receptor Antiinfectious, apoptosis, RNASE Metal-dependent hydrolase
Promoter hypermethylation resulting in gene silencing GSTP1 Carcinogen detoxification EDNRB Endothelin receptor ER (alpha and beta) Estrogen receptor LOH and point mutation PTEN TP53 (also p53) LOH and haploinsufficiency NKX3-1 CDKN1B (P27KlP1) Point mutations COPEB (also KLR6) Androgen receptor (AR) Amplification AR
Cell survival and proliferation, phosphatase Cell survival and proliferation, genome stability Cell differentiation and proliferation Cell proliferation, brake for proliferation
Transcription regulation Cell proliferation, survival and differentiation Cell proliferation, survival, and differentiation
Overexpressed at mRNA and protein level HTERT (telomerase) Cell immortality HPN (Hepsin) Transmembrane protease FASN Fatty-acid synthesis AMACR (racemase) Fatty-acid metabolism, branched chain EZH2 Transcription repressor, cell proliferation MYC Cell proliferation BCL2 Cell survival Polymorphisms affecting prostate cancer risks AR (CAG and GGC repeats) Cell proliferation, survival, and differentiation CYP17 Androgen metabolism SRD5A2 (5 Alpha reductase) Androgen metabolism Metastasis suppressor (down-regulated) KAI1 CD44 NME23 KISSI BRMS1 MAP2K4
development of marked inflammation in the adult rat’s prostate if they are carried out in strains that have a high propensity for autoimmune disease. The body’s defense against many infectious insults is to produce reactive oxygen, which is primarily produced by macrophages. Reactive oxygen can also occur from normal metabolism within the cell and has often been suggested as part of the aging process. As hydrogen from food metabolism interacts with oxygen to make water, they go through a series of oxidation states
involving single electron transfer resulting in free radicals that can be highly deleterious to DNA resulting in specific types of DNA oxidative damage. In addition, nitric oxide (NO), which is formed by NO synthetase activity in the metabolism of arginine, produces NO, a powerful oxidizing agent when combined with ROS. GSTPi is a powerful defender against these types of oxidative agents produced by inflammation, as well as protecting against adduct formation on the DNA caused by carcinogens. These free radicals can also be
Chapter 1 The Molecular and Cellular Biology of Urologic Cancers 7
squelched in the presence of vitamin E. Thus, vitamin E as a free radical scavenger has received popularity as a chemoprotective agent and is being tested in large clinical trials. Lipid peroxidation is another mechanism for protecting DNA, and it utilizes selenium in its action. Inflammation may be involved in the tissue specificity of cancer. Seminal vesicles, which rarely get cancer, have no inflammation like the prostates do. Furthermore, inflammation is greatly reduced in the prostates of people in Asia, and this reduction can be mimicked in animals fed diets high in soy. The role of estrogens in inflammation is also an intriguing possibility, particularly since the soy diet contains high levels of phytoestrogens that could serve as antiestrogens and block these effects.5 Much is left to discover in these new developing fields of carcinogenesis of the prostate, but there is little doubt that major inroads have been realized in the last 4 years by combining genetic and epigenetic concepts.4 We now have models that might help explain why only humans and dogs get prostate cancer, why the seminal vesicles are not at risk, and why the risks are so different in Asia and change with migration.5 Molecular targets are being identified by new microarray techniques, and clinical prevention trails are now underway in many centers. FAMILIAL CANCER Cancer clusters in some families could be the result of inherited genetic alterations or shared environmental factors. Single or multiple genes could be causing predisposition to cancer. Sporadic occurrence suggests aggregation by the adverse effects of the environment, such as pollutants and carcinogens, as well as socioeconomic differences and cultural habits, such as work, sexual, and dietary factors. It is now possible to apply statistical analysis to these inherited patterns, trying to correlate these with the time of diagnosis in order to determine if there is a genetic predisposition, inherited primarily through genes from either the mother or the father, termed autosomal. In this regard, Patrick C. Walsh and his colleagues have reported that there is a hereditary form of prostate cancer (HPC) with an early onset and a 3- to 9-fold increased incidence, depending on the number of first-degree relatives involved. Indeed, hereditary prostate cancer appears to be inherited in a Mendelian manner and is autosomal dominant, with a penetrance of approximately 85%. Intense efforts have been underway in many centers to find chromosomal linkage to this hereditary form of cancer and to identify the gene(s) involved in this increased cancer risk.7 It is hoped that these high-risk genes can be sequenced as they have been in breast cancer. In breast cancer, BRCA1 and BRCA2 have been identified as hereditary genes. Also, in colon cancer, 4 genes have been identified and, 3 of which are
mismatch DNA repair genes, termed MSH2, MLH1, PMS1, PMS2, as well as the APC tumor suppressor gene. Two kidney cancer genes have been identified to be WT1, in the Wilms’ tumor, and the VHL gene associated with von Hippel-Lindau syndrome, identified by Marston Linehan and his colleagues. It is most interesting that there is a familial tendency in both prostate and renal cell cancers but no such familial tendency has yet been identified for bladder cancer. However, only 10% of many types of cancers are inherited through a predisposing gene or genes, but 90% of cancers are acquired through living or by environmental insults; these later types are termed sporadic cancers. It is believed that if we identify the inherited genes that predispose to familial cancer, these genes will be the same targets that are altered by carcinogens, aging, or biologic damage in sporadic cancers. This is the basis for Knudson’s hypothesis, which has been proven in retinoblastoma. Since we inherit two genes, one each from our mother and father, we therefore have two alleles for every gene that can be slightly different in sequence (polymorphism) or in methylation (imprinting). If both genes are required to be knocked out to produce cancer, which is the case when a suppressor gene is eliminated, then inheriting the loss of one gene (loss of heterozygosity [LOH]) would increase your chances of getting cancer, because now an environmental insult only needs to eliminate the second allele to inactivate the suppressor gene. This increase in probability results in the early onset of cancer, because one of the two suppressor genes had already been inactivated at birth. The similarity that approximately 10% of all colon, breast, and prostate cancers are inherited, although the overall frequency of these genes in the population is about 0.3%, is one of the mysteries in cancer research. Is this similarity by chance or does it have a meaning? In addition, in each case when you inherit these predisposing genes you have an approximately 85% chance of getting the cancer, but 15% will not get cancer. One of the difficulties in locating cancer-causing genes is that once you have developed cancer, it is often accompanied by a genetic instability, which produces a series of changes in the genome that alter the cancerous properties of the cell. This temporal change in the cancer cell clones is called progression and produces a marked tumor cell heterogeneity. These genetic changes that ensue because of this instability can produce a cell with an increased growth rate, and then this clone will expand and dominate in the tumor. This phenomenon is termed “clonal selection,” and since it occurs with time, it is called tumor progression. Ultimately, cells may be selected with not only increased growth rate but also with more aggressive properties, and alterations in many cancer genes, such as p53, appear to be related to more aggressive tumors. Therefore, when a tumor is removed
8
Part I Principles of Urologic Oncology
from a patient and the karyotype or DNA is examined, it is possible to see tremendous changes in the chromosomes. There are cases of chromosomal deletions, amplifications, rearrangements, and duplications, which can result in changes in ploidy and abnormal amounts of DNA in the cancer cell nuclei. This was seen earlier in what we call karyotyping, but this only looked at the shapes and forms of chromosomes and their banding. Later it was possible to differentially stain cancer and normal DNA using either red or green markers as probes to stain and differentially compare the chromosomes. By looking at the presence or absence of the red and green markers on cancer chromosomes, it is possible to visualize changes in their karyotype. This technique has been termed comparative genome hybridization (CGH). Recently, all chromosomes can be painted a different color; a process termed spectral karyotyping (SKY). With this, it has been possible to find that in certain cancer chromosomes there is a gain in areas on one arm, and a simultaneous loss in areas on the other arm. In prostate cancer, this occurs with loss of material in the short arm (p) and a subsequent gain in the long arm (q) of the eighth chromosome; this is not a simple transposition. Some of these changes may be causal for cancer, but many are just associated with the properties of the tumor as it progresses and are simply epiphenomena. This produces the complex problems that the geneticists face when analyzing tumor cell chromosomes and DNA. Therefore, this requires the meticulous linking of the inherited chromosome changes within the lineages of the families with the tumor types. These linkage studies are most difficult and usually require years of work. New molecular probes and information from the Human Genome Project are speeding this process, and certainly automated and highthroughput systems are accelerating this search, which has been a most difficult problem for cancer research. Certainly, many candidate genes have been identified and are being verified or eliminated by painstaking work. The problem then will be to link specific sequences to gene functions, gene control, and disease. There will be much variation and polymorphism within the population, genetic types, and races. Several different types of each inherited cancer may exist. The genome can also change through aging, replication errors, and failures in DNA repair. This is a complex but critical problem in understanding genetic changes associated with cancer. Large populations will be required in these studies to assure accuracy.7
2.
3.
4.
CANCER GENES Cancer susceptibility is driven primarily by six types of genes: 1. Oncogenes. A series of over 60 genes have been identified that are activated or overexpressed and that
5.
have a positive effect in the induction of growth. These constitutive genes have a prefix like c-myc. If they are mutated and inserted by viruses this prefix changes to v, like v-src. Suppressor genes. Loss of the function of a suppressor gene essentially removes a brake on cell growth, thus permitting it to become up-regulated (examples are p53, Rb, and p16). DNA repair genes. Normal or induced errors in DNA copying, DNA damage from the environment, or oxidative damage must be corrected or the gene will be mutated or silenced. In colon cancer, a group of mismatch repair genes (MSH2, MLH1, PMS1, and PMS2) have all been shown to be inherited and to induce cancer by accumulation of DNA damage. We know little about how telomere damage is repaired or how repetitive DNA transposons are regulated. DNA defense genes. These genes protect the DNA from oxidative damage or electrophiles that can form adducts to the bases that are detrimental. There are enzymes that protect the cell against ROS that form free radicals and produce oxidative damage to the cell. As the mitochondria carry out their aerobic oxidation, 4 electrons are required to reduce molecular oxygen to water. In this process, partially reduced intermediates of oxygen produce superoxide, hydrogen peroxide, and hydroxyl radicals that are collectively known as ROS. ROS can also be caused by ionizing radiation, UV light, or certain chemicals in the environment. ROS converts guanine in DNA to 8-oxoguanine, which is highly mutagenic and preferentially mispairs with adenine during replication. There are enzymes, such as glutathioneS-transferase (GST), glutathione reductase, quinone reductase, superoxide dismutase, catalase, and other protective enzymes that inactivate electrophiles, carcinogens, and ROS. Carcinogens in our environment are often in a pro-form and need to be activated by type 1 enzymes or the active carcinogen needs to be inactivated by type 2 enzymes. For example, procarcinogens like benzpyrene are inactive and must be metabolized by epoxidases to form the active carcinogen that reacts with DNA; this represents a type 1 reaction. Type 2 reactions are represented by the family of glutathione transferases, glucuronosyltransferases, and quinone reductases, all of which can inactivate carcinogens or ROS. Types 1 and 2 enzymes can be induced or altered by environment, diet, or inheritance, altering the rate of cancer formation. There are several isoforms and polymorphisms; for example, GST-M is related to bladder and glutathione-S-transferase isoforms (GST-π) methylation to prostate cancer. Viral genes. Retroviruses, polyoma, adenoma, and papilloma viruses can also introduce genes into the
Chapter 1 The Molecular and Cellular Biology of Urologic Cancers 9
mammalian cell, which when expressed induce malignant transformation. This includes large T-antigen, E1, E6, and oncogenes. 6. DNA methylation genes. DNA methylation is altered in many cancers and for unknown reasons. Hypermethylation of CpG islands in promoter regions can silence genes. DNA methylation can vary in maternal and paternal genes, termed imprinting. Loss of imprinting (LOI) is a common change in cancers. At present, all of the above six mechanisms are being studied to determine what causes urologic cancers. At the moment, there is only definitive evidence that the VHL gene is associated with von Hippel-Lindau syndrome, and the WT1 gene is associated with Wilms’ tumor. The p53 gene is associated with bladder cancer but it may only be a progression marker, as it is in prostate cancer. No specific gene has yet been shown to be inherited in prostate cancer, although practically all of these tumors are associated with inactivation of one of the GST-π. As stated, this inactivation of expression is accomplished through methylation of the CpG islands in the promoter region, which down-regulates the gene. This genomic change is almost universal in both familial and sporadic prostate cancers but is not believed to be the inherited gene that causes the cancer, but we do not know what controls DNA methylation. Since both aging and cancer produce heterogeneity in the stability of various chromosomes, it is hard to eliminate this form of noise in the system, without careful study. In addition, many normal genes have different DNA sequences, which are called polymorphism. These polymorphisms are inherited and can produce different types of isozymes or genetic patterns that may or may not have effects on how these genes function. Some of these polymorphisms are certainly going to increase tendencies towards malignant transformation that would enhance the chances of acquiring cancer, which will add to the complexity. Many suppressor genes not only will be lost through mutation or genetic inactivation but can also be down-regulated and turned off by nongenetic or epigenetic means, such as DNA methylation. Many traits within the human body, resulting in specific phenotypes, do require many genes operating in concert to produce their specific phenotype. This polygenic phenomenon can be operating in some cancers. Indeed, there are multiple steps involved in the evolution of cancer. It is well known that multiple hits are required, resulting in multiple changes, which occur with time. It has been estimated that 3 to 6 changes may be the minimum requirement to produce a clone of cells with the properties to propagate the cancer to a lethal stage. It has been suggested that these hits are cumulative and may
not have to occur in a specific order, although this model has not been completely confirmed. Certainly, just inheriting one familial cancer gene seems to guarantee the rest of the hits, since there is often an 85% chance of developing cancer when an inherited gene is involved, an effect termed penetrance. How do the aforementioned oncogenes and suppressor genes function within the cell to cause cancer? They appear to regulate cell replication, death, and growth. There are about 60 oncogenes of primarily four types: 1. Genes for growth factors or their receptors (e.g., platelet-derived growth factor [PDGF], erb-B, and RET). 2. Genes affecting cell-signaling pathways, such as ras and src. 3. Genes acting as transcription factors that activate early growth genes, such as the myc oncogenes. 4. Genes affecting the cell cycle: Bcl-2 is an inhibitor of cell death that when overexpressed, blocks apoptosis and allows cells to survive and accumulate. Overexpressing factors that bind to suppressors can remove the brake. For example, MDM-2 removes the suppressor brake p53 by binding to it and inactivating it. Many virus proteins are expressed in an infected cell, such as large T, E1A, and E7, and have the ability to complex suppressor molecules, such as p53 and Rb. In summary, turning these genes on turns on cell growth. Suppressors are brake molecules that turn growth off. Removing the brake, of course, turns on the growth. These brakes can be removed either by inheriting the loss of this gene, by mutating the gene and activating it, or by turning off the gene through regulation, which is the case when the DNA in its promoter region is methylated. How do the suppressor genes function as brakes? Many of these genes are located in the nucleus and affect the cell cycle regulation. The Rb gene is present in all cells and codes for a master brake on the cell cycle that is discussed in the following. The p53 is one of the bestknown suppressors and is abnormally regulated in most cancers. It blocks the cell cycle by inducing a series of cell cycle kinase inhibitors. This p53 protein is activated when the cell detects damage, such as DNA breakage, and blocks the cell cycle at the G1/S checkpoint to allow time for DNA repair. If the damage is extensive the p53 induces abnormal cells to undergo a suicide through apoptosis. The p53 can also affect the mechanism of mitosis; abnormalities may result in mitotic dysjunction (Figure 1-3). MTS-1, also called p16, is another suppressor involved in the braking components of the cell cycle. Other suppressor genes function in the cytoplasm, such as APC, which is involved in colon cancer. APC may affect the cell adhesion molecule mechanisms by interacting
10
Part I Principles of Urologic Oncology
PDGF, myc, and Bcl-2. However, none of these have been shown to be involved in cancer as inherited factors. There are many candidate genes for familial prostate cancer, such as RNASEL for HPC-1 on 1q25-25; ELAC2 for HPC-2; and MSR-1 but as yet none have been confirmed to a point of certainty. Certainly these genes play a major role in urologic cancers in controlling growth and progression, but what is the inherited gene that sets off prostate cancer? This will soon be resolved, as many groups are rapidly mapping in on the target of candidate genes.6 MICROARRAYS AND PROTEOMICS
Figure 1-3 Schematic of how cyclin-dependent kinases (CDKs) are activated or inactivated in the cell cycle. The active kinases are bound to variable cyclins and phosphorylate Rb, thus releasing the Rb brake on the cell cycle.
with catenin-like molecules. DPC4 is involved in pancreatic cancer and interacts with the cell signaling mechanisms.1 NF-1 and NF-2 are suppressor genes involved in cell signaling pathways. Of great interest to the urologist is the WT1 gene, which is involved in the Wilms’ tumor of the kidney, and the VHL gene, which is involved in renal cell cancer accompanying von Hippel-Lindau syndrome. VHL can either be lost by inheritance or inactivated by methylation of the cytosine residues of the DNA located in the promoter region of this gene. The VHL gene appears, at the moment, to be involved in the regulation of transcription. Transcription is the conversion of the information of DNA into RNA through the action of RNA polymerase II that forms messenger RNA (mRNA). An important protein binds to the RNA polymerase II and controls the elongation of the mRNA. This transcription and elongation factor is termed elongin or S III. It appears that in normal cells, VHL forms a protein that binds to the elongin and is involved in the control of transcription elongation. When the VHL gene is missing or mutated, it loses its ability to complex to the elongin and, therefore, allows elongin to interact with RNA polymerase II, deregulating the process of mRNA elongation. VHL is the first suppressor gene that has been identified to control the level of transcriptional elongation. This raises the question: Why does the elongation result in cancer? It is believed that this may increase the expression of certain genes involved in growth control, such as myc or fos. In summary, the only two genes so far identified for urologic cancers that can be inherited and increase our incidence of cancer are VHL and WT1, which cause renal cell cancers. In urologic cancers, other suppressors have been implicated, such as Rb, p53, p16, and the oncogenes
DNA expressed as RNA can be reversed transcribed to obtain a c-DNA sample that can be hybridized to the specific DNA of the gene that was transcribed to make the original messenger RNA. By placing from 10,000 to 40,000 small snippets of DNA from identified genes onto a chip or a microscope slide, it is possible to hybridize the c-DNA made from the messenger RNA to the specific genes it represents. The gene targets are located on each small dot placed on the chip. With these high throughput techniques, it is possible to analyze thousands of gene expression patterns in one sample in a quantitative manner. This is possible by coloring these gene (c-DNA) expression products with red for the control cell, which can be normal, or by coloring green for the cancer cell (cDNA) and then by combining the red and green messenger RNA, the appearance of a red dot would indicate a gene that was expressed only in the normal cell. Likewise, the green dot would represent genes turned on only in the cancer cell. The expression of both red and green would form a yellow dot and would indicate expression in both cell types. With this type of microarray or with other forms of differential displays, it has been possible to implicate a series of genes that are turned off or on that may be involved in prostate cancer in comparison to normal as is shown in Table 1-1.6 Many of these genes have been activated or knocked out in transgenic mice, and their functions have been studied in many cases. For example, NKX3-1 is expressed in normal prostates and is decreased in prostate cancers. In mice that have lost one or more of these NKX3-1 genes abnormal duct development and hyperplasia occurs. It then goes on to form PIN. Likewise PTEN on 10q23 mutated in about onethird of human prostate cancers and correlates with high Gleason grade. PTEN is a phosphatase that inactivates PIP3 that is a signal of several growth factors, including IGF-1. PIP3 activates protein kinase AKT, which leads to inhibition of apoptosis causing increasing cell survival and a tumor. Increasing both PTEN and NKX3-1 increases the severity of high-grade PIN in animal models. The most consistent of these genomic alterations associated with cancer may be the GSTP1 gene, which is inactivated by hypermethylation of the promoter region
Chapter 1 The Molecular and Cellular Biology of Urologic Cancers 11
that occurs in over 90% of primary lesions of prostate cancer. The functions of the other genes in Table 1-1 are discussed in more detail in a recent review.6 Certainly the increased expression of a gene in the form of messenger RNA does not necessarily reflect the amount of protein or its posttranslational modification. In this regard, rapid development of proteomic techniques that give two-dimensional electrophoretic patterns of protein content based on their molecular weight and charge is providing additional means of identifying proteins that change during various stages of cancer and treatment. These isolated proteins can then be identified in sequence using new techniques utilizing mass spectrometry. Time of flight and fragmentation of proteins in mass spectrometers have been extremely useful especially when the proteins are first trapped by baiting them to specific binding elements on commercially developed probes. Certainly as these techniques become defined and standardized they will add a new armamentarium to the identification of new markers and targets. THE CONTROL OF THE CELL CYCLE, CELL DEATH, AND TUMOR GROWTH In normal tissues, the rate of cell replication and the rate of cell death are in a tightly controlled balance, but it is unknown how this balance is maintained. However, when an imbalance occurs, either through an increase in cell replication or a decrease in cell death, there is an accumulation of cells that forms the tumor. This balance involves growth factors, cell signaling, and control of the cell cycle, as well as apoptosis. DNA damage, aging, and senescence activate certain signals, which we believe to be “death” genes that cause the cell to commit suicide. Signaling of the cell cycle for growth and cell death is one of the most active areas of science. First we will review how the cell cycle functions. The cell is usually quiescent in the nongrowing phase, which is termed G0. Growth factors, steroids, and hormones can stimulate the cell to grow and undergo an active phase of biochemical events, termed G1 or the gap period that occurs before DNA synthesis. After the biochemical preparation in G1, the cell undergoes DNA synthesis, termed the S phase. Following the replication of the complete DNA, there is a second gap called G2, where the cell prepares itself for mitosis. Then the mitosis (M phase) ensues, in which the mitotic spindle separates the two sets of chromosomes. Then the nucleus reorganizes and the cell cycle is completed. Recently, there has been a tremendous amount of research delineating the biochemical controls of the cell cycle. There are specific checkpoints at the interface between each of these phases, in which the cell stops to determine its next decision. These decisions in the cycle are primarily controlled by the interaction of regulatory proteins to form
heterodimers with kinases that are either active or inactive. This in turn regulates their state of phosphorylation of growth suppressors. A kinase is an enzyme that phosphorylates a protein. In the cell cycle, these kinases are termed cyclin-dependent kinases (CDKs); there are approximately 7 of these enzymes (CDK2, CDK4, etc.). They are usually at a constant level and inactive as shown in Figure 1-3. These CDKs are activated at specific phases of the cell cycle by binding to a second type of molecule, called cyclins (termed cyclin A to H). These are termed cyclins because their concentration varies through the cycle, and it is these transient molecules that regulate the cell cycle. Therefore, you can activate cyclin kinases in a controlled manner by turning on the synthesis and degradation of the cyclins. Once the CDKs are activated by binding cyclins, they appear to regulate the cell cycle by phosphorylating and turning off the brakes within the nucleus that prevent cell growth. One of the primary brakes or suppressors in the nucleus is Rb, which, when unphosphorylated, is a checkpoint at G1/S and prevents the cycle from proceeding. When the cyclin kinase is activated, it phosphorylates the Rb, thus removing the brake and allowing the cell cycle to initiate DNA synthesis and to continue to complete growth to the daughter cell. CDKs can also be inactivated by binding to a group of CDK inhibitors (CDKIs). Examples of this type of inhibitor are p16, p21, and p27. If these inhibitors are induced, the cell cycle stops, growth is suppressed, and so a checkpoint is formed. How are these inhibitors induced? This occurs in part through the normal function of p53, which acts like an inducer and can upregulate these inhibitors. The p53 is usually turned on when cells are damaged. In this case, the cell wishes to make the decision not to proceed through cell cycle and to repair itself. In summary, expression of p53 is increased during cell and/or DNA damage and induces a braking system on the cell cycle to prevent defective cells from being made. If the p53 is damaged, lost, or down regulated, this checkpoint is eliminated. This results in damaged DNA proceeding and accumulating through each cell cycle and may result in the large amount of genetic instability and DNA damage that occur in cancer. We have just discussed most briefly how the cell cycle is regulated, but how does a cell determine to undergo cell death or apoptosis? Damage to the DNA is detected in part by a series of checkpoint including AMT, ATR, KU 70, and poly-ADP ribosylation. Broken ends of the DNA often bind KU 70 or have a special polymer added to them that is made from a breakdown product of nicotinamide-adenine dinucleotide (NAD). The polyADP ribosylation of the ends of damaged DNA appears to set off a signal that can induce cell death. Other ways to induce cell death are to remove the cell from its extracellular matrix (ECM) anchorage or to disturb
12
Part I Principles of Urologic Oncology
the cytoskeleton. This is termed anoikis; unknown signals from the cell periphery and integrin disruption are being signaled to the nucleus to induce cell death. In addition, there are large protein molecules like tumor necrosis factor (TNF), Fas-ligand and trail ligands that act conversely to growth factors and could be termed death factor. Their action is cell type specific. The TNF binds to two types of cell surface receptors and the Fasligand binds to its receptor. These complexes then involve the activation of a series of caspases (2, 3, 6, 7, and 9) and the release of cytochrome c from the mitochondria all in dynamic concert with either proapoptotic factor induction (Bid, Bad, Bax) or antiapoptotic factor suppression (Bc1-2, Bcl-xl). Sometimes growth factors can induce cell death in certain cell types. For example, tumor growth factor-β (TGF-β) can activate cell death in some epithelial cells. Other growth factors appear to induce cell death when they are absent; these include EGF and FGF2 and FGF7. Of great importance to the urologist is the fact that the absence of androgen on its receptor can induce cell death in the prostate. Therefore, when the androgen withdrawal occurs following castration, this absence of androgens induces rapid cell death in the prostate epithelial cells. This is, of course, the basis for the hormonal treatment of prostate cancer. In apoptosis, the fragmentation of the DNA produces a characteristic pattern of small DNA fragments that can be observed on gel electrophoresis to form the multiple pieces of short DNA of 170 bp surrounding the nucleosomes. These multiples of 170 produces a stepladder effect on DNA gel analysis. Once the DNA fragmentation occurs, it is irreversible and accompanied by the pro-
teolytic degradation of the nuclear architecture, destroying the lamins around the nuclear periphery and the internal nuclear matrix components. The cell then disintegrates under protease activity, and phagocytosis of the remaining components occurs, destroying the cell. This entire event of cell death has been termed “apoptosis” and is characterized by these morphologic and series of biochemical events. As there are brakes or suppressors of growth on the cell cycle, such as p53 and Rb, there are also brakes to stop cell death. One of the leading brakes, for example, is Bcl-2. When Bcl-2 is available, it blocks the process of cell death and therefore is termed a survival factor. How is the brake Bcl-2 removed? It can bind to a series of proteins and form a heterodimer. One of these Bcl-2-binding molecules is termed Bax, and now a family of these deathinducing molecules has been identified. Combining the Bcl-2 with Bax removes the brake and allows cell death to occur. CELL GROWTH FACTORS There is much direct and indirect signaling that occurs between cells and organs. As shown in Figure 1-4, this signaling can be broken down to various types or categories. Growth factors (GF) are of many types, and they bind to specific transmembrane receptors on the cell surface, setting off kinase cascades and structural information to induce cell growth or death. If the growth factor is made and operates on the cell in which it was manufactured, it is called an autocrine factor. Usually, the autocrine factors are secreted from the cell and then bind to their specific cell surface receptors. If the growth
Figure 1-4 Examples of the types of cell signaling. (Adapted from Partin AW, Coffey DS: In Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr (eds): Campbell’s Urology, 7th edition. Philadelphia, WB Saunders, 1997, with permission.)
Chapter 1 The Molecular and Cellular Biology of Urologic Cancers 13
factor operates within the cell, it is called an intracrine mechanism. If the growth factor diffuses to a neighboring cell, it is termed a paracrine stimulation. If the growth factor is transported through the circulation to distant cells, it is termed an endocrine effect. Other special factors can be transported by the nerves (neurocrine), or they may come from immune like cells (cytokine). Cells can also signal by direct communication through linkages of their structural elements. The ECM makes direct contact with the cell by binding to integrins, which are molecules that extend through the cellular membrane and link to the cytoskeleton within the cell. Cells can also “hold hands” with their neighbors by direct linkage of the cell adhesion molecules (CAMS), which form homodimers. These direct structural linkages, which transfer information in a vectral manner, allow the cell to sense its neighbors. This linkage is like a telephone area code and is one of the most active areas of research in cell biology. These combined units of structural elements form a tissue matrix system, as is shown in Figure 1-5. The CAMS
form a homopolymer with their neighbors. One of the most prominent of these is E-cadherin, which is a cell surface CAM and extends through the membrane of the cell and organizes cytoskeleton components, such as actin. It does that by interacting with an important molecule called catenin, which appears in several forms called α and β. In cancers, there is aberration in the expression of E-cadherin, whose expression can be regulated by methylation of the DNA in the promoter region for this gene. The linkage to actin can also be disrupted by components that can bind to the catenin, such as the suppressor APC, which has been delineated in colon cancer. The cytoskeleton can also be regulated in its organization by binding to receptors called integrins that detect ECM components, such as fibronectin. Aberrations in this linking system, which involves vinculin, tailin, and αactinin, disrupt the organization of the cytoskeleton components, such as actin. The cytoskeleton is made up of microtubules, actin, and keratins, which give the shape to the cell and a different structure to each cell type. The recognition of the cell
Figure 1-5 The dynamic tissue matrix system is composed of interlocking structural components that hardwire the cell to the nucleus and DNA. The proteins of the matrix are tissue specific.
14
Part I Principles of Urologic Oncology
structure, shape, and organization is the basis of histology. The cytoskeleton links directly to the nuclear matrix, which organizes the DNA into 50,000 loop domains, termed replicons. These loops of about 60,000 bp of DNA are anchored at their base onto the nuclear matrix, where DNA synthesis and DNA methylation can occur. Steroid hormone receptors bind to this nuclear matrix in a tissue-specific manner dictated by the receptors dimerization and interaction with coactivators on corepressors. It is this nuclear matrix protein pattern that makes up the tissue specificity. The nuclear matrix protein pattern is altered in cancer. This dynamic tissue matrix system is shown in its interactive form in Figure 1-5. In summary, what a cell touches determines what a cell does, and the disturbance in the tissue matrix system and its dynamic components cause the variation in shape that we term pleomorphism that is a hallmark of cancer. Only the pathologist can diagnose cancer, which is done by recognizing aberrations and variations in the nuclear structure and in the tissues and cell structure. Cancer is a disease of cell structure. CELL SIGNALING As mentioned, many factors can regulate cell growth and cell death. They do so by interacting with specific transmembrane receptors on the cell surface. Their ligands involve growth factors, cytokines, stress signals, ECM, and death signals, such as TNF. Once these ligands bind
to their cell surface receptors, which span the membrane and activate a series of kinases on the cytoplasmic portion of the receptor, they set off a cascade of phosphorylation that proceeds to the nucleus. The kinases can either be tyrosine kinases, which put phosphate groups on tyrosine, or serine kinases, which put phosphate groups on the serine molecules of the target substrate. Many of these kinases are opposed by phosphatases. Figure 1-6 demonstrates a few of these cascades of protein phosphorylations that are directed to the nucleus. Each large K indicates a kinase that is activated as the receptor signals down to the nucleus. A selection of five of the major kinase cascades involve a series of phosphorylations of kinase molecules that activate other kinase molecules to phosphorylate, finally reaching phosphorylation of nuclear factors. These four prominent kinase pathways are the jak/stat, MAP kinase, and the jnk/erk pathways and the PI-3 kinase. These phosphorylation pathways finally terminate in the nucleus to activate a series of transcription factors that induce the expression of specific genes of either growth and death or survival and senescence. The receptor tyrosine kinase receptor molecule can also link itself to a series of G-protein systems to activate these kinases or can act through another important mechanism that converts the lipids of the membrane into signaling molecules. For example, phospholipase C (PLC) can hydrolyze the lipid molecules of the membrane to become signals by making inositol phosphate (IP-3) or diacylglycerol (DAG). The IP-3 activates calcium
Figure 1-6 Brief example of 5 types of transmembrane receptor activating the phosphorylation cascade to activate nuclear function. K, kinase; KK, kinase that phosphorylates a kinase. See text for discussion.
Chapter 1 The Molecular and Cellular Biology of Urologic Cancers 15
release in the cell that is a signal. The DAG activates protein kinase C, which is another major kinase system also signaling to the nucleus. One of the most important cell signal pathways in prostate cancer is the PI-3 kinase that activates AKT and cascades to block the proapoptotic factor Bax and thus increases cell survival. The phosphorylation of AKT is countered by the phosphatase PTEN that is inactivated in many prostate cancers, thus increasing Bax phosphorylation and increasing cell survival. This has been only a brief simplified glimpse at some cell signaling pathways that are involved in cancer. STROMAL EPITHELIAL INTERACTIONS All of the aforementioned signaling mechanisms and many more come together and are synchronized in the cell organization forming the tissue that involves the interaction of many stromal and epithelial signals. The stroma talks to the epithelium and the epithelial cells talk to the stroma, both types are nurtured by blood vessels and nerves. The interface between the stromal and epithelial cells is conducted through the formation of the ECM, which
is formed by secretion and products made from both the stromal and epithelial cells, such as fibronectin, collagen, laminin, and proteoglycans. This structural support system organizes the structure of the cell and polarizes it to receive growth factors and signals that come from the stroma, epithelium, and endocrine hormones diffusing from the blood vessels. This action of growth factors steroids, and the ECM making the stromal–epithelial organization and crosstalk is shown in Figure 1-7, which is a diagram of the prostate, where the epithelium is composed of neuroendocrine, secretory epithelial, and basal cells. It is believed that the basal cells are the stem cells that differentiate to form both secretory and neuroendocrine cells. The stroma is made up of smooth muscle, fibroblast, and nerve cells. Threading their way through the stroma are the capillaries, lined by endothelial cells, and the immune cells, which can move in and out of the prostate. The capillaries bring the steroids, androgens, estrogens, and nutrients to the prostate. Testosterone is converted to the more active dihydrotestosterone (DHT) by 5-α-reductase in the stroma. In the stroma, the DHT stimulates fibroblast growth factor-7 (KGF), which then diffuses up and activates the receptors on the epithelial cells in a
Figure 1-7 Stromal-epithelial interactions in the prostate mediated by DHT regulated growth factors; +, stimulation; −, inhibition; NO, nitric oxide. (Adapted from Partin AW, Coffey DS: In Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr (eds): Campbell’s Urology, 7th edition. Philadelphia, WB Saunders, 1997, with permission.)
16
Part I Principles of Urologic Oncology
paracrine manner. DHT also stimulates fibroblast growth factor 2 (BFGF), which both feeds back in an autocrine effect on the stroma and has a paracrine effect on the epithelial cells. A similar stimulation is induced by DHT on the production of insulin-like growth factor II (IGF-II), which also has an autocrine and paracrine effect. Insulin-like growth factors are bound to a family of insulin-like growth factor binding proteins (IGFBP), which are also made by the stroma. DHT can diffuse from the smooth muscle into the epithelial cells, where it induces the synthesis of epidermal growth factor and TGF-α. In the epithelial cells, the androgen also induces production of IGFBP, which complexes the insulin-like growth factors and keeps it inactive. One of the main secretory proteins made by the prostate is PSA, which hydrolyzes the IGFBP to release active IGF-I and IGFII, which then can stimulate the growth of the epithelial cells. PSA is a major secretory protein in the ejaculate. This diagram shows some of the cross-talk between the stroma and epithelial cells via the testosterone and DHT induction of growth factors that can function in an autocrine and paracrine way to these cell components. It is also important to note that many neurotransmitters are made in the prostate, such as NO. NO is produced by the endothelial, immune, and nerve cells and can have a strong stimulatory effect on stromal and epithelial components how this entire system is organized in the embryo, grows to adult size and then becomes dysregulated to produce tumors with aging is the basis of much research. AGING AND TELOMERASE Although aging is involved in cancer, we know very little about what really brings about this irreversible and deteriorating effect. Certainly, accumulated damage from free radicals from reactive oxygen, as well as cross-linking and stiffening of collagen, are all key components in how we age. Importantly, there is also a biologic clock that counts each cell division; this brings about senescence. At the end of each chromosome are repetitive pieces of DNA called telomeres. When the cell divides each time, it loses a small amount of these telomeres, which is caused by the inability of the DNA synthesis mechanism to fully replicate the last little bit of terminal DNA. The loss of these repetitive pieces of DNA is therefore accumulative and acts as a mitotic clock, counting the cell cycles. After approximately 50 doublings, the telomeres of the cell have been reduced to a critical length, resulting in the cell’s senescence and death. Every cell is limited by this mitotic clock except cells that have learned how to become immortal. The immortal cells stabilize their telomeres by activating the enzyme called telomerase. Telomerase is an enzyme that carries its own small template made of RNA that is copied into telomere
units that allow the cell to replace the telomeres that are lost when the cell divides. In any cell in culture, telomerase has to be activated or the cells would not be immortal. This is also the case only in the stem cells and the germ cells. The other cells do not have telomerase activity and are subject to cell death as the mitotic clock ticks down counting each cell cycle. In cancer cells, telomerase is activated and the cells have become immortal. We have reported that telomerase is one of the best markers so far in denoting prostate cancer cells from normal and benign prostatic hypertrophy (BPH) cells. This will be a new diagnostic marker when applied in an appropriate manner. Telomerase is one of the most exciting frontiers in understanding senescence, immortality, and how the cancer cell has broken through this aging barrier to become immortal.6 Telomere shortening is one of the earliest molecular lesions in cancer and can initiate genetic instability by altering chromosome structure. OVERCOMING THE TUMOR CELL HETEROGENEITY: APTAMERS AND IN VITRO EVOLUTION One of the major obstacles in the treatment of urologic cancers is their tremendous heterogeneity. Although clinically appearing as a homogeneous tumor, it actually consists of a heterogeneous pool of cancer cell clones. When we apply any treatment, such as chemotherapy or radiotherapy, we select for subclones in the tumor that are resistant to our treatment. This is not related to the response of the tumor cells to our treatment but to their ability to use evolutionary techniques to escape any given therapy. There are now new technologies that will allow us to turn therapeutic evolution on the evolution of the tumor and thus beat the cancer at its own game. Aptamers can be small peptide, DNA, or RNA molecules that will bind in an antibody like fashion to any given target. Large pools of randomized molecules can be easily made and will provide the molecular diversity to let the tumor cells select the best binding molecules to all the different tumor cell clones. For example, by randomizing the four bases of a 15-nucleotide RNA sequence it is possible to create pools with more than 415 to 109 different molecules. A selection screen is set up in a way allowing us to select the best RNA molecules out of the random pool, that will bind with a high affinity and specificity to our tumor cells. Bound RNA species are then recovered and amplified. This enriched RNA fraction is then subjected to a new round of selection. After 10 to 20 rounds of selection, recovery, and amplification, the pool will contain RNA molecules with high binding specificity. Figure 1-8 gives an overview of a typical selection and amplification cycle that we have involved in in vitro evolution to prostate cancer cells. Those aptamers can then be analyzed and produced in large quantities. They
Chapter 1 The Molecular and Cellular Biology of Urologic Cancers 17
REFERENCES
Figure 1-8 Selection cycle for enriching the binding of a random (109) RNA (aptamers) pool to tumor cells. PCR, polymerase chain reaction for amplifying DNA; enriched RNA. The final selected aptamer binds specifically to the tumor cells.8
can be used as highly specific cancer probes, to improve diagnosis or, when linked to a cytotoxic “warhead,” as a new therapeutic approach to treat cancer.8 ACKNOWLEDGMENTS We wish to acknowledge the outstanding effort of Vivian Bailey in preparing this chapter and Don Vindivich in constructing the figures.
1. Levins M, Tjian R: Transcription regulation and animal diversity. Nature 2003; 424:147. 2. Bray D: Molecular networks: the top-down view. Science 2003; 301:1864. 3. Stuart GR, Holcroft J, De Boer JG, Glickman BW: Prostate mutations in rats induced by the suspected human carcinogen 2-amino-1-methyl-6-phenylimidazol [4,5-6] pyridine. Cancer; 60:266. 4. Nelson WG, De Marzo AM, Isaacs WB: Mechanisms of disease prostate cancer. N Engl J Med 2003; 349:366. 5. Coffey DS: Similarities of prostate and breast cancer; evolution, diet, and estrogens. Urology 2001; 57(Suppl 4A):31. 6. De Marzo AM, Nelson WG, Isaacs WB, Epstein JI: Pathological and molecular aspects of prostate cancer. The Lancet 2003; 361:955. 7. Easton DF, Schaid DJ, Whittemore AS, Isaacs WB: Where are the prostate cancer Genes?—A summary of eight genome wide searches. The Prostate 2003; 57:261. 8. Lupold SE, Hicks BJ, Lin Y, Coffey DS: Identification and characterization of nuclease stabilized RNA molecules that bind human prostate cancer cells via the prostate-specific membrane antigen. Cancer Res 2002; 62:4029.
C H A P T E R
2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations Martin G. Sanda, MD, and Ronald Rodriguez, MD, PhD
Over 50 years of scientific research following the discovery of DNA1 have led to recent insights that have set the stage for preclinical development of gene therapy strategies and their assessment in clinical trials. The enormous volume of scientific research that comprises the foundation for therapeutic use of molecular biology reflects the complexity of linking the most fundamental unit of life, the human genome, to direct clinical intervention. These profound complexities were manifest as several unforeseen adverse events in clinical gene therapy clinical trials observed concurrently with observed effective treatment by gene therapy.2,3 Consequently, the initial exuberant enthusiasm for clinical gene therapy has been tempered by an emerging respect for how the profound complexity of in vivo gene transfer faces obstacles to therapeutic efficacy and carries the potential for significant clinical toxicity. Preclinical studies have identified several therapeutic strategies based on gene replacement or gene transfer that, in some cases, have moved to evaluation in clinical trials. Gene therapy strategies under development include correcting tumor-specific genetic abnormalities by either inhibiting the function of oncogenes (abnormal tumor genes that promote tumor cell longevity or proliferation) or restoring functional tumor suppressor genes (such as genes that can regulate DNA repair), which are commonly functionally mutated or absent in cancer. Alternatively, the immune response of patients with cancers harboring any of these abnormalities can be stimulated by gene therapies based on use of recombinant tumor vaccines. Pivotal to all avenues of gene therapy is the gene transfer vector. GENE TRANSFER VECTORS As the vehicles for therapeutic gene delivery, gene transfer vectors delegate clinical prospects and limita18
tions. Gene transfer vectors can be generally classified as being of either viral or nonviral origin. Vector design is guided by their desired functions: efficiency of gene transfer, stability of gene expression, and safety of clinical use. Gene transfer efficiency indicates how well a vector delivers a recombinant gene to a target cell and how effectively the protein encoded by that gene is subsequently expressed. Highly efficient gene transfer is desirable in almost all clinical strategies using gene transfer. Two critical components determine gene transfer efficiency: gene delivery by the vector and activity of a vector’s expression cassette. The first determinant of efficiency, gene delivery, refers to a vector’s capacity for cellular attachment, entry, and delivery of the therapeutic gene (within an expression cassette) to a site such as the target cell nucleus at which gene expression can occur. Delivery mechanisms of each vector system are distinct.4–6 Cell surface density of specific receptors required for vector attachment, as well as stability of the vector itself in the micro-environment surrounding the target cell, affects a vector’s capacity for therapeutic gene delivery.7–9 The second principal determinant of vector efficiency is the vector expression cassette, which contains, in addition to the therapeutic gene, a promoter sequence controlling therapeutic gene transcription. Some vectors (such as poxviruses) encode their own machinery for gene transcription,6 while others rely entirely on preexisting polymerases in the target cell10; however, all vectors carry a promoter region flanking the therapeutic gene. The promoter profoundly affects therapeutic gene expression and vector efficiency.11 The stability of gene expression by a specific vector system depends on the intracellular localization of the
Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 19
therapeutic gene by the vector. Typically, episomal localization (when the therapeutic gene is not integrated in the target cell chromosome) leads to transient expression of the gene because most mammalian cells have efficient mechanisms for extruding episomal foreign DNA. In contrast, vectors that allow integration of the transferred gene into the host cell chromosomal DNA, such as retroviral vectors, provide longer duration of stable expression. Although stable, durable expression may be desirable in treating hereditary disorders and chronic disorders, it should be noted that transient gene expression might be sufficient for the purposes of using gene transfer for cancer treatment.10 RETROVIRUS VECTORS Retroviral vectors were used in the first clinical trials of gene therapy.12,13 Although retroviral vectors provide distinctly stable long-term expression of therapeutic genes, use of these vectors is limited by complexity of retroviral genetic engineering and vector purification as well as by safety obstacles.3,8,9 These vectors are currently being used predominantly in ex vivo gene transfer protocols, although in vivo gene transfer applications are emerging. Vector genome with therapeutic gene expression casette
Vector Production Production of replication-deficient retroviral vectors is accomplished with vector packaging cell lines (Figure 2-1). Vector particles secreted into packaging cell supernatant are purified and concentrated in preparation for use for gene transfer. Gene Delivery Cells targeted for gene transfer using the purified retroviral vector incorporate the vector by endocytosis via a specific receptor (Figure 2-2). Reverse transcriptase then converts vector RNA into DNA, which is then integrated into the target cell chromosomal DNA during target cell proliferation. This requirement for target cell proliferation as a prerequisite to transferred gene expression is unique to retroviral vectors; retroviral vectors thus do not readily transfer genes to quiescent cells.8,9 Gene Expression After integration of the retroviral vector expression cassette (the therapeutic gene flanked by sequences that Virus envelope or protein coat
Viral genome containing therapeutic gene expression cassette Factors for initiation of expression in targety cell
Transfection Viral vector packaging cell line
Assembled recombinant viral vector particles
Transfection
Vector complementary viral gene(s) Figure 2-1 Production of recombinant viral vectors for gene therapy. A schematic representation of retroviral vector production is shown; analogous systems are in use for the production of adenoviral and poxvirus vectors. For retroviral vector production, packaging cell lines in which the therapeutic gene has replaced retroviral gag, pol, and env genes (these genes are normally required for retrovirus particle production and packaging by infected cells). The packaging cell line has been co-transfected with these viral genes in trans to complement the replication defective vector genome, allowing the packaging cell line to produce and package replication-deficient viral vector particles. (Based on Danos O, Mulligan RC: Proc Natl Acad Sci USA 1988; 85:6460; Ghosh-Choudhury G, Haj-Ahmad Y, Brinkley P, et al: Gene 1986; 50:161; Mulligan RC: Science 1993; 260:926.)
20
Part I Principles of Urologic Oncology
Figure 2-2 Gene transfer by retrovirus vectors. Retroviral gene transfer is mediated by integration of the therapeutic gene into the target cell chromosomal DNA, and therefore requires target cell DNA replication. (Based on Danos O, Mulligan RC: Proc Natl Acad Sci USA 1988; 85:6460; Mulligan RC: Science 1993; 260:926; Crystal RG: Science 1995; 270:404; Miller N, Vile R: FASEB J 1995; 9:190.)
promote gene expression) into the chromosome of the target cell, the therapeutic gene is expressed by the target cell’s own polymerases and other mediators of gene expression. Because the therapeutic gene is integrated into the target cell genome, it is stably expressed by the cell long-term and is passed onto progeny should the cell continue to proliferate. Further contributing to long-term stability of retroviral transferred gene expression is the immunologically inert phenotype of these vector constructs: immune responses targeting the vector itself have not been an obstacle to retroviral vector use. Although stable genomic integration, as can be achieved with retroviral vectors, may be desirable for some therapeutic strategies (such as tumor suppressor gene replacement), stable and permanent alteration of the target cell genome in vivo also poses potential safety pitfalls such as potentially irreversible untoward genetic effects in vivo. Reflecting the profound in vivo effects of retrovirus vector integration into chromosomal integration, such vectors proved effective in treating severe combined immunodeficiency disease in children; however, cancers developed in some of these children that are believed to have been consequent to integration of the retroviral vector.3
Attributes and Applications Due to limitations in the functional concentration (or titer) of retroviral preparations, and rapid inactivation of unbound retrovirus in vivo, direct in vivo gene transfer using retroviral vectors has generally been inefficient, with only a small fraction of target cells expressing the transferred gene. Retrovirus vectors can, however, mediate highly efficient gene transfer ex vivo (Table 2-1).4 Cancer therapy applications of retroviral vectors have therefore predominantly involved ex vivo gene transfer, for example, to augment the immunogenicity of patientderived tumor cells (by introducing into such tumor cells an immunostimulatory gene) prior to use of such cells in vivo as a gene-modified tumor cell vaccine or for marker studies.12,14,15 Because retroviral gene transfer itself neither damages the host cell nor induces undesirable vector-specific immunity, these vectors are ideally suited for gene-modified cancer cell vaccine therapies seeking to elicit tumor-specific immunity. Despite early encouraging results of clinical trials that used retroviral vectors to create gene-modified tumor vaccine studies for renal cancer and prostate cancer, the recent observation of vector-induced leukemias in children undergoing retroviral gene replacement therapy3 will likely reduce enthusiasm
Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 21
Table 2-1 Attributes of Vectors for Therapeutic Gene Delivery Vector
Duration of Therapeutic Gene Expression
Efficiency of Gene Transfer
Other
Retrovirus
Stable long-term
Variable
Labile in vivo
Adenovirus
Transient
Highly efficient
Immunogenic
Poxvirus
Transient
Highly efficient
Immunogenic
Nonviral plasmid or naked DNA
Transient
Inefficient
Fewer safety concerns
for clinical applications to only those wherein stable chromosomal integration is required for the desired therapeutic effect. ADENOVIRUS VECTORS Interest in adenoviral vectors was prompted by their capacity for highly efficient gene transfer in vivo. The propensity of adenovirus vectors to induce nonspecific inflammation and a vector-specific immune response, however, has limited efficacy of this vector system in clinical trials evaluating adenovirus vectors for gene replacement therapy for noncancerous diseases.9,16 Moreover, an inflammatory response against the adenovirus vector has been suspected as possibly contributing to the first incidence of a fatal complication of gene therapy.2 Whether the efficacy of antitumor therapies using this vector system will be attenuated or augmented by inherent immunogenicity of adenoviral vectors remains to be elucidated. Vector Production Recombinant adenoviral vectors are rendered infectious but replication defective (while retaining their capacity to infect cells) by deletions in an early region DNA (E1) required for viral replication.5 The deleted E1 region and other regions of the adenovirus genome serve as sites for therapeutic genes by using shuttle plasmids and homologous recombination with complementary deletion mutants (see Figure 2-1). A packaging cell line (293 cells, a transformed human embryonic kidney cell line containing the adenovirus E1 DNA) transfected with the E1 deleted adenoviral vector containing a gene of interest is used to produce the replication-deficient adenoviral vectors.5 High concentrations of adenoviral vector (titer >1011 pfu/ml) can be readily purified. Gene Delivery Adenoviruses are taken up by the target cells via a twostep process, involving binding and internalization.
Binding occurs through the interaction of the knob of the protruding viral capsid fiber protein to its cellular receptor, referred to as Coxsackie and adenovirus receptor (CAR). Internalization occurs as a result of the interaction of the RGD motif of the viral penton base capsid protein with the cellular integrins (αVβ5 or αVβ3, Figure 2-3).9,17,18 After internalization, the vector is transported from the endosome to the cytoplasm, where the adenoviral protein coat is lost as the adenoviral DNA migrates to the nucleus. In the target cell nucleus, the vector remains epichromosomal and is not integrated into the target cell chromosome. Replication of the target cell is not required for therapeutic gene delivery. Gene Expression Nuclear localization of the adenoviral vector allows the target cell’s own polymerases and other mediators of gene expression to participate in expression of the therapeutic gene. However, because they remain epichromosomal, expression of adenoviral vector genes is transient, lasting only weeks.9 Attributes and Applications Adenovirus vectors are characterized by transient duration of gene expression in target cells, significant induction (by the vector) of inflammation and immunity, and capacity for highly efficient gene transfer in vivo (see Table 2-1). The transient gene expression associated with adenoviral vectors is less likely to constrain the utility of these vectors for cancer therapy than for other applications: gene-targeted immunotherapy, as well as apoptosis-inducing therapies, does not require permanent expression of therapeutic genes, and adenovirus vectors have been effectively applied for such therapeutic strategies in preclinical models.19,20 Indeed, the transient nature of adenovirus-mediated gene transfer circumvents the safety issue of irreversible undesirable genetic effects such as could be encountered with retroviral gene transfer.
22
Part I Principles of Urologic Oncology
Figure 2-3 Gene transfer by adenovirus vectors. Adenoviral vectors do not require target cell DNA replication for efficient gene transfer. However, nuclear localization of the vector DNA is required since target cell nuclear factors are used for gene expression. Because these vectors are epichromosomal, therapeutic gene expression is typically less durable than with retroviral vectors. (Based on Ghosh-Choudhury G, Haj-Ahmad Y, Brinkley P, et al: Gene 1986; 50:161; Crystal RG: Science 1995; 270:404; Miller N, Vile R: FASEB J 1995; 9:190.)
Adenovirus vectors are potent immunogens.16 Although potentially desirable for gene-targeted immunotherapies, the inherent immunogenicity of adenoviruses may also limit repeated administration of these vectors due to sensitization-induced inflammatory toxicity.9 Moreover, adenovirus-specific immunity may constrain in vivo gene transfer with adenoviral vectors by inducing humoral and cellular responses capable of eliminating the vector and further reducing duration of target gene expression.16 Despite these limitations, the receptivity of many human cells to adenoviral transfection, coupled with the relative stability and ease of production of adenoviral vectors, led to significant tumor reduction in several preclinical models of direct in vivo gene transfer and broad clinical applications.19–22 The immunogenicity of adenoviral vectors was found to carry potentially dire consequences; however, a systemic inflammatory response, possibly manifested by unrestricted complement activation, was implicated in the widely publicized death of Jesse Gelsinger, a patient who received a dose of 38 trillion adenovirus particles on a phase I trial of adenoviral gene therapy for an inherited hepatic enzyme deficiency.2 Nevertheless, early phase clinical studies using adenoviral vectors continue, and
utilizing adenoviral vectors for prostate cancer have resulted in encouraging biologic activity and is an area of active translational research.23–25 POXVIRUS VECTORS Vaccinia and other poxvirus vectors are derived from one of the greatest triumphs of post-classical medicine: the smallpox vaccine.6 Jenner’s discovery in 1798 that a bovine poxvirus was an effective human vaccine against smallpox eventually led to implementation of a concerted worldwide vaccination program by WHO, which was implemented in 1967, and Jenner’s prediction of “the annihilation of the smallpox” was finally realized in 1995, nearly 200 years after the introduction of poxvirus vaccines for human use. Current use of poxvirus vectors for experimental cancer therapy relate to the ability of these vectors to induce potent immune responses in vivo. Vector Production Because recombinant poxviruses are used as live, replication-competent viruses (albeit in attenuated or otherwise
Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 23
nonpathogenic forms when administered in vivo), production can be achieved by simply infecting specific host cells that allow productive infection.6 Genetically engineered packaging cell lines, such as those used for retrovirus or adenovirus vector production, are not required. Immunostimulatory cytokine, accessory molecule, or tumor antigen genes can be inserted into vaccinia or other poxvirus vectors by flanking these genes with poxvirus sequences in a “shuttle” plasmid and then introducing this plasmid into a cell that has been infected with whole vaccinia virus. Homologous recombination (as with adenoviral vector systems) in the vaccinia and shuttle plasmid co-transfected cells then leads to insertion of the gene of interest in a small proportion of the viral progeny (see Figure 2-1). Linking the therapeutic gene with an adjacent selectable marker gene allows subsequent purification and production of exclusively recombinant poxvirus containing the gene of interest.6 Up to 25,000 base pairs of foreign DNA can be accommodated by vaccinia vectors, representing the greatest size capacity of currently available recombinant viral vectors for transferred genes.6
cytoplasm and intracytoplasmic release of the virion complex core (Figure 2-4).6 The virion complex core contains the vector genome, as well as RNA polymerases and other enzymes required for expression of the vector genes; the vector remains in the cytoplasm, where gene expression controlled by elements contained in the virion complex core occurs.
Gene Delivery
Attributes and Applications
Infectious poxvirus virions enter the target cell via fusion of the virion lipoprotein envelope with the target cell
Poxvirus transfection is transient and eventually toxic to the target cell (see Table 2-1). The successful history of
Gene Expression Poxvirus vectors are unique in their ability to express therapeutic genes without requiring transport of the vector to the target cell nucleus. In contrast to other vector systems, which require host cell nuclear factors and enzymes for gene expression, poxviruses carry the apparatus for synthesis of translatable RNA (including virusencoded RNA polymerases, transcription factors, capping enzymes, and poly(A)polymerases) either prepackaged within the complex virus core or encoded within the viral genome itself.4 Expression cassettes in poxvirus vectors thus require unique poxvirus-specific promoter regions that can be recognized by viral transcription factors.
Figure 2-4 Gene transfer by poxvirus vectors. Poxvirus vector particles contain viral RNA polymerases, obviating any need for nuclear localization or chromosomal integration. Therapeutic gene expression occurs entirely in the target cell cytoplasm. (Based on Moss B: Science 1991; 2252:1662.)
24
Part I Principles of Urologic Oncology
vaccinia use for smallpox eradication and the relative ease of cloning genes into vaccinia vectors have uniquely poised vaccinia and other poxvirus vectors for use as recombinant tumor vaccines. As with adenovirus vectors, use of poxviruses for immunogene therapy is tempered by potentially competitive, antivector, immune response induction.26 NONVIRAL VECTORS: LIPOSOMAL GENE TRANSFER Nonviral approaches to gene therapy avoid disadvantages of viral vectors such as safety issues related to potential replication-competent virus formation and limited target cell diversity related to receptor requirements for viral envelope adsorption.7,9,10,17,18 The most extensively developed nonviral gene delivery systems are liposomemediated gene transfer and high-velocity particle-mediated gene transfer, also known as the “gene gun.” Vector Production Plasmid–liposome complexes for gene delivery are comprised of DNA formulated with cationic lipids. Most of the cationic lipid–DNA complexes commonly used for gene delivery in clinical trials are not true lipo-
somes containing plasmid DNA within a lipid envelope but are rather particulate complexes in which plasmid DNA is dispersed among the bound lipids.7,9,27 Gene Delivery These complexes promote cellular gene delivery by hydrophobic interaction and fusion of the lipid–DNA complex with the target cell membrane. Unlike viral vectors, however, no signal exists to facilitate transport of the plasmid DNA containing the therapeutic gene to the nucleus (Figure 2-5).7 Transfection efficiency is therefore typically relatively inefficient (see Table 2-1). DNA complexes with copolymers, in contrast, offer the added advantage of incorporation of targeting ligands, such as folate or transferrin. Early work in this regard has demonstrated enhanced gene transfer with systemic delivery of these targeted complexes.28,29 In contrast, high velocity particle-mediated gene transfer, or gene gun, technology allows the delivery of thousands of copies of DNA into targeted cells. This is achieved by coating 1–3 μm gold particles with plasmid DNA or mammalian chromosomal genomic DNA up to 44 kb in size; a gene gun is then used to deliver the particles in vivo by generating a high-pressure gas burst that accelerates the particles to a velocity sufficiently high for
Figure 2-5 Nonviral gene transfer by liposomal vectors. Liposomal vectors in current use are complexes of cationic lipids and plasmid DNA. Although relatively safe and immunologically inert, liposomal vectors require nuclear localization for access to target cell transcription factors. (Based on Ledley FD: Hum Gene Ther 1995; 6:1129; Crystal RG: Science 1995; 270:404.)
Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 25
EMERGING VECTORS AND OTHER GENE DELIVERY SYSTEMS
Figure 2-6 Nonviral gene transfer via particle bombardment (gene gun). In the helium pulse gene gun, motive force is generated by release of a high-pressure burst of helium gas from a reservoir (A) at a preset pressure (150-700 psi). A release valve (B) discharges helium through a cartridge (C) containing DNA-coated gold particles. After being dispersed by an exit nozzle (D), the DNA-coated gold particles (E) penetrate target cells or tissue with sufficient force to penetrate multiple cell layers and deliver plasmid DNA intracellularly. (Reprinted from Yang NS, Sun WH: Nat Med 1995; 1:481, with permission.)
penetration of multiple cell layers (Figure 2-6).8 As with lipid–DNA complex gene transfer, translocation of plasmid DNA to the nucleus after gene gun delivery is not a specifically targeted event. Gene Expression Plasmid DNA that does manage to translocate to the nucleus usually is not integrated into the target cell genome and remains epichromosomal (see Figure 2-5).5 Similar to adenoviral vectors, expression relies on target cell transcription factors and is typically relatively transient. Attributes and Applications The principal advantage of nonviral gene delivery systems, including cationic lipid–DNA complexes, the gene gun, and other nonviral delivery systems, is that these systems circumvent three potentially problematic characteristics of viral vectors: immune reactivity, reliance on viral receptor expression by target cells, and safety issues related to potential pathogenic recombinant contaminants in viral preparations. Enthusiasm and applicability of nonviral vectors are tempered by relatively inefficient gene delivery and transient therapeutic gene expression (see Table 2-1). As transient expression systems, nonviral and gene gun delivery systems have been useful for induction of antitumor immunity. Induction of cytokine secretion using the gene gun has been associated with reduction of renal cell carcinoma progression in a mouse model.30 Clinical studies using lipid–DNA complexes have shown induction of antitumor immune mediators in melanoma patients, and trials using these vectors for renal cell cancer are underway.27,31
The preceding discussion has focused on gene transfer vectors currently being used in clinical trials as investigative agents for urologic cancers. A variety of other novel viral, as well as nonviral, vectors are currently under development. Among emerging viral vectors are gene delivery constructs derived from herpesvirus, parvovirus, and adeno-associated viruses.32–34 Nonviral vectors under development include eukaryote-derived vectors such as Listeria monocytogenes and recombinant BCG, synthetic constructs such as dendrimers, and others.35 The ideal vector for most gene therapy applications will likely evolve as a hybrid vector merging the desirable properties of viral vectors with advantageous attributes of nonviral delivery systems.11 MOLECULAR TARGETS OF GENE THERAPY Gene therapy for urologic malignancy can be categorized into four distinct strategies based on the molecular target of gene transfer: immunogene therapy, direct tumor cell death induction, antioncogene therapy, and tumor suppressor gene restoration (Table 2-2). Immunogene therapy affects tumor growth indirectly by inducing a tumor-specific immune response either via immunostimulatory gene transfer ex vivo (followed by in vivo administration of genetically altered cells to induce a tumor-specific immune response) or via direct in vivo transfer of immunostimulatory or tumor antigen genes. Direct tumor cell death induction relies on delivery of genes encoding cellular toxins or apoptosisinducing proteins. Antioncogene therapy specifically inhibits or eliminates oncogene activity. Tumor suppressor gene restoration therapy inhibits tumor growth by restoring genes that prevent transformation of the normal cell but have been functionally disabled during carcinogenesis. The preclinical rationale for these gene therapy strategies, and consequent gene therapy clinical trials treating urologic cancers are discussed (Table 2-3). Immunogene Therapy Via Ex Vivo Gene Transfer Gene therapy via transfer of immunostimulatory genes to induce a tumor-specific immune response is perhaps the most extensively evaluated strategy of gene therapy to date. This is partly because early gene transfer systems limited gene therapy to strategies using ex vivo (rather than in vivo) gene transfer, and this approach is widely applicable as immunogene therapy using, for example, patient-derived cultured tumor cells for a gene-modified tumor cell vaccine.15,36–43 Generally, clinical applications of these studies used retroviral vectors as the vehicles for gene transfer.15,44 Strategies of immunogene therapy
26
Part I Principles of Urologic Oncology
Table 2-2 Characteristics of Gene Therapy Strategies in Current Clinical Trials Therapeutic Gene
Extent of Potential Efficacy In Vivo*
Relative Obstacles
Immunogene: ex vivo transfer
Systemic
Tissue procurement and cell culture required
Immunogene: in vivo transfer
Systemic
Vector-specific immunity may interfere with induction of tumor-specific immunity
Cyto-toxicity/apoptosis
Local-regional
Requirement for highly efficient gene delivery in vivo; possibility of cytotoxic injury to normal cells
Antioncogene/antisense
Local-regional
Requirement for highly efficient gene delivery in vivo and durable expression of therapeutic gene
Tumor suppressor
Local-regional
Requirement for highly efficient gene delivery in vivo and durable expression of therapeutic gene
*Based on current vector limitations.
Table 2-3 NIH-Approved Clinical Trials of Gene Therapy for Urologic Cancer Principal Investigator
Vector: Therapeutic Gene
Cancer Histology
Status
Immunotherapy: gene transfer ex vivo
Gansbacher Simons Simons Paulson
Retrovirus: IL-2 Retrovirus: GM-CSF Retrovirus: GM-CSF Liposome: IL-2
Renal cell Renal cell Prostate Prostate
Open Completed Open Pending
Immunotherapy: gene transfer in vivo
Vogelzang
Liposome: class I MHC Liposome: class I MHC Poxvirus-vaccinia: GM-CSF Poxvirus-vaccinia: PSA
Renal cell
Completed
Renal cell
Open
Transitional cell
Open
Prostate
Open
Strategy
Figlin Lattime Chen Cytotoxic
Scardino
Adenovirus: HSV-tk
Prostate
Open
Anti-oncogene
Steiner
Retrovirus: myc antisense
Prostate
Pending
Tumor suppressor gene restoration
Small
Adenovirus: Rb gene
Transitional cell
Pending
have also been formulated that rely on gene transfer in vivo.45–49 It is therefore useful to evaluate immunogene therapy strategies in the context of whether the particular strategy requires ex vivo gene transfer or in vivo gene transfer (see Table 2-2). Therapies using genetically modified, patient-derived cells for a genetically engineered tumor vaccine have comprised the principal use of ex vivo immunogene ther-
apy for urologic malignancies in preclinical studies and clinical trials as well. For these therapies, tumor cells isolated from fresh surgical specimens are genetically transduced during tissue culture with an immunostimulatory gene. The resected genitourinary cancer cells serve principally as vehicles for autologous tumor antigens and are transduced for immunostimulatory gene expression. The gene-modified tumor vaccine is typically irradiated ex
Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 27
vivo prior to being reinjected into the patient as a genetically engineered tumor cell vaccine (Figure 2-7). Initial preclinical studies evaluating this strategy of gene therapy showed that a tumor-specific, T-cell mediated immune response could be augmented by vac-
cination using tumor cells derived from the same tumor but transduced to secrete IL-2; such vaccination protected animals from subsequent tumor challenge.36,37 Gamma-interferon gene transfer was shown to promote a similar protective effect.38 Subsequently, transfer of
100
Treatment GROUP A Hanks BSS (control) GROUP B XRT-MLL GROUP C XRT-MLL + SOLUBLE huGM-CSF 8500 ng GROUP D XRT-MLL-MFG-huGM-CSF 140 ng/10/24
Percentage cancer free
80
CELL DOSE 5 X 106
60
40 (Wilcoxon P=0.001)
20
0 0
15
30
Vaccine Rx (Day 3,13,23)
45
60
75
90
105
120
135
150
Days after prostate cancer implantation
A
Primary culture
Immunostimulatory gene transfer
Surgery
Irradiation of human gene modified prostate cancer vaccine
Vaccination
B Figure 2-7 Immunogene therapy via ex vivo gene transfer. A, Preclinical models have shown that vaccination of tumor bearing animals with tumor cells that have been retrovirally transfected ex vivo to produce immunogene products (in this case GM-CSF) can induce complete or partial tumor regression at a distant metastatic site (as shown in the illustrated experiment using hormone-refractory Dunning rat prostate cancer). (Reprinted from Sanda MG, Ayyagari SR, Jaffee EM, et al: J Urol 1994; 151:622, with permission.) B, Schema of an analogous human gene therapy protocol being evaluated in an ongoing clinical trial based on experiments such as that in part-figure A. (Reprinted from Sanda MG, Simons JW: Urology 1994; 44:617, with permission.)
28
Part I Principles of Urologic Oncology
granulocyte-macrophage colony-stimulating factor (GM-CSF) and other immunostimulatory genes into tumor cells used for vaccination led to elimination of preestablished microscopic tumor cell deposits in animal models. Antitumor immune mediators (such as helper T cells, cytolytic T cells, NK cells, and dendritic cells) are activated by the expression of therapeutic immunostimulatory genes in close proximity to tumor-specific antigens present in the genetically engineered tumor vaccine cells. The immune mediators then circulate and, ideally, eradicate distant micrometastases. Preclinical in vivo efficacy of such gene-modified tumor cell vaccines has also been shown in several models of urologic malignancy, including renal cancer, bladder cancer, and prostate cancer (see Figure 2-7).14,40–43 Several clinical trials using immunogene therapy with ex vivo gene transfer specifically for urologic cancers are underway or forthcoming (see Table 2-3).15,44,50,51 Therapeutic genes encoding IL-2 and GM-CSF targeted prostate cancer or renal cell carcinoma in these studies. In one completed study, no dose limiting toxicities were encountered, and a dose-dependent lymphocyte infiltrate was noted at the vaccine site.15 The single patient who exhibited a partial response in this phase I study also showed the greatest DTH response in the study group, suggesting that GM-CSF secreting vaccine cells can induce tumor-specific immune responses with minimal toxicity. Evaluation of potential clinical efficacy with this strategy awaits a larger phase II study. A significant limitation of these ex vivo gene transfer therapies, however, is the need for cell culture of cancer cells that serve as targets for gene transfer (see Table 2-2). Problems associated with the need for cell culture include: requisite surgery to procure adequate tumor volumes for vaccine cell production; unreliable tumor cell yield with regard to both tumor cell number and tumorigenic genotype; and a requirement for cumbersome, expensive cell culture for each treated subject, limiting the widespread applicability of this therapy.15,41,52 To circumvent these limitations of ex vivo tumor cell culture for gene transfer, the development of nonretroviral gene transfer vectors has led to alternative immunogene therapies using in vivo gene transfer techniques. Immunogene Therapy Via In Vivo Gene Transfer The advent of vectors capable of efficient and safe direct gene transfer in vivo, such as poxvirus, adenovirus, and liposome vectors, has provided an avenue for overcoming problems unique to ex vivo gene transfer therapies such as the need for tumor cell procurement and culture (see Tables 2-1 and 2-2). Two general approaches using in vivo gene transfer for immunogene therapy have been developed through preclinical studies to the arena of clinical trials; one entails in vivo transfer of immunostimulatory
genes, and the other entails in vivo delivery of tumor antigen genes by recombinant viral vectors vaccines. In vivo gene transfer of immunostimulatory genes has been evaluated using poxvirus and liposomal vectors encoding GM-CSF, IL-2, IL-12, and other genes for therapy of renal, bladder, and prostate cancer.30,31,48,53 Rather than removing tumor cells to achieve genetic modification in vitro and then using the gene-modified cells as a vaccine, the gene transfer vector is administered directly into tumor in vivo, such as by intravesical instillation or intratumoral injection. The transfected tumor cells essentially function as an in situ vaccine to induce activity both against the transfected primary tumor site and distant metastases, without having undergone ex vivo processing and culture. A potential advantage of this approach is that genuine tumor antigen expression by the in vivo-transfected tumor cells is conserved, while interference by in vitro artifact antigens is avoided (see Table 2-2). This approach has also been extensively evaluated with other vector systems in nonurologic tumor models, and clinical trials in urologic and other tumors based on these studies have been undertaken.54–58 Some distinct advantages of bladder cancer and prostate cancer, specifically, support a focus on these malignancies with in vivo immunostimulatory gene transfer. First, regional targeting of localized bladder and prostate cancer is potentially readily achieved in these sites by either intravesical administration or transrectal prostatic injection. Second, prostate cancer immunogene therapy poses the possibility of using not only tumor antigens, but also potentially of normal prostate antigens (such as prostate-specific antigen [PSA], expressed in normal and malignant prostate cells alike) as targets of immune effector cells. Use of recombinant vectors encoding specific tumor antigens as agents for recombinant vaccination differs from other immunogene therapy strategies in that the viral vector itself provides the antigen to stimulate a tumor-specific immune response. In this setting, the patient’s tumor cells are not relied on as an effective antigen-presenting cell nor are they a required target of direct immunogene transfer. Instead of targeting tumor cells as the recipients of the therapeutic gene (as shown in Figure 2-4), systemically administered recombinant vector vaccines target professional antigen-presenting cells as recipients for the therapeutic gene (which in this strategy encodes a tumor antigen). By using antigenpresenting cells, such as dendritic cells, to induce immune mediators that then recognize and eliminate tumor cells, this strategy avoids potential tumor cell mechanisms for actively suppressing immune induction, such as secretion of TGF-β.59–61 Initial studies using recombinant vectors as tumor-specific vaccines focused on relatively simple vector constructs encoding a specific tumor antigen alone as the basis for induction of immunity. Along these lines,
Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 29
clinical trials have been conducted using a vaccinia vaccine encoding PSA for prostate cancer therapy.49,62 The goal of vaccinia-PSA immune gene therapy is to induce an immune response against any cells expressing PSA under the hypothesis that activated PSA-specific T cells will kill cancer cells that express PSA (as in the setting of recurrence after radical prostatectomy). Innate immune tolerance to PSA as a normal self-antigen, however, will need to be overcome to achieve the desired therapeutic effect. The efficacy of preclinical immunogene therapy studies should be viewed in context. When evaluated in highly lethal, nonimmunogenic tumor models, which most closely mimic human malignancy, the antitumor effect has been modest—in the range of 4-log kill. This would indicate that clinical efficacy of a gene-modified tumor cell vaccine approach may potentially be limited to an adjuvant setting. In addition, characteristics common among urologic cancers, including deficient class I MHC expression, overproduction of immunosuppressive TGF-β, and heterogeneous target tumor antigen expression, all represent potential immune evasion mechanisms that may impede efficacy of immunogene therapies. The immunogene therapy patient conversely may harbor generalized limitations to potential immune stimulation.63 In addition, immune responses against the vector backbone may interfere with tumor-specific immune effectors. A new generation of recombinant vector vaccines seek to address these and other obstacles by combining the advantages of immunostimulatory gene transfer and vector-encoded tumor antigen gene transfer in vectors designed to deliver two therapeutic genes in one vector: an immunostimulatory gene in tandem with a tumor antigen gene.46 Despite potential obstacles, therapeutic efficacy in the setting of transient gene transfer and durability of tumor-specific immunity comprise advantages of immunogene therapy that fuel continued clinical development. Gene Transfer for Direct Induction of Target Cell Death Hypothetical barriers to tumor therapy by transfer of cell death genes traditionally included the potential need for nearly 100% efficient gene transfer in vivo to achieve remission and lack of effective strategies for targeting tumor cells specifically without concurrent death induction in normal tissues. The availability of vectors that transfer genes efficiently in vivo, the discovery of bystander effects which allow transmission of cell death signals to nontransduced cells, the characterization of organized cell death (apoptosis) pathway abnormalities in cancer cells, and the development of dominant cell deathinducing genes, however, have all prompted a reevaluation of these hypothetical barriers (see Table 2-2).64–69
Three general approaches to targeting cell death (independent of tumor-specific immunity) are in development. First, gene transfer of a drug susceptibility gene (such as herpesvirus thymidine kinase, HSV-tk) renders target cells sensitive to subsequent gancyclovir-mediated cytotoxicity.70 Second, transfection of cellular toxin genes can induce cell injury, disruption, and necrosis. Third, gene transfer of dominant apoptosis-inducing genes can trigger organized cellular death, or apoptosis.71,72 Gene transfer of HSV-tk, as a means of rendering tumor cells susceptible to subsequent gancyclovirmediated cytotoxicity, was among the first approaches in efforts to induce tumor cell death via gene transfer.70,73,74 In this system, gancyclovir acts as a prodrug that becomes cytotoxic only after it is phosphorylated by HSV-tk. Mammalian cells normally lack HSV-tk; hence the requirement for gene transfer. Phosphorylation of gancyclovir by HSV-tk leads to the formation of gancyclovir triphosphate, a potent nucleotide competitor that interferes with DNA synthesis. A bystander effect, whereby nontransduced adjacent malignant cells are killed in part to the transfer of the toxic analog via gap junctions or apoptotic vesicles, was initially described in HSV-tk gene transfer studies.64 HSV-tk gene transfer can be accomplished by retroviral or adenoviral vectors in vivo. Due to ease and efficiency of use, adenoviral vectors have been used for HSV-tk gene transfer in animal models of prostate cancer in which in vivo delivery was accomplished by intratumoral injection.75 Subsequent systemic administration of gancyclovir led to significant reduction of tumor growth. This effect was synergistic with androgen withdrawal in a mouse model of androgen responsive prostate cancer.68 Clinical trials based on these findings and using intratumoral injection for delivery have been completed with modest PSA responses.24,76 A limitation of HSV-tk gene transfer is the need to coordinate and optimize administration of two agents: the sensitizing gene transfer vector and the prodrug gancyclovir. An alternative strategy for direct cytotoxicity is gene transfer of cellular toxin genes, such as ricin and diphtheria toxin, which disrupt protein synthesis resulting in lethal cellular injury.72 Although ricin gene transfer itself has not been applied to urologic tumors, direct administration of ricin gene products is cytotoxic to human prostate cancer cells, providing rationale for further development of this strategy.77 Adenoviruses encoding diphtheria toxin have demonstrated remarkable potency at eliminating established tumors;71,78 however, the extreme potency of the toxin makes it capable of killing nontarget cells, even when used with a tissuespecific promoter. Hence, unless better transcriptional control can be achieved, this approach will probably not be readily translated into clinical utility. Third and perhaps most promising of the gene therapy strategies, which aim to directly induce cell death, is
30
Part I Principles of Urologic Oncology
gene transfer of apoptosis-inducing genes. Organized cell death in the form of apoptosis differs from toxic or necrotic cellular disruption (such as ricin-mediated toxicity) in that apoptosis occurs as a normal entity of the eukaryotic life cycle in vivo, without concomitant inflammation or other local toxicity. Prostate biology revealed some of the earliest evidence for apoptosis as a normal component of cellular homeostasis, and prostate cancer was the first among several solid tumors whose growth and progression has been shown to result from defective apoptosis rather than augmented proliferation.79 Gene products involved in a cascade of intracellular events mediating apoptosis have been successfully targeted for induction of apoptosis in tumor cells. An ideal apoptosisinducing gene would induce apoptosis in tumor cells without altering homeostasis in normal cells. Candidate genes that may exhibit such selective effects to some degree include caspases and p53; the ability of adenoviral vectors encoding these genes to induce apoptosis in tumor cells in vitro and in vivo has been shown, and effects on normal cells and stem cells are under intensive study.20,22 Early findings indicate that gene transfer of Bclx-s with adenovirus vectors, for example, has little effect on normal cells while tumor growth was profoundly affected in vivo.20 Oncolytic Virotherapy During the late 1950s, a variety of viruses were evaluated as cancer therapeutics; however, with the advent of chemotherapy, improved radiotherapy, and the lack of specificity of virotherapy, these strategies were largely abandoned.80 In the early 1990s, however, a resurgence in this concept occurred, when a herpesvirus was specifically engineered to replicate selectively in central nervous system tumors.81 Subsequently, it was found that naturally occurring mutants of certain viruses were capable of selective replication in cancer cells defective in certain pathways. In the case of the E1B deleted Onyx-015 virus, replication occurred selectively in those cells that were defective in some way in the p53 axis of apoptosis regulation.82 Similarly, others discovered that the reovirus was capable of enhanced replication in those cells with activated ras.83 However, not all malignancies share the same path to oncogenesis. Hence, efforts were made to develop a conditionally replication-competent oncolytic adenovirus (CRAd), which would only replicate and passively lyse cells when it was in a particular cell type. The first of these CRAds was CV706, which preferentially replicated and lysed prostatic epithelial cells by virtue of the PSA promoter and enhancer that were used to activate the replicative genes, E1A and E1B.84 These CRAds demonstrated excellent activity and specificity in vitro and in vivo and hence were rapidly translated into clinical trials.23–25 The results of these initial trials have
also been encouraging in that they have demonstrated a clear dose response, with marked reductions of PSA occurring in most of the men treated at the higher dose levels. However, the response is limited, because the viral infection lasts less than 2 weeks and not all of the cancer cells are transduced by the replicating virus. Given enough time, all the patients with clinical response relapsed with a PSA progression. Of note, however, is the fact that when these viruses are given directly into the prostate, the presence of neutralizing antibodies had no significant clinical impact on the efficacy of the vector. Hence it appears that while such neutralizing antibodies may present a serious obstacle to systemic oncolytic viral therapy, it is of a lesser concern with local therapy. Recent advances in the understanding of adenoviral replication have discovered that the molecular pathways necessary for promoting viral replication are also pivotal in terms of sensitizing the cells to chemotherapy and radiation therapy. The combination of radiation therapy and CV706 results in a 6.7-fold enhancement of tumor reduction over the predicted response from the addition of the two treatments alone.85 This synergy of effect has led to a robust enthusiasm for further clinical translation. If oncolytic virotherapy can potentiate radiation therapy significantly, then the acceptance of this combination is likely to meet with less resistance. As urologists, this combination would be particularly attractive if the combined therapy could be administered contemporaneously through a brachytherapy platform. Like other molecular therapies, oncolytic adenoviral gene therapy is still highly experimental and in its early developmental stages. However, it is becoming increasingly clear that the earliest clinical utility of these methods will be in combination with conventional therapy and at least initially will be limited to local-regional delivery. Antioncogene Therapy: Approaches Using Antisense and Ribozyme Constructs Targeting oncogenes with gene transfer is theoretically advantageous because this strategy can potentially selectively affect tumor cell growth without affecting normal cells, which may lack functionally expression of the target oncogene. By exploiting the ability of complementary RNA strands to bind to each other, delivery of genes containing such complementary or “antisense” sequences to specific oncogenes can revert the tumorigenic phenotype by inhibiting expression of specific oncogenes in target tumor cells. Interference with translational machinery due to pairing of antisense RNA constructs with their oncogeneencoding RNA targets is one mechanism of antioncogene activity postulated as active in this strategy. By interfering with translation of oncogene RNA, oncogenic proteins are produced at much lower levels, if at all. In addition to interfering with translation, moreover, antisense constructs
Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 31
may activate endogenous ribonucleases, which in turn degrade the bound RNA. Regardless of the mechanism, the net effect of antisense therapy is the reduction of oncogenic protein expression due to binding of oncogene RNA by the antisense gene product (see Table 2-2). Although early antisense strategies focused on direct administration of short antisense oligonucleotides (sometimes modified for improved solubility), more recently the delivery of longer antisense constructs, as well as dominant negative mutation constructs, via recombinant vector systems has emerged.86–88 Retroviral transfer of a myc antisense gene (delivered by direct injection of retroviral vector into small prostate cancer nodules in rodents), for example, was found to impede in vivo prostate cancer growth in a rodent model.89 Based on these findings, a clinical trial of antioncogene therapy using intraprostatic injection of retroviral vector encoding antisense myc has been proposed.89 The discovery of ribozymes, or RNA sequences, that catalyze RNA cleavage and splicing, opened a promising extension of gene therapy strategies based on oncogene targeting via antisense recognition of oncogene RNA (Figure 2-8).90 Ribozymes can be designed to degrade RNA containing a short segment of complementary nucleotides. In theory, almost any RNA containing a unique 15-base pair or longer sequence can be specifically degraded by designing a ribozyme containing a complementary binding motif. Adenoviral vectors have been used to deliver oncogene specific ribozymes (for
example, targeting H-ras in a bladder cancer cell line) with consequent repression of in vivo tumorigenesis.91,92 The efficacy of this strategy in the setting of in vivo gene delivery remains as yet untested. However, the direct target specificity of ribozyme-targeted antioncogene therapy, in the setting of a well-characterized effector mechanism, suggests that ribozyme-based strategies may be the most promising antisense-based therapeutic strategy under current development. Tumor Suppressor Gene Restoration The observation that renal cell cancer tumorigenicity can be reversed by in vitro transfer of the von Hippel-Lindau (VHL) gene prior to full biochemical and functional characterization of the VHL gene product attests to the potential utility of gene therapy targeting tumor suppressor gene restoration.93,94 This observation indicates that restoring tumor suppressor genes may reverse tumorigenic potential of individual, in vitro transduced cells. Tumor suppressor gene transfer in vivo, however, has had less impressive effects than in vitro transfection.95 At least two factors may contribute to the discrepancy between in vitro and in vivo effects of tumor suppressor gene restoration: first, intratumoral injection of vectors into solid tumors is not a highly efficient approach for gene delivery—most of the vector is likely cleared before it accesses tumor cells, and the initial vector distribution in injected tissue is unlikely to be uniform. Second, stable
Figure 2-8 Antioncogene ribozyme consensus sequence. The hammerhead ribozyme contains three nonconserved helical regions (stems I, II, and III) along with the conserved sequence of the central core. Stems I and III, which determine the specificity of the ribozyme for its target, hybridize to target oncogene RNA. The target RNA is then cleaved at the site indicated by the arrow, disabling oncogene expression. Nucleotides designated as N can be any nucleotide. (Reprinted from Thompson JD, Macejak D, Couture L, Stinchcomb DT: Nat Med 1995; 1:277, with permission.)
32
Part I Principles of Urologic Oncology
long-term integration (as with a retrovirus vector) of the therapeutic suppressor gene, in the setting of 100% efficient in vivo transduction, would be required to arrest tumor growth (see Table 2-2). This strategy could be optimized by using vectors capable of stably integrating the transgene into the target cell genome, such as retroviral vectors, and also capable of highly efficient in vivo transduction, such as adenoviral vectors. In that no vector currently has both of these characteristics (see Table 2-1), using any vector system will have limited efficacy at present. For example, one potential tumor suppressor target, c-cam, is a cellular attachment molecule, which is absent in some prostate cancers, and thereby potentially contributes to the uninhibited and metastatic growth potential of these cells. Intratumoral injection of an adenoviral vector encoding c-cam, used to restore expression of this molecule in preestablished prostate cancer xenografts, slowed but did not reverse tumor progression (Figure 2-9).95 Similar effects have been seen with adenovirus vector-based therapy targeting restoration of other tumor suppressor genes. Despite these limitations, survival of tumor-bearing animals can be extended with in vivo suppressor gene restoration therapy, and a clinical trial that evaluates the efficacy of Rb gene delivery via intravesical instillation of
adenovirus vector has been proposed (see Table 2-3). The association of Rb gene abnormalities in bladder cancer and poor prognosis supports the rationale for intravesical adenovirus-Rb gene therapy.96 For many tumor suppressor genes, restoration of suppressor gene function alone may not suffice for cytoreduction of established tumors even in the theoretical setting of totally effective and durable in vivo tumor suppressor gene transfer. Most tumor suppressor genes do not encode signals for direct induction of cell death but rather affect tumor growth more indirectly, such as by regulating DNA repair, cellular attachment, or cell cycle control.97 In this setting, restoration of normal suppressor gene via gene transfer may require accompanying cytoreductive systemic or regional therapies (chemotherapy, radiation) to treat established tumors. The need for accompanying cytoreductive therapy is further evidenced by the transient expression associated with the most efficient vector systems—once transgene expression fades, the tumorigenic phenotype associated with absence of the suppressor gene will reappear (efficient in vivo vectors are required for this strategy as most, if not all, target cells must directly express, or confer expression via bystander effect, of the transferred gene for effective tumor reduction)
Figure 2-9 Tumor suppressor gene therapy inhibits tumor growth in animal models. Injection of adenovirus encoding c-cam1 (filled circles) into human prostate cancer nodules grown in nude mice reduced tumor growth compared to saline (filled triangle) and vector (open circle) controls. Delay of tumor growth without complete tumor remission is typical of strategies relying on local-regional injection of recombinant vectors encoding therapeutic tumor suppressor, antioncogene, or cytotoxicity genes. (Reprinted from Kleinerman DI, Zhang WW, Lin SH, et al: Cancer Res 1995; 55:2831, with permission.)
Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 33
Some tumor suppressor genes may also serve as gatekeepers for intracellular apoptosis-inducing signals. In addition to suppressing the tumorigenic growth potential of individual cells, restoration of these tumor suppressor genes should also be able to reduce established tumors via apoptosis induction. The inability of an adenoviral vector encoding p53 to eliminate preestablished malignancy, however, indicates that near-complete transduction of all tumor cells may be required for optimal therapeutic effect. This level of efficiency is clearly not achieved by direct solid tumor injection with currently available vectors. Improvements in vector and delivery systems will be needed to optimize this, and other, gene therapy strategies that rely on direct effects of gene transfer in the tumor cell target. FUTURE DIRECTIONS: TARGETING VECTOR SPECIFICITY Most vectors, which, at present, have shown functional efficacy in vivo, lack significant specificity in target cell attachment or restriction in transgene expression. The vector envelopes or coats of retroviruses, adenoviruses, and liposomal vectors enter cells via families of receptors that, as a group, are virtually ubiquitous. The promoters controlling transgene expression in these vectors are typically potent promoters susceptible to little or no regulation by the host cell. Targeting of gene therapy to specific
cells or tissues has therefore been achieved principally via the route of vector administration. The feasibility of conferring specificity via the administration route, in the case of urologic targets, has been demonstrated for renal cancer after renal tubule vector infusion and for bladder epithelium after intravesical instillation of viral vectors.98,99 This approach may be applicable to local-regional therapy of early stage, organ-confined malignancy (see Table 2-2). Systemic applications of cytotoxic, antioncogene, or tumor suppressor therapeutic gene transfer, however, will require specific targeting based not only on vector administration route but also on molecular rather than mechanical targeting. Molecular vector targeting can be achieved either by modifying tropism (altering the affinity of the vector coat for attachment and entry to a limited range of human target cells) or by restricting transcription (constructing expression cassettes containing promoters with selective activity in different tissues) (Figure 2-10). Modified Vector Tropism Two approaches have been used for modifying vector tropism. First, vectors can be derived from viruses with inherent tropism for a specific tissue target. Due to the relative paucity of molecular characterization of viruses with natural and specific tropism for the genitourinary tract, this approach has limited utility. Nevertheless, at
Figure 2-10 Restricting target cell specificity of recombinant viral vectors. The ability to specifically target gene delivery can facilitate systemic gene therapy with cytotoxic vectors. Approaches to confer specificity include: (A) engineering vector coat specificity; (B) restricting promoter-regulated transcription; (C) chemically modifying vector-target affinity. (Based on Miller N, Vile R: FASEB J 1995; 9:190.)
34
Part I Principles of Urologic Oncology
least one virus (BK virus, which has specific tropism for transitional epithelium) has shown potentially useful tropism specificity for transitional epithelium.100 Recombinant BK episomal vectors were constructed that led to reporter gene expression specifically in human transitional cell (TCC) lines that are relative to absent expression in other tumor cells. Limited characterization of the elements regulating BK specificity and lack of replication defective BK vectors, however, has limited further development of this vector system thus far. Second, molecular engineering and conjugate formation to alter the native vector coats has been used to confer specific tropism. In regards to retroviral vectors, engineering of envelope or vector coat sequences (pseudotyping) has been limited, principally due to the potential of functionally disrupting the ability of engineered envelopes to mediate target cell attachment and entry. Pseudotyping has thus succeeded in producing vectors with extended or altered target cell tropism, without more restricted target specificity per se.11 In contrast, a detailed analysis of the fiber gene has allowed the alteration of adenoviral tropism by either changing the knob domains for different adenoviral serotypes, or by specifically introducing targeting ligands into portions of the knob that are unimportant for fiber folding and viral assembly.101,102 Molecular conjugate formation has successfully conferred altered and refined specificity to adenoviral, liposomal, and retroviral vectors, alike. This has been achieved via covalent linkage of vectors with ligands such as growth factor receptors or antibody haptens, which confer the desired tropism for cells expressing the specific receptor and via noncovalent association of hybrid vector components.103–106 Restricted Transgene Expression: Transcriptional Targeting An alternative to vector targeting at the target cell binding level is to limit expression of therapeutic genes by regulating transcription with a promoter region having either tissue restricted activity, or preferential activity in malignant cells. Such promoter-regulated specificity has been used to target retroviral and adenoviral vectors alike.11,107 Tissue-specific promoters are potentially useful for regulating expression of cytotoxic genes in vectors targeting nonvital tissues, such as prostate, to widen potential therapeutic windows.108 To this end, vectors have been constructed with the promoter region that normally regulates PSA expression used to control expression of a reporter gene.109,110 Cloning of therapeutic cytotoxic genes, such as HSV-tk, into analogous vectors using tyrosinase promoter has been shown to inhibit tumor growth in melanoma animal models111; analogous vectors to target prostate cancer are under development.
In contrast to tissue-specific transcriptional targeting, oncogene-associated regulatory sequences may promote selective expression of therapeutic genes in tumor cells that harbor transcriptional overexpression of the oncogene. This has been demonstrated with a vector using ERBB2 promoter sequences to the cytotoxic gene cytosine deaminase; this vector conferred selective sensitivity on ERBB2-overproducing cells.112 SUMMARY Based on a growing volume of preclinical data, clinical trials of gene therapy for urologic cancer are underway. Therapeutic genes that are under current or forthcoming clinical study include immunogenes, cell death-inducing genes, antioncogenes, and tumor suppressor genes. Although systemic therapy with immunogenes is feasible, other gene therapy strategies, which do not rely on an intervening antitumor immune response, are at present limited to local-regional targeting. This constraint is largely due to limitations of gene transfer vectors, as well as in vivo gene delivery systems. Refinement of gene transfer vectors, such as hybrid vectors construction, is actively being pursued to broaden the utility and applicability of direct gene therapy strategies. The early phase of cancer gene therapy clinical trials should be viewed in context. Preclinical models predict modest, if any, therapeutic effects with current forms of human cancer gene therapy. Equally as important as clinical outcome in gene therapy clinical trials, however, are biologic surrogate endpoints to guide continued improvement of gene therapy strategies. The earliest clinical trials have indeed shown the ability of clinical gene therapy to alter biology of human urologic cancer.15,23–25 However, groundbreaking clinical trials of gene therapy have also been associated with significant toxicity, including a fatality and induction of vectorinduced leukemia.2,3 To attain its full potential, gene therapy must be approached with realistic expectations, respect for its potential toxicity, and a recognition of the need for its continued refinement.
REFERENCES 1. Watson JD, Crick FH: Molecular structure of nucleic acids. A structure for deoxyribose nucleic acid. Nature 1953; 171:737. 2. Marshall E: Gene therapy death prompts review of adenovirus vector. Science 1999; 286: 2244–2245. 3. Check E: Harmful potential of viral vectors fuels doubts over gene therapy. Nature 2003; 423:573–574. 4. Danos O, Mulligan RC: Safe and efficient generation of recombinant retrovirus with amphotropic and ecotropic host ranges. Proc Natl Acad Sci USA 1988; 85:6460.
Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 35 5. Ghosh-Choudhury G, Haj-Ahmad Y, Brinkley P, et al: Human adenovirus cloning vectors based on infectious bacterial plasmids. Gene 1986; 50:161. 6. Moss B: Vaccinia virus: a tool for research and vaccine development. Science 1991; 2252:1662. 7. Ledley FD: Nonviral gene therapy: the promise of genes as pharmaceutical products. Hum Gene Ther 1995; 6:1129. 8. Mulligan RC: The basic science of gene therapy. Science 1993; 260:926. 9. Crystal RG: Transfer of genes to humans: early lessons and obstacles to success. Science 1995; 270:404. 10. Yang NS, Sun WH: Gene gun and other non-viral approaches for cancer gene therapy. Nat Med 1995; 1:481. 11. Miller N, Vile R: Targeted vectors for gene therapy. FASEB J 1995; 9:190. 12. Rosenberg SA, Aebersold P, Cornetta K, et al: Gene transfer into humans – immunotherapy of patients with advanced melanoma, using tumor-infiltrating lymphocytes modified by retroviral gene transduction. N Engl J Med 1990; 323:570. 13. Blaese M: The ADA human gene therapy clinical protocol. Hum Gene Ther 1990; 1:327. 14. Dranoff G, Jaffee E, Lazenby A, et al: Vaccination with irradiated tumor cells engineered to secrete murine GM-CSF stimulates potent, specific, and long lasting anti-tumor immunity. Proc Natl Acad Sci USA 1993; 90:3539. 15. Simons JW, Jaffee EM, Weber C, et al: Bioactivity of human GM-CSF gene therapy using autologous irradiated renal cell carcinoma vaccines. Submitted. 16. Yang Y, Nunes F, Berencsi K, et al: Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci USA 1994; 91:4407. 17. Wickham TJ, Mathias P, Cheresh DA, Nemerow GR: Integrins αVβ5 and αVβ3 promote adenovirus internalisation but not virus attachment. Cell 1993; 73:309. 18. Seth P: Adenovirus-dependent release of choline from plasma membrane vesicles at an acidic pH is mediated by the penton base protein. J Virol 1994; 68:1204. 19. Addison CL, Braciak T, Ralston R, et al: Intratumoral injection of an adenovirus expressing IL-2 induces regression and immunity in a murine breast cancer model. Proc Natl Acad Sci USA 1995; 92:8522. 20. Shariat SF, Desai S, Song W, Khan T, Zhao J, Nguyen C, Foster BA, Greenberg N, Spencer DM, Slawin KM: Adenovirus-mediated transfer of inducible caspases: a novel “death switch” gene therapeutic approach to prostate cancer. Cancer Res 2001; 61:2562–2571. 21. Eastham JA, Hall SJ, Sehgal I, et al: In vivo gene therapy with p53 or p21 adenovirus for prostate cancer. Cancer Res 1995; 55:5151. 22. Yang C, Cirielli C, Capogrossi MC, Passaniti A: Adenovirus-mediated wild-type p53 expression induces apoptosis and suppresses tumorigenesis of prostatic tumor cells. Cancer Res 1995; 55(19):4210. 23. Weese TL, van der Poel H, Li S, et al: A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
cancer following radiation therapy. Cancer Res 2001; 61:7464. Miles BJ, Shalev M, Aguilar-Cordova E, et al: Prostatespecific antigen response and systemic T cell activation after in situ gene therapy in prostate cancer patients failing radiotherapy. Hum Gene Ther 2001; 12: 1955-67. Freytag SO, Khil M, Stricker H, et al: Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. Cancer Res 2002; 62:4968–76. Wang M, Bronte V, Chen PW, et al: Active immunotherapy of cancer with a non-replicating recombinant fowlpox virus encoding a model tumorassociated antigen. J Immunol 1995; 154: 4685. Nabel GJ, Nabel EG, Yang ZY, et al: Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans. Proc Natl Acad Sci USA 1993; 90:11307. Ogris M, Wagner E: Tumor-targeted gene transfer with DNA polyplexes. Somat Cell Mol Genet 2002; 27:85–95. Thomas M, Klibanov AM. Non-viral gene therapy: polycation-mediated DNA delivery. Appl Microbiol Biotechnol 2003; 62:27–34. Sun WH, Burkholder JK, Sun J, et al: In vivo cytokine gene transfer by gene gun reduces tumor growth in mice. Proc Natl Acad Sci USA 1995; 92:2889. Vogelzang NJ, Sudakoff G, McKay S, et al: A phase I study of intralesional (IL) gene therapy in metastatic renal cell cancer (RCC). Proc Annu Meet Am Soc Clin Oncol 1995; 14: A641. Johnson PA, Miyanohara A, Levine F, et al: Cytotoxicity of a replication-defective mutant of herpes simplex virus type I. J Virol 1992; 66:2952. Dupont F, Tenenbaum L, Guo LP, et al: Use of an autonomous parvovirus vector for selective transfer of a foreign gene into transformed human cells of different origin and its expression therein. J Virol 1994; 68:1397. Flotte TR, Afione SA, Conrad C, et al: Stable in vivo expression of the cystic fybrosis transmembrane conductance regulator with an adeno-associated virus vector. Proc Natl Acad Sci USA 1993; 90:10613. Pan ZK, Ikonomidis G, Lazenby A, et al: A recombinant Listeria monocytogenes vaccine expressing a model tumor antigen protects mice against lethal tumour cell challenge and causes regression of established tumours. Nat Med 1995; 1:471. Fearon ER, Pardoll DM, Itaya T, et al: Interleukin-2 production by tumor cells bypasses T helper function in the generation of an antitumor response. Cell 1990; 60:397. Gansbacher B, Gansbacher B, Bannerji R, Daniels B, et al: Retroviral vector-mediated gamma-interferon gene transfer into tumor cells generates potent and long lasting antitumor immunity. Cancer Res 1990; 50:7820. Gansbacher B, Zier K, Daniels B, et al: Interleukin 2 gene transfer into tumor cells abrogates tumorigenicity and induces protective immunity. J Exp Med 1990; 172:1217.
36
Part I Principles of Urologic Oncology
39. Golumbek PT, Lazenby AJ, Levitsky HI, et al: Treatment of established renal cell cancer by tumor cells engineered to secrete interleukin-4. Science 1991; 254:713. 40. Connor J, Bannerji R, Saito S, et al: Regression of bladder tumors in mice treated with interleukin-2 gene modified tumor cells. J Exp Med 1993; 177:1127. 41. Sanda MG, Ayyagari SR, Jaffee EM, et al: Demonstration of a rational strategy for human prostate cancer gene therapy. J Urol 1994; 151:622. 42. Moody DB, Robinson JC, Ewing CM, et al: Interleukin-2 transfected prostate cancer cells generate a local antitumor effect in vivo. Prostate 1994; 24:244. 43. Vieweg J, Rosenthal FM, Bannerji R, Heston WDW, Fair WR, Gansbacher B, Gilboa E: Immunotherapy of prostate cancer in the Dunning rat model: use of cytokine gene modified tumor vaccines. Cancer Res 1994; 54:1760. 44. Gansbacher B, Motzer R, Houghton A, Bander N: Immunization with Interleukin-2 secreting allogeneic HLA-A2 matched renal cell carcinoma cells in patients with advanced renal cell carcinoma. RAC Report 1992; 9206-022. 45. Kantor J, Irvine K, Abrams S, et al: Antitumor activity and immune responses induced by a recombinant carcinoembryonic antigen-vaccinia virus vaccine. J Natl Cancer Inst 1992; 84:1084. 46. Bronte V, Tsung K, Rao JB, et al: Il-2 enhances the function of recombinant poxvirus-based vaccines in the treatment of established pulmonary metastases. J Immunol 1995; 154:5282. 47. Lee SS, Eisenlohr LC, McCue PA, et al: Intravesical gene therapy: in vivo gene transfer using recombinant vaccinia virus vectors. Cancer Res 1994; 54:3325. 48. Lee SS, Eisenlohr LC, McCue PA, et al: In vivo gene therapy of murine tumors using recombinant vaccinia virus encoding GM-CSF. Proc Annu Meet Am Assoc Cancer Res 1995; 36:A1481. 49. Sanda MG, Smith D, Charles LG, et al: Recombinant vaccinia-PSA can induce a prostate-specific immune response in androgen-modulated human prostate cancer. Urology1999; 53:260–266. 50. Figlin RA: Phase I study of HLA-B7 plasmid DNA/DMRIE/DOPE lipid complex as an immunotherapeutic agent in renal cell carcinoma by direct gene transfer with concurrent low dose bolus IL-2 protein therapy. RAC Report 1995; 9508–121. 51. Paulson D, Lyerly HK: A phase I study of autologous human IL-2 gene modified tumor cells in patients with locally advanced or metastatic prostate cancer. RAC Report 1995; 9510-132. 52. Lahn M, Kohler G, Kulmburg P, et al: Parameters for successful establishment of primary and long-term tumor cell cultures from renal cell carcinoma, melanoma and colon carcinoma for cellular immunotherapy. Gene Ther 1994; 1:S15. 53. Kawakita M, Rao G, Ritchey JK, et al: Canary-pox virusmediated cytokine gene therapy induces tumor specific and non-specific immunity against mouse prostate tumor. J Urol 1996; 155:516A.
54. Cordon-Cardo C, Fuks Z, Drobnjak M, et al: Expression of HLA-A,B,C antigens on primary and metastatic tumor cell populations of human carcinomas. Cancer Res 1991; 51:6372. 55. Blades RA, Keating PJ, McWilliam LJ, et al: Loss of HLA class I expression in prostate cancer: implications for immunother-apy. Urology (in press). 56. Nouri AM, Hussain RF, Oliver RT: The frequency of major histo-compatibility complex antigen abnormalities in urological tumours and their correction by gene transfection or cytokine stimulation. Cancer Gene Ther 1994; 1:119. 57. Sanda MG, Restifo NP, Walsh JC, et al: Molecular characterization of defective antigen processing in human prostate cancer. J Natl Cancer Inst 1995; 87:280. 58. Lattime EC: Therapy of muscle-invasive bladder carcinoma with intravesical vaccinia. FDA Approval 1996: BB-IND-5002. 59. Torre-Amione G, Beauchamp RD, Koeppen H, et al: A highly immunogenic tumor transfected with a murine transforming growth factor type beta 1 cDNA escapes immune surveillance. Proc Natl Acad Sci USA 1990; 87:1486. 60. Inge TH, Hoover SK, Susskind BM, et al: Inhibition of tumor-specific cytotoxic T-lymphocyte responses by TGF-beta 1. Cancer Res 1992; 52:1386. 61. Miyamoto H, Kubota Y, Shuin T, et al: Expression of transforming growth factor-beta 1 in human bladder cancer. Cancer 1995; 75:2565. 62. Eder JP, Kantoff PW, Roper K, et al: A phase I trial of a recombinant vaccinia virus expressing prostate-specific antigen in advanced prostate cancer. Clin Cancer Res 2000; 6:1632-1638. 63. Catalona WJ, Chretien PB, Trahan EE: Abnormalities of cell-mediated immuno-competence in genitourinary cancer. J Urol 1974; 111:229–232. 64. Freeman SM, Abboud CN, Whartenby KA, et al: The bystander effect: tumor regression when a fraction of the tumor mass is genetically modified. Cancer Res 1993; 53:5274. 65. Symonds H, Krall L, Remington L, et al: p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell 1994; 78:703. 66. Oltvai ZN, Milliman CL, Korsmeyer SJ: Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell 1993; 74:609. 67. Boise LH, Gonzalez-Garcia M, Postema CE, et al: Bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 1993; 74:597. 68. Raffo AJ, Perlman H, Chen MW, et al: Overexpression of Bcl-2 protects prostate cancer cells from apoptosis in vitro and confers resistance to androgen-depletion in vivo. Cancer Res 1995; 55: 4438. 69. Martin S, Green DR: Apoptosis and cancer: failure of controls on cell death and cell survival. Crit Rev Oncol Hematol 1995; 18:137. 70. Furman PA, McGuirt PV, Keller PM, et al: Inhibition by acyclovir of cell growth and DNA synthesis of cells
Chapter 2 Gene Therapy for Urologic Cancer: Basic Principles, Prospects, and Limitations 37
71.
72.
73.
74.
75.
76.
77.
78.
79.
80. 81.
82.
83.
84.
85.
biochemically transformed with herpes virus genetic information. Virology 1980; 102:420. Li Y, McCadden J, Ferrer F, et al: Prostate-specific expression of the diphtheria toxin A chain (DT-A): studies of inducibility and specificity of expression of prostatespecific antigen promoter-driven DT-A adenoviralmediated gene transfer. Cancer Res 2002; 62:2576-82. Hoganson DK, Batra RK, Olsen JC, Boucher RC: Comparison of the effects of three different toxin genes and their levels of expression on cell growth and bystander effect in lung adenocarcinoma. Cancer Res 1996; 56:1315. Moolten FL, Wells JM: Curability of tumors bearing herpes thymidine kinase genes transferred by retroviral vectors. J Natl Cancer Inst 1990; 82:297. Culver KW, Ram Z, Wallbridge S, et al: In vivo gene transfer with retroviral vector-producer cells for treatment of experimental brain tumors. Science 1992; 256:1550. Hall SJ, Mutchnik SE, Shaker M, et al: Adenovirus mediated HSV-tk gene transduction and gancyclovir treatment for prostate cancer: suppression of metastasis in an orthotopic model and synergism with androgen ablation. J Urol 1996; 155:528A. Scardino PT, Thompson TC, Woo SLC: Phase I study of adenoviral vector delivery of the HSV-tk gene and the intravenous administration of gancyclovir in men with local recurrence of prostate cancer after radiation therapy. RAC Report 1996; 9601-144. Rodriguez R, Carducci MA, Bartkowski LM, Simons JW. Cytoreductive agents for prostate cancer gene therapy. Proc Am Assoc Cancer Res 1996; 37:346. Lee EJ, Jameson JL: Cell-specific Cre-mediated activation of the diphtheria toxin gene in pituitary tumor cells: potential for cytotoxic gene therapy. Hum Gene Ther 2002; 13:533–542. Kyprianou N, Isaacs JT: Activation of programmed cell death in the rat ventral prostate after castration. Endocrinology 1988; 122:552. Southam C: Present status of oncolytic virus studies. Ann New York Acad Sci 1960; 656–673. Martuza RL, Malick A, Markert JM, Ruffner KL, Coen DM: Experimental therapy of human glioma by means of a genetically engineered virus mutant. Science 1991; 252:854–856. Bischoff JR, Kirn DH, Williams A, et al: An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 1996; 274:373-376. Strong JE, Coffey MC, Tang D, Sabinin P, Lee PW: The molecular basis of viral oncolysis: usurpation of the Ras signaling pathway by reovirus. EMBO J 1998; 17:3351–3362. Rodriguez R, Schuur ER, Lim HY, Henderson GA, Simons JW, Henderson DR. Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells. Cancer Res 1997; 57:2559–2263. Chen Y, DeWeese T, Dilley J, et al: CV706, a prostate cancer-specific adenovirus variant, in combination with radiotherapy produces synergistic antitumor efficacy without increasing toxicity. Cancer Res 2001; 61: 5453–5460.
86. McManaway ME, Neckers LM, Loke SL, et al: Tumorspecific inhibition of lymphoma growth by an antisense oligodeoxynucleotide. Lancet 1990; 335:808. 87. Ogiso Y, Sakai N, Watari H, et al: Suppression of various human tumor cell lines by a dominant negative H-ras mutant. Gene Ther 1994; 1:403. 88. Georges RN, Mukhopadhyay T, Zhng Y, et al: Prevention of orthotopic human lung cancer growth by intratracheal instillation of a retroviral antisense k-ras construct. Cancer Res 1993; 53:1743. 89. Steiner MS and Holt JT: Gene therapy for the treatment of advanced prostate cancer by in vivo transduction with prostate-targeted retroviral vectors expressing antisense c-myc RNA. RAC Report 1995; 9509–123. 90. Thompson JD, Macejak D, Couture L, Stinchcomb DT: Ribozymes in gene therapy. Nat Med 1995; 1:277. 91. Kashani-Sabet M, Funato T, Tone T, et al: Reversal of the malignant phenotype by an anti-ras ribozyme. Antisense Res Dev 1992; 2:3. 92. Feng M, Cabrera G, Deshane J, et al: Neoplastic reversion accomplished by high efficiency adenoviralmediated delivery of an anti-ras ribozyme. Cancer Res 1995; 55:2024. 93. Chen F, Kishida T, Duh FM, et al: Suppression of growth of renal carcinoma cells by the von Hippel-Lindau tumor suppressor gene. Cancer Res 1995; 55:4804. 94. Iliopoulos O, Kibel A, Gray S, Kaelin WG: Tumour suppression by the von Hippel-Lindau gene product. Nat Med 1995; 1:822. 95. Kleinerman DI, Zhang WW, Lin SH, et al: Application of a tumor suppressor (C-CAM1)-expressing recombinant adenovirus in androgen-independent human prostate cancer therapy: a preclinical study. Cancer Res 1995; 55:2831. 96. Small EJ, Carroll PR: Gene therapy of bladder cancer using recombinant adenovirus containing the retinoblastoma gene (ACNRB): a phase I study. RAC Report 1996; 9601–145. 97. Cordon-Cardo C, Dalbagni G, Sarkis AS, Reuter VE: Genetic alterations associated with bladder cancer. Important Adv Oncol 1994; 71. 98. Moullier P, Friedlander G, Calise D, et al: Adenoviralmediated gene transfer to renal tubular cells in vivo. Kidney Int 1994; 45:1220. 99. Bass C, Cabrera G, Elgavish A, et al: Recombinant adenovirus-mediated gene transfer to genitourinary epithelium in vitro and in vivo. Cancer Gene Ther 1995; 2:97. 100. Cooper MJ, Miron S: Efficient episomal expression vector for human transitional carcinoma cells. Hum Gene Ther 1993; 4:557. 101. Gall J, Kass-Eisler A, Leinwand L, Falck-Pedersen E: Adenovirus type 5 and 7 capsid chimera: fiber replacement alters receptor tropism without affecting primary immune neutralization epitopes. J Virol 1996; 70:2116–2123. 102. Krasnykh VN, Mikheeva GV, Douglas JT, Curiel DT: Generation of recombinant adenovirus vectors with modified fibers for altering viral tropism. J Virol 1996; 70:6839–6846.
38
Part I Principles of Urologic Oncology
103. Wu GY, Zhan P, Sze LL, et al: Incorporation of adenovirus into a ligand-based DNA carrier system results in retention of original receptor specificity and enhances targeted gene expression. J Biol Chem 1994; 269:11542. 104. Chen J, Gamou S, Takayanagi A, Shimuzu N: A novel gene delivery system using EGF receptor mediatedendocytosis. FEBS Lett 1994; 338:167. 105. Michael SI, Huang CH, Romer MU, et al: Bindingincompetent adenovirus facilitates molecular conjugatemediated gene transfer by the receptor-mediated endocytosis pathway. J Biol Chem 1993; 268:6866. 106. Vieweg J, Boczkowski D, Roberson KM, et al: Efficient gene transfer with adeno-associated virus-based plasmids complexed to cationic liposomes for gene therapy of human prostate cancer. Cancer Res 1995; 55:2366. 107. Friedman JM, Babiss LE, Clayton DF, Darnell JE: Cellular promoters incorporated into the adenovirus genome: cell specificity of albumin and immunogloobulin expression. Mol Cell Biol 1986; 6:3791. 108. van der Poel HG, McCadden J, Verhaegh GW, et al: A novel method for the determination of basal gene
109.
110.
111.
112.
113.
expression of tissue-specific promoters: an analysis of prostate-specific promoters. Cancer Gene Ther 2001; 8:927–935. Taneja SS, Belldegrun A, Dardashti K, et al: In vitro target specific gene therapy for prostate cancer utilizing a prostate specific antigen promoter-driven adenoviral vector. Proc Annu Meet Am Assoc Cancer Res 1994; 35:A2236. Ko SC, Gotoh A, Kao C, et al: Tissue targeted toxic gene therapy for an androgen-independent and metastatic human prostate cancer model. Proc Am Assoc Cancer Res 1996; 37:349. Vile RG, Hart IR: Use of tissue-specific expression of the herpes simplex virus thymidine kinase gene to inhibit growth of established murine melanomas following direct intra-tumoral injection of DNA. Cancer Res 1993; 53:3860. Harris JD, Gutierrez AA, Hurst HC, et al: Gene therapy for cancer using tumor-specific prodrug activation. Gene Ther 1994; 1:170. Sanda MG, Simons JW: Gene therapy for urological cancer. Urology 1994; 44:617.
C H A P T E R
3 Principles and Applications of Radiation Oncology Steven J. Chmura, MD, PhD, Wendla Silverberg, MD, and Ralph R. Weichselbaum, MD
The treatment of both benign and malignant diseases with ionizing radiation (IR) began shortly after the discovery of x-rays by Wilhelm Roentgen in 1895.1 The therapeutic applications of IR were quickly realized when the first patient was treated by Emil Grubbe in 1896.2 Despite the initial enthusiasm in the clinical applications of IR, subsequent experimental and clinical experience demonstrated the adverse effects on normal tissues when attempting to treat tumors located deep below the skin. The development of implantable radioactive sources (brachytherapy) permitted high doses of radiation to be delivered directly to the tumor tissue while decreasing the normal tissue toxicity with the first prostate patient treated in 1909. The introduction of high-energy (megavoltage) external beam radiation therapy (EBRT) in the 1950s allowed treatment to a higher dose of tumors deep within the body, while decreasing the surface dose to the skin. Despite the advances in both the imaging of tumors and the hardware and software employed to deliver radiation therapy, normal tissue toxicity remains the limiting factor in most human malignancies. The following section reviews both the physical and biologic bases of radiation therapy. Advances in both biologic modifiers and new technologies to deliver radiation therapy that may increase tumor cell killing while limiting normal tissue complications are also discussed. Specific examples of particular interest for urologic oncology are highlighted. THE PHYSICS OF RADIATION THERAPY AND DELIVERY External Beam Radiation Therapy EBRT is used to treat many tumor types, including head and neck, gynecologic, thoracic, and genitourinary
malignancies. While earlier technologies utilized gamma rays from radioactive sources, such as cobalt (Co60) to deliver photon therapy, modern linear accelerators (Figure 3-1) generate and deliver either high-energy photons (x-rays) or charged particles (electrons). The x-rays are produced through the deceleration of highkinetic energy electrons (bremsstrahlung) within the head of the linear accelerator as they strike a tungsten target.3 After striking the target, the electrons emit x-rays with a spectrum ranging from zero energy to their maximum kinetic energy. The photons are emitted from a point source, much like a flashlight, that diverges in a cone shape. The energy of the photons decreases as the inverse square of the distance (1/d2) from the source (the inverse square law).3 Through advancements in technology, the energy of radiation therapy has been greatly increased since its clinical introduction, thus permitting treatment of tumors deep within the body. The beam quality or energy employed in a particular patient refers to the highest energy photons generated. Modern linear accelerator energies span from the kilovolt (kVp) to megavolt (MV) range. Outside of superficial treatment of such lesions, EBRT is almost exclusively delivered in the 4 to 18 MV range. For example, most prostate cancer patients are treated with energies ranging from 6 to 18 MV in order to spare superficial tissues and maximize the dose to the prostate. The photons decelerate exponentially as they interact with matter. The distance they travel through tissue is proportional to their initial energy (see above). Thus, higher energy beams are able to penetrate tissues deeper and result in fewer interactions at the skin surface. As the photons interact with matter, either superficially or deep within tissues, charged particles, such as electrons, are
39
40
Part I Principles of Urologic Oncology
Figure 3-1 Example of a modern linear accelerator used to deliver photons or electrons in the clinical setting.
set in motion that results in ionization and excitation of other atoms. The energy absorbed in tissue by the secondary charged particles represents the dose delivered. The accepted unit of dose is the gray (Gy), which is defined as the absorption of 1 J/kg. In radiation therapy clinical outcome papers, the terms centigray (cGy) or radians (rad) are commonly used with 1 cGy (or rad) representing 0.01 Gy. Prior to 3D treatment planning techniques, dose was prescribed to a point, for example, in the middle of a patient or in the middle of a tumor. With modern 3D treatment planning techniques, dose can also be prescribed to a volume of interest, for example, the tumor and areas of tumor spread. Current 3D planning terminology of dose refers to the minimum dose absorbed by the volume of the target. The interaction of the charged particles with tissue results in production of free radicals along with direct damage to DNA. The biologic effects of absorbed dose are discussed in detail later. Linear accelerators can also be configured to produce electrons by removing the tungsten target and guiding them through the accelerator toward the patient. Unlike the photons that comprise x-rays, an electron is a charged particle that travels a known range in tissue. By selecting the initial energy of the electrons, one can calculate the depth of tissue that will be irradiated. Tissues beyond that range receive little irradiation. Since electrons are charged particles, they interact directly with matter in tissue by depositing dose and causing damage to the tumor cell.
Other types of particles have been employed as therapeutic modalities, including neutrons4 and protons.5 Neutron beams are similar to photon beams in that their energy decreases exponentially in tissue. While neutron beams have been employed to treat a variety of tumor sites, including prostate and brain, they are seldom used clinically, as multiple randomized studies have failed to demonstrate a clear benefit when compared to photon therapy in terms of tumor control and normal tissue toxicity. Proton beams are generated by a cyclotron. These heavy charged particles are unique; they deposit their dose near the end of their range. This phenomenon, known as a Bragg peak, can be manipulated to deliver a high dose to a small tumor deep within the body while minimizing high doses to more superficial tissues.5 While there has been significant interest in expanding the therapeutic applications of proton therapy, the substantial cost of a cyclotron (proton production machine) along with limited clinical outcome data has resulted in very few of them being constructed around the world. As the technology to build cyclotrons becomes cheaper to implement, more are expected to be constructed. Theoretic and preliminary data suggest that proton therapy may be appropriate for prostate cancer treatment. Brachytherapy In contrast to EBRT, brachytherapy delivers dose through the placement of radioactive sources that remain in place either temporarily (minutes to days) or permanently. Initially, naturally occurring isotopes, such as radium, were used in brachytherapy. Newer artificially produced isotopes have replaced radium due to their wider availability and improved safety profiles. The prescribed dose in brachytherapy is normally defined based on a limited number of 2D tissue points. Increasingly, 3D dose prescriptions are becoming more common for brachytherapy. Intracavitary brachytherapy involves placement of the sources within a body cavity. For example, most intermediate- to advanced-stage cervical cancers are treated, in part, with a Fletcher-Suit applicator. A hollow tube (tandem) is inserted into the uterus, and two other hollow tubes (colpostats) are placed within the vagina against the lateral fornices. Dose is delivered through insertion of radioactive sources into the hollow tubes that are secured in place. The sources (cesium 137) remain in place for 3 to 4 days (low-dose rate [LDR] brachytherapy) depending on the clinical scenario and choice of the physician. Intracavitary brachytherapy has also been used to treat tumors of the head and neck, biliary tree, and bronchi. By placing the hollow cylinders or catheters before loading the radioactive sources (after loading), radiation exposure to the staff is minimized.
Chapter 3 Principles and Applications of Radiation Oncology 41
conform the dose to the target depends on many factors, including target location, external contour of the patient, tissue density, beam energies availability, and the EBRT hardware availability.10–12 Current 3D treatment planning and 3D treatment (3D-CRT) rely almost exclusively on computed tomography (CT)-based imaging to generate a customized plan for each patient. The following sections outline treatment planning and plan generation using a prostate patient as a model assuming that 3D treatment planning is available. Simulation and Patient Immobilization
Figure 3-2 Initial pelvic film immediately following implantation of permanent iodine125 prostate brachytherapy seeds. Due to subsequent swelling of the prostate, the seeds will move and rotate during the next 60 days when they are most radioactive.
Interstitial brachytherapy delivers dose directly within a tumor or surgical bed. Hollow flexible catheters are initially surgically inserted into the tumor or site of tumor resection. After 5 to 7 days of healing, radioactive needles are inserted into the catheters to deliver dose. Prostate brachytherapy involves the placement of permanent radioactive seeds (iodine 125) within the prostate (Figure 3-2). These seeds deliver a dose over the course of many months to the prostate and surrounding tissue. As discussed above, traditional LDR intracavitary brachytherapy is delivered over 3 to 4 days as an inpatient procedure or sources with a short half-life left in permanently as is the case with prostate brachytherapy. Recently, high-dose rate (HDR) techniques are increasing in popularity. High-activity iridium sources deliver dose rapidly, permitting patients to be treated as an outpatient requiring only minimal anesthesia. Clinical studies employing HDR have demonstrated efficacy in head and neck, cervix, and prostate.6–8 TREATMENT PLANNING AND DELIVERY As previously described, the dose to be delivered during EBRT is prescribed to a volume in 3D conformal radiation therapy (3D-CRT). The aim of the prescription is to uniformly irradiate the volume (target) while minimizing the dose to surrounding normal tissues.9 The ability to
Most prostate cancer patients are treated with fractionated (administered in multiple daily treatments) EBRT for 6 to 8 weeks. Patients normally lie supine on the treatment table as shown in Figure 3-1. In order to deliver dose to the prostate each day and minimize dose to the surrounding normal tissue (such as the rectum), the patient’s position on the table must be reproduced during each treatment. In addition, patient motion must be minimized during the treatment that normally lasts 5 to 15 minutes. Prior to initial treatment, a simulation of the actual treatment technique is performed to determine the ideal patient positioning. In order to ensure the reproducibility of the patient’s position, immobilization devices are constructed out of foam cradles that will be used on all subsequent patient treatment days. Through the use of these immobilization devices and newer imagining techniques, such as video-assisted setup, radiation therapists are able to reproduce patients’ positions to within millimeters daily. A CT simulator is a specialized scanner used to directly acquire CT data while the patient is immobilized in the desired treatment position. The CT data acquired from imaging guides radiation therapy planning by providing geometric information on external patient contour and tumor size, shape, and location relative to adjacent critical structures.13 Following the acquisition of the CT data, the physician defines three volumes to be used in the treatment planning process. The gross tumor volume (GTV) represents the tumor visible on the CT simulation data. The clinical target volume (CTV) is defined as the GTV and the draining lymphatic and other tissues that may contain microscopic disease. The planning target volume (PTV) is created based on expansion of the GTV and CTV in order to compensate for patient setup uncertainty, such as patient and organ motion. For a typical prostate patient plan, the PTV expansion typically ranges from 0.6 to 1 cm.14 Normal tissues are also defined in order to design a plan that will minimize the dose to those organs, such as the rectum. The treatment planning is based on the volumes entered by the physician following the simulation.
42
Part I Principles of Urologic Oncology
Treatment Planning
Treatment Delivery and Verification
Treatment planning software permits physicists and physicians to generate a dose distribution superimposed on the CT images and volumes that have been designed. Although the specifics of the treatment planning software may vary widely based on the technology available at institutions, certain variables are universally required for treatment planning. These variables include beam energy, type of beam (photon or electron), number beam angles, relative beam weights, and beam-modifying devices. Superficial tumors can be treated with either low-energy photon beams (100 to 250 kVp) or electron beams. Tumors deep within the body, such as the prostate, are treated with energies ranging from 6 to 18 MV and from 4 to 9 beam angles. For example, most prostate plans employ 4 to 5 beam angles with 6 MV photons. The beam modifying devices include customized shielding blocks that alter the quality, intensity, and shape of the beam. These are further discussed in the section on intensity modulated radiation therapy (IMRT). Dose volume histograms (DVH) provide a quantitative evaluation of treatment plans. The DVH represents the volume of a particular organ irradiated as a function of dose (Figure 3-3). These data coupled with known toxicity research aid the physician in selecting the proper treatment plan. For example, based on both retrospective and randomized data, most physicians planning a prostate treatment attempt to limit the volume of rectum receiving >70 Gy to <25% of the volume.
Linear accelerators deliver the beam of photons or electrons through a gantry that rotates 360 degrees around the patient (Figure 3-1). The rotation of the gantry around the table permits the beam to enter the patient’s body from any angle. The beam is shaped at each gantry angle by either a Cerrobend block cut by hand or a multileaf collimator (MLC). Cerrobend attenuates (blocks) nearly all of the beam energy.3 These custom blocks are designed for each field during the treatment planning stage, cut to the proper shape by a technician, and placed manually in the head (Figure 3-1) of the gantry each day of treatment. More recently, the MLC was developed to permit dynamic block shaping under computer control. A typical MLC consists of 80 to 120 leaves that are fixed to the gantry head and powered by small electric motors. The leaves are computer controlled and can be moved either before (static) or during treatment (IMRT, discussed later). The leaves attenuate the beam similar to the solid Cerrobend block permitting one to shape the beam to virtually any shape.15 Quality assurance is usually performed at least on a weekly basis through the use of verification (x-ray) films. These films are checked by the physician to ensure that the patient is positioned properly on the table and the field shape (either through a Cerrobend block or MLC) is correct. The treatment verification films are compared against those taken during the initial simulation process and the patients (or blocks) are moved to approximate the original planning position. Intensity Modulated Radiation Therapy
Figure 3-3 DVH from a head and neck cancer case planned with IMRT. The PTV contains the primary tumor and draining lymphatics plus a margin for microscopic disease and setup uncertainty. The IMRT permits the brain stem and spinal cord to receive a very low dose of RT compared to the PTV.
Recent advances in computer hardware and software have dramatically changed the way in which 3D treatment plans are constructed and EBRT is delivered to the patient. With traditional 3D treatment planning, EBRT is delivered with beams of uniform intensity and with a static beam shape (though the use of a block or MLC). (IMRT, as the name implies, permits nonuniform intensity beams to be delivered to the patient. By allowing the MLC to move during treatment, the shape of the beam at each gantry angle can be altered. By modulating the intensity and shape of the beam during treatment, high doses of radiation can be delivered to the PTV while minimizing dose to normal tissues.16 After the physician defines the GTV, CTV, and PTV and determines the normal tissue structures to avoid, the computer software employs sophisticated algorithms to compute the intensity and shape of the beam for each gantry angle. This process is known as inverse planning.63,64 While no randomized studies yet exist demonstrating the superiority of this approach in terms of tumor control or normal tissue complications compared to conventional treatment
Chapter 3 Principles and Applications of Radiation Oncology 43
believed that accumulation of DNA double-stand breaks (DSBs) are the main requirement for cell death to occur. Following DNA damage, both tumor cells and normal tissues respond by attempting to repair the damage, alter the cell cycle, induce gene transcription, or promote cell death.18,19 Cell death occurs through either a postmitotic (necrotic) or apoptotic death that are discussed later. The formation of ROS and the cellular response to DNA damage are also influenced by cell membrane receptors that initiate second messenger cascades that can mediate cell death.20–23 The following sections describe cellular response to IR and provide a brief overview of the biologic events that determine whether a cell will live or die following IR. IONIZING RADIATION Interacts with Cellular Targets and Generates Reactive Oxygen Species
Figure 3-4 Comparison of a conventional plan (top) with an IMRT plan in the pelvis used to treat an anal cancer patient. The arrows demonstrate that the IMRT plan conforms to the target delivering 100% of the prescribed dose, while the 2D plan delivers 100% of the dose to a large volume of normal tissue, including femoral heads and genitalia.
techniques, multiple prospective studies demonstrate at least equal tumor control compared to historical controls while greatly reducing normal tissue toxicity. For example, prostate cancer IMRT minimizes the volume of the bladder and rectum irradiated. This has permitted the dose delivered to the prostate to be increased from 66 to 70 Gy to over 81 Gy at some institutions.17 An example of a pelvic IMRT treatment plan from the University of Chicago compared to a conventional 3D plan (Figure 3-4) demonstrates that the patient treated with the IMRT plan will receive less dose to the normal tissue that surrounds the target. IONIZING RADIATION AND ITS INTERACTION WITH TUMOR CELLS AND NORMAL TISSUES While the therapeutic applications of x-rays were quickly realized since their introduction, the biologic basis by which IR kills both normal tissues and tumor cells is a subject of intense investigation. It is now clear that IR kills both tumor and normal tissues through several molecular mechanisms. The dose of IR absorbed in tissues interacts with matter either directly or indirectly through the hydrolysis of water and the formation of reactive oxygen species (ROS). While both single- and double-stranded DNA breaks occur following IR, it is
IR interacts with matter either directly or indirectly through production of ROS. IR causes ionization of cellular H2O that produces free hydroxyl radicals. These free radicals quickly interact with cellular targets. The damage to the cellular targets, such as cell membranes, proteins, and DNA, is deposited randomly and is a function of dose. Data demonstrate that damage by the shortlived free radicals represents a majority of the clinically relevant damage produced by conventional photon therapy and electron therapy.24 Experimental evidence demonstrates that double-strand breaks (DSBs) in the sugar phosphate backbone of DNA result in most of the cytotoxicity to both tumor cells and normal tissues. While many factors contribute to the extent of DNA damage following IR, cellular oxygen is critical as hypoxic cells are up to 3-fold more resistant to killing by IR compared to well-oxygenated cells.25 The presence of cellular oxygen prolongs the lifetime of free radicals and appears to fix free radical damage in the DNA. The difference between tumor cell killing in the presence and absence of oxygen is termed the oxygen enhancement ratio (OER). This is clinically relevant as tumor growth may outpace its ability to generate new tumor vasculature (angiogenesis). This growth results in areas of hypoxia and necrosis within the tumor.26 The hypoxic regions, while poorly vascularized, may remain resistant to IR during fractionated radiation therapy. As the tumor changes composition during fractionated RT, reoxygenation of the once poorly hypoxic regions may occur during some fractions of therapy, again providing a rationale for fractionated treatment. In contrast to conventional therapy, heavy charged particle radiation, such as proton therapy, kills almost exclusively through direct interaction with cellular targets and is thus not affected by oxygen levels.27 Thus, through both direct and indirect interactions with cellular structures, conventional EBRT damages cellular targets resulting in eventual cell death.
44
Part I Principles of Urologic Oncology
The accumulated damage to DNA and other structures eventually results in the inability of cells to divide (clonogenic death). The cell may undergo multiple cell divisions before clonogenic death occurs. The activation of programmed cell death (apoptosis) also plays a significant role in certain normal and tumor tissues and may occur within hours of exposure of cells to IR. These findings demonstrate that tumor cells with a low mitotic index (slow proliferation), such as some prostate cancers, may take many months for complete histologic regression.28 Accumulation of DNA Damage Following IR Induces A Cellular Repair Response The accumulation of damage, if not repaired, will result in the clonogenic or apoptotic death of cells. Cells that acquire damage not beyond repair, termed sublethal damage repair (SLDR), may repair the damage to the DNA between fractions of radiation. It is believed that many tumors have a poor repair response compared to the surrounding normal tissues. This concept is crucial in the attempt to permit recovery of normal tissues between daily fractions while continuing to kill tumor cells. By separating the doses of radiation, each day normal tissues can induce a repair response prior to the second dose of radiation. Tumor cells may be unable to repair their damage thus it will accumulate until clonogenic or apoptotic death occurs. This concept has been demonstrated in both in vitro and in vivo models of cell killing.29,30 The local environment of the cell also plays a role in its capacity to repair its damage or its decision to die following exposure to IR. Damage to cellular structures that may be potentially lethal (PLDR) while a cell is exposed to certain growth factors, such as oxygen concentration, and cell–cell contact may be repaired if postirradiation conditions are altered to enhance cell survival.31 Based on both in vitro and in vivo studies, Weichselbaum and others suggest that PLDR significantly contributes to radiation therapy failure.32–34 The understanding of these basic mechanisms has led to the development of agents and techniques to enhance the tumoricidal effects of IR. Therapeutic Ratio of Radiation Therapy The probability of tumor cure is a function of many variables, including tumor type, size, radiation dose, and fraction size. For example, microscopic (subclinical) disease from an epithelial-derived tumor is usually curable with as little as 45 to 50 Gy. However, this dose would be insufficient to cure microscopic disease derived from high-grade astrocytomas, a large epithelial tumor, or T2 prostate cancer. Most doses used in clinical practice have been empirically determined. The therapeutic ratio is defined as the probability of obtaining a tumor cure divided by the chance of a normal tissue complication.
Attempts to enhance the therapeutic ratio have come in the form of altered fractionation schemes, addition of radiation sensitizing agents, and use of radioprotectors. These are discussed later. Enhancement of the Tumoricidal Effects of IR with Radiation Sensitizers Clinical trials demonstrate that local control following radiation therapy is significantly worse than in patents with normal blood oxygen carrying capacity.35 Multiple studies have demonstrated improvements in outcome of patients treated with hyperbaric oxygen.36 In addition, compounds that act as hypoxic cell sensitizers, such as metronidazole and misonidazole, have been developed and employed clinically. Despite promising studies in vitro, few clinical studies have demonstrated improvement in outcome at the expense of significantly increased toxicity.37 While laboratory studies have demonstrated significant enhancement of the antitumor effects of hyperbaric oxygen or hypoxic cell sensitizers, the clinical application of these techniques has not led to significant therapeutic gain. Clinically, the most commonly employed agents to enhance radiation-mediated tumor cell killing are standard chemotherapeutics, such as 5-fluorouracil (5-FU), cisplatin (CDDP), and paclitaxel. Combined treatment with radiation therapy and chemotherapy has been demonstrated in randomized trials of head and neck, gynecologic, and lung cancers to be superior to treatment with radiation alone. While the mechanisms of radiosensitization vary, the combined use of these agents with IR has led to improvements in local control of disease and improved survival in many cancer sites. Protection of Normal Tissue Through the Use of Radioprotector Agents While the addition of chemotherapeutic agents to radiation therapy has enhanced the tumoricidal effects of IR, this benefit is usually accompanied by an increase in normal tissue toxicity. The balance between tumor cell killing and normal tissue toxicity defines the therapeutic ratio and ultimately limits the probability of cure. In order to increase the therapeutic ratio and limit toxicity to normal tissues, agents that protect tissues from radiation (radioprotectors) have been employed clinically. Originally developed in the 1950s by the department of defense, the radioprotector amifostine (Ethyol) acts as a scavenger of free radicals. Following intravenous delivery, the compound amifostine penetrates into normal tissues within minutes. However it is absorbed more slowly in the tumor tissue providing a rationale for preferential protection of normal tissues. Randomized studies in head and neck and pelvic malignancies have shown some
Chapter 3 Principles and Applications of Radiation Oncology 45
protection from expected radiation sequelae while not decreasing local control of disease.38 The use of amifostine use, however, remains fairly limited due to the expense of the compound, limited randomized clinical data, and often severe acute side effects including nausea and hypotension. Enhancement of the therapeutic ratio through gene therapy While attempts to employ gene therapy with cancer as a single modality have met with limited clinical success, laboratory and clinical data demonstrate that combining gene therapy with IR may improve tumor curability. Unlike combining IR with standard chemotherapy agents that often have overlapping toxicity, gene therapy can be tailored to target different and partially nonoverlapping mechanisms of tumor cell killing. Current research in gene therapy aims to: (1) replace mutated genes (p53) that may sensitize cells to IR; (2) deliver genes encoding pro-drug converting enzymes into tumor cells, allowing toxic agents to be generated in the tumor bed, thereby decreasing the risks of systemic toxicity; (3) construct genetically engineered viruses with therapeutic genes under the control of radiation inducible promoters; and (4) enhance replication competent viruses that proliferate preferentially in tumor cells following IR. While current technology limits the efficiency of gene transfer to tumor cells, radiation may enhance the “bystander effect” of specific gene therapy designs that employ a diffusible product.39–42 Clinical studies are currently underway employing a wide variety of these techniques. DNA Damage, the Cell Cycle, and Repair Tumors represent a heterogeneous population of growing cancer cells that are distributed unevenly throughout the cell cycle with most in the resting or G1 phase. As previously discussed, damage to the DNA represents the critical target for IR-induced cell death. In vitro and in vivo data demonstrate that the extent of DNA damage and tumor cell death is, in part, dependent on the phase of the cell cycle. While exceptions exist, the most sensitive phases of the cell cycle are G2/M. Cells are least sensitive to IR in late S-phases.43 Identification of differential sensitivity based on cell cycle provides further rationale for fractionated treatment regimens. Since tumor cells are an asynchronous population, after each fraction those in the most sensitive phases will be killed while the resistant phases will progress to other phases of the cycle. This process is termed reassortment. Thus, with standard EBRT with photons, fractionation permits cells to be exposed to radiation while the cells are in their most sensitive phases.
DNA damage induces cell cycle arrest. The cell signaling pathways that monitor DNA damage and initiate cell cycle arrest are referred to as checkpoint controls. For example, the commonly mutated tumor suppressor gene and transcription factor p53 promotes cell cycle arrest at the G1 checkpoint following DNA damage through transcription of p21 that inhibits progression to S-phase. The exact phase of the arrest is dependent on the genetic mutations present in the tumor cell. Arrest of the cell cycle in damaged cells represents an evolutionarily conserved survival mechanism to ensure the fidelity and transmission of genetic information. By preventing progression through the cycle, the damage induced by IR can be repaired before the cell continues to grow and divide. Failure to repair the damage leads to genetic instability and cell death.44 As previously noted, while IR induces both singleand double-strand DNA breaks, DSBs are responsible for most tumoricidal effects of IR. DNA damage is repaired in mammalian cells through two distinct molecular pathways: homologous recombination and nonhomologous recombination. Homologous recombination involves various repair proteins, such as rad51, that identify homologous DNA to be used as a template to direct error-free repair of the genetic information.45 However, the predominant mechanism of repair in human cells is nonhomologous recombination. During this process, DSBs are identified by protein complexes and the ends joined by ligases (xrcc4).46 Due to the simple end-joining and lack of a template for repair, nonhomologous recombination results in mutant chromosomes. The protein sensors of DSBs that initiate the repair cascade are a focus of intense investigation since inhibition of those sensors would sensitize tumor cells to IR. Ionization Radiation-Induced Cell Death: Apoptosis and Necrosis One major biologic determinant of radiation therapy failures is tumor radioresistance.47–49 As previously discussed, exposure of mammalian cells to IR results in a loss of cellular reproductive capability (mitotic death) by inducing DNA DSBs and lethal chromosomal aberrations.50 Morphologic characteristics of IR-induced mitotic death include multinucleated giant cells, cell–cell fusions, and loss of membrane integrity that is also a characteristic of necrotic cell death. Daughter cells with limited divisional potential can arise from lethally irradiated mother cells to form abortive colonies. Death during cell division due to lethal mutations or damaged chromosomes following IR is a well-studied mechanism of tumor cell killing.51 In contrast to necrotic death, apoptosis induced by IR results in activation of a genetic program initiated by
46
Part I Principles of Urologic Oncology
cytoplasmic or nuclear events culminating in cytoplasmic blebbing, chromatin condensation, and DNA fragmentation.52–54 The induction of apoptosis may occur immediately after irradiation (interphase death), after arrest in the G2 phase,55 or following one or more cell divisions.56,57 Apoptosis may represent an important mechanism of death in some cell types following IR, such as lymphomas.56 It has been proposed that the direct effects of x-rays on the nucleus and DSBs initiate a cascade of signaling events, such as p53 induction, that culminates in the activation of proteases (caspases) that execute the cell death program.55,56 While the signal to undergo apoptosis following IR is generally considered to originate in the nucleus,55,56,58,59 studies demonstrated that the production of the lipid second messenger ceramide from sphingomyelin hydrolysis immediately following IR contributes to the apoptotic response.60–62 Current research efforts aim to enhance the cytotoxicity of IR through development of small molecules that exploit the apoptotic program. THE CLINICAL PRACTICE OF RADIATION ONCOLOGY Definitive and Adjuvant Radiation Therapy Therapeutic radiation (RT), delivered via external beam or brachytherapy, by itself can cure many human malignancies, including head and neck, cervix, lymphoma, prostate, and pure seminomas. RT alone demonstrates equivalent local control compared with surgery in head and neck malignancies while better preserving normal organ function.63,64 Similar results have also been seen in early cervical cancer trials.65 To date, no completed randomized study employing modern surgical and radiation techniques for prostate cancer exists. RT is commonly employed as part of a combined modality approach in cancer therapy. It is routinely used as an adjuvant to surgical excision to sterilize potential microscopic disease in lymph nodes or from surgical margins. Preoperative RT is used for large unresectable tumors, such as sarcomas or rectal cancer, in an attempt to permit eventual surgical excision or organ conservation.66 More commonly, postoperative RT is employed following definitive surgical findings of margin status, tumor pathology, and stage of disease. The decision to employ postoperative RT can then be made and treatment type and dose tailored to the specific case. Common postoperative RT applications include tumors of the head and neck, lung, breast, genitourinary, gastrointestinal tract, and central nervous system. As previously discussed, chemotherapy may be combined with RT in order to increase tumor cell killing. Commonly, chemotherapy is given prior to RT (neoadjuvant) or simultaneously (concomitant) with RT. Recent
randomized studies demonstrate improvements in local control of disease, organ preservation, and overall survival when comparing RT alone with combined modality treatment in diseases that include the head and neck, bladder, cervix, esophagus, and lung. Postoperative chemoradiotherapy is also employed for gastric, rectal, and head and neck tumors. Concomitant RT appears to produce better local control in some disease sites while producing significant more acute toxicity. Thus, current clinical trials seek to identify more active chemotherapy agents with fewer overlapping toxicities and to determine the optimal timing and delivery of chemotherapy with RT. Palliative Radiation Therapy for Metastatic Disease Painful metastatic disease is effectively treated with a combination of pain medication and RT. Osseous metastases are commonly observed in advanced breast, lung, and prostate patients. Pain relief from an abbreviated course of RT can reduce or eliminate pain in 70% to 80% of cases.67 A recently completed randomized study by the Radiation Therapy Oncology Group (RTOG) compared a large single fraction of 8 Gy to the more conventionally used 10 fractions (3 Gy) to 30 Gy in breast and prostate patients.68 Equivalent outcome in terms of pain relief and complications were found suggesting that shorter courses of palliative RT may be as effective in the patient with metastatic disease. Longer follow-up is needed, however, to determine if long-term complications and duration of pain relief will remain equivalent. Patients who develop multiple cerebral metastases from lung, bladder, breast, and other tumors suffer neurologic sequelae from both the expanding tumor mass itself and subsequent edema formation. Combining initial steroid treatment with fractionated RT to the entire brain (typically 30 and 3 Gy fractions) improves neurologic function in over 50% of patients. Patients with a single brain metastasis benefit from combined surgical resection and postoperative RT. Spinal cord compression is also effectively treated with palliative RT. Again, the neurologic compromise is often treated with a combined modality approach. Highdose steroids reduce the surrounding edema and provide often rapid neurologic improvement. A recent randomized study demonstrates that surgical excision and stabilization of the vertebral bodies involved with tumor followed by RT provide superior pain relief and improvement of neurologic function compared with RT alone.69 In patients deemed surgically inoperable, RT is normally delivered in 3 Gy fractions to a total dose of 30 Gy. The dose of 30 Gy provides good tumor control while offering almost no additional risk that the radiation itself will damage the spinal cord.
Chapter 3 Principles and Applications of Radiation Oncology 47
Acute and Chronic Radiation Sequelae As previously stated, the therapeutic index of radiation therapy is defined as the probability of tumor cure divided by the probability of severe toxicity. The normal toxicity of radiation therapy is a function of the volume and type of tissue exposed to IR, dose fraction, and total dose. The currently employed radiation sensitizers, standard chemotherapy, also increase acute and chronic toxicity of RT. Acute radiation sequelae occur through damage to actively dividing normal tissues.70 Commonly seen acute toxicities during or shortly following fractionated radiation therapy include skin desquamation, diarrhea, and mucositis. Chronic sequelae normally develop months to years after radiation therapy and result from fibrosis and subsequent scarring of normal tissues. While acute toxicity can normally be managed during the course of treatment, chronic toxicity remains the limiting factor when determining the maximum dose to deliver in the effort to cure the tumor. The probability of causing a chronic toxicity in 5% of the treated population at 5 years is termed the TD5/5. Injury to a portion of certain organs (i.e., spinal cord) markedly impairs the function of the entire organ. For these organs radiation oncologists have developed empiric dose constraints to limit observed toxicity to almost 0%. For example, a dose of 45 to 50 Gy maximum to any point on the spinal cord is accepted as the standard of care. For other structures, such as the rec-
tum or lung, as the volume of tissue irradiated increases so does the probability of complications. An example of this volume and complication relationship is seen in the recently completed randomized 3D conformal doseescalation study for prostate cancer. In order to achieve better local control of low and intermediate risk prostate cancer with EBRT, Pollack et al. randomized patients to 78 Gy versus 70 Gy in 2 Gy fractions.69 With 100 months of follow-up, the 78-Gy group showed significantly better PSA-free survival in the intermediate risk group demonstrating that increased dose leads to more prostate cancer cures in this population. However, grade 2 (TABLE 3-1) or greater rectal complications were also increased. Upon further analysis a dose/volume relationship can be seen in terms of complications. If the percentage of rectum treated to >70 Gy was <25%, grade 2 or higher complications were <15%. However, if the volume exceeded 25%, the probability of complication rose to 45%. These data from randomized dose escalation series for prostate, as well as other disease sites, guide the radiation oncologist when balancing the desire to deliver higher dose for increased probability of cure with the chance of chronic complications. SUMMARY Radiation therapy has been used to treat cancer patients since 1896. The development of modern linear accelerators, sophisticated computer planning software, and an
Table 3-1 RTOG Toxicity Scoring System Organ
0
Grade 1
Grade 2
Grade 3
Grade 4
Large intestine/ rectum
None
Mild diarrhea and cramping with bowel movement < 5 times/day
Moderate diarrhea (bowel movement > 5 times/day) or excessive rectal mucus or mild but intermediate bleeding
Surgery is required due to bleeding or obstruction of bowel
Fistula or perforation develops
Spinal cord
None
Mild Lhermitte’s syndrome
Severe Lhermitte’s syndrome
Neurologic findings on examination that can be accounted for by damage at the level of spinal cord in the radiation field
Paraplegia
Bladder
None
Microscopic hematuria
Increased frequency of urination with occasional macroscopic hematuria
Severe frequency or dysuria Macroscopic hematuria Bladder capacity reduced to < 150 cc
Bladder capacity < 100 cc, hemorrhagic cystitis, or necrosis
48
Part I Principles of Urologic Oncology
increased understanding of the basic biology that underlies the cytotoxicity of IR has allowed the field to cure more human tumors, decrease the need for large and debilitating surgical procedures, and decrease the probability of complications. Current clinical trials in most disease sites demonstrate that combined modality therapy with chemotherapy and radiation remains superior to radiation alone despite the increase in toxicity. Future trials with more novel chemotherapeutic agents aim to provide similar radiation sensitization while decreasing the overlapping toxicities. More advanced molecular biology techniques have enabled gene therapy to be combined with radiation in order to achieve a similar goal. We expect the advancements in both hardware, software, and biology will lead to further increases in the therapeutic ratio in the future.
13.
14.
15.
16.
17.
REFERENCES 1. Roentgen W: On a new kind of rays [preliminary communication]. Translation of a paper read before the Physikalische-medicinischen Gesellschaft of Wurzburg on December 28, 1895. Br J Radiol 1931; 1(4):32–36. 2. Coutard H: Roentgentherapy of epitheliomas of the tonsillar region, hypopharynx and larynx from 1920 to 1926. Am J Roentgenol 1932; 1932(28):313–332. 3. Khan F: The Physics of Radiation Therapy, 2nd edition. Baltimore, MD, Williams and Wikins, 1994. 4. Laramore GE, et al: Fast neutron radiotherapy for locally advanced prostate cancer: results of an RTOG randomized study. Int J Radiat Oncol Biol Phys 1985; 11(9):1621–1627. 5. Bonnett DE: Current developments in proton therapy: a review. Phys Med Biol 1993; 38(10):1371–1392. 6. Leung TW, et al: High dose rate brachytherapy for carcinoma of the oral tongue. Int J Radiat Oncol Biol Phys 1997; 39(5):1113–1120. 7. Stitt JA, et al: High dose rate intracavitary brachytherapy for carcinoma of the cervix: the Madison system. I. Clinical and radiobiological considerations. Int J Radiat Oncol Biol Phys 1992; 24(2):335–348. 8. Rodriguez RR, Demanes DJ, Altieri GA: High dose rate brachytherapy in the treatment of prostate cancer. Hematol Oncol Clin North Am 1999; 13(3):503–523. 9. Purdy JA, Wong JW, Harms WB, Emami B, Matthews JW: State of the art of high energy photon treatment planning. Front Radiat Ther Oncol 1987; 21:4–24. 10. Graham MV, et al: Preliminary results of a prospective trial using three-dimensional radiotherapy for lung cancer. Int J Radiat Oncol Biol Phys 1995; 33(5):993–1000. 11. Sibley GS, et al: The treatment of stage III nonsmall cell lung cancer using high dose conformal radiotherapy. Int J Radiat Oncol Biol Phys 1995; 33(5):1001–1007. 12. Yang FE, et al: The potential for normal tissue dose reduction with neoadjuvant hormonal therapy in
18.
19. 20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
conformal treatment planning for stage C prostate cancer. Int J Radiat Oncol Biol Phys 1995; 33(5):1009–1017. Kuszyk BS, Ney DR, Fishman EK: The current state of the art in three-dimensional oncologic imaging: an overview. Int J Radiat Oncol Biol Phys 1995; 33(5):1029–1039. Roeske JC, et al: Evaluation of changes in the size and location of the prostate, seminal vesicles, bladder, and rectum during a course of external beam radiation therapy. Int J Radiat Oncol Biol Phys 1995; 33(5):1321–1329. Boyer AL, et al: Clinical dosimetry for implementation of a multileaf collimator. Med Phys 1992; 19(5):1255–1261. Ling CC, et al: Intensity-modulated radiation therapy. In Devita V, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology. Philadelphia, PA, Lippincott-Raven, 2001. Zelefsky MJ, et al: High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urol 2001; 166(3):876–881. Dizdaroglu M, Measurement of radiation-induced damage to DNA at the molecular level. Int J Radiat Biol 1992; 61(2):175–183. Dizdaroglu M: Oxidative damage to DNA in mammalian chromatin. Mutat Res 1992; 275(3–6):331–342. Lin X, Fuks Z, Kolesnick R: Ceramide mediates radiation-induced death of endothelium. Crit Care Med 2000; 28(Suppl 4):N87–N93. Billis W, Fuks Z, Kolesnick R: Signaling in and regulation of ionizing radiation-induced apoptosis in endothelial cells. Recent Prog Horm Res 1998; 53:85–92 (Discussion 93). Bodmer JL, Schneider P, Tschopp J: The molecular architecture of the TNF superfamily. Trends Biochem Sci 2002; 27(1):19–26. Sartorius U, Schmitz I, Krammer PH: Molecular mechanisms of death-receptor-mediated apoptosis. Chembiochem 2001; 2(1):20–29. Ward JF: DNA damage produced by ionizing radiation in mammalian cells: identities, mechanisms of formation, and reparability. Prog Nucleic Acid Res Mol Biol 1988; 35:95–125. Littbrand B, Revesz L: The effect of oxygen on cellular survival and recovery after radiation. Br J Radiol 1969; 42(504):914–924. Thomlinson H, Gray L: Histological structure of some human lung cancers and the possible implications for radiotherapy. Br J Cancer 1955; 9:539–563. Raju MR, et al: A heavy particle comparative study. Part III: OER and RBE. Br J Radiol 1978; 51(609):712–719. Cox JD, Kline RW: Do prostatic biopsies 12 months or more after external irradiation for adenocarcinoma, Stage III, predict long-term survival? Int J Radiat Oncol Biol Phys 1983; 9(3):299–303. Fowler JF: Review: total doses in fractionated radiotherapy—implications of new radiobiological data.
Chapter 3 Principles and Applications of Radiation Oncology 49
30. 31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44. 45.
46. 47.
Int J Radiat Biol Relat Stud Phys Chem Med 1984; 46(2):103–120. Hall E: Radiobiology for the Radiologist, pp 17–160. Philadelphia, PA, JB Lippincott, 1988. Hahn GM, Little JB: Plateau-phase cultures of mammalian cells: an in vitro model for human cancer. Curr Top Radiat Res Q 1972; 8(1):39–43. Weichselbaum RR, et al: Radiation-resistant and repairproficient human tumor cells may be associated with radiotherapy failure in head- and neck-cancer patients. Proc Natl Acad Sci USA 1986; 83(8):2684–2688. Weichselbaum RR, Schmit A, Little JB: Cellular repair factors influencing radiocurability of human malignant tumours. Br J Cancer 1982; 45(1):10–16. Guichard M, et al: Potentially lethal damage repair as a possible determinant of human tumour radiosensitivity. Radiother Oncol 1984; 1(3):263–269. Evans J, Bergsio P: The influence of anemia on the results of radiotherapy in carcinoma of the cervix. Radiology 1965; 84:709–712. Dische S, et al: Carcinoma of the cervix–anaemia, radiotherapy and hyperbaric oxygen. Br J Radiol 1983; 56(664):251–255. Lee DJ, et al: Results of an RTOG phase III trial (RTOG 85-27) comparing radiotherapy plus etanidazole with radiotherapy alone for locally advanced head and neck carcinomas. Int J Radiat Oncol Biol Phys 1995; 32(3):567–576. Buntzel J, et al: Selective cytoprotection with amifostine in concurrent radiochemotherapy for head and neck cancer. Ann Oncol 1998; 9(5):505–509. Ram Z, et al: The effect of thymidine kinase transduction and ganciclovir therapy on tumor vasculature and growth of 9L gliomas in rats. J Neurosurg 1994; 81(2):256–260. Tanaka T, Yamasaki H, Mesnil M: Stimulation of intercellular communication of poor-communicating cells by gap-junction-competent cells enhances the HSVTK/GCV bystander effect in vitro. Int J Cancer 2001; 91(4):538–542. Belyakov OV, et al: Direct evidence for a bystander effect of ionizing radiation in primary human fibroblasts. Br J Cancer 2001; 84(5):674–679. Andrade-Rozental AF, et al:, Gap junctions: the “kiss of death” and the “kiss of life.” Brain Res Brain Res Rev 2000; 32(1):308–315. Terasima T, Tolmach LJ: Variations in several responses of HeLa cells to x-irradiation during the division cycle. Biophysics J 1963; 3:11–15. Iliakis G: Cell cycle regulation in irradiated and nonirradiated cells. Semin Oncol 1997; 24(6):602–615. Kanaar R, Hoeijmakers JH, van Gent DC: Molecular mechanisms of DNA double strand break repair. Trends Cell Biol 1998; 8(12):483–489. Haber JE: The many interfaces of Mre11. Cell 1998; 95(5):583–586. Weichselbaum RR, et al: In vitro radiobiological parameters of human sarcoma cell lines. Int J Radiat Oncol Biol Phys 1988; 15(4):937–942.
48. Lowe SW, et al: p53 status and the efficacy of cancer therapy in vivo. Science 1994; 266(5186):807–810. 49. Lowe SW, et al: p53 is required for radiation-induced apoptosis in mouse thymocytes [see comments]. Nature 1993; 362(6423):847–849. 50. Hall EJ: Radiobiology for the Radiologist. New York, Harper & Row, 1988. 51. Radford IR: The level of induced DNA double-strand breakage correlates with cell killing after X-irradiation. Int J Radiat Biol Relat Stud Phys Chem Med 1985; 48(1):45–54. 52. Jacobson MD, Burne JF, Raff MC: Programmed cell death and Bcl-2 protection in the absence of a nucleus. EMBO J 1994; 13(8):1899–1910. 53. Raff MC, et al: Programmed cell death and the control of cell survival. Philos Trans R Soc Lond B Biol Sci 1994; 345(1313):265–268. 54. Weil M, et al: Constitutive expression of the machinery for programmed cell death. J Cell Biol 1996; 133(5):1053–1059. 55. Radford IR, Murphy TK: Radiation response of mouse lymphoid and myeloid cell lines. Part III. Different signals can lead to apoptosis and may influence sensitivity to killing by DNA double-strand breakage. Int J Radiat Biol 1994; 65(2):229–239. 56. Dewey WC, Ling CC, Meyn RE: Radiation-induced apoptosis: relevance to radiotherapy. Int J Radiat Oncol Biol Phys 1995; 33(4):781–796. 57. Martin SJ, Green DR: Apoptosis as a goal of cancer therapy. Curr Opin Oncol 1994; 6(6):616–621. 58. Szumiel I: Ionizing radiation-induced cell death. Int J Radiat Biol 1994; 66(4):329–341. 59. Sanchez Y, Elledge SJ: Stopped for repairs. Bioessays 1995; 17(6):545–548. 60. Kolesnick RN, Haimovitz-Friedman A, Fuks Z: The sphingomyelin signal transduction pathway mediates apoptosis for tumor necrosis factor, Fas, and ionizing radiation. Biochem Cell Biol 1994; 72(11–12):471–474. 61. Haimovitz-Friedman A, et al: Ionizing radiation acts on cellular membranes to generate ceramide and initiate apoptosis. J Exp Med 1994; 180(2):525–535. 62. Verheij M, et al: Requirement for ceramide initiated SAPK/JNK signaling in stress-induced apoptosis. Nature 1996; 380:75–78. 63. Million RR: Carcinomas of the oral cavity and oropharynx. Curative treatment with preservation of function. Front Radiat Ther Oncol 1993; 27:20–30. 64. Mendenhall WM, et al: Radiotherapy for carcinoma of the supraglottic. Otolaryngol Clin North Am 1997; 30(1):145–161. 65. Landoni F, et al: Randomised study of radical surgery versus radiotherapy for stage Ib-IIa cervical cancer. Lancet 1997; 350(9077):535–540. 66. Pahlman L, et al: Preoperative irradiation of primarily non-resectable adenocarcinoma of the rectum and rectosigmoid. Acta Radiol Oncol 1985; 24(1):35–39. 67. Price P, et al: Low dose single fraction radiotherapy in the treatment of metastatic bone pain: a pilot study. Radiother Oncol 1988; 12(4):297–300.
50
Part I Principles of Urologic Oncology
68. Hartsell WF, et al: Phase III randomized trial of 8 Gy in 1 fraction vs. 30 Gy in 10 fractions for palliation of painful bone metastases: preliminary results of RTOG 97-14. Int J Radiat Oncol Biol Phys 2003; 57(2 Suppl):S124. 69. Pollack A, et al: Prostate cancer radiation dose response: results of the M.D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002; 53(5):1097–1105.
70. Stevens K: The stomach and intestines. In Moss W, Cox JD (eds): Radiation Oncology, Rationale, Techniques, pp 362–408. St Louis, MO, CV Mosby, 1989.
C H A P T E R
4 Principles of Chemotherapy for Genitourinary Cancer David I. Quinn, MBBS, PhD, FRACP, Patrick J. Creaven, MD, PhD, and Derek Raghavan, MD, PhD
Cytotoxic chemotherapy has been in use for the management of advanced cancer for more than a century,1 arising from concepts developed by Lissauer, Ehrlich, and many others. The initial attempts at such treatment were characterized by a lack of specificity, with a fine balance between the toxicity to the tumor and that experienced by the host. As reviewed in detail elsewhere,1 during the past century, there has been some refinement in our application of chemotherapy to the treatment of cancer, predicated on an improved understanding of the biochemical basis of its action and a clearer insight into the cellular and molecular mechanisms underlying normal and malignant growth. TUMOR CELL BIOLOGY IN RELATION TO CHEMOTHERAPY The anticancer agents are a varied collection of drugs that act through a range of mechanisms predominantly focused on interference with cell reproduction. The differences between the growth characteristics of normal and malignant tissues form the major basis of the effective use of cytotoxic chemotherapy.2 Differences between the cellular transport characteristics of these agents may also contribute to the difference in response to some cytotoxics. It is also apparent that there are important differences between intracellular metabolic functions, such as the expression of glutathione, an intracellular scavenger that interacts with some alkylating agents and the platinum complexes to inactivate them. More recent data suggest that there may be subtle interactions between the expression of growth controlling factors (such as the receptor for the epidermal growth factor
[EGF]) and the impact of cytotoxic agents, with potential for resulting synergistic or antagonistic effects. Normal tissues are composed predominantly of a static population of cells (which rarely undergo cell division), an expanding population (which retain the ability to grow, under stringent physiologic control mechanisms) and a self-renewing population (for tissues that turn over rapidly, such as bone marrow and gastrointestinal mucosa). In this situation, balance is maintained between natural attrition and replacement. The static, or terminally differentiated, population usually includes cells that do not undergo cell division after fetal life, such as skeletal muscle and neuronal tissue. The cells of an expanding population do not normally undergo continuous growth and division but may respond to stress (such as injury) with a period of replacement growth. For example, hepatocytes can respond to surgical resection of liver tissue by re-entering the cell cycle and replacing the lost tissue. Another example of the expanding population is the stem cells found in the bone marrow; these normally rest in the G0 phase but can re-enter the cell cycle. The fact that they are predominantly in G0 may protect them, in part, from the effects of cytotoxic agents. By contrast, the self-renewing cell populations (e.g., gastrointestinal tract, hair follicles, bone marrow) are in a continuous proliferative state, with constant cell turnover, and are thus most commonly injured by cytotoxic chemotherapy; the static cell populations are the least vulnerable to the effects of chemotherapy. Malignant growth is essentially uncontrolled, occurring as a result of a breakdown in the mechanism(s) that turn off growth. The patterns that contribute to tumor
51
52
Part I Principles of Urologic Oncology
growth may include reduction in the duration of the cell cycle, a decrease in the rate of cell death, or an increase in recruitment of cells into the active cell cycle. In general, it appears that malignant growth follows a Gompertzian pattern,2 in which a period of exponential growth is followed by a slowing of the growth rate.3,4 This may occur through the tumor outgrowing its vascular supply,5 due to the development of toxic breakdown products associated with cellular turnover, or through other subtle cell–cell interactions. In addition to unregulated cell growth, malignancy is characterized by tissue invasion and metastasis, sustained angiogenesis, and evasion of apoptosis or programmed cell death.6 Cellular Kinetics and Cell Cycle Control The kinetics of tumor cell growth, both in vitro and in vivo, has been the subject of considerable study,2 although our concepts regarding this topic remain quite fluid. Surprisingly little information is available regarding the kinetics of human tumor growth,7 although a greater body of information is available regarding the growth of animal tumors.2 It is generally agreed that tumor cells grow through an orderly sequence of steps: 1. The initial growth phase (G1) is characterized by synthesis of RNA and protein, as well as DNA repair; this is a period of variable length, and its duration will determine the length of the total cell cycle of the individual cell. 2. This is followed by the synthetic (S) phase, in which new DNA is synthesized. 3. The cells progress through the G2 phase, in which the total DNA content is double that of the normal cell. 4. The mitotic (M) phase sees the division of the chromosomes and separation into two offspring cells. 5. After mitosis, the cells may spend a variable period of time in a resting state known as G0—the cells are out of active cycle and appear not to be affected by chemotherapy to any major extent. A detailed description of the molecular biology of cell cycle control is beyond the scope of this chapter, but the principles have been reviewed elsewhere.6,8,9 In brief, several candidate genes and growth factors appear to regulate the various steps of the cell cycle. Entry into G1 from S phase is regulated by a range of growth factors and interrelated molecular mechanisms culminating in retinoblastoma protein (pRb) phosphorylation. When hypophosphorylated, pRb blocks proliferation by sequestering and altering the function of E2F transcription factors that control the expression of banks of genes essential for the progression from G1 to S phase.10–13 Disruption of the pRb pathway liberates E2Fs and allows
unregulated cell proliferation. The classic negative regulator of cellular proliferation is transforming growth factor beta (TGFβ). TGFβ acts through a number of mechanisms to inhibit cell cycle progression.14 It directly induces increased production of cyclin-dependent kinase (CDK) inhibitors such as p15INK4B, p27Kip1, and p21Cip1.15–17 These proteins, in turn, act to block the activity of cyclin: CDK complexes responsible for pRb phosphorylation.18,19 TGFβ also suppresses the expression of the c-myc gene, which has a physiologic role in increasing the rate of G1 to S phase transition through mechanisms that are still being elucidated.20,21 EGF, which binds to a cell membrane associated receptor to initiate a chain of signal transduction, acts to increase the rate of cell cycle proliferation in part by decreasing the quantity of p27Kip1 present.22 In cell line experiments, blockade of the epidermal growth factor receptor (EGFR) results in increased p27Kip1 and arrest of the cancer cell in G1 phase as it is unable to transit into S phase.23 Furthermore, p53 regulates cell cycle progression through synthesis of the CDK inhibitor, p21Cip1.16 Hence, cellular transit through the G1/S transition may be influenced by a number of factors, including growth factor concentration and effect, receptor expression and activity, cell cycle regulatory molecule expression, and pRb action. For example, a more rapid cell cycle could arise from any or a combination of increased EGF concentration, EGFR receptor overexpression, loss of CDK inhibitor expression, cyclin overexpression, or retinoblastoma gene mutation. The net rate of cell proliferation is a synthesis of a multitude of potential effectors on the pRb pathway. Several oncogenes, such as ras, c-myc, and src have activity in the M phase of the cell cycle; in fact, they may actually interact in the process leading to activation of the M-phase promoting factor, which in turn controls entry into mitosis (the second major cell cycle control point at the G2/M phase transition).24 Variation in the activity of these oncogenes, whether induced by amplification, mutation, or exogenous regulators, can result in altered transition through mitosis.24–26 Tumor progression may be a function of a series of events that involve progressive loss of control over entry into the S phase and loss of regulation of M phase; such progression is due to genetic instability and is central to the evolution of malignancy.24 These changes may, in part, be contingent on the loss of M phase checkpoint function, a mechanism by which the cell cycle pauses transiently and allows checking of the accuracy of replication.27,28 The concept of the cell cycle is of great importance to our understanding of cytotoxic action. Most agents affect some aspect of the synthesis of DNA, RNA, or protein, acting at different points within the cell cycle. This may be very important when adding agents in a combination regimen, for example, the use of a spindle poison (such as
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 53
a vinca alkaloid) may hold up cells from entry into the G1 phase and thus reduce the impact of an agent that acts predominantly at that point of the cell cycle. In turn, inhibition of G1/S phase transition may invalidate the effect of agents that act at or subsequent to this point, such as topoisomerase inhibitors.29 These potential effects are limited by the fact that many agents act at multiple points in the cell cycle. Inhibition of checkpoint function may explain how tumor cells can be more vulnerable to the effects of cytotoxic agents than are normal cells—thus the vulnerability of cancer cells to agents that target the S phase or M phase may occur because the malignant cells proceed unchecked through the cell cycle despite a series of errors, whereas the normal cells stop at finite checkpoints while needed repairs occur. In addition, there is an increasing trend toward designing drugs that target specific parts of the cell cycle machinery. Examples of mitotic phase regulators include vinca alkaloids, taxanes, and epothilones30,31 whereas flavopiridol and UCN-01, which are currently under development, inhibit cyclin-dependent kinases active in G1/S phase transition.32–35 Cell cycle characteristics can be measured in several ways, including the use of labeling of mitoses,2 flow cytometry,36 and surrogate markers of cell cycle transit or proliferation such as Ki67 immunohistochemical index.37 When considering the biology of tumor growth as assessed by flow cytometry, the proportion of cells in G1 + S phases is thought to be most important, although the level of aneuploidy (proportion of cells that do not have a normal or diploid DNA content) appears to be important as a prognostic determinant in some tumors. Another more direct parameter of the cell cycle is measurement of tumor doubling time.2 Also of importance is the growth fraction (proportion of cells within a tumor that are in active proliferative phase), which can range from 25% to more than 90% in human tumors, often with areas of variation within individual tumor deposits. The rate of cell loss is also important—in most tumors, it is high, ranging from 70% to greater than 90%.2 In general, the length of the G1 phase is one of the primary determinants of proliferative behavior—thus, if G1 is short, the duration of the cell cycle is usually rapid, whereas cells with a long G1 or those that spend considerable time in G0 have a much longer cell cycle and are less sensitive to the impact of chemotherapy. The Balance between Cell Proliferation and Apoptosis Apoptosis or programmed cell death occurs in normal as well as neoplastic cells. The process is complex and regulated by a variety of molecular pathways. The best understood of these pathways center on the tumor suppressor gene, p53,38,39 and the oncogene, Bcl2.40 A detailed review of apoptosis is beyond the scope of this
chapter but has recently been reviewed.41–43 The interaction between cell proliferation and apoptosis determines the net growth of a tumor mass. These factors have been evaluated in relation to cancer development and progression in a number of human cancers, including prostate cancer (PC). Normal prostate epithelial cells have a very low replicative rate that results from replacement of the cell every 500 days and no net increase in cell number.44 In “low grade” prostatic intraepithelial neoplasia (PIN), epithelial cells undergo proliferation in excess of dying so that they have a doubling time of around 150 days. Upon development of “high grade” PIN, there is an increase in both replication and cell death so that there is no net increase in cells but the turnover time is around 56 days. Subsequent transition to invasive PC involves little change in proliferation but rather a reduction in cell death and a mean doubling time of around 500 days. Metastatic PC cells have both increased proliferation and cell death rates with a mean doubling time of around 33 days for lymph node and 54 days for bone metastases in hormone sensitive cases.44 In metastatic androgenindependent PC, there is no further increase in cellular proliferation and an increase in cell death. The reasons for this increase in cell death are unclear but may relate to local or general nutrient delivery. Hence, PC has a very long doubling time even in metastatic disease with relatively subtle changes in proliferation and cell death that mark transition between stages of the progression of the disease.44 The relative balance between proliferation as determined by cell cycle transit and programmed cell death varies between cancer types and may influence sensitivity to a variety of anticancer therapies. When PC is treated with androgen ablation, the result is increased apoptosis in a minority of cells with decreased proliferation in the majority of cells, demonstrating the importance of this balance in response to therapeutic interventions.45 In other tumors, varying amounts of reduction in cell proliferation and increase in apoptosis are seen among tumors exposed to hormonal and cytotoxic therapy.46 In urologic oncology, the balance between reduced cellular proliferation and increased cell death is best illustrated in the response of metastatic nonseminomatous germ cell tumors to chemotherapy. More than 90% of patients with this condition are cured. In responding to chemotherapy a major proportion of cancer cells undergo apoptosis. However, certain cells within the tumor, particularly within teratomatous elements, are resistant to apoptosis and undergo reduction in proliferative rate and may differentiate into “mature” teratoma.47–50 These areas may remain as quiescent masses for protracted periods of time but have the potential to de-differentiate and manifest cancer recurrence, which typically is resistant to further chemotherapy.51,52 Based on this, the therapeutic approach to these masses involves
54
Part I Principles of Urologic Oncology
surgical excision, particularly where teratoma has been identified in the primary tumor.53–55 Recent work suggests that mature teratoma may have a molecular signature that distinguishes it from cancer cells undergoing apoptosis and those that appear morphologically unaltered after chemotherapy.56 Whether this molecular approach will be of therapeutic utility remains to be seen. Clonality of Tumor Cell Populations In animal tumors, which tend to be clonal in nature, first order kinetics appear to apply in response to chemotherapy—that is, a dose of single-agent chemotherapy will kill a fixed proportion of tumor cells. For example, if a tumor mass containing 107 cells is treated with an agent that kills 90% of the cells, 9 × 106 cells will be killed by a single dose, leaving behind 106 viable cells (or 10% of the original tumor mass). A second dose will kill 9 × 105 cells, leaving 105 cells still alive. If treatment is not repeated, these cells will regrow, and the mass will rapidly return to its former size. This is also influenced by the proportion of cells that undergo spontaneous cell death, as well as the proliferative rate of any remaining viable cells. In the human setting, the situation is much more complex, as many human tumors appear not to be purely uniclonal in nature but rather are composed of multiple subpopulations of cells with different characteristics.52,57–61 It is not clear whether this is due to the evolution from single clonal populations (stem cells) or is due to initial evolution of multiple clones in response to an initial carcinogenic stimulus. Heterotypic signaling mechanisms between the diverse cell types that comprise a human tumor are likely important regulators of primary tumor cell proliferation and other malignant characteristics.62,63 PHARMACOLOGY OF ANTICANCER AGENTS The time course of drugs in the body is determined by the rates of drug absorption, distribution, metabolism, and excretion. The mathematical description of these rate processes is referred to as pharmacokinetics. Often the data can be fitted to mathematical models, which are simplified descriptions of the complex physiologic realities. Many of the processes involved are so-called “first order”; that is, the rate at which the process occurs is proportional to the drug concentration, although some processes that are enzyme or carrier-dependent follow Michaelis Menten kinetics in which the process is first order at low concentrations and zero order (i.e., occurring at a fixed rate) at high concentrations of the drug. Absorption Cytotoxic agents may be administered directly into the circulation (intravenous or arterial administration) or
by the extravascular approach, which includes oral, intramuscular, intrathecal, intravesical, and intraperitoneal routes. The route of extravascular delivery will influence absorption. Factors that determine the uptake characteristics of a drug include the structure and size of the molecule and its pKa and, thus, its solubility characteristics. The clinical activity of specific agents may vary substantially with the nature of the route and schedule of administration and consequent absorption. For example, cyclophosphamide can be administered orally in a dose of 100 mg/m2/day for 14 days to patients with advanced PC, and is well tolerated, causing only modest myelosuppression and gastrointestinal toxicity.64 When administered to similar populations of patients by intravenous bolus injection (e.g., 750 to 1000 mg/m2 every 3 weeks), the side effects may be more substantial65 with no apparent improvement in therapeutic outcome. Successful intravesical chemotherapy is predicated on the desire for cytotoxics to be active locally without systemic absorption, thus protecting the patient from systemic side effects while maximizing the concentration at the tumor surface. Thus, thiotepa, a small, readily absorbed molecule is potentially less useful in this context than larger molecules, such as doxorubicin or mitomycin C. 66–68 Furthermore, the level of systemic absorption of thiotepa can be increased if it is administered soon after transurethral tumor resection in the presence of a residual denuded bladder epithelium.69 Ultimately the key to therapeutic effectiveness of any cytotoxic agent is a function of the product of its concentration and the time available at the tumor site (C × T). Most cytotoxics are administered by intravenous or intraarterial routes, and the calculation of the actual plasma C × T equation is made accordingly. Distribution and Transport The amount of cytotoxic agent available at the tumor target and the length of time during which it is present determines its level of efficacy. Several factors will influence this, including the lipid solubility of the drug, its binding to protein and other carriers (with consequent variation on free drug concentrations), and the mechanisms available to allow entry into the tumor (such as passive diffusion or active transport). A major factor will be the plasma levels of the drug, a major determinant of which is its distribution characteristics. Following rapid intravenous injection, the plasma concentration (Cp ) of the drug will initially fall rapidly. With the elapse of time after the dose, the rate of decline will decrease. A plot of the natural logarithm (ln) Cp against time (semilog plot) will generally show two components of the plasma decay: an initial rapid component and a subse-
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 55
quent slower component, both of which have the characteristics of log-linear, that is, first order, processes. Mathematically, such plasma decay can be fitted to a two-compartment model in which the body is conceptualized as consisting of two compartments, a central compartment into which the drug is introduced and a peripheral or tissue compartment into which it diffuses, ultimately to equilibrium. The second component of the plasma decay consists of elimination processes consisting of metabolism or excretion. The rate of this second process will give the half-life of the drug in the body and is an important pharmacokinetic characteristic of all drugs (t1/2β). For some drugs, such as the anthracyclines, a third component of the plasma decay is seen indicating a so-called deep tissue compartment, usually corresponding to the binding of the drug to some tissue component, such as nucleic acid, from which the drug is slowly released. An even simpler model in which the body is regarded as a single compartment can sometimes be used; however, for many drugs it can lead to major errors in computing the important pharmacokinetic parameters. It is important to recognize that these “compartments” are mathematical constructs, which usually have little or no correspondence with actual physiologic compartments. The total area under the plasma concentration-times-time curve (AUC or C × T) is an important measure of the total exposure of the tissues to the drug. Other important pharmacokinetic parameters, which can be calculated from the indices of plasma decay, are the total body clearance (ClB) and the apparent volume of distribution (VD), the theoretical volume required to dissolve the total body content of the drug if it were uniformly distributed in the concentration found in plasma. In general, the drug is distributed between the intravascular, extracellular and intracellular water but has to cross a membrane to pass from one of these to another. In addition, certain sites are protected from easy drug access. Such sanctuaries are usually characterized by lower drug concentration than other tissues. Conversely, some drugs are disproportionately concentrated in particular tissues as exemplified by the accumulation of estramustine in prostatic tissue.70 The presence of sanctuary sites may be of real importance; for example, the blood-brain barrier appears to protect the brain against the local uptake of cytotoxic agents, and thus the brain may be the site of first relapse in tumors that are otherwise quite responsive to chemotherapy.71 Similarly, it appears that the testis may functionally constitute a sanctuary site against the effect of chemotherapy—up to a third of patients treated for metastatic testis cancer before surgical removal of the affected testis will have residual cancer within the testis at subsequent orchiectomy, despite the attainment of extratesticular complete response.72
Metabolism Drug metabolism may occur both outside and within tumor cells. There are two important types of metabolism of antitumor agents. Antitumor agents, which resemble normal metabolites, are often metabolized by the same mechanisms as the normal metabolites that they resemble. Most purine and pyrimidine antimetabolites require activation to a nucleotide (usually the triphosphate) in order to be active, and these reactions are carried out by the mechanisms in the cell used to metabolize the corresponding normal preformed purines and pyrimidines (the so-called salvage pathways). Some of the antifolates undergo polyglutamation by the mechanisms used for folates. Degradative pathways such as those responsible for reducing 5-fluorouracil (5-FU) to dihydro-5-fluorouracil and converting cytosine arabinoside to the corresponding uracil arabinoside by deamination,73–75 are also active in the cell. These reactions occur in the cells of the tumor and in the cells of normal tissues. In the case of capecitabine, a novel oral fluoropyrimidine carbamate, intracellular conversion of parent drug to 5-FU occurs preferentially so that there is more active drug in cancer tissue than adjacent normal cells.76,77 This occurs under the enzymatic effects of cytidine deaminase and thymidine phosphorylase, which metabolize capecitabine to 5′-deoxy-5-fluorocytidine, 5′deoxy-5-fluorouridine, and fluorouracil.76,78 In addition to these specific metabolic reactions, compounds that do not show resemblance to physiologic substrates are metabolized primarily in the liver by the pathways used for detoxification of xenobiotics. The most important of these is oxidation, often followed by conjugation. Oxidation is carried out by cytochrome P450, a family of enzymes located primarily in the microsomal or smooth endoplasmic reticulum fraction of the liver.79,80 This pathway is very nonspecific in terms of structural requirements and oxidizes most lipid soluble compounds. It is this pathway that is responsible for the initial oxidation of the oxazaphosphorine ring of the oxazaphosphorines cyclophosphamide and ifosfamide, a reaction leading to the conversion of these compounds to their active metabolites.81–84 Knowledge of the metabolism of cytotoxic agents is important in designing treatment strategies, for example, intravesical delivery of cyclophosphamide would make no sense, as the drug requires hepatic metabolism to its active form to be effective (see later). In the patient with hepatic dysfunction or failure, impaired hepatic conjugation and/or oxidation will alter the metabolism of doxorubicin, the taxanes, irinotecan, and the vinca alkaloids, whereas the microsomal activation of cyclophosphamide may be impaired in this clinical setting.85–91 Excretion Excretion of cytotoxic agents occurs predominantly in the kidneys and liver, and abnormalities in the function of
56
Part I Principles of Urologic Oncology
either or both organs may substantially influence the pattern of toxicity.85 Renal dysfunction will particularly affect the disposition of the platinum complexes, methotrexate, and bleomycin,92–95 and this may be an important issue in a patient with renal tract outflow obstruction due to a large primary tumor of bladder, prostate, or urethra or with obstruction from enlarged retroperitoneal nodes. Factors Modifying Pharmacokinetics Absorption of drugs may be affected by diseases of the GI tract, previous surgery, compounds that change the pH of the gut, coadministration of other drugs, and a variety of other factors.96–98 Distribution can be influenced by disease states, such as cardiac failure, ascites, pleural effusion, and edema.99 Age and amount of adipose tissue may have an impact on the clearance and toxic effects of cytotoxic agents. For example, obesity appears to reduce the clearance of both doxorubicin and ifosfamide,100,101 although it is not clear that this has an impact on toxicity of the individual drugs. Age may alter disposition of doxorubicin; for example, Robert and Hoerni102 demonstrated reduced clearance in older patients, compared with younger cohorts. Numerous factors have been shown to affect the rate at which drugs are metabolized by cytochrome P450 microsomal enzymes in the gut and liver.79,98,103A large number of compounds can induce P450, including phenobarbital, carbamazepine, rifampin, and phenytoin, chlorinated hydrocarbon insecticides, food additives, and tobacco consumption. Some antineoplastic agents may inhibit drug metabolism, as may the occurrence of hepatic disease.104,105 Excretion of compounds by the kidneys depends heavily on renal function. Coincidental administration of compounds that can compete for tubular reabsorption may have an effect on renal clearance of certain compounds,106 as may urinary pH if the compound is able to become ionized.94,107,108 MECHANISMS OF DRUG RESISTANCE There are several mechanisms of resistance to cytotoxic chemotherapy (Table 4-1). In general, these can be classified on the basis of cellular distribution. Intracellular factors include those that act at the cell surface, others within the cytoplasm, and those that function at the level of the nucleus. In addition, there are extracellular factors, such as those that affect the distribution and metabolism of the drugs, including competitors for cellular transport mechanisms. Some cytotoxic agents can be exported from tumor cells through a mechanism based on the cellular surface, the so-called multidrug efflux pump, which was originally characterized by the expression of a specific 170 kD protein complex, P-glycoprotein.109–111 It was initially
demonstrated that response to the cellular effects of agents as diverse as the vinca alkaloids, actinomycin D, estramustine, mitoxantrone, and doxorubicin is reduced in normal and malignant cells that express a protein complex on the cell surface, coded by a series of multidrug resistance (mdr) genes.112–114 This occurs as a result of reduced intracellular concentrations of the agents due to increased cellular efflux.115 Expression of the mdr phenotype may be present before therapy or appear as a result of induced resistance during treatment.116 More recent research has elucidated a diverse family of P-glycoproteins that acts physiologically to facilitate influx and efflux of xenobiotics from a variety of cells.117,118 Alteration in the expression and activity of these molecules can have a significant effect of drug pharmacokinetics both at a whole body and cellular level.119 Expression of mdr phenotype has been identified in renal carcinoma,120 although its significance has been difficult to define as most renal carcinomas are resistant to the available cytotoxic agents, and the presence/absence of this phenotype does not correlate with outcome. The study of the multidrug phenotype in bladder cancer cells has also proved to be a difficult problem, as the expression of P-glycoprotein in bladder cancer has been highly variable and inconstant.121–124 It has now been shown that expression of P-glycoprotein may be upregulated in resistant populations of bladder cancer cells after treatment with the MVAC regimen.125 In other tumor types, multidrug resistance can occur in the absence of expression of the 170 kD P-glycoprotein, whereas other proteins may be associated with very similar patterns of resistance,126 perhaps explaining this phenomenon in the absence of expression of this P-glycoprotein. Ultimately, apart from its predictive function, this work is unlikely to be of great importance unless the mdr phenotype can be overcome at a functional level.127 For example, the calcium channel blockers, such as verapamil, have been shown to reverse multidrug resistance,128 although the toxic side effects of this approach have precluded routine use while some data suggest that compensatory effects such as altered blood flow may diminish tumor sensitization at clinically attainable concentrations.129 Although clinical trials have not yet been published in bladder cancer, work initiated in our laboratories suggests that verapamil can overcome the impact of the mdr phenotype, at least in bladder cancer cell lines in vitro.130 Furthermore, Brandes et al.131,132 have shown that N,N-diethyl-2-[4-(phenylmethyl)phenoxy]-ethanamine (DPPE, Tesmilifene), an intracellular histamine antagonist, enhances the anticancer effect of cytotoxic agents and that DPPE may modulate the function of the P450 hepatic enzyme system and may alter the expression of multidrug resistance phenotype. They have shown that
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 57
Table 4-1 Mechanisms of Tumor Drug Resistance Example or Potential Cause Macro-pharmacokinetic mechanisms: ineffective dose of drug in the body Inadequate dose
Miscalculation or decreased dose due to prior excessive toxicity
Inadequate absorption
Short bowel syndrome after surgical resection or coingestion of drug binder such as cholestyramine
Induced metabolism
P450 microsomal enzyme-inducing drug for liver metabolized agent such as paclitaxel or docetaxel
Failure to metabolize to active drug
Ifosfamide or cyclophosphamide
Induced excretion Micro-pharmacokinetic mechanisms: ineffective intracellular concentration of drug Impaired tumor blood flow
Local radiotherapy or scarring after surgery, sanctuary site such as central nerves system or testis
Impaired tumor uptake
Methotrexate
Induced intracellular metabolism of drug to inactive or exportable metabolite
5-FU metabolism, methotrexate
Drug efflux
P-glycoprotein and doxorubicin
Pharmacodynamic intracellular mechanisms Mutated target that does not respond to drug
Tubulin mutations and taxane or vinca alkaloid therapy. Androgen receptor mutation for androgen deprivation
Overexpressed target that overcomes drug effect
Thymidylate synthetase and fluoropyrimidines
Compensation by cellular mechanisms
DNA repair enzyme over expression and platinum drugs. Apoptosis resistance due to mutated p53 or overexpressed Bcl2. Lack of cell cycle response due to pRB mutation, cyclin overexpression, or loss of CDK inhibition
DPPE appears to enhance the anticancer efficacy of cyclophosphamide against hormone-refractory PC (HRPC), an observation that we have confirmed for mitoxantrone.133 The mechanisms of resistance to the platinum coordination complexes have been studied in detail, particularly in relation to ovarian cancer and malignant melanoma. Although several mechanisms have been identified, including factors that influence cellular accumulation, signal transduction, ionic fluxes, and intracellular enzyme function,134,135 the function of the intracellular scavenger, glutathione (GSH), has increasingly been the focus of particular attention in the context of the resistance of bladder cancer to the effects of cisplatin. GSH is found in most mammalian cells and has many functions, including regulation of protein and DNA synthesis and detoxification. It appears to react with cisplatin, reducing its intra-
cellular availability. Inhibitors of GSH synthesis, such as buthionine sulfoximine, have been shown to cause a decrease in intracellular levels of GSH with a concomitant increase in the cytotoxicity of some anticancer agents, such as the alkylating agents, cisplatin136 and paclitaxel.137 Although much of the experimental data regarding the significance of glutathione in cisplatin resistance has been derived from models of ovarian cancer, very high levels of glutathione are present in cell lines derived from bladder cancer, and this may correlate with cisplatin resistance.138 It should be emphasized that our understanding of these mechanisms is relatively crude, and there appear to be other factors that influence the responsiveness of bladder cancer to cytotoxic chemotherapy. It appears that the expression of several oncogene products may influence resistance to cytotoxic agents. The exact nature of this interaction is not yet clear and is particularly difficult
58
Part I Principles of Urologic Oncology
to define as several of these products code for specific aspects of cellular growth control irrespective of exposure to cytotoxic agents. For example, it has been shown that the interaction of EGF and its specific receptor (EGFR) are involved in the regulation of growth of bladder cancer. However, in vitro treatment with EGF can increase cellular sensitivity of epithelial tumors to cisplatin.139,140 Conversely, it has also been shown that specific monoclonal antibodies and small molecules block EGFR function,141 and treatment with these agents plus cisplatin can cause a synergistic antitumor effect.142 These data are particularly difficult to interpret in view of the previously documented impact of expression of EGFR on the natural history of bladder cancer, and the demonstration that erbB-2 gene amplification and overexpression is an adverse prognostic determinant in bladder cancer.143–145 Recent clinical trials have not delineated a clear additive or synergistic effect of antiEGFR therapies with cytotoxic chemotherapy but this is not surprising given the conflicting preclinical model data available. Another complex relationship has been demonstrated between the expression of p53 (a suppressor gene product), growth regulation, and cytotoxic response in bladder cancer. Alterations of the p53 gene are among the most frequent genetic abnormalities found in human cancer146 and appear to have a broad range of postulated roles in cell growth control, including involvement in cellular repair and apoptosis.38 Apoptosis is regarded as one of the forms of physiologic cell death as it represents a genetically determined cellular sequence that is part of the normal tissue homeostatic mechanism. It has been shown that p53, which is normally present only transiently, can be induced to accumulate within the cell by exposure to cytotoxic agents, such as cisplatin and mitomycin C, and conversely that p53-dependent apoptosis modulates the cytotoxicity of radiotherapy, 5-FU, and doxorubicin.147–151 These issues may be of particular importance as it has already been postulated that p53 expression may constitute an independent prognosticator of response to the MVAC regimen.152,153 As p53 may be induced by cytotoxic exposure, it is possible that the timing of tissue sampling may be critical in determining the expression of this potential prognostic factor, especially if intravesical or systemic chemotherapy has been used previously. Models for Overcoming Drug Resistance of Tumor Populations: Clinical Implications Several models have been proposed to explain the varying levels of resistance to the impact of chemotherapy seen in human tumors. For example, Goldie and Coldman154 proposed that tumors have a spontaneous mutation rate and that the larger the number of tumor
cells, the greater the chance of spontaneous mutation. As a consequence, they proposed that the most effective mechanism for cancer killing would be to initiate chemotherapy early (with a small cellular burden) and to introduce multiple agents in an attempt to overcome the various mechanisms of resistance. To date, this hypothesis has not been validated in clinical trials, although most of the studies reported have been flawed and have not truly evaluated the principles of this hypothesis. Another model of resistance, proposed after a reassessment of the model presented by Goldie and Coldman,155 leads to the conclusion that cytotoxic agents can be used most effectively in sequence rather than as combination schedules. Thus an initial series of treatments with the less effective of two drugs would eliminate a proportion of the tumor cells present, leaving behind a resistant population that may respond to several courses of treatment with the more effective drug; in this way, it is postulated that the impact of the less effective therapy can be maximized.155 ASSESSMENT OF THE EFFICACY OF ANTICANCER TREATMENT The efficacy of anticancer treatment can be assessed in a variety of ways, depending on the endpoints under consideration. In most current studies, a reduction in tumor-related symptoms (subjective response), the development of tumor shrinkage (objective response), length of disease-free or overall survival or improvement in quality of life are regarded as significant indices of patient benefit in response to treatment. In order to assess these outcomes objectively and accurately, we use the process of the clinical trial wherein a defined population of patients, who fit specified criteria, are managed according to a defined protocol with specified measurement of outcome. A clinical trial may be one of two types66,156: (i) An “explanatory” trial has the primary aim of acquisition of information. Thus it usually only requires small numbers of patients and often has a biologic endpoint (e.g., tumor response). A typical example is the assessment of the new anticancer agent, gemcitabine, in the treatment of advanced bladder cancer, which provides the documentation of response and toxicity but does not give comparative information versus a standard type of treatment. It is often appropriate to report only the patients who are fully treated (complete the minimum requirements of the protocol of assessment) in order to minimize the chance of rejecting an active new approach. However, this may overestimate the potential benefit of the drug in the general patient population. (ii) A “pragmatic” trial is concerned with the assessment of comparative patient benefit, which can then be used as a guide to decision-making in treatment.
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 59
For example, the recent intergroup randomized trials that compare neoadjuvant intravenous chemotherapy plus locoregional treatment versus locoregional treatment alone for invasive bladder cancer are pragmatic trials and require large numbers of patients.157–159 As the goal of a pragmatic trial is to determine overall benefit to all eligible patients, endpoints should include both quality and quantity of survival, and it is important to report the outcome for all entered patients, irrespective of treatment received. Another classification of clinical trials is according to the descriptors, “phase I,” “phase II,” “phase III,” and “phase IV”. A phase I trial is designed to determine the appropriate clinical dosage of a new treatment (often being translated from preclinical studies) and to assess the side effects of this treatment. Such trials will often incorporate pharmacologic studies that will allow a clearer understanding of the distribution and metabolism of the novel agent in humans. Although anticancer response is recorded, this is not a primary endpoint of a phase I trial, and the process of consent must make patients understand that the chance of a significant tumor shrinkage is only small. Patients will often participate in such trials in the hope that they may secure the small percentage chance of success, or occasionally for reasons of altruism.160 Regrettably, it has become increasingly clear that patients often have a very poor understanding of the true purpose of phase I trials and of the small likelihood of individual patient benefit.161 Phase I trials are explanatory in nature and should be designed to minimize the expenditure of patient resources, usually with only 3 to 4 patients being entered at each dose level.162 These numbers allow relatively accurate identification and description of toxicity at each dose level, without the necessity to treat unreasonably large numbers of patients at potentially subtherapeutic doses. Unless the toxicity from a phase I trial is prohibitive or truly unpredictable and dangerous, the new agent will usually proceed to phase II testing. In most cases, an absence of antitumor activity in phase I testing will not necessarily preclude initial phase II assessment, although demonstration of activity in phase I testing tends to raise the priority of a novel agent for further investigation. Phase II trials are also explanatory and attempt to define the extent to which a new approach has antitumor activity. These studies usually involve treatment of defined groups of patients with a particular disease with a predetermined dosage of a novel agent, with assessment of tumor shrinkage and toxicity as primary endpoints. The demonstration of tumor shrinkage does not equate with long-term patient benefit, which is assessed subsequently in a phase III trial. Detailed mathematical assessments of patient numbers required to document true anticancer efficacy, minimizing false positive and false negative out-
comes, have been published elsewhere.163–165 In general, phase II studies require relatively small numbers of patients (usually less than 50, depending on the number of responses seen). Phase III trials are designed to define the role of a new treatment compared to a standard approach. These studies are pragmatic in concept and usually require randomization and relatively large numbers of patients. The number of required patients is predicated on the level of statistical confidence (power) that is required for the outcome. A more recent term, the “phase IV” trial, is used to describe a post-marketing study—that is, one in which a pharmaceutical company attempts to develop additional information regarding the indications for a newly approved agent (which is now being marketed); sometimes such studies are actually marketing (or “seeding”) studies, in which the primary purpose of the trial is to increase the level of interest or familiarity among physicians. The requirements of these clinical trials and a detailed discussion of the potential sources of error (Table 4-2) are beyond the scope of this chapter but have been reviewed elsewhere.66,166 SPECIFIC AGENTS COMMONLY USED AGAINST GENITOURINARY CANCERS Platinum Complexes Cisplatin (cis-diamminedichloroplatinum II) was introduced into the clinic in 1972 when observations by Rosenberg167 of its activity in interfering with the growth of Escherichia coli led to the demonstration of broadspectrum antitumor activity in experimental tumors. The lead compound of the platinum antitumor drugs, cisplatin (Figure 4-1), has contributed in a major way to the development of cure in testicular germ cell tumors and is highly active in combination in bladder cancer. The mode of action of the platinum complexes involves the formation of positively charged (electrondeficient) moieties that form adducts with DNA. These Table 4-2 Potential Sources of Error in Clinical Trials Failure to establish uniform reporting criteria of efficacy and toxicity Measurement error Bias in patient sampling: selection, exclusion Insufficient patient numbers Use of historical controls Stage migration Inadequate follow-up
60
Part I Principles of Urologic Oncology
O
O H3N
Cl
H3N
Pt H3N
NH2
O
H3N
NH2
O O
1
C
O
C
Pt
Pt Cl
O
O
2
3
Figure 4-1 Structures of cisplatin (1), carboplatin (2), oxaliplatin (3).
adducts are primarily intrastrand cross-links. Interstrand cross-links also form but in much smaller amounts. They are, however, much more lethal than the intrastrand cross-links. The contribution of the two types of adducts to the overall cytotoxicity of platinum complexes is a matter of dispute. Based on the sites of action of cisplatin, its major focus of activity is in the G1 and S phases of the cell cycle. Resistance to the platinum complexes may be due to impaired cell uptake of the drug,168 inactivation of the active species by intracellular thiols (primarily glutathione),138,69,170 and enhanced capacity of the cell to repair the damage to DNA.171–174 Cisplatin is usually administered intravenously or intraarterially, and in both instances it has been shown that its most dangerous toxic side effect, nephrotoxicity, is markedly reduced or eliminated if a high urine output is maintained (via enforced parenteral hydration before, during and after cisplatin administration, augmented by the use of mannitol, and in some instances small doses of furosemide). In early studies, cisplatin was administered for intravesical use by instillation through a urinary catheter, but unpredictable allergic reactions with occasional anaphylaxis were documented, and this indication is no longer under investigation. Measurement of total plasma platinum after administration of cisplatin shows a triphasic disappearance curve with half-life values of 20 minutes, 1 hour, and 24 hours92,175; the terminal phase probably reflects the slow release of platinum from plasma proteins. More than 90% of excretion is via renal mechanisms (a combination of glomerular filtration and tubular secretion), with less than 10% due to biliary excretion. The plasma decay of unchanged cisplatin generally has a monophasic pattern with a t1/2 of less than 1 hour.176 Renal failure, with acute tubular necrosis, degeneration, and interstitial edema, is the dose-limiting toxic effect, as noted above.177,178 Additional side effects of parenteral administration include severe nausea and vomiting, diarrhea, and occasional anaphylaxis. Ototoxicity, manifested by high frequency hearing loss, has been well documented, with a greater level of damage demonstrated by audiometry than on clinical grounds. With higher doses of cisplatin, and especially in
combination regimens that include the vinca alkaloids, neurotoxicity is an important side effect. This may present clinically as peripheral or autonomic neuropathy and may be seen more commonly on nerve conduction testing.179 A range of cardiovascular side effects has been reported, including hypertension, myocardial infarctions, EKG abnormalities, and an increased risk of peripheral thromboembolic phenomena and Raynaud’s phenomenon.180 However, in some cases, the relationship between cisplatin and these side effects is obscured by the impact of antecedent cigarette smoking by the population of patients under treatment. Myelosuppression may occur with standard doses of cisplatin, with anemia occurring in particular. Occasionally a Coombs’ positive hemolytic anemia has been documented. Leukopenia and thrombocytopenia occur sometimes but are usually not dose limiting. In an attempt to overcome the substantial toxic effects of this useful agent, a range of analogs has been developed in an effort to reduce toxicity without loss of activity (see later). Cisplatin is still among the most widely used cytotoxic agents in the management of genitourinary cancer. In addition to being one of the drugs of choice in the management of germ cell tumors and bladder cancer, cisplatin has activity against adenocarcinoma and small cell carcinoma of the prostate, adrenal cancer, and penile cancer. Carboplatin As noted earlier, cisplatin is one of the most active and useful agents in the management of genitourinary malignancy. However, its substantial toxicity has led to the search for analogs with equivalent anticancer activity but a reduced pattern of side effects, culminating in the introduction of several second-generation compounds into clinical trials. One of these, carboplatin, was developed largely at the Institute for Cancer Research in the United Kingdom and is now commercially available in the United States. While considerably less toxic than cisplatin (it has very little nephrotoxicity, considerably less neurotoxicity and ototoxicity, and produces much less nausea and vomiting), it is highly cross-resistant with the older compound. This may be related to the fact that once the
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 61
cyclobutanedicarboxylato-leaving group has separated from the molecule, the structure of the active hydrated species is identical to that of cisplatin (see Figure 4-1). Thus the major difference is in the kinetics of the formation of the active species.181 Carboplatin is much more stable in serum than cisplatin and diffuses into tissues rapidly so that only 24% of a dose is bound by plasma protein 4 hours after a dose.182 The terminal serum half-life of platinum is similar in patients given either carboplatin or cisplatin.93 The elimination of carboplatin occurs predominantly through the kidneys, where renal clearance closely parallels glomerular filtration rate.183,184On this basis, Calvert has developed a formula, based on creatinine clearance, that predicts safe carboplatin doses for individual patients relative to the chance of myelotoxicity, specifically thrombocytopenia.184 Carboplatin has activity in testicular, urothelial, and prostate185–187cancers but not renal cell cancer. Despite this it has failed to establish itself as first-line therapy in any urologic malignancy. Its equivalence with cisplatin has been demonstrated against lung cancer188,189 and in ovarian cancer,190,191 but this has not been the case in genitourinary cancer.192,193 Of particular importance, it appears that carboplatin is inferior to cisplatin for management of cancers of the testis and bladder. However, in combination carboplatin may be incorporated into regimens that will eventually prove to have favorable efficacy toxicity profiles compared to those incorporating cisplatin. The results of trials directed at proving this in urologic cancer have been inconclusive or disappointing to date.194–197 Carboplatin remains a well-tolerated, largely second-line therapy in a range of genitourinary malignancies. Oxaliplatin Oxaliplatin was synthesized by Kidani et al.,198 and there is evidence that in solutions containing high chloride content the oxalato group is replaced by chloride.199 The drug produces a characteristic peripheral neuropathy that is characterized by a cold-induced dysesthesia, which tends to be cumulative.200,201 Oxaliplatin has undergone extensive phase II and phase III clinical trials predominantly in gastrointestinal malignancies, while demonstrating some activity in a range of cancers including urothelial tumors in phase I testing.202 A group of German investigators has shown significant anticancer effect in patients with previously treated germ cell tumors. As a result of these trials, oxaliplatin has recently been licensed internationally for the treatment of colorectal cancer.203 It will be further evaluated in other primary tumor sites, including bladder cancer and germ cell tumors, for increased activity compared to cisplatin and carboplatin204,205 or for activity in platinum-resistant tumors.
Anticancer Antibiotics Bleomycin Bleomycin is isolated from the fungus Streptomyces verticullus and consists of a complex molecule of high molecular weight. It is composed predominantly of so-called A2 peptides, which contain a DNA-binding portion and an iron-binding component at the opposite end (Figure 4-2). Its primary action is to produce single-strand and double-strand breaks in DNA through the action of oxygen radicals formed in association with activation of the Fe++–bleomycin complex that binds to nitrogen-containing groups in the bleomycin molecule. The entire complex, consisting of Fe++–bleomycin–oxygen binds to DNA, through intercalation by the bithiazole groups of bleomycin, and DNA damage is created through the formation of superoxide or hydroxyl radicals. Tumor cells are most sensitive to the effects of bleomycin in late G2 or the M phase,206 although cells may also be killed in G1 phase.207 The mechanism of resistance to bleomycin has not been delineated with certainty, although it does appear that a cytosolic hydrolase may function to inactivate the drug.208 Bleomycin is administered either by subcutaneous bolus dosing, intravenously (bolus or continuous infusion) or by intramuscular injection. The optimal route has not been defined, although it is most commonly used (in combination with cisplatin and etoposide) as a weekly bolus dose. Bleomycin has a biphasic clearance, with t1/2α of about 20 minutes and a t1/2β of about 3 hours. Bleomycin is excreted predominantly via the kidneys, with more than 50% being excreted in the first 24 hours.95 Of importance, the dosage should be modified in a patient with impaired renal function, and caution should be used when the drug is administered after cisplatin, which can cause transient renal dysfunction. The major toxic effect of bleomycin is interstitial pneumonitis, the pathogenesis of which is poorly understood. The syndrome may be characterized by the evolution of subtle pulmonary symptoms, including cough, dyspnea on exertion, chest pain, and fever, or occasionally may be revealed only by changes in lung function tests. Pulmonary toxicity occurs especially in older patients, those who have previously received pulmonary or mediastinal irradiation, those with underlying lung disease, and in particular in cigarette smokers. In a study of the chronic toxic effects of bleomycin, we were unable to demonstrate major pulmonary toxicity in patients who did not smoke.179 In our experience, the acute toxicity of bleomycin can usually be ameliorated by corticosteroids, although care should be taken to avoid tapering the dose too quickly. Other side effects include mild myelosuppression, allergic reactions, fever, Raynaud’s phenomenon, and cutaneous pigmentation. The major indication for the use of bleomycin is in the management of germ cell tumors, and most attempts to
Part I Principles of Urologic Oncology
NH2 H2 N
NH2
O N
O
O
62
H
R1 N
O H2N H
H N
HO O
O
NH
N H
N
6
N
O HO
6
N O HO
1
CH3 N H
OH O
OH
BLEOMYCIN A2 –NH(CH2)3
S+ CH3
O
OH
NH2 OH
O
BLEOMYCIN B2 –NH(CH2)4
OH
+
N H
NH2
NH2
O
O
OH
O
OH
O O
CH2O
C
NH2
OH
OCH3
H2 N
O CH3
CH3O
N
N
O
OH 3
CH3
O 2
O NH2
HO
H N OH
O
HN
OH
O
HN
OH
OH N H
4
Figure 4-2 Structures of bleomycin (1), mitomycin C (2), doxorubicin (3), mitoxantrone (4).
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 63
delete it from standard protocols have resulted in reduced pulmonary toxicity but at the expense of a reduced cure rate.209,210 In addition, it has also been applied in some series to the management of advanced cancer of the penis. There appear to be no current indications for its use in the treatment of bladder cancer, renal carcinoma, or PC. Mitomycin C Mitomycin C is an anticancer and antibacterial antibiotic isolated from Streptomyces caespitosus.211 It is unusual in that it undergoes activation in a hypoxic environment, a characteristic of solid tumors. It is activated by visible (but not ultraviolet light) and is unstable in acidic and extreme basic conditions. Mitomycin is activated by reduction of a quinone moiety, mediated by microsomal enzymes, such as cytochrome reductase, DT-diaphorase, xanthine oxidase or cytochrome P450 reductase, or even by exposure to acidic pH. This releases a methanol side chain from the molecule and allowing an aziridine ring to open (see Figure 4-2). This exposes the alkylating site. The alkylating agent cross-links complementary DNA strands. Oxygen-free radicals may also participate in the cytotoxic function of mitomycin C through the production of DNA strand breaks.212,213 Mitomycin is usually administered by intravenous injection or through a urinary catheter for intravesical use. Its large molecular weight allows it to be retained within the luminal surface of the bladder, without significant systemic absorption. Because the drug is degraded at acid pH, the urinary pH must be maintained at alkaline levels for intravesical use. Because of its ubiquitous metabolism, mitomycin is cleared rapidly after intravenous or intraarterial injection. Renal excretion is minor (10% of administered dosage), and hepatic excretion seems to play only a minor role despite the importance of hepatic inactivation. Hepatic dysfunction does not appear to alter the pharmacokinetics of this drug to any great extent.214,215 The major toxic effect of mitomycin is myelosuppression, which involves platelet, leukocyte, and erythrocyte precursors.62 Of importance, this myelosuppression may be delayed and can occur 6 to 7 weeks after treatment. The level of myelosuppression correlates with dosage, and there appears to be a cumulative effect as well. Other side effects include gastrointestinal disturbances, occasional stomatitis, and renal toxicity.216,217 Mitomycin C can occasionally induce microangiopathic hemolytic anemia with associated renal failure (the hemolytic-uremic syndrome); this syndrome can be delayed in onset.216,217 Not infrequently, mitomycin C will cause interstitial pneumonitis, especially in high cumulative doses and in patients who have had prior chest irradiation; the syndrome is characterized by progressive cough and dysp-
nea, accompanied by changes in pulmonary function tests, and responds dramatically to high dose corticosteroids.218 Mitomycin C is a vesicant and causes extensive soft tissue reaction if extravasated; sometimes the ulceration will occur as a delayed phenomenon. The major indications for the use of mitomycin C include intravesical administration for superficial bladder cancer and intravenous administration for advanced bladder cancer; activity of mitomycin has also been demonstrated in the management of adenocarcinoma of the prostate and in advanced penile carcinoma. There is no routine role for this agent in the management of renal carcinoma, germ cell tumors, or adrenal carcinoma. Doxorubicin and Other Anthracyline Antibiotics Doxorubicin (Adriamycin) is a high molecular weight anthracycline antibiotic isolated from Streptomyces peucetius var. caesius. Its structure includes a water-soluble basic reducing amino sugar linked by a glycosidic bond to carbon atom 7 on the D ring of the chromophore aglycone, adriamycinone. This four-ring planar structure constitutes the anthraquinone nucleus (see Figure 4-2). Several analogs are in clinical use, including epirubicin (which differs in the steric configuration of the −OH group on the 4′ position of the daunosamine sugar) and idarubicin (which lacks an A ring −OCH3 substitution). A detailed discussion of each of these agents is beyond the scope of this review but has been covered elsewhere in detail.219 There appear to be several possible mechanisms of cytotoxic action of the anthracycline antibiotics, including the formation of free radicals, intercalation between nucleotide pairs in the DNA molecule, and the initiation of topoisomerase type II-dependent DNA fragmentation.220 Doxorubicin appears to be active in all phases of the cell cycle, with its maximal effect in S phase; however, it is not phase specific. For example, its topoisomerase type II function is concentrated in G2. Doxorubicin and epirubicin can be administered by bolus or continuous intravenous or intra-arterial injection or via urinary catheter for intravesical use. These drugs have a characteristic red color. Doxorubicin is extremely vesicant, and great caution should be used in its administration. After intravascular administration, the pharmacokinetics of doxorubicin and analogs are best represented by two- or three-compartment modeling.221 The plasma half-lives are 11 minutes, 3 hours, and 25 to 30 hours; it is likely that the long terminal phase is due to slow dissociation from DNA. These agents are rapidly distributed (into liver, lymph nodes, muscle, bone marrow, fat and skin but not central nervous tissue), and more than 70% is bound to plasma proteins. These drugs are extensively metabolized and are excreted predominantly in the bile and feces. Biliary
64
Part I Principles of Urologic Oncology
excretion accounts for more than 40% of each dose,87 whereas less than 10% is excreted in the urine. Obstructive hepatic dysfunction interferes with the disposition of these agents and mandates dose modification, whereas hepatocellular dysfunction without impaired conjugation does not seem to require these changes in dosing.222 One potentially attractive feature of idarubicin is its retention of antitumor activity when administered orally. Although apparently useful in the treatment of leukemia and lymphoma, its utility against the solid tumors appears more limited. The most common dose-limiting acute toxic effect is myelosuppression, with leukopenia at 10 to 14 days after treatment. Thrombocytopenia and anemia occur but are less clinically important. As noted above, doxorubicin is a significant vesicant and can produce extensive ulceration and soft tissue necrosis after extravasation. The other dose-limiting toxic effects are found in the heart. Doserelated cardiomyopathy has been extensively described223 and usually occurs with cumulative doses greater than 500 to 550 mg/m2 in previously untreated patients. These effects are more pronounced with conventional 3 weekly bolus dosing than if weekly low dose bolus dosing or 96-hour continuous low dose infusion is implemented. Other factors that predispose to cardiac toxicity include known cardiac disease, prior mediastinal or cardiac irradiation, age greater than 70 years, and chronic hypertension. In addition to cardiomyopathy, other cardiac effects have been recorded, including nonspecific EKG changes, occasional rhythm disturbances, an uncommon myocarditis-pericarditis syndrome, and rarely sudden death. It has been suggested that epirubicin may be less cardiotoxic than doxorubicin, although the contrary view has been expressed that equiactive doses of the two agents are equitoxic.224 Of importance, doxorubicin is a radiosensitizer and has a radiomimetic function—thus it will cause recall reactions in areas previously treated with radiotherapy.225 Other toxic effects include nausea, vomiting, stomatitis, and alopecia. The clinical indications for the use of this group of agents against the genitourinary cancers have been defined on the basis of the activity of doxorubicin. At present, it is still not clear whether the analogs, epirubicin and idarubicin, offer any clear advantage in this context. Doxorubicin has been identified as one of the agents of choice for use against superficial and advanced bladder cancer and has significant activity against adenocarcinoma and small cell carcinoma of prostate. In previous experience, in particular at the University of Indiana and at the Memorial Sloan Kettering Cancer Center in New York, doxorubicin was built into combination chemotherapy regimens for germ cell tumors but has been deleted in more recent trials, based on randomized trials in Indiana in which it appeared not to add to the
anticancer effect of standard cisplatin-based combination regimens. Limited activity against adrenal carcinoma has been recorded,226,227 but the drug appears to be inactive against renal carcinoma.228 Mitoxantrone Mitoxantrone is an anthracenedione, structurally related to the anthracyclines.229,230 In comparison with anthracyclines the structure of mitoxantrone maintains the planar polycyclic aromatic ring associated with intercalation but is without their characteristic sugar moiety associated with production of intracellular free radicals implicated in anthracycline cardiotoxicity (see Figure 4-2). It has characteristic blue color and is administered as an intravenous infusion.230 Mitoxantrone is highly protein bound in serum (>95%) and has a very large volume of distribution (450 to 5200 l/m2).231–235 It undergoes hepatic metabolism and biliary excretion with only around 7% of drug found unchanged in the urine.231 This suggests that dose reduction in liver disease may be warranted while adjustment for renal impairment may not be of value.236 The terminal half-life is long ranging from 8.9 to 189 hours.235,237,238 Mitoxantrone acts through DNA intercalation, DNA–protein cross-linkage and DNA–DNA linkage, and topoisomerase II inhibition.236 The major acute toxicity of mitoxantrone is myelosuppression, especially neutropenia, while nausea and vomiting tends to be mild. Cardiac toxicity occurs with mitoxantrone but is less common than with the anthracyclines. Alopecia secondary to mitoxantrone administration is normally mild.239 Mitoxantrone has significant activity in PC but not other genitourinary cancers.240,241 It has been licensed by the FDA for use in symptomatic HRPC based on the results of a randomized trial conducted by National Cancer Institute of Canada showing major improvement in quality of life.242–244 The potential role of mitoxantrone in earlier stage disease is under intense investigation245,246 and is the subject of a randomized trial being carried out by the Southwest Oncology Group. Drugs That Act Through Tubulin Modulation Vinca Alkaloids The vinca alkaloids, which occur naturally in the periwinkle (Catharanthus roseus), are formed from two multiplering planar units, an indole nucleus and a dihydroindole nucleus. The two most commonly used drugs, vincristine and vinblastine, are almost identical, differing only in a single substitution on the dihydroindole nucleus.247 They both act by binding to tubulin and inhibit microtubule assembly, which in turn inhibits mitotic spindle formation. This causes an accumulation of cells in
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 65
metaphase. Although the vinca alkaloids are thought to be cell cycle phase specific for mitosis, the cytotoxic effect probably occurs in S phase and its effect seen in the M phase. After intravenous administration, the vinca alkaloids are extensively bound by serum proteins and blood components and are rapidly cleared from the plasma and concentrated in various tissues. The disposition is triphasic,90,248 with a rapid initial half-life (t1/2α less than 5 minutes), t1/2β of 1 to 2 hours, and t1/2γ of 1 to 3 days. They approximate total body water in their distribution. The major route of excretion is hepatic,249 with appreciable amounts appearing in the stool, and liver disease may necessitate a change in dosage. A small component of excretion is urinary. Although similar in structure, the vinca alkaloids have substantially different profiles of toxicity. Vincristine is predominantly associated with neurologic side effects, including a range of peripheral sensorimotor neuropathic changes, autonomic neuropathy, jaw pain, and central nervous system effects. Less commonly vincristine causes myelosuppression, gastrointestinal effects, alopecia, and the syndrome of inappropriate ADH production. By contrast, vinblastine is associated with predominant myelosuppression (in particular granulocytopenia), more marked gastrointestinal toxicity (especially paralytic ileus), and alopecia; the neurologic toxicities, while quite prominent, occur less frequently and less severely than for vincristine. Both agents are significant vesicants. The vinca alkaloids have had particular application in the treatment of advanced germ cell tumors,250,251 small cell cancer of the prostate, and in bladder cancer (vinblastine, in particular)252 but appear to have less single agent activity in the treatment of prostate adenocarcinoma, adrenal carcinoma, and renal carcinoma. As noted earlier, the vinca alkaloids have substantial clinical activity against the urologic malignancies, in particular germ cell tumors and urothelial malignancy. For this reason, the development of new vinca alkaloids with a higher degree of experimental antitumor activity is of interest. A potentially promising new agent in this class is vinorelbine (Navelbine), which has been under investigation in Europe and has recently been introduced into the United States. The compound is 5′-noranhydrovinblastine. Although it shares the mode of action of the other vinca alkaloids, discussed earlier, in experimental systems it has less affinity for axonal microtubules compared with its affinity for the microtubules of the mitotic spindle. This indicates the possibility that it might produce interruption of mitosis at concentrations that would not give rise to neurotoxicity.253 It has also shown a higher degree of activity than vincristine or vinblastine against some experimental tumors.254,255 In phase I testing, neutropenia was the dose-limiting toxicity, and the maximam tolerated dose (MTD) was 35 mg/m2/week. It did give rise to peripheral neuropathy at higher doses, but this was
relatively mild.256 An initial study of the pharmacokinetics by Bore et al.,257using tritiated vinorelbine and also a radioimmunoassay, showed a low urinary excretion based on elimination. The primary excretion route was the feces, with 34% to 58.4% of the total dose being excreted by this route over a period of 21 days.257More recently, Rowinsky et al.258 published the results of a bioavailability study in which the drug was given intravenously and orally to the same patients. Bioavailability was 27% ± 14%. The volume of distribution was large, 20.02 ± 8.55 l/kg, and the terminal phase half-life was 18 hours. Plasma decay was triphasic.258 Vinorelbine has activity in HRPC259 but has not produced impressive results in limited trials in patients with testicular germ cell tumors, renal cell carcinoma, or urothelial cancer.204,260 The activity of vinorelbine in PC is apparently increased by the concurrent administration of estramustine but with the consequent side effects attributable to the estrogenic effects of that drug.261–263 The potential of this combination relative to other chemotherapeutic approaches in this setting remains to be determined. Taxanes A very important new class of drugs that is being extensively evaluated in a broad spectrum of tumor types is the taxanes. The two FDA-licensed drugs in this class are paclitaxel and docetaxel; the structures are shown in Figure 4-3. Paclitaxel is extracted from the bark of the western yew tree264; and, initially, this severely limited the supply of the drug for investigation. Compounded by the low water solubility of the drug, this slowed the development of the drug. However, these difficulties were overcome because of the interest generated by the high degree of activity of the drug in experimental systems and because the drug was shown to have a unique mode of action.265–270 The drug acts on the microtubules, but unlike the vinca alkaloids, which also interact with microtubules, the taxanes stabilize the microtubule. It has been shown that a microtubule is in dynamic equilibrium with the tubulin heterodimers, which make up its structure. These associate at one end and dissociate at the other. The action of the vinca alkaloids is to prevent the tubulin from binding and thus the microtubules undergo spontaneous disassembly. The action of the taxanes is the opposite. The microtubule is stabilized, so that growth continues by association of tubulin but disassembly does not occur. Thus the cell becomes filled with a tangle of elongated but functionally useless microtubules, leading to cell death. Paclitaxel has undergone very extensive testing and is approved for use in ovarian carcinoma271 and lung cancer. In phase I studies, it was initially given by short infusion.272,273 However, acute allergic reactions and
66
Part I Principles of Urologic Oncology
O R O
C
O O
R
O
R
R C NH C
CH
H
OH
C
O
OH
R HO
O
R=CH3
O O
C C
R
O
1
O HO H
CH3
O NH
H
HO O
O
H
CH3
O H
H3C H3C
OH H CH3
OH H3C
H
CH3
O
O
O
H O O H
O
CH3 2
Figure 4-3 Structures of paclitaxel (1), docetaxel (2).
disturbances of cardiac rhythm led to progressive lengthening of the infusion time to 24 hours, which became the standard for administration of the drug. When given by 24-hour infusion, the MTD was 200 to 275 mg/m2 given every 3 weeks. The dose-limiting toxicity was neutropenia, which was often profound but short lived and which relatively uncommonly led to toxic death.274 Other toxicities, as noted above, included acute cardiac effects (mainly arrhythmias), hypersensitivity reactions, peripheral neuropathy, and gastrointestinal toxicity. In a phase I study in leukemia,275 in which grade IV myelosuppression was accepted as routine, mucositis was the dose-limiting toxicity at a dose of 390 mg/m2. Total alopecia was another feature, and it involved the hair on the head, body hair, and eyelashes. It was subsequently recognized that paclitaxel-related cardiac arrhythmias276 (and in particular bradycardia, the most common of the paclitaxelrelated arrhythmias) are clinically less dangerous than initially feared. With suitable premedication with steroids, H1 and H2 histamine antagonists, the drug can be safely given by a 3-hour infusion.277 This markedly reduces the myelosuppression without apparently reducing the antitumor effect.278,279 One-hour infusion of the
drug is currently under evaluation. These developments are important in enabling the drug to be given on an outpatient basis. The pharmacokinetics of paclitaxel were evaluated during the early clinical studies using high performance liquid chromatography (HPLC) assay for the drug. Both a biphasic and a triphasic plasma decay have been described, with the terminal phase half-life being in the range of approximately 4 to 7 hours for the biphasic plasma decay and in the range of approximately 10 to 50 hours where a gamma phase was described.280 The earlier studies reported linear pharmacokinetics, but recent reports have indicated nonlinear pharmacokinetics with shorter infusions. Volumes of distribution have been variable in the reported studies and have been generally in the range of 50 to 100 l/m2; however, very large volumes of distribution have been described in the study reported by Huizing et al.281 Very little of the drug is eliminated unchanged through the kidneys and systemic clearance appears to result from metabolism, biliary excretion, and binding to tissue components. The main route of metabolism is by cytochrome P450-dependent hydroxylation, the principal hydroxylated metabolite in bile being 6-hydroxy paclitaxel.282 Of interest, cisplatin
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 67
given first in combination with paclitaxel is more toxic than the reverse sequence. This appears to be related to the fact that cisplatin inhibits the metabolism of paclitaxel, causing an increase in the area under concentration × time curve (AUC) of the latter drug.283 For the same schedule of administration, the degree of myelosuppression is related to the total drug exposure as measured by the AUC. A shorter infusion gives less toxicity for the same AUC than a longer infusion, suggesting that duration of exposure to a minimum cytotoxic concentration may be an important factor in the toxicity of the drug.284 Paclitaxel has shown antitumor activity in early studies of germ cell tumors and transitional cell carcinoma of the urothelium. Patients with germ cell tumors, with prior therapy, showed a 24% response rate to paclitaxel 250 mg/m2 24-hour infusion with 2 CR and 4 PR in 25 patients.285 Previously untreated patients with transitional cell carcinoma of the urothelium received the same dose and schedule of paclitaxel and showed a 42% response rate.286 Studies in renal cell carcinoma have been negative.287 Early studies with paclitaxel in HRPC show modest single agent activity,288 and subsequent trials have examined the potential of adding other agents to the taxanes including estramustine and carboplatin (see later).185,289 Docetaxel (taxotere, Figure 4-2) is a synthetic analog of paclitaxel that is prepared from 10 diacetyl baccatin III, a compound extracted from the needles of the European yew tree, Taxus baccata. It is thus derived from a biologically renewable source. It is more potent in vitro than paclitaxel.290 Although its mode of action is similar, it is reportedly active against cells, which are resistant to paclitaxel.290 It has undergone phase I testing in 1-hour, 2-hour, 6-hour, and 24-hour infusions291–293 and as a 1hour infusion daily for 5 days.294 The MTD ranged from 70 to 115 mg/m2, and neutropenia was dose limiting in all of the studies, although mucositis was also a major toxicity in the study of the 24-hour infusion.293 It has been suggested that anaphylactic reactions are less common with docetaxel than with paclitaxel but that skin toxicity may be more marked. Plasma decay is triphasic with a gamma phase t1/2γ of 11.8 ± 6.7 hours.292 Docetaxel has activity in HRPC,295 where it is currently most commonly combined with estramustine,296–298 urothelial cancer,299 penile cancer, and testis cancer. It has limited activity in renal cell carcinoma.300 At present, it is difficult to be dogmatic regarding the respective merits of paclitaxel and docetaxel with respect to antitumor efficacy, but it is quite clear that they have different spectra of toxicity. Estramustine Estramustine is constituted by the carbamate linkage of estradiol and nor-nitrogen mustard molecules and is
therefore best considered a combination hormonalcytotoxic therapy. However, the mechanism by which estramustine exerts its antineoplastic effect is unclear. Following oral ingestion estramustine phosphate is rapidly dephosphorylated and absorbed with a bioavailability of 37% to 75%.301 Concurrent ingestion of calcium rich foods, such as dairy products, can interfere with estramustine absorption.302 After absorption estramustine is metabolized to estromustine, which is preferentially taken up by and retained in prostate tissue and PC cells by estramustine-binding protein.303 Estramustine is metabolized in the liver and excreted in the bile with very minimal renal excretion.301 The terminal half-life of estromustine is 10 to 20 hours.301 As a single agent, estramustine has not demonstrated benefit over continued or alternate hormonal therapy in PC.304 However, in combination with selected cytotoxic agents, the current clinical wisdom is that estramustine appears to contribute to increased response,259,305–307 although this has not been proven in well-structured trials. While the mechanism for this is unclear, the effect of estramustine may occur through a phase activation of PC cells so that they are more sensitive to subsequent or concurrent cytotoxic effect. Estramustine alters cellular microtubular configuration and may have synergy with other drugs that act on microtubules such as taxanes (paclitaxel, docetaxel) and vinca alkaloids (vincristine, vinblastine, and possibly vinorelbine).305,308–310 Recent reports from phase I and phase II trials suggest that the combination of estramustine and docetaxel is well tolerated and produces a decrease of >50% in serum PSA in around 50% of HRPC cases treated.296,297,311–315 Given significant estrogenic side effects related to estramustine therapy, particularly thromboembolic phenomena, its place in combination therapy with cytotoxic agents for HRPC still requires proof of efficacy over the cytotoxic agents alone, as well as the optimization of dose and scheduling to minimize toxicity. Alkylating Agents The alkylating agents are a group of chemical compounds of diverse structure, which share the common property of labile, electrophilic alkyl groups that can react with most biologic molecules to form adducts. The alkyl groups can be added to oxygen, nitrogen, phosphorus, or sulfur atoms, and thus can function at extremely diverse sites. However their most important reactions are with the nitrogen atoms of DNA, particularly the N7 position of guanine residues, altering the structure or function of the DNA. These drugs are all cell cycle dependent, but not cell cycle specific; that is, they exert their effects on cells throughout the cell cycle (analogous to radiation). They appear most active against rapidly proliferating cells. Agents included in this group include
68
Part I Principles of Urologic Oncology
cyclophosphamide, ifosfamide, thiotepa, melphalan, nitrogen mustard, busulfan, chlorambucil, and the nitrosoureas. The alkylating agents, through their common mechanism of action, are potentially cytotoxic and carcinogenic. Although sharing common functional traits, differences in their chemical structures account for the variation in their pharmacologic characteristics. This is of particular importance as an explanation for why crossresistance may not occur in all situations. Cyclophosphamide Cyclophosphamide is 2-bis-(2-chloroethyl)aminotetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide monohydrate, a cyclic phosphamide ester of nor-nitrogen mustard. The monohydrate is not ionized and is lipid soluble. This agent is a bifunctional substituted nitrogen mustard, which must be activated in the liver before it is active. Its activation is a multistep process that occurs in the hepatic microsomal P450 enzyme system.83,316 There is thus no rationale to using the drug for intraarterial chemotherapy nor as an intravesically administered agent. It can be usefully administered as an oral agent (90% bioavailability) or intravenously. Hepatic inactivation is the major mechanism of active drug elimination, whereas after intravenous administration about 15% of the drug is excreted unchanged in the urine and the rest as metabolites. The plasma half-life is approximately 5 to 6 hours.316 As cyclophosphamide is bifunctional, it can cross-link the two strands of DNA, yielding an interstrand crosslink, or can produced intrastrand cross-links, or even can bind DNA to protein. The binding of the active metabolite of cyclophosphamide to DNA does not cause cell death per se; rather the cells progress slowly through the S phase and arrest and subsequently die in the G2 phase. Information regarding potential drug interactions with cyclophosphamide is relatively scant. As it must be metabolized by hepatic microsomes to be active, drugs, which induce this system (such as the barbiturates, phenytoin, and carbamazepine) may increase the conversion of cyclophosphamide to its metabolites; similarly cyclophosphamide may have an impact on the activity of the barbiturates. It has also been reported that cimetidine increases the toxicity of cyclophosphamide via a change in the concentration × time relationship of its active metabolites.317,318 Cyclophosphamide produces significant leukopenia and immunosuppression but is not usually associated with thrombocytopenia.83,89 Nausea and vomiting may occur, although usually in association with high dose intravenous usage. Similarly alopecia is more commonly associated with high dose administration. Of particular importance, excretion of acrolein, one of the metabolites,
which is particularly irritating to the bladder mucosa, can cause hemorrhagic cystitis, and this can lead to bladder fibrosis or even transitional cell carcinoma of the bladder. In the context of intravenous administration, this toxic effect can be avoided by the use of sodium-2-mercaptoethane sulfonate (MESNA), which is excreted in the urine, providing reactive thiols that bind to the acrolein, protecting the bladder mucosa. Occasionally, cyclophosphamide may cause interstitial pneumonitis, gonadal atrophy, anaphylaxis, and in higher doses, the syndrome of inappropriate ADH production and cardiotoxicity (including acute cardiac necrosis when given in transplant-intense dosage). The most common application of cyclophosphamide for genitourinary cancer is in the treatment of adenocarcinoma of the prostate,64,65 and it has also been used in the past in the treatment of advanced germ cell tumors.250,319 It is less frequently used for germ cell tumors in current practice because of the risks of carcinogenicity and infertility. The drug is inactive in the treatment of renal and adrenal carcinomas and has only limited activity in the treatment of bladder cancer. Ifosfamide Ifosfamide is a structural analog of cyclophosphamide, differing only in the position of one of the two chloroethyl groups. It is also a metabolically activated alkylating agent and must first undergo hydroxylation by hepatic microsomes.316 However, the change in its structure has resulted in changed pharmacology, and its activation within the liver occurs more slowly than for cyclophosphamide. Ifosfamide is well absorbed orally and can also be administered intravenously. Its pharmacology is similar to that of cyclophosphamide. Its plasma half-life has been reported to be as short as 5 to 6 hours, either after oral or intravenous administration,82,320 although Creaven et al.81 documented a plasma half-life of radioactively labeled ifosfamide of nearly 14 hours. In current clinical practice, it is most commonly administered intravenously, with schedules varying from a single infusion, to multiple-day schedules, with MESNA coverage to prevent hemorrhagic cystitis. Creaven et al.81 have suggested that the alkylating activity ratio of ifosfamide is 1:5, when compared to cyclophosphamide. The pattern of toxicity is similar to that of cyclophosphamide,81 but with less myelosuppression and a greater tendency to cause cystitis. In addition, ifosfamide has a greater prevalence of central nervous system toxicity, including altered mental status, cerebellar dysfunction, seizures, and extrapyramidal effects.81,321,322 It is not really clear whether there is a definite dose-response relationship for ifosfamide, and thus an optimal dose has not been defined.
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 69
Ifosfamide is currently used in salvage and high-risk regimens for advanced germ cell tumors323–235 and for metastatic urothelial cancer.326–328 In broad-based phase I and phase II trials, little activity has been reported in PC, although the drug has not been assessed since PSA has been introduced as a surrogate marker of response. Ifosfamide is inactive in renal carcinoma, but single agent activity has been identified in squamous cell carcinoma, including cancer of the penis.
O
O O O O O H O O O
Thiotepa N,N′,N′′-triethylenethiophosphoramide (thiotepa) is an aziridine drug, a polyfunctional alkylating agent, which can produce interstrand cross-links, DNA adducts and strand breaks, and a range of other DNA lesions.329 After IV injection the t1/2α was 7.7 minutes and the t1/2β 25 minutes in the study by Cohen et al.330 Thiotepa is administered by intravenous or intracavitary routes, the latter including intraperitoneal, intrathecal, and intravesical delivery. It is not a vesicant and does not cause local soft tissue reactions. In the standard dose range, thiotepa is associated with myelosuppression, both granulocytopenia and thrombocytopenia, as well as nausea, vomiting, headache, and occasionally alopecia. In transplant-intense doses, thiotepa may cause mucositis, cutaneous changes, and occasional organic brain syndrome.331 When administered intravesically, thiotepa causes little systemic toxicity unless used within a few days of extensive transurethral resection; thiotepa, a relatively small molecule, is absorbed significantly through an extensively denuded bladder surface. The major clinical application for thiotepa has been in the intravesical chemotherapy of superficial bladder cancer,67 although this agent is now used less frequently because of its risk of carcinogenicity and the development of more effective treatment options. Epipodophyllotoxins Podophyllotoxin, a derivative of the mandrake root, has been known to have antimitotic properties for more than half a century, and extracts of the mandrake root have been used for medicinal purposes for centuries.332 Although the early podophyllotoxin derivatives were excessively toxic, two derivatives (etoposide and teniposide) have shown substantial clinical activity with a tolerable profile of side effects.332–334 Although initially believed to act by binding to tubulin and inhibiting microtubule assembly, additional studies have suggested that the epipodophyllotoxins arrest cells in late S phase or early G2 phase,335 rather than at G2M. More recently, these agents have been shown to exert their anticancer effects by impeding the function of the topoisomerase II enzyme.336
O
H
O
O O
Figure 4-4 Structure of etoposide.
Each compound has a complex structure composed of a multiringed structure linked to a glucopyranoside sugar (see etoposide structure in Figure 4-4). Both drugs are routinely administered intravenously, although etoposide is now formulated for oral administration. The optimal schedule of administration has not been defined, although prolonged schedules (multiple daily short infusions or continuous infusion) are most commonly employed because of the phase-specific mode of action. The pharmacokinetics is biphasic, with half-life values of 90 minutes and 3 to 11 hours.334 After administration of radiolabeled etoposide to humans, 40% to 90% of radioactivity is recovered in the urine within 48 hours, fecal recovery is less than 20%, and biliary excretion is only minimal.332. The major toxicity of the epipodophyllotoxins is doserelated myelosuppression, with predominant leukopenia.333 Gastrointestinal complications, such as nausea, vomiting, and anorexia are usually mild. Other side effects include alopecia, headache, fever, and hypotension. Severe hypotension may occur if the drug is infused too rapidly, and this can occasionally be accompanied by bronchospasm or rarely by anaphylaxis. It is believed that these allergic phenomena may be due to the use of the diluent, cremophor. Etoposide phosphate, a watersoluble derivative that is rapidly hydrolyzed to etoposide in the plasma, is currently undergoing clinical trial. Recently there has been emerging information that etoposide is occasionally associated with iatrogenic acute myeloid leukemia, and such cases have now been recorded among patients cured of germ cell tumors.180 The indications for the use of the epipodophyllotoxins for genitourinary cancer are relatively limited, with the most common application being in the management of advanced germ cell tumors.250,251 Most studies have sug-
70
Part I Principles of Urologic Oncology
gested that there is only very limited activity against bladder cancer and prostatic adenocarcinoma, although there is a clear role for this drug in the treatment of small cell anaplastic PC. Etoposide is inactive in the treatment of renal carcinoma, and only scant data are available with respect to penile and adrenal cancers. Antimetabolites Antifolates The role of the antimetabolites in cancer treatment was first explored 50 years ago with the investigation of aminopterin, an analog of folic acid. This early work gave rise to the development of methotrexate, the 4-amino, 10-methyl analog of the parent compound, which has come to be one of the most widely used agents for the genitourinary cancers. Methotrexate inhibits dihydrofolate reductase (DHFR), an important enzyme in folic acid metabolism, which catalyzes the reduction of dihyrofolate to tetrahydrofolate. DHFR maintains the intracellular reduced folate pool, which in turn is required for the synthesis of thymidine and purines and thus for the production of DNA, RNA, and protein. Methotrexate undergoes polyglutamation intracellularly to varying extents; the polyglutamated forms do not traverse cellular membranes. Polyglutamation occurs to a greater extent in tumor cells than in normal cells, and this may explain the selective action of the drug. The polyglutamated form is retained preferentially within cells, sometimes for very lengthy periods337 and can directly inhibit other folate-dependent enzymes, including thymidylate synthase.338 Methotrexate may also cause single- and doublestranded breaks in DNA.339 It is most active against rapidly proliferating cells and appears to exert its major effect during S phase; and is thus classified as a cell cycle phase-specific antimetabolite. Methotrexate uses the same active transport mechanisms to enter cells as does folic acid. At least two such mechanisms have been identified, including a low-affinity carrier that transports methotrexate and reduced folates and a high-affinity system, which is more avid for reduced folates than for methotrexate. The metabolic block induced by methotrexate can be circumvented by the use of calcium leucovorin, which feeds into the folic acid cycle beyond the block of DHFR. Calcium leucovorin and its metabolite, 5-methyltetrahydrofolate, share the latter common transport mechanism with methotrexate. It appears that normal cells can be selectively rescued by calcium leucovorin, either because of differences in transport or because of differences in the rate of DNA synthesis between normal and cancer cells. The complex biochemistry of methotrexate, its reversal and mechanisms of resistance, is beyond the scope of this chapter but has been detailed elsewhere.340
Methotrexate may be given by oral, intramuscular, intravenous, intraarterial or intrathecal routes. An optimal dosing route and schedule has not been defined. A broad range of parenteral dosing has been reported, with doses as varied as in the range between 50 and 15,000 mg/m2, predicated on the ability to rescue normal tissues with calcium leucovorin. Caution must be exercised as the higher dose range is potentially lethal if sufficient leucovorin is not administered. Alkalinization (as measured by assessment of the urine pH), by increasing the solubility of the drug and of the 7-hydroxy metabolite will also reduce toxicity. Methotrexate levels must be monitored after high dose treatment to determine the length of leucovorin rescue. More than 50% of the drug is bound to plasma proteins. Methotrexate is widely distributed in the body. In standard doses, methotrexate is excreted unchanged in urine, whereas in high doses some metabolism of the drug occurs. Plasma decay of methotrexate is either biphasic or triphasic,341–343 with the terminal phase of excretion having been reported to be in the range of 10 to 26 hours. Methotrexate is highly schedule dependent; its toxicity is more a function of the time during which plasma levels are maintained above a minimum cytotoxic concentration than of the total AUC. Thus any factor that can lead to a prolonged low level of drug will greatly increase its toxicity. Principal among such factors are impaired renal function and localization in “third space” compartments such as pleural effusion or ascites with a slow release into the circulation. In these situations, methotrexate must be used with caution; rescue with leucovorin employed as necessary. The spectrum of toxicity of methotrexate is a function of age, dose, the use of calcium leucovorin, drug metabolism, drug interactions, and renal function.340,344 Patients may experience no toxic effects at all. Hematologic side effects include leukopenia, thrombocytopenia, and anemia. Gastrointestinal toxicity includes nausea, vomiting, diarrhea, and stomatitis. Hepatotoxicity has been reported in patients receiving chronic low dose oral therapy and in high dose parenteral administration. Occasionally, methotrexate can cause self-limited pneumonitis. One of the most dangerous toxic effects is the induction of renal failure, as adequate renal function is necessary to ensure satisfactory excretion of the drug. Methotrexate can cause skin rash, pruritus, urticaria, alopecia, and a range of other cutaneous side effects. Less commonly, central nervous toxicity can occur, especially after intrathecal administration. Fluoropyrimidines 5-Fluorouracil (5-FU) was synthesized to act as a false pyrimidine and thus to inhibit the formation of thymidine.345 There are several proposed mechanisms of action, including inhibition of thymidylate synthase by an
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 71
active metabolite (FdUMP), incorporation of the triphosphate 5-FUTP into RNA, and incorporation of the 2′ deoxy triphosphate 5-FdUTP into DNA.346 The presence of reduced folate is critical to the function of 5-FU in inhibiting thymidylate synthase. Gastrointestinal tumors with increased expression of thymidylate synthase, with or without increased levels of the metabolizing enzymes, thymidine phosphorylase, and dihydropyrimidine dehydrogenase, tend to be resistant to fluoropyrimidines.347 Testing for expression levels in individual tumors may identify genitourinary cancers with susceptibility to this group of drugs, but further testing of this hypothesis is required.348 5-FU can be administered by oral, intravenous, intraarterial, or intraperitoneal routes. Bioavailability is poor and erratic when the drug is given by mouth,349 and this route of administration is no longer used (however, see following discussion on modulation and capecitabine). When given intravenously the drug has an extremely short terminal phase half-life measured in minutes.73,350 This is due to its rapid degradation by dihydrouracil dehydrogenase (DHD) to 5,6-dihydro 5-FU that then undergoes ring rupture and is degraded to small molecules.346 A rare deficiency of this enzyme can lead to severe toxicity following administration of 5-FU.346 Because of its mode of action, 5-FU is an S-phase specific drug and this combined with its extremely short halflife would lead one to anticipate that it would be highly schedule dependent. However, paradoxically, rapid infusions of 5-FU are more toxic than the same dose given over a period of several hours. This is probably due to the fact, although that the drug itself has an extremely short plasma half-life, the persistence of the active metabolite FdUMP intracellularly is measured in days.351 The bolus injection of the drug probably temporarily exceeds the capacity of DHD, thus making drug available for conversion to active metabolites. The nucleoside derivative of 5-FU, 5-fluoro2′-deoxyuridine (FUdR, floxuridine) is extremely schedule dependent. The dose that can be given by short-term infusion is approximately three orders of magnitude greater than the dose that can be given when the drug is given by a long-term continuous infusion.352 A number of compounds have been used in conjunction with fluoropyrimidines to enhance their activity through biochemical modulation. These include interferon, PALA (N-phosphonoacetyl-L-aspartate), and leucovorin.353 Of these, leucovorin has been the most extensively investigated and has proven to be the most clinically useful by raising the response rate to 5-FU in colorectal cancer by a factor of about three.354 It acts by leading to stabilization of the ternary complex formed between the active metabolite FdUMP, the active site of the enzyme thymidylate synthase, and a reduced folate cofactor (5, 10 methylene tetrahydrofolate), which is derived from leucovorin.355 An investigational modulator eniluracil has been evaluated in a clinical trial setting.356–358 This compound, which
inhibits DHD, decreases the first-pass effect and enables 5-FU to be given orally. Capecitabine is an orally bioavailable prodrug of 5-FU.359 It is generally administered on a twice-daily basis either continuously or with a week-off therapy every 3 or 4 weeks. After absorption capecitabine is metabolized by hepatic carboxylesterase to 5′-deoxy-5-fluorocytidine and then converted to 5′-deoxy-5-fluorouridine by cytidine deaminase, which is also present in the liver.76 5′-Deoxy-5-fluorouridine then enters cells and is metabolized by thymidine phosphorylase to 5-FU. The result is a cellular 5-FU concentration that exceeds that achieved in the serum and surrounding normal tissue.76 Capecitabine has been evaluated as a potential alternative to 5-FU infusion in a number of cancer types.360.361 It has modest activity in renal cell carcinoma,362,363 but is yet to be fully evaluated in other genitourinary cancers. The primary toxicities of the fluoropyrimidines are gastrointestinal toxicity, stomatitis and diarrhea, and myelosuppression. The pattern of toxicity varies with the schedule of administration and is also influenced by the presence of modulators. Weekly bolus 5-FU produces mainly myelosuppression (primarily leukopenia). Loading dose 5-FU, prolonged infusions, and 5-FU used with leucovorin produce primarily gastrointestinal toxicity; cerebellar toxicity and cardiotoxicity have been described364 but are uncommon at standard doses. Capecitabine may produce tenderness and desquamation of the hands and feet (the so-called hand-foot syndrome), in addition to the side effects seen with other fluoropyrimidines. Gemcitabine A new pyrimidine antimetabolite, 2′deoxy-2′difluorocytidine (gemcitabine), has recently been introduced into clinical practice for urothelial and a range of other tumors. In preclinical systems gemcitabine showed very significant activity against experimental solid tumors365 and human tumor xenografts.75 Its structure is shown in Figure 4-5. Like cytosine arabinoside, an antimetabolite which it resembles structurally, it is activated intracellularly to the triphosphate, 2′deoxy-2′difluoro-cytidine 5′-triphosphate (dFdCTP), and in this form is incorporated into DNA.366–368 Gemcitabine entry to cells requires the presence of the nucleoside transporter system, with cells deficient in this transporter being gemcitabine resistant.366 The presence of dFdCTP within the cells inhibits its own degradation via deamination by deoxycytidine deaminase and promotes 2′deoxy-2′difluoro-cytidine phosphorylation by deoxycytidine kinase (dCK), at least in part by ribonucleotide reductase (RR) inhibition. Forced overexpression of cytidine deaminase,369 increased expression of RR370 and decreased expression of dCK371,372 are associated with decreased sensitivity to gemcitabine in cell line systems. The antineoplastic effect of gemcitabine derives, in part, from
72
Part I Principles of Urologic Oncology
NH2 N N HOCH2 O F
OH
F
Figure 4-5 Structure of gemcitabine.
dFdCTP incorporation into DNA instead of dCTP by polymerases involved in repair.373 However, RR is an S-phase specific, potentially rate-limiting enzyme for DNA synthesis. The activity of gemcitabine is cell cycle specific with blockade at the G1/S phase transition, perhaps suggesting that RR inhibition is an important contributor to gemcitabine antineoplastic effect. In the initial phase I clinical trial, the drug was given over a 30-minute infusion weekly for 3 weeks every 4 weeks. The maximum tolerated dose was 790 mg/m2 with myelosuppression, predominantly thrombocytopenia and anemia, being the dose-limiting toxicity.374,375 Other toxicities have been relatively mild. However, subsequent studies have shown that considerably higher doses can be given safely, particularly to patients with little or no prior therapy. In patients with nonsmall cell lung cancer and no prior therapy, O’Rourke et al.376 found that 2500 mg/m2 given over 4 hours every 2 weeks was below the MTD. Initial pharmacokinetic studies showed a rapid elimination of the drug with a median half-life of 8 minutes. The drug was rapidly converted to the corresponding uracil metabolite 2′,2′-difluorodeoxyuridine, which had a longer half-life, with a median of 14 hours. The active metabolite 2′,2′-difluorodeoxycytidine triphosphate was analyzed in circulating mononuclear cells. A peak was observed within 30 minutes of the end of the infusion and increased with dose up to a dose of 350 mg/m2. Beyond this dose, there was no increase in the active metabolite indicating saturation of the activation to the triphosphate.366 Subsequent study suggests that infusion of gemcitabine at a fixed dose rate of 10 mg/m2/minute produces an optimal cellular level of active metabolite.377,378 Infusion rates faster than this may result in a lower cellular exposure (area under the concentration curve concentration) of 2′,2′-difluorodeoxycytidine triphosphate by exceeding the rate at which the nucleoside transporter system and/or which the enzymes involved in producing this active metabolite
can act.378–381 The net result of faster infusions is that the maximal 2′,2′-difluorodeoxycytidine triphosphate concentration is achieved for a shorter time with the additional amount of drug wasted therapeutically but potentially contributory to side effects. On this basis and given that fixed dose rate infusion at 10 mg/m2/minute does not produce more toxicity than more rapid infusion, administration of gemcitabine in this manner is standard practice. Antitumor activity for gemcitabine against bladder cancer was noted in the phase I study by Pollera et al.382 in 14 patients receiving gemcitabine at doses greater than 875 mg/m2, they observed 1 CR and 2 PR. A response rate of 28% was observed in a phase II trial in previously untreated patients with bladder cancer.383 Subsequently, the combination of gemcitabine and cisplatin was assessed in a phase II trial with a response rate of 41%.384 This combination was then compared to MVAC in a randomized phase III trial and found to produce equivalent response and survival with better quality of life.375 De Mulder et al.385 noted response rate of 8.1% or 3 of 39 patients who could be evaluated in a phase II study of gemcitabine in renal cell carcinoma, with durable responses exceeding 12 months in 2 patients. Subsequently, researchers at the University of Chicago have reported on combination of gemcitabine with 5-FU in RCC with possible improved survival over historical controls and response rate of 17%.386 This study is currently being replicated with dose-scheduling variation and the incorporation of capecitabine instead of 5-FU. Phase II studies in PC are ongoing, but highly preliminary data suggest that gemcitabine may have some palliative benefit in the absence of major falls in serum PSA concentration,387 Gemcitabine has some activity in chemo-refractory testicular cancer388,389 and this is being pursued in further clinical trials. CAMPTOTHECINS An important group of drugs under active clinical development are analogs of camptothecin. Camptothecin was isolated from extracts of the Japanese tree Camptotheca acuminata by Wall et al.390 and shown to be active in experimental leukemia and some solid tumors. The structure of the camptothecins incorporates five rings (Figure 4-6). The fifth, or E, ring can exist in a closed ring lactone or an open ring hydroxy acid form. The closed ring form of camptothecin is highly water insoluble; however, the sodium salt of the open ring hydroxy acid form is water soluble. It was in this form that the compound was introduced into early clinical trials in the late 1960s. Phase I trials showed that the compound gave rise to substantial gastrointestinal toxicity and myelosuppression and also had a tendency to produce hemorrhagic cystitis.391,392 It showed antitumor activity
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 73
R3
R2
O
R1
N N
CH3CH2 OH
R1
O
R2
R3
O Irinotecan
Topotecan
N
N
C
O
OH
H
CH3CH2
(CH3)2NCH2
H
Figure 4-6 Structures of irinotecan (CPT-11), topotecan.
in the phase I studies, but a subsequent phase II study in gastrointestinal malignancies proved to be negative,393 and development of the compound was halted. Work continued in the laboratory on the mode of action of this compound, which proved to be unique.394–398 The compound combines with a cleavable complex formed between DNA and the enzyme topoisomerase I, an enzyme important in relieving the torsion that develops as the strands of DNA unwind for replication and transcription. The role of topoisomerase I is to cleave one of the strands of the DNA, thus allowing the supercoiled DNA to unwind. The combination of camptothecin with the cleavable complex prevents the resealing of the DNA and thus causes single-strand DNA breaks.397,399 Mutations in topoisomerase I mutations alter both DNA cleavage and unwinding, as well as the interaction with camptothecin.400 The identification of this unique mode of antitumor action stimulated the development of analogs of camptothecin that would be more soluble and more active. It was shown that the closed ring form of the E ring is essential for activity, being several orders of magnitude more active than the hydroxy acid form.401 This may account for the variable activity of camptothecin, which as noted above, was given as a sodium salt of the open ring hydroxy acid form. Several compounds were developed as analogs of camptothecin; to date, the two most important are irinotecan (CPT-11) and topotecan. The structures of these are shown in Figure 4-6.
Irinotecan Irinotecan is 7 ethyl 10[4-(1 pyridino)-1-pyridino] carbonoxy camptothecin. It is the most extensively evaluated of the newer camptothecins. In phase I studies, the drug showed major toxicities of leukopenia, nausea, and vomiting and diarrhea.402 On a weekly schedule the recommended dose for phase II studies was 100 mg/m2/week,403 and when intermittent doses were administered every 3 weeks,404 the recommended dose was 240 mg/m2. With intensive treatment of diarrhea with loperamide, dosing up to 750 mg/m2 every 3 weeks has been reported.405,406 A variety of other schedules have been reported, including a single dose every 4 weeks, 5-day continuous infusion every 3 to 4 weeks, and daily 3× every 3 weeks.402 CPT-11 is virtually inactive in vitro. To be activated, it must be hydrolyzed to 7-ethyl-10-hydroxy camptothecin (SN38), which is 3 orders of magnitude more active than the parent drug.407 Consequently, pharmacokinetic studies of the drug require the measurement of the total and the lactone forms of both CPT-11 and SN38. No relationship between nonmyeloid toxicity and any pharmacokinetic parameter was found in the study of Rowinsky et al.404 A relationship between AUC of total SN38 and percent decrease in absolute neutrophil count (ANC) was found using a sigmoidal Emax model. Irinotecan is still undergoing early phase trials in the genitourinary malignancies. The Southwest Oncology Group is conducting a phase II trial for patients with
74
Part I Principles of Urologic Oncology
advanced bladder cancer, and other studies in PC are ongoing. We are not aware of published data with respect to the utility of this agent in renal and other genitourinary cancers. Topotecan Topotecan is a semisynthetic water soluble camptothecin analog, which in preclinical systems is active against experimental tumors and against human xenografts. In early phase I trials, the drug was given daily for 5 days every 3 or 4 weeks.408,409 On this schedule, the doselimiting toxicity was neutropenia, and the recommended dose for phase II studies was 1.25 to 1.5 mg/m2. Subsequent studies have evaluated infusions of from 24 hours up to 21 days.410–412 With the 24-hour infusion, a dose of 1.5 mg/m2/week was recommended for phase II evaluation. Thrombocytopenia was more marked than neutropenia in the 21-day infusion study (MTD of 0.53–0.6 mg/m2/day in patients previously treated with cytotoxic therapy and 0.8 mg/m2/day in chemotherapy naïve patients). Of interest, granulocyte-colony stimulating factor (G-CSF) did not permit dose intensification in one study because dosing was limited by fatigue and thrombocytopenia.409 In pharmacodynamic studies, dose but not the AUC of the topotecan lactone could be related to mean percentage change in ANC by a sigmoidal Emax model. The dose required to produce a 50% decrease in ANC was 0.86 mg/m2/day, given daily for 5 days.408 Data on the activity of topotecan against genitourinary tumors is scant, but evaluation is ongoing. SUMMARY There is no current consensus on the optimal strategy for the clinical use of chemotherapy against cancers of the genitourinary tract. The most common approach has been to use combination regimens in preference to single agents, predicated largely on the success of combination chemotherapy for a variety of other solid tumors. There is no doubt that the introduction of the combination of cisplatin, etoposide, and bleomycin revolutionized the management of advanced germ cell tumors, providing a cure rate of up to 90%, compared to a cure rate of less than 40% with single agent treatment. Similarly, after several years of clinical development of combination regimens for bladder cancer, a seminal randomized trial revealed a survival benefit from the combination of MVAC compared to cisplatin alone in this context. A further landmark trial demonstrated that the combination of gemcitabine and cisplatin was equivalent in efficacy to MVAC but less toxic. Mitoxantrone has an established role in improving symptoms and quality of life in HRPC, while taxane-based combinations may provide a further
advance or at worst a further option in patients with this stage of disease. By contrast, randomized trials have not proved a role for combination chemotherapy in renal carcinoma and clinical practice in this areas is still in an early stage of evolution. At present, one of the major investigational emphases is the combination of conventional and novel cytotoxic agents with biochemical and biologic modulators that target the effectors of multidrug resistance, cellular regulation, and immunologic function. However, these studies are beyond the scope of this chapter on principles and applications of conventional chemotherapy. Further clinical trials to evaluate new approaches are required in the genitourinary cancers, and in particular those tumors that fail to respond to conventional firstline therapy. In addition to the need for new treatment strategies, careful definition of endpoints and appropriate design of clinical trials is essential if outcomes are to improve.
REFERENCES 1. Burchenal JH: The historical development of cancer chemotherapy. Semin Oncol 1977; 4:135–146. 2. Steel GG, Lamerton LF: Cell population kinetics and chemotherapy. I. The kinetics of tumor cell populations. Natl Cancer Inst Monogr 1969; 30:29–42. 3. Bassukas ID: Comparative Gompertzian analysis of alterations of tumor growth patterns. Cancer Res 1994; 54:4385–4392. 4. Ferrante L, Bompadre S, Possati L, Leone L: Parameter estimation in a Gompertzian stochastic model for tumor growth. Biometrics 2000; 56:1076–1081. 5. Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996; 86:353–364. 6. Hanahan D, Weinberg RA: The hallmarks of cancer. Cell 2000; 100:57–70. 7. Shackney SE, McCormack GW, Cuchural GJ, Jr: Growth rate patterns of solid tumors and their relation to responsiveness to therapy: an analytical review. Ann Intern Med 1978; 89:107–121. 8. Nurse P: A long twentieth century of the cell cycle and beyond. Cell 2000; 100:71–78. 9. Nurse P: Cyclin dependent kinases and cell cycle control (Nobel lecture). Chembiochem 2002; 3:596–603. 10. Weinberg RA: The retinoblastoma protein and cell cycle control. Cell 1995; 81:323–330. 11. Sherr CJ: The Pezcoller lecture: cancer cell cycles revisited. Cancer Res 2000; 60:3689–3695. 12. Ishida S, Huang E, Zuzan H, et al: Role for E2F in control of both DNA replication and mitotic functions as revealed from DNA microarray analysis. Mol Cell Biol 2001; 21:4684–4699. 13. Wu L, Timmers C, Maiti B, et al: The E2F1-3 transcription factors are essential for cellular proliferation. Nature 2001; 414:457–462.
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 75 14. Massague J, Blain SW, Lo RS: TGFbeta signaling in growth control, cancer, and heritable disorders. Cell 2000; 103:295–309. 15. Reynisdottir I, Massague, J: The subcellular locations of p15(Ink4b) and p27(Kip1) coordinate their inhibitory interactions with cdk4 and cdk2. Genes Dev 1997; 11:492–503. 16. Cordon-Cardo C: Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol 1995; 147:545–560. 17. Sherr CJ, Roberts, JM: CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 1999; 13:1501–1512. 18. Serrano M, Hannon GJ, Beach D: A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993; 366:704–707. 19. Toyoshima H, Hunter T: p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 1994; 78:67–74. 20. Alevizopoulos K, Vlach J, Hennecke S, Amati B: Cyclin E and c-myc promote cell proliferation in the presence of p16INK4a and of hypophosphorylated retinoblastoma family proteins. EMBO J 1997; 16:5322–5333. 21. Prall OW, Rogan EM, Musgrove EA, Watts CK, Sutherland RL: c-myc or cyclin D1 mimics estrogen effects on cyclin E-Cdk2 activation and cell cycle reentry. Mol Cell Biol 1998; 18:4499–4508. 22. Fan Z, Shang BY, LuY, Chou JL. Mendelsohn J: Reciprocal changes in p27(Kip1) and p21(Cip1) in growth inhibition mediated by blockade or overstimulation of epidermal growth factor receptors. Clin Cancer Res 1997; 3:1943–1948. 23. Peng D, Fan Z, Lu Y, et al: Anti-epidermal growth factor receptor monoclonal antibody 225 up-regulates p27KIP1 and induces G1 arrest in prostatic cancer cell line DU145, Cancer Res 1996; 56:3666–3669. 24. Li Q, Dang CV: c-myc overexpression uncouples DNA replication from mitosis. Mol Cell Biol 1999; 19:5339–5351. 25. Suzuki N, Del Villar K, Tamanoi F: Farnesyltransferase inhibitors induce dramatic morphological changes of KNRK cells that are blocked by microtubule interfering agents, Proc Natl Acad Sci U S A 1998; 95:10499–10504. 26. Moasser MM, Srethapakdi M, Sachar KS, Kraker AJ, Rosen N: Inhibition of Src kinases by a selective tyrosine kinase inhibitor causes mitotic arrest. Cancer Res 1999; 59:6145–6152. 27. Hartwell LH, Weinert TA: Checkpoints: controls that ensure the order of cell cycle events. Science 1989; 246:629–634. 28. Hartwell L H, Kastan MB: Cell cycle control and cancer. Science 1994; 266:1821–1828. 29. Park DS, Morris EJ, Greene LA, Geller HM: G1/S cell cycle blockers and inhibitors of cyclin-dependent kinases suppress camptothecin-induced neuronal apoptosis. J Neurosci 1997; 17:1256–1270. 30. Chen JG, Horwitz, SB: Differential mitotic responses to microtubule-stabilizing and microtubule-destabilizing drugs, Cancer Res 2002; 62:1935–1938.
31. Giannakakou P, Gussio R, Nogales E, et al: A common pharmacophore for epothilone and taxanes: molecular basis for drug resistance conferred by tubulin mutations in human cancer cells. Proc Natl Acad Sci U S A 2000; 97:2904–2909. 32. Jiang H Yang LY: Cell cycle checkpoint abrogator UCN01 inhibits DNA repair: association with attenuation of the interaction of XPA and ERCC1 nucleotide excision repair proteins. Cancer Res 1999; 59:4529–4534. 33. Carlson BA, Dubay MM, Sausville EA, Brizuela L,Worland PJ: Flavopiridol induces G1 arrest with inhibition of cyclin-dependent kinase (CDK) 2 and CDK4 in human breast carcinoma cells. Cancer Res 1996; 56:2973–2978. 34. Cartee L, Wang Z, Decker RH, et al: The cyclindependent kinase inhibitor (CDKI) flavopiridol disrupts phorbol 12-myristate 13-acetate-induced differentiation and CDKI expression while enhancing apoptosis in human myeloid leukemia cells. Cancer Res 2001; 61:2583–2591. 35. Senderowicz AM: The cell cycle as a target for cancer therapy: basic and clinical findings with the small molecule inhibitors flavopiridol and UCN-01. Oncologist 2002; 7(Suppl 3):12–19. 36. deVere White RW, Deitch AD, Jackson AG, et al: Racial differences in clinically localized prostate cancers of black and white men, J Urol 1998; 159:1979–1982. [Discussion 1982–1983.] 37. Khoo VS, Pollack A, Cowen D, et al: Relationship of Ki67 labeling index to DNA-ploidy, S-phase fraction, and outcome in prostate cancer treated with radiotherapy. Prostate 1999; 41:166–172. 38. Agarwal ML, Taylor WR, Chernov MV, Chernova OB, Stark GR: The p53 network. J Biol Chem 1998; 273:1–4. 39. Lane DP: Cancer p53, guardian of the genome. Nature 1992; 358:15–16. 40. Haldar S, Basu A, Croce CM: Bcl2 is the guardian of microtubule integrity, Cancer Res 1997; 57:229–233. 41. Sionov RV, Haupt Y: The cellular response to p53: the decision between life and death. Oncogene 1999; 18:6145–6157. 42. Oren M: Decision making by p53: life, death and cancer, Cell Death Differ 2003; 10:431–442. 43. Cory S, Adams JM: The Bcl2 family: regulators of the cellular life-or-death switch, Nat Rev Cancer 2002; 2:647–656. 44. Berges RR, Vukanovic J, Epstein JI, et al: Implication of cell kinetic changes during the progression of human prostatic cancer. Clin Cancer Res 1995; 1:473–480. 45. Westin P, Stattin P, Damber JE, Bergh A: Castration therapy rapidly induces apoptosis in a minority and decreases cell proliferation in a majority of human prostatic tumors. Am J Pathol 1995; 146:1368–1375. 46. Chang J, Ormerod M, Powles TJ, et al: Apoptosis and proliferation as predictors of chemotherapy response in patients with breast carcinoma, Cancer 2000; 89:2145–2152. 47. Kulkarni RP, Reynolds KW, Newlands ES, et al: Cytoreductive surgery in disseminated non-seminomatous germ cell tumours of testis, Br J Surg 1991; 78:226–229.
76
Part I Principles of Urologic Oncology
48. Baniel J, Foster RS, Gonin R, et al: Late relapse of testicular cancer. J Clin Oncol 1995; 13:1170–1176. 49. Steyerberg EW, Keizer HJ, Fossa SD, et al: Prediction of residual retroperitoneal mass histology after chemotherapy for metastatic nonseminomatous germ cell tumor: multivariate analysis of individual patient data from six study groups. J Clin Oncol 1995; 13:1177–1187. 50. Brenner PC, Herr HW, Morse MJ, et al: Simultaneous retroperitoneal, thoracic, and cervical resection of postchemotherapy residual masses in patients with metastatic nonseminomatous germ cell tumors of the testis, J Clin Oncol 1996; 14:1765–1769. 51. Ulbright TM, Loehrer PJ, Roth LM, et al: The development of non-germ cell malignancies within germ cell tumors. A clinicopathologic study of 11 cases. Cancer 1994; 54:1824–1833. 52. Orazi A, Neiman RS, Ulbright TM, et al: Hematopoietic precursor cells within the yolk sac tumor component are the source of secondary hematopoietic malignancies in patients with mediastinal germ cell tumors. Cancer 1993; 71:3873–3881. 53. Ledermann JA, Holden L, Newlands ES, et al: The longterm outcome of patients who relapse after chemotherapy for non-seminomatous germ cell tumours, Br J Urol 1994; 74:225–230. 54. Toner GC, Panicek DM, Heelan RT, et al: Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection. J Clin Oncol 1990; 8:1683–1694. 55. Steyerberg EW, Donohue JP, Gerl A, et al: Residual masses after chemotherapy for metastatic testicular cancer: the clinical implications of the association between retroperitoneal and pulmonary histology. Re-analysis of Histology in Testicular Cancer (ReHiT) Study Group. J Urol 1997; 158:474–478. 56. Mayer F, Stoop H, Scheffer GL, et al: Molecular determinants of treatment response in human germ cell tumors. Clin Cancer Res 2003; 9:767–773. 57. Brown JL, Russell PJ, Philips J, Wotherspoon J, Raghavan D: Clonal analysis of a bladder cancer cell line: an experimental model of tumour heterogeneity. Br J Cancer 1990; 61:369–376. 58. Quinn DI, Henshall SM, Head DR, et al: Prognostic significance of p53 nuclear accumulation in localized prostate cancer treated with radical prostatectomy. Cancer Res 2000; 60:1585–1594. 59. Suzuki H. Freije D, Nusskern DR, et al: Interfocal heterogeneity of PTEN/MMAC1 gene alterations in multiple metastatic prostate cancer tissues. Cancer Res 1998; 58:204–209. 60. Craft N, Chhor C, Tran C, et al: Evidence for clonal outgrowth of androgen-independent prostate cancer cells from androgen-dependent tumors through a two-step process. Cancer Res 1999; 59:5030–5036. 61. Xu X, Stower MJ, Reid IN, Garner RC, Burns PA: Molecular screening of multifocal transitional cell carcinoma of the bladder using p53 mutations as biomarkers. Clin Cancer Res 1996; 2:1795–800. 62. Olumi AF, Grossfeld GD, Hayward SW, et al: Carcinoma-associated fibroblasts direct tumor progression
63.
64.
65.
66.
67.
68.
69.
70. 71.
72.
73. 74.
75.
76.
77. 78.
of initiated human prostatic epithelium. Cancer Res 1999; 59:5002–5011. Henshall SM, Quinn DI, Lee CS, et al: Altered expression of androgen receptor in the malignant epithelium and adjacent stroma is associated with early relapse in prostate cancer. Cancer Res 2001; 61:423–427. Raghavan D, Cox K, Pearson BS, et al: Oral cyclophosphamide for the management of hormonerefractory prostate cancer. Br J Urol 1993; 72:625–628. Beckley S, Wajsman Z, Slack N, Mittelman A, Murphy GP: The chemotherapy of prostatic carcinoma. Scand J Urol Nephrol Suppl 1980; 55:151–162. Raghavan D, Tannock IF: Clinical trials in genitourinary oncology: what have they achieved? In Smith PH, Chisholm GD (eds): Combination Therapy in Urological Malignancy, pp 226–253. London, Springer Verlag, 1989. Richie JP: Intravesical chemotherapy. Treatment selection, techniques, and results. Urol Clin North Am 1992; 19:521–527. Doll DC, Weiss RB, Issell BF: Mitomycin: ten years after approval for marketing. J Clin Oncol 1985; 3:276–286. Highley MS, van Oosterom AT, Maes RA, De Bruijn EA: Intravesical drug delivery. Pharmacokinetic and clinical considerations. Clin Pharmacokinet 1999; 37:59–73. Hudes G: Estramustine-based chemotherapy. Semin Urol Oncol 1997; 15:13–19. Gerl A, Clemm C, Kohl P, Schalhorn A, Wilmanns W: Central nervous system as sanctuary site of relapse in patients treated with chemotherapy for metastatic testicular cancer. Clin Exp Metastasis 1994; 12:226–230. Reddel RR, Thompson JF, Raghavan D, et al: Surgery in patients with advanced germ cell malignancy following a clinical partial response to chemotherapy. J Surg Oncol 1983; 23:223–227. Pinedo HM, Peters GF: Fluorouracil: biochemistry and pharmacology. J Clin Oncol 1988; 6:1653–1664. Eliopoulos N, Cournoyer D, Momparler RL: Drug resistance to 5-aza-2′-deoxycytidine, 2′,2′-difluorodeoxycytidine, and cytosine arabinoside conferred by retroviral-mediated transfer of human cytidine deaminase cDNA into murine cells. Cancer Chemother Pharmacol 1998; 42:373–378. Merriman RL, Hertel LW, Schultz RM, et al: Comparison of the antitumor activity of gemcitabine and ara-C in a panel of human breast, colon, lung and pancreatic xenograft models., Invest New Drugs 1996; 14:243–247. Reigner B, Blesch K, Weidekamm E: Clinical pharmacokinetics of capecitabine. Clin Pharmacokinet 2001; 40:85–104. Twelves C: Vision of the future: capecitabine. Oncologist 2001; 6(Suppl 4):35–39. Ishikawa T, Sekiguchi F, Fukase Y, Sawada N, Ishitsuka H: Positive correlation between the efficacy of capecitabine and doxifluridine and the ratio of thymidine phosphorylase to dihydropyrimidine dehydrogenase activities in tumors in human cancer xenografts. Cancer Res 1998; 58:685–690.
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 77 79. Murray M: P450 enzymes. Inhibition mechanisms, genetic regulation and effects of liver disease. Clin Pharmacokinet 1992; 23:132–146. 80. Slaughter RL, Edwards DJ: Recent advances: the cytochrome P450 enzymes, Annals of Pharmacotherapy 1995; 29:619–624. 81. Creaven PJ, Allen LM, Cohen MH, Nelson RL: Studies on the clinical pharmacology and toxicology of isophosphamide (NSC-109724). Cancer Treat Rep 1976; 60:445–449. 82. Allen LM, Creaven PJ: Pharmacokinetics of ifosfamide. Clin Pharmacol Ther 1975; 17:492–498. 83. Colvin M: The comparative pharmacology of cyclophosphamide and ifosfamide. Semin Oncol 1982; 9:2–7. 84. Lind MJ, Margison JM, Cerny T, Thatcher N, Wilkinson P M: Comparative pharmacokinetics and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma. Cancer Res 1989; 49:753–757. 85. Powis G: Effect of human renal and hepatic disease on the pharmacokinetics of anticancer drugs. Cancer Treat Rev 1982; 9:85–124. 86. Benjamin RS, Riggs CE, Jr, Bachur NR: Plasma pharmacokinetics of adriamycin and its metabolites in humans with normal hepatic and renal function. Cancer Res 1977; 37:1416–1420. 87. Riggs CE, Jr, Benjamin RS, Serpick AA, Bachur NR: Bilary disposition of adriamycin. Clin Pharmacol Ther 1977; 22:234–241. 88. Grochow LB, Colvin M: Clinical pharmacokinetics of cyclophosphamide. Clin Pharmacokinet 1979; 4: 380–394. 89. Colvin M, Hilton J: Pharmacology of cyclophosphamide and metabolites. Cancer Treat Rep 1981; 65(Suppl 3):89–95. 90. Owellen RJ, Root MA, Hains FO: Pharmacokinetics of vindesine and vincristine in humans. Cancer Res 1977; 37:2603–2607. 91. Bruno R, Hille D, Riva A, et al: Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 1998; 16:187–196. 92. Gormley PE, Bull JM, LeRoy AF, Cysyk R: Kinetics of cis-dichlorodiammineplatinum. Clin Pharmacol Ther 1979; 25:351–357. 93. van der Vijgh WJ: Clinical pharmacokinetics of carboplatin. Clin Pharmacokinet 1991; 21: 242–261. 94. Chabner BA, Donehower RC, Schilsky RL: Clinical pharmacology of methotrexate. Cancer Treat Rep 1981; 65(Suppl 1):51–54. 95. Alberts DS, Chen HS, Liu R, et al: Bleomycin pharmacokinetics in man. I. Intravenous administration. Cancer Chemother Pharmacol 1978; 1:177–181. 96. Fleisher D, Li C, Zhou Y, Pao LH, Karim A: Drug, meal and formulation interactions influencing drug absorption after oral administration. Clinical implications. Clin Pharmacokinet 1999; 36:233–254. 97. Prescott LF: Gastrointestinal absorption of drugs. Med Clin North Am 1974; 58:907–916.
98. Quinn DI, Day RO: Drug interactions of clinical importance. An updated guide. Drug Saf 1995; 12:393–452. 99. Wagner JG: History of pharmacokinetics. Pharmacol Ther 1981; 12: 537–562. 100. Rodvold KA, Rushing DA, Tewksbury DA: Doxorubicin clearance in the obese. J Clin Oncol 1988; 6: 1321–1327. 101. Lind, MJ, Margison JM, Cerny T, Thatcher N, Wilkinson PM: Prolongation of ifosfamide elimination half-life in obese patients due to altered drug distribution. Cancer Chemother Pharmacol 1989; 25:139–142. 102. RobertJ, Hoerni B: Age dependence of the early-phase pharmacokinetics of doxorubicin. Cancer Res 1983; 43:4467–4469. 103. Testa B, Jenner P: Inhibitors of Cytochrome P-450s and their mechanism of action. Drug Metab Rev 1981; 12:1–117. 104. Tardiff RG, Dubois KP: Inhibition of hepatic microsomal enzymes by alkylating agents. Arch Int Pharmacodyn Ther 1969; 177:445–456. 105. Drayer DE: Pathways of drug metabolism in man. Med Clin North Am 1974; 58:927–944. 106. Liegler DG, Henderson ES, Hahn MA, Oliverio VT: The effect of organic acids on renal clearance of methotrexate in man. Clin Pharmacol Ther 1969; 10:849–857. 107. Sand TE, Jacobsen S: Effect of urine pH and flow on renal clearance of methotrexate. Eur J Clin Pharmacol 1981; 19:453–456. 108. Relling MV, Fairclough D, Ayers D, et al: Patient characteristics associated with high-risk methotrexate concentrations and toxicity. J Clin Oncol 1994; 12:1667–1672. 109. Valverde MA, Diaz M, Sepulveda FV, et al: Volumeregulated chloride channels associated with the human multidrug-resistance P-glycoprotein. Nature 1992; 355:830–833. 110. Juranka PF, Zastawny RL, Ling V: P-glycoprotein: multidrug-resistance and a superfamily of membraneassociated transport proteins. FASEB J 1989; 3:2583–2592. 111. Abraham EH, Prat AG, Gerweck L, et al: The multidrug resistance (mdr1) gene product functions as an ATP channel. Proc Natl Acad Sci U S A 1993; 90:312–316. 112. Speicher LA, Barone LR, Chapman AE, et al: P-glycoprotein binding and modulation of the multidrug-resistant phenotype by estramustine, J Natl Cancer Inst 1994; 86:688–694. 113. Abbaszadegan MR, Cress AE, Futscher BW, Bellamy WT, Dalton WS: Evidence for cytoplasmic P-glycoprotein location associated with increased multidrug resistance and resistance to chemosensitizers. Cancer Res 1996; 56:5435–5442. 114. Hazlehurst LA, Foley NE, Gleason-Guzman MC: Multiple mechanisms confer drug resistance to mitoxantrone in the human 8226 myeloma cell line. Cancer Res 1999; 59:1021–1028.
78
Part I Principles of Urologic Oncology
115. Goldstein LJ, Galski H, Fojo A, et al: Expression of a multidrug resistance gene in human cancers. J Natl Cancer Inst 1989; 81:116–124. 116. Chevillard S, Pouillart P, Beldjord C, et al: Sequential assessment of multidrug resistance phenotype and measurement of S-phase fraction as predictive markers of breast cancer response to neoadjuvant chemotherapy. Cancer 1996; 77:292–300. 117. Benet LZ, Cummins CL: The drug efflux-metabolism alliance: biochemical aspects. Adv Drug Deliv Rev 2001; 50(Suppl 1):S3-S11. 118. Cummins CL, Jacobsen W, Benet LZ: Unmasking the dynamic interplay between intestinal P-glycoprotein and CYP3A4. J Pharmacol Exp Ther 2002; 300:1036–1045. 119. Fricker G, Miller DS: Relevance of multidrug resistance proteins for intestinal drug absorption in vitro and in vivo, Pharmacol Toxicol 2002; 90:5–13. 120. Reinecke P, Schmitz M, Schneider EM, Gabbert HE, Gerharz CD: Multidrug resistance phenotype and paclitaxel (Taxol) sensitivity in human renal carcinoma cell lines of different histologic types. Cancer Invest 2000; 18:614–625. 121. Sugawara I: Expression and functions of P-glycoprotein (mdr1 gene product) in normal and malignant tissues, Acta Pathol Jpn 1990; 40:545–553. 122. Shinohara N, Nonomura K, Takakura F, et al: Expression of multidrug resistance gene product (P-glycoprotein) in transitional cell carcinomas of the upper urinary tract. Eur Urol 1994; 26:327–333. 123. Shinohara N, Liebert M, Wedemeyer G, Chang JH, Grossman HB: Evaluation of multiple drug resistance in human bladder cancer cell lines. J Urol 1993; 150:505–509. 124. Park J, Shinohara N, Liebert M, et al: P-glycoprotein expression in bladder cancer. J Urol 1994; 151:43–46. 125. Petrylak DP, Scher HI, Reuter V, O’Brien JP, CordonCardo C: P-glycoprotein expression in primary and metastatic transitional cell carcinoma of the bladder. Ann Oncol 1994; 5:835–840. 126. Barrand MA, Heppell-Parton AC, Wright KA, Rabbitts PH, Twentyman PR: A 190-kilodalton protein overexpressed in non-P-glycoprotein-containing multidrug-resistant cells and its relationship to the MRP gene. J Natl Cancer Inst 1994; 86:110–117. 127. Lum BL, Fisher GA, Brophy NA, et al: Clinical trials of modulation of multidrug resistance. Pharmacokinetic and pharmacodynamic considerations. Cancer 1993; 72:3502–3514. 128. Dalton WS, Grogan TM, Meltzer PS, et al: Drugresistance in multiple myeloma and non-Hodgkin’s lymphoma: detection of P-glycoprotein and potential circumvention by addition of verapamil to chemotherapy, J Clin Oncol 1989; 7:415–424. 129. Ramirez LH, Munck JN, Zhao Z, et al: Verapamilreversing concentrations induce blood flow changes that could counteract in vivo the MDR-1-modulating effects, Cancer 1994; 74:810–816. 130. Russell PJ, Palavidis Z, Rozinova E, et al: Characterization of a new human bladder cancer cell line. UCRU-BL-28. J Urol 1993; 150:1038–1044.
131. Brandes LJ, Simons KJ, Bracken SP, Warrington RC: Results of a clinical trial in humans with refractory cancer of the intracellular histamine antagonist, N, N-diethyl-2-[4-(phenylmethyl)phenoxy]ethanamine-HCl, in combination with various single antineoplastic agents. J Clin Oncol 1994; 12:1281–1290. 132. Brandes LJ, Bracken SP, Ramsey EW: N,N-diethyl-2[4-(phenylmethyl)phenoxy]ethanamine in combination with cyclophosphamide: an active, low-toxicity regimen for metastatic hormonally unresponsive prostate cancer. J Clin Oncol 1995; 13:1398–1403. 133. Raghavan D, Brandes LJ, Klapp K, et al: Phase II trial of mitoxantrone plus tesmilifene (DPPE) in hormonerefractory prostate cancer: high subjective and objective response in patients with symptomatic bone metastases. J Clin Oncol (in press). 134. Niedner H, Christen R, Lin X, Kondo A. Howell SB: Identification of genes that mediate sensitivity to cisplatin. Mol Pharmacol 2001; 60:1153–1160. 135. Guminski AD, Harnett PR, deFazio A: Scientists and clinicians test their metal-back to the future with platinum compounds. Lancet Oncol 2002; 3: 312–318. 136. Hospers GA, Meijer C, de Leij L, et al: A study of human small-cell lung carcinoma (hSCLC) cell lines with different sensitivities to detect relevant mechanisms of cisplatin (CDDP) resistance. Int J Cancer 1990; 46:138–144. 137. Liebmann JE, Hahn SM, Cook JA, et al: Glutathione depletion by L-buthionine sulfoximine antagonizes taxol cytotoxicity. Cancer Res 1993; 53:2066–2070. 138. Pendyala L, Creaven PJ, Perez R, Zdanowicz JR, Raghavan D: Intracellular glutathione and cytotoxicity of platinum complexes. Cancer Chemother Pharmacol 1995; 36:271–278. 139. Christen RD, Hom DK, Porter DC, et al: Epidermal growth factor regulates the in vitro sensitivity of human ovarian carcinoma cells to cisplatin. J Clin Invest 1990; 86:1632–1640. 140. Cenni B, Aebi S, Nehme A, Christen RD: Epidermal growth factor enhances cisplatin-induced apoptosis by a caspase 3 independent pathway. Cancer Chemother Pharmacol 2001; 47:397–403. 141. Fan Z, Masui H, Altas I, Mendelsohn J: Blockade of epidermal growth factor receptor function by bivalent and monovalent fragments of 225 anti-epidermal growth factor receptor monoclonal antibodies. Cancer Res 1993; 53:4322–4328. 142. Fan Z, Baselga J, Masui H, Mendelsohn J: Antitumor effect of anti-epidermal growth factor receptor monoclonal antibodies plus cis-diamminedichloroplatinum on well established A431 cell xenografts. Cancer Res 1993; 53:4637–4642. 143. Lipponen P, Eskelinen M: Expression of epidermal growth factor receptor in bladder cancer as related to established prognostic factors, oncoprotein (c-erbB-2, p53) expression and long-term prognosis. Br J Cancer 1994; 69:1120–1125. 144. Gorgoulis VG, Barbatis C, Poulias I, Karameris AM: Molecular and immunohistochemical evaluation of epidermal growth factor receptor and c-erb-B-2 gene
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 79
145.
146.
147.
148.
149.
150.
151.
152.
153.
154.
155.
156.
157.
158.
159.
160.
product in transitional cell carcinomas of the urinary bladder: a study in Greek patients. Mod Pathol 1995; 8:758–764. Chow NH, Chan SH, Tzai TS, Ho CL, Liu HS: Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder. Clin Cancer Res 2001; 7:1957–1962. Hollstein M, Sidransky D, Vogelstein B, Harris CC: p53 mutations in human cancers. Science 1991; 253:49–53. Fritsche M, Haessler C, Brandner G: Induction of nuclear accumulation of the tumor-suppressor protein p53 by DNA-damaging agents. Oncogene 1993; 8:307–318. Aas T, Borresen AL, Geisler S, et al: Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med 1996; 2:811–814. Lin X, Ramamurthi K, Mishima M, et al: p53 modulates the effect of loss of DNA mismatch repair on the sensitivity of human colon cancer cells to the cytotoxic and mutagenic effects of cisplatin. Cancer Res 2001; 61:1508–1516. Achanta G, Pelicano H, Feng L, Plunkett W, Huang P: Interaction of p53 and DNA-PK in response to nucleoside analogues: potential role as a sensor complex for DNA damage. Cancer Res 2001; 61:8723–8729. Cassinelli G, Supino R, Perego P, et al: A role for loss of p53 function in sensitivity of ovarian carcinoma cells to taxanes. Int J Cancer 2001; 92:738–747. Esrig D, Elmajian D, Groshen S, et al: Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 1994; 331:1259–1264. Sarkis AS, Bajorin DF, Reuter VE, et al: Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant MVAC. J Clin Oncol 1995; 13:1384–1390. Goldie JH, Coldman AJ: A mathematic model for relating the drug sensitivity of tumors to their spontaneous mutation rate. Cancer Treat Rep 1979; 63:1727–1733. Day RS: Treatment sequencing, asymmetry, and uncertainty: protocol strategies for combination chemotherapy. Cancer Res 1986; 46:3876–3885. Schwartz D, Lellouch J: Explanatory and pragmatic attitudes in therapeutical trials. J Chronic Dis 1967; 20:637–648. Crawford ED, Wood DP, Petrylak DP, et al: Southwest Oncology Group studies in bladder cancer. Cancer 2003; 97:2099–2108. de Wit R: Overview of bladder cancer trials in the European Organization for Research and Treatment. Cancer 2003; 97:2120–2126. Dreicer R, Roth B, Wilding G: Overview of advanced urothelial cancer trials of the Eastern Cooperative Oncology Group. Cancer 2003; 97:2109–2114. Daugherty C, Ratain MJ, Grochowski E, et al: Perceptions of cancer patients and their physicians involved in phase I trials. J Clin Oncol 1995; 13:1062–1072.
161. Ratain MJ, Mick R, Schilsky RL, Siegler M: Statistical and ethical issues in the design and conduct of phases I and II clinical trials of new anticancer agents. J Natl Cancer Inst 1993; 85:1637–1643. 162. Creaven PJ, Mihich E: The clinical toxicity of anticancer drugs and its prediction. Semin Oncol 1977; 4:147–163. 163. Staquet M, Sylvester R: A decision theory approach to phase II clinical trials. Biomedicine 1977; 26:262–266. 164. Lee YJ, Staquet M, Simon R, Catane R, Muggia F: Twostage plans for patient accrual in phase II cancer clinical trials. Cancer Treat Rep 1979; 63:1721–1726. 165. Simon R: Optimal two-stage designs for phase II clinical trials. Control Clin Trials 1989; 10:1–10. 166. Korn EL, Arbuck SG, Pluda JM, et al: Clinical trial designs for cytostatic agents: are new approaches needed? J Clin Oncol 2001; 19:265–272. 167. Rosenberg B, VanCamp L, Trosko JE, Mansour VH: Platinum compounds: a new class of potent antitumour agents. Nature 1969; 222:385–386. 168. Gottesman MM: Mechanisms of cancer drug resistance, Annu. Rev. Med 2002; 53:615–627. 169. Hospers GA, Mulder NH, de Jong B, et al: Characterization of a human small cell lung carcinoma cell line with acquired resistance to cis-diamminedichloroplatinum(II) in vitro. Cancer Res 1988; 48: 6803–6807. 170. Meijer C, Mulder NH, Hospers GA, Uges DR, de Vries EG: The role of glutathione in resistance to cisplatin in a human small cell lung cancer cell line. Br J Cancer 1990; 62:72–77. 171. Reed E: Platinum-DNA adduct, nucleotide excision repair and platinum based anti-cancer chemotherapy. Cancer Treat Rev 1998; 24:331–344. 172. Metzger R, Leichman CG, Danenberg KD, et al: ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. J Clin Oncol 1998; 16:309–316. 173. Lord RV, Brabender J, Gandara D, et al: Low ERCC1 expression correlates with prolonged survival after cisplatin plus gemcitabine chemotherapy in non-small cell lung cancer. Clin Cancer Res 2002; 8:2286–2291. 174. Ferry KV, Hamilton TC, Johnson SW: Increased nucleotide excision repair in cisplatin-resistant ovarian cancer cells: role of ERCC1-XPF. Biochem Pharmacol 2000; 60:1305–1313. 175. DeConti RC, Toftness BR, Lange RC, Creasey WA: Clinical and pharmacological studies with cisdiamminedichloroplatinum (II). Cancer Res 1973; 33:1310–1315. 176. Himmelstein KJ, Patton TF, Belt RJ, et al: Clinical kinetics on intact cisplatin and some related species. Clin Pharmacol Ther 1981; 29:658–664. 177. Safirstein R, Winston J, Goldstein M, et al: Cisplatin nephrotoxicity. Am J Kidney Dis 1986; 8:356–367. 178. Kelsen DP, Alcock N, Young CW: Cisplatin nephrotoxicity. Correlation with plasma platinum concentrations. Am J Clin Oncol 1985; 8:77–80. 179. Boyer M, Raghavan D, Harris PJ, et al: Lack of late toxicity in patients treated with cisplatin-containing
80
180. 181.
182.
183.
184.
185.
186.
187.
188.
189.
190.
191.
192.
193.
Part I Principles of Urologic Oncology combination chemotherapy for metastatic testicular cancer. J Clin Oncol 1990; 8:21–26. Boyer M Raghavan D: Toxicity of treatment of germ cell tumors. Semin Oncol 1992; 19:128–142. Calvert H, Judson I, van der Vijgh WJ: Platinum complexes in cancer medicine: pharmacokinetics and pharmacodynamics in relation to toxicity and therapeutic activity. Cancer Surv 1993; 17:189–217. Harland SJ, Newell DR, Siddik ZH, et al: Pharmacokinetics of cis-diammine-1,1-cyclobutane dicarboxylate platinum(II) in patients with normal and impaired renal function. Cancer Res 1984; 44:1693–1697. Egorin MJ, Van Echo DA, Tipping SJ, et al: Pharmacokinetics and dosage reduction of cisdiammine(1,1-cyclobutanedicarboxylato)platinum in patients with impaired renal function. Cancer Res 1984; 44:5432–5438. Calvert AH, Newell DR, Gumbrell LA, et al: Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989; 7:1748–1756. Kelly WK, Curley T, Slovin S, et al: Paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer. J Clin Oncol 2001; 19:44–53. Jungi WF, Bernhard J, Hurny C, et al: Effect of carboplatin on response and palliation in hormonerefractory prostate cancer. Swiss Group for Clinical Cancer Research (SAKK). Support Care Cancer 1998; 6:462–468. Bellmunt J, Albanell J, Gallego OS, et al: Carboplatin, methotrexate, and vinblastine in patients with bladder cancer who were ineligible for cisplatin-based chemotherapy. Cancer 1992; 70:1974–1979. Skarlos DV, Samantas E, Kosmidis P, et al: Randomized comparison of etoposide-cisplatin vs. etoposidecarboplatin and irradiation in small-cell lung cancer. A Hellenic Co-operative Oncology Group study. Ann Oncol 1994; 5:601–607. Scagliotti GV, De Marinis F, Rinaldi M, et al: Phase III randomized trial comparing three platinum-based doublets in advanced non-small-cell lung cancer. J Clin Oncol 2002; 20:4285–4291. Swenerton K, Jeffrey J, Stuart G, et al: Cisplatincyclophosphamide versus carboplatin-cyclophosphamide in advanced ovarian cancer: a randomized phase III study of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1992; 10:718–726. Alberts DS, Green S, Hannigan EV, et al: Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a phase III randomized trial in stages III and IV ovarian cancer. J Clin Oncol 1992; 10:706–717. Lokich J, Anderson N: Carboplatin versus cisplatin in solid tumors: an analysis of the literature. Ann Oncol 1998; 9:13–21. Go RS, Adjei AA: Review of the comparative pharmacology and clinical activity of cisplatin and carboplatin. J Clin Oncol 1999; 17:409–422.
194. Petrioli R, Frediani B, Manganelli A, et al: Comparison between a cisplatin-containing regimen and a carboplatin-containing regimen for recurrent or metastatic bladder cancer patients. A randomized phase II study. Cancer 1996; 77:344–351. 195. Bajorin DF, Sarosdy MF, Pfister DG, et al: Randomized trial of etoposide and cisplatin versus etoposide and carboplatin in patients with good-risk germ cell tumors: a multiinstitutional study. J Clin Oncol 1993; 11:598–606. 196. Horwich A, Sleijfer DT, Fossa SD, et al: Randomized trial of bleomycin, etoposide, and cisplatin compared with bleomycin, etoposide, and carboplatin in goodprognosis metastatic nonseminomatous germ cell cancer: a Multiinstitutional Medical Research Council/European Organization for Research and Treatment of Cancer Trial. J Clin Oncol 1997; 15:1844–1852. 197. Horwich A, Oliver RT, Wilkinson PM, et al: A medical research council randomized trial of single agent carboplatin versus etoposide and cisplatin for advanced metastatic seminoma. MRC Testicular Tumour Working Party. Br J Cancer 2000; 83:1623–1629. 198. Kidani Y, Noji M, Tashiro T: Antitumor activity of platinum(II) complexes of 1,2-diamino-cyclohexane isomers. Gann 1980; 71:637–643. 199. Pendyala L, Creaven PJ: In vitro cytotoxicity, protein binding, red blood cell partitioning, and biotransformation of oxaliplatin. Cancer Res 1993; 53:5970–5976. 200. Caussanel JP, Levi F, Brienza S, et al: Phase I trial of 5-day continuous venous infusion of oxaliplatin at circadian rhythm-modulated rate compared with constant rate. J Natl Cancer Inst 1990; 82:1046–1050. 201. Machover D, Diaz-Rubio E, de Gramont A, et al: Two consecutive phase II studies of oxaliplatin (L-OHP) for treatment of patients with advanced colorectal carcinoma who were resistant to previous treatment with fluoropyrimidines. Ann Oncol 1996; 7:95–98. 202. Extra JM, Espie M, Calvo F, et al: Phase I study of oxaliplatin in patients with advanced cancer. Cancer Chemother Pharmacol 1990; 25:299–303. 203. Shirota Y, Stoehlmacher J, Brabender J, et al: ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 2001; 19:4298–4304. 204. Bokemeyer C, Kollmannsberger C, Harstrick A, et al: Treatment of patients with cisplatin-refractory testicular germ-cell cancer. German Testicular Cancer Study Group (GTCSG). Int J Cancer 1999; 83:848–851. 205. Kollmannsberger C, Rick O, Derigs HG, et al: Activity of oxaliplatin in patients with relapsed or cisplatinrefractory germ cell cancer: a study of the German Testicular Cancer Study Group. J Clin Oncol 2002; 20:2031–2037. 206. Barranco SC, Humphrey RM: The effects of bleomycin on survival and cell progression in Chinese hamster cells in vitro. Cancer Res 1971; 31:1218–1223. 207. Barlogie B, Drewinko B, Schumann J, Freireich EJ: Pulse cytophotometric analysis of cell cycle perturbation
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 81
208.
209.
210.
211. 212.
213.
214.
215.
216.
217.
218.
219.
220.
221.
222.
223.
224.
with bleomycin in vitro. Cancer Res 1976; 36:1182–1187. Lazo JS, Boland CJ, Schwartz PE: Bleomycin hydrolase activity and cytotoxicity in human tumors. Cancer Res 1982; 42:4026–4031. Levi JA, Raghavan D, Harvey V, et al: The importance of bleomycin in combination chemotherapy for goodprognosis germ cell carcinoma. Australasian Germ Cell Trial Group. J Clin Oncol 1993; 11:1300–1305. Loehrer PJ, Sr, Johnson D, Elson P, Einhorn LH,Trump D: Importance of bleomycin in favorableprognosis disseminated germ cell tumors: an Eastern Cooperative Oncology Group trial. J Clin Oncol 1995; 13:470–476. Crooke ST, Bradner WT: Mitomycin C: a review. Cancer Treat Rev 1976; 3:121–139. Dusre L, Rajagopalan S, Eliot HM, Covey JM, Sinha BK: DNA interstrand cross-link and free radical formation in a human multidrug-resistant cell line from mitomycin C and its analogues. Cancer Res 1990; 50:648–652. Dusre L, Covey JM, Collins C, Sinha BK: DNA damage, cytotoxicity and free radical formation by mitomycin C in human cells. Chem Biol Interact 1989; 71:63–78. van Hazel GA, Kovach JS: Pharmacokinetics of mitomycin C in rabbit and human. Cancer Chemother Pharmacol 1982; 8:189–192. van Hazel GA, Scott M, Rubin J, et al: Pharmacokinetics of mitomycin C in patients receiving the drug alone or in combination. Cancer Treat Rep 1983; 67:805–810. Hanna WT, Krauss S, Regester RF, Murphy WM: Renal disease after mitomycin C therapy. Cancer 1981; 48:2583–2588. Valavaara R, Nordman E: Renal complications of mitomycin C therapy with special reference to the total dose. Cancer 1985; 55:47–50. Chang AY, Kuebler JP, Pandya KJ, et al: Pulmonary toxicity induced by mitomycin C is highly responsive to glucocorticoids. Cancer 1986; 57:2285–2290. Stewart CF, Ratain MJ: Topoisomerase interactive agents. In DeVita VTJ, Hellman S, Rosenberg, SA (eds): Cancer: Principles and Practice of Oncology, 6th edition, pp 415–430. Philadelphia, Lippincott, Williams and Wilkins, 2001. Tewey KM, Rowe TC, Yang L, Halligan BD, Liu LF: Adriamycin-induced DNA damage mediated by mammalian DNA topoisomerase II. Science 1984; 226:466–468. Benjamin RS: Pharmacokinetics of adriamycin (NSC123127) in patients with sarcomas. Cancer Chemother Rep 1974; 58:271–273. Chan KK, Chlebowski RT, Tong M, et al: Clinical pharmacokinetics of adriamycin in hepatoma patients with cirrhosis. Cancer Res 1980; 40:1263–1268. Von Hoff DD, Layard MW, Basa P, et al: Risk factors for doxorubicin-induced congestive heart failure. Ann Intern Med 1979; 91:710–717. Hortobagyi GN, Yap HY, Kau SW, et al: A comparative study of doxorubicin and epirubicin in patients with metastatic breast cancer. Am J Clin Oncol 1989; 12:57–62.
225. Greco FA, Brereton HD, Kent H, et al: Adriamycin and enhanced radiation reaction in normal esophagus and skin. Ann Intern Med 1976; 85:294–298. 226. Berruti A, Terzolo M, Pia A, Angeli A, Dogliotti L: Mitotane associated with etoposide, doxorubicin, and cisplatin in the treatment of advanced adrenocortical carcinoma. Italian Group for the Study of Adrenal Cancer. Cancer 1998; 83:2194–2200. 227. Decker RA, Elson P, Hogan TF, et al: Eastern Cooperative Oncology Group study 1879: mitotane and adriamycin in patients with advanced adrenocortical carcinoma. Surgery 1991; 110:1006–1013. 228. Law TM, Mencel P, Motzer RJ: Phase II trial of liposomal encapsulated doxorubicin in patients with advanced renal cell carcinoma. Invest New Drugs 1994; 12:323–325. 229. Koeller J, Eble M: Mitoxantrone: a novel anthracycline derivative. Clin Pharm 1988; 7:574–581. 230. Faulds D, Balfour JA, Chrisp P, Langtry HD: Mitoxantrone. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the chemotherapy of cancer. Drugs 1991; 41:400–449. 231. Smyth JF, Macpherson JS, Warrington PS, Leonard RC, Wolf CR: The clinical pharmacology of mitozantrone. Cancer Chemother Pharmacol 1986; 17:149–152. 232. Launay MC, Iliadis A, Richard B: Population pharmacokinetics of mitoxantrone performed by a NONMEM method. J Pharm Sci 1989; 78:877–880. 233. Batra VK, Morrison JA, Woodward DL, Siverd NS, Yacobi A: Pharmacokinetics of mitoxantrone in man and laboratory animals. Drug Metab Rev 1986; 17:311–329. 234. Hu OY, Chang SP, Law CK, Jian JM, Chen KY: Pharmacokinetic and pharmacodynamic studies with mitoxantrone in the treatment of patients with nasopharyngeal carcinoma. Cancer 1992; 69:847–853. 235. Ehninger G, Schuler U, Proksch B, Zeller KP, Blanz J: Pharmacokinetics and metabolism of mitoxantrone. A review. Clin Pharmacokinet 1990; 18:365–380. 236. Alberts DS, Peng YM, Bowden GT, Dalton WS, Mackel C: Pharmacology of mitoxantrone: mode of action and pharmacokinetics. Invest New Drugs 1985; 3:101–107. 237. Alberts DS, Peng YM, Leigh S, Davis TP, Woodward DL: Disposition of mitoxantrone in cancer patients. Cancer Res 1985; 45:1879–1884. 238. Van Belle SJ, de Planque MM, Smith IE, et al: Pharmacokinetics of mitoxantrone in humans following single-agent infusion or intra-arterial injection therapy or combined-agent infusion therapy. Cancer Chemother Pharmacol 1986; 18:27–32. 239. Weiss RB: Mitoxantrone: its development and role in clinical practice. Oncology 1989; 3:135–141. 240. Raghavan D, Coorey G, Rosen M, Page J, Farebrother T: Management of hormone-resistant prostate cancer: an Australian trial. Semin Oncol 1996; 23:20–23. 241. Kantoff PW, Halabi S, Conaway M, et al: Hydrocortisone with or without mitoxantrone in men with hormone-refractory prostate cancer: results of the cancer and leukemia group B 9182 study [see comments]. J Clin Oncol 1999; 17:2506–2513.
82
Part I Principles of Urologic Oncology
242. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996; 14:1756–1764. 243. Osoba D, Tannock IF, Ernst DS, Neville AJ: Healthrelated quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone. J Clin Oncol 1999; 17:1654–1663. 244. Wiseman LR, Spencer CM: Mitoxantrone. A review of its pharmacology and clinical efficacy in the management of hormone-resistant advanced prostate cancer. Drugs Aging 1997; 10:473–485. 245. DiPaola RS, Chenven ES, Shih WJ, et al: Mitoxantrone in patients with prostate specific antigen progression after local therapy for prostate carcinoma. Cancer 2001; 92:2065–2071. 246. Wang J, Halford S, Rigg A, et al: Adjuvant mitozantrone chemotherapy in advanced prostate cancer. BJU Int 2000; 86:675–680. 247. Nelson RL: The comparative clinical pharmacology and pharmacokinetics of vindesine, vincristine, and vinblastine in human patients with cancer. Med Pediatr Oncol 1982; 10:115–127. 248. Owellen RJ, Hartke CA, Hains FO: Pharmacokinetics and metabolism of vinblastine in humans. Cancer Res 1977; 37:2597–2602. 249. Jackson DV Jr, Castle MC, Bender RA: Biliary excretion of vincristine. Clin Pharmacol Ther 1978; 24:101–107. 250. Newlands ES, Begent RH, Rustin GJ, Parker D, Bagshawe KD: Further advances in the management of malignant teratomas of the testis and other sites. Lancet 1983; 1:948–951. 251. Williams SD, Birch R, Einhorn LH, et al: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 1987; 316:1435–1440. 252. Logothetis CJ, Dexeus FH, Finn L, et al: A prospective randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol 1990; 8:1050–1055. 253. Fellous A, Ohayon R, Vacassin T, et al: Biochemical effects of Navelbine on tubulin and associated proteins. Semin Oncol 1989; 16:9–14. 254. Cros S, Wright M, Morimoto M, et al: Experimental antitumor activity of Navelbine. Semin Oncol 1989; 16:15–20. 255. Photiou A, Sheikh MN, Bafaloukos D, Retsas S: Antiproliferative activity of vinorelbine (Navelbine) against six human melanoma cell lines. J Cancer Res Clin Oncol 1992; 118:249–254. 256. Mathe G, Reizenstein P: Phase I pharmacologic study of a new Vinca alkaloid: navelbine. Cancer Lett 1985; 27:285–293. 257. Bore P, Rahmani R, van Cantfort J, Focan C, Cano JP: Pharmacokinetics of a new anticancer drug, navelbine, in patients. Comparative study of radioimmunologic and radioactive determination methods. Cancer Chemother Pharmacol 1989; 23:247–251.
258. Rowinsky EK, Noe DA, Trump DL, et al: Pharmacokinetic, bioavailability, and feasibility study of oral vinorelbine in patients with solid tumors. J Clin Oncol 1994; 12:1754–1763. 259. Carles J, Domenech M, Gelabert-Mas A, et al: Phase II study of estramustine and vinorelbine in hormonerefractory prostate carcinoma patients. Acta Oncol 1998; 37:187–191. 260. Schmidinger M, Steger GG, Budinsky AC, et al: Vinorelbine and interferon-alpha2c as second-line therapy in metastatic renal cell carcinoma. Anticancer Drugs 2000; 11:175–179. 261. Sweeney CJ, Monaco FJ, Jung SH, et al: A phase II Hoosier Oncology Group study of vinorelbine and estramustine phosphate in hormone-refractory prostate cancer. Ann Oncol 2002; 13:435–440. 262. Oudard S, Caty A, Humblet Y, et al: Phase II study of vinorelbine in patients with androgen-independent prostate cancer. Ann Oncol 2001; 12:847–852. 263. Smith MR, Kaufman D, Oh W, et al: Vinorelbine and estramustine in androgen-independent metastatic prostate cancer: a phase II study. Cancer 2000; 89:1824–1828. 264. Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT: Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc 1971; 93:2325–2327. 265. Manfredi JJ, Parness J, Horwitz SB: Taxol binds to cellular microtubules. J Cell Biol 1982; 94: 688–696. 266. Parness J, Horwitz SB: Taxol binds to polymerized tubulin in vitro. J Cell Biol 1981; 91:479–487. 267. Schiff PB, Horwitz SB: Taxol stabilizes microtubules in mouse fibroblast cells. Proc Natl Acad Sci U S A 1980; 77:1561–1565. 268. Schiff PB, FantJ, Horwitz SB: Promotion of microtubule assembly in vitro by taxol. Nature 1979; 277:665–667. 269. Manfredi JJ, Horwitz SB: Taxol: an antimitotic agent with a new mechanism of action. Pharmacol Ther 1984; 25:83–125. 270. McGuire WP, Rowinsky EK, Rosenshein NB, et al: Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 1989; 111:273–279. 271. Arbuck SG, Christian MC, Fisherman JS, et al:. Clinical development of Taxol. J Natl Cancer Inst Monogr 1993:11–24. 272. Donehower RC, Rowinsky EK, Grochow LB, Longnecker SM, Ettinger DS: Phase I trial of taxol in patients with advanced cancer. Cancer Treat Rep 1987; 71:1171–1177. 273. Arbuck SG: Paclitaxel: what schedule? What dose?. J Clin Oncol 1994; 12:233–236. 274. Rowinsky EK, Onetto N, Canetta RM, Arbuck SG: Taxol: the first of the taxanes, an important new class of antitumor agents. Semin Oncol 1992; 19:646–662. 275. Rowinsky EK, Burke PJ, Karp JE, et al: Phase I and pharmacodynamic study of taxol in refractory acute leukemias. Cancer Res 1989; 49:4640–4647.
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 83 276. Rowinsky EK, McGuire WP, Guarnieri T, et al: Cardiac disturbances during the administration of taxol. J Clin Oncol 1991; 9:1704–1712. 277. Arbuck SG, Strauss H, Rowinsky E,et al: A reassessment of cardiac toxicity associated with Taxol. J Natl Cancer Inst Monogr 1993:117–130. 278. Schiller JH, Storer B, Tutsch K, et al: Phase I trial of 3-hour infusion of paclitaxel with or without granulocyte colony-stimulating factor in patients with advanced cancer. J Clin Oncol 1994; 12:241–248. 279. Eisenhauer EA, ten Bokkel Huinink WW, Swenerton KD, et al: European-Canadian randomized trial of paclitaxel in relapsed ovarian cancer: high-dose versus low-dose and long versus short infusion. J Clin Oncol 1994; 12:2654–2666. 280. Rowinsky EK, Wright M, Monsarrat B, Lesser GJ, Donehower RC: Taxol: pharmacology, metabolism and clinical implications. Cancer Surv 1993; 17:283–304. 281. Huizing MT, Keung AC, Rosing H, et al: Pharmacokinetics of paclitaxel and metabolites in a randomized comparative study in platinum-pretreated ovarian cancer patients. J Clin Oncol 1993; 11:2127–2135. 282. Monsarrat B, Alvinerie P, Wright M, et al: Hepatic metabolism and biliary excretion of Taxol in rats and humans. J Natl Cancer Inst Monogr 1993:39–46. 283. Rowinsky EK, Gilbert MR, McGuire WP, et al: Sequences of taxol and cisplatin: a phase I and pharmacologic study. J Clin Oncol 1991; 9:1692–1703. 284. Gianni L, Kearns CM, Giani A, et al: Nonlinear pharmacokinetics and metabolism of paclitaxel and its pharmacokinetic/pharmacodynamic relationships in humans. J Clin Oncol 1995; 13:180–190. 285. Motzer RJ, Bajorin DF, Schwartz LH, et al: Phase II trial of paclitaxel shows antitumor activity in patients with previously treated germ cell tumors. J Clin Oncol 1994; 12:2277–2283. 286. Roth BJ, Dreicer R, Einhorn LH, et al: Significant activity of paclitaxel in advanced transitional-cell carcinoma of the urothelium: a phase II trial of the Eastern Cooperative Oncology Group. J Clin Oncol 1994; 12:2264–2270. 287. Einzig AI, Gorowski E, Sasloff J, Wiernik PH: Phase II trial of taxol in patients with metastatic renal cell carcinoma. Cancer Invest 1991; 9:133–136. 288. Roth BJ, Yeap BY, Wilding G, et al: Taxol in advanced, hormone-refractory carcinoma of the prostate. A phase II trial of the Eastern Cooperative Oncology Group. Cancer 1993; 72:2457–2460. 289. Kang MH, Figg WD, Dahut W: Taxanes in hormone-refractory prostate cancer. Cancer Pract 1999; 7:270–272. 290. Ringel I, Horwitz SB: Studies with RP 56976 (taxotere): a semisynthetic analogue of taxol. J Natl Cancer Inst 1991; 83:288–291. 291. Tomiak E, Piccart MJ, Kerger J, et al: Phase I study of docetaxel administered as a 1-hour intravenous infusion on a weekly basis. J Clin Oncol 1994; 12:1458–1467. 292. Burris H, Irvin R, Kuhn J, et al: Phase I clinical trial of taxotere administered as either a 2-hour or 6-hour intravenous infusion. J Clin Oncol 1993; 11:950–958.
293. Bissett D, Setanoians A, Cassidy J, et al: Phase I and pharmacokinetic study of taxotere (RP 56976) administered as a 24-hour infusion. Cancer Res 1993; 53:523–527. 294. Pazdur R, Newman RA, Newman BM, et al: Phase I trial of Taxotere: five-day schedule. J Natl Cancer Inst 1992; 84:1781–1788. 295. Beer TM, Eilers KM, Garzotto M, et al: Weekly high-dose calcitriol and docetaxel in metastatic androgen-independent prostate cancer. J Clin Oncol 2003; 21:123–128. 296. Petrylak DP, Macarthur RB, O’Connor J, et al: Phase I trial of docetaxel with estramustine in androgen-independent prostate cancer. J Clin Oncol 1999; 17:958–967. 297. Savarese D, Taplin ME, Halabi S, et al: A phase II study of docetaxel (Taxotere), estramustine, and low-dose hydrocortisone in men with hormone-refractory prostate cancer: preliminary results of cancer and leukemia group B Trial 9780. Semin Oncol 1999; 26:39–44. 298. Petrylak DP: Docetaxel (Taxotere) in hormonerefractory prostate cancer. Semin Oncol 2000; 27:24–29. 299. Calabro F, Sternberg CN: High-risk metastatic urothelial cancer: chances for cure?, Curr Opin Urol 2002; 12:441–448. 300. Bruntsch U, Heinrich B, Kaye SB, et al: Docetaxel (Taxotere) in advanced renal cell cancer. A phase II trial of the EORTC Early Clinical Trials Group. Eur J Cancer.1994; 30A:1064–1067. 301. Gunnarsson PO, Andersson SB, Johansson SA, Nilsson T, Plym-Forshell G: Pharmacokinetics of estramustine phosphate (Estracyt) in prostatic cancer patients. Eur J Clin Pharmacol.1984; 26:113–119. 302. Gunnarsson PO, Davidsson T, Andersson SB, Backman C, Johansson SA: Impairment of estramustine phosphate absorption by concurrent intake of milk and food. Eur J Clin Pharmacol 1990; 38:189–193. 303. Walz PH, Bjork P, Gunnarsson PO, Edman K, HartleyAsp B: Differential uptake of estramustine phosphate metabolites and its correlation with the levels of estramustine binding protein in prostate tumor tissue. Clin Cancer Res 1998; 4:2079–2084. 304. Smith PH, Suciu S, Robinson MR, et al: A comparison of the effect of diethylstilbestrol with low dose estramustine phosphate in the treatment of advanced prostatic cancer: final analysis of a phase III trial of the European Organization for Research on Treatment of Cancer. J Urol 1986; 136:619–623. 305. Hudes G, Einhorn L, Ross E, et al: Vinblastine versus vinblastine plus oral estramustine phosphate for patients with hormone-refractory prostate cancer: A Hoosier Oncology Group and Fox Chase Network phase III trial. J Clin Oncol 1999; 17:3160–3166. 306. Bracarda S, Tonato M, Rosi P, et al: Oral estramustine and cyclophosphamide in patients with metastatic hormone refractory prostate carcinoma: a phase II study. Cancer 2000; 88:1438–1444. 307. Sumiyoshi Y, Hashine K, Nakatsuzi H, Yamashita Y, Karashima T: Oral estramustine phosphate and oral etoposide for the treatment of hormone-refractory prostate cancer. Int J Urol 2000; 7:243–247.
84 Part I Principles of Urologic Oncology 308. Sangrajrang S, Denoulet P, Millot G, et al: Estramustine resistance correlates with tau over-expression in human prostatic carcinoma cells. Int J Cancer 1998; 77:626–631. 309. Williams JF, Muenchen HJ, Kamradt JM, Korenchuk S, Pienta KJ: Treatment of androgen-independent prostate cancer using antimicrotubule agents docetaxel and estramustine in combination: an experimental study. Prostate 2000; 44:275–278. 310. Stein CA: Mechanisms of action of taxanes in prostate cancer. Semin Oncol 1999; 26:3–7. 311. Weitzman A, Shelton G, Zuech N, et al: Phase II study of estramustine combined with docetaxel in patients with androgen-independent prostate cancer. Proc Am Soc Clin Oncol, Atlanta, GA, 1999, p A1369. 312. Kreis W Budman D:. Daily oral estramustine and intermittent intravenous docetaxel (Taxotere) as chemotherapeutic treatment for metastatic, hormonerefractory prostate cancer. Semin Oncol 1999; 26:34–38. 313. Smith DC, Esper P, Strawderman M, Redman B,Pienta KJ: Phase II trial of oral estramustine, oral etoposide, and intravenous paclitaxel in hormone-refractory prostate cancer. J Clin Oncol 1999; 17:1664–1671. 314. Weitzman AL, Shelton G, Zuech N, et al: Dexamethasone does not significantly contribute to the response rate of docetaxel and estramustine in androgen independent prostate cancer. J Urol 2000; 163:834–837. 315. Kosty MP, Ferreira A, Bryntesen T, Grossman J: Weekly docetaxel and low-dose estramustine phosphate in hormone refractory prostate cancer: a phase II study. Proc Am Soc Clin Oncol, New Orleans, LA, 2000, p A1442. 316. Connors TA, Cox PJ, Farmer PB, Foster AB, Jarman M: Some studies of the active intermediates formed in the microsomal metabolism of cyclophosphamide and isophosphamide. Biochem Pharmacol 1974; 23: 115–129. 317. Dorr RT, Alberts DS: Cimetidine enhancement of cyclophosphamide antitumour activity. Br J Cancer 1982; 45:35–43. 318. Dorr RT, Soble MJ, Alberts DS: Interaction of cimetidine but not ranitidine with cyclophosphamide in mice. Cancer Res 1986; 46:1795–1799. 319. Motzer RJ, Bajorin DF, Bosl GJ:. “Poor-risk” germ cell tumors: current progress and future directions. Semin Oncol 1992; 19:206–214. 320. Cerny T, Margison JM, Thatcher N, Wilkinson PM: Bioavailability of ifosfamide in patients with bronchial carcinoma. Cancer Chemother Pharmacol 1986; 18:261–264. 321. Anderson NR, Tandon DS: Ifosfamide extrapyramidal neurotoxicity. Cancer 1991; 68:72–75. 322. Skinner R, Pearson AD, English MW, et al: Risk factors for ifosfamide nephrotoxicity in children. Lancet 1996; 348:578–580. 323. McCaffrey JA, Mazumdar M, Bajorin DF, et al: Ifosfamide- and cisplatin-containing chemotherapy as first-line salvage therapy in germ cell tumors: response and survival. J Clin Oncol 1997; 15:2559–2563.
324. Motzer RJ, Sheinfeld J, Mazumdar M, et al: Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. J Clin Oncol 2000; 18:2413–2418. 325. Loehrer PJ, Williams SD, Nichols CR, Einhorn LH: Clinical trials with ifosfamide: the Indiana University experience. Semin Oncol 1992; 19:35–39. 326. Roth BJ: Ifosfamide in the treatment of bladder cancer. Semin Oncol 1996; 23:50–55. 327. Bajorin DF, McCaffrey JA, Hilton S, et al: Treatment of patients with transitional-cell carcinoma of the urothelial tract with ifosfamide, paclitaxel, and cisplatin: a phase II trial. J Clin Oncol 1998; 16:2722–2727. 328. Bajorin DF, McCaffrey JA, Dodd PM, et al: Ifosfamide, paclitaxel, and cisplatin for patients with advanced transitional cell carcinoma of the urothelial tract: final report of a phase II trial evaluating two dosing schedules. Cancer 2000; 88:1671–1678. 329. Cohen NA, Egorin MJ, Snyder SW, et al: Interaction of N,N′,N′ ′-triethylenethiophosphoramide and N,N′, N′ ′-triethylenephosphoramide with cellular DNA. Cancer Res 1991; 51:4360–4366. 330. Cohen BE, Egorin MJ, Kohlhepp EA, Aisner J, Gutierrez PL: Human plasma pharmacokinetics and urinary excretion of thiotepa and its metabolites. Cancer Treat Rep 1986; 70:859–864. 331. Wolff SN, Herzig RH, Fay JW, et al: High-dose thiotepa with autologous bone marrow transplantation for metastatic malignant melanoma: results of phase I and II studies of the North American Bone Marrow Transplantation Group. J Clin Oncol 1989; 7:245–249. 332. Vogelzang NJ, Raghavan D, Kennedy BJ: VP-16-213 (etoposide): the mandrake root from Issyk-Kul. Am J Med 1982; 72:136–144. 333. Creaven PJ: The clinical pharmacology of VM26 and VP16-213. A brief overview. Cancer Chemother Pharmacol 1982; 7:133–140. 334. Slevin ML:. The clinical pharmacology of etoposide. Cancer 1991; 67:319–329. 335. Krishan A, Paika K, Frei E, III: Cytofluorometric studies on the action of podophyllotoxin and epipodophyllotoxins (VM-26, VP-16-213) on the cell cycle traverse of human lymphoblasts. J Cell Biol 1975; 66:521–530. 336. Yang L, Rowe TC, Liu LF: Identification of DNA topoisomerase II as an intracellular target of antitumor epipodophyllotoxins in simian virus 40-infected monkey cells. Cancer Res 1985; 45:5872–5876. 337. Jolivet J, Schilsky RL, Bailey BD, Drake JC, Chabner BA: Synthesis, retention, and biological activity of methotrexate polyglutamates in cultured human breast cancer cells. J Clin Invest 1982; 70:351–360. 338. Chu E, Drake JC, Boarman D, Baram J, Allegra CJ: Mechanism of thymidylate synthase inhibition by methotrexate in human neoplastic cell lines and normal human myeloid progenitor cells. J Biol Chem 1990; 265:8470–8478. 339. Borchers AH, Kennedy KA, Straw JA: Inhibition of DNA excision repair by methotrexate in Chinese hamster ovary cells following exposure to ultraviolet
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 85
340.
341.
342.
343.
344.
345.
346. 347.
348.
349. 350.
351.
352.
353.
354.
355.
irradiation or ethylmethanesulfonate. Cancer Res 1990; 50:1786–1789. Chu E, Mota AC, Fogarasi MC: Antimetabolites. In DeVita VTJ, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 6th edition, pp 388–415. Philadelphia, Lippincott, Williams and Wilkins, 2001. Huffman DH, Wan SH, Azarnoff DL, Hogstraten B:. Pharmacokinetics of methotrexate. Clin Pharmacol Ther 1973; 14:572–579. Stoller RG, Hande KR, Jacobs SA, Rosenberg SA, Chabner BA: Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. N Engl J Med 1977; 297:630–634. Stoller RG, Kaplan HG, Cummings FJ, Calabresi P: A clinical and pharmacological study of high-dose methotrexate with minimal leucovorin rescue. Cancer Res 1979; 39:908–912. Conaghan PG, Quinn DI, Brooks PM, Day RO: Hazards of low dose methotrexate. Aust N Z J Med 1995; 25:670–673. Heidelberger C, Chaudhuri NK, Dannenberg P, et al: Fluorinated pyrimidines: a new class of tumor inhibitory compounds. Nature 1957; 179:663. Diasio RB, Harris BE: Clinical pharmacology of 5-fluorouracil. Clin Pharmacokinet 1989; 16:215–237. Salonga D, Danenberg KD, Johnson M, et al: Colorectal tumors responding to 5-fluorouracil have low gene expression levels of dihydropyrimidine dehydrogenase, thymidylate synthase, and thymidine phosphorylase. Clin Cancer Res 2000; 6:1322–1327. Mizutani Y, Wada H, Ogawa O, et al: Prognostic significance of thymidylate synthase activity in bladder carcinoma. Cancer 2001; 92:510–518. Bruckner HW, Creasey WA: The administration of 5-fluorouracil by mouth. Cancer 1974; 33:14–18. Cano JP, Rigault JP, Aubert C, Carcassonne Y, Seitz JF: Determination of 5-fluorouracil in plasma by GC/MS using an internal standard. Applications to pharmacokinetics. Bull Cancer 1979; 66:67–74. Myers CE, Young RC, Chabner BA: Biochemical determinants of 5-fluorouracil response in vivo. The role of deoxyuridylate pool expansion. J Clin Invest 1975; 56:1231–1238. Creaven PJ, Rustum YM, Petrelli NJ, et al: Phase I and pharmacokinetic evaluation of floxuridine/leucovorin given on the Roswell Park weekly regimen. Cancer Chemother Pharmacol 1994; 34:261–265. Meropol NJ, Creaven PJ, Petrelli NJ: Metastatic colorectal cancer: advances in biochemical modulation and new drug development. Semin Oncol 1995; 22:509–524. Petrelli N, Herrera L, Rustum Y, et al: A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma. J Clin Oncol 1987; 5:1559–1565. Evans RM, Laskin JD, Hakala MT: Effect of excess folates and deoxyinosine on the activity and site
356.
357.
358.
359.
360.
361.
362.
363.
364.
365.
366.
367.
368.
369.
370.
of action of 5-fluorouracil. Cancer Res 1981; 41:3288–3295. Baker SD, Diasio RB, O’Reilly S, et al: Phase I and pharmacologic study of oral fluorouracil on a chronic daily schedule in combination with the dihydropyrimidine dehydrogenase inactivator eniluracil. J Clin Oncol 2000; 18:915–926. Khor SP, Amyx H, Davis ST, et al: Dihydropyrimidine dehydrogenase inactivation and 5-fluorouracil pharmacokinetics: allometric scaling of animal data, pharmacokinetics and toxicodynamics of 5-fluorouracil in humans. Cancer Chemother Pharmacol 1997; 39:233–238. Schilsky RL, Hohneker J, Ratain MJ, et al: Phase I clinical and pharmacologic study of eniluracil plus fluorouracil in patients with advanced cancer. J Clin Oncol 1998; 16:1450–1457. McGavin JK, Goa KL: Capecitabine: a review of its use in the treatment of advanced or metastatic colorectal cancer. Drugs 2001; 61:2309–2326. Van Cutsem E, Twelves C, Cassidy J, et al: Oral capecitabine compared with intravenous fluorouracil plus leucovorin in patients with metastatic colorectal cancer: results of a large phase III study. J Clin Oncol 2001; 19:4097–4106. Hoff PM, Cassidy J, Schmoll HJ: The evolution of fluoropyrimidine therapy: from intravenous to oral. Oncologist 2001; 6(Suppl 4):3–11. Wenzel C, Locker GJ, Schmidinger M, et al: Capecitabine in the treatment of metastatic renal cell carcinoma failing immunotherapy. Am J Kidney Dis 2002; 39:48–54. Oevermann K, Buer J, Hoffmann R, et al: Capecitabine in the treatment of metastatic renal cell carcinoma. Br J Cancer 2000; 83:583–587. Keefe DL, Roistacher N, Pierri MK: Clinical cardiotoxicity of 5-fluorouracil. J Clin Pharmacol 1993; 33:1060–1070. Hertel LW, Boder GB, Kroin JS, et al: Evaluation of the antitumor activity of gemcitabine (2′,2′-difluoro-2′deoxycytidine). Cancer Res 1990; 50:4417–4422. Heinemann V, Hertel LW, Grindey GB, Plunkett W: Comparison of the cellular pharmacokinetics and toxicity of 2′,2′ -difluorodeoxycytidine and 1-beta-Darabinofuranosylcytosine. Cancer Res 1988; 48:4024–4031. Heinemann V, Xu YZ, Chubb S, et al: Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2′,2′difluorodeoxycytidine. Mol Pharmacol 1990; 38:567-572. Heinemann V, Schulz L, Issels RD, Plunkett W: Gemcitabine: a modulator of intracellular nucleotide and deoxynucleotide metabolism. Semin Oncol 1995; 22:11–18. Neff T, Blau CA: Forced expression of cytidine deaminase confers resistance to cytosine arabinoside and gemcitabine. Exp Hematol 1996; 24:1340–1346. Goan YG, Zhou B, Hu E, Mi S, Yen Y: Overexpression of ribonucleotide reductase as a mechanism of resistance to 2,2-difluorodeoxycytidine in the human KB cancer cell line. Cancer Res 1999; 59:4204–4207.
86
Part I Principles of Urologic Oncology
371. Dumontet C, Fabianowska-Majewska K, Mantincic D, et al: Common resistance mechanisms to deoxynucleoside analogues in variants of the human erythroleukaemic line K562. Br J Haematol 1999; 106:78–85. 372. Ruiz van Haperen VW, Peters GJ: New targets for pyrimidine antimetabolites for the treatment of solid tumours. 2: Deoxycytidine kinase. Pharm World Sci 1994; 16:104–112. 373. Gandhi V, Legha J, Chen F, Hertel LW, Plunkett W: Excision of 2′,2′ -difluorodeoxycytidine (gemcitabine) monophosphate residues from DNA. Cancer Res 1996; 56:4453–4459. 374. Abbruzzese JL, Grunewald R, Weeks EA, et al: A phase I clinical, plasma, and cellular pharmacology study of gemcitabine. J Clin Oncol 1991; 9:491–498. 375. von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study,. J Clin Oncol 2000; 18:3068–3077. 376. O’Rourke TJ, Brown TD, Havlin K, et al: Phase I clinical trial of gemcitabine given as an intravenous bolus on 5 consecutive days. Eur J Cancer 1994; 30A:417–418. 377. Touroutoglou N, Gravel D, Raber MN, Plunkett W, Abbruzzese JL: Clinical results of a pharmacodynamically-based strategy for higher dosing of gemcitabine in patients with solid tumors. Ann Oncol 1998; 9:1003–1008. 378. Gandhi V, Plunkett W, Du M, Ayres M, Estey EH: Prolonged infusion of gemcitabine: clinical and pharmacodynamic studies during a phase I trial in relapsed acute myelogenous leukemia. J Clin Oncol 2002; 20:665–673. 379. Grunewald R, Abbruzzese JL, Tarassoff P, Plunkett W: Saturation of 2′ ,2′-difluorodeoxycytidine 5′-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine. Cancer Chemother Pharmacol 1991; 27:258–262. 380. Grunewald R, Kantarjian H, Du M, et al: Gemcitabine in leukemia: a phase I clinical, plasma, and cellular pharmacology study. J Clin Oncol 1992; 10:406–413. 381. Patel SR, Gandhi V, Jenkins J, et al: Phase II clinical investigation of gemcitabine in advanced soft tissue sarcomas and window evaluation of dose rate on gemcitabine triphosphate accumulation. J Clin Oncol 2001; 19:3483–3489. 382. Pollera CF, Ceribelli A, Crecco M, Calabresi F: Weekly gemcitabine in advanced bladder cancer: a preliminary report from a phase I study. Ann Oncol 1994; 5:182–184. 383. Stadler WM, Kuzel T, Roth B, Raghavan D, Dorr FA: Phase II study of single-agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol 1997; 15:3394–3398. 384. Kaufman D, Raghavan D, Carducci M, et al: Phase II trial of gemcitabine plus cisplatin in patients with metastatic urothelial cancer. J Clin Oncol 2000; 18:1921–1927. 385. De Mulder PH, Weissbach L, Jakse G, Osieka R, Blatter J: Gemcitabine: a phase II study in patients with
386.
387.
388.
389.
390.
391.
392.
393.
394.
395.
396.
397.
398. 399.
400.
advanced renal cancer. Cancer Chemother Pharmacol 1996; 37:491–495. Rini BI, Vogelzang NJ, Dumas MC, et al: Phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil in patients with metastatic renal cell cancer. J Clin Oncol 2000; 18:2419–2426. Morant R, Bernhard J, Maibach R, et al: Response and palliation in a phase II trial of gemcitabine in hormonerefractory metastatic prostatic carcinoma. Swiss Group for Clinical Cancer Research (SAKK). Ann Oncol 2000; 11:183–188. Hinton S, Catalano P, Einhorn LH, et al: Phase II study of paclitaxel plus gemcitabine in refractory germ cell tumors (E9897): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2002; 20:1859–1863. Bokemeyer C, Gerl A, Schoffski P, et al: Gemcitabine in patients with relapsed or cisplatin-refractory testicular cancer. J Clin Oncol 1999; 17:512–516. Wall ME, Wani MC, Taylor H: Isolation and chemical characterization of antitumor agents from plants. Cancer Treat Rep 1976; 60:1011–1030. Gottlieb JA, Guarino AM, Call JB, Oliverio VT, Block JB: Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC-100880). Cancer Chemother Rep 1970; 54:461–470. Muggia FM, Creaven PJ, Hansen HH, Cohen MH, Selawry OS: Phase I clinical trial of weekly and daily treatment with camptothecin (NSC-100880): correlation with preclinical studies. Cancer Chemother Rep 1972; 56:515–521. Moertel CG, Schutt AJ, Reitemeier RJ, Hahn RG: Phase II study of camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother Rep 1972; 56:95–101. Hsiang YH, Hertzberg R, Hecht S, Liu LF: Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 1985; 260:14873–14878. Hsiang YH, Liu LF: Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 1988; 48:1722–1726. Hsiang YH, Lihou MG, Liu LF: Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 1989; 49:5077–5082. Hsiang YH, Liu LF, Wall ME, et al: DNA topoisomerase I-mediated DNA cleavage and cytotoxicity of camptothecin analogues. Cancer Res 1989; 49:4385–4389. Liu LF: DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem 1989; 58:351–375. Hertzberg RP, Busby RW, Caranfa MJ, et al: Irreversible trapping of the DNA-topoisomerase I covalent complex. Affinity labeling of the camptothecin binding site. J Biol Chem 1990; 265:19287–19295. Li XG, Haluska P, Jr, Hsiang YH, et al: Identification of topoisomerase I mutations affecting both DNA cleavage and interaction with camptothecin. Ann N Y Acad Sci 1996; 803:111–127.
Chapter 4 Principles of Chemotherapy for Genitourinary Cancer 87 401. Hertzberg RP, Caranfa MJ, Holden KG, et al: Modification of the hydroxy lactone ring of camptothecin: inhibition of mammalian topoisomerase I and biological activity. J Med Chem 1989; 32: 715–720. 402. Slichenmyer WJ, Rowinsky EK, Donehower RC, Kaufmann SH: The current status of camptothecin analogues as antitumor agents. J Natl Cancer Inst 1993; 85:271–291. 403. Negoro S, Fukuoka M, Masuda N, et al: Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer. J Natl Cancer Inst 1991; 83:1164–1168. 404. Rowinsky EK, Grochow LB, Ettinger DS, et al: Phase I and pharmacological study of the novel topoisomerase I inhibitor 7-ethyl-10-[4-(1-piperidino)-1piperidino]carbonyloxycamptothecin (CPT-11) administered as a ninety-minute infusion every 3 weeks. Cancer Res 1994; 54:427–436. 405. Abigerges D, Armand JP, Chabot GG, et al: Irinotecan (CPT-11) high-dose escalation using intensive high-dose loperamide to control diarrhea. J Natl Cancer Inst 1994; 86:446–449. 406. Abigerges D, Chabot GG, Armand JP, et al: Phase I and pharmacologic studies of the camptothecin analog irinotecan administered every 3 weeks in cancer patients. J Clin Oncol 1995; 13:210–221.
407. Kaneda N, Nagata H, Furuta T, Yokokura T: Metabolism and pharmacokinetics of the camptothecin analogue CPT-11 in the mouse. Cancer Res 1990; 50:1715–1720. 408. Rowinsky EK, Grochow LB, Hendricks CB, et al: Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol 1992; 10:647–656. 409. Saltz L, Sirott M, Young C, et al: Phase I clinical and pharmacology study of topotecan given daily for 5 consecutive days to patients with advanced solid tumors, with attempt at dose intensification using recombinant granulocyte colony-stimulating factor. J Natl Cancer Inst 1993; 85:1499–1507. 410. Haas NB, LaCreta FP, Walczak J, et al: Phase I/pharmacokinetic study of topotecan by 24-hour continuous infusion weekly. Cancer Res 1994; 54:1220–1226. 411. Hochster H, Liebes L, Speyer J, et al: Phase I trial of low-dose continuous topotecan infusion in patients with cancer: an active and well-tolerated regimen. J Clin Oncol 1994; 12:553–559. 412. Hochster H, Liebes L, Speyer J, et al: Effect of prolonged topotecan infusion on topoisomerase 1 levels: a phase I and pharmacodynamic study. Clin Cancer Res 1997; 3: 1245–1252.
C H A P T E R
5 Immunotherapy: Basic Guidelines Jason B. Wynberg, MD, FRCSC, W. Marston Linehan, MD, and Richard Childs, MD
Harnessing the power of the immune system against malignant cells is often thought of as a relatively modern treatment modality for patients with advanced cancer. However, more than 100 years have passed since the first report was published by Dr. W. Coley documenting immune-mediated disease regression against cancer following injections of bacterial toxins directly into tumor lesions.1 Since then, investigators have gained tremendous insight into the mechanisms by which tumors are able to evade the innate immune system2–4 (Table 5-1) and remain resistant to “conventional” cancer immunotherapies. The steady expansion in our knowledge of tumor biology over the past few decades is gradually being translated into improvements in the efficacy and safety of cancer immunotherapeutics. CYTOKINE THERAPY Cytokines are protein molecules produced and secreted by immune and inflammatory cells that bind to complementary cytokine receptors resulting in either the stimulation or inhibition of immune cells. Cytokines usually act in an autocrine or paracrine fashion, in contrast to hormones, which typically act at a distance from their cells of origin. Following the binding of the cytokine to its receptor target, cell signaling is initiated through intracellular pathways, such as the Jak-STAT tyrosine kinase, Src, Zap70 and related proteins, phosphatidylinositol 3-kinase, IRS-1, IRIS-2, and phosphatases.5 Cytokines that typically up-regulate immune responses include interleukin-2 (IL-2) and interferon (IFN), whereas cytokines that typically down-regulate immune responses include transforming growth factor β, interleukin-6, and interleukin-10. Through their secretion of immunosuppressive cytokines (e.g., transforming growth factor β), certain tumors are able to directly impair the hosts’ immune defenses. Interestingly, some tumors can stimulate their own proliferation by secreting IL-2, which
88
binds to IL-2 receptors expressed on their cell surfaces. Administration of IL-2 at pharmacologic doses, as is done in the treatment of metastatic renal cell carcinoma (RCC), appears to directly interrupt this autocrine pathway.6,7 The field of cytokine therapeutics has grown dramatically since the development of recombinant DNA technology in the 1980s, which enabled cytokines to be produced in large quantities.8–10 A discussion of the cytokines commonly administered in the setting of advanced urologic malignancy is presented below. Interleukin-2 and Interferon-a Background In 1992, the Food and Drug Administration (FDA) approved high-dose IL-2 for the treatment of metastatic RCC.11 Although the precise mechanism accounting for tumor regression in RCC patients treated with IL-2 is not known,12 many in vitro effects of IL-2 on immune effector populations have been characterized (Table 5-2).13,14 Whereas IL-2 and resting lymphocytes separately fail to kill RCC tumor cells, prior incubation of the same lymphocytes with IL-2 significantly augments their in vitro tumor cytotoxicity. These observations provided some of the first preclinical evidence that the immune system could mediate antitumor effects, providing theoretical grounds for the pursuit of immune-based cancer therapy in humans. Unlike the interleukins, IFNs are a family of proteins secreted by leukocytes in response to viral infection and other antigenic stimuli. IFNs have powerful antiproliferative and immunoregulatory activity (Table 5-3),13 such as up-regulation of class I and class II major histocompatibility complex (MHC) molecules.15 When administered in a therapeutic setting, IFN-α is typically given as a subcutaneous injection. Due to its relatively short half-life, IFN-α is most commonly administered at least three times per week. Recently,
Chapter 5 Immunotherapy: Basic Guidelines 89
Table 5-1 Mechanisms of Tumor Escape from Immune System Tumor-related
Host-related
Decreased tumor Ag expression Decreased MHC class I expression Failure to express immune costimulatory molecules (e.g., B7.1) Production of immune inhibitors (e.g., TGFβ, IL-6, IL-10, free tumor Ag) Tumor antigens weakly immunogenic Induction of T cell apoptosis by tumor expression of Fas ligand (FasL)
Antigen-specific suppressor T cells Deficient presentation of tumor antigens by host antigen-presenting cells Failure of host effectors to reach the tumor (e.g., stromal barrier) Immune dysfunction due to carcinogen, infections, age
Development of T cell anergy or tolerance to tumor antigens
MHC, major histocompatibility complex; TGFβ, transforming growth factor β; Ag, antigen.
Table 5-2 Effects of Interleukin-2 Proliferation of T cells, B cells, NK cells, and monocytes Potentiation of Fas-mediated apoptosis of T cells to prevent clonal persistence Induction of antibody synthesis by B cells No direct anti-tumor activity
Table 5-3 Effects of Interferon-alfa Direct antiproliferative effects on tumor and other tissues Antiviral activity Occasionally promotes partial reversal of the malignant phenotype Increases expression of MHC molecules and tumorassociated Ags Activates T cells, augments NK cell function Upregulates macrophage antigen presentation Increases macrophage production of angiogenesis-inhibitor MHC, major histocompatibility complex; NK, natural killer; Ag, antigen.
investigators have shown that the serum half-life of IFNα-2b can be extended dramatically by covalently linking polyethylene glycol (PEG) to its histidine-34 moiety, thus making dosing schedules more convenient16. IFNs may have direct antitumor effects against a variety of malignancies, including hairy cell leukemia, cervical intraepithelial neoplasia, basal cell cancer, Kaposi’s sarcoma, melanoma, renal cell carcinoma, multiple myeloma, and chronic myelogenous leukemia.13
Cytokine Therapy as Treatment of Metastatic Renal Cell Carcinoma Despite early enthusiasm based on favorable outcome of pilot clinical trials, neither IL-2 nor IFN-α has proven to be a panacea for the treatment of metastatic RCC (Table 5-4).17–30 Unfortunately, the great majority of patients treated with either cytokine fail to respond, with median survival typically being 2 years or less. Despite their overall low response rate, however, some patients clearly benefit from treatment with IL-2 and IFN-α. Partial responses, defined as a ≥50% reduction in the sum of the products of maximal perpendicular diameters of all measurable metastatic lesions, occur in approximately 15% of patients treated with either IL-2 or IFN-α (see Table 5-4). Although partial responses can be associated with significant disease palliation, longterm survival in partial responders is a rare event. Among patients who achieve a complete response (defined as the complete disappearance of all evidence of metastatic disease for at least 1 month) to high-dose IL2 therapy, 60% to 90% remain alive and free of disease for 8–10 years after treatment. In contrast, virtually no evidence exists of long-term survival following IFNbased therapy (see Table 5-4). It is, therefore, not surprising that many urologists and oncologists consider high-dose IL-2 to be superior to IFN-α in the treatment of metastatic RCC. Nonetheless, many oncologists continue to treat metastatic RCC patients with IFN-α, largely due to concerns regarding the substantial toxicities associated with high-dose IL-2. Toxicities associated with high-dose IL-2 therapy are primarily the consequence of a cascade of cytokines being released from circulating leukocytes following drug exposure. This cytokine shower can significantly increase capillary permeability, leading to dramatic fluid shifts, reduced peripheral vascular resistance, and sometimes profound hypotension, renal failure, and pulmonary edema. The severity of these symptoms is dose dependent. Toxicities related to IFN therapy are also dose and schedule dependent, and include primarily
85 93 86 93 75 87 82 79 100 100 92 52 86
References Fisher et al.17 Yang et al.18 Dutcher et al.19 Yang et al.18 McDermott et al.21 Dutcher et al.22 Rogers et al.23 Negrier et al.24 Mickisch et al.25 Flanigan et al.26 Negrier et al.27 Motzer et al.29 Gleave et al.30*
Subcutaneous IL-2
Subcutaneous IL-2/IFN-α
91
145
147
92
42
70
33
47
94
150
71
156
255
N
12
15
13
11.1
17
13
10
20
NA
18
15.5
18
16.3
Median Survival (Months)
1
6
5
3
7
2
9
13
10
9
11
14
8
PR (%)
3
1
1
0
12
0
0
4
2
4
7
7
7
CR (%)
No long-term data available
No long term data available
One CR alive, NED at 10 years28
Not applicable—no CRs
No long-term data available
Not applicable—no CRs
No long-term data available
One CR alive at 49 (+) months
No long-term data available
50% of CRs alive, NED at median 10.1 years
90% of CRs alive, NED at >8 years20
73% of CRs alive, NED at median 9.3 years
>60% of CRs alive, NED at 10 years
Long-Term Survival of CRs
IL-2, interleukin-2; IFN-α, interferon-alpha; RCC, renal cell carcinoma; N, number of patients; CR, complete response; PR, partial response; IV, intravenous; mos., months; NED, no evidence of disease; NA, not available. Note: No treatment-related mortalities were experienced in any of the above studies, except for Fisher et al.17, in which 4% of patients receiving high-dose IL-2 died of treatment-related complications. *IFN-γ rather than IFN-α was used in this study.
Subcutaneous IFN
High-dose IV IL-2
Prior Nephrectomy (%)
Table 5-4 Treatment with Il-2 or IFN-α in Metastatic Clear Cell RCC
90 Part I Principles of Urologic Oncology
Chapter 5 Immunotherapy: Basic Guidelines 91
hematologic effects (i.e., bone marrow suppression and cytopenias) and flu-like symptoms.13,15,25 A large preliminary series of patients given high-dose IL-2 at the National Cancer Institute reported a 4% treatmentrelated mortality rate.17 Because this mortality rate approached the complete response rate with high-dose IL-2, many oncologists still consider it unacceptable to have one regimen-related death for every patient cured with this therapy. Since its initial use, the mortality rate related to highdose IL-2 therapy has dropped dramatically at the National Cancer Institute, with no deaths among the last 800+ patients treated. This improvement in outcome is likely multi-factorial, owing to alterations in eligibility criteria, the treatment regimen, and improvements in supportive care.31 Other groups similarly contend that high-dose IL-2 can be given safely when patients are carefully selected and treatment is given in a wellmonitored setting.32,33 Despite improvements in morbidity related to highdose IL-2 therapy, there has been considerable interest in the development of low-dose IL-2 regimens in the hope of reducing drug-related complications. A randomized study comparing high-dose versus low-dose IL-2 in the setting of metastatic RCC has recently been completed.18 The vast majority of patients enrolled on this trial (93%) had previously undergone cytoreductive nephrectomy. Although no regimen-related mortalities occurred in this study, toxicities were greater in the high-dose IL-2 arm compared to the low-dose IL-2 arm, especially in terms of clinically significant hypotensive episodes (36.4% versus 2.9%, respectively). The overall response rate (CR + PR) was higher in the high-dose versus the low-dose arm (21% versus 13%, p = 0.048). Importantly, the durability of responses among complete responders was superior in the high-dose arm (73% disease-free + an additional 18%
disease-free following a resection of limited recurrent disease = total 91% alive and disease-free at a median of 9.3 years) compared to the low-dose arm (50% alive and disease-free at a median of 10.1 years) (Figure 5-1A). However, no difference in overall survival was observed between the high-dose and low-dose cohorts (Figure 5-1B), again reflecting the unfortunate fact that complete responders to any form of IL-2 therapy are in the significant minority. Another prospective randomized study compared lowdose intravenous IL-2 (group 1) versus subcutaneous IFN-α-2a (group 2) versus both drugs combined (group 3) in patients with metastatic RCC.27 A total of 425 patients were randomized between 1992 and 1995 into one of three treatment groups. As with the previous trial, the majority of patients (>90%) enrolled in the study had undergone a prior nephrectomy. Toxicities were most evident among those receiving IL-2 (groups 1 and 3), including 67% who became hypotensive and 50% who experienced high fevers. Importantly, all patients ultimately recovered from these adverse events and returned to their pretreatment status. Response rates were 6.5%, 7.5%, and 18.6% (p < 0.01) for patients receiving IL-2, IFN-α-2a, and IL-2 plus IFN-α-2a, respectively. Although the response rate was higher among those receiving both IL-2 and IFN-α, no longterm survival benefit was observed in this group (Figure 5-2). Biochemotherapy is another field of research wherein chemotherapeutic drugs are administered concomitant with biologic agents, such as IL-2, in hopes of improving therapeutic indices. 5-Flurouracil (5-FU) has been the most widely used chemotherapeutic agent that has been combined with cytokines in the setting of advanced RCC, with response rates up to 30% in several small studies. However, the vast majority of responses are par-
1.0
1.0
0.7 0.6 0.5 Low dose
0.4 0.3
p2 = 0.04
0.2
0.8 0.7 0.5 0.4 0.3 0.1 0.0
24
36
48
60
72
84
Survival time in months
96 108 120 132
High dose (fail/total = 117/155)
0.2
0.0 12
High-dose versus low-dose (p = 0.41)
0.6
0.1 0
A
0.9
High dose
0.8
Proportion surviving
Proportion surviving
0.9
Low dose (fail/total = 121/150) 0
B
12
24
36
48
60
72
84
Survival time in months
Figure 5-1 A, Disease-free survival in patients achieving a complete response with high-dose or low-dose IL-2. B, Survival by treatment received—high-dose or low-dose IL-2. (From Yang JC, Sherry RM, Steinberg SM, et al: J Clin Oncol 2003; 21(16): 3127-3132, with permission.)
96 108 120 132
92
Part I Principles of Urologic Oncology
Overall survival (%)
100
Interferon alfa-2a
90
Interleukin-2 + interferon alfa-2a
80
Interleukin-2
70 60 50 40 30 20 10 0 0
6
12
18
24
30
36
Months after randomization Kaplan-Meier curves for overall survival among patients in the three treatment groups. Tick marks represent censored data on patiients who were alive or lost to follow-up. The results shown are from an intention-to-treat analysis. p = 0.55 for the comparison among the groups.
Figure 5-2 Overall survival in patients treated with IFN-α-2a with or without IL-2. (Based on Negrier S, Escudier B, Lasset C, et al: N Engl J Med 1998; 338(18):1272–1278, with permission.)
tial only, with no data supporting long-term disease-free survival using this approach.34 Reactive oxygen species (ROS) are released by tumor infiltrating monocytes and macrophages and inhibit cytokine-stimulated lymphocytes. Histamine dihydrochloride is a biogenic amine that inhibits the formation of ROS and has been used in clinical trials as an adjuvant to IL-2 and IFN-α with a view to reducing oxidative inhibition of lymphocytes.35 Although clinical efficacy has been observed in melanoma patients,36 no benefit has yet been observed in the setting of advanced RCC.37 Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) is a trans-membrane protein expressed on immune cells that plays a primary role in natural killer cell-mediated tumor surveillance. Based on its high specificity and cytotoxicity against tumor cells in vitro, TRAIL remains as an active area of research.38–40 Intravesical Interferon Therapy for the Treatment of Superficial Bladder Cancer Intravesical IFN-α is currently being evaluated as an immunotherapeutic agent in patients with superficial bladder cancer. Interim results from a national multicenter phase II trial of combination Bacille Calmette-Guerin (BCG) plus IFN-α-2b suggest that this agent has biologic activity in this setting.41 A total of 337 patients who could be evaluated with moderate to high-risk superficial tumors (BCG naïve = 206 patients, BCG failures = 131 patients) received induction, followed by maintenance courses of BCG + IFN-α. At a median follow-up of 24 months, the simple tumor recurrence rates were 35% for
BCG-naïve patients and 53% for BCG-failure patients. Kaplan– Meier estimates for freedom-from-disease were 71% and 61% for BCG-naïve patients and 53% and 40% for BCG-failure patients at 1 and 2 years, respectively. The toxicity-related premature dropout rate among BCG-naïve patients was 3.7% and among BCG-failure patients was 7.3%. This multicenter trial substantiates the earlier encouraging reports of the efficacy of combination BCG + IFN as upfront and salvage therapy for patients with moderate to high-risk superficial bladder cancer.41–43 Longer follow-up will be needed to define the ultimate role this cytokine will play in the treatment of superficial bladder cancer. Colony-Stimulating Factors Both granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) are recombinant cytokines that stimulate the bone marrow to increase production of neutrophils, monocytes, eosinophils, and dendritic cells. Both cytokines are used clinically to speed recovery from chemotherapy-induced neutropenia. Because GM-CSF also has immunomodulatory effects (Table 5-5),13,44 investigators have explored whether this agent has immunotherapeutic activity in RCC patients. Unfortunately, to date no significant clinical benefits have been attributable to this cytokine.45–48 BACILLE CALMETTE-GUERIN Intravesical BCG for bladder cancer represents one of the most clinically successful applications of nonspecific
Chapter 5 Immunotherapy: Basic Guidelines 93
Table 5-5 Effects of GM-CSF Activates macrophages, monocytes, and dendritic cells Enhances tumoricidal activity of macrophages and monocytes against tumor Upregulates macrophage antigen presentation Increases macrophage production of angiogenesis-inhibitor Enhances antibody-dependent cellular toxicity Chemotactic for monocytes and polymorphonuclear cells GM-CSF, granulocyte-macrophage colony-stimulating factor.
immunotherapy. The immunologic events associated with the BCG-induced antitumor responses are not well understood, however, it is clear that stimulation of T lymphocytes with subsequent T-cell cytokine secretion are downstream effects of BCG that are critical to its antitumor activity.49–51 The clinical results of intravesical BCG as treatment for patients with superficial bladder cancer are discussed in detail in Chapter 18. ADOPTIVE CELLULAR THERAPY Lymphokine-Activated Killer Cells Lymphokine-activated killer (LAK) cells are generated ex vivo by collecting circulating lymphocytes by large volume of lymphocytapheresis and incubating them in IL-2rich media for several days (Figure 5-3A). Although LAK cells have shown dramatic MHC class I nonrestricted cytotoxicity against RCC and other tumor cells in vitro, their clinical value in humans is questionable, as two phase III randomized trials failed to demonstrate a survival advantage in metastatic RCC patients treated with LAK cells + high-dose IL-2 compared to those who received high-dose IL-2 alone.52,53 Tumor-Infiltrating Lymphocytes Tumor-infiltrating lymphocytes (TILs) are lymphocytes (T cells + NK cells) that are extracted from fresh tumor specimens (e.g., nephrectomies) and expanded in vitro in IL-2-rich media (see Figure 5-3B). By virtue of their having infiltrated into tumor tissue and their previously demonstrated antitumor activity in vitro (class I MHC restricted), TILs are thought to contain a population of T cells that recognize antigens specific to the tumor. Following in vitro expansion, TILs are reinfused into the patient along with other immunomodulators, such as IL-2. A trial evaluating TIL + IL-2 in patients who failed in previous IL-2-based therapy for metastatic melanoma or RCC demonstrated a 14% response rate.54 Given the historical data showing the ineffectiveness of IL-2
retreatment in patients who had previously failed IL-2, these data provided indirect evidence suggesting in vivo activity of TIL in humans. However, in a follow-up multicenter, randomized phase III trial of TILs with IL-2 in the setting of metastatic RCC, patients who received TILs + IL-2 failed to have a survival advantage or improved response rate compared to those receiving IL-2 alone (see Figure 5-3B).55 Although unselected TILs appear to be of limited benefit in patients with metastatic RCC, a recent study demonstrated significant clinical benefits when TILs, prescreened in vitro for cytotoxicity against melanoma cells, were expanded and then given back to melanoma patients following nonmyeloablative immunosuppression (see Figure 5-3C).56 It has been hypothesized that immunodepleting chemotherapy given with this regimen may have created “immunologic space” or perhaps obliterated T-suppressor cell populations, allowing for an increased in vivo expansion of melanoma-toxic TIL. HEMATOPOIETIC CELL TRANSPLANTATION Approximately 35 years ago, allogeneic hematopoietic stem cell transplantation (HCT) was devised as a method to maximize the dose of chemotherapy that could be given to patients with advanced malignancies. It was hypothesized that patients with chemotherapy-resistant tumors might benefit from “dose-intensification,” largely based on evidence showing a dose–response relationship of some neoplasms to chemotherapy. The transplantation of HLA-matched hematopoietic stem cells (the allograft) is used as a means of regenerating hematopoiesis rendered defunct as a consequence of intensive chemotherapy (the conditioning regimen). The traditional method of harvesting hematopoietic stem cells is via multiple bone marrow aspirations from the posterior iliac crest under general anesthetic. Alternatively, G-CSF, GM-CSF, or even low-dose chemotherapy, can be used to mobilize bone marrow stem cells, which are then collected from the peripheral circulation by leukapheresis. The actual bone marrow transplant involves simply infusing the allograft into one of the patient’s peripheral or central veins. The infusion of the donor allograft (referred to as “day 0”) is usually performed 1–2 days following the completion of the conditioning regimen.57 The allograft consists of not only donor hematopoietic stem cells but also immune cells (including NK, B, and T-cells) that were eradicated in the patient by the conditioning regimen. Patients typically receive immunosuppressive drugs, such as cyclosporine (CSA), or tacrolimus, for the first 3–6 months following the procedure to prevent the donor immune cells from attacking normal host tissues, such as the liver, GI tract, or skin, a complication known as graft-versus-host disease (GVHD).
Tumor infiltrating lymphocytes (TILs) extracted from renal cell carcinoma
Lymphocytes isolated from circulating blood on days 8–10 ( ) (following IL-2)
In vitro screening of TILs against melanoma cells
1 4 7 10 13 16 19 22 25 28 31
1 4 7 10 13 16 19 22 25 28 31
1 4 7 10 13 16 19 22 25 28 31
Single treatment cycle (days)
Figure 5-3 Newer methods of adoptive immunotherapy. A, LAK cells. (Based on Law TM, Motzer RJ, Mazumdar M, et al: Cancer 1995; 76(5):824–832, with permission.) B, TIL cell. (Based on Figlin RA, Thompson JA, Bukowski RM, et al: J Clin Oncol 1999; 17(8):2521–2529, with permission.) C, Tumoricidal TILs. (Based on Dudley ME, Wunderlich JR, Robbins PF, et al: Science 2002; 298(5594):850–854, with permission.)
RCC, Renal cell carcinoma.
Immunodepleting chemotherapy.
Tumor with infiltrating lymphocytes (TILs).
Lymphocyte infusion.
Tumoricidal TILs + IL-2 14 days
Unselected TILs + IL-2 ⫻ 5 days
Lymphocytes + IL-2 ⫻ 5 days
Preparation of lymphocytes
Leukapheresis (collection of lymphocytes from peripheral blood).
Intravenous IL-2.
Immunodepleting C chemotherapy + Tumor infiltrating lymphocytes (TILs) Tumoricidal extracted from melanoma tumor TILs
Tumor infiltrating B lymphocytes (TILs)
Lymphokine A activated killer cells (LAK cells)
Collection of lymphocytes
Partial response in 6/13 melanoma patients; no complete responses56
No improvement in objective response rate over IL-2-alone regimen in metastatic RCC patients52,53,55
Results
94 Part I Principles of Urologic Oncology
Chapter 5 Immunotherapy: Basic Guidelines 95
In conventional myeloablative HCT, the primary antitumor effect comes from the high-dose chemotherapy and/or total body irradiation (conditioning regimen) (Table 5-6). The term “myeloablative” indicates that the patient’s bone marrow is totally obliterated as a result of these highly cytotoxic interventions. It is now known that powerful antitumor effects against those malignant cells surviving high-dose conditioning are generated by donor lymphocytes transplanted with the allograft. This allogeneic immune-mediated antineoplastic effect, called graft-versus-leukemia (GVL) or graft-versus-tumor (GVT), is capable of curing patients with a variety of treatment-refractory hematologic malignancies. Knowledge of RCCs susceptibility to immune effectors has recently led investigators to test allogeneic transplantation as a form of immunotherapy in patients with metastatic RCC. Pilot trials were based on the hypothesis that GVT effects, analogous to the GVL effect seen in leukemias and lymphomas, might be generated following the transplantation of allogeneic donor T cells.58 Nonmyeloablative Hematopoietic Cell Transplantation “Mega-dose” conditioning is largely responsible for the 25% to 35% regimen-related mortality associated with traditional myeloablative HCT. The powerful and curative capacity of the GVT effect has recently brought into question the need for toxic myeloablative conditioning regimens. Reduced intensity conditioning regimens or nonmyeloablative transplants were proposed as a potentially less toxic alternative to conventional HCT. In contrast to a myeloablative HCT, the primary antitumor effect in a nonmyeloablative HCT results from the immune cells that are transferred to the patient from the immunocompetent HLA-matched donor. In this setting, the conditioning regimen serves primarily to suppress the patient’s immune system just enough to prevent host rejection of the donor allograft (see Table 5-6). Accordingly, the dose of chemotherapy and toxicities related to the conditioning regimen are less following nonmyeloablative compared to myeloablative HCT. After donor cell engraftment, the patient’s hematopoietic
cells typically contain cells from both the patient and the donor, a condition referred to as mixed chimerism (in Greek mythology, a Chimaira was a fire-spouting monster with a lion’s head, goat’s body, and serpent’s tail).59 Mixed chimerism results in a “tolerogenic state,” meaning that the immune cells that develop from the donor’s engrafted cells are unable to kill the patient’s tumor. In order for these cells to acquire antitumor activity, the hematopoietic environment needs to transition to “full donor chimerism,” in which patient’s immune system is completely replaced by donor cells. This transformation is facilitated by the withdrawal of posttransplant immunosuppression (e.g., tacrolimus or cyclosporine) and the administration of donor lymphocyte infusions.60 Nonmyeloablative HCT is capable of inducing curative GVT effects against a number of hematologic malignancies. Equally important, preliminary data show the approach is associated with a lower risk of regimen-related mortality (7.5% to 18%) compared to conventional myeloablative procedures (25% to 35%). The improved toxicity profile observed with nonmyeloablative HCT has provided the basis for exploring allogeneic immunotherapy’s potential to induce GVT effects in patients with treatment-refractory solid tumors. Recently, a few groups have published the results of pilot trials investigating nonmyeloablative HCT for the treatment of cytokinerefractory metastatic RCC. The strategy used at the National Institutes of Health involves nonmyeloablative conditioning with a cyclophosphamide and fludarabinebased regimen, intended to induce host immunosuppression, followed by infusion of a G-CSF mobilized peripheral blood stem cell graft from an HLA-identical sibling donor (Figure 5-4). Ten of the first nineteen61 and subsequently 22 of the first 55 patients undergoing this approach had evidence for a GVT effect, including 6 patients who had a complete response and 15 with a partial response. Many of the responses were durable, including the first patient treated who remains in complete remission 512 years after transplantation. GVHD was the most common complication, with approximately two-thirds of the patients experiencing acute grade II–IV GVHD. However, patients developing this complication were more likely to have a disease response than those who never developed
Table 5-6 Allogeneic Hematopoietic Cell Transplantation (HCT) Conditioning Regimen
Source of Transplanted Cells
Mechanism of Tumor Regression
Myeloablative allogeneic HCT (Conventional HCT)
High-dose chemotherapy +/− Total Body XRT
HLA-compatible donor
Conditioning regimen and graft-versus-tumor effects
Non-myeloablative HCT (“Mini-transplant”)
Low-dose chemotherapy +/− Low-dose total body XRT
HLA-compatible donor
Immune mediated via graft-versus-tumor effects
HCT, Hematopoietic cell transplantation; HLA, Human leukocyte antigen; XRT, External beam radiation therapy.
96
Part I Principles of Urologic Oncology
Transfuse donor T-cells (DLI)
Nonmyeloablative chemotherapy Transplant day –7 –6 –5 –4 –3 –2 –1
30
45
60
100
GVT effect
Transfuse the allograft
Taper dose of cyclosporine Cyclosporine DLI, Donor lymphocyte infusion; GVT, Graft-versus-tumor.
Figure 5-4 Nonmyeloablative hematopoietic cell transplantation.
GVHD.61 Disease regression was typically delayed by 4–6 months following the procedure, and occurred after cyclosporine had been tapered and after T-cell chimerism had converted to predominantly donor in origin. Despite the advanced disease status of patients enrolled on this pilot trial, transplant-related mortality was relatively low, with 6 patients succumbing to nonrelapse-related mortality. Figure 5-5 shows a clinical response following nonmyeloablative HCT in a patient with metastatic RCC that
was refractory to high-dose IL-2. Preliminary experience would suggest that certain patient and tumor characteristics herald a better outcome, such as small tumor burden, lung-only disease, slow rate of tumor growth, and good patient performance status. Several other groups have recently reported graft-versus-RCC effects following nonmyeloablative HCT. Using cyclophosphamide and fludarabine for pretransplant conditioning, investigators at the University of Chicago achieved complete donor
Prior to graft-versus-tumor effect Day 100 Posttransplant
A-1
Day 100 Posttransplant
B-1 Following graft-versus-tumor effect Day 189 Posttransplant
A-2
Day 189 Posttransplant
B-2
Figure 5-5 Clinical response following nonmyeloablative hematopoietic cell transplantation in a patient with metastatic refractory RCC.
Chapter 5 Immunotherapy: Basic Guidelines 97
success of antiCD20 (Rituximab) for low-grade lymphomas and antiHER-2 (Herceptin) for breast carcinoma, monoclonal antibodies (mAbs) for treating cancer remain a very active area of research. Therapeutic monoclonal antibodies were originally derived from rodents. One of the major problems with murine antibodies is their immunogenicity; the patient’s immune system recognizes them as being foreign (Figure 5-6A), leading to an antibody attack against the mouse antibody (human antimouse antibody, HAMA). This host immune response not only neutralized the therapeutic potential of foreign antibody but also occasionally caused life-threatening anaphylactoid reactions.64 Two antibody design strategies were subsequently developed to overcome this problem.64,65 Chimeric antibodies are rodent–human antibody constructs, wherein the variable (antigen binding) region is of rodent origin and the constant (effector) region is of human origin (Figure 5-6B). Humanized antibodies are antibody constructs in which rodent gene segments coding for the antigen binding loops are grafted onto human antibodies (Figure 5-6C). More recently, phage display technology and transgenic approaches have enabled the production of entirely human recombinant antibodies.64,65
engraftment in 12 of 15 metastatic RCC patients undergoing an HLA-matched sibling transplant, four of whom had a partial response. None of the patients who rejected the allograft demonstrated a disease response.62 Investigators from Milan, Italy, reported 4 of 7 patients having a disease response following a nonmyeloablative transplant that used Thiotepa and fludarabine-based conditioning regimen.63 Although these pilot results are encouraging, this approach remains experimental and should be reserved for patients with metastatic RCC who have previously failed cytokine therapy, especially considering the risk of fatal complications (mostly severe GVHD) associated with the procedure. The primary outcome of these trials has been to establish evidence of GVT effects against this malignancy. Larger trials and refinements in the transplant technique to decrease the risk of GVHD are needed to define the role transplantation will ultimately play in their management of these patients. MONOCLONAL ANTIBODIES The potential of antibodies to function as “magic bullets” for the treatment of cancer has great appeal due to their tremendous target specificity. Based on the preliminary “Naked” antibody
Chimeric antibody
Rodent constant regions (heavy, light chains)
Human constant regions (heavy, light chains)
Rodent variable region (heavy, light-chain)
Rodent variable region (heavy, light-chain)
Rodent CDR (complementarity-determining region)
Rodent CDR (complementarity-determining region)
B
A
Humanized antibody
Human constant regions (heavy, light chains) Rodent variable region (heavy, light-chain) Rodent CDR (complementarity-determining region)
C Figure 5-6 Therapeutic rodent monoclonal antibodies (mAbs). A, Naked rodent mAb. B, Chimeric rodent-human mAb. C, Humanized mAb.
98
Part I Principles of Urologic Oncology
The first two antibodies to be approved by the FDA were Rituximab, a chimeric antiCD20 monoclonal antibody for treatment of low-grade non-Hodgkin’s lymphoma, as well as Herceptin, a humanized monoclonal antibody against HER-2 for the treatment of metastatic breast cancer. Both drugs have shown individual activity in cancer patients with chemotherapy refractory tumors. Research efforts are underway to develop effective antibodies against prostate-specific membrane antigen (PSMA) in prostate cancer and G250, a cell surface antigen in RCC (clear cell type). However, besides HAMA, a number of other factors limit the efficacy of antibody therapy including their ability to mediate cell death once they have bound to their tumor target (Table 5-7).64,65 Strategies are currently being developed to overcome these barriers in hopes of enhancing antibody efficacy. One such approach
Table 5-7 Barriers to Effective Antibody Cancer Therapy Mouse antibodies are immunogenic, provoking human anti-mouse antibody (HAMA) response Difficulty in identifying antigens that are expressed on tumor cells and not on normal cells Antigen-loss on tumor cell surface Adequate delivery of antibody to tumor depends on good vascularity of tumor Short half-life of some antibodies requires repeated administrations Antibodies are usually species-specific, limiting preclinical animal toxicology studies
involves the conjugation of effector moieties to the antibody to improve tumor killing (Table 5-8).64,65 Vascular endothelial growth factor (VEGF) promotes endothelial cell proliferation and is often secreted by tumors in order to establish and/or increase their blood supply. Clear-cell RCCs often produce and secrete high levels of VEGF due to mutations in the von HippelLindau tumor suppressor gene.66–68 A recent randomized, phase II trial was conducted to assess the efficacy of Bevacizumab, an anti-VEGF humanized monoclonal antibody, in the setting of advanced clear-cell RCC.69 One-hundred and sixteen patients were randomized to receive either placebo, low-dose Bevacizumab (3 mg/kg every 2 weeks), or high-dose Bevacizumab (10 mg/kg every 2 weeks). The vast majority (>89%) had previously undergone nephrectomy and received (and failed) IL-2 therapy. At a second interim evaluation (at a median follow-up time of 27 months from study entry), the National Cancer Institute data safety and monitoring board recommended closure of accrual on the basis of the difference between the placebo and high-dose Bevacizumab in the time to progression of disease (2.5 months and 4.8 months, respectively, p < 0.001 by log-rank test). Only 4 of 116 patients had objective responses (all of which were partial responses), and all of these had received high-dose Bevacizumab. In the high-dose cohort, the response rate was 10% (4 of 39 patients). At the last analysis, there were no significant differences in overall survival between groups ( p > 0.20 for all comparisons). Bevacizumab has further demonstrated antitumor activity in preclinical studies against hormone-refractory prostate cancer70 and in a phase II randomized trial (Bevacizumab + Fluorouracil/Leucovorin versus Fluorouracil/Leucovorin) in the setting of metastatic colorectal carcinoma.71
Table 5-8 Antibody Strategies in Cancer Therapy Ab-Conjugate
Mechanism of Tumor Cell Killing
“Naked” Ab (unconjugated)
CDC, ADCC, direct antiproliferative effects, idiotype/anti-idiotype network
Ab-radioisotope
Direct radiation-induced cytotoxicity
Ab-immunotoxin
Once inside the cell, toxin irreversibly blocks an essential metabolic process
Ab-drug
Tumoricidal drug internalized by tumor cell
Ab-photosensitizer
Photosensitizer-moiety produces oxygen free radical when exposed to light
Ab-Ab (bispecific Ab’s)
Unlike direct conjugations of effector agents to a single antibody, the effector and antigen-binding domains are bound to separate, covalently-linked antibodies
Ab-enzyme, then prodrug (ADEPT)
Enzyme-Ab conjugate administered first, followed by prodrug. Enzyme converts prodrug into active cytotoxic agent at tumor site only
Ab, antibody; CDC, complement-dependent cytotoxicity; ADCC, antibody-dependent cell-mediated cytotoxicity; ADEPT, antibody-dependent enzyme-mediated cytotoxicity
Chapter 5 Immunotherapy: Basic Guidelines 99
REFERENCES 1. Coley W: Further observations on the treatment of malignant tumors with the toxins of erysipelas and bacillus prodigious with a report of 160 cases. Johns Hopkins Hospital Bulletin 1896; 7:157–162. 2. Schreiber H: Tumor immunology. In Paul WE (ed): Fundamental Immunology, 4th edition, pp 1237–1270. Philadelphia, Lippencott-Raven Publishers, 1999. 3. Abbas AK, Lichtman AH, Pober JS: Immunity to tumors. In Abbas AK (ed): Cellular and Molecular Immunology, 4th edition, pp 384–403. Philadelphia, WB Saunders Co, 2000. 4. Shu S, Plautz GE, Krauss JC, Chang AE: Tumor immunology. JAMA 1997; 278(22):1972–1981. 5. Leonard WJ: Type I cytokines and interferons and their receptors. In Paul WE (ed): Fundamental Immunology, 4th edition, pp 741–774. Philadelphia, Lippencott-Raven Publishers, 1999. 6. Lin WC, Yasumura S, Suminami Y, et al: Constitutive production of IL-2 by human carcinoma cells, expression of IL-2 receptor, and tumor cell growth. J Immunol 1995; 155(10):4805–4816. 7. Oppenheim J, Fujiwara H: The role of cytokines in cancer. Cytokine Growth Factor Rev 1996; 7(3): 279–288. 8. Society for Leukocyte Biology— www.leukocytebiology.org. 9. International Society for Interferon and Cytokine Research—http://bioinformatics.weizmann.ac.il/ISICR/. 10. International Cytokine Society— http://bioinformatics.weizmann.ac.il/cytokine/. 11. Proleukin (registered trademark), Aldesleukin for injection [package insert]. 12. Whittington R, Faulds D: Interleukin-2. A review of its pharmacological properties and therapeutic use in patients with cancer. Drugs 1993; 46(3):446–514. 13. Rosenberg SA: Principles of cancer management: biologic therapy. In Vincent T, DeVita J, Hellman S, Rosenberg SA (eds): Cancer: Principles & Practice of Oncology, 6th edition, pp 307–333. Philadelphia, Lippencott Williams & Wilkins, 2001. 14. Abbas AK: Cellular and Molecular Immunology, 4th edition. Philadelphia, WB Saunders Co, 2000. 15. Kirkwood J: Cancer immunotherapy: the interferon-alpha experience. Semin Oncol 2002; 29(3 Suppl 7):18–26. 16. Bukowski RM, Tendler C, Cutler D, et al: Treating cancer with PEG intron: pharmacokinetic profile and dosing guidelines for an improved interferon-alpha-2b formulation. Cancer 2002; 95(2):389–396. 17. Fisher RI, Rosenberg SA, Fyfe G: Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 2000; 6(Suppl 1):S55–S57. 18. Yang JC, Sherry RM, Steinberg SM, et al: A randomized study of high and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003 (in press). 19. Dutcher JP, Atkins M, Fisher R, et al: Interleukin-2-based therapy for metastatic renal cell cancer: the Cytokine
20. 21.
22.
23.
24.
25.
26.
27.
28. 29.
30.
31.
32.
33.
Working Group experience, 1989–1997. Cancer J Sci Am 1997; 3 (Suppl 1):S73–S78. Dutcher J: Personal Communication, 2003. McDermott D: A randomized phase III trial of high-dose interleukin-2 vs. subcutaneous IL2/interferon in patients with metastatic renal cell carcinoma. Paper presented at the American Society of Clinical Oncology, May 12–15, 2001, San Francisco, CA. Dutcher JP, Fisher RI, Weiss G, et al: Outpatient subcutaneous interleukin-2 and interferon-alpha for metastatic renal cell cancer: five-year follow-up of the Cytokine Working Group Study. Cancer J Sci Am 1997; 3(3):157–162. Rogers E, Bredin H, Butler M, et al: Combined subcutaneous recombinant alpha-interferon and interleukin-2 in metastatic renal cell cancer: results of the Multicentre All Ireland Immunotherapy Study Group. Eur Urol 2000; 37(3):261–266. Negrier S, Caty A, Lesimple T, et al: Treatment of patients with metastatic renal carcinoma with a combination of subcutaneous interleukin-2 and interferon alfa with or without fluorouracil. Groupe Francais d’Immunotherapie, Federation Nationale des Centres de Lutte Contre le Cancer. J Clin Oncol 2000; 18(24):4009–4015. Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R: Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001; 358(9286):966–970. Flanigan RC, Salmon SE, Blumenstein BA, et al: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001; 345(23):1655–1659. Negrier S, Escudier B, Lasset C, et al: Recombinant human interleukin-2, recombinant human interferon alfa2a, or both in metastatic renal-cell carcinoma. Groupe Francais d’Immunotherapie. N Engl J Med 1998; 338(18):1272–1278. Negrier S: Personal communication, 2003. Motzer RJ, Murphy BA, Bacik J, et al: Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol 2000; 18(16):2972–2980. Gleave ME, Elhilali M, Fradet Y, et al: Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. Canadian Urologic Oncology Group. N Engl J Med 1998; 338(18):1265–1271. Kammula US, White DE, Rosenberg SA: Trends in the safety of high dose bolus interleukin-2 administration in patients with metastatic cancer. Cancer 1998; 83(4):797–805. Schwartz RN, Stover L, Dutcher J: Managing toxicities of high-dose interleukin-2. Oncology (Huntingt) 2002; 16(11 Suppl 13):11–20. Dutcher J, Atkins MB, Margolin K, et al: Kidney cancer: the Cytokine Working Group experience (1986–2001): part II. Management of IL-2 toxicity and studies with other cytokines. Med Oncol 2001; 18(3):209–219.
100
Part I Principles of Urologic Oncology
34. Dutcher J: Current status of interleukin-2 therapy for metastatic renal cell carcinoma and metastatic melanoma. Oncology (Huntingt) 2002; 16(11 Suppl 13):4–10. 35. Jorkov AS, Donskov F, Steiniche T, et al: Immune response in blood and tumour tissue in patients with metastatic malignant melanoma treated with IL-2, IFN alpha and histamine dihydrochloride. Anticancer Res 2003; 23(1B):537–542. 36. Agarwala SS, Glaspy J, O’Day SJ, et al: Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma. J Clin Oncol 2002; 20(1):125–133. 37. Donskov F, von der Maase H, Henriksson R, et al: Outpatient treatment with subcutaneous histamine dihydrochloride in combination with interleukin-2 and interferon-alpha in patients with metastatic renal cell carcinoma: results of an open single-armed multicenter phase II study. Ann Oncol 2002; 13(3):441–449. 38. Smyth MJ, Takeda K, Hayakawa Y, Nature’s TRAIL—on a path to cancer immunotherapy. Immunity 2003; 18(1):1–6. 39. Schmaltz C, Alpdogan O, Kappel BJ, et al: T cells require TRAIL for optimal graft-versus-tumor activity. Nat Med 2002; 8(12):1433–1437. 40. Smyth MJ, Cretney E, Takeda K, et al: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) contributes to interferon gamma-dependent natural killer cell protection from tumor metastasis. J Exp Med 2001; 193(6):661–670. 41. O’Donnell MA, Lilli K, Leopold C: Interim results from a national multicenter phase II trial of combination BCG plus interferon-alfa-2B for superficial bladder cancer. Paper presented at the American Urological Association Meeting, April 28, 2003, Chicago, IL. 42. Bazarbashi S, Raja MA, El Sayed A, et al: Prospective phase II trial of alternating intravesical Bacillus CalmetteGuerin (BCG) and interferon alpha IIB in the treatment and prevention of superficial transitional cell carcinoma of the urinary bladder: preliminary results. J Surg Oncol 2000; 74(3):181–184. 43. Stricker P, Pryor K, Nicholson T, et al: Bacillus CalmetteGuerin plus intravesical interferon alpha-2b in patients with superficial bladder cancer. Urology 1996; 48(6):957–961. [Discussion 961-962.] 44. Spitler LE: Adjuvant therapy of melanoma. Oncology (Huntingt) 2002; 16(1 Suppl 1):40–48. 45. Smith IJ, Kurt RA, Baher AG, et al: Immune effects of escalating doses of granulocyte-macrophage colonystimulating factor added to a fixed, low-dose, inpatient interleukin-2 regimen: a randomized phase I trial in patients with metastatic melanoma and renal cell carcinoma. J Immunother 2003; 26(2):130–138. 46. Schmidinger M, Steger G, Wenzel C, et al: Sequential administration of interferon-gamma, GM-CSF, and interleukin-2 in patients with metastatic renal cell carcinoma: results of a phase II trial. J Immunother 2001; 24(3):257–262. 47. Ryan CW, Vogelzang NJ, Dumas MC, Kuzel T, Stadler WM: Granulocyte-macrophage-colony stimulating factor in combination immunotherapy for patients with
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59. 60.
61.
metastatic renal cell carcinoma: results of two phase II clinical trials. Cancer 2000; 88(6):1317–1324. Wos E, Olencki T, Tuason L, et al: Phase II trial of subcutaneously administered granulocyte-macrophage colony-stimulating factor in patients with metastatic renal cell carcinoma. Cancer 1996; 77(6):1149–1153. Magno C, Melloni D, Gali A, et al: The anti-tumor activity of bacillus Calmette-Guerin in bladder cancer is associated with an increase in the circulating level of interleukin-2. Immunol Lett 2002; 81(3):235–238. Luo Y, Chen X, O’Donnell MA: Role of Th1 and Th2 cytokines in BCG-induced IFN-gamma production: cytokine promotion and simulation of BCG effect. Cytokine 2003; 21(1):17–26. Broghammer EL, Ratliff TL: Immunotherapy of urologic tumors: principles and progress. Urol Oncol 2002; 7(2):45–56. Law TM, Motzer RJ, Mazumdar M, et al: Phase III randomized trial of interleukin-2 with or without lymphokine-activated killer cells in the treatment of patients with advanced renal cell carcinoma. Cancer 1995; 76(5):824–832. Rosenberg SA, Lotze MT, Yang JC, et al: Prospective randomized trial of high-dose interleukin-2 alone or in conjunction with lymphokine-activated killer cells for the treatment of patients with advanced cancer. J Natl Cancer Inst 1993; 85(8):622–632. Lee DS, White DE, Hurst R, Rosenberg SA, Yang JC: Patterns of relapse and response to retreatment in patients with metastatic melanoma or renal cell carcinoma who responded to interleukin-2-based immunotherapy. Cancer J Sci Am 1998; 4(2):86–93. Figlin RA, Thompson JA, Bukowski RM, et al: Multicenter, randomized, phase III trial of CD8(+) tumorinfiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol 1999; 17(8):2521–2529. Dudley ME, Wunderlich JR, Robbins PF, et al: Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes. Science 2002; 298(5594):850–854. Vose JM, et al: Bone marrow transplantation. In Abeloff MD, Armitage JO, Lichter AS, Niederhuber JE (eds): Abeloff: Clinical Oncology, 2nd edition, p 482. Philadelphia, Churchill Livingstone Inc, 2000. Childs RW, Clave E, Tisdale J, et al: Successful treatment of metastatic renal cell carcinoma with a nonmyeloablative allogeneic peripheral-blood progenitor-cell transplant: evidence for a graft-versus-tumor effect. J Clin Oncol 1999; 17(7):2044–2049. Dorland’s On-Line Medical Dictionary. Childs RW: Nonmyeloablative blood stem cell transplantation as adoptive allogeneic immunotherapy for metastatic renal cell carcinoma. Crit Rev Immunol 2001; 21(1–3):191–203. Childs R, Chernoff A, Contentin N, et al: Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 2000; 343(11):750–758.
Chapter 5 Immunotherapy: Basic Guidelines 101 62. Rini BI, Zimmerman T, Stadler WM, Gajewski TF, Vogelzang NJ: Allogeneic stem-cell transplantation of renal cell cancer after nonmyeloablative chemotherapy: feasibility, engraftment, and clinical results. J Clin Oncol 2002; 20(8):2017–2024. 63. Bregni M, Dodero A, Peccatori J, et al: Nonmyeloablative conditioning followed by hematopoietic cell allografting and donor lymphocyte infusions for patients with metastatic renal and breast cancer. Blood 2002; 99(11):4234–4236. 64. Waldmann H, Gilliland LK, Cobbold SP, Hale G: Immunotherapy. In Paul WE (ed): Fundamental Immunology, 4th edition, pp 1511–1533. Philadelphia, Lippincott-Raven Publishers, 1999. 65. Welschof M, Krauss J (eds): Recombinant Antibodies for Cancer Therapy: Methods and Protocols, vol 207. Totowa, NJ, Humana Press, 2002. 66. Maxwell PH, Wiesener MS, Chang GW, et al: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999; 399(6733):271–275.
67. Mukhopadhyay D, Knebelmann B, Cohen HT, Ananth S, Sukhatme VP: The von Hippel-Lindau tumor suppressor gene product interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Mol Cell Biol 1997; 17(9):5629–5639. 68. Folkman J, Shing Y. Angiogenesis. J Biol Chem 1992; 267(16):10931–10934. 69. Yang JC, Haworth L, Sherry RM, et al: A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003; 349(5):427–434. 70. Fox WD, Higgins B, Maiese KM, et al: Antibody to vascular endothelial growth factor slows growth of an androgen-independent xenograft model of prostate cancer. Clin Cancer Res 2002; 8(10):3226–3231. 71. Kabbinavar F, Hurwitz HI, Fehrenbacher L, et al: Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003; 21(1):60–65.
C H A P T E R
6 Health-Related Quality of Life Issues in Urologic Oncology David F. Penson, M.D., M.P.H., and Mark S. Litwin, M.D., M.P.H.
The primary goal of health care providers when treating patients with urologic malignancies has traditionally been to prolong patient survival. However, as the past decade has brought new screening modalities and improvements in treatment, clinicians and researchers have begun to focus on other outcomes as well. In particular, as we have recognized that cancer and its treatment affects both quantity and quality of life in our patients, it has become clear that various components of well-being must also be addressed when treating individual patients with cancer or when conducting cancer clinical trials.1 While clinicians must still focus on “traditional” outcomes, such as 5- or 10-year survival rates, complete and partial responses, or serum tumor marker levels, the increased attention to patients’ overall well-being has generated interest in more “refined” endpoints in urologic oncology. One such endpoint is health-related quality of life (HRQOL). HRQOL encompasses a wide range of human experience, including the daily necessities of life, intrapersonal and interpersonal responses to illness, and activities associated with professional fulfillment and personal happiness.2 Importantly, HRQOL involves patients’ perceptions of their own health and ability to function in life. HRQOL is often confused with functional status. While functional status is an important dimension of HRQOL, there are numerous other aspects of HRQOL, including role function, vitality, mental health, pain, and psychosocial interactions, which are equally important. Despite the commonly held belief that this type of data cannot be easily collected, patients’ compliance with HRQOL questionnaires is usually high.3 The impact of HRQOL in clinical oncology is now considered so important that a cancer trial is considered incomplete without the inclusion of HRQOL outcomes.1,4 In this chapter, we review quality of life issues in urologic oncology. We initially review the methodology of
102
HRQOL research and discuss various instruments available to assess HRQOL in genitourinary cancers. We then briefly examine the current literature regarding the effect of urologic malignancies on quality of life. Necessarily, we focus primarily on prostate cancer, as this has the largest body of literature. However, we touch on quality of life issues in bladder, kidney, and testicular cancers as well. THE METHODOLOGY OF HEALTH-RELATED QUALITY OF LIFE RESEARCH HRQOL Instruments It is difficult for the novice to understand the task of objectively quantifying quality of life, which is an inherently qualitative phenomenon.5 However, the principles of psychometric test theory 6 may be applied to produce accurate assessments of HRQOL. HRQOL data are collected using patient-centered surveys, called instruments. Instruments can be self-administered by the patient or can be administered with the assistance of a neutral thirdparty interviewer in a standardized fashion. Instruments typically contain multiple questions, or items, that are organized into scales. Each scale measures a different aspect, or domain, of HRQOL. Domains can be general or disease-specific. General HRQOL domains address the components of overall well-being, while diseasespecific domains focus on the impact of particular organic dysfunctions that affect HRQOL.7 General HRQOL domains typically address general health perceptions, sense of overall well-being, and function in the physical, emotional, and social domains. Cancer-specific HRQOL domains focus on more directly relevant domains, such as anxiety about cancer recurrence, nausea from chemotherapy, or urinary incontinence from sphincter damage.
Chapter 6 Health-Related Quality of Life Issues in Urologic Oncology 103
Creation and Testing of New Instruments
Reliability
It is ill-advised to use casually constructed instruments in HRQOL research, as this can result in inaccurate data and flawed conclusions. Therefore, before an instrument is used in a clinical setting, statistical and psychometric testing must be performed to measure the survey’s reliability and validity. Because psychometric testing is so rigorous and time-intensive, it is always preferable to use an established, validated instrument when available. Another advantage of using published instruments in the collection of HRQOL data is that they allow researchers to compare new results to previously studied populations. If an appropriate, established HRQOL instrument is not available for the disease process one is interested in studying, it may be reasonable to design a new instrument. The first step in this difficult process is to pilot test the questionnaire to ensure that the patient population can easily understand and complete the survey. Pilot testing often reveals problems that the researchers may not notice, such as the inadvertent use of medical jargon that patients do not understand (leading to unanswered questions or inaccurate responses), use of diminutive print size (causing difficulty reading the question), or unclear wording (leading patients to misunderstand the question). After pilot testing, new instruments are evaluated for the two fundamental psychometric statistical properties of reliability and validity.
Reliability refers to how reproducible the scale is. In other words, what proportion of a patient’s test score is true and what proportion is due to random variation. Several types of reliability are typically assessed. Test–retest reliability is a measure of response stability over time. It is assessed by administering scales to patients at two distinct time points, typically 1 month apart. The correlation coefficients between the two scores reflect the stability of responses. Test–retest reliability is most easily assessed when the domain of interest is unlikely to change over short periods of time. When assessing test–retest reliability, one needs to ensure that the interval between administrations is not too long, as real change can occur in the variable, artificially deflating test–retest reliability coefficients. Internal consistency reliability is a measure of the similarity of an individual’s responses across several items, indicating the homogeneity of a scale.6 The statistic used to quantify the internal consistency of a scale is called Cronbach’s coefficient alpha.8 Generally accepted standards dictate that reliability statistics measured by these two methods should exceed 0.70.9 These and various other forms of reliability are reviewed in Table 6-1. Validity Validity refers to how well the scale or instrument measures the attribute it is intended to measure. Content validity,
Table 6-1 Types of Reliability Type of Reliability
Characteristics
Comments
Test–Retest
Measures the stability of responses over time, typically in the same group of respondents
Requires the administration of survey to a sample at two different and appropriate points in time. Time points that are too far apart may produce diminished reliability estimates that reflect actual change over time in the variable of interest
Intraobserver
Measures the stability of responses over time in the same individual respondent
Requires completion of a survey by an individual at two different and appropriate points in time. Time points that are too far apart may produce diminished reliability estimates that reflect actual change over time in the variable of interest
Alternate-form
Uses differently worded stems or response sets to obtain the same information about a specific topic
Requires two items in which the wording is different but aimed at the same specific variable and at the same vocabulary level
Internal consistency
Measures how well several items in a scale vary together in a sample
Usually requires a computer to carry out calculations
Interobserver
Measures how well two or more respondents rate the same phenomenon
May be used to demonstrate reliability of a survey or may itself be the variable of interest in a study
104
Part I Principles of Urologic Oncology
sometimes incorrectly referred to as face validity, is the nonquantitative assessment by experts of the scope and completeness of a proposed items and scales. It is more superficial than other types of validity, and considered by some not to be a true measure of validity at all.10 Nevertheless, it is almost always included in the early stages of instrument development, even if only as a general review of items by physicians or patients. Criterion validity requires the correlation of scale scores with other measurable health outcomes (predictive validity) and with results from other established tests (concurrent validity). For example, the predictive validity of a new HRQOL scale for bony pain in prostate cancer might be correlated with narcotic usage. Likewise, the concurrent validity of a new urinary incontinence scale in prostate or bladder cancer could be correlated with objective results on urodynamic testing. Construct validity is a measure of how meaningful the scale or survey instrument is when in practical use. It is often requires years of experience with a survey instrument to assess correctly. Often it is not calculated as a quantifiable statistic but as a gestalt of how well a survey instrument performs in a multitude of settings and populations over time. An overview of the various types of validity is presented in Table 6-2.
Many clinicians and researchers find the process and patient-centered data collection daunting and mistakenly believe that they can accurately estimate a patient’s quality of life. Numerous studies have documented that physicians tend to underestimate both the degree of symptoms and their negative effect on HRQOL.12–14 Therefore, it is usually preferable to obtain HRQOL data directly from patients; the treating physician should not attempt to estimate the patient’s HRQOL.
Collection of HRQOL Data
Established General HRQOL Instruments
In addition to using validated and reliable HRQOL instruments, clinicians and researchers must collect data in a manner that minimizes bias. For example, data regarding sexual dysfunction following radical prostatectomy should not be collected directly by the operating surgeon, as patients have an unconscious desire to produce responses that they think their physicians want to hear.11 This introduces measurement error. Therefore, it is always preferable that data be gathered by disinterested third parties or that instruments be self-administered by patients to avoid bias.
General HRQOL instruments focus on general domains of HRQOL and have been extensively researched and validated in many types of patients, including sick and well. Examples include the RAND Medical Outcomes Study 36-Item Health Survey (also known as the SF-36),16–20 the quality of well-being scale (QWB),21–25 the sickness impact profile (SIP),21,26,27 and the Nottingham health profile (NHP).21,28–31 All of these instruments assess the various general components of HRQOL, including physical and emotional functioning,
ESTABLISHED HRQOL INSTRUMENTS FOR USE WITH UROLOGIC MALIGNANCIES HRQOL instruments tend to be general or diseasespecific, depending on the domains addressed with the survey. When studying urologic cancers, it is preferable to use both general and disease-specific instruments, as disease-specific symptoms can have profound effects on both disease-specific HRQOL and patients’ general wellbeing and overall functional status. The broad effect of certain symptoms associated with urologic cancer may be overlooked if researchers do not use both general and disease-specific measures.15
Table 6-2 Types of Validity Type of Validity
Characteristics
Comments
Face
Casual review of how good an item or group of items appear
Assessed by individuals with no formal training in the subject under study
Content
Formal expert review of how good an item or series of items appear
Usually assessed by individuals with expertise in some aspect of the subject under study
Criteron: Concurrent
Measures how well the item or scale correlates with “gold standard” measures of the same variable
Requires the identification of an established, generally accepted gold standard
Criterion: Predictive
Measures how well the item or scale predicts expected future observations
Used to predict outcomes or events of significance that the item or scale might subsequently be used to predict
Construct
Theoretical measure or how meaningful a survey instrument is
Determined usually after years of experience by numerous investigators
Chapter 6 Health-Related Quality of Life Issues in Urologic Oncology 105
social functioning, and symptoms and have been thoroughly validated and tested. Cancer-Specific HRQOL Instruments for Use in Urology A number of cancer-specific instruments have long been available. However, recently, many have had modules developed that are specific for urologic disease. For example, the European Organization for Research and Treatment of Cancer (EORTC) Core Quality of Life Questionnaire (QLQ-C30)32 is a 30-item questionnaire that includes five scales (physical, role, emotional, cognitive, and social functioning), a global health scale, three symptom scales (fatigue, nausea/vomiting, and pain), and six single items concerning dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties due to disease. The EORTC QLQ-C30 can be used in patients with any type of cancer. However, a 20-item prostate cancer module has recently been developed that specifically includes a bowel symptom scale, urinary symptom scale and sexuality scale. This module has been validated and shown to be reliable in men with both localized33,34 and metastatic35 prostate cancer. Unfortunately, this instrument does not distinguish between function and bother in these domains. Another example of a cancer-specific HRQOL instrument that now has modules for various urologic malignancies is the Functional Assessment of Cancer Therapy (FACT).36–39 The main FACT instrument includes a set of 28 general items that pertain to all cancer patients (FACT-G). Each item contains a statement that a patient may agree or disagree with across a five-point Likert range. The FACT-G domains include well-being in four areas: physical, social-family, emotional, and functional. The FACT-P, a new module to measure HRQOL in men with prostate cancer, was recently validated and may prove useful in the future.40 There is also a FACT module for bladder cancer, although this has not been widely used or validated. The FACT may be accessed at http://www.facit.org/facit_questionnair.htm. HRQOL Instruments Designed Specifically for Use in Urologic Malignancies A number of instruments developed for use specifically in urologic cancers. In the past, most of the research focus has been in prostate cancer, and, therefore, there are more established instruments available for use in this malignancy. Recently, new HRQOL instruments have been developed for use in bladder and kidney cancer as well. In prostate cancer, the University of California, Los Angeles Prostate Cancer Index (UCLA PCI) was the first validated instrument specifically designed for use in this condition and has been the gold standard for measuring
prostate cancer-specific HRQOL.41,42 It is a 20-item, self-administered tool that takes about 10 minutes to complete. It is typically administered alongside the SF-36, a general HRQOL instrument.19 The 20 items of the UCLA PCI are specific for prostate cancer and comprise six scales (urinary function and bother, sexual function and bother, and bowel function and bother) from 0 to 100, with higher scores representing better outcomes. The UCLA PCI has now been used in several national and international studies and has recently been validated in Spanish.43 The UCLA PCI makes the important distinction between function and bother in the prostatespecific domains. This feature is significant because the bother experienced by patients does not necessarily correlate with the level of dysfunction.44 Although the UCLA PCI has been validated and is widely used, its focus on urinary incontinence does not attend to irritative voiding complaints. Hence, researchers at the University of Michigan developed the Expanded Prostate Cancer Index-Composite (EPIC). Building on the UCLA PCI, Wei et al.45 added 30 items to the existing disease-specific domains, for a total of 50 items. The EPIC added additional items to the three existing bother domains (urinary, sexual, and bowel), developed hormonal function and bother domains, and most importantly, expanded the urinary domain by adding items that capture irritative voiding symptoms. Therefore, the EPIC contains eight disease-specific domains: sexual function and bother, urinary function and bother, bowel function and bother, and hormonal function and bother. The urinary function domain contains two distinct subscales, urinary incontinence and urinary irritation/obstruction, each with a separate summary score. Because the disease-specific domains of the EPIC instrument include significantly more items than the original UCLA PCI, general HRQOL is typically measured using the 12-item RAND SF-1246 rather than the SF-36. HEALTH-RELATED QUALITY OF LIFE IN SPECIFIC UROLOGIC MALIGNANCIES Prostate Cancer Of all genitourinary tumors, prostate cancer is the malignancy with the largest body of HRQOL research. There are considerable data in both metastatic and localized disease because both prostate cancer and its treatment affect quality of life. In the case of metastatic prostate cancer, patients experience decrements in quality of life due to both painful bony lesions and hormone ablation therapy. Investigators have shown that as metastatic prostate cancer progresses from hormone-sensitive to hormone resistant disease, general HRQOL worsens accordingly.47 Kim et al.48 also noted that among patients
106
Part I Principles of Urologic Oncology
treated for metastases, those with progressive disease appeared to have worse quality of life than those with stable disease, particularly for pain, fatigue, sleep, and physical and role functioning. Studies have shown that treatment of advanced prostate cancer improves HRQOL. Albertsen et al.35 studied metastatic prostate cancer patients in remission on LHRH agonists and flutamide and found that their general HRQOL was indistinguishable from an age-matched control population of men without prostate cancer. While treatment of advanced prostate cancer appears to improve HRQOL, at least initially, the therapy itself can negatively affect HRQOL. This is of particular concern in men who present with advanced but asymptomatic prostate cancer, as, in these patients, the tumor itself probably has little impact on HRQOL. For example, Herr and O’Sullivan49 compared patients receiving hormonal therapy to those being observed for asymptomatic advanced disease. Patients who elected to observation until the development of symptoms had better HRQOL than those who opted for early intervention. In particular, men who received early therapy experienced significantly more fatigue and hot flashes that impacted quality of life than those who delayed treatment. Other studies note similar findings. For example, Green et al.50 demonstrated that early hormone ablation therapy was associated with worse sexual function and decreased role and social functioning. However, the patients who received early hormonal therapy did report better physical function than those who received deferred management. Although not a study of metastatic prostate cancer, researchers from the Prostate Cancer Outcomes Study (PCOS)51 compared men with localized disease who received hormone ablation therapy to men with localized disease who were observed. Those who elected hormone ablation therapy reported worse sexual function and more physical discomfort. Although all of these studies were observational in nature and therefore may have been influenced by selection bias, they all underscore the potential deleterious effects of hormone therapy on HRQOL. Once patients elect to receive treatment for metastatic prostate cancer, studies demonstrate that there is little difference in HRQOL outcomes between men undergoing medical versus surgical castration. Litwin et al.52 identified no differences in any of the general or diseasespecific domains of the RAND 36 Item Health Survey (SF-36) or the UCLA Prostate Cancer Index when comparing men who underwent orchiectomy to those receiving combined androgen blockade. Although the method of castration does not appear to have a significant impact on HRQOL, the presence or absence of additional androgen blocker therapy does influence HRQOL. In a clinical trial of 739 men with stage M1 prostate cancer, patients randomized to orchiectomy plus flutamide reported significantly more diarrhea than those who were
randomized to orchiectomy plus placebo.53 However, the negative impact of androgen receptor blockade on HRQOL due to gastrointestinal side effects may be less in patients receiving bicalutamide.54 Quality of life is of particular importance to men with hormone resistant disease where the goal of therapy is often palliative in nature. A number of studies have documented that various chemotherapeutic agents improve HRQOL in men with hormone-resistant disease. For example, Osoba et al.55 assessed HRQOL in 161 men randomized to receive prednisone alone versus prednisone and mitoxantrone over a 26-week follow-up period. At 6 weeks, patients taking prednisone alone showed no improvement in HRQOL scores, whereas those taking mitoxantrone plus prednisone showed significant improvements in global quality of life ( p = 0.009) and four functional domains ( p < 0.01). In the cross-over arm of the study, the addition of mitoxantrone to prednisone after failure of prednisone alone was associated with improvements in pain, pain impact, pain relief, insomnia, and global quality of life ( p < 0.003). After 18 weeks of therapy, those receiving mitoxantrone plus prednisone continued to improve in 11 of the 14 function and symptom scales of the HRQOL measures used. This study and others56,57 demonstrate that palliative chemotherapy can lessen the physical burden of prostate cancer in men with advanced hormone-resistant disease. Although these treatments may not prolong life expectancy, a documented quality of life advantage for a given treatment will result in benefit to the patient and should be strongly considered when choosing therapies. In the case of localized prostate cancer, most of the research examining HRQOL has focused on the effect of treatment on quality of life. However, even in the case of localized disease, prostate cancer itself appears to have an effect on HRQOL. Bacon et al.58 compared general HRQOL in 783 men from the Health Professionals Follow-up Study cohort with incidental prostate cancer to 1928 age-matched controls. They found that the men with localized prostate cancer had worse general health, vitality, social function, and role limitations due to physical and emotional problems (all p values <0.004) than the control subjects. Although the differences were small, this study demonstrates that localized prostate cancer itself may affect quality of life. All of the treatments for localized prostate cancer are associated with side effects, such as sexual, urinary or bowel dysfunction, which can impact quality of life. Although there are differences in disease-specific HRQOL outcomes between treatment, it appears there is no difference in general HRQOL outcomes between therapies, at least once the patient gets beyond the immediate posttreatment period. Penson et al.59 analyzed data from PCOS, a population-based cohort of 5672 men with prostate cancer followed for 2 years after diagnosis
Chapter 6 Health-Related Quality of Life Issues in Urologic Oncology 107
of localized disease. Of the 2693 analyzed, no differences were seen comparing various treatments for localized prostate cancer. Interestingly, men with sexual and urinary dysfunction had significantly worse outcomes in the bodily pain, mental health, role limitation, vitality, and overall health status domains of general HRQOL, when controlling for baseline function, treatment, and 27 other co-variates. This underscores the importance of understanding the effect of the various therapies for localized prostate cancer on disease-specific HRQOL. There is a significant body of literature examining disease-specific HRQOL outcomes after treatment for localized prostate cancer. A recent randomized, clinical trial comparing radical prostatectomy (RP) to watchful waiting (WW), quality of life data were available in 189 men who had RP and 187 who had WW (mean followup, 68 months). In the sexual domains, 55% of RP patients reported insufficient erections and 30% reported great distress due to their erectile dysfunction (as opposed to 30% and 17%, respectively, in the WW group). In urinary domains, 18% reported moderateto-severe urinary leakage and 9% reported great distress from this leakage (as opposed to 2% and 3%, respectively in the WW group). However, there were no differences between the two groups in overall distress from urinary symptoms, presumably due to a higher incidence of obstructive symptoms in the WW patients.60 Stanford et al.61 studied the 1291 men in PCOS who underwent RP for localized prostate cancer, noting that 8.4% of men were incontinent and 59.9% of men were impotent 2 years after surgery. Other studies have reported impotence rates ranging from 29%62 to 88.4%63 and incontinence rates from 4%64 to 33%63 after surgery. In contrast to radical prostatectomy, patients undergoing external beam radiotherapy (EBRT) tend to experience less urinary incontinence and sexual dysfunction but more bowel dysfunction and irritative voiding symptoms. For example, researchers compared long-term HRQOL outcomes in 120 men who underwent EBRT to 125 age-matched controls.65 At 8 years after treatment, 54% of patients and 31% of controls reported urinary problems, most of which were irritative in nature. In another study of 129 men undergoing EBRT, 15% reported urinary dysfunction to the extent that they had to modify their activities of daily living and 2% felt virtually housebound by their irritative voiding symptoms.66 Crook et al.67 studied bowel dysfunction in 192 men undergoing EBRT and noted that 25% reported moderate and 11% reported severe bowel changes. In another study of 200 EBRT patients, 59% reported gastrointestinal problems, although 90% of these problems were classified as minor.68 Finally, it is worth noting that, while the incidence of sexual dysfunction following EBRT appears to be initially less than that following surgery, it is not insignificant. In the study of long-term HRQOL follow-
ing EBRT mentioned above, 65% reported sexual dysfunction 8 years after EBRT.65 Similarly, another study that noted actuarial potency rates of 96, 75, 59, and 53% at 1, 20, 40, and 60 months after EBRT.69 In summary, EBRT also affects disease-specific HRQOL although somewhat differently than surgery. While interstitial brachytherapy (IB) is similar to EBRT in that radiation is delivered to the prostate in hopes of killing cancer cells, the effect of this treatment on disease-specific HRQOL is different, given the fact that higher doses of radiation can be targeted to the prostate with IB. In particular, men undergoing IB are at increased risk for experiencing irritative voiding symptoms. Lee et al.70,71 prospectively measured HRQOL in 31 men prior to IB and at 1, 3, 6, and 12 months posttreatment. At 3 months, patients were noted to have significant irritative voiding symptoms when compared to baseline (15 versus 8, respectively), as measured by the International Prostate Symptom Score (IPSS). By one year, however, mean irritative voiding scores had returned close to baseline (10 versus 8). Sexual and bowel dysfunction can also occur after IB, although not to the same degree as is seen after EBRT. In one cross-sectional study, 35 patients who were potent pretreatment were evaluated 6 months following IB. Eighty-seven percent retained their potency, while 3% reported rectal bleeding.72 With longer follow-up, Talcott et al.73 reported a 44% incidence of complete impotence, a 14% incidence in rectal urgency and a 6% incidence of rectal bleeding. Brandeis et al.74 compared 74 men who underwent radical prostatectomy to 48 men who received brachytherapy and 134 age-matched controls. They found that men who underwent radical prostatectomy had significantly worse outcomes in terms of urinary incontinence when compared to the brachytherapy patients. However, patients who underwent brachytherapy had significantly more irritative voiding symptoms than those who underwent prostatectomy. Interestingly, when asked about how much bother either type of urinary problem caused in the patient’s life, there was no differences between the groups. This study clearly demonstrates that men undergoing radical prostatectomy have more urinary incontinence than men undergoing brachytherapy, while those receiving brachytherapy report greater irritative voiding symptoms, although both groups experience similar levels of bother. Recently, a number of cross-sectional studies have been published comparing disease-specific HRQOL outcomes after surgery, external beam radiotherapy and interstitial brachytherapy. Although all three studies75–77 indicate that sexual dysfunction is common after all treatments for localized prostate cancer, the results in the urinary and bowel domains are somewhat contradictory. Wei et al.75 found no difference between IB and RP in mean urinary function scores, while both Davis et al.76 and Bacon et al.77 note significantly better urinary
108
Part I Principles of Urologic Oncology
function following IB when compared to surgery. This may be related to differences in patient selection or brachytherapy technique. Perhaps more interesting, however, are the results in the urinary bother domain, where both Wei et al.75 and Bacon et al.77report less bother in the surgery group than in the IB group. This may be related to irritative voiding symptoms often seen after brachytherapy. Wei et al. compared HRQOL outcomes in the urinary function:irritative domain and found men undergoing IB had significantly lower mean scores (72 out of 100) when compared to men undergoing EBRT (84 out of 100) or surgery (90 out of 100). Although these findings are useful when counseling patients who are choosing therapy for localized prostate cancer, one must remember that all of these studies were observational in nature, which can introduce selection bias and may influence patient-centered outcomes, such as HRQOL. Ultimately, a well-designed randomized clinical trial is needed. (Table 6-3).
cer patients. Despite this, there are still a number of reports examining HRQOL following treatment for muscle-invasive bladder cancer. As part of the rationale for performing orthotopic neobladder urinary diversion in these patients is to maintain normal body image and quality of life, the majority of studies have compared HRQOL following differing types of urinary diversion. For example, Bjerre and colleagues78 compared men undergoing cystectomy followed by either ileal conduit or orthotopic urethral Kock bladder substitution. They showed that urine leakage caused much less distress in those who underwent bladder substitution, while body image was surprisingly similar in both groups. Global satisfaction with life was high and similar in both groups. Hunt Raleigh et al.79 compared HRQOL among bladder cancer patients treated with ileal loop or neobladder and found no significant differences noted in general HRQOL between the two groups, although patients with ileal loop diversion were more likely to report a negative impact on their social activity. Hara et al. also compared HRQOL following orthotopic neobladder or ileal loop diversion and noted minimal differences in HRQOL outcomes.80 These studies, and others,81 imply that the type of urinary diversion has little impact on HRQOL outcomes in these patients.
Bladder Cancer There are considerably fewer reports studying HRQOL in bladder cancer patients. This is due, at least in part, to the lack of a validated HRQOL specific for bladder can-
Table 6-3 Results of Three Cross-sectional Studies Comparing Disease-specific Hrqol after Treatment for Localized Prostate Cancer Wei et al. study75
Bacon et al. study77
Davis et al. study76
Surgery
570
421
220
EBRT
127
221
188
IB
61
69
103
Urinary function
EBRT(93)*>IB(82)>RP(78)
EBRT(89)*>IB(87)*>RP(76)
IB(88)*>EBRT(87)*>RP(68)
Urinary bother
RP(8%)>EBRT(10%)>IB(28%)
EBRT(83)>RP(82)>IB(75)*
EBRT(83)*>IB(77)>RP(74)
Bowel function
RP(93)>EBRT(85)*>IB(76)*,†
RP(86)>EBRT(81)*>IB(80)*
RP(86)>IB(83)†>EBRT(77)*
Bowel bother
RP(3%)>EBRT(7%)>IB(17%)
RP(86)>EBRT(78)*>IB(72)*
RP(83)>IB(79)>EBRT(72)*
Sexual function
EBRT(39)>RP(34)>IB(27)†
IB(36)*>EBRT(34)*>RP(26)
IB(32)*>EBRT(26)*>RP(18)
Sexual bother
EBRT(46%)>RP(50%)>IB(60%)
IB(54)*>EBRT(51)*>RP(43)
IB(40)*=EBRT(40)*>RP(25)
Number of subjects
Domains
Note: Treatments are ranked by mean scores from best to worst, which are presented in the parenthesis. All HRQOL scores are 0 to 100 with higher scores being better quality of life. The one exception to this is the results from the bother domains in the Wei et al. study. As these results were not presented as summary scores, the numbers in parenthesis represent the percentage of patients who reported that symptoms in the particular domain were a moderate or big problem. No statistical testing was performed on the bother domains from the Wei et al. study. External beam radiotherapy and interstitial brachytherapy were not compared statistically in the Bacon et al. study. IB, interstitial brachytherapy; EBRT, external beam radiotherapy; RP, radical prostatectomy. *Statistically significantly different from radical prostatectomy at a p-value less than 0.05. †Statistically significantly different from EBRT at a p-value less than 0.05.
Chapter 6 Health-Related Quality of Life Issues in Urologic Oncology 109
In contrast, others have noted better HRQOL following continent urinary diversions, such as orthotopic neobladders. For example, Boyd et al.82 noted that selfimage was worse among patients with ileal conduits than in those with continent cutaneous Kock reservoirs, although no differences were seen in mental or emotional health indices. Dutta et al.83 compared patients undergoing orthotopic neobladder to those undergoing ileal loop following cystectomy for bladder cancer. Although the study was confounded by age and co-morbidity, the patients undergoing neobladder were found to have marginally better general HRQOL outcomes. Hardt et al.84 reported results from a prospective study of 44 patients undergoing radical cystectomy and either ileal loop (incontinent) diversion or continent diversion for bladder cancer. At 1 year after surgery, general HRQOL had returned to baseline in both groups, but general life satisfaction and social functioning were better in the continent diversion group while they were decreased following incontinent diversion. Finally, McGuire et al.85 compared HRQOL outcomes following incontinent or continent diversion and demonstrated that patients undergoing incontinent diversion had significantly decreased mental health. While these studies must all be considered preliminary, they do provide some support for the commonly held belief that continent diversions, such as orthotopic neobladders, result in better quality of life. More prospective data are needed to confirm this hypothesis. Kidney Cancer There are surprisingly few reports on HRQOL in kidney cancer patients. While a few of the reports of focused on HRQOL in patients with metastatic disease,86–89 recently a number of reports have focused on HRQOL following various surgical techniques for removal of the primary tumor. For example, Shinohara et al.90 compared HRQOL outcomes following either radical or partial nephrectomy for renal cell carcinoma. They noted that, while there were no differences in long-term survival or HRQOL, patients undergoing partial nephrectomy had better physical function in the immediate postoperative period than those undergoing radical nephrectomy. Clark et al.91 performed a similar study. While they noted no difference in overall HRQOL between partial and radical nephrectomy patients, they did find that patients with more intact renal parenchyma reported better physical health. Finally, Pace et al.92 compared HRQOL following laparoscopic or open radical nephrectomy. Again, while there were no differences in long-term general HRQOL outcomes, patients undergoing laparoscopic nephrectomy reported better HRQOL immediately postoperatively and returned to their baseline HRQOL state quicker. These studies indicate that the type of operation and the
surgical technique used appear to influence short-term HRQOL outcomes in kidney cancer. Testicular Cancer There has been minimal HRQOL research in patients treated for testis cancer. Joly et al.93 compared long-term HRQOL outcomes in testicular cancer survivors to agematched controls and found no differences. In another study, Fossa et al.94 studied HRQOL outcomes in men with good prognosis metastatic germ cell tumors. They noted that two years after treatment, 36% of patients had improved general HRQOL, while general HRQOL had deteriorated in 13% of patients. The remaining patients were effectively unchanged. Arai et al.95 used a Japanese translation of a questionnaire that had been validated in English to assess HRQOL in men treated for testicular cancer. Patients treated with chemotherapy (with or without retroperitoneal lymph node dissection), radiotherapy, and surveillance were compared. Working ability was better in the radiotherapy and chemotherapy groups. These patients also reported a greater overall satisfaction with life than those in the surveillance group. Weissbach et al.96 compared HRQOL outcomes in men undergoing retroperitoneal lymph node dissection (RPLND) or upfront chemotherapy for stage II nonseminomatous germ cell tumors as part of a prospective, multicenter clinical trial. HRQOL outcomes were similar between the two groups, leading the authors to recommend surgery for these patients, as chemotherapy could then be avoided in a considerable number of patients with little effect on quality of life. SUMMARY HRQOL is an essential outcome for patients with genitourinary malignancies. While patients are concerned with maximizing their life expectancy following a diagnosis of cancer, they are often just as concerned, if not more so, with maintaining their quality of life after treatment. Clinicians and researchers must be sensitive to this and focus more attention of the effects of therapy on cancer survivors’ quality of life. REFERENCES 1. Fayers PM, Jones DR: Measuring and analyzing quality of life in cancer clinical trials: a review. Stat Med 1983; 2:429. 2. Patrick DL, Erickson P: Assessing health-related quality of life for clinical decision-making. In Walker SR, Rosser RM (eds): Quality of Life Assessment: Key Issues in the 1990s, Chap. 19. Dordrecht, Kluwer Academic Publishers, 1993. 3. Sadura A, Pater J, Osoba D, et al: Quality of life assessment: patient compliance with questionnaire completion. J Natl Cancer Inst 1992; 84:1023.
110
Part I Principles of Urologic Oncology
4. Altwein J, Ekman P, Barry M, et al: How is quality of life in prostate cancer patients influenced by modern treatment? The Wallenberg Symposium. Urology 1997; 49:66. 5. Litwin MS: Measuring health related quality of life in men with prostate cancer. J Urol 1994; 152:1882. 6. Tulsky DA: An introduction to test theory. Oncology 1990; 4:43. 7. Patrick DL, Deyo RA: Generic and disease-specific measures in assessing health care status and quality of life. Med Care 1989; 27(Suppl):S217. 8. Cronbach LJ: Coefficient alpha and the internal structure of tests. Psychometrika 1951; 16:297. 9. Nunnally JC: Psychometric Theory, 2nd edition New York, McGraw-Hill, 1978. 10. Messick S: The once and future issues of validity: assessing the meaning and consequences of measurement. In Wainer H, Braun HI (eds):Test Validity, Hillside, NJ, Lawrence Erlbaum Associates, 1988. 11. Tannock IF: Management of breast and prostate cancer: how does quality of life enter the equation? Oncology 1990; 4:149. 12. Litwin MS, Lubeck DP, Henning JM, et al: Differences in urologist and patient assessments of health related quality of life in men with prostate cancer: results of the CaPSURE database. J Urol 1998; 159:1988. 13. Bennett CL, Chapman G, Elstein AS, et al: A comparison of perspectives on prostate cancer: analysis of utility assessments of patients and physicians. Eur Urol 1997; 32:86. 14. Crawford ED, Bennett CL, Stone NN, et al: Comparison of perspectives on prostate cancer: analyses of survey data. Urology 1997; 50:366. 15. Parkerson GR Jr, Connis RT, Broadhead WE, et al: Disease-specific versus generic measurement of healthrelated quality of life in insulin-dependent diabetic patients. Med Care 1993; 31:629. 16. Tarlov AR, Ware JE Jr, Greenfield S, et al: The Medical Outcomes Study. an application of methods for monitoring the results of medical care. JAMA 1989; 262:925. 17. Ware JE, Sherbourne CD, Davies AR: Developing and testing the MOS 20-item short-form health survey: a general population application. In Stewart AL, Ware JE (eds): Measuring Functioning and Well-Being: The Medical Outcomes Study Approach, Durham, NC, Duke University Press, 1992 18. Stewart AL, Hays RD, Ware JE: The MOS short-form general health survey: reliability and validity in a patient population. Med Care 1988; 26:724. 19. Ware JE Jr, Sherbourne CD: The MOS 36-item shortform health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992; 30:473. 20. McHorney CA, Ware JE Jr, Rogers W, et al: The validity and relative precision of MOS short- and long-form health status scales and Dartmouth COOP charts. Results from the Medical Outcomes Study. Med Care 1992; 30:MS253. 21. McDowell I, Ewell C: Measuring Health: A Guide to Rating Scales and Questionnaires. New York, Oxford University Press, 1987.
22. Kaplan RM, Bush JW, Berry CC: Health status: types of validity and the index of well-being. Health Ser Res 1976; 11:478. 23. Kaplan RM, Bush JW: Health-related quality of life measurement for evaluation research and policy analysis. Health Psychol 1982; 1:61. 24. Kaplan RM, Anderson JP: A general health policy model: update and applications. Health Ser Res 1988; 23. 25. Hays RM, Shapiro MF: An overview of generic healthrelated quality of life measures for HIV research. Quality Life Res 1992; 1: 91-97. 26. Deyo RA, Inui TS, Leininger JD, et al: Measuring functional outcomes in chronic disease: a comparison of traditional scales and a self-administered health status questionnaire in patients with rheumatoid arthritis. Med Care 1983; 21:180. 27. Bergner M, Bobbitt RA, Carter WB, et al: The sickness impact profile: development and final revision of a health status measure. Med Care 1981; 19:787. 28. Moinpour CM, Feigl P, Metch B, et al: Quality of life end points in cancer clinical trials: review and recommendations. J Natl Cancer Inst 1989; 81:485. 29. Hunt SM, McEwen J, McKenna SP: Measuring health status: a new tool for clinicians and epidemiologists. J Royal College General Practitioners 1985; 35:185. 30. McDowell IW, Martini CJM, Waugh W: A method for self-assessment of disability before and after hip replacement operations. Br Med 1978; J2:57. 31. Martini CJ, McDowell I: Health status: patient and physician judgements. Health Ser Res 1976; 11:508. 32. Aaronson NK, Ahmedzai S, Bergman B, et al: The European Organization for Research and the treatment of Cancer QLQ-C30: a quality of life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85:356. 33. Borghede G, Sullivan M: Measurement of quality of life in localized prostatic cancer patients treated with radiotherapy. Development of a prostate cancer-specific module supplementing the EORTC QLQ-C30. Quality Life Res 1996; 5:212. 34. Borghede G, Karlsson J, Sullivan M: Quality of life in patients with prostatic cancer: results from a Swedish population study. J Urol 1997; 158:1477. 35. Albertsen PC, Aaronson NK, Muller MJ, et al: Healthrelated quality of life among patients with metastatic prostate cancer. Urology 1997; 49:207. 36. Cella DF, Tulsky DS: Measuring quality of life today. Oncology 1990; 4:29. 37. Tulsky DS, Cella DF, Bonomi A, et al: Development and validation of new quality of life measures for patients with cancer. Proc Soc Behav Med 0990; 11:45. 38. Cella DF, Cherin EA: Quality of life during and after cancer treatment. Compreh Therapy 1988; 14:68. 39. Cella DF, Orofiamma B, Holland JC, et al: Relationship of psychological distress, extent of disease, and performance status in patients with lung cancer. Cancer 1987; 60:239. 40. Esper P, Mo F, Chodak G, et al: Measuring quality of life in men with prostate cancer using the functional assessment of cancer therapy-prostate instrument. Urology 1997; 50:920.
Chapter 6 Health-Related Quality of Life Issues in Urologic Oncology 111 41. Litwin MS, Hays RD, Fink A, et al: Quality-of-life outcomes in men treated for localized prostate cancer. JAMA 1995; 273:129. 42. Litwin MS, Hays RD, Fink A, et al: The UCLA Prostate Cancer Index: development, reliability, and validity of a health-related quality of life measure. Med Care 1998; 36:1002. 43. Krongrad A, Perczek RE, Burke MA, et al: Reliability of Spanish translations of select urological quality of life instruments. J Urol 1997; 158:493. 44. Litwin MS, Fink A, Hays RD, et al: Quality of life in men with prostate cancer: a pilot study. J Urol 1993; 149:494A. 45. Wei JT, Dunn RL, Litwin MS, et al: Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology 2000; 56:899. 46. Ware J Jr, Kosinski M, Keller SD: A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care 1996; 34:220. 47. Curran D, Fossa S, Aaronson N, et al: Baseline quality of life of patients with advanced prostate cancer. European Organization for Research and Treatment of Cancer (EORTC), Genito-Urinary Tract Cancer Cooperative Group (GUT-CCG). Eur J Cancer 1997; 33:1809. 48. Kim SP, Bennett CL, Chan C, et al: QOL and outcomes research in prostate cancer patients with low socioeconomic status. Oncology 1999; 13:823. 49. Herr HW, O’Sullivan M: Quality of life of asymptomatic men with nonmetastatic prostate cancer on androgen deprivation therapy. J Urol 2000; 163:1743. 50. Green HJ, Pakenham KI, Headley BC, et al: Coping and health-related quality of life in men with prostate cancer randomly assigned to hormonal medication or close monitoring. Psychooncology 2001; 11:401. 51. Potosky AL, Reeve BB, Clegg LX, et al: Quality of life following localized prostate cancer treated initially with androgen deprivation therapy or no therapy. J Natl Cancer Inst 2002; 94:430. 52. Litwin MS, Shpall AI, Dorey F, et al: Quality-of-life outcomes in long-term survivors of advanced prostate cancer. Am J Clin Oncol 1998; 21:327. 53. Moinpour CM, Savage MJ, Troxel A, et al: Quality of life in advanced prostate cancer: results of a randomized therapeutic trial [see comments]. J Natl Cancer Inst 0998; 90:1537. 54. Tyrrell CJ: Tolerability and quality of life aspects with the anti-androgen Casodex (ICI 176,334) as monotherapy for prostate cancer. International Casodex Investigators. Eur Urol 1994; 26:15. 55. Osoba D, Tannock IF, Ernst DS, et al: Health-related quality of life in men with metastatic prostate cancer treated with prednisone alone or mitoxantrone and prednisone [see comments]. J Clin Oncol 1999; 17:1654. 56. Litwin MS, Lubeck DP, Stoddard ML, et al: Quality of life before death for men with prostate cancer: results from the CaPSURE database. J Urol 2001; 165:871. 57. Turner SL, Gruenewald S, Spry N, et al: Less pain does equal better quality of life following strontium-89 therapy for metastatic prostate cancer. Br J Cancer 2001; 84:297.
58. Bacon CG, Giovannucci E, Testa M, et al: The association of treatment-related symptoms with qualityof-life outcomes for localized prostate carcinoma patients. Cancer 2002; 94:862. 59. Penson DF, Feng Z, Kuniyuki A, et al: General quality of life 2 years following treatment for prostate cancer: what influences outcomes? Results from the Prostate Cancer Outcomes Study. J Clin Oncol 2003; 21:1147. 60. Steineck G, Helgesen F, Adolfsson J, et al: Quality of life after radical prostatectomy or watchful waiting. N Engl J Med 2002; 347:790. 61. Stanford JL, Feng Z, Hamilton AS, et al: Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the Prostate Cancer Outcomes Study. JAMA 2000; 283:354. 62. Steiner MS: Current results and patient selection for nerve-sparing radical retropubic prostatectomy. Semin Urologic Oncol 1995; 13:204. 63. Kao T, Cruess D, Garner D, et al: Multicenter patient self-reporting questionnaire on impotence, incontinence and stricture after radical prostectomy. J Urol 2000; 163:858. 64. Murphy G, Mettlin C, Menck H, et al: National patterns of prostate cancer treatment by radical prostatectomy: results of a survey by the American College of Surgeons Commission on Cancer. J Urol 1994; 152:1817. 65. Fransson P, Widmark A: Late side effects unchanged 4–8 years after radiotherapy for prostate carcinoma: a comparison with age-matched controls. Cancer 1999; 85:678. 66. Franklin CI, Parker CA, Morton KM: Late effects of radiation therapy for prostate carcinoma: the patient’s perspective of bladder, bowel and sexual morbidity. Australas Radiol 1998; 42:58. 67. Crook J, Esche B, Futter N: Effect of pelvic radiotherapy for prostate cancer on bowel, bladder, and sexual function: the patient’s perspective. Urology 1996; 47:387. 68. Widmark A, Fransson P, Tavelin B: Self-assessment questionnaire for evaluating urinary and intestinal late side effects after pelvic radiotherapy in patients with prostate cancer compared with an age-matched control population. Cancer 1994; 74:2520. 69. Mantz CA, Nautiyal J, Awan A, et al: Potency preservation following conformal radiotherapy for localized prostate cancer: impact of neoadjuvant androgen blockade, treatment technique, and patientrelated factors [see comments]. Cancer J Scientific Am 1999; 5:230. 70. Lee WR, McQuellon RP, Harris-Henderson K, et al: A preliminary analysis of health-related quality of life in the first year after permanent source interstitial brachytherapy (PIB) for clinically localized prostate cancer. Int J Radiation Oncol Biol Phys 2000; 46:77. 71. Lee WR, McQuellon RP, Case LD, et al: Early quality of life assessment in men treated with permanent source interstitial brachytherapy for clinically localized prostate cancer. J Urol 1999; 162:403. 72. Arterbery VE, Frazier A, Dalmia P, et al: Quality of life after permanent prostate implant. Semin Surg Oncol 1997; 13:461.
112
Part I Principles of Urologic Oncology
73. Talcott JA, Clark JA, Stark PC, et al: Long-term treatment related complications of brachytherapy for early prostate cancer: a survey of patients previously treated. J Urol 2001; 166:494. 74. Brandeis J, Litwin M, Burnison C, et al: Quality of life outcomes after brachytherapy for early stage prostate cancer. J Urol 2000; 163:851. 75. Wei JT, Dunn RL, Sandler HM, et al: Comprehensive comparison of health-related quality of life after contemporary therapies for localized prostate cancer. J Clin Oncol 2002; 20:557. 76. Davis JW, Kuban DA, Lynch DF, et al: Quality of life after treatment for localized prostate cancer: differences based on treatment modality. J Urol 2001; 166:962. 77. Bacon CG, Giovannucci E, Testa M, et al: The impact of cancer treatment on quality of life outcomes for patients with localized prostate cancer. J Urol 2001; 166:1804. 78. Bjerre BD, Johansen C, Steven K: Health-related quality of life after cystectomy: bladder substitution compared with ileal conduit diversion. A questionnaire survey. Br J Urol 1995; 75:200. 79. Hunt Raleigh ED, Berry M, Montie JE: A comparison of adjustments to urinary diversions: a pilot study. JWOCN 1995; 22:58. 80. Hara I, Miyake H, Hara S, et al: Health-related quality of life after radical cystectomy for bladder cancer: a comparison of ileal conduit and orthotopic bladder replacement. Br J Urol Int 2002; 89:10. 81. Fujisawa M, Isotani S, Gotoh A, et al: Health-related quality of life with orthotopic neobladder versus ileal conduit according to the SF-36 survey. Urology 2000; 55:862. 82. Boyd S, Feinberg SM, Skinner DG, et al: Quality of life survey of urinary diversion patients: comparison of ileal conduits versus continent Kock ileal reservoirs. J Urol 1987; 138:1386. 83. Dutta SC, Chang SC, Coffey CS, et al: Health related quality of life assessment after radical cystectomy: comparison of ileal conduit with continent orthotopic neobladder. J Urol 2002; 168:164. 84. Hardt J, Filipas D, Hohenfellner R, et al: Quality of life in patients with bladder carcinoma after cystectomy: first results of a prospective study. Quality Life Res 2000; 9:1. 85. McGuire MS, Grimaldi G, Grotas J, et al: The type of urinary diversion after radical cystectomy significantly
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
impacts on the patient’s quality of life. Ann Surg Oncol 2000; 7:4. Litwin MS, Fine JT, Dorey F, et al: Health related quality of life outcomes in patients treated for metastatic kidney cancer: a pilot study. J Urol 1997; 157:1608. Kroger MJ, Menzel T, Gschwend JE, et al: Life quality of patients with metastatic renal cell carcinoma and chemoimmunotherapy–a pilot study. Anticancer Res 1999; 19:1553. Heinzer H, Mir TS, Huland E, et al: Subjective and objective prospective, long-term analysis of quality of life during inhaled interleukin-2 immunotherapy. J Clin Oncol 1999; 17:3612. Osband ME, Lavin PT, Babayan RK, et al: Effect of autolymphocyte therapy on survival and quality of life in patients with metastatic renal-cell carcinoma. Lancet 1990; 335:994. Shinohara N, Harabayashi T, Sato S, et al: Impact of nephron-sparing surgery on quality of life in patients with localized renal cell carcinoma. Eur Urol 2001; 39:114. Clark PE, Schover LR, Uzzo RG, et al: Quality of life and psychological adaptation after surgical treatment for localized renal cell carcinoma: impact of the amount of remaining renal tissue. Urology 2001; 57:252. Pace KT, Dyer SJ, Stewart RJ, et al: Health-related quality of life after laparoscopic and open nephrectomy. Surg Endosc 2003; 17:143. Joly F, Heron JF, Kalusinski L, et al: Quality of life in long-term survivors of testicular cancer: a populationbased case-control study. J Clin Oncol 2002; 20:73. Fossa SD, De Wit R, Roberts JT, et al: Quality of Life in Good Prognosis Patients With Metastatic Germ Cell Cancer: A Prospective Study of the European Organization for Research and Treatment of Cancer Genitourinary Group/Medical Research Council Testicular Cancer Study Group (30941/TE20). J Clin Oncol 2003; 21:1107. Arai Y, Kawakita M, Hida S, et al: Psychosocial aspects in long-term survivors of testicular cancer. J Urol 1996; 155:574. Weissbach L, Bussar-Maatz R, Flechtner H, et al: RPLND or primary chemotherapy in clinical stage IIA/B nonseminomatous germ cell tumors? Results of a prospective multicenter trial including quality of life assessment. Eur Urol 2000; 37:582.
C H A P T E R
7 Image-Guided Minimally Invasive Therapy Agnieszka Szot Barnes, M.D., M.S., and Clare M.C. Tempany, M.B., B.A.O., B.Ch.
The field of image-guided minimally invasive procedures has undergone a revolutionary change in the past decade. We have seen the development of advanced imageguided therapies for treatment of many different diseases, ranging from brain tumor resection and treatment to magnetic resonance (MR)-guided prostate brachytherapy and MR-monitored thermal therapies, such as cryotherapy. In the field of urologic oncology, today there are many image-guided procedures for obtaining diagnoses and guiding and delivering treatment. These range from simple biopsies to image-guided tumor ablations. Minimally invasive therapy is used to treat the disease by operating through natural body openings or small incisions, thereby reducing the cosmetic or loco-regional tissue damage and the potential complications of open surgery. By reducing the need for invasive surgery, hospitalization is shortened, with fewer complications and faster recovery. These procedures have been allowed by the development of improved surgical techniques and, perhaps more importantly, improved imaging techniques. Because direct visualization without surgical intervention is not possible, the ability to combine multiple imaging modalities to plan and execute the surgery has permitted the full use of the new surgical techniques. This combination of imaging and therapy is known as image-guided therapy (IGT). The purpose of IGT is to integrate the anatomic and physiologic information acquired before treatment with the therapy methods and allow the control and guidance of the treatment while it is being performed to improve the accuracy of treatment delivery. Not only can imageguidance improve targeting of cancer tissue during therapy but it can also spare adjacent tissues and organs from being damaged during treatment. IGT is a multidisciplinary field in which surgeons, radiologists, oncologists,
and computer experts combine efforts to integrate imaging systems with therapy systems. Image-guided minimally invasive therapy is experiencing rapid growth driven by the introduction of new imaging modalities and significant improvement of existing ones as well as improving computer performance. The most important advancements of this field include integrating preprocedure and intraprocedure imaging, further improving image quality, and testing the usability of the techniques in clinical settings. HISTORY IGT evolved over the years with major advances in imageguided neurosurgery spreading to other disciplines, including urologic oncology. In many cases, brain tumors may visually resemble healthy tissue to the naked eye or the extent of tumor invasion may be obscured by overlying healthy tissue. Before image guidance the procedures were performed without proper visualization of the extent of the tumor or its specific geometry. In the past decade or so, MR imaging (MRI) and computed tomography (CT) techniques have improved enormously. We have seen rapid MR scanners with high field strengths become standard clinical tools in many radiology departments around the world. New multidetector CT scanners allow rapid acquisition of high-resolution CT data sets that can now be reconstructed in coronal or sagittal planes. As the technology has advanced, the impact of the image data has expanded. Now imaging alone diagnoses nearly all renal cell carcinomas. Imaging alone stages the extent of vascular invasion by a renal cell tumor and plans the surgical approach. Three-dimensional (3D) reconstructions allow the surgeon to determine the feasibility of a partial nephrectomy.
113
114
Part I Principles of Urologic Oncology
The imaging of solid organs, both to identify pathology and to accurately locate critical structures, has become the province of x-ray CT and MRI. CT has been used primarily for guiding biopsies, although the advent of “CT fluoroscopy” has stimulated use in guiding interventional procedures, such as radiofrequency (RF) ablation. Intraoperative ultrasound (US) has been used with increasing success for many decades, particularly in the imaging of solid organs, which can be directly contacted by the probe, giving both excellent imagery and explicit orientation of the image. US is particularly useful in observing vascular structures, which are both important landmarks and vital structures to be avoided during the resection of solid organs. Laparoscopic US shares the imaging advantages of intraoperative use, but due to the small size of the imaging head and the offset required for endoscopic insertion, it could be more difficult to interpret the content and orientation of the images. The penetration of real-time CT and MRI into the broad range of surgical procedures has been slow, due to the complexity and cost of their implementation and difficult access to the patient. In the case of MRI, additional obstacles have been the incompatibility of surgical tools, devices and operating room equipment with the magnetic field environment and the challenge of interpreting the MR image, which may require extensive training and/or expert consultation. The attractiveness of MRI for guiding simple procedures, such as biopsies, was recognized as early as the mid-1980s. Many of the initial obstacles of real-time MRI guidance were overcome when an open MR scanner was introduced to guide neurosurgical procedures in Brigham and Women’s Hospital in Boston in December 1993. This new revolutionary method was envisioned by Dr. Ferenc Jolesz—radiologist and neurosurgeon—in 1987 when he began to put together a team of collaborators to create the “operating room of the future.”1 The 0.5 T intraoperative MR scanner was designed by GE Medical Systems (Signa SP) and installed in a designated MR therapy (MRT) suite.2 The scanner has a vertical gap that allows the physician to enter between the two magnets and makes it easy to access the patient to perform treatment (Figure 7-1). Images are generated using fast sequences resulting in near real-time imaging without disruption of the procedure. Initially, the scanner was used to guide percutaneous or transcranial biopsies but currently it is utilized in a variety of procedures from neurosurgery to prostate brachytherapy and biopsy. Since then, many other open configuration magnets have been introduced, including 0.2 T vertical-type magnets (Picker, Siemens) and shorter-bore magnets (Philips, Picker). Conventional 1.5 T magnets are also used to guide various procedures. The main disadvantage of
Figure 7-1 Open 0.5 T MR system for performing imageguided procedures.
these scanners is the difficulty they pose to accessing the patient during the procedure, while their main advantage is higher field strength and therefore better image quality. In the field of urology, IGT has advanced significantly from lithotripsy—shockwave removal of kidney stones under US or fluoroscopy guidance—to MR-guided procedures. While fluoroscopy remains a very popular method of image guidance in urology, it can expose both the patient and the physician to radiation. The advances in CT imaging made it possible to perform CT fluoroscopy in real time. These advances, including 3D reconstruction, play a large role in the guidance of urologic procedures, including CT-guided tumor ablations and CT-guided prostate brachytherapy and biopsy. Ultrasound guidance still remains very popular in clinical urology mainly because of its lower cost and portability, the possibility of real-time imaging, and the safety for both patient and urologist. Currently, many centers successfully use transrectal US (TRUS) to guide prostate biopsies and brachytherapy. MR has unique assets as a guidance modality, allowing not only target identification but also therapy monitoring. This is best illustrated by MR-guided focused ultrasound (MRgFUS). Finally, advances in MR imaging include image reconstruction in multiple planes, a higher signal-to-noise ratio that allows excellent differentiation between tissues, and new contrast agents to make feasible MRguided diagnostic techniques, such as MR angiography and MR spectroscopy. The creation of open interventional MR also made MR guidance possible for several urologic procedures, including prostate brachytherapy and biopsy.3
Chapter 7 Image-Guided Minimally Invasive Therapy 115
OVERVIEW OF CURRENT MR-GUIDED IMAGE-GUIDED THERAPY APPLICATIONS The field of MR imaging for guiding interventions and therapy is attracting considerable research attention. MRI is superior to any other method in brain tumor localization and assessment and therefore is an excellent method for surgical guidance. Tumor margins and extent can be well defined, which in turn provides the possibility of complete tumor eradication with minimal damage to healthy brain tissue. MR-guidance for neurosurgery provides substantial help in performing brain tumor surgery.3 The use of computerized navigation and 3D modeling further enhances precise tumor resection. These improvements in MR-guided neurosurgery techniques, including 3D modeling, have provided a framework for an MR-guided prostate intervention program guiding prostate cancer therapy with interstitial brachytherapy—the permanent placement of radioactive sources (commonly I-125) directly into the prostate. Prostate MRI, especially with combined endorectal and phase-array coils, provides images of even higher resolution and is used in prostate cancer staging, as well as in determination of extraprostatic disease with up to 82% accuracy.5,6 The T1- and T2-weighted images are helpful in differentiating between postbiopsy hemorrhage, which presents as a high T1 and a low T2 lesion, and prostate cancer, which presents as a low T1 and a low T2 lesion. Contrast-enhanced images and prostate spectroscopy are of great importance in distinguishing between normal and cancerous tissues. Bladder and prostate cancers may experience higher perfusion than does normal tissue, which is detected as signal enhancement following intravenous
injection of MR contrast agents (such as GadoliniumDTPA); relative peak enhancement, time to peak, and washout are of great importance in distinguishing and characterizing cancer.7–9 Added value comes from spectroscopy, where metabolic differences can distinguish between cancer and healthy tissues. Normal prostate metabolism is characterized by high citrate and low choline/creatinine levels, whereas in cancerous tissue these ratios are reversed.10 Prostate multivoxel spectra conveying metabolic information are superimposed on endorectal and multiphase-array MR anatomic images, allowing for precise localization of the tumor. Prostate imaging is now moving towards use of higher-field 3 T scanners, which provide images with higher signal-to-noise ratio, which in turn allow for better visualization of prostatic substructures and increased MR-spectroscopy resolution. The development of an interventional MR therapy (MRT) system has made it possible to perform prostate brachytherapy under MR guidance. Even at lower field strength than is routinely used for prostate cancer imaging (0.5 T versus 1.5 T), MRI provides images of good quality for target visualization, as well as identification of the urethra and rectum (see Figure 7-2 for comparison of 1.5 T and 0.5 T images). Computer software has been developed to provide dosimetry analysis, used for both treatment planning and monitoring based on intraoperative MR images.11 Image-processing methods adapted from brain surgery are available to further facilitate precise radiation delivery to the prostate gland while sparing surrounding tissues. Currently, treatment delivery with a robot assistance system is being developed and tested to improve radioactive seed placement.
Figure 7-2 Prostate gland segmentation and registration. Segmentation identifies PZ (solid arrow) and central gland (hollow arrow) in pre-therapy endorectal coil MR (1.5 T, left) and MR-guided therapy images 0.5 T, right). Registration matches the segmented areas in the different images.
116
Part I Principles of Urologic Oncology
After installation of the first interventional magnet at Brigham and Women’s hospital in 1993, several other centers were created at teaching hospitals around the country, including Stanford University and the University of Mississippi. Since then the number of centers has grown and now includes many more sites in the U.S. and overseas. A great strength of MRI lies in its sensitivity to temperature changes.12–14 This sensitivity allows specialists to monitor in real-time the delivery of several thermal energy treatments, including RF and laser therapy for brain tumors, and cryotherapy and high-intensity FUS for breast, prostate, liver, and uterine lesions. Currently, MRI is a very useful guidance method for cryotherapy— tumor ablation by use of freezing—because it allows for monitoring of the location and size of the ice ball in multiple dimensions.4 Intraoperative MR images are used to depict the slow expansion of the ice ball, as well as tissue damage caused by the freezing process. MR-guided FUS is a very promising method for noninvasive cancer treatment. While other minimally invasive therapies require direct insertion of special probes to reach the tumor, this method uses a high-intensity US beam focused on the target lesion (as seen on the MR image) without disruption of skin and other tissues. FUS is based on the use of acoustic energy and its secondary thermal effect, which cause thermal coagulation of the target tissue. As early as 1955, it was clinically shown that FUS was capable of destroying mammalian tissues.15 Broad use of this treatment method has been hindered by a lack of appropriate image-guidance techniques for the tumor-targeting, and most importantly for the real-time monitoring of temperature changes. The introduction of MR guidance provided an excellent method for monitoring treatment planning and delivery with direct temperature mapping (using MR phase-contrast techniques), as well as posttreatment confirmation of necrotic tissue changes.6 Using the MR images, the physician can identify the target lesions; temperature change during treatment delivery is monitored using MR temperature maps. A special transducer moves from one spot to another, following a pretreatment plan, until the entire volume is treated. To date, this method has been successfully used in the treatment of breast fibroadenomas, breast cancers, and uterine leiomyomas.16–18 Application of this treatment to prostate cancer, liver lesions, and brain tumors is currently under investigation. IMAGE-GUIDED THERAPY: ROLE OF IMAGE PROCESSING The key to IGT is the integration of a coordinated image process with the therapy process. Early problems with IGT included lack of integration of the imaging with therapy instruments, as well as difficulties with image
display and processing, especially when using MR processing. As the image processing technology improved, feedback from imaging to the therapy became possible and the role of imaging became more prominent, using MRI for intraoperative guidance as well as diagnosis. As the processing improved, imaging became almost instantaneous or “real-time,” allowing for tight integration of imaging and therapy. There are several components critical to all imageguided therapies; these are: planning, targeting, navigation, control, and monitoring. Pretreatment planning allows for the assessment of the approach that will provide the most effective eradication of the tumor and at the same time the least damage to the surrounding vital organs. For example, when delivering radiation therapy, pretreatment dosimetry planning determines the volume of the target and the placement of radiation sources. Targeting during IGT refers to precise pretreatment localization of all tumor targets that need to be treated and is essential for precise navigation of equipment during treatment delivery. Navigation refers to the guidance of surgical equipment during procedures to target the tumors precisely and spare healthy tissue. Current research efforts in the field of navigation are directed towards automatization of the procedure and increasing the use of surgical robots.19,20 Real-time controlling and monitoring of the treatment delivery by means of intraoperative imaging allows for necessary adjustments of the therapy to reflect movement of the tissues and permits alterations of he plan in response to initial therapy. Many different image postprocessing techniques have been developed to allow use of anatomic and functional information to improve tumor detection and treatment planning. These techniques include image segmentation, fusion, and registration. The purpose of image segmentation is to distinguish organs or structures of interest (e.g., prostate or its peripheral zone [PZ]) from the surrounding organs and tissue in order to perform volumetric and shape analyses, as well as treatment planning (see Figure 7-2). This is currently done by either manual outlining of the structure of interest or by semiautomated methods.21 The future of medical image segmentation is to automate the process and replace manual segmentation.22,23 Registration is a technique used to match images taken using different modalities, the same modality at different time points, or different imaging sequences (see Figure 7-2). The process involves mapping one image into the coordinate system of another image. Fusion is the merging of the anatomic and functional information provided by different imaging modalities into a single volume in order to provide better information about the underlying anatomy and tissue characteristics (Figure 7-3). Applications for fused images include not only IGT but also minimally invasive diagnosis and treatment planning.
Chapter 7 Image-Guided Minimally Invasive Therapy 117
Figure 7-3 MR-CT image fusion of prostate gland. Registration allows fusion of MR image (left) with CT image to yield fused image (right). Black arrows indicate radioactive seeds.
IMAGE-GUIDED MINIMALLY INVASIVE THERAPY IN UROLOGY Many of the image-guided minimally invasive therapies in urologic oncology are directed toward diagnosis and treatment of prostate cancer. In prostate procedures, IGT and diagnosis can be guided by different image modalities; transrectal TRUS (TRUS) is the most widely used method. TRUS provides good delineation of the prostate margin, simplicity of imaging, relatively low cost compared to other modalities, and availability. TRUS is a widely used technique for guidance of both prostate biopsies and brachytherapy. However, for prostate cancer diagnosis, the positive predictive value of this method remains quite low (17% to 57% for hypoechoic lesions, as summarized by Boges et al.24). Currently, research focuses on improving the accuracy of TRUS in the detection and staging of prostate cancer, including features such as power and color Doppler, 3D imaging, and elastography. CT guidance was used primarily for prostate biopsies but has also been introduced in prostate cancer therapy guidance.25 CT provides visualization of prostate boundaries and with the placement of a Foley catheter in the bladder allows for good visualization of the urethra that helps avoid urethral damage during treatment delivery. MR guidance of prostate procedures grew in importance after the development of the interventional MR scanner described earlier. Compared to US and CT imaging, MR imaging provides superior visualization of the prostate and its zonal anatomy, tumor location, and surrounding vital organs like the rectum, neurovascular bundles (NVBs), and urethra.
Minimally invasive image-guided procedures for early stage organ-confined prostate cancer include diagnosis using US-, CT- and MR-guided biopsy; and therapy using cryotherapy, CT-guided brachytherapy (CTBT), 2D transrectal US-guided brachytherapy (USBT)—both with and without external beam radiation therapy, with and without neo-adjuvant hormonal therapy; MR-guided brachytherapy (MRBT), with and without external beam radiation therapy; and FUS. In general, the group of patients that may benefit from IGT as monotherapy for prostate cancer is comprised of men with organ-confined disease. Lieberfarb et al.26 showed that in low-risk patients with clinical stage ≤ T2a (according to the American Joint Commission on Cancer Staging—AJCC system), PSA ≤10 ng/ml, and ≤ 50% positive biopsies, the likelihood of extracapsular extension (ECE) with or without positive margins was 18%, and seminal vesicle involvement was 2%. These patients may be “ideal” candidates for IGTs. For an overview of prostate therapy outcomes see Jani and Hellman (2003)27 and Peschel and Colberg (2003).28 Cryotherapy Cryotherapy refers to the application of low temperatures to necrotize the tumor. In addition to its use as a primary treatment for prostate cancer it has also been used as a salvage therapy after failure of radiation therapy.29–31 Cryosurgery was first proposed as a treatment for prostate disease in 1966.30 In the following years, several open transperineal procedures were performed under visual control. Because of many serious posttherapy
118
Part I Principles of Urologic Oncology
complications, including urethro-cutaneous and urethrorectal fistulas, cryosurgery was not commonly used until its revival with US guidance in 1993.33 Procedure Cryotherapy is usually performed with the patient placed in the lithotomy position and placed under general anesthesia. The specific technique and the number of freezing cycles vary slightly between centers, with 2 cycles used most commonly. After positioning of the TRUS probe, multiple suprapubic cryoprobes are placed using US guidance. To prevent damage to the urethra, a warming urethral catheter is placed. Thermal sensors are placed around the periphery of the gland to allow good temperature control in critical locations. At the end of the procedure, the cryoprobes are thawed and removed. A newer approach to the use of cryotherapy in imageguided interventions is MR-guided cryotherapy, which has the major advantage of allowing clear visualization of the “ice-ball” induced in the tissue, as it occurs. This allows for direct thermal monitoring of the treatment effect (Figure 7-4).
Because of the fairly recent revival of cryotherapy due to image guidance improvements, the long-term treatment results are still being investigated. Several groups reported their preliminary results following TRUS-guided cryotherapy. At 5 years, the progression-free rate defined as undetectable PSA (< 0.3 ng/ml) ranged from 48% to 77%, depending on patients’ risk factors.34,35
Outcomes
Figure 7-4 Axial MR image showing a percutaneous cryotherapy probe in the lateral aspect of the left kidney during an MR-guided cryoablation of a small renal cell carcinoma. The “black” ice-ball is clearly seen (solid arrow); note the close proximity of the left colon (hollow arrow).
Complications of the treatment included incontinence, urethral sloughing, rectal fistula, and perirectal abscess.34–36 Patients self-reporting erectile dysfunction (ED) following cryosurgery were many compared to other minimally invasive prostate cancer treatments, ranging from 53% to 87%.34–37 A recent study showed pilot results on a new “nerve sparing” cryosurgery with the preservation of potency in 7 of 9 treated men at a median follow-up of 36 months (range from 6 to 72 months).38 Brachytherapy Interstitial brachytherapy refers to the permanent placement of small radioactive sources directly into the prostate. These are typically iodine (I-125) or palladium sources contained within a titanium-jacket and measure about 4 mm in length. Similar to cryosurgery, interstitial brachytherapy can be used as a primary treatment or as a salvage therapy after external beam radiation or initial implant failure. 39–41 Interstitial brachytherapy for prostate cancer was introduced in the 1960s by Scardino and Carlton.42 The placement of radioactive seeds was performed using a freehand technique that did not provide homogenous seed distribution and resulted in both underdosing of tumors and overdosing of vital structures (rectum, urethra, NVBs). This resulted in many posttreatment complications, and the procedure was discontinued until its revival with US image guidance in 1983 by Holm and colleagues.43 Further improvements in imaging techniques and technology resulted in the first MR-guided implant being performed at 1997 at Brigham and Women’s Hospital in Boston.44
Ultrasound-Guided Brachytherapy Procedure A patient is placed in the lithotomy position, a Foley catheter is inserted, and general or spinal anesthesia is administered. The TRUS probe and probe stabilizer are positioned and the probe stepper is attached to the stabilizer. US images are obtained every 5 mm from the apex to the base. Some centers use designated treatment planning software for preplanning of the procedure.45 The images are transferred to a laptop computer connected to the US equipment. A 3D reconstruction of the prostate, urethra, and rectum is produced, and the dose of radiation to those structures is visualized. Dosevolume histograms and the number of radioactive seeds per needle are then calculated. The template for needle guidance is placed against the patient’s perineum. After insertion of each needle a sagittal mode of the US acquisition is also used to determine the depth of the needle insertion. Some centers use fluoroscopy to visualize seed placement.45
Chapter 7 Image-Guided Minimally Invasive Therapy 119
Although investigators used slightly different definitions of biochemical failure, the overall results of similar studies are quite consistent. At present, there are only a few studies presenting 10-years outcome data for prostate USBT. Biochemical disease-free survival rates after 10 years following treatment ranged from 70% to 87%.46–48 At 5 years, relapse-free survival rates reached 85% to 94% for the low-risk group, 77% to 82% for the intermediate-risk group, and 62% to 65% for the highrisk group.49–51 Reported complications following USBT included urinary incontinence, urethral strictures, cystitis, urinary retention, prostatitis, proctitis, rectal ulceration, and rectal fistulas. Transient irritation and obstruction of the urinary tract 2 to 6 months after treatment were common and about 10% of patients showed symptoms of acute urinary retention (AUR).52 Preservation of potency ranged from 64% to 79% at 3 years to 39% at 6 years. Pretreatment ED and a higher implant dose caused greater impotence.53–55 Outcomes
CT-Guided Brachytherapy Procedure The prostate gland immobilization before the procedure is similar to US-guided therapy. A Foley catheter, with radio-opaque wire to fluoroscopically localize the urethra, is placed, and general anesthesia is administered. Preoperative CT images collected using 5 mm slices are used to outline the prostate gland for treatment planning. Posteroanterior and lateral fluoroscopic images are used to determine needle position before seeds are deposited. The seeds are placed under fluoroscopic control. Recently, CT-guided transischiorectal stereotactic brachytherapy has been introduced and tested.56–58 This approach can be used in patients with larger prostates. Transischiorectal CT images acquired every 5 mm are used for pretreatment planning. The patient is placed in the prone position, a Foley catheter is inserted and spinal or epidural anesthesia is administered. A 3D stereotactic template used to guide needle placement is attached to the CT table and tilted at the same angle as the gantry. Electronic grids are superimposed on every second CT image to determine needle depth. CT images are used for needle visualization, placement corrections are introduced if necessary, and radioactive seeds are deposited. Biochemical disease-free survival rates reached 99% for low, 96% for intermediate, and 90% for the high-risk group at a median follow-up of 4.5 years (2 to 8 years).59 Treatment complications included urinary retention, incontinence, and rectal symptoms. Outcomes
MR-Guided Brachytherapy Patient Selection The patient selection criteria for this program in our institution are clinical stage T1cNXM0 (according to AJCC), PSA less than 10 ng/ml, biopsy Gleason score not more than 3 + 4, low cancer volume, and endorectal MRI demonstrating organ-confined disease. Patients with prior transurethral resection of the prostate (TURP) are excluded. We do not exclude men with larger-volume prostates, as pubic arch interference can be avoided in this approach. All patients undergo endorectal coil MRI for prostate cancer staging prior to the treatment visit (Figures 7-5 and 7-6). An MR radiologist assesses prostate gland volume, tumor location and volume, the presence or absence of extraglandular disease, seminal vesicle invasion (SVI), and possible spread to pelvic lymph nodes or bones. Procedure This multidisciplinary procedure uses many different computer, imaging and technical skills and therefore requires the cooperation of specialists from various medical and nonmedical fields, including radiation oncologists, medical physicists, radiologists, anesthesiologists, urologists, nurses, radiology technologists, and computer scientists. For the procedure the patient is placed in an open configuration 0.5 T Signa SP MR scanner in the lithotomy position. The patient is positioned on the table between two magnets with vertically oriented open space for easier access to the patient during the treatment (see Figure 7-1). A Foley catheter is inserted, skin prepared, the template for needle guidance placed against the patient’s perineum and secured, and a rectal obturator is inserted (Figure 7-7). T2-weighted MRI images are acquired in the axial, coronal, and sagittal planes. The radiologist uses the T2-weighted images (see Figure 7-2, right) to identify the peripheral zone (PZ), urethra, and anterior rectal wall on each axial MR slice. These are then outlined using the 3D Slicer surgical simulation software designed and operated by members of the Surgical Planning Laboratory (SPL) at Brigham and Women’s Hospital in Boston (Figure 7-8). The 3D Slicer is free, open-source software for two- and three-dimensional display, registration, and segmentation of medical images (see www.slicer.org for more information on 3D Slicer). Pretreatment planning, as well as calculation of the MRI-based peripheral zone as a clinical target volume (CTV), is then performed by the medical physicists using designated planning software.11 The number of I-125 seeds per catheter and the depth of catheter insertion are calculated. The physicians then insert each preloaded catheter into the prostate gland. After every catheter insertion, axial gradient-echo MR images are obtained in real-time and compared to the catheter’s expected location according to the plan. Dose volume
120
Part I Principles of Urologic Oncology
Figure 7-5 Endorectal coil MRI of prostate. Axial (left) and coronal (right) T2-weighted images provide superior visualization of the prostate and its zonal anatomy. White solid arrows indicate PZ, hollow arrows indicate central gland, and striped arrows indicate endorectal coil.
Figure 7-6 Prostate cancer. Axial T2-weighted erMRI image shows low signal lesion located in PZ (white arrow).
Figure 7-7 Close up view of a patient in the open 0.5T Signa SP magnet, during MR-guided prostate brachytherapy. The patient is in the lithotomy position and the perineal template used for catheter guidance is seen in the center.
histograms (DVH) for the CTV, anterior rectal wall, and urethra are recalculated, adjustment of the catheter placement is performed when necessary, and seeds are deposited. Approximately 6 weeks after the procedure, MRI and CT imaging of the prostate is performed to identify the location of radioactive seeds and calculate final DVHs. Since seeds can be well visualized on CT images, and the underlying anatomy is better depicted on MR images, MR-CT fused images are used to calculate dose distribution to the surrounding tissues (Figure 7-9).
Outcomes
Long-term biochemical outcomes were compared for similar patients over similar time frames between MR-guided brachytherapy and radical prostatectomy by D’Amico et al.60 At 5 years, PSA control was 95% for brachytherapy and 93% for RP patients (median follow-ups were 3.95 and 4.2 years for brachytherapy and RP patients, respectively). The percentage of positive prostate biopsies was found to be a significant predictor of the time to postbrachytherapy PSA failure. Short-term toxicity following MR-guided brachytherapy was rare, and no patient reported gastrointestinal or
Chapter 7 Image-Guided Minimally Invasive Therapy 121
Figure 7-8 Image segmentation using 3D Slicer surgical navigation software. PZ (solid arrow), rectal wall (hollow arrow), and urethra (striped arrow) are identified on T2-weighted image acquired in a 0.5 T scanner for MRBT planning.
Figure 7-9 MR-CT fusion of post-MRBT images. Post-therapy MR image (left) and CT image (middle) are fused resulting in MR-CT image (right) to allow better visualization of individual seeds and facilitate dose distribution calculation. Black arrows indicate radioactive seeds.
122
Part I Principles of Urologic Oncology
sexual dysfunction during the first month after treatment.61 Acute urinary retention (AUR) was observed in 12% of men within 24 hours of removal of the Foley catheter and was self-limiting within 1 to 3 weeks. MRdetermined prostate volume, transitional zone (TZ) volume, and total number of seeds were found to be significant predictors of AUR on univariate analysis. The TZ volume was the only significant predictor of AUR on multivariate logistic regression analysis. The authors concluded that benign prostatic hyperplasia (BPH) that results in larger TZ volume is the most important predictor of AUR. No urinary incontinence was seen at a median follow-up of 14 months (from 9 months to 2 years).62 MR-guided brachytherapy is a very new approach; thus, there is only one report to date summarizing long-term toxicity.63 Albert et al.63 found low incidence of rectal bleeding (8%) and no urethral strictures at a median follow-up of 2.8 years (0.5 to 5 years). While ED reached 82%, two-thirds of the patients reported good erectile function after sildenafil (Viagra). No radiation cystitis was estimated at 4 years after MRBT. Quality of life (QoL) outcomes collected using a previously validated questionnaire64 are currently being assessed, and early reports indicate that MR-guided prostate brachytherapy has better symptomatic outcomes than the conventional US-guided approach (J. Talcott, personal communication). Current research projects will continue to study the radiation dose distribution to vital organs and its impact on the side effects. Image-segmentation techniques are used to identify those important organs on endorectal coil MR images. Radiation dose to the organs can then be correlated with changes in patientreported QoL. Focused Ultrasound Surgery US-Guided High-Intensity Focused Ultrasound for Prostate Cancer This approach uses a high-intensity US beam that is focused on the target lesion, which then undergoes thermal coagulation. In 1996, Galet et al.65 were the first to evaluate clinical application of FUS for treatment of organ-confined prostate cancer. Procedure For the treatment the patient is placed in the lateral position and anesthetized. A suprapubic catheter is placed to assure urinary drainage, and an imaging and treatment probe is inserted into the rectum. The probe is surrounded with a balloon filled with cooling fluid to avoid overheating of the rectal wall. Target areas are identified using biplanar US imaging and the
treatment is planned. Therapy is performed using a 2.25 to 3-MHz transducer. Early results showed 56% to 100% therapy response rates when using Ablatherm probes; however, the criteria of PSA failure after FUS are still under debate.66–72 Blana et al.73 reported outcomes following FUS for localized prostate cancer at a median follow-up of 22.5 months (4 to 62 months). After a follow-up for 22 months, 87% of patients had a PSA level below 1ng/ml, and 93.4% had negative control biopsies. Reported treatment adverse effects included urinary tract infection, stress incontinence, rectal burn, rectourethral fistulas, urethral stricture, and impotence. MR-guided FUS for treatment of prostate disease is currently under investigation; initial animal tests appear very promising. FUS treatment can be monitored by thermal maps and contrast-enhanced MRI (Figure 7-10). Outcomes
Diagnosis US-Guided Prostate Biopsy Currently, diagnosis of prostate cancer is aided using TRUS to guide the biopsy and is a widely used and accepted procedure.74–76 However, the sensitivity and positive predictive value of sextant biopsy remain quite low, 60% and 25%, respectively.77–79 The first transperineal prostate biopsies under US control were performed in the mid-1980s, and a few years later TRUS become the primary modality for biopsy guidance.80 Initially, the sextant biopsy technique recommended the collection of six samples from the base, mid-gland, and apex on both sides. Subsequent literature, however, showed the advantages of increasing the number of samples to 10, 11, or even 12 to detect cancer with up to a 96% success rate. It was also recommended that the number of core biopsies increase with the prostate volume, since bigger gland sizes introduced high sampling error and therefore required more sampling.81–85 However, the ideal number of cores is still not clear. Procedure Prior to the insertion of the endorectal probe, the patient undergoes a digital rectal exam (DRE). The patient is positioned on the table in either litothomy or lateral decubitus position. The ultrasound probe is inserted and stabilized and the prostate volume is calculated using transverse and sagittal imaging. If the procedure is performed in lithothomy position, the template for needle guidance is placed against the patient’s perineum. The positions of needles are identified by grid coordinates on the template and the depth by the probe stepper attached to the probe stabilizer. These coordinates are used to guide biopsy under real-time US imaging. Biopsy is performed using an 18-gauge biopsy gun.
Chapter 7 Image-Guided Minimally Invasive Therapy 123
MR-Guided Prostate Biopsy In addition to being an excellent method for guiding prostate cancer therapy, MR imaging also appears to be useful for guiding diagnostic biopsy.86 Similar to its use in therapy, metabolic information from spectroscopy and dynamic contrast MR data can be combined with routine MR images to allow precise tumor targeting. Our group has adapted the interventional MR system to perform MR-guided prostate biopsy.86,87 This transperineal technique eschews endorectal devices and provides an excellent diagnostic alternative for patients who have undergone rectal surgeries and in whom US-guided procedure is impossible to perform. An additional group of men who can be benefited from MR-guided procedure are those with persistently rising PSA values and have had prior negative US-guided biopsies. Preliminary feasibility results of this method for facilitating prostate cancer diagnosis are promising.73 One of the unique aspects of this approach is the interactive imaging provided by using the 3D Slicer, as reported by Hata et al.86, which facilitates T2 imaging in “near-real time.” D’Amico et al.88 reported results of the procedure from two MRI-targeted lesions in a patient who could not undergo US-guided procedure because of previous rectal surgery. Several transurethral biopsies yielded negative results in this patient. Following MRguided biopsy, cancer was confirmed in 15% and 25% of the 2 cores. Figure 7-10 MR-focused US surgery of uterine fibroid. A, Coronal T2-weighted FSE image (4000/90) used for treatment planning. The sonication locations and sizes (circles and grid) were determined by the planning software from this prescription (and the tissue depth) and displayed on top of the treatment plan. During the treatment, the accumulated thermal dose (hollow arrow) was displayed on top of the treatment planning images. A dose threshold of 240 equivalent minimum at 43 ˚ C is displayed. B, Sagittal T2weighted image (2500/98) showing the treatment plan and the area that achieved the threshold thermal dose. C–D, Temperature sensitive phase-difference FSPGR images (39.9/19.7) acquired at peak temperature rise during two sonications, one imaged perpendicular to the direction of the US beam (Coronal, C), and one imaged parallel to the direction of the beam (sagittal, D). These images were used to estimate the thermal dose (white line) for each sonication. E–F, Result of the treatment. E, Sagittal contrast-enhanced gradient-echo image (245/1.8) acquired 2 days after US therapy. The nonenhancing area (white arrow) is clearly seen. F, Gross pathologic cut specimen showing the central area of hemorrhagic necrosis. (From Tempany MC et al: Radiology 2003; 226(3):902.)
Procedure Prior to the procedure, each patient undergoes endorectal coil MRI using a 1.5 T imaging system. The T1- and T2-weighted and contrast-enhanced images are collected, and multivoxel spectroscopy is performed. Using this information, the radiologist identifies biopsy targets. Patient positioning for the procedure and initial preparation is similar to MRBT except that an endorectal obturator may not be used in some cases with previous rectal surgery. Subsequently, T2-weighted images are collected at 3.5 mm intervals in a 0.5 T interventional system. The information from preprocedure and intraprocedure images are correlated and target lesions are identified. Computer software is used to calculate appropriate coordinates on the perineal template for the needle insertion, as well as needle insertion depth. Additionally, 0.5 T T2weighted images and intraprocedure fast gradient-echo images are loaded into the 3D Slicer software and displayed in an alternating fashion to provide real-time image guidance during biopsy. All target locations along with sextant biopsies of the PZ from the right and left apex, mid-gland, and base are sampled using MR-compatible 18 gauge biopsy guns. Figure 7-11 shows an axial view of the needle tip artifact in PZ after needle insertion and just before
124
Part I Principles of Urologic Oncology
A
B Figure 7-11 Biopsy needle artifact. Axial (A) and coronal (B) view of prostate gland on pre(left) and intra-MR-guided biopsy images (middle and right). The black arrow indicates the tip of the biopsy needle. (From D’Amico Av, Loeffter JS, Harris JR. Image guided diagnosis and treatment of cancer. Totowa, NJ, Humana Press, 2003.)
biopsy. This procedure is currently done under anesthesia as a day surgical procedure. It is well tolerated and offers a second-line biopsy approach in selected patients. SUMMARY
Figure 7-12 Biopsy needle antifact. Real-time 3D view of prostate gland on intra-MR-guided biopsy images.
The areas covered in this chapter serve to illustrate the significant advances that have occurred in image-guided procedures and therapy for both diagnosis and treatment of prostate cancer. These are only some of the many new IGT applications available today. As the imaging techniques continue to improve and as surgical approaches become even less invasive or completely noninvasive (as with FUS), the future looks very exciting for both urology patients and their doctors.
Chapter 7 Image-Guided Minimally Invasive Therapy 125
REFERENCES 1. Jolesz FA: 1996 RSNA Eugene P. Pendergrass New Horizons Lecture. 1997. 2. Silverman SG, Jolesz FA, Newman RW, et al: Design and implementation of an interventional MR imaging suite. Am J Roentgenol 1997; 168(6):1465–1471. 3. Chan DY, Solomon S, Kim FJ, Jarret TW: Image-guided therapy in urology. J Endourol 2001;15(February; 1): 105–110. 4. Jolesz FA, Nabavi A, Kikinis R: Integration of interventional MRI with computer-assisted surgery. J Magn Reson Imaging 2001; 13(1):69–77. 5. Comet-Batlle J, Vilanova-Busquets JC, Saladie-Roig JM, Gelabert-Mas A, Barcelo-Vidal C. The value of endorectal MRI in the early diagnosis of prostate cancer. Eur Urol 2003; 44(August; 2):201–207 (Discussion 207-8). 6. Hricak H, White S, Vigneron D, Kurhanewicz J, Kosco A, Levin D, et al: Carcinoma of the prostate gland: MR imaging with pelvic phased-array coils versus integrated endorectal-pelvic phased-array coils. Radiology 1994;193:703–709. 7. Barentsz JO, Engelbrecht M, Jager GJ, et al: Fast dynamic gadolinium-enhanced MR imaging of urinary bladder and prostate cancer. J Magn Reson Imaging 1999; 10(September; 3):295–304. 8. Huisman HJ, Engelbrecht MR, Barentsz JO: Accurate estimation of pharmacokinetic contrast-enhanced dynamic MRI parameters of the prostate. J Magn Reson Imaging 2001; 3(April; 4):607–614. 9. Engelbrecht MR, Huisman HJ, Laheij RJ, et al: Discrimination of prostate cancer from normal peripheral zone and central gland tissue by using dynamic contrastenhanced MR imaging. Radiology 2003; 229(October; 1): 248–254 (Epub 2003 August 27). 10. Coakley FV, Qayyum A, Kurhanewicz J. Magnetic resonance imaging and spectroscopic imaging of prostate cancer. J Urol 2003; 170(December; 6 Pt 2):S69–S75 (Discussion S75-6). 11. Kooy HM, Cormack RA, Mathiowitz G, Tempany C, D’Amico AV: A software system for interventional magnetic resonance image-guided prostate brachytherapy. Comput Aided Surg 2000; 5(6):401–413. 12. Cline HE, Hynynen K, Hardy CJ, et al: MR temperature mapping of focused ultrasound surgery. Magn Reson Med 1994; 31(6):628–636. 13. Jolesz FA, Hynynen K: Magnetic resonance image-guided focused ultrasound surgery. Cancer J 2002; 8(Suppl 1): S100–S112. 14. Hynynen K, Darkazanli A, Damianou CA, Unger E, Schenck JF: Tissue thermometry during ultrasound exposure. Eur Urol 1993; 23(Suppl 1):12–16. 15. Fry WJ, Barnard JW, Fry FJ, Krunins RF, Brennan JF: Ultrasonic lesions in mammalian central nervous system, Science 1955; 122:517. 16. Hynynen K, Pomeroy O, Smith DN, et al: MR imagingguided focused ultrasound surgery of fibroadenomas in the breast: a feasibility study, Radiology 2001; 219(1):176–185.
17. Huber PE, Jenne JW, Rastert R, et al: A new noninvasive approach in breast cancer therapy using magnetic resonance imaging-guided focused ultrasound surgery. Cancer Res 2001; 61(23):8441–8447. 18. Tempany CM, Stewart EA, McDannold N, et al: MR imaging-guided focused ultrasound surgery of uterine leiomyomas: a feasibility study. Radiology 2003; 226(3):897–905. 19. Chinzei K, Hata N, Jolesz FA, Kikinis R: Surgical assist robot for the active navigation in the intraoperative MRI: hardware design issues, http://www.spl.harvard.edu:8000/ pages/projects/robot-new/iros2000.pdf. 20. MR Compatible Surgical Robot System, http://www.aist.go.jp/MEL/soshiki/kiso/biomech/chin/M MM/mrmani0-e.htm. 21. Pham DL, Xu C, Prince JL: Current methods in medical image segmentation. Annu Rev Biomed Eng 2000; 2:315–337. 22. Soler L, Delingette H, Malandain G, et al: Fully automatic anatomical, pathological, and functional segmentation from CT scans for hepatic surgery. Comput Aided Surg 2001; 6(3):131–142. 23. EPIDAURE Research Project, http://www-sop.inria.fr/ epidaure/research.php. 24. Bogers HA, Sedelaar JP, Beerlage HP, et al: Contrastenhanced three-dimensional power Doppler angiography of the human prostate: correlation with biopsy outcome. Urology 1999; 54(July; 1):97–104. 25. Wallner K, Roy J, Zelefsky M, Fuks Z, Harrison, L: Fluoroscopic visualization of the prostatic urethra to guide transperineal prostate implantation. Int J Radiat Oncol Biol Phys 1994; 29(4):863–867. 26. Lieberfarb ME, Schultz D, Whittington R, et al: Using PSA, biopsy Gleason score, clinical stage, and the percentage of positive biopsies to identify optimal candidates for prostate-only radiation therapy. Int J Radiat Oncol Biol Phys 2002; 53(4):898–903. 27. Jani AB, Hellman S: Early prostate cancer: clinical decision-making. Lancet 2003; 361(9362):1045–1053. 28. Peschel RE, Colberg JW: Surgery, brachytherapy, and external-beam radiotherapy for early prostate cancer. Lancet Oncol 2003; 4(4):233–241. 29. Ellis DS: Cryosurgery as primary treatment for localized prostate cancer: a community hospital experience. Urology 2002; 60(2 Suppl 1):34–39. 30. Ghafar MA, Johnson CW, De La Taille A, et al: Salvage cryotherapy using an argon based system for locally recurrent prostate cancer after radiation therapy: the Columbia experience. J Urol 2001; 166(4):1333–1337 (Discussion 1337-8). 31. da la Taille A, Katz AE: Cryosurgery: Is it an effective option for patients failing radiation? Curr Opin Urol 2000; 10(5):409–413. 32. Gonder MJ, Soanes WA, Shulman S: Cryosurgical treatment of the prostate. Invest Urol 1966; 3(4):372–378. 33. Onik GM, Cohen JK, Reyes GD: Transrectal ultrasoundguided percutaneous radical cryosurgical ablation of the prostate. Cancer 1993; 72(4):1291–1299.
126
Part I Principles of Urologic Oncology
34. Donnelly BJ, Saliken JC, Ernst DS, et al: Prospective trial of cryosurgical ablation of the prostate: five-year results. Urology 2002; 60(4):645–649. 35. Long JP, Bahn D, Lee F, et al: Five-year retrospective, multi-institutional pooled analysis of cancer-related outcomes after cryosurgical ablation of the prostate. Urology 2001; 57(3):518–523. 36. Badalament RA, Bahn DK, Kim H, et al: Patient-reported complications after cryoablation therapy for prostate cancer. Arch Ital Urol Androl 2000; 72(4):305–312. 37. Robinson JW, Moritz S, Fung T: Meta-analysis of rates of erectile function after treatment of localized prostate carcinoma. Int J Radiat Oncol Biol Phys 2002; 54(4):1063–1068. 38. Onik G, Narayan P, Vaughan D, Dineen M, Brunelle R: Focal “nerve-sparing” cryosurgery for treatment of primary prostate cancer: a new approach to preserving potency. Urology 2002; 60(1):109–114. 39. Bice WS Jr, Freeman JE, Russell LF Jr, et al: Use of image coregistration in salvage prostate brachytherapy. Tech Urol 2000; 6(2):151–156. 40. Beyer DC: Permanent brachytherapy as salvage treatment for recurrent prostate cancer. Urology 1999; 54(5):880–883. 41. D’Amico AV: Analysis of the clinical utility of the use of salvage brachytherapy in patients who have a rising PSA after definitive external beam radiation therapy. Urology 1999; 54(2):201–203. 42. Scardino PT, Carlton CE: Combined interstitial and external irradiation for prostatic cancer. In Javadpour N (ed): Principles and Management of Urologic Cancer, pp 392–408. Baltimore, Williams and Williams, 1983. 43. Holm HH, Juul N, Pedersen JF, Hansen H, Stroyer I: Transperineal 125 iodine seed implantation in prostatic cancer guided by transrectal ultrasonography. J Urol 1983; 130(2):283–286. 44. D’Amico AV, Cormack R, Tempany CM, et al: Real-time magnetic resonance image-guided interstitial brachytherapy in the treatment of select patients with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1998; 42(3):507–515. 45. Kaplan ID, Holupka EJ, Meskell P, et al: Intraoperative treatment planning for radioactive seed implant therapy for prostate cancer. Urology 2000; 56(3):492–495. 46. Grimm PD, Blasko JC, Sylvester JE, Meier RM, Cavanagh W: Ten-year biochemical (prostate-specific antigen) control of prostate cancer with (125)I brachytherapy. Int J Radiat Oncol Biol Phys 2001; 51(1):31–40. 47. Ragde H, Elgamal AA, Snow PB, et al: Ten-year disease free survival after transperineal sonography-guided iodine-125 brachytherapy with or without 45-gray external beam irradiation in the treatment of patients with clinically localized, low to high Gleason grade prostate carcinoma. Cancer 1998; 83(5):989–1001. 48. Blasko JC, Grimm PD, Sylsvester JE, Cavanagh W: The role of external beam radiotherapy with I-125/Pd-103 brachytherapy for prostate carcinoma. Radiother Oncol 2000; 57(3):273–278.
49. Blasko JC, Grimm PD, Sylvester JE, et al: Palladium-103 brachytherapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2000; 46(4):839–850. 50. Potters L, Cha C, Oshinsky G, et al: Risk profiles to predict PSA relapse-free survival for patients undergoing permanent prostate brachytherapy. Cancer J Sci Am 1999; 5(5):301–306. 51. Beyer DC, Brachman DG: Failure free survival following brachytherapy alone for prostate cancer: comparison with external beam radiotherapy. Radiother Oncol 2000; 57(3):263–267. 52. Merrick GS, Butler WM, Tollenaar BG, Galbreath RW, Lief JH: The dosimetry of prostate brachytherapyinduced urethral strictures. Int J Radiat Oncol Biol Phys 2002; 52(2):461–468. 53. Merrick GS, Butler WM, Galbreath RW, et al: Erectile function after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002; 52(4):893–902. 54. Stock RG, Kao J, Stone NN: Penile erectile function after permanent radioactive seed implantation for treatment of prostate cancer. J Urol 2001; 165(2):436–439. 55. Talcott JA, Clark JA, Stark PC, Mitchell SP: Long-term treatment related complications of brachytherapy for early prostate cancer: a survey of patients previously treated. J Urol 2001; 166(2):494–499. 56. Koutrouvelis P, Lailas N, Katz S, et al: High- and low-risk prostate cancer treated with 3D CT-guided brachytherapy: 1- to 5-year follow-up. J Endourol 2000; 14(4):357–366. 57. Koutrouvelis PG, Three-dimensional stereotactic posterior ischiorectal space computerized tomography guided brachytherapy of prostate cancer: a preliminary report. J Urol 1998; 159(1):142–145. 58. Molloy JA, Williams MB: Treatment planning considerations and quality assurance for CT-guided transischiorectal implantation of the prostate. Med Phys 1999; 26(9):1943–1951. 59. Koutrouvelis PG, Lailas N, Katz S, et al: Prostate cancer with large glands treated with three-dimensional computerized tomography guided pararectal brachytherapy: up to 8 years of followup. J Urol 2003; 169(4):1331–1336. 60. D’Amico AV, Tempany CM, Schultz D, et al: Comparing PSA outcome after radical prostatectomy or magnetic resonance imaging-guided partial prostatic irradiation in select patients with clinically localized adenocarcinoma of the prostate. Urology 2003;62(6):1063–1067. 61. D’Amico A, Cormack R, Kumar S, Tempany CM: Realtime magnetic resonance imaging-guided brachytherapy in the treatment of selected patients with clinically localized prostate cancer. J Endourol 2000; 14(4):367–370. 62. Thomas MD, Cormack R, Tempany CM, et al: Identifying the predictors of acute urinary retention following magnetic-resonance-guided prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 47(4):905–908. 63. Albert M, Tempany CM, Schultz D, et al: Late genitourinary and gastrointestinal toxicity after magnetic resonance image-guided prostate brachytherapy with or without neoadjuvant external beam radiation therapy. Cancer 2003; 98(5):949–954.
Chapter 7 Image-Guided Minimally Invasive Therapy 127 64. Clark JA, Talcott JA: Symptom indexes to assess outcomes of treatment for early prostate cancer. Med Care 2001; 39(10):1118–1130. 65. Gelet A, Chapelon JY, Margonari J, et al: Prostatic tissue destruction by high-intensity focused ultrasound: experimentation on canine prostate. J Endourol 1993; 7(3):249–253. 66. Gelet A, Chapelon JY, Bouvier R, et al: Treatment of prostate cancer with transrectal focused ultrasound: early clinical experience. Eur Urol 1996; 29(2):174–183. 67. Gelet A, Chapelon JY, Bouvier R, et al: Transrectal high intensity focused ultrasound for the treatment of localized prostate cancer: factors influencing the outcome. Eur Urol 2001; 40(2):124–129. 68. Gelet A, Chapelon JY, Bouvier R, et al: Transrectal highintensity focused ultrasound: minimally invasive therapy of localized prostate cancer. J Endourol 2000; 14(6):519–528. 69. Chaussy CG, Thuroff S, High-intensive focused ultrasound in localized prostate cancer. J Endourol 2000; 14(3):293–299. 70. Gelet A, Chapelon JY, Bouvier R, Pangaud C, Lasne Y: Local control of prostate cancer by transrectal high intensity focused ultrasound therapy: preliminary results. J Urol 1999; 161(1):156–162. 71. Beerlage HP, Thuroff S, Debruyne FM, Chaussy C, de la Rosette JJ: Transrectal high-intensity focused ultrasound using the Ablatherm device in the treatment of localized prostate carcinoma. Urology 1999; 54(2):273–277. 72. Uchida T, Sanghvi NT, Gardner TA, et al: Transrectal high-intensity focused ultrasound for treatment of patients with stage T1b-2n0m0 localized prostate cancer: a preliminary report. Urology 2002; 59(3):394–398 (Discussion 398-9). 73. Blana A, Walter B, Rogenhofer S, Wieland WF. Highintensity focused ultrasound for the treatment of localized prostate cancer: 5-year experience. Urology 2004;63(2):297–300. 74. Lee F, Gray JM, McLeary RD, et al: Prostatic evaluation by transrectal sonography: criteria for diagnosis of early carcinoma. Radiology 1986; 158(1):91–95. 75. Lee F, Gray JM, McLeary RD, et al: Transrectal ultrasound in the diagnosis of prostate cancer: location, echogenicity, histopathology, and staging. Prostate 1985; 7(2):117–129. 76. Rifkin MD, Kurtz AB, Goldberg BB: Prostate biopsy utilizing transrectal ultrasound guidance: diagnosis of nonpalpable cancers. J Ultrasound Med 1983; 2(4):165–167.
77. Keetch DW, McMurtry JM, Smith DS, Andriole GL, Catalona WJ: Prostate specific antigen density versus prostate specific antigen slope as predictors of prostate cancer in men with initially negative prostatic biopsies. J Urol 1996; 156(2 Pt 1):428–431. 78. Terris MK: Sensitivity and specificity of sextant biopsies in the detection of prostate cancer: preliminary report. Urology 1999; 54(3):486–489. 79. Terris MK, McNeal JE, Freiha FS, Stamey TA: Efficacy of transrectal ultrasound-guided seminal vesicle biopsies in the detection of seminal vesicle invasion by prostate cancer. J Urol 1993; 149(5):1035–1039. 80. Applewhite JC, Matlaga BR, McCullough DL, Hall MC. Transrectal ultrasound and biopsy in the early diagnosis of prostate cancer. Cancer Control 2001; 8(March–April; 2): 141–150. 81. Eskew LA, Bare RL, McCullough DL. Systematic 5 region prostate biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol 1997; 157(January; 1):199–202 (Discussion 202-3). 82. Chang JJ, Shinohara K, Bhargava V, Presti JC Jr: Prospective evaluation of lateral biopsies of the peripheral zone for prostate cancer detection. J Urol 1998; 60(December; 6 Pt 1):2111–2114. 83. Chen ME, Troncoso P, Johnston DA, Tang K, Babaian RJ: Optimization of prostate biopsy strategy using computer based analysis. J Urol 1997; 58(December; 6): 2168–2175. 84. Babaian RJ, Toi A, Kamoi K, et al: A comparative analysis of sextant and an extended 11-core multisite directed biopsy strategy. J Urol 2000; 163(January; 1):152–157. 85. Naughton CK, Miller DC, Mager DE, Ornstein DK, Catalona WJ. A prospective randomized trial comparing 6 versus 12 prostate biopsy cores: impact on cancer detection. J Urol 2000; 164(August; 2):388–392. 86. Hata N, Jinzaki M, Kacher D, et al: MR imaging-guided prostate biopsy with surgical navigation software: device validation and feasibility. Radiology 2001; 220(1):263–268. 87. Cormack RA, D’Amico AV, Hata N, et al: Feasibility of transperineal prostate biopsy under interventional MR guidance. Urology 2000; 56(4):663–664. 88. D’Amico AV, Tempany CM, Cormack R, et al: Transperineal magnetic resonance image guided prostate biopsy. J Urol 2000; 164(2):385–387.
C H A P T E R
8 Adrenal Tumors E. Darracott Vaughan, Jr, MD
The major adrenal tumors that will be discussed in this chapter include adrenal cortical adenomas producing primary hyperaldosteronism and Cushing’s syndrome, adrenal cortical carcinoma, the incidentally identified adrenal mass, and pheochromocytoma. Actually, the most common tumors involved in the adrenal gland are metastatic tumors to the adrenal, and the management of such lesions generally is dependent on the treatment of the primary disease entity. It is fortunate that the diagnosis of adrenal disorders is extremely accurate using the combination of precise analytical methods for the measurement of the abnormal secretion of adrenal hormones and sophisticated radiographic techniques for the localization and characterization of specific adrenal lesions.1,2 The management of patients with adrenal tumors requires a clear understanding of the normal physiology of the adrenal medulla and cortex; a three-dimensional concept of the adrenal anatomy, as well as adjacent structures; and the knowledge of the various pathologic entities that may involve the adrenal. Moreover, the operating surgeon must be well aware of the nuances involved in the diagnosis of the different adrenal entities, be aware of potential intraoperative phenomena that are unique to these patients, and be alert to specific postoperative complications that may occur.3 This chapter will review the preoperative, intraoperative, and postoperative aspects of each of these specific entities and will outline surgical approaches with operative hints to guide those interested in adrenal surgery. The adrenal glands are paired retroperitoneal organs that lie within the perinephric fat, at the anterior, superior, and medial aspects of the kidneys. Their location in juxtaposition with other organs, as well as the periadrenal fat, renders them ideal for sectional imaging by computed tomography (CT). Thin-cut CT scanning allows precise identification of lesions as small as 0.5 cm. The CT scan remains the best imaging device for the identification of small adrenal lesions, whereas magnetic reso-
nance imaging (MRI) gives information concerning cell type and aids in the differentiation of adenomas from medullary tumors or metastatic carcinoma.4 Other advantages of MRI scanning will be discussed later. The right adrenal lies above the kidney posterior and lateral to the inferior vena cava (IVC) and its solitary venous drainage is via a short sturdy vein that enters the IVC in a posterior fashion. Hence, the right adrenal gland is best approached through a posterior or modified posterior incision.5 The left adrenal is in more intimate contact with the kidney, overlying the upper pole of the kidney with its anterior and medial surfaces behind the pancreas and splenic artery. It is best exposed through a flank approach or a thoracoabdominal approach if the lesion is large. The adrenals have a delicate, rich blood supply estimated to be 6 to 7 ml/g/min without a dominant adrenal artery. The inferior phrenic artery is the main blood supply with additional branches from the aorta and renal arteries. The small arteries penetrate the gland in a circumferential stellate fashion leaving both the anterior and posterior surfaces avascular (Figure 8-1). During adrenalectomy, an important technical goal is to divide the superior and lateral blood supplies to the adrenal first, allowing the adrenal to remain attached to the kidney, which can be used to draw the adrenal gland inferiorly and anteriorly during the resection. On the left side, the adrenal vein drains into the left renal vein; however, there is also a medially located phrenic drainage branch, which, if not appropriately ligated, can cause troublesome bleeding (Figure 8-2). The left adrenal vein is also a guide to the left renal artery, which often lies dorsal to the vein. One potential complication of left adrenalectomy is the inadvertent ligation of the apical renal arterial branch to the upper pole, which lies in close contact to the inferior border of an adrenal tumor. The basic physiology of the adrenal cortex and medulla, as well as the various pathologic entities, will be discussed under specific disorders.
131
132
Part II Adrenal Gland
Figure 8-1 Arterial supply of left and right adrenal glands.
CUSHING’S SYNDROME Cushing’s syndrome is the term utilized to describe the symptom complex caused by excessive circulating glucocorticoids. We must remember that the term is allencompassing and includes: patients with pituitary hypersecretion of adrenocorticotrophic hormone (ACTH) (corticotropin); Cushing’s disease, which accounts for 75% to 80% of patients with endogenous Cushing’s; adrenal adenomas or carcinomas; ectopic secretion of ACTH, or corticotropin-releasing hormone (CRH) syndrome.6 Before assuming that a patient has one of these pathologic entities, there should be a thorough questioning of the patient about the use of steroidcontaining preparations. At times patients are unaware that a substance they use, particularly creams or lotions, contains steroids, and if the patient is on any type of medication at all, it should be carefully reviewed for steroid content. There are few diseases in which the clinical appearance of the patient can be as useful in suspecting the diagnosis. Old photographs are helpful in documenting recent changes in appearance that occurred. The more common clinical manifestations of Cushing’s syndrome found in different series of patients are shown in Table 8-1. The clinical findings do not distinguish patients with Cushing’s disease from those with adrenal adenoma; however, patients with adrenal carcinoma are more likely to show virilization in the female or feminization in the male. Patients with ectopic ACTH may present with manifestations of the primary tumor. It is also important to remember that some nonendocrine
Figure 8-2 Venous drainage of left and right adrenal glands with particular attention to the intercommunicating vein on the left.
disorders mimic the clinical and even the biochemical manifestations of Cushing’s syndrome. These patients have been termed to have “pseudo”-Cushing’s syndrome; this may exist in patients with major depression or in patients with chronic alcoholism.6 There are a myriad of tests both to diagnose the presence of Cushing’s syndrome and then to identify which subentity is present. Fortunately, due to recent development of extremely accurate assays for urinary and plasma cortisol, as well as plasma corticotropin, this task has become much easier. The approach that has recently been reported by Orth6 is shown in Figure 8-3. The clinical diagnosis of Cushing’s syndrome is confirmed by the demonstration of cortisol hypersecretion. At the present time the determination of 24-hour urinary excretion of cortisol in the urine is the most direct and reliable index of cortical secretion. Orth recommends that urinary cortisol should be measured in two and preferably three consecutive 24-hour urine specimens, collected on an outpatient basis. Once the diagnosis has been established, the next chore is to determine whether there is Cushing’s disease due to hypersecretion of plasma corticotropin (ACTH) from the pituitary or primary adrenal disease. Herein is the major change in our approach to patients with Cushing’s disease. In the past, high- and low-dose dexamethasone suppression tests have been used to accomplish this task. At present, the low-dose dexamethasone is generally used to rule out pseudo-Cushing’s syndrome. The differentiation of corticotropin-dependent Cushing’s
Chapter 8 Adrenal Tumors 133
Table 8-1 Clinical Manifestations of Cushing’s Syndrome All* Disease† (%) (%)
Adenoma/ Carcinoma‡ (%)
Obesity
90
91
93
Hypertension
80
63
93
Diabetes
80
32
79
Centripetal obesity
80
—
—
Weakness
80
25
82
Muscle atrophy
70
34
—
Hirsutism
70
59
79
Menstrual abnormal/ sexual dysfunction
70
46
75
Purple striae
70
46
36
Moon facies
60
—
—
Osteoporosis
50
29
54
Early bruising
50
54
57
Acne/pigmentation
50
32
—
Mental changes
50
47
57
Edema
50
15
—
Headache
40
21
46
Poor healing
40
—
—
From Scott HW Jr: In Scott HW (ed): Surgery of the Adrenal Glands. Philadelphia, JB Lippincott Co, 1990, with permission. *Hunt and Tyrell, 1978. †Wilson, 1984. ‡Scott, 1973.
syndrome versus corticotropin-independent Cushing’s syndrome is determined by the concurrent late afternoon or midnight measurement of collection of blood for the simultaneous measurement of plasma corticotropin and cortisol. Thus, if the patient’s cortisol concentration is above 50 μg/dl and the corticotropin concentration is below 5 pg/ml, then the cortisol secretion is ACTH independent and the patient has a primary adrenal problem. In contrast, if the plasma corticotropin concentration is greater than 50 pg/ml, then the cortisol secretion is ACTH dependent and the patient has Cushing’s syndrome or ectopic ACTH or CRH syndrome.5 In situations where the two-site immunoradiometric assay test is not available, the high-dose dexamethasone suppression test has always been used as the standard test to differ-
entiate between pituitary and adrenal Cushing’s syndrome. Patients are given high-dose dexamethasone (2 mg every 6 hours for 2 days), and plasma cortisol and urinary free cortisol levels are measured. In patients with pituitary disease, there should be a 50% or greater suppression in cortisol. Patients with adrenal adenomas or carcinomas fail to suppress cortisol secretion. The highdose dexamethasone suppression test may also be useful to identify ectopic ACTH syndrome, where there is usually complete resistance to high-dose dexamethasone suppression. Treatment is obviously dependent on the underlying lesion. Patients with adrenal adenomas or carcinomas are generally treated with surgical extirpation of the lesions. Patients with Cushing’s disease have confirmation with pituitary CT or MRI and usually are treated with transsphenoidal pituitary tumor removal, and patients with ectopic ACTH have treatment directed towards the primary tumor. The surgical approach and preparation of patients with adrenal Cushing’s disease will be discussed later. If the patient is identified as having adrenal Cushing’s, the next step is radiographic localization with CT scanning.7 Adrenal adenomas are usually larger than 2 cm, solitary, and associated with atrophy of the opposite gland. The density is low because of the high concentration of lipid (Figure 8-4). Adrenal carcinomas are often indistinguishable from adenomas except for the larger size, carcinomas usually being greater than 6 cm.8 Necrosis and calcification are also more common in association with adrenal carcinomas but are not specific. Clearly, large irregular adrenal lesions with invasion represent carcinoma; however, metastatic carcinoma to the adrenal has the same appearance. MRI is not usually necessary in patients with Cushing’s syndrome unless the lesion is large; the rationale for MRI is to obtain anatomic information concerning surrounding structures or invasion of the IVC, a rare but well-recognized entity.9 Adrenal cortical scanning with iodinated cholesterol agents is no longer routinely utilized but can be helpful in differentiating functional adrenal tissue from other retroperitoneal lesions.10 INCIDENTALLY DISCOVERED ADRENAL MASSES The increased utilization of abdominal ultrasound and CT scanning has led to a new classification of adrenal lesions termed the “incidentally identified unsuspected adrenal mass” or “incidentaloma.”8 Our approach to the incidentally identified adrenal mass is shown in Figure 8-5. Several points do not warrant controversy. First, there is an agreement that all patients with solid adrenal masses should undergo biochemical assessment. If biochemical abnormalities are identified, the lesions should be treated as described elsewhere in the chapter, usually by removal
134
Part II Adrenal Gland
Figure 8-3 Identifying Cushing’s syndrome and its causes.
of the offending lesion. However, the extent of biochemical assessment has been reviewed, and a selective approach has been outlined that markedly limits cost without sacrificing diagnostic accuracy.11 A very limited evaluation is recommended, including tests only to rule out pheochromocytoma, potassium levels in hypertensive cases, and glucocorticoid evaluation only in the presence of clinical stigmata of Cushing’s syndrome or virilization. The second point that is not controversial is that nonfunctioning solid lesions larger than 5 cm should be removed. This is based on the finding that adrenal malignancies are almost always larger than 6 cm. However, we
feel that CT scanning may underestimate the size of an adrenal, and we suggest that exploration be performed when lesions are more than 5 cm on CT or MRI.12 Furthermore, if lesions are purely cystic by CT or MRI, cyst puncture is often not necessary and these lesions can be followed (Figure 8-6). The controversy arises in the management strategy for the solid adrenal lesions smaller than 5 cm in size. The current approach has been to use MRI imaging in this situation. Most adenomas appear slightly hypointense or isointense relative to the liver or spleen on T1-weighted images and slightly hyperintense or isointense relative to hepatic or splenic parenchyma
Chapter 8 Adrenal Tumors 135
Figure 8-4 CT scan of a patient with right adrenal adenoma.
Figure 8-5 Evaluation of incidentally found adrenal mass.
Figure 8-6 Multilocular benign renal cyst in an asymptomatic patient that was incidentally identified. A, CT scan showing left adrenal cyst. B, Coronal MRI showing the lobular suprarenal adrenal cyst. In this case, exploration was carried out because of multilocular nature. The cyst was benign.
136
Part II Adrenal Gland
on T2-weighted images. There is little change in the intensity from T1- to T2-weighted studies. In contrast, the general notion is that adrenal cortical carcinoma is hypointense relative to liver or spleen on T1-weighted images and hyperintense to the liver or spleen on T2weighted images. Thus, if the mean signal intensity ratio between the lesion and the spleen is over 0.8, it is unlikely that the lesion is a benign adenoma. However, it should be remembered that there are a number of entities other than adrenal carcinoma that can cause high intensity, including neural tumors, metastatic tumors to the adrenal, adrenal hemorrhage, and other retroperitoneal lesions.4,13,14 An additional study that has shown accuracy is the fine-needle adrenal biopsy guided by ultrasound or CT. In a large series from Finland, significant cytologic material was obtained in 96.4% and the accuracy to differentiate benign from malignant disease was 85.7%.15 However, the utilization of aspiration cytology requires an extremely experienced cytologist, and in fact there is often inability to distinguish an adrenal adenoma from a carcinoma even on pathologic review of the entire specimen. It is our general approach that if there is either any radiographic evidence that argues against a characteristic benign adenoma or any change in size of an adrenal lesion with repeated studies, then we feel that adrenalectomy is indicated. This fairly aggressive approach is justified in view of the extremely poor prognosis of patients when adrenal carcinoma is diagnosed, even when the lesion is localized. ADRENAL CARCINOMA Adrenal carcinoma is a rare disease with a poor prognosis. The incidence is estimated as 1 case per 1.7 million, accounting for only 0.02% of cancers. A practical subclassification for adrenal carcinomas is according to their ability to produce adrenal hormones. In a series by Luton et al.,16 79% of adrenal tumors were functional, a higher percentage than previously reported due to more sensitive assays. The varieties of functioning tumors are shown in Table 8-2. However, this classification is some-
Table 8-2 Classification of Adrenal Carcinoma Functional Cushing’s syndrome Virilization in females Increased DHEA, 17-ketosteroids Increased testosterone Feminizing syndrome in males Hyperaldosteronism Mixed combination of above Nonfunctional DHEA, dehydroepiandrosterone.
what contrived, since many of these tumors will produce multiple adrenal hormones and also because of the clear evidence that a tumor may secrete one hormone at one point in its natural history and additional hormones at a later phase when there is increased tumor mass. The most commonly identified functional tumor is one causing Cushing’s syndrome. The most common characteristic to delineate Cushing’s syndrome due to carcinoma rather than adenoma has been the presence of virilization with elevated 17-ketosteroid levels. More recently, the measurement of DHEA has been useful in identifying these patients. Other rare functional tumors include both testosterone- and estrogen-secreting adrenal cortical tumors. Rarely, virilization can occur in the absence of elevated urinary 17-ketosteroids and raises the possibility of pure testosterone-secreting ovarian or adrenal lesions.17 Of the two sites of origin, adrenal cortical tumors secreting testosterone are exceedingly rare. In contrast to other tumors described in this section, these tumors are usually small, less than 6 cm, and many behave in a benign fashion. In contrast, most feminizing tumors occur in males 25 to 50 years of age, and they are usually larger, often palpable, and highly malignant.18 Characteristically, the patients present with gynecomastia; in addition they may exhibit testicular atrophy, impotence, or decreased libido. We have also seen a presentation with infertility and oligospermia. These tumors secrete androstenedione, which is converted peripherally to estrogen. Other steroids may also be secreted, and the clinical picture may be mixed with associated cushingoid features. The management of adrenal cortical carcinoma is surgical removal of the primary tumor. The most common sites of metastasis include lung, liver, and lymph nodes.19 Often these tumors extend directly into adjacent structures, especially the kidney, and surgical removal may require removal of the primary tumor and adjacent organs, including the kidney, spleen, as well as local lymph nodes. Unfortunately, despite en bloc resection even in patients without evidence of metastatic disease, the 5-year survival rate is only approximately 50% with complete resection and 25% overall.20 Because of the poor prognosis there has been an intense search for effective adjunctive chemotherapy, but this search has been frustrating and it is generally believed that conventional chemotherapy is not effective, probably because of P-glycoprotein expression.21 The most success has been reported with the adrenolytic 1,1-dichloro2-(o-chlorophenyl)-2-(p-chlorophenyl)-ethane(o,p¢-DDD) or Mitotane. This DDT derivative has been shown to induce tumor response in 35% in a review of 551 cases reported in the literature.22 However, despite these response rates, survival time has not been prolonged and there is intense toxicity. Recently, it has been suggested that patients even without the presence of metastatic
Chapter 8 Adrenal Tumors 137
disease be given adjunctive o,p¢-DDD, and trials are currently in progress to determine if this approach is efficacious. In general, there is an extremely poor prognosis in patients with adrenal cortical carcinoma and an obvious need for the development of new treatment strategies.
of primary hyperaldosteronism is now identified by the combined findings of hypokalemia, suppressed plasma renin activity (PRA) despite sodium restriction, and a high urinary and plasma aldosterone level after sodium repletion in hypertensive patients. The current evaluation of patients suspected of having hyperaldosteronism is shown in Figure 8-7. The primary physiologic control of aldosterone secretion is angiotensin II (Figure 8-8). Other control mechanisms are ACTH and potassium. A clear knowledge of the physiology of the renin– angiotensin–aldosterone system (RAAS) is mandatory in order to understand the pathophysiology and evaluate patients with primary hyperaldosteronism.25,26 The critical sensor in the RAAS resides in the juxtaglomerular apparatus within the kidney. Thus, in response to a variety of stimuli, but primarily decreased renal perfusion, or a decreased intake of sodium, there is an increased renin release, formation of angiotensin II, and subsequent
HYPERALDOSTERONISM The term hyperaldosteronism originally was coined by Dr. Jerome Conn to describe the clinical syndrome characterized by hypertension, hypokalemia, hypernatremia, alkalosis, and periodic paralysis due to an aldosteronesecreting adenoma.23 We now realize that this metabolic syndrome can be caused by either a solitary adrenal adenoma or by bilateral adrenal zona glomerulosa hyperplasia. One of the clinical chores is to delineate patients with hyperplasia from those with adenoma.24 The syndrome
Hypertension
>3.6
Serum K
ⱕ3.6
ⱕ1.0
PRA
>1.0
Replete K and Na
1⬚ aldosteronism is unlikely
1⬚ aldosteronism is unlikely
24-hour urine: K > 40 mEq and Aldosterone > 15 mcg No
Check urine: Cortisol DOC
Adrenal CT scan
Hyperplasia or normal
Equivocal
Unilateral adenoma
Postural stimulation test (+) (or) Plasma 18 OHB > 100 ng% (or) Elevated urinary 18 OH-F, 18 oxo-F No
Yes Adrenal sampling
Not Lateralized
Medication
Lateralized
Adrenalectomy
Figure 8-7 Identifying primary hyperaldosteronism.
138
Part II Adrenal Gland
Effective circulating blood volume
RENAL potassium excretion
Renal perfusion pressure
Renal sodium retention
History physical exam BP x 3 > 140/90 Basic lab tests
Suspect pheochromocytoma
Juxtaglomerular apparatus
Aldosterone secretion
Angiotensinogen Angiotensin II Potassium balance
Converting enzyme
Renin release
Plasma norepinephrine Epinephrine
Elevated
Diagnosis pheochromocytoma
Dopamine Urinary catechols
Angiotensin I
Normal
Figure 8-8 Control of aldosterone secretion by means of interrelationships between the potassium and reninangiotensin feedback loops.
Localize CTT
− −
Venous sampling
MIBG
aldosterone secretion. Therefore, the term secondary hyperaldosteronism is utilized when there is increased renin secretion and secondary aldosterone production.27,28 The most common examples of secondary hyperaldosteronism would be renovascular hypertension and malignant hypertension. In contrast, with an adrenal adenoma or adrenal hyperplasia there is primary secretion of aldosterone and subsequently the sodium retention that occurs leads to a suppression of plasma renin activity. Therefore, returning to Figure 8-7, the hallmark of the entity is hypokalemia. However, some patients realize that weakness occurs with increased sodium intake and therefore restrict their sodium, and may have a more normal potassium than that first observed. Therefore, the entity should not be ruled out until the patient has sodium loading with 10 g of sodium a day for several weeks and repeat potassium measurements. A small subset of patients exhibits normokalemic hyperaldosteronism, and if there is a high index of suspicion for the disease, these patients should be studied further. If there is hypokalemia, a 24-hour urine should be collected demonstrating that there is urinary loss of potassium. The critical test is the measurement of plasma renin activity at a time when the patient is either on a low-sodium diet or is challenged with a diuretic. If the patient has hyperaldosteronism, the plasma renin activity remains inappropriately low despite sodium depletion. Because potassium is also a stimulus of aldosterone, the patient should be potassium repleted before measuring 24-hour urine and plasma aldosterone levels. Both of these values should be elevated in hyperaldosteronism. At this point the question is whether the patient has a unilateral adenoma or bilateral adrenal hyperplasia, and the imaging study of choice is an adrenal CT scan with 3 to 5-mm cuts through both adrenal glands. The next step that is traditionally performed would be adrenal vein sampling. The difficulty with adrenal vein sampling is obtaining adequate collections from the short, stubby, right adrenal vein, and when samples are collected, cortisol levels should also always be collected to ensure proper
MRI
Evaluate for other causes
+ +
α- blockade, then remove
Figure 8-9 Identifying pheochromocytoma.
catheter placement. An appropriate way of analyzing aldosterone levels is with comparative aldosterone/cortisol ratios from each side. It is our general policy to have positive lateralizing information, as well as a positive CT scan, before recommending exploration and unilateral adrenalectomy. However, more recently, in patients who have elevated plasma 18-hydroxy-B levels and elevated urinary 18-hydroxy-F levels, at times we have not required sampling when a clear adenoma was demonstrated on CT scan. In contrast, we have demonstrated a subset of patients with radiographic bilateral hyperplasia who will lateralize adrenal vein sampling for aldosterone. In this setting, we have performed unilateral adrenalectomy and a significant number of those patients have favorable biochemical and blood pressure responses, although most have required the continuation of some antihypertensive medication.24 Finally, in patients who have normal CT scans yet lateralize on sampling, if they show elevated 18-hydroxy products, we will operate; if not, we will follow those patients. The majority of patients with bilateral hyperplasia will not lateralize with adrenal vein sampling for aldosterone. Those patients are treated with spironolactone at an appropriate dose to control blood pressure. Often, they will need other medications, such as calcium channel blockers. PHEOCHROMOCYTOMA Pheochromocytoma is an uncommon entity, but one that has potentially lethal sequelae for the patient if not diagnosed. Therefore, it is generally felt that all patients with sustained hypertension should have the appropriate studies performed to rule out pheochromocytoma (Figure 8-9).29,30
Chapter 8 Adrenal Tumors 139
The clinical manifestations exhibited by patients with pheochromocytoma are due to the physiologic effects of the catecholamines, dopamine, epinephrine, and norepinephrine. However, other signs and symptom complexes exhibited may be extremely variable, including the asymptomatic patient in whom a lesion is picked up simply on CT scan. In all reported series, hypertension is by far the most common sign (Table 8-3). As far as the type of hypertension, the patients may have either sustained hypertension, paroxysmal or dramatic attacks of hypertension, or sustained hypertension with superimposed paroxysms. Most series have shown this latter constellation of findings to be the most common in patients with pheochromocytoma. In addition, the frequency of attacks among patients is quite variable, ranging from a few times a year to multiple daily episodes. In addition, the duration may be minutes or hours and the nature of the attacks can vary dramatically. Most patients will exhibit a paroxysm or an episode once a week, and most of the attacks will last less than an hour. Usually, the attacks occur in the absence of recognizable stimuli, but a number of factors—particularly exercise, posture, trauma, or a variety of other situations—may precipitate an attack. One specific entity is noteworthy: catecholamineinduced cardiomyopathy. 31 Patients with catecholamine-induced cardiomyopathy will present with decreased cardiac function and congestive heart failure, and it is mandatory that their cardiac status be stabilized with the use of appropriate a- and b-adrenergic blocking agents as well as a-methylparatyrosine (a tyrosine hydroxylase inhibitor) (Figure 8-10) to cut down on catecholamine production before surgery is contemplated. Generally, the cardiomyopathy is reversible, and the patients can be operated on within weeks or months after the initial diagnosis and treatment is instituted. An appreciable number of pheochromocytomas have been found in association with other disease entities and hereditary syndromes. These entities include the association of tumors of the glomus jugulare region, neurofibromatosis, Sturge-Weber syndrome, and the von Hippel-Landau and familial multiendocrine adenopathy (MEA) syndromes. Pheochromocytomas occur in MEA2, a triad including pheochromocytoma, medullary carcinoma of the thyroid, and parathyroid adenomas (Sipple’s syndrome). Pheochromocytomas may also be a part of MEA-3, which also includes medullary carcinoma of the thyroid, mucosal neuromas, thickened corneal nerves, ganglioneuromatosis, and frequently marfanoid habitus. It is now believed that the relatives of patients with all of these syndromes should be evaluated for the presence of occult pheochromocytoma. In addition, there is a wellknown entity of familial pheochromocytoma in which multiple members of the kindred will be found to have multiple lesions and all members of such families should be both screened and then followed for the appearance of
these tumors. The mechanism of the increased incidence of pheochromocytomas in association with neuroendocrine dysplasias and medullary carcinoma of the thyroid may be explained by the amine precursor uptake and decarboxylation (APUD) cell system of Pierce. The APUD cells derived from the neural crest of the embryo share common ultrastructural and cytochemical features and elaborate amines by precursor uptake and decarboxylation.32,33 The laboratory diagnosis of pheochromocytoma is now extremely accurate, utilizing the urinary plasma measurements of catecholamines and their by-products (see Figure 8-9). Extremely accurate assays exist for these amines.34 At the present time it is felt that urinary catecholamines remain the measurement of choice with the measurement of total urinary catecholamines and metanephrines. Approximately 95% of patients will have elevated levels of these substances. In the patient with a severe paroxysmal hypertension who presents in the midst of hypertensive crisis, the plasma catecholamines are almost always elevated and can be utilized. Stimulation or suppression tests are generally not utilized at the present time. The one situation where they may be useful is in the patient who appears to have essential hypertension but borderline elevated catecholamines, and in this setting a clonidine suppression test may be useful. Following a single 0.3-mg oral dose of clonidine the patients with neurogenic hypertension at rest show a fall in norepinephrine, whereas patients with pheochromocytomas do not.34 The radiographic test that is most useful in both identifying and characterizing neuroendocrine adrenal tumors, and in identifying surrounding structures, is the MRI scan. We have been impressed with the multiple uses of MRI scans in patients with pheochromocytoma. Therefore, the test is as accurate as a CT scan in identifying lesions and also has a characteristic bright light bulb appearance on the T2-weighted study (see Figure 8-10).3 In addition, sagittal and coronal imaging can provide excellent anatomic information concerning the relationship between the tumor and the surrounding vasculature. Therefore, we feel that the MRI should be the initial scanning procedure in patients with the biochemical findings of pheochromocytoma. An alternative approach that also is useful at times, particularly for residual or multiple pheochromocytomas, is the metaiodobenzylguanidine (MIBG) scan that images medullary tissue.35,36 This test may be more sensitive than CT or MRI picking up small extra-adrenal lesions and has major use in patients where multiple lesions are suspected. ADRENAL SURGERY Adrenalectomy is the treatment of choice in most patients who have undergone appropriate metabolic evaluation
140
Part II Adrenal Gland
Table 8-3 Symptoms Reported by 76 Patients (Almost all Adults) with Pheochromocytoma Associated with Paroxysmal or Persistent Hypertension Symptoms
Paroxysmal (37 Patients) (%)
Symptoms Presumably Due to Excessive Catecholamines or Hypertension Headache (severe) 92 Excessive sweating (generalized) 65 Palpitations ± tachycardia 73 Anxiety or nervousness (± fear of impending death, panic) 60 Tremulousness 51 Pain in chest, abdomen (usually epigastric), lumbar regions, lower abdomen, or groin 48 Nausea ± vomiting 43 Weakness, fatigue, prostration 38 Weight loss (severe) 14 Dyspnea 11 Warmth ± heat intolerance 13 Visual disturbances 3 Dizziness or faintness 11 Constipation 0 Paresthesia or pain in arms 11 Bradycardia (noted by patient) 8 Grand mal 5
P e r s i s t e n t (39 Patients) (%)
72 69 51 28 26 28 26 15 15 18 15 21 3 13 0 3 3
Manifestations Due to Complications Congestive heart failure ± cardiomyopathy Myocardial infarction Cerebrovascular accident Ischemic enterocolitis ± megacolon Azotemia Dissecting aneurysm Encephalopathy Shock Hemorrhagic necrosis in a pheochromocytoma Manifestations Due to Coexisting Diseases or Syndromes Cholelithiasis Medullary thyroid carcinoma ± effects of secretions of serotonin, calcitonin, prostaglandin, or ACTH-like substance Hyperparathyroidism Mucocutaneous neuromas with characteristic facies Thickened corneal nerves (seen only with slit lamp) Marfanoid habitus Alimentary tract ganglioneuromatosis Neurofibromatosis and its complications Cushing’s syndrome (rare) Von Hippel-Lindau disease (rare) Virilism, Addison’s disease, acromegaly (extremely rare) Symptoms Caused by Encroachment on Adjacent Structures or by Invasion and Pressure Effects of Metastases From Manger WM, Gifford RW Jr: Pheochromocytoma. In Laragh JH, Brenner BM (eds): Hypertension Pathophysiology Diagnosis and Management. New York, Raven Press, 1990, with permission.
Chapter 8 Adrenal Tumors 141
Figure 8-10 MRI of pheochromocytoma.
and have been found to have a surgical lesion. Although most adrenal tumors are removed with a laparoscopic approach, the principles of open adrenal surgery apply and warrant review. However, the surgeon must be aware that there are unique aspects to the care in these patients, including specific preoperative management as outlined in Table 8-4. Accordingly, patients with hyperaldosteronism who are generally healthy require spironolactone 100 to 400 mg/day to restore their potassium supply. Patients with Cushing’s syndrome have severe systemic effects from the hyperglucocorticoidism. They are often obese, have diabetic tendencies, are poor wound healers, easily sustain bony fractures, and are susceptible to infection. Thus, they are at high risk for complications. In selected patients with markedly elevated cortisol levels the preoperative use of metabolic blockers, such as metyrapone, is required to reverse some of the clinical findings prior to adrenalectomy. Certainly, glucocorticoid replacement is required throughout the surgical procedure and postoperatively until the function of the contralateral adrenal gland occurs. Finally, in patients with a pheochromocytoma, adrenergic blockade generally with Dibenzyline is required, and at times the blockade of catecholamine production with metyrosine is also useful as previously discussed. The additional preoperative evaluation that is mandatory in patients with
pheochromocytoma is consultation with the anesthesiologist, who can be well aware of the patient and can plan strategy for management.37 Thus, the management of patients with an adrenal disorder is approached on a team basis, including experienced endocrinologists, radiologists, anesthesiologists, and urologists or general surgeons. Numerous approaches can be made to the adrenal gland (Table 8-5). The proper approach depends on the underlying cause of adrenal pathology, the size of the adrenal, the side of the lesion, the habitus of the patient, and the experience and preference of the surgeon. In most cases, there are a number of different options available, and a careful review of all the variables is required before a choice is made. Thus, each case should be considered individually, although some approaches are preferable for a given disease. For example, in patients with large adrenal tumors, a thoracoabdominal approach is often utilized. In contrast, a posterior or modified posterior approach is preferred for small localized lesions. Finally, in patients with multiple lesions, either extra-adrenal or bilateral will be explored using a transabdominal chevron incision. Before describing the specific techniques, a number of unifying concepts warrant attention. First, adequate visualization is imperative, as the adrenal glands lie high in the retroperitoneum and quite posterior. Therefore, the
142
Part II Adrenal Gland
Table 8-4 Preoperative Management
Table 8-5 Surgical Approaches in Adrenal Disorder Approach
Treatment Primary hyperaldosteronism
Spironolactone, 100–400 mg/ day, 2–3 weeks Follow K+ until normal Blood pressure should fall
Primary hyperaldosteronism Posterior (left or right) Modified posterior (right) Eleventh rib (left > right) Posterior transthoracic
Cushing’s syndrome
Control of glucose abnormalities Documentation of osteoporosis Glucocorticoid replacement (before, during, and after surgery) Perioperative antibiotics
Cushing’s adenoma
Eleventh rib (left or right) Thoracoabdominal (large) Posterior (small)
Cushing’s disease Bilateral hyperplasia
Bilateral posterior Bilateral eleventh rib (alternating)
Adrenal carcinoma
Thoracoabdominal Eleventh rib Transabdominal
Bilateral adrenal ablation
Bilateral posterior
Pheochromocytoma
Transabdominal (chevron) Thoracoabdominal (large, usually right) Eleventh rib
Neuroblastoma
Transabdominal Eleventh rib
Pheochromocytoma
Adrenergic blockade Phenoxybenzamine (Dibenzyline), 20–160 mg/day Metyrosine (if needed) Volume expansion Crystalloid β-Blockade if cardiac arrhythmias (only after α-blockade established) Anesthesia consultation
From Vaughan ED Jr: Adrenal surgery. In Marshall FF (ed): Textbook of Operative Urology. Philadelphia, WB Saunders Co, 1996, with permission.
use of a headlight by both the surgeon and first assistant is critical, and hemostasis should be rigorously maintained. The operator should bring the adrenal down by initially exposing the cranial attachments and dividing the rich blood supply between either right-angled clips or utilizing a forceps cautery or the harmonic scalpel. Thus, it is often simplest to begin the dissection laterally, identifying the vascular supply and working around the cranial edge of the gland. The posterior surface is generally devoid of vasculature and after the gland is freed superiorly with gentle traction on the kidney, the gland can be brought inferiorly for control of the adrenal vein. The only tumor handled in a different fashion would be a pheochromocytoma where intent should be made to obtain control of the adrenal vein early so as to stabilize the patient from a burst of catecholamine release during manipulation. The adrenal gland is extremely friable and fractures easily, which can cause troublesome bleeding. Therefore, tension or traction should be maintained on the kidney or surrounding structures and not on the adrenal itself. The concept has been stated that the “patient should be dissected from the tumor,” a view that is particularly true for pheochromocytomas, in which the glands should not be manipulated (Figure 8-11).
From Vaughan ED Jr: Adrenal surgery. In Marshall FF (ed): Textbook of Operative Urology. Philadelphia, WB Saunders Co, 1996, with permission.
Posterior Approach The posterior approach can be used for either bilateral adrenal exploration or unilateral removal of small tumors (Figure 8-12). The bilateral approach is rarely utilized today because of our excellent localization techniques. It is now utilized primarily for ablative total adrenalectomy. The options for incisions are shown in Figure 8-12; generally rib resection is preferable to gain high exposure. After standard subperiosteal rib resection, care should be taken with the diaphragmatic release, and the pleura should be avoided, and the diaphragm swept cranially. The fibrofatty tissues within Gerota’s fascia are swept away from the paraspinal musculature, exposing a subdiaphragmatic “open space” that is at the posterior apex of the resection. The liver within the peritoneum is dissected off the anterior surface of the adrenal and the cranial blood supply is divided. Medially on the right, the IVC is visualized. The short, high adrenal vein entering the cava in a dorsolateral position is identified and can be clipped or ligated. The adrenal can then be drawn caudally by traction on the kidney. The adrenal arteries will issue from behind the IVC and these must be carefully clipped; otherwise, troublesome bleeding can occur.
Chapter 8 Adrenal Tumors 143
Figure 8-11 MRI of recurrent pheochromocytoma with an excellent demonstration of anterior crossing right renal vein, feeding lumbar vein, and involvement of right renal artery.
Finally, the adrenal is removed from the superior aspect of the kidney and care must be taken to avoid apical branches of the renal artery. On the left, the approach is similar with division of the splenorenal ligament given initial lateral exposure. The posterior approach can be modified for a transthoracic adrenal exposure to the diaphragm38; however, this more extensive approach is rarely necessary for small adrenal tumors. Modified Posterior Approach
Figure 8-12 Posterior approach to the adrenals.
Although the posterior approach has the advantage of rapid adrenal exposure and low morbidity, there are definite disadvantages. This approach may impair respiration, the abdominal contents are compressed posteriorly, and the visual field is limited. In addition, if bleeding occurs, it is difficult to extend the incision to gain a better exposure. Therefore, we have developed a modified posterior approach for right adrenalectomy utilizing the Gil-Vernet position.39 The approach is based on the anatomic relationship with the right adrenal, which lies deep posterior and high in the retroperitoneum behind the liver (Figure 8-13A). In addition, the short, stubby right adrenal vein enters the IVC posteriorly at the apex of the adrenal. Hence, we utilize an approach that is posterior, but the patient is in a modified position, similar to that used for a Gil-Vernet dorsal lumbotomy incision.40 The patient is first placed in a formal lateral flank position and then allowed to fall forward into the modified posterior position (see Figure 8-13B). Subsequently, the 11th or 12th rib is resected
144
Part II Adrenal Gland
Figure 8-13 Modified posterior approach to the right adrenal.
with care to avoid the pleura. The diaphragm then is dissected off the underlying peritoneum and liver in order to gain mobility. Similarly, the inferior surface of the peritoneum, closely associated with the liver, is sharply dissected from Gerota’s fascia, which is gently retracted inferiorly. It is of note that the adrenal gland is not identified during the early portion of the dissection, and because of the modified posterior approach, the surgeon can become disoriented if not thoroughly familiar with anatomic relationships. The adrenal will become visible in the depth of the incision as the final hepatic attachments are divided. The
lateral, empty space can be found exposing the posterior abdominal musculature and often the IVC. Multiple small arteries course behind the IVC and emerge over the paraspinal muscles, and these are clipped and divided. At this point the adrenal can usually be moved posteriorly against the paraspinal muscles exposing the anterior surface of the IVC below the adrenal gland. The major advantage of this approach is that the adrenal vein is easily identified because it emerges from the segment of the IVC exposed and courses up to the adrenal, which now rises toward the surgeon. In other flank or anterior positions the adrenal vein resides in its poste-
Chapter 8 Adrenal Tumors 145
rior relationship, requiring caval rotation and the chance of adrenal vein avulsion. After adrenal vein exposure, it is doubly tied and divided or clipped with right-angle clippers and divided (see Figure 8-13D). The remaining removal of the adrenal is as we previously described for the posterior approach. On the left side we do not use this modified approach and use a standard flank approach with a fairly small incision. We have used the modified posterior approach for all patients with right adrenal aldosterone-secreting tumors and for other patients with benign adenomas of less than 6 cm. We do not recommend the approach for patients with large lesions or malignant adrenal neoplasms. The approach has been used for patients with relatively small pheochromocytomas. Flank Approach The standard extrapleural, extraperitoneal 11th rib resection is excellent for either left or right adrenalectomy. After completion of the incision, the lumbocostal arch is utilized as a landmark showing the point of attachment of the posterior diaphragm to the posterior abdominal musculature. Gerota’s fascia, containing the adrenal and kidney, can be swept medially and inferiorly, giving exposure to the splenorenal ligament on the left, which should be divided to avoid splenic injury (Figure 8-14). Working anteriorly on the left, the spleen and pancreas within the peritoneum can be lifted cranially, exposing the anterior surface of the adrenal gland. On the right side, a similar maneuver is used to lift the liver within the peritoneum off the anterior surface of the adrenal. Quite often the adrenal gland cannot be identified precisely until these maneuvers are performed. One should not attempt to dissect into the body of the adrenal or to dissect the inferior surface of the adrenal off the
Figure 8-14 Release of splenorenal ligament early in exposure of left adrenal.
kidney. The kidney is useful for retraction. The dissection should continue from lateral to medial along the posterior abdominal and diaphragmatic musculature, with precise ligation or clipping of the small but multiple adrenal arteries. While the operator clips these arteries with one hand, the opposite hand is employed to retract both adrenal and kidney inferiorly. With release of the superior vasculature, the adrenal becomes easily visualized. On the left medially, the phrenic branch of the venous drainage must be carefully clipped or ligated (Figure 8-15). This vessel is not noted in most atlases but can cause troublesome bleeding if divided. The medial dissection along the crus of the diaphragm and aorta will lead to the renal vein; finally, the adrenal vein is controlled, doubly tied, and divided. The adrenal is then removed from the kidney with care to avoid the apical branches of the renal artery (see Figure 8-15). On the right side, the dissection is similar. However, after release of the adrenal from the superior vasculature, it is helpful to expose the IVC and divide the medial arterial supply. This maneuver allows mobilization of the cava for better exposure of the high posterior adrenal vein, which is doubly tied or clipped and divided (Figure 8-16).
Figure 8-15 Further exposure of left adrenal including phrenic vein.
146
Part II Adrenal Gland
Figure 8-16 Exposure of right adrenal with and without nephrectomy.
Patients with large adrenal carcinomas may require an en bloc resection of the adrenal and kidney following the principles of radical nephrectomy (see Figure 8-16). A major deviation from this technique is used for the patient with pheochromocytoma, in whom the initial dissection should be aimed toward early control and division of the main adrenal vein on either side. Obviously, in this setting, the anesthesiologist should be notified when
the adrenal vein is divided because a marked drop in blood pressure often occurs, even when the patient is adequately hydrated. After removal of the adrenal, inspection should be made for any bleeding and for pleural tears of the diaphragm. The kidney should also be inspected. The incision is closed without drains with interrupted 0 polydioxanone sutures.
Chapter 8 Adrenal Tumors 147
Thoracoabdominal Approach The thoracoabdominal 9th or 10th rib approach is utilized for large adenomas; for some large adrenal carcinomas, and for well-localized pheochromocytomas. The incision and exposure are standard, with a radial incision through the diaphragm and a generous intraperitoneal extension. The techniques described for adrenalectomy with the 11th rib approach are used. Transabdominal Approach The transabdominal approach is commonly selected for patients with pheochromocytomas, for children, and for some patients with adrenal carcinomas. The concept is to have the ability for complete abdominal exploration to identify either multiple pheochromocytomas or adrenal metastases. I use the transverse or chevron incision, which I believe gives better exposure of both adrenal glands than a midline incision. The rectus muscles and lateral abdominal muscles are divided, exposing the peritoneum. Upon entering the peritoneal cavity, the surgeon should gently palpate the para-aortic areas and the adrenal areas. Close attention is given to blood pressure changes in an attempt to identify any unsuspected lesions if the patient has a pheochromocytoma. This maneuver is less important today because of the excellent localization techniques previously discussed. In fact, with precise preoperative localization of the offending tumor, the chevron incision does not need to be completely symmetric and may be limited on the contralateral side. If the patient has a lesion on the right adrenal, the hepatic flexure of the colon is reflected inferiorly. The incision is made in the posterior peritoneum lateral to the kidney and carried superiorly, allowing the liver to be reflected cranially (Figure 8-17). Incision in the peritoneum is carried downward, exposing the anterior surface of the IVC to the entrance of the right renal vein. Once the cava is cleared, one or two accessory hepatic veins are often encountered, which should be secured (Figure 8-18B). These veins are easily avulsed from the cava and may cause troublesome bleeding. Ligation of these veins gives 1 to 2 cm of additional caval exposure of the short posterior right adrenal vein. Small accessory adrenal veins may also be encountered. The cava is then rolled medially, exposing the adrenal vein, which should be doubly tied or clipped and divided (Figure 8-18C). After control of the adrenal vein, it is simplest to proceed with the superior dissection, lifting the liver off the adrenal and securing the multiple small adrenal arteries arising from the inferior phrenic artery, which is rarely seen. The adrenal can be drawn inferiorly with retraction on the kidney, and the adrenal arteries traversing to the adrenal from under the cava can be secured with rightangled clips. The final step is removing the adrenal from the kidney.
Figure 8-17 Exposure of right adrenal and left adrenal utilizing a transabdominal approach.
Figure 8-18 Further transabdominal exposure of the right adrenal with ligation of an accessory right hepatic vein.
148
Part II Adrenal Gland
The left adrenal vein is not as difficult to approach because it lies lower, partially anterior to the upper pole of the kidney, and the adrenal vein empties into the left renal vein. Accordingly, on the left side, the colon is reflected medially, exposing the anterior surface of Gerota’s capsule; the initial dissection should involve identification of the renal vein (see Figure 8-17B). In essence, the dissection is the same as for a radical nephrectomy for renal carcinoma. Once the renal vein is exposed, the adrenal vein is identified, doubly ligated, and divided. After this maneuver the pancreas and splenic vasculature are lifted off the anterior surface of the adrenal gland. Because of additional drainage from the adrenal into the phrenic system, I generally continue the medial dissection early to control the phrenic vein. I then work cephalad and lateral to release the splenorenal ligament and the superior attachments of the adrenal. The remainder of the dissection is carried out as previously described. After removal of the tumor, regardless of size, careful inspection is made to ensure hemostasis and the absence of injury to adjacent organs. Careful abdominal exploration is carried out, after which the wound is closed with the suture material of choice. No drains are used. Patients with multiple endocrine adenopathy of family histories of pheochromocytoma, as well as pediatric patients, should be considered at high risk for multiple
lesions. Preoperative evaluation should identify these lesions, but, regardless, a careful abdominal exploration should be carried out. In patients with suspected malignant pheochromocytomas, en bloc dissections may be necessary to obtain adequate margins, a concept that also applies in patients with adrenal carcinomas. Evaluation with MRI to obtain transverse, coronal, and sagittal images is extremely useful to define clearly the adrenal relationships to the IVC and renal vessels as well as to localize the adrenal vein. In patients with pheochromocytomas, postoperative management includes maintenance of arterial and venous lines in an intensive care setting until they are stable. Often, 24 to 48 hours are required for the full effect of phenoxybenzamine, the α-blocking agent commonly given, to wear off and for normal α-receptor activity to be restored. PARTIAL ADRENALECTOMY The standard treatment for patients with the adrenal lesions described has been total adrenalectomy. However, there recently has been reported an excellent paper showing the utility of partial adrenalectomy in patients with primary hyperaldosteronism.41 I have not used partial adrenalectomy in a patient for normal contralateral adrenal, but certainly have used the technique in patients with bilateral disease (Figure 8-19). Thus, in
Figure 8-19 MRI showing bilateral adrenal pheochromocytoma in a patient with bilateral glomus jugulare tumors. A, Small right adenoma that was enucleated and which was partially resected. B, Large left bright pheochromocytoma that was totally removed.
Chapter 8 Adrenal Tumors 149
one patient with a pheochromocytoma on one side and a nonfunctioning adenoma on the other, the adenoma was simply enucleated from the adrenal. In a second patient with bilateral pheochromocytomas, the larger lesion was totally excised with partial adrenalectomy was utilized to remove the contralateral tumor. Care has to be taken to obtain thorough hemostasis when performing a partial adrenalectomy because of the vascular nature of the adrenal. Partial adrenalectomy or adrenal sparing surgery is most useful in patients at risk for multiple adrenal tumors, such as von Hippel-Landau kindreds.42,43,44 CRYOSURGERY Cryoablation is currently used as a surgical alternative for the treatment of prostatic, lung, brain, pharyngeal, and liver tumors. We have demonstrated in a canine model45 that adrenal cryoablation is effective in destroying adrenal tissue and is safe. We have successfully used the technique in one patient with primary hyperaldosteronism. Adrenal laparoscopic cryoablation may shorten operative time and be as effective as total adrenalectomy in patients with small lesions. ABLATION Successful adrenal ablation using transcatheter arterial infusion of ethanol has been described in 33 cases of primary hyperaldosteronism; the approach was successful in 27 cases (82%). Five patients required surgical adrenalectomy. This technique may be useful in the patient who is at high risk with use of general anesthesia.46 More recently, direct percutaneous tumor injection with ethanol has given excellent results in 41 patients with pheochromocytoma with reversal of hormonal abnormalities.47 LAPAROSCOPIC ADRENALECTOMY Laparoscopic adrenalectomy, first reported in 1991,48 is now the surgical approach of choice for adrenal removal in the majority of patients.49 The exceptions are patients with large irregular adrenal carcinoma where adjacent organs may be involved, large pheochromocytomas, patients with large adrenal hemorrhage, and in some cases of metastatic disease.
A variety of laparoscopic approaches to the adrenal exist.50,51 The lateral transperitoneal, anterior transperitoneal, lateral retroperitoneal, and posterior retroperitoneal techniques have been described similar to the rationale for an open approach. The laparoscopic approach depends on the patient’s habitus, the underlying pathology and the skill and experience of the operating surgeon.1 The results of these approaches mirror the results of open adrenalectomy with less morbidity and hospitalization time for the patient.52 The lateral transperitoneal approach is the technique most often reported in the literature. Most laparoscopic surgeons have extensive experience identifying, dissecting, and mobilizing the adjacent organs required in order to obtain adrenal exposure and removal. For this approach the patient is placed in a full lateral position (Figure 8-20A and B). Bilateral adrenalectomy requires repositioning and redraping. In contrast, the retroperitoneal approaches avoid dissection and mobilization of intra-abdominal viscera (Figure 8-21A and B). The major limitation is the small working space that compromises instrument placement and crossing of instruments can occur. The approach is best for patients with small adrenal tumors. Balloon inflation is used to dissect the retroperitoneal space. During this procedure, close blood pressure monitoring is necessary in patients with pheochromocytoma since the expanding balloon may compress the tumor with catechol release. Regardless of the approach utilized the principles of adrenal surgery previously described are the same. SUMMARY We are fortunate that our ability to diagnose the specific adrenal entities that mandate a surgical approach is extremely accurate. The combination of analytic methodology to measure the appropriate adrenocortical and medullary hormonal production and the radiologic techniques for localization are superb. The management of these adrenal disorders usually employing a laparoscopic approach following localization is highly successful, resulting in a reversal of both metabolic abnormalities and the hypertension that often accompanies these diseases. Indeed, this is a true success story with the evolution of these different techniques over the past 50 years.
150
Part II Adrenal Gland
Figure 8-20 A, Trocar placement for left transperitoneal adrenalectomy. The distribution is a mirror image of that used for the left side. Dissection of the left adrenal gland: the spleen (3), pancreas (4), left lobe of the liver (2), renal vein (5), and kidney are shown. The left adrenal vein (1) has been isolated. A clip is applied to the adrenal vein before dividing it (inset, right). The inset (left) shows the patient’s position on the operating table. B, Trocar placement for a right transperitoneal adrenalectomy: supra-umbilical trocar for camera (if only three trocars are used) or splenic retractor (if four trocars are used). Trocars at anterior axillary line and midaxillary line for instruments for dissection. Fourth trocar halfway between midline and anterior is shown. A clip is applied to the adrenal vein before dividing it (inset, right). The inset (left) shows the patient’s position on the operating table.
Figure 8-21 A, The retroperitoneal approach for the left adrenal gland (1): the adrenal vein (2) is seen anterior to the renal artery (4); the renal artery (4) and vein (6) are identified early in the dissection. The kidney (7) and ureter (8) are also depicted. The inset (left) shows the patient’s position on the operating table. Continued
Chapter 8 Adrenal Tumors 151
Figure 8-21 cont’d B, The retroperitoneal approach for the right adrenal gland (1): the adrenal vein (2) is seen at its takeoff from the vena cava (5); the renal artery (4) and vein (6) are identified early in the dissection. The kidney (7) and ureter (8) are also depicted. The inset (left) shows the patient’s position on the operating table.
REFERENCES 1. Vaughan ED Jr, Blumenfeld JD, Del Pizzo J, Schichman SJ, Sosa RE: The adrenals. In Walsh PC, Retik AB, Vaughan ED Jr, Wein AJ (eds): Campbell’s Urology, 8th edition. Philadelphia, WB Saunders Co, 2002. 2. Belldegrun A, Ritchie A, Figlin R, Oliver R, Vaughan ED Jr (eds): Renal and Adrenal Tumors. Oxford, Oxford University Press, 2003. 3. Taneja SS, Smith RB, Ehrlich RM (eds): Complications of Urologic Surgery Prevention and Management. Philadelphia, WB Saunders Co, 2001. 4. Lee MJ, Mayo-Smith WW, Hann PE, et al: State-of-theart MR imaging of the adrenal gland. Radiographics 1994; 14:1015–1029. 5. Vaughan ED Jr: Adrenal surgery. In Marshall FF (ed): Textbook of Operative Urology. Philadelphia, WB Saunders Co, 1996. 6. Orth DN: Cushing’s syndrome. N Engl J Med 1995; 32:791. 7. Teeger S, Papanicolaou N, Vaughan ED Jr: Imaging of adrenal masses. In Belldegrun A, Ritchie A, Figlin R, Oliver R, Vaughan ED Jr (eds): Renal and Adrenal Tumors. Oxford, Oxford University Press, 2003. 8. Murai M, Marumo K: Selection of patients with incidentally discovered adrenal masses for operation. In Belldegrun A, Ritchie A, Figlin R, Oliver R, Vaughan ED Jr (eds): Renal and Adrenal Tumors. Oxford, Oxford University Press, 2003. 9. Ng L, Libertino JM: Adrenal cortical carcinoma: diagnostic evaluation and treatment. J Urol 2003; 169: 1—11. 10. Nakajo M, Nakabeppu Y, Yonekura R, et al: The role of adrenocortical scintigraphy in the evaluation of unilateral
11.
12.
13.
14.
15.
16.
17.
18.
19. 20.
21.
incidentally discovered adrenal and juxtaadrenal masses. Ann Nucl Med 1993; 7(3):157–166. Ross NS, Aron DC: Hormonal evaluation of the patient with an incidentally discovered adrenal mass. N Engl J Med 1990; 323:1401. Cerfolio RJ, Vaughan ED Jr, Brenan TC, Hiruela ER: Accuracy of computed tomography in predicting adrenal tumor size. Surg Gynecol Obstet 1993; 176:307. Mayo-Smith WW, Lee MJ, McNicholas MM et al: Characterization of adrenal masses (<5 cm) by use of chemical shift MR imaging: observer performance vs. quantitative measures. AJR 1995; 165:91–95. Lubat E, Weinreb JC: Magnetic resonance imaging of the kidneys and adrenals. Top Magn Reson Imaging 1990; 2:17–36. Tikkakoski T, Taavitsainen M, Paivansalo M, et al: Accuracy of adrenal biopsy guided by ultrasound and CT. Acta Raiol 1991; 32:371–374. Luton J-P, Cerdas S, Billaud L, et al: Clinical features of adrenocortical carcinoma, prognostic factors and the effect of mitotane therapy. N Engl J Med 1990; 322:1195. Imperato-McGinley J, Young IS, Huang T, et al: Testosterone secreting adrenal cortical adenomas. Int J Gynaecol Obstet 1981; 19:421. Gabrilove JL, Sharma DC, Waitz HH, Dorfman R: Feminizing adrenal cortical tumors in the male: a review of 52 cases including a case report. Medicine 1965; 44:37. Richie JP, Gittes RF: Carcinoma of the adrenal cortex. Cancer 1980; 45:1957. Schulick RD, Brennan MF: Adrenocortical carcinoma. In Belldegrun A, Ritchie A, Figlin R, Oliver R, Vaughan ED Jr (eds): Renal and Adrenal Tumors. Oxford, Oxford University Press, 2003. Haak HR, van Seters AP, Moolenaar AJ, Fleuren GJ: Expression of P-glycoprotein in relation to clinical
152
22.
23. 24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
Part II Adrenal Gland manifestation, treatment and prognosis of adrenocortical cancer. Eur J Cancer 1993; 29A:1036–1038. Wooten MD, King DK: Adrenal cortical carcinoma. Epidemiology and treatment with mitotane and a review of the literature. Cancer 1993; 72:3145–3155. Conn JW: Primary hyperaldosteronism. A new clinical syndrome. J Lab Clin Med 1955; 45:3. Blumenfeld JD, Vaughan ED Jr.: Diagnosis and treatment of primary hyperaldosteronism. In Belldegrun A, Ritchie A, Figlin R, Oliver R, Vaughan ED Jr (eds): Renal and Adrenal Tumors. Oxford, Oxford University Press, 2003. Laragh JH, Angers M, Kelly WG, et al: The effect of epinephrine, norepinephrine, angiotensin II, and others on the secretory rate of aldosterone in man. JAMA 1960; 2:174–234. Laragh JH, Sealey JE: The renin-angiotensin-aldosterone system and the renal regulation of sodium, potassium, and blood pressure homeostasis. In Windhager EE (ed): Handbook of Physiology. New York, Oxford University Press, 1992. Vaughan ED Jr, Sosa RE: Renovascular hypertension and ischemic nephropathy. In Gillenwater JY, Grayhack JT, Howards SS, Mitchell ME (eds): Adult and Pediatric Urology, 4th edition, Chap 23, pp 973–998. Lippincott, Williams & Wilkins, 2002. Mann SJ, Atlas SA: Hypertensive emergencies. In Laragh JH, Brenner BM (eds): Hypertension, Pathophysiology, Diagnosis and Management. New York, Raven Press, 1995. Manger WM, Gifford RW Jr: Pheochromocytoma: a clinical review. In Laragh JH, Brenner BM (eds): Hypertension, Pathophysiology, Diagnosis and Management. New York, Raven Press, 1995. Walther MM, Eisenhoffer G, Pacak K, Linehan WM: Pheochromocytoma. In Belldegrun A, Ritchie A, Figlin R, Oliver R, Vaughan ED Jr (eds): Renal and Adrenal Tumors. Oxford, Oxford University Press, 2003. Imperato-McGinley J, Gautier T, Ehlers K, et al: Reversibility of catecholamine-induced dilated cardiomyopathy in a child with a pheochromocytoma. N Engl J Med 1987; 316:793–797. Bolande RP: The neurocrestopathias: a unifying concept of disease arising in neurocrest maldevelopment. Hum Pathol 1974; 5:409. Pearse AG, Polak JM: Cytochemical evidence for the neural crest origin of mammalian ultimobranchial C cells. Histochemie 1971; 27:96. Liu Z, Siragy HM, Carey RM: Diagnostic tests of adrenal cortical and medullary function. In Belldegrun A, Ritchie A, Figlin R, Oliver R, Vaughan ED Jr (eds): Renal and Adrenal Tumors. Oxford, Oxford University Press, 2003. Shapiro B, Copp JE, Sisson JC, et al: Iodine-131 metaiodobenzylguanidine for the locating of suspected pheochromocytoma: experience in 400 cases. J Nucl Med 1985; 26:576. Campeau RJ, Garcia OM, Correa OA, Rege AB: Pheochromocytoma: diagnosis by scintigraphy using iodine-131 metaiodobenzylguanidine. South Med J 1991; 84:1221–1230.
37. Malhotra V (ed): Anesthesia for Renal and Genitourinary Surgery. New York, McGraw-Hill, 1995. 38. Novick AC, Straffon RA, Kaylor W: Posterior transthoracic approach for adrenal surgery. J Urol 1989; 141:254. 39. Vaughan ED Jr, Phillips H: Modified posterior approach for right adrenalectomy. Surg Gynecol Obstet 1987; 165:453–455. 40. Gil-Vernet J: New surgical concepts in removing renal calculi. Urol Int 1965; 20:255–262. 41. Nakada T, Kubota Y, Sasagawa I, et al: Therapeutic outcome of primary aldosteronism: adrenalectomy versus enucleation of aldosterone-producing adenoma. J Urol 1995; 153:1775–1780. 42. Walther MM, Keiser HR, Choyke PL, et al: Management of hereditary pheochromocytoma in von Hippel-Lindau kindreds with partial adrenalectomy. J Urol 1999; 161:395–398. 43. Walther MM, Herring J, Choye PL, Linehan WM: Laparoscopic partial adrenalectomy in patients with hereditary forms of pheochromocytoma. J Urol 2000; 164:14–17. 44. Pavlovich CP, Walther MM: Partial adrenalectomy: indications and technique. In Belldegrun A, Ritchie A, Figlin R, Oliver R, Vaughan ED Jr (eds): Renal and Adrenal Tumors. Oxford, Oxford University Press, 2003. 45. Schulsinger DA, Sosa RE, Perlmutter AP, Vaughan ED Jr.: Acute and chronic interstitial cryotherapy of the adrenal. In Belldegrun A, Ritchie A, Figlin R, Oliver R, Vaughan ED Jr (eds): Renal and Adrenal Tumors. Oxford, Oxford University Press, 2003. 46. Ueno K, Nakajo M, Miayazono, N, et al: Transcatheter adrenal arterial embolization of cortisol-producing tumors: two cases of Cushing’s Syndrome. J Vascular Interventional Radiol 2000; 11:141. 47. Wang P, Zuo C, Qian Z, et al: CT-Guided percutaneous ethanol injection in the treatment of hyperfunctioning pheochromocytoma. J Urol 2003; 170:1132–1134. 48. Gagner M, Lacroix A, Bolte E: Laparoscopic adrenalectomy and Cushing’s syndrome and pheochromocytoma. N Engl J Med 1992; 327, 1003–1006. 49. Del Pizzo JJ, Shichman SJ, Sosa RE: Laparoscopic adrenalectomy: the New York-Prebyterian Hospital experience. J Endosc 2002; 16:591. 50. Meraney AM, Gill IS: Laparoscopic versus open adrenalectomy. In Belldegrun A, Ritchie A, Figlin R, Oliver R, Vaughan ED Jr (eds): Renal and Adrenal Tumors. Oxford, Oxford University Press, 2003. 51. Shichman S, Sosa RE, Vaughan ED Jr.: Lateral transperitoneal laparoscopic adrenalectomy. In Belldegrun A, Ritchie A, Figlin R, Oliver R, Vaughan ED Jr (eds): Renal and Adrenal Tumors. Oxford, Oxford University Press, 2003. 52. Baba S, Iwamura M: Laparoscopic adrenalectomy by the posterior lumbar approach. In Belldegrun A, Ritchie A, Figlin R, stetal (eds): Renal and Adrenal Tumors. Oxford, Oxford University Press, 2003.
C H A P T E R
9 Open and Laparoscopic Surgery of Adrenal Tumors David S. Wang, MD, and Howard N. Winfield, MD
The adrenal glands are known to harbor a variety of benign and malignant tumors. Due to the size and location of the adrenals, lesions of the adrenal gland are rarely detected because of local symptomatic growth. Instead, most adrenal tumors are diagnosed either incidentally or because of hormonal activity. In general, lesions that should be surgically removed include lesions that are hormonally active, tumors suspicious for adrenocortical carcinoma, or nonfunctioning adrenal lesions 5 cm or greater in size. Traditionally, surgical procedures involving the adrenal gland were performed through an open incision with a variety of approaches. In 1992, the laparoscopic approach to adrenalectomy was introduced,1 offering a less invasive alternative to open adrenalectomy. As experience with laparoscopic adrenalectomy is increasing, the indications for laparoscopic adrenalectomy have expanded while the absolute contraindications have diminished. Indeed, laparoscopic adrenalectomy has become the standard of care and the technique of choice for most benign adrenal lesions. This chapter reviews the basic diagnosis and hormonal evaluation, indications, preoperative considerations, and techniques of open and laparoscopic adrenalectomy for benign and malignant tumors of the adrenal gland. The full evaluation of the patient with an adrenal lesion is discussed in the previous chapter. DIAGNOSIS Adrenal lesions historically were diagnosed secondary to clinical manifestations of endocrinopathies. However, widespread use of abdominal ultrasound, computed tomography (CT) scanning, and magnetic resonance imaging (MRI) has led to the not-infrequent finding of the incidental adrenal mass. Figures 9-1 and 9-2 show
typical examples of adrenal lesions diagnosed on CT and MRI. The differential diagnosis of the incidental adrenal mass is extensive and includes the benign nonfunctioning adenoma, hormonally active cortical tumor, myelolipoma, pheochromocytoma, adrenocortical carcinoma, and metastatic lesion. Tumors diagnosed incidentally on CT scan or MRI are managed according to size and hormone functional status. Patients with hormonally active adrenal tumors, such as aldosteronoma, Cushing’s syndrome, or pheochromocytoma, should generally undergo surgical removal. Hormonal evaluation of these patients is critical because preoperative and postoperative considerations regarding hypertensive control, electrolyte imbalances, and fluid shifts are paramount to ensure good surgical outcomes and minimize complications. A summary of standard laboratory tests in the evaluation of an adrenal lesion is listed in Table 9-1. Most hormonally active tumors should be removed, particularly in the case of pheochromocytoma and cortisol-secreting tumors.2,3 Occasionally, medical management of aldosteronomas may be satisfactory to circumvent the need for surgical management, particularly in patients who are poor surgical candidates.4 However, side effects of pharmacotherapy may become intolerable. Hormonally inactive tumors have traditionally been managed according to size. Tumors less than 3 cm are almost always benign adenomas and generally require no further treatment unless clinical signs of hormonal activity develop. Tumors greater than 6 cm are worrisome for adrenocortical carcinomas, and thus surgical excision is recommended given the aggressive nature of adrenal cancer.5 Nonfunctional lesions between 3 and 5 cm generally require close follow-up with serial imaging studies every 6 months. These lesions should be removed if tumors demonstrate interval change in appearance or develop endocrine activity.
153
154
Part II Adrenal Gland
Table 9-1 Routine Laboratory Tests Useful in the Evaluation of Adrenal Lesions Frequency of Usage Cushing’s Syndrome 24-hour urine cortisol
Common
Plasma ACTH and plasma cortisol
Common
Low-dose dexamethasone suppression test Occasional
Figure 9-1 CT scan of the abdomen demonstrating left adrenal lesion (arrow).
High-dose dexamethasone suppression test
Occasional
Metapyrone stimulation test
Rare
Petrosal sinus ACTH measurement
Extremely rare
Hyperaldosteronism Unprovoked hypokalemia
Common
Plasma aldosterone level
Common
Urinary aldosterone level
Common
Aldosterone-to-renin ratio
Common
Postural stimulation test
Rare
Adrenal vein sampling of aldosterone
Extremely rare
Pheochromocytoma
Figure 9-2 MRI of the abdomen demonstrating left adrenal lesion (arrow).
As mentioned previously, lesions of the adrenal gland greater than 6 cm are worrisome for adrenal cancer. In one meta analysis, 105 of 114 adrenocortical carcinomas measured 6 cm or greater in diameter.6 Because CT scan can underestimate the size of lesions by as much as 1 cm,7 it is suggested that all lesions on CT scans that are 5 cm or greater be removed. In cases when there is concern for adrenal carcinoma with local extension into adjacent organs, such as the kidney, colon, or spleen, then open radical adrenalectomy with possible en bloc resection of adjacent organs is the preferred approach.8,9 More recently, improvements in radiologic imaging techniques, such as unenhanced and delayed enhanced CT with densitometry, chemical-shift MRI, and NP-59 scintigraphy, have further assisted in differentiating benign from malignant neoplasms.10
Plasma catecholamines
Common
Urine catecholamines
Common
Clonidine suppression test
Occasional
Adrenal vein sampling of catecholamines
Extremely rare
ALDOSTERONOMAS Primary hyperaldosteronism (Conn’s syndrome) is a rare etiology of hypertension (less than 1%). Other clinical manifestations of Conn’s syndrome arise from increased total body sodium content and a deficit in total body potassium. Symptoms include urgency, frequency, nocturia, muscle weakness, paresthesias, or visual disturbances.4,11 CT scan or MRI can detect adrenal adenomas as small as 1 cm. Laboratory manifestations include hypokalemia, elevated plasma and urinary aldosterone level, elevated serum aldosterone-to-renin ratio, and suppressed plasma renin activity.4,11 Once an important part of the evaluation, adrenal vein sampling is rarely used to confirm and localize the lesion.
Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 155
Once the diagnosis is confirmed, medical control of hypertension and correction of hypokalemia should be instituted at least several weeks prior to adrenalectomy. The most effective medication for management of hyperaldosteronism is spironolactone, a competitive antagonist of the aldosterone receptor.4 Side effects of aldosterone include hyperkalemia, sexual dysfunction, gynecomastia, gastrointestinal disturbances, and metabolic acidosis.12 Alternative medications include potassium-sparing diuretics, calcium channel blockers, and converting-enzyme inhibitors. 11 Hypertension is improved or cured in more than 90% of patients following adrenalectomy.13 CUSHING’S SYNDROME Cushing’s syndrome is used to describe the symptom complex that results from excess circulating glucocorticoids, regardless of etiology.3 Nonadrenal causes of hypercortisolism include pituitary adenomas, ectopic corticotrophin production, and exogenous steroid use. The urologist is most often confronted with an adrenal lesion as the etiology of Cushing’s syndrome. Cushing’s syndrome manifests with a variety of wellrecognized clinical features, including hypertension, truncal obesity, moon facies, easy bruising, and mood disorders. Diagnosis is confirmed by laboratory testing.3 Hypercortisolism is best diagnosed by 24-hour urinary cortisol measurement. The low-dose dexamethasone suppression test can be used to further diagnose Cushing’s syndrome if urinary cortisol measurement is equivocal. Abdominal CT scan and MRI can identify adrenal adenomas or bilateral adrenal hyperplasia. PHEOCHROMOCYTOMA Pheochromocytomas can be challenging tumors to treat because of the unique manifestations of chronic and acute catecholamine excess. Successful surgical management of pheochromocytoma requires close collaboration among the surgeon, endocrinologist, and anesthesiologist. It is essential to have an anesthesiologist familiar with pheochromocytoma that is able to adequately manage blood pressure intraoperatively and who is familiar with which anesthetic agents to avoid. In general, catecholamine excess results in hypertension, tachycardia, and a host of clinical manifestations. Laboratory diagnosis is made by elevated levels of catecholamines in the blood and urine. Radiographic diagnosis is achieved with either CT scan or MRI. MRI imaging classically demonstrates a bright image on a T2-weighted study. Additionally, metaiodobenzylguanidine (MIBG) nuclear medicine scanning can help confirm and localize pheochromocytomas. The treatment of choice for most pheochromocytomas is surgical excision. In the past, all pheochromo-
cytomas were treated through an open approach, with early control of the adrenal vein. However, with increasing experience worldwide with laparoscopic adrenalectomy, pheochromocytoma is no longer considered a contraindication to laparoscopic surgery. In fact, laparoscopic adrenalectomy for pheochromocytomas has now been performed successfully at many centers of laparoscopic excellence and reported in several series.14–16 Regardless of the surgical approach chosen, preoperative medical preparation is essential, and includes optimal control of blood pressure with alpha blockade or calcium channel antagonists.2 Beta-blockers may be used to control reflex tachycardia after initiation of alpha blockade. In addition, aggressive fluid expansion is necessary to increase circulating plasma volume and prevent postoperative hypotension. Close monitoring intraoperatively includes careful attention to blood pressure, central venous pressure, and urinary output. An arterial line and central venous line are routinely used, and occasionally a Swan-Ganz catheter is employed. Severe hypertension can be controlled with sodium nitroprusside or phentolamine, and hypotension can be controlled with fluid resuscitation and norepinephrine. ADRENOCORTICAL CARCINOMA Adrenocortical carcinoma is a rare malignancy with an estimated incidence of 0.5 to 2.0 cases per million annually.17,18 Although adrenal cancer is known to occur at all ages from early infancy to the 8th decade of life, there appears to be a bimodal distribution during the first decade of life in children and in the fourth or fifth decade of life in adults.19,20 The prognosis is uniformly poor, although pediatric patients generally have a better prognosis because they more commonly present earlier with a hormonal syndrome. The majority of adrenocortical carcinomas are functional, with 62% of adrenal cancers being functional in one study.17 The most common syndrome associated with adrenocortical carcinoma is Cushing’s syndrome. Typical clinical symptoms of adrenocortical carcinoma include abdominal pain, weight loss, fever, weakness, anorexia, nausea, and myalgia. Unfortunately, many of these symptoms are often associated with advanced disease. The primary treatment modality for suspected adrenocortical carcinomas is complete surgical excision of the tumor. Complete surgical excision appears to offer the patient the best chance of cure. In one series, the 5-year survival of adrenocortical carcinoma after surgery was 55% following complete removal with negative margins versus 5% for incomplete removal.21 When surrounding organs, such as kidney, colon, or spleen, are infiltrated by adrenocortical carcinoma, then en bloc excision of surrounding organs offers the patient the best chance of longterm survival. It is unclear whether the debulking of
156
Part II Adrenal Gland
tumors that cannot be excised completely offers a survival advantage. Radiation therapy and chemotherapy are largely ineffective for metastatic disease.18 The suspected adrenocortical carcinoma should be surgically approached in an open fashion rather than laparoscopic fashion. Because complete surgical excision of the adrenocortical carcinoma portends a much better prognosis, the ability to fully remove the lesion should not be compromised solely for decreasing patient morbidity. The additional patient morbidity endured following an open surgical procedure is insignificant if a more thorough excision is possible. The threshold to convert from a laparoscopic procedure to an open one should be low when there is a clinical suspicion of a malignant adrenal neoplasm. Laparoscopic adrenalectomy for suspected malignant neoplasm should be performed only by those with great experience in laparoscopic surgery, so that the surgeon can feel that an equivalent or even more thorough excision can be achieved by the laparoscopic approach.
phrenic artery, aorta, and renal artery. A complex arcade of small arteries enters the adrenal gland from the medial and superior border of the gland, and thus the anterior, posterior, and inferolateral surfaces of the adrenal gland are relatively avascular. The right and left adrenal glands have key anatomic differences in location and vasculature. The main right adrenal vein exits the gland from the superomedial surface and enters the inferior vena cava (IVC) directly. The longer left main adrenal vein exits the inferomedial aspect of the gland and drains into the left renal vein at an oblique angle. The right adrenal gland is more intimately related to the IVC than the left gland is related to the aorta. The capsule surrounding the adrenal gland is very fragile, and direct grasping of the adrenal gland can lead to parenchymal fracture resulting in persistent and troublesome bleeding. The lymphatic drainage of the adrenal gland includes all lateral aortic lymph node tissue between the diaphragm and ipsilateral renal artery.
PREOPERATIVE PATIENT EVALUATION AND PREPARATION
Open Surgical Approaches to the Adrenal Gland
Careful preoperative control and management of hormonally active tumors is critical prior to performing adrenal surgery, whether laparoscopic or open. Inadequate preoperative control of hormonally active lesions can lead to catastrophic intraoperative consequences. Close collaboration with an endocrinologist and anesthesiologist experienced with adrenal disorders is helpful. The urologist should have an understanding of the physiology of adrenal disorders in order to appropriately manage patients in the peri- and postoperative period with regard to fluid management, electrolyte abnormalities, and blood pressure control. Hormonally functional tumors must be adequately evaluated and appropriate preoperative interventions initiated in concert with an endocrinologist. Preoperatively, all patients should receive a mechanical bowel preparation. Clear liquids should be started the day before surgery. A broad-spectrum antibiotic should be administered on call to the operating room. OPEN SURGICAL TECHNIQUES Surgical Anatomy A thorough knowledge of the anatomy of the adrenal gland and its relationship to adjacent organs is essential to avoid intraoperative complications. Familiarity with the vascular supply of the adrenal gland is important in minimizing the chances of intraoperative hemorrhage. The adrenal gland, like the kidney, is enveloped by Gerota’s fascia; it is however located in a distinct fascial compartment that is separate from the kidney. The arterial supply to the adrenal gland arises from the inferior
There are a variety of approaches to the adrenal gland, including the flank, posterior, modified posterior, transabdominal, and thoracoabdominal approaches. The choice of surgical approach is influenced by the tumor pathology, size of the lesion, patient’s body habitus, and surgeon familiarity and preference. Lateral Flank Approach The standard extrapleural, extraperitoneal lateral flank approach offers excellent exposure to the adrenal gland. In addition, the lateral flank approach is familiar to most urologists. Generally, an incision above the 11th rib is utilized with or without resection of a rib. This approach is ideal for either left or right adrenalectomy. After adequate general anesthesia, a Foley catheter is inserted to decompress the bladder and an orogastric tube to decompress the stomach. Lower extremity pneumatic compression stockings are placed. The patient is then placed in the full lateral position with the flank over the flexion point of the operating table. The operating table is flexed 30 to 45 degrees and the kidney rest is raised. An axillary roll is placed under the contralateral arm. The patient is then carefully secured, and all pressure points are adequately padded. A supracostal incision above the 11th rib is made extending from the lateral border of the rectus abdominus muscle anteriorly to the sacrospinalis muscle posteriorly. The external oblique, internal oblique, latissimus dorsi, and serratus posterior inferior muscles are incised. The lumbodorsal fascia and transversus abdominus muscles are then incised to expose the peritoneum and preperitoneal fat. Care is taken to sweep away and avoid the peritoneum and the pleura.
Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 157
Once the flank is entered, the peritoneum and colon are dissected away from Gerota’s fascia and the kidney is partially mobilized. It is important to avoid dissecting the adrenal gland off of the surface of the kidney gland until mobilization of the adrenal gland is nearly complete. The kidney is extremely useful for downward retraction of the adrenal gland. The capsule of the adrenal gland is quite friable and should not be directly grasped in order to avoid fracturing the gland with resultant troublesome bleeding. In patients with pheochromocytoma, the adrenal vein should be controlled early in the procedure to limit catecholamine surges. The anesthesiologist should be notified when the adrenal vein is divided because occasionally a marked decrease in blood pressure can occur despite adequate fluid hydration. On the left side, the superior dissection of the adrenal gland is performed initially, taking care to clip or ligate the blood supply to the adrenal gland arising from the inferior phrenic vessels. The adrenal gland is dissected away from the diaphragm. Downward retraction on the
kidney optimizes exposure to the superior aspect of the adrenal gland. The lateral attachments of the left adrenal gland are generally relatively avascular and are therefore easily mobilized. Posteriorly, the adrenal arteries that arise from the aorta must be carefully ligated. Generally, the medial blood supply is taken last. Great care must be taken to avoid injury to the renal artery and vein. Once the left renal vein is identified, the left adrenal vein can be safely divided. The adrenal gland is then dissected free from the kidney and inspection should be made for bleeding. Dissection on the right side (Figure 9-3) differs only slightly from the left side. Again, the kidney is useful for downward retraction of the adrenal gland. The superior and lateral dissection of the adrenal gland should be performed initially, taking care to ligate the multiple small adrenal vessels supplying the gland. The medial dissection of the adrenal gland is next performed, carefully dividing small arterial vessels. The IVC must be exposed to allow for exposure of the adrenal vein. The right adrenal
Figure 9-3 Flank approach to right adrenal.
158
Part II Adrenal Gland
vein is short and broad and great care must be undertaken to prevent inadvertent avulsion. The right adrenal vein is ligated. Lastly, the right adrenal gland is dissected off of the superior surface of the kidney. In the case of adrenocortical carcinoma, en bloc radical nephrectomy is often necessary. The kidney should be removed, adhering to the general principles of oncologic surgery, without detaching it from the adrenal gland. If the tumor appears to be invading the colon, then subtotal colectomy may be required. Because the overall survival following complete surgical excision is improved, then every effort should be made to remove all of tumor if possible. After the adrenal gland is removed, inspection for hemostasis and injury to surrounding structures is performed. The flank incision is then closed in the standard fashion in layers. Thoracoabdominal Approach The thoracoabdominal approach (Figure 9-4), usually through an incision above the 9th or 10th rib, is most commonly used for very large tumors or suspected adrenal carcinomas. The incision is the same as the standard approach for a radical nephrectomy, described elsewhere in this text. The thoracoabdominal approach offers superior operative exposure and is particularly useful for large adrenocortical carcinomas. Figure 9-4 Thoracoabdominal approach to left adrenal.
Transabdominal Approach The transabdominal approach (Figure 9-5) is useful when exposure to both adrenal glands is necessary, particularly in pediatric patients. This approach is occasionally chosen for patients with large adrenal tumors or pheochromocytomas. The transabdominal approach allows for excellent exposure to both adrenal glands and allows for full and complete abdominal exploration. This is particularly help-
ful in pheochromocytomas, when tumors may be bilateral or may occur at sites distant from the adrenal gland. However, improved imaging techniques have allowed for more precise localization of pheochromocytomas, thus limiting the indications for this approach. The anterior abdominal approach is performed usually through a chevron incision, although a midline, subcostal,
Figure 9-5 Transabdominal approach to the adrenal.
Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 159
or transverse incision may also be employed. Generally, the type of incision for the anterior transabdominal approach is dictated by the size of the lesion, presence of bilateral lesions, patient body habitus, and surgeon preference. The patient is placed in the supine position with the kidney bar slightly elevated. A subcostal chevron incision is made in the upper abdomen, and all of the muscles of the anterior abdominal wall are divided. The peritoneum is then entered and the abdominal organs inspected for metastatic disease. The hepatic flexure must be reflected for right-sided tumors and the splenic flexure for leftsided tumors. On the right side, the duodenum is reflected (Kocher maneuver) to expose the IVC (Figure 9-5A). The kidney is used to provide traction to the adrenal gland, and direct grasping of the adrenal gland is minimized. The superior attachments of the adrenal gland are divided carefully, followed by the lateral adrenal gland attachments. The medial surface of the adrenal gland is freed by dividing arterial branches. The short right adrenal vein is divided and the remaining attachments of the adrenal gland are divided to release the specimen. On the left side, after identification of the adrenal gland and kidney, the superior attachments of the gland are divided first. The spleen and pancreas often must be dissected bluntly away from the adrenal gland (Figure 9-5B). The left adrenal vein is divided during the medial dissection of the gland and the adrenal gland is then freed from the superior surface of the kidney. Posterior Approach The posterior approach (Figure 9-6) is rarely used today because of improvements in diagnostic imaging. In the past, the posterior approach was used for bilateral adrenal exploration or for removal of small adrenal lesions. The posterior approach is performed through a subcostal incision and provides a limited surgical field. It does provide for direct access to the adrenal gland and is ideal for thin patients. The limited surgical field makes this unsuitable for excision of large adrenal masses and lesions that are suspicious for adrenocortical carcinoma. With the advent of laparoscopic surgery, there are no specific indications for the posterior approach. Most lesions that are small enough to be performed through a posterior approach should be removed laparoscopically. The patient is placed in the prone position with the table slightly flexed. The incision is placed at the level of the 11th or 12th rib. The incision is carried through the lumbodorsal fascia and the latissimus dorsi muscles. The pleura and peritoneum are swept away from the 11th and 12th ribs until Gerota’s fascia is identified. Gerota’s fascia is incised, and the posterior surface of
Figure 9-6 Posterior approach to the adrenal.
the kidney is exposed. Inferior retraction on the kidney allows for visualization of the adrenal gland on the superior surface of the kidney. Similar to the flank approach, the superior vessels supplying the adrenal gland are divided, the adrenal vein is ligated, and the adrenal gland is circumferentially mobilized. Again, care must be taken to ensure that the renal hilar vessels are not injured during the dissection. Modified Posterior Approach for Right Adrenalectomy A modified posterior approach (Figure 9-7) for accessing the right adrenal gland has been described.22 The patient is placed in a modified prone position, and the 11th or 12th rib is resected. The primary advantage of this approach is that the adrenal vein is identified more easily because it is seen emerging from the IVC toward the operating surgeon. Again, however, this approach is rarely used because most such tumors are removed by the laparoscopic technique.
160
Part II Adrenal Gland
Figure 9-7 Modified posterior approach to the right adrenal.
LAPAROSCOPIC SURGERY OF THE ADRENAL GLAND Indications for Laparoscopic Adrenalectomy The indications for laparoscopic adrenalectomy have expanded as more surgeons have become proficient with the technique and the advantages of this approach have become apparent. Laparoscopic adrenalectomy has, in many centers, become the surgical procedure of choice for the management of functional tumors less than 6 cm in size. Although the presence of pheochromocytoma was a relative contraindication for laparoscopic adrena-
lectomy in the past, it is clear that the procedure can be performed safely as long as the same precautions are taken as those for open surgery.14 The current indications for performing a laparoscopic adrenalectomy are listed in Table 9-2. There are few absolute contraindications to laparoscopic adrenalectomy. It is generally felt that a known or suspected primary adrenal carcinoma, particularly with extension into surrounding organs, should be removed by an open technique. Given the aggressive nature of the disease, the open approach allows for en bloc resection
Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 161
Table 9-2 Indications for Laparosocpic Adrenalectomy Aldosterone secreting adrenal gland, adenoma, or unilateral hyperplasia Cushing’s syndrome secondary to adrenocortical adenoma Non-functional adrenal mass ≤ 8 cm with negative metastatic workup Non-functional adrenal mass ≤ 8 cm with progressive growth on CT or MRI Adrenal pheochromocytoma (benign) ≤ 8 cm Solitary adrenal gland metastasis
and potential removal of surrounding organs.8 Other contraindications to laparoscopic adrenalectomy include uncorrectable coagulopathy and cardiopulmonary disease precluding general anesthesia. Patients who will not tolerate an open operation are generally poor candidates for laparoscopic adrenalectomy. Relative contraindications to laparoscopic adrenalectomy include previous abdominal surgery or significant morbidity. Lesions greater than 8 cm in size, even if not suspected to be primary adrenal carcinomas, should be approached cautiously because of the increased risk of hemorrhage and injury to surrounding viscera. With increasing experience in performing laparoscopic adrenalectomy, relative contraindications become less of a factor. A variety of approaches to laparoscopic adrenalectomy, including transperitoneal and retroperitoneal, have further decreased some relative contraindications. Occasionally, the urologist will encounter a patient with a suspected solitary metastatic lesion to the adrenal gland. If the lesion is less than 6 cm in size and not obviously adherent to surrounding viscera, then a laparoscopic approach is reasonable.23 The surgeon should be skilled in laparoscopic adrenalectomy before attempting to remove a solitary metastatic lesion given the more difficult surgical planes that are often present.
determining the approach. Most surgeons are familiar with the anterior transperitoneal approach, but many who have overcome the learning curve of the anterior transperitoneal approach are becoming skilled with the retroperitoneal approach.25–30 Although each approach has purported advantages and disadvantages, there is no clear-cut evidence that one is superior.31,32 Preoperative Preparation The preoperative evaluation and preparation of patients prior to undergoing laparoscopic adrenalectomy is identical to that prior to open adrenalectomy. All patients should undergo a mechanical bowel preparation on the day prior to surgery and a broad-spectrum antibiotic should be administered on the day of surgery. As with all laparoscopic procedures, the stomach should be decompressed with an orogastric tube and the bladder with a Foley catheter. Anterior Transperitoneal Approach for Right Adrenalectomy After general anesthetic by agents other than nitrous oxide, the patient is positioned with the right side elevated 45 to 70 degrees upward and the table slightly flexed at the level of the umbilicus. The patient should be positioned on a beanbag with extensive padding over pressure points. Figure 9-8 shows the general modified flank position used for laparoscopic adrenalectomy. Next, the patient should be secured with tape to allow the table to be tilted side to side so as to facilitate exposure. For a right laparoscopic adrenalectomy, four subcostal ports are used and placed two to three fingerbreadths below the costal margin, as depicted in Figure 9-9. Initial
Laparoscopic Surgical Approaches Perhaps no other urologic laparoscopic procedure has as many different surgical approaches as does adrenalectomy. Commonly used approaches to the adrenal gland include the transperitoneal approaches, and the posterior or lateral retroperitoneal approaches. Recently, a transthoracic approach has been described for patients who have undergone extensive previous transperitoneal and retroperitoneal surgery.24 Surgeon preference and experience appear to be the most important factors in
Figure 9-8 Patient positioning for right transperitoneal adrenalectomy.
162
Part II Adrenal Gland
Figure 9-9 Port placement for right transperitoneal adrenalectomy.
entry into the peritoneal cavity is made using the Veress needle just below the costal margin in the midclavicular line. Three or four additional ports are placed under direct vision; the most medial port is important for upward and medial retraction of the right lobe of the liver. Exposure of the right adrenal gland is dependent on adequate mobilization of the liver. Mobilization of the liver is the first step in exposing the right adrenal gland. Unlike laparoscopic nephrectomy, full mobilization of the ascending colon and hepatic flexure is unnecessary. Incision of the posterior
peritoneum and extension through the triangular ligaments of the liver allow for upward and medial retraction of the liver (Figure 9-10). A fixed retractor may be placed under the liver through an additional trocar port to allow the liver to remain out of the field of dissection for the remainder of the case. The IVC is eventually identified once there is adequate liver mobilization. Continued and careful dissection along the lateral surface of the IVC will reveal the right adrenal vein. The adrenal vein should then be divided between standard clips. Dissection is further
Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 163
Figure 9-10 T-shaped incision through the posterior peritoneum for left and right adrenalectomy. On right, incision from second part of the duodenum to triangular ligaments at liver edge and then lateral to hepatic flexure. On left, incision developed across phrenocolic and splenocolic ligaments and at inferior border of spleen (IVC, inferior vena cava; R, right; L, left).
continued towards the diaphragm, and the inferior phrenic vessels should next be identified and divided. The inferior pedicle of the adrenal gland is then released, separating the adrenal gland from the upper pole of the kidney. Gerota’s fascia is next incised at the junction of the upper pole of the kidney and the adrenal gland. There is often an arterial branch to the adrenal gland arising from the renal pedicle. Once the kidney is completely mobilized away from the adrenal gland, all that remains holding the adrenal gland in place is the relatively avascular lateral attachments, which are divided. Use of the harmonic scalpel can facilitate mobilization of the adrenal gland once the main vascular pedicles have been ligated. Once the adrenal gland is completely separated, it should be placed in a specimen retrieval bag and removed en bloc. Assuming adequate hemostasis, the laparoscopic ports are removed under direct vision and fascia closed with the Carter–Thomason fascial closure device. A drain is usually not necessary. The orogastric tube is removed at the conclusion of the procedure. Anterior Transperitoneal Approach for Left Adrenalectomy The patient is positioned with left side elevated 45 to 70 degrees with the table slightly flexed at the level of the umbilicus. Three or four trocars are placed in a mirror
Figure 9-11 Dissection of left adrenal gland allowing visualization of left adrenal vein.
image as for a right adrenalectomy. The important surrounding structures to identify when performing a transperitoneal left laparoscopic adrenalectomy include the spleen, tail of the pancreas, splenic flexure of the colon, and left kidney. Full mobilization of the splenic flexure of the colon is necessary to provide adequate exposure to the left adrenal gland. The first step after diagnostic laparoscopy is to incise the posterior peritoneum along the line of Toldt and mobilize the splenic flexure of the colon to allow the colon to fall medially. The splenocolic and lienorenal ligaments are then mobilized to allow the spleen to be safely separated from the field of dissection (Figure 9-10). This creates an adequate plane between the spleen and the upper pole of the left kidney. If necessary, the tail of the pancreas can be separated away from Gerota’s fascia to allow the pancreas to fall away with the spleen to provide more exposure. Next, Gerota’s fascia is incised between the upper pole of the left kidney and the adrenal gland. The left adrenal gland should not be grasped directly to avoid adrenal gland fractures, which are associated with troublesome bleeding. Dissection continues through the perirenal fibrofatty tissue. The inferior border of the adrenal gland is defined and the dissection continued medially. Medial dissection will eventually lead to the takeoff of the left adrenal vein emanating directly from the left renal vein (Figure 9-11). The left adrenal vein is then isolated, clipped, and divided. In the case of a pheochromocytoma, early exposure and ligation of the left adrenal vein is ideal to reduce the risk of a hypertensive crisis. We have found
164
Part II Adrenal Gland
it easiest to initially identify the left renal vein and determine the take-off of the left adrenal vein. Clipping of the adrenal vein at this juncture minimizes catecholamine surges. Again, the lateral attachments of the left adrenal gland should be saved until the remainder of the gland is mobilized. The superior aspect of the adrenal gland is then mobilized, taking care to divide the phrenic vessels supplying the gland. Once the superior and inferior borders of the gland are dissected adequately, attention is directed towards the head of the gland, which is adjacent to the aorta. The left adrenal vein is divided if not previously done. The left adrenal artery arising from the aorta is next divided. The adrenal gland has a highly variable vasculature, especially in larger lesions with increased blood supply. The use of a harmonic scalpel or hook cautery electrode can facilitate adrenal gland mobilization and adequately ligate small blood vessels supplying the gland. Lastly, the lateral attachments of the adrenal gland are divided to fully free the gland from all surrounding tissues. The specimen is then placed into a retrieval bag and removed intact. Closure is similar to that for the right adrenalectomy. Retroperitoneal Technique The retroperitoneal approach to the adrenal gland is particularly useful in the patient with a prior history of extensive abdominal surgery. Unlike the transperitoneal approach, the patient is positioned in the full flank position. Three or four ports are typically used. Patient positioning and port placement are as shown in Figure 9-12. Access into the retroperitoneum requires the creation of a working space using a dilating balloon (U.S. Surgical, Norwalk, CT). A Hasson technique is used to place the first port. A small 2-cm incision is made just below the tip of the 12th rib, and S-type retractors are used to split the muscles until the lumbodorsal fascia is identified. Once the
Figure 9-12 Patient positioning and trocar placement for retroperitoneal adrenalectomy (A = camera port; B and C = working ports).
lumbodorsal fascia is incised, access into the retroperitoneal space is confirmed by inserting one finger in and palpating the 12th rib, the iliac crest, and the psoas muscle. The trocar-mounted balloon is then inserted and inflated in order to mobilize Gerota’s fascia anteriorly away from the posterior abdominal wall. Carbon dioxide insufflation is then attached to the trocar to generate pneumoretroperitoneum at a pressure of 15 mm Hg. Once the primary port is inserted, the working ports are placed. The second port is placed posterior to the primary port, below the angle formed by the 12th rib and the paraspinous muscles. The third port is placed approximately 3 to 4 cm medial to the primary port in the anterior axillary line. The working ports are either 5 or 10 mm in size. The optional fourth port is placed in the anterior axillary line 5 to 7 cm inferior to the third port and may be used to assist with retraction throughout the duration of the case. Once pneumoretroperitoneum is established, identification of key landmarks helps to establish the orientation. The psoas muscle is usually easily seen and establishes longitudinal orientation. By retracting the kidney upwards and anteriorly, subsequent medial dissection will eventually reveal the great vessels running parallel to the psoas muscle. The renal artery can be identified by identifying pulsations, although full mobilization of the renal hilar vessels is generally not necessary during adrenalectomy. On occasion intraoperative ultrasonography may be helpful in identifying a small adrenal lesion in the midst of abundant perinephric fat. Left Adrenalectomy Dissection on the left side should be conducted along the psoas muscle to the upper pole of the kidney. Identification of the renal hilum allows for rapid identification of the left adrenal vein. The adrenal vein can be found along the inferomedial border of the adrenal gland. If difficulty is encountered identifying the left adrenal vein, the adrenal vein can be found by first locating the left renal vessels and noting the junction of the left adrenal vein with the left renal vein. Unlike a transperitoneal laparoscopic adrenalectomy, the dissection and identification of the left adrenal vein must be done from a posterior approach. Once the left adrenal vein is divided, the remainder of the adrenal gland can be detached, again trying to minimize direct grasping of the friable adrenal tissue. Generally, the lateral and inferior surface of the gland is dissected away from the kidney. The superior margin is dissected free by dividing the inferior phrenic vessels. The use of the harmonic scalpel is useful for complete mobilization of the adrenal gland. Once detached, the adrenal gland is placed in a specimen retrieval bag and then removed through the primary
Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 165
port, the largest incision. The remaining ports are then closed in the standard fashion. Right Adrenalectomy The right adrenalectomy proceeds using the same principles of retroperitoneal laparoscopy. The dissection proceeds along the psoas muscle in a superior direction. The kidney may be held anteriorly by an optional retractor. The right adrenal gland is situated more medial to the kidney than the left adrenal gland, and as such the upper pole of the kidney may interfere with exposure of the adrenal gland. The IVC is identified medial to the psoas. Along the posterolateral aspect of the IVC, the main adrenal vein is identified. Caution must be exercised when manipulating the main adrenal vein to prevent inadvertent avulsion. The adrenal vein is then clipped and divided. Once the adrenal vein is divided, then inferior and medial borders of the adrenal gland are dissected free from the right renal vein and the IVC. Small adrenal vessels can then be effectively ligated using the harmonic scalpel. The inferior phrenic vessels are then divided to release the adrenal gland and the specimen removed in the usual fashion. Posterior Retroperitoneal Approach The posterior retroperitoneal approach to the adrenal gland has been described.33 Purported advantages of this approach include less risk of injury to organs confined to the peritoneal or retroperitoneal cavity and is better suited for smaller tumors. With this technique, the operation is performed with the patient in the prone position. A 3 to 4-port technique is used following standard balloon dilatation. Gerota’s fascia is incised along the medial crus of the diaphragm. The medial surface of the adrenal gland, including the adrenal vessels, is exposed first before mobilization of the entire gland. Once the main vascular supply of the adrenal gland is divided, the remainder of the gland is dissected free. Although results with this technique are promising,34 experience with this approach is limited. Transthoracic Technique Recently, the technique of thorascopic transdiaphragmatic adrenalectomy has been described.24 This technique has potential for use when both the transperitoneal and retroperitoneal spaces have been violated by prior surgery. Following double lumen endotracheal intubation, the patient is placed in the prone position. A 4-port transthoracic technique is used. In order to gain exposure to the adrenal gland, the diaphragm is incised under ultrasonographic guidance
and the retroperitoneum entered. The adrenal gland is then identified and dissected free. Once the adrenal gland is removed, the diaphragm is repaired. A chest tube is kept in place at the conclusion of the procedure. Postoperative Care The advantages of the laparoscopic approach to the adrenal gland are immediately apparent in the postoperative period. The orogastric tube is removed immediately at the end of the operation and the Foley catheter removed as soon as the patient is ambulatory. Postoperative pain is controlled with parenteral narcotics in the first 24 hours, ketorolac or oral narcotics thereafter. Supplemental corticosteroids and appropriate antihypertensive medications are administered as needed depending on the type of tumor removed. Postoperative care can be coordinated in concert with an endocrinologist if necessary. Discharge is usually within 24 to 48 hours from surgery and full recovery requires 10 to 14 days. Complications of Laparoscopic Adrenalectomy The most significant intraoperative complication is hemorrhage. The adrenal gland is highly vascular which can result in troublesome bleeding if not adequately controlled.35 The use of a harmonic scalpel during dissection of the adrenal gland can limit the amount of hemorrhage. In addition, the adrenal gland itself is very easily fractured, often resulting in bleeding. Other intraoperative complications from laparoscopic adrenalectomy are similar to those for any laparoscopic procedure and can include injuries to the colon, small bowel, liver, gallbladder, pancreas, spleen, and diaphragm.35 In general, major complications occur less often as surgeon experience increases. Conversion to an open case should be done if hemorrhage is uncontrollable or intraoperative injury cannot be repaired through a laparoscopic approach. Results of Laparoscopic Adrenalectomy Worldwide experience with laparoscopic adrenal surgery has increased since its original introduction in 1992. Several centers have now reported large series in the literature documenting the decreased blood loss, shortened hospital stay, and faster return to normal activity. Selected recent series in the literature are summarized in Table 9-3. Gagner et al.46 reported on 100 consecutive laparoscopic adrenalectomy procedures performed through the transperitoneal approach. The mean operative time was 123 minutes with an estimated blood loss of 70 cc. In his series, the open conversion rate was 3%. Average length of hospital stay was 3 or less days, and morbidity was
91 176 216 115 161 118 52 172 50 21
28
14 100 23 100 67
Valeri37 (2002)
Kebebew et al.38 (2001)
Lezoche et al.31 (2001)
Salamon et al.30 (2001)
Guazzoni et al.39 (2001)
Suzuki et al.32 (2001)
Soulie et al.40 (2000)
Mancini et al.41 (1999)
Schichman et al.42 (1999)
Winfield et al.43 (1998)
Yoshimura et al.44 (1998)
Chee et al.45 (1998)
Gagner et al.46 (1997)
Gasman et al.29 (1997)
Terachi et al.47 (1997)
Rutherford et al.48 (1996)
Average
60
Number of Cases
MacGillivray36 (2002)
Reference
47.1
54
—
49.6
46
46.2
42
52.2
54
—
46.9
51.7
39.4
49.3
45.9
—
—
—
Age
Transperitoneal
Transperitoneal
23 retroperitoneal
Transperitoneal
8 transperitoneal 6 retroperitoneal
11 transperitoneal 17 retroperitoneal
Transperitoneal
Transperitoneal
Transperitoneal
52 retroperitoneal
78 transperitoneal 40 retroperitoneal
Transperitoneal
115 retroperitoneal
149 transperitoneal 67 retroperitoneal
Transperitoneal
Transperitoneal
Transperitoneal
Approach
153.5
124
240
97
123
135
375
219
219
132
135
171
160
118
100
168
92–148
183
OR Time (minutes)
98.6
—
77
70
70
Min
370
183
142
—
80
96.3
—
77
—
—
—
63
EBL (cc)
5.1
—
3.3
3
3
2.7
2.7
3
5.8
5
—
2.8
4
—
1.7
3.5
2
Hospital Stay (days)
36/1567 (2.3%)
0/67
3/100
0/23
3/100
0/14
0/28
0/21
0/50
12/172
1/52
6/118
4/161
1/118
4/216
0/176
2/91
0/60
Conversion Rate
Table 9-3 Selected Laparoscopic Adrenalectomy Series
3 DVT, 2 pulmonary emboli 1 port site hernia, 1 postoperative bleed
—
1 postop hematoma
12%, 3 DVT, 2 pulmonary embolus
1 pneumonia
4 blood transfusion 4 subcutaneous emphysema 2 postoperative bleeding
1 subcutaneous bleed 2 pneumothorax 1 pulmonary edema
10%
8.7%, 2 deaths
5.7% intraoperative 11.5% postoperative
2 paralytic ileus 4 shoulder tip pain
5.5%
3.5% intraoperative 12.1% postoperative
1 death, 1 hemoperitoneum, 1 wound infection
5.1%
2 postoperative hemorrhage, 1 port site bleed 1 UTI, 1 death from myocardial infarction
Complications
166 Part II Adrenal Gland
Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 167
encountered in 12% of patients. The lesions removed included pheochromocytomas, aldosteronomas, Cushing’s lesions, and others. In the largest published series identified in the literature by Lezoche et al.,31 a total of 216 laparoscopic adrenalectomies were performed through the anterior transperitoneal, lateral transperitoneal, and the posterior retroperitoneal approaches. The study was a combined experience of surgeons in Italy and The Netherlands. The average operating time of all approaches was 100 minutes with a conversion rate of only 1.9%. Average hospital stay for all approaches was 3 to 4 days. Comparison studies have been made between laparoscopic and open adrenalectomy to determine if there are significant benefits in the laparoscopic approach.43,44,48–54 In general, the operative times for laparoscopic surgery are longer than for the open technique, particularly early in the learning curve. However, the operative times decrease as surgeon experience increases. In addition, the laparoscopic approach offers less blood loss, significantly less postoperative narcotic use, overall shorter hospital stay, and a faster return to normal activity. The cost of a laparoscopic adrenalectomy was shown to be comparable to that of an open adrenalectomy in one study.55 Laparoscopic Adrenalectomy for Malignant Tumors Increased surgeon experience and comfort with laparoscopic adrenalectomies has led to performing laparoscopic adrenalectomies for larger and potentially malignant tumors. Henry et al.56 performed laparoscopic adrenalectomies on 19 patients with potentially malignant tumors, all of which were greater than 6 cm in size. Median operating time was 150 minutes, and conversion was necessary in two patients because of intraoperative evidence of invasive carcinoma. Six of the 19 patients had an adrenocortical carcinoma on pathologic diagnosis. One of these patients presented with a liver metastasis 6 months after surgery and died shortly after. The other 5 patients are alive with a follow-up ranging from 8 to 83 months. The authors concluded that laparoscopic adrenalectomy for carcinoma can be performed on select patients in experienced hands; however, conversion to open radical adrenalectomy should be performed if there is evidence of local tissue invasion observed during surgery. Laparoscopic adrenalectomy has also been safely performed in patients with solitary adrenal metastases. In a recent series by Heniford et al.,23 laparoscopic adrenalectomy was performed in 11 patients, 10 of whom had the adrenalectomy performed for metastatic disease. Average operative time was 181 minutes, and blood loss was minimal at 138 cc. One patient required conversion to an open approach due to local invasion of the tumor into the lateral wall of the vena cava, which was removed with the specimen. Ten of the 11 patients
were alive with a mean follow-up of 8.3 months. These data suggest that the laparoscopic approach to some malignant neoplasms either originating from or metastasizing to the adrenal gland is reasonable, but the conversion to an open procedure should be performed if local invasion is present. PARTIAL ADRENALECTOMY Adrenal sparing surgery for benign tumors, particularly aldosterone producing lesions, has been reported using both the open and laparoscopic techniques. However, the indications and techniques are unclear. Nakada et al.57 performed open partial adrenalectomy on 26 patients with primary hyperaldosteronism and noted no cases of recurrent disease at 5-year follow-up. Partial adrenalectomy has also been performed for patients with bilateral pheochromocytomas and the rare patient with the solitary adrenal gland. Laparoscopic partial adrenalectomy has also been described. Keschke et al.58 recently reported on 13 patients with primary hyperaldosteronism and a radiographically proven adrenal adenoma who underwent laparoscopic partial adrenalectomy. Exclusion criteria included tumors greater than 3 cm in size or centrally located tumors. Laparoscopic partial adrenalectomy has been reported for pheochromocytoma59 and may be useful in patients with von Hippel-Lindau disease. Laparoscopic instruments useful in performing partial adrenalectomy include harmonic scissors, bipolar coagulating forceps, and intraoperative ultrasound. Although the indications for open and laparoscopic partial adrenalectomy are unclear at this time, there are patients for whom adrenal sparing surgery should be considered. Possible indications for partial adrenalectomy include patients with solitary adrenal glands, aldosteronomas less than 3 cm in size, bilateral pheochromocytomas, and patients at risk for multiple adrenal tumors due to a hereditary syndrome.
REFERENCES 1. Gagner M, Lacroix A, Bolte E: Laparoscopic adrenalectomy in Cushing’s syndrome and pheochromocytoma. North Engl J Med 1992; 327:1033. 2. Walther MM, Keiser HR, Linehan WM: Pheochromocytoma: evaluation, diagnosis, and treatment. World J Urol 1999; 17:35–39. 3. Goldfarb DA: Contemporary evaluation and management of Cushing’s syndrome. World J Urol 1999; 17:22–25. 4. Blumenfeld JD, Vaughan ED Jr: Diagnosis and treatment of primary aldosteronism. World J Urol 1999; 17:15–21. 5. Murai M, Baba S, Nakashima J, et al: Management of incidentally discovered adrenal masses. World J Urol 1999; 17:9–14.
168
Part II Adrenal Gland
6. Belldegrun A, Hussain S, Seltzer S, et al: Incidentally discovered mass of the adrenal gland. Surg Gynecol Obstet 1986; 163:203–208. 7. Cerfolio RJ, Vaughan ED Jr, Brennan TG Jr, et al: Accuracy of computed tomography in predicting adrenal tumor size. Surg Gynecol Obstet 1993; 176:307–309. 8. Schulick RD, Brenna MF: Adrenocortical carcinoma. World J Urol 1999; 17:26–34. 9. Vaughan ED Jr: Surgical options for open adrenalectomy. World J Urol 1999; 17:40–47. 10. Teeger S, Papanicolaou N, Vaughan ED Jr: Current concepts in imaging of adrenal masses. World J Urol 1999; 17:3–8. 11. Ferriss JB, Beevers DG, Brown JJ, et al: Clinical, biochemical and pathological features of low-renin (“primary”) hyperaldosteronism. Am Heart J 1978; 95:375–388. 12. deGasparo M, Whitebread SE, Preiswerk G, et al: Antialdosterones: incidence and prevention of sexual side effects. J Steroid Biochem 1989; 32(1B):223–227. 13. Blumenfeld JD, Sealey JE, Schlussel Y, et al: Diagnosis and treatment of primary aldosteronism. Ann Intern Med 1994; 121:877–885. 14. Edwin B, Kazaryan AM, Mala T, et al: Laparoscopic and open surgery for pheochromocytoma. BMC Surg 2001; 1:2. 15. Salomon L, Rabii R, Soulie M, et al: Experience with retroperitoneal laparoscopic adrenalectomy for pheochromocytoma. J Urol 2001; 165:1871–1874. 16. Gotoh M, Ono Y, Hattori R, et al: Laparoscopic adrenalectomy for pheochromocytoma: morbidity compared with adrenalectomy for tumors of other pathology. J Endourol 2002; 16:245–249. 17. Ng L, Libertino JM: Adrenocortical carcinoma: diagnosis, evaluation, and treatment. J Urol 2003; 169:5–11. 18. Wajchenberg BL, Albergaria Pereira MA, Medonca BB, et al: Adrenocortical carcinoma: clinical and laboratory observations. Cancer 2000; 88:711–736. 19. Stratakis CA, Chrousos GP: Adrenal cancer. Endocrinol Metab Clin North Am 2000; 29:15–25. 20. Liou LS, Kay R: Adrenocortical carcinoma in children: review and recent innovations. Urol Clin North Am 2000; 27:403–421. 21. Schulick RD, Brennan MF: Long-term surival after complete resection and repeat resection in patients with adrenocortical carcinoma. Ann Surg Oncol 1999; 6:719–726. 22. Vaughan ED Jr, Phillips H: Modified posterior approach for right adrenalectomy. Surg Gynecol Obstet 1987; 165:453–455. 23. Heniford BT, Arca MJ, Walsh RM, et al: Laparoscopic adrenalectomy for cancer. Semin Surg Oncol 1999; 16:293–306. 24. Gill IS, Meraney AM, Thomas JC, et al: Thoracoscopic transdiaphragmatic adrenalectomy: the initial experience. J Urol 2001; 165:1875–1881. 25. Bonjer HJ, Sorm V, Berends FJ, et al: Endoscopic retroperitoneal adrenalectomy: lessons learned from 111 consecutive cases. Ann Surg 2000; 232:796–803.
26. Suzuki K: Laparoscopic adrenalectomy: retroperitoneal approach. Urol Clin North Am 2001; 28:85–95. 27. Soulie M, Mouly P, Caron P, et al: Retroperitoneal laparoscopic adrenalectomy: clinical experience in 52 procedures. Urology 2000; 56:921–925. 28. Baba S, Ito K, Yanaihara H, et al: Retroperitoneoscopic adrenalectomy by a lumbodorsal approach: clinical experience with solo surgery. World J Urol 1999; 17:54–58. 29. Gasman D, Droupy S, Koutani A, et al: Laparoscopic adrenalectomy: the retroperitoneal approach. J Urol 1998; 159:1816–1820. 30. Salomon L, Soulie M, Mouly P, et al: Experience with retroperitoneal laparoscopic adrenalectomy in 115 procedures. J Urol 2001; 166:38–41. 31. Lezoche E, Guerrieri M, Feliciotti F, et al: Anterior, lateral, and posterior retroperitoneal approaches in endoscopic adrenalectomy. Surg Endosc 2002; 16:96–99. 32. Suzuki K, Kageyama S, Hirano Y, et al: Comparison of 3 surgical approaches to laparoscopic adrenalectomy: a nonrandomized, background matched analysis. J Urol 2001; 166:437–443. 33. Nakagawa K, Murai M, Deguchi N, et al: Laparoscopic adrenalectomy: clinical results in 25 patients. J Endourol 1995; 9:265–267. 34. Baba S, Miyajima A, Uchida A, et al: A posterior lumbar approach for retroperitoneoscopic adrenalectomy: assessment of surgical efficacy. Urology 1997; 50:19–24. 35. Henry JF, Defechereux T, Raffaelli M, et al: Complications of laparoscopic adrenalectomy: results of 169 consecutive procedures. World J Surg 2000; 24:1342–1346. 36. MacGillivray DC, Whalen GF, Malchoff CD, et al: Laparoscopic resection of large adrenal tumors. Ann Surg Oncol 2002; 9:480–485. 37. Valeri A, Borrelli A, Presenti L, et al: The influence of new technologies on laparoscopic adrenalectomy. Surg Endosc 2002; 16:1274–1279. 38. Kebebew E, Siperstein AE, Duh QY: Laparoscopic adrenalectomy: the optimal surgical approach. J Laparoendosc Adv Surg Tech A 2001; 11:409–413. 39. Guazzoni G, Cestari A, Montorsi F, et al: Eight-year experience with transperitoneal laparoscopic adrenal surgery. J Urol 2001; 166:820–824. 40. Soulie M, Mouly P, Caron P, et al: Retroperitoneal laparoscopic adrenalectomy: clinical experience in 52 procedures. Urology 2000; 56:921–925. 41. Mancini F, Mutter D, Peix JL, et al: Experience with adrenalectomy in 1997. Apropos of 247 cases: a multicenter prospective study of the French-speaking Association of Endocrine Surgery. Chirurgie 1999; 124:368–374. 42. Shichman SJ, Herndon CD, Sosa RE, et al: Lateral transperitoneal laparoscopic adrenalectomy. World J Urol 1999; 17:48–53. 43. Winfield HN, Hamilton BD, Bravo EL, et al: Laparoscopic adrenalectomy: the preferred choice? A comparison to open adrenalectomy. J Urol 1998; 160:325–329.
Chapter 9 Open and Laparoscopic Surgery of Adrenal Tumors 169 44. Yoshimura K, Yoshioka T, Miyake O, et al: Comparison of clinical outcomes of laparoscopic and conventional open adrenalectomy. J Endourol 1998; 12:555–559. 45. Chee C, Ravinthiran T, Cheng C: Laparoscopic adrenalectomy: experience with transabdominal and retroperitoneal approaches. Urology 1998; 51:29–32. 46. Gagner M, Pomp A, Heniford BT, et al: Laparoscopic adrenalectomy: lessons learned from 100 consecutive procedures. Ann Surg 1997; 226:238–246. 47. Terachi T, Matsuda T, Terai A, et al: Transperitoneal laparoscopic adrenalectomy: experience in 100 patients. J Endourol 997; 11:361–365. 48. Rutherford JC, Stowasser M, Tunny TJ, et al: Laparoscopic adrenalectomy. World J Surg 1996; 20:758–760. 49. Schell SR, Talamimi MA, Udelsman R: Laparoscopic adrenalectomy for nonmalignant disease: improved safety, morbidity, and cost-effectiveness. Surg Endosc 1999; 13:30–34. 50. Vargas HI, Kavoussi LR, Bartlett DL, et al: Laparoscopic adrenalectomy: a new standard of care. Urology 1997; 49:673–678. 51. Bolli M, Oertli D, Staub J, et al: Laparoscopic adrenalectomy: the new standard? Swiss Med Wkly 2002; 132:12–16. 52. Hazzan D, Shiloni E, Golijanin D, et al: Laparoscopic vs open adrenalectomy for benign adrenal neoplasm. Surg Endosc 2001; 15:1356–1358.
53. MacGillivray DC, Schichman SJ, Ferrer FA, et al: A comparison of open vs laparoscopic adrenalectomy. Surg Endosc 1996; 10:987–990. 54. Miccoli P, Raffaelli M, Berti P, et al: Adrenal surgery before and after the introduction of laparoscopic adrenalectomy. Br J Surg 2002; 89:779–782. 55. Ortega J, Sala C, Garcia S, et al: Cost-effectiveness of laparoscopic vs open adrenalectomy: .small savings in an expensive process. J Laparoendosc Adv Surg Tech A 2002; 12:1–5. 56. Henry JF, Sebag F, Iacobone M, et al: Results of laparoscopic adrenalectomy for large and potentially malignant tumors. World J Surg 2002; 26:1043–1047. 57. Nakada T, Kubota Y, Sasagawa I, et al: Therapeutic outcome of primary aldosteronism: adrenalectomy versus enucleation of aldosterone-producing adenoma. J Urol 1995; 153:1775–1780. 58. Jeschke K, Janetschek G, Peschel R, et al: Laparoscopic partial adrenalectomy in patients with aldosteroneproducing adenomas: indications, technique, and results. Urology 2003; 61:69–72. 59. Kaouk JH, Matin S, Bravo EL, et al: Laparoscopic bilateral partial adrenalectomy for pheochromocytoma. Urology 2002; 60:1100–1103.
C H A P T E R
10 Diagnosis and Staging of Renal Cell Carcinoma Frederick A. Klein, MD, Judson R. Gash, MD, and W. Bedford Waters, MD
Renal cell carcinoma (RCC) accounted for 3% of all adult malignancies in 2003. Approximately 31,900 new cases were diagnosed in 2003 and 11,900 deaths occurred in the United States.1 Although the overall incidence of noncutaneous cancers fell by an average of 1.1% annually in the United States between 1992 and 1998, the incidence of RCC has risen by an average of 3.7% annually over the same period.1 This increased incidence has been attributed to the increased use of ultrasonography (US), computed tomography (CT) scan, and magnetic resonance imaging (MRI) for the evaluation of a variety of abdominal, back, or gastrointestinal complaints.2 RCC has been called the “internists tumor” in the past because of the multitude of constitutional symptoms that patients presented with.3,4 Now it is called the “radiologist tumor” because 25% to 40% are detected incidentally using these radiologic imaging modalities. INCIDENCE Incidence rates of RCC and mortality rates of kidney cancer have increased steadily over time in the United States.2,5 Between 1975 and 1995, incidence increased annually by 2.3% among white men, 3.1% among white women, 3.9% among black men, and 4.3% among black women. Since the mid-1980s, the incidence rates among blacks have exceeded those among whites of both sexes. Rapid increases in the incidence of kidney cancer also have been observed in other countries.5–9 Overall, approximately one-half of the RCCs reported to the U.S. Surveillance, Epidemiology, and End Results (SEER) program from 1975 to 1995 were diagnosed while localized, with regional and distant tumors comprising approximately 20% and 25%, respectively. In general, approximately 60% of
patients diagnosed with RCC survive 5 years after diagnosis, comparable to the expected survival experience for the general population. The survival patterns are similar for men and women. The overall 5-year relative survival rates, as well as survival rates by tumor stage at diagnosis have improved substantially over time for whites but not for blacks. The 5-year relative survival rates for black versus white men were (75% versus 89%) for localized disease. In contrast, black women had survival rates similar to white women. The race and gender differentials in survival patterns argue against early detection of preclinical tumors as the sole explanation for the increasing trends of RCC.5 A recent report analyzing population-based statistics from the SEER registry demonstrates an increase in detection of all stages of RCC but no change in the rate of advanced or metastatic disease. The rates of localized, regional, and distant RCC were 45%, 23%, and 32%, respectively, during 1973–1985 and 54%, 21%, and 25%, respectively, from 1986 to 1998. Plotting incidence rate versus diagnosis by year and by stage revealed a trend toward increased incidence in all three stages. The three groups had significantly different rates of incidence increase.10 Even with the increased use of abdominal imaging, there was no significant difference in renal cancer stage at presentation in 1986–1998, compared to 1973–1985. These results imply that the increased use of abdominal imaging may be detecting some indolent kidney cancers and further suggests that other factors may be contributing to an overall increase in the incidence of renal cancer. ETIOLOGY/RISK FACTORS The etiology of RCC is not known, although some risk factors are known. Cigarette smoking has at least a 30%
173
174
Part III Kidney and Ureter
to 50% increase in men and women. The risk has been shown to decline after smoking cessation. An association with other tobacco products, including cigars, pipes, and chewing tobacco, has not been consistently observed.5 Obesity, particularly in women, has a positive association. Obese persons have experienced elevated risks of 20% to more than 3-fold. The risks tend to rise with increasing levels of body mass index. The mechanism by which obesity predisposes to RCC is unclear. Obesity may influence risk by increasing the levels of endogenous estrogens5,11 and may increase the bioavailability of free insulin-like growth factors5,12 that may be involved in renal carcinogenesis.5,13 Hypertension and the long-term use of diuretics have been examined. The cumulative evidence suggests that of the two variables, hypertension itself, rather than diuretics, may have a role in the etiology of RCC. The mechanism by which high blood pressure may affect risk is unclear.5 Patients on long-term hemodialysis may develop cystic changes of the kidney with associated carcinoma. Ishikawa14 reported that 43% of 96 patients who were on dialysis for less than 3 years developed cystic disease and 79.3% of those who had been on dialysis for more than 3 years also developed cystic disease. Four patients had adenocarcinoma of the kidney; all 4 were in their 3rd and 4th decade and had been on dialysis for more than 5 years. In the United States, one series reported 17/31 (55%) developed cystic disease on hemodialysis and 3/12 (25%) on peritoneal dialysis. The incidence of developing cystic disease was 30% for patients on dialysis for less than 2 years, 33% for 2–4 years, and 67% for those dialyzed longer than 4 years. The calculated incidence reported for hemodialysis was 0.10% per patient per year and 0.08% per patient per year on continuous ambulatory peritoneal dislysis (CAPD). Solid renal tumors were found in 3/43 (6.9%) who had nephrectomy. Adult cystic disease of the kidney is felt to be a consequence of renal failure or a humoral factor rather than caused by hemodialysis itself.15 Other studies have shown the relative risk of RCC in patients with end-stage renal failure has been estimated to be 5- to 100-fold higher than in the general population.16–21 Current recommendations are to screen only patients with a long life expectancy and no major comorbidities with periodic ultrasound or CT beginning during the 3rd year on hemodialysis.16 Twenty-seven percent of patients with RCC will have a diagnosis of at least one other malignancy in their lifetime, the most common malignancies are breast cancer, prostate cancer, bladder cancer, and non-Hodgkin’s lymphoma. CLINICAL PRESENTATION In those patients presenting with signs or symptoms, 60% have hematuria, 50% have pain, and 30% have a mass. The classic triad of gross hematuria, flank pain, and
palpable mass is rarely found.22 When this classic triad is found, there is usually metastatic disease present. Before the use of US, CT, and MRI most patients presented with one of these signs or symptoms. Patients often presented with other signs and symptoms of advanced disease: weight loss, fever of unknown origin, and night sweats. Physical findings included palpable mass, nonreducing varicocele, bilateral lower extremity edema, palpable cervical/supraclavicular lymphadenopathy, abdominal bruit, penile/vaginal nodules, and caput medusa. Paraneoplastic syndromes are found in approximately 10% to 40% of patients with RCC (Table 10-1) as well as bizarre metastatic patterns with the disease.5 The presence of a paraneoplastic syndrome does not imply metastatic disease. For example, the presence of hepatic dysfunction (i.e., Stauffer’s syndrome) is manifested by an elevated alkaline phosphatase, α2-globulin, a prolonged partial thromboplastin, or hypoalbuminemia. Twenty percent to thirty percent have elevated serum bilirubin or transaminases.3,16 Other common findings include thrombocytopenia and neutropenia, and typical symptoms include fever and weight loss.3,16 Hepatic metastases must be excluded. Biopsy, when indicated, often demonstrates nonspecific hepatitis associated with a prominent lymphocytic infiltrate.16,23 Elevated serum levels of IL-6 have been found in patients with Stauffer’s syndrome, and it is believed that this and other cytokines may play a pathogenic role.16,24
Table 10-1 Paraneoplastic Syndromes Associated with Renal Cell Cancer Syndrome Anemia
Incidence (%) 20–40
Cachexia, fatigue, weight loss
33
Fever
30
Hypertension
24
Hypercalcemia
10–15
Hepatic-dysfunction (Stauffer’s syndrome)
3–6
Amyloidosis
3–5
Erythrocytosis
3-4
Enteropathy
3
Neuromyopathy
3
From Chow W, Devesa SS, Fraumeni JF Jr: Epidemiology of renal cell carcinoma. In Vogelzang NJ, Scardino PT, Shipley WU, Coffey DS (eds): Comprehensive Textbook of Genitourinary Oncology, 2nd edition, pp 101–110. Philadelphia, Lippincott Williams & Wilkins, 2000.
Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 175
Hepatic function normalizes after nephrectomy in 60% to 70% of cases. Persistence or recurrence of hepatic dysfunction is almost always indicative of the presence of viable tumor and thus portends a poor prognostic finding.16 These paraneoplastic syndromes may be due to specific hormone production by the tumor cells or an immune response to the tumor. Hormones produced by RCCs include parathyroid-like hormone, gonadotropins, placentolactogen, adrenocorticotrophic hormone-like substance, renin, erythropoietin, glucagons, human chorionic gonadotropin, and insulin.25,26 In general, treatment of paraneoplastic syndromes associated with RCC has required nephrectomy and/or systemic immunotherapy, and, except for hypercalcemia, medical therapies have not proven helpful.16 SERUM MARKERS Serum ferritin,27 erythropoietin,28 calcium,25 and renin3 levels have been shown historically to be significantly elevated and higher than controls in patients with RCC.29 Hematocrit and platelet levels can also prove credible in regards to prognosis and recurrence. Symbas et al.30 report a mean difference in survival of 59 months with pathologic stage IV RCC and a normal platelet count versus those with thrombocytosis (>400,000) when controlling for pathologic stage, nuclear grade, and cell type.29,30,31 Anemia and serum iron have also been useful as tumor markers for initial evaluation and follow-up.29,32 Normochromic and normocytic anemia and anemia of chronic diseases are the most common hematologic abnormalities associated with RCC.29 MOLECULAR MAKERS The search for better markers has increasingly moved toward the molecular level. The prognosis for patients with locally confined RCC is known to be variable and emphasis on morphologic character, proteins, antigens and other prognostic markers is being sought to aid in the diagnosis and prognosis of RCC.29 Molecular markers of proliferation like Ki-67, silver staining nucleolar organizer regions (AgNOR), and proliferating cell nuclear antigen (PCNA) are present in cycling cells and therefore have potential utility in estimating the biologic aggressiveness of a given tumor. AgNOR reflect transcription activity of ribosomal RNA and cellular mitotic activity. For some authors the AgNOR score is an independent prognostic factor associated with survival,33–35 whereas for others it is associated with histologic grade but is not an independent factor.36 PCNA is a protein synthesized during the late G1 and S phases of the cell cycle. For some authors a low PCNA index (less than 10%) is an independent positive predictor of disease-free survival but not of overall survival,37 whereas for others it
is associated with good survival.35,38,39 Ki-67 identifies an antigen of 395 kDa whose expression is detectable during the G1 phase, increases during S phase and rapidly decreases after mitosis. There is an agreement that Ki-67 is an excellent maker of proliferation in histologic material analyzed immunohistochemically. According to the result of several studies, the Ki-67 index is correlated with the histologic grade and stage,35,36,37 and might be a more powerful prognostic factor than the PCNA index. Rini and Vogelzang39 concluded that because Ki-67 is present in cells during all cell cycle phases, it provides a more accurate determination of the proliferation rate than the PCNA index but more multivariate studies are needed.29,35,39,40 Cell adhesion molecules and angiogenesis factors have also been evaluated. Cadherins are a large family of transmembrane proteins responsible for mediating cell-to-cell adhesion, and when expression decreases, their inherent ability to modulate and preserve epithelial integrity diminishes. Lack of E-cadherin expression correlates with aggressiveness in several tumors, but in RCC, only 20% express this glycoprotein.41 E-cadherin is localized to Bowman’s capsule and other tubular segments rather than the proximal tubular epithelium, calling into question whether it plays an integral role in RCC carcinogenesis.29 Shimazui42 has shown that cadherin-6 is the major one in the proximal renal tubules and the tumors themselves. His group found that aberrant expression of cahderin-6 connoted poor survival.29,42,43 Paul et al.44 have reproduced these data wherein the majority of RCCs with histology-associated poor prognosis (i.e., high-grade clear cell cancers and sarcomatoid renal tumors) showed aberrant expression. The tumor with a historically good prognosis (low-grade clear cell carcinomas and papillary cancers) exhibited normal cadherin-6 expression.29,44 Studies investigating the role of angiogenesis, using microvessel density (MVD) as a marker, as a correlate with the development of metastases have not been rewarding. There was no correlation to clinical stage, pathologic stage, or tumor grade.29,45 RCC is a vascular tumor, and its direct relationship to angiogenesis has yet to be completely determined.29 The p53 protein has also been studied in RCC. The p53 protein binds DNA and is believed to regulate transcription, acting as a “checkpoint” to induce cell cycle arrest.29,46 This tumor suppressor gene, when mutated, inactivates the normal function of DNA damage surveillance. Aneuploid cells originate, carcinogenesis occurs, and tumor progression can ensue.47 Mutant p53 proteins have a prolonged half-life and with accumulation are detectable with immunohistochemical analysis.48 However, controversy exists with regards to the frequency of the mutation in RCC, ranging from 4% to 40% of RCC specimens tested, and its resultant
176
Part III Kidney and Ureter
prognostic power. The clinical significance of p53 and other apoptotic markers has yet to be determined.29,49,50 Carbonic anhydrase IX (CAIX) protein, a member of the carbonic anhydrase family, is thought to play a role in the regulation of cell proliferation in response to hypoxic conditions and may be involved in oncogenesis and tumor progression.51–54. Constitutive expression of CAIX as a result of von Hippel-Lindau (VHL) protein mutations has been described for RCC.55 Recent studies now indicate that expression of CAIX is regulated by the hypoxia-inducible factor (HIF) 1 transcriptional complex that mediates expression of a number of genes in response to hypoxic conditions.56 It has been postulated that cell surface carbonic anhydrase regulate acid-base balance to optimize conditions in the tumor invasiveness.54 Acidification of the extracellular matrix is known to induce expression of angiogenic factors57 and may inhibit cellular immunity,58 which additionally promotes tumor aggressiveness. In addition, there is some evidence for the association of CAIX with loss of contact inhibition and anchorage dependence of cancer cells.59 Bui et al.51 have investigated CAIX as kidney cancer marker as an independent predictor of progression and survival. Immunohistochemical analysis using a CAIX monoclonal assay was performed on tissue microassays constructed from paraffin-embedded specimens from 321 patients treated by nephrectomy for clear cell RCC. CAIX staining was correlated with response to treatment, clinical factors, pathologic features, and survival. CAIX staining was present in 94% of clear cell RCCs. Survival tree analysis determined that a cutoff of 85% CAIX staining provided the most accurate prediction of survival. Low CAIX (≥85%) staining was an independent poor prognostic factor for survival for patients with metastatic RCC, with a hazard ratio of 3.10 ( p < 0.001). CAIX significantly substratified patients with metastatic disease when analyzed by T stage, Fuhrman grade, nodal involvement, and performance status ( p < 0.001, p = 0.001, p = 0.009, p = 0.005, respectively). For patients with nonmetastatic RCC and at high risk for progression, low CAIX predicted a worse outcome similar to patients with metastatic disease ( p = 0.058). CAIX status may potentially aid in the selection of patients who might benefit from IL-2 or CAIX-targeted therapies. Furthermore, patients with high-risk localized RCC and low CAIX may be potential candidates for adjuvant immunotherapy.51 MOLECULAR GENETICS To date, four major dominantly inherited forms of RCC have been described. RCC occurs in association with VHL disease. About 45% of patients with VHL disease have RCC, which is metastatic in half of the cases at diagnosis, often bilateral and multifocal, occurs in younger patients,
and has an equal male to female ratio. Tumors associated with VHL are predominantly of the clear cell type and are associated with germline mutations of the tumor suppressor gene, VHL gene, located on chromosome 3p. After extensive work, the VHL gene has been mapped to the 3p25–26 region and VHL inactivation by point mutation and allelic loss has been reported to occur in both sporadic and VHL-associated RCC. Specific sites or types of mutations within the VHL gene appear to correlate with specific phenotypic expression of the gene: VHL type I (VHL without pheochromocytomas) and VHL type II (VHL with pheochromocytomas). VHL disease is characterized by renal cysts, RCC (clear cell histology), retinal hemangiomas, hemangioblastomas of the cerebellum and spinal cord, pancreatic carcinomas and cysts, epididymal cysts and cystadenomas, and pheochromocytomas.60–68 The VHL gene product forms a complex that degrades two α subunits of HIF, an intracellular protein that plays an important role in regulating cellular responses to hypoxia, starvation, and other stresses.16,69 The HIFα subunits are transcription factors that regulate the expression of a number of proteins, including vascular endothelial growth factor (VEGF), the primary proangiogenic growth factor in RCC, contributing to the pronounced neovascularity associated with RCC,16,63,70 glucose transporter (GLUT-1), and transforming growth factor (TGF)-α. Hereditary papillary renal carcinoma (HPRC) is a hereditary cancer syndrome, which generally develops in older patients (50s and 60s). The affected individuals are at risk to develop bilateral, multifocal papillary RCC. Linkage analysis of the families led to the discovery of the HPRC gene on chromosome 7.71–73 This syndrome, which has an autosomal dominant inheritance pattern, is caused by missense mutations in the tyrosine kinase domain of the MET proto-oncogene at 7q31.73 Patients with germline or somatic mutations in the MET protooncogene develop a specific subtype of papillary renal carcinoma—papillary renal carcinoma type 1. In vitro and in vivo studies suggest that MET functions as a dominantly acting oncogene in HPRC and in sporadic papillary renal carcinoma.74 Patients with hereditary hair follicle tumors (fibrofolliculomas) on their face and neck have a high risk for developing kidney cancer (20% to 30%), lung cysts (90%), and pneumothorax (20%). Inherited fibrofolliculoma is called Birt-Hogg-Dubé syndrome (BHD). The BHD gene has been localized to the short arm of chromosome 17. BHD patients are at risk for the development of chromophobe RCC, oncocytic renal carcinoma, and oncocytoma.75–78 Familial renal oncocytoma is an entity currently undergoing evaluation and definition, in which multiple bilateral renal oncocytomas develop in affected family members. The genetic defect involved in the pathogenesis of familial renal oncocytoma has not yet been identi-
Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 177
fied. However, clues to the location of this gene have come from cytogenetic studies: one characterized by the loss of chromosomes 1 and Y,79 and the other by translocations involving the breakpoint region 11q13.68,80–82 The untreated natural history of familial renal oncocytoma is currently being studied.83 Hereditary leiomyomatosis renal carcinoma (HLRC) is another type of hereditary renal carcinoma. Affected HLRC individuals are at risk for the development of cutaneous leiomyomas, uterine leiomyomas (fibroids), and renal carcinoma. The HLRC renal tumors are of varying histologic type, but the predominate histologic phenotype is type 2 papillary renal carcinoma.84 PATHOLOGY RCCs originate from renal tubular cells. Renal cancer has an equal frequency on the right and left and is distributed equally throughout the kidney. Fifteen percent of tumors extend to the renal vein, and 8% extend to the vena cava. The histologic classification of RCC has undergone a major revision since 1990. Traditionally, renal cancers have been classified as clear cell, granular, sarcomatoid, and papillary types. Malignant renal epithelial neoplasms are now subdivided under the new classification system (Table 10-2) based on prominent morphologic features.85 Major changes include the addition of a new histologic subtype, the chromophobe cell carcinoma; the reclassification of granular cell tumors into other categories; and the recognition that sarcomatoid lesions represent poorly differentiated elements derived from other histologic subtypes, rather than a distinct tumor type.16,85–87 Common or conventional RCC accounts for approximately 70% to 80% of all RCCs. They are highly vascular and are typically yellow when
Table 10-2 Classification of Renal Cell Carcinoma Subtype
Incidence (%)
Affected Chromosomes
Conventional
70–80
3p, 17
Papillary
10–15
3q, 7, 12, 16, 17, 20, Y
Chromophobe
4–5
1, 2, 6, 10, 13, 17, 21
Collecting duct
<1
1q, 6p, 8p, 13q, 21q
Medullary cell
<1
Not defined
Oncocytoma
3–7
1, Y
From Störkel S, Ebie JN, Adlakha K, et al: Classification of renal cell carcinoma: Workgroup no. 1, Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 1997; 80:987–989.
bivalved. Microscopically they can include clear cell, granular cell, or mixed types.16 The loss of loci on the short arm of chromosome 3 has been the predominant mutation linked to clear cell carcinoma, the most common subtype of RCC.66,88 Allelic loss of 3p is now thought to be an early event in the pathogenesis of clear cell carcinoma, whereas others now consider additional allelic losses on chromosome 17 to be associated with advanced disease.89 Papillary RCC represents 10% to 15% of all RCCs. They can be inherited, multifocal, bilateral, and generally portend a more favorable prognosis. The cytogenetic features are associated with loss of Y chromosome along with trisomies of chromosomes 3q, 7, 12, 16, 17, and 20.85 Papillary RCC is more likely to be hypovascular, perhaps owing to lack of VHL mutations, which regulate VEGF, the primary proangiogenic molecule in RCC.16 The other genetic features of papillary RCC have been discussed earlier. Chromophobe cell carcinoma accounts for approximately 5% of all RCCs. It appears to be derived from the cortical portion of the collecting duct. Histologically, they are composed of two distinct cell types, those with granular eosinophilic cytoplasm and those with pale cytoplasm. Ultrastructural analysis shows numerous cytoplasmic microvesicles, and characteristic cytoplasm staining with Hale’s colloidal iron is typical.89,90 The clinical behavior of patients with chromophobe carcinoma shows that the majority of tumors appear to be localized to the kidney at the time of diagnosis. Although some may be large, clinical behavior seems to be similar to respective stages of clear cell carcinoma.90,91 However, Renshaw and colleagues92 reported a more adverse prognosis associated with chromophobe RCC. In their series, high-grade disease was common, and 7 of 25 patients eventually developed metastatic disease.16,92 Collecting duct, or Bellini’s duct, carcinomas represent a rare group of renal neoplasms. They arise from the distal portion of the nephron, commonly strike in a young population, and carry a usually poor prognosis. They are usually high grade, present at an advanced stage, and do not respond to conventional therapy. There is a frequent loss of heterozygosity at chromosome regions on 1q, 6p, 8p, 13q, and 21q.93 High density mapping of arm 1q in 13 collecting tumors shows an area of minimal deletion around the area located at 1q32.1–32.2 in 69% of examined specimens.94 Renal medullary carcinoma is a relatively new histologic subtype of RCC that occurs almost exclusively in association with the sickle cell trait. It is typically diagnosed in young African Americans often in the third decade of life.16,95 Many cases are both locally advanced and metastatic at the time of diagnosis. Most patients do not respond to therapy and succumb to their disease within several months.16,95 Histologically, this tumor shares many features with collecting duct carcinoma.
178
Part III Kidney and Ureter
The site of origin (renal papillae) and association with sickle cell trait suggest that a relatively hypoxic environment may contribute to tumorigenesis.16 RCC, unclassified, is a category reserved for malignant epithelial tumors that do not conform to any of the other subtypes. Of the total group of RCCs, they comprise approximately 4% to 5%.85,89 Specifically, composites of recognized subtypes, tumors with mucin production, and tumors with extensive sarcomatoid changes without recognizable epithelial elements are examples of this classification.89 Imaging Evaluation RCC may be radiologically discovered in one of two ways. It may be diagnosed in patients with symptoms, such as hematuria or pain or, alternatively, it may be found incidentally in patients undergoing imaging studies for other reasons. With the increasing utilization of cross-sectional modalities, such as CT and US, the majority of renal cell cancers are now discovered serendipitously.96 Once identified, renal masses usually require further characterization. Although imaging does not allow a histologic diagnosis, radiologic studies are critical to exclude benign entities, such as cysts, abscesses, and pseudomasses. Also, an attempt should be made to eliminate certain neoplastic conditions, such as angiomyolipomas, metastases, and lymphoma. Finally, imaging is indispensable in the staging of RCC. Many radiologic techniques are available for the detection, characterization, and staging of renal cell cancer, including intravenous urography, US, CT, MRI, nuclear medicine, and positron emission tomography (PET) imaging. Invasive angiography, once a bastion of renal evaluation, now plays little role in the diagnostic evaluation of RCC.
rounded bulge to the renal contour or displacing the collecting system (Figure 10-1). Calcifications, although observed in only about 10% of RCCs on the IVP, suggest neoplasm, especially when they are chunky and centrally located within the mass.98 Unlike cysts, which should not enhance and therefore appear lucent, a mass with density approaching that of surrounding renal parenchyma suggests enhancement and is worrisome for neoplasm. Uncommonly, RCC may present as diffuse enlargement of the kidney when the tumor is large or infiltrating. Diffuse replacement of the renal parenchyma or venous invasion may result in lack of normal renal function and nonvisualization on the IVP. Despite even the most suggestive findings, virtually all parenchymal masses identified on the IVP are nonspecific and thus require further evaluation. Since more than 80% of suspected renal masses on excretory urography are simple cysts or pseudomasses, ultrasound should be performed in most cases as the diagnosis of a cyst can usually be made with ultrasound and the workup terminated.99 However, if the mass has an appearance suggestive of a solid lesion, such as calcification or increased density, then a dedicated renal CT is an appropriate next test for further evaluation. Ultrasonography The ease of use, safety and wide availability of ultrasound make this an excellent and widely utilized modality for evaluation of the abdomen and pelvis, including the urinary tract. Perhaps as many as 50% of all diagnosed RCCs, therefore, are initially detected during an ultrasound examination100 Ultrasound is sensitive for the detection of renal masses, including RCC with sensitivity
Detection and Characterization Intravenous Urography For over five decades the intravenous pyelogram (IVP) has been the workhorse of imaging the urinary tract and detecting renal neoplasms. However, its limitations, including lack of sensitivity and specificity for renal masses, have been well known. Many renal masses may not be identifiable on the IVP, including those that are small, those that do not distort the collecting system, and those that do not create a bulge to the renal contour (intrasubstance lesions and lesions that are anteriorly or posteriorly oriented). Scrupulous technique, including nephrotomography, oblique views, and bowel prep, does improve sensitivity yet 15% of lesions greater than 3 cm will be missed and the insensitivity rises dramatically for smaller lesions with between 48% of masses of 2–3 cm and 79% of masses of 1–2 cm will not be visible.97 Most RCCs appear as a mass lesion on the IVP, creating a
Figure 10-1 4-cm RCC arising from the lower pole of the left kidney.
Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 179
approaching 100% for lesions larger than 2.5 cm, although there is diminishing sensitivity for smaller lesions.101 Tumors may be missed when they are isoechoic to renal parenchyma, small, or when the examination is technically difficult, such as with large patients; however, new technologies, including harmonic imaging, have resulted in dramatic improvements in image quality and should result in increased sensitivity even in these settings. Most RCCs at ultrasound appear as solid lesions (Figure 10-2). Earlier ultrasound reports suggested that most RCCs were hypoechoic; however, these were often large lesions at an advanced stage. Although RCC may have variable echogenicity, the majority of currently identified and smaller RCCs are in fact hyperechoic, sometimes markedly so, and may then be confused with angiomyolipomas.102 Several features have been assessed to try and distinguish RCC from the classically hyperechoic angiomyolipoma.103 A very hyperechoic lesion similar to renal sinus fat along with posterior shadowing favors the diagnosis of an acute myelogenous leukemia (AML) while a hypoechoic halo with small intratumoral cystic components suggests RCC.104 Unfortunately, there is too great an overlap of findings to allow a confident diagnosis and it is necessary to confirm the diagnosis of angiomyolipoma with CT. Along with echogenicity that is variable but often increased, RCCs often have illdefined or irregular interfaces with normal renal parenchyma and are frequently lobulated. Although Doppler waveform and color analysis have been analyzed with some success in differentiating renal masses at ultrasound, solid renal lesions remain nonspecific.105 True solid masses, however, must be differentiated from pseudomasses and normal variants. A prominent column of Bertin, renal hypertrophy adjacent to an area of scar, and fetal lobation can mimic a renal mass, although their
Figure 10-2 US demonstrating a 1.5-cm slightly hyperechoic renal cell carcinoma arising from the mid-pole of the right kidney.
normal echotexture and vascularity on color or power Doppler often allow a confident diagnosis. It is uncommon for RCC to appear predominately cystic on ultrasound. Most of these show thick septations or chunky calcifications and are not confused with benign lesions. Indeterminate cystic lesions should generally be evaluated with dedicated renal CT as occasionally benign lesions seen at CT may have a more malignant appearance on US. Septae may be exaggerated and appear more ominous and intervening normal renal tissue may look like tumor. Conversely, ultrasound may clarify indeterminate lesions seen at CT, including the hyperdense cyst and “too small to characterize” lesions. Hyperdense cysts seen at CT may appear entirely anechoic at ultrasound confirming its benign nature.106 Similarly, “too small to characterize” lesions on CT can be shown to be simple cysts in some circumstances, although the need to confirm these lesions with ultrasound or follow these is highly debatable.107 Despite the dramatic improvement in image quality, the role of ultrasound remains essentially the same in the evaluation and characterization of the renal mass. The study is useful for excluding moderate to larger tumors as well as identifying and distinguishing the simple cyst from the solid mass; however, the solid lesion remains nonspecific and requires further evaluation, typically with CT. Computed Tomography It is safe to say that the CT now forms the backbone of radiologic evaluation of the urinary tract, including the renal mass. The advent of multidetector spiral CT (MDCT) has further propelled CT to the forefront of urologic imaging including near isotropic imaging with scan thicknesses less than 1 mm and subsecond scanning speeds allowing imaging of the kidneys in multiple phases. This high spatial and temporal resolution combined with quantifiable density values (Hounsfield units, HU) and high contrast resolution makes CT excellent for RCC detection and characterization. Finally, the wide availability and relative safety of CT cinch its appeal. To take full advantage of the strengths of CT, however, scanning technique is critical. Virtually, all scans obtained for renal indications should include noncontrast scans of the kidneys. These scans can help to identify calcifications and hemorrhage but are most important as a baseline to assess lesion enhancement, a critical component to diagnosing malignancy. Four phases of enhancement may be evaluated with CT, including arterial phase, corticomedullary phase, nephrographic phase, and excretory phase. The nephrographic phase, occurring at approximately 90 seconds after contrast administration and when there is uniform cortical and medullary enhancement, is the most critical in mass detection and characterization and should be included in all renal CT
180
Part III Kidney and Ureter
studies.108,109 Corticomedullary phase, seen between 30 and 90 seconds, when there is predominant cortical enhancement but little contrast in the medulla, can be occasionally valuable for detecting hyperenhancing lesions and tumors in end stage renal disease, but may miss centrally located masses and may underestimate lesion enhancement.108 Excretory phase images obtained after 3–5 minutes may be useful for evaluating the collecting system for invasion or urothelial lesions. Arterial phase scans are used for CT angiography studies to aid surgical planning, especially when nephron sparring surgery is contemplated. Finally, delayed images may be used to assess lesion de-enhancement, suggesting enhancement and vascularity in “reverse,” when noncontrast images have not been obtained.110 Detection of RCC is accomplished with high sensitivity by a combination of an up-to-date helical scanner, scrupulous technique, and a careful, educated review of the images. Sensitivities of 95% for 8–15 mm lesions and essentially 100% for larger lesions are obtainable using helical technique and nephrographic phase images108 (Figure 10-3). Once identified, an attempt should be made to further characterize the mass and identify pseudomasses and normal variants, inflammatory lesions, benign tumors, and systemic or urothelial neoplasms. Focal renal hypertrophy, dromedary humps, and fetal lobulation may suggest a solid renal mass on noncontrast images; however, they are easily recognized on multiphasic images where their enhancement and homogeneity matches normal renal parenchyma on all sequences. Occasionally, acute infarcts or focal infection may mimic a mass but their infiltrating appearance and the clinical history usually allow a confident diagnosis. Urothelial neoplasms, typically transitional cell carcinoma, account for about 10% of renal malignancy and should be differentiated from RCC due to their distinct surgical thera-
Figure 10-3 Incidentally detected 1-cm RCC arising from the right kidney.
pies. Urothelial neoplasms that invade the kidney tend to have an infiltrating growth pattern rather than the expansile rounded enlargement, typical of RCC.111 Additionally, the epicenter of the mass should be in the renal pelvis. Retrograde pyelography, endoscopic biopsy, and urine cytology may be used to confirm the diagnosis. Secondary and systemic neoplastic involvement of the kidney can be seen with lymphoma and metastatic disease. Similar to urothelial lesions, these entities tend to have an infiltrative growth pattern maintaining the reniform shape of the kidneys.112 Also, these lesions are often multiple, bilateral and there is usually evidence of disease elsewhere. Renal medullary carcinomas, first described in 1995 and seen in African-American males with sickle cell trait, along with collecting duct carcinomas also show an infiltrating growth pattern, arise centrally in the medullary region and are often large and heterogeneous at presentation.112 Benign neoplasms account for 10% to 15% of renal tumors and are of increasing frequency with the now common incidental detection of smaller lesions.113 The presence of unequivocal fat (<10 HU) within a mass generally allows a confident diagnosis of a benign angiomyolipoma, with a few caveats. RCC can engulf renal sinus or perinephric fat and mimic an angiomyolipoma. Additionally, there have been a few case reports of adipose tissue within RCCs, although most of these also contained calcifications, which is distinctly rare in angiomyolipomas.114 Conversely, a small percentage, about 10%, of AMLs do not contain detectable fat and are indistinguishable from RCCs115 (Figure 10-4). Oncocytoma is the most common benign neoplasm and is being detected with increasing fre-
Figure 10-4 CT demonstrating a 6-cm necrotic RCC of the right kidney in a patient who also has a single 2-cm fatcontaining AML in the left kidney.
Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 181
Figure 10-5 Large right RCC mimicking an oncocytoma.
quency.116 When large, a central scar within an otherwise homogeneous mass may suggest the diagnosis, although overlapping imaging findings do not allow a radiographically confident distinction from RCC and resection is generally necessary for histologic confirmation (Figure 10-5). Smaller oncocytomas have imaging findings indistinguishable from RCC. The appearance of RCC on CT is somewhat variable depending on size, vascularity, degree of necrosis, hemorrhage, and to some extent cell type. Larger lesions tend to commonly have greater heterogeneity with necrosis and hemorrhage, whereas smaller lesions tend to be much more homogeneous. Vascularity and enhancement is a key feature of RCC. A minimum of 10 to 15-HU increase in attenuation is seen compared with baseline density, although many show much greater enhancement117 (Figure 10-6A and B). Chromophobe and papillary subtypes tend to be more hypovascular, whereas the more common conventional or clear cell types often show marked enhancement after contrast.118 Calcification is not uncommon in RCC, especially in papillary and chromophobe subtypes.23 Most renal cell cancers are rounded and expansile although a small percentage may be infiltrating, mimicking other infiltrating malignancies. Additionally, RCC may present as a cystic lesion and the evaluation of the complex renal cyst is a fairly common diagnostic problem for the urologist and radiologist (Figure 10-7). In 1986, Bosniak proposed a classification scheme for cystic renal masses.119 Criteria are shown in Table 10-3.120 Lesions meeting criteria for simple cysts and obviously malignant cystic masses, Bosniak categories I and IV lesions, respectively, are rarely problematic. Bosniak II and III lesions
Figure 10-6 Noncontrast CT (A) demonstrating a homogeneous hyperdense lesion within the upper pole of the left kidney mimicking a hyperdense cyst; however, after contrast (B) there was a 45-HU increase in lesion density typical of a RCC.
require more discussion. Bosniak II lesions are minimally complicated with thin nonenhancing septations or thin, linear calcifications, whereas Bosniak III lesions are more concerning and complex with thicker septations, walls, or calcifications. Bosniak II lesions are very likely benign while the incidence of malignancy for class III lesions may approach 50%, generally necessitating surgical resection. There have, however, been problems noted with this classification scheme. Some studies have shown an unacceptable frequency of malignancy in lesions classified as category II.121 In 1993, Bosniak added an IIF category for lesions slightly more complex and worrisome than typical class II cysts. These IIF lesions are usually closely followed (thus the “F”) rather than ignored or excised. One additional problem with the Bosniak scheme has been interobserver variability between class II and class III lesions. In one study, 60 of 227 lesions
182
Part III Kidney and Ureter
originally classified as class IIF or III lesions were reclassified when reviewed by a different radiologist.122 Despite its difficulties, however, the Bosniak classification of cystic renal masses remains a very useful framework for these difficult lesions, allowing evidenced-based therapy and further study. The trend of increasing incidence and improved survival rate in RCC are related to several factors, perhaps none more important than advances in computed tomography, which is the standard imaging technique for evaluation of RCC and the solid and complex cystic renal mass.113 Magnetic Resonance Imaging Just as technical advances have improved US and CT in recent years, MRI has made great strides with a primary
advance being the development of fast scanning sequences which allow breath-hold imaging and consequent motion artifact reduction, improved spatial resolution, and increased temporal resolution, including multiphasic renal evaluation similar to CT. This combined with its spectacular contrast resolution and multiplanar capabilities strengthen the role of MRI in renal mass evaluation and depiction as well as staging. High cost, relative lack of availability, and experience have so far limited its utility. The primary role for MRI has been when CT is contraindicated (renal insufficiency, contrast allergy), when CT is indeterminate or, in some settings, for staging. MRI is extremely sensitive to detecting enhancement and may therefore be especially useful in certain settings, such as small lesions, complex cysts, and hypovascular neoplasms. Imaging protocols should include T1 and T2 weighted, preferably breath-held, images along with gadolinium-enhanced sequences. The sensitivity of MRI for detecting renal masses is similar to CT, or perhaps slightly improved for polar lesions due to the ability to obtain direct coronal images.123 Like CT, the appearance of RCC on MRI is variable depending on various factors. Typically, the lesions are isointense to hypointense on T1 sequences, moderately hyperintense on T2, show enhancement after gadolinium, and demonstrate variable degrees of hemorrhage and necrosis (Figure 10-8). MRI, as yet, offers no significant advantage compared with CT for lesion characterization with interpretative principles as described in the CT section. In fact, objective assessment of enhancement is more complex and arbitrary compared to CT.124 For now, MRI remains a problem solver, however, the unceasing technologic advances sure to come, such as in MR spectroscopy, may propel this modality to the forefront of renal mass imaging. Nuclear Medicine and PET imaging
Figure 10-7 Cystic RCC arising from the lower pole of the left kidney.
Traditional nuclear medicine techniques, such as renograms and renal scans, play little role in the detec-
Table 10-3 Bosniak Criteria Cystic Renal Masses Criteria
I
II
III
IV
Wall
Thin
Thin
More than thin
Thick or nodular
Calcifications
None
Few, thin
Irregular
Coarse
Septations
None
Few, thin
More than a few
Thick, numerous
Density (HU)
0–20
0–20
0–20
More than 20
Enhancement
None
None
None
Present
From Kausik S, Segura JW, King BF Jr: Classification and management of simple and complex renal cysts. AUA Update Ser 2002; 21:82–87.
Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 183
Figure 10-8 Axial T2 weighted MRI reveals a large heterogeneous RCC.
tion and evaluation of renal masses. The occasional problematic pseudotumor may be confidently diagnosed as normal renal tissue with a renal scan although CT usually has little difficulty with this situation. PET scanning is limited in the evaluation of primary kidney lesions by the high intrinsic renal uptake of 18-fluoro-2-deoxyglucose (FDG), but early work has shown some promise in lesion characterization, especially in evaluating complex cysts where FDG uptake may be able to differentiate benign from malignant lesions.125 In another study, PET was 94% accurate in assessing suspicious renal masses identified on another imaging modality, although there was an inexplicable false negative in a patient with a 6-cm RCC.126 Renal Cell Carcinoma—Staging The most commonly used staging system for RCC prior to the 1990s was that proposed by Holland in accordance with the classification system developed by Robson, Murphy, Flocks, and Kadesky (Figure 10-9).127 The limitations of this classification scheme have been well defined and evidenced by the grouping in stage III that lumps lymphatic metastases (a very poor prognostic finding) with venous involvement that, even though may be extensive, can be treated with aggressive surgery and portend a good long-term outcome. Likewise, since the extent of nodal and venous involvement was not delineated in this system, the prognostic significance of these pathologic findings were lost. The tumor, nodes, and metastasis (TNM) system proposed by the International Union Against Cancer and
Figure 10-9 Robson classification for the staging of RCC.
modified by Hermanek and Schrott128 in 1990 represented a major improvement because it both separated lymphatic from venous involvement and quantified the extent of involvement of each system. After this system was popularized, there was easy global comparison of clinical and pathologic data that were found to correlate well with patient outcomes. In 1997, the International Union Against Cancer and the American Joint Committee on Cancer proposed a change in the TNM system that was widely adopted until the most recently adopted TNM system in 2002 (Table 10-4).129 Division between T1 and T2 tumors was originally 2.5 cm and was changed to 7 cm because it reflected the mean tumor size in a database where no prognostic significance or survival differences could be shown between cut points at 5, 7.5, and 10 cm.130 In 2002, the widely acceptable modification was dividing stage T1 into T1a representing tumor size of 4 cm or less and T1b representing tumor size between 4 and 7 cm. The rationale for this division is that tumors of 4 cm or less, unilateral and capsular confined, have excellent outcomes and T1a tumors are very amenable to nephron sparing procedures
184
Part III Kidney and Ureter
Table 10-4 Definition of TNM Primary tumor (T)
Regional lymph nodes (N)*
Distant metastasis (M)
Stage grouping
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Tumor 7 cm or less in greatest dimension, limited to the kidney
T1a
Tumor 4 cm or less in greatest dimension, limited to the kidney
T1b
Tumor more than 4 cm but not more than 7 cm in greatest dimension, limited to the kidney
T2
Tumor more than 7 cm in greatest dimension, limited to the kidney
T3
Tumor extends into major veins or invades adrenal gland or perinephric tissues but not beyond Gerota’s fascia
T3a
Tumor directly invades adrenal gland or perirenal and/or renal sinus fat but not beyond Gerota’s fascia
T3b
Tumor grossly extends into the renal vein or its segmental (muscle-containing) branches, or vena cava below the diaphragm
T3c
Tumor grossly extends into vena cava above diaphragm or invades the wall of the vena cava
T4
Tumor invades beyond Gerota’s fascia
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastases
N1
Metastases in a single regional lymph node
N2
Metastasis in more than one regional lymph node
MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
Stage I
T1
N0
M0
Stage II
T2
N0
M0
Stage III
T1
N1
M0
T2
N1
M0
T3
N0
M0
T3
N1
M0
T3a
N0
M0
T3a
N1
M0
T3b
N0
M0
T3b
N1
M0
T3c
N0
M0
T3c
N1
M0
Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 185
Table 10-4 Definition of TNM—cont’d Stage 4
T4
N0
M0
T4
N1
M0
Any T
N2
M0
Any T
Any N
M1
Histopathologic type The predominant cancer is adenocarcinoma; subtypes are clear cell and granular cell carcinoma. The use of the following grading system is recommended when feasible. Sarcomas and adenomas are not included. The histopathologic types are: Conventional (clear cell) renal carcinoma Papillary RCC Chromophobe renal carcinoma Collecting duct carcinoma Histologic grade (G) GX
Grade cannot be assessed
G1
Well differentiated
G2
Moderately differentiated
G3–4
Poorly differentiated or undifferentiated
From Kidney. In Greene FL, Page DL, Fleming ID, et al (eds): AJCC Cancer Staging Manual, 6th edition, pp 323–328. New York, Springer, 2002. *Laterality does not affect the N classification. Note: If a lymph node dissection is performed, then pathologic evaluation would ordinarily include at least eight nodes.
with outcomes equivalent to those treated with radical nephrectomy.131–133 Other changes in 1997 included simplifying the classification of the extent of nodal involvement and reclassifying the extent of venous tumor thrombi. It was emphasized that adrenal gland involvement by local tumor extension should be T3a because this situation has a better prognosis than isolated adrenal metastases that reflect hematogenous spread and portends a poor prognosis.134,135 In addition, stage T3a includes invasion of renal sinus fat because there is no rationale for including them in another category. Finally, it has been suggested that vena caval wall invasion has a worse prognosis than simply the cephalad extent of the tumor thrombus and should be classified as stage T3c.136 Clinical staging is important and has been shown to correlate directly with prognosis as well as play a critical role in appropriate preoperative planning. The clinical staging of RCC begins with a thorough history, physical examination, and selected laboratory tests. Symptoms and signs of significant weight loss (greater than 10% of body weight), any localized bone pain, a palpable mass, or lymphadenopathy, and/or a poor performance status suggest more advanced disease and a worse prognosis137,138 New onset of a nonreducing varicocele and lower extremity edema suggest venous involvement. Likewise, other constitutional symptoms of pain, fever, night sweats, and abnormal liver function tests, such as
alkaline phosphatase, α-glutamyltransferase, glutamic oxaloacetic transaminase, and glutamate pyruvate transaminase, an elevated sedimentation rate, and significant anemia all point to the likelihood of advanced disease.136,137 In the absence of either bone pain or elevations of serum alkaline phosphatase or calcium, it is uncommon for a patient to harbor skeletal metastases. The routine addition of a bone scan for the evaluation of bone metastases from RCC is not indicated. In fact, in a study by Koga et al.,139 the overall incidence of bone metastases was 17% in a group of all stages of RCC. Likewise, in all patients stages T1–T3, only 4 (1.8%) had osseous metastases without other metastatic sites, lymph node involvement, or localized bone pain. The TNM system is felt to be inadequate by some groups to describe prognosis in 2003. The addition of Fuhrman’s tumor grade and Eastern Cooperative Oncology Group (ECOG) patient performance status (PS) has been shown to be an important prognostic tool.140 Zisman et al.140 from University of California Los Angeles (UCLA) have described the UCLA Integrated Staging System (UISS). The medical records of 477 patients undergoing nephrectomy between 1989 and 1999 were evaluated. Median age was 61 years, maleto-female ratio was 2.2:1, and median follow-up was 37 months. Survival time was the primary end point assessed. Sixty-four possible combinations of stage,
186
Part III Kidney and Ureter
grade, and ECOG PS were analyzed and collapsed into distinct groups. The internal validity of the categories was challenged by a univariate analysis and a multivariate analysis testing for the accountability of each UISS category against independent variable shown to have impact on survival.140 Combining and stratifying 1997 TNM stage, Fuhrman’s grade and ECOG PS resulted in five stratification groups designated UISS, and numbered I–V. The overall 5-year survival for the UISS groups I–V, respectively, are: 94%, 67%, 39%, 23%, and 0% (Table 10-5). UISS is an emerging important prognostic tool for counseling patients with various stages of kidney cancer. It is currently being validated in two large-scale external databases.140 Imaging plays a crucial role in staging and treatment planning; however, only tests where the results affect the patient’s management should be performed. The diagnosis of RCC will most commonly be made incidentally by ultrasound or CT.141 Therefore, performing excretory urography is of no useful value. Although ultrasound can yield significant staging information, it is rarely used as the sole imaging modality. Limitations are associated with operator ability and interference by body habitus and overlying bowel gas. In the majority of cases, radiographic staging of RCC can be accomplished with the meticulous use of high quality abdominal CT and routine chest x-ray or chest CT. Staging accuracy for CT has been reported to be in the 90% to 91% range.117,142 Probably the greatest limiTable 10-5 UCLA Integrated Staging System (UISS)
UISS
TNM Stage
ECOGPS
Grade
I
I
0
1–2
II
I
0
3–4
II
Any
Any
III
0
Any
III
≥1
1
III
≥1
2–4
IV
0
1–2
IV
0
3–4
IV
≥1
1–3
IV
≥1
4
III
IV
V
Overall 5-Year Survival (%) 94
tation and most common staging error is determining extracapsular tumor extension into the perinephric fat and as such distinguishing stages T1a, T1b, and T2 from stage T3a. Perinephric stranding adjacent to renal cancers is a nonspecific sign and can represent edema, fibrosis, prominent engorged vessels or tumor, and falsely suggest capsular extension and a T3a lesion. Since, in the majority of cases tumor extension is microscopic, it does not change patient management and is of less clinical significance. Perinephric stranding has been reportedly seen in up to 50% of confirmed T1 and T2 lesions.142 On the other hand, to confidently suggest perinephric spread requires nodular soft tissue beyond the capsule. Although this finding has a 98% specificity, sensitivity is only 46% with the findings usually seen with larger lesions.142 (Figure 10-10) Another difficult issue is for CT to distinguish between abuttal and invasion of adjacent organs, such as liver, spleen, duodenum, and pancreas. Obliteration of fat places suggesting invasion can be difficult to evaluate on CT and lead to false positive results in 15% of cases.143 (Figure 10-11) In selected cases where more careful surgical planning is necessary, an MRI may be helpful.144 Regional lymph node involvement (N1–N2) portends a poor prognosis. CT must rely on anatomic size criteria to diagnose or exclude nodal disease and sensitivity and specificity will vary based on the size used to consider a node enlarged. Nodal size of 2 cm or greater usually is associated with malignancy. Using a threshold of 1 cm, false negative rates for microscopic metastases are low (4%), while the false positive rates have ranged from 3% to 43%.136,142,145,146 These false positive rates may even be higher in patients where venous invasion and tumor necrosis are present as a result of reactive hyperplasia. Because of this imaging unreliability, extirpative surgery should not be withheld without tissue confirmation of
67
39
23
0
From Zisman A, Pantuck AJ, Dorey F, et al: Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol 2001; 19:1649–1657.
Figure 10-10 Large right RCC with nodular soft tissue in the perinephric space consistent with transcapsular spread.
Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 187
Figure 10-11 Very large RCC with incontrovertible invasion of the liver.
malignancy by aspiration cytology or biopsy. MRI may be more reliable for distinguishing lymphadenopathy from vascular structures. Ipsilateral adrenal gland involvement by RCC has been found in up to 10% of radial nephrectomy specimens.147 With metastatic RCC, ipsilateral adrenal involvement has been found to be as high as 19.1% while the contralateral gland is affected in 11.5%.148 Patients at higher risk for adrenal involvement have an enlarged adrenal on CT, have an upper pole tumor, and/or have large tumors with extensive malignant replacement of the kidney. Microscopic invasion, of course, evades detection by any imaging modality; however, adrenal involvement with small mid- or lower pole lesions is reported to be as low as 1.9%.146 Therefore, with a normal adrenal gland on CT and small mid- and lower pole tumors, routine adrenal resection is not justified.149,150 Tumor extension or invasion into the renal vein, vena cava, or into the heart is a unique finding associated with RCC. The incidence of renal vein involvement and for caval extension at the time of surgical exploration has been reported to be between 10% and 39% and 4% and 25%, respectively.151–153 Reports of successful interior venacavotomy and tumor thrombectomy date back to 1913.154 Since there are better outcomes with complete surgical excision in these patients when compared to those with lymphatic invasion, accurate venous staging with a thorough knowledge of the extent of venous involvement is necessary for optimal surgical planning and management. The sensitivity and specificity of CT detecting vascular extension of tumor thrombus have been reported at 78% and 96%, respectively.143 Accuracy for caval involvement is greater (86%) than for renal vein involvement (50%).155 The CT findings suggestive of venous involvement include venous enlargement, abrupt change in the caliber of the vein, low density intraluminal filling defects, and the presence of collateral venous
tributaries. Enhancement of the thrombus and direct continuity with the primary tumor are typical of neoplastic thrombus. Bland thrombus, commonly seen below the level of the renal veins in lesions with large venous extension, shows no enhancement after contrast. False negatives occur in patients where a mass effect on the vein may make tumor thrombus identification difficult (more common on the right) and in situations where tumor hypervascularity alone causes venous enlargement and suggests thrombus.156 The superior most extent of venous invasion is particularly crucial to delineate especially when the thrombus extends above the diaphragm (T3c), as this takes careful surgical planning. Finally, venous extension into the wall of the renal vein or IVC may make resection impossible, but this is difficult to diagnose unless tumor is clearly seen extending beyond the venous wall into the perivascular tissues. Careful attention should also be paid on CT to the remainder of the kidney as well; especially when nephron-sparing surgery is contemplated. Multifocal RCC occurs in as many as 25% of patients who are candidates for partial nephrectomy.157 Although multicentric lesions tend to be small (from “microscopic” to 1 cm), as many as 50% of these may be detectable on preoperative imaging.158 Similarly, the contralateral kidney must be closely evaluated since bilateral disease is becoming more commonly recognized.159 Metastatic disease is not uncommonly identified at the time of staging and most often occurs in the lungs, bone, liver, and brain. Mediastinal and mesenteric nodes, pancreas, and other less common areas of distant dissemination may be seen. A careful search is prudent, especially for small lesions. Renal cell metastatic lesions are often hypervascular and aggressive in appearance. The question of whether to routinely obtain a chest CT for staging is commonly asked. In general, a routine anterioposterior and lateral plain chest film is sufficient to screen for parenchymal lesions but not for mediastinal nodes less than 2 cm.160 If enlarged lymph nodes are seen on abdominal CT or if lymphangitic metastases are suspected on plain chest film, chest CT is encouraged. Similarly, routine use of pelvic CT has been shown to produce negligible yield and is not routinely recommended.161 MRI has some advantages over CT for staging RCC. It is noninvasive, does not subject the patient to the risks of intravenous contrast, and provides high intrinsic contrast resolution permitting improved depiction of tumor thrombus extension and invasion, invasion of adjacent organs, and capsular extension. This is well shown in Figure 10-12. MRI has been advocated because of its ability to directly image in multiple planes although with today’s modern CT scanners, reconstruction in virtually all planes is possible without resolution loss. A recent study by Pretorius et al.162 has shown similar staging accuracies for CT and MRI. In addition,
188
Part III Kidney and Ureter
Figure 10-12 Axial MRI demonstrating low signal tumor thrombus involving the right renal vein to the level of the IVC.
several logistical and practical factors hinder MRI availability, including long scan times, lack of a consistent oral contrast agent, inability to image the lungs, claustrophobia issues, and contraindications, such as pacemakers. Finally, image quality can be unpredictable secondary to motion and other artifacts especially related to the inability to cooperate with multiple sequential breath-holds. MRI’s role is a problem-solver especially when CT findings are equivocal and in patients with renal insufficiency. Venacavography has predominantly been abandoned. For venous thrombus staging, it is invasive, has contrast risks, and risks of detaching tumor, may require superior vena cava puncture to determine the cephalad extent of the thrombus, and is subject to the inaccuracies created by slow flow and suboptimal contrast filling. In selected cases where MRI may be contraindicated and other staging modalities equivocal, transesophageal echo can be very accurate for establishing the cephalad extent of tumor thrombus. Transesophageal echo, however, is invasive.163 Positron Emission Tomography PET permits noninvasive measurement of biochemical as well as physiologic reactions. Positron-emitting radioisotopes labeled to endogenous biochemicals or drugs are injected intravenously and accumulate in various organ tissues depending on their biochemical or physiologic properties. Presently, the most commonly used agent is the glucose analog FDG. Normally, there is
high uptake in the brain, myocardium, kidneys, and bladder. The increased activity in the genitourinary system is due to the inability of the nephron to resorb filtered FDG in the convoluted tubule.164 Although PET-FDG has detected histologically confirmed RCCs, there have been significant false positives. A more important role for PET-FDG (presently under investigation) is for evaluation of metastatic disease and to detect recurrence or progression and response to systemic therapies. In one study, 10 of 10 patients were proven to have active progressive disease whereas only 7 of these 10 cases were positive with conventional imaging. In 5 patients with no evidence of disease or complete remission, PET-FDG studies were negative in all whereas conventional imaging was positive in three cases.165 In another study, PETFDG has been used to establish a response to cancer immunotherapy with interleukin (IL)-2. The lack of PET activity at prior active sites suggests fibrosis or necrosis and lack of activity within a previous active renal mass or lymph node suggests lack of viable cells and necrosis.166 In another recent study of the clinical role of PET-FDG, the detection and management of RCC, PET-FDG accurately detected local disease spread and metastatic disease in patients with RCC and altered treatment plans in 40%.116 Finally, in a study comparing PET-FDG to routine bone scan, PET-FDG sensitivity and accuracy were 100% and 100%, respectively, compared to bone scans that were 77.5% and 59.6%, respectively.167 Clearly, more data and experience are needed before PET-FDG is recommended for routine use in RCC. However, this technology with fusion imaging combining CT with PET, more accurate preoperative staging, and better patient care is on the horizon. Monitoring for Recurrence or Progression of Disease Follow-up algorithms for RCC remain controversial as there remains no systemic treatment regiment with highly satisfactory response rates that would significantly improve survival in an asymptomatic patient. Exceptions to this would be isolated renal fossa recurrences that are rare and solitary delayed metastases (also rare).168 Levy et al.169 from M.D. Anderson Cancer Center retrospectively reviewed the records of 286 patients with pathologic stage T1–T3 RCC of which 68 relapsed. For pT1 disease only, an annual chest x-ray and liver function tests were recommended. For pT2 and pT3 tumors, it was recommended to obtain chest radiographs every 6 months for 3 years, then annually, and perform surveillance abdominal CT scans at 24 and 60 months unless the patient becomes symptomatic. It was recommended that bone and brain surveillance studies only be performed for site-specific symptoms, elevated alkaline phosphatase, or the development of metastases at other sites.169 The use
Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 189
of periodic CT and/or ultrasound for patients with postpartial nephrectomy, however, is warranted.170 Evaluation of these patients can prove challenging as frequently there is a wedge-shaped or concave defect often filled with fat placed to help with hemostasis and decrease urinary extravasation. Hypodense areas of old hemorrhage may be present as well as perfusion defects secondary to devascularized surrounding tissue. For patients with renal insufficiency or contrast allergy, MRI is useful. “How often to obtain imaging” is controversial. However, every 6–12 months is acceptable. Similarly, it has been recommended that CT scans be done every 3–6 months postoperatively on patients having had “bench surgery” and autotransplant for RCC.171 Periodic relapse monitoring is also important in following patients with small indeterminate lesions on CT or ultrasound and on patients who have increased comorbidities where intervention would only be undertaken if substantial growth is documented. Birnbaum et al.172 studied a group of patients longitudinally looking at yearly growth rates on CT. They found the growth rate to be between 0 and 1.6 cm in diameter in a year with a mean growth rate of 0.5 cm. It, therefore, seems reasonable to obtain imaging every 6 months for 1 year and if there is no change, settle for yearly follow-up. Percutaneous Needle Aspiration Cytology and Biopsy for the Diagnosis of Renal Cell Carcinoma Percutaneous renal tumor sampling continues to be frowned on except for specific indications as outlined in Table 10-6. Although the risk of seeding normal tissue in the needle tract is small, it is likely that the true incidence is undeteresteimated.173 If seeding occurs, potentially curable organ-confined renal cancer is compromised. In general, a CT or ultrasound guided aspiration or biopsy is quick and safe, but may be associated with bleeding or arteriovenous fistula formation. Furthermore, there are significant equivocal or false negative results due to sampling error and the inability to conclusively differentiate oncocytomas from low-grade RCCs. Table 10-6 Indications for Percutaneous Biopsy or Aspiration of Renal Mass ●
When a lesion present in a patient with lymphoma persists after systemic response to therapy
●
Distinguish between primary neoplasia and metastatic disease
●
Differentiate between an infected cyst or abscess and neoplasm
●
Obtain tissue diagnosis in a patient who is not an operative candidate
REFERENCES 1. Jenal J, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 2003; 53:27–43. 2. Chow WH, Devesa SS, Warren JL, Fraumeni JF Jr: Kidney cancer incidence trends in the United States. JAMA 1999; 281:1628–1631. 3. Sufrin G, Chasan S, Golio A, et al: Paraneoplastic and serologic syndromes of renal adenocarcinoma. Semin Urol 1989; 7:158–171. 4. Gold PJ, Fefer A, Thompson JA: Paraneoplastic manifestations of renal cell carcinoma. Semin Urol Oncol 1996; 14:216–222. 5. Chow W, Devesa SS, Fraumeni JF Jr: Epidemiology of renal cell carcinoma. In Vogelzang NJ, Scardino PT, Shipley WU, Coffey DS (eds): Comprehensive Textbook of Genitourinary Oncology, 2nd edition, pp 101–110. Philadelphia, Lippincott Williams & Wilkins, 2000. 6. Parkin DM, Whelan SL, Ferlay J, et al: Cancer Incidence in Five Continents, vol VII [IARC Sci. Pub. No. 143]. Lyon, France, International Agency for Research on Cancer, 1997. 7. Jin F, Devesa SS, Zheng W, et al: Cancer incidence trends in urban Shanghai, 1972–1989. Int J Cancer 1993; 53:764–770. 8. McCredie M: Bladder and kidney cancers. In Doll R, Fraumeni JF Jr, Muir CS (eds) Cancer Surveys: Rends in Cancer Incidence and Mortality, pp 343–363. New York, Cold Spring Harbor Laboratory Press, 1994. 9. Liu S, Semenciw R, Morrison H, et al: Kidney cancer in Canada: the rapidly increasing incidence of adenocarcinoma in adults and seniors. Can J Public Health 1997; 8:99–104. 10. Hock LM, Lynch J, Balaji KC: Increasing incidence of all stages of kidney cancer in the last 2 decades in the United States: an analysis of surveillance, epidemiology and end results program data. J Urol 2002; 167:57–60. 11. Kumar A, Mittal S, Buckshee K, et al: Reproductive functions in obese women. Prog Food Nutr Sci 1993; 17:89–98. 12. Attia N, Tamborlane WV, Heptulla R, et al: The metabolic syndrome and insulin-like growth factor I regulation in adolescent obesity. J Clin Endocrinol Metab 1998; 83:1467–1471. 13. Narayan S, Roy D: Insulin-like growth factor I receptors are increased in estrogen-induced kidney tumors. Cancer Res 1993; 53:2256–2259. 14. Ishikawa I: Development of adenocarcinoma and acquired cystic disease of the kidney in hemodialysis patients. Princess Takamatsu Symp 1987; 18:77–86. 15. Chandhoke PS, Torrence RJ, Clayman RV, et al: Acquired cystic disease of the kidney: a management dilemma. J Urol 1992; 147:969–974. 16. Novick AC, Campbell SC: Renal tumors. In Walsh PC, Retik AB, Vaughan ED Jr, Wein AJ (eds) Campbell’s Urology, 8th edition, pp 2672–2731. Philadelphia, Saunders, 2002. 17. Ishikawa I, Saito Y, Onouchi Z, et al: A ten-year prospective study on the development of renal cell
190
18.
19. 20.
21.
22.
23.
24.
25.
26.
27.
28. 29.
30.
31.
32. 33.
34.
Part III Kidney and Ureter carcinoma in dialysis patients. Am J Kidney Dis 1990; 16:452–458. Matson MA, Cohen EP: Acquired cystic kidney disease: occurrence, prevalence, and renal cancers. Medicine 1990; 69:217–226. Ishikawa I: Uremic acquired renal cystic disease. Nephron 1991; 58:257–261. Levine E, Slusher SL, Grantham JJ, et al: Natural history of acquired renal cystic disease in dialysis patients. Am J Roentgenol 1991; 156:501–506. Levine E: Renal cell carcinoma in uremic acquired renal cystic disease: incidence, detection, and management. Urologic Radiol 1992; 13:203–210. Jayson M, Sanders H: Increased of serendipitously discovered renal cell carcinoma. Urology 1994; 51:203–205. Hanash KA: The nonmetastatic hepatic dysfunction syndrome associated with renal cell carcinoma (hypernephroma): Stauffer’s syndrome. Prog Clin Biol Res 1982; 100:310–316. Blay JY, Rossi JF, Eijdenes J, et al: Role of interleukin-6 in the paraneoplastic inflammatory syndrome associated with renal cell carcinoma. Int J Cancer 1997; 72:424–430. Gotoh A, Kitazawa S, Mizuno Y, et al: Common expression of parathyroid hormone-related protein and no correlation of calcium levels in renal cell carcinoma. Cancer 1993; 71:2803–2806. McDougal WS, Garnick MB: Clinical signs and symptoms of renal cell carcinoma. In Vogelzang NJ, Scardino PT, Shipley WU, Coffey DS (eds): Comprehensive Textbook of Genitourinary Oncology, 2nd edition, pp 111–115. Philadelphia, Lippincott Williams & Wilkins, 2000. Esen A, Ozen H, Ayhan A, et al: Serum ferritin: a tumor marker for renal cell carcinoma. J Urol 1991; 145:1134–1137. Sufrin G, Mirand EA, Moore RH: Hormones in renal cancer. J Urol 1977; 117:433–438. Northway RO, Ritenour CWM, Marshall FF: Renal cell carcinoma: an overview. AUA Update Ser 2001; 20:194–199. Symbas NP, Townsend MF, El-Galley R, et al: Poor prognosis associated with thrombocytosis in patients with renal cell carcinoma. BJU Int 2000; 86:203–207. O’Keefe SC, Marshall FF, Issa MM, et al: Thrombocytosis is associated with a significant increase in the cancer specific death rate after radical nephrectomy. J Urol 2002; 168:1378–1380. Yu C, Chen K, Chen M, et al: Serum iron as a tumor marker in renal cell carcinoma. Eur Urol 1991; 19:58–58. Yasunaga Y, Shin M, Miki T, et al: Prognostic factors of renal cell carcinoma: a multivariate analysis. J Surg Oncol 1998; 68:11–18. Delahunt B, Bethwaite PB, Nacey JN, et al: Proliferating cell nuclear antigen (PCNA) expression as a prognostic indicator for renal cell carcinoma: comparison with tumour grade, mitotic index, and silver-staining nucleolar organizer region numbers. J Pathol 1993; 170:471–477.
35. Méjean M, Oudard S, Thiounn N: Prognostic factors of renal cell carcinoma. J Urol 2003; 169:821–827. 36. Tannapfel A, Hahn HA, Katalinic A, et al: Prognostic value of ploidy and proliferation markers in renal cell carcinoma. Cancer 1996; 77:164–171. 37. Hofmockel G, Tsatalpas P, Muller H, et al: Significance of conventional and new prognostic factors for locally confined renal cell carcinoma. Cancer 1995; 76: 296–306. 38. Cronin KJ, Williams NN, Kerin MJ, et al: Proliferating cell nuclear antigen: a new prognostic indicator in renal cell carcinoma. J Urol 1994; 152:834–836. 39. Rini BI, Vogelzang NJ: Prognostic factors in renal carcinoma. Semin Oncol 2000; 27:213–220. 40. Haitel A, Weiner H, Migschitz B, et al: Proliferating cell nuclear antigen and MIB-I. An alternative to classic prognostic indicators in renal cell carcinomas? Am J Clin Pathol 1997; 107:229–235. 41. Katagiri A, Wantanabe R, Tomita Y: E-cadherin expression in renal cell cancer and its significance in metastasis and survival. Br J Urol 1995; 71:376–379. 42. Shimazui T, Giroldi L, Bringuier P, et al: Complex cadherin expression in renal cell carcinoma. Can Res 1996; 56:3234–3237. 43. Shimazui T, Oosterwijk E, Akaza H, et al: Expression of cadherin-6 as a novel diagnostic tool to predict prognosis of patients with E-cadherin-absent renal cell carcinoma. Clin Can Res 1998; 4:2419–2424. 44. Paul RF, Ewing C, Robinson J, et al: Cadherin 6, a cell adhesion molecule specifically expressed in the proximal tubule and renal cell carcinoma. Can Res 1997; 57:2741–2748. 45. MacLennan G, Bostwick D: Microvessel density in renal cell carcinoma: lack of prognostic significance. Urol 1995; 46:27–30. 46. Kuerbitz S, Plunkett B, Walsh W, et al: Wild-type p53 is a cell cycle checkpoint determinant following irradiation. Proc Natl Acad Sci U S A 1992; 89:7491–7495. 47. Hollstein M, Sidransky D, Vogelstein B, et al: p53 mutations in human cancers. Science 1991; 253:49–53. 48. Lane D, Benchimol S: p53 oncogene of anti-oncogene? Genes Dev 1990; 4:1–8. 49. Uhlman D, Nguyen P, Manivel C, et al: Association of immunohistochemical staining for p53 with metastatic progression and poor survival in patients with renal cell carcinoma. J Natl Can Inst 1994; 86:1470–1474. 50. Shina H, Igawa M, Urakami S, et al: Clinical significance of immunohistochemically detectable p53 protein in renal cell carcinoma. Eur Urol 1997; 31:73–80. 51. Bui MHT, Seligson D, Han K, et al: Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res 2003; 9:802–811. 52. Pastorek J, Pastorekova S, Callebaut I, et al: Cloning and characterization MN, a human tumor-associated protein with a domain homologous to carbonic anhydrase and a putative helix-loop-helix DNA binding segment. Oncogene 1994; 9:2877–2888.
Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 191 53. Wykoff CC, Pugh CW, Maxwell PH, Harris AL, Ratcliffe PJ: Identification of novel hypoxia dependent and independent target genes of the von Hippel–Lindau (VHL) tumour suppressor by mRNA differential expression profiling. Oncogene 2000; 19:6297–6305. 54. Ivanov S, Liao SY, Ivanova A, et al: Expression of hypoxia-inducible cell-surface transmembrane carbonic anhydrases in human cancer. Am J Pathol 2001; 158:905–919. 55. Ivanov SV, Kumin I, Wei MH, et al: Down-regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild-type von Hippel–Lindau transgenes. Proc Natl Acad Sci U S A 1998; 95:12596–12601. 56. Wykoff CC, Beasley NJ, Watson PH, et al: Hypoxiainducible expression of tumor-associated carbonic anhydrases. Cancer Res 2000; 60:7075–7083. 57. Shi Q, Abbruzzese JL, Huang S, et al: Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin Cancer Res 1999; 5:3711–3721. 58. Giatromanolaki A, Koukourakis MI, Sivridis E, et al: Expression of hypoxia-inducible carbonic anhydrase-9 relates to angiogenic pathways and independently to poor outcome in non-small cell lung cancer. Cancer Res 2001; 6l:7992–7998. 59. Parkkila S, Rajaniemi H, Parkkila AK, et al: Carbonic anhydrase inhibitor suppresses invasion of renal cancer cells in vitro. Proc Natl Acad Sci U S A 2000; 97:2220–2224. 60. Kovacs G, Erlandsson R, Boldog F, et al: Consistent chromosome 3p deletion and loss of heterozygosity in renal cell carcinoma. Proc Natl Acad Sci U S A 1988; 85:1571–1575. 61. Kovacs G, Frisch S: Clonal chromosome abnormalities in tumor cells from patients with sporadic renal cell carcinomas. Cancer Res 1989; 49:651–659. 62. Seizinger BR, Rouleau GA, Ozeius LJ, et al: von Hippel–Lindau disease maps to the region of chromosome 3 associated with renal cell carcinoma. Nature 1988; 332:268–269. 63. Gnarra JR, Tory K, Weng Y, et al: Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet 1994; 7:85–90. 64. Herman JG, Latif F, Weng Y, et al: Silencing of the VHL tumor-suppressor gene by DNA methylation in renal carcinoma. Proc Natl Acad Sci U S A 1994; 91:9700–9704. 65. Linehan WM, Lerman MI, Zbar B: Identification of the von Hippel–Lindau (VHL) gene: its role in renal cancer. JAMA 1995; 273:564–570. 66. Zbar B, Brauch H, Talmadge C, et al: Loss of alleles of loci on the short arm of chromosome 3 in renal cell carcinoma. Nature 1987; 327:721–724. 67. Zbar B: von Hippel–Lindau disease and sporadic renal cell carcinoma. Cancer Surv 1995; 25:219–232. 68. Walther MM, Enquist EG, Jennings SB, et al: Molecular genetics of renal cell carcinoma. In Vogelzang NJ, Scardino PT, Shipley WU, Coffey DS (eds): Comprehensive Textbook of Genitourinary Oncology,
69.
70.
71. 72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84. 85.
2nd edition, pp 116–128. Philadelphia, Lippincott Williams & Wilkins, 2000. Maxwell PH, Wiesener MS, Chang GW, et al: The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999; 399:271–275. Iliopoulos O, Levy AP, Jiang C, et al: Negative regulation of hypoxia-inducible genes by the von Hippel–Lindau protein. Proc Natl Acad Sci U S A 1996; 93: 10595–10599. Zbar B, Tory K, Merino M, et al: Hereditary papillary renal cell carcinoma. J Urol 1994; 151:561–566. Zbar B, Glenn G, Lubensky I, et al: Hereditary papillary renal cell carcinoma. Clinical studies in 10 families. J Urol 1995; 153:907–912. Schmidt L, Duh FM, Kishida T, et al: Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet 1997; 16:68–73. Zhuang Z, Park WS, Pack S, et al: Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nat Genet 1998; 20:66–69. Schmidt LS, Warren MB, Nickerson ML, et al: Birt–Hogg–Dube syndrome, a genodermatosis associated with spontaneous pneumothorax and kidney neoplasia, maps to chromosome 17p11.2. Am J Hum Genet 2001; 69:876–882. Herring JC, Enquist EG, Chernoff A, et al: Parenchymal sparing surgery in patients with hereditary renal cell carcinoma: 10-year experience. J Urol 2001; 165:777–781. Roth JS, Rabinowitz AD, Benson M, et al: Bilateral renal cell carcinoma in the Birt–Hogg–Dube syndrome. J Am Acad Dermatol 1993; 20:1055–1058. Pavlovich CP, Walther MM, Eyler RA, et al: Renal tumors in the Birt–Hogg–Dube syndrome. Am J Surg Pathol 2002; 26:1542–1552. Crotty TB, Lawrence KM, Moertel CA, et al: Cytogenetic analysis os six renal oncocytomas and a chromophobe cell renal carcinoma. Evidence that −Y, −1 may be a characteristic anomaly in renal oncocytomas. Cancer Genet Cytogenes 1992; 61:61–66. Fuzesi L, Gunawan B, Braun S, et al: Renal oncocytoma with a translocation t(9;11)(p23;q13). J Urol 1994; 152:471–472. Neuhaus C, Dijkhuizen T, van den Berg E, et al: Involvement of the chromosomal region 11q13 in renal oncocytoma: case report and literature review. Cancer Genet Cytogenes 1997; 94: 95–98. Walter TA, Pennington RD, Decker HJ, et al: Translocation t(9;11)(p23;q12): a primary chromosomal change in renal oncocytoma. J Urol 1989; 142:117–119. Weirich G, Glenn G, Junker K, et al: Familial renal oncocytoma: clinicopathological study of 5 families. J Urol 1998; 160: 335–340. Choyke PL, Glenn GM, Walther MM, et al: Hereditary renal cancers. Radiology 2003; 226:33–46. Störkel S, Ebie JN, Adlakha K, et al: Classification of renal cell carcinoma: workgroup no. 1, Union
192
86. 87. 88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
Part III Kidney and Ureter Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 1997; 80:987–989. Weiss LM, Gelb AB: Adult renal epithelial neoplasms. Am J Clin Pathol 1995; 103:624–634. Oyasu R: Renal cancer: histologic classification update. Int J Clin Oncol 1998; 3:125–133. Foster K, Crossey P, Cairns P, et al: Molecular genetic investigation of sporadic renal cell carcinoma: analysis of allele loss on chromosomes 3p, 5q, 11p, 17 and 22. Br J Cancer 1994; 69:230–234. Ritenour CWM, Northway RO, Marshall FF: Renal tumors. In Gillenwater JY, Grayhack JT, Howards SS, Mitchell ME (eds): Adult and Pediatric Urology, 4th edition, pp 611–639. Philadelphia, Lippincott Williams & Wilkins, 2002. Crotty T, Farrow G, Lieber M: Chromophobe cell renal carcinoma: clinicopathological features of 50 cases. J Urol 1995; 154: 964–967. Campbell SC, Russo P, Hamed G, et al: Chromophobe cell carcinoma of the kidney: a clinicopathologic study. Proc Am Urol Assoc 1996b; 155:299. Renshaw AA, Henske EP, Loughlin KR, et al: Aggressive variants of chromophobe renal cell carcinoma. Cancer 1996; 78:1756–1761. Polascik TJ, Cairns P, Epstein JI: Distal nephron renal tumors: microsatellite allelotype. Cancer Res 1996; 56:1892–1895. Steiner M, Goldman S, Fishman E, et al: The natural history of renal angiomyolipoma. J Urol 1993; 150:1782–1786. Davis C Jr, Mostofi F, Sesterhenn I: Renal medullary carcinoma. The seventh sickle cell nephropathy. Am J Surg Pathol 1995; 19:1–11. Homma Y, Kawabe K, Kitamura T, et al: Increased incidental detection and reduced mortality in renal cancer – recent retrospective analysis at eight institutions. Int J Urol 1995; 2:77–80. Warshauer DM, McCarthy SM, Street L, et al: Detection of renal masses: sensitivities and specificities of excretory urography/linear tomography, US and CT. Radiology 1988; 169:363–365. Daniel WW, Hartman GW, Witten DM, et al: Calcified renal masses: a review of ten years’ experience at the Mayo Clinic. Radiology 1972; 103:503. Einstein DM, Herts BR, Weaver R, et al: Evaluation of renal masses detected by excretory urography: costeffectiveness of sonography versus CT. Am J Roentgenol 1995; 164:371–375. Spouge AR, Wilson SR, Wooley B: Abdominal sonography in asymptomatic executives: prevalence of pathologic findings, potential benefits, and problems. J Ultrasound Med 1996; 15:763. Jamis-Dow CA, Choyke PL, Jennings SB, et al: Small (≤3-cm) renal masses: detection with CT versus US and pathologic correlation. Radiology 1996; 198: 785–788. Forman HP, Middleton WD, MElson GL, et al: Increasing frequency of detection of hyperechoic renal cell carcinomas. Radiology 1993; 188:431.
103 Yamashita Y, Ueno S, Makita O, et al: Hyperechoic renal tumors: anechoic rim and intratumoral cysts in US differentiation of renal cell carcinoma from angiomyolipoma. Radiology 1993; 188:179–182. 104. Siegel CL, Middleton WD, Teefey SA, et al: Angiomyolipoma and renal cell carcinoma: US differentiation. Radiology 1996; 198:789. 105. Kuijper D, Kruyt RH, Oudkerk M: Renal masses: value of duplex Doppler ultrasound in the differential diagnosis. J Urol 1994; 151:326. 106. Foster WL, Roberts L, Halvorsen RA, et al: Sonography of small renal masses with indeterminate density characteristics on computed tomography. Urol Radiol 1988; 10:59. 107. Davidson AJ, Hartman DS, Choyke PL, Wagner BJ. Radiologic assessment of renal masses: implications for patient care. Radiology 1997; 202:297–305. 108. Szolar DH, Kammerhuber F, Altziebler S, et al: Multiphasic helical CT of the kidney: increased conspicuity for detection and characterization of small (<3 cm) renal masses. Radiology 1997; 202:211–217. 109. Kopka L, Fischer U, Zoeller G, et al: Dual-phase helical CT of the kidney: value of the corticomedullary and nephrographic phase for evaluation of renal lesions and preoperative staging of renal cell carcinoma. Am J Roentgenol 1997; 169:1573–1578. 110. Macari M, Bosniak MA. Delayed CT to evaluate renal masses incidentally discovered at contrast-enhanced CT: demonstration of vascularity with de-enhancement. Radiology 1999; 213:674–680. 111. Gash J, Zagoria RJ, Dyer RB, Assimos DG: Imaging features of infiltrating renal lesions. Crit Rev Diagn Imaging 1992; 33:293–310. 112. Pickhardt PF, Lonergan GF, Davis CF Jr, Kashitani N, Wagner BF. Infiltrative renal lesions: radiologicpathologic correlation. Radiographics 2000; 20:215–243. 113. Zagoria RJ. Imaging of small renal masses. Am J Roentgenol 2000; 175:945–955. 114. DeAngelo P, Gash, JR, Horn AW, et al: Fat in renal cell carcinoma that lacks associated calcification. Am J Roentgenol 2002; 178:931. 115. Davidson AJ, Hartman DS, Choyke PL, Wagner BJ: Radiologic assessment of renal masses: implications for patient care. Radiology 1997; 202:297–305. 116. Dechet CB, Sebo T, Farrow G, et al: Prospective analysis of intraoperative frozen needle biopsy of solid renal masses in adults. J Urol 1999; 162:1282–1285. 117. Sheth S, Scatarige JC, Horton KM, et al: Current concepts in the diagnosis and management of renal cell carcinoma: role of multidetector CT and threedimensional CT. Radiographics 2001; 21:S237. 118. Kim JK, Kim TK, Ahn HJ, et al: Differentiation of subtypes of renal cell carcinoma on helical CT scan. Am J Roentgenol 2002; 178:1499. 119. Bosniak MA. The current radiological approach to renal cysts. Radiology 1986; 158:1–10. 120. Kausik S, Segura JW, King BF Jr: Classification and management of simple and complex renal cysts. AUA Update Ser 2002; 21:82–87.
Chapter 10 Diagnosis and Staging of Renal Cell Carcinoma 193 121. Wilson TE, Doelle EA, Cohan RH, Wojno K, Korobkin M: Cystic renal masses: a reevaluation of the usefulness of the Bosniak classification system. Acad Radiol 1996; 3:564–570. 122. Lang EK, Macchia RJ, Gayle B, et al: CT-guided biopsy of indeterminate renal cystic masses (Bosniak 3 and 2F): accuracy and impact on clinical management. Eur Radiol 2002; 12:2518–2524. 123. Rofsky NM, Bosniak MA: MR imaging in the evaluation of renal masses. MRI Clin North Am 1997; 5:67–81. 124. Ho VB, Allen SF, Hood MN, et al: Renal masses: quantitative assessment of enhancement with dynamic MR imaging. Radiology 2002; 224:695–700. 125. Goldberg MA, Mayo-Smith WW, Papanicolaou N, et al: FDG PET characterization of renal masses: preliminary experience. Clin Radiol 1997; 52(7):510–515. 126. Ramdave S, Thomas GW, Berlangieri SU, et al: Clinical role of F-18 fluorodeoxyglucose positron emission tomography for detection and management of renal cell carcinoma. J Urol 2001; 166:825–830. 127. Holland JM: Cancer of the kidney: natural history and staging. Cancer 1973; 32:1030. 128. Hermanek P, Schrott KM: Evaluation of the new tumor, nodes, and metastases classification of renal cell carcinoma. J Urol 1990; 144:238–242. 129. Thompson IM Jr, Andriole GL, Blumenstein B, et al: Kidney. In Greene FL, Page DL, Fleming ID, et al (eds): AJCC Cancer Staging Manual, 6th edition, pp 323–328. New York, Springer, 2002. 130. Guinan PD, Vogelzant NJ, Frengen AM, et al: Renal cell carcinoma: tumor size, stage and survival. J Urol 1995; 153:901–903. 131. Lerner SE, Hawkins CA, Blute ML, et al: Disease outcome in patients with low stage renal cell carcinoma treated with nephron sparing or dial surgery. J Urol 1996; 155:1868–1873. 132. Hafez KS, Fergary AF, Nocick AC: Nephron sparing surgery for localized renal cell carcinoma: impact of tumor size on patient survival, tumor recurrence and TNM staging. J Urol 1999; 162(6):1930–1933. 133. Lee CT, Katz J, Shi W, et al: Surgical management of renal tumors 4 cm or less in a contemporary cohort. J Urol 2000; 163:730–736. 134. Sagalowsky AK, Kadesky KT, Ewatt DM et al: Factors influencing adrenal metastasis in renal cell carcinoma. J Urol 1994; 151:1181–1184. 135. Sardock DS, Settel AP, Resnick MI: A new protocol for follow-up of renal cell carcinoma based on pathological stage. J Urol 1995; 154:28. 136. Hatcher PA, Anderson EE, Paulson DF, et al: Surgical management and prognosis of renal cell carcinoma invading the vena cava. J Urol 1991; 145:20–24. 137. Gelb AB: Renal cell carcinoma. Current prognostic factors. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 1997; 80:981–986. 138. Srigley JR, Hutter RV, Gelb AB, et al: Current prognostic factors – renal cell carcinoma: work group no. 4, Union Internationale Contre le Cancer (UICC)
139.
140.
141.
142.
143.
144. 145.
146.
147.
148.
149. 150.
151.
152.
153. 154.
155.
and the American Joint Committee on Cancer (AJCC). Cancer 1997; 80:994–996. Koga S, Tsuda S, Nishikid M, et al: The diagnostic value of bone scan in patients with renal cell carcinoma. J Urol 2001; 166(6):2126–2128. Zisman A, Pantuck AJ, Dorey F, et al: Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol 2001; 19:1649–1657. Homma Y, Kawabe K, Kitamura T, et al: Increased incidental detection and reduced mortality in renal cancer – recent retrospective analysis at eight institutions. Int J Urol 1995; 2:77–80. Johnson CD, Donnick NR, Cohan RH, et al: Renal adenocarcinoma: CT staging of 100 tumors. Am J Roentgenol 1987; 148(1):59–63. Bectol RE, Zagorie RJ: Imaging approach to staging of renal cell carcinoma. Urol Clin North Am 1997; 24:507–522. Choyke PL: Detection and staging of renal cancer. Magn Reson Imaging Clin North Am 1997; 5:29–47. Studer WE, Scherz S, Scheidegger J, et al: Enlargement of regional lymph nodes in renal cell carcinoma is often not due to metastases. J Urol 1990; 144(2/1): 243–245. Fein AB, Lee JKT, Balte DM, et al: Diagnosis and staging of renal cell carcinoma: a comparison of MR imaging and CT. Am J Roentgenol 1987; 148(4):749–753. Angervall L, Wahlquist L: Follow-up and prognosis of renal carcinoma in a series operated by perifascial nephrectomy combine with adrenalectomy and retroperitoneal lymphadenectomy. Eur Urol 1978; 4(1):13–17. Saitoh H, Nakayama M, Nakamurak K, et al: Distant metastasis of renal adenocarcinoma in nephrectomized cases. J Urol 1982; 127(6):1092–1095. Russo P: Renal cell carcinoma: presentation, staging, and surgical treatment. Semin Oncol 2000; 27:160–176. Gill IS, McClennan BH, Kenbl K, et al: Adrenal involvement from renal cell carcinoma: predictive valve of computerized tomography. J Urol 1994; 152:1082–1085. Horan JJ, Robertson CN, Choyke PL, et al: The detection of renal carcinoma extension into the renal vein and interior vena cava: a prospective comparison of venacavography and magnetic resonance imaging. J Urol 1989; 142(4):943–948. Ney C: Thrombosis of the interior vena cava associated with malignant tumors. J Urol 1946; 55(6):583–590. Arkless R: Renal carcinoma: how it metastasizes. Radiology 1965; 84(3):496–501. Berg A: Malignant hypernephroma of the kidney, its clinical course and diagnosis, with a description of the author’s method of radial operative cure. Surg Gynecol Obstet 1913; 17(4):463–471. Hietala S, Ekelund L, JungGerg B: Venous invasion in renal cell carcinoma: a correlate clinical and radiologic study. Urol Radiol 1998; 9(4):210–216.
194
Part III Kidney and Ureter
156. de Schepper A: “Nutcracker” phenomenon of the renal vein and venous pathology of the left kidney. J Belge Radiol 1972; 55(5):508–511. 157. When M, O’Toole K, Bixon R, et al: The incidence of multifocal renal cell carcinoma in patients who are candidates for partial nephrectomy. Urology 1995; 154:968. 158. Kletscher BA, Qian J, Bostwick PG, et al: Prospective analysis of multifocality in renal cell carcinoma: influence of histological pattern, grade, number, size, volume and DNA ploidy. J Urol 1995; 153:904. 159. Henriksson C, Geterwd K, Aldergorg F, et al: Bilateral asynchronous renal cell carcinoma: computed tomography at the contralateral kidney 10–43 years after nephrectomy. Eur Urol 1992; 22:209. 160. Zagoria RJ, Bechtold RE, Dyer RB: Staging of renal adenocarcinoma: role of various imaging procedures. Am J Roentgenol 1995; 184:363–370. 161. Fielding JR, Aliabadi N, Renshaw A, et al: Staging of 119 patients with renal cell carcinoma: the yield and cost-effectiveness of pelvic CT. Am J Roentgenol 1999; 172(1):23–25. 162. Pretorius EJ, Wickstrom L, Siegelman S: MR imaging of renal neoplasms. MRI Clin North Am 2000; 4:813. 163. Glazer A, Novick AC: Preoperative transesophageal echocardiography for assessment of resonance imaging. Urology 1997; 49:32–34. 164. Itoh CK, Seltzer MA, Frank WJ, et al: Positron emission tomography in urologic oncology. J Urol 1998; 159:347–356. 165. Bachor R, Kotzerke J, Gottfried HW, et al: Positron emission tomography in diagnosis of renal cell carcinoma. Urologe A 1996; 35:146–150.
166. Markoff DA, Thompson JA, Gold P, et al: Identification of Interleukin-2-induced complete response in metastatic renal cell carcinoma by FDG-PET despite radiographic evidence suggesting persistent tumor. Am J Roentgenol 1997; 169:1049–1058 (abstract). 167. Wu HC, Yen RF, Shen YY: Comparing whole body 18F1-deoxyglucose positron emission tomography and technetium-99m methylene diphosphate bone scan to detect bone metastases in patients with renal cell carcinomas – a preliminary report. J Cancer Res Clin Oncol 2002; 128(9):503–506. 168. Esrig P, Ahlering TE, Lieskovsky G, et al: Experience with fossa recurrence of renal cell carcinoma. J Urol 1992; 147:1491–1494. 169. Levy PA, Slaton JW, Swanson PA, et al: Stage specific guidelines for surveillance after radical nephrectomy for local renal cell carcinoma. J Urol 1998; 159(4):1163–2267. 170. Kovick AC: Renal-sparing surgery for renal cell carcinoma. Urol Clin North Am 1993; 10:277–282. 171. Stormant TJ, Bilhartz DL, Zincke H: Pitfalls of berch surgery and auto-transplantation for renal cell carcinoma. Mayo Clinic Proc 1992; 62:621–628. 172. Birnbaum BA, Bosniak MA, Megibow AJ, et al: Observations on the growth of renal neoplasms. Radiology 1990; 176:695–701. 173. Sheroy PP, Lakhkar BN, Ghosh MK, et al: Cutaneous seeding of renal oncocytoma by Chiba needle aspiration biopsy. Case Report. Acta Radiol 1991; 32(1):50–52.
C H A P T E R
11 Renal Cell Carcinoma: Localized Disease Kenneth Ogan, MD, and Fray F. Marshall, MD
Renal cell carcinoma (RCC) is a unique neoplasm because currently there is no effective systemic therapy once it has progressed beyond the kidney. Therefore, even more so than in other malignancies, prompt and effective treatment of localized RCC is of paramount importance. Over the past several decades, in part due to the diagnosis of smaller tumors with improved imaging modalities, there has been a paradigm shift in the treatment of localized renal tumors. First described by Robson et al.1 in 1968, open radical nephrectomy (ORN), including removal of the ipsilateral adrenal gland and an extended regional lymphadenectomy, became the standard of care for surgical extirpation of renal tumors for the following several decades. In the 1980s, Hohenfellner, Novick and others initiated nephron-sparing surgery (NSS), removing the renal tumor with a margin of normal parenchyma and sparing the remaining normal parenchyma.2,3 While originally reserved for patients that would be rendered functionally anephric with radical nephrectomy, nephron-sparing surgical procedures have been extended to the majority of patients with small cortical renal tumors (<4 cm), even in patients with a normal contralateral kidney. Over the past decade, the introduction of laparoscopic radical nephrectomy (LRN)4 and laparoscopic partial nephrectomy (LPN)5 has provided a minimally invasive treatment modality to the urologist’s surgical armamentarium for the treatment of localized renal tumors. Finally, in an effort to even further reduce the morbidities of open and laparoscopic procedures, energybased ablative techniques have been developed in which small renal tumors are destroyed and left in situ.6,7 EPIDEMIOLOGY AND CLINICAL PRESENTATION Malignant tumors of the kidney account for greater than 2% of cancer incidence and mortality. According to the
American Cancer Society (ACS), based on the rates from the National Cancer Institute’s (NCI) surveillance, Epidemiology and End Results (SEER) program, the estimated number of new cases and deaths from kidney cancer in the United States for 2004 was 12,480. Chow et al.8 have reported a rapidly increasing incidence of RCC between 1975 and 1995 in the United States. While the greatest increase was seen for localized tumors, the incidence also increased for advanced tumors. Thus, it is unlikely that this increased incidence is solely due to an increased detection rate, but it more likely represents a true increased incidence of RCC. The incidence rate in males is approximately twice that of females, with the peak age of diagnosis in the seventh and eighth decades of life. While Caucasians are affected more commonly than African Americans, the incidence and mortality rates are increasing at a greater pace in the African-American population.8 In the past, presentation with the classic triad of flank pain, abdominal mass, and hematuria was rarely associated with localized disease. Due to the protected location of the kidney within the retroperitoneum, the majority of symptomatic tumors present at an advanced stage. Fortunately, in the current day of routine ultrasonography (US), computed tomography (CT) imaging, and magnetic resonance imaging (MRI), this presentation is rare, and in fact, the majority of tumors are discovered incidentally.9 Incidental tumors have also been shown to be of a lower-stage than their symptomatic counterparts.10,11 Thompson and Peek11 reported that 82% of incidental tumors were stage I or stage II, whereas only 32% of symptomatic tumors were at early stage. Consequently, following treatment these incidental tumors also demonstrated improved 10-year survival compared to the symptomatic tumors (90% versus 30%).
195
196
Part III Kidney and Ureter
Importantly, these smaller, lower-staged tumors are more amenable to nephron-sparing and minimally invasive procedures. CLASSIFICATION AND HISTOPATHOLOGY The majority of kidney tumors originating in the renal cortex are adenocarcinomas, commonly called RCCs. The first attempt to classify renal tumors was by Grawitz12 when he attributed the origin of renal tumors to an ectopic adrenal rest and, therefore, called them “hypernephroma.” Since that time numerous classification systems have been developed to characterize renal tumors. Currently, most people adhere to the classification system developed in 1997 by the World Health Organization (WHO) in combination with the Union Internationale Contre le Cancer (UICC) and the American Joint Committee of Cancer (AJCC) (Table 11-1),13 which separates adult renal tumors into either benign or malignant categories. Of the malignant primary tumors of the kidney cortex, conventional clear cell carcinoma accounts for 70% to 80% of renal neoplasms.13,14 Papillary RCC is the second most common carcinoma, accounting for 10% to15% of renal neoplasms.15,16 Compared to clear cell carcinoma, papillary RCC has been associated with a better prognosis. The overall 5-year survival rates for papillary compared to conventional clear cell RCC have ranged between 82% to 90% and 44% to 54%, respectively.16,17 Chromophobe RCC accounts for approximately 5% of renal neoplasms. As with papillary RCC, chromophobe has been found to be associated with a better 5-year Table 11-1 Classification of Renal Cell Carcinoma Malignant neoplasms Conventional (clear cell) carcinoma Papillary renal carcinoma Chromophobe renal carcinoma Collecting duct carcinoma RCC unclassified Benign neoplasms Oncocytoma Papillary adenoma Metanephric adenoma From Storkel S, Eble JN, Adlakha K, et al: Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 1997; 80:987–989, with permission.
cumulative survival compared to conventional clear cell RCC.18 Collecting duct carcinoma is a rare type of RCC, accounting for only 0.4% to 2.6% of renal neoplasms.14,19,20 These tumors are characterized by an aggressive course with a high incidence of locoregional spread and metastases.21 Similarly, Davis et al. were the first to describe renal medullary carcinoma, which appears to be a variant of collecting duct carcinoma. This type of RCC is unique because it is exclusively found in black patients with either sickle trait or sickle cell hemoglobin disease.22,23 As with its collecting duct counterpart, this is a very aggressive disease with a dismal mean survival of 3.5±2.4 months following diagnosis.23–25 Finally, sarcomatoid RCC is no longer considered as a distinct histopathologic category but rather an ominous subtype. In the largest series to date, Mian et al.26 from M.D. Anderson Cancer Center reported a dismal median overall survival of only 9 months in 108 patients classified with sarcomatoid RCC. Thus, it is apparent that the histologic type of RCC strongly affects prognosis and may act as a guide to the institution of adjuvant systemic therapies. Conversely, the future of classification or identification of renal tumors will most likely be based on molecular, rather than histopathologic findings.27 RISK FACTORS The increased incidence of RCC has been noted across all stages and cannot be explained solely by the increased detection of incidental tumors. RCC incidence rates increased steadily between 1975 and 1995, by 2.3% among white men, 3.1% among white women, 3.9% among black men, and 4.3% among black women.8,28 While the greatest increase was seen for localized tumors, there was also an increase in kidney cancer-specific mortality during this time period. Thus, this suggests that there is a true increased incidence of renal cancer rather than just an increased rate of detection. Despite numerous epidemiologic studies, the etiology of RCC remains largely unknown. There are definitive genetic, dietary, and environmental risk factors for the development of RCC. Hereditary RCC syndromes place family members at a tremendous increased risk of RCC and should likely prompt early screening. Table 11-2 lists the most common inherited syndromes and the affected chromosomes associated with increased risks of developing RCC.29 Also, acquired renal cystic disease secondary to chronic hemodialysis has been associated with an increased risk of RCC.30 Similarly, renal transplantation, with its necessary immunosuppression, has been demonstrated to confer up to a 80-fold increased risk of developing RCC.31 There are numerous studies that consistently implicate smoking,32 hypertension,33 asbestos exposure,34 petroleum exposure,35 and frequent analgesic use36 as
Chapter 11 Renal Cell Carcinoma: Localized Disease
197
Table 11-2 Inherited Syndromes with an Increased Risk of RCC Inherited Disease
Chromosome
Characteristics
von Hippel-Lindau
3p25-p26
Hemangioblastoma of CNS/retina, pheochromocytoma, RCC (clear cell type), renal cysts, pancreatic cysts, and cystadenomas
Hereditary papillary renal carcinoma
c-MET proto-oncogene 7q31
High incidence of bilateral papillary RCC
Tuberous sclerosis 1
TSC1 on 9q34
Facial angiofibromas, peringual fibromas, renal angiomyolipomas
Tuberous sclerosis 2
TSC2 on 16p13.3
Facial angiofibromas, peringual fibromas, renal angiomyolipomas
Birt-Hogg-Dube
17p12-q11.2
Fibrofolliculomas, different histologic renal tumors, and pulmonary cysts associated with increased risk of pneumothorax
Modified from Godley P, Kim SW: Curr Opin Oncol 2002; 14:280–285, with permission.
risk factors for the development of RCC. There is conflicting evidence on the risks of specific dietary substances on the increased risk of RCC. However, obesity and a high body mass index (BMI) have been consistently noted in several studies to connote an increased risk of RCC.37–39 DIAGNOSIS Localized RCC rarely causes symptoms or physical findings on examination. What used to be called as the “internist’s tumor” is now found more commonly by the radiologist during evaluation of other ailments. Radiologic imaging of the kidneys for a suspected renal tumor can be performed with ultrasonography (US), intravenous pyelography (IVP), CT, or MRI. Angiography, which was routinely performed in the past, is currently a rare component of the radiologic evaluation. However, angiography may be a useful adjunct in preoperative planning prior to a complex partial nephrectomy and during angioinfarction of large tumors. The advantages of ultrasound include low cost, low morbidity, lack of potentially nephrotoxic contrast agents, and the ability to differentiate solid from cystic masses. These characteristics make ultrasonography the imaging modality of choice for a potential screening program. IVP has been the traditional imaging study of the upper urinary tract used in the evaluation of hematuria. The main advantage of IVP is the ability to detect small urothelial tumors. However, due to similar costs, increased time to perform the study, and lack of detailed cortical imaging, this study is being replaced by CT.40 The main advantage of MRI is the ability to determine the cranial extent of tumor thrombus extension and the presence of contiguous organ involvement. Finally, positron emission tomography (PET) is an emerging technology with potential applications for staging and detection of tumor recurrences.
TUMOR BIOPSY While the majority of solid renal tumors represent RCC, there are certain situations in that the preoperative diagnosis is less certain. Review of large radical nephrectomy series reports benign lesions in up to 20% of cases. Thus, in an effort to avoid needless nephrectomies for benign tumors, the debate arises whether preoperative biopsy is warranted in a proportion of these patients. Percutaneous biopsies can be performed by fine needle aspiration (FNA) or with hollow-bore needles under radiologic guidance. The FNA is less traumatic but must be sent for cytologic versus pathologic analysis. Opponents of renal tumor biopsies note the risk of tumor spread due to needle tract seeding and the possibility of obtaining false negative biopsies. With newer biopsy needles, this occurrence is rare. Wood et al.41 retrospectively reviewed 79 biopsies in 73 patients with renal masses. All tumors initially underwent FNA (22 gauge) with immediate cytologic analysis, followed by core biopsy (17 to 20 gauge). Biopsy samples were adequate for diagnosis in 74 of 79 (94%) cases. Of 49 positive biopsies, 15 (31%) involved non-RCCs. Of the 79 biopsies, 5 (6%) were false negative and all correlated to samples with insufficient tissue for diagnosis. The ultimate diagnosis was made on repeat biopsy or at surgery. Biopsy results altered treatment in 32 (44%) patients who did not undergo surgery because of biopsy results. There were no major complications or tumor track seeding reported at a mean follow-up or 30.4 months. Finally, the efficacy and safety of FNA was comparable to that of core biopsy specimens. Lechevallier et al.42 reported on 63 consecutive patients that underwent 18-gauge core biopsies for suspicious renal masses. Biopsy material was insufficient for analysis, suspicious for RCC and diagnostic in 15 (19%), 2 (3%), and 56 (78%) of cases, respectively. Biopsy revealed a benign lesion in 8 (13%) patients and a nonsurgical malignant tumor in 21 (33%) of patients. Thus,
198
Part III Kidney and Ureter
in theory, 29 (46%) of patients could have avoided surgery because of biopsy results. Finally, for those patients who had a nephrectomy (26 patients) for malignant disease, the accuracy of biopsy for histopathologic and Fuhrman nuclear grade evaluations was 89% and 78%, respectively. Importantly, there were no complications necessitating intervention from the biopsies and no evidence of tumor seeding at a mean follow-up of 29 ± 11 months. Finally, Harisinghani et al.43 looked at the accuracy of percutaneous renal biopsy of Bosniak III renal cysts, which are diagnostic dilemmas for the surgeon and patient. In their series of 28 biopsied category III lesions, 17 (60.7%) were malignant (16 RCCs and 1 lymphoma) and 11 (39.3%) were benign (6 hemorrhagic cysts, 3 inflammatory cysts, 1 metanephric adenoma, and 1 cystic oncocytoma). Seventeen of the 28 lesions (16 RCCs and 1 inflammatory cyst) underwent surgical resection after the biopsy. All resected lesions had pathologic diagnoses identical to the percutaneous imaging-guided biopsy results. The remaining 11 patients, who did not have surgery, had radiologic follow-up for a minimum of 1 year, with benign lesions showing no interval change. Thus, in these studies, surgery could have been avoided in 39% to 46% of cases, which begs the question of whether renal biopsies should be performed more frequently in selected patients. INDICATIONS FOR SURGERY Radiation and systemic therapy (chemotherapy or immunotherapy) are both ineffective treatment of localized RCC. Similarly, the results of systemic treatment for metastatic disease are poor. Thus, surgery is the treatment of choice for locally confined or locally advanced disease without regional or distant metastasis. There is recent evidence to suggest that surgical removal of the renal primary (cytoreductive surgery) in the midst of metastatic disease may also improve survival rates in combination with systemic immunotherapy.44,45 Therefore, one could make the argument that any resectable renal tumor, regardless of size, or presence of metastases, is a candidate for surgical removal if the patient has a high performance status (PS). For those patients with especially poor prognostic factors, some investigators have suggested testing tumor responsiveness to immunotherapy prior to cytoreductive nephrectomy to avoid the morbidity of surgery in patients unlikely to respond to systemic treatment.46 SURGICAL MANAGEMENT OF LOCAL DISEASE Robson et al.,1 in 1968, were the first to describe their results of radical nephrectomy for RCC. In this classic article, the authors describe the radical extirpation of the
tumor-bearing kidney and adrenal gland within Gerota’s fascia along with an extended lymph node dissection. Until recently, ORN, as described by Robson, was the standard of care for localized RCC. This “gold standard” has been challenged by the introduction of two concepts: elective NSS for small renal tumors and laparoscopic renal surgery, including radical and partial nephrectomy. Elective NSS is now considered by many to represent the standard of care for the management of small renal tumors, with 10-year cancer-specific survival rates similar to radical nephrectomy.47 LRN was first performed by Clayman et al.4 in 1991 for a tumor-bearing kidney. Since then, LRN has gained wide acceptance because of its decreased postoperative pain, decreased hospital stay and shortened convalescence compared to the open approach.48–50 Only recently a significant follow-up has been made available to demonstrate the laparoscopic approach to be oncologically equivalent to open surgery. Finally, ablative technologies are coming to fruition, in that tumors are destroyed with heat or cold energy and then left in situ following treatment. OPEN RADICAL NEPHRECTOMY Technique For details on “technique” see “Textbook of Operative Urology” by Marshall.51 Briefly, the kidney can be approached through several different incisions (flank, transperitoneal, thoracoabdominal), depending on the size and location of the tumor, the patient’s body habitus, and the surgeon’s preference. Whichever approach is taken, early ligation of the renal pedicle and removal of the kidney and tumor with adequate margins are mandatory (Figure 11-1). The flank approach is the most commonly performed incision for radical nephrectomy. For the flank incision, the patient is placed laterally on the operating table with the table flexed and the kidney rest elevated. The incision is usually made over the 11th or 12th rib, and a rib may need to be removed for exposure of the kidney. The goal is to stay extraperitoneal, as well as extrapleural. Early identification, access and ligation of the renal hilar vessels, and avoidance of the intraperitoneal cavity are the advantages of this approach. Disadvantages include risk of pneumothorax, which can be easily repaired without leaving a chest tube if identified intraoperatively, and relatively increased pain compared to other incisions because of division of the flank muscles. The transperitoneal approach is accessed via a subcostal, midline upper abdominal or chevron incision. The main advantages of the transperitoneal approach are the ability to examine surrounding intraabdominal structures, including the contralateral kidney, and the improved access to the hilar vessels for larger tumors. Disadvantages include poor exposure of the upper pole of
Chapter 11 Renal Cell Carcinoma: Localized Disease
199
Figure 11-1 Radical nephrectomy with division of hilar vessels.
the kidney and the increased risks of postoperative ileus and adhesions. Finally, the thoracoabdominal approach, while not often necessary, arguably provides the optimal exposure for large upper pole tumors and tumor thrombus into the vena cava. Entrance into the pleural cavity also allows for concomitant metastasectomy of isolated ipsilateral pulmonary lesions. Disadvantages include the need for a chest tube postoperatively and the risks of postoperative atelectasis. While it has been argued that the thoracoabdominal approach is associated with an increased risk of postoperative pain, Kumar et al.52 demonstrated no increase in postoperative pain or analgesic requirements in patients with a thoracoabdominal versus a flank incision. Thus, there are numerous approaches to the kidney for a radical nephrectomy, and the urologic surgeon must be familiar with each to tailor the approach to best suit the situation. LAPAROSCOPIC RADICAL NEPHRECTOMY The three laparoscopic approaches to LRN are transperitoneal, retroperitoneal, and hand-assisted laparoscopy
(HAL). The original description by Clayman and colleagues4 was a transperitoneal approach. The retroperitoneal approach was developed to mimic the open flank nephrectomy and allow the hilar vessels to be accessed and controlled quickly without violating the peritoneal cavity. Lastly, hand-assisted nephrectomy was developed to facilitate the procedure for the novice surgeon, to provide an alternative to open conversion and for large renal tumors and specimens, where HAL may help to expedite the procedure. Surgeon’s preference, laparoscopic procedure, patient anatomy, and history of prior surgery all impact the approach that is taken, but the ultimate goal of all three is to perform an adequate oncologic operation while minimizing morbidity. A preoperative consent form is signed, detailing the possible complications. Specifically for laparoscopic surgery, patients are instructed about the risks of open conversion, hypercarbia, and neuromuscular injury from prolonged positioning. For each of the three techniques, bowel preparation for the day prior to surgery is optional to prevent colonic distension from obscuring visualization. Patients are administered a second-generation cephalosporin intravenously and
200
Part III Kidney and Ureter
intraoperatively for routine prophylaxis. In case of rapid blood loss, the anesthesiologist must have adequate intravenous access with 2 large bore IV lines and, at the surgeon’s discretion, patients are typed and cross-matched for 2 units of packed red blood cells (RBCs). Of note, the anesthesiologist should be educated not to use nitrous inhalant as it can cause bowel distention and that temporary oliguria with insufflation is common and expected. Technique Transperitoneal A Foley catheter and orogastric tube are first placed while the patient is in the supine position. Patients are then positioned in a modified 45-degree flank position with meticulous care taken to pad all pressure points. The kidney rest is not elevated, and the bed is minimally flexed. The patients are then firmly secured to the operating table with 3-inch cloth tape. Once secured, prior to covering the patient with sterile drapes, the bed is tilted completely to the right and left sides to assure that the patient’s position does not change. For emergent conversion to an open procedure the patient is rotated on the bed into a supine position to make a subcostal incision and obtain immediate access to bleeding. Intraperitoneal access can be accomplished either with the Veress needle or an open Hassan technique. However, the authors use both; the Hassan technique is used exclusively in patients with multiple abdominal scars or when the Veress technique fails. We typically gain access at the umbilicus where the abdominal wall is the thinnest. The abdomen is temporarily insufflated to 20 mm Hg for trocar placement under direct laparoscopic visualization. We typically use a 3 or 4 port configuration for LRN. Once all trocars have been placed, the pneumoperitoneum is decreased to 15 mm Hg to reduce the possible complications of hypercarbia and decreased venous return. Initial dissection involves incising the posterior peritoneum at the line of Toldt and reflecting the colon medially to gain access to the retroperitoneum. In doing so the renocolic ligaments are divided to expose the kidney. On the left side, the splenocolic ligaments are divided and care is taken not to injure the tail of the pancreas. On the right side, the duodenum is reflected medially and the hepatocolic ligaments are divided to adequately expose the renal hilum. The ureter is then identified and mobilized superiorly with the gonadal vessels. The renal hilum is identified and then the artery and vein are sequentially divided using an Endo-GIA stapler (US Surgical, Norwalk, CT; Ethicon Endosurgical, Cincinnati, OH) or Weck locking polymer clips (Weck Closure Systems, Research Triangle Park, NC). We no longer use a titanium disposable clip appliers to control the artery. Finally,
the upper pole of the kidney is dissected free and the ureter and lateral attachments are divided to free the entire kidney. The kidney is placed in a specimen retrieval bag for intact removal or morcellation. The major advantage of the transperitoneal approach is the increased working space and multiple landmarks to guide the surgeon. In addition, the transperitoneal approach allows for extraction via a Pfannenstiel incision providing an excellent cosmetic result. Disadvantages include the need to reflect multiple abdominal structures to gain access to the kidney, including the spleen, pancreas, colon, liver, and duodenum. Manipulation of the bowel has been thought by some investigators to increase the risks of postoperative ileus compared to retroperitoneal approaches. Retroperitoneal The preoperative preparation is the same for the retroperitoneal as the transperitoneal approach. As described by Gill,53 the patient is placed in a 90-degree full flank position with the table flexed and the kidney rest elevated. Initial access is obtained through a 1 to 2-cm transverse incision located just below the tip of the 12th rib. The tissue layers are bluntly dissected down to the thoracolumbar fascia, which is incised sharply, gaining access to the retroperitoneum. Blunt finger dissection is performed between the psoas muscle and the posterior aspect of Gerota’s fascia. A balloon dilator (Origin MedSystems, Menlo Park, CA) may be positioned into this space and inflated to approximately 800 cm3 of air. A laparoscope is then inserted into the transparent balloon to confirm adequate placement within the retroperitoneum. The balloon is removed, a 10-mm blunt trocar is introduced through the skin incision, and the pneumoretroperitoneum is established at 15 mm Hg. Two additional trocars are placed under direct visualization at the lateral border of the erector spinae muscle just below the 12th rib and between the mid- and anterior axillary line, 3 cm cephalad to the iliac crest. Dissection begins with longitudinal incision of Gerota’s fascia anterior to the psoas muscle in the region of the renal hilum. The renal artery is then easily visualized, circumferentially dissected, clipped/stapled, and divided. The renal vein is anterior to the artery, exposed and divided using an Endo-GIA vascular stapler. Suprahilar dissection is performed along the medial aspect of the upper pole. Finally, the ureter and gonadal vessels are divided and the remainder of the kidney is mobilized outside of Gerota’s fascia. As with the transperitoneal approach the specimen is placed in a retrieval bag for either intact removal or morcellation. The proponents of retroperitoneal LRN have claimed that this approach is associated with less morbidity compared to transperitoneal LRN secondary to rapid access
Chapter 11 Renal Cell Carcinoma: Localized Disease
to the hilum and avoidance of the peritoneal cavity. In theory, avoiding the peritoneal cavity should decrease the incidence of postoperative ileus and inadvertent injury to intraperitoneal contents. McDougall et al.54 reported a faster return to oral intake in a retrospective comparison of patients undergoing retroperitoneal versus transperitoneal nephrectomy for benign disease. Conversely, Gill et al.55 recently prospectively compared the outcomes of transperitoneal versus retroperitoneal LRN in 88 consecutive patients. Although the retroperitoneal approach was associated with less surgical time, there was no significant difference in blood loss, complications, pain requirements, or hospital stay. The main theoretic disadvantage of this technique is the limited working space allotted. To the novice surgeon inexperienced with this technique, this technique may initially make orientation and dissection challenging. In addition, large renal specimens may be difficult to handle. Abbou et al.56 still recommend limiting retroperitoneal nephrectomy to T1 lesions. Hand-Assisted Hand-assisted LRN is the latest addition to the laparoscopic armamentarium. It has been criticized by “pure” laparoscopists because of the presumed increased morbidity associated with the incision necessary for hand insertion. However, Nelson et al.57 recently reviewed 22 hand-assisted and 16 standard laparoscopic radical nephrectomies and demonstrated that there was no difference in pain scores, hospital stay, or return to normal activity. Importantly, the operative time was significantly less in the hand-assist group (205 versus 270 minutes) and less of a learning curve to overcome. The HAL technique utilizes the same presurgical preparation as the transperitoneal technique, including patient positioning. Typically the nondominant hand is placed into the abdomen via an incision placed below the umbilicus with 2 to 3 accessory trocars for laparoscopic instruments. The initial steps of exposing the kidney are identical to that described for the transperitoneal technique. The kidney is then mobilized except for the upper pole, using both blunt and sharp dissection techniques. The ureter is divided prior to dividing the hilar vessels. This allows the surgeons hand to grasp the kidney and place the hilum on stretch. The fingers are then able to palpate, present, and if need be, compress the hilum during dissection. The hilar vessels are separately controlled and divided using an Endo-GIA stapler (US Surgical, Norwalk, CT; Ethicon Endosurgical, Cincinnati, OH) or Weck locking polymer clips (Weck Closure Systems, Research Triangle Park, NC). Finally, the upper pole attachments are released, and if the situation dictates, the adrenal gland is removed with the specimen en bloc. The specimen is delivered through the hand incision. All of
201
the new hand devices protect the extraction wound with an impermeable barrier. Thus, there is no need for an extraction bag device. There is no role for morcellation since the hand port incision is large enough for almost all specimens. Though not embraced by all surgeons, HAL has gained popularity within the private sector secondary to the short learning curve and quick operative times. For the “pure” laparoscopists, HAL may provide an alternative to conversion. Finally, having the hand in the operative field may provide distinct advantages in patients with large renal specimens or with prior abdominal surgery. Disadvantages to HAL include less working space secondary to the hand in the intraabdominal cavity. This is especially true in thin, small patients. The extraction site is limited to where the hand device is placed, typically lower midline, but rarely in a Pfannenstiel position. Finally, similar to the transperitoneal technique, HAL requires multiple abdominal structures to be reflected prior to exposing the kidney, which theoretically may lead to an increased incidence of injury to adjacent organs and prolonged ileus. Comparison of Laparoscopic Radical Nephrectomy to Open Radical Nephrectomy Intraoperative and Postoperative Parameters In general, the benefits of LRN have been in patient recovery from surgery. Numerous series have demonstrated that compared to ORN, laparoscopic patients incur less postoperative pain and need for analgesics, shorter hospitalization, and a reduced convalescence. Intraoperatively, ORN is advantageous, with shorter operative times, but also with an increased blood loss. Finally, opponents of laparoscopy criticize the increased costs associated with these procedures, secondary to costly equipment and prolonged operative times. However, Lotan et al., in a cost comparison analysis of LRN versus ORN, found that the laparoscopic approach was actually less costly due to reduced hospitalization costs secondary to shorter hospital stays. The laparoscopic approach, with its shorter convalescence, would be even more cost advantageous if cost from lost wages was included in the cost analysis (Table 11-3). Oncologic Adequacy The goal of any laparoscopic procedure should be to reproduce the efficacy of its open counterpart, while providing the benefits of the minimally invasive approach. One of the earliest surrogate endpoints to compare the oncologic adequacy of LRN to ORN was specimen weight and margin status. The specimen weight following LRN and ORN should be equivalent if the specimen is removed intact and approximately 20% less if the
Chapter 11 Renal Cell Carcinoma: Localized Disease
203
Table 11-4 Laparoscopic Radical Nephrectomy Oncologic Results Clinical Tumor Stage
Port Site or Renal Fossa Recurrence
157
T1-2,N0,M0
0
91
19.2
Dunn et al.48
61
T1-2,N0,M0
0
—
25
Gill et al.59
53
T1-2,N0,M0
0
—
13
Chan et al.63
67
T1-2,N0,M0
0
95
35.6
Portis et al.60
64
T1-2,N0,M0
1
98
54
147
T1-2,N0,M0
—
96
30 (median)
Study Cadeddu et al.62
Ono et al.58
Number of Patients
ogy, grade, and stage were accurately determined following morcellation. Only tumor size was not assessed. However, as noted, with modern imaging tumor size can be accurately measured preoperatively and incorporated into the tumor staging process. Meng et al.74 found that india ink covering of the specimens prior to morcellation allows for accurate determination of surgical margins. Therefore, accurate staging of morcellated renal tumors is possible following morcellation and should not be a concern. It is well established that specimen morcellation is a safe alternative to intact removal as long as the morcellation is performed in an impermeable entrapment sack. Urban et al.75 tested the permeability of 18 LapSacs (Cook Urologic, Spencer, IN) following porcine laparoscopic nephrectomy or nephroureterectomy with a high-speed electrical tissue morcellator. None of the sacks demonstrated permeability to bovine serum albumin, indigo carmine or mouse bladder tumor cells following morcellation. These results were confirmed by Landman et al.73 in 14 of 15 LapSacs that remained impermeable following morcellation. The one case of perforation occurred with a specimen that had been preserved in formalin. Clinically, Dunn et al.48 reported a series of 39 cases where the specimen was morcellated with no local or port site recurrences over 9 years. However, Fentie et al.72 have reported a case with a clinical stage T3 tumor with an isolated port site recurrence following laparoscopic nephrectomy and morcellation. Thus, while morcellation has been demonstrated to be safe, meticulous care must be taken to avoid tumor contamination during morcellation. In particular, to avoid entrapment sac violation and tumor spillage, laparoscopic visualization during morcellation is mandatory. Whether there is a clinical advantage to morcellation remains to be determined. Walther et al.76 compared specimen morcellation to intact removal and described decreased analgesic requirements and a shorter hospital
5-Year Cancer Specific Survival (%)
Mean Follow-Up (months)
stay. However, Gettman et al.77 showed no significant differences in subjective pain and activity scores, and time to return to normal activity. Ono et al.58 also demonstrated no significant differences in analgesic requirements (29 mg versus 29 mg analgesics) and convalescence (22.7 days versus 23.3 days) in the intact extraction group and morcellated group, respectively. These conflicting results call into question the benefits of specimen morcellation. This in combination with prolonged operative times, expenses associated with morcellation and risk of tumor spillage; all combine to make intact specimen removal our technique of choice. TUMOR THROMBUS Venal caval tumor thrombus has been reported in 4% to 10% of all patients with RCC.78–80 Venous extension is classified by the cranial extent of the tumor thrombus. While there are numerous classification schemes available, the one proposed by Skinner et al.80 is simple to use and has implications on the surgical approach and ultimate prognosis (Table 11-5). In 1913, Berg et al.81 were the first to remove an intracaval thrombus in a patient with RCC. Sosa et al.82 reported dismal results with no survivors at 1 year in patients undergoing nephrectomy alone, without removal of the vena caval thrombus. Conversely, numerTable 11-5 Classification of superior extent of RCC in the IVC Level 3
Level 2
Level 1
Intra-atrial tumor extension
Extension within the intrahepatic IVC but not into the atrium
Extension below the insertion of the hepatic veins
From Skinner DG, Pritchett TR, Lieskovsky G, et al: Ann Surg 1989; 210:387–392. (Discussion 392–394.), with permission.
204
Part III Kidney and Ureter
ous investigators have demonstrated long-term survival rates with removal of tumor thrombus at the time of radical nephrectomy, even with cranial extension into the atrium (Figure 11-2). There is considerable debate as to whether the presence of tumor thrombus independently portends a poor prognosis. Numerous reports have demonstrated encouraging 5-year survival rates of 32% to 64% in patients undergoing radical nephrectomy with removal of inferior vena caval thrombi.80,83,84 The survival rates decrease dramatically when tumor thrombus is associated with positive lymph nodes, distant metastasis and when the tumor thrombus invades into the wall of the inferior vena cava (IVC). The prognostic significance of the cranial extent of tumor thrombus has also been the point of contention. Skinner et al.,80 in a series of 53 patients, demonstrated 5-year survival rates for subhepatic, hepatic, and atrial thrombi of 35%, 18%, and 0%, respectively. Conversely, Staehler et al.85 found no difference in survival rates among patients with levels I to IV thrombi. Therefore, an aggressive surgical approach is
warranted in patients with tumor thrombi, regardless of cranial extent, without evidence of metastatic disease. ROLE OF ADRENALECTOMY The adrenal gland is easily removed en bloc using an ORN or LRN technique. However, most LRN series reserved ipsilateral adrenalectomy for patients with evidence of adrenal involvement on preoperative studies or large upper pole lesions where removal was required to ensure a negative margin.62 The major report that supports this practice comes from Tsui et al.,86 in that the records of 511 patients undergoing ORN with ipsilateral adrenalectomy were reviewed. The incidence of adrenal metastasis was 5.7%. Importantly, tumor stage correlated with the probability of adrenal involvement, with T4, T3, and T1 to T2 tumors accounting for 40%, 7.8%, and 0.6% of cases, respectively. Also, preoperative CT imaging demonstrated 99.6% specificity and a 94.4% negative predictive value. Similarly, Paul et al.87 evaluated 866 consecutive patients undergoing ORN with ipsilateral
Figure 11-2 Tumor thrombus with vena caval extension into the atrium.
Chapter 11 Renal Cell Carcinoma: Localized Disease
adrenalectomy. In their series, a total of 27 (3.1%) of adrenal metastasis were found. Of the 27 patients, 21 had multiple metastases at diagnosis and only 6 (0.7%) presented with solitary ipsilateral adrenal metastasis. Univariate and multivariate analysis revealed tumor size and M stage as best predictors of adrenal involvement. They concluded that adrenalectomy was not necessary if the tumor was less than 8 cm in size on preoperative CT imaging and there was no evidence of metastasis or extension from adjacent renal tissue. ROLE OF LYMPHADENECTOMY The incidence of lymph node metastasis in RCC ranges from 13% to 32%, with increasing incidence with higher stage tumors.88 The regional nodal drainage is different in the right and left sides.89 The left kidney most often drains to the para-aortic nodes in the lumbar region, whereas the right kidney drains primarily to the interaortocaval and paracaval nodes.89 Figure 11-3 demonstrates the borders of a lymph node dissection. Regretfully, secondary to the frequently aberrant drainage pattern of the
205
lymph nodes draining the kidney, an extended lymphadenectomy would be necessary to potentially remove all involved lymph nodes. Regional lymph node dissection for the treatment of RCC may be unnecessary in patients with no evidence of lymph node enlargement on preoperative studies or during surgery. Minervini et al.90 showed no difference in 5-year survival between a group of 108 patients who underwent radical nephrectomy alone versus 49 patients who underwent radical nephrectomy plus a regional lymph node dissection. Of the 49 patients with no suspicion of lymph node involvement, only 1 (2%) had a histologically confirmed positive node. This is in agreement with the results of the EORTC Genitourinary Group in that only 1.0% of patients with no suspicion of involvement had nodal disease.88 There is often variability in the surgical dissection and pathologic examination of nodal tissue. In patients with no evidence of nodal enlargement, a regional lymph node dissection (open or laparoscopic) is not frequently beneficial. Whether patients with evidence of suspicious lymph nodes garner any benefits from an extended dissection at
Figure 11-3 Lymph node dissection for RCC.
206
Part III Kidney and Ureter
the time of nephrectomy also remains controversial. Improved pathologic staging does provide information for guiding subsequent systemic immunotherapy. However, the data demonstrating improved survival rates in patients undergoing lymphadenectomy are based solely on nonrandomized retrospective studies,91,92 with multiple studies arguing against its utility.93,94 The only prospective trial comparing radical nephrectomy with and without lymphadenectomy (EORTC 30881) demonstrated no increase in morbidity with lymphadenectomy, but the results are too premature to determine any survival benefits.88 Importantly, a complete laparoscopic lymph node dissection can be performed if the surgeon desires. Several investigators reporting their results with laparoscopic retroperitoneal lymph node dissections for teste tumors have validated this.95,96 ROLE OF NEPHRECTOMY WITH ADVANCED DISEASE While RCC is being diagnosed at an earlier stage, approximately 30% of patients still present with metastatic disease, and 30% to 50% of initially localized tumors eventually progressing to metastatic disease.91,97 RCC is a unique cancer, in that removal of the primary tumor has been associated with rare spontaneous regression of metastasis.98 However, review of this phenomenon has demonstrated an overall incidence of only 0.7% compared to a mortality rate with nephrectomy of between 1% and 5%.99,100 Thus, nephrectomy alone in the face of metastatic disease is not generally curative and must be considered palliative. The debate arises whether nephrectomy with or without metastasectomy in combination with adjuvant immunotherapy improves response rates, and ultimately, patient survival. Surgical removal of the primary tumor along with isolated metastatic lesions has been demonstrated to be effective for colon cancer metastatic to the liver.101 Numerous retrospective studies have suggested a survival benefit for surgical extirpation of metastatic RCC lesions. van der Poel et al.102 reported on 152 resections of RCC metastases performed in 101 patients. Patients demonstrated a median survival of 28 months after the initial metastasectomy. Improved survival correlated with pulmonary metastases and a tumor-free interval of more than 2 years between primary tumor and metastasis. Surprisingly, the number of metastases and additional immuno- or radiation therapy did not influence survival. Numerous studies have suggested that cytoreductive nephrectomy prior to immunotherapy for unresectable metastatic RCC may improve response rates.103,104 Regretfully, these studies are retrospective and nonrandomized, making them subject to negative selection bias. Recently, however, the SWOG conducted a randomized prospective study examining the role of nephrectomy
prior to immunotherapy versus immunotherapy alone in patients with metastatic RCC.105 They found that while there was no significant difference in the radiologic response rates of metastatic deposits between the two groups, the nephrectomy group had a statistically significant improved survival (medial survival of 11.1 versus 8.1 months). Importantly, there was only one operative mortality, low operative morbidity (4.9%), and negligible delay to the institution of immunotherapy (median 19.9 days). Similarly, the EORTC Genitourinary Group prospectively demonstrated a delay in time to disease progression and an improved median survival in patients treated with cytoreductive nephrectomy prior to systemic immunotherapy.45 The only criticism with these two studies is that they lack a group of patients that only received nephrectomy, without immunotherapy. Thus, it is impossible to assess the true benefit of immunotherapy in the patients’ improved survival. Finally, to avoid the potential surgical morbidity of nephrectomy in patients who will not respond to immunotherapy, several investigators have proposed neoadjuvant immunotherapy, and reservation of surgery only for patients that demonstrate a response.106,107 Rackley et al.108 demonstrated a slightly higher objective response rate and longer median survival rates for patients treated with initial immunotherapy followed by surgery compared to patients who underwent primary nephrectomy and adjuvant immunotherapy. Krishnamurthi et al.46 reported on a selected population of 14 patients with metastatic RCC who underwent initial immunotherapy followed by surgical resection of primary and metastatic lesions. All 14 patients either had an objective response to immunotherapy (9) or stable disease (5) following immunotherapy. Their 3-year cancer-specific survival rate was an impressive 81.5%, suggesting that patients that respond favorable to initial immunotherapy may represent a biologically more favorable group. PARTIAL NEPHRECTOMY (OPEN OR LAPAROSCOPIC) The first report of a partial nephrectomy was by Wells in 1884 when he described this technique for a perirenal fibrolipoma.109 NSS was initially proposed for the surgical management of patients in that radical nephrectomy would render them functionally anephric. This consisted of patients with bilateral renal tumors, tumors in a solitary kidney, and patients with preexisting renal insufficiency. Due to the excellent results seen in these patient populations, the indications for NSS have expanded to include all patients with small renal tumors (<4 cm). Fergany et al.47 reported on their long-term results of NSS for sporadic RCC in 107 patients treated with partial nephrectomy prior to 1988. They reported 5- and
Chapter 11 Renal Cell Carcinoma: Localized Disease
10-year cancer-specific survival rates of 88.2% and 73%, respectively. Isolated recurrences in the ipsilateral kidney were seen in only 2 patients (4%) at a mean follow-up of 104 ± 57 months. These results are even more impressive considering that tumors were symptomatic in 68% of cases, bilateral in 50%, and more than 4 cm in 45%. A subset of patients (29) that met currently accepted indications for elective NSS (unilateral tumors <4 cm) demonstrated a 100% cancer-specific survival at 10 years. Importantly, although almost 40% of patients had preoperative renal insufficiency (creatinine ≥1.5 mg/dl), renal function was preserved in the majority of patients, with 100 patients (93%) maintaining adequate renal function to avoid dialysis. Technique Open3 and LPN adhere to the same operative principle; removal of the tumor with a margin of normal parenchyma. The main complications of this procedure are bleeding and urinoma formation. Bleeding can be minimized with hilar clamping or with the application of parenchymal compression and renal injury can be reduced through cold ischemia. Urinoma formation can be avoided through direct suture repair of any entry into the collecting system. Due to the inherent limitations of intracorporeal suturing and renal cooling, numerous adjunctive techniques have been developed to facilitate LPN.110–113 Nonetheless, this is an advanced laparoscopic procedure, which is best reserved for smaller exophytic tumors. With the advent of improved instrumentation and experience with the laparoscopic approach, Gill et al.114 have reported on an increasing experience treating larger, more complex central tumors, mimicking the open technique. Surgical Margin Historically, the surgical dictum has always been to excise at least a 1-cm margin of normal peritumoral renal parenchyma during partial nephrectomy to decrease the risk of local tumor recurrences. This principle was based on scant evidence and has recently been challenged. Lerner et al.115 reported similar local recurrence and survival rates in patients that underwent tumor enucleation compared to standard partial nephrectomy. Sutherland et al.116 reported on 41 patients, with a mean postoperative follow-up of 49 patients, who underwent partial nephrectomy for small renal tumors (mean size = 3.2 cm). With a median surgical margin of only 0.2 cm (range 0.05 to 0.70), no patient with a negative parenchymal surgical margin had a local recurrence at the resection area. Thus, for low stage tumors, margin size was irrelevant as long as the surgical bed was free of residual tumor. Importantly, multiple biopsies from the bed of the tumor resection should be performed to confer margin status. These results suggest that in lieu of a
207
negative margin, the extent of peritumoral normal parenchyma excised is not significant. RENAL TUMOR ABLATION With the advent of improved imaging modalities, the vast majority of renal tumors detected are of low grade and stage. In the past, options were limited to observation or partial/radical nephrectomy. While tumors less than 3-cm rarely metastasize, the natural history of RCC is unpredictable and observation may not be in the best interest of the patient for a disease with no effective systemic treatment.117,118 Thus, ablative therapy provides a minimally invasive modality for the treatment of these small tumors that minimizes the risks and morbidity traditionally associated with open or LPN. Cryoablation Cryoablation involves the destruction of cells by rapidfreeze thaw cycles, with complete necrosis of renal parenchyma occurring at temperatures of −19.4 ˚C or lower.119 Delworth et al.120 first described open renal cryoablation of an RCC in 1996, and since then it has been performed by several investigators laparoscopically6,121 and percutaneously.122 Gill et al.7 and Shingleton and Sewell123 recently reported on two large series of laparoscopic and percutaneous renal cryoablation, respectively. Gill et al.7 reported short-term follow-up of 32 patients undergoing laparoscopic renal cryoablations who had exophytic enhancing renal masses less than 4 cm in size. Anteriorly located tumors were approached via a transperitoneal route, while posterior and lateral tumors were approached retroperitoneally. Once exposed and verified with color Doppler ultrasound, the renal tumor was biopsied prior to cryoablation. Under direct laparoscopic and real-time ultrasonic visualization the tumor was punctured with a 4.8-mm cryoprobe, and the tumor was treated with a double freeze–thaw cycle. Treatment was stopped when the ice ball was seen to extend approximately 1 cm beyond the edge of the tumor. Follow-up imaging consisted of MRI scans obtained on postoperative day 1 and then at 1, 2, 3, 6, and 12 months. CT-guided core needle biopsies were obtained at 3 or 6 months. All procedures were performed laparoscopically without the need for open conversion. Mean tumor size by intraoperative ultrasound was 2 cm with an average blood loss of 66.8 ml (range 10 to 200). There were no major intraoperative complications and two minor postoperative complications that did not require surgical intervention. Among 20 patients imaged with MRI at 1 year, 5 patients had no cryolesion identified and 15 patients had a 66% reduction in cryolesion size. None of the 23 patients who had CT-guided biopsies at 3 or 6 months
208
Part III Kidney and Ureter
had evidence of residual cancer on histopathologic analysis. The authors noted that while CT-guided biopsies have a reported false-negative rate of 16%,124 the absence of cancer on all of the 23 biopsies is encouraging. However, they appropriately cautioned that long-term follow-up is warranted to assess the true efficacy of cryoablation for small renal tumors. Shingleton and Sewell123 initially reported their series of 20 patients treated with MRI-guided percutaneous cryoablation with a mean follow-up of 9.1 months (range 3 to 14). For this procedure, a high Telsa open MRI unit is necessary. The patients were administered a general anesthetic (18) or intravenous sedation (2) and placed prone on the interventional MRI docking table. Axial fast spin echo images were obtained to determine probe entry site and angle of insertion. The cryoprobe, which is 2 or 3 mm in diameter and 15 cm in length (Galil Medical, Tel Aviv, Israel) was then activated for a total of 3 freeze–thaw cycles. Periodic reimaging was performed to monitor ice ball propagation and to ensure treatment 5 mm beyond the edge of the mass while avoiding damage to the collecting system and surrounding structures. Following probe removal after the third cycle, the access sheath was packed with absorbable knitted fabric or absorbable gelatin sponge pledgets to facilitate hemostasis. Follow-up included MRI or CT scans at 1 week, and 1, 3, 6, and 12 months. The mean procedure time was 97 minutes (range 56 to 172) and there were no intraoperative complications. The only postoperative complication was a wound abscess. On follow-up CT scan or MRI imaging, only one mass of the 22 treated demonstrated continued contrast enhancement. This patient was subsequently retreated and 6-month follow-up imaging showed no residual enhancement. Overall 20 of the 22 masses either completely resolved or decreased in size. While routine post ablation biopsies were not performed, two core biopsies of tumors with rim enhancement were both negative for malignancy. As with Gill’s series, the mean follow-up was short at 9.1 months (range 3 to 14).
Recently, Shingleton and Sewell125 reported on longer-term follow-up of their series. A total of 65 patients were treated with percutaneous cryoablation and followed for a mean of 18 months (range 2 to 30). While 9 patients required more than one treatment for complete ablation, 60 patients were alive without evidence of local disease recurrence at last follow-up. As longer follow-up becomes available we will be better able to assess the true efficacy of this technology (Table 11-6). Radiofrequency Ablation Much of the experience using radiofrequency (RF) energy for ablative therapy has come from the treatment of liver tumors.131,132 Zlotta et al.133 were the first to describe the effects of RF ablation on human renal tumors prior to nephrectomy in 1997. Since then, RF energy has been utilized both laparoscopically111 and percutaneously130,134 for the treatment of small renal tumors. RF energy employs alternating electric current to agitate tissue ions in proximity to the probe, resulting in frictional heating of the tissue around the RF electrodes. Heating of tissues to 50 to 55 ˚C for 4 to 6 minutes produces irreversible cell damage while temperatures between 60 and 100 ˚C result in tissue coagulation and almost instantaneous cell death.135 Walther et al.136 demonstrated necrosis in 10 of 11 tumors treated intraoperatively by RF ablation prior to surgical removal. Gervais et al.134 were the first to report their experience with percutaneous RF ablation of 9 tumors in 8 patients. The mean tumor size was 3.3 cm (range 1.2 to 5.0) and all tumors showed contrast enhancement on preablation CT or MRI imaging. Seven of 9 tumors treated had biopsy proven RCC prior to ablation. Patients were anesthetized with intravenous sedation, and tumors were localized with ultrasound or CT guidance. RF ablation was performed with an RF generator (Cosman Coagulator CC-1; Radionics, Burlington, MA) and single (one 2.0 to 3.0-cm tip) or cluster of (three 2.5-
Table 11-6 Clinical Tumor Ablation Series Patients
Mean Tumor Size (cm)
Laparoscopic cryoablation
50
2.1
97% (30/31)†
18.8
Shingleton et al.127
Percutaneous cryoablation
35
3.7
86% (30/35)
12
Jacomides et al.128
Laparoscopic RF ablation
11
2.1
100% (11/11)
9.8
McGovern et al.129
Percutaneous RF ablation
17
1–5.5
84% (15/18)
6–36
Pavlovich et al.130
Percutaneous RF ablation
21
2.4
79% (21/24)
2.0
Author
Technique
Sung et al.126
*Successful ablation defined as no contrast enhancement on follow-up CT imaging. †Negative CT-directed biopsy at 3–6 months.
Successful Ablation*
Mean Follow-up (months)
Chapter 11 Renal Cell Carcinoma: Localized Disease
cm tip) cooled tip electrodes. Once the electrodes were appropriately positioned, the tumor was treated for 12 minutes at a current of 1500 to 1800 mA. The electrodes were repositioned in larger tumors to ensure complete tumor ablation, and additional treatments at a separate setting were necessary in 4 patients (total of 14 treatments). Unlike cryoablation, real-time ultrasound imaging is not effective in monitoring the RF lesions acutely.137 Therefore, the only true measure of treatment success is diligent follow-up imaging with or without image-guided biopsies. Gervais et al.134 performed CT or MRI at 1, 3, and 6 months, and then every 6 months thereafter. Percutaneous RF treatments are well tolerated, and 12 of the 14 treatments reported by Gervais et al.134 were conducted on an outpatient basis. There was one complication attributable to the RF ablation in a patient that sustained a large paranephric and renal pelvis hematoma necessitating a ureteral stent and blood transfusion. Follow-up imaging at 6 months demonstrated no tumor enhancement in all 5 exophytic tumors and all 3 tumors less than 3 cm. Conversely, 2 of the 3 central tumors measuring 4.4 and 5.0 cm, respectively, demonstrated persistent contrast enhancement necessitating repeat treatments. While these short-term results (mean followup = 10.3 months) are encouraging, the authors recommend this treatment only for exophytic tumors less than 3 cm in size. Pavlovich et al.130 reported their experience at The National Cancer Institute with percutaneous renal tumor ablation in patients with either von HippelLindau clear cell tumors or hereditary papillary RCC. Patients with CT scan demonstrating solid renal tumors 3 cm or less than enlarged during the previous year were considered candidates for ablative therapy. In conjunction with an interventional radiologist, the authors localized and targeted the tumors with either ultrasound or CT guidance. Then under intravenous sedation or general anesthesia, the RITA probe (RITA Medical Systems, Mountain View, CA) was positioned into the tumor and the electrodes deployed until the tumor volume was completely covered. The tumors were then treated to a target temperature of 70 ˚C for two or three 10 to 12-minute cycles, depending on the size and location of the tumors. A total of 21 patients underwent RF ablation of 24 tumors. The mean diameter of the tumors treated was 2.4 cm (range 1.5 to 3.0). All patients tolerated the procedure and were medically stable for discharge from the hospital within 24 hours. There were no major complications, though 2 patients suffered flank pain on ipsilateral hip flexion and 2 complained of skin numbness on the ipsilateral flank. Follow-up CT imaging at 2 months revealed absence of contrast enhancement in 19 of the 24 (79%) tumors treated. Of the 5 tumors that continued to
209
demonstrate persistent contrast enhancement, 4 did not reach target treatment temperature at each of the electrodes for the entire treatment period. While results are promising, 79% successful ablation is less than ideal. Recently, we have reported successful RF ablation in 12 of 13 tumors (93%) at a short-term follow-up of only 4.9 months. Laparoscopic RF ablation can also be performed for renal tumors that are not amenable to percutaneous ablation or for tumors that cannot be safely treated with LPN because of location. Yohannes et al.138 were the first to describe retroperitoneoscopic RF ablation of a solid renal mass in an 83-year old man. The tumor was 2.0 cm in size and located on the anterior surface of the kidney. Due to extensive comorbidities and renal insufficiency, laparoscopic RF ablation was performed rather than partial nephrectomy. The advantages of the laparoscopic approach are that it allows biopsy of the renal mass and overlying fat prior to ablation, and also provides direct visualization of the surrounding structures minimizing potential injury. Jacomides et al.128 have performed laparoscopic transperitoneal RF ablation of 11 tumors in 8 patients. The mean tumor size was 2.1 cm (range 1.0 to 3.6) with an average blood loss of only 44 cc (range 20 to 100). Biopsy of the tumors following ablation revealed RCC in 6 patients, acute myelogenous leukemia (AML) in 1 patient and 4 oncocytomas in a single patient who underwent multiple ablations. The only complication was transient elevation in serum creatinine to 1.8 mg/dl in the patient with multiple ablations. Follow-up CT imaging at 6 weeks lack of contrast enhancement in all of the tumors treated. The advantages of the laparoscopic approach are that anterior tumors can be safely treated, surrounding structures can be directly visualized and avoided, and adequate tissue specimens can be obtained for pathologic analysis. There have been reports of varying efficacy of RF, but this likely represents engineering and technical problems rather than a primary deficiency of RF. High-Intensity Focused Ultrasound High-intensity focused ultrasound (HIFU) is a noninvasive technique of delivering ultrasonic energy to a specific area within the body. The ultrasound energy can be focused into a small volume (1 cc) so that temperature at the treatment site reaches 90 ˚C and the intervening tissue between the transducer and target is theoretically unaffected. As with the other ablative technologies, the cells at the treatment site undergo coagulative necrosis and cell death. HIFU was first investigated as a nonsurgical treatment for experimental liver tumors in the rabbit model.139 Soon afterward, Foster et al.140 investigated the creation of prostatic
210
Part III Kidney and Ureter
lesions in the canine prostate with transrectally delivered HIFU. Subsequently, HIFU has been utilized clinically for the treatment of benign141 and malignant diseases142 of the prostate. Chapelon et al.143 were the first to explore the tissue effects of transcutaneous delivery of HIFU to kidneys in the canine model. Adams et al.144 subsequently investigated the feasibility of treating renal tumors with HIFU in the rabbit model. In their study, renal tumors were induced and then treated with HIFU by placing the transducer either on the kidney or transcutaneously. With the transducer on the kidney surface opposite the tumor location, the HIFU was able to create well-defined areas of necrosis of the tumor and renal parenchyma. Transcutaneous delivery resulted in less well-defined treatment areas, with only 7 of 9 rabbits demonstrating ablation of the tumors. Four of the rabbits suffered 1 cm skin burns in areas where the probe contacted the skin. Of note, there were no injuries to adjacent organs. Similar problems of inconsistent treatment zones and injuries to the skin have been noted in transcutaneous HIFU in the porcine model.145 In a phase 1 study in humans, Vallancien et al.146 treated 4 patients with T2 and T3 kidney tumors with pyrotherapy (HIFU) 2, 6, 8, and 15 days prior to nephrectomy. In all cases, histology demonstrated coagulative necrosis in the targeted tumor areas. As in the previous animal studies, there was one case of a superficial skin burn attributed to an error in dosimetry calculation. While HIFU represents the ultimate in minimally invasive treatment of small renal tumors, the problems of imprecise targeting and thermal burns to the overlying skin have prevented its widespread use. The Cyberknife, which has been extensively used for the treatment of brain tumors, is an additional extracorporeal means of renal tissue ablation currently being evaluated in animal models.147 PROGNOSTIC FACTORS A prognostic factor is a marker that can be used to determine progression of a disease or its arrest. Reliable prognostic factors for RCC would allow physicians to avoid ineffective treatment and enroll patients earlier in either conventional treatments or therapeutic trials. A recent review article by Mejean et al.148 separated prognostic factors into three separated subgroups of those associated with the tumor, the patient, and the treatment. Tumor stage, which reflects the anatomic extent of the tumor, is the most widely utilized prognostic factor for RCC. While there have been numerous staging systems developed, the TNM classification system (Table 11-7) has become the gold standard for most tumors, including
Table 11-7 2002 TNM Classification Primary Tumor (T) Tx: Primary tumor cannot be assessed T0: No evidence of primary tumor T1: Tumor 7 cm or less in greatest dimension, limited to the kidney T2: Tumor extends more than 7 cm in greatest dimension, limited to the kidney T3: Tumor extends into major veins or invades adrenal gland or perinephric tissues but not beyond Gerota’s fascia T3a: Tumor directly invades adrenal gland or perirenal and/or renal sinus fat but not beyond Gerota’s fascia T3b: Tumor grossly extends into the renal vein or its segmental (muscle-containing) branches, or vena cava below the diaphragm T3c: Tumor grossly extends into vena cava diaphragm or invades the wall of the vena cava T4: Tumor invades beyond Gerota’s fascia Regional Lymph Nodes (N) Nx: Regional lymph nodes cannot be assessed N0: No regional lymph node metastases N1: Metastases in a single regional lymph node N2: Metastasis in more than one regional lymph node Distant Metastasis (M) Mx: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis From Javidan J, Stricker HJ, Tamboli P, et al: Prognostic significance of the 1997 TNM classification of renal cell carcinoma. J Urol 1999; 162:1277–1281, with permission.
RCC. In 1997, the classification system was modified so that the transition point between T1 and T2 tumors was changed from 2.5 cm to the current size of 7 cm. This change was initially undertaken because multivariant analysis demonstrated improved survival stratification with the 7 cm cutoff.149,150 Subsequent analyses have suggested that 7 cm may be too high and that the T1 classification should be subclassified into T1a and T1b groups. However, the exact cutoff between these subgroups is debated, with studies proposing values of 4.0,151 5.5,152
Chapter 11 Renal Cell Carcinoma: Localized Disease
and 6.6 cm,150 respectively. A range between 4.0 and 4.5 cm seems most reasonable from pathologic, technical, and prognostic considerations. These issues will most likely be represented by modifications in The American Joint Committee on Cancer 6th Edition of TNM Staging. Venous involvement with tumor thrombus is relatively common in RCC compared to most tumors. The prognostic significance of tumor thrombi has been debated, most likely due to difficulties in differentiating tumor thrombus from blood clot and quantifying vascular invasion. Some investigators believe that tumor thrombus, no matter the level, is independently associated with a decreased prognosis.153,154 Others have demonstrated no differences in overall survival with the presence of tumor thrombi.155,156 The presence of gross, as well as microvascular, vascular invasion has been unanimously associated with an increased incidence of metastasis and reduced cancer-specific survival.157 Metastatic disease is associated with a poor prognosis. Prognostic factors identified by multivariant analysis include PS, number of sites, time to appearance, and location. Poor PS has been demonstrated to be independently associated with a decreased cancer-specific survival.158 Multiple metastatic sites have a worse prognosis compared to single metastatic deposits.159,160 The appearance of metastases within 12 months from the original diagnosis is associated with a poor prognosis.161,162 Finally, isolated metastatic disease within the lung tends to have a better prognosis compared to other organs.102 Complex histologic and molecular analysis of tumor specimens is becoming a routine part of determining tumor biology and ultimate prognosis. Histologic tumor type is readily available, with poor prognosis associated with collecting duct carcinoma,163 renal medullary carcinoma,24 and the presence of sarcomatoid features.164 Grading as described by Fuhrman and colleagues, which is based on nucleolar aspect, size and content, has been shown to be an independent determinant of prognosis in multiple studies.165,166 Nuclear morphometric studies have been demonstrated to correlate with prognosis, but most investigators have been disappointed with the ability of these parameters to offer independent prognostic information.167–169 Finally, molecular markers are an exciting area of research but none have reached common use in the clinical setting. Patient factors seem to be very important to the overall prognosis. As would be expected, patients present with “incidentalomas” were found to have tumors of lower stage and grade, with a lower incidence of metastases and longer survival compared to patients presenting with symptomatic tumors.170 As stated above, PS, which combines symptoms and comorbidities, has been noted as an independent prognostic variable in most series. The
211
Eastern Cooperative Oncology Group (ECOG) PS of 2 or greater has been associated with a poorer response to immunotherapy171,172 and shorter survival.153,159,173 Biologic factors, such as an increased erythrocyte sedimentation rate,174 elevated platelet counts,175 and hemoglobin concentration of less than 10 mg/dl,176 have been found to be poor prognostic factors. Finally, numerous investigators have attempted to combine multiple prognostic factors to further improve the overall accuracy. Kattan et al.177 from Memorial Sloane-Kettering Cancer Center developed a nomogram to predict recurrence after surgery for RCC combining the following predictor variables: patient symptoms, including incidental, local or systemic, histology, including chromophobe, papillary or conventional, tumor size, and pathologic stage. Similarly, Zisman et al.178 at the University of California at Los Angeles developed the UCLA Integrated Staging System (UISS) to stratify patients into survival groups after surgery. Combining and stratifying TNM staging, Fuhrman’s grade and ECOG PS resulted in five separate survival groups. The projected 2- and 5-year survival rates for the five groups were, respectively: I, 96% and 94%; II, 89% and 67%; III, 66% and 39%; IV, 42% and 23%; V, 9% and 0%. Both of these systems, compared to individual prognostic factors, provide the physician and patient a more accurate means of predicting survival. This will help better determine candidates for adjuvant therapy and enrollment in experimental trials. SCREENING The high proportion of incidentally discovered renal tumors combined with improved survival of these lower stage tumors suggests the possibility of screening for RCC. However, it must be remembered that RCC accounts for only 2% of solid renal tumors, and even in selected populations of patients with hematuria, the prevalence is only 3% to 6%.179,180 The US Preventative Services Task Force (1996) and the Canadian Task Force on the Periodic Health Examination both recommend against routinely screening asymptomatic patients for hematuria to identify those with urologic malignancies.181 Tosaka et al.182 performed screening ultrasounds in a population of 41,364 asymptomatic people and found only 19 (0.04%) renal adenocarcinomas. They calculated that for every cancer detected, 2177 ultrasounds had to be performed. Thus, they concluded that the immense cost incurred would be prohibitive, and that screening should be reserved for patients at risk, such as von Hippel-Lindau disease, hereditary RCC, and acquired renal cystic disease. Therefore, populationbased screening for renal cancer with urinalysis and renal imaging can only be recommended for patients at risk for a renal malignancy.
212
Part III Kidney and Ureter
SUMMARY The treatment of RCC has undergone a dramatic change over the past several decades. While the systemic treatment of advanced disease has made relatively little progress, surgical treatment of local RCC is continuously evolving. Recent studies have indicated that radical nephrectomy is warranted for certain patients in the face of metastatic disease. For all but the largest of renal tumors or the presence of renal vein thrombi, ORN has been replaced with LRN. Even these cases are starting to be tackled laparoscopically by some surgeons. Additionally, small renal tumors are being treated with nephron-sparing surgery, despite normal contralateral kidneys. Even open partial nephrectomy is now being challenged by exciting new laparoscopic and ablative techniques. While the longterm results of these techniques are still maturing, the initial results are very promising.
REFERENCES 1. Robson CJ, Churchill BM, Anderson W: The results of radical nephrectomy for renal cell carcinoma. Trans Am Assoc Genitourin Surg 1968; 60:122–129. 2. Chan DY, Marshall FF: Partial nephrectomy for centrally located tumors. Urology 1999; 54:1088–1091. (Discussion 1091–1092.) 3. Polascik TJ, Pound CR, Meng MV, et al: Partial nephrectomy: technique, complications and pathological findings. J Urol 1995; 154:1312–1318. 4. Clayman RV, Kavoussi LR, Soper NJ, et al: Laparoscopic nephrectomy: initial case report. J Urol 1991; 146:278–282. 5. Winfield HN, Donovan JF, Lund GO, et al: Laparoscopic partial nephrectomy: initial experience and comparison to the open surgical approach. J Urol 1995; 153:1409–1414. 6. Bishoff JT, Chen RB, Lee BR, et al: Laparoscopic renal cryoablation: acute and long-term clinical, radiographic, and pathologic effects in an animal model and application in a clinical trial. J Endourol 1999; 13:233–239. 7. Gill IS, Novick AC, Meraney AM, et al: Laparoscopic renal cryoablation in 32 patients. Urology 2000; 56:748–753. 8. Chow WH, Devesa SS, Warren JL, et al: Rising incidence of renal cell cancer in the United States. JAMA 1999; 281:1628–1631. 9. Jayson M, Sanders H: Increased incidence of serendipitously discovered renal cell carcinoma. Urology 1998; 51:203–205. 10. Konnak JW, Grossman HB: Renal cell carcinoma as an incidental finding. J Urol 1985; 134:1094–1096. 11. Thompson IM, Peek M: Improvement in survival of patients with renal cell carcinoma—the role of the serendipitously detected tumor. J Urol 1988; 140:487–490.
12. Grawitz P: Die Enstehung von Nierentumoren aus Nebennierengewebe. Arch Klin Chir 30:8241883. 13. Storkel S, Eble JN, Adlakha K, et al: Classification of renal cell carcinoma: Workgroup No. 1. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 1997; 80:987–989. 14. Kovacs G, Akhtar M, Beckwith BJ, et al: The Heidelberg classification of renal cell tumours. J Pathol 1997; 183:131–133. 15. Kovacs G: Molecular differential pathology of renal cell tumours. Histopathology 1993; 22:1–8. 16. Mancilla-Jimenez R, Stanley RJ, Blath RA: Papillary renal cell carcinoma: a clinical, radiologic, and pathologic study of 34 cases. Cancer 1976; 38:2469–2480. 17. Guinan PD, Vogelzang NJ, Fremgen AM, et al: Renal cell carcinoma: tumor size, stage and survival. Members of the Cancer Incidence and End Results Committee. J Urol 1995; 153:901–903. 18. Thoenes W, Storkel S, Rumpelt HJ: Human chromophobe cell renal carcinoma. Virchows Arch B Cell Pathol Incl Mol Pathol 1985; 48:207–217. 19. Fleming S, Lewi HJ: Collecting duct carcinoma of the kidney. Histopathology 1986; 10:1131–1141. 20. Thoenes W, Storkel S, Rumpelt HJ: Histopathology and classification of renal cell tumors (adenomas, oncocytomas and carcinomas). The basic cytological and histopathological elements and their use for diagnostics. Pathol Res Pract 1986; 181:125–143. 21. Kennedy SM, Merino MJ, Linehan WM, et al: Collecting duct carcinoma of the kidney. Hum Pathol 1990; 21:449–456. 22. Davidson AJ, Choyke PL, Hartman DS, et al: Renal medullary carcinoma associated with sickle cell trait: radiologic findings. Radiology 1995; 195:83–85. 23. Friedrichs P, Lassen P, Canby E, et al: Renal medullary carcinoma and sickle cell trait. J Urol 1997; 157:1349. 24. Avery RA, Harris JE, Davis CJ Jr, et al: Renal medullary carcinoma: clinical and therapeutic aspects of a newly described tumor. Cancer 1996; 78:128–132. 25. Davis CJ Jr, Mostofi FK, Sesterhenn IA: Renal medullary carcinoma. The seventh sickle cell nephropathy. Am J Surg Pathol 1995; 19:1–11. 26. Mian BM, Bhadkamkar N, Slaton JW, et al: Prognostic factors and survival of patients with sarcomatoid renal cell carcinoma. J Urol 2002; 167:65–70. 27. Young AN, de Oliveira Salles PG, Lim SD, et al: Beta defensin-1, parvalbumin, and vimentin: a panel of diagnostic immunohistochemical markers for renal tumors derived from gene expression profiling studies using cDNA microarrays. Am J Surg Pathol 2003; 27:199–205. 28. Marshall FF, Stewart AK, Menck HR: The National Cancer Data Base: report on kidney cancers. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1997; 80:2167–2174.
Chapter 11 Renal Cell Carcinoma: Localized Disease 29. Godley P, Kim SW: Renal cell carcinoma. Curr Opin Oncol 2002; 14:280–285. 30. Schillinger F: Acquired cystic kidney disease in renal insufficiency: a multicentre study. Group of Nephrologists of the East of France. Eur J Med 1993; 2:457–460. 31. Hoshida Y, Nakanishi H, Shin M, et al: Renal neoplasias in patients receiving dialysis and renal transplantation: clinico-pathological features and p53 gene mutations. Transplantation 1999; 68:385–390. 32. Kuper H, Boffetta P, Adami HO: Tobacco use and cancer causation: association by tumour type. J Intern Med 2002; 252:206–224. 33. Chow WH, Gridley G, Fraumeni JF Jr, et al: Obesity, hypertension, and the risk of kidney cancer in men. N Engl J Med 2000; 343:1305–1311. 34. Mandel JS, McLaughlin JK, Schlehofer B, et al: International renal-cell cancer study. IV. Occupation. Int J Cancer 1995; 61:601–605. 35. Lynge E, Andersen A, Nilsson R, et al: Risk of cancer and exposure to gasoline vapors. Am J Epidemiol 1997; 145:449–458. 36. Gago-Dominguez M, Yuan JM, Castelao JE, et al: Regular use of analgesics is a risk factor for renal cell carcinoma. Br J Cancer 1999; 81:542–548. 37. Lindblad P, Wolk A, Bergstrom R, et al: The role of obesity and weight fluctuations in the etiology of renal cell cancer: a population-based case-control study. Cancer Epidemiol Biomarkers Prev 1994; 3:631–639. 38. Mattioli S, Truffelli D, Baldasseroni A, et al: Occupational risk factors for renal cell cancer: a case— control study in northern Italy. J Occup Environ Med 2002; 44:1028–1036. 39. Shapiro JA, Williams MA, Weiss NS: Body mass index and risk of renal cell carcinoma. Epidemiology 1999; 10:188–191. 40. Lang EK, Macchia RJ, Thomas R, et al: Improved detection of renal pathologic features on multiphasic helical CT compared with IVU in patients presenting with microscopic hematuria. Urology 2003; 61:528–532. 41. Wood BJ, Khan MA, McGovern F, et al: Imaging guided biopsy of renal masses: indications, accuracy and impact on clinical management. J Urol 1999; 161:1470–1474. 42. Lechevallier E, Andre M, Barriol D, et al: Fine-needle percutaneous biopsy of renal masses with helical CT guidance. Radiology 2000; 216:506–510. 43. Harisinghani MG, Maher MM, Gervais DA, et al: Incidence of malignancy in complex cystic renal masses (Bosniak category III): should imaging-guided biopsy precede surgery? Am J Roentgenol 2003; 180:755–758. 44. Flanigan RC, Salmon SE, Blumenstein BA, et al: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001; 345:1655–1659. 45. Mickisch GH, Garin A, van Poppel H, et al: Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renalcell carcinoma: a randomised trial. Lancet 2001; 358:966–970.
213
46. Krishnamurthi V, Novick AC, Bukowski RM: Efficacy of multimodality therapy in advanced renal cell carcinoma. Urology 1998; 51:933–937. 47. Fergany AF, Hafez KS, Novick AC: Long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year follow-up. J Urol 2000; 163:442–445. 48. Dunn MD, Portis AJ, Shalhav AL, et al: Laparoscopic versus open radical nephrectomy: a 9-year experience. J Urol 2000; 164:1153–1159. 49. Parra RO, Perez MG, Boullier JA, et al: Comparison between standard flank versus laparoscopic nephrectomy for benign renal disease. J Urol 1995; 153:1171–1173. (Discussion 1173–1174.) 50. Ratner LE, Kavoussi LR, Sroka M, et al: Laparoscopic assisted live donor nephrectomy—a comparison with the open approach. Transplantation 1997; 63:229–233. 51. Marshall FF: Radical nephrectomy: flank approaches. In Marshall FF (ed): Textbook of Operative Urology, pp 248–255. Philadelphia, Pennsylvania, WB Saunders, 1996. 52. Kumar S, Duque JL, Guimaraes KC, et al: Short and long-term morbidity of thoracoabdominal incision for nephrectomy: a comparison with the flank approach. J Urol 1999; 162:1927–1929. 53. Gill IS: Retroperitoneal laparoscopic nephrectomy. Urol Clin North Am 1998; 25:343–360. 54. McDougall EM, Clayman RV: Laparoscopic nephrectomy for benign disease: comparison of the transperitoneal and retroperitoneal approaches. J Endourol 1996; 10:45–49. 55. Gill IS, Strzempkowski B, Kaouk J, et al: Prospective randomized comparison: transperitoneal vs retroperitoneal laparoscopic radical nephrectomy. J Urol 2002; 167:19. 56. Abbou CC, Cicco A, Gasman D, et al: Retroperitoneal laparoscopic versus open radical nephrectomy. J Urol 1999; 161:1776–1780. 57. Nelson CP, Wolf JS Jr: Comparison of hand assisted versus standard laparoscopic radical nephrectomy for suspected renal cell carcinoma. J Urol 2002; 167:1989–1994. 58. Ono Y, Kinukawa T, Hattori R, et al: Laparoscopic radical nephrectomy for renal cell carcinoma: a five-year experience. Urology 1999; 53:280–286. 59. Gill IS, Schweizer D, Hobart MG, et al: Retroperitoneal laparoscopic radical nephrectomy: the Cleveland clinic experience. J Urol 2000; 163:1665–1670. Lotan Y, Gettman MT, Roehrborn CG, et al: Laparoscopic nephrectomy is cost effective compared to open nephrectom in a large country hospital. JSLS 2003; 7:111–15 60. Portis AJ, Yan Y, Landman J, et al: Long-term follow-up after laparoscopic radical nephrectomy. J Urol 2002; 167:1257–1262. 61. Gill IS, Meraney AM, Schweizer DK, et al: Laparoscopic radical nephrectomy in 100 patients: a single center experience from the United States. Cancer 2001; 92:1843–1855. 62. Cadeddu JA, Ono Y, Clayman RV, et al: Laparoscopic nephrectomy for renal cell cancer: evaluation of efficacy and safety: a multicenter experience. Urology 1998; 52:773–777.
214
Part III Kidney and Ureter
63. Chan DY, Cadeddu JA, Jarrett TW, et al: Laparoscopic radical nephrectomy: cancer control for renal cell carcinoma. J Urol 2001; 166:2095–2099. (Discussion 2099–2100.) 64. Kruitwagen RF, Swinkels BM, Keyser KG, et al: Incidence and effect on survival of abdominal wall metastases at trocar or puncture sites following laparoscopy or paracentesis in women with ovarian cancer. Gynecol Oncol 1996; 60:233–237. 65. Lacy AM, Garcia-Valdecasas JC, Delgado S, et al: Postoperative complications of laparoscopic-assisted colectomy. Surg Endosc 1997; 11:119–122. 66. Schaeff B, Paolucci V, Thomopoulos J: Port site recurrences after laparoscopic surgery. A review. Dig Surg 1998; 15:124–134. 67. Vukasin P, Ortega AE, Greene FL, et al: Wound recurrence following laparoscopic colon cancer resection. Results of the American Society of Colon and Rectal Surgeons Laparoscopic Registry. Dis Colon Rectum 1996; 39:S20–S23. 68. Bangma CH, Kirkels WJ, Chadha S, et al: Cutaneous metastasis following laparoscopic pelvic lymphadenectomy for prostatic carcinoma. J Urol 1995; 153:1635–1636. 69. Stolla V, Rossi D, Bladou F, et al: Subcutaneous metastases after coelioscopic lymphadenectomy for vesical urothelial carcinoma. Eur Urol 1994; 26:342–343. 70. Rassweiler JJ, Paz A, Gaitonde KD, Seemann O, Frede T: Laparoscopic surgery for urologic malignancies—the risk of local recurrence and port site metastasis. J Urol 2002; 167, Abstract 84. 71. Castilho LN, Fugita OE, Mitre AI, et al: Port site tumor recurrences of renal cell carcinoma after videolaparoscopic radical nephrectomy. J Urol 2001; 165:519. 72. Fentie DD, Barrett PH, Taranger LA: Metastatic renal cell cancer after laparoscopic radical nephrectomy: long-term follow-up. J Endourol 2000; 14:407–411. 73. Landman J, Lento P, Hassen W, et al: Feasibility of pathological evaluation of morcellated kidneys after radical nephrectomy. J Urol 2000; 164:2086–2089. 74. Meng MV, Koppie TM, Duh QY, et al: Novel method of assessing surgical margin status in laparoscopic specimens. Urology 2001; 58:677–681. 75. Urban DA, Kerbl K, McDougall EM, et al: Organ entrapment and renal morcellation: permeability studies. J Urol 1993; 150:1792–1794. 76. Walther MM, Lyne JC, Libutti SK, et al: Laparoscopic cytoreductive nephrectomy as preparation for administration of systemic interleukin-2 in the treatment of metastatic renal cell carcinoma: a pilot study. Urology 1999; 53:496–501. 77. Gettman MT, Napper C, Corwin TS, et al: Laparoscopic radical nephrectomy: prospective assessment of impact of intact versus fragmented specimen removal on postoperative quality of life. J Endourol 2002; 16:23–26.
78. Hatcher PA, Anderson EE, Paulson DF, et al: Surgical management and prognosis of renal cell carcinoma invading the vena cava. J Urol 1991; 145:20–23. (Discussion 23–24.). 79. Nesbitt JC, Soltero ER, Dinney CP, et al: Surgical management of renal cell carcinoma with inferior vena cava tumor thrombus. Ann Thorac Surg 1997; 63:1592–1600. 80. Skinner DG, Pritchett TR, Lieskovsky G, et al: Vena caval involvement by renal cell carcinoma. Surgical resection provides meaningful long-term survival. Ann Surg 1989; 210:387–392. (Discussion 392–394.) 81. Berg AA: Malignant hypernephroma of the kidney. Its clinical course and diagnosis, with a description of the author’s method of radical operative cure. Surg Gynecol Obstet 1913; 17:463. 82. Sosa RE, Muecke EC, Vaughan ED Jr, et al: Renal cell carcinoma extending into the inferior vena cava: the prognostic significance of the level of vena caval involvement. J Urol 1984; 132:1097–1100. 83. Glazer AA, Novick AC: Long-term follow-up after surgical treatment for renal cell carcinoma extending into the right atrium. J Urol 1996; 155:448–450. 84. Montie JE, el Ammar R, Pontes JE, et al: Renal cell carcinoma with inferior vena cava tumor thrombi. Surg Gynecol Obstet 1991; 173:107–115. 85. Staehler G, Brkovic D: The role of radical surgery for renal cell carcinoma with extension into the vena cava. J Urol 2000; 163:1671–1675. 86. Tsui KH, Shvarts O, Barbaric Z, et al: Is adrenalectomy a necessary component of radical nephrectomy? UCLA experience with 511 radical nephrectomies. J Urol 2000; 163:437–441. 87. Paul R, Mordhorst J, Busch R, et al: Adrenal sparing surgery during radical nephrectomy in patients with renal cell cancer: a new algorithm. J Urol 2001; 166:59–62. 88. Blom JH, van Poppel H, Marechal JM, et al: Radical nephrectomy with and without lymph node dissection: preliminary results of the EORTC randomized phase III protocol 30881. EORTC Genitourinary Group. Eur Urol 1999; 36:570–575. 89. Marshall FF, Powell KC: Lymphadenectomy for renal cell carcinoma: anatomical and therapeutic considerations. J Urol 1982; 128:677–681. 90. Minervini A, Lilas L, Morelli G, et al: Regional lymph node dissection in the treatment of renal cell carcinoma: is it useful in patients with no suspected adenopathy before or during surgery? BJU Int 2001; 88:169–172. 91. Giuliani L, Giberti C, Martorana G, et al: Radical extensive surgery for renal cell carcinoma: long-term results and prognostic factors. J Urol 1990; 143:468–473. (Discussion 473–474.) 92. Herrlinger A, Schrott KM, Schott G, et al: What are the benefits of extended dissection of the regional renal lymph nodes in the therapy of renal cell carcinoma. J Urol 1991; 146:1224–1227.
Chapter 11 Renal Cell Carcinoma: Localized Disease 93. Ditonno P, Traficante A, Battaglia M, et al: Role of lymphadenectomy in renal cell carcinoma. Prog Clin Biol Res 1992; 378:169–174. 94. Siminovitch JP, Montie JE, Straffon RA: Lymphadenectomy in renal adenocarcinoma. J Urol 1982; 127:1090–1091. 95. Karayiannakis AJ, Makri GG, Mantzioka A, et al: Systemic stress response after laparoscopic or open cholecystectomy: a randomized trial. Br J Surg 1997; 84:467–471. 96. Rassweiler JJ, Frede T, Lenz E, et al: Long-term experience with laparoscopic retroperitoneal lymph node dissection in the management of low-stage testis cancer. Eur Urol 2000; 37:251–260. 97. Henriksson C, Haraldsson G, Aldenborg F, et al: Skeletal metastases in 102 patients evaluated before surgery for renal cell carcinoma. Scand J Urol Nephrol 1992; 26:363–366. 98. Nishiyama K, Shirahama T, Yoshimura A, et al: Expression of the multidrug transporter, P-glycoprotein, in renal and transitional cell carcinomas. Cancer 1993; 71:3611–3619. 99. de Riese W, Goldenberg K, Allhoff E, et al: Metastatic renal cell carcinoma (RCC): spontaneous regression, long-term survival and late recurrence. Int Urol Nephrol 1991; 23:13–25. 100. Oliver RT, Nethersell AB, Bottomley JM: Unexplained spontaneous regression and alpha-interferon as treatment for metastatic renal carcinoma. Br J Urol 1989; 63:128–131. 101. Ueno H, Mochizuki H, Hatsuse K, et al: Indicators for treatment strategies of colorectal liver metastases. Ann Surg 2000; 231:59–66. 102. van der Poel HG, Roukema JA, Horenblas S, et al: Metastasectomy in renal cell carcinoma: a multicenter retrospective analysis. Eur Urol 1999; 35:197–203. 103. Franklin JR, Figlin R, Rauch J, et al: Cytoreductive surgery in the management of metastatic renal cell carcinoma: the UCLA experience. Semin Urol Oncol 1996; 14:230–236. 104. Robertson CN, Linehan WM, Pass HI, et al: Preparative cytoreductive surgery in patients with metastatic renal cell carcinoma treated with adoptive immunotherapy with interleukin-2 or interleukin-2 plus lymphokine activated killer cells. J Urol 1990; 144:614–617. (Discussion 617–618.) 105. Flanigan RC, Yonover PM: The role of radical nephrectomy in metastatic renal cell carcinoma. Semin Urol Oncol 2001; 19:98–102. 106. Kim B, Louie AC: Surgical resection following interleukin 2 therapy for metastatic renal cell carcinoma prolongs remission. Arch Surg 1992; 127:1343–1349. 107. Sella A, Swanson DA, Ro JY, et al: Surgery following response to interferon-alpha-based therapy for residual renal cell carcinoma. J Urol 1993; 149:19–21. (Discussion 21–22.) 108. Rackley R, Novick A, Klein E, et al: The impact of adjuvant nephrectomy on multimodality treatment of metastatic renal cell carcinoma. J Urol 1994; 152:1399–1403. 109. Novick AC: Nephron-sparing surgery for renal cell carcinoma. Annu Rev Med 2002; 53:393–407.
215
110. Cadeddu JA: Re: Cable tie compression to facilitate laparoscopic partial nephrectomy. J Urol 2001; 166:219. 111. Gettman MT, Bishoff JT, Su LM, et al: Hemostatic laparoscopic partial nephrectomy: initial experience with the radiofrequency coagulation-assisted technique. Urology 2001; 58:8–11. 112. Gill IS, Munch LC, Clayman RV, et al: A new renal tourniquet for open and laparoscopic partial nephrectomy. J Urol 1995; 154:1113–1116. 113. Hubert J, Mourey E, Suty JM, et al: Water-jet dissection in renal surgery: experimental study of a new device in the pig. Urol Res 1996; 24:355–359. 114. Gill IS, Desai MM, Kaouk JH, et al: Laparoscopic partial nephrectomy for renal tumor: duplicating open surgical techniques. J Urol 2002; 167:469–475 (Discussion 475–476.) 115. Lerner SE, Hawkins CA, Blute ML, et al: Disease outcome in patients with low stage renal cell carcinoma treated with nephron sparing or radical surgery. J Urol 1996; 155:1868–1873. 116. Sutherland SE, Resnick MI, Maclennan GT, et al: Does the size of the surgical margin in partial nephrectomy for renal cell cancer really matter? J Urol 2002; 167:61–64. 117. Bosniak MA: Observation of small incidentally detected renal masses. Semin Urol Oncol 1995; 13:267–272. 118. Rendon RA, Stanietzky N, Panzarella T, et al: The natural history of small renal masses. J Urol 2000; 164:1143–1147. 119. Chosy SG, Nakada SY, Lee FT Jr, et al: Monitoring renal cryosurgery: predictors of tissue necrosis in swine. J Urol 1998; 159:1370–1374. 120. Delworth MG, Pisters LL, Fornage BD, et al: Cryotherapy for renal cell carcinoma and angiomyolipoma. J Urol 1996; 155:252–254. (Discussion 254–255.) 121. Gill IS, Novick AC, Soble JJ, et al: Laparoscopic renal cryoablation: initial clinical series. Urology 1998; 52:543–551. 122. Uchida M, Imaide Y, Sugimoto K, et al: Percutaneous cryosurgery for renal tumours. Br J Urol 1995; 75:132–136. (Discussion 136–137.) 123. Shingleton WB, Sewell PE Jr: Percutaneous renal tumor cryoablation with magnetic resonance imaging guidance. J Urol 2001; 165:773–776. 124. Zincke H, Dechet CB, Blute ML: Prospective analysis of needle biopsy of solid renal masses. J Urol 1999; 161(45):169. 125. Shingleton WB, Sewell PW: Percutaneous renal cryoablation—24 and 36 month follow-up. J Endourol 2002; 16:A133. 126. Sung GT, Meraney AM, Schweizer DK, et al: Laparoscopic renal cryoablation in 50 patients: intermediate follow-up. J Urol 2001; 165(S):158. 127. Shingleton WS, Sewell PE: Percutaneous renal cryoablation for renal tumors: one-year follow-up. J Urol 2001; 165(S):186. 128. Jacomides L, Ogan K, Watumull L, et al: Laparoscopic application of radio frequency energy enables in situ renal tumor ablation and partial nephrectomy. J Urol 2003; 169:49–53. (Discussion 53.)
216
Part III Kidney and Ureter
129. McGovern FJ, McDougal WS, Gervais D, et al: Percutaneous radiofrequency ablation of human renal cell carcinoma. J Urol 2001; 165(S):157. 130. Pavlovich CP, Walther MM, Choyke PL, et al: Percutaneous radio frequency ablation of small renal tumors: initial results. J Urol 2002; 167:10–15. 131. Curley SA, Izzo F, Ellis LM, et al: Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis. Ann Surg 2000; 232:381–391. 132. Wood TF, Rose DM, Chung M, et al: Radiofrequency ablation of 231 unresectable hepatic tumors: indications, limitations, and complications. Ann Surg Oncol 2000; 7:593–600. 133. Zlotta AR, Wildschutz T, Raviv G, et al: Radiofrequency interstitial tumor ablation (RITA) is a possible new modality for treatment of renal cancer: ex vivo and in vivo experience. J Endourol 1997; 11:251–258. 134. Gervais DA, McGovern FJ, Wood BJ, et al: Radiofrequency ablation of renal cell carcinoma: early clinical experience. Radiology 2000; 217:665–672. 135. Rhim H, Goldberg N, Dodd GD, et al: Essential techniques for successful radiofrequency thermal ablation of malignant hepatic tumors. Radiographics 2001; 21:S17–S39. 136. Walther MC, Choyke PL, Libutti SK: A phase 2 study of radio frequency interstitial tissue ablation of localized renal tumors. J Urol 2000; 163:1424. 137. Dupuy DE, Goldberg SN: Image-guided radiofrequency tumor ablation: challenges and opportunities—part II. J Vasc Interv Radiol 2001; 12:1135–1148. 138. Yohannes P, Pinto P, Rotariu P, et al: Retroperitoneoscopic radiofrequency ablation of a solid renal mass. J Endourol 2001; 15:845–849. 139. Yang R, Reilly CR, Rescorla FJ, et al: High-intensity focused ultrasound in the treatment of experimental liver cancer. Arch Surg 1991; 126:1002–1009. (Discussion 1009–1010.) 140. Foster RS, Bihrle R, Sanghvi N, et al: Production of prostatic lesions in canines using transrectally administered high-intensity focused ultrasound. Eur Urol 1993; 23:330–336. 141. Bihrle R, Foster RS, Sanghvi NT, et al: High intensity focused ultrasound for the treatment of benign prostatic hyperplasia: early United States clinical experience. J Urol 1994; 151(5):1271–1275. 142. Gelet A, Chapelon JY, Bouvier R: Treatment of organ confined prostatic cancer by high intensity ultrasound (HIFU) delivered by transrectal route: pilot study. J Urol 1995; 153: 629A. 143. Chapelon JY, Margonari J, Theillere Y, et al: Effects of high-energy focused ultrasound on kidney tissue in the rat and the dog. Eur Urol 1992; 22:147–152. 144. Adams JB, Moore RG, Anderson JH, et al: Highintensity focused ultrasound ablation of rabbit kidney tumors. J Endourol 1996; 10:71–75. 145. Watkin NA, Morris SB, Rivens IH, et al: High-intensity focused ultrasound ablation of the kidney in a large animal model. J Endourol 1997; 11:191–196.
146. Vallancien G, Chartier-Kastler E, Harouni M, et al: Focused extracorporeal pyrotherapy: experimental study and feasibility in man. Semin Urol 1993; 11:7–9. 147. Ponsky LE, Crownover RL, Rosen MJ, et al: The initial evaluation of the cyberknife technology for extracorporeal renal tissue ablation. Urology 2003; 61(3):498–501 148. Mejean A, Oudard S, Thiounn N: Prognostic factors of renal cell carcinoma. J Urol 2003; 169:821–827. 149. Javidan J, Stricker HJ, Tamboli P, et al: Prognostic significance of the 1997 TNM classification of renal cell carcinoma. J Urol 1999; 162:1277–1281. 150. Gettman MT, Blute ML, Spotts B, et al: Pathologic staging of renal cell carcinoma: significance of tumor classification with the 1997 TNM staging system. Cancer 2001; 91:354–361. 151. Hafez KS, Fergany AF, Novick AC: Nephron sparing surgery for localized renal cell carcinoma: impact of tumor size on patient survival, tumor recurrence and TNM staging. J Urol 1999; 162:1930–1933. 152. Kinouchi T, Saiki S, Meguro N, et al: Impact of tumor size on the clinical outcomes of patients with Robson State I renal cell carcinoma. Cancer 1999; 85:689–695. 153. Giberti C, Oneto F, Martorana G, et al: Radical nephrectomy for renal cell carcinoma: long-term results and prognostic factors on a series of 328 cases. Eur Urol 1997; 31:40–48. 154. Tongaonkar HB, Dandekar NP, Dalal AV, et al: Renal cell carcinoma extending to the renal vein and inferior vena cava: results of surgical treatment and prognostic factors. J Surg Oncol 1995; 59:94–100. 155. Elfving P, Mandahl N, Lundgren R, et al: Prognostic implications of cytogenetic findings in kidney cancer. Br J Urol 1997; 80:698–706. 156. Medeiros LJ, Gelb AB, Weiss LM: Renal cell carcinoma. Prognostic significance of morphologic parameters in 121 cases. Cancer 1988; 61:1639–1651. 157. Griffiths DF, Verghese A, Golash A, et al: Contribution of grade, vascular invasion and age to outcome in clinically localized renal cell carcinoma. BJU Int 2002; 90:26–31. 158. Palmer PA, Vinke J, Philip T, et al: Prognostic factors for survival in patients with advanced renal cell carcinoma treated with recombinant interleukin-2. Ann Oncol 1992; 3:475–480. 159. Elson PJ, Witte RS, Trump DL: Prognostic factors for survival in patients with recurrent or metastatic renal cell carcinoma. Cancer Res 1988; 48:7310–7313. 160. Miyao N, Oda T, Shigyou M, et al: Pre-operatively determined prognostic factors in metastatic renal cell carcinoma. Eur Urol 1997; 31:292–296. 161. Kavolius JP, Mastorakos DP, Pavlovich C, et al: Resection of metastatic renal cell carcinoma. J Clin Oncol 1998; 16:2261–2266. 162. Negrier S, Escudier B, Lasset C, et al: Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d’Immunotherapie. N Engl J Med 1998; 338:1272–1278.
Chapter 11 Renal Cell Carcinoma: Localized Disease 163. Chao D, Zisman A, Pantuck AJ, et al: Collecting duct renal cell carcinoma: clinical study of a rare tumor. J Urol 2002; 167:71–74. 164. Grabowski M, Huzarski T, Lubinski J, et al: Survival in patients with rare subtypes of renal cell carcinoma. BJU Int 2002; 89:599–600. 165. Bretheau D, Lechevallier E, de Fromont M, et al: Prognostic value of nuclear grade of renal cell carcinoma. Cancer 1995; 76:2543–2549. 166. Thrasher JB, Paulson DF: Prognostic factors in renal cancer. Urol Clin North Am 1993; 20:247–262. 167. Carducci MA, Piantadosi S, Pound CR, et al: Nuclear morphometry adds significant prognostic information to stage and grade for renal cell carcinoma. Urology 1999; 53:44–49. 168. Pound CR, Partin AW, Epstein JI, et al: Nuclear morphometry accurately predicts recurrence in clinically localized renal cell carcinoma. Urology 1993; 42:243–248. 169. Ruiz JL, Hernandez M, Martinez J, et al: Value of morphometry as an independent prognostic factor in renal cell carcinoma. Eur Urol 1995; 27:54–57. 170. Tsui KH, Shvarts O, Smith RB, et al: Renal cell carcinoma: prognostic significance of incidentally detected tumors. J Urol 2000; 163:426–430. 171. Fossa SD, Kramar A, Droz JP: Prognostic factors and survival in patients with metastatic renal cell carcinoma treated with chemotherapy or interferon-alpha. Eur J Cancer 1994; 30A:1310–1314. 172. Lissoni P, Barni S, Ardizzoia A, et al: Prognostic factors of the clinical response to subcutaneous immunotherapy with interleukin-2 alone in patients with metastatic renal cell carcinoma. Oncology 1994; 51:59–62. 173. van der Poel HG, Mulders PF, Oosterhof GO, et al: Prognostic value of karyometric and clinical characteristics
174.
175.
176.
177.
178.
179. 180.
181.
182.
217
in renal cell carcinoma. Quantitative assessment of tumor heterogeneity. Cancer 1993; 72:2667–2674. Ljungberg B, Grankvist K, Rasmuson T: Serum acute phase reactants and prognosis in renal cell carcinoma. Cancer 1995; 76:1435–1439. O’Keefe SC, Marshall FF, Issa MM, et al: Thrombocytosis is associated with a significant increase in the cancer specific death rate after radical nephrectomy. J Urol 2002; 168:1378–1380. Yasunaga Y, Shin M, Miki T, et al: Prognostic factors of renal cell carcinoma: a multivariate analysis. J Surg Oncol 1998; 68:11–18. Kattan MW, Reuter V, Motzer RJ, et al: A postoperative prognostic nomogram for renal cell carcinoma. J Urol 2001; 166:63–67. Zisman A, Pantuck AJ, Dorey F, et al: Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol 2001; 19:1649–1657. Carter WC III, Rous SN: Gross hematuria in 110 adult urologic hospital patients. Urology 1981; 18:342–344. Warshauer DM, McCarthy SM, Street L, et al: Detection of renal masses: sensitivities and specificities of excretory urography/linear tomography, US, and CT. Radiology 1988; 169:363–365. Grossfeld GD, Litwin MS, Wolf JS, et al: Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy— part I: definition, detection, prevalence, and etiology. Urology 2001; 57:599–603. Tosaka A, Ohya K, Yamada K, et al: Incidence and properties of renal masses and asymptomatic renal cell carcinoma detected by abdominal ultrasonography. J Urol 1990; 144:1097–1099.
C H A P T E R
12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy Andrew C. Novick, MD
Notwithstanding recent advances in our understanding of the genetics and biology of renal cell carcinoma (RCC), surgery remains the mainstay of curative treatment for this disease. Nevertheless, the role of surgery is changing with respect to both localized RCC and patients with metastatic disease. Nephron-sparing surgery has assumed an increasing role in the management of localized tumors. The advent of promising immunotherapy regimens and their adjunctive use with surgery offers new hope for patients with disseminated malignancy. This chapter will review the contemporary role of surgery and specific operative techniques in the management of patients with RCC. RADICAL NEPHRECTOMY Indications and Evaluation Radical nephrectomy is the treatment of choice for patients with localized RCC.1 The preoperative evaluation of patients with RCC has changed considerably in recent years due to the advent of new imaging modalities, such as ultrasonography, computed tomography (CT) scanning, and magnetic resonance imaging (MRI). In many patients, a complete preliminary evaluation can be performed using these noninvasive modalities. Renal arteriography is no longer routinely necessary prior to performing radical nephrectomy. All patients should undergo a metastatic evaluation including a chest X-ray, abdominal CT scan, and occasionally a bone scan; the latter is only necessary in patients with bone pain or an elevated serum alkaline phosphatase. Radical nephrectomy is occasionally done in patients with metastatic disease to palliate severe associated local symptoms, to allow entry into a biologic response modifier protocol, or concomitant with resection of a solitary metastatic lesion.
218
Involvement of the inferior vena cava (IVC) with RCC occurs in 3% to 7% of cases and renders the task of complete surgical excision more complicated. Yet, operative removal offers the only hope for cure and, when there are no metastases, an aggressive approach is justified. Five-year survival rates of 40% to 58% have been reported after complete surgical excision.2–5 The best results have been achieved when the tumor does not involve the perinephric fat and regional lymph nodes. The cephalad extent of vena caval involvement is not prognostically important and, even with intraatrial tumor thrombi, extended cancer-free survival is possible following surgical treatment when there is no nodal or distant metastasis.6 In planning the appropriate operative approach for tumor removal, it is essential for preoperative radiographic studies to define accurately the distal (craniad) limits of a vena caval tumor thrombus. RCC involving the IVC should be suspected in patients who have lower extremity edema, a varicocele, dilated superficial abdominal veins, proteinuria, pulmonary embolism, a right atrial mass, or nonfunction of the involved kidney. Currently, MRI is the preferred diagnostic study for demonstrating both the presence and distal extent of IVC involvement.7 Transesophageal echocardiography (TEE) and transabdominal color flow Doppler ultrasonography have also proven to be useful diagnostic studies in this regard. Inferior vena cavography is reserved for patients in whom an MRI or ultrasound study is either nondiagnostic or contraindicated. Renal arteriography is particularly helpful in patients with RCC involving the IVC since in 35% to 40% of cases, distinct arterialization of a tumor thrombus is observed. When this finding is present, preoperative embolization of the kidney often causes shrinkage of the
Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy
thrombus that facilitates its intraoperative removal. When adjunctive cardiopulmonary bypass with deep hypothermic circulatory arrest is considered, coronary angiography is also performed preoperatively.4 If significant obstructing coronary lesions are found, these can be repaired simultaneously during cardiopulmonary bypass. Radical nephrectomy encompasses the basic principles of early ligation of the renal artery and vein, removal of the kidney outside Gerota’s fascia, removal of the ipsilateral adrenal gland, and performance of a complete lymphadenectomy from the crus of the diaphragm to the aortic bifurcation.1 Perhaps the most important aspect of radical nephrectomy is removal of the kidney outside Gerota’s fascia, because capsular invasion with perinephric fat involvement occurs in 25% of patients. Removal of the ipsilateral adrenal gland is not routinely necessary unless the malignancy either extensively involves the kidney or is located in the upper portion of the kidney.8 Although lymphadenectomy allows for more accurate pathologic staging, the therapeutic value remains controversial. A study from Giuliani and associates suggests that a subset of patients with micrometastatic lymph node involvement may benefit from performance of a lymphadenectomy.9 At the present time, the need for routine performance of a complete lymphadenectomy in all cases is unresolved, and there remains a divergence of clinical practice among urologists with respect to this aspect of radical nephrectomy.
219
Surgical Anatomy The anatomic relationship of the kidneys to surrounding structures is illustrated in Figure 12-1. The kidneys are located on either side of the vertebral column in the lumbar fossa of the retroperitoneal space. Each kidney is surrounded by a layer of perinephric fat that is in turn covered by a distinct fascial layer termed Gerota’s fascia. Posteriorly, both kidneys lie on the psoas major and quadratus lumborum muscles. Posteriorly and superiorly, the upper pole of each kidney is in contact with the diaphragm. A small segment of the anterior medial surface of the right kidney is in contact with the right adrenal gland. However, the major anterior relationships of the right kidney are the liver, which overlies the upper twothirds of the anterior surface, and the hepatic flexure of the colon, which overlies the lower one-third. The second portion of the duodenum covers the right renal hilum. A small segment of the anterior medial surface of the left kidney is also covered by the left adrenal gland. The major anterior relationships of the left kidney are the spleen, body of the pancreas, stomach, and splenic flexure of the colon. Surgical Incisions The surgical approach for radical nephrectomy is determined by the size and location of the tumor as well as by the habitus of the patient.10 The operation is usually per-
Figure 12-1 The anatomic relationship of the kidneys to the surrounding structures. The liver is retracted superiorly in this illustration.
220
Part III Kidney and Ureter
formed through a transperitoneal incision to allow abdominal exploration for metastatic disease and early access to the renal vessels with minimal manipulation of the tumor. Occasionally, an extraperitoneal flank incision is employed in elderly patients or in patients with small tumors who are also classified as poor risks. The author prefers an extended subcostal or a bilateral subcostal incision for most patients undergoing radical nephrectomy (Figure 12-2). This incision provides better access to the lateral and superior portion of the kidney than a midline abdominal incision. When employing an anterior subcostal incision, the patient is in the supine position with a rolled sheet beneath the upper lumbar spine. The incision begins approximately one to two fingerbreadths below the costal margin in the anterior axillary line and then extends with a gentle curve across the midline, ending at the midportion of the opposite rectus muscle. The incision is carried through the subcutaneous tissues to the anterior fascia, which is divided in the direction of the incision. In the lateral aspect of the incision, a portion of the latissimus dorsi muscle is divided. The external oblique muscle is divided, exposing the fibers of the internal oblique muscle (Figure 12-3A). The rectus, internal oblique, and transversus abdominous muscles are divided along with the posterior rectus sheath (see Figure 12-3B and C). The peritoneal cavity is entered in the midline, and the ligamentum teres is divided (see Figure 12-3D). The thoracoabdominal approach is preferable for performing radical nephrectomy in patients with large tumors involving the upper portion of the kidney (Figure 12-4). It is particularly advantageous on the right side, where the liver and its venous drainage into the upper vena cava can limit exposure and impair vascular control as the tumor mass is being removed. Less need exists for a thoracoabdominal incision on the left side because the spleen and pancreas can usually be readily elevated away
Figure 12-2 Patient positioning for anterior subcostal transperitoneal incision.
from the tumor mass. The patient is placed in a semioblique position, with a rolled sheet placed longitudinally beneath the flank. The incision is begun in the 8th intercostal space, near the angle of the rib, and is carried across the costal margin to the midpoint of the opposite rectus muscle, above the umbilicus. The latissimus dorsi, external oblique, rectus, and intercostal muscles are divided in the direction of the incision (Figure 12-5A). The pleura is then opened to obtain complete exposure of the diaphragm (see Figure 12-5B and C). The diaphragmatic incision is made at the periphery about 2 cm inside its attachment at the chest wall with the incision then being carried around circumferentially to the posterior aspect of the diaphragm (see Figure 12-5D). Circumferential incision of the diaphragm obviates damage to the phrenic nerve and also creates a diaphragmatic flap, which can be pushed into the chest to provide complete exposure of the liver, which is then retracted
Figure 12-3 A and B, The various steps in performing an anterior subcostal transperitoneal incision are illustrated (see text for details).
Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy
221
Figure 12-3 cont’d C and D, The various steps performing an anterior subcostal transperitoneal incision are illustrated (see text for details).
upward (see Figure 12-5E). If further mobilization of the liver is needed, the right triangular ligament and coronary ligament can be incised to mobilize the entire right lobe of the liver upward. This maneuver provides excellent additional exposure of the suprarenal vena cava. Medial to the ribs, the internal oblique and transversus abdominous muscles are divided and the peritoneal cavity is entered. The kidney and great vessels may then be exposed by upward retraction of the liver and medial visceral mobilization (see Figure 12-5F ). Left Radical Nephrectomy After the peritoneal cavity is entered, a thorough exploration is done to rule out metastatic disease. The poste-
Figure 12-4 Patient positioning for a right thoracoabdominal incision.
rior peritoneum lateral to the left colon is incised vertically and the incision is carried upward to divide the lienorenal ligament. Care must be taken to avoid tearing the delicate capsule of the spleen. The plane between the kidney and adrenal gland posteriorly, and the pancreas and spleen anteriorly, is developed by blunt dissection. The left colon and duodenum are reflected medially, and the pancreas and spleen are reflected cephalad, with care taken not to injure the spleen or the pancreas (Figure 12-6). When adequate exposure of the kidney and great vessels has been obtained, a self-retaining ring retractor is inserted to maintain the operative field (Figure 12-7). The operation is initiated with dissection of the renal pedicle. The left renal vein is quite long as it passes over the aorta. The vein is mobilized completely by ligating and dividing gonadal, adrenal, and lumbar tributaries. The vein can be retracted to expose the artery posteriorly, which is then mobilized toward the aorta (Figure 12-8). The renal artery is ligated with 2.0 silk ligatures and divided, and the renal vein is then similarly managed. The kidney is mobilized outside Gerota’s fascia with blunt and sharp dissection as needed (Figure 12-9). Remaining vascular attachments are secured with nonabsorbable sutures or metal clips. Visualization of the upper vascular attachments is facilitated by downward retraction of the kidney. The ureter is then ligated and divided to complete the removal of the kidney and adrenal gland (Figure 12-10). The classic description of radical nephrectomy includes the performance of a complete regional lymphadenectomy. The lymph nodes can be removed en bloc with the kidney and adrenal gland or separately, following the nephrectomy. The lymph node dissection is
222
Part III Kidney and Ureter
Figure 12-5 The various steps in performing a thoracoabdominal incision are illustrated (see accompanying text).
begun at the crura of the diaphragm just below the origin of the superior mesenteric artery. A readily definable periadventitial plane is seen close to the aorta that can be entered. The dissection may then be carried along the aorta and onto the origin of the major vessels, to remove
all the periaortic lymphatic tissue. Care must be taken to avoid injury to the origins of the celiac and superior mesenteric arteries superiorly, as they arise from the anterior surface of the aorta. The dissection of the periaortic and pericaval lymph nodes is then carried
Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy
downward en bloc to the origin of the inferior mesenteric artery. The sympathetic ganglia and nerves are removed together with the lymphatic tissue. The cisterna chyli is identified medial at the right crus. Entering lymphatic vessels are secured to prevent the development of chylous ascites. Right Radical Nephrectomy On the right side, after entering the peritoneal cavity, the posterior peritoneum lateral to the right colon is incised vertically and the incision is carried high up along the vena cava to the level of the hepatic veins. The right colon and duodenum are reflected medially, and the liver and gallbladder are retracted upward (Figure 12-11). Care is taken to avoid trauma to the delicate hepatic veins, which may enter the vena cava at this level. When adequate exposure of the kidney and adrenal gland is obtained, a self-retaining ring retractor is inserted to maintain the operative field. The vena cava and renal vein are retracted medially and downward to expose the right renal artery. Alternatively, with a large medial tumor, the renal artery may be exposed between the vena cava and the aorta (Figure 12-12). Ligation of the renal artery and vein is performed as described on the left side with 2.0 silk ligatures. Since the right renal vein is usually short, ligation should take place at the level of its entrance to the vena cava. The remainder of the radical nephrectomy is performed as described for left-sided tumors. Radical Nephrectomy with Infrahepatic Vena Caval Involvement There are four levels of vena caval involvement in RCC that are characterized according to the distal extent of the tumor thrombus (Figure 12-13). A bilateral subcostal transperitoneal incision usually provides excellent exposure for performing radical nephrectomy and removal of a perirenal or infrahepatic IVC thrombus. For extremely large tumors involving the upper pole of the kidney, a thoracoabdominal incision may alternatively be used. After the abdomen is entered, the colon is reflected medially and a self-retaining ring retractor is inserted to maintain exposure of the retroperitoneum (Figure 12-14A). The renal artery and the ureter are ligated and divided, and the entire kidney is mobilized outside Gerota’s fascia leaving the kidney attached only by the renal vein (see Figure 12-14B,C). During the initial dissection, care is taken to avoid unnecessary manipulation of the renal vein and vena cava. The vena cava is then completely dissected from surrounding structures above and below the renal vein, and the opposite renal vein is also mobilized. It is essential to
223
obtain exposure and control of the suprarenal vena cava above the level of the tumor thrombus. If necessary, perforating veins to the caudate lobe of the liver are secured and divided to allow separation of the caudate lobe from the vena cava. This maneuver can allow an additional 2 to 3 cm length of vena cava to be exposed superiorly. The infrarenal vena cava is then occluded below the thrombus with a Satinsky venous clamp, and the opposite renal vein is gently secured with a small bulldog vascular clamp. Finally, in preparation for tumor thrombectomy, a curved Satinsky clamp is placed around the suprarenal vena cava above the level of the thrombus (see Figure 12-14D). The anterior surface of the renal vein is then incised over the tumor thrombus and the incision is continued posteriorly with scissors, passing just beneath the thrombus (see Figure 12-14E). In most cases, there is no attachment of the thrombus to the wall of the vena cava. After the renal vein has been circumscribed, gentle downward traction is exerted on the kidney to extract the tumor thrombus from the vena cava (see Figure 12-14F). After removal of the gross specimen, the suprarenal vena caval clamp may be released temporarily as the anesthetist applies positive pulmonary pressure; this maneuver can ensure that any small remaining fragments of thrombus are flushed free from the vena cava. When the tumor thrombectomy is completed, the cavotomy incision is repaired with a continuous 5-0 vascular suture (see Figure 12-14G). In occasional cases, there is direct caval invasion of the tumor at the level of the entrance of the renal vein and for varying distances. This requires resection of a portion of the vena caval wall. Narrowing of the caval lumen by up to 50% will not adversely affect maintenance of caval patency. If further narrowing appears likely, caval reconstruction can be performed with a free graft of pericardium. In some patients, more extensive direct growth of tumor into the wall of the vena cava is found at surgery. The prognosis for these patients is generally poor, particularly when hepatic venous tributaries are also involved, and the decision to proceed with radical surgical excision must be carefully considered. Several important principles must be kept in mind when undertaking en bloc vena caval resection. Resection of the infrarenal portion of the vena cava usually can be done safely, because an extensive collateral venous supply will be developed in most cases. With right-sided kidney tumors, resection of the suprarenal vena cava is also possible provided the left renal vein is ligated distal to the gonadal and adrenal tributaries, which then provide collateral venous drainage from the left kidney with leftsided kidney tumors. The suprarenal vena cava cannot be resected safely owing to the paucity of collateral venous drainage from the right kidney. In such cases, right renal
224
Part III Kidney and Ureter
Figure 12-6 After entering the peritoneal cavity, the colon is reflected medially to expose the left kidney and great vessels.
Figure 12-8 The left renal vein is mobilized by ligating its major branches to expose the artery posteriorly.
Figure 12-7 A self-retaining ring retractor is inserted to maintain exposure of the operative field.
Figure 12-9 After securing the pedicle and dividing the ureter, the kidney is mobilized outside Gerota’s fascia.
Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy
225
Figure 12-12 The right renal artery may be mobilized either lateral to the vena cava (below) or between the vena cava and the aorta (above). Figure 12-10 Remaining medial vascular attachments are secured and divided to complete the nephrectomy.
Radical Nephrectomy with Intrahepatic or Suprahepatic Vena Caval Involvement
Figure 12-11 After entering the peritoneal cavity, the right colon and duodenum are reflected medially to expose the right kidney and great vessels.
venous drainage can be maintained by preserving a tumor-free strip of vena cava augmented, if necessary, with a pericardial patch; alternatively, the right kidney can be autotransplanted to the pelvis or an interposition graft of saphenous vein may be placed from the right renal vein to the splenic, inferior mesenteric, or portal vein.
In patients with RCC and an intrahepatic or suprahepatic IVC thrombus, the difficulty of surgical excision is significantly increased. In such cases, the operative technique must be modified because it is not possible to obtain subdiaphragmatic control of the vena cava above the tumor thrombus. Several different surgical maneuvers have been used to provide adequate exposure, prevent severe bleeding, and achieve complete tumor removal in this setting.4 One described technique for obtaining vascular control involves temporary occlusion of the suprahepatic and intrapericardial portion of the IVC. To reduce hepatic venous congestion and troublesome backbleeding, the porta hepatis and superior mesenteric artery are also temporarily occluded. A disadvantage of this approach is that occlusion of the latter vessels can be safely tolerated for only 20 minutes. This approach is also not applicable in cases of tumor extension into the right atrium. At the Cleveland Clinic, we have preferred to employ cardiopulmonary bypass with deep hypothermic circulatory arrest for many patients with supradiaphragmatic tumor thrombi and for all patients with right atrial tumor thrombi. We initially reported a favorable experience with this approach in 43 patients,4 and a subsequent study has shown excellent long-term cancer-free survival following its use in patients with right atrial thrombi.6 The relevant technical aspects are subsequently described.
226
Part III Kidney and Ureter
Figure 12-13 Classification of inferior vena caval thrombi according to the distal extent of the thrombus as perineal, infrahepatic, intrahepatic, and suprahepatic.
A bilateral subcostal incision is used for the abdominal portion of the operation. After confirming resectability, a median sternotomy is made (Figure 12-15). Intraoperative monitoring is accomplished with an arterial line, a multiplelumen central venous pressure catheter, and a pulmonary artery catheter. Nasopharyngeal and bladder temperatures are monitored. Anesthesia is induced with either fentanyl, sufentanil, or thiopental and maintained with a narcotic inhalation agent.11 The kidney is completely mobilized outside Gerota’s fascia with division of the renal artery and ureter, such that the kidney is left attached only by the renal vein. The infrarenal vena cava and contralateral renal vein are also exposed. Extensive dissection and mobilization of the suprarenal vena cava are not necessary with this approach. Adequate exposure is somewhat more difficult to achieve for a left renal tumor. Simultaneous exposure of the vena cava on the right and the tumor on the left is not readily accomplished simply by reflecting the left colon medially. We have dealt with this by transposing the mobilized left kidney anteriorly through a window in the mesentery of the left colon while leaving the renal vein attached. This maneuver yields excellent exposure of the abdominal vena cava with the attached left renal vein and kidney. Precise retroperitoneal hemostasis is essential before proceeding with cardiopulmonary bypass due to the risk of bleeding associated with systemic heparinization. The heart and great vessels are now exposed through the median sternotomy. The patient is heparinized, ascending aortic and right atrial venous cannulae are placed, and cardiopulmonary bypass is initiated (Figure 12-16). When the heart fibrillates, the aorta is clamped
and crystalloid cardioplegic solution is infused. Under circulatory arrest, deep hypothermia is initiated by reducing arterial inflow blood temperature as low as 10 ˚ C . The head and abdomen are packed in ice during the cooling process. After approximately 15 to 30 minutes, a core temperature of 18 to 20 ˚C is achieved. At this point, flow through the perfusion machine is stopped and 95% of the blood volume is drained into the pump with no flow to any organ. The tumor thrombus can now be removed in an essentially bloodless operative field. An incision is made in the IVC at the entrance of the involved renal vein, and the ostium is circumscribed. When the tumor extends into the right atrium, the atrium is opened at the same time (Figure 12-17). If possible, the tumor thrombus is removed intact with the kidney. Frequently, this step is not possible because of the friability of the thrombus and its adherence to the vena caval wall. In such cases, piecemeal removal of the thrombus from above and below is necessary. Occasionally, a venous Fogarty catheter can be inserted into the vena cava to assist in extraction of the thrombus. Under deep hypothermic circulatory arrest, the entire interior lumen of the vena cava can be directly inspected to ensure that all fragments of thrombus are completely removed. Hypothermic circulatory arrest can be safely maintained for at least 40 minutes without incurring a cerebral ischemic event.12 In difficult cases, this interval can be extended either by maintaining “trickle” blood flow at a rate of 5 to 10 ml/kg/minute13 or by adjunctive retrograde cerebral perfusion.14 Following complete removal of all tumor thrombus, the vena cava is closed with a continuous 5-0 vascular
Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy
Figure 12-14 Technique of radical nephrectomy and vena cava thrombectomy with infrahepatic tumor thrombus (see text for details).
227
228
Part III Kidney and Ureter
Figure 12-15 Surgical incision for performing radical nephrectomy with removal of suprahepatic vena caval tumor thrombus.
suture and the right atrium is closed. As soon as the vena cava and right atrium have been repaired, rewarming of the patient is initiated. If coronary artery bypass grafting is necessary, this procedure is done during the rewarming period. Rewarming takes 20 to 45 minutes and is continued until a core temperature of approximately 37 ˚C is obtained. Cardiopulmonary bypass is then terminated. Decannulation takes place, and protamine sulfate is administered to reverse the effects of the heparin. Platelets, fresh-frozen plasma, desmopressin acetate, or their combination may be provided when coagulopathy is suspected. Aprotinin has also proven effective in reversing the coagulopathy associated with cardiopulmonary bypass but may induce thrombotic complications. Mediastinal chest tubes are placed but the abdomen is not routinely drained. In patients with supradiaphragmatic vena caval tumor thrombi that do not extend into the right atrium, venovenous bypass in the form of a caval-atrial shunt may be employed.15 In this approach, the intrapericardiac vena cava, infrarenal vena cava, and opposite renal vein are temporarily occluded. Cannulas are then inserted into the right atrium and infrarenal vena cava. These cannulas are connected to a primed pump to maintain adequate flow from the vena cava to the right heart (Figure 12-18). This avoids the obligatory hypotension associated with temporary occlusion alone of the intrapericardiac and infrarenal vena cava. Following the initiation of venovenous bypass, the abdominal vena cava is opened and the thrombus is removed. If bleeding from the hepatic veins is troublesome during extraction of the thrombus,
Figure 12-16 Cannulae are placed in the ascending aorta and right atrium in preparation for cardiopulmonary bypass.
the porta hepatis may also be occluded (Pringle maneuver). After removal of the thrombus, repair of the vena cava is performed as previously described. This technique is simpler than cardiopulmonary bypass with hypothermic circulatory arrest but may entail more operative bleeding. PARTIAL NEPHRECTOMY Recent interest in partial nephrectomy or nephronsparing surgery for RCC has been stimulated by advances in renal imaging, improved surgical techniques, the increasing number of incidentally discovered low-stage RCCs, and good long-term survival in patients undergoing this form of treatment. Partial nephrectomy entails complete local resection of a renal tumor while leaving the largest possible amount of normal functioning parenchyma in the involved kidney. Accepted indications for partial nephrectomy include situations in which radical nephrectomy would render the patient anephric with subsequent immediate need for dialysis. This encompasses patients with bilateral RCC or RCC involving a solitary functioning kidney. The latter circumstance may be present due to unilateral renal agenesis, prior removal of the contralateral kidney, or irreversible impairment of contralateral renal function represented by patients with unilateral RCC, and a functioning opposite kidney, when the opposite kidney is affected by a condition that might threaten its future function, such as calculus disease, chronic pyelonephritis, renal artery stenosis, ureteral reflux, or systemic diseases, such as diabetes and nephrosclerosis.15
Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy
229
Figure 12-17 The ostium of the renal vein is circumferentially incised and the right atrium is opened. Following removal of the tumor thrombus, the atriotomy and vena cavotomy incisions are closed.
Figure 12-18 Technique of venovenous bypass for removal of supradiaphragmatic vena caval tumor thrombus.
Recent studies have clarified the role of partial nephrectomy in patients with localized unilateral RCC and a normal contralateral kidney. The data indicate that radical nephrectomy and partial nephrectomy provide equally effective curative treatment for such patients who present with a single, small (<4 cm), and clearly localized RCC.16 The results of partial nephrectomy are less satisfactory in patients with larger (>4 cm) or multiple localized RCCs, and radical nephrectomy remains the treatment of choice in such cases when the opposite kidney is normal. The long-term renal functional advantage of partial nephrectomy with a normal opposite kidney requires further study. The technical success rate with partial nephrectomy is excellent, and long-term patient survival rates free of cancer are comparable with those obtained after radical nephrectomy, particularly for low-stage RCC (Table 12-1).17–20 The major disadvantage of partial nephrec-
tomy for RCC is the risk of postoperative local tumor recurrence in the operated kidney, which has occurred in 4% to 6% of patients. These local recurrences are most likely a manifestation of undetected microscopic multifocal RCC in the remnant kidney. The risk of local tumor recurrence after radical nephrectomy has not been studied, but it is presumably very low. We recently reviewed the results of partial nephrectomy for treatment of localized sporadic RCC in 485 patients managed at the Cleveland Clinic before December 1996.20 A technically successful operation with the preservation of function in the treated kidney was achieved in 476 patients (98%). The overall and cancerspecific 5-year patient survival rate in the series were 81% and 93%, respectively. Recurrent RCC developed postoperatively in 44 of 485 patients (9%). Sixteen patients (3.2%) developed local recurrence in the remnant kidney, whereas 28 patients (5.8%) developed metastatic disease.
230
Part III Kidney and Ureter
More recently, we received the long-term (10-year) results of partial nephrectomy in 107 patients with localized sporadic RCC treated before 1988.21 All patients were followed up for a minimum of 10 years or until death. Cancer-specific survival was 88.2% at 5 years and 73% at 10 years. Long-term preservation of renal function was achieved in 100 patients (93%). These results attest that partial nephrectomy is an effective therapy for localized RCC that can provide both long-term tumor control and the preservation of renal function. Evaluation of patients with RCC prior to partial nephrectomy must include a detailed history and physical examination, a laboratory evaluation including serum creatinine, liver function tests, and urinalysis or urine dipstick check to screen for preoperative proteinuria. Radiographic testing is used to rule out locally extensive or metastatic disease, including chest X-ray and abdominal CT, as well as possible bone scan and chest or head CT depending on the clinical circumstances. Partial nephrectomy is more technically challenging than en bloc removal of the kidney by radical nephrectomy, and it therefore requires a more detailed understanding of renal anatomy. Knowledge of the relationship of the tumor and its vascular supply to the collecting system and adjacent normal renal parenchyma is essential for preoperative assessment, which must include a plan for complete tumor removal and reconstruction of the renal remnant. Therefore, more extensive and invasive preoperative imaging studies are often obtained before partial nephrectomy, compared with radical nephrectomy. In some instances, this includes arteriography and occasionally venography. Arteriography has been used to delineate the intrarenal vasculature and may aid in the excision of the tumor while minimizing blood loss and injury to normal adjacent parenchyma. It is most useful for nonperipheral tumors encompassing two or more renal arterial segments. Selective renal venography is performed in patients with large or centrally located tumors to evaluate for intrarenal venous thrombosis and to assess the adequacy of venous drainage of the planned renal remnant. However, these radiographic studies provide only two-dimensional views, and the risks and costs of con-
ventional arteriography and venography are significant. Furthermore, these studies yield limited anatomic spatial interrelationships between the tumor, normal parenchyma, collecting system, and vascular supply. Advances in helical CT and computer technology now allow the production of high quality, three-dimensional images of the renal vasculature and soft tissue anatomy in any plane. New volume-rendering software allows realtime interactive stereoscopic viewing of these images and provides a topographic road map of the renal surface and multiplanar views of the intrarenal anatomy. This permits the complex renal anatomy to be evaluated by using a single unified study in a format that is familiar to the surgeon and consistent with intraoperative findings, thereby obviating mental reconstruction of several twodimensional imaging studies. A detailed prospective study at the Cleveland Clinic showed the utility of three-dimensional volume-rendering CT in accurately showing the renal parenchyma and vascular anatomy necessary for the performance of partial nephrectomy.22 The data from three-dimensional CT integrate essential information from angiography, venography, excretory urography, and conventional two-dimensional CT into a single preoperative staging test that diminishes the need for more invasive imaging. The use of a 3 to 5-minute videotape in the operating room provides concise, accurate, and immediate three-dimensional information to the surgeon during the dissection, allowing him or her to anticipate the subtleties of the anatomy. Three-dimensional, volume-rendered CT has become the imaging modality of choice before partial nephrectomy, allowing hilar dissection, tumor removal and reconstruction to proceed quickly and confidently. In patients with bilateral synchronous RCC, the kidney most amenable to a partial nephrectomy is usually approached first by the author. Then, approximately 1 month after a technically successful result has been documented, radical nephrectomy or a second partial nephrectomy is performed on the opposite kidney. Staging surgery in this fashion obviates the need for temporary dialysis if ischemic renal failure occurs following nephron-sparing excision of RCC.
Table 12-1 Results of Partial Nephrectomy for Renal Cell Carcinoma Series
No. Patients
Local Tumor Recurrence (%)
5-Year Cancer Specific Survival (%)
Steinbach et al.17
121
4.1
90
Lerner et al.18
185
5.9
89
Belldegrun et al.19
146
2.7
93
Cleveland Clinic20
485
3.2
92
Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy
It is usually possible to perform partial nephrectomy for malignancy in situ by using an operative approach that optimizes exposure of the kidney and by combining meticulous surgical technique with an understanding of the renal vascular anatomy in relation to the tumor. In the author’s experience, extracorporeal partial nephrectomy is rare if ever indicated. We employ an extraperitoneal flank incision through the bed of the 11th or 12th rib for almost all of these operations; we occasionally use a thoracoabdominal incision for very large tumors involving the upper portion of the kidney. These incisions allow the surgeon to operate on the mobilized kidney almost at skin level and provide excellent exposure of the peripheral renal vessels. With an anterior subcostal transperitoneal incision, the kidney is invariably located in the depth of the wound, and the surgical exposure is simply not as good. When performing in situ partial nephrectomy for malignancy, the kidney is mobilized within Gerota’s fascia while leaving intact the perirenal fat around the tumor. For small peripheral renal tumors, it may not be necessary to control the renal artery. In most cases, however, partial nephrectomy is most effectively performed after temporary renal arterial occlusion. This measure not only limits intraoperative bleeding but, by reducing renal tissue turgor, also improves access to intrarenal structures. In most cases, we believe that it is important to leave the renal vein patent throughout the operation. This measure decreases intraoperative renal ischemia and, by allowing venous backbleeding, facilitates hemostasis by enabling identification of small transected renal veins. In patients with centrally located tumors, it is helpful to occlude the renal vein temporarily to minimize intraoperative bleeding from transected major venous branches. When the renal circulation is temporarily interrupted, in situ renal hypothermia is used to protect against postischemic renal injury. Surface cooling of the kidney with ice slush allows up to 3 hours of safe ischemia without permanent renal injury. An important caveat with this method is to keep the entire kidney covered with ice slush for 10 to 15 minutes immediately after occluding the renal artery and before commencing the partial nephrectomy. This amount of time is needed to obtain core renal cooling to a temperature (approximately 20 ˚ C ) that optimizes in situ renal preservation. During excision of the tumor, invariably large portions of the kidney are no longer covered with ice slush and, in the absence of adequate prior renal cooling, rapid rewarming and ischemic renal injury can occur. Cooling by perfusion of the kidney with a cold solution instilled via the renal artery is not recommended due to the theoretical risk of tumor dissemination. Mannitol is given intravenously 5 to 10 minutes before temporary renal arterial occlusion. Systemic or regional anticoagulation to prevent intrarenal vascular thrombosis is not necessary.
231
A variety of surgical techniques are available for performing partial nephrectomy in patients with malignancy.23 These include simple enucleation, polar segmental nephrectomy, wedge resection, transverse resection, and extracorporeal partial nephrectomy with renal autotransplantation. All of these techniques require adherence to basic principles of early vascular control, avoidance of ischemic renal damage, complete tumor excision with free margins, precise closure of the collecting system, careful hemostasis, and closure or coverage of the renal defect with adjacent fat, fascia, peritoneum, or Oxycel. Whichever technique is employed, the tumor is removed with a surrounding margin of grossly normal renal parenchyma. Recent studies suggest that the width of the margin need not be more than 2 to 3 mm. Intraoperative ultrasound is very helpful in achieving accurate tumor localization, particularly for intrarenal lesions that are not visible or palpable from the external surface of the kidney.24 The argon beam coagulator is a useful adjunct for achieving hemostasis on the transected renal surface. If possible, the renal defect created by the excision is closed as an additional hemostatic measure. A retroperitoneal drain is always used as an additional hemostatic measure. A retroperitoneal drain is always left in place for at least 7 days. An intraoperative ureteral stent is placed only when major reconstruction of the intrarenal collecting system has been performed. In patients with RCC, partial nephrectomy is contraindicated in the presence of lymph node metastasis, because the prognosis for these patients is poor. Enlarged or suspicious looking lymph nodes should be biopsied before initiating the renal resection. When partial nephrectomy is performed, after excision of all gross tumor, absence of malignancy in the remaining portion of the kidney should be verified intraoperatively by frozen-section examinations of biopsy specimens obtained at random from the renal margin of excision. It is unusual for such biopsies to demonstrate residual tumor but, if so, additional renal tissue must be excised. Segmental Polar Nephrectomy In a patient with malignancy confined to the upper or lower pole of the kidney, partial nephrectomy can be performed by isolating and ligating the segmental apical or basilar arterial branch while allowing unimpaired perfusion to the remainder of the kidney from the main renal artery. This procedure is illustrated in Figure 12-19 for a tumor confined to the apical vascular segment. The apical artery is dissected away from the adjacent structures, ligated, and divided. Often, a corresponding venous branch is present, which is similarly ligated and divided. An ischemic line of demarcation will then generally appear on the surface of the kidney and will outline the segment to be excised. If this area is not obvious, a few
232
Part III Kidney and Ureter
milliliters of methylene blue can be directly injected distally into the ligated apical artery to better outline the limits of the involved renal segment. An incision is then made in the renal cortex at the line of demarcation, which should be several millimeters away from the visible edge of the cancer. The parenchyma is divided by sharp and blunt dissection, and the polar segment is removed. In cases of malignancy, it is not possible to preserve a strip of capsule beyond the parenchymal line of resection for use in closing the renal defect. Often a portion of the collecting system will be removed with the cancer during a segmental polar nephrectomy. The collecting system is carefully closed with interrupted or continuous 4-0 chromic sutures to ensure a watertight repair. Small transected blood vessels on the renal surface are identified and ligated with shallow figure-of-eight 4-0 chromic sutures. The edges of the kidney are reapproximated as an additional hemostatic measure, using simple interrupted 3-0 chromic sutures inserted through the capsule and a small amount of parenchyma. Before these sutures are tied, perirenal fat or Oxycel can be inserted into the defect for inclusion in the renal closure. If the collecting system has been entered, a Penrose drain is left in the perinephric space. Wedge Resection Wedge resection is an appropriate technique for removing peripheral tumors on the surface of the kidney, particularly ones that are larger or not confined to either renal pole. Because these lesions often encompass more than one renal segment, and because this technique is generally associated with heavier bleeding, it is best to perform wedge resection with temporary renal arterial occlusion and surface hypothermia. In performing a wedge resection, the tumor is removed with a surrounding margin of grossly normal renal parenchyma (Figure 12-20). The parenchyma is divided by a combination of sharp and blunt dissection. Invariably, the tumor extends deeply into the kidney, and the collecting system is entered. Often, prominent intrarenal vessels are identified as the parenchyma is being incised. These may be directly suture-ligated at that time, while they are most visible. After excision of the tumor, the collecting system is closed with interrupted or continuous 4-0 chromic sutures. Remaining transected blood vessels on the renal surface are secured with figure-of-eight 4-0 chromic sutures. Bleeding at this point is usually minimal, and the operative field can be kept satisfactorily clear by gentle suction during placement of hemostatic sutures. The renal defect can be closed in one of two ways. The kidney may be closed on itself by approximating the transected cortical margins with simple interrupted 3-0 chromic sutures, after placing a small piece of Oxycel at
the base of the defect. If this is done, there must be no tension on the suture line and no significant angulation of kinking of blood vessels supplying the kidney. Alternatively, a portion of perirenal fat may simply be inserted into the base of the renal defect as a hemostatic measure and sutured to the parenchymal margins with interrupted 4-0 chromic. After closure or coverage of the renal defect, the renal artery is unclamped and circulation to the kidney is restored. A Penrose drain is left in the perinephric space. Transverse Resection A transverse resection is done to remove large tumors that extensively involve the upper or lower portion of the kidney. This technique is performed using surface hypothermia after temporary occlusion of the renal artery (Figure 12-21). Major branches of the renal artery and vein supplying the tumor-bearing portion of the kidney are identified in the renal hilus, ligated, and divided. If possible, this should be done before temporarily occluding the renal artery to minimize the overall period of renal ischemia. After occluding the renal artery, the parenchyma is divided with blunt and sharp dissection, leaving a margin of grossly normal tissue around the tumor. Transected blood vessels on the renal surface are secured as previously described, and the hilus is inspected carefully for remaining unligated segmental vessels. An internal ureteral stent may be inserted if extensive reconstruction of the collecting system is necessary. If possible, the renal defect is sutured together with one of the techniques previously described. If this suture cannot be placed without tension or without distorting the renal vessels, a piece of peritoneum or perirenal fat is sutured in place to cover the defect. Circulation to the kidney is restored, and a Penrose drain is left in the perirenal space. Simple Enucleation Some RCCs are surrounded by a distinct pseudocapsule of fibrous tissue. The technique of simple enucleation implies circumferential incision of the renal parenchyma around the tumors simply and rapidly at any location, often with no vascular occlusion and with maximal preservation of normal parenchyma. Initial reports indicated satisfactory short-term clinical results after enucleation with good patient survival and low rate of local tumor recurrence. However, most recent studies have suggested a higher risk of leaving residual malignancy in the kidney when enucleation is performed.25 These latter reports include several carefully done histopathologic studies that have demonstrated frequent microscopic tumor penetration of the pseudocapsule that surrounds the neoplasm. These data indicate that it is not
Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy
Figure 12-19 Technique of segmental (apical) polar nephrectomy with preliminary ligation of apical arterial and venous branches.
233
234
Part III Kidney and Ureter
Figure 12-20 Technique of wedge resection for a peripheral tumor on the surface of the kidney. The renal defect may be closed on itself or covered with perirenal fat.
always possible to be assured of complete tumor encapsulation prior to surgery. Local recurrence of tumor in the treated kidney is a grave complication of partial nephrectomy for RCC, and every attempt should be made to prevent it. Therefore, it is the author’s view that a surrounding margin of normal parenchyma should be removed with the tumor whenever possible. This provides an added margin of safety against the development of local tumor recurrence and, in most cases, does not appreciably increase the technical difficulty of the operation. The technique of enucleation is currently employed only in occasional patients with von Hippel-Lindau disease and multiple low-stage encapsulated tumors involving both kidneys.26
Partial Nephrectomy for Renal Angiomyolipoma Renal angiomyolipomas (AMLs) are benign hematomas whose course may be complicated by pain, hematuria, hemorrhage, rupture, and even death. They may develop spontaneously or be part of the tuberous sclerosis complex, where they are often multiple and bilateral. These tumors have a propensity to grow, and treatment has been recommended for asymptomatic AMLs larger than 4 cm and symptomatic AMLs of any size.27 Partial nephrectomy and selective angioembolization are two renal-preserving treatment modalities available for patients with these benign neoplasms. Currently, there are few data reporting the efficacy and ability to preserve renal function by using selective
Figure 12-21 Figure of transverse resection for a tumor involving the upper half of the kidney.
Chapter 12 Surgery of Renal Cell Carcinoma, Including Partial Nephrectomy
embolization, and it is therefore best suited when a distinct and accessible renal arterial branch supplies the tumor exclusively and not the adjacent normal parenchyma. Partial nephrectomy is considered the preferred treatment in cases of bilateral tumors or tumors in a solitary kidney. AMLs are well suited to a nephronsparing approach for several reasons. Because these lesions are benign, the risk of residual microfocal disease is of less long-term significance. Furthermore, most AMLs are exophytic and maintain a distinct pseudocapsule that is readily identified and can be dissected to a narrow base. The amount of renal parenchyma that can be spared with an open procedure is usually much greater than one would predict radiographically. There are few published studies evaluating the efficacy of partial nephrectomy for patients with AMLs. Fazeli-Matin reported the largest series of 27 patients undergoing partial nephrectomy for renal AMLs ranging in size up to 26 cm.28 All kidneys maintained good function postoperatively, no patient required dialysis, and there were no recurrent AMLs or related symptoms identified at a mean follow-up time of 39 months. When surgical treatment for renal AMLs is indicated, partial nephrectomy can be performed with a high-rate of success, even in patients with larger tumors involving a solitary kidney.
REFERENCES 1. Robson CJ, Churchill BM, Anderson W: The results of radical nephrectomy for renal cell carcinoma. J Urol 1969; 101:297. 2. Schefft P, Novick AC, Straffon RA, Stewart BH: Surgery for renal cell carcinoma extending into the vena cava. J Urol 1978; 120:28. 3. Libertino JA, Zinman L, Watkins E: Long-term results of resection of renal cell cancer with extension into inferior vena cava. J Urol 1987; 137:21. 4. Novick AC, Kaye M, Cosgrove D, et al: Experience with cardiopulmonary bypass and deep hypothermic circulatory arrest in the management of retroperitoneal tumors with large vena caval thrombi. Ann Surg 1990; 212:472. 5. Neves RJ, Zincke H: Surgical treatment of renal cancer with vena cava extension. Br J Urol 1987; 59:390. 6. Glazer AA, Novick AC: Long-term follow-up after surgical treatment for renal cell carcinoma extending into the right atrium. J Urol 1996; 155:448. 7. Goldfarb DA, Novick AC, Lorgi R, et al: Magnetic resonance imaging for assessment of vena caval tumor thrombi: a comparative study with vena cavography and CT scanning. J Urol 1990; 144:1110. 8. Sagalowaky AI, Kadesky KT, Ewalt DM, Kennedy TJ: Factors influencing adrenal metastasis in renal cell carcinoma. J Urol 1994; 151:1181.
235
9. Giuliani L, Giberti C, Martorama G, Rovida S: Radical extensive surgery for renal cell carcinoma. J Urol 1990; 143:468. 10. Novick AC: Surgery of the kidney. In Campbell’s Urology, edited by Walsh PC, Retik AB, Stamey TA, Vaughan ED. W.B. Saunders Co., Philadelphia, 2002. 11. Welch M, Bazaral MG, Schmidt R, et al: Anesthetic management for surgical removal of renal cell carcinoma with caval or atrial tumor thrombus using deep hypothermic circulatory arrest. J Cardiothoracic Anesthesia 1980; 3:580. 12. Svenson L, Crawford E, Hess K, et al: Deep hypothermia with circulatory arrest. J Thoracic Cardiovascu Surg 1993; 106:19. 13. Mault J, Ohtake S, Klingensmith M, et al: Cerebral metabolism and circulatory arrest: effects of duration and strategies for protection. Ann Thoracic Surg 1993; 55:57. 14. Pagano D, Carey JA, Patel RL, et al: Retrograde cerebral perfusion: clinical experience in emergency and elective aortic operations. Ann Thorac Surg 1995; 59:393. 15. Burt M: Inferior vena caval involvement by renal cell carcinoma: use of venovenous bypass as adjunct during resection. Urol Clin N Am 1991; 18:437. 16. Butler BP, Novick AC, Miller DP, Campbell SA, Licht MR: Management of small unilateral renal cell carcinomas: radical versus nephron-sparing surgery. Urology 1995; 45:34. 17. Steinbach F, Stockle M, Muller SC, et al: Conservative surgery of renal cell tumors in 140 patients: 21 years of experience. J Urol 1992; 148:24–29. 18. Lerner SE, Hawksin CA, Blute ML, et al: Disease outcome in patients with low-stage renal cell carcinoma treated with nephron-sparing or radical surgery. J Urol 1996; 155:1868–1873. 19. Belldegrun A, Tsui KH, deKernion JB, et al: Efficacy of nephron-sparing surgery for renal cell carcinoma: analysis based on the new 1997 tumor-node-metastasis staging system. J Clin Oncol 1999; 17:2868–2875. 20. Hafez KS, Fergany AF, Novick AC: Nephron-sparing surgery for localized renal cell carcinoma: impact of tumor size on patient survival, tumor recurrence and TNM staging. J Urol 1999; 162:1930–1933. 21. Fergany AF, Hafez KS, Novick AC: Long-term results of nephron-sparing surgery for localized renal cell carcinoma: 10-year follow-up. J Urol 2000; 163:442–445. 22. Coll DM, Uzzo RG, Herts BR, et al: 3-dimensional volume-rendered computerized tomography for preoperative evaluation and intraoperative treatment of patients undergoing nephron-sparing surgery. J Urol 1999; 161:1097–1102. 23. Novick AC: Anatomic approaches in nephron-sparing surgery for renal cell carcinoma. Atlas of Urol Clin N Am 1998; 6:39. 24. Campbell SC, Fichtner J, Novick AC, et al: Intraoperative evaluation of renal cell carcinoma: a prospective study of the role of ultrasonography and histopathological frozen sections. J Urol 1996; 155:1191–1195.
236
Part III Kidney and Ureter
25. Marshall FF, Taxy JB, Fishman EK, Chang R: The feasibility of surgical enucleation for renal cell carcinoma. J Urol 1986; 135:231. 26. Spencer WF, Novick AC, Montie JE, Streem SB, Levin HS: Surgical treatment of localized renal carcinoma in von Hippel-Lindau disease. J Urol 1988; 139:507.
27. Oesterling JE: The management of renal angiomyolipoma. J Urol 1986; 135:1121–1124. 28. Fazeli-Matin S, Novick AC: Nephron-sparing surgery for renal angiomyolipoma. Urol 1998; 52:577–583.
C H A P T E R
13 Laparoscopic Radical and Partial Nephrectomy Sidney C. Abreu, MD, and Inderbir S. Gill, MD, MCh
At specialized centers worldwide, laparoscopic radical nephrectomy is now becoming established as routine practice for management of indicated patients with localized renal cell carcinoma.1,2 Current data indicate that, compared to open radical nephrectomy, the laparoscopic approach is associated with comparable operative time, decreased blood loss, superior recovery, improved cosmesis, and equivalent cancer control over an intermediate and long-term follow-up.3–5 While laparoscopic radical nephrectomy, practiced for over a decade now, has become an established procedure, laparoscopic partial nephrectomy, a considerably more technically challenging procedure, is a more recent innovation. However, ongoing advances in laparoscopic techniques and operator skills have allowed the development of a reliable technique of laparoscopic partial nephrectomy.6 Thus, laparoscopic partial nephrectomy is emerging as an attractive minimally invasive nephron-sparing option at select institutions. In this chapter, we present an update on laparoscopic radical and partial nephrectomy for the management of renal tumors. For each procedure, we describe the current indications and contraindications, laparoscopic operative technique, intraoperative and perioperative data, complications, oncologic outcome, and additional specific facets. In the future, it appears likely that minimally invasive techniques will become an established treatment option for treatment of a majority of kidney tumors, with open surgery being reserved for specific important indications. LAPAROSCOPIC RADICAL NEPHRECTOMY Current Indications and Contra-indications In the decade since the first laparoscopic radical nephrectomy, standardization of technique has allowed surgeons
to apply this minimally invasive approach to many patients with organ-confined kidney cancer who are candidates for radical nephrectomy. Even circumstances earlier considered relative contraindications, such as previous abdominal surgery,7 morbid obesity,8 tumors with level I renal vein thrombus,9 and cytoreductive surgery,10 are now amenable to this laparoscopic approach. In 2004, laparoscopic radical nephrectomy could be performed for most patients with organ-confined T1-T3aN0M0 renal tumors, who are not candidates for nephron-sparing surgery.5,11 Specific contraindications in 2004 include vena caval involvement, bulky lymphadenopathy, and locally invasive tumors.5,11 Large tumor size was earlier considered a relative contraindication. However, we believe this to be a decision based on the experience of the individual surgeon, and consider tumors as large as 15 cm to be amenable to laparoscopic excision.12 General contraindications for major abdominal laparoscopic surgery apply. Approach Selection From a technical standpoint, laparoscopic radical nephrectomy can be performed safely and efficaciously by either the transperitoneal or the retroperitoneal approach. The transperitoneal approach has been employed more commonly, primarily because of its “familiar” anatomic landmarks and the larger working space offered by this route. Nonetheless, since the kidney is a retroperitoneal organ, a direct “retroperitoneoscopic” approach has considerable logical appeal, thus avoiding the peritoneal cavity completely. Critics of the retroperitoneal approach point to its somewhat smaller initial working space, and a steeper learning curve. At the Cleveland Clinic we are equally technically comfortable
237
238
Part III Kidney and Ureter
with either approach. It is obvious to us that balloon dilation affords an adequate working space, and a sound knowledge of retroperitoneal surgical anatomy allows rapid identification of anatomic landmarks.13 Retroperitoneoscopy has the remarkable advantage of direct access to, and rapid control of, the renal artery and vein prior to any tumor manipulation.14,15 A prospective randomized study comparing transperitoneal and retroperitoneal approaches to laparoscopic radical nephrectomy at the Cleveland Clinic has shown both approaches to be comparable as regards blood loss, hospital stay, analgesia requirements, and convalescence. However, the retroperitoneal approach had the inherent advantages of a quicker renal hilar control and a shorter operative time.16 We believe that equal facility with both approaches will allow the experienced laparoscopic surgeon to select the appropriate technique for the particular case based on the individual patient’s characteristics. Two clinical situations where we prefer the retroperitoneal approach include morbid obesity and multiple prior abdominal surgeries.8,17 Surgical Technique The techniques of transperitoneal and retroperitoneal laparoscopic radical nephrectomy have been previously
reported1,18,19 Herein, we briefly describe both approaches. Transperitoneal Approach Typically, a 3- or 4-port approach is employed (Figure 13-1). The line of Toldt is incised to mobilize the colon, and this incision is transversally carried medially along the undersurface of the liver or spleen. On the right side, sharp dissection is used to mobilize the duodenum medially until the anterior aspect of the vena cava is exposed. The gonadal vein and ureter are identified and retracted laterally. Blunt dissection is performed between the inferior vena cava and the laterally retract gonadal vein/ ureter, to identify the psoas muscle. The ureter and gonadal vein are secured, divided, and tautly retracted laterally. Progressive cephalad dissection is performed along the lateral border of the inferior vena cava with the psoas muscle in clear view at all times until the renal vein, which is mobilized circumferentially. Anterolateral rotation of the completely free lower pole brings the posteriorly located renal artery into view. A single hemlock clip (Weck Closure Systems, Triangle Park, NC) is placed on the renal artery in-continuity at this time to arrest renal arterial inflow. The renal vein is controlled and transected with an Endo-GIA stapler (US Surgical, Norwalk, CT)
Figure 13-1 Port placement for transperitoneal left side radical nephrectomy.
Chapter 13 Laparoscopic Radical and Partial Nephrectomy
(Figure 13-2). The clip-occluded renal artery, now in clear view, is circumferentially mobilized, three clips are applied proximally towards the aorta and two towards the kidneys, and the renal artery is transected. During upper pole dissection, the adrenal gland is taken en bloc, if necessary. The adrenal vein is dissected and controlled with clips. The en bloc specimen is then completely freed and placed in an Endocatch bag for intact extraction. For a left-side procedure, it is again important (as on the right side) to enter the correct avascular fascial plane between the anterior surface of Gerota’s fascia and the posterior aspect of the descending mesocolon. It is also important to obtain complete mobilization of the spleen along its lateral border, which facilitates its medial displacement by gravity alone throughout the procedure. Occasionally, a distended descending colon and the spleen must be retracted medially with a fan retractor in order to expose the renal hilum. For this purpose, an additional port can be placed in the lower abdomen through a Pfannenstiel incision, the site of subsequent specimen extraction. Psoas muscle identification and renal hilar control are performed as described for the right-side procedure.
239
Retroperitoneal Approach Initially a horizontal 1.5-cm skin incision is made just below the tip of the 12th rib to gain entry into the retroperitoneal space. A trocar-mounted balloon dissection device (Origin Medsystems, Menlo Park, CA) is inserted immediately anterior to the psoas muscle and posterior to the Gerota’s fascia. Typically 800 to 1000 ml of air are instilled into the balloon for rapid and atraumatic creation of the working space in the retroperitoneum. The balloon dilatation outside and posterior to Gerota’s fascia effectively displaces the Gerota’s fascia covered kidney anteromedially, allowing direct access to the posterior aspect of the renal hilum (Figure 13-3). Laparoscopic examination from within the transparent balloon confirms adequate expansion of the retroperitoneum. Secondary cephalad or caudad balloon dilatation, as required by the clinical situation, further enlarges the retroperitoneal working space (Figure 13-4). Following balloon dilatation and removal, a 10-mm Bluntip trocar (Origin Medsystems, Menlo Park, CA) is placed as the primary port to prevent air leakage. Two secondary ports are placed under 30-degree laparoscopic visualization. A 10/12-mm port is placed three fingers breadths cephalad to the iliac crest, between the mid and
Figure 13-2 Renal artery and vein are sequentially controlled with clip-applier and Endo-GIA vascular stapler.
240
Part III Kidney and Ureter
Figure 13-3 Balloon dissection of the retroperitoneum. Upon inflating the balloon, the kidney is displaced anteromedially, allowing direct access to the renal hilum.
anterior axillary lines. For this purpose, the lateral peritoneal reflection must be clearly visualized laparoscopically and avoided. A second 10/12-mm port is placed at the lateral border of the erector spinae muscle just below the 12th rib (Figure 13-5). The kidney is retracted anterolaterally, placing the renal hilum on traction. Dissection is performed parallel to, and 1 to 2 cm anterior to, the psoas muscle, exposing the vertically pulsating renal artery. Visualization of the vertically oriented, distinct arterial pulsations indicates the location of the renal artery, which is circumferentially mobilized, clip-ligated, and divided. Next, the renal vein is controlled with an Endo-GIA stapler (US Surgical, Norwalk, CT). The specimen is then circumferentially mobilized en bloc with or without the adrenal gland. During mobilization of the specimen from the underside of the peritoneal envelope, use of electrocautery must be minimized in order to avoid the possibility of transmural thermal damage to the bowel. The entire dissection is performed outside Gerota’s fascia, mirroring established oncologic principles of open surgery. Organ entrapment is rapidly performed by using an Endocatch II bag (US Surgical, Norwalk, CT). The intact specimen is extracted extraperitoneally through a low, muscle-splitting Pfannenstiel incision.
Figure 13-4 Secondary cephalad balloon dilation is performed to further enlarge the initial retroperitoneal working space.
Chapter 13 Laparoscopic Radical and Partial Nephrectomy
241
Figure 13-5 Port placement during retroperitoneoscopy. A, Primary 10 mm port is placed at the tip of 12th rib. B, 10/12 mm port is placed at junction of lateral border of the erector spinae muscle with underside of 12th rib. C, 10/12 mm port is placed three fingers breadths cephalad to iliac crest, between mid and anterior axillary lines.
Results Worldwide intraoperative and perioperative results on laparoscopic radical nephrectomy are summarized in Table 13-1.
cera are out of sight during retroperitoneoscopy, they must never be out-of-mind, since they are separated only by the peritoneal layer, and are therefore susceptible to direct or transmural injury.
Complications
Specimen Extraction (Morcellate or Leave Intact)
In the hands of urologists with reasonable experience in minimally invasive techniques, laparoscopic radical nephrectomy is a safe procedure with a low incidence of complications similar to open surgery. Both the transperitoneal and retroperitoneal laparoscopic approaches are associated with a low incidence of open conversion varying from 0% to 8%.20–22 Worldwide intraoperative complications following laparoscopic radical nephrectomy are summarized in Tables 13-2 and 13-3. During laparoscopic radical nephrectomy, one must always be mindful of aberrant major vessels arising from the aorta.2,23 The superior mesenteric artery arises from the aorta more medially and superiorly than the left renal artery, and it is not accompanied by the respective vein. If there is any concern whether or not the isolated vessel is indeed the renal artery, it should be dissected and traced distally up to its entrance in the renal hilum. Injuries to intraperitoneal organs (i.e., liver, spleen, colon, duodenum) are rare. It is evident that lack of violation of the peritoneal cavity during retroperitoneal laparoscopy may minimize the chances of intraperitoneal organ injury. However, although peritoneal vis-
The author’s routine practice for extraction of the cancerous specimen aims to provide an intact specimen for accurate pathologic staging while achieving a superior cosmetic result. Valuable histopathologic information regarding the tumor stage, and completeness of tumor resection with negative surgical margins, cannot be reliably obtained following specimen morcellation. Although some argue that CT scanning can be used effectively for clinical tumor staging, it is well known that CT scan can overestimate tumor size and, more worrisomely, underestimate tumor stage when compared to final pathology in the individual patient.5,11 Moreover, data from many institutions, including ours, confirm that overall patient morbidity (analgesic requirement, hospital stay, convalescence) are similar between the intact extraction and morcellation techniques.25 Currently, we routinely perform intact specimen extraction through a low musclesplitting Pfannenstiel incision for male patients and through the vagina in the appropriate female patient. This approach minimizes any practical cosmetic disadvantage of intact extraction, while maintaining oncologic sanctity of the intact pathologic specimen.11,25
27/73
47 5.3 55/3† 5.5 172 39/21 452 3.4
Right side (%)
Tumor size (cm)
Transperitoneal/retroperitoneal
OR time (hour)
EBL (cc)
Morcellate/intact
Specimen weight (g)
LOS (days)
34/3 1
Minor/major
Open conversion
*Excluding 6 cases of open conversion. †Intentionally combined approached was used in 3 patients.
—
Intraoperative/postoperative
Complications (%)
5.1 (1.7–14)
53
Male (%)
2
11/3
—
1.6
554
0/100
212
2.8
54
55
61.8
63.5
Age (years)
100
Gill et al.11
60
Dunn et al.2
Number of patients
Author/Series
4
—
10/3
—
305
78/25
254
4.7
85/18
3.1 (1.1–4.8)
53
77
57.2
103
Ono et al.3
1
—
3/12
3.8
—
40/27
289
4.4
66/1
5.1 (1–13)
45
60
61
67
Chan et al.20
6
11/8
—
4.4
402
66/0
—
2.5
72/0
4.5 (1–9)*
50
—
35–92
72
Barrett et al.21
0
8/4
—
7.2
0/73
170
2.3
73/0
3.8 (3–6)
53
44
63.3
73
Janetschek et al.22
Table 13-1 Intraoperative and Perioperative Data on Laparoscopic Radical Nephrectomy: Worldwide Experience
242 Part III Kidney and Ureter
Transperitoneal
4
Superior mesenteric artery division/ open graft revascularization, death
Aberrant right lower pole artery/open conversion
Liver laceration during port placement/oxidize cellulose packing
Partial ischemia colitis/conservative treatment
Approach
Complications (%)
Vascular
Hemorrhage
Visceral
Bowel
*Retroperitoneal approach.
61
Number of patients
Bleeding from renal vein; Bleeding from the gonadal vein/ laparoscopic hemostasis without blood transfusion
Superior mesenteric artery ligation/ openreanastomosis to the aorta
3
Transperitoneal
60
Dunn et al.2
Injury to spleen/ conservative treatment
Bleeding in the hilar region precluding adequate visualization/ open conversion
2
Transperitoneal
72
Barret et al.21
2
Transp(27)/ Retrop(73)
100
Gill et al.11
Duodenal perfuration/ reintervention for open duodenojejunostomy; Descending colon injury/open surgical repair
Injury to spleen/ conservative treatment
Bleeding from renal Bleeding from renal artery (1), renal artery; Generalized vein(1)/open oozing in a patient conversion; Bleeding with ESRD/both from adrenal gland (1), cases* required open periureteric artery (1)*/ conversion, an open laparoscopic splenectomy was control and blood also performed in transfusion second case
Vena cava injury (2)/ open surgical suture repair
9
Transp(85)/ Retrop (18)
103
Ono et al.3
Table 13-2 Complications Following Laparoscopic Radical Nephrectomy
Siqueira et al.23
Author/series
Bowel injury during morcellation/open conversion for bowel resection and extensive irrigation
Injury to spleen/ conservative treatment
2
Transperitoneal
67
Chan et al.20
Chapter 13 Laparoscopic Radical and Partial Nephrectomy 243
244
Part III Kidney and Ureter
Table 13-3 Perioperative Complications Following Laparoscopic Radical Nephrectomy—Multicenter Experience with 157 Cases Ileus
4 (2.5%)
Urinary tract infection
2 (1.2%)
Pulmonary embolus*
2
Congestive heart failure†
1 (0.6%)
Transfusion
1
Incisional hernia
1
Wound infection
1
Seroma
1
Postoperative surgical exploration‡
1
Duodenal perforation§
1
Splenic injury¶
1
A sponge-stick is externally inserted into the sterilely prepared vagina and tautly positioned in the posterior fornix. Laparoscopically, a transverse posterior 3-cm colpotomy is created at the apex of the tented-up posterior fornix, and the drawstring of the entrapped specimen is delivered into the vagina (Figure 13-6). After laparoscopic exit is completed, the patient is placed in a supine lithotomy position. The specimen is extracted intact per vagina, and the posterior colpotomy incision repaired transvaginally. This approach is contraindicated in patients with pelvic adhesions from any etiology.27 Oncologic Outcome
Total
16 (10%)
Adapted with permission from Cadeddu JA, Ono Y, Clayman, RV: Urology 1998; 52:773. *Intraoperative mortality: postmortem examination indeterminate (possible carbon dioxide embolus). †One patient died of heart failure one month postoperatively. ‡Postoperative hemorrhage requiring exploratory laparotomy. §Perforation discovery on postoperative day 1. ¶Minor splenic injury identified intraoperatively and managed conservatively.
Specimen Extraction in Males During a transperitoneal approach, a Pfannenstiel skin incision is made at, or just below, the level of the pubic hairline. Straightforward access is gained into the peritoneal cavity after the anterior rectus fascia is incised transversally and the rectus muscle is separated at the midline. During a retroperitoneal approach, a similar low Pfannenstiel skin incision is performed although slightly lateralized towards the nephrectomy side.26 In order to avoid violation of the peritoneal cavity, the anterior fascia is incised obliquely at the lateral border of the rectus abdominis. Subsequently, the rectus muscle fibers are retracted medially, the posterior rectus fascia is incised, and the peritoneal membrane is reflected cephalad using finger dissection. Access is gained to the retroperitoneal space, and entrapped specimen is extracted. Alternatively, a muscle-splitting Gibson incision can be performed for intact specimen extraction during either the transperitoneal or retroperitoneal approach. Transvaginal Extraction in Females With the table set in a steep Trendelenburg position, bowel loops are retracted cephalad out of the pelvis.
To achieve optimal oncologic outcomes, established principles of renal cancer surgery must be respected. The excised surgical specimen must be removed in a hermetic sac to avoid contact with the abdominal wall.28 Either intact specimen extraction or morcellation are safe regarding oncologic outcomes. However, if morcellation is employed, care should be taken to avoid rare complications, such as sack perforation, with potential for bowel injury and tumor spillage. In the aggregate, laparoscopic radical nephrectomy does not result in an increased risk of port site seeding, local recurrence, or metastasis3,5,11,28 (Table 13-4). Cancer-free patient survival is the ultimate criterion of oncologic outcome. Portis et al.5 reported 5-year cancer specific survival for the laparoscopic radical nephrectomy similar to open surgery: 98% versus 92%. The authors also reported 5-year cancer specific survival of 97% following laparoscopic radical nephrectomy for T1Nx disease. These data compare favorably with existing reports of survival after conventional open total/radical nephrectomy for T1N0: 91% to 95%. Cicco et al.29 have reported a Kaplan–Meyer actuarial disease-free survival rate of 91% at 54 months following retroperitoneal laparoscopic radical nephrectomy. Wound seeding after open radical nephrectomy, although extremely rare, has been reported in 2 of 518 patients (0.4%). Similarly, a few port site recurrences have been reported following laparoscopic radical nephrectomy.28 Fentie et al.30 observed one port site seeding 25 months after radical nephrectomy for a grade 4 renal cell carcinoma. Castilho et al.31 reported multiple port site abdominal masses 5 months after the laparoscopic procedure in a patient with ascites. Although the etiology of port site recurrence remains unclear in these cases, in both procedures the specimens were extracted with morcellation. Local recurrence occurs occasionally following open radical nephrectomy and appeared to be related to the initial pathologic stage.30 As regards local recurrence following laparoscopic radical nephrectomy, Fentie et al.30 have reported an incidence of 5% (3/57), including the case with port site recurrence. Ono et al.3 have reported
Chapter 13 Laparoscopic Radical and Partial Nephrectomy
245
Figure 13-6 The drawstring of the closed Endocach II bag, previously grasped by the laparoscopic clamp, is delivered into the vagina.
1 case of local recurrence 43 months after the laparoscopic procedure. Although no concomitant port site seeding was observed in this case, the intact specimen could not be entrapped and was therefore removed without a bag through an additional incision. Distant metastases have been reported following laparoscopic radical nephrectomy. Cicco et al.29 reported 1 patient with metastatic disease 9 months after the laparoscopic procedure. Hepatic tumor metastasis followed a local recurrence in a patient who had a pT2G3 renal cell carcinoma and tumor-free surgical margins. Gill et al.11 reported 2 patients with dialysis-dependent, end-stage renal disease and pT1N0M0 renal cancer with negative surgical margins that had metastatic disease at 8 and 12 months, respectively.11
tution, 33 patients had larger, clinical stage T2 tumors, 7 cm or greater in size. Mean tumor size was 9.8 cm, with 17 tumors between 7 and 10 cm in size, and 16 tumors >10 cm in size.12 This group was compared to a contemporary group of 34 patients undergoing open radical nephrectomy for tumors >7 cm in size. Tumors >14 cm or with IVC thrombus were excluded from this study. Estimated blood loss (294 cc—lap; 837 cc—open; p-value: <0.001) and hospital stay (1.8 days—lap; 6.1 days—open; p-value: <0.001) were reduced in the laparoscopic group. Although there was a trend to less surgical complications in the laparoscopic group, this finding was not statistically significant (6.2% versus 23.5%; p-value: 0.08) (Table 13-5). Concomitant Adrenalectomy
Larger Renal Tumors With increasing experience, laparoscopic radical nephrectomy for larger (≥7 cm) can be performed efficaciously.12 Of the senior author’s overall experience with over 300 laparoscopic radical nephrectomies at our insti-
Performance of concomitant adrenalectomy depends on the site and size of the renal tumor and the presence of any abnormality in the adrenal gland on preoperative CT. Generally, ipsilateral adrenalectomy is not necessary if the preoperative CT scan clearly
246
Part III Kidney and Ureter
Table 13-4 Laparoscopic Radical Nephrectomy: Intermediate and Long-term Follow-up (Pathologically Confirmed RCC) Author/series
Cicco et al.29
Gill et al.11
Portis et al.5
Ono et al.3
Chan et al.20
Number of patients
41
80
64
103
67
Transperitoneal/retroperitoneal
All retroperitoneal
All retroperitoneal
52/12
85/18
All transperitoneal
Morcellate/intact
0/41
0/80
25/39
78/25
40/27
Pathologic tumor size (cm)
5.26 (2–9)
4.6 (1.7–14)
4.3 (2–10)
3.1 (1.1–4.8)
4.8 morcellate; 5.5 intact
Tumor grade
2.3±1.0
2±0.8
1.88
1.8±0.4
2.1±0.6
pT1
25
61
102
46
pT2
2
6
—
8
pT3a
9
9
1
8
pT3b
3
3
—
5
pT4
—
1
—
—
Port site recurrence
0
0
0
0
0
Local recurrence
1
0
1
1
0
Time after operation (months)
9.1
—
12
43
—
Metastasis
1
2
3
3
2
Cancer specific mortality
2*
1
1
0
2
Five-year disease-free (%)
—
—
98
89.7
95
Follow-up (months)
24.76 (2.4–52.7)
16.1 (1–36)
54 (0–94)
29 (3–95)
35.6 (12–111)
Pathologic tumor classification
*One patient was M+ at the time of diagnosis.
demonstrates the adrenal gland to be normal in size, shape, contour, and location, thereby showing it to be uninvolved by the renal tumor.32 In our initial series, en bloc adrenalectomy was performed in 72% of the patients. Adrenal-sparing was performed in the setting of bilateral radical nephrectomy, previous contralateral adrenalectomy, or elective preservation of the adrenal gland.11 Renal Vein Involvement We recently reported a series of 16 patients who underwent laparoscopic radical nephrectomy for pathologically confirmed renal cell cancer with either microscopic (8 patients) or gross (8 patients) tumor involvement of the renal vein. Microscopic involvement was incidentally identified on postoperative histopathology. Gross
involvement was identified on preoperative CT scan.33 In the group of patients with gross involvement of the renal vein, mean tumor size was 12.4 cm (6 to 20 cm). CT scan detected renal vein thrombus floating within the vein in 7 patients and invading the renal vein wall in 1 patient. All procedures were successfully completed laparoscopically, except for one open conversion due to intraoperative hemorrhage (1000 ml) (Table 13-6). Either the transperitoneal or retroperitoneal techniques were employed to perform right or left laparoscopic radical nephrectomy. After the renal artery was clipped and transected, the renal vein was dissected proximally towards the inferior vena cava. While the renal vein segment containing the thrombus clearly appeared full and bulky, the uninvolved, free-of-thrombus proximal renal vein segment was flat on laparoscopic examination. This established a clear line of demarcation, where the articulating
Chapter 13 Laparoscopic Radical and Partial Nephrectomy
247
Table 13-5 The Large (>7 cm, pt2) Renal Tumor—Laparoscopic Versus Open Radical Nephrectomy Laparoscopic Radical Nephrectomy (>7 cm) N=33 Mean tumor size (cm)
9.8
Open Radical Nephrectomy (>7 cm) N=34 10
Clinical status
p-value 0.52 0.66
Localized (%)
91.4
88.2
Metastatic (%)
8.6
11.8
Mean OR time (min)
199
200
0.35
Mean EBL (ml)
294
837
<0.001 0.12
Intraoperative complications (%)
6
18
Conversion to open surgery (%)
0
N/A
N/A
Mean LOS (days)
1.8
6.1
<0.001
MSO4 equivalent
22
400
<0.001
Postoperative complications (%)
20
26
0.52
4
8
0.018
890
719
0.17
RCC (%)
82
88
0.15
pT1
13
0
0.08
pT2
29
50
pT3
54
50
Convalescence (weeks) Specimen weight (g)
Positive surgical margins
1
0
0.32
Adapted with permission from Steinberg AP, Desai MM, Kaouk JH: J Endourol 2002; 16:A160 (abstract P28-21).
endoscopic gastrointestinal anastomosis (GIA) stapler was safely fired (Figure 13-7). Intraoperative laparoscopic ultrasonography with color Doppler is helpful to precisely delineate the proximal extent of the thrombus and should be used routinely. Placing the ultrasound probe over the thrombus-bearing distal segment of the renal vein reveals the intraluminal mass without venous blood flow. This is in remarkable contrast with the sonographic findings of the proximal thrombus-free segment of the renal vein, which shows evidence of turbulent flow from the vena cava without any intraluminal mass. Histologic evaluation confirmed renal cell carcinoma in all 8 cases, in which gross tumor was found within the renal vein. Inked surgical renal vein vascular margins were negative for cancer in all these 8 patients with gross venous
involvement. Over a mean follow-up of 9.5 months (5 to 16) no patient showed evidence of local recurrence, and 1 patient developed pulmonary metastasis.33 Cytoreductive Nephrectomy Laparoscopic radical nephrectomy has been performed in the setting of cytoreductive surgery as preparation for systemic immunotherapy. Walther et al.10 reported a series of 11 patients undergoing laparoscopic cytoreductive nephrectomy. Three procedures were converted to open surgery. The major complication rate in these series was significantly greater than current series of laparoscopic radical nephrectomy for organ-confined disease. The authors concluded that laparoscopy afforded quicker recovery and more rapid implementation of
248
Part III Kidney and Ureter
Table 13-6 Pre and Perioperative Data on Laparoscopic Radical Nephrectomy for Renal Tumor with Renal Vein Involvement Microscopic Renal Vein Thrombus±SD (Range)
Level I Gross Renal Vein Thrombus±SD (Range)
p-value
Number of points
8
8
N/A
Mean age (years)
62.8±9.7 (48–72)
55.9±6.7 (44–64)
0.15
Mean BMI
29.4±4.6 (25–37)
25.9±5.5 (21–36)
0.17
Number of men/women
6/2
5/3
N/A
Number of left/right
3/5
4/4
N/A
Mean centimeter tumor size
7.8±2.9 (4.7–13)
12.4±5.4 (6–20)
0.09
Number of tumor thrombus visible on preoperative imaging
1
8
N/A
Mean centimeter renal vein diameter on CT
N/A
3.3±6.5 (3–4)
N/A
Floating intraluminal
0
7
N/A
Invasive into vessel wall
1*
1
Number of renal vein thrombus enhancement
0
2
N/A
Approach transperitoneal/retroperitoneal
2/6
7/1
N/A
Mean minutes operative time
188.8±87.3 (75–330)
195.7±39.1 (150–270)
0.68
Mean milliliter estimated blood loss
381.9±393.7 (30–1125)
353.6±334.3 (75–1000)
0.91
Number of conversion to open surgery
0
1
>0.99
Mean days hospital stay
1.9±1.1 (1–4)
2.3±0.8 (1–3)†
0.33
Postoperative complications (Number)
Wound infection (1)
0
0.78
Number of renal vein thrombus type
Adapted with permission from Desai MM, Gill IS, Ramani AP: J Urol 2003; 169:487. *Questionable appearance on preoperative CT. †Excludes patient treated with open conversion.
treatment with interleukin-2 (37 days—laparoscopy with morcellation versus 67 days—open surgery; p-value: 0.006). Moreover, since accurate staging of the primary tumor is not a primary concern in the setting of metastatic disease, the authors suggested that tumor morcellation should be performed to further reduce surgical trauma.10 Financial Analysis Financial implications of laparoscopic radical nephrectomy are important factors in determining its wide dissemination within the urologic community. At our institution, we recently addressed this issue of cost-effectiveness of
laparoscopic radical nephrectomy. After overcoming the learning curve, laparoscopic radical nephrectomy was shown to be 12% less expensive than open radical nephrectomy. Nonetheless, the intraoperative costs, mainly related to disposable instrumentation and a slightly longer operative time, were 33% greater in comparison to the open radical nephrectomy. Postoperatively, the reduced nursing care and decreased hospitalization time resulted in a 68% lower postoperative costs.34 Furthermore, when the intangible nonhospital economic factors are considered, such as earlier patient return to the work-force, and increased productivity laparoscopic approach becomes even more financially advantageous and attractive.
Chapter 13 Laparoscopic Radical and Partial Nephrectomy
249
Figure 13-7 Thrombus bearing distal renal vein is clearly demarcated from uninvolved, proximal, flattened vein, and transected with a GIA stapler adjacent to the Vena Cava.
LAPAROSCOPIC PARTIAL NEPHRECTOMY Current Indications and Contraindications Initially, laparoscopic partial nephrectomy was reserved for only the select patient with the favorably located, small, peripheral, superficial, exophytic tumor.35–38 After gaining experience, we have carefully expanded our indications to include select patients with more complex tumors; those invading deeply into the parenchyma up to the collecting system or renal sinus, completely intrarenal tumor, tumor abutting the renal hilum, tumor in a solitary kidney, or a tumor substantial enough to require hemi-nephrectomy.6,39 Laparoscopic partial nephrectomy for these complex tumors is performed only in the setting of compromised or threatened global nephron mass wherein nephron preservation is an important consideration. In 2004, our absolute contraindications for laparoscopic partial nephrectomy include renal vein thrombus, multiple (>3) renal tumors, and 2 midpole, central, completely intrarenal tumor.40 Patients with a bleeding diathesis or renal failure-induced platelet dysfunction, and those on anticoagulant therapy, are at significantly increased risk for postoperative hemorrhage, and should be approached only with great caution
and adequate preoperative correction. Morbid obesity and a history of prior renal surgery may prohibitively increase the technical complexity of the procedure, and should be considered a relative contraindication for laparoscopic partial nephrectomy at this time. Three-dimensional computed tomography, with volume-rendered video reconstruction, is an important tool to determine candidacy for laparoscopic partial nephrectomy and to aid in preoperative planning.40 Finally, a substantive laparoscopic partial nephrectomy involves renal hilar control, transection of major intrarenal vessels, entry into and repair of the collecting system (usually), suture-control of parenchymal blood vessels, renal parenchymal reconstruction, all under ischemia conditions. Therefore, significant laparoscopic experience, including expertise with time-sensitive intracorporeal suturing is essential. Technique Laparoscopic partial nephrectomy (Table 13-7) can be performed either transperitoneally or retroperitoneally. Our technique has been described elsewhere.6,39
250
Part III Kidney and Ureter
Table 13-7 Technical Steps of Laparoscopic Partial Nehprectomy Cystoscopy, ureteral catheterization Port placement Hilar dissection/preparation for cross-clamping
Figure-of-8 sutures are specifically placed at the site of visible transected intrarenal vessels. Finally, the renal parenchyma is reconstructed using 0 Vicryl suture over prefashioned surgicel bolsters to complete a hemostatic renorrhaphy (Figure 13-11). A Jackson–Pratt drain is placed in all patients undergoing pelvicaliceal repair or if there is any concern about hemostasis.
Mobilize kidney Identify tumor Laparoscopic ultrasonography and circumferential scoring Renal hypothermia (if needed) Hilar cross-clamping (preceded by IV Mannitol) Tumor excision Pelvicaliceal repair (if necessary) Specific figure-of-8 sutures to control transected parenchymal vessels Hemostatic renorrhaphy over bolsters Unclamp hilum, confirm hemostasis Jackson–Pratt drain Adapted with permission from Gill IS, Desai MM, Kaouk JH, et al: J Urol 2002; 167:469.
Selection of laparoscopic approach depends on location of the tumor. The transperitoneal approach is preferred for anterior, lateral, and upper-pole tumors. Posterior or posterolaterally located tumors may be better approached retroperitoneoscopically. A ureteral catheter is inserted cystoscopically up to the renal pelvis. Essentially, our operative strategy involves preparation of the renal hilum for cross clamping, followed by mobilization of the kidney and isolation of the tumor. Transperitoneally, a Satinsky clamp is employed to occlude the renal hilum en bloc (Figure 13-8). Conversely, during retroperitoneoscopy, the renal artery and vein are dissected separately for individual placement of Bulldog clamps (Figure 13-9). Laparoscopic ultrasonography precisely delineates tumor size, intraparenchymal extension, distance from renal sinus, and rules out any preoperatively unsuspected secondary renal masses. An adequate margin of normal renal parenchyma is scored circumferentially around the tumor under sonographic guidance. The hilum is clamped, and the tumor is excised and entrapped within an Endocatch bag (USSC, Norwalk, CT). Injection of dilute indigo carmine through the ureteral catheter identifies any pelvicaliceal entry (Figure 13-10), which is suture repaired by intracorporeal laparoscopic techniques.
Laparoscopic Renal Hypothermia At the Cleveland Clinic, we have recently developed a laparoscopic technique of renal hypothermia with iceslush by laparoscopic techniques and evaluated its efficacy in 10 initial patients.41 An Endocatch-II bag is placed around the completely mobilized and defatted kidney, and its mouth is closed around the intact renal hilum. The renal hilum is occluded en bloc with a Satinsky clamp. The bottom of the bag is retrieved through a 12-mm port site and cut open. Finely crushed ice-slush is rapidly introduced into the bag to completely surround the kidney, thereby achieving renal hypothermia (Figure 13-12). Pneumoperitoneum is reestablished, and laparoscopic partial nephrectomy is performed after opening the bag and removing the ice from the vicinity of the tumor. Mean time required to introduce 600 to 750 cc of ice-slush around the kidney was 4 minutes. Using a needle thermocouple probe core renal temperature was documented to drop to the 5 to 19 ˚C range. Our laparoscopic technique of renal surface contact hypothermia with ice-slush mirrors the method routinely used during open partial nephrectomy.41 Further refinements in the laparoscopic ice delivery system are necessary to increase the efficiency of introduction of ice around the kidney. Results In our initial 50 patients, mean tumor size was 3 cm (range 1.4–7), and partial nephrectomy was performed for an imperative indication in 48% of patients. Warm ischemia time was 23 minutes, mean operative time was 3 hours, and mean hospital stay was 2.2 days. On pathology, renal cell carcinoma was confirmed in 68% of patients, all with a negative surgical margin.6 More recently, we have retrospectively compared 200 patients undergoing partial nephrectomy at The Cleveland Clinic either by the laparoscopic (n = 100) or open (n = 100) approach.42 Median tumor size was 2.8 cm in the laparoscopic group and 3.3 cm in the open group ( p = 0.005), and a solitary kidney was present in 7 and 28 patients, respectively ( p = 0.001). The tumor was located centrally in 35% and 33% of cases ( p = 0.83) and the indication for a partial nephrectomy was imperative in 41% and 54% of cases, respectively ( p = 0.001). Comparing the laparoscopic versus open groups, median surgical
Figure 13-8 Transperitoneal partial nephrectomy. A Satinsky clamp is used to obtain en bloc control the renal hilum.
Figure 13-9 Retroperitoneal partial nephrectomy. Bulldog clamps are used for individual control of mobilized renal artery and vein.
252
Part III Kidney and Ureter
Figure 13-10 Retrograde injection of diluted methylene blue via retrograde ureteral catheter clearly identifies the site of leakage.
time was 3 hours versus 3.9 hours ( p < 0.001), blood loss was 125 cc versus 250 cc ( p < 0.001), and warm ischemia time was 28 minutes versus 18 minutes ( p < 0.001). In the laparoscopic and open groups, analgesic requirement was 20.2 mg morphine sulfate equivalent versus 252.5 mg ( p < 0.001), hospital stay was 2 days versus 5 days ( p < 0.001), and convalescence averaged 4 weeks versus 6 weeks ( p < 0.001). No laparoscopic patient was converted to open surgery. The laparoscopic group had a higher incidence of intraoperative complications (5% versus 0%; p = 0.02) including hemorrhage (n = 3), ureteral injury (n = 1), and bowel serosal injury (n = 1). Postoperative complications (9% versus 14%; p = 0.27). Renal/urologic complications occurred in 7 patients in the laparoscopic group and 2 patients in the open group. Median preoperative serum creatinine (1.0 mg/dl versus 1.0 mg/dl) and postoperative serum creatinine (1.0 mg/dl versus 1.1 mg/dl) were similar ( p = 0.99). Pathology confirmed renal cell carcinoma in 75% of patients in the laparoscopic and 85% in the open group ( p = 0.003). Parenchymal margin of resection was positive in two
laparoscopic cases and no open cases ( p = 0.11); median width of margin was 4 mm in each group ( p = 0.11).42 No patient in the laparoscopic group developed a local or port site recurrence. No kidney was lost due to warm ischemic injury in this study of 200 patients. The worldwide single institutional experiences with laparoscopic partial nephrectomy are detailed in Table 13-8. Complications In the first 100 consecutive patients undergoing laparoscopic partial nephrectomy at the Cleveland Clinic, complications occurred in 29% of patients: intraoperative 5%, postoperative 9%, and late 15%.42 Intraoperative complications consisted of parenchymal hemorrhage in 3 patients, which were controlled laparoscopically without open conversion in each instance. Likely causes for the hemorrhage included an unoccluded renal artery, which was unsuspected in the setting of multiple vessels, and inadequate occlusion by the laparoscopic bulldog clamp. Additional intraoperative complications included a
Chapter 13 Laparoscopic Radical and Partial Nephrectomy
253
Figure 13-11 Renal parenchymal repair over bolsters.
ureteral injury repaired laparoscopically by ileal replacement (1), and a small, superficial, serosal bowel abrasion repaired laparoscopically without sequelae (1). All 100 partial nephrectomies were completed laparoscopically without open conversion.42 Postoperatively, urologic complications occurred in 7 patients: urine leak (3) of which 1 subsided spontaneously within 7–10 days, and 2 required restenting and percutaneous CT-guided needle aspiration; delayed nephrectomy for secondary hemorrhage 5 days postoperatively (1); an enlarging perineal hematoma successfully managed by percutaneous embolization (1); and hematuria which subsided spontaneously with bed rest (1). Late complications after discharge from the hospital occurred in 15% of patients: incisional hernia (3), wound infection (2), percutaneous embolization for perineal hematoma (1), congestive heart failure (1), hematuria (1), urine leak (1), wound dehiscence (1), pneumonia (1), and pulmonary embolism (1).42 A worldwide literature review of 97 patients undergoing laparoscopic partial nephrectomy revealed a major com-
plication rate of 10%.6 In a multicenter European experience in 53 patients, 4 cases (8%) were converted to open surgery, and urine leak was noted in 5 patients (10%).44 Financial Analysis Recently, we reviewed the financial data of 30 patients undergoing partial nephrectomy: laparoscopic (n = 15) and open (n = 15).45 All 30 patients in this retrospective study had a normal contralateral kidney and an uncomplicated perioperative course. Cost data, collected by the financial department of our institution, were divided into intraoperative and postoperative categories. Laparoscopic and open groups were comparable as regards tumor size (2.4 cm versus 2.5 cm; p = 0.50). Intraoperative costs were 20.1% greater for the laparoscopic group ( p < 0.001) and postoperative costs were 55% lesser for the laparoscopic group ( p < 0.001). Overall, hospital costs for laparoscopic partial nephrectomy were 15.6% less compared to open surgery ( p = 0.002).45
254
Part III Kidney and Ureter
Figure 13-12 The kidney is enclosed within the deployed Endocatch II bag. Finely crushed ice slush is being inserted into the mouth of the bag with a 30 cc syringe. The nozzle of the syringe has been cut off to facilitate rapid ice injection.
2.7
1.9
2.3
3.0
—
Hoznek38 (5)
Janetschek22 (25)
Harmon43,* (15)
Gill6 (50)
Overall (97)
No (43) Yes (54)
Yes
No
No
Yes (4) No (1)
No
21 (22)
18
3
0
0
0
—
Suture over bolsters
Argon beam coagulator, bolster
Bipolar, argon beam coagulator, glue
Harmonic, bipolar, glue
Argon beam coagulator, snare
Adapted with permission from Gill IS, Desai MM, Kaouk JH, et al: J Urol 2002; 167:469. *Two institutional experience.
2.5
McDougall37 (2)
Number of Calyceal Repair (%) Hemostasis
Hilar Control (Number)
References (Number of Points)
Mean Tumor Size (cm)
Wound Infection (1)
Postoperative Complications (Number)
275
270
368
287
225
225
Mean Estimated Blood Loss (cc)
—
3.0
2.8
2.7
2.6
7.1
Mean Operating Room Time (hour)
0
—
2.2
2.6
5.8
8
7
Mean Hospital Days
3 (3)
1 (2)
0
0
1 (20)
1 (50)
Number Urine Leak (%)
0.78
Table 13-8 Worldwide Single Institutional Experience with Laparoscopic Partial Nephrectomy for Tumor
10 (10)
6 (12)
0
3 (12)
1 (20)
—
Number Complication (%)
15.3
7.2
8
22.2
22
17
Follow up (months)
256
Part III Kidney and Ureter
REFERENCES 1. Clayman RV, Kavoussi R, Soper NJ, et al: Laparascopic nephrectomy: initial case report. J Urol 1991; 146:278-282. 2. Dunn MD, Portis AH, Shalav AL, et al: Laparoscopic versus open radical nephrectomy: a 9-year experience. J Urol 2000; 164:1153. 3. Ono Y, Kinukawa T, Hattori R, et al: The long-term outcome of laparoscopic radical nephrectomy for small renal cell carcinoma. J Urol 2001; 165:1867. 4. Cadeddu JA, Ono Y, Clayman RV, et al: Laparoscopic nephrectomy for renal cell cancer evaluation of efficacy and safety: a multicenter experience. Urology 1998; 52:773. 5. Portis AJ, Yan Y, Landman J, et al: Long-term follow-up after laparoscopic radical nephrectomy. J Urol 2002; 167:1257. 6. Gill IS, Desai MM, Kaouk JH, et al: Laparoscopic partial nephrectomy for renal tumor: duplicating open surgical techniques. J. Urol 2002; 167:469. 7. Parsons JK, Jarret TJ, Chow GK, et al: The effect of previous abdominal surgery on urological laparoscopy. J Urol 2002; 168:2387. 8. Matin SF, Gill IS, Hsu TH, et al: Laparoscopic renal and adrenal surgery in obese patients: comparison to open surgery. J Urol 1999; 162:665. 9. Savage SJ, Gill IS: Laparoscopic radical nephrectomy for renal cell carcinoma in a patient with level I renal vein tumor thrombus. J Urol 2000; 163:1243. 10. Walther MM, Lyne C, Libutti SK, et al: Laparoscopic cytoreductive nephrectomy as preparation for administration of systemic interleukin-2 in the treatment of metastatic renal cell carcinoma: a pilot study. Urology 1999; 53:496. 11. Gill IS, Meraney AM, Schweizer D, et al: Laparoscopic radical nephrectomy in a 100 patients: a single-center experience from the United States. Cancer 2001; 92:1843. 12. Steinberg AP, Desai MM, Kaouk JH, et al: The large (>7 cm; pT2) renal tumor: laparoscopic versus open radical nephrectomy. J Endourol 2002; 16:A160. (Abstract P28-21.) 13. Sung GT, Gill IS: Anatomic landmarks and time management during retroperitoneal laparoscopic radical nephrectomy. J Endourol 2002; 16:165. 14. Gill IS, Rassweiler JJ: Retroperitoneoscopic renal surgery: our approach. Urology 1999; 54:734. 15. Gill IS, Schweizer D, Hobart MG, et al: Retroperitoneal laparoscopic radical nephrectomy: the Cleveland Clinic experience. J Urol 2000; 163:1665. 16. Gill IS, Strzempkowski B, Kaouk J, et al: Prospective randomized comparison: transperitoneal versus retroperitoneal laparoscopic radical nephrectomy. J Urol 2002; 167:19. (Abstract 78.) 17. Steinberg AP, Ramani AP, Abreu SC, et al: Reoperative laparoscopy: Cleveland Clinic experience. J Endourol 2002; 16:A97. (Abstract P18-24.) 18. Gill IS: Retroperitoneal laparoscopic nephrectomy. Urol Clin North Am 1998; 25:343.
19. Gill IS: Laparoscopic radical nephrectomy for cancer. Urol Clin North Am 2000; 27:707. 20. Chan DY, Cadeddu JA, Jarrett TW, et al: Laparoscopic radical nephrectomy: cancer control for renal cell carcinoma. J Urol 2001; 166(6):2095–2099. 21. Barrett PH, Fentie DD, Taranger LA: Laparoscopic radical nephrectomy with morcellation for renal cell carcinoma: the Saskatoon experience. Urology 1998; 52:23. 22. Janetschek G, Jeschke K, Peschel R, et al: Laparoscopic surgery for stage T1 renal cell carcinoma: radical and wedge resection. Eur Urol 2000; 38:131. 23. Siqueira TM, Kuo RL, Gardner TA, et al: Major complications in 213 laparoscopic nephrectomy cases: the Indianapolis experience. J Urol 2002; 168:1361. 24. Cadeddu JA, Ono Y, Clayman RV: Laparoscopic nephrectomy for renal cell cancer: evaluation of efficacy and safety: a multicenter experience. Urology 1998; 52:773. 25. Kaouk JH, Gill IS: Laparoscopic radical nephrectomy: morcellate or leave intact? Rev Urol 2002; 4:38. 26. Matin S, Gill IS: Modified Pfannensteil incision for intact specimen extraction following retroperitoneoscopic renal surgery. Urology 61(4):830–832. 27. Gill IS, Cherullo EE, Meraney AM, et al: Vaginal extraction of the intact specimen following laparoscopic radical nephrectomy. J Urol 2002; 167:238. 28. Tsivian A, Sidi AA: Port site metastases in urological laparoscopic surgery. J Urol 2002; 169:1213. 29. Cicco A, Salomon L, Hoznek H: Carcinological risks and retroperitoneal laparoscopy. Eur Urol 2000; 38:606. 30. Fentie DD, Barrett PH, Taranger LA: Metastatic renal cell cancer after laparoscopic radical nephrectomy: long-term follow-up. J Endourol 2000; 14:407. 31. Castilho LN, Fugita OE, Mitre AI: Port site recurrences of renal cell carcinoma after videolaparoscopic radical nephrectomy. J Urol 2001; 165:519. 32. Gill IS, McClellan BL, Kerbl K, et al: Adrenal involvement from renal cancer: predictive value of computed tomography. J Urol 1994; 152:1082. 33. Desai MM, Gill IS, Ramani AP: Laparoscopic radical nephrectomy for cancer with level I renal vein involvement. J Urol 2003; 169:487. 34. Meraney AM, Gill IS: Financial analysis of laparoscopic versus open radical nephrectomy and nephroureterectomy. J Urol 2002; 167:1757. 35. Winfield HN, Donovan JF, Godet AS, et al: Laparoscopic partial nephrectomy: initial case report for benign disease. J Endourol 1993; 7:521. 36. Gill IS, Delworth MG, Munch LC: Laparoscopic retroperitoneal partial nephrectomy. J Urol 1994; 152:1539. 37. McDougall EM, Elbahnasy AM, Clayman RV: Laparoscopic wedge resection and partial nephrectomy—the Washington University experience and review of literature. J Soc Laparoendosc Surg 1998; 2:15. 38. Hoznek A, Salomon L, Antiphon P, et al: Partial nephrectomy with retroperitoneal laparoscopy. J Urol 1999; 162:1922.
Chapter 13 Laparoscopic Radical and Partial Nephrectomy 39. Desai MM, Gill IS, Kaouk JH, et al: Laparoscopic partial nephrectomy with suture-repair of the collecting system. Urology 2003; 61:99. 40. Gill IS: Minimally invasive nephron-sparing surgery. Urol Clin North Am 30(3):551–579. 41. Gill IS, Abreu SC, Desai MM, et al: Laparoscopic ice slush renal hypothermia for partial nephrectomy: the initial experience. J Urol 170(1):52–56. 42. Gill IS, Matin SF, Desai MM, et al: Comparative analysis of laparoscopic vs. open partial nephrectomy for renal tumors in 200 patients. J Urol 170(1):64–68.
257
43. Harmon WJ, Kavoussi LR, Bishoff JT, et al: Laparoscopic nephron-sparing surgery for solid renal masses using the ultrasonic shears. Urology 2000; 56:754. 44. Rassweiler JJ, Abbou C, Janetschek G, et al: Laparoscopic partial nephrectomy. The European experience. Urol Clin North Am 2000; 27:721. 45. Steinberg AP, Desai MM, Gill IS, et al: Financial analysis of laparoscopic versus open partial nephrectomy. J Endourol (in press).
C H A P T E R
14 Treatment of Advanced Renal Cell Carcinoma Tracey Krupski, MD, Hyung Kim, MD, Robert A. Figlin, MD, and Arie Belldegrun, MD
Advanced renal cell carcinoma (RCC) continues to present a major challenge for physicians. Approximately 20% to 30% of patients have metastatic RCC at the time of diagnosis, and metastatic RCC remains resistant to conventional oncologic therapies.1 Immunotherapy with interleukin-2 (IL-2) and interferon-α (IFN-α) remains the standard of care for metastatic RCC, however, response rates remain modest at 10% to 30%, and the median survival for patients presenting with metastatic RCC is 12 to 18 months. Despite the poor prognosis generally associated with advanced RCC, a unique characteristic of RCC is that in a small subset of patients durable remissions and long-term survival is possible. Spontaneous regression of primary and metastatic lesions in RCC is second only to melanoma in terms of regression rates. The most common pattern of disease regression is resolution of pulmonary metastasis after nephrectomy.2 Freed et al.3 found 51 cases of regression of RCC. Of these, 3 had no treatment of the primary lesion and 18 had histologic confirmation of regression. A review of the available literature by Snow and Schellhammer4 in 1982 found regression of metastatic renal tumors in fewer than 1% of cases. However, regression prior to primary therapy has also been documented. Disease stabilization, defined as a failure of sustained growth, has been documented in both primary RCC and metastatic foci.5 Oliver et al.6 observed 73 patients with metastatic RCC who received no treatment. In this series, 3 patients had complete regression and 2 patients had partial regression of disease. In addition, 5% of patients had stable disease. To treat RCC better, efforts have been directed at delineating the variables important in determining prognosis. Patients most likely to progress and die from RCC
258
can now be identified. Treatments associated with significant toxicities can be reserved for patients most likely to benefit from the therapy. An accurate stratification of patients based on risk factors will allow physicians to better interpret the results of clinical trials. As in the treatment of any malignancy, the ultimate goal is complete cure, and the remarkable examples of spontaneous regression of advanced RCC hold out the hope that with the right medical intervention, this is possible. EPIDEMIOLOGY OF RENAL CELL CARCINOMA RCC is the third most common genitourinary malignancy. It is estimated that 31,500 new cases of RCC, representing 3% of all cancers, will be diagnosed in the United States in 2003.7 In the United States since 1950, there has been a 126% increase in the incidence of RCC accompanied by a 36.5% increase in annual mortality.8 This phenomenon may partially be explained by the increased number of incidental tumors detected by widespread use of radiologic imaging. However, other unidentified factors are important, as the incidences of both localized and advanced RCC have increased. Not until the year 2002 did this trend stabilize. The rise in incidence for all stages from 1973 to 1997 was three times greater than rise in the rate of mortality. Consequently, the 5-year survival for all cases has nearly doubled from 34% in 1954 to 62% in 1996.8,9 Recently, obesity has been found to be a risk factor for death in several cancers, including kidney cancer. Calle et al.10 examined how obesity influenced the death rate from kidney cancer. A patient’s degree of obesity was determined by their body-mass index and categorized according to the World Health Organization’s classification system of
Chapter 14 Treatment of Advanced Renal Cell Carcinoma 259
normal range, grades 1, 2, and 3 overweight. As the degree of obesity increased, so did the relative risk of death from cancer with patients in the highest group having a 1.7 relative risk.
The natural history of RCC is complex and many factors impact the biologic behavior of these tumors. Various prognostic models that integrate clinically relevant variables have been proposed. The evaluation of biomolecular markers for staging and determining prognosis is an active area of investigation. However, until these biomolecular markers have been rigorously tested and validated, clinical variables, such as stage, grade and performance status, will continue to be the most important variables for assessing prognosis. Tumor Stage Stage categorizes the anatomic spread of RCC and is recognized as the most important prognosticator for RCC. Currently, the two most commonly used staging systems are the stages described by Flocks and Kadesky11 and modified by Robson12, and the TNM system proposed by the Union Internationale Contre le Cancer (UICC).13 The TNM system has been modified twice since its introduction. The change in 1997 entailed expanding the T1 stage from <2.5 to <7 cm. Tumor thrombus above the diaphragm became T3c instead of T4 and thrombus below the diaphragm was changed to T3b.14 Several studies have validated the latest modification of the TNM system.15–17 However, others have suggested that further changes to the 1997 modification will increase the discriminatory power of the staging system.18,19 The 1997 TNM staging system uses a 7-cm cutoff between T1 and T2 tumors. The T1 tumors are further stratified into those <4 cm, which are T1a, and those greater than 4 cm, which are T1b. Using the UCLA database, various cutoffs for separating T1 and T2 primary tumors were evaluated. Patients were optimally stratified when a 4.5-cm cutoff was used (Figure 14-1). In addition, the difference in survival was not statistically different between patients with 4.5 and 7-cm tumors and patients with tumors >7 cm.18 In a similar analysis of patients who underwent a partial nephrectomy, Hafez et al.20 suggested that a 4-cm cutoff should be used in the TNM staging system. Recently, collecting system invasion has been analyzed with respect to survival rates. Analysis of 895 patients found 124 patients with collecting system invasion. Multivariate analysis revealed a 1.4 times increased risk of death after controlling for tumor grade and stage. The difference in 3-year survival is most apparent in stage 1 tumors, where noninvaders had an 81% survival versus 67% for invaders.21 The Cleveland
100 ⱕ4.5 cm Survival (%)
Prognosis
Survival Using 4.5 cm Cut-off
75
P = 0.0001 P = NS
60
4.5 –7.0 cm >7.0 cm
25 0 0
12
24
36
48
60
72
Time from Nephrectomy (months)
Figure 14-1 The 4.5-cm cutoff provides optimal stratification of early-stage kidney cancer. This modification has been proposed to the TMN system.
Clinic’s experience with collecting system invasion is similar. Clear cell carcinoma most commonly invades, and when the stage is high, urothelial involvement has little impact on prognosis. However, low stage T2 lesions have a worse prognosis when urothelial invasion is involved.22 Grade and Histology The initial report correlating grade and patient outcome was published in 1932.23 In 1971, Skinner and colleagues noted the correlation between nuclear features and survival, and Fuhrman et al.24 subsequently developed the findings into a 4-tier grading system. Grade 1 has no observable nucleoli, grade 2 has small nucleoli, grade 3 has prominent nucleoli, and grade 4 has large pleomorphic atypical cells with prominent nucleoli. Analysis of patients from UCLA found the 5-year cancer-specific survival based on tumor grade is 89% for grade 1, 65% for grade 2, and 46% for grades 3 and 417 (Figure 14-4). Inspection of the Mayo clinic data revealed similar 5-year crude survival rates based on histologic grade (Zincke, personal communication). While nuclear grading clearly impacts outcome, the effect of histologic subtype on outcome is more variable. There are five main histologic subtypes of RCC recognized as a result of a collaborative effort between the UICC and the American Joint Committee on Cancer (AJCC) in 1997.14 Clear cell carcinomas account for 70% to 80% of RCC tumors while papillary tumors account for 10% to 15% and both arise from the proximal tubules. Chromophobe tumors arise from the intercalated cells of the collecting ducts and account for 5% of kidney cancers. Collecting duct or medullary carcinomas of the kidney are a rare and very aggressive form of kidney cancer. Chao et al.25 reported on 6 patients with collecting duct tumors. Tumors affected patients at a
260
Part III Kidney and Ureter
younger age, presented with stage IV disease, and had an average survival of 11.5 months. Renal medullary carcinoma occurs almost exclusively in African-Americans with sickle cell trait or disease and has a very poor prognosis. Sarcomatoid RCC is no longer considered a distinct histologic subtype but rather a high-grade form of RCC that portends poor prognosis. Sarcomatoid features are present in <5% of RCC and are typified by a spindle cell growth pattern.26 Ro et al.27 noted that in low stage disease, 2 factors independently predictive of a poorer prognosis were the amount of tumor necrosis and proportion of sarcomatoid tumor. Renal tumors that do not fit into one of the five histologic categories are designated as unclassified renal tumors.28 As molecular classification becomes available, it is expected that these tumors will either be categorized as one of the established subtypes or a new subtype will be defined. Each subtype has distinctive characteristics and biology that predict tumor behavior. Amin et al.29 reviewed 405 cases of renal tumors and assessed the role of histology in predicting outcome. They reported 5-year disease-specific survivals of 100%, 86%, 76%, and 24% for chromophobe, papillary, clear cell, and unclassified tumors, respectively. However, the limited number of histologic cases in each group precluded controlling for stage. Motzer et al.30 recently analyzed 64 patients with metastatic non-clear cell RCC and reported that patients who had chromophobe tumors also fared better than patients who originally had collecting duct or papillary histology. In 12 patients with chromophobe histology, 4 patients had survivals of over 3 years.
action between multiple prognostic factors. Using the UCLA kidney cancer database, 14 clinical variables were assessed for inclusion in a prognostic model. The 1997 TNM stage, tumor grade, and ECOG-PS were identified as strong predictors of prognosis and were combined to develop the 5-tiered UCLA integrated staging system (UISS) (Figure 14-2). Using the UISS the projected 2and 5-year survivals for patients in groups are: I, 96% and 94%; II, 89% and 67%; III, 66% and 39%; IV, 42% and 23%; V, 9% and 0% (Figure 14-3). This novel system for staging and predicting survival for patients with RCC is simple to use and superior to using stage alone in predicting survival.36 More recently, a simplified UISS algorithm has been developed that assigns patients with localized and metastatic RCC into either low, intermediate or highrisk groups.33 For each of the risk groups, a relevant set ULCA Integrated Staging System (UISS) TNM ECOG Stage PS
UISS
Grade
Overall 5 Yr Survival (%)
I
I
0
1– 2
94
II
I II
0 any
3–4 any
67
III III III
0 ≥1 ≥1
any 1 2–4
IV IV IV
0 0 ≥1
1–2 3–4 1–3
IV
≥1
4
III
IV V
39
23 0
Patient Performance Status The Karnovsky performance scale and the Eastern Cooperative Oncology Group performance status (ECOG-PS) scale measure the impact of multiple objective and subjective symptoms on the patient’s overall functional status. The ECOG-PS scale at the time of presentation is an important prognostic factor in patients with metastatic RCC and it is useful for selecting patients for treatments.31,32 ECOG-PS is an independent predictor for survival in patients with both metastatic and localized disease. Patients with RCC and an ECOG-PS score of 0 had a 81% 5-year survival while patients with an ECOG-PS score 1 to 4 had a 51% 5-year survival.33 Performance status was found by Elson34 to be one of the primary determinants of prognosis. Further, a decreased performance status was associated with reduced survival in a Memorial Sloan Kettering study by Motzer et al.35
Figure 14-2 From 14 possible variables, TMN stage, tumor grade and ECOG-PS proved to optimally stratify patient prognosis. UCLA Integrated Staging System (UISS) 100
I
75 II 50
III
25
0
IV
0
The UCLA Integrated Staging System Recent studies suggest that the ultimate clinical behavior of RCC can be predicted by considering a complex inter-
V
P = 0.001 12
24
36
48
60
72
84
96
Months
Figure 14-3 The UISS stratifies patients beyond stage alone. The difference in survival curves is clearly shown.
Chapter 14 Treatment of Advanced Renal Cell Carcinoma 261
of clinical outcome data was generated, including overall survival, disease-specific survival, freedom from recurrence in nonmetastatic (NM) patients, outcome after recurrence in NM patients, and freedom from progression in metastatic (M) patients undergoing cytoreductive nephrectomy and immunotherapy. This outcome data can now be used to predict prognosis of other patients. The Mayo Clinic also has developed an outcome prediction model called the SSIGN score. SSIGN represents stage, size, grade, and necrosis. Stage relates to the 1997 TMN system, while size refers to tumors >5 cm. This scoring system is designed to predict outcomes of patients with clear cell carcinoma.37 A postoperative nomogram also exists for RCC. Kattan’s nomogram predicts the 5year freedom from failure and utilizes the factors symptoms, histology, pathologic stage, and tumor size.38 Other stratification systems that address prognosis have been described. In 1998 Elson et al.34 developed a scoring system to determine the prognosis of advanced RCC by stratifying patients into 5 groups based on ECOG-PS performance status, time from diagnosis to metastasis, weight loss, previous chemotherapy, and number of metastatic sites.34 Most recently, Motzer et al.35 developed a model based on a study of 670 patients with advanced RCC treated at Memorial Sloan Kettering Cancer Center by defining the relationship of pretreatment clinical features and survival. Features associated with shorter survival on multivariate analysis included decreased performance scale, increased serum lactate dehydrogenase level, hypercalcemia, and having the primary tumor in place. Paraneoplastic signs and symptoms occur in 20% of patients diagnosed with RCC. Polycythemia, hypercalcemia, and hepatic dysfunction are the results of proteins elaborated by the tumor and constitute a paraneoplastic syndrome. Anemia of hypoalbuminemia is thought to be related to tumor volume. While in univariate analysis each of these impacts disease-specific survival significantly, multivariate analysis found only hypoalbuminemia, weight loss, anorexia, and malaise correlated with disease-specific survival. This analysis controlled for TMN stage, ECOG-PS, and Fuhrman grade. The presence of any one of these findings constitutes cachexia and impacts survival. Patients with localized RCC had a significantly worse disease-specific survival if they had a cachexia-related finding, as did those patients with metastatic RCC.39 Evaluation of Patient All patients diagnosed with RCC require a thorough workup for metastatic disease. In addition to a meticulous history and physical exam, the abdomen and pelvis should be imaged with a CT scan. A CXR or chest CT should be obtained to rule out pulmonary metastasis. Any
patient with metastatic RCC to the chest or abdomen should have an MRI or CT of the brain. A bone scan should be obtained in any patient with bone pain, elevated serum calcium or metastasis noted elsewhere. Paraneoplastic findings are common in RCC, and the history and laboratory evaluation should be directed to assess for cachexia, fever, night sweats, hypercalcemia, polycythemia, anemia, and hepatic dysfunction. A brain metastasis has the potential for producing severely debilitating and crippling effects. Any brain metastasis, regardless of the total extent of the disease, should be treated with radiation, surgery or both, prior to administering any further treatment. Regardless of organ, solitary metastatic lesions amenable to surgery should be resected. Although randomized studies are not available, surgical extirpation provides palliative benefits and may extend survival.40–42 One study found 66% of patients treated with immunotherapy and surgical resection of lung metastasis were alive with a median followup of 48 months.43 Slaton et al.44 reported on 15 patients who underwent resection of the primary tumor with concurrent resection of a metastatic site (8 lung, 3 bone, 2 nodal, 1 liver, and 1 contralateral adrenal). Nine received adjuvant immunotherapy. Seven had no evidence of disease, and 4 had stable metastasis at 17 months. Inferior Vena Cava Involvement Extension of tumor thrombus into the inferior vena cava (IVC) often poses a challenge to surgeons. However, several studies show it can be safely done.44,45 Zisman et al.45 compared surgical complications in patients with metastatic disease undergoing resection of the kidney and caval thrombus with patients undergoing a radical nephrectomy alone. There was no increase in surgical complications. Zisman et al.45 further found that in patients who had isolated caval involvement but no metastasis, the survival was not statistically different from those without the thrombus. In another retrospective analysis, patients with IVC thrombus and metastatic RCC who underwent both a nephrectomy and received immunotherapy had better survival than patients treated with either therapy alone.46 Lymph Node Involvement The older literature regarding lymphadenopathy reported conflicting results.47–49 The only randomized phase III trial to address the benefits of lymph node dissection during radical nephrectomy for patients with resectable, nonmetastatic RCC was performed by the European Organization for the Research and Treatment of Cancer Genitourinary Group in study # 30881. In this study, the dissection extended from the crus of the diaphragm inferiorly to the bifurcation of the aorta. The study random-
262
Part III Kidney and Ureter
ized 772 patients to undergo standard nephrectomy or nephrectomy with node dissection. The preliminary results have been reported. After preoperative staging, the incidence of unsuspected lymph node metastasis was 3.3%. The complication rates were not increased in the group undergoing lymph node dissection.50 Retrospective studies evaluating the role of lymphadenectomy in patients with clinically bulky lymph nodes suggest that lymph node dissection will improve survival. Vasselli et al.51 examined survival in patients with metastatic RCC. The patients without clinical evidence of lymphadenopathy had a 14.5-months survival as compared to an 8.5 median survival of those with positive nodes. Furthermore, survival was 3 months longer in those who underwent complete, or even incomplete, surgical extirpation of nodes as opposed to those deemed unresectable. The UCLA experience confirms the finding that clinically positive nodes in the setting of metastatic disease are associated with poor prognosis. In those patients, lymphadenectomy improves survival when performed on carefully selected patients undergoing cytoreductive nephrectomy prior to immunotherapy. It was noted that bulky lymph nodes almost never respond to immunotherapy and should be resected when possible52,53 (Figure 14-4). METASTATIC RENAL CELL CARCINOMA Role of Nephrectomy Before the era of immunotherapy, the natural history of metastatic RCC was not improved by debulking nephrectomy. deKernion et al.2 published the survival rates in patients with metastatic disease treated with nephrectomy alone. The 2- and 5-year survival rates were 25% and 13%, respectively. Nephrectomies were reserved for palliation of local symptoms, such as pain and hematuria. However, with the advent of modern immunotherapy, the role of cytoreductive nephrectomies Metastatic Patients and LND 1.00
Survival
0.75 Treated with IMT 63% LND No LND 71%
0.50 LND 0.25
P = 0.0002
0.00
No LND 0
12
24
36
n = 107 n = 22 48
60
72
84
96
Months
Figure 14-4 Among patients with metastatic RCC who are treated with immunotherapy, lymphadenectomy appears to confer a survival advantage.
for patients with metastatic RCC became a source of debate. In the 1980s, IFN-α was established, an effective therapy for metastatic RCC.54 In 1992, the Food and Drug Administration approved recombinant human IL-2 monotherapy for RCC. Several authors have noted a response to IL-2 immunotherapy with the primary tumor in place.55 However, advocates of neoadjuvant nephrectomy argued that the primary tumor may produce an immunosuppressive effect and that neoadjuvant nephrectomy will further improve the response to immunotherapy. Another argument for neoadjuvant nephrectomy was that the primary tumor rarely responses to immunotherapy. Wagner et al.56 at the National Cancer Institute reported a 6% extrarenal response to immunotherapy; however, there were no responses of the primary tumor. One of the primary concerns with neoadjuvant nephrectomy was that surgery would delay or even preclude administration of immunotherapy.57 However, several studies have examined this issue and found that immunotherapy can be given in a timely manner following surgery. The median time to delivery was 40 days.58 Laparoscopic nephrectomy has also been advocated as a modality that would decrease time to immunotherapy.59 Recently, the results of two multi-institutional randomized studies have been published and they establish cytoreductive nephrectomy, and immunotherapy improves survival in advanced RCC. Southwest Oncology Group (SWOG) trial 8949 began in 1989 and randomized 246 patients with metastatic RCC into 2 arms. Patients in first arm were treated with radical nephrectomy and IFN-α, and patients in the second arm were treated with IFN-α alone. Although the response rates were similar, the median survival was 8 months in the interferon-only arm compared to 12 months in the surgery in first arm (p = 0.02). The trend for increased survival was maintained for all stratification factors, including measurable disease, performance status, and site of metastasis.60 A multi-institutional, phase III study from Europe reached a similar conclusion. The EORTC-GU trial 30947 applied the same protocol as the SWOG study. The two arms included a combination arm consisting of nephrectomy followed by immunotherapy and a control arm that received immunotherapy alone. Both time to progression (p = 0.04) and survival (p = 0.3) were significantly improved in the combination arm over the control arm. Median survival was only 7 months in the interferon only arm and it was 17 months in the surgery plus interferon arm.61 These two trials are the first prospective studies demonstrating the benefit of nephrectomy in the modern immunotherapy era. Following the publication of the SWOG study, Pantuck et al.62 studied patients treated with nephrectomy
Chapter 14 Treatment of Advanced Renal Cell Carcinoma 263
and IL-2-based immunotherapy at UCLA. They retrospectively identified 89 patients who met the preoperative eligibility criteria used in the SWOG study. The median survival in these patients was 16.7 months with a 5-year survival of 19.6%. Figure 14-5 shows the Kaplan–Meier survival curve for this group superimposed on survival curves for the two groups in the SWOG study. An important caveat is that these studies enrolled and evaluated patients with favorable clinical features, such as good performance status and minimal number of metastatic sites. Therefore, the results of these studies may not apply to patients with higher-risk features. SYSTEMIC THERAPY RCC is refractory to chemotherapy and radiation therapy. However, it is responsive to systemic cytokine therapy. The most commonly used agents include IFN-α and IL-2. Interferon-α IFN-α, originally described as an antiviral agent, has broad immunoregulatory properties and has been shown to be effective in metastatic RCC. In one study, 1042 patients treated with IFN-α demonstrated an overall response rate of 12% with an average response time of 4 months.63 The dosing regimen of 5 to 20 million U/d of IFN-α appears to be effective with minimal toxicity.64 The toxicity associated with INF-α is usually seen several weeks after initiating treatment and includes malaise, myalgia, fever, chills, anorexia, weight loss, depression, and decreased cognitive function. Prophylactic use of acetaminophen, NSAIDs, and antihistamines is routine, and SWOG & UCLA Retrospective
100
P < 0.05
Survival
80 60
40 Nx + IL-2 20
Nx + IFN IFN
0 0
24
48
72
Figure 14-5 Kaplan–Meier survival curves for patients undergoing cytoreductive nephrectomy followed by either interferon or interleukin immunotherapy.
96
antidepressants are often used prophylactically as well. In an effort to minimize toxicity, various combinations of agents at various dosing schedules have been proposed. In the only randomized study to demonstrate a survival advantage for IFN-α, patients were randomized to receive vinblastine alone versus IFN-α and vinblastine. The median survival for the vinblastine only arm was 37.8 weeks and for the combination arm was 67.6 weeks (p = 0.0049).65 In an early report of a randomized trial comparing IFN-α versus medroxyprogesterone acetate (MPA), the 1-year survival in the IFN-α group was 43% compared to 31% in the MPA group.66 In other phase III trials, the addition of 5-fluorouracil (5-FU) or 13-cis-retinoic to IFN-α-based regimens did not significantly impact survival.64,67 In a randomized trial, 284 patients were treated with IFN-α alone or IFN-α plus 13-cis-retinoic acid. While progression free rates and overall survival were not statistically different, the median duration of response was higher in the group that received both IFN-α and 13-cis-retinoic acid, suggesting and 13-cis-retinoic acid may enhance the durability of the response to IFN-α68 An ongoing phase III ECOG trial is evaluating IFN-α alone versus IFN-α and thalidomide. The role of IFN-α as adjuvant therapy for high risk, localized RCC has also been evaluated in a randomized trial. An Italian study randomized 264 patients to IFN-α three times a week for 6 months or to observation following nephrectomy. After 62 months, the overall survival was 66% for both groups but disease-free survival was slightly lower in the IFN-α group.69 Therefore, there is currently no role for adjuvant immunotherapy in patients without documented metastatic disease. Interleukin-2 IL-2 was approved in 1992 by the Food and Drug Administration (FDA) for the treatment of mRCC based on a 14.5% response rate in 255 patients treated with high-dose IL-2. A follow-up study of the 255 patients originally presented to the FDA was published 8 years later. The median survival for all 255 patients was 16.3 months and 10% of all patients remained alive and disease free.70 IL-2 does not have any direct cytotoxic effects; however, it induces the immune system to produce a cytotoxic response against RCC. IL-2 is associated with significant toxicity due to vascular permeability.71 Major toxicities include vascular collapse, vascular leak syndrome, cardiac arrhythmias, fever, chills, diarrhea, hepatic dysfunction, and renal failure. IL-2 is administered either as low- or high-dose regimen. The high-dose regimen needs to be administered in a closely monitored inpatient setting with ready access to vasopressors. Patients should have normal or minimally impaired cardiac, renal, and pulmonary function. Approximately 50% of patients required vasopressor sup-
264
Part III Kidney and Ureter
port in one study.72 The high-dose regimen should preferably be used at referral centers with experience in administering high-dose IL-2 and managing related complications. The low-dose IL-2 regimen is associated with significantly less toxicity and can be administered on an outpatient basis. A review of 10 trials with over 500 patients involving high-dose intravenous IL-2 revealed a response rate of 19% with a median duration of 22 months.73 The response rates in studies using low-dose IL-2 with or without IFN-α were 11% to 17%74,75 These results are comparable to those seen with high-dose IL-2; however, high-dose IL-2 was more likely to produce complete responses that resulted in longer disease-free intervals. In a randomized 3 arm comparison of high-dose intravenous, low-dose intravenous and intermediate-dose subcutaneous IL-2 regimens, the response rates were 16%, 4%, and 11%, respectively.57 However, long-term survival results, which may confirm the improved durability of responses seen with higher-dose regimens, are not yet available. Recent work by the Cytokine Working Group examined the role of high-dose IL-2 in patients with locally advanced as well as M1 disease who were completely resected. They found no improvement in survival with the addition of IL-2 in these high-risk populations (ASCO 2003). NOVEL THERAPIES Passive Immunotherapy Immunotherapy is characterized as active when the agent induces a state of immune responsiveness against the tumor in the host or as passive when the immunologic agents are directly active against the tumor. Examples of passive immunotherapy include monoclonal antibody therapy and adoptive immunotherapy. The transfer of cells, which can mount an antitumor response, is coined adoptive immunotherapy. An example of adoptive therapy utilizes tumor-infiltrating lymphocytes (TIL), which are derived from the tumor and adoptively transferred to the tumor-bearing host. In 1980, the NCI isolated infiltrating lymphoid cells from solid tumors.76 These cells were expanded ex vivo using IL-2 and shown to have direct antitumor activity.77 In a murine model, TIL were effective in eliminating micrometastases.78 The initial single-institution studies showed great promise. Figlin et al.79 reported a 34.6% overall response rate to treatment with TIL. This lead to a multicenter randomized trial comparing CD8+TIL combined with IL-2 versus IL-2 alone. The response rate in the combination arm was 9.9% compared to 11.4% in the IL-2 alone arm. This lead the investigators to conclude that the combination of TIL and IL-2 was no better than IL-2 alone.80 However, it should be noted that 41% of the subjects randomized to the TIL arm did not receive the
TIL cells due to processing failure. At the present time, it may not be technically feasible to consistently deliver TIL-based treatment in a multi-institutional fashion. Active Immunotherapy Active immunotherapies sensitize effector cells (T lymphocytes) to target tumor antigens. A major obstacle in the search for an effective agent is the lack of tumor-specific antigen.81 However, carbonic anhydrase IX (CA-9) has recently been identified as a potential target. CA-9 is the only characterized protein that is widely expressed in RCC with 95% to 100% of the clear cell variant demonstrating expression. Further, this expression is specific to the primary tumor and metastatic deposits.82,83 The reason for this overexpression is a direct consequence of a mutation in the von Hippel-Lindau gene, which normally suppresses CA-9. A better understanding of the immune system and the molecular changes involved in tumor formation provide insight into better treatment strategies. An effective tumor vaccine needs to recruit cytotoxic T cells specific for RCC and antigen presentation is the first step. Dendritic cells (DC) are the primary antigen presenting cells for stimulating T cell mediated immune responses, and thus, manipulation of DC ex vivo to express tumorspecific antigen may yield a potent vaccine.84,85 In animal studies, DC-based tumor vaccines were more effective when combined with systemic cytokines. An elegant solution to avoid the toxicity of systemic therapy yet retain the synergy with a vaccine would be to engineer the DC ex vivo to express tumor antigen, as well as an immunomodulatory cytokine, such as GM-CSF. This allows for lower systemic levels of cytokine yet keeps high levels in the tumor itself. At UCLA, preclinical studies designed to assess the effectiveness of a fusion protein consisting of CA-9 and GM-CSF are currently underway. Heat shock protein represents another potential target for treating RCC. Heat shock protein normally functions to allow proper folding of intracellular polypeptides and aids with intracellular transport. They have been associated with degraded proteins from tumor. Heat shock protein vaccines have been shown to be effective against RCC in a clinical trial.86 A pivotal, 500-subject phase III trial of adjuvant HSP vaccine (Oncophage-Antigenic) in high-risk RCC is underway. Future studies will likely combine the heat shock protein with IL-2 or GMCSF. Antiangiogenic In RCC, increase in vascular endothelial growth factor (VEGF) and angiogenesis is a direct consequence of the VHL mutation commonly found in clear cell RCC. An
Chapter 14 Treatment of Advanced Renal Cell Carcinoma 265
understanding of this mechanism provides a straightforward rationale for targeting angiogenesis in RCC. Bevacizumab is a monoclonal antibody designed to neutralize VEGF. A randomized placebo-controlled study is ongoing to evaluate the effectiveness of high- and lowdose bevacizumab.87 In an early report of 110 patients randomized on the study, there was a highly significant prolongation in time to progression of high-dose bevacizumab compared to placebo. Three partial responses were seen in the high-dose group and none in the lowdose or placebo groups. Chemotherapy Gemcitabine is the latest chemotherapeutic agent to be used in clinical trials. A phase I trial initially evaluated multiple dosing regimens of 5-FU with weekly gemcitabine. The results of this work suggested antitumor activity against RCC, in particular. The most efficacious dosing regimen was defined by this study as well.88 A multiinstitutional phase II study used gemcitabine 600 mg/m(2) on days 1, 8, and 15 with continuous infusion of 5-FU 150 mg/m(2)/day for days 1 to 21. While no patient had a complete response, 7 of 39 had a partial response (17%).89 To increase this objective response rate, additional agents have been added to the regimen in a search for synergy. Neri et al.90 combined 1000 mg/m gemcitabine intravenously on days 1, 8, 15, and 28 with intramuscular IFN-α (1 MU) and 4.5 million IU of IL-2 subcutaneously for 6 months. The overall response rate was 28% and median survival was 20 months. No toxicity greater than grade 2 was noted and therefore this appears to be a well-tolerated regimen. Daily thalidomide was also added to the gemcitabine and 5-FU regimen with no improvement in response rate. Further, the addition of thalidomide was associated with an unacceptable rate of deep venous thrombosis.91 However, none of these trials was prospective nor have they employed a control arm or immunotherapy alone arm. Bone Marrow Transplantation Researchers at the National Heart, Lung and Blood institute expanded their research on graft-versus-leukemia reactions to graft-versus-tumor effects. Because mRCC is partially responsive to immunotherapy, the authors postulated that allogeneic lymphocytes from healthy donors would attack metastatic RCC. Nineteen patients underwent immunosuppression with cyclophosphamide and fludarabine followed by infusion of peripheral blood stem cell allograft from an HLA identical or single mismatch sibling. Transplantation-related deaths occurred in 2 patients, and 8 patients died of disease progression. However, 53% experienced disease regression. The three
complete responders remained in remission for an average of 22 months.92 SUMMARY Advanced RCC remains as a difficult problem for physicians. For metastatic RCC, immunotherapy with IFN-α or IL-2 remains as the standard of care, with typical response rates of about 20%. While nephrectomy followed by immunotherapy appears to be the most efficacious treatment, careful patient selection is imperative. Improved ability to define patient prognosis allow us to better select patients for various treatments. In an effort to improve response rates and minimize toxicity, novel approaches continue to be explored. Active areas of investigation include vaccines therapies, bone marrow transplantation and targeted pharmaceuticals.
REFERENCES 1. Kirkali Z, Tuzel E, Mungan MU: Recent advances in kidney cancer and metastatic disease. BJU Int 2001; 88:818–824. 2. deKernion JB, Ramming KP, Smith RB: The natural history of metastatic renal cell carcinoma: a computer analysis. J Urol 1978; 120:148–152. 3. Freed SZ, Halperin JP, Gordon M: Idiopathic regression of metastases from renal cell carcinoma. J Urol 1977; 118:538–542. 4. Snow RM, Schellhammer PF: Spontaneous regression of metastatic renal cell carcinoma. Urology 1982; 20:177–181. 5. Tandon PL, Kumar M, Hafeez MA: Metastasis from renal cell carcinoma twenty years after nephrectomy. A case report. Brit J Urol 1963; 35:30. 6. Oliver RT, Miller RM, Mehta A, et al: A phase 2 study of surveillance in patients with metastatic renal cell carcinoma and assessment of response of such patients to therapy on progression. Mol Biother 1988; 1:14–20. 7. Jemal A, Murray T, Samuels A, et al: Cancer statistics, 2003. CA Cancer J Clin 2003; 53:5–26. 8. Ries LAEM, Kosary CL, et al: SEER Cancer Statistics Review, 1973–1997. Bethesda, Maryland, National Cancer Institute, 2000. 9. Pantuck AJ, Zisman A, Belldegrun AS: The changing natural history of renal cell carcinoma. J Urol 2001; 166:1611–1623. 10. Calle EE, Rodriguez C, Walker-Thurmond K, et al: Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003; 348:1625–1638. 11. Flocks R, Kadesky M: Malignant Neoplasms of the kidney: analysis of 353 patients followed 5 years or more. Trans Am Assoc Genitourin Surg 1957; 49:105-110. 12. Robson CJ, Churchill BM, Anderson W: The results of radical nephrectomy for renal cell carcinoma. J Urol 1969; 101:297–301.
266
Part III Kidney and Ureter
13. Beahrs OH: Staging of cancer. CA Cancer J Clin 1991; 41:121–125. 14. Guinan P, Sobin LH, Algaba F, et al: TNM staging of renal cell carcinoma: workgroup no. 3. Union International Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 1997; 80:992–993. 15. Minervini R, Minervini A, Fontana N, et al: Evaluation of the 1997 tumour, nodes and metastases classification of renal cell carcinoma: experience in 172 patients. BJU Int 2000; 86:199–202. 16. Gettman MT, Blute ML, Spotts B, et al: Pathologic staging of renal cell carcinoma: significance of tumor classification with the 1997 TNM staging system. Cancer 2001; 91:354–361. 17. Tsui KH, Shvarts O, Smith RB, et al: Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria. J Urol 2000; 163:1090–1095. (Quiz 1295.) 18. Zisman A, Pantuck AJ, Chao D, et al: Reevaluation of the 1997 TNM classification for renal cell carcinoma: T1 and T2 cutoff point at 4.5 rather than 7 cm better correlates with clinical outcome. J Urol 2001; 166:54–58. 19. Gelb AB, Shibuya RB, Weiss LM, et al: Stage I renal cell carcinoma. A clinicopathologic study of 82 cases. Am J Surg Pathol 1993; 17:275–286. 20. Hafez KS, Fergany AF, Novick AC: Nephron sparing surgery for localized renal cell carcinoma: impact of tumor size on patient survival, tumor recurrence and TNM staging. J Urol 1999; 162:1930–1933. 21. Palapattu GSPA, Belldegrun AS, et al: Collecting system invasion in renal cell carcinoma: impact of prognosis and future staging strategies (in press). 22. Uzzo RG, Cherullo EE, Myles J, et al: Renal cell carcinoma invading the urinary collecting system: implications for staging. J Urol 2002; 167:2392–2396. 23. Hand JR, Broders AC: Carcinoma of the kidney: the degree of malignancy in relation to factors bearing on prognosis. J Urol 1932; 28:199. 24. Fuhrman SA, Lasky LC, Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982; 6:655–663. 25. Chao D, Zisman A, Pantuck AJ, et al: Collecting duct renal cell carcinoma: clinical study of a rare tumor. J Urol 2002; 167:71–74. 26. Goldstein NS: The current state of renal cell carcinoma grading. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 1997; 80:977–980. 27. Ro JY, Ayala AG, Sella A, et al: Sarcomatoid renal cell carcinoma: clinicopathologic. A study of 42 cases. Cancer 1987; 59:516–526. 28. Zisman A, Chao DH, Pantuck AJ, et al: Unclassified renal cell carcinoma: clinical features and prognostic impact of a new histological subtype. J Urol 2002; 168:950–955. 29. Amin MB, Tamboli P, Javidan J, et al: Prognostic impact of histologic subtyping of adult renal epithelial neoplasms: an experience of 405 cases. Am J Surg Pathol 2002; 26:281–291.
30. Motzer RJ, Bacik J, Mariani T, et al: Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. J Clin Oncol 2002; 20:2376–2381. 31. Fallick ML, McDermott DF, LaRock D, et al: Nephrectomy before interleukin-2 therapy for patients with metastatic renal cell carcinoma. J Urol 1997; 158:1691–1695. 32. Citterio G, Bertuzzi A, Tresoldi M, et al: Prognostic factors for survival in metastatic renal cell carcinoma: retrospective analysis from 109 consecutive patients. Eur Urol 1997; 31:286–291. 33. Zisman A, Pantuck AJ, Wieder J, et al: Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol 2002; 20:4559–4566. 34. Elson PJ, Witte RS, Trump DL: Prognostic factors for survival in patients with recurrent or metastatic renal cell carcinoma. Cancer Res 1988; 48:7310–7313. 35. Motzer RJ, Mazumdar M, Bacik J, et al: Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 1999; 17:2530–2540. 36. Zisman A, Pantuck AJ, Dorey F, et al: Improved prognostication of renal cell carcinoma using an integrated staging system. J Clin Oncol 2001;19:1649–1657. 37. Frank I, Blute ML, Cheville JC, et al: An outcome prediction model for patients with clear cell renal cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade and necrosis: the SSIGN score. J Urol 2002; 168:2395–2400. 38. Kattan MW, Reuter V, Motzer RJ, et al: A postoperative prognostic nomogram for renal cell carcinoma. J Urol 2001; 166:63–67. 39. Kim HL, Belldegrun AS, Freitas DG, et al: Paraneoplastic signs and symptoms of renal cell carcinoma: implications for prognosis. J Urol 2003; 170(6):2221-2224. 40. von der Maase H, Geertsen P, Thatcher N, et al: Recombinant interleukin-2 in metastatic renal cell carcinoma—a European multicentre phase II study. Eur J Cancer 1991; 27:1583–1589. 41. Koretz MJ, Lawson DH, York RM, et al: Randomized study of interleukin 2 (IL-2) alone vs IL-2 plus lymphokine-activated killer cells for treatment of melanoma and renal cell cancer. Arch Surg 1991; 126:898–903. 42. Kollender Y, Bickels J, Price WM, et al: Metastatic renal cell carcinoma of bone: indications and technique of surgical intervention. J Urol 2000; 164:1505–1508. 43. Tanguay S, Swanson DA, Putnam JB Jr: Renal cell carcinoma metastatic to the lung: potential benefit in the combination of biological therapy and surgery. J Urol 1996; 156:1586–1589. 44. Slaton JW, Balbay MD, Levy DA, et al: Nephrectomy and vena caval thrombectomy in patients with metastatic renal cell carcinoma. Urology 1997; 50:673–677. 45. Zisman A, Pantuck AJ, Chao DH, et al: Renal cell carcinoma with tumor thrombus: is cytoreductive nephrectomy for advanced disease associated
Chapter 14 Treatment of Advanced Renal Cell Carcinoma 267
46.
47.
48. 49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
with an increased complication rate? J Urol 2002; 168:962–967. Zisman A, Wieder JA, Pantuck AJ, et al: Renal cell carcinoma with tumor thrombus extension: biology, role of nephrectomy and response to immunotherapy. J Urol 2003; 169:909–916. Skinner DG, Vermillion CD, Colvin RB: The surgical management of renal cell carcinoma. J Urol 192; 107:705–710. Rafla S: Renal cell carcinoma. Natural history and results of treatment. Cancer 1970; 25:26–40. Giuliani L: Lymphadenectomy and renal cell carcinoma: why is there so much controversy? Eur Urol 1983; 9:374. Blom JH, van Poppel H, Marechal JM, et al: Radical nephrectomy with and without lymph node dissection: preliminary results of the EORTC randomized phase III protocol 30881. EORTC Genitourinary Group. Eur Urol 1999; 36:570–575. Vasselli JR, Yang JC, Linehan WM, et al: Lack of retroperitoneal lymphadenopathy predicts survival of patients with metastatic renal cell carcinoma. J Urol 2001; 166:68–72. Pantuck AJ, Zisma A, Dorey F, et al: Renal cell carcinoma with retroperitoneal lymph nodes: role of lymph node dissection. J Urol 2003; 169. Pantuck AJ, Zismon A, Dorey F: Renal cell carcinoma with retroperitoneal lymph nodes: impact on survival and benefits of immunotherapy. Cancer 2003; 97(12): 2995-3002. deKernion JB, Sarna G, Figlin R, et al: The treatment of renal cell carcinoma with human leukocyte alphainterferon. J Urol 1983; 130:1063–1066. Haas GP, Hillman GG, Redman BG, et al: Immunotherapy of renal cell carcinoma. CA Cancer J Clin 1993; 43:177–187. Wagner JR, Walther MM, Linehan WM, et al: Interleukin-2 based immunotherapy for metastatic renal cell carcinoma with the kidney in place. J Urol 1999; 162:43–45. Walther MM, Yang JC, Pass HI, et al: Cytoreductive surgery before high dose interleukin-2 based therapy in patients with metastatic renal cell carcinoma. J Urol 1997; 158:1675–1678. Levy DA, Swanson DA, Slaton JW, et al: Timely delivery of biological therapy after cytoreductive nephrectomy in carefully selected patients with metastatic renal cell carcinoma. J Urol 1998; 159:1168–1173. Walther MM, Lyne JC, Libutti SK, et al: Laparoscopic cytoreductive nephrectomy as preparation for administration of systemic interleukin-2 in the treatment of metastatic renal cell carcinoma: a pilot study. Urology 1999; 53:496–501. Flanigan RC, Salmon SE, Blumenstein BA, et al: Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001; 345:1655–1659. Mickisch GH, Garin A, van Poppel H, et al: Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal
62.
63. 64. 65.
66.
67.
68.
69.
70.
71.
72.
73. 74.
75.
76.
77.
cell carcinoma: a randomised trial. Lancet 2001; 358:966–970. Pantuck AJ, Belldegrun AS, Figlin RA: Nephrectomy and interleukin-2 for metastatic renal cell carcinoma. N Engl J Med 2001; 345:1711–1712. Wirth MP: Immunotherapy for metastatic renal cell carcinoma. Urol Clin North Am 1993; 20:283–295. Motzer RJ, Russo P: Systemic therapy for renal cell carcinoma. J Urol 2000; 163:408–417. Pyrhonen S, Salminen E, Ruutu M, et al: Prospective randomized trial of interferon alfa-2a plus vinblastine versus vinblastine alone in patients with advanced renal cell cancer. J Clin Oncol 1999; 17:2859–2867. Medical Research Council Renal Cancer Collaborators: Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Lancet 1999; 353:14–17. Negrier S, Escudier B, Lasset C, et al: Recombinant human interleukin-2, recombinant human interferon alfa2a, or both in metastatic renal-cell carcinoma. Groupe Francais d’Immunotherapie. N Engl J Med 1998; 338:1272–1278. Motzer RJ, Murphy BA, Bacik J, et al: Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol 2000; 18:2972—2980. Giorgio PPL, Boracchi P: Adjuvant interferon to radical nephrectomy in Robson’s stage II and III renal cell carcinoma: contradictory results in pN0 and pN1 patients. Proc ASCO, 1999. Fisher RI, Rosenberg SA, Fyfe G: Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 2000; 6(Suppl 1):S55–S57). Belldegrun A, Webb DE, Austin HA 3rd, et al: Effects of interleukin-2 on renal function in patients receiving immunotherapy for advanced cancer. Ann Intern Med 1987; 106:817–822. Yang JC, Rosenberg SA: An ongoing prospective randomized comparison of interleukin-2 regimens for the treatment of metastatic renal cell cancer. Cancer J Sci Am 1997; 3(Suppl 1):S79–S84. Milowsky MI, Nanus DM: Advanced renal cell carcinoma. Curr Treat Options Oncol 2001; 2:437–445. Yang JC, Topalian SL, Parkinson D, et al: Randomized comparison of high-dose and low-dose intravenous interleukin-2 for the therapy of metastatic renal cell carcinoma: an interim report. J Clin Oncol 1994; 12:1572–1576. Dutcher JP, Fisher RI, Weiss G, et al: Outpatient subcutaneous interleukin-2 and interferon-alpha for metastatic renal cell cancer: five-year follow-up of the Cytokine working group study. Cancer J Sci Am 1997; 3:157–162. Yron I, Wood TA Jr, Spiess PJ, et al: In vitro growth of murine T cells. V. The isolation and growth of lymphoid cells infiltrating syngeneic solid tumors. J Immunol 1980; 125:238–245. Belldegrun A, Muul LM, Rosenberg SA: Interleukin 2 expanded tumor-infiltrating lymphocytes in human renal
268
78.
79.
80.
81.
82.
83.
84.
85.
Part III Kidney and Ureter cell cancer: isolation, characterization, and antitumor activity. Cancer Res 1988; 48:206–214. Lafreniere R, Rosenberg SA: Adoptive immunotherapy of murine hepatic metastases with lymphokine activated killer (LAK) cells and recombinant interleukin 2 (RIL 2) can mediate the regression of both immunogenic and nonimmunogenic sarcomas and an adenocarcinoma. J Immunol 1985; 135:4273–4280. Figlin RA, Pierce WC, Kaboo R, et al: Treatment of metastatic renal cell carcinoma with nephrectomy, interleukin-2 and cytokine-primed or CD8(+) selected tumor infiltrating lymphocytes from primary tumor. J Urol 1997; 158:740–745. Figlin RA, Thompson JA, Bukowski RM, et al: Multicenter, randomized, phase III trial of CD8(+) tumorinfiltrating lymphocytes in combination with recombinant interleukin-2 in metastatic renal cell carcinoma. J Clin Oncol 1999; 17:2521–2529. Neumann E, Engelsberg A, Decker J, et al: Heterogeneous expression of the tumor-associated antigens RAGE-1, PRAME, and glycoprotein 75 in human renal cell carcinoma: candidates for T-cell-based immunotherapies? Cancer Res 1998; 58:4090–4095. Bui MH, Seligson D, Han KR, et al: Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res 2003; 9:802–811. Oosterwijk E, Ruiter DJ, Hoedemaeker PJ, et al: Monoclonal antibody G 250 recognizes a determinant present in renal cell carcinoma and absent from normal kidney. Int J Cancer 1986; 38:489–494. Mulders P, Tso CL, Gitlitz B, et al: Presentation of renal tumor antigens by human dendritic cells activates tumorinfiltrating lymphocytes against autologous tumor: implications for live kidney cancer vaccines. Clin Cancer Res 1999; 5:445–454. Geiger JD, Hutchinson RJ, Hohenkirk LF, et al: Vaccination of pediatric solid tumor patients with tumor
86.
87.
88.
89.
90.
91.
92.
lysate-pulsed dendritic cells can expand specific T cells and mediate tumor regression. Cancer Res 2001; 61:8513–8519. Amato RJML, Wood L, et al: Active specific immunotherapy in patients with renal cell carcinoma using autologous tumor derived heat shock proteinpeptide complex-96 vaccine, Proc ASCO, 1999. Yang JCHL, Steinberg SM, Rosenberg SA, Novotny WA: A randomized double-blind placebo-controlled trial of bevacizumab (anti-VEGF antibody) demonstrating a prolongation in time to progression in patient with metastatic renal cancer. Proc Am Soc Clin Oncol 2002; Abstract 15. Mani S, Vogelzang NJ, Bertucci D, et al: Phase I study to evaluate multiple regimens of intravenous 5-fluorouracil administered in combination with weekly gemcitabine in patients with advanced solid tumors: a potential broadly active regimen for advanced solid tumor malignancies. Cancer 2001; 92:1567–1576. Rini BI, Vogelzang NJ, Dumas MC, et al: Phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil in patients with metastatic renal cell cancer. J Clin Oncol 2000; 18:2419–2426. Neri B, Doni L, Gemelli MT, et al: Phase II trial of weekly intravenous gemcitabine administration with interferon and interleukin-2 immunotherapy for metastatic renal cell cancer. J Urol 2002; 168:956–958. Desai AA, Vogelzang NJ, Rini BI, et al: A high rate of venous thromboembolism in a multi-institutional phase II trial of weekly intravenous gemcitabine with continuous infusion fluorouracil and daily thalidomide in patients with metastatic renal cell carcinoma. Cancer 2002; 95:1629–1636. Childs R, Chernoff A, Contentin N, et al: Regression of metastatic renal cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation. N Engl J Med 2000; 343:750–758
C H A P T E R
15 Transitional Cell Carcinoma of the Renal Pelvis and Ureter: Evaluation and Treatment Badrinath R. Konety, MD, MBA, and Richard D. Williams, MD
Transitional cell carcinoma (TCC) of the upper urinary tract occurs less frequently than bladder cancer. The precise incidence of renal pelvic and ureteral cancers is difficult to discern since they are grouped with other kidney cancers. Ureteral cancers are less common than renal pelvic cancers. Renal pelvic tumors comprise 5% to 7% of all renal tumors.1–5 Worldwide statistics vary and are not accurate, since renal pelvis tumors are not reported separately. The highest incidence is found in Balkan countries (Bulgaria, Greece, Romania, and Yugoslavia), where urothelial cancers account for 40% of all renal cancers. The majority of renal pelvic and ureteral cancers are transitional cell in origin with squamous cell carcinoma (SCC) and adenocarcinoma forming a small minority.2,6,7 Ureteral tumors most frequently involve the lower-third of the ureter.7–10 Bilateral involvement or metachronous renal pelvic tumor development in the contralateral kidney occurs in about 2% of patients.11,12 The estimated incidence of TCC arising in the ureter and other portions of the urinary tract other than renal pelvis or bladder in the United States is 2450 cases for the year 2004, with 690 deaths occurring as a result of these tumors.3 TCC of any origin is uniformly fatal unless treated since it is almost never discovered incidentally at autopsy.13 Patients with Balkan nephropathy have a higher incidence of upper tract TCC and there is also an increased incidence of bilaterality in 10% of these patients but the tumors tend to be low grade.2,8,11,12,14 Patients with upper tract TCC are at risk of developing bladder TCC, with an estimated incidence of 15% to 60% within 5 years following the upper tract TCC.15,16 Patients with primary bladder TCC will develop upper tract TCC in 2% to 4% of cases, with a mean interval of
17 to 170 months.17,18 Based on karyotypic similarities between bladder and upper tract TCC, it is likely that similar risk factors affect both upper and lower tract tumors.19 The risk factors associated with increased incidence of upper tract TCC include recurrent bladder carcinoma in situ (CIS) after intravesical BCG therapy,20,21 and multifocal CIS in the bladder at the time of cystectomy.22–24 Up to 19% of patients with upper urinary tract TCC have been reported to initially present with metastatic disease.25 ETIOLOGY Workers in chemical, petrochemical, and plastic industries, aniline dye workers, and those exposed to coal, coke, tar, and asphalt are at increased risk for renal pelvis and ureteral TCC (relative risk = 4 to 5.5). Aniline dyes, β-naphthylamine and benzidine compounds have all been implicated as causative agents for upper tract TCC.26,27 TCC in various locations in the urinary tract can develop up to 18 years after exposure.27 However, most of these chemicals are more commonly associated with lower urinary tract tumors because it is believed that prolonged contact with parent compounds or metabolites in urine is required for induction of carcinogenesis. Cigarette smoking is a major risk factor for upper tract TCC. Cessation of smoking somewhat decreases the risk but does not eliminate it completely. Duration of smoking is the strongest predictor of risk.28 Balkan endemic nephropathy is a chronic tubulointerstitial disorder confined to the Balkan countries, which ultimately results in renal failure. Cancer of the renal pelvis is 100 to 200 times more frequent in these countries than in control
269
270
Part III Kidney and Ureter
regions.29 Analgesic abuse is another predisposing factor for the development of upper tract TCC. One study found the relative risk for abusers of phenacetin containing analgesics was 2.4 for men and 4.2 for women.29 The dose–effect relationship was noted for both phenacetin and aspirin. The latency period was 24 to 26 years. While phenacetin is no longer available in the United States, acetaminophen has similar metabolites to phenacetin and is widely used as an antipyretic. Case control studies have not revealed any significant association between routine acetaminophen use and bladder TCC or upper tract TCC.30 However, abuse of the drug has not been studied. Both Balkan nephropathy and phenacetin abuse are associated only with renal pelvis TCC. Renal papillary necrosis itself is not a necessary factor for the development of renal pelvis TCC, but the combination of phenacetin use and papillary necrosis causes a 20-fold increased risk for renal urothelial tumors, indicating that both are probably independent risk factors. Chronic bacterial infection with urinary calculi and obstruction may predispose to the development of urothelial cancer. SCC is the most common entity in these cases. Schistosomiasis may also predispose to SCC. Cyclophosphamide has also been implicated in the development of renal pelvis TCC. About 6 cases have been reported occurring after an average of 5 years following chemotherapy.31 Thorium dioxide (Thorotrast), which was used as a contrast agent for retrograde pyelograms about 70 years ago, is also known to be a causative factor since it supposedly causes vascular insufficiency and a foreign body response. Cancers tend to occur after a latency period of 20 years.32 DIAGNOSIS Upper tract TCC can present with ureteral obstruction or hematuria (gross or microscopic). It can be asymptomatic and discovered during upper tract surveillance after development of bladder TCC. An increased index of suspicion, especially in patients who have undergone BCG or other intravesical therapy for bladder TCC, is prudent since the incidence of upper tract cancer in these patients can be as high as 38%.33 These tumors can occur up to 15 years following successful treatment of bladder TCC, which mandates at least yearly surveillance of the upper tracts in these patients.34 Hematuria is the most common presenting symptom, occurring in 56% to 98% of patients.8,35,36 Flank pain is usually a sign of upper tract obstruction. Systemic symptoms, such as weight loss, anorexia, and lethargy, are late findings that can occur in 10% to 15% of patients.36–38 Radiographic Evaluation The traditional evaluation of the upper tract has included an intravenous pyelogram (IVP). While the IVP may
yield more precise anatomic information regarding the upper tract urothelium, it is laborious to perform and not all centers have the same level of expertise in performing and interpreting these studies. A well-performed IVP will reveal an abnormality in the majority of cases (Figure 15-1A,B). The finding of a non-functional kidney on IVP, which occurs in up to 50% of cases,8,37 can portend a worse prognosis.39 Classic signs for upper tract urothelial carcinoma on IVP include the “goblet” or “Bergmann’s sign,” which is a meniscus-shaped filling defect in the ureter. A “stipple” sign may be observed with contrast being trapped in the fronds of a papillary tumor, either in the renal pelvis or ureter. Retrograde pyelograms will demonstrate evidence of tumor in the form of filling defects or an intrinsic narrowing or stricture of the ureter in almost all cases (Figure 15-2).39 Stricture or stenosis more commonly occurs at the ureteropelvic junction or ureter and can indicate infiltrative disease.8 In patients who have undergone a cystectomy for prior bladder TCC, a loopogram or pouchogram obtained by instilling contrast into the ileal conduit or neobladder may be required to adequately visualize the upper tracts. Conventional upper tract imaging can yield false positive results in 36% to 60% of cases.40,41 An alternative to the IVP is a contrastenhanced CT scan, which is often required to optimally evaluate the renal parenchyma. Presence of a mass lesion protruding into the contrast-filled collecting system can usually be identified on the CT scan especially in cases of papillary tumors >1 cm in size (Figure 15-3). CT scanning is easier to perform and less labor-intensive, with greater standardization of technique, and has the specific advantage of distinguishing intrarenal stones from tumors if films are obtained before and after intravenous contrast administration. The curvilinear pattern of calcification occasionally observed in upper tract TCC is usually distinguishable by CT scan. A single shot (IVP) in the form of a plain abdominal X-ray immediately following the CT scan can capture an image of the contrast filled renal pelvis and ureters. More recently, CT urograms have been performed in order to obtain a threedimensional view of the calyces and ureters. They appear to be equivalent to an IVP in imaging the ureters.42 Thinly collimated axial images obtained during a single breath hold using a multirow detector CT scan are then reformatted to obtain a coronal image of the collecting system. The images are of higher resolution than those obtained using standard single detector helical CT scanning. CT urography can detect the majority of ureteric tumors with a sensitivity as high as 94%.43 CT urography, however, does expose the patient to a greater dose of radiation. Sensitivity for detecting upper tract malignancy can approach 100% with a specificity of 60%. The negative predictive value was 100% in one reported study.43 However, more experience with this technique is
Chapter 15 Transitional Cell Carcinoma of the Renal Pelvis and Ureter 271
Figure 15-1 IVP with tomographic and excretory phase images of a patient with invasive TCC of the right upper pole who presented with gross hematuria and pyelonephritis.
272
Part III Kidney and Ureter
needed before it can be widely employed. MR urography has also been used in a similar manner with slightly lower reported sensitivity of 80%.44 CT scanning or MRI can also be used to assess local extent of tumor and presence of metastatic disease. Cytology and Other Markers Urine cytology is a very specific method that can be used to diagnose TCC of the upper and lower urinary tracts (Figure 15-4A,B). It is very sensitive for high-grade papillary tumors and CIS but less so for low-grade disease7,45 and is also operator dependent. Positive upper tract cytologies in the absence of bladder disease identify the presence of upper tract TCC. Often retrograde pyelography and ureteroscopy fail to reveal a lesion in the upper tract even in the presence of frankly positive urine cytology. Upper tract or urine cytologies that do not revert to negative 6 months following a completely negative urologic workup may indicate indolent or latent disease that will be discovered subsequently.46 The value of obtaining upper tract washing for cytology in the presence of bladder TCC is questionable. Contamination from tumor cells in the bladder make it very difficult to accurately interpret these results, especially in the absence of a radiologic abnormality in the upper tracts.47 However, properly performed studies with simultaneous specimens being obtained from the bladder and upper tracts with the use of normal saline to keep the ureteral catheter clear of bladder urine until it has been placed in the ureter can be successful. Several urine-based markers have been studied to increase the accuracy of diagnosing upper tract cancer. Urinary levels of NMP22, a nuclear matrix protein-based marker, are found to be elevated in patients with upper tract cancer.48 However, the numbers of patients in these studies are small and the specificity is low, yet the sensitivity is higher than cytology for low-grade disease. The BTA stat test (Mentor Corp., Santa Barbara, CA) has a sensitivity of 82% and specificity of 89% compared to voided urine cytology (11% and 54%, respectively) or ureteral wash cytology (48% and 33%, respectively) for upper tract tumors.49 In one study, telomerase was detected using cells obtained from upper tract washings and measured using the telomeric repeat amplification protocol (TRAP) assay in 14 of 17 patients.50 In comparison, voided urine cytology detected only 2 of 13 cases and ureteral washing cytology detected only 8 of 15 cases.50 Studies conducted thus far have included small numbers of patients and more data are required from larger studies before any of these tests can be routinely recommended. Other markers, such as p27 (cyclindependent kinase inhibitor) expression in tumor tissue, can also help to predict prognosis of upper tract tumors. Low levels of p27 staining in tumors can be indicative of worse disease-free survival in these patients.51
Figure 15-2 Retrograde pyelogram obtained in the patient from Figure 15-1 demonstrating a filling defect in the right upper pole due to an infiltrative TCC.
Direct Endoscopic Evaluation Endoscopic evaluation, including retrograde pyelograms and brush biopsies, are usually performed to obtain a more definitive diagnosis following the detection of a positive upper tract cytology. Brush biopsy through an open-ended ureteral catheter was originally described by Gill et al.52 Brush biopsy has a sensitivity of up to 90% and a specificity of up to 88%.7,53,54 Ureteroscopic visualization using a flexible or semirigid ureteroscope and direct biopsy is also effective in diagnosing these tumors, with a sensitivity of 86% and specificity of 90%.53 Complications of brush biopsy or ureteroscopy include the risk of infection, ureteral or renal pelvic perforation, bleeding, mucosal flap injury, and mucosal edema with resultant ureteral obstruction. HISTOPATHOLOGY TCC is the most common histologic type of upper urinary tract cancer. Cancers may be papillary or sessile and multifocality is common. CIS can be particularly difficult to identify grossly and may vary from a whitish-appearing
Chapter 15 Transitional Cell Carcinoma of the Renal Pelvis and Ureter 273
Figure 15-3 Contrast enhanced CT scan of a patient with a large papillary Ta TCC (arrow) arising from the left renal pelvis, which led to spontaneous bleeding and a perinephric hematoma (arrow).
Figure 15-4 A, Urine cytology, low-grade papillary TCC. (Modified from Kleer E, Osterling JE: Prob Urol 1992; 6(3):531, with permission.) B, Urine cytology, high-grade papillary TCC. (Modified from Kleer E, Osterling JE: Prob Urol 1992; 6(3):531, with permission.)
274
Part III Kidney and Ureter
plaque, due to epithelial hyperplasia, to a velvety red patch from increased submucosal vascularity.2 Progression to invasive TCC can occur from a papillary, low-grade lesion or by transformation of CIS.2,55 Multiple tumors can occur by implantation of tumor cells onto mechanically disrupted mucosa or due to the “field effect” on the entire urothelium, which is believed to contribute to the multifocal nature of TCC. CIS or atypia of the lower ureters is found in 7% to 25% of patients undergoing cystectomy for bladder cancer.56 Presence of upper tract CIS is also more common in heavily pretreated patients who have failed multiple courses of intravesical agents, such as BCG.57 These tumors can occur long after treatment of bladder disease, which suggests that these patients will benefit from long-term follow-up. Many of these instances of upper tract CIS may be asymptomatic and diagnosed on work-up of positive urine or selective ureteral cytology. STAGING AND GRADING The most commonly used staging system for upper tract cancer is the TNM staging system (Table 15-1). Upper tract TCC spreads by direct invasion, mucosal seeding, hematologic and lymphatic routes. The most common sites of metastases are lung, bone, and liver. The likelihood of nodal metastases increases with increasing stage, with 48% of T3 tumors and 78% of T4 tumors presenting with nodal metastases.58 The traditional grading system for bladder TCC is also applicable to TCC of the upper urinary tract. Broder’s original grading system, as modified by Ash, grades tumors on a scale of 1 to 4, with grade 1 tumors being mainly papillomas and grade 4 tumors being highly anaplastic and poorly differentiated.2,59 The World Health Organization’s grading system, proposed by Mostofi, eliminates papillomas and grades tumors from grade 1 to grade 3. The most recent grading system now divides tumors into low grade or high grade.60 Papillomas and papillary urothelial neoplasms of low malignant potential (PUNLMP) are separated out as well. Low-grade tumors include those previously considered grade 1 and grade 1-2, while high-grade tumors are those considered grade 2, grade 2-3, and grade 3. Prognosis of upper tract tumors is clearly dependent on tumor stage. There is a progressive decrease in survival with increasing stage with the most significant drop being observed in stage T3 tumors, which involve perirenal or periureteral fat.61 When matched stage for stage, there does not appear to be a significant difference in survival between renal pelvis and ureteral tumors.62 Other factors correlated with survival in these patients include tumor grade, multifocality, concomitant bladder carcinoma, and ploidy.56 Tumor ploidy may be predictive of survival with aneuploid tumors, demonstrating 5- and 10-year survivals of 25% and 0%, respectively.63
Table 15-1 Staging Systems for Upper Tract Urothelial Tumors TNM staging system Primary tumor (T) Tx Primary tumor cannot be assessed T0 No evidence of primary tumor Ta Papillary noninvasive carcinoma Tis Carcinoma in situ T1 Tumor invades subepithelial connective tissue T2 Tumor invades the muscularis T3 (For renal pelvis only) Tumor invades beyond muscularis into peripelvic fat or the renal parenchyma T4 Tumor invades adjacent organs, or through the kidney into the perinephric fat Lymph nodes (N) Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single lymph node, 2 cm or less in greatest dimension N2 Metastasis in a single lymph node, more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, none more than 5 cm in greatest dimension N3 Metastasis in a lymph node, more than 5 cm in greatest dimension Distant metastasis (M) Mx Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis AJCC staging system in comparison to TNM AJCC stage TNM staging Stage 0 T0 Stage I Ta, Tis, T1, N0, M0 Stage II T2, N0, M0 Stage III T3, N0, M0 Stage IV T4 or any T, N+, M+
CONSERVATIVE SURGICAL MANAGEMENT Endoscopic Management The established standard of care for the management of upper tract TCC, regardless of stage or grade, is a radical nephroureterectomy with resection of a generous cuff of bladder. The first radical nephroureterectomy was reported by LeDantu and Albarran.64 This approach is based on the characteristic biologic behavior of these tumors. They tend to be multifocal, contralateral tumors are uncommon (<5%), and there is a high incidence of ipsilateral tumor recurrence after partial resection.65 Furthermore, prior to the advent of the smaller caliber and flexible endoscopes, conservative endoscopic management of these tumors was extremely difficult and fraught with errors in diagnosis and complications, rendering it obvi-
Chapter 15 Transitional Cell Carcinoma of the Renal Pelvis and Ureter 275
ously unpopular. Vest first reported the successful management of papillary ureteric tumors with local resection alone in 1945.66 Over the past two decades a number of authors have reported successful long-term endoscopic management of upper tract TCC. There are certain basic tenets that must be observed while adopting this approach. The patient must agree to submit to long-term close surveillance with repeated upper tract endoscopy, tumors should be of low grade and stage and the patient must understand that nephroureterectomy may still become necessary if there is evidence of stage or grade progression. Upper tract tumors can be visualized using ureteral contrast studies and ureteroscopy. Biopsies can be obtained using a 2.4Fr flat wire basket or a 3Fr flexible cup biopsy forceps, which can be placed through a flexible 7Fr ureteroscope or a 6.9Fr semirigid ureteroscope. This approach can successfully confirm the presence of upper tract TCC in up to 98% of cases.67 In their series of 51 patients, Keeley et al.68 found that ureteroscopic biopsy yielded a diagnosis of cancer in 94.1% of cases and histologic grading was possible in 82.4%. The 11.5Fr resection loop can also be used through the ureteroscope, particularly in sampling and/or treating distal ureteric tumors.69 Upper tract tumors are akin to bladder tumors in terms of the correlation between pathologic grade and stage. Low-grade tumors predominantly tend to be low stage and very few high-grade tumors are of low stage (Ta-T1).38,70 Previous studies indicate that almost all grade 1 tumors are Ta.70 Keeley et al.71 found that even low- to moderate-grade tumors tend to be of lower stage (Ta-T1) while 67% of high-grade tumors were muscle
invasive (T2-T3). Correlation between grade and stage determined on ureteroscopic biopsy samples and final pathologic grade/stage determined from the nephroureterectomy specimen tend to be more accurate in the case of proximal ureteral tumors than distal ureteral tumors.69 Following adequate biopsy sampling, the tumors are ablated using either a Nd:Yag laser or Holmium laser delivered through a 200 or 365 μm fiber. The holmium laser is used at a setting of 1 J and 10 Hz while the Nd:Yag is used at a 30 W setting.72 The holmium laser has a penetration depth of 0.5 mm while the Nd:Yag can penetrate 5 to 6 mm below the surface, which can result in ureteral wall damage and may go unnoticed until later.73 Some experienced endoscopists advocate using a combination of the two types of laser to achieve a more complete ablation of all of the tumors. A ureteral stent is left in place for 1 to 2 weeks following the procedure. In situations where postablation instillation of a chemotherapeutic agent, such as mitomycin is anticipated, an openended ureteral catheter can be left in place attached to a Foley catheter to facilitate upper tract access. Complications reported with this approach have been minimal. Ureteral perforation, ureteral strictures and incomplete tumor resection have all been reported. The incidences of ureteral perforation in the two largest recent series of endoscopic management of upper tract tumors have been 0%68 and 5.4%.74 Ureteral strictures tend to occur more frequently in patients who suffer a ureteral perforation, with an overall incidence of 8.6% (Table 15-2). This is higher than that observed with nononcologic ureteroscopy and laser use. One potential
Table 15-2 Results of Endoscopic Ablation of Upper Urinary Tract Tumors Subsequent Nephroureterectomy
Author
No. of Patients
Complication Rate
Recurrence (Site)
Englemeyer and Belig75
10
2/10 (20%)
2 (P), 5 (U)
—
Elliott et al.74
37
8/37 (22%)
8 (P), 9 (U), 19 (B)
6
3–132
Martinez-Pinero et al.76
28
12/28 (43%)
2 (P), 6 (U)
3
2–119
Keeley et al.68
41
2/41 (5%)
3 (P), 5 (U), 15 (B)
8
3–116
Chen et al.67
23
2/23 (9%)
5 (P), 8 (U), 7 (B)
4
8–103
Blute et al.53
13 (ureteral)
0%
2 (U); 4 (B)
0
6–50
8 (renal pelvis)
0%
1 (P)
0
12–48
Johnson77
3
33%
1 (U), 2 (B)
0
5–22
Schilling et al.78
10
0%
1 (B)
0
3–31
Modified from Chen GL, Bagley DH: J Endourol 2001; 15:399. P, renal pelvis; U, ureter; B, bladder.
Follow-Up (Months) 24–66
276
Part III Kidney and Ureter
reason for this may be that in the case of tumor ablation the laser energy is being directed against the urothelium, directly permitting a greater amount of damage to occur, while in the case of laser lithotripsy, the beam is directed away from the urothelium. TCC recurrence rates after endoscopic ablation have been comparable to those obtained with open resection of renal pelvis TCC (50% versus 45% to 65%, respectively).8 Overall, the recurrence rate of tumors in the renal pelvis is 37% and of those in the ureter is 43% after endoscopic management (see Table 15-2). Recurrences appear to be grade related, with 76% of kidneys with grade 1 tumors being cleared of all disease at one point, 64% of kidneys with grade 2 tumors being cleared of disease and only 40% of kidneys bearing grade 3 tumors being cleared of disease.68 However, in this same report, local recurrences occurred in 25% of those with grade 1 tumors and 44% of those with grade 2 tumors requiring repeat endoscopic treatment at mean follow-up times of 40.3 months and 27.6 months, respectively.68 Tumors smaller than 1.5 cm can also be cleared more effectively compared to larger tumors as evidenced by the difference in recurrence rates—25% versus 50%.68 An alternative endoscopic approach in patients with bulky renal pelvis tumors is percutaneous resection or ablation. While this approach has demonstrated equivalence with more traditional surgical approaches in terms of cancer control, case selection is critical.79 Percutaneous access is obtained through the upper or midpole calyx to gain easy access to the collecting system as well. Alternatively, the involved calyx can also be accessed and the tract dilated and a working sheath placed. The tumor is debulked using cold cup forceps and the base is resected using a standard resection loop. The base can also be fulgurated with electrocautery or a laser. A second look nephroscopy is typically performed 3 to 7 days later and the resection base biopsied again to rule out the presence of residual tumor.80 Disease-specific survival at a mean follow-up of 51 months using this approach is reported to be 100% for grade 1, 94% for grade 2, and 62% for grade 3 TCC.80 The procedure is invasive with increased risk of hemorrhage, extravasation, and possible tumor dissemination along the nephrostomy tract or into the retroperitoneum. The incidence of percutaneous tract seeding after nephrostomy and upper tract TCC resection is low. Most reports involve recurrences that have occurred following percutaneous access after nephroscopy81 or prolonged nephrostomy tube drainage.82–84 Very few reported cases in the literature have occurred after percutaneous resection of an upper tract TCC.85,86 Suggested methods to prevent nephrostomy tract or local recurrence after percutaneous access include maintaining low intrarenal pressures, using a 30Fr working sheath, use of sterile water, and keeping the irrigating solution at a height <40 cm above the patient.86 Resecting the nephrostomy tract and
performing adjuvant radiation after nephroureterectomy in this situation are also viable options.87 The percutaneous nephrostomy can also be utilized for instillation of chemotherapeutic/immunotherapeutic agents following the resection.88,89 Percutaneous resection is effective for low-grade tumors but the outcome of local resection for high-grade disease is dismal with 80% of patients dying of their disease in spite of subsequent nephroureterectomy in one series.90 Multiple resections may be required to clear the renal pelvis of disease. Seeding of the nephrostomy tract does not appear to be a significant occurrence as evidenced by absence of tumor in the tract resected at subsequent nephroureterectomy.90 Renal salvage is possible in 60% of patients with low-grade disease at a follow-up of 64 months.90 In patients who have biopsy-proven CIS or positive upper tract cytologies, instillation of BCG into the upper tract can be an effective therapy. This approach could also be used, in solitary kidneys or in poor surgical candidates for nephroureterectomy, as adjuvant therapy following either percutaneous or retrograde resection of renal pelvis tumors. Instillation can be performed either antegrade via a percutaneous nephrostomy tube or retrograde through a 4Fr or 5Fr ureteral catheter inserted temporarily. The BCG is instilled as a continuous infusion over 30 to 60 minutes (1 ml/minute) with the bag hanging 20 cm above the patient.88,89 The dose of BCG used is usually up to three times the intravesical dose91 and instillation is avoided in the presence of gross hematuria. Patients void following instillation and the treatment is repeated weekly for 6 weeks. In an analysis of data from at least eight previous studies, it appears that an initial response rate of 79% can be achieved with a follow-up ranging from 4 to 82 months. The response can be durable in several of these patients as observed by Okubo et al.,89 who obtained a long-term response over a median follow-up of 49 months in 6 of 9 (66%) of their initial responders. Other series have found a long-term response rate with renal preservation of around 50% for patients with CIS.91 Fever appears to be a common side effect in these patients and septicemia due to bacterial dissemination or systemic BCGosis can occur in these patients and could be lethal. In one series, the incidence of sepsis was 2 of 37 patients (5%).91 This mandates emergent evaluation with resuscitation, starting of triple antituberculous drug therapy with isoniazid (plus pyridoxine), rifampin, and ethambutol. Steroids may need to be used in addition if the patient is not responding to this regimen in the acute setting. Mitomycin instillation can also be used as initial treatment in place of BCG with similar results.92 Surgical Approaches Partial Ureterectomy Segmental ureteral resection is a viable curative option for tumors of the ureter. Judicious use of this option is
Chapter 15 Transitional Cell Carcinoma of the Renal Pelvis and Ureter 277
important, keeping in context the stage and grade of tumor. It is most applicable to low-grade, distal ureteral tumors. The 5-year survival for patients with grade 1 tumors, who have undergone partial ureterectomy, is 100%.93 The ipsilateral recurrence rate following segmental resection is low and the recurrent tumors also tend to be low grade94 (Table 15-3). Recurrent tumors usually tend to occur distal to the original tumor, though occasional proximal recurrences have been noted.95,99 Potential explanations for this include the presence of adjacent CIS that is undetected at the time of primary resection, seeding of the upper tract due to vesicoureteric reflux, or de novo occurrence of new tumors. Patients with grade 2, stage Ta or T1 tumors can also be managed by segmental resection of the ureter containing the tumor. Anderstrom et al.39 found a 100% survival rate in 16 patients managed in this manner at 83 months follow-up. The success of conservative resection for muscle invasive or high-grade disease is not as clear-cut. Leitenberger et al.100 found that 4 of 13 patients managed with partial ureterectomy or nephrectomy alone for high stage (≥pT2) disease developed ipsilateral recurrences. Other studies have found a low rate of ipsilateral recurrence in patients managed with conservative resection of high-grade tumors.38 However, it is possible that the lower duration of subsequent survival in these patients is too short to permit appearance of locally recurrent tumors. Removal of the kidney and only a portion of the ureter for a renal pelvic or proximal ureteric TCC has a high rate of recurrence in the remaining ureteric stump.8,37,101 The incidence of tumor recurrence is proportional to the residual length of ureter left behind, suggesting that it is a function of potentially affected urothelium left in situ.57,102,103 This observation has provided the impetus for complete ureterectomy in these patients. Zincke et al.93 found that recurrence rates following segmental resection for distal ureteral TCC was much lower than that for renal pelvis TCC following nephrectomy with partial ureterectomy (15% versus 62%, respectively).
Recurrent TCC are also more likely to be of higher grade and stage when they are located in the renal pelvis.8,104 Renal pelvis TCC also appear to have a higher likelihood of developing systemic disease subsequently (0%) as compared to ureteral TCC (19%). Hence, the more traditional nephroureterectomy is a better approach for renal pelvis or proximal ureteral TCC especially if they are of high grade or stage. Open Nephroureterectomy One of the major drawbacks of the open nephroureterectomy is the need for two separate incisions to enable complete excision of the distal ureter with a cuff of bladder mucosa. Typically, this is achieved by using a flank incision for the nephrectomy and an additional Gibson incision to access the distal ureter and bladder. It should also be noted that prior to proceeding with an open nephroureterectomy, it is essential to ensure that the bladder is tumor-free by means of a cystoscopy and possible biopsy. Several urologists have advocated an endoscopic approach to excising the distal ureter and bladder cuff transvesically, thereby avoiding the need for a second incision.105 The two principal endoscopic approaches have been a “stripping” technique wherein a ureteral catheter is placed and secured with a tie around the distal ureter. Following resection of the kidney and proximal two-thirds of the ureter, a resectoscope is used to circumscribe the mucosa around the ureteral orifice while applying upward traction on the catheter through the flank incision. This allows the intramural ureter to be detached from the bladder along with a rim of surrounding bladder mucosa.106,107 There are multiple variations to this approach with the orifice being cauterized to encourage closure or simply ligated. Another commonly used technique is the “pluck” approach. The ureteral orifice is circumscribed endoscopically using a resectoscope loop or a hook electrode until perivesical fat is visible.108,109 This denotes that the distal ureter is free from surrounding attachments and can then be extracted in
Table 15-3 Results of Segmental Ureteral Resection and Reimplantation for Localized Ureteric Tumors No. of Patients (n)
Local Ureteral Recurrences (%)
6
1/6 (16.6)
44.4
Zungri et al.96
35
3/35 (8.5)
86
Maier et al.97
17
3/17 (17.6)
41.4
7
1/7 (14.3)
93.6
21
1/21 (4.7)
83
Study Johnson and Babaian95
Wallace et al.98 Anderstrom et al39
Duration of Follow-Up (Months)
278
Part III Kidney and Ureter
continuity with the renal specimen through the flank incision. The mucosa around the opening in the bladder wall is fulgurated to cause scarring and sealing of this area. A drain is left in place postoperatively. Mean bladder recurrence rates using the two different approaches are comparable (19.3% versus 24%, respectively).105 However, a total of 9 patients (7%) have developed local recurrence at the site of the ureteral orifice with the pluck technique, which is of significant concern. Complication rates are higher with the stripping technique (10% versus 2.7%) and it may not be applicable in all cases.105 The main complications with the pluck technique are the risk of intraperitoneal extravasation, while ureteral catheter-related problems, such as breakage/dislodgement or retention of the catheter, are the main problems following the stripping approach. Prognosis and survival following traditional management of TCC of the renal pelvis and ureter are very dependent on stage and grade. The presence of renal parenchyma around the renal pelvis acts as an anatomic barrier and this impacts prognosis. Stage T3 renal pelvis TCC is associated with a 54% 5-year survival rate, while that of ureteral T3 tumors is 24%.8,36 Metastatic upper tract TCC has a dismal prognosis, with the majority of patients dying by 3 years and 0% of patients survive for 5 years, even with administration of adjuvant therapy.37,62 Overall reported stage-specific 5-year survival rates for upper tract TCC are 100% for Ta/CIS tumors, 92% for T1, 73% for T3, and 41% for T4 tumors.38 Median survival for those with stage T4 disease can be as short as 6 months. Overall median survival does not appear to differ significantly between patients who undergo segmental ureterectomy for a ureteral tumor compared to those who undergo a nephroureterectomy, and is reported to be as high as 58 months.38 Previous studies indicate a clear effect of both stage and grade on 5-year survival, with rates ranging from 54% to 75% for stage I/A/Tis, 43% to 87% for stage II/T1 or T1, 0% to 54% for stage III/C/T3, and 0% to 19% for stage IV/D/T4/N+ or M+.36 Most largescale studies for treatment outcomes for upper tract TCC using reported epidemiologic data from the American College of Surgeons or the Surveillance Epidemiology and End Results (SEER) program consider mainly renal pelvis TCC, which is grouped with kidney cancers and which renders the data hard to interpret. Most recent data from the American College of Surgeons National Cancer Database indicate that overall survival for cancers of the kidney and renal pelvis is 76% (Figure 15-5). Laparoscopic Nephroureterectomy Since the first report of a laparoscopic nephroureterectomy in a child by the Washington University group in 1991,110 this approach has rapidly gained acceptance and
is now considered the standard of care by many. Cancer control and complication rates are reported to be comparable to the open approach. The morbidity, as with other laparoscopic procedures, is significantly lower with shorter hospital stays and recovery times (Table 15-4). The efficacy of both transperitoneal and retroperitoneal laparoscopic nephroureterectomy appear to have similar advantages over the traditional open approach.111,119 A hand-assisted approach has been advocated by some as easier for traditional surgeons to master and as a means to allow better control and manipulation during the removal of large tumors or more complex cases. Using this approach Keeley et al.120 observed better retraction, dissection, and tactile feedback, which translated to shorter operative times than standard “pure” laparoscopic nephroureterectomy. The hand-assisted laparoscopic nephroureterectomy still requires a longer operative time compared to the traditional open nephroureterectomy but hospital stay, time to oral intake, time to resuming normal activity, and quality of life are better with the hand-assisted approach as determined by prospective studies.121 In a prospective comparison of the standard laparoscopic nephroureterectomy to the hand-assisted approach, Landman et al.111 found that complication rates were slightly lower with the hand-assisted approach (45% versus 31%). Operative time was shorter with the hand-assisted approach and there were no differences in hospital stay or postoperative pain medication requirements. Return to work times were 1 to 3 weeks longer in the hand-assisted group though this was not statistically significant. All three approaches appear to be oncologically equivalent as assessed by the incidence of recurrent tumors. Based on these data the laparoscopic or handassisted approaches are considered by many to be the standard of care. There is still some controversy about the best method of excising the lower ureter with a cuff of bladder mucosa while performing a laparoscopic nephroureterectomy. The methods described in the open nephroureterectomy section for endoscopic resection of the distal ureter transvesical to avoid a second incision are applicable to, or have been adapted for, use in conjunction with laparoscopic nephroureterectomy. Gill et al.122 have used an intravesical approach with needlescopic (2 mm) instruments. Small-sized laparoscopic instruments are placed transvesically and the bladder cuff around the ureteric orifice is circumscribed with electrocautery and dissected around a previously placed ureteral balloon catheter, which occludes the ureter and prevents tumor spillage. Dissection is carried out until the intramural portion of the ureter is free of all attachments and the lower ureter and bladder cuff can be extracted in continuity with the rest of the specimen. Shalhav et al.123 have proposed a combined laparoscopic and endoscopic approach. An occluding balloon catheter is placed in the ureter. The
Chapter 15 Transitional Cell Carcinoma of the Renal Pelvis and Ureter 279
100 90 80
Percent
70 60 50 40 30 20 10 0 At diag
After 1 year.
After 2 year.
After 3 year.
After 4 year.
After 5 year.
SURVIVAL I IV
When diagnosed on stage:
II Overall
III
Survial Reports, v2.0 −− March 9, 2004
Source: NCDB, Commission on Cancer, ACoS.
Five Year Survival Table fo Kidney and Renal Pelvis Cancer Cases Diagnosed in 1995 & 1996 All States/Data Reported from 1653 Hospitals Hospitals of type: All Stage
Cases
At dx
1 year
2 year
3 year
4 year
5 year
95% Confidence Interval
I
5147
100
93.10
87.96
82.87
77.66
73.91
72.53 - 75.29
II
15158
100
92.94
87.10
82.35
77.12
72.31
71.47 - 73.15
III
6334
100
82.76
70.78
62.79
55.96
50.59
49.17 - 52.01
IV
9423
100
33.75
17.66
11.22
8.17
6.49
5.91 - 7.07
Overall
39944
100
75.00
65.22
59.30
54.28
50.35
49.79 - 50.91
Source: NCDB, Commission on Cancer, ACoS/ACS.
Survival Reports, v2.0—March 9, 2004
Figure 15-5 Stage specific 5-year survival rates for kidney and renal pelvic tumors diagnosed 1995–1996. (Data from the National Cancer Database maintained by the American College of Surgeons, with permission.)
intramural ureter is unroofed using a hot Collins knife and a 1-cm cuff of bladder mucosa is circumscribed around the ureteric orifice using a resectoscope until perivesical fat is clearly visible. A rollerball electrode is used to fulgurate the edges of the ureter. A balloon catheter is replaced in the renal pelvis to prevent leakage of tumor into the retroperitoneum. The lower ureter is thus freed of all attachments and can then be extracted in continuity with the rest of the specimen. Other authors have reported simply resecting the ureteral orifice transvesically using a resectoscope.108 The availability of hand-assisted laparoscopy has also permitted a more standard approach using hand traction on the lower ureter to dissect it down to the bladder extravesically and
excise it along with a cuff of mucosa. All of the minimally invasive approaches run the risk of leaving a portion of the intramural ureter intact. CHEMOTHERAPY FOR ADVANCED DISEASE Upper tract urothelial cancers are fairly chemosensitive. Given the relatively low frequency of upper tract TCC compared to bladder TCC, very few trials have focused on developing chemotherapeutic regimens specific for upper tract disease. Single-agent and combination regimens that have shown activity in bladder TCC have been generally used to treat upper tract disease with similar efficacy. Most of the data cited below pertain to bladder
Retroperitoneal
Retroperitoneal
Transperitoneal
Retroperitoneal
Transperitoneal
Transperitoneal
Retroperitoneal
Transperitoneal (1 retroperitoneal)
Chung et al.112
Salomon et al.113
Keeley and Tolley114
Hobart et al.115
Shalhav et al.116
McNeill et al.117
Yoshino et al.118
Landman et al.111
NS, Not significant; B, bladder. *Median follow-up.
Approach
Study
11/0
23/1
25/3
25/0
17/2
18/3
4/0
6/14
Number of Cases/Open Conversions
Cystoscopic unroofing, cauterization
Stapled 2.5 cm cuff
Open bladder cuff
Stapled
Transvesical
Pluck
Open bladder cuff
Open bladder cuff
Method of Distal Ureter Resection
PTa-T1, Grade 1-4
PTa-T4, Grade 1-3
PT1-T3, grade 1-3
PTa-T3, grade 1-4
PTa-T4, grade 1-3
NS
PT2-T3, grade 2-3
NS
Pathology
190
304
199
278
NS
220
NS
Mean EBL (cc)
3.3
NS
5
3.6
2.2
NS
5.7
9
Mean LOS (days)
27.4
19*
35
39
6.4
NS
18
12.6
Mean Follow-up (Months)
Table 15-4 Comparison of Outcomes from Laparoscopic Nephroureterectomy with Open Nephroureterectomy
30% (B)
17.4% (B)
16%*
40% (28% B, 12% local)
NS
11%
25% (local)
15% (B)
Local Recurrence Rate
280 Part III Kidney and Ureter
Chapter 15 Transitional Cell Carcinoma of the Renal Pelvis and Ureter 281
TCC but has served as a basis for the chemotherapeutic approaches adopted for upper tract TCC. Single-agent chemotherapy with cisplatin, methotrexate, cyclophosphamide, or gemcitabine has yielded responses ranging from 25% to 35%.124,125 The methotrexate, vinblastine, adriamycin, cyclophosphamide (MVAC) regimen, which has a reported response rate as high as 70% in bladder TCC, can also be used for upper tract TCC.126,127 In direct comparisons, it is clear that combination therapy is more effective than single-agent therapy such as cisplatin.128 In one report, 20 patients with upper tract TCC were included in a randomized trial comparing MVAC with the cisplatin, cyclophosphamide, adriamycin (CISCA) regimen.129 There was no difference in response rates between these patients and those with primary bladder TCC. In spite of observed complete responses, there is a tendency for patients to relapse. Duration of response varies from 8.5 to 39 months.128 Alternative newer regimens, such as gemcitabine with cisplatin or paclitaxel with carboplatin have yielded response rates of 50% to 60%.130 A randomized trial comparing MVAC to gemcitabine with cisplatin obtained similar response rates, median overall survival, and duration of response.131 The gemcitabine/cisplatin regimen was much less toxic and better tolerated. It is now considered the de facto standard for the treatment of most urothelial cancers. A sequential approach has also been used to treat urothelial cancers. Adriamycin/gemcitabine followed by ifosfamide/paclitaxel/cisplatin has been used in an effort to maximize response while limiting toxicity.132 Results of randomized trials are awaited. Neoadjuvant chemotherapy has been used in upper tract disease and more so in bladder cancer. Large randomized trials have failed to show a clear survival benefit to this approach. One study using the cisplatin, methotrexate, vinblastine (CMV) regimen demonstrated a 5.5% higher survival in the neoadjuvant chemotherapy group at 3 years of follow-up, which was not statistically significant.133 The theoretical advantage of neoadjuvant chemotherapy in downstaging the tumor and allowing organ preservation by conservative surgery does not really exist for upper tract disease since the only candidates for such surgery are those with superficial disease. Data supporting the use of adjuvant chemotherapy in urothelial cancers are also weak and this applies to upper tract disease as well. Most trials have not shown a clear benefit and the advantage of routine adjuvant chemotherapy over salvage therapy at the time of recurrence is not well established.134–137 RADIATION THERAPY FOR UPPER TRACT TCC The use of radiation therapy as an adjuvant to surgery in patients with locally advanced upper tract TCC has been reported with variable results. Original studies suggested
that the use of adjuvant radiation may decrease the likelihood of local recurrence after nephroureterectomy in patients with locally advanced T3/T4 disease.138–140 Brookland and Richter139 treated 23 patients determined to have poor risk disease with surgery alone or surgery followed by adjuvant radiation. They found that 1 of 9 (11%) evaluable patients treated with adjuvant radiation developed local and distant recurrence, while 5 of 11 (42%) evaluable patients who were treated with surgery alone developed local or local and distant recurrence. Other authors report similar low rates of local recurrence with the use of adjuvant radiation therapy.138,141 The reported doses of radiation used have ranged from 40 to 50 Gy. Adequate and complete local control of tumor is important considering the fact that it can be an independent predictor of survival.142 Maulard-Durdux et al.143 reported the largest retrospective series, with 26 patients treated with adjuvant radiation of 45 Gy following complete surgical resection of primary tumor in patients with locally advanced disease, of whom 42% had regional nodal metastases. They noted a low local recurrence rate of 15% but the overall 5-year survival rate was not different than that obtained in historic series using surgery alone. These results highlight the fact that while local failure is important, most patients who die succumb to metastases, which is not in areas addressed by radiation. Hence, it is difficult to recommend routine adjuvant radiation even in patients with evidence of residual local disease. These individuals may benefit from adjuvant combination chemotherapy or a combination of radiosensitizing single-agent chemotherapy with cisplatin followed by radiation to optimize local control. OUTCOME Overall risk of recurrence after initial standard treatment of upper tract TCC, which has traditionally been open nephroureterectomy, has been related to stage and grade of tumor. Five-year survival can range from 100% for low-stage disease to 0% for T4 disease.70 More recent series have indicated a local recurrence rate of 23% to 27%.38,141 Almost 50% of these recurrences are in the bladder, with 9% occurring in the retroperitoneum, 18% in the remaining upper tract, and 22% being distant.38 In multivariate analysis, tumor stage and surgical procedure were related to the risk of recurrence.38 Only patient age and stage were indicative of survival in multivariate analysis. Local disease relapse tends to occur early and the median time to such recurrence can be 12 months.38 Follow-up of patients with upper tract TCC involves obtaining periodic IVP and/or CT scans to image the upper tracts and rule out local disease recurrence. While there is no established follow-up schedule that is known to be optimal, it is reasonable to base it on stage/grade of primary tumor and type of surgical procedure performed.
282
Part III Kidney and Ureter
We typically recommend obtaining an IVP 3 months postoperatively and a CT scan 6 months following surgery if the renal unit is left intact. Subsequent follow-up will include annual IVP and/or CT scan. In those who undergo nephroureterectomy, CT scans are obtained at yearly intervals for stage T2 or higher and biannual studies for lower stage disease. We also obtain a voided urine cytology and perform office cystoscopy to rule out the presence of bladder TCC in patients at 3-month intervals for the first 2 years, every 6 months for the following 2 years, and yearly thereafter following treatment of upper tract TCC.
REFERENCES 1. Fraley EE: Cancer of the renal pelvis. In Skinner DG, deKernion JB (eds): Genitourinary Cancer, p 134. Philadelphia, WB Saunders, 1978. 2. Melamed MR, Reuter VE: Pathology and staging of urothelial tumors of the kidney and ureter. Urol Clin North Am 1993; 20:333. 3. Jemal A, Tiwari RC, Murray T, et al: Cancer Statistics 2004. CA Cancer J Clin 2004; 54:8. 4. McLaughlin JK, Silverman DT, Fraumeni JF, et al: Cigarette smoking and cancers of the renal pelvis and ureter. Cancer Res 1992; 52:254. 5. Rubenstein MA, Walz BJ, Bucy JG: Transitional cell carcinoma of the kidney: 25-year experience. J Urol 1978; 119:594. 6. Bennington JL, Beckwith JB: Tumors of the kidney, renal pelvis and ureter. In Atlas of Tumor Pathology, 2nd series, Fascicle 12. Washington DC, Armed Forces Institute of Pathology, 1975. 7. Vicente J, Pilar L, Sole-Balcells FJ, et al: Transitional cell carcinoma in the upper urinary tract: diagnosis and management. Urol Int 1995; 2:7. 8. Mazeman E: Tumors if the upper urinary tract calyces, renal pelvis and ureter. Eur Urol 1976; 2:120. 9. Petkovic SD: Conservation of the kidney in operations for tumors of the renal pelvis and calyces. Br J Urol 1972; 44:1. 10. Murphy DM, Zincke H, Furlow WL: Management of high-grade transitional cell cancer of the upper tract. J Urol 1980; 125:25. 11. Huben RP, Mounzer AM, Murphy GP: Tumor grade and prognostic variables in upper tract urothelial tumors. Cancer 1988; 62:2016. 12. Krogh J, Kvist E, Rye B: Transitional cell carcinoma of the upper urinary tract: prognostic variables and post operative recurrences. Br J Urol 1991; 67:32. 13. Ressequie LT, Nobrega FT, Farrow GM, et al: Epidemiology of renal and ureteral cancer in Rochester, Minnesota, 1950-1974 with special reference to clinical and pathological features. Mayo Clin Proc 1978; 53:503. 14. Radovanovic Z, Krajinovic S, Jankovic S, et al: Family history of cancer among cases of upper urothelial tumors
15.
16.
17.
18.
19.
20. 21.
22.
23.
24.
25.
26. 27. 28.
29. 30.
31.
32.
33.
34.
in the Balkan nephropathy area. J Cancer Res Clin Oncol 1985; 110:181. Kakizoe T, Fujita T, Murase T, et al: Transitional cell carcinoma of the bladder in patients with renal pelvic and ureteral cancer. J Urol 1980; 124:17. Kimball FN, Ferris HW: Papillomatous tumor of the renal pelvis associated with similar tumors of the ureter and bladder. J Urol 1934; 31;257. Oldbring J, Cliffberg I, Mikulowski P, et al: Carcinoma of the renal pelvis and ureter following bladder carcinoma: frequency, risk factors and clinicopathologic findings. J Urol 1989; 141:1311. Rabbani F, Perrotti M, Russo P, et al: Upper tract tumors after an initial diagnosis of bladder cancer: argument for long term surveillance. J Clin Oncol 2001; 19:94. Fadl-Elmula I, Gorunova L, Mandahl N, et al: Cytogenetic analysis of upper urinary tract transitional cell carcinomas. Cancer Genet Cytogenet 1999; 115:123. Hudson M, Herr HW: Carcinoma in situ of the bladder. J Urol 1995; 153:564. Herr HW, Wartinger DD, Oettgen HF: Bacillus Calmette Guerin therapy for superficial bladder cancer: a 10-year follow-up. J Urol 1992; 147:1020. Zincke H, Garbeff PJ, Beahrs RJ, et al: Upper urinary tract transitional cell cancer after radical cystectomy for bladder cancer. J Urol 1994; 131:50. Malkowicz SB, Skinner DG: Development of upper tract carcinoma after cystectomy for bladder cancer. Urology 1990; 36:20. Sharma TC, Melamaed MR, Whitmore WF: Carcinoma in situ of the ureter in patients with bladder carcinoma treated by cystectomy. Cancer 1970; 26:583. Akaza H, Koiso K, Niijima T: Clinical evaluation of urothelial tumors of the renal pelvis and ureter based on a new classification system. Cancer 1987; 59:1369. Wallace D: Cancer of the bladder. Am J Roentgenol 1968; 102:581. Davies JM: Bladder tumors in electric cable industry. Lancet 1965; 2:143. Ross RK, Paganini-Hill A, Henderson BE: Analgesics, cigarette smoking and other risk factors for cancer of the renal pelvis and ureter. Cancer Res 1989; 49:1045. Petkovic SD: Epidemiology and treatment of renal pelvic and ureteral tumor. J Urol 1975; 14:858. Rosenberg L, Rao RS, Palmer JR, et al: Transitional cell cancer of the urinary tract and renal cell cancer in relation to acetaminophen use (United States). Cancer Causes Control 1998; 9:83. Levine E: Transitional cell carcinoma of the renal pelvis associated with cyclophosphamide therapy. Am J Roentgenol 1992; 159:1027. Verhaak RL, Harmsen AE, Van Urink AJM, et al: On the frequency of tumor induction in a Thorotrast kidney. Cancer 1974; 34:2061. Schwalb DM, Herr HW, Fair WR: The management of clinically unconfirmed positive urinary cytology. J Urol 1993; 150:1751. Herr HW, Cookson MS, Soloway SM: Upper tract tumors in patients with primary bladder cancer followed for 15 years. J Urol 1996; 156:1286.
Chapter 15 Transitional Cell Carcinoma of the Renal Pelvis and Ureter 283 35. Raabe NK, Fossa SD, Bjerkehagen B: Carcinoma of the renal pelvis. Scand J Urol Nephrol 1992; 26:357. 36. Guinan P, Vogelzang NJ, Sylvester J, et al: Renal pelvic cancer: a review of 611 patients treated in Illinois 1975–1985. Urology 1992; 40:393. 37. Kleer E, Oesterling JE: Transitional cell carcinoma of the upper tracts. Prob Urol 1992; 6:531. 38. Hall MC, Womack S, Sagalowsky AI, et al: Prognostic factors, recurrence and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology 1998; 52:594. 39. Anderstrom C, Johansson SL, Pettersson S, et al: Carcinoma of the ureter: a clinicopathological study of 49 cases. J Urol 1989; 142:280. 40. Gaboardi F, Bozzola A, Dotti E, et al: Conservative treatment of upper urinary tract tumors with Nd:Yag laser. J Endourol 1994; 8:37. 41. Igawa M, Urakami S, Shiina H, et al: Limitations of ureteroscopy in diagnosis of invasive upper tract urothelial cancer. Urol Int 1996; 56:13. 42. McTavish JD, Jinzaki M, Zou KH, et al: Multi-detector row CT urography: comparison of strategies for depicting the normal urinary collecting system. Radiology 2002; 225:783. 43. Caoili EM, Cohan RH, Korobkin M, et al: Urinary tract abnormalities: initial experience with multi-detector row CT urography. Radiology 2002; 222:353. 44. Zielonko J, Studniarek M, Markuszewski M: MR urography of obstructive uropathy: diagnostic value of the method in selected clinical groups. Eur Radiol 2003; 13:802. 45. Konety BR, Getzenberg RH: Urine based markers of urologic malignancy. J Urol 2001; 165:600. 46. Konety BR, Mitro M, Melhem M, et al: Diagnostic value of voided urine and bladder barbotage cytology in detecting transitional cell carcinoma of the urinary tract. Urol Int 1999; 62:26. 47. Sadek S, Soloway MS, Hook S, et al: The value of upper tract cytology after transurethral resection of bladder tumor in patients with bladder transitional cell cancer. J Urol 1999; 161:77. 48. Carpinito GA, Stadler WM, Briggman JV, et al: Urinary nuclear matrix protein as a marker for transitional cell carcinoma of the urinary tract. J Urol 1996; 156:1280. 49. Walsh IK, Keane PF, Ishak LM, et al: The BTA stat test: a tumor marker for the detection of upper tract transitional cell carcinoma. Urology 2001; 58:532. 50. Wu WJ, Liu LT, Huang CN, et al: The clinical implications of telomerase activity in upper tract urothelial cancer and washings. BJU Int 2000; 86:213. 51. Kamai T, Takagi K, Asami H, et al: Prognostic significance of p27 Kip1 and Ki-67 expression in carcinoma of the renal pelvis and ureter. BJU Int 2000; 86:14. 52. Gill WB, Lu C, Bibbo M: Retrograde brush biopsy of the ureter and renal pelvis. Urol Clin North Am 1979; 6:573. 53. Blute ML, Segura JW, Zincke H, et al: Impact of endourology on diagnosis and management of upper urinary tract urothelial cancer. J Urol 1989; 141:1298.
54. Sheline AM, Amendola MA, Pollack HM, et al: Fluoroscopically guided retrograde brush biopsy in the diagnosis of transitional cell carcinoma of the upper urinary tract: results in 45 patients. Am J Roentgenol 1989; 153:313. 55. Holtz F: Papillomas and primary carcinoma of the ureter: report of 20 cases. J Urol 1962; 88:380. 56. Donat SM, Herr HW: Transitional cell carcinoma of the renal pelvis and ureter: diagnosis, staging, management and prognosis. In Richie J, Oesterling JE (eds): Urologic Oncology, p 215. Philadelphia, WB Saunders, 1997. 57. Herr HW, Whitmore WF: Ureteral carcinoma in situ after successful intravesical therapy for superficial bladder tumors: incidence, pathogenesis and management. J Urol 1987; 138:292. 58. Freiha FS: Renal, renal pelvis and ureteral tumors: should retroperitoneal nodes be treated? Front Radiat Ther Oncol 1994; 28:155. 59. Bergkvist A, Ljungqvist A, Moberger G: Classification of bladder tumors based on the cellular pattern. Preliminary report of a clinical-pathological study of 300 cases with a minimum follow-up of eight years. Acta Chir Scand 1965; 130:371. 60. Epstein JE, Amin MB, Reuter VE, et al: The World Health Organization/International Society of Urologic Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Surg Pathol 1998; 22:1435. 61. Grabstald J, Whitmore WF, Melamed MR: Renal pelvic tumors. JAMA 1971; 218:845. 62. Das AK, Culley CC, Paulson DF, et al: Primary carcinoma of the upper urinary tract: effect of primary and secondary therapy on survival. Cancer 1990; 66:1919. 63. Blute ML, Tsushima K, Lieber MM, et al: Transitional cell carcinoma of the renal pelvis: nuclear deoxyribonucleic acid ploidy studied by flow cytometry. J Urol 1988; 140:944. 64. Haupt G: Transitional cell carcinoma of the ureter. J Endourol 2001; 15:409. 65. Strong DW, Pearse HD: Recurrent urothelial tumors following surgery for transitional cell carcinoma of the upper urinary tract. Cancer 1976; 38:2178. 66. Vest SA: Conservative surgery in certain benign tumors of the ureter. J Urol 1945; 53:97. 67. Chen GL, El-Gabry EA, Bagley DH: Surveillance of upper urinary tract transitional cell carcinoma: the role of ureteroscopy, retrograde pyelography, cytology and urinalysis. J Urol 2000; 164:1901. 68. Keeley FX, Culp DA, Bibbo M, et al: Diagnostic accuracy of ureteroscopic biopsy in upper tract transitional cell carcinoma. J Urol 1997; 157:33. 69. Guarnizo E, Pavlovich CP, Seiba M, et al: Ureteroscopic biopsy of upper tract urothelial carcinoma: improved diagnostic accuracy and histopathological considerations using a multi-biopsy approach. J Urol 2000; 153:52. 70. Heney NM, Nocks BN, Daly JJ, et al: Prognostic factors in carcinoma of the ureter. J Urol 1981; 125:632.
284
Part III Kidney and Ureter
71. Keeley FX, Bibbo M, Bagley DH: Ureteroscopic treatment and surveillance of upper urinary tract transitional cell carcinoma. J Urol 1997; 157:1560. 72. Chen GL, Bagley DH: Ureteroscopic surgery for upper tract transitional cell carcinoma: complications and management. J Endourol 2001; 15:399. 73. Bagley D, Erhard M: Use of the holmium laser in the upper urinary tract. Tech Urol 1995; 1:25. 74. Elliott DS, Blute ML, Patterson DE, et al: Long term follow-up of endoscopically treated upper urinary tract transitional cell carcinoma. Urology 1996; 47:819. 75. Englemeyer EL, Belis JA: Long-term ureteroscopic management of low grade transitional cell carcinoma of the upper urinary tract. Tech Urol 1996; 2:113. 76. Martinez-Pineiro JA, Matres-Garcia MJ, MartinezPineiro L: Endourologic treatment of upper tract urothelial carcinoma. Analysis of a series of 59 tumors. J Urol 1996; 156:377. 77. Johnson DE: Treatment of distal ureteral tumors using endoscopic argon photoirradiation. Lasers Surg Med 1992; 12:490. 78. Schilling A, Bowering R, Keiditsch E: Use of the neodymium:Yag laser in the treatment of ureteral tumors and urethral condylomata acuminata. Clinical experience. Eur Urol 1986; 12(Suppl 1):30. 79. Smith AD, Orihuela E, Crowley AR: Percutaneous management of renal pelvic tumors: a treatment option in selected cases. J Urol 1988; 140:745. 80. Jabbour ME, Smith AD: Primary percutaneous approach to upper urinary tract transitional cell carcinoma. Urol Clin North Am 2000; 27:739. 81. Tomera KM, Leary FJ, Zincke H: Pyeloscopy in urothelial tumors. J Urol 1982; 127:1088. 82. Sengupta S, Harewood L: Transitional cell carcinoma growing along an in-dwelling nephrostomy tube track. Br J Urol 1998; 82:591. 83. Sharma NK, Nicol A, Powell CS: Track infiltration following percutaneous resection of renal pelvic transitional cell carcinoma. Br J Urol 1994; 73:597. 84. Huang A, Low RK, DeVere White R: Nephrostomy tract tumor seeding following percutaneous manipulation of a ureteral carcinoma. J Urol 1995; 153:1041. 85. Fulgsig S, Krarup T: Percutaneous nephroscopic resection of renal pelvic tumors. Scand J Urol Nephrol 1995; 172 (Suppl):15. 86. Oefelein MG, MacLennan G: Transitional cell carcinoma recurrence in the nephrostomy tract after percutaneous resection. J Urol 2003; 170:521. 87. Clark PE, Streem SB: Endourologic management of upper tract transitional cell carcinoma. AUA Update Series, Vol. 18, Lession XVI, 1999. 88. Studer UE, Casanova G, Kraft R, et al: Percutaneous bacillus Calmette-Guérin perfusion of the upper urinary tract for carcinoma in situ. J Urol 1989; 142:975. 89. Okubo K, Ichioka K, Terada N, et al: Intrarenal bacillus Calmette–Guerin therapy for carcinoma in situ of the upper urinary tract: long term follow-up and natural course in cases of failure. BJU Int 2001; 88:343.
90. Goel MC, Mahendra V, Roberts JG: Percutaneous management of renal pelvic urothelial tumors: long-term follow-up. J Urol 2003; 169:925. 91. Thalmann GN, Markwalder R, Walter B, et al: Longterm experience with bacillus Calmette–Guerin therapy of upper tract transitional cell carcinoma in patients not eligible for surgery. J Urol 2002; 168:1381. 92. Eastham JA, Huffman JL: Technique of mitomycin C instillation in the treatment of upper tract urothelial tumors. J Urol 1993; 150:324. 93. Zincke H, Neves RJ: Feasibility of conservative surgery for transitional cell cancer of the upper urinary tract. Urol Clin North Am 1984; 11:717. 94. Pohar KS, Sheinfeld J: When is partial ureterectomy acceptable for transitional cell carcinoma of the ureter? J Endourol 2001; 15:405. 95. Johnson DE, Babaian RJ: Conservative surgical management for non-invasive distal ureteral carcinoma. Urology 1979; 13:365. 96. Zungri E, Chechile G, Algaba F, et al: Treatment of transitional cell carcinoma of the ureter: is the controversy justified? Eur Urol 1990; 17:276. 97. Maier U, Mertl G, Pummer K, et al: Organ-preserving surgery in patients with urothelial tumors of the upper urinary tract. Eur Urol 1990; 18:197. 98. Wallace DMA, Wallace DM, Whitfield HN, et al: The late results of conservative surgery for upper tract urothelial carcinomas. Br J Urol 1981; 53:537. 99. Palou J, Salvador J, Millan F, et al: Management of superficial transitional cell carcinoma in the intramural ureter. What to do? J Urol 2000; 163:744. 100. Leitenberger A, Beyer A, Altwein JE: Organ sparing treatment for ureteral carcinoma. Eur Urol 1996; 29:272. 101. Booth CM, Cameron KM, Pugh RCB: Urothelial carcinoma of the kidney and ureter. Br J Urol 1980; 52:430. 102. Kakizoe T, Fujita J, Kishi K, et al: Transitional cell carcinoma of the bladder in patients with renal pelvic and ureteral cancer. J Urol 1980; 124:17. 103. Strong DW, Pearse HD, Hodges CV, et al: The ureteral stump after nephroureterectomy. J Urol 1976; 115:654. 104. Charbit L, Gendreau MC, Cukier J, et al: Tumors of the upper urinary tract: 10 years of experience. J Urol 1991; 146:1243. 105. Laguna MP, de la Rosette JJ: The endoscopic approach to the distal ureter in nephroureterectomy for upper urinary tract tumor. J Urol 2001; 166:2017. 106. McDonald HP, Upchurch WE, Sturdevant CE: Nephroureterectomy: a new technique. J Urol 1952; 67:804. 107. McDonald DF: Intussusception ureterectomy: a method of removal of the ureteral stump at time of nephroureterectomy without an additional incision. Surg Gynecol Obstet 1953; 97:565. 108. Palou J, Caparros J, Orsola A, et al: Transurethral resection of the intramural ureter as the first step of nephroureterectomy. J Urol 1995; 154:43. 109. Abercrombie GF: Nephroureterectomy. Proc R Soc Med 1972; 65:1021.
Chapter 15 Transitional Cell Carcinoma of the Renal Pelvis and Ureter 285 110. Clayman RV, Kavoussi LR, Figenshau RS, et al: Laparoscopic nephroureterectomy: initial case report. J Laparoendosc Surg 1991; 1:343. 111. Landman J, Lev RN, Bhayani S, et al: Comparison of hand-assisted and standard laparoscopic radical nephroureterectomy for the management of localized transitional cell carcinoma. J Urol 2002; 167:2387. 112. Chung HJ, Chiu AW, Chen KK, et al: Retroperitoneoscopy assisted nephroureterectomy for the management of upper tract urothelial cancer. Min Invasive Ther 1996; 5:266. 113. Salomon L, Hoznek A, Cicco A, et al: Retroperitoneoscopic nephroureterectomy for renal pelvic tumors with a single iliac incision. J Urol 1999; 161:541. 114. Keeley FX, Tolley DA: Laparoscopic nephroureterectomy: making management of upper-tract transitional cell carcinoma entirely minimally invasive. J Endourol 1998; 12:139. 115. Hobart MH, Gill IS, Sung GT, et al: Radical nephroureterectomy for upper tract TCC: laparoscopy versus open surgery. J Endourol 1999; 13(Suppl 1):A44. 116. Shalhav AL, Dunn MD, Portis AJ, et al: Laparoscopic nephroureterectomy for upper tract transitional cell cancer: the Washington University experience. J Urol 2000; 163:1100. 117. McNeill SA, Chrisofos M, Tolley DA: The long-term outcome after laparoscopic nephroureterectomy: a comparison with open nephroureterectomy. BJU Int 2000; 86:619. 118. Yoshino Y, Ono Y, Hattori R, et al: Retroperitoneoscopic nephroureterectomy for transitional cell carcinoma of the renal pelvis and ureter: Nagoya experience. Urology 2003; 61:533. 119. Kawauchi A, Fujito A, Ukimura O, et al: Hand-assisted retroperitoneoscopic nephroureterectomy: comparison with the open procedure. J Urol 2003; 169:890. 120. Keeley FX, Sharma NK, Tolley DA: Hand-assisted laparoscopic nephroureterectomy. Br J Urol 1999; 83:504. 121. Seifman BD, Montie JE, Wolf JS Jr: Prospective comparison between hand-assisted laparoscopic and open surgical nephroureterectomy for urothelial carcinoma. Urology 2001; 57:133. 122. Gill IS, Sobel JJ, Miller SD, et al: A novel technique for the management of the en-bloc bladder cuff and distal ureter during laparoscopic nephroureterectomy. J Urol 1999; 161:430. 123. Shalhav AL, Elbahnasy AM, McDougall E, et al: Laparoscopic nephroureterectomy for upper tract transitional cell cancer: technical aspects. J Endourol 1998; 12:345. 124. McCaffrey JA, Dodd PM, Herr H, et al: Nonbladder primary site of transitional cell carcinoma (TCC) does not affect probability of response to MVAC or survival. J Clin Oncol 1998; 17(Suppl):337a. 125. Stadler WM, Kuzel T, Roth B, et al: Phase II study of single agent gemcitabine in previously untreated patients with metastatic urothelial cancer. J Clin Oncol 1997; 15:3394.
126. Sternberg CN, Yagoda A, Scher HI, et al: Preliminary results of M-VAC (methotrexate, vinblastine, adriamycin, cisplatin) for transitional cell carcinoma of the urothelium. J Urol 1985; 133:403. 127. Sternberg CN, Yagoda A, Scher HI, et al: Methotrexate, vinblastine, doxorubicin and cisplatin for advanced transitional cell carcinoma of the urothelium. Efficacy and patterns of response and relapse. Cancer 1989; 64:2448. 128. Loehrer PJS, Einhorn LH, Elson PJ, et al: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1992; 10:1066. 129. Logothetis CJ, Dexeus FH, Finn L, et al: A prospective, randomized trial comparing MVAC and CISCA chemotherapy for patients with metastatic urothelial tumors. J Clin Oncol 1990; 8:1050. 130. Vogelzang NJ, Stadler WM: Gemcitabine and other new chemotherapeutic agents for the treatment of metastatic bladder cancer. Urology 1999; 53:243. 131. von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000; 18:3068. 132. Dodd PM, McCaffrey JA, Hilton S, et al: Phase I evaluation of sequential doxorubicin, gemcitabine then ifosfamide, paclitaxel, cisplatin for patients with unresectable or metastatic transitional cell carcinoma of the urothelial tract. J Clin Oncol 2000; 18:840. 133. Anonymous: Neoadjuvant cisplatin, methotrexate, and vinblastine chemotherapy for muscle invasive bladder cancer: a randomized controlled trial. International collaboration of trialists. Lancet 1999; 354:533. 134. Studer UE, Bacchi M, Biedermann C, et al: Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: results of a prospective randomized trial. J Urol 1994; 152:81. 135. Stockle M, Meyenburg W, Wellek S, et al: Adjuvant polychemotherapy of non-organ confined bladder cancer after radical cystectomy revisited: long term results of a controlled prospective study and further clinical experience. J Urol 1995; 153:47. 136. Freiha FS, Reese J, Torti FM: A randomized trial of radical cystectomy versus radical cystectomy plus cisplatin, vinblastine and methotrexate chemotherapy for muscle invasive bladder cancer. J Urol 1996; 155:495. 137. Bono A, Benvenuti C, Gibba A: Adjuvant chemotherapy in locally advanced bladder cancer: final analysis of a controlled multicenter study. Acta Urol Ital 1997; 11:1241. 138. Babaian RJ, Johnson DE, Chan RC: Combination nephroureterectomy and postoperative radiotherapy for infiltrative ureteral carcinoma. Int J Radiat Oncol Biol Phys 1980; 6:1229. 139. Brookland RK, Richter MP: Postoperative irradiation of transitional cell carcinoma of the renal pelvis and ureter. J Urol 1985; 133:952.
286
Part III Kidney and Ureter
140. Batata MA, Whitmore WF Jr, Hilaris BS, et al: Primary carcinoma of the ureter: a prognostic study. Cancer 1968; 35:1626. 141. Cozad SC, Smalley SR, Austenfeld M, et al: Transitional cell carcinoma of the renal pelvis and ureter: patterns of failure. Urology 1995; 46:796. 142. Ozsahin M, Zouhair A, Villa S, et al: Prognostic factors in urothelial renal pelvis and ureter tumors: a
multicentre rare cancer network study. Eur J Cancer 1999; 35:738. 143. Moulad-Durdux C, Dufour B, Hennequin C, et al: Postoperative radiation therapy in 26 patients with invasive transitional cell carcinoma of the upper urinary tract: no impact on survival? J Urol 1996; 155:115.
C H A P T E R
16 Management of Upper Urinary Tract Transitional Cell Carcinoma Andrew J. Dreslin, MD, and Graeme S. Steele, MD
Transitional cell carcinoma (TCC) is a malignant disease that affects the urothelium of the urinary tract. Although TCC of the upper urinary tract accounts for only 5% of urothelial tumors, this incidence is increasing.1 This may be due in part to improved treatment and survival of patients with TCC of the bladder. In general, clinical symptoms and signs, such as dysuria and hematuria, do not differentiate between tumors of the upper and lower urinary tracts. However, patients with upper tract tumors may present with flank pain due to obstruction by tumor or blood clot (Figure 16-1). Constitutional symptoms of weight loss, fatigue, and anemia may indicate more advanced disease. Initial evaluation of suspected upper urinary tract tumors includes complete urinary tract imaging, urinary cytology, and direct endoscopic visualization. Traditionally, the intravenous pyelogram (IVP) was employed to detect filling defects within upper urinary tract. However, with increasing availability and decreasing costs, the computed tomography (CT) urogram provides detailed images not only of the urinary tract but also of the other abdominal structures, including regional lymph nodes. As a result, CT urography has replaced the IVP in many centers, where CT technology is readily available. In addition, retrograde pyelography at the time of cystoscopy to evaluate gross hematuria is widely employed to evaluate upper tract morphology (Figure 16-2). Technologic improvements in visual optics have allowed direct endoscopic visualization of the entire urinary tract. This advancement has readily provided the ability by visual inspection to differentiate soft tissue filling defects from renal and ureteral stones, in addition to the option of biopsy of suspected lesions and in some cases definitive treatment. Multiple treatment options now exist for tumors of the renal pelvis and ureter. Treatment decisions are based
largely on the histology of the tumor. Merely 20% to 30% of upper tract urothelial tumors are low-grade, papillary lesions with favorable prognosis.2 Multifocal tumors are common, the incidence of that is directly related to tumor grade.2 TCC has a high rate of ipsilateral recurrence following conservative management. Proximal-to-distal ipsilateral recurrence is common, while recurrence in a distal-to-proximal direction remains rare.3 In a retrospective study of 252 patients treated for upper tract TCC, tumor stage was a significant predictor of recurrence on multivariate analysis.4 This observation lends support to radical treatment of these tumors, although increasing evidence supports the use of more conservative approaches for low-grade and low-stage tumors. TCC of the renal pelvis and ureter can invade local structures or spread by lymphatic and hematogenous routes. Common sites of hematogenous metastasis include the lungs, liver, and bones. Lymphatic spread is initially to regional hilar, paraaortic, and paracaval nodes for renal pelvis and proximal ureteral tumors, while distal ureteral tumors invade pelvic nodes. Thus, a thorough preoperative evaluation is necessary prior to any decision on treatment strategy. This includes chest x-ray, abdominal CT, liver function tests, and occasional bone scans. In this chapter, several treatment strategies are discussed, including open radical nephroureterectomy (NU), laparoscopic NU, open nephron-sparing surgery, and endoscopic or percutaneous management. The technical aspects, as well as the indications, and advantages of each procedure are also discussed. OPEN RADICAL NEPHROURETERECTOMY Traditionally, open radical NU with excision of bladder cuff has been regarded as the gold-standard therapy for
287
288
Part III Kidney and Ureter
Figure 16-1 Left retrograde pyelogram (RPG) in a 66-year old male who presented with left flank pain and gross hematuria. RPG revealed a renal pelvic filling defect, which proved to be a well-differentiated TCC, and was managed by percutaneous resection.
Figure 16-2 Left retrograde pyelogram in a patient with gross hematuria showing filling defects due to transitional cell in the proximal ureter and renal pelvis. Metastatic evaluation revealed pulmonary parenchymal metastatic disease.
TCC of the upper urinary tract in patients with a normal functioning contralateral kidney. While this approach has some advantages in certain situations, laparoscopic NU is now regarded as the more appropriate approach in the majority of patients requiring NU for upper tract TCC. Open NU with excision of bladder cuff is still appropriate in very large, invasive tumors with possible local extension, including renal vein or vena caval involvement and gross lymphadenopathy. Furthermore, cytoreductive surgery in the setting of metastatic disease is often best accomplished by an open, rather than a laparoscopic, approach. Open NU with resection of bladder cuff can be performed through one or two incisions. The patient is placed in a flank-torque position allowing access to the kidney and lower abdomen. The surgical prep includes the flank, abdomen, and genitalia, providing for sterile bladder catheter placement at the beginning of the procedure. Table flexion or the use of a kidney rest usually provides improved surgical exposure of the kidney. An initial flank incision is made over the 11th or 12th rib, removing the tip of the 11th or 12th rib usually enhances access to the kidney and renal pedicle. This incision may
be extended towards the pelvis allowing dissection of the distal ureter and bladder cuff. Conversely, a second lower abdominal midline incision may be used for this part of the procedure. The use of an ipsilateral Gibson or Pfannenstiel incision may be substituted for a lower midline incision, although the increased muscle dissection with this approach may contribute to further postoperative morbidity. The flank dissection proceeds in a retroperitoneal or intraperitoneal fashion. Thoracoabdominal surgical exposures are hardly ever required. Either intraperitoneal or retroperitoneal dissection can easily accomplish exposure and dissection of the distal ureter and bladder. Open NU with resection of bladder cuff is commenced with radical nephrectomy, which includes removal of the kidney and surrounding Gerota’s fascia. The renal vessels are identified and tagged with a vessel loop prior to ligation. The renal artery is ligated and transected first, followed by the renal vein. A combination of nonabsorbable suture tie and hemostatic clips or suture ligature is used to secure the vessel stumps. As the incidence of adrenal involvement is low with renal pelvis and ureteral tumors, ipsilateral adrenalectomy may be
Chapter 16 Management of Upper Urinary Tract Transitional Cell Carcinoma 289
Figure 16-3 Open NU includes resection of the ureteral orifice and bladder cuff, usually accomplished with a ureteric catheter in situ to provide traction and ureteric exposure.
avoided in patients with distant tumors and normal preoperative imaging. After mobilizing the kidney and Gerota’s fascia, the ureter is dissected along its course to the bladder. To reduce the risk of tumor spillage, transection of the kidney from ureter is avoided. The distal ureteral dissection should include removal of the intramural ureter and a cuff of bladder mucosa. Recurrent TCC is seen in the ureteral stump of 23 % to 64% of patients following incomplete ureteral dissection.5-7 An anterior cystotomy allows access to the ureteral orifice and transmural ureter. Needlepoint electrocautery and counter-traction facilitate this portion of the dissection. Upon removing the kidney, ureter, and bladder cuff, the bladder defects are closed in two layers with absorbable suture. Alternatively, extravesical dissection of the intramural ureter avoids the creation of an anterior cystotomy. Traction on the dissected ureter brings the surgical plane into the field. Care must be taken to remove completely the transmural ureter and ureteral orifice as these may be the sites of recurrence. Again, the bladder defect is closed in two layers with absorbable sutures. A bladder catheter is left in situ for 7 to 10 days, then a cystogram determines adequate healing. An extravesical closed suction drain is used to detect a urine leak postoperatively (Figure 16-3).
Regional lymphadenectomy should be performed during radical NU. For the tumors of renal pelvis and proximal ureter ipsilateral hilar lymph nodes are dissected. The paraaortic nodes extending from the renal hilum to the aortic bifurcation are included with left-sided tumors. For right-sided tumors, paracaval and retrocaval nodes are dissected. With distal ureteral tumors, ipsilateral common iliac, external iliac, internal iliac, and obturator nodes are excised. Inclusion of a regional lymphadenectomy adds little additional operative time and postoperative morbidity, while it may provide therapeutic benefit for patients with local disease and identify patients who may benefit from adjuvant chemotherapy.8 Additional series suggest a possible therapeutic benefit for patients with lymph node positive disease.9 In general, NU (open or laparoscopic) remains the gold-standard therapy for patients with upper urinary tract TCC and a normal functioning contralateral kidney. Hall et al.4 reported decreased local recurrence following radical versus nephron-sparing surgery. In a review of 100 patients treated for upper urinary tract TCC, the 15-year cancer-specific survival was 69% for patients treated with radical NU compared to 25% for patients treated with nephron-sparing surgery.5 A 5-year survival advantage following radical NU was also seen in patients with low-grade disease, while the advantage was lost with high-grade tumors owing to the high incidence of metastatic disease.10 The importance of nephrectomy with total ureterectomy was seen in a series comparing simple nephrectomy versus radical NU in patients with TCC of the renal pelvis.11 The authors of the abovementioned references demonstrated a 5-year survival advantage of 84% versus 51% for the radical surgery. Contrary to the previous study, further benefit was seen in patients with high-grade tumors, with a 5-year survival of 74% versus 37% for radical NU and simple nephrectomy, respectively. The benefit of NU is well defined for patients with high-grade, organ-confined disease and may be of value in patients with locally advanced disease without evidence of systemic metastasis. In the setting of bilateral tumors, solitary kidney, or poorly functioning contralateral kidney, the benefit of NU must be weighed against the quality of life changes following radical surgery. LAPAROSCOPIC RADICAL NEPHROURETERECTOMY Laparoscopic NU has emerged as an effective alternative to open surgery in most patients with upper urinary tract TCC. Clayman et al.12 initially reported the use of laparoscopic technique for NU in a patient with TCC of the renal pelvis. Subsequently, multiple techniques have been described and include transperitoneal,13 retroperitoneal,14 and hand-assisted laparoscopy.15 The preferred
290
Part III Kidney and Ureter
approach is largely surgeon’s preference, although body habitus and tumor characteristics of the patient may guide this decision. The patient is positioned supine or oblique and is prepped in a similar fashion to the open procedure, again allowing access to a bladder catheter on the surgical field. In laparoscopic surgery, the use of table flexion or a kidney rest can make access to the upper pole kidney more difficult as the surgeon’s reach is limited by the length of the laparoscopic instruments. If total laparoscopic surgery is planned, cystoscopy with electrocautery dissection of the ureteral orifice and intramural ureter is performed at the beginning of surgery. At the Cleveland Clinic, laparoscopic radical NU comprises transvesical needlescopic-assisted cystoscopy detachment of the en bloc bladder cuff and ureter, followed by retroperitoneal removal of the kidney and ureter16 (Figure 16-4). Under cystoscopic control 2.2-mm needlescopic ports are inserted suprapubically into the bladder A ureteral catheter is cystoscopically passed into the ureteral orifice up to the renal pelvis, and the ureteral orifice is grasped with a needlescopic grasper inserted through the contralateral suprapubic port and retracted anteriorly. A 24Fr resectoscope with a pointed coagulating electrode is inserted per urethra alongside the ureteral catheter to resect a bladder cuff around the ureteral orifice. Anterior traction by the suprapubic grasper facilitates this dissection. For renal and ureteric dissection trocar site placement varies by surgeon preference, but usually involves the use of four or five trocars. A periumbilical trocar is placed initially by the Veras needle or open technique, and pneumoperitoneum is established to 15 mm Hg. A 30degree telescope is inserted through this port and the remaining trocars are placed under direct vision. Additional port sites may include ipsilateral lower quad-
rant, midline supraumbilical, or mid-axillary subcostal. This latter site is particularly of benefit in right-sided tumors to assist with retraction of the liver. Initially, the colon is mobilized medially by releasing the renocolic ligaments, allowing access to the kidney. The ureter is now identified at the lower pole of the kidney. By tracing the ureter towards the kidney, the renal hilum comes into view. First the renal artery then the renal vein are ligated and transected using a vascular stapling device. On freeing the kidney from its vessels, the remaining superior and lateral dissections of the kidney are performed. With the kidney completely mobilized, the dissection continues in a caudal direction along the ureter. Distal to the iliac vessels, the vas deferens in men or round ligament in women is encountered and ligated. The ureteral dissection is continued to the bladder. Traction on the ureter will evert the ureteral orifice and enable a vascular stapling device to ligate and transect the distal margin. The umbilical trocar site can be extended to allow removal of the specimen. Alternatively, the specimen can be morcellated in a specimen bag and removed through the trocar site. Finally, the fascial and skin layers of the port sites are closed. For hand-assisted laparoscopic NU, a lower midline or ipsilateral Gibson incision is used to place the handport (Figure 16-5). The surgery is continued in a manner similar to the total laparoscopic procedure. The surgeon’s hand is used for tactile sensation, retraction, and blunt dissection. When the dissection reaches the level of the iliac vessels, the surgeon may choose to release the pneumoperitoneum and complete the distal ureterectomy in an open technique through the hand-port.17 This hand-port also allows easy extraction of the intact specimen from the abdomen. In comparison to the total laparoscopic procedure, the hand-assisted approach decreases operating time without altering postoperative analgesic requirements or hospital stay.18
Figure 16-4 A, Laparoscopic NU can be performed via a retroperitoneal approach. Initially the balloon is inflated in a cephalad direction towards the kidney to create a working space. Finally the balloon is inflated along the anterior surface of the psoas muscle, displacing the ureter anteriorly and creating a working space towards the iliac vessels. B, Right laparoscopic NU showing patient position and three-port trocar approach.
Chapter 16 Management of Upper Urinary Tract Transitional Cell Carcinoma 291
The advantages of laparoscopic surgery compared to its open counterpart include the reports of decreased analgesic requirements, shorter hospital stay, and shorter convalescence.17,19-22 The efficacy of this procedure as a definitive cancer therapy is more difficult to establish given the limited number of series reporting long-term outcomes. McNeill et al.23 reported a series of 25 patients with upper urinary tract TCC treated by laparoscopic NU. With a mean follow-up of 33 months, there was no difference in overall survival compared to those patients treated with open surgery. In a comparable series, the crude and cancerspecific survivals for patients treated with open versus laparoscopic NU were similar after 24 months of followup.21 This study did note a greater number of patients with grade 4 tumors who had local retroperitoneal recurrence following laparoscopic surgery, suggesting that the open procedure may provide additional therapeutic benefit for patients with high-grade tumors. For patients with upper urinary tract TCC without local invasion, laparoscopic techniques of NU are proving to be a safe and effective alternative to open surgery with the advantage of shorter hospital stays and quicker recovery (Figure 16-6). OPEN NEPHRON-SPARING SURGERY Figure 16-5 Trocar and abdominal incisions for right and left hand-assisted laparoscopic NU.
Open nephron-sparing surgery, including partial nephrectomy for renal pelvis tumors and partial
Laparoscopy
Open
p Value
224.8 ± 64.3 58.9 (35–120) 173.5 ± 54.2
280.2 ± 73.8 — —
0.003
242 ± 267.4
696 ± 953.2
<0.0001
3.6 ± 1.0
5.4 ± 2.7
0.002
28 (67)
4 (11)
<0.001
7.0
—
—
Mean time to ambulation (days)
1.4 ± 1.0
2.5 ± 1.5
0.0003
Mean time to oral intake (days)
1.6 ± 1.2
3.2 ± 1.9
0.0004
Mean hospital stay (days)
2.3 ± 1.6
6.6 ± 1.9
<0.0001
Mean analgesics (mg morphine sulfate equivalent)
26 ± 24.3
228 ± 207.2
<0.0001
Mean duration Foley catheter (days)
7.6 ± 4.9
7.4 ± 3.6
0.97
Mean time to normal activities (weeks)
4.7 ± 9.4
8.2 ± 7.6†
0.002
Mean time of convalescence (weeks)
8.0 ± 10.1
14.1 ± 8.3†
0.007
Mean surgical time (mins):* Cystoscopy (mins) Laparoscopy (mins) Mean blood loss (cc) Mean intravenous fluids (l) No. concomitant adrenalectomy (%) Mean extraction incision (cm)
*Does not include time (approximately 45 minutes) to reposition patient. †Only available in 13 patients.
Figure 16-6 Intraoperative and postoperative data.
292
Part III Kidney and Ureter
ureterectomy for ureteral tumors, is a treatment option for patients in whom preservation of renal function is important. Indications for conservative surgery include solitary kidney, bilateral tumors, or baseline renal insufficiency. The patient is placed in the flank-torque position and prepped in a similar fashion to the open NU. For partial nephrectomy, an incision is made superficial to the 10th or 11th rib, and the dissection proceeds in a retroperitoneal, extrapleural, or thoracoabdominal manner. Gerota’s fascia is incised, and the kidney is mobilized completely. The renal vessels and ureter are identified and tagged with vessel loops. Cooling the kidney in a crushed ice slurry can reduce ischemic injury. Similarly, mannitol diuresis prior to vascular clamping can decrease parenchymal injury due to free radical formation. Upon clamping the renal vessels, the margin of dissection is defined with electrocautery of the renal capsule. In dissection, the blunt end of a scalpel blade is used to excise the tumor, the involved renal calyces, and surrounding margin of normal renal parenchyma. Areas of brisk bleeding are controlled with hemostatic microclips or over-sewn with 4-0 Prolene
suture. Following adequate hemostasis, the remaining renal pelvis is closed with 4-0 chromic sutures. The bed of dissection is cauterized with electrocautery or argon beam coagulator, and the parenchymal defect is closed with a series of 2-0 chromic mattress sutures. A closed suction drain is used to detect a urine leak postoperatively (Figure 16-7). Open segmental ureterectomy is a treatment option for invasive ureteral tumors when nephron-sparing surgery is required or for local low-grade tumors, which are too large for endoscopic management. Patients are placed in a flank position for proximal and mid-ureteral tumors or supine for distal ureteral tumors. The type of incision depends on the location of the tumor. For proximal and mid-ureteral tumors, a flank incision provides adequate exposure, while a Gibson or lower midline abdominal incision is used for distal tumors. Upon identifying the ureter and palpating the lesion, the ureter is clamped and ligated 2 cm proximal and distal to the affected area. Frozen sections of each free end are performed prior to ureteroureterostomy to ensure complete resection of the diseased segment. The ureter is mobilized Laparoscopy
Open
p Value
35
30
—
11.1(1–27)
34.4 (2.5–87)
<0.0001
8 (23) 5 3
11 (37) 8 3
0.42
6.6 (3–15)
10.5 (2–37)
2 6 0
1 10 2
Number of points with distant metastasis (%) Lung Liver Bone Lymph nodes
3 (8.6) 2 1 0 0
4 (13) 1 0 2 1
1.00
No. adjuvant systemic chemotherapy (%)*
4 (11)
4 (13)
1.00
No. deaths (%)
2 (6)
9 (30)
0.39
4 (2–6)
24 (2.5–67)
% Crude survival
97
94
0.59
% Ca specific survival
97
87
0.59
Number of points with complete followup greater than 1 month Mean months followup (range) No. bladder recurrence (on followup cystoscopy) (%) Multifocal Solitary Mean months to recurrence (range) No. subsequent bladder treatment Transurethral bladder tumor resection Transurethral bladder tumor resection, bacillus Calmette-Guerin Cystectomy
Mean months to death (range)
There were no retroperitoneal or port site/incisional recurrences with either technique. *Comprises 3 to 4 cycles of methotrexate, vinblastine, doxorubicin and cisplatin therapy.
Figure 16-7 Follow-up data comparing laparoscopic NU to open NU.
Chapter 16 Management of Upper Urinary Tract Transitional Cell Carcinoma 293
to allow sufficient length to enable a tension-free repair (Figure 16-8). If necessary, the kidney or bladder can be mobilized to provide additional ureteral length. Ureteroureterostomy is performed by spatulating each free end and anastomosing around a ureteral stent with 4-0 absorbable suture. When performing a distal ureterectomy, the repair proceeds with creation of an ureteroneocystostomy. This is performed through an anterior cystotomy in a refluxing or nonrefluxing manner using 4-0 absorbable suture. The use of a psoas bladder hitch may be required to lessen tension across the anastomosis.24 Again, a closed suction drain is used to monitor for a urine leak postoperatively (Figure 16-9). In the setting of a solitary kidney, bilateral tumor, or baseline renal insufficiency, nephron-sparing surgery may be employed for the treatment of upper urinary tract TCC. Ziegelbaum et al.25 reported the use of nephronsparing surgery for patients with TCC of the renal pelvis. The indication for conservative surgery was a solitary kidney in the majority of patients, and the tumors were primarily of low grade and low stage. In this series, 62% of patients remained disease-free up to 5 years postoperatively. For distal ureteral tumors, 83% disease-free survival has been observed following distal ureterectomy.24 In a large series of 224 patients with low-stage upper urinary tract TCC treated by NU, nephrectomy, or seg-
mental ureterectomy, no difference in overall survival was observed.26 The use of open nephron-sparing surgery is a viable treatment option for patients with lowgrade, low-stage TCC of the upper urinary tract who require preservation of renal function. ENDOSCOPIC MANAGEMENT Endoscopic evaluation of the upper urinary tract by antegrade or retrograde approach is useful for evaluation of symptoms, diagnosis of pathology, and more recently, definitive therapy of upper tract malignancy. Diagnostic ureteroscopy is performed on patients with lateralizing hematuria or abnormal cytology, a filling defect observed on radiographic evaluation and tumor at the ureteral orifice.2 It is also a critical tool employed for surveillance of patients treated for upper tract malignancy with renalsparing methods. With the advances in optical technology, smaller and flexible ureteroscopes are able to access most areas of the upper urinary tract including the renal pelvis and calyces. Ureteroscopy provides access to the upper urinary tract for evaluation and treatment of pathology while maintaining a closed urinary system. The rigid ureteroscope provides excellent visualization of the distal and mid-ureter, while flexible ureteroscopes are used to
Figure 16-8 Surgical technique for uretero-ureterostomy. Ureteral spatulation of wellvascularized ureteral ends and tension-free reapproximation with fine absorbable suture material usually results is a good surgical result. Intraoperative frozen section analysis is imperative to establish negative surgical margins.
294
Part III Kidney and Ureter
Figure 16-9 Distal ureterectomy and psoas hitch ureteral reimplantation is a well-recognized surgical option for patients with distal ureteral tumors, when the proximal upper tract is tumor free. Surgical principles once again include well-vascularized distal ureter and a tension free anastomosis.
access the proximal ureter and renal pelvis. Access to the lower pole calyx may be limited by the infundibulopelvic angle, which can exceed the deflection capability of flexible ureteroscopes. Patients are placed in the lithotomy position. Cystoscopy is performed initially for evaluation of the bladder mucosa and to gain access to the ureter using a guide wire. Although not always necessary with the use of small diameter instruments, atraumatic dilation of the ureteral orifice and intramural ureter allows easy passage of ureteroscopes into the upper urinary tract. This is accomplished by inserting an inflatable balloon dilator over a guide wire across the ureteral orifice. The balloon is inflated to 14 cm H2O for 1 to 2 minutes. Following dilation, a rigid ureteroscope is passed into the ureter under direct vision, or the flexible scope is passed over a guide wire using fluoroscopic guidance. Highpressure irrigation or pulse-irrigators used at a maximum of 40 cm H2O allows good visualization without the risk of ureteral perforation. The entire intraluminal ureter and renal pelvis are inspected on initial and subsequent evaluations. Several biopsy instruments are available for sampling areas of pathology. These include brush-biopsy forceps, cold-cup biopsy forceps, and resectoscopes, in which use is limited to larger rigid ureteroscopes. Complete resection of abnormal lesions can be accomplished with the biopsy
forceps or resectoscope. Bugbee electrocautery of the resected tissue bed fulgurates residual tumor and minimizes bleeding. Alternatively, various laser fibers may be used to ablate tumors following tissue biopsy. The neodymium:yttrium-argon-garnet (Nd:YAG) and holmium:YAG laser sources are commonly used. The 200 or 365 μm flexible fibers pass easily through the working channel of both rigid and flexible ureteroscopes, without significantly altering deflection. The holmium: YAG laser at 0.6 to 1 J and 10 Hz provides tissue ablation to a maximum of 5 mm.27 This is especially well suited for the thin-walled ureter. The Nd:YAG laser induces coagulation necrosis with subsequent sloughing of necrotic tumor. Dose characteristics of this laser source have been described following studies in the canine ureter.28 Consistent transmural necrosis and ureteral perforation were observed at doses of 20 W for 2 seconds. At higher power (60 W) and shorter duration (0.5 seconds), thermal injury extended into the muscle of the ureter without perforation and resulted in nonstrictured healing. In humans, settings of 20 W for 1 to 2 seconds are commonly used for tissue penetration of 5 to 6 mm.29 At the completion of treatment, a double-J ureteral stent is placed and left in situ until the tumor bed is completely healed, typically for 4 to 6 weeks (Figure 16-10).
Chapter 16 Management of Upper Urinary Tract Transitional Cell Carcinoma 295
Figure 16-10 Therapeutic options for upper tract TCC also include ureteroscopy and laser ablation, using an holmium:YAG laser. Careful follow-up, including ureteroscopy, brushings and cytology, is important to ensure a good outcome.
Percutaneous antegrade access to the renal sinus is employed to evaluate lesions inaccessible by flexible ureteroscopy or to resect large tumors of the renal pelvis. Under fluoroscopic guidance, a percutaneous nephrostomy tract is established. With placement of a 34F Amplatz sheath, the renal pelvis is accessed with a rigid or flexible nephroscope. Again, cold-cup biopsy forceps or a resectoscope is used to sample and resect the lesion. As with ureteroscopy, electrocautery or laser ablation is used to fulgurate the tumor bed following resection. Insertion of a 24F reentry nephrostomy tube allows easy access to the pelvis on a second-look procedure. Nephroscopic examination of the renal pelvis with random biopsies should always be performed within 4 weeks of tumor resection. The nephrostomy tube is removed after no suspicious areas are noted on nephroscopic examination and all random biopsies are negative.30 Percutaneous management is best reserved for tumors with a low risk of recurrence. These include solitary, papillary tumors that are less than 2 cm, low-grade, and lowstage.30 Other tumors are most appropriately managed by ureteroscopy if possible (Figure 16-11). Endoscopic management of upper urinary tract TCC is reserved for patients with previously mentioned indica-
Figure 16-11 Nephrostomy tract puncture sites. Peripheral calyceal tumor sites are best approached directly, while renal pelvic tumors are usually easily approached via lower or interpolar calyces.
tions for nephron-sparing surgery or who have a solitary, low-grade, and superficial tumor. Endoscopy is used only for biopsy and tissue diagnosis in patients who have suspected invasive disease, high-grade or multifocal tumor. In a comparison of patients with TCC of the upper urinary tract treated by percutaneous resection or open NU, there was no difference observed in the cancer-specific survival rates (Figure 16-12).31 Following tumor treatment, a high rate of recurrence is observed with reported rates ranging from 24% to 65%.1,3,30,32-35 The rate of recurrence has been directly associated with increasing grade of tumor in a several studies.1,2 The development of subsequent bladder tumors is also a concern with reported rates of 30% to 43% of patients, similar to other renal-sparing procedures.1,32 With a high rate of tumor recurrence, a strict surveillance protocol is employed for all patients treated with nephron-sparing surgery. This includes cystoscopy with retrograde pyelography and ureteroscopy every 3 months until tumor-free. This is followed by cystoscopy and retrograde pyelography every 3 months and ureteroscopy every 6 months.1 NU remains a treatment option for those patients with multiple recurrences. Overall, the preservation of renal units by complete endoscopic management ranges from 73% to 86% when primary tumors are low-grade and noninvasive.30,32,36
296
Part III Kidney and Ureter
Figure 16-12 Endoscopic technique for percutaneous removal of renal pelvic tumors. A, The bulk of the tumor is removed with grasping forceps. Following that the remaining tumor is resected using a standard resectoscope and cutting loop. B, Medial tumors pose increased risk because of renal vasculature and are therefore best managed by debulking biopsy followed by holmium:YAG laser ablation. C, Finally, ureteroscopy and laser ablation can be achieved with the flexible cystoscopy and a standard lower pole approach. D, Intraoperative and postoperative data comparing laparoscopic NU to open NU.
Chapter 16 Management of Upper Urinary Tract Transitional Cell Carcinoma 297
References 1. Chen GL, Bagley DH: Ureteroscopic management of upper tract transitional cell carcinoma in patients with normal contralateral kidneys. J Urol 2000; 164:1173–1176. 2. Huffman JL: Ureteroscopic management of transitional cell carcinoma of the upper urinary tract. Urol Clin North Am 1988; 15:419–424. 3. Palou J, Salvador J, Millan F, et al: Management of superficial transitional cell carcinoma in the intramural ureter: what to do? J Urol 2000; 163:744. 4. Hall MC, Womack S, Sagalowsky AI: Prognostic factors, recurrence, and survival in transitional cell carcinoma of the upper urinary tract: a 30-year experience in 252 patients. Urology 1998; 52:594–601. 5. Racioppi M, D’Addessi A, Alcini A, Destito A, Alcinin E: Clinical review of 100 consecutive surgically treated patients with upper urinary tract transitional tumors. Br J Urol 1997; 80:707–711. 6. Kakizoe T, Fujita J, Murase T, Matsumoto K, Kishi K: Transitional cell carcinoma of the bladder in patients with renal pelvic and ureteral cancer. J Urol 1980; 124:17–19. 7. Strong DW, Pearse HD, Tank ES Jr, Hodges CV: The ureteral stump after nephroureterectomy. J Urol 1976; 115:654–655. 8. Miyake H, Hara I, Gohji K, Arakawa S, Kamidono S: The significance of lymphadenectomy in transitional cell carcinoma of the upper urinary tract. Br J Urol 1998; 82:494–498. 9. Komatsu H, Tanabe N, Kubodera S, Maezawa H, Ueno A: The role of lymphadenectomy in the treatment of transitional cell carcinoma of the upper urinary tract. J Urol 1997; 157:1622–1624. 10. Murphy DM, Zincke H, Furlow WL: Management of high-grade transitional cell cancer of the upper urinary tract. J Urol 1981; 125:25–29. 11. Johansson S, Wahlquist L: A prognostic study of urothelial renal pelvic tumors: a comparison between the prognosis of patients treated with intrafascial nephrectomy and perifascial nephroureterectomy. Cancer 1979; 43:2525–2531. 12. Clayman RV, Kavoussi LR, Figenshau RS, Chandhoke PS, Albala DM: Laparoscopic nephroureterectomy: initial clinical case report. J Laparoendosc Surg 1991; 1:343–349. 13. Shalhav AL, Elbahnasy AM, McDougall EM, Clayman RV: Laparoscopic nephroureterectomy for upper tract transitional-cell cancer: technical aspects. J Endourol 1998; 12:345–353. 14. Gill IS, Soble JJ, Miller SD, Sung GT: A novel technique for management of the en bloc bladder cuff and distal ureter during laparoscopic nephroureterectomy. J Urol 1999; 161:430–434. 15. Keeley FX Jr, Sharma NK, Tolley DA: Hand-assisted laparoscopic nephroureterectomy. Br J Urol Int 1999; 83:504–505. 16. Gill IS, Sung GT, Hobart MG, et al: J Urol. 2000; 164(5): 1513–1522. 17. Chen J, Chueh SC, Hsu WT, Lai MK, Chen SC: Modified approach of hand-assisted laparoscopic
18.
19.
20.
21.
22.
23.
24.
25.
26.
27. 28.
29. 30.
31.
32.
33.
nephroureterectomy for transitional cell carcinoma of the upper urinary tract. Urol 2001; 58:930–934. Landman J, Lev RY, Bhayani S, et al: Comparison of hand assisted and standard laparoscopic radical nephroureterectomy for the management of localized transitional cell carcinoma. J Urol 2002; 167:2387–2391. Goel A, Hemal AK, Gupta NP: Retroperitoneal laparoscopic radical nephrectomy and nephroureterectomy and comparison with open surgery. W J Urol 2002; 20:219–223. Seifman BD, Montie JE, Wolf JS Jr: Prospective comparison between hand-assisted laparoscopic and open surgical nephroureterectomy for urothelial cell carcinoma. Urol 2001; 57:133. Shalhav AL, Dunn MD, Portis AJ: Laparoscopic nephroureterectomy for upper tract transitional cell cancer: the Washington University experience. J Urol 2000; 163:1100–1104. Keeley FX Jr, Tolley DA: Laparoscopic nephroureterectomy: making management of upper-tract transitional-cell carcinoma entirely minimally invasive. J Endourol 1998; 12:139–141. McNeill SA, Chrisofos M, Tolley DA: The long-term outcome after laparoscopic nephroureterectomy: a comparison with open nephrureterectomy. Br J Urol Int 2000; 86:619–623. Johnson DE, Babaian RJ: Conservative surgical management for noninvasive distal ureteral carcinoma. Urol 1979; 13:365–367. Ziegelbaum M, Novick AC, Streem SB, et al: Conservative surgery for transitional cell carcinoma of the renal pelvis. J Urol 1987; 138:1146–1149. Murphy DM, Zincke H, Furlow WL: Primary grade 1 transitional cell carcinoma of the renal pelvis and ureter. J Urol 1980; 123:629–631. Bagley D, Erhard M: Use of the holmium laser in the upper urinary tract. Tech Urol 1995; 1:25–30. Smith JA Jr, Lee RG, Dixon JA: Tissue effects of neodymium:YAG laser photoradiation of canine ureters. J Surg Oncol 1984; 27:168–171. Schmeller NT, Hofstetter AG: Laser treatment of ureteral tumors. J Urol 1989; 141:840–843. Orihuela E, Smith AD: Percutaneous treatment of transitional cell carcinoma of the upper urinary tract. Urol Clin North Am 1988; 15:425–431. Lee BR, Jabbour ME, Marshall FF, Smith AD, Jarrett TW: 13-year survival comparison of percutaneous and open nephroureterectomy approaches for management of transitional cell carcinoma of renal collecting system: equivalent outcomes. J Endourol 1999; 13:289–294. Elliott DS, Segura JW, Lightner D, Patterson DE, Blute ML: Is nephroureterectomy necessary in all cases of upper tract transitional cell carcinoma? Long-term results of conservative endourologic management of upper tract transitional cell carcinoma in individuals with a normal contralateral kidney. Urol 2001; 58:174–178. Bagley DH: Ureteroscopic laser treatment of upper urinary tract tumors. J Clin Las Med Surg 1998; 16:55–59.
298
Part III Kidney and Ureter
34. Martinez-Pineiro JA, Matres JG, Martinez-Pineiro L. Endourological treatment of upper tract urothelial carcinomas: analysis of a series of 59 tumors. J Urol 1996; 156:377–385. 35. Elliott DS, Blute ML, Patterson DE, Bergstralh EJ, Segura JW: Long-term follow-up of endoscopically
treated upper urinary tract transitional cell carcinoma. Urology 1996; 47:819–825. 36. Okada H, Eto H, Hara I, et al: Percutaneous treatment of transitional cell carcinoma of the upper urinary tract. Int J Urol 1997; 4:130–133.
C H A P T E R
17 Diagnosis and Staging of Bladder Cancer Michael J. Droller, MD
The standard approach in diagnosing and staging bladder cancer initially incorporates cystoscopic examination of the bladder and examination of urinary cytology to determine the presence of malignancy. Once the presence of a lesion is established, resection and pathologic evaluation of the tumor specimen (and occasionally of mucosal biopsies) are needed to document disease and characterize grade and stage (extension of the neoplasm into the bladder wall). Preliminary information on prognosis is inferred by the “snapshot” obtained through histopathologic examination and staging of the resected specimen (Figure 17-1).1,2 However, a deeper understanding of the implications of a particular tumor is based on an appreciation of where this snapshot fits into the natural history and pathogenesis of the specific diathesis represented by this lesion in the context of different developmental pathways of bladder cancer (Figure 17-2).3 Further, these are ultimately determined by genetic and molecular changes that correspond to intrinsic biologic behaviors of specific tumors and the potential for recurrence or progression (Figure 17-3).4 Characterization of a particular tumor’s pathogenesis may thus be as important clinically as the pathologic stage at the time of its resection in the individualization of treatment approaches, assessment of results of various “standardized” treatments, and design of new therapeutic approaches. This chapter discusses standard methods used to diagnose and stage bladder cancer. It will also review concepts that are being used increasingly to assess the intrinsic biologic potential of various forms of bladder cancer and to enhance our understanding of molecular changes that may determine their pathogenesis. INITIAL DIAGNOSIS OF BLADDER CANCER Bladder cancer is the fourth most prevalent noncutaneous malignancy in the United States.5 Over 54,000
new cases are diagnosed annually and over 12,000 individuals die of bladder cancer each year.5 Efforts to diagnose the possible presence of a urothelial cancer are generally initiated by occurrence of either gross or microscopic hematuria.6 The degree of hematuria has not been observed to correlate with either size, grade, or stage of a particular tumor. On the other hand, the presence of a bladder tumor may be more likely when gross hematuria, rather than microscopic hematuria, is the inciting event. Irritative symptoms suggestive of a cystitis with a sense of increased urgency and urinary frequency may occasionally be reported by a patient with bladder cancer, most often in the setting of carcinoma in situ (see later). The location of this entity at the trigone of the bladder, the bladder neck, or in the urethra should be suspected when irritative symptoms occur in the setting of urothelial cancer. Most often, however, hematuria is not accompanied by other symptoms. It is therefore referred to as “silent.” The occurrence of hematuria requires evaluation of the entire urinary tract since its source may not be exclusive to the bladder. Nor is the occurrence of hematuria necessarily indicative of the presence of a malignancy.7 Therefore, general imaging studies are performed to evaluate the kidney cortex, the renal pelvis, the ureters, and the bladder to search for malignancy or to identify another possible etiology. Although it has become increasingly common to perform sonography initially in such an evaluation, the efficacy of ultrasound in detecting upper tract urothelial lesions depends on the extent of the abnormality, as well as the experience and thoroughness of the radiologist performing the procedure.8 The major value of sonography in this setting lies in its ability to detect a renal mass and to determine whether it is solid or cystic. Additionally, it may be useful in identification
301
302
Part IV Bladder
Figure 17-1 Staging systems for bladder cancer are based on correlations between the layer to which a particular cancer has penetrated the bladder wall and the prognosis of that type of cancer. The original staging system (developed by Jewett HJ, Strong GH: J Urol 1946; 55:366) suggested distinctions between superficial and muscle-invasive disease. The superficial classification was subsequently divided into tumors confined to the mucosa (stage Ta) and tumors that penetrate the lamina propria (stage T1). Carcinoma in situ (stage Tis) is a superficial disease composed of neoplastic cells that replace the normal urothelium or undermine the normal urothelium and extend along the plane of the urothelium. Deep bladder tumors penetrate the muscularis propria either superficially (stage T2a) or deeply (stage T2b) or penetrate through the muscularis propria into the perivesical soft tissue either microscopically (stage T3a) or extensively (stage T3b). These distinctions are a change in the World Health Organization (WHO) classification system, which now combines all muscleinvasive tumors into one category (stage T2) rather than maintaining the separation that formerly had characterized the staging system (stage T2 for superficial invasion and stage T3a for deep muscle invasion). The involvement of lymph nodes is designated by the N category and involvement of adjacent structures is categorized as stage T4. This format implies a simple pattern of sequential development according to which early cancers appear as lower stages, and then progress to higher stages in sequence. However, this is not necessarily what characterizes the different forms of bladder cancer seen clinically. Rather, a variety of pathways that do not necessarily occur in sequence but are possibly interrelated may more accurately reflect the biology of the different forms of bladder cancer.
of a lesion within the renal pelvis or within the course of the ureter, a dilated possibly obstructed ureter, or an intraluminal-filling defect of the bladder itself (largely for tumors larger than 1 cm).9 Intravenous pyelography (IVP) provides definition of the contours of the upper tracts better than that obtained with sonography. However, pyelography may not reliably permit identification of small lesions of the renal parenchyma or renal pelvis or of bladder lesions <1 cm in diameter.10 Imaging of the bladder in various positions as it fills with contrast may allow visualization of one or multiple bladder tumors, and full distention of the bladder may be of particular usefulness to the radiologist in imaging a tumor on ultrasound. Retrograde pyelography may be useful in a patient with renal compromise or with contrast allergy in defining the anatomy of the upper tracts and in characterizing
any areas that appear abnormal or may not have been adequately visualized on IVP. Computed tomography (CT)11-13 and magnetic resonance imaging (MRI)14-17 can also be used to identify upper tract lesions, the presence of dilated ureter(s), and masses in the bladder. To this point, neither has been used as initial means of evaluating the cause of hematuria or as a first-line method in diagnosing bladder cancer. However, recent interest has focused on the use of CT scanning in providing 3D imaging of the urinary tract. Spiral CT scanning provides not only the quality of images achievable to visualize the kidney, ureter, and bladder on intravenous pyelogram but also provides cross-sectional imaging and 3D reconstruction, which can be used as an advantage in possibly staging a lesion if one is uncovered. The use of air insufflation to facilitate imaging of lesions in the bladder has been suggested to
Chapter 17 Diagnosis and Staging of Bladder Cancer 305
the upper tracts or the bladder and penetrated through to the soft tissues. MRI enhancement has been attempted by the use of gadolinium, T-weighted spin modalities, and use of a number of other agents in imaging a primary tumor and assessing its extent and penetration. MRI (and positron emission tomography [PET] scanning) has been used in identifying whether enlarged lymph nodes represent metastatic disease.15-21 In such instances, fine needle aspiration has been used to confirm whether or not metastatic disease is present (see later).22,23 Former teaching held that when an upper tract source of gross hematuria was suspected, upper tract imaging studies should be followed immediately by cystoscopy to facilitate localization of disease by visualizing blood emanating from a ureteral orifice. However, as upper tract lesions can now be visualized with greater reliability using current imaging techniques, the immediate need for cystoscopy has become less pressing. On initial imaging evaluation of a patient with hematuria, it may be of value to obtain urine for cytologic assessment. Although not particularly efficacious in the detection of low-moderate-grade disease (with sensitivities ranging between 10% and 50%), urinary cytology is useful in diagnosing urothelial cancers that are of high grade.24,25 Therefore, if a urinary cytology is positive, and upper tract imaging is negative, it may be expedient to proceed directly to cystoscopy under anesthesia so that multiple biopsies (see later) and resection of visible lesions can be performed. The same approach may be reasonable if a bladder tumor has been visualized on imaging studies. Further assessment with barbotage irrigation specimens may produce clusters of cells that suggest low-moderate-grade malignancy, but this may also correspond to instrumentation artifact. Therefore, barbotage has generally been used more specifically to provide increased numbers of cells for analysis by flow cytometry, which may detect abnormalities in individual cells when a urinary cytology has been interpreted as negative.26-28 Two products have recently been introduced to enhance detection of low-moderate grade urothelial cancers and to complement cytology in diagnosis of highgrade disease by employing fluorescent enhancement. The ImmunoCyt assay employs fluorescent-labeled antibodies to tumor antigens, obtaining a sensitivity of 70% to 80% in detecting low-moderate-grade tumors (versus that of urinary cytology with reports of sensitivity as low as 10% to 15% for grade 1 tumors and 50% to 60% for moderate-grade disease).29 The second assay, Vysion, incorporates fluorescent in situ hybridization (FISH) technology in identifying chromosomal abnormalities in voided or barbotage urinary specimens.30 The antibodies used in each assay are directed against molecules that may identify cancers with specific biologic pathways. Both assays may, therefore, offer the possibility of distin-
guishing between tumors that are of low malignant potential and those that are of high malignant potential (see later). The substantial overlap in labeling, however, may currently prevent full exploitation of this possibility. At the same time, use of these assays in conjunction with urinary cytology may permit the more reliable detection of urothelial cancers of all grades. Both the ImmunoCyt and the Vysion assays have a lower specificity than does urinary cytology. In this, urinary cytology remains the gold standard.31 It is therefore the balance between enhanced sensitivity of these assays in detecting disease of low malignant potential versus the increased sensitivity and specificity of urinary cytology in detecting disease of high malignant potential that must be considered in using these assays appropriately. During the past decade, much interest has been focused on the use of assays that detect tumor “markers” in the urine. One prominently advocated was an assay for bladder tumor “antigen” (BTA), a complement-related protein released from the lamina propria in the presence of tumor and inflammation.32 Unfortunately, the latter condition severely compromised this assay’s specificity.33 Moreover, the BTA assay also had inadequate sensitivity in detecting higher-grade disease.32 This led to the development of a point-of-care assay (BTA stat) and then a double-antibody sandwich assay (BTA trac) in assessing a complementrelated factor released into the urine in association with the presence of a urothelial malignancy.33 However, specificity of these assays was also affected by inflammation, compromising their usefulness. A urinary assay for nuclear matrix protein (NMP-22) had an improved sensitivity for detecting low-moderategrade disease and its specificity was better than that obtained with either of the BTA tests.34 Its validation in the detection of high-grade disease and its use in the setting of inflammatory conditions, however, appeared similarly to limit its use. Other assays (microsatellites, telomerase, hyaluronic acid/hyaluronidase, DD-23, fibrin gradation products [FDP], and many others) have shown promise in preliminary studies.35 However, validation regarding their reliability, their consistency, and their role in the diagnosis and assessment of urothelial cancer remains to be obtained. An evolving consensus is that their use may ultimately be found in monitoring for tumor recurrence in patients with a history of bladder cancer, and particularly in the setting of tumors that have low malignant potential, so that the interval between sequential invasive procedures for surveillance can be lengthened. After preliminary imaging of the upper tracts and bladder and an analysis of urinary cytology, cystoscopic examination is required to confirm the presence of malignancy, characterize its architecture, determine the multiplicity of disease, and determine whether there is diffuse mucosal involvement. Each helps assess the nature of the cancer diathesis.
306
Part IV Bladder
The sine qua non of diagnosis in urothelial cancer is transurethral resection of the tumor and pathologic evaluation of the surgical specimen. In addition, biopsies may be taken in the setting of positive urinary cytology randomly from several sites or directed on visualization of abnormal areas of the bladder mucosa. Directed biopsies typically include areas adjacent to the presenting lesion, areas of mucosal erythema, and areas at the bladder neck and within the prostatic urethra. Random biopsies of endoscopically normal areas of the urothelium are no longer taken routinely as part of the standard diagnostic approach in the evaluation of a bladder cancer diathesis when a preliminary cytology has been negative. Several studies have shown that such random biopsies are not likely to be informative and that the characterization of the tumor diathesis by pathologic evaluation of the resected specimen is generally sufficient for decisions regarding subsequent treatment.36 Thus, random biopsies are now generally only obtained when there is no endoscopically visible lesion, when upper tracts and urethra have no radiologic or visual abnormality, and urinary cytology is persistently positive. In these instances, biopsies are needed to identify the source of the positive cells. The configuration of the tumor as characterized endoscopically may suggest whether the tumor is superficially or more deeply invasive. A papillary lesion is more likely to be “superficial.” However, this alone does not permit a distinction to be made between those tumors that are mucosally confined (stage Ta) and those that infiltrate the lamina propria (stage T1) (see later).37 Occasionally, mucosally confined disease may be identified by being able to remove the lesion by “scraping” it with a cold loop. This can often be done with multiple very small papillary lesions, in which a well-developed fibrovascular core has not formed. Generally, however, electroresection is necessary to excise a papillary lesion. It is important that muscle fibers be visualized and sampled for accurate staging, particularly when a papillary tumor may have invaded the lamina propria. Several studies have observed an at least 20% involvement of the muscularis propria on repeat resection when initial resection suggested only lamina propria invasion and no muscle was present for accurate analysis.38 A vigorous resection, however, with its risk for penetration of the bladder wall, is generally not necessary to obtain adequate levels of tissue for staging. Papillary tumors should initially be resected flush with the bladder mucosa. Somewhat deeper resection can then be done to permit separate evaluation of the lamina propria and the superficial level of the muscularis propria. Care should be taken not to resect too deeply to avoid perforation of the bladder wall. In the setting of papillary disease the bladder wall may be quite thin and electroresection need not be carried more deeply than is required for accurate staging of the superficial bladder layers.
A “solid” or nodular (as distinct from papillary) tumor appearance implies a more deeply infiltrative diathesis.39,40 In such instances, the superficial (or intraluminal) portion of the solid tumor should be resected flush with the plane of the mucosa. Deeper resection to include the muscularis propria should then be done to determine the depth of infiltration and possibly distinguish between superficial and deep muscle invasion. Some have advocated even deeper resection to the level of the perivesical fat. However, extensiveness of disease can generally be determined without an aggressive resection such as this, and risk of perforation can be avoided. Bimanual examination of the bladder under anesthesia before and after transurethral resection may provide additional information on the extent of the tumor invasion. This is most informative when there is a large nodular or sessile tumor that may have extended through the bladder wall, or possibly involved adjacent structures. Inability to palpate a tumor mass prior to resection suggests that the tumor is possibly less extensively invasive. Palpation of a mass that is mobile suggests the presence of a nodular, infiltrative cancer that does not involve adjacent structures. Palpation of a mass that is fixed suggests that the cancer may have involved adjacent structures or the pelvic sidewalls. Palpation following resection that suggests less fixation may indicate a less extensive involvement of adjacent structures than had been surmised. However, any degree of palpability is generally an ominous finding. In attempting to assess the extent of invasive disease, bimanual palpation is highly subjective. Its greatest value may be in cases of large tumors that are extensively infiltrative, since these are more likely to be palpable and generally indicate an adverse prognosis, especially if they are palpable after resection. STAGING OF BLADDER CANCER Transurethral ultrasound,41 pelvic CT,42 and pelvic or endorectal (endovaginal) MRI43 imaging can be used to assess tumor extent prior to transurethral resection. Transurethral ultrasound examination has been reported to have a sensitivity of 90% and a specificity of 76% in determining whether a tumor is muscle-invasive.44 One report described that 24% of tumors staged as T1 by transurethral ultrasound had been overstaged and that 10% of tumors staged as T2 had been understaged. Correspondingly, 29% of stage T3b tumors (deep muscle invasion) were understaged and 5% of stage T3a tumors were overstaged by this modality. The sensitivity of CT scanning in detecting extravesical extension of a bladder cancer has ranged between 60% and 96%.12,14,42,45 Its specificity has ranged between 66% and 93%. Cumulative sensitivities and specificities have been calculated at 83% and 82%, respectively, implying that extravesical extension remains undetected in 17% of instances and is over-diagnosed in 18% of
Chapter 17 Diagnosis and Staging of Bladder Cancer 307
instances. CT scanning has had limited success in distinguishing between mucosally confined (stage Ta) and lamina propria-invasive tumors (stage T1) and between superficial and muscle-invasive (stage T2) diseases. It has been more useful in distinguishing between lesions that are only minimally invasive of the extravesicular soft tissues (stage T3a) and those that have involved these tissues extensively (stage T3b) or adjacent organs (stage T4). However, overstaging has occurred in two-thirds of patients with superficial disease, while understaging has been found in 30% of patients with muscle-invasive tumors. MRI has several features that theoretically would make it more accurate than CT scanning in the staging of bladder cancer. Its major advantage lies in images that can be obtained in multiple planes and in the demonstration of perivesical fat planes and boundaries of the prostate and seminal vesicles.15-17,42,43 T1-weighted images of the primary tumor can be contrasted with lowsignal intensity images of urine and high-signal intensity images of perivesical fat. T2-weighted images can be used to assess disruption of the muscle wall and invasion of other organs. The sensitivity for MRI in identifying extravesical tumor extension ranges between 60% and 100%, with a cumulative average of 73%. Specificity ranges between 60% and 100% with a cumulative average of 84%. Recent reports have described improved sensitivity and specificity in detecting muscle invasion (96.2% and 83.3%, respectively) with the use of gadolinium-DTPA enhanced MRI for tumor staging.43 In addition, improved accuracy has been obtained with newer MRI techniques. Improved staging accuracy with submillimeter pixel MRI, fast dynamic first pass MRI, fast low-angle shot images, oblique contrast-enhanced T1 weight, and rapid gradient echo sequence MRI have been used in attempts to improve the accuracy of staging both in terms of identifying depth of penetration into and through the bladder wall and identifying abnormalities in the pelvic lymph nodes.15-18 PET scanning in bladder cancer has not been studied extensively, and its role in staging is therefore unclear.1921 The radionuclides used are 18F-2-fluoro-2-deoxy-Dglucose (FDG) and L-(methyl)-11C-methionine (LCM). Both are primarily glucose derivatives and are used for PET scanning that exploits the hypermetabolic state of malignant tissues when compared with normal tissues. FDG is taken up by normal and malignant cells, and the glucose is phosphorylated for passage through the Embden-Meyerhof pathway.20 However, phosphorylated FDG cannot leave the cell and cannot be metabolized. This allows its detection by PET scanning. Since FDG is excreted in the urine, the bladder must be irrigated continuously to permit delineation of the bladder wall from the urine. Diagnosis of a primary bladder tumor and its separation from possible urinary artifact, however, may be difficult. In diagnosis of a bladder
cancer, studies have described a sensitivity of 86% to 100% and a specificity of 63% to 100%. The diagnosis of lymph node involvement or extension outside of the bladder may also be achieved using PET scanning with FDG. However, studies reported to this date have involved only small numbers of patients. Other studies have used LCM for diagnosis of bladder cancer and have employed calculations of specific uptake values in attempts to enhance discrimination between muscle invasion and extravesical extension of disease.21 Uptake of LCM by normal bladder tissue is low. Therefore, staging of disease is limited. Some have suggested that PET scanning with LCM may be useful in monitoring for responses to neoadjuvant chemotherapy or assessing regression of metastatic foci by evaluating persistence of uptake on PET scanning after treatment. Further study to assess these possibilities and definition of the costs involved in the use of this technique will determine its future usefulness. The staging of bladder cancer by each of these imaging modalities is limited by their inability to discern microscopic extension of disease and the relative dependence of each on disruption of normal “radiographic” tissue planes in identifying the extension of the cancer. The former may lead to understaging of disease, since extension of the cancer, even if only microscopic, may be associated with a greater likelihood of metastasis. The latter can lead to overstaging, since images suggesting disruption of the muscularis can be created by prior resection, inflammatory processes, or other therapeutic interventions. The critical element in ultimate characterization of a bladder cancer is its histopathologic appearance. The extent to which the cancer penetrates the bladder microscopically,46 the histologic appearance of the tumor cells and the architectural configuration of those cells (papillary versus nodular),40,47 whether or not bladder lymphatics or vasculature are involved by the cancer,40 and the nature of the urothelium adjacent to and at sites distant from the presenting lesion(s) (dysplasia or carcinoma in situ)48,49 are important in considering a tumor’s prognosis. Currently, staging of bladder cancer is based on the depth to which the cancer has penetrated the bladder wall.1,50 Although transurethral resection may be performed so as to provide specimens that permit determination of the extent of involvement by the cancer of different levels, inaccuracies generally prevail and tumors are often understaged.51 More definitive assessment may only be possible by analyzing a full thickness of the bladder wall obtained by partial cystectomy or total cystectomy specimens. This is clearly impractical in the majority of patients. Several reports have described transabdominal CT-guided needle biopsies to provide full-thickness bladder wall specimens to evaluate the depth of cancer infiltration.52 This technique has not gained general usage.
308
Part IV Bladder
Early attempts to characterize the prognosis of various forms of bladder cancer were based more on an analysis of their cellular appearance than their depth of penetration. Broders53 described different grades of disease and correlated those that were poorly differentiated with a more ominous prognosis and those that were well differentiated with a more benign prognosis. Although Aschner54 subsequently correlated an increasing depth to which a tumor had penetrated the bladder wall with a progressively worse prognosis, this system did not obtain widespread currency.54 It was not until the mid-1940s that Jewett and Strong55 proposed a classification of bladder cancer based on the depth of involvement of the bladder wall in association with the “curability” of the tumor by cystectomy. Initial observations were based on an autopsy series, in which those tumors that had penetrated deeply into the bladder wall were found in retrospect to have been “incurable.” In a subsequent study of cystectomy specimens, Jewett and Lewis56 proposed that tumors that had invaded only superficially were curable by cystectomy whereas those that had invaded the bladder wall more deeply were not. Subsequent refinements in staging have been based on more precise correlations between the depths of invasion of a tumor through the different layers of the bladder wall in association with prognosis, giving rise to the TNM classification.1,50 This consists of characterization of depth of penetration of the tumor (T), involvement of pelvic lymph nodes (N), and whether or not metastases were present (M). The objectives of such a system are to suggest prognosis, to form a basis for selecting treatment, to provide a standard for evaluating treatment results, and to facilitate the exchange of information through standardization of the classification of the disease being treated. The TNM system consists of a pretreatment clinical (c) classification and a postsurgical histopathologic (p) classification. The pretreatment clinical classification is based on imaging studies and impressions obtained both by endoscopic visualization of the cancer and bimanual examination. The histopathologic classification is based on specimens obtained by transurethral resection. Differences between these two classifications within individual categories may be substantial. Moreover, the latter may often be in substantial error (generally by understaging) when compared to assessments determined by full thickness bladder wall cystectomy specimens.57-59 Although correlating well with stage and biologic potential of disease, tumor grade has not been included in these classification systems. The most recent TNM classification for bladder tumors (1998)50 maintained the classifications for superficial tumors that were described in the 1992 TNM classification subsequently reviewed at the 4th International Consensus Meeting on bladder cancer in 1993.60 These classifications included carcinoma in situ (TIS), mucosally confined cancers (stage Ta), and cancers that had infiltrated
the lamina propria (stage T1). The classification for muscle invasive bladder tumors was unified in a single category of stage T2 disease (with subcategorization into stage T2a representing superficial invasion into muscularis propria and stage T2b representing invasion into the deeper component of the muscularis propria) and this was distinguished from stage T3 disease that represented either microscopic penetration into the perivesical soft tissues (stage T3a) or disease that had extensively infiltrated the soft tissues surrounding the bladder (stage T3b). These staging systems are identical to those that have been presented in the current American Joint Committee on Cancer’s (AJCC) staging system for 2002. In addition, various modifiers that characterize the tumor diathesis can be included in describing the stage and character of disease that is present at any particular time. For example, multiplicity of disease as this may be indicative of the increased risk for recurrence can be indicated by stating the number of tumors in parentheses following the pathologic stage of disease. The presence of lymphatic invasion or vascular invasion in the wall of the bladder, while not officially recognized as a component of the staging system, can be indicated as a modifier of either “l” or “v” in parentheses following the indication of pathologic stage. Ultimately, incorporation of molecular markers may be used to modify staging based on depth of invasion, and grade may also be useful in determining risk of progression. It is important to recognize in each of these that a particular stage provides only a snapshot as part of the pathogenesis of disease that may evolve with time. A more detailed discussion of a schema indicative of the different pathways of tumor development that represents the pathogenesis of disease in bladder cancer is provided in detail at the end of this chapter. Biologic Activity of Different Stages of Bladder Cancers Mucosally confined tumors (stage Ta), comprising 50% of all urothelial cancers at initial diagnosis (70% of all superficial cancers that are diagnosed as such in 70% to 75% of all urothelial cancers initially), have the best prognosis.61,62 A 70% recurrence rate has been associated with larger and multiple tumors at diagnosis. This could represent inadequate resection, increased likelihood of tumor cell implantation, or sites that were not endoscopically visible initially but that then “recurred” (becoming apparent clinically). Most mucosally confined tumors found likely to progress have been of high grade. These have comprised only 2% to 4% of all stage Ta cancers.62 Additionally, they have often been observed as a more diffuse micropapillary diathesis,63 or to have been accompanied by flat carcinoma in situ (see later) adjacent to or elsewhere in the bladder.48
Chapter 17 Diagnosis and Staging of Bladder Cancer 309
“Superficial” cancers that have invaded the lamina propria (stage T1) comprise 20% of all urothelial cancers on initial presentation (30% of all superficial cancers [70%] as staged initially).61 As with mucosally confined (stage Ta) tumors, these have a 70% rate of recurrence. Unlike the mucosally confined diathesis, however, stage T1 disease has a 20% to 30% possibility of progression.64,65 The high-grade tumors in this category (comprising 50% of all T1 cancers) appear most likely to progress.62 This is seen in 50% of these cancers, or in 25% of the entire group.66,67 High-grade lamina propria invasive tumors are often associated with urothelial abnormalities (dysplasia or carcinoma in situ) adjacent to the presenting lesion or at distant sites.48,68,69 These appear more likely to be aggressive, particularly if they are rapidly recurrent or do not respond to adjunctive intravesical BCG (see Chapter 18). It is highly important that the resection specimen includes the muscularis propria in the staging of these lesions. Several studies have documented muscle invasion on repeat resection in 10% to 20% of tumors initially staged as having only involved the lamina propria, particularly when extensive lamina propria invasion has been seen.38,70,71 In addition, the submucosal connective tissue (lamina propria) contains a muscle layer (muscularis mucosae), the thickness of which can vary from being either virtually absent to being quite prominent.72 In the latter instance, this muscle layer may be confused with the muscularis propria. Several reports have suggested the muscularis mucosae as a staging boundary, above which (stage T1a) tumors do not have a strong risk of progression and beneath which (stage T1b) there is a higher risk of progression to muscle invasive disease.73 Penetration of the muscular mucosae as an indication of a more aggressive cancer and its use in staging remains to be validated. At the same time, many of those tumors that invade more deeply appear to be more extensive while those that are more superficially invasive appear to be less extensive and may have invaded in only microscopic foci.74 This in itself may be more indicative of the intrinsic biologic potential of the particular tumor diathesis rather than of its topographically “prognostic” relation to muscularis mucosae fibers. In considering distinctions in the biologic potential of various forms of superficial bladder cancer, grade of the individual cells may be highly important as the manifestation of a particular biologic capability.75 This may be manifested in the development of generalized changes in the urothelium leading to expression of a more diffuse neoplastic diathesis known as carcinoma in situ.76 The ultimate natural history of this entity may reflect the intrinsic biology of the neoplastic diathesis and should be taken into account in the staging of a particular bladder cancer and in the implementation of the TNM staging system.
It is as yet unclear whether there are different forms of carcinoma in situ, and whether the variability and the manner in which carcinoma in situ presents may affect the heterogeneity of response of superficial disease (whether mucosally confined or invasive of the lamina propria) to different types of treatments.3,77 One form of carcinoma in situ is characterized by highly abnormal cells that involve the bladder mucosa diffusely and may actually undermine the normal mucosa in spreading in pagetoid fashion to cover broad areas of the bladder wall, possibly extending as well into the prostatic urethra and the lower ureters.78-80 Patients often present with symptoms of irritability, and urinary cytology is likely to be positive. Other forms of carcinoma in situ may be unifocal and occasionally more well differentiated. These may theoretically represent a less malignant form of this diathesis.81 The ominous prognosis ascribed to carcinoma in situ may have originally been based on its association with concomitant muscle-invasive transitional cell cancer.82 The muscle-invasive cancer rather than the carcinoma in situ, at least as diagnosed at that phase of its course, was probably the component that progressed and that was responsible for metastasis in the majority of such cases. However, knowing what we now know of the biology of this diathesis, the specific pathway in which neoplastic transformation had originally occurred and had led to this diathesis may in turn have led to the formation of nodular or sessile muscle-invasive disease with penetration into the bladder wall that was the form in which cancer was diagnosed on presentation.3,83,84 Once the entity of carcinoma in situ was appreciated and urinary cytology came into more common use, the diagnosis of this entity in association with more superficially invasive disease (a secondary form of diathesis) or as the only (primary) form of cancer that was present became more common. It therefore should not have been surprising to see an apparently prolonged and possibly nonprogressive course of carcinoma in situ when muscleinvasive cancer was not present. Indeed, several studies suggested that this form of cancer by itself might not pose a major threat as the cancer cells forming carcinoma in situ might lack the biochemical machinery necessary to become invasive.76,77,81 However, it is also possible that these observations represented lead-time biases in describing the course and risk of this diathesis. The ultimate ominous potential of carcinoma in situ has been more fully appreciated on the basis of molecular changes that characterize this diathesis.77,85-87 This has been supported further by its association with those forms of high-grade papillary cancer that may not have as yet invaded the muscularis propria. These have an ominous prognosis, rapid recurrence, and progression to muscle-invasion and metastasis soon after initial diagnosis. In long-term follow-up of carcinoma in situ, the
310
Part IV Bladder
incidence of progressive disease has been reported as 75% to 80% in patients with diffuse disease. Several additional observations are relevant. First, carcinoma in situ has been found to penetrate the lamina propria microscopically in 20% to 30% of cases.83 Second, high-grade carcinoma in situ appears to be more commonly associated with papillary and papillo-nodular tumors that are invasive of the lamina propria than with papillary tumors that are mucosally confined.48,76,84 When associated with the latter, the tumors may be micropapillary, and usually are high grade. Since those tumors that have invaded the lamina propria are more likely to become progressive, the carcinoma in situ associated with these may reflect a more aggressive diathesis as well. Third, several reports have suggested the development of solid or nodular tumors from foci of carcinoma in situ.84 If carcinoma in situ is the direct antecedent of nodular tumors, which are more deeply invasive when they become clinically apparent than are papillary tumors, the diagnosis of this type of carcinoma in situ may signify a particularly ominous neoplastic diathesis. The correct placement of carcinoma in situ within the generally accepted staging system remains unclear. All forms of bladder cancer have their origin in intraepithelial neoplastic transformation, which, by definition, produces “carcinoma in situ.” Indeed, pathologists often identify papillary mucosally confined tumors as papillary carcinoma in situ, notwithstanding low-moderate grade cells and the implication of disease with low malignant potential. However, despite its confinement technically to the mucosa, this diathesis is clearly quite different from the form of flat carcinoma in situ that is associated with lamina propria-invasive high-grade or muscle-invasive disease. Descriptions of cancers as “invasive” have generally implied their penetration of the bladder wall muscle (muscularis propria). Progressive depth of penetration into and through this layer has been correlated with an increased likelihood of metastasis. A majority of patients diagnosed with muscle invasive disease are diagnosed at this stage of disease at their initial presentation.88,89 These comprise 20% to 30% of all urothelial cancers at initial presentation. Muscle invasive cancers that arise from initially superficial tumors comprise only an additional 10% to 12%. This reflects calculations based on observations in stage T1 disease (since only 2% to 4% of stage Ta tumors progress) as follows: 1. 20% to 30% of T1 tumors (comprising 30% of all superficial tumors on initial diagnosis) are actually muscle-invasive on repeat resection (equals 6% to 9% of all superficial tumors or 4% to 6% of all urothelial cancers);61,62 2. 40% of initially high-grade T1 cancers are at risk for progression (representing an original 50%, less 20% which are already muscle invasive) but only 50% of
these progress, leaving 20% of stage T1 tumors (equaling 6% of all superficial tumors or 4% of all urothelial cancers).62,65,67 Approximately 50% of patients who present with muscle invasive disease are thought to have occult metastasis at diagnosis, these generally being expressed within 2 years regardless of aggressive locoregional treatment.89 The directness of these associations and inaccuracies of staging have led to a broad variability in suggested correlations. For example, tumors that have penetrated only the superficial muscle (stage T2) may have a better prognosis than those that have penetrated only the lamina propria (stage T1) but have done this extensively.90 Those that have a papillary configuration and have invaded in a broad front may have a better prognosis than those that have a nodular configuration and that have manifested a tentacular form of infiltration.91,92 Furthermore, cancers staged as T2 may have been infiltrative of only the muscularis mucosae (the muscle layer within the lamina propria) and not of the muscularis propria. And, even if truly invasive of the muscular propria, many of these may only have been very superficially invasive. Thus, despite having had the ability to infiltrate, they may have invaded at a less rapid rate and may have lacked the ability to penetrate lymphatics and vasculature and metastasize.92 Correspondingly, cancers staged as T1 may have been understaged in 10% to 20% of instances, since repeat resection has found residual cancer that was actually invasive of the muscularis propria.38,70,71 These, as well as those staged as T1 that are extensive in their penetration, may have a particularly aggressive biologic potential.65-67 When recurrent (or persistent) they may already have extended into the muscularis and even metastasized. At the 1993 bladder cancer consensus conference in Antwerp, a proposal was made that stage T3a tumors (those with deep muscle invasion) and stage T2 tumors (those with superficial muscle invasion) be combined in a single category of T2.93 Stage T2a would then comprise those tumors that had invaded only the superficial muscle (less than one-half the depth of the muscle layer) and stage T2b would comprise those that had invaded the deep muscle (deeper than half the depth of the muscle layer). Stage T3 would then designate tumor penetration into the perivesical tissue. Stage T3a would comprise those tumors that demonstrated only microscopic invasion beyond the muscularis and stage T3b would comprise those that had invaded more extensively into the extravesical tissues. The rationale for including all muscle-invasive cancers in one category reflected in part the problem of accurately determining the depth of muscle invasion by transurethral resection, as well as the impression that all cancers invading the muscle wall were likely to behave in a similar aggressive fashion regardless of their depth of penetration.94-96 It also reflected the concept that
Chapter 17 Diagnosis and Staging of Bladder Cancer 311
muscle-invasive tumors did not exhibit the same potential biologic behavior as did tumors that had extended through the full thickness of the bladder wall into the perivesical fat.97-99 Some have suggested that this new categorization fails to take into account several observations. First, those tumors that have penetrated only the superficial muscle appear to be less likely to be associated with metastasis and appear also to be more likely to be cured by a variety of surgical approaches.97,98 For example, many of these have shown no remaining cancer in the cystectomy specimen after initial extensive transurethral resection.89,100,101 In addition, treatment outcomes have often been more successful either in terms of time to disease recurrence or survival as for more deeply invasive disease.101-103 That more superficial muscle invasion has been associated more often with a papillary configuration, invasion in a broad front, and less frequent involvement of bladder wall lymphatics and vasculature than deep muscle-invasive cancer is supportive of distinctions between these diatheses (see later).91,92 Second, those tumors that have invaded the muscle layer more deeply appear to have an ominous prognosis similar to that of tumors that have involved perivesical soft tissues microscopically.93,94,99 This harks back to earlier staging categories that combined deep muscle invasion with extension into perivesical fat.55 Differences in clinical manifestation and treatment outcomes may be less restrictive than distinctions between these categories imply. Superficial muscle invasion has been associated with a papillary configuration and a pattern of infiltration that has been described as “broad front,” in which tumor cells penetrated the bladder wall muscle in large clusters of cells with a broad infiltrative margin.91,92 Such tumors have appeared to involve the bladder wall vasculature and lymphatics in only one-third of cases.47 In contrast, tumors that have invaded more deeply have been associated with a more nodular type of configuration and a pattern of infiltration that has been described as “tentacular,” in which tumor cells have appeared to “percolate” through the bladder wall in smaller clusters or as finger-like projections.47,91,92 Such tumors have been found to involve the bladder wall lymphatics and vasculature in at least two-thirds of instances.47 Stage T4 disease has been compartmentalized into stage T4a, representing tumor invasion of the prostate, uterus, or vagina, and stage T4b representing tumor invasion of the pelvic or abdominal wall. Conflicting observations have made definitive staging in these categories somewhat unclear. For example, 40% of cystectomy specimens have cancer involvement of the prostate.80,104 Traditionally thought to indicate an ominous prognosis, prostatic involvement may actually influence outcomes in a variable manner. If the cancer is mucosally confined while extending into the prostatic
urethra and prostatic ducts, prognosis will be less ominous than if the cancer has infiltrated into the prostatic stroma.80 An analogous situation may pertain in women. If there has been direct penetration only to the outer aspect of the anterior vaginal wall, prognosis may be less ominous than if there has been more extensive involvement of the vagina or penetration of the uterus. Evidence validating this suggestion has not been obtained. Direct involvement of other adjacent structures or fixation to the pelvic sidewalls is generally tantamount to the cancer being incurable. Distant metastatic disease is nearly invariably present in these situations even if only occult. Therefore, locoregional treatments generally fail.99,105,106 Involvement of regional lymph nodes has generally been interpreted as indicating an ominous prognosis.107 Several recent reports have suggested that prognosis may not be as grave when only microscopic metastases are found and only involve 1 to 2 regional lymph nodes.108,109,111 Under these circumstances, aggressive surgery with meticulous lymphadenectomy has been reported to produce 5-year survivals as high as 35%.108 Moreover, although gross involvement of the lymph nodes or involvement of more than two lymph nodes has previously been associated with a poor prognosis, recent studies have suggested that more extensive dissection of lymph nodes beyond the pelvis and inclusive of all pelvic nodes resulted in improved outcomes.110 Whether staging subdivisions according to the degree of lymph node involvement, number of lymph nodes involved, proportion of nodes involved per total number of lymph nodes removed, or differences between macroscopic versus microscopic disease play a role in outcomes and should adjust surgical treatment approaches remains to be validated. Distinctions in organ involvement by distant metastases have not been associated with variability of outcomes and survival. Therefore, staging subdivisions according to organ involvement have not been included in standard staging systems. PATHOGENIC PATHWAYS IN BLADDER CANCER Schematic depictions of bladder cancer staging systems in association with likelihood of progression have created the impression that the various cancer diatheses fall into a sequence of stages in their pathogenesis (see Figure 17-1). This has implied further that progression from the most superficial appearance histologically to the most extensive invasion is inexorable. Such schema, however, as they imply a sequence of stages, do not take into account issues in the pathogenesis of disease. The natural history of various forms of bladder cancer may instead reflect developmental pathways that, although interrelated, may be distinct from one another (see Figure 17-2). A schema that incorporates the concept of a variety of different developmental
312
Part IV Bladder
pathways can complement the standard concept of a sequence of stages in understanding the pathogenesis of different forms of bladder cancer. In this construct, stage of disease can be viewed as a snapshot in the evolving pathogenesis of disease. Although stage may remain consistent with time, changes may also occur. The stage at resection as manifest in the snapshot provided by the resection specimen may be used to suggest prognosis, but this may profitably be understood in the context of the potential pathogenesis of a particular tumor diathesis. Distinctions in the potential biologic behavior of a particular cancer at a specific point in time (either at initial diagnosis or at the time of recurrence) may be of use in determining whether aggressive treatment is indicated (even if a tumor appears to be at an “early” stage) or whether conservative treatment may be appropriate (even if a tumor appears to be more advanced). In considering a schema in which different pathways portray the biology of various types of bladder cancer, several developmental terms may be applied to describe the different processes that give rise to various forms of tumor diathesis. For example, papillary tumors may arise through a process that can be described as proliferative. Accordingly, transformed epithelial cells proliferate and produce tumors with a multilayered epithelium in papillary configuration surrounding a central fibrovascular core. The process of proliferation by itself may produce tumors that contain cells with a histologically normal appearance (low grade). Such tumors may lack the machinery necessary to invade the lamina propria aggressively, progress, and metastasize. Tumors that are comprised of histologically abnormal (high grade) cells may occur as the result of a process that can be termed “dysplasia” superimposed on the proliferative process. It is unusual to see papillary tumors that are high grade and truly mucosally confined. Indeed, this has been reported to occur in only 2% to 4% of all mucosally confined tumors.61,62 A high-grade histologic appearance in papillary tumors is more commonly seen when penetration of the basement membrane and invasion of the lamina propria has occurred.64–66 This difference in appearance conceptually suggests a developmental process that can be termed dysplasia. It may indicate a different biologic capability of these tumors such that they can proliferate but also infiltrate. Although low-grade, mucosally confined tumors could conceivably change during the course of their proliferation to become high-grade tumors that have acquired the biochemical machinery to penetrate into the sub-epithelial stroma, dysplasia may hypothetically have been the primary result of neoplastic transformation, leading to the development of a papillary high-grade urothelial cancer capable of invasion. The neoplastic pathway characterized predominantly by dysplasia could also lead to the development of cancer
cells that extend along the plane of the bladder mucosa,75,76,79 possibly undermine it, cause it to slough, and then themselves slough. Such cells lack cohesive and adhesive ability. Through proliferation and continued pagetoid spread, a high-grade flat neoplastic diathesis could occur that in some instances might lead to the development of either papillary tumors that extend into the lumen of the bladder or, more likely, nodular tumors that penetrate into the lamina propria and muscularis.59,68,81,83 Some have suggested that carcinoma in situ leads directly to infiltration of nodular disease into the bladder wall, so that silent carcinoma in situ is diagnosed initially in its muscle-invasive manifestation.84 The various staging systems have not as yet incorporated the genetic changes that characterize different cancers. Although many reports have focused on specific chromosomal and molecular changes that correlate with the propensity either towards proliferation or to invasion and metastasis,112–116 these have not as yet been fully validated. Therefore, they have not been incorporated into staging systems. They have, however, been correlated with different developmental pathways as suggested in schema for tumor pathogenesis.2,4,77,85 For example, aberrations of chromosome 9 have been seen in both low-grade, low-stage bladder tumors and higher grade, invasive tumors. This has suggested that loss of heterozygosity of chromosome 9 may occur early in the genesis of a variety of bladder cancers.117–120 It has also been shown that chromosome 9 is lost in each of several multifocal tumors within an individual patient, supporting the concept of a field change in the genesis of bladder cancer.121,122 Abnormalities in chromosome 9 have been associated with a proliferative diathesis.117,120 Specific foci for these changes have been variable, but all have been correlated with neoplastic transformation that is reflected in a proliferative diathesis and that characterizes the course of these tumors as one of recurrence rather than progression.120 Loss of heterozygosity of chromosomes other than chromosome 9 has been observed in high-grade, highstage tumors.77,86,87 Mutations in chromosome 17 with expression of higher levels of p53 have been identified in approximately half of all high-grade high-stage bladder cancers.86,123 Abnormalities in chromosome 17 have also been associated with tumors more likely to invade and metastasize.124–126 Several studies have also shown that carcinoma in situ expresses high levels of p53 mutations, and that it is not characterized by loss of heterozygosity of chromosome 9.86,87,127 This is in keeping with the apparently aggressive course implied by the presence of carcinoma in situ either alone as “primary” or in the setting of highgrade lamina propria or muscle invasive cancer as “secondary.”81,83,84 Other studies have demonstrated that only those lamina propria invasive tumors that express
Chapter 17 Diagnosis and Staging of Bladder Cancer 313
p53 progress to muscle invasion suggesting a commonality of pathways with the more aggressive tumor diatheses expressing abnormalities in chromosome 17. Most studies have been based on immunohistochemical studies. Some have been validated with analysis of selected sequence conformational polymorphisms. Taken together, initial changes in chromosome 9 may be followed by multiple sequential changes of other genes that may then lead to an invasive and potentially metastatic phenotype. Although these situations are complex, it may ultimately be possible to superimpose a molecular profile for a particular cancer on the snapshot stage of a tumor as determined by histopathologic analysis to determine not only the type of therapy that may be effective in a particular cancer diathesis but also to predict the outcome of particular treatment regimens in the context of the natural history and propensity of that diathesis based on its predicted pathogenesis.
REFERENCES 1. Green FL, Pate DL, Fleming ID, et al: AJCC cancer staging manual. Philadelphia, Springer, 2002. 2. Droller MJ: Bladder cancer: state of the art care cancer. Cancer J Clin 1998; 48:269. 3. Droller MJ: Bladder cancer. Curr Prob Surg 1981; 18:205. 4. Jones PA, Droller MJ: Pathways of development and progression in bladder cancer: new correlations between clinical observations and molecular mechanisms. Semin Urol 1993; 11:177. 5. Jemal A, Thomas A, Murray T, et al: Cancer statistics, 2002. CA Cancer J Clin 2002; 52:23. 6. Messing EM, Young TB, Hunt VB, et al: Urinary tract cancers found by home screening with hematuria dipstick in healthy men over 50 years of age. Cancer 1989; 64:2361. 7. Messing EM, Young TB, Hunt VB, et al: The significance of asymptomatic microhematuria in men 50 or more years old: findings of a home screening study using urinary dipsticks. J Urol 1987; 137:919–922. 8. Resnick MI: Overview: imaging of the genitourinary tract. In Droller MJ (ed): Surgical management of urologic disease, an anatomic approach, p 69. St. Louis, Mosby-Yearbook, 1992. 9. Denkhaus H, Crone-Munzebrock W, Huland H: Non-invasive ultrasound in detecting and staging bladder carcinoma. Urol Radiol 1985; 7:121. 10. Hatch TR, Barry JM: The value of excretory urography in staging bladder cancer. J Urol 1986; 135:49. 11. Barentsz JO, Witjes JA, Ruijs JH: What is new in bladder cancer imaging. Urol Clin N Am 1997; 24:583–602. 12. Caterino M, Giunta S. Finocchi V, et al: Primary cancer of the urinary bladder: CT evaluation of the T parameter with different techniques. Abdom Imaging 2001; 26:433–438. 13. Kim B, Semelka RC, Ascher SM, et al: Bladder tumor staging: comparison of contrast-enhanced CT, T1- and
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24. 25.
26.
27.
28.
T2-weighted MR imaging, dynamic gadoliniumenhanced imaging, and late gadolinium-enhanced imaging. Radiology 1994; 193:239–245. Husband JE, Olliff JFC, Williams MP, et al: Bladder cancer staging with CT and MR imaging. Radiology 1989; 173:435. Tanimoto A, Yuasa Y, Imai Y, et al: Bladder tumor staging: comparison of conventional and gadoliniumenhanced dynamic MR imaging and CT. Radiology 1992; 185:741–747. Nishimura K, Hido S, Nishio Y, et at: The validity of MRI in the staging of bladder cancer: comparison with CT and transurethral US. Am J Clin Oncol 1922; 18:217. Narumi Y, Kadota T, Inoue E, et al: Bladder tumors: staging with gadolinium-enhanced oblique MR imaging. Radiology 1993; 187:145–150. Barentsz JO, Jager G, Mugler JP III, et al: Staging urinary bladder cancer: value of T1-weighted threedimensional magnetization prepared-rapid gradient-echo and two-dimensional spin-echo sequences. Am J Roentgenol 1995; 164:109–115. Ahlstrom H, Malmstrom PU, Letocha H, et al: Positron emission tomography in the diagnosis and staging of urinary bladder cancer. Acta Radiol 1996; 37:180–185. Bender H, Schomburg A, Albers P, et al: Possible role of FDG-PET in the evaluation of urologic malignancies. Anticancer Res 1997; 17:1655–1660. Heicappel R, Muller-Mattheis V, Reinhardt M, et al: Staging of pelvic lymph nodes in neoplasms of the bladder and prostate by positron emission tomography with 2-[(18)F]-2-deoxy-D-glucose. Eur Urol 1999; 36:582–587. Boccon Gibod L, Katz M, Cochand B, et al: Lymphography and percutaneous fine needle node aspiration biopsy in the staging of bladder carcinoma. J Urol 1984; 132:24–26. Chagnon S, Cochand-Pirollert B, Gzaeil M, et al: Pelvic cancers: staging of 139 cases with lymphography and fine-needle aspiration biopsy. Radiology 1989; 173:103–106. Brown FM: Urine cytology. Is it still the gold standard for screening? Urol Clin N Am 2002; 27:25–37. Gregoire M, Fradet Y, Meyer F, et al: Diagnostic accuracy of urinary cytology, and deoxyribonucleic acid flow cytometry and cytology on bladder washings during follow-up for bladder tumors. J Urol 1997; 157:1660–1664. Badalament RA, Fair WR, Whitmore WF Jr, et al: The relative value of cytometry and cytology in the management of bladder cancer. Semin Urol 1988; 6:22. Billerey C, Lamy B, Bettard H, et al: Flow cytometry versus urinary cytology in the diagnosis and follow-up of bladder tumors: critical review of a 5-year experience. World J Urol 1993; 11:156. Bastacky S, Ibrahim S, Wilczynski SP, Murphy WM: The accuracy of urinary cytology in daily practice. Cancer 1999; 87:118–128.
314
Part IV Bladder
29. Mian C, Pycka A, Wiener W, et al: ImmunoCyt: a new tool for detecting transitional cell cancer of the urinary tract. J Urol 1999; 161:1486–1489. 30. Holling KC, King W, Sokolova IA, et al: A comparison of cytology and fluorescence in situ hybridization for the detection of urothelial carcinoma. J Urol 2002; 164:1768–1775. 31. Cajulis RS, Haines GK III, Frias-Hidvegi D, et al: Cytology, flow cytometry, image analysis, and interphase cytogenetics by fluorescence in situ hybridization in the diagnosis of transitional cell carcinoma in bladder washes: a comparative study. Diagn Cytopathol 1995; 13:214–223. 32. Sarosdy MF, de Vere White RW, Soloway MS, et al: Results of a multicenter trial using the BTA test to monitor for and diagnose recurrent bladder cancer. J Urol 1995; 154:379–383. 33. Leyh H, Marberer M, Conort P, et al: Comparison of the BTA stat test with voided urine cytology and bladder wash cytology in the diagnosis and monitoring of bladder cancer. Eur Urol 1999; 35:52–56. 34. Soloway MS, Briggman V, Carpinito GA, et al: Use of a new tumor marker, urinary NMP22, in the detection of occult or rapidly recurring transitional cell carcinoma of the urinary tract following surgical treatment. J Urol 1996; 156:363–367. 35. Konety BR, Getzenberg RH. Urine based markers of urological malignancy. J Urol 2001; 165:600–611. 36. Van der Meijden MA, Oosterlinck W, Brausi M, et al: Significance of bladder biopsies in Ta, T1 bladder tumors: a report from the EORTC Genito-Urinary Tract Cancer Cooperative Group. EORTC-GU Group Superficial Bladder Committee. Eur Urol 1999; 35:267–271. 37. Angulo JC, Lopez JI, Grignon DJ, et al: Muscularis mucosa differentiates two populations with different prognosis in stage T1 bladder cancer. Urology 1995; 44:47–53. 38. Klan R, Loy V, Huland H. Residual tumor discovered in routine second transurethral resection in patients with stage T1 transitional cell carcinoma of the bladder. J Urol 1991; 146:316–318. 39. Kakizoe T, Tobisu K, Takai K, et al: Relationship between papillary and nodular transitional cell carcinoma in the human urinary bladder. Cancer Res 1988; 48:2299. 40. Friedell GN, Parija GC, Nagy K, et al: The pathology of human bladder cancer. Cancer 1980; 45:1823. 41. Tomita Y, Kobayashi K, Saito T, et al: Use of miniature ultrasonic probe system for intravesical ultrasonography for transitional cell cancer of the urinary tract. Scand J Urol Nephrol 2000; 34:313–316. 42. Kim B, Semelka RC, Ascher SM, et al: Bladder tumor staging: comparison of contrast-enhanced CT, T1- and T2-weighted MR imaging dynamic gadoliniumenhanced imaging and late gadolinium-enhanced imaging. Radiology 1994; 193:239–245. 43. Scattoni V, Da Pozzo LF, Colombo R, et al: Dynamic gadolinium-enhanced magnetic resonance imaging in staging of superficial bladder cancer. J Urol 1996; 155:1594–1599.
44. Koraitim M, Kamal B, Metwalli N, et al: Transurethral ultrasonographic assessment of bladder carcinoma: its value and limitation. J Urol 1995; 154:375–378. 45. Beer M, Schmidt H, Riedl R: The clinical value of preoperative staging of bladder and prostatic cancers with nuclear magnetic resonance and computerized tomography. Urologe A 1989; 28:65–69. 46. Herr HW: Routine CT scan in cystectomy patients: does it change management? Urology 1996; 47:324–325. [Published erratum appears in Urology 1996; 47:785]. 47. Slack NH, Prout GR Jr: Heterogeneity of invasive bladder carcinoma and different responses to treatment. In Bonney WW, Prout GR (eds): Bladder Cancer, AUA Monographs, Vol. 1, p 212. Baltimore, Williams & Wilkins, 1980. 48. Althausen AF, Prout GR Jr, Daly JJ: Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 1976; 116:575–580. 49. Vicente J, Laguna MP, Duarte D, et al: Carcinoma in situ as a prognostic factor for G3pT1 bladder tumors. Br J Urol 1991; 68:380. 50. Epstein JL, Amin MB, Reuter VR, et al: The World Health Organization/International Society of Urological Pathology consensus classification of urothelial (transitional cell) neoplasms of the urinary bladder. Bladder Consensus Conference Committee. Am J Pathol 1998; 22:1435–448. 51. Paik ML, Scolieri MJ, Brown SL, et al: Limitation of computerized tomography in staging invasive bladder cancer before radical cystectomy. J Urol 2000; 163:1693–1696. 52. Malmstrom PU, Lonnemark M, Busch C, et al: Staging of bladder carcinoma by computer tomography-guided transmural core biopsy. Scan J Urol Nephrol 1993; 27:193. 53. Broders AC: Epithelioma of the genitourinary organs. Ann Surg 1922; 75:574. 54. Aschner PW: The pathology of vesical neoplasms. Its evaluation in diagnosis prognosis. JAMA 1928; 91:1697. 55. Jewett HJ, Strong GH: Infiltrating carcinoma of the bladder: relation of depth of penetration of the bladder wall to incidence of local extension and metastases. J Urol 1946; 55:366. 56. Jewett HJ, Lewis E: Infiltrating carcinoma of bladder: curability by total cystectomy. J Urol 1948; 60:107. 57. Fuller WA Jr: Staging of advanced bladder cancer. Current concepts and pitfalls (Review). Urol Clin N Am 1992; 19:663. 58. Herr HW: Staging invasive bladder tumors (Review). J Surg Oncol 1992; 51:217. 59. Kotake T, Flanigan RC, Kirkels W, et al: The current TNM-classification of bladder carcinoma: Is it as good as we need it to be. Int J Urol 1995; 2:36. 60. Hermanek P, Sobin LH: International Union Against Cancer: TNM Classification of Malignant Tumours, 2nd revision, 4th edition. Berlin, Springer-Verlag, 1992. 61. Heney NM, Nocks BN, Daly JJ, et al: Ta and T1 bladder cancer; location, recurrence, and progression. Br J Urol 1982; 54:152.
Chapter 17 Diagnosis and Staging of Bladder Cancer 315 62. Heney NM, Ahmed S, Flanagan MJ, et al: Superficial bladder cancer: progression and recurrence. J Urol 1983; 130:1083. 63. Cheng L, et al: Natural history of urothelial dysplasia of the bladder. Am J Surg Pathol 1999; 23:443–447. 64. Jakse G, Loidle W. Seeber G: Stage T1, grade 3 transitional cell carcinoma of the bladder: an unfavorable tumor: J Urol 1987; 137:39. 65. Abel PD, Hall RR, Williams G: Should T1 transitional cell carcinoma of the bladder still be classified as superficial?: J Urol 1988; 62:235. 66. Holmang S, Hedelin H, Anderstrom C, et al: The importance of the depth of invasion in stage G1 bladder carcinoma: a prospective cohort study. J Urol 1997; 157:800–804 [comment]. 67. Cheng I, Neumann RM, Weaver Al, et al: Predicting cancer progression in patients with stage T1 bladder carcinoma. J Clin Oncol 1999; 17:3182–3187. 68. Kakizoe T, Matumoto K, Nishio Y, et al: Significance of carcinoma in situ in association with bladder cancer. J Urol 1985; 133–395. 69. Vicente J, Laguna MP, Duarte D, et al: Carcinoma in situ as a prognostic factor for G3pT1 bladder tumours. Br J Urol 1991; 68:380–382. 70. Koloszy Z: Histopathological “self-control” in transurethral resection of the bladder tumours. Br J Urol 1991; 67:162. 71. Langenstroer P, See W: The role of a second transurethral resection for high-grade bladder cancer. Curr Urol Rep 2000; 1:204–207. 72. Engel P, Anagnostaki L, Braendstrup O. The muscularis mucosae of the human urinary bladder. Implications for tumor staging on biopsies. Scan J Urol Nephrol 1992; 26(Suppl):249–252. 73. Angulo JC, Lopez, JI, Grignon DJ, et al: Muscularis mucosa differentiates two populations with different prognosis in stage T1 bladder cancer. Urology 1995; 45:47–53. 74. Platz CE, Cohen MB, Jones MP, et al: Is microstaging of early invasive cancer of the urinary bladder possible or useful? Mod Pathol 1996; 9:1035–1039 [comment]. 75. Jordan AM, Weingarten J, Murphy WM: Transitional cell neoplasms of the urinary bladder. Can biological potential be predicted from histologic grading? Cancer 1987; 60:2761. 76. Lamm DL: Carcinoma in situ. Urol Clin N Am 1992; 19:499. 77. Spruck CH, Ohneseit PF, Gonzalez-Zulueta M, et al: Two molecular pathways to transitional carcinoma of the bladder. Cancer Res 1994; 54:784. 78. Jones PA, Droller MJ: Pathways of development and progression in bladder cancer: new correlations between clinical observations and molecular mechanisms. Semin Urol, 1993; 11:177–192. 79. Weinstein R, Miller AW III, Pauli BV: Carcinoma in situ: comments on the pathology of a paradox. Urol Clin N Am 1980; 18:523. 80. Wood DP, Montie JE, Pontes JE, et al: Transitional cell carcinoma of the prostate in cysto-prostatectomy
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91. 92. 93.
94.
95. 96.
97.
specimens removed for bladder cancer. J Urol 1989; 141:346. Herr HW: When is a cystectomy necessary in carcinoma in situ? In Murphy GP, Khoury S (eds): Therapeutic Progress in Urologic Cancers, p 511. New York, Alan R. Liss, 1989. Melicow M: Histological study of vesical epithelium intervening between gross neoplasms in total cystectomy. J Urol 1952; 68:261. Farrow GM, Utz DC: Observations on microinvasive transitional cell carcinoma of the urinary bladder. Clin Oncol 1982; 1:609. Kakizoe T, Tobisu K, Takai K, et al: Relationship between papillary and nodular transitional cell carcinoma in the human urinary bladder. Cancer Res 1988; 48:2299. Tsai YC, Nichols PW, Hiti Al, et al: Allelic losses of chromosome 9, 11 and 17, in human bladder cancer. Cancer Res 1990; 50:44. Sarkis AS, Dalbagni G, Cordon-Cardo C, et al: Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression. J Natl Cancer Inst 1993; 85:53. Hartmann A, Schlake G, Zaak D, et al: Occurrence of chromosome 9 and p53 alterations in multifocal dysplasia and carcinoma in situ of human urinary bladder. Cancer Res 2002; 62:809–818. Kaye KW, Lange PH: Mode of presentation of invasive bladder cancer: Reassessment of the problem. J Urol 1982; 128:31–33. Slack NH, Prout GR Jr: Heterogeneity of invasive bladder carcinoma and different responses to treatment. J Urol 1980; 123:644. Jewett HJ: Comments on the staging of invasive bladder cancer: two B’s or not two B’s: that is the question (apologies to Shakespeare, Hamlet, act 2, sc I, lines 1056). J Urol 1978; 119:39 (editorial). Fridell GN, Parija GC, Nagy K, et al: The pathology of human bladder cancer. Cancer 1989; 45:1823. Soto EA, Friedell GH, Tiltman AJ: Bladder cancer as seen in giant histologic sections. Cancer 1977; 39:447. Schroder FH, Cooper EH, Debruyne FMJ, et al: TNM classification of genitourinary tumors 987-position of the EORTC Genitourinary Group. Br. J Urol 1988; 62:502. Hendry WF, Rawson NSB, Turney L, et al: Computerization of urothelial carcinoma records: 16 years’ experience with the TNM system. Br J Urol 1990; 65:583. Herr HW: A proposed simplified staging system of invasive bladder tumors. Urol Int 1993; 50:17. Herr HW, Scher HI: Surgery of invasive bladder cancer: is pathologic staging necessary. Semin Oncol 1990; 17:590–597. Frazier HA, Robertson JE, Dodge RK, et al: The value of pathologic factors in predicting cancer specific survival among patients treated with radical cystectomy for transitional cell cancer of the bladder and prostate. Cancer 1993; 71:3993.
316
Part IV Bladder
98. Wishnow KI, Levinson AK, Johnson DE, et al: Stage B (P2/3A/N0) transitional cell carcinoma of bladder highly curable by radical cystectomy. Urology 1992; 39:12–16. 99. Roehrborn CG, Sagalowsky AI, Peters PC. Long-term patient survival after cystectomy for regional metastatic transitional cell carcinoma of the bladder. J Urol 1991; 146:36–39. 100. See WA, Fuller JR: Staging of advanced bladder cancer: current concepts and pitfalls. Urol Clin N Am 1992; 19:663. 101. Herr HW, Whitmore W Jr, Morse MJ, et al: Neoadjuvant chemotherapy in invasive bladder cancer: the evolving role of surgery. J Urol 1990; 144:1083–1088 [review]. 102. Herr HW: Conservative management of muscle infiltrating bladder cancer: prospective experience. J Urol 1987; 138:1162–1163. 103. Solsona E, Iborra I, Ricos, JV, et al: Feasibility of transurethral resection for muscle-infiltrating carcinoma of the bladder: prospective study. J Urol 1992; 147:1513–1515. 104. Schellhammer PF, Bean MA, Whitmore WF: Prostatic involvement by transitional cell carcinoma: pathogenesis, patterns and prognosis. J Urol 1988; 118:399. 105. Fossa SD, Ous S, Berner A: Clinical significance of the “palpable mass” in patients with muscle-infiltrating bladder cancer undergoing cystectomy after preoperative radiotherapy. Br J Urol 1991; 67:54–60. 106. Gospodarowicz MK, Rider WD, Keen CW, et al: Bladder cancer: long-term follow-up results of patients treated with radical radiation. Clin Oncol 1992; 3:155–161. 107. Smith JA Jr, Whitmore WF Jr: Regional lymph node metastases from bladder cancer. J Urol 1981; 126:591. 108. Skinner DG: Management of invasive bladder cancer: a meticulous pelvic lymph node dissection can make a difference. J Urol 1982; 128:34. 109. Lerner SP, Skinner DG, Lieskovsky G, et al: The rationale for en bloc pelvic lymph node dissection for bladder cancer patients with nodal metastases: long-term results. J Urol 1993; 149:758–765. 110. Paulson AL, Horn T, Steven K: Radical cystectomy: extending the limits of pelvic lymph node dissection improves survival for patients with bladder cancer confined to the bladder wall. J Urol 1998; 160:2015–2019. 111. Wishnow KI, Johnson DB, Ro YJ, et al: Incidence, extent, and location of unsuspected pelvic lymph node metastasis in patients undergoing radical cystectomy for bladder cancer. J Urol 1987; 137:408–412. 112. Theodorescu D: Commentary on genetic prognostic markers for transitional carcinoma of the bladder: from microscopes to molecules. J Urol 1996; 155:2. 113. Richter J, Jiang F, Gorog JP, et al: Marked genetic differences between stage pTa and stage pT1 papillary
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
bladder cancer detected by comparative genomic hybridization. Cancer Res 1997; 57:2860–2864. Chow NH, Cairns P, Eisenberger CF, et al: Papillary urothelial hyperplasia is a clonal precursor to papillary transitional cell bladder cancer. Int J Cancer 2000; 89:514–518. Presti JC, Jr., Reuter VE, Galan T, et al: Molecular genetic alterations in superficial and locally advanced human bladder cancer. Cancer Res 1991; 51:5405–5409. Baithun SI, Naase M, Blanes A, et al: Molecular and kinetic features of transitional cell carcinomas of the bladder: biological and clinical implications. Virchows Arch 2001; 438:289–297. Miyao N, Tsai YC, Lerner SP, et al: The role of chromosome 9 in human bladder cancer. Cancer Res 1993; 53:4066. Eleuteri P, Grollino MG, Pomponi D, et al: Chromosome 9 aberrations by fluorescence in situ hybridization in bladder transitional cell carcinoma. Eur J Cancer 2001; 37:1496–503. Stadler WM, Steinberg G, Yang X, et al: Alterations of the 9p21 and 9q33 chromosomal bands in clinical bladder cancer specimens by fluorescence in situ hybridization. Clin Cancer Res 2001; 7:1676–1682. Tsukamoto M, Matsuyama H, Oba K, et al: Numerical aberrations of chromosome 9 in bladder cancer. A possible prognostic marker for early tumor recurrence. Cancer Genet Cytogenet 2002; 134:41–45. Hafner C, Knuechel R, Zanardo L, et al: Evidence for oligoclonality and tumor spread by intraluminal seeding in multifocal urothelial carcinomas of the upper and lower urinary tract. Oncogene 2001; 20:4910–4915. Vriesema JL, Aben KK, Witjes JA, et al: Superficial and metachronous invasive bladder carcinomas are clonally related. Int J Cancer 2001; 93:699–702. Olumi AF, Tsai YC, Nicholes PW, et al: Allelic loss of chromosome 17p distinguishes high grade from low grade transitional cell carcinomas of the bladder. Cancer Res 1990; 50:7081. Fujimoto K, Yamada Y, Okajima E, et al: Frequent associations of p53 gene mutations in invasive bladder cancer. Cancer Res 1992; 52:1393. Esrig D, Spruck CH III, Nichols PW, et al: p53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage in bladder cancer. Am J Pathol 1993; 143:1389–1397. Dalbagni G, Ren ZP, Herr H, et al: Genetic alterations in p53 in recurrent urothelial cancer: a longitudinal study. Clin Cancer Res 2001; 7:2797–2801. Edwards J, Duncan P, Going JJ, et al: Loss of heterozygosity on chromosomes 11 and 17 are markers of recurrence in TCC of the bladder. Br J Cancer 2001; 85:1894–1899.
C H A P T E R
18 Superficial Transitional Cell Carcinoma of the Bladder: Management and Prognosis Murugesan Manoharan, MD, FRCS, and Mark S. Soloway, MD
Superficial transitional cell carcinoma (TCC) of the urinary bladder refers to tumor confined to the mucosa (Ta, Tis) or submucosa (T1). This is a heterogeneous disease with a variable natural history. At one end of the spectrum, low-grade Ta tumors have a low progression rate and require initial endoscopic treatment and surveillance but rarely represent a threat to the patient. At the other extreme, high-grade T1 tumors have a high malignant potential with significant progression and cancer death rates. Seventy percent of bladder tumors present as superficial disease. Approximately 70% of these tumors present as Ta lesions, 20% as T1, and 10% as Tis (carcinoma in situ). The true natural history of untreated noninvasive disease is not fully known. Many characteristics of TCC have been studied in an attempt to predict this variable tumor behavior. These include pathologic features, cytologic analysis, and biologic and molecular markers. Although thorough endoscopic tumor resection remains the principal treatment, intravesical agents have become important in the subgroup of tumors that are at risk of progression. In order to tailor treatment appropriately, the urologist should review the various prognostic factors and define the behavior of the tumors as precisely as possible. INITIAL EVALUATION Patient evaluation begins with a thorough history including exposure to smoking and other known carcinogens, physical examination, and urine analysis. Endoscopic assessment of the entire urethra and urinary bladder remains the most important diagnostic procedure. Modern flexible endoscopes with high-quality optics allow this to be performed safely, with minimal patient
discomfort, as an office examination.1 The anterior bladder wall and bladder neck regions are well visualized with flexible cystoscopy. Cold-cup biopsy is possible, although sufficient tissue to determine depth of invasion is difficult to obtain with small forceps. Hence, we prefer cystoscopy under anesthesia to obtain satisfactory biopsy. Upper tract radiologic visualization should be performed in all cases. Intravenous urography is sensitive in detecting papillary tumors, as well as in providing functional and anatomic information. Ultrasound has also been used for upper tract assessment, with the advantages of avoiding contrast reactions, radiation, and intestinal preparation. However, ultrasound is less sensitive in detecting small tumors. Retrograde ureteropyelography, with cytologic washings at the time of tumor resection, is useful to further assess suspicious or poorly imaged areas. In selected cases, CT scan may be useful in the initial evaluation. It is more sensitive in detecting small renal masses, urinary calculi and nonurologic lesions. The disadvantages include inability to visualize small urothelial lesions, cost, availability issues, and the need for contrast agents. If there is suspicion of a high-grade tumor, cytologic assessment is important. Bladder washings have a better yield than voided urine cytologies.2 Gentle barbotage using 50 ml of sterile saline with prompt cytology evaluation is suggested. ENDOSCOPIC MANAGEMENT Well-performed transurethral resection (TUR) remains the most important method for the diagnosis and treatment of primary and recurrent bladder tumors, despite the evolving role of intravesical therapy.
317
318
Part IV Bladder
Technologic improvements have dramatically improved this procedure.3 Videoendoscopy has been a major advance in all areas of endourology but particularly for bladder tumor resection. In addition to minimizing the surgeon’s exposure to body fluids, it allows all areas of the bladder, including the dome and anterior wall, to be resected with greater ease and improved magnification. It also provides documentation and improved teaching opportunities. Continuous-flow resection allows the urologist to control the degree bladder filling, thus reducing the risk of perforation, obturator nerve excitation, and resection time. Adequate anesthesia is important for safe, controlled resection, and patient comfort. In males, we prefer beginning the procedure with an optical dilator that provides calibration and dilation of the urethra with visual assessment prior to placement of the resectoscope.4 Saline barbotage for cytologic analysis should be performed first if high-grade tumor is suspected. The entire bladder should be examined using the 12-degree or 30degree and 70-degree lenses. The nature, number, location, and size of the lesions should be noted. The capacity of bladder, ureteral orifices and adjacent urothelium should be assessed. Papillary tumors should be systematically resected with a right angle or bladder wall loop, as appropriate. The bladder wall or angled loop is designed for resecting tumors located on the high lateral or posterior walls. The aim is to achieve complete resection of all tumors. Biopsy of the tumor base should be done either with cold-cup forceps or formal resection, which may involve the muscle. Specimens should be retrieved for histopathology. Suspicious mucosal areas should be biopsied with a coldcup forceps to minimize cautery artifact. The roller ball electrode is used to fulgurate all suspicious areas and to achieve hemostasis. A history or the presence of a high-grade tumor necessitates transurethral biopsy of the prostatic urethra. This is best performed with the resectoscope, as opposed to cold-cup forceps. One should sample the mucosa and underlying stroma from the bladder neck to the verumontanum. A bimanual examination should be performed. Catheter drainage is necessary if there is bleeding requiring irrigation, or if a deep resection has been performed. The majority of procedures can be performed on an outpatient or overnight basis.
Although close follow-up with endoscopic management of recurrences is appropriate for most low-grade Ta tumors, the adjuvant use of intravesical chemotherapeutic and immunotherapeutic agents is appropriate for high-grade T1 and CIS. In order to identify patients at higher risk of progression and recurrence, who may benefit from such therapy, numerous prognostic factors have been proposed (Table 18-1). These include wellestablished pathologic features, such as grade and stage, endoscopic features, cytologic characteristics, tumor cell products, and molecular genetic markers, such as p53. Although some of these prognostic factors have an established clinical role, some of the newer markers remain investigational. TUMOR GRADE Tumor grade is well established as an important prognostic factor for both new tumor occurrence and progression to invasion.5,6 Mostofi et al.7 introduced a World Health Organization’s (WHO) classification system for grading TCC as grades 1, 2, and 3 based on the degree of cellular differentiation. The WHO/International Society of Urologic Pathology (ISUP) consensus classification of 1998 distinguishes between papilloma, papillary urothelial neoplasm of low-grade potential (PUNLMP), lowand high-grade carcinoma. A solitary papillary, tumor with a fibrovascular core and no more than either seven or eight normal-appearing cell layers, is regarded by some as a papilloma. Others include these with grade 1 papillary carcinomas.8,9 The WHO’s grading system takes into account the degree of anaplasia as determined by increased cellularity, nuclear crowding, disturbance of Table 18-1 Prognostic Factors for Superficial Bladder Cancer Number of tumors Tumor size Tumor grade Tumor T stage Lymphatic invasion Carcinoma in situ Urine cytology
PATHOLOGIC PROGNOSTIC FACTORS
DNA ploidy
After complete endoscopic resection, approximately 30% to 80% of patients will develop additional tumors, usually of similar grade and stage. The majority of these lesions are new occurrences, as opposed to true recurrences, reflecting a generalized instability of the urothelium.
Blood group antigens Tumor cell products-EGFR, AMFR, PCNA Molecular genetic markers-p53; c-erb B-2; c-myc
Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 319
cellular polarity, the absence of differentiation from base to surface, pleomorphism, variations in nuclear shape and chromatin pattern, mitotic counts, and the presence of giant cells.7 This pattern is reproducible at the extremes (grades 1 and 3) but leaves grade 2 as a heterogeneous intermediate group.10,11 There is a strong correlation between higher grade and invasion, disease progression, metastases, and survival.5,6 Mortality from progression of grade 1 tumors is low (0% and 4% at 10 years).6,12 Another 3% recur as grade 3 tumors.1 Grade 3 tumors frequently progress to muscle invasion, however. This has been documented in 50% and 62% of cases, with a 35% 10-year actuarial survival rate.6 Predicting the behavior of grade 2 tumors is less well defined. For all grade 2 tumors, between 18% and 33% are reported to progress, with a 10-year actuarial survival of 87%.5,6 In an attempt to clarify the behavior of these heterogeneous tumors, Carbin et al.10,11 subclassified them into 2a and 2b based on nuclear pleomorphism and the number of mitoses. When progression was assessed, grade 2a tumors faired much better, with a 92% 5-year survival compared with 43% for grade 2b. This prognostic discrimination has been demonstrated elsewhere.13 Nuclear size (area) has also been used to stratify intermediate-grade tumors.14 The major criticism of multiple subclassification for clinical application has been subjectivity. The subclassification of Carbin et al.10 was demonstrated to be highly reproducible, with an interobserver agreement of 90%. However, inter- and intraobserver errors ranging from 50% to 87% have been reported for grade using reference pathologists in controlled trials.15 In clinical practice, most pathologists describe the tumor as low or high grade. The categorization of grade becomes increasingly important for T1 tumors. This group has a much higher risk of progression to muscle invasion than Ta tumors. In a series of T1 tumors, 50% of grade 3 and 22% of grade 2 tumors have progressed.12 Histologic Stage Depth of tumor invasion was first included as a marker of outcome by Jewett and Strong.16 It is now commonly used as a prognostic indicator and incorporated into staging systems including the current American Joint Committee on Cancer (AJCC) system.17 There is a significant difference in prognosis between Ta tumors, which are confined to the mucosa (not penetrating the basement membrane), and T1 tumors, which infiltrate the lamina propria. This difference has been documented for both tumor recurrence and progression. The difference in recurrence risk between the two stages is minimal. Grade, multiplicity, and size are more important in determining the recurrence rate.18 However, the
risk of stage progression is clearly higher for T1 tumors. Between 0% and 4% of Ta tumors and 27% to 46% of T1 tumors will progress to muscle invasion at 3 years.12,19–22 Long-term survival for Ta tumors is excellent. Ten-year survival rates are 95% for grade 1, 89% for grade 2, and 84% for grade 3 tumors.23 Twenty-year cancer-specific survival for Ta tumors is 89%, compared with 30% for T1 tumors. Clearly, careful evaluation for lamina propria invasion is important. Muscularis mucosa is identifiable as a landmark in 70% to 80% of TUR specimens.25 When absent, the larger arteries of the deep lamina propria are a useful landmark. The surgeon should attempt to minimize cautery artifact by using cold-cup biopsies or reducing the coagulation current. With papillary disease, the tumor base should be sampled carefully, submitting the underlying tissue as a separate specimen if necessary. The significance of the depth of lamina propria invasion has varied mainly due to difficulties in identifying the muscularis mucosae. In a series with three review pathologists, the concurrence rate for depth of invasion was only 50%.26 Despite this interobserver error, two series have used T1 subclassification and found it useful for prognostic discrimination. Younes et al.27 used the presence of invasion to, and beyond, the muscularis mucosae to subclassify T1 tumors. Superficial invasion, termed T1a, had a 75% 5-year survival compared with 14% for deep invasion (T1b). Using the same classification system, Hassui et al.25 reported a 7% progression rate for T1a and 53% for T1b, independent of tumor grade, number, and size. The deep lamina propria is rich in lymphatics, and this may explain why it is an important factor in progression to deep muscle invasion. The practical role of T1 subclassification needs further study to clarify its clinical application. Vascular and lymphatic invasion in general confer a poorer prognosis. In a study including Ta and T1 tumors, 7% had documented vascular or lymphatic invasion, with a 30% 6-year survival. These results were independent of grade.23 Clearly, it is important to exclude muscularis propria invasion. If there is any doubt, the urologist should resect the tumor site again to be certain of the stage. In a series of 46 patients who had a second TUR within 2 weeks of their first resection, 43% demonstrated residual tumor in the deep resection.28 Given the implication of muscle invasion, adequate tissue sampling to include muscle is essential. Reproducibility of Grade and Stage As indicated, there are limitations with the current staging and grading system for superficial tumors. This has implications for tailoring treatment for an individual patient, and for the analysis of prognostic factors in clinical trials.
320
Part IV Bladder
Ooms et al.15 with seven review pathologists, reported a high inter- and intraobserver error of grade. A similar discrepancy in stage with an intraobserver error of 50% has also been demonstrated.11,29–31 In reviewing a series of multicenter trials by tile Dutch Uro-Oncology Group, which utilized review pathology, the error of grading was 30%, with a tendency for local pathologists to undergrade.32 The error in T stage was 20%, with a tendency for local pathologists to overstage. The same problem has been reported in interpreting biopsies of normal-appearing urothelium in patients with superficial tumors. In one study, biopsies reported as “dysplasia” were reproduced only 60% of the time.33 In randomized trials, such distortion of pathologic results is balanced in both treatment and control arms and hence does not have a major impact on the outcome of a study.32 This variation becomes more significant, however, when comparing results between studies of “similar” pathologic stage. It also has an important implication in the management of an individual patient, particularly when identifying muscle-invasive disease. These limitations in staging and grading must be recognized. The important lesson is for the clinician to review the slides with the pathologist prior to any major treatment decision. Status of Bladder Mucosa Distant from the Tumor Any abnormality of the mucosa distant from the primary tumor provides prognostic information on recurrence rates. Recently, there has been increasing support for tumor cell implantation as one explanation for high recurrence rates.34,35 In general, any abnormal-appearing mucosa should be biopsied. A cold-cup technique is preferable, as it allows adequate tissue sampling without diathermy artifact. More controversial is the role of biopsy of normal-appearing mucosa. The incidence of associated changes in normal-appearing mucosa is between 10% and 50%.5,36,37 Dysplasia is reported in approximately 15%, with carcinoma in situ more variable (10% to 50%).37In general, CIS is more common with grade 3 tumors.37 The incidence of concurrent CIS in the prostatic urethra is reported to be between 16% and 30%.39,40 We believe that the magnification associated with videoendoscopy lessens the likelihood of CIS being found in normal-appearing bladder mucosa. Less well defined is the accuracy and reproducibility of dysplasia reported in a biopsy, and the true risk of progression for dysplasia.41–44 Progression for Ta and T1 tumors has been shown to increase from 8% to 30% when moderate or severe mucosal dysplasia was also present on biopsy.5 Others have suggested that moderate dysplasia like mild dysplasia is not a risk factor.41 More widespread use of cytology and improved endoscopic optics, particularly video magnification, have
reduced the role of mucosal biopsies. In an attempt to define the role of random biopsies in predicting recurrence and progression, Kiemeney et al.8 demonstrated that random biopsies did not significantly influence patient outcome. Biopsies gave no additional information to predict tumor behavior beyond stage, grade, tumor size, and number. Most patients with high-grade tumor will receive adjuvant treatment, regardless of the information from mucosal biopsies. Therefore, we infrequently perform mucosal bladder biopsies outside of clinical trials. ENDOSCOPIC FEATURES The number of primary tumors is a strong predictor of recurrence. The presence of two or more tumors increases the recurrence rate approximately 2-fold, and decreases the time to first recurrence.5,45–48 Heney et al.5 showed that the recurrence rate for multiple tumors increased from 18% to 43% for Ta disease and from 33% to 46% for T1 disease. Multiple primary tumors are also associated with a tendency for increasing grade with recurrence.48 There is an approximately 1.5-times increased risk of progression for multiple tumors.12,45 Tumor size is also a predictor of recurrence and progression. The risk of stage progression increases from 9% to 25% for tumors >5 cm.5 The time to first recurrence is also prognostic. A recurrence or new occurrence at 3 months has been shown to increase the risk of subsequent recurrence from 20% to between 70% and 85%.47,48 This emphasizes the importance of the disease status at the first follow-up cystoscopy.18 CYTOLOGIC PROGNOSTIC FACTORS Urine Cytology Urinary cytology performed on exfoliated urothelial cells in urine or bladder washings can be used to detect TCC. Care must be taken with specimen collection and handling to preserve exfoliated cells and avoid bacterial contamination. The yield for diagnosis of low-grade tumors is low, generally <30%.50 Recognition of subtle malignant features requires a skilled cytopathologist. However, cytology is highly sensitive for high-grade disease for both CIS and papillary tumors. Greater than 60% of papillary tumors and 90% of cases of CIS have positive cytology. The reduced cellular adherence of high-grade tumors results in a higher proportion of cells shed into the urine and thus detectable with cytology. This complements cytoscopy in the detection of high-grade TCC. Bladder wash cytology may provide more information on the presence or absence of CIS than random biopsies. It is important to provide relevant clinical history for accurate interpretation by the cytopathologist.
Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 321
In addition to identifying the method of specimen collection, it is important to note any history of previous treatment (radiation, chemotherapy, or immunotherapy), urinary infection, stones, recent surgery, or catheterization. All of these conditions may produce cells with nuclear features that may be confused with malignancy.57 The interpretation of a positive urine cytology requires knowledge of tumor status of the bladder. The absence of cancer in the bladder requires exclusion of CIS or high-grade disease in the upper tracts or prostatic urethra. Cytology also has a valuable role in follow-up of high-grade superficial tumors. DNA Ploidy DNA ploidy as assessed by flow cytometry has been used to assess TCC. In general, all grade 1 and most of the grade 2 tumors are diploid. Some grade 2 tumors are tetraploid, while others, and most of the grade 3 tumors are nontetraploid aneuploid. Variation in DNA content within a tumor is a significant limitation in the application of ploidy studies. There is a correlation between ploidy and tumor behavior. Of 229 grade 1 and grade 2 superficial tumors, Gustafson et al.53 showed that none of the diploid tumors progressed, while 35% of the aneuploid tumors progressed with a 21% death rate. Aneuploid tumors have also been shown to recur more frequently.54 There is conflicting evidence as to the ability of ploidy to independently predict progression over grade alone.55,56 Ploidy remains expensive, and has yet to establish a clinical role. We do not use this in decision-making. BIOLOGIC PROGNOSTIC MARKERS Blood Group Antigens There has been long-standing recognition of the prognostic importance of the loss or absence of blood group antigens from the tumor cell surface.57,58 This can be assessed by immunohistochemistry or red-cell adherence tests. However, the results are usually qualitative and the methodology subjective. The result is also dependent on the patient’s blood group, with group O being prone to false-negative results. An increased risk for progression has been documented with loss of antigen expression.58 This information appears to be independent of grade and stage.59 There is also an association with tumor recurrence rate60 and response to bacille Calmette-Guérin (BCG) treatment.61 Other cell surface antigens have also been correlated with prognosis. These include the Lewis surface antigens and the Thompson-Friedenreich antigen.62,63 Advances in immunostaining with monoclonal antibodies have allowed assessment of these antigens in urine, with
improved sensitivity and specificity64 They have not as yet found a role in clinical practice. Tumor Cell Products There have been numerous cell proteins that appear to correlate with tumor behavior. They perform various functions but often act as cell receptors. These include desmosomal glycoprotein,65transferrin receptor,66 and human milk fat globulin.67 Epidermal growth factor (EGF) receptor and basement membrane tissues have been more extensively studied. EGF receptor is reported to be an independent predictor for stage progression in Ta and T1 tumors.68 In addition, an increased recurrence rate from 7% to 17% has been noted for receptor-positive patients.69 This marker would appear to have potential clinical application on the basis of results to date. Various connective tissue components of the basement membrane have been studied as potential markers. The loss of laminin and type IV collagen in the basement membrane underlying noninvasive tumors correlates with increasing tumor progression.70 Cytogenic and Molecular Genetic Markers Although the majority of invasive bladder tumors commonly contain nondiploid and morphologically abnormal DNA, most superficial tumors are near diploid. Sandberg71 first identified abnormal DNA in Ta and T1 tumors, and demonstrated a relationship with risk of recurrence and progression. Chromosomal analysis for solid tumors has been simplified with the development of specific probes, such as fluorescent in situ hybridization (FISH) for DNA sequence analysis. RNA amino acid sequencing with polymerase chain reaction (PCR) has also contributed to the understanding of TCC. Both FISH and PCR can be performed on paraffin sections. Specific chromosomal abnormalities for bladder cancer have been identified on chromosomes 1, 5, 7, 9, 11, and 17.72–75 Abnormalities of chromosome 7 include alteration to the c-erb B oncogene, which codes for the EGF receptor. Loss of heterozygosity at chromosomes 9q, 11p, and 17p correlates with known tumor suppressor genes, namely, the Wilms’ tumor gene (WTG) and p53. Studies on the role of oncogenes and carcinogenesis have traditionally used rodent tumors, particularly the ras family.78–80 Unfortunately, it has not proven useful in the study of human TCC. Promising results have been demonstrated through molecular genetic work with oncogenes. The p53 oncogene (17p13-1 locus) codes for a nuclear phosphoprotein, whose major role appears to be in transcriptional regulation. The p53 is involved in DNA repair or induction of
322
Part IV Bladder
apoptosis for irreversibly damaged DNA. Hence, it is thought to function as a tumor suppressor gene.86 There are two forms of this gene product—the wild, or unaltered type, and the mutant form.82 Mutation of wild type results in the accumulation of mutant p53 protein within the tumor cell nucleus, due to a prolonged half-life. This leads to alterations in modulating activity.83 Mutant p53 can be easily detected immunohistochemically using monoclonal antibodies on fresh or fixed tumor specimens.84 Immunohistochemical changes have been shown to correspond to abnormalities with DNA sequence analysis.85–88 It must be recognized that the limitation of monoclonal immunohistochemistry is false-negative results,89 although this is reduced with the monoclonal antibody Pab-1801.89 Changes in p53 are the most commonly recognized genetic alterations in human malignancy, and correlate with tumor behavior.90 Mutations have been observed in 50% of high-stage bladder tumors.85–87,91 However, p53 changes and their relationship to tumor behavior in superficial tumors are less clear. Studies have utilized both immunohistochemistry and nucleic acid sequence analysis for assessment of Tis, Ta, and T1 tumors. Mutations have been observed in up to 65% of biopsies of primary Tis (pTis).92 Positivity for p53 has been demonstrated as an independent predictor of progression in a series of 33 pTis patients followed for 124 months.89 The results for Ta and T1 diseases are more variable. Positive mutant p53 staining has ranged between 8% and 95%,85,93–97 with a strong correlation between positivity and tumor grade.94,95,98 Several recent institutional reviews of Ta and T1 tumors utilizing multivariate analysis have demonstrated p53 status as a statistically significant prognostic factor for progression-free and overall survival.99,100 The disparity between numerous investigators is difficult to explain. Technical factors may play a role. In summary, the oncogene p53 is an encouraging prognostic marker for bladder cancer. Its clinical role in superficial disease will remain unclear until further large series with multivariate analyses are performed. The overexpression of other oncogenes, c-erb B-2 and c-myc, has also been observed and is more frequently in highgrade, high-stage TCC.101–103 Their role in superficial TCC has not been defined.
been resected and urinary cytology, if performed, is negative. Intravesical therapy can be subdivided into chemotherapy and immunotherapy. The decision to use intravesical treatment is dependent on numerous factors, including: tumor stage, grade, size, and multiplicity; the presence of CIS or positive urinary cytology; the sideeffect profile of each agent; and other patient-specific factors (Table 18-2). Economic factors may also play a part in the decision process. The ideal intravesical agent would have an antitumor effect against TCC, show no phase specificity in the cell cycle and have limited systemic and local toxicity on an acute and chronic basis. Much of the systemic toxicity associated with intravesical therapy is due to drug absorption. Factors associated with increased absorption include low molecular weight of the instilled drug, temporal relationship to the TUR, and extent of resection. Local toxicity with intravesical therapy is frequent and usually consists of irritative voiding symptoms or hematuria.104 Delaying the initiation of intravesical therapy for 10 or more days after resection will allow healing of the resected urothelium and may lessen the local and systemic side effects. Increasing exposure of the urothelium to the intravesical agent would seem to be important. This can be done by increasing the concentration and contact time of the drug. Some advocate asking the patient to lie in the prone position for part of the treatment.105 Others suggest that sterile water, instead of saline, as the diluent decreases the osmolality of the solution, thereby increasing the intracellular concentration of the drug.106 Recommended dosages, administration schedule, and duration of intravesical therapy have varied and are largely based on empiric data. Patients who receive intravesical therapy should be monitored for response. This includes endoscopy and bladder wash cytology. Appropriate end-points include recurrence, time to recurrence, progression in grade or stage, and time to progression. Patients are monitored for response 3 months after initiation of treatment. A complete response (CR) to treatment is defined as no tumor on endoscopy, negative cytology, and negative bladder biopTable 18-2 Indications for Intravesical Therapy Cumulative tumor size >5 cm
INTRAVESICAL THERAPY Rationale The high incidence of subsequent tumors after initial TUR, whether true recurrences or new occurrences, has led to the use of intravesical instillation of antineoplastic agents. This form of treatment can be used either therapeutically, to eradicate residual tumor after an incomplete TUR, or prophylactically, after all visible tumor has
Multiple tumors Multiple recurrences Stage T1 or high-grade TCC CIS or positive cytology Residual tumor
Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 323
sies. Anything less than a CR is considered as a treatment failure, as partial responders have the same incidence of progression as nonresponders.107 If any question exists as to the persistence of tumor, resection or biopsy is performed. In the face of a positive biopsy or cytology after intravesical treatment, it is less likely that another course with the same agent will be effective, and an alternative treatment should be used. BCG may be an exception, as a second 6-week course is beneficial in some instances. The stage and grade of the tumor recurrence will ultimately be the determinant of future treatment (e.g., cystectomy, TUR alone). Intravesical Chemotherapy Thiotepa Thiotepa is an antineoplastic alkylating agent related to nitrogen mustard that has been shown to eradicate existing tumors and delay the development of new tumors. The usual dosage is 30 to 60 mg in 30 to 60 ml of distilled water. The National Bladder Cancer Study Group found that the CR rate for 30 mg was equal to that for 60 mg. Hence, the lower dose is recommended.12 Duration of treatment is usually weekly for 6 to 8 weeks when given therapeutically and weekly for 4 to 6 weeks when given prophylactically. If maintenance is given, a monthly schedule is usually selected. A randomized cooperative study by the Medical Research Council found no statistically significant difference in tumor recurrence rates in patients receiving: (1) no intravesical therapy, (2) a single instillation of thiotepa at the time of resection, or (3) a single thiotepa instillation at the initial resection and 3-month intervals for a total of 5 treatments in a year. Median follow-up was almost 9 years. Thus, it appears that it is necessary to give more than 5 treatments of thiotepa in a year to make a significant difference in tumor recurrence. When used as a therapeutic agent, CR rates of 35% to 45% have been reported.14,115 Long-term use of thiotepa prophylaxis was evaluated by the National Bladder Cancer Collaborative Group.112 They reported that 53% of patients were tumor free at 2 years compared to only 27% of untreated patients. The benefits were only noted in patients with grade 1 lesions (51% treated with thiotepa were tumor free at 2 years versus 14% of the control group). Recurrence rates of grade 2 and grade 3 tumors were not significantly different than controls, suggesting that thiotepa is most effective in treating patients with low-grade tumors. Due to thiotepa’s low molecular weight (189 Da), it is absorbed more than any other intravesical agent. Myelosuppression occurs in up to 9% of patients, usually in the form of leukopenia or thrombocytopenia. Thus, white blood cell and platelet counts must be monitored during the course of therapy. In a study of 670 patients,
Soloway and Ford116 found that only 4% of patients suffered this side effect and none of the consequences were severe. Irritative voiding symptoms are common as with other intravesical agents. Overall, thiotepa is relatively safe and inexpensive, and is most effective for low-grade tumors. We believe that it is a reasonable choice for prophylaxis in patients with multiple, recurrent grade 1, Ta bladder tumors. Mitomycin C Mitomycin C (MMC) is a 329-kDa antitumor antibiotic, which inhibits DNA synthesis. There has never been a thorough dose response study with MMC. Most studies have used from 20 to 40 mg in 20 to 40 ml of water, weekly, for 8 weeks. Many studies have used MMC for residual TCC after incomplete resection (i.e., treatment rather than prophylaxis). Most patients in these studies were at high risk for recurrence, having a history of prior TCC. A study by the National Bladder Cancer Group involved treatment with 40 mg of MMC for 8 consecutive weeks.117 The study included 117 patients with CIS or grade 1 to grade 3 Ta or T1 disease. Each patient had failed a course of intravesical thiotepa. At 3 months, 27% of patients had a CR as defined by negative endoscopy, biopsy, and cytology. Another 9% had negative endoscopy and cytology but were not biopsied again. Despite a negative endoscopy, an additional 12% were not considered as complete responders, since their cytology was positive. Overall, 18% of patients with T1 disease, 29% with Ta disease, and 35% with CIS were rendered tumor free. The National Bladder Cancer Collaborative Group also compared MMC and thiotepa for treatment of TCC.118 Study participants received either 40 mg of MMC in 40 ml or 30 mg of thiotepa in 30 ml of sterile water, weekly, for 8 weeks. MMC patients had a statistically significant higher CR rate (39% versus 27% with thiotepa, p = 0.02). Ta grade 1 tumors responded best as in previously reported thiotepa studies. Soloway119 reported a series of 80 patients who received 8 weekly 40-mg instillations of MMC for treatment with evaluation for response at 12 weeks. All complete and some partial responders received monthly MMC for 1 year. Average follow-up was 40 months. Complete responses were noted in 37% (15 of 41) of Ta patients, 33% (7 of 21) of CIS patients, and 44% (8 of 18) of T1 patients. Twenty-six percent of patients eventually had a cystectomy and 15% developed muscle invasion. Nine percent (7 of 80) of the patients eventually died of bladder cancer. The initial response to MMC was predictive of the patient’s eventual outcome. Of those who had persistent TCC at 3 months, 34% later required cystectomy compared to only 13% of initial complete responders. Death from carcinoma of the bladder occurred in 12% of early
324
Part IV Bladder
treatment failures compared to only 3% of initial complete responders. It thus may be prudent to consider cystectomy for patients with high-grade TCC who do not have a CR with intravesical treatment. Huland et al.120 reported a randomized prospective study of MMC used for prophylaxis. Patients received either 20 mg of MMC in 20 ml every other week for up to 18 months or had a TUR alone. Only 10% of MMCtreated patients recurred compared to 51% of controls. Maier and Hobarth121 reported a study of 63 patients who received MMC prophylaxis over a 2-year period. The mean follow-up was 50 months. Fifty-two percent developed a recurrence. One-third (21 of 63) died while receiving MMC. Of the remaining 42 patients, 26% recurred at an average of 14 months after MMC was discontinued. The remaining 31 patients (48% of the original 63) remained tumor free for a mean 26 months after MMC was completed. The Medical Research Council has reported the 7-year follow-up of a 502-patient randomized multicenter trial involving the use of early instillation of MMC. After complete resection of Ta and TI tumors, patients were randomized to receive either no further treatment until the next endoscopy, a single instillation of 40 mg MMC within 4 hours of resection, or an instillation within 24 hours of resection and at 3-month intervals for 1 year (5 total doses). They found that the overall recurrence rates were lower and the interval to recurrence prolonged in patients receiving 1 or 5 instillations of MMC compared to controls. The estimated 5-year reduction in recurrence risk was 5% and 23% for the 1- and 5-dose regimens, respectively.122 Due to MMC’s molecular weight, systemic toxicity is rare. Local symptoms, primarily chemical cystitis, are relatively common (10% to 17%).117,120,123 A desquamating rash of the palms and genitalia is unique to MMC. It occurs in approximately 5% of patients and is thought to be a form of contact dermatitis. Occasionally, the rash is diffuse. Severe bladder contracture requiring cystectomy (4%) has also been reported myelosuppression is rare.104,119,124 In summation, MMC appears to be more effective than thiotepa. The toxicity of MMC is acceptable. The widespread use of MMC as a first-line therapy, however, is limited in the United States by its cost. Doxorubicin Best known as a systemic chemotherapeutic drug, this antitumor antibiotic has been shown to be an active intravesical agent. Doxorubicin is a 380-kDa intercalating agent. The vast majority of the literature comes from Japan, where doxorubicin is the most frequently used intravesical agent. The doses varied widely from 10 to 100 mg at various intervals. Therefore, there is no standard dose.
There have been a number of randomized studies using doxorubicin for prophylaxis. Niijima et al.125 reported findings from a randomized study of doxorubicin (30 mg in 30 ml, twice a week, for 4 weeks) plus TUR versus TUR alone. At a minimum 12 months’ follow-up, 70% (104 of 149) of patients receiving doxorubicin were recurrence free compared to 55% (77 of 139) who had a TUR alone. Kurth et al.126 found that 64% (58 of 86) of patients randomized to receive doxorubicin (50 mg in 30 ml, weekly, for 1 month then monthly for 1 year) in addition to TUR were recurrence free versus 52% (39 of 69) in the control group. Doxorubicin was not shown to be superior to thiotepa for prevention of superficial tumor recurrence in other controlled doubleblind studies.127,128 In a randomized trial comparing the efficacy of doxorubicin and BCG for CIS, Lamm et al.129 reported a 34% CR rate for doxorubicin. Median length of time to failure was 5 months. BCG was superior for treatment of CIS. Others have demonstrated up to a 70% CR rate with doxorubicin, but follow-up was short.130 Due to doxorubicin’s high molecular weight, absorption is low and myelosuppression rare. Cystitis is the primary toxicity, occurring in 25% of patients.104,124,131 Diminished bladder capacity occurs in up to 9% of patients and anaphylactic reactions have been seen.124,130 Overall, doxorubicin has been shown to be an effective agent for treatment and prophylaxis of TCC. Valrubicin (AD-32) AD-32 (N-trifluoroacetyladriamycin-14-valerate), an anthracycline derivative, is a semisynthetic analog of doxorubicin. AD-32 (MW 723) differs from doxorubicin (Adriamycin) in that it lacks cardiotoxicity, it is associated with less local toxicity, and it is lipophilic. AD-32 does not bind DNA but is an active inhibitor of DNA and RNA syntheses. Studies have focused on treating patients with CIS or superficial disease who failed with BCG treatment. Phase 1 trials of patients treated with AD-32 have been completed. Of the 35 courses given, 69% had some local toxicity, 31% grade 2 or grade 3. Irritative voiding symptoms accounted for all but three adverse events. Reducing the alcohol content in the diluent decreased these symptoms. There was negligible systemic absorption.133 Valrubicin has been approved by the FDA for treatment of BCG refractory carcinoma in situ, and further clinical trials in this group are in progress. Immunotherapy Bacille Calmette-Guérin Since BCG was initially identified as an effective intravesical agent for superficial bladder cancer, much has been
Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 325
learned about its actions. Still more remains to be elucidated.134 BCG is a live attenuated tuberculosis organism first developed from cultures at the Pasteur Institute of Lille.135 Its mechanism of action remains ill defined, but at least part of its effectiveness is due to an immunologic host response. T-cell-deprived animals do not respond to BCG. Furthermore, BCG must bind to urothelial cells to be active and binds by attaching to fibronectin.136 An immunologic cascade of events occurs causing a strong inflammatory response. The inflammatory response itself may have a deleterious effect on tumor cells. In addition, various cytokines are released including interleukins, which have known antineoplastic activity.134,136 The urologic literature is replete with reports on the efficacy of BCG. There is marked variability. This variability may be due to differences in the completeness of resection, tumor stage and grade, prior history of TCC, prior intravesical therapy, associated CIS, the number of instillations, the BCG substrain used, host immunologic factors, and length of follow-up. The optimal schedule for BCG administration has yet to be established. The number of milligrams per colony count differs among the numerous BCG substrains. The concept of 6 weekly instillations is arbitrary. An induction phase is necessary for the development of the immunologic response in the bladder. While most patients develop an inflammatory response with 6 instillations, some will require fewer and some may require more.137 Studies have shown that 19% to 26% of patients treated, who do not respond to an initial 6-week course of BCG, will respond to 6 additional weekly doses.108,109 Maintenance therapy is also controversial. Early studies showed no clear benefit to maintenance BCG to justify the increased risk of side effects.137 However, Lamm et al.129 recently reported results of a randomized, prospective Southwest Oncology Group’s (SWOG) trial of maintenance BCG for CIS, Ta, and TI diseases. After a 6-week induction course, patients received BCG in 3 weekly doses at 3 months, 6 months, and every 6 months for 3 years. In this study, maintenance therapy further reduced the tumor recurrence rate.138 However, the optimal timing of these maintenance doses whether monthly, 3-monthly, or even yearly has not been established. BCG for CIS The literature strongly supports the use of BCG for treatment of CIS. CR rates of 70% have been reported.139–142 Dejager et al. 141 reported on 123 patients from 6 phase 11 studies; patients received at least 6 weekly instillations of TICE BCG and 12 monthly maintenance doses. A 76% complete remission rate was reported, including a 71% (45 of 63) CR rate for patients who failed intravesical chemotherapy. A durable CR was seen in 50% of responders at a mean
follow-up of 48 months. Only 117 of responders subsequently required cystectomy versus 55% of nonresponders. However, no survival difference was noted between responders and nonresponders. Lamm et al.129 in the aforementioned randomized study of BCG versus doxorubicin for CIS, reported a 70% CR rate for BCG versus 34% for doxorubicin. The mean interval to treatment failure was 39 months for BCG compared to 5 months for doxorubicin. BCG for Prophylaxis Several randomized studies have compared the efficacy of TUR alone versus TUR plus BCG. Herr142 recently summarized the results of 5 such studies encompassing 437 patients. Overall, 70% of patients who received BCG prophylaxis were tumor free compared to 31% of patients who had TUR alone. Follow-up ranged from 12 to 60 months. To address the impact of BCG on disease progression, Herr et al.143 reviewed the 10-year follow-up of 86 patients with recurrent Ta, T1, and Tis diseases, who were randomized to either TUR plus 6 weeks of ArmandFrappier BCG or TUR alone. Crossover was available for patients in the TUR group who recurred. The 10-year progression-free and overall survival were 62% and 75%, respectively, for patients who received BCG and 37% and 53% for patients who had a TUR alone. The median progression-free survival was not reached for the BCG group and was 46 months for the “control” group. Fifteen of 18 patients who crossed over and received BCG did not have tumor progression. The authors concluded that BCG delayed both tumor progression and death in patients with superficial bladder cancer. BCG has also been compared to the most commonly used intravesical chemotherapeutic agents. Brosman144 and Marfinez-Pineiro,145 in separate studies, found BCG to be superior to thiotepa in reducing tumor recurrence.109 Lamm et al.146 reported the results of a SWOG’s comparison of BCG and doxorubicin in patients with rapidly recurring superficial TCC. The mean interval to recurrence in the patients with papillary tumors receiving BCG was 22 months versus 110 months in patients receiving doxorubicin. Vegt et al.147 recently reported the results of a randomized prospective study of 435 patients with pTa or pT1 disease comparing the efficacy of TICE BCG, RlVM-BCG, and MMC. Mean follow-up was 36 months. Patients underwent TUR followed by either 6 weeks of TICE or RIVM-BCG or 4 weeks of MMC followed by monthly doses for 6 months. Results are shown in Table 18-3. They concluded that MMC was equivalent to BCG in efficacy. Drug-induced cystitis, the most common local toxicity, and systemic side effects were significantly less in the MMC group.
326
Part IV Bladder
Table 18-3 Randomized Trial of TICE and RIVM BCG and MMC TICE BCG
RIVM-BCG
MMC
Recurrence Ta/TI
75 of 117 (64%)
62 of 134 (46%)
58 of 136 (43%)
Recurrence CIS
17 of 23 (74%)
9 of 15 (60%)
8 of 12 (67%)
Progression at recurrence
7 (5%)
8 (6%)
8 (6%)
From Vegt PDJ, Witjes JA, Wities WPJ, et al: J Urol 1995; 153:929, with permission.
In regard to T1 disease, Eum et al. reported a series of 30 patients with high-grade T1 disease treated with a 6-week course of Armand-Frappier BCG. After one course, 47% (14 of 30) had a negative cytology and biopsy at 6 months. Another 6 patients responded to a second 6-week course, for an overall CR rate of 66%. Four patients required a cystectomy for progression or recurrent TI tumor, and one patient had metastasis. All had failed a first course of BCG. Thus, the overall progression rate was 17%. Cookson and Sarosdy148 studied BCG for T1 disease in 86 patients. Patients underwent TUR prior to receiving a 6-week course of Pasteur BCG. Some patients received booster doses at 3, 6, and 12 months. Patients with recurrence had a repeat TUR followed by additional BCG either weekly or monthly. At a median follow-up of 59 months (range 9 to 149), 9170 were disease free. Of the 91%, 69% responded to the initial induction course and 22% were recurrence free after reresection and additional BCG. Progression to T2 disease occurred in only 7% of patients. They concluded that BCG was effective in the treatment of T1 tumors. Some patients in their study, however, were listed as having grade 1, T1 tumors. Grade 1, TI disease rarely, if ever, exists. This underscores the importance of pathology review. Nadler et al.149 reported that 23 of 66 (35%) patients who were disease free 2 years after treatment with BCG had tumor recurrence after 2 to 11 years of follow-up. Thus, lifelong monitoring after BCG is essential even with an excellent initial response to treatment. Cystitis is the most common side effect of BCG, occurring in up to 90% of patients. Hematuria occurs in up to one-third of patients and can be problematic. Major adverse reactions include fever over 103 ˚F (3%), granulomatous prostatitis (0.9%), and pneumonitis or hepatitis (0.7%). BCG sepsis, the most serious complication, occurs in 0.4% of patients. Thus far, 10 deaths from BCG sepsis have been reported. Caution should be used in administering BCG to patients who are immunocompromised or have liver disease. Treatment depends on the clinical situation but includes isoniazid 300 mg and rifampin 600 mg daily. In advanced cases, ethambutol 1200 mg daily is useful. Cycloserine 250 to 500 mg twice daily in combination with isoniazid and rifampin should
be used if the patient is septic. In addition, the coadministration of antituberculin agents with BCG to lessen side effects of treatment has been proposed.150 Interferon Interferons (IFN) are biologic response modifiers that are integrally associated with the immunologic cascade. IFN has antiproliferative and antiviral properties. It stimulates cytokine release and inhibits nucleotide synthesis. It stimulates macrophage function, enhances natural killer (NK) cell cytolytic activity, and activates B and T lymphocytes.151 The success of IFN-α-2b has been limited in several previously reported series of superficial TCC. The Northern California Oncology Group reported that 4 of 16 patients (25%) with superficial TCC had a CR with intravesical recombinant IFN-α-2b. In the same study, 6 of 19 patients with CIS had a CR. Of the 10 CRs in the study, 5 were durable at 18 to 37 months.153 Glashan154 reported on a series of 87 patients with CIS. Patients received either high-dose (100 million units) or low-dose (10 million units) IFN-α-2b, weekly for 12 weeks, then monthly up to a year. In the high-dose group, 20 of 47 (43%) had a CR compared to only 2 of 38 (5%) in the low-dose group. Interestingly, 6 of 9 patients who failed a course of BCG had a CR with IFNα2b. Seven patients in each group eventually required a cystectomy, 13 for disease progression. The median interval to cystectomy was 32 weeks for the high-dose group and 18 weeks for the low-dose group. The primary toxicity was a flulike syndrome occurring in 17% of highdose and 8% of low-dose patients. Local symptoms did not occur and no patient discontinued therapy due to side effects. Though the efficacy of IFN is inferior to BCG, it is being used more commonly in BCG failure patients. Keyhole-Limpet Hemocyanin Keyhole-limpet hemocyanin (KLH) is a high molecularweight immunogenic protein collected from the hemolymph of the mollusk Megathura crenulata. In humans, KLH induces both cell-mediated and humoral
Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 327
responses. KLH was initially used as a skin test to evaluate delayed-type hypersensitivity responses in humans.152 Olsson et al.155 first reported the use of KLH immunotherapy for superficial TCC of the bladder. Patients immunized with KLH were noted to have fewer tumor recurrences. In a prospective trial of 19 patients with a history of superficial TCC, prophylactic KLH injections were given after TUR. Of the 9 immunized patients, only 1 had a recurrence over 204 patient-months. In the nonimmunized group, 7 of 10 had a recurrence over 228 patient-months. In a randomized controlled study, Jurinic et al.156 found that KLH was more effective than MMC in prophylaxis against recurrent TCC. KLH (10 mg) was given intravesically following a 1-mg intracutaneous dose. Twenty-three patients received 20 mg of intravesical MMC. Fourteen percent of KLH patients recurred compared to 39% in the MMC group. In a subsequent nonrandomized single arm study, Jurinic et al. reported that 17 of 81 patients (21%) had recurrence of TCC after the same KLH regimen. No adverse effects were reported.152 Bropirimine Bropirimine is a pyrimidine that induces interferon, presumably leading to antineoplastic and immunomodulatory activities.157 Bropirimine is a unique agent for urothelial neoplasms, since it can be given orally in a phase 1 trial for treatment of CIS and papillary TCC; Sarosdy et al.158 reported that 6 of 26 patients who could be evaluated had a CR at 3 months. Five of 11 patients with CIS had a CR. The drug was most effective when given at high doses, 3 g/day for 3 consecutive days, weekly for 12 weeks. Only 1 of 10 papillary tumors regressed completely. In a subsequent phase 2 trial using high-dose bropirimine, 20 of 39 patients (51%) with CIS had a CR. This included 6 of 13 patients (46%) who were BCG failures. CRs lasted as long as 17 months. Flulike symptoms were the most common adverse effect occurring in 62% of patients.159 Further phase 2 trials of bropirimine alone and in combination with BCG are in progress. Combination Therapy Recent studies have shown that BCG and IFN-α have complementary and synergistic immunomodulatory and antitumoral activity. This allows reduction in the BCG dose used. This combination is efficacious in patients who failed BCG therapy. O’Donnell et al.189 reported 63% and 53% disease-free rates at 12 and 24 months in BCG refractory patients.189 Clinical studies suggest that combination of BCG and MMC is not advantageous over mitomycin alone. In high-grade tumors, complete resection of the tumor should be followed by immediate instillation of MMC
and subsequent 6-week BCG instillation. The immediate instillation of MMC decreases the tumor cell implantation and BCG should further reduce the recurrence and progression rate.190 Recommendations From the above data it is clear that BCG plus TUR is more beneficial than TUR alone for patients with highgrade TCC and T1 disease. Furthermore, BCG has been shown to prolong the interval to progression, while intravesical chemotherapy has not. BCG or MMC appears to be the agent of choice for CIS. For recurrent, low-grade Ta tumors, the optimal treatment is less clear. The likelihood of progression to muscle-invasive disease is very low (<5%). We recommend either no adjuvant therapy or intravesical chemotherapy. In this situation, the role of intravesical chemotherapy would be to prolong the tumor-free interval and decrease the cost and morbidity of frequent surgical procedures. Some studies show no significant difference between BCG and chemotherapy for lowgrade, low-stage disease,139 and as described above, the side-effect profile of BCG is not insignificant. Thus, we do not suggest BCG for grade 1 TCC. For grade 2 or grade 3 Ta tumors treatment should be individualized based on recurrence patterns. Either BCG or intravesical therapy may be appropriate in these situations. If intravesical chemotherapy fails, BCG would be a reasonable next step. If a patient were to fail a course of BCG, a second 6-week course could be considered. This may help avoid the morbidity of cystectomy in a subgroup of patients. Yet, this delay may allow disease progression and loss of curability with radical treatment. Herr et al.160 reported a series of 61 patients with highgrade superficial bladder cancer who were initially treated with BCG. At a follow-up ranging from 10 to 13 years, 12 patients (20%) died of metastatic urothelial cancer. Thus, in many cases, despite diligent follow-up, patients progress and die of bladder cancer. Biologic immune response modifiers other than BCG have been used to treat TCC. These cytokines can be administered orally or intravesically. Their mechanisms of action are not clearly defined. A host response appears to be central to their efficacy. Further elucidation of the mechanism of action of these agents, as well as controlled studies of various drug combinations at various doses, will better define their role in the treatment of Ta and TI TCC and CIS. TRANSITIONAL CELL CARCINOMA OF THE PROSTATIC URETHRA TCC of the prostatic urethra is usually found concomitant with or subsequent to TCC of the bladder. It is
328
Part IV Bladder
rarely primary. Analysis of cystoprostatectomy specimens has identified TCC of the prostate in 10% to 50% of cases. Involvement is more common with high-grade bladder tumors, occurring in 70% of men with primary CIS of the bladder. Since the presence of TCC of the prostate may alter the treatment strategy, a TUR biopsy of the floor of the prostatic urethra should be performed in all men with high-grade TCC of the bladder.162 The management and prognosis of TCC of the prostatic urethra depend on stage and grade. Although the UICC staging system indicates that all TCC of the prostate is stage T4, it seems prudent to substratify patients based on involvement of the prostatic urethra, ducts, or stroma.165 The prognosis for prostatic mucosal CIS and ductal involvement differs from that of stromal invasion. Furthermore, TCC involving the prostatic urethra primarily may be less lethal than the disease from the bladder infiltrating through the bladder wall to involve the prostate. Treatment of TCC of the prostatic urethra must take into consideration the status of the bladder (i.e., current TCC or prior history of TCC and treatment). Therapeutic options include intravesical chemotherapy, immunotherapy, or cystoprostatectomy (Figure 18-1). BCG has been the most widely studied agent for topical therapy. Initial concerns about obtaining effective contact with the prostatic urethra arose from observations of recurrence in the prostatic urethra after BCG therapy for TCC of the bladder. However, bladder neck incompetence following TUR would seem to allow adequate tissue contact for treatment. For disease confined to the
prostatic urethra, several series have documented CRs using BCG.168,169 Cystoprostatectomy is recommended for most cases of TCC involving the prostatic ducts or stroma.162 Concurrent urethrectomy is recommended because there is a 30% to 50% risk of urethral recurrence.171 The prognosis for urethral involvement relates to disease stage, with high-T-stage lesions associated with a grim outcome. PARTIAL AND RADICAL CYSTECTOMY With the current efficacy of quality endoscopic instruments and multiple intravesical agents, the majority of patients with superficial bladder cancer will not require radical surgery. The indications for cystectomy include failed intravesical therapy for high-grade disease (papillary or CIS), persisting or recurrent high-grade tumor, or progression to bladder muscle or prostatic stromal invasion (Table 18-4). Persistently positive urine cytology after intravesical treatment requires a thorough reevaluation of the bladder, in addition to reassessment of the upper tracts and the prostatic urethra in men. Localization and accurate restaging is necessary before considering cystectomy. Cystectomy should also be strongly considered when pathologic understaging is suspected. Hydronephrosis associated with a bladder tumor usually indicates muscle invasion. Staging error rates as high as 55% have been reported for T2 tumors.172,173 This reinforces the importance of careful pathologic review of all biopsy material.
High-grade bladder TCC (Ta, T1, CIS)
TUR biopsy of the prostatic urethra
CIS only
Ductal
stromal invasion
Negative
Intravesical therapy (if fails, cystoprostatectomy with urithrectomy)
Cystoprostatectomy with urethrectomy or intravesical therapy
Cystoprostatectomy with urethrectomy
Treat bladder tumor as indicated
Figure 18-1 Algorithm for evaluation and treatment of prostatic urethral TCC. (From Matzkin H, Soloway MS, Haredeman S: J Urol 1991; 146:1210, with permission.)
Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 329
Table 18-4 Indications for Cystectomy for Superficial Bladder Cancer Persistent or recurrent high-grade papillary tumor Persistent or recurrent CIS Progression to muscularis propria or prostatic stromal invasion TCC involving prostatic ducts
Consideration should be given to concurrent urethrectomy with cystectomy if there is widespread multifocal CIS, involvement of the prostatic urethra in men, or bladder neck and trigone in women. This probably precludes orthotopic urinary reconstruction to the urethra for these individuals, although some suggest that this is not an absolute contraindication with limited prostatic urethral involvement. Partial cystectomy has a limited role. There is a subgroup of superficial tumors in which this may be considered, such as tumors within bladder diverticula. Diverticulectomy should be performed with care to obtain adequate surgical margins and avoid tumor cell spillage. Surgery alone achieves a high cure rate for superficial TCC. Amling et al.174 reported cancer-specific 5-year survival rates of 88% for Ta, 76% for T1, and 100% for CIS. Pelvic lymph node metastases were present in 5.9%. Similar survival figures have been reported in other large series.175–177 FOLLOW-UP Since 30% to 80% of tumors will recur, close follow-up is important to diagnose and treat recurrence early. Flexible endoscopy and urinary cytology (for high-grade disease) are essential for follow-up. Historically this has been performed at 3-month intervals, and then tailored according to patterns of recurrence. The disease status at the initial 3-month cystoscopy is important in predicting future tumor behavior, and has become the basis of follow-up protocols.18–48 Treatment of papillary recurrence, or suspicious areas, is ideally performed under anesthesia, with rigid instrumentation, allowing adequate biopsies and thorough visual assessment. The mucosa distant from the tumor and the prostatic urethra in males should be sampled as previously outlined for high-grade primary tumors. Laser ablation via flexible endoscopy under topical anesthesia has been used to manage recurrences in selected cases.178,179 Laser is well tolerated, although there is a recognized risk of bowel injury.178 Diathermy has also been used180; 4-French electrodes are available to treat small lesions. Care must be taken to pass the elec-
trode at least 1 cm beyond the tip of the endoscope to avoid thermal damage to the fiberoptic system. Both techniques require a cooperative patient. There is considerable cost benefit for this strategy in appropriate individuals. It must be emphasized that representative histopathology is necessary to avoid undertreatment of innocent-appearing high-grade lesions.181 Protocols for cystoscopic follow-up have been proposed based on known prognostic factors, such as tumor size, number, histologic grade and stage, urine cytology, and DNA ploidy. Parmar et al.18 concluded that the likelihood of recurrence, and hence the need for follow-up cystoscopy, could be predicted simply and accurately by the number of tumors at initial presentation and the presence of recurrent tumor at the first 3-month cystoscopy risk categories and appropriate follow-up are summarized in Table 18-5. The power of this classification lies in the objectivity and reliability of these two prognostic factors. The safety and efficacy of this protocol have been demonstrated in a retrospective review of 232 patients.182 The duration of endoscopic follow-up for patients free of recurrence for many years has been debated. Morris et al.,183 in a longitudinal follow-up study of 179 patients with Ta and T1 TCC, documented recurrence risk over time. They reported that after a tumor-free interval of 2, 5, and 10 years, the risk of recurrence is 43%, 22%, and 2%, respectively. No patient had a recurrence after remaining tumor free for 12 years. No patient free of recurrence for 2 years progressed to muscle invasion or metastases. Holmang et al.24 reported that only 1 of 59 patients tumor free for 5 years progressed. They also observed that patients who had recurrences on 10 or more cystoscopic studies, or multiple recurrences over more than 4 years, continued to have recurrences until death or cystectomy. Urinary markers and cytology may have a role in longterm follow-up. Table 18-6 lists sensitivities and specificities for potentially useful urinary markers. The ideal Table 18-5 Follow-Up for Superficial Bladder Cancer Risk Category
Recommended Follow-Up
Single tumor with no recurrence at 3 months
Annual cystoscopy
Single tumor with recurrence at 3 months, or multiple tumors with no recurrence
3-monthly cystoscopy
Multiple tumors with recurrence at 3 months
Adjuvant treatment
From Parmar MKB, Friedman LS, Hargreave TB, et al: J Urol 1989; 142:284–288, with permission.
330
Part IV Bladder
Table 18-6 Urinary Markers for Follow-up of Superficial Bladder Cancer Number of Patients
Marker
Technique
LewisXantigen64
Immunocytology (bladder wash)
LewisXantigen184
Immunocytology
Basement membrane complex (Bard BTA)185
Latex agglutination
Autocrine motility factor (AMF) receptor186
Sensitivity (%)
Specificity (%)
101
81
86
89
85
85
499
40
82
Qualitative immunoassay
70
80
75
Nuclear matrix protein (NMP-22)*
Quantitative immunoassay
69
74
78
Hyaluronidase†
Quantitative ELISA assay
104
63 (high grade-99)
94
ELISA, enzyme-linked immunosorbent assay. *Data derived from Soloway MS, Briggman J, Carpinito G, et al: Use of a new tumor marker, urinary NMP22, in the detection of occult or rapidly recurring transitional cell carcinoma of the urinary tract following surgical treatment. Personal communication, 1995. †Data derived from Lokeshwar BL: Personal communication, November, 1995.
noninvasive bladder tumor marker would need to be nearly 100% sensitive before replacing follow-up cystoscopy. Voided urine cytology has excellent specificity and reasonable sensitivity in high-grade lesions. But in low-grade lesions, the sensitivity is low (25%). At present none of these tests can completely replace cystoscopy for surveillance. A positive cytology and a negative cystoscopy should prompt the clinician to investigate the patient further including random biopsies of the bladder, prostatic urethra and careful assessment of upper tracts. The frequency of radiologic follow-up depends on the individual’s risk of developing upper urinary tract tumors. This risk varies from 0.5% with low-grade bladder tumors24,187 to 15% with CIS.188 Intravenous pyelography should be performed every 2 to 5 years, accordingly. CASE HISTORIES Case 1 A 74-year old female presented with a 4-cm papillary bladder tumor. TUR confirmed a grade 3 T1 tumor with invasion to the level of the muscularis mucosae but not involving deep muscle (stage T1a).
Case 2 A 48-year-old woman presented with a 2-cm papillary tumor on the bladder trigone, near the ureteric orifice, with negative mucosal biopsies. Pathology confirmed a grade 3 Ta lesion that was strongly positive for p53 on immunohistochemical staining. Small papillary recurrences were resected at 13 and 21 months, all of which remained grade 3 Ta and p53-positive. Intravesical mitomycin (20 mg weekly for 5 weeks) was administered. The patient remains tumor free at 10 months following the last TUR. Case 2 Discussion Recent data suggest that p53-positive papillary tumors may be at increased risk for progression. These tumors initially recurred as high-grade noninvasive lesions, although they appear to have responded to a prophylactic course of mitomycin. BCG would have been an equally reasonable alternative and will be used with recurrence. Intravesical therapy could have been used at the time of diagnosis given the high tumor grade. Case 3
Case 1 Discussion Accurate staging is important when evidence of lamina propria invasion is present on initial biopsy. Restaging biopsy is essential. Confirmed lamina propria invasion and high grade puts this patient at high risk for both recurrence and progression. Intravesical BCG was administered weekly for 6 weeks, without evidence of recurrence.
A 66-year-old male underwent a TUR of the prostate for symptoms associated with benign prostatic hyperplasia. Surprisingly, the pathology noted grade 3 TCC involving the prostatic ducts. No bladder disease was detected on biopsy at a subsequent cystoscopy. The patient declined further treatment. A TUR biopsy at 24 months again demonstrated CIS involving prostatic ducts with no stromal invasion and no TCC of the bladder.
Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 331
Case 3 Discussion The management options for prostatic ductal involvement include intravesical BCG or cystoprostatectomy. A cystoprostatectomy with urethrectomy was performed confirming prostatic ductal CIS with extensive CIS of the bladder and one focus of lamina propria invasion. This demonstrates the problems of disease understaging, which is the major concern with intravesical treatment for both bladder and prostatic urethral TCC. Case 4 A 65-year old male presented with a 1-cm grade 3 Ta tumor involving the left wall of the bladder, which was completely resected. A large, wide-mouthed bladder diverticulum located on the right wall of the bladder was filled with a second grade 3 papillary tumor. Random bladder and prostatic urethral biopsies were negative. A TUR biopsy at 8 weeks revealed no evidence of tumor in the left wall. A partial cystectomy removing the bladder diverticulum was performed, confirming a grade 3 Ta tumor with associated CIS but negative surgical margins.
distal ureter stricture treated with distal ureterectomy and reimplantation. In follow-up she had a positive cytology but no evidence of tumor on bladder biopsy She received 6 weeks of BCG. Her irritative symptoms worsened. She later had dysplasia in the bladder documented by biopsy and received another 6-week course of MMC. She remained tumor free but presented with incapacitating irritative voiding symptoms and incontinence and a severely contracted bladder. She underwent a cystectomy and ileal conduit for severe bladder contracture. There was no cancer in the specimen. Case 6 Discussion This is a classic case of overtreatment with intravesical therapy and incapacitating iatrogenic morbidity. While intravesical agents may prolong recurrence-free survival, the side effects of treatment should not be underestimated. Case 7
A 74-year old female presented with a history of CIS and T1 grade 3 TCC of the bladder. After resection she was treated with 6 weeks of BCG.
A 75-year old woman presented with a history of superficial, low-grade TCC in 1983. She had been treated previously for interstitial cystitis. In 1988, she underwent a left nephroureterectomy for T1, grade 2 TCC of the ureter. In 1991, she was found to have CIS in the bladder and superficial tumor in the right distal ureter. A stent was placed and she received intravesical MMC. Four months later she had a resection of a T1, grade 3 bladder tumor. She was given a second 6-week course of BCG. Nine months later she had a TURBT, with pathology revealing a high-grade, muscle-invasive tumor with involvement of the right ureteral orifice and invasion of the bladder neck and urethra. Cystectomy with urinary diversion was performed. Pathology revealed a grade 3 T3 TCC. No adjuvant chemotherapy was given.
Case 5 Discussion
Case 7 Discussion
This case prompts consideration as to whether to give maintenance BCG. Early randomized studies showed no clear-cut advantage to giving maintenance BCG over a standard 6-week inductive course. Lamm et al.138 recently reported that not only can maintenance therapy reduce tumor recurrence but may also increase survival. The optimal timing of maintenance doses has not been clearly established. Given the patient’s age and risk of side effects, no maintenance therapy was given in this case.
This case illustrates the progression of a superficial lesion to a high-grade invasive tumor despite intravesical MMC, BCG, and close surveillance.
Case 4 Discussion Residual or high-grade noninvasive tumor involving a bladder diverticulum could be managed with diverticulectomy or cystoprostatectomy. Care must be taken to exclude and treat other foci of tumor, if bladder preservation is chosen. Case 5
Case 6 A 77-year old woman was diagnosed with multifocal CIS in 1990. She was treated with 6 weekly doses of intravesical MMC. At that time she had frequency and urgency, as well as perineal discomfort. In 1993, she had a right
REFERENCES 1. Soloway MS: Flexible cystourethroscopy: alternative to rigid instruments for evaluation of the lower urinary tract. Urology 1985; 25:472. 2. Matzkin H, Moinuddin S, Soloway MS: Value of urine cytology versus bladder washing in bladder cancer. Urology 1992; 39(3):201. 3. Soloway MS, Patel J: Surgical techniques for endoscopic resection of bladder cancer. Urol Clin North Am 1992; 19(3):467.
332
Part IV Bladder
4. Soloway MS: An optical dilator to obviate blind urethral dilation prior to endoscopic resections. Urol 1988; 31:427. 5. Heney NM, Ahmed S, Flanagan MJ, et al: Superficial bladder cancer: progression and recurrence. J Urol 1983; 130:1083. 6. Jordan AM, Weingarten J, Murphy WM: Transitional cell neoplasms of the urinary bladder: can biological potential be predicted from histological grading? Cancer 1987, 60:2766. 7. Mostofi FK, Sobin LH, Torlini H: Histological typing of urinary bladder tumors. International Histological Classification of Tumors No. 10. Geneva, World Health Organization, 1973. 8. Murphy WM, Beckwith JB, Farrow G: Tumors of the kidney, bladder and related urinary structures, pp 198–224. Washington, DC, Armed Forces Institute of Pathology, 1994. 9. Ayala AG, Ro JY: Premalignant lesions of the urothelium and transitional cell tumors. In Young RH (ed): Pathology of the Urinary Bladder, pp 65–101. New York, Churchill Livingstone, 1989. 10. Carbin BE, Elkman P, Gustafson H, et al: Grading of human urothelial neoplasms based on nuclear atypia and mitotic frequency 1: histological description. J Urol 1991; 145:968. 11. Carbin BE, Elkman P, Gustafson H, et al: Grading of human urothelial neoplasms based on nuclear atypia a mitotic frequency. II: prognostic importance. J Urol 1991; 145:972. 12. Kaubisch S, Lum BL, Reese J, et al: Stage TI bladder cancer: grade is the primary determinant for risk of muscle invasion. J Urol 1991; 146:28. 13. Pauwels RP, Schapers REM, Smeets AWGB, et al: Grad in superficial bladder cancer 1: morphological criteria. J Urol 1988; 61:129. 14. Blomjous CEM, Vos W, Schipper NW: The prognostic significance of selective nuclear morphometry in urine bladder carcinoma. Hum Pathol 1990; 21:409. 15. Ooms ECM, Anderson WAD, Alons CL, et al: Anal of the performance of pathologists in the grading of bladder tumors. Hum Pathol 1983; 14:140. 16. Jewett HJ, Strong GH: Infiltrating carcinoma of the bladder: relation of depth of penetration of bladder wall incidence of local extension and metastases. J Urol 1978 55:366. 17. Beahrs OH, Henson DE: The Manual for Staging of Cancer. AJCC. Philadelphia, Lippincott Raven, 1993. 18. Parmar MKB, Friedman LS, Hargreave TB, et al: Prognostic factors for recurrence follow-up policies in treatment of superficial bladder cancer: report from British Medical Research Council Subgroup on superficial bladder cancer. J Urol 1989; 142:284. 19. Abel PD, Hall RR, Williams G: Should pT1 transitional cell carcinoma of the bladder still be classified as superficial? Br J Urol 1988; 62:235. 20. Heney NM, Nocks BN, Daley JJ, et al: Ta and T1 bladder cancer: location, recurrence, and progression. Br J 1982; 54:152. 21. Williams JL, Hammonds JC, Saunders N: T1 bladder tumors. Br J Urol 1977; 49:663,
22. Birch BRP, Harland SJ: The pT1 G3 bladder tumor. Urology 1989; 64:109. 23. Anderstrom C, Johansson S, Nilsson S: The significance of lamina propria invasion on the prognosis of patient with bladder tumors. J Urol 1980; 124:23. 24. Holmdng S, Hedelin H, Anderstrom C, et al: The relationship among multiple recurrences, progression prognosis of patients with stages Ta and T1 transitional cell carcinoma of the bladder followed for at least 20 years. J Urol 1995; 153:18. 25. Hassui Y, Osada Y, Kitada S, et al: Significance of invasion of the muscularis mucosa on the progression of superficial bladder cancer. Urology 1994; 43:782. 26. Dixon JS, Gosling JA: Histology and fine structure muscularis mucosa of the human urinary bladder. J Anat 1983; 136:265. 27. Younes M, Sussman J, True LD: The usefulness level of muscularis mucosa in the staging of in, transitional cell carcinoma of the urinary bladder. Cancer 1990; 66:543. 28. KIan R, Loy V, Huland H: Residual tumor discovered routine second TUR in patients with T1 transition carcinoma of the bladder. J Urol 1991; 146:316. 29. Lynch CF, Platz CE, Jones MP, et al: Cancer registry problems in classifying invasive bladder cancer. J Natl Inst 1991; 83:429. 30. Abel PB, Henderson D, Bennett MK, et al: Differing interpretations by pathologists of the pT category grade of transitional cell carcinoma of the bladder. Urol 1988; 62:339. 31. Olsen LH, Overgaard S, Frederiksen P, et al: The reliability of staging and grading of bladder tumors: in misinformation of the pathologists’ diagnosis. Scand J Urol Nephrol 1993; 27:349. 32. Witjes JA, Kiemeney LALM, Schaafsma HE, et al: Influence of review pathology on study outcome randomized multicenter superficial bladder cancer trial. Br J Urol 1994; 7(3):172. 33. Richards B, Parmar MKB, Anderson CK, et al: Interpretation of biopsies of “normal” urothelium in patients with superficial bladder cancer. Br J Urol 1991; 67:369. 34. Sidransky D, Frost P, Von Eschenbach A, et al: Clonal 5 origin of bladder cancer. N Engl J Med 1992; 326:737. 35. Harris AL, Neal D: Bladder cancer-field versus clonal origin. N Engl J Med 1992; 326:759. 36. Soloway MS, Murphy W, Rao MK, et al: Serial multiple site biopsies in patients with bladder cancer. J Urol 1978; 120:57. 37. Kakizoe T, Maturnoto K, Nishio Y, et al: Significance of carcinoma in situ and dysplasia in association with bladder cancer. J Urol 1985; 133:395. 38. Kiemeney LALM, Witjes JA, Heijbroek RP, et al: Should random urothelial biopsies be taken from patients with primary superficial bladder cancer? A decision analysis. Br J Urol 1994; 73:164. 39. Hardeman SW, Perry A, Soloway MS: Transitional cell carcinoma of the prostate following intravesical therapy for transitional cell carcinoma of the bladder. J Urol 1988; 140:289.
Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 333 40. Montie JE, Mersky H, Levin HS: Transitional cell carcinoma of the prostate in a series of cystectomies: incidence and staging problems. J Urol 1986; 135:243A. 41. Wolf H, Hojgaard K: Urothelial dysplasia concomitant with bladder tumors as a determining factor for future new occurrences. Lancet 1983; 2(8342):134. 42. Althausen AF, Prout GR, Daly JJ: Noninvasive papillary carcinoma of the bladder associated with carcinoma-insitu. J Urol 1976; 116:575. 43. Smith G, Elton RA, Beynon LL, et al: Prognostic significance of biopsy results of normal looking mucosa in cases of superficial bladder cancer. Br J Urol 1983; 55:665. 44. Olsen PR, Wolf H, Schoeder T, et al: Urothelial atypia and survival rate of 500 unselected patients with primary transitional cell carcinoma of the urinary bladder. Scand J Urol Nephrol 1988; 22:257. 45. Lerman RL, Hulter RVP, Whitmore WF: Papilloma of the urinary bladder. Cancer 1970; 25:333. 46. Cutler SJ, Heney NM, Friedell GH: Longitudinal study of patients with bladder cancer: factors associated with disease recurrence and progression. In Bonney WW, Prout JR (eds): Bladder Cancer, p 35. Baltimore, Williams & Wilkins, 1982. 47. Lutzeyer W, Rubben H, Damm H: Prognostic parameters in superficial bladder cancer: an analysis of 315 cases. J Urol 1982; 127:250. 48. Fitzpatrick JM, West AB, Butler MR, et al: Superficial bladder tumors (stage pTa grades, 1&2): the importance of recurrence pattern following initial resection. J Urol 1986; 135:920. 49. Pagano F, Garbeglio A, Milani C, et al: Prognosis of bladder cancer 1: risk factors in superficial transitional cell carcinoma. Eur Urol 1987; 13:145. 50. Murphy WM, Soloway MS, Jukkola AF, et al: Urine cytology and bladder cancer. Cancer 1984; 53:1555. 51. Murphy WM: Current status of urine cytology in the evaluation of bladder neoplasms. Hum Pathol 1990; 21:886. 52. De Vita R, Forte D, Maggi F, et al: Cellular DNA content and proliferative activity evaluated by flow cytometry versus histopathological staging classifications in human bladder tumors. Eur Urol 1991; 19:65. 53. Gustafson H, Tribukait B, Esposti PL: DNA pattern, histological grade, and multiplicity related to recurrence rate in superficial bladder tumors. Scand J Urol Nephrol 1982; 16:135. 54. Gustafson H, Tribukait B, Esposti PL: DNA profile in tumor progression in patients with superficial bladder tumors. Urol Res 1982; 10:13. 55. Masters JRW, Camplejohn RS, Parkinson MC, et al: DNA ploidy and the prognosis of stage pT1 bladder cancer. Br J Urol 1989; 64:403. 56. Murphy WM, Chandler RW, Trafford RM: Flow cytometry of deparaffinised nuclei compared to histological grading for the pathological evaluation of transitional cell carcinoma. J Urol 1986; 135:694. 57. Newman AJ, Carlton C, Johnson S: Cell surface A,B, O blood group antigen as an indicator of malignant potential in stage A bladder carcinoma. J Urol 1980; 124:27.
58. Richie JP, Blute RD, Waisman J: Immunological indicators of prognosis in bladder cancer: the importance of cell surface antigens. J Urol 1980; 123:22. 59. Blasco E, Tarrado J, Belloso L, et al: T antigen: a prognostic indicator of high recurrence index in transitional cell carcinoma of the bladder. Cancer 1988; 61:1091. 60. Bergman S, Javadpour N: The cell surface antigen as an indicator of malignant potential in stage A bladder cancer. J Urol 1978; 119:49. 61. Sanders H, McCue P, Graham SD: ABO (H) antigens and beta-2 microglobulin in transitional cell carcinoma: predictors of response to intravesical BCG. Cancer 1991; 67:3024. 62. Johl BR, Hartzen SH, Hainau B: Lewis A antigen in transitional cell tumors of the urinary bladder. Cancer 1986; 58:222. 63. Langkilde NC, Wolf H, Milgard P, et al: Frequency and mechanism of Lewis antigen expression in human urinary bladder and colon carcinoma patients. Br J Cancer 1991; 63:583. 64. Golijanin D, Scherman Y, Shapiro A: Detection of bladder tumors by immunostaining of Lewis X antigen in cells from voided urine. Urology 1995; 46:173. 65. Conn IG, Vilela MJ, Garrod DR, et al: Immunohistochemical staining with monoclonal antibody 32-213 to desmosomal glycoprotein 1: its role in the histological assessment of urothelial carcinomas. Br J Urol 1990; 65:176. 66. Smith NW, Stutton GM, Walsh MD, et al: Transferrin receptor expression in primary superficial bladder tumors identifies patients who develop recurrences. Br J Urol 1990; 65:339. 67. Conn IG, Crocker J, Emtage LA, et al: Human milk fat globulin-2 as a prognostic indicator in superficial bladder cancer. J Clin Pathol 1988; 41:1191. 68. Neal DE, Scharples L, Smith K, et al: The epidermal growth factor receptor and the prognosis of bladder cancer. Cancer 1990; 65:1619. 69. Mellow K, Wright C, Kelly P, et al: Long term outcome related to epidermal growth factor receptor status in bladder cancer. J Urol 1995; 153:919. 70. Schapers RFM, Pauwels RPE, Havenith MG, et al: Prognostic significance of type IV collagen and laminin immunoreactivity in urothelial carcinomas of the bladder. Cancer 1990; 66:2583. 71. Sandberg AA: Chromosome markers and progression in bladder cancer. Cancer Res 1977; 37:2950. 72. Waldman FM, Carroll PR, Kerschmann R, et al: Centromeric copy number of chromosome 7 is strongly correlated with tumor grade and labeling index in human bladder cancer. Cancer Res 1981; 51:3807. 73. Fearon ER, Feinberg AP, Hamilton SH, et al: Loss of genes on the short arm of chromosome 11 in bladder cancer. Nature 1985; 318:377. 74. Hopman A, Moesker O, Smeets A, et al: Numerical chromosome 1, 7, 9, 11 aberrations in bladder cancer detected by in situ hybridization. Cancer Res 1991; 51:644. 75. Summers JL, Falor W, Ward R: A 10 year analysis of chromosomes in noninvasive papillary carcinoma of the bladder. J Urol 1981; 125:177.
334
Part IV Bladder
76. Tsai YC, Nichols PW, Hiti AL, et al: Allelic losses of chromosomes 9, 11, and 17 in human bladder cancer. Cancer Res 1990; 50:44. 77. Olumi AF, Tsai YC, Nichols PW, et al: Allelic loss of chromosome 17p distinguishes high grade from low grade transitional cell carcinoma of the bladder. Cancer Res 1990; 50:7081. 78. Agnantis NJ, Constantinidou A, Poulios C, et al: Immunohistochemical study of the ras oncogene expression in human bladder endoscopy specimens. Eur J Surg Oncol 1990; 16:153. 79. Viola MV, Fromowitz F, Oravez S, et al: Ras oncogene p2l. expression is increased in premalignant lesions and high grade bladder cancer. J Exp Med 1985; 161:1211. 80. Feinberg AP, Vogelstein B, Droller MJ, et al: Mutation affecting the 12th amino acid of the c-Ha-ras oncogene product occurs infrequently in human cancer. Science 1983; 220:1175. 81. Lane DP: p53 guardian of the genome. Nature 1991; 358:15. 82. Kasten MB, Onyekwere O, Sidransky D, et al: Participation of p53 protein in the cellular response to DNA damage. Cancer Res 1991; 51:6304. 83. Reich NC, Oren M, Levine AJ: Two distinct mechanisms regulate the levels of cellular tumor antigen p53. Mol Cell Biol 1993; 3:2143. 84. Harris AL: Telling change of base. Nature 1990; 350:377. 85. Fujimoto K, Yamada Y, Okajima E, et al: Frequent association of p53 gene mutation in invasive bladder cancer. Cancer Res 1992; 52:1393. 86. Sidransky D, von Eschenbach A, Tsai YC: Identification of p53 gene mutations in bladder cancers and urine samples. Science 1991; 252:706. 87. Lunec J, Challen C, Wright C, et al: c-erb B-2 amplification and identical p53 mutations in concomitant transitional carcinoma of the renal pelvis and urinary bladder. Lancet 1992; 339:439. 88. Iggo R, Gatter K, Bartek J, et al: Increased expression of mutant forms of p53 oncogene in primary lung cancer. Lancet 1990; 335:675. 89. Sarkis A, Dalbagni G, Cordon-Cardo C, et al: Association of p53 nuclear overexpression and tumor progression in carcinoma-in-situ of the bladder. J Urol 1994; 152:388. 90. Sidransky D, Mikkelsen T, Schwechheimer K, et al: Clonal expansion of p53 mutant cells is associated with brain tumor progression. Nature 1992; 355:846. 91. Oka K, Ishikana J, Bruner JM, et al: Detection of loss of heterozygosity in p53 gene in renal cell carcinoma and bladder carcinoma using the polymerase chain reaction. Mol Carcinog 1991; 4:10. 92. Spruck CH, Ohneseit PF, Gonzales-Sulueta M, et al: Two molecular pathways to transitional cell carcinoma of the bladder. Cancer Res 1994; 54:784. 93. Yoskimura I, Kudoh J, Saito S: p53 gene mutation in recurrent superficial bladder cancer. J Urol 1995; 153:1711. 94. Uchida T, Wada C, Ishida H, et al: p53 mutations and prognosis in bladder tumors. J Urol 1995; 153:1097.
95. Lipponen PK: Overexpression of p53 nuclear oncoprotein in transitional cell bladder cancer and its prognostic value. Int J Cancer 1993; 53:365. 96. Gardiner RA, Walsh MD, Allen S, et al: Immunohistological expression of p53 in primary pT1 transitional cell bladder cancer in relation to tumor progression. Br J Urol 1994; 73:526. 97. Sarkis A, Dalbagni G, Cordon-Cardo C, et al: Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker of disease progression. J Natl Cancer Inst 1993; 85:53. 98. Esrig D, Spruck C, Nichols P, et al: p53 nuclear protein accumulation correlates with mutations in the p53 gene, tumor grade, and stage, in bladder cancer. Am J Pathol 1993; 143:1389. 99. Dalbagni G, Cordon-Cardo C, Reuter V, et al: Tumor suppressor gene alterations in bladder carcinoma translational correlates to clinical practice. Surg Oncol Clin North Am 1995; 4:231. 100. Esrig D, Elmajian D, Groshen S, et al: Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 1994; 331:1259. 101. Sato K, Moriyama M, Mori S, et al: An immunohistological evaluation of c-er17 B-2 gene product in patients with urinary bladder carcinoma. Cancer 1983; 70:2493. 102. Moriyarria M, Akiyama T, Yamamoto T, et al: Expression of c-erli B-2 gene product in urinary bladder cancer. I Urol 1991; 145:423. 103. Masters JR, Vessey SG, Minn CF: c-nzyc oncoprotein levels in bladder cancer. Urol Res 1988; 16:341. 104. Lamm DL, Lamm LM: Benefits of intravesical chemotherapy for superficial disease. Contemp Urol 1989:3. 105. Walker MC, Masters JR, Parris CN, et al: Intravesical chemotherapy: in vitro studies on the relationship between dose and cytotoxicity. Urol Res 1986; 14:137. 106. Goos E, Masters JR: Intravesical chemotherapy: studies on the relationship between osmolality and cytotoxicity. J Urol 1986; 136:399. 107. Cant JD, Murphy WM, Soloway MS: Prognostic significance of urine cytology on initial follow up after intravesical mitomycin C for superficial bladder cancer. Cancer 1986; 57:2119. 108. Haaf EO, Dresner SM, Ratliff TL, et al: Two courses of intravesical bacillus Calmette-Guérin for transitional cell carcinoma of the bladder. J Urol 1986; 136:820. 109. Eure GR, Cundiff MR, Shellharnmer PF: Bacillus Calmette-Guérin therapy for high risk stage TI superficial bladder cancer. J Urol 1992, 152:376. 110. Soloway MS, Perito PE: Superficial bladder cancer: diagnosis, surveillance and treatment. J Cell Biochem 1992; 161(Suppl):120. 111. Soloway MS: Surgery and intravesical chemotherapy in the management of superficial bladder cancer. Semin Urol 1983; 11:23. 112. Prout GR Jr, Koontz WW Jr, Coombs LJ, et al: Longterm fate of 90 patients with superficial bladder cancer randomly assigned to receive or not to receive thiotepa. J Urol 1983; 130:677.
Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 335 113. MRC Working Party on Urological Cancer, Subgroup on Superficial Bladder Cancer: The effect of intravesical thiotepa on tumor recurrence after endoscopic treatment of newly diagnosed superficial bladder cancer. A further report with long-term follow-up of a Medical Research Council randomized trial. Br J Urol 1994; 73:632. 114. Soloway MS: Rationale for intensive intravesical chemotherapy for superficial bladder cancer. J Urol 1980; 123:461. 115. Soloway MS, Jordan AM, Murphy WM: Rationale for intravesical chemotherapy in the treatment and prophylaxis of superficial transitional cell carcinoma. Prog Clin Biol Res 1989; 310:215. 116. Soloway MS, Ford KS: Thiotepa-induced myelosuppression: review of 670 bladder instillations. J Urol 1983; 130:889. 117. Koontz WW Jr, Heney NM, Barton B, et al: Intravesical effects of mitomycin C in patients with superficial bladder carcinoma who have previously failed therapy with thiotepa. Urology 1985; 26:30. 118. Heney NM: First-line chemotherapy of superficial bladder cancer: mitomycin C versus thiotepa. Urology 1985; 26:27. 119. Soloway MS: Diagnosis and management of superficial bladder cancer. Semin Surg Oncol 1989; 5:247. 120. Huland H, Otto J, Droese M, et al: Long-term mitomycin C instillation after transurethral resection of superficial bladder carcinoma: influence on recurrence, progression, and survival. J Urol 1984; 132:27. 121. Maier U, Hobarth K: Long-term observation after intravesical metaphylaxis with mitomycin C in patients with superficial bladder tumors. Urology 1991; 37(5):481. 122. Tolley DA, Parmar MKB, Grigor KM, et al: The effect of intravesical mitomycin C on recurrence of newly diagnosed superficial bladder cancer: a further report with 7 years’ follow-up. J Urol 1996; 155:1223. 123. Nissenkorn I, Herrod H, Soloway MS: Side effects associated with intravesical mitomycin. J Urol 1981; 126:596. 124. Batts CN: Adjuvant intravesical therapy for superficial bladder cancer. Ann Pharmacother 1992; 26:1270. 125. Niijima T, Koiso K, Adaza H: Randomized clinical trial for chemoprophylaxis of recurrence in superficial bladder cancer. In Spitzy KH, Karrer K (eds): Proceedings of the 13th International Congress of Chemotherapy, pp 240–246, Vienna, 1983. 126. Kurth KH, Debruyne FJM, Senge T, et al: Adjuvant chemotherapy of superficial transitional cell carcinoma: an EORTC randomized trial comparing doxorubicin hydrochloride, ethoglucid and TUR-alone. Prog Clin Biol Res 1985; 162A:135. 127. Zincke H, Utz DC, Taylor WF, et al: Influence of thiotepa and doxorubicin instillation at time of transurethral surgical treatment of bladder cancer on tumor recurrence: a prospective, randomized, doubleblind, controlled trial. J Urol 1983; 129:505. 128. Llopis B, Gallego J, Mompo JA, et al: Thiotepa versus Adriamycin versus cis-platinum in the intravesical prophylaxis of superficial bladder tumors. Eur Urol 1985; 11:73.
129. Lamm DL, Blumenstein BA, Crawford ED, et al: A randomized trial of intravesical doxorubicin and immune-therapy with bacille Calmette-Guérin for transitional cell carcinoma of the bladder. N Engl J Med 1991; 325:1205. 130. Jackse G, Hofstadter F, Marsberger H: Topical doxorubicin hydrochloride therapy for carcinoma in situ of the bladder: a follow-up. J Urol 1984; 131:41. 131. Ausfield A, Beer M, Muhlethale J, et al: Adjuvant intravesical chemotherapy of superficial bladder cancer with monthly doxorubicin of intensive mitomycin: a comparison of two consecutive series. Eur Urol 1987; 13:10. 132. Sweatman TW, Parker RF, Israel M: Pharmacologic rationale for (AD-32): a preclinical study. Cancer Chemother Pharmacol 1991; 28:1. 133. Greenberg R, O’Dwyer F, Patterson L, et al: Intravesical AD-32 (N-trifluoroacetyladriamycin-14-valerate) in the treatment of patients with refractory bladder carcinoma—clinical efficacy, pharmacology, and safety. J Urol 1995; 153:233A. 134. Morales AM, Eidinger D, Bruce AW: Intracavitary bacillus Calmette-Guérin in the treatment of superficial bladder tumors. J Urol 1976; 116:180. 135. Guerin C: The history of BCG. In Rosenthal SR (ed): BCG Vaccination Against Tuberculosis, p 35. Boston, Little Brown & Co, 1957. 136. Ratliff TL, Haaff EO, Catalona WJ: Interleukin 2 production during intravesical bacillus Calmette-Guérin therapy for bladder cancer. Clin Immunol Immunopathol 1986; 40:375. 137. Brosman S: Bacillus Calmette-Guérin immunotherapy: techniques and results. Urol Clin North Am 1992; 19(3):557. 138. Lamm DL, Crawford ED, Blumenstein B, et al: Maintenance BCG immunotherapy of superficial bladder cancer: a randomized prospective Southwest Oncology Group Study (Abstract 242). J Urol 1992; 147(part 2): 274A. 139. Lamm DL: BCG in carcinoma-in-situ and superficial bladder tumors. EORTC Genitourinary Group. Monograph 1988; 5:497. 140. Herr HW, Laudone VP, Whitmore WF: An overview of intravesical therapy for superficial bladder tumors. J Urol 1987; 138:1363. 141. Dejager R, Guinan F, Lamm D, et al: Long-term complete remission in bladder carcinoma in situ with intravesical Tice bacillus Calmette-Guérin: overview analysis of six phase 11 clinical trials. Urology 1991; 38:507. 142. Herr HW: Intravesical BCG: current results, natural history and implications for urothelial cancer prevention. J Cell Biochem 1992; 161(Suppl):112. 143. Herr HW, Schwalb DM, Zhang ZF, et al: Intravesical bacillus Calmette-Guérin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial. J Clin Oncol 1995; 13:1404. 144. Brosman SA: Experience with bacillus Calmette-Guérin in patients with superficial bladder carcinoma. J Urol 1982; 128:27.
336
Part IV Bladder
145. Martinez-Pineiro JA: BCG vaccine in superficial bladder tumors: eight years later. Eur Urol 1989; 142:719. 146. Lamm DL, Crissinan J, Blumenstein BA, et al: Adriamycin versus BCG in superficial bladder cancer: a Southwest Oncology Group study. In Debruyne FMJ, van der Meijden APM (eds): BCG in Superficial Bladder Cancer, p 123. New York, Alan R Liss, 1989. 147. Vegt PDJ, Witjes JA, Wities WPJ, et al: A randomized study of intravesical mitomycin C, bacillus CalmetteGuérin Tice and bacillus Calmette-Guérin RIVM treatment in pTa-pT1 papillary carcinoma and carcinoma in situ of the bladder. J Urol 1995; 153:929. 148. Cookson MS, Sarosdy MF: Management of stage T1 superficial bladder cancer with intravesical bacillus Calmette-Guérin therapy. J Urol 1992; 148:797. 149. Nadler RB, Catalona WJ, Hudson MA, et al: Durability of the tumor-free response for intravesical bacillus Calrnette-Guérin therapy. J Urol 1994; 152:367. 150. Lamm DL: Complications of bacillus Calmette-Guérin immunotherapy. Urol Clin North Am 1992; 19:565. 151. Nelson B, Borden E: Interferons: biological and clinical effects. Semin Surg Oncol 1989; 5:391. 152. Sargent ER, Williams RD: Immunotherapeutic alternatives in superficial bladder cancer: interferon, interleukin 2 and keyhole limpet hemocyanin. Urol Clin North Am 1992; 19(3):581. 153. Torti F, Shortliffe L, Williams R, et al: Alpha-interferon in superficial bladder cancer: a Northern California Oncology Group study. J Clin Oncol 1988; 6:476. 154. Glashan RW: A randomized controlled study of intravesical et-2b-interferon in carcinoma in situ of the bladder. J Urol 1990; 144:658. 155. Olsson D, Rao C, Menzoian J, et al: Immunologic unreactivity in bladder cancer patients. J Urol 1972; 107:607. 156. Jurinic C, Engelmann U, Gasch J: Immunotherapy in bladder cancer with keyhole-limpet hemocyanin: a randomized study. J Urol 1988; 139:723. 157. Wierenga. W: Antiviral and other bioactivities of pyrimidinones. Pharmacol Ther 1985; 30:67. 158. Sarosdy MF, Lamm DL, Williams RD, et al: Phase I trial of oral bropirimine in superficial bladder cancer. J Urol 1992; 147:31. 159. Sarosdy MF, Lowe BA, Schellhammer PF, et al: Bropirimine immunotherapy of bladder CIS: positive phase 11 results of an oral interferon inducer. J Urol 1994; 13:304A. 160. Herr HW, Wartinger DD, Fair WR, et al: Bacillus Calmette-Guérin therapy for superficial bladder cancer: a ten year follow-up. J Urol 1992; 147:1020. 161. Zinke H, Utz DC, Farrow GM: Review of Mayo Clinic experience with carcinoma-in-situ. Urology 1985; 26(Suppl):39. 162. Matzkin H, Soloway MS, Hardeman S: Transitional cell carcinoma of the prostate. J Urol 1991; 146:1207. 163. Wood D, Montie J, Pontes J, et al: Transitional cell carcinoma of the prostate in cystoprostatectomy specimens removed for bladder cancer. J Urol 1989; 141:346. 164. Seemayer TA, Knaack J, Thelmo W, et al: Further observations on carcinoma-in-situ of the urinary bladder:
165.
166.
167.
168.
169.
170. 171.
172.
173.
174.
175. 176.
177.
178.
179.
180.
181.
182.
silent but extensive intraprostatic involvement. Cancer 1975; 36:514. Hardeman S, Soloway M: Transitional cell carcinoma of the prostate: diagnosis, staging and management. World J Urol 1988; 6:170. Hardeman S, Perry A, Soloway MS: Transitional cell carcinoma of the prostate following intravesical therapy for transitional cell carcinoma of the bladder. J Urol 1988; 140:289. Herr H, Pinsky C, Whitmore W, et al: Long term effect of intravesical bacillus Calmette-Guérin on flat carcinoma-in-situ of the bladder. J Urol 1986; 135:265. Bretton P, Herr H, Whitmore W, et al: Intravesical bacillus Calmette-Guérin therapy for in-situ transitional cell carcinoma of the prostatic urethra. J Urol 1989; 141:853. Hillyard R, Ladaga L, Schellhammer P: Superficial transitional cell carcinoma of the bladder associated with mucosal involvement of the prostatic urethra: results of treatment with intravesical bacillus Calmette-Guérin. J Urol 1988; 139:290. Hardeman S, Soloway MS: Urethral recurrence following radical cystectomy. J Urol 1990; 144:666. Schellhammer P, Bean M, Whitmore W: Prostatic involvement by transitional cell carcinoma: pathogenesis, patterns, and prognosis. J Urol 1977; 118:399. Hudson M: When intravesical measures fail: indications for cystectomy in superficial disease. Urol Clin North Am 1992; 19:601. Soloway MS, Lopez A, Patel J, et al: Results of radical cystectomy for transitional cell carcinoma of the bladder and the effect of chemotherapy. Cancer 1994; 73:1926. Amling C, Thraser J, Frazier H, et al: Radical cystectomy for stages Ta, Tis, & T1 transitional cell carcinoma of the bladder. J Urol 1994; 151:31. Bracken RB, McDonald WW, Johnson DE: Cystectomy for superficial bladder cancer. Urology 1981; 18:459. Malkowicz SB, Nicols P, Lieskovsky G, et al: The role of radical cystectomy in the management of high grade superficial bladder cancer (pA, p1, pis, & p2). J Urol 1990; 144:641. Pagano F, Bassi P. Galetti TP, et al: Results of contemporary radical cystectomy for invasive bladder cancer: a clinicopathological study with an emphasis on the inadequacy of tumor, nodes and metastases classification. J Urol 1991; 145:45. Smith JA: Laser surgery for transitional cell carcinoma. Technique, advantages and limitations. Urol Clin North Am 1992; 19(3):473. Tarantino A, Aretz T, Libertino J, et al: Is the neodymium YAG laser effective therapy for invasive bladder cancer? Urology 1991; 38:514. Herr H: Outpatient flexible cystoscopy and fulguration of recurrent superficial bladder tumors. J Urol 1990; 144:1365. Bianchi G, Nevelli P, Beltrami P, et al: Small urothelial carcinoma: diagnosis and treatment by cold cup forcep biopsy. J Urol 1990; 144:872. Reading J, Hall RR, Parmar MKB: The application of prognostic factor analysis for Ta/T1 bladder cancer in routine urological practice. Br J Urol 1995; 75:604.
Chapter 18 Superficial Transitional Cell Carcinoma of the Bladder 337 183. Morris SB, Gordon EM, Shearer RJ, et al: Superficial bladder cancer: how long should a tumor-free patient have check cystoscopies? Br J Urol 1995; 75:193. 184. Sheinfeld J, Reuter VE, Melamed MR, et al: Enhanced bladder cancer detection with the Lewis X antigen as a marker of neoplastic transformation. J Urol 1990; 143:285. 185. Sarosdy MF, De Vere White RW, Soloway MS, et al: Results of a multicenter trial using the BTA test to monitor for and diagnose recurrent bladder cancer. J Urol 1995; 154:379. 186. Korman HJ, Peabody JO, Cerny JC, et al: Autocrine motility factor receptor as a possible urine marker for transitional cell carcinoma of the bladder. J Urol 1996; 155:347. 187. Booth CM, Kellett MJ: Intravenous urography and the follow-up of carcinoma of the bladder. Br J Urol 1981; 53:246.
188. Miller EB, Eure GR, Schellharnmer PF, et al: Upper tract transitional cell carcinoma following treatment of superficial bladder cancer with BCG. Urology 1993; 42(l):26. 189. O’Donnell MA, Krohn J, DeWolf WC: Salvage intravesical therapy with interferon-α2b plus low dose bacillus Calmette-Guérin is effective in patients with superficial bladder cancer in whom bacillus CalmetteGuérin alone previously failed. J Urol 2001; 166:1300–1305. 190. Soloway MS, Sofer M, Vaidya A:. Contemporary management of stage T1 transitional cell carcinoma of the bladder. J Urol 2002; 167:1573–1583.
C H A P T E R
19 Prognosis and Management of Invasive Transitional Cell Carcinoma J. Matthew Hassan, MD, Sam S. Chang, MD, Michael S. Cookson, MD, and Joseph A. Smith, Jr, MD
Fifty-four thousand new cases of bladder cancer are diagnosed each year. It is the second most common genitourinary cancer and results in over 12,000 cancer-related deaths annually.1 Twenty percent to 25% of newly diagnosed bladder cancer consist of muscle-invasive disease,2 with the majority of these invasive bladder cancers demonstrating invasion at the time of diagnosis.3 While tumor grade and stage do influence progression, only approximately 15% of superficial tumors will eventually develop the characteristic features of muscle-invasion.4–6 For those that become muscle-invasive, however, the risk of metastasis and mortality unquestionably and dramatically rises.7 More than 90% of invasive and noninvasive bladder tumors are transitional cell carcinomas (TCCs). Invasive bladder cancer, however, can be of squamous cell carcinoma (3%), adenocarcinoma (2%), or small cell carcinoma (<1%) origin. TCCs may also contain focal areas of squamous or glandular differentiation. These have been traditionally classified and managed as TCC, but future investigation may demonstrate that these histologic variants are in fact associated with different outcomes and should be treated as different pathologic entities. This chapter will deal specifically with the prognosis and management of invasive TCC of the bladder. The management of muscle-invasive and metastatic TCC continues to evolve. The advent of multimodality therapy has begun to challenge the traditional view of radical cystectomy as the “gold standard” treatment for muscle-invasive bladder cancer. A multitude of new information about the cellular mechanisms and biology of bladder cancer has led to trials ultimately designed to improve patient outcome and survival. Herein, we will review the principles and concepts behind the biology of
338
muscle-invasive TCC, as well as current treatment recommendations with regards to surgery, adjunctive systemic therapy, and alternative therapies. TUMOR EXTENT EVALUATION Stage and Grade Transurethral resection (TUR) of a bladder tumor yields vital information to the urologist. The objective is to remove all visible tumors, if possible, and obtain tissue for pathologic evaluation. The two most commonly used prognostic indicators, clinical stage and histologic grade of the cancer, can be determined from this operative procedure. TUR under anesthesia is both diagnostic and therapeutic, especially in cases of superficial disease. Invasive bladder cancer consists of malignant transitional epithelial cells that extend beyond the connective tissue of the lamina propria and into the muscularis propria (T2) and surrounding perivesical fat and soft tissues (T3,4). For this reason, the presence of muscle detrusor cells in the resected tissue is essential to provide pathologic evidence of muscle invasion. Local muscular invasion classically has been described by three mechanisms.8 The majority (60%) advance “en bloc,” as a broad face below the primary epithelial lesion. Twenty-five percent spread with tentacle-like fronds. The remainder (10% to 15%) spread by laterally encroaching under normal adjacent mucosa. A more modern biochemical interpretation involves concepts of stimulation of neovascularization, the regulation of cellular motility, and the avoidance of detection from cellular surveillance mechanisms. The presence and degree of local invasion has been closely linked to poor outcomes both in time to metastasis
Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 339
and time to cancer-related death. According to the National Cancer Data Base, the overall 5-year survival rates for Ta, T1, T2, T3, and T4 tumors are 90%, 87%, 65%, 48%, and 23%, respectively.7 In other studies, the median survival for T2 tumors is 85 months, whereas for T4 tumors, the median survival is 29 months.9 Furthermore, a recent review of 1636 cases demonstrated a significant variation with stage and survival following radical cystectomy; 63% of patients with T2 disease survived 5 years, while only 18% of those with T4 disease survived as long.10 There is clear and persuasive evidence to suggest that the depth of infiltration correlates with curability of TCC. While this review focusses on muscle-invasive bladder cancer, there are forms of non–muscle-invasive TCC that have such a high propensity to invade that they merit inclusion. Carcinoma in situ (CIS) is confined to the urothelium, but 20% of patients treated with cystectomy for CIS are found to contain some elements of microscopic invasion.11 Between 40% and 83% of CIS tumors will ultimately progress to muscle-invasion.5 Likewise, T1 tumors have been shown to become invasive about one-half of the time.12 In addition, one-third have involvement of the posterior urethra, which, as discussed later, affects surgical treatment options.13 Pathologic T1 tumors may require a different surgical management than other noninvasive bladder tumors because of their propensity for invasion.14 Recently revised recommendations of management of high-grade (II and III) T1 cancers include transurethral re-resection of the previous tumor bed because incomplete resection is closely linked with invasion15,16 and because of the risk of understaging.17 In addition to tumor depth, the grade, or the degree of differentiation, of the tumor cells is of critical prognostic significance.18 Grading has traditionally been applied to superficial tumors to predict recurrence or progression.19,20 Patients with grade 1 and grade 2 tumors have approximately 10% risk of developing muscle-invasion, whereas one-third of patients with grade 3 tumors will eventually have invasive disease.21 More recently, efforts to grade muscle-invasive components have not demonstrated any prognostic significance in T2 disease.22 Other less commonly used methods to detect invasive disease and predict its course, such as the use of DNA ploidy and the expression of various growth factors and cell-cycle regulators, will be addressed in detail later. Metastatic Evaluation Prior to proceeding with management of locally invasive bladder cancer, the physician must determine the systemic extent of the tumor, specifically, if the cancer has metastasized. A close correlation between muscle-invasion and distant metastasis has been well documented.23 The most
frequent sites of metastasis are the pelvic lymph nodes. Among the pelvic lymph nodes, the obturator nodes and the external iliac nodes are involved most commonly in cases with positive nodes, 74% and 65% of the time, respectively. The presacral nodes (25%), common iliac nodes (20%), and paravesical nodes (16%) are involved with TCC less often.24 Other distant sites of metastasis for TCC include bone, lung, skin, liver, and less commonly, the brain and meninges.25 Few patients with distant metastases survive 5 years.26 Clearly, the identification of metastasis affects the decision-making process for tumor thought to be locally invasive. In order to complete the pretreatment clinical staging, the urologist must survey the patient to detect the most common metastatic lesions. In addition to performing a full physical examination, including bimanual palpation of the bladder before and after tumor resection,27 laboratory studies, such as renal and hepatic function panel, should be performed. In addition, a chest radiograph is appropriate to document evidence of pulmonary nodules consistent with tumor metastasis. Often, the initial test performed in evaluation of TCC is a computerized tomographic (CT) scan of the abdomen and pelvis.28,29 While this is a simple test and may assist in the detection of distant metastatic lesions, bulky retroperitoneal adenopathy, or obstructive hydroureteronephrosis, it has repeatedly been shown to be inaccurate in assessing the stage of the primary cancer, especially with small volume pelvic nodal disease.30,31 In addition to understaging tumors by not reliably detecting pelvic lymphadenopathy, CT also can overstage tumors because of the difficulty in distinguishing postbiopsy edema from residual tumor. Despite these shortcomings, CT scan remains the standard preoperative staging test. Because CT scanning is inadequate to detect pelvic nodes, MRI has been studied to determine better the extent of tumor.32,33 MRI can be particularly beneficial in patients who have renal insufficiency or a contrast allergy and cannot tolerate CT. The rate of detection of microscopic metastasis has compared similarly to CT,34 but some advocate its use in the staging of patients with deeply invasive TCC.35 There is still a significant amount of “mis-staging” (40%) of bladder tumors with MRI.36 Combined with its high cost, these doubts reduce the frequency of its use. Future advances in MRI, including endorectal coil enhancement37 and dynamic contrast imaging,38 may make it more accurate, but they have not been validated. The role of PET scanning has also been investigated for use in invasive TCC.39–41 An intrinsic problem is that fluoro-deoxy-glucose (FDG), the most commonly used radiopharmaceutical, is unsuitable for evaluation of bladder cancer due to intense accumulation in the urine.42 Because of this inability to image the bladder, efforts have been made to employ more specific tracers, which are not
340
Part IV Bladder
excreted in the urine. Early studies indicate that carbon-11 labeled choline may be helpful.43 Again, the cost of the study and current inaccuracies, however, make PET impractical for routine use. The most likely use of PET scanning in invasive bladder cancer may be to assist in detection of positive lymph nodes or distant metastatic lesions. The most accurate method to stage regional lymph nodes remains surgical, regional lymph node dissection. Performed as a separate procedure, it can reliably distinguish N+ from N0 patients and can be performed laparoscopically.44 While most believe there is an insignificant risk of port site tumor recurrence,45 others have argued that the risk may be greater in patients with bladder cancer. One study shows a 4% risk of port site recurrence following pelvic node dissection for bladder cancer compared to a negligible risk following lymphadenectomy for prostate cancer.46 The reason for this discrepancy between TCC and other genitourinary malignancies is unclear. The majority of time, however, regional lymph node dissection is performed at the time of radical cystectomy at a single operative setting. PROGNOSIS OF INVASIVE TRANSITIONAL CELL CARCINOMA Even in organ-confined, muscle-invasive bladder cancer (stage pT2N0M0) treated by radical cystectomy, approximately 50% of patients ultimately develop recurrences. In one recent study of 594 patients with organ-confined invasive cancer treated locally, 44% relapsed.47 Others have also shown 5-year survival rates following cystectomy for locally invasive bladder cancer to be 38% to 64%.7,48–51 Most patients with occult metastases develop overt clinical evidence of distant metastasis within 1 year.25 The above data imply that the current clinical staging and histologic grading systems on which urologists rely are insufficient. Except for the patients with extensive local disease or bulky lymphadenopathy, contemporary preoperative evaluation continues to understage patients with invasive TCC. While significant thought has been devoted to which superficial tumors will progress to invasion, equally intense research effort has been devoted to predicting which invasive tumors will metastasize. What has been shown is that there is a vast degree of biological heterogeneity to urothelial cancer. By combing through this cellular variability, it may be possible to identify particular genetic characteristics that will predict failure of conventional therapy. The identification of any prognostic factors for muscle-invasive bladder cancer would be of critical clinical utility. Advances in molecular genetics may provide the opportunity to better determine an invasive bladder tumor’s biological potential.52 One of the newest tech-
niques used in the investigation of TCC is cDNA microarrays. This is a high output method of studying the expression of thousands of genes on one tumor extract on a single slide rapidly and reproducibly. Many groups are employing this technique to try and determine the molecular profile of TCC.53–55 It is becoming apparent that there may not be a uniform treatment for every patient with muscle-invasive bladder cancer. Rather, clinically relevant subsets of bladder cancer patients may be identified, and selective treatments may be required for patients with specific tumor characteristics.56 While many correlations have been made with tumor progression, the use of markers has not been accepted into standard practice yet.57 The molecular changes that occur in the progression of invasive bladder cancer have been examined as potential prognostic factors and can be organized into 3 categories: (1) chromosomal alterations; (2) cell adhesion molecules and angiogenesis; and (3) loss of cell-cycle regulation involving tumor suppressor genes and oncogenes. Chromosomal Abnormalities As in many malignancies, the role of chromosomal abnormalities and DNA cytometry has been evaluated for bladder cancer.58 Abnormal number of chromosomes and chromosomes of abnormal morphology have been associated with an increased risk of bladder cancer recurrence and progression.59,60 Several studies correlate polysomy, especially of chromosome 7, or aneuploidy with progression of superficial bladder cancer.61–64 There has been very little work, however, that can demonstrate the same prognostic significance for muscle-invasive transitional carcinoma. In invasive cancer, DNA ploidy does not appear to statistically correlate with invasive cancer in stage, tumor recurrence, lymph node metastasis, or survival.65–67 In addition, abnormal chromosomal number or configuration has not been correlated with response to treatment. In patients with muscle-invasive disease, DNA ploidy has not predicted outcome for those receiving either preoperative radiation therapy68,69 or neoadjuvant chemotherapy.70 Growth Events The progression of TCC to invasion and metastasis requires a cascade of molecular events. Malignant cells must extend beyond their boundaries into the lamina propria and subsequently, the muscularis mucosa and perivesical fat. This process relies on cellular motility, proteolysis, proliferation, and angiogenesis. There is mounting evidence to suggest that alterations in the molecules that govern cell growth enable this progression. In addition, if one is able to detect at the molecular level these processes, one may identify a real-time marker for
Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 341
progression. The two most investigated of these growth control markers as indicators of prognostic significance in invasive TCC are cell adhesion molecules and angiogenesis factors. Cell Adhesion Molecules Various properties of neoplastic cells are altered, which enables invasion. These involve the relationship between cells, components of the extracellular matrix, and the underlying basal lamina. The physical relationships between cells are controlled by cell adhesion molecules like cadherins. E-cadherin, in particular, has been investigated and has been demonstrated to be a critical factor in facilitating the progression of bladder cancer.71 Not only is loss of E-cadherin associated with an invasive phenotype but also its normal expression decreases in direct proportion to the tumor stage.72 Others have also shown abnormal E-cadherin expression to be an independent predictor of disease progression following cystectomy, demonstrating an inverse relationship with stage, grade, likelihood of lymph node metastasis, and even overall survival.73 Investigation is also being performed on the prognostic value of E-cadherin-related cytoplasmic molecules. Cadherin function requires an intact network of catenins to network through the cytoskeleton. Abnormal expressions of alpha-, beta-, and gamma-catenin have been shown to significantly correlate with tumor stage, grade, and survival in patients with invasive bladder cancer.74 Other cellular adhesion molecules include the integrins family, which are transmembrane proteins that link epithelial cells to each other and the basal membrane. Critical cell–cell interaction occurs via integrins and the anchoring complex of desmosomes. In addition to contributing to the spread of CIS,75 abnormal expression of integrins have been linked to the proliferation of invasive bladder cancer. It has been shown that loss of the coexpression of alpha-6-beta-4 integrin and collagen VII, a component of this extracellular network, is prominent in progressively invasive urothelial cancer.76 Malignant urothelium has also been associated with abnormal expression of other cell-surface molecules like epidermal growth factor receptors. The interaction of these signaling molecules induces a wide variety of changes within the cell nucleus, including mitosis. Abnormal expression or production of these gene products may therefore upregulate growth and promote cancer cell motility.77 Multiple groups have demonstrated that the traditional signs of tumor aggressiveness, such as stage, grade, and survival, correlate with abnormal expression of epidermal growth factor.78–81 Cellular motility through the extracellular matrix relies on an array of enzymes like collagenases, which provide proteolysis. One such family of enzymes is the matrix
metalloproteinases, that contribute to the destruction of the basement membrane. Their role in the process of invasion of superficial tumors has been well described.82 Matrix metalloproteinases, however, have been suggested to play a role in the progression of invasion to metastasis as well.83 Their expression has been shown to be of prognostic significance in those patients who develop recurrence of their TCC following what appeared to be complete extirpation of their invasive cancers.84 Angiogenic Factors Like all solid tumors, TCC of the bladder requires angiogenesis to promote progression and growth. The angiogenic phenotype—the sum of the balance of stimulatory and inhibitory signals to the endothelium—not only determines the degree of neovascularity but also is evolving into an important prognostic factor in the outcome of bladder cancer.85 Some of the variables, which have been studied, include vascular endothelial growth factor (VEGF), thrombospondin-1 (TSP-1), and microvascular density. Several groups have looked at VEGF as a mediator of tumor angiogenesis. The VEGF serum level in patients with bladder cancer was significantly associated with tumor stage, grade, vascular invasion, and metastasis.86 VEGF expression has also been identified by multivariate analysis as a significant predictor of disease recurrence in patients who have undergone cystectomy with neoadjuvant chemotherapy.87 Thrombospondin-1 (TSP-1), an important component of the extracellular matrix, has also been identified as a potential prognostic angiogenic factor. It is a potent inhibitor of neovascularity and a reduction in its gene expression has been associated with disease progression of superficial TCC.88 Other groups have examined TSP1 expression in invasive disease. TSP-1 was significantly associated with disease recurrence and overall survival but not seen to behave independently of other tumor markers like p53.89 This may indicate that TSP-1 may have some inhibitory function but may be one mechanism of action of p53. A different method of quantifying vascular development is to evaluate microvessel density (MVD). MVD has been shown to be independently influential to disease recurrence and survival in muscle-invasive bladder cancer.87,90–92. In patients with an elevated MVD, there is a significantly higher rate of occult lymph node metastases in patients with clinically localized disease.93 Histologic efforts to assess other shape-related morphometric characteristics of the microvascularization as indicators of significant neovascularity have been demonstrated in superficial disease. In muscle-invasive disease, however, MVD is the only significant histologic indicator of prognosis that has been identified.94
342
Part IV Bladder
While a majority of studies have found a positive correlation between MVD and worsening prognosis, not all reports concur. Some have found MVD to be not significantly associated with lymph node status in patients with high-stage, high-grade bladder cancer.66 As will be addressed, many of the intergroup outcome variability may be secondary to differing treatments. It remains to be seen how treatment affects the upregulation of these various markers of progressive invasion.
As suggested earlier, not all investigators have found a direct link between p53 expression and prognosis in patients with muscle-invasive disease. One group found no correlation between mutation in the p53 and cancerspecific survival. Also, it has held no prognostic value in patients with T3b or greater disease106 or node-positive disease.107 These varying results may be due to multiple reasons including differences in assays, technique, and tumor heterogeneity.
Cell-Cycle Regulators—p53
Cell-Cycle Regulators—Others
TCC is thought to develop from genetic changes, which affect cell growth and proliferation. Two such genes, which can regulate the cell cycle, are tumor suppressor genes and proto-oncogenes. Both have been extensively studied in TCC.95 The p53 is a tumor suppressor gene located on chromosome 17p. It encodes a 5-kD protein that induces apoptosis in cells with evidence of DNA damage. Approximately one-half of all human cancers have evidence of mutations in the p53 gene.96 These mutations permit unabated cell growth by disrupting normal cellcycle checkpoints and apoptosis.97 There is evidence to support that p53 may also act by promoting other angiogenic factors already mentioned, such as VEGF and TSP-1,98 although this is debated particularly in the angiogenesis of bladder cancer.99 There is a vast amount of evidence to suggest that the dysregulation of p53 is critical in the development of TCC.100 When p53 undergoes mutation, its half-life typically increases, which causing accumulation of p53 in the cell nuclei. Advances in immunohistochemistry and molecular genetics have allowed researchers to detect easily the cellular buildup of abnormal p53. p53 mutations occur in the pathogenesis of TCC relatively early, and researchers have attempted to correlate varying expressions of abnormal p53 with patient outcome.101 While p53 has been associated with high rate of tumor progression in high-risk superficial disease,102 there has been inconsistent evidence to suggest the same for invasive bladder cancer. The nuclear overexpression of mutant p53 does appear to be more common in muscle-invasive disease according to a large meta-analysis from the International Study Initiative on Bladder Cancer. Of 1706 patients, p53 mutations appeared in only 25% of superficial disease versus 48% of muscle-invasive disease.103 It has been shown that nuclear overexpression in T2 or greater disease is associated with a worse prognosis, resulting in higher stage and grade, earlier development of metastases, and decreased survival.104,105 In other studies, p53 status was the only independent predictor of survival in those patients with clinically localized disease at the time of cystectomy.106
Other molecules that regulate the cell cycle have been associated with bladder cancer, and thus, have been investigated for their potential prognostic significance when detected in abnormal levels. One such gene is the retinoblastoma gene. It appears on chromosome 13q and when its protein product is phosphorylated by cyclindependent kinases, it activates genes critical to DNA replication. The retinoblastoma gene appears mutated in approximately one-third of bladder tumors.108 Loss of normal retinoblastoma function has been shown to result in statistically significant higher grade of TCC, along with a higher likelihood of invasion.109 Others have shown that abnormal expression of retinoblastoma in patients who have undergone radical cystectomy for muscle-invasive disease has a significant higher rate of recurrence and decreased survival.110 Interestingly, in the same study, those with both retinoblastoma dysregulation and p53 mutation fared more poorly than either individually. This may suggest a synergistic relationship between retinoblastoma and p53 in the promotion of tumor progression. Similarly, any other genetic mutation that affects the cyclin-dependent kinase systems, which phosphorylate the retinoblastoma gene product, may also promote cellular proliferation and malignant transformation.111 The p21 is a ras oncogene that transduces signals from the cell membrane to the nucleus and is actually induced by wildtype p53.112 This particular kinase inhibitor, under altered expression, has been shown to contribute to tumor progression. Mutated p21 emerges in several studies as an independent indicator of increased likelihood of recurrence and of decreased disease-free survival in patients undergoing radical cystectomy for muscle-invasive disease.113,114 A deficiency of p21 expression has also been shown to be correlated with poor response following systemic chemotherapy115 and radiation therapy.116 Another oncogene that has been suggested as a useful prognostic index for bladder cancer is erb-B-2. This oncogene codes for a growth factor receptor, which is functionally related to epidermal growth factor receptor. Its amplification and overexpression have been implicated as prognostic markers for recurrent superficial bladder tumors.117 Researchers, however, have been
Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 343
unable to link protein overexpression to tumor stage, grade, or disease progression in invasive bladder cancer patients.118,119. In terms of invasive TCC, erb-B-2 appears to not possess much predictive value at the present time. Transforming growth factor (TGF) is both a cellular regulator and a potent angiogenic factor. Serum levels of TGF have been shown to be more elevated in patients with muscle-invasive cancer than with superficial cancer.120 A recent work suggests that preoperative TGFbeta was an independent predictor of lymph-vascular invasion, lymph node metastasis, disease recurrence, and cancer-specific survival.121 Genetic Determinants of Treatment Response While the cellular components of TCC may someday elucidate its degree of aggressiveness, these markers may also serve to predict and determine tumor responsiveness to systemic chemotherapy. Theoretically, the molecules critical to cellular proliferation could modify tumor response by impairing apoptosis and altering cell-cycle kinetics. Thus, they may provide further prognostic information for patient management. The p53 tumor suppressor gene, by preventing programmed cell death, can enable cells to undergo malignant transformation. Likewise, if certain drugs rely on p53-mediation to achieve apoptosis, subtle mutations in p53 may render that bladder cancer line more chemoresistant for those medications. For example, the overexpression of p53 has been shown to be an independent prognostic factor for methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) failure and decreased survival in patients with T2 or T3a bladder cancer.122 In fact, it has been suggested that other agents like paclitaxel and gemcitabine be used in bladder cancer patients with p53 mutations.123 While some studies predict p53 as a marker for chemoresistance for certain cytotoxic agents, there have been equal data to suggest that p53 overexpression is associated with good treatment response. Some have identified p53-mutated tumors to respond better to adjuvant cis-platinum-based chemotherapy prior to cystectomy.56,124 Likewise, there have been several studies that demonstrate no correlation between p53 expression and response to chemotherapy. The p53 expression did not affect response to chemotherapy and did not predict overall survival for patients with invasive bladder cancer.125 In summary, the p53 status and response rate are conflicting regarding systemic chemotherapy and may depend on the particular chemotherapeutic agent. One particular reason for this may be the fact that p53 may be induced by exposure to chemotherapeutic agents. Therefore, uniform timing of the sampling and administration of the chemotherapy are essential for completely evaluating this prognostic parameter.
Investigators have evaluated the prognostic significance of p53 alteration and overexpression with regards to radiation therapy as well. As compared to chemotherapy, there is less evidence to suggest that there is a reliable correlation in treatment outcomes. Several groups have indicated no correlation of p53 status to local control, delay to metastasis, or overall survival.126–128 Others have suggested that p53 overexpression is associated with radiosensitivity,129,130 while yet others have argued for a correlation between radioresistance and overexpression.131 These varying reports indicate that p53 is not a reliable prognostic indicator for response to radiation therapy for invasive bladder cancer. Another molecule to consider regarding prognosis of treatment is P-glycoprotein, formerly known as the multidrug resistance (MDR) gene. Certain cytotoxic drugs have been demonstrated to be exported from tumor cells through a multidrug effusion pump. This pump activity is characterized by expression of P-glycoprotein, and can theoretically result in decreased efficacy of chemotherapeutic agents. While the phenomenon of upregulation of P-glycoprotein has been well documented following systemic chemotherapy for bladder cancer,132 the data concerning drug resistance and P-glycoprotein expression have been variable.133 Another molecule with possibly some prognostic significance for therapy is the intracellular scavenger, glutathione (GSH). GSH has been shown to react with free cisplatin, thus reducing the intracellular availability of the drug. The levels of GSH are upregulated in some lines of TCC and it is possible that this contributes to the mechanism of cisplatin resistance.134 In other cancer models, the administration of GSH inhibitors has been shown to increase response to cisplatin,135,136 but this has not yet been applied to bladder cancer. Conclusion The ultimate importance of the aforementioned data on clinical decision-making is still unclear. TCCs are clearly variable and complex. The continued unveiling of the intricacies of the cancer’s cellular biology will likely one day help determine prognosis and direct appropriate therapy. For now, the knowledge produced from investigations of the past will more specifically direct future clinical studies, thus, making them more clinically applicable. RADICAL CYSTECTOMY Radical cystectomy remains the gold standard therapeutic option for patients with muscle-invasive bladder carcinoma, and in the U.S., it is the most common treatment option. Despite alternatives that may appear appealing and may be appropriate for certain individuals, surgical removal still provides local control and chance
344
Part IV Bladder
for cure, to which other treatments attempt to compare themselves. Preoperative Evaluation and Preparation Patients with invasive bladder cancer often are elderly with significant competing comorbidities who require careful preoperative evaluation, and it is often the surgeon’s responsibility to ensure that an appropriate workup has been performed. Recently, Miller et al.137 have demonstrated an association between comorbid illness and adverse pathological and survival outcome following radical cystectomy. It is ultimately the surgeon’s responsibility to try and optimize the patient’s health status prior to cystectomy, and to determine if a patient is not a candidate for major surgery. It is important to realize that the goal of the preoperative assessment is to assess risk among these potential surgical candidates. Several reports have now confirmed the procedure that it can be performed safely with acceptable morbidity among the elderly, including those with high perioperative risk.138–140 Despite more “conservative” approaches, such as bladder sparing, age and even comorbidities should not be used as absolute deterrents when considering radical cystectomy as therapy for a potentially lethal cancer. Patients are seen preoperatively by an enterostomal nurse for counseling and optimal stoma site marking. This is recommended regardless of diversion type planned in the event that an orthotopic diversion is not technically feasible or contraindicated. Prior to surgery, patients undergo a mechanical and antibiotic bowel preparation usually performed in the outpatient setting after 1 to 2 days of a clear liquid diet. Patients are routinely admitted on the day of surgery with an estimated length of stay of between 5 and 7 days. Radical Cystectomy in Males Radical cystectomy is the standard treatment in the surgical management of male patients with muscle-invasive bladder cancer.141 In a male, the prostate and seminal vesicles are removed routinely along with the bladder and is the equivalent of an anterior exenteration. Reasons for routine removal of the prostate include direct extension of the bladder cancer into the prostatic urethra, as well as prostatic ductal or stromal involvement. There is also a risk of secondary malignancy, namely, prostatic adenocarcinomas, which has been detected in up to 40% of specimens in historical series.142,143 Recently, however, a series of 100 men who underwent prostate sparing at the time of radical cystectomy was reported.144 After careful patient selection, patients underwent TUR of the prostate with frozen section analysis at the time of cystectomy. In the absence of cancer in the TUR specimen, local recurrence occurred in
4.5%, 5%, and 8% of men with pTa/T1, pT2, and pT3, respectively. At 1-year follow-up, 97% are fully continent during the day and 95% are continent at night. Additionally, 82% of patients maintained potency with retrograde ejaculation due to the TUR, while 10% are partially potent and 8.1% are impotent. Clearly, longterm follow-up will be required to ensure continued excellent cancer control. As with other carcinomas, the importance of achieving a negative surgical margin is paramount to obtaining local cancer control and should not be compromised.145 A better understanding of the anatomic relationships of the neurovascular bundles with respect to the prostate combined with improved surgical technique has led to major improvements in functional outcomes.146 Retaining potency in men following radical cystectomy is also technically feasible and involves careful attention to the area of the prostatic pedicles, where nerve bundle injury is most likely.147–149 Currently, it has been reported that potency is preserved in about 50% of men with nerve-sparing techniques and there has been no apparent compromise in cancer control.149 Urinary reconstruction following cystectomy involves the reconnection of the ureters to an intestinal segment that allows for the drainage of urine. There are essentially three methods in which this can be accomplished: an ileal conduit, a continent cutaneous reservoir, or an orthotopic urinary diversion. Historically, the majority of patients underwent an ileal conduit, an incontinent form of urine drainage. Over the past decade, however, continent urinary diversions, especially orthotopic bladder reconstruction, have evolved from experimental surgery to become a commonly preformed method of urinary diversion. The detection of cancer in younger patients, the desire to maintain a normal body image, and the realization that quality of life can be improved by maintaining near-normal function after radical surgery, and improved surgical techniques have all contributed to the realization that continent urinary diversion is an option for a significant percentage of patients.150,151 Patient selection criteria include both patient factors and cancer factors. Relative contraindications to orthotopic urinary diversion include renal insufficiency (serum creatinine > 2 ng/dl), hepatic dysfunction, and the inability to perform self-catheterization should the need arise. An absolute contraindication in a male patient is the inability to achieve a negative cancer margin in the proximal urethra (prostatic apex). Although controversial, age alone is not a contraindication to orthotopic diversion and thus can be performed judiciously in men over the age of 70 years, and even in men with significant comorbidities.152 Prior pelvic radiation therapy is again a relative contraindication; however, there have been reports of successful orthotopic diversion in the setting of salvage cystectomy for failed radiation.153
Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 345
Increasing experience has expanded the possible applicability of orthotopic diversion. The impact of local recurrence on ileal neobladder function and survival was recently reported in a series of 357 men.154 Local recurrence developed in 43 patients (12%). Of the 43 patients with local recurrence at follow-up, 36 had local advanced cancer on the final pathological evaluation (stage pT3a or node-positive or greater), yet 40 maintained good neobladder function. The neobladder was removed only in 1 patient due to a neobladder to intestinal fistula. These data imply that most patients may anticipate normal neobladder function even in the presence of recurrent disease or until death. In addition, although it is unclear what the real likelihood is, the retained urethra in any form of urinary diversion must be carefully followed as a possible site of recurrence. Orthotopic neobladder construction involves the creation of an internal reservoir from some segment of bowel, most commonly this is 45 to 60 cm of ileum, detubularized and fashioned in either a “W configuration” (Hautmann) or “U shaped or J shaped” (Studer).150,155 While in the past there was a fear that orthotopic diversion would be associated with significantly higher rate of complication as compared to an ileal conduit, recent reports suggest that in properly selected patients the early complications rates are similarly acceptable.151,156 The functional results following orthotopic urinary reconstruction have been excellent. Daytime urinary continence rates range from 80% to 95% with differences largely due to definition of continence, methods in which the data are obtained, and length of followup.157–160 Nighttime continence is more problematic, with rates of 65% to 85% reported. The incidence of hyper-continence or urinary retention requiring selfcatheterization is approximately 3% to 5%. Men should be counseled preoperatively that while most men are continent in the day, they may experience some degree of incontinence at night and a protective pad may be required. Overall patient satisfaction with orthotopic neobladder substitution remains high with >95% of patients satisfied with their choice of diversion.161 Radical Cystectomy in Females In women, radical cystectomy for muscle-invasive bladder cancer has historically been the equivalent of an anterior exenteration. This includes removal of the uterus, fallopian tubes, ovaries, bladder, urethra, and a segment of anterior vaginal wall. This remains the gold standard. However, early detection combined with a desire to improve the functional outcomes, including sexual abilities and urinary control, has led surgeons to modify their techniques in selected patients, where preservation of disease-free urethra is possible. Although the majority of women still undergo ileal conduit urinary diversion or continent cutaneous diver-
sion, orthotopic urinary diversion has become increasingly viable as an option. Stein et al.162 and others subsequently have demonstrated the oncologic safety of orthotopic reconstruction in properly selected female patients. Exclusion criteria for orthotopic neobladder reconstruction include tumor involving the bladder neck, diffuse CIS, and a positive bladder neck margin at the time of radical cystectomy.162 In addition, females with large, palpable tumors along the anterior vaginal wall are not appropriate candidates. In properly selected patients, local recurrence rates have been extremely low and functional outcomes have been comparable to those reported among male patients.163–167 The technique and outcomes of orthotopic diversion in females have been well described.164,165 These technical refinements include avoidance of overlapping suture lines, the interposition of a vascularized omental pedicle, and preservation of the anterior vaginal wall.163 In patients with nonpalpable tumors, the plane between the posterior bladder wall and the anterior vaginal wall can be developed while ligating the posterior-lateral pedicles. The plane is developed to the level of the bladder neck, and the anterior and posterior dissections are connected with preservation of the bladder neck. It was recently reported that there is a very low incidence of secondary gynecologic malignancies at the time of cystectomy.168 In this series, only a single gynecologic malignancy was found and involvement of the uterus by direct extension of bladder cancer was discovered in only 2 patients, both of whom had clinical suspicion based on bimanual examination or preoperative imaging. Thus, in most women, the risk of gynecologic involvement of urologic malignancy is small and can usually be determined either preoperatively or at the time of surgery. The potential for improved functional outcomes and quality of life through preservation of gynecological organs, particularly among young women with invasive bladder cancer, is currently an area of ongoing research, and these younger women are more likely to be concerned about preservation of fertility and continuation of normal hormonal status.169 In properly selected patients, functional outcomes have been comparable to those reported among male patients.163–167 Daytime continence rates range from 70% to 95%, with high rates of overall satisfaction. There may be a higher rate of urinary retention regarding intermittent catheterizations, and all patients undergoing diversion should receive preoperative counseling regarding this, as well as other possible complications. Role of Lymphadenectomy Although it has long been a standard part of radical cystectomy, pelvic lymph node dissection has garnered more
346
Part IV Bladder
attention recently. This is derived in part from data demonstrated long-term disease-free survival among node-positive patients and benefit implied from the completeness of the lymph node dissection. It has been proposed that the therapeutic benefit of lymphadenectomy may be extended beyond the confines of the traditional pelvic template arguing in favor of a more extended node dissection.47,170,171 Recent studies have proposed that the actual number of nodes harvested may play a role in patient outcomes, and the greater the lymph nodes removed the better the survival.172,173 The concept of lymph node density, defined as the total number of positive lymph nodes divided by the total number of lymph nodes removed, has recently been reported to be an important prognostic indicator among patients with node-positive bladder cancer.174 The benefit of an extended dissection may be derived from both the removal of clinically apparent pathologic nodes and/or from undetected micrometastatic disease. Future studies that carefully document the overall number and location of lymph nodes removed (mapping) along with the number and location of positive nodes removed at the time of cystectomy using defined templates of dissection and possibly molecular staging will be important. Outcomes of Radical Cystectomy The long-term efficacy of radical cystectomy among patients with invasive bladder cancer has been demonstrated in terms of local control and disease-specific survival. Numerous series have demonstrated excellent local control and excellent 5- and 10-year survivals for patients with invasive bladder cancer treated with cystectomy.149,175–178 Long-term survival is best among those with organ-confined disease, and consistently 5-year survival is >70%.47,179,180 The presence of locally advanced or lymph node metastases is associated with a high rate of recurrence and argues in favor of combined neoadjuvant or adjuvant chemotherapy. In the largest contemporary series to date, investigators at the University of Southern California (USC) recently reported results in 1054 patients with a median follow-up of 10.2 years.47 In this series, the overall recurrence-free survival at 5- and 10-years was 68% and 60%, respectively. In patients with muscleinvasive disease (P2a and P3a), lymph node negative tumors had 89% and 87%, and 78% and 76% 5- and 10-year recurrence-free survival, respectively. In patients with nonorgan-confined bladder cancer (P3b, P4), lymph node-negative cancer demonstrated a significantly higher probability or recurrence with 5- and 10-year recurrence-free survival rates for P3b tumors were 62% and 61% and for P4 tumors were 50% and 45%, respectively. Clearly, these data support the aggressive surgical management of invasive bladder cancer. Durable local control
can be achieved with excellent long-term survival afforded as well. Complications of Radical Cystectomy Despite significant decrease in overall mortality and morbidity rates associated with cystectomy, complications can occur as an exacerbation of the patients preexisting comorbid conditions, arising from the bladder removal and those arising from the use of an intestinal segment. The mortality rate for radical cystectomy remains 1% to 2%, with a an overall early complication rate of about 25% to 30%.47,140,181–183 In one recent series of 304 patients, the overall major and minor complication rates were 4.9% and 30.9%, respectively, within the first 30 days.184 Postoperative ileus was the most common minor complication, affecting 18% of patients, which resolved with conservative management in all cases. Despite these improved results, the serious lifethreatening major complications, such as pulmonary emboli, myocardial infarction, and stroke, do occur and prompt recognition with appropriate intervention may avoid mortality. Radical cystectomy has been associated with significant blood loss and/or transfusion requirement, and complicating the surgical treatment of these patients is the significant number that have preoperative anemia. In one series, 45% of patients had anemia preoperatively. Median estimated blood loss was 600 ml (range 100 to 3000). Increased estimated blood loss was related to patient age; American Society of Anesthesiologists (ASA) score longer operative time and paralytic ileus. Overall, transfusion was required in 30% of patients with a median requirement of 2 units (range 1 to 10). The transfusion rate in male and female patients was 26% and 40%, respectively.185 These data support the need for continued refinement in surgical techniques designed to decrease blood loss, as well as for strategies designed to lower the need for blood transfusion during radical cystectomy. Role of Chemotherapy: Neoadjuvant Versus Adjuvant The rationale for including chemotherapy regimens before or after radical cystectomy is based on the presumption that this therapy may increase patient survival. Clearly, TCC is a chemosensitive malignancy and patients with metastatic disease can achieve a long-term cure.186–189 Even patients with large, bulky unresectable disease that cannot be cured by surgery alone can survive with the addition of chemotherapy for their treatment.190 Neoadjuvant chemotherapy in patients with advanced disease is becoming increasingly touted as the possible standard approach. This is based largely on two recent trials that have reported a benefit. An intergroup trial
Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 347
conducted by the Medical Reserve Crops (MRC) and the EORTC is the largest randomized trial (976 enrolled patients) examining neoadjuvant chemotherapy (CMV). The patients underwent some form of localized therapy (cystectomy alone, radiation therapy alone, or cystectomy and radiation therapy) after 3 cycles of CMV. Although initially there was no survival difference, the updated results did demonstrate a survival difference in those patients receiving neoadjuvant chemotherapy (p = 0.048).191 The second large trial that took almost 10 years to enroll its 307 patients was the SWOG-initiated Intergroup 0080 trial.192 The results are compelling; but as in most trials, criticisms can be made of methodology, as well as interpretation of results. The SWOG study utilized a one-sided testing and when two-sided hypothesis testing was performed, there was no statistical advantage in survival with neoadjuvant chemotherapy. Other studies that in themselves had viable criticisms have not demonstrated a survival benefit.193–195 Arguments exist for both approaches when considering chemotherapy regimens. With adjuvant chemotherapy, there is better pathologic staging and assessment of true disease burden within each patient.196 Recently, Herr et al.197 updated the Memorial Sloan-Kettering experience with postchemotherapy surgery in patients with unresectable or lymph node positive bladder cancer. Of 207 patients with unresectable or regionally metastatic bladder cancer, 80 (39%) underwent postchemotherapy surgery after treatment with a cisplatin-based chemotherapy regimen. No viable cancer was present at postchemotherapy surgery in 24 of the 80 cases (30%), pathologically confirming a complete response to chemotherapy. Of the 24 patients without residual cancer, 14 (58%) survived 9 months to 5 years after salvage surgery. Residual viable cancer was completely resected in 49 patients (61%), resulting in a complete response to chemotherapy plus surgery and 20 (41%) survived. Unfortunately, randomized trials with small numbers have given mixed results. The two studies that did not show a benefit to adjuvant chemotherapy examined nonmetastatic disease patients.198,199 Stockle et al.200 reported on 166 patients and demonstrated that those patients most likely to gain benefit from immediate chemotherapy were those with small volume lymph node involvement. Trials are currently in progress, including an examination of the impact of p53 status. Other trials looking at more advanced and node-positive patients are also accruing patients, including an EORTC trial examining surveillance versus immediate chemotherapy (M-VAC or gemcitabine plus cisplatin) after surgery. The CALGB 90104 study treats all patients with extravesical and/or nodepositive disease with a cis-platinum-based regimen. As with any treatment modality, proper patient selection is essential but in TCC it can be difficult. Delaying
radical cystectomy in itself clearly has a negative impact on patient pathology and survival.201–203 This negative impact on delay is true even in patients who undergo some type of therapy, such as radiation therapy, as verified by better survival in patients who undergo early cystectomy as opposed to late cystectomy.204 BLADDER-SPARING THERAPY: A MULTIMODALITY PARADIGM Rationale for Bladder Preservation In certain patients, radical cystectomy may not be the best option, and bladder preservation strategies for the treatment of invasive cancer have evolved for several reasons. Advances in the treatments of other malignant processes, such as breast and esophageal cancer, have demonstrated the effectiveness of this strategy. In bladder cancer, the majority of patients with recurrent and metastatic disease die of disease that is distant in location as opposed to local. In addition, despite its accepted standard as the treatment of choice, radical cystectomy does not ultimately result in a cure in a large number of patients and still represents a significant operative procedure with associated complications. Many bladder cancer patients are elderly, and although the number is decreasing with improvements in surgical techniques and perioperative care, there are patients who are “too ill” to undergo radical cystectomy. Although this approach has its appeal it remains only an option, and radical cystectomy continues to be the standard treatment of choice. Survival data for bladdersparing approach presented in a certain light can first appear promising, but it is difficult to compare directly how patient survival rates differ between bladder-sparing regimens and initial radical cystectomy. This is especially true when a significant number of patients do eventually require cystectomy, which is in fact only delayed by the bladder sparing approach. This strategy often requires a multitude of visits to different physicians requiring ofteninvasive procedures to attempt to monitor closely the patient’s condition and tumor status. In addition, bladder-sparing protocols are not in themselves inherently risk-free and have associated possible complications. To date, no prospective randomized trial has been performed comparing a multimodality bladder-sparing approach with radical cystectomy. Single Modality Approaches The success of TUR as a single modality has been used for many years depends on clinical stage and proper patient selection. Although an option, TUR alone cannot adequately treat the majority of patients with invasive carcinoma. Barnes et al.205 reported a 27% 5-year survival in patients with T2 bladder cancer. In highly
348
Part IV Bladder
selected series, 5-year survival rates have varied but have been as high as 67% in patients still with their bladder.206–208 Clearly, this approach is predicated on accurate evaluation and staging of the true and limited extent of muscle invasion. Even after repeated resections, however, occult invasive disease may still be present that would not be adequately treated by TUR alone.209 A single TUR, thus, would be an inadequate therapy. One of the major pitfalls to only endoscopic management of these tumors is the continued limitations of clinical understaging, which is present in 30% to 50% of cases.17 This is also true in patients treated with radiation therapy or neoadjuvant chemotherapy.196,210 In a selected few patients with limited disease of minimal depth and with no residual disease on repeat resection, this modality does have a role.15 By extending the boundaries of TUR, another bladder-sparing therapy approach using surgery is partial cystectomy. Once again, this approach could be advocated in a limited group of patients. Those patients who may be reasonable candidates would include small, single tumors, away from the trigone without related CIS.211–213 Although bladder capacity may be enough to maintain normal voiding patterns, this remaining bladder tissue serves as an area for recurrent disease or previously unrecognized disease. Localized recurrence in the form of new tumors or recurrent tumors occur anywhere between 15% and 75% of the time.211,212,214 This form of therapy should not be accepted as a standard treatment choice. Radiation therapy as a single modality is commonly employed in Europe and has been studied in the U.S. Conventional radiation therapy has local control rates of 30% to 50%.215–218 At M.D. Anderson, 135 patients were treated with primary external beam radiation therapy, with a 26% 5-year survival rate. Those patients with more advanced disease had a poor survival rate and less than a third achieved long-term local control.219 Similar survival rates have been demonstrated overseas.220,221 Patients who receive monotherapy radiation treatment tend to be older with greater comorbidities. But significant side effects, such as radiation cystitis, cannot be ignored.222 Unfortunately, as opposed to TUR or partial cystectomy, any type of salvage surgery is difficult, in one large series, <30% of patients who did not achieve a complete response to radiation underwent salvage cystectomy.215 Radiation as the only primary therapy has not been considered as equal treatment modality to cystectomy. Similarly, the role of chemotherapy continues to evolve but in no way should it be considered as a single treatment choice or as an acceptable alternative treatment choice to cystectomy. It cannot consistently eradicate the primary bladder tumor. This is the case even when there is an impressive response to disease outside of the bladder.
Multimodality Approach Single modality bladder-sparing therapy for muscle-invasive bladder cancer, including TUR, partial cystectomy, systemic chemotherapy, or radiation therapy have been demonstrated to result in insufficient local control when compared to cystectomy.223 In an attempt to maximize the efficacy of less invasive approaches and overcome their deficiencies, bladder-sparing approaches have combined different strategies to offer a comparable alternative to radical cystectomy. This inclusion of more than one approach seems to offer better oncologic cure rates and achieves bladder preservation at a higher rate than a single treatment choice.193,224–228 TUR and radiation therapy hopefully provide local control with chemotherapy providing a synergistic additive component and treating possible micrometastatic disease. Multiple variations of treatment algorithms have been studied. This large number of studies makes comparisons difficult. In general, however, after patients are diagnosed with muscle-invasive bladder cancer, they undergo “complete” resection of their tumor for local control, as well as attempting as accurate staging as possible. This is then followed by chemotherapy and external beam radiation. Oftentimes, the chemotherapy includes a platinum-based radiosensitizing chemotherapeutic agent (e.g., cisplatin). Patients are then carefully reevaluated by repeat cystoscopy and TUR. Only those patients with a complete response are candidates for continued bladder-sparing approach; those without complete response are recommended to undergo radical cystectomy. If bladder sparing is viable, patients receive additional radiation and chemotherapy with continued careful surveillance by cystoscopy, physical exam, and radiographs. Outcomes of Bladder-Sparing Approach Approximately 40% of patients survive 5 years with a bladder-sparing approach.193,224–228 In one of the largest randomized trials evaluating the role of chemotherapy in multimodality bladder preservation, the Radiation Therapy Oncology Group (RTOG) reported an overall 49% 5-year survival with an intact functioning bladder in 38%.193 The local recurrence rate in this series was 28%, and the study was stopped prematurely due to severe complications from the chemotherapy, including 3 deaths. Among these patients treated with bladder preservation strategies, life-long surveillance is required not only to monitor for progressive disease but also for superficial recurrences that may culminate in cystectomy in up to a third of these patients.229 Importantly, recurrence can occur after 5 years of disease-free survival. Also, induction treatment many times is not successful as up to 40% have an incomplete response and are recommended to undergo cystectomy.193 One recent study of a
Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 349
bladder-sparing approach, although not prospectively randomizing patients, did find better overall survival in those patients who did at some point undergo cystectomy (65% versus 40%).230 Complications of Bladder-Sparing Approach Bladder-sparing approaches may also be associated with adverse therapy-related side effects that can result in significant morbidity that negatively impacts on quality of life. Many patients cannot complete the recommended protocol of chemotherapy because of toxicity. This include nausea, fatigue, neutropenia, and GI complaints, such as diarrhea in up to 70% of patients.193 Also, there is mortality associated with only the induction portion of this algorithm (4% in one series193). This is actually a higher mortality rate than most cystectomy series. Furthermore, the long-term effects of these multimodality therapies may result in significant increased morbidity among those patients who demonstrate recurrent or progressive disease and ultimately require radical cystectomy. One important point is that although a patient may tolerate the chemotherapy and radiation changes to the bladder, symptoms that the patient may have caused by the disease process and/or previous therapy (e.g., TURBTs, intravesical therapies) are not at all altered or improved by bladder sparing. Such bladder dysfunction may be better addressed by bladder removal and urinary diversion. In addition, bowel symptoms and effect on small bowel and the rectum must also be considered. Moderate or severe symptoms can affect up to one-third of patients.231 In its present form, multimodality therapy aimed at bladder-preservation is best performed at select centers that have a dedicated and cooperative multidisciplinary team that can provide these patients with close clinical follow-up. Patients should also be made aware of the selection criteria and specifics of the associated with the various treatment protocols, including cost, before making an informed decision. Finally, the results of these various strategies should be objectively balanced against the results of contemporary radical cystectomy and orthotopic diversion. Attempting to spare the bladder requires complex and constant surveillance and assessment of patient status. There has to be a coordinated effort between patient and a number of disciplines, including surgery, radiation oncology, and oncology. This requires a dedicated effort by a team approach.225 Although not a primary concern, this approach is costly regardless of preservation of the bladder or ultimately requiring cystectomy.232
patients, quality of life may be as important as length of life or survival. Furthermore, among the long-term survivors of cancer therapy, the impact of cancer treatment on the HRQOL is even more profound, especially with radical cystectomy, one of the most potentially stressful and life-altering.233 One of the key reasons for bladder sparing approach is an attempt to avoid the morbidity and possible complications associated with loss of the bladder. Patients oftentimes do maintain adequate bladder function after chemotherapy and/or radiation, but the different types of urinary diversion now available make cystectomy and urinary diversion at least somewhat more acceptable if not desirable.231,234 Although more studies have been performed examining the impact of cystectomy on quality of life, many of these are inherently flawed.161,235–239 Most of these studies have compared quality of life in patients undergoing various types of urinary diversion and have been criticized for flaws in methodology. In addition, most are retrospective and so the actual quality of life comparison from baseline is not known. Also, as investigators have started realizing the value of validated instruments when gauging outcome after treatment,233,240 it has become clear that one does not yet exist for bladder cancer. It is important, therefore, to keep in mind that despite the perception that patients with neobladders enjoy a better quality of life compared to those with ileal conduits, the definitive study remains to be performed.228 Large, prospective longitudinal studies using both generic and disease-specific validated instruments are required. SUMMARY The diagnosis and treatment of muscle-invasive TCC continues to evolve. With each patient, multiple issues including patient selection, complexity of care, cost, survival outcomes, and quality of life measures must be carefully evaluated. An improved understanding of tumor biology coupled with a multimodality approach treatment strategy will hopefully provide continued improved results. Radical cystectomy currently remains the gold standard for patients with invasive bladder cancer; and modifications of surgery, urinary diversion, and perioperative care continue to translate into improved quality of life for patients. Continued research to discover and validate accurate tumor markers will provide further benefit for these patients.
REFERENCES Quality of Life Concerns Increasingly, health-related quality of life (HRQOL) has been recognized as an important outcome measure following the treatment of urologic malignancies. For many
1. Greenlee RT, Murray T, Bolden S, Wingo PA: Cancer statistics. CA Cancer J Clin 2000; 50:7. 2. Messing EM, Young TB, Hunt VB, et al: Comparison of bladder cancer outcome in men undergoing hematuria
350
3.
4.
5.
6.
7.
8.
9. 10. 11.
12.
13. 14.
15.
16.
17.
18.
19.
20.
21.
Part IV Bladder home screening versus those with standard clinical presentations. Urology 1995; 45:387. Kaye KW, Lange PH: Mode of presentation of invasive bladder cancer: reassessment of the problem. J Urol 1982; 128:31. Kurth KH, Denis L, Bouffioux C, et al: Factors affecting recurrence and progression in superficial bladder tumours. Eur J Cancer 1995; 31A:1840. Althausen AF, Prout GR Jr, Daly JJ: Non-invasive papillary carcinoma of the bladder associated with carcinoma in situ. J Urol 1976; 116:575. Lutzeyer W, Rubben H, Dahm H: Prognostic parameters in superficial bladder cancer: an analysis of 315 cases. J Urol 1982; 127:250. Fleshner NE, Herr HW, Stewart AK, et al: The National Cancer Data Base report on bladder carcinoma. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 1996; 78:1505. Jewett HJ, Eversole SL, Jr: Carcinoma of the bladder: characteristic modes of local invasion. J Urol 1960; 83:383. Prout GR Jr: Bladder carcinoma and a TNM system of classification. J Urol 1977; 117:583. Herr HW: Uncertainty, stage and outcome of invasive bladder cancer. J Urol 1994; 152:401. Farrow GM, Utz DC, Rife CC: Morphological and clinical observations of patients with early bladder cancer treated with total cystectomy. Cancer Res 1976; 36:2495. Cheng L, Bostwick DG: Progression of T1 bladder tumors: better staging or better biology? reply. Cancer 1999; 86: 910. Matzkin H, Soloway MS, Hardeman S: Transitional cell carcinoma of the prostate. J Urol 1991; 146:1207. Holzbeierlein JM, Smith JA Jr: Surgical management of noninvasive bladder cancer (stages Ta/T1/CIS). Urol Clin North Am 2000; 27:15. Herr HW: The value of a second transurethral resection in evaluating patients with bladder tumors. J Urol 1999; 162:74. Brauers A, Buettner R, Jakse G: Second resection and prognosis of primary high risk superficial bladder cancer: is cystectomy often too early? J Urol 2001; 165:808. Dutta SC, Smith JA Jr, Shappell SB, et al: Clinical under staging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy. J Urol 2001; 166:490. Reuter VE: Pathology of bladder cancer: assessment of prognostic variables and response to therapy. Semin Oncol 1990; 17:524. Jordan AM, Weingarten J, Murphy WM: Transitional cell neoplasms of the urinary bladder. Can biologic potential be predicted from histologic grading? Cancer 1987; 60:2766. Kaubisch S, Lum BL, Reese J, Freiha F, Torti FM: Stage T1 bladder cancer: grade is the primary determinant for risk of muscle invasion. J Urol 1991; 146:28. Torti FM, Lum BL, Aston D, et al: Superficial bladder cancer: the primacy of grade in the development of invasive disease. J Clin Oncol 1987; 5:125.
22. Jimenez RE, Gheiler E, Oskanian P, et al: Grading the invasive component of urothelial carcinoma of the bladder and its relationship with progression-free survival. Am J Surg Pathol 2000; 24:980. 23. Jewett HJ, strong GH: Infiltrating carcinoma of the bladder: relation of depth of penetration of the bladder wall to incidence of local extension and metastasis. J Urol 1946; 55:366. 24. Smith JA Jr, Whitmore WF Jr: Regional lymph node metastasis from bladder cancer. J Urol 1981; 126:591. 25. Babaian RJ, Johnson DE, Llamas L, Ayala AG: Metastases from transitional cell carcinoma of urinary bladder. Urology 1980; 16:142. 26. Loehrer PJ Sr, Einhorn LH, Elson PJ, et al: A randomized comparison of cisplatin alone or in combination with methotrexate, vinblastine, and doxorubicin in patients with metastatic urothelial carcinoma: a cooperative group study. J Clin Oncol 1992; 10:1066. 27. Fossa SD, Ous S, Berner A: Clinical significance of the “palpable mass” in patients with muscle-infiltrating bladder cancer undergoing cystectomy after pre-operative radiotherapy. Br J Urol 1991; 67:54. 28. Hodson NJ, Husband JE, MacDonald JS: The role of computed tomography in the staging of bladder cancer. Clin Radiol 1979; 30:389. 29. Kellett MJ, Oliver RT, Husband JE, Fry IK: Computed tomography as an adjunct to bimanual examination for staging bladder tumours. Br J Urol 1980; 52:101. 30. Herr HW: Routine CT scan in cystectomy patients: does it change management? Urology 1996; 47:324. 31. Paik ML, Scolieri MJ, Brown SL, Spirnak JP, Resnick MI: Limitations of computerized tomography in staging invasive bladder cancer before radical cystectomy. J Urol 2000; 163:1693. 32. Barentsz JO, Jager GJ, Witjes JA, Ruijs JH: Primary staging of urinary bladder carcinoma: the role of MRI and a comparison with CT. Eur Radiol 1996; 6:129. 33. Tekes A, Kamel IR, Imam K, et al: MR imaging features of transitional cell carcinoma of the urinary bladder. AJR Am J Roentgenol 2003; 180:771. 34. Jager GJ, Barentsz JO, Oosterhof GO, Witjes JA, Ruijs SJ: Pelvic adenopathy in prostatic and urinary bladder carcinoma: MR imaging with a three-dimensional TI-weighted magnetization-prepared-rapid gradientecho sequence. Am J Roentgenol 1996; 167:1503. 35. Robinson P, Collins CD, Ryder WD, et al: Relationship of MRI and clinical staging to outcome in invasive bladder cancer treated by radiotherapy. Clin Radiol 2000; 55:301. 36. Buy JN, Moss AA, Guinet C, et al: MR staging of bladder carcinoma: correlation with pathologic findings. Radiology 1988; 169:695. 37. Hayashi N, Tochigi H, Shiraishi T, Takeda K, Kawamura J: A new staging criterion for bladder carcinoma using gadolinium-enhanced magnetic resonance imaging with an endorectal surface coil: a comparison with ultrasonography. BJU Int 2000; 85:32. 38. Lawler LP: MR imaging of the bladder. Radiol Clin North Am 2003; 41:161.
Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 351 39. Harney JV, Wahl RL, Liebert M, et al: Uptake of 2-deoxy, 2-(18F) fluoro-D-glucose in bladder cancer: animal localization and initial patient positron emission tomography. J Urol 1991; 145:279. 40. Letocha H, Ahlstrom H, Malmstrom PU, et al: Positron emission tomography with L-methyl-11C-methionine in the monitoring of therapy response in muscle-invasive transitional cell carcinoma of the urinary bladder. Br J Urol 1994; 74:767. 41. Heicappell R, Muller-Mattheis V, Reinhardt M, et al: Staging of pelvic lymph nodes in neoplasms of the bladder and prostate by positron emission tomography with 2-[(18)F]-2-deoxy-D-glucose. Eur Urol 1999; 36:582. 42. Kosuda S, Fisher S, Wahl RL: Animal studies on the reduction and/or dilution of 2-deoxy-2-[18F]fluoroD-glucose (FDG) activity in the urinary system. Ann Nucl Med 1997; 11:213. 43. de Jong IJ, Pruim J, Elsinga PH, et al: Visualisation of bladder cancer using (11)C-choline PET: first clinical experience. Eur J Nucl Med Mol Imaging 2002; 29:1283. 44. Poulsen J, Krarup T: Pelvic lymphadenectomy (staging) in patients with bladder cancer laparoscopic versus open approach. Scand J Urol Nephrol Suppl 1995; 172:19. 45. Tsivian A, Sidi AA: Port site metastases in urological laparoscopic surgery. J Urol 2003; 169:1213. 46. Elbahnasy AM, Hoenig DM, Shalhav A, McDougall EM, Clayman RV: Laparoscopic staging of bladder tumor: concerns about port site metastases. J Endourol 1998; 12:55. 47. Stein JP, Lieskovsky G, Cote R, et al: Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1054 patients. J Clin Oncol 2001; 19:666. 48. Richie JP, Skinner DG, Kaufman JJ: Carcinoma of the bladder: treatment by radical cystectomy. J Surg Res 1975; 18:271. 49. Prout GR Jr: The surgical management of bladder carcinoma. Urol Clin North Am 1976; 3:149. 50. Pearse HD, Reed RR, Hodges CV: Radical cystectomy for bladder cancer. J Urol 1978; 119:216. 51. Raghavan D, Shipley WU, Garnick MB, Russell PJ, Richie JP: Biology and management of bladder cancer. N Engl J Med 1990; 322:1129. 52. Raghavan D: Molecular targeting and pharmacogenomics in the management of advanced bladder cancer. Cancer 2003; 97:2083. 53. Sanchez-Carbayo M, Socci ND, Charytonowicz E, et al: Molecular profiling of bladder cancer using cDNA microarrays: defining histogenesis and biological phenotypes. Cancer Res 2002; 62:6973. 54. Dyrskjot L, Thykjaer T, Kruhoffer M, et al: Identifying distinct classes of bladder carcinoma using microarrays. Nat Genet 2003; 33:90. 55. Sanchez-Carbayo M: Use of high-throughput DNA microarrays to identify biomarkers for bladder cancer. Clin Chem 2003; 49:23. 56. Tiguert R, Lessard A, So A, Fradet Y: Prognostic markers in muscle invasive bladder cancer. World J Urol 2002; 20:190.
57. Stein JP, Grossfeld GD, Ginsberg DA, et al: Prognostic markers in bladder cancer: a contemporary review of the literature. J Urol 1998; 160:645. 58. Wheeless LL, Badalament RA, de Vere White RW, Fradet Y, Tribukait B: Consensus review of the clinical utility of DNA cytometry in bladder cancer. Report of the DNA Cytometry Consensus Conference. Cytometry 1993; 14:478. 59. Sandberg AA: Chromosome changes in bladder cancer: clinical and other correlations. Cancer Genet Cytogenet 1986; 19:163. 60. Falor WH, Ward-Skinner RM: The importance of marker chromosomes in superficial transitional cell carcinoma of the bladder: 50 patients followed up to 17 years. J Urol 1988; 139:929. 61. Waldman FM, Carroll PR, Kerschmann R, et al: Centromeric copy number of chromosome 7 is strongly correlated with tumor grade and labeling index in human bladder cancer. Cancer Res 1991; 51:3807. 62. Norming U, Tribukait B, Nyman CR, Nilsson B, Wang N: Prognostic significance of mucosal aneuploidy in stage Ta/T1 grade 3 carcinoma of the bladder. J Urol 1992; 148:1420. 63. Richter J, Wagner U, Schraml P, et al: Chromosomal imbalances are associated with a high risk of progression in early invasive (pT1) urinary bladder cancer. Cancer Res 1999; 59:5687. 64. Watters AD, Going JJ, Grigor KM, Bartlett JM: Progression to detrusor-muscle invasion in bladder carcinoma is associated with polysomy of chromosomes 1 and 8 in recurrent pTa/pT1 tumours. Eur J Cancer 2002; 38:1593. 65. Hosaka Y: DNA ploidy pattern of flow cytometry as indicator of malignancy and prognosis in bladder cancer. Nippon Rinsho 1992; 50:2426. 66. Lianes P, Charytonowicz E, Cordon-Cardo C, et al: Biomarker study of primary nonmetastatic versus metastatic invasive bladder cancer. National Cancer Institute Bladder Tumor Marker Network. Clin Cancer Res 1998; 4:1267. 67. Desgrippes A, Izadifar V, Assailly J, Fontaine E, Beurton D: Diagnosis and prediction of recurrence and progression in superficial bladder cancers with DNA image cytometry and urinary cytology. BJU Int 2000; 85:434. 68. Jacobsen AB, Pettersen EO, Amellem O, et al: The prognostic significance of deoxyribonucleic acid flow cytometry in muscle invasive bladder carcinoma treated with preoperative irradiation and cystectomy. J Urol 1992; 147:34. 69. Granfors T, Duchek M, Tomic R, Roos G, Ljungberg B: Predictive value of DNA ploidy in bladder cancer treated with preoperative radiation therapy and cystectomy. Scand J Urol Nephrol 1996; 30:281. 70. Turkolmez K, Baltaci S, Beduk Y, Muftuoglu YZ, Gogus O: DNA ploidy and S-phase fraction as predictive factors of response and outcome following neoadjuvant methotrexate, vinblastine, epirubicin and cisplatin (M-VEC) chemotherapy for invasive bladder cancer. Scand J Urol Nephrol 2002; 36:46.
352
Part IV Bladder
71. Imao T, Koshida K, Endo Y, et al: Dominant role of E-cadherin in the progression of bladder cancer. J Urol 1999; 161:692. 72. Sun W, Herrera GA: E-cadherin expression in urothelial carcinoma in situ, superficial papillary transitional cell carcinoma, and invasive transitional cell carcinoma. Hum Pathol 2002; 33:996. 73. Bringuier PP, Umbas R, Schaafsma HE, et al: Decreased E-cadherin immunoreactivity correlates with poor survival in patients with bladder tumors. Cancer Res 1993; 53:3241. 74. Shimazui T, Schalken JA, Giroldi LA, et al: Prognostic value of cadherin-associated molecules (alpha-, beta-, and gamma-catenins and p120cas) in bladder tumors. Cancer Res 1996; 56:4154. 75. Harabayashi T, Kanai Y, Yamada T, et al: Reduction of integrin beta 4 and enhanced migration on laminin in association with intraepithelial spreading of urinary bladder carcinomas. J Urol 1999; 161:1364. 76. Liebert M, Washington R, Wedemeyer G, Carey TE, Grossman HB: Loss of co-localization of alpha 6 beta 4 integrin and collagen VII in bladder cancer. Am J Pathol 1994; 144:787. 77. Theodorescu D, Laderoute KR, Gulding KM: Epidermal growth factor receptor-regulated human bladder cancer motility is in part a phosphatidylinositol 3-kinase-mediated process. Cell Growth Differ 1998; 9:919. 78. Messing EM: Clinical implications of the expression of epidermal growth factor receptors in human transitional cell carcinoma. Cancer Res 1990; 50:2530. 79. Neal DE, Sharples L, Smith K, et al: The epidermal growth factor receptor and the prognosis of bladder cancer. Cancer 1990; 65:1619. 80. Messing EM: Growth factors and bladder cancer: clinical implications of the interactions between growth factors and their urothelial receptors. Semin Surg Oncol 1992; 8:285. 81. Mellon K, Wright C, Kelly P, Horne CH, Neal DE: Long-term outcome related to epidermal growth factor receptor status in bladder cancer. J Urol 1995; 153:919. 82. Ozdemir E, Kakehi Y, Okuno H, Yoshida O: Role of matrix metalloproteinase-9 in the basement membrane destruction of superficial urothelial carcinomas. J Urol 1999; 161:1359. 83. Ocharoenrat P, Modjtahedi H, Rhys-Evans P, et al: Epidermal growth factor-like ligands differentially upregulate matrix metalloproteinase 9 in head and neck squamous carcinoma cells. Cancer Res 2000; 60:1121. 84. Gohji K, Fujimoto N, Fujii A, et al: Prognostic significance of circulating matrix metalloproteinase-2 to tissue inhibitor of metalloproteinases-2 ratio in recurrence of urothelial cancer after complete resection. Cancer Res 1996; 56:3196. 85. Jayet C, Deperthes D, Leisinger HJ: Angiogenesis and bladder cancer: trendy prognostic factor or new therapeutic target? Ann Urol (Paris) 2002; 36:258. 86. Bernardini S, Fauconnet S, Chabannes E, et al: Serum levels of vascular endothelial growth factor as a
87.
88.
89.
90.
91.
92.
93.
94.
95.
96. 97.
98. 99.
100.
101.
102.
103.
prognostic factor in bladder cancer. J Urol 2001; 166:1275. Inoue K, Slaton JW, Karashima T, et al: The prognostic value of angiogenesis factor expression for predicting recurrence and metastasis of bladder cancer after neoadjuvant chemotherapy and radical cystectomy. Clin Cancer Res 2000; 6:4866. Goddard JC, Sutton CD, Jones JL, O’Byrne KJ, Kockelbergh RC: Reduced thrombospondin-1 at presentation predicts disease progression in superficial bladder cancer. Eur Urol 2002; 42:464. Grossfeld GD, Ginsberg DA, Stein JP, et al: Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression. J Natl Cancer Inst 1997; 89:219. Dickinson AJ, Fox SB, Persad RA, et al: Quantification of angiogenesis as an independent predictor of prognosis in invasive bladder carcinomas. Br J Urol 1994; 74:762. Bochner BH, Cote RJ, Weidner N, et al: Angiogenesis in bladder cancer: relationship between microvessel density and tumor prognosis. J Natl Cancer Inst 1995; 87:1603. Chaudhary R, Bromley M, Clarke NW, et al: Prognostic relevance of micro-vessel density in cancer of the urinary bladder. Anticancer Res 1999; 19:3479. Jaeger TM, Weidner N, Chew K, et al: Tumor angiogenesis correlates with lymph node metastases in invasive bladder cancer. J Urol 1995; 154:69. Korkolopoulou P, Konstantinidou AE, Kavantzas N, et al: Morphometric microvascular characteristics predict prognosis in superficial and invasive bladder cancer. Virchows Arch 2001; 438:603. Sidransky D, Messing E: Molecular genetics and biochemical mechanisms in bladder cancer. Oncogenes, tumor suppressor genes, and growth factors. Urol Clin North Am 1992; 19:629. Levine AJ: p53, the cellular gatekeeper for growth and division. Cell 1997; 88:323. Barbacid M: Oncogenes in human cancers and in chemically induced animal tumors. Prog Med Virol 1985; 32:86. Bouck N: p53 and angiogenesis. Biochim Biophys Acta 1996; 1287:63. Reiher FK, Ivanovich M, Huang H, et al: The role of hypoxia and p53 in the regulation of angiogenesis in bladder cancer. J Urol 2001; 165:2075. Smith ND, Rubenstein JN, Eggener SE, Kozlowski JM: The p53 tumor suppressor gene and nuclear protein: basic science review and relevance in the management of bladder cancer. J Urol 2003; 169:1219. Grossfeld GD, Muscheck M, Stein JP, et al: Cellular proliferation and cell-cell cycle regulatory proteins as prognostic markers for transitional cell carcinoma of the bladder. Adv Exp Med Biol 1999; 462:425. Lacombe L, Dalbagni G, Zhang ZF, et al: Overexpression of p53 protein in a high-risk population of patients with superficial bladder cancer before and after bacillus Calmette-Guerin therapy: correlation to clinical outcome. J Clin Oncol 1996; 14:2646. Schmitz-Drager BJ, Goebell PJ, Ebert T, Fradet Y: p53 immunohistochemistry as a prognostic marker in bladder
Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 353
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
cancer. Playground for urology scientists? Eur Urol 2000; 38:691. Esrig D, Elmajian D, Groshen S, et al: Accumulation of nuclear p53 and tumor progression in bladder cancer. N Engl J Med 1994; 331:1259. Hemal AK, Khaitan A, Dinda AK, et al: Prognostic significance of p53 nuclear overexpression in patients of muscle invasive urinary bladder carcinoma treated with cystectomy. Urol Int 2003; 70:42. Herr HW, Bajorin DF, Scher HI, Cordon-Cardo C, Reuter VE: Can p53 help select patients with invasive bladder cancer for bladder preservation? J Urol 1999; 161:20. Fleshner N, Kapusta L, Ezer D, Herschorn S, Klotz L: p53 nuclear accumulation is not associated with decreased disease-free survival in patients with node positive transitional cell carcinoma of the bladder. J Urol 2000; 164:1177. Horowitz JM, Park SH, Bogenmann E, et al: Frequent inactivation of the retinoblastoma anti-oncogene is restricted to a subset of human tumor cells. Proc Natl Acad Sci U S A 1990; 87:2775. Cairns P, Proctor AJ, Knowles MA: Loss of heterozygosity at the RB locus is frequent and correlates with muscle invasion in bladder carcinoma. Oncogene 1991; 6:2305. Cote RJ, Dunn MD, Chatterjee SJ, et al: Elevated and absent pRb expression is associated with bladder cancer progression and has cooperative effects with p53. Cancer Res 1998; 58:1090. Williams SG, Buscarini M, Stein JP: Molecular markers for diagnosis, staging, and prognosis of bladder cancer. Oncology (Huntingt) 2001; 15:1461. Cordon-Cardo C: Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol 1995; 147:545. Stein JP, Ginsberg DA, Grossfeld GD, et al: Effect of p21WAF1/CIP1 expression on tumor progression in bladder cancer. J Natl Cancer Inst 1998; 90:1072. Korkolopoulou P, Konstantinidou AE, Thomas-Tsagli E, et al: WAF1/p21 protein expression is an independent prognostic indicator in superficial and invasive bladder cancer. Appl Immunohistochem Mol Morphol 2000; 8:285. Jankevicius F, Goebell P, Kushima M, et al: p21 and p53 immunostaining and survival following systemic chemotherapy for urothelial cancer. Urol Int 2002; 69:174. Qureshi KN, Griffiths TR, Robinson MC, et al: Combined p21WAF1/CIP1 and p53 overexpression predict improved survival in muscle-invasive bladder cancer treated by radical radiotherapy. Int J Radiat Oncol Biol Phys 2001; 51:1234. Sauter G, Moch H, Moore D, et al: Heterogeneity of erbB-2 gene amplification in bladder cancer. Cancer Res 1993; 53:2199. Underwood M, Bartlett J, Reeves J, et al: C-erbB-2 gene amplification: a molecular marker in recurrent bladder tumors? Cancer Res 1995; 55:2422. Orlando C, Sestini R, Vona G, et al: Detection of c-erbB-2 amplification in transitional cell bladder
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
carcinoma using competitive PCR technique. J Urol 1996; 156:2089. Eder IE, Stenzl A, Hobisch A, et al: Transforming growth factors-beta 1 and beta 2 in serum and urine from patients with bladder carcinoma. J Urol 1996; 156:953. Shariat SF, Kim JH, Andrews B, et al: Preoperative plasma levels of transforming growth factor beta(1) strongly predict clinical outcome in patients with bladder carcinoma. Cancer 2001; 92:2985. Sarkis AS, Bajorin DF, Reuter VE, et al: Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant MVAC. J Clin Oncol 1995; 13:1384. Kielb SJ, Shah NL, Rubin MA, Sanda MG: Functional p53 mutation as a molecular determinant of paclitaxel and gemcitabine susceptibility in human bladder cancer. J Urol 2001; 166:482. Cote RJ, Esrig D, Groshen S, Jones PA, Skinner DG: p53 and treatment of bladder cancer. Nature 1997; 385:123. Qureshi KN, Griffiths TR, Robinson MC, et al: TP53 accumulation predicts improved survival in patients resistant to systemic cisplatin-based chemotherapy for muscle-invasive bladder cancer. Clin Cancer Res 1999; 5:3500. Jahnson S, Risberg B, Karlsson MG, et al: p53 and Rb immunostaining in locally advanced bladder cancer: relation to prognostic variables and predictive value for the local response to radical radiotherapy. Eur Urol 1995; 28:135. Ogura K, Habuchi T, Yamada H, Ogawa O, Yoshida O: Immunohistochemical analysis of p53 and proliferating cell nuclear antigen (PCNA) in bladder cancer: positive immunostaining and radiosensitivity. Int J Urol 1995; 2:302. Wu CS, Pollack A, Czerniak B, et al: Prognostic value of p53 in muscle-invasive bladder cancer treated with preoperative radiotherapy. Urology 1996; 47:305. Ribeiro JC, Barnetson AR, Fisher RJ, Mameghan H, Russell PJ: Relationship between radiation response and p53 status in human bladder cancer cells. Int J Radiat Biol 1997; 2:11. Rotterud R, Berner A, Holm R, Skovlund E, Fossa SD: p53, p21 and mdm2 expression vs the response to radiotherapy in transitional cell carcinoma of the bladder. BJU Int 2001; 88:202. Ong F, Moonen LM, Gallee MP, et al: Prognostic factors in transitional cell cancer of the bladder: an emerging role for Bcl-2 and p53. Radiother Oncol 2001; 61:169. Petrylak DP, Scher HI, Reuter V, O’Brien JP, CordonCardo C: P-glycoprotein expression in primary and metastatic transitional cell carcinoma of the bladder. Ann Oncol 1994; 5:835. Shinohara N, Liebert M, Wedemeyer G, Chang JH, Grossman HB: Evaluation of multiple drug resistance in human bladder cancer cell lines. J Urol 1993; 150:505. Pendyala L, Perez R, Weinstein A, Zdanowicz J, Creaven PJ: Effect of glutathione depletion on the cytotoxicity of cisplatin and iproplatin in a human
354
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
Part IV Bladder melanoma cell line. Cancer Chemother Pharmacol 1997; 40:38. Hospers GA, Mulder NH, de Jong B, et al: Characterization of a human small cell lung carcinoma cell line with acquired resistance to cisdiamminedichloroplatinum(II) in vitro. Cancer Res 1988; 48:6803. Liebmann JE, Hahn SM, Cook JA, et al: Glutathione depletion by L-buthionine sulfoximine antagonizes Taxol cytotoxicity. Cancer Res 1993; 53:2066. Miller DC, Taub DA, Dunn RL, Montie JE, Wei JT: The impact of co-morbid disease on cancer control and survival following radical cystectomy. J Urol 2003; 169:105. Chang SS, Alberts G, Cookson MS, Smith JA Jr: Radical cystectomy is safe in elderly patients at high risk. J Urol 2001; 166:938. Stroumbakis N, Herr HW, Cookson MS, Fair WR: Radical cystectomy in the octogenarian. J Urol 1997; 158:2113. Soulie M, Straub M, Game X, et al: A multicenter study of the morbidity of radical cystectomy in select elderly patients with bladder cancer. J Urol 2002; 167:1325. Skinner DG, Stein JP, Lieskovsky G, et al: 25-year experience in the management of invasive bladder cancer by radical cystectomy. Eur Urol 1998; 33(Suppl 4):25. Nixon RG, Chang SS, Lafleur BJ, Smith JJ, Cookson MS: Carcinoma in situ and tumor multifocality predict the risk of prostatic urethral involvement at radical cystectomy in men with transitional cell carcinoma of the bladder. J Urol 2002; 167:502. Wood DP Jr, Montie JE, Pontes JE, VanderBrug Medendorp S, Levin HS: Transitional cell carcinoma of the prostate in cystoprostatectomy specimens removed for bladder cancer. J Urol 1989; 141:346. Vallancien G, Abou El Fettouh H, Cathelineau X, et al: Cystectomy with prostate sparing for bladder cancer in 100 patients: 10-year experience. J Urol 2002; 168:2413. Herr HW: Extent of surgery and pathology evaluation has an impact on bladder cancer outcomes after radical cystectomy. Urology 2003; 61:105. Marshall FF, Mostwin JL, Radebaugh LC, Walsh PC, Brendler CB: Ileocolic neobladder post-cystectomy: continence and potency. J Urol 1991; 145:502. Pritchett TR, Schiff WM, Klatt E, Lieskovsky G, Skinner DG: The potency-sparing radical cystectomy: does it compromise the completeness of the cancer resection? J Urol 1988; 140:1400. Brendler CB, Steinberg GD, Marshall FF, Mostwin JL, Walsh PC: Local recurrence and survival following nerve-sparing radical cystoprostatectomy. J Urol 1990; 144:1137. Schoenberg MP, Walsh PC, Breazeale DR, et al: Local recurrence and survival following nerve sparing radical cystoprostatectomy for bladder cancer: 10-year followup. J Urol 1996; 155:490. Hautmann RE: 15 years experience with the ileal neobladder. What have we learned? Urologe A 2001; 40:360.
151. Parekh DJ, Gilbert WB, Koch MO, Smith JA Jr: Continent urinary reconstruction versus ileal conduit: a contemporary single-institution comparison of perioperative morbidity and mortality. Urology 2000; 55:852. 152. Parekh DJ, Clark T, O’Connor J, et al: Orthotopic neobladder following radical cystectomy in patients with high perioperative risk and co-morbid medical conditions. J Urol 2002; 168:2454. 153. Bochner BH, Figueroa AJ, Skinner EC, et al: Salvage radical cystoprostatectomy and orthotopic urinary diversion following radiation failure. J Urol 1998; 160:29. 154. Hautmann RE, Simon J: Ileal neobladder and local recurrence of bladder cancer: patterns of failure and impact on function in men. J Urol 1999; 162:1963. 155. Studer UE, Zingg EJ: Ileal orthotopic bladder substitutes. What we have learned from 12 years’ experience with 200 patients. Urol Clin North Am 1997; 24:781. 156. Gburek BM, Lieber MM, Blute ML: Comparison of Studer ileal neobladder and ileal conduit urinary diversion with respect to perioperative outcome and late complications. J Urol 1998; 160:721. 157. Parekh DJ, Gilbert WB, Smith JA Jr: Functional lower urinary tract voiding outcomes after cystectomy and orthotopic neobladder. J Urol 2000; 163:56. 158. Hautmann RE, de Petriconi R, Gottfried HW, et al: The ileal neobladder: complications and functional results in 363 patients after 11 years of followup. J Urol 1999; 161:422. 159. Madersbacher S, Mohrle K, Burkhard F, Studer UE: Long-term voiding pattern of patients with ileal orthotopic bladder substitutes. J Urol 2002; 167:2052. 160. Stein JP, Lieskovsky G, Ginsberg DA, Bochner BH, Skinner DG: The T pouch: an orthotopic ileal neobladder incorporating a serosal lined ileal antireflux technique. J Urol 1998; 159:1836. 161. Dutta SC, Chang SC, Coffey CS, et al: Health related quality of life assessment after radical cystectomy: comparison of ileal conduit with continent orthotopic neobladder. J Urol 2002; 168:164. 162. Stein JP, Esrig D, Freeman JA, et al: Prospective pathologic analysis of female cystectomy specimens: risk factors for orthotopic diversion in women. Urology 1998; 51:951. 163. Chang SS, Cole E, Cookson MS, Peterson M, Smith JA Jr: Preservation of the anterior vaginal wall during female radical cystectomy with orthotopic urinary diversion: technique and results. J Urol 2002; 168:1442. 164. Ali-el-Dein B, el-Sobky E, Hohenfellner M, Ghoneim MA: Orthotopic bladder substitution in women: functional evaluation. J Urol 1999; 161:1875. 165. Blute ML, Gburek BM: Continent orthotopic urinary diversion in female patients: early Mayo Clinic experience. Mayo Clin Proc 1998; 73:501. 166. Mills RD, Studer UE: Female orthotopic bladder substitution: a good operation in the right circumstances. J Urol 2000; 163:1501.
Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 355 167. Ghoneim MA: Orthotopic bladder substitution in women following cystectomy for bladder cancer. Urol Clin North Am 1997; 24:225. 168. Chang SS, Cole E, Smith JA Jr, Cookson MS: Pathological findings of gynecologic organs obtained at female radical cystectomy. J Urol 2002; 168:147. 169. Stenzl A, Draxl H, Posch B, et al: The risk of urethral tumors in female bladder cancer: can the urethra be used for orthotopic reconstruction of the lower urinary tract? J Urol 1995; 153:950. 170. Poulsen AL, Horn T, Steven K: Radical cystectomy: extending the limits of pelvic lymph node dissection improves survival for patients with bladder cancer confined to the bladder wall. J Urol 1998; 160:2015. 171. Leissner J, Hohenfellner R, Thuroff JW, Wolf HK: Lymphadenectomy in patients with transitional cell carcinoma of the urinary bladder; significance for staging and prognosis. BJU Int 2000; 85:817. 172. Konety BR, Joslyn SA, O’Donnell MA: Extent of pelvic lymphadenectomy and its impact on outcome in patients diagnosed with bladder cancer: analysis of data from the surveillance, epidemiology and end results program data base. J Urol 2003; 169:946. 173. Herr HW, Bochner BH, Dalbagni G, et al: Impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder cancer. J Urol 2002; 167:1295. 174. Stein JP: Editorial: contemporary concepts of radical cystectomy and the treatment of bladder cancer. J Urol 2003; 169:116. 175. Wishnow KI, Levinson AK, Johnson DE, et al: Stage B (P2/3A/N0) transitional cell carcinoma of bladder highly curable by radical cystectomy. Urology 1992; 39:12. 176. Ghoneim MA, el-Mekresh MM, el-Baz MA, el-Attar IA, Ashamallah A: Radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1026 cases. J Urol 1997; 158:393. 177. Gschwend JE, Dahm P, Fair WR: Disease specific survival as endpoint of outcome for bladder cancer patients following radical cystectomy. Eur Urol 2002; 41:440. 178. Dalbagni G, Genega E, Hashibe M, et al: Cystectomy for bladder cancer: a contemporary series. J Urol 2001; 165:1111. 179. Frazier HA, Robertson JE, Dodge RK, Paulson DF: The value of pathologic factors in predicting cancer-specific survival among patients treated with radical cystectomy for transitional cell carcinoma of the bladder and prostate. Cancer 1993; 71:3993. 180. Pagano F, Bassi P, Galetti TP, et al: Results of contemporary radical cystectomy for invasive bladder cancer: a clinicopathological study with an emphasis on the inadequacy of the tumor, nodes and metastases classification. J Urol 1991; 145:45. 181. Montie JE, Wood DP Jr: The risk of radical cystectomy. Br J Urol 1989; 63:483. 182. Rosario DJ, Becker M, Anderson JB: The changing pattern of mortality and morbidity from radical cystectomy. BJU Int 2000; 85:427. 183. Frazier HA, Robertson JE, Paulson DF: Complications of radical cystectomy and urinary diversion: a
184.
185.
186. 187.
188. 189.
190.
191.
192.
193.
194.
195.
196.
197.
retrospective review of 675 cases in 2 decades. J Urol 1992; 148:1401. Chang SS, Baumgartner RG, Wells N, Cookson MS, Smith JA Jr: Causes of increased hospital stay after radical cystectomy in a clinical pathway setting. J Urol 2002; 167:208. Chang SS, Smith JA Jr, Wells N, et al: Estimated blood loss and transfusion requirements of radical cystectomy. J Urol 2001; 166:2151. Sternberg CN, Calabro F: Neo-adjuvant chemotherapy in invasive bladder cancer. World J Urol 2001; 19:94. Bajorin DF: Plenary debate of randomized phase III trial of neoadjuvant MVAC plus cystectomy versus cystectomy alone in patients with locally advanced bladder cancer. J Clin Oncol 2001; 19:17S. Sternberg CN: Current perspectives in muscle invasive bladder cancer. Eur J Cancer 2002; 38:460. von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. J Clin Oncol 2000; 18:3068. Donat SM, Herr HW, Bajorin DF, et al: Methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy and cystectomy for unresectable bladder cancer. J Urol 1996; 156:368. Hall R, Updated results of a randomised controlled trial of neoadjuvant cisplatin©, methotrexate (M), and vinblastine (V) chemotherapy for muscle-invasive bladder cancer (Abstract 710). Proc Am Soc Clin Oncol 2002; 21:178A. Natale RB, Grossman HB, Blumenstein B, et al: SWOG 8710 (INT-0080): randomized phase III trial of neoadjuvant MVAC + cystectomy versus cystectomy alone in patients with locally advanced bladder cancer (Abstract 3). Proc Am Soc Clin Oncol 2001; 20:21. Shipley WU, Winter KA, Kaufman DS, et al: Phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of Radiation Therapy Oncology Group 89-03. J Clin Oncol 1998; 16:3576. Wallace DM, Raghavan D, Kelly KA, et al: Neoadjuvant (pre-emptive) cisplatin therapy in invasive transitional cell carcinoma of the bladder. Br J Urol 1991; 67:608. Bassi P, Pappagallo G, Cosciani S, et al: Neoadjuvant M-VAC of invasive bladder cancer: G. U. O. N. E. multicenter phase III trial. Eur Urol 1998; 33:142. Dodd PM, McCaffrey JA, Herr H, et al: Outcome of postchemotherapy surgery after treatment with methotrexate, vinblastine, doxorubicin, and cisplatin in patients with unresectable or metastatic transitional cell carcinoma. J Clin Oncol 1999; 17:2546. Herr HW, Donat SM, Bajorin DF: Post-chemotherapy surgery in patients with unresectable or regionally metastatic bladder cancer. J Urol 2001; 165:811.
356
Part IV Bladder
198. Bono AV, Benvenuti C, Reali L, et al: Adjuvant chemotherapy in advanced bladder cancer: Italian Uro-Oncologic Cooperative Group. Prog Clin Biol Res 1989; 303:533. 199. Studer UE, Bacchi M, Biedermann C, et al: Adjuvant cisplatin chemotherapy following cystectomy for bladder cancer: results of a prospective randomized trial. J Urol 1994; 152:81. 200. Stockle M, Wellek S, Meyenburg W, et al: Radical cystectomy with or without adjuvant polychemotherapy for non-organ-confined transitional cell carcinoma of the urinary bladder: prognostic impact of lymph node involvement. Urology 1996; 48:868. 201. Chang SS, Hassan JM, Cookson M, Wells N, Smith J: Delaying radical cystectomy for muscle invasive bladder cancer results in worse pathologic stage. J Urol 2003; 170:1085. 202. Gschwend JE, Fair WR, Vieweg J: Radical cystectomy for invasive bladder cancer: contemporary results and remaining controversies. Eur Urol 2000; 38:121. 203. Hautmann RE: Complications and results after cystectomy in male and female patients with locally invasive bladder cancer. Eur Urol 1998; 33(Suppl 4):23. 204. Abratt RP, Wilson JA, Pontin AR, Barnes RD: Salvage cystectomy after radical irradiation for bladder cancerprognostic factors and complications. Br J Urol 1993; 72:756. 205. Barnes RW, Bergman RT, Hadley HT, et al: Survival following transurethral resection of bladder carcinoma. Cancer Res 1977; 37:2895. 206. Herr H: Conservative management of muscle-infiltrating bladder cancer: prospective experience. J Urol 1987; 138:1162. 207. Solsona E, Iborra I, Ricos JV, et al: Feasibility of transurethral resection for muscle infiltrating carcinoma of the bladder: long-term followup of a prospective study. J Urol 1998; 159:95. 208. Henry K, Miller J, Mori M, et al: Comparison of transurethral resection to radical therapies for stage B bladder tumours. J Urol 1988; 140:964. 209. Malkowicz SB, Nichols P, Lieskovsky G, et al: The role of radical cystectomy in the management of high-grade superficial bladder cancer. J Urol 1990; 44:641. 210. Whitmore WF Jr, Batata MA, Ghoneim MA, Grabstald H, Unal A: Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. Trans Am Assoc Genitourin Surg 1977; 69:100. 211. Novick AC, Stewart BH: Partial cystectomy in the treatment of primary and secondary carcinoma of the bladder. J Urol 1976; 116:570. 212. Dandekar NP, Tongaonkar HB, Dalal AV, Kulkarni JN, Kamat MR: Partial cystectomy for invasive bladder cancer. J Surg Oncol 1995; 60:24. 213. Schoborg TW, Sapolsky JL, Lewis CW Jr: Carcinoma of the bladder treated by segmental resection. J Urol 1979; 122:473. 214. Resnick MI, O’Connor VJ Jr: Segmental resection for carcinoma of the bladder: review of 102 patients. J Urol 1973; 109:1007.
215. Jenkins BJ, Caulfield MJ, Fowler CG, et al: Reappraisal of the role of radical radiotherapy and salvage cystectomy in the treatment of invasive (T2/T3) bladder cancer. Br J Urol 1988; 62:343. 216. Mameghan H, Fisher RJ, Watt WH, et al: The management of invasive transitional cell carcinoma of the bladder. Results of definitive and preoperative radiation therapy in 390 patients treated at the Prince of Wales Hospital, Sydney, Australia. Cancer 1992; 69:2771. 217. Fossa SD, Waehre H, Aass N, et al:: Bladder cancer definitive radiation therapy of muscle-invasive bladder cancer. A retrospective analysis of 317 patients. Cancer 1993; 72:3036. 218. Hayter CR, Paszat LF, Groome PA, et al: A populationbased study of the use and outcome of radical radiotherapy for invasive bladder cancer. Int J Radiat Oncol Biol Phys 1999; 45:1239. 219. Pollack A, Zagars GK, Swanson DA: Muscle-invasive bladder cancer treated with external beam radiotherapy: prognostic factors. Int J Radiat Oncol Biol Phys 1994; 30:267. 220. Gospodarowicz MK, Hawkins NV, Rawlings GA, et al: Radical radiotherapy for muscle invasive transitional cell carcinoma of the bladder: failure analysis. J Urol 1989; 142:1448. 221. Duncan W, Quilty PM: The results of a series of 963 patients with transitional cell carcinoma of the urinary bladder primarily treated by radical megavoltage x-ray therapy. Radiother Oncol 1986; 7:299. 222. Feneley MR, Schoenberg MP: Bladder-sparing strategies for transitional cell carcinoma. Urology 2000; 56:549. 223. Kuczyk M, Machtens S, Bokemeyer C, et al: Surgical bladder preserving strategies in the treatment of muscle-invasive bladder cancer. World J Urol 2002; 20:183. 224. Kaufman DS, Shipley WU, Griffin PP, et al: Selective bladder preservation by combination treatment of invasive bladder cancer. N Engl J Med 1993; 329:1377. 225. Shipley WU, Kaufman DS, Heney NM, Althausen AF, Zietman AL: An update of selective bladder preservation by combined modality therapy for invasive bladder cancer. Eur Urol 1998; 33(Suppl 4):32. 226. Dunst J, Rodel C, Zietman A, et al: Bladder preservation in muscle-invasive bladder cancer by conservative surgery and radiochemotherapy. Semin Surg Oncol 2001; 20:24. 227. Zietman AL, Shipley WU, Kaufman DS: Organ-conserving approaches to muscle-invasive bladder cancer: future alternatives to radical cystectomy. Ann Med 2000; 32:34. 228. Bradley BA, Wajsman Z: The role of chemotherapy and radiation in organ-preservation strategies for muscle-invasive bladder cancer. World J Urol 2002; 20:167. 229. Zietman AL, Grocela J, Zehr E, et al: Selective bladder conservation using transurethral resection, chemotherapy, and radiation: management and consequences of Ta, T1, and Tis recurrence within the retained bladder. Urology 2001; 58:380.
Chapter 19 Prognosis and Management of Invasive Transitional Cell Carcinoma 357 230. Given RW, Parsons JT, McCarley D, Wajsman Z: Bladder-sparing multimodality treatment of muscle-invasive bladder cancer: a five-year follow-up. Urology 1995; 46:499. 231. Caffo O, Fellin G, Graffer U, Luciani L: Assessment of quality of life after cystectomy or conservative therapy for patients with infiltrating bladder carcinoma. A survey by a self-administered questionnaire. Cancer 1996; 78:1089. 232. Zietman AL, Shipley WU, Kaufman DS, et al: A phase I/II trial of transurethral surgery combined with concurrent cisplatin, 5-Fluorouracil and twice daily radiation followed by selective bladder preservation in operable patients with muscle invading bladder cancer. J Urol 1998; 160:1673. 233. Mansson A, Mansson W: When the bladder is gone: quality of life following different types of urinary diversion. World J Urol 1999; 17:211. 234. Lynch WJ, Jenkins BJ, Fowler CG, Hope-Stone HF, Blandy JP: The quality of life after radical radiotherapy for bladder cancer. Br J Urol 1992; 70:519.
235. Hardt J, Filipas D, Hohenfellner R, Egle UT: Quality of life in patients with bladder carcinoma after cystectomy: first results of a prospective study. Qual Life Res 2000; 9:1. 236. Hart S, Skinner EC, Meyerowitz BE, et al: Quality of life after radical cystectomy for bladder cancer in patients with an ileal conduit, cutaneous or urethral Kock pouch. J Urol 1999; 162:77. 237. Kitamura H, Miyao N, Yanase M, et al: Quality of life in patients having an ileal conduit, continent reservoir or orthotopic neobladder after cystectomy for bladder carcinoma. Int J Urol 1999; 6:393. 238. Skinner EC: Quality of life with reconstruction. Semin Urol Oncol 2001; 19:56. 239. Hobisch A, Tosun K, Kinzl J, et al: Life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion. Semin Urol Oncol 2001; 19:18. 240. van der Veen JH, van Andel G, Kurth KH: Quality-of-life assessment in bladder cancer. World J Urol 1999; 17:219.
C H A P T E R
20 Transurethral Surgery of Bladder Tumors Rabi Tiguert, M.D., Louis Lacombe, M.D., F.R.C.S.C., and Yves Fradet, M.D.
Cancers originating from the urothelium are responsible for 8% of all diagnosed tumors in men and 4% in women. In the United States alone, this corresponds to more than 56,000 new cases yearly,1 transitional cell carcinoma (TCC) accounting for approximately 90% of all cases.2 At the time of diagnosis, about 80% of bladder tumors are superficial and limited to the mucosa or submucosa (Ta, T1), while 20% invade the muscular layer of the bladder wall. In recent cohort studies of patients newly diagnosed with Ta, T1 tumors, a 55% recurrence rate was observed within 3 years,3,4 but previous studies had reported up to 70% recurrence within 5 years of the initial diagnosis.5 The majority of these recurrent tumors will remain superficial and progression to muscle invasive or metastatic cancer will occur in <10% of recurrent cases. These statistics underscore the overall importance of transurethral surgery as the primary and often only treatment modality for bladder cancer. Obviously, intravesical immunotherapy and chemotherapy have become important therapeutic modalities to prevent recurrence and progression of superficial bladder tumors. Nevertheless, the quality of the transurethral surgery has an important influence on the risk of tumor recurrence, since up to 41% of recurrent tumors were reported to occur at the site of the original resection in the National Bladder Cancer Collaborative Group study.6 Recent EORTC studies on variability of recurrence were linked to the experience of the surgeon. Endoscopic resection or fulguration of bladder tumor is usually effective, has low morbidity, and is associated with a rapid postoperative recovery. Transurethral resection (TUR) is the standard method for the initial diagnosis and staging of bladder cancer, as well as for the eradication of low-stage bladder tumor. Some infiltrating bladder cancers can also be treated primarily by TUR, with or without adjuvant radiation therapy or systemic chemotherapy.
358
Laser therapy, either as thermocoagulation of bladder tumors or as photodynamic therapy, is an alternative that has become part of the treatment armamentarium. Recent advances in fluorescent cystoscopy may influence visualization of tumors and enhance the completeness of resection. This chapter will review the indications, techniques, and outcomes of TUR, LASER thermocoagulation, and photodynamic therapy in the management of bladder cancer. TRANSURETHRAL RESECTION Preparation Before TUR of the first tumor, it is mandatory to study the upper urinary tract either by retrograde pyelogram or intravenous pyelogram (IVP) to rule out any associated tumor of the renal pelvis and/or ureters and to identify any hydroureteronephrosis, which is most often the result of tumor invasiveness. The IVP is usually normal in the presence of superficial bladder tumor with the exception of tumors directly overlying the ureteral orifice and causing obstruction. About 3% of patients with bladder cancer will concurrently or subsequently have an upper tract urothelial neoplasm. The presence of ureteral obstruction, particularly in the absence of intravesical involvement of the ureteral orifices, suggests a highstage, muscle-invasive, and metastatic tumor in more than 90% of the patients. If parameters of the preoperative work-up are suspicious for advanced stage disease or muscle invasive disease, then computed tomography (CT) scan of the abdomen and pelvis with injection may be a suitable alternative to IVP if thin cuts through the kidney and ureter are obtained. CT scan has the advantage of determining size of the bladder tumor and, to some extent, presence of local invasion or regional lymphadenopathy. Ureteral obstruction is a significant risk
Chapter 20 Transurethral Surgery of Bladder Tumors 359
factor of poor prognosis and has been associated with significantly lower, overall, and stage-specific, survival rates, despite radical surgery. More than 90% of patients with bilateral obstruction had disease with extravesical extension. One-third of patients with unilateral hydronephrosis had disease confined to the bladder, of whom 42% had tumor confined to the mucosa with no muscle invasion (p0-p1). These findings suggest that a significant proportion of patients with unilateral obstruction may have good outcome with cystectomy alone.7 Anesthesia Following the diagnosis of a bladder tumor, which is usually made in an office setting, the formal endoscopic evaluation, including biopsy-resection, is performed in the operating room and requires that the patient have an adequate anesthesia for the pelvic floor and bladder relaxation and thus a prior consultation with the anesthesiologist is required to provide a successful outcome. Anesthesia could be attempted either with spinal or general anesthesia. Other methods of anesthesia have been reported for removal of small tumors or performing cold-cup biopsies, including local anesthesia with intravesical instillations of lignocaine or with electromotive drug administration system (EMDA) that enhances bladder wall penetration of lidocaine. This approach has not been widely accepted.8,9 Bimanual Examination The bimanual examination is an integral part of the operative procedure for patients undergoing treatment for
bladder cancer. It is performed with the patient under anesthesia before tumor resection and should be repeated after the endoscopic procedure is completed. In the male patient, the urologist puts a finger in the rectum with the other hand placed suprapubically and palpates for any mass (Figure 20-1). In the female patient, bimanual examination is performed with two fingers in the vagina and the other hand placed suprapubically. The presence of a mass should be noted, along with the evidence of indurations or fixation to the adjacent organs or the pelvis walls. The disappearance of a movable mass after TUR is more likely consistent with a superficial tumor. When the mass is fixed or indurated or persists after TUR, it is more likely to be muscle-invasive tumor. Bimanual examination cannot distinguish benign from malignant bladder fixation in patients who underwent previous radiation therapy or had pelvic inflammatory disease. Instrumentation and Equipment Several instruments are potentially useful for the surgical removal of bladder tumors. At the time of the operative procedure, the urologist should have sufficient lenses, which consist of either a 12-degree or 30-degree lens, and a 70-degree lens. On the other hand, several loops may be available, including the 90-degree loop, which is usually used for resecting a tumor along the floor of the bladder, the trigone, or near the bladder neck. The angled loop is preferable to resect tumors located along the lateral walls, posterior wall, or dome. The roller or ball electrode is helpful to achieve hemostasis at the end of tumor resection and to cauterize small noninvasive papillary tumors or areas of diffuse carcinoma in situ (CIS).
Figure 20-1 Bimanual examination.
360
Part IV Bladder
Video Endoscopy The new generation of endoscopic video equipment is very attractive and its use is quickly becoming routine in private and teaching hospitals as instruction during endoscopic procedures takes on a new dimension. The advantage of the endoscopic video system is that all of the staff in the operating room feels that they are taking part in the procedure, which no longer isolates the urologist from the other members of the team. The likelihood of contamination of body fluids is negligible with endoscopic video procedures.
the bladder wall.10 Some cup biopsy forceps have an attachment for electrocautery that allows immediate coagulation of the bladder wall. A Bugbee electrode or resectoscope or roller may be used to cauterize bleeding vessels.11 Suspicious erythematous areas for CIS can be sampled by cold biopsy. There is almost no risk of bladder perforation, and the absence of electrocautery during removal helps preserve the architecture of the urothelium for pathology evaluation. The role of a cold-cup biopsy in normal appearing areas of the bladder is controversial.
Flexible Cystoscope
Technique for Transurethral Resection
Flexible cystoscope is often used for the initial diagnosis and follow-up of patients with bladder tumors in the office setting. It has less discomfort than rigid endoscopy especially in men. The entire urinary bladder mucosa can be examined with a single instrument, as well as bladder neck, by retrograde view. Small laser fibers or Bugbee electrode devices can be inserted through a flexible cystoscope to allow destruction of small, low-grade, noninvasive papillary tumors in the office setting.
The first step of TUR is to visualize the whole bladder mucosa, the trigone, ureteral orifices, bladder neck, and prostatic urethra (Figure 20-2). Sometimes it is difficult to visualize the dome especially in obese patient. In such circumstances, suprapubic manual pressure toward the resectoscope should be applied, the mucosa in the beginning of bladder filling is to be observed. The second step includes the report of any abnormality, such as erythematous areas, that could correspond to CIS or dysplasia. In our institution, we used a diagram to report the location, appearance (papillary or sessile), and size of all tumors, which is a part of the patient’s record. The sites of mucosal biopsies are also recorded on the diagram, as well as all the observed abnormalities during cystoscopy were also noted. Photographs of initial tumors and abnormal areas can be taken in order to be compared with the recurrent one. Following endoscopy, a resectoscope is used to remove all visible tumors. A continuous flow resectoscope has the advantage to maintain the
Cold-Cup Biopsy Cold-cup biopsy is used primarily to remove papillary tumors or to sample multiple areas of the bladder mucosa. The small size of the cup limits its indication to tumors generally <0.5 cm. Biopsy forceps exist for flexible cystoscope but most often a rigid cystoscope is used. The cup is closed over a papillary tumor, and with a twisting and pulling motion, the tumor is avulsed from
Figure 20-2 Transurethral resection of a bladder tumor.
Chapter 20 Transurethral Surgery of Bladder Tumors 361
bladder at a reduced capacity and thus minimize the risk of bladder perforation or stimulation of the obturator nerve. A 70-degree lens is used prior and after tumor resection to review the bladder, since there are locations in the bladder that are difficult to visualize with the 12-degree or 30-degree lens used with a resectoscope. After the resectoscope has been inserted, the resecting loop should be readily visible and the instrument should be checked for full excursion of the loop. The resecting loop should be passed beyond the tumor and then pulled back toward the viewing eye while applying the electrocautery. At some point, it is necessary to maintain the resectoscope loop in an extended fixed position and to move the resectoscope downward with a rocking motion parallel to the base of the tumor, similar to scraping a wall. Constant orientation is necessary during these maneuvers. With papillary tumors, the resecting loop is often used to elevate the tumor off the bladder wall before application of the electric current. The base of bladder tumors with small pedicle can often be resected in a whole piece. In larger tumors, however, early attempt to resect its base will result in a nonfixed tumor rendering the resection difficult. Resection of bladder tumors should ideally be performed in two steps: resection of the tumor and its base, which must include muscle wall. Care should be taken to limit coagulation artifact on the specimen for a better pathologic analysis. In patients with possible muscle invasive tumors or suspicion of CIS, a TUR of the prostatic urethra should be performed to rule out CIS or intraductal neoplasia in the prostate. Such information is important for counseling the patient in planning intravesical therapy, or cystectomy with orthotopic neobladder. Prostatic urethral sampling could be attempted either with superficial resection immediately proximal to the verumontanum on both sides at 5 and 7 o’clock, or by resection of the whole prostatic urethra for a complete sampling if cystectomy with prostate sparing is indicated.12 Irrigation Fluid The choice of irrigation fluid is important during a TUR of a bladder tumor, because of problems with electrical conduction, saline solution should not be used. The amino acid solutions used for TUR of the prostate are an option but are expensive and unnecessary, since the absorption of large amounts of irrigation fluids is rarely encountered with bladder tumor resection. Sterile water or isotonic irrigation fluid are mostly used. Management of Intraoperative Problems Some tumors may be difficult to resect because of their location, such as anterior bladder wall tumors, especially those located close to the bladder neck. By using differ-
ent techniques, a better exposure of these tumors could be obtained. By pushing down the anterior lower wall of the abdomen with the opposite hand, these tumors are usually brought to a better view. An assistant can carry out this manipulation if the surgeon prefers the twohanded instrument. However, even with the use of a long resectoscope, such tumors may remain inaccessible in a morbidly obese patient. In this uncommon setting, the resectoscope can be inserted by a perineal urethrostomy performed in the bulbar urethra over a metal sound to circumvent the suspensory ligament of the penis. After the TUR a Foley catheter is inserted into the penile urethra or through the perineal urethrostomy, which heals within 24 hours of removal of the catheter. Another method to remove these anterior bladder wall tumors has been described, which consists to perform a 2-cm incision in the skin that is deepened by blunt dissection to the fascial level. A nasal speculum is used to refract the fat and allow an incision to be made on the fascia. A finger is inserted to localize the bowel. A peanut or empty sponge stick holder is introduced through the opening and the TUR began with control of the tumor position. This technique has been used in 9 patients by the author who reported this technique. It is mandatory to carry out the TUR with usual precautions to avoid bladder perforation.13 Deep resection in the bladder neck area must be carefully performed. In females, TUR in such areas can create a vesicovaginal fistula. In men, it may result in trigonal undermining hampering further resection and even bladder catheterization. If an undermining trigone is apparent at the end of surgery, the catheter should be inserted with the help of a catheter guide. Tumors involving the ureteral orifice occur in approximately 10% to 15% of cases. Noninvasive tumors should be resected aggressively and resection may be pursued to remove the whole intramural ureter if a papillary tumor is found to extend in this area. Complete resection of a noninvasive papillary tumor will leave a bulging ureteral mucosa. To prevent stenosis of the orifice, fulguration and coagulation should be minimized in this area. If extensive coagulation is required or the ureteral mucosa does not appear to protrude satisfactorily, a ureteral catheter should be placed for a few days to allow initial healing and prevent ureteral obstruction. Resection of a ureteral orifice and the intramural portion of a ureter will result in vesicoureteral reflux. While reflux may increase the risk of upper urinary tract seeding, it also allows passage of endovesical immunotherapy or chemotherapy and ensuing preventive effect. TUR of tumors arising in an acquired bladder diverticulum is limited, since the absence of an underlying muscular component will result in a perforation. Only small superficial tumors should be resected or fulgurated in a diverticulum with a wide mouth. Otherwise, we can
362
Part IV Bladder
rely on laser therapy or intravesical immunotherapy or chemotherapy. If there is a doubt or a persistent tumor, a diverticulectomy by an extravesical approach should be performed after proper control of any present tumor. The goal of TUR treatment for superficial bladder tumors should be complete eradication of the tumors. If there are numerous tumors or bad visibility hampered by uncontrolled bleeding, surgery should be aborted and resumed 1 or 2 weeks after. Laser therapy and endovesical therapy may be an option for residual superficial bladder tumors. Sometimes, concurrent benign prostatic hyperplasia may be too large or protruding into the bladder and thus impeding TUR of bladder tumors. Ideally, the bladder tumor should be resected first and allow the healing before the prostate is resected in order to prevent tumor seeding in the prostatic fossa. In rare instances, the resection of the prostatic lobe is performed prior to the bladder tumor. There is a lack of increase of transitional cell tumors seeding of the prostatic fossa in previous reports when concomitant TUR of bladder tumor and prostate were performed. Mitomycin C has been shown to decrease the likelihood of bladder tumors seeding and it may be safe to administer a single instillation of 40 mg after the surgery. Second Look Resection On occasion, the pathologist will have difficulty determining whether the tumor has invaded the muscularis propria. As this is important to dictate therapy, these patients need to undergo a re-resection of the base of the tumor. In some instances, a second look resection is performed to resect any residual tumor left behind in 37% of cases.13 This maneuver will decrease the rate of bladder tumor recurrences and increase the number of bladder spared. We perform a second look resection usually 4 weeks after the initial one in the presence of T1G3 tumor invading more than 50% of the depth of the muscularis mucosa.14 TUR as Primary Treatment of Muscle Invasive Tumors TUR has been mainly reserved to treat superficial bladder tumors. However, some select patients with muscle invasive bladder cancer could be treated with TUR alone or associated with chemotherapy and radiation therapy. Several studies show that in selected patients, TUR achieves 5-year survival rates comparable to those achieved with radical cystectomy,15–17 and approximately 10% of cystectomy patients have no residual tumor (p0) found in the cystectomy specimen.16 This suggests that TUR can control some muscle-invasive bladder cancers. For patients with primary muscle-invasive bladder can-
cer, radical TUR is an acceptable bladder-sparing treatment strategy. TUR alone is justified only when the bladder tumor is clinically limited to the superficial muscle layer and when re-resection biopsies of the periphery and deep muscle in the tumor bed are negative for invasive carcinoma. Patients who have any evidence of residual tumor invasion are more likely to undergo incomplete resection and be understaged, which predisposes them to early local relapse or metastatic disease and higher risk of developing new invasive cancers in the bladder. Lifelong surveillance cystoscopy seems necessary to detect recurrent invasive tumors that can be successfully treated with salvage cystectomy. Even with close follow-up, patients who elect treatment by TUR alone assume some risk (at least 8% and possibly as high as 16%) that a recurrent invasive tumor in the retained bladder may eventually cause death from TCC. Postoperative Management Resection of smaller bladder tumors with very minimal bleeding may not require postoperative catheterization unless postoperative administration of mitomycin C is indicated. Furthermore, most endoscopic resections require a short period of bladder catheterization with a Foley catheter. The catheter can be removed when the hematuria has resolved and this is routinely observed on postoperative day one. Catheterization helps quantify both urine output and degree of hematuria. With a catheter in place, the bladder does not have to contract to empty, and this may beneficially reduce the amount of postoperative bleeding. On the other hand, bladder spasms may occur with the Foley catheter in place responding to anticholinergic therapy. Bleeding should be controlled at the time of surgery. When bleeding control is adequate, there is generally no need for three-way bladder irrigation. Catheter drainage may be indicated for longer periods of time if perforation has occurred or if tumor resection extends up to the limit of the bladder wall. Antibiotics are not required postoperatively; however, many urologists prescribe prophylactic oral antibiotics for a period of 3 to 5 days. Complications The most frequent encountered complications following TUR of bladder tumors are intra- and immediate postoperative bleeding with an incidence ranging from 2% to 13%. In a recent study, the complication rate was 5.1% in a series of 2821 patients.18 Hemorrhage The incidence of hemorrhage following TUR of bladder tumors ranges between 2% and 13%.18–20 This variability of incidence is due to the differences of the definition of
Chapter 20 Transurethral Surgery of Bladder Tumors 363
hemorrhage. The best way to prevent this bleeding is to perform a careful coagulation in the beginning of bladder filling after TUR to avoid the intravesical high pressure that stops temporarily the bleeding by compression of the vessels. Nevertheless, it is not uncommon to have an important postoperative bleeding in patients with crystal-clear irrigation fluid at the end of surgery. The risk of hemorrhage exists until the third week postoperative following scare sloughing. These secondary hemorrhages are seen when the coagulation of the tumor is extensive leading to a necrosis of the bladder wall. Bladder Perforation Bladder perforation was encountered in 0.9% to 5% of patients undergoing TUR of bladder tumors. It is probably underestimated since it is less reported in the literature. Many factors have been implicated including deep TUR, bad vision of the site to be resected, tumor located in a diverticulum, stimulation of the obturator nerve by an electrical current, and overdistension of the bladder. Thin bladder wall secondary to multiple TUR of bladder tumors is also at risk for perforation. Perforation of the bladder should be recognized whenever there is difficulty to distend the bladder; the quantity of fluid instilled in the bladder is greater than the recuperated one and also in the presence of an abdominal distension associated with a tachycardia. When there is a doubt a cystogram under fluoroscopy could be performed during the TUR. Perforations of the bladder are divided into two groups, intraperitoneal and extraperitoneal; the treatment is different in the two categories. Management of extraperitoneal bladder perforation is conservative, consisting of drainage of the bladder by a urethral catheter and administration of large spectrum antibiotics. Surgical or percutaneous drainage is rarely indicated and is dictated when there is an important urine leakage or a pelvic abscess. Intraperitoneal bladder perforation is classically managed surgically. The indication of exploratory surgery relies on the importance of the perforation, presence of a bowel traumatism, and the risk of infection. In some selected cases, it is possible to manage it conservatively in the absence of bowel perforation. Draining the bladder with a urethral catheter during a week together with antibiotic administration is sufficient. However, if there is no improvement with the conservative treatment, a surgical or laparoscopic exploration is mandatory to repair the bladder as a whole, as well as any concomitant bowel perforation. Urinary Infection The reported incidence of urinary infection following TUR of bladder tumor (TURBT) ranged from 2% to 39%. The etiology of urinary infection is controversial. It has been suggested that the bladder tumor is the reser-
voir site of the germs and during the TUR, the germs are dislocated and may be the source of infection.21 However, this observation was not confirmed by others who held the endoscopy maneuver responsible for urinary infection by inoculating germs into the bladder.22,23 Urethral Stricture The incidence of urethral stricture was 15% in males and 4% in females but less than one-third were symptomatic. The strictures were found distally in the urethra in 83% of the patients and could be treated with optical urethrotomy. The risk factors of urethral stenosis include longer duration of postoperative catheterization and use of larger size resectoscope. Furthermore, repeated transurethral instrumentations may increase the risk of stricture development.24 Obturator Nerve Reflex Obturator nerve reflex may be evoked while resecting lesions on the lower lateral wall and neck of the bladder, particularly in thin patients. This reflex will result in adductor spasms of the leg, as well as inward movement of the bladder wall during resection that could result in its perforation and to some extent in trauma to major pelvic vessels. The obturator reflex may be prevented by lowering the cutting current and avoiding distension of the bladder during resection of this area. If these maneuvers are not successful, d-tubocurarine and succinylcholine can be used during general anesthesia, or to block the obturator nerve as it passes through the obturator canal with infiltration by a local anesthetic as described previously by Augspurger.25 Ureteral Orifice Injury Ureteral orifices could be damaged when the tumor is localized inside the orifice or close to it, raising the risk of stricture and reflux vesicoureteral. Excretory urography should be performed within a few weeks after a TUR that has involved the periureteral area to detect hydronephrosis due to ureteral injury. Management of ureteral stricture post-TUR consists of antegrade or retrograde intraluminal dilatation with a risk of reflux. The risk of tumor seeding is 22-fold greater when there is a vesicoureteral reflux. No consensus has been reached to treat the reflux in patients with history of bladder tumors, but it seems reasonable to treat patients with reflux grade III, or having multiple recurrences of bladder tumors or tumors located near the orifices.26–28 Reabsorption Syndrome This is a rarely encountered complication when nonsaline irrigating fluid was used. This appears usually fol-
364
Part IV Bladder
lowing intraperitoneal bladder perforation. An extracellular hyper hydration was observed leading sometimes to severe hyponatremia causing cerebral edema with nausea, vomiting, and visual disturbances. The treatment consists of water restriction and diuretics.29 Bladder Explosion Intravesical explosion during endoscopic resection are rare but may be devastating. The formation of explosive gas, essentially an air–hydrogen mixture, results from carbonization of tissues (particularly with the coagulation current) and the introduction of air into the bladder during manipulation of the resectoscope. The nature of the bladder infusion liquid does not appear to play an important role. Prevention implies the use of a coagulation current of moderate power, the avoidance of air entering the bladder accidentally, and the continuous or repeated evacuation of the air bubble under the bladder vault.30–32
noncontact fiber with a 5-degree to 15-degree angle of divergence (Table 20-1). Surgical Techniques Laser fibers could be inserted through standard cystoscopes either flexible or rigid. For rigid cystoscope a modified Albarran apparatus is available. Energy emission is usually controlled with a foot pedal; 35 to 40 W is ample for necrosis. After visualization of the tumor, the laser fiber is introduced into the cystoscope and the tip is positioned 2 to 3 mm from the surface of the tumor. Often, the best way to appreciate the distance between the fiber tip and the tumor is to start approximately 1 cm away and slowly move closer to the tumor until the thermal changes become apparent. The end point of treatment is determined by visible changes in the tumor, which is characterized by a white discoloration (Figure 20-3). Advantages and Disadvantages of Laser Use
LASER SURGERY LASER is an acronym that stands for “light amplification by the stimulated emission of radiation.” It describes the physical process by which light energy is produced. A laser is a device that generates an intense beam of light that falls between the longest and the shortest wavelengths, in the infrared, visible, and the ultraviolet portions of the electromagnetic spectrum. The lasers are named by the laser medium (solid, liquid dye, or gas component), which when stimulated produces photons (laser light). During the last two decades, when the FDA approved the use of the Neodymium:YAG (Nd:YAG) (1984), Argon (1987), KTP (1988), and in 1992 the Holmium:YAG (Ho:YAG) lasers in urology, these surgical tools have been used to treat various urologic diseases, including superficial bladder tumors. The first reported study using lasers to treat superficial bladder tumors occurred more than 20 years ago.33, 34 The most of the clinical experience in the treatment of bladder cancer has been obtained using an Nd:YAG laser with an end-fire
One of the most important advantages of laser treatment is the lack of bleeding during surgery and in the postoperative period. Whether energy is applied directly to the center of the tumor initially or to the periphery, bleeding simply does not occur unless there is trauma to the treated area from the tip of the cystoscope or fiber. Catheter insertion is not required. Patients treated with Nd:YAG laser can immediately resume their daily activity with an extremely low risk of bleeding. Laser treatment appears to be less painful than electrocautery resection. Patients are able to perceive the laser energy and often describe it as a burning discomfort. Laser energy does not stimulate the obturator nerve. Therefore, contraction of the adductor muscles of the thigh is avoided. This helps to prevent bladder perforation. Laser treatment can be effective for tumors located in bladder diverticulum by delivering energy with either a flexible or rigid cystoscope. Even though the penetration depth of the laser energy exceeds the thickness of the diverticulum wall, free perforation rarely occurs.
Table 20-1 Different Laser Types Used in Urology Practice Laser Type
Wavelength (nm)
Energy Delivery
Endoscopic Uses
Tissue Penetration
KTP
532
Continuous wave
Yes
1.0 mm
Diode
800–1.1
Continuous wave or pulsed
Yes
Varies with wavelength
Nd:Yag
1064
Continuous wave
Yes
5.0 mm
Ho:YAG
2100
Pulsed
Yes
<0.5 mm
CO2
10,600
Continuous wave
No
0.1 mm
Chapter 20 Transurethral Surgery of Bladder Tumors 365
Figure 20-3 Nd:YAG laser-induced coagulation necrosis of a bladder tumor. (Courtesy of Dr. Guy Drouin.)
Disadvantages of laser fulguration include lack of histopathologic specimens for diagnosis. It is recommended to obtain tissue with TUR for proper grading and staging of the tumor. It requires some training and some manipulation with safety applications concern for the patient and the surgeon. The most feared complication of laser treatment is forward scatter of the energy with perforation of an adjacent organ even in the absence of bladder perforation. Bladder Tumor Recurrence Rate The clinical results achieved with laser treatment of superficial bladder cancer are comparable with the results of electrocautery resection. In a prospective study of 122 patients randomized for Nd:YAG laser (n = 62) or TUR (n = 60), new tumors in nontreated areas occurred in 12 patients in the laser group and in 13 patients in the TUR group. Thus, no difference in the recurrence rate was observed for laser and electrocautery treated patients.34 Fluoroscopic Cystoscopy The porphyrins are intermediate in the synthesis of heme,35 which all mammalian nucleotide cells have the ability to synthesize as HAEME-containing enzymes that are required for energy metabolism. The derivative of hematoporphyrins, like Photofrin, a derivative purified form of hematoporphyrin, can be used for photodetection of malignant cells, as well as photodynamic therapy. However, the latter product needs to be taken by mouth several days before treatment and one potential side effect of such medication is a skin photosensitization, which can last for 6 to 8 weeks. Another way to
Figure 20-4 A, Superficial TCC of the bladder on white light cystoscopy. B, Same tumors seen by fluorescence cystoscopy.
increase production of porphyrin is the use of 5-aminolevulinic acid (5-ALA), which could be administrated intravesically without any major side effects. The 5-ALA is a well-known precursor in the synthesis of protoporphyrin IX, the latter being the immediate precursor of heme. Accumulation of protoporphyrin IX is found in urothelial tumor tissue compared with unaffected urothelium (ratio 17:1). Thus, tumors fluoresce red under excitation with violet light at wavelength of 375 to 440 nm36 (Figure 20-4). The neoplastic cells can then be used as an endogenous photosensitizer under excitation with blue light, which produces red fluorescence. The use of porphyrin fluorescence has been studied to improve the diagnosis of superficial bladder cancer.37–39 Results from these publications have shown that fluorescence cystoscopy improved the detection rate of all malignant/dysplastic lesions by approximately
366
Part IV Bladder
18% to 76%. In cases of lesion of dysplasia/CIS, detection rate was improved from 50% to 140%.37–39 Furthermore, three recent studies have prospectively shown a decrease risk of residual tumor after TUR and a significantly improved recurrence-free survival at follow-up.40–42 Larger multicenter studies are ongoing to further evaluate the exact role of fluorescence cystoscopy in superficial bladder tumors.
REFERENCES 1. Jemal A, Thomas A, Murray T, et al: Cancer statistics. CA Cancer J Clin 2002; 52:23–47. 2. Weiss MA, Mills SE: Atlas of Genitourinary Tract Disorders, pp 12.5–12.10. Singapore, Gower Medical Publishing, 1989. 3. Allard P, Fradet Y, Têtu B, et al: Tumor-associated antigens as prognostic factors for recurrence in 382 patients with primary transitional cell carcinoma of the bladder. Clin Cancer Res 1995; 1:1195. 4. Kiemeney LA, Witjes JA, Heijbroek RP, et al: Predictability of recurrent and progressive disease in individual patients with primary superficial bladder cancer. J Urol 1993; 150:60. 5. Malmstrom PU, Busch C, Norlen BJ: Recurrence, progression and survival in bladder cancer: a retrospective analysis of 232 patients with greater or equal to 5-year follow-up. Scand J Urol Nephrol 1987; 21:185. 6. National Bladder Cancer Collaborative Group: Surveillance, initial assessment, and subsequent progress of patients with superficial bladder cancer in a prospective longitudinal study. Cancer Res 1977; 37:2907–2910. 7. Haleblian GE, Skinner EC, Dickinson MG, et al: Hydronephrosis as a prognostic indicator in bladder cancer patients. J Urol 1998; 160:2011–2014. 8. Holmang S, Aldenborg F, Hedelin H: Extirpation and fulguration of multiple superficial bladder tumor recurrences under intravesical lignocaine anesthesia. Br J Urol 1994; 73:177–180. 9. Jewett MA, Valiquette L, Sampson HA, et al: Electromotive drug administration of lidocaine as an alternative anesthesia for transurethral surgery. J Urol 1999; 161:482–485. 10. Beaghler M, Grasso M III: Flexible cystoscopic bladder biopsies: a technique for outpatient evaluation of the lower urinary tract urothelium. Urology 1994; 44:756–759. 11. Tauber R: Biopsy-coagulation forceps to simplify biopsy of the bladder. J Urol 1985; 133:783–785. 12. Vallancien G, Abou El Fettouh H, Cathelineau X, et al: Cystectomy with prostate sparing for bladder cancer in 100 patients: 10-year experience. J Urol 2002; 168:2413–2417. 13. Horan AH: Urologists at work. Method permitting easier resection of bladder tumors in the anterior midline. J Urol 2000; 164(1):106. 14. Rigaud J, Karam G, Braud G, et al: T1 bladder tumors: value of a second endoscopic resection. Prog Urol 2002; 12(1):27–30.
15. Herr HW: Conservative management of muscleinfiltrating bladder cancer: prospective experience. Urol 1987; 138:1162–1163. 16. Solsona E, Iborra I, Ricos JV, Monros JL, Dumont R: Feasibility of transurethral resection for muscleinfiltrating carcinoma of the bladder: prospective study. J Urol 1992; 147:1513–1515. 17. Herr HW: Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol 2001; 19:89–93. 18. Collado A, Chechile GE, Salvador J, Vicente J: Early complications of endoscopic treatment for superficial bladder tumors. J Urol 2000; 164:1529–1532. 19. Dick A, Barnes R, Hadley H, Bergman RT, Ninan CA: Complications of transurethral resection of bladder tumors: prevention, recognition and treatment. J Urol 1980; 124(6):810–811. 20. Kondas J, Szentgyorgyi E: Transurethral resection of 1250 bladder tumours. Int Urol Nephrol 1992; 24:35–42. 21. Appell RA, Flynn JT, Paris AM, Blandy JP: Occult bacterial colonization of bladder tumors. J Urol 1980; 124:345–346. 22. Goldwasser B, Bogokowsky B, Nativ O, et al: Urinary infections following transurethral resection of bladder tumors—rate and source. J Urol 1983; 129:1123–1124. 23. Badenoch DF, Murdoch DA, Tiptaft RC: Microbiological study of bladder tumors, their histology and infective complications. Urology 1990; 35:5–8. 24. Nielsen KT, Christensen MM, Olesen S: Urethral strictures after transurethral bladder tumor resection. Scand J Urol Nephrol 1989; 23(2):81–83. 25. Augspurger RR, Donohue RE: Prevention of obturator nerve stimulation during transurethral surgery. J Urol 1980; 123:170–172. 26. Mukamel E, Nissenkorn I, Glanz I, Vilcovsky E, Servadio C: Upper tract tumours in patients with vesicoureteral reflux and recurrent bladder tumours. Eur Urol 1985; 11:6–8. 27. De Torres Mateos JA, Banus Gassol JM, Palou Redorta J, Morote Robles J: Vesicorenal reflux and upper urinary tract transitional cell carcinoma after transurethral resection of recurrent superficial bladder carcinoma. J Urol 1987; 138:49–51. 28. Amar AD, Das S: Upper urinary tract transitional cell carcinoma in patients with bladder carcinoma and associated vesicoureteral reflux. J Urol 1985; 133:468–471. 29. Hahn RG: Transurethral resection syndrome after transurethral resection of bladder tumours. Can J Anaesth 1995; 42:69–72. 30. Viville C, de Petriconi R, Bietho L: Intravesical explosion during endoscopic resection. Apropos of a case. J Urol (Paris) 1984; 90:361–363. 31. Hansen RI, Iversen P: Bladder explosion during uninterrupted transurethral resection of the prostate. A case report and an experimental model. Scand J Urol Nephrol 1979; 13:211–212. 32. Ning TC Jr, Atkins DM, Murphy RC: Bladder explosions during transurethral surgery. J Urol 1975; 114:536–539.
Chapter 20 Transurethral Surgery of Bladder Tumors 367 33. Hofstetter A, Frank F, Keiditsch E, Bowering R: Endoscopic neodymium-YAG laser application for destroying bladder tumors. Eur Urol 1981; 7:278–282. 34. Beisland HO, Seland P: A prospective randomized study on neodymium-YAG laser irradiation versus TUR in the treatment of urinary bladder cancer. Scand J Urol Nephrol 1986; 20(3):209–212. 35. Moore MR, Disler PB: Biochemical diagnosis of the porphyrias. Clin Dermatol 1985; 3:24–40. 36. Koenig F, McGovern FJ: Fluorescence detection of bladder carcinoma. Urology 1997; 50:778–779. 37. Koenig F, McGovern FJ, Larne R, et al: Diagnosis of bladder carcinoma using protoporphyrin IX fluorescence induced by 5-aminolevulinic acid. BJU Int 1999; 83(1):129–135. 38. Kriegmair M, Baumgartner R, Knuchel R, et al: Detection of early bladder cancer by 5-aminolevulinic acid induced porphyrin fluorescence. J Urol 1996; 155:105–109.
39. Jichlinski P, Forrer M, Mizeret J, et al: Clinical evaluation of a method for detecting superficial transitional cell carcinoma of the bladder by light-induced fluorescence of protoporphyrin IX following topical application of 5-aminolevulinic acid: preliminary results. Laser Surg Med 1997; 20:402–408. 40. Kriegmair M, Zaak D, Rothenberger KH, et al: Transurethral resection for bladder cancer using 5-aminolevulinic acid induced fluorescence endoscopy versus white light endoscopy. J Urol 2002; 168:475–478. 41. Riedi CR, Daniltchenko D, Koenig F, et al: Fluorescence endoscopy with 5-aminolevulinic acid reduces early recurrence rate in superficial bladder cancer. J Urol 2001; 165:1121–1123. 42. Filbeck T, Pichhmeier U, Knuechel R, et al: Clinically relevant improvement of recurrence-free survival with 5-aminolevulinic acid induced fluorescence diagnosis in patients with superficial bladder tumors. J Urol 2002; 168:67–71.
C H A P T E R
21 Partial and Radical Cystectomy John P. Stein, MD, and Donald G. Skinner, MD
Radical cystectomy has traditionally been considered the standard of therapy for high-grade, invasive bladder cancer with the best survival results and lowest local recurrence rates reported to date.1,2 Radical cystectomy provides accurate pathologic staging of the primary bladder tumor and the regional lymph nodes that may then influence the decision for adjuvant chemotherapy based on clear pathologic criteria.3 Furthermore, advances in urinary diversion and lower urinary tract reconstruction to the urethra (orthotopic neobladder) have provided patients a more socially acceptable means to store urine, allowing volitional voiding per urethra without the need for a urostomy appliance, cutaneous stoma, or the need for catheterization in most instances. Currently, most men and women undergoing radical cystectomy are appropriate candidates for this form of urinary diversion.4 Improvements over the past several decades in medical, surgical, and anesthetic techniques have dramatically reduced the morbidity and mortality associated with radical cystectomy. Prior to 1970, the perioperative complication rate of radical cystectomy was reportedly close to 35%, with a mortality rate of nearly 20%. This has dramatically diminished to less than a 10% perioperative complication rate and 2% mortality rate reported in contemporary cystectomy series.1,2 In addition, radical cystectomy with en bloc pelvic lymphadenectomy provides optimal local control of the bladder tumor. Pelvic recurrence rates in patients following radical cystectomy are less than 10% for patients with node-negative bladder tumors, and 10% to 20% for patients with resected pelvic nodal metastases.1,2,5 Furthermore, transitional cell carcinoma (TCC) is generally resistant to radiation therapy even at high doses. To date, chemotherapy alone or as adjuvant therapy, coupled with bladder-sparing surgery, has yet to demonstrate equivalent recurrence and longterm survival rates compared to radical cystectomy alone.6,7
A dedicated effort has been made to improve the technique of radical cystectomy and provide an acceptable form of urinary diversion without compromise of a sound cancer operation.8–10 Certain technical issues regarding the surgical procedure of a radical cystectomy are critical in order to minimize local recurrence and positive surgical margins, and maximize cancer-specific survival. In addition, attention to surgical details is important in optimizing the successful outcomes of orthotopic diversion: maintaining the rhabdosphincter mechanism and urinary continence in these patients.10 PARTIAL CYSTECTOMY Although radical cystectomy is the standard therapy for high-grade, invasive bladder cancer, partial cystectomy may be an option in a few, very carefully selected individuals. Partial cystectomy has been considered an alternative surgical procedure to radical cystectomy in an attempt to preserve the bladder and maintain sexual function. Many of these quality-of-life issues have been significantly reduced with the development of continent urinary diversion (orthotopic reconstruction) and nervesparing approaches to radical cystectomy.4 Furthermore, when one considers the fact that bladder cancer is generally considered a panurothelial disease and rarely an isolated phenomena, this makes partial cystectomy an even less desirable surgical option. Despite the potential limitations of partial cystectomy, certain patients may not be suitable candidates for radical cystectomy, or simply refuse this form of therapy. Partial cystectomy may be considered in individuals with the following selection criteria: a unifocal tumor without evidence of atypia, or carcinoma in situ (cis) in the bladder; the ability to obtain at least a 2-cm circumferential margin around the tumor; a bladder tumor in a diverticulum; no previous history of bladder
368
Chapter 21 Partial and Radical Cystectomy 369
cancer. Relative contraindications to a partial cystectomy, multiple tumors, include: multiple tumors, cis of the prostatic urethra or ureters, and tumors involving the trigone and bladder neck or those with potential extravesical tumor extension. Patients with a small bladder capacity are also not ideal candidates for a partial cystectomy. Considering the aforementioned selection criteria, only a small percent of patients with bladder cancer are appropriate candidates for a partial cystectomy. Most reported studies of partial cystectomy are those reported prior to the era of orthotopic lower urinary tract reconstruction. In a 20-year experience at the Mayo clinic, only 199 of 3454 patients (6%) were considered appropriate candidates.11 Similarly, in a 10-year experience at the Cleveland Clinic, only 50 of 2000 patients (2.5%) underwent partial cystectomy for invasive bladder cancer.12 Although the role of a pelvic lymphadenectomy is controversial in partial cystectomy, it is becoming apparent that a meticulous, extended lymphadenectomy is important in patient outcome following radical cystectomy.13–16 An additional consideration in patients with bladder tumors undergoing partial cystectomy is the potential for significant tumor recurrence,17 and tumor spill and wound implantation occurring in at least 10% to 20% of patients without preoperative radiation therapy.18 This may be prevented with a high-dose, short course of preoperative radiation therapy.19 RADICAL CYSTECTOMY Preoperative Evaluation Complete clinical staging for bladder cancer should evaluate the retroperitoneum and pelvis along with the most common metastatic sites, including the lungs, liver, and bone. A chest x-ray, liver function tests, and serum alkaline phosphatase should be obtained routinely. Patients with an elevated serum alkaline phosphatase or with/ without complaints of bone pain should undergo a bone scan. A CT scan of the chest is obtained when pulmonary metastases are suspected by history, or because of an abnormal chest x-ray. A CT scan of the abdomen and pelvis is routinely performed to evaluate the pelvis and retroperitoneum for any significant lymphadenopathy or local contiguous spread. This radiographic study should also be performed in patients with suspected metastases, elevated liver functions tests, a bladder tumor associated with hydronephrosis, or in patients with an extensive primary bladder tumor that is either nonmobile or fixed; the results of which may impact on the decision for neoadjuvant therapy. However, CT scan of the primary bladder is neither sensitive nor specific enough to evaluate the degree of bladder wall tumor invasion, or to accurately determine pelvic lymph node involvement with tumor.20,21
En Bloc Radical Cystectomy and Pelvic-Iliac Lymphadenectomy: Surgical Technique Preoperative Preparation Patients undergoing radical cystectomy are admitted the morning prior to surgery. All patients receive a mechanical and antibacterial bowel preparation the day prior to surgery. Intravenous hydration must be considered in these patients to prevent dehydration on arrival to the operating room. In addition, all patients should be evaluated and counseled by the enterostomal therapy nurse prior to surgery. A clear liquid diet may be consumed until midnight, at which time the patient takes nothing per mouth. A standard modified Nichols bowel preparation22 is initiated the morning of admission: 120 ml of Neoloid per mouth at 9:00 a.m.; 1 g of neomycin per mouth at 10:00 a.m., 11:00 am, 12:00 noon, 1:00 p.m., 4:00 p.m., 8:00 p.m., and 12:00 midnight; and 1 g of erythromycin base per mouth at 12:00 noon, 4:00 p.m., 8:00 p.m., and 12:00 midnight. This regimen is generally well tolerated, obviates the need for enemas and maintains nutritional and hydrational support. Intravenous crystalloid fluid hydration is begun in the evening prior to surgery in those patients admitted to the hospital the day prior to surgery and maintained to ensure an adequate circulating volume as the patient enters the operating room. This may be particularly important in the elderly or frail patient with associated comorbidities. Patients over 50 years of age routinely undergo prophylactic digitalization prior to cystectomy unless a specific contraindication exists. Patients younger than 50 years of age are not routinely digitalized. Digoxin is given orally; 0.5 mg at 12:00 noon, 0.25 mg at 4:00 p.m., and 0.125 mg at 8:00 p.m. Our experience with preoperative digitalization in patients undergoing cystectomy has been positive and there is evidence suggesting that preoperative digitalization may decrease the risk of perioperative dysrhythmias and congestive heart failure in the elderly patient undergoing an extensive operative procedure.23,24 Attention to fluid management is important in these elderly patients particularly on postoperative days 3 and 4 when mobilization of third-space fluid is highest, subsequently necessitating liberal use of diuretics. In addition, intravenous broad-spectrum antibiotics are administered en route to the operating room, providing adequate tissue and circulating levels at the time of incision. Preoperative evaluation and counseling by the enterostomal therapy nurse is a critical component to the successful care of all patients undergoing cystectomy and urinary diversion. Patients determined to be appropriate candidates for orthotopic reconstruction are instructed how to catheterize per urethra should it be necessary postoperatively. All patients are site marked for a cutaneous stoma, instructed in the care of a cutaneous diversion (continent or incontinent form), and instructed in
370
Part IV Bladder
proper catheterization techniques should medical, technical, or oncologic factors preclude orthotopic reconstruction. The ideal cutaneous stoma site is determined only after the patient is examined in the supine, sitting, and standing position. Proper stoma site selection is important to patient acceptance, and to the technical success of lower urinary tract reconstruction should some form of cutaneous diversion be necessary. Incontinent stoma sites are best located higher on the abdominal wall, while stoma sites for continent diversions can be positioned lower on the abdomen (hidden below the belt line) since they do not require an external collecting device. The use of the umbilicus as the site for catheterization may be employed with excellent functional and cosmetic results. Patient Positioning The patient is placed in the hyperextended supine position with the superior iliac crest located at the fulcrum of the operating table (Figure 21-1). The legs are slightly abducted so that the heels are positioned near the corners of the foot of the table. In the female patient considering orthotopic diversion, the modified frogleg or lithotomy position is employed allowing access to the vagina. Care should be taken to ensure that all pressure points are well padded. Reverse Trendelenburg position levels the abdomen parallel with the floor and helps to keep the small bowel contents in the epigastrium. A nasogastric tube is placed, and the patient is prepped from nipples to mid-thigh. In the female patient the vagina is fully prepped. After the patient is draped, a 20-F Foley catheter is placed in the bladder and left to gravity drainage. A right-handed surgeon stands on the patient’s left-hand side of the operating table. Incision A vertical midline incision is made extending from the pubic symphysis to the cephalad aspect of the epigastrium. The incision should be carried lateral to the umbilicus on the contralateral side of the marked cutaneous stoma site. When considering the umbilicus as the site for a catheterizable stoma, the incision should be directed 2 to 3 cm lateral to the umbilicus at this location.
The anterior rectus fascia is incised, the rectus muscles retracted laterally, and the posterior rectus sheath and peritoneum entered in the superior aspect of the incision. As the peritoneum and posterior fascia are incised inferiorly to the level of the umbilicus, the urachal remnant (median umbilical ligament) is identified, circumscribed, and removed en bloc with the cystectomy specimen (Figure 21-2). This maneuver prevents early entry into a high-riding bladder and ensures complete removal of all bladder remnant tissue. Care is taken to remain medial and avoid injury to the inferior epigastric vessels (lateral umbilical ligaments), which course posterior to the rectus muscles. If the patient has had a previous cystotomy or segmental cystectomy, the cystotomy tract and cutaneous incision should be circumscribed full-thickness and excised en bloc with the bladder specimen. The medial insertion of the rectus muscles attached to the pubic symphysis can be slightly incised, maximizing pelvic exposure throughout the operation. Abdominal Exploration A careful, systematic intraabdominal exploration is performed to determine the extent of disease, and to evaluate for any hepatic metastases, or gross retroperitoneal lymphadenopathy. The abdominal viscera are palpated to detect any concomitant unrelated disease. If no contraindication exists at this time, all adhesions should be incised and freed. Bowel Mobilization The bowel is mobilized beginning with the ascending colon. A large right angle Richardson retractor elevates the right abdominal wall. The cecum and ascending colon are reflected medially to allow incision of the lateral peritoneal reflection along the avascular/white line of Toldt. The mesentery to the small bowel is then mobilized off its retroperitoneal attachments cephalad (toward the ligament of Treitz) until the retroperitoneal portion of the duodenum is exposed. This mobilization facilitates a tension-free ureteroenteric anastomosis if orthotopic diversion is performed. Combined sharp and blunt dissection facilitates mobilization of this mesentery along a characteristic avascular fibroareolar plane.
Figure 21-1 Proper patient positioning for cystectomy in the male patient. Note, the iliac crest is located at the break of the table.
Chapter 21 Partial and Radical Cystectomy 371
Figure 21-2 Wide excision of the urachal remnant and medial umbilical ligaments en bloc with the cystectomy specimen.
Conceptually, the mobilized mesentery forms an inverted right triangle; the base formed by the third and fourth portions of the duodenum, the right edge represented by the white line of Toldt along the ascending colon; the left edge represented by the medial portion of the sigmoid and descending colonic mesentery; and the apex represented by the ileocecal region (Figure 21-3). This mobilization is critical in setting up the operative field and facilitates proper packing of the intraabdominal contents into the epigastrium. The left colon and sigmoid mesentery are then mobilized to the region of the lower pole of the left kidney by incising the peritoneum lateral to the colon along the avascular/white line of Toldt. The sigmoid mesentery is then elevated off the sacrum, iliac vessels, and distal aorta in a cephalad direction up to the origin of the inferior mesenteric artery (Figure 21-4). This maneuver provides a wide mesenteric window through which the left ureter will pass (without angulation or tension) for the ureteroenteric anastomosis at the terminal portions of
the operation. This sigmoid mobilization also facilitates retraction of the sigmoid mesentery while performing the lymph node dissection. Care should be taken to dissect along the base of the mesentery and avoid injury to the inferior mesenteric artery and blood supply to the sigmoid colon. Following mobilization of the bowel, a self-retaining retractor is placed. The right colon and small intestine are carefully packed into the epigastrium with three moist lap pads, followed by a moistened towel rolled to the width of the abdomen. The descending and sigmoid colon are not packed, and they remain as free as possible, providing the necessary mobility required for the ureteral and pelvic lymph node dissection. Successful packing of the intestinal contents is an art and prevents their annoying spillage into the operative field. Packing begins by sweeping the right colon and small bowel under the surgeon’s left hand along the right sidewall gutter. A moist open lap pad is then swept with the right hand along the palm of the left hand, under the
372
Part IV Bladder
Figure 21-3 View of the pelvis from overhead; after the ascending colon and peritoneal attachments of the small bowel mesentery have been mobilized up to the level of the duodenum. This mobilization allows the bowel to be properly packed in the epigastrium and exposes the area of the aortic bifurcation, which is the starting point of the lymph node dissection.
viscera along the retroperitoneum, and sidewall gutter. In similar fashion, the left sidewall gutter is packed ensuring not to incorporate the descending or sigmoid colon. The central portion of the small bowel is packed with a third lap pad. A moist rolled towel is then positioned horizontally below the lap pads but cephalad to the bifurcation of the aorta. Occasionally, prior to placement of the first moist lap pad, a mobile greater omental apron can be used to facilitate packing of the intestinal viscera in a similar fashion to the lap pad. After the bowel has been packed, a wide Deaver retractor is placed with gentle traction on the previous packing to provide cephalad exposure. Ureteral Dissection The ureters are most easily identified in the retroperitoneum just cephalad to the common iliac vessels. They are carefully dissected into the deep pelvis (several centimeters beyond the iliac vessels) and divided between
two large hemoclips. A section of the proximal cut ureteral segment (distal to the proximal hemoclip) is sent for frozen section analysis to ensure the absence of carcinoma in situ or overt tumor. The ureter is then slightly mobilized in a cephalad direction and tucked under the rolled towel to prevent inadvertent injury. Frequently, an arterial branch from the common iliac artery or the aorta needs to be divided to provide adequate ureteral mobilization. In addition, the rich vascular supply emanating laterally from the gonadal vessels should remain intact and undisturbed. These attachments are an important blood supply to the ureter, which ensure an adequate vascular supply for the ureteroenteric anastomosis at the time of diversion. This is particularly important in irradiated patients. Leaving the proximal hemoclip on the divided ureter during the exenteration allows for hydrostatic ureteral dilation and facilitates the ureteroenteric anastomosis. In women, the infundibulopelvic ligaments are ligated and divided at the level of the common iliac vessels.
Chapter 21 Partial and Radical Cystectomy 373
Figure 21-4 View of the pelvis from overhead; after the ascending colon and small bowel have been packed in the epigastrium. Note that the sigmoid mesentery is mobilized off the sacral promontory and distal aorta up to the origin of the inferior mesenteric artery.
Pelvic Lymphadenectomy A meticulous pelvic lymph node dissection is routinely performed en bloc with radical cystectomy. The extent of the lymphadenectomy may vary depending on the patient and surgeon preference. An accumulating body of evidence suggests that an extended lymphadenectomy may be beneficial in patients undergoing cystectomy for high-grade, invasive bladder cancer.13–16 When performing a salvage procedure following definitive radiation treatment (>5000 rads), a pelvic lymphadenectomy is usually not performed because of the significant risk of iliac vessel and obturator nerve injury.25 For a combined common and pelvic iliac lymphadenectomy, the lymph node dissection is initiated 2 cm above the aortic bifurcation (superior limits of dissection), and the dissection extends laterally over the inferior vena cava to the genitofemoral nerve, representing the lateral limits of dissection. Distally, the lymph node dissection extends to the lymph node of Cloquet medially (on Cooper’s ligament) and the circumflex iliac vein laterally.
The cephalad portion (2 cm above the aortic bifurcation) of the lymphatics are ligated with hemoclips to prevent lymphatic leak, while the caudal (specimen) side is ligated only when a blood vessel is encountered. Frequently, small anterior tributary veins originate from the vena cava just above the bifurcation, which should be clipped and divided. In men, the spermatic vessels are retracted laterally and spared. In women, the infundibulopelvic ligament along with the corresponding ovarian vessels has been previously ligated and divided at the pelvic brim as previously described. All fibroareolar and lymphatic tissues are dissected caudally off the aorta, vena cava, and common iliac vessels over the sacral promontory into the deep pelvis. The initial dissection along the common iliac vessels is performed over the arteries, skeletonizing them. As the common iliac veins are dissected medially, care is taken to control small arterial and venous branches coursing along the anterior surface of the sacrum. Electrocautery is helpful at this location, which allows the adherent fibroareolar tissue to
374
Part IV Bladder
be swept off the sacral promontory down into the deep pelvis with the use of a small gauze sponge. Significant bleeding from these presacral vessels can occur if not properly controlled. Hemoclips are discouraged in this location as they can be easily dislodged from the anterior surface of the sacrum, resulting in troublesome bleeding. Once the proximal portion of the lymph node dissection is completed, a finger is passed from the proximal aspect of dissection under the pelvic peritoneum (anterior to the iliac vessels), distally toward the femoral canal. The opposite hand can be used to strip the peritoneum from the undersurface of the transversalis fascia and to connect with the proximal dissection from above. This maneuver elevates the peritoneum and defines the lateral limit of peritoneum to be incised and removed with the specimen. The peritoneum is divided medial to the spermatic vessels in men and lateral to the infundibulopelvic ligament in female patients. The only structure encountered is the vas deferens in the male or round ligament in females; these structures are clipped and divided. A large right-angled rake retractor (e.g., Israel) is used to elevate the lower abdominal wall, including the spermatic cord or remnant of the round ligament, to provide distal exposure in the area of the femoral canal. Tension on the retractor is directed vertically toward the ceiling, with care taken to avoid injury to the inferior epigastric vessels. This provides excellent exposure to the distal external iliac vessels. The distal limits of the dissection are then identified: the circumflex iliac vein crossing anterior to the external iliac artery distally, the genitofemoral nerve laterally, and Cooper’s ligament medially. The lymphatics draining the ipsilateral leg, particularly medial to the external iliac vein, are carefully clipped and divided to prevent lymphatic leakage. This includes the lymph node of Cloquet (also known as Rosenmüller), which represents the distal limit of the lymphatic dissection at this location. The distal external iliac artery and vein are then circumferentially dissected and skeletonized with care taken to ligate an accessory obturator vein (present in 40% of patients) originating from the inferomedial aspect of the external iliac vein. Following completion of the distal limits of dissection, the proximal and distal dissections are joined. The proximal external iliac artery and vein are skeletonized circumferentially to the origin of the hypogastric artery (Figure 21-5A). Care should be taken to clip and divide a commonly encountered vessel arising from the lateral aspect of the proximal external iliac vessels coursing to the psoas muscle. The external iliac vessels (artery and vein) are then retracted medially, and the fascia overlying the psoas muscle is incised medial to the genitofemoral nerve. On the left side, branches of the genitofemoral nerve often pursue a more medial course and may be intimately related to the iliac vessels, in which case they are excised. At this point, the lymphatic tissue surrounding the iliac vessels are composed of a medial and lateral components
attached only at the base within the obturator fossa. The lateral lymphatic compartment (freed medially from the vessels and laterally from the psoas) is bluntly swept into the obturator fossa by retracting the iliac vessels medially and passing a small gauze sponge lateral to the vessels along the psoas and pelvic sidewall (Figure 21-5B). This sponge should be passed anterior and distal to the hypogastric vein, directed caudally into the obturator fossa. The external iliac vessels are then elevated and retracted laterally, and the gauze sponge is carefully withdrawn from the obturator fossa with gentle traction using the left hand (Figure 21-6A). This maneuver effectively sweeps all lymphatic tissue into the obturator fossa and facilitates identification of the obturator nerve deep to the external iliac vein. The obturator nerve is best identified proximally and carefully dissected free from all lymphatics. The obturator nerve is then retracted laterally along with the iliac vessels (Figure 21-6B). At this point, the obturator artery and vein should be carefully entrapped between the index finger (medial to the obturator nerve) laterally and the middle finger medially with the left hand. This isolates the obturator vessels exiting the obturator canal along the pelvic floor. These vessels are then carefully clipped and divided ensuring to stay medial to the obturator nerve. The obturator lymph node packet is then swept medially toward the sidewall of the bladder, ligating small tributary vessels and lymphatics from the pelvic sidewall. The nodal packet will be removed en bloc with the cystectomy specimen. Ligation of the Lateral Vascular Pedicle to the Bladder Following dissection of the obturator fossa and dividing the obturator vessels, the lateral vascular pedicle to the bladder is isolated and divided. Developing this plane isolates the lateral vascular pedicle to the bladder; a critical maneuver in performing a safe cystectomy with proper vascular control. Isolation of the lateral vascular pedicle is performed with the left hand. The bladder is retracted toward the pelvis, placing traction and isolating the anterior branches of the hypogastric artery. The left index finger is passed medial to the hypogastric artery, posterior to the anterior visceral branches, and lateral to the previously transected ureter. The index finger is directed caudally toward the endopelvic fascia, parallel to the sweep of the sacrum. This maneuver defines the two major vascular pedicles to the anterior pelvic organs: the lateral pedicle—anterior to the index finger, composed of the visceral branches of the anterior hypogastric vessel; the posterior pedicle—posterior to the index finger, composed of the visceral branches between the bladder and rectum. With the lateral pedicle entrapped between the left index and middle fingers, firm traction is applied vertically and caudally. This facilitates identification and
Chapter 21 Partial and Radical Cystectomy 375
Figure 21-5 A, Technique of skeletonizing the external iliac artery and vein. Note, the vessels are completely dissected free up to the level of the origin of the hypogastric artery. This allows for the vessels to be carefully retracted medially and the psoas fascia incised to allow passage of a gauze sponge. B, Technique of passing a small gauze sponge lateral to the external iliac vessels and medial to the psoas muscle.
allowing individual branches off the anterior portion of the hypogastric artery to be isolated (Figure 21-7). The posterior division of the hypogastric artery, including the superior gluteal, iliolumbar, and lateral sacral arteries, is preserved to avoid gluteal claudication. Distal to this posterior division, the hypogastric artery may be ligated for vascular control but should not be divided since the lateral pedicle is easier to dissect if left in continuity. The largest and most consistent anterior branch to the bladder, the superior vesical artery, is usually isolated and individually ligated and divided easily. The remaining anterior branches of the lateral pedicle are then isolated and divided between hemoclips down to the endopelvic fascia, or as far as is technically possible. With blunt dissection the index finger of the left hand helps identify this lateral pedicle and protects the rectum as it is pushed medially. Right angle hemoclip appliers are ideally suited for proper placement of the clips. Each pair of hemoclips
is positioned as far apart as possible to ensure that 0.5 to 1 cm of tissue projects beyond each clip when the pedicle is divided. This prevents the hemoclips from being dislodged resulting in unnecessary bleeding. Occasionally, in patients with an abundance of pelvic fat, the lateral pedicle may be thick and require division into two manageable pedicles. The inferior vesicle vein serves as an excellent landmark as the endopelvic fascia is just distal to this structure. The endopelvic fascia just lateral to the prostate may then be incised, which helps to identify the distal limit of the lateral pedicle. Ligation of the Posterior Pedicle to the Bladder Following division of the lateral pedicles, the bladder specimen is retracted anteriorly exposing the cul-de-sac (pouch of Douglas). The surgeon elevates the bladder with a small gauze sponge under the left hand, while the assistant
376
Part IV Bladder
Figure 21-6 A, Technique of withdrawing the gauze sponge with the left hand. This aids in dissecting and clearing the obturator fossa, sweeping all fibroareolar and lymphatic tissue toward the bladder. B, Obturator fossa cleaned. This allows proper identification of the obturator nerve passing deep to the external iliac vein.
retracts on the peritoneum of the rectosigmoid colon in a cephalad direction. This provides excellent exposure to the recess of the cul-de-sac and places the peritoneal reflection on traction facilitating the proper division. The peritoneum lateral to the rectum is incised and extended anteriorly and medially across the cul-de-sac to join the incision on the contralateral side (Figure 21-8). An understanding of the fascial layers is critical for the appropriate dissection of this plane. The anterior and posterior peritoneal reflections converge in the cul-desac to form Denonvilliers’ fascia, which extends caudally to the urogenital diaphragm (Figure 21-9, large arrow). This important anatomic boundary in the male separates
the prostate and seminal vesicles anterior to the rectum posterior. The plane between the prostate and seminal vesicles, and the anterior sheath of Denonvilliers’ will not develop easily. However, the plane between the rectum and the posterior sheath of Denonvilliers’ (Denonvilliers’ space) should develop easily with blunt and sharp dissection. Therefore, the peritoneal incision in the cul-de-sac must be made slightly on the rectal side rather than the bladder side (see Figure 21-9, small arrow). This allows proper and safe entry and development of Denonvilliers’ space between the anterior rectal wall and the posterior sheath of Denonvilliers’ fascia (Figure 21-10). Employing a posterior sweeping motion of the fingers,
Chapter 21 Partial and Radical Cystectomy 377
Figure 21-7 Isolation of the lateral vascular pedicle. The left hand is used to define the right lateral pedicle, extending from the bladder to the hypogastric artery. This plane is developed by the index finger (medial) and the middle finger (lateral), exposing the anterior branches of the hypogastric artery. This vascular pedicle is clipped and divided down to the endopelvic fascia. Traction with the left hand defines the pedicle, allows direct visualization, and protects the rectum from injury.
the rectum can be carefully swept off the seminal vesicles, prostate, and bladder in men and off the posterior vaginal wall in women. This sweeping motion, when extended laterally, helps to thin and develop the posterior pedicle, which appears like a collar emanating from the lateral aspect of the rectum. Care should be taken as one develops this posterior plane more caudally as the anterior rectal fibers often are adherent to the specimen and can be difficult to bluntly dissect. In this region, just cephalad (proximal) to the urogenital diaphragm, sharp dissection may be required to dissect the anterior rectal fibers off the apex of the prostate in order to prevent rectal injury at this location. Particular mention should be made concerning several situations that may impede the proper development of this posterior plane. Most commonly, when the incision in the cul-de-sac is made too far anteriorly, proper entry into Denonvilliers’ space is prevented. Improper entry can occur in between the two layers of Denonvilliers’ fascia, or even anterior to this, making the posterior dissection difficult, increasing the risk of rectal injury. Furthermore, posterior tumor infiltration, or previous high-dose pelvic irradiation can obliterate this plane
making the posterior dissection difficult. To prevent injury to the rectum in these situations, only sharp dissection should be performed under direct vision. To prevent a rectal injury is to avoid blunt dissection with the finger in areas where normal tissue planes have been obliterated by previous surgery or radiation. Sharp dissection under direct vision will dramatically reduce the potential for rectal injury. If a rectotomy occurs, a 2- or 3-layer closure is recommended. A diverting proximal colostomy is not routinely required unless gross contamination occurs, or if the patient has received previous pelvic radiation therapy. If orthotopic diversion or vaginal reconstruction is planned, an omental interposition is recommended to prevent fistulization between suture lines. Once the posterior pedicles have been defined, they are clipped and divided to the endopelvic fascia in the male patient. The endopelvic fascia is then incised adjacent to the prostate, medial to the levator ani muscles (if not done previously), to facilitate the apical dissection. In the female patient, the posterior pedicles, including the cardinal ligaments, are divided 4 to 5 cm beyond the cervix. With cephalad pressure on a previously placed vaginal sponge stick, the apex of the vagina can be iden-
378
Part IV Bladder
Figure 21-8 The peritoneum lateral to the rectum is incised down into the cul-de-sac and carried anteriorly over the rectum to join the opposite side. Note that the incision should be made precisely so the proper plane behind Denonvilliers’ fascia can be developed safely.
tified and incised posteriorly just distal to the cervix. The vagina is then circumscribed anteriorly with the cervix attached to the cystectomy specimen. If there is concern about an adequate surgical margin at the posterior or base of the bladder, then the anterior vaginal wall should be removed en bloc with the bladder specimen; subsequently requiring vaginal reconstruction if sexual function is desired. It is our preference to spare the anterior vaginal wall if orthotopic diversion is planned. This eliminates the need for vaginal reconstruction, and helps maintain the complex musculofascial support system and helps prevent injury to the pudendal innervation to the rhabdosphincter proximal urethra, both important components to the continence mechanism in women. The anterior vaginal wall is then sharply dissected off the posterior bladder down to the region of the bladder neck (vesicourethral junction), which is identified by palpating
the Foley catheter balloon. At this point, the specimen remains attached only at the apex in men and vesicourethral junction in women. Anterior Apical Dissection in the Male Patient Once the cystectomy specimen is completely freed and mobile posteriorly, attention is directed anteriorly to the pelvic floor and urethra. All fibroareolar connections between the anterior bladder wall, prostate, and undersurface of the pubic symphysis are divided. The endopelvic fascia is incised adjacent to the prostate and the levator muscles are carefully swept off the lateral and apical portions of the prostate. It must be emphasized that minimal dissection is to be performed along the pelvic floor. The innervation to the rhabdosphincter and continence mechanism arises from the pudendal innervation
Chapter 21 Partial and Radical Cystectomy 379
Figure 21-9 Illustration of the formation of Denonvilliers’ fascia. Note that it is derived from a fusion of the anterior and posterior peritoneal reflections. Denonvilliers’ space lies behind the fascia. To successfully enter this space and facilitate mobilization of the anterior rectal wall off Denonvilliers’ fascia, the incision in the cul-de-sac is made close to the peritoneal fusion on the anterior rectal wall side, and not on the bladder side.
and courses along the pelvic floor.10 Therefore, any unnecessary dissection may disrupt this delicate innervation and may compromise the continence mechanism in patients undergoing orthotopic reconstruction. The superficial dorsal vein is identified, ligated, and divided. With tension placed posteriorly on the prostate, the puboprostatic ligaments are identified, and only
slightly divided just beneath the pubis, lateral to the dorsal venous complex that courses between these ligaments. Care should be taken in avoiding any extensive dissection in this region along the pelvic floor. The puboprostatic ligaments need only to be incised enough to allow for a proper apical dissection of the prostate. The apex of the prostate and membranous urethra now becomes palpable.
380
Part IV Bladder
Figure 21-10 After the peritoneum of the cul-de-sac has been incised, the anterior rectal wall can be swept off the posterior surface of the Denonvilliers’ fascia. This effectively defines the posterior pedicle that extends from the bladder to the lateral aspect of the rectum on either side.
Several methods can be performed to properly control the dorsal venous plexus. One may carefully pass an angled clamp beneath the dorsal venous complex, anterior to the urethra (Figure 21-11). The venous complex can then be ligated with a 2-0 absorbable suture and divided close to the apex of the prostate. If any bleeding occurs from the transected venous complex, it can be oversewn with an absorbable (2-0 polyglycolic acid) suture. In a slightly different fashion, the dorsal venous complex may be gathered at the apex of the prostate with a long Allis clamp (Figure 21-12). This may help better define the plane between the dorsal venous complex and anterior urethra. A figure-of-eight 2-0 absorbable suture can then be placed under direct vision anterior to the urethra (distal to the apex of the prostate) around the gathered venous complex (Figure 21-13). This suture is best placed with the surgeon facing the head of the table and holding the needle driver perpendicular to the patient. The suture is then tagged with a hemostat. This maneuver avoids the unnecessary passage of any instru-
ments between the dorsal venous complex and rhabdosphincter, which could potentially injure these structures and compromise the continence mechanism. After the complex has been ligated, it can be sharply divided with excellent exposure to the anterior surface of the urethra. Once the venous complex has been severed, the suture can be used to further secure the complex. The suture is then used to suspend the venous complex anteriorly to the periosteum to help reestablish anterior fixation of the dorsal venous complex and puboprostatic ligaments (Figure 21-14). This may enhance continence recovery. The anterior urethra is now exposed. Regardless of the aforementioned technique to control the dorsal venous complex, the urethra is then incised 270 degrees just beyond the apex of the prostate. A series of 20 polyglycolic acid sutures are placed in the anterior urethra, carefully incorporating only the mucosa and submucosa of the striated urethral sphincter muscle anteriorly. The catheter is clamped and divided, allowing two posterior sutures to be placed in the urethra, which should incorporate the rectourethralis muscle or the caudal extent of Denonvilliers’ fascia posteriorly. Following this, the posterior urethra is divided and the specimen removed. Alternatively, the dorsal venous complex can be sharply transected without securing vascular control of the dorsal venous complex. Cephalad traction on the prostate elongates the proximal and membranous urethra, and allows the urethra to be skeletonized laterally by dividing the so-called “lateral pillars,” extensions of the rhabdosphincter. The anterior two-third of the urethra is divided, exposing the urethral catheter. The urethral sutures are then placed. Six 2-0 polyglycolic acid sutures are placed, equally spaced, into the urethral mucosa and lumen anteriorly. The rhabdosphincter, the edge of which acts as a hood overlying the dorsal venous complex, is included in these sutures if the dorsal venous complex was sharply incised. This maneuver compresses the dorsal vein complex against the urethra for hemostatic purposes. The urethral catheter is then drawn through the urethrotomy, clamped on the bladder side, and divided. Cephalad traction on the bladder side with the clamped catheter occludes the bladder neck, prevents tumor spill from the bladder, and provides exposure to the posterior urethra. Two additional sutures are placed in the posterior urethra, again incorporating the rectourethralis muscle or distal Denonvilliers’ fascia. The posterior urethra is then divided and the specimen is removed. Bleeding from the dorsal vein is usually minimal at this point. If additional hemostasis is required, 1 or 2 anterior urethral sutures can be tied to stop the bleeding. Regardless of the technique, frozen section analysis of the distal urethral margin of the cystectomy specimen is then performed to exclude tumor involvement. If a cutaneous form of urinary diversion is planned, urethral preparation is slightly modified. Once the dorsal
Chapter 21 Partial and Radical Cystectomy 381
Figure 21-11 Control of the dorsal venous complex. A right-angled clamp can be passed posterior to the venous complex and anterior to the urethra. An absorbable suture can be passed to ligate the complex distal to the apex of the prostate.
Figure 21-12 The dorsal venous complex is gathered with an Allis clamp distal to the apex of the prostate. This maneuver will define the plane between the dorsal venous complex and urethra.
Figure 21-13 An absorbable suture is carefully passed in a figure-of-eight fashion anterior to the urethra around the gathered dorsal venous complex to control the vascular structure.
382
Part IV Bladder
Figure 21-14 The dorsal venous complex is completely divided. The previously placed suture is then used to further secure the venous complex. The complex is then fixed anteriorly to the periosteum.
venous complex is secured and divided, the anterior urethra is identified. The urethra is mobilized from above as far distally as possible into the pelvic diaphragm. With cephalad traction, the urethra is stretched above the urogenital diaphragm, a curved clamp is placed as distal on the urethra as feasible and divided distal to the clamp. Care must be taken avoid rectal injury with this clamp. This is prevented by placing gentle posterior traction with the left hand or index finger on the rectum and ensuring that the clamp is passed anterior. The specimen is then removed. This mobilization of the urethra will facilitate a late urethrectomy. The levator musculature can then be reapproximated along the pelvic floor to facilitate hemostasis. Anterior Dissection in The Female The wide female pelvis allows for better anterior exposure in women, particularly at the vesicourethral junction. However, urologists may be less familiar with pelvic surgery in women than in men. In addition, paravaginal vascular control may be troublesome in women, and the venous plexus anterior to the urethra is less well defined in women. When considering orthotopic diversion in female patients undergoing cystectomy, several technical issues are critical to the procedure in order to maintain the continence mechanism in these women.10 When developing the posterior pedicles in women, the posterior vagina is incised at the apex just distal to the cervix (Figure 21-15). This incision is carried anteriorly along the lateral and anterior vaginal wall forming a circumferential incision. The anterolateral vaginal wall is then grasped with curved Kocher clamps. This provides countertraction and facilitates dissection between the
anterior vaginal wall and the bladder specimen. Careful dissection of the proper plane will prevent entry into the posterior bladder and also reduce the amount of bleeding in this vascular area (Figure 21-16). Development of this posterior plane and vascular pedicle is best performed sharply and carried just distal to the vesicourethral junction (Figure 21-17). Palpation of the Foley catheter balloon assists in identifying this region. This dissection effectively maintains a functional vagina. In the case of a deeply invasive posterior bladder tumor in women, with concern of an adequate surgical margin, the anterior vaginal wall should be removed en bloc with the cystectomy specimen. After dividing the posterior vaginal apex, the lateral vaginal wall subsequently serves as the posterior pedicle and is divided distally. This leaves the anterior vaginal wall attached to the posterior bladder specimen. The Foley catheter balloon again facilitates identification of the vesicourethral junction. The surgical plane between the vesicourethral junction and the anterior vaginal wall is then developed distally at this location. A 1-cm length of proximal urethra is mobilized, while the remaining distal urethra is left intact with the anterior vaginal wall. Vaginal reconstruction by a clam shell (horizontal) or side-to-side (vertical) technique is required. Other means of vaginal reconstruction may include a rectus myocutaneous flap, detubularized cylinder of ileum, a peritoneal flap, or an omental flap. It is emphasized that no dissection to be performed anterior to the urethra along the pelvic floor. The endopelvic fascia should remain undisturbed and not to be opened in women considering orthotopic diversion. This prevents injury to the rhabdosphincter region and corresponding innervation, which is critical in maintaining the continence mechanism. Anatomic studies have demonstrated that the innervation to this rhabdosphincter region in women arises from branches off the pudendal nerve that course along the pelvic floor posterior to the levator muscles.26,27 Any dissection performed anteriorly may injure these nerves and compromise the continence status. This surgical principle similarly applies to the male patients as previously described. When the posterior dissection is completed (ensuring to dissect just distal to the vesicourethral junction), a Satinsky vascular clamp is placed across the bladder neck. The Satinsky vascular clamp placed across the catheter at the bladder neck prevents any tumor spill from the bladder. With gentle traction the proximal urethra is completely divided anteriorly, distal to the bladder neck and clamp. The female urethra is situated more anteriorly than in men, and the urethral sutures can be placed easily after the specimen is completely removed (Figure 21-18). A total of 10 to 12 sutures are placed. Frozen section analysis is performed on the distal urethral margin of the cystectomy specimen to exclude tumor. Once hemostasis
Chapter 21 Partial and Radical Cystectomy 383
Figure 21-15 In women, the vagina is incised distal to the cervix. Note that cephalad traction on the posterior aspect of the vagina facilitates the incision of the anterior vaginal wall. Slight dissection of the posterior vaginal wall off the rectum provides mobility to the vaginal cuff.
is obtained, the vaginal cuff may be closed in 2 layers with absorbable sutures. The vaginal cuff is then anchored via a colposacralpexy using a strut of Marlex mesh to the sacral promontory. This fixates the vagina without angulation or undo tension. Note, at the terminal portions of the operation, a well-vascularized omental pedicle graft is placed between the reconstructed vagina and neobladder, and secured to the levator ani muscles to separate the suture lines and prevent fistulization (Figure 21-19). If a cutaneous diversion is planned in the female patient, the posterior pedicles are developed as previously mentioned. Attention is then directed anteriorly and the pubourethral ligaments are divided. A curved clamp is placed across the urethra, and the anterior vaginal wall is opened distally and incised circumferentially around the urethral meatus. The vaginal cuff is closed as
previously described and suspended. Alternatively, a perineal approach is to be used for this dissection with complete removal of the entire urethra. Following removal of the cystectomy specimen, the pelvis is irrigated with warm sterile water. The presacral nodal tissue previously swept off the common iliac vessels and sacral promontory into the deep pelvis is collected, and sent separately for pathologic evaluation. Nodal tissue in the presciatic notch, anterior to the sciatic nerve, is also sent for histologic analysis. Hemostasis is obtained and the pelvis is packed with a lap pad, while attention is directed to the urinary diversion. The use of various tubes and drains postoperatively is important. The pelvis is drained for urine or lymph leak with a 1-in. Penrose drain for 3 weeks, and a large suction Hemovac drain for the evacuation of blood for 24 hours. A gastrostomy tube with an 18 French Foley
384
Part IV Bladder
Figure 21-16 Dissection of the anterior vaginal wall off of the bladder. Note caudal traction of the cystectomy specimen with countertraction applied to the vagina in a cephalad direction.
catheter is routinely placed utilizing a modified Stamm technique, which incorporates a small portion of omentum (near the greater curvature of the stomach) interposed between the stomach and the abdominal wall.28 This provides a simple means to drain the stomach and prevents the need for an uncomfortable nasogastric tube, while the postoperative ileus resolves. POSTOPERATIVE CARE A meticulous, team-oriented approach to the care of these generally elderly patients undergoing radical cystectomy helps reduce perioperative morbidity and mortality. Patients are best monitored in the surgical intensive care unit (ICU) for at least 24 hours or until stable. Careful attention to fluid management is imperative as third space fluid loss in these patients can be tremen-
dous and deceiving. Patients with compromised cardiac function or pulmonary function may require invasive cardiac monitoring with a pulmonary artery catheter placed prior to surgery to precisely ascertain the cardiac response to fluid shifts. A combination of crystalloid and colloid fluid replacement is given on the night of surgery, and converted to crystalloid on postoperative day 1. Prophylaxis against stress ulcer is initiated with an H2 blocker. Intravenous broad-spectrum antibiotics are continued in all patients and subsequently converted to oral antibiotics as the diet progresses. Pulmonary toilet is encouraged with incentive spirometry, deep breathing, and coughing. Prophylaxis against deep vein thrombosis is important in these patients undergoing extensive pelvic operations for malignancies. The anticoagulation is initiated in the recovery room with 10 mg of sodium warfarin via
Chapter 21 Partial and Radical Cystectomy 385
Figure 21-17 Dissection continues only slightly distal to the vesicourethral junction. This can be identified by palpation of the Foley balloon in the bladder.
a nasogastric or the gastrostomy tube. The daily dose is adjusted to maintain a prothrombin time in the range of 18 to 22 seconds. If the prothrombin time exceeds 22 seconds, 2.5 mg of vitamin K is administered intramuscularly to prevent bleeding. No systemic anticoagulation is used. Pain control by a patient-controlled analgesic system provides comfort and enhances deep breathing, and early ambulation. If digoxin was given preoperatively, it is continued until discharge. The gastrostomy tube is removed on postoperative day 7, or later if bowel function is delayed. The catheter and drain management is specific to the form of urinary diversion. Some patients may develop a prolonged ileus or some other complication that delays the quick return of oral intake. In such circumstances, total parenteral nutrition (TPN) is wisely instituted earlier rather than
later, in which situation the patient may become farther behind nutritionally. DISCUSSION Improvements in medical, surgical, and anesthetic therapy have reduced the morbidity and mortality associated with radical cystectomy. An anticipated perioperative mortality rate following cystectomy is 1% to 3%.1,2 The administration of preoperative therapy (radiation and/or chemotherapy) and the form of urinary diversion performed (continent or incontinent) do not appear to alter the mortality rate or the perioperative complication rate.1 Strict attention to perioperative details, meticulous surgery, and a team-oriented surgical and postoperative approach is the key to minimize morbidity and mortality,
386
Part IV Bladder
Figure 21-18 View of the female pelvis from above with open vaginal cuff and urethral suture placement.
Figure 21-19 Sagittal section of the female pelvis. Not a vascularized omental pedicle graft is situated between the reconstructed vagina/vaginal cuff and the neobladder. The graft is secured to the pelvic floor to prevent fistulization.
Chapter 21 Partial and Radical Cystectomy 387
and to ensure the best clinical outcomes following radical cystectomy. The development of orthotopic lower urinary tract reconstruction has dramatically lessened the impact of cystectomy on the quality of life of patients following removal of their bladder.7 Orthotopic diversion has eliminated the need for a cutaneous stoma, urostomy appliance, and the need for intermittent catheterization. Continence rates following orthotopic diversion are excellent, providing patients a more natural voiding pattern per urethra. Currently, orthotopic diversion should be considered the diversion of choice in all cystectomy patients and the urologist should have a specific reason why an orthotopic diversion is not performed. Patient factors, such as frail general health, motivation, associated comorbidity, and the oncologic issue of a positive urethral margin, will disqualify some patients. Nevertheless, the option of lower urinary tract reconstruction to the intact urethra has been shown to decrease physician’s reluctance and increase patient’s acceptance to undergo earlier cystectomy when the disease may be at a more curable stage.29 Currently, no equally effective alternative form of therapy for high-grade, invasive bladder cancer has evolved. Bladder cancer appears to be resistant to radiation therapy, even at high doses. Other bladder-sparing techniques employing chemotherapy alone, or in combination with radiation therapy have substantially higher local recurrence rates and do not appear to result in long-term survival or recurrence rates comparable to radical cystectomy.6,7 Whether patients have a better quality of life following cystectomy or following bladder-sparing protocols that require significant treatment to the bladder with the potential for tumor recurrence, has not been clarified. However, the authors firmly believe that the argument for bladder-sparing protocols has diminished with the advent and successful application of orthotopic diversion following radical cystectomy. Unlike any other therapy, radical cystectomy pathologically stages the primary bladder tumor and regional lymph nodes. This histologic evaluation will provide important prognostic information and may help identify high-risk patients who could benefit from adjuvant therapy. Patients with extravesical tumor extension, or with lymph node positive disease, are at risk for recurrence and should be considered for adjuvant treatment strategies. Additionally, the recent application of molecular markers, based on pathologic staging and analysis, may also serve to identify patients at risk for tumor recurrence who may benefit from adjuvant forms of therapy.30 In conclusion, a properly performed radical cystectomy with en bloc lymphadenectomy provides the best survival rates, with the lowest reported local recurrence rates for high-grade invasive bladder cancer. The surgical technique is critical to optimize the best clinical and technical outcomes with this procedure. Technical
advances in lower urinary tract reconstruction have allowed a reasonable alternative for patients following removal of the bladder and have improved the quality of life of these patients requiring removal of their bladder.
REFERENCES 1. Stein JP, Lieskovsky G, Cote R, et al: Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1054 patients. J Clin Oncol 2001; 19:666–675. 2. Ghoneim MA, El-Mekresh MM, El-Baz MA, El-Attar IA, Ashamallah A: Radical cystectomy for carcinoma of the bladder: critical evaluation of the results in 1026 cases. J Urol 1997; 158:393–399. 3. Skinner DG, Daniels J, Russell C, et al: The role of adjuvant chemotherapy following cystectomy for invasive bladder cancer: a prospective comparative trial. J Urol 1991; 145:459–467. 4. Stein JP, Skinner DG: Orthotopic bladder replacement. In Walsh PC, Retik AB, Vaughan ED, Wein AJ (eds): Campbell’s Urology, 8th edition, Chapter 108, pp 3835–3864. Philadelphia, WB Saunders, 2002. 5. Lerner SP, Skinner DG, Lieskovsky G, et al: The rationale for en bloc pelvic lymph node dissection for bladder cancer patients with nodal metastases: long-term results. J Urol 1993; 149:758–765. 6. Thrasher JB, Crawford ED: Current management of invasive and metastatic transitional cell carcinoma of the bladder. J Urol 1993; 149:957–972. 7. Montie JE: Against bladder sparing surgery. J Urol 1999; 162:452–457. 8. Stein JP, Skinner DG: Radical cystectomy in the female. In Montie JE (ed): Atlas of Urologic Clinics of North America, Vol 5, No 2, pp 37–64. Philadelphia, WB Saunders, 1997. 9. Stein JP, Skinner DG, Montie JE: Radical cystectomy and pelvic lymphadenectomy in the treatment of infiltrative bladder cancer. In Droller MJ (ed): Bladder Cancer: Current Diagnosis and Treatment, Chapter 10, pp 267–307. Totowa, NJ, Humana Press, 2001. 10. Stein JP, Quek MD, Skinner DG: Contemporary surgical techniques for continent urinary diversion: continence and potency preservation. In Libertino JA, Zinman LN (eds): Atlas of the Urologic Clinics of North America, Vol 9, pp 147–173. Philadelphia, WB Saunders, 2001. 11. Utz DC, Schmitz SE, Fugelso PD, et al: A clinicopathologic evaluation of partial cystectomy for carcinoma of the urinary bladder. Cancer 1973; 32:1075. 12. Novick AC, Stewart BH: Partial cystectomy in the treatment of primary and secondary carcinoma of the bladder. J Urol 1976; 116:570. 13. Herr HW, Bochner BH, Dalbagni G, et al: Impact of the number of lymph nodes retrieved on outcome in patients with muscle invasive bladder cancer. J Urol 2002; 167:1295–1298. 14. Leissner J, Hohenfellner R, Thuroff JW, Wolf H.K: Lymphadenectomy in patients with transitional cell
388
15.
16.
17. 18. 19.
20.
21.
22.
Part IV Bladder carcinoma of the urinary bladder; significance for staging and prognosis. Brit J Urol Int 2000; 85:817–823. Poulsen AL, Horn T, Steven K: Radical cystectomy; extending limits of pelvic lymph node dissection improves survival for patients with bladder cancer confined to the bladder wall. J Urol 1998; 160:2015. Stein JP, Cai J, Groshen S, Skinner DG: Risk factors for patients with pelvic lymph node metastases following radical cystectomy with en bloc cystectomy: the concept of lymph node density. J Urol 2003; 170:35–41. Faysal MH, Frieha FS: Evaluation of partial cystectomy for carcinoma of the bladder. Urology 1979; 14:352. Magri J: Partial cystectomy: review of 104 cases. Br J Urol 1962; 32:74. van der Werf-Messing B: Carcinoma of the bladder treated by suprapubic radium implants: the value of additional external irradiation. Eur J Urol 1969; 5:277. Voges GE, Tauschke E, Stockle M, Alken P, Hohenfellner R: Computerized tomography: an unreliable method for accurate staging of bladder tumors in patients who are candidates for radical cystectomy. J Urol 1989; 142:972–974. Pagano F, Bassi P, Galetti TP, et al:: Results of contemporary radical cystectomy for invasive bladder cancer: a clinicopathological study with an emphasis on the inadequacy of the tumor, nodes and metastases classification. J Urol 1991; 145:45–50. Nichols RL, Broido P, Condon RE, Gorbach SL, Nyhus LM: Effect of preoperative neomycin-erythromycin
23.
24. 25. 26.
27.
28.
29.
30.
intestinal preparation on the incidence of infectious complications following colon surgery. Ann Surg 1973; 178:453–462. Pinaud MLJ, Blanloeil YAG, Souron RJ: Preoperative prophylactic digitalization of patients with coronary artery disease: a randomized echocardiographic and hemodynamic study. Anesth Analg 1983; 62:685–689. Burman SO: The prophylactic use of digitalis before thorocotomy. Ann Thorac Surg 1972; 14:359–368. Crawford ED, Skinner DG: Salvage cystectomy after radiation failure. J Urol 1980; 123:32–34. Colleselli K, Stenzl A, Eder R, et al: The female urethral sphincter: a morphological and topographical study. J Urol 1998; 160:49–50. Grossfeld GD, Stein JP, Bennett CJ, et al: Lower urinary tract reconstruction in the female using the Kock ileal reservoir with bilateral ureteroileal urethrostomy: update of continence results and fluorourodynamic findings. Urology 1996; 48:383–388. Buscarini M, Stein JP, Lawrence MA, Skinner DG: Tube gastrostomy following radical cystectomy and urinary diversion: surgical technique and experience in 709 patients. Urology 2000; 56:150–152. Hautmann RE, Paiss T: Does the option of the ileal neobladder stimulate patient and physician decision toward earlier cystectomy? J Urol 1998; 159:1845–1850. Stein JP, Grossfeld GD, Ginsberg DA, et al: Prognostic markers in bladder cancer: a contemporary review of the literature. J Urol 1999; 160:645–659.
C H A P T E R
22 Selective Bladder Preservation by Combined Modality Treatment Donald S. Kaufman, MD, Alex F. Althausen, MD, Niall M. Heney, MD, FRCS, Anthony L. Zietman, MD, M. Dror Michaelson, MD, PhD, and William U. Shipley, MD
In the United States, the standard treatment of muscleinvasive transitional cell cancer of the bladder is radical cystoprostatectomy. This is an approach that results in 90% local control at 5 years but only 40% to 60% 5-year overall survival. The usual cause of death is the result of systemic spread of the primary tumor with the strong presumption that in the majority of cases micrometastatic disease is present at the time of cystectomy and the patients so afflicted are therefore destined to die of distant metastases. An analysis of cystectomy performed at Memorial Sloan Kettering Cancer Institute demonstrated a disease-specific survival of 67% with a median follow-up of 65 months and a median overall survival of only 45%.1 The clinical and pathologic stage of the disease is important in predicting long-term survival. The 5-year recurrence-free survival for muscle-invasive bladder cancer at the University of Southern California was 89% in P2 node-negative tumors, 50% in P4 node-negative tumors, and 35% in patients with node-positive tumors.2 The effects of cystoprostatectomy on quality of life have been carefully studied. The newest surgical techniques of nerve-sparing that may preserve male potency and help increase the likelihood of continence with orthotopic urinary diversions have made cystectomy more tolerable, but even the most enthusiastic proponents of orthotopic bladder construction would agree that a well-functioning natural bladder is superior in function to any of the technologic advances in bladder construction and reconstruction devised in the past decade. Present day combined modality treatment and selective bladder preservation by early response evaluation differ from previous approaches utilizing monotherapy.
These older approaches included: (1) transurethral resection alone done selectively for patients with small tumors, which represented less than 20% of all muscleinvading bladder tumors; (2) external beam radiation therapy as monotherapy; (3) systemic multidrug chemotherapy as monotherapy. Local control rates with radiation alone for muscle-invading tumors have been disappointingly low, and radiation as monotherapy has largely been abandoned.3–6 It is now clear that monotherapies of various types are in general unsuccessful in curing patients of invasive bladder cancer. Barnes et al.7 reported a 27% 5-year survival in 85 patients with well-and moderately differentiated T2 transitional cell carcinomas (TCCs) treated with transurethral resection alone. Sweeney et al.8 found that only 19% of patients with muscle-invasive tumors were selected for treatment by partial cystectomy, and these had a local recurrence rate of 38% to 78%. Hall et al.9 reported a 19% 3-year freedom from recurrence with chemotherapy alone in 27 patients with localized disease, utilizing cisplatin, methotrexate, vinblastine, and epirubicin. The local control rates for the monotherapies noted above are inadequate (Table 22-1) when compared to radical cystectomy with its local control rate of 90%. Attempts at bladder sparing must be selective, as not all patients are candidates for that approach. Favorable selection criteria include tumors that can be substantially removed by transurethral resection and making certain that a complete response following initial chemoradiation induction is achieved, as measured by follow-up cytology and cystoscopic biopsies. Only if there is a complete response of induction therapy, consolidation chemotherapy is recommended and that followed by adjuvant
389
390
Part IV Bladder
The results of trimodality therapy for muscle-invasive bladder cancer have led to further studies utilizing trimodality treatment with improved radiation techniques and the use of newer chemotherapeutic agents in innovative combinations in attempts to improve on the complete response rate and the long-term control rate in the treatment of muscle-invasive bladder cancer. Despite promising results there is reluctance among urologic surgeons to accept trimodality therapy as an alternative to cystectomy even in selected patients. In part, this is due to improvements in urinary diversion in patients undergoing cystectomy, but, more importantly, concern persists among urologists that only cystectomy has the potential to rid the patient of the disease permanently. Urologists have expressed the following widely held views as arguments against bladder sparing:
Table 22-1 Bladder Sparing with Monotherapy No. Recurrence of an Invasive Tumor (%)
No. Patients
Treatment Transurethral resection alone
331
2010
Radiation alone
949
4011
27
199
Chemotherapy alone
chemotherapy in those patients who have negative bladder biopsies following consolidation radiochemotherapy. If residual disease is found, cystectomy is recommended. The combination of transurethral resection, radiation, and chemotherapy has yielded better results than any of the monotherapies with an improved clinical complete response rate (Tables 22-2 and 22-3). Substantial improvements in local control have been reported with combined modality therapy.12–14,19 This generally consists of transurethral resection of the tumor for debulking with the goal a visibly complete tumor removal followed by radiation treatment with concurrent radiosensitizing chemotherapy. In the studies reported, the most commonly used radiosensitizing drugs have been cisplatin, 5-fluorouracil (5-FU), and paclitaxel, used either singly or in various combinations.
1. Superficial relapse is common and very difficult to treat after radiochemotherapy. 2. Radiation burns the bladder rendering it useless, with bleeding and scarring associated with frequency, urgency, nocturia, and perineal pain. 3. Innovative surgical techniques, including neobladders, continent diversion, and other technical advances, have been successful and are subject to continuing improvement, making bladder-sparing efforts unnecessary.
Table 22-2 Recent Results of Multimodality Treatment for Muscle-invasive Bladder Cancer
Multimodality Therapy Used
Number of Patients
5-year Overall Survival (%)
5-year Survival with Intact Bladder (%)
Study Location
References
External beam radiation + cisplatin
42
52
42
RTOG 85-12
Tester et al.12
TURBT, external beam radiation + cisplatin
79
52
41
University of Erlangen
Dunst et al.13
91
51
44 (4 years)
RTOG 88-02
Tester et al.14
TURBT, 5-FU, external beam radiation + cisplatin
120
63
NA
University of Paris
Housset et al.15,16
TURBT, external beam radiation + cisplatin or carboplatin
162 (93-cisplatin; 69-carboplatin)
55
44
University of Erlangen
Sauer et al.17
TURBT, ± MCV, external beam radiation + cisplatin
123
49
38
RTOG 89-03
Shipley et al.18
TURBT, MCV, external beam radiation + cisplatin
190
54
45
MGH
Shipley et al.19
TURBT, external beam radiation + cisplatin
123
49
NA
RTOG 97-06
Hagan et al.20
TURBT, MCV, external beam radiation + cisplatin
Chapter 22 Selective Bladder Preservation by Combined Modality Treatment 391
Table 22-3 RTOG Bladder Protocols (1985–2001): Trimodality Therapy with Cystectomy for Poorly Responding/Relapsing Patients Protocol
Induction Treatment
Patients
5-year Survival
Complete Response
85-12
TURBT, CP + XRT
42
52%
66%*
88-02
TURBT, MCV, CP + XRT
91
51%
75%*
89-03
TURBT, ± MCV then CP + XRT
123
49%
59%
95-06
TURBT, 5-FU plus CP + XRT
34
n.a.
67%
97-06
TURBT, CP + BID XRT adj. MCV
52
n.a.
74%
99-06
TURBT, TAX plus CP + XRT; adj. CP + GEM
84
n.a.
n.a.
TURBT, transurethral resection of bladder tumor; XRT, external beam irradiation; CP, cisplatin; 5-FU, 5-fluorouracil; MCV, methotrexate, cisplatin, vinblastine; TAX, paclitaxel; GEM, gemcitabine; n.a., not available. *Urine or bladder wash cytology not included in the evaluation of the bladder tumor response.
4. Once the patient has been treated with chemotherapy and radiation therapy to the bladder, radical cystectomy becomes more difficult to perform and is associated with considerable morbidity. 5. Chemotherapy with its attendants nausea, anorexia, weight loss, and malaise is permanently destructive of the quality of life. 6. Delay in cystectomy risks patients’ lives. Each of these concerns is dealt with in this chapter. In the past 15 years, the Radiation Therapy Oncology Group (RTOG) has completed six prospective protocols of combined modality therapy for patients with muscleinvasive cancer who are considered to be cystectomy candidates (see Table 22-3). Bladder preservation with intravesical surgery, chemotherapy, and radiation therapy are combined as initial treatment with radical cystectomy recommended for all incomplete responders. Five of the RTOG protocols were phase I to phase II trials of concurrent chemotherapy and radiation therapy and one protocol was a phase III trial testing the efficacy of adjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy. A total of 426 patients were entered on these trials with 5-year overall survival of 50%, with 3-quarters of those patients being cured of their bladder cancer, while maintaining a functioning bladder.21 Current protocols are directed towards potentially more effective chemotherapeutic regimens that will result in a high protocol compliance rate and possibly a higher overall survival rate. A bladder-sparing strategy may be offered to highly selected patients with the understanding that radical cystectomy is still an available option in those patients who fail combined radiation therapy and chemotherapy. Investigators have become interested in clinical trials with the demonstration that some older, as well as newer drugs, have considerable activity against metastatic blad-
der cancer (Tables 22-4 and 22-5). The list includes, in addition to cisplatin, methotrexate, vinblastine, ifosfamide, doxorubicin, gemcitabine, paclitaxel, and others. Not surprisingly, combinations of these drugs have been shown to be more effective than single agents in the percentage of complete remissions (CR) achieved. With the use of combination chemotherapy in advanced measurable disease, CR became a common achievement compared to Table 22-4 Single Agent Activity in Bladder Cancer—Older Agents Drug
Response Rate (%)
Cisplatin
12–28
Methotrexate
29–45
Doxorubicin
17
5-fluorouracil
15–17
Vinblastine
15
Mitomycin C
13–20
Table 22-5 Single Agent Activity in Bladder Cancer—Newer Agents Drug
Response Rate (%)
Paclitaxel
42–56
Ifosfamide
20–31
Gemcitabine
23–28
Carboplatin
13–15
Docetaxel
13
392
Part IV Bladder
a 15% to 20% rate of partial remission only utilizing a variety of single drugs, and with CR only rarely observed with single-agent treatments. Successful bladder-sparing treatment is, and should be, very selective with frequent examinations of patients’ bladders for signs of persistence or recurrence of disease. Several protocols have been written explicitly directing discontinuation of the bladder-sparing effort in favor of radical cystectomy at the earliest sign of failure of local control. All of the protocols have required for acceptance that patients be medically fit and willing to undergo cystectomy immediately on recognition that the disease is found to be active in the bladder. Available data clearly indicate that one-third of patients entering potential bladder-sparing protocols require radical cystectomy either during or after the completion of radiochemotherapy. Over the years since the initial report of the effectiveness of cisplatin as a single agent in 1980 and the report of cisplatinum given concurrently with radiation, it has become appreciated that bladder cancer is a heterogeneous disease, one with a rapid doubling time and with micrometastases often present at the time of cystectomy. It is important to review the evolution of the Massachusetts General Hospital (MGH) and national cooperative group approaches to bladder conservation. From 1981 to 1986, in a National Bladder Cancer Group protocol, cisplatin was first used as a radiation sensitizer. From 1986 to 1993, a phase II and phase III protocol utilized MCV as neoadjuvant drugs. From 1994 to 1998, twice daily (b.i.d.) radiation was introduced with concurrent cisplatin and 5-FU as radiation sensitizers and with adjuvant MCV. From 1999 to 2002, b.i.d. radiation was used, with cisplatin and paclitaxel as radiosensitizers and with adjuvant cisplatin/gemcitabine. In 2003, a new protocol was then opened, a randomized phase II program utilizing b.i.d. radiation in all patients with randomization in the radiosensitizing drugs to either cisplatin plus 5-FU or cisplatin/paclitaxel. The adjuvant regimen is to consist of cisplatin, gemcitabine, and paclitaxel, a threedrug regimen proven effective in the treatment of advanced measurable bladder cancer.22 The current eligibility criteria for bladder sparing include: (1) histologic proof of invasion of the muscularis propria; (2) normal upper tracts; (3) the absence of hydronephrosis; (4) adequate renal function; (5) a normal hemogram; (6) medical fitness for cystectomy; and (7) the absence of malignant lymphadenopathy on imaging studies utilizing CT or MRI, with biopsy as necessary. Protocols carried out between 1986 and 2002 at the MGH Cancer Center included as complete a transurethral resection of the tumor as safely as possible and with the exception of one study, in which neoadjuvant chemotherapy was employed, patients were treated following a transurethral resection with radiation and concomitant chemotherapy.23 From 1986 to 1993, we studied
the question of neoadjuvant multidrug systemic chemotherapy to reduce the appearance of distant metastases and increase cure rates. However, the 5-and 10-year metastasis-free survival rates were not influenced in any patient subgroup by the addition of two cycles of neoadjuvant MCV chemotherapy. The lack of efficacy of neoadjuvant MCV was confirmed in a previously reported phase III trial.18 We have not used neoadjuvant chemotherapy in subsequent protocols, directing our attention instead to adjuvant chemotherapy. The MGH experience with 190 patients with invasive bladder cancers with clinical stages T2–T4a entered on successive prospective protocols has recently been updated.19 A common feature of all of the protocols was early bladder tumor response evaluation and the selection of patients for bladder conservation on the basis of their initial response to transurethral resection of bladder tumor (TURBT) combined with chemotherapy and radiation therapy. Bladder conservation was reserved for those who had a complete clinical response at the midpoint in therapy (after a radiation dosage of 40 Gy). Approximately two-thirds of the total then received consolidation with additional chemotherapy and radiation therapy to a total tumor dose of 64 to 65 Gy. Incomplete responders were advised to undergo radical cystectomy, as were patients whose invasive tumors persisted or recurred after treatment. In these phase II and phase III protocols, the scheduling of the chemoradiation varied. In phase III study, multidrug chemotherapy as neoadjuvant treatment was evaluated compared without it and with all patients given TURBT plus concurrent cisplatin, and radiation therapy. The median follow-up for all surviving patients was 6.7 years with 81 patients having been followed for 5 years or more and 28 patients for 10 or more years.19 The 5- and 1-year actuarial overall survival rates were 54% and 36%, respectively (stage T2 62% and 41%, stages T3–T4a 47% and 31%). The 5-and 10-year disease-specific survivals are 63% and 59%, respectively (stage T2 74% and 66%, stages T3–T4a, 53% and 52%). The 5-and 10-year disease-specific survivals with an intact bladder are 46% and 45%, respectively (stage T2, 57% and 50%, stages T3–T4a 35% and 34%). The pelvic failure rate was 8.4%. No patient required cystectomy due to bladder morbidity. The overall survival rate is provided in Figure 22-1, and the disease-specific survival rate is stratified by clinical stage in Figure 22-2. The current schema for multimodality treatment of muscle-invasive bladder cancer is provided in Figure 22-3, and the risk of relapse with a superficial tumor following multimodality treatment is shown in Figure 22-4. The actuarial 5- and 10-year overall survivals and disease-specific survivals for all 190 patients and for some clinically important subgroups are shown in Table 22-6. The clinical stage (see Figures 22-1 and 22-2) signifi-
Chapter 22 Selective Bladder Preservation by Combined Modality Treatment 393
Overall survival 100
75 62%
Stage T2 (n 90)
50 47% 25
Stage T3−4a (n 100)
p 0.02 90 100
0 0
1
2
41 40 3
4
11 17
5
6
7
8
9
10
Time from protocol enrollment (years) Figure 22-1 Overall Survival. (From Shipley WU, Kaufman DS, Zehr E, Heney NM, Lane SC, Thakal HK, Althausen AF, Zietman AL: Urology 2002; 60:62–68, with permission.)
Disease-specific survival 100 74 %
Stage T2 (n 90)
75 53 % 50
Stage T3−4a (n 100)
25
p 0.01 90 100
0 0
1
2
40 40 3
4
5
11 17 6
7
8
9
10
Time from protocol enrollment (years) Figure 22-2 Disease-specific survival. (From Shipley WU, Kaufman DS, Zehr E, et al: Urology 2002; 60:62–68, with permission.)
cantly influences overall survival (p = 0.02) and diseasespecific survival (p = 0.01), as well as CR rate (stage T2, 71%, stages T3–T4a, 50%, p = 0.04) and the rate of subsequent distant metastases (stage T2, 22%, stages T3–T4a, 37%, p = 0.03). We also found higher 5- and 10-year disease-specific survivals with an intact bladder for stage T2 patients, 57% and 50%, respectively, than for stages T3–T4a patients, 35% and 24%, respectively, with a p value of 0.008. Neither the tumor grade nor the use of neoadjuvant chemotherapy significantly improved the CR rate (64%), overall survival, disease-specific survival, or distant metastasis-free survival. The presence of hydronephrosis significantly reduces the CR rate, 37%
versus 68%, p = 0.002. The 5- and 10-year disease-specific survivals for all 66 patients undergoing cystectomy are 48% and 41%, respectively, indicating the important contribution of this procedure in those patients treated with this approach. The tumor stage did not influence the 5- and 10-year disease-specific survivals in the 66 patients who are undergoing either an immediate cystectomy or a salvage cystectomy (stage T2, 57% and 39%, stages T3–T4a, 42% and 42%). Seventy-three (60% of 121) patients who were complete responders after induction therapy developed no further bladder tumors. Twenty-four percent subsequently developed only a superficial occurrence and 16% developed an invasive tumor. Twenty-nine patients with superficial recurrence were managed conservatively by transurethral resection and intravesical therapy. With a median follow-up of 4.1 years since conservative treatment of the superficial recurrence 18 (62%) have tumor-free bladders. Thus, 91 of the 121 initially complete responding patients (or 75%) have tumor-free bladders. Seven of the 29 required a subsequent cystectomy for further superficial or invasive recurrence. For these patients, the overall survival is comparable to the 74 who had no failure, but one-third of these patients required a salvage cystectomy.24 While there has been an understandable concern that bladder-sparing treatment with high-dose radiation might cause irreparable damage to bladder function, nearly all patients reported normal or near-normal function and this is borne out by objective measurements of bladder function, recently reported by Zietman et al.25 The quality of life in patients whose bladders have been preserved has been studied in several centers with the results summarized in Table 22-7. As reported by Zietman et al. in the study of the long-term results of trimodality therapy for invasive bladder cancer, 78% of patients had compliant bladders with normal capacity and flow parameters. Eighty-five percent had no urinary urgency or only occasional urgency. Twenty-five percent had occasional to moderate bowel control symptoms and 50% of men had preserved erectile function. The MGH QOL questionnaire results of the late effects of chemoradiation on bladder function are very similar to two European cross-sectional studies recently reported. In both the studies, over 74% of the patients reported good urinary function. In one of the studies all patients received concurrent chemotherapy and radiation treatment as in the MGH series,26 while in the other,27 the patients received radiation alone. Concurrent chemotherapy might, therefore, be inferred to add little in terms of bladder morbidity. Comparing our results to those of contemporary radical cystectomy series is confounded by the discordance between the clinical TURBT staging and pathologic (cystectomy) staging. A recent prospective evaluation from
394
Part IV Bladder
Biopsy-proven muscle-invasive bladder cancer
Transurethral resection of all visible tumor, if possible
Induction therapy with external beam radiation and radiosensitizing chemotherapy (weeks 1 to 3)
Repeat cystoscopy with transurethral biopsy (week 7)
Complete response (T0) OR only a superficial tumor (Ta, Tcis) at a new site
Any residual tumor at the original site OR a tumor (T1 or greater) at a new site
Proceed with consolidation chemoradiation therapy (weeks 8 to 9)
Repeat cystoscopy with transurethral biopsy (week 17)
Complete response
Superficial persistence
Muscle-invasive disease
Intravesical therapy or radical cystectomy
Radical cystectomy
Radical cystectomy (week 9)
Adjuvant chemotherapy
Adjuvant chemotherapy Adjuvant chemotherapy
Long-term cystoscopic surveillance Figure 22-3 Current schema for multimodality treatment of muscle-invasive bladder cancer. (From Michaelson MD, Zietman AL, Kaufman DS, Shipley WU: Invasive bladder cancer: the role of bladder-preserving therapy and neoadjuvant chemotherapy. Urologia Integrada Y De Investigacion (in press).
Chapter 22 Selective Bladder Preservation by Combined Modality Treatment 395
T2-4 TCC bladder Trimodality therapy n 190
Complete responders n 121 Invasive relapse n 16
No bladder relapse n 73 Superficial relapse n 32 Cystectomy n3
No treatment n1 Local therapy n 28
No further relapse n 18
Further superficial n7 cystectomy 4
Invasive n3 cystectomy 3
Figure 22-4 Outcome of 121 patients with clinical stages T2–T4 TCC of the bladder who had a CR to trimodality therapy (chemotherapy, induction radiation, and transurethral resection). (From Zietman AL, Grocela J, Kaufman DS, et al: Urology 2001; 58:380–385, with permission.)
Stockholm28 has documented that clinical staging is more likely to understate the extent of the disease with regard to penetration into muscularis propria or beyond than is pathologic staging. Thus, if any favorable outcome bias exists, it is in favor of the pathologically reported radical cystectomy series. The University of Southern California recently reported on 633 patients undergoing radical cystectomy with pathologic stages T2–T4a with an actuarial overall survival rate at 5 years of 48% and 10 years of 32%.2 The Memorial Sloan Kettering Cancer Center Contemporary Radical Cystectomy series showed that in 184 patients with tumors of pathologic stages P2–P4, the 5-year overall survival rate was 36%. The actuarial 5-year survival rate of all 269 patients undergoing radical cystectomy with pathologic stages ranging from P0 to P4 in this series was 45%.1 The results of these contemporary cystectomy series for muscle-invading bladder cancer are similar to the MGH series, as well as those from the University of Erlangen29 and the RTOG18 (Table 22-8). This similarity in survival is likely in part due to the prompt use of
salvage cystectomy when necessary in the selective bladder preservation series. The disease-specific survival rate of 40% at 10 years in the MGH series for patients having cystectomy underscores the need for close urologic follow-up with cystoscopic surveillance and prompt bladder removal when necessary. One of the concerns with bladder-sparing therapy is the risk of subsequent superficial relapses within the intact bladder, which could progress to life threatening malignancy once again. Long-term follow-up from the MGH series has examined this issue in detail in 121 patients with a complete response (see Figure 22-4). Sixty percent of patients did not have evidence of relapse after a median follow-up of 7.1 years. Of the 32 superficial recurrences, 10 have required cystectomy and 18 have been treated conservatively tumor-free bladders. Thus, 91, or 75%, of the 121 complete responding patients with a median follow-up of over 7 years have tumor-free bladders. The overall survival of those patients with a superficial recurrence is the same as those CR patients without a bladder recurrence.24
396
Part IV Bladder
Table 22-6 Survival Outcomes by Patient and Tumor Characteristics OVERALL SURVIVAL (%)
DISEASE-SPECIFIC SURVIVAL (%)
5 year
10 year
5 year
10 year
190
54 ± 7.5*
36 ± 8.3*
63 ± 7.5*
59 ± 8.0*
<75 years
155
55
40
65
60
>75 years
35
51
22
56
56
47
59
40
60
52
143
52
34
64
62
90
62
41
74
66
100
47
31
53
52
No
163
55
37
64
61
Yes
27
48
29
53
49
Patient Group All patients
No.
Age at entry p = 0.04
n.s.
Gender Female Male
p = 0.67
p = 0.50
Clinical Stage T2 T3–T4a
p = 0.02
p = 0.01
Hydronephrosis p = 0.15
p = 0.09
From Dunst J, Sauer R, Schrott KM, et al: Int J Radiol Oncol Biol Phys 1994; 30:261-266. *95% confidence interval.
Table 22-7 Results of a Urodynamic/QOL Analysis Long-term results of trimodality therapy for invasive bladder cancer 1. 78% have compliant bladders with normal capacity and flow parameters 2. 85% have no urgency or occasional urgency 3. 25% have occasional to moderate bowel control symptoms 4. 50% of men have normal erectile function
Thus, lifelong surveillance with cystoscopy is crucial in patients treated with bladder-sparing therapy. Prompt salvage therapy for either superficial or recurrent invasive disease likely has prevented a survival disadvantage. In an attempt to improve safety, as well as to increase efficacy, newer studies of multimodality therapy, utilizing newer chemotherapeutic agents, have recently shown a high degree of activity in metastatic transitional cell tumors. The major drugs in this category are gemcitabine and paclitaxel. Many recent studies have sug-
gested that paclitaxel is an active agent in TCCs and a phase II study of the combination of cisplatin and paclitaxel demonstrated a 50% response rate in 52 patients with metastatic disease.30 Three phase II trials demonstrated that gemcitabine combined with cisplatin is a well-tolerated active regimen.31–33 The combination of cisplatin and gemcitabine has been compared to methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) in a phase III study and the two combinations were shown to have similar efficacy in metastatic disease. The gemcitabine/cisplatin combination, however, was better tolerated and led to fewer hospital days for the treatment of toxic side effects.32 It is, therefore, considered by many to represent the new standard of care for metastatic TCC and is under investigation in the adjuvant setting as well. The latest national protocol for bladder-sparing treatment (RTOG 02-33) was approved in January 2003. This is a randomized phase II study comparing two combinations of radiosensitizing chemotherapy, each given concurrently with a short course of b.i.d. radiation treatment. Patients received either the combination of fluorouracil and cisplatin or paclitaxel and cisplatin. This is followed, in patients whose tumors are successfully controlled with chemotherapy and radiation, by a three-
Chapter 22 Selective Bladder Preservation by Combined Modality Treatment 397
Table 22-8 Invasive Bladder Cancer Survival Outcomes in Contemporary Series OVERALL SURVIVAL (%) Series
Stages
Number
5-Year
10-Year
USC2 (2001)
P2–P4a
633
48
32
MSKCC1 (2001)
P2–P4a
181
36
27
Cystectomy
Selective bladder preservation Erlangen29 (2002)
cT2–T4
326
45
29
MGH19 (2001)
cT2–T4a
190
54
36
RTOG18 (1998)
cT2–T4a
123
49
—
drug adjuvant treatment program utilizing cisplatin, gemcitabine, and paclitaxel. This regimen has shown the highest response rate yet observed in published reports in advanced measurable bladder cancer.22 The 10-year overall survival and disease-specific survival rates in our bladder-sparing protocols are comparable to the results reported with contemporary radical cystectomy. For patients of similar clinical and pathologic stage, one-third of patients treated on protocol with the goal of bladder sparing ultimately required a cystectomy. A trimodality approach with bladder preservation based on the initial tumor response is therefore safe and appropriate treatment with the majority of long-term survivors retaining functional bladders. It is clear, however, that lifelong bladder surveillance is essential because only prompt salvage therapy can prevent a focus of new or recurrent bladder cancer from disseminating. We would conclude that selective bladder sparing should be one of the approaches considered in the treatment of invasive bladder cancer. While it is not suggested that it will replace radical cystectomy, sufficient data now exist from many international prospective studies to demonstrate that it represents a valid alternative. This approach contributes significantly to the quality of life of patients so treated and represents a unique opportunity for urologic surgeons, radiation oncologists, and medical oncologists to work hand in hand in a joint effort to provide patients with the best treatment for this disease.
REFERENCES 1. Dalbagni G, Genega E, Hashibe M, et al: Cystectomy for bladder cancer: a contemporary series. J Urol 2001; 165:1111–1116.
2. Stein JP, Lieskovsky G, Cote R, et al: Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1054 patients. J Clin Oncol 2001; 19: 666–675. 3. Mameghan H, Fisher R, Mameghan J, et al: Analysis of failure following definitive radiotherapy for invasive transitional cell carcinoma of the bladder. Int J Radiat Oncol Biol Phys 1995; 31:247–254. 4. Jenkins BJ, Blandy JP, Caulfield JF, et al: Reappraisal of the role of radical radiotherapy and salvage cystectomy in the treatment of invasive bladder cancer. Br J Urol 1988; 62:343–346. 5. Gospodarowicz MK, Hawkins MV, Rawling GA, et al: Radical radiotherapy for muscle invasive transitional cell carcinoma of the bladder: failure analysis. J Urol 1989; 142:148–154. 6. DeNeve W, Lybeert ML, Goor C, et al: Radiotherapy for T2 and T3 carcinoma of the bladder: the influence of overall treatment time. Radiol Oncol 1995; 36:183–188. 7. Barnes RW, Dick AL, Hadley HL, et al: Survival following transurethral resection of bladder carcinoma. Cancer Res 1977; 37:2895–2898. 8. Sweeney P, Kursh ED, Resnick MI: Partial cystectomy. Urol Clin North Am 1992; 2(Suppl 2):75–87. 9. Hall RR, Robert JT, Marsh MM: Radical transurethral surgery in chemotherapy aiming at bladder preservation. In Splinter AW, Scher HI (eds): Neoadjuvant Chemotherapy in Invasive Bladder Cancer, pp 169–174. New York, Wiley Liss, 1990. 10. Herr HW: Conservative management of muscleinfiltrating bladder cancer: prospective experience. J Urol 1987: 138:1162–1163. 11. Scher HI, Shipley WU, Herr HW: Cancer of the bladder. In DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer: Principles and Practice of Oncology, 5th edition, pp 1300–1318. Philadelphia ; JB Lippincott, 1997. 12. Tester W, Porter A, Asbell S, et al: Combined modality program with possible organ preservation for invasive
398
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
Part IV Bladder bladder carcinoma: results of RTOG protocol 85-12. Int J Radiat Oncol Biol Phys 1993; 25:783–790. Dunst J, Sauer R, Schrott KM, et al: Organ-sparing treatment of advanced bladder cancer. A 10-year experience. Int J Radiat Oncol Biol Phys 1994; 30:261–266. Tester W, Porter A, Heaney J, et al: Neoadjuvant combined modality therapy with possible organ preservation for invasive bladder cancer. J Clin Oncol 1996; 14:119–126. Housset M, Maulard C, Chretien YC, et al: Combined radiation and chemotherapy for invasive transitional-cell carcinoma of the bladder: a prospective study. J Clin Oncol 1993; 11:2150. Housset M, Dufour E, Maulard-Durtux C: Concomitant 5-Fluorouracil, cisplatin and bifractionated split course radiation therapy for invasive bladder cancer. Proc Am Soc Clin Oncol 1997; 16:319A. Sauer R, Birkenhake S, Kuhn R, et al: Efficacy of radiochemotherapy with plating derivatives compared to radiotherapy alone in organ-sparing treatment of bladder cancer. Int J Radiat Oncol Biol Phys 1998; 40:121–127. Shipley WU, Winter KA, Kaufman DS, et al: A phase III trial of neoadjuvant chemotherapy in patients with invasive bladder cancer treated with selective bladder preservation by combined radiation therapy and chemotherapy: initial results of RTOG 89-03. Clin Oncol 1998; 16:357–383. Shipley WU, Kaufman DS, Zehr E, et al: Selective bladder preservation by combined modality protocol treatment: long-term outcomes of 190 patients with invasive bladder cancer. Urol 2002; 60:62–68. Hagan MP, Winter KA, Kaufman DS, et al: RTOG 97-06: initial report of a phase I/II trial of bladder conservation employing TURB, accelerated irradiation sensitized with cisplatin followed by adjuvant MCV chemotherapy. Int J Radiat Oncol Biol Phys 2001; 51(Suppl 1):20A. Shipley WU, Kaufman DS, Tester WJ, et al: Overview of bladder cancer trials in the radiation therapy oncology group. In Raghavan D (ed): Cancer Supplement (in press). Bellmunt J, Guillem V, Paz-Ares L, et al: Phases I and II study of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma of the urothelium. J Clin Oncol 2000; 18(18):3247–3255. Prout GR Jr, Shipley WU, Kaufman DS, et al: Preliminary results in invasive bladder cancer with transurethral resection, neoadjuvant chemotherapy and
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
combined pelvic irradiation plus cisplatin chemotherapy. J Urol 1990; 144:1128–1136. Zietman AL, Grocela J, Kaufman DS, et al: Selective bladder conservation using transurethral resection, chemotherapy and radiation: management and consequences of Ta, T1 and Tis recurrence within the retained bladder. Urol 2001; 58:380–385. Zietman AL, Sacco UE, Skowronski E, et al: Organ conservation as an alternative to radical cystectomy for invasive bladder cancer: urodynamic and quality of life evaluation of patients treated by trimodality therapy. Int J Radiat Oncol Biol Phys 2002; 54(2 Suppl 1) 62. Caffo O, Fellin G, Graffer U, et al: Assessment of quality of life after cystectomy or conservative therapy for patients with infiltrating bladder carcinoma. Cancer 1996; 78:1089–1097. Henningsohn L, Wijkstrom H, Dickman PW, et al: Distressful symptoms after radical radiotherapy for urinary bladder cancer. Radiother Oncol 2002; 60:215–225. Wijkstrom H, Norning U, Lagerkvist M, et al: Evaluation of clinical staging before cystectomy transitional cell bladder carcinoma, a long-term follow-up of 276 consecutive patients. Br J Urol 1998; 81:686–691. Rodel C, Grabenbauer GG, Kuhn R, et al: Combinedmodality treatment and selective organ preservation in invasive bladder cancer: long-term results. J Clin Oncol 2002; 20(14):3061–3071. Dreicer R, Manola J, Roth B, et al: Phase II study of cisplatin and paclitaxel in advanced carcinoma of the urothelium: an Eastern cooperative oncology group (ECOG) study. Clin Oncol 2000; 18:1056–1061. Kaufman DS, Raghavan D, Carducci M, et al: Phase II trial of gemcitabine plus cisplatin in patients with metastatic urothelial cancer. J Clin Oncol 2000; 18:1921–1927. Von der Maase H, Hansen SW, Roberts JT, et al: Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multicenter, phase III study. J Clin Oncol 2000; 18(17):3068–3077. Moore MJ, Winquist EW, Murray N, et al: Gemcitabine plus cisplatin, an active regimen in advanced urothelial cancer: a phase II trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 1999; 17(287):876–881.
C H A P T E R
23 Noncontinent and Continent Cutaneous Urinary Diversion Tracy M. Downs, MD, Maxwell V. Meng, MD, and Peter R. Carroll, MD
Urinary diversion is necessary in patients who undergo cystectomy for bladder cancer, as well as in some patients with severe functional or anatomic abnormalities of the lower urinary tract. Alternative urinary drainage may be either temporary or permanent. Permanent forms of urinary diversion can be accomplished by establishing direct continuity between the urinary tract and the skin or, more commonly, by interposing a segment of bowel between the urinary tract and skin. Nearly all segments of bowel have been described for use in urinary diversion, and despite extensive study, no single method or portion is ideal for all patients and clinical settings. The specific method of urinary diversion should be selected based on the indication for diversion, individual patient preference, anatomy, renal function, and overall health. Urinary diversions can be broadly categorized into those that are continent (i.e., store urine with intermittent drainage) and those that are noncontinent (i.e., continuous urine output). Continent forms of urinary diversion are achieved with either a continence mechanism to an abdominal stoma or with an orthotopic bladder substitute relying on intrinsic continence after anastomosis to the native urethra. Noncontinent types of urinary diversion generally act simply as a conduit through which the urine exits the body, thus requiring an external appliance to collect the urine. Although continence after reconstruction permits freedom from an external collection bag, these operations may be technically more difficult and associated with higher complication rates. Continent diversion, however, can benefit the patient with regard to psychologic aspects, with preserved self-image and sexuality. Overall, patients report a high level of satisfaction with both continent and noncontinent forms of urinary diversion.1 This chapter
describes permanent forms of cutaneous urinary diversion, both noncontinent and continent. Temporary forms of urinary diversion, such as percutaneous nephrostomy, are discussed elsewhere. PREOPERATIVE PREPARATION Preoperative counseling is crucial. The discussion should include the specific goals and complications of the planned procedure, as well as what the patient should expect after surgery in terms of changes in lifestyle. Noncontinent diversion may be the most appropriate alternative in the debilitated patient and those who lack the manual dexterity or motivation to care for a continent reservoir. In addition, a thorough history should be obtained, including previous surgical procedures, associated medical conditions, systemic diseases, and previous irradiation. The patient should be specifically questioned regarding a history of regional enteritis, ulcerative colitis, diverticulosis and diverticulitis, and other gastrointestinal problems; this helps identify which segment of bowel can be used or avoided. Although the ileal conduit is most popular, use of the colon has several advantages. Antireflux mechanisms are possible using the ileocecal valve or tenia, and the large lumen reduces the incidence of stomal stenosis. An assessment of renal function is important and preoperative imaging of the upper urinary tract can reveal abnormalities, such as nephrolithiasis, hydronephrosis, and renal scarring. Additional evaluation of the bowel by contrast imaging or endoscopy should be considered in patients with a history of gastrointestinal diseases or signs and symptoms suggesting such diseases. The patient’s overall state of health and fitness for surgery needs to be
399
400
Part IV Bladder
evaluated, especially in the older individual with bladder cancer and typical comorbidities. It is essential to address issues of stomal care before surgery. Patients who are physically or mentally challenged may need assistance from a family member or visiting nurse. In general, the collecting device is changed every 4 to 5 days. The stoma site should be carefully selected prior to surgery, and consultation and subsequent follow-up with an enterostomal therapist can be valuable. The patient is evaluated in both the sitting and standing position to ensure that the stoma is located away from bony prominences, fat folds, prior abdominal scars, and clothing waistbands (i.e., belts), all of which can make it difficult for the external appliance to fit securely. The usual site is located along a line from the anterior superior iliac spine and the umbilicus, at the lateral edge of the rectus abdominus muscle. It is important to bring the stoma through the rectus muscle to help prevent the development of a parastomal hernia. Adequate preoperative bowel preparation is important for reducing infectious complications. Patients are typically placed on a clear liquid diet 2 days prior to their scheduled procedure. A mechanical bowel prep (Golytely) is started one day prior to surgery and oral antibiotics (neomycin + erythromycin) are given after completion of the mechanical bowel prep. Systemic antibiotics are administered during the perioperative period. POSTOPERATIVE CARE Several general principles of postoperative care apply to the various types of urinary diversion. As with most intra-abdominal operations, paralytic ileus commonly occurs after using intestinal segments for urinary diversion. Thus, a nasogastric tube is routinely placed for gastric decompression and removed when bowel function returns. More recently, the nasogastric tube is removed immediately after the operation with infrequent need for replacement and improved patient’s comfort. In order to minimize antibiotic-associated complications, prophylactic antibiotics should be continued for only 24 hours after surgery. Fluid balance should be closely monitored and postoperative fluid replacement should be calculated from maintenance requirements, third-space loss, drain output, and systemic conditions leading to hypermetabolism. Serum electrolytes are checked for imbalances. Patients undergoing pelvic surgery are at risk for venous thromboembolic events, which can be reduced with the use of sequential compression devices and early ambulation. Incentive spirometry can improve pulmonary function and lessen respiratory complications. If ureteral stents are used, they are typically removed on the fifth postoperative day and after 3 weeks for an ileal conduit and continent diversion, respectively. Evidence of urinary
leak is provided by the volume of drain output and quantitation of fluid creatinine. In patients with a continent cutaneous or orthotopic diversion, a Foley catheter is used to drain the pouch. Manual irrigation of the catheter (60 to 100 ml saline) is performed at 4- to 6-hour intervals to prevent mucus obstruction. While hospitalized, patients become familiar with the catheterization and irrigation process. Plain radiography with instillation of iodinated contrast into the pouch is performed prior to removing the Foley catheter to ensure watertight integrity. If a suprapubic tube is placed at the time of surgery, it can be removed after the contrast imaging study or left as a safety valve, while the patient demonstrates adequate emptying by catheterization. At home, the patient continues to irrigate the pouch 2 to 3 times per day, helping eliminate mucus debris. Since continent reservoirs develop chronic bacteriuria, antibiotics should only be given if the patient is symptomatic. NONCONTINENT URINARY DIVERSIONS: SURGICAL TECHNIQUE Urinary Diversion to the Abdominal Wall Cutaneous Pyelostomy Cutaneous pyelostomy was originally reported by Immergut et al.2 as a method of diverting urine in children with tortuous, dilated ureters. The relative lack of subcutaneous fat, underdevelopment of the flank musculature, and renal mobility in children facilitate the operation.3 Although useful as a temporizing procedure in children with gross infection, urinary obstruction, and especially in the setting of renal failure, current indications are limited. The technique requires the presence of an extrarenal pelvis. Pyelostomy is an alternative to percutaneous nephrostomy in small infants, where placement of a nephrostomy tube can be difficult and long-term maintenance may pose a problem for parents.4 Technique. The renal pelvis is identified and mobilized through a subcostal incision. There is no need to mobilize the ureter or disrupt its collateral circulation. The kidney is rotated anteriorly, and a 3-cm incision is made in the renal pelvis well away from the ureteropelvic junction (Figure 23-1A). The renal pelvis is brought out to the skin incision and anastomosed to the skin using interrupted absorbable sutures (Figure 23-1B). The remainder of the incision is closed in the usual fashion. Cutaneous Ureterostomy The first cutaneous ureterostomy was performed by LeDentu in 1889 and represents a simple method of urinary diversion.5 End cutaneous ureterostomy has been used as a means of temporary diversion in infants and palliative diversion in adults6,7; delayed reconstruction after cutaneous ureterostomy can be successfully performed.8
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 401
Figure 23-1 A, The renal pelvis is incised for approximately 3 cm. B, The renal pelvis is anastomosed to the skin using interrupted sutures.
The advantages of cutaneous ureterostomy include decreased operative and recuperative times, as well as the use of an extraperitoneal approach.9 In addition, complications associated with the use of bowel, such as intestinal anastomosis and absorption of urinary constituents, are avoided.10 Disadvantages of cutaneous ureterostomy include the risk of stomal stenosis, chronic bacteriuria, and stone formation. A dilated ureter is usually necessary for a successful outcome, facilitated by the thick-walled, well-vascularized ureter.11 If both ureters are dilated and have adequate length, each can be brought out to the skin. If only one ureter is dilated, this should be used for the cutaneous ureterostomy with proximal transureteroureterostomy of the contralateral, nondilated ureter.8,12 Technique. When both ureters are dilated, a doublebarreled cutaneous ureterostomy is fashioned with the stoma on the side of the shorter ureter. In the case of unilateral ureteral dilation, the stoma is created on that side. Only a single stoma site, with one appliance, is required whether one or both ureters are brought to the skin. The ureter is mobilized extraperitoneally with careful preservation of the collateral blood supply. If possible, the ureter should be freed to the level of the bladder to maximize length. Prior to transecting the ureter, the ureter is measured to ensure that it is adequate.
If only a single ureter is obstructed, a simple stoma can be created by sewing the end of the ureter flush with the skin at the stoma site. Another option, when the ureter is narrow, is to create a V-flap stoma (Figure 23-2A–C). If both ureters are dilated, a single stoma can be created by suturing the ureters together, everting them and anastomosing the ends to the skin. Alternatively, a Z-plasty can be performed when the ureters are not adequately dilated (Figure 23-3A–C).12 When a single ureter is dilated, transureterostomy with retroperitoneal passage of the smaller ureter to the contralateral side is combined with the cutaneous ureterostomy. Both ureters need to be free from angulation and tension. The larger ureter is incised 2 cm on its medial aspect, and the smaller ureter is trimmed to the appropriate length and spatulated. The ureteral–ureteral anastomosis is performed using a running absorbable suture; ureteral stents may be placed prior to this portion. The stoma is fashioned as previously described for a single ureter. Conduits to the Abdominal Wall Ileal Conduit Seiffert13 first described an ureteroileocutaneous diversion in 1935. The procedure was subsequently popularized by Bricker14 and remains the most commonly used method of noncontinent urinary diversion in the United
402
Part IV Bladder
Figure 23-2 A, The ureter is brought through the skin and spatulated. B, C, The Ureter is everted and the anastomosis is performed using several interrupted absorbable sutures.
Figure 23-3 A–C, After making a Z-shaped incision, the ureters are spatulated on their lateral aspects and sutured to the skin.
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 403
States. Patient selection, proper stoma location, and careful technique in creating a well-vascularized stoma are all important to the success of the procedure. An ileal conduit may be contraindicated in patients with a history of regional enteritis or extensive pelvic irradiation.15 In these situations, a colon conduit may be preferable. The typical stoma is located in the right lower quadrant, as previously described. In order to minimize the absorptive surface of the bowel in contact with urine, the ileal segment should be as short as feasible. Reabsorption of urinary constituents does not cause a significant problem in patients with normal renal function but metabolic abnormalities may develop in those with renal insufficiency.16 Technique. The conduit is usually constructed using a segment of ileum approximately 15 cm proximal to the ileocecal valve. The exact length of the conduit varies with patient habitus but averages between 15 and 20 cm in most patients (Figure 23-4A). Preservation of the vascular supply to the ileal segment is vital. Transillumination of the mesentery helps identify the blood vessels supplying the bowel, and at least two major vascular arcades should be included with the ileal segment. Once the appropriate area of ileum is identified and isolated, the mesentery is divided proximally and distally with individual ligation of vessels. The bowel is divided between clamps or using a GIA stapler. Bowel continuity is reestablished by suturing or with the aid of stapling
devices. The ileal segment is brought below the level of the ileoileal reanastomosis. The conduit is positioned caudally, usually with the end in the right lower quadrant in an isoperistaltic direction; the base of the conduit is closed with either absorbable sutures or a stapler (Figure 23-4B). The left ureter is brought under the sigmoid mesocolon and both ureters are spatulated and reimplanted into the base of the conduit. The various types of ureteral anastomoses will be discussed later. Ureteral stents are placed and brought out via the abdominal stoma to facilitate urinary drainage and stent the anastomoses. The mesentery is reapproximated using nonabsorbable sutures to prevent internal bowel herniation. To create the stoma, a small circle of skin is excised at the premarked site, and the underlying cylinder of fat is removed. A cruciate incision is made in the anterior fascia, large enough to accommodate two fingers (Figure 23-5A). The stents and the end of the conduit are brought through the rectus abdominus muscle and fascia; the end of the conduit is then secured to the fascia (Figure 23-5B). If present, the distal staple line is excised and the stoma is everted to create a “rosebud” (Figure 23-5C). The stoma should ideally protrude, without tension, 2 to 3 cm above the surface of the skin. In patients with short mesentery or thick abdominal wall, a Turnbull loop can be created to maximize stomal vascularity.17 When properly constructed, both end- and loop-cutaneous stomas have comparable long-term results in patients with ileal conduits.18
Figure 23-4 A, An appropriate segment of ileum is selected, containing two major vascular arcades. B, The conduit is positioned in the right lower quadrant and the ureters are reimplanted into the base of the conduit.
404
Part IV Bladder
Figure 23-5 A, The rectus fascia is incised in a cruciate fashion. B, The end of the conduit is brought through the rectus muscle and anchored to the fascia. C, The stoma is everted and sutured to the skin.
Jejunal Conduit Jejunal conduit urinary diversion should be reserved for patients in whom other, more suitable options are unavailable. These include those with prior pelvic radiation, inflammatory bowel disease, or loss of the middle and distal ureters. Electrolyte disturbances are common in those with urinary conduits using the jejunum.19 Technique. As with other bowel segments incorporated into the urinary tract, the length of jejunum should be as short as possible to reduce metabolic abnormalities; in some cases, the stoma can be placed above the umbilicus. The site, distant from the belt line, should be carefully considered and marked before surgery. Patients who have received significant pelvic radiation may require transection of the ureters at the level of the true pelvis (pelvic inlet). The ureters are brought out from the retroperitoneum below the ligament of Treitz.20 An appropriate segment of jejunum is identified and isolated, as described for ileal conduits. It is important to
preserve an adequate blood supply to the segment. The jejunum is divided between either clamps or the GIA stapler and then continuity is restored. In contrast to the ileal conduit, the isolated jejunum should lie above the reanastomosed jejunum. The proximal end of the conduit is directed towards the retroperitoneum and the conduit is oriented in an isoperistaltic direction. The ureters are anastomosed to the jejunum, with placement of stents to reduce early postoperative electrolyte abnormalities.15 The mesenteric window is closed using nonabsorbable sutures. The stoma is created in the same fashion as described for an ileal conduit; the stoma is usually located in the right upper quadrant when using jejunum. Colonic Conduits The colon conduit was popularized by TurnerWarwick21 in 1960. Urinary conduits constructed from large intestine have several potential advantages when
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 405
compared to those made using small intestine. First, nonrefluxing ureteral anastomoses are possible using either a short tunnel through the teniae coli or the ileocecal valve. Second, stomal stenosis is less common due to the larger lumen of the colon. Third, a suitable segment of colon outside of the field of previous abdominal or pelvic irradiation is usually available. When use of the colon is anticipated, a preoperative contrast imaging study of the large bowel or colonoscopy should be considered. Ileocecal Conduit The ileocecal conduit was first described by Zinman and Libertino22 in 1975. This method utilizes the ileocecal valve as an antireflux mechanism for the ureters. Other advantages of this portion of bowel include the constant and abundant blood supply and location in the right lower quadrant, facilitating stoma formation.3 The ileocecal segment is rarely affected by generalized bowel disorders, such as diverticulitis. Technique. The blood supply of the ileocecal region is based on the ileocolic artery. The segment, including 10 cm of terminal ileum, is isolated and the appendix is removed. After restoring continuity between the ileum and ascending colon, the ureters are anastomosed directly into the ileal portion of the segment. The antire-
flux mechanism depends on the competency of the ileocecal valve, which can be reinforced by wrapping the redundant cecum around the ileum and securing this configuration with seromuscular sutures.22 The proximal portion of the conduit is fixed to the retroperitoneum, and the distal cecal portion is brought out to the skin. An everted stoma is created in the standard rosebud fashion. Transverse Colon Conduit The transverse colon conduit is well suited for patients who have received extensive pelvic irradiation, making the small bowel suboptimal, or situations where the distal ureters are damaged or absent. In situations of inadequate ureteral length, the transverse colon segment can be directly anastomosed to both renal pelves. Technique. A 15-cm segment of transverse colon is used for the conduit. The blood supply is based on the middle colic artery, and transillumination of the transverse mesocolon assists in identifying the appropriate segment (Figure 23-6A). The greater omentum is dissected from the superior aspect of the transverse colon and the mesentery is incised, with ligation of individual blood vessels. The colon is divided both proximally and distally, and bowel continuity is restored. The isolated transverse colonic segment should lie below the
Figure 23-6 A, An appropriate segment of transverse colon is selected. B, After colocolostomy, the ureters are brought into the abdominal cavity and the ureteral anastomoses are performed.
406
Part IV Bladder
reanastomosed transverse colon. Mobilization of the right colon can ensure that the colocolostomy is created without tension. The proximal end of the colon conduit is closed and fixed posteriorly. The ureters are mobilized and then the ends are spatulated and brought through the posterior peritoneum into the abdominal cavity. The ureters are reimplanted into the base of the conduit in either a direct or nonrefluxing manner and ureteral stents are placed (Figure 23-6B). A flap of peritoneum is fashioned to cover the ureteral anastomoses. A standard rosebud technique is used to create the stoma, which can be positioned on either side in the upper or lower quadrant. Sigmoid Colon Conduit The sigmoid colon conduit should be avoided in patients with a history of pelvic irradiation. In these cases, the superior hemorrhoidal artery is often injured, leaving an inadequate blood supply to the sigmoid segment. A sigmoid conduit is also questionable in those undergoing cystectomy because the vascular supply to the rectum may be compromised if the internal pudendal artery is ligated. However, the sigmoid can be used after pelvic exenteration, since it obviates the need for intestinal reanastomosis. A sigmoid colon conduit is commonly used for the management of benign conditions of the lower urinary tract, such as neurogenic bladder, requiring urinary diversion. Technique. The sigmoid colon is mobilized by lateral incision along the white line of Toldt; adequate mobilization makes the bowel reanastomosis easier. The optimal segment is identified, typically 10 to 12 cm in length. After short incisions in the mesentery are made, the proximal and distal ends of the colonic segment are divided. The superior hemorrhoidal artery can be divided for increased mobility. Bowel continuity is reestablished, with the conduit placed laterally to the anastomosis. The right ureter is brought under the sigmoid colon, and the ureters are sewn using either a direct or nonrefluxing technique. The preferred stoma site, created as previously described, is on the left side of the abdomen. CONTINENT URINARY DIVERSIONS: SURGICAL TECHNIQUE Continent cutaneous (i.e., nonorthotopic) techniques can be divided into two major categories: (1) urinary diversion into the rectosigmoid and (2) continent urinary pouches requiring clean intermittent catheterization. Because numerous variants of continent urinary diversion are used worldwide, a complete review of all operative techniques is beyond the scope of this chapter. This chapter focuses on the most commonly utilized and described continent urinary diversions.
RECTAL BLADDER URINARY DIVERSION The rectal bladder urinary diversions allow excretion of urine my means of evacuation. Innovative techniques have been advocated for separating the fecal and urinary streams, but all still employ the principle of ureterosigmoidostomy. Variations of the original ureterosigmoidostomy include the ureter ileosigmoidostomy, folded rectosigmoid bladder, and augmented valve rectum procedures, in which different segments of small intestine are anastomosed to the rectum. These operations will be grouped and discussed together as “rectal bladder urinary diversions.” In each of these operations, with the exception of certain types of augmented valve rectum procedures, the ureters are transplanted to the rectal stump and the proximal colon is managed by terminal sigmoid colostomy or, more commonly, by bringing the sigmoid to the perineum, using the anal sphincter to achieve both bowel and urinary control. Although these operations continue to enjoy some popularity abroad, they have never been widely accepted in the United States. Ureterosigmoidostomy Ureterosigmoidostomy can be regarded as the original continent urinary diversion with reports of this procedure dating as far back as the 1850s.23,24 Its appeal to the urologic surgeon has waned given issues of transplanting the ureters directly to an intact fecal stream and development of malignancy, and considerable complications, including hyperchloremic acidosis, hypokalemia with nephropathy, and pyelonephritis. Nevertheless, ureterosigmoidostomy offers a simple form of continent urinary diversion when compared with the newer techniques requiring complex refashioning of bowel segments.25,26 Currently, most urologists reserve the procedure only for those individuals of advanced age where adverse long-term sequelae are less important. Several other factors argue against the use of ureterosigmoidostomy. In patients with neurogenic bladder, there may be associated bowel or anal sphincter dysfunction. Individuals with dilated ureters are at increased risk for developing either obstruction or reflux, while extensive prior radiation may affect both the bowel and distal ureters. Patients with preexisting renal insufficiency are poor candidates for ureterosigmoidostomy or any continent diversion27,28; similarly, those with underlying hepatic dysfunction are at risk for developing ammonia intoxication.29 Preoperative evaluation of the patient should include barium enema and/or colonoscopy that would detect bowel disease, such as diverticulitis, polyps, or cancer. Incontinence of the mixture of stool and urine is a calamitous complication. Thus, an adequate test of preoperative anal sphincter integrity is mandatory and anal
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 407
sphincteric tone must be judged competent before one selects this procedure. Various tests have been proposed to measure sphincter function. The most useful are those that require the retention of an enema solution of both solid and liquid material for a specified time in the upright and ambulating positions without soilage. Bissada et al.26 use a saline retention enema that the patient holds for 1 hour, while Benson et al.15 advocate the use of a 400- to 500-ml thin mixture of oatmeal and water that the patient attempts to retain for 1 hour in the upright position.28 Technique If indicated, cystectomy is performed first. At the start of urinary diversion part of the procedure, a large-caliber (24Fr to 28Fr) red rubber catheter is placed in the rectum, advanced through the anus and sutured in place to the perianal skin. This tube should be advanced sufficiently far that it can be easily reached and remains in place after surgery to drain urine and potentially to decrease the risk of anastomotic leakage. A permanent end colostomy is created by dividing the descending sigmoid colon at the junction of its middle and lower thirds with complete closure of the distal rectosigmoid segment with absorbable sutures, rather than staples, to reduce the potential for postoperative calculus formation in the rectosigmoid reservoir. The proximal sigmoid colon is diverted to a premarked end colostomy stoma site. The most distal portion of the rectosigmoid is the preferred site for the ureteral anastomosis. In the Leadbetter technique,30 the left ureter is brought through the sigmoid mesentery. After both ureters have been mobilized, stay sutures are placed proximally and distally in an antimesenteric tenia 10 to 15 cm apart and a longitudinal incision of 5 to 7 cm is made. The distal end of the ureter is spatulated and a mucosal to mucosal anastomosis is performed with fine absorbable suture material (Figure 23-7). The muscularis of the tenia is then closed over the ureter with interrupted absorbable sutures to form the submucosal tunnel. The contralateral anastomosis is made in the same fashion; generally, the right ureter is anastomosed most distally. Goodwin and colleagues30a published their experience with the transcolonic (open colon technique) of ureteral anastomosis (Figure 23-8A–D). This technique differs from Leadbetter’s method in that the rectosigmoid is opened anteriorly and the ureters are brought through a separate submucosal tunnel in the posterior wall into the bowel lumen. The ureters are sutured, separately or conjoined (i.e., Wallace technique), to the mucosa from within the bowel lumen. After ureteral anastomosis and ureteral stent placement have been completed, the colon is closed with a simple 2-layer technique (see Figure 23-8C ). The
Figure 23-7 Leadbetter-Clarke ureterointestinal anastomosis. A linear incision is made in the taenia, the taenia is raised and the mucosa is identified. A small button of mucosa is removed and the ureter is spatulated and then sutured to the mucosa with 5-0 PDS. The sero-muscular layer is sutured over the ureter with care taken not to compromise or occlude the ureter.
inner layer is closed with a running suture of absorbable material taken through all layers of intestine, whereas the outer layer is closed with seromuscular nonabsorbable material. Although intubation of the ureters and stent placement are feasible using the Leadbetter technique of ureteral implantation, the transcolonic approach (anterior colotomy) (see Figure 23-8B) affords greater ease in directing the ureteral stents to the outside. The ureterocolonic anastomoses can be retroperitonealized. In addition, it is often helpful to suture the proximal end of the isolated rectosigmoid to the sacral promontory to prevent excessive mobility. One or 2 intraabdominal drains are typically placed, as well as a rectal tube. CONTINENT CATHETERIZABLE URINARY DIVERSIONS Numerous operative techniques have been developed for continent catheterizable urinary diversions. Patient selection is important in deciding which patients are most suitable for a continent catheterizable urinary diversion. To perform clean intermittent catheterization, it is paramount that one has good hand-eye coordination. Thus, patients with spinal cord injury (e.g., quadriplegia) or some with multiple sclerosis or other neurologic disorders may not be candidates. Patient with any cognitive condition, such as dementia, that could lead to a poor understanding of the catheterization process would not be an appropriate candidate. The choice of where to place the catheterizable stoma is based on the preference of the surgeon. The two most common sites are at the umbilicus and in the lower quadrant of the abdomen, through the rectus bulge and below
408
Part IV Bladder
Figure 23-8 A, The open colostomy approach is preferred because it allows the placement of indwelling ureteral stents bilaterally. B, The stents are directed to the outside through the lumen of the rectal tube. C, The colon is closed with a simple two-layer technique. The retroperitoneal windows are closed with a running suture.
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 409
Figure 23-8 cont’d D, The ureteral colonic anastomoses are retroperitonealized if possible. (From Walsh P, Retik A, Vaughn EJ, et al (eds): Campbell’s Urology, 8th ed, Philadelphia, WB Saunders, 2002.)
the “bikini line.” The latter site affords both men and women the opportunity to conceal the stoma. In certain patients the umbilicus is the preferred location. For example, in the individual confined to a wheelchair, the umbilical stoma location may have a lower incidence of stomal stenosis, especially when fashioning an appendiceal stoma. The umbilical location is also ideal in paraplegics because it allows easier catheterization without the need for chair transfer and disrobing. Cosmetically, the umbilical location of a stoma is typically indistinguishable from a normal umbilical dimple. Patients are instructed to cover the stomal site with a gauze or square adhesive bandage to avoid mucus soiling of clothing. CONTINENCE MECHANISM Perhaps the single most demanding technical aspect during creation of a continent urinary diversion is construction of the continence mechanism. It is the success or failure of this mechanism that ultimately determines the success or failure of the urinary diversion. Four surgical techniques have been incorporated to create a reliable, catheterizable continence mechanism: (1) appendiceal; (2) pseudoappendiceal tubes fashioned from ileum or right colon; (3) intussuscepted nipple valve or flap valve,
which avoids the need for intussusception; (4) the hydraulic valve (e.g., Benchekroun nipple).31 Two techniques of appendiceal continence mechanisms have been reported. Mitrofanoff43 reported excising the appendix with a button of cecum and reversing it on itself before tunneled reimplantation.44 Alternatively, Riedmiller et al.45 have left the appendix attached to the cecum and buried it into the adjacent taenia by rolling it back onto itself. A wide tunnel is created in the taenia extending 5 to 6 cm from the base of the appendix (Figure 23-9A,B) and windows are created in the mesoappendix between blood vessels. The appendix is folded cephalad into the tunnel, and seromuscular sutures are placed through the mesoappendix windows to complete the tunneling. The tip of the appendix is amputated and brought to the selected stomal site. For right colon pouches, an appendiceal tunneling technique is the simplest to perform. The in situ or transposed appendix is tunneled into the cecal taenia, similar to that of the previously described ureterocolonic anastomosis. Appendiceal continence mechanisms have been criticized for three reasons. First, the appendix may be unavailable in some patients because of prior appendectomy. Second, the appendiceal stump may be too short to reach the anterior abdominal wall or umbilicus, while still maintaining sufficient length for tunneling. Third, the
410
Part IV Bladder
large amount of mucus produced by an intestinal reservoir is more easily emptied or irrigated with a larger catheter (20 Fr to 22 Fr) rather than the typical smaller diameter catheter (14 Fr or 16 Fr) that is accommodated through an appendiceal stump. Several of these criticisms have been addressed by modifying surgical technique. In individuals who had a prior appendectomy, a pseudoappendiceal tube can be fashioned from ileum32 or from the wall of the right colon.33 In cases where the appendiceal stump is too short to reach the anterior abdominal wall or umbilicus, Burns and Mitchell34 lengthen the appendiceal stump by including a tubular portion of the proximal cecum. This has the added advantage of allowing a slightly larger stoma made of cecum that is less prone to stomal stenosis. Overall, the appendiceal or pseudoappendiceal continence mechanism remains a very attractive and reliable continence mechanism. The second major type of continence mechanism used in right colon pouches is the tapered and/or imbricated terminal ileum and ileocecal valve. The technique is rather simple, with imbrication or plication of the ileocecal valve region along with tapering of the more proximal ileum in the fashion of a neourethra35–37 and afford a reliable continence mechanism. The creation of intussuscepted nipple valves is the most technically demanding of continence mechanisms and also is associated with the highest rates of complication and reoperation. The procedure has a significant learning curve and, therefore, should probably not be chosen by the surgeon who infrequently constructs continent pouches. A major advance in nipple valve construction includes removal of mesenteric attachments from the middle 6 to 8 cm of bowel,38 thereby reducing the tethering effect of
the mesentery that otherwise induces eversion and effacement of the intussusception. A second major modification has been the attachment of the nipple valve to the reservoir wall itself. This has been achieved by 2 or 3 different stapling techniques, as well as by a suturing technique described by Hendren38 and King.39,40 Despite meticulous surgical technique and the most experienced surgeons, nipple valve failure can be anticipated in 10% to 15% of cases. In addition to being subject to slippage, nipple valves may develop ischemic atrophy; if this occurs, a new nipple valve must be fashioned from a new bowel segment. Several institutions have introduced numerous modifications of the original Kock technique for constructing a nipple valve given the disappointing long-term stability. The group at the University of Southern California has developed the T pouch using a flap valve.41 The procedure is much simpler, avoiding the need for intussusception, and is used to create both a continence mechanism and an antireflux mechanism. Benchekroun42 describes a hydraulic valve nipple. In this procedure, a small bowel segment is isolated and a reversed intussusception is carried out, apposing the mucosal surfaces of the small bowel. Tacking sutures are taken to a portion of the circumference of the intussusception to stabilize the nipple valve, while allowing urine to flow freely between the leaves of apposed ileal mucosa. The Benchekroun hydraulic ileal valve may be the one diversion in which reservoir detubularization actually impairs the continence rate because the valve mechanism depends on pouch pressure for continence. Without elevated pouch pressure, there is no forceful apposition of the serosal leaves of the valve. Although there are reports in the literature of reasonable success, concerns regard-
Figure 23-9 A and B, The appendix is left attached to the cecum and buried into the adjacent cecal taenia by rolling it back onto itself. A wide tunnel is created that extends 5 to 6 cm from the base of the appendix. Windows are created in the mesoappendix between blood vessels. The appendix is folded cephalad into the tunnel, and seromuscular sutures are placed through the mesoappendix.
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 411
ing the long-term durability of this mechanism have resulted in lack of widespread use. INTRAOPERATIVE POUCH TESTING Following pouch construction and completion of the continence mechanism, it is essential that both the pouch and continence mechanism be examined in detail in the operating room. Typically, the pouch is filled with saline or water, the catheter is removed, and the pouch is compressed lightly as the surgeon examines the pouch for any points of leakage, as well as observing the ability of the pouch to contain urine. Next, the pouch is recatheterized to ensure smooth passage of catheter passage. This is a critical maneuver because the inability to catheterize is a serious complication that often results in the need for reoperation. In general, all redundancy should be removed from the continence mechanism. It is often useful to secure the reservoir to the anterior abdominal wall in a manner that allows the reservoir to surround the aditus, preventing the development of a false passage or a kink and thereby facilitating catheterization. CONTINENT RESERVOIRS Continent Ileocecal Reservoirs Kock Pouch In 1982, Kock et al.46 reported the first 12 cases on their continent ileocecal reservoir, stimulating worldwide interest in continent urinary diversion procedures. However, the initial enthusiasm with this technique is tempered by a complication rate requiring additional surgery in half of patients, primarily for malfunction of the efferent valve. Since then, the Kock pouch has undergone several modifications. Skinner et al.47,48 have carefully studied and improved the technique over the years. Although some individuals still perform the original procedure, technical difficulties and significant complication rates have led to the procedure being abandoned by most urologic surgeons. This operation and the similarly constructed T pouch are the only catheterizable continent diversions that preserve the ileocecal valve. Technique. An 80-cm small bowel segment is isolated approximately 15 to 50 cm proximal to the ileocecal valve. A stapling device is used to isolate the segment of small bowel and the continuity of the small bowel is reestablished with closure of the mesenteric window to prevent incarceration of the bowel. Division of the mesentery should extend to the base of the mesentery to ensure sufficient mobility of the efferent limb of the pouch. Next, the proximal and distal 15 to 20 cm of the isolated segment are preserved for creation of the afferent and efferent nipple valves, and the
remaining 40 to 50 cm of the bowel segment are brought together as a U-shaped plate, with the apex directed to the proposed stoma site. The U-shaped plate is opened using electrocautery and an absorbable suture is used to close the posterior wall of the opened intestinal plate (Figure 23-10A–E). The proximal and distal valves are then created by intussuscepting approximately 10 cm of ileum at each end; the proximal 10 cm serves as the valve and the distal 5 to 10 cm the patch (Figure 23-10A). The middle 6 to 8 cm of the 10-cm proximal intussuscepted segment is denuded of mesentery by electrocoagulation on each side flush with the serosa of the ileum. Allis or Babcock clamps are passed through the open limbs, and intussuscepted nipple valves are created by pulling back the intraluminal bowel wall into the opening of the reservoir to be created (Figure 10B). In order to maintain the intussusception, 3 to 4 parallel rows of staples (TA-55, 4.8-mm staples) are placed along the entire length of the nipple valves (Figure 23-10C). To minimize the risk of stone formation, the distal 6 staples from each cartridge are removed before staple application to ensure that the tip of the valve is free of the staples. The nipple valve is then fixed by 1 or 2 stapling techniques to the back wall of the patch.39 A small buttonhole may be made in the back wall of the ileal plate so that the anvil of the stapler can be passed through the buttonhole and advanced into the nipple valve before application of the fourth row of staples (Figure 23-10D). If this is done, the buttonhole is oversewn with absorbable material. Alternatively, the anvil of the stapler can be directed between the two leaves of the intussuscipiens and the fourth row of staples used to fix the inner leaf of the nipple valve to the pouch wall (Figure 23-10E). Skinner advocates the use of an absorbable polyglycotic acid (PGA) mesh collar to anchor the base of the nipple valve to prevent late slippage or extussusception. A 2.5-cm wide strip of absorbable mesh is fashioned into a collar and passed through a separate window in the mesentery and sewn with seromuscular stitches to the bowel wall to secure the intussuscepted nipple from the outside (Figure 23-10F,G). The mesh of the efferent nipple can also be fixed to the abdominal wall to facilitate catheterization. The ureters are spatulated and endto-side, mucosa-to-mucosa anastomoses are performed to the free portion of the afferent nipple; each ureteral anastomosis is stented. The reservoir is then folded and closed with a single or double layer continuous absorbable suture. The abdominal stoma is created by suturing the efferent nipple valve to the rectus fascia at the predetermined site and a flush stoma is created. A Foley catheter is passed through the efferent limb and left inside the reservoir. Posteriorly the pouch is
412
Part IV Bladder
B
Figure 23-10 A, A 15-cm segment of terminal ileum is isolated and opened along its antimesenteric wall. The proximal 10 cm will serve as the continent intussusception and the distal 5 to 10 cm as the patch. The size of the patch varies according to the size of the excised segment. B, An Allis clamp or Babcock clamp is advanced into the ileal terminus, the full thickness of the intussuscipiens is grasped and it is prolapsed into the pouch. C, Three rows of 4.8-mm staples are applied to the intussuscepted nipple valve using the TA55 stapler. D, A small buttonhole is made in the back wall of the ileal plate to allow the anvil of the staples to be passed through and advanced into the nipple valve. E, The anvil of the stapler can be directed between the two leaves of the intussuscipiens and the fourth row of staples applied in this manner. This figure shows two valve mechanisms. In this instance, there would be only one.
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 413
Figure 23-10 cont’d F, A 2.5-cm-wide strip of absorbable mesh is placed through additional windows of Deaver at the base of each nipple valve the mesh strips are fashioned into collars. G, The collars are sewn to the base of the pouch, as well as to the ileal terminus with seromuscular sutures.
attached to the sacral promontory with interrupted sutures. T Pouch The group at the University of Southern California has devised a novel continence mechanism created entirely from ileum, based on a technique described by AbolEnein and Ghoneim49,50 and Bochner et al.51 AbolEnein and Ghoneim created an extramural serosal tunnel into which the ureters were implanted, with the extramural trough creating a pseudotunnel that prevented reflux with, theoretically, a lower risk of obstruction than either of the techniques of direct transmural ureteral implantation described by Goodwin, Leadbetter, or LeDuc et al.52 Stein et al.41 first reported on the use of a tapered ileal segment implanted into a serosal trough as the antireflux mechanism for neobladder.53 Stein et al.54 presented the early experience with a double T pouch as a replacement for the Kock pouch, detailing the technique in 9 patients (2 men and 7 women) followed a mean time of 12 months. Technique. A 70-cm segment of terminal ileum is isolated 15 to 20 cm from the ileocecal valve. The proximal isoperistaltic 10- to 12-cm segment is isolated and serves as the antireflux mechanism, while the distal 12- to 15-cm segment is isolated and rotated in an antiperistaltic fashion and becomes the cutaneous continence mechanism (Figure 23-11A,B). A short (2 to 3 cm) mesenteric incision is made to isolate the proximal limb (afferent antireflux limb), and a 4-cm incision is made for the distal limb (efferent continence limb), thereby preserving the major vascular arches. The proximal and distal
segments can be of various lengths, depending on ureteral length and the thickness of the anterior abdominal wall. The middle 44 cm of ileum is folded into a W, with each limb measuring 11 cm (Figure 23-11B). The afferent antireflux mechanism is created by opening the windows of Deaver between the mesenteric vascular arcades along the distal 3 to 4 cm. The efferent continence mechanism is created by opening the proximal 7 to 8 cm of vascular arcades (antiperistaltic) (Figure 23-11C). Quarter-inch Penrose drains are then placed in each window of Deaver to facilitate the passage of the 3-0 silk horizontal mattress sutures that are used to approximate the serosa of the corresponding 11-cm limbs of the W (Figure 23-11D). The 3- to 4-cm anchored portion of the proximal limb is then tapered over a 30Fr catheter and the 7- to 8-cm anchored portion of the efferent limb is tapered over a 16Fr catheter. In both portions, tapering is performed with a GIA stapler. In the efferent limb, care must be taken to create a gradual taper so that the catheter does not hit a false cul-de-sac (Figure 23-11E). The portions of the 11-cm W-limbs not forming the troughs are sutured together with a running suture of 3-0 PGA. The bowel is now incised along its antimesenteric border in the portion where the serosal trough exists and in close proximity to the medial PGA suture lines when beyond the two limbs (Figure 23-11F). The incised mucosa is then closed in 2 layers with a running suture of 3-0 PGA. The incised intestinal flaps (antimesenteric incision) are then sutured to each ostium with interrupted sutures of 3-0 PGA and the 2 ileal flaps sutured over each segment with a running suture of 3-0 PGA (Figure 23-11G). The reservoir is closed side-to-side in 2 layers with 3-0 PGA, completing its construction
414
Part IV Bladder
Figure 23-11 A, 70-cm segment of terminal ileum is isolated 15 to 20 cm from the ileocecal valve. B, Proximal 10-cm segment is isolated and rotated toward the reservoir in an antiperistaltic direction. C, The windows of Deaver are opened to allow the walls of the W reservoir to be apposed behind the valve mechanisms. Penrose drains are passed to guide suture passage.
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 415
Figure 23-11 Cont’d D, Some 3-0 silk horizontal mattress sutures are passed through each window. The distal continence mechanism is longer than the proximal antireflux mechanism. E, The proximal and distal mechanisms are tapered with a metal GIA stapler. F, The bowel is incised along its antimesenteric border where it will overlie the two Ts. Distal to the Ts, the bowel is incised closed to the approximated limbs of the reservoir. G, The ostia of the valves are secured to the bowel wall with interrupted absorbable sutures. The two flaps of ileum are closed over the Ts with running absorbable sutures.
416
Part IV Bladder
Figure 23-11 Cont’d H, The back wall of the reservoir is closed with running absorbable sutures. I, The lateral walls are folded medially and the construction completed with running absorbable sutures
(Figure 23-11H,I). The ureters are anastomosed endto-side over stents to the proximal limb, which has been closed with a running absorbable Parker-Kerr suture. The efferent limb is brought to the abdominal wall stoma site, the redundant ileum resected, and the stoma is matured. The reservoir lies immediately adjacent to the anterior abdominal wall. This procedure appears to have many advantages over the Kock pouch, but long term complications and durability of this technique cannot be assessed at this time because of small patient numbers and short follow-up. Mainz Pouch In 1986, Thüroff et al.55 presented initial results with a cecoileal reservoir (Mainz I pouch). A sutured ileoileal intussusception valve served as the continence mechanism in the first series of patients. Subsequently, the Mainz pouch has undergone considerable modification over the years primarily due to problems with the intussuscepted nipple valve.56–58 The operation has now been modified by replacing sutures with staples to prevent deintussusception and using the intact ileoce-
cal valve as a means of further stabilizing the intussusception.59 The technique described herein includes these modifications rather than the earlier versions of the operation. Technique. A 10- to 15-cm segment of cecum and ascending colon is isolated, along with two equal-sized loops of terminal ileum and an additional portion of ileum measuring 20 cm for the creation of the reservoir and the continence mechanism, respectively (Figure 23-12A). The entire colonic segment and distal segment of ileum are split open along the antimesenteric border, with care taken to preserve the ileocecal valve. These three bowel segments are folded in the form of an incomplete W, and the posterior aspects sutured together to form a broad posterior plate (Figure 23-12B). The ileal mesentery of the intact (nondetubularized) proximal ileum is freed of its mesentery for a distance of 6 to 8 cm and intussusception of the segment is achieved. The ileum is intussuscepted and stabilized with 2 rows of staples (TA 55 staples) (Figure 23-12C). Next, the intussuscepted ileum is pulled through the natural tunnel of the intact ileocecal valve and fixed to the ileocecal valve with two more rows of staples. The
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 417
third row of staples is applied to stabilize the nipple valve to the ileocecal valve (Figure 23-12D) and the fourth row of staples is applied inferiorly, securing the inner leaf of the intussusception to the ileal wall (Figure 23-12E). Both ureters are implanted by means of a 5-cm long submucosal tunnel at the uppermost part of the cecal portion of the reservoir. Next, the reservoir is folded on itself in a side-to-side fashion and closed with a single layer of continuous sutures to complete the pouch construction. A suprapubic tube is placed through a separate stab incision in the pouch and abdominal wall to ensure adequate drainage. The entire pouch is rotated cephalad and the intussuscepted ileum is brought to the umbilicus. A small button of skin is removed from the depth of the umbilicus and the ileal terminus is directed through this buttonhole (Figure 23-12F). The reservoir is secured to the posterior fascia with interrupted absorbable sutures, and the intussuscepted ileal limb is sewn similarly to the anterior fascia. Extra ileal length is resected, and the ileum is sutured to the umbilicus with interrupted absorbable sutures. Although the cutaneous stoma can be placed in several different locations, the preferred stoma site by the Mainz group is the umbilicus. The introduction of the more reliable appendiceal continence mechanism has greatly increased the acceptance of the Mainz I procedure. Starting in 1988, the in situ appendix was used for creation of the continence mechanism.60 The advantages of this modification are reducing of the operative time by 30 to 40 minutes, a shorter ileal segment, eliminating nipple sliding or prolapse, and reduced risk of stone formation with the absence of staples. The Mainz group has also developed 2 new techniques for construction of a Mitrofanoff (appendiceal) type of tube for use in patients whose appendix is either unsuitable or absent.33,61,62 Continent Right Colon Reservoirs with Intussuscepted Terminal Ileum Similar to the Mainz pouch, these right colon pouches use the nipple valve concept for continence by using the ileocecal valve. Unlike the Mainz pouch, the right colon is used solely for the construction of the pouch portion of the diversion. Several right colon pouches using the valve technology have been described—Indiana pouch, UCLA pouch, Duke pouch, LeBag pouch, Florida pouch, and the Penn pouch.63–65 These operations differ from one another by only minor features, predominantly related to the technique employed for stabilizing the nipple valve and the amount of large intestine harvested (Table 23-1). In this section, we discuss in detail only the Indiana and Penn pouches. In all instances, appendectomy is performed because the in situ appendix would serve as a nidus for infection and abscess formation. Table 23-2 lists
the urodynamic and continence rates for the continent cutaneous reservoirs from various published series. Indiana Pouch One of the first continent cutaneous pouches to gain wide acceptance in the urologic community was the Indiana pouch developed in 1985 by Rowland et al.88 The major contribution was the creation of a reliable continence mechanism. Originally, the entire ileal segment was buttressed with imbricating sutures to establish the continence mechanism. Pressure profile studies demonstrated that the continence zone was confined to the region of the ileocecal valve; therefore, imbricating sutures were only necessary in the region of the ileocecal valve.37 Technique. In the present form of an Indiana pouch, 20 to 25 cm of cecum and ascending colon are isolated along with 10 to 15 cm of terminal ileum (Figure 2313A). After bowel continuity is reestablished, appendectomy is performed and the appendiceal fat pad obscuring the inferior margin of the ileocecal junction is removed (Figure 23-13B). The entire right colon is detubularized along its antimesenteric border about three-fourths of its length starting from the distal end, and the cecum is partially spatulated. The ureters are anastomosed through a submucosal tunnel along the posterior colonic tenia. The continence mechanism consists of plicated terminal ileum, which reinforces the ileocecal valve. The ileal plication, consisting of 2 rows of Lembert sutures 8 to 10 mm apart, begins at the ileocecal valve and extends 3 to 4 cm proximally (Figure 23-13C); the continence mechanism is tested and when no leakage is present, a second layer of continuous silk sutures over a catheter (12Fr or 14Fr) is used to reinforce the suture line. Alternatively, the University of Miami group uses purse-string sutures in the same region of the ileum.37 In the Florida pouch, apposing Lembert sutures are applied on each side of the terminal ileum (Figure 23-13D). Any excess ileum is tapered over a catheter and removed using a GIA stapler. It is important to imbricate while the cecal reservoir is still open, allowing one to observe the gradual closure of the ileocecal valve. The pouch is formed by folding down the opened cecum in a Heineke-Mikulicz configuration and closing with continuous 2-0 PGA suture. Ureteral stents are placed and a suprapubic tube is brought through the lower abdominal wall. A 1-cm buttonhole is made in the skin, anterior and posterior fascia. The catheterizable ileal limb is advanced between the rectus muscles. Excess ileum is removed and a flush skin stoma is created. At Indiana, as well as other institutions, it was recognized that by only marsupializing a portion of the ascending colon, the cecal region maintained sufficient
418
Part IV Bladder
Figure 23-12 A, A 10- to 15-cm portion of cecum and ascending colon is isolated along with two separate equal-sized limbs of distal ileum and an additional portion of ileum measuring 20 cm. B, A portion of the intact proximal ileal terminus is freed of its mesentery for a distance of 6 to 8 cm.
peristaltic integrity to generate pressures high enough to overcome the continence mechanism. Variations on the Indiana pouch, including the Florida pouch,36 harvest the entire right colon and one-third to one-half of the transverse colon to create the reservoir. The University of Miami pouch37 retained the original Indiana pouch design but marsupialized the entire ascending colon and cecum and refashioned the pouch in a Heineke-Mikulicz configuration. Additional modifications to the Indiana reservoir allow more rapid construction with a lower complication
rate,89 such as the use of absorbable staples to fashion the reservoir. First introduced by Bejany and Politano,37 a GIA stapler with metal staples can facilitate fashioning of the efferent limb. Penn Pouch This ileocecal pouch, described by Duckett and Snyder44 in 1986, was the first continent diversion employing the Mitrofanoff principle, wherein the appendix served as the continence mechanism.
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 419
Figure 23-12 cont’d C, The intact ileum is intussuscepted and two rows of staples are taken on the intussuscipiens itself. D, The intussuscipiens is led through the intact ileocecal valve and a third row of staples is taken to stabilize the nipple valve to the ileocecal valve. E, A fourth row of staples is taken inferiorly, securing the inner leaf of the intussusception to the ileal wall.
420
Part IV Bladder
Figure 23-12 cont’d F, A button of skin is removed from the depth of the umbilical funnel and the ileal terminus is directed through this buttonhole. Excess ileal length is resected and ileum is sutured at the depth of the umbilical funnel.
Table 23-1 Comparison of Techniques of the Various Forms of Continent Right Colon Pouches with Intussuscepted Terminal Ileum Pouch
Year
Reservoir
Continence Mechanism
Ureteral Anastomosis
UCLA Pouch*
199463
Entire right colon + 15 cm distal ileum
Terminal ileum is tapered over a 14Fr Foley using a GIA stapler Ileal limb (nipple) is fixed against the wall of the continent reservoir with continuous sutures
LeDuc (tunneling technique)
Duke Pouch*
198764
Entire right colon + 15 cm distal ileum
Ileum is intussuscepted through the Tunneling technique ileocecal valve Ileal limb (nipple) is stabilized with sutures or staples A patch of mucosa is excised from the posterior cecal plate One entire thickness of the intussuscipiens is incised to reveal the inner leaf of the intussuscipiens (serosa)
Florida Pouch†
198736
Entire right colon + transverse colon (right 1/3 or 1/2) + 10 to 12 cm distal ileum
Similar to Indiana Pouch (exception: opposing Lembert sutures on each side of the terminal ileum to buttress the ileocecal valve
End-to-side (colonic segment) nonrefluxing
LeBag*
198665
20 cm right colon + 20 cm distal ileum
Standard nipple valve from intussuscepted ileum Staples are used to stabilize the nipple valve No mesh collar for nipple valve stabilization
Goodwin technique (similar to ureterosigmoidostomy)
*The long-term outcome of this pouch is unknown. †Ureteral obstruction occurred in 4.9% of patients with nontunneled ureterocolonic anastomosis; hyperchloremia in 70% of patients (only 4 patients required treatment for this electrolyte imbalance).
No. Patients 12 9 100 440
193 19 NR 29 29 91 14 70 21 81 50
References
Kock et al.66
Stein et al.67
Thuroff et al.68
Lampel et al.69
Gerharz et al.70
deKernion et al.71 Raz63
Rowland et al.72 Rowland et al.73 Scheidler et al.74 Carroll et al.75
Ahlering et al.76 Carroll et al.77 Rowland et al.78†
Bihrle et al.79‡
Pouch
Kock pouch
T pouch
Mainz pouch
UCLA pouch*
Indiana pouch
500 (mean) 733 (maximum)
291–508 291–508 NR 400–1500 675 (mean) 400–800 NR NR
560 (mean) 600–700
NR
NR
510–620
400–700
500
Volume (ml)
NR NR 93% 85.7%
≤20 intraluminal ≤20 intraluminal NR 24 (mean) reservoir 40 (mean) plicated ileal segment 15–25 resting pressure 41 (mean) plicated ileum NR 63 (mean) stapled ileum NR
NR
98.6% 85.7 NR
71% 88.2%
94%
NR NR 98%
93 93 NR NR
NR NR
NR
NR
NR
Daytime
CONTINENCE
90% stapled ileocecal intussusception 100%
NR
100%
NR
Overall
NR NR
NR
23–33 at half capacity 31–41 at full capacity NR
NR
NR
Pressure (cm H2O)
RESERVOIR
94%
NR NR 98%
76 76 NR NR
69% NR
NR
NR
NR
Continued
Nighttime
Table 23-2 Comparison of Continent Cutaneous Reservoirs: Reservoir Volume, Urodynamic Maximum Fill Pressures, and Continence Rates
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 421
11§ 107 7 10
75 NR
References
Lockhardt et al.80
Lockhardt et al.81
Webster et al.82
Bejany et al.83
Benson et al.84
Sumfest et al.85
Adams et al.86 Carr et al.87
Pouch
Florida pouch
Duke pouch*
U. Miami pouch
Penn pouch
Gastric pouch# 245 309
NR
≥750
750–800
500–700
400–1200 650 (mean) 550–1200 747 (mean)
Volume (ml)
35 end filling pressure 12.9
NR
20 at capacity (pouch) 20–30 tapered ileum (empty) 50–60 tapered ileum (at capacity) 20 at capacity
50 (near capacity)
10–58 at capacity 35 (mean)
28–55 at capacity
Pressure (cm H2O)
RESERVOIR
NR 100
96%
98.6%
100%
42.8%¶
97.5%
88%
Overall
NR NR
NR
NR
NR
NR
NR
NR
Daytime
CONTINENCE
NR NR
NR
NR
NR
NR
NR
NR
Nighttime
*The long-term outcome of these pouches is unknown. †The last 81 patients operated on by Rowland and associates underwent construction of a stapled efferent limb; In the last 20 patients, the reservoir was created with absorbable staples. ‡Mean follow-up in this study was 2.5 years. §8/11 patients had a continent colonic reservoir performed. ¶One patient suffered incontinence due to evagination of the intussusception; three patients had intermittent incontinence secondary to cecal segment hyperactivity. This was controlled with oxybutynin hydrochloride 5 to 10 mg TID. #Of the 12 patients, seven had urinary reservoirs totally constructed from stomach, and five had composite reservoirs. NR, not reported.
3 12
No. Patients
Table 23-2 Comparison of Continent Cutaneous Reservoirs—cont’d
422 Part IV Bladder
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 423
Figure 23-13 A, Segment of terminal ileum approximately 10 cm in length along with the entire right colon is isolated. B, Appendectomy is performed and the appendiceal fat pad obscuring the inferior margin of the ileocecal junction is removed by cautery. C, Interrupted Lembert sutures are taken over a short distance (3 to 4 cm) in two rows for the double imbrication of the ileocecal valve as described at Indiana University. D, Application of opposing Lembert sutures on each side of the terminal ileum.
424
Part IV Bladder
Technique. A segment of cecum up to the junction of the ileocolic and middle colic arteries is isolated, in addition to a similar length of terminal ileum. The isolated bowel is marsupialized on the antimesenteric borders and sutured to one another. The superior margin of the pouch is sutured transversely using absorbable material. Mitrofanoff technique. A button of cecum surrounding the origin of the appendix is circumscribed and the resulting cecal aperture closed with running absorbable suture. The mesentery of the appendix is dissected carefully from the base of the cecum, preserving the blood supply. The appendix is then reversed on itself, so that the cecal button can reach the anterior abdominal wall and the tip of the appendix can be directed to the taenia of the colon (Figure 23-14). The appendiceal tip is transected obliquely and spatulated prior to a tunneled appendiceal-taenial implantation. If additional appendiceal length is required, the variation proposed by Burns and Mitchell34 may be employed (cecal tube). An alternative technique can be applied when fashioning the continent catheterizable stoma. Riedmiller et al.45 leave the appendix attached to the cecum and bury it into the adjacent taenia by rolling it back onto itself. A wide tunnel is created in the taenia extending 5 to 6 cm from the base of the appendix. Windows are created in the
Figure 23-14 A segment of cecum up to the junction of the ileocolic and middle colic blood supplies along with a similar length of terminal ileum is isolated and marsupialized on the antimesenteric borders. A button of cecum surrounding the origin of the appendix is circumcised. The mesentery of the appendix is dissected carefully from the base of the cecum, preserving its blood supply.
mesoappendix between blood vessels. The appendix is folded cephalad into the tunnel and seromuscular sutures are placed through the mesoappendix windows to complete the tunneling. The tip of the appendix is amputated and brought to the selected stomal site. Gastric Pouches The stomach has many unique properties91 and can be used in selected circumstances. Advantages to using stomach as a urinary reservoir include diminished electrolyte reabsorption, inherent barrier to absorption of ammonium, absence of hyperchloremic acidosis, and reduced bacterial colonization in the acidic environment. Situations favoring consideration of the gastric urinary diversion include extensive irradiation of the lower bowel, preexisting metabolic acidosis or renal insufficiency, and patients in whom shortening the small bowel could result in malabsorption. Experience with gastric pouches and composite reservoirs has been reported in both the pediatric90 and adult populations.91,92 Technique. A 7- to 10-cm wedge-shaped segment is isolated from the greater curvature of the stomach, typically using a 70- to 90-mm GIA stapler. The incision is not extended to the lesser curvature because of the risk of vagal injury and resulting problems with gastric emptying. Before the gastric wedge is taken, the decision has to be made as to which gastroepiploic artery will serve as a pedicle for the gastric flap. The segment is preferentially mobilized on the left gastroepiploic vascular stalk by dividing the short gastric vessels proximal to the segment up to the gastric fundus (Figure 23-15A,B). If the left artery cannot be used, then the right gastroepiploic vessel is used and the small gastric vessels are ligated to the level of the pylorus. The stomach is then closed based on surgeon’s preference. A gastroduodenostomy or gastrojejunostomy tube is not mandatory unless the antrum of the stomach has been used. The gastric wedge is brought through the transverse mesocolon and the root of the small bowel to lie in a retroperitoneal position. The isolated wedge is refashioned into nearly a sphere by folding it back on itself and suturing the edges together with running absorbable material. Before closing the pouch, the ureters are reimplanted using the submucosal tunneling technique (Goodwin). A continent catheterizable reservoir can be constructed using appendix or the distal ureter tunneled submucosally into either the dome or posterior portion, respectively. If the distal ureter is used to create the continence mechanism, a proximal transureteroureterostomy can be performed. The free portion of the ureter can then be brought to the skin or to the introitus (female) or urethral stump (male) to serve as a catheterization portal. If neither option is available, a gastric tube and nipple can be created from a gastric flap.
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 425
Figure 23-15 A and B, A wedge-shaped segment of stomach whose greatest width is 7 to 10 cm is fashioned from the greater curvature. The left gastroepiploic artery is preferentially used as the blood supply for the isolated gastric wedge by dividing the short gastric vessels up to the gastric fundus. Alternatively, if there is a problem with the left artery, the right gastroepiploic vessel may be employed.
Alternatively, the wedge of stomach can be incorporated into a reservoir composed of detubularized ileum with or without tapering (Figure 23-16A–C). When stomach is used as a bladder augment or as a portion of a neobladder, the dysuria and hematuria syndrome has been reported, limiting use in sensate patients.93 The construction of reservoirs entirely from stomach has not seen widespread acceptance. Rather, use of stomach segments has been limited to bladder augmentation or as part of a composite reservoir.94,95 While the use of stomach has particular appeal in the pediatric population,95 its various unique intrinsic properties as a reservoir suggest that its use will continue in only selected clinical situations. URETEROINTESTINAL ANASTOMOSES Ureterointestinal anastomoses can be performed in either a refluxing (direct) or nonrefluxing fashion. Theoretically, a nonrefluxing anastomosis protects the upper urinary tract from infected urine and may decrease renal deterioration. This aspect, however, remains controversial. Reflux alone does not necessarily lead to upper urinary tract deterioration and is related to factors, such as infection, stones, and obstruction. Patients with nonrefluxing anastomoses have not been shown to have lower rates of bacterial colonization.96 There is no long-term evidence that patients without reflux have a lower rate of renal dysfunction. In addition, nonrefluxing techniques of ureteral anastomosis are associated with higher stricture rates. Both types of ureteral anastomoses can be performed into either the small or large bowel. In general, nonre-
fluxing anastomoses are easier to perform on the colon because of the presence of teniae coli. Numerous techniques of ureterointestinal anastomoses have been described and we present several common methods.52,97,98 Ureteral-Small Bowel Anastomoses Direct Anastomosis Bricker,14 in his description of ureteroileocutaneous diversion, used a freely refluxing, direct end-to-side ureteral anastomosis. It remains the simplest method of connecting the ureter to the ileum. After spatulation of the ureters, a small ellipse of bowel serosa and mucosa is excised from the site of implantation. The spatulated ureter is anastomosed directly to the bowel, with care taken to incorporate both the muscular and mucosal elements of the intestine (Figure 23-17A,B). Only small portions of the mucosa should be included to ensure that the mucosa everts and results in precise mucosa-tomucosa apposition. In contrast, if too much mucosa is included in the anastomosis, this can narrow the lumen of the ureterointestinal anastomosis. The anastomosis can be performed in 1 or 2 layers using interrupted absorbable sutures. Prior to completing the anastomosis, the ureter may be stented, especially if the patient is at risk for impaired wound healing. Wallace Technique In this method, the ureters are joined together prior to performing the ureterointestinal anastomosis99; the creation of a single, larger urinary segment may decrease the
426
Part IV Bladder
Figure 23-16 A, An 11-cm long segment of stomach is isolated on the right gastroepiploic blood supply with the use of a GIA-90 stapler. Usually, two staplers are required. B, A 22cm segment of ileum is then isolated, opened along its antimesenteric border and refashioned in a U shape.
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 427
Figure 23-16 cont’d C, The edges of the stomach are then sutured to edges of the ileum with a running absorbable suture of 2-0 PGA.
Figure 23-17 A and B, After removing a small ellipse of bowel, the ureter is spatulated and anastomosed directly to the bowel wall using interrupted absorbable sutures.
428
Part IV Bladder
risk of subsequent ureteroenteric stenosis. Each ureter is spatulated for a distance approximately equal to the diameter of the conduit. The ureters are joined together using a running absorbable suture and then anastomosed to the open proximal end of the bowel in a refluxing manner (Figure 23-18A,B). The anastomosis can be performed in 1 or 2 layers with absorbable sutures. The ureters may be stented. Tunneled Ureterointestinal Anastomosis In this method, the ureter is brought through a submucosal tunnel, creating a nonrefluxing anastomosis to the bowel.100 A short tunnel is made between the mucosal and seromuscular layers at each anastomotic site; saline can be injected submucosally using a small needle to aid with the dissection.101 Small plugs of mucosa are removed from the ends of each tunnel where the ureter enters the bowel lumen. After advancing each ureter through its tunnel, the ureter is anastomosed to the mucosa of the bowel.
lumen, a small ellipse of mucosa is excised. The ureter is anastomosed to the bowel mucosa (Figure 23-19B) and then the muscular layer of the tenia coli is reapproximated to create a tunnel over the ureter (Figure 23-19C). COMPLICATIONS General Complications Numerous complications may occur after all types of urinary diversion. Problems, both early and delayed, can results from surgical technique, the incorporation of intestine into the urinary tract, and the patient’s underlying disease processes. Early postoperative complications, such as hemorrhage, wound infection, dehiscence, urinary leakage, and bowel obstruction, are uncommon. Delayed complications, including problems with the stoma, metabolic abnormalities, renal deterioration, infection, and calculi, are encountered more frequently. Stoma Complications
Ureterocolonic Anastomoses The ureters can be implanted into the large bowel in either a direct refluxing fashion, as previously described for small bowel, or a nonrefluxing manner. In the latter, a 3-cm incision is made in a tenia coli (Figure 23-19A). The incision is carried through the muscular layer, sparing the mucosa. At the site of entry into the colonic
If patients are followed long enough, stomal complications are common and lead to significant dissatisfaction. Training in proper stomal care, preferably by an enterostomal therapist, is important in reducing these issues. The location of the stoma is also vital in optimizing the stoma, and guidelines for selecting the site have been previously outlined.
Figure 23-18 A, The ureters are spatulated and joined together using a running suture. B, The ureters are anastomosed to the open proximal end of the conduit.
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 429
Figure 23-19 A, A 3-cm incision is made in a tenia coli and a small ellipse of bowel mucosa is removed. B and C, The ureter is anastomosed to the mucosa and the muscular layer of the tenia is reapproximated.
Stomal stenosis is a common late complication of cutaneous ureterostomy, occurring in up to 50% of patients.102 The incidence of stenosis is lower when dilated, well-vascularized, thick-walled ureters are used. If the ureter is only minimally dilated, a V-flap technique may be beneficial. The treatment of stomal stenosis after cutaneous ureterostomy is surgical, generally necessitating urinary intestinal diversion. Stomal stenosis is also seen with other types of intestinal urinary conduits. In ureteroileal urinary diversion, the incidence of stenosis is as high as 42% in children and 6.7% in adults.103,104 Similar rates have been reported for jejunal conduits.20 Because the colon has a larger lumen, one would expect a lower rate of stomal stenosis. However, long-term studies still demonstrate a significant rate of stenosis, up to 61% in children.105,106 Stomal stenosis can lead to conduit elongation and upper urinary tract obstruction. The diagnosis can be made by passing a catheter through the stoma and measuring the volume of residual urine. The treatment consists of surgical revision of the stoma. Parastomal hernias are another delayed complications associated with intestinal urinary conduits. Parastomal hernia occurs more frequently with colon conduits (10% to 15%) compared with the use of small bowel. The risk of parastomal hernias is reduced by bringing the bowel through the rectus abdominus muscle and removing excess fat from the mesentery of the distal conduit near
the stoma. Large parastomal hernias should be repaired surgically. Problems with the skin around the stoma are common and can be categorized as infectious (i.e., fungal), irritative (e.g., urine), erosive (e.g., mechanical trauma), or pseudoverrucous.107 Treatment depends on the type and etiology of lesion present. In general, parastomal skin problems are greatly reduced with meticulous and gentle stoma care, the use of nonirritative adhesives, and a properly fitting appliance. The aperture in the appliance should be just slightly larger than the stoma itself to minimize erosion and prolonged contact between the skin and urine. Ureterointestinal Anastomotic Complications The use of soft Silastic stents reduces urinary extravasation, which may lead to periureteral scarring and ureterointestinal anastomotic strictures. In general, ureteral stents should be placed in those at risk for poor healing. Nonrefluxing anastomotic techniques have higher rates of stricture formation, although strictures can occur at or distant from the intestinal anastomosis. Many ureteral strictures can be successfully treated endoscopically with either dilation or incision; however, some will ultimately require open surgical repair. The incidence of ureteral obstruction and stomal stenosis for noncontinent urinary diversions is summarized in Table 23-3.
430
Part IV Bladder
Table 23-3 Complications of Noncontinent Intestinal Urinary Conduits References
No. Patients
Population
% Pyelonephritis
% Ureteral Obstruction
% Stones
% Stomal Stenosis
Ileal conduit Butcher et al.104
307
Adults
13.8
2.3
3.3
6.7
Johnson et al.108
181
Adults
5.5
15.5
3.3
3.9
Johnson and Lamy109
214
Adults
15.2
18.4
2.5
5.1
Sullivan et al.110
336
Adults
19.2
14.7
4.0
5.1
Middleton and Hendren103
90
Children
20
10
9
42
Shapiro et al.116
90
Children
16.7
22.3
8.9
38
242
Both
10.7
4.1
5.8
14
30
Both
—
3.3
—
6.6
Schmidt et al.112
22
Adults
—
4.5
—
0
Morales and Golimbu105
46
Both
17
Althausen et al.113
70
Both
Elder et al.106
41
Children
—
Both
13.6
Pitts and Muecke111 Jejunal conduit Golimbu and Morales20 Colon conduit
7.1
13 8.6 22
4.3 4.3 16
13 2.8 61.5
Ileocecal conduit Matsuura et al.114
147
Renal Complications Pyelonephritis, both early and late, can occur in all types of urinary diversion. The incidence of pyelonephritis with cutaneous ureterostomy has been reported to be 3%.8 A significantly greater incidence has been found in patients with ileal and colon conduits, as high as 20% in some series.110 Although many ureterocolonic anastomoses are performed using nonrefluxing techniques, even patients without reflux of urine develop bacterial colonization of the upper urinary tract.96 Pyelonephritis should be treated with specific antibiotic therapy based on cultures and susceptibility of the infecting organism. The sample of urine should be obtained by direct catheterization of the stoma rather than simply from the collection device. Renal deterioration has been associated with all forms of intestinal urinary diversion. This deterioration can be
9.5
5.4
2
attributed to pyelonephritis, reflux, or obstruction (e.g., stones, ureteral stricture). The risk of renal dysfunction increases with time, with obstruction representing a major cause.110 The reported incidence is variable, but ranges from 18% to 56% and from 8% to 48% for ileal and colon conduits, respectively.103,105,106,113, 115, 116 Urinary Calculi Any patient with an intestinal urinary diversion is at risk for urinary stone formation, with an incidence of 5% to 10% in adults and 4% to 16% in children. Many factors contribute to the formation of these stones.117 Staples used during conduit construction can serve as a nidus for stones. Bacteriuria exists in most patients with a urinary conduit, where the presence of urease-producing organisms
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 431
can lead to struvite stones. The concomitant metabolic acidosis in many individuals leads to hypocitraturia and hypercalciuria, further exacerbating the risk of nephrolithiasis.118 In patients with an ileal conduit urinary diversion, hyperoxaluria and calcium oxalate stones may also result from the use of the terminal ileum. The terminal ileum absorbs bile salts and plays a key role in fat metabolism. When the terminal ileum is excluded from the intestinal tract, faulty bile salt and fat absorption leads to saponification of both calcium and magnesium within the gut lumen. Decreased cation binding with free gut oxalate causes increased oxalate absorption and hyperoxaluria. The management of stones after urinary diversion can be difficult. Stones located in the upper tract can be treated using a combination of percutaneous and retrograde endoscopic techniques along with shock wave lithotripsy.119 Shock wave lithotripsy should be avoided when there is stricture distal to the stone.119 Close monitoring is crucial because the cause is often multifactorial and recurrence rates are high. Those patients with struvite stones may benefit from chronic suppressive antibiotics and/or a urease inhibitor. Metabolic Complications Metabolic abnormalities are common after the introduction of bowel into the urinary system (Table 23-4). These include electrolytes disturbances, altered drug kinetics, osteomalacia, and nutritional disturbances. The severity of metabolic problems is determined by length and specific segment of bowel used, renal function, concentration of urinary solutes, and degree of urinary stasis.16 Direct drainage of the urine via cutaneous ureterostomy and pyelostomy avoids these metabolic problems. Electrolyte Disturbances The use of jejunum as a urinary conduit may result in hyponatremic, hypochloremic, hyperkalemic metabolic acidosis in up to 40% of patients.19 Clinical symptoms include nausea, vomiting, anorexia, weakness, and lethargy. These electrolyte changes are the expected result of normal intestinal physiology. The jejunum is unable to maintain a large solute gradient; therefore,
electrolytes move between the extracellular fluid and urine within the conduit. The magnitude and direction of electrolyte shifts are dependent on the differential concentration of the electrolytes. Sodium and chloride are lost into the urine, while potassium and urea are reabsorbed. The loss of sodium leads to decreased extracellular fluid volume and reduced renal blood flow, causing activation of the renin–angiotensin system and subsequent stimulation of aldosterone production by angiotensin II. Aldosterone increases reabsorption of hydrogen and excretion of potassium into the distal renal tubule with resultant acidosis and intracellular potassium release, respectively. The reabsorption of urea and dehydration leads to azotemia. Treatment of the jejunal conduit syndrome consists of oral sodium chloride replacement. Metabolic acidosis can occur when either the ileum or colon is used as a urinary conduit. Both sodium and chloride are absorbed across the bowel surface, with chloride absorption greater than sodium. This results in a net loss of bicarbonate into the urine; renal insufficiency contributes to the severity of the acidosis. Excess potassium is excreted into the urine as a result of chronic acidosis. Since the ileum has greater capacity for absorbing urinary potassium compared to the colon, patients with an ileal conduit tend to have normal total body potassium, while those with a colon conduit have total body potassium depletion. The treatment for electrolyte abnormalities associated with ileal and colon diversions is alkalinization with oral bicarbonate or citrate. Altered Drug Metabolism Phenytoin toxicity has been reported in patients with intestinal urinary conduits.120 Any drug that is excreted by the kidneys unchanged and can be reabsorbed by the intestine has the potential for toxicity. Patients with continent urinary diversion and receiving methotrexate chemotherapy are at risk for toxicity; a catheter should be placed in the reservoir during methotrexate administration. Nutritional Disturbances Vitamin B12 is absorbed in the distal ileum. Deficiency of this vitamin, occasionally the result of using this bowel
Table 23-4 Metabolic Complications Associated with Use of Bowel for Urinary Diversion Segment
Complications
Treatment
Jejunum
Hypochloremic metabolic acidosis
Sodium chloride
Hyperkalemia
Volume replacement
Hyperchloremic metabolic acidosis
Alkalinizing agent (sodium or potassium citrate)
Hypokalemia (colon > ileum)
Block chloride transport (chlorpromazine, nicotinic acid)
Ileum + Colon
432
Part IV Bladder
segment, results in megaloblastic anemia and peripheral neuropathy. As mentioned earlier, loss of the terminal ileum impairs bile salt reabsorption and leads to decreased uptake of fat-soluble vitamins (A, D, E, K). The patient may have chronic diarrhea from the combination of fat malabsorption, excess bile salts, and loss of the ileocecal valve. Cholestyramine and agents that reduce bowel motility can be used when the diarrhea persists. Chronic acidosis leads to osteomalacia in adults and rickets in children.121 Bone remineralization can be accomplished with oral alkalinization therapy and supplementation with calcium and vitamin D. Continence Mechanism Complications One aspect of right colon pouches that has been criticized is loss of the ileocecal valve. Although some patients experience frequent bowel movement in the short term, the majority reports regular bowel function through intestinal adaptation or use of pharmacologic therapy. Nevertheless, some patients develop striking diarrhea and/or steatorrhea after loss of the ileocecal valve. This may be particularly true in the pediatric patient in whom there is underlying neurogenic bowel (e.g., myelomeningocele). A limitation of stapled nipple valves is the potential for stone formation on exposed staples. This has been significantly decreased by the omitting staples at the tip of the intussuscepted nipple valve as suggested by Skinner et al.39 However, more proximal staples occasionally erode into the pouch and serve as a nidus for stone formation. These stones are usually manageable with endoscopic intact extraction with forceps or after fragmentation using electrohydraulic, ultrasonic, or laser lithotripsy. Although exposed staples may serve as a nidus for stone formation, continent urinary diversion itself results in greater urinary excretion of calcium, magnesium, and phosphate compared with ileal conduit diversion.118 Thus, all patients undergoing continent diversion are at an increased risk for the formation of reservoir stones. “Pouchitis” is a condition that is manifested by pain in the region of the pouch and increased pouch contractility. Although occurring infrequently, pouchitis may result in temporary failure of the continence mechanism because of the hypercontractility of the bowel segment employed for construction of the pouch. The patient typically presents with a history of sudden explosive discharge of urine through the continence mechanism, rather than dribbling incontinence, along with discomfort in the region of the pouch. Appropriate antibiotic therapy usually results in the resolution of symptoms. We have found that a short course of antibiotics (i.e., 3 days) is not successful in treating pouch infections, perhaps due to the larger amount of foreign material within intes-
tinal pouches (mucus and sediment) when compared to the native bladder. Intestinal crypts may also serve as bacterial sanctuaries. Therefore, a minimum 10-day course of antibiotic administration is indicated for treating infection; of course, pyelonephritis may require longer courses of therapy. Urinary retention is an infrequent but serious occurrence in continent pouches. It is most commonly seen with continence mechanisms consisting of a nipple valve. If the chimney of the nipple valve is not near the abdominal surface, the catheter can be directed into folds of bowel rather than into the nipple valve proper such that poor drainage is achieved. Pouch urinary retention represents a true emergency, and the patient must seek immediate attention so that catheterization and drainage is promptly performed. The use of a coudé-tipped catheter is often helpful in this regard, and, rarely, a flexible cystoscope is needed. After the immediate problem has been addressed by emptying the pouch, a catheter is left indwelling for 2 to 3 days to allow the edema and trauma to the catheterization portal to resolve. Subsequently, the patient should be observed for the ability to successfully catheterize on a number of occasions. The appropriate angle of entry can be taught until the patient is comfortable with the use of the new catheter; our preference is to routinely use coudé catheters with nonnipple valve pouches. Intraperitoneal rupture of catheterizable pouches has been reported.122–125 In general, this occurs more commonly in the neurologic patient in whom sensation of pouch fullness may be less distinct. Oftentimes, associated mild abdominal trauma, such as a fall, is antecedent to the rupture. Patients with rupture require immediate pouch decompression and radiologic studies. For patients with large defects, surgical exploration and repair are required. If the amount of urinary extravasation is small and the patient does not have an acute abdomen, catheter drainage and antibiotic administration may suffice in treating intraperitoneal rupture. However, patients managed conservatively require careful monitoring. If there are any signs of progressive peritonitis, surgical exploration and repair are imperative. Complications by Specific Type of Urinary Diversion Overall complication rates, reoperation rates, and mortality rates are reported in Table 23-5 for each different continent cutaneous reservoir. Ureterosigmoidostomy The most serious immediate complication from ureterosigmoidostomy is anuria if the anastomosis is not
100 440
193
19 29 91 70 21 81 50 11 107 7 75 NR
Thuroff et al.68
Lampel et al.69
Gerharz et al.70
deKernion et al.71
Rowland et al.73 Scheidler et al.74 Ahlering et al.76 Carroll et al.77 Rowland et al.78† Bihrle et al.79‡
Lockhardt et al.80 Lockhardt et al.81
Webster et al.82
Benson et al.84
Sumfest et al.85
Mainz pouch
UCLA pouch
Indiana pouch
Florida pouch
Duke pouch¶
U. Miami pouch
Penn pouch
NR
NR
0
NR 0
0 1.1 1.4 0 0 0
0
0
NR
0
0
NR
25
NR
NR 12.4
20.6 NR 13 NR 12.3 20
NR
NR
12
7
0
10.6
21
NR
NR 10.3
NR NR 17.1 NR 28.4 14
NR
NR
37
18*
11.1
19.1%
NR
14.2%
NR 1.9%§
NR NR NR 4.7% NR 0%
NR
NR
NR
NR
NR 1.9%
NR NR NR 0% NR NR
NR
2.8%
1.9% Ileal nipple
18% appendix stoma
6.8% 3% ileal nipple patients 0%
NR
11.7% ileal nipple 14.7% appendiceal stoma
NR
NR
Complication rates are reservoir related complications. *11 patients had valve prolapse or incontinence; none of these problems were noted in later series after the nipple valve stabilization had been modified. †The last 81 patients operated on by Rowland and associates underwent construction of a stapled efferent limb; in the last 20 patients, the reservoir was created with absorbable staples. ‡Mean follow-up in this study was 2.5 years. §No specific comments regarding stomal stenosis. This percentage represents the number of cases reported as having catheterization difficulties. ¶The long-term outcome of these pouches is unknown. NR, not reported.
NR
NR
28.5%
NR 3.7%
17.2% 26% 4% to 10% 4.7% 17.3% 4%
NR
24% appendix stoma 12% ileal nipple
11% (nipple revision) NR
NR
11.1%
9
NR NR
Stein et al.67
58 29
T Pouch
16.7 16.2
NR 7.6%
0 1.9
12 489
Koch et al.66 Skinner et al.125
Kock Pouch 58% 10–15%
Pouch Stones
Pouch
Table 23-5 Comparison of Continent Cutaneous Reservoirs: Reoperation Rate, Mortality and Complication Rates COMPLICATIONS (%) No Reoperation Study Patients Rate Mortality (%) Early Late Stomal Stenosis
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 433
434
Part IV Bladder
stented. Anuria after removal of the ureteral stents indicates bilateral obstruction, likely secondary to tissue edema. In both cases, percutaneous nephrostomy tubes should be placed, especially in patients with fever or flank pain. Urinary leakage from the ureterocolonic anastomosis or from the colostomy incision can occur early in the postoperative period. The incidence of this complication can be minimized by watertight ureterocolonic anastomoses, use of ureteral stents, and continuous drainage of the rectal contents. Proper drainage of the rectal contents can be achieved by using two rectal tubes that have multiple perforations. Stents and tubes should be irrigated regularly (4 to 6 hours) to ensure patency. If the patient is stable, it is reasonable to wait because the leak may seal by itself. In patients in whom significant leaks persist, treatment options include immediate reoperation and reanastomosis, percutaneous nephrostomy tube placement, or cutaneous diversion. Renal deterioration can occur late secondary to obstruction, reflux, and ascending infections. When the rectal tube is removed, the patient must be closely monitored for the development of hyperchloremic acidosis. Because this is common, empiric bicarbonate replacement may be initiated immediately. Potassium citrate should also be considered at the outset because of the risk for hypokalemia. In patients who cannot maintain electrolyte homeostasis with oral medication, nighttime rectal urinary drainage is mandated. The incidence of colorectal cancer after ureterosigmoidostomy is 3.5% to 13.3%, representing an 80- to 550-fold greater risk when compared the general population.126–128 Due to the concern for developing malignancy, it is suggested that patients have routine monitoring for blood in the stool, cytologic examination of the urine-feces mixture, and annual colonoscopy. Barium enemas are contraindicated because of the potential for reflux of this material, which could lead to a septic event. Kock Pouch Skinner et al. have the most experience with this technique and reported early and late complication rates of 16.2% and 22%, respectively. The reoperation rate approaches 10% to 15% in their last series, mostly for correction of sliding of the continence nipple or erosion of the stabilizing efferent nipple collar into the lumen. Upper urinary tract deterioration, electrolyte imbalance, and stone formation are rare. Mainz Pouch In the mid-1990s, the 10- and 12-year experience with the Mainz pouch and the variations created by its developers was presented.56,57 The early complication rate was 12%; complications included mechanical ileus requiring open revision (1.6%), pouch leakage requiring revision (0.9%), wound dehiscence (0.7%), and fatal pulmonary
emboli (0.7%). The late complication rate was 37% and was predominantly attributable to the pouch. Stomal failure requiring open revision occurred in 45 patients (8%) and was directly related to the continence mechanism. Only 2 of 46 patients (1.4%) with an appendiceal continence mechanism were incontinent, but stomal stenosis occurred in 21%. The stapled ileocecal intussusception described previously is the current standard, with a reduction of long-term incontinence rates to 10%. Other late complications include ureteral reimplants in 4.9%, stomal stenosis in 11.7% of patients with an ileal nipple, and 14.7% of patients with an appendiceal stoma. Patients who developed calculi within the pouch (6.8%) were primarily treated with percutaneous procedures for stone removal. Despite the loss of the terminal ileum, it has been rare to see a significant drop in serum vitamin B12 levels, and very few patients have developed a macrocytic anemia or neurologic symptoms. Twentyfive percent of patients are taking oral alkalinization drugs to avoid metabolic acidosis. Additionally, since 1988 the incontinence rate has been only 3.2%, and less than 2% of the patients with an appendiceal continence mechanism have been incontinent. Gerharz and associates58 from Marburg, Germany, reported a single institution experience with the Mainz I ileocecal pouch. From 1990 to 1996, 202 consecutive patients underwent continent diversion, 96 with a submucosally embedded in situ appendix and 106 with an intussuscepted ileal nipple. All patients had an umbilical stoma. In 172 of 200 patients (85%), no stomal complications occurred. In 17 of 96 patients (18%) with an appendiceal stoma, 23 revisions were performed for stomal stenosis. In contrast, only 13 of 106 patients (12%) with an intussuscepted ileal nipple developed a stomal problem. However, these patients required more invasive, major procedures for correction, and the stomas with an appendiceal stenosis could usually be repaired with a minor procedure. Three patients with an ileal nipple (3%) developed pouch calculi, whereas none of the patients with an appendiceal continence mechanism developed stones. As a result, the authors concluded that when available, the appendix should be the intestinal continence mechanism of choice. Indiana Pouch The reoperation rate, mainly caused by complications with the efferent limb, was 26%. Because of the high rate of nighttime incontinence in Rowland’s series,35 Ahlering and colleagues129 detubularized the entire cecum to avoid high pressure contractions from the cecum. Complete detubularization seems to be superior to ileal or sigmoid colon patches. Elegant urodynamic studies were conducted in Indiana pouch variants by Carroll et al.130 They found
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 435
only 86% of patients totally continent in a small series. However, their pouch capacities exceeded 650 ml. Peak contractions of 47 cm H2O were recorded at capacity. Gastric Pouches Over a 10-year period from January 1985 to June 1995, Carr and Mitchell96 reported on the use of stomach in 12 patients. Seven had urinary reservoirs totally constructed from stomach and 5 had composite reservoirs. They report continence in all patients but that the continence mechanisms have oftentimes required revision. The average bladder capacity was 309 ml, and average compliance was 12.9 ml/cm H2O. When stomach is used as a bladder augment or as a portion of a neobladder, a dysuria and hematuria syndrome has been reported.94 QUALITY OF LIFE With improvements in surgical technique and experience, orthotopic urinary reconstruction is a viable alternative in many patients. The lack of a stoma or the need for an appliance or catheterization should benefit patient acceptance and self-image. Whether these changes translate into an improved quality of life remains unclear. Early reports merely examined the impact of conduit creation in patients receiving an ileal conduit. Overall, these studies do not demonstrate a negative effect from a noncontinent urinary diversion. Fossa et al.131 found that few patients experienced a reduction in general quality of life (13%) or restriction in professional and daily functioning (16%); however, the instrument used was not a validated survey. Similarly, Cespedes et al.132 reported that 83% of patients had no change or an increase in activity level after ileal conduit creation. Others have found an improved quality of life (60% to 80%) after surgery and ileal conduit diversion; this may reflect improvements in urinary function in a population without cancer and does not directly compare outcomes with other forms of reconstruction. Hart et al.133 compared quality of life after radical cystectomy for cancer and reconstruction using an ileal conduit, cutaneous Kock pouch, or urethral Kock pouch. No significant differences were noted among these groups with respect to overall quality of life, emotional distress, and problems with social, physical, or functional activities. Most patients (95%) rated quality of life as good to excellent, although urinary and sexual functions were significantly affected in all groups. Over half of patients with ileal conduits reported frequent difficulty in caring for the collection device and 30% had occasional problems with skin irritation. The influence of disease-related factors on the measurements of a nonvalidated questionnaire instru-
ments confounds these data. Bjerre et al.134 also compared the ileal conduit with Kock pouch and found no differences in body image, partner relations, and global life satisfaction. Despite a higher quality of life measurement in those with a neobladder, nearly all patients in both groups (>90%) felt in good health or comparable to people of similar age. McGuire et al.135 used the validated Rand 36-Item Health Survey (SF-36) to measure quality of life in patients with bladder cancer undergoing cystectomy and urinary diversion. No difference in the physical component summary (PCS) score was apparent after ileal conduit, neobladder, and Indiana pouch construction when compared to age- and sex-based population norms. However, patients with ileal conduits had significantly decreased mental quality of life (p = 0.01), while those with other forms of diversion were similar to matched population norms. Several more recent studies have applied validated surveys to address this question. Fujisawa et al.136 also used the SF-36 survey to assess effects of different forms of urinary reconstruction. There were no significant differences between patients with an ileal conduit and neobladder at follow-up of 45 and 31 months, respectively. Although similar in both groups, role-physical functioning and role-emotional function were lower than U.S. population norms. Dutta et al.137 assessed both general health and cancer-specific aspects in 112 patients using the SF-36 and Functional Assessment of Cancer Therapy-General (FACT-G) questionnaires, respectively. SF-36 scores were significantly better for patients with a neobladder compared with an ileal conduit (p = 0.008); however, after controlling for age and disease variables, the differences were less (p = 0.09). Global satisfaction in both groups was high (>85%). They conclude that patients with an orthotopic neobladder enjoy a marginal increase in quality of life when compared with patients receiving an ileal conduit. Using the QLQ-C30 and an institutional questionnaires, Hobisch et al.138 provided stronger evidence that the neobladder is associated with improved quality of life relative to the ileal conduit. Overall satisfaction was 97% in patients with an orthotopic neobladder and 35% in patients with an ileal conduit, respectively. Table 23-6 summarizes the literature concerning quality of life after ileal conduit diversion using validated instruments. The recognition that quality of life is an important treatment outcome in urologic malignancies is a recent phenomenon. This is particularly true for radical cystectomy, where surgery entails not only radical extirpation for cancer cure but also requires complex reconstruction of the urinary tract. Although the data do not demonstrate a clear advantage to orthotopic or continent reservoirs, it appears that these procedures provide excellent quality of life, with minimal increase in morbidity, and should be strongly considered when technically feasible.
436
Part IV Bladder
Table 23-6 Studies of Quality of Life (QOL) After Urinary Diversion Utilizing Validated Instruments (All Compared with Ileal Conduit) References
Number
Type
Instrument
Cystectomy
Results
Bjerre et al.134
67
Kock neobladder
Qualitative interview
Yes
Higher QOL with neobladder Similar overall satisfaction
Hart et al.133
224
Koch*
Validated†
Yes
No differences in QOL Urinary problems, sexual dysfunction
Fujisawa et al.136
56
Neobladder
SF-36
Yes
No difference in QOL Both lower in role-physical, emotional Overall high satisfaction
McGuire et al.135
92
Neobladder, Indiana
SF-36
Yes
Conduit reduced mental health component Physical component similar to norms
Hobisch et al.138
102
Neobladder
QLQ-C30‡
Yes
High QOL with neobladder Lower satisfaction with conduit
Dutta et al.137
112
Neobladder
SF-36, FACT-G
Yes
No differences on multivariate analysis High satisfaction with both
Satoh142
45
Ileocecal rectal bladder
QLQ-C30
Yes
Conduit worse in three domains
Hara143
85
Neobladder
SF-36
Yes
Both with lower QOL than norms Lower role-emotional with conduit
*Both cutaneous and urethral. †Adapted from various validated questionnaires. ‡European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire 30.
Conversely, the ileal conduit is preferable in some patients and this alone does not result in a significant reduction in overall quality of life. Patients can continue with an active, normal lifestyle after nearly all of the reconstructive options. Complete preoperative discussion and explanation of the various forms of urinary reconstruction are crucial factors in patient preparation for the changes in their quality of life. NOVEL TECHNIQUES The realm of laparoscopy in urology has evolved from diagnosis to simple procedures (e.g., renal biopsy) to complete organ removal and now to complex reconstruction. Many reports have documented the use of minimally invasive techniques to create noncontinent and continent urinary drainage. The earliest descriptions of laparoscopic urinary drainage in humans involved the creation of cutaneous ureterostomy for palliation in advanced pelvic malignancy. Laparoscopy, both transperitoneal and retroperitoneal, was used to identify
and mobilize the ureter so that anastomosis to the skin was possible. The initial model for performing the ileal conduit was described by Sanchez de Badajoz et al.139 in 1992. Case reports describe successful operations in 2 patients requiring supravesical diversion without pelvic exenteration. It is important to note that the bowel exclusion, reanastomosis, and ureteroileal anastomoses were performed extracorporeally via a port site. With the development of laparoscopic devices and experience with intracorporeal suturing, more centers are attempting laparoscopic ileal conduits. In combination with laparoscopic radical cystectomy, most surgeons are performing at least a portion of the operation through an extended port site or the specimen extraction incision. Fergany and colleagues140 have developed a porcine model where the entire ileal conduit is performed intracorporeally, demonstrating technical feasibility, as well as excellent short- and long-term outcomes in these animals. These experiences formed the basis for the operation in 2 patients undergoing radical cystoprostatectomy with ileal conduit for bladder
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 437
Table 23-7 Experience with Laparoscopic Ileal Conduit Cystectomy
Completely Time Intracorporeal (hours)
EBL (ml)
Follow-up
Complications
1
No
No
6.3
NR
3 months
None
Vara-Thorbeck145
1
No
No
4
NR
4 months
None
Sanchez de Badajoz146
1
Yes
No
8
NR
1 year
None
Gill147
2
Yes
Yes
10.8
1100
NR
None
Potter et al.141
1
No
Yes
4.5
NR
5 years
Ileus
Gupta148
5
Yes
Yes
7.5
360
2 years
Bowel obstruction
References
Number
Kozminski144
*1 unit blood transfusion. NR, not reported.
cancer; again, the entire operation, including bowel manipulation and suturing, was completed entirely within the abdomen. Potter et al.141 also reported the long-term follow-up (5 years) in a patient, where supravesical diversion was created by a pure laparoscopic ileal conduit. Table 23-7 summarizes the literature regarding surgical outcomes with laparoscopic ileal conduit urinary diversion. The role of minimally invasive surgery in urinary diversion remains unclear. Although promising, further studies are needed to confirm benefits, such as reduced pain and shorter hospitalization. Moreover, the technique must mimic the open operation in that complications are minimal and durable results are achieved, given the challenging nature of the operation.
REFERENCES 1. Boyd S, Feinberg S, Skinner D, et al: Quality of life survey of urinary diversion patients: comparison of ileal conduits versus continent Kock ileal reservoirs. J Urol 1987; 138:1386. 2. Immergut M, Jacobson J, Culp D: Cutaneous pyelostomy. J Urol 1969; 101:276. 3. Gleeson M, Griffith D: Urinary diversion. Br J Urol 1990; 66:113. 4. Rosen M, Roth D, Gonzales EJ: Current indications for cutaneous ureterostomy. Urology 1994; 43:92. 5. Whitmore WJ: Ureteral diversion. In Bergman H (ed): The Ureter, p 603. New York, Harper & Row, 1967. 6. Sarduy G, Crooks K, Smith J: Results in children managed by cutaneous ureterostomy. Urology 1982; 19:486. 7. Young JJ, Ajedia F: Further observations on flank ureterostomy and cutaneous transureteroureterostomy. J Urol 1966; 95:327.
8. Rainwater L, Leary F, Rife C: Transureteroureterostomy with cutaneous ureterostomy: a 25-year experience. J Urol 1991; 146:13. 9. Persky L, McDougal W, Kedia K: Transureteroureterostomy: an adjunct to cystectomy. Urology 1980; 16:20. 10. Chute R, Sallade R: Bilateral side-to-side cutaneous ureterostomy in the midline for urinary diversion. J Urol 1961; 85:280. 11. Rinker J, Blanchard T: Improvement of the circulation of the ureter prior to cutaneous ureterostomy: a clinical study. J Urol 1966; 96:44. 12. Straffon R, Kyle K, Corvalan J: Techniques of cutaneous ureterostomy and results in 51 patients. J Urol 1970; 143:138. 13. Seiffert L: Die “Darm-siphonblase.” Arch Klin Chir 1935; 183:569. 14. Bricker E: Bladder substitution after pelvic evisceration. Surg Clin North Am 1950; 30:1511. 15. Benson M, Olsson C: Urinary diversion. In Walsh P, Retik A, Stamey T, et al (eds): Campbell’s Urology, 6th edition. Philadelphia, WB Saunders Co, 1992. 16. McDougal W: Metabolic complications of urinary intestinal diversion. J Urol 1992; 147:1199. 17. Turnbull RJ, Hewitt C: Loop-end myotomy ileostomy in the obese patient. Urol Clin North Am 1978; 5:423. 18. Chechile G, Klein E, Bauer L: Functional equivalence of end and loop ileal conduit stomas. J Urol 1992; 147:582. 19. Klein E, Montie J, Montague D: Jejunal conduit urinary diversion. J Urol 1986; 135:244. 20. Golimbu M, Morales P: Jejunal conduits: technique and complications. J Urol 1975; 113:787. 21. Turner-Warwick R: Colonic urinary conduits. Proc R Soc Med 1960; 53:1032. 22. Zinman L, Libertino J: Ileocecal conduit for temporary and permanent urinary diversion. J Urol 1975; 113:317. 23. Simon J: Ectopia vesicae (absence of the anterior walls of the bladder and pubic abdominal parietes): operation for
438
Part IV Bladder
directing the orifices of the ureters into the rectum: temporary success; subsequent death; autopsy. Lancet 1852; 2:568. 24. Smith T: An account of an unsuccessful attempt to treat extroversion of the bladder by a new operation. St Barth Hosp Rep 1879; 15:29. 25. Allen T: Editorial comment. J Urol 1995; 153:1431. 26. Bissada N, Morcos R, Morgan W, et al: Ureterosigmoidostomy: Is it a viable procedure in the age of continent urinary diversion and bladder substitution? J Urol 1995; 153:1429. 27. Ambrose S: Ureterosigmoidostomy. In Glenn J (ed): Urologic Surgery, pp 511–520. Philadelphia, JB Lippincott, 1983. 28. Spirnak J, Caldamone A: Ureterosigmoidostomy. Urol Clin North Am 1986; 13:285. 29. Silberman R: Ammonia intoxication following ureterosigmoidostomy in a patient with liver disease. Lancet 1958; 2:937. 30. Leadbetter W: Consideration of problems incident to performance of ureteroenterostomy: report of a technique. J Urol 1951; 65:818. 30a. Goodwin WE. Ureterosigmoidoscopy (open transcolonic ureterointestinal anastomosis. In Cooper P (ed): The craft of surgery; p 1367, Boston; Little, Brown & Co, 1964.) 31. Benchekroun A: Hydraulic valve for continence and antireflux: a 17 year experience of 210 cases. Scand J Urol Nephrol Suppl 1992; 142:70. 32. Woodhouse C, MacNeily A: The Mitrofanoff principle. Br J Urol 1994; 74:447. 33. Lampel A, Hohenfellner M, Schultz D, et al: Submucosal seromuscular tube and submucosal bowel flap tube: two new stoma techniques for Mainz pouch continent cutaneous urinary diversion. J Urol 1995; 153:305A. 34. Burns M, Mitchell M: Tips on constructing the Mitrofanoff appendiceal stoma. Contemporary Urol 1990;2:10. 35. Rowland R, Mitchell M, Bihrle R: The cecoileal continent urinary reservoir. World J Urol 1985; 3:185. 36. Lockhart J: Remodeled right colon: an alternative urinary reservoir. J Urol 1987; 138:730. 37. Bejany D, Politano V: Stapled and nonstapled tapered distal ileum for construction of a continent colonic urinary reservoir. J Urol 1988; 140:491. 38. Hendren W: Urinary diversion and undiversion in children. Surg Clin North Am 1976; 56:425. 39. Skinner D, Boyd S, Lieskovsky G: Clinical experience with the Kock continent ileal reservoir for urinary diversion. J Urol 1984; 132:1101. 40. King L: Protection of the upper tracts in undiversion. In King L, Stone A, Webster G (eds): Bladder Reconstruction and Continent Urinary Diversion, pp 127–153. Chicago, Year Book Medical, 1987. 41. Stein J, Lieskovsky G, Ginsberg D, et al: The T pouch: an orthotopic ileal neobladder incorporating a serosal lined ileal antireflux technique. J Urol 1998; 159:1836.
42. Benchekroun A: The ileocecal continent bladder. In King L, Stone A, Webster G (eds): Bladder Reconstruction and Continent Urinary Diversion, pp 224–237. Chicago, Year Book Medical, 1987. 43. Mitrofanoff P: Cystostomie continente transappendiculaire dans le traitement des vessies neurologiques. Chir Pediatr 1980; 21:297. 44. Duckett J, Snyder HI: Use of the Mitrofanoff principle in urinary reconstruction. Urol Clin North Am 1986; 13:271. 45. Riedmiller H, Steinbach F, Thuroff J, et al: Continent appendix stoma—a modification of the Mainz pouch technique. Presented at the EAU Congress, Amsterdam, 1990. 46. Kock N, Nilson A, Nilsson L, et al: Urinary diversion via a continent ileal reservoir: clinical results in 12 patients. J Urol 1982; 128:469. 47. Skinner D: The Kock pouch for continent urinary reconstruction focusing on the afferent segment and the reservoir. Scand J Urol Nephrol Suppl 1992; 142:77. 48. Skinner D, Lieskovsky G, Boyd S: Continent urinary diversion. J. Urol 1989; 141:1323. 49. Abol-Enein H, Ghoneim M: A novel uretero-ileal reimplantation technique: the serous lined extramural tunnel. A preliminary report. J Urol 1994; 151:1193. 50. Abol-Enein H, Ghoneim M: Optimization of ureterointestinal anastomosis in urinary diversion: an experimental study in dogs. III. A new antireflux technique for ureteroileal anastomosis: a serous lined extramural tunnel. Urol Res 1993; 21:135. 51. Bochner B, Stein J, Ginsberg D, et al: A serous lined antireflex valve: in vivo fluorourodynamic evaluation of antireflux continence mechanism. J Urol 1998; 160:112. 52. LeDuc A, Camey M, Teillac P: An original antireflux ureteroileal implantation technique: long-term followup. J Urol 1987; 137:1156. 53. Stein J, Buscarini M, DeFilippo R, et al: Application of the T pouch as an ileo-anal reservoir. J Urol 1999; 162:2052. 54. Stein J, Lieskovsky G, Skinner D: T-mechanism applied to urinary diversion: the orthotopic T-pouch ileal neobladder and cutaneous double T-pouch ileal reservoir. Tech Urol 2001; 3:209. 55. Thuroff J, Alken P, Riedmiller H: The Mainz pouch (mixed augmentation ileum ′n zecum) for bladder augmentation and continent diversion. World J Urol 1985; 3:179. 56. Stein R, Young M, Doi Y, et al: Continent urinary diversion using the Mainz pouch I technique—ten years later. J Urol 1995; 153:251A. 57. Lampel A, Fisch M, Stein R, et al: Continent diversion with the Mainz pouch. World J Urol 1996; 14:85. 58. Gerharz E, Kohl U, Weingartner K, et al: Complications related to different continence mechanisms in ileocecal reservoirs. J Urol 1997; 158:1709. 59. Thuroff J, Alken P, Riedmiller H, et al: 100 cases of Mainz pouch: continuing experience and evolution. J Urol 1988; 140:283.
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 439 60. Riedmiller H, Steinbach F, Thuroff J, et al: Continent appendix stoma: a modification of the Mainz pouch technique. AUA 85th Annual Meeting, 13–17 May, New Orleans, 1990. 61. Lampel A, Hohenfellner M, Schultz-Lampel D, et al: In situ tunneled bowel flap tubes: 2 new techniques of a continent outlet for Mainz pouch cutaneous diversion. J Urol 1995; 153:308. 62. Lampel A, Thuroff J: Bowel-flap tubes for continent urinary diversion. World J Urol 1998; 16:235. 63. Raz S: The UCLA Neobladder. 1994 (edited by J. deKernion). 64. Webster G, King L: Further commentary: cecal bladder. In King L, Stone A, Webster G (eds): Bladder Reconstruction and Continent Urinary Diversion, pp 206–208. Chicago, Year Book Medical, 1987. 65. Light J, Scardino P: Radical cystectomy with preservation of sexual and urinary function: use of the ileocolonic pouch (Le Bag). Urol Clin North Am 1986; 13:261. 66. Kock N, Nilson A, Nilsson L, et al: Urinary diversion via a continent ileal reservoir: clinical results in 12 patients. J Urol 1982; 128:469. 67. Stein J, Lieskovsky G, Skinner D: The double-T-pouch: a novel continent cutaneous ileal reservoir. J Urol1999; 161:253A (pg 67). 68. Thuroff J, Alken P, Riedmiller H, et al: 100 cases of Mainz pouch: continuing experience and evolution. J Urol 1988; 140:283. 69. Lampel A, Fisch M, Stein R, et al: Continent diversion with the Mainz pouch. World J Urol 1996; 14:85. 70. Gerharz E, Kohl U, Weingartner K, et al: Complications related to different continence mechanisms in ileocecal reservoirs. J Urol 1997; 158:1709. 71. deKernion J, Raz S, Wahle G, et al: The UCLA neobladder: clinical urodynamic and metabolic results. J Urol 1994; 151:242A (no. 59). 72. Rowland R, Mitchell M, Bihrle R: The cecoileal continent urinary reservoir. World J Urol 1985; 3:185. 73. Rowland R, Mitchell M, Bihrle R, et al: Indiana continent urinary reservoir. J Urol 1987; 137:1136. 74. Scheidler D, Klee L, Rowland R, et al: Update on the Indiana continent urinary reservoir. J Urol 1989; 141:302A. 75. Carroll P, Presti JJ, McAnnich J, et al: Functional characteristics of the continent ileocecal urinary reservoir: mechanisms of urinary continence. J Urol 1989; 142:1032. 76. Ahlering T, Weinberg A, Razor B: Modified Indiana pouch. J Urol 1991; 145:1156. 77. Carroll P, Presti JJ: Comparison of plicated and stapled continent ileocecal stoma. Urology 1992; 40:107. 78. Rowland R: Present experience with the Indiana pouch. World J Urol 1996; 14:92. 79. Bihrle R: The Indiana pouch continent urinary reservoir. Urol Clin North Am 1997; 24:773. 80. Lockhart J: Remodeled right colon: an alternative urinary reservoir. J Urol 1987; 138:730.
81. Lockhart J, Pow-Sang J, Persky L, et al: Results, complications and surgical indications of the Florida pouch. Surg Gynecol Obstet 1991; 173:289. 82. Webster G, Bertram R: Continent catheterizable urinary diversion using the ileocecal segment with stapled intussusception of the ileocecal valve. J Urol 1986; 135:465. 83. Bejany D, Politano V: Stapled and nonstapled tapered distal ileum for construction of a continent colonic urinary reservoir. J Urol 1988; 140:491. 84. Benson M, Olsson C: Cutaneous continent urinary diversion. In Walsh P, Retik A, Vaughn EJ, et al (eds): Campbell’s Urology, Vol 4, 8th edition, Section 13 Urologic Surgery. Philadelphia, Elsevier Science, 2003. 85. Sumfest J, Burns M, Mitchell M: The Mitrofanoff principle in urinary reconstruction. J Urol 1993; 150:1875. 86. Adams M, Mitchell M, Rink R: Gastrocystoplasty: an alternative solution to the problem of urological reconstruction in the severely compromised patient. J Urol 1988; 140:1152. 87. Carr M, Mitchell M: Continent gastric pouch. World J Urol 1996; 14:112. 88. Rowland R, Mitchell M, Bihrle R: The cecoileal continent reservoir. World J Urol 1985; 3:185. 89. Rowland R: Present experience with the Indiana pouch. World J Urol 1996; 14:92. 90. Adams M, Mitchell M, Rink R: Gastrocystoplasty: an alternative solution to the problem of urological reconstruction in the severely compromised patient. J Urol 1988; 140:1152. 91. Lockhart J, Davies R, Cox C, et al: The gastroileal pouch: an alternative continent urinary reservoir for patients with short bowel, acidosis and/or extensive pelvic radiation. J Urol 1993; 150:46. 92. Austin P, DeLeary G, Homsy Y, et al: Long-term metabolic advantages of a gastrointestinal composite urinary reservoir. J Urol 1997; 158:1704. 93. Nguyen D, Bain M, Salmonson K, et al: The syndrome of dysuria and hematuria in pediatric urinary reconstruction with stomach. J Urol 1993; 150:707. 94. Gosalbez R, Padron O, Singla A, et al: The gastric augment single pedicle tube catheterizable stoma: a useful adjunct to reconstruction of the urinary tract. J Urol 1994; 152:2005. 95. Carr M, Mitchell M: Continent gastric pouch. World J Urol 1996; 14:112. 96. Gonzales R, Reinberg Y: Localization of bacteriuria in patients with enterocystoplasty and nonrefluxing conduits. J Urol 1987; 138:1104. 97. Yang W: Yang needle tunneling technique in creating antireflux and continent mechanisms. J Urol 1993; 150:830. 98. Hirdes W, Hoekstra I, Vliestra H: Hammock anastomoses: a nonrefluxing ureteroileal anastomosis. J Urol 1988; 139:517. 99. Wallace D: Ureteric diversion using a conduit: a simplified technique. Br J Urol 1966; 38:522. 100. Starr A, Rose D, Cooper J: Antireflux ureteroileal anastomosis in humans. J Urol 1975; 113:170.
440
Part IV Bladder
101. Menon M, Yu G, Jeffs R: Technique for antirefluxing ureterocolonic anastomosis. J Urol 1982; 127:236. 102. Feminella J, Lattimer J: A retrospective analysis of 70 cases of cutaneous ureterostomy. J Urol 1971; 106:538. 103. Middleton AJ, Hendren W: Ileal conduit in children at the Massachusetts general hospital from 1955 to 1970. J Urol 1976; 115:591. 104. Butcher HJ, Sugg W, McAfee C, et al: Ileal conduit method of ureteral urinary diversion. Ann Surg 1962; 156:682. 105. Morales P, Golimbu M: Colonic urinary diversion: 10 years of experience. J Urol 1975; 113:302. 106. Elder D, Moisey C, Rees R: A long-term follow-up of the colonic conduit operation in children. Br J Urol 1979; 51:462. 107. Borglund E, Nordstrom G, Nyman C: Classification of peristomal skin changes in patients with urostomy. J Am Acad Dermatol 1988; 19:623. 108. Johnson DE, Jackson L, Guinn GA: Ileal conduit diversion for carcinoma of the bladder. South Med J 1970; 63:1115. 109. Johnson DE, Lamy SM: Complications of a single stage radical cystectomy and ileal conduit diversion: review of 214 cases. J Urol 1977; 117:171. 110. Sullivan J, Grabstald H, Whitmore WJ: Complications of ureteroileal conduit with radical cystectomy: review of 336 cases. J Urol 1980; 124:797. 111. Pitts WJ, Muecke E: A 20-year experience with ileal conduits: the fate of the kidneys. J Urol 1979; 122:154. 112. Schmidt JD, Buchsbaum HJ, Jacobo EC: Transverse colon conduit for supravesical urinary tract diversion. Urology. 1976; 8:542. 113. Althausen A, Hagen-Cook K, Hendren WI: Nonrefluxing colon conduit: experience with 70 cases. J Urol 1978; 120:35. 114. Matsuura T, Tsujihashi H, Park Y, et al: Assessment of the long-term results of ileocecal conduit urinary diversion. Urol Int 1991; 46:154–158. 115. Schwarz G, Jeffs R: Ileal conduit urinary diversion in children: computer analysis of follow-up from 2 to 26 years. J Urol 1975; 114:285. 116. Shapiro S, Lebowitz R, Colodny A: Fate of 90 children with ileal conduit urinary diversion a decade later: analysis of complications, pyelography, renal function and bacteriology. J Urol 1975; 114:289. 117. Dretler S: The pathogenesis of urinary tract calculi occurring after ileal conduit diversion. I. Clinical study. II. Conduit study. III. Prevention. J Urol 1973; 109:204. 118. Terai A, Arai Y, Kawakita M, et al: Effect of urinary intestinal diversion on urinary risk factors for urolithiasis. J Urol 1995; 153:37. 119. Wolf JJ, Stoller M: Management of upper tract calculi in patients with tubularized urinary diversions. J Urol 1991; 145:266. 120. Savarirayan F, Dixey G: Syncope following ureterosigmoidostomy. J Urol 1969; 101:844.
121. McDougal W, Koch M, Shands CI, et al: Bony demineralization following urinary intestinal diversion. J Urol 1988; 140:853. 122. Kristiansen P, Mansson W, Tyger J: Perforation of continent cecal reservoir for urine twice in one patient. Scand J Urol Nephrol 1991; 25:279. 123. Thompson S, Kursh E: Delayed spontaneous rupture of an ileocolonic neobladder. J Urol 1992; 148:1890. 124. Wantanabe K, Kato H, Misawa K, et al: Spontaneous perforation of an ileal neobladder. Br J Urol 1994; 73:460. 125. Skinner D, Lieskovsky G, Boyd S: Continent urinary diversion. J Urol 1989; 141:1323. 126. Silverman S, Woodhouse C, Strachan J, et al: Long-term management of patients who have had urinary diversions into colon. Br J Urol 1986; 58:634. 127. Stewart M: Urinary diversion and bowel cancer. Ann R Coll Surg Engl 1986; 68:98. 128. Kalble T, Mohring K, Tricker A, et al: Adenocarcinoma of the colon following ureterosigmoidostomy. Akt Urol 1989; 20:173. 129. Ahlering T, Weinberg A, Razor B: Modified Indiana pouch. J Urol 1991; 145:1156. 130. Carroll P, Presti JJ, McAnnich J, et al: Functional characteristics of the continent ileocecal urinary reservoir: mechanisms of urinary continence. J Urol 1989; 142:1032. 131. Fossa S, Reitan J, Ous S, et al: Life with an ileal conduit in cystectomized bladder cancer patients: expectations and experience. Scand J Urol Nephrol 1987; 21:97. 132. Cespedes R, McGuire E, Donat S, et al: Bladder preservation and continent urinary diversion in T3b transitional cell carcinoma of the bladder. Semin Urol Oncol 1996; 14:103. 133. Hart S, Skinner E, Meyerowitz B, et al: Quality of life after radical cystectomy for bladder cancer in patients with an ileal conduit, cutaneous or urethral Koch pouch. J Urol 1999; 162:77. 134. Bjierre B, Johansen C, Steven K, et al: Health-related quality of life after cystectomy: bladder substitution compared with ileal conduit diversion: a questionnaire survey. Br J Urol 1995; 75:200. 135. McGuire M, Grimaldi G, Grotas J, et al: The type of urinary diversion after radical cystectomy significantly impacts on the patient’s quality of life. Ann Surg Oncol 2000; 7:4. 136. Fujisawa M, Isotani S, Gotoh A, et al: Health-related quality of life with orthotopic neobladder versus ileal conduit according to the SF-36 survey. Urology 2000; 55:862. 137. Dutta S, Chang S, Coffey C, et al: Health related quality of life assessment after radical cystectomy: comparison of ileal conduit with continent orthotopic neobladder. J Urol 2002; 168:164. 138. Hobisch A, Tosun K, Kinzl J, et al: Life after cystectomy and orthotopic bladder versus ileal conduit urinary diversion. Semin Urol Oncol 2001; 19:18.
Chapter 23 Noncontinent and Continent Cutaneous Urinary Diversion 441 139. Sanchez de Badajoz E, del Rosal Samaniego J, Gomez Gamez A, et al: Laparoscopic ileal conduit. Arch Esp Urol 1992; 45:761. 140. Fergany A, Gill I, Kaouk J, et al: Laparoscopic intracorporeally constructed ileal conduit after porcine cystoprostatectomy. J Urol 2001; 166:285. 141. Potter S, Charambura T, Adams JN, et al: Laparoscopic ileal conduit: five year follow-up. Urology 2000; 56:22. 142. Satoh S, Sato K, Habuchi T, et al: Health-related quality of life of ileoceccal rectal bladder compared with ileal conduit diversion: a questionnaire survey. 2002; 9: 385. 143. Hara I, Miyake H, Hara S, et al: Health-related quality of life after radical cystectomy for bladder cancer: a comparison of ileal conduit and orthotopic bladder replacement. 2002; 89:10.
144. Kozminski M, Partamian KO. Case report of laparoscopic ileal loop conduit. J Endourol 6:147-150, 1992 145. Sanchez de Badajoz E, Gallego Perales JL, Reche Rosado A, et al. J Endourol 9:59-62, 1995 146. Vara-Thorbeck C, Sanchez de Badajoz E. Laparoscopic ileal loop conduit. Surg Endosc 8:114-5, 1993 147. Gill IS, Fergany A, Klein EA, et al: Laparoscopic radical cystoprostatectomy with ileal conduit performed completely intracorporeally: the initial 2 cases. Urology 2000 56(1): 26-29. 148. Gupta NP, Gill IS, Fergany A, et al. Laparoscopic radical cystectomy with intracorporeal ileal conduit diversion: five cases with a 2-year follow-up. BJV Int 90:391-396, 2002.
C H A P T E R
24 Orthotopic Bladder Substitution in the Male and Female Celi Varol, MD, Fiona C. Burkhard, MD, Werner W. Hochreiter, MD, and Urs E. Studer, MD
Orthotopic bladder substitutions are here to stay and have become the main option following cystectomy. Improvement in cosmetic results and documented increases in quality-of-life outcomes will encourage more urologists to perform such surgical procedures.1,2 Excellent long-term results following orthotopic bladder substitution can be attained, provided that attention is given to appropriate preoperative patient selection, specific intraoperative surgical details, and, most importantly, meticulous postoperative patient follow-up. The general principles of patient selection and follow-up apply to both sexes with only the obvious anatomic and operative variations to be taken into account in each case. Although bladder substitutions in men have been widely performed over the past two decades and are an accepted mode of urinary diversion, trepidation still exists when considered in women. Currently, the majority of cystectomies performed in women are for malignant bladder disease, where the risk of metachronous or synchronous urethral transitional cell tumor recurrence and voiding dysfunction are the main factors preventing this from being a routine procedure. With evolving data over the last decade, a less cautious approach to female bladder substitution is developing. The rarity of urethral recurrence reported and a better understanding of the natural history of transitional cell carcinoma (TCC) has led to more appropriate patient selection in women undergoing bladder substitution surgery. Advances in surgical techniques together with increased understanding of the pelvic anatomy, general physiology, and female continence mechanism have resulted in improved functional outcomes emulating those in men. The ileal low pressure bladder substitute with an afferent tubular segment is easily constructed and has documented good long-term functional results in both
sexes.3,4 To achieve such results, certain essential factors need to be considered during specific time periods. These are segregated in this chapter into the preoperative, operative, and postoperative periods. PREOPERATIVE PATIENT SELECTION AND ASSESSMENT The preoperative assessment is identical to that for any radical cystectomy case, where bone, lung, and lymph node metastases must be excluded. Besides establishing patient operability, major liver, renal, bowel, or mental insufficiency must be recognized, as these may be contraindications for a bladder substitution.5 Mental Capacity and Compliance A successful outcome of a bladder substitution requires the cooperation of the patient and the willingness to comply with long-term follow-up. Adequate mental capacity to comprehend the basic function of the bladder substitute with sufficient physical dexterity is needed. The patient needs to be educated to ensure satisfactory longevity of the bladder substitute. If this is not possible or a question of compliance exists, an alternative form of treatment should be discussed. A dedicated nurse who specializes in the education and rehabilitation of patients with bladder substitutions should be routinely involved in the preoperative selection process. Renal Function The commonest biochemical abnormalities detected following bladder substitution are metabolic acidosis and
443
444
Part IV Bladder
electrolyte abnormalities. The frequency and severity observed depends on the length and type of intestinal segment used, duration of urine contact with the bowel, and the compensatory functional reserve of the kidneys. Preoperative renal function with a serum creatinine level of ≤150 μmol/l is required to limit such complications. Malignant ureteric obstruction or any other mechanical causes of renal insufficiency, where improvement of renal function can be expected with surgery, may be taken into account.6,7 Hepatic Function To maintain a metabolic equilibrium following surgery adequate liver function is needed in bladder substitute candidates. The bowel mucosa of the bladder substitute allows ammonium from the urine to shift into the circulation. In a urinary tract infection with a urease splitting organism, the ammonium load becomes even more important. In the presence of liver insufficiency hyperammonemia can result in dehydration, neurologic disorders and eventual coma.8 Bowel Function The gastrointestinal tract allows up to 60 cm of ileal resection without major repercussions, provided that the ileocecal valve remains intact. When utilizing longer ileal segments of 60 to 100 cm or the ileocecal valve, longterm bowel motility disturbances may result.9 Therefore, if ileum is resected, an attempt should always be made to preserve the terminal ileum and the ileocecal valve, as this not only minimizes the risk of bowel dysfunction but also maintains vitamin B12 and bile salt metabolism. Evidence of prior bowel disease, resection or radiation needs to be elucidated as it results in functional bowel shortening causing malabsorption or diarrhea when further bowel is used for a bladder substitute. Preservation of the right colon allows an extended length of left colon to be used for reconstruction with lesser malabsorption side effects. This is because fluid reabsorption occurs predominantly in the right colon, whilst the left colon serves more as a conduit. However, even with right colon preservation, metabolic complications will still occur.8,10 Anastomotic Margin Biopsy and Urethral Recurrence: Urethral tumor recurrence is an uncommon phenomenon following bladder substitution, with a reported incidence of 2% to 4%.11–14 The main factor appears to be the closeness of the primary tumor in the bladder to the urethral sphincter. In men, the prostatic urethral length allows for more separation from the bladder tumor than in women, when the tumor is in the trigone. Positive
biopsies from the paracollicular region in the prostatic urethra or the bladder neck in women (site of urethral anastomosis) are associated with a high likelihood of a urethral recurrence. These patients require a urethrectomy and should not be considered for an orthotopic bladder substitute. Infiltration by urothelial tumors (superficial or stromal) of the proximal prostatic urethra, carcinoma in situ, and multifocal transitional cancer in the bladder confer a higher chance of urethral recurrence.11,14 These findings are not absolute contraindications to the performance of a bladder substitution but require close follow-up with urethral wash cytology. Management of urethral recurrence with CIS can be performed with BCG therapy, attaining a success rate of approximately 80%. These results, however, cannot be replicated in the presence of papillary or invasive urethral tumor recurrence where urethrectomy is advocated.14 Continence Identification of incontinence prior to surgery, especially in females is essential. Urge incontinence is likely to be treated by cystectomy; however, stress incontinence, which is due to inadequate sphincter function, needs to be further evaluated by urodynamic assessment with an urethral pressure profile. Patients with a grade I genuine stress incontinence, a normal functional urethral length, a hypermobile bladder neck and absence of a large cystocele should benefit from a bladder substitute. However, if there is documented evidence for a shortened functional urethral length or intrinsic sphincter deficiency, incontinence following an orthotopic bladder substitute can be expected. General Preoperative Patient Preparation On the evening prior to the operation, a liquid diet is implemented with two high colonic enemas. In contrast, colonic bladder substitutes require a full mechanical bowel preparation (Glycoprep). Application of compression stockings and subcutaneous deep venous thrombosis prophylaxis should be commenced the evening before surgery. Injections should be given in the upper body to prevent pelvic lymphocele formation. OPERATIVE TECHNIQUE To achieve a good functional result, the bladder substitution has to have a good capacity, a low-pressure system made of detubularized bowel segments with minimal outlet resistance and preserved sphincter function. There are certain critical surgical steps that need to be followed during the cystectomy to achieve these properties. These steps vary slightly between the genders in regards to the obvious pelvic anatomy and the position of the respective
Chapter 24 Orthotopic Bladder Substitution in the Male and Female 445
neurovascular bundles that supply the pelvic floor and the urethral sphincter. The general principles, however, remain the same in the performance of the cystectomy with the construction of the bladder substitute not being particular to either sex. The following points should be noted carefully during the cystectomy and formation of the bladder substitute for optimal surgical outcome. Cystectomy Nerve Preservation Preservation of the autonomic nerves to the sphincter and urogenital diaphragm is controversial, but we feel that it should be attempted on the nontumor bearing side (in bladder cancer) as it will increase the chance of potency in the male and aid urinary continence in both sexes.15 These nerves originate from the inferior hypogastric plexus and continue as the pelvic plexus lying dorsal to the bladder in the pararectal/paravaginal area, ending as the paraprostatic neurovascular bundle or paravaginal plexus prior to supplying the urogenital diaphragm, sphincter, and erectile organs. Probably equally important is the preservation of the intrapelvic branch of the pudendal nerve.16 In benign pathology, bilateral nerve-sparing cystectomy should be performed with simultaneous prostatic capsule preservation in the male. In the male, the critical areas to preserve the pelvic plexus and neurovascular bundles are in the dorsomedial pedicles of the bladder, lateral to the seminal vesicles, and
the paraprostatic neurovascular bundles. At the seminal vesicles, minimal trauma should occur by dissecting close to them on the lateral wall in an antegrade fashion, away from the pelvic plexus, without touching it. The pelvic plexus will be located dorsolateral at this point and will continue onto the dorsomedial border of the prostatic capsule. If the dorsomedial pedicle of the bladder is severed too far dorsally, the nerves are at risk of being transected here.17 A nerve-sparing prostatectomy should be performed by freeing the dorsolateral neurovascular bundle off the prostatic capsule. On the contralateral tumor bearing side, the dorsomedial pedicle of the bladder should be resected along the pararectal/presacral plane and the prostatic neurovascular bundles removed with the prostate if necessary. A female nerve-sparing cystectomy requires similar attention during ligation of the dorsomedial pedicle of the bladder. Care is taken during the dissection of the lateral vagina as the neurovascular bundles lie in the lateral paravaginal wall. The dissection needs to be in the anterolateral paravaginal plane, close to the bladder base on the nontumor bearing side. This can be facilitated by the use of sponge-holding forceps in the vagina. On the tumor bearing side, the preparation goes along the dorsolateral aspect of the vaginal wall where the anterior vaginal wall is removed en bloc with the cystectomy specimen (Figure 24-1). The proximal part of the paravaginal plexus will therefore be severed here (Figure 24-2). The intrapelvic branches of the pudendal nerve that also innervate the external sphincter mechanism pass under
Figure 24-1 The preparation goes along the dorsolateral aspect of the vaginal wall where the anterior vaginal wall is removed en bloc with the cystetectomy specimen.
446
Part IV Bladder
the endopelvic fascia along the medial aspect of levator ani.18 Therefore, minimal trauma to the endopelvic fascia should occur by only incising it in a ring-like fashion at the junction of the urethra and bladder neck. On the contralateral tumor bearing side, the paravaginal tissue is widely excised as far as the pararectal region to remove the lymphatics that drain the bladder base together with the autonomic nerves (see Figure 24-10). Atraumatic Dissection of The Urethra Sharp, atraumatic dissection of the urethra with limited use of only bipolar electrocautery at the prostatic apex in men and bladder neck in females is essential. Maximum urethral length must be retained. Preservation of the puboprostatic and pubourethral ligaments and incision of the endopelvic fascia along the bladder neck in female patients will allow for more urethral stability and improved continence.19 In women, preserving the autonomic nerve supply to the proximal one-third of the urethra will also maintain its tubular shape. If this is denervated, a flaccid, hypotonic urethra results, which tends to kink. If in doubt of the innervation, the proximal one-third of the urethra should be resected. This may result in dribble incontinence when walking due to the shortened functional urethral length. The pudendal nerve still innervating the distal two-thirds of the urethra and pelvic floor will maintain continence at times of sudden increased abdominal pressure, such as during coughing.19,20 Ureters The ureters need to be mobilized en bloc with all their paraureteric tissue. This allows for preservation of the blood supply to the proximal ureter, whilst division of the ureters at the level of the iliac bifurcation, allows en bloc removal of the distal ureter and paraureteric lymphatic vessels with the cystectomy specimen. The left ureter is mobilized retrocolic and superior to the inferior mesenteric artery when transposed to the paracaval side, without kinking and free of tension. Ureteric anastomoses should not be obstructive in nature and antireflux ureteric reimplantation is not required in a low pressure ileal bladder substitute.21,22 Orthotopic Ileal Bladder Substitute Ileal Segment Resection The intraoperative epidural anesthesia (containing local anesthetics) will cause bowel contraction and, therefore, must be switched off at least 1 hour prior to the measurement of bowel length. This is to ensure accurate bowel length measurement resulting in ideal reservoir dimension. A 54- to 56-cm segment of ileum is isolated 25 cm proximal to the ileocecal valve. The length of the
Figure 24-2 The proximal part of the paravaginal plexus is severed in a ring-like fashion at the junction of the urethra and bladder neck.
ileum segment is measured along the border of the ileal mesentery without stretching the bowel. The distal mesenteric incision transects the main vessels, whereas the proximal incision must be shorter in order to preserve the main vessels perfusing the future reservoir segment (Figure 24-3). A 4-0 polyglycolic acid single layer seromuscular running suture is used to restore the bowel continuity in a cephalad position, as well as close its mesenteric window. Both ends of the isolated ileal segment are closed with a single layer 4-0 polyglycolic acid seromuscular running suture. The distal 40- to 44-cm end of the ileal segment is opened along its antimesenteric border (Figure 24-4). Ureteroileal Anastomosis The ureters are spatulated 1.5 to 2 cm and anastomosed by two 4-0 polyglycolic acid running sutures using the Nesbit technique in an end-to-side fashion to two longitudinal 1.5- to 2-cm long incisions along the paramedian antimesenteric border of the afferent tubular ileal segment (Figure 24-5). This segment is 12 to 14 cm in
Chapter 24 Orthotopic Bladder Substitution in the Male and Female 447
Figure 24-3 Prepare 54- to 56-cm long ileal segment for the bladder substitute. Note the different incision depths of the ileal mesentery proximally and distally, in order to preserve the blood supply.
length. The distal ureteric adventitia is sutured to the afferent ileal segment to remove tension on the anastomosis and to cover it. The ureters are stented with 8 F catheters. To prevent dislocation of the catheters, a rapidly absorbable 4-0 polyglycolic acid suture is placed through the ureter and catheter together and loosely tied, not compromising the ureteric blood flow (see Figure 24-5). The ureteric catheters are passed through the wall of the most distal end of the afferent tubular segment, where it is covered by the fat of the mesentery (Figure 24-6). This provides a “covered” canal in the reservoir wall following withdrawal of the ureteric catheters. Construction of The Bladder Substitute and Urethral Anastomosis For the reservoir construction, the two medial borders of the opened U-shaped distal part of the ileal segment are oversewn with a single continuous 2-0 polyglycolic
acid seromuscular layer. The base of the “U” is folded over between the two limbs of the “U” (see Figure 24-6), resulting in a spherical reservoir consisting of four crossfolded ileal segments. After closure of the lower half of the anterior wall and most of the upper half, the surgeon’s finger is introduced through the remaining opening to determine the most caudal part of the reservoir. An 8- to 10-mm diameter hole is cut out of the pouch wall avoiding the suture line (Figure 24-7). The anastomoses must sit flat with the pelvic floor in the male and the pelvic floor/anterior vaginal wall in the female. A funnel-shaped outlet, which would kink, must at all times be avoided as it may result in outlet obstruction (Figure 24-8). Six 2-0 polyglycolic acid seromuscular sutures are placed between the hole in the reservoir wall and the membranous urethra (Figure 24-9). An 18 F urethral catheter is inserted before tying the six sutures. A 10 F cystostomy tube is placed into the reservoir through its mesenteric fat prior to total closure of the reservoir
448
Part IV Bladder
Figure 24-4 Close the mesenteric window, avoiding deep sutures in the mesentery of the terminal ileum to that of the mesentery of the bladder substitute, in order not to compromise circulation. The distal 40- to 44-cm end of the ileal segment is opened along its antimesenteric border.
(Figure 24-10). One 20 F silicon drain is placed into the pelvis and one near the ureteric anastomosis. POSTOPERATIVE MANAGEMENT Good long-term results can only be achieved by vigilant postoperative management and regular long-term followup. This will allow potential complications to be recognized early and minimize morbidity to the patient and the bladder substitute. The in-hospital postoperative period should be utilized for patient education and to help adjust to their bladder substitute. A bladder substitute that functions well should have no infection, no incontinence, no acidosis, and no or minimal postvoid residual urine.7 Early Postoperative Period The patients are stationed in a high dependency ward for the first 24 to 48 hours. Postoperatively all patients have
a nasogastric tube, urethral catheter, suprapubic catheter, wound drains, and two ureteric catheters. We use single ‘J’ or ureteric catheters (8 F) to stent the ureteric anastomoses that are exteriorized through the bladder substitute. This minimizes urine contact and absorption with the bladder substitution mucosa and allows accurate fluid balance measurements. The suprapubic and transurethral catheters need to be gently flushed but vigorously aspirated with saline 0.9% every 6 hours. This is mandatory to prevent any mucous clots and subsequent catheter blockages, which may lead to bladder substitution rupture. This risk is highest when bowel activity returns whilst the urethral catheter is still in situ. Abdominal bloating can be limited and bowel function return accelerated with subcutaneous neostigmine methylsulfate 3 to 6 × 0.5 mg/day commenced on the third day and additionally in smokers with nicotine patches. The ureteric catheters are removed sequentially on the 5th to 8th postoperative days. Total parenteral nutrition (without
Chapter 24 Orthotopic Bladder Substitution in the Male and Female 449
Figure 24-5 Perform a simple end-to-side Nesbit technique with a 4-0 polyglycolic acid running suture for the ureteroileal anastomosis.
lipid supplementation) is commenced and tapered once an oral diet is reintroduced. Patients undergo regular chest physiotherapy and are encouraged to mobilize on the first postoperative day. Late Postoperative Period A cystogram is performed on the 8th to 10th postoperative day. If this excludes any urinary extravasations, the suprapubic catheter is removed first, followed by the urethral catheter 2 days later. This allows for the puncture site from the suprapubic catheter in the bladder substitute to seal. A urine sample should be sent for culture when the urethral catheter is removed. A bladder substitution is not colonized with bacteria like a urinary conduit, so any evidence of a bacteriuria or urinary tract infection must be treated. Following removal of all catheters, a quinolone antibiotic is implemented as prophylaxis for 5 days. The patient is instructed to void in a sitting position every 2 hours during the day and 3 hourly with the help
of an alarm clock at night. The normal sensory voiding reflex is lost following a cystectomy, requiring the patient to initially wake up twice at night. Using two alarm clocks allows for a less interrupted sleep. Voiding needs to occur by relaxation of the pelvic floor, followed by slight abdominal straining. This is aided by hand pressure on the lower abdomen and bending forwards. Initially, effectiveness of reservoir emptying is monitored with in-out catheterization and ultrasound to detect any postvoid residual urine. This can later then be monitored by suprapubic ultrasound alone. Effective sphincter training is taught by performing a digital rectal examination and requesting the contraction of the anal sphincter only and not the abdominal or gluteal muscles. The patient reproduces this task initially 10 times hourly, maintaining contraction for 6 seconds and as continence is achieved on a regular daily basis. This seems to build up resting tone and also with repetition, the patient learns to perform it by reflex prior to certain physical activities, thereby preventing any stress incontinence. Men may suffer from postmicturition dribble inconti-
450
Part IV Bladder
Figure 24-6 The two medial borders of the antimesenteric opened U-shaped distal ileum segment is oversewn with a single layer seromuscular running suture. The base of the “U” is folded over and tied between the two limbs of the “U” as shown by the arrow.
nence, which can be managed by instructing the patient to “milk” the urethra empty at the end of a void.23 The voiding interval is gradually increased from 2 to 4 hourly. This is performed in hourly aliquots and only when the patient remains continent for the specified time period allocated. (That is, when the patient is continent for 2 hours, the voiding period is increased to 3 hours. This is only increased to 4 hours when continence at 3 hours is achieved.) The patient must try not to void before the allotted time period even if dribble incontinence ensues. The aim is to achieve a gradually distended reservoir capacity of 500 ml, which will result in a low-pressure system and therefore continence. This can be best understood by Laplace’s law (pressure = wall tension/radius), where if the radius of the reservoir increases, the pressure will decrease. As the reservoir pressure decreases below the urethral closing pressure, continence will be attained. The time to continence depends on good counseling with regular and effective sphincter training, surgical technique where nerve preservation to the urethra and pelvic floor is achieved, and the age of the patient.
Metabolic Management As a metabolic acidosis is the commonest biochemical abnormality following a bladder substitution, the urologist, as well as the patient, should be aware of the symptoms it can cause in order to be able to rapidly implement therapy (Table 24-1). The presence of fatigue, nausea, vomiting, or epigastric burning should alert the urologist to a metabolic acidosis. H2-blockers or proton pump inhibitors should not be given for epigastric pain, as they would worsen the metabolic acidosis. The base excess is monitored with a venous blood gas analysis every second day and immediately corrected if in a negative parameter. This is performed with sodium bicarbonate 2 to 6 g/day in ileal bladder substitutions. In virtually all patients, short-term treatment of their metabolic acidosis with NaHCO3 medication will be needed. This is ceased within 3 months time, as the mucosa of the reservoir becomes more resilient to electrolyte and fluid exchange. In the early postoperative period, hypoosmolar urine remains in prolonged contact with the mucosa of the
Chapter 24 Orthotopic Bladder Substitution in the Male and Female 451
Figure 24-7 The caudal part of the reservoir is closed completely and the cranial part almost completely by a single 2-0 polyglycolic acid running seromuscular suture. A finger is introduced through the remaining opening of the reservoir and an 8- to 10-mm hole is cut into the most caudal part of the reservoir, close to the mesentery and 2 to 3 cm away from the suture edge that resulted from cross-folding the ileal segment.
Figure 24-8 The reservoir-urethral anastomosis must be flat and not funnel-shaped to prevent subsequent kinking and outlet obstruction.
452
Part IV Bladder
Figure 24-9 Six seromuscular 2-0 polyglycolic acid sutures are placed between the reservoir and the membranous urethra. These are tied after inserting an 18 F urethral catheter. The catheter is used as a track to guide the reservoir onto the urethra. Cystostomy and ureteric catheters are placed through the fat of the mesentery.
reservoir. The ileum reaches equilibrium by shifting salt (NaCl) into the reservoir and simultaneously absorbing acid (H+) in the form of ammonium into the blood stream. This will result in a hypovolemic salt loosing state with an associated metabolic acidosis.8 These patients have a rapid drop in body weight due to dehydration and anorexia. Daily body weight monitoring is essential in the postoperative recovery period. Patients need to consume 2 to 3 l of fluids per day that is supplemented with increased salt intake in their diet to combat any saltlosing syndrome.5 LONG-TERM FOLLOW-UP The successful results of ileal low-pressure orthotopic bladder substitution are not only due to the simplicity of
the operative technique but also the meticulous longterm regular follow-up that is instituted. Only this way the optimal reservoir function and prevention of potential delayed complications will be recognized and managed effectively. A suggested schema is illustrated (Table 24-2). A total of 12% of patients will have positive urinary cultures.24 Associated causes, such as postvoid residual urine, need to be identified, and presence of inguinal or abdominal hernias that can prevent adequate reservoir emptying needs to be treated. Protruding mucosa or stricture at the urethral-reservoir anastomosis may also be the factors that can be easily managed transurethrally. Diurnal continence of up to 83% in women and 90% in men with nocturnal rates over 80% at 12 months should be achieved in both sexes.15 Incontinence rates tend to increase in the absence of a nerve-sparing cystec-
Chapter 24 Orthotopic Bladder Substitution in the Male and Female 453
Figure 24-10 After cystostomy tube placement into the reservoir, the cephalad part of the pouch is closed completely; 20 F silicon drains are placed into the pelvis and near the ureteric anastomosis.
Table 24-1 Symptoms of Metabolic Acidosis Fatigue Anorexia Dyspepsia and heartburn Nausea and vomiting Weight loss
tomy, in the older patients and 5 years following a cystectomy. The incontinence is generally minimal and not debilitating with normal transurethral voiding achievable in up to 97% of patients.4 It is also important to recognize that the limited understanding of orthotopic bladder substitutions by other medical professions may result in ignorant decisions regarding patient care; therefore, direct referral or contact with the initial treating institution is recommended.
454
Part IV Bladder
Table 24-2 Follow-up Schema for Patients with Bladder Substitute Months After Surgery
3
6
12
18
24
30
36
42
48
54
60
Clinical examination
x
x
x
x
x
x
x
x
x
x
x
Urine culture
x
x
x
x
x
x
x
x
x
x
x
Body weight
x
x
x
x
x
x
x
x
x
x
x
Blood tests*
x
x
x
x
x
x
x
x
x
x
x
Folic acid, vitamin B12 Chest x-ray
x
IVU Renal ultrasound
x
x
x x
x
Bone scan (only if ≥pT3 and each N+)
x
x
Pelvic/abdominal CT-Scan (only if ≥pT3 and each N+)
x
Postvoid residual Urethral wash cytology
x
x
x
x
x
x
x
x
x
x
x
x x
x
x
x
x
x
x
x
x
x
x x
x x
x
x
x
x
x
x
x x
*Hb, Na+, K+, Cl−, bicarb., creatinine, urea, ALP, gamma GT, AST, LDH, and venous blood gas analysis.
REFERENCES 1. Hobisch A, Tosun K, Kemmler G, et al: Life after cystectomy and orthotopic neobladder versus ileal conduit urinary diversion. Semin Urol Oncol 2001; 19(1):18–23. 2. Yoneda T, Igawa M, Shiina H, Shigeno K, Urakami S: Postoperative morbidity, functional results and quality of life of patients following orthotopic neobladder reconstruction. Int J Urol 2003; 10(3):119–125. 3. Doherty A, Burkhard F, Holliger S, Studer UE: Bladder substitution in women. Curr Urol Rep 2001; 2(5):350–356 (review). 4. Madersbacher S, Möhrle K, Burkhard F, Studer UE: Long-term voiding pattern of patients with ileal orthotopic bladder substitutes. J Urol 2002; 167(5):2052. 5. Mills RD, Studer UE: Guide to patient selection and follow-up for orthotopic bladder substitution. Contemp Urol 2001; 2:35–40. 6. Skinner DG, Studer UE, Okada K, et al: Which patients are suitable for continent diversion or bladder substitution following cystectomy or other definitive local treatment? Int J Urol 1995; 2(Suppl):105. 7. Studer UE, Burkhard F, Danuser HJ, Thalmann G: Keys to success in orthotopic bladder substitution. Can J Urol 1999; 6(5):876. 8. Mills RD, Studer UE: Metabolic consequences of continent urinary diversion. J Urol 1999; 161:1057–1066.
9. Hofmann AF: Bile acid malabsorption caused by ileal resection. Arch Intern Med 1972; 130:597. 10. Proano M, Camilleri M, Phillips SF, Brown ML, Thomford GM: Transit of solids through the human colon: regional quantification in the unprepared bowel. Am J Physiol 1990; 258(6 Pt 1):G856–G862. 11. Freeman JA, Thomas A, Esrig D, et al: Urethral recurrence in patients with orthotopic ileal neobladders. J Urol 1996; 156(5):1615–1619. 12. Yossepowitch O, Dalbagni G, Golijanin D, et al: Orthotopic urinary diversion after cystectomy for bladder cancer: implication for cancer control and patterns of disease recurrence. J Urol 2003; 169(1):177–181. 13. Hautmann RE, Miller K, Steiner U, Wenderoth U: The ileal neobladder: 6 years of experience with more than 200 patients. J Urol 1993; 150(1):40–45. 14. Studer UE, Danuser H, Hochreiter W, et al: Summary of 10 years’ experience with an ileal low-pressure bladder substitute combined with an afferent tubular isoperistaltic segment. World J Urol 1996; 14:29–39. 15. Turner WH, Danuser H, MoehrleK, Studer UE: The effect of nerve sparing cystectomy technique on postoperative continence after orthotopic bladder substitution. J Urol 1997; 156(6):2118. 16. Hugonnet CL, Danuser HJ, Springer JP, Studer UE: Urethral sensitivity and the impact on urinary continence
Chapter 24 Orthotopic Bladder Substitution in the Male and Female 455
17. 18.
19.
20.
21.
in patients with an ileal bladder substitute after cystectomy. J Urol 2001; 165:1502–1505. Burkhard FC, Studer UE: Orthotopic bladder substitution. Curr Opin Urol 2000; 10(4):343–349. Borirakchanyavat S, Aboseif SR, Carroll PR, Tanagho EA, Lue TF: Continence mechanism of the isolated female urethra: an anatomical study of the intrapelvic somatic nerves. J Urol 1997; 158(3 Pt 1):822—826. Mills RD, Studer UE: Female orthotopic bladder substitution: a good operation in the right circumstances. J Urol 2000; 163(5):1501–1504. Doherty A, Burkhard F, Holliger S, Studer UE: Bladder substitution in women. Curr Urol Rep 2001; 2(5):350–356. Thoeny HC, Sonnenschein MJ, Madersbacher S, Vock P, Studer UE: Is ileal orthotopic bladder substitution with
an afferent tubular segment detrimental to the upper urinary tract in the long term? J Urol 2002; 168(5):2030–2034. 22. Studer UE, Siegrist T, Casanova GA, et al: Ileal bladder substitute: antireflux nipple or afferent tubular segment? Eur Urol 1991; 20(4):315–326. 23. Bader P, Hugonnet CL, Burkhard F, Studer UE: Inefficient urethral milking secondary to urethral dysfunction as an additional risk factor for incontinence after radical prostatectomy. J Urol 2001; 166(6):2247–2252. 24. Varol C, Burkhard FC, Thalmann GN, Studer UE: Urethral recurrence following cystectomy for bladder cancer; prevention and detection in patients with orthotopic bladder substitutes. J Urol 2003; 169(Suppl 4):103.
C H A P T E R
25 Cancer of the Prostate: Detection and Staging Anthony V. D’Amico, MD, PhD, and Michael W. Kattan, PhD
The goal of a staging system is to predict cancer-specific survival as accurately as possible using readily available pretreatment parameters. These parameters define stages that correspond to rates of disease-specific survival following standard therapy that increase in a clinically significant manner as the clinical stage decreases. Validated algorithms1–3 currently exist that provide accurate estimates of prostate-specific antigen (PSA) failure based on pre-treatment clinical parameters following surgery or radiation therapy (RT) for patients with clinically localized disease. However, PSA failure may not translate into death from prostate cancer for all patients because men with prostate cancer are generally over the age of 60 and often have competing causes of mortality.4 Therefore, current efforts are aimed at defining a staging system based on pretreatment factors that accurately represent rates of prostate cancer-specific mortality (PCSM) following current standard therapies. AMERICAN JOINT COMMISSION ON CANCER STAGING SYSTEM Historically, staging defines the anatomic extent of a disease and tumor volume remains the most important single determinant of prognosis for many cancers. The current 2002 American Joint Commission on Cancer (AJCC) staging system5 for patients with adenocarcinoma of the prostate is based solely on the findings of the digital rectal examination (DRE) or transurethral resection of the prostate (TURP). However, the introduction of the serum PSA has changed the presentation of prostate cancer worldwide. The vast majority of patients now present with nonpalpable PSA detected (i.e., clinical category T1c) disease.6 By grouping most of today’s patients into a single T1c-category, the 2002 AJCC stag-
ing system is limited in its ability to stratify patients into clinically distinct groups based on cancer-specific outcomes. PROGNOSTIC FACTORS Combined Modality Staging Prior studies1,2 have confirmed that the serum PSA level, 2002 AJCC clinical T-category, and biopsy Gleason score are independent predictors of time to PSA failure following either radical prostatectomy (RP) or external beam RT. Combined modality staging was developed to utilize these independent and clinically significant predictors of PSA outcome following definitive therapy to define prognostic groups. Risk groups based on the PSA, biopsy Gleason score, and the 2002 AJCC clinical T-category that stratify the risk of PSA failure following RP or RT are illustrated in Figures 25-1 and 25-2, respectively.3 This risk stratification algorithm, which was originally defined based on PSA failure rates, has also been shown to stratify time to PCSM following RT using simply the PSA and biopsy Gleason score as illustrated in Figure 25-3.7 Recently, a fourth parameter, the percent positive prostate biopsies, has been shown in a validated prognostic factor analysis to provide clinically useful information regarding PSA outcome following either RP8 or external beam RT9 for intermediate risk patients as shown in Figures 25-4 and 25-5, respectively. This parameter has also been shown to be predictive of time to PCSM following RT10 in the intermediate risk group, forming the basis for a 2-tiered risk group stratification as shown in Figure 25-6. Molecular markers (such as p53, bcl-2, Ki-67, and c-erb-b2), neuroendocrine markers (such as neuron-specific enolase and chromogranin A), histopathologic markers
459
Prostate cancer specific survival
100 90 % bNED Survival
80 70 60 50 40 30
Low risk Intermediate risk High risk
20 10 0 0
1
2
3
4
5
6
7
8
9
100 90 80 70 60 50 40 30
Low risk Intermediate risk High risk
20 10 0
10
0
2
1
3
Time in years 1020 693 414
704 407 198
422 203 91
4
5
6
7
8
9
10
15 12 12
4 4 7
2 3 5
1 3 4
Time in years
156 99 35
51 29 9
110 106 92 72 56 155 147 125 93 66 150 144 130 107 71
13 6 1
Number at risk
38 44 49
28 25 28
Number at risk
Figure 25-1. Prostate-specific antigen outcome following radical prostatectomy stratified by the pretreatment risk group for patients with clinically localized disease. Low risk: PSA ≤ 10 ng/ml and biopsy Gleason ≤ 6, and 2002 AJCC category T1c or T2a. Intermediate risk: PSA > 10 to 20 ng/ml or biopsy Gleason 7 or 2002 AJCC category T2b. High risk: PSA > 20 ng/ml or biopsy Gleason 8 to 10 or 2002 AJCC category T2c.
Figure 25-3. Prostate cancer-specific survival following external beam radiation therapy stratified by the pretreatment risk group for patients with clinically localized disease. Low risk: PSA ≤ 10 ng/ml and biopsy Gleason ≤ 6. Intermediate risk: PSA > 10 to 20 ng/ml or biopsy Gleason 3 + 4. High risk: PSA > 20 ng/ml or biopsy Gleason ≥ 4 + 3.
100 90 100 90
70 60
80
50
% bNED survival
PSA 0utcome
80
40 30
Low risk Intermediate risk High risk
20 10 0 0
1
2
3
4
5
6
7
8
9
10
5 4 8
3 3 3
3 2 1
2 1 1
Time in years 90 88 70 46 173 167 112 69 118 115 83 47
34 45 30
26 24 18
16 10 14
Number at risk Figure 25-2. Prostate-specific antigen outcome following external beam radiation therapy stratified by the pretreatment risk group for patients with clinically localized disease. Low risk: PSA ≤ 10 ng/ml and biopsy Gleason ≤ 6, and 2002 AJCC category T1c or T2a. Intermediate risk: PSA > 10 to 20 ng/ml or biopsy Gleason 7 or 2002 AJCC category T2b. High risk: PSA > 20 ng/ml or biopsy Gleason 8 to 10 or 2002 AJCC category T2c.
70 60 50 40 30
< 34% 34−50% > 50%
20 10 0 0
1
2
3
4
5
6
7
109 19 12
79 13 7
153 7 4
Time in years 366 150 163
309 99 104
259 75 69
201 51 44
149 31 23
Number at risk Figure 25-4. Prostate-specific antigen outcome following radical prostatectomy stratified by the percent of positive prostate biopsies for intermediate-risk patients with clinically localized disease.
Prostate cancer-specific survival (%)
Chapter 25 Cancer of the Prostate: Detection and Staging 461
100 90 % bNED survival
80 70 60 50 40 30
< 34% 34−50% > 50%
20 10 0 0
1
2
3
4
5
100 90 80 70 60 50 40 30
Iog rank p < 0.0001 Low + Int 50% High + Int > 50%
20 10 0 0
1
2
83 45 59
50 23 36
24 6 16
4
5
6
7
8
9 10 11 12
Time in years
Time in years 96 49 62
3
12 4 8
8 3 3
206 175
155 153
79 89
37 38
6 12
13 3
Number at risk Number at risk Figure 25-5. Prostate-specific antigen outcome following external beam radiation therapy stratified by the percent of positive prostate biopsies for intermediate-risk patients with clinically localized disease.
(such as microvessel density and ploidy), imaging approaches (such as color Doppler), PSA derivatives (such as PSA velocity, PSA density, and free PSA), and reverse transcriptase polymerase chain reaction (rtPCR) to examine PSA-expressing cells in the peripheral blood, bone marrow, and pelvic lymph nodes all have been examined11–15 to assess their ability to predict PSA outcome following definitive local therapy for patients with clinically localized disease. While many of these factors have been predictive of PSA outcome on univariable analysis, they await testing in a multivariable model that accounts for the established prognostic factors to determine their clinical significance. Radiologic Staging The ability of computerized tomography, pelvic coil magnetic resonance imaging (MRI), and transrectal ultrasound (TRUS) to identify extracapsular extension (ECE) and/or seminal vesicle invasion (SVI) for patients with clinically localized disease based on the DRE is limited. The accuracy of these studies does not exceed 60%,16,17 and therefore none of these studies is recommended for staging patients with clinical stage T1 or stage T2 disease. Patients with more advanced disease (stage T3 or stage T4) as determined by DRE should have a computed tomographic (CT) scan or MRI scan of the pelvis to assess
Figure 25-6. Prostate cancer-specific survival following external beam radiation therapy stratified by the percent of positive prostate biopsies for intermediate-risk patients with clinically localized disease.
for pelvic lymphadenopathy. A bone scan is generally recommended to identify metastatic disease and is indicated for patients with either clinical stage T3 or stage T4 disease, biopsy Gleason score of 4 + 3 or higher, a PSA level greater than 20 ng/ml, or clinical symptoms. The role of endorectal MRI (erMRI) has been evaluated for patients with clinical stage T1c or stage T2 disease to assess whether information regarding pathologic stage and PSA outcome following RP was provided.18 In experienced hands, the erMRI finding of T3 versus T2 disease was 80% accurate in predicting pathologic stage. However, the erMRI did not add clinically meaningful information for the vast majority of the patients (low risk and high risk) after accounting for the pretreatment PSA level, biopsy Gleason score, clinical T-category, and the percent positive prostate biopsies. In the intermediate risk patients, however, the erMRI provided a clinically relevant stratification of 5-year PSA outcome as shown in Figure 25-7. At present, however, outside of high risk localized of locally advanced prostate cancer, imaging of the pelvis with erMRI to assess for evidence of pelvic lymphadenopathy or evidence of ECE or SVI remains under investigation. Pretreatment Nomograms A popular tool for predicting outcomes in prostate cancer is the nomogram. Strictly speaking, a nomogram is a series of lines with point values, which one manipulates
462
Part V Prostate Gland and Seminal Vesicles
nomograms have been developed and validated for predicting biochemical failure for patients treated with surgery, brachytherapy, and external beam RT.3,21–7 They are presented in Figures 25-8 to 25-10. They predict biochemical failure, and future nomograms are necessary for predicting more distant and clinically relevant endpoints, such as metastasis and death. These prediction models are available in software for the palm and desktop computers from http://www.nomograms.org.
100 90 % bNED Survival
80 70 60 50 40 30
MR T2 MR T3
20
SUMMARY
10 0 0
1
2
3
4
5
46 4
28 4
The 2002 AJCC staging system is limited in its ability to provide accurate information regarding time to PCSM for individual patients who present with the most common clinical category of T1c disease. However, algorithms for predicting PSA outcome following RP or external beam RT that are based on pretreatment clinical parameters that include the PSA level, biopsy Gleason score, and 2002 AJCC clinical T-category have been validated.1–3 Nevertheless, given the competing causes of mortality that exist in men undergoing definitive treatment for localized prostate cancer, many men who sustain PSA failure will not live long enough to develop clinical evidence of distant disease and far fewer will die from the disease. Although pretreatment riskbased staging systems predicting the endpoint of PCSM7,26 have been published, none has been validated in the PSA era. Studies are currently ongoing to define a validated pretreatment staging system that can accurately predict time to PCSM following surgery or RT for prostate cancer.
Time in years 162 29
137 19
100 14
64 4
Number at risk Figure 25-7. Prostate-specific antigen outcome following radical prostatectomy stratified by the erMRI T-category for intermediate-risk patients with clinically localized disease.
by drawing straight lines to obtain a prediction.19 The term is attributed to Professor Maurice d’Ocagne in 1889.20 The primary advantage of nomograms, relative to other paper-based approach, such as tables, is that nomograms maintain a continuous prediction model, resulting in greater predictive accuracy. Pretreatment
Preoperative nomogram for PSA recurrence Points PSA
0
10
20
40
50
60
1
23 4 6 7 8 9 101 2
T2c
T3a
0.1 T2a
30
70
80
90
100
16 20 30 45 70 110
Clinical stage T1c
T1ab T2b 2+3 3+2
Biopsy gleason sum
2+2
3+3
4+ 3+4
Total points 0
20
40
60
80
100
120
140
160
180
200
60-month recurrence free prob. .96
.93 .9 .85 .8
.7 .6 .5 .4 .3 .2 .1 .05
Figure 25-8. Pretreatment nomogram for patient considering surgery. (Adapted with permission from Kattan MW, Eastham JA, Stapleton AMF, et al: J Natl Cancer Inst 1998; 90(10):766–771.)
Chapter 25 Cancer of the Prostate: Detection and Staging 463
3D conformal radiation therapy nomogram for PSA recurrence 0
Points
10
20
30
40
50
60
70
80
4
5 6 7
910
90
100
Pretreatment PSA 0.3
1 T2a T3ab T3c
2
3
80
100
25 50 100
Clinical stage T1c
T2b T2c
357
9
Bx. gleason sum 24 6
Dose (Gy)
8
10
86.4 72 No
68 64.8
Hormones Yes
Total points 0
20
40
60
120
140
160
180
60 month Rec. free prob. 0.99
0.98 0.95
0.9
0.8 0.7 0.5 0.3 0.1 0.01
Figure 25-9. Pretreatment nomogram for patient considering external beam radiation. (Adapted with permission from Kattan MW, Zelefsky, Kupelian PA, et al: J Clin Oncol 2000; 18:3352–3359.
Brachytherapy nomogram for PSA recurrence 0
10
20
30
40
50
60
70
80
90
100
Points 0.8
Pretreatment PSA 0.6
1
42
2
3
4 5 6
8 10
15 20
30 40
60 80 100
7
Biopsy GI.Sum 536
8 T2a
97 clinical stage T2b T1c No
XRT
Yes
Total points 0
10
20
30
40
50
60
70
80
90 100 110 120 130
60-month Rec. free prob. 0.99
0.98
0.96 0.93 0.9
0.8 0.7 0.6 0.5 0.4 0.25 0.12
Figure 25-10. Pretreatment nomogram for patients considering brachytherapy. (Adapted with permission from Kattan MW, Potters, L, Blasko JC, et al: Urology 2001; 58(3):393–399.)
464
Part V Prostate Gland and Seminal Vesicles
REFERENCES 1. Kattan MW, Eastham JA, Stapleton AMF, Wheeler TM, Scardino PT: A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. JNCI 1998; 90:766–771. 2. D’Amico AV: Combined-modality staging for localized adenocarcinoma of the prostate. Oncology 2001; 15:1049–1059. 3. Graefen M, Karakiewicz PI, Cagiannos I, et al: A validation of two preoperative nomograms predicting recurrence following radical prostatectomy. Urol Oncol 2002; 7:141–146. 4. From the National Center for Health Statistics: National Vital Statistics 2002; 50:1–120. 5. Greene FL, Page DL, Fleming ID, et al: American Joint Committee on Cancer, Manual for staging cancer, 6th edition, pp 337–346. New York, Springer, 2002. 6. Catalona WJ, Smith DS, Ratliff TL, Basler JW: Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993; 270:948–954. 7. D’Amico AV, Cote K, Loffredo M, Renshaw AA, Chen MH: Pre-treatment predictors of time to cancer specific death following prostate specific antigen failure. J Urol 2003; 169(4):1320–1324. 8. D’Amico AV, Whittington R, Malkowicz SB, et al: Clinical utility of the percentage of positive prostate biopsies in defining biochemical outcome after radical prostatectomy for patients with clinically localized prostate cancer. J Clin Oncol 2000; 18:1164–1172. 9. D’Amico AV, Schultz D, Silver B, et al: The clinical utility of the percent positive prostate biopsies in predicting biochemical outcome following external beam radiation therapy for patients with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2001; 49:679–684. 10. D’Amico AV, Keshaviah A, Manola J, et al: The clinical utility of the percent of positive prostate biopsies in predicting prostate cancer specific and overall survival following radiation therapy for patients with localized prostate cancer. Int J Radiat Oncol Biol Phys 2002; 53:581–587. 11. Ismail MT, Petersen RO, Alexander AA, Newschaffer C, Gomella LG: Color Doppler imaging in predicting the biologic behavior of prostate cancer: correlation with disease-free survival. Urol 50:906–912. 12. Yang RM, Naitoh J, Murphy M, et al: Low P27 expression predicts poor disease-free survival in patients with prostate cancer. J Urol 1998; 159:941–945. 13. Stapleton AM, Zbell P, Kattan MW, et al: Assessment of the biologic markers p53, Ki-67, and apoptotic index as
14.
15.
16.
17.
18.
19. 20. 21.
22.
23.
24.
25.
26.
predictive indicators of prostate carcinoma recurrence after surgery. Cancer 1998; 82:168–174. Waltregny D, de Leval L, Menard S, de Leval J, Castronovo V: Independent prognostic value of the 67-kd laminin receptor in human prostate cancer. J Natl Cancer Inst 1997; 89:1224–1228. Berruti A, Dogliotti L, Mosca A, et al: Circulating neuroendocrine markers in patients with prostate carcinoma. Cancer 2000; 88:2590–2597. Platt JF, Bree RL, Schwab RE: The accuracy of CT in the staging of prostatic carcinoma. Am J Radiol 1987; 149:315–321. Rifkin MD, Zerhouni A, Gatsonis CA, et al: Comparison of magnetic resonance imaging and ultrasonography in staging early prostate cancer. Results of a multi-institutional cooperative trial. NEJM 1990; 323:621–629. D’Amico AV, Whittington R, Malkowicz SB, et al: Endorectal magnetic resonance imaging as a predictor of biochemical outcome following radical prostatectomy for men with clinically localized prostate cancer. J Urol 2000; 164:759–763. Hankins TL: Blood, dirt and nomograms. Hist Sci Soc 1999; 90:50–80. Banks J. Nomograms, Vol 6. New York, Wiley, 1985. Kattan MW, Eastham JA, Stapleton AMF, Wheeler TM, Scardino PT: A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 1998; 90(10):766–771. Kattan MW, Potters L, Blasko JC, et al: Pretreatment nomogram for predicting freedom from recurrence after permanent prostate brachytherapy in prostate cancer. Urology 2001; 58(3):393–399. Kattan MW, Zelefsky MJ, Kupelian PA, et al: Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer. J Clin Oncol 2000; 18:3352–3359. Graefen M, Karakiewicz P, Cagiannos I, et al: A validation of two preoperative nomograms predicting recurrence following radical prostatectomy in a cohort of European men. Urol Oncol 2002; 7(4):141–146. Graefen M, Karakiewicz PI, Cagiannos I, et al: International validation of a preoperative nomogram for prostate cancer recurrence following radical prostatectomy. J Clin Oncol 2002; 20(15):3206–3212. Roach M, Lu J, Pilepich MV, et al: Four prognostic groups predict long-term survival from prostate cancer following radiotherapy alone on radiation therapy oncology group clinical trials. Int J Radiat Oncol Biol Phys 2000; 47:609–615.
C H A P T E R
26A Clinically Localized (Stage T1a-T2c) Adenocarcinoma of the Prostate: Surgical Management and Prognosis Maxwell V. Meng, MD, and Peter R. Carroll, MD
Prostate cancer remains a major health concern in the U.S. and throughout the world. The institution of screening protocols, based on the combination of digital rectal examination and serum prostate specific antigen (PSA) testing, has increased the opportunity for cancer cure by allowing earlier diagnosis at lower stages of disease. Over the past decade, advances in both surgical and therapeutic radiation therapy techniques have revolutionized the ability to adequately treat prostate cancer while simultaneously reducing treatment-related morbidity. This chapter focuses on the management and outcomes of patients with clinically localized (stages T1a to T2c) cancer of the prostate. RADICAL PROSTATECTOMY Rationale for Treatment Proponents of screening for prostate cancer cite the disease prevalence and mortality, ability to effectively treat localized cancers, and inability to cure metastatic disease as compelling reasons for this practice.1 Despite the numerous factors supporting early prostate cancer detection, controversy continues to surround the need for, and specific choice of, intervention.2 This is particularly true for radical prostatectomy. Definitive surgery is not only curative for most organ-confined tumors (stages T1 to T2) but is also associated with limited morbidity and is amenable to selective use with adjuvant therapy in high-risk patients. Nevertheless, the potential for operative and postoperative morbidity exists and surgery may not be necessary in men with lower-risk disease who may be candidates for surveillance alone.
Natural History of Prostate Cancer Ultimately, the role and necessity of surgical removal of the prostate from men with cancer can only be determined in appropriately designed clinical trials. The most relevant endpoint of these studies is the impact of prostatectomy on overall survival. Prior published reports evaluating various prostate cancer treatments are not applicable to contemporary patients. Currently, there are several ongoing randomized trials seeking to compare active therapy with watchful waiting.3 The results of a recent study from the Scandinavian International Union against Cancer provide evidence that radical prostatectomy significantly reduces disease-specific mortality.4 A total of 695 men with clinical stages T1b, T1c, or T2 prostate cancer were randomized to either watchful waiting or prostatectomy. During a median follow-up of 6.2 years, there was no difference between the two groups with respect to overall survival; however, death due to prostate cancer in the surveillance cohort (8.9%) was greater than that observed in the surgery cohort (4.6%, p = 0.02). In addition, men after surgery had a lower risk of distant metastases (hazard ratio 0.63). Although there was no reduction in overall mortality, a difference is likely to be noted with longer follow-up given the significant reduction in metastases in those managed with surgery. This important study supports the utility of early detection and treatment of prostate cancer in selected patients. Although it appears that surgery for localized prostate cancer impacts disease-specific outcomes, the rational selection of therapy remains complex, and examination of other data provides information regarding the natural history of untreated prostate cancer. Chodak et al.5 analyzed the pooled data of 823 men (cT1-2) from six
465
466
Part V Prostate Gland and Seminal Vesicles
nonrandomized studies treated prior to the era of PSA testing. The risk of metastases was significant and dependent on tumor grade—2.1% per year, 5.4% per year, and 13.5% per year for well differentiated, moderately differentiated, and poorly differentiated tumors, respectively. At 15 years, the fraction of patients with metastatic disease was 40%, 70%, and 85% in these groups, respectively (Table 26A-1). Albertsen et al.6 analyzed the long-term outcome of 451 men with clinical stage T1-2 tumors managed with immediate or delayed hormonal therapy. Again, tumor grade was the important factor determining patient outcome. The cancer-specific mortalities in men with Gleason sums 2 to 4, 5 to 7, and 8 to 10 were 9%, 28%, and 51%, respectively. Overall, 46% of men treated expectantly living 15 years or more will die of prostate cancer and lose approximately one-third of their remaining life expectancy, even at older age of diagnosis (i.e. >75 years).6,7 Fleming et al.8 attempted to address questions regarding the selection of surveillance or definitive therapy using decision analysis. In their Markov model, they incorporated estimates of progression to metastatic disease with watchful waiting from review of the literature, efficacy of radical prostatectomy based on pathologic stage, and arbitrary reductions in survival after surgery due to impact on quality of life to determine which strategy resulted in a greater survival advantage. Based on the data selected for their model, the authors reported that surgical intervention for prostate cancer provided limited benefit to the patient, relative to expectant management, with well-differentiated tumors. In men with moderate or poorly differentiated tumors, they stated that treatment offered less than 1-year improvement in qualityadjusted life expectancy in those men 60 to 65 years old and that treatment was harmful in men over age 70. Thus, they conclude that selection of watchful waiting in men with localized prostate cancer is a feasible alternative to radical prostatectomy. Application of the model by other investigators, using other estimates of disease progression and efficacy of treatment, resulted in much different results. Beck et al.9 utilized progression data from Table 26A-1 Development of Metastases in Men with Localized Prostate Cancer Treated Conservatively PERCENT Histologic Grade
WITH
METASTASES
10 Years
15 Years
1
19
40
2
42
70
3
74
85
From Chodak GW, Thisted RA, Gerber GS, et al: N Engl J Med 2002; 330: 781–789.
the work of Chodak et al. and calculated survival benefit from surgery. In contrast to the study of Fleming et al., the estimated survival advantage in men with well differentiated, moderately differentiated, and poorly differentiated tumors increased to 1.0, 2.4, and 2.7 years, respectively. Selection of Patients for Radical Prostatectomy Despite the disparate result of the various publications and controversy regarding the “best” treatment, it is clear that selection of therapy needs to be based on several patient and tumor factors. In general, radical prostatectomy is considered in men with a life expectancy greater than 10 years, a duration during which an untreated cancer may progress and/or metastasize. In addition, the patients should be free of serious comorbidities and be able to tolerate a major operation. With respect to cancer variables, the tumor should be both clinically significant and at a stage where surgical extirpation is likely to be curative. These aspects of tumor behavior and biology are often difficult to assess based on traditional measures, such as digital rectal examination, serum PSA, and Gleason grade. Thus, more accurate determinations of outcome have been developed and are currently commonly applied to aid in the appropriate selection of men for radical prostatectomy, as well as other definitive treatments. Pretreatment Risk Stratification The most commonly used risk assessment criteria include serum PSA, clinical tumor stage (T stage), and Gleason grade on biopsy. Recently, the extent of disease, assessed by systematic biopsy (e.g., percent positive biopsies), has been shown to have prognostic significance and such information may be incorporated into the assessment of pretreatment risk. In general, the role of imaging modalities, such as transrectal ultrasonography, computed tomography (CT), and magnetic resonance imaging/spectroscopy, is limited in initial risk stratification, except in those with advanced disease. Due to widespread screening efforts, men are increasingly diagnosed with early stage disease (i.e., T1c). The risk for disease recurrence after radical prostatectomy increases with higher clinical stage. In men with stage T1c, 5-year PSA-free survival after radical prostatectomy is greater than 85%, while those with palpable but localized (cT2) have disease-free rates between 70% and 80%.10 Serum PSA levels can vary within any clinical stage but usually correlate with tumor volume and, therefore, pathologic stage and outcome after surgery. As reported by Ohori and Scardino,11 progression-free survival 5 years after prostatectomy in men with PSA ≤ 4.0 ng/ml, 4.1 to 10 ng/ml, 10.1 to 20 ng/ml, and >20 ng/ml was 94%, 85%, 66%, and 38%, respectively. These values are
Chapter 26A Clinically Localized (Stage T1a-T2c) Adenocarcinoma of the Prostate 467
comparable to those reported by others. In the study from Catalona et al.,12 7-year progression-free survival was 93% in men with serum PSA ≤ 2.5 ng/ml, 80% with PSA 2.5 to 4.0 ng/ml, 76% with PSA 4.1 to 10 ng/ml, and 40% with PSA >10 ng/ml. Walsh et al.13,14 reported 10-year rates of 87%, 75%, 30%, and 28% for PSA groups of <4 ng/ml, 4.1 to 10 ng/ml, 10.1 to 20 ng/ml, and >20 ng/ml, respectively. Gleason grade, as determined by biopsy, is a significant predictor of outcomes after radical prostatectomy. With increasing tumor grade, the likelihood of disease recurrence increases. Five and 10-year disease-free survival in patients with Gleason sum 2 to 4 are approximately 90% but drop to approximately 60% for those men with sum of 7. Over half of men with Gleason sum 8 to 10 will develop PSA recurrence at 5 years.10 In addition to clinical factors, pathologic information obtained from the prostatectomy specimen can provide prognostic information. This includes variables, such as pathologic stage, total tumor volume, surgical margin status, and tumor grade in the specimen. The development of predictive nomograms and models has allowed the prediction of both pathologic stage and clinical outcome (i.e., PSA-free survival), based on standard pretreatment variables, and may increase the accuracy of risk assessment over the use of clinical stage, PSA level, and Gleason score alone.15–17 The nomograms published by Partin et al.18 predict the pathologic stage of disease, thus helping one decide the role of surgery based on the categorical estimation of organ-confined, established capsular penetration, seminal vesical invasion, and lymph node involvement.15,16 In applying the Partin nomograms, it is important to point out that adverse pathologic features alone, such as seminal vesicle invasion or extracapsular disease, may not preclude surgical therapy. From the experience of Catalona et al.,12 over 70% of patients with unconfined disease and 35% of those with seminal vesicle invasion have long-term (10 years) cancer-free survival with prostatectomy alone (no adjuvant therapy). Kattan and colleagues, rather than estimating pathologic stage as an outcome, created a continuous scale, based on PSA, clinical stage, and Gleason grade, to calculate the probability that a patient remains free of biochemical recurrence at 5 years after surgery.17 They have created a similar postoperative nomogram, predicting freedom from progression 7 years after surgery based on PSA, Gleason sum in the prostatectomy specimen, and individual pathologic features.19 These models can be easily applied in the clinical setting using a web-based (www.mskcc.org/nomograms/prostate) or computer calculation. In order to simplify pretreatment risk stratification, a three-group system has been developed based on PSA, clinical stage, and biopsy Gleason score. One that is commonly applied categorizes patients as low-risk patients
(cT1c or T2a and Gleason sum 2 to 6 and PSA <10 ng/ml), intermediate-risk (cT2b, Gleason sum 7, or PSA 10 to 20 ng/ml), or high-risk (cT2c or Gleason sum 8 to 10 or PSA >20 ng/ml).20 In low-risk patients, it should be mentioned that excellent outcomes might be achieved with a variety of modalities, including watchful waiting in selected patients. Although progression occurs slowly within this population, eventual active treatment is likely in men who are young or have elevated PSA levels.21 High-risk patients can undergo radical prostatectomy with acceptable morbidity and reasonable rates of local control; however, long-term cure is less likely and if surgery is selected, the patient must realize that adjuvant or secondary treatment may be necessary. Although categorization of patients into fewer (e.g., 3 or 4) risk groups simplifies the situation, it is important to point out that prognostic power can be reduced. This is particularly true for those patients with intermediate- and high-risk disease, where significant overlap occurs and discrimination of clinical outcome is less accurate.22,23 The development of additional models incorporating novel and/or molecular determinants of tumor behavior will allow identification of patients most likely to benefit from prostatectomy, as well as those who may benefit from adjuvant treatments. Pelvic Lymph Node Dissection Contemporary series of patients undergoing radical prostatectomy demonstrate that the risk of pelvic lymph node metastases is low, typically between 4% and 9%.24,25 This is largely due to the earlier detection of cancers at lower stage, as well as the refined selection of patients undergoing surgery with reduced likelihood of nodal involvement. Thus, pelvic lymphadenectomy may not be routinely indicated for all patients undergoing radical prostatectomy. However, the detection of positive lymph nodes provides important prognostic information and should be performed in those patients at higher risk, as determined by nomogram or risk-group stratification. Traditionally, it was thought that all patients with lymph node metastases experience recurrence after prostatectomy and therefore identification would spare patients an ineffective, and potentially morbid, operation. Recent data question the paradigm and may renew interest in both pelvic lymphadenectomy and more aggressive surgical therapy. In addition, at the time of radical retropubic prostatectomy, the pelvic lymph nodes are easily accessible and removal can be performed with minimal morbidity; in general, unless the lymph nodes appear grossly involved, frozen section analysis is unnecessary. Heidenreich et al.26 extended the boundaries of the pelvic lymphadenectomy in 103 patients, including the external and internal iliac, obturator, common iliac, and presacral lymph nodes. They found a high rate of nodal
468
Part V Prostate Gland and Seminal Vesicles
metastases (26%) in patients undergoing increased sampling, suggesting that if lymph nodes are to be sampled, the standard limits may be inadequate. Nearly all men with proven pelvic lymph node metastases will have biochemical relapse with 5 to 7 years after surgery. Thus, radical prostatectomy with distant disease has been avoided because of limited benefit to the patient. In a retrospective, nonrandomized study, Cadeddu et al.27 compared 10-year survival in men with proven lymph node involvement who did and did not undergo radical prostatectomy. Overall, men fared better if the prostate had been removed and there was a suggestion of improved survival in this cohort. Similarly, Ghavamian et al.28 demonstrated an overall survival advantage at 10 years in men with pTxN+ prostate cancer undergoing prostatectomy and orchiectomy, compared with those with orchiectomy alone. More recently, data from Messing et al.29 indirectly address this question. In a prospective randomized trial of 98 men undergoing radical prostatectomy and pelvic lymph node dissection, an improvement in survival was observed in men receiving immediate hormonal therapy for microscopic lymph node disease compared to those men receiving delayed hormonal therapy at the time of disease progression. This difference, at a median follow-up of 7.1 years, was statistically significant ( p = 0.02) with 77% of men in the immediate-therapy group alive without disease at last
evaluation. Not only does this support the concept of immediate androgen deprivation in those men with node-positive prostate cancer but also raises the issue of whether complete excision via prostatectomy and lymph node dissection plays a role in improving cancer outcomes even in those with regional metastases. Results of Radical Prostatectomy The techniques of radical retropubic and perineal prostatectomy are covered elsewhere in this book. Therefore, we describe cancer outcomes and morbidity related to such surgery in this section. Due to an improved understanding of periprostatic anatomy, increased surgeon experience, and refinement in anesthesia and perioperative patient care, morbidity from prostatectomy has been reduced from that seen in previous decades. Early and Intraoperative Complications Table 26A-2 summarizes perioperative data from contemporary series of patients undergoing radical retropubic prostatectomy. Operative mortality, defined as death within 30 days of surgery is exceedingly rare (<0.3%) but is more common with increasing age and comorbidity.30,32,35–38 In the 2001 report from Lepor et al.,32 a single death occurred in 1000 consecutive operations
Table 26A-2 Perioperative Morbidity and Mortality of Radical Retropubic Prostatectomy
Complication
Washington University (n = 1870)30
Mayo Clinic (n = 1000)31
NYU (n = 1000)32
Toulouse (n = 620)33
Baylor (n = 472)34
Number
Number
Number %
Number %
Number %
%
%
Mortality
3
0.2
0
0
1
0.1
1
0.2
2
0.4
Rectal injury
3
0.2
6
0.6
5
0.5
3
0.5
3
0.6
Colostomy
—
—
0
0
0
0
—
—
0
0
Ureteral injury
—
—
—
—
1
0.1
0
0
1
0.2
Myocardial infarction
9
0.7
7
0.7
5
0.5
1
0.2
2
0.4
Pulmonary embolism
22
1.7
6
0.6
2
0.2
5
0.8
5
1
DVT
8
0.6
14
1.4
2
0.2
14
2.3
6
1.3
Sepsis
—
—
—
—
—
—
1
0.2
3
0.6
Wound problem
17
1.3
9
0.9
9
0.9
6
1
14
2.9
Lymphocele
—
—
—
—
1
0.1
14
2.3
10
2.1
Anastomotic stricture
—
—
87
8.7
—
—
3
0.5
42
9.0
Chapter 26A Clinically Localized (Stage T1a-T2c) Adenocarcinoma of the Prostate 469
(0.1%). The perioperative mortality rate at UCSF is 0.13%. Similarly, complications, including myocardial infarction (0.1% to 0.4%), deep venous thrombosis (1.1%), and pulmonary embolism (0.75%) are less frequent with modern perioperative care and are likely to decline further with continued experience and refinements in technique.30,32,36,37 Begg et al.39 examined variations in morbidity after prostatectomy using the SEER-Medicare database. In examining the record of 11,522 patients who underwent prostatectomy, neither hospital volume nor surgeon volume was significantly associated with surgery-related death. However, postoperative morbidity, as well as late urinary complications (stricture or fistula), was lower when surgery was performed in very-high-volume hospitals ( p = 0.03) and by very-high-volume surgeons ( p < 0.001). The most common intraoperative problem is hemorrhage. Significant variations in the estimated blood loss
and need for blood transfusion have been reported, with the perineal approach associated with lower reported values (Tables 26A-3 and 26A-4).28,29,35,38 In general, the average blood loss in recent series is less than 1000 ml and the use of nonautologous blood transfusion is less than 5%; our experience with current mean blood loss and transfusion rate is 486 ml and 1%, respectively, in our last 400 patients. However, the individual surgeon or institutional experience dictates the need to donate autologous blood. Postoperative bleeding requiring exploration is rare (<0.5%).35 Rectal injury is also uncommon, estimated to occur in 0.5% of men.35,39 These can be typically managed with primary closure, omental coverage, dilation of the anal sphincter, and antibiotics even without preoperative bowel preparation. A routine diverting colostomy is rarely performed (0% to 0.06%) but may be necessary in those with prior radiation exposure or extensive contamination.
Table 26A-3 Estimated Blood Loss During Radical Retropubic Prostatectomy Institution
Number
Mean EBL (ml)
Range (ml)
316
1020
100–4320
65*
1420
200–2500
65†
1605
250–3500
220
300
100–1500
1728
600
—
Baylor42
954
800
150–5000
NYU32
1000
819
SD 14.9
UCSF
400
486
100–1200
Mayo Clinic40 Washington University41
Toulouse33 Mayo Clinic35
*With
internal iliac artery occlusion. internal iliac artery occlusion.
†Without
Table 26A-4 Summary of Radical Perineal Prostatectomy Series
Series
Number
Blood Loss (ml)
Hospitalization (days)
Continence (%)
Potency (%)
Positive Margins (%)
PSA-Free Survival (%)
Follow-Up (Mean Months)
Frazier43
122
565
12
96
77
29
—
—
Lance44
190
802
—
65
8
43
82
42.9
Sullivan45
138
416
4.5
72
—
9
70
30
Weldon46
200
—
—
—
—
44
79
35
Weldon47
110
645
—
95
70
—
—
—
Parra48
500
270
1.5
94
47
16
—
—
470
Part V Prostate Gland and Seminal Vesicles
Injuries to the obturator nerve and ureter are rare (both <0.1%) and can be managed intraoperatively by direct reanastomosis and ureteroneocystostomy, respectively.11,32,49 Late Complications The majority of patients experience an uneventful postoperative course, resuming oral intake and ambulation the first day after surgery. In the U.S., men are safely discharged between 1 and 5 days after surgery with the urethral catheter in place.32,38 With the interest in earlier removal of the catheter (<10 days), rates of urinary retention have increased and may approach 20%.50 Development of an anastomotic stricture occurs in approximately 1% to 10% of patients.11,32,38 Other complications, including incisional hernia, lymphocele, ileus, and inguinal hernia, are all less than 1%, while rates of rehospitalization are less than 5%.11,32,38 Outcomes After Radical Prostatectomy Cancer Control Contemporary methods of radical prostatectomy for patients with clinically localized disease are generally associated with very good outcomes. Several endpoints can be evaluated—overall survival, cause-specific survival, and biochemical relapse-free survival. Paulson et al.51 reported a 90% cancer-specific survival at 13.5 years after radical perineal prostatectomy for patients with organ-confined and specimen-confined diseases. In an analysis of men treated with radical retropubic prostatectomy at the Mayo clinic, Zincke et al.35,52 reported crude and cause-specific survival rates of 75% and 90%, respectively. The crude survival rates at 10 and 15 years after surgery were similar to those of agematched men from the general population without prostate cancer. Despite the excellent results of radical prostatectomy, between 22% and 50% of patients thought to have organ-confined cancer are found to have disease beyond the prostate on careful pathologic examination of the surgical specimen.18,20,53,54 Given the protracted natural history of prostate cancer and the fact that residual and/or recurrent disease may respond to secondary therapy, postoperative follow-up with serum PSA testing is an important endpoint in subsequent evaluation. Nearly all recurrent clinical and metastatic disease is preceded by a rising PSA, with only a few sporadic reported cases of recurrence in the absence of a detectable serum PSA level. Biochemical failure is defined as either the persistence of a detectable PSA after surgery or the development of a detectable PSA in those with a previously undetectable postoperative level. The threshold constituting a detectable serum PSA varies among investiga-
tors, and the use of ultrasensitive or hypersensitive PSA assays improves the lead-time for early detection of recurrence.55,56 Amling et al.57 analyzed the effect of using various PSA cut points defining biochemical failure after radical prostatectomy in a cohort of 2782 men with clinically localized disease (stages cT1 to T2). Five- and 10-year rates of PSA recurrence varied greatly, depending on whether the threshold was 0.2, 0.3, 0.4, or 0.5 ng/ml. Clinical progression was directly related to the maximum PSA reached within 3 years of surgery. Using definitions requiring multiple increases in PSA, such as that proposed by American Society for Therapeutic Radiology and Oncology for biochemical failure after radiation therapy, gave misleading results with overestimation of short-term failure but improved long-term recurrence-free outcomes. They conclude that a PSA cut point of 0.4 ng/ml may be most reasonable, with the lack of continuation of PSA progression in many of those with PSA values between 0.2 and 0.4 ng/ml; this may balance the identification of patients with actual cancer recurrence at risk for subsequent clinical progression with sparing unnecessary adjuvant therapy in men with low but detectable PSA levels. Radical retropubic prostatectomy is associated with overall 5- and 10-year actuarial biochemical progressionfree survival rates ranging from 59% to 84% and from 47% to 75%, respectively (Table 26A-5).35,59,60,63 Biochemical relapse-free survival following radical perineal prostatectomy ranges from 70% to 82% with mean follow-up of 30 to 43 months (see Table 26A-4).43–45 Biochemical relapse typically occurs 8 years prior to any evidence of clinical disease recurrence; this is reflected by higher clinical disease-free rates at 5 (84% to 86%) and 10 (72% to 78%) years. The variability in outcomes across different reports and techniques likely reflects differences in patient selection, definition of biochemical failure, and to a lesser extent variations in surgical technique. In two contemporary radical prostatectomy series from the Cleveland Clinic and The Johns Hopkins Hospital, totaling more than 2000 men, no patient showed signs of clinical disease in the absence of PSA failure.56,60 Following PSA recurrence, up to 68% of men progressed to clinical disease at a median follow-up of 19 months. The use of adjuvant therapy, such as radiation or androgen deprivation, at the time of PSA recurrence reduced the rate of clinical disease progression (21%). Without adjuvant or salvage therapy, metastatic disease developed in 34% of patients at a median actuarial time of 8 years after PSA failure. Han et al.61 recently reported the long-term biochemical disease-free and cancer-specific survival in 2404 patients managed with radical prostatectomy at The Johns Hopkins Hospital. Mean follow-up was 6.3 years (range 1 to 17) and 26% of patients (n = 621) were followed at least for 10 years. Overall actuarial PSA progres-
Chapter 26A Clinically Localized (Stage T1a-T2c) Adenocarcinoma of the Prostate 471
Table 26A-5 Biochemical Relapse-Free Survival Following Radical Retropubic Prostatectomy Number
5-Year (%)
10-Year (%)
15-Year (%)
Washington University58
1778
78*
—
Baylor20
1000
78
UCLA59
601
Institution
Mayo Clinic35
Cleveland Clinic60
Johns Hopkins61 UCSF62
Outcome
Follow-Up (Years)
—
PSA < 0.6 ng/ml
Mean 4.0
75
75†
PSA < 0.4 ng/ml
Mean 4.4
69
47
—
PSA < 0.4 ng/ml
Median 2.8
86
78
—
Clinically free of disease
70
52
—
PSA < 0.2 ng/ml
85
72
—
Clinically free of disease
59
—
—
PSA < 0.2 ng/ml
84
—
—
Clinically free of disease
2404
84
74
66
PSA < 0.2 ng/ml
Mean 6.3
666
78
—
—
PSA < 0.2 ng/ml
Median 3.1
3170
423
Mean 5.0
Median 4.3
*7-year results. †14-year results.
sion-free, metastasis-free, and cancer-specific survivals were: 84%, 96%, and 99% at 5 years; 74%, 90%, and 96% at 10 years; 66%, 82%, and 90% at 15 years, respectively. These data are similar to those reported by Catalona et al.58 and Hull et al.20 (see Table 26A-5). Clinical and pathologic stage, pretreatment PSA, and pathologic Gleason score are all predictors of progression after surgery (Table 26A-6).11 Catalona et al.12 reported 79% and 66% 7-year disease-free survivals in those with stage cT1c and stage cT2, respectively. From the Johns Hopkins series, patients with clinical stage ≤ T2 had 5-, 10-, and 15-year recurrence-free survival rates of 86%, 76%, and 71%, respectively, compared to 60% and 49% in patients with T3a disease (15-year data unavailable).61 At 10 years, Hull et al.20 observed >80% and 67% PSA-free survival in those with clinical stages T1 and T2, respectively. Seven-year progression-free survival was 93%, 80%, 76%, and 40% in PSA ranges of <2.5, 2.5 to 4.0, 4.1 to 10, and >10 ng/ml, respectively.12 The 10-year recurrence-free data from Johns Hopkins are comparable: 91% for ≤ 4 ng/ml, 79% for 4.1 to 10 ng/ml, 57% for 10.1 to 20 ng/ml, and 48% for >20 ng/ml.61 Higher Gleason grade, both on diagnostic biopsy and in the surgical specimen, is associated with increased risk of disease recurrence. Seven-year progression-free survival was 84% in patients with Gleason sum 2 to 4, 68% with Gleason sum 5 to 7, and 48% with Gleason sum 8 to 10.12 Han et al.61 reported 10-year recurrence-free rates of 91%, 79%, 57%, and 48% for Gleason sums ≤ 6, 3 + 4, 4 + 3, and 8 to 10, respectively.
Pathologic stage is one of the most important prognostic factors, with increasing rates of recurrence with extraprostatic extension with negative surgical margins, positive surgical margins, seminal vesicle invasion, and lymph node metastases. Actuarial recurrence-free survival in patients with organ-confined disease (i.e., ≤pT2) is 97% at 5 years, 93% at 10 years, and 84% at 15 years. Comparable data were reported by Hull et al.20 At 10 years, those with organ-confined and nonorgan-confined tumors experienced 92% and 53% progression-free survivals, respectively. Men with pathologic stages T1-2, T3a/b, T3c, and N+ had 10-year actuarial PSA-free survivals of 92%, 71%, 37%, and 7%, respectively. At UCSF, patients with pathologically confined disease (pT2, all grades) have a 5-year PSA progression-free actuarial survival rate of 80%, compared with 57% in those with higher stages. The incidence of positive surgical margins has varied greatly, ranging between 10% and 68%.64–66 The finding of a positive margin on the prostatectomy specimen would suggest incomplete removal of the tumor and is associated with a 2- to 4-fold increased risk of progression.20 Nevertheless, those men with a positive margin may experience reasonable long-term recurrence-free survival (36% at 10 years) without adjuvant therapy; the reported 10-year results for those with negative margins is 81%. In an attempt to reduce the incidence of positive surgical margins while performing nerve-sparing radical retropubic prostatectomy, we examined the utility of intraoperative frozen section analysis.67 In 101 men, intraoperative frozen section was performed on the surgical
472
Part V Prostate Gland and Seminal Vesicles
Table 26A-6 Risk Factors for Progression After Radical Prostatectomy (Multivariate Analysis) Variable
Relative Risk (95% CI)
p Value
Preoperative parameter Clinical stage
0.0071
T1a,b versus T1c
0.6
T1c versus T2a
0.1
T1c versus T2b
2.47 (1.52–4.03)
0.0003
T1c versus T2c
1.91 (1.06–3.42)
0.0304
Biopsy Gleason sum 2–4 versus 5–6
0.15
5–6 versus 7
2.6 (1.75–3.87)
<0.0001
5–6 versus 8–10
3.21 (1.72–5.97)
0.0002
Clinical and pathologic parameters Clinical stage
0.15
Biopsy Gleason sum
0.12
Specimen Gleason sum
0.0008
2-4 versus 5-6
2.48 (1.34–4.58)
0.0038
5-6 versus 7
2.48 (1.34–4.58)
0.0038
5-6 versus 8-10
4.55 (2.19-9.42)
<0.0001
Extracapsular extension
0.0019
Focal versus none
2.17 (1.20–3.92)
0.011
Established versus none
2.72 (1.56–4.74)
0.0004
Focal versus established
0.13
Surgical margin Positive versus negative
4.37 (2.90–6.58)
<0.0001
2.61 (1.70–4.01)
<0.0001
3.31 (2.11–5.20)
<0.0001
Seminal vesicle involvement Present versus absent Lymph node metastases Present versus absent
margin thought to be at risk of tumor involvement. If the margin was positive, additional tissue was excised. Findings of intraoperative examination were identical to those of final permanent section in 91% of cases. Of the 15 patients with a positive frozen section, 11 had identical findings on permanent pathologic sections. In this
group, 12 (80%) had no evidence of tumor in additionally resected tissue. Overall, the positive and negative predictive values for intraoperative frozen section analysis were 73% and 94%, respectively. The risk of recurrence in patients with either positive or negative intraoperative frozen section findings was similar. These
Chapter 26A Clinically Localized (Stage T1a-T2c) Adenocarcinoma of the Prostate 473
data suggest that intraoperative frozen section analysis may be applied during radical prostatectomy to spare the neurovascular bundles in selected patients. In order to improve simplify, as well as increase the accuracy of assessment of postoperative prognosis, clinical and pathologic features have been combined. A multivariate analysis from Johns Hopkins found that pathologic stage, Gleason score, and surgical margin status were the best predictors of the probability of cancer recurrence.68 The risk stratification scheme, discussed above, is able to categorize patients into low-, intermediate-, and high-risk groups with 5-year recurrence-free survival rates of 98%, 73%, and 65%, respectively.20 Although radical prostatectomy is fairly effective even in higher-risk patients, early identification of those at risk for eventual primary treatment failure help select men appropriate for adjuvant therapy and enrollment in clinical trials.
Table 26A-7 Risk Factors for Urinary Incontinence After Radical Prostatectomy Variable
p Value*
Patient weight (continuous)
0.0002
Obstructive urinary symptoms
0.004
TURP
0.001
Blood loss (continuous)
0.016
Nerve resection
0.001 (0.015)
Anastomotic stricture
0.001 (0.015)
Patient age (continuous)
0.001 (0.0001)
Anastomotic method
0.001 (0.0001)
*In univariate analysis; numbers in parenthesis represent p values in multivariate analyses.
Urinary Function After radical prostatectomy, immediate postoperative incontinence may occur in up to 80% of patients. More contemporary series report a significantly lower rate of immediate incontinence.30,32,69 The wide variability in incontinence rates reported in the literature is due to improvements in surgical technique, as well as differing definitions of what constitutes urinary continence. Approximately 90% of men who undergo radical prostatectomy will be continent at 1 year, when the definition is no regular use of pads and/or no leakage with moderate exercise. Severe and persistent incontinence, defined as leakage with normal activity or the need for ≥ 3 pads per day, occurs in 1% to 6% of patients.70 Most major centers report urinary incontinence rates less than 10%. In 593 patients undergoing surgery by Walsh, some degree of stress urinary incontinence was present in 8%; the remaining 92% of patients were completely continent.71 The group from Baylor reported the median time to recovery of continence was 1.5 months, with 92% and 95% of patients continent at 1 and 2 years, respectively.72 Factors associated with incontinence after radical prostatectomy are listed in Table 26A-7. At UCSF, a contemporary cohort of patient undergoing radical retropubic prostatectomy (n = 217) was surveyed anonymously using a detailed, validated questionnaire, including the University of California, Los Angeles/Rand Prostate Cancer Index quality-of-life urinary domain questions. At 1 year after surgery, overall continence (defined above) was 98%, with immediate continence in 23% and 55% of patients continent by 1 month. Catalona et al.12 noted that 96% and 87% of men younger and older than 70 years, respectively, recovered continence
within 18 months; more recently, half of patients have immediate recovery of urinary control. In a national survey including 1796 men undergoing radical prostatectomy who were continent before the operation, 19% required pads daily and 3.6% were totally incontinent.73 The National Institutes of Healthsponsored Prostate Cancer Outcomes study found that 8.5% of men reported “severe” incontinence.74 It is important to note that despite the presence of urinary incontinence, most patients were minimally bothered and highly satisfied with their treatment. This has been confirmed in a recent randomized study comparing radical prostatectomy with watchful waiting.75 Despite a higher incidence of urinary leakage with radical prostatectomy (49%), overall well being and subjective qualityof-life assessment were not significantly different from the watchful waiting group. We recently examined the impact of even minimal urinary leakage after radical prostatectomy on healthrelated quality of life.76 Postoperative assessment of urinary health-related quality of life, using the urinary function and bother subscales of the University of California Los Angeles Prostate Cancer Index, American Urologic Association Symptom Index, and a single question assessing satisfaction, was performed in 168 men at a mean of 75 weeks after surgery. Overall, 87% reported no pad use while 12% used one pad daily. Statistically significant differences were observed between these groups with respect to mean function score ( p < 0.0001), mean bother score ( p < 0.0001), and change in AUA quality-of-life score ( p < 0.0001). Overall satisfaction was higher in the no pad group (87.1) compared to the singlepad group (50.9; p < 0.0001).
474
Part V Prostate Gland and Seminal Vesicles
Erectile Function Until the description of the anatomy and location of the autonomic branches of the pelvic plexus innervating the corpora cavernosa, men were expected to be impotent after radical prostatectomy.77 Identification of these nerves allowed modification of the surgical technique and attempted preservation of potency in men undergoing removal of the prostate.78 Quinlan et al.79 reported outcomes in 600 men aged 34 to 72 years undergoing radical prostatectomy. Of 503 men with preoperative sexual function followed at least 18 months, 68% remained potent after surgery. Studies have found that multiple factors are involved in the preservation of potency.30,79,80 In the Johns Hopkins’ experience, these included age, stage, and preservation or excision of the neurovascular bundles.79 Potency was preserved in 91% younger than 50 years, 75% in men 50 to 60 years, 58% in men 60 to 70 years, and 25% in men older than 70 years. With increasing age, preservation of both neurovascular bundles was more important in potency. After controlling for other variables, the presence of more advanced stage (nonorgan-confined, seminal vesicle invasion) was associated with increased risk of impotence. Similarly, Rabbani et al.80 identified patient age, preoperative potency, and extent of neurovascular bundle preservation as predictors of potency recovery. At 3 years following surgery, 76%, 56%, and 47% of those aged <60, 60 to 65, and >65 years were potent. Men with only partial preoperative erection and unilateral neurovascular preservation were less likely (47% and 25%, respectively) to recover potency. Potency after radical perineal prostatectomy has been documented in smaller series, with rates near 70%.43,51 As with urinary function after prostatectomy, a wide range of success has been reported for postoperative potency (3% to 46%). This variability is due to patient selection, surgeon expertise, definition of potency, and means of assessing sexual function. In men with erectile dysfunction after a bilateral nerve-sparing prostatectomy, sildenafil may be efficacious.81–83 Between 43% and 75% of such patients may respond to sildenafil; conversely, few men benefit if both neurovascular bundles have been excised or ligated.
4.
5.
6.
7.
8.
9.
10.
11. 12.
13.
14.
15.
16.
17.
REFERENCES 1. Walsh PC: Prostate cancer kills: strategy to reduce death. Urology 1994; 44:463–466. 2. Thompson IM: Counseling patients with newly diagnosed prostate cancer. Oncology (Huntingt) 2000: 14:119–126. 3. Wilt TJ, Brawer MK: Prostate cancer intervention versus observation trial: a randomized trial comparing radical prostatectomy versus expectant management for
18.
19.
treatment of localized prostate cancer. J Urol 1994; 152:1910–1914. Holmberg L, Bill-Axelson A, Helgesen F, et al: A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002; 347:781–789. Chodak GW, Thisted RA, Gerber GS, et al: Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994; 330:242–248. Albertsen PC, Fryback DG, Storer BE: Long-term survival among men with conservatively treated localized prostate cancer. J Am Med Assoc 1995; 274:626–631. Albertsen PC, Hanley JA, Gleason DF, Barry MJ: Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. J Am Med Assoc 1998; 280:975–980. Fleming C, Wasson JH, Albertsen PC et al: A decision analysis of alternative treatment strategies for clinically localized prostate cancer. Prostate Patient Outcomes Research Team. J Am Med Assoc 1993; 269:2650–2658. Beck JR, Kattan MW, Miles BJ: A critique of the decision analysis for clinically localized prostate cancer. J Urol 1994; 152:1894–1899. Walsh PC: The natural history of localized prostate cancer: a guide to therapy. In Campbell’s Urology. Philadelphia, WB Saunders, 1998. Ohori M, Scardino PT: Localized prostate cancer. Curr Probl Surg 2002; 39:833–957. Catalona WJ, Ramos CG, Carvalhal GF: Contemporary results of anatomic radical prostatectomy. CA Cancer J Clin 1999; 49:282–296. Walsh PC, Partin AW, Epstein JI: Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. J Urol 1994; 152:1831–1836. Pound CR, Partin AW, Epstein JI, Walsh PC: Prostatespecific antigen after anatomic radical retropubic prostatectomy: patterns of recurrence and cancer control. Urol Clin North Amer 1997; 24:395–406. Partin AW, Yoo J, Carter HB, et al: The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 1993; 150:110–114. Partin AW, Mangold LA, Lamm DM, et al: Contemporary update of prostate cancer staging nomograms (Partin tables) for the new millennium. Urology 2001; 58:843–848. Kattan MW, Eastham JA, Stapleton AM: A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 1998; 90:766–771. Partin AW, Kattan MW, Subong EN, et al: Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer: a multi-institutional update. J Am Med Assoc 1997; 277:1445–1451. Kattan MW, Wheeler TM, Scardino PT: Postoperative nomogram for disease recurrence after radical
Chapter 26A Clinically Localized (Stage T1a-T2c) Adenocarcinoma of the Prostate 475
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
prostatectomy for prostate cancer. J Clin Oncol 1999; 17:1499–1507. Hull GW, Rabbani F, Abbas F, et al: Cancer control with radical prostatectomy alone in 1,000 consecutive patients. J Urol 2002; 167:528–534. Koppie TM, Grossfeld GD, Miller D, et al: Patterns of treatment of patients with prostate cancer initially managed with surveillance: results from the CapSure database. Cancer of the prostate strategic urological research endeavor. J Urol 2000; 164:81–88. Grossfeld GD, Latini DM, Lubeck DP, et al: Predicting disease recurrence in intermediate and high-risk patients undergoing radical prostatectomy using percent positive biopsies: results from CapSure. Urology 2002; 59:560–565. Moul JW, Connelly RR, Lubeck DP, et al: Predicting risk of prostate specific antigen recurrence after radical prostatectomy with the center for prostate disease research and cancer of the prostate strategic urologic research endeavor databases. J Urol 2001; 166:1322–1327. Bishoff JT, Reyes A, Thompson IM, et al: Pelvic lymphadenectomy can be omitted in selected patients with carcinoma of the prostate: development of a system of patient selection. Urology 1995; 45:270–274. Danella JF, deKerion JB, Smith RB, Steckel J: The contemporary incidence of lymph node metastases in prostate cancer: implications for laparoscopic lymph node dissection. J Urol 1993; 149:1488–1491. Heidenreich A, Varga Z, von Knobloch R: Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy: high incidence of lymph node metastasis. J Urol 2002; 167:1681–1686, 2002. Cadeddu JA, Partin AW, Epstein JI, Walsh PC: Stage D1 (T1-3, N1-3, M0) prostate cancer: a case-controlled comparison of conservative treatment versus radical prostatectomy. Urology 1997; 50:251–255. Ghavamian R, Bergstralh EJ, Blute ML, et al: Radical retropubic prostatectomy plus orchiectomy versus orchiectomy alone for pTxN+ prostate cancer: a matched comparison. J Urol 1999; 161:1223–1227. Messing EM, Manola J, Sarosdy M, et al: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999; 341:1781–1788. Catalona WJ, Carvalhal GF, Mager DE, Smith DS: Potency, continence, and complication rates in 1870 consecutive radical retropubic prostatectomies. J Urol 1999; 162:433-438. Lerner SE, Blute ML, Lieber MM, Zincke H: Morbidity of contemporary radical retropubic prostatectomy for localized prostate cancer. Oncology (Huntingt) 1995; 9:379–382. Lepor H, Nieder AM, Ferrandino MN: Intraoperative and postoperative complications of radical retropubic prostatectomy in a consecutive series of 1000 cases. J Urol 2001; 166:1729–1733. Leandri P, Rossignol G, Gautier JR, Ramon J: Radical retropubic prostatectomy: morbidity and quality of life. J Urol 1992; 147:883–887.
34. Dillioglugil O, Leibman BD, Leibman NS, et al: Risk factors for complications and morbidity after radical retropubic prostatectomy. J Urol 1997; 157:1760–1767. 35. Zincke H, Oesterling JE, Blute ML, et al: Long-term (15 years) results after radical prostatectomy for clinically localized prostate (stage T2c or lower) prostate cancer. J Urol 1994; 152:1850–1857. 36. Lu-Yao GL, Albertsen P, Warren J, Yao SL: Effect of age and surgical approach on complications and short-term mortality after radical prostatectomy: a population-based study. Urology 1999; 54:301–307. 37. Thompson IM, Middleton RG, Optenberg SA, et al: Have complication rates decreased after treatment for localized prostate cancer? J Urol 1999; 162:107–112. 38. Hu JC, Gold KF, Pashos CL, et al: Temporal trends in radical prostatectomy complications from 1991 to 1998. J Urol 2003; 169:1443–1448. 39. Begg CB, Riedel ER, Bach PB, et al: Variations in morbidity after radical prostatectomy. N Engl J Med 2002; 346:1138–1144. 40. Rainwater LM, Segura JW: Technical consideration in radical retropubic prostatectomy: blood loss after ligation of dorsal venous complex. J Urol 1990; 143:1163–1165. 41. Kavoussi LR, Myers JA, Catalona WJ: Effect of temporary occlusion of hypogastric arteries on blood loss during radical retropubic prostatectomy. J Urol 1991; 146:362–365. 42. Eastham JA, Scardino PT: Radical prostatectomy. In Campbell’s Urology. Philadelphia, WB Saunders, 1998. 43. Frazier HA, Robertson JE, Paulson DF: Radical prostatectomy: the pros and cons of the perineal versus retropubic approach. J Urol 1992; 147:888–890. 44. Lance RA, Freidrichs PA, Kane CJ, et al: A comparison of radical retropubic with perineal prostatectomy for localized prostate cancer within the uniformed services urology research group. BJU Int 2001; 87:61–65. 45. Sullivan LD, Weir MJ, Kinahan JF, Taylor DL: A comparison of the relative merits of radical perineal and radical retropubic prostatectomy. BJU Int 2000; 85:95–100. 46. Weldon VE, Tavel FR, Neuwirth H, Cohen R: Patterns of positive specimen margins and detectable prostate specific antigen after radical perineal prostatectomy. J Urol 1995; 153:1565–1569. 47. Weldon VE, Tavel FR, Neuwirth H: Continence, potency and morbidity after radical perineal prostatectomy. J Urol 1997; 158:1470–1475. 48. Parra RO: Analysis of an experience with 500 radical perineal prostatectomies in localized prostate cancer. J Urol 2000; 163A:284–285. 49. Walsh PC: Anatomic radical retropubic prostatectomy. In Campbell’s Urology. Philadelphia, WB Saunders, 1998. 50. Patel R, Lepor H: Removal of urinary catheter on postoperative day 3 or 4 after radical retropubic prostatectomy. Urology 2003; 61:156–160. 51. Paulson DF: Impact of radical prostatectomy in the management of clinically localized disease. J Urol 1994; 152:1826–1830. 52. Zincke H, Bergstralh EJ, Blute ML, et al: Radical prostatectomy for clinically localized prostate cancer:
476
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
Part V Prostate Gland and Seminal Vesicles long-term results of 1143 patients from a single institution. J Clin Oncol 1994; 12:2254–2263. Grossfeld GD, Chang JJ, Broering JM, et al: Does the completeness of prostate sampling predict outcome for patients undergoing radical prostatectomy? Data from the CapSure database. Urology 2000; 56:430–435. Han M, Partin AW, Zahurak M et al: Biochemical (prostate specific antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. J Urol 2003; 169:517–523. Yu H, Diamandis EP, Prestigiacomo AF, Stamey TA: Ultrasensitive assay of prostate-specific antigen used for early detection of prostate cancer relapse and estimation of tumor-doubling time after radical prostatectomy. Clin Chem 1995; 41:430–434. Pound CR, Partin AW, Eisenberger MA, et al: Natural history of progression after PSA elevation following radical prostatectomy. J Am Med Assoc 1999; 281:1591–1597. Amling CL, Bergstralh EJ, Blute ML, et al: Defining prostate specific antigen progression after radical prostatectomy: what is the most appropriate cut point? J Urol 2001; 165:1146–1151. Catalona WJ, Smith DS: Cancer recurrence and survival rates after anatomic radical retropubic prostatectomy for prostate cancer: intermediate-term results. J Urol 1998; 160:2428–2434. Trapasso JG, deKerion JB, Smith RB, Dorey F: The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol 1994; 152:1821–1825. Kupelian PA, Katcher J, Levin HS, et al: Stage T1-2 prostate cancer: a multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy. Int J Radiat Oncol Biol Phys 1997; 37:1043–1052. Han M, Partin AW, Pound CR, et al: Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am 2001; 28:555–565. Carroll PR, Meng MV, Downs TM, Grossfeld GD: Radical retropubic prostatectomy. In Prostate Cancer. Hamilton, Decker, 2002. Catalona WJ, Smith DS: 5-year tumor recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994; 152:1837–1842. Wieder JA, Soloway MS: Incidence, etiology, location, prevention and treatment of positive surgical margins after radical prostatectomy for prostate cancer. J Urol 1998; 160:299–315. Blute ML, Bostwick DG, Seay TM et al: Pathologic classification of prostate carcinoma: the impact of margin status. Cancer 1998; 82:902–908. Grossfeld GD, Tigrani VS, Nudell D, et al: Management of a positive surgical margin after radical prostatectomy: decision analysis. J Urol 2000; 164:93–99.
67. Goharderakhshan RZ, Sudilovsky D, Carroll LA, et al: Utility of intraoperative frozen section analysis of surgical margins in region of neurovascular bundles at radical prostatectomy. Urology 2002; 59:709–714. 68. Epstein JI, Partin AW, Sauvageot J, et al: Prediction of progression following radical prostatectomy: a multivariate analysis of 721 men with long-term followup. Am J Surg Pathol 1996; 20:286–292. 69. Goluboff ET, Saidi JA, Mazer S, et al: Urinary continence after radical prostatectomy: the Columbia experience. J Urol 1998; 159:1276–1280. 70. Wahle GR: Urinary incontinence after radical prostatectomy. Semin Urol Oncol 2000; 18:66–70. 71. Steiner MS, Morton RA, Walsh PC: Impact of anatomical radical prostatectomy on urinary continence. J Urol 1991; 145:512–515. 72. Eastham JA, Goad JR, Rogers E, et al: Risk factors for urinary incontinence after radical prostatectomy. J Urol 1996; 156:1707–1713. 73. Murphy GP, Mettlin C, Menck H, et al: National patterns of prostate cancer treatment by radical prostatectomy: results of a survey by the American College of Surgeons Commission on Cancer. J Urol 1994; 152:1817–1819. 74. Stanford JL, Feng Z, Hamilton AS, et al: Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer. J Am Med Assoc 2000; 283:354–360. 75. Steineck G, Helgesen J, Adolfsson J, et al: Quality of life after radical prostatectomy or watchful waiting. N Engl J Med 2002; 347:790–706. 76. Cooperberg MR, Master VA, Carroll PR: Health related quality of life significance of single pad urinary incontinence following radical prostatectomy. J Urol 2003; 170:512–515. 77. Walsh PC, Donker PJ: Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982; 128:492–497. 78. Walsh PC: Anatomic radical prostatectomy: evolution of the surgical technique. J Urol 1998; 160:2418–2424. 79. Quinlan DM, Epstein JI, Carter BS, et al: Sexual function following radical prostatectomy: influence of preservation of neurovascular bundles. J Urol 1991; 145:998–1002. 80. Rabbani F, Stapleton AM, Kattan MW, et al: Factors predicting recovery of erections after radical prostatectomy. J Urol 2000; 164:1929–1934. 81. Zippe CD, Jhaveri FM, Klein EA, et al: Role of Viagra after radical prostatectomy. Urology 2000; 55:241–245. 82. Zippe CD, Kedia S, Kedia AW, Pasqualotto F: Sildenafil citrate (Viagra) after radical retropubic prostatectomy: pro. Urology 1999; 54:583–586 (editorial). 83. Blander DA, Sanchez-Ortiz RF, Wein AJ, Broderick GA: Efficacy of sildenafil in erectile dysfunction after radical prostatectomy. Int J Impot Res 2000; 12:165–168.
C H A P T E R
26B Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy W. Robert Lee, MD, MS
Management of men with clinically localized (T1-2) prostate cancer is one of the most controversial areas in all of oncology. Treatment options include expectant management, radical prostatectomy (RP), external beam radiation therapy (EBRT), and interstitial brachytherapy (IB), with or without additional EBRT.1 The results of newer approaches, including high intensity focused ultrasound (HIFU) and cryotherapy, have demonstrated some promise but they will not be discussed here. The gold standard for treatment efficacy is considered to be the randomized clinical trial (RCT). To date the number of RCT comparing definitive treatments in men with T1-2 prostate cancer is very few, and in some cases the trials have methodologic flaws that preclude interpretation.2,3 Given the relative paucity of level I evidence, clinicians and their patients rely on retrospective, nonrandomized historic case series for treatment recommendations. The potential for bias in these historic series is well known. Several characteristics of prostate cancer make interpretation of available information difficult. In the first place, the long natural history of clinically localized prostate cancer makes it very difficult to demonstrate a beneficial effect of any therapeutic procedure. D’Amico4 has quantified prostate cancer-specific mortality during the first decade in men with T1-2 prostate cancer treated with RP or EBRT in the prostatespecific antigen (PSA) era. This report included more than 7000 men (4946 treated with RP and 2370 treated with EBRT) from 44 treating institutions. The rate of prostate cancer specific mortality (PCSM) was dependent on pretreatment risk grouping and primary treatment. In men treated with EBRT, the rate of PCSM at 10 years was <5% for men with low-risk disease, rising to approximately 10% in the intermediate-risk group and nearly 25% in the high-risk group. If aggressive local treatment
is to affect the natural history of the disease, especially in men with favorable disease, it will not be apparent for several years following treatment. In addition, many men with prostate cancer are beyond the age of 65 at diagnosis and have competing comorbidities. In a report including more than 1400 men treated with EBRT on Radiation Therapy Oncology Group (RTOG) trials between 1975 and 1992, more than 50% of men died of other causes.5 Other reports of men managed with expectant management illustrate the same phenomenon.6 The competing risk from other causes of mortality (cerebrovascular disease, cardiovascular disease) makes it difficult to demonstrate that treating prostate cancer reduces overall mortality. Finally, temporal trends confound any statements about treatment efficacy. With the advent of PSA screening, significant stage migration has been documented.7,8 Men treated in 2003 in general have less disease than men treated in the late 1980s. Treatment techniques have also evolved in the past two decades. RP has been refined, and morbidity has been reduced. Techniques of radiation therapy (EBRT or IB) have also evolved. Thus, the results reported from men treated 15 years ago may not be representative of what is achievable with current methods. The preceding paragraphs should emphasize the difficulties inherent in interpreting the available literature as it relates to the management of men with T1-2 prostate cancer. In this chapter, biochemical relapsefree survival (BRFS) (incorporating PSA into the definition of disease-free survival) will be emphasized. The use of PSA as an endpoint has a number of advantages and disadvantages, which are discussed in a previous section. Patient-reported endpoints, including health-related quality of life (HRQOL) after definitive treatment is considered elewhere.
477
478
Part V Prostate Gland and Seminal Vesicles
RISK STRATIFICATION A number of variables have been reported to be independent predictors of BRFS following radiation therapy (EBRT or IB) for clinically localized prostate cancer. These variables include Gleason grade, pretreatment PSA level, and clinical T stage.9–15 In hopes of accurately predicting biochemical outcome following definitive treatment, a number of investigators have combined these variables to produce risk groupings.10,16,17 One of the more commonly used risk stratifications was first described by D’Amico.10 In a single-institution setting with BRFS as the endpoint, the D’Amico risk stratification system successfully classified patients into three groups (low, intermediate, and high) regardless of treatment received (RP, EBRT, or IB). A recent report has demonstrated that the D’Amico risk groupings also predict prostate cancer-specific survival.4 The results with radiation therapy should be presented according to risk grouping. HISTORIC PERSPECTIVE, EXTERNAL BEAM RADIATION THERAPY Megavoltage EBRT for clinically localized prostate cancer has been in use since the late 1950s following the development of Co60 teletherapy and linear accelerators.18 Over the ensuing years a number of advances in technology have allowed for modifications in the treatment planning process. As late as the early 1990s most men treated with EBRT were treated with conventional methods. In this paradigm, the treatment planning process relied on two-dimensional plain radiographs for target localization and shielding of normal tissues. This method did not allow direct visualization of the prostate gland. The location of the prostate was estimated based on bony landmarks and radio-opaque contrast in nearby normal tissues. With the development of more sophisticated treatment planning software, three-dimensional conformal radiation therapy (3DCRT) was born. In 3DCRT, the target organ and any relevant nearby normal tissues are outlined on sequential computed tomography (CT) images. These outlines are then reconstructed to allow shaping of the radiation portal to conform to the shape of the target organ (Figure 26B-1). As outlined later, 3DCRT techniques allow for an increase in dose to the prostate gland without a significant increase in normal tissue complications. Intensity-modulated radiation therapy (IMRT) is a further refinement of 3DCRT. With IMRT the fluence of linear accelerator photon beams are modulated to create more ideal dose distributions. Potential advantages of IMRT versus 3DCRT include a greater conformality of radiation dose about the target organ and a much steeper
Figure 26B-1 Example of beam-shaping used for 3DCRT. A, Antero-posterior beam. B, Right lateral beam. C, Oblique beam
dose gradient that results in reduced total dose to nearby normal tissues.19 IMRT is gradually being introduced into community practice although the availability remains somewhat limited at this time. TECHNIQUE OF EBRT Widespread availability of the necessary equipment should permit all men treated with EBRT for prostate cancer to be approached using 3DCRT. CT simulators
Chapter 26B Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy 479
Table 26B-1 Volume Recommendations of the International Commission of Radiation Units and Measurements (ICRU Report 50) Parameters
Definition
GTV
Palpable or visible extent of tumor
CTV
GTV plus margins for subclinical disease
PTV
CTV plus margins for organ motion and daily set-up error
are becoming commonplace in radiation therapy departments, but even if conventional simulators are used, the information obtainable from CT or magnetic resonance (MR) should be incorporated into the treatment planning process. These newer techniques should be approached in a systematic fashion. With the introduction of 3DCRT, a new terminology is required (Table 26B-1).20 In this vocabulary, the gross tumor volume (GTV) represents the tumor which is palpable or visible on imaging. The clinical target volume (CTV) includes the GTV plus any additional structures that are felt to be at risk for microscopic involvement (seminal vesicles or pelvic lymph nodes). The planning target volume (PTV) includes the CTV plus a margin that accounts for organ motion and set-up error. In most cases of prostate cancer, the CTV to PTV margin is 5 to 10 mm. Many clinicians will use nonuniform margins with the smallest CTV to PTV margins posteriorly in the vicinity of the rectum.21 A variety of beam arrangements have been described ranging from a coplanar, four-field technique to a noncoplanar seven-field approach. Megavoltage energies (>6 MV) are recommended. Immobilization devices are commonly used to decrease set-up error, reducing the CTV to PTV margin.20,22,23 In an attempt to reduce the CTV to PTV margin further, a number of investigators have localized the prostate daily prior to delivering treatment. Common techniques include transabdominal ultrasound localization of the prostate24 and the use of implanted fiducial markers.25 Elective irradiation of the pelvic lymph nodes has been debated for more than 30 years. In men with a low risk of pelvic lymph node involvement according to the Partin tables26 or the Roach formula,27 it is difficult to justify treating the lymph nodes. In men with more advanced disease, a recent RTOG trial argues in favor of including the pelvic lymph nodes.28 Patients with a risk of pelvic lymph nodes of >15% were enrolled in this fourarm trial. Preliminary results indicate that elective radiation therapy to the pelvic lymph nodes when combined with neoadjuvant androgen deprivation improves BRFS. In the absence of compelling data to argue the contrary, in patients receiving radiation therapy with a risk of
lymph nodes above 15%, elective pelvic nodal irradiation should be strongly considered. BIOCHEMICAL RELAPSE-FREE SURVIVAL: EXTERNAL BEAM RADIATION THERAPY Soon after the discovery of PSA in the serum of men with prostate cancer this protein began to be used to monitor the results of therapy.29 Early reports indicated that measured serum PSA would decrease in the first several months for the majority of men with T1-2 prostate cancer treated with EBRT.30–32 Soon thereafter radiation oncologists began to incorporate PSA into the definition of disease-free survival. In the early 1990s, a number of different definitions of BRFS following EBRT were developed and reported in the peer-reviewed literature. The multiple definitions led to considerable difficulties in deciding when biochemical relapse had occurred and made comparisons and interpretation of published reports difficult. In an attempt to reconcile the numerous definitions of biochemical relapse, the American Society of Therapeutic Radiology and Oncology (ASTRO) convened a conference to discuss the role of PSA measurements after radiation therapy. The result of this conference was the publication of the ASTRO Consensus Definition (ACD) of biochemical failure.33 The ACD defined biochemical failure as three consecutive rises from a nadir value, and the time to failure was the midpoint between the nadir value and the first rise. To date, the utilization of the ACD is not universal.34 Weaknesses of the present definition have been identified.35–37 Despite these problems many investigators continue to report their results using the ACD, and the results reported in this chapter will rely on the ACD unless otherwise stated. A number of series providing external beam radiation results according to prognostic grouping are outlined in Table 26B-2.12,16,17,38 The definition of the low-risk group is relatively consistent between series but there are differences in the higher risk categories across series. This likely explains the consistent results observed in the low-risk group, whereas the BRFS results in the higher risk groups are slightly different. A brief summary of each report follows. Shipley et al.38 and others published a pooled analysis examining BRFS following EBRT in 1999. In this report, data from 1765 patients with T1-2 prostate cancer treated between 1988 and 1995 at six separate institutions were collected and analyzed. None of these patients were treated with ADT. Fifty-one percent of patients were treated with 3DCRT. The median follow-up was 4.1 years and the minimum follow-up was 24 months. The ACD was used to calculate BRFS. The 5-year estimate of BRFS for all patients was 65.8% (95% CI 62.8 to 68). Recursive partitioning analysis of pretreatment PSA level, clinical T-stage, and Gleason score produced four
480
Part V Prostate Gland and Seminal Vesicles
Table 26B-2 Five-year BRFS Following EBRT for T1-2 Prostate Cancer According to Prognostic Group Authors Shipley et al.
Zelefsky et al.
Kupelian et al.
D’Amico et al.
No. Patients
Tx Dates
Median Follow-Ups
Median Dose (Gy)
Prognostic Group
1765
1988–1995
4.1 years
69.4
743
628
381
1988–1995
1990–1998
1988–2000
3 years
51 months
3.8 years
75.6
70.2
70.4
5-Year BRFS
Reference No.
I
81
38
II
69
III
47
IV
29
Favorable
85
Intermediate
65
Unfavorable
35
Favorable
90*
Unfavorable
59*
Low
78
17
12
16
Intermediate <34% 65 Intermediate >34% 35 High
40
*Eight-year BRFS.
prognostic groups. According to prognostic group the 5-year BRFS ranged from 81% to 29%. Only 5% of biochemical relapses occurred beyond 5 years. This paper provides a good benchmark of the results achievable with EBRT in the early 1990s. Zelefsky et al.17 have reported on 743 men treated at the Memorial Sloan-Kettering Cancer Center between 1988 and 1995. These men were treated according to a phase I dose-escalation study to assess the toxicity of high-dose 3DCRT. Ninety-six men were treated to 68.4 Gy, 266 treated to 70.2 Gy, 320 to 75.6 Gy, and 61 patients treated to 81 Gy. One hundred and ninety-five (26%) patients were in clinical stage T3. Two hundred and thirteen patients (29%) received neoadjuvant androgen deprivation therapy (ADT) to reduce the size of the prostate gland and reduce the total dose to the bladder and rectum. The median follow-up was 36 months with 22% of patients followed for 4 to 8 years. The 5-year rate of BRFS was dependent on T stage (T1-2 versus T3), pretreatment PSA (<10 versus = 10), and Gleason score (= 6 versus >6). Patients without poor risk features (T1-2, PSA < 10, Gleason score = 6) experienced a BRFS of 85%. The 5-year BRFS in men with a single poor risk feature was 65% and 35% in men with more than one poor risk feature. Prescription dose of greater than or equal to 75.6 Gy was also an independent predictor of BRFS.
Kupelian et al.12 have published the results of 628 men with T1-2 treated with EBRT at the Cleveland Clinic between 1990 and 1998. Patients were treated to doses between 68 and 78 Gy (median 70.2 Gy). Conformal techniques were used in 321 (51%) of patients. Twentythree percent of patients were treated with ADT for a median of 6 months. The median follow-up was 51 months and an average of 8.7 PSA levels were obtained per patient in follow-up. The 8-year rate of BRFS for all patients was 70%. On multivariable analysis T stage, pretreatment PSA, Gleason score, and neoadjuvant ADT were all independent predictors of BRFS. The authors divided patients into a favorable group (T1-2a, Gleason score < 6, and pretreatment PSA < 10) and an unfavorable group (T2b or T2c, or Gleason score > 6, or pretreatment PSA > 10). The 8-year BRFS were 90% and 59% for the favorable and unfavorable groups respectively. In the unfavorable group, total doses above 72 Gy were associated with improved BRFS, 75% versus 41% (p < 0.001). D’Amico and colleagues have reported a retrospective cohort study of 381 men treated with EBRT between 1988 and 2000.16 All men were treated with conformal methods. The median central axis dose was 70.4 Gy. No patient received ADT. The median follow-up is 3.8 years (range 1 to 12.9 years).
Chapter 26B Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy 481
The estimates of BRFS at 8 years following treatment were dependent on prognostic group. The 8-year BRFS in the low-risk group (T1-2a, Gleason score < 7, and pretreatment PSA < 10) was 78% (95% CI 72 to 83). The intermediate-risk group (PSA > 10 but <20, Gleason score 7, or T-2b) was divided further according to the percent positive biopsies (<34% versus >34%). The 8-year BRFS in the low volume intermediate-risk group was 65% (95% CI 58 to 72) compared to 35% (95% CI 12 to 55) in the high volume intermediate-risk group. The 8-year BRFS was 40% (95% CI 28 to 52) in the high-risk group. Summarizing this information, it is clear that pretreatment variables can be combined to create prognostic groups. In men with favorable-risk disease, EBRT is associated with 5-year BRFS of 78% to 90%. Men with intermediate- and high-risk features experience 5-year BRFS at 5 years of approximately 65% and 35%, respectively. EBRT alone to conventional doses (70 Gy) appears insufficient in men with T1-2 disease and intermediate- or high-risk features. THE EVIDENCE FOR DOSE ESCALATION Several reports from patients treated in the pre-PSA era suggested that improved results were possible in men with locally advanced and/or high-grade disease with doses above 70 Gy.39,40 In fact, a randomized trial from Shipley and investigators at the Massachusetts General Hospital demonstrated improved local control in patients with high-grade disease when a proton boost [to 75.6 cobalt Gray equivalent (CGE)] was added to photon irradiation.41 A number of contemporary series provide evidence that doses above 72 Gy may benefit patients with T1-2 prostate cancer.12,17,42 Results from these series are outlined in Table 26B-3. All of these series are nonrandomized and the follow-up is generally shorter in men treated to higher doses. The ASTRO definition is very sensitive to length of follow-up making the conclusions from these nonrandomized reports less than definitive. The investigators at M.D. Anderson Hospital have reported 5-year results from a randomized trial comparing conventional dose (70 Gy) EBRT to high-dose (78 Gy) EBRT.43 Three hundred and one men were randomized and are eligible for analysis. Patients were treated between 1993 and 1998. The primary endpoint of the trial was BRFS. The two arms were well matched with respect to known prognostic factors. With a median follow-up of 60 months, the 6-year BRFS was improved in the 78-Gy arm versus the 70-Gy arm, 70% versus 64%, p = 0.03 (Figure 26B-2A). A subset analysis using a stratification variable included in the randomization process indicated that the benefit from the high-dose treatment was restricted to patients with a pretreatment PSA above 10 ng/ml. In those patients with
a pretreatment PSA above 10 ng/ml, the BRFS was 62% in the 78-Gy arm versus 42% in the 70-Gy arm, p = 0.03 (Figure 26B-2B). In patients with a PSA below 10 ng/ml, there was no evidence of a treatment effect according to radiation dose with BRFS of 75% in both arms, p = nonsignificant (NS) (Figure 26B-2C). As the total dose to the prostate gland increases, the possibility of increased rectal or urinary morbidity has been examined in a number of studies. One prospective trial has concluded that 3DCRT produces fewer late effects than conventional techniques when similar doses are used.44 The dose-limiting toxicity in most reports of dose escalation appears to be rectal bleeding.45–47 The time course of the development of gastrointestinal complications is shorter than the time course of the development of genitourinary complications so that late bladder toxicity may not yet be evident. In the randomized trial from M.D. Anderson Hospital of 78 Gy versus 70 Gy, the rate of Grade 2 or greater rectal complications was higher in the 78-Gy arm, 26% versus 12% (p = 0.001).43 The results from this trial and other reports indicate that rectal injury following 3DCRT is a function of dose and volume.43,45–47 The RTOG has recently completed a multi-institutional phase I/phase II dose-escalation trial of 3DCRT (RTOG 94-06). Late toxicity of the first three dose levels (68.4, 73.8, and 79.2 Gy) has been published.48,49 To date no Grades 4 to 5 toxicities have been observed and the rate of Grade 3 toxicity is less than 5%. The rates of GI/GU morbidity are lower than observed with historic controls to lower dose levels using conventional approaches. This observation has led to the development and activation of a randomized phase III trial comparing 79.2 to 70.2 Gy (RTOG P-0126). The improved conformality of IMRT compared to 3DCRT offers the possibility of further dose escalation without an increase in normal tissue injury. One of the largest experiences with this new approach has been described by Zelefsky et al.50 In this report, the early toxicity and biochemical results from 772 men treated at Memorial Hospital between 1996 and 2001 are outlined. Ninety percent of these men were treated to a dose of 81 Gy and 10% were treated to 86.4 Gy. The late rectal and urinary toxicity was much lower than expected. The actuarial probability of Grade 2 or greater rectal toxicity was 4%, while the analogous rate of Grade 2 or greater urinary toxicity was 15% with most of the urinary toxicity manifest as urethra symptoms requiring medication. Although the follow-up is relatively short (24 months), the BRFS is encouraging. The 3-year rates of BRFS is 92%, 86%, and 81% according to the low-, intermediate-, and high-risk groups, respectively. Preliminary results from other institutions are available51 but longer follow-up is required to assess 5 to 10-year BRFS and long-term morbidity.
Figure 26B-2 A, BRFS curves of M.D. Anderson phase III randomized trial, including all patients. B, BRFS curves of M.D. Anderson phase III randomized trial, including only patients with a pretreatment PSA greater than or equal to 10 ng/ml. C, BRFS curves of M.D. Anderson phase III randomized trial, including only patients with a pretreatment PSA less than 10 ng/ml. Table 26B-3 Five-Year BRFS Following EBRT for Prostate Cancer According to Prescription Dose Authors
No. Patients Tx Dates
Median Follow-ups
Dose Group (Gy)
Prognostic Group
Hanks et al.
618
53 month
Low (<72.5)
PSA <10, favorable
77
High (=72.5)
PSA <10, favorable
89
Low (<76)
PSA <10, unfavorable
70
High (=76)
PSA <10, unfavorable
92
Low (<76)
PSA 10–19.9, favorable
72
High (=76)
PSA 10–19.9, favorable
86
Low (<76)
PSA 10–19.9, unfavorable
51
High (=76)
PSA 10–19.9, unfavorable
82
Low (<76)
PSA >20, favorable
23
High (=76)
PSA >20, favorable
63
Low (<76)
PSA >20, unfavorable
29
High (=76)
PSA >20, unfavorable
26
Low (64–70)
Low risk
83
High (75–81)
Low risk
95
Low (64–70)
Intermediate risk
55
High (75–81)
Intermediate risk
78
Low (64–70)
High risk
23
High (75–81)
High risk
53
Low (<72)
Favorable
81
High (=72)
Favorable
98
Low (<72)
Unfavorable
41
High (=72)
Unfavorable
75
Zelefsky et al.
530
Kupelian et al. 738
1988–1997
1988–1995
1986–1999
36 months
45 months
5-year Reference BRFS No. 42
17
12
Chapter 26B Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy 483
ADT AND EXTERNAL RADIATION THERAPY FOR T1-2 PROSTATE CANCER The results from nonrandomized historic comparisons of patients treated with EBRT with or without ADT have suggested a benefit to ADT,12,52 although this observation has not been universal.17 It is possible that the effect of ADT is not observed in the Memorial series because of the consistently high prostate doses. These results that demonstrate a benefit to ADT combined with EBRT in T1-2 prostate cancer must be considered hypothesis generating as often the follow-up is shorter in the ADT group that will lead to a perceived improvement in BRFS using the ACD. The results from four phase III randomized trials comparing EBRT alone to EBRT combined with ADT in men with locally advanced disease have been published.53–56 In all studies, the addition of ADT has produced improved local control, decreased rates of distant metastases, and improved disease-free survival. Overall survival was improved in two studies.53,54 Although the inclusion criteria are different for each of these three studies, most patients included in these studies had locally advanced disease. For instance, only 9% of patients in the EORTC study had T1-2 tumors and none of the patients in RTOG 86-10 had nonpalpable disease. The magnitude of benefit for the addition of ADT to EBRT in men with T1-2 prostate cancer is unknown. Randomized trials from the RTOG and the Dana-Farber Cancer Center investigating the impact of short-term (4 to 6 months) neoadjuvant ADT in men with T1-2 prostate have been completed but have yet to be reported. HISTORIC PERSPECTIVE, INTERSTITIAL BRACHYTHERAPY Brachytherapy is a general term used to describe the placement of a radioactive source(s) into or near (Gk. “Brachy” = near) a tumor. The source can be placed permanently or reside temporarily. Brachytherapy is used in the treatment of many solid tumors, including breast, head and neck, gynecologic, and thoracic neoplasms. The history of prostate brachytherapy extends nearly 100 years beginning in the first decade of the 20th century in Paris. A number of renowned urologists have contributed to the history of prostate brachytherapy. The first technique was described by Pasteau and Degrais in 1911.57 Their approach relied on temporary intraurethral placement of radium capsules. Soon thereafter, Hugh Hampton Young obtained some radium and modified the Paris technique by designing his own device to hold the radium. A surgeon at the Memorial Hospital in New York, Benjamin Barringer, was the first to describe an interstitial approach using radon capsules.58
These capsules were far smaller than the radium capsules and allowed for easier placement. In the 1960s, Whitmore and Carlton popularized the open retropubic approach using permanent I-125 sources.59,60 The modern closed IB procedure was originally described by Holm et al.61 and was further developed by Blasko et al.62 The present widespread utilization of permanent prostate brachytherapy (PPB) is the result of prostate screening and improved technology that currently allows for an outpatient procedure that generally can be accomplished in 1 to 2 hours. The earliest prostate brachytherapy procedures using radium or radon involved temporary sources. In the 1970s low-dose rate Ir-192 was used as a temporary prostate brachytherapy (TPB) source.63,64 This procedure required surgical exposure of the prostate. The open procedure allowed for guidance of transperineal, template aided after-loading needles into the prostate gland. The needles were manually directed by way of a suprapubic surgical incision. After the needles were positioned, Ir-192 ribbons were manually loaded. The typical dose-rate ranged from 0.5 to 1.0 Gy per hour delivering a total dose of 30 to 35 Gy over 2 to 3 days. EBRT (35 to 45 Gy) would follow. The initial results with this procedure were encouraging but several disadvantages, including the necessity for an open procedure and radiation exposure from manual loading, have limited the use of temporary LDR prostate brachytherapy to very few centers at present. TECHNIQUE OF PERMANENT PROSTATE BRACHYTHERAPY The modern technique of PPB includes three components: (1) treatment planning, (2) placement of the sources, and (3) an evaluation of the implant quality. In the early work of Ragde and Blasko, the three components were separated in time but advances in imaging and treatment planning software have led to these components being compressed. In some centers, all three components are completed in the operating room at the same sitting.65 Brachytherapy treatment planning determines the optimal radiation dose distribution for an individual patient depending on the size and shape of the prostate gland. A number of different dose distribution philosophies have been described. Most practitioners will use some sort of peripheral loading scheme to reduce the dose to the urethra and maximize dose to the peripheral zone. In patients with very low-risk features, some authors have used MR guidance to target only the peripheral zone of the prostate gland.66 Transrectal ultrasound images are generally used for the treatment planning but other imaging modalities have been described. Two radioisotopes are in common use in the United States: I-125 and Pd-103. Each of these isotopes possesses
484
Part V Prostate Gland and Seminal Vesicles
Table 26B-4 Prescription Doses (Gy) for PPB According to Isotope Radioisotope
Dose (Gy), PPB Alone
I-125
144
Pd-103
115–125
Dose (Gy), PPB plus EBRT* 100–110 80–90
*Combined with EBRT (40–50 Gy).
a low-dose rate and low energy relative to the isotope used for temporary brachytherapy (Ir-192). The radiation dose prescribed differs according to isotope and whether brachytherapy is used alone (monotherapy) or combined with EBRT (combined modality therapy, CMT) (Table 26B-4).67 The low energy of the sources simplifies radiation protection precautions and patients can be discharged from the hospital immediately. The radioactive sources are usually placed transperineally using some form of perineal template and ultrasound guidance (although MR- and CT-guided approaches have been described). Two techniques of source deposition are commonly employed. In the preloaded technique, brachytherapy needles with sources and spacers are prepared beforehand and with each needle placement multiple sources are deposited. In the afterloading approach, a specially designed brachytherapy “gun” is used to deposit one source at a time. In either case, the needle or gun can be visualized and placed in the desired location. Close monitoring of the source deposition process allows the operator to recognize and adjust for changes that may occur intraoperatively (prostate gland movement, prostate gland swelling, and source movement). Some form of postprocedure dosimetric evaluation is mandatory.68 Most investigators use CT for this assessment but other methods have been described. With commercially available software it is possible to import CT images and outline the prostate gland and nearby structures (urethra, rectum, penile bulb, etc.). Automated algorithms have been designed to identify the sources. Based on the delineation of the prostate and the location of the sources, isodose distributions can be calculated and dose-volume histograms created (Figure 26B-3). The accurate delineation of prostate volumes on CT images following brachytherapy can be difficult. Postoperative prostate swelling and degradation of the image secondary to the metallic sources can lead to disagreement amongst reviewers.69 A standard definition of a “good implant” has yet to be universally accepted by the brachytherapy community. There is early evidence that delivering at least 90% of the prescription dose to 90% of the prostate gland results in improved BRFS.70,71 Although preliminary work is
B Figure 26B-3 Postimplant CT scan images through the midgland (A) with resulting dose-volume histogram (B). From the dose-volume histogram it is clear that 94% of the prostate is encompassed by the 100% isodose line, while the vast majority of the urethra is receiving less than 150% of the prescription dose.
emerging, acceptable doses to normal tissues (urethra, rectum, penile bulb) are much less clear. TECHNIQUE OF TEMPORARY PROSTATE BRACHYTHERAPY TPB also benefitted from the advances in ultrasound and treatment planning computers in the 1980s. The simultaneous development of high-dose rate afterloading machines stimulated a number of investigators across the globe to refine the methods of TPB.
Chapter 26B Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy 485
High-dose rate (HDR) afterloading machines are devices that contain a single high-intensity Ir-192 source (5 to 10 Ci). The source is attached to the end of a wire that is controlled by the machine. The machine can precisely position the source and keep it there for a specified period of time (usually measured in seconds). The source can thus be moved within needles to a number of locations allowing the treating physician to create a dose distribution of virtually any shape or size. Most HDR prostate brachytherapy techniques utilize transrectal ultrasound to guide the needles into place within and around the prostate.72 A variety of perineal templates have been devised to assist needle placement. In some centers, ultrasound-based treatment planning allows treatment to be delivered at the time of the needle placement.73 Most sites use CT images for the treatment planning process. HDR needles are identified, and the prostate gland is contoured on the CT images. Nearby structures (urethra, rectum) are identified, and a the desired dose is delivered to the prostate while limiting the dose to the urethra and rectum. Once a plan has been generated, the afterloading machine delivers the treatment by moving the source to different locations within the HDR catheters in a sequential manner. Typical treatment times range from 5 to 10 minutes. Typically patients receive multiple treatments over the course of 6 to 36 hours. Due to the high energy of the Ir-192 source, a specially shielded room is required for treatment. Most clinicians have combined HDR brachytherapy with 4 to 5 weeks of EBRT although HDR monotherapy is taking place in a few centers. Dose-fractionation schedules differ between institutions and despite attempts, no consensus has been reached as to the best treatment schedule.
BIOCHEMICAL RELAPSE-FREE SURVIVAL FOLLOWING PROSTATE BRACHYTHERAPY As with patients treated with EBRT, serum PSA levels decline soon after treatment with PPB. The ACD is commonly used to define BRFS following PPB, although the ACD was not originally intended for this purpose. Some advocate the use of a nadir definition following PPB instead of the ACD.74 The results outlined in this section use a number of different definitions to define BRFS making comparisons problematic. Compared to men treated with EBRT, men treated with PPB are more likely to manifest a sudden increase in serum PSA to be followed by a decline. Authors have described this phenomenon as PSA bounce or PSA spike.75–77 The incidence of this phenomenon ranges from 17% to 35% depending on the definition utilized. The median time to PSA spike is 18 to 24 months and mostly occurs within the first 5 years. The magnitude of PSA bounce has been as large as 15 ng/ml, although most bounces are less than 3 ng/ml. Two reports find PSA spikes to be more common in younger men, which may reflect an increased level of sexual activity.76,77 To date in three separate reports, there has been no correlation between PSA bounce and subsequent BRFS.75–77 Clinicians should be aware of this phenomenon and exercise caution prior to instituting salvage therapy. The results described later are divided according to whether patients are treated with monotherapy (PPB alone) or CMT (PPB plus EBRT). CMT has been recommended over monotherapy for a number of reasons: increased intraprostatic dose; treatment of extracapsular prostate cancer; and as a form of insurance to “fill in” the areas of reduced dose that may result from a suboptimal implant. Some institutions use CMT selectively in men
Table 26B-5 BRFS Following PPB for T1-2 Prostate Cancer No. Patients
P/I
Percentage of T1/T2
Median PSA
Follow-ups (months)
BRFS (years)
97
I/P
13/87
18
NS
18
76 (2)
392
I/P
6/92
20
7.3
30
80 (5)
66
P
23/77
20
NS
41
0–85 (5)
Blasko9
230
P
30/70
40
7.3
41.5
83.5 (9)
Ragde85
147
I
22/78
0
8.8*
93
66 (12)
Zelefsky15
248
I
58/42
25
7
48
71 (5)
Brachman et al.82
695
I/P
17/83
15
NS
51
64 (7)
Grimm84
125
I
24/76
0
5.1
~78
85 (10)
Authors Stock86 Grado et al.83 D’Amico16
Percentage of Gleason Score > 6
486
Part V Prostate Gland and Seminal Vesicles
with high-risk features,78 whereas others use CMT in all patients regardless of T stage, PSA, and Gleason score.79 The necessity of supplemental EBRT in patients treated with PPB has yet to be demonstrated. No randomized trials have been reported. The addition of supplemental EBRT to PPB increases patient’s and physician’s time commitment with a resulting increase in costs.80 There is also the possibility that combination therapy will increase morbidity and decrease HRQOL compared to PPB or EBRT alone.81 The hypothesis that supplemental EBRT improves results is currently being tested in a recently activated randomized trial of the RTOG (RTOG P-0232). This trial includes measurements of patient-reported HRQOL. BIOCHEMICAL RELAPSE-FREE SURVIVAL: PPB ALONE Table 26B-5 summarizes the results achieved with PPB alone in men with clinically localized prostate cancer.9,10,15,82–86 PSA-based disease-free survival is 63% to 93% at 5 years in selected patients treated with PB alone. Two published reports with the longest follow-up report 10-year actuarial estimates of BRFS to be 66% to 85%.85,87 Brief descriptions of a few selected series are provided later. Blasko et al.9 have reported on a consecutive series of 230 men with T1-2 prostate cancer treated with Pd-103 alone at the Seattle Prostate Institute between 1988 and 1995. The majority of patients (56%) presented with palpable T2a disease and 40% were classified as having a Gleason score of 7 or higher. The median PSA was 7.3 ng/ml. Seventy-five percent of men had a pretreatment PSA below 10 ng/ml. Two consecutive PSA elevations were required for biochemical recurrence. The median follow-up was 41.5 months. The estimate of BRFS was 83.5% (95% CI 78.3 to 88.7) at 9 years. Pretreatment PSA and Gleason score were found to be predictive of BRFS on univariate analysis. Grouping patients into three risk categories according to T stage, Gleason score and pretreatment PSA value demonstrated significant differences in BRFS. Zelefsky et al.15 have provided an update of the experience at Memorial Hospital. These authors reported on 248 men treated with prostate brachytherapy alone between 1989 and 1996. All men were treated with I-125. The median age was 65. Most men (58%) had nonpalpable disease. Twenty-four percent of men had a Gleason score of 7 or higher. The median pretreatment PSA was 7 ng/ml, and 78% of men had a PSA of less than 10 ng/ml. Three rises in PSA was defined as evidence of recurrence, and the median follow-up was 48 months (range 12 to 126 months). The authors categorized patients into previously published prognostic groups according to T stage, Gleason score, and pretreatment
PSA. The 5-year estimate of disease-free survival for all patients was 71%. The 5-year estimates of disease-free survival according to prognostic risk groups were as follows: 88% for favorable risk; 77% for intermediate risk; and 38% for high risk (p < 0.0001). Grimm et al.87 recently published an update of the Seattle experience with prostate brachytherapy as monotherapy. The authors reported on 125 men treated between January 1998 and December 1990 with I-125 prostate brachytherapy alone. These men were carefully selected and had very favorable pretreatment characteristics. The clinical T stage was less than or equal to T2a in 85% of men, and all men had a Gleason score of 6 or less. Forty-three percent of men had a pretreatment PSA below 4 ng/ml and more than 75% had a pretreatment PSA below 10 ng/ml. Patients were routinely followed with physical examination and serum PSA determinations at 3 to 6-month intervals during the first 5 years and yearly thereafter. The median follow-up was 81.4 months. These authors used two consecutive PSA rises as evidence of failure. Disease-free survival was estimated by the Kaplan–Meier method. Eight men were documented to have clinical failures (4 with positive prostate biopsy and 4 with positive bone scan). All clinical failures were diagnosed within 5 years. Eight additional patients were found to have biochemical evidence of disease recurrence. The Kaplan–Meier estimate of biochemical disease-free survival in this cohort is 85.1% (95% CI 79.3 to 90.9) at 10 years. The only variable that predicted for BDFS in this cohort was pretreatment PSA. The authors then provided a comparison to a cohort of 97 men treated by the same authors early in their prostate brachytherapy experience. The authors reported on 97 men treated between January 1986 and December 1987. The demographic characteristics of this earlier cohort were similar to the later cohort, but the BDFS was significantly worse in the men treated in 1986 and 1987 (10 Yr BDFS 65% versus 87%, p = 0.0002). The authors concluded that the superior results in the later patients were the result of refinements in the prostate brachytherapy technique. In weighing the available evidence about the efficacy of PPB, several important points should be considered. Each and every report represents a retrospective, singleinstitution experience. The extent to which the results achieved at centers of excellence are generalizable to general community practice is unknown. The Seattle group has provided the best evidence that a learning curve exists for the PB procedure in that the BRFS rates are inferior in the group of patients treated early in their experience despite similar pretreatment characteristics. Differences in patient selection criteria, brachytherapy techniques, experience of the brachytherapists, and definitions of biochemical relapse preclude any definitive statements comparing techniques, isotopes, etc. From an
Chapter 26B Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy 487
Table 26B-6 Five-Year BRFS Following PPB for T1-2 Prostate Cancer According to Prognostic Groups Authors Blasko9
Zelefsky15
Grimm84
No. Patients
Follow-Ups (Months)
Isotope
Risk Category
5-Year BRFS (%)
Pd-103
Low
94
103
48.9
107
39.5
Intermediate
82
20
45.5
High
65
Favorable
88
92
Intermediate
77
22
Unfavorable
38
Low
87*
Intermediate
79*
Low
88
15
Intermediate
32
19
High
NA
112
I-125
97
I-125
27 D’Amico16
32
41.0
Pd-103
*Ten-year BRFS.
Table 26B-7 BRFS Following PPB Combined with EBRT for T1-2 Prostate Cancer Author
No. Patients
Ragde85
82
Blasko78
Isotope(s)
Implant MPD* (Gy)
EBRT Dose (Gy)
EBRT Fields
Follow-Ups (Years)
BRFS (%) (Years)
125-I
110
45
4-field: P-SV
10
79 (10)
231
125-I/103-Pd
110/90
45
4-field: P-SV
5
79 (9)
Lederman et al.89
348
125-I/103-Pd
110/90
45
4-field
4
77 (6)
Critz79
689
125-I
120
45
P-SV-PPT
4
88 (6)
Dattoli et al.88
124
103-Pd
90
41
Limited Pelvic
3.8
76 (4)
*Matched peripheral dose.
evidence-based perspective, the value of these results should be considered limited; multi-institutional, prospective trials are required. PSA OUTCOME STRATIFIED BY RISK GROUP Just as in patients treated with EBRT, results following PPB according to prognostic grouping have been published. Table 26B-6 summarizes the available information from those authors who reported results with PPB alone according to risk groups.9,10,15,87 The 5-year BRFS ranges from 88% to 94% in men with low-risk disease treated with PPB alone. Patients with more unfavorable features
have 5-year BRFS of 32% to 65%, suggesting that PPB alone is not adequate in these higher risk patients. This observation has led many authors to recommend supplemental EBRT or ADT (or both) in these men. Results with CMT are outlined in the following section. The use of ADT with PPB is discussed as follows. BIOCHEMICAL RELAPSE-FREE SURVIVAL: PPB COMBINED WITH EBRT The results from five centers with a significant experience with CMT (PPB plus EBRT) are outlined in Table 26B-7.78,79,85,88,89 All patients in these reports were treated
488
Part V Prostate Gland and Seminal Vesicles
after 1986 and have had continuous PSA follow-up available. The closed transperineal method of PPB was used in all cases. Three reports originate from centers where CMT is used in all prostate cancer cases,79,88,89 and two are from institutions that select CMT for higher risk patients, reserving PPB alone for patients with low-risk disease.78,85 Ragde et al.85 have described the results in 82 men treated with PPB (I-125, 110 Gy maximum permissible dose [MPD]) and EBRT (45 Gy). All men were treated between January 1987 and December 1989 so that the follow-up is quite long (median 122 months). These patients were selected for CMT based on high-risk features. The vast majority of men (84%) had palpable disease, although only four men were felt to have clinical extracapsular disease (T3). The mean PSA in this group was 14.7 ng/ml (sd 21.2), and 18 men (24%) had a Gleason score above 6. ADT was not used. The ACD was used to calculate BRFS. The 10-year estimate of BRFS was 79%. Blasko et al.78 have reported on 231 men treated with PPB (I-125, 110 Gy; Pd-103, 90 Gy) and EBRT (45 Gy). The median follow-up was 58 months. During this period, some men were treated with monotherapy, and the use of supplemental EBRT was at the discretion of the physician. The mean PSA was 15.6 ng/ml, and 35% of patients presented with a Gleason score above 7. No patients received ADT. The ACD was used to calculate BRFS. The results of BRFS were provided according to the prognostic groupings of Zelefsky. Ten-year BRFS estimates were 87%, 85%, and 62% for low-, intermediate-, and high-risk groups, respectively. In this report, the authors did compare the results with CMT to monotherapy according to risk group and found no group that benefitted from the addition of EBRT. Lederman et al.89 have reported on 348 patients with T1-3a disease treated with PPB (I-125, 110 Gy; Pd-103, 90 Gy) and EBRT (45 Gy). In this report, PPB was performed prior to EBRT. No patient received ADT. The median follow-up was 44 months. One hundred and sixty-four (50%) men had a pretreatment PSA above 10 ng/ml and 119 (34%) were assigned a Gleason score between 7 and 10. Only 17 (4.6%) men had T3 disease. The ACD was not used to define BRFS. Instead, biochemical failure was defined as the use of ADT anytime following treatment, or a serum PSA > 5.0 ng/ml at last follow-up, or two consecutive rises in serum PSA > 0.5 ng/ml. The estimated BRFS at 6 years for the entire group was 77% (95% CI 72% to 82%). The authors divided patients into risk groups according to pretreatment PSA, T stage, and Gleason score. The estimates of BRFS were 88%, 75%, and 51% for the low-, intermediate-, and high-risk groups, respectively. The results from the radiation therapy clinics of Georgia have been summarized recently.79 Six hundred
and eighty-nine men were treated between 1992 and 1996 and received an I-125 implant (120 Gy) followed in 3 weeks by EBRT (45 Gy). The median follow-up was 4 years. Twenty-eight (4%) men had a Gleason score above 7 and 44 (6%) had a pretreatment PSA above 20. No patient received ADT. As is the custom with these investigators, the ACD was not used to calculate BRFS. Instead, an absolute value of = 0.2 was used to define cure. Patients are censored if the PSA is declining (but not =0.2) at the time of analysis. The 5-year estimate of BRFS is 88%. Dattoli et al.88 have recently updated their experience with CMT in patients with high-risk features. They have reported on 161 men with T1-3 prostate cancer treated with PPB (Pd-103, 80 Gy) and EBRT (41.4 Gy). The PPB was performed for 4 weeks following EBRT. The median follow-up for nonfailing patients was 7 years. Approximately 25% of patients had a pretreatment PSA above 20. Approximately 20% of the patients were assigned a Gleason score above 7. The ACD was not used calculate BRFS. Instead, a PSA level of =0.2 ng/ml defined the absence of disease. The 10-year estimate of BRFS is 79%. The BRFS from two series that provide results according to prognostic grouping are summarized in Table 26B-8.78,89 Although the amount of information is small, it appears that patients with favorable (and perhaps intermediate-) risk disease do well with CMT, but patients with high-risk features do not fare nearly as well, suggesting that they may benefit from effective systemic therapy combined with local therapy. ADT AND PERMANENT PROSTATE BRACHYTHERAPY FOR T1-2 PROSTATE CANCER The use of ADT combined with PPB is common. In recent reports, ADT has been combined with PPB in 7% to 69% of cases.90 ADT may be utilized for three purposes: (1) to downsize the prostate to facilitate PPB; (2) to decrease morbidity; and (3) to improve cure rates. It is clear that 3 to 6 months of ADT will lead to a 30% to 40% reduction in prostate volume on transrectal US measurements.91 It is not clear that ADT reduces morbidity. In fact there at least is an evidence that ADT prior to PPB may increase acute urinary morbidity and decrease sexual function.92,93 The question whether ADT improves cure rates is more complicated. Whether the results of randomized trials showing a benefit for the addition of ADT to EBRT in patients with locally advanced disease can be extrapolated to lower risk patients treated with PPB is not known. The results from nonrandomized historic comparisons of patients treated with PPB with or without ADT have been inconsistent. Some reports indicate an improvement in BRFS94,95 while others do not.96 Given that most authors use the ACD in
Chapter 26B Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy 489
Table 26B-8 BRFS Following PPB Combined with EBRT for T1-2 Prostate Cancer According to Prognostic Groups Authors
No. Patients
Blasko78
231
Lederman et al.89
348
BRFS Time Point (years)
Low (%) (N)
Intermediate (%) (N)
High (%) (N)
10
87 (75)
85 (104)
62 (52)
5
88 (165)
75 (124)
51 (59)
Table 26B-9 BRFS Following HDR Brachytherapy and EBRT Authors
No. Patients
Percentage of T1-2
Median Follow-ups
Implant Dose (Gy)
No. Fractions
EBRT Dose (Gy)
BRFS (%) (years)
Borghede et al.97
50
76
45 months
20
2
50
84*
Dinges et al.98
82
26
24 months
18–20
2
45
53 (2)
Kovacs and Galalae99
144
68
8 years
30†
2
40
73 (8)‡
Mate et al.72
104
90
45 months
12–16
4
50.4
84 (5)§
Martinez100
207
91
4.4 years
16.5–23
2–3
46
74 (5)
*Eighteen-month crude rate. †Prescription dose to the peripheral zone. ‡Three consecutive PSA rises, all above 1.0 ng/ml. §For patients with pretreatment PSA < 20 ng/ml.
these reports, any results favoring the addition of ADT should be questioned. In all series, the follow-up is shorter in patients receiving ADT (representing a temporal trend seen nationwide), and the ACD is extraordinarily sensitive to length of follow-up. Randomized trials examining the value of ADT combined with PPB are required to make conclusive statements. BIOCHEMICAL RELAPSE-FREE SURVIVAL: HDR TEMPORARY PROSTATE BRACHYTHERAPY To date most reports of HDR brachytherapy have focused on men with T1-2 with intermediate- or highrisk features (>T2b, Gleason score > 6, pretreatment PSA >10), and the number of men with favorable disease included in these reports is small. The BRFS results of several series are summarized in Table 26B-9.72,97–100 The patients included in these series are very heterogeneous. BRFS is defined very differently with some series using an absolute PSA level to define cure and others relying on a rising PSA to define recurrent disease; only two of the series use the ACD to calculate BRFS. In some series, pretreatment ADT is given, making interpretation difficult. A small number of investigators have developed phase II protocols to examine the efficacy of HDR brachytherapy alone (without EBRT).101,102 Follow-up is too short to report BRFS, but the acute morbidity appears to be tolerable.
PARTICLE BEAM THERAPY Particle beams used in the treatment of prostate cancer include neutrons and photons. Early randomized trials suggested a benefit to neutron therapy in men with locally advanced disease but an increase in complications was noted.103 The complications were attributed to inadequate collimation and inability to shield normal tissues near the prostate. It is now possible to use conformal methods with neutrons, and the results remain encouraging.104 For the time being, however, the lack of treatment facilities with neutron capabilities limit the use of this modality. The number of proton facilities in the United States is similarly small, although many new sites are under construction. The physical characteristics of proton beams are fundamentally different than those of photon beams. The dose gradient outside of the PTV is much steeper with proton beams and may result in lower morbidity. The largest experience to date is from investigators at Loma Linda.105 The early results appear similar to the results achieved with 3DCRT. Comparison trials of proton beam versus photon beam therapy are ongoing.
REFERENCES 1. Millikan R, Logothetis C: Update of the NCCN guidelines for treatment of prostate cancer. Oncology (Huntingt) 1997;11(11A):180–193.
490
Part V Prostate Gland and Seminal Vesicles
2. Hanks GE, More on the Uro-Oncology Research Group Report of radical surgery vs. radiotherapy for adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 1988;14(5):1053–1054. 3. Paulson DF, Lin GH, Hinshaw W, et al: Radical surgery versus radiotherapy for adenocarcinoma of the prostate. J Urol 1982;128(3):502–504. 4. D’amico AV, Moul J, Carroll PR, et al: Cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. J Clin Oncol 2003;21(11; 6-1-2003):2163–2172. 5. Roach M III, Lu J, Pilepich MV, et al: Long-term survival after radiotherapy alone: Radiation Therapy Oncology Group prostate cancer trials. J Urol 1999;161(3):864–868. 6. Albertsen PC, Hanley JA, Gleason DF, et al: Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998;280(11; 9-16-1998):975–980. 7. Jhaveri FM, Klein EA, Kupelian PA, et al: Declining rates of extracapsular extension after radical prostatectomy: evidence for continued stage migration. J Clin Oncol 1999;17(10):3167–3172. 8. Ung JO, Richie JP, Chen MH, et al: Evolution of the presentation and pathologic and biochemical outcomes after radical prostatectomy for patients with clinically localized prostate cancer diagnosed during the PSA era. Urology 2002;60(3):458–463. 9. Blasko JC, Grimm PD, Sylvester JE, et al: Palladium-103 brachytherapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2000;46(4; 3-1-2000):839–850. 10. D’amico AV, Whittington R, Malkowicz SB, et al: Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280(11; 9-16-1998):969–974. 11. D’amico AV, Whittington R, Malkowicz SB, et al: Pretreatment nomogram for prostate-specific antigen recurrence after radical prostatectomy or external-beam radiation therapy for clinically localized prostate cancer. J Clin Oncol 1999;17(1):168–172. 12. Kupelian PA, Elshaikh M, Reddy CA, et al: Comparison of the efficacy of local therapies for localized prostate cancer in the prostate-specific antigen era: a large single-institution experience with radical prostatectomy and external-beam radiotherapy. J Clin Oncol 2002;20(16; 8-15-2002):3376–3385. 13. Merrick GS, Butler WM, Galbreath RW, et al: H. Five-year biochemical outcome following permanent interstitial brachytherapy for clinical T1–T3 prostate cancer. Int J Radiat Oncol Biol Phys 2001;51 (1; 9-1-2001):41–48. 14. Zagars GK, Pollack A, von Eschenbach AC: Prognostic factors for clinically localized prostate carcinoma: analysis of 938 patients irradiated in the prostate specific antigen era. Cancer 1997;79(7; 4-1-1997):1370–1380. 15. Zelefsky MJ, Hollister T, Raben A, et al: Five-year biochemical outcome and toxicity with transperineal CT-planned permanent I-125 prostate implantation for
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
patients with localized prostate cancer. Int J Radiat Oncol Biol Phys 2000;47(5; 7-15-2000):1261–1266. D’amico AV, Whittington R, Malkowicz SB, et al: Biochemical outcome after radical prostatectomy or external beam radiation therapy for patients with clinically localized prostate carcinoma in the prostate specific antigen era. Cancer 2002;95(2; 7-15-2002): 281–286. Zelefsky, M. J., Leibel, S. A., Gaudin, P. B., et al: Dose Escalation With Three-Dimensional Conformal Radiation Therapy Affects the Outcome in Prostate Cancer. Int J Radiat Oncol Biol Phys 6-1-1998;41(3): 491-500. Ray, G. R., Cassady, J. R., and Bagshaw, M. A. Definitive Radiation Therapy of Carcinoma of the Prostate. A Report on 15 Years of Experience. Radiology 1973;106(2):407-18. Reinstein, L. E., Wang, X. H., Burman, C. M., et al: A Feasibility Study of Automated Inverse Treatment Planning for Cancer of the Prostate. Int J Radiat Oncol Biol Phys 1-1-1998;40(1):207-14. Prescribing, recording, and reporting photon beam therapy. ICRU Report 50. Bethesda, MD; 1993. Report No.: 9. Pickett, B., Roach, M., III, Verhey, L., et al: The Value of Nonuniform Margins for Six-Field Conformal Irradiation of Localized Prostate Cancer. Int J Radiat Oncol Biol Phys 4-30-1995;32(1):211-8. Fiorino, C., Reni, M., Bolognesi, A., et al: Set-Up Error in Supine-Positioned Patients Immobilized With Two Different Modalities During Conformal Radiotherapy of Prostate Cancer. Radiother Oncol 1998;49(2):133-41. Malone, S., Szanto, J., Perry, G., et al: A Prospective Comparison of Three Systems of Patient Immobilization for Prostate Radiotherapy. Int J Radiat Oncol Biol Phys 10-1-2000;48(3):657-65. Lattanzi, J., McNeeley, S., Hanlon, A., et al: Ultrasound-Based Stereotactic Guidance of Precision Conformal External Beam Radiation Therapy in Clinically Localized Prostate Cancer. Urology 2000;55(1):73-8. Pouliot, J., Aubin, M., Langen, K. et al: (Non)-Migration of Radiopaque Markers Used for on-Line Localization of the Prostate With an Electronic Portal Imaging Device. Int J Radiat Oncol Biol Phys 7-1-2003;56(3): 862-6. Partin, A. W., Kattan, M. W., Subong, E. N., et al: Combination of Prostate-Specific Antigen, Clinical Stage, and Gleason Score to Predict Pathological Stage of Localized Prostate Cancer. A Multi-Institutional Update. JAMA 5-14-1997;277(18):1445-51. Roach M III, Marquez C, Yuo HS, et al: Predicting the risk of lymph node involvement using the pretreatment prostate specific antigen and gleason score in men with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1-1-1994;28(1; 1-11994):33–73. Roach M III, DeSilvio M, Lawton C, et al: Phase III trial comparing whole-pelvic versus prostate-only
Chapter 26B Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy 491
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
radiotherapy and neoadjuvant versus adjuvant combined androgen suppression: Radiation Therapy Oncology Group 9413. J Clin Oncol 2003;21(10; 5-15-2003): 1904–1911. Stamey TA, Yang N, Hay AR., et al: Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987;317(15; 10-8-1987): 909–916. Kaplan I, Prestidge BR, Cox RS, et al: Prostate specific antigen after irradiation for prostatic carcinoma. J Urol 1990;144(5):1172–1175. Kaplan ID, Cox RS, Bagshaw MA: A model of prostatic carcinoma tumor kinetics based on prostate specific antigen levels after radiation therapy. Cancer 1991;68(2; 7-15-1991):400–405. Zagars GK, Pollack A: Kinetics of serum prostate-specific antigen after external beam radiation for clinically localized prostate cancer. Radiother Oncol 1997;44(3): 213–221. Consensus Statement: Guidelines for PSA following radiation therapy. American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys 1997;37(5):1035–1041. McMullen KP, Lee WR: A structured literature review to determine the use of the American Society for Therapeutic Radiology and Oncology Consensus Definition of Biochemical Failure. Urology 2003;61(2):391–396. Horwitz EM, Uzzo RG, Hanlon AL, et al: Modifying the American Society for Therapeutic Radiology and Oncology Definition of Biochemical Failure to minimize the influence of backdating in patients with prostate cancer treated with 3-dimensional conformal radiation therapy alone. J Urol 2003;169(6):2153–2157. Kattan MW, Fearn PA, Leibel S, et al: The definition of biochemical failure in patients treated with definitive radiotherapy. Int J Radiat Oncol Biol Phys 2000;48(5; 12-1-2000):1469–1474. Vicini FA, Kestin LL, Martinez AA: The importance of adequate follow-up in defining treatment success after external beam irradiation for prostate cancer. Int J Radiat Oncol Biol Phys 1999;45(3; 10-1-1999): 553–561. Shipley WU, Thames HD, Sandler HM, et al: Radiation therapy for clinically localized prostate cancer: a multi-institutional pooled analysis. JAMA 1999;281(17; 5-5-1999):1598–1604. Hanks GE, Martz KL, Diamond JJ: The effect of dose on local control of prostate cancer. Int J Radiat Oncol Biol Phys 1988;15(6):1299–1305. Perez CA, Walz BJ, Zivnuska FR, et al: Irradiation of carcinoma of the prostate localized to the pelvis: analysis of tumor response and prognosis. Int J Radiat Oncol Biol Phys 1980;6(5):555–563. Shipley WU, Verhey LJ, Munzenrider JE, et al: Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. Int J Radiat Oncol Biol Phys 1995;32(1; 4-30-1995):3–12.
42. Hanks GE, Hanlon AL, Pinover WH, et al: Dose selection for prostate cancer patients based on dose comparison and dose response studies. Int J Radiat Oncol Biol Phys 2000;46(4; 3-1-2000):823–832. 43. Pollack A, Zagars GK, Starkschall G, et al: Prostate cancer radiation dose response: results of the M. D. Anderson phase III randomized trial. Int J Radiat Oncol Biol Phys 2002;53(5; 8-1-2002):1097–1105. 44. Dearnaley DP, Khoo VS, Norman AR, et al: Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomised trial. Lancet 1999;353(9149; 1-23-1999): 267–272. 45. Hanlon AL, Schultheiss TE, Hunt MA, et al: Chronic rectal bleeding after high-dose conformal treatment of prostate cancer warrants modification of existing morbidity scales. Int J Radiat Oncol Biol Phys 1997;38 (1; 4-1-1997):59–63. 46. Lee WR, Hanks GE, Hanlon AL, et al: Lateral rectal shielding reduces late rectal morbidity following high dose three-dimensional conformal radiation therapy for clinically localized prostate cancer: further evidence for a significant dose effect. Int J Radiat Oncol Biol Phys 1996;35(2; 5-1-1996):251–257. 47. Storey MR, Pollack A, Zagars G, et al: Complications from radiotherapy dose escalation in prostate cancer: preliminary results of a randomized trial. Int J Radiat Oncol Biol Phys 2000;48(3; 10-1-2000):635–642. 48. Michalski JM, Purdy JA, Winter K, et al: Preliminary report of toxicity following 3D radiation therapy for prostate cancer on 3DOG/RTOG 9406. Int J Radiat Oncol Biol Phys 2000;46(2; 1-15-2000):391–402. 49. Ryu JK, Winter K, Michalski JM, et al: Interim report of toxicity from 3D conformal radiation therapy (3D-CRT) for prostate cancer on 3DOG/RTOG 9406, level III (79.2 Gy). Int J Radiat Oncol Biol Phys 2002;54 (4; 11-15-2002):1036–1046. 50. Zelefsky MJ, Fuks Z, Hunt M, et al: High-dose intensity modulated radiation therapy for prostate cancer: early toxicity and biochemical outcome in 772 patients. Int J Radiat Oncol Biol Phys 2002;53(5; 8-1-2002): 1111–1116. 51. Mohan DS, Kupelian PA, Willoughby TR: Short-course intensity-modulated radiotherapy for localized prostate cancer with daily transabdominal ultrasound localization of the prostate gland. Int J Radiat Oncol Biol Phys 2000;46(3; 2-1-2000):575–380. 52. D’amico AV, Schultz D, Loffredo M, et al: Biochemical outcome following external beam radiation therapy with or without androgen suppression therapy for clinically localized prostate cancer. JAMA 2000;284(10; 9-13-2000): 1280–1283. 53. Bolla M, Collette L, Blank L, et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002;360(9327; 7-13-2002):103–106. 54. Granfors T, Modig H, Damber JE, et al: Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer
492
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
Part V Prostate Gland and Seminal Vesicles with or without pelvic lymph node involvement: a prospective randomized study. J Urol 1998;159(6): 2030–2034. Lawton CA, Winter K, Murray K, et al: Updated results of the phase III Radiation Therapy Oncology Group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;49 (4; 3-15-2001):937–946. Pilepich MV, Winter K, John MJ, et al: Phase III Radiation Therapy Oncology Group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001;50 (5; 8-1-2001):1243–1252. Aronowitz JN: Dawn of prostate brachytherapy: 1915–1930. Int J Radiat Oncol Biol Phys 2002;54 (3; 11-1-2002):712–718. Aronowitz JN: Benjamin Barringer: originator of the transperineal prostate implant. Urology 2002; 60(4):731–734. Eastham JA, Kattan MW, Groshen S, et al: Fifteen-year survival and recurrence rates after radiotherapy for localized prostate cancer. J Clin Oncol 1997; 15(10):3214–3222. Zelefsky MJ, Whitmore WF Jr: Long-term results of retropubic permanent 125iodine implantation of the prostate for clinically localized prostatic cancer. J Urol 1997;158(1):23–29. Holm HH, Juul N, Pedersen JF, et al: Transperineal 125iodine seed implantation in prostatic cancer guided by transrectal ultrasonography. J Urol 1983; 130(2):283–286. Blasko JC, Ragde H, Grimm, PD, et al: Prostate brachytherapy: importance of technique. J Clin Oncol 1996;14(6):1965–1967. Martinez A, Benson RC, Edmundson GK, et al: Pelvic lymphadenectomy combined with transperineal interstitial implantation of iridium-192 and external beam radiotherapy for locally advanced prostatic carcinoma: technical description. Int J Radiat Oncol Biol Phys 1985;11(4):841–847. Puthawala AA, Syed AM, Austin PA, et al: Long-term results of treatment for prostate carcinoma by staging pelvic lymph node dissection and definitive irradiation using low-dose rate temporary iridium-192 interstitial implant and external beam radiotherapy. Cancer 2001;92(8; 10-15-2001):2084–2094. Nag S, Ciezki JP, Cormack R, et al: Intraoperative planning and evaluation of permanent prostate brachytherapy: report of the American Brachytherapy Society. Int J Radiat Oncol Biol Phys 2001;51 (5; 12-1-2001):1422–1430. D’amico AV, Cormack R, Tempany CM, et al: Real-time magnetic resonance image-guided interstitial brachytherapy in the treatment of select patients with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1998;42(3; 10-1-1998):507–515.
67. Nag S, Beyer D, Friedland J, et al: American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999;44 (4; 7-1-1999):789–799. 68. Nag S, Bice W, DeWyngaert K, et al: The American Brachytherapy Society recommendations for permanent prostate brachytherapy postimplant dosimetric analysis. Int J Radiat Oncol Biol Phys 2000;46(1; 1-1-2000): 221–230. 69. Lee WR, Roach M III, Michalski J, et al: Interobserver variability leads to significant differences in quantifiers of prostate implant adequacy. Int J Radiat Oncol Biol Phys 2002;54(2; 10-1-2002):457–461. 70. Potters L, Cao Y, Calugaru E, et al: A comprehensive review of CT-based dosimetry parameters and biochemical control in patients treated with permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2001;50(3; 7-1-2001):605–614. 71. Stock RG, Stone NN, Tabert A, et al: A dose-response study for I-125 prostate implants. Int J Radiat Oncol Biol Phys 1998;41(1; 4-1-1998):101–108. 72. Mate TP, Gottesman JE, Hatton J, et al: High dose-rate afterloading 192iridium prostate brachytherapy: feasibility report. Int J Radiat Oncol Biol Phys 1998;41(3; 6-1-1998):525–533. 73. Martinez AA, Kestin LL, Stromberg JS, et al: Interim report of image-guided conformal high-dose-rate brachytherapy for patients with unfavorable prostate cancer: the William Beaumont phase II dose-escalating trial. Int J Radiat Oncol Biol Phys 2000;47(2; 5-1-2000): 343–352. 74. Critz FA: A standard definition of disease freedom is needed for prostate cancer: undetectable prostate specific antigen compared with the American Society of Therapeutic Radiology and Oncology Consensus Definition. J Urol 2002;167(3):1310–1313. 75. Cavanagh W, Blasko JC, Grimm PD, et al: Transient elevation of serum prostate-specific antigen following (125)I/(103)Pd brachytherapy for localized prostate cancer. Semin Urol Oncol 2000;18(2):160–165. 76. Critz FA, Williams WH, Benton JB, et al: Prostate specific antigen bounce after radioactive seed implantation followed by external beam radiation for prostate cancer. J Urol 2000;163(4):1085–1089. 77. Stock RG, Stone NN, Cesaretti JA: Prostate-specific antigen bounce after prostate seed implantation for localized prostate cancer: descriptions and implications. Int J Radiat Oncol Biol Phys 2003;56(2; 6-1-2003): 448–453. 78. Blasko JC, Grimm PD, Sylsvester JE, et al: The role of external beam radiotherapy with I-125/Pd-103 brachytherapy for prostate carcinoma. Radiother Oncol 2000;57(3):273–278. 79. Critz FA, Williams WH, Levinson AK, et al: Simultaneous irradiation for prostate cancer: intermediate results with modern techniques. J Urol 2000;164(3 Pt 1):738–741.
Chapter 26B Clinically Localized Adenocarcinoma of the Prostate: Radiation Therapy 493 80. Brandeis J, Pashos CL, Henning JM, et al: A nationwide charge comparison of the principal treatments for early stage prostate carcinoma. Cancer 2000;89(8; 10-15-2000): 1792–1799. 81. Brandeis JM, Litwin MS, Burnison CM, et al: Quality of life outcomes after brachytherapy for early stage prostate cancer. J Urol 2000;163(3):851–857. 82. Brachman DG, Thomas T, Hilbe J, et al: Failure-free survival following brachytherapy alone or external beam irradiation alone for T1-2 prostate tumors in 2222 patients: results from a single practice. Int J Radiat Oncol Biol Phys 2000;48(1; 8-1-2000):111–117. 83. Grado GL, Larson TR, Balch CS, et al: Actuarial disease-free survival after prostate cancer brachytherapy using interactive techniques with biplane ultrasound and fluoroscopic guidance. Int J Radiat Oncol Biol Phys 1998;42(2; 9-1-1998):289–298. 84. Grimm PD, Blasko JC, Sylvester JE, et al: 10-year biochemical (prostate-specific antigen) control of prostate cancer with (125)I brachytherapy. Int J Radiat Oncol Biol Phys 2001;51(1; 9-1-2001):31–40. 85. Ragde H, Korb LJ, Elgamal AA, et al: Modern prostate brachytherapy. prostate specific antigen results in 219 patients with up to 12 years of observed follow-up. Cancer 2000;89(1; 7-1-2000):135–341. 86. Stock RG, Stone NN, DeWyngaert, et al: Prostate specific antigen findings and biopsy results following interactive ultrasound guided transperineal brachytherapy for early stage prostate carcinoma. Cancer 1996;77(11; 6-1-1996):2386–2392. 87. Grimm PD, Blasko JC, Sylvester JE, et al: 10-year biochemical (prostate-specific antigen) control of prostate cancer with (125)I brachytherapy. Int J Radiat Oncol Biol Phys 2001;51(1; 9-1-2001):31–40. 88. Dattoli M, Wallner K, True L, et al: Long-term outcomes after treatment with external beam radiation therapy and palladium 103 for patients with higher risk prostate carcinoma: influence of prostatic acid phosphatase. Cancer 2003;97(4; 2-15-2003):979–983. 89. Lederman GS, Cavanagh W, Albert PS, et al: Retrospective stratification of a consecutive cohort of prostate cancer patients treated with a combined regimen of external-beam radiotherapy and brachytherapy. Int J Radiat Oncol Biol Phys 2001;49(5; 4-1-2001):1297–1303. 90. Lee WR: The role of androgen deprivation therapy combined with prostate brachytherapy. Urology 2002;60(3, Suppl 1):39–44. 91. Gleave ME, Goldenberg SL, Chin JL, et al: Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and pathological effects. J Urol 2001;166(2):500–506. 92. Crook J, McLean M, Catton C, et al: Factors influencing risk of acute urinary retention after TRUS-guided permanent prostate seed implantation. Int J Radiat Oncol Biol Phys 2002;52(2; 2-1-2002):453–460. 93. Hollenbeck BK, Dunn RL, Wei JT, et al: Neoadjuvant hormonal therapy and older age are associated with
94.
95. 96.
97.
98.
99.
100.
101.
102.
103.
104.
105.
adverse sexual health-related quality-of-life outcome after prostate brachytherapy. Urology 2002; 59(4):480–484. Merrick GS, Butler WM, Galbreath RW, et al: Five-year biochemical outcome following permanent interstitial brachytherapy for clinical T1–T3 prostate cancer. Int J Radiat Oncol Biol Phys 2001;51(1; 9-1-2001): 41–84. Stone NN, Stock RG: Prostate brachytherapy: treatment strategies. J Urol 1999;162(2):421–426. Potters L, Torre T, Ashley R, et al: Examining the role of neoadjuvant androgen deprivation in patients undergoing prostate brachytherapy. J Clin Oncol 2000;18(6):1187–1192. Borghede G, Hedelin H, Holmang S, et al: Irradiation of localized prostatic carcinoma with a combination of high dose rate iridium-192 brachytherapy and external beam radiotherapy with three target definitions and dose levels inside the prostate gland. Radiother Oncol 1997; 44(3):245–250. Dinges S, Deger S, Koswig S, et al: High-dose rate interstitial with external beam irradiation for localized prostate cancer—results of a prospective trial. Radiother Oncol 1998;48(2):197–202. Kovacs G, Galalae R: Fractionated perineal highdose-rate temporary brachytherapy combined with external beam radiation in the treatment of localized prostate cancer: Is lymph node sampling necessary? Cancer Radiother 2003;7(2):100–106. Martinez AA, Gustafson G, Gonzalez J, et al: Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer. Int J Radiat Oncol Biol Phys 2002;53(2; 6-1-2002):316–327. Martinez AA, Pataki I, Edmundson G, et al: Phase II prospective study of the use of conformal high-dose-rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: a feasibility report. Int J Radiat Oncol Biol Phys 2001;49(1; 1-1-2001):61–69. Yoshioka Y, Nose T, Yoshida K, et al: High-dose-rate interstitial brachytherapy as a monotherapy for localized prostate cancer: treatment description and preliminary results of a phase I/II clinical trial. Int J Radiat Oncol Biol Phys 2000;48(3; 10-1-2000):675–681. Russell KJ, Caplan RJ, Laramore GE, et al: Photon versus fast neutron external beam radiotherapy in the treatment of locally advanced prostate cancer: results of a randomized prospective trial. Int J Radiat Oncol Biol Phys 1994;28(1; 1-1-1994):47–54. Lindsley KL, Cho P, Stelzer KJ, Koh WJ, AustinSeymour M, Russell KJ, Laramore GE, Griffin TW: Fast neutrons in prostatic adenocarcinomas: worldwide clinical experience. Recent Results Cancer Res. 1998;150:125–136. Slater JD, Rossi CJ Jr, Yonemoto LT, et al: Conformal proton therapy for early-stage prostate cancer. Urology 1999;53(5):978–984.
C H A P T E R
27 Regionally Advanced Adenocarcinoma of the Prostate (T3-4N+M0): Management and Prognosis Mary Frances McAleer, MD, PhD, and Richard K. Valicenti, MD
Adenocarcinoma of the prostate is considered to be regionally advanced once malignant cells are identified outside the prostatic capsule (T3a), have invaded the seminal vesicle(s) (T3b), or involve adjacent bladder, rectum, musculature, or pelvic wall (T4). Also, included in this category are tumors with nodal metastases (N1-3).1 While the overall incidence of prostate cancer in the U.S. rose with the widespread institution of prostate-specific antigen (PSA) screening in the early 1990s, the percentage of patients presenting with regionally advanced disease has decreased.2,3 Using pretreatment PSA level, Gleason score and clinical stage, Partin et al.4 were the first to demonstrate that the risk of regional spread of prostate cancer can be estimated. Although the actual diagnosis of regionally advanced prostate cancer requires biopsy or pathology demonstrating adenocarcinoma with extra-prostatic spread, multimodality staging (combined use of tumor stage, pretreatment PSA, and Gleason score) is an important and useful method to identify men at high risk of subclinical regionally advanced disease.5 GENERAL MANAGEMENT OF REGIONALLY ADVANCED PROSTATE CANCER Locoregional therapy for T3 or greater adenocarcinoma of the prostate, including radical prostatectomy (RP) (with or without lymphadenectomy) and radiation therapy alone, have not resulted in improved disease-specific or overall survival (OS) in these patients, with the majority demonstrating clinically overt metastases by 10 years.6–8 Given these poor outcomes with monotherapy, the recent NCCN guidelines and patterns of care prostate cancer decision tree advocate the use of androgen deprivation both as neoadjuvant cytoreductive ther494
apy in conjunction with external beam radiation therapy (EBRT) to enhance local control and disease-free survival, and as adjuvant systemic treatment for management of occult metastatic disease.9,10 ANDROGEN DEPRIVATION THERAPY Rationale Androgens have been shown to stimulate the growth and proliferation of neoplastic prostate cells both in vitro and in vivo by interacting with androgen receptors on these cells.11–14 Inhibition of this interaction by hormone therapy has been shown to reduce gross tumor volume significantly.15 This theoretically leads to increased tumor blood flow and decreased tumor hypoxia, which, in turn, may allow for improved treatment outcomes with locoregional treatment. Androgen deprivation may additionally improve therapeutic results by eradicating distant micrometastatic disease not controlled by surgery or radiation therapy alone. The mechanism of these effects is thought to involve the induction of apoptosis in the targeted prostate cells, which may have an additive or even synergistic effect when combined with the DNAdamaging action of radiation.16,17 Methods of Androgen Deprivation Orchiectomy The most commonly used method of androgen deprivation worldwide is orchiectomy. Surgical castration has been shown to remove 95% of circulating testosterone, with long-lasting reduction of serum levels of this hormone. Orchiectomy has both economic and compliance advantages over the other methods of androgen deprivation
Chapter 27 Regionally Advanced Adenocarcinoma of the Prostate (T3-TN + M0) 495
discussed later.18 The psychologic ramifications of this approach, however, have limited its widespread use in the U.S. Estrogen Supplementation Estrogens are thought to act either indirectly by suppressing pituitary gonadotropin, which, in turn, inhibits testicular testosterone synthesis, or by directly binding to prostate cell hormone receptors and thereby competitively blocking receptor binding by androgens. Use of the synthetic estrogen diethylstilbestrol (DES) by the Veterans Administration Cooperative Urologic Research Group (VACURG) was the first exogenous hormone therapy given for prostate cancer. DES at doses of 5 mg/day showed similar survival to orchiectomy and improved cancer-specific survival; however, cardiovascular mortality was increased with DES treatment.19 Reducing the DES dose to 1 mg/day resulted in equivalent survival as with the higher dose, but castrate levels of testosterone were not achieved.19,20 Side effects of estrogenic therapy, such as fluid retention, gynecomastia, and decreased libido, have resulted in its infrequent use in clinical practice. Progesterone Supplementation Medroxyprogesterone (Provera) and megestrol (Megace), two progestins, also suppress gonadotropin release and thus interfere with testosterone production.21 These agents have not been found to inhibit serum androgen levels completely or for any prolonged period of time, however, and therefore they are not used as monotherapeutic agents.
Antiandrogens Antiandrogens function as competitive inhibitors of testosterone by binding to the androgen receptors on prostate cells. The two classes of antiandrogens include steroidal and nonsteroidal agents. The former include aminoglutethimide, cyproterone acetate (Androcur), and megestrol, which additionally suppress testosterone by hypothalamic and pituitary negative feedback mechanisms. The nonsteroidal antiandrogens, namely, flutamide, bicalutamide (Casodex) and nilutamide, block androgen uptake and function in prostate cells primarily at the level of the androgen receptor. In contrast to the steroidal antiandrogens, the nonsteroidal agents do not decrease gonadotropin or testosterone levels, and thus have been shown to maintain libido and potency. Of the nonsteroidal antiandrogens, bicalutamide has higher binding affinity and longer area under the curve (half-life of 7 to 10 days) with a dose of 50 mg daily being equivalent to 750 mg/day (250 mg every 8 hours) of flutamide (half-life of 5 to 6 hours).28 Diarrhea and, less frequently, but more serious hepatic toxicity are side effects of flutamide therapy.29 Bicalutamide is associated with more breast tenderness and gynecomastia than castration.30 Preliminary results of two multi-institutional randomized trials comparing bicalutamide monotherapy (150 mg daily) to surgical or medical (goserelin 3.6 mg every 28 days) castration in patients with nonmetastatic prostate cancer demonstrated equivalent survival with median follow-up of over 200 weeks.30 Although longer follow-up is needed, bicalutamide monotherapy may provide a quality of life advantage over castration with the preservation of sexual function in patients treated with the antiandrogen.
Luteinizing Hormone Releasing Hormone Analogs Luteinizing hormone releasing hormone (LHRH) analogs, such as goserelin (Zoladex) and leuprolide (Lupron), function by initially inducing luteinizing hormone (LH) and follicle stimulating hormone (FSH) release by the pituitary followed by a gradual inhibition (after 1 to 2 weeks) of these hormones. This activity results in an initial increase (1 to 2 days) then decrease of testosterone to castrate levels (by 20 to 28 days).22 LHRH agonists have been shown in randomized trials to be as efficacious as orchiectomy or DES in the treatment of advanced prostate cancer.23,24 The initial transient elevation of testosterone associated with LHRH agonist use has resulted in exacerbation of pain in approximately 10% of patients with metastatic disease and is thought to be due to a flare reaction of tumor cell proliferation.25,26 To avoid this flare reaction, antiandrogens (see later) are frequently coadministered either temporarily or continuously with the LHRH analogues.27 The principle side effects of LHRH agonists are impotence, decreased libido, testicular atrophy, and hot flashes.
ANDROGEN DEPRIVATION AND RADIATION THERAPY Multivariate analysis of data from a prospective trial of the Radiation Therapy Oncology Group (RTOG study 75-06) investigating pretreatment factors associated with disease outcome revealed that hormonal therapy either prior to or during radiation therapy for prostate carcinoma correlated with improved local tumor control.31 As a result, androgen deprivation has been studied prospectively in conjunction with radiation therapy in two contexts: (1) neoadjuvantly as cytoreductive therapy in patients with bulky primary tumors; (2) adjuvantly in patients at increased risk for micrometastatic disease. Each of these approaches is presented in detail later. Radiation Therapy with Neoadjuvant Hormonal Therapy Based on the promising results of RTOG 75-06 noted earlier, as well as on the observation of >94% primary
496
Part V Prostate Gland and Seminal Vesicles
tumor clearance in both a phase II randomized study examining the efficacy and toxicity of megestrol and DES with definitive EBRT for locally advanced prostate cancer (RTOG 83-07), and a similar phase II trial (RTOG 85-19) investigating flutamide and goserelin cytoreduction with EBRT the RTOG conducted a phase III trial (86-10) comparing EBRT with and without hormonal therapy given prior to and during the radiation treatment.31–34 The patients enrolled in RTOG 86-10 had bulky T26-T4 prostate cancers, with 91% being lymph node negative.35 The androgen deprivation method used in this phase III trial consisted of two months of goserelin (3.6 mg subcutaneously every 28 days) and flutamide (250 mg orally 3 times daily) prior to EBRT (45 to 50 Gy pelvic RT plus 20 to 25 Gy prostate boost) with continued hormonal therapy during the radiation treatment. There were 456 patients who could be evaluated in RTOG 86-10, with 226 patients in the androgen deprivation arm and 230 patients in the EBRT-only arm. The recently reported long-term update of this study (median 6.7-year follow-up) revealed that the 8-year local control rate was significantly higher in the patients treated with neoadjuvant hormonal therapy (NHT) and EBRT (42%) than in the EBRT-only group (30%, p = 0.016).35 The incidence of distant metastases was also significantly lower in the patients with androgen deprivation (34% versus 45%, p = 0.04). The actuarial and biochemical disease-free survival rates were also significantly improved in these patients (33% versus 21%, p = 0.004; and 24% versus 10%, p < 0.0001, respectively). While there was no difference in OS of all patients in the two groups, a survival benefit was observed in patients with Gleason score 2 to 6 receiving the hormone treatment (70% versus 52%, p = 0.015). The treatment delivered in both arms of RTOG 86-10 was relatively well tolerated, the highest frequency of treatment termination being attributed to flutamide toxicity (16%). The main criticism of this study is that initial staging was based on digital rectal examination (DRE) and not PSA or biopsy results. Nevertheless, this study set the standard for future trials and clinical application of combination therapy for regionally advanced prostate cancer. One such prospective randomized trial from Canada investigated 64.8 Gy EBRT alone (n = 41), versus flutamide and LHRH agonist therapy delivered either 3 months prior to EBRT (n = 43) or 3 months prior to, during, and 6 months following EBRT (n = 36) for patients with T2a to T4 adenocarcinoma of the prostate.36 Trans-rectal ultrasound (TRUS)-guided biopsies performed at 24 months following EBRT showed 65%, 28%, and 5% residual cancer in each group, respectively (p = 0.00001). While there is apparent local benefit of prolonged androgen deprivation versus NHT with EBRT, no other clinical outcome measures were reported to support a survival advantage with the use of
neoadjuvant or prolonged hormonal therapy in these patients. Radiation Therapy with Adjuvant Hormonal Therapy The use of androgen deprivation as adjuvant systemic therapy with EBRT in patients with regionally advanced adenocarcinoma of the prostate has been studied prospectively by several groups. One of the earliest reports of adjuvant hormonal therapy and radiation therapy in patients with T3-4NxM0 prostate cancer was a 15year follow-up by Zagars et al.37 Patients in this study were randomized either to EBRT alone or to EBRT plus DES until relapse or death. Significant improvement in actuarial disease-free survival was seen in patients receiving the DES with EBRT (63%) in contrast to those treated with EBRT alone (35%). No difference in clinical local tumor control or OS was detected, however, in part because of DES use in relapsed patients receiving EBRT-only, and also because of increased intercurrent mortality in patients initially receiving DES with EBRT. A phase III trial by the RTOG (study 85-31) examined the effect of EBRT (44 to 46 Gy to pelvis with 20 to 25 Gy prostate boost or 60 to 65 Gy to prostatic bed if postprostatectomy) either with or without adjuvant goserelin (3.6 mg subcutaneously every 28 days) in patients with locally advanced prostate cancer. Goserelin was administered to 477 patients during the last week of EBRT or at relapse to 468 patients initially treated with EBRT-only. Statistically significant reduction in rates of local failure and distant metastases, and improvement in biologic and clinical response rates were observed in patients receiving goserelin adjuvantly versus at relapse, both were at 5- and 8-year follow-up.38,39 No difference in OS was detected in the initial versus relapse hormonal therapy groups at 5 years (75% versus 71%) or at 8 years (49% versus 47%). Subset analysis of patients with Gleason score 8 to 10 (without prostatectomy) did demonstrate significant benefit of adjuvant androgen deprivation with respect to both OS and cause-specific failure compared with hormonal therapy at relapse.39 A similar phase III study was conducted by the European Organization for Research on Treatment of Cancer (EORTC) that investigated EBRT (≤50 Gy to pelvis with 20 Gy prostate/seminal vesicle boost) with or without hormonal therapy (cyproterone 150 mg orally 3 times daily for 4 weeks starting 1 week prior to EBRT and goserelin starting day 1 of EBRT and continuing for 3 years) in patients with prostate cancer at high risk for metastatic disease (high grade T1-2 or any grade T3-4, no nodal disease at/above common iliac chains, M0). After median follow-up of 5.5 years, statistically significant reduction in rates of locoregional failure and distant metastases, and improvement in biologic and clinical response rates were again observed in the group receiving
Chapter 27 Regionally Advanced Adenocarcinoma of the Prostate (T3-TN + M0) 497
Percentage of patients
adjuvant hormonal therapy as reported in RTOG 8610.40,41 In contradistinction to the RTOG 85-31 results, however, the use of adjuvant hormonal therapy in the EORTC study was associated with significantly improved disease-specific survival (94% with hormonal therapy versus 79% without hormonal therapy, p = 0.0001) and OS (78% with hormonal therapy versus 62% without hormonal therapy, p = 0.0002) (Figure 27-1). While the EORTC study is of great importance in justifying the use of early adjuvant androgen deprivation in the treatment of regionally advanced prostate cancer, this study is not without its criticisms. First, patients were stratified by clinical stage and histologic grade and not by PSA or biopsy findings. Second, local control was deter100 90 80 70 60 50 40 30 20 10 0
mined by TRUS and DRE, not by PSA or biopsy. Third, the 5-year survival results for the EBRT-only arm is lower than expected for this group (compare with RTOG 85-31 results). Finally, the 5-year follow-up period is considered short for prostate cancer trials. The duration of androgen deprivation required for therapeutic benefit in patients with regionally advanced prostate cancer is not yet established. The effect of 2-year maintenance adjuvant goserelin therapy versus observation alone following 4 months of goserelin and flutamide therapy (2 months prior to and 2 months during EBRT) in patients with T2b-4 disease was investigated in RTOG study 92-02. Treatment response at 4.8-year follow-up reflects the findings of RTOG 85-31,
79% (72−86%) Combined treatment 62% (52–72%)
Radiation therapy
p = 0.001 (overall log-rank test)
0
1
2
3
4
5 6 Years
7
8
9
10 No. who died
No. patients at risk Radiotherapy
208 183 139
96 67
39
23
10
6
1
58
Combined treatment
207 190 144 111 82
55
39
19
7
0
35
Percentage of patients
A 85% (78–92%)
100 90 80 70 60 50 40 30 20 10 0
Combined treatment
Radiotherapy
48% (38–58%) p < 0.001 (overall log-rank test)
0
1
2
3
4
5 6 Years
7
8
9
No. with disease progression
No. patients at risk Radiotherapy Combined treatment
208 163 107
10
59 38
19
11
5
3
1
78
207 189 138 108 78
51
36
16
5
0
20
B Figure 27-1 A, Kaplan-Meier estimate of OS. B, Disease-free survivals in EORTC study. The number of patients at risk for the event at each time point is the total number of patients less the number of patients in whom disease progressed or who were lost to follow-up.40
498
Part V Prostate Gland and Seminal Vesicles
with significantly decreased rates of local progression, distant metastases, and biochemical failure in patients receiving long-term androgen suppressive therapy compared with short-term suppression. No OS benefit was detected (79% long-term suppression versus 77% shortterm suppression, p > 0.05). Subset analysis did demonstrate both disease-specific survival (90% versus 78%, p = 0.007) and OS (80% versus 69%, p = 0.02) advantage with the longer duration hormonal therapy in patients with Gleason scores 8 to 10.42 The results of this study support the continued use and study of long-term androgen deprivation in patients with poorly differentiated or locally advanced prostate cancer. Further support of long-duration hormonal therapy in patients at high risk for subclinical metastatic prostate cancer comes from a Swedish prospective randomized trial that investigated the effect of orchiectomy in patients receiving EBRT (versus EBRT-only) for pelvis-confined T1-4, N0-3, M0 disease.43 This trial, originally designed to accrue 400 patients, was terminated early after enrolling only 91 patients because of a high frequency of disease progression in the patients receiving EBRT alone. Among patients with nodal positive disease, a significant reduction in disease progression (61% versus 31%) and overall mortality (61% versus 38%) was observed after a median follow-up time of 9.3 years. While OS was improved in node negative patients treated with EBRT alone than in those with lymph node metastases, no difference was seen in either group treated with EBRT and orchiectomy, suggesting a benefit of early hormonal therapy in locally advanced prostate cancer. The issue of early versus delayed hormonal therapy in patients with T2-4 or asymptomatic M+ prostate adenocarcinoma was addressed by the Medical Research Council (MRC) Prostate Cancer Working Party Investigation Group.44 In this trial, 934 patients with expected survival of ≥12 months were randomized at the physicians’ discretion to receive hormonal therapy (orchiectomy or LHRH agonist with flare protection) either early (within 6 weeks of presentation) or deferred until disease progression. There was a statistically significant reduction in diseasespecific mortality in both patients with no known metastases, as well as with any M status (0, X or +) receiving immediate hormonal therapy (54% versus 70% and 62% versus 71%, respectively) at 10 years follow-up. There was also an increased risk of major complications including cord compression, extra-skeletal metastases, or ureteral obstruction in the delayed hormone group. The OS of patients in both treatment groups was lower than that observed in other studies (26% at 10 years). Timing and Duration of Hormonal Therapy with Radiation Although the studies outlined earlier demonstrate improved local and distant control with both neoadjuvant
and adjuvant hormonal therapy in conjunction with EBRT, OS time was increased only in patients or subsets of patients receiving androgen deprivation early and for prolonged duration. One phase III trial conducted by the RTOG (94-13) was designed to compare NHT (androgen deprivation using goserelin or leuprolide with flutamide 2 months before and during EBRT, arms 1 and 2) directly with adjuvant therapy (androgen deprivation 4 months after EBRT, arms 3 and 4) to patients with high-risk localized prostate cancer irradiated either 70.2 Gy to the prostate only (arms 2 and 4) or 50.4 Gy to the whole pelvis with a 19.8 Gy prostate boost (arms 1 and 3). Roach et al.45 reported initial results in 1323 patients after median follow-up of 59.3 months. Significant progression-free survival (PFS) at 4 years was observed in patients receiving NHT and whole pelvis irradiation versus NHT and prostate-only irradiation (59.6% versus 44.3%, p = 0.001). Four-year PFS in patients receiving adjuvant hormonal therapy with either whole pelvis or prostate-only RT was comparable to that of patients given NHT and prostate-only RT. While OS was similar in all 4 treatment arms (88%, 83%, 81%, and 82%, respectively), there is a trend for improved OS in the NHT/whole pelvis RT group. Longer duration followup is needed, however, since the median survival in these patients is not likely to be reached for several years. There are several other phase III trials currently ongoing designed to address the issue of timing and duration of androgen deprivation in patients with locoregionally advanced prostate cancer. These are discussed in the section “Future Directions.” ANDROGEN DEPRIVATION AND PROSTATECTOMY RP is typically reserved for patients with clinically organconfined disease (T1-2, N0, M0); pelvic lymph node dissection being recommended for those with Gleason score 5 to 6 and PSA ≥ 20 ng/ml, Gleason score ≥ 7 and PSA ≥ 15 ng/ml, or clinical T3N0M0.9 Clinical assessment of extent of disease in prostate adenocarcinoma has been found to underestimate the actual degree of disease spread in approximately 50% of cases.46–49 Additional therapy for patients with known or suspected extraglandular disease includes preoperative hormonal therapy or postoperative hormonal therapy with or without radiation treatment. Prostatectomy and Neoadjuvant Hormonal Therapy Preoperative androgen deprivation has been investigated in several prospective randomized trials to test the hypothesis that tumors initially considered nonoperable (clinical T3, Nx, or greater) could be rendered resectable
Chapter 27 Regionally Advanced Adenocarcinoma of the Prostate (T3-TN + M0) 499
after 3 months of hormonal treatment.50–52 The rate of positive surgical margins in these studies was significantly reduced by 40% to 60% in patients receiving the hormonal therapy compared with those treated by surgery alone. This effect on margin status, however, has not translated into any therapeutic improvement, there being no difference in biochemical or clinical recurrence rates in both treatment groups. This lack of therapeutic benefit has been attributed, in part, to insufficient follow-up, underpowered study design, or inadequate duration of hormone therapy. To address the issue of optimal length of androgen deprivation required before RP, the Canadian Urologic Oncology Group designed a phase III trial comparing 3-month versus 8-month preoperative treatment with leuprolide and flutamide in patients with T1b-T2 adenocarcinoma of the prostate. Gleave et al.53 recently presented the 3-year follow-up results of this study. Prolonged androgen deprivation in these patients was associated with significant reduction in preoperative PSA levels (75.1% versus 43.3% with PSA < 0.1 ng/ml, p < 0.0001), positive surgical margins (12% versus 23%, p = 0.0106), and incidence of lymph node metastasis (0.4% versus 3.1%, p = 0.038). The longer duration of hormone therapy was also associated with significantly more patients clinically downsized based on DRE or TRUS evaluation. Prolonged androgen deprivation was associated with more toxicity, 87% of patients treated for 8 months reporting hot flashes versus 72% of those treated for 3 months (p < 0.0001). Longer follow-up is required to assess the effect of duration of preoperative hormonal therapy on clinical and biochemical outcomes in these patients. Prostatectomy and Adjuvant Hormonal Therapy The role of adjuvant hormonal therapy in patients found to have positive nodal metastasis after RP with pelvic lymphadenectomy for T1-2 prostate cancer was prospectively investigated by Messing et al.54 In this study, patients were randomized to immediate hormonal therapy (goserelin or orchiectomy) versus observation until disease progression. After a median follow-up of >7 years, the early use of androgen deprivation was associated with significant improvement in PFS (77% versus 18%, p < 0.001), cause-specific survival (92% versus 69%, p < 0.01), as well as OS (85% versus 65%, p = 0.02), compared with patients receiving delayed hormonal therapy. The incidence of side effects, most commonly hot flashes, gastrointestinal disturbances, and gynecomastia, were reported in up to 20% to 60% of patients receiving the adjuvant therapy. One criticism of this trial is that hormonal therapy alone (without RP) could have produced similar results but no study would be conducted today to test such a hypothesis.
Secondary analysis of RTOG 85-31 examined the effect of immediate versus delayed goserelin therapy in postprostatectomy patients found to have extra-capsular extension to the resection margin and/or seminal vesicle invasion before initiation of EBRT.55 In contrast with Messing’s results, no difference was detected in rates of local progression, distant relapse, or OS in the two groups, with only prolonged freedom from biochemical relapse being noted in patients receiving immediate hormonal therapy at 5-year follow-up. Duration of androgen deprivation, as well as the addition of EBRT, may account for the survival difference noted in these two trials. TOXICITY Each of the various treatment modalities for regionally advanced adenocarcinoma of the prostate has associated adverse side effects, which need to be taken into account when managing patients with this disease. Both acute and late complications associated with the use of EBRT for locoregionally advanced prostate cancer have been described; the former includes increased urinary frequency, dysuria, diarrhea, and rectal urgency; and the latter includes urethral stricture, hematuria, urinary and fecal incontinence, rectal bleeding, and impotence.56–59 While the incidence of bowel and bladder complications following EBRT has been reported at or below 10%, impotence is at least twice this rate by 2 years following treatment, with additional men reporting loss of potency at longer follow-up intervals. The occurrence of adverse side effects from radiation for prostate adenocarcinoma is not unexpectedly correlated to total dose of radiation delivered.60,61 New technologic advances in the delivery of radiation to the prostate, such as intensity-modulated radiation therapy, are designed to reduce toxicity to adjacent normal structures. The reports on the effectiveness of this type of targeted therapy on tumor control and side effect profile are eagerly anticipated. The side effects associated with the various hormonal therapies for prostate adenocarcinoma have previously been delineated in the section “Androgen Deprivation Therapy” and are summarized in Table 27-1. The effect of combination androgen deprivation with EBRT on adverse treatment sequelae has recently become the focus of several reports. Schultheiss et al.60 observed an increased risk of late gastrointestinal and genitourinary toxicity in patients treated with NHT as opposed to those receiving EBRT alone. A study from the Italian National Institute for Cancer Research also identified adjuvant androgen deprivation as a significant independent predictor of late rectal toxicity at 2 years in patients treated with three-dimensional conformal radiation therapy.62 This
500
Part V Prostate Gland and Seminal Vesicles
Table 27-1 Mechanism of Action and Major Side Effects of Hormonal Agents Agent
LHRH
LH
FSH
Testosterone
Side Effect(s)
Estrogens
—
↓
—
—
Gynecomastia, thrombosis
LHRH agonist (short-term use)
↑
↑
↑
↑
Flare reaction
LHRH agonist (long-term use)
↑
↓
—
↓
Hot flashes, loss of libido, osteoporosis, muscle wasting
LHRH agonist+Antiandrogen
↑
↑
↑
Inhibited
Hot flashes, no flare, GI side effects, gynecomastia
Antiandrogen (steroidal)
↑
↓
—
Inhibited
Hot flashes, GI side effects, gynecomastia
Antiandrogen (nonsteroidal)
—
—
—
Inhibited
Gynecomastia
GnRH antagonist
Inhibited
↓
↓
↓
Histamine release
effect appears to be related to duration of hormonal therapy, with treatment in excess of 9 months being associated with decreased rectal tolerance to radiation.63 The effect of combined modality therapy on sexual potency was examined in patients enrolled in RTOG 8610. Preservation of sexual potency was similar for both patients receiving EBRT or EBRT with hormonal therapy, with 81% return of sexual potency for the latter compared to 74% for the men receiving EBRT-only.35 This finding was confirmed by the use of validated selfadministered questionnaires given at baseline and serially after treatment, with change in sexual function scores and overall quality of sex life being similar for both groups.64 However, additional studies suggest that the use of long duration androgen deprivation for periods >6 months may increase the likelihood of decreased libido secondary to failure of testosterone level normalization following combined radiation and hormonal therapy.65 As patients with advanced adenocarcinoma of the prostate can be expected to demonstrate continued improvement in OS, with 5-year survival rates currently being reported at ~70% (Table 27-2), the topic of treatment-related toxicity and effect on quality of life will become ever more important areas of investigation and targets for improved treatment design. Based on the evidence, concerns of adverse side effects should not necessarily deter clinicians from recommending to men with locoregionally advanced prostate cancer combined short duration (4 to 6 months) NHT and EBRT. OUTCOMES AND PROGNOSIS Adenocarcinoma of the prostate is characteristically a slow growing malignancy with high 10-year survival rates being reported for early stage disease.66 Analysis of the survival data of patients with prostate cancer enrolled in the prospective, randomized clinical trials described in
the earlier sections suggests that even with locoregionally advanced disease, men can expect to live on average 8 years regardless of treatment modality employed (see Table 27-2). It is estimated that this number will likely increase with the widespread institution of PSA screening both with earlier initial diagnosis and identification of relapse/disease progression. Roach et al.67 examined >1500 men treated with radiation therapy alone on RTOG phase III trials 75-06, 77-06, 85-31, and 86-10; and they identified factors associated with poorer overall and disease-specific survival. These adverse prognostic factors include high Gleason score, advanced clinical stage, and positive nodal status, and of these, Gleason score was found to be the single most important predictor of death in these patients. In a more recent analysis by this group (specifically addressing the impact of race on survival), patients treated with EBRT, both with and without hormonal therapy, were included, and Gleason score, clinical T stage, and lymph node status again demonstrated prognostic value with respect to overall and diseasespecific survivals.69 In addition, low pretreatment PSA levels and addition of hormonal therapy were found to be associated with improved outcomes in these patients. Currently, the use of PSA testing is commonly employed in the follow-up of patients diagnosed with adenocarcinoma of the prostate. Biologic control and relapse based on PSA values have been reported in recent studies.38,39,41,42 To date, however, no clear correlation between biologic failure and decreased survival has been established (perhaps due to the long natural history of this disease), and the significance of this biomarker relative to patient outcome needs to be further elucidated. FUTURE DIRECTIONS The randomized trials investigating therapeutic options for patients with locoregionally advanced adenocarcinoma
Chapter 27 Regionally Advanced Adenocarcinoma of the Prostate (T3-TN + M0) 501
Table 27-2 Survival Data from Trials of Hormonal Therapy for Prostate Cancer Study
References
Arm
5-year OS (%)
RTOG 86-10
35
RT
68
44
NHT+RT
72
53
RT+early HT
75
49
RT+late HT
71
47
RT
62
NA
RT+HT
78
NA
NHT+RT
78
NA
NHT+RT+HT
79
NA
RT
~70
NA
RT+orchiect
~80
NA
Early HT
n.a.
38*
Delayed HT
n.a.
29*
NHT+WPRT
88
NA
NHT+PRT
83
NA
NA
WPRT+HT
81
NA
NA
PRT+HT
82
NA
NA
RP? HT
85
85†
RP? observe
70
65†
RTOG 85-31
EORTC
RTOG 92-02
Swedish
MRC
RTOG 94-13
Messing
38–39
40–41
42
43
44
46
55
8-year OS (%)
p Value
Median Survival (year)
NS
<8 ~8
NS
8 8
0.0002
NA NA
NS
NA NA
NS
~8 not met
NS not reported NS
0.02
NA
NA NA
NA, not available; NS, not significant ( p > 0.05); NHT, neoadjuvant hormonal therapy; WPRT, whole pelvis RT; PRT, prostate-only RT. *10-year OS. †7-year OS.
of the prostate conducted over the past two decades have not significantly changed the practice of urologists or radiation oncologists. The reason for this is due in large part to flawed protocol design (e.g., non-PSA based stratification schemas) and evaluation of treatment modalities (such as perineal prostatectomy or DES use) already outdated by the time the trials were reported. The effects of the various treatments on local symptom control and on quality of life were also frequently overlooked. The goal of future clinical trials examining the efficacy and patterns of failure in regionally advanced prostate cancer is to ensure better study design by taking into account patient selection, tumor characteristics, prognostic factors and staging methods and by including quality of life and cost-benefit issues in addition to survival, locoregional control, and distant, clinical or biochemical failure as study endpoints.
There are several prospective randomized studies currently underway designed to address the timing and duration of hormonal therapy (either alone or in conjunction with other treatment modalities), as well as the benefit of hormonal therapy in low-risk patients versus intermediate-risk patients with prostate cancer. These are briefly discussed in the next paragraph. The National Cancer Institute of Canada has a phase III trial investigating hormonal therapy (pharmaceutical or surgical) with or without EBRT for patients with stage III/stage IV disease. A phase III study being conducted by the EORTC (22961) was designed to address the question of duration of androgen blockade (observation versus continued 2.5-year treatment) following initial 6 months of hormonal therapy with EBRT for patients with T1c-2b, N1-2 or T2c-4, N0-2 prostate cancer. The length of total androgen suppression is also being investigated
502
Part V Prostate Gland and Seminal Vesicles
by the RTOG in a phase III study (99-10), which is randomizing intermediate risk patients to 8 versus 28 weeks of hormonal therapy prior to concurrent androgen deprivation and EBRT. The RTOG is additionally looking at the role of radiation therapy with or without androgen deprivation both in low-risk (T1b-2b, Nx-0, PSA < 20 ng/ml) patients (RTOG 94-08) and in postoperative (pT3N0M0 or pT2N0M0 with positive margins) patients (RTOG 96-01 and RTOG 00-11). The results of these and other prospective randomized trials are expected to provide important information regarding the future care and management of patients with regionally advanced adenocarcinoma of the prostate. REFERENCES 1. American Joint Commission on Cancer Staging Manual, 5th edition. Philadelphia, Lippincott-Raven Publishers, 1997. 2. Stephenson RA, Smart CR, Mineau GP, et al: The fall in incidence of prostate carcinoma. On the downside of a prostate specific antigen induced peak in incidence—data from the Utah Cancer Registry. Cancer 1996; 77:1342–1348. 3. Catalona WJ, Smith DS, Ratliff TL, et al: Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993; 270:948. 4. Partin AW, Kattan MW, Subong ENP, et al: Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer: a multi-institutional update. JAMA 1997; 277:1445. 5. D’Amico AV: Combined-modality staging for localized adenocarcinoma of the prostate. Oncology 2001; 15:1049–1075. 6. Duncan W, Warde P, Catton CN, et al: Carcinoma of the prostate: results of radical radiotherapy (1970–1985). Int J Radiat Oncol Biol Phys 1993; 26:203–210. 7. Zagars GK, von Eschenbach AC, Ayala AG: Prognostic factors in prostate cancer: analysis of 874 patients treated with radiation therapy. Cancer 1993; 72:1709–1725. 8. Epstein JI, Partin AW, Sauvageot J, et al: Prediction of progression following radical prostatectomy: a multivariate analysis of 721 men with long-term followup. Am J Surg Pathol 1996; 20:286–292. 9. Millikan R, Logothetis C: Update of the NCCN guidelines for treatment of prostate cancer. Oncology 1997; 11:180–193. 10. Coia LR, Hanks GE: Quality assessment in the U.S.A.: how the patterns of care study has made a difference. Semin Radiat Oncol 1997; 7:146–156. 11. Limonta P, Dondi D, Marelli MM, et al: Growth of the androgen-dependent tumor of the prostate: role of androgens and of weakly expressed growth modulatory factors. J Steroid Biochem Mol Biol 1995; 53:401–405.
12. deLaumont Y, Veilleux R, Dufour M, et al: Characteristics of the biphasic action of androgens and of the potent antiproliferative effects of the new antiestrogen EM-139 on cell cycle kinetic parameters in LNCaP human prostatic cancer cells. Cancer Res 1991; 51:5165–5170. 13. Manni A, Bartholomew M, Caplan R, et al: Androgen priming and chemotherapy in advanced prostate cancer: evaluation of determinants of clinical outcome. J Clin Oncol 1988; 6:1456–1466. 14. Fowler JE Jr, Whitmore WF Jr: The response of metastatic adenocarcinoma of the prostate to exogenous testosterone. J Urol 1981; 126:372–375. 15. Pinault S, Tetu B, Gagnon J, et al: Transrectal ultrasound evaluation of local prostate cancer in patients treated with LHRH agonist and in combination with flutamide. Urology 1992; 39:254–261. 16. Zietman AL, Prince E, Nakfoor BM, et al: Androgen deprivation and radiation therapy: sequencing studies using the Sinology in vivo tumor system. Int J Radiat Oncol Biol Phys 1997; 38:1067–1071. 17. Lim JD, Hasegawa M, Sikes C, et al: Supra-additive apoptotic response of R3327-G rat prostate tumors to androgen ablation and radiation. Int J Radiat Oncol Biol Phys 1997; 38:1071–1078. 18. Bayoumi AM, Brown AD, Garber AM: Cost effectiveness of androgen suppression therapies in advanced prostate cancer. J Natl Cancer Inst 2000; 92:1731–1739. 19. Byar DP: The veterans administration cooperative urologic research group’s studies of cancer of the prostate. Cancer 1993; 32:1126. 20. Shearer RJ, Hendry WF, Sommerville IF, et al: Plasma testosterone: an accurate monitor of hormone treatment of prostatic cancer. Br J Urol 1973; 45:668. 21. Geller J, Albert J, Yen SSC: Treatment of advanced cancer of prostate with megestrol acetate. Urology 1978; 12:537–541. 22. Faure N, Lemay A, Larouche B, et al: Preliminary results on the clinical efficacy and safety of androgen inhibition by an LHRH agonist alone or combined with an antiandrogen in the treatment of prostatic carcinoma. Prostate 1983; 4:601–624. 23. Soloway MS, Chodak G, Vogelzang NJ, et al: Zoladex versus orchiectomy in treatment of advanced prostate cancer: a randomized trial. Urology 1991; 37:46. 24. The Leuprolide Study Group: Leuprolide versus diethylstilbestrol for metastatic prostate cancer. N Engl J Med 1984; 311:1281. 25. Waxman J, Man A, Hendry WF, et al: Importance of early tumor exacerbation in patients treated long-acting analogues of gonadotrophin releasing hormone for advanced prostatic cancer. Br Med J 1985; 291:1387. 26. Thompson I M, Zeidman EJ, Rodriguez FR: Sudden death due to disease flare with luteinizing hormone-releasing hormone agonist therapy for carcinoma of the prostate. J Urol 1990; 144:1479. 27. Labrie F, Dupont A, Belanger A, et al: Flutamide eliminates the risk of disease flare in prostatic cancer patients treated with a luteinizing hormone-releasing hormone agonist. J Urol 1987; 138:804.
Chapter 27 Regionally Advanced Adenocarcinoma of the Prostate (T3-TN + M0) 503 28. Schellhammer PF, Sharifi R, Block NL: Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind randomized, multicenter trial. Urology 1997; 50:330–336. 29. Crownover RL, Holland J, Chen A, et al: Flutamideinduced liver toxicity including fatal hepatic necrosis. Int J Radiat Oncol Biol Phys 1996; 34:911–915. 30. Iversen P, Tyrrell CJ, Kaisary AV, et al: Casodex (bicalutamide) 150-mg monotherapy compared with castration in patients with previously untreated nonmetastatic prostate cancer: results from two multicenter randomized trials at a median follow-up of 4 years. Urology 1998; 51:389–396. 31. Pilepich MV, Krall JM, Sause W T, et al: Prognostic factors in carcinoma of the prostate-analysis of RTOG study 75-06. Int J Radiat Oncol Biol Phys 1987; 13: 339. 32. Pilepich MV, Krall JM, John MJ, et al: Hormonal cytoreduction in locally advanced carcinoma of the prostate treated with definitive radiotherapy: preliminary results of RTOG 83-07. Int J Radiat Oncol Biol Phys 1989; 16:813. 33. Pilepich MV, John MJ, Krall JM, et al: Phase II Radiation Therapy Oncology Group study of hormonal cytoreduction with flutamide and Zoladex in locally advanced carcinoma of the prostate treated with definitive radiotherapy. Am J Clin Oncol 1990; 13:461. 34. Pilepich MV, Buzydlowski JW, John MJ, et al: Phase II trial of hormonal cytoreduction with megestrol and diethylstilbestrol in conjunction with radiotherapy for carcinoma of the prostate: outcome results of RTOG 83-07. Int J Radiat Oncol Biol Phys 1995; 32:175–180. 35. Pilepich MV, Winter K, John MJ, et al: Phase III Radiation Therapy Oncology Group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001; 50:1243–1252. 36. Laverdiere J, Gomez JL, Cusan L, et al: Beneficial effect of combination therapy administered prior and following external beam radiation therapy in localized prostate cancer. Int J Radiat Oncol Biol Phys 1997; 37:247–252. 37. Zagars GK, Johnson DE, von Eschenbach AC, et al: Adjuvant estrogen following radiation therapy for stage C adenocarcinoma of the prostate: long-term results of a prospective randomized study. Int J Radiat Oncol Biol Phys 1988; 14:1085–1091. 38. Pilepich MV, Caplan R, Byhardt RW, et al: Phase III trial of adjuvant androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group protocol 85-31. J Clin Oncol 1997; 15:1013–1021. 39. Lawton CA, Winter K, Murray K, et al: Updated results of the phase III radiation therapy oncology group (RTOG) trial 85-31 evaluating the potential benefit of androgen suppression following standard radiation therapy for unfavorable prognosis carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001; 49:937–946.
40. Bolla M, Gonzalez D, Warde P, et al: Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997; 337:295–300. 41. Bolla M, Collette L, Blank L, et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomized trial. Lancet 2002; 360:103–106. 42. Hanks G, Lu J, Machtay M, et al: RTOG protocol 92-02: a phase III trial of the use of long term androgen suppression following neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of prostate. ASCO Abstr 1284, 2000. 43. Granfors T, Modig H, Jan-Erik D, et al: Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study. J Urol 1998; 159: 2030–2034. 44. Medical Research Council Prostate Cancer Working Party Investigators Group: Immediate versus deferred treatment for advanced prostate cancer: initial results of the Medical Research Council Trial. Br J Urol 1997; 79:235–246. 45. Roach M III, DeSilvio M, Lawton C, et al: Neoadjuvant hormonal therapy (NHT) with whole-pelvis (WP) radiotherapy (RT) improves progression-free survival (PFS): RTOG (Radiation Therapy Oncology Group) 9413, a phase III randomized trial. ASCO Abstr 711, 2002. 46. D’Amico AV, Whittington R, Malkowicz SB, et al: A multivariate analysis of clinical and pathological factors that predict for prostate specific antigen failure after radical prostatectomy for prostate cancer. J Urol 1995; 154:131. 47. Gerber GS, Thisted RA, Scardino PT, et al: Results of radical prostatectomy in men with clinically localized prostate cancer. JAMA 1996; 276:44. 48. Kattan MW, Stapleton AM, Wheeler TM, et al: Evaluation of a nomogram used to predict the pathologic stage of clinically localized prostate carcinoma. Cancer 1997; 79:528. 49. Partin AW, Kattan MW, Subong EN, et al: Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer: a multi-institutional update. JAMA 1997; 277:1445–1451. 50. Soloway MS, Sharifi R, Wajsman Z, et al: Randomized prospective study comparing radical prostatectomy alone versus radical prostatectomy preceded by androgen blockade in clinical stage B2 (T2bNxM0) prostate cancer. J Urol 1995; 154:424. 51. Goldenberg SL, Klotz LH, Srigley J, et al: Randomized, prospective, controlled study comparing radical prostatectomy alone and neoadjuvant androgen withdrawal in the treatment of localized prostate cancer. J Urol 1996; 156:873. 52. Fair WR, Cookson MS, Stroumbakis N, et al: The indications, rationale, and results of neoadjuvant androgen deprivation in the treatment of prostatic cancer. Memorial
504
53.
54.
55.
56.
57.
58.
59. 60.
Part V Prostate Gland and Seminal Vesicles Sloan-Kettering Cancer Center results. Urology 1997; 49:46. Gleave ME, Goldenberg SL, Chin JL, et al: Randomized comparative study of 3 versus 8-month neoadjuvant hormonal therapy before radical prostatectomy: biochemical and pathological effects. J Urol 2001; 166:500–507. Messing EM, Manola J, Sarosdy M, et al: Immediate hormonal treatment compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. New Engl J Med 1999; 341:1781–1788. Corn BW, Winter K, Pilepich MV: Does androgen suppression enhance the efficacy of postoperative irradiation: a secondary analysis of RTOG 85-31. Urology 1999; 54:495–502. Dearnaley DP, Khoo VS, Norman AR, et al: Comparison of radiation side-effects of conformal and conventional radiotherapy in prostate cancer: a randomized trial. Lancet 1999; 353:267–272. Schultheiss TE, Hanks GE, Hunt MA, et al: Incidence of and factors related to late complications in conformal and conventional radiation and treatment of cancer of the prostate. Int J Radiat Oncol Biol Phys 1995; 32:643–649. Roach M III, Chinn DM, Holland GP, et al: A pilot survey of sexual function and quality of life following 3D conformal radiotherapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1996; 35:869–874. Litwin M: Measuring health related quality of life in men with prostate cancer. J Urol 1994; 152:1882–1887. Schultheiss TE, Lee WR, Hunt MA, et al: Late GI and GU complications in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys 1997; 37:3–11.
61. Hanks GE, Schultheiss TE, Hanlon AL, et al: Optimization of conformal radiation treatment of prostate cancer: report of a dose escalation study. Int J Radiat Oncol Biol Phys 1997; 37:543–550. 62. Sanguineti G, Agostinelli S, Foppiano F, et al: Adjuvant androgen deprivation impacts late rectal toxicity after conformal radiotherapy of prostate carcinoma. Br J Cancer 2002; 86:1843–1847. 63. Vavassori V, Cozzarini C, Bianchi C, et al: Androgen deprivation and prostate gland shrinkage during conformal radiotherapy. Int J Radiat Oncol Biol Phys 2002; 51:18–19. 64. Chen CT, Valicenti RK, Lu JD, et al: Does hormonal therapy influence sexual function in men receiving 3D conformal radiation therapy for prostate cancer? Int J Radiat Oncol Biol Phys 2001; 50:591–595. 65. Padula GD, Zelefsky MJ, Venkatraman ES, et al: Normalization of serum testosterone levels in patients treated with neoadjuvant hormonal therapy and threedimensional radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2002; 52:439–443. 66. Johansson JE, Adami HO, Andersen SO, et al: High 10-year survival rate in patients with early, untreated prostatic cancer. JAMA 1992; 267:2191–2196. 67. Roach M III, Lu J, Pilepich MV, et al: Long-term survival after radiotherapy alone: radiation therapy oncology group prostate cancer trials. J Urol 1999; 161:864–868. 68. Roach M III, Lu J, Pilepich MV, et al: Race and survival of men treated for prostate cancer on radiation therapy oncology group phase III randomized trials. J Urol 2003; 169:245–250.
C H A P T E R
28 Metastatic Adenocarcinoma of the Prostate Miah-Hiang Tay, MBBS, MRCP, and William K. Oh, MD
The clinical profile of newly diagnosed prostate cancer has changed considerably over the past decade. A so-called “stage shift” has occurred, coinciding with the widespread use of serum prostate-specific antigen (PSA) testing for prostate cancer screening. As a result, fewer patients are diagnosed initially with metastatic disease. Between 1986 and 1992, 12% of patients presented with metastatic prostate cancer, but by 1998, only 6% of patients with prostate cancer had metastases at presentation.1 Important advances in the treatment of metastatic prostate cancer have been made since Huggins and Hodges2 first showed that palliation of metastatic disease could be achieved by androgen deprivation therapy (ADT). Despite progress, however, prostate cancer remains a significant problem in the United States. With an estimated 28,900 deaths in 2003, it is the second leading cause of cancer death among men. HORMONE-SENSITIVE METASTATIC PROSTATE CANCER There has been little change in the primary concept that guides the initial treatment of metastatic prostate cancer. Indeed it was over 60 years ago that prostate cancer was first shown to be androgen dependent. Since that time, there has been an increase in the number of therapeutic options, as well as controversies regarding the optimal form and timing of ADT. In particular, issues, such as the role of combination androgen blockade (CAB) versus luteinizing hormone releasing hormone (LHRH) agonist monotherapy, the duration of treatment and the proper timing of therapy have been debated recently. Androgen Deprivation Therapy: Standards of Care The standard of care today for a man diagnosed with metastatic prostatic cancer is the initiation of ADT. The
original method used to achieve ADT was bilateral surgical orchiectomy.3,4 Castration by orchiectomy is permanent and is the treatment modality to which other forms of ADT have been compared.5 ADT can be achieved medically by treatments, such as estrogens and LHRH agonists. Seidenfeld et al.6 performed a systematic review of various forms of ADT, analyzing 24 randomized trials with over 6600 patients with metastatic disease. No survival difference was noted between surgical and medical castration using LHRH agonists. Trials comparing the estrogen, diethylstilbestrol (DES), with orchiectomy or LHRH agonists also revealed no significant difference in survival. However, DES had a higher risk of thromboembolism, which has limited its use as a primary modality for ADT in the United States. LHRH agonists have become the most commonly used method of ADT in the United States. This preference is partly explained by the negative psychologic effects patients associate with surgical castration. In a survey of 159 men with newly diagnosed prostate cancer given a choice of either bilateral orchiectomy or LHRH agonist therapy, only 22% chose orchiectomy.7 Despite these findings, orchiectomy does offer several advantages, including lack of the tumor flare response associated with initiation of LHRH agonists and a significantly lower overall cost.8 Leuprolide acetate and goserelin acetate are commonly used LHRH agonists and are available in 1-, 3-, and 4-month depot formulations. Both agents have comparable efficacy, with the primary difference being the route of delivery. Leuprolide acetate is administered intramuscularly, while goserelin acetate is deposited subcutaneously as a pellet. Newer systems of delivery for leuprolide are available, which employ a tiny osmotic pump that allows for once yearly dosing. As these drugs
505
506
Part V Prostate Gland and Seminal Vesicles
are LHRH agonists, an initial LH surge is seen with resultant increase in testosterone in the initial 1 to 2 weeks following administration. Though this effect diminishes over a month, there is a risk that such a testosterone flare may cause an acute growth of cancer, leading to such complications as spinal cord compression and bladder outlet obstruction in some patients.9,10 Hence, antiandrogen therapy is typically administered for at least 1 month and should be started several days to 2 weeks prior to the initiation of LHRH agonist, if possible.11 LHRH pure antagonists, such as abarelix, are being investigated as an alternative to LHRH agonists. Studies comparing abarelix and LHRH agonists have suggested that these agents are comparable in efficacy, though there is no associated testosterone flare.12,13 Estrogenic drugs were used for many years as the primary means of medical castration in men with metastatic prostate cancer. In the 1960s and 1970s, the VA Cooperative Urological Research Group (VACURG) performed a series of randomized trials designed to evaluate estrogenic therapies for prostate cancer.14 Their conclusions were: (1) DES at 5 mg/day leads to excess cardiovascular deaths, though there were fewer prostate cancer-related deaths; (2) estrogen and orchiectomy were equivalent and the two together were no better than either alone; (3) DES at 1 mg/day was as effective as 5 mg/day without excess cardiovascular toxicity. Thus doses of DES between 1 and 3 mg/day became the standard medical therapy for metastatic prostate cancer in the United States. However, because of the toxicity of DES, other forms of nonsurgical hormonal ablation have been sought over the years. Natural estrogens, such as ethinyl estradiol, and other synthetic estrogens, such as polyestradiol phosphate (PEP), have been investigated; and indeed these drugs have been extensively evaluated and continue to be used outside of the United States. Combined Androgen Blockade Though the testicles produce up to 95% of circulating androgens, the adrenal glands produce a small but potentially significant amount. After medical or surgical castration, the adrenal glands become an important source of androgen.5 Despite the dramatic response to ADT, prostate cancer eventually becomes hormone refractory with a median progression-free survival of 18 to 24 months and a median survival of 24 to 30 months. Based on the concept that prostate cancer in a “castrate” environment may be sustained by androgen from the adrenal glands, many randomized trials have been performed to determine whether combined androgen blockade (CAB) using either medical or surgical castration together with an antiandrogen is superior to castration alone. Many of these trials were underpowered and used different methods of castration and/or antiandrogens, which may have
led to contradictory results. For example, an influential Intergroup study (INT-0036) compared leuprolide acetate with or without flutamide in 603 men with metastatic prostate cancer.15 Both progression-free (16.5 months versus 13.9 months) and overall survivals (35.6 months versus 28.3 months) were significantly longer in patients treated with CAB than those treated with leuprolide alone. In addition, a subgroup analysis found that the greatest benefits were seen in patients with good performance status and minimal disease. Two other studies, EORTC 00853 and the Anandron International Study, also showed that CAB favored an improved median survival compared to orchiectomy alone.16,17 On the other hand, some clinical trials have failed to demonstrate a benefit to CAB.18–22 The largest and most important of these was also an Intergroup trial (INT-0105). One thousand three hundred and seventy eight patients were randomized to surgical orchiectomy plus flutamide versus orchiectomy alone. Although a 10% survival benefit for the combination arm was seen, it was not statistically significant. This result was different from INT-0036, which showed a 7-month absolute survival advantage in favor of the CAB compared with leuprolide monotherapy. In addition, INT-0105 failed to show a survival advantage for patients with minimal disease. Two reasons could explain these discrepant findings. The primary difference between these trials was the use of surgical castration in INT-0105, in which case tumor flares cannot occur. It is possible that the primary value of antiandrogen therapy is in suppression of a tumor flare in patients with metastatic disease. Furthermore, INT-0105 allowed the use of salvage antiandrogen therapy in patients who progressed on leuprolide acetate. Since this was not allowed for patients on INT-0036, any added benefit to up-front CAB may have been abrogated by the use of delayed CAB in INT-0105. Several meta-analyses have been performed to determine the overall impact of CAB. The largest metaanalysis is from the Prostate Cancer Trialists’ Collaborative Group, which analyzed 27 clinical trials with over 8000 men, the majority with metastatic disease.23 This analysis indicated that the addition of antiandrogen to androgen suppression therapy improved 5-year survival by approximately 2% or 3% depending on whether the analysis included or excluded cyproterone acetate, respectively. Whether this additional small benefit should alter the standard of care of single modality LHRH agonists or orchiectomy as first line treatment for patients with metastatic prostate cancer is controversial, especially when the additional cost and side effects of antiandrogen therapy are considered. In summary, though it is a controversial area, no compelling evidence exists for routine CAB use in patients with hormone sensitive metastatic prostate cancer. Both LHRH agonists and surgical orchiectomy have equivalent
Chapter 28 Metastatic Adenocarcinoma of the Prostate 507
clinical efficacy and can be considered as primary means of ADT, though an antiandrogen should be used for at least 1 month to block a tumor flare response associated with LHRH agonists. Nonsteroidal antiandrogens can be subsequently added upon disease progression after primary ADT. Estrogen therapy is also a choice for primary ADT, but toxicity has generally made estrogen use rare in the United States, though it is more popular in Europe. Timing of Hormonal Therapy In the VACURG trials, overall survival in patients with asymptomatic metastatic disease was not significantly improved by early use of DES compared to placebo.14 However, conclusions from this study may not justify delaying the use of hormonal therapy in a patient with metastatic prostate cancer in the modern era. Since the 1970s, newer and safer androgen ablation therapies have been developed that abrogate the significant cardiovascular risks of DES. Furthermore, there are now three studies that support the earlier use of ADT for metastatic prostate cancer, though some of these data remain indirect. In an EORTC study, Bolla et al.24 studied the role of long term adjuvant hormonal therapy following definitive radiotherapy for high-risk patients, including those with lymph node disease. In this randomized placebocontrolled study of 415 patients, actuarial 5-year survival for the radiotherapy plus goserelin arm was significantly higher than the radiotherapy-alone arm (79% versus 62%, respectively; p = 0.001). In another trial by Medical Research Council (MRC) in the United Kingdom, the authors reported that immediate hormonal therapy with orchiectomy or an LHRH agonist for men with locally advanced or asymptomatic metastatic prostate cancer significantly reduced the need for transurethral resection for local progression, rates of pathologic fracture, spinal cord compression, ureteral obstruction, and incidence of bone metastasis as compared to men randomized to deferred therapy.25 In addition, deaths attributable to prostate cancer occurred more frequently in men whose treatment was deferred (257 versus 203; p = 0.001). Unfortunately, this study was criticized for the potential bias created by different follow-up schedules between the two arms, resulting in a number of patients not receiving hormonal therapy in the deferred arm (54% of whom died from prostate cancer). A third study that supports earlier ADT use is a study by Messing et al.,26 in which 98 men with pelvic lymph node involvement were randomized to early ADT or observation following radical prostatectomy. At 7 years of follow-up, 7 of 47 (15%) men in the immediate therapy arm had died, compared to 18 of 51 (35%) men in the delayed arm (p = 0.02). In summary, there is growing evidence that earlier ADT may confer a survival benefit compared with significantly delayed therapy, although the optimal timing of
ADT is poorly defined. This is especially true in the PSA era, when evidence of recurrence by PSA generally predates metastatic disease by many years.27 Contemporary guidelines for when to initiate hormonal therapy incorporate factors such as PSA doubling time, patient concerns over libido, and quality of life, and disease characteristics, such as Gleason score. Little justification can be made for withholding ADT in the presence of metastatic disease, whether symptomatic or not. Further study is needed to determine the optimal timing of ADT. ALTERNATIVE APPROACHES TO HORMONAL THERAPY ADTs, such as LHRH agonists and orchiectomy, are associated with a growing list of previously underappreciated toxicities. ADT induces castrate levels of testosterone, causing side effects, such as hot flashes, loss of libido, and osteoporosis. As a result, patients are seeking alternative hormonal treatments, including intermittent therapy and antiandrogen monotherapy. Antiandrogens may have less toxicity than ADT, for instance, with libido and physical capacity. However, randomized trials suggest that antiandrogen monotherapy is inferior to standard ADT in controlling metastatic disease, though the difference is not marked. Intermittent Androgen Deprivation Prostate cancer progresses from a hormone sensitive to hormone refractory state by several possible mechanisms. First, there is preferential expansion of androgenindependent clones that are present within the tumor at the time ADT is started. Second, there is an upregulation of growth factors as a result of adaptation of cancer cells to the androgen-depleted environment, as well as activation of alternative pathways in androgen receptor signaling. Finally alternate paracrine and autocrine pathways appear to develop that sustain tumor growth.28 By intermittently depriving prostate cancer cells of androgen stimulation, the aim is to delay the time to androgen independence and preserve the sensitivity of the cancer cells to further ADT in the future. Another potential advantage of intermittent androgen deprivation is an improvement in quality of life with improvements in libido, erectile function, energy level, and bone density during the period when ADT is suspended. Intermittent androgen deprivation is usually achieved with LHRH agonists until the serum PSA falls to undetectable levels (or at least a nadir <4 ng/ml), at which time therapy is held. During the first cycle of treatment, ADT typically continues for at least 6 to 9 months after the nadir has been achieved. Androgen deprivation is resumed once the PSA climbs to an arbitrary fixed level, for instance, 50% of the initial pretreatment value, an
508
Part V Prostate Gland and Seminal Vesicles
absolute PSA level >5 to 10 ng/ml or (rarely) clinical evidence of disease. Current data for intermittent ADT indicate that about half of patients have resolution of the side effects from treatment during the rest period.29–32 More importantly, the disease tends to remain responsive to subsequent androgen suppression therapy, although the treatment-free intervals shorten with each subsequent cycle. Nonetheless, there are several important unresolved questions, such as its potential impact on survival in comparison with continuous ADT. Randomized trials comparing these two forms of treatment are currently in progress. Until the results of these trials are known, intermittent androgen deprivation remains investigational. Peripheral Androgen Blockade Antiandrogen monotherapy has been extensively evaluated in phases II and III trials as initial hormonal therapy for advanced prostate cancer.6,13,33 Flutamide is active when used as a single agent but inferior to both DES and orchiectomy in randomized trials. High-dose bicalutamide has been compared to CAB in at least two large randomized studies in men with locally advanced or metastatic prostate cancer. Though both studies suggested that highdose bicalutamide was equivalent to CAB for nonmetastatic disease, one of these trials demonstrated a survival benefit in metastatic disease for CAB. There was also evidence that bicalutamide monotherapy was better tolerated, with improved libido and physical capacity. The use of antiandrogens as single agents is accompanied by an increase in gonadotropins due to competition in the hypothalamus of the antiandrogen with circulating androgens. Sustained gonadotropin increase results in enhanced testosterone secretion, which may override the antiandrogen effect. The inability to demonstrate a role for antiandrogens alone, their cost, and their toxicity spectrum have prevented wide acceptance of antiandrogen monotherapy as the initial therapy for advanced prostate cancer. The 5-alpha-reductase inhibitor finasteride has minimal activity as monotherapy for prostate cancer. However, finasteride lowers dihydrotestosterone levels and, when added to the antiandrogens flutamide or bicalutamide, demonstrates additional PSA suppression. This combination may also spare libido and erectile function, as testosterone is not depleted. Phase II studies of finasteride plus flutamide show significant activity in hormone sensitive prostate cancer with 72% to 95% achieving a complete PSA response.34–36 However, in the absence of randomized data, combined flutamide and finasteride therapy remains investigational. SECONDARY HORMONAL THERAPY Despite a response rate of over 80% to 90% with primary ADT, nearly all men with metastatic disease progress
after an average of 18 to 24 months. The mechanism by which prostate cancer becomes hormone refractory is poorly understood. A small number of patients who relapse may in fact have noncastrate levels of testosterone and, in this situation, surgical orchiectomy should be considered. The majority of patients who progress after primary ADT in fact do have castrate testosterone levels. Despite disease progression, many investigators advocate continuing ADT. There is evidence of a persistent population of hormone sensitive cells, which may regrow if testosterone is allowed to return to normal levels. One retrospective analysis showed that continuing ADT was associated with a survival benefit of 2 to 6 months compared with discontinuation in the hormone-refractory setting.37 Secondary hormonal maneuvers may benefit some patients after failing primary androgen ablation. In these patients, responses may be elicited through the following pathways: (1) enhanced blocking of residual serum androgens to the androgen receptor; (2) reduction in adrenal androgen production; (3) binding of agents to other nuclear receptors in the prostate cancer cells (Table 28-1). About 20% to 30% of patients will experience a significant PSA decline after antiandrogen withdrawal, lasting from 3 to 5 months, although individual responses can last for over 2 years. Flutamide paradoxically can activate specific mutant androgen receptors cloned from prostate cancers, which may provide a mechanism to explain the antiandrogen withdrawal syndrome.38 The blockade of residual serum androgens may be achieved using antiandrogens. In one of the first large series of 209 men, Labrie et al.39 reported an overall response of 34.5% with addition of flutamide after failing initial hormonal therapy with orchiectomy, DES, or an LHRH agonist. The mean duration of response was 24 months. After antiandrogen withdrawal, another antiandrogen may be considered, as antiandrogens do not appear to have complete cross-resistance in their mechanism of action. The use of a second antiandrogen is predicated on the possibility that despite their functional similarities, antiandrogens interact differently with the androgen receptor. There is evidence, for example, that in the LNCaP cell line, flutamide acts as a partial agonist (and not an inhibitor), whereas bicalutamide maintains an inhibitory function.40 Bicalutamide at dose of 150 to 200 mg have been used in clinical trials in patients who progressed after primary hormonal manipulation. Expected response rates from this second line treatment range from 15% to 40%. Unfortunately, the response is typically short-lived, with progression-free survival of about 4 months.41,42 The adrenal gland is the main source of androgens following effective castration. Suppressing adrenal androgens has been demonstrated with ketoconazole and
Chapter 28 Metastatic Adenocarcinoma of the Prostate 509
Table 28-1 Secondary Hormonal Therapy >50% PSA Decline (%)
Measurable Response (%)
153
15–33
13
134
23–24
0
14
50
NR
Aminoglutethimide
583
NR
9
Ketoconazole
204
78–80
16
Low-dose steroids
241
18–22
NR
DES
405
21–86
NR
PC-SPES
114
45–81
NR
Therapy Antiandrogen withdrawal
Number
Second antiandrogen Bicalutamide Nilutamide Adrenal androgen inhibitors
Estrogens
NR, not reported.
aminoglutethimide. Ketoconazole is effective in suppressing testicular and adrenal androgen production. In vitro experiments also suggest a possible direct cytotoxic effect of ketoconazole on prostate cancer cells. Older studies in androgen-independent prostate cancer using high-dose ketoconazole plus replacement steroids showed measurable responses in approximately 15%. Three recent trials of high-dose ketoconazole demonstrate much higher response rates using PSA endpoints. Small et al.43 treated 48 patients with 400 mg tid in a phase II trial and found PSA declines of 50% or greater in 63%. In another trial of 45 patients treated with highdose ketoconazole, Millikan et al.44 showed a 40% PSA response rate using a similar dose. In CALGB 9583, concurrent antiandrogen withdrawal and high-dose ketoconazole demonstrated a 27% PSA response rate and a 13% measurable response rate.45 Increased gastric pH decreases drug absorption, so ketoconazole should be taken on an empty stomach and, if possible, in the absence of H2 blockers or antacids. Though toxicity is generally mild or moderate, including nausea, diarrhea, fatigue, and skin changes, some patients require discontinuation of the drug because of toxicity. A recent phase II study suggests that similar response rates may be obtained with half the traditional dose (i.e., 200 mg tid), with fewer apparent side effects.46 In a review of 13 clinical trials of aminoglutethimide plus hydrocortisone, there was an overall partial response rate of 9%. Aminoglutethimide toxicity includes fatigue, nausea, skin rash, orthostatic hypotension, and ataxia.
Estrogens and their analogs also have some activity in patients with hormone-refractory disease. Using 1 mg DES in 21 men who failed with ADT, Smith et al.47 demonstrated a response rate of 43% based on more than 50% decrease in PSA level. Its utility in prostate cancer has been unfortunately limited by the risk of thromboembolic complications but nevertheless is a potentially useful drug in this setting. DES is no longer marketed in the United States but is available through compounding pharmacies. PC-SPES was supplement consisting of 8 different herbs and showed estrogenic activity. Its efficacy in both androgen sensitive and androgen insensitive prostate cancer was demonstrated in several trials.48–50 Despite of its potential, PC-SPES has been taken off the market when it was recently found to contain synthetic agents, such as warfarin and DES. CHEMOTHERAPY In the traditional view of chemotherapy in hormonerefractory prostate cancer (HRPC), there is either no or little impact in the history of the disease. Two reviews from 1985 suggested that the response with chemotherapy is poor.51,52 In the first review of 17 randomized clinical trials by Eisenberger et al.,53 total response rate was 4.5%, while a second review of 26 trials performed in the late 1980s showed an overall response rate of only 8.7%. However, recent studies with new drugs and combinations have shown that prostate cancer is in fact chemosensitive. At the same time, new endpoints of
510
Part V Prostate Gland and Seminal Vesicles
paclitaxel and docetaxel have moderate activities.57,58 Estramustine, by itself, also has modest activity.59 The activity of this drug is not due to the estrogen moiety as first thought to be but rather due to its ability to disrupt mitotic activity through the binding of the microtubule assembly proteins.60 Although estramustine has been studied in combination with other chemotherapeutic agents, it is the synergism with other antimicrotubule agents (paclitaxel and docetaxel) that have generated enthusiasm. PSA response rates ranging from 50% to 65% and from 39% to 82% for estramustine plus paclitaxel or docetaxel, respectively, have been reported in several clinical studies. In spite of the high activity of the combination therapy, the optimal dose and schedule in HRPC are yet to be defined. In fact, the added value of estramustine in these combinations is counterbalanced by significant toxicity. Several groups have tested the efficacy of single agent docetaxel chemotherapy with reported PSA response ranging from 41% to 47% and less toxicity.58,61 The Southwest Oncology Group has completed a phase III study with over 600 patients randomized either to estramustine and docetaxel or mitoxantrone and prednisone. Overall survival is the primary endpoint and results are pending. Many other chemotherapeutic drugs have also been tested, including etoposide, vinblastine, and cyclophosphamide. In general, these have modest single agent activity in HRPC. On the other hand, results of triple drug combination have also been published. One such regimen consists of weekly paclitaxel, estramustine, and
treatment, such as PSA response and parameters of quality of life, as well as better supportive measures and improvement in the management of comorbid conditions, have allowed a resurgence of interest in the use of chemotherapy to palliate advance disease.54 Two randomized trials reestablished the promise of chemotherapy in HRPC, both analyzing mitoxantrone and a corticosteroid.55,56 In the first study with 161 symptomatic patients, Tannock et al.55 showed that mitoxantrone plus prednisone significantly improved pain control compared to prednisone alone (29% versus 12%; p = 0.01). The duration of palliation in the chemotherapy arm also was significantly longer (43 weeks versus 18 weeks; p < 0.0001). In a second study by Kantoff et al.56 242 patients with HRPC were randomized to receive either mitoxantrone and hydrocortisone or hydrocortisone alone. Although there was no significant difference in survival, a trend towards longer time-to-progression and time-to-treatment-failure in the combination arm was evident (3.7 months versus 2.3 months; p = 0.25). Furthermore, there was a higher percentage of patients in the combination arm who achieved a >50% maximum reduction in PSA (38% versus 22%; p = 0.008), as well as a trend for improved pain control. Despite a lack of survival benefit, mitoxantrone was approved for palliative use in HRPC patients and has become the standard of care to which future agents will be compared (Table 28-2). Taxanes combinations are among the most active regimens tested to date in phase II trials. As single agents,
Table 28-2 Chemotherapy Regimen
Number
>50% PSA Decline (%)
Measurable Response (%)
Paclitaxel
41
33–60
22–33
Paclitaxel/estramustine
62
53–61
38–44
Paclitaxel/estramustine/VP-16
40
45
65
Paclitaxel/estramustine/carboplatin
88
67–100
17–45
Docetaxel
113
41–47
28–33
Docetaxel/estramustine
131
63–82
17–57
38
71
47
199
38
NR
Vinorelbine
77
17–36
13–66
Vinorelbine/estramustine
25
24–65
NR
Vinorelbine/estramustine/VP-16
25
56
32
Docetaxel/estramustine/carboplatin Mitoxantrone/steroid
NR, not reported.
Chapter 28 Metastatic Adenocarcinoma of the Prostate 511
carboplatin. In 56 patients treated, 50% or greater PSA declines were seen in 67% and median survival was 20 months.62 Unfortunately, the trial was complicated by thromboembolic event in 25% of the patients. Current estramustine-based clinical trials now also include lowdose warfarin to decrease the risk of thromboembolism. Following hormonal therapy failure, chemotherapy may control disease progression, as well as to palliate symptoms. Although mitoxantrone chemotherapy is the first to be approved for treatment of hormone-refractory disease, the most active therapies are probably taxanebased. As chemotherapy continues to make inroads into management of prostate cancer, patients should be encouraged to participate in clinical trials. BONE-DIRECTED THERAPIES Skeletal complications are a major cause of morbidity for men with advanced prostate cancer. Over 80% of men with metastatic prostate cancer have radiologic evidence of bone involvement. Palliative external beam radiotherapy has been used for decades for relief of bone pain, but recently, bisphosphonates and radiopharmaceutical agents have been approved for use in HRPC. There are three potential uses of bisphosphonates in advanced prostate cancer: (1) to prevent osteopenia that commonly accompanies the use of ADT; (2) to prevent or delay skeletal complications in men with bone metastasis; (3) to relieve pain from bony disease as well. In the United States, zoledronic acid is a bisphosphonate approved for use in HRPC. The landmark randomized, placebo-controlled trial of zoledronic acid in patients with HRPC with bone metastasis was reported by Saad et al.63 In this trial, there were significantly more skeletalrelated events in men receiving placebo compared to zoledronic acid (44.2% versus 33.2%; p = 0.021). Skeletal-related events were defined as bone fractures, spinal cord compression, surgery to bone, radiotherapy to bone, or a change in antineoplastic agents. The time to first skeletal event was also significantly longer in the arm receiving zoledronic acid (363 days versus 321 days; p = 0.021). In another study, using high-dose clodronate as adjuvant therapy, the time to development of symptomatic bone metastasis in 311 men with prostate cancer was 23.6 months in those receiving clodronate compared with 19.3 months in placebo arm (p = 0.08).64 However, significantly more dose reductions were required in clodronate arm due to adverse events (93 versus 108, hazard ratio, 0.75). Strontium-89 (89St) chloride, samarium-153 (153Sm), and 32-phosphorus (32-P) are approved radiopharmaceutical agents for treatment of symptomatic bone metastases. There have been no comparative studies between the different radioisotopes although the pain response rates and the patterns of pain relief with differ-
ent radioisotopes appear similar. However, the main toxicity of these radiopharmaceutical agents is potentially severe and prolonged myelosuppression, which may render a patient not suitable to participate in any potential clinical trials with chemotherapy in future. SUMMARY There is no doubt that significant progress has been made in treatment of metastatic prostate cancer. ADT remains the mainstay of treatment; LHRH agonists, orchiectomy, and estrogen therapy are all standard methods of achieving ADT. Alternative methods of hormonal treatment include intermittent ADT and peripheral androgen blockade. After progression on initial ADT, secondary hormonal therapies and chemotherapy have growing promise in both palliating patients and potentially controlling disease, though randomized trials are ongoing. Current research is focused on several areas with promise of better therapeutics against prostate cancer in the future. Promising therapeutic approaches include antisense oligonucleotides, vaccines, angiogenesis inhibitors, and signal transduction inhibitors.65–69
REFERENCES 1. SEER Cancer Statistics Review—NCI, Bethesda, MD (available at http://seer.cancer.gov/csr/1975_2000/). 2. Huggins C, Hodges C: Studies on prostate cancer, effects of castration of estrogens and androgen injection on serum phosphatase in metastatic carcinoma of the prostate. Cancer Res 1941; 1:293–297. 3. Zhang XZ, Donovan MP, Williams BT, et al: Comparison of subcapsular and total orchiectomy for treatment of metastatic prostate cancer. Urology 1996; 47:402–404. 4. Bergman B, Damber JE, Tomic R: Effects of total and subcapsular orchidectomy on serum concentrations of testosterone and pituitary hormones in patients with carcinoma of the prostate. Urol Int 1982; 37:139–144. 5. Robinson MR, Thomas BS: Effect of hormonal therapy on plasma testosterone levels in prostatic carcinoma. Br Med J 1971; 4:391–394. 6. Seidenfeld J, Samson DJ, Hasselblad V, et al: Singletherapy androgen suppression in men with advanced prostate cancer: a systematic review and meta-analysis. Ann Intern Med 2000; 132:566–577. 7. Cassileth BR, Soloway MS, Vogelzang NJ, et al: Patients’ choice of treatment in stage D prostate cancer. Urology 1989; 33:57–62. 8. Chon JK, Jacobs SC, Naslund MJ: The cost value of medical versus surgical hormonal therapy for metastatic prostate cancer. J Urol 2000; 164:735–737. 9. Smith JA Jr., Glode LM, Wettlaufer JN, et al: Clinical effects of gonadotropin-releasing hormone analogue in
512
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
Part V Prostate Gland and Seminal Vesicles metastatic carcinoma of prostate. Urology 1985; 25:106–114. Debruyne FM, Fernandez del Moral P, Geboers AD: LHRH-analogues therapy for metastatic prostate cancer. Prog Clin Biol Res 1988; 260:27–39. Labrie F, Dupont A, Belanger A, et al: Flutamide eliminates the risk of disease flare in prostatic cancer patients treated with a luteinizing hormone-releasing hormone agonist. J Urol 1987; 138:804–806. McLeod D, Zinner N, Tomera K, et al: A phase III, multicenter, open-label, randomized study of abarelix versus leuprolide acetate in men with prostate cancer. Urology 2001; 58:756–761. Iversen P, Tyrrell CJ, Kaisary AV, et al: Casodex (bicalutamide) 150-mg monotherapy compared with castration in patients with previously untreated nonmetastatic prostate cancer: results from two multicenter randomized trials at a median follow-up of 4 years. Urology 1998; 51:389–396. The Veterans Administration Co-operative Urological Research Group: Treatment and survival of patients with cancer of the prostate. Surg Gynecol Obstet 1967; 124:1011–1017. Crawford ED, Eisenberger MA, McLeod DG, et al: A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989; 321:419–424. Keuppens F, Denis L, Smith P, et al: Zoladex and flutamide versus bilateral orchiectomy. A randomized phase III EORTC 30853 study. The EORTC GU Group. Cancer 1990; 66:1045–1057. Bertagna C, De Gery A, Hucher M, et al: Efficacy of the combination of nilutamide plus orchidectomy in patients with metastatic prostatic cancer. A meta-analysis of seven randomized double-blind trials (1056 patients). Br J Urol 1994; 73:396–402. Tyrrell CJ, Altwein JE, Klippel F, et al: Multicenter randomized trial comparing Zoladex with Zoladex plus flutamide in the treatment of advanced prostate cancer. Survival update. International Prostate Cancer Study Group. Cancer 1993; 72:3878–3879. Iversen P, Suciu S, Sylvester R, et al: Zoladex and flutamide versus orchiectomy in the treatment of advanced prostatic cancer. A combined analysis of two European studies, EORTC 30853 and DAPROCA 86. Cancer 1990; 66:1067–1073. Boccardo F, Decensi A, Guarneri D, et al: Zoladex with or without flutamide in the treatment of locally advanced or metastatic prostate cancer: interim analysis of an ongoing PONCAP study. Italian Prostatic Cancer Project (PONCAP). Eur Urol 1990; 18(Suppl 3):48–53. Fourcade RO, Cariou G, Coloby P, et al: Total androgen blockade with Zoladex plus flutamide vs. Zoladex alone in advanced prostatic carcinoma: interim report of a multicenter, double-blind, placebo-controlled study. Eur Urol 1990; 18(Suppl 3):45–47. Beland G, Elhilali M, Fradet Y, et al: Total androgen ablation: Canadian experience. Urol Clin North Am 1991; 18:75–82. Prostate Cancer Trialists’ Collaborative Group: Maximum androgen blockade in advanced prostate cancer: an
24.
25.
26.
27.
28.
29.
30. 31.
32.
33.
34.
35.
36.
37.
38.
39.
overview of the randomized trials. Lancet 2000; 355:1491–1498. Bolla M, Collette L, Blank L, et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomized trial. Lancet 2002; 360:103–106. The Medical Research Council Prostate Cancer Working Party Investigators Group: Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. Br J Urol 1997; 79:235–246. Messing EM, Manola J, Sarosdy M, et al: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 1999; 341:1781–1788. Pound CR, Partin AW, Eisenberger MA, et al: Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999; 281:1591–1597. Galbraith SM, Duchesne GM: Androgens and prostate cancer: biology, pathology and hormonal therapy. Eur J Cancer 1997; 33:545–554. Crook JM, Szumacher E, Malone S, et al: Intermittent androgen suppression in the management of prostate cancer. Urology 1999; 53:530–534. Klotz L: Hormone therapy for patients with prostate carcinoma. Cancer 2000; 88:3009–3014. Higano CS, Ellis W, Russell K, et al: Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: a pilot study. Urology 1996; 48:800–804. Gleave M, Bruchovsky N, Goldenberg SL, et al: Intermittent androgen suppression for prostate cancer: rationale and clinical experience. Eur Urol 1998; 34(Suppl 3):37–41. Kolvenbag GJ, Iversen P, Newling DW: Antiandrogen monotherapy: a new form of treatment for patients with prostate cancer. Urology 2001; 58:16–23. Fleshner NE, Trachtenberg J: Combination finasteride and flutamide in advanced carcinoma of the prostate: effective therapy with minimal side effects. J Urol 1995; 154:1642–1645 (Discussion 1645-6). Ornstein DK, Rao GS, Johnson B, et al: Combined finasteride and flutamide therapy in men with advanced prostate cancer. Urology 1996; 48:901–905. Brufsky A, Fontaine-Rothe P, Berlane K, et al: Finasteride and flutamide as potency-sparing androgen-ablative therapy for advanced adenocarcinoma of the prostate. Urology 1997; 49:913–920. Taylor CD, Elson P, Trump DL: Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol 1993; 11:2167–2172. Small EJ, Vogelzang NJ: Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm. J Clin Oncol 1997; 15:382–388. Labrie F, Dupont A, Giguere M, et al: Benefits of combination therapy with flutamide in patients relapsing after castration. Br J Urol 1988; 61:341–346.
Chapter 28 Metastatic Adenocarcinoma of the Prostate 513 40. Veldscholte J, Berrevoets CA, Mulder E: Studies on the human prostatic cancer cell line LNCaP. J Steroid Biochem Mol Biol 1994; 49:341–346. 41. Joyce R, Fenton MA, Rode P, et al: High dose bicalutamide for androgen independent prostate cancer: effect of prior hormonal therapy. J Urol 1998; 159:149–53. 42. Scher HI, Liebertz C, Kelly WK, et al: Bicalutamide for advanced prostate cancer: the natural versus treated history of disease. J Clin Oncol 1997; 15:2928–2938. 43. Small EJ, Baron AD, Fippin L, et al: Ketoconazole retains activity in advanced prostate cancer patients with progression despite flutamide withdrawal. J Urol 1997; 157:1204–1207. 44. Millikan R, Baez L, Banerjee T, et al: Randomized phase 2 trial of ketoconazole and ketoconazole/doxorubicin in androgen independent prostate cancer. 2001; 6:111–115. 45. Oh WK: Secondary hormonal therapies in the treatment of prostate cancer. Urology 2002; 60:87–92 (Discussion 93). 46. Harris KA, Weinberg V, Bok RA, et al: Low dose ketoconazole with replacement doses of hydrocortisone in patients with progressive androgen independent prostate cancer. J Urol 2002; 168:542–545. 47. Smith DC, Redman BG, Flaherty LE, et al: A phase II trial of oral diethylstilbestrol as a second-line hormonal agent in advanced prostate cancer. Urology 1998; 52:257–260. 48. Oh WK, George DJ, Hackmann K, et al: Activity of the herbal combination, PC-SPES, in the treatment of patients with androgen-independent prostate cancer. Urology 2001; 57:122–126. 49. DiPaola RS, Zhang H, Lambert GH, et al: Clinical and biologic activity of an estrogenic herbal combination (PC-SPES) in prostate cancer. N Engl J Med 1998; 339:785–791. 50. Small EJ, Frohlich MW, Bok R, et al: Prospective trial of the herbal supplement PC-SPES in patients with progressive prostate cancer. J Clin Oncol 2000; 18:3595–3603. 51. Tannock IF: Is there evidence that chemotherapy is of benefit to patients with carcinoma of the prostate? J Clin Oncol 1985; 3:1013–1021. 52. Eisenberger MA, Simon R, O’Dwyer PJ, et al: A reevaluation of nonhormonal cytotoxic chemotherapy in the treatment of prostatic carcinoma. J Clin Oncol 1985; 3:827–841. 53. Oh WK, Kantoff PW: Management of hormone refractory prostate cancer: current standards and future prospects. J Urol 1998; 160:1220–1229. 54. Dawson NA, McLeod DG: The assessment of treatment outcomes in metastatic prostate cancer: changing endpoints. Eur J Cancer 1997; 33:560–565. 55. Tannock IF, Osoba D, Stockler MR, et al: Chemotherapy with mitoxantrone plus prednisone or prednisone alone for symptomatic hormone-resistant prostate cancer: a Canadian randomized trial with palliative end points. J Clin Oncol 1996; 14:1756–1764.
56. Kantoff PW, Halabi S, Conaway M, et al: Hydrocortisone with or without mitoxantrone in men with hormonerefractory prostate cancer: results of the cancer and leukemia group B 9182 study. J Clin Oncol 1999; 17:2506–2513. 57. Trivedi C, Redman B, Flaherty LE, et al: Weekly 1-hour infusion of paclitaxel. Clinical feasibility and efficacy in patients with hormone-refractory prostate carcinoma. Cancer 2000; 89:431–436. 58. Picus J, Schultz M: Docetaxel (Taxotere) as monotherapy in the treatment of hormone-refractory prostate cancer: preliminary results. Semin Oncol 1999; 26:14–18. 59. Hudes G: Estramustine-based chemotherapy. Semin Urol Oncol 1997; 15:13–19. 60. Stearns ME, Tew KD: Estramustine binds MAP-2 to inhibit microtubule assembly in vitro. J Cell Sci 1988; 89(Pt 3):331–342. 61. Berry W, Dakhil S, Gregurich MA, et al: Phase II trial of single-agent weekly docetaxel in hormone-refractory, symptomatic, metastatic carcinoma of the prostate. Semin Oncol 2001; 28:8–15. 62. Kelly WK, Curley T, Slovin S, et al: Paclitaxel, estramustine phosphate, and carboplatin in patients with advanced prostate cancer. J Clin Oncol 2001; 19:44–53. 63. Saad F, Gleason DM, Murray R, et al: A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002; 94:1458–1468. 64. Dearnaley D, Sydes MR, et al. Preliminary evidence that oral clodronate delays symptomatic progression of bone metastases from prostate cancer: first results of MRC Pr05 trial (abstract). Proc Am Soc Clin Oncol 2001; 20:174a. 65. Signoretti S, Montironi R, Manola J, et al: Her-2-neu expression and progression toward androgen independence in human prostate cancer. J Natl Cancer Inst. 2000; 92(23): 1918–1925. 66. Simons JW, Mikhak B, Chang JF, et al: Induction of immunity to prostate cancer antigens: results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor using ex vivo gene transfer. Cancer Res 1999; 59:5160–5168. 67. Vaishampayan U, Fontana J, Du W, et al: An active regimen of weekly paclitaxel and estramustine in metastatic androgen-independent prostate cancer. Urology 2002; 60:1050–1054. 68. O’Reilly MS, Boehm T, Shing Y, et al: Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell 1997; 88:277–285. 69. Murphy GP, Tjoa B, Simmons SJ, et al: Phase II prostate cancer vaccine trial: report of a study involving 37 patients with disease recurrence following primary treatment. Prostate 1999; 39:54–59.
C H A P T E R
29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy Misop Han, MD, and William J. Catalona, MD
The management of clinically localized prostate cancer has undergone substantial changes over the past two decades. Widespread screening with serum prostatespecific antigen (PSA) testing and digital rectal examination has allowed much earlier detection of prostate cancer during this era.1,2 In addition, the modification of surgical technique by Walsh has allowed better hemostasis, improved visualization during dissection, and preservation of neurovascular bundles supplying corpora cavernosa.3 As a result, a skilled surgeon can perform radical prostatectomy with a high cure rate, while preserving urinary continence and erectile potency in the majority of patients. Thus, since 1990, radical prostatectomy has been the most commonly performed treatment for clinically localized prostate cancer.4 In a landmark study, Holmberg et al.5 recently reported on the first prospective, randomized trial showing that radical prostatectomy reduces the rates of metastases and death from prostate cancer. Consequently, the rationale for treating clinically localized prostate cancer surgically is convincing. In this chapter, we discuss patient selection, surgical technique, outcomes, and complications of anatomic radical retropubic prostatectomy using the senior author’s surgical series of more than 3500 anatomic radical prostatectomies as an example. The outcomes are similar to those of other previously reported, large radical prostatectomy series in the PSA era.6,7 It is not only representative of large modern prostatectomy series but also includes all men who underwent surgery in the analysis, even those with known adverse prognostic features. PATIENT SELECTION An ideal candidate for radical prostatectomy should have a life expectancy of at least 10 years, a completely resectable and biologically significant tumor, and no
514
comorbidity that might make the operation unacceptably risky. Actuarial life tables can project the life expectancy of U.S. men,8 and with appropriate adjustment for comorbidities, life expectancy can be estimated for the individual patient. After confirming the likelihood of a sufficiently long life expectancy, the next step in patient selection is to identify those with potentially curable disease. Radical prostatectomy provides the best chance for cure for men whose tumor is confined to the prostate gland. As a result of widespread screening for prostate cancer and more restrictive preoperative patient selection, the proportion of men with organ-confined or specimenconfined disease has increased in recent years. 9 However, the lack of accuracy of conventional radiographic imaging studies in staging prostate cancer has been disappointing. Therefore, nomograms predicting the pathologic stage based on preoperative clinical and pathologic parameters have been widely used to identify patients who are likely to benefit from the surgical resection and those who are not.10,11 Alternatively, nomograms predicting postsurgical or postradiation therapy recurrence-free survival probabilities also are sometimes useful for patients.12–14 For patients with a low probability of resectable disease or a short life expectancy due to age or comorbidity, an alternative treatment to surgery should be recommended. For the patient to have realistic expectations concerning postoperative potency and continence outcomes, the surgeon should provide the patient with relevant information on the nerve-sparing aspect of radical prostatectomy during the preoperative consultation. Anatomic nerve-sparing radical retropubic prostatectomy is a safe choice without compromising cancer control in appropriately selected patients. Nerve-sparing radical prostatectomy is inappropriate in men with locally advanced
Chapter 29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 515
disease, especially if the primary goal of the surgery is cancer control. The feasibility of the nerve-sparing surgery is questionable when a patient has extensive involvement by cancer of prostate biopsies, palpable evidence on digital rectal examination of possible extraprostatic extension, a serum PSA level >10 ng/ml, a biopsy Gleason score >7, poor quality erections preoperatively, a lack of interest and/or willingness of a partner in restoring potency, or the presence of other medical conditions that may adversely affect potency, such as diabetes mellitus, hypertension, psychologic or psychiatric diseases, neurologic diseases, and medications. Therefore, it is important to review the clinicopathologic features of the tumor and the patient’s medical history and erectile function status before embarking on a nerve-sparing operation. After discussing the prospects for preservation of potency, information on the treatment of erectile dysfunction should be imparted. This should include providing information on phosphodiesterase inhibitors, intraurethral and intracorporal vasodilators, vacuum erection devices, venous flow constrictors, and artificial penile prostheses. The discussion should include the anticipated postoperative erectile rehabilitation program to be used and the timing of the return of erections that usually begins 3 to 6 months postoperatively and lasts for up to 36 months. If erectile function is of paramount importance to the patient, he can be reassured that erections can be almost always restored, regardless of whether or not nerve-sparing surgery can be successfully performed. Finally, the surgeon should discuss possible need for and potential side effects of adjuvant radiation therapy or hormonal therapy if the final pathology report reveals adverse prognostic features. At the end of the preoperative counseling session, if nerve-sparing radical retropubic prostatectomy is appropriate, the patient and his spouse or partner should sign an informed consent form authorizing a surgeon to perform the procedure. SURGICAL TECHNIQUE Before the operation, a first-generation cephalosporin antibiotic is given intravenously. After a general endotracheal or regional anesthesia is administered, thigh-high elastic hose are placed on the patient. Sequential compression devices are used only in patients with increased risk for thromboembolic complications. The patient is positioned with his legs on spreader bars, and the operating table is dorsiflexed with the break just above the patient’s anterosuperior iliac spine (Figure 29-1). The abdomen and genitalia are appropriately prepped and draped. There are eight key steps in performing anatomic nerve-sparing radical prostatectomy: (1) a limited pelvic lymphadenectomy; (2) incision of the endopelvic fascia
and the puboprostatic ligaments; (3) ligation, proximal and distal suture ligation, and transection of the dorsal venous complex; (4) dissection of the prostate from the neurovascular bundles; (5) vascular control and transection of the prostatic pedicles; (6) transection and reconstruction of the bladder neck; (7) dissection of the seminal vesicles and ampullary portions of the vasa deferentia; and (8) performance of the vesicourethral anastomosis. These steps are described in detail here with corresponding illustrations. 1. Limited Pelvic Lymphadenectomy A superficial midline (or transverse) lower abdominal incision is made with a scalpel. The linea alba is incised and the space of Retzius is entered. Taking care to avoid disrupting the lymphatic tissue lateral to the external iliac vein and to avoid compression of the vein itself, a Balfour retractor is placed. A modified pelvic lymphadenectomy is performed, removing only the lymph nodes medial to the external iliac vein. Care is taken during the lymphadenectomy to preserve any accessory arterial branches to the corpora cavernosa that arise from the distal external iliac or obturator arteries. The obturator nerve is identified and preserved. In most incidences, the patient elects to have the prostate gland removed, even if there are pelvic lymph node metastases; otherwise, the excised lymph node packet is sent for frozen-section examination. If the frozen section examination reveals metastatic cancer, it is unlikely that the patient will be cured by radical prostatectomy, and the operation is terminated. Lymphadenectomy is optional in patients who are at low risk for pelvic lymph node metastases by virtue of a low Gleason grade, low PSA, and low biopsy tumor volume. After completing the lymphadenectomy, the adipose and areolar tissues are swept gently from the anterior surface of the prostate and the endopelvic fascia to expose the puboprostatic ligaments. Care is taken to avoid injury to the perforating branches of Santorini’s plexus that pierce the endopelvic fascia between the puboprostatic ligaments and pass cephalad on the anterior surface of the prostate gland and bladder. 2. Incision of the Endopelvic Fascia and the Puboprostatic Ligaments The endopelvic fascia is incised in the groove between the levator ani muscles and the lateral border of the prostate (Figure 29-2). Inside the endopelvic fascia, the lateral surface of the prostate is covered by a smooth, glistening membrane overlying the lateral portion of Santorini’s plexus. Strands of the levator ani muscles are gently dissected off the prostate to the level of the urogenital diaphragm. Often, venous tributaries pass from
516
Part V Prostate Gland and Seminal Vesicles
Figure 29-1 Positioning of the patient. A,Legs are separated on spreader bars. B, The operating table is flexed with the break just above the patient’s anterosuperior iliac spine.
the levator ani muscles to the prostate just lateral to the puboprostatic ligaments. These vessels are either cauterized, secured with hemostatic clips, or ligated laterally, and then clamped medially with a delicate snub-nose right-angle clamp. After the vein is transected sharply, its medial portion is ligated. When the endopelvic fascia has been opened from the base to the apex of the prostate, the superficial branch of Santorini’s plexus is gently retracted medially, and the puboprostatic ligaments are placed on stretch and divided close to the pubic symphysis (Figure 29-3). Care is taken not to divide the puboprostatic ligaments too medially or too far under the pubic symphysis to avoid injuring the dorsal venous complex. 3. Suture Ligation and Transection of the Dorsal Venous Complex After the puboprostatic ligaments have been divided, the lateral surfaces of the urethra are palpated. The groove
between the anterior surface of the urethra and the dorsal venous complex is developed with a pinching motion of the left index finger and thumb. The plane between the urethra and the dorsal venous complex is then developed gently, first with a large right-angle clamp. This facilitates tight ligation of the dorsal venous complex. After the dorsal venous complex has been ligated, it is also suture ligated in a slightly more caudal site with a 2-0 chromic catgut suture on a CT-1 needle (Figure 29-4). A suture ligature is also placed in the anterior surface of the prostate to reduce the back-bleeding from Santorini’s plexus (Figure 29-5). The right-angle clamp is then passed behind the dorsal venous complex and the jaws of the clamp are spread. The dorsal venous complex is transected with electrocautery or a scalpel (Figure 29-6). Back-bleeding from the dorsal venous complex is controlled with figure-ofeight 3-0 sutures. It is important to obtain good hemostasis so that the apical dissection of the prostate may be
Chapter 29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 517
Figure 29-2 The endopelvic fascia is incised in the groove between the levator ani muscles and the lateral border of the prostate.
Figure 29-3 The puboprostatic ligaments are placed on stretch and incised.
518
Part V Prostate Gland and Seminal Vesicles
Figure 29-4 The dorsal venous complex is suture ligated with a 2-0 chromic catgut suture on a CT-1 needle.
Figure 29-5 To reduce back-bleeding from Santorini’s plexus, the cephalad aspect of the dorsal venous complex is suture ligated.
Chapter 29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 519
Figure 29-6 The dorsal venous complex is transected with a right-angle clamp jaws spread behind the complex.
performed in a relatively bloodless field. If the dorsal venous complex ligature slips off, the complex is oversewn using a 3-0 chromic catgut suture on a 5/8-circle needle. The goal in oversewing the complex is to pass the suture just through the lateral borders of the complex itself in its anterior, middle, and posterior aspects, respectively. Wide, imprecisely placed sutures may damage the neurovascular bundles. The anterior surface of the urethra is palpated between the neurovascular bundles. The circumurethral sphincter muscle and the anterior wall of the urethra are incised with a scalpel just distal to the apex of the prostate without dissecting around the lateral or posterior surfaces of the urethra (Figures 29-7 and 29-8). The incision should not be carried too far lateral, where it may injure the neurovascular bundles. The urethral catheter is exposed and carefully hooked with a delicate right-angle clamp. Gentle traction on the clamp in a cephalad direction exposes the posterior urethral wall. The catheter is divided and placed on cephalad traction, the posterior urethral wall is sharply transected. Fibromuscular bands tethering the apex of the prostate to the pelvic floor are incised using sharp dissection (Figure 29-9). The rectourethralis muscle is incised, exposing the prerectal fat. 4. Separation of the Prostate from the Neurovascular Bundles The lateral pelvic fascia is incised from the apex of the prostate to the base. A delicate right-angle clamp may be
used to elevate the lateral pelvic fascia from the underlying veins on the surface of the prostate. Small perforating vessels are secured with hemoclips, ties, or ligatures to ensure adequate hemostasis. The posterolateral groove between the prostate and the neurovascular bundles is developed using sharp and blunt dissection, allowing the prostate to assume a more anterior position in the pelvis. The lateral aspect of the prostate is then dissected from the neurovascular bundles, allowing the bundles to retract laterally. In a case of extensive fibrosis, the dissection is performed sharply. The dissection is carried cephalad until the portion of Denonvilliers’ fascia covering the ampullary portions of the vasa deferentia and the seminal vesicles is exposed (Figure 29-10). Denonvilliers’ fascia is incised with the cautery. The Metzenbaum scissors are then used to develop the proper plane of dissection for the prostatic vascular pedicles. If there is continued bleeding from the periurethral tissues and apical pedicles of the prostate, hemostatic sutures should be placed at this juncture to avoid continued blood loss during the remainder of the procedure. 5. Vascular Control and Transection of Prostatic Pedicles The prostatic pedicles are divided by inserting the rightangle clamp medial to them, with the tip of the clamp directed almost parallel to the lateral surface of the prostate. The prostatic pedicle is ligated or hemoclipped laterally, taking care to place the tie or clip medial to the
520
Part V Prostate Gland and Seminal Vesicles
Figure 29-7 The circumurethral external sphincter muscle fibers are incised to expose the urethra.
Figure 29-8 The anterior wall of the urethra is incised with a scalpel without dissecting around the lateral or posterior surfaces of the urethra.
Chapter 29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 521
Figure 29-9 The apical pedicles of the prostate may require suture ligation. Fibromuscular bands tethering the apex of the prostate to the pelvic floor are incised using sharp dissection. The prostate gland is dissected from neurovascular bundles.
Figure 29-10 The dissection is carried cephalad until the portion of Denonvilliers’ fascia covering the ampullary portions of the vasa deferentia and the seminal vesicles is exposed. Denonvilliers’ fascia is incised with the cautery. Denonvilliers’ fascia is incised to expose vascular pedicles at prostate base.
522
Part V Prostate Gland and Seminal Vesicles
neurovascular bundle (Figure 29-11). The pedicle is divided close to the prostate. This dissection is performed on both sides to a point just cephalad to the seminal vesicles. Care is taken when dissecting near the seminal vesicles to avoid injuring the neurovascular bundles that are situated just lateral to the seminal vesicles. The seminal vesicles are freed from the bladder base using sharp and blunt dissection, and a large right-angle clamp is used to further develop this plane. Two hemostatic sutures of 3-0 chromic catgut are placed in the lateral bladder pedicles cephalad to the seminal vesicles, one just lateral to the prostate and another just medial to the neurovascular bundles. The lateral bladder neck fibers are then partially incised with the cautery but are not incised through their entire thickness. 6. Transection and Reconstruction of the Bladder Neck The anterior bladder neck is transected with electrocautery in the natural groove between the bladder and the prostate. The bladder neck opening is enlarged with scissors, and the catheter is pulled through and used as a tractor on the prostate (Figure 29-12). The posterior bladder neck is incised with the cautery. The muscular attachments between the bladder and prostate are divided using electrocautery and/or hemostatic clips for hemostasis.
7. Dissection of Seminal Vesicles and Ampullary Portions of the Vasa Deferentia The seminal vesicles are dissected first along their lateral edges, carrying the plane of dissection medially. Many small perforating arteries enter the lateral and terminal portions of the seminal vesicles. These are secured with small hemoclips. The ampullae are freed, using sharp and blunt dissection, and then are clipped and transected. After the seminal vesicles have been dissected to their tips and the hemoclips placed, the surgical specimen is removed. At this point, the pelvis is carefully inspected for hemostasis. Small bleeders on the neurovascular bundles may require 4-0 absorbable suture ligatures. It is important not to use the cautery for hemostasis on the neurovascular bundles, to avoid cautery injury to the cavernosal nerves. Suture ligatures of 3-0 or 4-0 absorbable material are placed in the “pockets” of the seminal vesicle pedicles on the medial aspects of the neurovascular bundles to ensure good hemostasis in this difficult-tovisualize region. 8. Vesico-Urethral Anastomosis Reconstruction of the bladder neck begins by placing a continuous running everting suture of 3-0 chromic catgut that encompass bladder mucosa and underlying muscle for a distance of nearly the entire anastomotic
Figure 29-11 Prostate base pedicle is ligated or hemoclipped laterally, taking care to place the tie medial to the neurovascular bundle.
Chapter 29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 523
Figure 29-12 The anterior bladder neck is transected in the natural groove between the bladder and the prostate. The bladder neck opening is enlarged with scissors. The ureteral orifices are identified.
circumference (Figure 29-13). The bladder neck is then reconstructed in a tennis racket fashion, with the handle of the racket directed posteriorly. The bladder neck closure is accomplished in two layers with a continuous 3-0 chromic catgut suture on the first layer and a continuous 2-0 chromic catgut suture on the second layer. Care should be taken to avoid compromising the ureteral orifices. The bladder neck is closed to a size of approximately 22Fr to 24Fr. An 18Fr catheter with a 30-ml balloon is passed through the urethra. While an assistant exerts pressure on the perineum with a sponge forceps to better expose the cut end of the urethra (Figure 29-14), double-armed 2-0 chromic catgut sutures are used for the vesicourethral anastomosis (Figure 29-15). A 5/8-circle needle is used to place the sutures in the urethra from inside to outside, avoiding placing the suture into the neurovascular bundles. The tip of the catheter is grasped and brought out of the wound to expose the posterior lip of the cut end of the urethra. The posterior sutures are similarly placed. The anterior sutures are placed at the 10 o’clock and 2 o’clock positions and the posterior sutures are placed at the 5 o’clock and 7 o’clock positions. The other ends of the sutures containing an SH 3/8-circle needle are placed in the corresponding positions of the bladder neck from inside to outside. These sutures encompass mucosa and muscle and exit at the edge of the mucosa. The catheter tip is placed in the bladder, and
the bladder neck is guided gently toward the cut end of the urethra. The anastomotic sutures are tied carefully under direct vision. The bladder is then irrigated free of clots, a single suction drain is placed in the pelvis and brought out the lower end of the wound. The incision is closed with #1 loop Maxon running sutures on the fascia, 2-0 chromic catgut suture on the subcutaneous tissue, and a 4-0 polyglycolic acid subcuticular suture on the skin. The skin incision is covered with Steri-Strips. Postoperative Care Patients are ambulated with assistance once the night of surgery, 5 times on the first postoperative day and 7 times on the second postoperative day. A clear liquid diet is given on the night of surgery, advancing to a regular diet as tolerated on the following days. A suction drain and dressing are removed on the second postoperative day. Intravenous antibiotics are discontinued after the suction drain is removed. For analgesia, Ketorolac (30 to 60 mg) is given intravenously every 6 hours for the first 48 hours. It may be supplemented sparingly with morphine, as needed. Antibiotic ointment is applied to the urethral meatus around the catheter 4 to 6 times a day until the catheter removal. Most patients are discharged from the hospital on the second or third postoperative day. The catheter may be removed on either the seventh, 10th, or 14th postoperative day, depending on the perceived
524
Part V Prostate Gland and Seminal Vesicles
Figure 29-13 A continuous running mucosa-everting suture of 3-0 chromic catgut is placed for a distance of nearly the entire anastomotic circumference.
Figure 29-14 Perineal pressure is applied with a sponge forceps to better expose the cut end of the urethra.
Chapter 29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 525
Figure 29-15 Double-armed 2-0 chromic catgut sutures are used for the vesicourethral anastomosis.
amount of tension on the vesicourethral anastomosis. A cystogram is not performed before removing the catheter unless an anastomotic leak is suspected. The catheter should not be removed before 7 days, as 10% to 15% of men may experience urinary retention from edema and require recatheterization.15,16 Oral fluoroquinolone is given 1 day before and 1 week following the catheter removal. Daily Kegel exercises are performed in four sets of 10, before the surgery and following the catheter removal until continence returns. A protective pad or diaper is used until a complete urinary control is achieved. The first postoperative serum PSA level is measured 2 weeks or more after the operation. CANCER CONTROL OUTCOME The most important objective of radical prostatectomy is cancer control. To cure prostate cancer with radical prostatectomy, the patient must have a resectable tumor and the surgery must completely encompass the tumor.9 A rising serum PSA level is usually the earliest evidence of recurrence or progression following surgery.17 Followup data are still not sufficiently mature to effectively evaluate cancer-specific survival trends. For example, in large contemporary radical retropubic prostatectomy series, including the current series, actuarial 10-year cancerspecific survival ranged between 96% and 98%.6,7,18 Therefore, biochemical recurrence (detectable serum PSA)-free survival has been used frequently as a surrogate in evaluating the treatment efficacy in radical retropubic prostatectomy series.
An analysis of the senior author’s series, including more than 3170 men who underwent anatomic radical retropubic prostatectomy between 1983 and 2002, including those with adverse prognostic features, has been presented.18,19 Cancer progression was defined as detectable serum PSA (>0.2 ng/ml), local recurrence, or distant metastases. With a median follow-up of 4.5 years (mean 5.3, range 0 to 18), cancer progression occurred in 19% of the men following radical prostatectomy. Actuarial 10-year cancer progression-free survival probability was 67%. Cancer progression following radical prostatectomy was strongly associated with many clinical and pathologic parameters, including Gleason grade, clinical, and pathologic tumor stage, era of treatment, and patient age. For example, preoperative serum PSA level was inversely associated with both the rate of organ-confined disease and the 10-year progression-free survival rate. Patient selection and the duration and frequency of follow-up monitoring are critical in determining outcomes as well. Therefore, factors other than treatment effectiveness can influence treatment outcomes. Accordingly, caution is indicated in comparing the results of contemporary radical prostatectomy series using different patient selection criteria and follow-up protocols. URINARY CONTINENCE OUTCOME The overall urinary continence outcome following nerve-sparing radical retropubic prostatectomy was excellent in the current series. More than 93% of men
526
Part V Prostate Gland and Seminal Vesicles
achieved complete urinary continence, defined as requiring no protection for daily activities.19 The return of urinary continence was strongly associated with the age of the patient. For example, more than 95% of men younger than age 50 were continent following surgery. In contrast, 85% of men above age 70 were continent postoperatively. There was no significant difference in continence rate according to the era. Only 4 men (0.2%) eventually required an artificial urinary sphincter placement for stress urinary incontinence. POTENCY OUTCOME There are several possible goals of the nerve-sparing aspect of radical retropubic prostatectomy. Patients with intact libido and erectile potency want to maintain current quality of erections or erections sufficient for penetration with the help of oral medication, such as phosphodiesterase inhibitors. Others with poor quality erections preoperatively might accept erections that at least offer some rigidity to provide sensory satisfaction for both sexual partners. The erectile potency in the current series was defined as an ability to maintain erections strong enough for penetration with or without the help of oral phosphodiesterase inhibitor. The return of erectile potency following radical retropubic prostatectomy was strongly associated with the age of the patient, preoperative potency status, nervesparing status (bilateral sparing versus partial sparing), and the era of surgery (1980s versus 1990s).19 More than 75% of men younger than age 60 regained potency following bilateral nerve-sparing radical retropubic prostatectomy. For men below age 50, more than 95% recovered potency following surgery, in the modern era. Between 62% and 72% of men in their 60s became potent following bilateral nerve-sparing surgery. Finally, there was a significant improvement in recovery of potency in men treated in the 1990s compared to those treated in the 1980s, even after correcting for the age and nerve-sparing status. COMPLICATIONS The hospital cancer registry survey performed by the American College of Surgeons reported a perioperative (within 30 days of surgery) mortality rate of 0.4% following radical prostatectomy.20 There was no intraoperative or immediate postoperative mortality in the current series. With a careful selection of patients and performance of necessary cardiovascular evaluation, perioperative mortality can be largely avoided. The overall complication rate of radical prostatectomy was 8% in the current series. Initially, the complications occurred more commonly in older men, but the overall complication rate gradually decreased with the surgeon’s
experience. The most common complications of anatomic nerve-sparing radical retropubic prostatectomy included anastomotic stricture/bladder neck contracture, thromboembolic complications (deep vein thrombosis and pulmonary embolism), and postoperative inguinal hernia occurrence. In the current series, the rate of anastomotic stricture/bladder neck contracture decreased from 8% in the 1980s to <1% in the 1990s. Similarly, a drastic decrease in thromboembolic events was observed with the rate decreasing from 3% to 1% during the past 20 years. Other less frequent complications (<1%) associated with radical prostatectomy included infection, lymphocele formation, neurologic deficit, and cardiovascular events. Anastomotic stricture can be initially managed with a gentle, serial dilation. Alternatively, a careful internal urethrotomy can be performed. For a long and persistent stricture, a transurethral resection of the scar tissue above the external sphincter may be necessary. After resection, triamcinolone can be injected via cystourethroscopic approach to prevent inflammatory response and subsequent, recurrent scar formation. Inadvertent injury to the obturator nerve can occur during the pelvic lymphadenectomy. One management option is to treat it conservatively with physical therapy since some patients usually do not exhibit significant thigh adductor deficit following the injury.21 Otherwise, a primary nerve repair can be attempted. When a tension-free primary nerve repair is not feasible, a nerve grafting can be performed utilizing either the sural nerve or the lateral antebrachial cutaneous nerve.22 An injury to the ureter can occur inadvertently during the transection of bladder neck or the dissection of the lateral prostate pedicles. When recognized, a simple mobilization of the ureter and ureteroneocystostomy should be performed. The reimplanted ureter can be cannulated using a 5Fr or 8Fr pediatric-feeding tube to prevent an edema at the reimplantation site. Usually, a rectal injury can be repaired primarily using a multiple layer closure.23 However, a diverting colostomy should be strongly considered in men with a large rectal defect or a history of pelvic radiation therapy. A diverting colostomy should also be considered in those on a long-term preoperative steroid therapy. A vesicorectal fistula can develop following anatomic radical retropubic prostatectomy. This uncommon, iatrogenic fistula can be repaired using a transrectal, transsphincteric (York-Mason) approach with excellent results.24–26 SUMMARY Anatomic nerve-sparing radical retropubic prostatectomy provides excellent cancer control with an acceptable rate of complications in appropriately selected
Chapter 29 Anatomic Nerve-Sparing Radical Retropubic Prostatectomy 527
patients. Many clinical and pathologic parameters are associated with cancer control and return of urinary continence and potency following surgery. Over the past 2 decades, widespread screening for prostate cancer and better patient selection have resulted in a favorable shift of these parameters and improved surgical outcomes. The treatment outcomes following radical prostatectomy will most likely continue to improve as active screening for prostate cancer is expanded in the future. REFERENCES 1. Catalona WJ, Smith DS, Ratliff TL, Basler JW: Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993; 270:948–954. 2. Catalona WJ, Smith DS, Ratliff TL, et al: Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 1991; 324:1156–1161. 3. Walsh PC, Donker PJ: Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982; 128:492–497. 4. Stanford JL, Stephenson RA, Coyle LM, et al: Prostate Cancer Trends 1973–1995, SEER Program. National Cancer Institute, NIH, Bethesda, 1999. 5. Holmberg L, Bill-Axelson A, Helgesen F, et al: A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002; 347:781–789. 6. Han M, Partin AW, Pound CR, Epstein JI, Walsh PC: Long-term biochemical disease-free and cancer-specific survival following anatomic radical retropubic prostatectomy. The 15-year Johns Hopkins experience. Urol Clin North Am 2001; 28:555–565. 7. Hull GW, Rabbani F, Abbas F, et al: Cancer control with radical prostatectomy alone in 1000 consecutive patients. J Urol 2002; 167:528–534. 8. Arias E: United States life tables, 2000. Natl Vital Stat Rep 2002; 51:1–38. 9. Han M, Partin AW, Piantadosi S, Epstein JI, Walsh PC: Era specific biochemical recurrence-free survival following radical prostatectomy for clinically localized prostate cancer. J Urol 2001; 166:416–419. 10. Partin AW, Kattan MW, Subong EN, et al: Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 1997; 277:1445–1451 [see comments, published erratum appears in JAMA 9 July, 1997; 278(2):118]. 11. Partin AW, Mangold LA, Lamm DM, et al: Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium. Urology 2001; 58:843–848.
12. Kattan MW, Eastham JA, Stapleton AM, Wheeler TM, Scardino PT: A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 1998; 90:766–771. 13. Han M, Partin AW, Zahurak M, et al: Biochemical (prostate specific antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. J Urol 2003; 169:517–523. 14. Kattan MW, Zelefsky MJ, Kupelian PA, et al: Pretreatment nomogram for predicting the outcome of three-dimensional conformal radiotherapy in prostate cancer. J Clin Oncol 2000; 18:3352–3359. 15. Dalton DP, Schaeffer AJ, Garnett JE, Grayhack JT: Radiographic assessment of the vesicourethral anastomosis directing early decatheterization following nerve-sparing radical retropubic prostatectomy. J Urol 1989; 141:79–81. 16. Lepor H, Nieder AM, Fraiman MC: Early removal of urinary catheter after radical retropubic prostatectomy is both feasible and desirable. Urology 2001; 58:425–429. 17. Pound CR, Christens-Barry OW, Gurganus RT, Partin AW, Walsh PC:: Digital rectal examination and imaging studies are unnecessary in men with undetectable prostate specific antigen following radical prostatectomy. J Urol 1999; 162:1337–1340. 18. Roehl KA, Antenor JA, Catalona W: Cancer recurrence and survival rates after anatomic radical retropubic prostatectomy in 3032 consecutive patients. J Urol 2002; 167 (Suppl 4):1364. 19. Catalona W, Roehl KA, Antenor JA: Potency, continence, complications, and survival analysis in 3032 consecutive radical retropubic prostatectomies. J Urol 2002; 167 (Suppl 4):625. 20. Mettlin CJ, Murphy GP, Sylvester J, et al: Results of hospital cancer registry surveys by the American College of Surgeons: outcomes of prostate cancer treatment by radical prostatectomy. Cancer 1997; 80:1875–1881. 21. Kirdi N, Yakut E, Meric A, Ayhan A: Physical therapy in a patient with bilateral obturator nerve paralysis after surgery. A case report. Clin Exp Obstet Gynecol 2000; 27:59–60. 22. Millesi H: Techniques for nerve grafting. Hand Clin 2000; 16:73–91, viii. 23. Lepor H, Nieder AM, Ferrandino MN: Intraoperative and postoperative complications of radical retropubic prostatectomy in a consecutive series of 1000 cases. J Urol 2001; 166:1729–1733. 24. Bukowski TP, Chakrabarty A, Powell IJ, et al: Acquired rectourethral fistula: methods of repair. J Urol 1995; 153:730–733. 25. Prasad ML, Nelson R, Hambrick E, Abcarian H: York Mason procedure for repair of postoperative rectoprostatic urethral fistula. Dis Colon Rectum 1983; 26:716–720. 26. Wood TW, Middleton RG: Single-stage transrectal transsphincteric (modified York-Mason) repair of rectourinary fistulas. Urology 1990; 35:27–30.
C H A P T E R
30 Radical Perineal Prostatectomy Philipp Dahm, MD, Johannes Vieweg, MD, and David F. Paulson, MD
Modern radical perineal prostatectomy (RPP) traces its origins back to 1904, when Dr. Hugh Hampton Young performed the first prostatectomy to treat prostate cancer using the perineal approach. Today, RPP remains an attractive modality to treat localized prostate cancer, having retained its distinct advantage over alternative surgical approaches: It provides the most direct access to the prostate gland. This characteristic is reflected in the low perioperative morbidity of this approach, which has led some to perform RPP as outpatient surgery.1 Meanwhile, its long-term efficacy in treating clinically organ-confined disease has been established in large patients series with extended follow-up of over 20 years.2–5 Compared to radical retropubic prostatectomy (RRP), RPP allows prostatic dissection in a relatively avascular surgical field, providing good exposure for reconstruction of the urethrovesical anastomosis and allowing dependent postoperative drainage of the prostatic fossa. Modifications of the classic RPP allow sparing of the neurovascular bundles to preserve potency with equal efficacy as in RRP.6,7 If capsular invasion is suspected, wide field dissection of the prostate permits the removal of the prostate with the same margin of extracapsular tissue as RRP.8,9 While the inability to perform a simultaneous staging pelvic node dissection was previously considered a major disadvantage of the perineal approach, the recent trend towards detection of prostate cancer at earlier stages combined with the availability of accurate staging nomograms have made staging lymph node dissections unnecessary in most patients.10–12 These features make modern RPP an attractive treatment choice for patients with organ-confined prostate cancer that should be offered to patients as part of an individualized, rational approach to the surgical management of localized disease. Since the resurgence of the perineal approach will likely continue, it appears prudent for contemporary urologists to familiarize themselves with this procedure.
528
PATIENT SELECTION The main indication for RPP is the primary treatment of localized adenocarcinoma of the prostate, and many contemporary patients of the prostate-specific antigen (PSA) era with newly diagnosed prostate cancer are excellent RPP candidates. Modern staging algorithms, based on clinical stage, serum PSA level, and Gleason score, allow an accurate prediction of local extent and the likelihood of regional lymph node spread, thereby obviating the need for a staging node dissection in most patients. A bilateral pelvic lymph node dissection (BPLND) is recommended in patients with poorly differentiated disease Gleason scores of 8 to 10. In addition, patients with a PSA ≥ 20 ng/ml should undergo a BPLND. According to patients’ and surgeons’ preferences, BPLND may be performed through an open minilaparotomy or by laparoscopic technique. Either approach may be performed as a separate procedure, yet more commonly BPLND is completed immediately before RPP under the same anesthesia and frozen sections of the sampled nodes are analyzed during the time of repositioning. The perineal approach has few contraindications, the most important being the inability of the patients to assume an exaggerated lithotomy position due to conditions, such as spinal stenosis, hip ankylosis, or a history of vertebral fractures. If vertebral mobility is in question, the position may be readily simulated at the time of the preoperative office visit. While obese patients may benefit from a perineal approach by avoiding the dissection of deep layers of abdominal adipose tissue, a subset of massively obese patients with a “large barrel abdomen” may not be suitable candidates because of the high ventilatory pressures (in excess of 40 mm Hg) required during general anesthesia. These patients should be counseled about the possibility that RPP cannot be performed for the above reasons and alternative treatment forms should be discussed beforehand.
Chapter 30 Radical Perineal Prostatectomy 529
While a large prostate (greater than 80 or 100 g) has been cited as a relative contraindication for the perineal approach, it is the relative size of the prostate to the distance between the ischial tuberosities that determines the width of the surgical field. A digital rectal examination (DRE) in the office prior to surgery provides a good estimate of the spatial proportions and the feasibility of RPP in very large prostates but it requires some clinical experience for making this judgment. Transrectal ultrasound examinations have not been helpful in our experience. SURGICAL TECHNIQUE Patient Preparation and Positioning RPP is routinely performed after same day admission. Due to the proximity of the anus and rectum to the incision line and plane of dissection, particular emphasis is placed on a thorough mechanical and antibiotic bowel preparation at home. The patient is placed in an exaggerated lithotomy position taking care to pad all extremities well and avoid overextension. The perineum is correctly positioned by bringing the sacrum downwards on the table until the buttocks reach approximately 15 cm beyond the edge. A bolster is placed below the sacrum to further elevate the pelvis. Correct positioning places the perineum parallel to the floor to provide optimal exposure. Following a routine preparation of a wide surgical field, the patient is draped in such a way that a DRE is possible at the beginning of the case to reorient the surgeon to the individual anatomy and confirm correct placement of the prostate retractor. The anus is then covered by an impermeable drape and excluded from the sterile surgical field for the remainder of the case. Access to the Prostate Skin incision is made approximately 1.5 cm above the anal verge and extended posterolaterally on either side, medial to the ischial tuberosities. The central tendon is identified and divided. An anterior retractor is then placed and the rectourethralis muscle identified as a fibromuscular band in the midline, which is partially swept to the side and partially divided. At this point, the prostate is separated from the posterior surface of the rectum in the midline by gentle, blunt dissection. A moist gauze is placed over the rectum to protect it from inadvertent injury and displacement is maintained by a retractor blade. Dissection of the Prostate Classic perineal prostatectomy proceeds with a transverse incision of Denonvilliers’ fascia followed by exposure of the apex of the prostate using a combination of sharp and
blunt dissection. The dorsal venous complex is not encountered and the urethra may be divided with precision in a relatively avascular field. A Young retractor or straight Lowsley prostatic retractor aids in further dissection of the posterior and the lateral aspects of the prostate. It is important to adequately dissect free the anterior bladder neck so that a tension-free vesicourethral anastomosis can later be achieved. The prostatovesical junction is identified and the prostate is sharply cut away from the bladder. After sharp entry into the bladder between 10 o’clock and 2 o’clock, the Young retractor is withdrawn and a Foley catheter is passed through between the prostate and the bladder neck to serve as a retractor device. Intravenous indigo-carmine may be administered to aid in visualization of the ureteral orifices as the prostate is dissected away from the circular detrusor fibers. Finally, the posterolateral pedicles, vas deferens, and seminal vesicles are isolated, clipped, and transected. Complete excision of the seminal vesicles is readily achieved 13 in most patients; however, is felt to rarely benefit the patient from an oncologic perspective. Bladder Neck Reconstruction and Urethrovesical Anastomosis Once hemostasis is established, the bladder neck is reconstructed. The bladder mucosa is averted to minimize the risk of stricture formation, and the bladder neck is approximated in a racket-handle fashion. Two of the racket-handle sutures and two additional sutures tied to the bladder neck at 10 o’clock and 2 o’clock position serve as Vest sutures to align the urethrovesical anastomosis and are later brought out through the perineal body and tied. Four anastomotic sutures are routinely used that are placed and tied under direct vision over an 18 French urinary catheter to establish a watertight anastomosis. The operating field is copiously irrigated and a DRE is performed to rule out rectal injury. A soft drain is placed and the fibers of the rectourethralis, levator ani, and central tendon are approximated thereby obliterating any dead space and restoring the anatomy, followed by closure of the skin. Postoperative Care From the operating room the patient is taken to the recovery room, where he is typically monitored for approximately 2 hours to ensure appropriate recovery from general anesthesia, adequate urinary drainage, and good pain control. Since the average blood-loss in RPP is low and averages at <500 cc, postoperative transfusions are a rare event. Oral analgesics are started in the recovery room. Patients will routinely tolerate a clear liquid diet the evening of surgery and advance to their regular preoperative diet on the morning of postoperative day 1.
530
Part V Prostate Gland and Seminal Vesicles
The drain is left in place until postoperative day 2 or the time of the patient’s first bowel movement. At that time the patient is instructed to either take an antiseptic sitz bath or alternatively to clean himself using a hand-held shower. Criteria for patient discharge are the ability to tolerate a regular diet, ambulate without assistance, as well as good pain control with oral analgesics. These criteria are normally met towards the end of postoperative day 1 and patients are typically discharged home by the morning of postoperative day 2. MODIFICATIONS OF CLASSIC RPP Nerve-Sparing Radical Perineal Prostatectomy Preservation of the neurovascular bundles is as feasible in RPP as in RRP, yet requires an intimate understanding of the course of the neurovascular bundles as viewed from the perineum to prevent unintended injury. The procedure differs in that initially a vertical instead of a transverse incision of the posterior layer of Denonvilliers’ fascia is made. Reflection of this layer over the apex of the prostate gland and laterally, allows establishing a plane between the prostate and the neurovascular bundles. Posterolateral dissection of the prostate is kept close to the prostatic substance and small clips rather than electrocautery are used to achieve hemostasis. Finally, care is taken not to inadvertently injure the neurovascular bundles, which course in close proximity, when dissecting out the tips of the seminal vesicles. Wide-Field Dissection Radical Perineal Prostatectomy Patients at high risk for extracapsular extension may be considered for a wide-field dissection of the prostate, which encompasses the lateral pelvic fascia and sacrifices both neurovascular bundles. The prostate is exposed as described. However, after the rectum is displaced posteriorly, a surgical plane is developed between the posterior layers of Denonvilliers’ fascia, the anterior rectal surface posteriorly and the levator musculature anteriorly. The prostate remains surrounded by the periprostatic lateral pelvic fascia. All fibrovascular pedicles are divided as far away from the prostate as possible. The seminal vesicles are dissected as described but clipped and dissected at such a level to include the neurovascular bundle. Additionally, wider margins of the bladder neck may be taken to achieve negative margins followed by reconstruction as described. COMPLICATIONS OF RPP Ureteral Injury Problems in reconstruction of the bladder neck may occur if the posterior margin of the incision has been
carried so close to the ureteral orifices, either for oncologic reasons or inadvertently. In this case, the ureteral orifices can be stented using open-ended ureteral catheters followed by bladder neck closure from 6 o’ clock to 12 o’clock of the detrusor musculature only, not incorporating the bladder mucosa. The stents are brought out separately, secured and typically left in place for 5 to 7 days. Alternatively, the ureteral orifice may be reimplanted through the perineal incision. The limited exposure, however, makes this maneuver technically challenging. Should primary ureteral reimplantation not be feasible, patients may alternatively be managed by placing a percutaneous nephrostomy tube on postoperative day 1. This delay will allow for some degree of dilatation of the collecting system to occur which facilitates tube placement. Ureteral reimplantation may then be performed in a delayed fashion using an abdominal approach, ideally at 6 to 12 weeks postoperatively. Rectal Injury Rectal injury is a well-recognized risk of radical prostate surgery. It is a potentially concerning, but rare complication of the perineal approach, with an incidence of 1% to 3% in the hands of experienced surgeons.9 The risk of rectal injury in RPP relates to the intimate relationship of the plane of initial dissection to the rectum and most commonly occurs either at the time of dissection of the rectourethralis muscle or during placement of the posterior weighted retractor. With strict adherence to the correct surgical technique and careful placement of the retractors, however, injury appears avoidable in most cases. If rectal injury does occur, prompt recognition and appropriate management may minimize subsequent morbidity to the patient. This should consist in copious irrigation of the surgical field followed by primary closure of the defect in several layers using an absorbable monofilament. A diverting colostomy is rarely necessary, unless gross fecal soiling is present, which is not encountered if the patient has been adequately prepared using both mechanical and antibiotic bowel preparations. Postoperative management includes the use of broad-spectrum antibiotics and maintaining patients on a clear liquid diet for 3 days. Placement of a rectal tube is unnecessary. The outlined management usually results in uncomplicated healing of the rectal injury with no adverse consequences to the patient. Lower Extremity Neuropraxia Lower extremity neuropraxia is a unique problem associated with the exaggerated lithotomy position. While it is relatively common in the immediate postoperative setting occurring in up to 25% of patients, symptoms are usually transient and consist of sensory deficits below the
Chapter 30 Radical Perineal Prostatectomy 531
knee only.14 These symptoms invariably resolve, in most cases prior to the patients discharge from the hospital on postoperative day 2. The etiology of these injuries is mostly attributable to a stretch injury to the sciatic or common peroneal nerve, less often due to direct compression injury to the sensory nerves of ankle of foot. The recognition of the mechanisms of injury, often resulting from a lack of awareness by inexperienced operating room personnel has resulted in a significant reduction of this problem at our institution. In addition, a recent study from our institution suggests that the likelihood of postoperative lower extremity neuropraxia correlates with surgery time; patients with a surgery time of greater than 2 hours were twice as likely to report symptoms than patients who’s procedure was completed in less time. Based on these findings it appears critical to minimize the amount of time patients spend in the exaggerated lithotomy position. If neuropraxia does occur, management is expectant and conservative. Further diagnostic work-up is usually not indicated unless neurologic symptoms are progressive, suggesting a different etiology, such as spinal stenosis or a herniated disk. DISEASE CONTROL RPP has been demonstrated to achieve long-term disease control in patients with clinically organ-confined
prostate cancer. The Duke Radical Perineal Prostatectomy Database represents one of the largest series of radical prostatectomy patients from a single institution and is based solely on RPP patients. A large cohort of patients who underwent RPP at our institution have been followed for clinical, biochemical, and radiographic evidences of recurrent disease for an extended period of time of up to 20 years, offering the unique opportunity to study the long-term outcome of patients that chose this approach as treatment for clinically localized prostate cancer. Outcome is best described as time to cancer-associated death, which is used for any death associated with recurrent disease irrespective of treatment as documented by a rising PSA level of ≥0.5. In addition, pathologic staging using the categories “organ-confined” (OC), “specimen-confined” (SC), and “margin positive” (MP) provides a robust classification system that has withstood the many changes of the TNM system over the last 2 decades, yet carries important prognostic implications. The overall 10- and 15-year cancer-associated survival rates for all RPP candidates in this series (n = 2006) are 84.5 ± 1.4% and 71.7 ± 2.3%, respectively. Figure 30-1 illustrates the strong prognostic impact of local extent; 15-year cancer-associated survival rates for patients with organ-confined, specimen and margin positive disease are 86.6 ± 2.5, 70.7 ± 6.5, and 49.8 ± 4.4, respectively. In addition, the Gleason score of the prostatectomy
10
Probability of cancer-associated survival
.9
OC (n = 1179)
.8 .7
SC (n = 399)
p = 0.001
.6 .5 .4
MP (n = 428) .3 .2 .1 0.0 0 2006
2
4 1222
6
8 884
10
12 249
14
16 106
18
20 Follow-up (years) 35 Patients at risk
Figure 30-1 Kaplan-Meier analysis of cancer-associated survival of patients following RPP (n = 2006) grouped by tumor extent, applying the categories organ-confined (OC), specimen-confined (SC), and margin-positive (MP).
532
Part V Prostate Gland and Seminal Vesicles
specimen, as a marker for the biologic aggressiveness of the tumor, has consistently demonstrated an impact on long-term survival15 as illustrated in Figure 30-2. Fifteen-year cancer-associated survival rates for patients with Gleason score 5 to 6, 7, and 8 to 10 are 81.1 ± 3.4%, 67.3 ± 4.6%, and 49.2 ± 6.1%, respectively. When combining both prognostic variables one finds that patients with the most unfavorable combination of margin positive, high Gleason score disease of 8 to 10 (n = 146) experience extended survival periods with 10- and 15-year cancer-associated survival rates of 43.1 ± 6.8% and 31.3 ± 8.2%, respectively. These findings emphasize the need for long follow-up periods when studying prostate cancer and suggest that many current series of alternative curative therapies lack follow-up of sufficient duration to permit comparison with the results of radical surgery. While the use of different staging systems and endpoints of outcome cloud a direct comparison between RPP and RRP, the disease control achieved by RPP and RRP may be considered equivalent.16,17 URINARY CONTINENCE Urinary continence is one of the most significant outcome parameters of radical surgery for prostate cancer and perineal prostatectomy achieves excellent urinary continence rates, ranging between 92% and 96%,
depending on the type of definition used.5,18 Urinary continence is typically achieved early in the postoperative course; Weldon et al.18 reported a return of continence (defined as “no routine pad use”) in 23% of patients at 1 month, 56% by 3 months, and 90% by 6 months. It has furthermore been suggested that patients may seek to minimize adverse outcomes when discussing them with their surgeon, and physician and patient assessment of urinary symptoms following radical prostatectomy may differ significantly.19,20 Thus, more recent investigations have utilized validated instruments that are self-administered to more comprehensively characterize urinary function and minimize potential bias.21,22 In a prospective study at our institution of 78 RPP candidates that underwent RPP in a standardized technique and applying a definition of urinary incontinence of greater than “occasional dribbling” we found a proportion of patients selfreporting urinary incontinence of 35.9%, 15.4%, 5.1%, and 3.7% after 3, 6, 9, and 12 months, respectively. Meanwhile, 5.6% of patients had some degree of preexisting urinary incontinence when questioned prior to surgery and applying the same definition. These results may be regarded as preliminary, based on a small cohort of patients. Nevertheless, they compare favorably with the reported self-assessed urinary incontinence rates reported in a series of RRP patients reported by Wei et al.22 and document the early and consistent return of urinary continence following RPP in a majority of patients.
10
GS 2−4 (n = 85)
Probability of cancer-associated survival
.9
GS 5−6 (n = 888)
.8 .7
p = 0.001
.6
GS 7 (n = 704)
.5 .4
GS 8−10 (n = 292)
.3 .2 .1 0.0
0 1969
2
4 1222
6
8 884
10
12 249
14
16 106
18
20 Follow-up (years) 35 Patients at risk
Figure 30-2 Kaplan-Meier analysis of cancer-associated survival of patients following RPP (n = 1969) grouped by Gleason score (GS), applying the GS categories 2 to 4, 5 to 6, 7, and 8 to 10.
Chapter 30 Radical Perineal Prostatectomy 533
POTENCY The nerve-sparing modification of RPP may be regarded as equally effective as the retropubic approach6,7,23 and is offered to select patients with favorable preoperative staging characteristics. These include patients with clinically organ-confined disease, a serum PSA ≤ 10 ng/ml and a Gleason score ≤ 6. It has been our personal practice to offer the bilateral nerve-sparing approach only to those patients with a single positive biopsy core. Therefore, most patients undergo a unilateral nervesparing RPP with deliberate sacrifice of the neurovascular bundle on the side where biopsies are positive, suggesting the location of the bulk of the tumor. When reviewing the potency rates following RPP at our institution, Frazier et al.6 found 77% of patients to be potent 1year after nerve-sparing RPP. Weldon et al.18 additionally analyzed the time course to recovery of potency and found that potency returned in 50% of patients after 1 year and in 70% after 2 years. An additional, important observation was the strong inverse correlation of the rate of successful potency sparing and increasing age. Potency returned in all patients <50 years of age but only 29% of older patients. It appears important to emphasize these two aspects pertaining to the recovery of potency—the extended time interval necessary and the decreased potential for functional recovery with increasing age—with the patient prior to surgery to generate realistic expectations with regard to the level of postoperative sexual functioning that may be anticipated.
unexpected high prevalence of occasional fecal incontinence symptoms in 11.5% of patients (9/78) prior to surgery. Of these 9 patients, 3 suffered from involuntary stool leakage once a week or less frequently, yet 6 patients experienced this symptom at least once daily. Meanwhile, only 2 patients (2.6%) identified fecal incontinence as greater than a “very small problem.” All bowel-related symptoms, including involuntary stool leakage, were transiently increased 1 month following RPP yet returned to baseline levels within 3 to 6 months postoperatively. Compared to their individual baseline, 15.4%, 7.7%, 5.1%, and 3.9% of patients reported worsened symptoms of fecal incontinence after 3, 6, 9, and 12 months, respectively (Figure 30-3). When analyzing the rate of fecal incontinence in patients who denied preoperative problems (n = 69) the incidence after 12 months was only 2.9%, which is considerably lower than the range of 15% to 18% previously reported by Bishoff et al.24 Potential explanations for this discrepancy include differences in the patient populations, as well as a recall bias in the previous study, resulting in the inadvertent inclusion of patients with some degree of preexisting fecal incontinence that was not accounted for retrospectively. Finally, the patients in the study reported by Bishoff et al.,24 underwent surgery at least 1 year prior to the time they were questioned. While our results give us no indication that fecal incontinence initially improves and then subsequently deteriorates, information about the longterm outcome of the patients remains pending. Longer follow-up of our cohort of patients may allow us to characterize the incidence of fecal incontinence further.
FECAL INCONTINENCE A recent study suggested that RPP is associated with a high risk of postoperative fecal incontinence.24 These findings were based on a retrospective study of two groups of patients—from the authors’ institution and from a nationwide database. Patients in either group denied any preexisting preoperative fecal incontinence, yet reported fecal incontinence rates of 18% and 15%, respectively, at least 1 year following RPP. A particular concerning observation of this study was that a majority of patients did not seek medical assistance for the problem of involuntary stool leakage despite detrimental effects to their quality of life. The suggestion that fecal incontinence may be common after RPP, yet underappreciated because it is not routinely addressed during follow-up, prompted us to design a study to evaluate the incidence of bowel-related symptoms and complaints, and fecal incontinence in particular, following RPP. Using a validated patient self-assessment tool we performed a longitudinal assessment of bowel function and bowel-related bother of 78 consecutive patients undergoing RPP, while accounting for preoperatively determined baseline characteristics for comparison. We found an
QUALITY OF LIFE FOLLOWING RPP Quality of life is being increasingly recognized as an important complementary endpoint, when considering treatment options for prostate cancer. A small number of well-designed studies addressing this issue have been reported that provide longitudinal rather than cross-sectional observations and include a measurement of quality of life before initiation of therapy, allowing each patient to serve as his own control. Litwin et al.25 investigated the recovery of general and prostate-specific quality of life in 247 men following RRP. The authors found that 21% of patients reached their individual baseline level of HRQOL in the urinary domain within 3 months following surgery, and 56% by 12 months. In the bowel domain, over two-thirds of patients recovered their baseline scores by 3 months, and >90% recovered by 12 months. Meanwhile, sexual function and bother took longer to return, and was recovered by 33% and 51% of patients within 1 year, respectively. To our knowledge, no dedicated investigation of the recovery of HRQOL in RPP patients has been published, yet preliminary data from a cohort of 78 patients
534
Part V Prostate Gland and Seminal Vesicles
10 .9
Probability of stool leakage
.8 .7 .6 .5 .4 .3 .2 .1 0.0 0
1
2
3
4
5
6
7
8
9
10
11
12
Time after RPP (months)
Figure 30-3 Kaplan-Meier analysis of the probability of patients (n = 78) to experience worsening symptoms of involuntary stool leakage compared to their individual preoperative status, based on responses to a validated patient self-assessment instrument, the EPIC, completed by patients prior to surgery, at 4 weeks, 3, 6, 9, and 12 months following RPP.
who underwent RPP at our institution with a minimum follow-up of 6 months have recently become available. The patients have been studied longitudinally prior to surgery, after 1 month and subsequently at 3-month intervals following RPP using a validated patient selfassessment tool, the Expanded Prostate Cancer Index Composite (EPIC).21 The mean age was 60.3 years (range 43 to 78) and the majority (78.2%) of patients were treated using a non nerve-sparing approach. Of these patients, 47.1% and 81.7% recovered their individual urinary and bowel-related HRQOL within 3 months following RPP (Table 30-1). While based on a small
number of patients, these results compare favorably with the available RRP data, particularly with respect to the urinary domain. SUMMARY Modern RPP constitutes an excellent treatment modality for select patients with clinically organ-confined prostate cancer. Features of this approach include documented long-term disease control, favorable functional results, low morbidity, and fast patient recovery. These characteristics make RPP an attractive treatment choice that
Table 30-1 Longitudinal Assessment of the Recovery of Health-related Quality of Life (HRQOL) Scores in the Domains Urinary, Bowel, and Sexual within 12 Months Following RPP 1 Month (n = 78)
3 Months (n = 71)
6 Months (n = 78)
9 Months (n = 66)
12 Months (n = 64)
Urinary (%)
19.5
47.1
71.8
78.8
82.8
Bowel (%)
35.1
81.7
92.3
90.9
90.6
Sexual (%)
19.4
20.6
20.3
24.6
23.3
Patients were assessed prior to surgery, after 4 weeks, and subsequently at 3 months intervals using the EPIC, a validated patient self-assessment tool. HRQOL scores of each patient were calculated on a scale of 0 to 100 for every domain. Patients were considered to have recovered their individual level of HRQOL if they reached a score within ±10 points of their baseline value.
Chapter 30 Radical Perineal Prostatectomy 535
should be offered to patients as part of an individualized, rational approach to the surgical management of localized disease. REFERENCES 1. Ruiz-Deya G, Davis R, Srivastav SK, Wise, AM, Thomas R: Outpatient radical prostatectomy: impact of standard perineal approach on patient outcome. J Urol 2001; 166:581. 2. Belt E, Schroeder FH: Total perineal prostatectomy for carcinoma of the prostate. J Urol 1972; 107:91. 3. Iselin CE, Robertson JE, Paulson DF: Radical perineal prostatectomy: oncological outcome during a 20-year period. J Urol 1999; 161:163. 4. Paulson DF, Robertson JE, Daubert LM, Walther PJ: Radical prostatectomy in stage A prostatic adenocarcinoma. J Urol 1988; 140:535. 5. Gibbons RP: Total prostatectomy for clinically localized prostate cancer: long-term surgical results and current morbidity. NCI Monographs 1988; 123. 6. Frazier HA, Robertson JE, Paulson DF: Radical prostatectomy: the pros and cons of the perineal versus retropubic approach. J Urol 1992; 147:888. 7. Weldon VE, Tavel FR: Potency-sparing radical perineal prostatectomy: anatomy, surgical technique and initial results. J Urol 1988; 140:559. 8. Korman HJ, Leu PB, Huang RR, Goldstein NS: A centralized comparison of radical perineal and retropubic prostatectomy specimens: is there a difference according to the surgical approach? J Urol 2002; 168:991. 9. Thrasher JB, Paulson DF: Reappraisal of radical perineal prostatectomy. Eur Urol 1992; 22:1. 10. Gingrich JR, Paulson DF: The impact of PSA on prostate cancer management. Can we abandon routine staging pelvic lymphadenectomy? Surg Oncol Clin N Am 1995; 4:335. 11. Partin AW, Mangold LA, Lamm DM, et al: Contemporary update of prostate cancer staging nomograms (Partin tables) for the new millennium. Urology 2001; 58: 843. 12. Parra RO, Isorna S, Garcia PM, Cummings JM, Boullier JA: Radical perineal prostatectomy without pelvic lymphadenectomy: selection criteria and early results. J Urol 1996; 155:612.
13. Vordos D, Delmas V, Hermieu JF, et al: Can a precise vesiculectomy be performed during radical prostatectomy? Prog Urol 2001; 11:1259. 14. Price DT, Vieweg J, Roland F, et al: Transient lower extremity neurapraxia associated with radical perineal prostatectomy: a complication of the exaggerated lithotomy position. J Urol 1998; 160:1376. 15. Iselin CE, Box JW, Vollmer RT, et al: Surgical control of clinically localized prostate carcinoma is equivalent in African-American and white males. Cancer 1998; 83:2353. 16. Sullivan LD, Weir MJ, Kinahan JF, Taylor DL: A comparison of the relative merits of radical perineal and radical retropubic prostatectomy. BJU Int 2000; 85:95. 17. Lance RS, Freidrichs PA, Kane C, et al: A comparison of radical retropubic with perineal prostatectomy for localized prostate cancer within the Uniformed Services Urology Research Group. BJU Int 2001; 87:61. 18. Weldon VE, Tavel FR, Neuwirth H: Continence, potency and morbidity after radical perineal prostatectomy. J Urol 1997; 158:1470. 19. Gray M, Petroni GR, Theodorescu D: Urinary function after radical prostatectomy: a comparison of the retropubic and perineal approaches. Urology 1999; 53:881. 20. Wei JT, Montie JE: Comparison of patients and physicians rating of urinary incontinence following radical prostatectomy. Semin Urol Oncol 2000; 18:76. 21. Wei JT, Dunn RL, Litwin MS, Sandler HM, Sanda MG: Development and validation of the expanded prostate cancer index composite (EPIC) for comprehensive assessment of health-related quality of life in men with prostate cancer. Urology 2000; 56:899. 22. Wei JT, Dunn RL, Marcovich R, Montie JE, Sanda MG: Prospective assessment of patient reported urinary continence after radical prostatectomy. J Urol 2000; 164:744. 23. Weldon VE: Technique of modern radical perineal prostatectomy. Urology 2002; 60:689. 24. Bishoff JT, Motley G, Optenberg SA, et al: Incidence of fecal and urinary incontinence following radical perineal and retropubic prostatectomy in a national population. J Urol 1998; 160:454. 25. Litwin MS, Melmed GY, Nakazon T: Life after radical prostatectomy: a longitudinal study. J Urol 2001; 166:587.
C H A P T E R
31 Laparoscopic Radical Prostatectomy Guy Vallancien, MD, and Xavier Cathelineau, MD
HISTORY Laparoscopic surgery, which was developed in gynecology during the 1940s, was used in gastrointestinal surgery from 1986 onward, especially following development of the technique by Philippe Mouret in Lyon and François Dubois in Paris. It was not, however, immediately extended to the field of urology. The first laparoscopic nephrectomy was performed in 1990 by Ralph Clayman in St. Louis, but the urologic community remained reticent for a long time about the value of these time-consuming techniques, which had only limited indications. From 1995 onward, the development of intracorporeal suture, allowing repair of anomalies of the ureteropelvic junction and nephrectomies for cancer, led to a renewed interest in laparoscopy. In 1992, the first attempt to perform laparoscopic prostatectomy in two cases was published by Schuessler et al.1 in an abstract presented to the American Urology Association Congress. In 1997, the same team published 9 cases of laparoscopic radical prostatectomy and reached the conclusion that this technique did not provide any advantages over open surgery due to the duration and difficulty of the operation, especially when performing the vesicourethral anastomosis. In the same year, Raboy et al.2 published a case of extraperitoneal radical prostatectomy. In December 1997, Richard Gaston (Bordeaux, France), in a personal communication, indicated that he had performed a transperitoneal radical prostatectomy in less than 6 hours. Six weeks later, Guillonneau and Vallancien3,4 started to perform their first radical prostatectomies. Five months later, Abbou,5 in Créteil, also started to perform this new surgical technique. Laparoscopy requires appropriate instruments, an intellectual investment (long training) and a physical investment (this surgery is more tiresome than open surgery). Most importantly, surgeons must be assisted by
536
motivated teams, composed of instrument nurses, scrub nurses, anesthetists, and the hospital administration. It would be impossible to perform laparoscopic surgery without such an environment. INDICATIONS AND CONTRAINDICATIONS Indications The indications of laparoscopic radical prostatectomy are exactly the same as the open radical prostatectomy. The development of the laparoscopic procedure has not changed the indications and the selection of the patient candidates to a surgical treatment. The best indication is probably the young patient, whose PSA is <15 ng/ml, with less than 50% of positive biopsies and Gleason score <8. Laparoscopic radical prostatectomy is feasible for some selected T3N0M0, with condition not preserving the neurovascular bundles and informing the patient of possible complementary treatment. Salvage laparoscopic radical prostatectomy is also feasible after radiation therapy or brachytherapy, but the patient has to be informed of the risk of temporary colostomy. Contraindications Anesthetic Contraindications There are no specific anesthetic contraindications for laparoscopic radical prostatectomy. Contraindications for this procedure are the same as those for all laparoscopic procedures. The main absolute contraindication for laparoscopic approach is high-intracranial pressure whatever its origin (primary or secondary to intracranial process). The relative anesthetic contraindications are: severe emphysema, severe cardiac injury, chronic respiratory
Chapter 31 Laparoscopic Radical Prostatectomy 537
disease, and glaucoma. Those contraindications have to be underlined specifically for extraperitoneal approach. Effectively, there is an increased partial pressure of carbon dioxide (pCO2) during all the extraperitoneal procedure, which requires increased minute ventilation, in order to maintain a p CO 2 between 30 and 35 mm Hg. Anatomic Contraindications There are no anatomic contraindications for laparoscopic radical prostatectomy. Obviously, some cases are more difficult, and especially at the beginning of the experience, the surgeon has to take care of those difficulties and probably select the best cases. Difficult Cases Different factors can increase the difficulty of the procedure, especially: ● ● ●
Previous hormonotherapy Previous TURP or prostatectomy Prostatitis
All of these factors can modify the prostatic and periprostatic tissues and make the surgery really difficult. Moreover, very big prostate (more than 100 g) increase the difficulty of the dissection. According to his experience, the surgeon has probably to avoid those cases at the beginning of his learning curve. In any case, conversion is not a shame but a sign of wisdom. OPERATIVE TECHNIQUE Transperitoneal Approach: the Montsouris Technique6 Medical Preparation Prophylactic antibiotics are not given to the patient; they do not decrease the risk of infection but can induce selection of bacteria, especially enterococci. Thromboembolic complications are prevented by injection of low molecular weight heparin on the day before the operation, which is continued for at least 7 days postoperatively, associated with varicose veins stocking during hospitalization. No gastrointestinal or skin preparation is required. Installation of the Patient The operation is performed under general anesthesia. The patient is placed in the dorsal supine position, with the lower limbs in abduction allowing intraoperative access to the rectum.
An exaggerated Trendelenburg position is essential, at least for the initial posterior phase of the operation. The upper limbs are positioned alongside the body to avoid the risk of stretch injuries to the brachial plexus. An adhesive elastic bandage is placed in cross fashion over the thorax, which ensures better comfort for the patient than shoulder rests. The surgeon stands to the left of the patient and the assistant stands to the right. The camera is attached to a voice-controlled robotic arm. Material There is no specific instrument for laparoscopic radical prostatectomy. As for all the others laparoscopic procedures adapted material is primordial. All the instruments had to be checked before the procedure, especially bipolar forceps and scissors, in order to detect a leak, which could induce a burning of intraabdominal organ. Main Steps of the Operation Insufflation is performed with a Veress needle in the umbilicus or left hypochondrium. The 10-mm trocar for the scope is placed in the umbilicus. Four other trocars are used for the surgeon and the assistant, arranged according to the surgeon’s usual practice; either in a triangular pattern (the operator uses a left pararectal trocar and a right pararectal trocar, and the assistant uses a trocar in the right iliac fossa and an interumbilico-pubic trocar) or in a parallel pattern (the operator uses a trocar in the left iliac fossa and a left pararectal trocar, and the assistant uses two symmetrical trocars on the right side). Pelvic lymph node dissection with frozen section examination is performed according to the preoperative findings. The operation comprises seven successive steps: 1. Posterior phase. The posterior peritoneum is incised over the vasa deferentes, which are sectioned, and the seminal vesicles are completely dissected. The median part of Denonvilliers’ fascia is incised. 2. Anterior phase. The anterior parietal peritoneum is incised from one umbilical artery to the other providing access to the retropubic space after section of the urachus. The pelvic fascia is incised as far as the puboprostatic ligaments, which are sectioned. The prostatic apex is completely dissected. Santorini’s venous plexus and the preprostatic venous drainage are then ligated with 2/0 Vicryl (this stitch can also be placed after the dissection of prostatic vascular pedicles, just before cutting the uretra).
538
Part V Prostate Gland and Seminal Vesicles
3. Vesicoprostatic dissection is performed by preserving, as far as possible, the fibers of the bladder neck. Dissection of the posterior surface of the bladder neck provides access to the plane of the seminal vesicles and vasa deferentes. 4. Dissection of prostatic pedicles and neurovascular bundles. The prostatic vascular pedicles are selectively coagulated with bipolar forceps. Neurovascular bundles are preserved depending on anatomical and oncological conditions. 5. Section of the urethra. The urethra is sectioned away from the prostatic apex. The rectourethralis muscle is also sectioned and the prostate is then completely released (a bougie in the rectum can be useful to identify the rectum in the case of difficult posterior dissection). 6. Vesicourethral anastomosis. It is performed by interrupted 3/0 Vicryl sutures. An 18 F Foley catheter is inserted. The absence of anastomotic leak is verified intraoperatively. 7. Extraction of the operative specimen. The prostate is placed in a laparoscopic bag and removed by enlarging the umbilical incision. A Redon drain is inserted in the retropubic space or the pouch of Douglas. The 5-mm trocar orifices are closed in one layer and the 10-mm trocar orifices are closed in two layers. Postoperative Management The bladder catheter is left in place for 3 to 7 days depending on the quality of the suture (cystography is not performed). Analgesia is limited to paracetamol (8 g by intravenous injection) during the first 24 hours, followed, on D1, by oral paracetamol/dextropropoxyphene pro re nata (p.r.n.) Major analgesics are not administered routinely but are prescribed p.r.n. The IV infusion is stopped on D1. Oral fluids are started on D1 and a normal diet can generally be resumed on D2. Variants of the Transperitoneal Approach Transperitoneal Approach With Initial Anterior Approach Rassweiler et al.7,8 reported their experience with a modified version of the Montsouris technique. They perform an initial anterior approach providing access to the retropubic space. The pelvic fascia is incised, the puboprostatic ligaments are sectioned, and Santorini’s venous plexus is ligated. The urethra is then sectioned, and when the neurovascular bundles are preserved, they are dissected in an ascending direction. The vesicoprostatic dissection is then performed, prior to dissection of the seminal vesicles and section of
the vasa deferentes. The anastomosis is then performed with interrupted sutures. Overall, this technical modification is designed to reproduce the various steps of retropubic prostatectomy. Number of Trocars Most teams6,9,10 performing laparoscopic radical prostatectomy use 5 trocars, which may be arranged in different ways according to the surgeon’s usual practice. Rassweiler et al.7,8 add a sixth 5-mm trocar at Mac Burney’s point, which is designed to improve exposure, especially during seminal vesicle dissection. Use of an Arm for the Scope The use of an arm for the scope provides valuable assistance when performing a laparoscopic procedure, such as radical prostatectomy, as it ensures a fixed image and frees one of the assistant’s hands, allowing more active participation in the operative procedure. Many teams6–10 use a voice-controlled robotic arm (AESOP), but other types of arms are also available, especially less expensive, manually guided, compressed air arms. Modalities of Dissection of Neurovascular Bundles Preservation of the neurovascular bundles precludes the use of mechanical staplers for section of the superior prostatic pedicles. Control and section of these pedicles and preservation of neurovascular bundles require precise dissection, ideally performed by selective bipolar coagulation6,9,11 or even the use of clips.10 The choice between these two approaches is a matter of personal preference, as neither technique has been shown to be superior. Technical Modalities of Vesicourethral Anastomosis The vesicourethral anastomosis can be performed with interrupted sutures or a running suture. Whatever the choice, the rules are the same and especially the necessity of using both hands with forehand and backhand. The running suture has the advantage of being less time-consuming, but it requires constant, good quality traction to ensure a perfectly leak proof suture. In every case, the operator’s experience and that of his team appear to be essential for both the rapidity and the quality of the procedure. Extraperitoneal Approach In 1997, Raboy et al.2 described, for the first time, their experience of extraperitoneal laparoscopic radical
Chapter 31 Laparoscopic Radical Prostatectomy 539
prostatectomy. In 2001, Bollens et al.12 reported their experience of 46 cases performed according to this technique. The scope is introduced via a 10-mm trocar placed at the inferior margin of the umbilicus. Four trocars are used: two 10-mm trocars placed in the left iliac fossa and right iliac fossa; a 5-mm trocar is introduced about 5 cm above the pubic symphysis; and the last 5-mm trocar is placed in the right flank. The first phase of the procedure consists of creation of a prevesical working space. Bladder neck dissection is performed prior to seminal vesicle dissection. The pelvic fascia is then incised and Santorini’s venous plexus is ligated. The neurovascular bundles are then dissected before coagulation and section of the superior prostatic pedicles. Denonvilliers’ fascia is then incised, releasing the posterior surface of the prostate. The apex is then dissected and the urethra is sectioned. The anastomosis is performed by interrupted sutures. Overall, the advantages of the extraperitoneal approach, according to its supporters, would be a reduction of the risk of damage to intraperitoneal organs and a similar surgical approach to that of open retropubic prostatectomy. Its disadvantages would be a limited working space and the difficulty of the anastomosis due to the more limited mobilization of the bladder. We reviewed 200 consecutive procedures performed in Montsouris Institute by two surgeons; 100 transperitoneal procedures were compared to the first 100 extraperitoneal cases. This study showed equivalent results in term of operative, postoperative, and pathological data.
● ●
● ●
Dissection Extraction of surgical specimen and removal of trocars Early postoperative phase Late postoperative phase
Complications of Patient Positioning The main complications at this step are: ● ● ●
Compartment syndrome Peripheral neuropathy Scapular pain
The risk is related to protections used for the positioning and also, obviously, to the length time of the procedure. So, the surgeon has always to check by himself the protections of the patients and to take care of the length time of the operation (conversion is sometimes the best solution). Those complications are exceptional (<0.1%), and their risk decrease significantly with experience of the surgeon and his team. Complications of Insufflation and Trocar Placement The main risk is vascular or bowel injuries with the first trocar. There is no rule to use or not open laparoscopic procedure and the choice depends on the usefulness and the experience of each team. Small vessels injury can also occur during the placement of other trocars, especially epigastric artery (0.3%).
PERIOPERATIVE COMPLICATIONS Improvement of the surgical technique has allowed a reduction of the morbidity of radical prostatectomy. Comparative studies of the complications according to the surgical technique are often difficult and must always take into account not only the operator’s level of experience with the technique but also the patient characteristics and finally the modalities of evaluation of complications, especially functional complications. The morbidity is related not only to the technique itself but also to the patient’s comorbidities, particularly the ASA3 score13 and blood loss. The mortality rate is currently close to 0%, regardless of the technique used (retropubic, perineal or laparoscopic)14–17 (Tables 31-1 and 31-2). Considering the different phase of the laparoscopic procedure, the complications can be divided according each step: ● ●
Patient positioning Insufflation and placement of trocars
Intraoperative Complications Blood Loss Median intraoperative bleeding reported by experienced teams performing retropubic prostatectomy varies between 1000 and 1500 ml.14,19 Dillioglugil19 reported a transfusion rate of 29% for all the series and 15% for the last 135 patients among a total of 472. For Catalona,14 using the technique of hemodilution, most of the patients received autologous transfusion during or after surgery and 9% need also heterologous postoperative transfusion. In the same series, the rate of hematoma was 0.05%. The median blood loss during laparoscopic prostatectomy varies from 370 ml20 to 1230 ml11 for patient series with a comparable experience.11,20 The transfusion rates for these two series were 7% and 30%, respectively, at the beginning of their experience. Guillonneau et al.17 reported, for the last 100 patients, a mean estimated blood loss of 290 ml and a transfusion rate of 3.5%. The rate of hematoma in this series was 1%.
540
Part V Prostate Gland and Seminal Vesicles
Table 31-1 Complications of Radical Prostatectomy Lepor et al.39
Catalona et al.14 (14)
*Guillonneau et al.17
*Rassweiler et al.11
150
1000
1870
567
180
Study Number of patients Rectal injury
6/0.6
3/2
5/0.5
1/0.05
8/1.4
1.1
Ileocolic injury
nc
nc
nc
nc
4/0.7
nc
Ileus
nc
nc
4/0.4
nc
6/1.1
2.8
Bladder injury
nc
nc
nc
nc
9/1.6
nc
Ureteral injury
nc
7/4.7
1/0.1
1/0.05
3/0.5
0
Deep venous thrombosis
13/1.3
4/2.7
2/0.2
39/2
2/0.4
0
Pulmonary embolism
7/0.7
nc
4/0.4
nc
0
0
Anastomotic leakage
nc
15/10
2/0.2
nc
46/8.1
2.2
Lymphocele
1/0.1
3/2
1/0.1
11/0.6
1/0.2
0
Hydronephrosis
nc
nc
nc
nc
nc
2.8
Acute renal failure
Nc
2/1.3
nc
nc
1/0.2
nc
Pelvic hematomas
1/0.1
nc
nc
nc
5/0.9
8.9
Wound
/0.9
nc
9/0.9
15/0.8
7/1.2
0.6
Nerve injury
nc
nc
1
5/0.3
3/0.5
0
Myocardiac infarction
7/0.7
0
5/0.5
2/0.1
0
nc
Cerebral vascular accident
nc
nc
nc
0
0
nc
Death
nc
1/0.7
1/0.1
0
0
nc
Anastomotic stricture
nc
nc
10/1
71/3.8
nc
2.8
Total complications
35/3.5
143/8
95/16.7
nc
*Laparoscopic approach.
Table 31-2 Evolution of the Complication Rate with Experience in Laparoscopy (Montsouris Experience) Patients 1–200
Patients 200–400
Patients 400–567
25
19
14
Mean operative time (minutes )
234
190
180
Mean estimated blood loss (ml)
372
398
350
Lymphadenectomy (%)
Transfusions (%)
7.5
5
3.8
Conversions (%)
3.5
0
0
Number rectal injuries
3
1
4
Reinterventions (%)
6
7
9
Chapter 31 Laparoscopic Radical Prostatectomy 541
Digestive Injuries
Urinary Incontinence
Digestive injuris are rare and directly related to the operator’s experience and to the patient’s history (especially previous radiation therapy). The rate of rectal injuries is similar regardless of the technique (retropubic or laparoscopic), ranging from 0.5% to 2%.11,19–21 In laparoscopic procedure, using a rectal bougie can help to identify the rectal wall but cannot ensure risk-free surgery.
The quality of continence after radical prostatectomy is difficult to assess (Table 31-3), as reflected by the marked variability of incontinence rates reported in the literature. This variability is related to three main factors: definition of incontinence, modalities of evaluation, and follow-up. The definition of incontinence varies considerably from one study to another; total absence of protection or use of a maximum of one protection. Geary et al.23 reported that 80.1% of patients did not require any protection, while Eastham et al., 32 considering patients who required a maximum of one protection to be continent, reported that 91% of patients were continent. No consensus has therefore been reached concerning the definition of incontinence. In Table 31-2, continence is defined as complete absence of either occasional or permanent protection. The modalities of evaluation also vary from one author to another: clinical interview by the surgeon, clinical interview by another doctor, self-administered questionnaire. The method of data collection is essential to obtain perfectly objective information. Development of a validated questionnaire, based on a standardized definition, would facilitate comparison of the various results reported in the literature.27,30 The follow-up also frequently differs from one series to another. Although about one-half of patients are “dry” between 1 and 3 months, and most are dry at 1 year, some patients can still recover for up to 2 years. A follow-up of at least 12 months is therefore essential.23,28,32,33 Furthermore, the main predisposing factor for postoperative incontinence appears to be age >70 years.14,16,24,32,34 The respective roles of preoperative continence, stage of the disease, and development of anastomotic stenosis are also discussed.14,15,23,29,32 Finally, some authors consider that certain technical modifications appear to facilitate preservation of continence: quality of apical dissection,15 neurovascular bundle preservation,25 preservation of the bladder neck, and preservation of puboprostatic ligaments. In any case, experience of the surgeon is an essential factor to improve the recovery of continence.
Ureteric Injuries Ureteric injuries are also rare, occurring in 0.05% to 0.3% of cases, regardless of the technique. Complications of Specimen Extraction and Trocar Removal The complications that can occur are: bleeding from orifice of 10 mm trocar and ileum injury (with the endobag or during the opening for extraction of the specimen). These complications are exceptional. Early Postoperative Complications Thromboembolic Complications Thromboembolic complications constitute the main cause of postoperative mortality in open procedure.1,22 Dillioglugil19 reported 2% of thromboembolic accidents, while Rassweiler11 and Guillonneau17 reported <0.5% of thromboembolic accidents. Prophylactic anticoagulation and early mobilization (especially after laparoscopic procedure) decrease the frequency of these complications. Anastomotic Leaks Anastomotic leaks are often missed when minimal and correctly drained, and their incidence is therefore often underestimated. Length time of bladder catheter has to be directly related to the quality of the anastomosis. Lymphoceles Lymphoceles are now less frequent, whatever the way laparoscopic or open, due to better selection of patients requiring pelvic lymph node dissection. Late Postoperative Complications Urinary incontinence and impotence are the two most frequent and most disabling functional sequelae. Stenosis of the vesicourethral anastomosis is observed more rarely.
Impotence As for continence, objective evaluation of sexual potency encounters a number of difficulties: absence of a consensual definition of sexual potency, various methods of evaluation, and variable follow-up (Table 31-4). The definition of sexual potency varies according to the criteria adopted: erection with or without sexual intercourse and erection allowing sexual intercourse.
542
Part V Prostate Gland and Seminal Vesicles
Table 31-3 Continency Study Catalona et al.14
Number of Points
Follow-Up (months)
Evaluation
Mean Age
=1 Pad/Day (%) 8
1325
50
Physician
63(38-79)
Geary et al.23
458
>18
Physician
64.1±0.3
Leandri et al.24
620
12
Physician
68 (46–84)
5
Steiner25
593
12
Physician
? (34–76)
5.50
*Turk et al.9
125
9
Physician
60 (37–72)
8
50
6
Physician
63 (47–71)
15
*Bollens et al.12
19.90
Igel et al.22
692
*Rassweiler et al.7
100
6
Questionnaire
68 (55–74)
22
Fontaine et al.26
116
51.6
Patient quest
65.2 (48–76)
19.80
McCammon et al.27
203
40.3
Patient quest
63.7 (43–73)
23.70
Jonler et al.28
86
22.5
Patient quest
64 (49–75)
47
Bates et al.29
83
22
Patient quest
65 (49–73)
24
Walsh et al.15
64
18
Patient quest
57 (36–67)
7
145
12
Patient quest
62.3 (40–80)
13
94
12
Patient quest
61.5
39
567
12
Patient quest
63 (49–77)
21
29
12
Patient quest
64.8 (47–77)
13.80
Wei and Montie30 Talcott et al.31 *Guillonneau et al.17 *Hoznek et al.10
Physician
21
*Laparoscopic approach.
The methods of evaluation of sexual potency are also very heterogeneous, as shown in Table 31-4: clinical interview by the surgeon, clinical interview by another doctor, self-administered questionnaire. The possible use of a treatment for erectile dysfunction, not systematically reported, also makes it difficult to compare various series. Follow-up also constitutes an important parameter in this evaluation. While a large number of series have demonstrated the possibility of late recovery, most studies are limited to a relatively short follow-up. The assessment of recovery of sexual function requires a follow-up of at least 18 months.15,36 Other elements must also be taken into account: quality of erections before surgery, patient’s age, and type of surgery (preservation of one or two neurovascular bundles). Moreover, the surgeon’s experience is essential for preserving the neurovascular bundles. Finally, the selection of patients eligible for preservation of neurovascular bundles is an important factor, rarely mentioned in the literature.14
Anastomotic Stenosis Stenosis of the vesicourethral anastomosis occurs in 0.5% to 4% of cases.14 ONCOLOGIC RESULTS The aim of laparoscopic procedure that is to increase the quality of the dissection and to reduce the morbidity is only acceptable if the oncologic efficacy is demonstrated. For patients with organ-confined disease, at 3 years, Catalona et al.14 had a recurrence-free survival of 93%. Similar results are observed by the Johns Hopkins group where their 5-year recurrence-free was 97% for organ-confined cancer. In retropubic approach, the rate of positive margins range between 15% and 40% depending on the experience of the team and the preservation or not of the neurovascular bundles. In their experience of laparoscopy, after 3 years, Guillonneau et al.37 observed that 92% of the pT2a and pT2b had a PSA < 0.1 ng/ml. Among the patients with a PSA < 10 ng/ml
Chapter 31 Laparoscopic Radical Prostatectomy 543
Table 31-4 Potency Study
Number of Points
Leandri et al.24
620
Igel et al.22
692
*Turk et al.9
44
*Bilatéral *Unilatéral *Rassweiler et al.11 *Unilatéral Geary et al.23 Bilatéral
Mean Age 68
60
Follow-up Months 12
?
Evaluation
Impotence (%)
Physician
29
Intercourse
Physician
97.5
Erection
Physician
41
Intercourse with sildenafil
5
nc
39
nc
100
68
?
Physician
10 459
64.1
18
Questionnaire
Intercourse 6/10
Intercourse with sildenafil or PGE1
44.4
Intercourse
69
68.1
Unilatéral
203
86.7
Catalona et al.14
858
Bilatéral
798
32
60
53
Unilatéral
63
18
Definition
Questionnaire
33.5
Intercourse
Fowler et al.35
739
?
24
Patient quest + questionnaire
79
Erection
Walsh et al.15
64
57
18
Patient quest
14
Intercourse 1/3 with sildenafil
62.9
18
Patient quest + questionnaire
59
Intercourse
Stanford et al.34
1291
Bilatéral
44
Unilatéral
46.6
No preservation
34.4
Talcott et al.31
94
Bilatéral
19
*Bollens et al.12
50
*Bilateral *Hoznek et al. *Laparoscopic approach.
61.5
63
12
6
Patient quest
64.8
12
Incomplete erection
1/6
Intercourse with sildenafil or PGE1
11/25
Erection (intercourse?)
Patient quest
6 25
4/19
Patient quest
544
Part V Prostate Gland and Seminal Vesicles
and a Gleason score < 7, 95.5% had a PSA < 0.2 ng/ml. The overall rate of positive margin was 17%. No port seeding was observed. REMOTE-CONTROLLED ASSISTED RADICAL PROSTATECTOMY Laparoscopy is probably a transitional technique between open surgery and remote-controlled surgery. As it is no longer necessary to open the abdomen to operate and almost all of the necessary instruments can be introduced via trocars, it is only logical to develop remotecontrolled surgery for the following reasons; the laparoscopy position is not very ergonomic. The surgeon stands to the side of the patient and has to operate by crossing his hands over the midline, especially for sutures. This position can cause scapular pain. The vesicourethral suture at the bottom of the lesser pelvis is also a difficult procedure, requiring an experienced operator to ensure a good quality anastomosis. Many papers have been written on experimental remote-controlled surgery in animals, but very few have yet been published in man. A first series of 10 cases of remote-controlled assisted radical prostatectomy has been published.38 The operating time was 9 hours. It should be noted that this team started to perform remote-controlled assisted radical prostatectomy without any previous experience of laparoscopic surgery. Abbou et al.39 published 1 case and, more recently, Guglielmo et al.40 and Pasticier et al.41 also published their cases. In the United States, Tewari et al.42 in Detroit, after 1 year of training in pelvic laparoscopy, have acquired a certain experience with remote-controlled laparoscopic surgery (70 cases). The Institut Montsouris experience, based on 30 cases, together with the cases operated in Detroit, illustrates the following advantages of remote-controlled surgery: good ergonomy for the surgeon, whose forearms are supported to allow precise manipulation of the joysticks. A possible reduction of the amplitude of displacement of the remote-controlled robotic arms and especially 6 degrees of freedom, allowing rotation of the remotecontrolled needle holders in all directions, makes suturing much easier. The 3D vision provided by a dual scope is extremely precise, but it is not specific to remotecontrolled surgery. The disadvantages of remote-controlled surgery, at the present time, are the absence of practical bipolar coagulation to ensure reliable hemostasis and intraoperative bleeding is slightly greater than with that of laparoscopy. As good quality bipolar coagulation is essential to ensure an optimal laparoscopic procedure, engineers are currently working to rapidly develop this instrument. The future of surgery is clearly remote-controlled surgery, as it is less tiring for the surgeon and ensures more precise sutures.
Teaching could be ensured by virtual reconstitution of prostatectomies from operative videos. The trainee surgeon would be able to practice on the operating console in the same position as when performing remotecontrolled laparoscopic surgery. Finally, a senior surgeon would be able to control two or three operating rooms, each equipped with a remotecontrolled system and console operated by a junior surgeon. The senior surgeon would be in a separate room, supervising the external and endoscopic screens of each room under his direction. His console could be connected in a fraction of a second to the other operating consoles in the event of difficulties. Such “industrialization of surgery” will probably considerably change our everyday practice. Performing surgery at distant sites would appear to be more difficult; a surgeon would still need to be present on site to insert the trocars and to treat any complications. The transmitted image could be used to help another surgeon seeking advice, but there is no future for remote-controlled surgery of the entire procedure. In conclusion, remote-controlled surgery does not currently provide any significant benefit for the patient. Bleeding is higher than with laparoscopic surgery, but the development of a hemostasis system, such as good quality bipolar forceps, should reduce bleeding. Suture is easier, but a surgeon experienced in laparoscopy can achieve similar results. For the operator, the operation is less tiring and the various procedures are facilitated. Virtual teaching systems must be developed to allow young operators to learn the basic techniques of remote-controlled surgery. REFERENCES 1. Schuessler WW, Schulam PG, Clayman RV, Kavoussi LR: Laparoscopic radical prostatectomy: initial short-term experience. Urology 1997; 50(6):854–857. 2. Raboy A, Ferzli G, Albert P: Initial experience with extraperitoneal endoscopic radical retropubic prostatectomy. Urology 1997; 50(6):849–853. 3. Guillonneau B, Cathelineau X, Barret E, Rozet F, Vallancien G: Laparoscopic radical prostatectomy: technical and early oncological assessment of 40 operations. Eur Urol 1999; 36:14–20. 4. Guillonneau B, Vallancien G: Laparoscopic radical prostatectomy: the Montsouris experience. J Urol 2000; 163:418. 5. Abbou CC, Salomon L, Hoznek A, et al: Laparoscopic radical prostatectomy: preliminary results. Urology 2000; 55(5):630–634. 6. Guillonneau B, Vallancien G: Laparoscopic radical prostatectomy: the Montsouris technique. J. Urol 2000; 163:1643. 7. Rassweiler J, Sentker L, Seemann O, et al: Heilbronner laparoscopic radical prostatectomy. Technique and results after 100 cases. Eur Urol 2001; 40:54–64.
Chapter 31 Laparoscopic Radical Prostatectomy 545 8. Rassweiler J, Seeman O, Hatzinger M, Frede T: Laparoscopic anatomical radical prostatectomy: experience after 600 cases. J Urol 2003; 169(4):249. 9. Turk I, Deger S, Winkelmann B, Schonberger B, Loening SA: Laparoscopic radical prostatectomy. Technical aspects and experience with 125 cases. Eur Urol 2001; 40(1):46–52 [Discussion 53]. 10. Hoznek A, Salomon L, Olsson LE, et al: Laparoscopic radical prostatectomy. The Creteil experience. Eur Urol 2001; 40(1):38–45. 11. Rassweiler J, Sentker L, Seemann O, Hatzinger M, Rumpelt HJ: Laparoscopic radical prostatectomy with the Heilbronner technique: an analysis of the first 180 cases. J Urol 2001; 166(6):2101–2108. 12. Bollens R, Vanden BM, Roumeguere T, et al: Extraperitoneal laparoscopic radical prostatectomy. Results after 50 cases. Eur Urol 2001; 40(1):65–69. 13. Koch MO, Smith JA Jr: Clinical outcomes associated with the implementation of a cost-efficient program for radical retropubic prostatectomy. Br J Urol 1995; 76(1):28–33. 14. Catalona WJ, Carvalhal GF, Mager DE, Smith DS: Potency, continence and complication rates in 1870 consecutive radical retropubic prostatectomies. J Urol 1999; 162(2):433–438. 15. Walsh PC, Marschke P, Ricker D, Burnett AL: Patient-reported urinary continence and sexual function after anatomic radical prostatectomy. Urology 2000; 55:58–61. 16. Zincke H, Bergstralh EJ, Blute ML, et al: Radical prostatectomy for clinically localized prostate cancer: long-term results of 1143 patients from a single institution. J Clin Oncol 1994; 12(11):2254–2263. 17. Guillonneau B, Rozet F, Cathelineau X, et al: Perioperative complications of laparoscopic radical prostatectomy: the Montsouris 3-year experience. J Urol 2002; 167(1):51–56. 18. Lepor H, Nieder A, Ferrandino M: Intraoperative and postoperative complications of radical retropubic prostatectomy in a consecutive series of 1000 cases. J Urol 2001; 166:1729–1733. 19. Dillioglugil O, Leibman BD, Leibman NS, et al: Risk factors for complications and morbidity after radical retropubic prostatectomy. J Urol 1997; 157(5):1760–1767 (review). 20. Guillonneau B, Rozet F, Barret E, Cathelineau X, Vallancien G: Laparoscopic radical prostatectomy: assessment after 240 procedures. Urol Clin North Am 2001; 28(1):189–202. 21. Guillonneau B, Gupta R, El Fettouh H, et al: Laparoscopic management of rectal injury during laparoscopic radical prostatectomy. J Urol 2003; 169(5):1694–1696. 22. Igel TC, Barrett DM, Segura JW, Benson RC Jr, Rife CC: Perioperative and postoperative complications from bilateral pelvic lymphadenectomy and radical retropubic prostatectomy. J Urol 1987; 137(6):1189–1191. 23. Geary ES, Dendinger TE, Freiha FS, Stamey TA: Incontinence and vesical neck strictures following radical retropubic prostatectomy. Urology 1995; 45(6):1000–1006 (review).
24. Leandri P, Rossignol G, Gautier JR, Ramon J: Radical retropubic prostatectomy: morbidity and quality of life. Experience with 620 consecutive cases. J Urol 1992; 147(3 Pt 2):883–887. 25. Steiner MS: Continence-preserving anatomic radical retropubic prostatectomy. Urology 2000; 55:427–435. 26. Fontaine E, Izadifar V, Barthelemy Y, Desgrippes A, Beurton D: Urinary continence following radical prostatectomy assessed by a self-administered questionnaire. Eur Urol 2000; 37(2):223–227. 27. McCammon KA, Kolm P, Main B, Schellhammer PF: Comparative quality-of-life analysis after radical prostatectomy or external beam radiation for localized prostate cancer. Urology 1999; 54(3):509–516. 28. Jonler M, Madsen FA, Rhodes PR, et al: A prospective study of quantification of urinary incontinence and quality of life in patients undergoing radical retropubic prostatectomy. Urology 1996; 48(3):433–440. 29. Bates TS, Wright MP, Gillatt DA: Prevalence and impact of incontinence and impotence following total prostatectomy assessed anonymously by the ICS-male questionnaire. Eur Urol 1998; 33(2):165–169. 30. Wei JT, Montie JE: Comparison of patients’ and physicians’ rating of urinary incontinence following radical prostatectomy. Semin Urol Oncol 2000; 18(1):76–80. 31. Talcott JA, Rieker P, Propert KJ, et al: Patient-reported impotence and incontinence after nerve-sparing radical prostatectomy. J Natl Cancer Inst 1997; 89(15):1117–1123. 32. Eastham JA, Kattan MW, Rogers E, et al: Risk factors for urinary incontinence after radical prostatectomy. J Urol 1996; 156(5):1707–1713 (review). 33. Donnellan SM, Duncan HJ, MacGregor RJ, Russell JM: Prospective assessment of incontinence after radical retropubic prostatectomy: objective and subjective analysis. Urology 1997; 49(2):225–230. 34. Stanford JL, Feng Z, Hamilton AS, et al: Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer: the prostate cancer outcomes study. JAMA 2000; 283(3):354–360. 35. Fowler FJ Jr, Barry MJ, Lu-Yao G, et al: Patient-reported complications and follow-up treatment after radical prostatectomy. The National Medicare experience: 1988–1990 (updated June 1993). Urology 1993; 42(6):622–629. 36. Kim ED, Nath R, Slawin KM, et al: Bilateral nerve grafting during radical retropubic prostatectomy: extended follow-up. Urology 2001; 58(6):983–987. 37. Guillonneau B, Gerard C, El Fettouh H, et al: Mid-term oncological follow-up of laparoscopic radical prostatectomy: mono-institutional experience based on 800 consecutive patients. In 97th Annual Meeting, AUA, Orlando, May 2002. 38. Binder J, Kramer W: Robotically assisted laparoscopic radical prostatectomy. BJU Int 2001; 87:408–410. 39. Abbou CC, Hoznek A, Salomon L, et al: Laparoscopic radical prostatectomy with a remote controlled robot. J Urol 2001; 165:1964–1966.
546
Part V Prostate Gland and Seminal Vesicles
40. Guglielmo B, Nakada SY, Rassweiler JJ: Future developments and perspectives in laparoscopy. Eur Urol 2001: 40:84–91. 41. Pasticier G, Rietbergen JBW, Guillonneau B, et al: Robotically assisted laparoscopic radical prostatectomy: feasibility study in men. Eur Urol 2001; 40:70–74.
42. Tewari A, Desari R, Hemal A, et al: A prospective comparison of robot-assisted anatomic prostatectomy and conventional radical retropubic prostatectomy (RRP): the Vattikuti Urology Institute Experience. J Urol 2003; 169(4):78.
C H A P T E R
32 Complications of Surgical Treatment for Localized Prostate Cancer Glen W. Barrisford, MD, and Michael P. O’Leary, MD, MPH
In developed countries prostate cancer represents the most commonly detected malignancy and the second leading cause of cancer death in men over 50. In the year 2000, over 180,000 American men were newly diagnosed.1 Despite the 30% lifetime risk of developing prostate malignancy, the protracted course of this disease only results in a comparatively low 3% risk of death.2 The number of prostate cancer deaths has been estimated to rise in accordance with an aging worldwide population. However, the emphasis on screening and early detection, through digital rectal examination (DRE) and prostate-specific antigen (PSA) testing, has resulted in a downward trend in the United States. Accordingly, 77% of newly detected cancers will be limited to the prostate (T1 to T2).3 The objective of treatment for localized prostate malignancy is cure. Historically, prostatectomy has been treatment of choice. Originally described in 1894 by Fuller,4 prostatectomy was performed via the suprapubic approach. However, this method was a blind 15-minute procedure that required digital enucleation of the gland. In 1900, Freyer5,6 completed a series of 1600 cases that carried a 5% mortality. This mortality was considered diminutive in the absence of antimicrobials and blood product replacement. In 1947, Millin7 introduced the retropubic prostatectomy, which was summarily embraced as the new method of choice. Several modifications and new techniques followed, but radical change did not again take place until 1979. At this time, a more complete description of the surgical anatomy resulted in an innovative and meticulous surgical approach to the dissection of the prostate and with preservation of the neurovascular bundles.8,9 The anatomic prostatectomy described by Walsh10 offered several advantages, includ-
ing preservation of the cavernous nerves, improved hemostasis, superior exposure, and a very defined apical dissection. These improvements, coupled with improvements in anesthesia and surgical care, have lead to a steady decline in morbidity and mortality over the last 20 years.11 Despite the great success of surgical treatment for localized prostate disease, the complications remain significant. Persistent imperfections of surgical therapy have encouraged clinicians to seek other, less morbid nonsurgical treatment modalities. Alternatives to surgical therapy have included watchful waiting,12,13 transperineal prostate brachytherapy,14,15 external and conformal beam radiation therapy, cryotherapy, and laser ablation. However, these alternative modalities offer an equally complex combination of risks and benefits. Ultimate choice of treatment is therefore a comprehensive decision based on a number of factors, including patient preference and physician bias. This chapter addresses several central topics. First, the discussion will focus on the surgical complications. Second, the methods designed to reduce risks will be considered. Third, the treatment options for the presented complications will be evaluated. To conclude, there will be consideration of quality-of-life evaluation and treatment satisfaction in the setting of common complications. SURGICAL APPROACHES The anatomic prostatectomy (radical retropubic prostatectomy) described by Walsh remains the mainstay of current surgical technique. Many variations and modifications are utilized, but the critical elements are near universal. The dissection can be completed in a retrograde
547
548
Part V Prostate Gland and Seminal Vesicles
or anterograde fashion with judicious preservation of the circular fibers of the bladder neck and neurovascular bundles.16 In comparison to the 5% mortality described by Freyer, contemporary series utilizing the anatomic retropubic prostatectomy carry a morbidity and mortality in the range of 0% to 1.7%.10 Perineal prostatectomy remains as an alternative to radical retropubic prostatectomy. The main advantages include an avascular field, improved exposure for vesicourethral anastomosis, and dependent postoperative drainage.10 However, there are several disadvantages. First, there exists a requirement for two incisions to complete the pelvic lymph node dissection. Second, this method presents a more difficult anatomic approach for the task of preserving the neurovascular bundles. Additionally, the perineal approach is contraindicated in individuals who have undergone prior open prostate surgery, in those who are obese patients, and in patients with musculoskeletal conditions that would prohibit exaggerated lithotomy positioning. Laparoscopic prostatectomy has recently gained widespread recognition following its initial description in 1999.17–19 However, there exists ongoing debate regarding the benefits. For the individual surgeon, it is a technically demanding procedure with a relatively steep learning curve. Initial cases often require extended operative time and result in increased urinary leakage and rectal injuries.20 These differences eventually become statistically insignificant once the preliminary obstacles have been overcome. In experienced hands, the laparoscopic approach offers a reduction in lymphoceles, wound infection, pulmonary embolism, pneumonia, and anastomotic stricture.20 Laparoscopic prostatectomy offers potential new alternatives for reducing surgical morbidity and improving the results of radical prostate surgery. PATIENT SELECTION Preoperative evaluation and appropriate patient selection is the critical first step in complication reduction. At our institution, the preoperative evaluation begins in the urologic clinic with a complete history, physical examination, and appropriate screening. Criteria for selection of the surgical candidate includes: biopsy proven histologic presence of prostate malignancy; clinically established localized disease (T1 to T2); a life expectancy of >10 years; absence of surgical contraindications (comorbid conditions); and informed consent of the patient. Under the guidance of the anesthesia team, the assessment continues in the preadmission testing center. The American Society of Anesthesiology (ASA) scoring system is utilized to estimate the risks associated with various existing comorbidities. Additional evaluation is tailored to the individual patient. In the absence of further preoperative assessment, the patient returns on the morning of surgery.
Several general guidelines are followed when preparing for operative therapy. Radical prostatectomy should be delayed 4 to 8 weeks following transrectal ultrasound guided biopsy10,21 and 3 to 4 months following transurethral resection of the prostate.21 The purpose of this delay is to afford resolution of the postprocedure inflammatory response, resulting in a more precise intraoperative dissection. At our institution, bowel preparation and autologous blood donation are offered but are not routinely undertaken. Transfusion rates approximate 20%. Perioperative pain control is established with intravenous narcotic boluses and 48 hours of standing dose ketorolac. Transition to oral narcotics routinely occurs by postoperative day 1. The expected length of hospital stay is 2 days. The average cost of hospitalization (in the absence of physician reimbursement) is approximately $25,500. OPERATIVE COMPLICATIONS Hemorrhage predominates as the most common intraoperative complication associated with prostatectomy. Venous hemorrhage may occur during pelvic lymphadenectomy and originates from branches of the hypogastric vein. Additionally, venous backbleeding from the Doral vein complex can occur during several stages of the procedure, including incision of the endopelvic fascia, division of the puboprostatic ligaments, and during exposure of the prostatic apex. Expected blood loss is typically 1 liter,22 and is routinely greater during nervesparing approaches. Persistent hemorrhage characteristically resolves once the dorsal vein complex is divided and ligated. Rectal injury is a rare complication of radical prostate surgery (0% to 5.3%),22–26 typically occurring during the apical dissection while developing a plane between the rectum and Denonvilliers’ fascia. In the event of injury, the rectum should be repaired in 2 layers with an interposed pedicle of omentum. This method has been associated with a low incidence of rectourethral fistula and abscess formation.23,24 Rectal injuries that are not identified intraoperatively carry the highest probability of fistula formation. Intestinal diversion can usually be avoided, with the exception of patients who have received previous pelvic irradiation. In these cases, diversion should be the standard of care. Ureteral injury is another rare complication that occurs on the order of 1%.25 This injury classically occurs during extended pelvic lymph node dissection at the iliac bifurcation or while dissecting the posterior aspect of the bladder neck. Injuries are more commonly associated with advanced stages of disease and are repaired with ureteroneocystostomy if identified intraoperatively. Nerve injury is another rare complication associated with pelvic lymph node dissection. These injuries often
Chapter 32 Complications of Surgical Treatment for Localized Prostate Cancer 549
occur from sharp dissection or as a result of retractor positioning. The two most commonly injured nerves are the obturator and the femoral. Obturator nerve injury may result in a thigh abduction deficit, whereas femoral nerve injury may lead to distressing weakness of the quadriceps, combined with anteromedial thigh paresthesia. Intraoperative identification of these injuries indicates primary repair with fine absorbable sutures. Injury that is not identified intraoperatively is managed conservatively with physical therapy. The majority of patients will eventually fully recover from these injuries. POSTOPERATIVE COMPLICATIONS Early Complications In the immediate postoperative, period the most common and potentially devastating complications include thromboembolism, pulmonary embolism, and myocardial infarction. Subcutaneous heparin, sequential compression devices, and early ambulation have all been successfully utilized postoperatively to minimize risks. Recent series have demonstrated a 0.8% to 2.7% thromboembolic complication rate.21 Prophylactic low dose heparin has not been associated with increased risks of postoperative bleeding. Additionally, intraoperative Trendelenburg positioning has been thought to enhance passive venous drainage of the lower extremities. Myocardial infarction remains an uncommon, though grave, complication, requiring special efforts to minimize risks. Specific preoperative evaluation and perioperative management recommendations are addressed in highrisk patients during the preoperative assessment. The coordination of the surgical, anesthesia, and cardiology teams is crucial in order to implement optimum cardiovascular medical management. Likewise early recognition of symptoms and intervention are essential in appropriately managing this complication. Wound infection/dehiscence, seroma, lymphocele formation, and delayed hemorrhage are all uncommon early postoperative complications. Sterile technique and perioperative gram-positive prophylactic antibiotic coverage is utilized to reduce the risk of wound infection. Appropriate fascial closure, hemostasis, and lymphostasis reduce risks for dehiscence, hemorrhage, and lymphocele, respectively. Hematoma or lymphocele formation may require computed tomography (CT)-guided drainage in order to prevent the development of a pelvic abscess. Anastomotic disruption commonly occurs in the early postoperative period when the Foley catheter is unintentionally dislodged. Intraoperative testing of the balloon establishes catheter integrity. Further methods to prevent dislodgment include secure catheter anchorage via intraoperative cystotomy and attachment of the catheter to an abdominal wall button. In the event that the catheter is
unintentionally removed, a single attempt at replacement can be initiated with a smaller caliber coude tip catheter. If the catheter does not easily pass on the first attempt, placement should be undertaken under direct vision with cystoscopy. If catheter removal occurs after postoperative day 5, the patient can be safely monitored without catheter reinsertion.21 Anastomotic leakage is another rare early complication of radical prostate surgery. Typically the vesicourethral anastomosis consists of 4 to 6 precisely placed sutures. Leakage can occur when the anastomotic integrity is incomplete or compromised. The observation of high serous output from the surgical drains suggests urinary leakage. To verify suspected urinary leakage, a creatinine level can be measured in the drain output. Drain output creatinine that mirrors urinary creatinine is diagnostic of an anastomotic leak. The majority of small anastomotic leaks resolve spontaneously or with extended Foley catheter drainage. In the setting of a large leak, urinoma formation can occur and may require CTguided drainage. Late Complications Bladder Neck Contracture Bladder neck contracture is a late complication of prostatectomy. It is known to occur weeks to months postoperatively and typically presents with urinary incontinence and/or a weak urinary stream. Generally, bladder neck contracture is thought to be an uncommon complication. However, it has been reported in 3% to 12% of cases.10 It is suspected to be a consequence of poor vesicourethral anastomotic quality. The construction of a dependable anastomosis requires adequate vascularity and an impermeable seal. Meticulous surgical technique, hemostasis, eversion of the bladder neck, superior mucosal apposition, and the use of 4 to 6 fine absorbable sutures promotes a proper anastomosis. Intraoperative bleeding can lead to pelvic hematoma and the formation of an anastomotic disruption. Poor surgical technique can lead to urinary extravasation and subsequent periurethral scarring. This scarring can lead to urinary stricture and incontinence. Bladder neck contracture is a difficult diagnosis to establish when overflow incontinence is the only presenting complaint. Evaluation includes measurement of postvoid residual urine volumes and identification using urethroscopy. Once the diagnosis is established it can be treated with dilation. Typically, 1 to 2 dilation procedures will resolve the contracture. Rarely dilation can result in a perforation into the rectum and result in a rectourethral fistula. This can become a very challenging problem. Failure of dilation can be resolved with incisions made in the bladder neck at the 12 o’clock, 3 o’clock, and 9 o’clock positions.
550
Part V Prostate Gland and Seminal Vesicles
Urinary Incontinence Urinary incontinence has been considered by many to be the most distressing and disabling complication of prostate surgery. Prior to the description of the anatomic prostatectomy, total urinary incontinence was observed in 10% of men.27 Fortunately, complete urinary incontinence is now an uncommon occurrence. However, lesser degrees of incontinence exist and represent one of the most important quality-of-life measures in radical prostatectomy patients. Historically assessing the complication rate has been a challenge. In extensive academic series, incontinence rates have been reported in 0.3% to 12.5% of patients.28–30 However, some degree of urinary leakage was reported in 30% of men according to the National Medicare Experience.31 The wide range of reported incontinence could be attributed to varied definitions applied by both physicians and patients. As a consequence, studies reported in the literature have been difficult to interpret. Several questionnaires have been developed in order to standardize the definition of incontinence, in turn allowing for greater comparison among studies. Normal urinary continence is achieved when a stable compliant detrusor is coupled with a competent bladder outlet (sphincter mechanism). The sphincter mechanism is considered as two functionally distinct units, the proximal and distal urethral sphincters. The proximal sphincter mechanism consists of the bladder neck, prostate, and prostatic urethra to the level of the verumontanum. The distal urethral sphincter is comprised of mucosal infolding, longitudinal smooth muscle, striated muscle, and the intrinsic periurethral rhabdosphincter distal to the verumontanum. Passive continence is maintained by the striated urethral sphincter. It consists of slow twitch fibers that are capable of maintaining tone over prolonged periods of time. This is in comparison to, periurethral levator ani muscle fibers, which are fast twitch and are associated with rapid forceful muscle contraction. This mechanism is designed to maintain continence during events that raise intra-abdominal pressure. Failure of the sphincter mechanism leads to urinary incontinence. The proximal sphincter mechanism is removed during radical prostatectomy and the distal sphincter mechanism is then solely responsible for the maintenance of urinary continence. A number of risk factors have been thought to be associated with increased risk of urinary incontinence following radical prostatectomy. Patient age at surgery, preoperative continence status, previous transurethral resection of the prostate, anastomotic stricture, stage of disease, surgical technique, and experience of the surgeon have been evaluated to determine significance with respect to postoperative continence. Greater inconti-
nence rates are observed with advancing age. This has been attributed to rhabdosphincter atrophy32 and neural degeneration.33,34 Preoperative urinary incontinence can persist postoperatively. More advanced stages of disease are likely to be associated with greater dissection and lead to increased rates of incontinence. Surgical technique and surgeon’s experience have also been determined to be significant factors in predicting postoperative continence rates.35 Evaluation of postoperative incontinence begins with a complete history and physical examination. Type and severity of incontinence, precipitating factors, number of daily episodes, and degree of protection (pads, penile clamp, etc.) required should be established. A history consistent with stress incontinence has been associated with the existence of sphincter dysfunction.36 Initial blood tests may incorporate blood urea nitrogen, creatinine, and PSA (to detect cancer recurrence). Measurement of postvoid residual urine volume and noninvasive uroflow are included in the initial evaluation. However, urodynamic testing remains the most valuable method available to accurately diagnose the cause of urinary incontinence. Cystourethroscopy can also be utilized to evaluate the mucosal surfaces, vesicourethral anastomosis, and bladder wall, but it is particularly useful for direct visualization if surgical intervention is considered. The problem of postoperative urinary incontinence can be dealt with effectively at many levels. Therapy should be tailored to maximize patient’s quality of life and minimize additional risks and complications. Many patients will meet the criteria for urinary incontinence but do not consider it to negatively impact quality of life. It is vital to identify patient bother and expectations of treatment. Once the diagnosis has been established, the problem can be addressed in a stepwise fashion. Fluid restriction, behavioral modification, anticholinergic/tricyclic antidepressant medication and pelvic floor exercises have been utilized to address postoperative urinary incontinence attributed to bladder dysfunction. For patients with significant urinary complaints who fail these methods, augmentation cystoplasty,37 or neuromodulation (not yet studied in postprostatectomy patients) can be considered. Sphincter dysfunction can be addressed similarly with biofeedback and pelvic floor exercises. In cases of sphincter dysfunction, these methods have met with mixed results with respect to restoration of continence. However, they have been effective in reducing the postoperative interval required to regain continence.38 Alpha agonists (ephedrine, phenylpropanolamine) and imipramine have been used in females with sphincteric (stress) urinary incontinence but have not been evaluated in prostatectomy patients. These agents are unlikely to offer substantial results and will likely be of limited use.39 Bulking agents injected beneath the urethral mucosa
Chapter 32 Complications of Surgical Treatment for Localized Prostate Cancer 551
(glutaraldehyde cross-linked bovine collagen, silicone macroparticles) have offered short-term efficacy. The difficult identification of anatomic landmarks and scarring has resulted in low rates of total dryness. Sling procedures have been used in limited cases as prophylaxis during radical prostate surgery. A rectus muscle fascial sling has effectively resulted in earlier and more complete return of urinary continence.40 The most efficacious procedure available to address urinary incontinence is the artificial urinary sphincter. It has been widely used for treating urinary incontinence of various etiologies.41–44 Of those receiving an artificial urinary sphincter 77% have been satisfied and have reported a significant reduction in the number of pads used for protection.45 In cases refractory to all forms of therapy urinary diversion has been employed to relieve intolerable incontinence. A better understanding of the pelvic floor anatomy has resulted in improved continence rates. Despite the various modalities used to treat urinary incontinence it remains a difficult problem. A number of intraoperative techniques have been utilized to preserve urinary continence. Bladder neck preservation,46 intussusception,27 and tubularization (preservation of functional urethral length)47,48 have provided efficacy in reducing postoperative time to continence. Unfortunately, these techniques have not offered an improvement in overall continence. A longer functional urethral length has been associated with greater continence.31,35 Consequently, preoperative evaluation of the functional urethral length via endorectal magnetic resonance imaging may offer predictive information regarding postoperative continence rates.49 Such information could influence patient choice of therapy. Sparing of the puboprostatic46 ligament and maintenance of the urethral mucosal vascularity have not been shown to affect,30 postoperative continence rates.50 Erectile Dysfunction When Young described radical perineal prostatectomy in 1903, the procedure had been associated with a 60% mortality.51 Following Young’s anatomic description mortality was reduced to 16.6% (incontinence 13%).52 At that time preservation of potency had not been deemed a priority. Consequently, over 60% of patients were left with erectile dysfunction. Despite the reduction of mortality over time, emphasis had not shifted toward preservation of potency until the nerve-sparing approach was described by Walsh and Donker.9 Subsequent to the development of the anatomic prostatectomy, preservation of potency soon became a reasonable objective. Potency has been defined as the ability to establish and maintain an erection that is suitable for intercourse. In a large series, 503 patients were deemed preoperatively potent. Postoperatively 68% were found to have retained erectile function. Age, stage of disease, and extent of
nerve sparing (unilateral or bilateral) were substantial factors affecting potency.53,54 Younger age, less advanced disease and preservation of both neurovascular bundles were all found to be associated with greater postoperative erectile function. Postoperatively patients often may experience a wide variety of emotions related to a change in body image, the possibility of cancer recurrence, incontinence, erectile dysfunction, and a change in relationship dynamics. During the months following surgery erectile dysfunction may be partially attributed to psychogenic factors. However, preoperative and postoperative libido measurements by O’Leary et al.55 brief sexual function inventory was not found to be significantly different from age matched controls. Despite the numerous reasons to have psychogenic erectile dysfunction, the majority of patients have been found to have an organic origin as determined by nocturnal penile tumescence or Rigiscan studies.56 The origin of the erectile dysfunction is likely multifactorial but largely a result of neurovascular damage and preexisting disease. Treatment for postprostatectomy erectile function has been addressed at several levels of invasiveness. Patient desire to regain potency should dictate the vigor of the treatment regimen. An initial wait and see approach has been advocated to allow spontaneous recovery of erectile function. Resolution of surgical inflammation, tissue healing, and resolution of neuropraxia can take 1 to 2 years. After that time it is reasonable to assume that greater improvement is unlikely. Vacuum erection devices offer a mildly effective noninvasive therapy. However, the ring used to maintain tumescence may serve to prolong natural revitalization.57 Intraurethral prostaglandin therapy (MUSE) became widely popular in 1997. Initial reports boasted a 57% to 70% success, with a disproportionate 20% satisfaction rate.58 However, intraurethral therapy offered a less invasive option for men than the more invasive intracavernosal injection therapy (Caverject/PGE1/trimix). Since 1983, intracavernosal therapy has been highly effective, once men overcome the fear of self-injection. It has been associated with pain (14%), penile fibrosis (2% to 15%), cumbersome mixtures, and relative expense.59 Sildenafil, a selective phosphodiesterase-5 inhibitor, gained wide popularity in 1998 as the first oral therapy for erectile dysfunction. Initial trials reported a 43%60 response rate, while subsequent trials report satisfaction rates from 15% to 80%.61–63 Despite the mixed response rates it became the best selling medication of all time and soon became the first line of therapy for erectile dysfunction. Penile prosthesis has remained the most invasive and last line of therapy. In the event of treatment failure at all levels a prosthetic device can be placed with great efficacy. Since 1973, these devices have successfully restored potency. Infrequent infections can occur and may require
552
Part V Prostate Gland and Seminal Vesicles
explanation of the device. Fortunately, those cases are the rare exception. Erectile dysfunction has historically been a low profile problem of great magnitude. Over the last 2 decades research has focused on improving the quality of life in postprostatectomy patients. Treatment efficacy continues to rise while delivery methods become less invasive. The future for therapy in erectile dysfunction will likely rely on more selective and mechanistically varied oral agents, and neurogenic and vascular growth factors aimed at the restoration/preservation of function. Quality of Life Quality of life has become a central theme to consider when counseling patients with localized prostate disease. Over the last decade several nonsurgical therapies have arisen that may offer less objectionable side effects while providing a comparable rate of survival. Patients are less likely to seek a therapy that will provide a lower quality of life. In order to evaluate patient satisfaction with radical prostatectomy a number of questionnaires have been created, validated, and administered.64,65 These patient surveys report that the primary concern remains survival, and than a strong concern for urinary incontinence and erectile dysfunction. Difficulty with continence and potency are most associated with a decrease in a patient’s perception of his own well-being.21 However, as surgical techniques have improved in treating prostate cancer and as our ability to manage complications has also improved, more men have and will continue to be effectively treated for this very common cancer.
REFERENCES 1. Greenlee RT, Murray T, Bolden S, Wingo PA: Cancer statistics, 2000. CA Cancer J Clin 2000; 50:7–33. 2. Kirby RS, Brawer MK, Denis LJ: Prostate Cancer, 3rd edition, p 7. Oxford, UK, Health Press Limited, 2001. 3. Sylvester J, Blasko JC, Grimm P, Radge H: Interstitial implantation techniques in prostate cancer. J Surg Oncol 1997; 66:65–75. 4. Fuller E: The question of priority in the adoption of the method of total enucleation, suprapubically, of the hypertrophied prostate. Ann Surg 1905; 41:520. 5. Freyer PJ: A new method of performing prostatectomy. Lancet 1900; 1:774. 6. Freyer PJ: One thousand cases of total enucleation of the prostate for radical cure of enlargement of that organ. Br Med J 1912; 2:868. 7. Millin T: Retropubic urinary surgery. London, Livingstone, 1947. 8. Reiner WG, Walsh PC: An anatomical approach to the surgical management of the dorsal vein and Santorini’s
9.
10. 11.
12.
13.
14.
15.
16. 17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
plexus during radical retropubic surgery. J Urol 1979; 121:198–200. Walsh PC, Donker PJ: Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982; 128:492–497. Walsh PC: Campbell’s Urology, 6th edition, pp 2865–2886. Philadelphia, WB Saunders, 1992. Thompson IM, Middleton RG, Optenberg SA, et al: Have complication rates decreased after treatment for localized prostate cancer? J Urol 1999; 162:107. Holmberg L, et al: A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 2002; 347(11):781–789. Steineck G, Helgesen F, Adolfsan J, et al: Quality of life after radical prostatectomy or watchful waiting. N Engl J Med 2002; 347(11):790–796. Albert M, et al: Late genitourinary and gastrointestinal toxicity following magnetic resonance image guided prostate brachytherapy with or without neoadjuvant external beam radiation therapy. In press. Shah SA, Cima R, Benoit E, et al: Rectal-urethral fistulas after prostate brachytherapy. Diseases of Colon and Rectum. In press. Pontes J: Radical prostatectomy. In Surgery of Genitourinary Pelvic Tumors, p 73. New York, Wiley-Liss, 1993. Guillonneau B, Vallancien G: Laparoscopic radical prostatectomy: initial experience and preliminary assessment after 65 operations. Prostate 1999; 39(1):71–75. Guillonneau B, Vallancien G: Laparoscopic radical prostatectomy: the Mountsouris experience. J Urol 2000; 163:418. Dahl DM, et al: Laparoscopic radical prostatectomy: initial 70 cases at a US university medical center. Urology 2002; 60(5):859–863. Rassweiler J, et al: Laproscopic versus open radical prostatectomy: a comparative study at a single institution. J Urol 2003; 169:1689–1693. Shekarriz B, Upadhyay J, Wood DP: Intraoperative, perioperative, and long term complications of radical prostatectomy. Urol Clin N Am 2001; 28(3):639–653. Rainwater LM, Segura JW: Technical consideration in radical retropubic prostatectomy: blood loss after ligation of dorsal venous complex. J Urol 1990; 143:1163. Borland RN, Walsh PC: The management of rectal injury during radical retropubic prostatectomy. J Urol 1992; 147:905. Harpster LE, Rommel FM, Sieber PR, et al: The incidence and management of rectal injury associated with radical prostatectomy in a community based urology practice. J Urol 1995; 154:1435. Hautman RE, Sauter TW, Wenderoth UK: Radical retropubic prostatectomy: morbidity and urinary continence in 418 consecutive cases. Urology 1994; 43:47. Guilloneau B, et al: Laparoscopic [correction of laparoscopic] management of rectal injury during laparoscopic [correction of laparoscopic] radical prostatectomy. J Urol 2003; 169(5):1694–1696. Walsh PC, Marschke PL: Intussusception of the reconstructed bladder neck leads to earlier continence after radical prostatectomy. Urology 2002; 59(6):934–938.
Chapter 32 Complications of Surgical Treatment for Localized Prostate Cancer 553 28. Schroder FH, van den Ouden D: Incontinence after radical prostatectomy-a study of 188 patients. J Urol 1992; 147(Suppl):465A (abstract 1009). 29. Steiner MS, Morton RA, Walsh PC: Impact of anatomical radical prostatectomy on urinary incontinence. J Urol 1991; 145:512. 30. Rudy DC, Woodside JR, Crawford ED: Urodynamic evaluation of incontinence in patients undergoing modified Campbell radical retropubic prostatectomy: a prospective study. J Urol 1984; 132:708. 31. Fowler FJ, et al: Patient-reported complications and follow-up treatment after radical prostatectomy. The National Medicare Experience: 1988–1990. Urology 1993; 42:622. 32. Burnett AL, Mostwin JL: In situ anatomical study of the male urethral sphincter complex: relevance to continence preservation following major pelvic surgery. J Urol 1998; 160:1301. 33. Hollabaugh RS, Dmochowski RR, Kneib TG, et al: Preservation of putative continence nerves during radical retropubic prostatectomy leads to more rapid return of urinary continence. Urology 1998; 51:960. 34. Narayan P, Konety B, Aslam K, et al: Neuroanatomy of the external urethral sphincter: implications for urinary continence preservation during radical prostate surgery. J Urol 1995; 153:337. 35. Eastham JA, Kattan MW, Rogers E, et al: Risk factors for urinary incontinence after radical prostatectomy. J Urol 1996; 156:1707. 36. Chao R, Mayo ME: Incontinence after radical prostatectomy: detrusor or sphincteric causes. J Urol 1995; 154:16. 37. Flood HD, Malhorta SJ, O’Connell HE, et al: Long term results and complications using augmentation cystoplasty in reconstructive urology. Neurourol Urodynam 1995; 14:297. 38. Van Kampen M, De Weerdt W, Van Poppel H, et al: Effect of pelvic-floor reeducation on duration and degree of incontinence after radical prostatectomy: a randomized controlled trial. Lancet 2000; 355:98. 39. Carlson KV, Nitti VW: Prevention and management of incontinence following radical prostatectomy. Urol Clin N Am 2001; 28(3):595–612. 40. Jorion JL: Rectus fascial sling suspension of the vesicourethral anastomosis after radical prostatectomy. J Urol 1997; 157:926. 41. Elliott DS, Barrett DM: Mayo clinic long-term analysis of the functional durability of the AMS 800 artificial urinary sphincter: a review of 323 cases. J Urol 1998; 159:1206. 42. Gundian JC, Barrett DM, Parulkar BG: Mayo clinic experience with the AS800 artificial urinary sphincter for urinary incontinence after transurethral resection of prostate or open prostatectomy. Urology 1993; 41:318. 43. Perez LM, Webster GD: Successful outcome of artificial urinary sphincters in men with post-prostatectomy urinary incontinence despite adverse implantation features. J Urol 1992; 148:1166. 44. Scott FB: The artificial urinary sphincter. Experience in adults. Urol Clin N Am 1989; 16:105.
45. Gousse AE, et al: Artificial urinary sphincter for postradical prostatectomy urinary incontinence: long-term subjective results. J Urol 2001; 166:1755–1758. 46. Deliveliotis C, et al: Radical prostatectomy: bladder neck preservation and puboprostatic ligament sparing-effects on continence and positive margins. Urology 2002; 60(5):855–858. 47. Peyromaure M, Ravery V, Boccon-Gibod L: The management of stress urinary incontinence after radical prostatectomy. Br J Urol 2002; 90:155–161. 48. Connolly JA, Presti JC Jr, Carroll PR: Anterior bladder neck tube reconstruction at radical prostatectomy preserves functional urethral length-a comparitive urodynamic study. Br J Urol 1995; 75:766–770. 49. Coakley FV, et al: Urinary continence after radical retropubic prostatectomy: relationship with membranous urethral length on preoperative endorectal magnetic resonance imaging. J Urol 2002; 168:1032–1035. 50. John H, Suter S, Hauri D: Effect of radical prostatectomy on urethral blood flow. Urology 2002; 59(4):566–569. 51. McCullough AR: Prevention and management of erectile dysfunction following radical prostatectomy. Urol Clin N Am 2001; 28(3):613–627. 52. Young HH, Davis DM: Neoplasms of the urogenital tract. In Young’s Practice of Urology, pp 653–654. Philadelphia, WB Saunders, 1926. 53. Quinlan DM, Epstein JI, Carter BS, et al: Sexual function following radical prostatectomy: influence of preservation of neurovascular bundles. J Urol 1991; 145:998. 54. Rabbani F, et al: Factors predicting recovery of erections after radical prostatectomy. J Urol 2000; 164:1929–1934. 55. O’Leary MP, Fowler FL, Lendrking WR, et al: A brief male sexual function inventory for urology. Urology 1995; 46:697–706. 56. Sohn MH, Seeger U, Sikora R, et al: Criteria for examiner-independent nocturnal penile tumescence and rigidity monitoring (NPTR): correlations to invasive diagnostic diagnostic methods. Int J Impot Res 1995; 5:59–68. 57. Montorsi F, Guazzoni G, Strambi L, et al: Recovery of spontaneous erectile function after nerve sparing radical retropubic prostatectomy with and without early intracavernous injections of alprostadil. J Urol 1997; 158:1408–1410. 58. Costabile RA, Spevak M, Fishman IJ, et al: Efficacy and safety of transurethral alprostadil in patients with erectile dysfunction following radical prostatectomy. J Urol 1998; 160:1325–1328. 59. Evans C: Complications of intracavernosal therapy for impotence. In Carson C, Kirby R, Goldstein I (eds): Textbook of Erectile Dysfunction, pp 365–370. Oxford, Isis Medical Media, 1999. 60. Pfizer data on file. New York, Pfizer, 1998. 61. Marks LS, Duda C, Dorey FJ, et al: Treatment of erectile dysfunction with sildenafil. Urology 1999; 53:19–24. 62. Zippe CD, Jhaveri FM, Klein EA, et al: Role of Viagra after radical prostatectomy. Urology 2000; 55:241–245. 63. Zagaja GP, et al: Sildenafil in the treatment of erectile dysfunction after radical prostatectomy. Urology 2000; 56(4):631–634.
554
Part V Prostate Gland and Seminal Vesicles
64. Sebesta M, et al.: Questionnaire-based outcomes of urinary incontinence and satisfaction rates after radical prostatectomy in a national study population. Urology 2002; 60(6):1055–1058.
65. Penson DF, Litwin MS, Aaronson NK: Health related quality of life in men with prostate cancer. J Urol 2003; 169:1653–1661.
C H A P T E R
33 Seminal Vesicles: Diagnosis, Staging, Surgery, and Management Nelson N. Stone, MD, Richard G. Stock, MD, and Pamela Unger, MD
Malignant tumors of the seminal vesicles are uncommon. The most frequent etiology results from secondary extension from prostate cancer. The diagnosis of prostate cancer within the vesicles requires pathologic assessment of seminal vesicle tissue. Unlike with prostate cancer, where an elevated prostate-specific antigen (PSA) or an indurated nodule motivates the urologist to perform a biopsy, there are few indications for sampling seminal vesicle tissue. Generally, there are no presenting signs or symptoms that would indicate tumor of the seminal vesicles. However, pain, a sensation of prostate congestion, irritative bladder symptoms, hematospermia or hematuria may suggest to the clinician that a digital rectal and prostate exam is indicated.1–6 A palpable mass, involving the base of the prostate in association with an elevated PSA, usually indicates the presence of prostate cancer. However, a normal PSA, in association with a lesion that seems to occupy just the seminal vesicles may indicate a primary process. If this is the case, further investigation is warranted. More common benign lesions, such as seminal vesicle cysts, as well as uncommon lesions, such as papillary adenomas, cystadenomas, fibromas, myomas, and schwannomas have been reported.1–6 Primary tumors of the vesicles include adenocarcinoma, rhabdomyosarcoma, squamous cell carcinoma, myosarcoma, hemangiosarcoma, cystadenocarcinoma phyllodes, and seminoma.7 DIAGNOSIS AND EVALUATION Biopsy is warranted when a suspicious lesion of the vesicles is encountered and can be most easily accomplished by the transrectal ultrasound-guided route. Additional evaluation will depend on the pathology, with asymptomatic benign lesions requiring no further testing.
Primary malignancies should undergo extensive radiologic evaluation to help ascertain the feasibility of surgical or radiotherapeutic intervention. Transrectal ultrasound-guided biopsy of the vesicles is easy to perform and for the most part is done the same way as prostate biopsy.8–16 The only differences is that the spring-loaded needle should be positioned just posterior to the wall of the seminal vesicle so the core will include both posterior and anterior walls and not puncture the base of the bladder (Figure 33-1). The cores of tissue are similar to prostate cores and, when normal, should not be difficult for the pathologist to interpret. The decision to perform a seminal vesicle biopsy when evaluating patients with a diagnosis of prostate cancer is controversial. Several studies have determined the accuracy of performing such biopsies, although the number of biopsies (ranging from 1 to 6 cores) and where to take them has not been standardized. Wymenga et al.15 performed 2 biopsies at the junction of the seminal vesicles prior to radical prostatectomy. Eighty-three out of 138 had positive biopsies and the accuracy was 91%. PSA, clinical stage, and Gleason score were all predictive of SV involvement. Okihara et al.16 performed SV staging biopsies in 244 men with prostate cancer and found 31% positive. The number of cores taken varied with their clinical indication for the biopsies. Ninety underwent RP and no false positive biopsies were encountered. Stone described a technique where 6 seminal vesicle biopsies were taken, 3 from each side at a separate setting.13 With this technique, 15% of patients were found to have vesicle involvement. Linzer and associates7 compared the 6 biopsy method (n = 222) to a cohort of 187 men who had radical prostatectomy and developed indications for vesicle biopsy (Table 33-1). Univariate and multivariate analyses demonstrated a PSA > 10 ng/ml, Gleason score ≥ 7,
555
556
Part V Prostate Gland and Seminal Vesicles
and clinical stage T2b (1992 AJCC) independently predicted for involvement of the vesicles.7 Based on these data, the following indications for seminal vesicle biopsy were developed: PSA > 10 ng/ml or stage T2b or greater or Gleason score ≥ 7. In contrast, Fowler found no advantage in performing a seminal vesicle biopsy in conjunction with the prostate biopsy.17 He performed only one biopsy that was taken at the time of the initial prostate biopsy. These data suggest that if seminal vesicle staging is to be performed, at least 4 biopsies should be taken and they should not be performed at the time of the primary prostate biopsy. Tables or nomograms have also been used to predict extraprostatic disease.18–20 Penson et al.19 used the Partin tables to assess the probability of extraprostatic extension in 1162 men from the CapSure database. The calculated receiver operating characteristics curve area was 0.726
for predicting seminal vesicle involvement. While nomograms are predictive of seminal vesicle involvement, they are not a substitute for biopsy. In planning a patient’s treatment, the confirmed presence of vesicle involvement will influence further diagnostic evaluation and the eventual treatment decision. Endorectal coil magnetic resonance imaging (MRI) has also been used to detect extracapsular extension and seminal vesicle invasion.20 The MRI has a high specificity when it detects SV involvement, but a sensitivity of <50% is suggesting that it often misses smaller tumors.21 Pathologic confirmation, by biopsy will most likely be required if the MRI is suggestive of vesicle involvement. If the urologist aggressively stages the high-risk prostate cancer patient using the seminal vesicle biopsy, then a diagnosis of extraprostatic extension can be made in advance of definitive therapy. Advance knowledge of seminal vesicle involvement may preclude recommendations for standard radical prostatectomy, external beam irradiation, or brachytherapy. In addition, patients with seminal vesicle involvement are at increased risk for pelvic lymph node metastases.12,13 One-third of men with biopsy detected seminal vesicle involvement will have metastases to the pelvic lymph nodes. These patients should probably undergo pelvic lymph node dissection prior to considering definitive therapy.12,13,16 TREATMENT OPTIONS FOR PATIENTS WITH SEMINAL VESICLE INVOLVEMENT The treatment of patients with seminal vesicle involvement from prostate cancer will depend on whether it was discovered following prostatectomy or if it was identified by biopsy prior to definitive therapy. The literature seems to indicate that the former is the more common scenario. The options for treating patients following prostatectomy include observation, adjuvant radiation therapy, or hor-
Figure 33-1 Transrectal ultrasound guided biopsy of the seminal vesicles.
Table 33-1 Likelihood of Encountering Prostate Cancer Involving the Seminal Vesicles either by Trus-Guided Seminal Vesical Biopsy (SVB, n = 222) Prior to Radiation Therapy or Following Radical Prostatectomy (RP, n = 187) Clinical Characteristics
Positive SVB in Radiation Patients
SV Involvement in RP Patients
PSA 10–20 ng/ml
11/63 (17%)
6/39 (15%)
0.78
PSA > 20 ng/ml
17/53 (32%)
22/165 (13%)
0.98
T2b
19/96 (20%)
14/66 (21%)
0.82
T2c
11/37 (30%)
2/13 (15%)
0.31
Gleason score 7–10
23/62 (37%)
8/40 (20%)
0.06
From Linzer DG, Stock RG, Stone NN, et al: Urology 1996; 48:757–761.
p-Value
Chapter 33 Seminal Vesicles: Diagnosis, Staging, Surgery, and Management 557
monal therapy. The argument for treatment is the high recurrence rate, while the argument for observation and deferred therapy is the lack of randomized studies indicating an advantage of one over the other. The choice to administer some forms of adjuvant therapy results form the high relapse rate. Sofer et al.22 assessed the outcomes of 812 men of whom 106 (13%) were found to have seminal vesicle involvement following radical prostatectomy. At an average follow-up of 48 months follow-up, 53% of the entire cohort were free of disease (PSA < 0.4 ng/ml). In an analysis of prognostic variables only patients with a PSA > 10 ng/ml showed a higher recurrence rate (70% versus 30%, p < 0.001). The 5-year likelihood of being disease free with seminal vesicle involvement was 35%. Van den Ouden et al.23 performed radical prostatectomy on a group of 83 men with T3 prostate cancer. Of these patients, 64 (77%) were found with extracapsular extension and/or growth into the seminal vesicles. At a median follow-up of 52 months, 19% demonstrated local recurrence and 57% PSA relapse. Actuarial biochemical progression at 5 years for the pT3G1-2 patients was 61% and for the pT3G3 group 100%. Van Poppel et al.24 described 110 men who had radical prostatectomy for T3 prostate cancer. Five-year PSA-free survival for the entire group was 40%. Lerner et al.25 reported on 812 patients with clinical T3 treated at the Mayo Clinic. Of the 812 patients, 290 (35.7%) had pT3c (seminal vesicle involvement) disease. PSA-free survival (>0.2 ng/ml) at 5 years for the entire cohort was 41% and at 10 years was 30%. Ten-year cause specific for the pT3c group was 60%. Several other reports of men who underwent radical prostatectomy with seminal vesicle involvement demonstrate similar results26–30 (Table 33-2). Adjuvant radiation therapy has been used in the setting of positive margins and seminal vesicle involvement
with mixed results. The lack of randomized data comparing adjuvant versus no treatment have hampered decisionmaking. Choo et al.31 analyzed 125 patients with a positive resection margin or pT3 disease of whom 73 were treated with adjuvant radiation therapy and 52 were followed expectantly. Radiation therapy was delivered a median of 3.4 months post-RP with a 4-field technique to a dose of 60 to 66 Gy. The clinical target volume (CTV) was limited to the prostate bed, and if the seminal vesicles were pathologically involved, they were also included in the CTV. The treatment volume included a 1-cm margin around the CTV. A Cox proportional hazards model of relapse-free probability versus time demonstrated adjuvant radiation therapy (0.22, p = 0.0008), PSA preprostatectomy (1.022, p = 0.029) and seminal vesicle involvement (2.03, p = 0.09) as important variables. Unfortunately, there was no independent seminal vesicle analysis. Patients with seminal vesicle involvement are at risk for local and systemic recurrence. The exact incidence of each and whether local failure presages systemic relapse has never been fully defined. Gibbons et al.32 reported a 44% local failure rate following radical prostatectomy in patients with seminal vesicle involvement. In a 15-year follow-up study, up to 83% of patients have been reported with local recurrence if the radical prostatectomy specimen contained pT3 disease.33 In looking for local recurrence, Medini et al.34 analyzed 40 men who were found to have elevated PSA 9 to 96 months postprostatectomy. Of the 40 patients, 25 had a positive surgical margin and 6 had involvement of the seminal vesicles. Twenty-eight were found to have recurrent local disease as determined by transrectal biopsy. Zeitman et al.35 performed a review of residual disease after radical surgery or radiation therapy in patients with prostate cancer. He noted a 12% to 68% risk of local
Table 33-2 Comparison of Current Series of Patients with Seminal Vesicle Implant to Biochemical Freedom from PSA Failure Following Radical Prostatectomy with Vesicle Involvement Study
Number
Definition
Rate (%)
Years
Catalona and Bigg26
86
>0.6
32
5
D’Amico et al.27
39
>0.2
5
2
Kupelian et al.28
60
>0.2
20
6
Sofer et al.22
66
>0.4
35
5
Trapasso et al.29
93
>0.4
56
5
Zeitman et al.30
12
>0.2
4
4
Van den Ouden et al.23
83
2 increases above 0.1
29
5
Current
32
ASTRO
74
7
558
Part V Prostate Gland and Seminal Vesicles
Figure 33-2 A, Axial image showing two implant needles at “C1” and “c1” positions within the seminal vesicles. The bladder with Foley balloon can be seen just above. Arrow points to anterior rectal wall. B, Longitudinal image of implant needle in anterior seminal vesicle wall. The bladder is above and to the left. The arrow points to the posterior wall of the SV. A Mick applicator will be used to deposit two seeds, one proximal and one just above prostate base.
recurrence, which was associated with a poorer prognosis. In a review of patients with T2 to T3 disease receiving radiation therapy, between 27% and 100% were found to have positive biopsies, including 27% treated with EBRT plus AU-198 seeds and 28% with EBRT plus I-125 seeds.36,37 Planning a radiation treatment field that adequately boosts dose to encompass disease that has extended into the seminal vesicles has not been addressed. While dose escalation trials have been performed on high-risk prostate cancer patients and have demonstrated an advantage to doses in excess of 75 Gy, no studies have specifically addressed these higher doses in the seminal vesicles.38,39 The problem in adequately targeting the seminal vesicles with the higher doses and sparing the rectum, bladder base, and ureters has probably prevented an adequate treatment to this region. Centers that choose to treat high-risk prostate cancer with a combination of brachytherapy and beam irradiation risk under treatment if the disease has extended into the seminal vesicles. Stock et al.40 have shown that the implant provides very little radiation dose to the seminal vesicles if the implant is limited to the prostate. The most proximal 20% of seminal vesicle tissue (SV1) received a median of 35% of the prostate dose while the next cephalad 20% (SV2) received just 3%. With external radiation dose of 45 Gy in this situation, adequate treatment of the seminal vesicle extension would be inadequate. In the same study, Stock et al.40 demonstrated in a small cohort of 5 patients with seminal vesicle tumor how to boost the SV dose with an implant technique developed for this purpose (Figure 33-2A and B). The postimplant prostate D90/SV1 D90 ranged from 63% to 97% (median 80%) and the
prostate D90/SV2 D90 ranged from 19% to 88% (median 52%). A multimodality treatment program has been developed to address these high-risk prostate cancer patients with biopsy proven SV involvement.41,42 The protocol consists of three parts: neoadjuvant and concomitant hormonal therapy, partial palladium-103 implant (planning dose 83 to 90 Gy) with seeds placed in the prostate and seminal vesicles followed 2 months later with 45 Gy of conformal EBRT, which includes a 1.5-cm margin around the prostate and seminal vesicles (Figure 33-3). High-risk patients undergo routine evaluation, which includes bone and CT scanning. Seminal vesicle biopsies identify those patients with vesicle involvement (Figure 33-4A,B). Laparoscopy can exclude the 25% to 35%, who may harbor micrometastatic disease in the pelvic lymph nodes. Treatment is begun with 3 months of complete androgen blockade. Preimplant prostate volume is determined with an extra 10 cc added to account for the seminal vesicles. The real-time method of seed implantation where total activity is identified by nomogram and planning done in the operating room is used.43–45 The patient is brought to the OR and placed in the lithotomy position. The probe is advanced to the base of the bladder until the tips of the seminal vesicles are no longer visible. The probe is then retracted until the seminal vesicles appear under the bladder base. The seminal vesicles are contoured at 5-mm intervals, which is continued when the prostate is reached to encompass both the prostate base and seminal vesicles. The contouring is continued to the prostate apex. The physicist can then match these structures, as well as urethra and rectum, in order to perform the intraoperative planning (Figure 33-5A,B).
Chapter 33 Seminal Vesicles: Diagnosis, Staging, Surgery, and Management 559
Stage T3c prostate cancer
Laparoscopic pelvic lymph node dissection
Node negative
Node positive
3 months LHRHa plus antiandrogen
Hormonal therapy
partial Pd-103 implant to prostate and seminal vesicles Dose 100 Gy (NIST 99)
2 month break continue HT
45 Gy conformal EBRT to prostate and SV continue HT till end of radiation
Figure 33-3 Flow chart of treatment protocol for high-risk prostate cancer patients with biopsy proven seminal vesicle involvement.
Figure 33-4 A, Pretreatment biopsy: seminal vesicle with lamina propria extensively infiltrated with prostatic adenocarcinoma (Gleason’s pattern 4 + 4, total score 8). The seminal vesicle epithelium shows mild nuclear pleomorphism and atypia, which is a normal degenerative finding (arrow) (H/E, 200×). B, Posttreatment biopsy: seminal vesicle that is negative for prostatic adenocarcinoma. Focally, the seminal vesicle glands contain intraluminal secretions (arrow). Endothelium in a small vessel shows nuclear atypia consistent radiation effect (arrowhead) (H/E, 200×).
Once the intraoperative planning is complete, the peripheral needles are placed. The implant is performed in two phases, with placement of the peripheral needles and sources first, followed by the interior needles and
sources. With the use of intraoperative planning software (VariSeed 7.0, Varian, Palo Alto, CA) in an interactive fashion, the plan continually evolves as each seed is placed. The Mick Applicator (Mick Radionuclear
560
Part V Prostate Gland and Seminal Vesicles
Figure 33-5 A, Axial image from planning computer (VariSeed, Varian, Palo Alto, CA) demonstrating intended needle and seen positions in seminal vesicles with isodose contours superimposed. Center isodose contour represents 100% of prescription (100 Gy palladium-103). B, 3D representation of completed implant showing the prescription dose cloud covering the prostate and proximal seminal vesicles.
Chapter 33 Seminal Vesicles: Diagnosis, Staging, Surgery, and Management 561
Figure 33-6 A, Postimplant CT image of seminal vesicle seed implant with bladder above rectum below. The 80% and 100% isodose contours encompass the vesicles with very little dose distributed to bladder or rectum. B, Coverage of SV at base of prostate.
Instruments, Mount Vernon, NY) permits each seed to be placed individually, maximizing the ability to conform the radiation dose cloud to the prostate and seminal vesicles (see Figure 33-5B). Postimplant dosimetry is performed 1 month after the implant is used in part to confirm prostate and seminal
vesicle doses and to aid in the external beam planning (Figure 33-6A,B). Two months postimplant 45 Gy of conformal external beam is given, limited to the prostate and seminal vesicles with a margin of 1.5 cm. The hormonal therapy is continued till the end of the external beam (total length of time 9 months). Routine prostate
562
Part V Prostate Gland and Seminal Vesicles
100
100
0
Survival Function Censored 0
3
5
8
Years
Figure 33-7 Kaplan-Meier estimates of PSA freedom from failure defined as being free from 3 consecutive PSA rises above a nadir (ASTRO). Of the 32 patients treated, 8 have failed. The 7-year freedom from failure is 74%. The median PSA for these 24 is <0.1 ng/ml.
and seminal vesicle biopsies were performed 2 years after completion of treatment (see Figure 33-4A,B). Biopsies were repeated in the case of rising PSA. To date, no patients have demonstrated evidence of local recurrence. The results of this multimodality approach have been highly effective and safe.41,42 An update of previously published data continues to demonstrate the efficacy of this approach in 32 men with biopsy confirmed seminal vesicle involvement followed a minimum of 3 years. Initial PSA ranged from 4 to 88 ng/ml (mean 22.2, median 16.3), Gleason score was 4 to 6 in 9 (28.1%), 7 in 13 (40.6%), and 8 to 9 in 10 (31.3%). Clinical stage was T1c to T2a in 3 (9.4%), T2b in 3 (9.4%), T2c in 18 (56.2%), and T3 in 8 (25%). Follow-up was a mean of 5 years (2.5 to 8). PSA failure was defined as three consecutive rises above the nadir (ASTRO). Eight patients have met the criteria for failure yielding a 7-year actuarial freedom from biochemical failure of 74% (Figure 33-7). Neither presenting PSA nor stage predicted for biochemical outcome. There was a trend for higher Gleason score and worse outcome (Figure 33-8). Overall morbidity with this regimen has been acceptable. No patients have experienced a grade 3 or grade 4 rectal injury. One patient (3%) with a history of prior TURP has minor stress incontinence. Testosterone levels have returned to above 200 ng/dl in the majority of patients. The data from the multimodality approach suggest that there may be an advantage with this approach over radical prostatectomy (see Table 33-2). There are several possible explanations for these favorable results. The implant patients were treated with 9 months of hormonal therapy and the current PSA readings might result from
Percent free from PSA failure
Percent free from PSA failure
90 80 70 60 50
Gleason 8−10
40 30
Gleason −7
20 p = 0.128
10 0
0
3
5
Gleason 4−6 8
Years
Figure 33-8 PSA freedom from failure for Gleason score 4 to 6 (100%), 7 (67%), and 8 to 10 (60%). Although the differences were not significant, there does appear to be worse outcome for patients with Gleason score 8 to 10 in the seminal vesicles.
a continued state of androgen deprivation. Only one patient still had a testosterone level below 50 ng/dl while the rest had values above 200. Therefore, it is not likely that these favorable results are a reflection of persistent hormonal therapy effects. It is likely that the shortterm hormonal therapy benefits these patients, probably from a combination of cytoreduction during the neoadjuvant phase and additive effects during the treatment phase. There is both animal model and clinical data to support this concept.46–49 There may be no benefit in continuing the hormone therapy beyond the end of radiation if all of the local tumor can be eradicated with the shorter-term treatment and high radiation doses. Testosterone production will recover in most men treated with luteinizing hormone releasing hormone agonists if given for less than a year.49 In contrast, longerterm administration of these agents is likely to result in permanent hypogonadism. The improvement in results with the multimodality approach cannot be explained on the basis of prolonged hormonal therapy usage noted in trials where androgen deprivation has been administered for a prolonged period.49 In fact, almost all of the patients had a return in serum testosterone levels, suggesting that persistent androgen deprivation does not explain these favorable results. It is likely that this regimen eradicates all of the local disease, which was evident by the negative biopsies, especially in those patients with PSA progression. In contrast, when seminal vesicle involvement was found in the prostatectomy specimen, local relapse was quite common.22–29 The difference in PSA-free relapse between these data and the prostatectomy data implies that difference may be accounted for by the persistence
Chapter 33 Seminal Vesicles: Diagnosis, Staging, Surgery, and Management 563
of residual adenocarcinoma following an inadequate prostate resection. It is not unreasonable to believe that residual disease would remain following prostatectomy in patients with seminal vesicles involvement.
14.
SUMMARY
15.
Primary tumors of the seminal vesicles are uncommon. Extension of prostate cancer into the vesicles should be identified prior to consideration for definitive therapy. A monotherapy approach to management of this disease will most likely fail. A combined therapeutic approach either with radiation or surgery should be considered for this difficult disease.
References 1. Latchamsetty KC, Elterman L, Coogan CL: Schwannoma of a seminal vesicle. Urology 2002; 60:515. 2. Iqbal N, Zins J, Klienman GW: Schwannoma of the seminal vesicle. Conn Med 2002; 66:259–260. 3. Patel B, Gujral S, Jefferson K, et al: Seminal vesicle cysts and associated anomalies. BJU Int 2002; 90:265–271. 4. Berger AP, Bartsch G, Horninger W: Primary rhabdomyosarcoma of the seminal vesicle. J Urol 2002; 168:643. 5. Yanagisawa N, Saegusa M, Yoshida T, Okayasu I: Squamous cell carcinoma arising from a seminal vesicular cyst: possible relationship between chronic inflammation and tumor development. Pathol Int 2002; 52:249–253. 6. Tabata K, Irie A, Ishii D, et al: Primary squamous cell carcinoma of the seminal vesicle. Urology 2002; 59:445. 7. Linzer DG, Stock RG, Stone NN, et al: Seminal vesicle biopsy: accuracy and implications for staging of prostate cancer. Urology 1996; 48:757–761. 8. Peabody JO, Korman HJ, Amin MB: Miscellaneous tumors of the genitourinary tract. In Vogelzang NJ, Scardino PT, Coffey DS (eds): Comprehensive Textbook of Genitourinary Oncology, pp 1152–1158. Baltimore, Williams and Wilkens, 1996. 9. Mukamel E, deKernion JB, Hannah J, et al: The incidence and significance of seminal vesicle invasion in patients with adenocarcinoma of the prostate. Cancer 1987; 59:1535–1538. 10. Vallencien G, Bochereau G, Wetzel O, et al: Influence of preoperative positive seminal vesicle biopsy on the staging of prostate cancer. J Urol 1994; 152:1152–1156. 11. Allepuz Lossa C, Sanz A, Velez JI, et al: Seminal vesicle biopsy in prostate cancer staging. J Urol 1995; 154:1407–1411. 12. Stock RG, Stone NN, Ianuzzi C, et al: Seminal vesicle biopsy and laparoscopic pelvic lymph node dissection. Implications for patient selection in the radiotherapeutic management of prostate cancer. Int J Radiat Oncol Biol Phys 1995; 33:815–821. 13. Stone NN, Stock RG, Unger P: Indications for seminal vesicle biopsy and laparoscopic pelvic lymph node
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
dissection in the men with localized carcinoma of the prostate. J Urol 1995; 154:1393–1396. Terris MK, McNeal JE, Freiha FS, et al: Efficacy of transrectal ultrasound-guided biopsies in the detection of seminal vesicle invasion by prostate cancer. J Urol 1993; 149:1035–1039. Wymenga LF, Duisterwinkel FJ, Groenier K, Mensink HJ: Ultrasound-guided seminal vesicle biopsies in prostate cancer, Prostate Cancer Prostatic Dis 2000; 3:100–106. Okihara K, Kamoi K, Lane RB, et al: Role of systematic ultrasound-guided staging biopsies in predicting extraprostatic extension and seminal vesicle invasion in men with prostate cancer. J Clin Ultrasound 2002; 30:123–131. Pandey P, Fowler JE, Seaver LE, et al: Ultrasound guided seminal vesicle biopsies in men with suspected prostate cancer. J Urol 1995; 154:1798–1801. Roach M, Chen A, Song J, et al: Pretreatment prostate-specific antigen and Gleason score predict the risk of extracapsular extension and the risk of failure following radiotherapy in patients with clinically localized prostate cancer. Semin Urol Oncol 2000; 18:108–114. Penson DF, Grossfeld GD, Li YP, et al: How well does the Partin nomogram predict pathological stage after radical prostatectomy in a community based population? Results of the cancer of the prostate strategic urological research endeavor. J Urol 2002; 167:1653–1657. D’Amico AV, Whittington R, Malkomicz SB, et al: Critical analysis of the ability of the endorectal coil magnetic imaging scan to predict pathologic stage, margin status, and post-operative prostate specific antigen failure in patients with clinically organ confined prostate cancer. J Clin Oncol 1995; 14:1770–1777. Cornud F, Flam T, Chauveinc L, et al: Extraprostatic spread of clinically localized prostate cancer: factors predictive of pT3 tumor and of positive endorectal MR imaging examination results. Radiology 2002; 224:203–210. Sofer M, Savoie M, Kim SS, et al: Biochemical and pathological predictors of the recurrence of prostatic adenocarcinoma with seminal vesicle invasion. J Urol 2003; 169:153–156. Van den Ouden D, Hop WCJ, Schroder FH: Progression and survival of patients with locally advanced prostate caner (T3) treated with radical prostatectomy as monotherapy. J Urol 1998; 160:1392–1397. Van Poppel H, Goethuys H, Callewaert P, et al: Radical prostatectomy can provide a cure for well selected clinical stage T3 prostate cancer. Eur Urol 2000; 38:372–379. Lerner SE, Blute MI, Zinke H: Extended experience with radical prostatectomy for clinical stage T3 prostate cancer: outcome and contemporary morbidity. J Urol 1995; 154:1447–1452. Catalona WJ, Bigg SW: Nerve-sparing radical prostatectomy: evaluation of results after 250 patients. J Urol 1990; 143:538–544. D’Amico A, Whittington R, Malkowicz S: A multivariate analysis of clinical and pathological factors that predict for
564
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
Part V Prostate Gland and Seminal Vesicles prostate specific antigen failure after radical prostatectomy for prostate cancer. J Urol 1995; 154:538–548. Kupelian P, Kathcher J, Levin H, et al: Correlation of clinical and pathologic factors with rising prostate-specific antigen profiles after radical prostatectomy alone for clinically localized prostate cancer. Urology 1996; 48:249–260. Trapasso JG, deKernion JG, Smith RB, et al: The incidence and significance of detectable levels of serum PSA after radical prostatectomy. J Urol 1994; 152:1816–1825. Zeitman AL, Edelstein RA, Coen JJ, et al: Radical prostatectomy for adenocarcinoma of the prostate: the influence of preoperative and pathologic findings on biochemical disease free outcomes. Urology 1994; 43:828–833. Choo R, Hruby G, Hong J, et al: Positive resection margin and/or pathologic T3 adenocarcinoma of prostate with undetectable postoperative prostatespecific antigen after radical prostatectomy: to irradiate or not? Int J Radiat Oncol Biol Phys 2003; 52: 674–680. Gibbons RP, Cole BS, Richardson G, et al: Adjuvant radiotherapy following radical prostatectomy: results and complications. J Urol 1986; 135: 65–68. Jewett HJ, Eggleston JC, Yawn DH: Radical prostatectomy in the management of carcinoma of the prostate: probable causes of some therapeutic failures. J Urol 1972; 107:1034–1040. Medini E, Medini I, Reddy PK, Levitt SH: Delayed/salvage radiation therapy in patients with elevated prostate specific antigen levels after radical prostatectomy. Cancer 1996; 78:1254–1259. Zeitman AL, Shipley WU, Willett CG: Residual disease after radical surgery or radiation therapy for prostate cancer. Cancer 1993; 71:959–969. Scardino PT, Wheeler TM: Local control of prostate cancer with radiotherapy: frequency and prognostic significance of positive results of postirradiation prostate biopsy. Monogr Natl Cancer Inst 1988; 7:95–103. Schellhammer PF, El-Mahdi AM, Higgins AM, et al: Prostate biopsy after definitive treatment by interstitial 125 iodine implant or external beam radiation therapy. J Urol 1987; 137:897–901. Pollack A, Zagers GK, Starkschall G: Prostate cancer radiation dose response: results of the M.D. Anderson phase II randomized trial. Int J Radiat Oncol Biol Phys 2002; 53:1097–1105.
39. Hanks GE, Hanlon AL, Epstein B, et al: Dose response in prostate cancer with 8–12 years follow-up. Int J Radiat Oncol Biol Phys 2002; 54:427–435. 40. Stock RG, Lo YC, Gaildon MS, Stone NN: Does prostate brachytherapy treat the seminal vesicles? A doseresponse histogram analysis of seminal vesicles in patients undergoing combined Pd-103 prostate implantation and external beam irradiation. Int J Radiat Oncol Biol Phys 1999; 45:385–389. 41. Stone NN, Stock RG: Prostate brachytherapy: treatment strategies. J Urol 1999; 162:421–426. 42. Stock RG, Stone NN: Preliminary toxicity and prostatespecific antigen response to a phase I/II trial of neoadjuvant hormonal therapy, Pd-103 brachytherapy, and 3D conformal external beam irradiation in the treatment of locally advanced prostate cancer. Brachytherapy 2002; 1:2–10. 43. Stone NN, Hong S, Lo YC, et al: Comparison of intraoperative dosimetric implant representation to post-implant dosimetry in patients receiving prostate brachytherapy. Brachytherapy 2003; 2:17–25. 44. Stone NN, Stock RG: Brachytherapy for prostate cancer: Real time three dimensional interactive seed implantation. Tech Urol 1995; 1:72–80. 45. Stock RG, Stone NN, Lo YC, et al: Post-implant dosimetry for I-125 prostate implants: definitions and factors affecting outcome. Int J Radiat Oncol Biol Phys 2000; 48: 899–906. 46. Cahlon O, Stock RG, Kollmeier M, Stone NN: Hormonal therapy, brachytherapy and external beam irradiation in the treatment of high risk prostate cancer, post-treatment and PSA outcomes. Bracytherapy 2003; 2:P-72. 47. Zeitman AL, Nakfoor BM, Prince EA, et al: The effect of androgen deprivation and radiation therapy on an androgen-sensitive murine tumor: an in vitro and in vivo study. Cancer J Sci Am 1997; 3:31–36. 48. Pilepich MV, Winter K, John MJ, et al: Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001; 50:1243–1252. 49. Bolla M, Collette L, Blank L, et al: Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomized trial. Lancet 2002; 360:103–106.
C H A P T E R
34 Testis Tumors: Diagnosis and Staging Avrum Jacobson, MDCM, and Paul H. Lange, MD
DIAGNOSIS Introduction Testicular germ cell tumors (GCTs) typically strike men in the prime of their lives. It is the most common malignancy in men aged 20 to 35, and the second most common malignancy in men aged 35 to 39.1 On a positive note, however, GCTs have become a paradigm of the potential of translational cancer research. Advancements in imaging, tumor markers, surgical techniques, and most importantly, the introduction of cisplatin-based chemotherapy have drastically impacted morbidity and mortality, improving overall survival from 10% in the 1970s to 90% today.2 Despite these advances, 20% of patients who present with metastasis still succumb to their disease.3 Delay in diagnosis continues to be a major concern. Bosl et al.4 reported a median delay from onset of symptoms to pathologic diagnosis of 85 days. In 285 cases initially seen by primary care physicians, only 56% were suspected of malignancy, despite testicular signs being noted in 92%. A British study reported even more abysmal results with a mean delay in presentation to medical care of 5.5 months.5 In both studies, delay was associated with higher stage, and in the later study, mortality doubled from 8% to 16% if delay was greater than 6 months.4,5 In our own institution, we continue to see rare young men referred by outside physicians who have been diagnosed by retroperitoneal mass biopsy without ever having had a testicular examination. Clearly, there is a great need for educational programs. The general public should be indoctrinated in the need for regular selfexamination of the testis, as well as periodic physical examination performed by a physician. The physicians must be aware that any mass within the testicle should be considered malignant until proven otherwise, and that in
such cases urgent referral to a specialist is crucial. In addition, physicians must understand that GCTs are high among the differential diagnoses for a retroperitoneal mass of unknown primary in a young man. All such men should, at the very least, undergo a thorough genital examination and have testicular serum markers drawn. Presentation The most common presentation of GCTs is that of a painless testicular mass. However, although only 10% present with an acute painful scrotum,6 some pain has been reported in up to 32%.7 Neither pain nor testicular tenderness should not dissuade one from making the diagnosis of malignancy. A history of trauma should also not decrease the index of suspicion, as 4% of GCT patients give such a history.7 It is possible that either the trauma draws their attention to their testicular abnormality, or that the tumor increases the sensitivity of the testis to a degree of trauma that would otherwise not have brought the patient to medical attention. Occasionally, pain prevents a proper assessment of the testis. If, in such cases, epididymitis or orchitis is diagnosed, the patient should be treated and followed very closely for reexamination. If malignancy can still not be ruled out, an ultrasound should be obtained. In the vast majority of cases, however, the key to diagnosis is a wellexecuted genital examination. The physical examination of the testes is best performed with the patient standing and the physician seated facing him. The testis is palpated between the thumb and the first 2 fingers. The normal testis should be examined first to establish a baseline. The normal testis should be homogeneous, freely mobile, and distinct from the epididymis and other cord structures. Any area
567
568
Part VI Testis
within the testis itself, which appears fixed, firm, or nodular, should be considered highly suspicious. Seventy percent of GCTs are discovered by self-examination and an additional 15% are discovered by physician examination.7 Patients may also seek attention for symptoms of disseminated disease. At diagnosis, 50% are found to have metastasis; signs and symptoms of these, however, are found in approximately 10%.4 Patients may complain of generalized weakness, fatigue, and weight loss. Abdominal pain, back pain, GI disturbances, or lower extremity edema can arise secondary to retroperitoneal adenopathy, and pulmonary metastasis may manifest as dyspnea, cough, or hemoptysis. Manifestations of other sites of metastasis include headaches, seizures, or other palpable masses, most commonly in the left supraclavicular area. Other presenting symptoms include infertility and a 3% incidence of gynecomastia,7 which is believed to be secondary to an estrogen/testosterone imbalance caused by the effect of human chorionic gonadotropin (hCG) on Leydig cells. Serum Tumor Markers Tumor markers can be considered to be biologic attributes of malignant cells that help to distinguish them from normal cells. These may be uniquely identified with certain neoplasms or may be normal constituents, which, in the face of a tumor, are expressed in abnormal locations and/or quantities, or display abnormal functions. In GCTs, perhaps more than any other tumor, the serum tumor markers, including α-fetoprotein (AFP), hCG, and lactate dehydrogenase (LDH), play a key role in all aspects of clinical management. Their role in diagnosis is perhaps best illustrated in the 5% to 7% of GCTs that present with extragonadal primaries.8 These lesions often present as poorly differentiated carcinomas of unknown origin; positive immunohistochemical staining for AFP or hCG, or elevated serum levels, can confirm the diagnosis. In testicular primaries, serum markers retain a critical diagnostic role. Nonseminomatous GCTs (NSGCT) present with elevated AFP or hCG in 85% of cases (AFP alone in 40%, hCG alone in 50% to 60%).9 Seminoma, on the other hand, by definition, never presents with elevated AFP, but detectable hCG is present in 10% to 25% of cases.10 In the context of a testicular mass, elevated markers are practically pathognomonic, and can, to a degree, predict histology. AFP is the dominant serum protein of the early embryo and although detectable at birth, levels fall by age 1 to the minimal level seen in adults (<10 mg/dl). Trophoblastic cells, which are present in embryonal carcinoma, teratocarcinoma, and yolk sac tumor, are responsible for its production. These elements are never present in pure choriocarcinoma or seminoma.11 This has important ramifications, as in the presence of a positive AFP,
even when histology demonstrates only pure seminoma, the patient should be treated according to NSGCT protocols. AFP elevation has been associated with other malignant and benign processes. These include pancreatic, gastric, and lung cancer,12 as well as liver disease, pregnancy, ataxia telangiectasia, and tyrosenemia.12,13 However, in the clinical context of GCTs, these other diagnosis are rarely a source of confusion. HCG is a biologically active hormone, secreted by the placental syncytiotrophoblasts, which is responsible for maintaining the corpus luteum. Elevated serum concentrations have been reported in hepatic, pancreatic, gastric, pulmonary, breast, renal, and bladder tumors, as well as multiple myeloma.12 Levels >10,000 IU/l, however, are seen almost exclusively in pregnancy, gestational disorders, or GCTs.14 Forty percent to 60% of patients with GCTs will have an elevated hCG. This includes essentially all patients with choriocarcinoma, 80% of those with embryonal carcinoma, and 10% to 25% of those with seminoma.10 LDH is elevated in a wide spectrum of illnesses and, thus in GCTs, LDH has not been shown to have a strong predilection for certain histologies. Its usefulness in diagnosis is therefore somewhat limited. Nonetheless, LDH has been shown to reflect tumor burden15 and be an important indictor of prognosis.16,17 Routine LDH levels are therefore recommended in all GCT patients.18,19 Other markers, which have been proposed for GCTs, include placental alkaline phosphatase (PLAP) and neuron-specific enolase (NSE). PLAP, although widely accepted as a reliable histologic marker for seminoma, has largely been abandoned as a serum marker. Although elevated in 50% to 72% of seminoma,20–22 specificity is poor. Elevated levels can be detected in smokers and in other malignancies, including lung, ovary, breast, and gastrointestinal.23,24 Even among nonsmokers, positive predictive value has been shown to be less than 50%.24 NSE, which has been found to be a useful marker in neuroendocrine tumors, initially showed promise as a marker in GCTs, especially seminoma. Further investigation, however, failed to demonstrate clinical utility25, and investigational interest has waned. Imaging Scrotal ultrasound (U/S) is the current standard for testis imaging. It is essential for suspicious (as opposed to definite) testicular masses found on physical examination and also for those patients in whom physical examination is limited either by pain or by a hydrocele. In addition, in patients who present with extragonadal GCTs, U/S may reveal an occult testis primary. U/S is generally easy to obtain, noninvasive, inexpensive, and accurate. Newer high frequency transducers (5 to 10 MHz) can detect lesions as small as 1 to 2 mm. U/S can also distinguish
Chapter 34 Testis Tumors: Diagnosis and Staging 569
cystic from solid masses with 100% accuracy and intratubular from extratubular testicular with 99% accuracy.26 Cyst can be seen within the tunica albuginea but are uncommon, especially among younger men, within the testis itself. In men older than 60, testicular cysts can be seen in 8% to 10%; these occur near the mediastinum at the superior/lateral aspect of the testis and must fulfill all criteria of simple cyst.26 Solid lesions within the testes, that are malignant, cannot be distinguished absolutely from those that are benign for reasons that we will now discuss. The normal testis is uniformly heterogeneous on U/S. Seminomas typically appear as well-defined hypoechoic masses within the substance of the testis, without calcification or cystic components. NSGCTs, on the other hand, are typically inhomogeneous hypoechoic, normoechoic, or hyperechoic masses, with a higher incident of cystic components and echogenic foci.27–29 U/S cannot distinguish histology among NSGCT but has been shown to distinguish correctly seminoma from nonseminoma in 70% of cases.29 In addition, U/S does not provide accurate local staging information. The tunica albuginea is poorly seen and even in seminoma where more precise borders are present, only 44% of patients are staged accurately. In NSGCT, this figure drops to 8%.29 Parenchymal changes may occur in infection, inflammation, vascular insult, or trauma, which may mimic a tumor on ultrasound. Infective changes, on appropriate therapy, should improve within 2 weeks. However, severe orchitis with microabscesses may not resolve and may appear identical to necrosis and hemorrhage. Small infarcts and intratesticular hematomas may also mimic tumor and be slow to resolve.26 In these settings, one must use clinical judgment and explore surgically if any doubt remains; keeping in mind that excision of a diseased benign testis is certainly preferable than retaining tumor. The testis can also be well visualized with MRI. The normal testis displays homogeneous signal intensity on both T1 and T2 weighted images. The hallmark of a tumor is loss of high signal intensity on T2. On T1, in contrast, tumors can be difficult to distinguish from normal parenchyma. After gadolinium, however, brisk heterogeneous enhancement may be seen, providing clear visualization of the lesion.30 NSGCT are markedly heterogeneous and can be differentiated from seminoma in almost all cases. Differentiating NSGCT from hematoma, and seminoma from benign lesions, however can be difficult or even impossible. Also, despite good visualization of the tunica albuginea, local staging remains poor. Partial volume averaging and similar intensities between the tumor and tunica albuginea makes assessment of invasion difficult. Finally, the mediastinum testis can be difficult to see, and local tumor extension into this structure is therefore inaccurate.30
Thus, in general, MRI provides good imaging of testicular neoplasms but has not been shown to have any advantage over the cheaper and more easily accessible scrotal ultrasound, an exception to this is possibly cryptorchid (especially intraabdominal) testes. STAGING Introduction Prior to 1997, there was no consensus on staging of testicular GCTs. Most staging systems were based on the model introduced by Boden and Gibb31 in 1951, which divided the disease into 3 stages: I, limited to the testis, II, spread to the retroperitoneum, and III, spread beyond the retroperitoneum. Other systems generally kept this basic format, subdividing stage II based on the size of the retroperitoneal adenopathy. As well, different systems were intended for seminoma and nonseminoma, and for clinical staging and pathologic staging.12,32–35 The plethora of systems, each with its own subtleties led to confusion and difficulty in comparing data from various institutions. In 1997, the American Joint Committee on Cancer (AJCC) introduced an internationally accepted consensus classification.36 This system, which will be discussed in detail later, provided much needed uniformity. Staging Modalities Testis tumors generally spread initially through lymphatic channels, which follow the embryologic origin of the testis to the retroperitoneum. The primary landing site of right testicular tumors is intraaortocaval, at the level of the second lumbar vertebra, and the primary landing site of left tumors is paraaortic (i.e., to the left side of the aorta), just below the renal hilum.37 Hematologic dissemination can also occur, and is manifested most often as lung metastasis; however, more advanced disease can present with involvement of the liver, bone, or brain. The AJCC recommends radiographic assessment of the chest, abdomen, and pelvis.36 Routine bone scan and brain imaging are generally unnecessary unless clinically indicated, as these locations are extremely rarely the sole metastatic site, and their presence is often accompanied by symptoms. The current standard for imaging the chest, abdomen, and pelvis is CT scan of the abdomen and pelvis, and plain CXR. CT chest should be performed if the CXR is abnormal or if CT abdomen reveals metastasis. Although CT scan has become the imaging modality of choice for the retroperitoneum, the ideal lymph node size criterion has not been firmly established. Using the conventional, but arbitrary, cutoff of 1 cm, 22% to 44% of metastasis can be missed.38 As expected, as smaller sizes are applied, sensitivity improves and specificity worsens. Stomper et al.39 evaluated various size criteria;
570
Part VI Testis
at 5, 10, and 15 mm, sensitivity was found to be 88%, 73%, and 58% respectively, and specificity was found to be 44%, 60%, and 76% respectively. A study out of Indiana University examined transaxial lymph node diameter as a continuous variable between 0 and 25 mm. They found that the highest overall accuracy was reached at a diameter of 8 mm. At that level, sensitivity was 66.7% and specificity was 94.4%. Separate analysis revealed that enlarged nodes within the expected landing zone were more likely to represent true metastasis. Using a cutoff of 10 mm outside the predicted landing zone and 3 mm within, a sensitivity and specificity of 90.7% and 53.3%, respectively, were attained.40 Other modalities, which have been utilized to evaluate the retroperitoneum, include ultrasound, MRI, lymphography, positron emission tomography (PET) scan, and laparoscopic lymph node dissection. Ultrasound examination of the retroperitoneum is often limited either by bowel gas or by patient obesity. Even in cases where a good quality examination can be obtained, ultrasound is markedly inferior to CT scan. Subtle lymph node metastases are generally impossible to diagnose, and even nodes between 2 and 2.5 cm are accurately found in only 60%.26 Ultrasound is generally uninformative unless bulky lymphadenopathy is present, and even then, CT is preferable for more precise anatomic information and for follow-up comparison. MR, on the other hand, provides excellent imaging of the retroperitoneum with overall accuracy of approximately 80%. Studies, however, have shown no additional benefit over CT.41,42 One clear advantage is the ability of MR to distinguish lymph node from vessel in the absence of contrast. In patients in whom intravenous contrast is ill advised, MR is a sound alternative. Bipedal lymphangiogram has largely been replaced with CT scan. Although imaging of retroperitoneal nodes is fair, with a positive predictive value of 83% and negative predictive value of 69%,43 lymphography is invasive and, as such, has inherent morbidity. Complications include fever, local pain, wound infection, lymphadenitis, and pulmonary dysfunction. As well, reactive changes can increase difficulty of future surgery, and imaging above L2 is poor, as at that level many lymphatic vessels coalesce into the thoracic duct. The only advantage of lymphography over other imaging is that abnormal architecture can be detected in the absence of enlargement. Normally the lymphatic sinusoids pick up contrast well, while follicles pick up very little. This produces a characteristic appearance of homogeneously distributed droplets. Replacement of a node by tumor can produce a filling defect, or compression of sinusoidal system can produce an inhomogeneous contrast scattered throughout the node, termed “foamy.” In addition, typi-
cal meandering collaterals often accompany obstruction of the lymphatic system.44 Although it has been suggested that patients with stage I GCTs undergo lymphangiogram prior to initiating watchful waiting,43 in 174 patients with a negative work up (including negative CT and tumor markers), lymphangiogram found only 4% unsuspected metastases and another 2% had false positive findings.45 Today, there is little role for lymphography in the management of testicular GCTs. PET scan demonstrates uptake of the glucose analog 18-fluoro-2 deoxyglucose, and relies on the fact that many tumors have a high rate of glycolysis. In GCTs, however, PET scan has not been widely investigated. In a German study, PET slightly out performed CT scan in 50 GCT patients staged at initial diagnosis. Sensitivity was 87% versus 73%, with equal specificity of 94%. CT scanners in that study, however, were not standardized, and pick up on PET scan of small positive lymph nodes was still poor.46 In another European study, PET scan upstaged 3 of 31 patients, although management remained unchanged.47 At present, PET scanning for initial staging remains mainly investigational, but clearly further study is warranted. Parenthetically, in assessing postchemotherapy residual masses, PET still holds some promise for differentiating viable tumor, teratoma, and necrosis. The gold standard for staging of the retroperitoneum is a formal retroperitoneal lymph node dissection. Despite all available modalities, 23% to 30% of clinical stage I patients are found to harbor retroperitoneal disease.48–51 In high risk patients, this number increases to approximately 50%.50,51 Recently, specialized centers have attempted to lessen operative morbidity by performing the dissection laparoscopically. As a staging procedure, outcomes have been excellent, with, to our knowledge, no retroperitoneal recurrences.52,53 However, although it is clear that open RPLND is therapeutic in addition to diagnostic, the therapeutic benefit of laparoscopic RPLND remains unproven. This question arises because the laparoscopic groups have treated their stage IIA patients with 2 cycles of chemotherapy, a practice that is not common after RPLND, as after surgery alone these patients have been shown to have recurrence rates of only 8% to 20%.54 In our institution, we are convinced that the laparoscopic dissection can exactly mimic the open technique. Therefore, we do not routinely administer adjuvant therapy for our stage IIA group but remain watchful to our results and other groups in that. Finally, what staging modality is best for chest imaging? Although CT is obviously more sensitive than CXR, this does not always equate with being a superior test. The issue with CT of the chest is that there is a high incidence in the general population of small lesions seen on
Chapter 34 Testis Tumors: Diagnosis and Staging 571
CT, which are entirely benign. The morbidity of finding such lesions can, at times, be considerable; either requiring excision for pathologic diagnosis or leading to incorrect staging and treatment. One study found that in 42 patients, with a negative abdominal CT, only 4.4% had chest involvement. All were diagnosed on both CXR and CT scan, while CT scan picked up 3 additional lesions were found to be benign. In patients with positive abdominal CT scan, on the other hand, the rate of pulmonary metastasis was considerably higher at 40%. In this group, CT chest picked up an additional 12.5% of patients missed on CXR alone. In addition, 3 cases of extrapulmonary metastasis were identified as well.55 1997 American Joint Committee On Cancer Staging System The 1997 AJCC staging of testis tumors depends on the determination of T (tumor), N (node), M (metastases), and S (serum tumor markers), categories. Although the TNM classification is commonly used among various malignancies, the S category is unique to testis tumor and is a reflection of the importance of serum markers in the management of this disease. Primary Tumor Histologic evaluation of the radical orchiectomy specimen is required for the T classification. The tumor should be sampled extensively, including all grossly diverse areas, as well as the junction of tumor and the nonneoplastic testis, and at least one section remote from the tumor. Whenever possible, sections should include overlying tunica albuginea. New to this system, is the introduction of lymphvascular invasion into staging (Table 34-1). This modification assists the clinician to better differentiate stage I patients at high risk of harboring undetected retroperitoneal metastasis (stage IB) from those at lower risk (stage IA) (Table 34-2); if lymphvascular invasion is present, 50% are found on RPLND to be understaged stage II, while if lymphvascular invasion is absent, this drops to only 18% to 23%.49,56 Another factor also commonly used in the same fashion is the percent embryonal carcinoma in the specimen; however, pathologic tumor type is inherently not a staging factor, and indeed, is not included in the TNMS system. Regional Lymph Nodes Interaortocaval, paraaortic, paracaval, preaortic, precaval, retroaortic, and retrocaval lymph nodes, as well as nodes along the spermatic vein, are considered regional.
Intrapelvic, external iliac, and inguinal nodes are considered regional only after scrotal or inguinal surgery prior to presentation with a testicular tumor. All other nodes are considered distant and are staged within the M classification. For pathologic staging, it is critical that the pathologist carefully examines and liberally samples the specimen, including cystic, fibrotic, hemorrhagic, necrotic, and solid areas. The number of lymph nodes involved with tumor should be recorded, as should any evidence of extranodal involvement. Distant Metastasis The International Germ Cell Cancer Collaborative Group (IGCCCG), a panel of leading experts from around the world, retrospectively studied prognostic factors in 5662 patients with metastatic testicular GCT, all of whom received cisplatin (or carboplatin) containing chemotherapy regiments. Based on this work, such patients could be categorized into good, intermediate, or poor prognostic groups. The presence of liver, bone, brain, or other nonpulmonary visceral metastasis, was shown, in NSGCT, to be a poor prognostic factor with a 5-year survival rate of 47%. In seminoma, although no poor risk group was found, the most important prognostic factor was again the presence of nonpulmonary visceral metastases, placing patients in the intermediate prognosis group with a 5-year survival of 72% (Table 34-3).57 This information was integrated into the staging system by subdividing the M1 category into M1a and M1b (see Table 34-1). Serum Tumor Markers For staging purposes, AFP, hCG, and LDH should be performed immediately after orchiectomy and, if elevated, repeated serially after orchiectomy to assess for persistent elevation. In the absence of disease, markers should decline according to their half-lives: <7 days for AFP and <3 days for hCG. The subdivisions of the S category (see Table 34-1) were adapted from the IGCCCG,57 and play an extremely important role, not only in prognosis, but also in the management of testicular GCTS. Patients with no other evidence of metastatic disease with persistent marker elevation after orchiectomy are labeled stage 1S (see Table 34-2). These patients are almost always found to have disseminated disease and are better treated with chemotherapy than surgery.58 Patients with S2 or S3 marker levels with evidence of only regional nodal disease are upstaged to stage III, and again are better treated with chemotherapy, and, in the case of S3, perhaps even with more aggressive regiments.
572
Part VI Testis
Table 34-1 2002 AJCC TNMS Staging Classification Primary Tumor (pT)
Pathologic
Clinical
pNX
Regional lymph nodes cannot be assessed
pN0
No regional lymph node metastasis
pN1
Metastasis with a lymph node mass 2 cm or less in greatest dimension and less than or equal to 5 nodes positive, none more than 2 cm in greatest dimension
pN2
Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or more than 5 nodes positive, none more than 5 cm; or evidence of extranodal extension of tumor
Tumor stage is generally determined after orchiectomy at which time a pathologic stage is assigned Pathologic pTX
Primary tumor cannot be assessed (if no radical orchiectomy has been performed, TX is used)
pT0
No evidence of primary tumor (e.g., histologic scar in testis)
pTis
Intratubular germ cell neoplasia (carcinoma in situ)
pT1
pT2
Tumor limited to testis and epididymis without vascular/lymphatic invasion; tumor may invade into tunica albuginea but not into tunica vaginalis Tumor limited to the testis and epididymis with vascular/lymphatic invasion, or tumor extending through the tunica albuginea with involvement of the tunica vaginalis
pN3
Metastasis with a lymph node mass more than 5 cm in greatest dimension
Distant Metastasis (M) MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
M1a
Nonregional nodal or pulmonary metastasis Distant metastasis other than to nonregional lymph nodes and lungs
pT3
Tumor invades the spermatic cord with or without vascular/lymphatic invasion
M1b
pT4
Tumor invades the scrotum with or without vascular/lymphatic invasion
Serum Tumor Markers (S)
Regional Lymph Nodes (N)
SX
Markers studies not available or not performed
Clinical
S0
Marker study levels within normal limits
S1
LDH < 1.5 × N and
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
hCG (mIU/ml) < 5000 and
N1
Metastasis within a lymph node mass 2 cm or less in greatest dimension; or multiple lymph nodes, none more than 2 cm in greatest dimension
AFP (ng/ml) < 1000
N2
N3
Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, any one mass greater than 2 cm but not more than 5 cm in greatest dimension Metastasis with a lymph node mass more than 5 cm in greatest dimension
S2
LDH 1.5 − 10 × N or HCG (mIU/ml) 5000 − 50,000 or AFP (ng/ml) 1000 − 10,000
S3
LDH > 10 × N or HCG (mIU/ml) > 50,000 or AFP (ng/ml) > 10,000
Chapter 34 Testis Tumors: Diagnosis and Staging 573
Table 34-2 Staging Classification (Stage Groups) Stage grouping Stage 0
pTis
N0
M0
S0
Stage I
pT1-4
N0
M0
SX
Stage IA
pT1
N0
M0
S0
Stage IB
pT2-4
N0
M0
S0
Stage IS
Any pT/Tx
N0
M0
S1-3
Stage II
Any pT/Tx
N1-3
M0
SX
Stage IIA
Any pT/Tx
N1
M0
S0-1
Stage IIB
Any pT/Tx
N2
M0
S0-1
Stage IIC
Any pT/Tx
N3
M0
S0-1
Stage III
Any pT/Tx
Any N
M1
SX
Stage IIIA
Any pT/Tx
Any N
M1a
S0-1
Stage IIIB
Any pT/Tx
N1-3
M0
S2
Stage IIIB
Any pT/Tx
Any N
M1a
S2
Stage IIIC
Any pT/Tx
N1-3
M0
S3
Stage IIIC
Any pT/Tx
Any N
M1a
S3
Stage IIIC
Any pT/Tx
Any N
M1b
Any S
Table 34-3 International Germ Cell Consensus Classification Nonseminoma
Seminoma
Good prognosis Testis/retroperitoneal primary
Any primary site
And No nonpulmonary visceral metastasis
And No nonpulmonary visceral metastasis
And Good markers
And Nomal AFP, any HCG, any LDH
AFP < 1000 ng/ml and HCG < 5000 IU/l (1000 ng/ml) and LDH < 1.5 upper limit of normal 5-year PFS 89%
5-year PFS 82%
5-year survival 92%
5-year survival 86% Continued
574
Part VI Testis
Table 34-3—cont’d Nonseminoma
Seminoma
Intermediate prognosis Testis/retroperitoneal primary
Any primary site
And No nonpulmonary visceral metastasis
And Nonpulmonary visceral metastasis
And Intermediate markers
And Nomal AFP, any HCG, any LDH
AFP > 1000 ng/ml and <10,000 ng/ml or HCG > 5000 IU/l and <50,000 IU/l or LDH > 1.5 × N and <10 × N 5-year PFS 75%
5-year PFS 67%
5-year survival 80%
5-year survival 72%
Poor prognosis Mediastinal primary Or Nonpulmonary visceral metastasis Or Poor markers AFP > 10,000 ng/ml or HCG > 50,000 IU/l or LDH > 10 × upper limit of normal 5-year PFS 41% 5-year survival 48%
REFERENCES 1. Richie JP: Detection and treatment of testicular cancer. CA Cancer J Clin 1993; 43:151–175. 2. Richie JP: Advances in the diagnosis and treatment of testicular cancer. Cancer Invest 1993; 11(6):670–675. 3. McCaffrey JA, Bajorin DF, Motzer RJ, et al: Risk assessment for metastatic testis cancer. Urol Clin NA 1998; 25(3):389–395. 4. Bosl GJ, Goldman A, Lange PH, et al: Impact of delay in diagnosis on clinical stage of testicular cancer. Lancet 1981; 2:970–973. 5. Nikzas D, Champion AE, Fox M: Germ cell tumours of testis: prognostic factors and results. Eur Urol 18:242–247. 6. Richie JP, Steele GS: Neoplasms of the testis. In Walsh PC, Retik AB, Vaughan ED, Wein A (eds) Campbell’s Urology, 8th edition. Philadelphia, PA, WB Saunders, 2002.
7. Kennedy BJ, Schmidt JD Winchester DP, et al: National survey of patterns of care for testis cancer. Cancer 1987; 60:1921–1930. 8. Bokemeyer C, Hartmann JT, Fossa SD, et al: Extragonadal germ cell tumors: relation to testicular neoplasia and management options. APMIS 2003; 111:49–63. 9. Small EJ, Torti FM: Testes. In Abeloff MD, Armitage JO, Lichter AS, Niederhuber JE (eds) Abeloff Clinical Oncology, 2nd edition. Philadelphia, PA, Churchill Livingston, 2000. 10. Klein EA: Tumor markers in testis cancer. Urol Clin North Am 1993; 20:67–73. 11. Javadpour N: Significance of elevated serum alphafetoproteins (AFP) in seminoma. Cancer 1980; 45:2166. 12. Richie JP: Neoplasms of the testis. In Walsh PC, Retik AB, Stamey TA, Vaughan ED (eds). Campbell’s Urology, 6th edition. Philadelphia, PA, WB Saunders, 1992.
Chapter 34 Testis Tumors: Diagnosis and Staging 575 13. Bloomer JR, Waldmann TA, McIntire KR, et al: Serum alpha-fetoprotein levels in patients with nonneoplastic liver disease. Gastroenterology 1973; 65:530. 14. Bower M, Rustin GJS: Serum tumor markers and their role in monitoring germ cell cancers of the testis. In Vogelzang NJ, Scardino PT, Shipley WU, Coffey DS (eds): Comprehensive Textbook of Genitourinary Oncology, 2nd edition. Philadelphia, PA, Lippincott Williams and Wilkins, 1999. 15. Boyle LE, Samuels ML: Serum LDH activity and isoenzyme patterns in nonseminomatous germinal (NSG) testis tumors. Proc Am Soc Clin Oncol 1977; 18:278. 16. Mencel PJ, Motzer RJ, Mazumdar M, et al: Advanced seminoma; treatment results, survival, and prognostic factor in 142 patients. J Clin Oncol 1994; 12:120–126. 17. Stoter G, Bosl GJ, Droz JP, et al: Prognostic factors in metastatic germ cell tumors. Porg Clin Biol Res 1990; 357:313–319. 18. National Comprehensive Cancer Network Practice Guidelines in Oncology, Vol 1, Testicular Cancer. Rockledge, PA, 2003. 19. Laguna MP, Pizzocaro G, Klepp O, et al: EAU guidelines on Testicular Cancer. Eur Urol 2001; 40:102–110. 20. Albrecht W, Bonner E, Jeschke K, et al: PLAP as a marker for germ cell tumors. In Jones NG, Appleyard I, Harnden P, Joffe JK (eds): Germ Cell Tumours IV. London, John Libbey & Co, 1998. 21. Koshida K, Nishino A, Yamamoto H, et al: The role of alkaline phosphatase isoenzymes as a tumor marker for testicular germ cell tumors. J Urol 1991; 146:57. 22. Lange PH, Millan JL, Stigbrand T, et al: Placental alkaline phosphatase as a tumor marker for seminoma. Cancer Res 1982; 42:3244. 23. Muensch HA, Maslow WC, Azama F, et al: Placental-like alkaline phosphatase. Reevaluation of the tumor marker with exclusion of smokers. Cancer 1986; 58:1689. 24. Nielsen OS, Muntro AJ, Duncan W, et al: Is placental alkaline phosphatase (PLAP) a useful marker for seminoma? Euro J Cancer 1990; 26(10):1049–1054. 25. Gross AJ, Dieckmann KP: Neuron-specific enolase: a serum marker in malignant germ-cell tumors? Euro Urol 1993; 24(2):277–278. 26. Benson CB: The role of ultrasound in diagnosis and staging of testicular cancer. Semin Urol 1988; 6(3):189–202. 27. Richie JP, Birnholz J, Garnick MB: Ultrasonography as a diagnostic adjunct for the evaluation of masses in the scrotum. Surg Gyn Obs 1982; 154:695–698. 28. Schwerk WB, Schwerk WN, Rodeck G: Testicular tumors: prospective analysis of real-time US patterns and abdominal staging. Radiology 1987; 164:369–374. 29. Marth D, Scheidegger J, Studer UE: Ultrasonography of testicular tumors. Urol Int 1990; 45(4):237–240. 30. Oyen R, Verellen S, Drochmans A, et al: Value of MRI in the diagnosis and staging of testicular tumors. JBR BTR 1993; 76:84–89. 31. Boden G, Gibb R: Radiotherapy and testicular neoplasms. Lancet 1951; 2:1195. 32. Maier JG, Sulak MH: Radiation therapy in malignant testis tumors. Cancer 1973; 32:1217–1226.
33. Doornbos JF, Hussey DH, Johnson DE: Radiotherapy for pure seminoma of the testis. Radiology 1975; 116:401–404. 34. Ball D, Barrett A, Peckham MJ: The management of metastatic seminoma testis. Cancer 1982; 50:2289–2294. 35. Crawford ED, Smith RB, DeKernion JB: Treatment of advanced seminoma with preradiation chemotherapy. J Urol 1983; 129:752–756. 36. Fleming ID, Cooper JS, Henson DE, et al. (eds): Testis. In American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 5th edition. Philadelphia, PA, Lippincott-Raven, 1997. 37. Donohue JP, Zachary JM, Maynard BR: Distribution of nodal metastasis in nonseminomatous testis cancer. J Urol 1982; 128:315–320. 38. Hilton S, Herr HW, Teitcher JB, et al: CT detection of retroperitoneal lymph node metastasis in patients with clinical stage I testicular nonseminomatous germ cell cancer: assessment of size and distribution criteria. AJR 1997; 169(2):521–525. 39. Stomper PC, Fung CY, Socincki MA, et al: Detection of retroperitoneal metastasis in early stage nonseminomatous testicular cancer: analysis of different CT criteria. AJR 1987; 149:1187–1190. 40. Leibovitch I, Foster RS, Kopecky KK, et al: Improved accuracy of computerized tomography based clinical staging in low stage nonseminomatous germ cell cancer using size criteria of retroperitoneal lymph nodes. J Urol 1995; 154:1759–1763. 41. Ellis JH, Bies JR, Kopecky KK, et al: Comparison of NMR and CT imaging in the evaluation of metastatic retroperitoneal lymphadenopathy from testicular carcinoma. J Comput Assist Tomogr 1984; 8(4):709–719. 42. Hogeboom WR, Hoekstra HJ, Mooyaart EL, et al: Magnetic resonance imaging of retroperitoneal lymph node metastases of nonseminomatous germ cell tumours of the testis. J Surg Oncol 1993; 19:429–437. 43. Bussar-Maatz R, Weissbach L: Retroperitoneal lymph node staging of testicular tumours. BJU 1993; 72:234–240. 44. Casellino RA: Lymphography. In Pollack HM, McClennan BL (eds): Pollack Clinical Urography, 2nd edition. Philadelphia, PA, WB Saunders, 2000. 45. Wishnow KI, Johnson DE, Tenney D: Are lymphangiograms necessary before placing patients with nonseminomatous testicular tumors on surveillance? J Urol 1989; 141:1133–1135. 46. Cremerius U, Wildberger JE Borchers H, et al: Does positron emission tomography using 18-fluoro-2deoxyglucose improve clinical staging of testicular cancer? Results of a study of 50 patients. Urology 1999; 54:900–904. 47. Hain SF, O’Doherty MJ, Timothy AR, et al: Fluorodeoxyglucose PET in the initial staging of germ cell tumours. Eur J Nucl Med 2000; 27(5):590–594. 48. Donohue JP, Thornhill JA, Foster RS: Retroperitoneal lymphadenectomy for clinical stage A testis cancer (1965–1989): modifications of technique and impact on ejaculation. J Urol 1993; 149:237–243.
576
Part VI Testis
49. Klepp O, Olsson AM, Henrikson H, et al: Prognostic factors in clinical stage I nonseminomatous germ cell tumors of the testis: multivariate analysis of a prospective multicenter study. Swedish-Norwegian testicular cancer group. J Clin Oncol 1990; 8:509–518. 50. Albers P, Siener R, Kliesch S, et al: Risk factors for relapse in clinical stage I nonseminomatous testicular germ cell tumors: results of the German testicular cancer study group trial. J Clin Oncol 2003; 21:1505–1512. 51. Hermans BP, Sweeney CJ, Foster RS, et al: Risk of systemic metastases in clinical stage I nonseminomatous germ cell testis tumor managed by retroperitoneal lymph node dissection. J Urol 2000; 163:1721–1724. 52. Janetschek G, Hobisch A, Peschel R, et al: Laparoscopic retroperitoneal lymph node dissection. Urology 2000; 55:136–140. 53. Nelson JB, Chen RN, Bishoff JT, et al: Laparoscopic retroperitoneal lymph node dissection for clinical stage I nonseminomatous germ cell testicular tumors. Urology 1999; 54:1064–1067.
54. Richie JP, Kantoff PW: Is adjuvant chemotherapy necessary for patients with stage B1 testicular cancer? J Clin Oncol 1991; 9:1393–1396. 55. See WA, Hoxie L: Chest staging in testis cancer patients: imaging modality selection based upon risk assessment as determined by abdominal computerized tomography scan results. J Urol 1993; 150:874–878. 56. Hoskin P, Dilly S, Easton D, et al: Prognostic factors in stage I nonseminomatous germ cell testicular tumors managed by orchiectomy and surveillance: implications for adjuvant chemotherapy. J Clin Oncol 1986; 4:1031–1036. 57. The International Germ Cell Collaborative Group: International germ cell consensus classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997; 15(2):594–603. 58. Davis BE, Herr HW, Fair WR, et al: The management of patients with nonseminomatous germ-cell tumors of the testis with serologic disease only after orchiectomy. J Urol 1994; 152:111–114.
C H A P T E R
35 Seminoma: Management and Prognosis Michael A. S. Jewett, MD, FRCSC, FACS, Rishikesh Pandya, MCh, DNB, MS, and Padraig Warde, MB, BCh, BAO
Testicular cancer is uncommon and accounts for only 1% to 2% of all cancers in North America, but it is the most common solid malignancy in men 20 to 35 years of age.1 The vast majority (98%) are primary germ cell tumors (GCTs). Of GCTs, approximately 60% are seminomas and most usually present as an asymptomatic testicular mass.1,2 The identification of prognostic factors in patients with both early and advanced disease has helped to refine management strategies for these patients. The management of patients with testicular tumors is significantly affected by histology and disease extent. Treatment results with seminoma have been good for many years because of the relatively low metastatic rate and high radiosensitivity. More recent advances in chemotherapy (CT) have improved the cure rate to >95% overall. The postorchidectomy management of the stage I group seminoma patients is focused on reducing the side effects of therapy. Treatment options include surveillance, adjuvant radiation therapy (RT), retroperitoneal lymphadenectomy, and adjuvant CT. Adjuvant retroperitoneal RT remains the treatment of choice in most centers. The success of surveillance in stage I nonseminomatous germ cell testis tumors, the establishment of curative CT for advanced disease, and the improvements in computed tomography for staging have led to reexamination of the standard treatment approach in some centers. Also, while the acute morbidity of the relatively low-dose RT used in this setting is minimal, there are reports of impaired spermatogenesis, increased rates of gastrointestinal symptoms and peptic ulceration on long-term follow-up, and increasing concern regarding the possible induction of second malignancies by RT. However, the low relapse rates following radiation, the
lack of apparent serious morbidity with adjuvant RT, the lack of long-term follow-up in surveillance studies, and the increased cost of surveillance have all dissuaded most clinicians from abandoning the traditional treatment approach.3 Stage II group patients with small bulk retroperitoneal lymphadenopathy have a high probability of long-term disease control with RT.4 Stage II group patients with large masses and stage III group patients are managed by CT. EPIDEMIOLOGY The age distribution of testicular cancer is similar in all Caucasian populations. There is a small peak in early childhood around 2 years of age, with rates then remaining low until 15 years of age.5 There is a second peak in young adults around 25 to 40 years of age and the rate then declines with a small peak again between 65 and 75 years of age. Testicular cancers occurring in childhood and in the young adult years are usually GCTs, while those occurring after age 65 are principally nongerm cell malignancies, mainly lymphomas. Nonseminomatous tumors are more common in childhood and in the 15-to-30 age group, while seminomas are seen more frequently in slightly older (25 to 45 years) patients. In 2003, it is estimated that there will be approximately 7500 new cases and probably 300 deaths due to testicular cancer in the U.S.6 The current incidence of testicular cancer in the white U.S. population is 6:100000 males per year and in Canada it is 4:100000.7,8 The cumulative lifetime risk of developing a GCT is 0.2%.5 The incidence of testicular tumors is rising but the reasons are not well understood. The incidence rate has doubled in the past 30 years, and
577
578
Part VI Testis
while most patients present with early-stage curable disease, the continued rising incidence of these tumors presents a challenge. Weir et al.2 reported that the incidence of testicular GCT (TGCT) has risen in Ontario by 60% between 1964 and 1996. Seminomas have increased by 72% and nonseminomas by 45%. From SEER data, the overall incidence of TGCT rose over 44% from 3.35 to 4.84 per 100,000 men between 1973 to 1978 and 1994 to 1998. Among white men, the incidence rose 52% from 3.69 in 1973 to 1978 to 5.62 per 100,000 men in 1994 to 1998. Among black men, the overall incidence of TGCT rose 25% from 0.83 in 1973 to 1978 to 1.04 per 100,000 men in 1994 to 1998.1. The incidence in England and Wales was 5.4 in 1997 compared with 2.9 per 100,000 person-years in 1971.9 Similar increases in incidence have been reported in other populations with European ancestry, including Australia, New Zealand, and Europe itself.10 Geographically, the highest incidence of testicular cancers is seen in Denmark (8.4 per 100,000 men per year) and Switzerland (8.8 per 100,000 per year).5 It is known that the incidence is lower in nonwhites compared to whites. Low incidence rates are seen in other ethnic groups, such as Americans of Chinese and Japanese descent. However, a high incidence of testicular cancer is seen in some nonwhite populations, such as the Maoris in New Zealand and Native Americans. ETIOLOGY Cryptorchidism affects 0.7% of men and is the only condition that has been definitely associated with an increased risk of testicular cancer.7,11 The mechanisms are unknown. Pure seminoma is the most common tumor histology observed in cryptorchid testes.11 Impalpable cryptorchid testes may be detected with 91% and 95% accuracy by ultrasound and CT, respectively. The pattern of nodal metastasis may be different from that of scrotal primary tumors with a much higher incidence of pelvic nodal involvement.12 There is ongoing research to define the genetics of susceptibility to testicular cancer. An international consortium has been established to collect pedigrees of patients and their families who are thought to have increased susceptibility. A gene on the X chromosome (Xp27) has been identified. Patients with a family history of testis cancer, undescended testes, and bilateral testicular cancers are being studied to identify further susceptibility genes.13 There may be a relation between estrogenic exposure in utero and testicular cancer, and there is evidence that environmental pollutants with estrogenic or antiandrogenic activity result in hormonal disruption and are responsible for the steadily increasing incidence of testicular cancer.14,15 The increased incidence of germ cell cancers among men with testicular atrophy, testicular dysgenesis, cryptorchidism, and infertility suggests a common etiologic
relation between germ cell cancers and these genital abnormalities. SYMPTOMS The commonest mode of presentation is a painless swelling of the testis but a few patients complain of pain or heaviness in the affected side. A hard, nontender testis mass that cannot be transilluminated is diagnostic of a testicular cancer until proven otherwise. Occasionally, presentation with loss of libido or infertility leads to detection of a testicular mass. Acute presentations with symptoms resembling torsion, hematospermia, varicocele, or thrombosis of the pampiniform plexus are rare. Nipple tenderness or breast swelling is noted in approximately 5% of patients. Back pain as a result of metastatic lesion is a very rare presentation. Any history of cryptorchidism, orchiopexy, or any other inguinal or scrotal surgeries should be elicited, as these may be relevant to etiology or pattern of metastasis. When RT is being considered, the presence of inflammatory bowel disease (IBD), previous abdominal or pelvic surgeries, or any other intraabdominal diseases should be ruled out. PRIMARY SURGERY AND STAGING Radical inguinal orchiectomy is usually the initial treatment that is both diagnostic of the tumor type and therapeutic. It is curative in approximately 75% of patients with clinical stage I disease. An intraoperative excisional biopsy of the testicular mass for frozen-section evaluation after delivery of the testis from the scrotum may prevent unnecessary orchiectomy in the small proportion of patients who are ultimately found to have benign testicular masses, but it is not routinely performed if the mass is large or clinically malignant in appearance. Measurement of the serum tumor markers alphafetoprotein (AFP), the beta subunit of human chorionic gonadotropin (β-hCG), and lactate dehydrogenase (LDH) play an important role in the diagnosis, treatment, and establishment of prognosis. A detectable AFP is an indication of nonseminomatous elements, which mandates treatment as a nonseminoma. Up to 40% of patients with pure seminomas have low but detectable levels of (β−hCG) and >200 ng/ml of (β−hCG) suggests metastatic disease or nonseminomatous elements.16 LDH is a useful marker in cases of advanced seminoma and therapy can be monitored by serial measurements.17,18 Placental alkaline phosphatase is nonspecific and has not generally been found useful in the management of seminoma.18 The half-lives of AFP and β-hCG are 5 days and 24 hours, respectively. The tumor markers are measured serially, immediately before or at the time of radical
Chapter 35 Seminoma: Management and Prognosis 579
orchidectomy. If elevated, measurements should be repeated until the level(s) normalize or plateau (the later indicates residual metastatic disease). Staging investigations should include a chest x-ray and a CT scan of the abdomen and pelvis. Patients with retroperitoneal lymphadenopathy should also have a CT scan of the chest and a bone scan. Clinical staging of testis tumors is now generally done according to the 2002 UICC TNM staging system (see staging chart as Table 35-1). Seminoma is clinically confined to the testis at diagnosis (T1–4, N0, M0, or stage I group) in approximately 75% of men. The disease is characterized by an orderly, predictable spread pattern from the testis to paraaortic lymph nodes at or below the renal hilar and then to distant sites, including mediastinal and supraclavicular lymph nodes, lung, and bone. Approximately 20% of patients have involvement of regional lymph nodes at presentation (any T, N1-3, M0, or stage II group), most commonly paraaortic nodes. Distant metastases are evident at diagnosis (any T, Any N, M1, or stage III group) in only 5% of patients. Nonstandard surgical approaches (scrotal violations), including scrotal orchiectomy, open testicular biopsy, and fine needle aspiration, have historically been condemned as potentially complicating further treatment and compromising patient prognosis.19 Capelouto et al.20 showed that although statistically significant differences were found in the local recurrence rate among the scrotal violation and inguinal group studies, the overall local recurrence rates were small (2.9% versus 0.4%, respectively) and did not occur in stage I group seminoma patients. There were no statistical differences in distant recurrences or survival rates in all groups analyzed. Patients with scrotal violation who did not receive prophylactic local therapy fared as well as those who did. Patients with stage I disease and scrotal violation should not necessarily be disqualified from surveillance protocols or subjected to adjuvant local therapy.
Classical seminoma is usually seen in the fourth decade of life. The typical histologic picture is sheets of relatively large cells with clear cytoplasm and densely staining nuclei with 10% to 15% of them showing syncytiotrophoblastic elements and 20% showing lymphocytic infiltration. β-hCG levels are proportionate to the extent of syncytiotrophoblastic cells. Anaplastic seminoma also occurs in the fourth decade. This histologic subtype may indicate a poorer prognosis but this is not supported by the results with surveillance.27 Increased mitotic activity, microinvasion, nuclear pleomorphism, and cellular anaplasia are its typical features. β-hCG levels are elevated in 36%, 25% present with higher stage disease, and almost half of these patients have extragonadal extension of the primary tumor. Spermatocytic seminoma is a histologic variant that occurs in the elderly, around the sixth decade. They are large multinodular fleshy gelatinous and hemorrhagic tumors. Under the microscope they have solid sheets of cells interrupted by pseudoglandular patterns. Nests of cells in edematous stroma with occasional lymphocytic infiltrates can be seen. Spermatocytic seminomas do not metastasize, so radical orchiectomy is an adequate treatment. Warde et al.28 showed that on univariate analysis, tumor size (relapse-free rate or RFR: = 4 cm 87% versus >4 cm 76%; p = 0.003), rete testis invasion (RFR: 86% when absent versus 77% when present, p = 0.003), and the presence of SVI (small vessel invasion) (RFR: 86% when absent versus 77% when present, p = 0.038) were predictive of relapse. 28 On multivariate analysis, tumor size (= 4 cm) and invasion of the rete testis remained important predictors for relapse. Thus, the size of the primary tumor and rete testis invasion are important prognostic factors for relapse in patients with stage I seminoma when managed with surveillance. PATTERNS OF SPREAD
PATHOLOGY Testicular Intraepithelial Neoplasia Testicular intraepithelial neoplasia (TIN), previously referred to as carcinoma-in-situ (CIS), is the precursor to all TGCTs except spermatocytic seminoma.21 Furthermore, virtually all cases of TIN in postpubertal men will progress to invasive cancer if given sufficient time.22 The incidence of TIN in the contralateral testis of men with a unilateral GST is approximately 5%, which approximates the incidence of second contralateral testicular tumors.23–26 There are three histologic subtypes of seminoma: classical (70% to 85%), anaplastic (10% to 30%), and spermatocytic (2% to 12%).
The N staging of the testicular tumor depends on the number and size of involved retroperitoneal lymph nodes. Spread is primarily lymphatic and is predictable. Surgical mapping studies by Donohue et al.,29 Weissbach and Boedefeld,30 and other workers have defined the patterns of metastasis in terms of its landing sites or stations. For right-sided tumors, the first station is the interaortocaval nodes, then the precaval and preaortic; for leftsided, first station is paraaortic and preaortic and then the interaortocaval nodes. The presence of more caudal metastatic nodes is generally seen in high volume disease or with aberrant lymphatic drainage. Contralateral spread is more common from right-sided tumors than left, especially in high volume disease.
580
Part VI Testis
Table 35-1 Staging (UICC 2002) DEFINITIONS Pathologic
Primary Tumor (T)(1)
■
pTX Primary tumor cannot be assessed (if no radical orchiectomy has been performed, TX is used)
■
pT0 No evidence of primary tumor (e.g., histologic scar in testis)
■
pTis Intratubular germ cell neoplasia (carcinoma in situ)
■
PT1 Tumor limited to the testis and epididymis without vascular/ lymphatic invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis
■
pT2 Tumor limited to the testis and epididymis with vascular/ lymphatic invasion, or tumor extending through the tunica albuginea with involvement of the tunica vaginalis
■
PT3 Tumor invades the spermatic cord with or without vascular/lymphatic invasion
■
pT4 Tumor invades the scrotum with or without vascular/lymphatic invasion
Clinical ■
Pathologic
Notes 1. Except for pTis and pT4, extent of primary tumor is classified as radical orchiectomy. TX may be used for other categories in the absence of radical mechiactomy.
Primary Tumor (T) Tumor stage is generally determined after orchiectomy at which time a pathologic stage is assigned. Regional Lymph Nodes (N)
Clinical Regional Lymph Nodes (N) ■ NX Regional lymph nodes cannot be assessed
■
pNX Regional lymph nodes cannot be assessed
■
pN0 No regional lymph node metastasis
■
N0 No regional lymph node metastasis
■
pN1 Metastasis with a lymph node mass 2 cm or less in greatest dimension and less than or equal to 5 nodes positive, none more than 2 cm in greatest dimension
■
N1 Metastasis with a lymph node mass 2 cm or less in greatest dimension; or multiple lymph nodes, none more than 2 cm in greatest dimension
■
pN2 Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or more than 5 nodes positive, none more than 5 cm; or evidence of extranodal extension of tumor
■
■
pN3 Metastasis with a lymph node mass more than 5 cm in greatest dimension
N2 Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, any one mass greater than 2 cm but not more than 5 cm in greatest dimension
■
N3 Metastasis with a lymph node mass more than 5 cm in greatest dimension
Clinical
Pathologic
Distant Metastasis (M)
■
■
MX Distant metastasis cannot be assessed
■
■
M0 No distant metastasis
■
■
M1 Distant metastasis
■
■
M1a Non-regional nodal or pulmonary metastasis
■
■
M1b Distant metastasis other than to non-regional lymph nodes and lungs Biopsy of metastatic site performed ■ Y ■ N Source of pathologic metastatic specimen_____
Chapter 35 Seminoma: Management and Prognosis 581
Table 35-1 Staging—cont’d Serum Tumor Murder (S) (N indicates the upper limit of normal for the LDH assay) ■
■
SX Marker studies not available or not performed
■
■
S0 Marker study levels within normal limits
■
■
S1 LDH < 1.5 × N AND hCG (mIu/ml) < 5000 AND AFP (ng/ml) < 1000
■
S2 LDH 1.5–10 × N OR
■
hCG (mIu/ml) 5000–50,000 OR AFP (ng/ml) 1000–10,000 ■
S3 LDH > 10 × N OR
■
hCG (mIu/ml) > 50,000 OR AFP (ng/ml) > 10,000 Clinical
Pathologic
Stage Grouping
■
■
0
pTis
N0
M0
S0
■
■
I
pT1-4
N0
M0
SX
■
■
IA
pT1
N0
M0
S0
■
■
IB
pT2
N0
M0
S0
pT3
N0
M0
S0
pT4
N0
M0
S0
■
■
IS
Any pT/Tx
N0
M0
S1–3
■
■
II
Any pT/Tx
N1–3
M0
SX
■
■
IIA
Any pT/Tx
N1
M0
S0
Any pT/Tx
N1
M0
S1
Any pT/Tx
N2
M0
S0
Any pT/Tx
N2
M0
S1
Any pT/Tx
N3
M0
S0
Any pT/Tx
N3
M0
S0
■
■
■
■
IIB
IIC
■
■
III
Any pT/Tx
Any N
M1
SX
■
■
IIIA
Any pT/Tx
Any N
M1a
S0
Any pT/Tx
Any N
M1a
S1
Any pT/Tx
N1–3
M0
S2
Any pT/Tx
Any N
M1a
S2
■
■
IIIB
Notes Additional Descriptiors Lymphatic Vessel Invasion (L) LX Lymphatic vessel invasion cannot be asscesed L0 No lymphatic vessel invasion L1 Lymphatic vessel invasion Venous Invasion (V) VX Venous invasion cannot be assumed V0 No venous invasion V1 Microscoic venous invasion V2 Macroscopic venous invasion
Continued
582
Part VI Testis
Table 35-1 Staging—cont’d ■
■
IIIC
Any pT/Tx
N1-3
M0
S3
Any pT/Tx
Any N
M1a
S3
Any pT/Tx
Any N
M1b
Any S
Residual Tumor (R) ■ RX Presence of residual tumor cannot be assessed ■ R0 No residual tumor ■ R1 Microscopic residual tumor ■ R2 Macroscopic residual tumor Additional Descriptors For identification of special cases of TNM or pTNM classifications, the “m” suffix and “y,” “r,” and “a” prefixes are used. Although they do not affect the stage grouping, they indicate cases needing separate analysis. ■
m suffix indicates the presence of multiple primary tumors in a single site and is recorded in parentheses: pT(m)NM.
■
y prefix indicates those cases in which classification is performed during or following initial multimodality therapy. The cTNM or pTNM category is identified by a “y” prefix. The ycTNM or ypTNM categories the extent of tumor actually present at the time of that examination. The “y” categorization is not an estimate of tumor prior to multimodality therapy.
■
r prefix indicates a recurrent tumor when staged after a disease-free interval, and is identified by the “r” prefix rTNM.
■
a prefix designates the stage determined at autopsy: aTNM.
Indicate on diagram primary tumor and regional nodes involved.
Prognostic Indicators (if applicable)
Involvement of inguinal, pelvic, and iliac lymph nodes is uncommon except in cases of (i) prior pelvic or abdominal surgery where the normal lymphatic drainage may be disturbed, (ii) seminomas arising in a cryptorchid testis, (iii) congenital anomalies of the genitourinary tract, (iv) bulky paraaortic lymphadenopathy, and (v) possibly postscrotal orchiectomy with incision of the tunica albuginea and with tumor invasion of tunica vaginalis or the lower third of the epididymis.31–33
PREVENTION AND EARLY DETECTION The identification of TIN as a precursor of TGCT has raised the possibility that the development of invasive testicular cancer can be prevented by treating TIN. The incidence of TIN in the general population is low at 0.7%; however, the diagnosis should be considered in high-risk patients, including those with a history of cryptorchidism, presumed extragonadal GCT, androgen
Chapter 35 Seminoma: Management and Prognosis 583
insensitivity syndrome, with intersex syndromes or gonadal dysgenesis, and in patients with contralateral GCTs.34,35 It has been suggested that men with a unilateral tumor should undergo biopsy of the contralateral testis, preferably at the time of ipsilateral orchiectomy with the aim of identifying and treating TIN before progression to invasive disease.36 Those with a small, soft contralateral testis and severe oligospermia or aspermia are at a higher risk that appears to justify biopsy if treatment is going to be recommended. Men with a normal testicular biopsy can be reassured that their risk of a contralateral tumor is <1%.23 Those with a positive biopsy should be considered for testicular RT using a fractionated dose of 20 Gy that has been reported to eradicate TIN and prevent the development of invasive cancer.22 Leydig cell function with androgen production appears to be preserved in most patients.35,37 Testicular self-examination has been advocated by many for the early detection of invasive tumors but its usefulness is unproven. There is no evidence to indicate that a screening program would be of benefit; however, there is a need for education about the early signs and symptoms of testicular cancer to reduce delay at presentation. Patients with unilateral TGCTs and cryptorchidism should practice transmissible spongiform encephalopathy (TSE). An ultrasound can be done for early detection and intervention if a tumor is suspected. Testicular microlithiasis has been considered a precursor of testicular cancer. The term testicular microlithiasis refers to the high intensity signals that are recorded on ultrasound, where microcalcifications are within the tubules. 38–40 Patients with testicular microlithiasis found on ultrasound along with associated risk factors, such as infertility or cryptorchidism, may require close follow-up considering its association with testicular neoplasia.39 MANAGEMENT OF CLINICAL STAGE I (T1–4, N0, M0) GROUP Stage I seminoma represents the most common presentation of the disease, representing 70% to 80% of all new cases.3,41 For the past 20 years, clinical experience with surveillance has demonstrated that, after orchiectomy, survival is equivalent to the outcome with adjuvant RT, which remains the standard of care. With surveillance, many patients can avoid unnecessary therapy but require close follow-up, and a proportion will progress and require further treatment. For this latter reason, it is important to identify potential prognostic factors for occult metastatic disease so that patients at high risk of relapse can be treated with adjuvant treatment after sur-
gery. The optimal follow-up program for surveillance has not been determined and has evolved over time. Abdominal radiation to the paraaortic lymph nodes is highly effective with rare in-field relapse.42 Acute side effects are modest although long-term follow-up has revealed a slight increase in secondary malignancy.43,44 Primary chemotherapy for high-risk patients is not widely practiced in North America, in part because strong prognostic factors have not been defined.45 Role of Surveillance Surveillance is feasible in patients with seminoma because of the predictable recurrence pattern, the availability of high quality abdominal imaging, which allows recurrences to be detected at an early stage, and the effectiveness of chemotherapy at curing even patients with advanced disease. Surveillance is a safe alternative to adjuvant RT in stage I seminoma. It avoids unnecessary treatment and treatment-induced morbidity in the majority of patients and does not compromise cure. Newly diagnosed patients at Princess Margaret Hospital (PMH) are usually offered both surveillance and immediately RT, and most opt for surveillance. Nevertheless, surveillance is not yet an accepted alternative to RT in many centers for several reasons. It requires a commitment by both patient and physician to long-term intensive monitoring with regular physical examination, chest x-ray, CT imaging of the abdomen and pelvis, and measurement of serum LDH, AFP and β-hCG. A number of prospective nonrandomized studies of surveillance have been conducted over the past 15 years. The largest reported series are the PMH and Danish Testicular Carcinoma Study Group’s (DATECA) trials.46 In the PMH study of 241 patients, 5-year actuarial relapse-free survival was 86% with a median follow-up of 7.3 years.3 In the DATECA study, 19% of patients had failed with a median follow-up of 48 months.41 Other studies with greater than 36-month follow-up have reported similar relapse rates. Site of relapse was similar in all surveillance studies with the vast majority recurring in the paraaortic and interaortocaval nodes, 33 of 37 (89%) and 41 of 49 (82%) in the PMH and DATECA studies, respectively. While the median time to relapse ranged from 12 to 18 months, recurrences have been reported as late as 9 years from diagnosis.47,48 This implies the need for ongoing follow-up over an extended period. Patients who choose surveillance but are poorly compliant with follow-up may compromise their outcome by delaying the diagnosis of recurrence until a late stage when more intensive therapy is necessary or cure is not possible. Hao et al.49 described two deaths among poorly compliant patients with nonseminomatous testicular cancers on surveillance, but none among patients who attended regularly for follow-up.
584
Part VI Testis
Finally, at least one economic analysis has suggested that surveillance may be more costly to the health care budget than immediate RT, although the costs of managing treatment-induced second malignancies and the psychologic and social costs to patients were not considered.50 Prognostic factors for relapse have been identified.51 A list of studies comparing these prognostic factors is provided in Table 35-2. In the PMH series, only age (≤34 years) and tumor size (>6 cm) were associated with
relapse.48 Among 57 patients who had no adverse prognostic factors (age > 34, tumor size < 6 cm, and no lymphvascular invasion), tumor relapse was 6% at 5 years. In the DATECA study, primary tumor size was the only risk factor. Risk of relapse at 4 years was 6%, 18%, and 36% among patients with tumors <3 cm, 3 to 6 cm, and >6 cm, respectively.46 In a series published by the group at Royal Marsden, only the presence of lymph vascular space involvement was associated with relapse (9% versus 17%).52
Table 35-2 Prognostic Factors for Relapse in Stage I Seminoma Patients on Surveillance Series Horwich, 1992, n = 103
von der Masse, 1993, n = 261
Relapse (%) 18
20
Factor
Strata
SVI*
No
10
Yes
20
Size
Histology
Necrosis
Rete testis
Warde, 1997, n = 201
15
Size
Age
SVI
18
Size
Worde et al. 1999, n = 638 Rete testis
SVI
*SVI, Small vessel invasion by tumor.
<3 cm
Relapse (%)
6
3–5.9 cm
18
>6 cm
36
Spermatocytic
0
Classical
16
Anaplastic
33
No
14
Yes
23
No
14
Yes
23
<6 cm
12
>6 cm
33
<34
9
>34
21
No
14
Yes
31
<4 cm
13
>4 cm
24
No
14
Yes
24
No
14
Yes
23
Chapter 35 Seminoma: Management and Prognosis 585
Effective surveillance for seminoma implies efficacious therapy for patients who relapse. In the DATECA and PMH series, most patients were treated with retroperitoneal RT. Second relapse post-RT was 19% in the PMH series and 11% in the DATECA series. Although this relapse rate is higher than de novo treated patients, it is important to recognize that this represents a subset of patients who have already failed surveillance. Overall failure for the entire cohort is similar to upfront RT, and almost 100% of patients are cured regardless of choice of therapy postorchiectomy. An additional concern about surveillance is the ability to detect retroperitoneal disease at a small volume (<5 cm) such that recurrence can be managed with RT without the need for cytotoxic chemotherapy. In the PMH experience, a similar number of patients managed with surveillance (13 of 241) and adjuvant RT (10 of 254) ultimately required chemotherapy as part of their treatment regimen. It is difficult to determine the incidence of this phenomenon from the reported literature, as in many centers chemotherapy is routinely used at relapse; also in many isolated cases, patients had known contraindications. Role of Adjuvant Radiation Therapy for Dose Reduction The traditional management of patients with stage I seminoma following radical orchiectomy is with RT directed to the paraaortic lymph nodes below the diaphragm and the ipsilateral common and external iliac lymph nodes to the level of the mid-obturator foramen. The inguinal lymph nodes may or may not be included depending on the estimated risk of inguinal involvement. The radiation dose is typically 25 to 30 Gy in 15 to 20 daily fractions. Patients experience fatigue and mild gastrointestinal upset during therapy that is usually readily controlled with 5-hydroxytryptamine antagonists for nausea and antimotility agents for cramping and diarrhea. These side effects typically resolve within a few weeks of completing RT, although fatigue may occasionally persist longer. Numerous reports have documented long-term disease control rates of approximately 95% following radiation.27,53,54 Recurrences within the irradiated volume are extremely rare if treatment is planned and delivered appropriately, and follow-up imaging of the abdomen and pelvis is therefore not required. The few recurrences that do arise typically involve the mediastinal or supraclavicular lymph nodes or the lung parenchyma and can usually be detected with a combination of regular physical examination and chest x-ray. The majority of these patients are salvaged with chemotherapy administered at the time of relapse, and overall cure rates approach 100%. While the acute side effects of radiation that develop during treatment are usually self-limiting and of minimal
consequence, the side effects that arise months or years after the treatment is finished may have long-term consequences. Chronic gastrointestinal symptoms may develop, and an increased incidence of peptic ulceration particularly after abdominal radiation doses in the range of 30 to 45 Gy has been reported.55,56 The germinal epithelium of the testis is one of the most sensitive tissues in the body to ionizing radiation, and doses as low as 20 cGy (<1% of the dose that is usually used to treat seminoma) are sufficient to transiently elevate gonadotropins and reduce sperm counts.57,58 Even with shielding of the remaining testis, the scatter radiation dose results in a significant risk of infertility in previously fertile men.59 However, the most dire consequence of radiation for seminoma may be the increased risk of second malignant tumors within the irradiated volume many years after treatment. Radiation-induced tumors must be distinguished from the development of a second GCT, which occurs in about 5% of patients with seminoma and reflects an underlying predisposition.25,26 The largest study of second malignant non-GCTs in patients with testicular cancer was a cooperative effort involving over 28,000 patients from 16 population-based cancer registries.44 The actuarial excessive risk of developing a second malignancy increased progressively with time from diagnosis of testicular cancer, and was 18% at 25 years. The risk was the same for seminoma and nonseminomatous tumors. RT was associated with a 2- to 6-fold increased risk of leukemia, as well as an increased risk of solid tumors of the gastrointestinal and genitourinary tracts. Chemotherapy that included alkylating agents was associated with a 7- to 10-fold excessive risk of leukemia. Role of Modified Adjuvant Radiation Therapy Given these concerns about abandoning adjuvant RT entirely in patients with clinical stage I seminoma in favor of surveillance, alternate management strategies have emerged that aim to reduce the toxicity of RT by reducing either the radiation dose or the volume that is treated. A radiation dose of 25 Gy in 20 daily fractions controls microscopic seminoma in paraaortic lymph nodes with a probability approaching 100%. The doseresponse relationship for seminoma below this level is unknown, although there are isolated reports of in-field recurrences after fractionated doses of 15 and 21 Gy.60,61 There is experience in the United Kingdom using a radiation dose of 20 Gy in 8 daily fractions. The treatment was well tolerated, and there was only one in-field recurrence among 263 patients. It is difficult to compare these results to more conventional dose-fractionation schemes because of differences in daily fraction size (2.5 Gy versus 1.25 to 2 Gy, respectively). Total dose and fraction size both influence the biologic effectiveness of a course of RT. The Medical Research Council of the United
586
Part VI Testis
Kingdom (MRC, UK) has conducted a phase III randomized study comparing high- and low-dose radiation schedules with equal fraction size (30 Gy in 15 fractions versus 20 Gy in 10 fractions). The results of this study, which are not yet available, should better define the lowest dose that is necessary to reliably control microscopic deposits of seminoma. However, small to modest reductions in dose of this magnitude may not necessarily translate into a reduced risk of infertility or second malignancy, especially if treatment is administered in an otherwise conventional fashion to encompass the paraaortic and ipsilateral pelvic lymph nodes. Paraaortic relapse accounts for 85% of recurrences in seminoma patients on surveillance, whereas recurrence in the ipsilateral iliac lymph nodes is seen in <10% of patients.46,48,52 In addition, surgicopathologic series of patients with clinical stage I nonseminomatous testicular cancer have demonstrated ipsilateral common iliac nodal involvement in only about 10% of cases.29 One of the most important factors determining the radiation dose to the remaining contralateral testis, and therefore the risk of infertility, is the distance from the inferior edge of the radiation field to the scrotum.59 With this knowledge, several investigators have proposed limiting the radiation fields to treat only the paraaortic nodes.42,62–64 An MRC, UK, randomized phase III study comparing conventional paraaortic and ipsilateral pelvic radiation to paraaortic RT alone in 478 patients was recently reported, and showed no difference in disease-free survival between the two arms.42 There were four iliac lymph node recurrences in patients who received paraaortic irradiation alone, and none in patients treated with paraaortic and ipsilateral pelvic radiation. Sperm counts after treatment were significantly higher in the paraaortic group. This study is likely to significantly influence the standard of RT practice for patients with stage I seminoma, in that a greater proportion will receive paraaortic radiation alone. However, the small risk of iliac lymph node recurrence remains problematic. The other usual sites of recurrence after paraaortic RT alone are the inguinal, mediastinal, and supraclavicular lymph nodes and the lung parenchyma.42,63 These areas are easily followed by physical examination and chest x-ray, but regular CT imaging may be necessary to detect pelvic recurrence at an early stage. The advantage of paraaortic RT alone is therefore diminished, particularly in comparison to surveillance. A compromise may be to irradiate the paraaortic and ipsilateral common iliac lymph nodes by positioning the inferior border of the radiation fields at the lower aspect of the sacroiliac joints.65 This encompasses the lymph nodes that are typically removed at lymphadenectomy in patients with nonseminomatous tumors.66 The external iliac and inguinal nodes are not treated but are unlikely to harbor occult metastases. This approach has the potential to reduce the scatter dose to
the remaining testis and preserve fertility without the requirement for ongoing pelvic surveillance.67 Role of Primary Chemotherapy The effectiveness of multiagent cisplatin-containing chemotherapy in advanced seminoma has lead to at least 4 studies of adjuvant chemotherapy with one or two courses of single-agent carboplatin in patients with stage I disease as an alternative to RT or surveillance.68–70 Median follow-up was 24 to 74 months. Only 2 of the 160 patients developed a recurrence. Treatment was well tolerated without significant acute morbidity. There was minimal disruption of normal lifestyle and fertility did not appear to be compromised.68,71,72 However, notwithstanding these promising results, the use of chemotherapy in this setting must be approached cautiously. The experience is small, and the follow-up remains short. Late recurrences may yet arise and the long-term toxicity of this treatment, particularly with respect to the induction of leukemia, is not known.44 The MRC, UK is presently comparing a single cycle of carboplatin to adjuvant RT in a randomized study that should help to clarify the relative efficacy and toxicity of these treatments. Several studies have reported that adjuvant chemotherapy yields higher cure rates in relapsed surveillance patients compared with those who underwent adjuvant RT , reinforcing the value of adjuvant chemotherapy for stage I seminoma. MANAGEMENT OF CLINICAL STAGE II (ANY T, ANY N, M0) GROUP Only about 20% of patients have clinically evident involvement of paraaortic lymph nodes at diagnosis and are classified as having stage II disease. The number of patients is too small to mount phase III clinical trials of management, and treatment decisions are generally based on reports from single institutions where patients have been treated in a uniform fashion.54,73–76 The most important prognostic factor in stage II seminoma is the bulk of the retroperitoneal tumor, measured as the axial diameter of the largest lymph node or lymph node mass visible on CT scan. Patients who are staged according to the 2002 UICC TNM classification are stratified into 3 groups reflecting nodal masses of <2 cm (stage IIA), 2 to 5 cm (stage IIB), and >5 cm (stage IIC). Approximately 70% of stage II patients have small bulk retroperitoneal disease at presentation with lymph nodes that are <5 cm.76 Lymph node size was the only factor that predicted recurrence in 80 patients with stage II seminoma treated with RT at PMH.76 The 5-year RFR in patients with nodal disease of <5 cm was 89%, compared to 44% in patients with bulkier disease. In total, 16 of 80 patients
Chapter 35 Seminoma: Management and Prognosis 587
treated with radiation developed recurrence, most commonly in mediastinal or supraclavicular lymph nodes, lung, or bone. Thirteen patients were treated with chemotherapy at relapse, and 9 were free of disease at last follow-up. The other 4 patients plus 2 additional patients who did not receive salvage chemotherapy died of progressive seminoma. In contrast, no recurrences or deaths were seen in the 19 patients who received initial chemotherapy, even though 14 had nodal masses >5 cm in size. These results support the continued use of primary RT in stage II patients with small bulk lymphadenopathy. However, the high failure rate following RT in patients with bulky retroperitoneal disease, the fact that not all patients with recurrence were salvaged, and the apparently better outcome of similar patients who were treated with chemotherapy at diagnosis mandates primary chemotherapy instead of radiation in this population. Tumor bulk should not be the only parameter used to decide on treatment of retroperitoneal disease in patients with stage II seminoma. Other patient and tumor-related factors should also be considered. Lymph node masses that are situated laterally may necessitate irradiating a large volume of one or both kidneys or the liver in order to adequately encompass the tumor. The same situation may arise in cases of abnormal anatomy, such as with horseshoe or pelvic kidney. These patients are better treated with chemotherapy because of an unacceptably high risk of radiation toxicity. Patients in whom RT and chemotherapy are contraindicated or the diagnosis is uncertain should be considered for retroperitoneal lymph node dissection.77 RT offers a high probability of controlling metastatic seminoma in lymph nodes <5 cm in size. The treatment volume includes the gross tumor, as well as the paraaortic and ipsilateral common and external iliac lymph nodes. The radiation dose is typically 25 Gy in 20 daily fractions plus a boost of a further 10 Gy in 5 to 8 fractions to the gross lymphadenopathy. A CT scan with the patient in the treatment position is used to ensure that the gross tumor is adequately encompassed by the radiation fields and that the minimal possible volume of kidney and liver is irradiated. The contralateral iliac lymph nodes may also be treated in cases where lymphadenopathy in the low paraaortic area is deemed to increase the risk of these nodes being involved by tumor. However, this is probably of most concern in patients with bulky retroperitoneal lymphadenopathy, who are better treated with primary chemotherapy as discussed previously.33 Adjuvant radiation of supraclavicular lymph nodes in patients with stage II disease has been recommended by some, although it is not justified on a routine basis in view of the low risk of isolated supraclavicular recurrence (5% of patients with retroperitoneal nodal masses >5 cm in
the PMH series), the ease with which supraclavicular lymph nodes can be followed clinically, the availability of effective salvage chemotherapy, the possibility of compromising bone marrow reserve for subsequent chemotherapy should it be necessary, and the potential for radiation-induced cardiac toxicity.54,78,79 Patients with gross retroperitoneal lymphadenopathy require follow-up imaging of the abdomen after treatment until complete regression of disease has occurred. Residual retroperitoneal masses are frequently seen that may either regress slowly over time or remain stable. A stable persistent mass often represents fibrosis or necrosis and only the minority contain active tumor.80–82 However, the possibility of a nonseminomatous component to explain the persistence needs to be kept in mind even in patients whose primary tumors show pure seminoma.76 The Memorial Sloan-Kettering Cancer Center (MSKCC) has the largest reported experience with the management of residual retroperitoneal masses in seminoma.82 The most common sites of recurrence following RT in stage II patients with small bulk lymph node metastases are mediastinal or supraclavicular nodes, lung, and bone.76 Most relapsing patients are cured with chemotherapy, which underscores the importance of regular follow-up with clinical examination and chest x-ray after radiation. CT imaging of the abdomen and pelvis is not necessary after complete resolution of abdominal disease. In the PMH series, 4 of the 16 patients who recurred had bone metastases, and 3 of these 4 presented with spinal cord compression as the first sign of recurrence.76,83 Therefore, all patients with unexplained back pain require a bone scan to exclude metastases, and those with new onset neurologic deficits require urgent imaging of the spine with magnetic resonance imaging or myelography. MANAGEMENT OF CLINICAL STAGE III (ANY T, ANY N, ANY M) GROUP Approximately 20% of testicular seminoma patients have metastatic disease; 15% in the regional lymph nodes and 5% in distant organ metastasis (stage III).84 Multiagent cisplatin-based chemotherapy is effective treatment for patients with distant metastases at diagnosis (stage III), and even those with very advanced disease are frequently cured.85 The most important factor predicting survival of patients with stage III seminoma is the presence or absence of nonpulmonary visceral metastases. The International Germ Cell Consensus Group reported that stage III patients with nonpulmonary visceral metastases had a 67% 5-year disease-free survival, compared to 82% in patients with only lung or lymph node involvement.83 Liver or brain metastases, which are rarely seen in patients with seminoma, carried a particularly poor prognosis
588
Part VI Testis
with reported disease-free survivals of 50% and 57%, respectively. The evolution of chemotherapy for metastatic seminoma has paralleled the evolution of chemotherapy for nonseminomatous GCTs. Cisplatin and carboplatin are the most active single agents and are responsible for the high cure rates, particularly when combined with other drugs. Historically, the most commonly used regimens consisted of cisplatin plus vinblastine, cyclophosphamide, actinomycin-D and bleomycin (VAB-6), or cisplatin plus vinblastine and bleomycin (PVB).81,86 The vinblastine in the PVB regimen was replaced by etoposide (BEP) with no difference in outcome but a significant reduction in neuromuscular toxicity.87 Investigators at the MSKCC later showed that 4 cycles of cisplatin and etoposide (EP) produced equivalent long-term disease-free survival to bleomycin-containing regimens without the risk of pulmonary toxicity associated with bleomycin.88 EP is now the most widely used regimen for initial treatment of metastatic seminoma. Salvage treatment for patients who develop progressive disease after first-line chemotherapy most often consists of combinations of cisplatin, ifosfamide, and vinblastine.89 High-dose chemotherapy with autologous bone marrow transplantation should be considered for patients who fail more conventional therapy. There is no role for routine surgery or RT in the management of stage III seminoma, although there may be specific indications in individual patients. Surgery should be considered for residual clinical or radiographic abnormalities in the retroperitoneum or at other sites following chemotherapy, extrapolating from the experience with nonseminomatous tumors.90 Surgery and RT may be useful in achieving rapid tumor debulking in situations where normal tissue function is compromised, such as with brain metastases or spinal cord compression.91,92 EFFECTS OF TREATMENT Acute With the low doses of RT used in seminoma, acute complications are minor in most patients. Mild nausea and vomiting are common. A small proportion of patients require regular antiemetics and are unable to complete daily tasks while receiving RT. Diarrhea develops in a minority of patients. An increased incidence of peptic ulceration in patients treated with 30 to 45 Gy has been reported. Chronic Late Gonadal Toxicity Germinal epithelium is highly radiosensitive and although the contralateral testis is not directly located in the field, scatter dose can be significant and profoundly diminish spermatogenesis. A radiation dose between 20 and 50 cGy may produce temporary aspermia, and doses
>50 cGy may preclude recovery of spermatogenesis.93 Scrotal shielding does limit this somewhat but cannot assure protection in all patients. In men who recover spermatogenesis after RT for seminoma, there is no evidence of an increased incidence of genetic anomalies among their offspring.93 Limiting the RT field to paraaortic and common iliac has reduced the concern regarding post-RT infertility. Elevated LH values with normal testosterone values have been observed after infradiaphragmatic irradiation.94 Second Malignancy Patients with seminoma are at higher risk of later secondary cancers in addition to an increased risk of contralateral GCTs; they are at risk for other neoplasms, some of which may be related to treatment and others related to genetic/environmental exposures unrelated to treatment.44,95–97 Cancers that may arise secondary to treatment are an important consideration for possible surveillance versus radiation for stage I seminoma. Travis et al.44 reported on the risk of second cancers among 28,843 long-term survivors of testicular cancer, of which 15,000 had seminoma. Overall, seminoma patients had a 42% increased rate of second cancers. Risks were significantly elevated among patients treated initially by RT but not chemotherapy although the absolute number in the chemotherapy cohort was relatively small (n = 560). Subsequent reanalysis of these data also suggests that chemotherapy also elevated the risk of leukemia.43 Specific cancers that were detected at higher than expected rates included leukemia, colon, renal, gastric, pancreatic, and bladder. Overall risk of second non–germ cell malignancy was 18.2% at 25 years. Ruther et al.98 assessed second malignancies among 839 patients with 4year follow-up. Among this cohort, of whom the vast majority had RT , an excess number of renal cancers were noted. Although it is difficult to determine to what degree these incidence rates would drop by active surveillance, most investigators believe that a significant proportion of these cases are iatrogenic in nature. Psychologic Toxicity The vast majority of men with seminoma suffer no psychologic sequelae from their illness.99 Some studies suggest that these patients have an improved outlook on life compared to their state prior to the detection of testicular cancer and to that of age-matched controls. Isolated patients, however, suffer severe psychologic symptoms in the domains of sexuality, parenthood, distress, and social upheaval. Data of the psychologic distress of surveillance versus up-front active therapy are few. One study suggests that men on surveillance have fewer sexual problems than men on active treatment.100
Chapter 35 Seminoma: Management and Prognosis 589
Loss of one or both testes may cause psychologic distress related to the feeling of decreased masculinity and changed body image. Testicular prostheses are helpful in many cases, especially bilateral tumors; however, many unilaterally orchiectomized patients frequently regard them as not necessary. In spite of residual treatment and disease-related morbidity (Raynaud’s phenomena, peripheral sensory neuropathy, dry ejaculate, and hypogonadism) in one-third of patients, most patients cope satisfactorily with the long-term posttreatment distress and do not report a major reduction of health-related quality of life. Fertility In testicular cancer patients, the overall paternity rates are probably reduced by 15% to 30% compared with the normal population. After standard RT or standard chemotherapy most patients are oligo or azoospermic for 6 to 12 months, but sperm production recovers within the following 2 years.101 The risk adapted treatment of testicular cancer preserves fertility in many patients, such as the use of paraaortic fields instead of RT to paraaortic and iliac region, increased use of surveillance protocols, the development of nerve-sparing retroperitoneal lymphadenectomies, which are now being practiced laparoscopically, reduction of number of chemotherapy cycles and the use of spermatogenesis saving cytostatics. Infertility and subfertility are major issues in the healthrelated quality of life in the young testicular cancer survivor. Pretreatment cryopreservation of the semen technique should be used to offer an option for parenthood to these patients. Assisted reproductive technique can be offered in pretreatment or posttreatment cases having low sperm count.102 Rectal probe electroejaculation or sperm aspiration techniques can be used in patients with emission problems of the ejaculate posttreatment.103 MANAGEMENT OF RESIDUAL MASSES Residual retroperitoneal masses remain in 20% to 80% of cases after chemotherapy and the management remains controversial. Different approaches have been reported, including surgery, RT, and surveillance. Surgery is technically more difficult in seminomas compared to nonseminomas after chemotherapy because of extensive fibrosis. Complete excision is often difficult and only biopsies are performed. The percent of viable seminoma is low at 10% to 20% and viable disease only seems to present in well-delineated residual masses 3 cm or greater. RT has been proposed for postchemotherapy residual masses, although it may increase the risk of a second solid tumor and decrease hematologic tolerance to salvage chemotherapy in cases of relapse. Surveillance is an option based on the spontaneous regression of residual masses.
The largest reported series is from the MSKCC with 55 cases; 32 (58%) underwent complete resection and 23 had multiple biopsies only. In 27 patients the mass was >3 cm in diameter and 8 of these had residual tumor.82 Of the 8 with positive histologic findings 6 were seminomas, complete resection was possible in 6, 4 seminomas, and 2 teratomas. By CT scan characteristics well-defined lesions were more likely to be completely resected (78%) than poorly defined masses (44%). Unfortunately, the intervals from the completion of chemotherapy to surgery and the pretreatment sizes were not reported. Ravi et al.104 reported similar findings in 107 patients, in whom 43 had residual tumor. Nineteen underwent surgery and in 11 patients who had well-defined masses >3 cm in diameter, 6 had positive histology. Flechon et al.105 reported that viable tumor cells were noted only in residual masses 3 cm or greater (13%) and 50% of residual masses disappeared during surveillance. A recent report has suggested that the routine use of RT in this setting is of little value, in part reflecting the low incidence of active tumor in residual masses and the possibility of nonseminomatous elements that are less radio-responsive.106 While it appears that surgery should be reserved for postchemotherapy residual masses >3 cm in diameter and those <3 cm should be observed, it is also evident that surgery may be complicated due to excessive fibrosis following the chemotherapy and that there is a risk of perioperative mortality. Laparoscopic technique is being used at many centers for nonseminomas in an attempt to reduce the morbidity of the open retroperitoneal lymph node dissection. The advantages of decreased pain, shorter hospital stay and convalescence, and superior cosmesis make laparoscopic retroperitoneal lymph node dissection a promising procedure for choice.107 Further studies are needed as it may be safer to follow masses, even >3 cm, to determine if they will decrease in size. The natural history of residual masses in seminoma is not well defined. It may be one of gradual shrinkage unless nonseminomatous elements or a second primary are present. OTHER ISSUES AND MANAGEMENT OF UNUSUAL CASES Patients With High hCG β-hCG > 200 ng/ml are suggestive of metastatic disease and/or there may be nonseminomatous elements as the cause.16 Thus, the higher levels of β-hCG normally should arouse a suspicion for nonseminomatous tumors. Weissbach and Busser-Maatz108 (in a large prospective study of seminomas) found 31% of patients with β-hCG secreting tumors were more likely to have metastases in retroperitoneal lymph nodes. In seminoma, β-hCG is an indicator of tumor burden rather than a sign of tumor aggressiveness. A high hCG with negative imaging
590
Part VI Testis
studies is suggestive of retroperitoneal or distant occult metastatic disease. Bilateral Tumors The reported incidence of bilateral synchronous or metachronous testicular germ cell tumors is 0.5% to 7%. Approximately 5% are bilateral.25,26,109 Several studies have reported an increasing incidence possibly due to increased overall survival and earlier age of onset.109,110 Frequent examination of the remaining testis after treatment of a unilateral tumor, including self-examination by patients, is important to detect a second GCT early when small and confined to the testis. Bilateral inguinal orchiectomy has been the standard management in this situation. However, patients then require life-long androgen replacement therapy, which may be associated with sexual dysfunction, mood swings, and a general impairment of quality of life. Partial orchidectomy with preservation of some normal testicular tissue and androgen production has been proposed as an alternative to orchiectomy.111–113 Heidenreich and coworkers reported 52 metachronous and 17 synchronous bilateral testicular germ cell tumor patients who underwent an organ-sparing approach. As expected, approximately 60% had seminoma, 20% embryonal carcinoma, 15% mature teratoma, and 8% mixed GCT. The mean tumor diameter was 15 mm. Eighty-two percent of patients had associated TIN and the residual testis was treated with 18 Gy of local radiation. On mean follow-up of 91 months (3 to 191 months) 98.6% patients had no evidence of disease and only 1 had died of disease. There was no local relapse in 46 patients who received local radiation. Testosterone levels were normal in 85% of patients, and clinical hypogonadism occurred in about 10%. For tumors of 20 mm and less, tumor enucleation may be a reasonable alternative to bilateral orchiectomy. Horseshoe or Ectopic Kidney Horseshoe kidney occurs in approximately 1 in 400 of the general population. There is an association between renal fusion abnormalities and cryptorchidism, which in turn is associated with an increased incidence of testicular neoplasms.114 There are two main problems in the management of GCTs associated with horseshoe or pelvic kidney. The first is related to the technical problem of delivery of RT in patients with seminoma. In a number of cases of horseshoe kidney, a large part of the renal parenchyma lies within the standard radiation volume and directly overlies the regional lymph nodes. The delivery of a standard radiation dose would be associated with an unacceptable risk of radiation nephritis. The second problem is related to the possible abnormalities in lymphatic drainage of the testis and therefore the possi-
bility of relapse when the standard radiation fields are used. Unusual patterns of relapse have been observed in patients managed by surveillance, confirming concerns regarding abnormal lymphatic pathways.115 For these reasons, postorchiectomy surveillance in stage I and chemotherapy in stage II have usually been recommended. Retroperitoneal lymphadenectomy is another option for patients unwilling to follow the surveillance program. This approach has been reported to be both safe and effective in selected cases where it was performed although surgeons must be aware of the potential for anomalous vasculature.116,117 Inflammatory Bowel Disease Preexisting morbid conditions like IBD have to be taken into consideration when RT is planned. Radiation leads to increased gastrointestinal bleeding, peptic ulceration, and long-term incidence of stenosis. SEMINOMA IN PATIENTS WITH IMMUNOSUPPRESSION AND HUMAN IMMUNODEFICIENCY VIRUS INFECTION Testicular neoplasms appear to be 20 to 50 times more prevalent among patients on immunosuppression compared to the general population and in patients who are seropositive for human immunodeficiency virus (HIV).118,119 The interpretation of staging investigations for seminoma can be difficult in the later patients because of the benign lymphadenopathy that is frequently associated with HIV infection. A compilation of the reported experience with testicular tumors in HIVpositive patients showed a higher than expected frequency of stage II disease (58% versus 20%).119 This may be attributable at least in part to the false assignment of patients with HIV to stage II because of benign paraaortic lymphadenopathy. However, it is also possible that seminoma may have a more aggressive clinical course in HIV-positive patients. The majority of patients described in the literature have received standard treatment. RT and chemotherapy appear to be well tolerated except in patients with very advanced immunosuppression.119 Most patients are cured. Overall survival is usually determined by the severity of immunosuppression and the complications of the acquired immunodeficiency syndrome (AIDS) rather than by seminoma.119,120 Following renal transplant there are cases reported of seminomas.49,121,122 In such patients stages I and II have usually been treated with postoperative RT, but the concerns regarding potential damage to the transplanted kidney may dictate surveillance. Short-term follow-up of these patients does not suggest a higher risk of relapse, but the available data are limited.
Chapter 35 Seminoma: Management and Prognosis 591
THE NONCOMPLIANT PATIENT As the cure rate for patients with stages I and II seminomas approaches 100%, problems with patient compliance with treatment or follow-up recommendations may affect the outcome more than choice of therapy. Every large cancer center has experience with patients refusing conventional therapy or failing to attend for follow-up with eventual death due to disease. Although Hao et al.49 reported that compliance with clinical evaluations in patients with nonseminomas was 61.5% in year 1 and 35.5% in year 2, compliance with CT was only 25% and 11.8% in years 1 and 2, respectively. The compliance with this surveillance program was poor but this study was too small to demonstrate whether poor compliance adversely affects overall survival; other studies show no relation to survival. Patient education regarding the diagnosis, available treatment options and outcome in testis tumors, and need for regular evaluation should be given high priority. MANAGEMENT OF SEMINOMA IN CRYPTORCHID TESTES The management of seminoma presenting in cryptorchid testis depends on the location of the primary tumor and the extent of the disease. The awareness of orchiopexy early in childhood appears to have led to a significant drop in the incidence of patients presenting with tumors in uncorrected cryptorchids. Giving similar doses of radiation and adjusting the size of the paraaortic and pelvic radiation fields to cover the known extent of disease can achieve comparable survival.123 EXTRAGONADAL GERM CELL TUMORS Extragonadal germ cell tumors (EGCTs) have a similar histology to testicular GCTs but are found in other parts of the body, in the absence of a testicular mass. They account for 1% to 5% of all GCTs and, like testicular GCTs, tend to occur in young men, although the median age of presentation is 5 to 10 years older than with testicular GCTs.124 Ten percent of adult EGCTs occur in women, usually as ovarian dysgerminomas. In infants, EGCTs are more common than testicular primary tumors (usually sacrococcygeal teratomas).125,126 An increased incidence of EGCTs is seen with Klinefelter’s syndrome.126 Overall, patients with extragonadal GCTs (especially NSGCTs) have a worse prognosis than patients with testicular primaries. In a recent review of published results of chemotherapy for mediastinal tumors, 28 of 37 (76%) patients with seminomatous histology were disease free in comparison to 90 of 204 patients (44%) with nonseminomatous tumors.127 The use of aggressive regimens for patients with nonseminomatous tumors has been recom-
mended, and a 5-year survival of 73% has been reported with the use of cisplatin + vincristine + methotrexate + bleomycin + actinomycin D + cyclophosphamide +etoposide (POMB/ACE) chemotherapy.128 SUMMARY Testicular seminoma is highly curable with currently available treatments. There is good evidence that patients with stage I disease can be managed equally well after radical orchiectomy with either adjuvant RT or surveillance. Current areas of investigation in stage I patients include optimization of the RT treatment technique to minimize toxicity and the use of 1 or 2 cycles of single-agent carboplatin instead of RT or surveillance. Patients with small bulk stage II disease are treated effectively with RT. Patients with bulky stage II or stage III disease should receive 4 cycles of etoposide and cisplatin (EP) or equivalent chemotherapy. Overall, more than 95% of patients with seminoma are cured with this strategy. The current challenge for clinicians is to maintain high cure rates while minimizing toxicity and individualizing therapy to the specific social, emotional, and economic circumstances of each patient. It is important to continue to study the long-term consequences of current treatment strategies, particularly with respect to serious late side effects that might ultimately compromise the longevity of patients with seminoma diagnosed and treated decades earlier. The treatment objectives not only include long-term survival but should include a near normal quality of life. It is important that modifications in surgery, radiation, and chemotherapy, as well as advanced care to improve the quality of life in terms of sexual function, fertility, and problems of hormone replacement be integrated into current management strategies as they become available, and that the doctrine established as a result of years of successful treatment not present an insurmountable barrier to changes that may enhance the therapeutic ratio and improve overall patient outcome. REFERENCES 1. McGlynn KA, et al: Trends in the incidence of testicular germ cell tumors in the United States. Cancer 2003; 97(1):63–70. 2. Weir HK, Marrett LD, Moravan V: Trends in the incidence of testicular germ cell cancer in Ontario by histologic subgroup, 1964–1996. CMAJ 1999; 160(2):201–205. 3. Warde P, Jewett MA: Surveillance for stage I testicular seminoma: is it a good option? Urol Clin North Am 1998; 25(3):425–433. 4. Milosevic MF, Gospodarowicz M, Warde P: Management of testicular seminoma. Semin Surg Oncol 1999; 17(4):240–249.
592
Part VI Testis
5. Parkin DM, Muir CS: Cancer Incidence in Five Continents. Comparability and quality of data. IARC Sci Publ 1992; 120:45–173. 6. Parker SL, et al: Cancer statistics, 1997. CA Cancer J Clin 1997; 47(1):5–27. 7. Brown N: Cryptorchidism—a significant risk factor for testicular cancer. Br J Gen Pract 1991; 41(348):305. 8. Prener A, Engholm G, Jensen OM: Genital anomalies and risk for testicular cancer in Danish men. Epidemiology 1996; 7(1):14–19. 9. Power DA, et al: Trends in testicular carcinoma in England and Wales, 1971–1999. BJU Int 2001; 87(4):361–365. 10. Huyghe E, Matsuda T, Thonneau P: Increasing incidence of testicular cancer worldwide: a review. J Urol 2003; 170(1):5–11. 11. Abratt RP, Reddi VB, Sarembock LA: Testicular cancer and cryptorchidism. Br J Urol 1992; 70(6):656–659. 12. Klein FA, et al: Inguinal lymph node metastases from germ cell testicular tumors. J Urol 1984; 131(3): 497–500. 13. Rapley EA, et al: Localisation of susceptibility genes for familial testicular germ cell tumour. APMIS 2003; 111(1):128–133 [Discussion 33-5]. 14. Swerdlow AJ, et al: Risks of breast and testicular cancers in young adult twins in England and Wales: evidence on prenatal and genetic aetiology. Lancet 1997; 350(9093):1723–1728. 15. Klotz LH: Why is the rate of testicular cancer increasing? CMAJ 1999; 160(2):213–214. 16. Ruther U, et al: Role of human chorionic gonadotropin in patients with pure seminoma. Eur Urol 1994; 26(2):129–133. 17. Edler von Eyben F, et al: Serum lactate dehydrogenase isoenzyme. 1. An early indicator of relapse in patients with testicular germ cell tumors. Acta Oncol 1995; 34(7):925–929. 18. Nielsen OS, et al: Is placental alkaline phosphatase (PLAP) a useful marker for seminoma? Eur J Cancer 1990; 26(10):1049–1054. 19. Herr HW, Sheinfeld J: Is biopsy of the contralateral testis necessary in patients with germ cell tumors? J Urol 1997; 158(4):1331–1334. 20. Capelouto CC, et al: A review of scrotal violation in testicular cancer: Is adjuvant local therapy necessary? J Urol 1995; 153(3 Pt 2):981–985. 21. Skakkebaek NE, et al: Carcinoma-in-situ of the testis: possible origin from gonocytes and precursor of all types of germ cell tumours except spermatocytoma. Int J Androl 1987; 10(1):19–28. 22. Giwercman A, von der Maase H, Skakkebaek NE: Epidemiological and clinical aspects of carcinoma in situ of the testis. Eur Urol 1993; 23(1):104–110 [Discussion 111-4]. 23. Dieckmann KP, Loy V: Prevalence of contralateral testicular intraepithelial neoplasia in patients with testicular germ cell neoplasms. J Clin Oncol 1996; 14(12):3126–3132. 24. Dieckmann KP, Classen J, Loy V: Diagnosis and management of testicular intraepithelial neoplasia
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36. 37.
38.
39.
40.
41.
(carcinoma in situ)—surgical aspects. APMIS 2003; 111(1):64–68 [Discussion 68-9]. Wanderas EH, Fossa SD, Tretli S: Risk of a second germ cell cancer after treatment of a primary germ cell cancer in 2201 Norwegian male patients. Eur J Cancer 1997; 33(2):244–252. Osterlind A, et al: Risk of bilateral testicular germ cell cancer in Denmark: 1960–1984. J Natl Cancer Inst 1991; 83(19):1391–1395. Warde P, et al: Stage I testicular seminoma: results of adjuvant irradiation and surveillance. J Clin Oncol 1995; 13(9):2255–2262. Warde P, et al: Prognostic factors for relapse in stage I seminoma managed by surveillance: a pooled analysis. J Clin Oncol 2002; 20(22):4448–4452. Donohue JP, Zachary JM, Maynard BR: Distribution of nodal metastases in nonseminomatous testis cancer. J Urol 1982; 128(2):315–320. Weissbach L, Boedefeld EA, FTTTS Group: Localization of solitary and multiple metastases in stage II nonseminomatous testis tumor as basis for a modified staging lymph node dissection in stage I. J Urol 1987; 138:77–82. Gauwitz MD, Zagars GK: Treatment of seminoma arising in cryptorchid testes. Int J Radiat Oncol Biol Phys 1992; 24(1):153–159. Li YX, et al: Seminoma arising in corrected and uncorrected inguinal cryptorchidism: treatment and prognosis in 66 patients. Int J Radiat Oncol Biol Phys 1997; 38(2):343–350. Mason MD, et al: Inguinal and iliac lymph node involvement in germ cell tumours of the testis: implications for radiological investigation and for therapy. Clin Oncol (R Coll Radiol) 1991; 3(3):147–150. Giwercman A, et al: Evidence for increasing incidence of abnormalities of the human testis: a review. Environ Health Perspect 1993; 101(Suppl 2):65–71. Giwercman A, et al: Current concepts of radiation treatment of carcinoma in situ of the testis. World J Urol 1994; 12(3):125–130. Rorth M, et al: Carcinoma in situ in the testis. Scand J Urol Nephrol Suppl 2000; 205:166–186. Petersen PM, et al: Endocrine function in patients treated for carcinoma in situ in the testis with irradiation. APMIS 2003; 111(1):93–98 [Discussion 98-9]. Freeman A, Rowbotham C, Parkinson MC: The prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old. J Urol 2003; 169(4):1474. Holm M, et al: The prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old. J Urol 2002; 168(3):1108 [author reply 1108-9]. Peterson AC, et al: The prevalence of testicular microlithiasis in an asymptomatic population of men 18 to 35 years old. J Urol 2001; 166(6):2061–2064. Steele GS, et al: The National Cancer Data Base report on patterns of care for testicular carcinoma, 1985–1996. Cancer 1999; 86(10):2171–2183.
Chapter 35 Seminoma: Management and Prognosis 593 42. Fossa SD, et al: Optimal planning target volume for stage I testicular seminoma: a medical research council randomized trial. Medical Research Council Testicular Tumor Working Group. J Clin Oncol 1999; 17(4):1146. 43. Travis LB, et al: Treatment-associated leukemia following testicular cancer. J Natl Cancer Inst 2000; 92(14):1165–1171. 44. Travis LB, et al: Risk of second malignant neoplasms among long-term survivors of testicular cancer. J Natl Cancer Inst 1997; 89(19):1429–1439. 45. Fiveash J, Sandler HM, Controversies in the management of stage I seminoma. Oncology (Huntingt) 1998; 12(8):1203–1212 [Discussion 1212-21]. 46. von der Maase H, et al: Surveillance following orchidectomy for stage I seminoma of the testis. Eur J Cancer 1993; 29A(14):1931–1934. 47. Michael H, et al: The pathology of late recurrence of testicular germ cell tumors. Am J Surg Pathol 2000; 24(2):257–273. 48. Warde P, et al: Prognostic factors for relapse in stage I testicular seminoma treated with surveillance. J Urol 1997; 157(5):1705–1709 [Discussion 1709-10]. 49. Hao D, et al: Compliance of clinical stage I nonseminomatous germ cell tumor patients with surveillance. J Urol 1998; 160(3 Pt 1):768–771. 50. Sharda NN, Kinsella TJ, Ritter MA: Adjuvant radiation versus observation: a cost analysis of alternate management schemes in early-stage testicular seminoma. J Clin Oncol 1996; 14(11):2933–2939. 51. Warde P, et al: Long term outcome and cost in the management of stage I testicular seminoma. Can J Urol 2000; 7(2):967–972 [Discussion 973]. 52. Horwich A, et al: Surveillance following orchidectomy for stage I testicular seminoma. Br J Cancer 1992; 65(5):775–778. 53. Fossa SD, Aass N, Kaalhus O: Radiotherapy for testicular seminoma stage I: treatment results and long-term post-irradiation morbidity in 365 patients. Int J Radiat Oncol Biol Phys 1989; 16(2):383–388. 54. Dosmann MA, Zagars GK: Post-orchiectomy radiotherapy for stages I and II testicular seminoma. Int J Radiat Oncol Biol Phys 1993; 26(3):381–390. 55. Hamilton C, et al: Radiotherapy for stage I seminoma testis: results of treatment and complications. Radiother Oncol 1986; 6(2):115–120. 56. Hamilton C, et al: Radiotherapy for stage I seminoma testis: results of treatment and complications. Radiother Oncol 1986; 6(2):115. 57. Centola GM, et al: Effect of low-dose testicular irradiation on sperm count and fertility in patients with testicular seminoma. J Androl 1994; 15(6): 608–613. 58. Joos H, et al: Endocrine profiles after radiotherapy in stage I seminoma: impact of two different radiation treatment modalities. Radiother Oncol 1997; 43(2):159–162. 59. Fraass BA, et al: Peripheral dose to the testes: the design and clinical use of a practical and effective gonadal shield. Int J Radiat Oncol Biol Phys 1985; 11(3):609–615.
60. Lester SG, Morphis JG II, Hornback NB: Testicular seminoma: analysis of treatment results and failures. Int J Radiat Oncol Biol Phys 1986; 12(3): 353–358. 61. Dosoretz DE, et al: Megavoltage irradiation for pure testicular seminoma: results and patterns of failure. Cancer 1981; 48(10):2184–2190. 62. Sultanem K, et al: Para-aortic irradiation only appears to be adequate treatment for patients with stage I seminoma of the testis. Int J Radiat Oncol Biol Phys 1998; 40(2):455–459. 63. Kiricuta IC, Sauer J, Bohndorf W: Omission of the pelvic irradiation in stage I testicular seminoma: a study of postorchiectomy paraaortic radiotherapy. Int J Radiat Oncol Biol Phys 1996; 35(2):293–298. 64. Read G, Johnston RJ: Short duration radiotherapy in stage I seminoma of the testis: preliminary results of a prospective study. Clin Oncol (R Coll Radiol) 1993; 5(6):364–366. 65. Thomas GM: Alternative management options to radiation therapy for stage I and IIA testicular seminoma. Int J Radiat Oncol Biol Phys 1994; 28(2):547–548. 66. Donohue JP, et al: Primary retroperitoneal lymph node dissection in clinical stage A non-seminomatous germ cell testis cancer. Review of the Indiana University experience 1965–1989. Br J Urol 1993; 71(3): 326–335. 67. Schmidberger H, et al: Radiotherapy in stages IIA and IIB testicular seminoma with reduced portals: a prospective multicenter study. Int J Radiat Oncol Biol Phys 1997; 39(2):321–326. 68. Dieckmann KP, et al: Adjuvant carboplatin treatment for seminoma clinical stage I. J Cancer Res Clin Oncol 1996; 122(1):63–66. 69. Aparicio J, et al: Multicenter study evaluating a dual policy of postorchiectomy surveillance and selective adjuvant single-agent carboplatin for patients with clinical stage I seminoma. Ann Oncol 2003; 14(6):867–872. 70. Reiter WJ, et al: Twelve-year experience with two courses of adjuvant single-agent carboplatin therapy for clinical stage I seminoma. J Clin Oncol 2001; 19(1): 101–104. 71. Steiner H, et al: Long-term experience with carboplatin monotherapy for clinical stage I seminoma: a retrospective single-center study. Urology 2002; 60(2): 324–328. 72. Dieckmann K-P, et al: Adjuvant carboplatin treatment for seminoma clinical stage I. J Cancer Res Clin Oncol 1996; 122:63–66. 73. Tsatalpas P, et al: Diagnostic value of 18F-FDG positron emission tomography for detection and treatment control of malignant germ cell tumors. Urol Int 2002; 68(3):157–163. 74. Hultenschmidt B, et al: Results of radiotherapy for 230 patients with stage I-II seminomas. Strahlenther Onkol 1996; 172(4):186–192. 75. Vallis KA, et al: Radiotherapy for stages I and II testicular seminoma: results and morbidity in 238 patients. Br J Radiol 1995; 68(808):400–405.
594
Part VI Testis
76. Warde P, et al: Management of stage II seminoma. J Clin Oncol 1998; 16(1):290–294. 77. Warszawski N, Schmucking M: Relapses in early-stage testicular seminoma: radiation therapy versus retroperitoneal lymphadenectomy. Scand J Urol Nephrol 1997; 31(4): 355–359. 78. Hanks GE, Peters T, Owen J: Seminoma of the testis: long-term beneficial and deleterious results of radiation. Int J Radiat Oncol Biol Phys 1992; 24(5):913–919. 79. Lederman GS, et al: Cardiac disease after mediastinal irradiation for seminoma. Cancer 1987; 60(4):772–776. 80. Loehrer PJ Sr, et al: Chemotherapy of metastatic seminoma: the Southeastern Cancer Study Group experience. J Clin Oncol 1987; 5(8):1212–1220. 81. Fossa SD, et al: The treatment of advanced metastatic seminoma: experience in 55 cases. J Clin Oncol 1987; 5(7):1071–1077. 82. Herr HW, et al: Surgery for a post-chemotherapy residual mass in seminoma. J Urol 1997; 157(3):860–862. 83. International Germ Cell Cancer Collaborative Group: International germ cell consensus classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997; 15(2):594–603. 84. Porcaro AB, et al: Management of testicular seminoma advanced disease. Report on 14 cases and review of the literature. Arch Ital Urol Androl 2002; 74(2):81–85. 85. Gholam D, et al: Advanced seminoma—treatment results and prognostic factors for survival after first-line, cisplatin-based chemotherapy and for patients with recurrent disease: a single-institution experience in 145 patients. Cancer 2003; 98(4):745–752. 86. Stanton GF, et al: VAB-6 as initial treatment of patients with advanced seminoma. J Clin Oncol 1985; 3(3):336–339. 87. Williams MP, Husband JE, Heron CW: Intrathoracic manifestations of metastatic testicular seminoma: a comparison of chest radiographic and CT findings. Am J Roentgenol 1987; 149(3):473–475. 88. Mencel PJ, et al: Advanced seminoma: treatment results, survival, and prognostic factors in 142 patients. J Clin Oncol 1994; 12(1):120–126. 89. Miller KD, et al: Salvage chemotherapy with vinblastine, ifosfamide, and cisplatin in recurrent seminoma. J Clin Oncol 1997; 15(4):1427–1431. 90. Toner GC, et al: The management of testicular cancer in Victoria, 1988–1993. Urology Study Committee of the Victorian Co-operative Oncology Group. Med J Aust 2001; 174(7):328–331. 91. Mackey JR, Venner P: Seminoma with isolated central nervous system relapse, and salvage with craniospinal irradiation. Urology 1998; 51(6):1043–1045. 92. Bokemeyer C, et al: Treatment of brain metastases in patients with testicular cancer. J Clin Oncol 1997; 15(4):1449–1454. 93. Senturia YD, Peckham CS, Peckham MJ: Children fathered by men treated for testicular cancer. Lancet 1985; 2(8458):766–769. 94. Petersen PM, Skakkebaek NE, Giwercman A: Gonadal function in men with testicular cancer: biological and
95.
96.
97. 98. 99.
100.
101.
102.
103.
104.
105.
106.
107.
108. 109.
110.
111.
112. 114.
115.
clinical aspects. APMIS 1998; 106(1):24–34 [Discussion 34-6]. Moller H, et al: Incidence of second primary cancer following testicular cancer. Eur J Cancer 1993; 29A(5): 672–676. van Leeuwen FE, et al: Second cancer risk following testicular cancer: a follow-up study of 1909 patients. J Clin Oncol 1993; 11(3):415–424. Travis LB, Curtis RE, Hankey BF: Second malignancies after testicular cancer. J Clin Oncol 1995; 13(2):533–534. Ruther U, et al: Second malignancies following pure seminoma. Oncology 2000; 58(1):75–82. Caffo O, et al: Quality of life after radiotherapy for early-stage testicular seminoma. Radiother Oncol 2001; 59(1):13–20. Tinkler SD, Howard GC, Kerr GR: Sexual morbidity following radiotherapy for germ cell tumours of the testis. Radiother Oncol 1992; 25(3):207–212. Brennemann W, et al: Pretreatment follicle-stimulating hormone: a prognostic serum marker of spermatogenesis status in patients treated for germ cell cancer. J Urol 1998; 159(6):1942–1946. Hallak J, et al: Investigation of fertilizing capacity of cryopreserved spermatozoa from patients with cancer. J Urol 1998; 159(4):1217–1220. Rosenlund B, et al: In-vitro fertilization and intracytoplasmic sperm injection in the treatment of infertility after testicular cancer. Hum Reprod 1998; 13(2):414–418. Ravi R, et al: The management of residual masses after chemotherapy in metastatic seminoma. BJU Int 1999; 83(6): 649–653. Flechon A, et al: Management of post-chemotherapy residual masses in advanced seminoma. J Urol 2002; 168(5):1975–1979. Duchesne GM, et al: Radiotherapy after chemotherapy for metastatic seminoma—a diminishing role. MRC Testicular Tumour Working Party. Eur J Cancer 1997; 33(6):829–835. Ogan K, et al: Laparoscopic versus open retroperitoneal lymph node dissection: a cost analysis. J Urol 2002; 168(5):1945–1949 [Discussion 1949]. Weissbach L, Bussar-Maatz R: hCG-positive seminoma. Eur Urol 1993; 23(Suppl 2):29–32. Patel SR, Richardson RL, Kvols L: Synchronous and metachronous bilateral testicular tumors. Mayo Clinic experience. Cancer 1990; 65(1):1–4. Coogan CL, et al: Bilateral testicular tumors: management and outcome in 21 patients. Cancer 1998; 83(3):547–552. Heidenreich A, Weissbach L, Holt W, et al: Organ sparing surgery for malignant germ cell tumor of the testis. J Urol 2001; 166(6):2161–2165. Richie JP: Organ sparing surgery for malignancy germ cell tumor of the testis. J Oncl 2003; 21(1):87. Li, FP, Fraumeni JF: Testicular cancers in children: epidemiologic characteristics. J Natl Cancer Inst 1972; 48(6):1575–1581. Elyan SA, Reed DH, Ostrowski MJ, et al: Problems in the management of testicular seminoma associated with a
Chapter 35 Seminoma: Management and Prognosis 595
116.
117.
118.
119.
120.
121.
122.
horseshoe kidney. Clin Oncol (R Coll Radiol) 1990; 2(3):163–167. Key DW, Moyad R, Grossman HB: Seminoma associated with crossed fused renal ectopia. J Urol 1990; 143(5):1015–1016. Sogani PC, Whitmore WF Jr: Retroperitoneal lymphadenectomy for germ cell tumor of testis in association with horseshoe kidney. Urology 1981; 18(5):446–452. Lyter DW, Bryant J, Thackeray R, et al: Incidence of human immunodeficiency virus-related and nonrelated malignancies in a large cohort of homosexual men. J Clin Oncol 1995; 13(10):2540–2546. Leibovitch I, Baniel J, Rowland RA, et al: Malignant testicular neoplasms in immunosuppressed patients. J Urol 1996; 155(6):1938–1942. Timmerman JM, Northfelt DW, Small EJ: Malignant germ cell tumors in men infected with the human immunodeficiency virus: natural history and results of therapy. J Clin Oncol 1995; 13(6):1391–1397. Dieckmann KP, Due W, Offermann G: Testicular seminoma in an immunosuppressed renal transplant recipient. Br J Urol 1989; 63(5):549–550. Villalona-Calero MA, Ducker T, Holasek M, et al: Management of testicular seminoma following organ transplantation. Med Pediatr Oncol 1992; 20(4):338–340.
123. Sham JS, Choy P, Chan KW et al: Seminoma of normally-descended and cryptorchid testis. Eur J Surg Oncol 1990; 16(1):33–36. 124. Shirdasani RA: Extragonadal germ-cell tumours. In Scher H, Raghavan D, Leibel S, Lange P (eds): Principles and Practice of Genitourinary Oncology, p 751. Philadelphia, Lippincott-Raven Publishers, 1997. 125. Mann JR, Pearson D, Barrett A, et al: Results of the United Kingdom Children’s Cancer Study Group’s malignant germ cell tumor studies. Cancer 1989; 63(9):1657–1667. 126. Nichols CR, Heereina NA, Palma C, et al: Klinefelter’s syndrome associated with mediastinal germ cell neoplasms. J Clin Oncol 1987; 5(8):1290–1294. 127. Droz JP, Horwich A: Extragonadal germ cell tumours. In Vogelzang NJ, Scardino P (eds): Comprehensive Textbook of Genitourinary Oncology. Baltimore, Williams & Wilkins, 1995. 128. Bower M, Brock C, Holden L, et al: POMB/ACE chemotherapy for mediastinal germ cell tumours. Eur J Cancer 1997; 33(6):838–842. 129. Worde P, Specht L, von der Masse H, et al: Prognostic factors for relapse in Stage I seminoma managed by surveillance (abstract). J Urol 1999; 161:158.
C H A P T E R
36 Nonseminomatous Germ Cell Testis Tumors: Management and Prognosis Randall G. Rowland, MD, PhD
The survival rates for patients with testis cancer have improved dramatically over the last 30 years. This has been especially true for nonseminomatous germ cell testis tumors (NSGCTT). There are several factors involved in this improvement in survival: improved diagnostic tools, such as serum markers; better imaging studies; improved surgical techniques; effective chemotherapeutic agents; multimodal therapy when appropriate; and increased public awareness. The high rate of cure of NSGCTT has allowed us to concentrate on reducing the morbidity and mortality of the treatments, while maintaining the high rate of efficacy. Fertility can even be preserved in the majority of patients using modified templates and nerve-sparing techniques during radical retroperitoneal lymph node dissection (RPLND). This chapter will focus on the diagnoses, staging, treatments, and outcomes of NSGCTT. DIAGNOSIS Germ cell testis tumors (GCTT) are the most common solid tumors in males from the age of 20 to 35 years.1 GCTTs have been reported in patients from infants to age 89 years. NSGCTTs account for approximately 60% of all GCTTs.2 Any mass in the testicle has to be considered a potential GCTT until proven otherwise. GCTTs must also be considered as a possibility in patients with scrotal pain and/or swelling, the presence of a hydrocele, or a hematocele after relatively minor scrotal trauma. Production of human chorionic gonadotropin (HCG) by some tumors causes patients to present with gynecomastia or breast tenderness. Metastases of GCTT have made some patients present with hemoptysis from pul-
596
monary lesion or back pain from large retroperitoneal adenopathy. Physical examination of the testicle still plays a major role in the evaluation of the patient. It is important to differentiate a mass in the testicle versus the epididymis or cord structures. Scrotal ultrasound is perhaps the best and most readily available imaging study for suspected GCTTs. Ultrasound scans facilitate the location of scrotal masses, as well as giving us information on the homogeneity or heterogeneity of the mass. Scrotal ultrasounds may give some insight regarding the cell type(s) in a mass. Pure seminomas tend to be very homogeneous masses (Figure 36-1), while mixed GCTTs may have a heterogeneous echo pattern (Figure 36-2). The finding of cystic structures in a mass suggests the presence of teratoma (Figure 36-3). Serum markers are also helpful in making the diagnosis of testis cancer. Overall approximately 70% of patients with testis cancer will have elevated alpha-fetoprotein (AFP) and/or HCG levels in their blood. The clinical test for HCG is a radioimmunoassay that measures the beta chain of the HCG and is designated B-HCG. Yolk sac cell tumors produce AFP with rare exception. HCG is made by syncytio-trophoblasts, which are present in all cases of choriocarcinoma and in about 10% of cases of pure seminoma. Lactate dehydrogenase (LDH) is sometimes used as a measure of tumor bulk; however, the author does not find this text useful in clinical practice. Placental alkaline phosphatase (PLAP) is present in up to 84% of patients with seminoma. PLAP is falsely elevated in a high percentage of smokers, which could negate the value of the marker.3
Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 597
Figure 36-1 Sagittal ultrasound of testis with a central mass, which was a seminoma. Note the homogeneity of the mass.
RADICAL ORCHIECTOMY VERSUS PARTIAL ORCHIECTOMY The standard approach for making the definitive diagnosis of testicular cancer has been the radical orchiectomy performed by removing the testicle using an inguinal approach. This approach helps prevent crosscontamination of the testicular lymphatics to the inguinal lymphatics. The vas deferens and the gonadal vessels are ligated and divided at the level of the internal inguinal ring. An organ-sparing approach has been advocated by some authors.4,5 In this approach, the testicle is still delivered through an inguinal incision, except the mass in the testicle is excised. The testis is reconstructed and returned to the scrotum. This technique is a benefit in patients with a solitary testis or an intratesticular lesion that is questionable with respect to its being a testicular tumor. The down-side of a local excision is the potential for leaving a finger of a lesion or a satellite lesion behind.
Transscrotal needle biopsy of testicular masses is discouraged for two reasons. First, there can easily be a sampling error that would not give a true representation of the pathology present. Second, there is a possibility for cross-contamination for the testicle lymphatics with the scrotal/inguinal lymphatics.
PATHOLOGY Histologic study of the orchiectomy specimen should include documenting the cell type(s) present in the tumor and the T stage of the tumor. Extensive sampling of the testis should be performed to allow a careful and thorough determination of the cell types that are present. T stage can be accurately assessed by careful observation and extensive histologic sampling. Tumors can be intratubular (CIS) or invasive. The cell types of germ cell tumors that occur are shown in Table 36-1. Approximately 40% of patients present with pure
598
Part VI Testis
Figure 36-2 Sagittal ultrasound of testis with a mass, which was a mixed germ cell tumor. Note the more heterogeneous character of the mass.
seminoma and 60% present with nonseminomatous cell elements either as a pure cell type or more commonly as mixed cell type tumors.2 The determination of cell types present in a testicular tumor is very important in terms of treatment. Pure seminomas, including spermatocytic seminomas, are treated with a different approach than tumors with nonseminomatous elements. Table 36-2 shows the American Joint Commission on Cancer’s (AJCC) definitions of the pathologic T stages of testicular tumors.6 CLINICAL STAGING Once the histologic diagnosis of testicular cancer is documented, the patient should have clinical staging performed to allow the formulation of a treatment plan to best fit the patient’s needs. Clinical staging involves assessment of the patient using tumor markers before and after orchiectomy, radiologic imaging studies of the chest, abdomen and pelvis, and physical examination to document any adenopathy or abdominal masses. Care should also be
taken to evaluate the contralateral testis since bilateral synchronous or metachronous testicular tumors do occur. Serum Markers AFP and HCG should be rechecked after orchiectomy in all patients, but especially in those patients with elevated serum markers prior to orchiectomy. If the tumor was localized in the testis only, orchiectomy should cause the markers to return to normal. If tumor remains, the markers may not return to normal. When following the serum marker level, the time after orchiectomy and the serum half-life of each marker must be considered. The serum half-life of AFP is approximately 5 days and that of HCG is about 1 day. Markers that either fall at a lower than expected rate or rising are indicative of persistent disease. When LDH is used as a marker, it is usually considered in terms of its percentage or number of times the normal value. LDH has a half-life of approximately 3 days.
Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 599
Figure 36-3 Sagittal ultrasound of testis with two adjacent masses. Note the hypoechoic areas, which correspond to cystic areas of teratoma.
Table 36-1 Germ Cell Testicular Tumors
Table 36-2 Pathologic Stage of The Primary Tumor (T)
Precursor lesions
Intratubular germ cell neoplasia (CIS)
pTX
Primary tumor cannot be assessed
Tumors of one histologic type
Seminoma Spermatocytic seminoma Embryonal carcinoma Yolk sac tumor (endodermal sinus tumor) Choriocarcinoma Teratoma Mature Immature With malignant component(s) Monodermal variants Carcinoid tumor Primitive neuroectodermal tumor
pT0
No evidence of primary tumor (e.g., histologic scar in testis)
pTis
Intratubular germ cell neoplasia (carcinoma in situ)
PT1
Tumor limited to the testis and epididymis without vascular/lymphatic invasion; tumor may invade into the tunica albuginea but not the tunica vaginalis
pT2
Tumor limited to the testis and epididymis with vascular/lymphatic invasion, or tumor extending through the tunica albuginea with involvement of the tunica vaginalis
PT3
Tumor invades the spermatic cord with or without vascular/lymphatic invasion
pT4
Tumor invades the scrotum with or without vascular/lymphatic invasion
Tumors of more Mixed germ cell tumors than one (specifically individual types) histologic type
These T stages are based on the pathologic findings from orchiectomy specimens.
600
Part VI Testis
Imaging Studies
Physical Examination
The goal of imaging studies is to detect any nodal or visceral tumor involvement. Based on the known patterns of spread of testicular tumors by lymphatics and rarely by vasculature, the studies need to cover the chest, both pulmonary parenchyma and the mediastinum, the abdomen, again the viscera and the retroperitoneal lymph nodes, and the pelvis. The chest was initially evaluated by standard chest x-rays and whole lung tomograms. With the advent of computed axial tomography (CT) and subsequent improvement in CT techniques, CT scans have become the most frequent modality for doing initial clinical staging of the chest. Chest involvement more frequently occurs as peripheral pulmonary nodules in cases of low volume metastases and with the addition of mediastinal adenopathy in more advanced cases. It is important to examine the lung fields using both soft tissue settings and bone window settings. This allows parenchymal lesions to be evaluated for the presence of calcification, which leads to a finding of pulmonary granuloma rather than metastasis. Figures 36-4 and 36-5 show CT scans of a patient with metastatic pulmonary lesions. Notice that the lesions visible in Figure 36-4 do not appear in Figure 36-5, which indicates a lack of calcification. The abdomen and retroperitoneum were originally evaluated by intravenous pyelograms (IVPs) to look for evidence of displacement of the kidneys or ureters by retroperitoneal masses. The CT scan made it possible to much more accurately evaluate the abdominal viscera and retroperitoneum. There has been some debate related to the size threshold of retroperitoneal lymph nodes that is considered abnormal and likely to represent metastases. Many authors have picked a 1-cm threshold in evaluating retroperitoneal lymph nodes. Using this criterion, the sensitivity has been reported at approximately 70%. The specificity has been approximately 94%.7 Liebovitch and his associates at Indiana reported setting their size threshold at 3 mm for lymph nodes that are in the areas most likely to have nodal metastases and kept the 1-cm threshold for any other adenopathy. This increased the sensitivity to 91% but decreased the specificity to 52%.8 Using CT techniques, the sensitivity will most likely not rise about 75% because approximately 25% of patients who have normal imaging studies and still undergo surgical staging will have microscopic or small volume macroscopic retroperitoneal metastases.9 Figure 36-6 shows typical CT findings in a patient with low volume retroperitoneal lymphadenopathy, while Figure 36-7 shows higher volume retroperitoneal disease. MRI scan and PET scan have been tried in evaluation of patients with testicular cancer.7,10 As of this time, neither of these techniques offer significant advantages over CT scans in terms of initial staging of patients.
Patients should be carefully examined for adenopathy (inguinal, axillary, or cervical). The physician needs to check for neck, abdominal, or scrotal masses. The contralateral testis should be examined with great care for any possible intratesticular masses. Scrotal ultrasound is again very helpful in evaluating the contralateral testis. Clinical Stage Designations Assigning a clinical stage requires consideration of the pathologic T stage (see Table 36-2), the clinical N stage (Table 36-3), the clinical M stage (Table 36-4), and the S stage (Table 36-5).6 The T stage is based on the pathologic findings from the orchiectomy specimen. The clinical regional node stage (N) is based on imaging studies of the abdomen and pelvis. The distant metastases stage (M) is assigned based on evidence from imaging studies as well. The serum marker stage (S) is determined by the preorchiectomy marker determinations for the initial clinical staging.6 The pT, N, M, and S data are used to assign the patient to a clinical stage group as shown in Table 36-6. These clinical stage groups are used as a basis for treatment recommendations and outcomes analysis. TOOLS OF TREATMENT The various treatment modalities for testis cancer, including observation, are presented in the following prior to specific treatment recommendation for the clinical stage groups. Observation In patients with a low risk for nodal or metastatic disease, observation may be appropriate. The criteria for observing patients who present with localized testicular cancer are shown in Table 36-7. Primary tumor stage and cell types present along with the cell type proportions are used along with imaging study findings and marker levels to determine eligibility for observation. Table 36-8 presents the tests and examinations recommended for use in patients who will have observation as their primary treatment modality. The frequency recommended for tests and examinations decreases with time since the risk of recurrence diminishes with time. Primary Retroperitoneal Lymph Node Dissection: Surgical Staging and Treatment RPLND techniques have undergone significant evolution over the last 40 years. In the 1960s the concept of
Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 601
Figure 36-4 Chest x-ray of a patient who presented with hemoptysis from metastatic testicular cancer.
“more is better” prevailed and the limits of RPLND were extended. Figure 36-8 illustrates the limits of dissection that were established.11 The dissection was performed in an en bloc style from the diaphragm to the level of the bifurcation of the common iliac arteries and laterally from ureter to ureter. The ipsilateral gonadal vessels were removed completely. Although this dissection was performed safely with low morbidity and mortality rates, virtually all patients lost their ability to have ejaculatory
fluid emission secondary to the removal of the postganglionic sympathetic nerve fibers that traversed the field of dissection. In the 1980s efforts were made to preserve emission in patients first by modifying the templates of dissection based on the knowledge of the distribution of positive lymph nodes in patients with low volume metastatic disease.12,13 Figures 36-9 and 36-10 show the limits of dissection generally adopted for low-stage (stage I or stages IIA and IIB)
602
Part VI Testis
Figure 36-5 CT scan of chest of patient with metastases to the lungs (arrows) from a primary testicular cancer.
disease with right- and left-sided primary tumors, respectively. The dissections within the limited templates were still performed with the en bloc technique. This offered preservation of the contralateral sympathetic systems. The success rates at preserving emission were greater on rightsided dissection than on the left-sided dissection. Later in the 1980s and early 1990s a prospective nerve-sparing technique was developed and adopted using the modified templates. A better understanding of the anatomy of the lumbar sympathetic nerves allowed this technique to be applied very successfully in terms of preservation and maintenance of the efficacy of the dissection as measured by continued low tumor relapse rates.14,15 Figure 36-11 shows a diagram of the lumbar sympathetics and the postganglionic branches as would be seen in a right-sided modified template dissection. The postganglionic fibers are best identified as they emerge under the medial edge of the vena cava in the interaortocaval zone. Figure 36-12 shows the typical arrangements of the left lumbar sympathetic fibers as they travel anteriorly and caudally onto the aorta. These
nerves are best identified by dissecting along the posterior body wall from lateral to medial until the lumbar sympathetic chain is identified. The use of these prospective nerve-sparing techniques has resulted in preservation of emission in almost all patients.16 A laparoscopic approach to RPLND (LRPLND) for low-stage disease was first performed in 1992 by two European groups.17,18 These series reported favorable initial results for conversion to open procedures, 1/34 and 2/125, respectively.17,18 After the learning curve had been overcome, the mean operating times were 248 minutes in Rossweiler’s series, 219 minutes for clinical stage I patients in Jauetschek’s series for clinical stage I patients, and 226 minutes for clinical stage IIB patients. In both series together there was only one retroperitoneal recurrence. Ogan et al.19 compared the cost of LRPLND versus open RPLND. Open RPLND was less costly at $7162 than LRPLND at $7804 for operative costs. LRPLND showed a cost advantage for hospital stay costs. If an LRPLND patient’s surgery took under 5 hours and his
Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 603
Figure 36-6 Abdominal CT scan of a patient with a prominent small interaortocaval lymph node consistent with metastatic testicular cancer.
hospital stay was less than 2.2 days, the overall cost of LRPLND was less than open surgery. With the increase in the number of surgeons performing laparoscopic surgery, more patients will have the opportunity to be treated laparoscopically. It should be noted, however, that LRPLND is an advanced laparoscopic procedure that should only be performed by advanced laparoscopists. The AJCC has defined classifications for pathologic nodal status that are valuable for planning the treatment for patients and assessing results of these treatments. Table 36-9 shows these definitions. Postchemotherapy RPLND Generally, patients with bulky retroperitoneal disease (stage IIc) or disseminated disease (stages IIIA to IIIC) are treated initially with systemic chemotherapy. Surgical resection is usually used in those patients who do not achieve a complete response to chemotherapy to resect
any residual disease apparent on physical examination or imaging studies. Once gross nodal involvement occurs, retrograde lymphatic flow can occur with the subsequent spread of tumor to nodes that would not ordinarily be involved. As a result the limits of dissection are usually those of the full bilateral template (see Figure 36-8). Depending on the location of nodal involvement noted on imaging studies, the nervesparing technique may be used in zones where no obvious nodal involvement has occurred. When a contralateral zone can be dissected with a nerve-sparing technique, up to 89% of the patients can have preservation of emission.20 Laparoscopic postchemotherapy RPLND (LPCRPLND) has been reported by Palese et al.21 Five of 7 patients had successful completion of laparoscopic procedures. Two required conversion to open surgery. There were 3 cases with major complications and 1 with minor complications. The authors concluded that LPCRPLND should be attempted only in selected patients with small volume radical masses.
604
Part VI Testis
Figure 36-7 Abdominal CT scan of a patient with bulky retroperitoneal metastases (stage IIC), which compresses the vena cava.
Table 36-3 Clinical Regional Node Stage (N) NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis with a lymph node mass 2 cm or less in greatest dimension; or multiple lymph nodes, none more than 2 cm in greatest dimension
N2
N3
Table 36-4 Distant Metastases (M) MX
Distant metastasis cannot be assessed
Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or multiple lymph nodes, any one mass greater than 2 cm but not more than 5 cm in greatest dimension
M0
No distant metastasis
M1
Distant metastasis
M1a
Nonregional nodal or pulmonary metastasis
Metastasis with a lymph node mass more than 5 cm in greatest dimension
M1b
Distant metastasis other than to nonregional lymph nodes and lungs
These nodal stages are based on imaging studies.
Evidence of metastases is based on imaging studies.
Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 605
Table 36-5 Serum Marker Status (S)
Table 36-7 Criteria for Primary Observation
SX
Marker studies not available or not performed
Primary tumor: pT1
S0
Marker study levels within normal limits
S1
LDH < 1.5 × N* AND hCG (mIU/ml) < 5000 AND AFP (ng/ml) < 1000
AFP, B-hCG: normal or return to normal after or orchiectomy
S2
S3
Embryonal carcinoma component ≤ 40% No teratomatous elements
LDH 1.5 – 10 × N OR hCG (mIU/ml) 5000–50,000 OR AFP (ng/ml) 1000-10,000
No choriocarcinoma No nodal or metastatic masses by imaging studies (N0, M0)
LDH > 10 × N OR HCG (mIU/ml) > 50,000 OR AFP (ng/ml) > 10,000
*N indicates the upper limit of normal for the LDH assay.
Chemotherapy Primary Short Course or Adjuvant Chemotherapy for Low-Stage Disease (Stages I, IIA and IIB)
Table 36-6 Clinical Stage Groups Stage 0
pTis
N0
M0
S0
Stage 1
PT1–4
N0
M0
SX
Stage IA
pT1
N0
M0
S0
Stage IB
pT2 pT3 pT4
N0 N0 N0
M0 M0 M0
S0 S0 S0
Stage IS
Any pT/Tx
N0
M0
S1–3
Stage II
Any pT/Tx
N1–3
M0
SX
Stage IIA
Any pT/Tx Any pT/Tx
N1 N1
M0 M0
S0 S1
Stage IIB
Any pT/Tx Any pT/Tx
N2 N2
M0 M0
S0 S1
Stage IIC
Any pT/Tx Any pT/Tx
N3 N3
M0 M0
S0 S1
Stage III
Any pT/Tx
Any N
M1
SX
Stage IIIA
Any pT/Tx Any pT/Tx
Any N Any N
M1a M1a
S0 S1
Stage IIIB
Any pT/Tx Any pT/Tx
N1–3 Any N
M0 M1a
S2 S2
Stage IIIC
Any pT/Tx Any pT/Tx
N1–3 Any N
M0 M1a
S3 S3
Any N
M1b
Any S
Any pT/Tx
Primary chemotherapy has been a treatment option for patients with clinical stages I, IIA, or IIIB. Since 1985, two cycles of bleomycin, etoposide, and cisplatin (BEP) have been the standard therapy in this setting.22-24 Schefer et al.25 reported a trial of a single course of BEP for high-risk stage I NSGCTT. In the adjuvant setting, the Indiana group has reported on 86 patients receiving 2 courses of BEP after RPLND for pN1 disease or pN2 disease.22 Kondagunta and Motzer26 published the Memorial Sloan-Kettering Cancer Center experience using cisplatin and etoposide (EP) as adjuvant treatment for pN2 patients. Primary Chemotherapy for High-Stage Disease The addition of cisplatin to Velban and bleomycin (PVB) revolutionized the treatment of metastatic testicular cancer in 1974.27 The standard treatment of metastatic testicular cancer changed to cisplatin, etoposide, and bleomycin (BEP) in 1984 after a randomized trial showed that the BEP treatment was more effective and had a lower rate of toxicity.28 The next area to be studied was trying to reduce the intensity of chemotherapy to reduce toxicity while maintaining efficacy. In order to be able to do this effectively, a system for stratification of the risk level of patients with high-stage tumors was needed. Several attempts were made to define the risk categories. Starting in 1991 an international group, the International Germ Cell Cancer Cooperative Group (IGCCCG), was started. In 1997 this group published its validated definitions of good prognosis, intermediate prognosis, and poor prognosis groups.29 The definitions of the groups for NSGCTs are shown in Table 36-10. These groups are often equated to minimal risk, moderate risk, and high risk for the patients. Treatment choices are frequently made on the basis of
606
Part VI Testis
Figure 36-8 Drawing of the margins of dissection for a full bilateral RPLND. The hatched areas represent the right and left suprahilar zones, which are removed en bloc with the interaortocaval zone and left periaortic zone, respectively.
minimal-to-moderate risk categories versus high-risk categories. Second-Line or Salvage Chemotherapy For patients who did not achieve a complete response with primary chemotherapy and still had positive markers, salvage or second-line chemotherapy was tried. EP was tried starting in 1978 at Indiana for salvage treatment.30 From
1984 to 1989, vinblastine, ifosfamide, and cisplatin were used at Indiana for second-line therapy.31 Motzer et al.32 reported the use of 4 courses of paclitaxel, ifosfamide, and cisplatin (TIP) for second-line chemotherapy.32 Hinton et al.33 have reported a phase II Eastern Cooperative Oncology Group (ECOG) trial of paclitaxel and gemcitabine in refractory germ cell tumors. High-dose chemotherapy with antologous bone marrow transplantation was tried at Indiana University
Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 607
Figure 36-9 Modified template for an en bloc or prospective nerve-sparing RPLND for a patient with a right-sided tumor.
between 1986 and 1989. Broun et al.34 reported the use of high-dose carboplatin and etoposide with bone marrow transplant rescue.34 A more recent report using the same approach was made from the University of Michigan by Ayash et al.35 The use of paclitaxel in salvage regimens along with cisplatin and/or ifosfamide has been reported by Kollmannsberger et al.36 from Germany.36 Another new approach for salvage therapy was reported by Rick et al.37 from Berlin. They used 3 cycles of TIP followed by 1 cycle of high-dose carbo-
platin, etoposide, and thiotepa (CET).37 The patients had rescue with antologous stem-cell transplantation. There are several additional trials still in progress. TREATMENT BY STAGE This section will present treatment alternatives by clinical stage. The tools of treatment and general follow-up routines have been presented in the previous section. When results are available from several series and are
608
Part VI Testis
Figure 36-10 Modified template for an en bloc or prospective nerve-spring RPLND for a patient with a left-sided tumor.
similar, the percentages after various treatments or periods of observation will be given on the treatment option algorithms shown in Figures 36-13 to 36-15. Clinical Stage I For patients with clinical stage IA, there are three possible choices: observation, primary RPLND, or short course primary chemotherapy (see Figure 36-13). The criteria for observation are given in Table 36-7. The suggested followup testing for observation is shown in Table 36-8. Overall
approximately 70% of patients observed for clinical stage IA disease will remain disease free. Approximately 30% will relapse over a 4-year period. Most relapses will occur within the first year and nearly 90% within 2 years. Patients on observation who relapse are treated based on their stage at relapse. Those who relapse with stage IIA disease or stage IIB disease are treated as shown in Figure 36-14, while those with stage IIC disease or stage III disease are treated as shown in Figure 36-15. Stage IA patients may also be treated by RPLND (modified template-nerve-sparing technique if fertility is
Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 609
Figure 36-11 A view of the interaortocaval zone with the patient’s head to the right. Note the right-sided postganglionic sympathetic nerve branches emerge from under the vena cava obliquely in a caudal-anterior direction onto the anterior surface of the aorta. The branches usually are located just cephalad to the lumber (suture around one).
Figure 36-12 A view of the right and left lumbar sympathetic trunks and the postganglionic branches with the patient’s head to the right. Branches from each side join at the hypogastric plexus around the origin of the inferior mesenteric artery. Branches from the hypogastric plexus cross the area of the bifurcation of the aorta and travel caudally to the pelvic plexus.
610
Part VI Testis
Table 36-8 Primary Observation Schema Year 1
Year 2
Years 3–4
Years = 5
Serum markers
Monthly
Bimonthly
Biannually
Annually
Chest x-ray
Monthly
Bimonthly
Biannually
Annually
CT scans (chest, abdomen, and pelvis)
Quarterly
Semiannually
Annually
—
Physical examination
Bimonthly
Every 4 months
Biannually
Annually
Table 36-9 Pathologic Nodal Stage (PN) pNX
Regional lymph nodes cannot be assessed
pN0
No regional lymph node metastasis
pN1
Metastasis with a lymph node mass 2 cm or less in greatest dimension and less than or equal to 5 nodes positive, none more than 2 cm in greatest dimension
pN2
Metastasis with a lymph node mass more than 2 cm but not more than 5 cm in greatest dimension; or more than 5 nodes positive, none more than 5 cm; or evidence of extranodal extension of tumor
pN3
Metastasis with a lymph node mass more than 5 cm in greatest dimension
Nodal status is determined from RPLND specimens.
Table 36-10 IGCCCG NSGCT Definitions Good prognosis Testis/retroperitoneal primary and No nonpulmonary visceral metastases and AFP < 1000 ng/ml and HCG < 5000 IU/1 and LDH < 1.5 × N* Intermediate prognosis
Testis/retroperitoneal primary and No nonpulmonary visceral metastases and AFP = 1000 and = 10,000 ng/ml and/or HCG = 5000 and = 50,000 IU/1 and/or LDH = 1.5 × N and = 10 × N
Poor prognosis Mediastinal primary or Nonpulmonary visceral metastases or AFP = 10,000 ng/ml and/or HCG = 50,000 IU/1 and/or LDH = 10 × N *N = upper limit of normal.
an issue) or primary short course chemotherapy. RPLND has been performed more in the United States, while chemotherapy has been used more frequently in Europe. For clinical stage IB patients, RPLND has been the more prevalent treatment and chemotherapy has been used less frequently in the U.S. In clinical stage IB, patients who have T4 disease, a hemiscrotectomy is also usually performed if it was not already completed as part of the radical orchiectomy. RPLNDs in clinical stages IA and IB patients yield negative lymph nodes in approximately 70% of the patients, while the remaining 30% have positive lymph nodes (pN1 or pN2) despite negative markers and imaging studies. Patients with clinical stage is used to be treated routinely with RPLND. Davis et al.38 recommended the use of primary chemotherapy instead of RPLND because of the high relapse rate after RPLND. In the last several years, the Indiana group has recommended primary chemotherapy in these patients.39 Primary chemotherapy for stages IA, IB, or S has low relapse and death rates (1% to 2% and <1%, respectively) for an overall progression-free long-term survival rate of about 97%.40 Most series involved 2 courses of BEP and several have used 3 courses of BEP. In an attempt to reduce toxicity, a single course of BEP has been, and is being, tried by several groups. A series by Corti et al.41 in 1997 reported no relapses in 18 stage I NSGCTT patients with 1 course of cisplatin-based chemotherapy with a median follow-up of 46.9 months. Studies by the German Testicular Cancer Study Group are on-going. The overall survival rates for patients with stage I NSGCTT is between 97% and 99% for observation series or primary chemotherapy and 98% to 100% in patients treated with primary RPLND. Long-term morbidity, mortality, and treatment-induced infertility are very low. Good results are, of course, predicated on reliable patients and compulsive medical caregivers. Clinical Stages IIA and IIB Clinical Stages IIA and IIB accounts for approximately 40% of NSGCTT patients at presentation. An algorithm for treatment of these patients is shown in Figure 36-14.
Treatment of clinical stages I NSGCIT (40%) Stage IA pT1
Stage IB pT 2−4
Stage IS pT 1−4
OR OR
OR
Primary RPLND with hemiscrotectomy for pT4 only
Observation
No relapse (70%)
relapse (30%)
Nodes (−) (70%)
Primary short course chemotherapy
Nodes (+) (30%)
Complete remission (97%)
Partial remission or progression (2-3%)
Observation (see Table 36-11)
PC-RPLND (see Figure 36−15 PC-RPLND arm
OR Adjuvant chemotherapy (see Figure 36-14 RPLND arm)
Observation (see Table 36-11)
Continued observation (see Table 36-8)
IIA,B (see figure 14)
IIC,III (see figure 15)
Figure 36-13 Schematic drawing of the treatment options and stratifications based on tumor or marker parameters for clinical stage I NSGCTT.
Treatment of clinical stages II A and B (40%)
Chemotherapy (2−4 courses)
OR
RPLND
Complete remission (67%)
Partial remission, no response, or progression (33%)
Nodes (−) markers (−)
Nodes (+)
Observation (see Table 36-11)
PC-RPLND (see Figure 36-15 PC-RPLND arm)
Observation (see Table 36-15)
Post-Op markers (+)
Post-Op markers (−)
OR Adjuvant chemotherapy (3-4 courses)
Observation
Figure 36-14 Schematic drawing of treatment options and stratifications based on tumor and marker parameters for patients with stages IIA and IIB NSGCTT.
Adjuvant chemotherapy (2 courses)
612
Part VI Testis
Treatment of clinical stages II C and III (20%) Primary chemotherapy
CR (70%)
PR (30%)
Observation
Markers (+)
Markers (−) Relapse (10%)
Localized disease
Diffuse disease
OR
Post-chemo, RPLND Surgical resection (RPLND +/− thoracotomy)
Scar (44%)
Teratoma (44%)
Bone marrow transplant (BMT)
Salvage chemo
Cancer (12%)
Complete resection
Incomplete resection
Observations (see Table 12)
OR Salvage chemotherapy
Observation
BMT
PR
CR
BMT
Observation
Figure 36-15 Schematic drawing of treatment options and stratifications based on tumor and marker parameters for patients with stage IIC/stage III NSGCTT.
Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 613
There are two main treatment pathways or options: primary chemotherapy and primary RPLND. As in clinical stage I, primary chemotherapy is favored more in Europe, while primary RPLND is favored in the U.S. Primary chemotherapy usually consists of 2 to 4 courses of cisplatin-based multiagent treatment. Horwich et al.42 reported 122 patients with stage IIA or stage IIB NSGCTT treated with 4 courses of cisplatinbased combination chemotherapy. Overall 97% of the patients were disease free with a median follow-up of 5.5 years. In stage IIA patients, 17% required a PC-RPLND, while 39% of stage IIB patients required this surgery. In a randomized trial by the German Testicular Cancer Study Group, 87 patients received primary chemotherapy with 3 courses of BEP or carboplatin, etoposide and bleomycin (CEB). Two-thirds achieved complete remission (CR) with chemotherapy alone, while one-third required PC-RPLND. With a 3-year follow-up, 11% total in this arm relapsed.43 The patients treated with primary chemotherapy for stage IIA disease or stage IIB disease that achieve a CR can be followed using the same schedule as primary RPLND follow-up as shown in Table 36-11. Those patients requiring PC-RPLND are treated as shown on the PC-RPLND arm of Figure 36-15 and follow as shown in Table 36-12. Primary RPLND has been the predominant treatment of stages IIA and IIB NSGCTT in the U.S. for the last 4 decades. The templates for dissection and the dis-
section techniques have evolved over this time period as presented in the section “Tools of Treatment.” In those patients with a desire to remain fertile, the modified template, prospective nerve-sparing technique is the usual treatment. Sometimes the dissection is extended to a bilateral template in the presence of medium volume nodal disease (2 to 5 cm). Emission is preserved in nearly all patients in whom the nerve-sparing technique is employed. Operative complication rates run in the range of 8% to 12%, the reoperation rate is about 1% and the operative and postoperative mortality rate is approximately 0.25%. In those patients with pathologically negative nodes (pN0), observation is appropriate with a follow-up schedule as shown in Table 36-11. The overall relapse rate in pN0 patients is in the range of 7% to 12% with retroperitoneal recurrences within the field of dissection being about 1%. For patients who have pathologically positive lymph nodes (pN+), there are two options: observation or adjuvant chemotherapy. Relapse in patients with pathologically positive nodes is related to nodal tumor volume. In those patients with pN1 tumors, the relapse rate is in the range of 15% to 20%. For patients with pN2 tumors, the relapse rate runs between 30% and 50%, while it is 50% to 90% in patients with pN3 tumors. Most centers that treat testicular cancer tailor the recommendations for adjuvant chemotherapy based on the risk of recurrence, which is related to the pN stage as
Table 36-11 Follow-Up After Primary RPLND Year 1
Year 2
Years 3–4
Years = 5
Serum markers
Monthly
Bimonthly
Semiannually
Annually
Chest x-ray
Monthly
Bimonthly
Semiannually
Annually
CT scans (chest, abdomen, and pelvis)
None*
None*
None*
None*
Physical examination
Bimonthly
Every 4 months
Semiannually
Annually
*CTs are needed for patients with teratoma in the nodes or with cancer in the nodes and normal serum markers using the same schedule as shown in Table 36-8.
Table 36-12 Follow-Up After Postchemotherapy RPLND Pathology—Necrosis Only Year 1
Year 2
Years 3–4
Years = 5
Serum markers
Bimonthly
Every 4 months
Biannually
Annually
Chest x-ray
Bimonthly
Every 4 months
Biannually
Annually
CT scans (chest, abdomen, and pelvis)
None
None
None
None
Physical examination
Every 4 months
Biannually
Biannually
Annually
Pathology—teratoma or cancer without serum marker elevation—as earlier and add CT scans as in Table 36-8.
614
Part VI Testis
shown earlier. When adjuvant therapy is used, it usually consists of 2 courses of BEP or EP.26,44 Subsequent relapse rates are around 1%. Overall treatment mortality rates are less than 1%. If patients had pathologically positive lymph nodes pN+ and positive postoperative markers, full course chemotherapy is given. The same applies for pN0 patients who relapse after observation. The overall cure rate for stages IIA and IIB patients using the treatment scheme shown in Figure 36-14 is 97% to 99%. Clinical Stage IIC and/or Stage III Based on the very high recurrence rate for patients with stage IIC/stage III NSGCTT after RPLND, these patients have been treated with primary chemotherapy first since combination cisplatin-based treatment became available in the mid-1970s to late 1970s. Figure 36-15 shows how these patients are usually treated. Approximately 70% of patients with stage IIC/stage III disease will achieve a CR after 3 or 4 courses of BEP or similar combination. Fortunately, 90% of these CR patients will enjoy a durable response, while 10% will relapse. About 30% of the patients with stage IIC/stage III disease will only achieve a partial response (PR). This group of patients and the patients who relapse after a primary chemotherapy CR are stratified for further treatment by marker status. If the serum markers are negative, the patients have a PC-RPLND without/with additional surgical procedures to clear the retroperitoneum using the full bilateral template as shown in Figure 36-8 and remove any other metastases in the chest or neck. The majority of these patients will only require the PC-RPLND. Patients who have a PC-RPLND for a PR after primary chemotherapy have a 44% incidence of necrosis only, a 44% incidence of teratoma, and a 12% chance of active cancer in the tissue removed. Patients those have necrosis only and/or teratoma can be observed as per Table 36-12. If active cancer is found in the tissue removed at PC-RPLND, patients are stratified by complete or incomplete surgical resections. For those patients in whom complete resection was possible, observation as shown on Table 36-11 is used. If tumor resection was incomplete, patients are treated by salvage chemotherapy (often VIP) or high-dose chemotherapy with autologous bone marrow transplantation based on the good-to-moderate or poor prognosis status as defined by the IGCCCG classification shown in Table 36-10. For patients who were treated with primary chemotherapy and had a PR with persistently positive markers, treatment is determined by the imaging studies. If a
patient has a well-localized disease and all abnormal areas are respectable, a surgical approach is taken. This may require procedures in addition to the PC-RPLND, such as a thoracotomy or cervical lymph node dissection. Depending on the extent of disease, the procedures may need to be performed in more than one sitting. In these same circumstances, the patients with positive markers after a PR from primary chemotherapy are treated with either salvage chemotherapy or high-dose chemotherapy with autologous bone marrow transplantation. The choice of treatment approach is again usually determined based on the IGCCCG prognosis classifications as discussed earlier. Fortunately, the patients who present with stage IIC/stage III account for only 20% of all patients with NSGCTT. A high percentage of patients enjoy a durable CR with primary chemotherapy [70% CR minus 10% of these with relapse (7%) = 63%]. Approximately 75% of patients who are treated with PC-RPLND after PR or relapse after chemotherapy will have a long-term survival without or with salvage or high-dose chemotherapy and autologous bone marrow transplantation. This yields a long-term survival or “cure” rate for stage IIC/stage III of approximately 90%, which is a dramatic improvement before the era of cisplatin-based chemotherapy. SUMMARY The treatment of NSGCTT has changed markedly over the last 4 decades. The morbidity and mortality from treatment have decreased in this same period, while survival rates have increased for all stages of disease. There are ongoing efforts to further reduce the amount and severity of treatment used for this disease. The preservation of fertility for these patients through modifications in surgical techniques and the intensity of chemotherapy has been a major area of progress. Careful reporting of results, complications, late recurrences, and the development of secondary malignancies will be important in guiding future modifications of treatment schemes for this disease.
REFERENCES 1. Patton JF, Hewitt CB, Mallis N: Diagnosis and treatment of tumors of the testis. JAMA 1959; 171:2194. 2. Johnson DE: Epidemiology. In Johnson DE (ed): Testicular Tumors, 2nd edition, p 37. Flushing, NY, Medical Examination Publishing, 1976. 3. Weissbach L, Bussar-Maatz R, Mann K: The value of tumor markers in testicular seminomas. Results of a prospective multicenter study. Eur Urol 1997; 32(1):16–22. 4. Gomes PJ, Rustin GJ: Attempted preservation of one gonad in patients with bilateral germ cell tumours. Clin Oncol (R Coll Radiol) 1996; 8(6):397–399.
Chapter 36 Nonseminomatous Germ Cell Tests Tumors: Management and Prognosis 615 5. Heidenreich A, Weissbach L, Holtl W, et al: Organ sparing surgery for malignant germ cell tumor of the testis. 2001; 166(6):2161–2165. 6. AJCC. Cancer Staging Handbook, 6th edition. New York, Springer, 2002. 7. Cremerius U, Wildberger JE, Borchers H, et al: Does positron emission tomography using 18-fluoro-2deoxyglucose improve clinical staging of testicular cancer? Results of a study in 50 patients. Urology 1999; 54(5):900–904. 8. Leibovitch I, Foster RS, et al: Identification of clinical stage A nonseminomatous testis cancer patients at extremely low risk for metastatic disease: a combined approach using quantitive immunohistochemical, histopathologic, and radiologic assessment. J Clin Oncol 1998; 16(1):261. 9. Hermans BP, Sweeney CJ, Foster RS, et al: Risk of systematic metastases in clinical stage I nonseminoma germ cell testis tumor managed by retroperitoneal lymph node dissection. J Urol 2000; 163:1721–1724. 10. Hogeboom WR, Hoekstra HJ, Mooyaart EL, et al: Magnetic resonance imaging of retroperitoneal lymph node metastases of non-seminomatous germ cell tumours of the testis. Eur J Surg Oncol 1993; 19(5):429–437. 11. Donohue JP: Surgery for testis cancer: a changing perspective. Proc Inst Med Chic 1980; 33(2):42. 12. Pizzocaro G, Salvioni R, Zononi F: Unilateral lymphadenectomy in intraoperative stage I NSGCT. J Urol 1985; 134:485–489. 13. Richie JP: Modified retroperitoneal lymphadenectomy for patients with clinical stage I testicular cancer. Semin Urol 1988; 6:216–222. 14. Jewett MA, Kong YS, Goldberg SD, et al: Retroperitoneal lymphadenectomy for testis tumor with nerve sparing for ejaculation. J Urol 1988; 139(6):1220–1224. 15. Donohue JP, Foster RS, Rowland RG, et al: Nerve-sparing retroperitoneal lymphadenectomy with preservation of ejaculation. J Urol 1990; 144(2 Pt 1): 287–291. 16. Donohue JP, Thornhill JA, Foster RS, et al: Retroperitoneal lymphadenectomy for clinical stage A testis cancer (1965 to 1989): modifications of technique and impact on ejaculation. J Urol 1993; 149(2):237. 17. Rassweiler JJ, Frede T, Lenz E, et al: Long-term experience with laparoscopic retroperitoneal lymph node dissection in the management of low-stage testis cancer. Eur Urol 2000; 37(3):251–260. 18. Janetschek G, Peschel R, Hobisch A, Bartsch G: Laparoscopic retroperitoneal lymph node dissection. J Endourol 2001; 15(4):449–453. 19. Ogan K, Lotan Y, Koeneman K, et al: Laparoscopic versus open retroperitoneal lymph node dissection: a cost analysis. J Urol 2002; 168(5):1945–1949. 20. Jacobsen KD, Ous S, Waehre H, et al: Ejaculation in testicular cancer patients after post-chemotherapy retroperitoneal lymph node dissection. Br J Cancer 1999; 80:249–255. 21. Palese MA, Su LM, Kavoussi LR: Laparoscopic retroperitoneal lymph node dissection after chemotherapy. Urology 2002; 60(1):130–134. 22. Behnia M, Foster R, Einhorn LH, et al: Adjuvant bleomycin, etoposide and cisplatin in pathological stage II
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
non-seminomatous testicular cancer. The Indiana University experience. Eur J Cancer 2000; 36(4):440–442. Amato R, Banks E, Ro J, Swanson DA: Postorchiectomy adjuvant chemotherapy for patients with clinical stage I non-seminomatous germ cell tumors of the testis (NSGCTT) at high risk for relapse. Proc ASCO 18:157. Studer UE, Burkhard FC, Sonntag RW: Risk adapted management with adjuvant chemotherapy in patients with high risk clinical stage I nonseminomatous germ cell tumor. J Urol 163:1785–1787. Schefer H, Mattmann S, Borner M, et al: Single course adjuvant bleomycin, etoposide, and cisplatin (BEP) for high risk stage I non-seminomatous germ cell tumors (NSGCT). Proc ASCO 2000; 19:340a. Kondagunta GV, Motzer RJ: Adjuvant chemotherapy for stage II nonseminomatous germ-cell tumors. Semin Urol Oncol 2002; 20(4):239–243. Einhorn LH, Donohue J: Cis-diamminedichloroplatinum, vinblastine, and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern Med 1977; 87(3):293–298. Williams SD, Birch R, Einhorn LH, et al: Treatment of disseminated germ-cell tumors with cisplatin, bleomycin, and either vinblastine or etoposide. N Engl J Med 1987; 316(23):1435–1440. The International Germ Cell Cancer Collaborative Group: International germ cell consensus classification: a prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 1997; 15:594–603. Williams SD, Einhorn LH, Greco FA, et al: VP-16-213 salvage therapy for refractory germinal neoplasms. Cancer 1980; 46(10):2154–2158. Loehrer PJ Sr, Gonin R, Nichols CR, et al: Vinblastine plus ifosfamide plus cisplatin as initial salvage therapy in recurrent germ cell tumor. J Clin Oncol 1998; 16:2500–2504. Motzer RJ, Sheinfeld J, Mazumdar M, et al: Paclitaxel, ifosfamide, and cisplatin second-line therapy for patients with relapsed testicular germ cell cancer. J Clin Oncol 2000; 18:2413–2418. Hinton S, Catalano P, Einhorn LH, et al: Phase II study of paclitaxel plus gemcitabine in refractory germ cell tumors (E9897): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol 2002; 20(7):1859–1863. Broun ER, Nichols CR, Kneebone P, et al: Long-term outcome of patients with relapsed and refractory germ cell tumors treated with high-dose chemotherapy and autologous bone marrow rescue. Ann Intern Med 1992; 117(2):124–128. Ayash LJ, Clarke M, Silver SM, et al: Double doseintensive chemotherapy with autologous stem cell support for relapsed and refractory testicular cancer: the University of Michigan experience and literature review. Bone Marrow Transplant 2001; 27(9):939–947. Kollmannsberger C, Mayer F, Kuczyk M, et al: Treatment of patients with metastatic germ cell tumors relapsing after high-dose chemotherapy. World J Urol 2001; 19(2):120–125. Rick O, Bokenmeyer C, Beyer J, et al: Salvage treatment with paclitaxel, ifosfamide, and cisplatin plus high-dose
616
Part VI Testis
carboplatin, etoposide, and thiotepa followed by autologous stem-cell rescue in patients with relapsed or refractory germ cell cancer. J Clin Oncol 2001; 19:81–88. 38. Davis BE, Heu HW, Fair WR, Bosl GJ: The management of patients with nonseminomatous germ cell tumors of the testis with serologic disease only after orchiectomy. J Urol 1994; 152:111–113. 39. Saxman SB, Nichols CR, Foster RS, et al: The management of patients with clinical stage I nonseminomatous testicular tumors and persistently elevated serologic markers. J Urol 1996; 155(2):593–594. 40. Albers P, Perabo FGE, Melchior D, Siener R: Adjuvant chemotherapy in stage I and stage II testicular cancer. World J Urol 2001; 19:76–81.
41. Corti OD, Foneron BA, Troncoso SL: Treatment of stage I nonseminomatous testicular cancer with one cycle of adjuvant chemotherapy. Actas Urol Esp 1997; 21:961–963. 42. Horwich A, Norman A, Fischer C, et al: Primary chemotherapy for stage II nonseminomatous germ cell tumors of the testis. J Urol 1994; 151(1):72–77. 43. Weissbach L, Bussar-Maatz R, Flechtner H, et al: RPLND or primary chemotherapy in clinical stage IIA/B nonseminomatous germ cell tumors? Results of a prospective multicenter trial including quality of life assessment. Eur Urol 2000; 37(5):582–594. 44. Williams SD, Stablein DM, Einhorn LH, et al: Immediate adjuvant chemotherapy versus observation with treatment at relapse in pathological stage II testicular cancer. N Engl J Med 1987; 317:1433–1438.
C H A P T E R
37 Nongerm Cell Tumors of the Testis Aaron J. Milbank, MD, Howard S. Levin, MD, and Eric A. Klein, MD
Nongerm cell tumors of the testis comprise a heterogeneous group of benign and malignant neoplasms, which may be primary or metastatic. As a group they account for only 5% to 6% of all testicular neoplasms, the remaining testicular tumors being of germ cell origin (Figure 37-1). The most commonly occurring primary tumors of nongerm cell origin are classified as sex cord/stromal tumors or tumors of specialized gonadal stroma. These tumors may be associated with somatic or constitutional chromosomal syndromes. Other less commonly encountered primary tumors include mesenchymal tumors from nonspecialized stroma, such as blood vessels or smooth muscle, tumors arising from hematopoietic cells, and a multitude of other benign tumors, which mimic malignant lesions. In addition, a number of malignancies from other sites may rarely present initially in the testis or as a late sign of more diffuse disease. Certain populations are at higher risk for the development of germ cell and nongerm cell testis tumors; multiple cases of malignant lymphoma (ML) and malignant germ cell tumors in patients with the acquired immune deficiency syndrome and other forms of immunosuppression have been reported.1,2 A useful practical classification of nongerm cell testicular tumors is presented in Table 37-1. Most primary tumors of nongerm cell origin are biologically benign. The clinical presentation of these tumors is similar to, and often indistinguishable from, those of germ cell origin. Common presenting symptoms include testicular pain and enlargement, which may be of prolonged duration. Breast tenderness or enlargement may also be present. Physical examination typically confirms the presence of testicular swelling or intratesticular mass. Most primary nongerm cell tumors appear as discrete hypoechoic lesions on ultrasonography, while leukemic or lymphomatous infiltration demonstrate enlargement with multiple focal or diffuse areas of decreased echogenicity. The presence of diffuse unilat-
eral or bilateral testicular enlargement, rather than a discrete mass on physical examination or scrotal ultrasonography, suggests a secondary rather than primary neoplasm. Peripheral lymphadenopathy is rare with primary nongerm cell tumors and should prompt a search to exclude a primary tumor from another site, notably lymphoma. Gynecomastia, loss of libido or other signs of feminization may be present with some tumors (notably Leydig or Sertoli cell tumors) due to active secretion of estrogens, alterations in serum estrogen/testosterone ratios or peripheral aromatization of testosterone.3 Serum levels of human chorionic gonadotropin hCG and alpha fetoprotein (AFP) will be normal. All of these clinical features may also be present with primary germ cell tumors, and histologic examination of the affected testicle is the sine qua non for distinguishing these tumor types and determining the need for further evaluation and treatment. In adults with a palpably normal opposite testis, inguinal orchiectomy without frozen section is considered standard therapy. Occasionally a nongerm cell tumor or other benign process may be strongly suspected based on presenting signs and symptoms and/or the ultrasonographic appearance of the lesion. In these cases and in patients with a solitary testis or atrophic contralateral testis, inguinal exploration and excisional biopsy with the intent of sparing the uninvolved ipsilateral testis should be considered. In such instances, frozen section examination (FSE) of the excised tumor is necessary to exclude the presence of malignancy. Elert et al.4 recently retrospectively reviewed their experience with 354 patients who underwent inguinal exploration, isolation of the testicle, and biopsy with FSE. With respect to malignant versus benign, FSE correctly categorized all lesions. Within the malignant category, 9% of the tumors were incorrectly identified (nonseminoma versus seminoma or vice versa), a finding which did not affect the intraoperative management. In all such cases, the
617
618
Part VI Testis
Figure 37-1 Embryologic origin of testis tumors.
Table 37-1 Classification of Nongerm Cell Testicular Tumors Tumors of Specialized Stroma
Tumors of Generalized Stroma
Hematologic Tumors
Miscellaneous Tumors
LCT
Vascular tumors
Lymphoma
Carcinoid
Sertoli cell tumor
Smooth and skeletal muscle tumors
Leukemia
Epidermoid cyst
Plasmacytoma
Adenocarcinoma of the rete testis
Granulosa cell tumor Mixed tumor
Adenomatoid tumor
Metastatic tumors
Incompletely differentiated tumors
Mesothelioma
Ovarian surface epithelial—type tumors
clinical aspects and topography of the mass should be shared with the pathologist. In cases with equivocal findings on frozen section, inguinal orchiectomy should be performed in patients with a normal contralateral testis. Frozen section is also useful in identifying MLs so that fresh tissue can be used for tumor phenotyping. A description of individual tumor types with characteristic clinical and pathologic features and recommendations for management follows.
PRIMARY TUMORS OF SEX CORD/STROMAL ORIGIN Leydig Cell Tumors Clinical Presentation Leydig cell tumors (LCTs) comprise approximately 1% to 3% of testicular tumors. They occur in males of all ages with predominance in children older than 4 and adults in the third to sixth decade. In prepubertal boys they produce isosexual precocity with penile enlarge-
Chapter 37 Nongerm Cell Tumors of the Testis 619
ment, sexual hair growth, increased bone growth, deepened voice, and aggressive behavior as a consequence of increased testosterone production by the neoplasm. Clinical signs and symptoms are usually manifest before the discovery of the neoplasm, which may be impalpable and difficult to detect with ultrasonography.5 In postpubertal males, LCTs usually present with a unilateral painless testicular mass or incidentally as a mass discovered during physical examination. Only 30% have signs of increased hormonal function, and in contrast to the prepubertal group affected adults exhibit feminization, with unilateral or bilateral gynecomastia, impotence, and hair loss.3 LCTs have been reported in cryptorchid testes before and after orchidopexy, in the contralateral testis of a 40-year old, 7 years after orchiectomy for a mixed malignant germ cell tumor, in association with Klinefelter’s syndrome and tuberous sclerosis, in the descended testicle of a man with contralateral cryptorchidism, and in multiple asymptomatic men presenting for evaluation of infertility.6–11 There is some evidence from animal studies that lack of regulation of steroid production/conversion may be etiologically associated with LCTs. Overexpression of aromatase has been shown to induce LCTs in transgenic mice.12 Activating mutations of the gene encoding the luteinizing hormone receptor have been described.13
10 cm in diameter (Figure 37-2). They may be bilateral.14 The microscopic appearance is variable with a spectrum of cell shapes extending from polygonal to spindled. Leydig cell nuclei are generally round with a small single nucleolus but binucleate, multinucleate, and giant cells with giant nuclei may be present (Figure 37-3). Mitotic figures are generally sparse. Cell cytoplasm is usually eosinophilic and sometimes ground glass in appearance but may be vacuolated depending on the amount of intracytoplasmic lipid. Approximately 40% of LCTs contain intracytoplasmic Reinke’s crystals. Lipochrome pigment may also be present in varying amounts. The tumor cells may grow in sheets, cords, and tubular formations. Capillaries are abundant between aggregates of epithelial cells. The stroma may be loose or dense and hyaline. The
Pathologic Characteristics The gross appearance of LCTs is characteristically mahogany or yellow-brown in color, rubbery, discrete, nonencapsulated, and nonnecrotic. LCTs vary considerably in size ranging from nonpalpable to more than
Figure 37-2 Benign LCT. Discrete nonencapsulated soft tan 2.2 cm mass in bivalved testis in 29-year-old man with left testicular mass and bilateral gynecomastia.
Figure 37-3 LCT. Twenty-year-old with enlarged testis. The testicular parenchyma was substantially replaced by a yellow-brown mass. The Leydig cells contain round uniform nuclei and eosinophilic granular cytoplasm (H&E × 31.2).
620
Part VI Testis
ultrastructural appearance resembles that of other steroid hormone-producing cells. LCTs stain positively for lipid. In tumors of prepubertal males seminiferous tubules adjacent to the neoplasm have shown response to local androgen manifested as proliferative activity of germinal epithelium with development to the spermatid stage.15 Seminiferous tubules in the contralateral testis and distant from the tumor in the ipsilateral testis typically retain prepubertal morphology. Conversely, in postpubertal men seminiferous tubules adjacent to feminizing LCTs show reduced spermatogenesis and thickening of the tunica propria. Approximately 10% of LCTs are malignant and over 30 such cases have been reported. Malignant LCTs are larger than benign LCTS have no clinical endocrine hyperfunction and have a shorter clinical duration prior to orchiectomy.16 The absolute criterion for malignancy of an LCT is metastasis, but other morphologic features that strongly suggest malignancy include large tumors, marked cellular anaplasia, frequent or atypical mitoses, infiltrating margin and necrosis16 (Figure 37-4). Invasion of lymphatics and/or blood vessels are also suggestive of malignancy (Figure 37-5). Cheville et al.17 retrospectively reviewed their experience with 30 LCTs, 23 without metastasis, and 7 with metastasis to identify predictors of malignancy. They found that the following features were significantly associated with metastatic behavior: presence of cytologic atypia, necrosis, angiolymphatic invasion, increased mitotic activity, atypical mitotic figures, infiltrative margins, extension beyond the testicular parenchyma, DNA aneuploidy, and increased MIB-1 activity. Tumors associated with metastasis tended to be larger (mean 4.7 cm versus 2.6 cm) and occur in older patients (mean age 62 years versus 48 years) than
Figure 37-4 Malignant LCT. Sixty-three-year-old man noted enlargement and soreness of the testis for 4 to 5 weeks. The testis measured 6 × 7 × 7 cm and was almost totally replaced by a bulging light tan to dark brown variegated mass with multiple apparent septae. (Photograph courtesy of California Tumor Tissue Registry.)
tumors not associated with metastasis. Metastases usually occur within months to years after the original diagnosis but initial metastasis has been recorded as late as 17 years after orchiectomy.18 In this latter case, the retroperitoneal metastasis exhibited sarcomatoid differentiation. Initial metastasis is usually to retroperitoneal lymph nodes, but subsequent metastases involve remote lymph nodes and possibly viscera. Benign LCTs generally have diploid DNA content whereas malignant LCTs generally have aneuploid DNA by flow cytometry.19,20 Ulbright et al.21 recently reported 19 cases of LCTs with unusual features—adipose metaplasia, calcification (sometimes with ossification), and spindle cell growth.
Figure 37-5 Malignant LCT, same case as in Figure 37-4. Neoplastic Leydig cells are present within a vein. The tumor thrombus shows central necrosis (H&E × 15.6).
Chapter 37 Nongerm Cell Tumors of the Testis 621
Follow-up was reported for 6 of 8 cases exhibiting spindle cell growth. Two patients developed metastases and both had malignant features apart from spindle cells. The other 4 did not have malignant features and were free of disease from 2.3 to 6 years after orchiectomy. Recognizing that adipose tissue may be present in LCTs may prevent the misdiagnosis of extratesticular growth or LCT associated with congenital adrenal hyperplasia (see later). Similarly, the recognition that spindle cells may be identified with LCTs may limit misclassification of such tumors as sarcomas. Tumors in Males with Congenital Adrenal Hyperplasia An important distinction must be made between LCTs and the testicular masses in the salt-wasting form of congenital adrenal hyperplasia (CAH). In CAH males from the neonatal period to adulthood may develop bilateral testicular or peritesticular masses, which are histologically similar to LCTs (Figures 37-6 and 37-7).22,23 One recent study identified testicular tumors ranging in size from 0.2 to 4 cm in 16 of 17 adolescents and adults with CAH (both salt-wasting and not salt-wasting).24 The cells of these masses do not contain Reinke’s crystals but do contain abundant lipochrome pigment that gives the gross tumors a brown or black appearance. These masses resemble those in patients with Nelson’s syndrome. The fact that the masses often disappear after corticosteroid therapy and are sensitive to ACTH stimulation suggests they are of adrenocortical origin. Davis et al.25 described one instance of a malignant LCT in a patient with CAH.
Figure 37-6 Probable congenital adrenal hyperplasia. Twenty-nine-year-old man had right testicular enlargement for 2 years. Left testis was removed 4 years earlier and demonstrated a similar mass. Bivalved testis demonstrates a dark mahogany colored bilobed 6.8 cm mass replacing testicular parenchyma.
In order to avoid inappropriate orchiectomy in patients with CAH, and because of their response to corticosteroid therapy and the risk of adrenal insufficiency if these patients are not treated with corticosteroids after orchiectomy, it is important to distinguish true LCT from CAH with testicular masses. Evaluation and Management In children presenting with precocious puberty, biochemical evaluation is necessary to distinguish primary LCT from Leydig cell hyperplasia secondary to CAH. The presence of a unilateral tumor with normal serum or
Figure 37-7 Probable congenital adrenal hyperplasia mimicking LCT. Same case as in Figure 37-6. Uniform cells contain similar-appearing round nuclei and granular cytoplasm containing fine brown pigment (H&E × 128).
622
Part VI Testis
urinary levels of DHEA, androstenedione, and 17hydroxyprogesterone strongly favors the diagnosis of primary LCT, while bilateral testicular and/or peritesticular masses or those associated with abnormalities of steroid biosynthesis favor CAH. In either instance serum testosterone levels may be elevated. ACTH stimulation and dexamethasone suppression tests are occasionally necessary to establish tumor origin. Gabrilove et al.3 reviewed 37 cases of feminizing LCTs of the testis, 5 of which were in prepubertal boys. In 20 patients where estrogens were measured, 13 had high urinary titers. Serum estrogen levels may also be elevated with a concomitant reduction in serum testosterone. Gonadotropin levels will vary with associated levels of serum androgens and estrogens. The treatment of LCT is surgical excision. In cases where the diagnosis of LCT is not suspected preoperatively, inguinal orchiectomy is the procedure of choice. In children and adults, in whom the diagnosis is suspected, a testis-sparing enucleation or excisional biopsy is acceptable provided that histologic confirmation of the lesion is obtained by frozen section. Following tumor excision the endocrinologic manifestations of the tumor typically disappear in adults. In children with symptoms of short duration the signs of masculinization generally abate and puberty will proceed normally. However, in some children with long-standing symptoms the signs of precocious puberty will persist. The management of Leydig cell hyperplasia associated with CAH begins with the hormonal evaluation described earlier. Some authors have advocated needle biopsies of such lesions to ascertain the presence or absence of Reinke’s crystals.23,26 If the crystals are not identified, treatment with corticosteroid may be initiated and orchiectomy may be deferred. These lesions often diminish in size. Unfortunately, the probability of demonstrating Reinke’s crystals on needle biopsy is low. Virtually all LCTs in children and 90% of LCTs in adults are benign, have a good prognosis, and require no therapy other than excision. Patients with malignant tumors have a poor prognosis and usually die within 2 years after the discovery of metastatic disease. Patients in whom a malignant tumor is suspected on histopathology should undergo a metastatic evaluation, including chest x-ray, abdominal and pelvic CT scan, and biochemical evaluation in the hopes of identifying a usable tumor marker. The optimum management of patients with malignant LCT following excision of the primary lesion is unknown. There are no available data to evaluate the benefit of prophylactic retroperitoneal lymphadenectomy versus observation in patients with disease clinically localized to the testis. In a review of the management of 32 patients with established metastatic LCT, Bertram et al.27 reported no objective responses to radiation therapy, minimal or no benefit to various combinations of chemotherapy (including platinum-based
regimens), and only isolated reports of benefit from resection of low-volume or solitary metastatic deposits. Complete responses to mitotane have been reported but the patients ultimately relapsed and died of progressive disease.28 Sertoli Cell Tumor Clinical Presentation A variety of Sertoli cell tumors (SCTs) have been described, which together comprise only 1% of testicular tumors. The principal cell types are classic Sertoli cell tumor (CSCT), sclerosing Sertoli cell tumor (SSCT), large cell calcifying Sertoli cell tumor (LCCSCT), and Sertoli cell adenoma (SCA) associated with androgen insensitivity syndrome (AIS). All but the last of these variants typically present with painless testicular enlargement and occur in males of any age. SCA in AIS occurs in phenotypic females. Gynecomastia is present in about 20% of cases of SCA and is a typical feature of malignant SCTs. SCTs are to be distinguished from microscopic or barely grossly visible masses of persistent immature tubules that have been termed Pick’s adenomas or androblastomas, which are often seen in cryptorchid testes and have no malignant potential. Pathologic Characteristics Classic sertoli cell tumor. On gross inspection CSCTs
are generally circumscribed and yellow, tan or white, and may be hemorrhagic (Figure 37-8). Microscopically, they grow in tubules, cords, sheets, aggregates and occasional retiform configurations separated by fibrovascular septae (Figure 37-9). Nuclei are round to ovoid and may contain nucleoli. Tumor cell cytoplasm may be pale or eosinophilic and may contain lipid vacuoles. The latter finding in a tumor with a diffuse growth pattern may be confused with the appearance of an LCT. The stroma of
Figure 37-8 Sertoli cell tumor. The tumor is a discrete 8 mm, nonencapsulated, nonnecrotic, firm mass in a 44-year-old man.
Chapter 37 Nongerm Cell Tumors of the Testis 623
Figure 37-9 Sertoli cell tumor. The tumor contains solid uniform tubular structures with round to oval nuclei and prominent nucleoli. The tubules are surrounded by basement membrane. Elsewhere, similar-appearing cells lack lumens and grow in more solid configurations (H&E × 62.2).
a CSCT may be scant or abundant and hyalinized. Most CSCTs behave in a benign fashion, but up to 30% of CSCTs may be malignant as evidenced by the presence of local invasion and metastases. Young et al.29 reviewed 60 cases of CSCT. Age at presentation ranged from 15 to 80 years (mean 45 years) and the size of the tumors ranged from 0.3 to 15 cm (mean 3.6 cm). Long-term follow-up (>5 years) was available for 16 patients; 9 patients were alive with no evidence of disease, 4 were alive with recurrent disease and 3 were dead with the cause of death attributed to recurrent SCT. The following pathologic features were correlated with a malignant course: tumor diameter greater than 5 cm, necrosis, moderate to severe nuclear atypia, vascular invasion, and >5 mitoses per 10 high power fields. Only 1 of 9 benign cases exhibited more than 1 of these features; 5 of 7 of the malignant cases exhibited 3 or more. Sclerosing sertoli cell tumor. SSCT is a recently
described entity. Zukerberg et al.30 described 10 patients aged 18 to 80 years (median 30) with SSCT. The tumors generally presented as a painless mass, with one arising in a cryptorchid testis and another in a testis that had undergone orchiopexy. All tumors were unilateral and ranged from 0.4 to 4.0 cm in diameter. Eight of 10 tumors were l.5 cm or less. The tumors were well demarcated, hard, and yellow-white to tan. Microscopically 9 of 10 tumors were discrete. The 10th tumor invaded the rete testis, epididymis, and blood vessels. The tumors contained simple and anastomosing tubules, large cellular
aggregates, and cords of epithelial cells. The cells were medium sized with rounded vesicular to dark nuclei. The epithelial elements proliferated in a dense hyaline stroma within which were entrapped nonneoplastic seminiferous tubules lined by immature Sertoli cells. No patient showed evidence of malignant behavior, including the 80-year old man with histologic evidence of invasion. Several cases have been reported subsequent to the report by Zukerberg et al.31 bringing the total number of cases reported to 12. Large cell calcifying sertoli cell tumor. Proppe and
Scully,32 in 1980 characterized unusual and distinctive tumors of the testis in 10 patients as LCCSCTs. Since then, at least 35 additional LCCSCTs have been reported.33–35 Age at presentation ranges from 5 to 48 years with the majority less than age 20. As of 1995, only 2 reported cases were deemed malignant.36 There have been subsequent reports of malignant cases.37 The tumor has been associated with a variety of somatic syndromes, including Carney’s syndrome (cardiac myxomas, spotty skin pigmentation, endocrine abnormalities, and schwannomas), Peutz-Jeghers syndrome (gastrointestinal polyposis and mucocutaneous pigmentation), adrenal cortical hyperplasia, primary pigmented adrenal cortical disease, LCTs of the testis, acromegaly, pituitary gigantism, Cushing’s syndrome, acidophilic adenoma of the pituitary gland, gynecomastia, isosexual precocity, and AIS.33,34,38 A recent review of Carney’s syndrome identified 26 reported cases of testicular tumors in patients with Carney’s syndrome, most of proven LCCSCT
624
Part VI Testis
pathology.39 The neoplasms may involve the entire testis but in general are 4 cm or less in maximum dimension. They are frequently multifocal, bilateral in approximately 40%, and are well circumscribed. On cross-section the masses are yellow-tan sometimes with calcific foci. Microscopically, the tumor grows both within seminiferous tubules and within the interstitium. Within tubules the neoplastic cells are large with abundant pink cytoplasm and expand the tubules. Some tubules have a markedly thickened tunica propria, which extends into tubular lumens as eosinophilic spherules. The interstitial tumor is composed of cords, nests, and trabeculae. The tumor cells range from 12 to 25 μm in diameter and have ground glass or finely granular cytoplasm. Transitions between intratubular and interstitial growth may be seen. Calcific rounded nodules, plaques, and masses may be present as intratubular and extratubular aggregates. Of the first 35 reported cases of LCCSCT, metastasis was observed in 2 cases.35 However, in 1997, Kratzer et al.35 reported 6 malignant and 6 benign LCCSCTs. Malignant tumors were more likely to be unilateral (all 8 cases to date), solitary, occurred in older patients (mean age 39 versus 17 for benign cases), and occurred in the absence of a genetic syndrome. Pathologic features that were more frequently identified in the malignant cases included the following: size >4 cm, extratesticular growth, necrosis, high-grade cytologic atypia, vascular space invasion, and more than 3 mitoses per 10 high power fields. All malignant cases exhibited at least 2 of these features; all benign cases exhibited none of these features. Sertoli cell adenoma associated with androgen insensitivity syndrome. AIS is caused by defective or absent
cellular androgen receptors. As a result, patients with complete AIS are phenotypic females with a shallow vagina and absent Wolffian duct derivatives. The patients have 46 XY karyotypes, and bilateral intraabdominal testes that frequently contain nodular masses comprised of multiple tubules lined almost exclusively by Sertoli cells (Figure 37-10). Hamartomas contain small tubules lined by immature Sertoli cells and may have hyperplastic Leydig cells and ovarian type stroma. Young and Scully40 and Rutgers and Scully41 distinguish between hamartomas and pure SCA, which is comprised exclusively of tubules lined by Sertoli cells (Figure 37-11). Although the SCA may be a monomorphic manifestation of a hamartoma, some SCAs achieve sizes up to 25 cm in diameter. SCAs and hamartomas are completely benign. Rarely, other types of sex cord-stromal tumors have been reported in AIS, including a few malignant tumors.42 While the SCAs and hamartomas are benign, it is well to remember that these masses are occurring in cryptorchid testes, and malignant germ cell tumors, principally malignant intratubular germ cell neoplasia and seminomas may develop concomitantly. Approximately 30% of
Figure 37-10 Sertoli cell adenoma of right testis in patient with AIS. The patient was a 17-year-old virilized phenotypic female. In the right orchiectomy specimen is a firm 1.6-cm nonencapsulated tan nodule. The white firm areas at the bottom of the photographs of the testes are smooth muscle masses at the medial portion of the testes and are of probable müllerian duct origin.
patients with complete AIS will develop malignant germ cell tumors by age 50.40 Evaluation and Management Most SCTs are not suspected preoperatively and are diagnosed only at the time of orchiectomy performed for a testicular mass. In the context of a known associated syndrome, the presence of the LCCSCT variant may be suspected preoperatively by the presence of testicular calcifications on scrotal ultrasound, but this finding is not specific to LCCSCT. When suspected, a testis-sparing surgical approach as described for LCT may be considered remembering that rare LCCSCTs may be malignant and that some may be multifocal. Histologically, benign tumors require no further therapy, although long-term follow-up may be indicated, as the occurrence of metastatic disease has been reported as long as 15 years after initial diagnosis. For metastatic lesions, involvement of the retroperitoneal nodes is frequent and there are several case reports of long-term complete remission following retroperitoneal lymphadenectomy. Experience with chemotherapy for malignant SCTs is limited and the response rate is undefined. There are reported cases of complete responses to multiagent chemotherapy.43 Granulosa Cell Tumors Clinical Presentation Two forms of granulosa cell tumors have been described in males, adult and juvenile. Nineteen cases of adult granulosa cell tumor (AGCT) of the testis have been reported in the literature, although additional sex cord-
Chapter 37 Nongerm Cell Tumors of the Testis 625
Figure 37-11 Sertoli cell adenoma. Same patient as in Figure 37-10. The SCA is on the right and is comprised of discrete uniform tubules lined by Sertoli cells. The larger tubules on the left are of the nonadenomatous testis and are separated by prominent Leydig cells (H&E × 31.2).
stromal tumors with granulosa cell differentiation have been reported.44–46 The majority have presented as scrotal masses with testicular enlargement ranging from 2 months to 15 years in the described cases. The patient with a mass of 15 years duration had delayed testicular descent and 2 other patients had been cryptorchid. Five tumors have had associated estrogenic clinical manifestations (gynecomastia). Four of these patients had lymph node or visceral metastases and 2 patients died of their disease. One patient developed metastases 121 months after diagnosis and died of disease 13 months later. Juvenile granulosa cell tumors (JGCT) rarely arise in infants over 6 months old and in all probability arise in utero. A total of 48 cases have been reported.47 Fifty percent of cases were diagnosed in newborns and 90% by 6 months of age (mean 1 month, range 0 to 11 months). They have been associated with 45XO/46XY and 45XO/46XY iso(Yq) karyotypes and numerous other forms of mosaicism.48 The tumors are generally found in descended testes although they have been discovered in undescended and torsed testes. The tumor is not associated with isosexual precocity. The testis harboring this tumor is usually enlarged, solid, and/or cystic (Figure 37-12). Pathologic Characteristics The reported AGCTs ranged in size from 4 microscopic lobules to 13 cm and were well circumscribed.44 They have been described as brownish, white, yellow, and pink
Figure 37-12 Juvenile granulosa cell tumor. One-month-old boy with left testicular mass. The testis measured 3 × 2.5 × 1.5 cm. The surface was smooth and red-tan. On cut sections, there was a variegated red to yellow lobulated parenchyma with cystic areas up to 5 mm in diameter. (Photograph and case courtesy of California Tumor Tissue Registry.)
and either solid or cystic. Two patients with metastases had hemorrhagic or friable and necrotic foci in their tumors. Their microscopic appearance has resembled that of ovarian granulosa cell tumor with solid, cystic, insular, gyriform, and trabecular patterns. Individual granulosa cells have been described as fairly uniform with scanty cytoplasm, indistinct cell borders, and longitudi-
626
Part VI Testis
nal nuclear grooves in elongate cells. Jimenez-Quintero et al.44 recorded up to 26 mitotic figures in 50 high power microscopic fields. Tumor cells have been described as positive for vimentin and negative for keratin or epithelial membrane antigen. JGCT are grossly multicystic and contain follicular structures of varying size lined by one to multiple layers of cells and contain pale eosinophilic or basophilic intraluminal material (Figures 37-12 and 37-13). The stroma is fibrous and may contain groups of cells that resemble theca cells and granulosa cells, which do not resemble the cells of AGCT. Lawrence et al.48 found only a few grooved cells in a minority of tumors. In the JGCTs the granulosa cells have round to oval nuclei and pale to eosinophilic cytoplasm. Tumor granulosa cells stain positively for vimentin and some cells stain positively for keratin and S100 protein with immunoperoxidase stains.49 The cells that resemble theca cells have been demonstrated to stain positively for muscle-specific actin, vimentin, and focally for desmin with immunoperoxidase stains. Mitoses may be numerous. Tumor cells may be present in relationship to seminiferous tubules and have even been described within a seminiferous tubule. The differential diagnosis of JGCT of the testis consists of those tumors developing in the neonatal period. Probably most congenital testicular tumors and those discovered in the first 4 months of life are JGCTs rather than yolk sac tumors. Yolk sac tumors may be solid and/or cystic and may have macrocystic or microcystic areas. However, definitive areas diagnostic for yolk sac tumor, including Schiller-Duval bodies and immunoperoxidase staining for AFP, are absent in JGCT. Levels of serum
AFP are normally elevated in the neonate relative to adult values, so serum AFP levels are of no value in the diagnosis of this tumor. Evaluation and Management The diagnosis of AGCT is not usually established until the time of orchiectomy and surgical excision may be curative. There is insufficient experience with malignant forms of this tumor to comment on therapy. JGCT can be suspected on the basis of patient age and karyotype. They are invariably benign and are cured by excision. Although follow-up in many cases is still limited, none of the 48 reported cases have been associated with recurrence.47 MIXED SEX CORD/GONADAL STROMAL TUMORS AND INCOMPLETELY DIFFERENTIATED TUMORS Tumors of mixed histology occasionally occur and may consist of some areas with recognizable elements mixed with incompletely differentiated cells resembling ovarian stroma (Figure 37-14). A recently described transgenic mouse model suggests that at least some of these neoplasms may arise from tumors, that begin as SCTs.50 Like pure forms, tumors of mixed histology and incompletely differentiated tumors present as an isolated testicular mass usually without endocrinologic signs or symptoms and are diagnosed at the time of orchiectomy (Figure 37-15). Most are biologically benign but some metastatic tumors have been described.51,52 Treatment is by inguinal orchiectomy. Retroperitoneal lymph node dissection may
Figure 37-13 Juvenile granulosa cell tumor. Same patient as in Figure 37-2. Multiple small cysts and areas of solid polyhedral to rounded cells comprise the tumor. Elsewhere, larger follicles were present (H&E × 31.2).
Chapter 37 Nongerm Cell Tumors of the Testis 627
Figure 37-14 Incompletely differentiated gonadal stromal tumor. Testicular mass in 46-yearold. Interlacing fascicles of basophilic spindled cells with large uniform nuclei resemble cells of ovarian stroma (H&E × 62.2).
Figure 37-15 Incompletely differentiated gonadal stromal tumor; 2.2-cm tan nonencapsulated, subcapsular tan firm mass. Same patient as in Figure 37-14.
have value in some cases with metastasis.53 Good responses to platinum-based chemotherapy have been described for metastatic disease.54 Miscellaneous Tumors Epidermoid Cysts Epidermoid cysts are benign lesions, which typically present as a painless testicular mass and are frequently noted incidentally on physical examination. They occur
Figure 37-16 Epidermoid cyst. Eighteen-year-old with 3month history of nontender mass of left testis. The testis contains a well-circumscribed 2-cm cyst with a 1-mm thick gray wall filled with yellow-white friable cheesy material.
slightly more commonly on the right side and rarely are much larger than 2 to 3 cm. Grossly they appear as a usually solitary cyst containing laminated keratinous material (Figure 37-16). Histologically they are composed of a squamous lining and filled with keratin.55 Treatment has historically been by orchiectomy, but there are several reports in the literature describing a characteristic appearance of this lesion on ultrasound, which may allow diagnosis preoperatively.56 The ultrasonographic appearance of a markedly heterogeneous intratesticular
628
Part VI Testis
mass with or without alternating hypoechoic and hyperechoic layers surrounded by a hypoechoic or echogenic rim and absence of blood flow on color Doppler sonography suggest the diagnosis of a testicular epidermoid cyst. Although these criteria are not diagnostic, they may strengthen the indication for excisional biopsy. In such cases, inguinal exploration and excisional biopsy seem reasonable, especially in children or patients with a solitary testicle or bilateral lesions.57,58 Epidermoid cysts have rarely been reported in a patient with Klinefelter’s syndrome, and we have seen another such patient (Figure 37-17).59 Rete Testis Carcinoma Clinical presentation. Orozco and Murphy60 reported
one case and reviewed 43 cases of rete testis carcinoma (RTC) that have been recorded in the literature through 1992. The patients have ranged in age from 17 to 91 years of age with a mean of 50 years. The clinical onset may or may not be associated with pain. Testicular enlargement averaged about 2 years in duration but had been present for 5 years in four instances. Serum tumor markers were not elevated. All patients were treated by orchiectomy and some were also treated with radiotherapy, chemotherapy, and retroperitoneal lymphadenectomy. Of the reviewed patients, 33% died of RTC, 75% within a year of diagnosis. Twenty patients were alive at the time of the report, 80% free of disease at a maximum 2-year follow-up.
Pathologic characteristics. RTCs are poorly circum-
scribed gray nodules at the hilus of the testis. Most tumors are single, but multiple masses have been reported. Reported tumors have ranged in size from 1 to 15 cm. Histologically, RTCs are adenocarcinomas. The predominant growth pattern is papillary with solid, spindled, and cystic areas less common (Figures 37-18 and 37-19). Tumor cells are columnar to cuboidal with acidophilic to amphophilic cytoplasm. Nuclei are enlarged, pleomorphic and round to oval with coarsely granular chromatin and sometimes prominent nucleoli. Mitoses may be frequent. The tumors stain negative for mucin, occasionally positive for CEA, and positive for vimentin, epithelial membrane antigen, and keratin with immunoperoxidase stains. Immunoperoxidase stains are negative for AFP, hCG, and PSA. The diagnosis of RTC should be made in cases where the tumor is present in the hilus of the testis, where there is a transition from histologically normal rete testis to RTC, where primary testicular tumors of germ cell and nongerm cell origin and mesothelioma can be excluded, and where extratesticular origin can be reasonably excluded on a histologic and clinical basis. The histologic distinction between an RTC and adenoma or hyperplasia of the rete testis should not be difficult. Evaluation and management. RTCs are usually found
incidentally by palpation or at the time of orchiectomy for a testicular mass. They may be suspected on preoperative examination or ultrasound by a hilar location
Figure 37-17 Epidermoid cyst. Sixteen-year-old with cystic testicular mass. The cyst is lined by flattened squamous epithelium. Laminated keratin is present in the left upper corner. Mostly flattened seminiferous tubules lined by Sertoli cells are present beneath the cyst. Leydig cells are prominent. The patient was subsequently found to have Klinefelter’s syndrome (H&E × 31.2).
Chapter 37 Nongerm Cell Tumors of the Testis 629
Figure 37-18 RTC. Forty-seven-year-old with recurrent hydrocele and firm nontender mass at the superior pole of the right testis. Orchiectomy specimen contained numerous irregular firm 1- to 4-cm nodules with involvement of epididymis. Papillary and solid neoplasm involves the rete testis, surrounding and projecting into rete testis lumens (H&E × 31.2).
Figure 37-19 RTC. Same case as in Figure 37-18. Glandular spaces are lined by epithelial cells with round to oval, pleomorphic, enlarged nuclei with prominent nucleoli. Glands are infiltrating connective tissue (H&E × 62.2).
or involvement of the epididymis. Initial therapy is orchiectomy followed by a staging evaluation for distant disease.61 One long-term complete remission has been reported following retroperitoneal lymphadenectomy for micrometastatic disease. Chemotherapy for disseminated disease has generally been unsuccessful.61
Malignant Mesothelioma of the Tunica Vaginalis Clinical presentation. Malignant mesothelioma (MM)
is a rare lesion. The literature consists of 81 cases with the largest series reported by Jones et al. in 1995.62,63 The age range is 7 to 80 years with a mean of 53.5 years.
630
Part VI Testis
Two-thirds of patients were over 50 years at the time of diagnosis. Most patients presented with a benign appearing hydrocele with or without an inguinal or scrotal mass. Of those patients who were asked about asbestos exposure, 41% had some degree of occupational exposure. The large majority of patients had a hydrocele sac studded with papillary excrescences from several millimeters to several centimeters (Figure 37-20). In some cases, a mass involved the spermatic cord, other paratesticular structures, or rarely, the testis proper. MM that extended beyond the confines of the hydrocele invaded local structures, including spermatic cord, epididymis, testis, and penile, scrotal and lower abdominal wall skin. Jones’ series includes follow-up on 52 patients (6 months to 15 years, mean 2.8 years). Twenty-five patients developed distant metastases. The principle sites of metastasis were retroperitoneal and inguinal lymph nodes, other lymph nodes and lung. Retroperitoneal and inguinal lymph node involvement was present at the time of diagnosis in 9 and 4 cases, respectively. Of the 52 patients with follow-up data, 44% died of disease, 17% were alive with disease, and 38% had no evidence of disease. The latter figure should be considered with caution since late recurrence of well-differentiated epithelial MM has been observed. Forty-six percent of patients who presented with tumor confined to the hydrocele sac were free of disease at 2 years compared with 5.3% of patients who presented with local invasion of the spermatic cord, skin, testis, or with distant metastasis. In a review of 74 cases of MM of the tunica vaginalis, Plas et al.64 found a median survival time of 23 months.
Pathologic characteristics. Seventy-five percent of the
tumors described by Jones et al.62 were epithelial and 25% were biphasic. Epithelial tumors grew in a tubular and/or papillary growth pattern (Figure 37-21). Cellular anaplasia was variable with some tumors comprised of bland cells without mitotic activity growing in a papillary pattern on fibrous stalks with others containing large eosinophilic cells with hyperchromatic irregular nuclei, prominent nucleoli, and frequent mitoses growing in an infiltrating tubular pattern. Tumor stroma was usually dense. Psammoma bodies were occasionally present. The majority of tumors, even the best differentiated, showed some degree of stromal invasion. MMs with a biphasic pattern had a sarcomatous component with spindled cells of variable differentiation, sometimes containing numerous mitotic figures. MM must be distinguished from a number of benign and malignant lesions. Mesothelial cell hyperplasia, although prominent in a hernia sac, is rarely present in a hydrocele and does not contain the fibrous stalks characteristic of the papillary MM. Adenomatoid tumor is a benign tumor derived from mesothelial cells but has a characteristic gland-like architecture and cytology that distinguishes it from MM. It is far more difficult to distinguish MM from metastatic adenocarcinoma, RTC, and serous borderline tumors of müllerian origin (ovarian surface epithelial type) that resemble ovarian tumors of borderline malignancy, which may involve the testis or paratesticular tissue.65 Borderline serous tumors generally have broad papillae with stratified epithelial cells having a more columnar appearance, some of which are
Figure 37-20 Papillary mesothelioma. Fifty-three-year-old man with recurrent left hydrocele. The tunica vaginalis is studded with yellow-tan excrescences from 0.2 to 1.0 cm in maximum dimension.
Chapter 37 Nongerm Cell Tumors of the Testis 631
Figure 37-21 Papillary mesothelioma. Same case as in Figure 37-20. The tumor is multifocal and comprised of a complex papillary growth lined by a single layer of mesothelial cells with oval, prominently nucleolated nuclei growing on fibrous stalks. The patient is free of MM 5 years after orchiectomy (H&E × 3 1.2).
ciliated. Immunohistochemical stains may be useful in distinguishing between these two tumors since serous tumors are frequently positive for Leu-M1, B72.3, CEA, and CA125, whereas MMs are negative for these antigens.65 MMs are usually positive for CK 5/6 and calretinin. RTC may be associated with a hydrocele and focally may have a histologic resemblance to MM, but if the criteria of diagnosis enumerated earlier are adhered to, there should be no problem distinguishing the two entities. Electron microscopy may also help distinguish the entities since mesothelial cells have long thin, bushy microvilli, and epithelial cells of rete testis origin do not. As in the pleura and peritoneum, there may rarely be a problem distinguishing MM from metastatic adenocarcinoma. The same immunohistochemical stains used to distinguish müllerian papillary serous tumors are useful in distinguishing metastatic adenocarcinomas from MM. Adenocarcinomas, that may be of gastrointestinal origin should stain positively for Leu-Ml, B72.3, and CEA and may contain intracytoplasmic mucin. Evaluation and management. MM is usually not sus-
pected preoperatively; 97.3% are encountered incidentally during hydrocelectomy.64 When the initial presentation is a scrotal mass, inguinal orchiectomy should be performed with en bloc excision of involved adjacent structures. If the tumor is incidentally discovered during a transscrotal procedure, frozen section should be performed and inguinal orchiectomy completed at the same sitting or soon thereafter after consul-
tation with the patient. Orchiectomy is associated with a lower local recurrence rate compared with hydrocelectomy (11% versus 36%, respectively) although no difference in overall survival has been demonstrated.64 A metastatic evaluation is appropriate but there is little experience in the literature to address the issues of surveillance, adjuvant chemotherapy, or prophylactic retroperitoneal or inguinal lymphadenectomy. Metastatic Tumors Symptomatic metastatic nonhematologic tumors of the testis occur only rarely. Price and Mostofi66 identified only 38 metastatic carcinomas involving the testis suitable for study at a time when the AFIP had 1600 primary testicular tumors. Four of the patients had bilateral tumors. Only 6 tumors were clinically symptomatic, generally due to testicular enlargement. The majority of tumors in their report were discovered at autopsy. Of the 38 tumors, 14 were from the lung and 12 were from the prostate gland. Tiltman67 found metastases in 6 of 248 autopsies in males with metastatic carcinoma. Testicular metastases occurred in 2 of 12 cases of prostate carcinoma, 2 of 9 cases of malignant melanoma, 1 of 4 cases of malignant pleural mesothelioma, and 1 of 89 cases of carcinoma of the lung. Haupt et al.68 reviewed the literature through 1982 and found the most common tumors metastasizing to the testes were (in descending order) carcinomas of the prostate and lung, malignant melanoma, and carcinomas of the kidney, stomach, and
632
Part VI Testis
pancreas. These findings emphasize the relative rarity of metastases to the testis and the fact that in most patients testicular involvement will be discovered incidentally despite a known history of cancer. Only 24 cases of testicular enlargement as the primary manifestation of a tumor metastasis have been reported. These included primary tumors of the prostate, kidney, and GI tract, some of which were initially thought to represent primary testicular tumors even after histologic examination. Grossly metastatic tumors are generally multinodular (Figure 37-22). Microscopically, the tumor grows in the interstitium and may be within endothelial-lined spaces. The morphology of the tumor may be characteristic of the primary tumor (Figure 37-23). Treatment for tumors metastatic to the testis is directed at the underlying malignancy. Carcinoid Tumors Carcinoid tumor (CT) involving the testis and testicular adnexa represents a special problem inasmuch as both primary and metastatic tumors may have similar morphology. The nests of tumor grow in an insular pattern with groups of uniform centrally nucleated cells having fine nuclear chromatin and granular eosinophilic cytoplasm (Figure 37-24). The majority of CTs stain positively with argentaffin and argyrophil stains and for chromogranin, neuron-specific enolase, and other polypeptides with immunoperoxidase stains. ZavalaPompa et al.69 indicated that 9 of 62 testicular CTs
Figure 37-22 Metastatic undifferentiated carcinoma, small cell type, of lung. Seventy-six-year-old man with left testicular mass and previous history of undifferentiated small cell carcinoma of lung. Metastatic confluent nodules of neoplasm are present in the lower left portion of the testis.
reported through 1992 were metastatic. The largest of the metastatic CTs on which data were recorded was 2.5 cm, and 3 patients had symptoms of the carcinoid syndrome. Most patients with metastatic CTs died within a year although one patient survived for 12 years. Factors that favor a metastatic origin for a CT are bilaterality, involvement of peritesticular structures, absence of a teratomatous component, and the presence of carcinoid syndrome symptomatology. Most primary testicular carcinoids are cured with inguinal orchiectomy. However,
Figure 37-23 Metastatic prostatic adenocarcinoma. Fifty-eight-year-old man with bilateral orchiectomy for prostate cancer. One testis contained a firm tan irregular mass. Solid aggregates of tumor and neoplastic glands expand the interstitium adjacent to a seminiferous tubule (H&E × 31.2).
Chapter 37 Nongerm Cell Tumors of the Testis 633
Figure 37-24 Carcinoid tumor. Forty-two-year-old male with enlarged right testis and epididymis containing a 3.5-cm yellow to red, firm to fibrous mass. The tumor is comprised of solid nests and cysts growing in an insular pattern. Tumor cells contain uniform, centrally nucleated cells with fine nuclear chromatin and granular eosinophilic cytoplasm (H&E × 3 1.2). (Case courtesy of California Tumor Tissue Registry.)
all patients should have a metastatic evaluation and retroperitoneal lymphadenectomy should be considered in those tumors associated with teratoma. Other Miscellaneous Tumors A variety of other uncommon and usually benign lesions may mimic more aggressive testicular tumors. Simple cysts have been described in 17 patients of all ages and ranging in size from 1 to several centimeters in diameter but are probably more common.70 Histologically, they are lined by flat or cuboidal epithelium and have a benign appearance. Cysts may be suspected preoperatively by a smooth-walled, anechoic appearance on ultrasound. Adenomatoid tumors are benign mesenchymal proliferations that usually arise from the epididymis but may also arise from the tunica albuginea and may infiltrate testicular parenchyma. Two reports of true intratesticular adenomatoid tumors have been published.71,72 These tumors present as painless enlargement and are firm or hard to palpation (Figures 37-25 and 37-26). Fibromas and fibrous pseudotumors of the testicular tunics presenting as hard painful or incidentally discovered masses have also been reported. Granulomatous orchitis and malakoplakia are benign inflammatory conditions usually diagnosed following orchiectomy. They have characteristic histologic appearances, which are pathognomonic. All of these lesions are cured by orchiectomy or simple excision and are important mostly to be differentiated from
malignant testicular tumors and, in the case of malakoplakia and granulomatous orchitis, from ML.
Hematologic Tumors Malignant Lymphoma Clinical presentation. While MLs comprise only a
small percentage of testicular tumors, they account for more than 50% of testicular tumors in men over age 65. About 80% of testicular MLs occur in men over age 50. The neoplasm generally presents as a unilateral, painless,
Figure 37-25 Adenomatoid tumor of epididymis. The epididymal specimen consists of a discrete white uniform rubbery 0.9-cm nodule in a 44-year-old man.
634
Part VI Testis
Figure 37-26 Adenomatoid tumor of epididymis. Same patient as in Figure 37-25. Glandlike structures lined by flattened cells infiltrate collagenous tissue. Numerous intraluminal and intracytoplasmic vacuoles of varying size are present, creating a spider-web appearance in some areas (H&E × 31.2).
intrascrotal mass. About 5% of men present with bilateral synchronous involvement, and approximately 20% with a unilateral presentation will develop lymphomatous involvement of the opposite testis. Bilateral disease may occur in the absence of any other systemic disease.73 Generally, the diagnosis of ML is first made at the time of orchiectomy. Only a small percentage of patients have a history of antecedent lymphoma. Of 127 men with ML of the testis, Gowing74 reported only 8 with antecedent ML and 13 with active lymphoma elsewhere at the time of orchiectomy.
in the working formulation, 10 immunoblastic, 6 small noncleaved, and 6 were NOS. Of those tumors that were immunophenotype 33 were of B-cell lineage, one was of T lineage, and 5 were of indeterminate lineage. Irrespective of cell type, the pattern of infiltration is similar. Tumor cells proliferate in the interstitium separating seminiferous tubules, infiltrating the tunica propria and blood vessel walls, eventually obliterating many tubules and vessels (Figure 37-27). Sections may contain no recognizable testicular parenchyma. Tumor cells may extend into the rete testis, epididymis, tunica albuginea, or peritesticular soft tissue.
Pathologic characteristics. The neoplasm mainly
involves the testis but often extends into the epididymis or spermatic cord. The testis is enlarged, sometimes massively, and on cut section is partially or extensively replaced by an ill-defined tan-grey mass. The tumor merges imperceptibly with testicular parenchyma. Tumor consistency is more rubbery than hard, and necrosis may be present. The large majority of testicular lymphomas are diffuse non-Hodgkin’s type. Gowing74 indicated that 41% of the British Testicular Tumor Panel cases were poorly differentiated lymphocytic lymphomas and 59% were large cell lymphomas (undifferentiated “stem cell reticulum cell type”). They had no cases of Hodgkin’s disease among their 127 cases. Virtually all types of ML other than Hodgkin’s disease occur in the testis. Ferry et al.75 in 1994 reported 64 ML, which presented primarily in the testis. Of these, 53 were diffuse large cell lymphoma of which 27 were of noncleaved type
Evaluation and management. The prognosis of men
with ML of the testis has been poor. Gowing74 indicated 62% of their patients died of disseminated ML. Only 12 of 124 patients (10%) survived 5 years after orchiectomy. In a more recent study, Ferry et al.75 found 20 of 55 patients (36%) to be free of disease a median of 49 months after orchiectomy, 6 (11%) were alive with disease and 29 (53%) died of ML. With careful staging of ML it is apparent that prognosis is related to the stage of the disease at the time of orchiectomy. Turner et al.76 reported 60% disease-free survival in stage I ML contrasted with a 17% disease-free survival for stages II, III, and IV. Turner et al.’s cases were classified according to the Rappaport system and the working classification of non-Hodgkin’s lymphomas. In the latter classification, the large cell noncleaved, large cell cleaved, and diffuse mixed lymphomas were designated intermediate grade
Chapter 37 Nongerm Cell Tumors of the Testis 635
Figure 37-27 ML, diffuse large cell type. A 225-g 9.5 cm in maximum dimension testis was subtotally replaced by a dark tan, focally hemorrhagic, focally necrotic, ill-defined mass. An extensive cellular infiltrate greatly expands the interstitium and compresses seminiferous tubules. The individual cells contain large, variably shaped, prominently nucleolated nuclei with sparse cytoplasm (H&E × 62.2).
lymphomas, and immunoblastic lymphoma, Burkitt’s lymphoma and diffuse undifferentiated lymphomas were designated as high-grade lymphomas. Eight of 17 men with intermediate grade ML were alive and well with an average follow-up of 24 months. There were no survivors among 6 men in the high-grade group whose average survival was 13 months. Thus, grade appears to be another prognostic variable. Stage I disease, unilateral right-sided ML, and microscopic sclerosis were also associated with an improved prognosis in Ferry et al.’s study.75 In 2001, Lagrange et al.77 reviewed their experience with 84 cases of primary testicular lymphoma. The median age at presentation was 67 (range 17 to 85). Forty-two patients presented with stage I disease, 19 with stage II, and 23 with stage III/IV. Using the REAL classification, 75% of the patients exhibited diffuse large Bcell histology. Treatment was generally multimodal and involved orchiectomy and chemotherapy ± radiation. A complete response was obtained in 72.6% of patients (100%, 68%, and 33% for stages I, II, and III/IV, respectively). However, median survival was 32 months (52, 32, and 12 months for stages I, II, and III/IV, respectively). Zucca et al.,78 in 2003, examined their experience with 373 patients with primary testicular diffuse large B-cell lymphoma. The median age at diagnosis was 66 years. Anthracycline-based chemotherapy was used in 68%, prophylactic intrathecal chemotherapy in 18%, and prophylactic scrotal radiotherapy in 36%. Median survival
was 4.8 years, but the survival curves showed no clear evidence of a substantial portion of cured patients. There was a 52% relapse rate at a median follow-up of 7.6 years. Relapses occurred in the CNS in 15% of the patients, occasionally as late as 10 years postorchiectomy. The authors identified a continuous risk of contralateral testicular recurrence in those patients not receiving scrotal radiotherapy. On multivariate analysis, lack of Bsymptoms, use of anthracyclines, and scrotal radiotherapy were associated with longer survival. Evidence is accumulating that primary testicular lymphoma in children has a very different natural history.79–81 Most lymphomas involving the testicle are secondary lesions in patients with diffuse extrascrotal lymphoma. Only 10 cases of primary testicular lymphoma in children have been reported. All have shared similar histology (follicular large cell lymphoma) and, despite the aggressive histologic appearance, a good prognosis. Most patients have been treated with orchiectomy and multiagent chemotherapy. The 10 reported cases include children ranging in age from 3 to 11 years. None of the tumors has demonstrated the presence of bcl-2 protein. The size of the tumors ranged from 2 to 4 cm. All 10 patients are reported to be free of disease with follow-up ranging from 7 to 59 months. It is clear that some cases of ML originate in the testis. Although rare survivals have been reported following orchiectomy alone, this is certainly insufficient therapy since the large majority of men ultimately develop extratesticular
636
Part VI Testis
ML. Extratesticular involvement tends to occur in several areas, including Waldeyer’s ring and the central nervous system. Turner et al.’s76 series also suggests that MLs at these sites may have been present at the time of orchiectomy. Ferry et al.’s75 data indicate that MLs that relapsed in the testis tended to be extranodal, and that ML presenting in the testis tended to have lymphoma in extranodal sites, notably bone, CNS, skin, orbit, paranasal sinuses, stomach, nose, thyroid, and larynx.75 Treatment should be based on stage and histologic type of lymphoma. Plasmacytoma Plasma cell neoplasms involving the testis are rare and have the same implications as ML. The tumors are bilateral and sequential in about 20% of men. Tumors generally manifest as painless enlargement and are part of a systemic process sometimes identified prior to orchiectomy. Tumors may be associated with hydroceles and, on at least two occasions, the diagnosis was made on the basis of cytologic analysis of hydrocele fluid.82 All patients with sufficient follow-up reviewed by Levin and Mostofi83 and all 7 in the literature until that time succumbed to systemic disease. The mean age at the time of diagnosis was 55 years with only 8 patients under 50 and the youngest aged 26. There have been 42 reported cases of testicular plasmacytoma, only 10 of which had no documented systemic myeloma.82,84,85 The gross and microscopic appearances of plasmacytoma are similar to those of ML, the only difference being the cell type, which is a neoplastic plasma cell of variable morphology (Figure 37-28). Leukemia Leukemic involvement of the testis is common. In an autopsy study, Givler86 found 63% of 140 males with
Figure 37-28 Plasmacytoma. Massive enlargement and complete replacement of testicular parenchyma by a lobulated gray-yellow 11-cm mass in a 42-year-old man.
acute leukemia (AL) and 22% of 76 males with chronic leukemia (CL) had testicular involvement. All varieties of AL were represented. It is recognized that children with acute lymphoblastic leukemia (ALL) in bone marrow remission may have recurrence first demonstrated in the testis. In Givler’s study, 8 children with ALL developed testicular masses while receiving chemotherapy. Five of the children were in hematologic remission and the testicular masses were either the sole evidence of leukemia or associated with other extramedullary leukemic masses. Hematologic relapse followed in all cases. In 5 of 8 cases, testicular involvement was bilateral. In cases of ALL following completion of chemotherapy, biopsy of the testes to rule out occult leukemic involvement is part of some current protocols. Neither palpation nor radiographic studies, such as ultrasound or MRI, are sufficiently sensitive to the presence of leukemic infiltrates to obviate the need for biopsy. Buchanan et al.87 reported that one-third of patients with overt testicular recurrence of ALL treated with an intense protocol exhibited prolonged second remissions with the potential for cure. Only a small percentage of patients will develop testicular recurrence following a negative biopsy. The interstitial pattern of testicular involvement in ALL is similar to that of ML. Occasionally ALL involvement of the testis produces a massive enlargement (Figure 37-29). Tumors of Generalized Stroma Tumors of generalized stroma (blood vessels, smooth muscle, and other supporting stroma), also known as mesenchymal tumors, rarely occur in the testis. Petersen70 reported a total of 26 such tumors described in the literature, most of which (62%) were malignant. The histologies of the benign tumors included 5 hemangiomas, 3 hemangioendotheliomas, 1 leiomyoma, and 1
Figure 37-29 Acute lymphocytic leukemia. Massive replacement of right testis by a cream-colored, focally hemorrhagic, ill-defined mass in a 10-year-old with an 8-year history of treated ALL.
Chapter 37 Nongerm Cell Tumors of the Testis 637
myxoid neurofibroma. The malignancies included 14 rhabdomyosarcomas, 1 osteosarcoma, and 1 leiomyosarcoma. The microscopic appearance of these tumors is similar to those that occur at more typical sites. Most of these patients presented with testicular enlargement and underwent inguinal orchiectomy with the diagnosis of a mesenchymal tumor made only after surgical excision of the testis. Benign tumors found in this manner do not require further evaluation or treatment. Rhabdomyosarcomas of the testis proper occur less frequently than in paratesticular locations but should be similarly treated with retroperitoneal lymphadenectomy, chemotherapy, and radiation, depending on stage. Testis Tumors in Acquired Immunodeficiency Syndrome Patients infected with HIV or with full-blown AIDS appear to be at a 20- to 50-times higher risk of developing primary or secondary testis tumors.88 Testis tumors are the third most common HIV-associated/AIDS-associated malignancy.88 The first 2 cases of germ cell tumors of the testis in AIDS patients were reported in 1985.89 Wilson et al.89 reported 5 of 3015 HIV positive men presenting with testicular tumors over a 5-year period, an incidence of 0.2%, more than 50 times the incidence of testis tumors in the general population. There have been additional cases of testis tumors described in the AIDS population in the urologic literature, including seminoma and mixed nonseminomatous germ cell tumors, Kaposi’s sarcoma, MLs, and plasmacytomas.90 Some of these cases presented with testicular swelling as the initial and primary manifestation of HIV infection,91 and some of these patients presented with symptoms of acute prostatitis or epididymo-orchitis and were initially treated with antibiotics before returning with complaints of progressive testicular enlargement. Reported cases were ultimately managed by inguinal orchiectomy and additional therapy based on tumor histology and status of the patient’s immune system. These reports highlight the need for a high index of suspicion for testicular tumors in men at risk for HIV who present with testicular enlargement. Testicular and Paratesticular Tumors of Ovarian Surface Epithelial Type Prior to 1995, 17 cases had been reported of testicular and paratesticular tumors of ovarian surface epithelial type, when Jones et al. reported an additional 5 cases of paratesticular serous carcinoma.92,93 These occurred in an age range of 11 to 68 years with a median of 47 years in Young et al.’s series of testicular and paratesticular tumors and in a range of 16 to 42 years with a mean of 31 years in Jones et al.’s series of paratesticular serous carcinoma. The majority of tumors of ovarian surface epithe-
lial origin are paratesticular, but at least 7 principally involved testicular parenchyma. Other areas of involvement included the tunica vaginalis and the testicularepididymal groove at the upper pole of the testis. The majority of cases have been of serous borderline type, but serous papillary carcinoma, mucinous cystadenoma, and cystadenocarcinoma, endometrioid adenoacanthoma, clear cell carcinoma, and Brenner tumors have been reported.92,93 These tumors may be derived from müllerian duct remnants, the tunica vaginalis, or both. Most borderline serous tumors behave in a benign fashion if completely excised, but the clear cell adenocarcinoma and two cases of papillary serous carcinoma behaved in a malignant fashion, one causing metastasis and death and another having extensive abdominal recurrence.93 A third patient without demonstrable recurrence has persistent elevation of serum CA125.93 It is important to recognize the müllerian nature of these neoplasms and to accurately distinguish between borderline and frankly malignant variants. The differential diagnosis of müllerian surface epithelial tumors includes germ cell tumors, rete testis adenocarcinoma, mesothelioma of the tunica vaginalis, and metastatic adenocarcinoma. Germ cell tumors, because they are the most frequent tumor in this region, must be considered in the differential diagnosis, but only teratomas with mucinous glandular differentiation or transitional cell foci might remotely be considered in the differential diagnosis of mucinous or Brenner variants of müllerian tumors. As described earlier, rete testis adenocarcinomas have a combination of diagnostic features that must be recognized for a correct diagnosis. Paratesticular and tunica vaginalis MM may closely resemble paratesticular and tunica vaginalis borderline serous müllerian tumors. MMs are about three times more frequent. Müllerian tumors stain positively for keratin and frequently for CEA, B72.3, BER-EP4, EMA, Leu-M1, S-100 protein, and PLAP, whereas MMs stain positively for cytokeratins, including CK 5/6 and calretinin.65 Although borderline serous tumors and epithelial MMs may have papillary configurations, borderline serous tumors generally have stratified nuclei and may be ciliated, whereas MMs are lined by a single cell layer. Metastatic carcinomas to the testis, tunica vaginalis and paratesticular tissues are rare but should be considered in the differential diagnosis.
REFERENCES 1. Buzelin F, Karam G, Moreau A, Wetzel O, Gaillard F: Testicular tumors and the acquired immunodeficiency syndrome. Eur Urol 1994; 26:71–76. 2. Mueller N: Overview of the epidemiology of malignancy in immune deficiency. J Acquir Immune Defic Syndr 1999; 21(S1):S5–S10.
638
Part VI Testis
3. Gabrilove JL, Nicolis GL, Mitty HA, Sohval AR: Feminizing interstitial cell tumor of the testis: personal observations and a review of the literature. Cancer 1975; 35:1184–1202. 4. Elert A, Olbert P, Hegele A, et al: Accuracy of frozen section examination of testicular tumors of uncertain origin. Eur Urol 2002; 41(3):290–293. 5. Richter-Unruh A, Wessels HT, Menken U, et al: Male LH-independent sexual precocity in a 3.5-year-old boy caused by a somatic activating mutation of the LH receptor in a Leydig cell tumor. J Clin Endocrinol Metab 2002; 87(3):1052–1056. 6. Dieckmann K, Loy V: Metachronous germ cell and Leydig cell tumors of the testis: Do testicular germ cell tumors and Leydig cell tumors share common etiologic factors? Cancer 1993; 72:1305–1307. 7. Poster RB, Katz DS: Leydig cell tumor of the testis in Klinefelter syndrome: MR detection. J Comput Assis Tomogr 1993; 17:480–481. 8. Calleja RK, Rice A, Bullock KN: Unilateral Leydig cell tumour associated with a contralateral undescended testis. BJU Int 1999; 83(1):152. 9. Hekimgil M, Altay B, Yakut BD, et al: Leydig cell tumor of the testis: comparison of histopathological and immunohistochemical features of three azoospermic cases and one malignant case. Pathol Int 2001; 51(10):792–796. 10. Mostafid H, Nawrocki J, Fletcher MS, Vaughan NJ, Melcher DH: Leydig cell tumour of the testis: a rare cause of male infertility. Br J Urol 1998; 81(4):651. 11. Soria JC, Durdux C, Chretien Y, et al: Malignant Leydig cell tumor of the testis associated with Klinefelter’s syndrome. Anticancer Res 1999; 19(5C):4491–4494. 12. Fowler KA, Gill K, Kirma N, Dillehay DL, Tekmal RR: Overexpression of aromatase leads to development of testicular Leydig cell tumors: an in vivo model for hormone-mediated testicular cancer. Am J Pathol 2000; 156(1):347–353. 13. Liu G, Duranteau L, Carel JC, et al: Leydig-cell tumors caused by an activating mutation of the gene encoding the luteinizing hormone receptor. N Engl J Med 1999; 341(23):1731–1736. 14. Masoudi JF, Van Arsdalen K, Rovner ES: Organ-sparing surgery for bilateral Leydig cell tumor of the testis. Urology 1999; 54(4):744. 15. Gittes RF, Smith G, Conn CA, Smith F: Local androgenic effect of interstitial cell tumor of the testis. J Urol 1970; 104:774–777. 16. Kim F, Young RH, Scully RE: Leydig cell tumors of the testis. A clinicopathologic analysis of 40 cases and review of the literature. Am J Surg Pathol 1985; 9:177. 17. Cheville JC, Sebo TJ, Lager DJ, Bostwick DG, Farrow GM: Leydig cell tumor of the testis: a clinicopathologic, DNA content, and MIB-1 comparison of nonmetastasizing and metastasizing tumors. Am J Surg Pathol 1998; 22:1361–1367. 18. Gulbahce HE, Lindeland AT, Engel W, Lillemoe TJ: Metastatic Leydig cell tumor with sarcomatoid differentiation. Arch Pathol Lab Med 1999; 123(11):1104–1107.
19. Palazzo JP, Petersen RO, Young RH, Scully RE: Deoxyribonucleic acid flow cytometry of testicular Leydig cell tumors. J Urol 1994; 152:415–417. 20. McCluggage WG, Shanks JH, Arthur K, Banerjee SS: Cellular proliferation and nuclear ploidy assessments augment established prognostic factors in predicting malignancy in testicular Leydig cell tumours. Histopathology 1998; 33(4):361–368. 21. Ulbright TM, Srigley JR, Hatzianastassiou DK, Young RH: Leydig cell tumors of the testis with unusual features: adipose differentiation, calcification with ossification, and spindle-shaped tumor cells. Am J Surg Pathol 2002; 26(11):1424–1433. 22. Kirkland RT, Kirkland JL, Keenan BS, et al: Bilateral testicular tumors in congenital adrenal hyperplasia. J Clin Endocrinol Metab 1977; 44:369–378. 23. Rich MA, Keating MA, Levin HS, Kay R: Tumors of the adrenogenital syndrome: an aggressive conservative approach. J Urol 1998; 160(5):1838–1841. 24. Stikkelbroeck NM, Otten BJ, Pasic A, et al: High prevalence of testicular adrenal rest tumors, impaired spermatogenesis, and Leydig cell failure in adolescent and adult males with congenital adrenal hyperplasia. J Clin Endocrinol Metab 2001; 86(12):5721–5728. 25. Davis JM, Woodroof J, Sadasivan R, Stephens R: Case report: congenital adrenal hyperplasia and malignant Leydig cell tumor. Am J Med Sci 1995; 309:63–65. 26. Levin HS: Tumors of the testis in intersex syndromes. Urol Clin North Am 2000; 27(3):543–551. 27. Bertram KA, Bratloff B, Hodges GF, Davidson H: Treatment of malignant Leydig cell tumor. Cancer 1991; 68:2324–2329. 28. van der Hem KG, Boven E, van Hennik MB, Pinedo HM: Malignant Leydig cell tumor of the testis in complete remission on o,p′-dichlorodiphenyldichloroethane. J Urol 1992; 148(4):1256–1259. 29. Young RH, Koelliker DD, Scully RE: Sertoli cell tumors of the testis, not otherwise specified: a clinicopathologic analysis of 60 cases. Am J Surg Pathol 1998; 22(6):709–721. 30. Zukerberg LR, Young RH, Scully RE: Sclerosing Sertoli cell tumor of the testis: a report of 10 cases. Am J Surg Pathol 1991; 15:829–834. 31. Gravas S, Papadimitriou K, Kyriakidis A: Sclerosing Sertoli cell tumor of the testis—a case report and review of the literature. Scand J Urol Nephrol 1999; 33(3):197–199. 32. Proppe KH, Scully RE: Large-cell calcifying Sertoli cell tumor of the testis. Am J Clin Pathol 1980; 74:607–619. 33. Proppe KH, Dickerson GHL: Large-cell calcifying Sertoli cell tumor of the testis. Hum Pathol 1982; 13:1109–1114. 34. Tetu B, Ro JY, Ayala AG: Large cell calcifying Sertoli cell tumor of the testis: a clinicopathologic, immunohistochemical and ultrastructural study of two cases. Am J Clin Pathol 1991; 96:717–722. 35. Kratzer SS, Ulbright TM, Talerman A, et al: Large cell calcifying Sertoli cell tumor of the testis: contrasting features of six malignant and six benign tumors and a review of the literature. Am J Surg Pathol 1997; 21(11):1271–1280.
Chapter 37 Nongerm Cell Tumors of the Testis 639 36. Nogales FF, Andujar M, Zuluaga A, Garcia-Puche JL: Malignant large cell calcifying Sertoli cell tumor of the testis. J Urol 1995; 153:1935–1937. 37. Cano-Valdez AM, Chanona-Vilchis J, DominguezMalagon H: Large cell calcifying Sertoli cell tumor of the testis: a clinicopathological, immunohistochemical, and ultrastructural study of two cases. Ultrastruct Pathol 1999; 23(4):259–265. 38. Dryer L, Jacyk WK, du Plessis DJ: Bilateral large-cell calcifying Sertoli cell tumor of the testes with Peutz–Jeghers syndrome: a case report. Pediatr Dermatol 1994; 11:335–337. 39. Washecka R, Dresner MI, Honda SA: Testicular tumors in Carney’s complex. J Urol 2002; 167(3):1299–1302. 40. Young RH, Scully RE (eds): Testicular Tumors, pp 140–150. Chicago, ASCP Press, 1990. 41. Rutgers JL, Scully RE: Pathology of the testis in intersex syndromes. Semin Diagn Pathol 1987; 4:275–291. 42. Wysocka B, Serkies K, Debniak J, Jassem J, Limon J: Sertoli cell tumor in androgen insensitivity syndrome—a case report. Gynecol Oncol 1999; 75(3):480–483. 43. Athanassiou AE, Barbounis V, Dimitriadis M, Pectasidis D, Bafaloukos D: Successful chemotherapy for disseminated testicular Sertoli cell tumour. Br J Urol 1988; 61(5):456–457. 44. Jimenez-Quintero LP, Ro JY, Zavala-Pompa A, et al: Granulosa cell tumor of the adult testis: a clinicopathologic study of seven cases and a review of the literature. Hum Pathol 1993; 24:1120–1126. 45. Al-Bozom IA, El-Faqih SR, Hassan SH, El-Tiraifi AE, Talic RF: Granulosa cell tumor of the adult type: a case report and review of the literature of a very rare testicular tumor. Arch Pathol Lab Med 2000; 124(10):1525–1528. 46. Morgan DR, Brame KG: Granulosa cell tumour of the testis displaying immunoreactivity for inhibin. BJU Int 1999; 83(6):731–732. 47. Nieto N, Torres-Valdivieso MJ, Aguado P, et al: Juvenile granulosa cell tumor of the testis: case report and review of literature. Tumori 2002; 88(1):72–74. 48. Lawrence WD, Young RH, Scully RE: Juvenile granulosa cell tumor of the infantile testis. Am J Surg Pathol 1985; 9:87–94. 49. Tanaka Y, Sasaki Y, Tachibana K, et al: Testicular juvenile granulosa cell tumor in an infant with X/XY mosaicism clinically diagnosed as true hermaphroditism. Am J Surg Pathol 1994; 18:316–322. 50. Paquis-Flucklinger V, Rassoulzadegan M, Michiels J-F: Experimental Sertoli cell tumors in the mouse and their progression into a mixed germ cell-sex cord proliferation. Am J Pathol 1994; 144:454–459. 51. Lawrence WD, Young RH, Scully RE: Sex cord-stromal tumors. In Talerman A, Roth LM (eds): Pathology of the Testis and its Adnexa, Vol 7, Chap 4, Contemporary Issues in Surgical Pathology, pp 67–92. New York, Churchill Livingstone, 1986. 52. Dieckmann K-P, Loy V: Response of metastasized sex cord gonadal stromal tumor of the testis to cisplatin-based chemotherapy. J Urol 1994; 151:1024–1026. 53. Gohji K, Higuchi A, Fujii A, Kizaki T: Malignant gonadal stromal tumor. Urology 1994; 43:244–247.
54. Stewart DA, Stewart DJ, Mai KT: Active chemotherapy for metastatic stromal cell tumor of the testis. Urology l993; 42:732–734. 55. Price EB Jr: Epidermoid cysts of the testis: a clinical and pathologic analysis of 69 cases from the testicular tumor registry. J Urol 1969; 102:708–731. 56. Cho JH, Chang JC, Park BH, Lee JG, Son CH: Sonographic and MR imaging findings of testicular epidermoid cysts. AJR Am J Roentgenol 2002; 178(3):743–748. 57. Ross JH, Kay R, Elder J: Testis sparing surgery for pediatric epidermoid cysts of the testis. J Urol l993; 149:353–356. 58. Davi RC, Braslis KG, Perez JL, Soloway MS: Bilateral epidermoid cysts of the testis. Eur Urol 1996; 29(1):122–124. 59. Baniel J, Perez JM, Foster RS: Benign testicular tumor associated with Klinefelter’s syndrome. J Urol 1994; 151:157–158. 60. Orozco RE, Murphy WM: Carcinoma of the rete testis: case report and review of the literature. J Urol l993; 150:974–977. 61. Stein JP, Freeman JA, Esrig D, Chandrasoma PT, Skinner DG: papillary adenocarcinoma of the rete testis: a case report and review of the literature. Urology 1994; 44:588–594. 62. Jones MA, Young RH, Scully RE: Malignant mesothelioma of the tunica vaginalis. A clinicopathologic analysis of 11 cases with review of the literature. Am J Surg Pathol 1995; 19:815–825. 63. Iczkowski KA, Katz G, Zander DS, Clapp WL: Malignant mesothelioma of tunica vaginalis testis: a fatal case with liver metastasis. J Urol 2002; 167(2 Pt 1):645–646. 64. Plas E, Riedl CR, Pfluger H: Malignant mesothelioma of the tunica vaginalis testis: review of the literature and assessment of prognostic parameters. Cancer 1998; 83(12):2437–2446. 65. De Nictolis M, Tommasoni S, Fabris G, Prat, J: Intratesticular serous cystadenoma of borderline malignancy. A pathological, histochemical and DNA content study of a case with long-term follow-up. Virchows Archiv A Pathol Anat 1993; 423:221–225. 66. Price EB Jr, Mostofi FK: Secondary carcinoma of the testis. Cancer 1957; 10:592–595. 67. Tiltman AJ: Metastatic tumors of the testis. Histopathology 1979; 3:31–37. 68. Haupt HM, Mann RB, Trump DL, Abeloff MD: Metastatic carcinoma involving the testis. Clinical and pathologic distinction from primary testicular neoplasms. Cancer 1984; 54:709–714. 69. Zavala-Pompa A, Ro JY, el-Naggar A, et al: Primary carcinoid tumor of testis. Immunohistochemical, ultrastructural and DNA flow cytometric study of three cases with a review of the literature. Cancer 1993; 72:1726–1732. 70. Peterson RO (ed): Urologic Pathology, 2nd edition, p 451. Philadelphia, JB Lippincott, 1992. 71. Horstman WG, Sands JP, Hooper DG: Adenomatoid tumor of testicle. Urology 1992; 40(4):359–361.
640
Part VI Testis
72. Samad AA, Pereiro B, Badiola A, Gallego C, Zungri E: Adenomatoid tumor of intratesticular localization. Eur Urol 1996; 30(1):127–128. 73. Hurley LJ, Burke CR, Shetty SK, et al: Bilateral primary non-Hodgkin’s lymphoma of the testis. Urology 1996; 47(4):596–598. 74. Gowing NFC: Malignant lymphoma of the testis. In Pugh RCB (ed): Pathology of the Testis, pp 334–355. Oxford, Blackwell Scientific Publications, 1976. 75. Ferry JA, Harris NL, Young RH, et al: Malignant lymphoma of the testis, epididymis and spermatic cord. A clinicopathologic study of 69 cases with immunophenotypic analysis. Am J Surg Pathol 1994; 18:376–390. 76. Turner RR, Colby TV, MacKintosh FR: Testicular lymphomas, a clinicopathologic study of 35 cases. Cancer 1981; 48:2095–2102. 77. Lagrange JL, Ramaioli A, Theodore CH, et al: Radiation Therapy Group and the Genito-Urinary Group of the French Federation of Cancer Centres. Non-Hodgkin’s lymphoma of the testis: a retrospective study of 84 patients treated in the French anticancer centres. Ann Oncol 2001; 12(9):1313–1319. 78. Zucca E, Conconi A, Mughal TI, et al: Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the international extranodal lymphoma study group. J Clin Oncol 2003; 21(1):20–27. 79. Pakzad K, MacLennan GT, Elder JS, et al: Follicular large cell lymphoma localized to the testis in children. J Urol 2002; 168(1):225–228. 80. Finn LS, Viswanatha DS, Belasco JB, et al: Primary follicular lymphoma of the testis in childhood. Cancer 1999; 85(7):1626–1635. 81. Pileri SA, Sabattini E, Rosito P, et al: Primary follicular lymphoma of the testis in childhood: an entity with peculiar clinical and molecular characteristics. J Clin Pathol 2002; 55(9):684–688.
82. Suzuki K, Shioji Y, Morita T, Tokue A: Primary testicular plasmacytoma with hydrocele of the testis. Int J Urol 2001; 8(3):139–140. 83. Levin HS, Mostofi FK: Symptomatic plasmacytoma of the testis. Cancer 1970; 25:1193–1203. 84. Reddi VR, Anne GP, Rani AV, et al: Primary plasmacytoma of testis. Report of a case. Indian J Cancer 1998; 35(4):152–155. 85. Fischer C, Terpe HJ, Weidner W, Schulz A: Primary plasmacytoma of the testis. Case report and review of the literature. Urol Int 1996; 56(4):263–265. 86. Givler RL: Testicular involvement in leukemia and lymphoma. Cancer 1969; 23:1290–1295. 87. Buchanan GR, Boyett JM, Pollock BH, et al: Improved treatment results in boys with overt testicular relapse during or shortly after initial therapy for acute lymphoblastic leukemia. A Pediatric Oncology Group Study. Cancer 1991; 68:48–55. 88. Leibovitch I, Baniel J, Rowland RG, et al: Malignant testicular neoplasms in immunosuppressed patients. J Urol 1996; 155(6):1938–1942. 89. Wilson WT, Frenkel E, Vuitch F, Sagalowsky AI: Testicular tumors in men with human immunodeficiency virus. J Urol 1992; 147:1038–1040. 90. Ramadan A, Naab T, Frederick W, Green W: Testicular plasmacytoma in a patient with the acquired immunodeficiency syndrome. Tumori 2000; 86(6):480–482. 91. Munver R, Donehower RC, Kronz JD, Polascik TJ: HIV infection presenting as an unusually large pure yolk sac tumor of the testis. J Urol 2000; 164(5):1653–1654. 92. Young RH, Scully RE: Testicular and paratesticular tumors and tumor-like lesions of ovarian common epithelial and Mullerian types. Am J Clin Pathol 1986; 86:146–152. 93. Jones MA, Young RH, Srigley JR, Scully RE: Paratesticular serous papillary carcinoma. A report of six cases. Am J Surg Pathol 1995; 19:1359–1365.
C H A P T E R
38 Radical Orchiectomy and Retroperitoneal Lymph Node Dissection Richard S. Foster, MD, Ashraf Mosharafa, MD, and Richard Bihrle, MD
RADICAL ORCHIECTOMY General Considerations Approximately 95% of primary intratesticular tumors are of germ cell origin. The other 5% of tumors consist of a variety of benign and malignant lesions. These include Leydig cell and Sertoli cell tumors, adrenal cortical rests, and other benign lesions.1 Similarly, secondary tumors of the testis may occur rarely and mainly are hematopoietic in origin. Hence, patients presenting with a tumor that is intratesticular are usually found histologically to have a germ cell tumor. Most patients present with a palpable intratesticular mass. Typically, the mass is firm and definitely different from the consistency of normal testicular tissue. If such a lesion is discovered, immediate determination of serum alpha fetoprotein and beta-HCG is necessary and the elevation of either of these markers confirms the diagnosis of a germ cell tumor. If the tumor is palpable, testicular ultrasound is not necessary and the patient may be taken immediately to radical inguinal orchiectomy. Alternatively, if there is doubt as to the diagnosis, transscrotal ultrasound is useful and the finding of an intratesticular abnormality on testicular ultrasound in a patient in the appropriate age range for germ cell tumors may confirm the diagnosis. Magnetic resonance imaging has been studied in the diagnosis of testicular tumors but is rarely needed clinically.2 Historically, radical inguinal orchiectomy meant removal of the testis and cord but sometimes also included an extension of the incision and palpation of the retroperitoneum.3 With modern imaging and staging techniques this extension of the incision to palpate the retroperitoneum is not necessary. Currently, radical
inguinal orchiectomy includes an inguinal approach to high ligation of the spermatic cord at the internal ring and the subsequent removal of the testis. It is typically performed as an outpatient procedure. The technique is relatively straightforward; an inguinal incision is made parallel to the inguinal ligament and the dissection is carried through the subcutaneous tissues to the aponeurosis of the external oblique. The external ring is identified, and the aponeurosis of the external oblique is split from the external ring to the internal ring. Cremasteric fibers are divided and the ilioinguinal nerve is identified and dissected from the cord structures. Next, the cord is dissected from the inguinal floor and circumferential control is attained at the internal ring. If the decision has been made to perform inguinal orchiectomy, the cord is divided into 2 segments with a large clamp, after which the segments are ligated with permanent sutures and/or suture ligatures. Sometimes it is necessary to dissect the peritoneum away from the medial aspect of the cord prior to performing ligation. Typically, after ligating the cord the cord stump retracts into the abdomen through the internal ring. This facilitates removal of the cord stump at subsequent retroperitoneal lymph node dissection (RPLND). After ligation of the cord the dissection is carried distally with subsequent mobilization of the testis through the upper part of the scrotum and division of the gubernacular fibers. If the testis tumor is so large that it cannot be easily delivered through the opening in the scrotum, the incision is extended on to the scrotum in order to remove the testis intact. After hemostasis is obtained the aponeurosis of the external oblique and Scarpa’s fascia are subsequently closed. Typically, the skin is closed using a running subcuticular suture.
641
642
Part VI Testis
If the diagnosis is unclear at the time of exploration and a frozen section is necessary, the same steps are performed with the exception of early division of the cord. Typically, if a frozen section is to be obtained, a tourniquet is applied to the cord at the internal ring after which the testis is mobilized up into the incision. Drapes are placed over the incision and the frozen section is done away from the incision itself so as to not spill tumor into the incision. Subsequently, if a frozen section diagnosis confirms a germ cell tumor, the radical orchiectomy is completed. The reasoning behind an inguinal approach to a germ cell tumor of the testis is to avoid spilling tumor into the wound. Typically, germ cell tumor implants and if tumor is spilled into the inguinal area, potentially another area of lymphatic drainage (inguinal nodes) is contaminated. Historically, if a scrotal approach to a testis tumor was carried out, a subsequent recommendation was made to perform hemi-scrotectomy so as to avoid contamination of the inguinal lymphatics. With the advent of systemic chemotherapy this procedure now is rarely necessary although the inguinal approach to radical orchiectomy continues to be the standard of care and should be appropriate management for any patient presenting with a germ cell tumor of the testis.4 Approximately 1% to 2% of all patients who present with a testicular germ cell tumor will develop a subsequent tumor on the contralateral side.5 Historically, radical inguinal orchiectomy was performed for the second tumor and the patient was placed on testosterone supplementation so as to maintain libido and sexuality. It is now clear that small secondary tumors at the polar aspects of the testis can be managed by partial orchiectomy with good long-term results. Most series of partial orchiectomy have recommended postoperative radiation therapy to the testis, which prevents local recurrence and eradicates carcinoma in situ in the remaining testicular tissue.6 The benefit of this approach is that over the long term these patients are able to sustain production of androgens from the remaining Leydig cells and therefore do not need supplementation. However, the postoperative radiation therapy effectively eliminates fertility, and therefore the benefit of partial orchiectomy is to maintain adequate androgen serum levels. RETROPERITONEAL LYMPH NODE DISSECTION The germ cell tumors of the testis are not only chemosensitive but also “surgery sensitive.” Even after lymphatic metastasis has occurred, the surgical removal of involved lymph nodes may be curative from 50% to 75% of the time, dependent on the volume of metastatic disease.7,8 Most other cancers (breast, colon, lung, etc.) are not surgically curable if lymphatic metastasis occurs; germ cell testis tumors are surgically curable in the face
of lymphatic metastasis. From a urologic point of view, this is perhaps the most unique aspect of the surgical treatment of germ cell tumors. Hence, since surgery may be curative in many patients with metastatic germ cell tumor, urologic oncologists necessarily need to understand and be proficient in techniques of removal of lymph nodes in the retroperitoneum. RPLND is essentially two different operations; one operation for low-stage disease in patients who have not received chemotherapy and a completely different operation for those patients who require an RPLND for a residual mass after chemotherapy. These two techniques are discussed separately. RETROPERITONEAL LYMPH NODE DISSECTION FOR LOW-STAGE DISEASE Low-stage seminoma is not managed surgically and the discussion here relates only to low-stage nonseminoma. Clinical stage I disease is defined as no evidence of metastasis on radiologic imaging. Typically, this involves CT scanning of the abdomen and chest. Some prefer only a chest x-ray as opposed to a CT of the chest. Additionally, serum alpha fetoprotein and beta-hCG should have normalized after radical orchiectomy or alternatively should be decaying based on normal half-lives of approximately 5 days for alpha fetoprotein and 11⁄2 days for beta-hCG.9 If the patient has no evidence of metastasis on radiologic imaging but these markers are not normalizing according to half-life, the patient should be treated with chemotherapy because of the high probability of having occult systemic disease.10,11 Several alternatives for management exist in clinical stage I that in the short term yield roughly the equivalent chance for survival. These alternatives include RPLND (with nerve sparing), surveillance with chemotherapy at relapse, or primary chemotherapy. Pro and con arguments exist for each of these approaches depending on long-term side effects, psychologic issues, access to health care, etc. As opposed to surveillance, the benefits of RPLND include the immediate determination of pathologic stage, the avoidance of chemotherapy (since many of these patients are cured with surgery alone), and the elimination of the necessity of using CT scans of the abdomen in follow-up. Conversely, the follow-up period after RPLND is only 2 years, whereas patients managed on surveillance have to be followed for a longer period of time.12 Similarly, the main benefit of surveillance is that patients who have no metastasis receive no treatment and only patients documented to have metastatic disease are subject to any sort of therapy. Approximately 30% of clinical stage I patients are subsequently found to have metastatic disease.13 Generally, metastatic tumor is found in retroperitoneal lymphatics. Rarely, the retroperitoneum is normal and metastasis is
Chapter 38 Radical Orchiectomy and Retroperitioneal Lymph Node Dissection 643
hematogenous only. Hence, the high probability of retroperitoneal metastasis is the rationale for performing RPLND. Risk factors identified in the orchiectomy specimen may increase the probability of metastasis to 50%, but prediction of metastasis at a higher level than 50% is not possible.14 Therefore, clinical stage I patients will have a 50% to 70% chance of having normal lymph nodes removed. Since some patients who undergo RPLND for clinical stage I disease have no metastasis, it is important and pertinent to limit the morbidity of the procedure. Currently, RPLND for low-stage disease has an acceptably very low morbidity, which consists of about a 1% chance of developing a subsequent small bowel obstruction and a 3% to 5% chance of an abdominal incisional hernia.15 The operative procedure is approximately 2 to 2 hours in length. Transfusions are not required and the average hospitalization is about 3.3 days. Return to full physical activity occurs in three to 6 weeks depending on age of the patient and body habitus. TECHNIQUE FOR LOW-STAGE DISEASE In low-stage nonseminoma mapping studies have shown that metastatic spread is unilateral.16 Hence, for a patient presenting with a right-sided primary, the involved lymphatics are usually interaortocaval, precaval, and right paracaval (Figure 38-1). Similarly, for a left-sided primary, the involved lymphatics are typically left paraaortic and preaortic (Figure 38-2). Though historically full bilateral RPLND was performed (Figure 38-3), these mapping studies illuminated the fact that a unilateral template could be used. This was important since a unilateral template dissection preserved contralateral sympathetics important for emission and ejaculation. These so-called modified templates preserved ejaculation at the 30% to 90% level, depending on individual technique.7,8 In order to further minimize morbidity, it was necessary to improve the technique to maintain emission and ejaculation at a higher level. These modifications were termed nerve sparing since nerve-sparing RPLND involves the prospective dissection of efferent sympathetic fibers followed by removal of lymphatics based on a unilateral template (Figure 38-4).17,18 Thus, nerve-sparing RPLND preserves sympathetic nerves bilaterally whereas a template dissection preserves only contralateral nerves. The prospective dissection and preservation of efferent sympathetic fibers maintains emission and ejaculation at the 99% level. Right Nerve-Sparing RPLND A midline incision is made and a self-retaining retractor is used. A general palpation and inspection of the abdomen is performed and in the rare circumstance of
Figure 38-1 The template of dissection for a patient presenting for a right-sided primary is displayed.
discovery of higher-volume metastasis than was predicted by preoperative scans, a full bilateral dissection may be required. Currently, CT scans are high resolution and the intraoperative discovery of unsuspected high-volume metastasis is rare. After palpation and inspection an incision is made in the posterior peritoneum from the cecum to the area of the ligament of Treitz. The root of the small bowel and the right colon are reflected to the patient’s right and held in place with self-retaining retractors. The template of dissection includes the interaortocaval, precaval, and right paracaval lymph nodes. The so-called “split and roll” maneuver is employed. This is essentially a vascular isolation technique whereby lymphatic tissue is split at the 12 o’clock position over vessels and rolled laterally away from those vessels. RPLND is a vascular procedure. First, the split maneuver is performed over the left renal vein and tissue is rolled inferiorly. The anterior aspect of the aorta is identified posterior to the left renal vein and the split maneuver is carried out on the 12 o’clock position of the aorta from the crossing of the left renal vein
644
Part VI Testis
Figure 38-2 The template of dissection for a left-sided primary is displayed.
distally to the origin of the inferior mesenteric artery. Tissue is rolled medially into the interaortocaval zone in order to determine whether or not a lower pole rightsided precaval renal artery is present. Attention is then turned to the vena cava. The split maneuver is performed at the 12 o’clock position on the vena cava (Figure 38-5). The origin of the right gonadal vein is identified and divided between silk ties. It is subsequently dissected to the internal ring at which point the cord stump from the radical orchiectomy is identified, mobilized from the internal ring, and the specimen is removed as right gonadal vein. The roll maneuver is then performed on the vena cava after which all lumbar veins passing posteriorly from the cava to the posterior body wall are identified and divided between silk ties (Figure 38-6). Typically, the efferent sympathetic fibers from the right sympathetic chain pass cephalad to these lumbar veins. Care must be taken to not injure the nerves in the course of dividing the veins. The nerves are then dissected away from lymphatic tissue and placed in vessel loops. Typically, the right-sided nerves coalesce in the interaor-
Figure 38-3 Full bilateral RPLND includes the removal of right paracaval, interaortocaval, left peri-aortic, and interiliac nodal packages.
tocaval area and then pass distally into the interiliac area at the bifurcation of the aorta. Attention is then turned back to the aorta at which point the split maneuver is continued along the distal aorta and right common iliac artery. The nerves have been previously dissected and therefore are avoided in the process of this split maneuver. Tissue is rolled medially into the interaortocaval area and the right-sided lumbar arteries are divided between ties. The renal artery is typically seen passing over the crus of the diaphragm and lymphatic tissue, is dissected away from it. Finally, the right ureter is dissected laterally away from lymphatic tissue after which the right paracaval and interaortocaval nodal packages are dissected from the posterior body wall (Figure 38-7). Clips are used as necessary to secure lymphatics or to gain hemostasis from the lumbars as they penetrate the posterior body wall. Cautery is also helpful in this regard. After irrigation the posterior peritoneum is closed. Closure of the abdominal incision is performed using a looped absorbable suture.
Chapter 38 Radical Orchiectomy and Retroperitioneal Lymph Node Dissection 645
Figure 38-5 Viewed from the patient’s left side, the split maneuver on the superior portion of the aorta and the vena cava as performed for a right modified nerve-sparing RPLND is displayed.
Technique for Left-Sided Nerve-Sparing RPLND
Figure 38-4 The anatomy of retroperitoneal sympathetic nerves in relationship to the vascular structures is shown.
For a left-sided dissection, after palpation and inspection has been performed, an incision is made in the posterior peritoneum lateral to the left colon. The left colon is mobilized medially and held in place with self-retaining retractors. The first step in a left-sided dissection is to identify the efferent sympathetic fibers. Typically, these can be seen coursing anterior to the left common iliac artery and can be dissected away from lymphatic tissue and placed in vessel loops (Figure 38-8). If these fibers are not easily seen at this level an alternative approach is to mobilize the left ureter laterally and roll lymphatic tissue off the psoas muscle to expose the sympathetic chain. The efferent fibers can then be seen passing from the sympathetic chain to the interiliac area. After the nerve
Figure 38-6 Mobilization of the vena cava is performed by rolling lymphatic tissue away from the vena cava, identifying the lumbar veins and subsequently dividing them. The three lumbar veins passing to the posterior body wall are shown in the figure prior to division.
646
Part VI Testis
Figure 38-7 In a completed right modified nerve-sparing RPLND all lymphatic tissue is removed in the interaortocaval and right para-caval packages. Shown in the figure are the mobilized vena cava, the sympathetic chain, and the efferent sympathetic fibers in vessel loops.
Figure 38-9 The lymphatic tissue has been rolled away from the left side of the aorta. Two lumbar arteries passing posteriorly are seen. A silk tie has been passed around one in preparation for subsequent ligation distally and division of the lumbar artery.
fibers are identified they are dissected slightly proximally. In a left-sided dissection, the lymphatics intermingle with the efferent fibers and the dissection is technically slightly more difficult because of this. The split maneuver is performed over the left renal vein and tissue is rolled inferiorly. The origin of the left gonadal vein is identified, dissected, and divided between silk ties. The left gonadal vein is then dissected to the internal ring at which point the cord stump is mobilized from the internal ring and the left gonadal vein specimen is removed.
Next, the split maneuver is performed on the aorta from the crossing of the left renal vein distally to the bifurcation of the left common iliac artery. The bifurcation of the left common iliac represents the lower boundary of the dissection. Tissue is rolled into the left paraaortic area and the left-sided lumbar arteries are identified, dissected, and divided between silk ties (Figure 38-9). Care must be taken to determine whether or not lower pole renal arteries exist and these should be preserved if possible. The ureter is dissected laterally away
Figure 38-8 In this figure the anatomy of left-sided sympathetic efferent fibers is shown. Note the confluence of the fibers anterior to the left common iliac artery. Right-sided fibers join the left-sided fibers in the inter-iliac area.
Chapter 38 Radical Orchiectomy and Retroperitioneal Lymph Node Dissection 647
from the lymphatic tissue and this represents the lateral boundary of the dissection. Finally, lymphatic tissue is dissected off the posterior body wall as one package taking care to avoid the sympathetic chain and the efferent sympathetic fibers passing into the interiliac area. At the renal hilum lymphatic tissue is dissected away from the renal artery and clips are applied at the crus of the diaphragm. The left colon is then placed back in the anatomic position and the abdomen is closed as noted earlier with a running, looped absorbable suture. POSTOPERATIVE MANAGEMENT Historically, nasogastric tubes were used because of the suspicion of the postoperative paralytic ileus. Currently, no postoperative nasogastric decompression is necessary. Patients are given liquids the day after the procedure and subsequently are advanced to full diet. The average hospitalization for this procedure is around 3 days and return to full physical activity is three to 6 weeks. Patients are followed postoperatively with chest x-rays, physical examination, and determination of serum alpha-fetoprotein and beta-hCG. This monitoring typically is performed for 2 years. The frequency of these examinations is contingent on the pathologic stage. CT scans of the abdomen are not necessary postoperatively.
POSTCHEMOTHERAPY RETROPERITONEAL LYMPH NODE DISSECTION Indications Patients who present with high volume distant metastatic germ cell cancer are typically managed with systemic chemotherapy. After the administration of systemic chemotherapy, if serum alpha-fetoprotein and beta-hCG have normalized and no evidence of metastatic tumor remains on radiographic imaging, patients are observed. The probability of relapse in this clinical situation is low and hence observation is reasonable. Some centers advocate postchemotherapy RPLND in the absence of persistent radiographic tumor if the transverse diameter of disease in the retroperitoneum before chemotherapy was >3 cm.19 However, the practice at Indiana University is to observe patients with a complete clinical remission.20 If patients normalize serum markers and have persistent tumor on radiographic imaging in the retroperitoneum, postchemotherapy RPLND is advised (Figure 38-10). Histologically, remaining tumor consists of teratoma in 40% to 60% of cases, fibrosis and necrosis in approximately 40% of cases, and persistent germ cell cancer (or nongerm cell cancer arising in a teratoma) in 5% to 10% of cases. The surgical removal of teratoma or cancer is therapeutic and hence the rationale for RPLND in these clinical situations is solid. However, the surgical
Figure 38-10 CT scan performed after chemotherapy in a patient with normal alpha fetoprotein and beta-hCG. Pathologically the resected tumor proved to be teratoma.
648
Part VI Testis
removal of necrosis confers no survival advantage on the patient and it would be desirable to select such patients preoperatively so as to avoid postchemotherapy RPLND. It is very difficult to clinically select for patients who have only necrosis and therefore RPLND is advised for any persistent mass. Exceptions to this rule include those patients with pure seminoma managed with systemic chemotherapy and some highly selected patients with no teratoma in the orchiectomy specimen who experience a dramatic response to systemic chemotherapy. However, controversy exists in the management of the postchemotherapy mass in pure seminoma patients. Some advocate resection of the mass if it is >3 cm in transverse diameter; at Indiana University these patients are observed because of the high probability of the mass containing fibrosis only.21,22 Rarely, postchemotherapy RPLND is recommended in patients who have not experienced a normalization of serum AFP or HCG. These are very highly selected patients who have failed all systemic chemotherapy but have a persistent retroperitoneal mass. Since beta-HCG and/or alpha fetoprotein are elevated, germ cell cancer remains within the mass. Postchemotherapy RPLND in this situation is termed “desperation RPLND” but is capable of curing such patients around 30% of the time.23 It is truly remarkable that in this situation of chemo refractory metastatic disease surgery remains a therapeutic option. Testis cancer is a unique and interesting disease. TECHNIQUE OF POSTCHEMOTHERAPY RPLND Generally, postchemotherapy RPLND is a full bilateral dissection, which includes the resection of tumor and lymphatics from the crus of the diaphragm to the bifurcation of the common iliac arteries, from ureter to ureter. The reasoning behind performing a full bilateral dissection is that mapping studies showed that the higher volume of metastasis, the greater the likelihood of bilateral retroperitoneal disease. It is clear, however, that highly selected patients do not require full bilateral RPLND and that the likelihood of bilateral disease in some patients is very low. Typically, these are patients who have been administered so-called good risk chemotherapy and initially presented with relatively low volume metastatic disease to the retroperitoneum. However, generally, full bilateral RPLND is recommended. The type incision is contingent on the position and size of the tumor. Depending on the individual patient, a midline, chevron, supra 11th extra pleural approach, or thoracoabdominal approach may be used. The same techniques employed in low-stage disease are used in postchemotherapy RPLND. These techniques include the split and roll technique and in highly selected patients, nerve sparing. However, in postchemotherapy RPLND
there is commonly a fibrotic and desmoplastic reaction in the retroperitoneum that makes tumor and lymphatics quite adherent to surrounding structures, such as the aorta, the vena cava, and the renal arteries and veins. Dissection along the great vessels should be in an extra adventitial plane so as to not weaken these vessels, which can lead to significant vascular problems. Surgeons who undertake postchemotherapy RPLND should be well versed in techniques of vascular control and repair, as this essentially is a vascular procedure. The “subtraction” technique was initially described by Donohue. This technique employs the prospective dissection of the vessels away from tumor followed by resection of tumor and lymphatics from the posterior body wall (Figure 38-11). Hence, after the incision is made, the retroperitoneum is exposed by incising in the posterior peritoneum from the foramen of Winslow distally around the cecum up to the area of the inferior mesenteric vein. The inferior mesenteric vein is divided and the right colon and root of the small bowel is dissected off the retroperitoneum and retracted onto the patient’s chest with a self-retaining retractor. Typically, tumor does not invade the mesentery but sometimes may invade the duodenum, which requires resection of duodenum and subsequent repair. Fortunately, invasion of the duodenum is relatively rare and typically the bowel is easily dissected onto the patient’s chest. The split maneuver is then performed on the left renal vein and tissue is rolled inferiorly. The anterior aspect of the aorta is identified and the split maneuver is performed on the aorta at the 12 o’clock position from the crossing of the left renal vein distally to the origin in the inferior mesenteric artery. For full bilateral dissection the inferior mesenteric artery is typically dissected and divided between silk
Figure 38-11 The subtraction concept involves the mobilization of great vessels away from retroperitoneal tumor and lymphatics with a subsequent resection of tumor and lymphatics from the posterior body wall. In this figure the aorta is being mobilized from tumor and lymphatics.
Chapter 38 Radical Orchiectomy and Retroperitioneal Lymph Node Dissection 649
ties. This allows the left mesocolon to be retracted laterally. Because testis cancer is typically a disease of young men, the vascularity of the left colon is maintained through collaterals and colon ischemic has not occurred in these postchemotherapy patients. The dissection is then carried distally along the aorta and along both common iliac arteries. The split maneuver is continued and subsequently tissue is rolled medially and laterally off the aorta and the common iliac arteries. Lumbar arteries are subsequently identified and divided. Typically, three lumbar arteries exist on each side of the aorta and their position is fairly predictable. Superiorly, the left gonadal vein is divided from the left renal vein, and the left renal vein and left renal artery are dissected from lymphatics and tumorous tissue. Attention is then turned to the vena cava. A similar split maneuver at the 12 o’clock position is performed on the vena cava. The origin of the right gonadal vein is divided and subsequently tissue, tumor, and lymphatics are rolled medially and laterally from the vena cava. The lumbar veins are identified, dissected, and divided between ties. The position and size of the lumbar veins is not as predictable as arterial lumbar anatomy. Lymphatics and tumor are dissected from the right renal artery as it passes over the lower portion of the crus of the diaphragm. Similarly, the ureters are dissected laterally away from the lymphatics and tumorous tissue. The gonadal vein is removed along with the cord stump, depending on the laterality of the primary. Finally, as the vessels and ureters have been dissected away from the tumor and lymphatics, these lymphatic packages are dissected from the posterior body wall. Typically, in full bilateral RPLND there will be four packages: the right paracaval, interaortocaval, left para-aortic, and interiliac. The bowel is then placed back in anatomic position and secured in anatomic position with running absorbable sutures. The bowel is run to make sure there is no evidence of any retractor injury, after which closure of the abdomen is performed. SPECIAL CONSIDERATIONS Preoperatively, postchemotherapy RPLND patients are given informed consent indicating that intraoperative decisions may be necessary. The decision to resect adjacent organs, such as bowel or kidneys, requires intraoperative judgment.24 A decision to resect an adjacent organ depends on the amount of adherence to the tumor and also the clinical situation. For instance, the threshold for resecting an adjacent organ is much lower in desperation RPLND as opposed to straightforward RPLND performed for a patient with low volume tumor and normal markers. However, a partial removal of tumor is not therapeutic and surgeons performing RPLND should have the mind set to remove all palpable and visual tumor.
Figure 38-12 Postchemotherapy, full bilateral RPLND with bilateral nerve sparing. Such patients maintain emission and ejaculation and if recovery from chemotherapy is complete may maintain fertility.
Nerve sparing is possible in some patients who undergo postchemotherapy RPLND.25 Indeed, some of these patients may recover fertility after recovery from the effects of chemotherapy. Again, the decision to perform nerve sparing is dependent on the clinical situation and intraoperative findings (Figure 38-12). The complications of postchemotherapy RPLND are generally more significant and frequent compared to primary RPLND.26 The major source of postoperative morbidity relates to the lungs, as many of these patients have received bleomycin as a part of the chemotherapeutic regimen. Typically, an effort is made to restrict fluids perioperatively so that if bleomycininduced ARDS occurs the patient is not volume overloaded. Other complications of postchemotherapy RPLND include ileus, lymphatic or chylous ascites, and other complications associated with a major surgical procedure. Nasogastric tubes are used variably and the hospitalization is typically more lengthy compared to primary RPLND. SUMMARY Germ cell tumors of the testis are not only chemo sensitive but also surgery sensitive. For optimal care of a patient with germ cell cancer chemotherapeutic therapies and surgical techniques are complimentary. Surgeons who perform these procedures should be well versed in techniques of vascular mobilization and control. Finally, though some of these procedures may be time consuming and arduous providing, excellent long-term outcomes are possible after complete surgical removal of metastatic tumor.
650
Part VI Testis
REFERENCES 1. Ulbright TM, Amin MB, Young RH: Tumors of the Testis, Adnexa, Spermatic Cord, and Scrotum. Washington, Armed Forces Institute of Pathology, 1999. 2. Thurnher S, Hricak H, Carroll PR, et al: Imaging the testis: comparison between MR staging and us. Radiology 1988; 167:633. 3. Hinman F: The operative treatment of tumors of the testicle with the report of thirty cases treated by orchiectomy. JAMA 1914; 63:2009. 4. Our scrotal violation paper. 5. Kristianslund S, Fossa SD, Kjellevold K: Bilateral malignant testicular germ cell cancer. Br J Urol 1986; 58:60. 6. Heidenreich A, Weissbach L, Holtl W, et al: Organ sparing surgery for malignant germ cell tumor of the testis. J Urol 2001; 166:2161. 7. Richie JP: Clinical stage I testicular cancer: the role of modified retroperitoneal lymphadenectomy. J Urol 1990; 144:1160. 8. Donohue JP, Thornhill JA, Foster RS, et al: Retroperitoneal lymphadenectomy for clinical stage A testis cancer (1965 to 1989): modifications of technique and impact on ejaculation. J Urol 1993; 149:237. 9. Nichols CR, Timmerman R, Foster RS, et al: Neoplasms of the testis in cancer medicine. Baltimore, Williams & Wilkins, 1997 10. Davis BE, Herr HW, Fair WR, et al: The management of the patients with nonseminomatous germ cell tumors of the testis with serologic disease only after orchiectomy. J Urol 1994; 152:111. 11. Saxman SB, Nichols CR, Foster RS, et al: The management of patients with clinical stage I nonseminomatous testicular tumors and persistently elevated serologic markers. J Urol 1996; 155:587. 12. Sharir S, Foster RS, Donohue JP, et al: What is the appropriate follow-up after treatment? Semin Urol Oncol 1996; 14:45. 13. Roeleveld TA, Horenblas S, Meinhardt W, et al: Surveillance can be the standard of cave for stage I nonseminomatous testicular tumors and even high risk patients. J Urol 2001; 166:2166.
14. Read G, Stenning SP, Cullen MH, et al: Medical research council prospective study of surveillance for stage I testicular teratoma. J Clin Oncol 1992; 10:1762. 15. Baniel J, Foster RS, Rowland RG, et al: Complications of primary retroperitoneal lymph node dissection. J Urol 1994; 152:424. 16. Donohue JP, Zachary J, Maynard B. Distribution of nodal metastases in nonseminomatous testis cancer. J Urol 1982; 128:315. 17. Jeweh MA, Kong YS, Goldberg SD, et al: Retroperitoneal lymphadenectomy for testis tumor with nerve sparing for ejaculation. J Urol 1988; 139:1220. 18. Donohue JP, Foster RS, Rowland RG, et al: Nervesparing retroperitoneal lymphadenectomy with preservation of ejaculation. J Urol 1990; 144:287. 19. Toner GC, Panicek DM, Heelan RT, et al: Adjunctive surgery after chemotherapy for nonseminomatous germ cell tumors: recommendations for patient selection. J Clin Oncol 1990; 8:1683. 20. Debono DJ, Heilman DK, Einhorn LH, et al: Decision analysis for avoiding post chemotherapy surgery in patients with disseminated nonseminomatous germ cell tumors. J Clin Oncol 1997; 15:1455. 21. Motzer R, Bosl G, Heelan R, et al: Residual mass: an indication for further therapy in patients with advanced seminoma following systemic chemotherapy. J Clin Oncol 1987; 5:1064. 22. Schutlz SM, Einhorn LH, Conces DJ, et al: Management of post chemotherapy residual mass in patients with advanced seminoma: Indiana University experience. J Clin Oncol 1989; 7:1497. 23. Donohue JP, Leibovitch I, Foster RS, et al: Integration of surgery and systemic therapy: results and principles of integration. Semin Urol Oncol 1998; 16:65. 24. Our nephrectomy paper. 25. Wahle, GR, Foster RS, Bihrle R, et al: Nerve-sparing retroperitoneal lymphadenectomy after primary chemotherapy for metastatic testicular carcinoma. J Urol 1994; 152:428. 26. Baniel J, Foster RS, Rowland RG, et al: Complications of postchemotherapy retroperitoneal lymph node dissection. J Urol 1994; 152:424.
C H A P T E R
39 Retroperitoneal Tumors: Diagnosis, Staging, Surgery, Management, and Prognosis S. Bruce Malkowicz, MD, and Victor Ferlise, MD
Retroperitoneal tumors are uncommon lesions that are important to the urologist because they occur in our surgical domain and often involve urologic organs. These lesions often present as very large lesions, which have been relatively indolent. Because of their rarity (0.5% to 1.0% of adult malignancies) it is important to be aware of the systematized approach to the treatment of these tumors. Beyond the attempt to attain complete surgical resection, it is difficult to outline the optimal treatment scheme for these lesions since there are few large cohorts of patients treated in a similar fashion. Additionally, many clinical reports have a combination of extremity, as well as retroperitoneal lesions mixed together in the results. The clinical assessment of these lesions and the surgical approach to therapy is fairly well outlined and remains the foundation of treatment. Radiation therapy and chemotherapy for these lesions continue to evolve, although their overall efficacy in retroperitoneal lesions is unclear. Primary sarcomas of the genitourinary organs are even rarer than primary retroperitoneal sarcomas. When radical extirpation is possible, it is usually the appropriate option, although in some instances, such as bladder lesions, other choices do exist. The evaluation of adjuvant and salvage therapies for these lesions is limited. But overall frequently with these lesions it is required to reorganize and appropriately treat these lesions. PRIMARY RETROPERITONEAL SARCOMA Incidence and Etiology Retroperitoneal sarcomas are rare tumors that account for only 0.1% to 0.2% of all malignant tumors and approximately 10% to 20% of all soft tissue sarcomas.1
Less than one-half of all retroperitoneal tumors are retroperitoneal sarcomas. Generally, 15% to 20% of retroperitoneal tumors are benign (e.g., lipoma). The remainders comprise lymphomas or primary urologic tumors.2 Approximately 500 to 1000 new cases of retroperitoneal sarcoma are diagnosed each year. Incidence figures on specific genitourinary sarcomas are difficult to establish due to the rarity of such lesions.2,3 Retroperitoneal sarcomas arise most commonly in the 5th and 6th decade of life, but age incidence may span from the 2nd to 8th decades.3,4 There is a slight male predominance but no distinct ethnic or racial distribution. While any histologic pattern may be seen at any age, rhabdomyosarcoma generally clusters in younger patients, even excluding the pediatric population, and malignant fibrous histiocytoma is usually seen in older age groups. Generally, these lesions are not associated with other conditions and a pattern of familial transmission has not been demonstrated. However, rare patients with neurofibromatosis may develop malignant schwannomas at an anatomic site.5 There is little known of the etiology of retroperitoneal sarcomas. Radiation injury, prior trauma, and environmental exposure to agents, such as dioxin and asbestos, have been implicated.6,7 Radiation may predispose patients to the development of sarcomas. Approximately 0.1% of patients treated with radiation therapy who survive >5 years may develop a sarcoma at that site.8 To qualify as a postradiation sarcoma a lesion must meet specific established criteria.6 In these cases, the sarcoma has to develop within the radiated field and prior documentation stating that the area was normal must be established. Additionally, histologic confirmation of the diagnosis is necessary, and a latency of at least 3 years is 651
652
Part VI Testis
required. There appears to be no difference in the incidence of postradiation-induced disease between those patients treated with orthovoltage and megavoltage. The most common postradiation tumor is the malignant fibrous histiocytomas (MFHs) followed by osteosarcoma and fibrosarcoma. Most of these postradiation-induced lesions appear to be of high grade and generally have poorer survival.8 Earlier epidemiologic studies reported that exposure to herbicides, such as dioxin and wood preservatives, may contribute to the development of retroperitoneal sarcomas.9 More recent data are mixed in its findings and may be affected by the particular herbicide used and the degree of dioxin contamination.10 In studies of Vietnam era soldiers exposed to Agent Orange, no significant association was found between the development of sarcomas and exposure in case control studies.11 In some industrial studies, an association was noted between dioxin exposure and the development of sarcomas if the exposure was prolonged (>1 year) and the period significant (over 20 years).12 No distinct viral or immunologic etiologies have been proposed for the development of retroperitoneal sarcomas. PATHOLOGY Retroperitoneal sarcomas arise primarily from soft tissues of fibrous and adipose origin, as well as muscle, nerve, and lymphatic tissues. These tissues are derived from primitive mesenchyme from the mesoderm with some contribution from neuroectoderm.13 Their location allows for a rather long indolent preclinical course at that time the tumor can grow to significant proportions. This growth may result in local areas of necrosis or liquefaction as the tumor outstrips its vascular supply. In classic reviews of these lesions the common tissue distribution in descending order is liposarcoma, leiomyosarcoma, and fibrosarcoma followed by other histologies.4,14–26 MFH figures much more prominently in contemporary series; however, owing to intensive pathologic interest in defining this disorder, many tumors previously described as variants of fibrosarcoma or liposarcoma have been reclassified as MFH.27,28 Therefore, fibrosarcoma has been replaced in frequency order by this condition. Although a well-developed understanding of the fundamental pathology of these lesions has not yet emerged, evaluation of the cytogenetic alterations in many sarcomas is beginning to suggest some molecular themes. Several of these tumors display specific chromosomal translocations. Although the translocations appear unique for specific tumors [t(12;16)(q13;p11) in myxoid liposarcoma] nearly all of these translocations result in the production of novel, tumor-specific, chimeric, transcription factors. These factors interact with the upstream regulatory component of a
gene and can significantly affect the expression of that gene at the messenger RNA level. The nucleic acid binding domain of the chimeric transcription factor confers target specificity within the tissue genome, while the transcription factor portion of this novel protein determines the transactivation potential and expression level of the target gene.29–31 Additionally, the development of extra abnormal chromosomes (ring chromosomes and giant rods) involving chromosome 12 can result in the amplification of certain gene products, such as MDM2 and SAS. MDM2 can be involved in p53 inactivation that can contribute to carcinogenesis32,33 Additionally, alterations in cell cycle regulating elements, such as CDK4, have been demonstrated.34 Novel these insights into sarcoma pathology may provide approaches for future therapeutic strategies directed at these lesions. Benign Lesions Lipomas Lipomas consist almost entirely of mature fat and are uncommonly found in the retroperitoneum (Table 39-1). They are probably the most common soft tissue tumor in man. Most of these lesions occur superficially but they may occur in other areas, such as the retroperitoneum. Deep lipomas within the retroperitoneum are usually not as well circumscribed as their superficial counterparts and can conform to irregular spaces in this body space.35,36 The adipocytes are normal or slightly larger in appearance and have a well-developed vascular network. There is very little in the way of nuclear irregularity. Differing levels of fibrous connective tissue can be found in these lesions. The rim of the lipocyte is reactive for S100 protein. While the majority of these masses are idiopathic in nature, they can occasionally be a manifestation of steroid lipomatosis. Pelvic lipomatosis while not a distinct tumor per se was first described in 1959 as an overgrowth of fat in the perivesical and perirectal area. It is a hyperplastic rather
Table 39-1 Benign Lesions of the Retroperitoneum Lipoma Pelvic lipomatosis Myelolipoma Leiomyoma Ganglioneuroma Hemangiopericytoma Schwannoma
Chapter 39 Retroperitoneal Tumors 653
neoplastic entity which can create a space occupying lesion. Approximately two-thirds of patients are AfricanAmerican and women are rarely affected.37 The growth is diffused rather than nodular and often it is difficult to distinguish it from normal adipose tissue. The condition may be associated with cystitis glandularis.38 The general clinical course is slowly progressive and may result in the need for urinary diversion.39 Occasionally fat necrosis in these lesions can be mistaken for sarcomatous degeneration.40 Myelolipoma This is a tumor-like growth of mature fat and bone marrow elements. Although it usually occurs in the adrenal gland, it can be seen as an isolated pelvic lesion.41,42 It is distinct from extra-medullary hematopoietic tumors which are usually multiple and generally associated with mild proliferative diseases and skeletal disorders. These generally occur in patients older than 40 years of age and are rarely >5 cm in size.43 They are usually found as incidental imaging findings. The adrenal gland can create inferior renal displacement due to radiolucent mass. Pathologically, it may display the features of a lipoma or have a darker appearance if myeloid elements predominate. Adrenal myelolipoma development may be secondary to prolonged stress and excessive stimulation with adrenocorticotropic hormones.
rate of metastasis depends on the degree of tumor differentiation, with nearly 90% of poorly differentiated tumors metastasizing.46–48 Significant advances in cytogenetics has allowed the reclassification of these lesions on a molecular basis (Table 39-2). Well-differentiated and dedifferentiated
Table 39-2 Malignant Lesions of the Retroperitoneum and Histologic Subclassifications Liposarcoma Myxoid liposarcoma Well differentiated Lipoma-like Inflammatory Sclerosing Differentiated Round cell Pleomorphic Leiomyosarcoma Malignant fibrous histiocytoma (MFH)
Leiomyoma These, generally rare lesions, are seen in a distribution that represents smooth muscle tissue in the body. They are overwhelmingly found in the female genital tract but have also been reported in the urinary bladder. There are occasional reports of these tumors in the retroperitoneum, where they can grow asymptomatically to a considerable size. Leiomyomas stain positive for desmin, which separates them from their malignant counterpart. Extension of these lesions from the uterus into the vascular system can create tumor thrombi not unlike those seen with renal lesions.44 Malignant Lesions Liposarcoma Liposarcomas are among the most common of primary retroperitoneal tumors that are often distinguished by their large dimensions and range of subtypes. These lesions are found with their peak incidence between ages 40 and 60.45 They account for 10% to 15% of sarcomas and approximately 20% of these lesions arise in the retroperitoneum. One unfortunate clinical feature of these lesions is their great tendency to recur often within the first 6 months after surgery. The principal tissue type is usually recapitulated at the time of recurrence. The
Storiform-pleomorphic Myxoid MFH MFH-giant cell type Inflammatory MFH Fibrosarcoma Rhabdomyosarcoma Embryonal Botryoid Alveolar Pleomorphic Spindle cell Malignant hemangiopericytoma Malignant peripheral nerve sheath tumors (malignant schwannoma) Synovial sarcoma Angio sarcoma
654
Part VI Testis
lesions are a continuum of lesions based on the genetic abnormality of giant and ring chromosomes usually involving chromosome 12. Gene amplification, particularly MDM2 drives their pathology.49,50 Myxoid and round cell, cell lesions (poorly differentiated myxoid) are another continuum, which have fusion transcripts caused by translocations in chromosomes 16 and 12 as their principle pathologic feature. Pleomorphic liposarcomas are rare and poorly understood.51 Unlike benign lipomas, liposarcomas may bear little resemblance to classic fat filled structures. The gross lesion is usually described as having a “fish flesh” appearance, and while generally encapsulated, it can often display invasive characteristics. Besides the retroperitoneum, these lesions arise in the deep soft tissues of the proximal extremities. They generally present as very large lesions when originating from the retroperitoneum. Myxoid liposarcoma is the most common liposarcoma usually occurring in the lower extremity. It accounts for 50% of sarcomas and represents a large proportion of retroperitoneal lesions. Its peak presentation is in the fifth decade. They display a background of stellate mesenchymal cells, and a prominent capillary pattern often described as a “chicken wire” (Figure 39-1). The distinct cell is the lipoblast that is similar to the fetal adipocyte. These cells are noted by a lipid vacuole that scallops the nucleus. This creates the lipoma-like appearance of these
lesions (Figure 39-2). These lesions have as their common pathology fusion proteins as mentioned previously. Higher-grade lesions tend to demonstrate a higher number of p53 mutations.52 The round cell subtype is also referred to as a lipoblastic variant and is distinguished by sheets of round cells with lipoblastic differentiation. These lesions are considered the most aggressive part of the spectrum of myxoid lesions. Well-differentiated liposarcomas mostly resemble lipomas and are usually designated as low grade. They are a common sarcoma of later life. Subvariants include the lipoma like, inflammatory, sclerosing, and differentiated. The first 3 variants are often confused with benign processes, such as scarring or inflammation, while the differentiated subtype is often noted in long-standing retroperitoneal lesions and considered higher grade. Generally, these lesions are now considered as a group with dedifferentiated lesions since they share genetic similarities. Pleomorphic liposarcoma comprises 10% to 15% of liposarcomas and are defined as a high-grade malignant variant with very bizarre nuclei and huge lipoblasts. Leiomyosarcoma This tumor accounts for <10% of all soft tissue sarcomas, yet it is a significant percentage of retroperitoneal sarcomas since almost half of them appear in this region. They
Figure 39-1 Myxoid liposarcoma displaying myxoid vascular pattern and minimal lipoblasts (H&E × 250).
Chapter 39 Retroperitoneal Tumors 655
Figure 39-2 Myxoid liposarcoma displaying lipoblasts and myxoid matrix (250 ×).
have a 2:1 female to male presentation and generally occur in middle age (mean age 60). The molecular pathology of these lesions is not understood. They are usually categorized by site of origin (soft tissue, vascular, or superficial) although many of the soft tissue lesions are felt to originate from smaller blood vessels. On imaging examinations, however, they appear to have moderate to low vascularization. Grossly, low-grade leiomyosarcoma can be difficult to distinguish from leiomyomas, but higher-grade lesions display a more infiltrative flesh-like appearance.53 Lowgrade lesions are often distinguished from leiomyomas by their chromatin pattern and the number of mitoses (>5 mitoses per high power field) present in the specimen. Again, a continuum exists in the pathologic progression of these smooth muscle lesions; therefore, the cut point between benign, moderate and high grade may sometimes be arbitrary. There is little evidence of sarcomatous degeneration from benign leiomyomas. The characteristic pathologic finding of a leiomyosarcoma is malignant spindle cells with “cigar”-shaped nuclei. The muscle fascicles interweave. These tumors immunohistochemically stain for smooth muscle myosin, vimentin, actin, and less often for desmin. They stain negative for S-100. Ultrastructural features include bundles of thin cyto-filaments that can help distinguish leiomyosarcomas from other lesions. The rare retroperitoneal variants of these tumors are leiomyosarcomas, which originate from the great vessels.54 These occur predominantly in women. Tumors of the iliac
vessels usually present with lower extremity edema, while those of the inferior vena cava can display findings consistent with Budd-Chiari syndrome.55 Resection of these lesions is recommended when anatomically feasible. Survival, however, is usually <2 years and many inferior vena caval tumors are unresectable because of the intrahepatic location of many of these lesions. Malignant Fibrous Histiocytoma MFH was originally described in 1963 and has come to be the predominant histologic diagnosis for contemporarily reported soft tissue sarcomas.56 It was defined as a sarcoma of primary histocytic origin, yet it is now felt that it is a lesion derived from fibroblast differentiation. Many pleomorphic variants of fibrosarcoma, liposarcoma, and rhabdomyosarcoma have been reclassified into this category. With the thorough evaluation of a tumor specimen, distinct regions of leiomyosarcoma, liposarcoma, and other soft tissue sarcomas may be identified. In such cases, the tumor may be defined by those findings and the mention of associated MFH pattern.57 These lesions are most often seen on the extremities and are less common in the retroperitoneum. Their molecular pathology is unclear. An analysis of these lesions in the retroperitoneum suggests that many of these could be reclassified as a dedifferentiated liposarcoma.58 Several subtypes of MFH that may coexist in a particular lesion: storiform-pleomorphic, myxoid, giant cell, and
656
Part VI Testis
inflammatory. The angiomatoid variant is seen almost exclusively in the extremities and trunk.59 Storiform-pleomorphic variant has a distinct but not pathognomonic pinwheel pattern caused by the collagen pattern of curling fascicles of cells (Figure 39-3). It is the most common variant, usually comprising 40% to 60% of most series. While this pattern may predominate, it may not be present throughout the lesion in question. Areas of collagen or foamy cells may also be encountered. The nuclei tend to be irregular and large with discernible mitosis. The constellation of tissue histology and nuclear irregularities in addition to the inflammatory components differentiate this lesion from benign entities. Myxoid MFH make 25% of this overall tumor type. It is often difficult to distinguish it from liposarcoma, yet the myxoid MFH has little neutral fat but is rich in mucopolysaccharide residing in intracytoplasmic vacuoles. MFH giant cell type is distinguished by large benign appearing osteoclasts. Multinucleated giant cells and the stoma comprise the malignant components of this lesion. If cartilage or osteoid is detected, these lesions are classified as a soft tissue osteosarcoma, which usually has a poorer prognosis than MFH. Inflammatory malignant fibrous histiosarcoma is rare and often difficult to distinguish from benign processes, such as nodular fascitis, when the presentation is truncal or extremity. A neutrophilic infiltrate is generally noted
with matrix of reticular cells. Often an exact diagnosis is not made until a recurrence is biopsied. Fibrosarcoma Fibrosarcomas are malignant tumors of fibroblast origin. They have a range of gradation and grossly display a classic “fish flesh” pattern with hemorrhage and necrosis. Low-grade lesions can display a herringbone—spindleshape histologic pattern. On retrospective review, these lesions are often reclassified as MFH or as a desmoid lesion (aggressive fibromatosis). Therefore, these lesions represent a smaller proportion of primary retroperitoneal tumors than previously reported. There is a greater incidence of blood bone metastases with this tumor to the lung and bones.60 Rhabdomyosarcoma Rhabdomyosarcoma comprises a minor percentage of reported retroperitoneal sarcomas, yet it is a significant lesion in pediatric oncology, as well as pediatric tumors associated with the genitourinary system. This topic is dealt with extensively in Chapter 49. These lesions are generally classified as embryonal, botryoid, alveolar, or pleomorphic, with spindle cell more recently described as a subtype of the embryonal form.61,62 The pathology of these lesions is
Figure 39-3 Storiform pattern of malignant fibrous histiocytoma (250 ×).
Chapter 39 Retroperitoneal Tumors 657
associated with chromosomal abnormalities and the fusion transcripts associated with these translocations. Embryonal rhabdomyosarcoma comprises more than half of all rhabdomyosarcomas and has a large array of anatomic locations, including the genitourinary tract and retroperitoneum. It can range from very welldifferentiated lesions to poorly differentiated lesions and express the multiple stages of muscle development. Botryoid lesions are an anatomic variant of the embryonal type and are generally seen in hollow viscera. The spindle cell subtype is noted for its favorable clinical behavior. Alveolar rhabdomyosarcoma accounts for approximately 20% of rhabdomyosarcomas and tend to occur more frequently in the extremities. The tumor is arranged in aggregates of round or oval cells that create irregular spaces reminiscent of alveoli. These tissues may be surrounded by fibrous septae, and areas of necrosis are not uncommon. Pleomorphic rhabdomyosarcoma comprise 5% of adult rhabdomyosarcomas and generally occur in older patients. It generally occurs in the extremities and is similar to MFH in appearance. The absence of cross-striations makes diagnosis difficult. With all rhabdomyosarcomas, immunostaining for desmin, myoglobin, and musclespecific actin is useful. Malignant Hemangiopericytoma These rare lesions originate from pericytes, which are unique cells that arborize about small vessels and capillaries. Their contractile properties allow them to control microvascular flow and permeability. Less than 200 of these lesions have been described, yet 25% of them have occurred in the retroperitoneum or pelvis. They are usually well circumscribed, and if possible complete surgical excision is warranted. Hemangiopericytomas display a rich vascular pattern and stain positive for factor VIIIa. They are negative for desmin and actin. The clinical behavior of these lesions is difficult to predict, but metastases may develop in 20% to 50% of cases. Those lesions with >4 mitoses per 10 HPF have a worse prognosis.64,65
there is usually a lag time of 5 months from initial symptoms to diagnosis. The principle clinical finding is abdominal mass and abdominal pain (60% to 80%).1 Many patients also experience nausea and vomiting and weight loss (20% to 30%). Neurologic findings are noted in 30% of patients.66 Lower extremity edema is seen in 17% to 20% of patients, while urinary symptoms are surprisingly rare, seen in 3% to 5% of patients in most series. Physical examination will generally demonstrate a protuberant abdomen that may be accompanied by an appearance of extremity wasting. Peripheral or inguinal adenopathy may be present although lymphadenopathy is not usually associated with these tumors (<5%).65 Lower extremity edema and or increased abdominal wall venous markings suggest the presence of vena caval compression or obstruction. Diagnostic imaging is imperative to delineate the anatomic limits of the lesion and assess the integrity and function of adjacent organs. This is most appropriately demonstrated with cross-sectional imaging68,69 (Figure 39-4). Important issues to address with this modality are bilateral renal function, the presence or absence of visceral metastases, and lymphadenopathy. Attention should also be given to the axial skeleton. Tumor involvement of neural foramina suggest unresectability of the lesion. Germ cell tumors, which should be suspected in young men and diagnosed through a thorough physical examination and testicular ultrasound, are usually distinguished on computed tomography (CT) scan from other primary retroperitoneal lesions. This is also generally true for lymphomas. The CT scan, however, is not
DIAGNOSIS Because of their slow growth and anatomic location, retroperitoneal tumors (usually sarcomas) tend to grow to a large size before they are detected. In a recent series of MFHs, the average size at diagnosis for extremity lesions was 5 cm, while retroperitoneal lesions were 16.5 cm in size,27 thus such lesions can often be enormous by usual pathologic standards. While the age at presentation is distributed across a large spectrum, the majority of patients are diagnosed with retroperitoneal tumors in the sixth decade of life. Since the progression of symptoms is slow,
Figure 39-4 CT image demonstrates massive right-sided liposarcoma with suggestion of internal fibrous bands displacing the liver and right-sided retroperitoneal structures.
658
Part VI Testis
particularly diagnostic for the multiple tumor histologies of primary retroperitoneal tumors besides a liposarcoma with high fat content. Earlier literature attests to the value of intravenous urography, upper and lower gastrointestinal (GI) series, and angiography in defining displacement and delineating function. Advances in cross-sectional imaging have largely supplanted this multistudy approach, and the application of magnetic resonance arteriography allows for the delineation of vascular involvement by these uncommon lesions. From a practical standpoint, CT and magnetic resonance imaging (MRI) are complimentary rather than redundant and should be employed as needed.70 In some cases, imaging will not provide a reasonable diagnosis; in that case, a biopsy prior to definitive resection may need to be performed. Classic references suggest that percutaneous needle biopsies of these retroperitoneal masses are generally unsatisfactory even when aided with imaging techniques, such as ultrasound or CT.21 More recent sources indicate that diagnosis may be a function of experience with these lesions and that percutaneous biopsy or even needle aspiration may be quite satisfactory.71,72 Due to the uncommon nature of these lesions at most centers, it would seem appropriate to obtain a correct tissue diagnosis with a reasonable tissue sample when the diagnosis is in question. In specific cases, an intraoperative biopsy may be indicated to diagnose the lesion or differentiate it from a lymphoma or germ cell tumor. In those instances, care must be taken to obtain the sample from a solid part of the lesion and employ meticulous technique to avoid any tumor spillage. This is accomplished through appropriate draping of the operative field, excellent hemostasis, and meticulous closure with covering of the wound.21 Laparoscopic sampling, while possible, would probably not be feasible in most of these patients. Tumor specimens should be sent for frozen section and touch preparations prepared to establish a diagnosis. In the appropriate patient, the serum tumor markers (beta-HCG and alpha fetoprotein) for germ cell tumors should be obtained preoperatively. There are no specific serum tumor markers for primary retroperitoneal sarcomas, yet vanillylmandelic acid (VMA) may be elevated in the rare case of ganglioneuroma or extra adrenal pheochromocytoma. STAGING The primary determinant of staging for primary retroperitoneal tumors is the tumor grade. The grading is based on a G1 to G3 or G4 scale, and stage grouping is done through the TNM system. Because of the impact of tumor grade this is often referred to as a GTMN system (Table 39-3).72 Tumor grading is determined by several factors, including atypical mitosis, cytoplasmic and nuclear pleomorphism, and necrosis.73,74 Grade 1 lesions are denoted
by few mitoses, acellularity, minimal alterations of the nucleus, few or absence of nucleoli. Scoring often takes into consideration other factors, such as tumor size and patient age. Grade 2 lesions display small to moderate size nucleoli, moderate nuclear pleomorphism, irregular chromatin distribution, and a moderate amount mitosis. Areas of necrosis may be noted in the microscopic field. Grade 3 lesions are characterized by numerous mitoses, gross chromatin clumping, moderate or considerable necrosis, and variation in nuclear morphology. The distinction between T1 and T2 lesions is made at 5 cm. Clinical staging beyond physical examination should also include a bone scan and a dedicated chest CT, as well as an abdominal/retroperitoneal CT scan with attention to the liver. Bilateral renal function must be determined preoperatively. In experienced hands, cross-sectional scanning alone may provide enough local staging information. Since these lesions are rare, however, any question regarding the extent of contiguous organ involvement should be answered by the appropriate confirmatory imaging test (e.g., upper GI series). Laboratory tests may provide some diagnostic discrimination, yet generally add little to a staging evaluation. Detailed evaluation of sarcomas can be found in the NCCN sarcoma practice guidelines.75 SURGERY Extirpative surgery is the principle and most effective form of therapy for primary retroperitoneal tumors. Preoperative planing to assess the extent of the disease is essential since successful surgery is defined by complete excision of the mass with adequate margins of normal tissue. A complete resection rate between 38% and 78% (average 55%) is reported in many large series14–26,75,76 (Table 39-4). In several large series of retroperitoneal sarcomas, univariate and multivariate analyses of independent treatment variables have been performed. In over 280 patients, a complete resection was the single most important positive predictive feature.77 Intermediate or high tumor grade is a strong negative feature.20,78–80 In most reported series, intermediate and high-grade lesions comprise 55% to 70% of the tumors described. Tumor histology, tumor size, or patient age were not significant factors in survival in multivariable analysis.81,82 Therefore, carefully planned and skillfully executed surgical therapy is critical for any chance at long-term success.83,84 Operative Technique The classic approach for surgery on these lesions is described through long midline incisions or chevron incisions. The tumors are usually right-sided or leftsided; however, few actually rising from the midline. A full flank position, such as that employed for renal stone surgery, is discouraged since it can limit exposure to the
Chapter 39 Retroperitoneal Tumors 659
full retroperitoneum or abdomen.1,21 Since these lesions are not compartmentalized by the retroperitoneum, they can cross many anatomic boundaries. It is important, therefore, to determine the potential for resectability, beyond that presupposed through imaging. This is first accomplished by developing a subadventitial plane along
the lateral borders of the great vessels extending dorsally between the spine and psoas and quadratus muscles (Figure 39-5). In this manner one can determine if the tumor has spread along a spinal nerve route and into the spinal foramina or even further into the spinal cord. If this is the case, the tumor is generally considered unre-
Table 39-3 American Joint Commission on Cancer GTNM Classification and Stage Grouping of Soft Tissue Sarcomas Tumor grade G1
Well differentiated
G2
Moderately differentiated
G3
Poorly differentiated
G4
Undifferentiated
Primary tumor T1
Tumor ≤ 5 cm in greatest diameter
T1a
Superficial tumor
T1b
Deep tumor
T2
Tumor > 5 cm in greatest diameter
T2a
Superficial tumor
T2b
Deep tumor
Regional lymph node involvement N0
No known metastasis
N1
Verified metastases to lymph nodes
Distant metastasis M0
No known distant metastasis
M1
Known distant metastasis
Stage grouping Stage 1A
Low grade, small (G1-2, T1a or b, N0, M0)
Stage 1B
Low grade, large, superficial (G1-2, T2a, N0, M0)
Stage IIA
Low grade, large, deep (G1-2, T2b, N0, M0)
Stage IIB
High grade, small (G3-4, T1b.N0, M0)
Stage IIC
High grade, large, superficial G3-4, T2a, N0, M0
Stage III
High grade, large, deep G3-4, T2b, N0, M0
Stage IV
Nodal or distant metastases Any G, any T, N1, M0 or any G, any T, any N, M1 Continued
660
Part VI Testis
Table 39-3—cont’d DEFINITIONS Clinical Pathologic ■
■
Primary Tumor (T) TX Primary tumor cannot be assessed
■
■
T0
No evidence of primary tumor
■
■
T1
Tumor 5 cm or less in greatest dimension
■
■
T1a superficial tumor(1)
■
■
T1b deep tumor
■
■
T2
■
■
T2a superficial tumor(1)
■
■
T2b deep tumor
Notes 1. Superficial tumor is located exclusively above the superficial fascia without invasion of the fascia; deep tumor is located either exclusively beneath the superficial fascia, superficial to the fascia with invasion of or through the fascia, or both superficial yet beneath the fascia. Retroperitoneal, mediastinal, and pelvic sarcomas are classified as deep tumors. 2. Ewing’s sarcoma is classified as G4.
Tumor more than 5 cm in greatest dimension
Regional lymph nodes (N) ■
■
NX Regional lymph nodes cannot be assessed
■
■
N0
No regional lymph node metastasis
■
■
N1
Regional lymph node metastasis
Distant metastasis (M) ■
■
MX Distant metastasis cannot be assessed
■
■
M0
No distant metastasis
■
■
M1
Distant metastasis Biopsy of metastatic site performed
■
Y
■
N
Source of pathologic metastatic specimen __________________ Stage Grouping ■
■
■
■
I
II
T1a
N0
M0
G1-2
G1
Low
T1b
N0
M0
G1-2
G1
Low
T2a
N0
M0
G1-2
G1
Low
T2b
N0
M0
G1-2
G1
Low
T1a
N0
M0
G3-4
G2-3
High
T1b
N0
M0
G3-4
G2-3
High
T2a
N0
M0
G3-4
G2-3
High
G2-3
High
■
■
III
T2b
N0
M0
G3-4
■
■
IV
Any T
N1
M0
Any G Any G
High or low
Any T
N0
M1
Any G Any G
High or low
Chapter 39 Retroperitoneal Tumors 661
Table 39-3—cont’d Histologic Grade (G)
Notes
■
GX
Grade cannot be assessed
Additional Descriptors
■
G1
Well differentiated
Lymphatic vessel invasion (L)
■
G2
Moderately differentiated
■
G3
Poorly differentiated
■
G4
Poorly differentiated or undifferentiated (four-tiered systems only)(2)
LX Lymphatic vessel invasion cannot be assessed L0 No lymphatic vessel invasion L1 Lymphatic vessel invasion Venous Invasion (V) VX V0 V1 V2
Residual Tumor (R) ■
RX
Presence of residual tumor cannot be assessed
■
R0
No residual tumor
■
R1
Microscopic residual tumor
■
R2
Macroscopic residual tumor
Venous invasion cannot be assessed No venous invasion Microscopic venous invasion Macroscopic venous invasion
Table 39-4 Pooled Data on Complete Versus Partial Resection Series
No. of Patients
Resection (No. %) Complete
Mean Survival (Months)
Partial
Complete
Partial
Complete Resection 5–Yr Survival (%)
Dalton et al.19
116
63/54
25/21
72
13
54
Jacques et al.20
86
43/50
34/39.5
65
28
74
McGrath et al.18
47
18/38
18/38
120
24
70
Glenn et al.22
50
37/74
8/16
40
—
38
Karakouis et al.24
68
27/40
7/10
84
48
64
Kilkeny et al.26
63
49/78
10/16
41
9
48
Zornig et al.23
51
30/59
21/41
60
—
35
267/55.5
123/25.6
70.3
24.4
TOTAL
481
sectable. It has also been suggested that the lateral incision of the peritoneum into the deep body wall is important to explore on a level posterior to the spinous processes (see Figure 39-5). If the operator’s fingers can be bi-manually palpated, this sarcoma is considered resectable. It is imperative in the preoperative period that both the patient and the surgeon realize the potential need for en bloc resection of affected organs. This can include vascular structures, as well as the kidney, portion of the diaphragm, liver, stomach, gall bladder, spleen, pancreas, and gut. In review of several series, up to 68% of operations required resection of an adjacent organ to insure
54.7
adequate negative margins. The most frequently resected organs are listed in decreasing order in (Table 39-5). A recent review reported that 20% of patients undergoing surgery for a retroperitoneal sarcoma required nephrectomy. The majority of them (72%) underwent this during their initial resection. The usual reason for nephrectomy was total encasement of the organ, followed by dense adherence to the kidney, and less often direct invasion of the renal unit.85 While a Dacron graft can be employed to replace a portion of resected aorta, there is debate among surgeons with regard to the need for venous reconstruction. Many feel that the venous collaterals that develop secondary to vena caval compression
662
Part VI Testis
Determination of resectability Operative maneuvers
1 2 IVC A o 2
Psoas major muscle Quadratus lumbarum muscle Vertebra
Spinal cord
Figure 39-5 Transabdominal approach to determine resectability of a primary retroperitoneal sarcoma. Pertinent maneuvers consist of intraabdominal assessment of visceral and vascular contents and retroperitoneal assessment of attachment to musculoskeletal and spinous structures.
Table 39-5 Organs Sacrificed During Complete Resection of Sarcoma Organ
Frequency of Resection (%)
Kidney
32–46
Colon
25
Adrenal gland
18
Pancreas
15
Spleen
10
are adequate to allow for appropriate drainage from otherwise vascularly compromised organs. When bowel viability is questionable, it should be resected if possible. Although many visceral organs can be resected, unresectability is usually denoted by sarcomatosis, nerve root involvement, pelvic sidewall involvement, malignant ascites, or the presence of distant metastasis.1,21 When defining the operative field it is often necessary to release multiple intraabdominal adhesions. This must be performed meticulously since an enterotomy and subsequent fistula formation can cause major morbidity. Tactile, as well as visual perceptions, aids in avoiding violation of the bowel. In addition, the use of sharp curved Mayo scissors rather than Metzenbaum scissors may aid in avoiding this complication. During the dissection of a large tumor mass, it is often necessary to shift the location of the dissection when one particular area becomes difficult due to concerns of a clear margin or the potential for vascular damage. A centripetal dissection allows
one to dissect those areas that are amenable to dissection, and which in turn may free up a previously more constrained area of the operative field.86 Morbidity and mortality rates for contemporary surgical series are acceptable. An operative mortality of 2% to 7% with morbidity rates of 6% to 25% is the norm. Hemorrhage, intra-abdominal abscess, and enterocutaneous fistula are the most commonly described complications. Another surgical technique is the modified thoracoabdominal approach, which has been developed and popularized by Skinner. Those familiar with the technique feel that it allows maximum exposure to the posterior retroperitoneum, which is often a difficult area to assess through a midline incision. Additionally, it provides access and control to the ipsilateral great vessels above the diaphragm. Whether a left- or right-sided procedure is performed, excellent exposure can be developed in the contralateral retroperitoneal region without difficulty. A technique described here is a summary of Skinner’s approach.87 With the thoracoabdominal approach, patient positioning is critical. The patient is not placed in a “pure flank” position, similar to that used in stone surgery. Rather, a modified flank position is employed. The contralateral leg is flexed 90 degrees, and the hip is flexed approximately 30 degrees. The ipsilateral shoulder and chest is placed 20 degrees off the horizontal with the arm brought across the chest and placed in an adjustable armrest. The pelvis is at most rotated 10 degrees off the horizontal, and this position is maintained with a role sheet. The table is fully hyperextended with the break located above the iliac crest. The patient is secured with wide adhesive tape, and the ipsilateral leg is supported on a pillow. A mid-axillary incision is carried in the mid-axillary line from the 8th, 9th, or 10th rib. The height of this incision is based on the size of the primary lesion. It extends over the rib and costochondral junction into the epigastrium and then proceeds inferiorly as a midline incision into the pelvis. The rib is resected subperiosteally and the costochondral junction is divided. The rectus muscle is divided and retracted laterally. In most instances, the peritoneum will be opened, and the bowel contents mobilized superiorly. This mobilization is based on the superior mesenteric artery pedicle. It is important that this artery be identified initially, and care is taken not to traumatize it. In many instances, the inferior mesenteric artery may have to be resected. Most care should be taken to maintain the marginal artery. In most instances, a large bowel section will be avoided, yet if there is a question of viability at the end of the case, any suspect area of bowel should be resected. Vena cava obstruction may be associated with any right-sided lesions, and if this is the case, it is usually best to resect the vena cava en bloc with removal of the tumor. Often, a right nephrectomy
Chapter 39 Retroperitoneal Tumors 663
may also be required. If this maneuver is performed, it is best to maintain vascular connection between the vena cava and left renal vein to decrease the possibility of acute or long-term renal insufficiency. In general, the aorta can be dissected free of large retroperitoneal tumors but rarely may require replacement with a Dacron graft. During dissection or mobilization of the great vessels, care must be taken to control the lumbar vessels with ligation and division to avoid problematic bleeding. While the distal vessels may be controlled with hemoclips, it is appropriate to ligate the lumbar vessel at its origin on its great vessel. In the case of significant bleeding, the vessel tear can be controlled with the use of a Judd or Allis clamp. While the possibility of spinal devascularization exists, it is very uncommon due to the significant collateral blood supply to the spine from the artery of the Adamkiewicz. In younger patients, the potential for ejaculatory dysfunction is significant. SURGICAL OUTCOME The classic overall survival for patients presenting with retroperitoneal sarcomas is poor. In a multiinstitutional review, the 2-, 5-, and 10-year mean survivals for patients with this disease were 56%, 34%, and 18%, respectively.21 Recent series suggest 2-year survivals of over 70% and 5-year survivals of 50% to 60% in patients without metastases.88,89 The effective surgical management of retroperitoneal tumors has been limited by their size at presentation that often results in secondary organ involvement. This has a poor impact on the ability to achieve negative surgical margins even with the resection of adjacent organs. Historically, a complete surgical resection with negative margins was achieved in 50% to 60% of patients. The more recent series demonstrate complete resection rates in the 60% to 80% range, which may be due to improvements in imaging, preoperative planning, and surgical technique. Those patients who achieve a complete resection display superior survival to those patients with incomplete resection of their tumors (see Table 39-4). This is also supported in laboratory models.90 In an analysis of microscopic margins, however, positive margins at this level of pathologic resolution had little impact on recurrence-free survival.91 On the average, the 5-year survival of patients with completely resected tumors is 54% compared to 17% for incomplete resections at 10 years, this difference is 45% to 17%. Thus, a nearly 40% survival advantage is seen at 5 to 10 years in those patients with complete surgical resection of their lesion (Figure 39-6). Tumor recurrence after complete surgical resection, however, is significant. There is a 72% chance of local recurrence at 5 years and a 90% chance of recurrence at 10 years in most series. These data imply fairly poor survival at 15 years.21
Proportion Surviving 1.0 81
0.8
54
0.6
45 0.4
34 17
0.2
8
0.0 0
2 Complete Resection
5 Years
10 Incomplete Resection
Figure 39-6 Patient survival as a function of completeness of the surgical resection. The data represent x complete resections and y incomplete resections from collected series.
Reoperative surgery for the treatment of recurrent retroperitoneal sarcoma can be of value. Over 60% of patients may be experienced a complete resection.88 In one series, 30 patients with a previous complete resection of the primary lesion experienced local tumor recurrence at a mean interval of 23 months. Sixty percent of these patients were rendered free of disease after reoperative surgery. To accomplish this, 33% of these patients required the resection of adjacent viscera. Those patients who achieved a complete resection with a second operation had a 33-month median survival compared to a 14month median survival in those patients who did not experience a second complete resection.92 The role of subtotal resection has never been clearly established, yet some data suggest that this may have some positive value compared to palliative or debulking surgery. The argument for the possible value of incomplete resection has been made the management of liposarcomas. In a series of 55 patients, 75% received symptom relief from their surgery and partial resection compared with biopsy or exploration alone had a significant impact on increased survival (26 months versus 4 months).93 In another report, 22 patients with complete resection of tumor displayed a similar median survival to 15 patients with subtotal resection (median survival >120 months) compared to those only having a partial palliative resection or exploration (12 to 20 months).94 An aggressive surgical approach in cases where near complete resection can be obtained has also been advocated by others.24 There is no set protocol for the postoperative monitoring of patients with primary retroperitoneal sarcoma, but recommendations can be made given the rapidity of recurrence, the advantage of reresection, and the lethality of this condition. It would be appropriate to perform an abdominal CT scan, chest x-ray, and biochemistry profile with complete blood count (CBC) every 6 months. A
664
Part VI Testis
Proportion Surviving 1.0 83 0.8
74
0.6 54
42
0.4 24
0.2
11
0.0 0
2 G 2,3 Tumors
5 Years
10 G 1 Tumors
Figure 39-7 Patients’ survival as a function of tumor grade in cases of primary retroperitoneal sarcoma. The data represent 50 low-grade and 80 high-grade tumors from collected series.
series. It is associated with a lower rate of local recurrences and fewer GI complications, yet peripheral neuropathies are more frequent, and it is difficult to demonstrate a survival advantage with its use.100–104 Combined modality therapy with external beam and radiation with surgery and IORT (15 Gy) is being explored. It appears that such intensive regimens are tolerable up to 50.4 Gy of EBRT.105 Additionally, the use of brachytherapy postoperatively in primary or recurrent disease has been explored using different techniques up to 32 Gy.106,107 These techniques are feasible yet significant side effects can be encountered when they are applied to the upper abdomen. Newer radiation delivery techniques, such as intensity modulated radiation therapy (IMRT), are being explored for the treatment of these lesions.108,109 CHEMOTHERAPY
lengthening of this follow-up interval should be considered only after 5 years. Data support the concept that close follow-up allows for early detection less bulky recurrences that allow for more successful salvage surgery.95 The effect of tumor grade on patient survival cannot be underestimated. Low-grade lesions display a 50% survival advantage over intermediate- and high-grade lesions at 5 years (74% to 24%) and a 30% survival at 10 years (42% to 11%) (Figure 39-7). This is demonstrated even in the face of total surgical resection. While aggressive surgical resection of retroperitoneal sarcoma serves as the foundation of therapy for this condition, the high local recurrence rate and eventual mortality from this disease has prompted the exploration of adjuvant therapeutic modalities.
Multimodal therapy for extremity sarcoma has provided an inference for the role of chemotherapy in retroperitoneal lesions. The majority of large-scale chemotherapy trials, however, comprise patients with extremity disease, so these findings may not be directly applicable. Overall, the argument for adjuvant therapy seems reasonable since the potential for distant recurrence is significant with retroperitoneal lesions. The data in this regard have been somewhat contradictory, yet a metaanalysis of these studies suggests a slight advantage for the use of adjuvant doxorubicin therapy to decrease the risk of death and recurrence in patients with high-grade extremity lesions.99 Such therapy is associated with toxicity, however, and has not gained considerable acceptance for retroperitoneal lesions.110
RADIATION THERAPY
Metastatic Disease
The role of radiation therapy in the treatment of soft tissue sarcomas has been established by the advances in extremity lesions. Unfortunately, the radiosensitivity of adjacent soft visceral organs in the retroperitoneum has limited the direct transfer of such techniques to lesions in this region.96,97 While extremity tumors are treated in the dose range of 60 to 64 Gy, most series of retroperitoneal lesions are treated in the 40- to 55-Gy range. In general, one sees a decrease in local recurrences compared to historic controls at the cost of increased gastrointestinal complications (nausea, vomiting, and enteritis). It is difficult to demonstrate a significant improvement in survival, and on multivariable analysis the completeness of the surgical resection and the grade of the tumor have the most significant bearing on outcomes.98–100 Intraoperative radiation therapy (IORT) has been employed as a surgical adjuvant in several small
Approximately 20% of patients with soft tissue retroperitoneal sarcoma will present with metastatic disease. Those patients who recur after treatment for localized disease generally do so by 60 months.111,112 Those patients who recur demonstrate disease at multiple sites (47%) or display a local recurrence (30%). Isolated pulmonary lesions occur in approximately 20% of patients. Three-year survival in patients undergoing complete excision of lung-only lesions is 38%.113 Doxorubicin is the foundation for chemotherapy in advanced sarcoma.114,115 The general response rate is 20% to 25%, but sustained complete responses are uncommon. Other classic agents demonstrating activity include dacarbazine, ifosfamide, methotrexate, and cyclophosphamide. In several phase III studies, however, combination treatments were not superior to singleagent doxorubicin.116–118 Other phase III studies have not demonstrated superior response, yet they do show
Chapter 39 Retroperitoneal Tumors 665
significant increased toxicity (myelosuppression and cardiac) with the addition of other agents.119 Another combination regimen of mesna, adriamycin (doxorubicin), ifosfamide, and dacarbazine (MAID) has been successful in neoadjuvant programs for extremity sarcomas compared to historic controls, yet less data are available with regard to other soft tissue sites.120,121 In general, salvage therapy for patients has been associated with poor responses and little in the way of quality of life advantages.121 More recently, gemcitabine has been investigated as an initial agent in advanced disease and for salvage therapy. As a single agent the results have been disappointing with response rates below 5% in either setting.122–124 The combination of gemcitabine and docetaxel in patients with unresectable leiomyosarcoma, however, demonstrated a 10% complete response and an overall response of 53%. It was felt to be a tolerable and active combination in treated and untreated patients.125 Disseminated intraperitoneal spread of disease is very difficult to treat. A novel approach is the application of photodynamic therapy.126 In a preliminary report, patients underwent surgical debulking and were treated with photofrin and laser light. Of initial 11 patients, 5 demonstrated no evidence of disease over a range of 2 to 17 months. The advancement of such technologies and the implementation of small molecule therapy may provide improved outcomes for such patients in the future.
Table 39-6 Common Genitourinary Sarcomas in Decreasing Order of Frequency Renal Leiomyosarcoma Liposarcoma Malignant fibrous histiocytoma Hemangiopericytoma Rhabdomyosarcoma Osteogenic sarcoma Bladder Leiomyosarcoma Rhabdomyosarcoma Osteogenic sarcoma Liposarcoma Malignant fibrous histiocytoma Fibrosarcoma Prostate Leiomyosarcoma
ADULT URINARY TRACT SARCOMA
Rhabdomyosarcoma
Primary sarcomas arising from the genitourinary system are extremely rare lesions overall and comprise only 1% to 2% of urologic tumors in adults. Only 800 to 1000 such tumors have been described from multiple genitourinary sites. Although many small clusters go unreported, practice principles in the diagnosis and treatment of these tumors must therefore be derived from anecdotal pooled data.127,128 General treatment principles are also extrapolated and applied from the clinical experience with primary retroperitoneal sarcomas. These lesions behave differently from pediatric genitourinary sarcomas, notably pediatric rhabdomyosarcoma, which is discussed separately in Chapter 49. Thus, treatment strategies, especially for advanced disease, tend to be empiric. Despite their rarity, the collective data regarding sarcomas of the genitourinary tract provide significant data with regard to clinical presentation and clinical outcome that provide rough guidelines for treatment when these uncommon lesions are encountered. The most common sarcomatous lesions of the urinary system originate in the spermatic cord and paratesticular structures, which are not strictly speaking retroperitoneal. In decreasing incidence, sarcomas of the kidney, the bladder, and the prostate are encountered (Table 39-6).
Fibrosarcoma Spindle cell sarcoma Spermatic cord, testis, paratestis Leiomyosarcoma Rhabdomyosarcoma Liposarcoma Fibrosarcoma Malignant fibrous histiocytoma
RENAL SARCOMA Approximately 1% to 2% of kidney tumors are true renal sarcomas. This excludes the sarcomatoid variant of renal cell carcinoma (RCC) that demonstrates spindle cells or giant cells and a rapidly progressive clinical course. The most frequent histologic subtypes of sarcoma encountered in the kidney are listed in Table 39-6. Leiomyosarcoma is the most common renal sarcoma, comprising 30% to 40% of most reported series.
666
Part VI Testis
Liposarcoma and MFH are then encountered in near equal frequency. Other histologies include rhabdosarcoma, osteosarcoma, and hemangiopericytoma.129–132 Renal sarcoma usually presents at a slightly younger age than the average patient with RCC with pain and flank mass as the common symptoms. Hematuria is seen less frequently with classic RCC. They have no distinguishing imaging characteristics but tend to be hypervascular. When small, they are hard to distinguish from RCC, but hypovascularity combined with contiguous tumor spread may suggest sarcoma. Treatment for renal sarcoma is similar to RCC, namely, wide surgical excision. The principles for a standard radical nephrectomy conform to those for sarcoma surgery, and the modified thoracoabdominal approach is particularly suited to large lesions. As is the case in all soft tissue sarcomas, tumor size reflected in complete resectability, and grades are the major determinants of clinical outcome. There are no data to support chemotherapy or radiation in the adjuvant setting, and it is unlikely that these modalities will confer a survival benefit for patients with advanced disease. The overall 5year survival for these patients is approximately 30%. Those individuals with liposarcoma or hemangiopericytoma perform much better than patients with leiomyosarcoma. The survival rate at 5 years is in the 80% to 90% range for liposarcoma yet <50% for leiomyosarcoma. This more than likely a reflection of tumor grade at presentation.127,128,131 Patients with renal sarcoma should adhere to close postoperative follow-up, including more frequent evaluation of the renal bed, since local recurrence is the rule rather than the exception with sarcomas. Therapy for advanced disease usually consists of single agent doxorubicin-based chemotherapy or multiagent doxorubicinbased chemotherapy. While responses may be seen, sustained complete responses are not reported. URINARY BLADDER In the adult, primary urinary bladder sarcomas are very rare with roughly 200 cases reported in the medical literature.127,128 They comprise approximately 0.1% to 0.2% of all primary bladder tumors, yet present in a manner similar to typical bladder tumors. Most patients display hematuria, dysuria, or urinary frequency as the presenting signs and symptoms of their lesions. On imaging studies they can display upper urinary tract obstruction or filling defects of the bladder.131–135 The diagnosis can usually be made by transurethral resection of the bladder tumor. Pelvic and abdominal imaging with CT or MRI is useful in perioperative staging. The most common tumor histology in adult bladder sarcoma is leiomyosarcoma, followed by rhabdomyosarcoma. These lesions of muscle origin comprise 70% to 80% of all adult bladder sarco-
mas. Liposarcoma, MFH, and osteosarcoma account for <5% each of bladder sarcoma.136,137 A recent report also collected a cohort of 10 angiosarcomas the majority of which responded poorly to therapy (Engel). The development of some bladder sarcomas has been attributed to the secondary effects of radiation therapy or chemotherapy exposure.138,139 The treatment of bladder sarcoma results in exceptionally good outcomes for a tumor type generally expected to perform poorly. Cystectomy and diversion in combination with other treatment modalities can result in 5-year disease-free survivals of 62%.140 Smaller, selected cystectomy series have demonstrated similar findings.136 Significant long-term disease-free survival rates have also been achieved with less aggressive surgery. In an earlier series from Memorial Sloan Kettering Cancer Center, 14 of 15 patients with resectable bladder tumors displayed no evidence of disease 1 to 9 years after surgery, this included 4 patients who underwent partial cystectomy.127 In a more recent series from the same institution, 7 of 10 patients with bladder sarcoma are alive without evidence of disease with over 5 years of follow-up, including 2 patients treated only with transurethral resection of 2 cm leiomyosarcomas of the bladder.131 Other series have demonstrated that lowgrade lesions can respond reasonably well to organ-sparing therapy.141 These data suggest that bladder preservation is a reasonable option in the treatment of this disease especially in the case of leiomyosarcoma. Partial cystectomy is a reasonable option if wide (3 to 4 cm) margins can be obtained. Involvement of the trigone or more distal structures, however, would suggest total cystectomy and continent reconstruction as an appropriate option. Although the data are anecdotal, the use of chemotherapy and external beam radiation may be appropriate in patients with bladder sarcoma at high risk for local or distant recurrence. Overall 5-year survival for patients with bladder sarcomas is 60%. Those patients with adult rhabdomyosarcoma of the bladder have a poorer prognosis than their pediatric counterparts and adults with leiomyosarcoma. The 5-year survival for patients with adult rhabdomyosarcoma is approximately 30%. Angio sarcoma is a very rare bladder lesion (10 reported cases) that is highly progressive. It responds best to multimodal oncologic therapy.142 PROSTATE Approximately 150 reported cases of primary sarcoma of the prostate have been reported.127,128,135,143,144 Given the estimated yearly incidence of prostate cancer at over 220,000 cases, these lesions comprise <0.1% of primary prostate tumors. The majority of prostate sarcomas is either leiomyosarcoma (50%) or rhabdomyosarcoma (30%). The remainders of tumors are distributed over
Chapter 39 Retroperitoneal Tumors 667
multiple tissue types. In general, patients with prostate sarcoma tend to present somewhat younger than the typical patient with adenocarcinoma of the prostate. The most common presenting symptom is bladder outlet obstruction and dysuria. A combination of symptoms and a palpable mass (often smooth) on physical examination lead to endoscopic evaluation and needle biopsy diagnosis. The majority of patients present with regional or local disease, while 10% to 20% of patients may have metastases. Cystoprostatectomy has generally been the treatment of choice for these tumors since most are large at the time of diagnosis, also because usually defined tissue planes may be obliterated by these tumors. In the case of extensive retroperitoneal disease it may be preferable to perform a total pelvic exenteration to achieve complete local control. Since the potential for total continent reconstruction of both the urinary and lower GI tract exists, this aggressive approach is a more favorable option than double ostomies or palliative therapy.145 As in the case of bladder sarcoma, a pelvic lymph node dissection should accompany the exenterative procedure since nodal involvement, especially in rhabdomyosarcoma, can exist. In general, patients with prostate sarcoma have an unfavorable outcome. The average 5-year survival is approximately 25%. Patients with leiomyosarcoma have a 40% 5-year survival, while those with rhabdomyosarcoma have a 0% to 10% 5-year survival. A recent series of these lesions demonstrated a 3- and 5-year survival of 43% and 38%. The factors most associated with a good outcome were the absence of metastatic disease at presentation and the finding of negative surgical margins.146 It is difficult to assess the value of combined adjuvant therapy, but in the case of high-grade or extensive disease, a doxorubicin-based protocol and the addition of external beam radiation would be appropriate. PARATESTICULAR TUMORS The most common primary genitourinary sarcomas are those of the paratestis, spermatic cord, and testis proper.127,128,131,147,148 Almost 300 cases of such lesions have been reported. The majority of these lesions from muscle origin and are either rhabdomyosarcoma or leiomyosarcoma (50% of tumors). Liposarcomas and fibrosarcomas are commonly seen, along with a distribution of other rare lesions. The most common benign tumor of the spermatic cord, however, is a lipoma, while the most common benign lesion of the paratesticular region is an adenomatoid tumor. These lesions segregate into an adolescent-early adult and older age group (over 50) with the majority of rhabdomyosarcomas concentrated in the younger patients. Rhabdomyosarcomas also have a greater predilection for occurring in an intrascrotal area. Liposarcoma and leiomyosarcoma generally occur in
older age groups and can occur anywhere along the inguinal to paratesticular region and are often found in the inguinal region. It is unusual to have a sarcoma in the testicular parenchyma. Patients with paratesticular sarcomas have a firm palpable mass in the scrotum or the spermatic cord. Any lesions of the scrotal contents should be evaluated with ultrasound and all solid lesions should be classically treated with inguinal exploration biopsy and radical orchiectomy if indicated. Transscrotal exploration should not be performed. Further therapy for these is dictated by tissue histology. Postoperative radiation therapy can be administered especially if it appears that one has not achieved negative margins after the initial surgery.149 Rhabdomyosarcoma and leiomyosarcoma generally perform poorly. It is necessary to assess these patients for the presence of metastatic disease, particularly retroperitoneal lymph node involvement. In the absence of gross disease, a retroperitoneal lymph node dissection is appropriate, especially in the case of rhabdomyosarcoma where the incidence of positive retroperitoneal nodes may be >50%.149–151 It has also been advocated for MFH and fibrosarcomas of the cord. If gross nodal or distant metastatic disease is detected, doxorubicin-based chemotherapy is the classic treatment for advanced disease and is generally employed in the presence of microscopic metastasis. Those patients with liposarcoma generally show nearly complete cure through local excision.151 Ninety percent of patients may be treated in this fashion, but local recurrence have been reported and can result in fatalities. True primary sarcoma of the testis is exceedingly rare with only 16 cases reported in the literature the mean patient age was 32 with a range from 3 to 86. The majority of lesions were leiomyosarcomas, and spindle cell sarcomas were the next most frequent histology.85 Carcinosarcoma is a very rare lesion. It is a malignant mixed tumor with sarcomatous and carcinomatous components. There are <100 reported cases, and the majority of these affect the urinary bladder.152,153 It appears that these lesions have a clonal origin similar to bladder tumors but that additional unique changes lead to this aggressive phenotype.154 This has been reported in the prostate and kidney. Patient outcomes are uniformly poor, and treatment for this disease beyond radical surgery is anecdotal. SUMMARY Genitourinary sarcomas are exceedingly rare lesions, which are not amenable to controlled clinical trials. Precise standards for clinical care are therefore difficult to establish. While the management of renal sarcomas differs little from the classic management of renal tumors, it is interesting to note that bladder sarcoma is a very treatable disease, in which cure may be obtained in
668
Part VI Testis
many cases without the loss of function. Prostate sarcomas are best treated with very aggressive surgery, and the outcome of paratesticular sarcomas is very much affected by primary histology. In urologic sarcomas, there appears to be a role for lymph node dissections in conjunction with primary therapy, which is different than the clinical recommendations for primary retroperitoneal sarcomas. Adult rhabdomyosarcoma generally responds less well than its pediatric counterpart even when successful pediatric, therapeutic protocols are employed. In all instances of genitourinary sarcoma, the overall lack of sustained responses to doxorubicin-based therapy suggests that patients with advanced disease should be enrolled in novel protocols.
REFERENCES 1. McGrath PC: Retroperitoneal sarcomas. Semin Surg Oncol 1994; 10:364. 2. Jemal A, Thomas A, Murray T, Thun M: Cancer statistics, 2002. CA Cancer J Clin 2002; 52:23–47. 3. Mack TM: Sarcomas and other malignancies of soft tissue, retroperitoneum, peritoneum, pleura, heart, mediastinum, and spleen. Cancer 1995; 75:211. 4. Pack GT, Tabah EJ: Primary retroperitoneal tumors: a study of 120 cases. Surg Gynecol Obstet 1954; 99: 209–231, 313–341 (International Abstracts of Surgery). 5. Woodruff JM: Peripheral nerve tumors showing glandular differentiation (glandular schwannoma). Cancer 1976; 32: 2399. 6. Arlen M, Higinbotham NL, Huvos AG, et al: Radiationinduced sarcoma of bone. Cancer 1971; 28:1087. 7. Bailar JC: How dangerous is dioxin? N Engl J Med 1991; 324:260. 8. Laskin WB, Silverman TA, Enzinger FM: Postradiation soft tissue sarcomas: an analysis of 53 cases. Cancer 1988; 62:2330. 9. Hardell L, Sandstrom A: Case-control study: soft tissue sarcoma and exposure to phenoxyacetic acids or chlorophenols. Br J Cancer 1979; 39:711. 10. Zahn SH, Fraumeni JF, Semin J: The epidemiology of soft tissue sarcomas. Oncology 1997; 24:504–513. 11. Greenwald P, Kovasznay B, Collins DN, et al: Sarcomas of soft tissues after Vietnam service. JNCI 1984; 73:1107. 12. Suruda AJ, Ward EM, Fingerhut MA: Identification of soft tissue sarcoma deaths in cohorts exposed to dioxin and to chlorinated naphthalenes. Epidemiology 1993; 4:14. 13. Economou JS, Sondak VK, Eilber FR: General considerations, In Eilber FR (ed): The Soft Tissue Sarcomas, p 3. Orlando, Grune and Stratton, 1987. 14. Bose B: Primary malignant retroperitoneal tumors: analysis of 30 cases. Can J Surg 1979; 22:215. 15. Armstrong JR, Cohn I Jr: Primary malignant retroperitoneal tumors. Am J Surg 1965; 110:937.
16. Coran AG, Crocker DW, Wilson RE: A twenty-five year experience with soft tissue sarcomas. Am J Surg 1970; 119:288. 17. Oriana S, Bonardi P, Preda F: Primary retroperitoneal tumors. Tumori 1977; 63:397. 18. McGrath PC, Neifeld JP, Lawrence W Jr, et al: Improved survival following complete excision of retroperitoneal sarcomas. Ann Surg 1984; 200:200. 19. Dalton RR, Donohue JH, Mucha P, et al: Management of retroperitoneal sarcomas. Surgery 1989; 106:725. 20. Jacques DP, Coit DG, Hajdu SI, Brennan MF: Management of primary and recurrent soft-tissue sarcoma of the retroperitoneum. Ann Surg 1990; 212:51. 21. Storm FK, Mahvi DM: Diagnosis and management of retroperitoneal soft-tissue sarcoma. Ann Surg 1991; 214:2. 22. Glenn J, Sindelar WF, Kinsella T, et al: Results of multimodality therapy of resectable soft-tissue sarcomas of the retroperitoneum. Surgery 1985; 97:316. 23. Zornig C, Weh HJ, Krull A, et al: Retroperitoneal sarcoma in a series of 51 adults. Eur J Surg Oncol 1992; 18:475. 24. Karakousis CP, Velez AF, Emrich LJ: Management of retroperitoneal sarcomas and patient survival. Am J Surg 1985; 150:376. 25. Rossi CR, Nitti M, Foletto S, et al: Management of primary sarcomas of the retroperitoneum. Eur J Surg Oncol 1993; 19:355. 26. Kilkenny JW III, Bland KI, Copeland EM, et al: Retroperitoneal sarcoma: the University of Florida experience. J Am Coll Surg 1996;182: 329. 27. Rooser B, et al: Malignant fibrous histiocytoma of soft tissue. Cancer 1991; 67:499. 28. Pezzi CM, Rawlings MS, Esgro JJ, et al: Prognostic factors in 227 patients with malignant fibrous histiocytoma. Cancer 1992; 69:2098. 29. Crozat A, et al: Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature 1993; 363:640. 30. Ladanyi M: The emerging molecular genetics of sarcoma translocations. Diagn Mol Pathol 1995; 4(3):162. 31. Panagopoulos I, Hoglund M, Mertcus F, et al: Fusion of the EWS and CHOP genes in Myxoid lipo sarcoma. Oncogene 1996; 12:489–496. 32. Berner JM, Forus A, Elkakoun A, et al: Separate amplified regions encompassing CDK4 and MDM2 in human sarcomas. Genes Chrom Cancer 1996; 17:254. 33. Elkahloun AG, Bittner M, Heskius K, et al: Molecular cytogenetic characterization and physical morphology of Rg-13-15 amplification in human cancers. Genes Chromosomes Cancer 1996; 17(4):205–214. 34. Pilotti S, Della Torre G, Lavarino C, Sozzi G, et al: Molecular abnormalities in liposarcoma: role of MDM2 and CDK4-containing amplicons at 12q13-22. J Pathol 1998; 185:188–190. 35. DeWeerd JH, Dockerty MB: Lipomatous retroperitoneal tumors. Am J Surg 1952; 84:397. 36. Mowat AP, Clark CG: Presacral lipomata. Br J Surg 1961; 49:230. 37. Heyns CF: Pelvic lipomatosis: a review of its diagnosis and management. J Urol 1991; 146:267.
Chapter 39 Retroperitoneal Tumors 669 38. Yalla SV, Ivker M, Burros HM, et al: Cystitis glandularis with perivesical lipomatosis: frequent association of two unusual proliferative conditions. Urology 1975; 5:383. 39. Klein FA, Vernon-Smith MJ, Kasenetz I, et al: Pelvic lipomatosis: 35 year experience. J Urol 1988; 139:998. 40. Andac N, Baltacioglu F, Cimsit NC, Tuney D, et al: Fat necrosis mimicking liposarcoma in a patient with pelvic lipomatosis. CT findings. J Urol 2003; 27:109–111. 41. Sanders R, Nabil B, Curry N, et al: Clinical spectrum of adrenal myelolipoma: analysis of 8 tumors in 7 patients. J Urol 1995; 153:1791. 42. Chenkt F: Extra-adrenal myelolipoma. Am J Clin Pathol 1982; 78:386. 43. Fowler MR, Williams RB, Alba JM, et al: Extra-adrenal myelolipomas compared with extramedullary hematopoietic tumors: a case of presacral myelolipoma. Am J Surg Pathol 1992; 6:363. 44. Clement PH: Intravenous leiomyomatosis of the uterus. Pathol Annul 1988; 23:153. 45. Kindblom LG, Angervall L, Svendsen P: Liposarcoma: a clinicopathologic, radiographic and prognostic study. Acta Pathol Microbiol Scand 1975; 253:1. 46. Spittle MF, Newton KA, Mackenzie DH: Liposarcoma: a review of 60 cases. Br J Cancer 1971; 24:696. 47. Weiss SW, Rao VK: Well-differentiated liposarcoma (atypical lipoma) of deep soft tissue of the extremities, retroperitoneum and miscellaneous sites: a follow-up study of 92 cases with analysis of the incidence of “dedifferentiation”. Am J Surg Pathol 1992; 16:1051. 48. Enterline HT, Culberson JD, Rochlin DB, et al: Liposarcoma. A clinical pathological study of 53 cases. Cancer 1960; 13:932–950. 49. Forus A, Larramendy ML, Meza-Zepeda LA, Bjerkehagen B, et al: Dedifferentiation of a well-differentiated liposarcoma to a highly malignant metastatic osteosarcoma: amplification of 12q14 at al stages and gain of 1q22-q24 associated with metastases. Cancer Genet Cytogenet 2001; 125:100–111. 50. Pilotti S, Della Torre G, Lavarino C, Sozzi G, et al: Molecular abnormalities in liposarcoma: role of MDM2 and CDK4-containing amplicons at 12q13-22. J Pathol 1998; 185:188–190. 51. Dalcin P, Sciot R, Panagopoulouz I, et al: Additional evidence of a t(R:22) with EWS/CHOP fusion in myxoid liposarcoma. J. Path 1997; 182:437. 52. Deitos AP, Dogliani C, Piccinin S, et al: Molecular abnormalities of the p53 pathway in dedifferentiated liposarcoma. J Pathol 1997; 181:8. 53. Shmookler BM, Lauer DH: Retroperitoneal leiomyosarcoma: a clinicopathologic analysis of 36 cases. Am J Surg Pathol 1983; 7:269. 54. Demers ML, Curley SA, Romsdahl MM: Inferior vena cava leiomyosarcoma. J Surg Oncol 1992; 51:89. 55. Cardell BS, McGill DAF, Williams F: Leiomyosarcoma of inferior vena cava producing Budd-Chiari syndrome. J Pathol 1971; 104:283. 56. Ozzello L, Stout AP, Murray MR: Cultural characteristics of malignant histiocytomas and fibrous xanthomas. Cancer 1963; 16:331.
57. Weiss SW: Malignant fibrous histiocytoma: a reaffirmation. Am J Surg Pathol 1982; 6:773. 58. Coindre JM, Mariani O, Chibbon F, Mairal A, et al: Most malignant fibrous histiocytomas developed in the retroperitoneum are dedifferentiated liposarcomas: a review of cases initially diagnosed as malignant fibrous histiocytoma 2003; 16:256–262. 59. Costa MJ, Weiss SW: Angiomatoid malignant fibrous histiocytoma: a follow-up study of 108 cases with evaluation of possible histologic predictors of outcome. Am J Surg Pathol 1990; 14:1126. 60. Bizer LS: Fibrosarcoma: report of 64 cases. Am J Surg 1971; 121:586. 61. Horn RC, Enterline HT: Rhabdomyosarcoma: a clinicopathological study of 39 cases. Cancer 1958; 11:181. 62. Cavazzana AO, Schmidt D, Ninfo V, et al: Spindle cell rhabdomyosarcoma: a prognostically favorable variant of rhabdomyosarcoma. Am J Surg Pathol 1992; 16:229. 63. Enzinger FM, Smith BH: Hemangiopericytoma: an analysis of 106 cases. Hum Pathol 1976; 7:61. 64. Zirkin RM: Retroperitoneal hemangiopericytoma. Int Surg 1977; 62:395. 65. Douglas JL, Mitchell R, Short DW: Retroperitoneal hemangiopericytoma. Br J Surg 1966; 53:31. 66. Cohan RH, Baker ME, Cooper C, et al: Computed tomography of primary retroperitoneal malignancies. J Comput Assit Tomogr 1988; 12:804. 67. Fong Y, Coit DG, Woodruff JM, Brennan MF: Lymph node metastasis from soft tissue sarcoma in adults: analysis of data from a prospective database of 1772 sarcoma patients. Ann Surg 1993; 217:72. 68. Neifeld JP, Walsh JW, Lawrence W Jr: Computed tomography in the management of soft tissue tumors. Surg Gynecol Obstet 1982; 155:535. 69. Chang AE, Matory YL, Dwyer AJ, et al: Magnetic resonance imaging versus computed tomography in the evaluation of soft tissue tumors of the extremities. Ann Surg 1987; 205:340. 70. Bland KI, McCoy DM, Kinard RE, et al: Application of magnetic resonance imaging and computerized tomography as an adjunct to the surgical management of soft tissue sarcomas. Ann Surg 1987; 205:473. 71. Barth RJ, Merino MJ, Solomon, et al: A prospective study of the value of core needle biopsy and fine needle aspiration in the diagnosis of soft tissue masses. Surgery 1992; 112:536. 72. Lopez-Rios F, Perez-Barrios A, Alberti N, Vargas J, et al: Fine-needle aspiration biopsy of the retroperitoneum: a series of 111 cases not including specific organs. Diagn Cytopathol 2002; 27:85–89. 73. Leyvraz S, Costa J: Histological diagnosis and grading of soft-tissue sarcomas. Semin Surg Oncol 1988: 4:3. 74. Kulander BG, Polissar L, Yang CY, et al: Grading of soft tissue sarcomas: necrosis as a determinant of survival. Mod Pathol 1989; 2:205. 75. Benjmark S, Hafstrom L, Jonsson PE, et al: Retroperitoneal sarcoma treated by surgery. J Surg Oncol 1980; 14:307.
670
Part VI Testis
76. Catton CN, O’Sullivan B, Kotwall C, et al: Outcome and prognosis in retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys 1994; 29:1005. 77. Cody II HS, Turnbull AD, Fortner JG, et al: The continuing challenge of retroperitoneal sarcomas. Ann Surg 1984; 200:200. 78. Singer S, Corson JM, Demetri GD, et al: Prognostic factors predictive of survival of truncal and retroperitoneal soft-tissue sarcoma. Ann Surg 1995; 221:185. 79. Bevilacqua RG, Rogatoko A, Hajdu SI, Brennan MF: Prognostic factors in primary retroperitoneal soft-tissue sarcomas. Arch Surg 1991; 126:328. 80. Alvarenga JC, Ball AB, Fisher C, et al: Limitations of surgery in the treatment of retroperitoneal sarcoma. Br J Surg 1991; 78:912. 81. Ferrario T, Karakousis CP: Retroperitoneal sarcomas: grade and survival. Arch Surg 2003, 138:248–251. 82. Wurl E, Lautenschlager C, Meye A, Schmidt H, et al: A multifactorial prognostic mode for adult soft tissue sarcoma considering clinical, histopathological and molecular data. Anticancer Res 2000; 20:2065–2072. 83. Bautista N, Su W, O’Connell T: Retroperitoneal softtissue sarcomas: prognosis and treatment of primary and recurrent disease. Am Surg 2000, 66:832–836. 84. Malerba M, Doglietto GB, Pacelli F, Carriero C, et al: Primary retroperitoneal soft tissue sarcomas: results of aggressive surgical treatment. World J Surg 1999, 23:670–675. 85. Russo P, Kim Y, Ravindran S, Huang W, Brennan MF: Nephrectomy during operative management of retroperitoneal sarcoma. Ann Surg Oncol 1997; 4:421–424. 86. Fernandez-Trigo V, Surgarbaker PH: Sarcomas involving the abdominal and pelvic cavity. Tumori 1993; 79:77. 87. Skinner DG: Considerations for management of large retroperitoneal tumors: use of the modified thoracoabdominal approach. J Urol 1977; 117:605. 88. Lewis JJ, Leung D, Woodruff JM, Murray F, et al: Retroperitoneal soft-tissue sarcoma. Ann Surg 1998; 228:355–365. 89. Stoeckle E, Coindre JM, Bonvalot S, Kantor G, et al: Prognostic factors in retroperitoneal sarcoma. Cancer 2001; 92:359–368. 90. Tsivian A, Lev-Chelouche D, Shtabsky A, Issakov J, et al: Aggressive resection of retroperitoneal sarcoma is superior to simple excision: an animal study using a novel model for retroperitoneal sarcoma. J Surg Oncol 2002; 81:144–147. 91. Stojadinovic A, Leung D, Hoos A, Jaques DP, et al: Analysis of the prognostic significance of microscopic margins in 2084 localized primary adult soft tissue sarcomas. Ann Surg 2002; 235:424–434. 92. Wang YN, Zhu WQ, Shen ZZ, et al: Treatment of locally recurrent soft tissue sarcomas of the retroperitoneum: report of 30 cases. J Surg Oncol 1994; 56:213. 93. Shibata D, Lewis JJ, Leung DH, Brennan MF: Is there a role for incomplete resection in the management of retroperitoneal liposarcomas? J Am Coll Surg 2001, 193:373–379.
94. Shiloni E, Szold A, White DE, Freund HR: High-grade retroperitoneal sarcomas: role of an aggressive palliative approach. J Surg Oncol 1993; 53:197. 95. Gupta AK, Cohan RH, Francis IR, Sondak VK, et al: CT of recurrent retroperitoneal sarcomas. AJR 2000, 174:1025–1030. 96. Suit HD, Mankin HJ, Wood WC, Proppe KH: Preoperative, intraoperative, and postoperative radiation in the treatment of primary soft tissue sarcomas. Cancer 1985; 55:2659. 97. O’Sullivan B, Ward I, Catton C: Recent advances in radiotherapy for soft-tissue sarcoma. Curr Oncol Rep 2003; 5:274–281. 98. Youssef E, Fontanesi J, Mott M, Kraut M, et al: Long-term outcome of combined modality therapy in retroperitoneal and deep-trunk soft-tissue sarcoma; analysis of prognostic factors. Int J Radiat Oncol Biol Phys 2002; 54:514–519. 99. Gilbeau L, Kantor G, Stoeckle E, Lagarde P, et al: Surgical resection and radiotherapy for primary retroperitonea soft tissue sarcoma. Radiother Oncol 2002; 65:133–136. 100. Petersen IA, Haddock MG, Donohue JH, Nagorney DM, et al: Use of intraoperative electron beam radiotherapy in the management of retroperitoneal soft tissue sarcomas. Int J Radiat Oncol Biol Phys 2002; 52:469–475. 101. Sindelar WF, Kinsella TJ, Chen PW, et al: Intraoperative radiotherapy in retroperitoneal sarcomas. Final results of a prospective, randomized, clinical trial. Arch Surg 1993; 128:402. 102. Willett CG, Suite HD, Tepper JE, et al: Intraoperative electron beam radiation therapy for retroperitoneal soft tissue sarcoma. Cancer 1991; 68:278. 103. Gieschen HL, Spiro IJ, Sutt HD, Mark PJ, et al: Longterm results of intraoperative electron beam radiotherapy for primary and recurrent retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys 2001; 50:127–131. 104. Alektiar KM, Hu K, Anderson L, Brennan MF: Highdose-rate intraoperative radiation therapy (HDR-IORT) for retroperitoneal sarcomas. Int J Radiat Oncol Biol Phys 2000; 47:157–163. 105. Pisters PW, Ballo MT, Fenstermacher MJ, Feig BW: Phase I trial of preoperative concurrent doxorubicin and radiation therapy, surgical resection, and intraoperative electron-beam radiation therapy for patients with localized retroperitoneal sarcoma. J Clin Oncol 2003; 21:3092–3097. 106. Jones JJ, Catton CN, O’Sullivan B, Couture J: Initial results of a trial of preoperative external-beam radiation therapy and postoperative brachytherapy for retroperitoneal sarcoma. Ann Surg Oncol 2002; 9:346–354. 107. Classen J, Hehr T, Lamprecht U, Zumbragel A, et al: Hyperfractionated 192Ir brachytherapy for recurrent retroperitoneal sarcoma: a technique for delivery of local tumor boost dose. Strahlenther Onkol 2003; 179:118–122. 108. Koshy M, Landry JC, Lawson JD, Esiashvili N, et al: Potential for toxicity reduction using intensity
Chapter 39 Retroperitoneal Tumors 671
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
modulated radiation therapy (IMRT) for retroperitoneal sarcoma. Int J Radiat Oncol Biol Phys 2003; 57:448–449. Greiner RH, Munkel G, Blattman H, et al: Conformal radiotherapy for unresectable retroperitoneal soft tissue sarcoma. Int J Radiat Oncol Biol Phys 1992; 22:333. Zalupski MM, Ryan JR, Hussein ME, et al: Systemic adjuvant chemotherapy for soft tissue sarcomas of the extremities. Surg Oncol Clin NA 1993; 2:621. Potter DA, Glenn J, Kinsella T, et al: Patterns of recurrence in patients with high grade soft-tissue sarcomas. J Clin Oncol 1985; 3:353. Weingrad DW, Rosenberg SA: Early lymphatic spread of osteogenic and soft-tissue sarcomas. Surgery 1978; 84:231. Putnam JB Jr, Roth JA: Resection of sarcomatous pulmonary metastases. Surg Oncol Clin North Am 1993; 2:673. Gottlieb JA, Baker LJ, O’Bryan RM, et al: Adriamycin (NSC 123127) used alone and in combination for soft tissue and bone sarcoma. Cancer Chemother Rep 1975; 6:271. Borden EC, Amato DA, Rosenbaum C, et al: Randomized comparison of three Adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol 1987; 5:840. Yap BS, Baker LH, Sinkovics JG, et al: Cyclophosphamide, vincristine, Adriamycin and DTIC (CyVADIC) combination chemotherapy for the treatment of advanced sarcomas. Cancer Treat Rep 1980; 64:93. Edmonson JH, Ryan LM, Blum RH, et al: Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas. J Clin Oncol 1993; 11:1269. Antman KH, Crowley J, Balcerzak SP, et al: An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 1993; 11:1276. Santoro A, Tursz T, Mouridsen H, et al: Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first-line treatment of advanced soft tissue sarcomas: a randomized study of the European organization for research and treatment of cancer soft tissue and bone sarcoma group. J Clin Oncol 1995; 113:1537. DeLaney TF, Spiro IJ, Suit HD, Gebhardt MC, et al: Neoadjuvant chemotherapy and radiotherapy for large extremity soft-tissue sarcomas. Int J Radiat Oncol Biol Phys 2003, 56:1117–1127. O’Sullivan B, Bell RS: Has “MAID” made it in the management of high-risk soft-tissue sarcoma? Int J Radiat Oncol Biol Phys 2003; 56:1117–1127. Okuno S, Edmonson J, Mahoney M, Buckner JC, et al: Phase II trial of gemcitabine in advanced sarcomas. Cancer 2002, 94:3225–3229. Okuno S, Ryan LM, Edmonson JH, Priebat DA, et al: Phase II trial of gemcitabine in patients with advanced sarcoma: (E1797): a trial of the Eastern Cooperative Oncology Group. Cancer 2003, 97:1969–1973.
124. Svancarova L, Blay JY, Judson IR, van Hoesel QG, et al: Gemcitabine in advanced adult soft-tissue sarcomas. A phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 2002; 38:556–559. 125. Hensley ML, Maki R, Venkatraman E, Geller G, et al: Gemcitabine and docetaxel in patients with unresectable leiomyosarcoma: results of a phase II trial. J Clin Oncol 2002; 20:2824–2831. 126. Bauer TW, Hahn SM, Spitz FR, Kachur A, et al: Preliminary report of photodynamic therapy for intraperitoneal sarcomatosis. Ann Surg Oncol 2001; 8:254–259. 127. Herr HW: Sarcoma of the urinary tract. In Dekernion JB, Paulson DF (eds): Genitourinary Cancer Management, p 259. Philadelphia, Lea & Febiger, 1987. 128. Tsukamoto T, Lieber MM: Sarcomas of the kidney, urinary bladder, prostate, spermatic cord, paratestis, and testis in adults. In Raaf JH (ed): Soft Tissue Sarcomas. Diagnosis and Treatment, p 201. St. Louis, Mosby, 1993. 129. Grignon DJ, Ayala AG, Ro JY, et al: Primary sarcoma of the kidney. A clinicopathologic and DNA flow cytometric study of 17 cases. Cancer 1990; 65:1611. 130. Mayes DC, Fechner RE, Gillenwater JY: Renal liposarcoma. Am J Surg Pathol 1990; 14:268. 131. Russo P, Brady MS, Conlon K, et al: Adult urological sarcoma. J Urol 1992; 147:1032. 132. Sen SE, Malek RS, Farrow GM, et al: Sarcoma and carcinosarcoma of the bladder in adults. J Urol 1985; 133:29. 133. Taylor RE, Busuttil A: Case report: adult rhabdomyosarcoma of bladder, complete response to radiation therapy. J Urol 1989; 142:1321. 134. Mills SE, Bova GS, Wick MR, Young RH: Leiomyosarcoma of the urinary bladder. A clinicopathologic and immunohistochemical study of 15 cases. Am J Surg Pathol 1989; 13:480. 135. Ahlering TE, Weintraub P, Skinner DG: Management of adult sarcomas of the bladder and prostate. J Urol 1988; 140:1397. 136. Harrison GSM: Malignant fibrous histiocytoma of the bladder. Br J Urol 1986; 58:457. 137. Oesterling JE, Epstein JI, Brendler CB: Malignant fibrous histiocytoma of the bladder. Cancer 1990; 66:1836. 138. Kerr KM, Grigor KM, Tolley DA: Rhabdomyosarcoma of the adult urinary bladder after radiotherapy for carcinoma. Clin Oncol 1989; 1:115. 139. Kawamura J, Sakurai M, Tsukamoto K, Tochigo H: Leiomyosarcoma of the bladder eighteen years after cyclophosphamide therapy for retinoblastoma. Urol Int 1993; 51:49. 140. Rosser CJ, Slaton JW, Izawa JI, Levy LB, et al: Clinical presentation and outcome of high-grade urinary bladder leiomyosarcoma in adults. Urology 2003; 61:1151–1155. 141. Martin SA, Sears DL, Sebo TJ, Lohse CM, et al: Smooth muscle neoplasms of the urinary bladder: a clinicopathologic comparison of leiomyoma and leiomyosarcoma. Am J Surg Pathol 2002; 26:292–300.
672
Part VI Testis
142. Engel JD, Kuzel TM, Moceanu MC, Oefelein MG, et al: Angiosarcoma of the bladder: a review. Urology 1998; 52:778–784. 143. Yum M, Miller JC, Agarwal BL: Leiomyosarcoma arising in atypical fibromuscular hyperplasia (phyllodes tumor) of the prostate with distant metastasis. Cancer 1991; 68:910. 144. Palmer MA, Viswanath S, Desmond D: Adult prostatic rhabdomyosarcoma. Br J Urol 1993; 71:489. 145. Skinner DG, Sherrod A: Total pelvic exenteration with simultaneous bowel and urinary reconstruction. J Urol 1990; 144:1433. 146. Sexton WJ, Lance RE, Reyes AO, Pisters PW, et al: Adult prostate sarcoma: the M.D. Anderson Cancer Center experience. J Urol 2001; 166:521–525. 147. Merimsky O, Terrier P, Bonvalot S, Le Pechoux C, et al: Spermatic cord sarcoma in adults. Acta Oncol 1999; 38:635–638. 148. Coleman J, Brennan MF, Alektiar K, Russo P: Adult spermatic cord sarcomas: management and results. Ann Surg Oncol 2003; 10:669–675. 149. Sclama AD, Berger BM, Cherry JM, et al: Malignant fibrous histiocytoma of the spermatic cord: role of
150.
151.
152.
153. 154.
retroperitoneal lymphadenectomy in management. J Urol 1983; 130:577. Torosian MH, Wein AJ: Liposarcoma of the spermatic cord: case report and review of the literature. J Surg Oncol 1987; 34:179. Wiener ES, Anderson JR, Ojimba JI, et al: Controversies in the management of paratesticular rhabdomyosarcoma: is staging retroperitoneal lymph node dissection necessary for adolescents with resected paratesticular rhabdomyosarcoma? Semin Pediatr Surg 2001; 10:146–152. Grossman HB, Sonda LP, Lloyd RV, Gikas PW: Carcinosarcoma of bladder: evaluation by electron microscopy and immunohistochemistry. Urology 1984; 24:387. Wick MR, Young RH, Malvesta R, et al: Prostatic carcinosarcomas. Am J Clin Pathol 1989; 92:131. Halachmi S, DeMarzo AM, Chow NH, et al: Genetic alterations in urinary bladder carcinosarcoma: evidence of a common clonal origin. Eur Urol 2000; 37:350–357.
C H A P T E R
40 Urethral Cancer Robert C. Flanigan, MD
Urethral cancer is a rare disorder in both men and women. Because of the differences in etiology, presentation, cell type, and treatment between the two sexes, this chapter will address male and female urethral cancer separately.
urethra and bulbomembranous urethra are squamous cell cancers in 90% and 80% of cases, respectively.5 An understanding of the normal and abnormal urethral urothelium is, therefore, important to the understanding of cancer development, local invasion, and metastases.
MALE URETHRAL CANCER
PATHOLOGY Normal Urothelium
Cancer of the male urethra typically occurs in the 5th decade of life but cases have been described from ages 13 to 90.1 The etiologies that have been shown to be related include chronic infection or inflammation, urethral stricture, sexually transmitted disease, and human papillomavirus 16 (HPV 16).2 The incidence of urethral stricture in men who develop urethral cancer ranges from 24% to 76% and most often involves the bulbomembranous urethra. Because the development of cancer in a chronic stricture patient is often insidious, the urologist should have a high index of suspicion and a low threshold to biopsy a urethral stricture in this setting, especially when the stricture is rapidly recurrent or does not otherwise respond well to treatment. It is estimated that nearly one-quarter of patients with urethral cancer have a history of sexually transmitted disease and that over 90% of these patients are symptomatic at presentation.3 The most common presenting clinical signs of urethral cancer are bleeding, perineal pain, decreased force of stream due to stricture or obstruction, urinary frequency or dysuria, or urinary fistula. Location and histologic type are the keys to categorization of male urethral strictures.4 The frequency of cancer by site is bulbomembranous urethra (60%), penile urethra (30%), and prostatic urethra (10%). Eighty percent are squamous cancers, 15% transitional cell, and 5% adenocarcinomas or undifferentiated tumors. The histologic subtypes, as expected, vary with anatomic site, based largely on the typical lying cells of that area (Figure 40-1). Thus, carcinomas of the prostatic urethra are typically transitional cell (90%), while cancers of the penile
Normal transitional urothelium is composed of 3 to 7 layers of transitional cells with large umbrella cells overlapping the cells of the intermediate cell layers that in turn rest on a basal cell layer. Below the epithelium lies the lamina propria and submucosal layer. The submucosal layer contains the muscularis mucosa and multiple vascular spaces. Below the submucosal layer lies the urethral muscle. The diminished barrier to tumor extension presented by the thin muscular layer explains the ready access of tumor to the paraurethral space.6 Abnormalities of the Urothelial Layer Abnormalities of the urothelial layer can range from hyperplasia to carcinoma. Hyperplasia may be further subdivided into epithelial hyperplasia, inverted papilloma, von Brunn’s nests, and cystitis cystica. Metaplasia Metaplastic lesions of the urothelium include cystitis glandularis (believed to be a precursor of urothelium adenocarcinoma), nephrogenic adenoma, and squamous metaplasia. Dysplasia Dysplasia of the urethra may take the form of atypical hyperplasia, mild atypia, moderate atypia, or severe
675
676
Part VII Urethra and Penis
tional cell epithelium may occur in the absence of visible bladder tumor, its association with either a concurrent or prior bladder tumor significantly increases the risk of progression to invasion. The cystoscopic appearance of carcinoma in situ is often misleading in that a normal-appearing epithelium is the most common finding. A reddened or velvety patch of erythematous mucosa should, however, suggest the possibility of carcinoma in situ. Carcinoma in situ, like papillary urothelial cancer, is more common in men than in women. Because carcinoma in situ frequently presents with irritative voiding symptoms, the patient is often misdiagnosed as suffering from prostatism, urinary tract infection, or neuropathic bladder dysfunction. Cytopathologic studies of voided urine are positive in 85% to 90% of patients with carcinoma in situ. The natural history of carcinoma in situ is unpredictable. Early in its evolution, carcinoma in situ may produce no symptoms, and, in fact, patients with focal asymptomatic carcinoma in situ have been reported to generally display a protracted clinical course with low likelihood of development of invasive cancer. In contrast, patients with more diffuse or symptomatic carcinoma in situ, especially in association with a history of bladder cancer, often display a poor prognosis despite definitive therapy. Figure 40-1 Anatomic regions of the male urethra and corresponding histology and histopathology.
atypia. In addition, leukoplakia of the urethra may occur. Dysplastic urothelium exhibits histologic changes that are intermediate between normal urothelium and carcinoma in situ. It is generally felt that lesions on the severe end of this spectrum are neoplastic rather than dysplastic. Superficial Carcinomas Superficial carcinomas of the urethral urothelium include carcinoma in situ and cancers involving the epithelium and submucosal layers. Histologically, these cancers are either transitional cell, squamous, or adenocarcinomas. Carcinoma In Situ Histologically, carcinoma in situ is characterized by a poorly differentiated cancer involving only the urothelium. A loss of cellular cohesiveness, widening of the intracellular spaces, separation of cells from the basement membrane, and a loss of the superficial umbrella cell layer is characteristic. Carcinoma in situ may occur focally or diffusely within the urothelium. It is often associated with high-grade and high-stage transitional cell cancers. Although carcinoma in situ of the transi-
Papillary Transitional Cell Carcinoma TCC is generally graded on a scale of 1 to 3 (some systems grade from 1 to 4). Grade 1 TCCs differ from normal epithelium by having an increased number of epithelial cell layers. With increasing grade, abnormalities of nuclear morphology, loss of cellular polarity, abnormalities of the normal cellular maturation from the basal to superficial layers, nuclear crowding, and increased nuclear-to-cytoplasmic ratio are seen. In addition, prominent nucleoli with clumping of the chromatin and an increased number of mitoses may be appreciated. Squamous Cell Carcinoma and Adenocarcinoma In the United States, squamous cell carcinomas account for approximately 80% of urethral cancers. These tumors are commonly associated with a chronic inflammatory process involving the urothelium, including the presence of a chronic foreign body (e.g., an indwelling catheter, urinary tract calculi, or recurrent urinary tract infections). Generally, a greater proportion of patients with squamous cell carcinoma, as compared with TCC, present with advanced disease at the time of diagnosis. Adenocarcinoma of the urethra is an uncommon lesion accounting for very small percentage of urethral cancers.
Chapter 40 Urethral Cancer 677
NATURAL HISTORY Numerous chromosomal abnormalities have been found to be associated with the development of TCC, including chromosome 9 loss, c-myc amplification, Y chromosome loss, and p53, p21, and erb-B-2 abnormalities. Of these, chromosome 9 loss and p53 abnormalities may be the most important. Loss of heterozygosity of chromosome 9 seems to be an early event associated with the formation of papillary tumors, whereas p53 gene deletion seems to be associated with the formation of dysplasia and carcinoma in situ. By the time a TCC invades the lamina propria, both of these genetic events have typically occurred. Chromosome 9 deletion is felt to result in a homozygous deletion of the MTS-1 gene (a tumor-suppressor gene), and it is a frequent event in TCC but not a driving force in tumor progression. P53 is a tumor-suppressor gene located at 17p13.1, which codes for a DNA-binding protein involved in the regulation of transcription. Deletion of this gene results in an overexpression of the p53 (missense mutation), leading to an extension of the half-life of the protein. p53 and another transcription-mediating gene, p21, are associated with progression of TCC. The natural history and molecular biology of squamous cell and adenocarcinomas of the urothelium are less well understood than that of TCC. Squamous cell carcinoma is an invasive lesion with a nodular infiltrative growth pattern. It is postulated that nitrosamines produced by bacteria in infected urine act as carcinogens and tumor promoters. A recent study of cytogenetics in squamous cell urethra cancer has demonstrated involvement of chromosomes Y, 2, 3, 4, 6, 7, 8, 11, and 20 but of interest, not chromosomes 9 and 17, which are widely involved in transitional cell cancer.7 Evaluation and Staging The TNM staging system is based on the depth of invasion of the primary tumor, the presence of regional lymph node involvement, and the presence of distant metastases (Table 40-1). The diagnosis and staging of urethral cancer begins with physical examination of the external genitalia, urethra, rectum, and perineum. Cystoscopy and bimanual examination-underanesthesia are often useful. Transurethral or percutaneous needle biopsy of the lesion is performed. Cytologic studies of first voided urine may be helpful. Local involvement, including involvement of regional lymphatics and contiguous structures, as well as estimation of the extent of local disease, is best determined by MR or CT imaging. MR is particularly helpful in determining invasion of the corporal bodies.8 Treatment Surgical excision remains the primary therapy for male urethral cancers. The extent of resection depends on the
extent of involvement of the surrounding tissues and can vary from transurethral excision or local resection to partial or total penile amputation. The treatment of urethral cancer can also be divided into three areas of urethral involvement: the penile urethra and fossa navicularis, the bulbomembranous urethra, and the prostatic urethra. The prognosis of urethra cancers is dependent on the type of cancer, site of the lesion (distal better than proximal), the depth of invasion, and the ability to achieve complete local control.9 A summary of prognosis by site of involvement is given in Table 40-2. Penile Urethra and Fossa Navicularis Cancers When distal urethral cancer is superficial, papillary, or in situ, transurethral resection and fulguration may be employed. When the cancer invades the corpus spongiosum, more aggressive therapy is indicated and may include urethrectomy with sparing of the corpora cavernosa (penile-sparing), partial penectomy with an adequate margin (2 cm), and total penectomy. Partial penectomy is most useful in cancers that involve the distal half of the penis. In any case, the advantages of tissueconserving approaches must be balanced against the probability of local recurrence and death from metastatic disease.10 Ilioinguinal lymphadenectomy is indicated in the presence of palpable nodes but the value of prophylactic node dissection has not been demonstrated in this disease. Bulbomembranous Cancers Superficial lesions of the bulbomembranous urethra are quite rare but have been successfully managed by transurethral resection and local excision with end-toend urethral reanastomosis. In general, radical excision seems to be the best approach, employing radical cystoprostatectomy combined with total penectomy and bilateral pelvic lymphadenectomy. In severe cases, extending the en bloc excision to include the pubic rami and urogenital diaphragm has been recommended.11,12 Prostatic Urethral Cancers Primary carcinoma of the prostatic urethra is rare. In this setting, transitional cell and adenocarcinomas are the most common histologies. It is imperative to rule out extension of these cancers from the bladder, as this presentation is far more common than tumor arising in the prostatic urethra. Patients typically present with hematuria or obstructive symptoms and rarely with prostatic induration on digital rectal exam (a sign of advanced disease). Diagnosis may require both transurethral biopsy and transrectal ultrasound-guided needle biopsy. Superficial papillary or in situ cancers may be managed
678
Part VII Urethra and Penis
Table 40-1 Urethral Cancer TNM Staging System Primary tumor (T) (male and female) Tx
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Ta
Noninvasive papillary, polypoid, or verrucous carcinoma
Tis
Carcinoma in situ
T1
Tumor invades subepithelial connective tissue
T2
Tumor invades any of the following: corpus spongiosum, prostate, periurethral muscle
T3
Tumor invades any of the following: corpus cavernosum, beyond prostatic capsule, anterior vagina, bladder neck
T4
Tumor invades other adjacent organs
Transitional cell carcinoma of the prostate Tis-pu
Carcinoma in situ, involvement of the prostatic urethra
Tis-pd
Carcinoma in situ, involvement of the prostatic ducts
T1
Tumor invades subepithelial connective tissue
T2
Tumor invades any of the following: prostatic stroma, corpus spongiosum, periurethral muscle
T3
Tumor invades any of the following: corpus cavernosum, beyond prostatic capsule, bladder neck (extra prostatic extension)
T4
Tumor invades other adjacent organs (invasion of the bladder)
Regional lymph nodes (N) Nx
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in a single lymph node, 2 cm or less in greatest dimension
N2
Metastasis in a single lymph node, more than 2 cm but <5 cm in greatest dimension; or in multiple nodes, none >5 cm
N3
Metastasis in a lymph node >5 cm in greatest dimension
Distant metastasis (M) Mx
Presence of distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
successfully by transurethral resection in select patients.13 In the great majority of cases, however, the cancer involves the prostatic stroma and is typically treated by cystoprostatectomy with total urethrectomy and bilateral pelvic lymphadenectomy. The outlook in this setting is poor, with reported 5-year survival ranging from 6% to 26%.14
OPERATIVE TECHNIQUES FOR MALE URETHRA CANCERS Partial and Total Urethrectomy in the Male Patient with Primary Urethral Carcinoma Distal urethral carcinoma in the male includes all tumors distal to the bulbous urethra.15 These tumors may be managed by transurethral resection, partial penectomy,
Chapter 40 Urethral Cancer 679
Table 40-2 Treatment Survival for Urethral Cancer Site
Treatment
Fossa navicularis
Partial penectomy
Penile
Partial or total penectomy
Bulbomembranous
No. Patients
Survival
12
11 (92%)
100
34 (34%)
Total penectomy, urethrectomy, cystoprostatectomy
64
10 (16%)
Prostatic superficial
Transurethral resection
45
39 (87%)
Invasive
Cystoprostatectomy, urethrectomy
78
29 (37%)
Figure 40-2 A, Patient position for radical cystoprostatectomy. Umbilicus is placed over break of table, and table is fully flexed and tilted into Trendelenburg’s position, until legs are parallel to floor. B, Patient position for urethrectomy. Leg braces are elevated until hips are flexed 60 degrees and knees are fully extended.
or partial penectomy with perineal urethrostomy. Standard positioning techniques are pictured in Figure 40-2. For patients with posterior urethral cancers, total urethrectomy with cystoprostatectomy is typically undertaken. The patient is placed in the lithotomy position with special attention to abduction of the legs. After radical cystectomy and lymphadenectomy is completed, the membranous urethra is dissected from the urogenital diaphragm using finger dissection. Attention is then directed to the perineum. A midline or inverted Y incision is made in the anterior perineum overlying the central tendon (Figure 40-3). The superficial and deep fascia
are incised and the bulbocavernosus muscle divided in the midline and reflected laterally to expose the bulbous urethra. A perineal ring retractor (e.g., Turner-Warwick or Omni) provides good exposure. After a segment of the urethra is isolated by incising Buck’s fascia overlying the inferior lateral grooves between the corpus spongiosum and the corpus cavernosum and dividing its superomedial attachments, a Penrose drain is advanced through the defect and used to create countertraction on the corpus spongiosum during the remaining distal dissection (Figure 40-3B). The plane between corpus spongiosum and corpus cavernosus is remarkably easy to develop in most cases, although inadvertent laceration of the tunica albuginea of the corpora cavernosa may produce considerable hemorrhage, which is most readily controlled with continuous 3-0 chromic or polyglycolic acid (PGA) sutures. During distal dissection, the penis becomes inverted and the plane between the corpus spongiosum and corpora cavernosa is lost. A decision must be made whether or not to preserve the fossa navicularis at this point. Preservation of the fossa navicularis may be helpful in allowing for more adequate placement and seating of the tips of a penile prosthesis at a later date. If the fossa navicularis is to be resected, the penile meatus is circumscribed using a tear-shaped incision and the fossa navicularis is mobilized from the glans penis and pulled into the perineal incision (Figure 40-5). Defects in the glans penis are closed with interrupted 2-0 chromic or PGA sutures. Isolation of the proximal urethra at the bulbomembranous junction is the most difficult aspect of the procedure. Dissection is carried in a posterior and lateral direction with special care to identify and secure branches of the pudendal arteries entering at the 4 o’clock and 8 o’clock positions (Figure 40-4). Small hemoclips or 3-0 chromic/PGA sutures are particularly useful for this maneuver. The urethrectomy is completed by mobilizing the most proximal bulbous urethral spongiosum and by dissecting the remaining membranous urethra from the urogenital diaphragm. At this point, the appropriate plane of dissection may be best appreciated
680
Part VII Urethra and Penis
Figure 40-3 Total urethrectomy with cystoprostatectomy.
Chapter 40 Urethral Cancer 681
Figure 40-4 Control of the bulbar arteries fudging urethrectomy.
Figure 40-5 Inverted T-incision on glans penis and dissection of glanular urethra.
by combined perineal and abdominal palpation and inspection. The perineal wound is carefully irrigated and a suction or Penrose drain is positioned in the bed of the bulbous urethra and brought out through a separate stab wound (Figure 40-6). Reapproximation of the bulbocavernosus muscle is undertaken in the midline using 2-0 chromic or PGA sutures. The subcutaneous tissue is closed with interrupted 3-0 chromic or PGA sutures and the skin is closed with interrupted 3-0 nylon sutures. The shaft of the penis is wrapped loosely with gauze or is covered with a self-adhering dressing of some variation. Exposure of the tip of the glans penis in
Figure 40-6 Closure of the perineal incision and placement of the Jackson-Pratt drain.
682
Part VII Urethra and Penis
order to permit prompt identification of postoperative ischemia is important. Total Urethrectomy in the Male Patient in Association with Cystectomy The procedure for concomitant urethrectomy at the time of cystoprostatectomy is very similar to that described previously for the treatment of primary urethral cancer. The bulbomembranous and prostatic urethral segments are those most often involved by extension of the primary bladder cancers; thus careful dissection of these areas is essential. This part of the dissection can be considerably more difficult when urethrectomy follows cystoprostatectomy by more than several weeks.16 In such cases, a Foley catheter must be placed to the proximal end of the urethra and secured in place by suturing to the meatus, and dissection carried to the proximal extent of the catheter. Dissection of the proximal urethra should be done carefully and methodically because extensive traction on the urethra may avulse the proximal portion as a result of extensive fibrosis in this area. Drainage of the proximal urethral bed using a Jackson-Pratt or Penrose drain is suggested.
FEMALE URETHRAL CANCERS Urethral cancer is more common in women than men (ratio 4:1). Risk factors include race (Caucasian more common), age (>50 years most common), a history of chronic inflammation or irritation, urinary tract infections, or proliferative lesions, including caruncles, papillomas, adenomas, and leukoplakia. Most women present with urethral bleeding, urinary symptoms, and a palpable mass or induration. Tumors may be papillary, fungating, or ulcerating and may cause induration of the anterior vaginal wall. Odor producing necrosis and discharge may occur. Local extension is not uncommon and may involve the bladder neck, vagina, or vulva. Metastases to regional lymphatics are common, occurring in up to one-third of patients at presentation. Anterior urethral cancers drain into the superficial and deep inguinal nodes whereas posterior urethral tumors drain into the external iliac, hypogastric, and obturator nodes. Female urethral cancer often produces systemic metastases without regional node involvement. Generally, therefore, groin dissection is reserved for those patients who have palpable lymphadenopathy without distant spread of cancer.19 Pathology
Radiation Therapy and Multimodal Therapy Radiation therapy alone may be adequate to control small lesions in the distal urethra.17 Radiation may be delivered using brachytherapy or intracavitary techniques. Chemotherapy using MVAC or paclitaxel and ifosfamide have recently been reported to successfully treat transitional cell cancers of the urethra.18
As with male urethral cancer, the urethral cancer cell type in women is related to the site of urethra involved and may be squamous, transitional cell, or adenocarcinomas (Figure 40-7). Carcinomas of the proximal or posterior urethral are typically locally advanced and high grade, whereas distal cancers are, in general, low grade and less extensive. Overall, squamous cell cancers are most common
Figure 40-7 Anatomic regions of the female urethra and corresponding histology and histopathology.
Chapter 40 Urethral Cancer 683
(60%), followed by transitional cell (20%), adenocarcinoma (10%), undifferentiated or sarcomatous (8%), and melanoma (2%).
rior exenteration with wide resection of the vagina in most cases. Partial and total urethrectomy can be useful in selected cases of female urethral cancer.
Evaluation and Staging
OPERATIVE TECHNIQUES FOR PARTIAL AND TOTAL URETHRECTOMY IN THE FEMALE Partial and Total Urethrectomy in the Female Patient with Primary Urethral Cancer
Pelvic examination combined with cystoscopy and biopsy is the cornerstones of diagnosis. The TNM staging system is similar to that of male urethral cancer and is shown in Table 40-1. Prognosis has been reported in various studies to be dependent on tumor size, location in the urethra (posterior versus anterior), histology, and extent of disease (early versus advanced) (Table 40-3).20 In one series of 76 patients, 5-year disease-specific survival was 89% for low-stage tumors compared to 33% for high-stage tumors.21 Treatment Although local excision may suffice for low grade, lowstage tumors, single modality therapy often fails to adequately control advanced cancer and is associated with a 20% 5-year survival and a local recurrence rate exceeding 65%.22 As with male urethral cancer, treatment options vary considerably with site of urethral involvement: distal or proximal. Distal Urethral Cancer Distal cancers, as stated above, are more often superficial and well localized with infrequent lymph node metastases. Local excision is often sufficient and is accomplished by circumferential excision of the involved urethra with adjacent portions of the anterior vagina. Spatulation of the remaining urethra with approximation to the adjacent vagina and labia is associated with preservation of continence in most cases. Proximal Urethral Cancer Proximal urethral cancers are most often aggressive and invasive and require extensive resection, including ante-
The female patient with primary urethral cancer is prepared for anterior exenteration with mechanical and antibiotic bowel preparation, systemic antibiotics, and intravenous hydration. In those patients presenting with tumors of the distal third of the urethra that are confined to the mucosa, submucosa, or periurethral musculature, a distal urethrectomy may be appropriate. Distal urethrectomy is performed with the patient in the lithotomy position after full vaginal and abdominal preparation. A weighted speculum is used to improve visualization of the urethral orifice. A traction suture ligature of 0 or 2-0 silk is passed through the urethral meatus or the surrounding periurethral tissue. An encircling incision is then made around the meatus (Figure 40-8). After sharp dissection of the urethral meatus, a longitudinal incision is made on the vaginal mucosa overlying the epithelium to approximately 2 cm beyond the point of palpable induration. Sharp dissection then circumscribes the urethra, which is transected at the previously determined proximal extent of dissection. Frozen sections of the proximal urethral margin should be evaluated to document the absence of microscopic involvement of the urethra at that point. Mucosal edges of the remaining urethra may then be approximated to the vaginal mucosa using 3-0 chromic or PGA sutures. A 16 to 18 French Foley catheter is inserted into the bladder to provide urinary drainage. Vaginal repair is then completed using an interrupted or running 2-0 or 3-0 chromic or PGA suture. Povidone-iodine soaked vaginal packing is left within the vaginal vault and is removed on postoperative day 1. In those patients in whom tumor extends microscopically beyond the point of palpable induration, and/or
Table 40-3 Prognosis for Early and Advanced Tumors Stage
Treatment
Early
Radiation therapy Surgery Radiation therapy plus surgery
Advanced
Radiation therapy Radiation therapy plus surgery
No. Patients
Survival
140
94 (67%)
24
20 (83%)
5
4 (80%)
157
54 (34%)
39
21 (54%)
684
Part VII Urethra and Penis
Figure 40-8 Technique for resection of the distal third of the female urethra.
those patients with proximal urethral cancers in whom proximal urethral involvement of the tumor is established preoperatively, total urethrectomy, vulvectomy, clitorectomy, and anterior exenteration may be required to remove the tumor with an adequate margin.23 In selected cases, resection of the pubic rami may also be necessary.24 The female candidate for total urethrectomy is prepared in a fashion similar to that described for partial urethrectomy. The operation is generally begun abdominally, where radical cystectomy and pelvic lymph node dissections are performed in the standard fashion. In addition, salpingo-oophorectomy and hysterectomy are also performed in most cases. Resection of the anterior urethra en bloc with the abdominal structures proceeds along the lines described previously. Complete excision of the anterior compartment of the perineum may require a gracilis flap to provide for adequate pelvic floor support (Figure 40-9).25 Resection of the pubic rami is undertaken only in very extensive tumors because it may be associated with significant complications, including sacroiliac joint disruption and perineal hernia formation.26 It is important to preserve vulvar skin whenever possible and to remove the specimen en bloc so as to avoid contamination of the operative field by tumor spillage. After completion of the extirpative aspects of the procedure, urinary diversion is completed. Multimodal Therapy Because of the dismal results with single modality therapies in female urethral cancers, attempts to provide a multimodal approach have been undertaken. In a recent
Figure 40-9 In extensive pelvic/perineal exenteration, the urethra and external genitalia in continuity with the pelvic structures are removed. The pubic rami are identified and prepared for excision by freeing the overlying subcutaneous tissue, the suspensory ligament of the penis, and the various muscular attachments. The outlines of exenteration of the bone are indicated by the dotted lines.
report, 6 women were managed with high-dose rate brachytherapy, anterior exenteration, and external beam radiation therapy with 4 patients receiving adjuvant platinum-based chemotherapy. Despite this approach, 3 of 6 patients had distant metastases at a mean follow-up of 21 months.27 In another series, surgery was combined with either neoadjuvant or adjuvant radiation therapy in 12 patients, resulting in a 44% 5-year cause-specific survival.20 A single case of squamous cell cancer successfully managed with external beam radiation therapy and cisplatin, and 5-fluorouracil has been reported.28
REFERENCES 1. Weiner JS, Liu ET, Walther PJ: Oncogenic human papillomavirus type 16 is associated with squamous cell cancer of the male urethra. Cancer Res 1992; 52:5018–5023. 2. Cupp MR, Reza MS, Goellner JR, et al: Detection of human papillomavirus DNA in primary squamous cell carcinoma of the male urethra. Urology 1996; 48:551–555. 3. Dalbagni G, Zhang ZF, Lacombe L, Herr HW: Male urethral carcinoma: analysis of treatment outcome. Urology 1999; 53:1126–1132. 4. Mostofi FK, Davis CJ, Sesterhenn IA: Carcinoma of the male and female urethra. Urol Clin North Am 1992; 19:347–358. 5. Grigsby PW, Herr HW: Urethral tumors. In Volgelzang N, Scardino PT, Shipley WU, Coffey DS (eds): Comprehensive Textbook of Genitourinary
Chapter 40 Urethral Cancer 685
6.
7.
8.
9.
10.
11. 12.
13.
14. 15. 16.
17.
Oncology, pp 1133–1139. Baltimore, Williams & Wilkins, 2000. Flanigan RC, Kim FJ: Neoplastic disease of the pelvis, ureter, bladder and urethra. In Textbook of Nephrology, 4th edition. Philadelphia, Lippincott, Williams & Williams,2001. Fadl-Elmula I, Gorunova L, Mandahl N, Elfving P, Heim S: Chromosome abnormalities in squamous cell carcinoma of the urethra. Genes, Chromosomes Cancer 1998; 23:72–73. Vapnek JM, Hricak H, Carroll PR: Recent advances in imaging studies for staging of penile and urethral carcinoma. Urol Clin North Am 1992; 19:257–266. Zeidman EJ, Desmond P, Thompson I: Surgical treatment of carcinoma of the male urethra. Urol Clin North Am 1992; 19:359–372. Davis JW, Schellhammer PF, Schlossberg SM: Conservative surgical therapy for penile and urethral carcinoma. Urology 1999; 53(2):386–392. Mackenzie AR, Whitmore WF: Resection of the pubic rami for urologic cancer. J Urol 1968; 100:546–551. Klein EA, Herr HW, Whitmore WF, et al: Inferior pubic rami resection with en bloc radical excision for invasive proximal urethral carcinoma. Cancer 1983; 51:1238–1242. Bretton PR, Herr HW: Intravesical BCG for in situ transitional cell carcinoma involving the prostatic urethra. J Urol 1989; 141:853–856. Hall RR, Robinson MC: Transitional cell carcinoma of the prostate. Eur Urol Update Series 1998; 7:1–7. Mandler JI, Pool TL: Primary carcinoma of the male urethra. J Urol 1966; 96:67–72. Brendler CB: Urethrectomy. In Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr (eds): Campbell’s Urology, 6th edition, pp 2774–2781. Philadelphia, WB Saunders, 1992. Sailer SL, Shipley WU, Wang CC: Carcinoma of the female urethra: a review of results with radiation therapy. J Urol 1988; 140:1–5.
18. VanderMolen LA, Sheehy PF, Dillman RO: Successful treatment of transitional cell carcinoma of the urethra with chemotherapy. Cancer Invest 2002; 20(2):206–207. 19. Grigsby PW, Herr HW: Urethral tumors. In Volgelzang N, Scardino PT, Shipley WU, Coffey DS (eds): Comprehensive Textbook of Genitourinary Oncology, pp 1133–1139. Baltimore, Williams & Wilkins, 2000. 20. Grigsby PW: Carcinoma of the urethra in women. Int J Radiat Oncol Biol Phys 1998; 41(3):535–541. 21. Dalbagni G, Zhang ZF, Lacombe L, Herr HW: Female urethral carcinoma: an analysis of treatment outcome and a plea for a standardized management strategy. Br J Urol 1998; 82:835–841. 22. Narayan P, Konety B: Surgical treatment of female urethral carcinoma. Urol Clin North Am 1992; 19:373–382. 23. Grabstald H, Hilaris B, Henschke U, Whitmore WF: Cancer of the female urethra. JAMA 1966; 197:835–842. 24. Klein FA, Whitmore WF, Herr HW, et al: Inferior pubic rami resection with en bloc radical excision for invasive proximal urethral carcinoma. Cancer 1983; 51:1238–1242. 25. Johnson DE, Lo RR: Tumors of the penis, urethra and scrotum. In deKernion JB, Paulson DF (eds): Genitourinary Cancer Management, pp 219–270. Philadelphia, Lea & Febiger, 1987. 26. MacKenzie AR, Whitmore WF: Resection of the pubic rami for urologic cancer. J Urol 1968; 100:546–551. 27. Dalbagni G, Donat SM, Eschwege P, Herr HW, Zelefsky MJ: Results of high dose rate brachytherapy, anterior pelvic exenteration and external beam radiotherapy for carcinoma of the female urethra. J Urol 2001; 166(5):1759–1761. 28. Lee KC: Carcinoma of the female urethra responsive to moderate dose chemoradiotherapy. J Urol 2000; 163:905–906.
C H A P T E R
41 Urethrectomy Sanjaya Kumar, MD
INDICATIONS Over the years, the indications for urethrectomy have changed. The trend has shifted towards preservation of the urethra. The indications for preserving the urethra have been liberalized for several reasons. These include the widespread utilization of orthotopic neobladders in both men and women, better understanding of the anatomy of the female urethra, and importantly the reduced risk of urethral recurrence following orthotopic urinary diversion.1 Currently, the absolute indication to remove the urethra includes the involvement of the urethra by carcinoma. The single most important predictor of recurrent disease in the male urethra is transitional cell carcinoma (TCC) involvement of the prostatic urethra, specially the stroma.2–4 The single most important predictor of recurrent disease in the female urethra is involvement of tumor at the bladder neck.5,6 However, the absolute indication for a prophylactic urethrectomy includes the histologic evidence of cancer at the urethral margin at the time of cystectomy in both men and women. A urethrectomy may be performed simultaneously during a cystoprostatectomy for transitional cell cancer, if the prostatic urethra is involved by tumor at the time of the cystectomy, or at a later time, should there be a recurrence of tumor in the urethra. Ideally, a complete urethrectomy is performed, both in males and females. However, in males, under certain circumstances, such as when there is a superficial isolated solitary recurrence, following an orthotopic neobladder, a partial or segmental urethrectomy may be performed, provided it is surgically feasible. OPERATIVE TECHNIQUE Urethrectomy in the Male Simultaneous Urethrectomy with Cystoprostatectomy Pelvic dissection. A simultaneous urethrectomy with
cystoprostatectomy is performed for TCC of the bladder
686
involving the urethra. The prostatic urethra is usually involved and this determination is made from prior staging resection and biopsy. A frozen section analysis of the membranous urethra is always undertaken at the time of cystoprostatectomy. Positive findings will necessitate abandoning the orthotopic neobladder and performing a complete urethrectomy. If the patient is not able to tolerate the simultaneous procedure, the urethrectomy can be performed at a later date. For a concomitant radical cystoprostatectomy, the patient is positioned in a lithotomy position to allow access to the abdomen, pelvis, and the perineum. Modified stirrups or boots are usually used that allow the position of the patient to be modified in a sterile fashion during the urethrectomy (Figure 41-1). All pressure points must be carefully padded and protected. A twoteam approach may be more expeditious. Once the dissection for the cystoprostatectomy is complete, attention is directed towards performing an en bloc urethrectomy. At this point the dorsal venous complex and other attachments have been divided and the bladder and prostate are in continuity with the membranous urethra. The membranous urethra is dissected from the urogenital sinus using blunt and sharp dissection. An umbilical tape is passed under the urethra, below the apex of the prostate. Gentle traction on the tape facilitates dissection in a plane between the urethral smooth muscle and the striated muscle of the urogenital diaphragm. The dissection is performed carefully to visualize the bleeders and preserve the neurovascular bundles located posterolateral to the urethra (Figure 41-2). The use of electrocautery should be minimized if a nerve-sparing technique is being adopted.7 Once the membranous urethra has been completely mobilized from the urogenital diaphragm, attention is directed towards dissecting the anterior urethra. Secondary urethrectomy is difficult at this location due to scarring from previous cystoprostatectomy. The procedure can result in shredding of the urethra,
Chapter 41 Urethrectomy 687
Figure 41-1 A, Patient position for radical cystoprostatectomy. Umbilicus is placed over break of table, and table is fully flexed and tilted into Trendelenburg’s position, until legs are parallel to floor. B, Patient position for urethrectomy. Leg braces are elevated until hips are flexed 60 degrees and knees are fully extended. (From Brendler CB, Schlegel PN, Walsh PC: J Urol 1990; 144:270–273.)
incomplete resection, and risk injury to bowel. It is therefore important at this time to dissect the urethra as far distally as is safely possible. Attention is now directed towards the perineum. However, if a frozen section specimen of the urethra is necessary, the urethra should be tied before transaction to prevent tumor spillage. The urethra may be deliberately divided here if the patient is unable to withstand anesthesia for the additional time necessary to perform the anterior urethrectomy. The urethrectomy can then be performed as a secondary procedure several weeks later. Perineal dissection. The lithotomy position can now
be exaggerated by tilting the boots up. An inverted Yshaped incision is made in the skin of the perineum between the scrotum and the anal verge (Figure 41-3). The subcutaneous tissue is divided to expose the bulbocavernous muscle. The bulbocavernous muscle is divided in the midline (Figure 41-4). Two Richardson retractors or ring retractors are used to keep the wound open. The corpus spongiosum is now dissected. The urethra can be palpated through the urethral catheter. In a secondary urethrectomy, a metal sound (Van Buren) can be used instead of a catheter. Pinch the catheter surrounded by the urethra by the fingers and using a Metzenbaum scissors expose the dorsal aspect of the urethra. Create adequate space between the urethra and corpus caver-
nosum to pass a quarter inch Penrose drain around the urethra (Figure 41-5). The dorsum of the urethra is usually adherent to the corpus cavernosum. Traction on the Penrose and sharp dissection in this plane allows separation of the urethra from the corpus cavernosum. The pointed tip electrocautery on a low setting works well in this midline plane (Figure 41-6). Cavernosal bleeding and minor rents can be closed with 2-0 Vicryl/monofilament absorbable sutures. Distal dissection and traction on the urethra eventually results in inversion of the penis into the wound (Figure 41-7A,B). Once the dissection reaches the urethral tip, the fossa navicularis and the meatus are cored out. Alternatively, the penis is straightened, and either a wedge or a T-shaped incision made of the ventral aspect of the glans penis. The fossa navicularis and the meatus can now be dissected (Figure 41-8). Strict hemostasis is ensured. The glans penis is reconstructed with 3-0 chromic catgut or monofilament absorbable sutures. For cosmetic reasons, under certain circumstances, the fossa navicularis can be preserved. Once the distal urethra is completely mobilized and disconnected from the glans penis, the proximal urethra is freed from the perineal investments. The bulbar urethral arteries are posterolateral to the bulb. These are carefully secured (Figure 41-9). Anteriorly, the urethra is dissected under the pubic symphysis (Figure 41-10). Eventually, dissections around the urethra, from the pelvis above and the perineum below, meet up in a common plane (when combined with cystoprostatectomy), through the urethra genital diaphragm. It is important to dissect close to the urethra to avoid injury to the erector nerves. The urethra is now completely mobilized. It can either be removed separately or pulled from the abdominal side and removed en bloc with the cystectomy specimen. In a secondary urethrectomy, the very last proximal end of the urethra is surrounded by scar tissue and is carefully dissected. The operator must safeguard against urethral avulsion, at the pelvis, by avoiding undue traction on the urethra. The urethra must be removed in its entirety (Figure 41-11A,B) while the surgeon is cognizant of potential injury to underlying bowel. The wound is irrigated with antibiotic solution, strict hemostasis ensured and closed in layers. The bulbocavernous muscles and the urogenital diaphragm are reapproximated with 2-0/3-0 absorbable sutures. A number 7 french Jackson-Pratt drain is left indwelling for 24 to 48 hours in the urethral bed and brought out through a separate stab incision (Figure 41-12). The subcutaneous tissue is closed with 3-0 absorbable sutures. Additional layers may need to be reapproximated in the pelvic area to close all dead space. The skin is closed with 4-0 Monocryl. Either Steri-Strips or Dermabond can be used for additional support. A gentle compressive dressing with Kerlex sponges is then applied.
688
Part VII Urethra and Penis
Figure 41-2 A, Urethra is ligated with 1-0 silk suture to prevent spillage of urine around catheter (NVB, neurovascular bundle; Pros, prostate). B, Mobilization of membranous urethra from urogenital diaphragm with Kitner dissector. C, Further mobilization of membranous urethra. D, Lateral view shows membranous urethra (Ur) fully mobilized with neurovascular bundles displaced posterolaterally. E, Urethra is transected, and catheter is drawn cephalad into wound. Neurovascular bundles are seen intact, lateral to the urethra. (From Brendler CB, Schlegel PN, Walsh PC: J Urol 1990; 144:270–273.)
Total Anterior Urethrectomy in the Male Complete anterior urethrectomy may be performed as a secondary procedure for TCC or as a primary procedure for nontransitional cell cancers of the anterior urethra. This procedure is performed for transitional cell cancer of the prostatic urethra, as a staged procedure, if a cystoprostatectomy with concomitant urethrectomy cannot be completed in a primary setting. Total anterior urethrectomy is also performed for recurrent transitional cell cancer of the anterior urethra. The details of the proce-
dure are similar to those mentioned in the section on perineal dissection. The extent of urethral resection for nontransitional cell cancer of the urethra depends on the pathology and stage of the cancer. Most of the distal urethral tumors are low stage and proximal urethral tumors are high stage.8 Thus, surgery for tumors in the anterior urethra may vary from transurethral resection, segmental resection, and partial penectomy to total penectomy with perineal urethrostomy. Tumors of the bulbomembranous and prostatic urethra are generally advanced at the time of presentation and
Chapter 41 Urethrectomy 689
Figure 41-5 Mobilization of urethra off corpus cavernosa facilitated using a Penrose drain. (From Graham SD Jr (ed): Glenn’s Urologic Surgery, 5th edition, pp 461–466. Philadelphia, Lippincott, Williams and Wilkins, 1998.)
Figure 41-3 Perineal skin incision for urethrectomy. (From Hinman F, et al: Atlas of Urologic Surgery, 2nd edition. Amsterdam, Elsevier Science, 1998.)
Figure 41-4 Division of bulbocavernous muscle and exposure of urethra. (From Graham SD Jr (ed): Glenn’s Urologic Surgery, 5th edition, pp 461–466. Philadelphia, Lippincott, Williams and Wilkins, 1998.)
Figure 41-6 Use of electrocautery to dissect the urethra from the corpus cavernosum. (From Hinman F, et al: Atlas of Urologic Surgery, 2nd edition. Amsterdam, Elsevier Science, 1998.)
690
Part VII Urethra and Penis
Figure 41-7 Distal dissection of the urethra resulting in inversion of the penis. (A from Hinman F, et al: Atlas of Urologic Surgery, 2nd edition. Amsterdam, Elsevier Science, 1998; B courtesy Sanjaya Kumar, M.D.)
are treated with total penectomy and urethrectomy, prostatectomy and continent cutaneous urinary diversion. It has recently been proposed that locally advanced male anterior urethral carcinoma be treated with multimodal treatment, including chemoradiation and extirpative surgery.9 Urethrectomy in the Female Primary urethral cancer in women is rare. Although women have a lower incidence of transitional cell cancer than men, urethral cancer per se is 4 times more common in women than men. The common urethral cancers include squamous cell (60%), transitional cell (20%), and adenocarcinoma (15%). Primary transitional cell cancer of the urethra is very rare. In patients with transitional cell cancer of the bladder a total urethrectomy is usually performed at the time of the cystectomy, unless the patient is a candidate for an orthotopic neobladder. Distal urethrectomy is performed in patients with tumors of the distal one-third of the urethra, preferably for tumors close to the meatus.
Urethrectomy for Small Distal Tumors The patient is placed in a lithotomy position. Trendelenburg position helps better visualization of the anterior vaginal wall. A Foley catheter is inserted in the urethra and a weighted speculum is placed in the vagina. The labia are retracted with silk sutures (Figure 41-13). The urethral meatus is circumscribed with a purse string sutures. A circumferential incision is made around the urethra (Figure 41-14). Palpation of the Foley catheter allows the urethra to be dissected out in a plane between the full thickness of the urethra and the surrounding tissues. The anterior vaginal wall may be incorporated en bloc in the posterior dissection to obtain negative margin. Proximal dissection of the urethra is complete if a reasonable margin (5 mm) proximal to the tumor is achieved. The urethra is tied with a silk suture to prevent tumor spillage and the distal urethra transected (Figure 41-15). Negative margins are confirmed by frozen section. The proximal cut edge of the urethra is now approximated with 3-0 absorbable sutures to the vaginal mucosa to create a neoorifice
Chapter 41 Urethrectomy 691
A
B Figure 41-8 A, Incision used for dissection of the urethral meatus and the glandular urethra (B). Note that the penis has been placed in its normal anatomic position.
Figure 41-10 Dissection of the proximal urethra at the urogenital diaphragm. (From Brendler CB, Schlegel PN, Walsh PC: J Urol 1990; 144:270–273.)
(Figure 41-16). The anterior vaginal wall is also closed with absorbable sutures. The proximal urethra and the vaginal mucosa may need to be mobilized to achieve a tension-free anastomosis. A Foley catheter is left indwelling for 7 days and a vaginal pack for about 24 hours. Treatment of Larger Distal or Proximal Urethral Tumors
Figure 41-9 Anatomy and ligation of bulbar urethral arteries. A, B, Ligation of bulbar urethral arteries with hemoclips. C, Lateral view shows relationship between internal pudendal and bulbar arteries, and ischium and inferior ramus of pubis. The bulbar arteries should not be fulgurated to prevent injury to internal pudendal arteries from which they arise and which provide arterial supply to corpora cavernosa. (From Brendler CB, Schlegel PN, Walsh PC: J Urol 1990; 144:270–273.)
Extensive dissection of the mid to proximal urethra can result in incontinence. If the tumor is not involving the bladder neck, then a distal urethrectomy is performed, including a cuff of the bladder neck. The bladder is preserved, augmented, and a continent cutaneous urinary diversion performed. The patient will need to catheterize the augmented continent bladder. This approach is employed for squamous cell carcinoma and adeno carcinoma of the urethra. Bladder preserving techniques cannot be performed for transitional cell cancer, as they are a field defect change mandating a cystectomy. The patient is positioned in a lithotomy position. There are 3 steps to the operation. The first step includes an abdominal part where the bladder neck and proximal urethra are dissected. However, if there is involvement of the bladder neck by tumor, a radical cystectomy may be necessary. Rarely, resection of the pubic ramus, vulva,
692
Part VII Urethra and Penis
Figure 41-11 A, Completed proximal urethrectomy. Dissection of bulbar urethra is completed without difficulty, because the membranous urethra has previously been mobilized through the pelvis. B, Specimen: total anterior urethra, including fossa navicularis. (A from Brendler CB, Schlegel PN, Walsh PC: J Urol 1990; 144:270–273; B courtesy Sanjaya Kumar, M.D.)
Figure 41-12 Closure of the perineal incision and placement of the Jackson-Pratt drain. [From Walsh PC (ed): Campbell’s Urology, 6th edition. Philadelphia, WB Saunders, 1992.]
Figure 41-13 Exposure of urethra and vagina.
Chapter 41 Urethrectomy 693
Figure 41-14 Placement of suture around urethral meatus and incision of urethra and anterior vaginal wall.
Figure 41-15 Transection of distal urethra.
and pelvic tissues may be necessary. In the face of lymph node involvement or extensive tumor, given the poor prognosis, only palliative procedures should be performed. The perineal dissection is next. It is similar but more extensive than that for distal urethrectomy. Sometimes, a more extensive dissection of the anterior vaginal wall is necessary to achieve complete tumor resection. If the anterior vaginal tissue cannot be sufficiently mobilized to close the defect, gracilis flaps can be raised to close the defect. The third stage is closure of the bladder neck, bladder augmentation, and creation of a continent reservoir. Details of these procedures have been described elsewhere in this book. SUMMARY Urethrectomy is well tolerated in both males and females. Postoperative edema and ecchymosis is common but obtaining meticulous hemostasis and anatomic closure can minimize postoperative hematomas and infection. Overall cosmetic results are excellent. Urethral stenosis in females can be easily managed with dilations. Cancer control depends on the histology, stage, and grade of the tumor. In general, urethrectomy alone results in excellent cure rates for low stage and low-grade tumors. The cure rate for more advanced tumors is limited despite extensive surgery.
Figure 41-16 Creation of neourethral orifice and closure of anterior vaginal wall.
REFERENCES 1. Naitoh J, Aronson WJ, DeKernion JB: Urethral cancer in women. In Graham SD Jr (ed): Glenn’s Urologic Surgery, 5th edition, pp 461–466. Philadelphia, Lippincott, Williams and Wilkins, 1998.
694
Part VII Urethra and Penis
2. Kakizoe T, Tobisu K: Transitional cell cancer of the urethra in men and women associated with bladder cancer. Jpn J Clin Oncol 1998; 28(6):357–359. 3. Hardeman SW, Soloway MS: Urethral recurrence following radical cystectomy. J Urol 1990; 144:666–669. 4. Levinson KA, Douglas EJ, Wishnow KI: Indications for urethrectomy in an era of continent urinary diversion. J Urol 1990; 144:73–75. 5. Stenzl A, Draxl H, Posch B, et al: The risk of urethral tumors in female bladder cancer: can the urethra be used for orthotopic reconstruction of the urinary tract? J Urol 1995; 153:950–955. 6. Freeman JA, Tarter TA, Esrig D, et al: Urethral recurrence in patients with orthotopic ileal neobladders. J Urol 1996; 156:1615–1619.
7. Brendler CB, Schlegel PN, Walsh PC: Urethrectomy with preservation of potency. J Urol 1990; 144:270–273. 8. Gheiler EL, Tfilli MV, Tiguert R, et al: Management of primary urethral cancer. Urology 1998; 52(3):488–493. 9. Dalbagni G, Zhang ZF, Lacombe L, Herr HW: Male urethral carcinoma: analysis of treatment outcome. Urology 1999; 53(6):1126–1132. 10. Aronson WJ, Naitoh J, DeKernion JB: Carcinoma of the male urethra. In Graham SD Jr (ed): Glenn’s Urologic Surgery, 5th edition, pp 467–474. Philadelphia, Lippincott, Williams and Wilkins, 1998.
C H A P T E R
42 Squamous Cell Carcinoma of the Penis: Diagnosis and Staging Kevin R. Loughlin, MD, MBA
INCIDENCE The incidence of squamous cell carcinoma of the penis varies widely according to geographic distribution. In the United Sates and most industrialized countries, squamous cell carcinoma of the penis is a rare malignancy, accounting for <1% of all male cancers.1,2 The incidence in the United States has been estimated to be 1 to 2 cases per 100,000 males per year.2,3 However, in societies that are more agrarian and where circumcision is less common, the incidence of squamous cell cancer of the penis is much higher. Reddy et al.4 have reported that penile cancer comprises 16.7% of all cancer in parts of India, and Dodge and Linsell5 have reported that penile cancer accounts for 12.2% of all cancers diagnosed in Uganda. EPIDEMIOLOGY Squamous cell carcinoma of the penis is virtually unknown in populations where neonatal circumcision is routinely practiced. Maden et al.6 have reported that the risk for penile cancer was 3.2 times greater in men who were never circumcised and 3.0 times greater in men who underwent circumcision after the neonatal period. These authors also identified a 2.8-times-increased risk for penile cancer among current smokers compared to men who never smoked.6 Penile squamous cell carcinoma most typically occurs in men in the sixth and seventh decades of life; however, it can occur in men below the age of 40.3 Racial predilection has not been clearly proven, and any observed racial differences are more likely due to socioeconomic or environmental factors.7 There appears to be an infectious component to the etiology of squamous penile cancer. Maden et al.6 have reported a strong correlation between a history of genital warts and subsequent development of penile cancer.
These authors reported that the risk of penile cancer among men who reported a history of genital warts was 5.9 times that of men who reported no such history.6 Beyond the link between a history of condylomata and subsequent penile cancer, there is strong molecular biologic evidence demonstrating an association between human papillomavirus (HPV) infection and subsequent penile cancer. Iwasawa et al.8 examined 111 untreated penile carcinomas retrospectively and found 70 to be positive for HPV DNA by polymerase chain reaction. In situ hybridization analysis found the HPV to be localized in the nuclei of the malignant cells. Similar findings have been published by Scinicariello et al.9 They demonstrated that HPV 16 DNA was incorporated into the host’s genome in a primary squamous cell carcinoma and its lymph node metastases using Southern blot analysis and two-dimensional gel electrophoresis. These findings suggest a causal relationship between HPV and penile squamous cell carcinoma. Other reports have shown a similar relationship between HPV 16 and cervical cancer.10 Such relationships raise the question of whether penile and cervical carcinomas may, in some instances, be considered venereal disease.11 DIFFERENTIAL DIAGNOSIS The clinician must be aware of several pathologic conditions of the penis that may mimic squamous cell carcinoma. Buschke-Löwenstein tumors may grossly be indistinguishable from squamous cell carcinoma. Buschke-Löwenstein tumors also resemble condyloma acuminatum and have been referred to as “giant condyloma.” However, they differ in that Buschke-Löwenstein tumors can invade and penetrate tissue, whereas condyloma acuminatum cannot. Despite the ability to invade locally, Buschke-Löwenstein tumors rarely metastasize.
695
696
Part VII Urethra and Penis
However, as with condylomata acuminatum and squamous cell carcinoma, the etiology of some BuschkeLöwenstein tumors appears to be viral. HPV types 6 and 11 have been identified in some of these lesions.12 Erythroplasia of Queyrat and Bowen’s disease are both considered carcinoma in situ of the penis. Erythroplasia was first described by Queyrat13 as a red, velvety lesion found on the glans penis or prepuce. The lesion may be ulcerative or painful. Histologically, the mucosa appears to be replaced by atypical, hyperplastic cells with hyperchromatic nuclei and mitotic figures. Bowen’s disease refers to an intraepithelial neoplasm of the skin associated with a high occurrence of subsequent internal malignancy. 14 However, the terms “Bowen’s disease of the penis” and “erythroplasia of Queyrat” are used interchangeably. Visceral disease is not associated with carcinoma in situ of the penis. HPV has also been identified in carcinoma in situ of the penis.15 PRESENTATION Squamous cell carcinoma of the penis occurs almost exclusively in uncircumcised men. The cancer typically begins as a small lesion on the glans. The primary lesion may be either exophytic or flat and ulcerative. The local lesion can grow to invade the entire glans, shaft, and corpora. The only reliable means of diagnosis is biopsy and histologic examination. No definite therapy, surgical or medical, should be instituted prior to histologic diagnosis. It is not unusual for many of these patients to delay seeking medical attention, and it has been reported that 15% to 50% of patients have the penile lesion for >1 year prior to diagnosis.16,17 Pain is usually not a presenting complaint, although weakness, weight loss, and fatigue can be present as a result of chronic suppuration. The physical examination should note the size and extent of the local lesion. In addition, there should be careful palpation of the inguinal areas to determine if adenopathy is present. LABORATORY STUDIES AND STAGING There are no tumor markers for penile carcinoma. However, several investigators have reported an association between penile carcinoma and hypercalcemia.18,19 Sklaroff and Yagoda19 reported that 17 of 81 patients with penile carcinoma treated at Memorial SloanKettering were hypercalcemic. Hypercalcemia seemed to be related to the bulk of the disease and may resolve with surgical excision of inguinal metastases.20 Parathormonelike substances can be produced by the primary tumor or metastases.21 The most common sites of metastatic spread of penile cancer are the inguinal lymph nodes, the pelvic lymph
nodes, lung, and bone. Cavernosography, lymphangiography, computed tomography (CT), ultrasonography, and magnetic resonance imaging (MRI) have all been utilized to stage the local lesion and metastatic extent of penile cancer. Despite reports of its accuracy, cavernosography is normally not performed because of the invasive nature of the technique.22 Horenblas et al.23 examined the role of lymphangiography, CT, and fine-needle aspiration in penile cancer staging. In 98 patients with penile cancer, they found that CT scan provided accurate local staging in 74% of the patients. Lymphangiography was utilized in 19 patients to assess regional (inguinal and pelvic) lymph node status. All 6 patients with pathologically proven negative nodes had negative lymphangiograms; however, of the 13 patients with pathologically proven positive nodal involvement, 9 had negative lymphangiograms and 4 were positive, for a sensitivity of 31% and a specificity of 100%. Fine-needle aspiration was used to evaluate the inguinal nodes only in 18 patients. In this cohort, aspiration cytology had a sensitivity of 71% and a specificity of 100%. The use of ultrasound in the staging of primary penile cancer was first reported in 2 patients in 1989.24 A larger experience was reported by Horenblas et al.25 In their group of 16 patients, accurate assessment of the depth and extent of the primary lesion was only achieved in 7 patients (44%). Ultrasound was most limited in differentiating invasion of subepithelial tissue from corpus spongiosum in the glans. However, determination of invasion into the corpus cavernosum was clearly demonstrated in all cases where it was present. MRI has also been used to stage penile carcinoma. deKervilier et al.26 reported their preliminary experience with MRI and staging penile cancer. They found that MRI correctly staged local tumors in 7 of 9 cases. T2weighted sequences were most useful, and they recommended that spin-echo T2-weighted sequences should be used in evaluating such patients. Aspiration of nodes under either fluoroscopic or computed tomographic guidance has been reported as an additional staging technique. However, like other biopsy techniques, false negatives can occur.27 In addition to radiographic staging of penile cancer, Cabanas28 introduced the concept of “sentinel node biopsy.” This concept was based on the belief that penile cancer first spreads to a group of nodes located superomedial to the junction of the saphenous and femoral veins in the area of the superficial epigastric vein. However, subsequent reports29–31 have failed to confirm the efficacy of the sentinel node biopsy and such a staging procedure is no longer recommended. Finally, in addition to staging the local lesion and regional lymph nodes, all patients with penile cancer should have a baseline chest x-ray and bone scan.
Chapter 42 Squamous Cell Carcinoma of the Penis 697
STAGING SYSTEMS Two major staging systems have been commonly employed to stage penile cancer. The Jackson system, introduced in 1966,32 is the oldest system used (Table 42-1). A newer system, the TNM classification, is widely accepted and is now more commonly used than the Jackson system (Table 42-2).
A more recent staging system that incorporates the histologic degree of differentiation and the extent of local invasion of the primary tumor has been recently proposed by Heyns et al.33 Their staging system appears in Table 42-3. It provides a predictive distinction between T1 and T2-4 tumors and indicates that lymphadenectomy can be avoided in T1 tumors but should be performed in all patients with T2 to T4 tumors.
Table 42-1 Classification for Carcinoma of the Penis Stage I (A)
Tumors confined to glans, prepuce, or both
Stage II (B)
Tumors extending onto shaft of penis
Stage III (C)
Tumors with inguinal metastasis that are operable
Stage IV (D)
Tumors involving adjacent structures; tumors associated with inoperable inguinal metastasis or distant metastasis
Table 42-2 TNM Classification of Penile Carcinoma Primary tumor (T) Tx
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ
Ta
Noninvasive verrucous carcinoma
T1
Tumor invades subepithelial connective tissue
T2
Tumor invades corpus spongiosum or cavernosum
T3
Tumor invades urethra or prostate
T4
Tumor invades other adjacent structures
Regional lymph nodes (N) Nx
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in a single superficial, inguinal lymph node
N2
Metastases in multiple or bilateral superficial inguinal lymph nodes
N3
Metastasis in deep inguinal or pelvic lymph node(s) unilateral or bilateral
Distant metastases (M) Mx
Distant metastasis cannot be assessed
M0
No distant metastases
M1
Distant metastases
Table 42-3 Heyns Classification of Penile Carcinoma-Primary Lesion T1
Grade 1–2 with invasion through dermis
T2
Any grade with invasion through the corpus spongiosum or cavernosum
T3
Any grade with invasion of the urethra
T4
Grade 3, regardless of invasion
SUMMARY Penile cancer is a rare malignancy in regions where circumcision is routinely practiced. A careful physical examination and radiographic imaging are necessary to stage local and distant involvement of the tumor. A biopsy and pathologic confirmation of the diagnosis must be obtained prior to initiating treatment.
REFERENCES 1. Grabstald H: Cancer of the penis. J Cont Ed Urol 1979; 18:15. 2. Sufrin G, Huben R: Benigh and malignant lesions of the penis. In Gillenwater JY, Grayback JT, Howard SS, Duckett JW (eds): Adult and Pediatric Urology, 2nd edition, pp 1643–1681. St. Louis, Mosby, Year Book, 1991. 3. Schellhammer PF, Jordon GH, Schlossberg SM: Tumors of the penis. In Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr (eds): Campbell’s Urology, 6th edition, pp 1264–1298. Philadelphia, WB Saunders Co, 1992. 4. Reddy CRRM, Raghavaigah NV, Mouli KC: Prevalence of carcinoma of the penis with special reference to India. Int Surg 1978; 60:470. 5. Dodge OG, Linsell CA: Carcinoma of the penis in Uganda and Kenya Africa. Cancer 1963; 16:1255. 6. Maden C, Sherman KJ, Beckmann AM, et al: History of circumcision, medical conditions, sexual activity and risk of penile cancer. J Natl Cancer Inst 1993; 85:19. 7. Hall NEL, Schottenfeld D: Penis. In Shottenfeld D, Fraumens JF Jr (eds): Cancer Epidemiology and Prevention, p 964. Philadelphia, WB Saunders, 1982. 8. Iwasawa A, Kumanoto Y, Fujnaga K: Detection of human papilloma virus deoxyribonucleic acid in penile carcinoma by polymerase chain reaction and in situ hybridization. J Urol 1993; 149:59.
698
Part VII Urethra and Penis
9. Scinicariello F, Rudy P, Saltzstein D, et al: Human papilloma virus 16 exhibits a similar integration pattern in primary squamous cell carcinoma of the penis and its metastasis. Cancer 1992; 70:2143. 10. Rohan T, Mann V, McLaughlin J, et al: PCR detected genital papilloma virus infection: prevalence and association with risk factors for cervical cancer. Int J Cancer 1991; 49:856. 11. Loughlin KR: Penile cancer. Curr Opin Urol 1993; 3:415. 12. Boshart M, Zor Hausen H: Human papilloma virus (HPV) in Buschke-Löwenstein tumors: physical state of the DNA and identification of a tandem duplication in the noncoding region of a HPV 6 subtype. J Virol 1986; 58:963. 13. Queyrat L: Erythroplasia du gland. Sec Franc Dermatol Syphilol 1911; 22:378. 14. Bowen J: Precancerous dermatoses: a review of two cases of chronic atypical epithelial proliferation. J Cutan Dis 1912; 30:241. 15. Pfister H, Haneke E: Demonstration of human papilloma virus type 2 DNA in Bowen’s disease. Arch Dermatol Res 1984; 276:123. 16. Hardner J, Bhanalaph T, Murphy GP, et al: Carcinoma of the penis: analysis of therapy in 100 consecutive cases. J Urol 1972; 108:428. 17. Gursel EO, Georgourtzos C, Uson AC, et al: Penile cancer. Urology 1973; 1:569. 18. Rudd FV, Rott RK, Skoglund RW, Ansell JS: Tumor induced hypercalcemia. J Urol 1972; 107:986. 19. Sklaroff RB, Yagoda A: Penile cancer: natural history and therapy. In Chemotherapy and Urological Malignancy, pp 98–105. New York, Springer, 1982. 20. Block NL, Rosen P, Whitmore WF: Hemipelvectomy for advanced penile cancer. J Urol 1973; 110:703. 21. Malakoff AF, Schmidt JD: Metastatic carcinoma of penis complicated by hypercalcemia. Urology 1975; 5:519.
22. Raghavaiah NV: Corpus cavernosogram in the evaluation of carcinoma of the penis. J Urol 1978; 120:423. 23. Horenblas S, Van Tinteren H, Delemarre JF, et al: Squamous cell carcinoma of the penis: accuracy of tumor, nodes and metastasis classification system and role of lymphangiography, computerized tomography scan and fine needle aspiration cytology. J Urol 1991; 146:1279. 24. Yamashita T, Ogawa A: Ultrasound in penile cancer. Urol Radiol 1989; 11:174. 25. Horenblas S, Kroger R, Gallee MPW, et al: Ultrasound in squamous cell carcinoma of the penis: a useful addition to clinical staging. Urology 1994; 43:702. 26. deKervilier E, Ollier P, Desgrandchamps F, et al: Magnetic resonance imaging in patients with penile carcinoma. Br J Radiol 1995; 68:704. 27. Scappini P, Piscioli F, Pusiol T, et al: Penile cancer aspiration biopsy cytology for staging. Cancer 1986; 58:1526–1533. 28. Cabanas R: An approach to the treatment of penile carcinoma. Cancer 1977; 39:456. 29. Catalona WJ: Role of lymphadenectomy in carcinomas of the penis. Urol Clin North Am 1980; 7:785. 30. Perinetti EP, Crane DC, Catalona WJ: Unreliability of sentinel lymph node biopsy for staging penile carcinoma. J Urol 1980; 124:734. 31. Wespes E, Simon J, Schulmann CC: Cabanas’ approach: Is sentinel node biopsy reliable for staging of penile carcinoma? Urology 1986; 28:278. 32. Jackson SM: The treatment of carcinoma of the penis. Br J Surg 1966; 53:33. 33. Heyns CF, VanVollenhaven P, Steenkamp JW, Allen FJ, Van Velden DJ: Carcinoma of the penis – appraisal of a modified tumor-staging system. Br J Urol 1997; 80:307–312.
C H A P T E R
43 Superficial Carcinoma of the Penis: Management and Prognosis Jay S. Belani, MD, and Gerald L. Andriole, MD
Penile cancer is a rare entity in developed nations. In the United States only 0.3% of all cancers diagnosed are malignancies of the penis.1 The annual incidence rate in the U.S. and Europe is about 0.5 to 1 per 100,000 men,1 which has remained constant over the past 5 decades.2 In other countries the incidence varies based on hygienic standards and culture. The incidence is much higher in developing countries, such as Mexico, China, India, and many African countries. In addition, as socioeconomic conditions improve in developing countries, the rates of cancer have declined. Cancer of the penis usually occurs in elderly men. The rate of cancer abruptly increases at about age 60 and peaks at 80 years old.1,3 This trend seems to be evident worldwide; however, those countries with a higher incidence of the disease seem to have an earlier age of onset. In the U.S., blacks are more commonly diagnosed than whites by about 2:1.1 However, decreased rates of circumcision and a lower socioeconomic status may be confounding factors in the statistics.1,2 The most common malignancy of the penis is squamous cell carcinoma (SCC), accounting for about 95% of cases.3,4 Other rare neoplasms include malignant melanoma, basal cell carcinoma, sarcoma, Paget’s disease, lymphoreticular malignancy, and metastasis from other sources. In addition, transitional cell carcinoma (TCC) of the urethra can involve the penis by local spread.
ventrally. Buck’s fascia provides a dense layer of covering around the corpora. Superficial to Buck’s fascia lie the superficial penile fascia and skin. The arterial supply of the penis is derived from branches of the penile artery, which arises from the pudendal artery. The penile artery divides into the bulbourethral artery, deep artery (AKA: cavernosal artery), and dorsal penile artery.5 Three venous systems drain the penis: the superficial, intermediate, and deep.6 The superficial system drains the skin of the dorsal penis and prepuce. The intermediate system is made up of the deep dorsal veins and circumflex veins, which drain into Santorini’s plexus along the prostate. The deep system consists of the cavernosal and crural veins, which are the main drainage system of the corpora cavernosa and drain into the internal pudendal vein. Penile lymph vessels drain into one of two inguinal nodal groups: superficial or deep. In general, most lymphatic channels from the body of the penis and prepuce travel to the superficial inguinal nodes. The glans may drain into the superficial or deep inguinal nodes.5 More proximal lymphatic drainage generally occurs in a stepwise fashion. The superficial nodes drain into the deep inguinal nodes, which, in turn, drain into the pelvic lymph nodes. Lymphatic drainage is not uniform and significant cross-communication occurs. Hence, tumors may spread to ipsilateral, contralateral, or bilateral lymph node chains (Figures 43-1 and 43-2).7
ANATOMY Knowledge of penile anatomy is essential in comprehending the pathophysiology, staging, and management options of penile cancer. The penis is made up of two corpora cavernosa dorsally and the corpus spongiosum
SQUAMOUS CELL CARCINOMA Presentation, Signs and Symptoms Carcinoma of the penis may present as an area of erythema, induration, ulceration, or nonhealing sore. Some
699
700
Part VII Urethra and Penis
Superficial dorsal vein Dorsal artery
Deep dorsal vein
Buck’s fascia
Cavernosal artery Corpus cavernosum
Urethra Corpus sponglosum
Figure 43-1 Cross-sectional diagram of penile shaft.
About 50% of patients will present with inguinal lymphadenopathy.11 Physical examination is important in the diagnosis of penile cancer. Size, location, fixation, and extent of corporal body involvement must be evaluated. Both inguinal regions should be palpated for lymphadenopathy and the penile base and scrotum should be inspected.10 Rarely, the primary tumor may be concealed by the prepuce, and a patient may present with inguinal suppuration, ulceration, or hemorrhage as a result of lymph node metastasis. Other rare presentations are urinary fistula, urinary retention, and destruction or self-amputation of the phallus. Penile carcinoma exhibits two growth patterns: fungating and exophytic, or ulcerative and infiltrative.12,13 Fungating tumors usually present as a papillary verrucous lesion on the glans or prepuce. Ulcerating tumors present as a small, erythematous ulcer, usually on the glans. As ulcerating lesions grow they infiltrate into deeper tissues and are more likely to metastasize than fungating tumors. Lateral destruction occurs as the tumor involves the deeper tissues. NATURAL HISTORY
Figure 43-2 Diagram of penile lymphatic drainage.
patients experience persistent bleeding or eventual sloughing and self-amputaion.10 About 47% present with a mass or nodule, 35% with an ulcer, and 17% with an inflammatory lesion or bleeding.11 Only 0.7% of cases are diagnosed incidentally on a circumcision specimen. The site of origin is more commonly distal, with 48% occurring on the glans, 21% on the prepuce, 9% in both locations, and 6% along the coronal sulcus.11 Direct extension of the distal tumor to the shaft occurs in 14% of cases.11 A delay in diagnosis between the initial finding of a penile lesion and presentation to the physician is typically between 3 and 26 months, with an average of 10 months and 60% of lesions are larger than 2 cm at diagnosis.
SCC usually begins as a superficial growth along the glans or prepuce and spreads locally. As it grows, Buck’s fascia provides a strong barrier for deeper infiltration; however, if left untreated, the tumor will erode into the corpus cavernosum. Hematogenous spread usually does not occur despite the extensive vascular network within the corpus cavernosa. Fistula formation may result with urethral involvement. Metastasis to the superficial inguinal nodes is more likely to occur if the prepuce is initially involved, while metastasis to both the superficial and deep inguinal nodes occurs with glans involvement. Spread then goes to the pelvic nodes. Bilateral or crossinguinal lymph node involvement is possible given the rich anastomoses between lymphatics in the subcutaneous tissue that cross the midline.13 At presentation about 50% of patients have inguinal lymphadenopathy on examination. About 55% of these patients have inflammatory inguinal lymphadenopathy from infection of the primary tumor, while 45% have metastatic tumor.11,13 Less than 2% have visceral spread of disease at presentation.13 DIAGNOSIS Lynch and Krush showed that patients with penile cancer delay seeking medical attention longer than patients with other cancers.14 Gursel and Hardner each found that between 15% and 50% of patients delay diagnosis for greater than 1 year.15,16 Moreover, Hardner showed a worse prognosis for patients with delayed presentation.15
Chapter 43 Superficial Carcinoma of the Penis: Management and Prognosis 701
Given the fact that most tumors begin as superficial lesions, and that many patients delay presentation, it is vitally important to biopsy all suspicious lesions at time of presentation, especially if the lesion fails to resolve after a short course of conservative treatment. The biopsy is done to confirm the diagnosis of carcinoma and determine the extent of invasion. If the lesion is small, an excisional biopsy may be performed. If it is large, an incisional biopsy, taken from the periphery to include normal epithelium, is adequate. If the lesion is suspected to be hidden by a phimotic foreskin, then a preputial slit should be performed. There have been no reported cases of spread as a result of the dorsal slit or biopsy.10,17 Lastly, in some cases, circumcision may be done to obtain an adequate tissue sample. GRADING AND STAGING Histology Histologically, SCC of the penis has been categorized by extent of malignant transformation, i.e., carcinoma in situ (CIS) and invasive SCC. CIS represents a full thickness of atypical epithelial squamous cells. Both Bowen’s disease and erythroplasia of Queryat represent premalignant lesions that have this growth pattern. In addition, CIS is often found in association with invasive SCC.18 Two classification systems, described by Broder and Cubilla, for invasive SCC have been proposed. Broder’s classification of SCC of the skin has been applied to penile lesions. Table 43-1 summarizes the system. Increasing grade has been associated with an increased risk of inguinal metastasis. The chance of spread to inguinal nodes for
Table 43-1 The Broder’s Classification System For Grading SCC Grade
Histology
I
Cells well differentiated with keratinization
grades 1, 2, and 3 tumors is between 0% to 29%, 26% to 65%, and 80% to 100%, respectively.20–23 A second histologic classification system has been proposed by Cubilla et al,24 which divides penile cancers into four categories: superficial spread, vertical growth, verrucous, and multicentric. Table 43-2 describes each type. Villavicencio et al.20 studied 81 patients and defined prognostic values with each category. About 70% of the patients evaluated had a superficial spreading SCC. About 66% of these patients were found to be disease free at an average of 61 months after treatment, and 35% were found to have lymphatic spread. Vertical growth implies a worse prognosis. About 90% of these tumors are usually high-grade lesions, and only 30% are disease free at 5 years. Verrucous growth tumors usually are of low grade and all cases have been found to be disease free at 5 years follow-up. Staging Staging of penile SCC was introduced by Jackson in 196625 and is shown in Table 43-3. Stage I lesions are confined to the glans or prepuce. Stage II lesions extend along the penile shaft. Stage III tumors involve the Table 43-2 Classification for SCC of the Penis Category
Description
Superficial spreading Centrifugal growth usually restricted to superficial layers Vertical growth
Spread is vertical with little radial growth
Verrucous
Usually large, exophytic lesions
Multicentric
Two or more foci of histologic spread
From Cubilla AL, Barreto J, Caballero C, et al: Am J Surg Pathol 1993; 17:753.
Keratin pearls II–III
IV
Increased nuclear atypia and mitotic activity
Table 43-3 Jackson Staging System
Fewer keratin pearls
Stage
Description
Markedly increased nuclear pleomorphism and mitotic activity
I
Tumor confined to glans or prepuce
II
Invasion into shaft or corpora; no nodal or distant metastasis
III
Tumor confined to penis; operable inguinal nodal metastasis
IV
Tumor involves adjacent structures; distant metastasis and/or inoperable inguinal nodes
Necrosis No keratin pearls Lymphatic and perineural invasion Deeply invasive From Broders AC: Ann Surg 1921; 73:141.
From Jackson SM: Br J Surg 1966; 53:33.
Chapter 43 Superficial Carcinoma of the Penis: Management and Prognosis 703
spread beyond the foreskin requires a more aggressive resection. More proximal lesions may require a more extensive resection and multiple biopsies of the margins are warranted to rule out residual disease.8 Moreover, in patients with severe phimosis or chronic balanoposthitis, Huben recommends 5000 cGy of radiation therapy over 5 weeks to eradicate any occult disease after circumcision.34
cases, the patient may be better served by a total penectomy and perineal urethrostomy.34 Studies have shown a local recurrence rate up to 19% with a 2-cm proximal tumor-free margin.42 McDougal32 showed that 90% of patients with superficial, local diseases will be cured after partial penectomy. Moreover, Hardner et al.15 illustrated that partial penectomy is as effective as total penectomy as long as an adequate margin is obtained.
PARTIAL PENECTOMY Lesions of the glans penis can be managed with partial penectomy as long as a 1.5- to 2.0-cm margin is obtained to limit local recurrence.8,37,38 Simple wedge resection has a higher recurrence rate. Local excision is associated with a 40% to 50% recurrence rate and is not adequate for any T2 or larger lesion.34,38,39 Surgical Technique The penis is thoroughly scrubbed with Betadine and the distal penis containing the tumor is covered with a sterile surgical glove or condom. A tourniquet is applied to the base of the penis to minimize blood loss. An incision is made circumferentially 1.5 cm proximal to the tumor margin at the dorsal aspect and about 2.0 to 2.5 cm proximal to the tumor at the ventral aspect. The subcutaneous vessels are coagulated and the superficial dorsal vein is ligated and divided. Buck’s fascia is incised and the deep dorsal artery and vein are ligated and divided. The cavernosal bodies are then transected about 1.5 cm proximal to the tumor margin, and the cavernosal arteries are ligated. The urethra should be dissected free with a 1cm stump left in place distal to the cavernosal bodies. The specimen is then evaluated by frozen section to exclude tumor at the margins. If tumor is found, then a more proximal resection is done. Once resection is complete, the corpora are closed with a horizontal mattress suture. The tourniquet is loosened and any remaining bleeding is controlled. The urethra is spatulated and the excess skin is brought over the exposed cavernosa. The urethra is anastomosed to a buttonhole in the skin. A Foley catheter is usually left in place for 5 days while the anastomosis heals.35,40 Results Usually patients have excellent control of their urinary stream and adequate length for intercourse if at least 2 to 3 cm of the shaft is left in place. Jensen41 showed that 45% of patients with a 4- to 6-cm and 25% of patients with a 2- to 3-cm stump are able to have sexual intercourse. If too short a phallic stump is left, it may be engulfed in the suprapubic fat pad and the patient will have difficulty voiding in the standing position. In these
Complications Complications of partial penectomy include infection, hemorrhage, and stenosis of the urethral meatus. Infection can occur as a result of spread of bacteria from the perineum or inoculation from the primary tumor itself. Infection is minimized by perioperative and postoperative antibiotics covering skin flora. Wound infections are best managed by open drainage and allowing the area to heal by secondary intention. Bleeding is best avoided by attention to hemostasis after the tourniquet is removed. Meatal stenosis is minimized with a wide spatulation of the urethra. The problem is best managed with dilation using meatal sounds or meatotomy.40 TOTAL PENECTOMY Total penectomy is usually reserved for proximal lesions where an adequate proximal margin would not be obtained via partial penectomy. It is the most extensive means of local surgical excision and has the least risk of local recurrence, amongst all surgical options. Surgical Technique Preparation of the penis is similar to that of partial penectomy, and the tumor is covered in a sterile glove or condom. The anus is draped outside the operative field. A vertical elliptical incision is made around the base of the penis 2 cm from the tumor margin. Ventrally, Buck’s fascia is incised and the corpus spongiosum is separated from the corpus cavernosum. The urethra is isolated and divided. Dorsally, the suspensory ligament is divided and the deep dorsal arteries and veins are ligated and divided at the level of the urogenital sinus. The corpus cavernosa are transected 2 cm proximal to the tumor margin. The corpora are then closed in similar fashion as described for partial penectomy. A 1.5-cm elliptical incision is made in the perineum and the skin and subcutaneous tissue are excised. The urethra is tunneled through the subcutaneous tissue to this opening, ensuring that it has not kinked or twisted. It is then spatulated and anastomosed to the skin with interrupted absorbable suture. The skin over the penile defect is closed elevating the scrotum anteriorly and an 18 French silicone catheter is left in place.35,40
704
Part VII Urethra and Penis
Complications Similar to partial penectomy, complications include infection, hemorrhage, and perineal urethrostomy stricture. Bleeding and wound infection are less common than with partial penectomy.34 Strictures of the perineal urethrostomy are usually more difficult to manage, and conservative management with intermittent catheterization may fail. Surgical revision may be required. Lastly, delayed, extended lymphatic drainage has been described, and is usually managed with conservative management.34 IMPACT OF TOTAL AND PARTIAL PENECTOMY Opjordsmoen and Fossa43 showed that men with radiation therapy had improved sexual function than those who had undergone partial penectomy. About 83% of patients had normal or slightly reduced sexual function after radiation therapy, while 66% of patients had severely reduced sexual function after partial penectomy. In addition, the study suggested that those patients who had local excision with laser therapy had worse sexual function than those after radiation therapy. None of the patients studied underwent Mohs’ micrographic surgery. Despite the impaired sexual function, Opjordsmoen and Fossa43 showed that 7 out of 25 patients preferred a compromise in survival to impaired sexual function, while 17 out of 25 preferred long-term survival to penis-sparing modalities. Hence, when treating patients with SCC of the penis, all options should be discussed when choosing a course of management. MOHS’ MICROGRAPHIC SURGERY
excised until no tumor is seen microscopically. Using microscopic mapping, all tumor margins are inspected and normal tissue is spared.34,44 Fixed Tissue Technique The technique is similar to the fresh tissue technique; however, a fixative paste, zinc chloride, is used to mark the surface of the specimen. Excision is then performed and processed with horizontal sectioning. The technique is repeated until no neoplastic cells are seen. The difference is that the patient returns each consecutive day for fixative application and serial sectioning. The process can take between 1 to 7 days depending on the extent of the lesion.44 Effectiveness Five-year cure rate is about 74%, which Mohs suggests is an improvement given that most tumors he treated were large and recurrent after other treatment methods.44 Mohs describes an 86% cure rate for stage I tumors, 62% for stage II, and 0% for stage III disease. These rates are higher than other local treatment options.45 Because of the inability to cure stage III disease, Mohs’ micrographic surgery is best reserved for small stages I and II lesions. Complications Risks of Mohs’ surgery are minimal. Infection and bleeding have been described. In addition, delayed healing can occur, as 80% of lesions are usually left to heal by secondary intention.46
Mohs’ studies showed that SCC of the skin sends out thin sheets of tumor cells along the path of least resistance, like nerve sheaths, blood vessel adventitia, or fascial planes.44 This explains why some tumors recur after excision with a clearly visualized negative margin. Hence, Mohs described a technique of maximal tissue sparing and complete tumor excision—Mohs’ micrographic surgery. Studies have shown cure rates and tissue sparing to be superior than other tissue-sparing techniques.44–46
LASER THERAPY
Surgical Technique
Surgical Technique
Two techniques have been described: fresh tissue technique and fixed tissue technique.
The technique of laser excision involves one of two types of lasers: the Nd:YAG laser or carbon dioxide laser. The Nd:YAG laser penetrates the tissue and causes coagulation up to 3 to 4 mm deep. It does not vaporize much tissue at the surface, and keeps the structural integrity intact. On the other hand, the carbon dioxide laser minimally penetrates into deeper layers. It is a better cutting laser than the Nd:YAG and creates less of a defect. Hence, studies have suggested that the
Fresh Tissue Technique The main tumor mass is debulked. Residual tumor is then serially excised and evaluated microscopically in horizontal sectioning. The areas of residual disease are mapped and the adjacent areas are excised. All tissue is
In 1976, Hofstetter and Frank47 first used laser energy to treat penile carcinoma and preserve the phallus. Recent studies have suggested that, if done with attention to meticulous technique, laser therapy provides as good or better tumor control compared to partial and total penectomy without the functional impairment and poor cosmetic result.48,49
Chapter 43 Superficial Carcinoma of the Penis: Management and Prognosis 705
carbon dioxide laser is better for superficial, noninvasive tumors (i.e., CIS), while the Nd:YAG laser is better suited for more invasive disease (i.e., T1 or possibly T2 disease).50 Prior to treatment the tumor site is biopsied to determine the depth of penetration and grade of tumor. Circumcision may be performed if the tumor is on the foreskin or glans. The extent of the lesion is mapped with 5% acetic acid for 20 minutes. The acid helps demarcate suspicious areas by staining them white. The laser energy is then applied to the marked areas with a 3-mm margin around the perimeter of the tumor site. Effectiveness Recurrence rates have ranged between 6% and 26%, depending on the histologic grade and tumor stage. Unfortunately, Tietjen and Malek51 suggest that dysplastic tissue may be left behind and up to a 26% of patients recur. Overall, though, they found an 8.3% local recurrence for CIS and a 14.3% local recurrence rate for T1 lesions, compared to a rate as low as 6% and 10% in the literature, respectively (Table 43-5). Complications Complications from laser treatment of penile cancers are minimal. Pain at the site may persist especially if infection develops. Preputial lymphedema has also been described in uncircumcised men. Frimberger et al.49 showed that all patients treated with laser coagulation were satisfied with the cosmetic result. Seventy-five percent of patients had functional erections for intercourse, no patients developed meatal strictures, and no patient needed psychologic counseling as a result of the treatment. The disadvantages of laser therapy include the lack of accurate pathologic staging and identification of tumorfree margins. Instead, a biopsy at the base of excision is performed to rule out any further extension. Hence, van Bezooijen et al.50 have argued that laser therapy should only be used for superficial disease or if the depth is
within 3 mm of the surface. Moreover, Tietjen and Malek51 have suggested that laser therapy probably leaves some dysplastic premalignant tissue behind, hence it is important to follow these patients closely for evidence of recurrence, and treat any recurrence expeditiously. RADIATION THERAPY The effectiveness of radiation therapy for penile cancer treatment is controversial since there are multiple different modalities and no uniform dosage has been used. Most data come from small, retrospective studies. Proponents of radiation therapy for penile cancer advocate that it preserves penile function and eliminates the distress of possible amputation.54 Surgical excision, either partial or total penectomy, results in significant functional and psychologic morbidities.43,54–56 T1 and T2 penile carcinomas have been cured by radiation therapy; however, significant complications can occur, depending on the type of radiation given. Radiation therapy can be used for the primary lesion via external beam or interstitial therapy. The advantage of radiation therapy is that it provides local control, and in cases of failure, salvage surgical control may be performed. Moreover, healing after salvage surgery is usually not impaired, despite the local radiation. In treating the primary lesion, some suggest that all patients undergo circumcision to evaluate the extent of the primary tumor and possibly provide debulking. Circumcision minimizes some of the complications, by decreasing the edema and mucosal irritation and reducing the risk of secondary infection.57 Ravi et al.58 have suggested that circumcision is not necessary if the foreskin can be retracted easily and kept in that position while the radiation is given. However, if phimosis is present or the lesion cannot be assessed accurately, then circumcision or a dorsal slit is warranted. BRACHYTHERAPY Interstitial brachytherapy is the use of radiation sources implanted within the site of the tumor. The tumor site is
Table 43-5 Local Recurrence after Laser Ablative Therapy Follow-Up (months) Tietjen and Malek51 Windahl and Hellsten52 Rothenberger53
Tumor Stage (n)
Recurrence (%)
Tis (17), T1 (14)
8.3, 14.3
8–94
T1 (7), T2 (8)
14, 12
13–36
T1(9), T2 (8)
22, 0
12–117
Van Bezooijen et al.50
6–75
Tis (19)
26
Frimberger et al.49
7–168
Tis (17), T1(10)
5.8, 10
706
Part VII Urethra and Penis
transfixed with needles containing a radioactive substance. Historically, this has been radon, however, more recently other radioisotopes, including iridium-192, cobalt-60, tantalum-111, and gold-190, have been used. Usually, a dose of 70 Gy is given over 5 to 7 days. The technique of implantation involves using a Plexiglas template with drilled holes to guide the needles into proper position. This ensures accuracy for a homogenous radiation dose to the entire tumor bed. Brachytherapy has been most successful in T1 and T2 diseases. Studies have shown a local recurrence rate of between 12% and 25%, a penile conservation rate of 67% to 83%, and a disease-free survival rate of 85% to 95% (Table 43-6). 59–63 Most failures occurred in lesions >4 cm. Kiltie et al.61 reported a local failure rate of 60% for tumors >4 cm and 14% for tumors <4 cm. Mazeron et al.64 showed a local failure rate of 11% for tumors <2 cm, 26% for tumors 2 to 4 cm and 50% for tumors >4 cm. Hence, brachytherapy is mainly recommended for tumors <4 cm and superficial or moderately infiltrating.64 Complications of brachytherapy include skin necrosis, urethritis, urethral stricture disease, pigmentation, or telangiectasias. Sexual potency is usually preserved.65 EXTERNAL BEAM RADIATION External beam radiation has been used for superficial invasive carcinoma or CIS. It is used to deliver a low dose of radiation therapy to a superficial area with a 1- to 2 cm margin. Gerbaulet and Lambin57 have argued that a low dose of therapy with a high total dose effectively treats the lesion and minimizes the risk of fibrosis. For example, a 2-Gy fraction can be given per day to a total of 65 to 70 Gy. Problems with external beam radiation include a prolonged treatment time of 6 to 7 weeks and difficulty in reproducing the area of radiation.
Local control rates for external beam radiation therapy ranges from 50% to 90%.65 Sarin et al.66 studied 59 patients who received external beam therapy and found a 5- and 10-year local control rate of 51% and 48%, respectively. McLean et al.67 found a recurrence rate of 28% (5 of 18) for T1 and T2 tumors. Thirty-three percent of patients required penectomy because of local recurrence in 5 patients and complications in 1 patient. Table 43-7 summarizes recent studies and the effective control rate. Complications include acute skin irritation and desquamation and penile soreness or swelling, acutely. Long-term complications include urethral stricture and meatal stenosis, which is usually managed with dilation. Uncommonly, penile necrosis may develop and only a few patients will have a loss of potency.65,68 MANAGEMENT OF INGUINAL NODES Inguinal lymph node status provides important prognostic information in managing penile carcinoma. Overall, those patients without lymph node metastasis have a 5-year survival of about 85%, while those with metastasis only have a 50% 2-year survival.11 The dilemma, however, revolves around the inaccuracy of determining inguinal node spread. About 50% of patients with palpable inguinal nodes will have metastasis and about 20% of patients without palpably enlarged nodes will have spread.15,32,56 These data incorporate both stage I and stage II diseases. Patients with superficial SCC are unlikely to have inguinal spread. McDougal et al.32 showed that patients with stage I disease approach a 100% survival rate free of tumor after local excision alone. Stage II disease is more likely to have indolent lymphatic metastasis, and an inguinal lymphadenectomy may be prudent.32,33,71 Figure 43-3 provides an algorithm for management of
Table 43-6 Effectiveness of Brachytherapy
Number of Cases Crook et al.59
30
% Local Recurrence (Years Follow-Up) 15 (2)
Penile Conservation (%) 83
24 (5)
Disease-Free Survival (%) (Years Follow-Up) 95 (2) 89 (5)
Kiltie et al.61
31
25 (5)
74.8
85.4 (5)
Rozan et al.62
184
12 (3)
78
88 (5)
15 (5) Soria et al.63
72
25
82
Delannes et al.60
51
18
67
Chapter 43 Superficial Carcinoma of the Penis: Management and Prognosis 707
Table 43-7 Effectiveness of External Beam Therapy Sarin et al.66
McLean et al.67
Sagerman et al.69
Fossa et al.70
Grabstald et al.68
Number of patients
59
18
12
11
10
Local control rate (%) (years follow-up)
51 (5)
65
66
73
90 (6–10)
48 (10)
Superficial, well-differentiated tumor*
Palpable nodes
Nonpalpable nodes
Treat with antibiotics for 4−6 weeks
Observe**
Nonpalpable nodes
Palpable nodes
Observe**
Lymph node dissection
* Primary tumor is T1 after circumcision, partial or total penectomy. ** Exam every 2 months for 2 years, then every 6 months.
Figure 43-3 Algorithm for management of lymphadenopathy for superficial penile cancer.
inguinal nodes in patients with low stage SCC of the penis. SUMMARY Penile cancer rarely occurs in the North America and European nations. SCC accounts for 95% of cases and superficial tumors have an excellent prognosis, especially if the patient presents without inguinal lymphadenopathy. The gold standard for management includes surgical excision. Partial penectomy may be performed if a 1.5-cm margin is obtained, otherwise, total penectomy is indicated. Because of the functional and psychologic impairment that results from surgical excision, Mohs’ micrographic surgery, laser ablation, and radiation therapy have also been performed. Each has its own advantages and complications. Overall, though, each approach works well for small, stage I or stage II disease and hold the advantage that if tumor recurs, surgical excision can be done at a later date.
REFERENCES 1. Gloeckler-Ries LAHB, Edwards BK (eds): Cancer Statistics Review 1973–1987, National Cancer Institute, National Institutes of Health Publication No. 90-2789. Bethesda, National Institute of Health, 1990. 2. Huben RP: Biology of penile cancer. In Ragavan D, Scher HI, Leibel SA, et al (eds): Principles and Practice of Genitourinary Oncology, pp 921–936. Philadelphia, Lippincott-Raven, 1997. 3. Lucia MS, Miller GJ: Histopathology of malignant lesions of the penis. Urol Clin North Am 1992; 19:227. 4. Chesney TM, Murphy WM (eds): Diseases of the Penis and Scrotum, p 392. Philadelphia, WB Saunders, 1989. 5. Dewire D, Lepor H: Anatomic considerations of the penis and its lymphatic drainage. Urol Clin North Am 1992; 19:211. 6. Moore KL, Dalley AF: Clinically Oriented Anatomy. Philadelphia, Lippincott Williams & Wilkins, 1999. 7. Johnson DE, Costello AJ: Anatomy of the penis and groin. In Ragavan D, Scher HI, Leibel SA, et al (eds): Principles and Practice of Genitourinary Oncology, pp 913–920. Philadelphia, Lippincott-Raven, 1997. 8. Bissada NK: Conservative extirpative treatment of cancer of the penis. Urol Clin North Am 1992; 19:283. 9. Clemente CD Anatomy: A Regional Atlas of the Human Body, 4th edition, p 414. Philadelphia, Lea & Febiger, 1987. 10. Burgers JK, Badalament RA, Drago JR: Penile cancer. Clinical presentation, diagnosis, and staging. Urol Clin North Am 1992; 19:247. 11. Sufrin G, Huben RP: Benign and malignant lesions of the penis. In Gillenwater JY, Grayhack JT, Howards SS, et al: Adult and Pediatric Urology, Vol 2, 3rd edition, pp 1997–2042. St. Louis, Mosby, 1996. 12. Huben RP: Clinical presentation and staging of penile cancer. In Ragavan D, Scher HI, Leibel SA, et al: Principles and Practice of Genitourinary Oncology, pp 937–942. Philadelphia, Lippincott-Raven, 1997. 13. Ayala AG, Ro JY: Pathology of penile cancer. In Ragavan D, Scher HI, Leibel SA, et al: Principles and Practice of Genitourinary Oncology, pp 927–936. Philadelphia, Lippincott-Raven, 1997. 14. Lynch HT, Krush AJ: Delay factors in detection of cancer of the penis. Nebr State Med J 1969; 54:360. 15. Hardner GJ, Bhanalaph T, Murphy GP, et al: Carcinoma of the penis: analysis of therapy in 100 consecutive cases. J Urol 1972; 108:428.
708
Part VII Urethra and Penis
16. Gursel EO, Georgountzos C, Uson AC, et al: Penile cancer. Urology 1973; 1:569. 17. Dean AL: Epithelioma of the penis. J Urol 1935; 33:252. 18. Humphrey PA: Pathology of carcinoma of the penis. In Hamdy FC, Basler JW, Neal DE, et al: Management of Urologic Malignancies, pp 507–511. London, Churchill Livingstone, 2002. 19. Broders AC: Squamous cell epithelioma of the skin. Ann Surg 1921; 73:141. 20. Villavicencio H, Rubio-Briones J, Regalado R, et al: Grade, local stage and growth pattern as prognostic factors in carcinoma of the penis. Eur Urol 1997; 32:442. 21. Solsona E, Iborra I, Ricos JV, et al: Corpus cavernosum invasion and tumor grade in the prediction of lymph node condition in penile carcinoma. Eur Urol 1992; 22:115. 22. Fraley EE, Zhang G, Manivel C, et al: The role of ilioinguinal lymphadenectomy and significance of histological differentiation in treatment of carcinoma of the penis. J Urol 1989; 142:1478. 23. Horenblas S, van Tinteren H, Delemarre JF, et al: Squamous cell carcinoma of the penis. III. Treatment of regional lymph nodes. J Urol 1993; 149:492. 24. Cubilla AL, Barreto J, Caballero C, et al: Pathologic features of epidermoid carcinoma of the penis. A prospective study of 66 cases. Am J Surg Pathol 1993; 17:753. 25. Jackson SM: The treatment of carcinoma of the penis. Br J Surg 1966; 53:33. 26. Harmer MH: TNM Classification of Malignant Tumours, 3rd edition. Geneva, International Union Against Cancer, 1978. 27. Beggs JH, Spratt JS: Epidermoid carcinoma of the penis. J Urol 1964; 91:166. 28. Derrick FC Jr, Lynch KM Jr, Kretkowski RC, et al: Epidermoid carcinoma of the penis: computer analysis of 87 cases. J Urol 1973; 110:303. 29. Hoppmann HJ, Fraley EE: Squamous cell carcinoma of the penis. J Urol 1978; 120:393. 30. Yu HH, Lam P, Leong CH, et al: Carcinoma of the penis: report of 52 cases with reference to lymphography and ilioinguinal block dissection. Clin Oncol 1978; 4: 47. 31. Abi-Aad AS, deKernion JB: Controversies in ilioinguinal lymphadenectomy for cancer of the penis. Urol Clin North Am 1992; 19:319. 32. McDougal WS, Kirchner FK Jr, Edwards RH, et al: Treatment of carcinoma of the penis: the case for primary lymphadenectomy. J Urol 1986; 136:38. 33. McDougal WS: Carcinoma of the penis: improved survival by early regional lymphadenectomy based on the histological grade and depth of invasion of the primary lesion. J Urol 1995; 154:1364. 34. Huben RP: Surgical management of penile cancer. In Ragavan D, Scher HI, Leibel SA, et al: Principles and Practice of Genitourinary Oncology, pp 949–955. Philadelphia, Lippincott-Raven, 1997. 35. Das S: Penile amputations for the management of primary carcinoma of the penis. Urol Clin North Am 1992; 19:277.
36. Young HH: A radical operation of the cure of cancer of the penis. J Urol 1931; 26:295. 37. Kline EA: Partial and total penectomy for cancer. Urol Clin North Am 1991; 18:161. 38. Lynch DF Jr, Pettaway CA: Tumors of the penis. In Walsh PC, Retik AB, Vaughan ED Jr, et al: Campbell’s Urology, 8th edition, Vol 4, p 2945. Philadelphia, WB Saunders, 2002. 39. Hanash KA, Furlow WL, Utz DC, et al: Carcinoma of the penis: a clinicopathologic study. J Urol 1970; 104:291. 40. Andriole GL, Miller DC, Colberg JW, et al: Surgical management of penile cancer. In Vogelzang NJ, Scardino PT, Shipley WU, et al: Comprehensive Textbook of Genitourinary Oncology, 2nd edition, p. 1057. Philadelphia, Lippincott, Williams & Wilkins, 2000. 41. Jensen MO: Cancer of the penis in Denmark 1942 to 1962 (511 cases). Dan Med Bull 1977; 24:66. 42. Horenblas S, van Tinteren H, Delemarre JF, et al: Squamous cell carcinoma of the penis. II. Treatment of the primary tumor. J Urol 1992; 147:1533. 43. Opjordsmoen S, Fossa SD: Quality of life in patients treated for penile cancer. A follow-up study. Br J Urol 1994; 74:652. 44. Mohs FE, Snow SN, Larson PO: Mohs micrographic surgery for penile tumors. Urol Clin North Am 1992; 19:291. 45. Mohs FE, Snow SN, Messing EM, et al: Microscopically controlled surgery in the treatment of carcinoma of the penis. J Urol 1985; 133:961. 46. Brown MD, Zachary CB, Grekin RC, et al: Penile tumors: their management by Mohs micrographic surgery. J Dermatol Surg Oncol 1987; 13:1163. 47. Hofstetter A, Frank F: The Neodymium-YAG Laser in Urology. Basel, Hoffman-LaRoche, 1980. 48. Pettaway CA: Nd:YAG laser therapy for penile carcinoma. Editorial comment. J Urol 2002; 168:2421. 49. Frimberger D, Hungerhuber E, Zaak D, et al: Penile carcinoma. Is Nd:YAG laser therapy radical enough? J Urol 2002; 168:2418. 50. van Bezooijen BP, Horenblas S, Meinhardt W, et al: Laser therapy for carcinoma in situ of the penis. J Urol 2001; 166: 1670. 51. Tietjen DN, Malek RS: Laser therapy of squamous cell dysplasia and carcinoma of the penis. Urology 1998; 52:559. 52. Windahl T, Hellsten S: Laser treatment of localized squamous cell carcinoma of the penis. J Urol 1995; 154:1020. 53. Rothenberger KH: Value of the neodymium-YAG laser in the therapy of penile carcinoma. Eur Urol 1986; 12(Suppl 1):34. 54. Narayana AS, Olney LE, Loening SA, et al: Carcinoma of the penis: analysis of 219 cases. Cancer 1982; 49:2185. 55. Wajsman Z, Moore RH, Merrin CE, et al: Surgical treatment of penile cancer: a follow-up report. Cancer 1977; 40:1697. 56. Kossow JH, Hotchkiss RS, Morales PA: Carcinoma of penis treated surgically. Analysis of 100 cases. Urology 1973; 2:169.
Chapter 43 Superficial Carcinoma of the Penis: Management and Prognosis 709 57. Gerbaulet A, Lambin P: Radiation therapy of cancer of the penis. Indications, advantages, and pitfalls. Urol Clin North Am 1992; 19:325. 58. Ravi R, Chaturvedi HK, Sastry DV: Role of radiation therapy in the treatment of carcinoma of the penis. Br J Urol 1994; 74:646. 59. Crook J, Grimard L, Tsihlias J, et al: Interstitial brachytherapy for penile cancer: an alternative to amputation. J Urol 2002; 167:506. 60. Delannes M, Malavaud B, Douchez J, et al: Iridium-192 interstitial therapy for squamous cell carcinoma of the penis. Int J Radiat Oncol Biol Phys 1992; 24:479. 61. Kiltie AE, Elwell C, Close HJ, et al: Iridium-192 implantation for node-negative carcinoma of the penis: the Cookridge Hospital experience. Clin Oncol (R Coll Radiol) 2000; 12:25. 62. Rozan R, Albuisson E, Giraud B, et al: Interstitial brachytherapy for penile carcinoma: a multicentric survey (259 patients). Radiother Oncol 1995; 36:83. 63. Soria JC, Fizazi K, Piron D, et al: Squamous cell carcinoma of the penis: multivariate analysis of prognostic factors and natural history in monocentric study with a conservative policy. Ann Oncol 1997; 8:1089. 64. Mazeron JJ, Langlois D, Lobo PA, et al: Interstitial radiation therapy for carcinoma of the penis using iridium 192 wires: the Henri Mondor experience (1970–1979). Int J Radiat Oncol Biol Phys 1984; 10:1891.
65. Krieg R, Hoffman R: Current management of unusual genitourinary cancers. Part 1: Penile cancer. Oncology (Huntingt) 1999; 13:1347. 66. Sarin R, Norman AR, Steel GG, et al: Treatment results and prognostic factors in 101 men treated for squamous carcinoma of the penis. Int J Radiat Oncol Biol Phys 1997; 38:713. 67. McLean M, Akl AM, Warde P, et al: The results of primary radiation therapy in the management of squamous cell carcinoma of the penis. Int J Radiat Oncol Biol Phys 1993; 25:623. 68. Grabstald H, Kelley CD: Radiation therapy of penile cancer: six to ten-year follow-up. Urology 1980; 15:575. 69. Sagerman RH, Yu WS, Chung CT, et al: External-beam irradiation of carcinoma of the penis. Radiology 1984; 152:183. 70. Fossa SD, Hall KS, Johannessen NB, et al: Cancer of the penis. Experience at the Norwegian Radium Hospital 1974–1985. Eur Urol 1987; 13:372. 71. Lynch DF Jr, Schellhammer PF: Contemporary concepts in ilioinguinal lymphadenectomy for squamous cell carcinoma of the penis. AUA Update Series, 1997; 16:256. 72. Cabanas RM: Anatomy and biopsy of sentinel lymph nodes. Urol Clin North Am 1992; 19:267.
C H A P T E R
44 Invasive Carcinoma of the Penis: Management and Prognosis Shahin Tabatabaei, MD, and W. Scott McDougal, MD
EPIDEMIOLOGY Carcinoma of the penis is an uncommon malignancy in the United States comprising <1% of all malignancies in males. This translates into 1 to 2 cases per 100,000 population per annum. The American Cancer Society predicts that 1400 new cancer cases will occur in 2004. The peek incidence is in the sixth and seventh decades of life. In other portions of the world, particularly in Asia, Africa, and South America, however, it is a more common disease. There appear to be no racial predilections.
been circumcised neonatally.5,6 It is believed that neonatal circumcision has a protective effect, particularly for invasive carcinoma. Tseng et al.7 discovered that neonatal circumcision was inversely associated with invasive carcinoma (odds ratio [OR] = 0.41; 95% confidence interval [CI] = 013 to 1.1) but not carcinoma in situ (CIS). Phimosis
The etiology is somewhat controversial; however, several facts are quite clear. The presence of a foreskin, phimosis, chronic inflammatory conditions, treatment with psoralen and ultraviolet A (PUVA) photochemotherapy, exposure to human papillomavirus (HPV), and history of smoking appear to have the most evidence suggesting that they may play a role in the development of this disease.
Almost one-half of individuals with cancer of the penis have had a history of phimosis. Hellberg et al.8 found a 65-fold relative risk for penile SCC among males with phimosis in a Swedish case control study. Phimosis is one of the strongest predictors of invasive carcinoma.6–8 It is hypothesized that men with phimosis are more likely to retain smegma. Smegma can cause epithelial hyperplasia and mild to moderate atypia of the squamous epithelium of the preputial sac in men with phimosis.9
Lack of Circumcision/Presence of Foreskin
Chronic Inflammatory Conditions
Circumcision has been established as a prophylactic measure that reduces the risk of penile cancer.1–4 Penile squamous cell carcinoma (SCC) is rare among Jews and Muslims, who practice circumcision during the neonatal period and childhood, respectively. While penile cancer is common in Africa, it is rare among the Ibos of Nigeria, who practice ritual male circumcision soon after birth.5 Indeed it is rare to find cancer of the penis in a patient who has been circumcised at birth. In a case control study, neonatal circumcision was associated with a 3-fold decreased risk, albeit 20% of penile cancer patients had
The association of chronic inflammation and irritation, burned areas, preexisting scars, and draining sinuses is well established as predisposing factors for SCC in other parts of the body. The same observation has been made for penile cancer.10 Hellberg et al.8 reported that 45% of patients had at least one episode of balanitis, while 8% of controls were affected by balanitis. Lichen sclerosis et atrophicus (LSA) is a chronic inflammatory skin condition of unknown etiology. The autoimmune response that is triggered by trauma, injury, or infection has been suggested as its predisposing
ETIOLOGY
710
Chapter 44 Invasive Carcinoma of the Penis 711
cause.5,11 Nasca et al.12 reported that 5.8% of their 86 patients with LSA developed penile cancer in a 10-year follow-up study. Bissada et al.13 reported the development of SCC in postcircumcision scars in 15 patients. Smoking A history of smoking is an independent risk factor for the development of penile cancer.6–8,14,15 The incidence of penile cancer among men who had ever smoked cigarettes was 2.4 times that of men who had never smoked.7 Although the exact cause is not known, the accumulation of nitrosamines in genital secretions has been suggeted.8 Ultraviolet Light Irradiation Treatment with PUVA photochemotherapy has been considered as a strong risk factor for penile cancer. In a 12.3-year prospective study of 892 men in a cohort of patients with psoriasis, who had been treated with oral methotrexate and PUVA, Stern16 identified 14 patients (1.6%) with 30 genital neoplasms. Recently Aubin et al.17 questioned the high prevalence of penile cancer in men treated by PUVA and suggested the carcinogenesis is probably dose dependent. Cervical Cancer in the Partner An association of penile cancer and cervical cancer in partners of patients with penile cancer has been suggested by several authors.18–21 Hellberg, however, has clearly showed that these studies had methodologic flaws and his review of 1064 penile cancer cases in Sweden did not show any association with cervical cancer in their partners.22 Other recent studies also found either weak or no risk elevation of penile cancer in men who had partners with cervical cancer.23–25 Human Papillomavirus Infection HPV infection is a sexually transmitted disease with a very high rate of infectivity. The infection is characterized by a high rate of spontaneous clearance. At least 75 different types of HPV have been identified and these types vary not only in their DNA sequences but also in their clinical manifestations.26,27 Different HPV types have been demonstrated in association with different genital lesions. Clinically, 85% of grossly visible genital condylomas (condyloma acuminata) or anogenital warts contain HPV type 6 and/or HPV type 11.26 In contrast, microscopic lesions identified in the male partners of women with cervical dysplasia were shown to contain HPV types 16 or 18 in 60% to 75% of the cases.26,28 These are the lesions that become visible only by acetowhitening. The causal role of certain
types of HPV in the development of intraepithelial neoplasia and carcinoma of the female cervix is well supported by experimental and epidemiologic data. The relative risk patterns of the 15 most common HPV types implicated in cervical neoplasm have been assessed and categorized. These include low-risk group (HPV 6, 11, 42, 43, 44), intermediate-risk group (HPV 31, 33, 35, 51, 52, 58), and high-risk group (HPV 16, 18, 45, 56). The DNA of high-risk HPV types has been detected in a substantial subset of penile SCC. Dillner et al.5 noted up to 40% of penile cancer lesions were positive for HPV with PCR method in two large series, with the majority of cases positive only for HPV 16 or 18. So far, a few seroepidemiologic studies indicate that exposure to HPV is indeed a major risk factor for penile cancer. We could not find any study to confirm the causal effect of this association. The presence of HPV E6 and E7 oncoproteins may explain the carcinogenic effect of the viral infection. E6/E7 genes immortalize human keratinocyte on transfection and directly stimulate cell proliferation. Furthermore, E6/E7 oncoproteins bind to the tumor suppressor proteins p53 and Rb (retinoblastoma), respectively. E6 binds to ubiquitin-dependent proteinase, which promotes the degradation of p53. E7 displaces the transcription factor E2F from the Rb protein and alters the cell cycle.27 However, we are not aware of any study that has investigated the expression of E6 and E7 oncoproteins in penile cancer specimens. Chromosomal instability,29 cooperation with activated oncogenes, methylation of viral and cellular DNA sites, and telomerase activation are some of the other potential mechanisms of HPV oncogenicity.30–32 PATHOLOGY Worldwide reports indicate that 95% of penile cancers are SCC. Sarcomas account for 4% to 5% of the remaining cancers. Rarely, other cancers, such as melanoma and basal cell carcinoma, arise in the penis. Premalignant Lesions The terminology of premalignant penile lesions is one of the major areas of confusion in the nomenclature of penile lesions. Premalignant lesions of the penis may be categorized into two groups as follows. (1) Lesions that are sporadically associated with SCC of the penis: bowenoid papulosis of the penis, balanitis xerotica obliterans (BXO), cutaneous horn of the penis and Buschke-Löwenstein tumor (Verrucous carcinoma, Giant condyloma acuminatum). (2) Lesions that are at risk of developing into invasive SCC of the penis: CIS of the penis (erythroplasia of Queyrat and Bowen’s disease).
712
Part VII Urethra and Penis
Bowenoid Papulosis Bowenoid papulosis, although histologically similar to CIS, usually has a benign course.33,34 Patterson et al.33 evaluated 51 patients with bowenoid papulosis and showed that the lesion usually occurs in young men (mean age 29.5 years). Lesions occur most commonly on the penile shaft and are usually multicentric, pigmented papules ranging from 2 to 30 mm. Smaller lesions may coalesce into larger ones.33 The etiology of bowenoid papulosis is unknown, although viral (particularly HPV), chemical, and immunologic causes have been suggested.33,35 The diagnosis is confirmed by excisional biopsy. Histologically, bowenoid papulosis is characterized by varying degrees of hyperkeratosis, parakeratosis, irregular acanthosis, and papillomatosis. As mentioned previously, histologically these lesions are similar to CIS, but bowenoid papulosis shows more maturation of keratinocytes and displays different growth patterns relative to CIS.33,36–38,39 Treatment includes surgical excision or elimination of the lesion by electrodesiccation, cryotherapy, laser fulguration, or topical 5-fluorouracil cream. Spontaneous regression has been reported.33 Balanitis Xerotica Obliterans BXO is the term applied to LSA of the glans penis and prepuce. This disorder most often occurs in uncircumcised, middle-aged men and may precede, coexist with, or progress to the penile SCC.40–43 Although initially asymptomatic, most patients complain of penile discomfort and/or pain, difficult urination secondary to meatal stricture, and painful erection. On examination, BXO presents as a well-defined marginated white patch on the glans penis or prepuce that may involve the urethral meatus. In chronic cases, the lesion is firm due to a thick underlying fibrosis. Diagnosis is made by biopsy. Histologically, active lesions show pronounced orthokeratotic hyperkeratosis accompanied by striking atrophy of the epidermis, which is very distinctive. Rete pegs are usually lost and collagen on the upper third of the dermis is homogenized. The treatment of BXO is usually difficult and depending on the severity consists of surgical excision, topical steroid cream, and/or laser therapy. Meatal stenosis may need repeated dilatations or even formal meatoplasty. Cutaneous Horn A cutaneous horn is an overgrowth and cornification of the epithelium that forms a solid protuberance. This is characterized by severe hyperkeratosis, dyskeratosis, and acanthosis. Penile horn is a rare form of cutaneous horn, with only 18 cases reported in North America.44 These
lesions are considered premalignant and one-third of cases reported have been malignant at presentation.45,46. Surgical excision with a margin of normal tissue around the base of the lesion has been very successful in treating it. Most malignant penile horns are of low grade, but metastasis has been reported. Therefore, wide local excision and close follow-up to detect early metastasis is suggested for malignant forms.46–48 Buschke-Löwenstein Tumor, Verrucous Carcinoma, Giant Condyloma Acuminatum Whether the Buschke-Löwenstein tumor or giant condyloma and verrucous carcinoma are the same or different lesions is controversial. Histologically, the tumor is composed of wide, circular rete pegs that usually extend to the deep tissue. There is no sign of anaplasia in the pegs’ squamous cells. The pegs are surrounded with inflammatory cells. These lesions are locally invasive and may be quite aggressive. They destroy adjacent structures by local invasion. They rarely, if ever, metastasize. Treatment is directed at eradicating the local disease. This can be achieved by local excision of the tumor and avoiding extensive excision of normal penile tissue. In rare cases, total penectomy is indicated for large, infiltrative lesions. Carcinoma In Situ, Bowen’s Disease, Erythroplasia of Queyrat Bowen’s disease and erythroplasia of Queyrat are the same histologically but occur in different locations. Erythroplasia of Queyrat is CIS of the penile glans or prepuce, while Bowen’s disease is CIS of the shaft or remainder of the genitalia and perineal area. CIS of the penis is a velvety red, well-circumscribed lesion that usually involves the glans, or less frequently, the prepuce or shaft of the penis. Histologically, they are described as atypical hyperplastic cells in a disordered array, with vacuolated cytoplasm and mitotic figures at all levels. The epithelial rete extends into the submucosa and appears elongated and widened. Increased microvascular density with surrounding inflammatory infiltrates, predominantly with plasma cells, present in the submucosal layer. Up to one-third of patients with CIS of the penis may also have invasive carcinoma of the penis.49 Diagnosis is based on adequate biopsies of the lesion with sufficient depth to rule out invasion. These lesions respond well to limited local excision with minimal interference with penile anatomy. Circumcision is usually an adequate treatment for CIS of the prepuce. It seems that local fulguration with electrocautery is not able to adequately eradicate the tumor. Radiation therapy has been successfully used for this tumor.50
Chapter 44 Invasive Carcinoma of the Penis 713
Topical use of 5-fluorouracil at 5% concentration has shown excellent results.51,52 Successful use of CO2 or Nd:YAG laser and liquid nitrogen have also been reported with excellent cosmetic results.53–56 Invasive Carcinoma of the Penis Ninety-five percent of cancers of the penis are SCC. Histologically, the lesion contains heavy keratinization, epithelial pearl formation, increased mitotic activity, and hyperchromatic, enlarged nuclei. Various histologic patterns, such as classic, basaloid, verrucous, sarcomatoid and adenomatoid, may be present. SCC may be divided histologically into well differentiated, moderately differentiated and poorly differentiated grades according to the classification of Broders.57 This classification was recently confirmed by Maiche et al.,58 who proposed four grades but with similar prognostic significance. Several authors have also studied the type of spread. Cubilla et al.59 studied a whole-organ-section of 66 patients with SCC of the penis and identified four types of growth: superficially spreading squamous carcinoma (42%), vertical invasive carcinoma (32%), verrucous carcinoma (18%), and multicentric carcinoma (8%). They found that 82% of patients with vertical growth versus 42% of patients with superficially spreading growth have inguinal lymph node metastasis. The distinction as to degree of differentiation is particularly important as a potential predictor for metastatic disease to the groin.60–62 It is even more powerful when combined with tumor depth of invasion.60 The remaining 5% of malignancies involving the penis include the sarcomas (angiosarcoma, fibrosarcoma, myelosarcoma, Kopasi’s sarcoma), 63–66 melanoma,67,68 basal cell carcinoma,69,70 and lymphoma. Other tumors, which have been reported on very rare occasions, include rhabdomyosarcoma,71 epithelial sarcoma, malignant schwannoma, myxosarcoma, and neurofibrosarcoma. Approximately 50% of SCCs are well differentiated, 30% are moderately differentiated, and 20% are poorly differentiated.60 Nine percent of lesions are found on the glans and prepuce, 21% on the prepuce, 48% on the glans, and 14% on the prepuce, glans, and shaft. Thus, 92% of SCCs of the penis involve the glans and/or prepuce. Approximately 6% involve the coronal sulcus and only 2% of SCCs are found on the shaft with no lesions elsewhere. NATURAL HISTORY Carcinoma of the penis usually presents as a small papillary, exophytic, or flat ulcerative lesion that does not resolve spontaneously. This ulcer extends gradually and may ultimately involve the entire glans or penis. It seems
that flat, ulcerative tumors are usually less differentiated and are overall associated with earlier nodal metastases. SCC of the penis is considered a locoregional malignancy. The lymphatic system is the primary route for metastases. The disease first spreads to the superficial and deep inguinal nodes, followed by the pelvic nodes, long before distant metastases occur. Enlarged inguinal lymph nodes occur in 30% to 60% of patients at presentation.72–75 Half of these patients actually harbor cancer in the regional nodes. Lymph node involvement with the cancer may also be present in 20% of patients with negative palpable nodes.76–78 Up to 60% of the patients may have tumor metastasis to the contralateral inguinal nodes.79 The presence and extent of inguinal lymph node metastases are the most important prognostic factors in men with SCC of the penis.72,80–83 Lymph node metastasis causes chronic infection and skin necrosis. Untreated, the majority of patients die within 1 year of diagnosis from sepsis, hemorrhage secondary to tumor erosion into the femoral vessels, and/or inanition.84 Distant metastases to the lung, liver, bone, or brain are uncommon.76,78,85 PRESENTATION The presence of penile lesion is the first presentation. This could range from a subtle small papule or pustule that does not heal to a large exophytic, fungating lesion. Sometimes it presents as superficial, erythematous erosion. These lesions occur most commonly on the glans and prepuce and less commonly on the coronal sulcus and penile shaft. If the primary lesions were ignored due to their location under a phimotic foreskin, the patient may present with a mass in the inguinal area. This could be due to the lymph node enlargement secondary to inflammatory response, or metastases. This mass may become ulcerative, suppurative, or hemorrhagic. These lesions are usually painless. In the late stage of the disease the patient may experience weakness, weight loss, loss of appetite, fever, and malaise. DIAGNOSIS Unfortunately, there is often a significant delay in diagnosis due to patient and/or physician factors. The patient’s delay is usually due to embarrassment, guilt, fear, or ignorance. Delay in seeking medical care may be as long as 1 year and may include up to 50% of the patients.86 Physician’s delay in diagnosis and treatment is usually due to prolongation of a conservative approach (long course of antibiotics, antifungal, or topical steroid therapy), or misdiagnosis.
714
Part VII Urethra and Penis
PHYSICAL EXAMINATION A thorough physical examination is crucial for the diagnosis and accurate staging. The penile lesion should be evaluated with regard to location, appearance, size, and depth of involvement. Fixation of the lesion to the adjacent structures, such as corporal bodies, needs to be documented. The scrotum, base of the penis, and perineum should be examined for any possible tumor extension. Rectal examination complements the examination and rules out gross involvement of the perineal body or the presence of a pelvic mass. The inguinal area needs to be inspected and palpated thoroughly for any possible lymph node enlargement. This is a crucial part of physical examination and we cannot overemphasize its importance. Biopsy Histologic confirmation of penile cancer should be obtained by a biopsy from the penile lesion. The biopsy is important to evaluate the depth of invasion, tumor differentiation (grade), and the presence of vascular invasion. This information is very helpful to accurately stage the tumor and allows the surgeon to discuss the therapeutic options with the patient. Although it is possible to perform the biopsy (with frozen section diagnosis) and partial or total penectomy in one session, we do not advocate this approach due primarily to psychologic reasons. Loss of the phallus is psychologically devastating to the patient and most patients need some time to cope with the diagnosis. The interval between the biopsy and the definitive radical surgery will allow the patient and his physician to establish their relationship and address the psychologic aspects of the treatment to decrease the enormous tension and stress that ensues following the ablative surgery. Imaging Knowledge of the extent and depth of the primary tumor and the involvement of inguinal lymph nodes prior to any surgical intervention is crucial in patients with penile cancer. In practice, this decision is usually based on findings from a physical examination. Various imaging modalities have been used for this purpose, including ultrasonography, computed tomography (CT) scan, and magnetic resonance imaging (MRI) scan. Due to the poor soft tissue resolution of CT scan, ultrasound and MRI are clearly superior to CT scan in the evaluation of primary tumor extension. Ultrasound cannot precisely detect tumor extension in the glans penis area. Ultrasound, however, has shown adequate resolution to detect corpus cavernosum invasion, owing to the thick tunica albuginea that is readily
visible with 7.5 MHz linear array small parts transducer.87–90 In extensive infiltrating tumors, ultrasound’s ability to delineate corporal invasion is compromised significantly.91 MRI has been tested in several studies and it appears that it is the most sensitive method for determining corpus cavernosal infiltration but at the cost of lower specificity.91–95 Lont et al.91 have recently compared the accuracy of physical examination to MRI or ultrasound in the evaluation of primary tumor extension and concluded that physical examination alone is a reliable method for predicting corporal involvement. MRI and ultrasound may be reserved only to examine tumors in which the physical examination is equivocal in determining tumor extension. CT scan relies on lymph node size for detecting metastasis. MRI evaluates the lymph node size and its signal intensity. Unfortunately, neither of these image modalities is able to differentiate benign versus malignant lymph node enlargement. Furthermore, their sensitivity and specificity drop remarkably in normal-sized lymph nodes. Presently, CT scan and MRI scan do not add additional information over thorough physical examination, especially in patients with no palpable inguinal lymph nodes. Recently, we reported the use of lymphotropic superparamagnetic nanoparticles, as an MRI contrast agent, in evaluating lymph node metastasis in prostate cancer patients.96 Our early experience of applying this noninvasive technique in a few penile cancer patients is encouraging. More studies are required to establish the role of this technique in patients with penile cancer. STAGING An ideal staging system allows accurate prognosis and assists in determining an optimal treatment. Unfortunately, the staging system of carcinoma of the penis is not universally accepted and each system carries its own flaws. Considering that penile cancer is a locoregional disease, accurate evaluation of the regional lymph nodes plays a major role in staging. The original Jackson system (Table 44-1) is not particularly helpful clinically in selecting who is most likely to have groin disease.97 The tumor-nodes-metastasis (TNM) system is a bit better (Table 44-2) but again suffers from inability to predict the incidence of positive regional lymph nodes. With the TNM system it is difficult to assign nodal status before definitive therapy. Combining the TNM system with tumor differentiation (grade) improves the prognostic ability for regional nodal involvement60 (Table 44-3). Considering the low incidence of penile cancer, multicenter prospective studies are needed to validate and improve the staging system.
Chapter 44 Invasive Carcinoma of the Penis 715
TREATMENT Local Treatment of the Primary Lesion For lesions that are small and involve only the dermis (<1 cm in diameter), Mohs’ micrographic surgery may be appropriate.98–100 This involves serial local excision of the primary tumor in thin layers, with thorough microscopic examination of each layer. This technique has the advantage of preserving the part but is limited to very Table 44-1 Jackson Staging System Stage I
Tumor confined to glans or prepuce
Stage II
Tumor invasive into the shaft or corpora. No palpable adenopathy
Stage III
Palpable metastases to the groin, which are resectable
Stage IV
Inoperable groin nodes or distant metastases
superficial lesions and is generally not particularly applicable for most cancers of the penis. Advocates of cryotherapy101 and laser therapy suggest that the local lesions can be destroyed with preservation of the part. For lesions involving only the dermis, they may be extremely successful. For lesions involving the subcutaneous tissue and/or corpora, successful eradication is less likely and the local recurrence rate is significant. Laser therapy as a minimally invasive treatment has the following outcomes: When the Nd:YAG is used as primary therapy for patients with CIS, the local recurrence rate is 6%; for lesions that invade the subcutaneous tissue, the recurrence rate is between 10% and 20%; for lesions that invade the corpora, the recurrence rate ranges between 50% and 100%.102 External beam radiation therapy carries with it a 61% recurrence rate103 with an unacceptably high stricture rate. Local lesions may be treated with brachytherapy with considerable success, particularly in patients with T1 to T2 penile cancer, who insist on preserving the
Table 44-2 American Joint Committee on Cancer (AJCC) Staging System for Penile Cancer Primary tumor (T) Tx
Primary tumor cannot be assessed
To
No evidence of primary tumor
TIS
CIS
Ta
Noninvasive verrucous carcinoma
T-1
Tumor invades subepithelial connective tissue
T-2
Tumor invades corpus spongiosum or cavernosum
T-3
Tumor invades urethra or prostate
T-4
Tumor invades other adjacent structures
Regional Lymph nodes (N) Nx
Regional lymph nodes cannot be assessed
N0
No regional node metastasis
N1
Metastasis in a single superficial, inguinal lymph node
N2
Metastasis in multiple or bilateral superficial inguinal lymph nodes
N3
Metastasis in deep inguinal or pelvic lymph node(s), unilateral or bilateral
Distant metastasis (M) Mx
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
716
Part VII Urethra and Penis
Table 44-3 Depth of Invasive/Grade Staging System T Stage Stage I
The tumor is superficial with no extension into the subcutaneous tissue
Stage IIA
Locally invasive tumor without involvement of the corpora, well or moderately differentiated T1, NO
Stage IIB
The tumor invades the corpora or it is poorly differentiated
T1, T2, NO
Stage III
Persistent palpable inguinal nodes
N-1, N-2
Stage IV
Bulky groin nodes with invasion extending outside the node, pelvic node involvement, distant metastases
N-3, N-4
part.104,105 Crook et al.105 showed that 76% of patients with T1 to T2 diseases were free of tumor locally for 5 years. Still, the most effective local therapy is surgical excision, although the cosmetic defects can be major. If the lesion is located on the foreskin only, circumcision is appropriate. However, this approach is associated with a 30% local recurrence rate. Partial penectomy is the most effective method of dealing with the disorder provided one can establish a 2-cm proximal margin. This carries with it a 6% recurrence rate. Total penectomy has the least risk of local recurrence and is only employed when the tumor replaces the entire penis or when it is located at the base of the shaft. It results in a significant cosmetic defect and many patients have considerable psychologic issues during the postoperative period.81,106–109 Treatment of the Inguinal Lymph Nodes The status of the inguinal lymph nodes is the most important prognostic factor in men with invasive SCC of the penis.72,80–83 SCC of the penis tends to spread locally to regional lymph nodes and distant metastasis is rare. Therefore, even in patients with local lymph node metastases, regional lymphadenectomy alone can be curative and should be performed.76,81,110,111 Studies suggest that inguinal lymphadenectomy offers 30% to 60% cure rate to patients with inguinal node metastases. If the tumor extends to the pelvic lymph nodes the success rate drops to <10%. Unfortunately, there is currently no effective chemotherapeutic and/or radiation therapeutic option available for patients with disease extending beyond the inguinal lymph nodes. Most of these patients will succumb to disease within 1 to 2 years.78,112 The lymphatic drainage of the penis is as follows: ●
●
●
The prepuce drains with the shaft skin to the superficial inguinal nodes. The glans drains with the corporal bodies to the deep inguinal nodes. The deep inguinal nodes drain to the pelvic nodes.
●
To, TIS, Ta, NO
Rarely, deeply invasive tumors, particularly those at the base of the penis, may bypass the groin and drain directly to the pelvic nodes.
There are multiple cross-communications so those lesions on one side of the penis may in fact metastasize to the contralateral groin. On physical examination approximately 50% of patients have palpable nodes. Often these nodes are inflammatory due to infection of the primary lesion. Therefore, a patient should be restaged after the primary lesion has been eradicated, the wound has been closed, and the patient is infection free. This generally requires 6 weeks of antibiotics following closure of the penile wound. If patients are reevaluated, those with palpably negative groin nodes will have a 20% incidence of metastatic disease if all patients are subjected to a groin dissection. Tumor grade and depth of invasion (stage) have significant prognostic value in predicting lymph node involvement.60,81,111,113 While almost 30% of patients with grade I penile SCC have inguinal lymph node involvement, about 80% of grade III tumors have positive inguinal lymph nodes.60,114 In patients whose primary lesion involves the corpora (T2) and the tumor is poorly differentiated, approximately 80% of such patients will in fact have positive groin nodes.60,111 If there are discrete palpable lymph nodes, approximately 86% of patients with high-grade tumors will have pathologically positive nodes on dissection. The issue of controversy involves whether preemptive lymphadenectomy should be performed. Because lymphadenectomy carries with it some morbidity and because there is a defined number of patients who would undergo lymphadenectomy needlessly if all patients were subjected to regional groin dissection, a watch-and-wait approach has been adopted over the years. Unfortunately, this relegates patients with nonpalpable microscopic disease to a much worse survival. Patients who have groin dissections and have nonpalpable microscopic disease have a markedly improved survival over those in whom the microscopic disease is allowed to
Chapter 44 Invasive Carcinoma of the Penis 717
develop into palpable disease at which point a groin dissection performed.60,78,80,81,115 It has been suggested that a sentinel lymph node biopsy would be predictive of the status of the groin so that an unnecessary groin dissection could be avoided.116–118 Unfortunately, the location of the sentinel node, which is most often located between the superficial epigastric and the superficial external pudendal vein, is variable. Therefore, its clinical use has not been found to be reliable by others.119–122 To overcome the anatomic variability of the sentinel node and based on the experience with breast and melanoma cancers,123 intraoperative lymph node mapping (IOLM) has been proposed recently. Injection of a vital blue dye and/or technetium-labeled colloid around the primary lesion allows the surgeon to follow its drainage to a single or a few lymph nodes in the inguinal region.124–126 Selective biopsies of these nodes assist to outline the extent of the lymph node dissection. In the absence of any sentinel node involvement, some would argue that there is no need for radical inguinal lymph node dissection (high negative predictive value). In a recent report by Horenblas et al.,127 55 patients were scanned and biopsied. One-third were found not to have surgical findings that correlated with scintigraphy. Twenty percent had positive nodes and 6% of patients, who were found to have negative nodes within a 3-year period, were found to develop evidence of positive groin nodes. Thus, this methodology does eliminate a number of patients who would needlessly undergo a groin dissection at the expense of subjecting all patients to groin sentinel node biopsies. The number of false-negatives is at least 6% as the follow-up in the current contemporary series is too short to determine the true false-negative rate. New modalities for lymph node imaging, particularly with lymphotropic contrast agents used with MRI, are extremely exciting. Based on our early experience with this technology at Massachusetts General Hospital, MR lymphangiogram, in all likelihood will have a diagnostic efficacy sufficient to predict who should and who should not receive a groin dissection. Unfortunately, at this time tumor differentiation and stage of tumor combined are as predictive as the modalities, such as sentinel node biopsies either with or without blue dye. Thus, poorly differentiated tumors have a 80% to 100% incidence of metastatic disease, moderately differentiated tumors a 46% incidence, and well-differentiated tumors a 24% incidence of groin metastasis. In tumors that have not invaded into corpora there is only a 5% to 11% incidence of metastatic disease, whereas if the corpora are invaded, there is a 61% to 75% incidence of groin metastases. Thus, we have proposed a modified staging system60 (see Table 44-3). Stages I and IIA diseases have an extremely low likelihood of metastatic groin disease (0% to 12%)
and their survival in our experience is close to 100%. Patients with IIB disease have a 78% to 88% incidence of groin metastases. In this group in whom watchful waiting is employed there is a 17% 5-year survival; in those who undergo an immediate lymphadenectomy there is a 92% survival; those who have a delayed lymphadenectomy when nodes become palpable have a 33% survival. Patients with stage III disease who undergo an immediate lymphadenectomy have a 75% survival, whereas if no lymphadenectomy is performed there is a 33% survival.60 Thus, it is clear that patients who have nonpalpable microscopic metastases to the groin and have a groin dissection have a much better prognosis than do those in whom the lymphadenectomy is performed when nodal disease becomes palpable. The problem, of course, is to determine who is most likely to have microscopic metastases without subjecting a large group of patients to an unnecessary operation since the morbidity of the operation on occasion is not inconsequential.112,113,128–130 Inguinal lymphadenectomy is not without significant complications. Series from the literature report: skin edge necrosis, 8% to 50%; major flap necrosis, 5%; wound infection, 10% to 15%; lymphedema, 25% to 50%; seroma formation, 6% to 16%; death, 0% to 1%.128,130–132 A second operation is required in approximately 15% of patients.132 If the lymph node dissection is performed for microscopic nonpalpable disease, the complication rate is much less. In our experience the complications are as follows: small wound seroma, 15%; minor skin edge necrosis not requiring a secondary procedure, 20%; minor, selflimited lymphedema, 20%; prolonged lymphedema, 5%. None have required secondary operations. The group at MD Anderson has also reported similar results.132 In our opinion, currently, the most predictive method of determining the probability of microscopic nodal metastases is grade of primary tumor combined with depth of invasion. Sentinel node biopsy as employed with blue dye and technetium may be helpful in selected cases. For the present, patients who have clinically negative groins and have a grade III lesion invasive to the corpora should have bilateral groin dissections. If the groin dissection is positive, a pelvic lymphadenectomy should subsequently be performed on the ipsilateral side. It is our preference to do the bilateral groin dissection in patients with any grade III tumor or any tumor whose primary lesion invades the corpora. Perhaps the sentinel node biopsy may be useful in these latter patients, as only about 60% of them will harbor microscopic metastatic disease. Of course patients with persistently palpable groin nodes should undergo a groin dissection. In this group, approximately 86% of patients will have metastatic disease. It is our preference to perform the bilateral superficial and deep node dissections in one setting. When the permanent pathology has returned, a pelvic
718
Part VII Urethra and Penis
lymphadenectomy is performed on the positive side. Our technique is described in Glenn’s Urologic Surgery133 Although some would suggest that a pelvic lymphadenectomy is not likely to impact survival, on occasion we have found an isolated positive node in the pelvis that resulted in long-term survival. Besides, the knowledge of pelvic node status has prognostic significance and allows us to consider adjuvant chemotherapy in positive cases. On occasion a groin dissection must be performed for palliative reasons. Under these circumstances large tissue defects may be created in the process of removing all visible tumor. These defects can be closed with an abdominal advancement flap as we have previously described.134 Following closure of the wound, radiation therapy may be given to the pelvis for palliation; however, invariably these patients will suffer significant external genitalia lymphedema, which can be quite disabling in the final stages of life. The Role of Radiation and Chemotherapy in Squamous Cell Carcinoma of the Penis The role of radiation and topical chemotherapy for the primary lesion has been discussed previously. Several nonrandomized studies have reviewed the role of radiation therapy for the treatment of metastatic inguinal nodes.79,135 The results are overall dismal and indicate the role of radiation therapy, merely as a palliative measure at the present time.136 Due to the limited number of cases and lack of prospective studies, an optimal chemotherapy protocol has not yet been developed. Most of the chemotherapy regimens are based on the results of chemotherapy trials in SCC of the head and neck. Cisplatin, methotrexate, bleomycin, and vincristine have been used alone or in combination. It appears that adjuvant or neoadjuvant use of chemotherapy agents may be beneficial and result in partial response in many cases.137–140 The optimal chemotherapy regimen remains to be determined. FUTURE CHALLENGE In the future, the optimum treatment of penile cancer needs to be developed. This requires more knowledge of the tumor biology. Furthermore, a staging system needs to be revised to allow more accurate prediction of tumor extension prior to surgery. New imaging technologies, including lymphotropic agents, need to be applied to improve the staging accuracy. A multidisciplinary approach incorporating surgical ablation, applying various energy modalities (i.e., radiation, laser, cryotherapy, thermotherapy, high intensity focused ultrasound, etc.)
and chemotherapy protocols, needs to be developed to optimize disease-free status.
REFERENCES 1. Schoen EJ: The status of circumcision of newborns. N Engl J Med 1990; 322(18):1308–1312. 2. Brinton LA, Li JY, Rong SD, et al: Risk factors for penile cancer: results from a case-control study in China. Int J Cancer 1991; 47(4):504–509. 3. Melmed EP, Pyne JR: Carcinoma of the penis in a Jew circumcised in infancy. Br J Surg 1967; 54(8):729–731. 4. Kochen M, McCurdy S: Circumcision and the risk of cancer of the penis. A life-table analysis. Am J Dis Child 1980; 134(5):484–486. 5. Dillner J, von Krogh G, Horenblas S, et al: Etiology of squamous cell carcinoma of the penis. Scand J Urol Nephrol Suppl 2000; 205:189–193. 6. Maden C, Sherman KJ, Beckmann AM, et al: History of circumcision, medical conditions, and sexual activity and risk of penile cancer. J Natl Cancer Inst 1993; 85(1):19–24. 7. Tsen HF, Morgenstern H, Mack T, et al: Risk factors for penile cancer: results of a population-based case-control study in Los Angeles County (United States). Cancer Causes Control 2001; 12(3):267–277. 8. Hellberg D, Valentin J, Eklund T, et al: Penile cancer: Is there an epidemiological role for smoking and sexual behaviour? Br Med J (Clin Res Ed) 1987; 295(6609):1306–1308. 9. Reddy CR, Devendranath V, Pratap S: Carcinoma of penis-role of phimosis. Urology 1984; 24(1):85–88. 10. Bain L, Geronemus R: The association of lichen planus of the penis with squamous cell carcinoma in situ and with verrucous squamous carcinoma. J Dermatol Surg Oncol 1989; 15(4):413–417. 11. Powell JJ, Wojnarowska F: Lichen sclerosus. Lancet 1999; 353(9166):1777–1783. 12. Nasca MR, Innocenzi D, Micali G: Penile cancer among patients with genital lichen sclerosus. J Am Acad Dermatol 1999; 41(6):911–914. 13. Bissada NK, Morcos RR, el-Senoussi M: Postcircumcision carcinoma of the penis. I. Clinical aspects. J Urol 1986; 135(2):283–285. 14. Daling JR, Sherman KJ, Hislop TG, et al: Cigarette smoking and the risk of anogenital cancer. Am J Epidemiol 1992; 135(2):180–189. 15. Harish K, Ravi R: The role of tobacco in penile carcinoma. Br J Urol 1995; 75(3):375–377. 16. Stern RS: Genital tumors among men with psoriasis exposed to psoralens and ultraviolet A radiation (PUVA) and ultraviolet B radiation. The photochemotherapy follow-up study. N Engl J Med 1990; 322(16):1093–1097. 17. Aubin F, Puzenat E, Arveux P, et al: Genital squamous cell carcinoma in men treated by photochemotherapy. A cancer registry-based study from 1978 to 1998. Br J Dermatol 2001; 144(6):1204–1206.
Chapter 44 Invasive Carcinoma of the Penis 719 18. Martinez I: Relationship of squamous cell carcinoma of the cervix uteri to squamous cell carcinoma of the penis among Puerto Rican women married to men with penile carcinoma. Cancer 1969; 24(4):777–780. 19. Graham S, Priore R, Graham M, et al: Genital cancer in wives of penile cancer patients. Cancer 1979; 44(5):1870–1874. 20. Cocks PS, Peel KR, Cartwright RA, et al: Carcinoma of penis and cervix. Lancet 1980; 2(8199):855–856. 21. Cocks PS, Adib RS, Hunt KM: Concurrent carcinoma of penis and carcinoma-in situ of the cervix in a married couple. Case report. Br J Obstet Gynaecol 1982; 89(5):408–409. 22. Hellberg D, Nilsson S: Genital cancer among wives of men with penile cancer. A study between 1958 and 1982. Br J Obstet Gynaecol 1989; 96(2):221–225. 23. Maiche AG, Pyrhonen S: Risk of cervical cancer among wives of men with carcinoma of the penis. Acta Oncol 1990; 29(5):569–571. 24. Iversen T, Tretli S, Johansen A, et al: Squamous cell carcinoma of the penis and of the cervix, vulva and vagina in spouses: is there any relationship? An epidemiological study from Norway, 1960–1992. Br J Cancer 1997; 76(5):658–660. 25. Hemminki K, Dong C: Cancer in husbands of cervical cancer patients. Epidemiology 2000; 11(3):347–349. 26. Zderic SA, Carpiniello VL, Malloy TR, et al: Urological applications of human papillomavirus typing using deoxyribonucleic acid probes for the diagnosis and treatment of genital condyloma. J Urol 1989; 141(1):63–65. 27. Mandell GL, Bennett JE, Dolin R: Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases. Edinburgh, Churchill Livingstone, 2000. 28. Schneider A, Kirchmayr R, De Villiers EM, et al: Subclinical human papillomavirus infections in male sexual partners of female carriers. J Urol 1988; 140(6):1431–1434. 29. Mullokandov MR, Kholodilov NG, Atkin NB, et al: Genomic alterations in cervical carcinoma: losses of chromosome heterozygosity and human papilloma virus tumor status. Cancer Res 1996; 56(1):197–205. 30. Lazo PA, Gallego MI, Ballester S, et al: Genetic alterations by human papillomaviruses in oncogenesis. FEBS Lett 1992; 300(2):109–113. 31. Rosl F, Arab A, Klevenz B, et al: The effect of DNA methylation on gene regulation of human papillomaviruses. J Gen Virol 1993; 74(Pt 5): 791–801. 32. Anderson S, Shera K, Ihle J, et al: Telomerase activation in cervical cancer. Am J Pathol 1997; 151(1):25–31. 33. Patterson JW, Kao GF, Graham JH, et al: Bowenoid papulosis. A clinicopathologic study with ultrastructural observations. Cancer 1986; 57(4):823–836. 34. Su CK, Shipley WU: Bowenoid papulosis: a benign lesion of the shaft of the penis misdiagnosed as squamous carcinoma. J Urol 1997; 157(4):1361–1362. 35. Zelickson AS, Prawer SE: Bowenoid papulosis of the penis. Demonstration of intranuclear viral like particles. Am J Dermatopathol 1980; 2(4):305–308.
36. Wade TR, Kopf AW, Ackerman AB: Bowenoid papulosis of the penis. Cancer 1978; 42(4):1890–1903. 37. Peters MS, Perry HO: Bowenoid papules of the penis. J Urol 1981; 126(4):482–484. 38. Wade TR, Ackerman AB: Bowenoid papulosis. J Am Acad Dermatol 1981; 4(2):235. 39. Bhojwani A, Biyani CS, Nicol A, et al: Bowenoid papulosis of the penis. Br J Urol 1997; 80(3):508. 40. Dore B, Grange P, Irani J, et al: Atrophicus sclerosis lichen and cancer of the glans. J Urol 1989; 95(7):415–418. 41. Campus GV, Alia F, Bosincu L: Squamous cell carcinoma and lichen sclerosus et atrophicus of the prepuce. Plast Reconstr Surg 1992; 89(5):962–964. 42. Pride HB, Miller OF III, Tyler WB: Penile squamous cell carcinoma arising from balanitis xerotica obliterans. J Am Acad Dermatol 1993; 29(3):469–473. 43. Simonart T, Noel JC, De Dobbeleer G, et al: Carcinoma of the glans penis arising 20 years after lichen sclerosus. Dermatology 1998; 196(3):337–338. 44. Lowe FC, McCullough AR: Cutaneous horns of the penis: an approach to management. Case report and review of the literature. J Am Acad Dermatol 1985; 13(2 Pt 2):369–373. 45. Raghavaiah NV, Soloway MS, Murphy WM: Malignant penile horn. J Urol 1977; 118(6):1068–1069. 46. Fields T, Drylie D, Wilson J: Malignant evolution of penile horn. Urology 1987; 30(1):65–66. 47. Goldstein HH: Cutaneous horns of the penis. J Urol 1933; 30:367–374. 48. Winterhoff E, Sparks JA: Penile horn. J Urol 1951; 66(5):704–707. 49. Mikhail GR: Cancers, precancers, and pseudocancers on the male genitalia. A review of clinical appearances, histopathology, and management. J Dermatol Surg Oncol 1980; 6(12):1027–1035. 50. Grabstald H, Kelley CD: Radiation therapy of penile cancer: six to ten-year follow-up. Urology 1980; 15(6):575–576. 51. Goette DK, Elgart M, DeVillez RL: Erythroplasia of Queyrat. Treatment with topically applied fluorouracil. JAMA 1975; 232(9):934–937. 52. Goette DK, Carson TE: Erythroplasia of Queyrat: treatment with topical 5-fluorouracil. Cancer 1976; 38(4):1498–1502. 53. Rosemberg SK, Fuller TA: Carbon dioxide rapid superpulsed laser treatment of erythroplasia of Queyrat. Urology 1980; 16(2):181–182. 54. Madej G, Meyza J: Cryosurgery of penile carcinoma. Short report on preliminary results. Oncology 1982; 39(6):350–352. 55. Rosemberg SK: Carbon dioxide laser treatment of external genital lesions. Urology 1985; 25(6): 555–558. 56. Landthaler M, Haina D, Brunner R, et al: Laser therapy of bowenoid papulosis and Bowen’s disease. J Dermatol Surg Oncol 1986; 12(12):1253–1257. 57. Broders AC: Squamous cell epithelium of the skin. Ann Surg 1921; 73:141–143.
720
Part VII Urethra and Penis
58. Maiche AG, Pyrhonen S, Karkinen M: Histological grading of squamous cell carcinoma of the penis: a new scoring system. Br J Urol 1991; 67(5):522–526. 59. Cubilla AL, Barreto J, Caballero C, et al: Pathologic features of epidermoid carcinoma of the penis. A prospective study of 66 cases. Am J Surg Pathol 1993; 17(8):753–763. 60. McDougal WS: Carcinoma of the penis: improved survival by early regional lymphadenectomy based on the histological grade and depth of invasion of the primary lesion. J Urol 1995; 154(4):1364–1366. 61. Theodorescu D, Russo P, Zhang ZF, et al: Outcomes of initial surveillance of invasive squamous cell carcinoma of the penis and negative nodes. J Urol 1996; 155(5):1626–1631. 62. Heyns CF, van Vollenhoven P, Steenkamp JW, et al: Carcinoma of the penis–appraisal of a modified tumour-staging system. Br J Urol 1997; 80(2): 307–312. 63. Moore SW, Wheeler JE, Hefter LG: Epitheloid sarcoma masquerading as Peyronie’s disease. Cancer 1975; 35(6):1706–1710. 64. Mabogunje O: Kaposi sarcoma of glans penis. Urology 1981; 17(5):476–478. 65. Parsons MA, Fox M: Malignant fibrous histiocytoma of the penis. Eur Urol 1988; 14(1):75–76. 66. Rasbridge SA, Parry JR: Angiosarcoma of the penis. Br J Urol 1989; 63(4):440–441. 67. Manivel JC, Fraley EE: Malignant melanoma of the penis and male urethra: 4 case reports and literature review. J Urol 1988; 139(4):813–816. 68. de Bree E, Sanidas E, Tzardi M, et al: Malignant melanoma of the penis. Eur J Surg Oncol 1997; 23(3):277–279. 69. Goldminz D, Scott G, Klaus S: Penile basal cell carcinoma. Report of a case and review of the literature. J Am Acad Dermatol 1989; 20(6):1094–1097. 70. Ladocsi LT, Siebert CF Jr, Rickert RR, et al: Basal cell carcinoma of the penis. Cutis 1998; 61(1):25–27. 71. Dalkin B, Zaontz MR: Rhabdomyosarcoma of the penis in children. J Urol 1989; 141(4):908–909. 72. Srinivas V, Morse MJ, Herr HW, et al: Penile cancer: relation of extent of nodal metastasis to survival. J Urol 1987; 137(5):880–882. 73. Solsona E, Iborra I, Ricos JV, et al: Corpus cavernosum invasion and tumor grade in the prediction of lymph node condition in penile carcinoma. Eur Urol 1992; 22(2):115–118. 74. Ayyappan K, Ananthakrishnan N, Sankaran V: Can regional lymph node involvement be predicted in patients with carcinoma of the penis? Br J Urol 1994; 73(5):549–553. 75. Lopes A, Rossi BM, Fonseca FP, et al: Unreliability of modified inguinal lymphadenectomy for clinical staging of penile carcinoma. Cancer 1996; 77(10):2099–2102. 76. Beggs JH, Spratt JS Jr: Epidermoid carcinoma of the Penis. J Urol 1964; 91(2):166–172. 77. Hardner GJ, Bhanalaph T, Murphy GP, et al: Carcinoma of the penis: analysis of therapy in 100 consecutive cases. J Urol 1972; 108(3):428–430.
78. Kossow JH, Hotchkiss RS, Morales PA: Carcinoma of penis treated surgically. Analysis of 100 cases. Urology 1973; 2(2):169–172. 79. Ekstrom T, Edsmyr F: Cancer of the penis: a clinical study of 229 cases. Acta Chir Scand 1958; 115:25–29. 80. Johnson DE, Lo RK: Management of regional lymph nodes in penile carcinoma. Five-year results following therapeutic groin dissections. Urology 1984; 24(4):308–311. 81. McDougal WS, Kirchner FK Jr, Edwards RH, et al: Treatment of carcinoma of the penis: the case for primary lymphadenectomy. J Urol, 1986; 136(1):38–41. 82. Ravi R: Prophylactic lymphadenectomy vs observation vs inguinal biopsy in node-negative patients with invasive carcinoma of the penis. Jpn J Clin Oncol 1993; 23(1):53–58. 83. Ornellas AA, Seixas AL, Marota A, et al: Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol 1994; 151(5):1244–1249. 84. Staubitz WJ, Lent MH, Mack FG, et al: Carcinoma of the Penis. Cancer 1955; 8:371. 85. Johnson DE, Fuerst DE, Ayala AG: Carcinoma of the penis. Experience with 153 cases. Urology 1973; 1(5):404–408. 86. Gursel EO, Georgountzos C, Uson AC, et al: Penile cancer. Urology 1973; 1(6):569–578. 87. Yamashita T, Ogawa A: Ultrasound in penile cancer. Urol Radiol 1989; 11(3):174–177. 88. Dorak AC, Ozkan GA, Tamac NI, et al: Ultrasonography in the recognition of penile cancer. J Clin Ultrasound 1992; 20(9):624–626. 89. Herbener TE, Seftel AD, Nehra A, et al: Penile ultrasound. Semin Urol 1994; 12(4):320–332. 90. Horenblas S, Kroger R, Gallee MP, et al: Ultrasound in squamous cell carcinoma of the penis; a useful addition to clinical staging? A comparison of ultrasound with histopathology. Urology 1994; 43(5):702–707. 91. Lont AP, Besnard AP, Gallee MP, et al: A comparison of physical examination and imaging in determining the extent of primary penile carcinoma. BJU Int 2003; 91(6):493–495. 92. Hricak H, Marotti M, Gilbert TJ, et al: Normal penile anatomy and abnormal penile conditions: evaluation with MR imaging. Radiology 1988; 169(3):683–690. 93. Kawada T, Hashimoto K, Tokunaga T, et al: Two cases of penile cancer: magnetic resonance imaging in the evaluation of tumor extension. J Urol 1994; 152(3):963–965. 94. de Kerviler E, Ollier P, Desgrandchamps F, et al: Magnetic resonance imaging in patients with penile carcinoma. Br J Radiol 1995; 68(811):704–711. 95. Kageyama S, Ueda T, Kushima R, et al: Primary adenosquamous cell carcinoma of the male distal urethra: magnetic resonance imaging using a circular surface coil. J Urol 1997; 158(5):1913–1914. 96. Harisinghani MG, Barentsz J, Hahn PF, et al: Noninvasive detection of clinically occult lymph-node metastases in prostate cancer. N Engl J Med 2003; 348(25):2491–2499 [comment].
Chapter 44 Invasive Carcinoma of the Penis 721 97. Jackson SM: The treatment of carcinoma of the penis. Br J Surg 1966; 53(1):33–35. 98. Mohs FE: Chemosurgery: microscopically controlled surgery for skin cancer—past, present and future. J Dermatol Surg Oncol 1978; 4(1):41–54. 99. Mohs FE, Snow SN, Messing EM, et al: Microscopically controlled surgery in the treatment of carcinoma of the penis. J Urol 1985; 133(6):961–966. 100. Mohs FE, Snow SN, Larson PO: Mohs micrographic surgery for penile tumors. Urol Clin North Am 1992; 19(2):291–304. 101. Farrell AM, Dawber RP: Squamous cell carcinoma of the penis. J Am Acad Dermatol 1998; 38(3):504–505. 102. Frimberger D, Hungerhuber E, Zaak D, et al: Penile carcinoma. Is Nd:YAG laser therapy radical enough? J Urol 2002; 168(6):2418–2421 [Discussion 2421]. 103. Zouhair A, Coucke PA, Jeanneret W, et al: Radiation therapy alone or combined surgery and radiation therapy in squamous-cell carcinoma of the penis? Eur J Cancer 2001; 37(2):198–203. 104. Kiltie AE, Elwell C, Close HJ, et al: Iridium-192 implantation for node-negative carcinoma of the penis: the Cookridge Hospital experience. Clin Oncol 2000; 12(1):25–31. 105. Crook J, Grimard L, Tsihlias J, et al: Interstitial brachytherapy for penile cancer: an alternative to amputation. J Urol 2002; 167(2 Pt 1):506–511. 106. Hanash KA, Furlow WL, Utz DC, et al: Carcinoma of the penis: a clinicopathologic study. J Urol 1970; 104(2):291–297. 107. Jensen MO: Cancer of the penis in Denmark 1942 to 1962 (511 cases). Dan Med Bull 1977; 24(2):66–72. 108. Opjordsmoen S, Fossa SD: Quality of life in patients treated for penile cancer. A follow-up study. Br J Urol 1994; 74(5):652–657. 109. Opjordsmoen S, Waehre H, Aass N, et al: Sexuality in patients treated for penile cancer: patients’ experience and doctors’ judgement. Br J Urol 1994; 73(5):554–560. 110. Fraley EE, Zhang G, Manivel C, et al: The role of ilioinguinal lymphadenectomy and significance of histological differentiation in treatment of carcinoma of the penis. J Urol 1989; 142(6):1478–1482. 111. Horenblas S, van Tinteren H: Squamous cell carcinoma of the penis. IV. Prognostic factors of survival: analysis of tumor, nodes and metastasis classification system. J Urol 1994; 151(5):1239–1243. 112. Skinner DG, Leadbetter WF, Kelley SB: The surgical management of squamous cell carcinoma of the penis. J Urol 1972; 107(2):273–277. 113. Lopes A, Hidalgo GS, Kowalski LP, et al: Prognostic factors in carcinoma of the penis: multivariate analysis of 145 patients treated with amputation and lymphadenectomy. J Urol 1996; 156(5):1637–1642. 114. Horenblas S, van Tinteren H, Delemarre JF, et al: Squamous cell carcinoma of the penis. III. Treatment of regional lymph nodes. J Urol 1993; 149(3):492–497. 115. Fegen P, Persky L: Squamous cell carcinoma of the penis: its treatment, with special reference to radical node dissection. Arch Surg 1969; 99(1):117–120.
116. Cabanas RM: an approach for the treatment of penile carcinoma. Cancer 1977; 39(2):456–466. 117. Cabanas RM: Anatomy and biopsy of sentinel lymph nodes. Urol Clin North Am 1992; 19(2):267–276. 118. Cabanas RM, Application of the sentinel node concept in urogenital cancer. Recent Results Cancer Res 2000; 157:141–149. 119. Perinetti E, Crane DB, Catalona WJ: Unreliability of sentinel lymph node biopsy for staging penile carcinoma. J Urol 1980; 124(5):734–735. 120. Wespes E, Simon J, Schulman CC: Cabanas approach: is sentinel node biopsy reliable for staging penile carcinoma? Urology 1986; 28(4):278–279. 121. Srinivas V, Joshi A, Agarwal B, et al: Penile cancer–the sentinel lymph node controversy. Urol Int 1991; 47(2):108–109. 122. Pettaway CA, Pisters LL, Dinney CP, et al: Sentinel lymph node dissection for penile carcinoma: the M.D. Anderson Cancer Center experience. J Urol 1995; 154(6):1999–2003. 123. Morton DL, Wen DR, Wong JH, et al: Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg 1992; 127(4):392–399. 124. Han KR, Brogle BN, Goydos J, et al: Lymphatic mapping and intraoperative lymphoscintigraphy for identifying the sentinel node in penile tumors. Urology 2000; 55(4):582–585. 125. Valdes Olmos RA, Tanis PJ, Hoefnagel CA, et al: Penile lymphoscintigraphy for sentinel node identification. Eur J Nucl Med 2001; 28(5):581–585. 126. Tanis PJ, Lont AP, Meinhardt W, et al: Dynamic sentinel node biopsy for penile cancer: reliability of a staging technique. J Urol 2002; 168(1):76–80. 127. Horenblas S, Jansen L, Meinhardt W, et al: Detection of occult metastasis in squamous cell carcinoma of the penis using a dynamic sentinel node procedure. J Urol 2000; 163(1):100–104. 128. Ornellas AA, Seixas AL, de Moraes JR: Analyses of 200 lymphadenectomies in patients with penile carcinoma. J Urol 1991; 146(2):330–332. 129. Kamat MR, Kulkarni JN, Tongaonkar HB: Carcinoma of the penis: the Indian experience. J Surg Oncol 1993; 52(1):50–55. 130. Ravi R: Morbidity following groin dissection for penile carcinoma. Br J Urol 1993; 72(6):941–945. 131. Johnson DE, Lo RK: Complications of groin dissection in penile cancer. Experience with 101 lymphadenectomies. Urology 1984; 24(4):312–314. 132. Bevan-Thomas R, Slaton JW, Pettaway CA: Contemporary morbidity from lymphadenectomy for penile squamous cell carcinoma: the M.D. Anderson Cancer Center Experience. J Urol 2002; 167(4):1638–1642. 133. Graham SD, Kean TE, Glenn JF: Glenn’s Urologic Surgery. Philadelphia, Lippincott Williams & Wilkins, in press. 134. Tabatabaei S, McDougal WS: Primary skin closure of large groin defects after inguinal lymphadenectomy for penile cancer using an abdominal cutaneous advancement flap. J Urol 2003; 169(1):118–120.
722
Part VII Urethra and Penis
135. el-Demiry MI, Oliver RT, Hope-Stone HF, et al: Reappraisal of the role of radiotherapy and surgery in the management of carcinoma of the penis. Br J Urol 1984; 56(6):724–728. 136. Vaeth JM, Green JP, Lowy RO: Radiation therapy of carcinoma of the penis. Am J Roentgenol Radium Ther Nucl Med 1970; 108(1):130–135. 137. Pizzocaro G, Piva L: Adjuvant and neoadjuvant vincristine, bleomycin, and methotrexate for inguinal metastases from squamous cell carcinoma of the penis. Acta Oncol 1988; 27(6b):823–824.
138. Hussein AM, Benedetto P, Sridhar KS: Chemotherapy with cisplatin and 5-fluorouracil for penile and urethral squamous cell carcinomas. Cancer 1990; 65(3):433–438. 139. Dexeus FH, Logothetis CJ, Sella A, et al: Combination chemotherapy with methotrexate, bleomycin and cisplatin for advanced squamous cell carcinoma of the male genital tract. J Urol 1991; 146(5):1284–1287. 140. Shammas FV, Ous S, Fossa SD: Cisplatin and 5-fluorouracil in advanced cancer of the penis. J Urol 1992; 147(3):630–632.
C H A P T E R
45 Penectomy and Ilioinguinal Lymphadenectomy Donald F. Lynch, Jr., MD
In North America, cancer of the penis is an uncommon disease, but it is a substantial health problem in parts of Africa, South America, and Asia. Squamous cell carcinoma (SCC), the most common penile cancer, is a malignancy, like testicular cancer, where the behavior of the tumor is reasonably predictable, and where regional disease may be curable by timely surgical intervention. Patients with Buschke-Löwenstein tumors (verrucous carcinoma of the penis) are usually managed with local excision but on occasion may require partial or total penectomy. Similarly, patients with Kaposi’s sarcoma of the penis may occasionally require surgical excision or partial penectomy. These tumor types do not metastasize, and further management generally involves only interval follow-up. Squamous carcinoma is a far more ominous diagnosis; these tumors have a propensity for metastasis to the inguinal lymph nodes and beyond. With squamous carcinoma, the size of the primary tumor, its location on the penis, the grade of the tumor, and the depth of invasion determine the extent of surgical treatment that will be required.1–3 This information comes from biopsy of the lesion and from careful physical examination. The goal of surgery for localized carcinoma of the penis is complete excision of the tumor with adequate tissue margins. Some superficial lesions of the glans or shaft may be amenable to wide excision or to treatment using laser surgery or Mohs’ micrographic surgery, while superficial tumors limited to the prepuce may sometimes be managed with circumcision.4,5 In the case of large tumors (>2.0 cm), lesions that are located so that an adequate margin of resection cannot be achieved, or cancers that invade the tunica albuginea, corpora, or urethra, limited resection may not be possible, and partial or total penectomy will be required. Additionally, patients who develop recurrent tumor following unsuccessful attempts
at wide excision or who recur subsequent to laser therapy may also require penectomy. SURGICAL PROCEDURES FOR THE PRIMARY LESION Biopsy Histology of any penile tumor must be confirmed with an adequate biopsy. Most penile cancers are SCCs, which spread by local invasion early in their course. Such tumors metastasize to regional lymph nodes as they progress in size and depth to involve the highly vascular structures of the penis. Histologic confirmation of tumor depth is important in assessing the need for inguinal lymphadenectomy, as well as in determining whether adequate margins of resection are possible so as to permit partial penectomy. Several recent studies suggest that tumor grade also is an important determinant in prognosis and is an important consideration in assessing the risk of inguinal metastases.2,3 Penile biopsy may be done as a separate procedure, or may done in conjunction with frozen-section confirmation as a prelude to definitive partial or total penile amputation. Full informed consent must be obtained prior to such a procedure. Biopsy is performed by excising a 1- to 1.5-cm wedge of tissue, which includes the margin of the tumor and provides normal tissue adjacent to the lesion to be examined for tumor infiltration (Figure 45-1). The incision may be closed with interrupted 2-0 or 3-0 chromic gut after that a sterile compressive dressing is applied. There have been no reports of tumor dissemination from biopsy of penile cancers.6 Partial Penectomy Partial penectomy is the surgical treatment of choice for tumors of the glans and distal penile shaft where a margin
723
724
Part VII Urethra and Penis
Figure 45-1 Biopsy of penile tumor, including normal tissue for comparison.
of at least 2 cm of normal tissue can be achieved. In the appropriately selected patient, this procedure should provide a penile stump of sufficient length to allow the patient to void while standing. If an adequate stump cannot be assured, total penectomy with creation of a perineal urethrostomy is preferable. The incidence of recurrent tumor following partial penectomy has been reported as ranging from 0% to 6%. Five-year survival rates of 70% to 80% following a properly performed partial penectomy have been noted when inguinal nodes are free of metastatic disease.6,7
If the patient has not been receiving antibiotic therapy prior to surgery, intravenous antibiotics are administered preoperatively. A broad-spectrum cephalosporin, which can be converted to oral therapy 48 to 72 hours following surgery, is preferred. With the patient in the supine position, the entire penis and scrotum are scrubbed with povidone-iodine solution, and the lesion is then covered with a sterile glove or sponge secured with a sterile rubber band. A 7/8-inch Penrose drain is used as a tourniquet about the base of the penis (Figure 45-2A). A transverse incision is made over the dorsum of the penis 2.0 cm proximal to the most proximal tumor margin and carried circumferentially around the shaft. The superficial dorsal vessels are fulgurated, and the corpora are then sharply divided down to the urethra, taking care to ligate the deep dorsal vessel complex (Figure 45-2B). The distal urethra is dissected free approximately 1 cm proximally and distally, maintaining the 2-cm margin, to allow for spatulation and creation of a neomeatus. The amputation is then completed. The corporal stumps are closed with interrupted mattress sutures of 2-0 Vicryl (Figure 45-2B and C). The tourniquet is then removed and further hemostasis obtained. The urethra is spatulated and sutured to the skin of the shaft with 3-0 or 4-0 Vicryl or Dexon. The remaining shaft skin is closed using 3-0 absorbable suture (Figure 45-2D). An 18Fr Foley catheter is placed to straight drainage for 24 to 48 hours, and the wound is dressed. Alternatively, the penile shaft skin can be excised to create a flap dorsally. This can be folded ventrally to cover the stump of the penis, and the urethra spatulated and brought through a buttonhole in the flap. The flap edges are sutured with 3-0 Vicryl, and excess flap skin is then excised as needed. Additional stump length can sometimes be gained by dividing the suspensory ligament of the penis, dividing
Figure 45-2 Partial penectomy.
Chapter 45 Penectomy and Ilioinguinal Lymphadenectomy 725
the ischiocavernosus muscle, and mobilizing the crura from the inferior pubis. The scrotum is incised along the raphe and reconstructed superior to the transposed phallus.8 These maneuvers may provide 1 or 2 cm of additional length and avoid the need for a total penectomy in selected cases. Total Penectomy Total penectomy is the treatment of choice in patients where the lesion is located too proximally on the shaft to permit a partial amputation. The patient is placed in standard lithotomy position, and the penis, scrotum, lower abdomen, and perineum prepared with povidoneiodine solution. The tumor is covered with a glove or dressing. An elliptical incision is begun over the pubis and carried around the base of the penis to the midportion of the scrotal raphe (Figure 45-3A). The corpus spongiosum is exposed ventrally and mobilized to the urogenital diaphragm. It is transected distal to the bulb, taking care to assure a 2-cm margin from the lesion (Figure 45-3B and C ). Dorsally, the incision is carried
down through Buck’s fascia, and the deep dorsal venous complex is identified and traced to the symphysis pubis (Figure 45-3D). The dorsal vein complex is clamped, ligated with 2-0 silk suture and divided at this point. The suspensory ligament of the penis is divided, and with downward traction on the penile shaft, the corpora cavernosa are identified and dissected from their attachments to the inferior pubis. The corpora are individually ligated with 0 Vicryl suture and divided behind the pubis. Following amputation of the penis, a 1-cm ellipse of skin is excised from the region of the perineal body midway between the rectum and scrotum. Using blunt dissection, a tunnel is developed in the perineal subcutaneous tissue, and the urethra grasped and directed through this passage, taking care not to create excessive angulation. Excess urethra is excised and the urethral stump spatulated and secured to the perineal skin with 30 chromic or Vicryl sutures (Figure 45-3E). After 3/4inch Penrose drains are placed in the subcutaneous space, the primary incision is sutured with interrupted 3-0 Vicryl transversely, which closes the suprapubic wound and serves to elevate the scrotum off of the perineum
Figure 45-3 Total penectomy. (See text for details.)
726
Part VII Urethra and Penis
(Figure 45-3E and F ). The wound is dressed and an 18Fr Foley catheter is placed to straight drainage for 48 to 72 hours. The patient is maintained on broad-spectrum antibiotic therapy for 7 to 10 days. MANAGEMENT OF REGIONAL DISEASE A thorough understanding of the lymphatic drainage of the penis is essential to stage the patient, to monitor his progress following initial surgical intervention, and to deal with regional disease if it is present at diagnosis or develops subsequent to primary treatment. While penile cancer, like testis cancer, remains one of the few malignancies for which regional lymphadenectomy can be curative, controversy exists regarding the timing and indications for inguinal and pelvic lymphadenectomy, as well as the extent of the surgery required. Anatomic Considerations For the surgeon performing inguinal lymphadenectomy, a thorough knowledge of the anatomy of the groin region is essential. Inguinal anatomy has been meticulously described by Daseler, who performed a series of 450 inguinal lymphadenectomies for a variety of tumors, and whose technique has been viewed as the standard for penile cancer.7 The boundaries of the classical lymphadenectomy and their relationship to significant anatomic landmarks are illustrated in Figure 45-4. Fascial Planes The lower abdomen has two superficial fascial compartments, Scarpa’s and Camper’s fasciae. Camper’s fascia is a fibrofatty layer that is continuous from the lower abdomen onto the thigh. At the scrotum, it fuses with the deeper Scarpa’s fascia to form the tunica dartos. Scarpa’s fascia is comprised of a distinct fibrous sheath. From the abdomen, it crosses the inguinal ligament and fuses with the fascia lata of the thigh about 1 cm inferior to Poupart’s ligament, forming Holden’s line. Within the pelvis, the iliac fascia invests the iliopsoas muscle and also covers the femoral nerve. The iliac fascia fuses with the transversalis fascia at the inguinal ligament. The inguinal ligament is formed by the aponeurosis of the external oblique muscle and runs from the anterior superior iliac spine to the pubic tubercle. The internal oblique muscle attaches to the lateral half of the inguinal ligament, and the transversus abdominis to its outer third. Femoral Triangle (of Scarpa) The femoral triangle is formed by the inguinal ligament, the medial margin of the sartorius muscle, and the medial border of the adductor longus muscle. It is covered by
Figure 45-4 Limits of dissection for both the classical (Daseler) lymphadenectomy (solid line) and the modified (Catalona) lymphadenectomy (dashed line). Relation of the femoral vein, saphenous vein, and sentinel node group to the dissections is shown.
the fascia lata except for the fossa ovalis, an opening through which the greater saphenous vein passes to empty into the femoral vein below. Passing through the femoral triangle are the femoral vessels and nerve. The vessels are invested within the femoral sheath that is formed by extensions of the transversalis fascia, which passes below the inguinal ligament. This sheath is comprised of three compartments: the medial containing the lymph nodes and lymphatic trunks, the middle the femoral vein, and the lateral the femoral artery. Lateral to the artery within the iliac fascia is the femoral nerve (Figure 45-5). Veins The femoral vein enters the femoral triangle at its apex, medial to the femoral artery. About 4 cm below Poupart’s ligament, it receives the greater saphenous vein anteriorly and the profunda femoris vein posteriorly. The greater saphenous vein originates at the dorsal venous arch of the foot and ascends medially, passing posterior
Chapter 45 Penectomy and Ilioinguinal Lymphadenectomy 727
Figure 45-5 Relationship of femoral anatomy—nerve, artery, vein, lymph nodes—at the level of the fossa ovalis.
to the medial epicondyle at the knee. It ascends in the superficial fascia of the thigh and empties into the femoral vein after passing through the fossa ovalis. Just before the fossa ovalis, it receives the superficial epigastric and external pudendal veins medially and the accessory saphenous
and circumflex iliac veins laterally (Figure 45-6). The femoral vein passes below the inguinal ligament to become the external iliac vein, which joins with the internal iliac (hypogastric) vein at the level of the sacroiliac joint to form the common iliac vein. The paired common iliac veins empty into the inferior vena cava at the level of the fifth lumbar vertebra. Arteries The common iliac arteries arise from the terminal aorta and divide at the level of the sacral promontory into the internal and external iliac arteries. The internal iliac passes posteromedially and divides to supply the pelvic musculature and pelvic organs. The external iliac artery passes below the inguinal ligament to become the femoral artery, which supplies the lower limb. Just prior to passing beneath the inguinal ligament, the external iliac artery gives off the medial inferior epigastric artery and the lateral circumflex iliac artery. Just after passing beneath the inguinal ligament, the femoral artery gives off the superficial epigastric artery, the superficial circumflex iliac artery, the superficial and deep external pudendal arteries, and the profunda femoris artery (Figure 45-7). The femoral artery continues past the apex of the femoral triangle and terminates in the lower third of the adductor magnus, where it becomes the popliteal artery. Nerves
Figure 45-6 Superficial inguinal nodes, inguinal ligament, and major venous structures.
The femoral nerve lies beneath the iliac fascia lateral to the femoral vessels and outside of the femoral sheath. It is usually not visualized in the inguinal dissection, as the femoral nodal tissue lies medial to the vessels within the femoral sheath. Other nerves that may be encountered in
728
Part VII Urethra and Penis
Figure 45-7 Surgical approaches to inguinal and pelvic node dissections.
the groin are the ilioinguinal and lateral cutaneous nerve of the thigh. The obturator nerve and genitofemoral nerves are encountered in the course of the pelvic lymphadenectomy. Lymphatics Lymphatic drainage of the penis is to the superficial and deep inguinal lymph nodes and to the pelvic nodes. The superficial inguinal nodes are comprised of from 4 to 25 nodes lying within Camper’s fascia, superficial to the deep fascia of the thigh, and closely associated with the saphenous vein (see Figure 45-6). Rouviere’s classic study of inguinal anatomy divides the superficial inguinal nodes into five zones with the sentinel nodes lying within zone 2, just medial to the femoral vein around the superficial epigastric and superficial external pudendal veins.7,8 The deep inguinal nodes—usually 1 to 3 on a side—lie below the fascia lata medial to the femoral vein (Figure 45-8E and F). Lymphatic drainage of the prepuce and penile skin commences in the ventral penile skin, drains superficial to Buck’s fascia in a dorsolateral direction and then courses proximally along the dorsum of the penis to the
superficial inguinal nodes. From the glans penis, lymphatic drainage coalesces at the frenulum and passes laterally to the dorsal penis, deep to Buck’s fascia paralleling the deep dorsal vein. One pathway is to the deep femoral node chain, which includes the femoral node of Cloquet or Rosenmüller. An additional lymphatic pathway may course along the inguinal canal to the lateral retrofemoral node, the most superficial of the external iliac chain. The drainage of the corporal bodies also accompanies the deep dorsal vein of the penis, anastomosing freely with the presymphyseal lymphatic plexus at the base of the penis and draining into both superficial and deep inguinal nodes. Because of this network, metastatic involvement of both inguinal regions is possible. Further drainage from the base of the penis occurs via channels following the femoral canals proximally into the external iliac and pelvic nodes.7–10 The pelvic nodes include the external iliac group, the internal iliac or hypogastric nodes, and the common iliac chain. The external iliac group—usually 8 to 10 nodes— lies anterior and medial to the external iliac vein. The hypogastric nodes—4 to 6 in number—are located
Chapter 45 Penectomy and Ilioinguinal Lymphadenectomy 729
Figure 45-8 Modified (Catalona) technique for inguinal lymphadenectomy. A, Inguinal incisions. B, Fascia lata exposed. C, Mobilization of lymphatic tissues around saphenous vein and femoral vessels. D, Superficial inguinal dissection has been completed. Note that the saphenous vein has been preserved. E, Limits of the modified (solid lines) and full or classical (Daseler) inguinal lymphadenectomy (dashed line) demonstrating the deep inguinal nodes and the lower extent of the external iliac nodes (node of Cloquet or Rosenmüller). F, Dissection of the deep inguinal nodes.
730
Part VII Urethra and Penis
around the hypogastric vein, and the common iliac chain—4 to 10 nodes—is located medial to or sometimes posterior to the common iliac vessels. Metastasis to the pelvic lymph nodes without involvement of the inguinal nodes is an extremely rare event and appears to be based on a single report by Schreiner.11 Such metastatic spread has not been observed in many recent studies.1,12–14 Therefore, in the setting of negative superficial and deep inguinal node dissections and a negative pelvic computed tomography (CT) scan, resection of the pelvic nodes is not required. Sentinel Node Biopsy The concept of the sentinel node was proposed by Cabanas, and postulates that there is a node or group of nodes—lying between the superficial external pudendal vein and the superficial epigastric vein—where the earliest metastasis from a penile tumor will occur consistently (see Figure 45-6).10,14 It was postulated that a negative sentinel node biopsy in the presence of clinically negative groins indicated that further inguinal dissection was unnecessary. Five-year survivals of 90% have been reported in this setting. However, subsequent reports of the development of metastases following a negative sentinel node biopsy have suggested that sentinel node biopsy may not be consistently reliable.15–17 Most surgeons treating penile cancer no longer use the sentinel node biopsy technique.18,19 In a patient where the sentinel node biopsy has been performed, the original biopsy incision should be excised with the lymphadenectomy specimen. Considerations in Inguinal and Ilioinguinal Lymphadenectomy Because lymph node enlargement and lymphangiitis due to infection of the primary tumor is common at the time of diagnosis, all patients with penile cancer should receive 4 to 6 weeks of antibiotic therapy before undergoing inguinal lymphadenectomy. At the completion of this course of treatment, the groins are carefully examined for the presence of abnormal nodes. Thirty percent to 60% of patients who present with penile cancer have palpable inguinal nodes, and following antibiotic therapy, half of these nodes will harbor metastases.19,20 When metastases are detected clinically in one groin, contralateral metastases will be present in 60% of cases due to the crossover of lymphatics at the base of the penis.6 Consequently, in this situation contralateral inguinal lymphadenectomy should be performed. It is generally accepted that patients with low-grade, noninvasive tumors and clinically negative inguinal nodes may safely be managed expectantly if close follow-up with careful groin examinations every 2 months for at
least 2 years can be assured.1,2,12 Unreliable patients or others who cannot be provided adequate follow-up are best served by prompt inguinal lymphadenectomy. Considerable debate has raged over the years regarding immediate or delayed lymphadenectomy in patients with clinically negative groins. There has been support for expectant management of patients with invasive (T2 to T4) lesions and no palpable inguinal adenopathy, with surgical intervention undertaken only when lymphadenopathy develops. This avoids the substantial morbidity associated with groin dissection. In those patients who later develop clinically positive nodes, delayed lymphadenectomy can provide cure in 30% to 50%.1,21–23 However, recent series support prophylactic inguinal lymphadenectomy in these cases, citing ultimate mortality rates of up to 20% in patients who are followed until they develop clinically positive nodes before undergoing inguinal exploration.1,2,6,12,21,23,24,25,26 It would appear that in these patients, the window of opportunity to provide a cure has been lost. In a patient with low-grade, low-stage tumor where unilateral groin metastases develop some time after surgical treatment of the primary, inguinal lymphadenectomy of only the involved groin is required.6 While this would seem to contradict recommendations outlined above, bilateral occult metastases present from diagnosis that become clinically apparent later should manifest themselves at about the same time. Consequently, the lack of clinically detectable nodes on the side contralateral to a late-developing groin metastasis suggests that the clinically negative nodes were not involved from the outset. Preoperative staging of the pelvic, common iliac, and paraaortic nodes with CT or magnetic resonance imaging (MRI) scan and, where indicated, with needle biopsy, is essential. While survival has followed resection of tumor limited to the external iliac nodes, no patient with common iliac or paraaortic metastases has survived.12,27 Fine needle aspiration of suspicious nodes in these areas may confirm metastatic tumor and thus avoid unnecessary surgery. The most important predictor of ultimate survival continues to be primary tumor stage—the presence or absence of nodal disease.2,28 Occasionally, palliative groin dissection may be required, even in the face of extensive regional or distant metastases. Lymphadenopathy, which threatens to erode through the inguinal skin or invade into the femoral vessels, may need to be removed to avoid pain, inguinal infection, or serious hemorrhage.29 Avoiding Complications from Inguinal Lymphadenectomy Despite the encouraging prognosis for many patients with inguinal metastases who undergo inguinal or ilioinguinal lymphadenectomy, there has been a long-standing
Chapter 45 Penectomy and Ilioinguinal Lymphadenectomy 731
reluctance on the part of surgeons to subject patients to this procedure because of the 30% to 50% incidence of major morbidity associated with it.22,25,28,30 Complications include lymphocele, substantial lower limb lymphedema, skin loss, and infection. Skin flap necrosis can be minimized by selecting the appropriate incision, by careful tissue handling, by careful attention to skin flap thickness with excision of ischemic flap margins, and by transposing the head of the sartorius muscle to cover the defect left over the femoral vessels. Use of intravenous fluorescein dye and a Woods’ lamp intraoperatively to assess viability of wound edges is a useful adjunct.31 Lower limb lymphedema can be reduced by careful attention to intraoperative ligation of lymphatics, by immobilization of the limb or limbs in the postoperative period, and by suction drainage of the lymphadenectomy site. Elastic support hose should be used in the immediate postoperative period and may be required long term in many patients. Wound infection can be minimized by intensive preoperative antibiotic therapy to reduce infection and inflammation from the primary and by the use of prophylactic antibiotics.30,32 Thrombotic problems may be avoided through the use of subcutaneous heparin in the perioperative period, particularly when the full classical inguinal and pelvic dissection is combined with prolonged bed rest postoperatively. Technique of Inguinal Lymphadenectomy Figure 45-7 shows the various incisions described for inguinal and ilioinguinal lymphadenectomy. Many surgeons prefer the oblique incision below and parallel to the inguinal crease because it maintains the integrity of the inguinal ligament, and because it preserves the cutaneous blood supply that runs parallel to the inguinal ligament (Figures 45-7A and D and 45-8A). If the patient has impalpable lymph nodes following antibiotic therapy but has histologically confirmed grade 2 or grade 3 invasive disease, a modified, somewhat limited inguinal lymphadenectomy as described by Catalona33 is performed. If bilateral palpable inguinal nodes persist, a full bilateral ilioinguinal lymphadenectomy, using the classical limits of dissection is undertaken. In the event one groin normalizes following antibiotic therapy but the other remains abnormal, a superficial inguinal dissection is performed on the normal side with frozen-section evaluation. If this is negative, a full ilioinguinal dissection is then performed on the contralateral abnormal side. Generally, pelvic node dissection is done through a low midline incision giving access to both right and left pelvic node groups (see Figure 45-7D). The dissection technique for this part of the operation is familiar to urologists, as it is similar to the technique used in bladder cancer staging, except that the dissection of the external iliac nodes is carried more distally under the inguinal
ligament to include all iliac and deep inguinal nodes there. If only one groin is involved, a unilateral pelvic node dissection may be done through an oblique low abdominal incision (Figure 45-7E) and may provide some diminished patient morbidity.18 Modified Inguinal Lymphadenectomy While some patients with clinically negative groins will have impalpable metastatic disease, many will not. This coupled with the morbidity associated with the classical inguinal lymphadenectomies described by Daseler and Baranofsky has made surgeons reluctant to subject patients to these procedures, even when tumor characteristics indicate that lymphadenectomy would be advisable.7,34 Catalona33 and Puras and Rivera35 have described modifications of the classical dissection that are aimed at reducing many of the unpleasant sequelae of the classical operation.33,35 All patients are treated with 4 to 6 weeks of oral broad-spectrum antibiotics following excision of the primary tumor. A clear liquid diet the day prior to surgery is prescribed, and the patient is given cleansing enemas the night before surgery. Antiembolism compressive stockings are used. The patient is placed in a supine position after spinal anesthesia is first administered. A Foley catheter is placed to straight drainage. The scrotum and penis are then retracted out of the field and draped off. The legs are then abducted and externally rotated to best expose the anteromedial thigh and groin. A pillow is placed beneath the knees for support. A 6- to 8-cm incision is then made 3 to 4 cm below the inguinal ligament and parallel to it (see Figure 45-8A). The incision is carried down to Scarpa’s fascia. Gentle sponge traction is used to separate the skin edges (Figure 45-8B). The subcutaneous tissue in Camper’s layer is carefully preserved, and meticulous handling of these tissues and the skin edges must be observed throughout. Stay sutures of 2-0 or 3-0 silk and skin hooks are helpful to avoid injuring the wound edges. The saphenous vein and its tributaries are identified, and the superficial areolar and node-bearing tissue is gently dissected off the vein downward to the fascia lata (Figure 45-8C). The venous branches emptying into the saphenous vein are carefully ligated and divided. The saphenous vein is preserved (Figure 45-8D). Large lymphatics and small venous branches must be carefully and meticulously ligated or fulgurated. The dissection is carried superiorly to approximately 2 cm above the inguinal ligament where it is carried down to the fascia of the external oblique muscle (Figure 45-8E). The dissection is carried inferiorly to about 4 cm below the incision. In Catalona’s operation, the lower limit of dissection is the lower border of the fossa ovalis (Figure 45-8F ). Other surgeons carry the dissection
732
Part VII Urethra and Penis
slightly lower, although there is not much superficial nodal tissue in this area. The specimen of superficial nodal tissue is oriented, labeled, and sent for frozensection evaluation. If the nodes are negative, the wound is thoroughly irrigated with sterile water and closed in layers, taking care to eliminate any potential spaces. A closed suction drainage system is placed (Figures 45-9C and 45-10F ) and remains for 5 to 7 days during that time the patient is maintained at complete bed rest. Classic Inguinal Lymphadenectomy (after Daseler) When known positive nodes are present, or when metastatic disease is confirmed by frozen section during a limited inguinal dissection, a classic radical inguinal lymphadenectomy is performed.9 An incision of 6 to 8 cm is made parallel to the inguinal ligament and about 3 to 4 cm inferior to it. The incision is carried down to
Scarpa’s fascia, and the saphenous vein is identified. This is ligated with 2-0 silk sutures and divided. The superficial nodal tissue is systematically mobilized, beginning in the superomedial quadrant, freeing the tissue towards the junction of the saphenous vein with the femoral vein at the fossa ovalis. The sentinel node tissue is identified and tagged with a suture. Dissection is extended above the inguinal ligament 2 cm, and the limits of the standard dissection, as outlined in Figure 45-4, are utilized. Next, the venous tributaries of the saphenous vein are meticulously ligated and divided, as well as any large lymphatics. The saphenous vein is carefully dissected down to the fossa ovalis and the junction with the femoral vein is identified, clamped, divided, and ligated. The fascia lata is opened and excised with all the nodal tissue superficial to it. This exposes the femoral sheath and Scarpa’s triangle. The lateral aspect of this dissection is the medial border of the sartorius, and the medial border of the adductor longus comprises the medial side.
Figure 45-9 Completed full classical lymphadenectomy. Note that the fascia lata has been more widely excised and that the saphenous vein has been divided. The proximal head of the sartorius muscle is transposed to cover the femoral vessels. Meticulous closure with suction drainage and complete bed rest for 4 or 5 days is essential to avoid wound complications. (See text for details.)
Chapter 45 Penectomy and Ilioinguinal Lymphadenectomy 733
The femoral sheath is opened from the inguinal ligament to the apex of the femoral triangle. Within the sheath are the femoral vein, the femoral artery lateral to it, and fatty areolar tissue containing the deep inguinal nodes medially (see Figure 45-5). The femoral nerve is lateral to the artery and is not encountered in the usual dissection. The vein is gently retracted laterally to allow dissection of tissue from the lateral and anterolateral aspect of the vein. Nodal and areolar tissue is then dissected from anterior to the artery and between the artery and vein (Figure 45-9A). The nodes are dissected to below the inguinal ligament to the node of Cloquet (or
Rosenmüller), the most proximal of the deep inguinal chain. One to 5 nodes are usually encountered. About 5 to 8 cm below the inguinal ligament, the profunda femoris artery arises on the lateral aspect of the femoral artery. This must be carefully dissected and preserved, especially if myocutaneous flap coverage may later be required. The wound is then irrigated carefully and careful attention is given to all bleeders and lymphatics. The sartorius muscle is separated sharply from its origin on the anterior superior iliac spine and mobilized medially to cover the now exposed femoral vessels (Figure 45-9B).34,36
Figure 45-10 Management of the ulcerated groin with vascular involvement. If required, a Gore-tex vascular graft is placed. Transposition of a myocutaneous flap based on the gracilis muscle is used to cover the inguinal defect. (See text for details.)
734
Part VII Urethra and Penis
Drainage using a closed suction catheter apparatus is placed, and the wound is carefully closed in layers. Several sutures are used to secure Camper’s fascia to the anterior aspect of the muscles to close potential space and discourage lymphocele formation (Figure 45-9C).35 The skin edges are carefully assessed, using intravenous fluorescein and the Woods’ lamp if necessary, and any questionably viable skin is excised. The wound is then meticulously closed in layers. The patient is maintained at complete bed rest with compressive stockings in place for 5 to 7 days. Subcutaneous heparin is given. The Foley catheter is discontinued after 24 to 48 hours. Closed suction is maintained for 5 days. Management of Enlarged or Ulcerated Nodes and Femoral Vessel Involvement SCC is characterized by aggressive local invasion into surrounding tissues. Large inguinal nodes, particularly when the patient presents for treatment late or after an extended period of neglect, will have invaded the overlying skin of the groin and may ulcerate through it in extreme cases (Figure 45-10A). Induration of the skin is suggestive of such local invasion. In this setting, the tumor is excised leaving a 2-cm margin of normal skin around the indurated or ulcerated area (Figure 45-10B). A radical ilioinguinal lymphadenectomy is performed, and all tumor is completely resected. In some instances, there may be involvement of the femoral vessels, particularly the vein. Resection of the anterior wall of the vein with reconstruction using a saphenous vein graft or Gore-tex patch may be required (Figure 45-10C and D).36 In some instances of severe involvement, the vein may be ligated and excised. Large skin defects may be closed with a tensor fascia lata or gracilis myocutaneous graft (Figure 45-10E).33,37,38 Such a graft may be based over the hip and swung medially and superiorly to cover a groin defect (Figure 45-10F). Again, all postoperative precautions recommended for the classical radical lymphadenectomy should be employed for patients undergoing this procedure. REFERENCES 1. Fraley EE, Zhang G, Manivel C, et al: The role of ilioinguinal lymphadenectomy and the significance of histological differentiation in the treatment of carcinoma of the penis. J Urol 1989; 142:1478 2. McDougal WS: Carcinoma of the penis: improved survival by early regional lymphadenectomy based on the histological grade and depth of invasion of the primary lesion. J Urol 1995; 154:1364. 3. Theodorescu D, Russo P, Zhang ZF, et al: Outcomes of initial surveillance of squamous cell carcinoma of the penis and negative nodes. J Urol 1996; 155:1626.
4. Mohs FE, Snow SN, Larson PO: Mohs micrographic surgery for penile tumors. Urol Clin North Am 1992; 19:291. 5. Bissada NK: Conservative extirpative treatment of cancer of the penis. Urol Clin North Am 1992; 19:283. 6. Ekstrom T, Edsmyr F: Cancer of the penis: a clinical study of 229 cases. Acta Chir Scand 1958; 115:25. 7. Daseler E, Anson B, Riemann A: Radical excision of the inguinal and iliac lymph nodes. Surg Gynec Obstet 1948; 87:679. 8. Rouviere HA: Anatomy of the Human Lymphatic System. Ann Arbor, MI, Edward Bros., 1938 [Tobias MJ (trans)]. 9. Dewire D, Lepor H: Anatomic considerations of the penis and its lymphatic drainage. Urol Clin North Am 1992; 19:211. 10. Riveros M, Garcia R, Cabanas RM: Lymphangiography of the dorsal lymphatics of the penis: technique and results. Cancer 1967; 20:2026. 11. Schreiner BF: Treatment of epithelioma of the penis based on a study of 60 cases. Radiology 1929; 13:353. 12. Srinivas V, Morse MJ, Herr HW, et al: Penile cancer: relation of extent of nodal metastases to survival. J Urol 1987; 137:880. 13. Horenblas S, Van Tinteren H, Dellemarre JFM, et al: Squamous cell carcinoma of the penis III. Treatment of regional lymph nodes. J Urol 1993; 149:492. 14. Cabanas RM: An approach for the treatment of penile carcinoma. Cancer 1977; 39:456. 15. Perinetti EP, Crane DC, Catalona WJ: Unreliability of sentinel node biopsy for staging penile carcinoma. J Urol 1980; 124:734. 16. Wespes E, Simon J, Schulman CC: Cabanas approach: Is sentinel lymph node biopsy reliable for staging penile carcinoma? Urology 1986; 28:278. 17. Fowler JE Jr: Sentinel node biopsy for staging penile cancer. Urology 1984; 23:352. 18. Fowler JE: Mastery of Surgery: Urology. Boston, MA, Little Brown Co., 1991. 19. Pettaway CA, Pisters LL, Colin PN, et al: Sentinel lymph node dissection for penile carcinoma: the MD Anderson Cancer Center experience. J Urol 1995; 154:1999. 20. Johnson DE, Lo RK: Management of regional lymph nodes in penile carcinoma: five-year results following therapeutic groin dissections. Urology 1986; 28:308. 21. Catalona WJ: Role of lymphadenectomy in carcinoma of the penis. Urol Clin North Am 1980; 7:85. 22. Narayana AS, Olney LE, Loening SA, et al: Carcinoma of the penis: analysis of 229 cases. Cancer 1982; 49:2185. 23. Lesser JH, Schwarz H II: External genital carcinoma: results of treatment at Ellis Fischel State Cancer Hospital. Cancer 1955; 8:1021. 24. McDougal WS, Kirchner FK Jr, Edwards RH, et al: Treatment of carcinoma of the penis: The case for primary lymphadenectomy. J Urol 1986; 136:38. 25. Beggs JH, Spratt JS Jr: Epidermoid carcinoma of the penis. J Urol 1964; 91:166. 26. Fossa SD, Hall KS, Johanssen MB: Carcinoma of the penis: experience at the Norwegian Radium Hospital: 1974–1985. Eur Urol 1987; 13:372.
Chapter 45 Penectomy and Ilioinguinal Lymphadenectomy 735 27. Ornellas AA, Seixas AL, Morota A, et al: Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol 1994; 151:1244. 28. deKernion JB, Tynbery P, Persky L, et al: Carcinoma of the penis. Cancer 1973; 32:1256. 29. Ferrigni RG, Novicki DE: Complications of lymphadenectomy in urologic surgery. Atlas Urol Clin North Am 1995; 3:105. 30. Herr HW: Surgery of penile and urethral cancer. In Walsh PC, Retik AB, Stamey TA, Vaughan ED Jr (eds): Campbell’s Urology, 6th edition. Philadelphia, WB Saunders, 1992. 31. Smith JA, Middleton RG: The use of fluorescein in radical inguinal lymphadenectomy. J Urol 1979; 122:754. 32. Lynch DF, Schellhammer PF: Partial penectomy, total penectomy, and radical inguinal lymphadenectomy. In
33.
34.
35. 36. 37. 38.
Krane RJ, Siroky MB, Fitzpatrick JM (eds): Operative Urology. New York, Churchill Livingstone, 2000. Catalona WJ: Modified inguinal lymphadenectomy for carcinoma of the penis with preservation of the saphenous veins: technique and preliminary results. J Urol 1988; 140:306. Spratt JS Jr, Shieber W, Dillard BM: Anatomy and Surgical Techniques of Groin Dissection. St Louis, Mosby, 1965. Puras A, Rivera J: Inguinal and pelvic lymphadenectomy for penile cancer. Atlas Urol Clin North Am 1995; 3:81. Baranofsky ID: Technique of inguinal node dissection. Surgery 1948; 24:555. Hill HL, Nahai F, Vasconez LO: The tensor fascia lata myocutaneous free flap. Plast Reconstr Surg 1978; 61:517. Staubitz WJ, Melbourne HL, Oberkircher OJ: Carcinoma of the penis. Cancer 1955; 8:371.
C H A P T E R
46 Neuroblastoma Michael C. Carr, MD, PhD, and Michael E. Mitchell, MD
Neuroblastoma is the second most common solid tumor in infants and children. Virchow,1 in 1864, was the first to speculate that its origin was neural, and he considered it a glioma. Marchand, in 1891,2 noted the histologic similarities between neuroblastoma and developing sympathetic ganglia. Following Wright’s use of the term “neuroblastoma” in 1910, there has been little debate with regard to origin of the tumor. Herxheimer3 demonstrated that fibrils in neuroblastoma stained with a specific neural silver stain helping establish the true origin of this tumor. There was little published in the literature earlier this century, with Blacklock4 noting only 116 cases in the literature, to which he added 18 of his own. At that time, neuroblastoma was fourth in order of frequency of malignant tumors in children. The number of cases described increased to 623 by 1953,5 and today it remains the fourth most common malignancy in childhood, being less common than leukemia, brain tumors, and lymphoma. Cushing and Wolbach6 reported for the first time a transformation of neuroblastoma into benign ganglioneuroma laying the foundation for a greater understanding of its biologic variability. Later descriptions noted that this event generally occurred in infants <6 months of age. Beckwith and Perrin7 noted microscopic foci of neuroblastoma cells in the adrenal glands in a number of infants under 3 months of age who died from other causes. These were termed “neuroblastoma in situ,” and were estimated to occur approximately 40 times more frequently than the number of neuroblastoma cases clinically diagnosed. Recession of these foci appeared to be complete after 3 months of age. Biochemical activity associated with neuroblastoma was initially noted due to elevated levels of urinary pressor amines.8 It has subsequently been recognized that elevated levels of norepinephrine, its precursors and metabolites occurs in patients with this tumor.
ETIOLOGY Neuroblastoma develops from neural crest cells in the embryo. These cells give rise to sympathetic neuroblasts, which are found in the adrenal medulla, autonomic ganglia, and peripheral nerve sheaths. Other tumors that can arise from these cells include ganglioneuroma and ganglioneuroblastoma. The former may cause considerable morbidity secondary to spread to contiguous organs but does not metastasize. The latter is known to metastasize about 20% of the time and has greater malignant potential than ganglioneuroma. Knudson and Strong,9 noting the apparent genetic influence, suggested that 20% of cases arise in children predisposed to the tumor by a dominant transmittable mutation. Later work suggested that familial cases result from a prezygotic mutation and that nonfamilial cases result from a postzygotic somatic mutation. Neuroblastomas are characterized cytogenetically by deletion of the short arm of chromosome 1, doubleminute chromatin bodies (dmins), and homogeneously staining regions (HSRs).10,11 The latter two abnormalities reflect gene amplification, whereas the former may represent deletion of a tumor suppressor gene. No other specific karyotypic abnormalities have been detected thus far. Flow cytometry of DNA content provides a way of measuring total DNA content, which correlates with the modal chromosome number. Determination of the DNA index (DI) of neuroblastomas from infants provides important information that may be predictive of response to particular chemotherapeutic regimens, as well as outcome.12–14 Tumors with “hyperdiploid” DNA content (DI = 1) are more likely to have lower stages of disease and to respond to cyclophosphamide and doxorubicin, whereas those with a “diploid” DNA content (DI = 1) are more likely to have advanced stages of
739
740
Part VIII Pediatric Malignancies
disease and do not respond to this combination.15 This analysis provides no information about specific chromosome rearrangements (deletions, translocation, or gene amplification) but does correlate with biologic behavior. The discovery of extrachromosomal dmins and chromosomally integrated HSRs is a cytogenetic manifestation of gene amplification.16,17 The region amplified is derived from the distal short arm of chromosome 2, containing the proto-oncogene N-myc. Brodeur et al.18 have demonstrated that N-myc amplification occurs in 25% to 30% of primary neuroblastomas from untreated patients, and amplification is associated primarily with advanced stages of disease. Subsequent studies have shown that N-myc amplification was associated with rapid tumor progression and a poor prognosis. Amplification was found in only 5% to 10% of patients with low stage of disease or stage IV-S but 30% to 40% of advanced disease patients.19 It is almost always present at the time of diagnosis and, thus, appears to be an intrinsic biologic property in a distinct subset with a poor prognosis.20 There is a correlation between N-myc copy number and expression, and tumors with amplification expressed Nmyc at much higher levels than are seen in tumors without amplification. Finally, there is heterogeneity in the level of expression among the tumors that have a singlecopy of N-myc, but higher expressing single-copy tumors do not appear to be a particularly aggressive subset.21,22 Deletions of the short arm of chromosome 1 are found in 70% to 80% of the near-diploid tumors that have been karyotyped. This cytogenetic finding is commonly associated with more advanced stages of disease, whereas tumors from patients with lower stages are more likely to be hyperdiploid or triploid with very few structural rearrangements. The deletions of chromosome 1 are variable but generally map to a region (1p36) that may contain a suppressor gene important in malignant transformation or progression. Recent molecular studies have shown a strong correlation between loss of heterozygosity (LOH) for chromosome 1p and N-myc amplification, suggesting that these two events may be related.23 An allelic loss on the long arm of chromosome 14 also has been noted suggesting that there may be another suppressor gene involved in the pathogenesis of neuroblastomas.
first year of life and another quarter between 1 and 2 years of age. This is a younger age of presentation than that for Wilms’ tumor. Unlike other childhood tumors, a low incidence of associated congenital anomalies exists. However, brain and skull defects have been noted in 2% of patients with neuroblastoma.26 An association with neurofibromatosis and Hirschbrung’s disease has been noted.27 PATHOLOGY Arising from primitive, pleuripotential sympathetic cells (sympathogonia) derived from neural crest, neuroblastomas are found in a variety of locations. The adrenal medulla or cells in the adjacent retroperitoneal tissues on the posterior abdominal wall account for 50% to 80% of neoplasms in most reported series. The second most common location is within the posterior mediastinum usually in paravertebral sites. The remaining neoplasms occur in derivatives of the neural crest within the pelvis, cervical region, lower abdominal sympathetic chain, rarely within the posterior cranial fossa, or other locations. Macroscopically, the growths are lobular, soft in consistency, and weigh between 80 and 150 g. The cut surface is red-gray in color, and areas of hemorrhage and necrosis may be obvious as the tumor increases in size. Calcification is not infrequent and this can help in the radiologic localization (Figure 46-1). Histologically, the cells are small and dark like lymphocytes and frequently are arranged in masses without any true pattern. It is one of the “small blue round cell” tumors of childhood (e.g., lymphomas, neuroectodermal tumor, and rhabdomyosarcoma). In characteristic lesions,
INCIDENCE Neuroblastoma accounts for 8% to 10% of all childhood tumors and is the most common malignant tumor of infancy. In the United States the incidence is 10.5 per million per year in white children and 8.8 per million per year in black children <15 years of age.24,25 Male predominance is noted but is slight, 1.1 to 1. The incidence is underestimated because of the occurrence of spontaneous regression of neuroblastoma in situ. Approximately one-third of cases are diagnosed in the
Figure 46-1 Typical adrenal neuroblastoma with areas of hemorrhage and necrosis. Tumor encircles aorta (straight arrow) with kidney seen at left (curved arrow). (Courtesy Dr. Kathleen Patterson, Seattle, WA.)
Chapter 46 Neuroblastoma 741
rosettes are formed when the tumor cells occupy the periphery and the young nerve fibrils grow into the center of each rosette (Figure 46-2). The fully differentiated, and benign, counterpart of neuroblastoma is the ganglioneuroma, composed principally of mature ganglia, neuropil, and schwannian cells. Ganglioneuroblastoma defines a heterogenous group of tumors with histopathologic features reflecting the spectrum of maturation of neuroblastoma and ganglioneuroma. These may be either focal or diffuse, depending on the pattern seen, but diffuse ganglioneuroblastoma is associated with less aggressive behavior. Multiple sections should be examined to categorize these tumors accurately because viability and histopathologic features are variable. Hematoxylin–eosin staining and light microscopy is often not enough to distinguish these tumors from other “small round blue cell” tumors of childhood. Immunohistochemical techniques and electron microscopy are helpful additions to light microscopy. Monoclonal antibodies recognizing neural filaments, synaptophysin, and neuron-specific enolase will stain neuroblastoma.28 Electron microscopy visualizes the dense core, membrane-bound neural secretory granules in addition to microfilaments, and parallel arrays of microtubules within the neuropil (Figure 46-3).29 A histology-based prognostic classification that has gained wide-spread acceptance was developed by
Shimada et al.30 The system is formulated around patient age and the following histologic features: the presence or absence of schwannian stroma; the degree of differentiation; the mitosis-karyorrhexis index (MKI). A retrospective evaluation of the Shimada’s method in 295 patients treated by the Children’s Cancer Study Group (CCSG) identified favorable and unfavorable patient subsets. The histologic patterns were independently predictive of outcome whereas stage was prognostically less important than histologic grade.31,32 A simplified system has been devised, which predicts a favorable outlook based on presence of calcification and a low mitotic rate (=10 mitoses/10 high power field).33 A grading system was developed for finding tumors with both features (grade 1), with the presence of only one of these features (grade 2), or the absence of both features (grade 3). When these grades were combined with age (≤1 year or >1 year) and surgicopathologic staging, low- and high-risk groups emerged, which were clearly correlated with the Shimada’s favorable and unfavorable groups. The result of this analysis has led to the formation of the International Neuroblastoma Pathology Classification System. A recent study has analyzed the morphologic features of neuroblastoma (schwannian stroma-poor tumors) in clinically favorable and unfavorable groups. This study reaffirmed the prognostic impact of Shimada’s criteria and demonstrated that additional morphologic features, such as prominent nucleoli and
Figure 46-2 Histologically, the cells comprising neuroblastoma are small with darkly staining nuclei and inconspicuous cytoplasm. Rosettes composed of tumor cells surround neuropil material (arrows). (Courtesy Dr. Kathleen Patterson, Seattle, WA.)
742
Part VIII Pediatric Malignancies
Figure 46-3 Electron microscopy showing dense core neural secretory granules (straight arrows) with microtubules (curved arrow) characteristic of neuroblastoma. (Courtesy Dr. Kathleen Patterson, Seattle, WA.)
undifferentiated and poorly differentiated neuroblasts, cellularity and nuclear size provide additional critical relevance partly independent of the patient’s age at diagnosis.34 The analysis of these tumors at the cytogenetic and molecular level revealed ploidy changes, amplification of the oncogene MYCN, deletions of chromosome 1p, gains of chromosome arm 17q, and deletions of 11q. It was demonstrated that in infants, DNA content was significantly linked to tumor stage, with advanced stages seen in diploid tumors. Hyperdiploidy is mainly observed in low-stage tumors of younger patients with a favorable clinical outcome, whereas diploid tumors are associated with advanced tumor growth and significantly reduced survival probability.35 Approximately 35% of all neuroblastomas have 1p deletions of variable lengths36 with poor outcomes seen in patients with large 1p deletions than patients with short or interstitial deletions.37 Amplified MYCN is one of the most prominent genomic abnormalities of neuroblastoma, being prototypic for the significance of protooncogene amplification and tumor agenesis. Amplified MYCN correlates with advanced-stage disease; in the absence of amplified MYCN, overall survival is approximately 60% over a 5-year period, but only 10% of patients survived a 1-year period when MYCN was amplified at more than 10 copies.38 The most frequent genomic alteration in neuroblastoma is a gain of 17q, seen in about 50% of tumors. Such a gain was significantly associated with tumor progres-
sion.39 A recent collaborative study from 6 European centers identified 17q gain as the most powerful prognostic factor in survival and multivariant analysis with other clinical and tumor genetic parameters, including 1p deletion and MYCN amplification.40 PRESENTATION Neuroblastoma most often presents as an abdominal mass (65% discovered at the time of routine medical examination or by the parents). Infants tend to have more thoracic and cervical primary tumors. The tumor is usually asymmetric and located in the supraumbilical region, the hypochondrium, or the flank often extending beyond the midline. Tumors which arise from the adrenal or suprarenal sympathetic chain are more lateral whereas the medially located tumors may arise from the periaortic sympathetic chain. These tumors may then grow through the intervertebral foramina and produce spinal cord compression. Neuroblastomas can arise from anywhere along the sympathetic chain; about 14% arise in the chest in infants over 1 year of age, but only 0.5% in the cervical region. Tumors arising from the cervical sympathetic ganglion may produce Horner’s syndrome. In about 1% of patients, a primary tumor cannot be found. The majority of children with neuroblastoma are diagnosed by the age of 5 years, and it rarely occurs after age 10. Metastatic extension of neuroblastoma occurs in two patterns, lymphatic and hematogenous. Approximately
Chapter 46 Neuroblastoma 743
70% of all patients will present with metastatic disease at diagnosis. Regional lymph node metastasis will be noted in 35% of patients with apparently localized disease. Tumor spread to lymph nodes outside the cavity of origin is considered to be disseminated disease. These children may have a better prognosis if no other metastatic disease is found.41 Hematogenous metastasis occurs most often to bone marrow, bone, liver, and skin. Rarely, disease may spread to lung and brain parenchyma, usually as a manifestation of relapsing- or end-stage disease. The proportion of patients presenting with localized, regional, or metastatic disease is age dependent. The incidence for localized tumors, regional lymph node spread, and disseminated disease is 39%, 18%, and 25%, respectively, in infants (18% with stage IV-S) compared to 19%, 13%, and 68%, respectively, in older patients. Several classical signs and symptoms have been associated with metastatic neuroblastoma. Proptosis and periorbital ecchymosis are frequent and result from retrobulbar and orbital infiltration with tumor. Hutchinson syndrome describes widespread bone marrow and bone disease, causing bone pain, limping, and irritability in the younger child. Skin involvement is seen exclusively in infants with Evan’s stage IV-S tumors42 and is characterized by nontender, bluish subcutaneous nodules. Disseminated disease may manifest as failure to thrive and fever, the latter observed most often in the presence of bone metastasis. These are usually seen as lytic lesions on skeletal radiographs. Rarely, patients may present with the complication of catecholamine secretion by the neuroblastoma, which may include headache, hypertension, palpitations, and diaphoresis. The tumor may also lead to watery diarrhea secondary to vasoactive intestinal polypeptide.
DIAGNOSTIC EVALUATION Minimum criteria for establishing the diagnosis of neuroblastoma include43: (1) an unequivocal pathologic diagnosis is made from tumor tissue by standard methods, including immunohistology or electron microscopy if necessary; or (2) bone marrow contains unequivocal tumor cells (i.e., syncytia) and urine contains increased urinary catecholamine metabolites (SD > 3 above the mean, corrected for age). Since neuroblastoma often secretes catecholamines, urinary levels of vanillylmandelic acid (VMA) or homovanillic acid (HMA) should be elevated.44 A 24-hour urine was previously recommended, but normalizing VMA and HMA excretion to the milligram creatinine in the sample makes a timed collection unnecessary and it avoids false negative results due to dilution. Table 46-1 outlines the minimum testing to define the clinical stage of disease.43 The evaluation often begins with an abnormal ultrasound, which demonstrates the mass, distinguishing a solid mass from a hydronephrotic kidney. It can also demonstrate lymph node enlargement, tumor extension, and liver metastasis, although the CT or magnetic resonance imaging provide greater sensitivity (Figures 46-4 to 46-6). Most centers in the U.S. rely on 99mTc-diphosphonate scintigraphy for the evaluation of bone disease. Because of the biochemical activity of neuroblastoma, meta-iodobenzylguinidine (MIBG) scintigraphy becomes an attractive tool.45 The compound is taken up by catecholaminergic cells, which includes most neuroblastomas. Thus, it becomes a very specific and sensitive method of assessing the primary tumor and focal metastatic disease. There exists great variability in the number of bone marrow aspirates or biopsies done at different institutions.
Table 46-1 Minimum Recommended Tests for Determining Extent of Disease36 Tumor Site
Tests
Primary
Three-dimensional measurement of tumor by CT scan or MR or ultrasound
Metastases
Bilateral posterior iliac bone marrow aspirates and core biopsies (4 adequate specimens necessary to exclude tumor) Bone radiographs and either scintigraphy by 99mTc-diphosphonate or 131I-(or 123I-) meta-iodobenzylguanidine (MIBG) or both Abdominal and liver imaging by CT scan or MR or ultrasound Chest radiograph (AP and lateral) and chest CT scan
Markers
Quantitative urinary catecholamine metabolites (VMA and HVA)
Note: For evaluation of bone metastases, 99mTc-diphosphonate scintigraphy is recommended for all patients and is essential if MIBG scintigraphy is negative in bone. (From Brodeur, GM, Castleberry, RP: Neuroblastoma. In Pizzo PA, Poplack DG (eds): Principles and Practice of Pediatric Oncology, 2nd edition, p 750. Philadelphia, J.B. Lippincott, 1993.)
744
Part VIII Pediatric Malignancies
Recent data support the increased yield of bone marrow biopsies versus aspirates. The international conferees on neuroblastoma staging recommended two bone marrow aspirates and two biopsies, that is one of each from each of the posterior iliac crests.43 Core biopsy specimens must contain at least 1 cm of marrow (excluding cartilage). STAGING The current, favored staging system is based on clinical, radiographic, and surgical evaluation of children with neuroblastoma. The International Neuroblastoma Staging System (INSS) allows for uniformity in staging of patients, facilitating clinical trials, and biologic studies around the world (Table 46-2).43 The Children’s Oncology Group (COG) risk-based schema is based on three factors: patient age at diagnosis, certain biologic characteristics of the patient’s neuroblastoma tumor, and the stage of the tumor as defined by INSS.
Figure 46-4 CT scan of 4-year old with IV contrast showing right adrenal neuroblastoma with diffuse calcification, seen adjacent to liver. A, aorta; K, left kidney. (Courtesy Dr. Edward Weinberger, Seattle, WA.)
PROGNOSTIC CONSIDERATIONS The COG is investigating a risk-based neuroblastoma treatment plan that assigns risk-based on patients’ age, INSS stage, and tumor biology (Table 46-3).46 The treatment plan is based on the risk group, with low-, intermediate-, and high-risk groups having an overall survival of >90%, 70% to 90%, and >30%, respectively, 3 years after diagnosis. The overall prognosis of patients with stages I, II, and IV-S is between 75% and 90%, while those with stage III and IV have only a 10% to 30% 2-year diseasefree survival. Age is a sufficient prognostic variable, with the outcome of infants under 1 year of age being substantially better than those >1 year. Origin of the tumor is another important variable, as patients with adrenal primaries have poorer outcomes than those with other origins. A number of biologic variables have been assessed that may help predict the ultimate outcome for a patient. Hyperdiploid tumor DNA is associated with a favorable prognosis,47 while N-myc amplification is associated with a poor prognosis regardless of patient age.48–50 A high proportion of proliferating tumor cells may independently predict poor prognosis.51 Expression of the gene encoding one of the high-affinity neurotrophin receptors (TRK-A) is associated with good prognosis tumors.52 Increased levels of telomerase RNA,53 elevated serum ferritin,54 elevated serum lactate dehydrogenase,55 and the presence of neuroblastoma cells in bone marrow during or after chemotherapy are each associated with poor prognosis.55–58 TREATMENT As with most solid malignant neoplasms, complete surgical removal is the most effective form of therapy. Surgery
Figure 46-5 CT scan of 1-year old with IV contrast showing extensive right adrenal neuroblastoma invading into right kidney, encircling aorta (A) and extending beyond the midline. (Courtesy Dr. Edward Weinberger, Seattle, WA.)
is also used to make a diagnosis, provide tissue for biologic studies, surgically stage the tumor, and to attempt excision of the tumor. Delayed primary or second-look surgery determines the response to therapy. Based on the INSS criteria, the operative protocol incorporates the following: (1) The resectibility of primary or metastatic tumor should be determined in light of tumor location, mobility, relationship to major vessels, ability to control blood supply, and overall prognosis of patient. Modern chemotherapy effectively consolidates and decreases the size of primary tumors and large lymph
Chapter 46 Neuroblastoma 745
Figure 46-6 A, Chest x-ray with subtle right paravertebral curvilinear stripe (arrowheads) raising possibility of right paravertebral mass. B and C, Coronal T1-weighted MRI images. B represents more posterior view showing large mass between right kidney and vertebral bodies. C demonstrates multilobulated right paravertebral mass extending through three contiguous neural foramina into spinal canal with effacement of spinal cord. (Courtesy Dr. Edward Weinberger, Seattle, WA.)
746
Part VIII Pediatric Malignancies
Table 46-2 International Neuroblastoma Staging System (INSS) Stage I
Localized tumor confined to the area of origin; complete gross excision, with or without microscopic residual disease; identifiable ipsilateral and contralateral lymph nodes negative microscopically
Stage IIA
Unilateral tumor with incomplete gross excision; identifiable ipsilateral and contralateral lymph nodes negative microscopically
Stage IIB
Unilateral tumor with complete or incomplete gross excision; with positive ipsilateral regional lymph nodes; identifiable contralateral lymph nodes negative microscopically
Stage III
Tumor infiltrating across the midline with or without regional lymph node involvement; or, unilateral tumor with contralateral regional lymph node involvement; or, midline tumor with bilateral lymph node involvement
Stage IV
Dissemination of tumor to distant lymph nodes, bone, bone marrow, liver, and/or other organs (except as defined in stage IV-S)
Stage IV-S
Localized primary tumor as defined for stage 1 or stage 2 with dissemination limited to liver, skin, and/or bone marrow (limited to infants <1 year of age). Marrow involvement should be minimal (<10% of total nucleated cells identified as malignant by bone biopsy or dry bone marrow aspirate). More extensive bone marrow involvement would be considered stage 4 disease
node metastasis. Therefore, there is little place for the less predictable surgical assaults of previous years. (2) Nonadherent, intracavitary lymph nodes should be sampled. Gross examination during surgery may be inaccurate for detecting or ruling out lymph node metastasis in up to 25% of cases.59 Lymph nodes adherent to and removed en bloc with the primary tumor do not alter the outcome of the patient.60 Ideally, lymph nodes superior and inferior to the primary tumor should be sought and sampled, and location documented. Lymph node sampling in patients with high thoracic, low cervical, or large abdominal primary tumors that are unresectable may be problematic. Other prognostic factors may be utilized in these situations, and thus, the value of additional information regarding lymph node involvement is questionable. (3) Routine biopsy of the liver in situations involving an abdominal neuroblastoma without evidence of metastatic disease has been advocated. This practice has come into question, particularly due to the sensitivity of clinical staging by CT or MR. Until the INSS criteria for staging are prospectively studied in all age groups, routine biopsy of liver during initial surgery in patients with primary abdominal tumors remains appropriate. The surgical approach to neuroblastoma is best regarded as a vascular-type procedure. Neuroblastoma rarely invades the tunica media of large blood vessels but can involve the tunica adventitia. The appropriate plane of dissection usually exists beneath the tunica adventitia. Following partial exposure of the circumference of each vessel, the tumor is segmentally removed as complete vessel dissection occurs.60 The approach to an extensive left-sided abdominal tumor or preaortic tumor is through a long, supraumbilical, transverse incision. The left colon is reflected medi-
ally, followed by mobilizing of spleen, stomach, and pancreas. This is best accomplished by maintaining the plane between the mesocolon and Gerota’s fascia. The viscera are reflected as far as the midline and placed in an intestinal bag, so that the tumor is exposed. The first stage of the operation involves exposure of the arterial wall from below the distal limit of the tumor to just above the proximal limit of the tumor. The origin of the main visceral arteries are often noted at this time. Further dissection focuses on the distal extent of the tumor, along the external or common iliac artery. Surgeon and assistant each pick up the adventitia, allowing longitudinal dissection along the middle of the vessel. The subadventitial plane has been entered, establishing the plane for the remainder of the operation. Proximal dissection proceeds to the tumor, incising along the middle of the vessel down to tunica media. Bipolar cautery is of considerable benefit. Sympathetic nerves on the left will be transected, and an attempt should be made to preserve the nerves on the right. The aortic bifurcation is encountered and the dissection proceeds to the inferior mesenteric artery. If there is a large bulk of tumor, retrograde dissection may be helpful. Further dissection cephalad leads to the origin of the gonadal arteries and left renal vein crossing the aorta at the same level. Considerable tumor bulk can be encountered in this area. It is usually possible to identify the vein before entering the lumen. Dissection of 4 to 5 cm of vein will allow for retraction and adequate dissection beneath the aorta. Aortic dissection may be difficult at this level due to tumor adherence and the two gonadal arteries. Dividing the gonadal arteries and maintenance of the appropriate plane of dissection allow for safe dissection. Cephalad to the vein is the origin of the left renal
Chapter 46 Neuroblastoma 747
Table 46-3 Children’s Oncology Group Neuroblastoma Risk Group Assignment Schema INSS Stage
Age
MYCN
Shimada’s Histology
DNA Ploidy
Risk Group
1
0–21 years
Any
Any
Any
Low
2A/2B*
<365 days
Any
Any
Any
Low
≥365 days to 21 years
NonAmp
Any
—
Low
≥365 days to 21 years
Amp
Fav
—
Low
≥365 days to 21 years
Amp
Unfav
—
High
<365 days
NonAmp
Any
Any
Intermediate
<365 days
Amp
Any
Any
High
≥365 days to 21 years
NonAmp
Fav
—
Intermediate
≥365 days to 21 years
NonAmp
Unfav
—
High
≥365 days to 21 years
Amp
Any
—
High
<365 days
NonAmp
Any
Any
Intermediate
<365 days
Amp
Any
Any
High
≥365 days to 21 years
Any
Any
—
High
<365 days
NonAmp
Fav
>1
Low
<365 days
NonAmp
Any
=1
Intermediate
<365 days
NonAmp
Unfav
Any
Intermediate
<365 days
Amp
Any
Any
High
3†
4†
IV-S‡
Biology defined by
MYCN status: amplified (Amp) versus nonamplified (NonAmp) Shimada’s histopathology: favorable (Fav) versus unfavorable (Unfav) DNA Ploidy: DI ≥ 1; hypodiploid tumors (with DI <1) will be treated as a tumor with a DI > 1 (DI < 1 [hypodiploid] to be considered favorable ploidy)
*INSS 2A/2B symptomatic patients with spinal cord compression, neurologic deficits or other symptoms will be treated on the LOW RISK NB Study with immediate chemotherapy for 4 cycles (Course 1). †INSS 3 or 4 patients with clinical symptoms as above (or in the investigator’s opinion it is in the best interest of the patient) will receive immediate chemotherapy. ‡INSS IV-S infants with favorable biology and clinical symptoms will be treated on the LOW RISK NB study with immediate chemotherapy until asymptomatic (2 to 4 cycles). Clinical symptoms defined as: respiratory distress with or without hepatomegaly or cord compression and neurologic deficit or IVC compression and renal ischemia; or genitourinary obstruction; or gastrointestinal obstruction and vomiting; or coagulopathy with significant clinical hemorrhage unresponsive to replacement therapy.
artery and just proximal to this is the superior mesenteric artery (SMA). Thus, at the level of the renal artery, the plane of dissection should become perpendicular to the anterolateral wall of the artery rather than directly anteriorly. This plane is then maintained as far as the diaphragm, where normal tissue is usually encountered. With clearing of the anterior surface of the proximal aorta, the origins of the celiac artery and SMA are identified. These vessels are exposed and cleared, with the
SMA usually being the easier vessel to dissect free. Once this artery is mobilized, the celiac artery and its branches are given attention. This area can be difficult but by dissecting as before and maintaining the subadventitial plane, success is achieved. Frequently, two diaphragmatic branches arise from the trunk of the celiac artery or just proximally from the aorta, and these are divided. The left gastric artery may also be sacrified without concern. Once the two main intestinal arteries are immobilized,
748
Part VIII Pediatric Malignancies
the right side of the aorta may be exposed with the right renal artery next being encountered. The tumor at this location may be attached posteriorly to the crus of the hemidiaphragm. Once its main attachments are divided, the tumor is removed. The tumor that has been attached between the celiac artery and SMA usually adheres to the posterior surface of the pancreas as well. In dissecting this from the pancreas, the termination of the splenic vein and its junction with superior mesenteric vein are exposed. It is uncommon to see dense adherence in this region.60 Following the removal of the preaortic tumor proximally, the left renal artery should be exposed and dissected free. This can be fairly tedious but is possible. When tumor is deep within the renal hilum, nephrectomy may be necessary. Once the renal artery is displayed, the primary tumor can be mobilized and excised. The remaining areas to be cleared lie below the level of the renal vessels and posterior to the length of the aorta. These areas do not present any unusual difficulty. As many as possible of the lumbar arteries should be preserved, but no untoward consequences have followed division of up to 5 arteries.60 Finally, if there is considerable tumor bulk posterior to the inferior venae cava, reflection of the ascending colon may be necessary to achieve complete tumor clearance. In general, thoracic procedures become more an exercise of rib clearance rather than a vascular-type operation. Pelvic tumors may provide some difficulty with regard to access. An extended Pfannenstiel-type incision, altered in that the recti are detached from the pubis, provides optimal exposure, but access may still be difficult. The anatomy is complicated by the presence of nerves of the sacral plexus, particularly with formal dissection of the internal iliac vessels. Once again, formal systematic and planned exposure of the important structures before tumor removal is of great value.60 Surgical complication rates in neuroblastoma range from 5% to 25%.61,62 The incidence increases in instances of aggressive abdominal resection of tumors at diagnosis. Reported complications include nephrectomy, hemorrhage, postoperative intussusception or adhesions, injury to renal vessels with subsequent renal failure, and neurologic defects, such as Horner’s syndrome. Avoidance of surgical risk in infants who have better survival is recommended. Downstaging of the tumor with chemotherapy followed by surgical resection is the favored approach. Chemotherapy The mainstay of management in neuroblastoma is chemotherapy. A number of effective chemotherapeutic agents have been identified that include cyclophosphamide, cisplatin, doxorubicin, vincristine, etoposide, and teniposide, which alone yield complete response or
partial response rates ranging from 34% to 45%. A combination of agents are used that take advantage of drug synergism, mechanisms of cytotoxicity, and differences in side effects. Cyclophosphamide and cisplatin are noncell cycle-specific agents often used in combination with cell cycle-dependent drugs (doxorubicin, teniposide). Using these combinations has resulted in improved response rates in children with advanced neuroblastoma. The chemotherapy is given in phases, which include induction, consolidation, and maintenance phases. The COG risk stratification schema is currently being utilized in the treatment of most patients with neuroblastoma in North America. This risk-based neuroblastoma treatment plan assigns each patient to a low-, intermediate-, or high-risk group. Thus, in patients without metastatic disease, initial surgery is performed to establish the diagnosis, to resect as much of the primary tumor as safely possible, to accurately stage the disease via sampling of regional lymph nodes that are not adherent to the tumor, and to obtain adequate tissue for biologic studies. Treatment of Low Risk Disease Treatment for patients categorized as low risk (Table 46-3) consists most commonly of surgery alone but in some cases surgery combined with 6 to 12 weeks of chemotherapy. Chemotherapy consists of carboplatin, cyclophosphamide, doxorubicin, and etoposide. Clearly the dose of each agent is kept low in order to minimize permanent injury from the chemotherapy regimen.63 Treatment of Intermediate Risk Disease Patients categorized as intermediate risk (Table 46-3) are treated with surgery and 12 to 24 weeks of the same chemotherapy regimen as described above.64 Treatment of High Risk Disease In contrast, patients categorized as high risk (Table 46-3) are generally treated with aggressive multiagent chemotherapy comprising very high doses of carboplatin, cyclophosphamide, doxorubicin, etoposide, and ifosphamide with high-dose cisplatin. After a response to chemotherapy, resection of the primary tumor should be attempted, followed by myeloablative chemotherapy, sometimes total-body irradiation, and autologous stem cell transplantation. Irradiation of residual tumor and original sites of metastasis is often performed before, during or after myeloablative therapy. After recovery, patients are treated with oral 13-cis-retinoic acid for 6 months. Both myeloablative therapy and retinoic acid improve outcome in patients categorized as high risk.65 See Table 46-4 for a summary.
Chapter 46 Neuroblastoma 749
Table 46-4 Disease-Free Survival (2 years) Based on Risk Category and Age Risk Category
Low
Intermediate
High
Patient Age (years)
INSS Stage
Two-Years Disease-Free Survival (%)
All
1
>90
All
2A
85
<1
2B/3
87/89
<1
4S
57–90
>1
2B/3
59
<1
4
75
>1
4
40/15†
*Personal observation, RP Castleberry. †Difference relates to complete versus partial surgical resection, respectively. Modified from Brodeur, 1993.
Radiation Therapy Despite the radiosensitive nature of neuroblastoma in culture models, clinical response has been variable.66 Historically, radiation has been used in the multimodality management of residual neuroblastoma, bulky unresectable tumors, and disseminated disease. Radiation therapy is reserved for patients with symptomatic life or organ threatening tumor that does not respond rapidly enough to chemotherapy, or for intermediate-risk patients whose tumor has responded incompletely to both chemotherapy and attempted resection and also have unfavorable biologic characteristics. Radiation therapy to the primary site is recommended for high-risk patients even in cases of complete resection. Urgent Chemotherapy Symptomatic spinal cord compression necessitates immediate treatment with chemotherapy. Neurologic recovery is more likely the less the severity of compromise and the shorter the duration of symptoms. Neurologic outcome appears to be similar whether cord compression is treated with chemotherapy, radiation therapy, or surgical laminectomy. However, laminectomy may result in later scoliosis, and chemotherapy is often needed whether or not surgery or radiation is used.67,68 The COG neuroblastoma treatment plan recommends immediate chemotherapy for cord compression in patients classified as low risk or intermediate risk. Observation Without Surgery of Localized, Presumed Adrenal Neuroblastoma in Infants Studies suggest that selected presumed neuroblastomas detected in infants by screening may safely be observed
without obtaining a definitive histologic diagnosis and without surgical intervention, thus avoiding potential complications of surgery in the newborn.69,70 The experience with tumors detected by mass urinary catecholamine metabolite screening in Japan appears to be applicable to tumors detected by prenatal or perinatal ultrasound in the United States. Twenty-six infants with presumed Evans stages I, II, or IV-S by imaging, urinary VMA, and HVA levels less than 50 mcg/mg of creatinine, no tumor involvement of great vessels or invasion into the spinal canal and tumor size <5 cm were observed with frequent imaging. Biopsy and tissue diagnosis were not obtained initially. Progression of tumor size was noted in one-third of the infants with resection without any apparent increase in stage being accomplished. All had favorable biologic features. In the remainder, following observation for 6 to 73 months, no surgery had been performed, the VMA and HVA had normalized, and in several cases the tumors have become undetectable by imaging.69 The COG is currently investigating systematic observation without surgery for infants with presumed small Evans stage I adrenal neuroblastoma detected by prenatal or perinatal ultrasound. FUTURE CONSIDERATIONS The identification of various prognostic markers of neuroblastoma allow for a more precise determination of biologic potential. A statistically significant association has been noted with tumors of low histologic grade along with DI of more than 1 (hyperdiploid), single copy of Nmyc gene per haploid genome, and a serum lactic dehydrogenase of <1500 IU/l. High histologic grade was associated with a DI of 1, amplified N-myc gene, and an LDH of 1500 or more, factors that are associated with aggressive behavior.71 The use of these prognostic factors
750
Part VIII Pediatric Malignancies
allow for appropriate risk-specific therapy and the development of optimal treatment protocols for childhood neuroblastoma. Identification of individuals who are predisposed to develop the tumor has become increasingly important. Cytogenetic studies have demonstrated alterations of chromosome 1p, reaching a frequency of more than 70%.72 Alterations of 1p are also seen in significant frequency in other types of cancers, including colon cancer, alveolar rhabdomyosarcoma, hepatoblastoma, and ductal carcinoma of the breast.73 Progress is being made that should reveal whether specific genetic information is commonly altered in neuroblastomas and, if so, what its significance is for tumorigenesis. Urinary catecholamine metabolites are commonly elevated in neuroblastoma but unfortunately are not as reliable tumor markers as alpha fetoprotein or beta-human chorionic gonadotropin for following germ cell tumors. With greater understanding of the tumor biology, new markers, such as telomerase RNA, serum ferritin, and neurotrophin receptor, may prove useful for following response to therapy, as well as early relapse. Treatment strategies continue to evolve as clinical response improves. The goals now are to maximize the response and yet minimize the overall morbidity of treatment. Newer modalities currently under investigation include monoclonal antibody therapy with or without GM-CSF following chemotherapy,74 targeted radiation therapy with 131I MIBG,75 tandem myeloablation and stem cell transplantation,76,77 and inclusion of myeloblative doses of 131I MIBG prior to stem cell transplantation.78 The knowledge gained from the ongoing biologic studies will continue to be applied to the clinical arena as mechanisms of neuroblastoma transformation and progression are elucidated.
REFERENCES 1. Virchow R: Die Krankenhaften Geschwulste, Vol 11, p 149. Berlin, Germany, Hirschwald, 1864. 2. Marchand F: Beitrage zur Kenntniss der normalen und pathologischen Anatomic der Glandula carotica und der Nebennieren Festschriff fur Rudolph. Virchows Arch 1891; 5:578. 3. Herxheimer G: Uebur Tumoren des Nebennierenmarkes, insbesondere das Neuroblastoma sympaticum. Beitr Pathol Anat 1914; 57:112. 4. Blacklock JWS: Neurogenic tumours of the sympathetic system in children. J Pathol Bacteriol 1934; 39:27–48. 5. Phillips R: Neuroblastoma. Ann R Coll Surg Engl 1953; 12:29–47. 6. Cushing H, Wolbach SB: The transformation of a malignant paravertebral sympathicoblastoma into a benign ganglioneuroma. Am J Pathol 1927; 3:203.
7. Beckwith J, Perrin E: In situ neuroblastoma: A contribution to the natural history of neural crest tumors. Am J Pathol 1963; 43:1089. 8. Mason GH, Hart-Nercer J, Miller EJ, et al: Adrenalinesecreting neuroblastoma in an infant. Lancet 1957; 2:322. 9. Knudson AGJ, Strong LC: Mutation and cancer: statistical study of retinoblastoma. J Natl Cancer Inst 1976; 57:675. 10. Brodeur GM, Fong CT: Molecular biology and genetics of human neuroblastoma. Cancer Genet Cytogenet 1989; 41:153. 11. Balaban-Malenbaum G, Gilbert F: Relationship between homogeneously staining regions and double minute chromosomes in human neuroblastoma cell lines. Prog Cancer Res Ther 1980; 12:97. 12. Look AT, Hayes FA, Nitschke R, et al: Cellular DNA content as a predictor of response to chemotherapy in infants with unrectable neuroblastoma. N Engl J Med 1984; 311:231. 13. Gansler T, Chatten J, Varello M, et al: Flow cytometric DNA analysis of neuroblastoma. Correlation with histology and clinical outcome. Cancer 1986; 58:2453. 14. Taylor SR, Locker J: A comparative analysis of nuclear DNA content and N-myc gene amplification in neuroblastoma. Cancer 1990; 65:1360. 15. Look AT, Hayes FA, Schuster JJ, et al: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma. A Pediatric Oncology Group Study 1997; 9:581. 16. Biedler JL, Ross RA, Shanske S, Spengler BA: Human neuroblastoma cytogenetics: search for significance of homogeneously staining regions and double minute chromosomes. Prog Cancer Res Ther 1980; 12:81. 17. Brodeur GM: Neuroblastoma – clinical applications of molecular parameters. Brain Pathol 1990; 1:47. 18. Brodeur GM, Seeger RC, Schwab M, et al: Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage. Science 1984; 224:1121. 19. Brodeur GM: Molecular Biology and Genetics of Human Neuroblastoma. Boca Raton, CRC Press, 1990. 20. Brodeur GM, Hayes FA, Green AA, et al: Consistent N-myc copy number in simultaneous or consecutive neuroblastoma samples from sixty individual patients. Cancer Res 1987; 47:4248. 21. Nisen PD, Waber PG, Rich MA, et al: N-myc oncogene RNA expression in neuroblastoma. J Natl Cancer Inst 1988; 80:1633. 22. Slavc I, Ellenbogen R, Jung W-H, et al: N-myc gene amplification and expression in primary human neuroblastoma. Cancer Res 1990; 50:1459. 23. Fong C, White PS, Peterson K, et al: Loss of heterozygosity for chromosomes 1 to 14 defines subsets of advanced neuroblastomas. Cancer Res 1992; 52:1780. 24. Young JLJ, Ries LG, Silverberg E, et al: Cancer incidence, survival and mortality for children younger than 15 years. Cancer 1986; 58:598. 25. Voute PA: Neuroblastoma. In Sutow WW, Fernbach DJ, Vietti TJ (eds): Clinical Pediatric Oncology, p 559. St. Louis, Mosby, 1984.
Chapter 46 Neuroblastoma 751 26. Miller RW, Fraumeni JF, Hill JA: Neuroblastoma: Epidemiologic approach to its origin. Am J Dis Child 1968; 115:253. 27. Hope JW, Borns PF, Berg PK: Roentgenologic manifestations of Hirschbrung’s disease in infancy. Am J Roentgenal Radium Ther Nucl Med 1965; 95:217. 28. Dehner LP: Pathologic anatomy of classic neuroblastoma: including prognostic features and differential diagnosis. In Pochedly C (ed): Neuroblastoma: Tumor Biology and Therapy, p 111. Boca Raton, CRC Press, 1990. 29. Triche TJ, Askin FB, Kissane JM: Neuroblastoma, Ewing’s sarcoma and the differential diagnosis of small-, round-, blue-cell tumors. In Finegold M (ed): Pathology of Neoplasia in Children and Adolescents, p 145. Philadelphia, PA, WB Saunders, 1986. 30. Shimada H, Chatten J, Newton WA Jr, et al: Histopathologic prognostic factors in neuroblastic tumors: definition of subtypes of ganglioneuroblastoma and an age-linked classification of neuroblastomas. J Natl Cancer Inst 1984; 73:405. 31. O’Neill JA, Littman P, Blitzer P, et al: The role of surgery in localized neuroblastoma. J Pediatr Surg 1985; 20:708. 32. Evans AE, D’Angio GJ, Propert K, Anderson J, Hann H-WL: Prognostic factors in neuroblastoma. Cancer 1987; 59:1853. 33. Joshi V, Canto A, Altshuler G, et al: Prognostic significance of histopathologic features of neuroblastoma: a grading system based on the review of 211 cases from the Pediatric Oncology Group. Proc Am Soc Clin Oncol 1991; 10:311 (abstract). 34. Ambros IM, Hata J, Joshi VV, et al: Morphologic features of neuroblastoma (schwannian stroma-poor tumors) in clinically favorable and unfavorable groups. Cancer 2002; 94(5):1574–1583. 35. Cohn SL, Rademaker HR, Salwen WA, et al: Analysis of DNA ploidy and proliferative activity in relation to histology and N-myc amplification in neuroblastoma. Am J Pathol 1990; 136(5):1043–1052. 36. Takayama H, Suzuki T, Mugishima H, et al: Deletion mapping of chromosomes 14q and 1p in human neuroblastoma. Oncogene 1992; 7(6):1185–1189. 37. Takeda O, Homma C, Maseki N, et al: There may be two tumor suppressor genes on chromosome arm 1p closely associated with biologically distinct subtypes of neuroblastoma. Genes Chrom Cancer 1994; 10(1):30–39. 38. Seeger RC, Brodeur H, Sather A, et al: Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med 1985; 313(18):1111–1116. 39. Caron H: Allelic loss of chromosome 1 and additional chromosome 17 material are both unfavorable prognostic markers in neuroblastoma. Med Pediatr Oncol 1995; 24(4):215–221. 40. Brown N, Cotterill S, Lastowska M: Gain of chromosome arm 17q and adverse outcome in patients with neuroblastoma. N Engl J Med 1999; 340(5):1954–1961. 41. Rosen EM, Cassady JR, Frantz CN, et al: Neuroblastoma: The Joint Center for Radiation Therapy/Dana-Farber Cancer Institute/Children’s Hospital experience. J Clin Oncol 1984; 2:714.
42. Evans AE, D’Angio GJ, Randolph JA: A proposed staging for children with neuroblastoma. Children’s Cancer Study Group A. Cancer 1971; 27:374. 43. Brodeur GM, Seeger RC, Barrett A, et al: International criteria for diagnosis, staging and response to treatment in patients with neuroblastoma. J Clin Oncol 1988; 6:1874. 44. LaBrosse EH, Com-Nougue C, Zucker JM, et al: Urinary excretion of 3-methoxy-4-hydroxymandelic acid and 3methoxy-4-hydroxyphenylacetic acid by 288 patients with neuroblastoma and related neural crest tumors. Cancer Res 1980; 40:1995. 45. Voute PA, Hoefnagel CA, Marcuse HR, de Kraker J: Detection of neuroblastoma with 131I-metaiodobenzylguanidine. Prog Clin Biol Res 1985; 175:389. 46. Neuroblastoma Treatment, www.cancer.gov. 47. Ladenstein R, Ambros IM, Pötschger U, et al: Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children’s Cancer Group study. J Clin Oncol 1998; 16(4):1256–1264. 48. Brodeur GM, Azar C, Brother M, et al: Neuroblastoma. Effect of genetic factors on prognosis and treatment. Cancer 1992; 70(6 Suppl):1685–1694. 49. Look AT, Hayes FA, Shuster JJ, et al: Clinical relevance of tumor cell ploidy and N-myc gene amplification in childhood neuroblastoma: a Pediatric Oncology Group study. J Clin Oncol 1991; 9(4):581–591. 50. Tonini GP, Boni L, Pession A, et al: MYCN oncogene amplification in neuroblastoma is associated with worse prognosis, except in stage 4s: the Italian experience with 295 children. J Clin Oncol 1997; 15(1):85–93. 51. Krams M, Hero B, Berthold F, et al: Proliferation marker K1-S5 discriminates between favorable and adverse prognosis in advanced stages of neuroblastoma with and without MYCN amplification. Cancer 2002; 94(3):854–861. 52. Nakagawara A, Arima-Nakagawara M, Scavarda NJ, et al: Association between high levels of expression of the TRK gene and favorable outcome in human neuroblastoma. N Engl J Med 1993; 328(12):847–854. 53. Poremba C, Hero B, Goertz HG, et al: Traditional and emerging molecular markers in neuroblastoma prognosis: the good, the bad and the ugly. Klin Padiatr 2001; 213(4):186–190. 54. Hann HW, Evans AE, Siegel SE, et al: Prognostic importance of serum ferritin in patients with stages III and IV neuroblastoma: the Children’s Cancer Study Group experience. Cancer Res 1985; 45(6):2843–2848. 55. Shuster JJ, McWilliams NB, Castleberry R, et al: Serum lactate dehydrogenase in childhood neuroblastoma. A Pediatric Oncology Group recursive partitioning study. Am J Clin Oncol 1992; 15(4):295–303. 56. Berthold F, Trechow R, Utsch S, et al: Prognostic factors in metastatic neuroblastoma. A multivariate analysis of 182 cases. Am J Pediatr Hematol 1992; 14(3):207–215. 57. Burchill SA, Lewis IJ, Abrams KR, et al: Circulating neuroblastoma cells detected by reverse transcriptase polymerase chain reaction for tyrosine hydroxylase mRNA ae an independent poor prognostic indicator in stage 4 neuroblastoma in children over 1 year. J Clin Oncol 2001; 19(6):1795–1801.
752
Part VIII Pediatric Malignancies
58. Seeger RC, Reynolds CP, Gallego R, et al: Quantitative tumor cell content of bone marrow and blood as a predictor of outcome in stage IV neuroblastoma: a Children’s Cancer Group study. J Clin Oncol 2000; 18(24):4067–4076. 59. Smith EI, Nitschke R, Shochat S, et al: Lack of significance of involved lymph nodes attached to localized neuroblastoma. A Pediatric Oncology Group study. Proc Am Soc Clin Oncol 1987; 6:219 (abstract). 60. Kiely EM: The surgical challenge of neuroblastoma. J Pediatr Surg 1994; 29:128. 61. Castleberry RP, Kun L, Shuster JJ, et al: Radiotherapy improves the outlook for children older than one year with POG stage C neuroblastoma. J Clin Oncol 1991; 9:789. 62. Azizkjan RG, Shaw A, Chandler JG: Surgical complications of neuroblastoma resection. Surgery 1985; 97:514. 63. Strother DR: Children’s Oncology Group: Phase III Study of Primary Surgical Therapy in Children With Low-Risk Neuroblastoma, COG-P9641, Clinical trial, Active. 64. Baker D: Children’s Oncology Group: Phase III Study of Combination Chemotherapy in Children with Intermediate-Risk Neuroblastoma, COG-A3961, Clinical trial, Active. 65. Matthay KK, Villablanca JG, Seeger RC, et al: Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group. N Engl J Med 1999; 341(16):1165–1173. 66. Weichselbaum RR, Epstein J, Little JB: In vitro cellular radiosensitivity of human malignant tumors. Eur J Cancer 1976; 36:47. 67. Katzenstein HM, Kent PM, London WB, et al: Treatment and outcome of 83 children with intraspinal neuroblastoma: the Pediatric Oncology Group experience. J Clin Oncol 2001; 19(4):1047–1055. 68. De Bernardi B, Pianca C, Pistamiglio P, et al: Neuroblastoma with symptomatic spinal cord compression at diagnosis: treatment and results with 76 cases. J Clin Oncol 2001; 19(1):183–190.
69. Nishihira H, Toyoda Y, Tanaka T, et al: Natural course of neuroblastoma detected by mass screening: a 5-year prospective study at a single institution. J Clin Oncol 2000; 18(16):3012–3017. 70. Holgersen LO, Subramanian S, Kirpeker M, et al: Spontaneous resolution of antenatally diagnosed adrenal masses. J Pediatr Surg 1996; 31(1):153–155. 71. Joshi VV, Cantor AB, Brodeur GM, et al: Correlation between morphologic and other prognostic markers of neuroblastoma. Cancer 1993; 71:3173. 72. Brodeur GM, Green AA, Hayes FA, et al: Cytogenetic features of human neuroblastomas and cell lines. Cancer Res 1981; 41:4678. 73. Schwab M: Amplification of N-myc as a prognostic marker for patients with neuroblastoma. Semin Cancer Biol 1993; 4:13. 74. Kushner BH, Kramer K, Cheung NK: Phase II trial of the anti-G(D2) monoclonal antibody 3F8 and granulocyte-macrophage colony-stimulating factor for neuroblastoma. J Clin Oncol 2001; 19(22): 4189–4194. 75. Garaventa A, Bellagamba O, Lo Piccolo MS, et al: 131I-metaiodobenzylguanidine (131I-MIBG) therapy for residual neuroblastoma: a mono-institutional experience with 43 patients. Br J Cancer 1999; 81(8):1378–1384. 76. Frappaz D, Michon J, Coze C, et al: LMCE3 treatment strategy: results in 99 consecutively diagnosed stage 4 neuroblastomas in children older than 1 year at diagnosis. J Clin Oncol 2000; 18(3):468–476. 77. Kletzel M, Katzenstein HM, Haut PR, et al: Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chicago Pilot II Study. J Clin Oncol 2002; 20(9):2284–2292. 78. Miano M, Garaventa A, Pizzitola MR, et al: Megatherapy combinint 131I-metaiodobenzylguanidine and high-dose chemotherapy with hematopoietic progenitor cell rescue for neuroblastoma. Bone Marrow Transplant 2001; 27(6):571–574.
C H A P T E R
47 Wilms’ Tumor Michael L. Ritchey, MD, and Max J. Coppes, MD, PhD, MBA
The management of Wilms’ tumor has evolved considerably since its description nearly a century ago by Max Wilms. Wilms, a German surgeon,1 was the first to propose that all the various elements of the tumor were derived from the same cell. His careful pathologic description of this tumor, also referred to as nephroblastoma, led to the association of his name with this tumor. Initially, surgery held the only hope of cure. The first attempt at a nephrectomy in a child was probably performed by Hueter in 1876.2 Unfortunately, the patient died during the surgical procedure. Ten years later, Kocher, in Bern, Switzerland, performed the first successful nephrectomy in a child. At first the ultimate outcome for patients with Wilms’ tumor remained poor. By the late 1930s, improvements in surgical technique provided a survival of 30%. The introduction of radiation therapy as an effective adjuvant treatment resulted in improved survival,3 although it was not until the introduction of effective chemotherapy in the 1950s that a dramatic improvement in survival was achieved.4 First, Farber from Boston reported the effectiveness of dactinomycin (AMD), then workers at M.D. Anderson Cancer Center introduced vincristine (VCR) for the treatment of this disease.5 Due to the rarity of this tumor it was recognized in the early 1970s that multicenter collaboration was necessary to conduct the needed clinical research to improve outcome. The cooperative group studies conducted by the National Wilms’ Tumor Study Group (NWTSG) in North America and the International Society of Paediatric Oncology (SIOP) in Europe have ultimately provided excellent survival rates for children with this malignant disorder. This chapter reviews the major contributions of these clinical trials, some of the molecular genetic changes associated with this tumor, and outlines the current treatment strategies. EPIDEMIOLOGY Embryonal neoplasms of childhood, named because their morphologic appearance resembles that observed during
embryogenesis, have provided important information regarding cancer biology and development. Of particular interest is Wilms’ tumor, which comprises up to onethird of pediatric embryonal tumors. In North America, the annual incidence in children under the age of 15 years is 7 per million.6 Therefore, approximately 450 new cases should be expected each year. The overall median age at diagnosis is 3.5 years, although for boys it is 6 months lower than for girls. The disease occurs nearly equally in girls and boys worldwide.7 The incidence shows some ethnic variation with slightly higher rates reported for the black populations and a lower incidence in Asian children. Environmental factors are not that important a role in the etiology of Wilms’ tumor.8 Of greater interest is the genetic epidemiology of Wilms’ tumor. For many years Wilms’ tumor has been associated with a number of congenital abnormalities, including sporadic aniridia, hemihypertrophy, and genitourinary malformations.9,10 A number of recognizable syndromes are associated with an increased incidence of Wilms’ tumor (Table 47-1). These may be divided into syndromes characterized by overgrowth and those lacking overgrowth. Genitourinary abnormalities, such as hypospadias, cryptorchidism, and renal fusion anomalies, are seen in association with Wilms’ tumor in 4.5% of patients with Wilms’ tumor.11 Of particular interest is the recognition of the Denys-Drash syndrome12,13 in children presenting with ambiguous genitalia. The Denys-Drash syndrome is characterized by ambiguous genitalia and renal mesangial sclerosis, usually resulting in end-stage renal failure and Wilms’ tumor.14 Genetic studies indicate that the DenysDrash syndrome is associated with specific mutations of WT1, one of the Wilms’ tumor genes on the short arm of chromosome 11.15,16 It should be noted that the phenotype can vary considerably. Any patient with Wilms’ tumor and renal dysfunction, with or without a genitourinary abnormality, should be evaluated for a WT1 mutation. 753
754
Part VIII Pediatric Malignancies
Table 47-1 Incidence of Congenital Anomalies Associated with Wilms Tumor Patients Reported to the National Wilms’ Tumor Study Anomaly
Rate (per 1000)
Aniridia
7.6
BWS
8.4
Hemihypertrophy
33.8
Genitourinary anomalies Hypospadias
13.4
Cryptorchidism
37.3
Hypospadias and cryptorchidism
12.0
The incidence of aniridia in patients with Wilms’ tumor is 1.1%, much higher than the incidence in the general population, which is estimated at 1:50,000 to 1:100,000. Wilms’ tumor will develop in >30% of children with the aniridia, genitourinary malformations and mental retardation (AGR syndrome). In the presence of Wilms’ tumor, the term WAGR syndrome is used (Wilms’ tumor and AGR). Most children with the WAGR syndrome suffer from a constitutional deletion on band 13 of the short arm of chromosome 11.17 Syndromes with overgrowth features at risk for the development of Wilms’ tumor include hemihypertrophy, which may occur alone or as part of the BeckwithWiedemann syndrome (BWS), Perlman, Soto, and the Simpson-Golabi-Behmel syndromes.11,18,19 BWS is a rare congenital overgrowth disorder characterized by visceromegaly (splenomegaly, hepatomegaly), macroglossia, and hyperinsulinemic hypoglycemia.18,19 Most cases of BWS are sporadic, but 15% exhibit heritable characteristics with apparent autosomal dominant inheritance. Patients with BWS are predisposed for certain cancers, in particular embryonal neoplasms (adrenocortical neoplasms and hepatoblastoma). The incidence of Wilms’ tumor in this patient population is <5%. Children with BWS found to have nephromegaly (kidneys greater than or equal to the 95th percentile of age adjusted renal length) are at the greatest risk for the development of Wilms’ tumor.20 Children with BWS are also at an increased risk to develop bilateral tumors.21 A review of NWTS-3 and NWTS-4 patients found that 21% of the BWS patients had either synchronous or metachronous bilateral tumors. Screening with serial renal ultrasounds has been recommended in children with aniridia, hemihypertrophy, and BWS. Review of most studies suggests that 3 to 4
months is the appropriate screening interval. Tumors detected by screening will generally be a lower stage.22,23 Retrospective reviews have been unable to determine if early detection had an impact on patient survival. Children with BWS can also develop nonmalignant renal lesions.24 Recognition of these benign lesions is important to avoid unnecessary nephrectomy when new lesions are identified on screening ultrasound. GENETICS Our knowledge of the genetic alterations involved in the development of Wilms’ tumor has grown substantially over the past two decades. Initially, the genetics of Wilms’ tumor was thought to be very similar to that of retinoblastoma (a childhood tumor of the retina), since both tumors can occur bilaterally and/or affect several members of the same family, although the latter is more common in retinoblastoma than it is in Wilms’ tumor. Also, as in retinoblastoma, when Wilms’ tumor occurs bilaterally, the age at presentation is younger than in cases where the disease is limited to one kidney, suggesting a constitutional defect that predisposes that child to tumor formation. The younger age at diagnosis is also found in children with specific, Wilms’ tumor predisposing, congenital anomalies, such as aniridia.11 However, it is now clear that the genetic alterations leading to the development of Wilms’ tumor are more complex than those of retinoblastoma and in fact involves multiple genes.25 Analysis of the different median ages at presentation between groups of patients led Alfred Knudson in the early 1970s to propose a “two-hit” model for the development of retinoblastoma and Wilms’ tumor.26 His hypothesis predicts that two rate-limiting events are necessary for tumor development. He predicted that children with a genetic susceptibility to cancer already have a constitutional (prezygotic) genetic alteration, either inherited from one of the parents or resulting from a spontaneous (de novo) mutation. In these children, only one additional (postzygotic) genetic alteration would suffice for Wilms’ tumor to develop. By contrast, children that do not have a constitutional genetic alteration, and therefore are not susceptible to cancer, require two postzygotic (or somatic) genetic events for Wilms’ tumor to develop. Since the probability of one somatic event occurring is higher than that of two independent ones, children with a constitutional genetic alteration have a greatly increased likelihood of developing cancer as compared to children that do not carry a constitutional genetic defect. Two genetic regions, both on the short arm of chromosome 11, have been linked to Wilms’ tumor development. The first evidence of band 13 of the short arm of chromosome 11 (11p13) being involved in the development
Chapter 47 Wilms’ Tumor 755
of Wilms’ tumor was the detection of cytogenetically visible deletions of this region in patients with the WAGR syndrome. The deletion in these patients is not restricted to their Wilms’ tumor cells but is present in all body cells (i.e., constitutional deletions).27 According to Knudson’s two-hit hypothesis, the constitutional 11p13 deletion was proposed to represent the first of two events, the second event being somatic in these patients. Similarly, the loss of heterozygosity (LOH) for 11p13 DNA markers demonstrated in approximately one-third of sporadic Wilms’ tumors26,28 also suggested that chromosome 11p13 was involved in the development of Wilms’ tumor. In fact, both observations implied the presence of a tumor suppressor gene at 11p13, a notion that was confirmed in 1990.29–31 Once cloned, alterations of the Wilms’ tumor suppressor gene WT1 at 11p13 were shown in tumor DNA obtained from patients with sporadic Wilms’ tumors, as well as in the constitutional DNA of patients with a genetic predisposition to Wilms’ tumor.32 WT1, which is expressed transiently in the developing kidney and also in specific cells of the gonads, is required for normal genitourinary development and specifically of importance for the differentiation of the renal blastema.33 Constitutional point mutations in the zinc finger DNA-binding region of WT1 give rise to the Denys-Drash syndrome, characterized by pseudohermaphroditism, early renal failure with diffuse mesangial sclerosis, and Wilms’ tumor.16 A second Wilms’ tumor locus (already designated WT2) has been identified on chromosome 11p15.5.34 This same chromosomal region has also been linked to the BWS.35 Although this region has revealed at least 10 imprinted (expressed preferentially from one of the parent alleles) genes, for now, it is not known whether a single gene is responsible for both disorders or adjacent genes independently for each disease. The presence of imprinted genes and the observation that in Wilms’ tumors showing LOH for 11p15 DNA markers, it is invariably the maternal allele that is lost36, suggest that the paternal and maternal genes in this region are functionally unequal. In keeping with this, some BWS patients have been shown to have two paternal copies of chromosome 11p in addition to the maternal copy (trisomy 11p15), while in some patients with BWS who seem to have grossly normal karyotypes (i.e., no trisomy), both copies of chromosome 11 are in fact found to be inherited from the father, a condition termed uniparental isodisomy.37 Apparently in BWS, expression is required from two paternal 11p15 alleles, while in Wilms’ tumor the first of two events almost always occurs on the paternal 11p15 allele. Other molecular abnormalities studied in Wilms’ tumor patients seem to be related to outcome rather than development. Of these, loss of chromosomal material, as determined by LOH, on the long arm of chromosome 16, demonstrated in ~20% of tumors36,38, and on the
short arm of chromosome 1, shown in ~11% of tumors39, are clinically of greatest importance. In a preliminary study, tumor-specific loss of either region (16q or 1p) was correlated with poor outcome, independently from stage or histology at initial presentation.39 A larger group of patients has been studied to confirm this observation. CLINICAL PRESENTATION The typical presentation of Wilms’ tumor is that of a large asymptomatic abdominal mass, often found incidentally. Other presentations include acute abdominal pain mimicking appendicitis or some other intraabdominal event. This is often the result of tumor rupture with hemorrhage into the retroperitoneum or the peritoneal cavity. Hematuria is found in approximately one-fourth of children at diagnosis, but only gross hematuria warrants further evaluation to exclude tumor extension into the renal pelvis and ureter. Hypertension is also present in about 25% of cases.40 Vascular tumor extension into the renal vein and inferior vena cava (IVC) can result in atypical presentations.41,42 For example, a varicocele, particularly one that persists when the child is supine, may be secondary to obstruction of the spermatic vein due to tumor thrombus. However, varicocele, hepatomegaly due to hepatic vein obstruction, ascites, or congestive heart failure are only found in less than 10% of patients with intracaval or atrial tumor extension.41 Very rarely the tumor can embolize to the pulmonary artery with catastrophic consequences. PREOPERATIVE EVALUATION Laboratory evaluation should include a complete blood count, liver function tests, and renal function tests. Serum calcium should also be checked. Hypercalcemia should alert the physician for the possible presence of either congenital mesoblastic nephroma (CMN) or rhabdoid tumor of the kidney (RTK), rather then Wilms’ tumor.40 A coagulation screen should be obtained to exclude acquired von Willebrand’s disease. The coagulation defect underlying the acquired von Willebrand’s disease in patients with Wilms’ tumor can be corrected preoperatively with the administration of DDAVP. Modern imaging modalities provide detailed information regarding origin and extent of intra-abdominal tumors. There has been considerable debate regarding the role of imaging studies in the staging and management of children with Wilms’ tumor.43,44 Imaging studies can often establish the correct diagnosis before surgery (Figure 47-1). In addition, imaging studies can help the surgeon to plan for a major surgical procedure. There is an increased incidence of surgical complications in Wilms’ tumor patients with an incorrect preoperative
756
Part VIII Pediatric Malignancies
Figure 47-1 CT scan of a large left Wilms’ tumor with a small rim of functioning renal parenchyma.
diagnosis.45 Preoperative imaging will establish the presence of a functioning contralateral kidney prior to performing a nephrectomy. Ultrasonography is the initial investigation performed in a child with a palpable abdominal mass. This study can distinguish between solid and cystic lesions, and also determine if the mass is of intrarenal or extrarenal in origin. During ultrasonography, the patency of the IVC should be assessed to exclude extension of tumor thrombus into the IVC (Figure 47-2) that occurs in 4% of Wilms’ tumor patients.41,42 Computed tomography (CT) may be useful, but visualization of the IVC is often hin-
dered by unopacified blood due to an inadequate bolus injection of contrast. If the ultrasound is inconclusive, magnetic resonance imaging (MRI) is recommended to establish IVC patency.42,46,47 One of the unanswered questions regarding imaging is the role of CT and MRI scans in determining the extent of disease, i.e., stage.43,44 Since survival is correlated with stage (and histology), NWTSG investigators keep stressing the need for accurate staging.48 The current NWTSG staging system utilizes surgery and pathology findings only. There have been no studies to compare data obtained by imaging to those obtained by the surgeon during nephrectomy in assessing extrarenal extent. Occasionally, preoperative CT can suggest extracapsular tumor extension when there is irregularity of the tumor margin or evidence of regional adenopathy when lymph nodes are demonstrated physically separate from the tumor mass. However, enlarged retroperitoneal lymph nodes are common in children and often reactive. Moreover, even intraoperative lymph node evaluation by the surgeon does not correlate well with histopathologic findings49 and one would therefore expect similar difficulties when correlating histopathology with imaging studies. Preoperative imaging can be useful to identify groups of patients that are best treated with chemotherapy prior to attempts at surgical excision.50,51 One important group is children with bilateral Wilms’ tumors (BWTs). The recommended treatment of these children is preoperative chemotherapy to shrink the tumors rather than upfront surgery. This approach facilitates preservation of renal parenchyma.50,52 CT and MRI will detect most bilateral lesions but can miss some lesions <1 cm in diameter.53 Primary nephrectomy has been shown to be
Figure 47-2 Ultrasound that depicts intracaval thrombus (arrow).
Chapter 47 Wilms’ Tumor 757
associated with an increased incidence of surgical complications in patients with either extensive intravascular tumor involvement or tumors that require en bloc resection of other organs to achieve complete excision.45 As noted above, IVC extension can and should be identified during the preoperative imaging evaluation. Identifying visceral involvement by CT is much more difficult. The majority of children identified as having possible invasion of the liver on CT later prove to be negative at surgery.54 CT may be able to detect deep seated liver metastases but is much more predictive for absence of liver invasion.55 The most common site of distant metastases is within the lungs, present at diagnosis in 8% of patients. The majority of these lesions can be identified on routine chest x-ray films. However, some children are only identified to have pulmonary metastases by chest CT.56,57 There continues to be some debate regarding the management of these patients.58,59 Not all small lesions seen on CT are due to metastatic disease. Some lesions identified on CT only represent benign lesions, e.g., histoplasmosis, granuloma or round atelectasis. An important question is whether chest x-ray-negative, CT-positive patients require the same adjuvant treatment as those with a positive x-ray.59,60 Meisel et al.60 reviewed 53 children enrolled in NWTS-3 and NWTS-4 who had a negative chest roentgenogram but were identified with metastatic lesions on a chest CT. There was no difference in survival in those patients treated according to the local extent of the abdominal disease alone. They did note fewer pulmonary relapses in patients that did not receive pulmonary irradiation, but more deaths are attributable to lung toxicity. Other investigators have also noted an increased risk of recurrent disease in favorable histology (FH) patients with pulmonary densities detected on CT alone when pulmonary irradiation was omitted.56,61 Uncommon sites of metastases can occur in renal tumors other then Wilms’ tumor. A radionuclide bone scan and skeletal survey are both recommended if a histologic diagnosis of clear cell sarcoma of the kidney (CCSK) or renal cell carcinoma (RCC) is confirmed. Both of these have a propensity to metastasize to the skeleton.44,48,62,63 RTK and CCSK are associated with brain metastases, and MRI of the brain should be obtained in the early postoperative period. DIFFERENTIAL DIAGNOSIS RTK, CCSK, and RCC do not have any distinguishing radiographic features that will allow a preoperative diagnosis unless unusual sites of metastases (bone, brain) are evident.62–67 RTK is more typically seen in infants and very young children with a mean age of 13 months. RCC generally presents after the age of 5 years, and it is the most common renal malignancy in the second decade of
life.66,67 Neuroblastoma is the most common solid abdominal malignancy in childhood but in most cases can be distinguished by its extrarenal location and excretion of catecholamines and its metabolites in the urine. Rarely, neuroblastoma will arise within the kidney making the distinction difficult. Renal angiomyolipoma is only rarely seen in childhood and is associated with tuberous sclerosis.68,69 Demonstration of fat within a renal lesion by CT scan preoperatively should alert the surgeon of the presence of this tumor. Another tumor commonly seen in infancy is CMN. This is generally a benign lesion found in approximately 2% of childhood renal tumors. Most patients are under the age of 6 months at the time of diagnosis.70 In fact the typical presentation is that of a newborn with an abdominal mass. A number of cases have been diagnosed prenatally (Figure 47-3). However, FH Wilms’ tumor and RTK can also present in the first few months of life.63,71 Nephrectomy is curative for most patients with CMN,70 although there have been reports of local recurrence, more common in those with cellular histology and occasionally metastases.72–74 Adequacy of surgical resection and age at diagnosis in these patients appear to be more important predictors of relapse than histology.75 In addition to age at presentation, other clinical parameters can aid the clinician in narrowing the diagnostic possibilities. For example, a renal mass developing in a child with hemihypertrophy, BWS, or aniridia is most likely to be a Wilms’ tumor. Bilateral or multicentric renal tumors are also highly suggestive of Wilms’ tumor. PATHOLOGY On gross examination, Wilms’ tumor is usually a soft, lobulated and tan or light gray in color. Hemorrhagic or necrotic areas are frequently noted. The microscopic features of Wilms’ tumor classically consist of three components in varying proportions: blastema, stroma, and epithelium. Tumors that consist predominately of one of these elements are encountered in 60% of cases and still considered Wilms’ tumor.76 Blastemal predominant tumors are important in that they behave more aggressively with early metastatic spread and more advanced disease at presentation.77 The stromal component can differentiate into striated muscle, cartilage, or fat. Wilms’ tumors with predominant rhabdomyomatous elements were once thought to behave less aggressively, but recent evidence suggests that they are no different from the typical, triphasic, Wilms’ tumor.76 The most important determinants of outcome are histopathology and tumor stage. Analysis of early NWTS patients identified a group of patients with unfavorable histopathologic features, associated with
758
Part VIII Pediatric Malignancies
Figure 47-3 CT scan of a large CMN in a 2-day-old infant that was detected on antenatal ultrasound.
increased rates of relapse and death.78 These “unfavorable histology” tumors are responsible for 50% of tumor deaths in the NWTSG studies but account for only 10% of patients.79 Three distinct tumors were originally included in this unfavorable subgroup: (a) Wilms’ tumor with extreme nuclear atypia (anaplasia); (b) RTK; (c) CCSK. The latter two tumor groups have been reclassified and are now considered to be distinct entities from Wilms’ tumors. CCSK accounts for 3% of renal tumors reported to the NWTSG. Its recognition is quite important in order that appropriate adjuvant therapy be instituted. The use of doxorubicin has resulted in an improved outcome for these children.48,62 RTK is a highly malignant tumor that accounts for 2% of renal tumors registered to the NWTSG.48,63 RTK is now considered a sarcoma of the kidney and not of metanephric origin.49 The prognosis of RTK remains dismal with conventional chemotherapeutic regimens and new treatment strategies are being developed for the management of these children. Anaplasia is a feature of Wilms’ tumor that is associated with resistance to chemotherapy. It is therefore not surprising that the incidence of anaplasia reported by the NWTSG investigators (5%) is very similar to that reported in the SIOP studies (5.3%),76 where all tumors are pretreated with chemotherapy, but the anaplasia persists after treatment.80 Anaplastic features are rare in the first 2 years of life, but the incidence increases to 13% in children age 5 years or older.81 Anaplastic Wilms’ tumors
are further stratified into focal and diffuse anaplasia, based on a topographic principle.82 Focal anaplasia requires that the anaplastic nuclear changes be confined to a specified region of the primary tumor and absent from the surrounding portions of the lesion. Diffuse anaplasia on the other hand is diagnosed when anaplasia is present in more than one portion of the tumor or if found in any extrarenal or metastatic site. Confirming the notion that anaplasia is more a marker of chemoresistance than inherent aggressiveness of the tumor, outcome is generally excellent only if the tumor is completely removed, i.e., stage I tumor.83 Precursor Lesions Lesions apparently representing Wilms’ tumor precursors are found in 30% to 40% of kidneys removed for Wilms’ tumor.83 Nephrogenic rests are defined as foci of abnormally persistent nephrogenic cells that can develop into Wilms’ tumor.84 Two distinct categories of nephrogenic rests have been identified. The most common is the perilobar nephrogenic rest (PLNR) that is found in the periphery of the kidney. There is a higher prevalence of PLNR in children with Wilms’ tumor and hemihypertrophy or the BWS (Table 47-2). Intralobar nephrogenic rests (ILNRs) on the other hand can be found anywhere within the renal lobe (Figure 47-4). Children with the WAGR syndrome or the Denys-Drash syndrome are more likely to have ILNRs. In the presence of
Chapter 47 Wilms’ Tumor 759
multiple or diffuse nephrogenic rests the term “nephroblastomatosis” is used. The natural history of nephrogenic rests, occasionally found in kidneys without tumors,85 is not entirely clear. Some undergo spontaneous regression, others hyperplastic changes, producing relatively large tumors. While the histopathologic differential diagnosis between hyperplastic nephrogenic rests and Wilms’ tumor can be very difficult (the exact criteria for distinguishing these two lesions remain to be defined), the surgical management of both disorders is similar. Multiple rests in one kidney are highly suggestive of the presence of nephrogenic rests in the other kidney since these lesions usually involve both kidneys. Consequently, the presence of ILNRs or PLNRs identiTable 47-2 Prevalence of Nephrogenic Rests Patient Population
ILNR (%)
PLNR (%)
Infant autopsies
0.01
1
Renal dysplasia
Unknown
3.5
Unilateral Wilms’ tumor
15
25
Synchronous bilateral Wilms’ tumor
34–41
74–79
Metachronous bilateral Wilms’ tumor
63–75
42
Beckwith-Wiedemann, hemihypertrophy
47–56
70–77
Aniridia
84–100
12/20
Drash syndrome
78
11
fies patients at risk for the development of contralateral Wilms’ tumor. This is particularly the case for children younger than 12 months of age who have PLNRs.86 These and other high-risk children need careful followup imaging of the contralateral kidney (Table 47-3). Biologic Parameters As survival of children with FH Wilms’ tumor has continued to improve, traditional staging factors, e.g., tumor size, histology, lymph node metastases, are now less able to predict risk for tumor progression or relapse in FH patients. Stratification of FH Wilms’ tumor patients into low-risk and high-risk groups for relapse, independent of tumor stage, would allow intensification of treatment for those with an increased risk of relapse. Research has now focused on molecular or biologic factors. The NWTSG has established a central tumor bank to maintain biologic specimens from all patients entered on the study. As noted previously, LOH for a portion of the long arm of chromosome 16 has been found in 20% of Wilms’ tumor patients.25,38 A prospective study of 232 patients registered on the NWTS found that patients with 16q LOH had a statistically significantly poorer 2-year relapse-free and overall survival than those without LOH for chromosome 16q.39 In addition, LOH for chromosome 1p markers, occurring in approximately 11% of Wilms’ tumors,39 is also associated with an increased risk of relapse, although of borderline statistical significance. Another potential marker is telomerase; a reverse transcriptase that maintains chromosome ends, compensating for the loss of DNA that occurs in replication. High telomerase activity has been found to be an unfavorable prognostic feature for several types of cancers. In a case-cohort study of 78 patients with FH Wilms’ tumor, telomerase enzyme activity, expression of hTR,
Figure 47-4 A, Illustration of renal lobe showing characteristic locations of ILNR (dark gray) and PLNR (black). (From Beckwith JB: Med Pediatr Oncol 1993; 21:158–168, with permisssion). B, PLNR composed of blastemal cells just beneath the renal capsule (H&E 40×).
760
Part VIII Pediatric Malignancies
Table 47-3 Recommended Follow-up Imaging Studies for Children with Renal Neoplasms of Proven Histology and Free of Metastases at Diagnosis Tumor Type
Study
Schedule Following Therapy
Favorable histology Wilms’ tumor; Stage I anaplastic Wilms’ tumor
Chest films
6 weeks and 3 months postop; then q. 3 q. 6 months × 3, yearly × 2
Irradiated patients only
Irradiated bony structures*
Yearly to full growth, then q. 5 years indefinitely†
Without NRs, Stages I and II
Abdominal ultrasound
Yearly × 3
Without NRs, Stage III
Abdominal ultrasound
As for chest films
With NRs, any stage‡
Abdominal ultrasound
q. 3 months × 10, q. 6 months × 5, yearly × 5
Stage II and III anaplastic
Chest films
As for favorable histology
Abdominal ultrasound
q. 3 months × 4; q. 6 months × 4
Chest films
Like favorable histology
Skeletal survey and bone scan
Like CCSK
Brain MRI and/or opacified CT skeletal survey and bone scan
When CCSK is established; then q. 6 months × 10
Chest films
As for favorable histology
Brain MRI and/or opacified CT
As for CCSK
Chest films
As for favorable histology
Abdominal ultrasound
q. 3 months × 6
RCC
CCSK
Rhabdoid tumor
Mesoblastic nephroma§
Modified from D’Angio GJ, Rosenberg H, Sharples K, Kelalis P, Breslow N, Green DM: Med Pediatr Oncol 1993; 21:205–212, with permission. *To include any irradiated osseous structures. †To detect second neoplasms, benign (osteochondromas) or malignant. ‡The panelists at the first International Conference on Molecular and Clinical Genetics of Childhood Renal Tumors; Albuquerque, New Mexico, May 1992, recommended a variation: q. 3 months for 5 years or until age 7, whichever comes first. §Data from the files of Dr. J.B. Beckwith reveal that 20 of 293 MN patients (7%) relapsed or had metastases at diagnosis; 4 of the 20 in the lungs, one of the 4 at diagnosis. All but 1 of the 19 relapses occurred within 1 year. Chest films for MN patients may be elected on a schedule, such as q. 3 months × 4, q. 6 months × 2.
the RNA component of telomerase, and mRNA expression of high telomerase reverse transcriptase (hTERT), the gene that encodes the catalytic component of the enzyme, were measured.87 All had detectable expression of hTR and 97% had detectable hTERT transcript. The hTERT mRNA levels correlated with the risk of recurrence even after adjustment for tumor stage. A larger study is underway to determine whether this is an independent prognostic indicator. The proliferative rate of tumor cells can be estimated by the measurement of DNA content. Several studies have correlated cell DNA content, measured by flow cytometry, and prognosis in Wilms’ tumor patients. Normal somatic cells have a diploid DNA content, cells in mitosis are tetraploid and tumor cells with gross kary-
otypic abnormalities in number are labeled aneuploid. Aneuploid DNA histograms are found more commonly in anaplastic Wilms’ tumors,88 although it is not necessarily associated with poor prognosis.89 While tetraploid histograms in stage III and stage IV patients are indicative of poor outcome, it remains to be determined whether DNA ploidy is a more accurate predictor of survival than histology and stage.90 More recently, investigators have started using cDNA array technology to develop tumor-specific molecular profiles in the hope to distinguish bad from good actors among the low-stage FH tumors. While a promising approach, solid data have yet to be published. The growth of solid tumors is critically dependent on the induction of neovascularity by angiogenic cytokines.
Chapter 47 Wilms’ Tumor 761
Table 47-4 Staging System of the National Wilms Tumor Study Stage I
Tumor limited to the kidney and completely excised. The renal capsule is intact and the tumor was not ruptured prior to removal. There is no residual tumor
Stage II
Tumor extends through the perirenal capsule, but is completely excised. There may be local spillage of tumor confined to the flank or the tumor may have been biopsied. Extrarenal vessels may contain tumor thrombus or be infiltrated by tumor
Stage III
Residual non-hematogenous tumor confined to the abdomen: lymph node involvement, diffuse peritoneal spillage, peritoneal implants, tumor beyond surgical margin either grossly or microscopically, or tumor not completely removed
Stage IV
Hematogenous metastases to lung, liver, bone, brain, etc.
Stage V
Bilateral renal involvement at diagnosis
Vascular endocrine growth factor (VEGF) is an angiogenic cytokine detected with increased frequency and quantity in experimental and clinical specimens of Wilms’ tumor.91 In experimental animals, lung metastases were far more likely to occur in animals with VEGF positive tumors. The potential of anti-VEGF therapy to suppress tumor growth has also been assessed.92,93 Tumors were induced in kidneys of nude mice by the injection of tumor cells. After 1 week, administration of anti-VEGF antibody resulted in a >95% reduction in tumor weight and abolished lung metastases. In Wilms’ tumor there are no biologic markers available yet that could mimic the function of alpha fetoprotein in the management of germ cell tumors. Nevertheless, several biologic markers have been studied, including serum renin and prorennin, serum erythropoietin, neuron-specific enolase (NSE), and hyaluronic acid (HA), HA stimulating activity (HASA), and hyaluronidase.40 PROGNOSTIC CONSIDERATIONS Histopathology and tumor stage are the most important predictors of survival in Wilms’ tumor patients. The current staging system is summarized in Table 47-4. For NWTS-4, the distribution by stage of FH tumors was stage I 40%, stage II 27%, stage III 22%, and stage IV 11%.94 Both the surgeon and pathologist have responsibility for determining local tumor stage. Surgical and pathologic features that are associated with an increased risk for relapse lead to a higher-stage designation. Stage I tumors are limited to the kidney and completely resected. NWTSG pathologists have identified several pathologic variables predictive of tumor relapse in patients with stage I FH tumors.95 These are invasion of the tumor capsule, presence of an inflammatory pseudocapsule, renal sinus invasion, and tumor in the intrarenal vessels. Analysis of these variables found that one or more of these features were present in 24 stage I FH
patients from NWTS-3 those developed tumor relapse.95 Tumor extension into the soft tissues of the sinus or the presence of tumor cells in blood or lymphatic vessels of the renal sinus is now considered stage II. Tumors that penetrate the renal capsule or the presence of tumor cells in the perirenal fat are also classified as stage II tumors. Tumor spillage during removal of the tumor increases the stage. Local spills confined to the renal bed are considered stage II and do lead to an increased risk of abdominal relapse.96 Diffuse spill into the peritoneal cavity is considered stage III. Wilms’ tumor usually metastasizes to regional lymph nodes, the lungs, and the liver. Patients with lymph node metastases are classified as stage III and require local radiation therapy following surgery. Since the presence of lymph node metastases mandates more intensive treatment and is associated with poorer outcome, it is important for the surgeon to obtain adequate lymph node sampling during nephrectomy in order to allow appropriate staging. In patients that do not have lymph nodes examined pathologically, there is an increased incidence of abdominal relapse, most notable for stage I patients.96 Approximately 85% of hematogenous metastases at presentation are reported in the lungs, while about 15% present with liver involvement.97 Other sites of metastases, such as bone, mediastinum, and spinal cord, are uncommon. SURGICAL MANAGEMENT Although most of the improvement in survival of children with Wilms’ tumor is attributable to introduction of effective chemotherapy and radiation therapy, surgery continues to play a very important role in its successful treatment. The preoperative evaluation of a child with an abdominal mass can generally be completed in 48 hours in most medical centers. Emergent operation is not necessary unless there is evidence of active bleeding. The surgeon is responsible for safely removing the tumor and
762
Part VIII Pediatric Malignancies
assessing the local tumor stage. This requires a thorough exploration of the abdominal cavity via a generous transperitoneal incision. The flank approach should not be used, as regional staging and examination of the contralateral kidney are not possible. The liver is palpated and regional lymph nodes are examined for evidence of tumor spread. The colon and its mesentery are then reflected off the tumor and a radical nephrectomy is performed with sampling of regional lymph nodes. Formal lymph node dissection is not required.49 Ligation of the renal vessels is performed prior to mobilization of the tumor, but only if exposure is adequate. More importantly, the surgeon should be certain that the contralateral renal vessels, aorta, iliac, or superior mesenteric arteries have not been mistakenly ligated.98 Gentle handling of the tumor throughout the procedure is mandatory to avoid tumor spillage as these patients have an increased risk for abdominal relapse.48,96 Additionally, patients with diffuse tumor spill are considered stage III and require more intensive therapy with whole abdominal irradiation and the use of doxorubicin. Prior to ligation of the renal vein, palpation of the vein and IVC should be performed to exclude intravascular tumor extension. The majority of patients with IVC extension will fortunately be identified by imaging studies obtained prior to surgery.41,42,99 Extension of tumor into the extrarenal vessels does not adversely affect prognosis if it is completely excised. For vena caval involvement below the level of the hepatic veins, the caval thrombus can be removed via cavotomy after proximal and distal vascular control is obtained. Generally, the thrombus will be free-floating, but if there is adherence of the thrombus to the caval wall, the thrombus can often be delivered with the passage of a Fogarty or Foley balloon catheter. Patients with atrial extension may require cardiopulmonary bypass for thrombus removal.100 Certain operative findings may suggest intravascular extension when it has not been correctly diagnosed preoperatively. For example, excessive bleeding from dilated superficial and retroperitoneal collaterals is a clue to obstruction of the vena cava. More ominous is the finding of sudden unexplained hypotension, which can result from embolization of the tumor thrombus.101 Primary surgical resection of inferior vena caval or atrial tumor extension is associated with increased surgical morbidity.45 Several reports have demonstrated that these patients can best be managed by shrinkage of tumor and thrombus with preoperative chemotherapy.42,51,102 This approach facilitates complete removal of the tumor with decreased morbidity. While there has been one report of tumor embolus during chemotherapy,103 this complication can also occur prior to or during surgical removal of the tumor.101
Occasionally, patients will present with massive tumors that are surgically unresectable. Heroic surgery with radical en bloc resection of the tumor and adjacent organs is not justified. Such operations are associated with increased surgical morbidity.45 In addition, the gross appearance of the tumor at the time of surgery can be misleading in interpreting tumor extent. These tumors often compress and adhere to adjacent structures without frank invasion; and in the majority of cases, tumor invasion is not confirmed after the adjacent visceral organs are removed.45 The appropriate management of tumors that are inoperable at presentation is tumor biopsy followed by chemotherapy. This approach almost always reduces the bulk of the tumor and renders it resectable.104,105 Usually, there is adequate size reduction within 6 weeks. Serial imaging studies are helpful in assessing response. Patients who fail to respond to chemotherapy can subsequently be considered for preoperative irradiation that may produce enough shrinkage to facilitate nephrectomy. One disadvantage of using preoperative therapy is that there is loss of important staging information. Patients with unresectable tumors treated with preoperative chemotherapy with or without additional radiation therapy should be considered stage III and treated accordingly.105 Therefore, it is very important that tumors are not determined to be unresectable on the basis of preoperative imaging alone. The morbidity of the surgical procedure should not be overlooked in the management of children with Wilms’ tumor. NWTS-4 patients undergoing primary nephrectomy had an 11% incidence of surgical complications.106 The most common complications encountered are hemorrhage and small bowel obstruction45,106,107 SIOP investigators have reported a lower rate of complications when nephrectomy is performed after preoperative chemotherapy.108 A prospective study comparing the incidence of surgical complications between NWTSG and SIOP is underway. COOPERATIVE GROUP TRIALS National Wilms’ Tumor Study Group Many early accomplishments in the treatment of children with Wilms’ tumor were made by individuals and large single institutions, but as survival improved larger numbers of patients were needed to conduct prospective randomized trials to answer therapeutic questions. Thus, in North America, both pediatric cooperative groups, the Children’s Cancer Group (CCG), and the Pediatric Oncology Group (POG) initially initiated clinical trials within their own group but subsequently decided to collaborate within the NWTSG. Meanwhile, investigators in Europe formed the Société International d’Oncologie Pédiatrique (SIOP) in an attempt to improve the outcome of children with Wilms’ tumor.
Chapter 47 Wilms’ Tumor 763
NWTS-1 and NWTS-2
NWTS-4
There were many important findings as a result of the early clinical trials NWTS-1 (1969 to 1973) and NWTS2 (1974 to 1978).109,110 For example, postoperative local irradiation was shown to be unnecessary for group I patients. Also, combination chemotherapy of vincristine (VCR) and AMD was found to be more effective than the use of either drug alone. The addition of doxorubicin (DOX) was shown to improve survival of higher-stage patients. However, even more important findings were the identification of unfavorable histologic features of Wilms’ tumor, and of prognostic factors that allowed refinement of the staging system stratifying patients into high-risk and low-risk treatment groups.111 After the completion of NWTS-1 and NWTS-2, it was recognized that the presence of lymph node metastases had an adverse outcome on survival. Children with lymph node metastases, as well as those with diffuse tumor spill, were found to be at increased risk of abdominal relapse. Therefore, such patients were considered stage III and given whole abdominal irradiation. These findings were incorporated into the design of NWTS-3 to try and decrease the intensity of therapy for the majority of low-risk patients while maintaining overall survival.
The goals of the NWTS-4 (1986 to 1994) were to further decrease treatment intensity for patients with favorable prognosis, while trying to maintain their excellent survival. In addition, this was the first clinical pediatric cancer trial to evaluate the economic impact of two different treatment approaches. Pulse-intensive regimens utilized simultaneous administration of agents at more frequent intervals to decrease the number of clinic visits and hence the cost of cancer treatment. NWTS-4 demonstrated that while the administered drug doseintensity was greater on pulse-intensive regimens, these regimens, which indeed are cost effective, produce less hematologic toxicity than the standard regimens.113 Patients treated with pulse-intensive regimens achieved equivalent survival compared to those treated with standard chemotherapy regimens.94 Treatment durations of approximately 6 and 15 months were found to be equally effective in patients with stages II to IV/FH tumors.114 Children with anaplastic Wilms’ tumors were randomized in NWTS-3 and NWTS-4 to receive VCR, AMD, DOX, or those three drugs with the addition of cyclophosphamide. There was no difference in outcome between the regimens for children with focal anaplasia who had a prognosis similar to that for FH patients.115 For stages II to IV diffuse anaplasia, the addition of cyclophosphamide to the three-drug regimen improved the 4-year relapse-free survival (27.2% versus 54.8%).
NWTS-3 In NWTS-3, patients with stage I, FH Wilms’ tumor were treated successfully with a 10-week regimen of VCR and AMD, considerably decreasing the amount of chemotherapy administered and, as a consequence, the total duration of treatment.48 The 4-year relapse-free survival was 89%, and the overall survival was 95.6%. Stage II FH patients treated with AMD and VCR without postoperative radiation therapy (XRT) had an equivalent survival, 4-year overall survival of 91.1%, to patients that received the same treatment plus DOX, demonstrating the cardiotoxic drug DOX is not necessary for the successful treatment of this group of patients. The dosage of abdominal irradiation for stage III FH patients was reduced to 1080 cGy. This was shown to be as effective as 2000 cGy in preventing abdominal relapse if DOX was added to VCR and AMD. The 4-year relapse-free survival for stage III patients was 82% in NWTS-3, the 4-year overall survival was 90.9%. Patients with stage IV FH tumors received abdominal (local) irradiation based on the local tumor stage. In addition, they all received 1200 cGy to both lungs. In combination with VCR, AMD, and DOX, the 4-year relapse-free survival was 79% and the overall survival was 80.9%.112 There was no statistically significant improvement in survival when cyclophosphamide was added to the three-drug regimen.
NWTS-5 The recently closed intergroup study, NWTS-5, was a single-arm therapeutic trial. Patients were not randomized for therapy, but instead biologic features of the tumors were prospectively assessed. The goal of this study was to verify the preliminary findings that LOH for chromosomes 16q and 1p are useful in identifying patients at increased risk for relapse.39 However, many other biologic factors can be studied with the use of banked tumor specimens collected on all enrolled patients.87 This tumor bank is available to all investigators and will be useful to evaluate new prognostic factors that may be identified in the future. If molecular genetic markers are predictive of clinical behavior, they may be used in subsequent clinical trials to further stratify patients for therapy. Accrual of patients for the NWTS-5 study was completed in late 2001. At this time, results from NWTS5 have not been published, as data need further maturation. Current recommendations for treatment are outlined in Table 47-5. These represent the treatment regimens used in NWTS-5. Treatment for patients with stage I or stage II FH and stage I anaplastic Wilms’ tumor is the same. Patients with stage III FH and stage II and stage III focal anaplasia are treated with AMD, VCR, and DOX
764
Part VIII Pediatric Malignancies
Table 47-5 Treatment Protocol for National Wilms Tumor Study-5 Stage/Histology
Radiation Therapy
Chemotherapy
Stages I and II FH
None
EE-4A; pulse-intensive AMD plus VCR (18 weeks)
1080 cGy*
DD-4A; pulse-intensive AMD, VCR and DOX (24 weeks)
Yes†
Regimen I: AMD, VCR, DOX, CPM, and etoposide
Yes†
Regimen RTK: carboplatin, etoposide, and CPM tumor of the kidney
Stage I anaplasia Stages III and IV FH Stages II to IV focal anaplasia Stages II to IV diffuse anaplasia Stages I to IV CCSK Stages I to IV rhabdoid
*Stage IV/FH patients are given radiation based on the local tumor stage. †Radiation therapy is given to all CCSK and RTK patients. Consult protocol for specific treatment. AMD, dactinomycin; VCR, vincristine; DOX, doxorubicin; CPM, cyclophosphamide; FH, favorable histology.
and 1080 cGy abdominal irradiation. Patients with stage IV FH tumors receive abdominal irradiation based on the local tumor stage and 1200 cGy to both lungs. Children with stages II to IV diffuse anaplasia and stages I to IV CCSK are treated with a regimen combining VCR, DOX, cyclophosphamide, and etoposide. Children with all stages of RTK were treated with carboplatin, cyclophosphamide, and etoposide. All these patients receive irradiation to the tumor bed. One portion of the NWTS-5 study examined the role of surgery alone for children under 2 years of age with stage I FH tumors weighing under 550 g has been published.116 This study was based on preliminary observation of favorable outcomes on small numbers of such patients when postoperative adjuvant therapy had been omitted.117,118 It was suspended when the number of tumor relapses exceeded the limit allowed by the design of the study. Seventy-five patients were enrolled. The sites of relapse were the lung in 5 children and the renal bed in 3 patients. The 2-year disease-free survival rate was 86.5%. The 2-year survival rate of this cohort of patients with small tumors is 100% with a median followup of 2.84 years,116 and extended follow-up continues. Observation of untreated children may yield interesting information on the role of chemotherapy in decreasing the incidence of contralateral relapse in patients with NRs. Three of these children (4%) have developed metachronous contralateral tumors.116 International Society of Pediatric Oncology The randomized trials conducted by SIOP differ from those of the NWTSG in that patients receive therapy prior to surgery. Also, no routine histopathologic diagnosis is obtained prior to commencing treatment. The
rationale for the SIOP approach is that preoperative chemotherapy will make the tumor less prone to intraoperative rupture or spill.119–120 The European investigators also indicate that preoperative therapy leads to a more favorable stage distribution at the time of surgery,122 as a result of which fewer patients will require postoperative radiation therapy. Preoperative treatment can indeed produce dramatic reduction in the size of the primary tumor facilitating surgical excision (Figure 47-5). The SIOP investigators use tumor extent as found at the time of delayed (postchemotherapy) surgery to determine local tumor stage. However, this postchemotherapy stage may inadequately define the risk of intra-abdominal recurrence in nonirradiated patients.121 The SIOP staging system separates stage II into “node-negative” and “node-positive” groups. In SIOP-6, patients with “postchemotherapy stage II” were randomized to receive or not receive abdominal irradiation. An unacceptable increase in the number of intra-abdominal recurrences in nonirradiated patients was noted, although survival rates for both groups were not significantly different.121 As a result, stage II node-negative patients are now given an anthracycline as part of the chemotherapy regimen. Consequently, a larger percentage of SIOP patients are now receiving a cardiotoxic drug than do patients registered to NWTSG studies. The significance of this is discussed later in the section on late effects. Of interest, when one compares the numbers of patients receiving abdominal irradiation, the incidence has decreased for both groups. The overall survival figures are comparable between the SIOP and NWTSG.114,123,124 The SIOP group has studied the pathologic changes in the tumor after preoperative therapy to help guide treatment decisions. This approach features the importance of Wilms’ tumor responsiveness as distinguished
Chapter 47 Wilms’ Tumor 765
Figure 47-5 A, MRI scan of a large inoperable Wilms’ tumor. B, After 6 weeks of chemotherapy the same tumor has dramatically decreased in size.
from its aggressiveness; the latter is more important in determining tumor stage at diagnosis. In SIOP-9, pathologic review of the resected specimens after chemotherapy revealed completely necrotic (defined as <1% of viable tumor) Wilms’ tumor in approximately 10% of specimens.125 Of these patients, 98% had no evidence of disease at 5 years (1 nontumor death). These patients are now considered to be “low-risk tumors” by SIOP. The other low-risk tumors are CMN, cystic partially differentiated nephroblastoma, nephroblastoma with fibroadenomatous features, and nephroblastoma of
highly differentiated epithelial type. In the latest SIOP Wilms’ study, stage I low-risk tumors did not receive chemotherapy after nephrectomy. Intermediate-risk tumors were defined as mixed type nephroblastoma, focal anaplasia, regressive type nephroblastoma, epithelial type nephroblastoma, and stromal type nephroblastoma.126 High-risk tumors are diffuse anaplasia and nephroblastoma-blastemal type. The latter is defined as viable tumor in more than 1/3 of the mass and 2/3 of the viable tumor consists of blastema. Although the proportion of patients with blastemal
766
Part VIII Pediatric Malignancies
predominant tumors is decreased after chemotherapy, these patients had a 31% relapse rate in the SIOP-9 study.125 These patients require more intensive treatment after nephrectomy. BILATERAL WILMS’ TUMORS Synchronous BWT occurs in about 5% of children with metachronous lesions developing in only 1%.50,52,127 Therapy for patients with BWT is focused on sparing renal parenchyma to decrease the risk for renal failure noted in these children.50,52,127,128 Review of NWTSG patients found that 9.1% of children with synchronous BWT and 18.8% of metachronous BWT developed renal failure.129 The most common cause of renal failure was bilateral nephrectomy for persistent or recurrent tumor in the remaining kidney after initial nephrectomy. Therefore, avoiding total nephrectomy at initial surgery is advised. The NWTSG recommends that all children with BWT should receive chemotherapy prior to surgical resection. At initial surgical exploration, bilateral biopsies should be obtained for histopathologic confirmation of disease in both kidneys and definition of the histologic subtype. Examination for extrarenal spread is performed. If suspicious lymph nodes or other disease is noted, this should be biopsied and a surgical stage assigned. In NWTS-5, patients with FH and stage I or stage II disease were given AMD and VCR, while those with stage III or stage IV FH also received DOX. The patient is given 6 weeks of chemotherapy and then reassessed with imaging studies. Experience from SIOP has shown that most of the reduction in tumor volume will occur early. In SIOP-9, the reduction in tumor volume was 48% after 4 weeks and increased to 62% after 8 weeks of chemotherapy.123,124 Although this difference was not of significance for unilateral tumors, further shrinkage may facilitate a parenchymal sparing approach. It is important to recognize that response of the tumor by imaging does not always correlate with the histologic response. A clinically good response (by imaging) is usually associated with a pathologically good response in terms of regressive histologic changes.130 The converse is not always true. Important data on histology of postchemotherapy specimens has been collected by SIOP investigators. Although this information has only been reported for children with unilateral tumors, the information can be extrapolated to those with BWT. The distribution of histologic subtypes is different in children treated with preoperative chemotherapy compared to those undergoing primary surgery.83,125,130 Differentiation of the tumor after chemotherapy has been noted by several investigators. Stromal predominant tumors were noted in 14%
patients treated with preoperative chemotherapy compared to 1.6% of children undergoing primary nephrectomy in NWTS-4. Epithelial predominant tumors also were noted with increased frequency. The latter two types are often associated with a poor clinical response to therapy as determined by preoperative imaging. There is a less marked reduction in tumor volume after chemotherapy but lower rates of relapse.125,130 The prognosis for patients with these tumor types is excellent if the tumors are completely excised. These tumors do seem to be more resistant to therapy when seen at higher stages. Another histologic subtype that often fails to shrink with chemotherapy is fetal rhabdomyomatous nephroblastoma.131,132 Some tumors with complete necrosis and predominantly regressive changes can increase in size during therapy. There is a 10% incidence of anaplasia in BWT.50,128 The incidence of anaplasia is higher in girls than boys.50,128 There can be discordance in the pathology between the two kidneys. Tumor size or other gross features does not correlate with histology, and careful examination of both specimens is required. This information demonstrates the importance of obtaining biopsy specimens in patients those are not responding to chemotherapy. In some of these children, further chemotherapy will not lead to tumor shrinkage. Therefore, if the patient has not responded, reexploration with biopsy of the tumor should be performed in 12 weeks. At the time of the second look procedure, partial nephrectomy or wedge excision of the tumor is performed whereever possible. If extensive tumor involvement precluding partial resection is still present after preoperative therapy, complete excision of tumor from the least involved kidney is performed. If this leaves a viable kidney, nephrectomy of the other kidney is carried out. Occasionally, bilateral nephrectomy is indicated. This will result in the need for dialysis. Indeed the most common cause of renal failure in NWTS patients is bilateral nephrectomy for persistent tumor.129 If transplantation is later considered, a waiting period of 2 years is recommended to ensure that the patient does not develop metastatic disease.133 TREATMENT OF RELAPSES Children with relapsed Wilms’ tumor have a variable prognosis, depending on the initial stage, site of relapse, time from initial diagnosis to relapse and prior therapy. Adverse prognostic factors include relapse <12 months after diagnosis, prior treatment with DOX, and intraabdominal relapse in patients who had previously received abdominal irradiation.134 The risk of tumor relapse in NWTS-3 at 3 years was 9.6%, 11.8%, 22%, and 22%, respectively, for stages I to IV. Relapses
Chapter 47 Wilms’ Tumor 767
occurred in 36% of stages I to III and 45% of stage IV patients with unfavorable histology.48 LATE EFFECTS OF CANCER TREATMENT One consequence of the tremendous improvement in survival of children with malignancies is that there are many long-term survivors who have been exposed to both radiation and chemotherapeutic agents. These children require long-term surveillance, as the sequelae of this therapy may not be evident for many years. One of the more serious concerns is the increased risk for second malignant neoplasms (SMN). Investigators from the NWTSG have noted a 1.6% cumulative incidence of SMNs at 15 years posttreatment.135 Prior treatment for relapse, the amount of abdominal irradiation, and use of DOX were all associated with an increased incidence of SMNs. Another risk associated with DOX is cardiac toxicity. Congestive heart failure is a well-known acute complication of treatment with anthracycline and the incidence is dose related.136 For NWTS-1, NWTS-2, NWTS-3, and NWTS-4 patients, the cumulative frequency of congestive heart failure was 4.4% at 20 years after diagnosis among patients treated initially with doxorubicin.137 The relative risk of congestive heart failure was increased in females by cumulative doxorubicin dose, lung irradiation, and left abdominal irradiation. Numerous other organ systems are subject to the late sequelae of anticancer therapy. An early report of NWTSG patients found that musculoskeletal problems, such as scoliosis, were 7 times more common in children those were treated with radiation.138 A more recent review of 2778 NWTSG patients found that reduction in stature following RT to the pediatric spine is dose dependent and age dependent. However, average height deficits observed at maturity for children receiving doses currently recommended by the NWTSG are clinically nonsignificant.139 Damage to reproductive systems can lead to problems with hormonal dysfunction and/or infertility. Female Wilms’ tumor patients who received abdominal radiation have a 12% incidence of ovarian failure.140 In addition, women with prior abdominal radiation have the potential for adverse pregnancy outcomes.141,142 Perinatal mortality rates are higher, and infants are more likely to have low birth weights.143 Gonadal radiation in males can result in temporary azoospermia and hypogonadism.144 The severity of damage to the testis is dependent on the dose or radiation. There has been concern about the late occurrence of renal dysfunction in children who have undergone nephrectomy. Patients have been found to develop proteinuria, hypertension, and renal insufficiency secondary to focal glomerulosclerosis, which has been attributed to
hyperfiltration injury.144,145 There is both clinical and experimental evidences of hyperfiltration damage of remnant nephrons after a loss of renal mass.146 Most experimental studies involve a loss of >3/4 of the total renal mass, but there is only limited data assessing renal function long term in children following unilateral nephrectomy.147,148 While several studies have found no significant alterations in renal function following unilateral nephrectomy for Wilms’ tumor,149–151 other reports have noted an increased incidence of proteinuria and decreased glomerular filtration rate (GFR).147,148,152,153 However, clinically important hypertension or renal insufficiency is rare. One of the more important risk factors for a decrease in GFR is the amount of radiation to the remaining kidney. The correlation of functional impairment with the renal radiation dose was reported by Mitus et al.154 a review of 100 children treated for Wilms’ tumor. The incidence of impaired creatinine clearance was significantly greater for children who received >1200 cGy to the remaining kidney, and all cases of overt renal failure occurred in patients who had received more than 2300 cGy. The concern of renal dysfunction has led some centers to consider parenchyma-sparing procedures for unilateral tumors.155,156 Because the majority of tumors are too large for partial nephrectomy at presentation, the patient must be given preoperative chemotherapy, after that less than 10% of patients may then be amenable to partial nephrectomy. However, in order to scientifically justify this approach, many children would have to be treated accordingly to demonstrate its benefits since the incidence of renal failure is quite low for unilateral Wilms’ tumor. A review of the NWTSG database found that <0.2% of unilateral Wilms’ tumor patients developed renal failure. Moreover, the majority of these patients suffered from the Denys-Drash syndrome, a disorder whereby all patients invariably develop end-stage renal disease irrespective of the cancer therapy.129 A recent report from the NWTSG did find an increased risk of renal failure in children with Wilms’ tumor who also had aniridia or genitourinary abnormalities.157 The cumulative risk of renal failure at 20 years was 38% for the patients with aniridia. REFERENCES 1. Zantinga AR, Coppes MJ: Max Wilms (1867–1918): the man behind the eponym. Med Pediatr Oncol 1992; 20:515–518. 2. Zantinga AR, Coppes, MJ: Historical aspects of the identification of the entity Wilms’ tumor, and of its management. Hematol Oncol Clin North Am 1995; 9:1145–1155. 3. Priestly JT, Schulte TL: The treatment of Wilms’ tumor. Urology 1942; 47:7–10.
768
Part VIII Pediatric Malignancies
4. Farber S: Chemotherapy in the treatment of leukemia and Wilms’ tumor. JAMA 1966; 198:826–836. 5. Sutow WW: Chemotherapy in childhood cancer (except leukemia). An appraisal. Cancer 1965; 18:1585. 6. Birch JM, Breslow N: Epidemiologic features of Wilms’ tumor. Hematol Oncol Clin North Am 1995; 9:1157–1178. 7. Breslow N, Olshan A, Beckwith JB, et al: Ethnic variation in the incidence, diagnosis, prognosis and follow-up of children with Wilms’ tumor. J Natl Cancer Inst 1994; 86:49–51. 8. Olshan AF, Breslow NE, Daling JR, et al: Wilms’ tumor and paternal occupation. Cancer Res 1990; 50:3212–3217. 9. Miller RW, Fraumeni JF, Manning MD: Association of Wilms’ tumor with aniridia, hemihypertrophy and other congenital malformations. N Engl J Med 1964; 270:922–927. 10. Clericuzio CL: Clinical phenotypes and Wilms’ tumor. Med Pediatr Oncol 1993; 21:182–187. 11. Breslow NE, Beckwith JB: Epidemiological features of Wilms’ tumor: results of the National Wilms’ Tumor Study. J Natl Cancer Inst 1982; 68:429–436. 12. Denys P, Malvaux P, Van Den Berghe H, Tanghe W, Proesmans W: Association d’un syndrome anatomo-pathologique de pseudohermaphrodisitism masculin, d’une tumeur de Wilms, d’une nephropathie parenchymateuse dt d’un mosaicism XX/XY. Arch Fr Pediatr 1967; 24:729–39. 13. Drash A, Sherman F, Hartmann WH, Blizzard RM: A syndrome of pseudohermaphroditism, Wilms’ tumor, hypertension and degenerative renal disease. J Pediatr 1970; 76:585–593. 14. Jadresic L, Leake J, Gordon I, et al: Clinicopathologic review of twelve children with nephropathy, Wilms’ tumor, and genital abnormalities (Drash syndrome). J Pediatr 1990; 117:717–725. 15. Pelletier J, Bruening W, Kashtan CE, et al: Germline mutations in the Wilms’ tumor suppressor gene are associated with abnormal urogenital development in Denys-Drash syndrome. Cell 1991; 67:437–447. 16. Coppes MJ, Huff V, Pelletier J: Denys-Drash syndrome: relating a clinical disorder to genetic alterations in the tumor suppressor gene WT1. J Pediatr 1993; 123:673–678. 17. Riccardi VM, Sujansky E, Smith AC, Francke U: Chromosomal imbalance in the aniridia-Wilms’ tumor association: 11p interstitial deletion. Pediatrics 1978; 61:604–610. 18. Sotelo-Avila C, Gonzalez-Crussi F, Fowler JW: Complete and incomplete forms of Beckwith-Wiedemann syndrome: Their oncogenic potential. J Pediatr 1980; 96:47–50. 19. Beckwith JB: Macroglossia, omphalocele, adrenal cytomegaly, gigantism and hyperplastic visceromegaly. Birth Defects: Original Article Series 1969; 5:188–196. 20. Debaun MR, Siegel MJ, Choyke PL: Nephromegaly in infancy and early childhood: a risk factor for Wilms’ tumor in Beckwith-Wiedemann syndrome. J Pediatr 1998; 132:401–404. 21. Porteus MH, Norkool P, Neuberg D, et al: Characteristics and outcome of children with Beckwith-
22.
23.
24.
25.
26.
27.
28. 29.
30.
31.
32. 33. 34.
35.
36.
37.
38.
Wiedemann syndrome and Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 2000; 18:2026–2031. Green DM, Breslow NE, Beckwith JB, Norkool P: Screening of children with hemihypertrophy, aniridia, and Beckwith-Wiedemann syndrome in patients with Wilms’ tumor: a report from the National Wilms’ Tumor Study. Med Pediatr Oncol 1993; 21:188–192. Choyke PL, Siegel MJ, Craft AW, et al: Screening for Wilms’ tumor in children with Beckwith-Wiedemann syndrome or idiopathic hemihypertrophy. Med Pediatr Oncol 1999; 32:196–200. Choyke PL, Siegel MJ, Oz O, et al: Nonmalignant renal disease in pediatric patients with Beckwith-Wiedemann syndrome. Am J Roentgenol 1998; 171:733–737. Coppes MJ, Haber DA, Grundy P: Genetic events in the development of Wilms’ tumor. N Engl J Med 1994; 331:586–590. Knudson AG, Strong LC: Mutation and cancer: a model for Wilms’ tumor of the kidney. J Natl Cancer Inst 1972; 48:313–324. Koufos A, Hansen MF, Lampkin BC, et al: Loss of alleles at loci on human chromosome 11 during genesis of Wilms’ tumor. Nature 1984; 309:170–172. Huff V: Inheritance and functionality of Wilms’ tumor genes. Cancer Bull 1994; 46:255–259. Bonetta L, Kuehn SE, Huang A, et al: Wilms’ tumor locus on 11p13 defined by multiple CpG island-associated transcripts. Science 1990; 250:994–997. Call KM, Glaser T, Ito CY, et al: Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cell 1990; 60:509–520. Gessler M, Poustka A, Cavenee W, et al: Homozygous deletion in Wilms’ tumour of a zinc-finger gene identified by chromosome jumping. Nature 1990; 343:774–778. Coppes MJ, Campbell CE, Williams BRG: The role of WT1 in Wilms’ tumorigenesis. FASEB J 1993; 7:886–895. Kreidberg JA, Sariola H, Loring JM, et al: WT-1 is required for early kidney development. Cell 1993; 74:679. Reeve AE, Sih SA, Raizis AM, Feinberg AP: Loss of allelic heterozygosity at a second locus on chromosome 11 in sporadic Wilms’ tumor cells. Mol Cell Biol 1989; 44:711–719. Koufos A, Grundy P, Morgan K, et al: Familial Wiedemann-Beckwith syndrome and a second Wilms’ tumor locus both map to 11p15.5. Am J Human Genet 1989; 44:711–719. Coppes MJ, Bonetta L, Huang A, et al: Loss of heterozygosity mapping in Wilms’ tumor indicates the involvement of three distinct regions and a limited role for non-disjunction or mitotic recombination. Genes, Chromosomes & Cancer 1992; 5:326–334. Grundy P, Telzerow P, Haber D, et al: Chromosome 11 uniparental isodisomy predisposing to embryonal neoplasms. Lancet 1991; 338:1079. Maw MA, Grundy PE, Millow LJ, et al: A third Wilms’ tumor locus on chromosome 16q. Cancer Res 1992; 52:3094–3098.
Chapter 47 Wilms’ Tumor 769 39. Grundy PE, Telzerow PE, Breslow N, et al: Loss of heterozygosity for chromosomes 16q and 1p in Wilms’ tumor predicts an adverse outcome. Cancer Res 1994; 54:2331–2333. 40. Coppes MJ: Serum biological markers and paraneoplastic syndromes in Wilms’ tumor. Med Pediatr Oncol 1993, 21:213–221. 41. Ritchey ML, Kelalis PP, Breslow N, et al: Intracaval and atrial involvement with nephroblastoma: Review of National Wilms’ Tumor Study-3. J Urol 1988; 140:1113–1118. 42. Shamberger RC, Ritchey ML, Haase GM, et al: Intravascular extension of Wilms’ tumor: Report of the National Wilms’ Tumor Study Group. Ann Surg 2001; 234:116–121. 43. Cohen MD: Staging of Wilms’ tumor. Clin Radiol 1993; 47:77–81. 44. D’Angio GJ, Rosenberg H, Sharples K, et al: Position paper: imaging methods for primary renal tumors of childhood: Cost versus benefits. Med Pediatr Oncol 1993; 21:205–212. 45. Ritchey ML, Kelalis PP, Breslow N, et al: Surgical complications following nephrectomy for Wilms’ tumor: a report of National Wilms’ Tumor Study-3. Surg Gynecol Obstet 1992; 175:507–514. 46. Weese DL, Applebaum H, Taber P: Mapping intravascular extension of Wilms’ tumor with magnetic resonance imaging. J Pediatr Surg 1991; 26:64–67. 47. Laissy JP, Menegazzo D, Debray MP, et al: Renal carcinoma: diagnosis of venous invasion with Gd-enhanced MR venography. Eur Radiol 2000; 10:1138–1143. 48. D’Angio GJ, Breslow N, Beckwith JB, et al: Treatment of Wilms’ tumor: results of the Third National Wilms’ Tumor Study. Cancer 1989; 64:349–360. 49. Othersen HB Jr, DeLorimer A, Hrabovsky E, et al: Surgical evaluation of lymph node metastases in Wilms’ tumor. J Pediatr Surg 1990; 25:3:1–2. 50. Blute ML, Kelalis PP, Offord KP, et al: Bilateral Wilms’ Tumor. J Urol 1987; 138:968–973. 51. Ritchey ML, Kelalis PP, Haase GM, et al: Preoperative therapy for intracaval and atrial extension of Wilms’ tumor. Cancer 1993; 71:4104–4110. 52. Montgomery BT, Kelalis PP, Blute ML, et al: Extended follow-up of bilateral Wilms’ tumor: results of the National Wilms’ Tumor Study. J Urol 1991; 146:514–518. 53. Ritchey ML, Green DM, Breslow NE, Norkool P: Accuracy of current imaging modalities in the diagnosis of synchronous bilateral Wilms’ tumor. Cancer 1995; 75:600–604. 54. Ng YY, Hall-Craggs MA, Dicks-Mireaux C, Pritchard J: Wilms’ tumour: Pre- and post-chemotherapy CT appearances. Clin Radiol 1991; 43:255–259. 55. Thomas PRM, Shochat SJ, Norkool P, et al: Prognostic implications of hepatic adhesion, invasion, and metastases at diagnosis of Wilms’ tumor. Cancer 1991; 68:2486–2488. 56. Wilimas J, Douglass EC, Magill HL, Fitch S, Hutsu HO: Significance of pulmonary computed tomography at diagnosis in Wilms’ tumor. J Clin Oncol 1988; 6:1144–1146.
57. Wooton SL, Rumack CM, Albano EA, et al: Pulmonary metastases in Wilms’ tumor. Pediatr Radiol 1994; 24:463. 58. Cohen MD: Current controversey: Is CT scan of the chest needed in patients with Wilms’ tumor? J Pediatr Hematol Oncol 1994; 16:191. 59. Green DM, Fernbach DJ, Norkool P, Kollia G, D’Angio GJ: The treatment of Wilms’ tumor patients with pulmonary metastases detected only with computed tomography: a report from the National Wilms’ Tumor Study. J Clin Oncol 1991; 9:1776–1781. 60. Meisel JA, Guthrie KA, Breslow NE, et al: Significance and management of computed tomography detected pulmonary nodules: a report from the National Wilms’ Tumor Study Group. Int J Radiat Oncol Biol Phys 1999; 44:579–585. 61. Owens CM, Veys PA, Pritchard J, et al: Role of chest computed tomography at diagnosis in the management of Wilms’ tumor: a study by the United Kingdom Children’s Cancer Study Group. J Clin Oncol 2002; 20:2768–2773. 62. Argani P, Perlman EJ, Breslow NE, et al: Clear cell sarcoma of the kidney: a review of 351 cases from the National Wilms’ Tumor Study Pathology Center. Am J Surg Pathol 2000; 24:4–18. 63. Amar AM, Tomlinson G, Green DM, et al: Clinical presentation of rhabdoid tumors of the kidney. J Pediatr Hematol Oncol 2001; 23:105–108. 64. Glass RBJ, Davidson AJ, Fernbach SK: Clear cell sarcoma of the kidney: CT, sonographic and pathologic correlation. Radiology 1991; 180:715–717. 65. White KS, Grossman H: Wilms’ and associated renal tumors of childhood. Pediatr Radiol 1991; 21:81–88. 66. Broecker B: Renal cell carcinoma in children. Urology 1991; 38:54–56. 67. Raney RB Jr, Palmer N, Sutow WW, et al: Renal cell carcinoma in children. Med Pediatr Oncol 1983; 11:91–98. 68. Blute ML, Malek RS, Segura JW: Angiomyolipoma: a clinical metamorphosis and concepts for management. J Urol 1988; 139:20–24. 69. Ewalt DH, Sheffield E, Sparagana SP, et al: Renal lesion growth in children with tuberous sclerosis complex. J Urol 1998; 160:141–145. 70. Howell CJ, Othersen HB, Kiviat NE, et al: Therapy and outcome in 51 children with mesoblastic nephroma: a report of the National Wilms’ Tumor Study. J Pediatr Surg 1982; 17:826–830. 71. Ritchey ML, Azizkhan RG, Beckwith JB: Neonatal Wilms’ tumors. J Pediatr Surg 1995; 30:856–859. 72. Gormley TS, Skoog SJ, Jones RV, Maybee D: Cellular congenital mesoblastic nephroma: What are the options? J Urol 1989; 142:479–483. 73. Joshi VV, Kasznica J, Walters TR: Atypical mesoblastic nephroma. Pathologic characterization of a potentially aggressive variant of conventional congenital mesoblastic nephroma. Arch Pathol Lab Med 1986; 110:100–106. 74. Heidelberger KP, Ritchey ML, Dauser RC, McKeever PE, Beckwith JB: Congenital mesoblastic nephroma metastatic to the brain. Cancer 1993; 72:2499–2502.
770
Part VIII Pediatric Malignancies
75. Beckwith JB: Congenital mesoblastic nephroma. When should we worry? Arch Pathol Lab Med 1986; 110:98–99. 76. Schmidt D, Beckwith JB: Histopathology of childhood renal tumors. Hematol Oncol Clin North Am 1995; 9:1179–1200. 77. Beckwith JB, Zuppan CE, Browning NG, et al: Histological analysis of aggressiveness and responsiveness in Wilms’ tumor. Med Pediatr Oncol 1996; 27:422–428. 78. Beckwith JB, Palmer NF: Histopathology and prognosis of Wilms’ tumor. Results from the National Wilms’ Tumor Study. Cancer 1978; 41:1937–1948. 79. Breslow NB, Churchill G, Beckwith JB, et al: Prognosis for Wilms’ tumor patients with nonmetastatic disease at diagnosis – results of the Second National Wilms’ Tumor Study. J Clin Oncol 1985; 3:521–531. 80. Weirich A, Schmidt D, Harms D, et al: Distribution of subtypes in standard Wilms’ tumor after pre-operative chemotherapy and its possible influence of the patients cure rate. Med Pediatr Oncol 1994; 23:217. 81. Bonadio JF, Storer B, Norkool P, et al: Anaplastic Wilms’ tumor: clinical and pathological studies. J Clin Oncol 1985; 3:513–520. 82. Faria P, Beckwith JB, Mishra K, et al: Focal versus diffuse anaplasia in Wilms’ tumor—new definitions with prognostic significance: a report from the National Wilms’ Tumor Study Group. Am J Surg Pathol 1996; 20: 909–920. 83. Zuppan CW, Beckwith JB, Weeks DA, Luckey DW, Pringle KC: The effect of preoperative therapy on the histologic features of Wilms’ tumor. An analysis of cases from the Third National Wilms’ Tumor Study. Cancer 1991; 68:385–394. 84. Beckwith JB, Kiviat NB, Bonadio JF: Nephrogenic rests, nephroblastomatosis, and the pathogenesis of Wilms’ tumor. Pediatr Pathol 1990, 10:1–36. 85. Beckwith JB: Nephrogenic rests and the pathogenesis of Wilms’ tumor: developmental and clinical considerations. Am J Med Genet 1998; 79:268–273. 86. Coppes MJ, Arnold M, Beckwith JB, et al: Factors affecting the risk of contralateral Wilms’ tumor development. Cancer 1999; 85:1616–1625. 87. Dome JS, Chung S, Bergemann T, et al: High telomerase reverse transcriptase (hTERT) messenger RNA level correlates with tumor recurrence in patients with favorable histology Wilms’ tumor. Cancer Res 1999; 59:4301–4307. 88. Douglass EC, Look AT, Webber B, et al: Hyperdiploidy and chromosomal rearrangements define the anaplastic variant of Wilms’ tumor. J Clin Oncol 1986; 4:975. 89. Rainwater LM, Hosaka Y, Farrow GM, et al: Wilms’ tumors: relationship of nuclear deoxyribonucleic acid ploidy to patient survival. J Urol 1987; 138:974–977. 90. Layfield LJ, Ritchie AWS, Ehrlich R: The relationship of deoxyribonucleic acid content to conventional prognostic factors in Wilms’ tumor. J Urol 1989; 142:1040–1043. 91. Kayton ML, Rowe DH, O’Toole KM, et al: Metastasis correlates with production of vascular endothelial growth factor in a murine model of human Wilms’ tumor. J Pediatr Surg 1999; 34:743–748.
92. Rowe DH, Huang J, Kayton ML, et al: Anti-VEGF antibody suppresses primary tumor growth and metastasis in an experimental model of Wilms’ tumor. J Pediatr Surg 2000; 35:30–33. 93. Huang J, Moore J, Soffer S, et al: Highly specific antiangiogenic therapy is effective in suppressing growth of experimental Wilms’ tumors. J Pediatr Surg 2001; 36:357–361. 94. Green DM, Breslow N, Beckwith JB, et al: Comparison between single-dose and divided-dose administration of dactinomycin and doxorubicin for patients with Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 1998; 16: 237–245. 95. Weeks DA, Beckwith JB, Luckey DW: Relapseassociated variables in stage I, favorable histology Wilms’ tumor. Cancer 1987; 60:1204–1212. 96. Shamberger RC, Guthrie KA, Ritchey ML, et al: Surgery-related factors and local recurrence of Wilms’ tumor in National Wilms’ Tumor Study 4. Ann Surg 1999; 229:292–297. 97. Breslow N, Churchill G, Nesmith B, et al: Clinicopathologic features and prognosis for Wilms’ tumor patients with metastases at diagnosis. Cancer 1986; 58:2501–2511. 98. Ritchey ML, Lally KP, Haase GM, Shochat SJ, Kelalis PP: Superior mesenteric artery injury during nephrectomy for Wilms’ Tumor. J Pedatr Surg 1992; 27:612–615. 99. Ritchey ML, Othersen HB Jr, deLorimier AA, et al: Renal vein involvement with nephroblastoma: a report of National Wilms’ Tumor Study 3. Eur Urol 1990; 17:139–144. 100. Nakayama DK, deLorimier AA, O’Neill JA Jr, et al: Intracardiac extension of Wilms’ tumor: a report of the National Wilms’ Tumor Study. Ann Surg 1986; 204:693–697. 101. Shurin SB, Gauderer MWL, Dahms BB, Conrad WG: Fatal intraoperative pulmonary embolization of Wilms’ tumor. J Pediatr 1982; 101:559–562. 102. Dykes EH, Marwaha RK, Dicks-Mireaux C, et al: Risks and benefits of percutaneous biopsy and primary chemotherapy in advanced Wilms’ tumour. J Pediatr Surg 1991;26:610–612. 103. Borden TA: Wilms’ tumor and pulmonary embolism. Soc Pediatr Urol Newsletter 1992:27–29. 104. Bracken RB, Sutow WW, Jaffe N, Ayala A, Guarda L: Preoperative chemotherapy for Wilms’ tumor. Urology 1982; 19:55–60. 105. Ritchey ML, Pringle K, Breslow N, et al: Management and outcome of inoperable Wilms’ tumor. a report of National Wilms’ Tumor Study. Ann Surg 1994; 220:683–690. 106. Ritchey ML, Shamberger RC, Haase G, et al: Surgical complications after nephrectomy for Wilms’ tumor: report from the National Wilms’ Tumor Study Group. Pediatrics 1999; 104:816–817. 107. Ritchey ML, Kelalis P, Breslow N, Etzioni R, Haase G: Small bowel obstruction following nephrectomy for Wilms’ tumor. Ann Surg 1993; 218:654–659.
Chapter 47 Wilms’ Tumor 771 108. Godzinski J, Tournade MF, deKraker J, et al: Rarity of surgical complications after postchemotherapy nephrectomy for nephroblastoma. Experience of the International Society of Paediatric Oncology—Trial and study “SIOP-9”. International Society of Paediatric Oncology Nephroblastoma Trial and Study committee. Eur J Pedatr Surg 1998; 8:83–86. 109. D’Angio GJ, Evans AE, Breslow N, et al: The treatment of Wilms’ tumor: results of the National Wilms’ Tumor Study. Cancer 1976; 38:633–646. 110. D’Angio GJ, Evans A, Breslow N, et al: The treatment of Wilms’ tumor: results of the Second National Wilms’ Tumor Study, Cancer 1981; 47:2302–2311. 111. Farewell VT, D’Angio GJ, Breslow N, Norkool P: Retrospective validation of a new staging system for Wilms’ tumor. Cancer Clin Trials 1981; 4:167–171. 112. Green DM, Breslow N, Evans I, et al: The treatment of children with stage IV Wilms’ tumor. A report from the National Wilms’ Tumor Study Group. Med Pediatr Oncol 1996; 26:147–152. 113. Green DM, Breslow NE, Evan I, et al: Effect of dose intensity of chemotherapy on the hematological toxicity of the treatment of Wilms’ tumor. A report from the National Wilms’ Tumor Study. Am J Pediatr Hematol Oncol 1994; 16:207–212. 114. Green DM, Breslow NE, Beckwith JBB, et al: Effect of duration of treatment on treatment outcomes and cost of treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 1998; 16:3744–3751. 115. Green DM, Beckwith JB, Breslow NB, et al: The treatment of children with Stage II-IV anaplastic Wilms’ tumor. A report from the National Wilms’ Tumor Study. J Clin Oncol 1994; 12:2126–2131. 116. Green DM, Breslow NE, Beckwith JB, Ritchey ML, et al: Treatment with nephrectomy only for small, stage I/favorable histology Wilms’ tumor. A Report From The National Wilms’ Tumor Study Group. J Clin Oncol 2001; 19:3719–3724. 117. Larsen E, Perez-Atayde A, Green DM, et al: Surgery only for the treatment of patients with stage I (Cassady) Wilms’ tumor. Cancer 1990; 66:264–266. 118. Green DM, Beckwith JB, Weeks DA, et al: The relationship between microsubstaging variables, tumor weight and age at diagnosis of children with stage I/favorable histology Wilms’ tumor. A report from the National Wilms’ Tumor Study. Cancer 1994; 74:1817–1820. 119. Lemerle J, Voûte PA, Tournade MF, et al: Preoperative versus postoperative radiotherapy, single versus multiple courses of actinomycin D, in the treatment of Wilms’ tumor: preliminary results of a controlled clinical trial conducted by the International Society of Pediatric Oncology (SIOP). Cancer 1976; 38:647–654. 120. Lemerle J, Voûte PA, Tournade MF, et al: Effectiveness of preoperative chemotherapy in Wilms’ tumor: results of an International Society of Pediatric Oncology (SIOP) clinical trial. J Clin Oncol 1983; 1:604–609. 121. Tournade MF, Com-Nougue C, Voûte PA, et al: Results of the Sixth International Society of Pediatric Oncology
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133. 134.
135.
136.
Wilms’ tumor trial and study: a risk-adapted therapeutic approach in Wilms’ tumor. J Clin Oncol 1993; 11:1014–1023. deKraker J, Weitzman S, Voûte PA: Preoperative strategies in the management of Wilms’ tumor. Hematol Oncol Clin North Am 1995; 9:1275–1286. Tournade MF, Com-Nogoue, deKraker J, et al: Optimal duration of preoperative chemotherapy in unilateral and nonmetastatic Wilms’ tumor in children over 6 months of age: Result of the 9th SIOP Wilms’ tumor trial and study. J Clin Oncol 2001; 19:488–500. Graf N, Tournade MF, deKraker J: The role of preoperative chemotherapy in the management of Wilms’ tumor. Urol Clin North Am 2000; 27:443–454. Boccon-Gibod L, Rey A, Sandstedt B, et al: Complete necrosis induced by preoperative chemotherapy in Wilms’ tumor as an indicator of low risk: Report of the International Society of Pediatric Oncology (SIOP) Nephroblastoma Trial and Study 9. Med Pediatr Oncol 2000; 34:183–190. Vujanic GM, Sandstedt B, Harms D, et al: Revised International Society of Pediatric Oncology (SIOP) working classification of renal tumors of childhood. Med Pediatr Oncol 2002; 38:79–82. Coppes MJ, deKraker J, Van Dijken PJ, et al: Bilateral Wilms’ tumor: Long-term survival and some epidemiological features. J Clin Oncol 1989; 7:310–315. Kumar R, Fitzgerald R, Breatnach F: Conservative surgical management of bilateral Wilms’ tumor: results of the United Kingdom Children’s Cancer Study Group. J Urol 1998; 160:1450–1453. Ritchey ML, Green DM, Thomas P, et al: Renal failure in Wilms’ tumor patients: a report of the NWTSG. Med Pediatr Oncol 1996; 26:75–80. Weirich A, Leuschner I, Harms D, et al: Clinical impact of histologic subtypes in localized non-anaplastic nephroblastoma treated according to the trial and study SIOP-9/GPOH. Ann Oncol 2001; 12:311–319. Maes P, Delemarrre J, deKraker J, Ninane J: Fetal rhabdomyomatous nephroblastoma: a tumour of good prognosis but resistant to chemotherapy. Eur J Cancer 1999; 35:1356–1360. Anderson J, Slater O, McHugh K, et al: Response without shrinkage in bilateral tumor: significance of rhabdomyomatous histology. J Pediatr Hematol Oncol 2002; 24:31–34. Penn I: Renal transplantation for Wilms’ tumor: report of 20 cases. J Urol 1979; 122:793–794. Grundy P, Breslow N, Green DM, et al: Prognostic factors for children with recurrent Wilms’ tumor: results from the second and third National Wilms’ Tumor Study. J Clin Oncol 1989; 7:638–647. Breslow NE, Takashima JR, Whitton JA, et al: Second malignant neoplasms following treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 1995; 13:1851–1859. Gilladoga AC, Manuel C, Tan CT, et al: The cardiotoxicity of adriamycin and daunomycin in children. Cancer 1976; 37:1070–1078.
772
Part VIII Pediatric Malignancies
137. Green DM, Grigoriev YA, Nan B, et al: Congestive failure after treatment for Wilms’ tumor. A report from the National Wilms’ Tumor Study Group. J Clin Oncol 2001; 19:1926–1934. 138. Evans AE, Norkool P, Evans I, Breslow N, D’Angio GJ: Late effects of treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. Cancer 1991; 67:331–336. 139. Hogeboom CJ, Grosser SC, Guthrie KA, Thomas PR, D’Angio GJ, Breslow NE: Stature loss following treatment for Wilms’ tumor. Med Pediatr Oncol 2001; 36:295–304. 140. Stillman RJ, Schinfeld JS, Schiff I, et al: Ovarian failure in long term survivors of childhood malignancy. Am J Obstet Gynecol 1987; 139:62–66. 141. Li FP, Gimbrere K, Gelber RD, et al: Outcome of pregnancy in survivors of Wilms’ tumor. JAMA 1987; 257:216–219. 142. Green DM, Peabody EM, Nan B, et al: Pregnancy outcome after treatment for Wilms’ tumor: a report from the National Wilms’ Tumor Study Group. J Clin Oncol 2002; 20:2506–2513. 143. Kinsella TJ, Trivette G, Rowland J, et al: Long-term follow-up of testicular function following radiation for early-stage Hodgkin’s disease. J Clin Oncol 1989; 7:718–724. 144. Scully RE, Mark J, McNeely BU: Case records of the Massachusetts General Hospital. NEJM 1985; 312:1111–119. 145. Welch TR, McAdams AJ: Focal glomerulosclerosis as a late sequela of Wilms’ tumor. J Pediatr 1986; 108:105–109. 146. Anderson S, Meyer TW, Brenner BM: The role of hemodynamic factors in the initiation and progression of renal disease. J Urol 1985; 363–368.
147. Argueso LR, Ritchey ML, Boyle ET Jr, et al: Prognosis of the solitary kidney after unilateral nephrectomy in childhood. J Urol 1992; 148:747–751. 148. Robitaille P, Mongeau JG, Lortie L, Sinnassamy P: Long-term follow-up of patients who underwent nephrectomy in childhood. Lancet 1985; 1:1297–1299. 149. Barrera M, Roy LP, Stevens M: Long-term follow-up after unilateral nephrectomy and radiotherapy for Wilms’ tumor. Pediatr Nephrol 1989; 3:430–432. 150. Bhisitkul DM, Morgan ER, Vozar MA, Langman CB: Renal functional reserve in long-term survivors of unilateral Wilms’ tumor. J Pediatr 1990; 118:698–702. 151. Bailey S, Roberts A, Brock C, et al: Nephrotoxicity in survivors of Wilms’ tumour in the North of England. Br J Cancer 2002; 87:1092–1098. 152. Levitt GA, Yeomans E, Dicks Mireaux C, et al: Renal size and function after cure of Wilms’ tumor. Br J Cancer 1992; 66:877–882. 153. Donckerwolcke RM, Coppes MJ: Adaptation of renal function after unilateral nephrectomy in children with renal tumors. Pediatr Nephrol 2001; 16:568–574. 154. Mitus A, Tefft M, Feller FX: Long-term follow-up of renal function of 108 children who underwent nephrectomy for malignant disease. Pediatrics 1969; 44:912–921. 155. McLorie GA, McKenna PH, Greenberg M, et al: Reduction in tumor burden allowing partial nephrectomy following preoperative chemotherapy in biopsy proved Wilms’ tumor. J Urol 1991; 146:509–513. 156. Moorman-Voestermans C, Aronson D, Staalman CR, et al: Is partial nephrectomy appropriate treatment for unilateral Wilms’ tumor? J Pediatr Surg 1998; 33:165–170. 157. Breslow NE, Takashima JR, Ritchey ML, et al: Renal failure in the Denys-Drash and Wilms’ tumor-aniridia syndromes. Cancer Res 2000; 60:4030–4032.
C H A P T E R
48 Rhabdomyosarcoma of the Pelvis and Paratesticular Structures Hsi-Yang Wu, MD, and Howard M. Snyder III, MD
One of the goals in pediatric oncology is to individualize therapy for the low-risk patient versus the high-risk patient. Therefore, the least amount of chemotherapy and radiation for the low-risk patient, which will achieve a cure, is desirable, since it decreases long-term morbidity. For the high-risk patient, molecular identification of poor prognostic factors can suggest that intensified treatment is necessary. The management of rhabdomyosarcoma (RMS) remains controversial, because while a combination of surgery, chemotherapy, and radiation therapy is more successful than any single modality approach, the optimal timing and dose of each remains unclear. This is evident when reviewing the different approaches to the disease taken by North American and European groups. To maintain an overall perspective in reviewing the literature on RMS, it is useful to remember three key points: 1. Chemotherapy cures microscopic disease. 2. Residual mass does not equal disease. 3. Radiation therapy renders pathology very difficult to read. Twenty percent of RMS involves the bladder, prostate, vagina, or paratesticular area. The incidence peaks between ages 2 to 4 and 15 to 19. The tumor is nonencapsulated, grows rapidly, and spreads to regional lymph nodes, as well as hematogenously. In the United States, patients are managed by Intergroup Rhabdomyosarcoma Study Group (IRSG) protocols. (The IRSG is now the Children’s Oncology Group Soft Tissue Sarcoma Committee.) These studies have been ongoing since 1972 to achieve better survival with less morbidity. Three-year patient survival, which was only 40% to 73% prior to chemotherapy, has improved to 86% in IRS-IV with vincristine, dactinomycin, and cyclophos-
773
phamide (VAC). Failure-free survival at 3 years is now 77%.1 During the same time, the surgical approach has changed from exenterative surgery to organpreserving surgery following chemotherapy. The functional bladder salvage rate has risen from 25% to 60% with this change in management. IRS-V was designed to evaluate new agents, such as topotecan for advanced disease, while attempting to decrease cyclophosphamide and XRT dosing for low-risk patients. Unlike neuroblastoma, there are no plans for high-dose chemotherapy followed by bone marrow transplantation in advanced disease since there are no data showing that this has been helpful.2,3 PATHOLOGY AND MOLECULAR BIOLOGY RMS consists of small, blue, round cells (similar to neuroblastoma, Ewing’s sarcoma, non-Hodgkin’s lymphoma, and leukemia) with a microscopic appearance of spindle cells resembling fetal skeletal muscle. The cells derive from undifferentiated mesoderm and, therefore, can be present in tissues, which do not normally express skeletal muscle. One surgical problem is that although there may appear to be a pseudocapsule, the tumor will often infiltrate through the tissue. Multiple biopsies are required to ensure that the excision is complete. Embryonal pathology, which is a favorable factor, accounts for 90% of genitourinary RMS. Sarcoma botryoides (bunch of grapes) is a polypoid form of embryonal pathology, which occurs in hollow organs like the bladder. Alveolar pathology, which tends to occur in extremities, is less favorable. Anaplastic and undifferentiated pathologies rarely occur in genitourinary tumors (Figure 48-1). Desmin and actin stains are sometimes useful in determining the diagnosis. Current lab efforts have found genetic translocations between chromosomes 1;13 (favorable) and 2;13 (very
774
Part VIII Pediatric Malignancies
Figure 48-1 Histologic subtypes of RMS: A, embryonal; B, spindle cell; C, botryoid; D, alveolar. (H/E 33X.) (Courtesy Dr. Philip Faught.)
high risk) to be prognostic markers for survival in patients with alveolar tumors with metastatic disease.4 Unfortunately, there are no good molecular markers for embryonal tumor behavior that can be followed at the present time.3 PRESENTATION AND EVALUATION Bladder and prostate primaries tend to present with urinary retention, a palpable lower abdominal mass, gross hematuria, and tend to be located at the trigone and bladder neck (Figure 48-2). The tumors have a 2.5/1 male
predominance. Sometimes, a child can void a piece of the tumor per urethra. In females, the sarcoma botryoides type of tumor can prolapse through the urethra. Occasionally, the tumor can project posteriorly and cause constipation. Determining which organ the tumor arose from can be difficult, but initial treatment does not depend on this distinction. Computed tomography (CT) or magnetic resonance imaging (MRI) (T2 weighted) of the pelvis is the initial study. MRI may give better resolution of tumor invasion. Vaginal primaries present with vaginal bleeding or an introital mass and tend to occur on the anterior vaginal
Figure 48-2 Sarcoma botryoides of bladder base showing characteristic polypoid appearance on cystogram.
Chapter 48 Rhabdomyosarcoma of the Pelvis and Paratesticular Structures 775
wall. CT or MRI (T2 weighted) of the pelvis is the initial study. Uterine primaries were formerly considered to be a disease of older females, but more recent studies suggest that they present at the same age as vaginal primaries and can be successfully treated with limited excision followed by chemotherapy. Hysterectomy is rarely carried out.5 Vulvar and cervical lesions tend to occur in teenagers.6 Staging for bladder, prostate, and vaginal primaries is completed by endoscopic examination and biopsy of the lesion. Cold-cup biopsy will give better results than using a resectoscope loop, since cautery artifact can make interpretation difficult. If the lesion does not appear to involve the mucosa of the bladder, prostate, or vagina, then a needle biopsy may be necessary via a percutaneous (transperineal), transrectal, or laparoscopic approach. Paratesticular RMS has two peak incidences, in the 3- to 4-month-old boy and in the teenager. The biologic activity of the tumor is different between the neonate and the teenager (90% versus 63% failure-free survival at 3 years).1 The primary tumor presents as a painless scrotal mass. Scrotal ultrasound, serum βHCG, and AFP should be obtained to confirm that the mass is not a testicular primary. Imaging of the retroperitoneum by CT or MRI is usually carried out before surgery. Thirty percent to forty percent will have microscopic metastases to the retroperitoneum. The tumor is resected, along with the testis in a radical inguinal orchiectomy. Pathologic staging of retroperitoneal lymph nodes is currently recommended for patients 10 years of age or older, regardless of radiologic findings, and in patients <10 years of age with retroperitoneal disease visible on CT or MRI.3 Metastatic workup for all lesions is completed with a chest x-ray (and possibly chest CT), liver function tests, bone scan and bone marrow biopsy.
Table 48-1 Preoperative Staging T1
Confined to organ of origin, a: ≤5 cm in size, b: >5 cm in size
T2
Extension or fixed to surrounding tissue, a: ≤5 cm in size, b: >5 cm in size
N0
Regional nodes clinically negative
N1
Regional nodes clinically positive
Nx
Unknown
M0
No distant metastasis
M1
Metastasis present
Stage I
Vaginal and paratesticular RMS, any T, any N, M0
Stage II
Bladder/prostate RMS, T1a or T2a, N0 or Nx, M0
Stage III
Bladder/prostate RMS (T1a or T2a) and N1, M0, OR (T1b or T2b), any N, M0
Stage IV
Any tumor with M1
Table 48-2 Postoperative Grouping Group 1: Localized disease, completely excised, no microscopic residual A
Confined to site of origin, completely resected
B
Infiltrating beyond site of origin, completely resected
Group 2: Total gross resection
STAGING
A
Gross resection with microscopic local residual
The IRS study includes both preoperative staging and postoperative grouping (Tables 48-1 and 48-2). The IRSI to IRS-III studies grouped patients based on completeness of resection, introducing biases (shifting patients from group 1 to group 3), which are not seen with the use of the TNM system in IRS-IV and IRS-V. Eighty percent of bladder and prostate primaries are group 3 (gross residual), whereas 50% of nonbladder/prostate primaries are group 1 (complete resection), with about 20% in group 2 (complete gross resection, with microscopic or nodal tumor) and group 3, respectively.7
B
Regional disease with involved lymph nodes, completely resected with no microscopic residual
C
Microscopic local and/or nodal residual
GENERAL APPROACH Chemotherapy/Radiation In IRS-IV, VAC was shown to be as effective as two other three drug regimens (VIE/VAE: ifosfamide, etoposide).1
Group 3: Incomplete resection or biopsy with gross residual Group 4: Distant metastases
Since cyclophosphamide is cheaper and has less toxicity, VAC is the current standard chemotherapy. The addition of doxorubicin or melphalan to VAC has not been beneficial. In IRS-V, low-risk patients are randomized to receive either VA or VAC, plus or minus XRT. Intermediate-risk patients receive chemotherapy and XRT and are randomized to VAC or VAC alternating with vincristine, topotecan, and cyclophosphamide.
776
Part VIII Pediatric Malignancies
High-risk patients receive CPT-11 (irinotecan), VAC, and XRT.3 In IRS-IV, hyperfractionated radiation therapy did not achieve better results than conventional radiation therapy.8 For IRS-V, patients with group 1 embryonal pathology will not receive XRT. For other patients, the dose of radiation to the residual primary will be higher than to microscopic residual disease, and metastases will be irradiated as well.3 Surgery as treatment of gross residual disease after chemotherapy is still an option. At the Children’s Hospital of Philadelphia, we have favored this approach, mainly because of the difficulty of interpreting the pathology after radiation. Surgery The goal of the initial procedure is to obtain adequate tissue for a definitive diagnosis. If possible, one should remove the tumor without removing the affected organ, except in the case of paratesticular tumors. If excision is not possible, chemotherapy will be given with a plan for a second look operation. In follow-up staging, a biopsy is needed during the second look to confirm whether a residual mass is tumor. The tumor can involute more rapidly than the supporting stroma, so gross residual masses may not contain any viable tumor. The goal of the definitive operation is a good, radical, but pelvic organ-sparing operation. If microscopic residual disease is found, brachytherapy or external beam radiation therapy can be used. Exenteration is reserved for patients who have failed previous therapies. In Europe, an alternate approach is to give primary chemotherapy without any attempt at initial local control (radiation therapy or surgery), and to offer local therapy based on the initial chemotherapy response.9,10 Review of the pathology may reveal persistent rhabdomyoblasts in a patient who has received as much chemotherapy as can safely be given. Currently, there is debate concerning the malignant potential of these cells, which represent matured rhabdomyoblasts.11,12 Normally, resection of the involved organ is carried out. However, if this would require destruction of a functional bladder, observation with frequent radiologic follow-up may be an option to consider. Relapse Five-year survival after relapse is 64% for botryoid embryonal, 26% for other embryonal, and 5% for alveolar or undifferentiated pathology. Survival after relapse was also improved in lower-stage embryonal lesions at the time of diagnosis: 52% stage I, 20% stages II and III, and 12% stage IV.13
TREATMENT AND OUTCOME Bladder and Prostate Chemotherapy and Radiation IRS-III included intensified chemotherapy (dactinomycin, VP-16) and 6 weeks of XRT, increasing the functional bladder salvage rate from 25% to 60%. For persistent disease, group 2 was treated with 41 Gy and group 3 was treated with 50 Gy. At 24 weeks, a third operative evaluation was performed with consideration for exenteration.14 The difficulty with radiation therapy is that since the tumors tend to be located at the bladder neck, even the lowest dose (41 Gy) that the radiation oncologists are willing to deliver may significantly risk urinary continence. Current attempts at limiting radiation toxicity to adjacent organs involve both conformal radiation therapy and brachytherapy. The long-term risk of radiation vasculitis, which is inevitably progressive, as well as possible bony pelvis deformity in these children, is another issue to consider. Therefore, one must sometimes weigh whether preserving a bladder without an outlet is better than removing the bladder entirely.15,16 Surgery for Bladder Primaries While a full retroperitoneal lymphadenectomy is not necessary, any suspicious lymph nodes along the great vessels between the obturator fossa and the renal veins should be removed. Multiple frozen-section biopsies of the bladder are obtained around the tumor. If these are negative, and the tumor is amenable to partial cystectomy with a 2- to 3-cm margin, then the bladder does not need to be entirely removed. If the tumor extends down the urethra, then the symphysis should be split to gain better access. After completing distal dissection of the urethra, the symphysis is closed with absorbable suture. With this improved exposure, it is also possible to perform a nerve-sparing dissection. The placement of brachytherapy catheters for afterloading (to treat microscopic positive margins if needed) should be considered. For patients who require total cystectomy, we have often placed Dexon mesh across the abdomen to hold the intestines out of the pelvis at the level of the sacral promontory. This is done by attaching it to the sacral promontory and wrapping it around the sigmoid. This limits the exposure of the bowel to the radiation field if postoperative radiation is required. The final surgical decision is whether to proceed with continent urinary reconstruction at the same time. We believe that it is not wise to perform the reconstruction at the same time, unless the patient is both motivated and able to perform clean intermittent catheterization to drain a urinary reservoir. For the younger patients who are not ready to manage a urinary reservoir, we have either brought up the remaining bladder plate with ureterovesical junctions
Chapter 48 Rhabdomyosarcoma of the Pelvis and Paratesticular Structures 777
intact as a vesicostomy, or performed low end-cutaneous ureterostomies, with the ureters placed side-by-side as a single stoma on the abdominal wall. Surgery for Prostate Primaries The technique is similar to that for localized prostatic adenocarcinoma. The use of nerve-sparing procedures may preserve erectile potency in these patients. Splitting the symphysis is useful as it is essential to remove the urethra to the mid-bulbar level. The placement of brachytherapy catheters for afterloading (to treat microscopic positive margins if needed) should be considered. Outcome In IRS-I and IRS-II, half of the patients survived with intact bladders, whereas the other half had either total or partial cystectomy. In those patients with intact bladders, function (as assessed by questionnaire) was normal in 73%, whereas 8% had incontinence and 9% had frequency and nocturia. Overall renal function as assessed by serum BUN and creatinine was normal in 95%, although 29% of the patients had abnormal renal scans, which was often hydronephrosis in the setting of a urinary diversion.15 In IRS-I to IRS-III, over 25% of patients treated with partial cystectomy had complications of gross hematuria, bladder contracture, or incontinence. The risk of complications increased as the XRT dose raised over 40 Gy.16 More recent outcomes show that 50% of patients were managed with biopsy, 37% had partial cystectomy, and 13% had prostatectomy. Patients with embryonal pathology had an 83% 3-year failure-free survival, compared to 40% in those with alveolar pathology. However, all patients with group 4 (metastatic) prostate disease died.14
patients were treated with surgery and chemotherapy, 19% required additional radiation therapy, 21% were treated with biopsy and chemotherapy alone, and 12% were managed with biopsy, chemotherapy, and radiation therapy. (There were insufficient data regarding local therapy for the remaining patients.) Five-year patient survival and failure-free survival were 82% and 69%.6 In IRS-IV, only 19% of patients required wide excision of vaginal tumors.18 Age between 1 and 9 was a favorable factor for survival (94% versus 76%).6 The experience of the International Society of Pediatric Oncology (SIOP) in Europe has been similar, although they prefer intracavitary brachytherapy for local control rather than hysterectomy.19 Paratestis Chemotherapy and Radiation In IRS-I to IRS-III, all patients underwent retroperitoneal lymph node dissection (RPLND).1 Based on the European experience that 17 of 19 patients with clinical stage I disease were cured with adjuvant chemotherapy alone20; RPLND was not recommended in IRS-IV for stage I disease with a normal CT of the abdomen and pelvis. This led to a significant understaging of disease based on radiologic evaluation alone and a decrease in failure-free survival because patients with negative CT scan did not receive radiation. Thirty percent of those patients who were clinically stage I and over 10 years of age required retreatment. Since the outcome for patients <10 years old with stage I disease was good in IRS-IV, those patients who are <10 years old have stage I disease, and negative abdominal/pelvic CT are treated with VA (vincristine, dactinomycin) only in IRS-V. All patients with stage I disease who are 10 years or older undergo RPLND regardless of CT findings. Group 2 tumors (positive lymph nodes on pathology) are treated with radiation therapy and VAC.21
Vagina/Uterus Chemotherapy and Radiation
Surgery
Primary treatment with VAC chemotherapy is usually successful, and a biopsy 8 to 12 weeks after chemotherapy is recommended. Pelvic lymph node dissection is not necessary. Vaginectomy or hysterectomy should only be considered for persistent disease after a complete course of chemotherapy.17 Rhabdomyoblasts on biopsy are evidence of chemotherapy response, and therefore further chemotherapy, instead of resection, is the proper treatment. Radiation therapy should only be used for persistent disease or relapse.17,18
During inguinal orchiectomy, frozen section of the proximal cord should reveal no tumor. If one makes a scrotal incision for what turns out to be a solid paratesticular mass, chemotherapy will often cure residual disease. However, some cases have required hemiscrotectomy due to tumor infiltration. The technique for RPLND is identical to that used for retroperitoneal involvement by testicular tumors. Ipsilateral template and nerve-sparing techniques can be used to maintain ejaculation.22
Outcome
Outcome
Surgery and chemotherapy cure most cases of vaginal RMS. In the overall IRS-I to IRS-IV experience, 42% of
Three-year patient survival and failure-free survival are 92% and 81%, respectively, for group 1 tumors overall.
778
Part VIII Pediatric Malignancies
The failure-free survival was worse than the 95% achieved in IRS-III, although the patient survival rate is the essentially the same as the 96% achieved in IRS-III. Again, this was felt to be due to understaging when the retroperitoneal lymph nodes were not pathologically evaluated. Those patients more than 10 years old only had a 63% survival, leading to the recommendation that all patients of that age undergo RPPLND.1 COMPLICATIONS The majority of patients have acute toxicity from the chemotherapy; 90% developed myelosuppression, 55% developed significant infections, and renal toxicity was seen in 2%.1 Most relapses occur within 3 years of initial diagnosis.13 Late recurrences can occur in patients who are treated with chemotherapy alone. Out of 883 patients, 10 developed a secondary cancer. Patients with preexisting renal abnormalities were at a higher risk of death (5% versus 1%).1 The experience from IRS-I and IRS-II suggests a 27% long-term urinary complication rate, with incontinence being the major issue. Twenty-nine percent required sex hormone replacement and 11% were shorter than expected.15 If radiation therapy has been used, there is an increased risk of a secondary neoplasm, often another sarcoma, in the radiation field. Complications specific to surgical treatment include intestinal obstruction, anejaculation, and lower extremity edema after RPLND. However, this series evaluated therapy from 1972 to 1984, and current techniques may result in better outcomes.23
4.
5.
6.
7.
8.
9.
10.
11.
SUMMARY RMS is treated with a combination of surgery, chemotherapy, and radiation. Bladder, prostate, and vaginal primaries are treated with biopsy followed by chemotherapy, reresection, and radiation with periodic reevaluations. Paratesticular primaries receive chemotherapy after orchiectomy and possibly require a RPLND if spread to the retroperitoneum is seen or if the boy is >10 years of age.
12.
13.
14.
REFERENCES 15. 1. Crist WM, Anderson JR, Meza JL, et al: Intergroup Rhabdomyosarcoma Study-IV: Results for patients with nonmetastatic disease. J Clin Oncol 2001; 19:3091–3102. 2. Carli M, Colombatti R, Oberlin O, et al: High-dose melphalan with autologous stem cell rescue in metastatic rhabdomyosarcoma. J Clin Oncol 1999; 17:2796–2803. 3. Raney RB, Anderson JR, Barr FG, et al: Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of Intergroup Rhabdomyosarcoma Study Group experience and
16.
17.
rationale for Intergroup Rhabdomyosarcoma Study V. J Ped Hem/Oncol 2001; 23:215–220. Sorenson PH, Lynch JC, Qualman SJ, et al: PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the Children’s Oncology Group. J Clin Oncol 2002; 20:2672–2679. Corpron C, Andrassy RJ, Hays CM, et al: Conservative management of uterine rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Studies III and IV Pilot. J Pediatr Surg 1995; 30:942–944. Arndt CAS, Donaldson SS, Anderson JR, et al: What constitutes optimal therapy for patients with rhabdomyosarcoma of the female genital tract? Cancer 2001; 91:2454–2468. Barksdale EM, Weiner ES: Rhabdomyosarcoma. In Pediatric Surgery. Philadelphia, WB Saunders, 2000. Donaldson SS, Neza J, Breneman JC, et al: Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma – a report from the IRSG. Int J Radiat Oncol Biol Phys 2001; 51:718–728. Flamant F, Rodary C, Rey A, et al: Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence. Results of the second study of the International Society of Pediatric Oncology: MMT84. Eur J Cancer 1998; 34:1050–1062. Koscielniak E, Harms D, Henze G, et al: Results of treatment for soft tissue sarcoma in childhood and adolescence: A final report of the German cooperative soft tissue sarcoma study CWS-86. J Clin Oncol 1999; 17:3706–3719. Ortega JA, Rowland J, Monforte H, et al: Presence of well-differentiated rhabdomyoblasts at the end of therapy for pelvic rhabdomyosarcoma: implications for the outcome. J Pediatr Hem/Oncol 2000; 22:106–111. Leuschner I, Harms D, Mattke A, et al: Rhabdomyosarcoma of the urinary bladder and vagina. Am J Surg Pathol 2001; 25:856–864. Pappo AS, Anderson JR, Crist WM, et al: Survival after relapse in children and adolescents with rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study Group. J Clin Oncol 1999; 17:3487–3493. Paidas CN: Results of rhabdomyosarcoma of the bladder and prostate: Is bladder preservation successful? In American Academy of Pediatrics Meeting, Chicago, IL, Section on Surgery, 2000. Raney B, Heyn R, Hays DM, et al: Sequelae of treatment in 109 patients followed 5 to 15 years after diagnosis of sarcoma of the bladder and prostate. Cancer 1993; 71:2387–2394. Hays DM, Raney RB, Wharam MD, et al: Children with vesical rhabdomyosarcoma (RMS) treated by partial cystectomy with neoadjuvant or adjuvant chemotherapy, with or without radiotherapy. J Pediatr Hem/Oncol 1995; 17:46–52. Andrassy RJ, Weiner ES, Raney RB, et al: Progress in the surgical management of vaginal rhabdomyosarcoma: a
Chapter 48 Rhabdomyosarcoma of the Pelvis and Paratesticular Structures 779 25-year review from the Intergroup Rhabdomyosarcoma Study Group. J Pediatr Surg 1999; 34:731–735. 18. Andrassy RJ: Modern approach to rhabdomyosarcoma of the vagina and uterus. In American Academy of Pediatrics Meeting, Chicago, IL, Section on Surgery, 2000. 19. Martelli H, Oberlin O, Rey A, et al: Conservative treatment for girls with nonmetastatic rhabdomyosarcoma of the genital tract: a report from the study committee of the International Society of Pediatric Oncology. J Clin Oncol 1999; 17:2117–2122. 20. Olive D, Flamant F, Zucker JM, et al: Paraaortic lymphadenectomy is not necessary in the treatment of localized paratesticular rhabdomyosarcoma. Cancer 1984; 54:1283–1287.
21. Weiner ES, Anderson JR, Ojimba JI, et al: Controversies in the management of paratesticular rhabdomyosarcoma: Is staging retroperitoneal lymph node dissection necessary for adolescents with resected paratesticular rhabdomyosarcoma? Semin Pediatr Surg 2001; 10:146–152. 22. Donohue JP, Foster RS, Rowland RG, et al: Nervesparing retroperitoneal lymphadenectomy with preservation of ejaculation. J Urol 1990; 144:287–291. 23. Heyn R, Raney B, Hays D, et al: Late effects of therapy in patients with paratesticular rhabdomyosarcoma. Intergroup Rhabdomyosarcoma Study Committee. J Clin Oncol 1992; 10:614–623.
C H A P T E R
49 Prepubertal Testicular Tumors Peter D. Metcalfe, MD, and Darius J. Bägli, MD, CM, FRCSC, FAAP
Pediatric testicular tumors differ significantly from their adult counterparts in several fundamental aspects. They are less common, have different histologic distribution, and they are more likely to be benign. There is also a much higher incidence of metastases to the pediatric testicle, primarily of lymphopoietic origin. The reported incidence of pediatric testicular tumors is between 0.5 and 2 per 100,000 children, and they account for 1% of solid tumors in this age group.1–3 Their rarity has prompted collaborative efforts at data collection, and the development of the Prepubertal Testicular Tumor Registry by the Section of Urology of the American Association of Pediatrics (AAP) in 1980. PRESENTATION Eighty percent to ninety percent of patients present with a painless mass.3–5 Trauma and swelling (5%) and hydrocele (2%) are the next most common modes of presentation.3 Leydig cell or granulosa tumors may present with manifestations of testosterone production.6 Serology is a fundamental part of the initial evaluation. Given the preponderance of yolk sac tumors, alpha fetoprotein (AFP) is very useful in the evaluation of the prepubertal testicular mass. However, because it is produced during normal fetal development, AFP may be elevated beyond adult norms in neonates.7 Because most yolk sac tumors in this age group are not associated with mixed germ cell tumors, human chorionic gonadotropin (HCG) is not elevated. Scrotal ultrasound is an invaluable adjunct to treatment, as the age of the child or the presence of a large, tense hydrocele precludes a good physical examination.8 Sensitivity for detecting testicular neoplasia approaches 100%9 and is accurate in distinguishing intratesticular from extratesticular lesions in up to 90% of cases.10 However, the specificity of the histologic diagnosis afforded by ultrasound is much lower, and differentiation
780
between benign from malignant masses is not always demonstrable sonographically.11–14 Color doppler can demonstrate increased vascularity, increasing the specificity of a malignant process.12 Teratoma may be suspected by a characteristic solid and cystic appearance,15,16 and epidermoid cysts may have an onionskin or target appearance17 on ultrasound. HISTOLOGIC TUMOR TYPES Yolk Sac Tumors Previous historic data suggested that yolk sac tumors were the most commonly diagnosed testis tumor in the pediatric population, and this has been confirmed by AAP registry data. It comprised 62% to 63% of their tumors.3,18 However, other retrospective, single institution reviews have incidences of 66%,1 19%,5 and 8%.19 Most diagnoses occur in boys <2 years of age, with the median age 16 months in data from both the AAP18 and the Hospital for sick children (HSC) in Toronto, Canada.19 In managing pediatric yolk sac tumors, it is important to remember the physiologic elevations of AFP in the neonatal age group. Production from the gastrointestinal tract or the liver can result in levels as high as 50,000 ng/ml in the neonate.20 Physiologic elevations diminish quickly after birth but most remain above adult levels for up to 8 months.7 The prolonged half-life of 33 days during months 2 to 4 of life implies an element of neonatal production.7 AFP binding affinity to concanavalin A may be useful in the assessing an elevation from a benign versus a malignant source.21 Staging is according to the Children’s Cancer Group/Pediatric Oncology Group system. Stage I is defined as tumor confined to testis; stage II as microscopic disease within the scrotum or spermatic cord and retroperitoneal adenopathy is < 2 cm; stage III has retroperitoneal nodes >2 cm, but without visceral metastases; and stage IV is defined by distant metastases.
Chapter 49 Prepubertal Testicular Tumors 781
Eighty-five percent of patients present with stage I disease.8 Unlike adults, in this age group, retroperitoneal lymph node dissection (RPLND) has been associated with a high rate of complications, including chylous ascites, bowel obstruction, gastrointestinal bleeding, ligation of the renal artery, and a 10% to 40% incidence of ejaculatory dysfunction.22 Improved clinical staging with computed tomography (CT) and AFP combined with the success of cisplatin, etoposide, and bleomycin chemotherapy has reduced the role of RPLND for yolk sac tumors. Contemporary indications are limited to a persistent retroperitoneal mass, an elevated AFP postorchiectomy with no radiographic evidence of metastatic disease, or an unknown AFP preoperatively.8 Disease-free survival at 5 years is comparable to that in the adult population, with the results of stages II to IV reported at >90%.23,24 Liu et al.25 demonstrated a 10% 5-year survival advantage (91% versus 100%) using 2 doses of cisplatin, vincristine, and bleomycin in stage I disease. Teratoma The recently published 2002 AAP registry data listed teratoma as accounting for 23% of testis tumors, a marked increase from the 14% published in 1993.3,18 Single institution studies have shown an incidence of up to 60%,1,19,26 where it exceeds the incidence of yolk sac tumors.20,26 This discrepancy may be accounted for by an underreporting of benign tumors in the registry data.19,26 Median age at presentation is 13 to 16 months, with a range of 0 to 146 months.18,19 There are at least two reports of an antenatal diagnosis of teratomas.19,27 Preoperative findings consistent with a teratoma include normal serology, as these tumors neither secrete nor stain for AFP.20,28–30 Scrotal ultrasonography may show characteristic cystic areas with septa and solid stromal elements,10,31 but the specificity is only 50% to 59%.14,16,31 Mature teratomas in the prepubescent male contrast sharply with their adult counterparts, as metastasis from teratoma have never been reported in children.3,18,26,32 The benign properties of this tumor are likely responsible for the increasing the popularity of treatment with partial orchiectomy. The finding of immature elements does not deter from its benign natural history, provided all other investigations are in keeping with localized disease.33 Rhabdomyosarcoma Although a paratesticular tumor, it is included in this discussion because it is an important consideration in the differential diagnosis of a pediatric scrotal mass.4 It is the most frequent tumor of paratesticular origin and, despite its aggressive behavior, has recently been associated with a good prognosis.34 The efforts of the Intergroup
Rhabdomyosarcoma Study (IRS) have been credited with the dramatic improvement in survival from 10% in the 1960s to over 70%.35 Paratesticular rhabdomyosarcomas are generally considered separate from other genitourinary rhabdomyosarcomas because of the difference in treatment and prognosis.34 The progenitor cell of the rhabdomyoblast is believed to be premature striated muscle derived from embryonic mesenchyme. The most common subtype is embryonal rhabdomyosarcoma, which also accounts for 97% of paratesticular cases.36 Microscopically, the cells are primarily spindle shaped with abundant cytoplasm resembling those of a 7- to 10-week fetus.37 Most paratesticular rhabdomyosarcoma patients (81%) present with a scrotal mass.36 Serum markers are used to rule out primary testicular processes. Ultrasound is very sensitive in differentiating testicular masses from paratesticular masses,5,11,16 and thereby increases the probability that the scrotal lesion is a rhabdomyosarcoma. If discrete scrotal lymphatic drainage is violated during transscrotal surgery for rhabdomyosarcoma in particular, a hemiscrotectomy is recommended.38 The success of chemotherapy developed during the IRS studies I to III has resulted in RPLND no longer being required in all cases.39 This most recent protocol mandates that patients with localized disease receive vincristine and actinomycin for 1 year, with more advanced stages requiring actinomycin and cyclophosphamide in longer, more intense regimes, combined with radiation therapy. IRS-IV allowed for CT surveillance of the retroperitoneum, and this demonstrated that children under the age of 10 years do not require an RPLND, as their incidence of metastatic nodal disease was significantly less. Moreover, successful treatment with chemotherapy was above 95%.40 However, in those boys over the age of 10 years, there is a 50% incidence of retroperitoneal disease, and an ipsilateral RPLND is recommended.41,42 Positive lymph node metastasis mandates radiation therapy, as this is associated with a significantly worse prognosis.42 Children younger than 10 years of age have been reported to have up to a 97% 5-year survival, while those older than 10 years had an 84% 5-year survival.43 Overall survival using IRS-II and IRS-I is 89% at 3 years, and 93% for localized disease.44,45 Survivals estimated from IRS-III and IRS-IV are 96% and 92%, respectively, the difference not achieving statistical significance (p = 0.30).42 This success has resulted in a secondary goal of reducing the morbidity of treatment and identifying biologic characteristics to allow a more selective treatment regimens.46 Epidermoid Cysts This universally benign entity accounts for 2% to 10% of childhood testicular tumors3,18,19,26,27 and are less common
782
Part VIII Pediatric Malignancies
than in the adult population. Histologically, they consist of a cyst wall filled with keratinizing squamous epithelium,47 and their origin is thought to represent the monodermal development of a teratoma.48,49 Epidermoid cysts are hormonally inactive and usually present as a smooth, firm intratesticular mass. They have a characteristic ultrasonographic appearance that is consistent with the histology: a central hypoechoic mass with through transmission, a surrounding echogenic rim, or mixed internal echogenicity.50–52 However, while ultrasound can raise the index of suspicion it cannot rule out a malignant process. Testis conserving surgery is accepted by many urologists as the standard of care for this benign tumor.* There have never been any reports of metastases nor associations with intratubular germ cell neoplasia. The benign nature suggested by physical examination, serology, and ultrasound, however, requires confirmation by frozen section before organ sparing can be performed safely. Gonadal Stromal Tumors This subgroup of tumors comprises Leydig cell, Sertoli cell, and juvenile granulosa tumors, and accounts for 8% to 11% of pediatric testicular tumors.3,18 Although the majority follows a benign course, reports of metastases do exist. These tumors are unique as they are often hormonally active. Leydig cell tumors account for approximately 10% of cases of male precocious puberty.6 Both adult Leydig cell and Sertoli cell tumors have a 10% malignancy rate in the adult population. This appears to be much lower in the pediatric population, but at least 5 cases of metastatic disease have been reported.54–56 No reliable histologic characteristics have been identified, but invasion of the spermatic cord may be an important prognostic finding.6 Metastatic Sertoli cell tumor is reported to be responsive to combination chemotherapy.56 Juvenile granulosa tumors typically present in the neonatal period. The median age at presentation in the latest AAP registry was 0.1 months, with a range of 0 to 6 months. The clinical behavior has been universally benign.18 Other Pediatric Testicular Tumors Gonadoblastoma may develop from a dysgenetic testis. This tumor most commonly presents with virilization of a phenotypic female, often harboring some degree of an XY karyotype.57 The tumor usually arises from an intraabdominal testis and histologically resembles a seminoma. Spread beyond the testicle has not been reported.1,4,57 Connective tissue tumors arising from the testis that have been reported include neuroblastoma, hemangiofi*References 13, 33, 48, 49, 53.
broma, hamartoma, leiomyoma, and neuroectodermal tumor. Malignant tumors include leiomyosarcoma, fibrosarcoma, and reticular cell sarcoma. Metastases to the Testis Infiltration of the testis with acute lymphoblastic leukemia (ALL) is a common cause of a prepubertal testicular mass and may be bilateral.4,26 Hematologic malignancies accounted for half of testicular biopsy results in a single institution review.19 Children with bulky ALL at diagnosis have up to a 20% incidence of experiencing testicular metastases.58 Synchronous testicular metastases at the time of initial ALL diagnosis are associated with a poor prognosis.59 The testicle is the second most common site of a relapse of an extra-medullary ALL. Moreover, Askin et al.58 found occult testicular leukemia in 8.5% of biopsies in patients in clinical remission. Follicular, Hodgkin’s, and Burkitt’s lymphomas can also present in the testicle and have a favorable prognosis if the tumor is completely intraparenchymal.60 TESTIS PRESERVING SURGERY The high incidence of benign tumors and the ability to exclude malignancy histologically account for the increasing use of testis-sparing surgery in the prepubertal population. First advocated by Weissbach in 1984 for a solitary testicle,61,62 it has been advocated as the surgical procedure of choice for all potentially benign tumors.18 The combination of negative serology, an ultrasound that excludes a paratesticular mass, and the presence of salvageable testicular tissue in a prepubertal patient should invite consideration of a testicular preserving approach. After early control of the spermatic cord, a frozen section is obtained as a final determinant. Frozen section is very accurate in differentiating benign from malignant tumor, and is an essential confirmatory step.62,63 If the presumptive diagnosis is a teratoma, sufficient normal tissue should be analyzed to rule out pubertal changes, as the latter would necessitate radical orchiectomy. A treatment algorithm incorporating the principal benign pathologies and position for nonradical surgery is depicted in Figure 49-1. SUMMARY Testicular tumors in the prepubertal population are a distinct entity compared to their adult counterparts. There is a predisposition towards benign tumors, while mixed germ cell tumors are very rare. Serum HCG is not helpful, while an elevated AFP must be interpreted with caution in the neonate. Ultrasound is an excellent and invaluable tool, essential for the determination of a
Chapter 49 Prepubertal Testicular Tumors 783
History and physical consistent with painless scrotal mass in prepubertal patient
Testicular ultrasound
Paratesticular rhabdomyosarcoma
Confirms or suggests malignancy
Suggests mature teratoma, epidermoid cyst; salvageable parenchyma
Baseline AFP serology
Plan parenchymal sparing surgery; control cord, intraoperative frozen section
Benign histology confirmed on frozen section? Technically salvageable parenchyma? NO TO EITHER
YES TO BOTH Proceed with testis preserving procedure: enucleate tumor, sample parencymal bed as indicated
Radical orchiectomy
Figure 49-1 Treatment algorithm for the prepubertal patient with a painless scrortal mass.
testicular from a paratesticular tumor. Although not accurate enough to be definitive, ultrasound may help to predict benign histology. However, frozen histopathology is the final arbiter of any testis-sparing procedure. Characteristics of both the pediatric patients the tumors themselves make testicular preserving surgery a viable option.
REFERENCES 1. Brosman SA: Testicular tumors in prepubertal children. Urology 1979; 13(6):581–588. 2. Kaplan GW, et al: Prepubertal yolk sac testicular tumors—report of the testicular tumor registry. J Urol 1988; 140(5 Pt 2): 1109–1112.
784
Part VIII Pediatric Malignancies
3. Kay R: Prepubertal testicular tumor registry. J Urol 1993; 150(2 Pt 2): 671–674. 4. Skoog SJ: Benign and malignant pediatric scrotal masses. Pediatr Clin North Am 1997; 44(5):1229–1250. 5. Aragona F, et al: Painless scrotal masses in the pediatric population: prevalence and age distribution of different pathological conditions—a 10 year retrospective multicenter study. J Urol 1996; 155(4): 1424–1426. 6. Thomas JC, Ross JH, Kay R: Stromal testis tumors in children: a report from the prepubertal testis tumor registry. J Urol 2001; 166(6): 2338–2340. 7. Wu JT, Book L, Sudar K: Serum alpha fetoprotein (AFP) levels in normal infants. Pediatr Res 1981; 15(1): 50–52. 8. Grady RW: Current management of prepubertal yolk sac tumors of the testis. Urol Clin North Am 2000; 27(3): 503–508 (ix). 9. Benson CB, Doubilet PM, Richie JP: Sonography of the male genital tract. Am J Roentgenol 1989; 153(4): 705–713. 10. Krone KD, Carroll BA: Scrotal ultrasound. Radiol Clin North Am 1985; 23(1): 121–139. 11. Rifkin MD, et al: Diagnostic capabilities of high-resolution scrotal ultrasonography: prospective evaluation. J Ultrasound Med 1985; 4(1): 13–19. 12. Luker GD, Siegel MJ: Pediatric testicular tumors: evaluation with gray-scale and color Doppler US. Radiology 1994; 191(2): 561–564. 13. Altadonna V, et al: Simple cysts of the testis in children: preoperative diagnosis by ultrasound and excision with testicular preservation. J Urol 1988; 140(6): 1505–1507. 14. Tackett RE, et al: High resolution sonography in diagnosing testicular neoplasms: clinical significance of false positive scans. J Urol 1986; 135(3): 494–496. 15. Bauer S, Hendren H: Infantile cystic teratoma of the testis: Children’s Hospital experience and review of the literature. J Urol 1998; 159(163) (abstract No. 624). 16. Polak V, Hornak M: The value of scrotal ultrasound in patients with suspected testicular tumour. Int Urol Nephrol 1990; 22(5): 467–473. 17. Maxwell AJ, Mamtora H: Sonographic appearance of epidermoid cyst of the testis. J Clin Ultrasound 1990; 18(3): 188–190. 18. Ross JH, Rybicki L, Kay R: Clinical behavior and a contemporary management algorithm for prepubertal testis tumors: a summary of the Prepubertal Testis Tumor Registry. J Urol 2002; 168(4 Pt 2): 1675–1678 (Discussion 1678-9). 19. Metcalfe PD, Farivar-Mohseni H, Farhat W, et al: Pediatric testicular tumors: contemporary incidence and efficacy of testicular preserving surgery. J Urol 2003; 170(6pt1):2412–2415 (Discussion 2415–2416). 20. Grady RW, Ross JH, Kay R: Epidemiological features of testicular teratoma in a prepubertal population. J Urol 1997; 158(3 Pt 2): 1191–1192. 21. Lahdenne P, et al: Biphasic reduction and concanavalin A binding properties of serum alpha-fetoprotein in preterm and term infants. J Pediatr 1991; 118(2): 272–276. 22. Green DM: The diagnosis and treatment of yolk sac tumors in infants and children. Cancer Treat Rev 1983; 10(4): 265–288.
23. Hawkins EP, et al: Nongerminomatous malignant germ cell tumors in children. A review of 89 cases from the Pediatric Oncology Group, 1971–1984. Cancer 1986; 58(12): 2579–2584. 24. Huddart SN, et al: The UK Children’s Cancer Study Group: testicular malignant germ cell tumours 1979–1988. J Pediatr Surg 1990; 25(4): 406–410. 25. Liu P, et al: Sonographic findings of testicular teratoma with pathologic correlation. Pediatr Radiol 1992; 22(2): 99–101. 26. Khoury AE, Bagli DJ, et al: Prepubertal testicular and paratesticular tumors. . J Urol 1996; 155: 392 (abstract). 27. Siu SS, et al: Prenatal diagnosis of intra-abdominal mature testicular teratoma. J Ultrasound Med 2001; 20(11): 1257–1260. 28. Rushton HG, et al: Testicular sparing surgery for prepubertal teratoma of the testis: a clinical and pathological study. J Urol 1990; 144(3): 726–730. 29. Gupta DK, Kataria R, Sharma MC: Prepubertal testicular teratomas. Eur J Pediatr Surg 1999; 9(3): 173–176. 30. Klein EA: Tumor markers in testis cancer. Urol Clin North Am 1993; 20(1): 67–73. 31. Kennedy PT, et al: Ultrasonography of intratesticular lesions: its role in clinical management. Ulster Med J 1999; 68(2): 54–58. 32. Brown NJ: Teratomas and yolk-sac tumours. J Clin Pathol 1976; 29(11): 1021–1025. 33. Walsh C, Rushton HG: Diagnosis and management of teratomas and epidermoid cysts. Urol Clin North Am 2000; 27(3): 509–518. 34. Blyth B, et al: Paratesticular rhabdomyosarcoma: results of therapy in 18 cases. J Urol 1990; 144(6): 1450–1453. 35. Crist WM, et al: Prognosis in children with rhabdomyosarcoma: a report of the intergroup rhabdomyosarcoma studies I and II. Intergroup Rhabdomyosarcoma Committee. J Clin Oncol 1990; 8(3): 443–452. 36. Raney B Jr, et al: Primary site as a prognostic variable for children with pelvic soft tissue sarcomas. J Urol 1986; 136(4): 874–878. 37. Patton RB, Horn RC Jr.: Rhabdomyosarcoma: clinical and pathological features and comparison with human fetal and embryonal skeletal muscle. Surgery 1962; 52:572. 38. Rogers DA, et al: Indications for hemiscrotectomy in the management of genitourinary tumors in children. J Pediatr Surg 1995; 30(10): 1437–1439. 39. Crist WM, et al: Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol 2001; 19(12): 3091–3102. 40. Rodney C, Flanant F, Maurer H, et al: Initial lymphadenectomy is not necessary in localized and completely resected paratesticular rhabdomyosarcoma. Med Pediatr Oncol 1992; 20: 430 (abstract). 41. Kattan J, et al: Paratesticular rhabdomyosarcoma in adult patients: 16-year experience at Institut Gustave-Roussy. Ann Oncol 1993; 4(10): 871–875. 42. Wiener ES, et al: Controversies in the management of paratesticular rhabdomyosarcoma: Is staging retroperitoneal lymph node dissection necessary for adolescents with resected paratesticular
Chapter 49 Prepubertal Testicular Tumors 785
43.
44. 45. 46.
47.
48.
49.
50.
51. 52.
rhabdomyosarcoma? Semin Pediatr Surg 2001; 10(3): 146–152. Wiener ES, et al: Retroperitoneal node biopsy in paratesticular rhabdomyosarcoma. J Pediatr Surg 1994; 29(2): 171–177 (Discussion 178). Maurer HM, et al: The Intergroup Rhabdomyosarcoma Study-I. A final report. Cancer 1988; 61(2): 209–220. Maurer HM, et al: The Intergroup Rhabdomyosarcoma Study-II. Cancer 1993; 71(5): 1904–1922. Shapiro DN, et al: Relationship of tumor-cell ploidy to histologic subtype and treatment outcome in children and adolescents with unresectable rhabdomyosarcoma. J Clin Oncol 1991; 9(1): 159–166. Shah KH, Maxted WC, Chun B: Epidermoid cysts of the testis: a report of three cases and an analysis of 141 cases from the world literature. Cancer 1981; 47(3): 577–582. Ross JH, Kay R, Elder J: Testis sparing surgery for pediatric epidermoid cysts of the testis. J Urol 1993; 149(2): 353–356. Heidenreich A, et al: Organ preserving surgery in testicular epidermoid cysts. J Urol 1995; 153(4): 1147–1150. Cohen EL, et al: Epidermoid cyst of testicle. Ultrasonographic characteristics. Urology 1984; 24(1): 79–81. Nichols J, et al: Epidermoid cyst of testis: a report of 3 cases. J Urol 1985; 133(2): 286–287. Shapeero LG, Vordermark JS: Epidermoid cysts of testes and role of sonography. Urology 1993; 41(1): 75–79.
53. Eisenmenger M, et al: Epidermoid cysts of the testis: organ-preserving surgery following diagnosis by ultrasonography. Br J Urol 1993; 72(6):955–957. 54. Kolon TF, Hochman HI: Malignant Sertoli cell tumor in a prepubescent boy. J Urol 1997; 158(2): 608–609. 55. Kapoor HL, et al: Malignant interstitial cell tumour of testis in a child. Indian J Cancer 1988; 25(4): 241–245. 56. Sharma S, Seam RK, Kapoor HL: Malignant Sertoli cell tumour of the testis in a child. J Surg Oncol 1990; 44(2): 129–131. 57. Scully RE: Gonadoblastoma. A review of 74 cases. Cancer 1970; 25(6): 1340–1356. 58. Askin FB, et al: Occult testicular leukemia: testicular biopsy at three years continuous complete remission of childhood leukemia: a Southwest Oncology Group Study. Cancer 1981; 47(3): 470–475. 59. Godinho C, et al: Testicular relapse in acute lymphoblastic leukemia. The experience of a pediatrics service. Acta Med Port 1995; 8(11): 613–618. 60. Lamm DL, Kaplan GW: Urological manifestations of Burkitt’s lymphoma. J Urol 1974; 112(3): 402–405. 61. Weissbach L, Altwein JE, Stiens R: Germinal testicular tumors in childhood. Report of observations and literature review. Eur Urol 1984; 10(2): 73–85. 62. Elert A, et al: Accuracy of frozen section examination of testicular tumors of uncertain origin. Eur Urol 2002; 41(3): 290–293. 63. Tokuc R, et al: Accuracy of frozen section examination of testicular tumors. Urology 1992; 40(6): 512–516.
INDEX Ablation adrenal tumors with, 149 renal tumor with, 207–210, 208t cryoablation in, 207–208, 208t CT with, 208, 209 HIFU, 209–210 MRI with, 208, 209 radiofrequency, 208–209, 208t ACD. See ASTRO Consensus Definition ACTH. See Adrenocorticotrophic hormone Acute leukemia (AL) nongerm cell tumors of, 636 Acute lymphocytic leukemia (ALL) nongerm cell tumors of, 636, 636f Acute myelogenous leukemia (AML) diagnosis of, 179, 180, 180f Acute urinary retention (AUR) brachytherapy with, 119 Adaptive cellular therapy immunotherapy with, 93, 94f LAK, 93, 94f TIL, 93, 94f ADCC. See Antibody-dependent cellmediated cytotoxicity Adenocarcinoma of prostate androgen deprivation therapy for, 494–502, 497f, 500t, 501t adjuvant hormonal with radiation therapy in, 496–498, 497f alternative approaches with, 507–508 aminoglutethimide in, 495 antiandrogens as, 495 bicalutamide in, 495 CAB with, 505, 506, 508 cyproterone acetate in, 495 EBRT with, 494, 496–498, 499, 500, 501, 502 EORTC and, 496–497, 497f, 501, 501t, 506, 507 estrogen supplementation as, 495 flutamide in, 495 FSH in, 495, 500t goserelin in, 495 intermittent adenocarcinoma and, 507–508 leuprolide in, 495 LH in, 495, 500t LHRH in, 495, 496, 498, 500t, 505–507, 508, 511 medroxyprogesterone in, 495 megestrol in, 495 methods of, 494–495
Adenocarcinoma of prostate (Continued) NHT with radiation therapy in, 495–496 nilutamide in, 495 orchiectomy as, 494–495 PEP with, 506 peripheral androgen blockade and, 508 progesterone supplementation as, 495 prostatectomy with, 498–499 radiation therapy with, 495–498, 497f rationale in, 494 RTOG and, 495–498, 499, 500, 501t, 502 secondary hormonal therapy and, 508 standards of care in, 505–506 timing of, 498, 507 toxicity with, 499 future directions for, 500–502 interstitial brachytherapy for, 483–489, 484f, 484t, 485t, 487t, 489t BRFS following, 485–489, 485t, 487f, 489f HDR, 488–489, 489t historic perspective on, 483 PPB EBRT combined in, 486–488, 487t PPB technique in, 483–484, 484f T1-2 cancer with, 488 TPB technique in, 484–485 management of, 465–474, 466t, 468t, 469t, 471t, 472t, 473t, 494–502, 497f, 500t, 501t general, 494 metastasis of, 505–511, 509t, 510t bone-directed therapies for, 511 chemotherapy for, 509–511, 510t hormone therapy for, 505–509, 509t summary of, 511 outcomes for, 500 particle beam therapy for, 489 prognosis for, 465–474, 466t, 468t, 469t, 471t, 472t, 473t, 494–502, 497f, 500t, 501t radiation therapy for, 477–489, 478f, 479t, 480t, 481t, 482f, 484f, 484t, 485t, 487t, 489t ACD with, 479, 483, 485, 487–488 adjuvant hormonal with, 496–498, 497f ADT and, 479, 480, 482–483, 486, 487, 488 androgen deprivation therapy with, 495–498, 497f ASTRO with, 479, 481
Adenocarcinoma of prostate (Continued) biochemical relapse-free survival with, 477, 478, 479–481, 480t, 481t, 482, 482f, 485–489, 485t, 487f, 489f CT scan with, 478, 483, 484, 484f CTV with, 478–479, 479f 3DCRT with, 478–479, 478f, 482, 489 dose escalation with, 481–482, 481t EBRT historic perspective, 478 EBRT technique for, 478–479, 479f GTV with, 478–479, 479f HIFU with, 477 IMRT with, 478, 482 MR with, 478, 483 NHT with, 495–496 PSA levels with, 477–478, 479, 480, 481t, 482f, 485, 485f, 486–488, 487t PTV with, 478–479, 479f risk stratification with, 478 RTC with, 477 RTOG with, 477, 478, 482, 483, 485 T1-2 PC in, 477, 482–483 timing/duration of hormonal therapy with, 498 radical prostatectomy for, 465–474, 466t, 468t, 469t, 471t, 472t, 473t biopsy Gleason sum with, 471, 472f blood loss during, 469, 469f cancer control with, 469f, 470–473, 471f, 472f CT scan assessment with, 466 early complications with, 468–470, 468f, 469f erectile function after, 474 hospitalization days with, 469f intraoperative complications with, 468–470, 468f, 469f late complications with, 470 lymph node metastases with, 472t mortality with, 468f MRI assessment with, 466 obturator nerve injury from, 470 outcomes after, 469f, 470–474, 471f, 472f, 473f patient selection for, 466 PC natural history and, 465–466, 466t pelvic lymph node dissection with, 467–468 pretreatment risk stratification with, 466–467 PSA risk assessment with, 466–467, 470, 471f
Page numbers followed by f indicate figures; page numbers followed by t indicate tables.
787
788 Index Adenocarcinoma of prostate (Continued) PSA survival with, 469f rectal injury from, 469 results of, 468 risk factors with, 472f, 473f seminal vesicle involvement with, 472f treatment rationale, 465 urinary function with, 473, 473f urinary incontinence after, 473, 473f regionally advanced, 494–502, 497f, 500t, 501t androgen deprivation and prostatectomy for, 498–499 androgen deprivation and radiation therapy for, 494–498, 497f androgen deprivation therapy for, 494–502, 497f, 500t, 501t future directions for, 500–502 outcomes for, 500 prognosis for, 500 toxicity with, 499–500 urethral cancer pathology with, 674 Adenomatoid tumor of epididymis nongerm cell tumors of, 618t, 633, 633f, 634f Adenovirus vectors applications of, 21–22, 21t attributes in, 21–22, 21t gene delivery in, 21 gene expression in, 21 gene therapy with, 21–22, 21t, 22f, 26t vector production in, 21 ADEPT. See Antibody-dependent enzymemediated cytotoxicity Adrenal carcinoma adrenal tumors with, 136–137, 136t adrenocortical, 155–156 classification of, 136t Cushing’s syndrome with, 136 DHEA with, 136 gynecomastia with, 136 Mitotane with, 136 oligospermia with, 136 Adrenal tumors ablation for, 149 carcinoma, 136–137, 136t classification of, 136t Cushing’s syndrome with, 136 DHEA with, 136 gynecomastia with, 136 Mitotane with, 136 oligospermia with, 136 cryosurgery for, 149 Cushing’s syndrome and, 131, 132–133, 133t, 134f ACTH with, 132–133 CRH with, 132–133 description of, 132, 155 diagnosis of, 132, 134f, 154t, 155 manifestations of, 133t diagnosis of, 153–154, 154f, 154t CT scan in, 153, 154f Cushing’s syndrome in, 154t hyperaldosteronism in, 154t MRI in, 153, 154f pheochromocytoma in, 154t
Adrenal tumors (Continued) hyperaldosteronism in, 137–138, 137f, 138f aldosterone secretion with, 138, 138f CT scan for, 137f, 138 diagnosis of, 154t, 155 hypernatremia with, 137 hypertension with, 137, 137f, 154–155 hypokalemia with, 137–138, 155 PRA with, 137, 137f RASS with, 137 secondary, 138 incidentally discovered, 133–136, 135f CT scan in, 133–136, 135f MRI in, 134, 135f ultrasound in, 133 laparoscopic surgery for, 149, 150–151f, 160–167, 161f, 161t, 162f, 163f, 164f, 166t anterior transperitoneal approach in, 161–164, 162f, 163f approaches to, 161 complications of, 165 indications for, 160–161, 161t left adrenalectomy in, 163–165, 163f malignant tumors in, 167 posterior retroperitoneal approach in, 165 postoperative care with, 165 preoperative preparation in, 161, 161f references to, 166t results of, 165 retroperitoneal technique in, 164, 164f right adrenalectomy in, 161–163, 162f, 165 transthoracic technique in, 165 pheochromocytoma in, 138–139, 138f, 140t, 141f, 142t, 143f, 148f APUD with, 139 cardiomyopathy with, 139 CT scan for, 139, 155 diagnosis of, 155 glomus jugulare tumors with, 139, 148f identifying, 138, 138f, 154t MEA syndromes with, 139 MIBG scan for, 139, 155 MRI scan for, 139, 141f, 143f, 148f, 155 neurofibromatosis with, 139, 140t Sturge-Weber syndrome with, 139 surgical approach to, 155 symptoms of, 140t, 155 von Hippel-Landau with, 139, 140t physiological understanding for, 131, 132f arterial supply in, 132f CT in, 131 IVC in, 131, 132f MRI in, 131 venous drainage in, 132f summary of, 149 surgery for, 139–149, 142t, 143f, 144f, 145f, 146f, 147f, 148f, 153–167, 154f, 154t, 157f, 158f, 159f, 160f, 161f, 161t, 162f, 163f, 164f, 166t
Adrenal tumors (Continued) urologic oncology and, 131–151, 132f, 133t, 134f, 135f, 136t, 137f, 138f, 140t, 141f, 142t, 143f, 144f, 145f, 146f, 147f, 148f, 150f, 151f, 153–167 Adrenalectomy adrenal tumors treated with, 139–149, 142t, 143f, 144f, 145f, 146f, 147f, 148f approaches to, 141, 142t Cushing’s syndrome in, 141, 142t flank approach to, 145–147, 145f, 146f, 156–158, 157f hyperaldosteronism in, 142t lateral flank approach in, 156–158, 157f left, 163–165, 163f modified posterior approach to, 143–145, 144f, 159, 160f nephrectomy with, 146, 146f partial, 148–149, 148f, 167 pheochromocytoma in, 142t posterior approach to, 142–143, 143f, 159, 159f preoperative management with, 141, 142t RCC with, 204–205 right, 161–163, 162f, 165 thoracoabdominal approach to, 158, 158f transabdominal approach to, 147–148, 147f Adrenocortical carcinoma Cushing’s syndrome with, 155 description of, 155–156 Adrenocorticotrophic hormone (ACTH) Cushing’s syndrome with, 132–133 ADT. See Androgen deprivation therapy EBRT with, 482–483 PPB with, 487 radiation therapy for adenocarcinoma with, 479, 480, 482–483, 486, 487, 488 Adult granulosa cell tumors (AGCT) nongerm cell tumors as, 624–625, 626 AFP. See α-fetoprotein AGCT. See Adult granulosa cell tumors Agent Orange retroperitoneal tumors from, 652 AgNOR. See Silver staining nucleolar organizer regions AGR syndrome. See Aniridia, genitourinary malformations and mental retardation syndrome AIS. See Androgen insensitivity syndrome AJCC. See American Joint Committee of Cancer AL. See Acute leukemia Aldosterone secretion hyperaldosteronism with, 138, 138f Alkylating agents genitourinary cancer treatment with, 67–68 ALL. See Acute lymphocytic leukemia American Joint Committee of Cancer (AJCC), 196, 196t, 259 bladder cancer staging with, 308, 319 PC staging with, 462, 549–461 TCC staging of, 274t testis tumors staging with, 569, 571, 572t
Index 789 American Society of Therapeutic Radiology and Oncology (ASTRO) radiation therapy for adenocarcinoma with, 479, 481 Amine precursor uptake and decarboxylation (APUD) pheochromocytoma with, 139 Aminoglutethimide androgen deprivation therapy with, 495 AML. See Acute myelogenous leukemia Amyloidosis RCC associated with, 174t Anastomotic margin biopsy orthotopic bladder substitution with, 444 Androgen deprivation therapy (ADT) prostate adenocarcinoma treated with, 494–502, 497f, 500t, 501t adjuvant hormonal with radiation therapy in, 496–498, 497f alternative approaches with, 507–508 aminoglutethimide in, 495 antiandrogens as, 495 bicalutamide in, 495 CAB in, 505, 506, 508 cyproterone acetate in, 495 EBRT with, 494, 496–498, 499, 500, 501, 502 EORTC and, 496–497, 497f, 501, 501t estrogen supplementation as, 495 flutamide in, 495 FSH in, 495, 500t goserelin in, 495 intermittent ADT in, 507–508 leuprolide in, 495 LH in, 495, 500t LHRH in, 495, 496, 498, 500t, 505–507, 508, 511 medroxyprogesterone in, 495 megestrol in, 495 methods of, 494–495 NHT with radiation therapy in, 495–496 nilutamide in, 495 orchiectomy as, 494–495 PEP in, 506 peripheral androgen blockade and, 508 progesterone supplementation as, 495 prostatectomy with, 498–499 radiation therapy with, 495–498, 497f rationale in, 494 RTOG and, 495–498, 499, 500, 501t, 502 secondary hormonal therapy and, 508 standards of care in, 505–506 timing/duration of, 498 timing in, 507 toxicity with, 499 seminal vesicles treatment options with, 562 Androgen insensitivity syndrome (AIS) SCA with, 622, 624 Angiogenic factors MVD with, 341–342 TCC with, 341–342 TSP-1 with, 341 VEGF with, 341
Aniridia, genitourinary malformations and mental retardation syndrome (AGR syndrome) Wilms’ tumor with, 754, 754t, 759t Anorexia orthotopic bladder substitution with, 453t Anthracycline antibiotics genitourinary cancer treatment with, 62f, 63–64 Antiandrogens androgen deprivation therapy with, 495 Antibody-dependent cell-mediated cytotoxicity (ADCC) immunotherapy with, 98t Antibody-dependent enzyme-mediated cytotoxicity (ADEPT) immunotherapy with, 98t Anticancer antibiotics anthracycline antibiotics, 62f, 63–64 bleomycin, 61–63, 62f doxorubicin, 62f, 63–64 mitomycin, 62f, 63 mitoxantrone, 62f, 64 Antifolates genitourinary cancer treatment with, 70 Antimetabolites genitourinary cancer treatment with, 70 Antioncogene therapy gene therapy with, 30–31 APUD. See Amine precursor uptake and decarboxylation ASTRO. See American Society of Therapeutic Radiology and Oncology ASTRO Consensus Definition (ACD) radiation therapy for adenocarcinoma with, 479, 483, 485, 487–488 Atraumatic urethra dissection orthotopic bladder substitution with, 446 Bacille Calmette-Guerin (BCG) bladder cancer treated with, 92–93 IFN and, 92 immunotherapy with, 92–93, 94f TCC prognostic markers with, 321 TCC with, 276 Balanitis xerotica obliterans (BXO) penis carcinoma with, 711, 712 Ball electrode TUR instrumentation with, 359 BCG. See Bacille Calmette-Guerin Beckwith-Wiedemann syndrome (BWS syndrome) Wilms’ tumor with, 754, 754t, 759t Benchekroun nipple urinary diversion approach of, 409 Benign lesions ganglioneuroma as, 652t hemangiopericytoma as, 652t leiomyoma as, 652t, 653 lipomas as, 652–653, 652t myelolipoma as, 652t, 653 retroperitoneal tumors with, 652–653, 652t Schwannoma as, 652t BEP. See Bleomycin, etoposide and cisplatin BHD. See Birt-Hogg-Dubé
Bicalutamide androgen deprivation therapy with, 495 Bilateral pelvic lymph node dissection (BPLND) RPP patient selection and, 528 Biochemical relapse-free survival (BRFS) adenocarcinoma of prostate with, 477, 478, 479–481, 480t, 481t, 482, 482f, 485–489, 485t, 487f, 489f brachytherapy with, 485, 485t dose escalation and, 481t, 482, 482f EBRT with, 479–481, 480t HDR brachytherapy with, 488–489, 489t PPB alone with, 485–486, 485t PPB EBRT combined with, 486–488, 487t, 489t Birt-Hogg-Dubé (BHD) RCC with, 176, 197t Bladder cancer. See also Bladder preservation; Transitional cell carcinoma cystectomy for, 328–329, 329t indications for, 328, 329t partial, 329 radical, 328–329 development pathways of, 303f dysplasia in, 303f hyperplasia in, 303f lymphatic permeation in, 303f vascular permeation in, 303f diagnosis of, 301–313, 302f, 303f, 304f follow-up for, 329–330, 329t genetic changes with, 304f invasive carcinoma in, 304f lymphatic permeation in, 304f vascular permeation in, 304f HRQOL with, 108–109 mucosa distant from tumor in, 320 staging of, 301, 302f, 303f, 308–313 AJCC in, 308 carcinoma in situ in, 310 dysplasia in, 312 lymph node involvement in, 311 muscle-invasive cancer in, 310–311 TNM classification in, 308, 309 statistics on, 338 TUR for anesthesia for, 359 bimanual examination for, 359, 359f bladder cancer diagnosis with, 306, 338 Bladder-sparing therapy with, 347–348 bladder tumors with, 358–365, 359f, 360f, 364t, 365f complications with, 362–364 equipment for, 359–360 fluoroscopic cystoscopy for, 365 instrumentation for, 359–360 intraoperative problem management in, 361–362 irrigation fluid in, 361 laser surgery for, 364–365, 364t, 365f postoperative management in, 362 preparation for, 358–359 primary muscle invasive tumor treatment with, 362
790 Index Bladder cancer (Continued) second look resection in, 362 TCC bladder with, 317–318 TCC diagnosis with, 338 technique for, 360–361 types of, 338 Bladder explosion TUR complications with, 364 Bladder perforation TUR complications with, 363 Bladder preservation 5-FU, 391t 5-FU for, 390, 390t chemotherapy for, 389, 390t combined modality treatment for, 389–397, 390t, 391t, 393f, 394f, 395f, 396t, 397t MCV for, 390t monotherapy’s influence on, 389, 390t multimodal treatment schema for, 394f multimodality treatment results for, 390, 390t outcome of, 395f, 396t radiation therapy for, 389, 390t RTOG and, 391 single agent activity in, 391, 391t 5-FL, 391t carboplatin, 391t cisplatin, 391, 391t docetaxel, 391t doxorubicin, 391t gemcitabine, 391t ifosfamide, 391t methotrexate, 391, 391t mitomycin C, 391t paclitaxel, 391, 391t vinblastine, 391t TUR for, 389, 390t, 394f TURBIT for, 390t, 392 Bladder-sparing therapy complications of, 349 multimodality approach to, 348 outcomes of, 348–349 quality of life concerns with, 349 rationale for, 347 single modality approaches to, 347–348 TCC with, 347–349 TUR in, 347–348 Bleomycin genitourinary cancer treatment with, 61–63, 62f Bleomycin, etoposide and cisplatin (BEP) NSGCT treatment with, 606 Bone marrow transplantation RCC with, 265 Bosniak classification, 182, 182t Bosniak lesions RCC diagnosis with, 181–182 Bowenoid papulosis penis carcinoma with, 712 Bowen’s disease penis carcinoma with, 712–713 BPLND. See Bilateral pelvic lymph node dissection
Brachytherapy CT-guided, 119 outcome of, 119 procedure for, 119 HDR, 488–489, 489t HRQOL with, 107 IGT with, 118–122, 120f, 121f MR-guided, 114f, 115f, 119–122, 120f, 121f outcome of, 120–122 patient selection for, 119 procedure for, 114f, 115f, 119–120, 120f, 121f TURP and, 119 penis carcinoma with, 705–706 prostate adenocarcinoma treated with, 483–489, 484f, 484t, 485t, 487t, 489t BRFS following, 485–489, 485t, 487f, 489f historic perspective on, 483 PPB EBRT combined in, 486–488, 487t PPB technique in, 483–484, 484f T1-2 cancer with, 488 TPB technique in, 484–485 radiation oncology with, 40–41, 42f ultrasound guided, 118–119 BRFS. See Biochemical relapse-free survival Bropirimine bladder TCC with, 327 Bulbourethral cancer in, 3, 4f Buschke-Löwenstein tumor penis carcinoma with, 712, 723 BWS syndrome. See Beckwith-Wiedemann syndrome BXO. See Balanitis xerotica obliterans CAB. See Combination androgen blockade CAH. See Congenital adrenal hyperplasia CAIX. See Carbonic anhydrase IX Camptothecins genitourinary cancer treatment with, 72–74, 73f irinotecan as, 73–74, 73f topotecan as, 73f, 74 CAMS. See Cell adhesion molecules Cancer genes DNA methylation, 9 DNA repair, 8 molecular biology of, 8–10 oncogenes, 8 suppressor, 8 viral, 8–9 CAPD. See Continuous ambulatory peritoneal dislysis Carbonic anhydrase IX (CAIX) RCC with, 176 Carboplatin bladder preservation with, 391t genitourinary cancer treatment with, 60–61, 60f Carcinogens molecular biology of, 4–5 Carcinoid tumors (CT) nongerm cell tumors as, 618t, 632–633, 633f
Carcinoma in situ (CIS). See also Testicular Intraepithelial neoplasia bladder cancer staging with, 310.339 laparoscopic partial nephrectomy for, 231 penis carcinoma with, 712–713 seminoma with, 579 Transurethral resection (TUR), 359 Cardiomyopathy pheochromocytoma with, 139 Carney’s syndrome LCCSCT with, 623–624 Case histories TCC bladder, 330–331 CDC. See Complement-dependent cytotoxicity CDKI. See Cycle kinase inhibitor Cell adhesion molecules (CAMS), 13, 13f TCC with, 341 Cell-cycle regulators TCC prognosis with, 342–343 erb-B-2 in, 342–343 P53 in, 342 retinoblastoma gene in, 342 TGF in, 343 Cellular biology aging/telomerase in, 16 aptamers in, 16–17 cancer genes in, 8–10 DNA methylation, 9 DNA repair, 8 oncogenes, 8 suppressor, 8 viral, 8–9 carcinogens in, 4–5 cell cycle in, 11–12, 12f cell signaling in, 12f, 14–15, 14f CGH in, 8 epigenetic effects in, 3–4, 4f familial cancer in, 7–8 inflammation in, 5–7, 6t microarrays in, 10–11 proteomics in, 10–11 SKY in, 8 stromal epithelial interactions in, 15–16, 15f tumor cell heterogeneity in, 16–17, 17f urologic cancers in, 3–17, 4f, 6t, 10f, 12f, 13f, 14f, 15f, 17f CGH. See Comparative genome hybridization Chemotherapy agents used in, 59–74, 60f, 62f, 66f, 69f, 72f, 73f alkylating agents as, 67–68 anthracycline antibiotics as, 62f, 63–64 anticancer antibiotics as, 61–64, 62f antifolates as, 70 antimetabolites as, 70 bleomycin as, 61–63, 62f camptothecins as, 72–74, 73f capecitabine as, 71 carboplatin as, 60–61, 60f cisplatin as, 59–60, 60f cyclophosphamide as, 68 docetaxel as, 66f, 67 doxorubicin as, 62f, 63–64
Index 791 Chemotherapy (Continued) epipodophyllotoxin as, 69–70, 69f estramustine as, 67 etoposide as, 69, 69f fluoropyrimidines as, 70–71 gemcitabine as, 71–72, 72f ifosfamide as, 68–69 irinotecan as, 73–74, 73f methotrexate as, 70 mitomycin as, 62f, 63 mitoxantrone as, 62f, 64 oxaliplatin as, 60f, 61 paclitaxel as, 65–67, 67f platinum complexes as, 59–61, 60f taxanes as, 65–67, 67f thiotepa as, 69 topotecan as, 73f, 74 tubulin modulation drugs as, 64–65 vinca alkaloids as, 64–65 anticancer agent pharmacology of, 54–56 absorption in, 54 distribution in, 54–55 excretion in, 55–56 factors modifying, 56 metabolism in, 55 transport in, 54–55 bladder TCC with, 323–324 doxorubicin in, 324 MMC in, 323–324, 326t thiotepa in, 323 valrubicin in, 324 drug resistance mechanisms in, 56–58, 57t models for overcoming, 56–58, 57t genitourinary cancer treatment with, 51–74, 57t, 59t, 60f, 62f, 66f, 69f, 72f, 73f macro-pharmacokinetic mechanisms with, 57t micro-pharmacokinetic mechanisms with, 57t penis carcinoma with, 718 pharmacodynamic intracellular mechanisms with, 57t prostate adenocarcinoma treated with, 509–511, 510t RMS treated with, 773–774 stage I seminoma with, 586 summary of, 74 TCC radical cystectomy with, 346–347 treatment efficacy assessment for, 58–59, 59t classification by phase in, 59 explanatory trial in, 58 pragmatic trial in, 58–59 tumor cell biology related to, 51–54 cell cycle control in, 52–53 cell proliferation/apoptosis balance in, 53–54 cellular kinetics in, 52–53 clonality in, 54 EGF in, 51 EGFR in, 52 PC, 53 Chimeric antibodies, 97, 97f Chromosome TCC with abnormalities in, 340
Chronic leukemia (CL) nongerm cell tumors of, 636 CIS. See Carcinoma in situ CISCA. See Cisplatin, cyclophosphamide, adriamycin Cisplatin bladder preservation with, 391, 391t genitourinary cancer treatment with, 59–60, 60f Cisplatin, cyclophosphamide, adriamycin (CISCA) TCC chemotherapy treatment with, 281 Cisplatin, methotrexate, vinblastine (CMV) TCC chemotherapy treatment with, 281 Cisplatin, Velban and bleomycin (PVB) NSGCT treatment with, 605 CL. See Chronic leukemia Classic Sertoli cell tumors (CSCT) nongerm cell tumors as, 622–623, 622f, 623f pathologic characteristic of, 622–623, 622f, 623f Clinical target volume (CTV) brachytherapy and, 119–120 radiation oncology with, 41 radiation therapy for adenocarcinoma with, 478–479, 479f CMV. See Cisplatin, methotrexate, vinblastine Cold-cup biopsy TUR equipment including, 360 Colonic conduits noncontinent cutaneous urinary diversion with, 404–406, 405f ileocecal conduit for, 405 sigmoid colon conduit for, 406 transverse colon conduit for, 404–406, 405f Colony-stimulating factor (CSF) cytokine therapy with, 92, 93t HCT with, 93 immunotherapy with, 92, 93, 93t Combination androgen blockade (CAB) androgen deprivation therapy with, 505, 506, 508 peripheral androgen blockade and, 508 prostate adenocarcinoma treated with, 505, 506, 508 Comparative genome hybridization (CGH) cancer with, 8 Complement-dependent cytotoxicity (CDC) immunotherapy with, 98t Computed tomography (CT). See also Multidetector spiral computed tomography bladder cancer diagnosis with, 302, 304, 306, 339 hyperaldosteronism with, 137f, 138 IGT with, 113–114, 117f, 119 incidentaloma with, 133–136, 135f MRI v., 182, 187 NSGCT staging with, 601, 603f, 604f, 605f, 611t, 614t partial nephrectomy for, 230–231
Computed tomography (CT) (Continued) PC staging with, 461 penis carcinoma with, 714 pheochromocytoma with, 139 prostatectomy assessed with, 466 radiation therapy for adenocarcinoma with, 478, 483, 484, 484f radical nephrectomy with, 218 RCC staging with, 186–188, 186f renal diagnosing with, 179–182, 180f, 181f, 182f, 197 renal tumor ablation with, 208, 209 retroperitoneal tumors diagnosis of, 657–658, 657f RMS evaluation with, 767–768 RPLND with, 642, 647, 647f seminal vesicles treatment options with, 558, 563f squamous cell carcinoma of penis with, 696 TCC diagnosis with, 271–272 testis tumors staging with, 569–571 Wilms’ tumor evaluation with, 756, 756f, 758f Conditionally replication-competent oncolytic adenovirus (CRAd), 30 Condyloma acuminatum penis carcinoma with, 712 Congenital adrenal hyperplasia (CAH) Leydig cell tumors v., 621, 621f Continent mechanism appendiceal approach to, 409 Benchekroun nipple approach to, 409 cutaneous urinary diversion with, 409–411, 410f flap valve approach to, 409 four surgical techniques for, 409 hydraulic valve approach to, 409 intussuscepted nipple valve approach to, 409 pseudoappendiceal approach to, 409 Continent reservoirs cutaneous urinary diversion with, 411–427, 412f, 413f, 414f, 415f, 416f, 417f, 418–420f, 421f, 422f, 422t, 423–424t, 425f, 426f, 427f, 428f, 436–437 Duke pouch, 422t, 424t Florida pouch, 422t, 424t gastric pouch, 424t, 426–427, 427f, 428f, 436–437 Indiana pouch, 416–421, 422t, 423–424t, 425f, 436 Kock pouch, 411–413, 412f, 413f, 423t, 436 LeBag, 422t Mainz pouch, 414–416, 418–420f, 423t, 436 Penn pouch, 424t, 426, 426f T pouch, 413–414, 414f, 415f, 416f, 417f, 423t U. Miami pouch, 424t UCLA pouch, 422t, 423t Continuous ambulatory peritoneal dislysis (CAPD) RCC with, 174
792 Index Core Quality of Life Questionnaire (QLQ-C30) cutaneous urinary diversion influence in, 437–438, 438t HRQOL measured with, 105 Corticotropin-releasing hormone (CRH) Cushing’s syndrome with, 132–133 CRAd. See Conditionally replicationcompetent oncolytic adenovirus CRH. See Corticotropin-releasing hormone Cryoablation renal tumor ablation with, 207–208, 208t Cryosurgery adrenal tumors with, 149 Cryotherapy ED with, 118 IGT with, 117–118, 118f MR image of, 118f outcomes of, 118 procedure of, 118 Cryptorchid testes seminoma with, 591 CSCT. See Classic Sertoli cell tumors CSF. See Colony-stimulating factor CT. See Carcinoid tumors; Computed tomography CT-guided brachytherapy (CTBT) IGT with, 117 CTBT. See CT-guided brachytherapy CTV. See Clinical target volume Cushing’s syndrome ACTH with, 132–133 adrenal carcinoma with, 136 adrenal tumors and, 131, 132–133, 133t, 134f adrenalectomy for, 141, 142t CRH with, 132–133 description of, 132, 155 diagnosis of, 132, 134f, 154t, 155 LCCSCT with, 623 manifestations of, 133t Cutaneous horn penis carcinoma with, 712 Cutaneous pyelostomy noncontinent cutaneous urinary diversion with, 400, 401f technique for, 400, 401f Cutaneous ureterostomy noncontinent cutaneous urinary diversion with, 400–401, 402f technique for, 401, 402f Cutaneous urinary diversion complications with, 430–437, 433t, 435t continent, 406–427, 407f, 408f, 409f, 410f, 412f, 413f, 414f, 415f, 416f, 417f, 418f, 419f, 420f, 421f, 422f, 422t, 423–424t, 425f, 426f, 427f surgical technique for, 406 continent catheterizable urinary diversions for, 407–409 continent mechanism in, 409–411, 410f continent reservoirs for, 411–427, 412f, 413f, 414f, 415f, 416f, 417f, 418–420f, 421f, 422f, 422t, 423–424t, 425f, 426f, 427f, 428f, 436–437
Cutaneous urinary diversion (Continued) Duke pouch, 422t, 424t Florida pouch, 422t, 424t gastric pouch, 424t, 426–427, 427f, 428f, 436–437 ileocecal, 411–416, 412f, 413f, 414f, 415f, 416f, 417f, 418–420f, 421f, 422f, 422t, 423–424t Indiana pouch, 416–421, 422t, 423–424t, 425f, 436 Kock pouch, 411–413, 412f, 413f, 423t, 436 LeBag, 422t Mainz pouch, 414–416, 418–420f, 423t, 436 Penn pouch, 424t, 426, 426f right colon, 416–427, 422t, 423–424t, 425f, 426f, 427f, 428f, 436–437 T pouch, 413–414, 414f, 415f, 416f, 417f, 423t U. Miami pouch, 424t UCLA pouch, 422t, 423t continent v. noncontinent, 399 intraoperative pouch testing for, 411 laparoscopic ileal conduit for, 438, 439t nasogastric tube for, 400 noncontinent, 400–406, 401f, 402f, 403f, 404f, 405f colocolostomy in, 405f colonic conduits for, 404–406, 405f cutaneous pyelostomy for, 400, 401f cutaneous ureterostomy for, 400–401, 402f ileal conduit for, 401–403, 403f, 404f ileocecal conduit for, 405 jejunal conduit for, 404 rectus fascia incision in, 404f renal pelvis incision in, 401f sigmoid colon conduit for, 406 technique, 400, 401, 401f, 402f, 403, 403f, 404f, 405, 405f, 406 transverse colon conduit for, 404–406, 405f novel techniques for, 438–439, 439t postoperative care for, 400 preoperative preparation for, 399–400 quality of life with, 437–438, 438t rectal bladder urinary diversion for, 406–407, 407f, 408f ureterointestinal anastomoses with, 427–430, 429f, 430f, 431f Cycle kinase inhibitor (CDKI), 9, 11 Cyclophosphamide genitourinary cancer treatment with, 68 Cyclosporine (CSA) HCT with, 93 Cyproterone acetate androgen deprivation therapy with, 495 Cystectomy. See also Partial cystectomy; Radical cystectomy orthotopic bladder substitution with, 445–446, 445f, 446f, 453f TCC bladder with, 328–329, 329t indications for, 328, 329t
Cystectomy (Continued) partial, 329 radical, 328–329 urethrectomy with, 680 Cystogram orthotopic bladder substitution with, 449 Cystoprostatectomy urethrectomy with, 686–688, 687f, 688f, 689f, 690f, 691f, 692f, 693f pelvic dissection in, 686, 687, 687f, 688f perineal dissection in, 687–688, 689f, 690f, 691f, 692f, 693f Cytokine therapy CSF with, 92, 93, 93t IFN with, 88–89, 89t, 90t, 91–92, 92f IL2 with, 88–89, 89t, 90t, 91, 91f, 92, 92f immunotherapy with, 88–92, 89t, 90t, 91f, 92f intravesical interferon therapy with, 92 MHC with, 88, 89t RCC with, 88, 89–92, 90t superficial bladder cancer treated with, 92 Cytology TCC prognostic factors with, 320–321 DNA ploidy in, 321 urine in, 320–321 Cytoreductive nephrectomy, 247–248 Denonvilliers’ fascia Radical cystectomy with, 279f, 377, 378f, 380, 380f radical prostatectomy incision of, 521f RRP incision in, 529 wide-field dissection RRP with, 530 Denys-Drash syndrome Wilms’ tumor with, 753, 758, 759t DHEA adrenal carcinoma with, 136 Digital rectal exam (DRE) PC staging with, 549 RPP patient selection with, 529 US-guided prostate biopsy with, 122 Dioxin retroperitoneal tumors from, 652 Direct ureterointestinal anstomoses, 427–430, 429f DLI. See Donor T-cells Docetaxel bladder preservation with, 391t genitourinary cancer treatment with, 66f, 67 Donor T-cells (DLI) HCT with, 96f Dorsal venous complex radical prostatectomy with, 516–519, 518f, 519f, 520f, 521f Dose volume histograms (DVH) brachytherapy and, 120 radiation oncology with, 42, 42f Doxorubicin bladder preservation with, 391t bladder TCC with, 324 genitourinary cancer treatment with, 62f, 63–64
Index 793 DRE. See Digital rectal exam Duke pouch complications with, 435t continent colon pouches compared to, 422t continent reservoirs compared to, 424t reoperation rate with, 435t urinary diversion with, 422t, 424t, 435t DVH. See Dose volume histograms Dyspepsia orthotopic bladder substitution with, 453t Dysplasia urethral cancer pathology with, 673–674 Eastern Cooperative Oncology Group patient performance status (ECOG PS) RCC staging with, 186–187, 186t, 260–261 EBRT. See External beam radiation therapy ECE. See Extracapsular extension ECM. See Extracellular matrix ECOG PS. See Eastern Cooperative Oncology Group patient performance status ED. See Erectile dysfunction EGCT. See Extragonadal germ cell tumors EGF. See Epidermal growth factor EGFR. See Epidermal growth factor receptor 18-fluoro-2-d3oxyglucose (FDG) bladder cancer diagnosis with, 306, 339 RCC diagnosis with, 183, 188–189 Endopelvic fascia radical prostatectomy incision of, 515–516, 517f, 518f EORTC. See European Organization for Research and Treatment of Cancer EPIC. See Expanded Prostate Cancer IndexComposite Epidermal growth factor (EGF) tumor cell biology and, 51 Epidermal growth factor receptor (EGFR) tumor cell biology and, 52 Epidermoid cysts nongerm cell tumors of, 618t, 627–628, 627f, 628f testicular tumors in pediatrics, 781–782 Epigenetic effects HAT in, 3–4 HDAC in, 4 methylation in, 4 RNAi in, 4 urologic cancers with, 3–4, 4f Epipodophyllotoxin genitourinary cancer treatment with, 69–70, 69f Erb-B-2 TCC prognosis with, 342–343 Erectile dysfunction (ED) cryotherapy with, 118 Erythrocytosis RCC associated with, 174t Erythroplasia of Queyrat penis carcinoma with, 710–711 Estramustine chemotherapy with, 67 Estrogen supplementation androgen deprivation therapy with, 495
Etoposide genitourinary cancer treatment with, 69, 69f European Organization for Research and Treatment of Cancer (EORTC) androgen deprivation therapy and, 496–497, 497f, 501, 501t, 506, 507 HRQOL measured with, 105 Expanded Prostate Cancer Index-Composite (EPIC) HRQOL measured with, 105 External beam radiation therapy (EBRT) ADT and, 479, 480, 482–483, 486, 487, 488 androgen deprivation therapy for, 494, 496–498, 499, 500, 501, 502 BRFS through, 479–482, 480t, 481t CT scan with, 478, 483, 484, 484f 3DCRT with, 478–479, 478f, 482, 489 dose escalation with, 481–482, 481t HCT with, 95t historic perspective of, 478, 478f HRQOL with, 107, 108, 108t IMRT with, 478 interstitial brachytherapy with, 483–489, 484f, 484t, 485t, 487t, 489t BRFS following, 485 historic perspective on, 483 PPB technique in, 483–484, 484f, 486–488, 487t TPB technique in, 484–485 MR with, 478, 483 penis carcinoma with, 704, 705t prostate adenocarcinoma treated with, 477–489, 478f, 479t, 480t, 481t, 482f, 484f, 484t, 485t, 487t, 489t PSA levels with, 486–488, 487t radiation oncology with, 39–40, 40f RMS treated with, 773–774 seminal vesicles treatment options with, 558, 560f T1-2 PC in, 477, 482–483 technique of, 478–479, 479t CTV with, 478–479, 479t GTV with, 478–479, 479t PTV with, 478–479, 479t Extracapsular extension (ECE) IGT influence on, 117 PC staging with, 461 Extracellular matrix (ECM), 11, 12f, 13f Extragonadal germ cell tumors (EGCT) seminoma with, 591 Extramustine genitourinary cancer treatment with, 67 FACT. See Functional Assessment of Cancer Therapy Familial renal oncocytoma RCC with, 176–177 Fatigue orthotopic bladder substitution with, 453t FDA. See Food and Drug Administration FDG. See 18-fluoro-2-d3oxyglucose FDP. See Fibrin gradation products α-fetoprotein (AFP) nongerm cell tumors with, 617, 626 serum tumor markers of, 568, 596, 598
Fibrin gradation products (FDP) bladder cancer diagnosis with, 305 Fibrosarcoma malignant lesions of, 653t, 656 Fine needle aspiration (FNA) RCC with, 197–198 FISH. See Fluorescent in situ hybridization 5-fluorouracil (5-FU) Bladder preservation with, 391t 5-FU. See 5-fluorouracil Flap valve urinary diversion approach of, 409 Flexible cystoscope TUR equipment including, 360 Florida pouch complications with, 435t continent colon pouches compared to, 422t continent reservoirs compared to, 424t reoperation rate with, 435t urinary diversion with, 422t, 424t, 435t Fluorescent in situ hybridization (FISH) bladder cancer diagnosis with, 305 TCC prognostic markers with, 321 Fluoropyrimidines genitourinary cancer treatment with, 70–71 Fluoroscopic cystoscopy TUR with, 365 Flutamide androgen deprivation therapy with, 495 Focused ultrasound surgery (FUS) IGT with, 114, 116, 122 Follicle stimulating hormone (FSH) androgen deprivation therapy for, 495, 500t Food and Drug Administration (FDA) IL-2 approval by, 88 valrubicin approval by, 324 Fossa navicularis cancer, 675, 677t FSH. See Follicle stimulating hormone Functional Assessment of Cancer Therapy (FACT) cutaneous urinary diversion influence in, 438t HRQOL measured with, 105 G-CSF. See Granulocyte colony-stimulating factor Ganglioneuroma benign lesions of, 652t Gastric pouch complications with, 436–437 continent reservoirs compared to, 424t urinary diversion with, 424t, 426–427, 427f, 428f, 436–437 Gastrointestinal anastomosis (GIA) LRN with, 247, 249f GCT. See Testis tumors Gemcitabine bladder preservation with, 391t Gene therapy adenovirus vectors for, 21–22, 21t, 22f, 26t antioncogene therapy for, 30–31, 31f antisense construct approach to, 30–31
794 Index Gene therapy (Continued) emerging vectors for, 25 future directions in, 33–34, 33f gene transfer vectors for, 18–19 liposomal gene transfer for, 21t, 24–25, 24f, 25f, 26t modified vector tropism in, 33–34 molecular targets of, 25–33, 26t, 27f, 31f, 32f direct induction of, 26t, 29–30 immunogene therapy (ex vivo) in, 25–28, 26t, 27f immunogene therapy (in vivo) in, 23f, 26t, 28–29 nonviral vectors for, 21t, 24–25, 24f, 25f, 26t oncolytic virotherapy for, 30 other delivery systems for, 25 poxvirus vectors for, 21t, 22–24, 23f, 26t restricted transgene expression in, 34 retrovirus vectors for, 19–21, 19f, 20f, 21t, 26t ribozyme construct approach to, 30–31, 31f summary of, 34 target cell death with, 26t, 29–30 targeting vector specificity in, 33–34, 33f transcriptional targeting in, 34 tumor suppressor gene restoration in, 31–33, 32f urologic cancers treated with, 18–34, 19f, 20f, 21t, 22f, 23f, 24f, 25f, 26t, 27f, 31f, 32f, 33f Genitourinary cancer agents used against, 59–74, 60f, 62f, 66f, 69f, 72f, 73f alkylating agents as, 67–68 anthracycline antibiotics as, 62f, 63–64 anticancer antibiotics as, 61–64, 62f antifolates as, 70 antimetabolites as, 70 bleomycin as, 61–63, 62f camptothecins as, 72–74, 73f capecitabine as, 71 carboplatin as, 60–61, 60f cisplatin as, 59–60, 60f cyclophosphamide as, 68 docetaxel as, 66f, 67 doxorubicin as, 62f, 63–64 epipodophyllotoxin as, 69–70, 69f estramustine as, 67 etoposide as, 69, 69f fluoropyrimidines as, 70–71 gemcitabine as, 71–72, 72f ifosfamide as, 68–69 irinotecan as, 73–74, 73f methotrexate as, 70 mitomycin as, 62f, 63 mitoxantrone as, 62f, 64 oxaliplatin as, 60f, 61 paclitaxel as, 65–67, 67f platinum complexes as, 59–61, 60f taxanes as, 65–67, 67f thiotepa as, 69 topotecan as, 73f, 74 tubulin modulation drugs as, 64–65 vinca alkaloids as, 64–65
Genitourinary cancer (Continued) anticancer agent pharmacology for, 54–56 absorption in, 54 distribution in, 54–55 excretion in, 55–56 factors modifying, 56 metabolism in, 55 transport in, 54–55 chemotherapy principles for, 51–74, 57t, 59t, 60f, 62f, 66f, 69f, 72f, 73f drug resistance mechanisms with, 56–58, 57t models for overcoming, 56–58, 57t macro-pharmacokinetic mechanisms with, 57t micro-pharmacokinetic mechanisms with, 57t pharmacodynamic intracellular mechanisms with, 57t summary of, 74 treatment efficacy assessment for, 58–59, 59t classification by phase in, 59 explanatory trial in, 58 pragmatic trial in, 58–59 tumor cell biology and, 51–54 cell cycle control in, 52–53 cell proliferation/apoptosis balance in, 53–54 cellular kinetics in, 52–53 clonality in, 54 EGF in, 51 EGFR in, 52 PC, 53 Gerota’s fascia radical nephrectomy with, 224f, 226, 239 GF. See Growth factor GIA. See Gastrointestinal anastomosis Giant condyloma acuminatum penis carcinoma with, 712 Gleason score radical prostatectomy with, 471, 472f seminal vesicles diagnosis of, 556, 556t, 564f Glomus jugulare tumors pheochromocytoma with, 139, 148f Glucose transporter (GLUT-1) RCC with, 176 GLUT-1. See Glucose transporter Glutathione (GSH), 57 TCC prognosis with, 343 Glutathione-S-transferase pi (GSTPi) inflammation with, 5–6, 6t GM-CSF. See Granulocyte-macrophage colony-stimulating factor Gonadal stromal tumors, 782 Gonadoblastoma, 782 Goserelin androgen deprivation therapy with, 495 Graft-versus-host disease (GVHD) HCT with, 93, 95–96, 97 Graft-versus-leukemia (GVL) HCT with, 93 Graft-versus-tumor (GVT) HCT with, 93, 96f, 97 Granulocyte colony-stimulating factor (G-CSF) cytokine therapy with, 92
Granulocyte colony-stimulating factor (Continued) HCT with, 93 immunotherapy with, 92, 93 Granulocyte-macrophage colonystimulating factor (GM-CSF) cytokine therapy with, 92, 93t HCT with, 93 immunotherapy with, 92, 93, 93t, 264 Granulosa cell tumors clinical presentation of, 624–625 evaluation of, 626 management of, 626 nongerm cell tumors as, 618t, 624–626, 625f, 626f pathologic characteristic of, 625–626, 625f, 626f Gross tumor volume (GTV) radiation oncology with, 41 radiation therapy for adenocarcinoma with, 478–479, 479f Growth factor (GF), 12–14, 12f, 13f GSH. See Glutathione GSTPi. See Glutathione-S-transferase pi GTV. See Gross tumor volume GVHD. See Graft-versus-host disease GVL. See Graft-versus-leukemia GVT. See Graft-versus-tumor Gynecomastia adrenal carcinoma with, 136 HA. See Hyaluronic acid HA stimulating activity (HASA) Wilms’ tumor pathology with, 761 HAL. See Hand-assisted laparoscopy HAMA. See Human antimouse antibody Hand-assisted laparoscopy (HAL) LRN with, 199 HASA. See HA stimulating activity HAT. See Histone acetyl transferases HCG. See Human chorionic gonadotropin HCT. See Hematopoietic cell transplantation HDAC. See Histone deacetylation HDR techniques. See High-dose rate techniques Health-related quality of life (HRQOL) brachytherapy influencing, 107 cutaneous urinary diversion with, 437–438, 438t EBRT influencing, 107, 108, 108t established instruments for, 104–105 cancer-specific, 105 EORTC as, 105 EPIC as, 105 FACT as, 105 general, 104–105 NHP as, 104 QLQ-C30 as, 105 QWB as, 104 SF-36 as, 104 SIP as, 104 UCLA PCI as, 105 urologic malignancy specific, 105 IB influencing, 107–108, 108t
Index 795 Health-related quality of life (Continued) instrument methodology for, 102–104, 103t, 104t IPSS measuring, 107 RP v. WW in, 107 specific urologic malignancies with, 105–109, 108t bladder cancer in, 108–109 kidney cancer in, 109 prostate cancer in, 105–108, 108t testicular cancer in, 109 summary of, 109 urologic oncology issues with, 102–109, 103t, 104t, 108t Hemangiopericytoma benign lesions of, 652t malignant lesions of, 653t, 657 Hematologic tumors nongerm cell tumors of, 618t, 633–636, 635f Hematopoietic cell transplantation (HCT) CSA and, 93 CSF and, 93 DLI with, 96f GVHD with, 93, 95–96, 97 GVL with, 93 GVT with, 93, 96f, 97 immunotherapy with, 93–97, 95t, 96f myeloablative condition in, 95, 95t, 96f RCC treated with, 95–97, 96f T-cells with, 93, 96, 96f XRT conditioning for, 95t Hemorrhage TUR complications with, 362–363 Hereditary leiomyomatosis renal carcinoma (HLRC) RCC with, 177 Hereditary papillary renal carcinoma (HPRC) RCC with, 176, 197t Hereditary prostate cancer (HPC), 7 HIF. See Hypoxia-inducible factor HIFU. See High-intensity focused ultrasound High-dose rate (HDR) techniques prostate adenocarcinoma treated with, 488–489, 489t radiation oncology with, 41 High-intensity focused ultrasound (HIFU) radiation therapy for adenocarcinoma with, 477 renal tumor ablation with, 209–210 High performance liquid chromatography (HPLC), 66 High telomerase reverse transcriptase (hTERT) Wilms’ tumor pathology with, 780 Histone acetyl transferases (HAT) epigenetic effects with, 3–4 Histone deacetylation (HDAC) epigenetic effects with, 4 HIV. See Human immunodeficiency virus HLRC. See Hereditary leiomyomatosis renal carcinoma Hormone-refractory PC (HRPC), 57 Hormone therapy. See Androgen deprivation therapy Horner’s syndrome neuroblastoma with, 742, 748
Horseshoe kidney seminoma with, 592 HPC. See Hereditary prostate cancer HPLC. See High performance liquid chromatography HPRC. See Hereditary papillary renal carcinoma HPV. See Human papillomavirus HRPC. See Hormone-refractory PC hTERT. See High telomerase reverse transcriptase Human antimouse antibody (HAMA) immunotherapy with, 97–98, 98t Human chorionic gonadotropin (HCG) serum tumor markers of, 568, 597, 599 Human immunodeficiency virus (HIV) seminoma patients with, 592 testis tumors and, 637 Human papillomavirus (HPV) penis carcinoma with, 711 squamous cell carcinoma of penis with, 695–696, 710 Humanized antibodies, 97 Hyaluronic acid (HA) Wilms’ tumor pathology with, 761 Hydraulic valve urinary diversion approach of, 409 Hyperaldosteronism adrenal tumors with, 137–138, 137f, 138f adrenalectomy for, 142t aldosterone secretion with, 138, 138f CT scan for, 137f, 138 diagnosis of, 154t hypernatremia with, 137 hypertension with, 137, 137f hypokalemia with, 137–138 PRA with, 137, 137f RASS with, 137 secondary, 138 Hypercalcemia RCC associated with, 174t Hyperchloremic metabolic acidosis cutaneous urinary diversion with, 433t Hyperkalemia cutaneous urinary diversion with, 433t Hypernatremia, 137 Hypertension hyperaldosteronism with, 137, 137f RCC associated with, 174t Hypochloremic metabolic acidosis cutaneous urinary diversion with, 433t Hypokalemia cutaneous urinary diversion with, 433t hyperaldosteronism with, 137–138 Hypoxia-inducible factor (HIF) RCC with, 176 IB. See Interstitial brachytherapy IBD. See Inflammatory bowel disease ICU. See Intensive care unit IFN. See Interferon Ifosfamide bladder preservation with, 391t genitourinary cancer treatment with, 68–69
IGCCCG. See International Germ Cell Cancer Collaborative IGT. See Image-guided therapy IL-2. See Interleukin-2 Ileal conduit noncontinent cutaneous urinary diversion with, 401–403, 403f, 404f technique for, 403, 403f, 404f Ileal segment resection orthotopic bladder substitution with, 446, 447f, 448f Ileocecal conduit noncontinent cutaneous urinary diversion with, 405 ILNR. See Intralobar nephrogenic rest Image-guided therapy (IGT) brachytherapy with, 118–122, 120f, 121f CT-guided, 119 MR-guided, 114f, 115f, 119–122, 120f, 121f ultrasound guided, 118–119 cryotherapy for, 117–118, 118f ED with, 118 MR image of, 118f outcomes of, 118 procedure of, 118 CT in, 113–114, 117f, 119 CTBT with, 117 current applications overview of, 115–116, 115f diagnosis in, 122–123 ECE minimized with, 117 FUS in, 114, 116, 122 history of, 113–114, 114f image processing role of, 116, 117f minimal invasiveness of, 113–125, 114f, 115f, 117f, 118f, 120f, 121f, 123f, 124f MR-guided prostate biopsy in, 123–124, 123f, 124f procedure for, 123–124 MRBT with, 117 MRI in, 113–125, 114f, 115f, 117f, 118f, 120f, 121f, 123f, 124f MRT in, 114, 115 rapid growth in, 113 summary of, 124–125 surgery focused ultrasound in, 122 outcome of, 122 procedure for, 122 prostate cancer with, 122 therapy/image integration with, 116 TRUS in, 114, 117, 118, 122 US-guided prostate biopsy in, 122–123 DRE with, 122 procedure for, 122–123 ImmunoCyt bladder cancer diagnosis with, 305 Immunogene therapy ex vivo, 25–28, 26t, 27f gene therapy with, 23f, 25–29, 26t, 27f in vivo, 23f, 26t, 28–29 Immunosuppression patients seminoma with, 590
796 Index Immunotherapy adaptive cellular therapy as, 93, 94f LAK, 93, 94f TIL, 93, 94f basic guidelines for, 88–98, 89t, 90t, 91f, 92f, 93t, 94f, 95t, 96f, 97f, 98t BCG as, 92–93, 94f, 324–326, 326t bladder TCC with, 324–326, 326t CIS with, 325, 326t prophylaxis with, 325–326 bladder TCC with, 324–327 bropirimine in, 327 cytokine therapy in, 88–92, 89t, 90t, 91f, 92f CSF with, 92, 93t IFN with, 88–89, 89t, 90t, 91–92, 92f IL2 with, 88–89, 89t, 90t, 91, 91f, 92, 92f intravesical interferon therapy with, 92 MHC with, 88, 89t RCC with, 88, 89–92, 90t superficial bladder cancer treated with, 92 HAMA in, 97–98, 98t HCT as, 93–97, 95t, 96f CSA and, 93 CSF and, 93 DLI with, 96f GVHD with, 93, 95–96, 97 GVL with, 93 GVT with, 93, 96f, 97 myeloablative condition in, 95, 95t, 96f RCC treated with, 95–97, 96f T-cells with, 93, 96, 96f XRT conditioning for, 95t IFN in, 326 KLH in, 326–327 monoclonal antibodies in, 97–98, 97f, 98t IMRT. See Intensity modulated radiation therapy Incidentaloma adrenal tumors as, 133–136, 135f CT scan in, 133–136, 135f MRI in, 134, 135f ultrasound in, 133 Indiana pouch complications with, 435t, 436 continent reservoirs compared to, 423t reoperation rate with, 435t technique for, 420–421, 422t, 425f urinary diversion with, 416–421, 422t, 423–424t, 425f, 435t, 436 Inferior vena cava (IVC) adrenal anatomy with, 131, 132f RCC involvement with, 261 tumor thrombus with, 203–204, 203t, 204f, 227f, 228f, 229, 229f Inflammation GSTPi in, 5–6, 6t molecular biology of, 5–7, 6t PIN in, 5 ROS in, 5–6 Inflammatory bowel disease (IBD) seminoma with, 590
Intensity modulated radiation therapy (IMRT) radiation oncology with, 42–43, 42f, 43f radiation therapy for adenocarcinoma with, 478 retroperitoneal tumors with, 664 Intensive care unit (ICU) radical cystectomy with, 384 Interferon (IFN) background of, 88–89, 89t bladder TCC treated with, 326 immunotherapy with, 88–89, 89t, 90t, 91–92, 92f intravesical interferon therapy with, 92 RCC treatment with, 89, 90t, 91–92, 263 superficial bladder cancer treated with, 92 systemic therapy with, 263 Interleukin-2 (IL-2) background of, 88–89, 89t FDA approval of, 88, 263 immunotherapy with, 88–89, 89t, 90t, 91, 91f, 92, 92f RCC treatment with, 88, 89, 90t, 91–92, 263–264 systemic therapy with, 263–264 International Germ Cell Cancer Collaborative (IGCCCG) NSGCT treatment and, 606, 611t, 615 testis tumors staging of, 571, 573t International Prostate Symptom Score (IPSS) HRQOL with, 107 Interstitial brachytherapy (IB) HRQOL with, 107–108, 108t Intralobar nephrogenic rest (ILNR) Wilms’ tumor pathology with, 758–759, 758f Intraoperative radiation therapy (IORT) retroperitoneal tumors with, 664 Intraperitoneal rupture cutaneous urinary diversion with, 434 Intravenous pyelogram (IVP) bladder Cancer diagnosis with, 302 RCC diagnosing with, 178, 178f, 197 upper urinary tract TCC with, 287 Intravesical interferon therapy superficial bladder cancer treated with, 92 Intravesical therapy bladder TCC with, 322–327, 322t, 326t chemotherapy for, 323–324 doxorubicin in, 324 MMC in, 323–324, 326t thiotepa in, 323 valrubicin in, 324 combination therapy, 327 immunotherapy for, 324–327 BCG in, 324–326, 326t bropirimine in, 327 IFN in, 326 KLH in, 326–327 rationale for, 322–323, 322t recommendations in, 327 Intussuscepted nipple valve urinary diversion approach of, 409
Ionizing radiation (IR) apoptosis in, 45–46 cellular repair response in, 44 cellular target interacts with, 43–44 cycle and, 45 DNA damage accumulation with, 44, 45 DNA repair following, 45 induced cell death with, 45–46 necrosis in, 45–46 normal tissue protection in, 44–45 OER in, 43 PLDR in, 44 radiation oncology with, 43–46 radiation sensitizers for, 44 radioprotector agents in, 44–45 ROS with, 43–44 SLDR in, 44 therapeutic ratio in, 44, 45 tumor cell interactions with, 43 tumoricidal effect enhancement in, 44 IORT. See Intraoperative radiation therapy IPSS. See International Prostate Symptom Score IR. See Ionizing radiation Irinotecan genitourinary cancer treatment with, 73–74, 73f IVC. See Inferior vena cava IVP. See Intravenous pyelogram Jackson staging system penis carcinoma with, 714, 715t Penis SCC with, 701t, 702 Jejunal conduit noncontinent cutaneous urinary diversion with, 404 JGCT. See Juvenile granulosa cell tumors Juvenile granulosa cell tumors (JGCT) nongerm cell tumors as, 625, 625f, 626 Keyhole-limpet hemocyanin (KLH) bladder TCC with, 326–327 Kidney cancer HRQOL with, 109 KLH. See Keyhole-limpet hemocyanin Klinefelter’s syndrome LCT with, 619 Kock pouch complications with, 435t, 436 continent reservoirs compared to, 423t reoperation rate with, 435t technique for, 411–413, 412f, 413f urinary diversion with, 411–413, 412f, 413f, 423t, 435t, 436 L-(methyl)-11C-methionine (LCM) bladder cancer diagnosis with, 306 Lactate dehydrogenase (LDH) serum tumor markers of, 568, 597, 599 LAK. See Lymphokine-activated killer cells Laparoscopic adrenalectomy adrenal tumors with, 149, 150–151f Laparoscopic ileal conduit cutaneous urinary diversion with, 438, 439t
Index 797 Laparoscopic nephroureterectomy TCC with, 278–279 Laparoscopic partial nephrectomy complications of, 252–283 contraindications for, 249 financial analysis of, 283 indications for, 249 renal hypothermia with Endocatch II bag in, 250, 254f renal parenchymal repair in, 253f results of, 250–252, 255t technique for, 249–250, 250t, 251f, 252f, 253f bulldog clamp in, 251f methylene blue injection in, 252f Satinsky clamp in, 251f Laparoscopic radical nephrectomy (LRN) approach selection for, 237–238 complications of, 241, 243t, 244t concomitant adrenalectomy with, 245–246 contra-indications for, 237 cytoreductive, 247–248 financial implications of, 248 follow-up for, 246t indications for, 237 larger renal tumors with, 245, 247t oncologic outcome of, 244–245 ORN v., 201–203, 202t, 247t blood loss in, 202t convalescence time in, 202t, 247t mean tumor size in, 247t morcellation in, 202–203 oncologic adequacy in, 201–202 operating room time in, 202t, 247t postoperative complications in, 247t RCC with, 199–203, 202t, 237–248, 238f, 239f, 240f, 241f, 242t, 243t, 244t, 245f, 246t, 247t, 248t, 249f renal vein involvement with, 246–247, 248t, 249f results of, 241, 242t specimen extraction with, 241–244, 245f female, 244, 245f male, 244 technique for, 200–201, 238–240, 238f, 239f, 240f, 241f balloon dilation in, 240f clip-applier in, 239f GIA stapler in, 247, 249f HAL, 201 retroperitoneal, 200–201, 239–240, 240f, 241f transperitoneal, 200, 238–239, 238f, 239f three approaches to, 199 HAL, 199 retroperitoneal, 199 transperitoneal, 199 Laparoscopic renal hypothermia, 250, 254f Large cell calcifying Sertoli cell tumors (LCCSCT) Carney’s syndrome with, 623–624 Cushing’s syndrome with, 623 nongerm cell tumors as, 622, 623–624
Large cell calcifying Sertoli cell tumors (LCCSCT) (Continued) pathologic characteristic of, 623–624, 625f Peutz-Jeghers syndrome with, 623 Laser surgery advantages/disadvantages with, 364–365 bladder tumor recurrence rate with, 365 techniques of, 364 TUR with, 364–365, 364t, 365f types of CO2, 364t diode, 364t Ho:Yag, 364, 364t KTP, 364, 364t Nd:Yag, 364, 364t, 365, 365f Laser therapy penis with, 704–705, 705t complications in, 705 effectiveness with, 705, 705t surgical technique in, 704–705 LCCSCT. See Large cell calcifying Sertoli cell tumors LCM. See L-(methyl)-11C-methionine LCT. See Leydig cell tumors LDH. See Lactate dehydrogenase LeBag continent colon pouches compared to, 422t urinary diversion with, 422t Leiomyoma benign lesions of, 652t, 653 Leiomyosarcoma malignant lesions of, 653t, 654–655 Leukemia nongerm cell tumors of, 618t, 636, 636f Leuprolide androgen deprivation therapy with, 495 Leydig cell tumors (LCT) CAH v., 621, 621f clinical presentation of, 618–619 evaluation of, 621–622 Klinefelter’s syndrome with, 619 management of, 621–622 nongerm cell tumors of, 618–622, 618f, 618t, 619f, 620f, 621f pathologic characteristics of, 619–621, 620f Reinke’s crystals in, 619, 621 LH. See Luteinizing hormone LHRH. See Luteinizing hormone releasing hormone Lichen sclerosis et atrophicus (LSA) Penis carcinoma with, 710 Lipomas benign lesions of, 652–653, 652t Liposarcoma malignant lesions of, 653–654, 653t, 654f, 655f Liposomal gene transfer applications of, 21t, 25 attributes in, 21t, 25 gene delivery in, 24–25, 24f, 25f gene expression in, 25 gene therapy with, 21t, 24–25, 24f, 25f, 26t vector production in, 24
LRN. See Laparoscopic radical nephrectomy LSA. See Lichen sclerosis et atrophicus Luteinizing hormone (LH) androgen deprivation therapy for, 495, 500t Luteinizing hormone releasing hormone (LHRH) androgen deprivation therapy with, 495, 496, 498, 500t, 505–507, 508, 511 seminal vesicles treatment options with, 560f Lymph nodes bladder cancer staging with, 311 radical prostatectomy with, 472f RCC involvement with, 261 TCC staging with, 274t testis tumors staging of, 571, 572t Lymphadenectomy avoiding complications with, 730–731 classic inguinal type, 732 considerations in, 730 modified inguinal type, 729f, 731–732, 732f pelvic radical cystectomy with, 373–374, 375f, 376f penectomy and, 728, 729f, 730–732, 732f radical nephrectomy with, 222 radical prostatectomy with, 515 RCC with, 205–206, 205f TCC radical cystectomy with, 345–346 technique of, 728f, 729f, 731 Lymphangiogram testis tumors staging with, 570 Lymphokine-activated killer cells (LAK) immunotherapy with, 93, 94f Macrophage scavenger receptor (MSR-1) prostate cancer, 5, 6t Magnetic resonance (MR), 113 Mainz pouch complications with, 435t, 436 continent reservoirs compared to, 423t reoperation rate with, 435t technique for, 414–416, 418–420f urinary diversion with, 414–416, 418–420f, 423t, 435t, 436 Malignant fibrous histiocytoma (MFH) malignant lesions of, 652, 653t, 655–656, 656f Malignant lesions fibrosarcoma as, 653t, 656 leiomyosarcoma as, 653t, 654–655 liposarcoma as, 653–654, 653t, 654f, 655f malignant fibrous histiocytoma as, 653t, 655–656, 656f malignant hemangiopericytoma as, 653t, 657 retroperitoneal tumors with, 653–657, 653t, 654f, 655f, 656f rhabdomyosarcoma as, 653t, 656–657 Malignant lymphoma (ML) clinical presentation of, 633–634 evaluation of, 634–636 management of, 634–636
798 Index Malignant lymphoma (ML) (Continued) nongerm cell tumors of, 618t, 633–636, 635f pathologic characteristics of, 634, 635f Malignant mesothelioma (MM) clinical presentation of, 629–630, 630f evaluation of, 631 management of, 631 nongerm cell tumors of, 629–631, 630f, 631f pathologic characteristics of, 630–631, 631f Massachusetts General Hospital (MGH), 392, 393 MDCT. See Multidetector spiral computed tomography MDR. See Multidrug resistance MEA syndrome. See Multiendocrine adenopathy syndrome Medroxyprogesterone androgen deprivation therapy with, 495 Megestrol androgen deprivation therapy with, 495 Metabolic acidosis orthotopic bladder substitution with, 450, 453t Metaiodobenzylguanidine (MIBG) pheochromocytoma scanned for, 139, 155 Metaplasia urethral cancer pathology with, 673 Metastatic tumors nongerm cell tumors as, 618t, 631–632, 632f Methotrexate bladder preservation with, 391, 391t genitourinary cancer treatment with, 70 Methotrexate, vinblastine, adriamycin, cyclophosphamide (MVAC) TCC chemotherapy treatment with, 281 TCC prognosis with, 343 Methylation epigenetic effects with, 4 MFH. See Malignant fibrous histiocytoma MGH. See Massachusetts General Hospital MIBG. See Metaiodobenzylguanidine Microvessel density (MVD) RCC with, 175 TCC prognosis with, 341–342 Mitomycin C (MMC) bladder preservation with, 391t bladder TCC with, 323–324, 326t genitourinary cancer treatment with, 62f, 63 Mitotane adrenal carcinoma with, 136 Mitoxantrone genitourinary cancer treatment with, 62f, 64 ML. See Malignant lymphoma MM. See Malignant mesothelioma MMC. See Mitomycin C Mohs’ micrographic surgery for, 704, 723 complications in, 704 effectiveness of, 704 fixed tissue technique in, 704
Mohs’ micrographic surgery for, (Continued) fresh tissue technique in, 704 technique in, 704 Molecular biology aging/telomerase in, 16 aptamers in, 16–17 cancer genes in, 8–10 DNA methylation, 9 DNA repair, 8 oncogenes, 8 suppressor, 8 viral, 8–9 carcinogens in, 4–5 cell cycle in, 11–12, 12f cell signaling in, 12f, 14–15, 14f CGH in, 8 epigenetic effects in, 3–4, 4f familial cancer in, 7–8 inflammation in, 5–7, 6t microarrays in, 10–11 proteomics in, 10–11 SKY in, 8 stromal epithelial interactions in, 15–16, 15f tumor cell heterogeneity in, 16–17, 17f urologic cancers in, 3–17, 4f, 6t, 10f, 12f, 13f, 14f, 15f, 17f Monoclonal antibodies immunotherapy with, 97–98, 97f, 98t Montsouris technique laparoscopic radical prostatectomy with, 537 Morcellation ORN v. LRN with, 202–203 MR. See Magnetic resonance MR-guided brachytherapy (MRBT) IGT with, 114f, 115f, 117, 119–122, 120f, 121f outcome of, 120–122 patient selection for, 119 procedure for, 114f, 115f, 119–120, 120f, 121f TURP and, 119 MR imaging (MRI) bladder cancer diagnosis with, 302, 304, 306–307, 339 CT v., 182, 187 current applications overview of, 115–116, 115f FUS guided by, 116 history of, 113–114, 114f IGT with, 113–125, 114f, 115f, 117f, 118f, 120f, 121f, 123f, 124f incidentaloma with, 134, 135f laser therapy with, 116 NSGCT staging with, 600 PC staging with, 461 penis carcinoma with, 714–717 pheochromocytoma with, 139, 141f, 143f, 148f prostatectomy assessed with, 466 radiation therapy for adenocarcinoma with, 478, 483 radical nephrectomy with, 218 RCC diagnosing with, 182, 183f, 197 RCC staging with, 186f, 187–188
MR imaging (MRI) (Continued) renal tumor ablation with, 208, 209 retroperitoneal tumors diagnosis with, 658 RMS evaluation with, 772–774 Seminal vesicles diagnosis with, 557 squamous cell carcinoma of penis, 696 TCC diagnosis with, 271–272 temperature sensitivity of, 116 Wilms’ tumor evaluation with, 756 MR therapy (MRT) IGT with, 114, 115 MRBT. See MR-guided brachytherapy MRI. See MR imaging MRT. See MR therapy MSR-1. See Macrophage scavenger receptor Multidetector spiral computed tomography (MDCT) renal diagnosing with, 179 Multidrug resistance (MDR) TCC prognosis with, 343 Multiendocrine adenopathy syndrome (MEA syndrome) pheochromocytoma with, 139 MVAC. See Methotrexate, vinblastine, adriamycin, cyclophosphamide MVD. See Microvessel density Myeloablative condition HCT with, 95, 95t, 96f Myelolipoma benign lesions of, 652t, 653 NAD. See Nicotinamide-adenine dinucleotide National Bladder Cancer Collaborative Group, 303 National Wilms’ Tumor Study Group (NWTSG), 753, 756, 758, 762–764 Nausea orthotopic bladder substitution with, 453t Nephrectomy adrenalectomy with, 146, 146f cytoreductive, 247–248 laparoscopic partial complications of, 252–283 contraindications for, 249 financial analysis of, 283 indications for, 249 renal hypothermia with, 250, 254f renal parenchymal repair in, 253f results of, 250–252, 255t technique for, 249–250, 250t, 251f, 252f, 253f laparoscopic radical approach selection for, 237–238 complications of, 241, 243t, 244t concomitant adrenalectomy with, 245–246 contra-indications for, 237 financial implications of, 248 follow-up for, 246t indications for, 237 larger renal tumors with, 245, 247t oncologic outcome of, 244–245 ORN v., 201–203, 202t, 247t
Index 799 Nephrectomy (Continued) RCC with, 199–203, 202t, 237–248, 238f, 239f, 240f, 241f, 242t, 243t, 244t, 245f, 246t, 247t, 248t, 249f renal vein involvement with, 246–247, 248t, 249f results of, 241, 242t specimen extraction with, 241–244, 245f technique for, 200–201, 238–240, 238f, 239f, 240f, 241f three approaches to, 199 open radical, 198–199, 199f, 201–203, 202t hilar vessel division in, 199f technique for, 198–199, 199f ORN v. LRN, 201–203, 202t blood loss in, 202t convalescence time in, 202t morcellation in, 202–203 oncologic adequacy in, 201–202 operating room time in, 202t partial, 230–235, 233f, 234f AML with, 235 CT for, 230–231 segmental polar, 232, 233f simple enucleation, 235 in situ, 231 transverse resection, 234–235, 234f wedge resection, 232–234, 234f radical laparoscopic HAL, 199 ORN v., 201–203, 202t RCC with, 199–203, 202t retroperitoneal, 199, 200–201 technique for, 200–201 three approaches to, 199 transperitoneal, 199, 200 radical type, 218–230, 219f, 220f, 221f, 222f, 223f, 224f, 225f, 226f, 227f, 228f, 229f, 230t anterior subcostal transperitoneal incision in, 220, 220f, 221f bilateral subcostal incision in, 220 CT scan for, 218 diaphragmatic incision in, 220 evaluation for, 218–219 Gerota’s fascia in, 224f, 226, 239 indications for, 218–219 IVC with, 222–226, 227f, 228f left side, 220–222, 224f, 225f lymphadenectomy with, 222 MRI for, 218 renal vein in, 224f right side, 222, 225f ring retractor with, 224f suprahepatic vena cava with, 226–230, 228f, 229f surgical anatomy with, 219, 219f surgical incisions in, 219–220, 220f, 221f, 222f TEE for, 218 thoracoabdominal approach in, 220, 222f, 223f thrombectomy with, 227f RCC with, 206–207 advanced disease with, 206
Nephrectomy (Continued) partial version of, 206–207 surgical margin in, 207 technique in, 207 Nephroblastoma. See Wilms’ tumor Nephroureterectomy laparoscopic, 278–279, 280t laparoscopic v. open, 280t open, 277–278, 280t TCC with, 277–279, 280t Nerve preservation orthotopic bladder substitution with, 445–446, 445f, 446f Nesbit technique orthotopic bladder substitution with, 449f Neuroblastoma classification of, 741–742 diagnostic evaluation of, 743–744, 743t, 744f, 745f etiology of, 739–740 future considerations with, 751–752 Horner’s syndrome with, 742, 748 incidence of, 740 pathology of, 740–742, 740f, 741f, 742f presentation of, 742–743 prognostic considerations with, 744, 747t staging of, 744, 746t treatment for, 744–750 Neurofibromatosis pheochromocytoma with, 139, 140t Neuromyopathy RCC associated with, 174t Neuron-specific enolase (NSE) serum tumor markers of, 568 Wilms’ tumor pathology with, 761 Neurovascular bundles laparoscopic radical prostatectomy dissection of, 538 radical prostatectomy with separation of, 519, 521f NHP. See Nottingham health profile NHT with radiation therapy in androgen deprivation therapy for, 495–496 Nicotinamide-adenine dinucleotide (NAD), 11 Nilutamide androgen deprivation therapy with, 495 NMP-22. See Nuclear matrix protein Nongerm cell tumors acquired immunodeficiency syndrome with, 637 adenomatoid tumor of epididymis as, 618t, 633, 633f, 634f carcinoid tumors of, 618t, 632–633, 633f epidermoid cysts as, 618t, 627–628, 627f, 628f generalized stroma tumors of, 636–637 granulosa cell tumors as, 618t, 624–626, 625f, 626f clinical presentation of, 624–625 evaluation of, 626 management of, 626 pathologic characteristic of, 625–626, 625f, 626f hematologic tumors of, 618t, 633–636, 635f HIV and, 637
Nongerm cell tumors (Continued) leukemia as, 618t, 636, 636f Leydig cell tumors as, 618–622, 618f, 618t, 619f, 620f, 621f CAH v., 621, 621f clinical presentation of, 618–619 evaluation of, 621–622 Klinefelter’s syndrome with, 619 management of, 621–622 pathologic characteristics of, 619–621, 620f Reinke’s crystals in, 619, 621 malignant lymphoma as, 618t, 633–636, 635f clinical presentation of, 633–634 evaluation of, 634–636 management of, 634–636 pathologic characteristics of, 634, 635f malignant mesothelioma as, 629–631, 630f, 631f clinical presentation of, 629–630, 630f evaluation of, 631 management of, 631 pathologic characteristics of, 630–631, 631f metastatic tumors of, 618t, 631–632, 632f miscellaneous tumors of, 627–636, 627f, 628f, 629f, 630f, 631f, 632f, 633f, 634f, 635f, 636f mixed sex cord/gonadal stromal tumors as, 626–637, 627f, 628f, 629f, 630f, 631f, 632f, 633f, 634f, 635f, 636f ovarian surface epithelial type tumors of, 637 plasmacytoma as, 618t, 636, 636f Rete testis carcinoma as, 628–629, 629f clinical presentation of, 628 evaluation of, 628–629 management of, 628–629 pathologic characteristics of, 628, 629f Sertoli cell tumors as, 618t, 622–624, 622f, 623f, 624f, 625f clinical presentation of, 622 evaluation of, 624 management of, 624 pathologic characteristics of, 622–624, 622f, 623f, 624f, 625f sex cord/stromal origin with, 618–626, 618f, 618t, 619f, 620f, 621f, 622f, 623f, 624f, 625f, 626f testis tumors as, 617–637, 618f, 618t, 619f, 620f, 621f, 622f, 623f, 624f, 625f, 626f, 627f, 628f, 629f, 630f, 631f, 632f, 633f, 634f, 635f, 636f Nonseminomatous germ cell tumors (NSGCT) clinical staging of, 598–600, 601f, 602f, 603f, 604f, 604t, 605t CT scan for, 600, 602f, 603f, 604f, 610t, 613t designations in, 600, 604t, 605t imaging studies for, 600, 601f, 602f, 603f, 604f MRI for, 600 PET scan for, 600 serum markers for, 598
800 Index Nonseminomatous germ cell tumors (NSGCT) (Continued) diagnosis of, 597, 598f, 599f, 600f ultrasound for, 597, 598f, 599f, 600f pathology of, 598–600, 600t AJCC classifications of, 599, 604 radical v. partial orchiectomy for, 598 serum tumor markers of, 568 AFP, 568, 597, 599 HCG, 568, 597, 599 LDH, 568, 597, 599 NSE, 568 NSGCT, 568 PLAP, 568, 597 summary of, 615 treatment by stage for, 607f, 608–615, 609f, 610f, 612f, 613f, 614t stage I, 609–611, 612f, 613f stage IIA/IIB, 611–615, 612f, 614t stage IIC/III, 607, 609f, 610f, 612f, 613f, 615 treatment tools for, 601–608, 607f, 608f, 609f, 610f, 611t adjuvant chemotherapy as, 606 BEP as, 606 high-stage disease with chemotherapy as, 606–607 IGCCCG with, 606, 611t, 615 observation as, 601, 611t postchemotherapy RPLND as, 604–606, 607f primary RPLND as, 601–604, 607f, 608f, 609f, 610f, 611t primary shot course chemotherapy as, 606 PVB as, 606 salvage chemotherapy as, 607–608 second-line chemotherapy as, 607–608 Nonviral vectors applications of, 21t, 25 attributes in, 21t, 25 gene delivery in, 24–25, 24f, 25f gene expression in, 25 gene therapy with, 21t, 24–25, 24f, 25f, 26t vector production in, 24 Nottingham health profile (NHP) HRQOL measured with, 104 NSE. See Neuron-specific enolase NSGCT. See Nonseminomatous germ cell tumors Nuclear matrix protein (NMP-22) bladder cancer diagnosis with, 305 Obturator nerve reflex TUR complications with, 363 OER. See Oxygen enhancement ratio Oligospermia adrenal carcinoma with, 136 Oncocytoma familial renal, 176–177 RCC mimicked by, 181f RCC risk factor of, 196t Oncologic adaquacy ORN v. LRN with, 201–202
Oncolytic virotherapy gene therapy with, 30 Open nephroureterectomy TCC with, 277–278 Open radical nephrectomy (ORN) LRN v., 201–203, 202t blood loss in, 202t convalescence time in, 202t mean tumor size in, 247t morcellation in, 202–203 oncologic adequacy in, 201–202 operating room time in, 202t postoperative complications in, 247t RCC with, 198–199, 199f, 201–203, 202t, 247t Orchiectomy androgen deprivation therapy with, 494–495 ORN. See Open radical nephrectomy Orthotopic bladder substitution long-term follow-up for, 452–454, 454t blood tests in, 454t body weight in, 454t bone scan in, 454t chest x-ray in, 454t clinical examination in, 454t CT scan in, 454t folic acid in, 454t IVU in, 454t postvoid residual in, 454t renal ultrasound in, 454t urethral wash cytology in, 454t urine culture in, 454t males/females with, 443–454, 445f, 446f, 447f, 448f, 449f, 450f, 451f, 452f, 453f, 453t, 454t operative technique for, 444–448, 445f, 446f, 447f, 448f, 449f, 450f, 451f, 452f, 453f atraumatic urethra dissection as, 446 bipolar electrocautery in, 446 bladder construction as, 447–448, 450f, 451f, 453f cystectomy as, 445–446, 445f, 446f, 453f ileal segment resection as, 446, 447f, 448f mesenteric window close in, 448f nerve preservation in, 445–446, 445f, 446f Nesbit technique in, 449f orthotopic ileal bladder substitute as, 446, 447f, 448f U-shaped distal ileum in, 450f ureteroileal anastomosis as, 446–447, 449f, 450f ureters in, 446 urethral anastomosis as, 447–448, 450f, 451f, 453f patient assessment for, 443–444 postoperative management for, 448–452, 453t anorexia in, 453t cystogram for, 449 dyspepsia in, 453t fatigue in, 453t
Orthotopic bladder substitution (Continued) heartburn in, 453t Laplace’s law in, 450 late period, 449–450 metabolic acidosis in, 450, 453t metabolic acidosis symptoms in, 453t metabolic management in, 450–452, 453t nausea in, 453t sitting in, 449 ultrasound in, 449 vomiting in, 453t weight loss in, 453t preoperative patient selection for, 443–444 anastomotic margin biopsy in, 444 bowel function in, 444 compliance in, 443 continence in, 444 general preparation for, 444 hepatic function in, 444 mental capacity in, 443 renal function in, 443–444 urethral recurrence in, 444 Oxaliplatin genitourinary cancer treatment with, 60f, 61 Oxygen enhancement ratio (OER), 43 P53 gene TCC prognosis with, 342 Paclitaxel bladder preservation with, 391, 391t genitourinary cancer treatment with, 65–67, 67f Papillary transitional cell carcinoma urethral cancer pathology with, 674 Papillary urothelial neoplasms of low malignant potential (PUNLMP) TCC staging with, 274 Parastomal hernias cutaneous urinary diversion with, 431 Paratesticular tumors retroperitoneal tumors with, 667 Partial cystectomy, 368–369 Particle beam therapy prostate adenocarcinoma treated with, 489 PC. See Prostate cancer PCNA. See Proliferating cell nuclear antigen PCSM. See Prostate cancer-specific mortality PDGF. See Platelet-derived growth factor Pediatric testicular tumors, 780–785 Penectomy partial penis, 703, 723–725, 724f complications in, 703 impact of, 704 results in, 703 surgical technique in, 703 total penis, 703–704, 725–726, 725f complications in, 704 impact of, 704 surgical technique in, 703 Penile urethra cancer, 675, 677t
Index 801 Penis brachytherapy for, 705–706 external beam radiation for, 706, 707t inguinal node management with, 706–707, 707f invasive carcinoma of, 710–718, 715t, 716t Buschke-Löwenstein tumor in, 712, 723 laser therapy for, 704–705, 705t complications in, 705 lymphadenectomy for, 728f, 729f, 730–732, 732f Mohs’ micrographic surgery for, 704, 723 partial penectomy for, 703 radiation therapy for, 705 SCC of, 695–697, 697t, 699–701, 701t, 702, 702t summary of carcinoma of, 707 superficial carcinoma of, 699–707, 700f, 701t, 702t, 705t, 706t, 707f, 707t superficial SCC of, 702–703 surgical procedures for, 723–732, 724f, 725f, 726f, 727f, 728f, 729f, 732f total penectomy for, 703–704 complications in, 704 impact of, 704 surgical technique in, 703 Penn pouch complications with, 435t continent reservoirs compared to, 424t reoperation rate with, 435t urinary diversion with, 424t, 426, 426f, 435t PEP. See Polyestradiol phosphate Percutaneous needle aspiration cytology RCC diagnosis with, 189, 189t Perilobar nephrogenic rest (PLNR) Wilms’ tumor pathology with, 758–759, 758f Permanent prostate brachytherapy (PPB) prostate adenocarcinoma treated with, 483–484, 484f, 486–488, 487t PET. See Positron emission tomography Peutz-Jeghers syndrome LCCSCT with, 623 Pharmacology of anticancer agents absorption in, 54 distribution in, 54–55 drug resistance mechanisms with, 56–58, 57t models for overcoming, 56–58, 57t excretion in, 55–56 factors modifying, 56 genitourinary cancer and, 54–56 macro-pharmacokinetic mechanisms with, 57t metabolism in, 55 micro-pharmacokinetic mechanisms with, 57t pharmacodynamic intracellular mechanisms with, 57t transport in, 54–55 Pheochromocytoma adrenal tumors with, 138–139, 138f, 140t, 141f, 142t, 143f, 148f adrenalectomy for, 142t APUD with, 139
Pheochromocytoma cardiomyopathy with, 139 CT scan for, 139 glomus jugulare tumors with, 139, 148f identifying, 138, 138f, 154t MEA syndromes with, 139 MIBG scan for, 139, 155 MRI scan for, 139, 141f, 143f, 148f neurofibromatosis with, 139, 140t Sturge-Weber syndrome with, 139 symptoms of, 140t von Hippel-Landau with, 139, 140t PIN. See Prostatic interepithelial neoplasia Placental alkaline phosphatase (PLAP) serum tumor markers of, 568, 597 Planning target volume (PTV) radiation oncology with, 41, 42f radiation therapy for adenocarcinoma with, 478–479, 479f PLAP. See Placental alkaline phosphatase Plasma renin activity (PRA) hyperaldosteronism with, 137, 137f Plasmacytoma nongerm cell tumors of, 618t, 636, 636f Platelet-derived growth factor (PDGF), 9 Platinum complexes carboplatin, 60–61, 60f cisplatin, 59–60, 60f genitourinary cancer treatment with, 59–61, 60f oxaliplatin, 60f, 61 PLDR. See Potentially lethal damage repair PLNR. See Perilobar nephrogenic rest Polyestradiol phosphate (PEP) androgen deprivation therapy with, 506 Positron emission tomography (PET) bladder cancer diagnosis with, 305, 307, 339 FDG with, 183, 188–189, 339 NSGCT staging with, 600 RCC diagnosing with, 178, 182–183, 188–189, 197 testis tumors staging with, 570 Potentially lethal damage repair (PLDR), 44 Pouchitis cutaneous urinary diversion with, 434 Poxvirus vectors applications of, 21t, 23–24 attributes in, 21t, 23–24 gene delivery in, 23 gene expression in, 23 gene therapy with, 21t, 22–24, 23f, 26t vector production in, 19f, 22–23 PPB. See Permanent prostate brachytherapy PRA. See Plasma renin activity Prepubertal testicular tumours, 780–785 Pretreatment nomograms PC staging with, 263f, 461–262 Progesterone supplementation androgen deprivation therapy with, 495 Proliferating cell nuclear antigen (PCNA) RCC with, 175 Prostate cancer (PC). See also Adenocarcinoma of prostate bulbourethral v., 3, 4f burnt meat and, 5
Prostate cancer (PC) cell proliferation/apoptosis balance in, 53 detection of, 460f, 461f, 462f, 463f, 549–463 GSTPi in, 5–6, 6t HPC and, 7 HRQOL with, 105–108, 108t brachytherapy influencing, 107 EBRT influencing, 107, 108, 108t IB influencing, 107–108, 108t IPSS measuring, 107 RP v. WW in, 107 inflammation with, 5–7, 6t localized, 547–552 operative complication with, 548–449 patient selection with, 548 postoperative complication with, 449–552 surgical approaches to, 547–548 MR-guided biopsy for, 123–124, 123f, 124f procedure in, 123–124 MRBT for, 120f MSR-1 in, 5, 6t natural history of, 465–466, 466t PIN in, 5 RNASEL in, 5, 6t ROS in, 5–6 staging of, 460f, 461f, 462f, 463f, 549–463 AJCC system for, 462, 549–461 combined modality, 460f, 461f, 549–461 CT scan in, 461 DRE with, 549 ECE in, 461 MRI in, 461 PCSM with, 460f, 461f, 462, 463, 549 pretreatment nomograms in, 263f, 461–262 prognostic factors in, 460f, 461f, 462f, 463f, 549–463 PSA in, 460f, 461f, 462f, 463f, 549–463 radiologic, 461, 462f RT with, 460f, 461f, 462f, 463, 463f, 549 summary for, 262 SVI in, 461 TRUS in, 461 TURP with, 549 surgery focused ultrasound for, 122 outcome of, 122 procedure for, 122 surgical treatment complications with, 547–552 bladder neck contracture, 549 early postoperative, 549 erectile dysfunction, 451–452 late postoperative, 549–452 operative, 547–549 postoperative, 549–452 quality of life as, 452 urinary incontinence, 450–451 US-guided biopsy for, 122–123 DRE with, 122 procedure for, 122–123
802 Index Prostate cancer-specific mortality (PCSM) PC staging with, 460f, 461f, 462, 463, 549 Prostate-specific antigen (PSA) external beam radiation therapy with, 460f, 461f PC staging with, 460f, 461f, 462f, 463f, 549–463 pretreatment nomogram for, 463f radiation therapy for adenocarcinoma with, 477–478, 479, 480, 481t, 482f, 485, 485f, 486–488 radical prostatectomy with, 462f RPP patient selection with, 528 seminal vesicles diagnosis of, 555–558, 556t, 557t, 561, 562, 564f Prostate-specific membrane antigen (PSMA) immunotherapy with, 98 Prostatic interepithelial neoplasia (PIN) prostate cancer with, 5 Prostatic pedicles laparoscopic radical prostatectomy dissection of, 538 radical prostatectomy with transection/ control of, 519–522, 522f Prostatic urethra CIS only, 328f cystoprostatectomy for, 328f ductal, 328f intravesical therapy for, 328f stromal invasion, 328f TCC in, 327–328, 328f Prostatic urethral cancer, 675–676, 677t PSA. See Prostate-specific antigen PSMA. See Prostate-specific membrane antigen Psoralen and ultraviolet A (PUVA) penis carcinoma photochemotherapy with, 709, 711 PTV. See Planning target volume Puboprostatic ligaments radical prostatectomy incision of, 515–516, 517f PUNLMP. See Papillary urothelial neoplasms of low malignant potential PUVA. See Psoralen and ultraviolet A PVB. See Cisplatin, Velban and bleomycin PVB as NSGCT treatment with, 606 QLQ-C30. See Core Quality of Life Questionnaire Quality of well-being scale (QWB) HRQOL measured with, 104 QWB. See Quality of well-being scale Radiation oncology applications of, 39–48, 40f, 41f, 42f, 43f, 47t brachytherapy in, 40–41, 42f clinical practice of, 46–47, 47t acute/chronic radiation sequelae in, 47 adjuvant RT in, 46 definitive RT in, 46 palliative RT in, 46 RT in, 46–47
Radiation oncology CTV in, 41 DVH in, 42, 42f EBRT in, 39–40, 40f GTV in, 41 HDR techniques for, 41 IMRT in, 42–43, 42f, 43f ionizing radiation in, 41–46 apoptosis in, 45–46 cellular repair response in, 44 cellular target interacts with, 43–44 cycle and, 45 DNA damage accumulation with, 44, 45 DNA repair following, 45 induced cell death with, 45–46 necrosis in, 45–46 normal tissue protection in, 44–45 OER in, 43 PLDR in, 44 radiation oncology with, 43–46 radiation sensitizers for, 44 radioprotector agents in, 44–45 ROS with, 43–44 SLDR in, 44 therapeutic ratio in, 44, 45 tumor cell interactions with, 43 physics of, 39–41, 40f, 41f principles of, 39–48, 40f, 41f, 42f, 43f, 47t PTV in, 41, 42f summary of, 47–48 treatment planning/delivery for, 41–43, 42f, 43f Radiation sensitizers, 44 Radiation Therapy Oncology Group (RTOG) androgen deprivation therapy and, 495–498, 499, 500, 501t, 502 bladder preservation and, 391, 391t radiation therapy for adenocarcinoma with, 477, 478, 482, 483, 485 Radiation therapy (RT). See also Brachytherapy males urethral cancer with, 680 PC staging with, 460f, 461f, 462f, 463, 463f, 549 penis carcinoma with, 705, 718 prostate adenocarcinoma treated with, 477–489, 478f, 479t, 480t, 481t, 482f, 484f, 484t, 485t, 487t, 489t ACD with, 479, 483, 485, 487–488 adjuvant hormonal with, 496–498, 497f ADT and, 479, 480, 482–483, 486, 487, 488 androgen deprivation therapy with, 495–498, 497f ASTRO with, 479, 481 biochemical relapse-free survival with, 477, 478, 479–481, 480t, 481t, 482, 482f, 485–489, 485t, 487f, 489f CT scan with, 478, 483, 484, 484f CTV with, 478–479, 479f 3DCRT with, 478–479, 478f, 482, 489 dose escalation with, 481–482, 481t EBRT historic perspective, 478 EBRT technique for, 478–479, 479f
Radiation therapy (RT) (Continued) GTV with, 478–479, 479f HIFU with, 477 IMRT with, 478, 482 MR with, 478, 483 NHT with, 495–496 PSA levels in, 486–488, 487t PSA with, 477–478, 479, 480, 481t, 482f, 485, 485f, 486–488 PTV with, 478–479, 479f risk stratification with, 478 RTC with, 477 RTOG with, 477, 478, 482, 483, 485 T1-2 PC in, 477, 482–483 timing/duration of hormonal therapy with, 498 retroperitoneal tumors with, 664 RMS treated with, 773–774 seminal vesicles treatment options with, 557–558, 557t stage I seminoma with, 587–588 Radical cystectomy abdominal exploration in, 370 adjuvant v. neoadjuvant, 346–347 bladder treated with, 368, 369–387, 370f, 371f, 372f, 373f, 375f, 376f, 377f, 378f, 379f, 380f, 381f, 382f, 383f, 384f, 385f, 386f bowel mobilization in, 370–372, 372f, 373f chemotherapy with, 346–347 complications of, 346 Denonvilliers’ fascia in, 279f, 377, 378f, 380, 380f discussion of, 385–387 dorsal venous complex in, 380, 381f, 382f female patient anterior dissection in, 382–384, 383f, 384f, 385f, 386f female pelvic sagittal section in, 386f females with, 345 gauze sponge withdrawing in, 376f ICU for, 384 iliac artery skeletonizing in, 375f incision in, 370, 371f lateral vascular pedicle ligation in, 374–375, 377f lymphadenectomy with, 345–346 male patient anterior dissection in, 378–382, 381f, 382f males with, 344–345 outcomes of, 346 overhead pelvic view in, 372f, 373f overview of, 343–344 patient positioning in, 370, 370f pelvic lymphadenectomy with, 373–374, 375f, 376f peritoneum incision in, 378f posterior pedicle ligation in, 375–378, 378f, 379f, 380f postoperative care for, 384–385 preoperative evaluation for, 344, 369–370 counseling in, 369–370 patients over 50 in, 369 preparation for, 344 TCC with, 343–347 urachal remnant excision in, 371f
Index 803 Radical cystectomy (Continued) ureteral dissection in, 372 vaginal incision in, 383f vaginal wall dissection in, 384f, 385f vascular pedicle isolation in, 377f Radical orchiectomy CT scan with, 642, 647, 647f general considerations for, 641–642 RPLND for low-stage disease with, 642–647, 643f, 644f, 645f, 646f left-sided nerve-sparing in, 645–646, 646f postoperative management in, 646 right nerve-sparing in, 643–645, 645f, 646f technique for, 643–647, 643f, 644f, 645f, 646f RPLND for postchemotherapy disease with, 647–649, 647f, 648f, 649f indications for, 647–648, 647f special considerations for, 649, 649f technique of, 648–649, 648f RPLND with, 641–649, 643f, 644f, 645f, 646f, 647f, 648f, 649f summary of, 649 Radical perineal prostatectomy (RPP), 528–534, 531f, 532f, 534f, 534t complications of, 530–531 disease control with, 531–532, 531f, 532f fecal incontinence following, 533 modification of, 530 nerve-sparing, 530 wide-field dissection, 530 patient selection for, 528–529 BPLND with, 528 DRE in, 529 PSA levels in, 528 potency following, 533 quality of life following, 533–534 summary of, 534 surgical technique for, 529–530 urinary continence following, 532 Radical prostatectomy. See also Radical perineal prostatectomy adenocarcinoma of prostate with, 465–474, 466t, 468t, 469t, 471t, 472t, 473t anatomic nerve-sparing retropubic, 514–527, 516f, 517f, 518f, 519f, 520f, 521f, 522f, 523f, 524f, 525f bladder neck transection/reconstruction for, 522, 523f cancer control outcome of, 525 complications of, 526 Denonvilliers’ fascia incision for, 521f dorsal venous ligation/transection for, 516–519, 518f, 519f, 520f, 521f endopelvic fascia incision for, 515–516, 517f, 518f limited pelvic lymphadenectomy for, 515 neurovascular bundies separation for, 519, 521f patient selection for, 514–515 potency outcome of, 526
Radical prostatectomy (Continued) prostatic pedicles transection/control for, 519–522, 522f puboprostatic ligaments incision for, 515–516, 517f summary of, 526 surgical technique for, 515–523, 516f, 517f, 518f, 519f, 520f, 521f, 522f, 523f, 524f, 525f urinary continence outcome of, 525–526 vesico-urethral anastomosis for, 522–523, 524f, 525f androgen deprivation therapy with, 498–499 biopsy Gleason sum with, 471, 472f blood loss during, 469, 469f cancer control with, 469f, 470–473, 471f, 472f CT scan assessment with, 466 early complications with, 468–470, 468f, 469f erectile function after, 474 hospitalization days with, 469f intraoperative complications with, 468–470, 468f, 469f laparoscopic, 536–544, 540t, 542t, 543t anastomotic leaks from, 541 anastomotic stenosis from, 542 anatomic contraindications for, 537 anesthetic contraindications for, 536–537 anterior phase in, 537 blood loss from, 539, 540t contraindications for, 536–537 difficult cases for, 537 digestive injuries from, 541 extraperitoneal approach for, 538–539 history of, 536 impotence from, 541–542, 543t indications for, 536 insufflation/trocar positioning complications for, 539 intraoperative complications for, 539 main operation steps for, 537–538 material for, 537 medical preparation for, 537 Montsouris technique in, 537 neurovascular bundles dissection in, 538 number of trocars for, 538 oncological results from, 542–544 patient installation in, 537 patient positioning complications for, 539 perioperative complications for, 539–542, 540t posterior phase in, 537 postoperative complications for, 541 postoperative management for, 538 prostatic pedicles dissection in, 538 specimen extraction complications for, 541 specimen extraction in, 538 surgical technique for, 537–538 thromboembolic complications for, 541
Radical prostatectomy (Continued) transperitoneal approach to, 537 transperitoneal approach variants for, 538 ureteric injuries from, 540t, 541 urethra section in, 538 urinary incontinence from, 541 vesicoprostatic dissection in, 538 vesicourethral anastomosis in, 538 late complications with, 470 lymph node metastases with, 472t mortality with, 468f MRI assessment with, 466 obturator nerve injury from, 470 outcomes after, 469f, 470–474, 471f, 472f, 473f patient selection for, 466 PC natural history and, 465–466, 466t pelvic lymph node dissection with, 467–468 pretreatment risk stratification with, 466–467 PSA risk assessment with, 466–467, 470, 471f PSA survival with, 469f rectal injury from, 469 remote-controlled assisted, 544 results of, 468 risk factors with, 472f, 473f seminal vesicle involvement with, 472f treatment rationale, 465 urinary function with, 473, 473f urinary incontinence after, 473, 473f Radical prostatectomy (RP) HRQOL with, 107 PSA with, 459, 462f Radiofrequency ablation RCC with, 208–209, 208t RAND Medical Outcomes Study (SF-36) cutaneous urinary diversion influence in, 437–438, 438t HRQOL measured with, 104 Randomized clinical trial (RTC) radiation therapy for adenocarcinoma with, 477 RASS. See Renin-angiotensin-aldosterone system RCC. See Renal cell carcinoma Reabsorption syndrome TUR complications with, 363–364 Reactive oxygen species (ROS) inflammation with, 5–6 IR with, 43–44 Rectal bladder urinary diversion cutaneous urinary diversion with, 406–407, 407f, 408f taenia incision in, 407f technique in, 407, 407f, 408f ureterointestinal anastomosis in, 407f ureterosigmoidostomy in, 406–407 Reinke’s crystals LCT with, 619, 621 Renal cell carcinoma (RCC) active immunotherapy for, 264 heat shock protein with, 264 VHL gene with, 264
804 Index Renal cell carcinoma (RCC) (Continued) adrenalectomy with, 204–205 advanced, 258–265, 259f, 260f, 262f, 263f amyloidosis associated with, 174t anemia associated with, 174t antiangiogenic for, 264–265 biopsy for, 197–198 bone marrow transplantation for, 265 cachexia associated with, 174t chemotherapy for, 265 classification of, 177–178, 177t, 196, 196t Bellini’s duct, 177, 177t Benign neoplasms, 196t chromophobe cell, 177, 177t, 196, 196t collecting duct, 177, 177t, 196t conventional type, 196t metanephric adenoma, 196t oncocytoma, 196t papillary, 177, 177t, 196t renal medullary, 177–178, 177t unclassified type, 178, 196t clinical presentation with, 174–175, 174t, 195–196 cytokine therapy for, 88, 89–92, 90t diagnosing of, 173–183, 174t, 177t, 178f, 179f, 180f, 181f, 182f, 182t, 183f, 197 AML in, 179, 180, 180f Bosniak classification in, 182, 182t Bosniak lesions in, 181 CT for, 179–182, 180f, 181f, 182f, 197 FDG for, 183, 188–189 imaging evaluation for, 178 IVP for, 178, 178f, 197 MDCT for, 179 MRI for, 182, 183f, 197 nuclear medicine and, 182–183 oncocytoma mimicked in, 181f percutaneous biopsy in, 189, 189t percutaneous needle aspiration cytology in, 189, 189t PET for, 178, 182–183, 188–189, 197 ultrasonography for, 178–179, 179f, 197 disease progression in, 189 enteropathy associated with, 174t epidemiology of, 195–196, 258–262, 259f, 260f grade with, 259–260 histology with, 259–260 IVC involvement with, 261 patient evaluation with, 261 patient performance status with, 260 prognosis in, 259 tumor stage in, 259, 259f UISS with, 260–261, 260f erythrocytosis associated with, 174t etiology of, 173–174 fever associated with, 174t FNA for, 197–198 grade of, 259–260 HCT for, 95–97, 96f hepatic-dysfunction associated with, 174t histology of, 259–260 histopathology of, 196, 196t hypercalcemia associated with, 174t
Renal cell carcinoma (RCC) (Continued) hypertension associated with, 174t immunotherapy for, 88, 89–92, 90t, 95–97, 96f incidence rates of, 173 inheritance of, 176–177 BHD in, 176, 197t familial renal oncocytoma in, 176–177 GLUT-1 in, 176 HLRC in, 177 HPRC in, 176, 197t TGF in, 176 tuberous sclerosis in, 197t VHL in, 176, 197t laparoscopic partial nephrectomy for, 230–235, 233f, 234f AML with, 235 complications of, 252–283 contraindications for, 249 CT for, 230–231 financial analysis of, 283 indications for, 249 renal hypothermia with, 250, 254f renal parenchymal repair in, 253f results of, 250–252, 255t segmental polar, 232, 233f simple enucleation, 235 in situ, 231 technique for, 249–250, 250t, 251f, 252f, 253f transverse resection, 234–235, 234f wedge resection, 232–234, 234f laparoscopic radical nephrectomy for, 199–203, 202t approach selection for, 237–238 complications of, 241, 243t, 244t concomitant adrenalectomy with, 245–246 contra-indications for, 237 cytoreductive, 247–248 financial implications of, 248 follow-up for, 246t HAL, 199, 201 indications for, 237 larger renal tumors with, 245, 247t oncologic outcome of, 244–245 ORN v., 201–203, 202t, 247t RCC with, 199–203, 202t, 237–248, 238f, 239f, 240f, 241f, 242t, 243t, 244t, 245f, 246t, 247t, 248t, 249f renal vein involvement with, 246–247, 248t, 249f results of, 241, 242t retroperitoneal, 199, 200–201 specimen extraction with, 241–244, 245f technique for, 200–201, 238–240, 238f, 239f, 240f, 241f three approaches to, 199 transperitoneal, 199, 200 localized, 195–212, 196t, 197t, 199f, 202t, 203t, 204f, 205f, 208f, 210t lymphadenectomy with, 205–206, 205f metastatic, 262–263, 263f IFN for, 262 nephrectomy in, 262–263, 263f SWOG study of, 262–263
Renal cell carcinoma (RCC) (Continued) molecular genetics with, 176–177 molecular markers with, 175–176 AgNOR, 175 CAIX protein, 176 HIF, 176 MVD, 175 PCNA, 175 VHL protein, 176 monitoring for recurrence with, 189 nephrectomy with, 206–207 advanced disease with, 206 partial type, 206–207 surgical margin in, 207 technique in, 207 neuromyopathy associated with, 174t novel therapies for, 264–265 open radical nephrectomy for, 198–199, 199f, 201–203, 202t LRN v., 201–203, 202t technique for, 198–199, 199f paraneoplastic syndromes associated with, 174–175, 174t passive immunotherapy for, 264 TIL with, 264 pathology of, 177–178, 177t patient performance status with, 260 prognostic factors for, 210–211, 210t TNM classification with, 210–211, 210t radical nephrectomy for, 218–230, 219f, 220f, 221f, 222f, 223f, 224f, 225f, 226f, 227f, 228f, 229f, 230t anterior subcostal transperitoneal incision in, 220, 220f, 221f bilateral subcostal incision in, 220 CT scan for, 218 diaphragmatic incision in, 220 evaluation for, 218–219 Gerota’s fascia in, 224f, 226, 239 indications for, 218–219 IVC with, 222–226, 227f, 228f left side, 220–222, 224f, 225f lymphadenectomy with, 222 MRI for, 218 renal vein in, 224f right side, 222, 225f ring retractor with, 224f suprahepatic vena cava with, 226–230, 228f, 229f surgical anatomy with, 219, 219f surgical incisions in, 219–220, 220f, 221f, 222f TEE for, 218 thoracoabdominal approach in, 220, 222f, 223f thrombectomy with, 227f renal tumor ablation with, 207–210, 208t cryoablation in, 207–208, 208t CT with, 208, 209 HIFU, 209–210 MRI with, 208, 209 radiofrequency, 208–209, 208t retroperitoneal tumors, 665–666, 665t risk factors with, 173–174, 196–197, 197t screening for, 211
Index 805 Renal cell carcinoma (RCC) (Continued) SEER reporting of, 173 serum markers with, 175 staging of, 183–189, 183f, 184–185t, 186f, 186t, 187f, 188f, 189t, 259 CT in, 186–188, 186f ECOG PS in, 186–187, 186t, 260–261 MRI in, 186f, 187–188 Robson classification in, 183, 183f TNM system in, 183–185, 184–185t, 186, 186t, 259, 259f, 260 UISS in, 186–187, 186t, 259–260, 260f Stauffer’s syndrome associated with, 174t summary of, 212 surgery for, 218–235, 219f, 220f, 221f, 222f, 223f, 224f, 225f, 226f, 227f, 228f, 229f, 230t, 233f, 234f indications for, 198 systemic therapy for, 263–264 IFN in, 263 IL-2 in, 263–264 treatment of, 258–265, 259f, 260f, 262f, 263f tumor biopsy for, 197–198 tumor thrombus with, 203–204, 203t, 204f, 227f, 228f, 229, 229f Renal hypothermia nephrectomy Endocatch II bag in, 250, 254f Renin-angiotensin-aldosterone system (RASS) hyperaldosteronism with, 137 Rete testis carcinoma (RTC) clinical presentation of, 628 evaluation of, 628–629 management of, 628–629 nongerm cell tumors of, 628–629, 629f pathologic characteristics of, 628, 629f Retinoblastoma gene TCC with, 342 Retroperitoneal lymph node dissection (RPLND) CT scan with, 642, 647, 647f low-stage disease treated with, 642–647, 643f, 644f, 645f, 646f left-sided nerve-sparing in, 645–646, 646f postoperative management in, 646 right nerve-sparing in, 643–645, 645f, 646f technique for, 643–647, 643f, 644f, 645f, 646f NSGCT treatment with, 600–605, 606f, 607f, 608f, 609f, 610t postchemotherapy, 603–605, 606f primary, 600–603, 606f, 607f, 608f, 609f, 610t postchemotherapy disease treated with, 647–649, 647f, 648f, 649f indications for, 647–648, 647f special considerations for, 649, 649f technique of, 648–649, 648f radical orchiectomy with, 641–649, 643f, 644f, 645f, 646f, 647f, 648f, 649f general considerations for, 641–642 summary of, 649 testis tumors staging with, 570, 571
Retroperitoneal technique laparoscopic surgery with, 164, 164f Retroperitoneal tumors adult urinary tract sarcoma and, 665, 665t Agent Orange and, 652 benign lesions with, 652–653, 652t ganglioneuroma as, 652t hemangiopericytoma as, 652t leiomyoma as, 652t, 653 lipomas as, 652–653, 652t myelolipoma as, 652t, 653 Schwannoma as, 652t chemotherapy for, 664–665 metastatic disease and, 664–665 diagnosis of, 657–658, 657f CT scan in, 657–658, 657f MRI in, 658 dioxin and, 652 incidence/etiology of, 651–652 malignant lesions with, 653–657, 653t, 654f, 655f, 656f fibrosarcoma as, 653t, 656 leiomyosarcoma as, 653t, 654–655 liposarcoma as, 653–654, 653t, 654f, 655f malignant fibrous histiocytoma as, 653t, 655–656, 656f malignant hemangiopericytoma as, 653t, 657 rhabdomyosarcoma as, 653t, 656–657 paratesticular tumors with, 667 pathology of, 652–657, 652t, 653t, 654f, 655f, 656f prostate with, 666–667 radiation therapy for, 664 IMRT, 664 IORT, 664 renal sarcoma and, 665–666 staging of, 658, 659t–661t summary of, 667–668 surgery for, 658–663, 661t, 662f, 662t operative technique in, 658–663, 661t, 662f, 662t organs sacrificed during, 662t partial v. complete resection in, 658, 661t transabdominal approach in, 662f surgical outcome for, 663–664, 663f, 664 urinary bladder with, 666 wood preservatives and, 652 Retrovirus vectors applications of, 20–21 attributes in, 20–21 gene delivery in, 19 gene expression in, 19–20, 19f gene therapy with, 19–21, 19f, 20f, 21t, 26 vector production in, 19 Rhabdomyosarcoma (RMS) bladder/prostate treatment for, 774–775 bladder primaries surgery in, 774–775 chemotherapy in, 774 outcome of, 775 prostate primaries surgery in, 775 radiation therapy in, 774
Rhabdomyosarcoma (RMS) (Continued) complications with, 776 evaluation of, 772–773, 772f CT scan for, 772–773 MRI for, 772–773 general approach to, 773–774 chemotherapy for, 773–774 radiation therapy for, 773–774 relapse with, 774 surgery for, 774 XRT for, 773–774 histologic subtypes of, 772f malignant lesions of, 653t, 656–657 molecular biology of, 771–772, 772f paratestis treatment for, 775–776 chemotherapy in, 775 outcome for, 775–776 radiation therapy in, 775 surgery in, 775 pathology of, 771–772, 772f pediatric scrotal mass and, presentation of, 772–773, 772f staging of, 773, 773t summary of, 776 vagina/uterus treatment for, 775 chemotherapy in, 775 outcome for, 775 radiation therapy in, 775 Ring retractor radical nephrectomy with, 224f RMS. See Rhabdomyosarcoma RNASEL prostate cancer with, 5, 6t Robson classification in RCC staging with, 183, 183f ROS. See Reactive oxygen species RP. See Radical prostatectomy RPLND. See Retroperitoneal lymph node disection; Retroperitoneal lymph node dissection RPP. See Radical perineal prostatectomy RT, Radiation therapy RTC. See Randomized clinical trial; Rete testis carcinoma RTOG. See Radiation Therapy Oncology Group SAMS. See Substratum adhesion molecules SCA. See Sertoli cell adenoma SCC. See Squamous cell carcinoma Schwannoma benign lesions of, 652t Sclerosing Sertoli cell tumors (SSCT) nongerm cell tumors as, 622, 623 pathologic characteristic of, 623 SCT. See Sertoli cell tumors Second malignant neoplasms (SMN) Wilms’ tumor with, 767 SEER. See U.S. Surveillance, Epidemiology, and End Results Seminal vesical biopsy (SVB) Seminal vesicles diagnosis of, 555, 556t Seminal vesicle invasion (SVI) brachytherapy and, 119 PC staging with, 461
806 Index Seminal vesicles diagnosis of, 555–557, 556f, 556t Gleason score in, 556, 556t, 564f MRI in, 557 PSA in, 555–558, 556t, 557t, 561, 562, 564f SVB in, 555, 556t transrectal ultrasound in, 555, 556f treatment options for, 557–565, 557t, 559f, 560f, 561f, 562f, 563f, 564f adjuvant radiation therapy, 557–558, 557t androgen deprivation in, 562 CT scan with, 558, 563f EBRT in, 558, 560f hormone therapy in, 562 laparoscopy in, 558 LHRH in, 560f multimodal, 558–565, 560f, 561f, 562f, 563f, 564f Seminoma clinical stage I management of, 585–588, 586t adjuvant radiation therapy in, 587–588 primary chemotherapy in, 588 prognostic factors in, 586–587, 586t surveillance’s role in, 585–587, 586t clinical stage II management of, 588–589 clinical stage III management of, 589–590 cryptorchid testes with, 593 early detection of, 584–585 EGCT with, 593 epidemiology of, 579–580 etiology of, 579 HIV patients with, 592 immunosuppression patients with, 592 noncompliant patients with, 593 other issues with, 591–592 pathology of, 581, 582t–584t prevention of, 584–585 primary surgery for, 580–581 residual masses management for, 591 spread pattern of, 581–584 staging for, 580–581, 582t–584t summary of, 593 symptoms of, 580 TIN with, 581 treatment effects with, 590–591 chronic, 590–591 fertility in, 591 late gonadal toxicity in, 590 psychologic toxicity in, 590–591 second malignancy in, 590 unusual cases management for, 591–592 bilateral tumors in, 592 high HCG patients in, 591–592 horseshoe/ectopic kidney in, 592 IBD in, 592 Sertoli cell adenoma (SCA) nongerm cell tumors as, 622, 624, 624f, 625f pathologic characteristic of, 624, 624f, 625f Sertoli cell tumors (SCT) clinical presentation of, 622 evaluation of, 624
Sertoli cell tumors (SCT) management of, 624 nongerm cell tumors as, 618t, 622–624, 622f, 623f, 624f, 625f pathologic characteristics of, 622–624, 622f, 623f, 624f, 625f Serum tumor markers AFP, 568, 597 HCG, 568, 597 LDH, 568, 597 NSE, 568 NSGCT, 568 PLAP, 568, 597 testis tumors with, 568 SF-36. See RAND Medical Outcomes Study Sickness impact profile (SIP) HRQOL measured with, 104 Sigmoid colon conduit noncontinent cutaneous urinary diversion with, 406 Silver staining nucleolar organizer regions (AgNOR) RCC with, 175 Simpson-Golabi-Behmel syndrome Wilms’ tumor with, 755 SIOP. See Société International d’Oncologie Pédiatrique SIP. See Sickness impact profile SKY. See Spectral karyotyping SLDR. See Sublethal damage repair SMN. See Second malignant neoplasms Société International d’Oncologie Pédiatrique (SIOP) Wilms’ tumor with, 753, 762, 764–766, 765f cooperative group trials for, 764–766, 765f Southwest Oncology Group (SWOG) bladder TTC study by, 325 metastatic RCC study by, 262–263 Spectral karyotyping (SKY) cancer with, 8 SPL. See Surgical Planning Laboratory Squamous cell carcinoma (SCC) chemotherapy treatment in, 718 inguinal lymph node treatment for, 716–718, 716t penis with brachytherapy for, 705–706 circumcision for, 702–703, 710 classification of, 697t CT scan with, 696 diagnosis of, 700–701 diagnosis/staging of, 695–697, 697t differential diagnosis of, 695–696 epidemiology of, 695 external beam radiation for, 706, 707t grading in, 700, 701t histology in, 701 HPV in, 695–696, 710 incidence of, 695 inguinal node management with, 706–707, 707f Jackson staging system for, 701t, 702 laboratory studies in, 696 laser therapy for, 704–705, 705t
Squamous cell carcinoma (SCC) (Continued) Mohs’ micrographic surgery for, 704, 723 MRI with, 696 natural history of, 700 occurrence of, 723 partial penectomy for, 703 presentation in, 696, 699–700 radiation therapy for, 705 staging in, 696–697, 701–702, 701t staging systems for, 697, 697t summary of carcinoma of, 707 superficial carcinoma of, 699–707, 700f, 701t, 702–703, 702t, 705t, 706t, 707f, 707t surgical excision for, 702 symptoms in, 696, 699–700 TNM staging system for, 702, 702t total penectomy for, 703–704 primary lesion treatment for, 715–716 radiation therapy for, 718 urethral cancer pathology with, 674 SSCT. See Sclerosing Sertoli cell tumors Stauffer’s syndrome RCC associated with, 174t Stoma stenosis cutaneous urinary diversion with, 431 Stone formation cutaneous urinary diversion with, 434 Stromal epithelial interactions, 15–16, 15f Sturge-Weber syndrome pheochromocytoma with, 139 Sublethal damage repair (SLDR), 44 Substratum adhesion molecules (SAMS), 13f Suprahepatic vena cava radical nephrectomy with, 226–230, 228f, 229f Surgery adrenal gland approach in, 156 adrenal tumors with, 139–149, 142t, 143f, 144f, 145f, 146f, 147f, 148f, 153–167, 154f, 154t, 157f, 158f, 159f, 160f, 161f, 161t, 162f, 163f, 164f, 166t anatomic nerve-sparing radical prostatectomy, 514–527, 516f, 517f, 518f, 519f, 520f, 521f, 522f, 523f, 524f, 525f bladder neck transection/reconstruction for, 522, 523f Denonvilliers’ fascia incision for, 521f dorsal venous ligation/transection for, 516–519, 518f, 519f, 520f, 521f endopelvic fascia incision for, 515–516, 517f, 518f limited pelvic lymphadenectomy for, 515 neurovascular bundies separation for, 519, 521f patient selection for, 514–515 prostatic pedicles transection/control for, 519–522, 522f puboprostatic ligaments incision for, 515–516, 517f vesico-urethral anastomosis for, 522–523, 524f, 525f anatomy in, 156
Index 807 Surgery (Continued) approaches to, 141, 142t Cushing’s syndrome in, 141, 142t cutaneous urinary diversion in appendiceal approach to, 409 Benchekroun nipple approach to, 409 colocolostomy in, 405f colonic conduits for, 404–406, 405f complications with, 430–437, 433t, 435t continent, 406–427, 407f, 408f, 409f, 410f, 412f, 413f, 414f, 415f, 416f, 417f, 418f, 419f, 420f, 421f, 422f, 422t, 423–424t, 425f, 426f, 427f continent catheterizable urinary diversions for, 407–409 continent mechanism in, 409–411, 410f continent reservoirs for, 411–427, 412f, 413f, 414f, 415f, 416f, 417f, 418–420f, 421f, 422f, 422t, 423–424t, 425f, 426f, 427f, 428f, 436–437 continent v. noncontinent, 399 cutaneous pyelostomy for, 400, 401f cutaneous ureterostomy for, 400–401, 402f Duke pouch, 422t, 424t flap valve approach to, 409 Florida pouch, 422t, 424t four surgical techniques for, 409 gastric pouch, 424t, 426–427, 427f, 428f, 436–437 hydraulic valve approach to, 409 ileal conduit for, 401–403, 403f, 404f ileocecal, 411–416, 412f, 413f, 414f, 415f, 416f, 417f, 418–420f, 421f, 422f, 422t, 423–424t ileocecal conduit for, 405 Indiana pouch, 416–421, 422t, 423–424t, 425f, 436 intraoperative pouch testing for, 411 intussuscepted nipple valve approach to, 409 jejunal conduit for, 404 Kock pouch, 411–413, 412f, 413f, 423t, 436 laparoscopic ileal conduit for, 438, 439t LeBag, 422t Mainz pouch, 414–416, 418–420f, 423t, 436 nasogastric tube for, 400 noncontinent, 400–406, 401f, 402f, 403f, 404f, 405f novel techniques for, 438–439, 439t Penn pouch, 424t, 426, 426f postoperative care for, 400 preoperative preparation for, 399–400 pseudoappendiceal approach to, 409 quality of life with, 437–438, 438t rectal bladder urinary diversion for, 406–407, 407f, 408f rectus fascia incision in, 404f renal pelvis incision in, 401f right colon, 416–427, 422t, 423–424t, 425f, 426f, 427f, 428f, 436–437
Surgery (Continued) sigmoid colon conduit for, 406 T pouch, 413–414, 414f, 415f, 416f, 417f, 423t taenia incision in, 407f transverse colon conduit for, 404–406, 405f U. Miami pouch, 424t UCLA pouch, 422t, 423t ureterointestinal anastomoses with, 407f, 427–430, 429f, 430f, 431f ureterosigmoidostomy in, 406–407 Wallace technique for, 430, 430f flank approach to, 145–147, 145f, 146f, 156–158, 157f hyperaldosteronism in, 142t laparoscopic partial nephrectomy complications of, 252–283 contraindications for, 249 financial analysis of, 283 indications for, 249 renal hypothermia with, 250, 254f renal parenchymal repair in, 253f results of, 250–252, 255t technique for, 249–250, 250t, 251f, 252f, 253f laparoscopic radical nephrectomy, 218–230, 219f, 220f, 221f, 222f, 223f, 224f, 225f, 226f, 227f, 228f, 229f, 230t anterior subcostal transperitoneal incision in, 220, 220f, 221f approach selection for, 237–238 bilateral subcostal incision in, 220 complications of, 241, 243t, 244t concomitant adrenalectomy with, 245–246 contra-indications for, 237 CT scan for, 218 cytoreductive, 247–248 diaphragmatic incision in, 220 evaluation for, 218–219 financial implications of, 248 follow-up for, 246t Gerota’s fascia in, 224f, 226, 239 indications for, 218–219, 237 IVC with, 222–226, 227f, 228f larger renal tumors with, 245, 247t left side, 220–222, 224f, 225f lymphadenectomy with, 222 MRI for, 218 oncologic outcome of, 244–245 ORN v., 201–203, 202t, 247t RCC with, 199–203, 202t, 237–248, 238f, 239f, 240f, 241f, 242t, 243t, 244t, 245f, 246t, 247t, 248t, 249f renal vein in, 224f renal vein involvement with, 246–247, 248t, 249f results of, 241, 242t right side, 222, 225f ring retractor with, 224f specimen extraction with, 241–244, 245f suprahepatic vena cava with, 226–230, 228f, 229f
Surgery (Continued) surgical anatomy with, 219, 219f surgical incisions in, 219–220, 220f, 221f, 222f technique for, 200–201, 238–240, 238f, 239f, 240f, 241f TEE for, 218 thoracoabdominal approach in, 220, 222f, 223f three approaches to, 199 thrombectomy with, 227f laparoscopic radical prostatectomy, 537–538 anterior phase in, 537 main operation steps for, 537–538 medical preparation for, 537 Montsouris technique in, 537 neurovascular bundles dissection in, 538 patient installation in, 537 posterior phase in, 537 prostatic pedicles dissection in, 538 specimen extraction in, 538 transperitoneal approach to, 537 urethra section in, 538 vesicoprostatic dissection in, 538 vesicourethral anastomosis in, 538 lateral flank approach in, 156–158, 157f lymphadenectomy in, 728f, 729f, 730–732, 732f management of TCC through, 274–279, 275t, 277t, 279f modified posterior approach to, 143–145, 144f, 159, 160f nephrectomy with, 146, 146f neuroblastoma treatment with, 746–750 open radical nephrectomy (ORN) LRN v., 201–203, 202t RCC with, 198–199, 199f, 201–203, 202t, 247t open surgical techniques in, 156–159, 158f, 159f, 160f orthotopic bladder substitution, 443–454, 445f, 446f, 447f, 448f, 449f, 450f, 451f, 452f, 453f, 453t, 454t atraumatic urethra dissection as, 446 bipolar electrocautery in, 446 bladder construction as, 447–448, 450f, 451f, 453f cystectomy as, 445–446, 445f, 446f, 453f ileal segment resection as, 446, 447f, 448f long-term follow-up for, 452–454, 454t mesenteric window close in, 448f metabolic acidosis in, 450, 453t nerve preservation in, 445–446, 445f, 446f Nesbit technique in, 449f operative technique for, 444–448, 445f, 446f, 447f, 448f, 449f, 450f, 451f, 452f, 453f orthotopic ileal bladder substitute as, 446, 447f, 448f patient assessment for, 443–444
808 Index Surgery (Continued) postoperative management for, 448–452, 453t preoperative patient selection for, 443–444 U-shaped distal ileum in, 450f ureteroileal anastomosis as, 446–447, 449f, 450f ureters in, 446 urethral anastomosis as, 447–448, 450f, 451f, 453f partial adrenalectomy in, 148–149, 148f partial nephrectomy for, 230–235, 233f, 234f AML with, 235 CT for, 230–231 segmental polar, 232, 233f simple enucleation, 235 in situ, 231 transverse resection, 234–235, 234f wedge resection, 232–234, 234f partial penectomy in, 701 PC treatment complications with, 547–552 pheochromocytoma in, 142t posterior approach to, 142–143, 143f, 159, 159f preoperative management with, 141, 142t, 156 procedures for penis in, 723–732, 724f, 725f, 726f, 727f, 728f, 729f, 732f radical cystectomy abdominal exploration in, 370 adjuvant v. neoadjuvant, 346–347 bladder treated with, 368, 369–387, 370f, 371f, 372f, 373f, 375f, 376f, 377f, 378f, 379f, 380f, 381f, 382f, 383f, 384f, 385f, 386f bowel mobilization in, 370–372, 372f, 373f chemotherapy with, 346–347 complications of, 346 Denonvilliers’ fascia in, 279f, 377, 378f, 380, 380f discussion of, 385–387 dorsal venous complex in, 380, 381f, 382f female patient anterior dissection in, 382–384, 383f, 384f, 385f, 386f female pelvic sagittal section in, 386f females with, 345 gauze sponge withdrawing in, 376f ICU for, 384 iliac artery skeletonizing in, 375f incision in, 370, 371f lateral vascular pedicle ligation in, 374–375, 377f lymphadenectomy with, 345–346 male patient anterior dissection in, 378–382, 381f, 382f males with, 344–345 outcomes of, 346 overhead pelvic view in, 372f, 373f overview of, 343–344
Surgery (Continued) patient positioning in, 370, 370f pelvic lymphadenectomy with, 373–374, 375f, 376f peritoneum incision in, 378f posterior pedicle ligation in, 375–378, 378f, 379f, 380f postoperative care for, 384–385 preoperative evaluation for, 344, 369–370 preparation for, 344 TCC with, 343–347 urachal remnant excision in, 371f ureteral dissection in, 372 vaginal incision in, 383f vaginal wall dissection in, 384f, 385f vascular pedicle isolation in, 377f radical laproscopic, 149, 150–151f, 160–167, 161f, 161t, 162f, 163f, 164f, 166t radical perineal prostatectomy, 529–530 radical prostatectomy, 465–474, 466t, 468t, 469t, 471t, 472t, 473t biopsy Gleason sum with, 471, 472f blood loss during, 469, 469f cancer control with, 469f, 470–473, 471f, 472f CT scan assessment with, 466 early complications with, 468–470, 468f, 469f erectile function after, 474 hospitalization days with, 469f intraoperative complications with, 468–470, 468f, 469f late complications with, 470 lymph node metastases with, 472t mortality with, 468f MRI assessment with, 466 obturator nerve injury from, 470 outcomes after, 469f, 470–474, 471f, 472f, 473f patient selection for, 466 PC natural history and, 465–466, 466t pelvic lymph node dissection with, 467–468 pretreatment risk stratification with, 466–467 PSA risk assessment with, 466–467, 470, 471f PSA survival with, 469f rectal injury from, 469 results of, 468 risk factors with, 472f, 473f seminal vesicle involvement with, 472f treatment rationale, 465 urinary function with, 473, 473f urinary incontinence after, 473, 473f RCC, indications for, 198 RMS treated with, 774–776 seminoma, 578–579 TCC with, 276–279, 277t, 279f, 287–296, 288f, 289f, 290f, 291f, 292f, 293f, 294f, 295f, 296f
Surgery (Continued) endoscopic management for, 293–295, 295f, 296f laparoscopic nephroureterectomy in, 278–279, 280t, 289–291, 290f, 291f laparoscopic v. open nephroureterectomy in, 219f, 220f, 280t open nephron-sparing surgery for, 291–293, 292f, 293f open nephroureterectomy in, 277–278, 280t, 287–289, 289f, 291f open segmental ureterectomy for, 292–293, 293f, 294f partial ureterectomy in, 276–277, 277t thoracoabdominal approach to, 158, 158f total penectomy for, 703–704 complications in, 704 impact of, 704 surgical technique in, 703 transabdominal approach to, 147–148, 147f, 158–159, 158f TUR anesthesia for, 359 bimanual examination for, 359, 359f bladder cancer diagnosis with, 306, 338 Bladder-sparing therapy with, 347–348 bladder tumors with, 358–365, 359f, 360f, 364t, 365f complications with, 362–364 equipment for, 359–360 fluoroscopic cystoscopy for, 365 instrumentation for, 359–360 intraoperative problem management in, 361–362 irrigation fluid in, 361 laser surgery for, 364–365, 364t, 365f postoperative management in, 362 preparation for, 358–359 primary muscle invasive tumor treatment with, 362 second look resection in, 362 TCC bladder with, 317–318 TCC diagnosis with, 338 technique for, 360–361 Surgical Planning Laboratory (SPL), 119 SVB. See Seminal vesical biopsy SVI. See Seminal vesicle invasion SWOG. See Southwest Oncology Group Systemic therapy IFN in, 263 IL-2 in, 263–264 RCC with, 263–264 T-cells HCT with, 93, 96, 96f T pouch complications with, 435t continent reservoirs compared to, 423t
Index 809 T pouch (Continued) reoperation rate with, 435t technique for, 413–414, 414f, 415f, 416f, 417f urinary diversion with, 413–414, 414f, 415f, 416f, 417f, 423t, 435t Taxanes docetaxel as, 66f, 67 genitourinary cancer treatment with, 65–67, 67f paclitaxel as, 65–67, 67f TCC. See Transitional cell carcinoma TEE. See Transesophageal echocardiography Telomerase urologic cancers with, 16 Telomeric repeat amplification protocol (TRAP) TCC diagnosis with, 272 Temporary prostate brachytherapy (TPB) prostate adenocarcinoma treated with, 484–485, 488, 489t BRFS with, 488, 489t technique in, 484–485 Teratoma, testis tumors, 781 Testicular cancer HRQOL with, 109 Testicular germ cell tumors (GCT). See Testis tumors Testicular intraepithelial neoplasia (TIN) seminoma with, 581 Testis tumors diagnosis of, 567–568 introduction, 567 presentation of, 567–568 imaging of, 568–569 nongerm cell tumors of, 617–637, 618f, 618t, 619f, 620f, 621f, 622f, 623f, 624f, 625f, 626f, 627f, 628f, 629f, 630f, 631f, 632f, 633f, 634f, 635f, 636f acquired immunodeficiency syndrome with, 637 adenomatoid tumor of epididymis as, 618t, 633, 633f, 634f carcinoid tumors of, 618t, 632–633, 633f epidermoid cysts as, 618t, 627–628, 627f, 628f generalized stroma tumors of, 636–637 granulosa cell tumors as, 618t, 624–626, 625f, 626f hematologic tumors of, 618t, 633–636, 635f HIV and, 637 Klinefelter’s syndrome with, 619 leukemia as, 618t, 636, 636f Leydig cell tumors as, 618–622, 618f, 618t, 619f, 620f, 621f malignant lymphoma as, 618t, 633–636, 635f malignant mesothelioma as, 629–631, 630f, 631f metastatic tumors of, 618t, 631–632, 632f
Testis tumors (Continued) miscellaneous tumors of, 627–636, 627f, 628f, 629f, 630f, 631f, 632f, 633f, 634f, 635f, 636f mixed sex cord/gonadal stromal tumors as, 626–637, 627f, 628f, 629f, 630f, 631f, 632f, 633f, 634f, 635f, 636f ovarian surface epithelial type tumors of, 637 plasmacytoma as, 618t, 636, 636f Reinke’s crystals in, 619, 621 Rete testis carcinoma as, 628–629, 629f Sertoli cell tumors as, 618t, 622–624, 622f, 623f, 624f, 625f sex cord/stromal origin with, 618–626, 618f, 618t, 619f, 620f, 621f, 622f, 623f, 624f, 625f, 626f serum tumor markers of, 568 AFP, 568 HCG, 568 LDH, 568 NSE, 568 NSGCT, 568 PLAP, 568 staging of, 569–574, 572t, 573t, 574t AJCC in, 569, 571, 572t bipedal lymphangiogram for, 570 CT scan for, 569–571 distant metastasis in, 571, 572t IGCCCG with, 571, 573t introduction to, 569 modalities of, 569–571 PET scan for, 570 primary tumor in, 571, 572t regional lymph nodes in, 571, 572t RPLND for, 570, 571 serum tumor markers in, 571, 572t TGF. See Transforming growth factor Therapeutic radiation (RT) adjuvant, 46 definitive, 46 palliative, 46 radiation oncology clinical practice and, 46–47, 47t Thiotepa bladder TCC with, 323 genitourinary cancer treatment with, 69 Three-dimensional conformal radiation therapy (3DCRT) radiation therapy for adenocarcinoma with, 478–479, 478f, 482, 489 3D Slicer surgical simulation software, 119, 120f 3DCRT. See Three-dimensional conformal radiation therapy Thrombenectomy radical nephrectomy with, 227f Thrombospondin-1 (TSP-1) TCC prognosis with, 341 TIL. See Tumor-infiltrating lymphocytes TIN. See Testicular Intraepithelial neoplasia TNF. See Tumor necrosis factor TNM. See Tumor, nodes, and metastasis Topotecan genitourinary cancer treatment with, 73f, 74
Toxicity androgen deprivation therapy with, 499 TRAIL. See Tumor necrosis factor-related apoptosis-inducing ligand Transesophageal echocardiography (TEE) radical nephrectomy for, 218 Transforming growth factor (TGF) RCC with, 176 TCC prognosis with, 343 Transitional cell carcinoma (TCC) biologic prognostic markers for, 321–322 BCG in, 321 blood group antigens as, 321 cytogenic markers as, 321–322 FISH as, 321 molecular genetic markers as, 321–322 tumor cell products as, 321 WTG in, 321 bladder-sparing therapy for, 347–349 bladder with, 317–331, 318t, 322t, 326t, 328f, 329t, 330t chemotherapy for, 279–281, 323–324 CISCA regimen in, 281 CMV regimen in, 281 doxorubicin in, 324 MMC in, 323–324, 326t MVAC regimen in, 281 thiotepa in, 323 valrubicin in, 324 cytologic prognostic factors for, 320–321 DNA ploidy in, 321 urine cytology in, 320–321 diagnosis of, 270–272, 271f, 272f, 273f bladder mucosa distant from tumor in, 320 CT scan in, 271–272, 273f, 339 cytology in, 272, 273f endoscopic evaluation in, 272 MRI in, 271–272, 339 other markers in, 272 radiographic evaluation in, 270–272, 271f, 272f, 273f TRAP in, 272 tumor extent evaluation in, 338–340 tumor metastatic evaluation in, 339 tumor stage and growth in, 338–339 endoscopic management of, 274–276, 275t, 317–318, 320 etiology in, 269–270 evaluation of, 269–274, 271f, 272f, 273f, 274t, 317 grading of, 274, 318 histopathology of, 272–274, 319 intravesical therapy for, 322–327, 322t, 326t BCG in, 324–326, 326t bropirimine in, 327 chemotherapy, 323–324 combination therapy, 327 doxorubicin in, 324 IFN in, 326 immunotherapy in, 324–327 KLH in, 326–327 MMC in, 323–324, 326t rationale for, 322–323, 322t recommendations in, 327
810 Index Transitional cell carcinoma (TCC) (Continued) thiotepa in, 323 valrubicin in, 324 management of, 338–349 outcome for, 281–282 prognosis for, 320–322, 338–349 angiogenic factors with, 341–342 biologic markers in, 321–322 cell adhesion molecules with, 341 cell-cycle regulators with, 342–343 chromosomal abnormalities with, 340 conclusion about, 343 cytologic factors in, 320–321 erb-B-2 with, 342–343 genetic determinants with, 343 growth events with, 340–341 MDR gene with, 343 MVAC with, 343 MVD with, 341–342 P53 with, 342 retinoblastoma gene with, 342 summary of, 349 TGF with, 343 treatment response with, 343 TSP-1 with, 341 VEGF with, 341 prostatic urethra with, 327–328, 328f CIS only, 328f cystoprostatectomy for, 328f ductal, 328f intravesical therapy for, 328f stromal invasion, 328f radiation therapy for, 281 radical cystectomy for, 343–347 adjuvant v. neoadjuvant, 346–347 chemotherapy with, 346–347 complications of, 346 females with, 345 lymphadenectomy with, 345–346 males with, 344–345 outcomes of, 346 overview of, 343–344 preoperative evaluation for, 344 preparation for, 344 renal pelvis and ureter with, 269–282, 271f, 272f, 273f, 274t, 275t, 277t, 279f, 280t staging of, 274, 274t, 319–320 AJCC in, 274t, 319 distant metastasis in, 274t lymph nodes in, 274t primary tumor in, 274t PUNLMP in, 274 reproducibility of, 319–320 TNM in, 274, 274t surgical approaches to, 276–279, 277t, 279f, 287–296, 288f, 289f, 290f, 291f, 292f, 293f, 294f, 295f, 296f endoscopic management for, 293–295, 295f, 296f, 317–318 laparoscopic nephroureterectomy in, 278–279, 280t, 289–291, 290f, 291f laparoscopic v. open nephroureterectomy in, 219f, 220f, 280t
Transitional cell carcinoma (TCC) (Continued) open nephron-sparing surgery for, 291–293, 292f, 293f open nephroureterectomy in, 277–278, 280t, 287–289, 289f, 291f open segmental ureterectomy for, 292–293, 293f, 294f partial ureterectomy in, 276–277, 277t surgical management of, 274–279, 275t, 277t, 279f BCG with, 276 percutaneous resection with, 276 results of, 277, 279f SEER on, 277, 279f survival with, 279f treatment of, 274–282, 275t, 277t, 279f, 280t upper urinary tract, 287–296, 288f, 289f, 290f, 291f, 292f, 293f, 294f, 295f, 296f endoscopic management for, 293–295, 295f, 296f initial evaluation for, 287 IVP for, 287 laparoscopic radical nephroureterectomy for, 289–291, 290f, 291f open nephron-sparing surgery for, 291–293, 292f, 293f open radical nephroureterectomy for, 287–289, 289f, 291f open segmental ureterectomy for, 292–293, 293f, 294f Transrectal US (TRUS) IGT with, 114, 117, 118, 122 PC staging with, 461 seminal vesicles diagnosis with, 555, 556f Transurethral resection of bladder tumor (TURBIT) bladder preservation, 390t, 392 Transurethral resection of the prostate (TURP) brachytherapy and, 119 PC staging with, 549 Transurethral resection (TUR) anesthesia for, 359 bimanual examination for, 359, 359f bladder cancer diagnosis with, 306, 338 bladder preservation with, 389, 390t, 394f Bladder-sparing therapy with, 347–348 bladder tumors with, 358–365, 359f, 360f, 364t, 365f complications with, 362–364 bladder explosion in, 364 bladder perforation in, 363 hemorrhage in, 362–363 obturator nerve reflex in, 363 reabsorption syndrome in, 363–364 ureteral orifice injury in, 363 urinary infection in, 363 urinary stricture in, 363 equipment for, 359–360 cold-cup biopsy in, 360 flexible cystoscope in, 360 video endoscopy in, 360
Transurethral resection (TUR) (Continued) fluoroscopic cystoscopy for, 365 instrumentation for, 359–360 ball electrode as, 359 CIS with, 359 intraoperative problem management in, 361–362 irrigation fluid in, 361 laser surgery for, 364–365, 364t, 365f advantages/disadvantages with, 364–365 bladder tumor recurrence rate with, 365 techniques of, 364 types of, 364t postoperative management in, 362 preparation for, 358–359 CT scan in, 358 IVP in, 358 primary muscle invasive tumor treatment with, 362 second look resection in, 362 TCC bladder with, 317–318 TCC diagnosis with, 338 technique for, 360–361 Transverse colon conduit noncontinent cutaneous urinary diversion with, 404–406, 405f TRAP. See Telomeric repeat amplification protocol TRUS. See Transrectal US TSP-1. See Thrombospondin-1 Tubulin modulation drugs genitourinary cancer treatment with, 64–65 Tumor, nodes, and metastasis (TNM) bladder cancer staging with, 308, 309 penis carcinoma staging with, 714, 715t Penis SCC staging with, 700, 700t RCC prognostic factors with, 210–211, 210t RCC staging with, 183–185, 184–185t, 186, 186t, 259, 259f TCC staging with, 274, 274t Tumor-infiltrating lymphocytes (TIL) immunotherapy with, 93, 94f, 264 Tumor necrosis factor-related apoptosisinducing ligand (TRAIL), 92 Tumor necrosis factor (TNF), 12 Tumor thrombus RCC with, 203–204, 203t, 204f, 227f, 228f, 229, 229f Tunneled ureterointestinal anstomoses, 430 TUR. See Transurethral resection TURBIT. See Transurethral resection of bladder tumor TURP. See Transurethral resection of the prostate U. Miami pouch complications with, 435t continent reservoirs compared to, 424t reoperation rate with, 435t urinary diversion with, 424t, 435t
Index 811 UCLA Integrated Staging System (UISS) RCC grade with, 259 RCC staging with, 186–187, 186t, 260, 260f UCLA PCI. See University of California, Los Angeles Prostate Cancer Index UCLA pouch complications with, 435t continent colon pouches compared to, 422t continent reservoirs compared to, 423t reoperation rate with, 435t urinary diversion with, 422t, 423t, 435t UICC. See Union Internationale Contre le Cancer UISS. See UCLA Integrated Staging System Ultrasound (US). See also Focused ultrasound surgery brachytherapy guided by, 118–119 AUR with, 119 outcome of, 119 procedure for, 118–119 incidentaloma with, 133 NSGCT diagnosis with, 597, 598f, 599f, 600f prostate cancer surgery focused with, 122 RCC diagnosing with, 178–179, 179f, 197 renal tumor ablation with, 209–210 Wilms’ tumor evaluation with, 756, 756f Union Internationale Contre le Cancer (UICC), 196, 196t, 259 University of California, Los Angeles Prostate Cancer Index (UCLA PCI) HRQOL measured with, 105 Upper urinary tract transitional cell carcinoma in endoscopic management for, 293–295, 295f, 296f initial evaluation for, 287 IVP for, 287 laparoscopic radical nephroureterectomy for, 289–291, 290f, 291f open nephron-sparing surgery for, 291–293, 292f, 293f open radical nephroureterectomy for, 287–289, 289f, 291f open segmental ureterectomy for, 292–293, 293f, 294f Ureteral orifice injury TUR complications with, 363 Ureteral-small bowel anstomoses, 427–430, 429f Ureterectomy partial TCC with, 276–277, 277t Ureterocolonic anstomoses, 430, 431f Ureteroileal anastomosis orthotopic bladder substitution with, 446–447, 449f, 450f Ureterointestinal anastomotic cutaneous urinary diversion complications with, 431, 432t cutaneous urinary diversion with, 427–430, 429f, 430f, 431f direct type, 427–430, 429f rectal bladder urinary diversion with, 407f refluxing v. nonrefluxing, 427
Ureterointestinal anastomotic (Continued) small bowel, 427–430, 429f tunneled, 430 ureterocolonic, 430, 431f Wallace technique for, 430, 430f Ureterosigmoidostomy cutaneous urinary diversion complications with, 434–436 Ureterosignoidostomy rectal bladder urinary diversion with, 406–407 Ureters orthotopic bladder substitution with, 446 Urethral anastomosis orthotopic bladder substitution with, 447–448, 450f, 451f, 453f Urethral cancer evaluation of, 675, 676t females with, 680–682, 680f, 681t, 682f fossa navicularis, 675, 677t males with, 673–680, 674f, 676t, 677f, 677t, 678f, 679f multimodal therapy for, 680 operative techniques for, 676–680, 677f, 678f, 679f radiation therapy for, 680 urethrectomy with cystectomy for, 680 natural history of, 675–676 partial/total urethrectomy for, 676–680, 677f, 678f, 679f pathology of, 673–680, 674f, 676t, 677f, 677t, 678f, 679f penile urethra, 675, 677t prostatic urethral cancer as, 675–676, 677t staging of, 675, 676t treatment of, 675, 677t Urethral recurrence orthotopic bladder substitution with, 444 Urethrectomy cystectomy with, 680 females urethral cancer with, 681–682, 682f indications for, 686 male urethral cancer with, 676–680, 677f, 678f, 679f operative technique for, 686–692, 687f, 688f, 689f, 690f, 691f, 692f, 693f, 694f bulbar urethral arteries in, 691f bulbocavernous muscle division in, 689f cystoprostatectomy with, 686–688, 687f, 688f, 689f, 690f, 691f, 692f, 693f electrocautery in, 689f female urethrectomy in, 690 larger distal tumors in, 691–692 patient position in, 687f pelvic dissection in, 686–687, 687f, 688f perineal dissection in, 687, 688, 689f, 690f, 691f, 692f, 693f proximal tumors in, 691–692 small distal tumors in, 690–691, 693f, 694f
Urethrectomy (Continued) total male anterior urethrectomy in, 688–690 summary of, 692 Urethrovesical anastomosis RRP with, 529 Urinary infection TUR complications with, 363 Urinary stricture TUR complications with, 363 Urologic cancers adenovirus vectors gene therapy for, 21–22, 21t, 22f, 26t aging/telomerase with, 16 aptamers with, 16–17 bulbourethral with, 3, 4f cancer genes and, 8–10 carcinogens in, 4–5 cell cycle with, 11–12, 12f cell signaling with, 12f, 14–15, 14f cellular biology of, 3–17, 4f, 6t, 10f, 12f, 13f, 14f, 15f, 17f CGH with, 8 enigmas of, 3, 4f epigenetic effects in, 3–4, 4f families and, 7–8 gene therapy for, 18–34, 19f, 20f, 21t, 22f, 23f, 24f, 25f, 26t, 27f, 31f, 32f, 33f gene therapy molecular targets of, 25–33, 26t, 27f, 31f, 32f gene transfer vectors for, 18–19 inflammation with, 5–7, 6t liposomal gene transfer for, 21t, 24–25, 24f, 25f, 26t microarrays with, 10–11 modified vector tropism in, 33–34 molecular biology of, 3–17, 4f, 6t, 10f, 12f, 13f, 14f, 15f, 17f nature v. nurture in, 4 nonviral vectors gene therapy for, 21t, 24–25, 24f, 25f, 26t oncolytic virotherapy for, 30 poxvirus vectors therapy for, 21t, 22–24, 23f, 26t prostate with, 3, 4f proteomics with, 10–11 restricted transgene expression in, 34 retrovirus vectors therapy for, 19–21, 19f, 20f, 21t, 26t ribozyme construct approach to, 30–31, 31f SKY with, 8 stromal epithelial interactions with, 15–16, 15f target cell death with, 26t, 29–30 targeting vector specificity in, 33–34, 33f transcriptional targeting gene therapy for, 34 tumor cell heterogeneity in, 16–17, 17f tumor suppressor gene restoration for, 31–33, 32f US. See Ultrasound
812 Index U.S. Surveillance, Epidemiology, and End Results (SEER) RCC reported by, 173 TCC surgical results from, 277, 279f Valrubicin bladder TCC with, 324 Vascular endocrine growth factor (VEGF) Wilms’ tumor pathology with, 761 Vascular endothelial growth factor (VEGF) immunotherapy with, 98 RCC antiangiogenic with, 264–265 TCC prognosis with, 341 VEGF. See Vascular endocrine growth factor; Vascular endothelial growth factor Verrucous carcinoma penis carcinoma with, 712 Vesico-urethral anastomosis radical prostatectomy with, 522–523, 524f, 525f Vesicoprostatic dissection laparoscopic radical prostatectomy with, 538 Vesicourethral anastomosis laparoscopic radical prostatectomy with, 538 VHL. See Von Hippel-Lindau Video endoscopy TUR equipment including, 360 Vinblastine bladder preservation with, 391t Vinca alkaloids genitourinary cancer treatment with, 64–65 Vomiting orthotopic bladder substitution with, 453t
Von Hippel-Lindau (VHL) gene, 31 immunotherapy with, 264 pheochromocytoma with, 139, 140t RCC with, 176, 197t, 264 Vysion bladder cancer diagnosis with, 305 WAGR syndrome. See Wilms’ tumor and AGR syndrome Wallace technique ureterointestinal anastomoses with, 430, 430f Watchful waiting (WW) HRQOL with, 107 WHO. See World Health Organization Wilms’ tumor AGR syndrome with, 754, 754t, 759t bilateral Wilms’ tumor and, 766 BWS syndrome with, 754, 754t, 759t clinical presentation of, 755 cooperative group trials for, 762–766, 764t, 765f NWTS-1, 763 NWTS-2, 763 NWTS-3, 763 NWTS-4, 763 NWTS-5, 763–764, 764t SIOP in, 764–766, 765f Denys-Drash syndrome with, 753, 758, 759t differential diagnosis of, 757, 758f epidemiology of, 753–754, 754t genetics of, 754–755 late effects of treatment for, 767 pathology of, 757–761, 758f, 758t, 760t biologic parameters in, 759–761
HA with, 761 HASA with, 761 hTERT with, 760 ILNR with, 758–759, 758f NSE with, 761 PLNR with, 758–759, 758f precursor lesions in, 758–759, 758f, 758t, 760t VEGF with, 761 postoperative evaluation of, 755–757, 756f CT scan for, 756, 756f, 758f MRI for, 756 ultrasound for, 756, 756f prognostic consideration for, 761, 761t relapse treatment for, 766–767 Simpson-Golabi-Behmel syndrome with, 754 SMN with, 767 surgical management of, 761–762 WAGR syndrome with, 754, 758, 759t Wilms’ tumor and AGR syndrome (WAGR syndrome) Wilms’ tumor with, 754, 758, 759t Wilms’ tumor gene (WTG) TCC prognostic markers with, 321 Wood preservatives retroperitoneal tumors from, 652 World Health Organization (WHO), 196, 302 WTG. See Wilms’ tumor gene WW. See Watchful waiting XRT. See External beam radiation therapy
