Urologic Oncology

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