Basic and Advanced Techniques in Prostate Brachytherapy

Basic and Advanced Techniques in Prostate Brachytherapy Edited by Adam P Dicker MD PhD Associate Professor and Director...

Author: Adam P. Dicker | Gregory Merrick | Leonard Gomella | Richard K. Valicenti | Frank Waterman

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Basic and Advanced Techniques in Prostate Brachytherapy Edited by Adam P Dicker MD PhD Associate Professor and Director Division of Experimental Radiation Oncology Department of Radiation Oncology, Kimmel Cancer Center Jefferson Medical College of Thomas Jefferson University Hospital Philadelphia, PA, USA Gregory S Merrick MD Director, Schiffler Cancer Center Wheeling, WV, USA Frank M Waterman PhD Professor of Medical Physics Department of Radiation Oncology Thomas Jefferson University Philadelphia, PA , USA Richard K Valicenti MD Associate Professor and Clinical Director of Radiation Oncology Department of Radiation Oncology Bodine Center for Cancer Treatment Philadelphia, PA , USA Leonard G Gomella MD The Bernard W Godwin Professor of Prostate Cancer, and Chairman, Department of Urology Thomas Jefferson University Philadelphia, PA , USA

LONDON AND NEW YORK A MARTIN DUNITZ BOOK

© 2005 Martin Dunitz Ltd, a member of the Taylor & Francis Group plc First published in the United Kingdom in 2005 by Martin Dunitz, Taylor & Francis Group plc, 2 Park Square, Milton Park, Abingdon, Oxfordshire OX41 4RN Tel: +44 (0) 20 7017 6000 Fax.: +44 (0) 20 7017 6699 E-mail: [email protected] Website: http://www.dunitz.co.uk This edition published in the Taylor & Francis e-Library, 2006. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk.” All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior permission of the publisher or in accordance with the provisions of the Copyright, Designs and Patents Act 1988 or under the terms of any licence permitting limited copying issued by the Copyright Licensing Agency, 90 Tottenham Court Road, London W1P 0LP. Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention. Although every effort has been made to ensure that drug doses and other information are presented accurately in this publication, the ultimate responsibility rests with the prescribing physician. Neither the publishers nor the authors can be held responsible for errors or any consequences arising from the use of information contained herein. For detailed prescribing information or instructions on the use of any product or procedure discussed herein, please consult the prescribing information or instructional material issued by the manufacturer. A CIP record for this book is available from the British Library. ISBN 0-203-49170-X Master e-book ISBN

ISBN 0-203-59591-2 (Adobe eReader Format) ISBN 1 84184 298 2 (Print Edition) Distributed in the USA by Fulfilment Center Taylor & Francis 10650 Tobben Drive Independence, KY 41051, USA Toll Free Tel: +1 800 634 7064 E-mail: [email protected] Distributed in Canada by Taylor & Francis 74 Rolark Drive Scarborough, Ontario M1R 4G2, Canada Toll Free Tel: +1 877 226 2237 E-mail: [email protected] Distributed in the rest of the world by Thomson Publishing Services Cheriton House North Way Andover, Hampshire SP10 5BE, UK Tel: +44 (0) 1264 332424 E-mail: [email protected] Composition by EXPO Holdings Sdn Bhd, Malaysia

Contents List of Contributors Acknowledgments

1. Introduction Adam P Dicker, Gregory S Merrick, Frank M Waterman, Richard K Valicenti, and Leonard G Gomella Part I Understanding the problem: fundamentals of pathology and implications for brachytherapy 2. Effect of radiotherapy on prostate histopathology and assessment of residual cancer Kenneth A Iczkowski and David G Bostwick 3. What should you ask your pathologist when contemplating minimally invasive therapy Robert O Petersen 4. Detailed mapping of prostate cancer: implications for brachytherapy Michael E Chen, Dennis A Johnston, and Patricia Troncoso 5. Defining permanent prostate brachytherapy target volumes from evaluation of whole-mount prostatectomy specimens Brian J Davis, Thomas M Pisansky, John C Cheville, and Torrence M Wilson 6. Prostate cancer staging: PSMA-based serum assays and radioscintigraphy Ganesh V Raj and Thomas J Polascik Part II Treatment choices: perspectives from the physician and patient 7. Treatment decisions: surgery versus brachtherapy. A urologist’s perspective Michael Perrotti and Leonard G Gomella 8. Treatment decisions: which therapy? A patient’s perspective William J Hilsman

viii xx

1

4

6

24

39 49

61

83

84

96

Part III Pretreatment and real-time planning for permanent, low dose rate prostate brachytherapy 9. Brachytherapy from the urologist’s perspective Phuong Huynh and Howard J Korman 10. Sonographic anatomy of the prostate Ethan J Halpern 11. What to look for when choosing treatment-planning software for prostate brachytherapy Yan Yu 12. Treatment planning for low and high dose rate brachytherapy Marco Zaider and Eva K Lee 13. Planning an implant: preoperative versus intraoperative planning Ronald D Ennis 14. The Wheeling approach to treatment planning for prostate brachytherapy Wayne M Butler and Gregory S Merrick 15. The Seattle Prostate Institute approach to treatment planning for permanent implants John Sylvester 16. 103Pd brachytherapy: rationale, design, and evaluation Michael J Dattoli 17. Ultrasound-guided 103Pd prostrate brachytherapy Jerrold Sharkey, Zucel Solc, William Huff, Raymond J Behar, Stanley D Chovnick, Ramon Perez, Juan N Otheguy, and Richard I Rabinowitz 18. Optimizing real-time, interactive, ultrasound-guided prostate brachytherapy Glenn A Healey 19. Real-time prostate brachytherapy: transition from intraoperative nomogram planning to virtual planning Nelson N Stone, Jeffrey H Chircus, and Richard G Stock 20. The ProSeed approach: a multi-center study of the results of brachytherapy training Nelson N Stone, Jeffrey H Chircus, Richard G Stock, Joseph Presser, and the ProSeed team 21. Functional image registration in brachytherapy Takashi Mizowaki and Marco Zaider 22. A novel prostate brachytherapy technique: use of preloaded needles without spacers. The Frankford Hospital experience Eric L Gressen, Jinyu Xue, Frank M Waterman, and Jay Handler 23. Radioimmunoguided prostate brachytherapy Rodney J Ellis

104

105 119 135

142 157 164

178

202 251

269

277

293

304 319

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24. Prostate brachytherapy under local anesthesia Sandra Arthurs, and Kent Wallner 25. The impact of hormonal therapy on pubic arch interference Adam P Dicker, Christopher T Chen, JD Liu, Richard K Valicenti, and Frank M Waterman 26. Using the needle manipulation ruler Brian J Moran 27. Using the perineal pressure applicator device Brian J Moran 28. Permanent prostate brachytherapy using sources embedded in absorbable vicryl suture and a preplanned, preloaded needle technique W Robert Lee and Brian J Davis 29. The Utrecht technique in RAPIDStrand™ afterloading Jan J Battermann, Ina M Schulz, Marinus A Moerland, and Marijke van Deursen 30. The PIPER prostate brachytherapy planning system Yan Yu 31. Robot-aided and 3D TRUS-guided intraoperative prostate brachytherapy Aaron Fenster, Lori Gardi, Zhouping Wei, Gang Wan, Chandima Edirisinghe, Donal B Downey 32. Initial experience with the FIRST system in Utrecht Jan J Battermann, Ina Schulz, Marinus A Moerland, and Marijke van Deursen Part IV Treatment planning and techniques for high dose rate prostate brachytherapy 33. High dose rate 192Ir prostate brachytherapy Kas R Badiozamani, Timothy P Mate, and James Gottesman 34. High dose rate prostate brachytherapy. Treatment planning and results from Memorial Sloan-Kettering Cancer Center Yoshiya Yamada 35. High dose rate afterloading 192Ir prostate brachytherapy Alvaro Martinez, Jeffrey Demanes, Razvan Galalae, Howard J Korman, Hagen Bertermann, Carlos Vargas, Jose Gonzalez, and Gary Gustafson 36. High dose rate brachytherapy in patients with high IPPS, large glands, or with prior TURP Glen Gejerman Part V Combination of external beam radiotherapy and prostate brachytherapy

344 351

363 369 374

383

388 395

417

432

433 446

456

481

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503 37. Combining external beam radiotherapy with prostate brachytherapy: issues and rationale Clarissa Febles and Richard K Valicenti 515 38. The role of external beam radiotherapy and permanent prostate brachytherapy in patients with localized prostate cancer Louis Potters 39. Simultaneous irradiation for prostate cancer: disease-free survival rates 527 Frank A Critz Part VI Permanent radioactive seeds: issues and features 40. Radioactive sources for interstitial brachytherapy Manny R Subramanian, Krishnan Suthanthiran and Anatoly Dritschilo 41. RADIOCOIL: a coiled wire brachytherapy source Piran Sioshansi 42. InterSource® brachytherapy seeds John Russell and Jaclyn Collins 43. The customized monofilament: a new approach to permanent prostate brachytherapy Matthew Bouffard Part VII Postimplant: analysis of postimplant dosimetry

536

537 547 564 570

580

44. Salvage of suboptimal prostate seed implantation: re-implantation of an 581 underdosed region of the prostate base Lesley Hughes, Frank M Waterman, and Adam P Dicker 590 45. Can prostate brachytherapy treat potential extraprostatic disease? Ashish Patel, Frank M Waterman, and Adam P Dicker Part VIII Quality of life and posttreatment sequelae after prostate brachytherapy 46. Health-related quality of life following prostate brachytherapy W Robert Lee and Deborah Watkins-Bruner 47. Rectal complications following permanent seed implants Louis Potters 48. Sexual function following permanent prostate brachytherapy Gregory S Merrick and Wayne M Butler

599

600 607 617

49. Prostrate-specific antigen bounce following prostrate brachytherapy Frank A Critz 50. Factors predicting for urinary incontinence following prostate brachytherapy Tracy L McElveen, Frank M Waterman, Hayeon Kim, and Adam P Dicker Index

631 641

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List of Contributors

Sandra Arthurs Department of Radiation Oncology University of Washington VA Hospital 1660 South Colombian Way, Building 33 Seattle WA 98108 USA Kas R Badiozamani Radiation Oncology Virginia Mason Medical Center 1100 Ninth Ave Seattle, WA 98111, USA Jan J Battermann University Medical Centre Utrecht Department of Radiation Oncology Heidelberglaan 100 PO Box 85500 3508 GA Utrecht The Netherlands Raymond J Behar Urology Health Center and Advanced Research Institute 5652 Meadow Lane New Port Richey Florida USA Hagen Bertermann Department of Urology Kiel University Germany David Bostwick Bostwick Laboratories 2807 North Parham Road

Richmond VA 23294 USA Matthew Bouffard Advanced Care Medical 115 Hurley Road, Building 3A Oxford, CT 06478 USA Wayne M Butler Schiffler Cancer Center Wheeling Hospital 1 Medical Park Wheeling WV 26003 USA Christopher T Chen Department of Radiation Oncology Kimmel Cancer Center Jefferson Medical College of Thomas Jefferson University Philadelphia PA 19107 USA Michael E Chen Department of Urology The University of Texas MD Anderson Cancer Center 1515 Holcombe Boulevard Box 26 Houston TX 77030 USA John C Cheville Departments of Laboratory Medicine and Pathology Mayo Clinic and Foundation Rochester MN USA Jeffrey H Chircus Northwest Hospital Center Baltimore Maryland USA Stanley D Chovnick Urology Health Center and Advanced Research Institute 5652 Meadow Lane New Port Richey Florida 34652 USA Jaclyn Collins Ibt, Inc.

Suite 107 6000 Live Oak Parkway Norcross GA 30093, USA Frank A Critz Radiotherapy Clinics of Georgia 2349 Lawrenceville Highway Decatur, GA 30033, USA Michael J Dattoli Dattoli Cancer Center and Brachytherapy Research Institute 2803 Fruitville Road FA 34327, USA Brian J Davis Department of Radiation Oncology Mayo Clinic 200 First St SW Building Dk R Rochester MN 55905, USA Jeffrey Demanes California Endocuritherapy Cancer Center 3012 Summit St, Suite 2675 Oakland, CA, USA Marijke van Deursen University Medical Centre Utrecht Department of Radiation Oncology Heidelberglaan 100 PO Box 85500 3508 GA Utrecht The Netherlands Adam P Dicker Department of Radiation Oncology Kimmel Cancer Center Thomas Jefferson University 111 South 11th Street Philadelphia PA 19107, USA Donal B Downey Imaging Research Laboratories Robarts Research Institute 100 Perth Dr London, ON, N6A 5K8 Canada Anatoly Dritschilo Department of Radiation Medicine Georgetown University Medical Center 3970 Reservation Road NW Washington, DC 20007, USA Chandima Edirisinghe Imaging Research Laboratories

Robarts Research Institute 100 Perth Dr London, ON, N6A 5K8 Canada Rodney J Ellis Stark Radiation Oncology Inc. 2600 Sixth St SW Canton OH 44710, USA William J Ellis Department of Urology School of Medicine University of Washington Box 356510 Seattle WA 98195, USA Ronald D Ennis Department of Radiation Oncology Columbia University College of Physicians & Surgeons 622 West 168th Street New York NY 10032, USA Clarissa Febles Department of Radiation Oncology Thomas Jefferson University Philadelphia PA, USA Aaron Fenster Imaging Research Laboratories Robarts Research Institute 100 Perth Dr London, ON, N6A 5K8, Canada Razvan Galalae Department of Radiation Oncolody Kiel University Arnold-Heller Str 9 24105 Kiel, Germany Lori Gardi Imaging Research Laboratories Robarts Research Institute 100 Perth Dr London, ON, N6A 5K8 Canada Glen Gejerman Department of Radiation Oncology Hackensack University Medical Center 30 Prospect Avenue Hackensack NJ 07601, USA Leonard G Gomella Thomas Jefferson University

1025 Walnut Street Philadelphia PA 19107, USA Jose Gonzalez Department of Urology William Beaumont Hospital 1915 E 14 Mile Road Birmingham, MI 48009 USA James Gottesman Department of Urology Swedish Medical Center Suite 1210 1221 Madison Street Seattle WA 98104 USA Eric L Gressen Department of Radiation Oncology Frankford Hospital Torresdale Division Knights & Red Lion Roads Philadelphia PA 19114 USA Gary Gustafson Department of Radiation Oncology William Beaumont Hospital Royal Oak, MI, USA Ethan J Halpern Department of Radiology Division of Ultrasound Thomas Jefferson University Philadelphia PA 19107 USA Jay Handler Department of Urology Frankford Hospital Torresdale Division Knights & Red Lion Roads Philadelphia PA 19114 USA Glenn A Healey Maine General Cancer Care Maine General Medical Center 149 North Street Waterville ME 04901 USA William J Hilsman DTI International, Inc. 501 Addison Court

Philadelphia, PA 19147–1403, USA William Huff Huff, Ferras and Associates 3530 Fairview Street Safety Harbor Florida 34695 USA Lesely Hughes Department of Radiation Oncology Kimmel Cancer Center Thomas Jefferson University 111 South 11th Street Philadelphia PA 19107 USA Phuong N Huynh Chief Resident Department of Urology William Beaumont Hospital 3535 W.Thirteen Mile Road, Suite 438 Royal Oak MI 48073–6769 USA Kenneth A Iczkowski Department of Pathology Veteran Affairs Medical Center 1601 S.W.Archer Road Gainsville FL 32608, USA Dennis A Johnston Department of Mathematics P.O. Box 97328 Waco, TX 76798, USA Hayeon Kim Kimmel Cancer Center Department of Radiation Oncology Jefferson Medical College of Thomas Jefferson University Philadelphia PA, USA Howard J Korman William Beaumont Hospital Department of Urology 3601 W Thirteen Mile Rd #501 Royal Oak MI 48073 USA Eva K Lee School of Industrial and Systems Engineering Georgia Institute of Technology 765 Ferst Street Atlanta GA 30332

USA W Robert Lee Wake Forest University School of Medicine Department of Radiation Oncology Medical Center Boulevard Winston Salem NC 27157 USA J D Liu Alvaro Martinez Department of Radiation Oncology William Beaumont Hospital USA Timothy Mate Seattle Prostate Institute 1101 Madison Seattle WA 98104 USA Tracy L McElveen Kimmel Cancer Center Department of Radiation Oncology Jefferson Medical College of Thomas Jefferson University Philadelphia PA USA Gregory S Merrick Schiffler Cancer Center One Medical Park Wheeling WV 26003 USA Takashi Mizowaki Department of Therapeutic Radiology & Oncology Graduate School of Medicine Kyoto University 54 Shogoin-Kawahara-cho Sakyo Kyoto 606–8507, Japan Marinus A Moerland University Medical Centre Utrecht Department of Radiation Oncology Heidelberglaan 100 PO Box 85500 3508 GA Utrecht The Netherlands Brian J Moran Chicago Prostate Cancer Center One Oak Hill Ctr Ste 100 Westmont IL 60559, USA

Juan N Otheguy Urology Health Center and Advanced Research Institute 5652 Meadow Lane New Port Richey Florida 34652, USA Ashish Patel Department of Radiation Oncology Thomas Jefferson University 1025 Walnut St Philadelphia, PA 19017 USA Ramon Perez Urology Health Center and Advanced Research Institute 5652 Meadow Lane New Port Richey Florida 34652 USA Michael Perrotti Department of Urology Thomas Jefferson University 1025 Walnut St Philadelphia, PA 19017, USA and Director of Urologic Oncology Saint Peter’s Cancer Care Center 317 South Manning Road Albany, NY 12208, USA Robert O Petersen Department of Pathology Jefferson Medical College 132 South 10th Street Philadelphia PA 19107 USA Thomas M Pisansky Division of Radiation Oncology Mayo Clinic and Foundation Rochester MN USA Thomas J Polascik Division of Urology Duke University Medical Center Durham, NC 22710 USA Louis Potters New York Prostate Institue

South Nassau Community Hospital Oceanside, NY 11572 USA Joseph Presser ProSeed Inc. 8195 Industrial Blvd Covington, GA 30014, USA Richard I Rabinowitz Urology Health Center and Advanced Research Institute 5652 Meadow Lane New Port Richey Florida 34652 USA Ganesh V Raj Department of Urology Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York, NY 10021, USA John Russel IBt Inc. 6000 Live Oak Parkway Suite 107 Norcross GA 30093 USA or IBt sa Zone Industriel C 7180 Seneffe Belgium Ina Schulz University Medical Centre Utrecht Department of Radiation Oncology Heidelberglaan 100 PO Box 85500 3508 GA Utrecht The Netherlands Jerrold Sharkey Urology Health Center and Advanced Research Institute 5652 Meadow Lane New Port Richey FL 34652 USA Piran Sioshansi Formerly President, CEO and Founder RadioMed Corporation One Industrial way

Tyngsboro, MA 01879, USA Zucel Solc West Coast Radiotherapy Center, Inc 6449 38th Ave North, Suite C-3 St Petersburg FL 33710 USA Richard G Stock Department of Radiation Oncology Mount Sinai School New York NY USA Nelson N Stone Department of Urology Mount Sinai Medical Center 1184 Fifth Avenue Box 1236 New York NY 10029 USA Manny R Subramanian Research and Development Best Medical 7643 Fullerton Road Springfield VA 22153 USA Krishnan Suthanthiran Best Medical International 7643 Fullerton Road Springfield, VA 22153, USA and Department of Radiation Medicine Georgetown University School of Medicine Washington DC, USA John Sylvester Seattle Prostate Institute 1101 Madison Seattle WA 98104 USA Patricia Troncoso Professor of Pathology M.D.Anderson Cancer Center Department of Pathology, Box 85 1515 Holcombe Blvd. Houston TX 77030 USA Richard K Valicenti Department of Radiation Oncology Bodine Center for Cancer Treatment

111 South 11th Street Philadelphia PA 19107 USA Carlos Vargas Department of Radiation Oncology William Beaumont Hospital 3601 Thirteen Mile Road Royal Oak MI 48073 USA Kent Wallner Department of Radiation Oncology University of Washington VA Hospital 1660 South Colombian Way, Building 33 Seattle WA 98108 USA Gang Wan Imaging Research Laboratories Robarts Research Institute 100 Perth Dr London, ON, N6A 5K8 Canada Frank M Waterman Department of Radiation Oncology Kimmel Cancer Center Jefferson Medical College of Thomas Jefferson University Philadelphia PA 19107 USA Deborah Watkins-Bruner Population Science & Radiation Oncology Prostate Cancer Risk Assessment Program Fox Chase Cancer Center 7701 Burholme Ave Philadelphia PA 19111 USA Zhouping Wei Imaging Research Laboratories Robarts Research Institute 100 Perth Dr London, ON, N6A 5K8 Canada Torrence M Wilson Department of Urology Mayo Clinic and Foundation Rochester MN USA

Jinyu Xue Department of Radiation Oncology Kimmel Cancer Center Thomas Jefferson University Hospital 111 South 11th St Philadelphia, PA 19107, USA Yoshiya Yamada 1275 York Avenue Box 22 Room SM18 New York NY 10021 USA Yan Yu Department of Radiation Oncology University of Rochester Medical Center 601 Elmwood Avenue, Box 647 Rochester NY 14642 USA Marco Zaider Department of Medical Physics Memorial Sloan Kettering Cancer Center 1275 York Avenue New York NY 10021 USA

Acknowledgments

I would like to thank Dr Kent Wallner for teaching me the art of prostate brachytherapy during my training in radiation oncology at the Memorial Sloan-Kettering Cancer Center. I would like to acknowledge the help and support of Dr Walter J Curran, Jr for the prostate brachytherapy program at Jefferson Medical College of Thomas Jefferson University. Dr Frank Waterman has been a true colleague, collaborator, and friend. His unselfish assistance was instrumental to the success of the prostate brachytherapy program. I would like to thank the staff at Martin Dunitz Publishers, especially Mr Alan Burgess and Ms Maire Harris. My parents Zachary and Roslyn Dicker who supported my numerous interests and aspirations. To Carolyn, Michal, Shimshon, and Yeduda for allowing me to pursue this project. Adam Dicker

This book is dedicated to the memory of Dr Jeffery Berger, a talented physician-scientist and friend.

1 Introduction Adam P Dicker, Gregory S Merrick, Frank M Waterman, Richard K Valicenti and Leonard G Gomella Prostate cancer poses significant biologic, economic and personal burdens on our healthcare system and society in general. Because of an aging population and the implementation of routine PSA screening, the incidence of prostate cancer has increased dramatically with the number of new cases projected to reach approximately 200000 per year within the next decade. Fortunately, since the mid-1990s prostate cancer causespecific mortality has decreased—likely due to earlier diagnosis and better therapeutic options including prostate brachytherapy. Since the mid-1980s, prostate brachytherapy has been utilized increasingly as a potentially curative treatment for patients of all ages with clinically localized prostate cancer. This resurgence of interest in brachytherapy was primarily due to the routine availability of transrectal ultrasonography, the development of a closed transperineal approach and sophisticated treatment planning software. These imaging and planning advances dramatically improved the accuracy of seed placement. In addition, computerized tomography (CT)-based postoperative dosimetry provided the ability to evaluate implant quality and proactively influence outcome. Prostate brachytherapy represents the ultimate three-dimensional conformal therapy, permitting dose escalation far exceeding other radiation modalities with cancericidal treatment margins substantially larger than those obtainable with radical prostatectomy. Although the majority of the brachytherapy literature has demonstrated biochemical results and morbidity profiles that compare favorably with radical prostatectomy and external beam radiation therapy series, it has become increasingly apparent that efficacy and morbidity are highly dependent on implant quality. Sophisticated dosimetric analyses have demonstrated that cure rates, urinary and rectal complications and potency preservation are related to specific source placement patterns and the subsequent dose gradients produced. Our upcoming challenges include ensuring that high-quality brachytherapy is translatable from the subspecialist to the community practitioner, the development of intraoperative planning and dosimetry to maximize optimal dose distributions, improved intraoperative technique to include better delivery systems and imaging capabilities, and the development of evidence-based algorithms for patient selection and supplemental therapies including external beam radiation therapy and androgen deprivation therapy. Although other prostate brachytherapy textbooks are available, to date none have been written exclusively for physician education. In this book, we present an overview of prostate brachytherapy to include rationale, patient selection, technique, dosimetry, morbidity and biochemical outcome. In order to provide a balanced view of the currently available knowledge of prostate brachytherapy outcomes and controversies, physicians

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from multiple prostate cancer disciplines with varying opinions of brachytherapy’s role in the mainstream prostate cancer armentarium have been included. We believe the future of prostate brachytherapy is bright and that time will definitively document long-term biochemical durability along with a favorable quality-of-life profile. Additional developments in the field will continue to require close interaction between genitourinary oncologists (both urologic and radiation) and medical physicists to further refine patient selection, technique and evaluation. This prostate brachytherapy textbook, with its varying opinions, provides intellectual stimulus for fruitful discussion, examines the advantages and shortcomings of brachytherapy, and helps establish guidelines to improve the general practice of prostate brachytherapy.

Part I Understanding the problem: fundamentals of pathology and implications for brachytherapy

2 Effect of radiotherapy on prostate histopathology and assessment of residual cancer Kenneth A Iczkowski and David G Bostwick Introduction There are about thirty articles in the published literature about the pathology of irradiated prostate cancer. This represents 0.3% of all Medline citations on prostate cancer over the past thirty years. Changes after brachytherapy resemble those after external beam therapy, although some findings are peculiar to brachytherapy (see below). The rate of postradiation therapy positive biopsy varies widely, ranging from 19% to 93% based on patient selection factors, the interval from treatment, the number of biopsy samples obtained, the use of other therapies, and, perhaps most importantly, histologic interpretation.1 Factors that determine the likelihood of a positive biopsy include pretreatment clinical stage, cancer grade, posttreatment serum, prostate-specific antigen (PSA), and digital rectal examination. There are three main problems with interpretation: (1) false-negative biopsies resulting from sampling variation; (2) false-positive biopsies due to slow regression of tumor; and (3) biopsies showing residual tumor of indeterminate viability. In this chapter we evaluate the diagnostic criteria for a positive biopsy after radiotherapy and the prognostic significance of these findings. Consideration of the effects of irradiation on the benign prostate serves as a baseline for interpreting changes in cancer. Pathologic findings following radiotherapy The diversity of histopathologic changes in the prostate after radiotherapy have been well-described,2–6 but treated specimens continue to challenge the surgical pathologist. The difficulty of biopsy interpretation after treatment is multifactorial and includes separation of carcinoma from its many mimics, identification of small foci of carcinoma, and separation of treatment effects in normal tissue from recurrent or persistent carcinoma.2,3,7–13 As more patients choose radiotherapy, particularly brachytherapy, and as these patients are observed for longer intervals, pathologists bear an increasing burden to discriminate irradiated benign acini from irradiated adenocarcinoma.1,14,15

Effect of radiotherapy on prostate

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Benign tissue, including hyperplasia The degree of histologic change caused by radiation in benign or hyperplastic acini varies with the dose and duration of irradiation and interval from therapy onset.11,16 Changes include acinar atrophy, distortion with loss of cytoplasm, and decreased ratio of acini to stroma (Figure 2.1). Nuclear changes include nuclear enlargement (86% of cases) and prominent nucleoli (50%).3 Acinar secretory cells are more sensitive to irradiation necrosis than basal cells; the basal cell layer is the proliferative compartment in benign acini. Consequently, atypical basal cell hyperplasia is seen in 57% of cases (Figure 2.2),3 defined as basal cell proliferation with prominent nucleoli in >10% of cells. Stroma may be fibrotic, with paucicellular scarring, and vascular changes include intimal thickening and medial fibrosis (Table 2.1).2 Pathologists must be aware of these changes because they preclude the usual reliance on nuclear and nucleolar size to help identify prostate cancer. More atypia of benign glands was noted after brachytherapy than after external beam therapy in a comparative study of 44 cases, and our experience verifies this. This atypia seems to persist longer after brachytherapy as well. With external beam therapy, there was less atypia in men biopsied 48 months after treatment compared to those biopsied at a shorter interval after treatment. (In some cases, however, abnormal findings persisted to a variable degree for 10 years.) In contrast, no decrease in atypia over time was noted in men treated with brachytherapy.17

Figure 2.1 Compared to untreated glands (left), benign irradiated prostate (right) shows glandular shrinkage, with cells showing loss of cytoplasm.

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Figure 2.2 Atypical basal cell hyperplasia in irradiated glands (right). Nuclei are larger than those from the same patient pretreatment (left). This cytologic atypia can also occur in secretory cells and can exceed the degree of atypia commonly used as a criterion for cancer. Table 2.1 Histopathologic findings in benign prostatic tissue in postirradiation needle biopsies at the time of PSA (biochemical) failure Hispathologic Endings Inflammation Atrophy Postatrophic hyperplasia Acinar distortion Decreased acinsr/stromal ratio Basal cell hyperplasia Atypical basal cell hyperplasia Hyperplastic (proloferative) change Squamous metaplasia Eosinophilic metaplasia Stromal changes Stromal fibrosis Stromal edema Stromal calcification

Percentage of cases 39 79 18 54 86 68 57 11 0 21 93 21 21

Effect of radiotherapy on prostate

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Hemosiderin deposition Atypical fibroblasts Necrosis Granulation tissue formation Myointimal proliferation Cytologic changes Nuclear pyknosis Nuclear enlargement Prominent nucleoli Bizarre nuclei Cytoplasmic vacuolization Intraluminal contents Crystalloids Mucin Eosinophilic granular secretions Corpora amylacea

0 25 0 0 11 75 86 50 54 29 0 4 39 32

High grade prostatic intraepithelial neoplasia After radiotherapy, prostatic intraepithelial neoplasia (PIN) retains characteristic features of untreated PIN and is readily recognized in biopsy and prostatectomy specimens (Figure 2.3). The salient microscopic features include nuclear crowding, nuclear overlapping and stratification, nuclear hyperchromasia, and prominent nucleoli. The basal cell layer is present but often fragmented. The most common patterns of PIN after treatment, the tufting and micropapillary patterns, are similar to those reported in untreated prostates.18 The only radio therapy-related observations were occasional cytoplasmic vacuolation or sloughing of epithelium into the lumen.16,19 The prevalence of high grade PIN accompanying cancer is 82–100% of non-irradiated radical prostatectomy specimens.18,20 It was noted in only 62% of cases after radiotherapy,19 a decreased prevalence, similar to that seen after

Figure 2.3 Cells of irradiated high grade prostate intraepithelial neoplasia (PIN) retain nuclear stratification, but

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have nuclear enlargement and hyperchromasia. androgen ablation (50%).20 Volume of PIN without radiotherapy,19 averaged 1.32 cm3 compared to 0.12 cm3 after radiotherapy.18 One study paradoxically noted a higher prevalence (70%) of PIN after radiotherapy than expected,21 but these investigators failed to employ accepted diagnostic criteria for PIN, so their results are not comparable with those of the authors,19 or others. High grade PIN was reported in 9% of posttherapy biopsies,22 but sampling limitation underestimates the prevalence. It is possible that radiation alters the phenotype of PIN such that recognition is obscured. No significant correlation was seen between PIN in postirradiation salvage prostatectomy specimens and cancerspecific survival or other clinicopathologic data.19 For isolated high grade PIN in needle biopsies, the general recommendation has been to perform repeat biopsies in order to rule out cancer. Use of 12-core sampling rather than sextant sampling, however, diminishes the positive predictive value of isolated high grade PIN for cancer, possibly obviating the need for repeat biopsy unless clinical suspicion is high.23 Adenocarcinoma Just as most prostate cancer grows slowly, it is slow to regress, with histologic changes evolving at least 12 months after the completion of irradiation therapy. Needle biopsy is of limited value prior to about 12–18 months owing to ongoing tumor cell death (Table 2.2).2 Slow tumor death is attributed to the fact that radiotherapy causes necrosis only after a prostate cell has gone through cell division,24 and to long tumor doubling time. After this period, biopsy is a good method for assessing local tumor control,

Table 2.2 Histopathologic findings in prostatic adenocarcinoma in postirradiation biopsies Hispathologic findings Gleason score <7 7 >7 Percentage of cancer involvement ≤10 11–40 41–80 81–100 Number of cancer foci 1 2–4 >5 Combined score of radiation effect* 0–2 (minimal)

Percentage of cases 17 48 35 31 28 35 6 36 50 14 52

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3–4 (moderate) 38 5–6 (severe) 10 Infiltrative growth 100 Perineural invasion 31 Atrophic change 10 Nuclear pyknosis 72 Nuclear enlargement 93 Prominent nucleoli 79 Percentage of cytoplasmic vacuolization <10 45 10–50 45 >50 10 Inflammation 0 Stromal desmoplasia 76 Necrosis 0 Intraluminal contents Crystalloids 3 Mucin 21 Eosimophilic secretions 24 Corpora amylacea 0 Concomitant high-grade PIN 7 * Radiation effect was quantified using the scoring system described by Crook and co-workers.22 (Crook JM, Bahadur YA, Robertson SJ, Perry GA, Esche BA, Evaluation of radiation effect, tumor differentiation, and prostate specific antigen in sequential prostate biopsies after external beam radiotherapy for patients with prostate carcinoma. Cancer 1997; 79:81–89,)

but complete histologic resolution of cancer may take 2–3 years.22 Sampling variation is minimized by obtaining multiple specimens.2,19,22,25–30 The therapeutic success of radiotherapy for prostate cancer requires complete or nearcomplete eradication of tumor. Conventional external beam radiotherapy misses 20% to 35% of the target volume when compared with three-dimensional conformal planning with dose escala tion.31 Brachytherapy techniques will probably improve local cancer control and prolong survival.32 Evaluation of local tumor control is assisted by digital rectal examination and transrectal ultrasound. Posttherapy serum PSA correlates with posttherapy biopsy results, including degree of radiation effect.11 Crook et al diagnosed postradiotherapy biopsies as indeterminate in 33% of first biopsies (median 13 months), 24% of second biopsies (28 months), 18% of third biopsies (36 months), and 7% of fourth biopsies (44 months).22 These figures are higher than the 1.5–9.0% of biopsies with atypical indeterminate findings in unselected non-irradiated series,7,12 highlighting the increased diagnostic challenge after radiotherapy. The identification of cancer in needle biopsy specimens after radiotherapy has a significant impact on patient management; positive needle biopsies portend a worse prognosis.1,15,33–38 The histologic diagnosis of cancer without radiation effect relies on both architectural and cytoplasmic atypia. In simplest terms, radiotherapy causes cytologic atypia of benign glands, forcing the pathologist to discriminate cancer almost totally on architectural findings. Changes vary widely among patients.11 Radiotherapy causes shrinkage of

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cancer glands and loss of cytoplasm (Figure 2.4). Features most helpful for the diagnosis of cancer after radiotherapy are mostly architectural: infiltrative growth (Figure 2.5), perineural invasion, intraluminal crystalloids, blue mucin secretions, the absence of corpora amylacea, and the presence of concomitant high grade PIN (Table 2.2). Paneth cell-like change can be seen in 32% of biopsies.11 Occasionally, cytologic findings such as double nucleoli in a secretory cell, can be helpful (Figure 2.6). Cancer grade and DNA ploidy after radiotherapy Postirradiation Gleason grade and DNA ploidy are independent prognostic factors in patients with prostate cancer who fail radiotherapy.26 There is a slight shift after therapy toward nondiploid cancer, higher Gleason grade, and high tumor stage, indicating increasing biologic aggressiveness and cancer dedifferentiation after radiation.26,30,35,39 Particularly in grade 4 cancer, radiotherapy may cause disappearance of glandular lumina, resulting in grade 5 morphology (Figure 2.7). The authors found a good correlation of Gleason grade between postirradiation salvage prostatectomy and treated biopsy specimens.26,40 Needle biopsies underestimated prostatectomy Gleason grade in 35% of cases and overestimated grade in 14% of cases, similar to the findings in studies of patients who were not treated by radiotherapy.38,40–45 By comparison, in 316 patients who underwent radical prostatectomy without prior androgen deprivation or radiotherapy, Gleason grade in needle biopsies under

Figure 2.4 Irradiated cancer glands (right) retain an angulated, infiltrative pattern and luminal secretions, as seen pretreatment (left). The degree of cytologic atypia is paradoxically less than in some benign irradiated glands.

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Figure 2.5 The infiltrative pattern is characteristic of cancer in this irradiated gland. Cytoplasm is moderate and clear to finely granular in this case.

Figure 2.6 In this irradiated cancer, the finding of double nucleoli (upper left) together with an infiltrative pattern helps establish the diagnosis of residual cancer. estimated prostatectomy grade in 40% of cases and overestimated grade in 25% of cases.40 Siders and Lee evaluated matched preradiation and postradiation specimens from 58 patients and found a 24% increase in the number of poorly differentiated cancers (Gleason score 8–10) and a shift toward aneuploid cancer in 31% of pretreatment diploid cancers.5 Similarly, others found an increase in tumor grade following irradiation,16–30 suggesting that the higher grade cancer frequently found after treatment was related to a process of clonal evolution that resulted in cancer progression and tumor dedifferentiation. Some investigators recommend grading of cancer in specimens after radiotherapy, recognizing that the biologic significance of grade may be different from that in untreated cancer.26 The authors believe that Gleason grade in postirradiation

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needle biopsy specimens provides useful predictive information and recommend its use in this setting,3 despite suggestions to the contrary.46

Figure 2.7 High grade prostate cancer pretreatment (left) loses any remnant of glandular lumina after irradiation (right), consistent with evolution of a higher grade tumor clone. Clinical significance of postradiation biopsy results Digital rectal examination for the detection of radiation failure is imprecise unless there is gross cancer recurrence.47 Consequently, some clinicians favor postirradiation biopsy for the preclinical detection of recurrence, thereby allowing earlier intervention with salvage therapy; others consider routine postirradiation biopsy justifiable only in a research setting. Studies suggest that if prostatic carcinoma is not histologically ablated by radiotherapy after 12 months, it is probably biologically active.2,28,40 The rate of positive findings on biopsy varies from 20% to 93% following external beam radiotherapy,22,27,29,48–51 and from 5% to 55% following brachytherapy.46 This wide variation is attributable to selection of patients with broad ranges of pretreatment serum PSA, stage and grade of tumor, number of biopsy cores taken (more in contemporary studies), and radiation dosage. Interobserver variability may be an extra source of variation, as discussed below. A positive biopsy result within 12 to 18 months of external beam radiotherapy may contain cancer in regression, and 30% of patients show eventual clearance of tumor at a mean time of 30 months after radiotherapy.52 Kuban and Schellhammer have shown that a positive biopsy result after 12–18 months predicted clinical recurrence in approximately

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80% of patients; remarkably, approximately 20% had no evidence of cancer at 10 years’ follow-up.1 However, one of us (DGB) has reviewed the histopathologic findings from that study and noted an original diagnostic error rate of about 10%, calling the results into question. Crook et al extended this interval to 24 months, eliminating biopsies prior to that from their study because delayed tumor progression was seen in 30% of patients.22 At 24–36 months, the biopsy result was one of two independent predictors of outcome, along with PSA nadir. Perineural invasion of cancer, however, was not an independent prognosticator in patients undergoing brachytherapy.53 Conversely, 30% of patients with local or distant failure had negative findings on biopsy.48 An identical 30% positive rebiopsy rate was found in men suspected of having cancer but whose initial TRUSguided biopsy was negative.54 This underscores the role of sampling variation: the falsepositive rate of biopsy is 23% based on repeat biopsies in untreated men with prior positive biopsy.55 Interobserver reproducibility in the diagnosis of cancer in postradiation biopsies varies moderately. Miller et al found a ‘false-positive’ rate of 15% (4/26 specimens) and a ‘false-negative’ rate of 3% (2/70 specimens).56 Jones et al classified 107 cases signed out by non-subspecialty pathologists and found 1 false-positive and 9 false-negative cases.57 However, 5 of 6 cases classified as suspicious by nonsubspecialty pathologists were negative according to at least two of a panel of three specialty urologic pathologists, again showing some tendency toward overdiagnosis. Urologic pathologists disagreed with each other in 3% (3/107) cases; two of three agreed with 23% of cases and all agreed with 74% of cases. Mean Kappa value was 0.66, indicating only moderate reproducibility. Radiotherapy combined with androgen ablation Neoadjuvant androgen deprivation therapy (ADT) appears to have an additive or synergistic effect with external beam radiotherapy. In one study, 31 patients were treated with ADT before radiotherapy, and only 3 (10%) had cancer on posttherapy biopsy compared to 44 of 106 men (41%) treated with radiotherapy alone (p= 0.004).16 Androgen ablation probably also potentiates brachytherapy. Scoring radiation effect in the benign prostate To determine whether the severity and extent of radiation changes in the prostate are of prognostic value, Crook and colleagues graded nuclear and cytoplasmic changes in biopsy specimens following external beam radiotherapy.22 Cytoplasmic and nuclear changes were each graded on a 0–3 scale, and added together for a score of 0–6. They found that grading of radiation effect in the noncancerous prostate correlated with serum PSA nadir, immunoreactivity for proliferating cell nuclear antigen (PCNA), and local cancer recurrence.22 Patients did poorly if there was little or no evidence of radiation change in the needle biopsy, suggesting incomplete coverage of the prostate by the therapeutic field or radiation-resistant foci as the source of local failure. Goldstein and co-workers consider grading nuclear and cytoplasmic changes useful in a threeyear

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prospective study of patients receiving brachytherapy.46 They also noted that the presence of adenocarcinoma on posttreatment biopsy was an important predictor of failure. Salvage radical prostatectomy specimens, conversely, demonstrated great discrepancy with biopsies in the scoring of radiation effect after external beam radiotherapy.26 In needle biopsy specimens, 48% had moderate or severe radiation effect compared with only 6% of radical prostatectomy specimens. These findings suggest that scoring of radiation effect in needle biopsies may also overestimate the effectiveness of brachytherapy and could be misleading. This discrepancy could also explain why cytologic atypia in benign glands was observed in 98% of posttatectomy specimens after radiotherapy for urothelial irradiation biopsies,11 and 77% of prostates in cystoproscarcinoma.58 Quantification of radiation effect is of questionable relevance in patients who fail to be cured by radiotherapy. Differential diagnosis of prostate cancer after radiotherapy In the authors’ experience, atypical basal cell hyperplasia most frequently mimics treated cancer following irradiation. Atypical basal cell hyperplasia is defined as basal cell proliferation with more than 10% of cells exhibiting prominent nucleoli. These cells were present in 57% of cases in the authors’ recent study of salvage prostatectomies and seemed to represent a nonspecific host response to radiation injury. Immunohistochemical and other findings after radiotherapy Prostatic acid phosphatase, prostate-specific antigen, and keratin 34βE12 No definite method exists for the assessment of tumor viability after irradiation. Presence of secretory cells can be documented by reactivity for prostatic acid phosphatase (PAP), leading one group of investigators to suggest that tumor cells capable of protein production probably retain the potential for cell division and consequent metastatic spread.59 Expression of prostate-specific antigen (PSA) (Figure 2.8) and pan-cytokeratin often persists after therapy. In a recent small study, residual carcinoma was present in 6 of 14 cases after brachytherapy. PSA reactivity was noted to be decreased in glands that show radiation effect.60 Basal cell cytokeratin (34βE12) expression also persists after radiotherapy in benign and atrophic glands, helping to visualize treated adenocarcinoma (Figure 2.9). Some authors report an indeterminate rate of 33% on first posttherapy biopsy, decreasing to 7% on fourth biopsy.53 However, in our experience, indeterminate findings occur in fewer than 10% of cases with the use of this immunostain on serial sections.25 Particularly with use of the steam-EDTA optimized method,61 basal cell cytokeratin helps exclude the cancer mimics mentioned above: atypical basal cell hyperplasia, atypical adenomatous hyperplasia, sclerosing adenosis, and postatrophic hyperplasia.

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Proliferation markers MIB-1 (Ki-67) immunoreactivity in pretreatment needle biopsies independently predicts postirradiation recurrence,62 and helps determine optimal radiation dose. In

Figure 2.8 No immunostain can prove viability of residual cancer, but when viability is in question (left), prostatespecific antigen (PSA) indicates that secretory cells are present, suggesting viability (right).

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Figure 2.9 Absence of immunoreactivity for basal cell cytokeratin 34βE12 can confirm that small atypical glands are cancer (left, 60×; right, 160×). postradiotherapy prostate biopsy specimens, retention of proliferating cell nuclear antigen (PCNA),52,63 or Mib-1 (Ki-67)26,52 immunoreactivity correlates with local cancer recurrence (p=0.004). After brachytherapy, residual carcinoma that shows radiation injury also has a minimal (<5%) Ki-67 reactivity.60 Furthermore, prostate cancer in salvage prostatectomies is proliferative in 96% of cases, showing increased Mib-1 immunostaining.26 The mean Ki-67 labeling index in recurrent prostate cancer after radiation is increased (mean: 7.0%) when compared with the index in prostatectomy series without prior radiotherapy (mean: 2.7%) (unpublished data, DG Bostwick, MD). Oncogenes and tumor suppressor genes Prostate cancer after radiotherapy has increased p53 nuclear accumulation, although some other results suggest no significant difference.64 Prendergast and co-workers studied 18 patients with locally recurrent prostate cancer after radiotherapy and found that 72% had p53 nuclear immunoreactivity.65 Of five patients for whom the results of preradiation biopsies were available, all had p53 immunoreactivity. The immunohistochemical findings correlated with single strand conformational polymorphism and DNA sequencing analysis.65 These findings suggest that p53 alterations are present before radiotherapy and may serve as a pretherapy factor predictive of cancer recurrence. Glutathione S-transferase pi (GST-π) is a detoxifying enzyme that inactivates reactive oxygen free radical species by conjugation with glutathione. Most prostate cancers do not

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express GST-π, and loss of GST-π expression is considered as a phenotype associated with malignant transformation.66 p21WAF1 and p27Kip1 are members of the KIP family of cell cycle proteins and inhibit several cyclin-dependent kinase complexes. Functional loss of the cycle-dependent inhibitors has been implicated in carcinogenesis and cancer progression. Loss of p27Kip1 expression in prostatic and nonprostatic malignancies is p21WAF1 function has been implicated in the failure of associated with a more aggressive phenotype.67 Loss of irradiation response, and p21 has been shown to be an independent prognostic factor in prostate carcinoma. The authors detected p21WAF1 nuclear immunoreactivity in cancer cells in 39 (75%) of 52 patients (median nuclear immunoreactivity, 5%; range: 0–80%); p27Kip1 nuclear immunoreactivity was detected in all 52 patients (median nuclear immunoreactivity, 50%; range: 5–90%). Five-year distant metastasis-free and cancer-specific survival rates were 71% and 82% for patients with low expression of p21 (≤5%), compared with 94% and 100% for patients with high expression of p21 (>5%) (p=0.02 and 0.01, respec tively).67 Five-year distant metastasisfree survival and cancer-specific survival rates were 91% and 82% for patients with low expression of p27 (<50%), compared with 88% and 96% for patients with high expression of p27 (≥50%) (p=0.06 and 0.01, respectively). Antiapoptosis genes Early growth response-1 (Egr-1) gene is an early response gene, in the family of c-jun and c-fos. Egr-1 activation is required for the cellular response to radiation injury. The authors noted overexpression of Egr-1 in prostate cancer, which increased with Gleason grade.68 Ahmed et al later found that Egr-1 immunohistochemical expression correlated with treatment failure. The overexpressed Egr-1 is in a mutant form which does not transactivate the usual target genes TP53, pRB, and Bax.69 Egr-1 may come to be used as part of a panel with a proliferation marker to predict prognosis. Microvessel density In a study by Hall and co-workers,70 microvessel density was higher in cancer specimens from patients who failed radiotherapy than in patients who did not fail; however, the results were not analysed independently of cancer grade. Nuclear morphometry The degree to which nuclei deviate from circularity predicts the prognosis of patients with stage 2 prostate cancer. This observation was applied to biopsies from men treated with external beam irradiation. A prognostic factor score incorporating two parameters, suboptimal circle fit and feretdiameter ratio, predicted cancer-free survival (p=0.0014).71 Summary Substantial and characteristic changes occur in the microscopic appearance and immunophenotype of the hyperplastic prostate and adenocarcinoma following androgen

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deprivation therapy and radiotherapy. These changes are rarely seen in untreated cancer, and in the authors’ opinion, the combinations of features following therapy are sufficiently distinctive that pathologists can usually recognize them. Pathologists must be aware of these distinct changes because of the reliance placed on nuclear and nucleolar size in the identification of prostate cancer, particularly in small specimens and lymph node metastases. References 1. Kuban DA, Schellhammer PF. Prognostic significance of post-irradiation prostate biopsies. Oncology 1993; 7:29–38. 2. Bostwick DG, Egbert BM, Fajardo LF. Radiation injury of the normal and neoplastic prostate. Am J Surg Pathol 1982; 6:541–551. 3. Cheng L, Cheville JC, Bostwick DG. Diagnosis of prostate cancer in needle biopsies after radiation therapy. Am J Surg Pathol 1999; 23:1173–1183. 4. Schellhammer PF, Ladaga LE, El-Mahdi A. Histologic characteristics of prostate biopsies after 125 iodine implantation. J Urol 1980; 123:700–705. 5. Siders DB, Lee R Histologic changes of irradiated prostatic carcinoma diagnosed by transrectal ultrasound. Hum Pathol 1992; 23:344–351. 6. Siders DB, Lee F, Mayman DM. Diagnosis of prostate cancer altered by ionizing radiation with and without neoadjuvant antiandrogen hormonal ablation. In: Foster CS, Bostwick DG, eds. Pathology of the prostate. Philadelphia, WB Saunders, 1998:315–326. 7. Iczkowski KA, Bostwick DG. Prostate biopsy interpretation: current concepts, 1999. Urol Clin North America 1999; 26:435–452. 8. Iczkowski KA, MacLennan GT, Bostwick DG. Atypical small acinar proliferation suspicious for malignancy in prostate needle biopsies: Clinical significance in 33 cases. Am J Surg Pathol 1997; 21:1489–1495. 9. Eble JN. Variants of prostatic hyperplasia that resemble carcinoma. J Urol Pathol 1998; 8:3–20. 10. Epstein JI. Diagnostic criteria of limited adenocarcinoma of the prostate needle biopsy. Hum Pathol 1993; 26:223–229. 11. Gaudin PB. Histopathologic effects of radiation and hormonal therapies on benign and malignant prostate tissues. J Urol Pathol 1998; 8:55–67. 12. Iczkowski KA, Bassler TJ, Schwob VS, et al. The diagnosis of “suspicious for malignancy” in prostate biopsies. Urology 1998; 51:749–758. 13. Grignon DJ, Sakr WA. Histologic effects of radiation therapy and total androgen blockade on prostate cancer. Cancer 1995; 75:1837–1841. 14. Mettlin CJ, Murphy GP, Cunningham MP, et al. The national cancer data base report on race, age, and region variations in prostate cancer treatment. Cancer 1997; 80:1261–1266. 15. Zietman AL, Shipley WU, Willett CG. Residual disease after radical surgery or radiation therapy for prostate cancer: Clinical significance and therapeutic implications. Cancer 1993; 71:959–969. 16. Gaudin PB, Zelefsky MJ, Leibel SA, et al. Histopathologic effects of three-dimensional conformal external beam radiation therapy on benign and malignant prostate tissues. Am J Surg Pathol 1999; 23:1021–1031. 17. Magi-Galluzzi C, Sanderson H, Epstein JI. Atypia in non-neoplastic prostate glands after radiotherapy for prostate cancer. Mod Pathol 2002; 15:171A. 18. Qian J, Wollan P, Bostwick DG. The extent and multicentricity of high-grade prostatic intraepithelial neoplasia in clinically localized prostatic adenocarcinoma. Hum Pathol 1997; 28:143–148.

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19. Cheng L, Cheville JC, Pisansky TM, et al. Prevalence and distribution of prostatic intraepithelial neoplasia in salvage radical prostatectomy specimens after radiation therapy. Am J Surg Pathol 1999; 23:803–808. 20. Ferguson J, Zincke H, Ellison E, et al. Decrease of prostatic intraepithelial neoplasia following androgen deprivation therapy in patients with stage T3 carcinoma treated by radical prostatectomy. Urology 1994; 44:91–95. 21. Arakawa A, Song S, Scardino PT, et al. High grade prostatic intraepithelial neoplasia in prostates removed following irradiation failure in the treatment of prostatic adenocarcinoma. Pathol Res Pract 1995; 191:868–872. 22. Crook JM, Bahadur YA, Robertson SJ, et al. Evaluation of radiation effect, tumor differentiation, and prostate specific antigen staining in sequential prostate biopsies after external beam radiotherapy for patients with prostate carcinoma. Cancer 1997; 79:81–89. 23. Lefkowitz GK, Sidhu GS, Torre P, et al. Is repeat prostate biopsy for high-grade prostatic intraepithelial neoplasia necessary after routine 12-core sampling? Urology 2001; 58:999–1003. 24. Mostofi FK, Sesterhenn IA, Davis CJ. A pathologist’s view of prostatic carcinoma. Cancer 1993; 71:906–932. 25. Brawer MK, Nagle RB, Pitts W, et al. Keratin immunoreactivity as an aid to the diagnosis of persistent adenocarcinoma in irradiated human prostates. Cancer 1989; 63:454–460. 26. Cheng L, Sebo TJ, Bergstralh EJ, et al. Predictors of survival in prostate cancer patients treated with salvage radical prostatectomy after irradiation failure. Cancer 1998; 83:2164–2171. 27. Dugan TC, Shipley WU, Young RH, et al. Biopsy after external beam radiation therapy for adenocarcinoma of the prostate: correlation with original histologic grade and current prostate specific antigen levels. J Urol 1991; 146:1313–1316. 28. Helpap B, Koch V. Histological and immunohistochemical findings of prostatic carcinoma after external or interstitial radiotherapy. J Cancer Res Clin Oncol 1991; 117:608–614. 29. Kabalin JN, Hodge KK, McNeal JE, et al. Identification of residual cancer in the prostate following radiation therapy: role of transrectal ultrasound guided biopsy and prostate specific antigen. J Urol 1989; 142:326–331. 30. Wheeler JA, Zagars GK, Ayala AG. Dedifferentiation of locally recurrent prostate cancer after radiation therapy: Evidence of tumor progression. Cancer 1993; 71:3783–3787. 31. Haken RKT, Perez-Tamayo C, Tesser RJ, et al. Boost treatment of the prostate using shaped, fixed fields. Int J Radiat Oncol Biol Phys 1989; 16:193–200. 32. Hanks GE, Corn BW, Lee WR, et al. External beam irradiation of prostate cancer: Conformal treatment techniques and outcome for the 1990s. Cancer 1995; 75:1972–1977. 33. Kaplan ID, Prestidge BR, Bagshaw MA, et al. The importance of local control in the management of prostate cancer. J Urol 1992; 147:917–921. 34. Kuban DA, Schellhammer PF. Prognostic significance of post-irradiation prostate biopsies. Oncology 1993; 7:29–38. 35. Pontes JE, Montie J, Klein E, et al. Salvage surgery for radiation failure in prostate cancer. Cancer 1993; 71:976–980. 36. Prestidge BR, Kaplan I, Cox RS, et al. Predictors of survival after positive post-irradiation prostate biopsy. Int J Radiat Oncol Biol Phys 1993; 28:17–22. 37. Prestidge BR, Kaplan I, Cox RS, et al. The clinical significance of a positive post-irradiation prostate biopsy without metastasis. Int J Radiat Oncol Biol Phys 1992; 24:403–408. 38. Zagars GK, von Eschenbach AC, Ayala AG, et al. The influence of local control on metastatic dissemination of prostate cancer treated by external beam megavoltage radiation therapy. Cancer 1991;68: 2370–2377. 39. Ahlering TE, Lieskovsky G, Skinner DG. Salvage surgery plus androgen deprivation for radioresistant prostatic adenocarcinoma. J Urol 1992; 147:900–902. 40. Bostwick DG. Gleason grading of prostatic needle biopsies: Correlation with grade in 316 matched prostatectomies. Am J Surg Pathol 1994; 18:796–803. 41. Bostwick DG. Grading prostate cancer. Am J Clin Pathol 1994; 102 (4 suppl 1):538–556.

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42. Mills SE, Fowler JE. Gleason histologic grading of prostatic carcinoma: Correlations between biopsy and prostatectomy specimens. Cancer 1996; 57:346–349. 43. Spires SE, Cibull ML, Wood DP, et al. Gleason histologic grading in prostatic carcinoma: Correlation of 18-gauge core biopsy with prostatectomy. Arch Pathol Lab Med 1994; 118:705– 708. 44. Steinberg DM, Sauvageot J, Piantadosi S, et al. Correlation of prostate needle biopsy and radical prostatectomy Gleason grade in academic and community settings. Am J Surg Pathol 1997; 21:566–576. 45. Thickman D, Speers WC, Philpott PJ, et al. Effect of the number of 1core biopsies of the prostate on predicting Gleason score of prostate cancer. J Urol 1996; 156:110–113. 46. Goldstein NS, Martinez A, Vicini F, Stromberg J. The histology of radiation therapy effect on prostate adenocarcinoma as assessed by needle biopsy after brachytherapy boost: correlation with biochemical failure. Am J Clin Pathol 1998; 110:765–775. 47. Letran JL, Brawer MK. Management of radiation failure for localized prostate cancer. Prostate Cancer Prostatic Dis 1998; 1:119–127. 48. Freiha FS, Bagshaw MA. Carcinoma of the prostate: results of postirradiation biopsy. Prostate 1984; 5:19–24. 49. Forman JD, Oppenheim T, Liu H, et al. Frequency of residual neoplasm in the prostate following three-dimensional conformal radiotherapy. Prostate 1993; 23:235–243. 50. Herr HW, Whitmore WF. Significance of prostatic biopsies after radiation therapy for carcinoma of the prostate. Prostate 1982; 3:339–350. 51. Scardino PT, Frankel JM, Wheeler TM, et al. The prognostic significance of post-irradiation biopsy results in patients with prostatic cancer. J Urol 1986; 135:510–516. 52. Crook J, Malone S, Perry G, et al. Postradiotherapy prostate biopsies: what do they really mean? Results for 498 patients. Int J Radiat Oncol Biol Phys 2000; 48:355–367. 53. Merrick GS, Butler WM, Galbreath RW, et al. Perineural invasion is not predictive of biochemical outcome following prostate brachytherapy. Cancer J 2001; 7:404–412. 54. Fleshner NE, O’Sullivan M, Fair WR. Prevalence and predictors of a positive repeat transrectal ultrasound-guided needle biopsy of the prostate. J Urol 1997; 158:505–508. 55. Rabbani F, Stroumbakis N, Kava BR, et al. Incidence and clinical significance of false-negative sextant prostate biopsies. J Urol 1998; 159:1247–1250. 56. Miller EB, Ladaga LE, El-Mahdi AM, Schellhammer PF. Reevaluation of prostate biopsy after definitive radiation therapy. Urology 1993; 41:311–316. 57. Jones EC, Srigley J, Daya D, et al. The assessment of post-radiation prostatic needle biopsies for residual adenocarcinoma: a study of interobserver agreement. Mod Pathol 2002; 15:166A. 58. Sheaff MT, Baithun SI. Effects of radiation on the normal prostate gland. Histopathology 1997; 30:341–348. 59. Mahan DE, Bruce AW, Manley PN, et al. Immunohistochemical evaluation of prostatic carcinoma before and after radiotherapy. J Urol 1980; 124:488–492. 60. Sprouse JT, Smathers SL, Wallner K, True LD. Histologic and immunophenotypic features after prostate brachytherapy. Am J Clin Pathol 1999; 112:548. 61. Iczkowski KA, Cheng L, Crawford BG, Bostwick DG. Steam heat with an EDTA buffer and protease digestion optimizes immunohistochemical expression of basal cell-specific antikeratin 34βE12 to discriminate cancer in prostatic epithelium. Mod Pathol 1999; 12:1–4. 62. Scalzo DA, Kallakury BVS, Gaddipati RV, et al. Cell proliferation rate by MIB-1 immunohistochemistry predicts postradiation recurrence in prostatic adenocarciomas. Am J Clin Pathol 1998; 109:163–168. 63. Crook J, Robertson S, Esche B. Proliferative cell nuclear antigen in postradiotherapy prostate biopsies. Int J Radiat Oncol Biol Phys 1994; 30:303–308. 64. Rakozy C, Grignon DJ, Sarkar FH, et al. Expression of bcl-2, p53, and p21 in benign and malignant prostatic tissue before and after radiation therapy. Mod Pathol 1998; 11:892–899.

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65. Prendergast NJ, Atkins MR, Schatte EC, et al. p53 immunohistochemical and genetic alterations are associated at high incidence with post-irradiation locally persistent prostate carcinoma. J Urol 1996; 155:1685–1692. 66. Brooks JD, Weinstein M, Lin X, et al. CG island methlyation changes near the GSTP1 gene in prostatic intraepithelial neoplasia. Cancer Epidemiol Biomarkers Prev 1998; 7:531–536. 67. Cheng L, Lloyd RV, Weaver AL, et al. The cell cycle inhibitors p21WAF1 and p27 KIP1 are associated with survival in patients treated by salvage prostatectomy after radiation therapy. Clin Cancer Res 2000; 6:1896–1899. 68. Eid MA, Kumar MV, Iczkowski KA, et al. Expression of early growth response-1 genes in human prostate cancer. Cancer Res 1998; 58:2461–2468. 69. Ahmed MM, Chendil D, Lele S, et al. Early growth response-1 gene: potential radiation response gene marker in prostate cancer. Am J Clin Oncol 2001; 24:500–505. 70. Hall MC, Troncoso P, Pollack A, et al. Significance of tumor angiogenesis in clinically localized prostate carcinoma treated with external beam radiotherapy. Urology 1994; 44:869– 875. 71. Hurwitz MD, DeWeese TL, Zinreich ES, et al. Nuclear morphometry predicts disease-free interval for clinically localized adenocarcinoma of the prostate treated with definitive radiation therapy. Int J Cancer (Pred Oncol) 1999; 84:594–597.

3 What should you ask your pathologist when contemplating minimally invasive therapy? Robert O Petersen Introduction Central to the choice of definitive therapy for prostate cancer whether surgery, radiation, hormonal, or watchful waiting, is the prediction of tumor stage. Protocols designed to detect possible distant and/or local progression have been standardized. In addition, the 1990s witnessed the development of numerous models or nomograms designed to provide pretherapy prediction of organ containment or extraprostatic extension. Foremost among these nomograms are the ‘Partin Tables’ introduced in 1993 with multiple subsequent revisions and updates.1–4 These nomograms combine the information of: (1) clinical stage determined by digital rectal examination (DRE); (2) serum prostate-specific antigen (PSA) level; and (3) Gleason score of the needle biopsy. The American Brachytherapy Society (ABS) utilizes these same three parameters to form the basis of ‘suitability criteria’ in evaluating patients for this form of definitive therapy.5–8 An analysis of these parameters has repeatedly demonstrated that DRE-determined clinical stage and serum PSA used individually or in combination, have limited discriminatory value. Only the Gleason grade has a measure of objectivity and has proven predictive value. The dramatic change in the patient population during the mid and late 1990s, characterized by a significant decrease in patient age, serum PSA levels and recorded tumor volumes has added ‘stress to the system’. Patients are frequently identified in screening programs by elevations of serum PSA without accompanying abnormal DRE (stage T1c). Recognizing a minimal PSA level elevated above a previously established baseline with all determinations less than 4 ng/mL, is observed in increasing numbers of patients. The predictive value of nomograms constructed on a patient population not characterized by these presentations is currently under study. Throughout this past decade the predictive value of the needle biopsy Gleason score has been repeatedly demonstrated. This chapter will address the contributions, and

Table 3.1 Prognostically important information from prostate needle biopsies 1. Gleason score 2. Number of positive biopsies 3. Tumor volume in needle biopsies 4. Site of positive biopsies

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5. Perineural invasion 6. Histologic variants of prostate carcinoma

indeed, the limitations of Gleason grading, and six additional morphologic parameters (also provided by analysis of prostate needle biopsies) are listed in Table 3.1. Future nomograms will probably incorporate those additional features proving to increase their sensitivity and positive predictive value. Gleason grading of prostate carcinoma in needle biopsies The grading of prostate carcinoma dates back approximately 80 years. During this period, as many as thirty proposed tumor grading protocols have appeared in the literature. Among all the proposed protocols, only the Gleason grading system introduced in 1966 has emerged to achieve world-wide acceptance during the past decade.11–13 Exclusive of tumor stage, it is the only morphologic parameter to be of proven prognostic importance.13 The Gleason grade of the tumor identified in needle biopsies has demonstrated value in pretherapy prediction of capsular penetration, seminal vesicle involvement, positive surgical margins, pelvic lymph node metastases, and posttherapy biochemical failure and cancer-specific survival following definitive therapy. Multiple nomograms, foremost the Partin nomograms, for predicting pathologic stage from preoperative clinical and pathologic parameters, utilize the Gleason grading system.1,3,4,14 Gleason grading recognizes five histologic patterns of tumor proliferation which were formalized and illustrated by Dr Gleason. Cytologic features, although contributing to the diagnosis of prostate carcinoma, are not considered in the Gleason grading criteria. Recognizing the typical heterogeneity of tumor patterns, the grading system recognizes a predominant and minority pattern. Thus, the final Gleason score results from the addition of the two numbered patterns, for example, 3+2(5), 4+3(7). The potential range of Gleason scores is 1+1(2) to 5+5(10). Cumulative experience has demonstrated the majority of prostate carcinomas have Gleason scores 5–7, with fewer than 10% of cases Gleason 2–4, and approximately 20% of cases Gleason 8–10. In recent studies, the significance of tertiary patterns contributing <5% of the tumor volume in needle biopsies has been evaluated.15,16 The results suggest prognostic importance, a finding to be confirmed in future studies. Currently, it is recommended that this additional pattern information be included in a note, and not in a formal modification of the Gleason score in the diagnosis. A similar notation of a tertiary score that represents the highest Gleason pattern, regardless of the volume contribution, should be included because it has possible prognostic implications.15,16 Reflecting the significant difference in clinical aggressiveness of Gleason 6 and Gleason 7 (the latter containing a component of Gleason pattern 4), multiple studies have addressed the significance of Gleason pattern 4 and 5 in needle biopsies. Loch et al (1995) demonstrated that the largest tumor in the prostatectomy specimen could be predicted by the side of the greatest volume of Gleason 4/5 pattern in the diagnostic biopsies.17 Conrad et al (1998) observed significant increase in risk of pelvic node metastases when Gleason 4/5 patterns were observed in needle biopsies.18 Taneja et al (1999) reported among patients with bilaterally positive biopsies, a significant association

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of the biopsy site positive for Gleason 4/5 and the site of extraprostatic extension of tumor in the prostatectomy specimen.19 Most recently, Noguchi et al (2001) reported the presence of Gleason 4/5 significantly reduced the probability that the prostate tumor was clinically insignificant (<0.2 cc).20 The Brachytherapy Quality Assurance Group of the American Brachytherapy Society recognized the significant increased aggressiveness of pattern 4, recommending bachytherapy, as monotherapy, be reserved only for patients with biopsy Gleason scores <8.6 Although Gleason grading of prostatic needle biopsies is the cornerstone of therapeutic decision making, a discussion of its contribution would be incomplete without considering its limitations demonstrated in daily practice. Grading, in the final analysis, is an exercise of interpreting morphologic features and the application of established Gleason criteria. The subjectivity is always present, but frequently difficult to quantitate. Intra- and interobserver variability of Gleason grade assignment is regrettably not infrequent. Interobserver variability is currently commonly encountered when prostate biopsies are reviewed in referral pathology departments.21 Indeed, variability of interpretation among experienced urologic pathologists has been documented.22 If the ‘experts’ disagree, it is not a major surprise that Gleason grading errors by less experienced pathologists commonly occur. The most frequent error of biopsy interpretation of prostatic cancer is undergrading with frequencies of 26–57% (Table 3.2).23–35 Overgrading occurs, although less frequently (5–26%). Studies of the clinical implications of the spectrum of Gleason scores, originating from the same major institutions reporting concordance of biopsy and prostatectomy Gleason scores ranging from 26% to 58% (mean: 42%) is sobering. The tendency of undergrading is not uniform throughout the Gleason grade spectrum. The highest frequency of undergrading occurs in the range of Gleason 2–4. Epstein has stated that the diagnosis of Gleason score 2–4 should not be made on needle biopsies, acknowledging the high frequency of undergrading associated with this diagnosis.21 The lowest frequency occurs in the spectrum of Gleason 8–10. The extent of the non-concordance of Gleason grading reported in the literature, has been acknowledged, but not emphasized. Equal emphasis has been placed on the substantially higher concordance if it is combined with plus and minus one Gleason score. This form of ‘concordance’ produces a range of 62–95%, clearly more acceptable. However, on closer inspection, a different interpretation emerges. The clinical significance of undergrading a carcinoma found to be Gleason 5 or 6 in the prostate specimen has marginal clinical significance. However, when a Gleason 7 is interpreted as Gleason 5 or 6 on biopsy, the consequences are not trivial. The frequency of such undergrading is 39–90%. Table 3.2 reviews 15 Gleason grading concordance studies demonstrating that prostate cancers interpreted as Gleason 5 and 6 represented undergrading of Gleason 7 neoplasms in 31%, and 45% of cases, respectively. When undergrading of Gleason 7 occurs, the inherent increased aggressiveness of Gleason pattern 4 is not being recognized preoperatively, with the resultant flaw in the preoperative predictive power of accurate Gleason grading. Explanations of this non-concordance include: (1) nonrepresentative sampling of the tumor: (2) small volume of tumor in the needle biopsy; and (3) failure to recognize invasive features (pattern 3) or gland fusion (pattern 4). In recent studies, documented tumor volumes appear to be decreasing in the era of PSA screening, with the anticipated

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effect on this component of grading error. With increasing experience, and exposure to computer teaching programs

Table 3.2 Biopsy/prostatectomy concordance studies

Total cases Conco rdance 1 2 Under grade (%) Over grade (%) Clust ered Conco rdance Bx 3–6 % Glea son 3 6 Bx 7 10 % Glea son 7–10 Bx 6 % Glea son >6 Bx 5 5 % Glea son >6 Bx 7 % Glea son <7

Spires Bost Kojima Paul Hump Thick Stein ’94 wick ‘95 son hrey man berg U. ‘94 MDA ‘94 ‘95 ‘96 ‘97 Kent Mayo Duke Wash Comm JHH ucky Clinic U unity

Cook Danz Dja son iger van ’97 ’97 ‘98 MSSK NYMC U Texas

67

226

316

135

58% 34% 48%

734 50

124

499

Kok Ega sal, vad ‘00 ‘01 Istan Upp bul sala U. 144 121

Altay ‘01 U EGE

Nog Pete uchi rson* ‘01 TJUH Stan ford

57

222 223

100

415

37% 45% 45% 47% 36% 84% 26– 42% 58% 74% 89% 93% 77% N.I. 90% 91% 98% 100% 100% N.I. 100% 50.1% 45% 39% 42% 46% 36% 26– 43% 57% 12.8% 10% 16% 18% 18% 10% 5– 15% 26%

42% 26% 28%

58% 31%

34%

93% 74% 94% 67% 76% 62% 97% 93% 100% 79% 96% 85% 26% 40% 46% 43% 48% 57%

95% 90% 100% 94% 36% 54%

72% 88% 46%

14% 25% 5%

14% 26% 15%

7%

14%

17%

61% 50% 18%

41% 81% 65%

64% 61%

64%

72% 75% 75% 71% N.I. 67% 18– 58% 75%

92% 79% 98%

84% 60% 67%

88% 80%

87%

73% 75% 92% 62% N.I. 80% 67– 67% 98%

50% 61% 90%

40% 29% 50%

38% 50%

45%

46% 40% 38.5% 25% N.I. 34% 25– 45% 90%

0

46% 80%

29% 6%

37%

29% 39%

21%

24% 17% 4%

6%

22% 2%

15% 33% 27%

13% 21%

16%

29% 26% 11% 71% N.I. 22% 2– 16% 27%

56% N.I. 39% 0– 31% 87%

* Unpublished study by author

of Gleason grading, diagnostic accuracy will improve. The component of Gleason nonconcordance attributable to non-representative sampling will probably always be present with potential for undergrading. In summary, the predictive value of the Gleason score of prostate carcinoma identified in needle biopsies is established and has been incorporated into virtually all nomograms designed to preoperatively predict tumor pathologic stage. The predictive value of the Gleason score is enhanced when combined with other preoperative parameters. The problem of undergrading is significant, and underscores the importance of reliable and accurate interpretation of the pathologic features contributing to Gleason grade assignment in needle biopsies.

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Number of positive biopsies As a measurable preoperative parameter it is intuitive that the higher the number of positive biopsies, the larger the prostate carcinoma, and the higher the probability of local and distant spread (higher pathologic stage). The formal studies published testing this hypothesis are numerous and reflect continuing refinement of biopsy protocols during the 1990s. The introduction of the ‘sextant biopsy protocol’ by Hodge et al occurred in 1989.36 A significant improvement in diagnostic yield was achieved compared to previously employed ‘directed biopsies’. The effectiveness of the sextant protocol was confirmed in later studies.37–40 Indeed, its effectiveness prompted studies to evaluate the frequency of detection of clinically insignificant tumors.41,42 Clinically unimportant tumors were variously reported to constitute 27%, 4% of the cases with two or more, and one positive biopsy, respectively.41,42 The limitations of the sextant protocol soon appeared to dominate reported studies. The adverse influence of increased gland size on the diagnostic yield was reported.39,40 Numerous studies investigated the frequency of false-negative biopsies when the sextant protocol was used.43–48 In vitro sextant biopsies performed on prostatectomy specimens known to harbor adenocarcinoma, second sextant biopsies performed immediately at the time of initial presentation, or before prostatectomy were reported. False-negative biopsies with a frequency of 20–45% were observed employing the above protocol designs.43–48 This reported rate of false-negative biopsies prompted the next generation of studies designed to include previously unexamined intraprostatic locations, including the transition zones and the lateral subcapsular areas.49–51 Again, increasing the number of biopsies significantly increased the diagnostic yield.49–51 Initially the ‘5-zone region’ protocol introduced by Eskew et al (1998), was followed by 10-biopsy and 12-biopsy protocols.49 Concern about the possible resultant increase in identification of clinically insignificant tumors was again put to rest. Appropriately designed studies, measuring the tumor volume and pathologic stage of prostatectomy specimens, demonstrated no significant increased detection of clinically unimportant tumors.51–53 Throughout this period of nomogram development and refinement, increasing numbers of patients were coming to clinical attention via prostate-specific antigen (PSA) screening programs, as a group harboring smaller neoplasms (clinical stage T1c). The percentage of patients with significantly elevated PSA (>20 ng/mL) decreased while the frequency of patients with PSA <10, indeed, <4 progressively increased. The contribution of clinical staging (DRE) and serum PSA has correspondingly diminished and the need to exploit information from the needle biopsies intensified. Within this historical background, studies demonstrated that the number of positive biopsies significantly related to the frequency of: (1) positive surgical margins; and (2) positive pelvic lymph nodes.54–57 The relationship was reported as linear in many studies, others showing ‘cut-off’ numbers of three or more positive biopsies.58–60 Importantly, the presence of tumor in only one biopsy in a sextant series did not significantly relate to the subsequent identification of insignificant tumor in prostatectomy specimens.61 A similar lack of predictive value to identify insignificant tumor was being reported in studies of biopsy tumor volume.

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Tumor volume in needle biopsies The predictive value of biopsy tumor volume has been the subject of many studies, the majority involving the sextant biopsy protocol.50,54,58,60,62,63 Various endpoints were examined, including pathologic stage and tumor volume, both determined after prostatectomy. Clinically significant tumors were reported to be reliably identified by biopsies containing >50% tumor volume and >3 mm of tumor in as few as one or two biopsies.42,65–67 Extraprostatic tumor extension is reliably predicted by tumor volume in biopsies, as determined by multivariate analysis.50,62 In several studies, Gleason grade, number of positive biopsies, and biopsy tumor volume, used in combination, proved to be the most reliably significant predictor of extraprostatic extension of tumor.42,60,68 Finally, similar to the failure of low number positive biopsies failing to reliably detect insignificant tumors, minimal (<3 mm) tumor volume in biopsies did not reliably identify these patients.65,66,69,70 Site of positive biopsy Limited studies addressing the clinical significance of the site of positive biopsies have been reported.17,19,48,56,58,71,72 The importance of positive biopsies in the prostate base has been observed. Badalament et al (1996) demonstrated that bilateral positive prostate base biopsies were found to significantly relate to the risk of extraprostatic extension.58 Tigrani et al (1999) reported the same association of bilateral positive biopsies in the prostate base associated with elevated risk of positive surgical margins in prostatectomy specimens.56 Taneja et al (1999) observed the combination of positive prostate base biopsies, biopsy tumor volume >50% and Gleason score >8 significantly predicted extraprostatic extension.19 In contrast, Epstein et al (1999) reported that no pattern of positive biopsies reliably predicted risk of extraprostatic extension.47 Perineural invasion The clinical significance of perineural invasion observed in prostate needle biopsies is currently undecided.13,62–64,73–77 Initial interest in perineural invasion is appropriately attributed to the studies of Villers et al (1988).78 These authors studied the anatomical details of the prostatic neurovascular bundle, and reported that 50% of cases accomplished capsular penetration exclusively via perineural space invasion and extension. Additional cases demonstrated both perineural invasion and direct capsule invasion. Prostatectomy specimens demonstrated perineural invasion in excess of 80% of cases, including examples with organ-confined tumor. Perineural invasion observed in the apex was assocaited with an elevated risk of positive surgical resection margins.78 The implications of this form of prostatic carcinoma spread were obvious in the era of nerve-sparing prostatectomies. Nervesparing on the ipsi-side of perineural invasion identified in needle biopsies would be inappropriate.74

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The reported frequency of perineural invasion in prostate needle biopsies in five studies ranged from 16.8% to 47% (mean: 27%).54,63,74,75,79 Numerous studies attempted to determine if this morphologic feature in needle biopsies was an independent predictor of extraprostatic extension, or alternatively, a predictor of PSA failure following radiation therapy or prostatectomy.54,62,80–82 The results are decidedly mixed. Five studies reported perineural invasion to be a significant predictor on univariate analysis of: (1) pathologic stage; (2) PSA failure following definitive therapy; and (3) risk of positive surgical margins.54,62,80–82 Independent predictive value on multivariate analysis has been reported in four studies, all related to PSA failure following definitive therapy (radiation therapy or prostatectomy).73,74,76,77,83 Currently, acknowledging that the matter requires further study, it is recommended that the presence of perineural invasion be reported in needle biopsy specimens.84 Histologic variants of prostate carcinoma Uncommon histologic variants of prostate carcinoma, some with biologic characteristics impacting on patient management are listed in Table 3.3. Virtually all are reported in the literature in the form of case reports and the current cumulative knowledge of these variants is incomplete. Clinically significant information about: (1) clinical behavior; and (2) response to various therapy protocols have been documented. Basal cell carcinoma/adenoid cystic carcinoma These prostate carcinomas have been reported in fewer than 30 patients, mostly in the last decade.85–89 These patients most commonly present with bladder outlet obstruction, importantly, without accompanying elevation of serum PSA. Limited available information affords that most are at low pathologic stage and demonstrate limited aggressive tendencies. One reported patient died with tumor metastases.89 The tumor is PSA-negative, and therefore posttherapy monitoring of serum PSA is not appropriate. No reported cases have been treated with radiation therapy. Carcinoid tumors of the prostate These tumors have been reported in approximately 20 patients, only five demonstrating ‘pure’ examples of this

Table 3.3 Histologic variants of prostate carcinoma 1. Basal cell/Adenoid cystic carcinoma 2. Carcinoid 3. Ductal carcinoma 4. Lymphoepithelial carcinoma 5. Signet-ring cell carcinoma 6. Small cell undifferentiated (neuroendocrine) carcinoma 7. Squamous cell carcinoma 8. Transitional cell carcinoma

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neoplasm.90–96 The majority of prostatic carcinoid tumors are a histologic component admixed with typical prostatic adenocarcinoma. None of the patients demonstrated the carcinoid syndrome. Follow-up is limited, but five patients were reported to have died of tumor-related causes with metastases. These neoplasms are to be differentiated from the more frequent and aggressive small cell undifferentiated (neuroendocrine) carcinomas (see discussion below). Ductal carcinoma of the prostate This is currently the most controversial variant of prostate carcinoma. Originally reported in the 1960s as ‘endometriaP carcinoma, an interpretation now abandoned in favor of the overwhelming evidence of prostatic origin (these neoplasms are PSA-positive).97–99 Having settled this aspect of histogenesis, the current debate centers on whether there is a nosologic entity of ‘ductal’ carcinoma, or whether these neoplasms represent extensive intraductal spread of a typical (acinar) prostatic adenocarcinoma.100–106 This matter unresolved aside, the greatest clinical significance of neoplasms demonstrating extensive ductal involvement is that they demonstrate an elevated frequency of high stage at presentation and increased aggressiveness.102,103 Mention should be made of the diagnostic challenge these cases frequently pose when encountered in needle biopsies. The differential diagnosis of cribriform high grade prostatic intraepithelial neoplasia (PIN) or intraductal spread of prostate carcinoma (as a component of invasive malignancy) may be unresolvable without additional biopsies.106,108 Immunohistochemical staining for basal cells (high molecular weight cytokeratin) does not resolve the issue. Definitive therapy—prostatectomy or radiation therapy—should not be instituted before the diagnosis of invasive carcinoma is established. Lymphoepithelioma-like prostatic adenocarcinoma One example of this has been reported. The patient was treated by radical prostatectomy, the pathologic stage determined to be pT3c, and was reported alive without evidence of progression at 15 months.107 Experience with greater numbers of cases will determine if this prostatic neoplasm’s inherent biologic behavior is similar to lymphoepithelioma-like carcinomas in other sites of origin. Signet-ring cell carcinomas of the prostate These appear in the literature as case reports and a few small series.108–110 The limited information distilled from the literature indicates that most are aggressive neoplasms with a high stage at initial presentation. All are PSApositive, and the majority of these neoplasms are mucin-positive. Their behavior reflects the high Gleason grade (pattern 4 or 5). Small cell undifferentiated neuroendocrine carcinomas (SCUCa) These are the most frequent histologic variants of prostate carcinoma with 80% of the 220 cases reported since 1990.111–120 The majority of the reported cases are present at the

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time of initial presentation, with approximately 20% of cases ‘evolving’ from typical prostatic adenocarcinomas, frequently following hormonal and/or radiation therapy. SCUCa are commonly high stage at initial presentation, with fewer than 5% of reported patients surviving two years after the diagnosis. These neoplasms are frequently associated with only modest, or no elevations of serum PSA.115 Approximately 10% are associated with paraneoplastic syndromes.118–120 No standardized effective therapy has evolved, several reports outline chemotherapy protocols.114,116 The neoplasms are hormone-refractory. Squamous cell carcinoma This is rarely primary in the prostate gland. In the literature, 36 cases have been located half of which have been reported since 1980.121,122 Like transitional cell carcinomas of the prostate, these patients frequently present with urinary retention without elevations of serum PSA. Spread beyond the prostate is common at the time of initial presentation. A wide spectrum of primary therapies has been employed with limited success. Of 19 patients with provided follow-up information, 15 were alive with tumor or had died of tumor-related causes. Primary transitional cell carcinoma of the prostate This is rare, the overwhelming majority representing secondary involvement of a urinary bladder primary tumor.123–125 Prostatic involvement by transitional cell carcinoma is not associated with elevations of serum PSA. The neoplasm is not responsive to hormonal therapy. Radical prostatectomy, with or without postoperative radiation, appears to be the most effective therapy in the limited studies providing therapy information. Adjuvant chemotherapy has recently been introduced, the therapeutic benefit of which awaits further evaluation in this clinical setting.125 Finally, currently ongoing and future studies may clarify the clinical utility and predictive value of: (1) DNA ploidy; (2) microvessel density; and (3) proliferation markers. To date, these potential adjunct parameters do not contribute to therapy decisions because of the preliminary state of data collection. Summary In summary, the cornerstone of therapeutic decision making rests on models or nomograms developed in the early 1990s. Increasing experience has supported multiple revisions and updates of the widely utilized ‘Partin Tables’. Most nomograms are based on evaluations of clinical stage (digital rectal examination: DRE), serum prostatespecific antigen (PSA), and biopsy Gleason score. The characteristics of the patient population have dramatically changed with significantly greater numbers of cases identified by PSAscreening programs. The mean age, serum PSA level, and tumor size have all progressively and significantly decreased in recent years. The inherent insensitivity of clinical stage determination by DRE and the serum PSA have corresponding diminishing discriminatory properties in the stage T1c patient population. By default, the biopsy

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Gleason score assumes a greater role in preoperative therapeutic decisions. Additional morphologic parameters derived from prostate needle biopsies, supplementing the Gleason score, include: (1) the number of positive biopsies; (2) the volume of tumor in the needle cores; (3) the site of positive biopsies; (4) the presence of perineural invasion; (5) certain histologic variants of prostatic carcinoma. The future will further clarify their value in preoperative stage prediction, and one hopes, be supplemented by additional parameters, such as DNA ploidy, microvessel density, and proliferation markers. References 1. Partin AW, Yoo J, Carter HB, et al. The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 1993; 150:110–114. 2. Kattan MW, Stapleton AMF, Wheeler TM, Scardino PT. Evaluation of a nomogram used to predict stage of clinically localized prostate carcinoma. Cancer 1997; 79:528–537. 3. Blute ML, Bergstralh EJ, Partin AW, et al. Validation of Partin tables for predicting pathological stage of clinically localized prostate cancer. J Urol 2000; 164:1591–1595. 4. Partin AW, Mangold LA, Lamm DM, et al. Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millennium. Urology 2001; 58:843–848. 5. Stock RG, Stone NN. The effect of prognostic factors on therapeutic outcome following transperineal prostate brachytherapy. Semin Surg Oncol 1997; 13:454–460. 6. Nag S, Beyer D, Friedland J, Grim P, Nath R. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999; 44:789–799. 7. Roach M, Chen A, Song J, et al. Pretreatment prostate-specific antigen and Gleason score predict the risk of extracapsular extension and the risk of failure following radiotherapy in patients with clincally localized prostate cancer. Semin Urol Oncol 2000; 18:108–114. 8. Pisansky TM, Davis BJ. Predictive factors in localized prostate cancer: implications for radiotherapy and clinical trial design. Semin Urol Oncol 2000; 18:93–107. 9. Middleton RG, Smith JA. Radical prostatectomy for stage B2 prostatic cancer. J Urol 1982; 127:702–703. 10. Kibel AS, Krithivas K, Shamel LB, et al. Constitutive expression of high levels of prostatespecific antigen in the absence of prostate carcinoma. Urology 1996; 48:741–746. 11. Gleason DF Classification of prostatic carcinomas. Cancer Chemother Rep 1966; 50:125–212. 12. Gleason DF. Histologic grading and clinical staging of prostatic carcinoma. In: Tannenbaum M, ed. Urologic pathology: The prostate. Philadelphia: Lea & Febiger, 1977:171. 13. Bostwick DG, Grlignon DJ, Hammond MEH, et al. Prognostic factors in prostate cancer. College of American Pathologists consensus statement 1999. Arch Pathol Lab Med 2000; 124:995–1000. 14. Ross PL, Scardino PT, Kattan MW. A catalog of prostate cancer nomograms. J Urol 2001; 165:1562–1568. 15. Yang XJ, Lecksell K, Potter SR, Epstein JI. Significance of small foci of Gleason score 7 or greater prostate cancer on needle biopsy. Urology 1999; 54:528–532. 16. Pan C-C, Potter SR, Partin AW, Epstein JI. The prognostic significance of tertiary Gleason patterns of higher grade in radical prostatectomy specimens. A proposal to modify the Gleason grading system. Am J Surg Pathol 2000; 24:563–569. 17. Loch T, McNeal JE, Stamey TA. Interpretation of bilateral positive biopsies in prostate cancer. J Urol 1995; 154:1078–1083.

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18. Conrad S, Graefen M, Pichlmeier U, et al. Systemic sextant biopsies improve preoperative prediction of pelvic lymph node metastases in patients with clinically localized prostatic carcinoma. J Urol 1998; 159:2023–2029. 19. Taneja SS, Penson DF, Epelbaum A, et al. Does site specific labeling of sextant biopsy predict the site of extracapsular extension in radical prostatectomy surgical specimen? J Urol 1999; 152:1078–1083. 20. Noguchi M, Stamey TA, McNeal JE, Yemoto CM. Relationship between systematic biopsies and histological features of 222 radical prostatectomy specimens: lack of prediction of tumor significance for men with nonpalpable prostate cancer. J Urol 2001; 166:104–110. 21. Epstein JI. Gleason score 2–4 adenocarcinoma of the prostate on needle biopsy. A diagnosis that should not be made [Editorial]. Am J Surg Pathol 2000; 24:477–478. 22. Allsbrook W, Lane R, Lane C. Interobserver reproducibility of Gleason’s grading system. Mod Pathol 1998; 11:75A. 23. Spires SE, Cibull ML, Wood DP, et al. Gleason histologic grading in prostatic carcinoma. Correlation of 18-gauge core biopsy with prostatectomy. Arch Pathol Lab Med 1994; 118:705– 708. 24. Bostwick DG. Gleason grading of prostatic needle biopsies. Correlation with grade in 316 matched prostatectomies. Am J Surg Pathol 1994; 18:796–803. 25. Paulson DF. Impact of radical prostatectomy in the management of clinically localized disease. J Urol 1994; 152:1826–1839. 26. Kojima M, Toncoso P, Baabaian RJ. Use of prostate-specific antigen and tumor volume in predicting needle biopsy grading error. Urology 1995; 45:807–812. 27. Humphrey PA, Baty J, Keetch D. Relationship between serum prostate specific antigen, needle biopsy findings, and histopathologic features of prostatic carcinoma in radical prostatectomy tissues. Cancer 1995; 75:1842–1849. 28. Thickman D, Speers WC, Philpott PJ, Shapiro H. Effect of the number of core biopsies of the prostate on predicting Gleason score of prostate cancer. J Urol 1996; 156:110–113. 29. Steinberg DM, Sauvageot J, Piantaodosi S, Epstein JI. Correlation of prostate needle biopsy and radical prostatectomy Gleason grade in academic and community settings. Am J Surg Pathol 1997; 21:566–576. 30. Cookson MS, Fleshner NE, Soloway SM, Fair WR. Correlation between Gleason score of needle biopsy and radical prostatectomy specimen: Accuracy and clinical implications. J Urol 1977; 157:559–562. 31. Danziger M, Shevchuk M, Antonescu C, et al. Predictive accuracy of transrectal ultrasoundguided prostate biopsy: Correlations to matched prostatectomy specimens. Urology 1997; 49:863–867. 32. Djavan B, Kadesky K, Klopukh, B et al. Gleason scores from prostate biopsies obtained with 18-gauge biopsy needles poorly predict Gleason scores of radical prostatectomy specimens. Eur Urol 1998; 33:261–270. 33. Koksal IT, Ozcan F, Kadioglu TC, et al. Discrepancy between Gleason scores of biopsy and radical prostatectomy specimens. Eur Urol 2000; 37:670–674. 34. Egavad L, Norlen BJ, Norberg M. The value of multiple core biopsies for predicting the Gleason score of prostate cancer. BJU Int 2001; 88:716–721. 35. Altay B, Kefi A, Nazli O, Killi R, et al. Comparison of Gleason scores from sextant prostate biopsies and radical prostatectomy specimens. Urol Int 2001; 67:14–18. 36. Hodge K, McNeal JE, Terris MK, Stamey TA. Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J Urol 1989; 142:71–75. 37. Norberg M, Egevad L, Holmberg L, et al. The sextant protocol for ultrasound-guided core biopsies of the prostate underestimates the presence of cancer. Urology 1997; 50:562–566. 38. Uzzo RG, Wei JT, Waldbaum RS, et al. The influence of prostate size on cancer detection. Urology 1995; 46:831–836.

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39. Karakiewicz PI, Bazinet M, Aprikian AG, et al. Outcome of sextant biopsy according to gland volume. Urology 1997; 49:55–59. 40. Vashi AR, Wojno KJ, Gillespie B, Oesterling JE. A model for the number of cores per prostate biopsy based on patient age and prostate gland volume. J Urol 1998; 159:920–924. 41. Terris MK, McNeal JE, Stamey TA. Detection of clinically significant prostate cancer by transrectal ultrasound-guided systemic biopsies. J Urol 1992; 148:829–832. 42. Epstein JI, Walsh PC, Carmichael M, Brendler CB. Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA 1994; 271:368–374. 43. Epstein JI, Walsh PC, Sauvageot J, Carter HB. Use of repeat sextant and transition zone biopsies for assessing extent of prostate cancer. J Urol 1997; 158:1886–1890. 44. Rabbani F, Stroumbakis N, Kava BR, et al. Incidence and clinical significance of false-negative sextant prostate biopsies. J Urol 1998; 158:1247–1250. 45. Svetec D, McCabe K, Peretsman S, et al. Prostate rebiopsy is a poor surrogate of treatment efficacy in localized prostate cancer. J Urol 1998; 159:1606–1608. 46. Levine MA, Ittman M, Melamed J, Lepor H. Two consecutive sets of transrectal ultrasound guided sextant biopsies of the prostate for the detection of prostate cancer. J Urol 1998; 159:471–476. 47. Epstein JI, Walsh PC, Akingba G, Carter HB. The significance of prior benign needle biopsies in men subsequently diagnosed with prostate cancer. J Urol 1999; 162:1649–1652. 48. Presti JC, Chang JJ, Bhargaa V, Shinohara K. The optimal systemic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial. J Urol 2000; 163:163–167. 49. Eskew LA, Woodruff RD, Bare RL, McCullough DL. Prostate cancer diagnosed by the 5 region biopsy method is significant disease. J Urol 1998; 160:794–796. 50. Ravery V, Goldblatt L, Royer B, et al. Extensive biopsy protocol improves the detection rate of prostate cancer. J Urol 2000; 164:393–396. 51. Gore JL, Shariat SF, Miles BJ, et al. Optimal combinations of systematic sextant and laterally directed biopsies for the detection of prostate cancer. J Urol 2001; 165:1554–1559. 52. Brossner, C, Bayer G, Madersbacher S, et al. Twelve prostate biopsies detect significant cancer volumes (>0.5 mL). BJU Int 2000; 85:705–707. 53. Chan TY, Chan DY, Lecksell K, et al. Does increased needle biopsy sampling of the prostate detect a higher number of potentially insignificant tumors? J Urol 2001; 165:2181–2184. 54. Ravery V, Boccon-Gibod LA, Dauge-Geffroy MC, et al. Systematic biopsies accurately predict extracapsular extension of prostate cancer and persistent/recurrent detectable PSA after radical prostatectomy. Urology 1994; 44:371–376. 55. Narayana P, Gajendran V, Taylor SP, et al. The role of transrectal ultrasound-guided biopsybased staging, preoperative serum prostate-specific antigen, and biopsy Gleason score in prediction of final pathologic diagnosis in prostate cancer. Urology 1995; 46:205–212. 56. Tigrani VS, Bhargava V, Shinohara K, Presti JC. Number of positive systematic sextant biopsies predicts surgical margin status at radical prostatectomy. Urology 1999; 54:689–693. 57. Hammerer P, Huland H, Sparenberg A. Digital rectal examination, imaging, and systematicsextant biopsy in identifying operable lymph node-negative prostatic carcinoma. Eur Urol 1992; 22:281–287. 58. Badalament RA, Miller MC, Peller PA, et al. An algorithm for predicting nonorgan confined prostate cancer using the results obtained from sextant core biopsies with prostate specific antigen level. J Urol 1996; 156:1375–1380. 59. Egawa S, Suyama K, Matsumoto K, et al. Improved predictability of extracapsular extension and seminal vesicle involvement based on clinical and biopsy findings in prostate cancer in Japanese men. Urology 1998; 52:433–440. 60. Sebo TJ, Bock BJ, Cheville JC, et al. The percent of cores positive for cancer in prostate needle biopsy specimens is strongly predictive of tumor stage and volume at radical prostatectomy. J Urol 2000; 163:174–178.

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61. Wang X, Brannigan RE, Rademaker AW, et al. One core positive prostate biopsy is a poor predictor of cancer volume in the radical prostatectomy specimen. J Urol 1997; 158:1431–1435. 62. Bostwick DL, Qian J, Bergstralh E, et al. Prediction of capsular perforation and seminal vesicle invasion in prostate cancer. J Urol 1996; 155:1361–1367. 63. Egan AJM, Bostwick DG. Prediction of extraprostatic extension of prostate cancer based on needle biopsy findings: Perineural invasion lacks significance on multivariate analysis. Am J Surg Pathol 1997; 21:1496–1500. 64. Rubin MA, Bassily N, Sanda M, et al. Relationship and significance of greatest percentage of tumor and perineural invasion on needle biopsy in prostatic adenocarcinoma. Am J Surg Pathol 2000; 24:183–189. 65. Dietrick DD, McNeal JE, Stamey TA. Core cancer length in ultrasound-guided systemic sextant biopsies; a preoperative evaluation of prostate cancer volume. Urology 1995; 45:987–992. 66. Irwin MB, Trapasso JG. Identification of insignificant prostate cancers: analysis of preoperative parameters. Urology 1994; 44:862–868. 67. Weldon VE, Tavel FR, Neuwirth H, Cohen R. Failure of focal prostate cancer on biopsy to predict focal prostate cancer: the importance of prevalence. J Urol 1995; 154:1074–1077. 68. Wills ML, Sauvageot J, Partin AW, et al. Ability of sextant biopsies to predict radical prostatectomy stage. Urology 1998; 51:759–764. 69. Bruce RG, Rankin WR, Cibull ML, et al. Single focus of adenocarcinoma in the prostate biopsy specimen is not predictive of the pathologic stage of disease. Urology 1996; 45:75–79. 70. Gardner TA, Lemer ML, Schlegel PN, et al. Microfocal prostate cancer: biopsy cancer volume does not predict actual tumour volume. Br J Urol 1998; 81:839–843. 71. Sanwick JM, Dalkin BL, Nagle RB. Accuracy of prostate needle biopsy in predicting extracapsular tumor extension at radical retropubic prostatectomy: application in selecting patients for nerve-sparing surgery. Urology 1998; 52:814–819. 72. Tombal B, Tajeddine N, Cosyns JP, et al. Does site-specific labeling and individual processing of sextant biopsies improve the accuracy of prostate biopsy in predicting pathological stage in patients with T1c prostate cancer? BJU Int 2002; 89:543–548. 73. Bonin SR, Hanlon AL, Lee WR, et al. Evidence of increased failure in the treatment of prostate carcinoma patients who have perineural invasion treated with three-dimensional conformal radiation therapy. Cancer 1997; 79:75–80. 74. de la Taille A, Katz A, Bagiella E, et al. Perineural invasion on prostate needle biopsy: an independent predictor of final pathologic stage. Urology 1999; 54:1039–1043. 75. Vargas SO, Jiroutek M, Welch WR, et al. Perineural invasion in prostate needle biopsy specimens. Correlation with extraprostatic extension at resection. Am J Clin Pathol 1999; 111:223–228. 76. Ozcan F. Correlation of perineural invasion on radical prostatectomy specimens with other pathologic prognostic factors and PSA failure. Eur Urol 2001; 40:308–312. 77. Sebo TJ, Cheville JC, Riehle DL, et al. Perineural invasion and MIB1 positivity in addition to Gleason score are significant preoperative predictors of progression after radical retropubic prostatectomy for prostate cancer. Am J Surg Pathol 2002; 26:431–439. 78. Villers A, McNeal JE, Redwine EA, et al. The role of perineural space invasion in the local spread of prostatic adenocarcinoma. J Urol 1989; 142:763–768. 79. Bastacky SI, Walsh PC, Epstein JI. Relationship between perineural tumor invasion on needle biopsy and radical prostactectomy capsular penetration in clinical stage B adenocarcinoma of the prostate. Am J Surg Pathol 1993; 17:336–341. 80. Epstein JI. The role of perineural invasion and other biopsy characteristics as prognostic markers for localized prostate cancer. Semin Urol Oncol 1998; 16:124–128. 81. Stone NN, Stock RG, Parikh D, et al. Perineural invasion and seminal vesicle involvement predict pelvic lymph node metastasis in men with localized carcinoma of the prostate. J Urol 1998; 160:1722–1726.

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82. D’Amico AV, Wu Y, Chen, M-H, et al. Perineural invasion as a predictor of biochemical outcome following radical prostatectomy for select men with clinically localized prostate cancer. J Urol 2001; 165:126–129. 83. Anderson PR, Hanlon AL, Patchefsky A, et al. Perineural invasion and Gleason 7–10 tumors predict increased failure in prostate cancer patients with pretreatment PSA <10 ng/ml treated with conformal external beam radiation therapy. Int J Radiat Oncol Biol Phys 1998; 41:1087– 1092. 84. Iczkowski KA, Bostwick DG. Prostate biopsy 1999: strategies and significance of pathological findings. Semin Urol Oncol 1999; 17:177–186. 85. Frankel K, Craig JR. Adenoid cystic carcinoma of the prostate. Report of a case. Am J Clin Pathol 1974; 62:639–645. 86. Denholm SW, Webb JN, Howard GCW, Chisholm GD. Basaloid carcinoma of the prostate gland: histogenesis and review of the literature. Histopathology 1992; 20:151–155. 87. Devaraj LT, Bostwick DG. Atypical basal cell hyperplasia of the prostate. Immunophenotypic profile and proposed classification of basal cell proliferations. Am J Surg Pathol 1993; 17:645– 659. 88. Yang XJ, McEntee M, Epstein JI. Distinction of basaloid carcinoma of the prostate from benign basal cell lesions by using immunohistochemistry for bcl-2 and Ki-67. Hum Pathol 1998; 28:1447–1450. 89. Manrique JJ, Albores-Saavedra J, Orantes A, Brandt H. Malignant mixed tumor of salivarygland type, primary in the prostate. Am J Clin Pathol 1978; 70:932–937. 90. Azzopardi JG, Evans DJ. Argentaffin cell in prostatic carcinoma: Differentiation from lipofuscin and melanin in prostatic epithelium. J Pathol 1971; 104:247–251. 91. Turbat-Herrara EA, Herrera GA, Gore I, et al. Neuroendocrine differentiation in prostatic carcinomas: a retrospective autopsy study. Arch Pathol Lab Med 1988; 112:1100–1105. 92. Whelan T, Gatfield CT, Robertson S, et al. Primary carcinoid of the prostate in conjunction with multiple endocrine neoplasia lib in a child. J Urol 1995; 153:1080–1082. 93. Miki T, Kuroda M, Kiyohara H, et al. Primary carcinoid tumor of the prostate: report of a case. Nippon Hinyokika Gakkai Zasshi 1980; 71:264–272. 94. Wasserstein PW, Goldman RL. Diffuse carcinoid of prostate. Urology 1981; 18:407–409. 95. Almagro UA. Argyrophilic prostatic carcinoma: case report with literature review on prostatic carcinoid and ‘carcinoid-like’ prostatic carcinoma. Cancer 1985; 55:608–614. 96. Rojas-Corona RR, Chen L, Mahedevia PS. Prostatic carcinoma with endocine features; A report of a neoplasm containing multiple immunoreactive hormonal substances. Am J Clin Pathol 1987; 88:759–762. 97. Melicow MM, Pachter MR. Endometrial carcinoma of prostatic utricle (uterus masculinus). Cancer 1967; 20:1715–1722. 98. Epstein JI, Woodruff JM. Adenocarcinoma of the prostate with endometrioid features. A light microscopic and immunohistochemical study often cases. Cancer 1986; 57:111–119. 99. Vale JA, Patel A, Ball AJ, et al. Endometrioid carcinoma of the prostate: a misnomer? J Roy Soc Med 1992; 85:394–396. 100. Samaratunga H, Singh M. Distribution pattern of basal cell detected by cytokeratin 34 beta E12 in primary prostatic duct adenocarcinoma. Am J Surg Pathol 1997; 21:435–440. 101. McNeal JE, Yemoto CEM. Spread of adenocarcinoma within prostatic ducts and acini. Morphologic and clinical correlations. Am J Surg Pathol 1996; 20:802–814. 102. Wilcox G, Soh S, Chakraborty S, et al. Patterns of high-grade prostatic intraepithelial neoplasia associated with clinically aggressive prostate cancer. Hum Pathol 1998; 29:1119– 1123. 103. Rubin MA, de la Taille A, Bagiella E, et al. Cribriform carcinoma of the prostate and cribriform prostatic intraepithelial nenoplasia. Incidence and clinical implications. Am J Surg Pathol 1998; 22:840–848.

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104. Bock BJ, Bostwick DG. Does prostatic ductal carcinoma exist? Am J Surg Pathol 1999; 23:781–785. 105. Brinker DA, Potter SR, Epstein JI. Ductal adenocarcinoma of the prostate diagnosed on needle biopsy. Correlation with clinical and radical prostatectomy findings and progression. Am J Surg Pathol 1999; 23:1471–1479. 106. Kronz JD, Shaikh AA, Epstein JI. Atypical cribriform lesions on prostate biopsy. Am J Surg Pathol 2001; 25:147–155. 107. Adlakha K, Bostwick DG. Lymphoepithelioma-like carcinoma of the prostate. A new histologic variant of prostatic adenocarcinoma. J Urol Pathol 1994; 2:319–325. 108. Giltman LI. Signet ring adenocarcinoma of the prostate. J Urol 1981; 126:134–135. 109. Guerin D, Hasan N, Keen CE. Signet ring cell differentiation in adenocarcinoma of the prostate: a study of five cases. Histopathology 1993; 22:367–371. 110. Torbenson M, Dhir R, Nangia A, et al. Prostatic carcinoma with signet ring cells: A clinicopathologic and immunohistochemical analysis of 12 cases, with review of the literature. Mod Pathol 1998; 11:552–559. 111. Newmark SR, Dluhy RG, Bennett AH. Ectopic adrenocorticotropin syndrome with prostatic carcinoma. Urology 1973; 2:666–668. 112. Tetu B, Ro JY, Ayala AG, et al. Small cell carcinoma of the prostate: I. A clinicopathologic study of 20 cases. Cancer 1987; 59:1803–1809. 113. Christopher ME, Seftel AD, Sorenson K, Resnick MI. Small cell carcinoma of the genitourinary tract: An immunohistochemical, electron microscopic and clinicopathological study. J Urol 1991; 146:382–388. 114. Amato RJ, Logothetis CJ, Hallinan R, et al. Chemotherapy for small cell carcinoma of prostatic origin. J Urol 1992; 147:935–937. 115. Schwartz LH, LaTrenta LR, Bonaccio E, et al. Small cell and anaplastic prostate cancer: correlation between CT findings and prostatespecific antigen level. Radiology 1998; 208:735– 738. 116. Lopez Cubillana P, Martinez Barba E, Prieto A, et al. Oat-cell carcinoma of the prostate. Diagnosis, prognosis and therapeutic implications. Urol Int 2001; 67:209–212. 117. Helpap B, Kollermann J. Undifferentiated carcinoma of the prostate with small cell features: immunohistochemical subtyping and reflections on histogenesis. Virchows Arch 1999; 434:385–391. 118. Carey RM, Varma SK, Drake CR, et al. Ectopic secretion of corticotropin-releasing factor as a cause of Cushing’s syndrome. A clinical, morphologic and biochemical study. N Eng J Med 1984; 311:13–20. 119. Smith DC, Tucker JA, Trump DL. Hypercalcemia and neuroendocrine carcinoma of the prostate: A report of three cases and a review of the literature. J Clin Oncol 1992; 10:499–505. 120. Haukaas SA, Halvorsen OJ, Nygaard SJT, Paus E. Cushing’s syndrome in prostate cancer. Urol Int 1999; 63:126–129. 121. Kahler JE. Carcinoma of the prostate gland; a pathologic study. J Urol 1939; 41:557–574. 122. Nabi G, Ansari MS, Singh II, et al. Primary squamous cell carcinoma of the prostate: A rare clinicopathological entity. Report of 2 cases and review of literature. Urol Int 2001; 66:216– 219. 123. Cheville JC, Dundore PA, Bostwick DG, et al. Transitional cell carcinoma of the prostate. Clinicopathologic study of 50 cases. Cancer 1998; 82:703–707. 124. Matzkin H, Soloway MS, Hardeman S. Transitional cell carcinoma of the prostate. J Urol 1991; 146:1207–1212. 125. Takashi M, Sakata T, Nagai T, et al. Primary transitional cell carcinoma of prostate: case with node metastasis eradicated by neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin (M-VAC) therapy. Urology 1990; 36:96–99.

4 Detailed mapping of prostate cancer: implications for brachytherapy Michael E Chen, Dennis A Johnston, and Patricia Troncoso Introduction Study of the distribution of tumor foci within the prostate may have implications for optimizing locally directed therapies for prostate cancer, such as brachytherapy, cryotherapy, or, in the future, direct intraprostatic injection of antineoplastic agents. However, prostate carcinoma is well known to exhibit considerable histologic and anatomical heterogeneity within the gland. Such heterogeneity makes it difficult to summarize the distribution of prostate cancer foci. Previous studies have been limited to written descriptions of tumor distribution, or to schematic diagrams of a small number of cases superimposed on prostate crosssections.1–4 We have developed a computer-based methodology that graphically summarizes the tumor distribution of a large number of prostate cancer cases on to sections of a paradigm prostate. This system allows the display of relative tumor concentrations in different regions of the prostate. We have used such plots of tumor distribution to devise improved biopsy strategies to detect prostate cancer. Materials and methods A total of 180 radical prostatectomy specimens from 1990 to 1996 were serially sectioned and regions of tumor mapped for each gland as previously described.6 Cases were non-consecutive. Sections of the apex and base were not mapped. The outlines of each prostate gland and the tumor foci within each gland were then digitized into the computer. The boundary between the peripheral zone and transition zone of each prostate was also entered. The central zone was not outlined because it generally lacked welldefined anatomic boundaries, and was present predominantly at the prostate base, a region not completely included in our model. Only 0.5% of all tumor foci (Table 4.1) were found in the central zone. The peri

Table 4.1 Number and zonal distribution of cancer foci in 180 radical prostatectomy specimens Number of foci per specimen One focus Greater than one focus Range Mean Median

31 (17%) 149 (83%) 1–10 3.37 3.0

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Number of cancer foci by zone Peripheral zone (PZ) 448 (74%) Transition zone (TZ) 141 (23%) Central zone (CZ) 3 (0.5%) Zone indeterminate 15 (2.5%) Zonal distribution of cancer foci per specimen Foci in PZ only 67 (37%) Foci in PZ and TZ 93 (52%) Foci in TZ only 3 (2%) Foci in PZ and CZ 2 (1%) Foci of indeterminate origin 15 (8%) Dominant focus origin in cases with PZ and TZ foci Peripheral zone 60 (65%) Transition zone 33 (35%) Indeterminate cancers were generally large cancers occupying multiple zones, whose zone of origin could not be determined.

urethral region was also not mapped because its small size, poor anatomic definition, and lack of tumor. A technique of three-dimensional (3D) histograms was developed to demonstrate the aggregate locations of prostate tumors. A paradigm prostate was used to map the tumor foci. This prostate was chosen because it represented a typical prostate shape. This paradigm prostate was then used to standardize the height and width of other

Figure 4.1 Summary distribution of all cancer foci plotted in a 256 level grayscale scheme (a), and in a pseudocolor scheme (b) for the same

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paradigm prostate section. The corresponding grayscale and pseudocolor tables are shown to the right of the respective prostate sections. For details regarding interpretation of the grayscale and pseudo-color schemes, see the text. prostates at a given length. All prostates were normalized to a 100% length scale. Thus, the dimensions of a given prostate were normalized to the paradigm prostate model. For any normalized pixel that contained tumor, an increment of one was added to a 180×140×19 matrix. The 3D histograms were then plotted as contour plots with 256 levels of gray or pseudo-color (Figure 4.1). Black pixels indicate absence of tumor, and white pixels indicate maximum tumor frequency, with shades of gray or pseudocolor indicating intermediate frequencies. The plots thus contain quantitative information. For the pseudocolor scheme, pixels plotted in red to white thus represent areas where tumor occurred from 50% to 100% of the maximum rate. Results Of the 180 cases, 24 (13%) were T1c classification. The median prostate-specific antigen (PSA) for these cases was 7.45 ng/mL, median gland weight was 38.0 g, 26 prostates (14%) had tumors with Gleason scores of 6 or less. A total of 108 (60%) prostates had a Gleason score of 7, and the remainder of glands (46 cases, 26%) had Gleason scores of 8 or more. Median total tumor volume was 1.39 cm3. Most prostates contained more than one tumor focus (149 cases, 83%, see Table 4.1). Most tumor foci (448 foci, 74%) were located in the peripheral zone. There were only three prostates (2%) that contained tumor foci located exclusively in the transition zone. The computer plot of the aggregate distribution of all tumor foci for all cases is shown in Figure 4.2. As can be seen tumor foci are concentrated in the posterolateral peripheral zone of the prostate. Peripheral zone foci tended to be concentrated from apex to midgland. At the base, peripheral zone foci tended to diverge laterally. An additional concentration of tumor is found in the anterior transition zone, reflecting the predominant location of these transition zone tumors. A plot of an individual prostate with tumor exclusively located in the transition zone (Figure 4.3) again emphasizes the typical anteromedial location of such tumors. Cases were stratified by patient prostate-specific antigen (PSA) levels. Increased PSA levels correlated with increased total tumor volume, peripheral zone tumor volume, and transition zone tumor volumes (data not shown). The computer plots of tumor distribution stratified by PSA levels reflect this correlation (Figure 4.4). As shown in Figure 4.5, cases with Tlc classification (non-palpable tumor on digital rectal examination) exhibited relatively more tumor in the transition zone. This appeared to be due to a relative decrease in peripheral zone tumor volume; transition zone tumor volume for Tlc cases was not significantly different than other cases (data not shown). Cases with

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a Gleason score of 6 or less (Figure 4.6) also exhibited relatively more tumor in the transition zone. For these cases, peripheral zone tumor volume was decreased and transition zone tumor volume was increased (data not shown). In contrast, large glands (greater than 50 g) had relatively less transition zone cancer (Figure 4.7). In addition, in large glands it was not uncommon to see peripheral zone tumors ‘pushed’ peripherally by prominent transition zone adenomatous tissue (Figure 4.8). Discussion Our studies confirm the heterogeneous nature of prostate cancer. Our overall results are generally consistent with previous reports.1,2 Prostate cancer is typically multifocal and multizonal. The predominant location of tumors is in the posterolateral peripheral zone (PZ) of the prostate. PZ tumors were preferentially concentrated from apex to mid-gland, and diverged laterally as they neared the base. Transition zone (TZ) cancers were focused anteriorly, near the midline. Cases with non-palpable tumors (T1c classi-fication) had increased TZ tumors. Other studies have also reported this finding.7,8 Cases with a Gleason score of 6 or less also had relatively more TZ tumors. Unlike T1c cases, this appears to be due to both a decrease in PZ tumor volume and an increase in PZ tumor volume. TZ tumors tend to be well-differentiated and usually have a Gleason score equal to or less than that of any PZ tumors in the same gland. We suggest that the development of large TZ tumors occurs primarily in the context of well-differentiat

Figure 4.2 Top row: Summary distribution of all cancer foci: 19 virtual cross-sections from the 180×140×19 pixel matrix are displayed. The first section on the

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upper left represents the basal most section. The last section on the lower right represents the section near the apex. Outlines of the urethra and the boundary between the peripheral zone (PZ) and transition zone (TZ) are also traced. Tumor distribution is superimposed on the outlines of a chosen paradigm prostate. For interpretation of the pseudo-color scheme see Figure 4.1 and the text.

Figure 4.3 Serial sections of a prostate with tumor exclusively present in the transition zone. Tumor foci are in red. For this case, the classification was Tlc. The PSA level was 9.9 ng/mL The specimen Gleason score was 6, and the gland weight was 61 g. Tumor volume was 6.22 cm3.

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Figure 4.4 The distribution of tumor foci for cases stratified by patient prostate-specific antigen (PSA) level. Slices 3, 7, 11, 15, 19 from the original 19 slice matrix are displayed. See Figure 4.1 for the pseudo-color key, and Figure 4.2 for the slice locations.

Figure 4.5 Distribution of tumor in cases stratified by Tlc (non-palpable) versus other classifications. Slices 3, 7, 11, 15, 19 from the original 19 slice matrix are displayed. See Figure 4.1

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for the pseudo-color key, and Figure 4.2 for the slice locations. ed PZ tumors. If the PZ tumors are more poorly differentiated, it is probable that such tumors would grow rapidly and be detected prior to the development of large TZ cancers. In large glands with large TZs secondary to benign prostatic hyperplasia, it was not unusual to see PZ cancers compressed toward the edge of the prostate. Large glands also had less TZ cancer. We have reported previously that large glands have a higher frequency of small volume cancers (<0.5 cm3).9 We have suggested that for at least some of these large prostates, small incidental cancers were detected because of an elevated PSA level caused largely by the enlarged adenomatous tissue, and not by significant cancer. We emphasize, however, that the findings are statistical summaries. For a given individual case, the distribution of prostate cancer foci within the gland cannot be predicted with certainty from clinical parameters. The findings of digital rectal examination (DRE), or the location of

Figure 4.6 Distribution of tumor in cases stratified by the Gleason score of the prostate specimen. Slices 3, 7, 11, 15, 19 from the original 19 slice matrix are displayed. See Figure 4.1 for the pseudo-color key, and Figure 4.2 for the slice locations.

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Figure 4.7 Tumor distribution by gland weight. Slices 3, 7, 11, 15, 19 from the original 19 slice matrix are displayed. See Figure 4.1 for the pseudo-color key, and Figure 4.2 for the slice locations.

Figure 4.8 Serial sections of a large prostate with a prominent transition zone. Tumor foci are in red. A tenth apical section is not displayed. For this case, the classification was T1c. The PSA level was 11.6 ng/mL The

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specimen Gleason score was 6, and the gland weight was 85 g. Tumor volume was 0.06 cm3. prostate cancer in biopsy cores, do not correlate absolutely with final pathologic findings.10–12 Hypoechoic regions noted on transrectal ultrasound may suggest areas of cancer, but are not completely specific.13,14 Given the unpredictable distribution of cancer foci in an individual case, it is prudent, indeed imperative, that all regions of the prostate be sufficiently treated, with the exception of the periurethral region. Indeed, commonly used modified peripheral loading schemes aim to accomplish these two goals. Nevertheless, knowledge of the probability of cancer within any given region of the prostate may be useful in developing the treatment plan. Within the bounds of wellestablished criteria for implant design (dose conformation to the prostate, relative implant uniformity, and reduction of dose to the urethra), we suggest that the brachytherapist may also wish to consider the likelihood of cancer within certain regions of the prostate. Certainly, careful attention should be given to the posterolateral and anteromedial prostatic regions in the course of planning and implantation. The boundary between the peripheral zone and the transition zone is usually readily identifiable on transrectal ultrasound. We suggest that in cases where there is a prominent transition zone, that the brachytherapist take into account the likely displacement of the peripheral zone tumors toward the outer edge of the prostate. A degree of inhomogeneity is inherent to any brachytherapy treatment plan, with ‘hot spots’ centered around each seed implant. Some have suggested that doses 20% higher than prescription may have some increased biologic effect.15 Although it is a matter of speculation how such high doses (above prescription and centered around each individual source) ultimately affects tumor, the brachytherapist may wish to consider incorporating areas of high cancer probability (the posterolateral prostate and the anterior prostate near the midline) within higher isodose regions, after all other primary considerations have been met. References 1. McNeal JE, Redwine EA, Freiha FS, Stamey TA. Zonal distribution of prostatic adenocarcinoma. Correlation with histologic pattern and direction of spread. Am J Surg Path 1988; 12:897–906. 2. Wheeler TM. Anatomic considerations in carcinoma of the prostate. Urol Clin North Am 1989; 16:623–634. 3. Babaian RJ, Troncoso P, Ayala A. Transurethral-resection zone prostate cancer detected at cystoprostatectomy. A detailed histologic analysis and clinical implications. Cancer 1991; 67:1418–1422. 4. Tiguert R, Gheiler EL, Tefilli MV, et al. Racial differences and prognostic significance of tumor location in radical prostatectomy specimens. Prostate 1998; 37:230–235. 5. 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; 163:152–157. 6. Chen ME, Johnston DA, Tang K, et al. Detailed mapping of prostate carcinoma foci: biopsy strategy implications. Cancer 2000; 89:1800–1809.

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7. Elgamal AA, Van Poppel HP, Van de Voorde WM, et al. Impalpable invisible stage T1c prostate cancer: characteristics and clinical relevance in 100 radical prostatectomy specimens—a different view [See comments]. J Urol 1997; 157:244–250. 8. Stamey TA, Sozen TS, Yemoto CM, et al. Classification of localized untreated prostate cancer based on 791 men treated only with radical prostatectomy: common ground for therapeutic trials and TNM subgroups. J Urol 1998; 159:2009–2012. 9. Chen ME, Troncoso P, Johnston D, et al. Prostate cancer detection: relationship to prostate size. Urology 1999; 53:764–768. 10. Mueller EJ, Crain TW, Thompson IM, et al. An evaluation of serial digital rectal examinations in screening for prostate cancer. J Urol 1988; 140:1445–1447. 11. Cupp MR, Bostwick DG, Myers RP, Oesterling JE. The volume of prostate cancer in the biopsy specimen cannot reliably predict the quantity of cancer in the radical prostatectomy specimen on an individual basis. J Urol 1995; 153:1543–1548. 12. Wang X, Brannigan RE, Rademaker AW, et al. One core positive prostate biopsy is a poor predictor of cancer volume in the radical prostatectomy specimen. J Urol 1997; 158:1431–1435. 13. Carter HB, Hamper UM, Sheth S, et al. Evaluation of transrectal ultrasound in the early detection of prostate cancer. J Urol 1989; 142:1008–1010. 14. Flanigan RC, Catalona WJ, Richie JP, et al. Accuracy of digital rectal examination and transrectal ultrasonography in localizing prostate cancer. J Urol 1994; 152:1506–1509. 15. Ling CC, Roy J, Sahoo N, et al. Quantifying the effect of dose inhomogeneity in brachytherapy: application to permanent prostatic implant with 1251 seeds. Int J Radiat Oncol Biol Phys 1994; 28:971–978.

5 Defining permanent prostate brachytherapy target volumes from evaluation of wholemount prostatectomy specimens Brian J Davis, Thomas M Pisansky, John C Cheville, and Torrence M Wilson Introduction The goals of treatment with primary radiotherapy are cancer cure with organ preservation. The treatment goals are achieved, in part, because cancer cells are generally more sensitive to the cytotoxic effects of ionizing radiation as compared to normal tissue. Nevertheless, normal tissue tolerance to radiotherapy may limit the radiation dose that may be delivered to a given anatomical site. Therefore, information regarding cancer location as it relates to normal adjacent tissue is relevant to the appropriate delivery of radiation therapy. Such information may be determined by analysis of pathologic data from primary surgical therapy. In cancer of the prostate, detailed histopathologic study of prostatectomy specimens and analysis of patient pretreatment prognostic factors has led to the development of various nomograms for predicting the presence of adverse pathologic features. Such nomograms may then be used to influence treatment approaches based on predicting the extent and location of cancer. In the radiotherapeutic management of prostate cancer, the key issues revolve around determining the risk of lymph node involvement (LNI), seminal vesicle involvement (SVI), and extraprostatic extension (EPE). The terminology, ‘extraprostatic extension’ (EPE), is preferred instead of ‘extracapsular extension’ (ECE), because the prostate does not have a complete capsule around it.1,2 As such, prostate cancer penetrating beyond the margin of the prostate at a location where a capsule is absent would not be appropriately termed ‘ECE’, a misnomer in such a circumstance, but rather EPE. Current standards for defining the brachytherapy treatment volume While many groups have reported their practice regarding defining treatment volumes for prostate brachytherapy, one may consider two sources as representative of current standards in this area: (1) Radiation Therapy Oncology Group (RTOG) clinical trials; and (2) an American College of Surgeons Oncology Group (ACOSOG) clinical trial. Prerequisite to a discussion of treatment volume definitions is knowledge of the International Commission on Radiation Units and Measurement (ICRU) report number 58.3 The relevant terminology from this ICRU report includes the gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV). In prostate cancer radiotherapy, the CTV is usually defined as the GTV, which is the prostate itself,

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with or without the seminal vesicles. A noted exception is the situation where a specifically defined nodule within the prostate or a dominant intraprostatic lesion is treated or boosted to a higher dose.4 The rationale for treatment of the entire prostate is that prostate cancer is usually found to be multifocal approximately 50–80% of the time.5–8 Therefore, treatment of the entire prostate is a rational approach. RTOG trial 98–05 was a multi-institutional Phase I/II trial for treatment of men with early stage and low risk prostate cancer that accrued 98 patients. The first results of this trial were reported in 2002.9 The CTV included preimplant transrectal ultrasound (TRUS) definition of the prostate. The PTV included an enlargement of the CTV by 2–3 mm in the lateral and anterior dimensions and 5 mm in the superior (cephalad) and inferior (caudad) dimensions, but no enlargement posteriorly near the rectum. Thus, the prostate dimensions are increased 1.0 cm in the superior-inferior direction, 4–6 mm in the lateral dimension, and 2–3 mm in the anterior-posterior dimension. In two subsequent trials, P0126 and P-0232, treatment volumes are defined in a similar manner. The ACOSOG trial uses an identical set of criteria for treatment volumes as the RTOG trials. Consequently, these described treatment margins may be viewed as a standard for permanent prostate brachytherapy but not necessarily a universal one in that some experienced practitioners have reported using treatment margins that vary from those described. Serial sectioning of wholemount prostatectomy specimens A number of reports describe the process of whole-mounting a prostate specimen harvested from a radical prostatectomy.10,11 While variations exist in institutional practice, common aspects of these approaches to whole-mounting include specimen weighing, measuring, fixation in buffered formalin, and inking, along with separate removal of the apex and the base. Seminal vesicles are sectioned from their base and preserved in their entirety from their proximal to distal ends. As illustrated in Figure 5.1, the prostate is sectioned contiguously in 3–5 mm sections from base to apex in planes roughly perpendicular to the rectal wall and urethra. Most sections appear similar to those observed by axial TRUS imaging. Seminal vesicles

Figure 5.1 Schematic of the wholemounting process of radical prostatectomy specimens. EPE, extraprostatic extension.

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may be sectioned in axial or sagittal sections. All sections are mounted on glass slides and frequently require the use of slides larger than those typically employed in routine histopathology. Tumor maps are duplicated for each slide and show critical features including locations of EPE, positive margins, and tumor foci. In the Mayo series, specimens were obtained during the period 1991–1993 as reported by Bostwick et al.10 The following discussion is organized first by considering prostate cancer location and prosatectomy findings as they pertain to the urethra, the chosen anatomical center of the prostate, and then progressing outwards. Issues related to the risk of SVI or LNI have been addressed elsewhere and will not be reviewed within the scope of this chapter.12 Urethra-cancer distance The location of cancer immediately adjacent to the urethra is relevant in permanent prostate brachytherapy (PPB) in considering the degree of peripheral loading and ‘urethral sparing’ that is acceptable. Detailed measurement of the proximity of cancer immediately adjacent to the urethra was first described by Leibovich et al in 2000.13 The method of measurement is illustrated in Figures 5.2a, b. A total of 350 specimens were evaluated in this series. The urethra-cancer distance was determined by measuring the radial distance between the urethral mucosa and the nearest focus of cancer. No linear shrinkage factor due to tissue processing was used in the study as it was estimated to be only 4.35–7.7%.14,15 Urethra-cancer distance was correlated with clinical, pathologic, and laboratory factors by univariate and multivariate analysis. In 17% of the patients, the cancer abutted the urethra and in 84% of the cases, the nearest focus of cancer was within 5 mm of the urethra. A decreasing urethra-cancer distance was associated with an increased rate of cancer recurrence. Multivariate analysis revealed that decreasing urethra-cancer distance was associated with increased serum prostate-specific antigen (PSA), Gleason score in the biopsy specimen, and percent of biopsy specimen with Gleason pattern 4 or 5. Characteristics of the study cohort were such that a considerable portion of patients would have been candidates for PPB monotherapy, if judged on clinical stage, preoperative PSA, and Gleason biopsy score alone. A total of 39.7% of patients were clinical stage T2a or less, 54.5% had serum PSA of 9.9 or less, and 46% had Gleason biopsy score of 6 or less. Two subsequent studies have also examined the urethra-cancer distance. Rubin et al examined 52 specimens associated with low risk features and determined the frequency of cancer within the transitional zone.16 The study

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Figure 5.2 (a) Illustration of wholemount section showing the method of measurement of the urethra—cancer distance. X identifies the location of the rethra. The darkened region of the sectioned prostate illustrates prostate cancer, and the measurement A shows the minimal urethra—cancer distance. (b) Section of prostate illustrating the urethra—cancer distance measurement. found that even among specimens with peripheral zone cancer only, periurethral cancer was common. The closest urethra-cancer distance per specimen ranged from 0.07 mm to 1.9 mm with a median of 0.6 mm for all cases. In 86% of the cases, the urethra-cancer distance was 1 mm or less. Rukstalis et al examined 112 patients treated from 1998 to 2000 by radical perineal prostatectomy with median preoperative PSA of 7.0 (range: 0.7– 200 ng/mL), and a median Gleason score of 6 (range: 4–10).17 The location of cancer foci with respect to the urethra were evaluated by zonal anatomy including the transition and peripheral zdnes along with locations in the apex, mid and base of the prostate. In all sets, the median minimum distance from cancer foci to the urethra was 1 mm or less. The mean distance ranged from 0.5 mm to 1.6 mm. In all of these three series, the minimum urethracancer distance was frequently less than 1 mm and a majority of the measurements were less than 5 mm. No studies have suggested that the volume of periurethral cancer is small, although, to our knowledge, detailed data on the cancer volume as a function of radial distance from the urethra have not been published. Clearly, the resources to generate such data exist, but it is doubtful in reviewing presently available data that the findings will reveal small, yet close, amounts of cancer adjacent to the entire course of the urethra. Therefore, the implication of these

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findings with respect to the practice of PPB is that treatment of the urethral wall and mucosa is necessary to facilitate eradication of the cancer. Furthermore, there is no suggestion that significant reduction in radiation dosage to the urethra and periurethral region is warranted based on these histopathologic data alone. It appears evident from these data that there is not a reasonable basis to argue in favor of significant urethral dose de-escalation in the present day practice of PPB. Also relevant to these considerations are that a number of studies have attempted to correlate urethral radiation dosimetry with urinary morbidity,18 but few have found a clear association. In a study by Merrick et al19 an analysis of urethral dosimetry of 13 patients of 425 undergoing implantation who developed urethral strictures was performed. It was determined that dose to the prostatic urethra was not predictive of stricture, but the extent and magnitude of the high dose regions within the prostate were predictive. In view of these findings, it is therefore considered acceptable practice that the urethra remains part of the CTV in treatment planning and should receive the prescription dose, but should not be unnecessarily overtreated as would be typical of a uniform source loading pattern. These data and studies may be reasonably interpreted as supporting the current approach of using a peripherally loaded seed distribution with the urethra receiving the prescription dose. A similar interpretation of these data has also been espoused by Merrick et al.20 Intraprostatic tumor volume and multifocality A number of investigators have examined intraprostatic tumor volume and the extent of multifocality. Intraprostatic tumor volume has been shown to correlate with outcome in a radical prostatectomy series.21 It is an accepted concept that with all other factors being equal, an increased intraprostatic tumor volume is associated with a decreased rate of tumor eradication with radiotherapeutic management. Empiric data from other cancers including head and neck cancer,22 and brain metastases,23 demonstrate that larger tumors require greater doses of radiation to achieve local control than do smaller ones. Therefore, knowledge of data on intraprostatic tumor volume is relevant in considering definitive treatment of prostate cancer by PPB. In the Mayo series of whole-mount prostatectomy specimens, intraprostatic tumor volume was determined in those patients with clinical factors associated with eligibility criteria for PPB monotherapy or brachytherapy combined with external beam radiotherapy (EBRT). These criteria have been set forth by Nag et al24 in the American Brachytherapy Society (ABS) recommendations for patient selection and include serum PSA <20, Gleason sum ≤ 7, and clinical tumor classification
Table 5.1 Clinical characteristics in 313 patients treated by radical prostatectomy. 15 Clinical stage (AJCC 1997)

T1a

3

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T1b 8 T1c 40 T2a 91 T2b 171 Preoperative PSA (ng/mL) 0–3.9 63 4–9.9 95 10–19.9 155 Specimen Gleason score 3 2 4 14 5 107 6 21 7 169 AJ ICC, American Joint Committee on Cancer; PSA, prostate-specie antigen.

Mean tumor volume was found to be 6.7 cc, whereas the median tumor volume was found to be 2.6 cc. Other studies have demonstrated that tumor volume less than 0.2 cc or less than 0.5 cc is frequently found in patients with PSA < 4, T1c tumor stage and Gleason sum of 6 or less.26 Such patients have a low rate of biochemical failure,27 with prostate brachytherapy and a low rate of prostate cancer specific mortality with primary surgical or radiotherapeutic management.28 The radial distance and volume of extraprostatic extension Prior studies have examined extraprostatic extension (EPE) in terms of the area of capsular perforation,29 or the linear extension along or parallel to the prostatic capsule.30 These data do not provide the critical measurement applicable to prostate brachytherapy because the steepest radiation dose gradient is in the direction away from the center of the implanted prostate and not in a direction circumferential or tangential to it.31 Consequently, more recent studies have examined whole-mount prostatectomy series to determine the radial extent of EPE. This distance measures the radial extent of prostate cancer from the prostate capsule, if present at that location, or from the prostate margin roughly perpendicular to the edge of the prostate. The urethra is used as the anatomical origin of this radial measurement whenever possible. The method of measurement is shown in Figures 5.3a, b. Two series provide detailed measurements of radial EPE, the results of which are summarized in Table 5.2. In the Mayo Clinic series a total of 376 specimens were evaluated from patients with clinically organ-confined prostate cancer and no prior hormonal or radiation therapy.32 Detailed measurements of EPE were made and information regarding extraprostatic tumor density and presence of positive surgical margins at the EPE measurement site were noted. In this series, a total of 78 patients with T2 or less clinical stage and no prior history of hormonal or radiation therapy had EPE measurements at sites without positive margins. In the series by Sohayda et al from the Cleveland Clinic,33 38 patients met such criteria. The results of these two studies for patients with clinically organ confined prostate cancer are remarkably alike. In the Mayo

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Clinic series, the range of radial EPE was 0.04–4.0 mm in such patients and in the Cleveland Clinic series, it was 0.1–5.0 mm. Median EPE distances in the two series were 0.5 mm and 1.1 mm, but the Cleveland Clinic series also included patients with clinical T3 tumors. Mean EPE distances in the two series in patients with EPE were 0.8 mm and 1.7 mm, and 90% of low risk patients had EPE that was within 2.0–3.3 mm of the outer edge of the prostate.

Figure 5.3 (a) Schematic representation of the prostate from which the radial extraprostatic extension (EPE) distance was measured with inset shown.32 (b) Schematic representation of the radial EPE distance corresponding to the inset in Figure 53a.32 (Reproduced with permission from Cancer 1999, 85:2630–2637. © 1999)

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Table 5.2 Comparison of results of two published studies on the radial distance of extraprostatic extension (EPE).32,33 Characteristic

Mayo Clinic32 Cleveland Clinic33

No. patients 376 No. with EPE 105 No. with
265 92 38 More recent Yes (6%) Yes (6%) Yes Yes 0.1–5.0 mm 1.1 mm 1.7 mm 3.3 mm

The implications of these studies are that a treatment margin of 3–5 mm from the prostate edge will encompass the vast majority of EPE of tumor in prostate cancer patients deemed appropriate for permanent prostate brachytherapy (PPB) monotherapy. The dose beyond this 3–5 mm margin typically extends another 5 mm beyond this boundary before it declines by 50% when iodine-125 (125I) sources are employed.15,31 Treatment of EPE within this dose fall-off region may well be effective because treatment of EPE in the posterior peripheral zone is constrained by the presence of the rectum. Indeed, RTOG clinical trial 9805 specified a posterior treatment margin of 0 mm from the CTV to the PTV. Other series with a long follow-up also report using a 0 mm treatment margin posteriorly at the mid-gland.27,34 Butzbach et al performed a detailed examination of 22 patients treated with palladium (103Pd) PPB monotherapy and a 3–5 mm margin and determined from postimplant CT-based dosimetry that the dose margin met these criteria.35 Also of relevance is the fact that the amount of cancer in extraprostatic locations is small compared to the volume of intraprostatic cancer. In a study based on the Mayo Clinic whole-mount series,15 the volume of extraprostatic cancer excluding seminal vesicle involvement (SVI) was estimated from a volume formula using the known area of capsular penetration, radial EPE distance, number of EPE sites on the specimen and the estimated cancer density. The formula and illustration of this calculation are shown in Figure 5.4. Extraprostatic cancer volume ranged from 0 cc to 4.6 cc with a mean of only 0.06 cc. The ratio of extraprostatic to intraprostatic cancer volume ranged from 0% to 18% with a mean ratio of only 0.4%. The interpretation of these data suggests that the dose required to treat this small extraprostatic cancer volume may not be as great as that

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Figure 5.4 Schematic representation of the calculation of extraprostatic extension (EPE) cancer volume.15 (Reproduced with permission from Tech Urol 2000, 6:70–76. © 2000) required to treat intraprostatic cancer. Consequently, it is likely that within the region of dose fall-off at the periphery of the prostate small amounts of clinically occult prostate cancer are effectively treated if they are even present at all. However, one should not infer from this supposition that the dose margins set for the PTV should be altered but rather that satisfactory results reported with PPB monotherapy for local control relate to the margin incorporated into defining the PTV. Portions of the PTV margin may be identical to the prostate margin and yet still effectively treat small amounts of extraprostatic cancer within this dose fall-off region. Other factors likely play a more important role in effective treatment of EPE. The most relevant factor relates to the accuracy and resolution of the imaging modalities employed in guiding and documenting PPB source placement. Intra- and interobserver variability of postimplant segmentation of the prostate from CT images occurs between experienced practitioners. In a study by Dubois et al36 this variability in segmentation resulted in differences in prostate dimensions by CT that were typically 5 mm. Statistically significant differences were also found in determination of prostate volume. Similarly, studies by Lee et al37 and Al-Qaisieh,38 have demonstrated that this interobserver variability results in differences in estimation of postimplant dosimetry that are significant in terms of judging the adequacy of an implant. Another factor that may play a role in treatment of extraprostatic extension includes accuracy of seed placement, which, on average, is typically no better than 2.5–5 mm.39–41 Furthermore, seed migration typically occurs in approximately 1% of all loose seeds implanted,42,43 and has been correlated with planned placement of extraprostatic seeds.43 Such migration of seeds

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placed in the periphery of the prostate may work to decrease the extent of the prescription dose in few areas. Although addressed elsewhere in detail in this text, these data also deserve interpretation in the context of giving combined EBRT with PPB. While some advocate treatment of all PPB patients with supplemental EBRT, Potters et al performed a detailed multivariate analysis on over 600 patients treated with either PPB monotherapy alone or combined with EBRT.44 These analyses demonstrated that the radiation dosimetry parameter D90 is the third most important predictor of biochemical failure following Gleason score and serum PSA. Combining EBRT with PPB was insignificant in terms of offering a reduction in biochemical recurrence. Nevertheless, a ‘learning curve’ for clinicians newly engaged in PPB has been described and is associated with marginal dosimetry in early cases.45 Consequently, EBRT given as a supplement to a prostate implant having a suboptimal seed distribution may serve to treat regions of occult EPE at the prostate periphery. Conclusions Detailed histopathologic study of whole-mount prostatectomy specimens from patients with clinically organconfined cancer has provided data useful for evaluating treatment volumes as they relate to the contemporary radiotherapeutic management of prostate cancer. The current practice of permanent prostate brachytherapy includes treatment of the entire urethra to the prescription dose and use of a treatment margin that readily allows for effective therapy of the radial distance and volume of extraprostatic cancer. References 1. Sakr WA, Wheeler TM, Blute M, et al. Staging and reporting of prostate cancel—sampling of the radical prostatectomy specimen. Cancer 1996; 78(2):366–368. 2. Ayala AG, Ro JY, Babaian R, et al. The prostatic capsule: does it exist? Its importance in the staging and treatment of prostatic carcinoma. Amer J Surg Path 1989; 13(l):21–27. 3. International Commission on Radiation Units and Measurements. In: Chassagne D, Dutreix A, eds. Dose and volume specifications for reporting interstitial therapy. ICRU Report No. 58, 1997. 4. Xia P, Pickett B, Vigneault E, et al. Forward or inversely planned segmental multileaf collimator IMRT and sequential tomotherapy to treat multiple dominant intraprostatic lesions of prostate cancer to 90 Gy. Int J Radiat Oncol Biol Phys 2001; 51(1):244–254. 5. Djavan B, Susani M, Bursa B, et al. Predictability and significance of multifocal prostate cancer in the radical prostatectomy specimen. Tech Urol 1999; 5(3):139–142. 6. Douglas TH, McLeod DG, Mostofi FK, et al. Prostate-specific antigen-detected prostate cancer (stage T1c): an analysis of whole-mount prostatectomy specimens. Prostate 1997; 32(1):59–64. 7. Epstein JI, Steinberg GD. The significance of low-grade prostate cancer on needle biopsy. A radical prostatectomy study of tumor grade, volume, and stage of the biopsied and multifocal tumor. Cancer 1990; 66(9):1927–1932. 8. Smith DS, Catalona WJ. The nature of prostate cancer detected through prostate specific antigen based screening. J Urol 1994; 152(5 Pt 2):1732–1736.

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9. Lee WR, Scott C, Lawton C, et al. Health-related quality of life (HRQOL) in men treated with prostate brachytherapy alone on radiation therapy oncology group (RTOG) Trial 98–05. Int J Radiat Oncol Biol Phys 2002; 54(2S):47–48. 10. Bostwick DG, Myers RP, Oesterling JE. Staging of prostate cancer. Semin Surg Oncol 1994; 10(1):60–72. 11. Miller GJ, Cygan JM. Diagnostic correlations with whole mounts of radical prostatectomy specimens. Monogr Pathol 1992; 34:183–197. 12. Pisansky TM, Blute ML, Hillman DW, et al. The relevance of prostatectomy findings in brachytherapy selection for localized prostate cancer. Cancer 2002; 95:513–519. 13. Leibovich BC, Blute ML, Bostwick DG, et al. Proximity of prostate cancer to the urethra: implications for minimally invasive ablative therapies. Urology 2000; 56(5):726–729. 14. Schned AR, Wheeler KJ, Hodorowski CA, et al. Tissue-shrinkage correction factor in the calculation of prostate cancer volume. Am J Surg Pathol 1996; 20(12):1501–1506. 15. Davis BJ, Haddock MG, Wilson TM, et al. Treatment of extraprostatic cancer in clinically organ confined prostate cancer by permanent interstitial brachytherapy: Is extraprostatic seed placement necessary? Tech Urol 2000; 6:70–77. 16. Rubin MA, Bagiella E, Ennis RD. Urethral sparing techniques in prostate brachytherapy and cryosurgery: Is cancer also being spared? Int J Radiat Oncol Biol Phys 2002; 54(2)S:39–40. 17. Ruckstalis DB, Goldknopf JL, Crowley EM, Garcia FU. Prostate cryoablation: a scientific rationale for future modifications. Urology 2002; 60(2A)S: 19–25. 18. Crook J, McLean M, Catton C, et al. Factors influencing risk of acute urinary retention after TRUS-guided permanent prostate seed implantation. Int J Radiat Oncol Biol Phys 2002; 52(2):453–460. 19. Merrick GS, Butler WM, Tollenaar BG, et al. The dosimetry of prostate brachytherapy-induced urethral strictures. Int J Radiat Oncol Biol Phys 2002; 52(2):461–468. 20. Merrick GS, Wallner KE, Butler WM. Permanent interstitial brachytherapy for the management of carcinoma of the prostate gland. J Urol 2003; 169(5):1643–1652. 21. Stamey TA, McNeal JE, Yemoto CM, et al. Biological determinants of cancer progression in men with prostate cancer. JAMA 1999; 281(15):1395–1400. 22. Million RR, Cassisi NJ, Mancuso AA, et al. Management of the neck for squamous cell carcinoma. In: Management of head and neck cancer: a multidisciplinary approach, 2nd edn. Million RR, Cassisi NJ, eds. Philadelphia: JB Lippincott, 1994. 23. Nieder C, Berberich W, Nestle U, et al. Relation between local result and total dose of radiotherapy for brain metastases. Int J Radiat Oncol Biol Phys 1995; 33(2):349–355. 24. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 1999; 44:789–799. 25. Sebo TJ, Cheville JC, Riehle DL, et al. Predicting prostate carcinoma volume and stage at radical prostatectomy by assessing needle biopsy specimens for percent surface area and cores positive for carcinoma, perineural invasion, Gleason score, DNA ploidy and proliferation, and preoperative serum prostate specific antigen: a report of 454 cases. Cancer 2001; 91(11):2196– 2204. 26. Krumholtz JS, Carvalhal GF, Ramos CG, et al. Prostate-specific antigen cutoff of 2.6 ng/mL for prostate cancer screening is associated with favorable pathologic tumor features. Urology 2002; 60(3):469–473. 27. Blasko, J, Grimm P, Sylvester J, et al. Palladium-103 brachytherapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2002; 46:839–850. 28. D’Amico AV, Moul J, Carroll PR, et al. Cancer-specific mortality after surgery or radiation for patients with clinically localized prostate cancer managed during the prostate-specific antigen era. J Clin Oncol 2003; 21(11):2163–2172. 29. Stamey TA, McNeal JE, Freiha FS, Reedwind E. Morphometric and clinical studies on 68 consecutive radical prostatectomies. J Urol 1988; 139:1235–1241.

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30. Epstein JI, Carmichael JM, Pizov G, Walsh PC. Influence of capsular penetration on progression following radical prostatectomy: a study of 196 cases with long-term follow-up. J Urol 1993; 150:135–141. 31. Dawson JE, Wu T, Roy T, et al. Dose effects of seed placement deviations from pre-planned positions in ultrasound guided prostate implants. Radiother Oncol 1994; 32:268–270. 32. Davis BJ, Pisansky TM, Wilson TM, et al. The radial distance of extraprostatic extension of prostate cancer: implications for prostate brachytherapy. Cancer 1999; 85:2630–2637. 33. Sohayda C, Kupelian PA, Levin HS, Klein EA. Extent of extracapsular extension in localized prostate cancer. Urology 2000; 55(3):382–386. 34. Grimm PD, Blasko JC, Sylvester JE, et al. 10-year biochemical (prostate-specific antigen) control of prostate cancer with I-125 brachytherapy. Int J Radiat Oncol Biol Phys 2001; 51(1):31–40. 35. Butzbach D, Waterman FM, Dicker AP. Can extraprostatic extension be treated by prostate brachytherapy? An analysis based on postimplant dosimetry. Int J Radiat Oncol Biol Phys 2001; 51:1196–1199. 36. Dubois DF, Prestidge BR, Hotchkiss LA, et al. Intraobserver and interobserver variability of MR imaging- and CT-derived prostate volumes after transperineal interstitial permanent prostate brachytherapy. Radiology 1998; 207(3):785–789. 37. Lee WR, Roach M 3rd, Michalski J, et al. Interobserver variability leads to significant differences in quantifiers of prostate implant adequacy. Int J Radiat Oncol Biol Phys 2002; 54(2):457–461. 38. Al-Qaisieh B, Ash D, Bottomley DM, et al. Impact of prostate volume evaluation by different observers on CT-based post-implant dosimetry. Radiother Oncol 2002; 62:267–273. 39. Yu Y, Waterman FM, Suntharalingam N, et al. Limitations of the minimum peripheral dose as a parameter for dose specification in permanent 125I prostate implants. Int J Radiat Oncol Biol Phys 1996; 34(3):717–725. 40. Roberson PL, Narayana V, McShan DL, et al. Source placement error for permanent implant of the prostate. Med Phys 1997; 24(2):251–257. 41. Davis BJ, Herman MG, LaJoie WN, et al. Supplemental implantation for suboptimal permanent prostate brachytherapy: a prostate phantom study. Radiother Oncol 2000; 55S:91–92. 42. Tapen EM, Blasko JC, Grimm PD, et al. Reduction of radioactive seed embolization to the lung following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998; 42:1063–1067. 43. Eshleman JS, Davis BJ, Pisansky TM, et al. Radioactive seed migration to the chest following transperineal interstitial permanent prostate brachytherapy: extraprostatic seed placement correlates with migration. Int J Radiat Oncol Biol Phys 2004; 59(2):419–425. 44. Potters L, Cao Y, Calugaru E, et al. A comprehensive review of CT-based dosimetry parameters and biochemical control in patients treated with permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2001; 50(3):605–614. 45. Lee WR, deGuzman AF, Bare RL, et al. Postimplant analysis of transperineal interstitial permanent prostate brachytherapy: evidence for a learning curve in the first year at a single institution. Int J Radiat Oncol Biol Phys 2000; 46(1):83–88.

6 Prostate cancer staging: PSMA-based serum assays and radioscintigraphy Ganesh V Raj and Thomas J Polascik Introduction With the advent of the serum prostate-specific antigen (PSA) assay, men are being diagnosed with prostate cancer at earlier stages. Statistical algorithms, such as the Partin and Kattan nomograms, that incorporate multivariate analyses of several pretreatment variables, provide the clinician with valuable data regarding the likelihood of extraprostatic disease.1,2 For example, a man with newly diagnosed prostate cancer, with a serum PSA of 5.0 ng/mL, a Gleason score of 6 (3+3), and a clinical stage T1c lesion has, according to the Partin Tables, an 80% (78–83) chance of organ-confined disease, 19% (16–21) probability of extraprostatic extension, and 0% (0–1) chance of lymph node invasion.1 With such a high likelihood of organconfined disease, this patient may be a candidate for brachytherapy, external beam radiation, or radical prostatectomy as definitive local treatment for prostate cancer. Recent multi-institutional reports of over 4100 patients treated with radical prostatectomy demonstrated that only 61% of early, non-palpable, PSA-detected tumors (clinical stage T1c, TNM staging, AJCC 2002 guidelines) were organconfined.3–5 However, for any individual patient, the disease is either organ-confined (0%) or not organ-confined (100%). Accurate detection of clinically significant extraprostatic extension (EPE) of prostate cancer at the time of diagnosis would both avoid unnecessary non-curative local therapy as well as identify a subset of patients who could benefit from more aggressive therapeutic interventions. Several approaches including reverse transcriptase polymerase chain reaction (RT-PCR) amplification technologies and alternative prostate-specific markers, such as prostatic acid phosphatase (PAP), have not demonstrated a higher sensitivity and specificity of detection of EPE of newly diagnosed prostate cancer.6–7 Computed tomography (CT) and magnetic resonance imaging (MRI) have been largely ineffective for demonstrating lymph node metastases due to low sensitivity and high false-negative rates. Several attempts were made initially to increase the sensitivity of imaging studies to detect prostate cancer, using radiolabeled monoclonal antibodies (indium-111; 111I) directed against antigens unique to the prostate. Radiolabeled antibodies against both PSA and prostatic acid phosphatase (PAP) were shown to have poor sensitivity in limited early clinical trials.8 However, a US Food and Drug Administration (FDA) approved radiolabeled antibody against the prostate-specific membrane antigen (PSMA), capromab pendetide, marketed under the name ProstaScint® (Cytogen, Princeton, NJ), showed significant promise to detect soft tissue metastases in prostate cancer patients. The

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ProstaScint scan has been shown to detect metastatic lesions as small as 5 mm and hence is associated with a higher sensitivity to detect prostate cancer.9,10 The sensitivity, specificity, and overall accuracy of this radionuclide scan has been reported to be 62%, 72%, and 88% in early analyses,11 and up to 75%, 86%, and 81% in more recent studies, respectively.12–14 In this chapter, we examine the utility of serum and radiological assays directed against PSMA in accurately staging prostate cancer. Serum PSMA assays PSMA, a 100 kD type II transmembrane glycoprotein originally characterized by the monoclonal antibody (mAb) 7E11 (Figure 6.1), has a high tissue-specificity, with expression primarily restricted to the prostate (PSMA references). PSMA is expressed in benign prostatic epithelium, benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN), and prostate cancer.15–19 Interestingly, immunoreactivity of PSMA has been shown to be elevated in PIN and prostate cancer relative to benign prostatic epithelium, with further increased expression of PSMA noted in higher Gleason score tumors, metastatic, and

Figure 6.1 PSMA (prostate-specific membrane antigen) protein structure. PSMA is a transmembrane protein, with distinct extracellular, transmembrane, and intracellular domains. Location of the epitope targeted by the ProstaScint antibody is also shown. (Reproduced with the permission of Cytogen Corporation, Princeton, NJ.) Table 6.1 Characterisitics of PSMA as a marker for prostate 1. Expression is highly specific for prostatic tissue 2. Expression level increased in most prostate cancers 3. Expression level increased with higher Gleason score

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4. Expression level increased with tumor-associated neovasculature 5. Expression level increased at sites of metastatic spread, especially bones 6. Expression level increased with androgen-independent prostate cancer

hormone-refractory disease.15–19 PSMA is also expressed on the surface of tumorassociated but not normal blood vessels. Although the physiologic role of PSMA remains unknown, its expression profile of PSMA makes it an excellent marker for the detection of prostate cancer (Table 6.1). Circulating PSMA in the serum of patients with prostate cancer can be detected using enzyme-linked immunoabsorbent assays (ELISA) and Western blots. Serum PSMA levels have been noted to be elevated in patients with prostate cancer.20 In some patients with hormone-refractory tumors, in whom the serum PSA levels are low, elevated levels of serum PSMA have been noted.20 However, initial hopes that serum PSMA assays could serve an adjunct role in the detection of prostate cancer have not materialized. Serum PSMA assays have been plagued by an inconsistent detection of serum PSMA levels, with some investigators reporting an inability to detect serum PSMA.19 Most of the initial studies with serum PSMA were performed with the 7E11 antibody, which is directed against an intracytoplasmic domain of PSMA. Other antibodies directed against extracytoplasmic domains of PSMA have been developed; however their utility in detecting serum PSMA or staging prostate cancer remains unproven. Additional serum assays incorporating RT-PCR to amplify PSMA in circulating cells have been explored. RTPCR allows for a 109-fold amplification of the signal and may detect a single cell expressing the signal RNA in a background of 109 cells that do not express the targeted sequence.21 If the targeted sequence is highly specific for a tumor or tissue type, then identification of expression of that sequence outside the primary tumor site would indicate that tumor cells have spread beyond the primary site. In other words, detection of the target tissue-specific RNA expression in sites of known clinical metastasis or routes of dissemination suggests micrometastatic deposits or circulating tumor cells. The tissue-specific expression of PSMA in prostatic epithelial cells offers the possibility of using PSMA gene expression as a marker for the detection of occult metastases of prostate cancer. Initial reports utilizing nested primers against PSMA detected circulating cells expressing PSMA in 48/77 patients with prostate cancer, compared to only 7/77 in whom PSA gene expression could be detected.21 However, additional results have been disappointing. Ghossein concluded that while RT-PCR of PSMA was able to detect circulating cells expressing PSMA in up to 63% of patients, it was not sensitive enough to warrant changes in clinical management.22 Currently, this RT-PCR assay for PSMA does not have a proven utility in staging prostate cancer. Future advances in molecular staging may involve quantitative real-time RT-PCR.6 Overall, despite initial promise, serum PSMA assays have been plagued by inconsistency in detection. At the moment, these assays should be considered investigational and not yet ready for clinical application.

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ProstaScint scan A scintigraphic 111I-radiolabeled murine monoclonal antibody reactive with PSMA forms the basis for the capromab pendetide imaging study (ProstaScint®, Cytogen Corporation, Princeton, NJ). The FDA-approved ProstaScint scan utilizes an immunoglobulin G (IgG) murine monoclonal antibody 7E-11-C5.3 (directed against an intracellular N-terminal epitope) conjugated with the linker-chelator glycyl-tyrosyl-(N, diethylenetriaminepentaacetic acid)-lysine (GYK-DTPA) (Figure 6.2). Prior investigations have demonstrated 111In-capromab pende-tide immunoscintigraphy to be safe with mild adverse effects and minimally elevated human antimouse antibody (HAMA) levels on rare occasions.10,11,24 Patients who undergo radioimmunoscintigraphy receive an intravenous injection containing 5.0 mCi of 111In-radiolabeled monoclonal antibody followed by

Figure 6.2 Schematic of the ProstaScint antibody. An immunoglobulin G (IgG) murine monoclonal antibody 7E-11-C53 (directed against an intracellular Nterminal epitope) is conjugated with the linker-chelator glycyl-tyrosyl-(N, diethylenetriaminepentaacetic acid)lysine (GYK-DTPA) and a gammaemitting radionucleotide indium-111 (111In). (Reproduced with the permission of Cytogen Corporation, Princeton, NJ.) planar and cross-sectional, single-photon emission computed tomography (SPECT) images (Figure 6.3). Due to the kinetics of antibody binding, imaging with this agent is best performed approximately 72–120 hours after administration of the isotope. The 2.8 day half-life of 111In facilitates this imaging time interval. Repeat studies are performed 72–120 hours after injection to allow for clearance from the vascular and intestinal

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structures. (Note. imaging times reflect clinical trial experiences and package insert.) Clinical studies have shown that asymmetrical vessels or bone marrow distribution can lead to a false interpretation of the scan without initial and delayed images. Expertise is required for proper interpretation of these scans, making it imperative that the nuclear medicine physician undergo training to become adept at interpretation and to understand the need for proper image acquisition. More details on ProstaScint image acquisition and analyses can be found in the excellent review by Blend and Sodee.25 In a preliminary Phase I study, 40 men with known distant prostate cancer metastases underwent a ProstaScint

Figure 6.3 Normal biodistribution of the capromab pendetide uptake is shown at day 0 and day 4 after administration of the radiolabeled antibody in different planes. (Reproduced with permission from Cytogen Corporation, Princeton, NJ.) scan. There were no adverse reactions. The ProstaScint scan detected bone metastases in 55% of men, including 12 of 14 men receiving hormonal therapy. Soft tissue lesions detected by immunoscinitigraphy were subsequently confirmed in 4 of 6 men.26 In another report, 19 men with biopsy-proven prostate cancer underwent a preoperative ProstaScint scan and pelvic CT or MRI, prior to bilateral pelvic lymph node dissection. The ProstaScint scan detected four of eight men with positive lymph nodes, with a detection threshold in respect to nodal size of 5 mm or greater. Two false-positive scans were noted. The overall sensitivity and specificity of the ProstaScint scan were 44% and 86%, respectively. The authors concluded that ProstaScint scan is safe and capable of detecting soft tissue nodal disease.27

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Although the ProstaScint scan has not been used to formally assess metastatic spread to the bones, initial data suggest that traditional bone scintigraphy is more specific for detection of osseous prostate cancer. In addition, capromab pendetide accumulates in fracture sites and areas of inflammation resulting from arthritis, bursitis, or tendonitis. Thus, the ProstaScint scan is not useful for detection of disease spread to the bones. Two possible clinical uses for ProstaScint include the detection of lymph node disease and occult metastases prior to primary therapy, or the site of relapse in those with a detectable PSA after definitive local therapy. ProstaScint scan in preoperative staging In many men presenting with localized prostate cancer and high-risk criteria (eg PSA≥10 ng/mL, Gleason score ≥7, clinical stage ≥T2b), a thorough preoperative lymph node staging is important since there is a strong association between lymph node involvement and the presence of distant metastasis. With lymph node involvement, cancerspecific survival is decreased and surgery or radiotherapy alone is likely not curative. In a recent series of men with clinically localized prostate cancer treated with radical prostatectomy, the actuarial 10 year metastasis-free survival was 99% for patients with organ-confined disease and 68% for those with micrometastases to the pelvic lymph nodes.5 Most prostate cancers are thought to spread through the lymphatic channels in a sequential manner, usually first involving the obturator, then internal iliac followed by the external iliac lymph nodes. Later, it progresses distally to the common iliac, retroperitoneal, and mesenteric lymph nodes, and eventually into the mediastinal and supraclavicular lymph nodes. Occasional skip metastases may be noted. The ProstaScint scan can simultaneously evaluate the entire body for lymph node spread (Figures 6.4– 6.6). Although pelvic lymphadenectomy is considered to be the gold standard to determine lymphatic metastases, this procedure largely only samples the middle chain of the external iliac lymphatic vessels and does not provide information about other nodal groups or alternative lymphatic drainage patterns. In a study of over 750 autopsy cases of prostate cancer with metastases, Saitoh et al determined that there was an alternate lymphatic drainage pattern of prostate cancer involving the paraaortic lymph node chain alone.28 These authors found that over 50% of 23 cases with metastases confined to the lymph nodes involved the paraaortic nodes in the absence of pelvic nodal involvement. In a large autopsy study of 1589 patients with prostate cancer, 415 of whom had concurrent lymphatic involvement, paraaortic nodal disease (75%) was seen more often than cancer in the pelvic lymph nodes (55%).29 The metastatic pattern of prostate cancer from these autopsy studies is surprisingly similar to that seen with the ProstaScint scan. In one study, 23% of patients showed uptake of capromab pendetide in paraaortic nodes and 22% in pelvic lymph nodes (Figure 6.6).13 In a separate report, 12 of 152 evaluable patients had evidence of soft tissue metastases by 111In-capromab pendetide immunoscintigraphy in areas outside the field of the pelvic lymph node dissection and were negative for malignancy within the field of the pelvic lymph node dissection.30 Thus, the absence of pelvic lymph node involvement by histologic examination does not exclude the presence of metastatic soft tissue disease. Results from both autopsy and ProstaScint scans suggest

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that prostate cancer has an alternative lymph node pattern of metastasis. In this respect, 111 In-capromab pendetide immunoscintigraphy may be a more sensitive indicator of soft tissue involvement since it can evaluate the whole body for metastatic disease. In another clinical trial, investigators scanned radical prostatectomy candidates before surgery who were considered to be at relatively high risk (a Gleason score ≥7, PSA ≥20 ng/mL, clinical ≥T3 disease, or equivocal CT or MRI suggesting evidence of lymph node metastasis) for lymph node metastasis.31,32 Of the 64 patients with surgically confirmed pelvic lymph node metastases, 40 ProstaScint scans were interpreted as positive, giving the ProstaScint scan a superior (62%) sensitivity compared to CT (4%) or MRI (15%) in the same group. Logistic regression analyses demonstrated that the ProstaScint scan was the most powerful single predictor of metastatic disease when compared with any other variable, including PSA or Gleason score. For patients with a PSA≥40 ng/mL and a Gleason sum ≥7, the positive predictive value of radioimmunoscintigraphy was greater than 80%.31 In their analyses of 48 men undergoing pelvic lymph node dissection and biopsy of scan-positive areas prior to radical prostatectomy, Hinkle and colleagues showed that the ProstaScint scan had a 75% sensitivity and 86% specificity.14,33 Further, in a study of 275 patients receiving

Figure 6.4 Normal biodistribution of capromab pendetide. Serial sections of the whole body imaging showing normal capromab pendetide uptake at days after administration of the radiolabeled antibody. (Reproduced with permission from Drs Terence

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Wong and Edward Coleman, Duke University Medical Center, Durham, NC) treatment for prostate cancer with nodal disease or metastatic disease determined by either surgery or bone scan, respectively, Murphy et al found that incorporation of ProstaScint, PSA level, and bone scan results into artificial neural networks indicated that ProstaScint results were a significant prognostic variable for non-localized cancer.34–36 Another study of 198 patients with high risk preoperative parameters (mean PSA: 57.2 ng/mL, mean biopsy Gleason score: 7.1) examined the utility of the ProstaScint scan in comparison to or in combination with several clinical algorithms to evaluate the probability of lymph node involvement.30 This study used histologic verification of the pelvic lymph nodes obtained by surgical lymphadenectomy as a basis to compare the utility of the clinical algorithms and 111In-capromab pendetide immunoscintigraphy for predicting lymph node involvement. PSMA expression correlated with histologic findings, and 88% of PSMA-positive lymph nodes had histologic evidence of metastatic prostate cancer. In contrast, none of the PSMA negative lymph nodes were found to have cancer present. Comparing surgical lymphadenectomy specimens with PSMA staining and the ProstaScint scan is the best available model for such a comparison despite the fact that as many as 33% of patients with clinically localized prostate cancer have isolated metastases in lymphatic chains distinct from the boundaries of the standard pelvic lymph node dissection.1,2 For example, a man with a clinical classification T3a tumor, PSA level of 21 ng/mL, and biopsy Gleason score of 8 has the following probabilities of lymph node metastases according to the various algorithms: 33% (Roach et al),37 42% (Partin et al),1 43% (Bluestein et al),38 and 70% (Sands et al).39 The positive predictive value (PPV) of the clinical algorithms ranged from 40.5% to 46.6% with an area under the receiveroperating-characteristic (ROC) curve of 0.52 to 0.61. The

Figure 6.5 Detection of metastatic disease. Whole body imaging shows

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uptake of capromab pendetide at various locations outside the prostate in a patient with metastatic spread of disease after a radical prostatectomy. (Reproduced with permission from Cytogen Corporation, Princeton, NJ.) 111

In-capromab pendetide scan had a sensitivity of 67%, a specificity of 80%, a positive predictive value (PPV) of 66.7%, and a negative predictive value (NPV) of 73%, with an area under the ROC curve of 0.71. Combining the results of the 111In-capromab pendetide scan with one or more clinical algorithms using logistic regression analysis increased the PPV to 72%.30 Since the PPV is the most important measure to determine whether a patient would benefit from staging lymphadenectomy prior to definitive local therapy, this study suggests that 111In-capromab pendetide immunoscintigraphy is a strong independent predictor and that combining the results of the nuclear scan with clinical algorithms increases the predictive power to determine the likelihood of lymph node metastases. However, data from other investigators are not congruent with these findings.40 In a smaller series of 22 patients undergoing staging pelvic lymphadenectomy and radical surgery, the preoperative ProstaScint scan was evaluated with definitive histological data. Of nine areas of ProstaScint uptake, only one was noted to be a true positive, while five areas showing no ProstaScint uptake were noted to be false negative, giving this scan a 17% sensitivity, 90% specificity, 94% NPV, and 11% PPV. In summary, in men newly diagnosed with prostate cancer and with high risk of lymph node involvement, ProstaScint immunoscintigraphy may detect lymph node metastases not identified by CT or MRI. Currently, ProstaScint does not appear to be an important part of the initial assessment of most patients with low risk pathological features (low serum PSA, Gleason score ≤6 ng/mL, clinical stage ≤T2a). The ProstaScint scan may help to provide more accurate staging of clinically localized prostate cancer prior to definitive therapy and may help guide clinical decision making in patients with intermediate risk and high risk characteristics. However, the significance of an incongruent positive or negative result is not currently clear. Further, long-term data on the clinical utility of the ProstaScint scan is lacking at the present time and needs to be evaluated in randomized controlled trials. ProstaScint scan in detection of recurrent disease Several studies have demonstrated that over 30% of men will experience biochemical recurrence (elevation in the serum PSA level above the limit of detection) of prostate cancer after definitive treatment with long-term (greater than 10 years) follow-up.3–5,41–43 Cancer recurrence may

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Figure 6.6 Detection of cancer spread to lymph nodes, (a) Biopsy confirmed cases of spread to periaortic lymph nodes and (b) internal iliac lymph nodes in patients with newly diagnosed prostate cancer prior to definitive local intervention. (Reproduced with permission from Cytogen Corporation, Princeton, NJ.) occur locally in the prostatic fossa, or may be seen in the regional nodes, or other distant sites. The site of cancer recurrence may potentially identify the utility of local salvage interventions or systemic therapy (i.e. patients with localized recurrence may be candidates for salvage local therapy), while those with distant recurrence should consider systemic therapy. Classification of recurrent prostate cancer into locally recurrent or systemic disease has been limited by available radiologic imaging techniques. Traditionally, most patients evaluated for an elevated postsurgical serum PSA level undergo a CT scan or bone

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scintigraphy. CT scans of the abdomen and pelvis require tumor deposits, in general, to be greater than 10–15 mm prior to detection, and further, the finding of radiographically enlarged lymph nodes is not diagnostic of cancer.44,45 Bone scans are limited to the potential detection of bone metastasis, and often are associated with a high serum PSA level (>40 ng/mL).46,47 Thus, the sensitivity of CT and bone scans is technically limited and ineffective for differentiating local from distant disease for patients with early evidence of biochemical progression (detectable serum PSA).47,48 Thus, the requirement of a sufficiently large tumor burden prior to detection by conventional radiographic studies or digital rectal examination, and biopsies of the prostatic fossa precludes their use in directing treatment of patients with early recurrent prostate cancer. Here again, we examine the utility of radioimmunoscintigraphy directed against PSMA to accurately stage prostate cancer prior to and after definitive treatment. Preliminary results from the ProstaScint Study Group suggest that ProstaScint imaging can help differentiate between local and distant recurrence in patients with prostate cancer in whom the only evidence of disease after definitive therapy is a detectable PSA level (average 28.7 ng/mL, median: 13.8). In this study of 48 men, the ProstaScint scan was positive in 38 men, with 3 showing uptake localized to the prostatic fossa only and 35 showing evidence of disease beyond the prostatic fossa.49 What is the sensitivity of detection of the ProstaScint scan in recurrent prostate cancer? Or, put another way, how early after biochemical failure can the ProstaScint scan show uptake? In one study, 68% (23/34) of patients with biochemical failure after surgical intervention and serum PSA ≤ 4.0 ng/mL showed evidence for capromab pendetide uptake, in comparison to 75% (12/16) with serum PSA levels >4.0 ng/mL.50 In a large multicenter study of 877 patients with a mean serum PSA of 8.9 ng/mL after surgical resection of the prostate, a 10-fold increase in serum PSA was associated with a 1.23-fold higher risk of a positive capromab pendetide uptake in the prostatic fossa.51 Additional studies have suggested that a low serum PSA level after primary treatment of prostate cancer may be associated with a negative ProstaScint scan.11,34,45 In a published series of 255 patients with biochemical evidence of disease after radical prostatectomy and having a mean postoperative serum PSA level of 1.1 ng/mL, 185 (73%) demonstrated uptake of the monoclonal antibody.52 Localized uptake (prostatic fossa only) (Figure 6.7) was detected in 78 patients (30.6%), regional uptake (regional nodes ± prostatic fossa, with no evidence of distant uptake) in 109 patients (42.8%), and distant uptake (any uptake in distant nodes and/or bone) in 75 patients (29.4%). No minimum serum PSA level was necessary for

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Figure 6.7 Detection of recurrent disease. Biopsy confirmed case of recurrence in the prostatic fossa in a 54-year-old patient with PSA 2.4 ng/mL after radical prostatectomy. (Reproduced with permission of Cytogen Corporation, Princeton, NJ.) Table 6.2 Utility of 111In-capromab pendetide scintigraphy (ProstaScint®) for detecting disease recurrence in patients with serum PSA≤4.0 ng/mL study

serum PSA cutoff No. patients Positive scans Local uptake

Sodee et al51 3.6 ng/mL Elgamal et al34 1.0 ng/mL Petronis et al50 4.0 ng/mL Raj et al52 4.0 ng/mL

8 38 34 255

7(88%) 4 (50%) 30 (79%) 14(37%) 23 (68%) Not reported 185 (72%) 78 (30.6%)

monoclonal antibody uptake, either locally, regionally, or distantly (Table 6.2). Overall, the data indicate that the true utility of the ProstaScint scan lies in the detection and localization of early recurrent disease after definitive local intervention. If uptake of the monoclonal antibody represents cancer recurrence, the implication is that the ProstaScint scan may help to clinically stratify patients with biochemical failure after definitive local therapy into those with local, regional, or distant recurrent disease.36,53 Pelvic radiation given to all patients with biochemical failure demonstrates a sustained remission in about half over a 12 month period.54 However, the utility of salvage therapy is controversial, with other reports indicating less favorable outcomes.55– 57 The utility of the ProstaScint scan in differentiating local from distant recurrence after radical prostatectomy is to better select patients for possible salvage therapy to the prostatic bed and avoid unnecessary salvage treatment in those with metastatic disease.43,49,58,59

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The clinical importance of localized ProstaScint uptake in directing therapeutic options was explored in one interesting study.60 This study involved ProstaScint scanning of 32 men who had biochemical evidence of recurrence (PSA >0.3 ng/mL) following definitive local intervention and prior to salvage radiation therapy. Durable complete response to radiation therapy (PSA<0.3 ng/mL) for more than 6 months was achieved in 70% (16/23) of men with no evidence of radiolabeled antibody uptake outside the prostatic fossa. A follow-up study indicated that 61% still had durable complete response at longer follow-up (>35 months), suggesting that the treatment effectively ablated the recurrent tumor. In contrast, of nine men who had evidence of radiolabeled antibody uptake outside the prostatic fossa, only 2 (22%) had durable complete response to salvage radiation therapy. In another study, in a subset of 95 patients for whom the site of recurrence was established, a positive ProstaScint scan was found to have 73% sensitivity, 53% specificity, and an 89% positive predictive value (PPV) of the site of disease.52 Regional uptake of the antibody (n=60) was found to correlate with disease with 76% sensitivity, 54% specificity, and 90% PPV. Distant uptake of the antibody (n=46) was found to correlate with disease with 69% sensitivity, 58% specificity and 90% PPV. In comparison, a positive CT and/or bone scan result (n=20) was associated with 21% sensitivity, 63% specificity, and 65% PPV of disease detection. These data taken together suggest that ProstaScint imaging can be used to differentiate between patients who may respond to salvage local therapy after failed definitive local therapy. However, in a recent report, for patients with postprostatectomy biochemical relapse who received salvage radiation therapy (RT), presalvage RT In-mab scan findings outside the prostate fossa were not predictive of biochemical control after RT.61 Using an American Society of Therapeutic Radiation and Oncology (ASTRO) definition of PSA failure, in men with a positive scan in at least one location (n=14), the cumulative 2 year PSA control after salvage RT was 0.38±0.13 compared with 0.31±0.13 for men with a normal antibody scan in and outside the prostate fossa (n=15). Clearly, randomized controlled prospective trials are needed to evaluate the true utility of the ProstaScint scan as an adjunct to clinical decision making. Limitations of the ProstaScint scan The primary limitation of our and other studies is a lack of histological confirmation of the ProstaScint signal. Previous studies have indicated that a positive ProstaScint scan correlates well with histologic evidence of metastatic prostate cancer.10,32,33,62,63 Clinical follow-up data in a few patients with disease progression in one study suggest a correlation between regions of uptake and metastatic lesions, but the numbers of patients are too small for meaningful analyses.52 The limited and variable follow-up also does not allow for computation of the true clinical utility of this scan to detect recurrence. Further, the followup data may have a selection bias and may enhance the apparent effectiveness of this scan. Longer follow-up is needed to determine whether ProstaScint immunoscintigraphy correlates with clinical outcomes. Second, since the ProstaScint scan employs a murine monoclonal antibody, consideration must also be given to human antimouse antibody (HAMA) reaction.

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Although rare, this host response against the antibody may present a risk for a hypersensitivity reaction, as represented by urticaria, bronchospasm, or even hypotension and anaphylaxis. HAMA formation occurred in 8% after the initial and 19% following the secondary infusion of antibodies. However, the HAMA reaction was transient and mild, and not associated with any adverse outcomes. Administration of the ProstaScint scan to patients, who have HAMA to a prior mouse antibody exposure, may elicit a stronger immune HAMA response and should be used with caution. Hyperbilirubinemia, hypotension, and hypertension occurred in 1% of patients in clinical trials. To overcome this, murine antibodies have now been ‘humanized’ with recombinant DNA technology. Third, as previously mentioned, the target of the ProstaScint scan with the 7E-11 antibody is an epitope on the intracellular domain of PSMA. In general, antibodies that target an intracellular epitope are thought to be at a distinct disadvantage in comparison to those targeting extracellular epitopes. If the antigen is intracellular, targeting with antibodies should theoretically only react with those tumor areas at which cell necrosis permeabilizes the cell membrane to the antibody. These may be relevant in rapidly growing tumors that outgrow their blood supply and thus have areas of cell death. Generally, prostate cancer grows slowly and it does not have areas of necrosis, unless visualized after androgen deprivation therapy. However, the true in vivo situation with monoclonal antibody directed against 7E-11 is not known. Fourth, pooling of radiolabeled antibodies in a wellvascularized tumor can give the appearance of a positive scan when compared to background. Thus, it is not surprising that the occasional hypervascular renal tumor may show a false-positive ProstaScint uptake, reflecting more the temporal pooling of the antibody rather than reaction with PSMA epitope. Similarly, asymmetric blood vessels, aneurysms, varices, and other vascular malformations may give false-positives: however, careful correlation with blood-pooled images should eliminate these diagnoses. Further, capromab pendetide may nonspecifically accumulate in inflammatory lymph nodes. Focal uptake in an abnormal location, like cervical lymph nodes, without corresponding uptake in the abdominal or pelvic lymph nodes, should be cautiously interpreted and confirmed with clinical, radiological, or tissue findings. Lastly, the skill required to interpret nuclear scintigraphy is paramount in the analysis of the ProstaScint scan. Trained radiologists must be familiar with the detailed anatomy of the human pelvis to interpret normal and abnormal capromab pendetide uptake. Cytogen Corporation requires training and certification in a special training program (Partners in Excellence) so that the nuclear medicine radiologist can accurately interpret the scan. The correlation with three-dimensional (3D) imaging and superimposition of ProstaScint images with CT, positron emission tomography (PET), or MRI may ultimately be required to delineate the true utility of radiolabeled monoclonal antibodies (Figures 6.9 and 6.10). ProstaScint and brachytherapy Although most of the published data examine the utility of ProstaScint scan before and after radical prostatectomy, many conclusions are also applicable to brachytherapy. Fusion of pelvic CT and ProstaScint scans has been used to individualize brachytherapy

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implantation, with placement of additional seeds in areas of high ProstaScint uptake, while at the same time decreasing the dose to normal structures, where possible.64 One important caveat to note for post-brachytherapy recurrence, in contrast to the data presented for radical prostatectomy series, is concerns that after brachytherapy, residual normal prostate tissue expressing PSMA may be present. Following brachytherapy, uptake of capromab pendetide in the periprostatic or perirectal soft tissue may be seen due to chronic inflammation. This situation can persist for years after treatment, making it more difficult to diagnose residual or recurrent disease within the radiation field. However, in a majority of cases, there was less epithelial atypia in periprostatic tissue biopsied >48 months after treatment compared with those with a shorter interval between biopsy and treatment.65 The true utility of ProstaScint scinitigraphy in these patients is to examine the lymph nodes for any evidence of metastatic spread of disease (Figure 6.8). Clearly, as evidenced for patients after radical prostatectomy, the ProstaScint scan can detect lesions in lymph nodes with a greater degree of sensitivity than traditional imaging modalities of CT and bone scanning. Fusion imaging combining MRI with the ProstaScint scan may have a higher sensitivity and specificity (Figure 6.9). Future developments In 1997, new monoclonal antibodies reactive to the extracellular domain of PSMA were identified. The coupling of one of these antibodies, J591, with indium-111 has shown promise in both radioimmunolocalization and radioimmunotherapy of recurrent disease in preliminary trials.66 Newer scans using dual isotope imaging involving simultaneous indium-111 monoclonal antibody and

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Figure 6.8 Detection of recurrent disease after brachytherapy. Whole body imaging showing capromab pendetide uptake in a patient with rising PSA 6 months after brachytherapy for localized prostate cancer. (Reproduced with permission from Dr Samuel Kipper, Pacific Coast Imaging, Irvine, CA.)

Figure 6.9 Detection of recurrent disease after brachytherapy. Fusion imaging with a CT scan demonstrating

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localized capromab pendetide uptake in a patient with rising PSA 6 months after brachytherapy for localized prostate cancer. (Reproduced with permission from Dr Samuel Kipper, Pacific Coast Imaging, Irvine, CA.)

Figure 6.10 Co-registration with CT scanning. Co-registration with CT scanning shows extraprostatic uptake of capromab pendetide in a patient with newly diagnosed prostate cancer. (Reproduced with permission from Drs Terence Wong and Edward Coleman, Duke University Medical Center, Durham, NC.) technetium-99 RBC (red blood cell) SPECT acquistion help subtract the vascular component of the scans and help minimize the false-positive signals seen in highly

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vascular tissues.67 Further, three-dimensional image reconstruction and CT/MRI overlay may improve the accuracy of the ProstaScint scan (Figure 6.10).68,69 Conclusions Although PSMA appears to be an optimal marker for prostate cancer, serum PSMA assays have been plagued by inconsistency in detection and are not yet ready for clinical application. PSMA-based immunoscintigraphy appears to have a smaller threshold for detection of extraprostatic soft tissue spread of prostate cancer before and after definitive local intervention. Enhanced sensitivity of the ProstaScint scan over traditional imaging modalities may be related to the increased detectability of the radiolabeled antibody.70–72 Fewer prostate cells and thus smaller lesions may be needed for a positive signal on a ProstaScint scan. In men newly diagnosed with prostate cancer and with a high risk of lymph node involvement, 111In-capromab pendetide immunoscintigraphy may detect lymph node metastases not detectable by CT or MRI. The ProstaScint scan may help provide more accurate staging of clinically localized prostate cancer prior to definitive therapy in patients with intermediate risk and high risk pathological features. However, long-term data on the clinical utility of the ProstaScint scan needs to be evaluated in randomized controlled trials. Many studies have shown that the ProstaScint imaging can help differentiate between local and distant recurrence in patients with prostate cancer in whom the only evidence

Table 6.3 Current indications for ProstaScint scans For primary prostate cancer • Staging patients who are at high risk (Gleason score>7, PSA>10, stage>cT2b) for metastatic disease • When evaluating patients with discordant PSA, Gleason score, and clinical stages For recurrent prostate cancer • For staging patients with early as with early biochemical failure after definitive local theraphy to help guide clinical decision making

of disease after definitive therapy is a detectable prostatespecific antigen (PSA) level. Several preliminary reports indicate that ProstaScint imaging may be used to differentiate between patients who may respond to salvage local therapy after failed definitive local therapy. The current indications for the ProstaScint scan are outlined in Table 6.3. While this radioimmunoscintigraphy scan holds much promise in elucidating the biology of prostate cancer, its utility in clinical decision making has not been clearly proven. Large scale randomized controlled studies are needed to establish the prognostic significance of a positive ProstaScint scan.

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References 1. Partin AW, Kattan MW, Subong MS, et al. Combination of prostatespecific antigen, clinical stage and Gleason score to predict pathological stage of localized prostate cancer: a multiinstitutional update. JAMA 1999; 277:1445–1451. 2. Kattan MW, Eastham JA, Stapleton AMF, et al. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 1998; 90:766–771. 3. Pound CR, Partin AW, Epstein JI, Walsh PC. PSA following anatomical radical retropubic prostatectomy: patterns of recurrence and cancer control. Urol Clin North Am 1997; 24:395– 406. 4. Pound CR, Partin AW, Eisenberger MA, et al. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999; 281:1591–1597. 5. Han M, Partin AW, Zahurak M, et al. Biochemical (prostate specific antigen) recurrence probability following radical prostatectomy for clinically localized prostate cancer. J Urol 2003; 169(2):517–523. 6. Gomella LG, Raj GV, Moreno JG. Reverse transcriptase polymerase chain reaction for prostate specific antigen in the management of prostate cancer. J Urol 1997; 158(2):326–337. 7. Polascik TJ, Oesterling JE, Partin AW. Prostate specific antigen: a decade of discovery—what we have learned and where we are going. J Urol 1999; 162(2):293–306. 8. Babaian RJ, Lamki LM. Radioimmunoscintigraphy of prostate cancer. Semin Nucl Med 1989; 19(4):309–321. 9. Murphy GP, Maguire RT, Rogers B, et al. Comparison of serum PSMA, PSA levels with results of Cytogen-356 ProstaScint scanning in prostatic cancer patients. Prostate 1997; 33:281–285. 10. Haseman MK, Reed NL, Rosenthal SA. Monoclonal antibody imaging of occult prostate cancer in patients with elevated prostatespecific antigen: Positron emission tomography and biopsy correlation. Clin Nucl Med 1996; 21:704–713. 11. Haseman MK, Rosenthal SA, Polascik TJ. Capromab pendetide imaging of prostate cancer. Cancer Biother Radiopharm 2000; 15(2):131–140. 12. Kahn D, Williams RD, Seldin DW, et al. Radioimmunoscintigraphy with 111-indium labeled CYT-356 for the detection of occult prostate cancer recurrence. J Urol 1994; 152:1490–1495. 13. Kahn D, Williams RD, Manyak MJ, et al. 111In-capromab pendetide in the evaluation of patients with residual or recurrent prostate cancer after radical prostatectomy. J Urol 1998; 159:2041–2047. 14. Hinkle GH, Burgers JK, Neal CE, et al. Multicenter radioimmunoscintigraphic evaluation of patients with prostate carcinoma using indium111 capromab pendetide. Cancer 1998; 83:739– 747. 15. Wright GL, Haley C, Beckett ML, Schellhammer PF. Expression of prostate-specific membrane antigen in normal, benign and malignant prostate tissues. Urol Oncol 1995; 1:18–28. 16. Sweat SD, Pacelli A, Murphy GP, Bostwick DG. Prostate-specific membrane antigen expression is greatest in prostate adenocarcinoma and lymph node metastases. Urology 1998; 52(4):637–640. 17. Silver DA, Pellicer I, Fair WR, et al. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res 1997; 3(1):81–85. 18. Lapidus RG, Tiffany CW, Isaacs JT, Slusher BS. Prostate-specific membrane antigen (PSMA) enzyme activity is elevated in prostate cancer cells. Prostate 2000; 45(4):350–354. 19. Chang SS, Heston WD. The clinical role of prostate-specific membrane antigen (PSMA). Urol Oncol 2002; 7(1):7–12.

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20. Douglas TH, Morgan TO, McLeod DG, et al. Comparison of serum prostate specific membrane antigen, prostate specific antigen, and free prostate specific antigen levels in radical prostatectomy patients. Cancer 1997; 80(1):107–114. 21. Raj GV, Moreno JG, Gomella LG. Utilization of polymerase chain reaction technology in the detection of solid tumors. Cancer 1998; 82(8):1419–1442. 22. Ghossein RA, Osman I, Bhattacharya S, et al. Detection of prostatic specific membrane antigen messenger RNA using immunobead reverse transcriptase polymerase chain reaction. Diagn Mol Path 1999; 8(2):59–65. 23. Su SL, Boynton AL, Holmes EH, et al. Detection of extraprostatic prostate cells utilizing reverse transcription-polymerase chain reaction. Semin Surg Oncol 2000; 18(1):17–28. 24. Sodee DB, Conant R, Chalfant M, et al. Preliminary imaging results using In-111 labeled CYT356 (ProstaScint®) in the detection of recurrent prostate cancer. Clin Nucl Med 1996; 21:759– 767. 25. Blend MJ, Sodee DB. ProstaScint: An update. In: LM Freeman ed. Nuclear medicine annual. Philadelphia: Lippincott, Williams & Wilkins, 2001:109–138. 26. Wynant GE, Murphy GP, Horoszewicz JS, et al. Immunoscintigraphy of prostatic cancer: preliminary results with 111In-labeled monoclonal antibody 7E11-C5.3 (CYT-356). Prostate 1991; 18(3):229–241. 27. Babaian RJ, Sayer J, Podoloff DA, et al. Radioimmunoscintigraphy of pelvic lymph nodes with 111indium-labeled monoclonal antibody CYT-356. J Urol 1994; 152(6):1952–1955. 28. Saitoh H, Yoshida K, Uchijima Y, et al. Two different lymph node metastatic patterns of a prostatic cancer. Cancer 1990; 65(8):1843–1846. 29. Bubendorf L, Schopfer A, Wagner U, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol 2000; 31(5):578–583. 30. Polascik TJ, Manyak MJ, Haseman MK, et al. Comparison of clinical staging algorithms and 111indium-capromab pendetide immunoscintigraphy in the prediction of lymph node involvement in high risk prostate carcinoma patients. Cancer 1999; 85(7):1586–1592. 31. Manyak MJ, Hinkle GH, Olsen JO, et al. Immunoscintigraphy with 111In-Capromab Pendetide: Evaluation before definitive therapy in patients with prostate cancer. Urology 1999; 54:1058– 1063. 32. Manyak MJ. Clinical applications of radioimmunoscintigraphy with prostate-specific antibodies for prostate cancer. Cancer Control 1998; 5(6):493–499. 33. Hinkle GH, Burgers JK, Olsen JO, et al. Prostate cancer abdominal metastases detected with Indium In-111 Capromab Pendetide. J Nucl Med 1998; 39:650–653. 34. Elgamal AA, Troychak MJ, Murphy GP. ProstaScint scan may enhance identification of prostate cancer recurrences after prostatectomy, radiation, or hormone therapy: analysis of 136 scans of 100 patients. Prostate 1998; 37(4):261–269. 35. Murphy GP, Elgamal AA, Troychak MJ, Kenny GM. Follow-up ProstaScint scans verify detection of occult soft-tissue recurrence after failure of primary prostate cancer therapy. Prostate 2000; 42(4):315–317. 36. Murphy GP, Snow PB, Brandt J, et al. Evaluation of prostate cancer patients receiving multiple staging tests, including ProstaScint scintiscans. Prostate 2000; 42(2): 145–149. 37. Roach M III, Marquez C, Hae-Sook Y, et al. Predicting the risk of lymph node involvement using the pre-treatment prostate-specific antigen and Gleason score in men with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1994; 28:33–37. 38. Bluestein DL, Bostwick DG, Bergstralh EJ, Oesterling JE. Eliminating the need for bilateral pelvic lymphadenectomy in select patients with prostate cancer. J Urol 1994; 151:1315–1320. 39. Sands ME, Zagars GK, Pollack A, von Eschenbach AC. Serum prostate-specific antigen, clinical stage, pathologic grade, and the incidence of nodal metastases in prostate cancer. Urology 1994; 44:215–220. 40. Ponsky LE, Cherullo EE, Starkey R, et al. Evaluation of preoperative ProstaScint scans in the prediction of nodal disease. Prostate Cancer and Prostatic Diseases 2002; 5(2):132–135.

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41. Partin AW, Pound CR, Clemens JQ, et al. Serum PSA after anatomical radical prostatectomy: the Johns Hopkins experience after 10 years. Urol Clin North Am 1993; 20:713–725. 42. Partin AW, Pearson JD, Landis PK, et al. Evaluation of serum prostate specific antigen velocity after radical prostatectomy to distinguish local recurrence from distant metastasis. Urology 1994; 43(5):649–659. 43. Moul JW. Prostate specific antigen only progression of prostate cancer. J Urol 2000; 163(6): 1632–1642. 44. Kramer S, Goricj J, Gottfried HW, et al. Sensitivity of computed tomography in detecting local recurrence of prostatic carcinoma following radical prostatectomy. Br J Radiol 1997; 70(838):986–991. 45. Seltzer MA, Barbaric Z, Belldegrun A, et al. Comparison of helical computerized tomography, positron emission tomography and monoclonal antibody scans for evaluation of lymph node metastases in patients with prostate specific antigen relapse after treatment for localized prostate cancer. J Urol 1999; 162(4):1322–1328. 46. Cher ML, Bianco FJ, Lam JS, et al. Limited role of radionuclide bone scintigraphy in patients with prostate specific antigen elevations after radical prostatectomy. J Urol 1998; 160(4):1387– 1391. 47. Manyak MJ, Javitt MC. The role of computerized tomography, magnetic resonance imaging, bone scan, and monoclonal antibody nuclear scan for prognosis prediction in prostate cancer. Semin Urol Oncol 1998; 16(3):145–152. 48. Tempany CM, Zhou X, Zerhouni EA, et al. Staging of prostate cancer: results of Radiology Diagnostic Oncology Group project comparison of three MR imaging techniques. Radiology 1994; 193:47–54. 49. Levesque PE, Nieh PT, Zinman LT, et al. Radiolabeled monoclonal antibody indium 111labeled CYT-356 localizes extraprostatic recurrent carcinoma after prostatectomy. Urology 1998; 51:978–984. 50. Petronis JD, Regan F, Lin K. Indium-111 capromab pendetide imaging to detect recurrent and metastatic prostate cancer. Clin Nucl Med 1998;23(10):672–677. 51. Sodee DB, Malguria N, Faulhaber P, et al. Multicenter prostascint imaging findings in 2154 patients with prostate cancer. Urology 2000; 56:988–993. 52. Raj GV, Partin AW, Polascik TJ. Clinical utility of indium 111capromab pendetide immunoscintigraphy in the detection of early, recurrent prostate carcinoma after radical prostatectomy. Cancer 2002; 94(4):987–996. 53. Fang DX, Stock RG, Stone NN, et al. Use of radioimmunoscintigraphy with indium-111labeled CYT-356 (ProstaScint) scan for evaluation of patients for salvage brachytherapy. Tech Urol 2000; 6(2):146–150. 54. Anscher MS, Clough R, Dodge R. Radiotherapy for a rising prostatespecific antigen after radical prostatectomy: the first 10 years. Int J Radiat Oncol Biol Phys 2000; 48(20):369–375. 55. Cadeddu JA, Partin AW, DeWeese TL, Walsh PC. Long-term results of radiation therapy for prostate cancer recurrence following radical prostatectomy. J Urol 1998; 159(1):173–177. 56. Vicini FA, Ziaja EL, Kestin LL, et al. Treatment outcome with adjuvant and salvage irradiation after radical prostatectomy for prostate cancer. Urology 1999; 54(1):111–117. 57. Peschel RE, Robnett TJ, Hesse D, et al. PSA based review of adjuvant and salvage radiation therapy vs. observation in postoperative prostate cancer patients. Int J Cancer 2000; 90(1):29– 36. 58. Lamb HM, Faulds D. Capromab pendetide. A review of its use as an imaging agent in prostate cancer. Drugs Aging 1998; 12(4):293–304. 59. Burgers JK, Hinkle GH, Haseman MK. Monoclonal antibody imaging of recurrent and metastatic prostate cancer. Semin Urol Oncol 1995; 13:103–112. 60. Kahn D, Williams RD, Haseman MK, et al. Radioimmunoscintigraphy with In-111-labeled capromab pendetide predicts prostate cancer response to salvage radiotherapy after failed radical prostatectomy. J Clin Oncol 1998; 16(1):284–289.

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61. Thomas CT, Montie JE, Sandler HS, et al. Evaluation of agreement rates between radionuclide bone scintigraphy and radioimmunoscintigraphy with Indium-111-Capromab Pendetide (ProstaScint) in patients with rising PSA after definitive prostate cancer treatment. J Clin Oncol 2003; 21(9):1715–1721. 62. Anderson RS, Eifert B, Tartt S, King P. Radioimmunoguided surgery using Indium-111 Capromab Pendetide (ProstaScint) to diagnose supraclavicular metastasis from prostate cancer. Urology 2000; 56(4):66. 63. Ellis RJ, Kim EY, Conant R, et al. Radioimmunoguided imaging of prostate cancer foci with histopathological correlation. Int J Radiat Oncol Biol Phys 2000; 49(5):1281–1286. 64. Ellis RJ, Sodee DB, Spirnak JP, et al. Feasibility and acute toxicities of radioimmunoguided prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 48(3):683–687. 65. Magi-Galluzzi C, Sanderson H, Epstein JI. Atypia in nonneoplastic prostate glands after radiotherapy for prostate cancer: duration of atypia and relation to type of radiotherapy. Am J Surg Pathol 2003; 27(2):206–212. 66. Yao D, Trabulsi EJ, Kostakoglu L, et al. The utility of monoclonal antibodies in the imaging of prostate cancer. Semin Urol Oncol 2002; 20(3):211–218. 67. Carroll MJ, El-Megadmi H, Elnaas S, et al. P18. Prostate cancer: combined Prostascint SPET/CT/blood pool imaging. Nucl Med Commun 2003; 24(4):473. 68. Quintana JC, Blend MJ. The dual-isotope ProstaScint imaging procedure: clinical experience and staging results in 145 patients. Clin Nucl Med 2000; 25(1):33–40. 69. Sodee DB, Ellis RJ, Samuels MA, et al. Prostate cancer and prostate bed SPECT imaging with ProstaScint®: semi-quantitative correlation with prostatic biopsy results. Prostate 1998; 37:140– 148. 70. Freeman LM, Krynyckyi BR, Li Y, et al. National Prostascint study group. The role of (111)In Capromab Pendetide (Prosta-ScintR) immunoscintigraphy in the management of prostate cancer. Q J Nucl Med 2002; 46(2):131–137. 71. Lange PH. PROSTASCINT scan for staging prostate cancer. Urology 2001; 57(3):402–406. 72. Sartor O, McLeod D. Indium-111-capromab pendetide scans: an important test relevant to clinical decision making. Urology 2001; 57(3):399–401.

Part II Treatment choices: perspectives from the physician and patient

7 Treatment decisions: surgery versus brachytherapy. A urologist’s perspective Michael Perrotti and Leonard G Gomella Introduction Prostate cancer is the most common cancer in men in the United States, and is the second most common cause of mortality. An estimated 230 110 men will be diagnosed with prostate cancer in the year 2004, accounting for approximately 33% of incident cancer cases in men, with 29 900 expected deaths from this disease.1 We have learned that prostate cancer is not a disease unique to the elderly. In 1991, prostate cancer claimed the lives of 12 306 men aged 55 to 74 years and 20 909 men above age 75.2 Available information regarding the anticipated natural history of disease, as well as available published prognostic nomograms,3,4 may serve as a reference when counseling patients regarding their newly diagnosed prostate cancer, and may provide assistance in clinical decision making to both physician and patient. It is generally recognized that to reduce the risk of death from prostate cancer in the male with clinically localized disease and life expectancy of at least 10 years, an effective treatment must be employed. As there are several available therapies, disease outcome prognostication, as well as information regarding therapy specific health-related quality of life outcomes have become increasingly important. Efforts have been directed not only toward patient education regarding available treatment modalities, but anticipated outcome with regard to disease control and side effect profile. In this chapter, the cogent issues related to the modalities of radical prostatectomy and prostate brachytherapy will be discussed as they relate to the patient with newly diagnosed clinically organ-confined prostate cancer. Natural history of prostate cancer We have learned a great deal about the natural history of prostate cancer.5–7 In one widely referenced study, investi gators utilizing the Connecticut Tumor Registry provided estimates of survival based on a competing risk analysis for men diagnosed with clinically localized prostate cancer managed conservatively.5 Patients were stratified by age at diagnosis and primary tumor histology using the Gleason scoring system,8 and followed for up to 10 to 20 years after diagnosis. These investigators reported that although the risk of death from prostate cancer was low in men diagnosed with Gleason score 2–4 disease, men with Gleason score 5 or 6 tumors faced a modest risk of death, and men with Gleason score 7–10 disease faced a high risk of death (Table 7.1) when

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managed conservatively. Lu-Yao and Yoa reported on a population-based study comprised of 59 876 cancer registry patients aged 50–79 years.9 The purpose of their study was to ascertain overall and prostate-cancer-specific survival in men treated with prostatectomy, radiotherapy, or conservative management. For patients managed with surveillance, 10 year prostatecancer-specific survival for grade 1 (Gleason 2–4), grade 2 (Gleason 5–7), and grade 3 (Gleason 8–10) cancer were 93%, 77%, and 53%, respectively.

Table 7.1 Risk of death at 15 years in men with newly diagnosed prostate cancer managed conservatively Gleason score Risk of death from prostate cancet at 15 yrs 2–4 5 6 7 8–10

4–7% 6–11% 18–30% 42–70% 60–87%

Evidence for the effectiveness of PSA screening As we are barely 10 years beyond the development and wide utilization of the serum prostate-specific antigen (PSA) test, it is too early to assess the ability of PSA screening to reduce prostate cancer mortality by altering the unfavorable natural history of this disease. There are, however, other measures to determine the effectiveness of this screening test.10 Since the introduction of PSA screening in the late 1980s, investigators utilizing the National Cancer Institute’s Surveillance Epidemiology and Ends Results (SEER) Database, have reported changes in the diagnosis of prostate cancer that are consistent with an effective screening test.11 These changes include a significant downward trend in the age at diagnosis, concomitant with a downward shift in stage of disease at diagnosis. The majority of cancers diagnosed in the PSA era are moderately differentiated (International Classification of Diseases of the World Health Organization grade 2; Gleason 5, 6, 7) and organ-confined.11 These findings would indicate the detection of potentially lethal cancers while amenable to definitive local therapy. In a separate study, International Classification of Diseases of the World Health Organization grade 3 (Gleason 8, 9, 10) prostate cancers were shown to be less likely metastatic at diagnosis, and more likely to be treated definitively between 1990 to 1994 compared with 1980 to 1984.12 Given the known natural history of moderately and poorly differentiated tumors (see Table 7.1), and the complications of metastatic prostate cancer,13 this evidence for the effectiveness of PSA screening is encouraging as we await mature prostate cancer mortality data. We also await the results of the Scandinavian Prostate Cancer Group Study and the Prostate Cancer Intervention Versus Observation Trial (PIVOT).14 These two large prospective randomized controlled studies compare radical prostatectomy and watchful waiting as treatment modalities for localized prostate cancer.

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Radical prostatectomy PSA non-progression rates Radical retropubic prostatectomy gained widespread popularity in the early 1980s after the introduction by Dr Walsh of a series of technical modifications based on an improved understanding of the prostatic and periprostatic surgical anatomy.15,16 Further refinement of the operative technique has continued into the contemporary era,17,18 and several large series,19–22 now provide actuarial PSAbased 5-, 7-, and 10-year PSA non-progression rates following radical prostatectomy for patients with localized

Table 7.2 PSA non-progression (bNED) rates in contemporary radical prostatectomy series for localized disease Study

No patients

5yrs

bNED rate 7 yrs 10 yrs

Hopkins 1623 80% – 68% Wash U 1778 – 81% – Baylor 1120 76% – 71% Mayo 2518 77% 68% – PSA, prostate-specific antigen; bNED, biochemical with no evidence of disease.

Table 7.3 PSA non-progression (bNED) rates at 7 years following radical prostatectomy stratified by preoperative serum PSA Preoperative PSA {ng/mL} 7 yr bNED rate <2.5 93% 2.6–4.0 88% 4.1–9.9 76% >10 49% See Table 7.2 for abbreviations.

disease (Table 7.2). In the series by Catalona and Smith,20 PSA non-progression following radical prostatectomy was found to be favorably influenced by lower preoperative serum PSA level, nonpalpable localized clinical stage (i.e. T1c), lower tumor grade, and localized pathologic stage (i.e. pT2). In their report, 1778 men with localized disease underwent radical retropubic prostatectomy. Preoperatively, the serum PSA was 2.5 or less in 124 men (7.7%), 2.6–4.0 in 127 men (7.9%), 4.1–9.9 in 924 men (57.2%), and 10 or greater in 440 men (27.2%). Preoperative serum PSA correlated with 7 year bNED (biochemical with no evidence of disease) rate (Table 7.3), with resultant influence in the bNED for the entire cohort. Gleason score similarly impacted on bNED rate. A total of 218 men (12%) had well-differentiated (Gleason 2–4) tumors, 1375 men (77%) had moderately differentiated (Gleason 5–7) tumors, and 185 men (10%) had poorly differentiated (Gleason 8–10) tumors. Seven-year PSA non-progression rate was correlated with tumor grade (Table 7.4). The PSA non-progression rate of 68% and 48%

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for moderate and poorly differentiated tumors, respectively, is encouraging given the recognized aggressiveness of

Tabble 7.4 PSA non-progression (bNED) rates at 7 years following radical prostatectomy stratified by Gleason score Gleason score 7 yr bNED rate 2–4 84% 5–7 68% 8–10 48% See Table 7.2 for abbreviations.

Table 7.5 Prostate-cancer-specific 10 year survival rate from diagnosis in a population-based study of 59 876 men with localized prostate cancer Group Prostatectomy Radiotherapy Surveillance 1 2 3

94% 87% 67%

90% 76% 53%

93% 77% 45%

these tumors. Such results, from large single center patient cohorts with intermediate to long term follow-up duration, illustrate the effectiveness of radical prostatectomy in the management of localized prostate cancer. Evidence for the effectiveness of radical prostatectomy also comes from the population-based study reported by Lu-Yao and Yao.9 This study comprised 59 876 cancer registry patients aged 50–79 years, the prostate-cancer-specific survival in men treated with prostatectomy and radiation therapy was reported (see Table 7.5). By the intentionto-treat approach (i.e. included even if prostatectomy abandoned secondary to positive lymph nodes), 10 year prostate-cancer-specific survival in the prostatectomy cohort (n=24 257) for grade 1 (Gleason 2–4), grade 2 (Gleason 5–7), and grade 3 (Gleason 8–10) tumors was 94%, 87%, and 67%, respectively. The 10 year prostatecancer-specific survival for the cohort treated with radiation therapy for grade 1, 2, and 3 tumors, was 90%, 76%, and 53%, respectively. However, in the absence of a prospective study design, these data should not be used to compare outcomes following radical prostatectomy and radiation therapy. Prostate brachytherapy PSA non-progression rates Prostate brachytherapy, or permanent interstitial implantation, for the management of prostate cancer has undergone dramatic changes since its first report in 1910.27 Since that initial approach using a radium source inserted through a urethral catheter, advances in this field have been influenced by the availability of newer isotopes, and more accurate access to the prostate gland. A renewed interest in permanent interstitial implantation was seen in the 1960s via the open retropubic approach,24,25 but it was realized that this

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approach was flawed by technical limitations, and is truly considered of historical interest in the modern era of prostate cancer therapy. In the present era, prostate brachytherapy is administered percutaneously via a perineal route according to a computerized preplan template. Ongoing improvements in template design, imaging, prostate stabilization, and technique have improved the accuracy of this procedure. Prostate brachytherapy as monotherapy in modern practice utilizes either palladium103 (103Pd) or iodine-125 (125I). The doses prescribed for these two isotopes are different. 103 Pd has a half-life of 17 days and a dose-rate of 18–20 cGy per hour, whereas 125I has a half-life of 59 days and a dose-rate of 7 cGy per hour.26 Based on these differences, a dose of 145 Gy for 125I is felt to be equivalent to a dose of 115 Gy for 103Pd.27 The actual dose delivered to the prostate gland, or postimplant dosimetric isodose curve, likely impacts on the biochemical relapse rate, and the American Brachytherapy Society (ABS) recommends that postimplant dosimetry be performed on all patients. Using 125I, Stock and associates have shown that when the dose delivered to 90% of the prostate (D90) was >140 Gy, a significantly improved relapse-free rate was observed compared to lower D90 levels.28 Ragde and associates have reported their results using prostate brachytherapy in 551 patients.29 In this series, 320 patients (group 1) were treated with implant alone, whereas 231 patients (group 2) who were felt to be higher risk also received 45 Gy of external beam radiotherapy in addition to implant. Among group 1 patients, those with a Gleason score 2–5 received 125I to a matched peripheral dose (MPD) of 160 Gy, those with a Gleason score 7–10 received 103Pd to an MPD of 115 Gy, and those with a Gleason score 6 were treated with either isotope. The pretreatment clinical parameters for this cohort are displayed in Table 7.6. The median follow-up was 55 months, with 152 patients followed for 5 years and 28 patients followed for 7 years. The reported 7 year actuarial freedom from biochemical failure, defined as a serum PSA level ≤1.0ng/mL, was 80%. That the 5 and 7 year actuarial freedom from biochemical failure correlated with pretreatment serum PSA level is illustrated in Table 7.7, similar to radical prostatectomy. Grimm and associates recently reported on a cohort of 125 men undergoing prostate brachytherapy as monotherapy.30 Brachytherapy as monotherapy in this study was limited to men with Gleason scores of 6 or less. In the reported cohort, 86% were clinical stage T2a or less, and

Table 7.6 Pretreatment clinical stage, serum PSA and Gleason score, in a total of 1006 patients undergoing prostate brachytherapy Status No. patients (total 551) Pretreatment clinical stage T1a 6 T1b 10 T1c 59 T2a 207 T2b 87 T2c 4 Serum PSA

Treatment decisions 0–4 4.1–10 10.1–20 >20 Gleason score 2–4 5–6 7–10

89 88 159 57 16 130 161 22

Table 7.7 Influence of pretreatment serum PSA (ng/mL) on biochemical freedom from disease (bNED) rate in 320 patients undergoing prostate brachytherapy as monotherapy Pretreatment PSA 5 yrsa 7 yrsb 0–4 95% 4.1–10 87% 10.1–20 77% >20 65% a 152 patients at risk. b 28 patients at risk.

87% 83% 72% 49%

77% had pretreatment PSA value of 10 ng/mL or less. Using a definition similar to that of the American Society of Therapeutic Radiation and Oncology (ASTRO), the 10 year actuarial biochemical progression-free survival was 87%. A widely referenced study is that reported by D’Amico and colleagues.31 In this retrospective investigation, actuarial freedom from PSA failure was evaluated in 1874 men with prostate cancer treated with radical prostatectomy (n=888), external beam radiotherapy (EBRT), (n=766) or interstitial implant with or without neo-adjuvant androgen deprivation therapy (ADT) (n=218). The median follow-up duration for the brachytherapy cohort was 41 months. Biochemical failure was defined according to the ASTRO 1996 consensus statement for all study patients.32 This defined biochemical failure as three consecutive rising PSA values each obtained at least 3 months apart and the time of PSA failure defined as the midpoint between the time of PSA nadir and the time of the first rising PSA value. The relative risk (RR) of PSA failure in low risk patients (i.e. clinical state T1c/T2a and pretreatment PSA≤10 ng/mL and Gleason≤6) undergoing brachytherapy alone or brachytherapy plus neo-adjuvant ADT, was 1.1 and 0.5, respectively compared with radical prostatectomy. The RR of PSA failure in intermediate risk (i.e. clinical stage T2b or Gleason score 7 or PSA>10 ng/mL) and high risk (i.e. clinical stage T2c or Gleason≥8 or PSA >20 ng/mL) patients treated with brachytherapy alone were 3.1 and 3.0, respectively, compared to radical prostatectomy. No significant benefit was seen with a short course of neo-adjuvant ADT administered in the brachytherapy plus androgen deprivation cohort, and this is in accordance with other reports.33,34 Brachman and associates reported freedom from biochemical progression after prostate brachytherapy monotherapy of 53% for pretreatment PSA levels of 10–20 ng/mL

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and 28% for Gleason score 7.35 Other investigators, however, have reported more favorable results for brachytherapy as monotherapy in intermediate and high risk disease. For patients with Gleason score of at least 7 or PSA greater than 10 ng/mL, Blasko and colleagues reported a nine-year freedom from biochemical progression of 82% with 103Pd monotherapy.36 For patients with pretreatment PSA levels >20 ng/mL the 9 year freedom from biochemical progression was reported to be 65%.37 Dattoli and colleagues reported that 62% of patients with Gleason score 8–9 tumors and 70% of patients with pretreatment PSA>20 ng/mL were biochemically disease free (PSA <1.0) at five years after moderate doses of external beam radiation therapy followed by 103Pd boost.37 Quality of life measures after local therapy It is difficult to define the incidence and quantify the degree of toxicity in men undergoing definitive therapy for prostate cancer, in part due to a lack of conformity in reporting these data in the literature. The Prostate Cancer Outcomes Study is a population-based longitudinal cohort study which has evaluated the changes in urinary and sexual function in men who have undergone radical prostatectomy for clinically localized prostate cancer.38 In this population-based study, patients randomly identified through the Surveillance, Epidemiology, and End Results cancer registries were offered the opportunity to complete a 6 and/or 12 month survey and a 24 month survey related to demographics, medical history, urinary, bowel, and sexual function at baseline and during the past month, satisfaction with treatment and quality of life. Men diagnosed with localized prostate cancer between 1 October 1994 and 31 October 1995 and who underwent radical prostatectomy within 6 months of diagnosis were eligible, and the reported analysis included 1042 men aged 39–89 years. At the time of the 24 month survey, 11.9% of patients experienced incontinence more than twice daily, and 3.3% required three or more pads per day. Level of bother due to urinary symptoms improved over time, with 8.7% of patients reporting that incontinence was a moderate-to-severe problem at 24 months. Age was related to the level of urinary control, frequency of incontinence, and bother. Interestingly, only 56.4% of men were younger than 65 years at diagnosis in the present study. Among men under 60 years of age at diagnosis, 0.7% reported no urinary control at 24 months and 10% reported over two episodes of incontinence per day. For men aged 65–74 years, these values were 0.9% and 15.7%, respective-ly, and for men aged 75–79 years, these values were 13.8% and 40.8%, respectively. With regard to sexual function, 72.7% of men reported erections that were satisfactory for intercourse at baseline prior to radical prostatectomy. The proportion with erections firm enough for sexual inter-course at 24 months was influenced by age at diagnosis (<60yrs: 39%; 60–64 yrs: 21.7%; 65–74 yrs: 15.3%; 75–79 yrs: 19.1%) and whether a nerve-sparing procedure was attempted (34.4% of non-nerve sparing; 41.4% of unilateral nerve sparing; 44% of bilateral nerve sparing). Younger men reported more frequent sexual activity at each survey period, and more often reported that sexual function was a moderate-to-severe problem compared to older men. Approximately half the patients were delighted or pleased with their surgery, and 4% were dissatisfied. At 18 or more months following surgery, 71.5% reported that they would make the same choice again, and 7.3% reported that they would not choose radical prostatectomy again.

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In a report from the Prostate Cancer Outcomes Study,39 health outcomes following radical prostatectomy and EBRT were compared in a population-based cohort. Two years after treatment, men undergoing radical prostat-ectomy were more likely than men receiving EBRT to be incontinent (9.6% vs 3.5%), to have higher rates of impo-tence (79.6% vs 61.5%), greater rate of needing treatment for urinary stricture (17.4% vs 7.2%), and lower incidence of proctitis (1.6% vs 18.7%). To our knowledge, a population-based study evaluating prostatic brachytherapy as monotherapy has not been reported. Wei and associates have reported on the healthrelated quality of life (HRQOL) following prostate brachytherapy, utilizing a crosssectional survey from a single academic institution administered to patients undergoing radical prostatectomy, prostate brachytherapy, or EBRT, and to age-matched controls.40 In this investigation, general HRQOL was evaluated with the RAND SF-36, general cancer-related QOL was assessed using FACT-G, and general prostate cancer-related QOL was measured using the FACT-P. Instruments utilized to measure domains specific to localized prostate cancer and therapy were the AUASI, and a modified expansion of the UCLAPCI (EPIC). Among 1355 eligible patients, 1014 consented to participate and completed required questionnaires (response rate: 74.8%). General HRQOL measures did not detect significant differences between therapy groups and controls. Radical prostatectomy was associated with worse urinary incontinence (p<0.0001) and sexual HRQOL (p<0.0001) than controls. External beam radiotherapy was associated with worse bowel (p<0.0001) and sexual (p<0.0001) HRQOL than controls. Prostate brachytherapy was associated with significantly worse urinary irritative (p<0.0001), urinary obstructive (p<0.0001), bowel (p<0.0001), and sexual (p<0.0001) HRQOL, and showed marginal adverse urinary incontinence (p=0.01). As this is a single institution study, and not population-based, it should simply serve to represent that center’s experience, and generalizations should be made with caution. Other investigators have indicated the potential for increased urinary toxicity after prostate brachytherapy compared to external beam radiotherapy.41 The rates of urinary retention and 5 year risk of urethral stricture following prostate brachytherapy vary widely in the literature, and have been reported to be 2–22%,41–50 and 5–12%,41,43,51,52 respectively. Merrick and colleagues have reported that urinary symptoms peak at 2 weeks postimplant and return to baseline at a median of 6 weeks,42 and there is evidence that the use of alpha-blockers results in a faster return to baseline pre-brachytherapy urinary symptom scores.53 These same investigators from the Schiffler Cancer Center recently evaluated long-term urinary quality of life after prostate brachytherapy utilizing the EPIC and AUASI questionnaires.54 At a median follow-up duration of 64 months, no significant difference in urinary symptoms between treated men and men in a demographically matched control group was observed. Rectal complications primarily consist of mild proctitis. Rectal bleeding will be seen in 4–11%, and long term dysfunction is uncommon.55,56 The incidence of erectile dysfunction following prostate brachytherapy has been reported over a wide range (6–90%), with Stock and colleagues recently reporting an erectile dysfunction rate of 41% in patients potent prior to treatment.57

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Conclusions Prostate cancer is a lethal disease, and significant differences in disease specific outcome in large populationbased series now available are seen between treatment and surveillance groups, particularly in those cohorts with moderately and poorly differentiated tumors. There is evidence from these same series to support the effectiveness of radical prostatectomy in treating localized disease. The morbidity of this effective therapy has been reported from investigators utilizing the National Cancer Institute’s SEER cancer registry, the results of which would indicate an acceptable morbidity profile, particularly in the male ≤65 years of age at diagnosis, and that level of satisfaction with treatment is high. The allure of prostate brachytherapy as monotherapy is its effectiveness in cancer control in reported series, and its once time administration, often on an outpatient basis. Prostate brachytherapy as monotherapy has been reserved, primarily, for the patient with favorable clinical stage, low serum PSA, and a Gleason score of ≤6, although some investigators have reported favorable results in intermediate and high risk patients. Reports are accruing that would indicate a morbidity profile associated with prostate brachytherapy with regard to urinary and bowel bother and erectile function that is not negligible. It is anticipated that disease outcome prognostication, as well as information regarding therapy-specific healthrelated quality of life outcomes, will remain paramount in counseling the patient with newly diagnosed clinically localized prostate cancer. The available information to date should assist the clinician and patient in this endeavor. References 1. Jemal A, Tiwari RC, Murray T, et al. Cancer Statistics, 2004. CA Cancer J Clin 2004; 54:8–29. 2. Miller BA, Ries LAG, Hankey BF, et al. SEER cancer statistics review: 1973–1991 (NIH Publication 94–2789). Bethesda, MD: National Cancer Institute: 1994. 3. Kattan MW, Eastham JA, Stapleton AMF, et al. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 1998; 90:766–771. 4. Ross PL, Scardino PT, Kattan MW. A catalog of prostate cancer nomograms. J Urol 2001; 165:1562–1568. 5. Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998; 280:975–980. 6. Johansson JE, Holmberg J, Johansson S, et al. Fifteen-year survival in prostate cancer: a prospective, population based study in Sweden. JAMA 1997; 277:467–471. 7. Chodak GW, Thisted RA, Gerber GS, et al. Results of conservative management of clinically localized prostate cancer. N Eng J Med 1994; 330:242–248. 8. Gleason DF. Histologic grading and clinical staging of carcinoma of the prostate. In: Tannenbaum M, ed. Urologic pathology. Philadelphia: Lea & Febiger, 1977:171–198. 9. Lu-Yao GL, Yao S. Population-based study of long-term survival in patients with clinically localized prostate cancer. Lancet 1997; 349:906–910.

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10. Gann PH. Interpreting recent trends in prostate cancer incidence and mortality [Editorial comment]. Epidemiology 1997; 8:117–120. 11. Farkas A, Schneider D, Perrotti M, et al. National trends in the epidemiology of prostate cancer, 1973 to 1994: Evidence for the effectiveness of prostate-specific antigen screening. Urology 1998; 52:444–448. 12. Perrotti M, Rabbani F, Farkas A, et al. Trends in poorly differentiated prostate cancer 1973 to 1994: Observations from the surveillance, epidimiology and end results database. J Urol 1998; 160:811–815. 13. Perrotti M. Prostate cancer: management of complications of the disease and its therapy. In: Resnick MI, Thompson IM, eds. Advanced therapy of prostate disease. London: Decker, 2000:446–541. 14. Wilt TJ, Brawer MK. The prostate cancer intervention versus observation trial (PIVOT). Oncology 1997; 11:1133–1139. 15. Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982; 128:492–497. 16. Walsh PC, Lepor H, Eggleston JC. Radical prostatectomy with preservation of sexual function: anatomical and pathological considerations. Prostate 1983; 4:473–485. 17. Klein EA. Modified apical dissection for early continence after radical prostatectomy. Prostate 1993; 22:217–223. 18. Licht MR, Klein EA. Continence-enhancing modifications for radical prostatectomy. In: Resnick MI, Thompson IM, eds. Advanced therapy of prostate disease. London: Decker, 2000:219–228. 19. Pound CR, Partin AW, Epstein JI, Walsh PC. Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am 1997; 24:395–406. 20. Catalona WJ, Smith DS. Cancer recurrence and survival rates after anatomic radical retropubic prostatectomy for prostate cancer: intermediate term results. J Urol 1998; 160:2428–2434. 21. Shalev M, Miles BJ. Radical retropubic prostatectomy for clinical stage T1b-T2 prostate cancer. In: Resnick MI, Thompson IM, 2000:202–209. eds. Advanced therapy of prostate disease. London: Decker, 22. Blute ML, Bergstralh EJ, Iocca A, et al. Use of Gleason score, prostate specific antigen, seminal vesicle and margin status to predict biochemical failure after radical prostatectomy. J Urol 2001; 165:119–125. 23. Paschkis R, Tittinger W. Radiumbehandlung eines prostata-sarkoms. Wien Klin Wochenschr 1910; 23:1715–1716. 24. Carlton CE, Scardino PT. Long-term results after combined radioactive gold seed implantation and external beam radiotherapy for localized prostate cancer. In: Coffey DS, Resnick MI, Dorr FA, Karr JP, eds. A multidisciplinary analysis of controversies in the management of prostate cancer. New York: Plenum, 1988:109–121. 25. Zelefsky MJ, Whitmore WE Long-term results of retropubic permanent I–125 implantation of the prostate for clinically localized prostate cancer. J Urol 1977; 158:23–30. 26. Grimm PD, Blasko JC, Ragde H, et al. Does brachytherapy have a role in the treatment of prostate cancer? Hematol Oncol Clin North Am 1996; 10:653–673. 27. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999; 44:789–799. 28. Stock RG, Stone NN, Tabert A, et al. A dose-response study for I-125 prostate implants. Int J Radiat Oncol Biol Phys 1998; 41:101–108. 29. Ragde H, Blasko JC, Grimm PD et al. Brachytherapy for clinically localized prostate cancer: results at 7- and 8-year follow-up. Semin Surg Oncol 1997; 13:438–443.

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30. Grimm PD, Blasko JC, Sylvester JE, et al. 10-year biochemical (prostate-specific antigen) control of prostate cancer with 125I brachytherapy. Int J Radiat Oncol Biol Phys 2001; 51:31– 40. 31. D’Amico, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280:969–974. 32. Cox JD for the American Society for Therapeutic Radiology and Oncology Consensus Panel. Consensus statement: guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997; 37:1035–1041. 33. Vicini FA, Kini VR, Spencer W, et al. The role of androgen deprivation in the definitive management of clinically localized prostate cancer treated with radiation therapy. Int J Radiat Oncol Biol Phys 1999; 43:707–713. 34. Potters L, Torre T, Ashley R, et al. Examining the role of neoadjuvant androgen deprivation in patients undergoing prostate brachytherapy. J Clin Oncol 2000; 18:1187–1192. 35. Brachman DG, Thomas T, Hilbe J, et al. Failure-free survival following brachytherapy alone or external beam irradiation alone for T1–2 prostate tumors in 2222 patients: results from a single practice. Int J Radiat Oncol Biol Phys 2000; 48:111–117. 36. Blasko JC, Grimm PD, Sylvester JE. Palladium-103 brachytherapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2000; 46:839–850. 37. Dattoli M, Wallner K, True L, et al. Prognostic role of serum prostatic acid phosphatase for 103Pd-based radiation for prostatic carcinoma. Int J Radiat Oncol Biol Phys 1999; 45:853–856. 38. 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; 283:354–360. 39. Potosky AL, Legler J, Albertson PC, et al. Health outcomes after prostatectomy or radiotherapy for prostate cancer: results from the Prostate Cancer Outcomes Study. J Natl Cancer Inst 2000; 92:1582–1592. 40. 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; 20:557–566. 41. Zelefsky MJ, Wallner KE, Ling CC, et al. Comparison of the 5-year outcome and morbidity of three dimensional conformal radiotherapy versus transperineal permanent iodine-125 implantation for early stage prostate cancer. J Clin Oncol 1999; 17:517–522. 42. Merrick GS, Butler WM, Lief JH, et al. Temporal resolution of urinary morbidity following prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 47:121–128. 43. Zelefsky MJ, Hollister T, Raben A, et al. Five-year biochemical outcome and toxicity with transperineal CT-planned permanent I-125 prostate implantation for patients with localized prostate cancer. Int J Radiat Oncol Biol Phys 2000; 47:1261–1266. 44. Wallner K, Roy J, Harrison L. Tumor control and morbidity following transperineal I-125 implantation for stage T1/T2 prostate carcinoma. J Clin Oncol 1996; 14:449–453. 45. Terk MD, Stock RG, Stome NN. Identification of patients at increased risk for prolonged urinary retention following radioactive seed implantation of the prostate. J Urol 1998; 160:1379–1382. 46. Al-Booz H, Ash D, Bottomley DM, et al. Short term morbidity and acceptability of Iodine-125 implantation for localized carcinoma of the prostate. Br J Urol 1999; 83:53–56. 47. Storey MR, Landgren RC, Cottone JL, et al. Transperineal Iodine-125 implantation for the treatment of clinically localized prostate cancer: 5 year tumor control and morbidity. Int J Radiat Oncol Biol Phys 1999; 43:565–570. 48. Gelblum DY, Potters L, Ashley R, et al. Urinary morbidity following ultrasound-guided transperineal prostate seed implantation. Int J Radiat Oncol Biol Phys 1999; 45:59–67. 49. 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; 47:905–908.

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50. Kang SK, Chou RH, Dodge RK, et al. Acute urinary toxicity following transperineal prostate brachytherapy using a modified Quimby loading method. Int J Radiat Oncol Biol Phys 2001; 50:937–945. 51. Ragde H, Blasko JC, Grimm PD, et al. Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate cancer. Cancer 1997; 80:442–453. 52. Merrick GS, Butler WM, Tollenaar BG, et al. The dosimetry of prostate brachytherapy-induced urethral strictures. Int J Radiat Oncol Biol Phys 2002; 52:461–468. 53. Merrick GS, Butler WM, Wallner KE, et al. Prophylactic versus therapeutic alpha-blockers after permanent prostate brachytherapy. Urology 2002; 60:650–655. 54. Merrick GS, Butler WM, Wallner KE, et al. Long-term urinary quality of life after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2003; 56:454–461. 55. Merrick GS, Butler WM, Dorsey AT, et al. Rectal function following prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 48:667–674. 56. 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; 166:494–499. 57. Stock RG, Kao J, Stone NN. Penile erectile function after permanent radioactive seed implantation for treatment of prostate cancer. J Urol 2001; 165:436–439.

8 Treatment decisions: which therapy? A patient’s perspective William J Hilsman Introduction This chapter describes my personal experience in dealing with the issue of decision making for prostate cancer, and how I used available information on the disease to go about making my decision whether to have combined hormone therapy, external beam radiation, and brachytherapy. Many resources are available to patients today thanks to advances in technology. The guidance and information provided by my physicians was an essential element in my treatment decision, but I stress that the final decision was mine. How it all began I had just landed in San Diego, California. It was just past 5:30 pm on a warm May day in 1994. I was checking my office answering machine while waiting for my luggage. There was a message from my doctor Colonel Ken Torrington, at Walter Reed Army Medical Center (WRAMC) asking me to call him. A signal went off in my head. I had just completed my annual physical at WRAMC a few days before, and Dr Torrington had said he felt a little nodule on the prostate during the digital rectal examination. He said he wanted to see what my prostate-specific antigen (PSA) was—blood had been taken the morning of my physical—and he would call me. I knew there was such a thing as a PSA test, but I never paid much attention to it. When I got to him on the phone, he said my PSA had increased from 3.7 to 4.9, and said I should call my urologist Dr David McLeod to schedule a biopsy. For the next few weeks before the scheduled biopsy—I admit—I was just a little more than anxious. I went to the library and found books on prostate cancer. I wanted to get as much information as I could before ‘B’ day—biopsy day. On 7 June, 1994,1 reported to WRAMC for my biopsy. Again, I will admit that I was a little scared. I was prepared for the biopsy by Dr McLeod, and the procedure began. I was watching the TV screen and listening to Dr McLeod as he performed the transcrectal ultrasound (TRUS). He measured the prostate gland as being 39 mL in volume, explained to me what he was doing, and then gave me the good news! ‘I believe we are looking at a calcium deposit that is causing the rough feeling. I am not going to do the biopsy. I just do not believe in any action like a biopsy unless I think it is necessary’. He then said, ‘Let’s wait and check the PSA again in 6 months’. I was elated, but I was also a lot

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smarter than I was a month ago. I now knew something about prostate cancer and was sure I would get a lot smarter…a lot, lot smarter very quickly. Since I was living in the Philadelphia area and WRAMC was in Washington, DC, I decided to consult with a local urologist at Thomas Jefferson University Hospital. This began my association with Dr Leonard Gomella. As Dr McLeod said to me, ‘You now have two of the best urologists in the nation, Dr Gomella and me’. I agreed. In November 1994, the PSA went up to 5.3. Six months later, it was still 5.3. Then we started to see a decrease: July 1995, 5.0; May 1996, 4.7. Meanwhile, I was getting more educated. I read as many publications as I could find and joined many websites to get information. Then came my PSA result in July 1997. One remembers some events with the greatest of clarity. I was on my way to Washington in my car when I called on my cell phone to Dr Gomella’s office: 6.2 said the nurse. No signals went off this time—just ‘damn’. I knew that a jump from 4.7 to 6.2 in one year was a strong indicator for cancer. Dr Gomella ordered a free PSA, which I did. This was good news, or so I thought. My free PSA was 24.9%. Below 14%, I was told, was bad. However, at the same time, Dr Gomella suggested it was time to do a biopsy. His digital rectal examination told him there was a change. For the most part, the biopsy was a non-event: six sticks. Again I watched. I asked for the volume as they finished—79 cc. Again, no signals, just ‘damn’. I remembered the 39 cc reading from 1994.1 knew enough from my reading that I was getting closer to what I did not want to hear. I could probably never tell you about any department store experience I ever had, except at Nordstrom in Alexandria, Virginia. As I was leaving the store, I called my answering machine and had a message to call Dr Gomella. I was just leaving to get in my car, so I called him from my car phone just as I was going by the Washington monument—you do remember these things. ‘Your biopsy is back, and you do have cancer’. That was the message. Again, I was very calm, and I knew what I wanted to know next. ‘In how many cores?’ I asked. ‘Two of the six’, he replied. ‘One side or two?’ I asked. ‘One side’, he said. ‘What was the Gleason?’ I wanted to know—‘(3+3) 6’, he said. Okay. I knew with a PSA of 6.2, a Gleason of 6, and the way we had followed the case, that I had a high probability of having caught the cancer early. ‘When do we schedule the bone scan and CAT (computed tomographic) scan?’ I asked. I was just about to go on a two week vacation with my family—wife, four kids, and six grandkids. ‘When you get back’, he said. I felt OK with that. Now I knew I had reached the stage of laying out a plan that would lead me to making my decision on the procedure I would follow. I knew that if the bone scan, and CAT scan were negative, I had some alternatives for treatment, and I knew what they were. Just to be sure of where I was, I took my slides to WRAMC for a second reading: (3+3) 6 in one, (3+2) 5 in the other. Basically the same result. Informing the family I knew one issue I had to face early was on informing my family. Cancer! Oh, my God! One hardly needs to say that announcing cancer to family members can be very

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traumatic. In my case, it was not so bad, for one reason above all. I knew a great deal about my condition. I knew I had it early. I knew what options were out there, and I knew I had a good medical team behind me. As I discussed the diagnosis with my family, I was calm, knowledgeable, and prepared. It made all of the difference in the world. The analysis phase My reading and discussions with individuals who had been recently diagnosed and my many, many inputs from different Internet websites, had focused me on the different options to include radical prostatectomy (RP), external beam radiation therapy (EBRT), brachytherapy (seeding), combined hormone therapy (CHT), cryosurgery, and watchful waiting.1 I discarded cryosurgery early on. I felt that it was just too experimental for me at that time.2–4 A little further into the analysis, I dismissed watchful waiting.5 I had, in fact, done that for 3 years. I was still comparatively young—65 years old. I pretty well knew that if I chose brachytherapy, I would have to do CHT to bring the size of my prostate down.6 Therefore, I laid out a strategy to get informed opinions from my doctors. I began with Dr Gomella, and to his credit, he was immediately open and suggested that I get different opinions. He staged me at T2b and suggested that I was indeed a candidate for RP.7 He went on to say that he wanted me to meet Dr Adam Dicker, in the Department of Radiation Oncology at Jefferson Hospital, and get a second opinion from Dr Dicker. He also suggested that I see Dr McLeod at WRAMC for his opinion. Dr Dicker staged my cancer at T2b, and suggested that I was also a candidate for brachytherapy.8 Dr Dicker explained his background. He had worked under Dr Kent Wallner at Sloan Kettering, one of the pioneers in brachytherapy. He went on to say that on the Jefferson team was Dr Frank Waterman, the physicist who shared in the planning, also from Sloan Kettering. I decided I wanted to know more about the team, so I spent 2 to 3 hours at Jefferson working with the physicist team to understand the role they play in the procedure. I understood how important and critical the planning was, and understood how they did it at Jefferson. I liked what I saw. Meanwhile, I joined an internet site, seedpods@rattler. cameron.edu. On the site were patients and doctors who had had experience with brachytherapy. I learned more about the procedure and the decision process, especially the question as to seeding alone;9,10 seeding with EBRT;11 and seeding, EBRT, and CHT. I also found different approaches to brachytherapy—the high dose radiation method practiced in Seattle and Tulsa,12 and the seeding followed by EBRT as practiced by the Radiotherapy Clinics of Georgia (RCOG) versus the EBRT followed by seeding more commonly used at other hospitals. I studied types of seeds—iodine or palladium.13 I felt very good after my education, especially that I understood the procedure and the risks. I then went for my third and fourth opinions at WRAMC in Washington. Dr David McLeod, like Dr Gomella, one of the best urologists in the nation in my mind, also suggested that I was a candidate for RP, but he also arranged for me to meet with Dr John Halligan, their radiation oncology team leader. Dr Halligan spent 3 hours with me explaining all the pros and cons. I was extremely impressed by Dr Halligan and his total dedication, professionalism, and knowledge of the treatments. He also suggested that I get a fifth opinion from one of the nation’s best known brachytherapists, Dr Dan Clark, at

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the Northern Virginia Center in Alexandria, Virginia. Dr Clark had one more protocol he used in diagnosing whether or not the cancer was contained. He used an endorectal coil magnetic resonance imaging (MRI). This procedure showed that the cancer was near the extremity of the gland. Dr Clark staged my cancer at T2c. He suggested from his analysis and the size of my prostate that I was a candidate for CHT plus EBRT plus seeding. He also felt that I was a candidate for RP. Decision time I now had my analysis phase complete. I first had to decide on radical prostatectomy or radiation. This was not an easy choice because I saw merit in both approaches. As Dr McLeod said, ‘If I take it out, I’ll bottle it in a jar, and you can take it home and be rid of it’. But, he also said that he felt he could only save nerves on one side because of his feel of the gland and the biopsy report. I knew that incontinence and impotence were potential side effects. I really made my decision against RP based on a philosophy I had used throughout my life. If I have a choice, I will do the less invasive procedure unless it makes no sense at all. Although RP had a good 15 years of track record statistics, and seeding had only 8 years at the time, I was very comfortable with the 8 year reports (1997) coming out of Seattle.9 So my first decision was made. RP was eliminated. My next choice, did I want to do EBRT alone, as recommended by some of my friends who have had prostate cancer. I decided I did not. I did not like the odds. Did I want the brachytherapy alone? I did not. Again, I went to the Partin tables, that had been developed at Johns Hopkins University, looked at the odds—PSA 6.2, Gleason (3+3) 6, and a staging of T2b/T2c—and decided I wanted to go with the protocol recommended by Dr Clark. I understood that the combination therapy was not widely practiced and could have the risk of increased side effects. I then met with Drs Gomella and Dicker at Jefferson and CHT, EBRT, and brachytherapy were agreed on. So, another decision had been made. Now, for the final decision: Where to have it done? I considered strongly Dr McLeod and the team at WRAMC, RCOG in Georgia, Dr Clark in Alexandria, and Drs Dicker and Gomella at Jefferson. I chose the Jefferson team for the following reasons: (1)1 felt very comfortable with Dr Adam Dicker and the radiation oncology team; (2) I also knew Dr Gomella would be in the operating room as a part of the team; and (3) Dr Waterman’s physics team was behind me: in other words, I felt I had a great team working with me; (4) the Kimmel Cancer Center of Thomas Jefferson University Hospital was an excellent center to have behind me if something went wrong or I had a reccurrence; and (5) I really liked the Jefferson protocol, which kept the patient overnight to help assure that the catheter, when it came out, would not have to go back. (Most other hospitals have patients in by 1:00 pm and out by 5:00 pm.) I had made my decision. I knew it was right. I never looked back.

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Let the process begin Combined hormone therapy (CHT) was first. I went in for my first 90 day Lupron shot and began a flutamide regime in September 1997.14 Flutamide was stopped after 90 days because of liver issues. My aspartate aminotransferase (AST) and alanine aminotransferase (ALT) readings increased significantly. Lupron was continued. In January 1998, the original time planned for external beam radiotherapy (EBRT), we still did not like the size of the prostate nor its closeness to the bladder, so a 2 month delay was imposed. I began a 28 session EBRT (six directional, not four) in March, which was completed in April. On Thursday, 28 May, I was seeded at the Bodine Cancer Center of Thomas Jefferson University Hospital in Philadelphia, Pennsylvania. I was administered 68 iodine125 seeds by Dr Adam Dicker who was assisted by Dr Leonard Gomella. My team (a good thought—cmy team’) recommended general anesthesia but would have done a spinal if I had insisted. Again research! I went with the general anesthesia, mostly on the advice of my team who wanted to be able to be as precise and accurate as they could and felt this was a better procedure for them. I had no trouble then or later. While I was asleep, the team implanted the seeds and checked to see if any seeds had gone to the bladder. Then I went back to the CAT scan equipment so my team could see how we did. Quoting Dr Dicker, the plot was ‘gorgeous’. I’m not sure I would have used this term on my prostate—but I loved it! As I mentioned earlier, my team also kept their seed implants (SI) patients overnight with the catheter in place. I already knew I liked the idea from my own research on the internet and inputs from previous patients. I was not hungry that evening, but I ate a little and drank lots of water. I am sure I passed at least two blood clots during the night—maybe more. The catheter came out at 6:00 am the next day. I did enjoy breakfast. My first attempt at urination was not a stream, was not a dribble, but a spray—either sit down or use the bottle provided. I walked back to the hotel at 11:00 am. I had a lot of urgency and burning until 4:00 pm when I passed a dime-sized blood clot. Things got better at the end of day one. I treated my wife and myself to dinner at one of Philadelphia’s finest restaurants. I still had some urgency, some mild burning, and had to make lots of visits at night—but otherwise I felt great. For these problems, my team had given me Flomax tablets, 0.4 mg (tamulosin hydrochloride) if I felt I needed it. I chose not to use it at that time. But I did take some ibuprofen. Observations and lessons learned • Stay tuned to the rest of your body with your general practitioner as you enter into this treatment. • In my early research, when I found that WRAMC and Bethesda Naval Medical Center were doing brachytherapy, I knew we were past the experimental stage. • I feel that the triple hit of CHT, EBRT, and SI was best for my future even though it took a long time.

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• Although there is controversy as to whether magnetic resonance imaging (MRI) is necessary due to the cost, in my case it was used to lay out my plan of attack in August 1997 and for the SI plan in 1998. It was good for me. • Two weeks before my diagnosis in 1997, my free PSA/ ratio came back at 24.9%— reference range less than 14% indicating cancer. The free PSA really missed it in my case. • I feel that the overnight stay with catheter was a good decision. • I feel that confidence in the team—my team—is critical to the program. • I feel that good diet/nutrition are essential for success. For the rest of my life—low fat, lots of vegetables and fruit, a planned vitamin and herb program, lots of soya, two glasses of the finest wine with dinner, and a good exercise program—that is where I will be. • The flutamide issue, which can be seen with any of the non-steroidal antiandrogens, could have been serious if we were not monitoring the AST and ALT at my quarterly blood tests. In the small print of flutamide information, it suggests some patients could have this adverse liver reaction, as I did. My doctors did follow this and my advice to others is to watch it. • I handled almost 9 months of Lupron with no difficulty. In my opinion, soya was very important in this process. I had major hot flashes, but not real problems. I did find myself a bit quick tempered. • I knew of the weight gain problem with CHT, and fought it successfully with diet and exercise. (I did a 2 week ‘get healthy with diet and exercise’ program at the beginning to be as healthy as possible.) I weighed 182 pounds in July 1997 and 177 pounds on seeding day. Some people may not find a 5 pound loss significant, but most people are reporting weight gains during CHT. Thus, in my opinion, diet and exercise are an important aspect of the process. • I experienced no difficulty during the 28 sessions of EBRT totaling 50.4 Gy. I was impressed with the physics of six-dimension EBRT practiced at the Kimmel Cancer Center as I studied the plots and computer graphics and the way the team went about the procedure. • I am convinced that having researched the issue and obtaining as much information as I had, allowed me to operate under what we would call the ‘Doctrine of No Surprises’— a great benefit.

And now for the rest of the story As the time of writing, I am six years past seeding day, and my PSA continues to be less than 0.100. I did have some side effects. Lupron was continued 3 months past seeding. My weight went up to 193 pounds. I am back to 180 today. Eight months past seeding, I started to have trouble with urinating. I started using Flomax and have this problem under control now. I started with one tablet a day. I then went to one tablet every other day, then one tablet every third day. Today, I no longer need Flomax. I did have one more nasty complication, which lasted 4 to 5 months, January through May of 1999. In January, 1 started rectal bleeding every 2 or 3 days—heavy ‘clotting’. This stopped in February. Then, in April, I took a 10 minute amusement park ride, like

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riding fast on a horse with no previous experience. That night was absolute misery— urgency burning. Things got worse for 2 or 3 more weeks. I was experiencing rectal bleeding (clots) every 3 days. By the end of May, I was improving. We decided to take a look anyway since there had been some bleeding. I had a flexible sigmoidoscopy. Lying on the table and watching the TV screen was an experience. What I clearly saw was the result of radiation sunburn. When I saw it I could understand why I felt the burning. In my case, the burning was most intense while I was urinating with the most intensity in the rectum. It was so intense that at times it brought tears to my eyes. It also seemed to get right to my nerves and rattle me from my fingertips to my toes. The flexible sigmoidoscopy itself had caused the burning to get worse. I have no idea or proof as to whether the protocol I followed made any difference, or whether I would have healed doing nothing. All I can say is I have beaten the problem. The burning and bleeding stopped in about 2 months. First, I followed a natural nutritional regimen of Seacure, a white fish dietary protein supplement with omega-3 fatty acids, and L-glutamine, an amino acid, suggested by a few individuals on my internet site. Second, I added colostrum, another dietary supplement from sheep’s milk, to the program. Third, I kept taking my regular supplements that included Saw Palmetto, E, C, Q-10, zinc, selenium, green tea, and my multivitamins. Because I could feel some swelling in the rectal area, I also went back to my successful treatment immediately after seeding—ibuprofen. Today and tomorrow As all prostate cancer survivors know, there is no free lunch in any choice we make to fight the disease. As of today and this chapter, I can only say that side effects are not an issue, and most important, a PSA of less than 0.100 has to lift anyone’s spirits. But, I also know the fight will continue for the rest of my life. There will be some anxiety as I do my annual PSA. I continue to educate myself on what others are doing, and what else is new in the fight for the cure. Maybe most importantly, those of us who are as fortunate as I, have the opportunity to help others who are just beginning the fight, or even those who might never have to face the problem. I had input and recommendations from outstanding urologists and radiation oncologists, but the final decision was mine—the patient—as I believe it should be. I used resources available, such as seedpods on the internet. Today, I dedicate myself to helping others as they meet the challenge of surviving prostate cancer, as others helped me to meet the challenge. I dedicate myself to help others as I have been helped in the past. My door is always open. I am a telephone call or an email away. References 1. Drachenberg DE. Treatment of prostate cancer; Watchful waiting, radical prostatectomy, and cryoablation. Semin Surg Oncol 2000; 18:37. 2. Porter MP, Ahaghotu CA, Leoning SA, et al. Disease-free and overall survival after cryosurgical monotherapy for clinical stages B and C carcinoma of the prostate: A 20-year followup [See comments]. J Urol 1997; 158:1466.

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3. Badalament RA, Bahn DK, Kim H, et al. Patient-reported complications after cryoablation therapy for prostate cancer. Urology 1999; 54:95. 4. Gould RS. Total cryosurgery of the prostate versus standard cryosurgery versus radical prostatectomy: Comparison of early results and the role of transurethral resection in cryosurgery. J Urol 1999; 162:1653. 5. Kattan MW, Cowen ME, Miles BJ. A decision analysis for treatment of clinically localized prostate cancer [see comments]. J Gen Intern Med 1997; 12:299. 6. Blank KR, Whittington R, Arjomany B, et al. Neoadjuvant androgen deprivation prior to transperineal prostate brachytherapy: Smaller volumes, less morbidity. Cancer J Sci Am 1999; 5:370. 7. Jacqmin D. Indications and results of radical prostatectomy. Cancer Radiother 1997; 1:418. 8. Bey P. Indications and results of exclusive radiotherapy in early prostatic adenocarcinoma. Cancer Radiother 1997; 1:431. 9. Ragde H, Blasko JC, Grimm PD, et al. Brachytherapy for clinically localized prostate cancer: Results at 7- and 8-year follow-up [Published erratum appears in Semin Surg Oncol 1998; 14:185]. Semin Surg Oncol 1997; 13:438. 10. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999; 44:789. 11. Andreopoulos D, Piatkowiak M, Krenkel B, et al. Combined treatment of localized prostate cancer with HDR-Iridium 192 remote brachytherapy and external beam irradiation. Strahlenther Onkol 1999; 175:387. 12. Mate TP, Gottesman JE, Hatton J, et al. High dose-rate after loading 192Iridium prostate brachytherapy: Feasibility report. Int J Radiat Oncol Biol Phys 1998; 41:525. 13. Sharkey J, Chovnick SD, Behar RJ, et al. Outpatient ultrasoundguided palladium 103 brachytherapy for localized adenocarcinoma of the prostate: A preliminary report of 434 patients [See comments]. Urology 1998; 51:796. 14. Migliari R, Muscas G, Murru M, et al. Antiandrogens: A summary review of pharmacodynamic properties and tolerability in prostate cancer therapy. Arch Ital Urol Androl 1999; 71:293.

Part III Pretreatment and real-time planning for permanent, low dose rate prostate brachytherapy

9 Brachytherapy from the urologist’s perspective Phuong N Huynh and Howard J Korman Historical perspective The goal of prostate brachytherapy is to induce cytotoxic events by placing radioactive sources into the tumor to mediate an irreversible radiation-induced break in the double strand DNA through free radicals.1 This technique, first described by Pasteau in 19132 and Barringer in 1917,3 involved placement of radium-containing needles into the prostate (Table 9.1). Young performed transperineal brachytherapy in the United States by the 1920s.4 By the 1950s, Flocks et al were placing permanent seeds using radioactive gold-198 (198Au).5 In the 1960s Whitmore et al6 at Memorial Sloan Kettering Cancer Center popularized the open retropubic implantation of radioactive iodine125 (125I) into the prostate by the ‘free hand’ technique combined with pelvic lymphadenectomy. Although this resulted in suboptimal distribution of seeds and poor dosimetry,7,8 this method remained popular throughout the 1980s. Complications attendant to this method included lymphocele, abscess and hematoma formation, pelvic cellulitis, impotence and rectourethral fistulae. The latter complication was most commonly seen in patients who required subsequent transurethral resection of the prostate (TURP) or external beam radiotherapy (EBRT).9

Table 9.1 Timeline of prostatic brachytherapy Early 1900s Radium needles, transperineal approach 1950s Permanent gold-198 seeds 1960–1980s Permanent iodine-125 seeds, retropubic approach (free hand) 1980s Transrectal ultrasound and template guided approach 1986 Introduction of PSA Early 1990s High dose rate iridium-192 brachytherapy 1996 ASTRO Criteria

Prostate brachytherapy was further revolutionized by Holm et al who detailed closed transperineal implantation with transrectal ultrasound (TRUS) and template guidance in 1983.10 This clearly improved the accuracy of radioactive seed placement by allowing transperineal visualization of the needle and by guiding the insertion of seeds into the prostate as compared to the free hand open retropubic approach. Ragde brought this concept to the United States when maturing open retropubic implantation results showed

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a higher recurrence rate than treatment with EBRT or radical prostatectomy (RP).11 A conceptually similar approach using computed tomography (CT) was developed,12 but the ultrasound-guided approach was easily disseminated to other institutions and therefore become the mainstream approach. By 1987, retropubic implantation was essentially abandoned. The technique described by Carlton et al13 of implantation of 198Au seeds combined with EBRT resulted in 5-year survival rates of 71%, 59%, and 46% and 10-year survival rates of 54%, 26% and 40% for stages B1, B2 and C1 respectively.14 Better outcomes were achieved with the open retropubic approach. The initial open retropubic prostate brachytherapy results from the 1970s demonstrated overall 5-year survival rates of 95%, 64%, and 59% for stage B1, B2 and C lesions, respectively, but the tumor-free survival rates were noted only to be 66%, 30% and 21% for the respective stages.15–17 Subsequent results reflecting changes in technology showed better survival data. Advances in imaging were essential to the resurgence of brachytherapy. The biplanar mechanical sector endocavitary probes were not introduced until the late 1980s which Stone used to perform real-time ultrasound implantation of seeds.18 By 1996, Bruel & Kjaer had developed the superior biplanar linear array endorectal probe by designing new components.19 This probe was superior to the mechanical sector probe because it allowed clear visualization of the anterior rectal wall in the sagittal view. Current software allows live monitoring of each seed’s position and radiation fields created. Although a dosimetric treatment plan can be calculated using preimplant TRUS images,20 intraoperative dosimetric planning (real-time technique)21 has also been performed with software advances. This uses a nomogram or reference table to order the sources once the patient has been placed in position. Intraoperative planning is now the preferred means of prostate brachytherapy as recommended by the American Brachytherapy Society.22 Another development is the use of CT images in conjunction with a three-dimensional (3D) software program to study postimplantation dosimetry and to generate dose-volume histograms, providing an understanding of seed placement in the prostate gland while avoiding toxicity to the rectum and urethra.23 This quality check allows essential measurements of delivered doses to the prostate gland and surrounding areas. Postimplantation CT is usually not performed until 2 to 6 weeks after the procedure due to postimplantation edema, depending on the kind of seeds used.24 Impact of PSA testing The treatment of prostate cancer has been significantly changed by the use of prostatespecific antigen (PSA) testing. The introduction of PSA testing in the 1980s for early detection and monitoring of prostate cancer dramatically increased the diagnosis of prostate cancer with a peak incidence in 1992. The disease-specific mortality peaked in 1993 and has continued to decline since that time.25–27 Carter et al were able to quantify the diagnostic lead time from PSA testing.28 Using a PSA cutoff of 4.0 ng/mL, they found that 78% of localized prostate cancer could be diagnosed a median of 4.9 years earlier than by clinical diagnosis alone. Additionally, metastatic disease could be detected with an elevated PSA level by more than 11 years before clinical diagnosis alone. Gann et al found similar results for men with ten years of follow-up.29 Using a PSA cutoff value of

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4.0 ng/mL, they found the diagnostic lead time for all prostate cancer diagnoses to be 5.4 years and for fatal prostate cancer to be 3.6 years. The spurious effect of lead time causes an increase in 5-year survival, resulting in a larger number of patients who are likely to survive at least 5 years, which may skew data on the impact of treatment for prostate cancer.30 Therefore, the effectiveness of prostate cancer treatment is more accurately measured in prostate cancer mortality rates.28 Although mortality rates have been declining, this appears to be due to multiple factors and not solely due to improvement in treatment. Most notably, PSA screening has led to stage migration, resulting in increased organconfined prostate cancer detection, between 70% and 80% of those screened.31–34 Similarly, the incidence and mortality rates of metastatic prostate cancer have steadily declined, suggesting that PSA testing may be a factor in the decrease in prostate cancer mortality rates.34 Furthermore, the year of diagnosis was found to be an independent predictor of the likelihood for cure.30,35 This observation suggests that the increased rate of organ-confined disease has resulted in increased disease-free survival. Finally, widespread use of androgen deprivation for early tumor recurrence may delay disease progression allowing other competing comorbidities to be the cause of death. In summary, it appears that the effect of PSA testing has caused stage migration towards detecting locally confined, low volume prostate cancer. This has likely contributed to better survival statistics regardless of treatment modality. Results Since the introduction of serum PSA in 1986, treatment outcomes have been measured in terms of biochemical disease-free periods. However, a standardized definition of biochemical failure after radiation therapy was not developed until the 1996 American Society of Therapeutic Radiology and Oncology (ASTRO) Consensus Conference.36 Failure was defined as three consecutive increases in the PSA levels (3 to 4 months apart in the first 2 years, then every 6 months thereafter) with the date of failure backdated to midway between the PSA nadir and the date of first increase. According to implant monotherapy studies before the ASTRO definition of biochemical failure, the 5- and 10year actuarial rates of freedom from biochemical relapse were 87% to 95% for patients with low risk features (Gleason 6 or less, PSA 10 ng/mL or less, and clinical stages T2a or less).37–39 Those definitions of biochemical failure varied from an absolute posttreatment PSA value being greater than 0.5 ng/mL to posttreatment PSA being greater than pretreatment PSA. Grimm et al reported a learning curve by demonstrating differences in progression-free survival in patients of low risk before and after 1988.40 Certainly, definitions of biochemical failure differ between surgery and radiotherapy. Standardized definitions allowing accurate comparisons of the two most commonly used curative treatment modalities must be agreed upon to give any real hope of meaningful comparative studies.

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Isotopes Several choices of isotopes for permanent seed implantation exist. While external beam radiation delivers high energies from linear accelerators (6–15 MeV), low energies are emitted from 125I and palladium-103 (103Pd). 125I has a half-life of approximately 60 days and emits 27 keV of energy. Introduced in 1986, 103Pd has a half-life of 17 days and emits 21 keV of photon energy. Theoretically, there is a more rapid fall-off at the borders of the implantation when 103Pd seeds are used which reduces the dose to normal surrounding structures but is less forgiving in terms of tumor aim. No randomized published trials comparing outcomes and toxicity rates of 125I and 103Pd exist, but clinical data that have been reported do not indicate any difference in biochemical control or outcome.41,42 As recommended by the American Association of Physicists in Medicine, the doses for 125I and 103Pd are 145 Gy and 124 Gy, respectively.43 Treatment options For men with low risk features of prostate cancer permanent interstitial brachytherapy is a proven and effective treatment option. Using the standardized ASTRO definition of biochemical failure, the 5 to 10-year biochemical control rates of low risk patients ranged from 65% to 93%44–46 using 125I and 103Pd seeds. The American Brachytherapy Society recommends monotherapy47 for men with favorable risk prostate cancer. 125I and 103Pd permanent radioactive seeds are also known as Low Dose Rate (LDR) brachytherapy. High Dose Rate (HDR) brachytherapy is being used to circumvent many problems inherent with LDR, and it is also being used as monotherapy to treat favorable risk prostate cancer.48,49 This development has been possible with computer and software advancements. HDR brachytherapy uses high intensity iridium-192 (192Ir) sources stored in a computer-controlled lead safe called a remote afterloader. 192Ir emits gamma radiation of 400 keV which has far more penetrating energy than 125I and 103Pd. Martinez et al48 described this technique. After transperineal placement of needles into the prostate gland via ultrasound guidance, an intraoperative dosimetric treatment plan is developed by using an online optimization software program.49,50 A CT scan confirms needle positions. The 192Ir sources are transferred to the needles by the computer-controlled remote afterloader for a prescribed treatment time period (typically 10–15 minutes), delivering a precise dose depending on the dwell times. Since the sources are retrieved after the prescribed treatment times, no radioactive sources remain in the patients. In summary, their ‘smart seed technique’48 of conformal HDR provides several benefits over conventional LDR because the treatment period is reduced from weeks to minutes. In addition, the source position and dwell times are more accurately controlled resulting in a better dose distribution. Also, real-time technique allows better source targeting, and the patients go home without being radioactive. Furthermore, the risk of seed migration is eliminated. Preliminary 3-year actuarial biochemical disease free rates

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Table 9.2 Treatment strategies for unfavorable risk or locally advanced prostate CA Brachytherapy with supplemental EBRT Dose escalating 3-D conformal radiotherapy Conforms! HDR brachytherapy boost plus EBRT Neoadjuvant hormonal therapy plus EBRT Neoadjuvant and adjuvant hormonal therapy plus conformal HDR brachytherapy

were 94% for low risk features and 55% for high risk features (PSA>20 ng/mL, Gleason>7, or Stage≥T3) as reported by Yoshioka et al51 for conformal HDR brachytherapy monotherapy. For patients with unfavorable risk or locally advanced prostate cancer, the optimal treatment modality remains unclear (Table 9.2). The survival rates with RP and low dose EBRT (monotherapy or adjuvant) are suboptimal.52–54 Brachytherapy has been combined with EBRT in these patients. This strategy is employed to treat the periprostatic tissues also. There are no randomized studies comparing brachytherapy monotherapy to EBRT with brachytherapy boost. But in multivariate analysis, there were no statistical differences in treatment outcomes when supplemental EBRT was added to brachytherapy for this group of patients.44,55,56 Treatment strategies now include dose escalating conformal radiotherapy and neoadjuvant hormonal deprivation with EBRT. Dose escalating conformal radiotherapy is accomplished by 3-D conformal radiotherapy,57 or by conformal HDR brachytherapy boost plus EBRT.49,58 In theory, dose escalation is needed to achieve tumoricidal radiation doses in tumor cells radioresistent at conventional dose levels. 3-D conformal radiotherapy developed with CT advancement in the early 1990s. 3-D imaging of the target gland was possible, allowing radiation beams to conform to the shape of the target gland. This allowed more accurate delivery of radiation to the target gland with lower doses to the surrounding normal tissues. Patients were, therefore, able to be treated with higher doses safely. It appears that doses greater than 75 Gy are needed for acceptable tumor control,54,59 achieving a greater than 85% 5-year biochemical control rate for prostate cancer with an unfavorable risk factor. The boost method of dose escalation using conformal HDR brachytherapy is interdigitated at the end of weeks 1 and 3 of the 5-week radiotherapy course. Martinez et al58 have shown a 5-year actuarial biochemical control rate of 87% (high dose group receiving 92 Gy or greater) for patients with Gleason 7 or greater, or PSA 10 ng/mL or greater. Mate et al49 showed similar results of a biochemical control rate of 84% at 5 years for those with pretreatment PSA levels of greater than 10 ng/mL. The role of hormonal therapy in conjunction with radiotherapy remains unclear. Possibly, hormonal ablation and radiotherapy can produce a synergistic cytotoxic effect to the tumor cells for local control, and hormonal ablation can subclinically control micrometastases outside of the irradiated areas.60 Bolla et al61 showed in a randomized, prospective trial that there is a survival advantage in those with locally advanced prostate cancer treated with neoadjuvant hormonal therapy at the initiation of EBRT and continued for 3 years. This is consistent with other study findings.62,63 Patients with intermediate and high risk features who undergo brachytherapy often receive hormonal

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therapy as a result of extrapolation from the EBRT data, but there remains no definitive evidence of benefit from hormonal manipulation for brachytherapy.42,64 The Radiation Therapy Oncology Group (RTOG) has investigational trials to address questions of duration and benefits of hormonal therapy. RTOG 94–08 was designed to determine if hormonal ablation played a role in low and intermediate risk prostate cancers treated with EBRT with 4 months total of hormonal therapy. RTOG 99–10 compares 28 weeks to 8 weeks of neoadjuvant hormonal therapy followed by EBRT for intermediate risk prostate cancer. Based on the above data, we routinely use neoadjuvant and adjuvant hormonal therapy (1 versus 2 years) in combination with conformal HDR for high volume, high grade disease as part of an in-house, randomized protocol at our institution. Side effects Acute and late complications for permanent interstitial brachytherapy have been described (Table 9.3). Some acute complications that can occur include perineal pain, ecchymosis and swelling. Temporary urinary retention can occur at reported rates ranging from 2 to 34%.65,66 This troublesome complication can be substantially ameliorated with administration of prophylactic alphablockers for up to 6 weeks.67 Late complications include urethral stricture disease, hemorrhagic cystitis, radiation proctitis, impotence, and urinary incontinence, especially in those who had prior TURP.9,68,69,70,71 The 5-year actuarial risk of urethral stricture has been reported to be 5% to 12%,11,72,73 likely correlating with the amount of urethral dosage received. Some problems were resolved with urethral dilation alone while others required more invasive treatment. Seed migration to the pulmonary vasculature is approximately 10–22%,74 but no detrimental events have been reported in the literature. The standard tool most commonly used to described complications from radiotherapy is the RTOG morbidity scoring scheme which consists of grades 0 to 4 to characterize acute and late gastrointestinal and genitourinary complications. For conformal HDR brachytherapy the rates of RTOG grade 3 and 4 late gastrointestinal complications were less than 5%, and 0% to 0.5%, respectively as reported by Yoshioka et al51 and Martinez et al.58 Rectal complications were usually self-limiting and consisted of mild proctitis with rectal bleeding peaking at a median of 8 months with an incidence of 4% to 11%.75,76 Rectal bleeding usually correlates with rectal dose, but studies have failed to correlate prostate size with rectal complications.75,76 The rates of grade 3 and 4 late genitourinary complications were 8% and 0%,58 respectively. There have been wide ranging reports of erectile dysfunction after brachytherapy, but generally a rate of 50% within 5 years of implantation can be expected.77 Erectile dysfunction after radiotherapy tends to have a gradual onset with loss of function that may not peak until 2–3 years after treatment. This contrasts with RP where erectile dysfunction is immediate with gradual return of function with time if nerve-sparing procedures have been

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Table 9.3 Side effects of radiotherapy Genitourinary

Gastrointestinal Others

Urinary retention Constipation Secondary malignancies Urinary incontinence Fecal urgency Ecchymosis Hemorrhagic cystitis Fecal incontinence Seed migration Urethral stricture disease Hematochezia Perineal pain and swelling Urethral necrosis and obstruction Fistulae Fistulae Erectile dysfunction

performed. Fortunately, erectile dysfunction after radiotherapy is often responsive to sildenafil citrate.78 Preimplantation erectile dysfunction is a strong predictor of subsequent problems as shown by Stock et al.79 At 6 years they found that there was a 70% potency rate for men without pretreatment erectile dysfunction versus only a 34% potency rate for men with suboptimal pretreatment erections. Similar findings were reported by Merrick et al.80 In another study without pretreatment erectile function assessment, the 5-year actuarial impotency rate reported with conformal HDR brachytherapy boost was 51%. Impotence occurred at a median interval of 0.7 year, and no difference in impotence rates was found with different brachytherapy boost doses.58 Comparative studies Several studies have compared outcomes of RP to permanent interstitial brachytherapy,11,81,82 but these retrospective and inter-institutional studies had confounding variables including pathologic interpretations of both biopsies and prostatectomy specimens, clinically staging, pretreatment PSA, and level of expertise in delivering treatment. It is doubtful that the perfect randomized, prospective trial will ever be performed given the difficulty of finding patients who would be willing to be randomized and given the different definitions of treatment failure. Most recently reported outcomes for favorable risk prostate cancer treatment have been similar for RP, permanent interstitial brachytherapy alone, and EBRT alone.83 However, surveys continue to show that for men with moderately differentiated, clinically localized prostate cancer and a life expectancy of 10 years or greater, urologists heavily favor RP while radiation oncologists strongly prefer radiotherapy as the primary treatment modality.84,85 Several works have shown that the life expectancy of men with prostate cancer is directly related to their tumor grade.86–89 From a urological perspective, most favorable risk prostate cancer patients are likely to have a long life expectancy. Surgical extirpation theoretically can eliminate the risk of late cancer-related failure that may occur from either persistence or new occurrence of prostate cancer after radiotherapy. Furthermore, pathologic staging is obtained with surgery and follow-up is more straight forward as the PSA should become undetectable and remain so if the patient is disease free. One small but significant disadvantage to radiotherapy is the risk of radiation-induced secondary malignancies. Two large studies have described these events in detail.90,91 The risk of any second solid tumor was approximately 6% overall. This rate increases

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proportionately to the number of years survived after initial treatment, especially after 10 years of survival. Most frequent second solid organ malignancies were bladder, lung and rectal carcinoma. Compared to patients treated surgically, irradiated patients had an 85% increase in risk of developing sarcoma in the radiated field although they found no increase in the rate of leukemia. These facts contribute to the bias of urologists toward surgery for younger men with a greater than 20 year life expectancy. Hence, younger men are more commonly treated with RP and older men with radiotherapy. Contraindications There are many contraindications to consider in selecting patients for brachytherapy (Table 9.4). Men with prostate glands of ≥50 cm3 are often not candidates for brachytherapy due to the higher inherent risk of urinary morbidity and technical difficulties with pubic arch interference. This problem, however, can be overcome using neoadjuvant hormonal therapy for cytoreduction and by using the realtime implantation method.92–94 Traditionally, prior TURP was a contraindication to brachytherapy due to its inherent risks of urinary incontinence, but subsequent studies have shown improved rates of urinary incontinence in these men using peripheral loading technique with realtime seeding placement to avoid placing sources too close to the urethra.95,96 Still, at our institution we tend to avoid brachytherapy for patients who have undergone TURP. Prostatitis and significant obstructive symptomatology are relative contraindications to brachytherapy. These patients may fare better with prostatectomy especially in voiding status. Voiding symptoms can be quantified by the international prostate symptom score (IPSS)97 which allows comparative studies of outcomes of different treatment modalities. Although there were no pretreatment IPSS data, Krupski et al98 found that the radical retropubic prostatectomy group had significantly lower posttreatment total and obstructive IPSS symptom scores than the brachytherapy monotherapy group. Furthermore, the irritative and obstructive symptoms were much more pronounced in the brachytherapy with supplemental EBRT group than the RP group.

Table 9.4 Relative contraindications for brachytherapy Prostate glands ≥50 cm3 Prior TURP Prostatitis Significant voiding symptoms Inflammatory bowel disease

Men with inflammatory bowel disease may be treated with brachytherapy,” but we prefer to avoid radiotherapy, whether brachytherapy or EBRT, due to potential increased bowel toxicity. However, RP is not contraindicated for these patients. Obese men can be effectively treated for favorable risk prostate cancer with permanent interstitial brachytherapy.100 If an RP is planned, we prefer the perineal approach over the retropubic approach.

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Conclusions There have been dramatic improvements in radiation delivery systems. These advancements along with prostate cancer stage migration have led to a resurgence of brachytherapy being performed separately and together by radiation oncologists and urologists. As with all prostate cancer treatments, appropriate patient selection will lead to the best results and should balance both disease free survival and quality of life issues. Selection should be based upon age, overall health, patient attitudes and concerns, disease stage and grade, and prostate size. Neoadjuvant and adjuvant androgen ablation can be used to help facilitate technical aspects of brachytherapy and may improve longterm efficacy of treatment. Hopefully, long-term randomized studies will help guide both radiation oncologists and urologists in providing the most case appropriate care for patients with prostate cancer. References 1. Elkind MM. DNA damage and cell killing: cause and effect? Cancer 1985; 56:2351–2363. 2. Pasteau O, Degrais P. The radium treatment of cancer of the prostate. Journal d’Urologie (Paris) 1913; 4:341–366. 3. Barringer BS. Radium in the treatment of carcinoma of the bladder and prostate. JAMA 1917; 68:1227. 4. Young H. Technique of radium treatment of cancer of the prostate and seminal vesicles. Surg Gynecol Obstet 1992; 34:93–98. 5. Flocks R, Kerr H, Elkins H, et al. The treatment of carcinoma of the prostate by interstitial radiation with radioactive gold: A follow-up report. J Urol 1959; 71:628–633. 6. Whitmore W, Hilaris B, Grabstald H. Retropubic implantation of iodine-125 in the treatment of prostate cancer. J Urol 1972; 108:918–920. 7. Kuban DA, El-Mahdi AM, Schelhammer PF. I-125 interstitial implantation for prostate cancer: What have we learned 10 years later? Cancer 1989; 63:2415–2420. 8. D’Amico A, Coleman C. Role of interstitial radiotherapy in the management of clinically organconfined prostate cancer: The jury is still out. J Clin Oncol 1996; 14:304–315. 9. Herr HW. Pelvic lymphadenectomy and iodine-125 implantation. In: Johnson DE, Boileau MA, eds. Genitourinary tumors: fundamental principles and surgical techniques. New York: Grune & Stratton, 1982; 63. 10. Holm HH, Juul N, Pedersen JF, et al. Transperineal I-125 iodine seed implantation in prostatic cancer guided by transrectal ultrasonography. J Urol 1983; 130:283–286. 11. Ragde H, Blasko JC, Grimm PD, et al. Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 1997; 80:442–453. 12. Wallner K, Chiu-Tsao ST, Roy J, et al. An improved method of computerized tomographyplanned transperineal 125iodine prostate implants. J Urol 1991; 146:90–95. 13. Carlton CE Jr, Dawoud F, Hudgins P, et al. Irradiation treatment of carcinoma of the prostate: a preliminary report based on 8 years of experience. J Urol 1972; 108:924–927. 14. Scardino PT, Guerriero WG, Carlton CE Jr. Surgical staging and combined therapy with radioactive gold grain implantation and external irradiation. In: Johnson DR, Boileau MA, eds. Genitourinary tumors: fundamental principles and surgical techniques. New York: Grune & Stratton, 1982.

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15. Grossman HB, Batata M, Hilaris B, Whitmore WF Jr. 125-I implantation for carcinoma of prostate. Further follow-up of first 100 cases. Urology 1982; 20:591–598. 16. Catalona WJ. Prostate cancer. New York: Grune & Stratton, 1984. 17. Sogani PC, Whitmore WF Jr, Hilaris BS, Batata MA. Experience with interstitial implantation of iodine 125 in the treatment of prostatic carcinoma. Scand J Urol Nephrol 1980; 55:205–211. 18. Stone NN, Ramin SA, Wesson MF, et al. Laparoscopic pelvic lymph node dissection combined with real-time interactive transrectal ultrasound guided transperineal radioactive seed implantation of the prostate. J Urol 1995; 153:1555–1560. 19. Stone NN, Stock RG. Practical considerations in permanent brachytherapy for localized adenocarcinoma of the prostate. Urol Clin North Am 2003; 30:351–362. 20. Blasko J, Grimm P, Ragde H. Brachytherapy and organ preservation in the management of carcinoma of the prostate. Semin Radiat Oncol 1993; 3:240–249. 21. Kaplan I, Holupka E, Morrisey M. MRI-ultrasound fusion for 125-iodine prostate implant treatment planning. Int J Radiat Oncol Biol Phys 1998; 42(suppl 1):421–426. 22. Nag S, Ciezki JP, Cormack R, et al. Intraoperative planning and evaluation of permenant prostate brachytherapy: report of the American Brachytherapy Society. Int J Radiat Oncol Biol Phys 1995; 32:219–225. 23. Stone NN, Stock RG, DeWyngaert JK, et al. Prostate brachytherapy: improvements in prostate volume measurements and dose distribu-tion using interactive ultrasound guided implantation and threedimensional dosimetry. Radiat Oncol Investig 1995; 3:185–195. 24. Yue N, Chen Z, Peschel R, et al. Optimum timing for image-based dose evaluation of 125-I and 103-Pd prostate seed implants. Int J Radiat Oncol Biol Phys 1999; 45:1063–1072. 25. Stanford JL, Stephenson RA, Coyle LM, et al. Prostate cancer trends 1973–1995, SEER program. NIH publication. Bethesda, MD: National Cancer Institute, 1998. 26. Hankey BF, Feuer EJ, Clegg LX, et al. Cancer Surveillance Series: interpreting trends in prostate cancer: I. Evidence of the effects of screening in recent prostate cancer incidence, mortality, and survival rates. J Natl Cancer Inst 1999; 91:1017–1024. 27. Potosky AL, Miller BA, Albertsen PC, Kramer B. The role of increasing detection in the rising incidence of prostate cancer. JAMA 1993; 273:548–552. 28. Carter HB, Pearson JD, et al. Longitudinal evaluation of prostate specific antigen levels in men with and without prostate disease. JAMA 1992; 267:2215–2220. 29. Gann PH, Hennekens CH, Sampfer MJ. A prospective evaluation of plasma prostate specific antigen for detection of prostatic cancer. JAMA 1992; 273:289–294. 30. Kessler B, Albertsen P. The natural history of prostate cancer. Urol Clin North Am 2003; 20:219–226. 31. Shroder FH. Screening for prostate cancer. Urol Clin North Am 2003; 30:239–251. 32. Amling CL, Blute ML, Lerner SE, et al. Influence of prostate-specific antigen testing on the spectrum of patients with prostate cancer undergoing radical prostatectomy at a large referral practice. Mayo Clin Proc 1998; 73:401–406. 33. Jhaveri FM, Klein EA, Kupelian PA, et al. Declining rates of extracapsular extension after radical prostatectomy: evidence for continued stage migration. J Clin Oncol 1999; 17:3167– 3172. 34. Newcomer LM, Stanford JL, Blumenstein BA, et al. Temporal trends in rates of prostate cancer: declining incidence of advanced stage disease, 1974 to 1994. J Urol 1997; 158:1127– 1130. 35. Han W, Partin AW, Piantadosi S, et al. Era specific biochemical recurrence-free survival following radical prostatectomy for clinically localized prostate cancer. J Urol 2001; 166:416– 419. 36. Cox JD. The American Society of Therapeutic Radiology and Oncology Consensus Panel. Consensus Statement Guidelines for PSA Failure Following Radiation Therapy. Int J Radiat Oncol Biol Phys 1997; 37:1035–1041.

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37. Wallner K, Roy J, Harrison L. Tumor control and morbidity following transperineal iodine 125 implantation for stage T1/T2 prostatic carcinoma. J Clin Oncol 1996; 14:449–453. 38. Blasko JC, Wallner K, Grimm PD, Ragde H. Prostate specific antigen based disease control following ultrasound guided 125-iodine implantation for stage T1/T2 prostatic carcinoma. J Urol 1995; 154:1096–1099. 39. Ragde H, Blasko JC, Grimm PD, et al. Brachytherapy for clinically localized prostate cancer: results at 7- and 8-year follow-up. Semin Surg Oncol 1997; 13:438–443. 40. Grimm PD, Blasko JC, Sylvester JE, et al. 10-year biochemical (prostate-specific antigen) control of prostate cancer with 125-iodine brachytherapy. Int J Radiat Oncol Biol Phys 2001; 51:31–40. 41. Cha C, Potters L, Ashley R, et al. Isotope selection for patients under-going prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999; 45:391–395. 42. Potters L, Torre T, Ashely R, et al. Examining the role of neoadjuvant androgen deprivation in patients undergoing prostate brachyther-apy. J Clin Oncol 2000; 18:1187–1191. 43. Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial brachytherapy sources: recommendations of the AAPM Radiation Therapy Committee Task Group No. 43. Med Phys 1995; 22:209–234. 44. Blasko JC, Grimm PD, Sylvester JE et al. Palladium-103 for prostate carcinoma. Int J Radiat Oncol Biol Phys 2001; 46:839–850. 45. Stone NN, Stock RG. Permanent seed implantation for localized adenocarcinoma of the prostate. Curr Urol Rep 2002; 3:201–206. 46. Ragde H, Grado GI, Nadir BS. Brachytherapy for clinically localized prostate cancer: thirteen year disease-free survival of 769 consecutive prostate cancer patients treated with permanent implants alone. Arch Esp Urol 2001; 54:739–747. 47. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachy-therapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999; 44:789–799. 48. Martinez AA, Pataki I, Edmundson G, et al. Phase II prospective study of the use of conformal high-dose-rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: a feasibility report. Int J Radiat Oncol Biol Phys 2001; 49:61–69. 49. Mate TP, Gottesman JE, Hatton J, et al. High dose-rate afterloading iridium-192 prostate brachytherapy: Feasibility report. Int J Radiat Oncol Biol Phys 1998; 41:525–533. 50. Edmundson GK, Yan D, Martinez A. Intraoperative optimization of needle placement and dwell times for conformal prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995; 33:1257– 1263. 51. Yoshioka Y, Takayuki N, Yoshida K, et al. High-dose rate brachyther-apy as monotherapy for localized prostate cancer: a retrospective analysis with special focus on tolerance and chronic toxicity. Int J Radiat Oncol Biol Phys 2003; 56:213–220. 52. Morgan WR, Bergstralh EJ, Zincke H. Long-term evaluation of rad-ical prostatectomy as treatment for clinical stage C (T3) prostate cancer. Urology 1993; 41:113–120. 53. Gerber GS, Thisted RA, Chodak GW, et al. Results of radical prosta-tectomy in men with locally advanced prostate cancer: Multi-insti-tutional pooled analysis. Eur Urol 1997; 32:385– 390. 54. Hanks GE, Diamond JJ, Krall JM, et al. A ten-year follow-up of 682 patients treated for prostate cancer with radiation therapy in the United States. Int J Radiat Oncol Biol Phys 1987; 13:499–505. 55. Grado G, Larson T, Balch C, et al. Actuarial disease-free survival after prostate cancer brachytherapy using interactive techniques with biplane ultrasound and fluoroscopic guidance. Int J Radiat Oncol Biol Phys 1998; 42:289–298. 56. Potters L, Cha C, Oshinsk G, et al. Risk profiles to predict PSA relapse-free survival for patients undergoing permanent prostate brachytherapy. Cancer J Sci Am 1999; 5:301–305.

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57. Hanks GE, Lee WR, Hanlon AL, et al. Conformal technique dose escalation for prostate cancer: biochemical evidence of improved cancer control with higher doses in patients with pretreatment prostate-specific antigen >10 ng/mL. Int J Radiat Oncol Biol Phys 1996; 35:861– 868. 58. Martinez A, Gonzalez J, Spencer W, et al. Conformal high dose rate brachytherapy improves biochemical control and cause specific sur-vival in patients with prostate cancer and poor prognostic factors. J Urol 2003; 169:974–980. 59. Hanks G, Hanlon A, Pinover W, et al. Survival advantage for prostate cancer patients treated with high-dose three-dimensional conformal radiotherapy. Cancer J Sci Am 1999; 5:152–158. 60. Vicini FA, Vargas C, Edmundson G, et al. The role of high-dose rate brachytherapy in locally advanced prostate cancer. Semin Radiat Oncol 2003; 13:98–108. 61. Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N NEng J Med 1997; 337:295–300. 62. Pilepich M, Krall J, Talsarraj M, et al. Androgen deprivation with radiation therapy compared with radiation therapy alone for local-ly advanced prostatic carcinoma—a randomized comparative trial of the Radiation Therapy Oncology Group. Urology 1995; 45:616–623. 63. Laverdiere J, Gomez JL, Cusan L, et al. Beneficial effect of combina-tion therapy administered prior and following external beam radia-tion therapy in localized prostate cancer. Int J Radiat Oncol Biol Phys 1997; 37:247–252. 64. Lee LN, Stock RG, Stone NN. Role of hormonal therapy in the man-agement of intermediateto high-risk prostate cancer treated with permanent radioactive seed implantation. Int J Radiat Oncol Biol Phys 2002; 52:444–452. 65. Blasko J, Ragde H, Grimm PD. Transperineal ultrasound-guided implantation of the prostate: morbidity and complications. Scand J Urol Nephrol 1991; 137:113–118. 66. Locke J, Ellis W, Wallner K, et al. Risk factors for acute urinary reten-tion requiring temporary intermittent catheterization after prostate brachytherapy: a prospective study. Int J Radiat Oncol Biol Phys 2002; 52:712–719. 67. Merrick GS, Butler WM, Wallner KE, et al. Prophylactic versus ther-apeutic alpha-blockers after permanent prostate brachytherapy. Urology 2002; 60:650–655. 68. Kleinberg L, Wallner K, Roy J, et al. Treatment-related symptoms during the first year following transperineal 125-iodine prostate implantation. Int J Radiat Oncol Biol Phys 1994; 28:985–990. 69. Desai J, Stock RG, Stone NN, et al. Acute urinary morbidity follow-ing 125-iodine interstitial implantation of the prostate gland. Radiat Oncol Investig 1998; 6:135–141. 70. Kang SK, Chou RH, Dodge RK. Gastrointestinal toxicity of transper-ineal interstitial prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002; 53:99–103. 71. Snyder KM, Stock RG, Hong SM, et al. Defining the risk of develop-ing grade 2 proctitis following 125-iodine prostate brachytherapy using a rectal dose volume histogram analysis. Int J Radiat Oncol Biol Phys 2001; 50:335–341. 72. Zelefsky MF, Hollister T, Raben A, et al. Five-year biochemical outcome and toxicity with transperineal CT-planned permanent I-125 prostate implantation for patients with localized prostate cancer. Int J Radiat Oncol Biol Phys 2000; 47:1261–1266. 73. Merrick GS, Butler WM, Tollenaar BG, et al. The dosimetry of prostate brachytherapy-induced urethral strictures. Int J Radiat Oncol Biol Phys 2002; 52:461–468. 74. Merrick GS, Butler WM, Dorsey AT, et al. Seed fixity in the prostate/periprostatic region following brachytherapy. Int J Radiat Oncol Biol Phys 2002; 46:215–220. 75. Merrick GS, Butler WM, Dorsey AT, et al. Rectal function following prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 48:667–674. 76. Snyder KM, Stock RG, Hong SM, et al. Defining the risk of developing grade 2 proctitis following 1251 prostate brachytherapy using a rectal dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 2001; 50:335–341.

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77. Merrick GS, Wallner KE, Butler WM. Management of sexual dysfunction after prostate brachytherapy. Oncology 2003; 17:52–62. 78. Merrick GS, Butler WM, Lief JH, et al. Efficacy of sildenafil citrate in prostate brachytherapy patients with erectile dysfunction. Urology 1999; 53:1112–1116. 79. Stock RG, Kao J, Stone NN. Penile erectile function after permanent radioactive seed implantation for treatment of prostate cancer. J Urol 2001; 165:436–439. 80. Merrick GS, Butler WM, Galbreath RW, et al. Erectile function after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002; 52:893–902. 81. Polascik R, Pound CR, DeWeese TL, et al. Comparison of radical prostatectomy and iodine 125 interstitial radiotherapy for the treatment of clinically localized prostate cancer: a 7-year biochemical (PSA) progression analysis. Urology 1998; 51:884–890. 82. Ramos CG, Carvalhal GF, Smith DS, et al. Retrospective comparison of radical retropubic prostatectomy and 125 iodine brachytherapy for localized prostate cancer. J Urol 1999; 161:1212–1215. 83. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280:969–974. 84. Moore MJ, O’Sullivan BO, Tannock IF. How expert physicians would wish to be treated if they had genitourinary cancer. J Clin Oncol 1988; 6:1736–1745. 85. Fowler FJ Jr, McNaughton Collins M, Albertsen PC, et al. Comparison of recommendations by urologists and radiation oncologists for treatment of clinically localized prostate cancer. JAMA 2000; 283:3217–3222. 86. Johansson JE, Holmberg L, Johansson S, et al. Fifteen-year survival in prostate cancer. A prospective, population-based study in Sweden. JAMA 1997; 277:467–471. 87. Chodak GW, Thisted RA, Gerber GS, et al. Results of conservative management of clinically localized prostate cancer. N Eng J Med 1994; 330:242–248. 88. Aus G, Hugosson J, Norlen L. Long term survival and mortality in prostate cancer treated with noncurative intent. J Urol 1995; 154:460–465. 89. Lu-Yao GL, Yao SL. Population-based study of long-term survival in patients with clinically localised prostate cancer. Lancet 1997; 349:906–910. 90. Brenner DJ, Curtis RE, Hall EJ, Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer 2000; 88:398–406. 91. Neugut AI, Ahsan H, Robinson E, Ennis RD. Bladder carcinoma and other second malignancies after radiotherapy for prostate carcinoma. Cancer 1997; 79:1600–1604. 92. Kucway R, Vicini F, Huang R, et al. Prostate volume reduction with androgen deprivation therapy before interstitial brachytherapy. J Urol 2002; 167:2443–2447. 93. Whittington R, Broderick A, Arger P, et al. The effect of androgen deprivation on the early changes in prostate volume following transperineal ultrasound guided interstitial therapy for localized carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1999; 44:1107–1110. 94. Stone NN, Stock RG. Prostate brachytherapy in patients with prostate volumes >/=50 cm3: dosimetric analysis of implant quality. Int J Radiat Oncol Biol Phys 2000; 46:1199–1204. 95. Wallner K, Lee H, Wasserman S, Dattoli M. Low risk of urinary incontinence following prostate brachytherapy in patients with a prior transurethral resection of the prostate. Int J Radiat Oncol Biol Phys 1997; 37:565–569. 96. Stone NN, Ratnow ER, Stock RG. Prior transurethral resection does not increase morbidity following real-time ultrasound guided prostate seed implantation. Tech Urol 2000; 6:123–127. 97. Barry MJ, Fowler FJ Jr, O’Leary MP, et al, for the Measurement Committee of the American Urological Association. The American Urological Association symptom index for benign prostatic hyperplasia. J Urol 1992; 1549–1557. 98. Krupski T, Petroni GR, Bissonette EA, Theodorescu D. Quality-oflife comparison of radical prostatectomy and interstitial brachytherapy in the treatment of clinically localized prostate cancer. Urology 2000; 55:736–742.

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99. Grann A, Wallner K. Prostate brachytherapy in patients with imflammatory bowel disease. Int J Radiat Oncol Biol Phys 1998; 40:135–138. 100. Merrick GS, Butler WM, Wallner K, et al. Permanent prostate brachytherapy-induced morbidity in patients with grade II and III obesity. Urology 2002; 60:104–108.

10 Sonographic anatomy of the prostate Ethan J Halpern Introduction This chapter explores the anatomy of the prostate gland with particular emphasis on those aspects of the sonographic appearance that are relevant to the radiation oncologist. Sonographic anatomy is demonstrated and correlated with the histologically defined zonal glandular anatomy. Common anatomical variants are illustrated, as well as the pathologic basis for the growth patterns of prostate cancer. Gross anatomy The normal prostate is a well-defined, smoothly marginated gland situated below the bladder and above the symphysis pubis. Although the prostate may be visualized through a full urinary bladder by transabdominal sonography, it is more clearly visualized with transrectal sonography. The transrectal approach places the ultrasound transducer immediately adjacent to the prostate and provides high resolution images with transmit frequencies in the range of 6–10 MHz. Sonographic measurements of the prostate should be obtained in two orthogonal planes (Figure 10.1). As the urethra exits from the bladder it courses caudally and anteriorly along the long axis of the prostate. The urethra is visible on the sagittal midline imaging plane used for the anterior-posterior and cranio-caudal measurements. The cranial aspect of the prostate just under the bladder is denoted as the base of the prostate. The base of the prostate is clearly defined against the bladder. The apex of the prostate is adjacent to the muscles of the pelvic floor. The inferior margin of the prostate at the apex may be difficult to define sonographically from the adjacent periurethral tissues. The symphysis pubis is usually visible anterior to the region of the prostatic apex (Figure 10.1c). Mean dimensions of the young adult prostate are 3.3 cm in-height, 2.4 cm in thickness, and 4.1 cm in width,1 with a sonographic volume of 12.9–37.1 cc.2 The seminal vesicles and vasa deferentia are paired structures on either side of midline just above the prostate (Figure 10.2). These structures extend cranial to the prostate and posterior to the bladder. Often, both seminal vesicles may be imaged together on a single axial image. However, in some cases the orientation of the seminal vesicle requires independent imaging of each side. The two seminal vesicles should be relatively similar in size, and each seminal vesicle should taper in caliber as it approaches the midline, producing a ‘beak sign’.3 The typical size of a seminal vesicle is 27–50 mm in length and 12–15 mm in thickness.4,5 The vas deferens is generally visible just superior to the body of the ipsilateral seminal vesicle. The ampullary portion of the vas, adjacent to the

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midline, is the largest and most easily visualized portion of the vas deferens. The distal vas deferens courses medial to the seminal vesicle, and joins with the ipsilateral seminal vesicle to form an ejaculatory duct as it enters the base of the prostate. The two ejaculatory ducts course through the base of the prostate to enter the urethra at the verumontanum. Although there is no true epithelial capsule around the prostate, a thin layer of fibromuscular stroma (no more than half a millimeter in thickness) surrounds the prostate, resulting in a smooth glandular contour. The fascial planes surrounding the prostate are a caudal continuation of the hypogastric sheath and contain many neurovascular structures. Sonographically, these fascial planes appear as welldefined echogenic tissue around the prostate. Vascular structures are often visible within these planes with color Doppler imaging. The venous plexus of Santorini is contained within the fascia of Zukerkandl anterior to the prostate. The prostatic arteries are within the lateral pelvic fascia on either side of the prostate. The neurovascular bundles responsible for male potency usually lie between the prostate and the rectum, along Denonvilliers fascia. Small perforating vessels and neural structures enter the

Figure 10.1 Sagittal (a) and transverse (b) transrectal images obatined for measurement of the prostate. Transverse view (c) near the apex of the prostate. The cranio-caudal and anterior-posterior dimension are measured on the sagittal image. The

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transverse dimension is obatined in the axial plane at the level that demonstrates the largest transverse diameter. Arrows mark the hypoechoic internal sphincter that surrounds the proximal prostatic urethra. A solid line parallels the urethra and demonstrates the anterior angulation at the level of the verumontanum. Transverse view near the apex of the prostate (c) demonstrates the public bone on each side of the public symphysis (arrows). It may be difficult to determine the presise smooth sphincter blends with the tissues of the external sphincter near the apex of the prostate.

Figure 10.2 Transrectal sonography of the seminal. Transverse midline view just above the prostate (a) demonstartes a seminal vesicle on each side with a normal tapered appearance toward the midline. Arrows demonstrate the ampullary portion of the vas deferens on either side of the

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midline, just superior to the medial aspect of the seminal vesicle. Transverse view at a slightly more cranial level (b) again demonstrates the vas deferens (arrows) medial to each seminal vesicle. In a different patient (c), the two seminal vesicles could not be imaged in a single plane. An angled transverse view of the right side is presented to demonstrate the right seminal vesicle and associated vas deferns (arrow). prostate from the neurovascular structures in the adjacent fascial planes, and represent a potential pathway for spread of prostate cancer through the prostatic capsule.6 Zonal anatomy of the prostate For the purposes of zonal anatomy, we consider the young adult prostate prior to the onset of benign prostatic hyperplasia. The anterior one third of this ideal prostate is composed of non-glandular tissue: the anterior fibromuscular stroma. This fibromuscular stroma is stretched around the lateral and posterior margins of the gland as a thin capsule. The remaining two thirds of the prostatic parenchyma are glandular tissue. The zonal anatomy of this tissue has been described in detail by McNeal.7,8 Zonal anatomy of the prostate is defined with respect to the prostatic urethra. The verumontanum is a raised ridge of tissue along the posterior aspect of the prostatic urethra. The young adult urethra measures approximately 15 mm proximal to the verumontanum and 15 mm distal to the verumontanum. The urethra is angled forward by about 35 degrees at the verumontanum (Figure 10.1). The upper portion of the prostatic urethra is surrounded by muscular fibers from the bladder that form the internal sphincter. These fibers are often sonographically visible as a hypoechoic region around the proximal prostatic urethra (Figure 10.1). The internal sphincter ends above the verumontanum. A thin muscular layer called the distal smooth sphincter surrounds the urethra from the verumontanum to the prostatic apex, and merges with the external striated sphincter below the prostate. The zonal anatomy defined by McNeal divides the glandular tissue of the prostate into four zones: Periurethral glands with limited glandular development empty into the urethra through lateral line ducts along the course of the prostatic urethra. The glands of this periurethral zone are confined within the muscular tissue that surrounds the urethra. This muscular tissue may limit glandular development in this zone. The periurethral zone accounts for 1% of the glandular tissue in the prostate. Transition zone tissue is composed of two lobes of glandular tissue on either side of the urethra. The transition zone glands drain into the urethra at the verumontanum, just

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above the ejaculatory duct openings. In the absence of benign prostatic hyperplasia, transition zone glands are found only above the level of the verumontanum, and the transition zone accounts for no more than 5% of the glandular tissue in the prostate. Central zone glands surround the ejaculatory ducts as they course toward the verumontanum. The central zone exists only above the verumontanum, and ducts from this zone empty into the urethra at the verumontanum. The central zone accounts for 25% of the glandular tissue in the prostate. Peripheral zone glands surround the central zone at the base of the gland, and also form the bulk of the glandular parenchyma below the level of the verumontanum. These glands drain into the urethra on either side of the verumontanum as well as below the verumontanum along the crista urethralis—a posterior midline crest that extends along the urethra. The peripheral zone accounts for 70% of the glandular tissue in the prostate. For sonographic purposes, the periurethral and transition zones comprise the inner gland, while the central and peripheral zones comprise the outer gland. The inner gland and outer gland can be distinguished from each other by differences in their echotexture. The individual zones within the inner gland and the individual zones within the outer gland are not sonographically distinguishable. The normal outer gland is homogeneously echogenic, and is usually more echogenic than the inner gland. The inner gland is often heterogeneous in its appearance due to the presence of benign prostatic hyperplasia. The inner gland and the outer gland are separated by the surgical capsule which defines the plane of enucleation for suprapubic prostatectomy. The surgical capsule is not a true anatomic structure, but is often defined by linear deposition of corpora amylacea or calcification that is sonographically visible. Benign prostatic hyperplasia The classic zonal anatomy as defined by McNeal is observed only in the young adult prostate. As a male ages, the glandular distribution changes due to benign prostatic hyperplasia.9 Benign prostatic hyperplasia results in enlargement of the inner gland due to an increase in the number of glandular elements as well as hypertrophy of the tissues.10 Benign prostatic hyperplasia is most marked in the transition zone, but is also noted in the periurethral zone. Since prostate cancer is a disease of older men, most men with prostate cancer demonstrate some degree of benign prostatic hyperplasia. Benign prostatic hyperplasia results in a nodular enlargement of the inner gland (Figure 10.3). Often the two lobes of the transition zone are seen to enlarge on the two sides of midline. Enlargement of the transition zone stretches and thins the outer gland tissue, and may stretch the urethra and deviate it posteriorly. The enlarged transition zone often extends below the level of the verumontanum. When the periurethral glands are involved, the resulting hyperplasia may result in an enlarged ‘median

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Figure 10.3 Transverse (a) and sagittal (b) views of the prostate in a patient with benign prostatic hyperplasia. The hypoechoic inner gland is surrounded by the more echogenic outer gland. Inner gland enlargement is demonstrated on both sides of midline on the transverse view (a). The urethra (not visible due to shadowing in the midline) is compressed and stretched between the two lobes of the transition zone. The sagittal view (b) demonstrates inner gland enlargement bulging into the base of the bladder. Calipers mark the cranio-caudal and anterior-posterior dimensions. lobe’. Although there is no true median lobe, this term is used to refer to midline enlargement of the prostate that bulges into the base of the bladder. Enlargement of the prostate with benign prostatic hyperplasia may result in a marked change in the overall shape and position of the prostate. The enlarged transition zone may become the dominant glandular component of the prostate. As the gland becomes more globular in shape, it may extend anteriorly over the symphysis pubis. Among patients referred for brachytherapy, benign prostatic hyperplasia is an important cause of public arch interference to the introduction of seeds through a perineal approach. In addition to the glandular enlargement associated With benign prostatic hyperplasia, this process also results in a more heterogeneous appearance of the gland. Hypoechoic hyperplastic nodules visible within the inner gland may be indistinguishable from hypoechoic masses of cancer. Due to the high prevalence of benign prostatic hyperplasia in middle aged to elderly males, it is impossible to use grayscale sonographic criteria to detect cancer within the inner gland.

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Prostatic calcifications are often related to the presence of benign prostatic hyperplasia. Calcifications are commonly seen along the surgical capsule as well as in the periurethral tissues (Figure 10.4), but dystrophic calcification may be present throughout the hyperplastic inner gland. Acoustical shadowing from these calcifications may complicate the visualization and placement of seeds for brachytherapy. Ductal ectasia of the seminal vesicles is commonly associated with benign prostatic hyperplasia (Figure 10.5). The enlarged inner gland compresses the ejaculatery ducts as they course to the verumontanum, resulting in relative obstruction. The tubules within the seminal vesicles as well as the vasa deferentia may dilate secondary to this obstruction. In a patient with cancer of the prostate, it is often impossible to determine whether obstruction of the seminal vesicles is related to benign prostatic hyperplasia or to the cancer. Cystic changes are often found in areas of benign hyperplasia (Figure 10.6). Although this finding is most commonly found in the inner gland, cystic areas of hyperplasia may be seen within the outer gland as well. Both cystic change and calcification of the glandular parenchyma may also be related to prostatitis. In my experience, cystic changes in the prostate are overwhelmingly associated with benign disease. Finally, benign prostatic hyperplasia is associated with a distortion of the normal pattern of blood flow within the prostate. The young adult prostate demonstrates capsular flow with perforating branches that radiate toward the urethra at the center of the gland (Figure 10.7). Enlargement of the inner gland associated with benign prostatic hyperplasia distorts this radial pattern of flow, and results in increased flow to the hyperplastic inner gland. Areas of increased Doppler flow in the inner gland may mimic the increased flow associated with prostate cancer. Cysts of the prostate Cysts of the prostate are relatively common and should be recognized by their characteristic location. Müllerian duct

Figure 10.4 Benign prostatic hyperplasia. Transverse view of the prostate (a) demonstrates enlargement

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of the inner gland with calcification along the left side of the surgical capsule (arrows). Transverse view in a second patient (b) demonstrates periurethral calcification (arrow).

Figure 10.5 Ductal ectaisa of the seminal vesicles. A transverse midline image of the seminal vesicles (a) demonstrates mild bilateral ductal ectasia. The dialted ducts appear slightly hypoechoic to the remainder of the seminal vesicle. In another patient with more obvious ductal ectasia, both the right (b) and left (c) seminal vesicles demonstrate obvious fluidfilled tubular structures (arrows). The ipsilateral vas deferens is visible above each seminal vesicle. cysts are the most common congenital cyst of the prostate. The Müllerian duct cyst is a remnant of the Müllerian tubercle, and is commonly seen in the midline, near the base of the prostate. Müllerian duct cysts may extend or arise above the prostate. Ejaculatery duct cysts are common acquired cysts that arise along the course of the ejaculatory ducts on either side of the midline, but may appear to lie in the midline. Ejaculatory duct cysts are

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often associated with ejaculatory duct obstruction,11 but Müllerian cysts may also result in ejaculatory duct obstruction.12 Aspiration of an ejaculatory duct cyst should demonstrate the presence of spermatozoa. Sperm is not present in a

Figure 10.6 Cystic changes associated with benign hyperplasia. Transverse image through the mid-gland (a) demonstrates a large area along the right peripheral zone with multiple small cystic structures, a single cyst in the inner gland and several tiny cysts in the left peripheral zone (arrows). Transverse image through the apex in a different patient (b) demonstrates larger cystic spaces on both side of the apex of the prostate (calipers). These may arise in the outer gland, or may represent extension of inner gland material to the apex secondary to benign prostatic hyperplasia. Müllerian cyst. The distinction between these two entities is rarely of clinical importance. Nonetheless, it is important to recognize these common cystic entities. Other cysts of the prostate are less common. Cysts of the seminal vesicle are much less common than ductal ectasia of the seminal vesicles (Figure 10.5). The seminal vesicles, vas deferens, and ejaculatory duct are Wolffian structures. Congenital anomalies and true cysts of the seminal vesicle may be associated with other Wolffian anomalies.13 Cysts of the seminal vesicles are associated with ipsilateral renal agenesis in two thirds of cases.14 The prostatic utricle is a tiny pouch along the verumontanum. Dilatation of the prostatic utricle to larger than 4 mm with loss of epithelial papillations results in a utricular cyst.5 Utricular cysts communicate with the urethra and may result in post-void dribbling.15 Utricular cysts are associated with other anomalies of the genitourinary system including hypospadias, incomplete testicular descent, and renal agenesis.16

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Sonographic appearance of prostate cancer Adenocarcinoma of the prostate arises most frequently in the outer gland.17–19 It is generally accepted that cancer of the prostate appears hypoechoic on sonography. Unfortunately, only about half of all cancers within the prostate are sonographically visible. This maybe related, in part, to the growth pattern of adenocarcinoma of the prostate. Prostate cancer infrequently presents as a solitary round mass. Rather, prostate cancer tends to be multifocal with infiltrative growth along a path that is parallel to the capsule of the gland. The growth pattern tends to respect both the surgical capsule and the prostatic capsule as barriers to spread. Although many cancers of the prostate are not visible, a recent study suggests that sonographically visible tumor on grayscale imaging is more likely to be hypervascular on Doppler imaging, and to have a significantly higher Gleason score.20 The classic sonographic appearance of prostate cancer is that of a hypoechoic mass (Figure 10.8). The hypoechoic nature is best appreciated on transverse images which allow a side to side comparison of the prostatic parenchyma. Other sonographic features include a focal bulge of the prostate contour, or an irregularity of the margin of the gland. The thin fibromuscular stroma surrounding the prostate is responsible for the smooth appearance of the margin of the gland. When this capsule is invaded by tumor, the smooth contour of the gland is lost and the margin may appear irregular. The prostatic capsule invaginates around the ejaculatory ducts, and is incomplete in the region of the prostatic apex. These two areas are relative weak points for extracapsular spread of prostate cancer.5 Spread of cancer to a seminal vesicle may be visualized as asymmetry of the seminal vesicles or as loss of the normal tapered appearance of the medial aspect of a seminal vesicle. Color Doppler evaluation of the normal prostate gland demonstrates the presence of blood flow in a symmetric radial pattern extending from the capsule toward the urethra.21 Cancer may be associated with focal areas of increased flow (Figure 10.9).22–24 Recent studies suggest that power Doppler offers an extended dynamic range,25

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Figure 10.7 Transverse color (a) and power (b) Doppler images demonstrate normal flow at the base to mid-gland of the prostate. Symmetric flow along both sides of the gland is present with perforating vessels oriented toward the center of the prostate. In two patients with benign prostatic hyperplasia (c and d) increased flow is present within the hyperplastic inner gland. There is distortion of the normal radial flow pattern. and may be even more sensitive than color Doppler for the detection of prostate cancer.26– Nonetheless, at this time, neither grayscale nor Doppler techniques are sufficiently accurate to direct radiation therapy to limited portions of the gland.

28

Posttreatment appearance of the prostate After prostatectomy, the urethrovesical anastomosis should present a smooth, tapered appearance from the bladder neck to the urethral sphincter (Figure 10.10).29 Tissue related to the prostate and seminal vesicles is removed during radical prostatectomy.

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Nonetheless, post prostatectomy scans often demonstrate portions of the seminal vesicles that have not been removed. The more superior and lateral portions of the seminal vesicles may not be removed at surgery. After radiation therapy the prostate appears shrunken, and may be difficult to visualize. Brachytherapy seeds are visible as bright foci with acoustical shadowing. After external beam therapy, the gland may appear quite hypoechoic and heterogeneous. Recurrence of prostate tumor in the prostate bed can present as a focal solid nodule or as a complex solid and cystic lesion.30 After radical prostatectomy, locally recurrent masses are found most frequently in the perianastomotic area, but can also be found in adjacent structures.31 Local recurrence after radiation therapy may be very difficult to identify within the shrunken, heterogeneous

Figure 10.8 Transverse sonography of the prostate at the mid-gland level. A focal hypoechoic area at the posterolateral aspect of the right peripheral zone (arrows) corresponds to a Gleason score 8 cancer growing along the capsule of the prostate. There is a less well-defined hypoechoic appearance on the left side, but all biopsy specimens from this area returned benign tissue. prostate. The presence of recurrent disease can only be confirmed by biopsy (Figure 10.10). Conclusions The prostate gland surrounds the urethra as it courses out of the bladder. Anteriorly, the prostate is composed of fibromuscular tissue which is rarely involved by disease

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processes. The glandular portion of the prostate is located laterally and posteriorly. The glandular prostate is divided into four zones: the periurethral, transition, central, and peripheral zones. Benign prostatic hyperplasia occurs exclusively in the inner gland, primarily in the transition zone, but also in the periurethral glands. Adenocarcinoma of the prostate arises most commonly in the peripheral zone or central zone, is often multifocal and grows parallel to the capsule of the gland. Both the surgical capsule and the prostatic capsule serve as relative barriers to the spread of prostatic cancer. The seminal vesicles and vasa deferentia are located above the prostate. Due to local defects in

Figure 10.9 Gray sclae (a), color Doppler (b), and power Doppler (c) transverse images through the midgland level of the prostate. A hypoechoic mass on the left side of the glands is marked by arrows (a). Both color and power Doppler studies demonstrate hypervascularity (arrows) that extends along the peripheral zone anterior to the mass identified by grayscale sonography. Targeted biopsy cores of the left mid-gland

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demonstrated that both the gray scale and Doppler findings corresponded to a Gleason score 7 cancer. Normal prostate tissue was identified on sextant biopsy of the right mid-gland.

Figure 10.10 Post-radical prostatectomy. The normal postprostatectomy appearance (a) demonstrates a smooth taper at the vesicourethral junction. Although the anastomosis was normal, a small focal nodule was found (b) and measured (calipers). Biopsy of this nodule (c) demonstrated recurrent adenocarcinoma. the prostatic capsule, local spread of prostate cancer may invade directly into the seminal vesicles or out the apex of the gland. An understanding of these anatomical considerations and their sonographic appearance is critical for adequate treatment of adenocarcinoma of the prostate.

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References 1. Fornage BD. Normal US anatomy of the prostate. Ultrasound Med Bio 1986; 12:1011–1021. 2. Watanabe H, Igari D, Tanahashi Y, et al. Measurements of size and weight of prostate by means of transrectal ultrasonography. Tohoku J Exp Med 1974; 114:277–285. 3. Lee F, Torp-Pederson ST, Siders DB, et al. Transrectal ultrasound in the diagnosis and staging of prostatic carcinoma. Radiology 1989; 170:609–615. 4. Aboul-Azm TE. Anatomy of the human seminal vesicles and ejaculatory ducts. Arch Androl 1979; 3:287–292. 5. Villers A, Terris MK, NcNeal JE, Stamey TA. Ultrasound anatomy of the prostate: the normal gland and anatomical variations. J Urol 1990; 143:732–738. 6. Villers A, McNeal JE, Redwine EA, et al. The role of perineural space invasion in the local spread of prostatic adenocarcinoma. J Urol 1989; 142:763–768. 7. McNeal JE. The zonal anatomy of the prostate. Prostate 1981; 2:35–49. 8. McNeal JE. Normal and pathologic anatomy of prostate. Urology 1981; 17(suppl):1 1–16. 9. Glynn RJ, Campion EW, Bouchard GR, Silbert JE. The development of benign prostatic hyperplasia among volunteers of the Normative Aging Study, Am J Epidemiol 1985; 121:78– 90. 10. McNeil JE. Origin and evolution of benign prostatic enlargement. Investig Urol 1978; 15:340– 345. 11. Littrup PJ, Lee F, McLeary RD, et al. Transrectal ultrasound of the seminal vesicles and ejaculatory ducts: clinical correlation. Radiology 1988; 168:626–628. 12. Halpern EJ, Hirsch IH. Sonographically guided transurethral laser incision of a Müllerian duct cyst for treatment of ejaculatory duct obstruction. Am J Roentgenology 2000; 175:777–778. 13. Carvalho HA, Paiva JLB, Santos VHV, et al. Ultrasonic recognition of a cystic seminal vesicle with ipsilateral renal agenesis. J Urol 1986; 135:1267–1268. 14. Heaney JA, Pfister RC, Meares EM. Giant cyst of the seminal vesicle with renal agenesis. Am J Roentgenology 1987; 149:139–140. 15. Shabsigh R, Lerner S, Fishman IJ, Kadmon D. The role of ultrasonography in the diagnosis and management of prostatic and seminal vesicle cysts. J Urol 1989; 141:1206–1209. 16. Nghiem HT, Kellman GM, Sandberg SA, Craig BM. Cystic lesions of the prostate. Radiographics 1990; 10:635–650. 17. McNeal JE. Origin and development of carcinoma in the prostate. Cancer 1969; 23:24–33. 18. McNeal JE, Price HM, Redwine EA, et al. Stage A versus stage B carcinoma of the prostate: Morphologic comparison and biologic significance. J Urol 1988; 139:61–65. 19. McNeal JE, Redwine EA, Freiha FS, Stamey TA. Zonal distribution of prostatic adenocarcinoma. Correlation with histologic pattern and direction of spread. Am J Surg Pathol 1988; 12(12):897–906. 20. Cornud F, Hamida K, Flam T, et al. Endorectal color doppler sonography and endorectal MR imaging features of nonpalpable prostate cancer: correlation with radical prostatectomy findings. Am J Roentgenol 2000; 175(4):1161–1168. 21. Neumaier CE, Martinoli C, Derchi LE, et al. Normal prostate gland: examination with color Doppler US. Radiology 1995; 196:453–457. 22. Lavoipierre AM, Snow RM, Frydenberg M, et al. Prostatic cancer: role of Doppler imaging in transrectal sonography. Am J Radiol 1998; 171:205–210. 23. Shigeno K, Igawa H, Shiina H, et al. The role of colour Doppler ultrasonography in detecting prostate cancer. BJU Int 2000; 86:229–233.

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24. Cornud F, Hamida K, Flam T, et al. Endorectal color Doppler sonography and endorectal MR imaging features of nonpalpable prostate cancer: correlation with radical prostatectomy findings. Am J Roentgenol 2000; 175:1161–1168. 25. Rubin JM, Bude RO, Carson PL, et al. Power Doppler US: A potentially useful alternative to mean frequency-based color Doppler US. Radiology 1994; 190:853–856. 26. Downey DB, Fenster A. Three-dimensional power Doppler detection of prostatic cancer. Am J Roentgenol 1995; 165:741. 27. Sakarya ME, Arslan H, Unal O, et al. The role of power Doppler ultrasonography in the diagnosis of prostate cancer: a preliminary study. Br J Urol 1998; 82:386–388. 28. Okihara K, Kojima M, Nakanouchi T, Okada K, Midi T. Transrectal power Doppler imaging in the detection of prostate cancer. BJU Int 2000; 85:1053–1057. 29. Wasserman NF, Kapoor DA, Hildebrandt WC, et al. Transrectal US in evaluation of patients after radical prostatectomy: I. Normal postoperative anatomy. Radiology 1992; 185:361–366. 30. Wasserman NF, Kapoor DA, Hildebrandt WC, et al. Transrectal US in evaluation of patients after radical prostatectomy: II. Transrectal US and biopsy findings in the presence of residual and early recurrent prostatic cancer. Radiology 1992; 185:367–372. 31. Leventis AK, Shariat SF, Slawin KM. Local recurrence after radical prostatectomy: Correlation of US features with prostatic fossa biopsy findings. Radiology 2001; 219:432–439.

11 What to look for when choosing treatmentplanning software for prostate brachytherapy Yan Yu Introduction Computerized treatment planning and dosimetry are an essential component in modern radiation therapy, including brachytherapy. With the widespread use of tomographic imaging such as computed tomography, magnetic resonance imaging, and ultrasound, three-dimensional image-based, anatomy-specific treatment planning is now commonplace in external beam radiotherapy. Continued technical advancement such as intensity modulated radiation therapy (IMRT) and image-guided therapy are also beginning to come into routine clinical use. At the same time, significant advances in brachytherapy planning and guidance have taken place, especially in the treatment of prostate cancer. The transrectal ultrasound (TRUS) imaging format lends itself naturally to 3D anatomy-based planning and dosimetry. Interstitial seed placement under TRUS guidance affords remarkable flexibility in terms of customizing the dose distribution to target the known disease and to spare critical structures in real time. Indeed, it may be argued that modern prostate brachytherapy is so far the most comprehensive image-guided therapy with dose intensity modulation. Continued evolution of treatment planning software plays an important role in the growth of this field. The choice of treatment planning software functionalities can directly influence the practice style of the users’ brachytherapy program. For example, the American Brachytherapy Society (ABS) categorized prostate brachytherapy planning into three distinctive levels (Table 11.1), ranging from idealized planning to dynamic dosimetry.1 The functional requirements of the corresponding planning software increase in complexity. It is important that the brachytherapy team is familiar with the capabilities and limitations of the planning system selected. The requisites Image acquisition Ultrasound equipment in common use for prostate brachytherapy usually has one or more video output formats, including real-time, live video images. The most direct method of image acquisition and import to the

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Table 11.1 American Brachytherapy Society (ABS) terminology for elements of intraoperative planning Level Terminology

Definition

0 1

None Creation of a plan in the operating room just before the implant procedure with immediate execution of the plan Stepwise refinement of the treatment plan using dose calculations derived from image-based needle position feedback Constant updating of dose calculations of implanted sources using continuous seed position feedback

2 3

Preplanning Intraoperative preplanning Interactive planning Dynamic dose calculation

treatment planning system is via ‘frame-grabbing’, a method to convert video frames into computer image formats, such as bitmap or JPG. Either an internal video capture/framegrabber card or an external USB (sometimes ‘fire wire’) connection is needed on the treatment planning computer. If the prostate volume study is performed at equal slice intervals, it suffices to be able to define the starting z-position, the z-increment, or decrement after each image capture, and the direction of the scan (base to apex or vice versa). Note that if x increases from patient right to patient left, y increases from posterior to anterior, then z needs to increase from base to apex to ensure a right-handed coordinate system. If intraoperative treatment planning and dosimetry is not anticipated by the brachytherapy team, then only still image import is required. Bitmap or JPG image formats can be conveniently transferred and manipulated across computer platforms, although DICOM image transfer is increasingly available, such as from ultrasound PACS systems. In the case of DICOM transfer, care should be taken to verify that the z (or baseapex) positions are correctly identified to the treatment planning system. Image segmentation Image segmentation is often referred to as contouring. In prostate brachytherapy, the anatomical structures that need to be contoured are the prostate, rectum, and urethra. Other structures of potential relevance include the bladder, pubic arch, penile bulb, neurovascular bundles, and tumor foci. At a minimum, the treatment-planning software should permit the user to interactively draw each selected contour over the grayscale image. When using TRUS images, it is necessary to establish the on-screen grid locations so as to correctly register the segmented versus the actual anatomy. This is usually accomplished by identifying two known template holes on the TRUS image. It is also useful to allow fine adjustment in positioning the software template grid, which may be used to account for any systematic shift of, for example, the stabilizing needles versus the ultrasound grid. Realigning the software grid is analogous to shifting the brachytherapy template; it invalidates any dosimetry plan previously generated.

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TG-43 formalism As the National Institute of Standards and Technology (NIST) standardizes the calibration of each type of clinical brachytherapy sources, the seed manufacturers will need to specify their activity range in terms of the air kerma strength according to the American Association of Physicists in Medicine (AAPM) Task Group 43 (TG-43) formalism.2 The traditional unit of activity in mCi is replaced by the air kerma strength in units of µGy/h m2, or ‘U’. A simple method of estimating dose at distance r away from a seed is then: 1.44×(half-life)×(air kerma strength)× (dose rate constant)×(radial dose function)× (anisotropy constant)/r2, using consistent units of time. The dose rate constant, radial dose function, and anisotropy constant are specific to each design of the radioactive seed, and are commonly determined by two independent dosimetry studies (measurement and/or calculation). The treatment-planning system must therefore allow definition of different seed designs and user input/modification of the dosimetry parameters. Conversion factors between the air kerma strength and mCi activity of different seeds can be found in textbooks or calculated from the dose rate constant; however, the reader is cautioned that such conversion factors may be subject to change as the calibration standard or the dose rate constant is revised. Isodose and dose-volume histogram Isodose display as color overlay over grayscale images is a standard feature of most treatment-planning systems. A useful additional functionality is numerical display of the dose at any location pointed to by the cursor on the image. The user is therefore able to quickly determine the dose delivered by the dosimetric plan to any anatomical structure of concern. The user interface should also allow rapid ‘paging’ through the different image planes (e.g. by providing thumbnail panels that may be browsed/ magnified). The dose-volume histogram (DVH) is a standard method for evaluating the volumetric irradiation of a given anatomical structure previously segmented. The cumulative volume (either in cm3 or as percent of total volume) of the anatomical structure receiving greater than or equal to a given dose (either in Gy or as percent of the prescribed dose) is plotted versus the dose. In prostate brachytherapy, certain parametric evaluators of implant quality have evolved into routine clinical use. For example, the AAPM,3 as well as the ABS,4 recommended the use of the following parameters: 1. The values of D100, D90, and D80 (the dose that covers 100%, 90%, and 80% of the prostate, respectively). 2. The values of V200, V150, V100, V90, and V80 (the fractional volume of the prostate that receives 200%, 150%, 100%, 90%, and 80% of the prescribed dose, respectively). These DVH values should be conveniently obtainable by table look-up or interpolation from the treatmentplanning output.

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Calculation of the DVH essentially involves sampling the dose at points distributed within the anatomical structure. Treatment-planning software generally uses one of two methods for selecting these points—random sampling or uniform sampling. In either method, sufficient points must be calculated to generate reliable DVH parameters, which need to be balanced with the speed of calculation. The dose-surface histogram (DSH) is similar to the DVH in concept except that the dose is calculated by sampling points distributed on a surface instead of within a volume. The DSH is a more suitable measure of dose to the anterior rectal wall because it should be less dependent on the rectal content at the time of imaging and less distorted by the much lower dose to the posterior rectum. The DSH is also conceptually more suited to the urethra, where Volume’ may be considered meaningless. Postimplant computed tomography dosimetry The current technique for evaluating individual implants as recommended by the ABS is computed tomography (CT)-based postimplant dosimetry.4 For this purpose, the treatment planning system should be able to import DICOM image sets, display CT images with window/ level control, and facilitate contouring of the anatomy and identification of seeds. A particularly useful feature of the software is automatic identification of seeds on CT. This is readily achievable using standard imageprocessing techniques; however, because a single seed may be imaged on two or more adjacent CT slices, an algorithm must be provided to eliminate redundant identification. A simple algorithm is to let the user specify the number of resulting seeds desired, and then to combine the nearest neighbors iteratively until the desired seed count results. The one shortcoming of this method is the assumption of a specified number of seeds: the user must independently determine the number of seeds in the patient (e.g. using plane films), which may be different from that implanted due to migration and seed loss. More sophisticated algorithms involve image analysis in two and three dimensions (in-plane and adjacent plane thresholding and region growth) using the expected size of the seed as prior knowledge to determine the actual number of seeds present in the volume of interest. It is also possible to determine the orientation of some of the seeds using such an algorithm, although the efficacy of incorporating anisotropic dose distribution around seeds has not been established in prostate brachytherapy. Advanced tools Auto-segmentation Automatic contouring of the prostate and rectum on TRUS is a very useful tool in prostate brachytherapy planning, particularly intraoperative planning. Traditionally, the prostate is outlined on the planning computer before the preplan is generated, and again outlined on the TRUS screen in the operating room after patient positioning. There is therefore significant timesaving if the autosegmentation tool produces consistent and accurate results. In one method,5 a generic 3D model of the prostate is initially incorporated into the algorithm by prior training based on expert’s manual segmentation

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of a variety of TRUS series. For a given TRUS series to be segmented, the unique properties of the prostate morphology are first determined by image processing and used to individualize the 3D model. Using a technique called ‘principal component analysis’, a best fit between boundary points found by image processing and known prostate morphologies is solved by the algorithm, which then translates into prostate contours on each TRUS slice. The entire process takes approximately 1 minute on a computer. Inverse planning In inverse planning, the user of the treatment planning system specifies the planning goals and constraints, such as the prescribed dose to the target volume, dose limits to organs at risk, dose uniformity, etc., and the planning software automatically generates solutions (i.e. dosimetric plans, that completely or partially satisfy the goals and constraints). In external beam radiation therapy, inverse planning is increasingly being relied upon to produce optimized conformal and intensity modulated radiotherapy (IMRT) plans. In prostate brachytherapy, inverse planning is so far primarily used in computer-aided intraoperative planning with optimization.6–8 The ability to rapidly (within 1 minute) produce a host of dose plans, each selected for optimizing aspects of the treatment intent (goals and constraints), is an attractive feature in a planning software. If the optimization algorithm embedded in the inverse planning engine is multi-objective, it is then not uncommon to include dose escalation to previously identified tumor foci (e.g. from magnetic resonance spectroscopy, sonoelastography, or biopsy results), mapped on to intraoperative TRUS using image registration or by reference to anatomical landmarks. Pubic arch interference may be avoided by blocking out the available optimization space anterior to the pubic arch projection. A novel capability of inverse planning in brachytherapy is its ability to incorporate sensitivity analysis on the dosimetric plans when the radioactive sources are subject to random displacements simulating what is typically found in actual implants.9 As expected, the extent of tolerance to seed misplacement is not equal among different dosimetric plans, and should depend on the locations of the seeds relative to areas of likely underdosage. A delicately planned seed distribution will tend to suffer greater underdosage in the hands of inexperienced practitioners compared to a’robust’ plan taking into account potential placement uncertainties. The sensitivity analysis functionality simulates this effect by assuming a Gaussian distribution of displacements in the seed distribution using a standard error reflective of the practitioner’s experience. Needle tracking Whereas the preplan relies on accurate reproduction of the prostate geometry between the preplanning and the intraoperative volume studies, intraoperative preplanning allows any interval volume changes as well as changes in the relationship between prostate, rectum, and urethra to be accounted for. In both techniques, however, the dosimetry reflects an idealized (i.e. perfect) needle and seed placement in their planned locations. The technique of needle tracking was designed to provide realistic (rather than idealistic) dosimetry evaluation in real time by accounting for needle splaying (i.e. deviation from the planned grid location, as observed on TRUS as the needle is being placed). The actual

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hyperechoic spot of the needle is identified by the user in one ‘mouse click’ on the planning computer’s screen that displays the live ultrasound in its transverse view. If one assumes that the needle deviation is zero at the mid-thickness of the template, then a straight line can be drawn from that point to the needle tip at known depth in the prostate. Then for each z-location corresponding to an intended seed deposition, a set of ∆x and ∆y for the leftright and anterior-posterior deviations can be calculated by linear interpolation, which is different for each seed (greater deviations towards the base). The dose distribution is immediately updated to show any changes in target coverage and/or critical structure sparing. All of the above steps may be completed even before the seeds are deposited into tissue, therefore this tool can be used to help the clinicians decide if it is necessary to reposition the needle before committing to the seed placement. Intraoperative seed detection Although the needle tracking technique turns an idealized dosimetry plan to a realistic dose distribution reflective of the actual needle positions, it is not meant to replace postimplant dosimetry because the actual seed positions can be perturbed by the withdrawal of the needle or tissue elasticity. Intraoperative seed detection will overcome this limitation. A set of closely spaced 2D TRUS scans of the prostate containing implanted seeds is acquired, resulting in a 3D volume ultrasound dataset. Electromagnetic (EM), optical, or mechanical sensors can be used to map the 2D ultrasound scan planes into the 3D ultrasound volume. Among these, EM positional sensors are the most commonly used method in radiological 3D ultrasound. Its accuracy for intraoperative brachytherapy was first established by Watanabe and Anderson.10 A small EM emitter is attached to the handle of the ultrasound probe, and an EM receiver is positioned 50–100 cm away in a stationary location. Linear and rotational movement of the EM emitter relative to the receiver is tracked in real-time and translated into probe motion, which is registered with the corresponding image capture. On the treatmentplanning system, image-processing techniques involving statistical and texture analysis as well as neural networks are then applied to the image set to distinguish actual seeds from such artifacts as air gaps, bleeding, and calcification.11 Dosimetry is recalculated based on the actual seed positions detected from postimplant TRUS, which also displays the prostate anatomy. These procedures may be completed in 1–2 minutes from the 3D ultrasound scan to dose recalculation. It is therefore possible to perform intraoperative seed detection not only at the end of the implant when all the planned seeds have been deposited, but also incrementally after a group of needles is delivered. In the latter case, opportunity still exists to compensate for any imperfections in previous seed placement by re-optimization of the remaining plan or additional seed insertion. This method of intraoperative postimplant dosimetry directly overcomes the dilemma in CT-based postimplant dosimetry where the patient usually cannot benefit from the knowledge gained from the dose assessment.

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Summary The field of prostate brachytherapy planning is now sufficiently mature that the requisite functionalities are widely available in any software system specifically designed for this purpose. Advanced features, such as the tools discussed in the previous section, are designed to present a great variety of real-time data to the brachytherapist during the procedure for making more informed decisions regarding dosimetry. Although the practice style of the brachytherapy team can be significantly altered by treatmentplanning technology, the ultimate goal is to allow increased dosimetric knowledge to directly benefit the patient under treatment. This is the driving force in the continued evolution of treatment-planning software for prostate brachytherapy. References 1. Nag S, Ciezki JP, Cormack R, et al. Intraoperative planning and evaluation of permanent prostate brachytherapy: Report of the American Brachytherapy Society. Int J Radiat Oncol Biol Phys 2001; 51:1422–1430. 2. Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial brachytherapy sources: Recommendations of the AAPM Radiation Committee Task Group No. 43. Med Phys 1995; 22:209–234. 3. Yu Y, Anderson LL, Li Z, et al. Permanent prostate seed implant brachytherapy: Report of the American Association of Physicists in Medicine Task Group No. 64. Med Phys 1999; 26:2054– 2076. 4. Nag S, Bice W, DeWyngaert K, et al. The American Brachytherapy Society recommendations for permanent prostate brachytherapy postimplant dosimetric analysis. Int J Radiat Oncol Biol Phys 2000; 46:221–230. 5. Liu H, Cheng G, Rubens D, et al. Automatic segmentation of prostate boundaries in transrectal ultrasound (TRUS) imaging. Proc SPIE 2002; 4684:412–423. 6. Yu Y, Zhang JB-Y, Brasacchio RA, et al. Automated treatment planning engine for prostate seed implant brachytherapy. Int J Radiat Oncol Biol Phys 1998; 43:647–652. 7. Messing E.M, Zhang JB-Y, Rubens DJ, et al. Intraoperative optimized inverse planning for prostate brachytherapy: Early experience. Int J Radiat Oncol Biol Phys 1999; 44:801–808. 8. Zelefsky MJ, Yamada Y, Cohen G, et al. Postimplantation dosimetric analysis of permanent transperineal prostate implantation: improved dose distributions with an intraoperative computer-optimized conformal planning technique. Int J Radiat Oncol Biol Phys 2000; 48:601– 608. 9. Yu Y. Multiobjective decision theory for computational optimization in radiation therapy. Med Phys 1997; 24:1445–1454. 10. Watanabe Y, Anderson LL. A system for nonradiographic source localization and real-time planning of intraoperative high dose rate brachytherapy. Med Phys 1997; 24:2014–2023. 11. Cheng G, Liu H, Liao L, Yu Y. Dynamic brachytherapy of the prostate under active image guidance In: WJ Niessen, MA Viergeva (eds) Medical Image Computing and ComputerAssisted Intervention—MICCAI 2001, 4th International Conference, Utrecht, The Netherlands, October 14–17, 2001, Proceedings. Lecture notes in Computer Science 2208. Berlin, Springer, 2001.

12 Treatment planning for low and high dose rate brachytherapy Marco Zaider and Eva K Lee Introduction Treatment planning in brachytherapy consists of a sequence of steps that include the following: •Selection of appropriate sources •Localization of potential source positions •Dose prescription •Treatment plan design and verification. In this chapter we shall discuss these topics as applied to the brachytherapy of prostate cancer. Although the methodology described below reflects (unavoidably) accepted practice at Memorial Sloan-Kettering Cancer Center (MSKCC), the emphasis is on those aspects that—at least in our view—should define standard of care in prostate brachytherapy. Currently, for instance, a majority of prostate implants appears to be performed using preplanned source distributions, while here we strongly advocate the use of intraoperative computer-optimized planning—a technique used routinely at MSKCC and at several other institutions. Selection of appropriate sources In brachytherapy, radioactive isotopes are selected based on two criteria: (1) the energy of the ionizing particle; and (2) the decay rate of the radionuclide. Low energy sources are preferred because of their evident advantage in terms of radiation protection (see Table 12.1). They also offer better flexibility in designing conformal plans, as well as avoiding excess irradiation of healthy tissues that surround the target. The main benefit of high energy sources is that (dosimetrically) they cover a larger volume and thus fewer sources may be needed. The decay rate of the radionuclide may have radiobiological implications because it determines the initial dose rate, short-lived radioactive sources having, for the same total dose, a larger initial dose rate. Indeed, for a temporary implant of duration t, the total dose delivered, D(t), is given by: (1)

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Table 12.1 Physical characteristics of radioactive sources currently used in brachytherapy Isotope E/MeV Eγ(max)/Mev T1/2β 192

Ir

0.380

Air kerma rate coastant/cGy/h cm2/mCi cm2/mCi

HVL (Pb)/cm

0.67

74.2 4.11 0.3 days 125 I 0.028 – 60.2 1.32 0.002 days 103 Pd 0.021 – 17 days 1.296 0.002 HVL represents half-value layer and indicates the thickness of material that will reduce the fluence of uncharged particle to half.

where λ is the decay constant and T1/2 (=0.693/λ) is the half-life of the isotope. In particular, for a permanent implant: (2) It goes without saying that long-lived radionuclides are not appropriate for permanent implants. Another important issue in the context of source selection is the relative biological effectiveness (RBE) of the radiation field. Low energy sources tend to have higher RBE values.1,2 For instance, the RBE of iodine-125 (125I) has been extensively studied and results of 1.2–2 have been reported for the dose rate range of 0.03–9 Gy/h.3 Similarly, for palladium-103 (103Pd) a study performed at 0.07–0.8 Gy/h reported RBE values of 1.9±0.7.3–6 Table 12.1 lists the main physical characteristics of radiation sources used in prostate brachytherapy: iridium-192 (192Ir) is used for high dose rate (HDR) treatments, and 125I and 103Pd are used for low dose rate (LDR) permanent implants. The air kerma rate constant (Γδ), relates the activity, A, of a radionuclide emitting photons to its kerma rate. Specifically, Γδ is ‘the quotient of by A, where is the air kerma rate due to photons of energy greater than δ, at a distance 1 cm in vacuo from a point source of this nuclide’:7 (3) Γδ is measured in units of m2Gy s−1 Bq−1. Localization of potential source positions In permanent prostate implants potential source positions are localized with respect to a template that is placed in a fixed position relative to the treatment region (the prostate gland). The template, shown in Figure 12.1, has a rectangular pattern of holes; needles are inserted through the template grid and seeds are placed along each needle at positions (typically, in multiples of 0.5 cm) determined by the treatment plan. A series of parallel

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ultrasound (US) images is taken through the prostate and firmware in the ultrasound unit overlays a grid of dots on to these images that correspond to the template holes (Figure 12.2). The grid coordinates on the template and the distance of the US image away from the template uniquely identify the 3D coordinates of each potential seed position relative to the gland anatomy. It is often the case that, as they penetrate into the prostate, inserted needles deviate from the initial

Figure 12.1 Template used in a prostate permanent implant.

Figure 12.2 The grid superimposed on the ultrasound image provides the (x, y) coordinates of the inserted needles. Potential seed positions (x, y, z) are along these needles. The third

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coordinate (z) is determined by the position of the ultrasound probe (equivalently, by the image number). grid coordinates. However modern planning systems have provisions for taking this into account in dosimetric calculations. High dose rate (HDR) prostate treatment (administered at MSKCC as a boost before external radiation therapy) is performed with remote afterloader machines.

Figure 12.3 Template and flexiguide tubes used in high dose rate (HDR) prostate treatment. A template, similar to that used for permanent low dose rate (LDR) implants, is employed to place flexiguide tubes into the prostate (Figure 12.3). Potential stopping positions for the 192Ir source are obtained via computed tomography (CT) of the prostate with the source-guiding needles inserted in it. A difficulty in this approach is the fact that the catheters’ relative positions inside the target are not the same as the original perineal grid

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coordinates and thus their coordinates may vary from one slice to the next (Figure 12.4). In our treatment-planning system, catheters are digitized on each CT slice (Figure 12.5), their trajectory fitted to a third degree polynomial (spline fitting) and then equidistant stopping positions are calculated analytically and entered in the planning software (Figure 12.6).

Figure 12.4 Scout image of a high dose rate (HDR) prostate implant.

Figure 12.5 In each computed tomography (CT) slice the location of catheters is digitized (green or yellow circles). The trajectory of each catheter is then reconstructed and stopping positions, 0.5 cm apart, are calculated and stored in the planning software.

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Dose prescription In prostate brachytherapy, the dose prescription is made relative to the clinical target. Specifically, the recommended procedure is to use the minimum peripheral dose (mPD), which is the largest dose isodose surface that completely surrounds the target (Figure 12.7).8 Often, this is found to be too restrictive (and perhaps unrealistic in terms of being able to implement the plan) and a different type of prescription makes use of D90, which means that one stipulates that a dose equal to or larger than the

Figure 12.6 Reconstructed catheter geometry and stopping positions.

Figure 12.7 Dose prescription for a permanent prostate implant. In this 2D ultrasound image the white line delineates the prostate and the 100%

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isodose line (mPD=144 Gy) is shown in green. Green dots indicate seeds and red dots show unused seed locations along needles. prescription dose (144 Gy for permanent implants, 5–6 Gy/fraction for HDR treatments) be delivered to at least 90% of the target volume. The determination that the treatment plan achieves the required mPD or D90 can be made with the aid of dose-volume histograms (DVH), which plot as a function of dose, D, the probability that a randomly selected voxel volume receives a dose of at least D (this is, of course, the cumulative probability distribution of dose in the target volume). An example is given in Figure 12.8, which shows the DVH as planned for an HDR treatment of the prostate. In this case the prescription dose, 5.5 Gy, covers 96% of the target.

Figure 12.8 Dose-volume histogram (DVH) for a HDR treatment plan (prescription dose: 5.5 Gy). Treatment plan design and verification In brachytherapy, planning means finding a pattern of sources (of given strength) that is consistent with dosimetric constraints—typically, a minimum dose for the target and a maximum dose for the healthy tissues adjacent to the target. The search for this optimal source distribution may be performed using iterative (trial and error) methodology or—as described here—using computer-based optimization. For the latter, a mathematical model is usually developed that includes the essential dosimetric constraints, and an objective function (often user-specific). The objective function is a mathematical expression that measures the quality of the dose distribution. This metric can be selected according to the desire of the planner in the characteristics of the resulting plan. The model is then solved

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by some algorithms. Search algorithms used in brachytherapy treatment planning include exact algorithm, such as branch-and-bound, or heuristic approaches as in simulated annealing,9 and genetic algorithm. Branchand-bound algorithm is a tree search approach that works by searching through the set of all feasible plans (those which satisfy all the input constraints in the model) and returns an optimal plan that provides the best objective value. When allowed to run to completion, this approach will return a provenoptimal plan. Heuristics procedures work somewhat differently. Depending on the design, the search does not necessarily return plans that satisfy all the imposed constraints, rather, the search attempts to obtain seed patterns which provide the least violation to the imposed constraints. Furthermore, there is no information on whether one obtains an optimal seed configuration or not. Instead, the termination of heuristics algorithms is based on the number of iterations that the users input. At each iteration the algorithm obtains a plan and will evaluate its associated objective function value. If the objective function is better than the incumbent plan, it will be updated. Treatment-planning models The planning problem consists of determining if each possible source location should be implanted with a radioactive source or not. Hence, the decision variables are the location of the grid position. Mathematically, this can be modeled as an integer program—a mathematical model that consists of integer decision variables.10–12 In our case, it is the ‘yes’ or ‘no’ decision of placing a seed or not at each possible location. Mathematically, let xj be a 0/1 decision variable for recording the placement of a source at grid position, j. The total dose, D(P), at point P is given by: (4) where n is the number of potential source positions, R. is a vector that gives the coordinates of grid position j, ||P−Rj|| is the Euclidian distance between P and R, and D(r) is the dose contribution to P from a source at distance r away (within the point source approximation). For each point of interest one can define upper (UP) and lower (LP) dose limits that D(P) must satisfy: (5)

Generally, it is not possible to have all points P satisfy these constraints, in which case there will be no feasible solution [xj] to this problem. Instead, one attempts to maximize the number of points that satisfy these inequalities. This is achieved in the following manner. Let UP+MP denote the absolute maximum acceptable dose at point P, and similarly LP−NP for the absolute minimum dose. Further, let, WP, VP be binary (0/1) variables that indicate whether Eqs (5) are satisfied (when equal to 1) or not (when equal to 0). With this, the constraints, Eqs (5), become:

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(6)

and the sum: (7) which depends on the configuration [xj], gives the total number of points P that satisfy the original constraints, Eqs(5). The optimization problem consists of maximizing the objective function, F. All points P need not have the same clinical importance; for instance, avoiding urethral toxicity (a common side effect) may be more important than satisfying the condition of dose uniformity across the target. This is addressed by assigning different weights, αP and βP, to vP and wP, respectively, and maximizing instead: (8) The problem described by the expression, Eq (8), and constraints, Eq (6), is known as a linear integer programing (IP) problem because the objective function is linear in the unknown variables and since these variables can take only integer (here 0 or 1) values. Other objectives can also be employed. For example, instead of maximizing the number of points which satisfy the original constraints Eqs (5), one can employ non-negative continuous variables yP and ZP to capture the deviations of the dose level at a given point from its target lower and upper bounds, respectively. In this case, Eqs (5) become: (9)

and the sum F() becomes: (10) When the target bounds LP and UP are expressed as multiples of a target prescription dose, TP, another natural approach is to capture the deviations from TP directly.13 In our model, this can be achieved by replacing constraints Eq (9) with: (11) where yP is a continuous variable, unrestricted in sign. In the objective, one can then minimize the q norm of the vector y of all deviations, that is, minimize:

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(12) In this case, the problem becomes a quadratic 0/1 integer program. Algorithms commonly used for solving this problem are now described. Algorithms Branch-and-bound The classical approach to solving linear 0/1 mixed integer programs (MIP) is branch-andbound. This is a tree search approach where, at each node of the tree, certain binary variables are fixed to zero or one, and the remaining binary variables are relaxed (i.e., allowed to assume any value between zero and one). This results in a linear program (LP) being associated with each node of the tree. The LP at the root node is simply the original 0/1 MIP instance with all of the binary variables relaxed. The tree is constructed such that the binary variables fixed in a parent node will be fixed identically in any of its children, and each child will have an additional binary variable fixed to zero or one. Typically, children are formed in pairs as follows. Assume that the LP at a given node is solved, and one or more of the relaxed binary variables is fractional in the optimal solution. One selects such a fractional binary variable and branches on it. That is, two child nodes are formed; one with the selected binary variable fixed to zero, and the other with the selected binary variable fixed to one. Of course, each child also inherits all of the fixed binary variables of its parent. Note that the objective value of a child node can be no greater (in the case of maximization) than the objective value of its parent. If the linear program at a given node is solved and the optimal solution happens to have integral values for all the relaxed binary variables, then this solution is feasible for the original 0/1 MIP. Once a feasible solution for the original problem is found, the associated objective value can be used as a lower bound (in the case of maximization) for the objective values of LPs at other nodes. In particular, if an LP at another node is solved, and its objective value is less than or equal to the lower bound, then none of its children could yield a feasible solution for the original MIP with a greater objective value than the one already obtained. Hence, no further exploration of this other node is needed, and the node is said to be fathomed. Two other criteria for fathoming a node are obvious: if the associated LP is infeasible, or if the optimal solution of the LP has integral values for all relaxed binary variables, then no further exploration of the node is required. In the latter case, the optimal objective value of the LP will be compared with the current lower bound, and the lower bound will be updated if needed. The tree search ends when all nodes are fathomed. A variety of strategies have been proposed for intelligently selecting branching variables and nodes to process. However, no strategy stands out as being best in all cases. What has become clear from recent research in computational MIP is that branch-andbound is most effective when coupled with other computational devices, such as problem preprocessing, primal heuristics, global and local reduced-cost fixing, and cutting planes. The reader can refer to the article by Lee for a concise description of branch-and-bound methods for integer programing.14 The books by Schrijver,15 Nemhauser and Wolsey,16 and Parker and Rardin,17 contain detailed expositions on integer programing and related computational issues. Branch-andbound algorithms designed for determining optimal

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seed locations for prostate implants can be found in Gallagher and Lee,10 Lee and Zaider,12 and Lee et al.18 Genetic algorithm This was first proposed in connection with the optimal allocation of trials in 1973.19,20 A genetic algorithm is a heuristic optimization method modeled on the biological mechanisms of evolution and natural selection.21,22 In nature, the characteristics of an organism are encoded in streams of DNA known as chromosomes. Likewise, in a genetic algorithm a potential solution to a problem is encoded as a stream of symbols over a given alphabet. Given an initial population of individuals (i.e. potential solutions encoded as symbol streams), a subset of the population is selected to parent offspring for the next generation. The parent selection process is stochastic, but biased towards selecting those individuals that are most fit, as measured by a preselected fitness function (e.g. the objective function that one is trying to optimize). After the parents are selected, they are paired off and mated. That is, subsections of two-parent symbol streams are interchanged, forming two new members for the next generation. This is analogous to crossover in biological reproduction, where a child’s genetic composition is a combination of its parents. Mutations are also possible. This is typically implemented by randomly selecting a child symbol stream and randomly altering one of its symbols. In order to ensure that the current best solution is not lost, the strategy of elitism can be employed. That is, the data stream with the highest fitness value is passed on unchanged to the next generation. This is implemented by simply overwriting one of the newly created children. The algorithm can be terminated after a specified number of generations have been created (usually several thousands), or by examining when the difference between the maximum and minimum fitness values between consecutive generations remains less than a specified threshold for a number of generations. On termination, the individual in the final generation with the largest fitness value is selected as the operative solution to the problem at hand. Several authors discuss implementation of genetic algorithms for prostate implants.11,23–25 Simulated annealing This is also referred to as Monte Carlo annealing, probabilistic hill climbing, statistical cooling, and stochastic relaxation,26 and was first described as a heuristic for solving computer design problems,27 and the traveling salesman problem.28 Simulated annealing is the application of statistical mechanics principles to combinatorial optimization. It has proven effective in generating near-optimal solutions for certain large problems. Annealing is a process in which a solid is heated beyond its melting point and then cooled slowly and carefully into a perfect lattice. The crystalline structure of the perfect lattice represents a minimization of free energy for the solid. The cooling process determines if the ground state is achieved or if the solid retains a locally optimal lattice structure with crystal imperfections. The Metropolis algorithm was developed to characterize cooling schedules that would produce favorable results.29 The central feature of the algorithm is the Metropolis condition: as the solid is cooled, the current configuration of the atoms is accepted with a certain probability and rejected otherwise. At non-zero temperatures, transitions out of local optima are always possible. Thus, the free energy is not monotonically decreased.

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Simulated annealing applies these concepts to a combinatorial optimization problem. The cost function, or objective, assumes the role of the free energy function. The set of feasible solutions is analogous to the states of a solid. Let f(i) be the value of the cost function for solution i. Suppose the objective is to minimize f. A transition from state i to state j is accepted according to the following distribution: (13) The parameter c is an artificial ‘temperature’ that is usually reduced as the number of iterations increases. At large values of c, large increases in the objective are accepted while for smaller values only small increases are accepted. Note that decreases in the objective are always accepted. The cooling schedule is the method by which c is decreased. A simple cooling schedule specifies co as the initial temperature and a parameter β such that ck=βk co.27 Other cooling schedules have been proposed.26 The implementation of simulated annealing requires the following: (1) a concise representation of the state space; (2) a method for randomly generating state transitions; (3) an objective function measuring the cost/benefit of transitions; and (4) cooling schedule parameters and stop criterion.27 Asymptotic convergence of the algorithm under various conditions on the generation and acceptance distributions has been proven.30 The sequence of state transitions produces a discrete time Markov chain. The method can be generalized to problems producing continuous time and continuous state space Markov chains.30,31 Solutions arbitrarily close to optimal usually require exponential run times, but the asymptotic behavior can be approximated in polynomial time.26 The neighborhood structure of a problem determines which solutions are accessible in one transition from the current solution. For small problems, the neighborhood structure can have a large impact on the time to find good solutions. For problems with a large number of solutions and a relatively uniform distribution of values of the cost function, structure plays a lesser role.9,26,32,33 Examples In this section, a two-variable integer program is solved using branch-and-bound.14 The most infeasible integer variable is used as the branching variable, and best-bound is used for node selection. Consider the problem: (14)

Initially, the set of active problems, L, consists of just this problem IP0. The solution to the LP relaxation is x01=2.5, x02=3.75, with value zR0=62.5. The most infeasible integer variable is x1, so two new subproblems are created, IP1 where x1≥3 and IP2 where x1≤2, and L={IP1, IP2}.

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Both problems in L have the same bound 62.5, so assume the algorithm arbitrarily selects IP1. The optimal solution to the LP relaxation of IP1 is x11=3, x12=2.5, with value zR1=59. The most infeasible integer variable is x2, so two new subproblems of IP1 are created, IP3 where x2≥3 and IP4 where x2≤2, and now L={IP2, IP3, IP4}. The algorithm next examines IP2, since this is the problem with the best bound. The optimal solution to the LP-relaxation is x21=2, x22=4, with value zR2=58. Since x2 is integral feasible, zIP, the incumbent lower bound, is then updated to 58 and IP2 is fathomed. Both of the two subproblems remaining in L have the best bound greater than 58, so neither can yet be fathomed. Since these two subproblems have the same bound 59, assume the algorithm arbitrarily selects IP3 to examine next. LP relaxation to this problem is infeasible, since it requires that x satisfy x1≥3, x2≥3 and 5x1+2x2≤2 simultaneously. Therefore, zR3=−∞, and this node can be fathomed by bounds since zR3≤zIP. That leaves the single problem IP4 in L. The solution to the LP relaxation of this problem is x41=3.2, x42=2, with value zR4=57.6. Since zR4≤zIP, this subproblem can also be fathomed by

Figure 12.9 A branch-and-bound example. bounds. The set L is now empty, hence x2 is an optimal solution for the integerprograming problem IP0. The progress of the algorithm is indicated in Figure 12.9. Each box contains the name of the subproblem, the solution to the LP relaxation, and its associated objective value.

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References 1. Wuu CS, Zaider M. A calculation of the relative biological effectiveness of 125I and 103Pd brachytherapy sources using the concept of proximity function. Med Phys 1998; 25:2186–2189. 2. Wuu CS, Kliauga P, Zaider M, Amols HI. Microdosimetric evaluation of relative biological effectiveness for 103Pd, 125I, 241 Am, and 192Ir brachytherapy sources. Int J Radiat Oncol Biol Phys 1996; 36:689–697. 3. Ling CC, Li WX, Anderson LL. The relative biological effectiveness of I-125 and Pd-103. Int J Radiat Oncol Biol Phys 1995; 32:373–378. 4. Nath R, Meigooni AS, Melillo A. Some treatment planning considerations for Pd-103 and I-125 permanent interstitial implants. Int J Radiat Oncol Biol Phys 1992; 22:1131–1138. 5. Zellmer DL, Shadley JD, Gillin MT. Comparisons of measured biological response and predictions from microdosimetric data applicable to brachytherapy. Radiat Prot Dosimetry 1994; 52:395–403. 6. Zellmer DL, Gillin MT, Wilson JR Microdosimetric single event spectra of yb-169 compared with commonly used brachytherapy sources and teletherapy beams. Int J Radiat Oncol Biol Phys 1992; 23:627–632. 7. International Commission on Radiation Units and Measurements (ICRU). Radiation quantities and unit. Washington, DC: ICRU, 1980. 8. Anderson LL, Nath R, Olch AJ, et al. American Endocurietherapy Society recommendations for dose specifications in brachytherapy. Endocur/Hypertherm Oncol 1991; 7:1. 9. Pouliot J, Tremblay D, Roy J, Filice S. Optimization of permanent I-125 prostate implants using fast simulated annealing. Int J Radiat Oncol Biol Phys 1996; 36:711–720. 10. Gallagher RJ, Lee EK. Mixed integer programming optimization models for brachytherapy treatment planning. Proceedings/AMIA Annual Fall Symposium 1997; 278–282. 11. Lee EK, Gallagher RJ, Silvern D, et al. Treatment planning for brachytherapy: an integer programming model, two computational approaches and experiments with permanent prostate implant planning. Phys Med Biol 1999; 44:145–165. 12. Lee EK, Zaider M. Mixed integer programming approaches to treatment planning for brachytherapy. Ann Op Res, Optimization Med 2003; 119:147–163. 13. Brahme A. Optimization of the 3-dimensional dose delivery and tomotherapy. Int J Imag Syst Technol 1995; 6:1. 14. Lee EK. Branch-and-bound methods. In: Mauricio GC, Resende, Pardalos PM, eds. Handbook of applied optimization. Oxford University Press, 2001. 15. Schrijver A. Theory of linear and integer programming. Chichester, UK: Wiley, 1986. 16. Nemhauser GL, Wolsey LA. Integer and combinatorial optimization. New York: Wiley, 1988. 17. Parker RG, Rardin RL. Discrete optimization. Boston: Academic Press, 1988. 18. Lee EK, Gallagher RJ, Silvern D, et al. Treatment planning for brachytherapy: an integer programming model, two computational approaches and experiments with permanent prostate implant planning. Phys Med Biol 1999; 44:145–165. 19. Holland JH. Erratum: Genetic algorithms and the optimal allocation of trials. SIAM J Comput 1974; 3:326. 20. Holland JH. Genetic algorithms and the optimal allocation of trials. SIAM J Comput 1973; 2:88–105. 21. Buckles BP, Petry F. Genetic algorithms. Los Alamitos, CA: IEEE Computer Society Press, 1992. 22. Wasserman PD. Advanced methods in neural computing. New York: Van Nostrand Reinhold, 1993. 23. Yu Y, Schell MC. A genetic algorithm for the optimization of prostate implants. Med Phys 1996; 23:2085–2091.

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24. Silvern DA. Automated OR prostate brachytherapy treatment planning using genetic optimization. Thesis/Dissertation, Columbia University, New York. 25. Yang G, Reinstein LE, Pai S, et al. A new genetic algorithm technique in optimization of permanent I-125 prostate implants. Med Phys 1998; 25:2308–2315. 26. Aarts EHL, Korst J. Simulated annealing and Boltzmann machines: a stochastic approach to combinatorial optimization and neural computing. Chichester, UK: Wiley, 1989. 27. Kirkpatrick S, Gelatt CD, Vecchi MP. Optimization by simulated annealing. Science 1983; 220:671–680. 28. Cerny V. Thermodynamical approach to the traveling salesman problem: an efficient simulation algorithm. J Optimiz Theory Applic 1985; 45:41–51. 29. Metropolis NA, Rosenbluth A, Rosenbluth M, et al. Equation of state calculations by fast computing machines. J Chem Phys 1953; 21:1087–1092. 30. Aarts EHL, Korst JHM, Lenstra JK. Chapter 8: Simulating annealing. In: Aarts EHL, Lenstra JK, eds. Local search in combinatorial optimization. Chichester, UK: Wiley, 1997:91–120. 31. Hajek B. A tutorial of theory and applications of simulated annealing. Proceedings of the 24th Conference on Decision and Control, 1985:755–759. 32. Sloboda RS. Optimization of brachytherapy dose distribution by simulated annealing. Med Phys 1992; 19:964. 33. Anderson LL. Plan optimization and dose evaluation in brachytherapy. Semin Radiat Oncol 1993; 3:290–300.

13 Planning an implant: preoperative versus intraoperative planning Ronald D Ennis Preoperative planning The prostate brachytherapy procedure developed by the Seattle group included a volume study as an integral part of the process. During this preoperative procedure, images of the prostate were obtained at 5 mm intervals from base to apex.1 These images were then used to perform preoperative treatment planning. The required positions of the seeds and needles were determined during this process. Needles were preloaded prior to the implant procedure itself as determined by the preplan. During the implant procedure, the patient was positioned in similar manner to the position during the preoperative volume study and the prostate position was reproduced. Then, the preloaded needles were placed into the prostate in the predetermined positions under ultrasound guidance. This preoperative volume study session was novel and held out several advantages. First, a dosimetry-driven implant could be performed. The alternative brachytherapy technique was pioneered by Stock and Stone at Mt Sinai Hospital (New York) and advocated also by Grado.2,3 In this technique, the number of seeds placed was determined based on time-honored tables of activity per volume and rules of thumb for the ratio of seeds placed in the central versus peripheral regions of the implanted volume. The Seattle approach allowed one to prescribe a particular dose and then determine the optimal position of the seeds and needles to achieve this dose. Since dose is the biologically important parameter, it was logical to attempt to deliver a particular dose to the prostate and to plan accordingly. Performing the volume study preoperatively allowed the physicist/dosimetrist the time to optimize the plan, since the volume study was typically performed a few weeks prior to the procedure itself. Aside from the prescription dose, several other parameters can be varied, such as the degree of inhomogeneity within the prostate, and the dose to the adjacent normal tissues. The preplanning process allowed different plans to be evaluated to achieve these multiple goals. An additional advantage of preoperative planning was that the end result of the preplanning process was to determine the locations of each seed. Since several seeds will typically be placed at different depths along a particular x, y position, a single needle could be loaded for each of these positions and unloaded in a single train thereby simplifying the implant procedure itself and obviating the need to place each seed individually. The preliminary results of prostate brachytherapy performed by the Seattle group were impressive and inspired many others to adopt their technique.1 However, several problems with the preoperative volume study were appreciated. First, matching the prostate position, size, and shape of the preplan to that which existed at the time of the

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procedure itself was not always easily achievable. Differences in patient positioning and differences induced by anesthesia, which is used only during the brachytherapy procedure itself, are the presumed causes of the discrepancy. Data supporting these concerns are provided by a report from Messing et al. in which they analyzed the change in prostate volume between the preplan and the intraoperative evaluation.4 There were significant changes in volume (greater than 5%) in 4 out of 5 patients. In addition, these investigators evaluated the dosimetric results of an implant if it precisely followed the preplan without any intraoperative adjustments. The mean fraction of volume underdosed was 22.6% with a range of 6.4–64.9%. In addition, a second problem associated with the preplanning volume study is the need for two sessions, which is cumbersome for patients and physicians and expensive if both sessions are performed in an operating room setting. Because of these concerns, several institutions began to perform the volume study and the treatment planning in the operating room at the time of the procedure. The most important component necessary to perform this was computer software that could help perform a treatment plan quickly. In addition, those performing the treatment plan had to be knowledgeable and experienced enough to know how many seeds to order for a particular size prostate and be able to optimize the plan quickly in the operating room. Some groups developed their own software, while others adapted commercially available software to this task. More rapid methods for loading seeds into needles were also needed to make this process feasible and several manufacturers developed different loading devices to speed this part of the process. Alternatively, some institutions used the Mick™ applicator (Mick Radio-Nuclear Instruments, Bronx, NY) in which individual seeds are implanted, obviating the need to load needles in a specific pattern as determined by the treatment plan. Successful implementation of this new approach would require that similar or superior plans could be developed in the operating room in a reasonable amount of time. In addition, the quality of the implant as assessed by postimplant dosimetry should be at least as good, but ideally better, than that achieved with a separate volume study. Finally, clinical outcome regarding disease control and toxicity should be at least as good, but preferably better, than that achieved previously. Intraoperative preplanning Time requirements and dosimetric results Investigators from the University of Rochester, NY were the first to describe the development and implementation of an intraoperative preplanning method.4 They developed their own software known as Prostate Implant Planning Engine for Radiotherapy (PIPER). The software employed a genetic algorithm approach. The program is given certain required dosimetric parameters and then solves the problem. Additionally, it has a feature that includes in the optimizations the uncertainty associated with actual seed placement (i.e. it can provide an optimal plan given that seeds will be placed with an error in location). In this study Messing et al. compared the plans of 10 patients. Each patient underwent a preoperative volume study and a preplan was calculated using the PIPER. When the patient was brought to the operating room, an

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intraoperative preplan was developed. The time for each step of the process was quantified. Then median time to capture the transverse ultrasound images on to the planning computer was 4 minutes, the median time for image segmentation was 10 minutes, the median time to run the PIPER was 2.2 minutes and the time to evaluate the plan was 2 minutes. Thus, the overall time for the intraoperative planning process was approximately 18 minutes. The plan derived in the standard preoperative fashion and in the intraoperative fashion were similar as assessed by the peripheral uniformity number, the uniformity number, and the fractional spread of the differential dose-volume histogram around the mean tumor dose. Formal comparison by more traditional dosimetric parameters was not performed. A visual display of the pure dose-volume histograms, (i.e. dose to number of cc of PTV, rather than the more common fraction of PTV receiving at least the dose) is provided in display form and do suggest that there are some differences between the two plans. No comparison of postimplant dosimetry was performed. At Columbia University College of Physicians and Surgeons, Gewanter et al. implemented an intraoperative preplanning procedure using commercially available software.5 We analyzed the time required to perform the procedure and compared the dosimetric parameters of the first 10 patients treated in this manner with the previous 10 patients treated with the standard preoperative volume study. Performance of the intraoperative planning was performed using the commercially available software known then as MMS (Multimedia Systems Inc, Charlottesville, VA). Varian Inc (Palo Alto) has subsequently bought this company and the software is currently marketed under the name of Variseed™. The steps involved in the procedure and the mean time it took for each step were as follows: (1) positioning the patient and the ultrasound probe in the proper position, 26 min; (2) capturing the ultrasound images on the treatment planning computer at 5 mm intervals, 4 min; (3) image segmentation, 8 min; (4) performing the treatment plan, 18 min; (5) loading the seeds into the needles as determined by the plan, 17 min; and (6) implanting the seeds in the prostate under ultrasound guidance, 57 min. Overall, the intraoperative preplanning implants took additional time. However, including the time from the preoperative volume study session negated this difference. A key component of the Columbia technique is the planning optimization function in the Variseed™ program. This allows one to enter the dosimetric requirements and then it attempts to solve the problem. One can then add some human intelligence to modify the computerderived plan to achieve one’s goals. This optimization algorithm makes its calculations quite rapidly. In our study the mean time for treatment planning was 18 minutes. The preimplant plan dosimetry was equivalent between the two plans as assessed by the important parameters of %D80 and %D90 suggesting that it is possible to create plans in the operating room that are similar to those performed after a preoperative volume study has been performed. The %V100 was 100% in the standard approach and 99% in the intraoperative planning group. This difference was statistically significant, but obviously not clinically significant. In addition, the %D100 was 100% for the preplan

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versus 93% for intraoperative planning. However, it is well known that the D100 is very sensitive to small differences and not a clinically useful parameter.6 A more important measure of the acceptability of this approach is the postimplant dosimetric analysis. In our data, the dosimetric parameters were equivalent in those plans developed in the standard manner versus those planned in the operating room as assessed by the %D80, %D90, %D100, and %V100. Thus, we showed that comparable preoperative and postoperative dosimetry was achieved, and that the time to perform the procedure was acceptable. At the Cleveland Clinic Foundation this procedure was also implemented although the planning was done manually rather than by an optimization algorithm.7 In this retrospective report the results of 113 patients implanted during a time period in which both intraoperative and preoperative planning were performed on a similar number of patients were analyzed. The time required for the intraoperative and preoperative planning techniques was not reported. In their investigation, the intraoperative patients were implanted with a higher activity/volume and had a higher preoperative V100 and V80. The postoperative dosimetry was not surprisingly also superior as assessed by V80, V90, V100, V150, V200, and D90. Thus, they demonstrated that intraoperative planning could be performed, even with manual planning, and achieve excellent quality implants. However, these results should not be taken to demonstrate that intraoperative preplanning results in superior postimplant dosimetry since the preplans of those cases were also superior. Beyer et al. at Arizona Oncology Services developed a time-efficient intraoperative technique.8 Their technique is a hybrid of the Mt Sinai approach and the dosimetricdriven approach of the Seattle group. (In fact, the Mt Sinai group now performs their implants in a similar hybrid fashion.9) In this technique, standard needle positions are used for all patients. Needles are placed into these positions while the treatment plan using these positions is developed. Modifications in the plan are then manually performed to optimize the plan and then carried out. Doing planning and needle placement at the same time markedly shortens the procedure time. In the eight patients analyzed, the time needed to place the needles, perform the plan, and implant the seeds was a mean of only 25 minutes compared with 100 minutes in the Columbia study. Although no statistical analysis of the dosimetric data was performed, the postimplant dosimetry was excellent and comparable among those implanted with their preoperative planning technique they had used previously or the new intraoperative planning technique. The disadvantages of this approach are that it is not a truly dose optimized approach as most needle positions are fixed from the outset. In addition, in the interest of time, normal structures are not contoured and their dose-volume histograms not calculated nor examined. Kaplan et al. from the Joint Center for Radiation Therapy at Harvard University described performing intraoperative planning in 107 patients.10 The mean time from transrectal ultrasound placement until the patient left the room was a reasonable 104.2 minutes. The exact method of treatment planning was not specified. They performed the traditional preoperative planning and intraoperative planning in five patients. The DVHs are displayed graphically but no formal comparisons were made. The rectal doses appeared consistently lower in the intraoperative plans, but no other clear differences were demonstrated.

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D’Amico et al, also from Harvard University, have developed a novel prostate brachytherapy protocol.11 At their institution, magnetic resonance imaging (MRI) in the operating room is used to image the prostate and guide implantation of the peripheral zone only. Intraoperative planning, using software they developed, is performed in this protocol. The time each step takes in their protocol has not been described, but the intraoperative DVH analysis of the first nine patients revealed excellent coverage of the peripheral zone. In conclusion, intraoperative preplanning can be performed and results in similar dosimetric outcome as the traditional preoperative preplanning. Taking into account the time required for the preoperative volume study, there is no increase in overall time. In an effort to shorten the procedure time, some have developed a hybrid approach in which a limited form of intraoperative dosimetry is performed with certain parameters of the implant (e.g. needle positions) set from the outset. Whether an unrestricted intraoperative preplanning approach or a hybrid approach is superior remains to be seen. Intraoperative planning on the basis of needle position The next step in intraoperative planning is to plan on the basis of actual needle location instead of based on a planned needle position in a preplan. Zelefsky et al. from Memorial Sloan-Kettering Cancer Center have reported on such an approach.12 In their approach, images of the prostate are captured onto the treatment planning computer only after needles have been placed in the prostate. A software program developed by the investigators then attempts to optimize the seed placement while satisfying the goals of dose delivery to the prostate, urethra, and rectum. The postimplant dosimetric analysis of 30 patients treated with this approach was compared with that of 30 patients they had treated previously with the Mt. Sinai approach and 30 patients treated with a computed tomographic (CT)-based preoperative planning approach. The time to perform their procedure was not presented. However, the dosimetric results of the intraoperative plan were superior to the combined results of the other two groups as assessed by multiple dosimetric parameters. For example, the %D90 was 116% for the intraoperative planning versus 94% for the Mt. Sinai technique and 88% for the CT-based preoperative planning technique. Urethral and rectal doses were also lower. The limitation of this and this limits the ability of the planning process to approach is that the needle positions are predetermined optimize the seed distribution. A more ideal approach would be to allow the planning process full freedom to optimize all parameters and then adjust for inaccurate needle placement as it occurs. Cormack et al, from Harvard University, have developed such an approach in their MRIdriven program discussed above.13,14 The initial plan is not constrained to any particular needle position. However, after each needle is placed an MRI scan is performed and the needle track identified. If the needle placement is inaccurate by more than a few millimeters, it is repositioned. If not, the seeds are deposited along the track. The plan is then recalculated accounting for the actual needle position. At the end of the procedure, additional seeds are placed in areas needing these on the basis of the intraoperative analysis. In their report describing this technique, 14 of 15 patients required a median of two additional needles containing five additional seeds to optimize the coverage.

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Unfortunately, intraoperative MRI is not widely available. Therefore, the challenge is for other investigators to develop conceptually similar approaches that can be more widely adopted. Future directions The approaches discussed above, however, are still not based on actual seed position. Ideally, each seed’s position should be determined at the time of the procedure and dosimetry calculated on that basis. Several techniques are being pursued to achieve this goal. Investigators from Riverside Research Institute are developing ultrasoundbased techniques to identify each seed within the prostate.15 Resonance, signature, and elastographic methods are being pursued. Although still under development, these approaches hold promise to perform seed position-based intraoperative postimplant dosimetry. In addition, since they are performed using ultrasound, they would be widely applicable since most institutions perform ultrasoundbased implants. An alternative approach would be to obtain digital radiographs from multiple angles to obtain images of the seeds. These images could be captured by a software program, which would then determine each seed’s position in three dimensions and then calculate the resultant dose distribution. Registering the radiograph-derived dose dis tribution to the ultrasound prostate images would allow the dose distribution to be overlaid on the ultrasound images. Then, areas of insufficient seed placement could be identified and fixed. Such a program is under development at Memorial Sloan-Kettering Cancer Center.16 References 1. Blasko JC, Grimm PD, Ragde H. Brachytherapy and organ preservation in the management of carcinoma of the prostate. Semin Radiat Oncol 1993; 3:240–249. 2. Stock RG, Stone NN, DeWyngaert JK, et al. Prostate specific antigen findings and biopsy results following interactive ultrasound guided transperineal brachytherapy for early stage prostate carcinoma. Cancer 1996; 77:2386–2392. 3. Grado GL, Larson TR, Balch CS, et al. Actuarial disease-free survival after prostate cancer brachytherapy using interactive techniques with biplane ultrasound and fluoroscopic guidance. Int J Radiat Oncol Biol Phys 1998; 42:289–298. 4. Messing EM, Zhang JBY, Rubens DJ, et al. Intraoperative optimized inverse planning for prostate brachytherapy: Early experience. Int J Radiat Oncol Biol Phys 1999; 44:801–808. 5. Gewanter RM, Wuu C-S, Laguna JL, et al. Intraoperative preplanning for transperineal ultrasound-guided permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 48:377–380. 6. Yu Y, Waterman FM, Suntharalingam N, Schulsinger A. Limitations of the minimum peripheral dose as a parameter for dose specification in permanent I-125 prostate implants. Int J Radiat Oncol Biol Phys 1996; 34:717–725. 7. Wilkinson DA, Lee EJ, Ciezki JP, et al. Dosimetric comparison of preplanned and OR-planned prostate seed brachytherapy. Int J Radiat Oncol Biol Phys 2000; 48:1241–1244. 8. Beyer DC, Shapiro RH, Puente F. Real-time optimized intraoperative dosimetry for prostate brachytherapy: A pilot study. Int J Radiat Oncol Biol Phys 2000; 48:1583–1589.

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9. Stock RG, Stone NN, Lo YC. Intraoperative dosimetric representation of the real-time ultrasound-guided prostate implant. Tech Urol 2000; 6:95–98. 10. Kaplan ID, Meskell EJ, Soon SJ, et al. Intraoperative treatment planning for radioactive seed implant therapy for prostate cancer. Urology 2000; 56:492–495. 11. 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; 42:507–515. 12. Zelefsky MJ, Yamada Y, Cohen G, et al. Postimplantation dosimetric analysis of permanent transperineal prostate implantation: Improved dose distributions with an intraoperative computer-optimized conformal planning technique. Int J Radiat Oncol Biol Phys 2000; 48:601– 608. 13. Cormack RA, Tempany CM, D’Amico AV. Optimizing target coverage by dosimetric feedback during prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 48:1245–1249. 14. Cormack RA, Kooy H, Tempany CM, D’Amico AV. A clinical method for real-time dosimetric guidance of transperineal I-125 prostate implants using interventional magnetic resonance imaging. Int J Radiat Oncol Biol Phys 2000; 46:207–214. 15. Feleppa EJ, Ramachandran S, Alam SK, et al. Novel methods of analyzing radio-frequency echo signals for the purpose of imaging brachytherapy seeds used to treat prostate cancer. Medical Imaging 2002; Ultrason Imaging Signal Processing 2002; 4687:127–138. 16. Todor DA, Cohen GN, Amols HI, et al. Film-based 3D seed reconstruction in brachytherapy. Phys Med Biol 2002; 47:2031–2048.

14 The Wheeling approach to treatment planning for prostate brachytherapy Wayne M Butler and Gregory S Merrick Introduction Favorable brachytherapy results have been obtained with a variety of planning and intraoperative techniques, of which no method has proven superior.1,2 Although quality is easy to conceptualize, it is more difficult to quantitate. It is universally accepted that an adequate implant should encompass the target volume, but no consensus exists as to what represents the target. In addition, tolerance urethral and rectal doses have not been welldefined and the significance and degree of dose homogeneity throughout the implanted region remains unclear. Initially, the Seattle group utilized a uniform seedloading philosophy.3 However, because a purely uniform loading scheme produces a high central dose which may adversely affect the urethra,4 this loading philosophy has evolved into an approach using fewer central needles and more peripheral seeds. The American Association of Physicists in Medicine (AAPM) Task Group No. 56 (TG56) recommended that treatment plans be ‘designed to place seeds peripherally to improve dose homogeneity and to reduce unnecessary radiation damage to the urethra’.5 The American Brachytherapy Society (ABS) also recommended the adoption of modified peripheral loading techniques to minimize the length of the urethra receiving >200% of the prescription dose.6 In general, four seed-loading philosophies (uniform loading, peripheral loading, modified uniform loading, and modified peripheral loading) have been utilized in prostate brachytherapy.7 In a survey by the ABS, a modified peripheral loading approach was used by 75% of brachytherapists, while 25% used a modified uniform approach.8 Although most brachytherapy programs utilize a spectrum of loading approaches, our approach, based on a modified uniform philosophy, has been used almost exclusively. Even in patients with a pretreatment prostate-specific antigen (PSA) <10 ng/mL, approximately 50% manifest extracapsular extension of malignant disease at the time of radical prostatectomy.9 Thus, treatment of the periprostatic region remains paramount. Our approach has the benefit to maximally respect urethral and rectal tolerance with the ability to aggressively irradiate sites of extracapsular disease. At the periphery of the implant target volume, the radiation dose decreases by up to 20 Gy per mm.10 Edema can also affect the actual dose of radiation delivered to the prostate gland and extracapsular regions.11 The utilization of treatment margins, however, significantly decreases the effect of edema on postoperative dosimetry.11,12 Merrick and colleagues have previously reported that implant prescription doses of radiation measured via day 0 dosimetry can

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consistently be delivered to both the prostate and periprostatic region with the utilization of extracapsular seed placement.13–16 In this chapter, we describe our planning approach utilizing a manual algorithm for a modified uniform/ peripheral seed loading approach and provide a rationale for such an approach along with recommendations for implant design and evaluation. Preplanning philosophy Our preplanning techniques and intraoperative procedures have previously been described.1,2 In our preplanned approach, a transrectal ultrasound volumetric study of the prostate gland is obtained in the ultrasound suite prior to the operative procedure. The study is obtained at 5 mm intervals extending from the proximal seminal vesicles/ bladder neck/base of the prostate gland to the apex. Prior to obtaining the ultrasound, a urinary catheter is placed so that the urethra can be identified on each ultrasound slice. A planning target volume (PTV, prostate plus periprostatic margin) is determined by a 3–8 mm enlargement in all dimensions (with limitations on posterior extension) with a resultant PTV approximately twice the ultrasound volume. The margin extent and hence the enlargement of the

Figure 14.1 Transverse ultrasound images illustrating enlargement of the prostate volume (white line) to the planning target volume (PTV, black line). The urethra, identified by the presence of a catheter, is also marked by a small, central white circle, (a) Section near mid-gland, 25 mm inferior to the base, (b) Section 35 mm

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inferior to the base and 5 mm superior to the apex. ultrasound volume to the PTV is patient-specific and considers such factors as regions of likely extracapsular extension and the presence of a transurethral resection of the prostate (TURP). The prescription dose is then prescribed to the PTV with margin. The rationale for this extracapsular margin is based on pathologic measures of the probability of microscopic extracapsular disease,9 and estimates that seed uncertainty is approximately 5 mm longitudinally and 3 mm in transverse dimensions.17 As such, the cross-sectional area of the PTV on any slice is at least as large as the area of the prostate with margin on the next larger adjoining slice. The two ultrasound images of a 31 cm3 prostate in Figure 14.1 illustrate a typical relationship between the urethra, prostate, and PTV on transverse slices taken near mid-gland and near the apex. Generous periprostatic margins are of great utility in patients with any risk of extracapsular extension and a low risk of pelvic lymph node involvement/distant metastases. Our prostate implant philosophy results in a mean periprostatic margin of 6.5±1.8 mm. These treatment margins may potentially result in prostate cancer cures with a monotherapeutic approach for patients with low, intermediate, and potentially even selected high risk disease.18 This volume dose escalation has been obtained without any increased risk of urinary, rectal, or sexual dysfunction compared to other seed-loading approaches.19,20 To deliver the prescribed dose to the PTV, it is necessary to irradiate a volume larger than the PTV given the constraints of using a single seed strength throughout the implant and fixed grid coordinates for seed placement. If necessary, seeds may be placed outside the PTV to ‘pull’ the dose out to the defined margin rather than use seeds of greater strength placed entirely within the PTV to ‘push’ the dose out. Preplanning dosimetry In our program, a ‘lower case’ plan is generated to deliver the minimal peripheral dose (mPD) which is the minimum dose covering 100% of the defined volume (D100) to the PTV with margin. For palladium-103 (103Pd), mean strengths of 2.8 U/seed and 2.2 U/seed are used for 125 Gy monotherapy and 90 Gy boost techniques, respectively, while for iodine-125 (125I) monotherapy, average seed strengths of 0.54 U/seed are used. Table 14.1 summarizes mean treatment planning parameters used in the implementation of modified uniform loading during calendar years 2001 and 2002. Because 6–10 extra seeds are ordered and routinely implanted to extend dose into the proximal seminal vesicles and increase dose in the peripheral zone of the prostate, the actual number of seeds implanted is listed in Table 14.2 rather than the number planned. Although most volume studies and preplans are completed a week before the implant, the plans for some long distance referrals, particularly men requiring neo-adjuvant hormones, cannot be completed in time for an accurate

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Table 14.1 Mean treatment planning parameters used for modified uniform loading over the past 2 years Parameter

125

Overall

103

I

145 Gy

Pd

90 Gy

115 Gy

125 Gy

Ultrasound volume (cm3) 33.6±9.4 37.5±9.0 31.6±10.8 35.4±7.3 35.0±8.9 Planning volume (cm3) 66.4±13.7 72.4±13.4 63.4±15.7 68.4±9.9 69.0±12.9 Planning margin (mm) 5.2±0.6 5.1±0.5 5.2±0.6 5.1±0.6 5.2±0.5 Enlargement factor 2.02±0.22 1.96±0.14 2.07±0.24 1.96±0.19 2.01±0.21 Number of seeds* 129±16 127±14.0 122±16 135±12 135±15 Number of needles 27±3 28±4 26±3 28± 3 28±3 Seed strength (U) 0.542±0.0 10 2.16±0.09 2.57±0.07 2.80±0.10 * This is the number of seeds actually implanted, which exceeded the number of seeds in the preplan by 6–10 extra seeds. These extra seeds required an additional 4–6 needles.

Table 14.2 Preimplant dosimetric evaluation criteria using appropriate seed strengths from Table 14.1 Evaluated quantity

Parameter*

Value 125

I

103

Pd

Patient specific needs TX volume, URP, etc. primary importance >99.8% volume Coverage of the planning volume V100 125%–140% mPD D90 40%–55% volume 55%–70% volume Dose homogeneity V150 15% volume 15%–20% volume High dose volume V200 UV125 80%–100% volume 50%–100% volume <15% volume <25% volume Urethra volume coverage UV150 UD50 130%–145% mPD 120%–140% mPD 140%–150% mPD 130%–160% mPD Urethra dose UD10 * V100, V150 and V200 are the percentage of the planning target volume (PTV) covered by 100, 150 and 200% of the prescribed dose (mPD), respectively, D90 is the minimum dose covering 90% of the PTV. UV125 and UV150 are percent volume of the urethra at the defined mPD. UD50 and UD10 are the minimum doses covering 50% and. 10%, respectively, of the urethra volume.

seed order to be placed with the seed vendor. An estimate for the number of seeds is made using a regression equation based on the ultrasound prostate volume, and the volume is adjusted as needed for the use of hormones by analytical equations. For example, the initial prostate volume is diminished by weeks of a luteinizing-hormonereleasing hormone (LH-RH) agonist approximately as: (1)

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The number of seeds implanted follows a power law equation because the enlargement ratio, PTV/ultrasound volume, is non-linear when a consistent margin is applied to each prostate. The equation for the number of 103Pd seeds needed is given by: (2) A similar equation is used for 125I where the coefficient is 3.83 and the power is 0.381. Figure 14.2 is a graph of Eq (2) predicting the number of 103Pd seeds from the prostate volume for a monotherapy implant of 125 Gy and using a seed strength of 2.80 U. Modified uniform loading places seeds on a 10 mm uniform grid followed by modifications that place additional seeds on the lateral and anterior periphery and reduce the linear density of seeds in the central needles, but leave two thirds of the total seeds on the original uniform grid points.1 The modification of uniform loading improves dose homogeneity and urethral sparing (which is defined

Figure 14.2 Graph of the power law Eq(2) predicting the number of implanted seeds from the prostate volume for a 125 Gy monotheraphy 103 Pd implant using seeds of strength 2.80 U. (U=cGY/cm2×h).

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as a dose to the urethra of 100–140% mPD) because in any uniform distribution of seeds, the dose would be greatest centrally due to the cumulative effects. Two planes defining the boundaries of the uniform grid are the base plane of the prostate and the posterior border. In the posterior implant plane, a needle may occupy the intersection of the sagittal mid plane with this plane or a position 0.5 cm lateral to the intersection. This choice identifies the main uniform loading grid as ‘upper case’ or ‘lower case’, where the sagittal midline column on the template is labeled ‘D’ and the columns 0.5 mm lateral to it ‘c’ and ‘d’. In our program, only lower case plans are used. Needles pass through all valid lattice points on a cm2 grid at mid-gland that are within the PTV plus any valid gridpoints that are within a 2 mm margin of the PTV drawn on the midgland slice. These needles extend to the base plane that defines the starting plane for valid seed positions in 10 mm increments along each needle. All needles are planned to deposit seeds at the base plane unless the seed would be more than 10 mm outside the PTV at the base. A similar margin applies to seeds deposited on the apical plane, but a 4 mm margin outside the PTV limits seed deposition from other planes. If the apex does not fall at an integer number of cm from the base, the uniformly spaced seeds do not end at the apical plane, and the seed ‘trains’ are extended 0.5 cm inferior to the apex with the PTV of the apical plane used as a guide for valid gridpoints occupied by these seeds. The first modification to uniform loading places needles on the lateral and anterior periphery. These needles will deposit seeds with a 1 cm spacing, but the starting points are offset from the base by 5, 15, or 25 mm and are also offset 5 mm in the y direction and usually 5 mm in the x direction from the uniform loading grid. Valid needle paths are no more than 5 mm inside the PTV or 3 mm outside at midgland, and valid seed deposition points are no more than 5 mm inside or outside the PTV on the relevant halfinteger offset transverse image. At this point in the planning process, all needle paths, both uniform and peripheral, are checked to ensure that they contain at least two seeds with a uniform 10 mm spacing throughout the length of each needle. The second modification reduces the linear seed density in 4–6 central main grid needles. In all cases, these needles retain the first and last seed in the source train while one or two of the remaining seeds are discarded and replaced with spacers or Mick applicator offsets. All plans are evaluated for each implant based on detailed dosimetry, which includes dose-volume histograms (DVHs) of the PTV and urethra as well as the dose profile points in the center of the urethra. Utilizing this algorithm, a V100 (volume of the target area receiving 100% of the prescribed dose) typically equals 100% and V105 exceeds 99.5%. Although there is no consensus regarding the optimum degree of dose homogeneity or its measure, particular care is taken to limit the volume of the target area receiving 150% of the prescribed dose (V150) to approximately 40–55% for 125I implants1,2 and 55–70% for 103Pd implants. In addition, particular attention is taken to limit the volume of the target area receiving 200% (V200) to <15% of the PTV for 125I and <25% for 103Pd. By reducing the linear density of seeds in the central needles, the volume of the urethra (UV) receiving a dose greater than 150% of the mPD (UV150) is maintained <15% of the urethral volume for 125I and <25% for 103Pd. In terms of centroid dose points, the urethral dose is maintained between 110% and 140% of the prescribed dose (average dose 115–120%). Because all uniform loading needle paths within the body of the prostate are used, some needle paths may transect or pass very near the

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urethra, and some point doses may be very high. However, in executing the preplan, the path of the urethra is confirmed in the operating room and the intended nearby needle paths are displaced several mm to avoid the urethra. We do not routinely calculate a rectal dose via the preplan. The prescribed dose, however, encompasses the posterior border of the PTV with a 4 mm margin. The significance and utility of dose uniformity parameters such as V150 in determining the quality of an implant and urethral dose parameters in minimizing urethral morbidity remains unknown. Highly inhomogeneous implants (V150>90% volume) make the concept of prescribed dose less meaningful, may increase the likelihood of radiation morbidity, and probably do little to increase tumor control so long as V100 and D90 are adequate. Although many loading approaches can achieve an adequately low dose near the urethra, the modified uniform loading approach results in greater dose homogeneity measured in terms of DVH slope and orthogonal dose profiles without creating a high dose annulus around the urethra. These guidelines are utilized for all implanted patients except those who have previously undergone a transurethral resection of the prostate (TURP). These patients are implanted with a peripheral technique which explicitly places no needles within 5 mm of the urethra and limits the urethral dose to approximately 110% mPD. Preimplant evaluation Multiple postoperative dosimetric analyses have evaluated the actual dose distribution following prostate brachyther apy and have made suggestions/recommendations regarding quality.12–16,21–29 The ABS recommends that postoperative dosimetry be defined in terms of a V100 and D90.6 We have previously defined recommendations regarding preimplant evaluation.1,2 Our preimplant evaluation adheres to the criteria in Table 14.2. It is ensured that each ultrasound slice has been appropriately enlarged and that the dose has been prescribed to completely cover the PTV. The V100 for the PTV should be >99.8% and D90 125–140% of mPD. Urethral dosimetry is defined in terms of the average dose, UD50, and the UV150. These parameters should be <140% of mPD, and <15% of the urethral volume for 125I and <25% for 103Pd. With this approach, 99% of our implants have utilized 21–33 needles per preplan. In addition, at least two seeds are placed in each implant needle because of seed uncertainty.17 Figure 14.3 is a typical dose-volume histogram of the PTV, ultrasound prostate, and urethra illustrating the dosimetric guidelines discussed above. The urethra is clearly ‘cooler’ than the PTV or prostate with a V150 of 12% volume, but the entire urethra receives 125% of mPD. The PTV, overall, lies at higher dose than the prostate because the first modification to uniform loading added seeds to the anterior and lateral periphery of the PTV and the second modification reduced the density of seeds in the middle of the prostate to reduce and homogenize the urethral dose. Figure 14.4 illustrates the homogeneity of dose throughout the volume by tracing dose profiles along the urethra in one plot and along a vertical line coinciding with the ‘D’ implant column at the midgland. Although peripheral loading can achieve similar homogeneity along the urethra, profiles perpendicular to the urethra are far from uniform in dose. The vertical profile of Figure 14.4b, which is relatively flat from the posterior to anterior border of the PTV

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using modified uniform loading, would have pronounced peaks at the anterior and posterior borders with a deep valley between them to spare the urethra. Translation of preimplant quality to postimplant dosimetry Using the above treatment-planning approach, day 0 computer tomography (CT)-based dosimetry had resulted in extracapsular treatment margins of 6.5 and 9.6 mm at the 100% and 75% isodose lines, respectively.30 With the exception of the bladder neck and posterior prostate border, the 100% isodose margin was 5 mm for all evaluated slices. In the course of treatment planning and implantation, approximately 35% of seeds are placed in extracapsular locations, and the overall seed fixity was >98%.16 Investigators at Thomas Jefferson University have also reported the ability to aggressively treat the extracapsular region.31 In addition, it

Figure 14.3 Preplan dose-volume histograms (DVH) of the planning target volume (PTV, solid line), ultrasound prostate (dashed line), and urethra (dotted line) for the patient whose prostate is illustrated in Figure 14.1. To deliver a boost dose of 90 Gy with 103Pd seeds of strength 2.14 U, 117 seeds in 26 needles were planned. The steep slope of the curves at 50%

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volume coverage indicates the homogeneity of the implant. The DVH of the PTV typically lies at higher dose than the prostate because of seeds added to the anterior and lateral periphery of the PTV while the prostate has a reduced density of seeds in the middle to reduce the urethral dose. has been reported that day 0 brachytherapy treatment margins outperform other dosimetric parameters, such as V100 and D90, in predicting 2 year prostate-specific antigen (PSA) response following brachytherapy.32 In terms of day 0 postimplant dosimetric parameters, the crucial coverage values, V100 and D90, average 97.0% ±2.7% volume and 120%±11% of mPD, respectively, with no difference between isotopes. Mean urethral average and maximum doses are 113%±13% of mPD and 126%±17% of mPD, respectively, but there is a significant difference between 125I and 103Pd doses with the latter isotope about 6% cooler. A similar isotopic dose divergence applies to the rectum where the mean anterior rectal average and maximum point doses are 38%±14% of mPD and 58%±23% of mPD, respectively. The ability to obtain generous extracapsular margins such as those we have reported,30 calls into question the need for supplemental external beam radiation therapy (EBRT) in selected intermediate and high risk patients. Extensive pathologic evaluation of radical prostatectomy specimens at the Mayo Clinic and Cleveland Clinic have reported the mean extent of extracapsular extension to be 0.5 mm and 1.1 mm, respectively.33,34 The maximum extracapsular extension at the Mayo and Cleveland Clinics was 4.4 mm and 10.0 mm, respectively.30,31 Both studies concluded that brachytherapy margins of 5 mm should encompass all extracapsular disease in approximately 99% of cases deemed suitable for radical prostatectomy. Discussion No generally accepted seed-loading philosophies have been adopted by the brachytherapy community, although the AAPM and the ABS have recommended peripheral loading techniques.5,6 Despite marked differences in planning and intraoperative techniques, biochemical outcomes and complication rates have been comparable. Vicini and coworkers reported the frequency of various prostate brachytherapy preplanning approaches with 27% of brachytherapists using a nomogram, 11% a least squares optimization technique, 35% dose specification criteria not stated, and 11% uniform, 9% differentially positioned, and 6% peripherally positioned.35 In our program, a modified uniform loading approach has been used because of greater dose homogeneity in

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Figure 14.4 Profiles illustrating dose homogeneity using modified uniform loading in the patient whose prostate is illustrated in Figure 14.1. (a) Urethral dose moving inferiorly from the planning target volume (PTV) base at 0 mm to the PTV apex at 45 mm. (b) Posterior to anterior dose profile at mid-gland. The posterior border of the PTV is at 0 mm and the interior border

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at 32.5 mm. The urethra is at +17 and the rectum is below −5 mm. terms of the DVH slope (Figure 14.3) and orthogonal dose profiles (Figure 14.4).1,2 In a modified uniform approach, misplacement of a single seed results in little change to the dose distribution in comparison to peripherally loaded techniques.36 Despite the increased number of seeds needed to cover our significantly enlarged PTV, there is no actual point dose escalation within the prostate gland. Our approach, however, does result in a greater integral dose secondary to the therapeutic doses delivered to the extracapsular region. Yu and coworkers noted the uniformity of the dose within the target volume is poor if all of the seeds are placed within the prostate gland, but dose uniformity is improved if periprostatic seeds are utilized.37 In contrast, they reported that the use of extracapsular seeds did not improve the dose coverage to the prostate. Ling and coworkers reported a radiobiologic model of dose inhomogeneity in permanent 125I implants with the conclusion that doses 20–30% greater than the dose that provides 99% coverage of the target volume increased tumor cell kill and local control probability, but that higher doses did not further improve the results.38 One of the most obvious differences in implant philosophies is the presence or absence and the extent of periprostatic margin. In an ABS survey, Prete and coworkers reported that approximately 60% of brachytherapists added margins around the prostate gland and used periprostatic seeds with an average margin of 5 mm.8 Waterman and coworkers reported that edema had a minimal effect on day 0 dosimetry when the implant was planned with margin versus prostate only volumes.11,12 Butler and coworkers also reported that small prostates were more adversely affected by edema than large prostates.11 The identification of the urethra on the preplan further improves the ability to generate a plan that respects urethral tolerance. Volume parameters such as UV200 and UV150 should be kept small as should the similar dosimetric parameters UD10 and UD25, which are the minimal doses received by 10 and 25% of the urethra, respectively. In the ABS survey, Prete et al reported that two-thirds of respondents identified the urethra on the preplan.8 Previously, Wallner et al reported that urinary morbidity was associated with a maximum urethral dose >400 Gy.20 The ABS has recommended a modified peripheral loading technique to minimize the length of the urethra receiving >200% of the prescribed dose.6 With our technique, we have never encountered a dose of such magnitude (exceeding either 200% of mPD or 400 Gy) on the postimplant evaluation. We do not explicitly define rectal doses on the preplan. The posterior border of the target volume, however, is implanted with a dosimetric margin of 4 mm. Our group has previously reported detailed rectal dosimetry with the conclusion that the anterior rectal mucosa can on average receive 100% and 120% of the prescribed dose to lengths of 10 mm and 5 mm, respectively, without significant rectal toxicity.13,18 The ABS guidelines did not address rectal tolerance or formulate recommendations.6 Faithful execution of the preplan does not guarantee equivalent quality parameters on the postplan. Utilizing our guidelines, we have published day 0 dosimetric results with a V100, V150, and D90 of approximately 94%, 46%, and 108% with the caveat that these implants used approximately 6–7% extra seeds beyond the preplan.13 Resolution of edema is expected to increase these dosimetric values by 5–10%.39 Dose is paramount to

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securing long-term biochemical control.24 With day 30 dosimetry, Stock and colleagues reported a D90 threshold of 140 Gy for optimal biochemical disease-free outcome following 125I monotherapy.27 Recently reported biochemical results, however, have suggested that the dose threshold in terms of percent mPD may be less for 103Pd than for 125 40,41 I. Conclusions Despite a multitude of preplanning and intraoperative techniques and seed-loading philosophies, multiple groups have reported comparable results in terms of biochemical disease-free survival and complication rates. None of the seed-loading philosophies or differences in intraoperative techniques have proven superior. We, however, are strong proponents of a modified uniform seed-loading approach because of the ability to deliver a relatively homogeneic dose to the prostate gland with a periprostatic margin, the ability to routinely maintain the average urethral dose at approximately 115% of the prescription dose, and the fact that a modified uniform approach is ‘more forgiving’ of local and systemic errors in seed placement. References 1. Butler WM, Merrick GS, Lief JH, et al. Comparison of seed loading approaches in prostate brachytherapy. Med Phys 2000; 27:381–392. 2. Merrick GS, Butler WM. Modified uniform seed loading for prostate brachytherapy: Rationale, design and evaluation. Tech Urol 2000; 6:78–84. 3. Blasko JC, Grimm PD, Ragde H. Brachytherapy and organ preservation in the management of carcinoma of the prostate. Semin Radiat Oncol 1993; 3:240–249. 4. Roy JN, Ling CC, Wallner KE, et al. Determining source strength and source distribution for a transperineal prostate implant. Endocurie Hypertherm Oncol 1996; 12:35–42. 5. Nath R, Anderson LL, Meli JA, et al. Code of practice for brachytherapy physics: Report of the AAPM Radiation Therapy Task Group Committee No. 56. Med Phys 1997; 24:1557–1598. 6. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999; 44:789–799. 7. Prestidge BR. Radioisotopic implantation for carcinoma of the prostate: Does it work better than it used to? Semin Radiat Oncol 1998; 8:124–131. 8. Prete JJ, Prestidge BR, Bice WS, et al. A survey of physics and dosimetry practice of permanent prostate brachytherapy in the United States. Int J Radiat Oncol Biol Phys 1998; 40:1001–1005. 9. Partin AW, Mangold LA, Lamm DM, et al. Contemporary update of prostate cancer staging nomograms (Partin Tables) for the new millenium. Urology 2001; 58:843–848. 10. Dawson JE, Wu T, Roy T, et al. Dose effects of seed placement deviations from preplanned positions in ultrasound guided prostate implants. Radiother Oncol 1994; 32:268–270. 11. Butler WM, Merrick GS, Dorsey AT, et al. Isotope choice and the effect of edema on prostate brachytherapy dosimetry. Med Phys 2000; 27:1067–1075. 12. Waterman FM, Yu N, Corn BW, et al. Edema associated with I-125 or Pd-103 prostate brachytherapy and its impact on post-implant dosimetry: An analysis based on serial CT acquisition. Int J Radiat Oncol Biol Phys 1998; 41:1069–1077.

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13. Merrick GS, Butler WM, Dorsey AT, et al. Potential role of various dosimetric quality indicators in prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999; 44:717–724. 14. Merrick GS, Butler WM, Dorsey AT, et al. The dependence of prostate postimplant dosimetric quality on CT volume determination. Int J Radiat Oncol Biol Phys 1999; 44:1111–1117. 15. Merrick GS, Butler WM, Lief JH, et al. The effect of prostate size and isotope selection on dosimetric quality following permanent seed implantation. Tech Urol 2001; 7:233–240. 16. Merrick GS, Butler WM, Dorsey AT, et al. Seed fixity in the prostate/periprostatic region following brachytherapy. Int J Radiat Oncol Biol Phys 2000; 46:215–220. 17. Roberson PL, Narayana V, McShan DL, et al. Source placement error for permanent implant of the prostate. Med Phys 1997; 24:251–257. 18. Blasko JC, Grimm PD, Sylvester JE, et al. Palladium-103 brachytherapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2000; 46:839–850. 19. Merrick GS, Wallner KE, Butler WM. Permanent interstitial brachytherapy in the management of carcinoma of the prostate gland. J Urol 2003; 169:1643–1652. 20. Merrick GS, Wallner KE, Butler WM. Minimizing prostate brachytherapy-related morbidity. Urology 2003; 62:786–792. 21. Merrick GS, Butler WM, Dorsey AT, et al. Rectal dosimetric analysis following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999; 43:1021–1027. 22. Willins J, Wallner K. CT-based dosimetry for transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1997; 39:347–353. 23. Wallner K, Roy J, Harrison L. Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995; 32:465–471. 24. Willins J, Wallner K. Time-dependent changes in CT-based dosimetry of I-125 prostate brachytherapy. Radiat Oncol Investig 1998; 6:157–160. 25. Prestidge BR, Bice WS, Kiefer ET, Prete JJ. Timing of computed tomography-based postimplant assessment following permanent transperineal prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998; 40:1111–1115. 26. Moerland MA, Wijrdeman HK, Beersma R, et al. Evaluation of permanent I-125 prostate implants using radiography and magnetic resonance imaging. Int J Radiat Oncol Biol Phys 1997; 37:927–933. 27. Stock RG, Stone NN, Tabert, A, et al. A dose response study for I-125 prostate implants. Int J Radiat Oncol Biol Phys 1998; 41:101–108. 28. Snyder KM, Stock RG, Hong SM, et al. Defining the risk of developing grade 2 proctitis following 125I prostate brachytherapy using a rectal dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 2001; 50:335–341. 29. Waterman FM, Dicker AP. Probability of late rectal morbidity in 125I prostate brachytherapy. Int J Radiat Oncol Biol Phys 2003; 55:342–353. 30. Merrick GS, Butler WM, Wallner KE, et al. Extracapsular radiation dose distribution following permanent prostate brachytherapy. Am J Clin Oncol 2003; 26:E178-E189. 31. Butzbach DA, Waterman FM, Dicker AP. Can extraprostatic extension be treated by permanent prostate brachytherapy using palladium-103? An analysis based on post-implant dosimetry. Int J Radiat Oncol Biol Phys 2001; 51:1196–1199. 32. Choi ST, Wallner K, Merrick G, et al. Treatment margins predict biochemical outcomes after prostate brachytherapy. Cancer J 2004; 10:175–180. 33. Davis BJ, Pisansky TM, Wilson TM, et al. The radial distance of extraprostatic extension of prostate carcinoma. Cancer 1999; 85:2630–2637. 34. Sohayda C, Kupelian PA, Levin HS, et al. Extent of extraprostatic extension in localized prostate cancer. Urology 2000; 55:382–386. 35. Vicini FA, Kini VR, Edmundson G, et al. A comprehensive review of prostate cancer brachytherapy: defining an optimal technique. Int J Radiat Oncol Biol Phys 1999; 44:483–491.

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36. Roy JN, Ling CC, Wallner KE, Anderson LL. Determining source strength and source distribution for a transperineal prostate implant. Endocurie/Hypertherm Oncol 1996; 12:35–42. 37. Yu Y, Waterman FM, Suntharalingam N, Schulsinger A. Limitations of the minimum peripheral dose as a parameter for dose specification in permanent 125I prostate implants. Int J Radiat Oncol Biol Phys 1996; 34:717–725. 38. Ling CC, Roy J, Sahoo N, et al. Quantifying the effect of dose inhomogeneity in brachytherapy: application to permanent prostatic implant with 125I seeds. Int J Radiat Oncol Biol Phys 1994; 28:971–978. 39. Yue N, Dicker AP, Nath R, Waterman FM. The impact of edema on planning 125I and 103Pd implants. Med Phys 1999; 26:763–767. 40. Kollmeier MA, Stock RG, Stone NN. Biochemical outcomes following prostate brachytherapy with 5-year minimum follow-up: The importance of patient selection and implant quality. Int J Radiat Oncol Biol Phys 2002; 54(ASTRO 2002):35. 41. Wallner K, Merrick G, True L, et al. I-125 versus Pd-103 for low risk prostate cancer: Preliminary PSA outcomes from a prospective randomized multicenter trial. Int J Radiat Oncol Biol Phys 2003; 57:1297–1303.

15 The Seattle Prostate Institute approach to treatment planning for permanent implants John Sylvester A brief history of prostate radioactive implants • In 1903 Alexander Graham Bell wrote ‘…there is no reason why a tiny fragment of radium sealed in a fine glass tube should not be inserted into the very heart of the cancer, thus acting directly upon the disease material. Would it not be worthwhile making experiments along this line?’ • In 1910, Hugh Hampton Young (developer of the radical prostatectomy) used intraurethral radium for the treatment of prostate cancer, with encouraging results. He performed approximately 500 prostate brachytherapy procedures and 25 radical prostatectomies from 1915 to 1927. • In 1930, Flocks first injected radioactive gold into the prostate for the treatment of cancer. • In the early 1970s, Willet Whitmore and Basil Hilaris at Memorial Sloan-Kettering Cancer Center, New York, were the first physicians to perform I125 prostate seed implants. An abdominal incision was used to implant the seeds directly into the exposed gland. • In 1983, Hans Holm, University of Copenhagen, Denmark, was the first physician to perform the ‘closed’ or ‘non-surgical’ implant method, which utilized transrectal ultrasound (TRUS). • In 1985, Haakon Ragde, John Blasko, and Peter Grimm, further modified Holm’s approach in Seattle, Washington. They began using this treatment in November 1985. • In 1987 Tim Mate and James Gottesman begin a temporary seed implant program (HDR) at the Swedish Medical Center, Seattle • In the 1990s, a dramatic increase in permanent seed implantation occurs in the United States. There are advances in dosimetry, patient selection, and implant technique. Seed implantation is linked with dosimetry and patient selection. The past 18 years have led to a continual refinement in patient selection, dosimetry, and technique. Background Brachytherapy has been used in the definitive treatment of prostate cancer since the early 1900s. One of the earliest reported experiences was the series of 100 patients treated by Denning published in 1922.1 However, they were not able to accurately measure radiation doses in that era, complication rates were significant and control rates poor.

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Brachytherapy lost ground to surgery as surgical and anesthetic techniques advanced. During the 1960s to 1990s megavoltage external beam radiotherapy (EBRT) became more popular as it had relatively fewer side effects than surgery and similar survival rates. In the late 1960s Carlton and Scardino used permanent interstitial gold-198 (198Au) (radioactive gold) seeds combined with EBRT.2 At Memorial Sloan-Kettering Cancer Center (MSKCC) the use of radioactive iodine-125 (125I) seeds was pioneered.3 Using an open laporatomy approach, the seeds were placed directly into the surgically exposed prostate. The goal was to achieve a uniform distribution of seeds using a nomogram table to calculate the appropriate number of seeds for a given seed activity. In those patients in whom orthogonal x-rays revealed a high quality seed distribution (matched peripheral dose of >140 Gy) achieved a local control rate of 60%. In those with a matched peripheral dose of <120 Gy the local control was only 20%. Hilaris and colleagues reported a 70% 15 year survival in B1 patients treated with high quality 125I seed implantation.4–10 These results were at least as good as the best contemporary surgical and EBRT series in that era. However, the limited technology in the 1970s prevented this retropubic technique from consistently achieving high quality implants. This inconsistency contributed to brachytherapy, once again, falling out of favor. Technical breakthroughs The 1980s saw the introduction of multiple technologic advances that led to the rebirth of prostate brachytherapy.11 Puthawala et al, at Long Beach Memorial Hospital in southern California, pioneered transperineal low dose rate temporary interstitial brachytherapy (performed at time of open laporatomy) combined with EBRT.12 Martinez et al used a transperineal applicator to guide the placement of the radioactive implant.13 In Denmark, Holm et al were the first to perform 125I seed implantation via a transperineal approach using transrectal ultrasound guidance for the placement of the sources.14 This technique promised to allow consistently accurate placement of radioactive seeds. This major technologic advancement combined with improved patient selection due to prostate-specific antigen (PSA) screening and improved radiation treatment planning systems allowed the Seattle team to consistently deliver high quality implants to appropriately staged patients with appropriate doses of radiation based on the MSKCC experience. Thus, in November 1985 Blasko and Ragde preformed the first preplanned transrectal ultrasound guided template guided transperineal permanent 125I seed implant in the United States. Dosimetry/treatment planning The primary advantage to permanent seed implantation is the ability to deliver significantly higher doses of radiation to the prostate and several millimeters (mm) margin in a single outpatient setting than any other form of radiation therapy. However, dose inhomogeneity is unavoidable due to the fact that individual radioactive sources (seeds) are emitting radiation separately. Thus, hot spots (areas of higher doses of radiation) occur adjacent to the seeds and colder areas (lower doses of radiation) further away from the seeds will inevitably occur. Despite this inhomogeneity the radiobiologic

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effective dose of permanent seed implantation has been shown to be higher than more homogeneous radiation therapy approaches, such as three-dimensional conformal radiotherapy (3D-CRT) and intensity modulated radiotherapy (IMRT).15 With inhomogeneous dosimetry, standardization of the prescription dose is necessary. In the days of the retropubic approach a ‘matched peripheral dose’ was used to describe the dose delivered to a volume equal to an ellipsoid volume with the same average volume of the prostate being treated. This description can be confusing. Treatment planning software and prostate volume evaluations have improved so that most radiation oncologists use minimal peripheral dose (MPD) to describe their prescription dose now. The MPD describes the minimum dose delivered to the periphery of the target volume. The target volume may vary from one center to the next. At some centers, the target volume equals the prostate with little to no margin, at others (Seattle Prostate Institute, Schiffler Cancer Center, Seattle Veterans Administration, etc.) it equals the prostate plus several millimeters of margin.11 Most centers prescribe 145 Gy MPD for 125I monotherapy implants and 120–130 Gy for palladium-103 (103Pd) monotherapy implants.16 In Seattle, we currently use 145 Gy and 110 Gy for 125I monotherapy and boost implants respectively. We prescribe 125 Gy and 100 Gy for 103Pd monotherapy and boost implants. Due to the inhomogeneity issue two different centers may prescribe the same MPD but have significantly different internal isodose curve dosimetry. These variations are common because of philosophic differences from center to center in seedloading patterns, seed activity, and dosimetry (uniform vs peripheral vs modified approaches). From 1985 to 1991, the Seattle team used a pure uniform dosimetry approach. A relatively high number of low activity seeds were evenly distributed through the prostate. Urethral visualization techniques were not employed. As a result, the central prostate doses were in excess of 150–300% of the prescription dose (depending on gland size). Seed spacing was planned to be 1 centimeter (cm) from seed center to seed center. This form of dosimetry has the advantage of requiring less precision in seed placement, as each seed contributes less than 1% of the total prescription dose. However, there is a scalloping-in effect at the edges of the implant, which could result in underdosing the edges of the gland, and there is an overdosage of the central (urethral) portion of the gland (Figure 15.1). These high central doses resulted in increased urinary morbidity in patients who previously, or subsequently, underwent a transurethral resection of the prostate (TURP).17 A pure peripheral implant is one in which the seeds are placed around the periphery of the gland, usually just inside the capsule. These implants typically require a lower number of higher activity seeds. One would expect these patients (especially TURP patients) to experience less urinary toxicity due to lower urethral doses (Figure 15.2).18 Unfortunately, even slight misplacement of a few seeds can result in underdosage of the periphery of the prostate and overdosage of the urethra (if seeds migrate centrally) or rectum (if seeds migrate posteriorly). The lower number of seeds in these implants decreases the cost of the implant, but these are technically more challenging to perform. The initial biochemical relapse-free survival (BRFS) reports from centers using this technique were not as high as those achieved with the Seattle approach.19,20

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Figure 15.1 Uniform loading.

Figure 15.2 Peripheral loading. The modified uniform peripheral loading dosimetric approach merges the best of both philosophies. This planning approach (like the uniform approach) still uses a relatively high number of low activity seeds, thus decreasing the dosimetric errors that would occur if a seed is misplaced or migrates after it is placed. However, additional seeds are placed in the periphery of the gland, the base, and apex, and fewer seeds are placed centrally adjacent to the urethra. This reduces the likelihood of a scalloping-in effect of the isodose curves at the gland periphery and reduces the dose to the urethra. This would be expected to result in improved BRFS and less urethral toxicity than the pure uniform or pure peripheral approaches. As a result, the vast majority of centers in the United States (including the Seattle Prostate Institute) currently use this dosimetric approach (Figure 15.3). The needle loading pattern used in the Seattle Prostate Institute is simple, symmetrical, and utilizes a minimum number of needles. No plans with only one seed in a needle are ever accepted, and the num

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Figure 15.3 Modified uniform loading. ber of needles with only two seeds is kept to a minimum (Figure 15.4). Dose The Memorial Sloan-Kettering Cancer Center (MSKCC) noted better local control rates (in the retropubic era) when postoperative (postop) dosimetry revealed a matched peripheral dose of >140 Gy. In 1985, Dr Blasko of the Seattle team chose to prescribe a dose of 160 Gy (144 TG–43) minimal peripheral dose (MPD) in order to achieve 140 Gy on postop dosimetry. Fortunately, this chosen dose seems to have subsequently been supported by outcome analyses. Grimm et al published local control rates of 97%, based on digital rectal examination (DRE) and postimplant biopsies in patients treated with 125I monotherapy treated with a prescription dose on 160 Gy (144Gy, TG-43).21 Further support of this general dose level comes from reported experiences in New York City from Stock et al at Mt Sinai Medical Center and also from Potters and colleagues at MSKCC. Stock reported improved BRFS in patients treated with 125I achieving an MPD of ≥140 Gy on postop dosimetry (computer tomographic-based).19 Potters et al noted better BRFS in patients achieving a D90 of > 90% of the prescription dose treated with 103 Pd or 125I monotherapy.22 These studies were single institution retrospective reviews, involving a relatively small number of patients. However, based on the data from Seattle, Mt Sinai, and the old retropubic and newer modern transrectal ultrasound (TRUS) guided data from MSKCC, a dose of approximately 140 Gy for 125I monotherapy or a D90 of 90% in monotherapy patients (prescribed to approximately 145 Gy MPD for 125I and 125–130 Gy 103Pd, TG-43) seems reasonable. Using the modified uniform approach a significant portion of the peripheral zone of the prostate falls within the 150%

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Figure 15.4 Needle loading report. isodose curves, this translates into a dose of 215 Gy (in 125I monotherapy cases). Isotope selection Palladium-103 and iodine-125 have different photon energies and half-lives, thus different prescription doses are used in order to achieve virtually identical BRFS and long term toxicity outcomes. Much is written about isotope selection because of these differences, but both 103Pd and 125I isotopes are very low energy level sources (21 KeV and 28 KeV, respectively). Both are prescribed to very high doses compared to 3D-CRT and IMRT. The big picture is that the similarities outweigh the differences. Not surprisingly, there is no convincing clinical evidence that one isotope is superior to the other in terms of BRFS or toxicity. In general, the Seattle team usually uses 125I for Gleason scores 2–7 and 103Pd for Gleason scores 6–10. Since the majority of the patients treated have Gleason scores 6 and 7, the isotope used depends more on physician and

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patient preference than clinical evidence. For example, if one prefers to use a seed with a low chance of migration 125I RAPID Strand™ would be used. If one wanted the radiation exposure to relatives to be a shorter duration 103Pd would be used. The seed activity ordered by the Seattle Prostate Institute physicians is usually 0.27 mCi for 125I boosts and 0.297 or 0.326 for larger and smaller glands treated with 125I monotherapy. For 103Pd we use 1.1 mCi for boosts and 1.5–1.7 mCi for monotherapy implants. Limiting the activity to a selected number of activities per isotope helps to improve the consistency of the implants and leads to less chance of errors. The Seattle Prostate Institute approach Treatment planning New patients usually undergo a transrectal ultrasound volume study (TRUVS) immediately prior to their initial consultation. This study, done in the clinic without anesthesia or antibiotics, is used to map out precisely the size and shape of the prostate, rule out pubic arch blockage problems, and evidence of prior surgery (transurethral resection of the prostate; TURP). Thus, it is used for treatment planning and to aid in patient selection. This allows for a more detailed and thorough initial consultation. Some centers prefer to carry out this investigation in the operating room (OR) at the time of the implant procedure itself. The patient undergoes a bowel prep prior to entering the clinic, including an enema. He is positioned in the treatment position (extended lithotomy). The probe is placed into the rectum and the prostate identified on the ultrasound monitor. The mid-gland is identified and centered on the brachytherapy treatment-planning grid. The posterior edge of the gland is positioned approximately 1 mm below the posterior row. We use row number 2 (instead of 1.5 for Siemens™ and row 1.5 instead of 1.0 for B&K™ ultrasound equipment) as the posterior row because this places less pressure on the prostate itself. This results in an image that is not as clear and sharp (vs that achieved if row 1.0 is the posterior row), but the image quality is still acceptable. Our philosophy is that avoidance of gland shape distortion is more important. Thus, the patient is more comfortable (and still) and the gland is not as distorted as it would be if we used row number 1. Individual transverse images of the prostate are captured by the ultrasound technologist in 5 mm increments, from the base and to the apex. On each image, the prostate circumference is outlined and printed. Sagittal images are taken to verify the length of the prostate. The pubic arch is then identified and overlaid on the largest prostate image. The frequency used is 5.0 megahertz (MHz), this frequency penetrates the gland better than higher frequencies, allowing better visualization of the anterior aspect of the prostate. The base image is identified as the 0.0 retraction plane, the slice adjacent to the base is the 0.5 retraction plane, and so on until the final apical slice is identified and printed. The number of transverse images should be equal to two times the length of the gland plus 1. A 3.5 cm long prostate should have eight transverse images printed out. If the patient is known to have a history of a TURP, a urethrogram is performed at the time of the volume study to better identify the TURP defect. Every effort is used to avoid prostate distortion and the probe angle is measured and noted for future reference.

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The TRUVS images are evaluated by the radiation oncologist, usually at the time of the initial consultation. Target volumes will then be outlined if the patient decides to proceed with permanent interstitial radioactive seed implantation. Target volumes and implant dosimetry Target volumes can be outlined by the radiation oncologist directly on the printed TRUVS images, or on the treatment-planning computer. In Seattle, we outline directly on the printed image, as it is faster for the physician. The dosimetrist then transfers the prostate outlines and the target volume outlines into the treatment-planning system. The goal is to adequately cover, with our 100% iso-dose curve, the prostate and several millimeters of margin outside the prostate. This additional margin is not circum-ferential. There is more margin given laterally than poste-riorly or anteriorly. The anterior-most extent of our planning target volume (PTV) is the anterior most extent of the prostate itself. The posterior-most extent is our posterior row (row 2.0 for Siemens™ and 1.5 for B&K™) (Figure 15.5). In general the PTV outlined for any one par-ticular transverse image approximately equals the prostate volume of whichever adjacent transverse prostate volume is largest. The margins are particularly large at the base and the apex. The base and apex have no adjacent planes (cranial or caudal) to place seeds, so to achieve an adequate dose at these extreme ends of the implant we add extra seeds laterally and anteriorly at the apex and laterally and posteriorly (in the seminal vesicles) at the base. This preplan is run by the dosimetrist. Then it is reviewed and tweaked by the radiation oncologist. Then it is reviewed by the physicist, and finally approved by the radiation oncologist. This preplan can be thought of as a road map that the radiation oncologist and urologist use in the OR. The preimplant dose-volume histograms (DVH) for 125I implants are V100 of 99–100%, V150 of 30–40%, and V200 of less than 20%. The DVHs for 103Pd are similar except that V150 is planned for approximately 50%. When using stranded sources the central needles adjacent to the urethra are always loaded with loose seeds, not stranded seeds, even when a ‘special load (fewer seeds in the middle of the needle and more spacers)’ is not needed. Typically, the central 4 needles are ‘special loads’ to keep the urethral dose less than 120–150% of the prescription dose. The integration of a high number of radioactive seeds distributed in a symmetrical modified uniform loading

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Figure 15.5 The Trus volume study. dosimetry plan that includes a margin beyond the prostate, results in a robust and relatively ‘bullet-proof’ treatment plan. The Seattle Prostate Institute uses this approach because one can safely modify the needle positions or the ultrasound probe angle in the OR if the prostate shape or size is somewhat different than noted during the preplan, without sacrificing the ultimate dosimetric outcome. Moreover, it is reproducible from one radiation oncologist/ urologist team to another and requires minimal OR time and personnel. The symmetry of the implant and basic pattern reduces the possibility of placing a needle into the wrong position. Implant technique The procedure itself is performed in the ambulatory surgical center at Swedish Hospital. A team approach combining the expertise of the radiation oncologists and regional urologists has always been utilized. The OR team typically consists of the radiation oncologist, the urologist, the anesthesiologist, the nuclear medicine technologist (seedorderer, seed-loader, and room radiation surveyor), and two OR nurses. We typically implant 5–7 patients a day three days a week. The procedure can be performed under general or spinal anesthesia, 95% of our cases are done under the latter. The time it takes from the start of one case to the start of the next (in the same OR room, including room turnover, anesthesia, patient positioning, equipment set-up, seed implantation, fluoroscopy, cystoscopy, postimplant surgery notes, discharge instructions and orders, and discussion with family members) is typically 1 hour. The seed implantation portion itself takes about 15–25 minutes. The nurses retrieve the needle box containing the needles in their proper grid coordinates already preloaded by the nuclear medicine technologist (in the adjacent room) with the selected isotope and activity (Figure 15.6). The activity and loading pattern and isotope is double checked by the radiation oncologist. After spinal anesthesia is accomplished the patient is precisely positioned squarely and symmetrically on the OR table, in an extended lithotomy position (Figure 15.7). Patients with larger prostate

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volumes typically are a bit more extended than those with smaller prostate volumes. The ultrasound probe is inserted visualizing the prostate. The mid-gland is centered on the grid as per the volume study (Figure 15.8). The gland height, thickness, and width are double-checked. The urethra is visualized with aerated KY Jelly™ (Figure 15.9). This is used instead of a catheter because it will not distort the shape of the urethra or prostate as can a catheter, and it allows clear visualization of the sulci on either side of the veru montanum. After correct positioning of the patient, ultrasound probe, and connection of probe to the stabilization apparatus (which holds the ultrasound probe, stepper unit, and needle guidance template), the needle insertion begins. The base is reverified; the base image should show a small amount of prostate anterior to the seminal vesicles (‘a head and bowtie appearance’) (Figure 15.10). Individual preloaded needles are inserted one at a time, one row at a time in the transverse image mode with the image 1.0 cm (2 clicks on the stepper unit) from the base. The needles are inserted at the 1.0 retraction plane (instead of at the 0.0 retraction plane) for three reasons: (1) to better visualize each needle; (2) to avoid bladder trauma; and (3) to more readily visualize prostate drift (Figure 15.11). We work one row at a time moving from the anterior most row (placing the needles and then depositing those needles’ seeds) to the second anterior-most row depositing their seeds, and so on

Figure 15.6 Preloaded needles with seeds.

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Figure 15.7 The extended lithotomy position. until the final posterior-most row of needles and their seeds are deposited. Each needle placed has its position called off by the OR nurse, and double checked by the radiation oncologist, on the second copy of the plan attached to the ultrasound unit. After the needle is placed by the radiation oncologist or urologist the final positioning is double checked (in the x and y dimensions) by both radiation oncologist and urologist. After a typical row of needles is inserted, under transverse imaging, to a depth that usually is at the 1.0

Figure 15.8 The ultrasound grid: midgland.

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Figure 15.9 Urethra visualized clearly by using aerated KY JellyTM retraction plane the spacing is adjusted so that each needle is approximately 1.0 cm apart from each other and the central needles are a minimum of 5 mm away from the urethra (from base to apex) (Figure 15.12). Then the needles are advanced to their final preplanned retraction plane (e.g. 0.0 or 0.5) and any final x- and y-coordinate adjustments are made. Then the depth of the needle is double checked by measuring with a ruler (Figure 15.13). Finally, the probe is lined up on the lateral most needle and switched to the sagittal image mode. It is in the sagittal image mode that final depth adjustments are made, by the radiation oncologist, and verified by the urologist (Figure 15.14). The stylet distance from the needle hub is measured to ensure proper seed positioning within the needle and the needle is then slowly withdrawn, while holding the stylet in place, sowing a row of radioactive 103Pd or 125I seeds (Figures 15.15 and 15.16). This process continues one row at a time from the anterior-most row to the posteriormost row. During the procedure the prostate position within the ultrasound grid is continually adjusted. The base plane is also closely tracked and movement of the prostate in the cranial direction adjusted for. The combination of transverse imaging at the 1.0 retraction plane and seed depositing at the correct pre

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Figure 15.10 The base should be identified accurately. The prostate and seminal vesicles should be seen (‘a head and bowtie’ appearance). planned depth under the sagittal image plane makes it easy to make these frequent minor adjustments throughout the implant procedure, thus eliminating the chance of underdosing the base or overdosing the rectum or urethra. When working on the posterior row the needles are inserted so that 2–3 mm of prostate tissue is visible poste rior to the needles in the mid plane (Figure 15.17). The needles are tracked on transverse and/or sagittal imaging from base to apex to ensure proper distance exists between the needle and the rectum. Adjusting the angle of the probe can create more space between the needle and the rectum at the apex of the prostate (Figure 15.18). Sometimes, the posterior row needles are inserted in the template at a higher row number (i.e. row 2.5 instead of the usual 2.0 level) so that the angle conforms to the rectum in a more optimal orientation, thus avoiding having the needle and seeds too close to the rectum at the apex of the prostate yet still posterior enough at the base of the prostate. A final fluoroscopic and ultrasound qualitative evaluation is carried out at the end of the procedure. Postoperative computed tomography (CT) quantitative evaluation is done the next day as an outpatient. The postop plan is evaluated not only for DVH values but also for isodose curve shapes and coverage. The goal being adequate coverage of the prostate plus a lateral margin and avoidance of doses over 150% of the prescription dose to any portion of the urethra and the rectum. Urethral doses usually fall in the 95–120% isodose ranges (Figure 15.19). Results The goal of seed implantation is elimination of prostate cancer, thus patients can avoid the debilitating effects of

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Figure 15.11 Insert needles while 1 cm from base.

Figure 15.12 A row of needles in position.

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Figure 15.13 Establish a reference depth.

Figure 15.14 Final depth adjustments in the sagittal image mode.

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Figure 15.15 Seed number verification.

Figure 15.16 Withdraw needle over stylet.

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Figure 15.17 In the posterior row of needles, 2–3 mm of prostate tissue is visible. metastatic disease and death, while experiencing a reasonably good quality of life and minimal inconvenience. Surrogate endpoints are used, such as biochemical relapsefree survival (BRFS). As noted above, data closely link BRFS with postimplant CT dosimetry. The Seattle Prostate Institute has recently evaluated the day 1 postop dosimetry of over 2000 consecutively treated patients. The patients were treated with the TRUVS, dosimetric planning philosophy, and the OR technique noted above. Day 1 postop dosimetry reveals consistent achievement of high quality implants. The average D90 is 102% of the prescription dose (Table 15.1). A small number of individual patients were under a D90 of 90%, but virtually all of these patients had undergone prior TURP and were purposely planned

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Figure 15.18 The angled position of the ultrasound probe allows more space between the needle and the rectum at the apex of the prostate.

Figure 15.19 Post-implant CT-based dosimetry.

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Table 15.1 All patients (2115): day I dose—volume histogram (DVH) analysis: 4/2003. (Reproduced with the permission of the Seattle Prostate Institute.) Vol. No. seeds V100 V150 D90 Mean 37

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91% 55% 102%

to receive a slightly lower dose to the TURP defect region. Currently, the shape of the isodose curves within the implant volume is analyzed to ensure adequate margin beyond the edge of the prostate is obtained and the urethra achieves less than 150% of the minimal peripheral dose (MPD) on every transverse image. Biochemical relapse-free survival Biochemical relapse-free survival (BRFS) is used as the endpoint for disease control due to the long natural history of prostate cancer, which results in a large portion of patients (even biochemical failure patients) dying of other diseases other than prostate cancer. The BRFS reports from the Seattle Prostate Institute concern patients diagnosed and treated in the late 1980s and early 1990s. These patients are from a different era than those currently treated with 3D-CRT, IMRT, and HDR brachytherapy. Multiple studies from the surgical and radiotherapy literature show that patients treated a decade ago do more poorly in terms of BRFS than patients today. This is probably due to a variety of factors, such as improved Gleason scoring, stage migration, improved imaging, improved treatment techniques, PSA screening, etc. Thus, it is impressive that the results of seed implantation in these patients from 1987 to 1994 (many of whom were Gleason underscored, had no postop CT dosimetry, were treated without sagittal imaging, and with reusable needles) compare so favorably to more recent series. Grimm reported the Seattle experience with 125I monotherapy. From 1988 to 1990 a total of 125 patients were consecutively treated with 125I.21 These were low and intermediate risk patients, based on the risk cohort system used by MSKCC, Seattle Prostate Institute, and others. The average follow-up of the non-deceased patients was 94.5 months. The local control rate by digital rectal examination (DRE) and biopsy was 97%. The metastatic disease rate was 3%. The low and intermediate risk patients experienced a 10 year BRFS of 87% and 76%, respectively. A modification of the American Society of Therapeutic Radiology and Oncology (ASTRO) definition of BRFS is used in all the Seattle Prostate Institute reports where only two rises in prostate-specific antigen (PSA) are needed to define a patient as a failure instead of the ASTRO criteria of three consecutive rises. This increases the sensitivity of detecting a biochemical failure by approximately 20%. There were a significant proportion of patients in this and all the Seattle reports that were classified by the community hospital general pathologists as having Gleason score 2–4 disease. These patients were in all likelihood undergraded as they were diagnosed by ultrasound-guided needle biopsies, the patients assigned Gleason score 2–4 cancers BRFS were slightly (not statistically significant) worse than the Gleason score 5–6 patients, and when randomly reviewed later were upgraded by an

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average of two Gleason scores. This undergrading phenomenon has also been reported elsewhere in the urologic literature.23–26 Blasko et al reported the Seattle experience with 103Pd monotherapy.27 These patients had higher Gleason scores than the patients treated with 125I monotherapy Grimm et al reported.21 A total of 232 patients were treated with 103Pd monotherapy from 1/89 to 12/95, the average follow-up was 49 months. The local control rate was also 97%. The metastatic disease rate was 6%. The 5 year BRFS for the low, intermediate, and high risk patients was 94%, 82%, and 65% respectively (but only a small number of high risk patients were treated with 103Pd monotherapy). Those patients with Gleason score 7–10 disease and a PSA ≤10 ng/mL experienced a 5 year BRFS of 80%. None of the patients in the above reports by Blasko and Grimm received any androgen ablation therapy. Sylvester et al reported on the patients treated with androgen ablation plus either 125I or 103Pd monotherapy. These patients received an average of 5 months of androgen ablation for a variety of reasons including downsizing, high risk features, and/or for patients to have time to think about their options (the latter was usually by outside nonSeattle physicians). The 5 year BRFS for the low, intermediate, and high risk patients was 90%, 80%, and 60%, respectively, both for those patients treated with seed implantation alone and also for those treated with androgen ablation plus seed implantation. Thus, the addition of short course androgen ablation to seed implantation did not improve (or worsen) the BRFS in any risk group. The mean follow-up was similar in each group.28 The Seattle experience with short course androgen ablation combined with EBRT plus 125 I or 103Pd (combination radiation therapy) in high risk patients revealed no significant improvement in the 5 year BRFS.29 The BRFS of patients treated with androgen ablation plus combination radiation therapy was no better than that experienced by patients treated with combination radiation therapy alone. Blasko et al reported the 5 year BRFS of patients treated with 125I or 103Pd with or without external beam radiotherapy (EBRT).30 Again there was no significant improvement in BRFS in those that received the supplemental EBRT. However, this was a retrospective review and the patients typically received the supplemental EBRT for a reason, they were felt to be higher risk (within each risk group) than the patients treated without the supplemental beam. They often received the supplemental beam because of a higher number of positive biopsy cores involved with disease on sextant biopsies or perineural invasion. Thus, this paper was not able to answer the question whether or not the addition of supplemental EBRT will improve BRFS. Sylvester et al recently reported the 10 year BRFS of the Seattle patients treated with EBRT plus 125I/103Pd. The 10 year BRFS for the low, intermediate, and high risk patients treated with combination therapy were 85%, 77%, and 47%, respectively using the simple risk grouping method (SRG) typically used by us, MSKCC, etc.31 If the D’Amico risk grouping (DRG) formula is used the BRFS for the low, intermediate, and high risk groups were 86%, 90%, and 48%, respectively. When the Mt Sinai risk grouping system (MRG) favored by Stock and Stone19 is used, the 10 year BRFS were 84%, 93%, and 57% for the low, intermediate, and high risk groups, respectively. The 10 year BRFS of intermediate risk patients treated with 125I/103Pd monotherapy during that time period was 73% and 79% using the SRG and MRG methods, respectively. The 5 year BRFS

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outcomes of radical prostatectomy at The Hospital of the University of Pennsylvania and at Brigham and Women’s Hospital, and of 3D-CRT radiotherapy at MSKCC and of 103Pd seed monotherapy in Seattle are shown in Table 15.2. Also in Table 15.2 are the 10 year BRFS of 125I monotherapy and of combination seed implantation plus 45 Gy EBRT (using three different risk grouping systems). Side effects Temporary acute side effects of seed implantation are expected to include frequent urination, urgency to urinate, and a slow urinary stream. These side effects occur in virtually all implanted patients to some degree. The risk of urinary incontinence in the Seattle experience in patients without TURPs is less than 1%. Those patients with a history of prior TURP who were treated in the late 1980s with uniform loading dosimetry experienced a greater than 30% rate of urinary incontinence (usually stress incontinence).32 Treatment with alpha blockers usually relieves acute obstructive symptoms significantly, until prostate swelling has subsided.33 These acute obstructive urinary symptoms resolve in the majority of patients by 6–12 months status postimplantation.34 In order to reduce the dose to the urethra, seeds are place more than 5 mm from the urethra at time of implantation. The urethra is visualized with aerated KY Jelly™.35 The risk of rectal complications with seed implantation monotherapy is 3% in the Seattle experience and 7% if EBRT is combined with seed implantation. The vast majority of patients who experience radiation proctitis have grade 1 or grade 2, and respond well to suppositories, stool softeners, and a low roughage diet, if any treatment is needed at all.32,36 We recommend that biopsies and/or electrocauterization of the anterior rectal wall adjacent to the prostate are avoided. These invasive maneuvers may lead to ulcer and/or fistula formation. Summary Modern transperineal permanent 125I/103Pd seed implantation of the prostate has increased in popularity over the past 20 years because of technical advances, such as transrectal ultrasound and transperineal guidance, and computerized treatment planning, as well as early diagnosis due to PSA screening, and improved information flow aided in part by the internet and media. The current Seattle approach attempts to minimize potential for treatment errors, postoperative dosimetry variance and complications by combining preplanning with a symmetrical modified

Table 15.2 Biochemical relapse-free survival (BRFS) outcomes at 5 years and 10 years Risk group

5 yr BRFS 10 yr BRFS Surgery 3D-CRT Seeds Seeds Seeds+EBRT 38 37 27 21 D’Amko Zelefsky Bksko Grimm Sylvester31 (HUP) (B&W) (MSKCC) (Seattle) (Seattle) (Seattle) (Seattle) (Seattle)

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(SRG)

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(MRG)

(DRG)

Low 85% 83% 90% 94% 87% 85% 84% 86% Intermediate 65% 50% 70% 82% 76% 77% 93% 90% High 22% 28% 47% 65% – 47% 57% 48% 3D-CRT, three-dimensioual conforms! radiotherapy; DRG, D’Amico risk grouping; SRG, simple risk grouping; MRG, Mt Sinai risk grouping; HUP, Hospital University of Pennsylvania; B&W, Brighouse and Williams,

uniform-peripheral loading philosophy (which treats the prostate plus a 4–8 mm margin), meticulous intraoperative technique, and careful patient selection. The 5 and 10 year BRFS with this one day outpatient treatment matches or exceeds the best reports in the surgical and EBRT literature. The Seattle results with prostate brachytherapy are currently being reproduced at several other centers. References 1. Denning CL. Carcinoma of the prostate seminal vesicles treated with radium. Surg Gynecol Obstet 1922; 34:99–118. 2. Scardino P, Carlton C. Combined interstitial and external irradiation for prostatic cancer. In: Javadpour N, ed. Principles and management of urologic cancer. Baltimore, Williams & Wilkins, 1983:392–408. 3. Whitmore WF Jr, Hilaris B, Grabstald H. Retropubic implantation to iodine 125 in the treatment of prostatic cancer. J Urol 1972; 108:918–920. 4. DeLaney TF, Shipley WU, O’Leary MP, et al. Preoperative irradiation, lymphadenectomy, and 125iodine implantation for patients with localized carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1986; 12:1779–1785. 5. Fuks Z, Leibel SA, Wallner KE, et al. The effect of local control on metastatic dissemination in carcinoma of the prostate: long-term results in patients treated with 125I implantation. Int J Radiat Oncol Biol Phys 1991; 21:537–547. 6. Giles GM, Brady LW. 125-Iodine implantation after lymphadenectomy in early carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1986; 12:2117–2125. 7. Kuban DA, el-Mahdi AM, Schellhammer PF. I-125 interstitial implantation for prostate cancer. What have we learned 10 years later? Cancer 1989; 63:2415–2420. 8. Schellhammer PF, Whitmore WF, Kuban DA, et al. Morbidity and mortality of local failure after definitive therapy for prostate cancer. J Urol 1989; 141:567–571. 9. Kovacs G, Galalae R, Loch T, et al. Prostate preservation by combined external beam and HDR brachytherapy in nodal negative prostate cancer. Strahlenther Onkol 1999; 175(suppl 2):87–88. 10. Hilaris B, Fuks Z, Nori D, et al. Interstitial irradiation in prostatic cancer: Report of 10-year results. In: Rolf, ed. Interventional radiation therapy techniques/brachytherapy. Berlin: Springer, 1991:235. 11. Sylvester J, Blasko JC, Grimm P, et al. Interstitial implantation techniques in prostate cancer. Surg Oncol 1997; 66:65–75. 12. Puthawala A, Syed A, Tansey L. Temporary iridium implant in the management of carcinoma of the prostate. Endocurie Hypertherm Oncol 1985; 1:25–33. 13. Martinez A, Edmundson GK, Cox RS, et al. Combination of external beam irradiation and multiple-site perineal applicator (MUPIT) for treatment of locally advanced or recurrent prostatic, anorectal, and gynecologic malignancies. Int J Radiat Oncol Biol Phys 1985; 11:391– 398.

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14. Holm HH, Juul N, Pedersen JF, et al. Transperineal 125-iodine seed implantation in prostatic cancer guided by transrectal ultrasonography. J Urol 1983; 130:283–286. 15. Ling CC. Permanent implants using Au-198, Pd-103 and I-125: radiobiological considerations based on the linear quadratic model. Int J Radiat Oncol Biol Phys 1992; 23:81–87. 16. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999; 44:789–799. 17. 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; 166:494–499. 18. Wallner K, Lee H, Wasserman S, Dattoli M. Low risk of urinary incontinence following prostate brachytherapy in patients with a prior transurethral prostate resection. Int J Radiat Oncol Biol Phys 1997; 37:565–569. 19. Stock RG, Stone NN, Tabert A, et al. A dose-response study for I-125 prostate implants. Int J Radiat Oncol Biol Phys 1998; 41:101–108. 20. Wallner K, Roy J, Zelefsky M, et al. Short-term freedom from disease progression after I-125 prostate implantation. Int J Radiat Oncol Biol Phys 1994; 30:405–409. 21. Grimm P, Blasko J, Sylvester JE, et al. 10-year biochemical (prostatespecific antigen) control of prostate cancer with 125-I brachytherapy. Int J Radiat Oncol Biol Phys 2001; 51:31–40. 22. Potters L, Cao Y, Calugaru E, et al. A comprehensive review of CTbased dosimetry parameters and biochemical control in patients treated with permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2001; 50:605–614. 23. Steinberg D, Sauvageot J, Piantadosi S, Epstein J. Correlation of prostate needle biopsy and radical prostatectomy Gleason grade in academic and community settings. Am J Surg Pathol 1997; 21:566–576. 24. Epstein J. Gleason score 2–4 adenocarcinoma of the prostate on needle biospy. Am J Surg Pathol 2000; 24:477–478. 25. Iczkowski KA, Bostwick DG. The pathologist as optimist: cancer grade deflation in prostatic needle biopsies [Editorial]. Am J Surg Pathol 1998; 22:1169–1170. 26. Allsbrook WC Jr, Mangold KA, Johnson MH, et al. Interobserver reproducibility of Gleason grading of prostatic carcinoma: urologic pathologists. Hum Pathol 2001; 32:74–80. 27. Blasko JC, Grimm PD, Sylvester JE, et al. Palladium-103 brachytherapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2000; 46:839–850. 28. Sylvester JE, Blasko JC, Grimm PG, Cavanagh W. 125-Iodine/ 103-Palladium brachytherapy with or without neoadjuvant brachytherapy for early stage prostate cancer. Int J Radiat Oncol Biol Phys [Abstract] 2000; 48:310. 29. Sylvester JE, Blasko JC, Grimm PG, et al. Impact of short course androgen ablation on the biochemical progression free survival of high risk prostate cancer patients managed with permanent brachytherapy. Int J Brachyther 2001; July-Sept: 173–180. 30. Blasko JC, Grimm PD, Sylvester JE, Cavanagh W. The role of external beam radiotherapy with I-125/Pd-103 brachytherapy for prostate carcinoma. Radiother Oncol 2000; 57:273–278. 31. Sylvester JE, Blasko JC, Grimm PG, et al. 10 year biochemical relapse free survival functions following brachytherapy with external beam radiotherapy for patients with localized prostate cancer: the Seattle experience. Int J Radiat Oncol Biol Phys 2003; 57:944–952. 32. Blasko JC, Grimm PD, Ragde H. 6 and 7 year results of permanent seed implantation. In: Transperineal brachytherapy: Into the mainstream. Seattle, WA: Pacific NW Cancer Foundation, 1995. 33. Grier D. Complications of permanent seed implantation. J Brachyther Int 2001; 17:205–210. 34. Lee WR, Hall MC, McQuellon RP, et al. A prospective quality-of-life study in men with clinically localized prostate carcinoma treated with radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy. Int J Radiat Oncol Biol Phys 2001; 51:614–623.

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35. Sylvester JE, Grimm PD, Blasko JC. Urethral visualization during transrectal ultrasound guided interstitial implantation for early stage prostate cancer. In: Annual Meeting of the Radiological Society of North America, Chicago, IL, 1998. 36. Snyder K, Stock R, Hong S, et al. Defining the risk of developing grade 2 proctitis following 125 I prostate brachytherapy using a rectal dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 2001; 50:335–341. 37. Zelefsky MJ, Fuks Z, Hunt M, et al. High dose radiation delivered by intensity modulated conformal radiotherapy improves the outcome of localized prostate cancer. J Urol 2001; 166:876–881. 38. D’Amico AV, Whittington R, Malkowicz SB, et al. Clinical utility of the percentage of positive prostate biopsies in defining biochemical outcome after radical prostatectomy for patients with clinically localized prostate cancer [See comments]. J Clin Oncol 2000; 18:1164–1172.

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16 Pd brachytherapy: rationale, design, and evaluation Michael J Dattoli The controversy: palladium-103 vs iodine-125

Palladium-103 (103Pd) and iodine-125 (125I) are the most commonly used radioisotopes for permanent prostate brachytherapy. The choice of palladium versus iodine is typically based on physician preference, although it is sometimes driven by the patient. While the controversy continues regarding which is the superior source, palladium has long been my isotope of choice, a preference that dates back to my experience with both 103Pd and 125 I at New York University Medical Center and Memorial SloanKettering in the mid 1980s. My research and clinical practice in Tampa during the following decade and my more recent Sarasota experience have confirmed the advantage of 103Pd even for low grade prostate malignancies. While there have been no definitive (prospective, randomized) human clinical trials to date comparing tumorcontrol rates with 103Pd and 125I, studies have reported a lower complication rate for 103Pd,1 and a faster recovery rate from radiation-induced prostatitis.2 Peschel and colleagues also noted that ‘the radiobiology model predicts the log 10 cell kill for 103Pd implant will be greater than that of an 125I implant for all tumor doubling times (high grade tumors and low grade tumors)’. Both palladium and iodine are effective implant sources, and both have the advantage over other therapies of continuous rather than fractionated delivery (Table 16.1). But

Table 16.1 A comparison of radiotherapy modalities for treatment of localized (locoregional) prostate cancer Modality 3D-CRT IMRT Protons/Neutrons 103 Pd/125I Brachytherapy (Monotherapy) HDR 192Ir (Monotherapy) 3D-CRT/IMRT and 103Pd/ 125I EBRT and HDR 192Ir

Typical dose (cGy)

Delivery

7000–8000 Fractionated 7000–9000 Fractionated 7000–8000 Fractionated 12 500/14 400 Continuous ? Fractionated 4000–5000 Fractionated/ 8000–12 000 Continuous 4000–5000 Fractionated 1500–2500 Fractionated 3D-CRT, three-dimensional conformal external beam radiotherapy; IMRT, intensity modulated radiotherapy; HDR, high dose rate, 192Ir, iridium-192; EBRT, external beam radiotherapy.

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I have found the short-lived, predictable side effects associated with 103Pd to be especially attractive in the context of a large brachytherapy-based practice. The following discussion is not intended to settle the debate, but rather to explain my rationale for choosing 103Pd. Radiobiology and the dose rate phenomenon The physics of 103Pd versus 125I has been rigorously studied (Figures 16.2–16.4). A 103Pd implant is usually planned to deliver an 11 500–12 500 cGy to full decay at an initial dose rate of approximately 20 cGy per hour. 125I implants deliver radiation at a dose rate of approximately 5–10 cGy per hour. The half-life of 103Pd is 17 days compared to 60 days with 125I. With palladium, most of the radiation dosage is delivered in 3 months compared to up to one year with iodine. While dose delivery is as stated, side effects with each isotope may be longer due to clinical lag time. Results favoring palladium might be expected given the radiobiological considerations. Most radiobiological data

Figure 16.1 Prescription doses EBRT vs 125I and 103Pd. EBRT, external beam radiotherapy.

Figure 16.2 Half-life of 103Pd vs 125|.

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Figure 16.3 Average photon energy of 103 Pd and 125|.

Figure 16.4 Initial dose rate to prostate periphery: 103Pd vs 125|. are derived from theory or based on in vitro studies. It is known that radiobiological effect (RBE) decreases with decreasing dose rate primarily as a result of the tumor’s ability to repair potentially lethal and sublethal damage, but also because of recruitment of a relatively quiescent subpopulation of cells and repopulation of initial target cell populations. If the dose rate is too low, tumors associated with rapid cell cycles (e.g. 2–5 days) may not be effectively killed. Although no human clinical data with longterm follow-up are available, the higher dose rate of 103Pd would theoretically be more successful in eradicating aggressive and rapidly proliferating tumors. In this regard, it should be noted that low energy photons have a higher linear energy transfer (LET), associated with higher RBE. The greater radiobiological effect is presumably the outcome of greater energy delivered per cell that the photon traverses. The average energy of 103Pd photons is 21 keV (photons of 20, 23, 40, and 357 keV are emitted) as compared to 28 keV with 125I (photons of 27, 31, and 36keV are emitted). Thus, palladium would be expected to have a slightly higher LET and RBE compared to iodine. In vivo and in vitro studies In vivo animal models (e.g. studies of rat prostate tumors) and also in vitro studies do in fact demonstrate a significant benefit with 103Pd for higher grade tumors, but also an

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advantage in low grade tumors. A study by Nag and colleagues demonstrated the tumoricidal effect of 103Pd was greater than 125I by a factor of two or more.3 The RBE of 103 Pd versus 125I was compared by Ling and colleagues using rat embryo cells transfected with Ha-ras oncogene. While the applicability of results from such experiments to the clinic is limited, this study reported an RBE of 1.9 for palladium versus 1.4 for iodine.4 These favorable 103Pd results may be based at least in part on the dose-rate phenomenon. Only one piece of data,5 suggested that 125I might be more effective for low grade tumors while 103Pd would be superior for high grade carcinomas. This was a highly theoretical model based on the biologic effective dose (BED) formula, with questionable alpha/beta ratio assumptions. The study has virtually no clinical applicability, as the central mathematical equation used to calculate the cell survival level relied on variables about which little or nothing is known when applied to human prostate cancer. Changes in source calibration Both 103Pd and 125I were affected by source calibration changes that were implemented in the late 1990s. Several alterations of apparent activity were applied to 103Pd, as summarized by an American Brachytherapy Society (ABS) article.6 The recommended prescription dose for monotherapy is now 12 500 cGy, with the adoption of the National Institute of Standards and Technology (NIST)-99 air-kerma strength standard for 103Pd using the new doserate constants, which are unique to each manufacturer. In the case of 125I, the American Association of Physicists in Medicine (AAPM) Radiation Therapy Committee Task Group No. 43 (TG-43) recommended changing over to air-kerma parameters established by the Interstitial Collaborative Working Group (ICGW).7,8 The 125I prescription dose changed from 16 000 cGy to 14 400 cGy.9,10 Overall, these changes in nominal dose represent approximately a 10% decrease for 125I and an 8% increase for 103Pd (Figures 16.5 and 16.6). While the alterations in stated doses may not be of major clinical significance, they should not be ignored, especially when published data spans the time frame in which these dosimetry changes were implemented. Because of the lower energy of photons emitted by 103Pd compared to 125I (21 keV ave. vs 28 keV ave.), radial dose fall-off is more steep at any distance from 103Pd sources, especially since attenuation coefficients (e.g. tis

Figure 16.5 Nominal 103Pd doses before and after adoption of NIST wide angle free-air chamber (WAFAC) calibration.

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Figure 16.6 Nominal prescription dose changes for 125I before and after adoption of TG-43 calculations. sue, scatter, other seeds) increase rapidly with decreasing photon energy and are in fact exponential. Therefore, at greater distance from a 103Pd implant, the dose is significantly reduced when compared to 125I. At a distance of 10 cm in tissue, the dose of 103Pd is approximately one tenth that of 125I.11 This is not insignificant clinically and shows that tissue penetration is distinctly dissimilar between the two isotopes despite their energies being relatively similar. The same phenomenon, however, may lend itself to ‘cold’ spots if palladium seeds are not accurately placed. Further source comparisons Produced in a cyclotron by bombarding rhodinium with protons, 103Pd decays via electron capture and conversion to rhodinium-103. 125I is produced from xenon in a nuclear reactor, and decays via electron capture and conversion to tellurium. The Theraseed® 103 Pd source is manufactured by Theragenics, the largest supplier of palladium. Alternative models of the 125I source are available from a number of manufacturers including Nycomed-Amersham, Best Industries, and CR Bard. The marketplace for seeds is increasingly competitive, and the costs of 125I and 103Pd are roughly similar, regardless of activity. 125I offers a greater range of source strengths, and is available either as loose seeds or suture-mounted 125I (RAPIDStrand™). 103 Pd sources have the same dimensions as 125I sources (4.5×0.8 mm), but the two sources appear differently on radiographs depending on the manufacturer.12,13 The two isotopes employ different radiodense markers. 125I is adsorbed on a silver filament, which is encased in a titanium capsule. The inner wire is visible radiographically, but the outer capsule is not. 103Pd is plated on radiolucent graphite rods, with a lead wire at the center of the source to make it radiographically visible. Disadvantages associated with 103Pd are primarily associated with the short half-life. They require replacement and/or dosimetric corrections if not used at the initial planning date. This rarely allows for re-utilization of the isotope. Also, as discussed below, technical accuracy of source placement with 103Pd is more demanding. As such, I always advise newcomers to use 125I first, since iodine is far more forgiving of geographical misses than is 103Pd. Anisotrophy is a minor consideration for both 103Pd and 125I. Both sources have more dose attenuation at the ends than at the central plane because of absorption at the ends of the metal capsule and also absorption by the silver or aluminum carrier. If the source

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distribution were uniformly aligned, the decreased dose at the ends of the source might affect dose distribution. In current practice, however, source orientation is more random, and allows for a uniform correction factor, assuming random source rotation from the longitudinal prostatic axis. There would be little clinical benefit derived from calculating the actual anistrophic effect. 103 Pd seeds are generally used at a source strength of 1.0–1.8 mCi (NIST-99). The lower activity sources are typically used for boost implants combined with supplemental external radiation, although I have most commonly used 1.4 mCi for both mono therapy and combined treatment. The source strength for 125I runs from 0.3 mCi to 0.9 mCi. Dicker and colleagues reported that the difference in average energy between 103Pd and 125 I has only minor effects on most planning parameters.14 While noting that both isotopes were similarly effective with long potential tumor doubling time (Tpot), the Dicker study also demonstrated that 103Pd was more effective with short Tpot. Ling had previously argued that the shorter acting isotope should be used to treat tumors with more rapid proliferation rates (shorter Tpot) to allow less time for cell repopulation.5 Source insertion There are two principal means for inserting 103Pd and 125I sources: the Mick applicator® and preloaded needles. In my practice, I primarily employ the Mick applicator® because it allows for ad hoc seed placement and greater flexibility with intraoperative planning. There are other advantages as well. The device causes less radiation exposure to personnel, and less preparation is required compared to the tedious process of preloading sources into needles. The Mick applicator® is also more cost effective in a large brachytherapy practice, as a limited number of needles are used per patient. Imaging techniques The resurgence of interest in prostate brachytherapy over the past two decades was primarily driven by the technological innovation of transrectal ultrasound (TRUS), which allows for real-time imaging during treatment planning and is also used for monitoring intraoperative needle placement. TRUS imaging is supplemented by computerized tomography (CT) and endorectal magnetic resonance imaging (MRI). Each imaging modality has its advantages and disadvantages. TRUS, MRI, and CT images all reveal pretreatment prostate contours and are used in tandem to determine the number and placement of implant sources. While the appearance of the prostatic and periprostatic regions varies qualitatively between the imaging modalities, the size and shape of the prostate are fairly consistent between techniques if interpreted correctly. The visualization of prostate margins with these complementary modalities ultimately determines the radioactivity required and where it is placed. TRUS and color-flow Doppler ultrasound At our institution, color-flow Doppler ultrasound is utilized since it provides enhanced visualization and greater definition compared to the conventional grayscale technique.15–

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18

While there is an art to interpreting both spectral and power color-flow Doppler images, tumors tend to demonstrate increased perfusion or hypervascularity as findings consistent with malignancy. The standard TRUS shows hypoechogenic areas typically as darker shades of gray. A color-flow Doppler ultrasound may show the same image, but it provides additional insight into how much perfusion of blood is going into the region and can reveal whether just one prostate nodule is involved or if there is more cancer dispersed throughout the gland (Figures 16.7 and 16.8). In addition, biopsies guided by color-flow Doppler ultrasound have the advantage of showing the optimal sites from which to secure tissue samples.16,17 Once the initial diagnosis has been established, I typically request that the specimen slides be reviewed by a pathologist who specializes in prostate pathology.

Figure 16.7 Color-flow Doppler ultrasound imaging for tumor delineation, (a) CFD, right mid cancer, axial image, (b) CFD, base cancer, longitudinal image. (Reproduced with permission from Feleppa EJ, et al. Ultrasonic Spectrum analysis and neural-network classification as a basis for ultrasonic imaging to target brachytherapy of prostate cancer. Brachytherapy 2002; 1(1):48–53.)

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Figure 16.8 Prostate brachytherapy using color-flow Doppler optimization. (Reproduced with permission from Feleppa EJ, et al. Ultrasonic spectrum analysis and neural-network classification as a basis for ultrasonic imaging to target brachytherapy of prostate cancer. Brachytherapy 2002; 1(1):48–53.) The sharp definition of TRUS images can potentially help to minimize interobserver and intraobserver variability, although differences of 5% to 25% have been reported when patients are scanned in succession by the same observer.19,20 For scans performed in succession by two different observers, an approximate 10% variability has been reported.19 There are conflicting reports in the literature as to whether or not TRUS images accurately measure prostate volume when compared to that determined by the prostatectomy specimen. Rahmouni and colleagues found that TRUS volume was 70% of that determined by the resected gland.21 Other studies have reported less of a discrepancy between TRUS and resected prostate volumes.22 The dif ferences reported in these studies may reflect discrepancies in TRUS interpretations, disparate formulas used to measure volume (elliptical volume formula vs step-section planimetry), and differences in equipment and in methods used to process specimens. Operator and team experience are probably inversely proportional to such discrepancies as reported elsewhere. It should also be noted that prostate volume and shape can change when patients are anesthetized. Volumetric inconsistencies can also stem from physiologic changes. Measured by TRUS or MRI, prostate volume can change from day-to-day by approximately 10%. This variation is consistent with both modalities and may reflect actual changes in volume rather than inconsistent technique.23 The impact of such reproducibility problems on clinical results is unknown. It is possible that miscalculated low volumes could lead to inadequate dose coverage of the prostatic periphery, and miscalculated high volumes could lead to complications due to

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over-radiation of normal tissue.24 Such potential problems in treatment planning and evaluation can be avoided by registration and crossreferencing the TRUS, MR, and CT imaging techniques. Even with the wide variation in how the modalities are implemented, clinical results with transperineal brachytherapy appear highly favorable. Effective planning and operator skill appear to be the most significant factors of practical consequence. CT and MRI The main advantages of the CT scan over the other modalities are that CT offers a finer delineation of sources and more accurate imaging of the pubic bones. In addition, the CT requires less patient preparation and is less operator dependent than TRUS. The CT scan is widely used for postimplant dosimetry and quality control. The lack of real-time imaging is the primary disadvantage of CT-based implants. While CT scans provide less defined images of the outer prostatic contour and internal architecture, CT images do accurately delineate the spatial relationship between the prostate, rectum and pubic bones. As with TRUS, there are conflicting studies in the literature with regard to the volumetric accuracy of CT scans. Roach and colleagues found CT volumes were approximately 30% larger than MRI volumes.21 Wallner has suggested that the volumes in that study (and those in a similar study by the Fox Chase Cancer Center,25) were excessive because ‘the levator ani musculature was included within the target volume’ (Wallner et al).26 A University of Washington study compared TRUS and CT volumes drawn independently by three observers (Badiozamani, Wallner, and Blasko). They reported the imaging modalities were consistent in measuring anteriorposterior, lateral, and cranialcaudal dimensions.27,28 The significance of this finding is that CT and TRUS images are actually in close correspondence in determining preimplant volumes. When interpreted correctly, the CT and TRUS volumes are interchangeable. Endorectal MR images (obtained in the gland deformed by the endorectal balloon coil) show markedly sharper prostatic margins than either TRUS or CT. Image interpretation with MRI is therefore less operator-dependent and more reproducible. CT scans lack the attenuation patterns and high-resolution details associated with MRI. Magnetic resonance spectroscopic imaging (MRSI) is the most discriminating test in terms of both the internal architecture of the prostate gland and determining whether or not there is extracapsular extension (EPE). With its high degree of detail, the endorectal MRI can show whether or not there is rectal or seminal vesicle involvement. Bladder invasion can also be detected by an endorectal MRI, while it’s not commonly seen with a CT scan or an ultrasound study. Zaider and colleagues reported a biologic-based optimization technique that registers MRSI images to intraoperative ultrasound images in order to achieve dose escalation to intraprostatic tumor deposits.29 Similarly, Mizowaki and colleagues reported on integrating functional imaging modalities with the registration of MRSI to TRUS and CT images.30 At our institution, most patients undergo an endorectal MRI (preferably MRSI) in addition to TRUS and CT prior to prostate brachytherapy. The only reason a patient would not have an MRI is if his insurance company does not cover it and the patient

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cannot afford the test, as it is expensive. The cost of a diagnostic pelvic MRI is at least two to three times higher than the cost for a TRUS or CT. Setting aside cost considerations, the art of brachytherapy planning and design depends in large part on optimal integration of these complementary imaging modalities. Preimplant dosimetry and planning The purpose of preimplant dosimetry is to determine the number of sources that will be used and where they will be placed. At my institution, a pretreatment study utilizing color-flow Doppler ultrasound generally takes place 2–3 days prior to treatment. Preplanning obviates the need for prolonged intraoperative planning. Indeed, the most appealing aspect of preplanning is the increased time available to evaluate and refine the plan. Without use of preplanning images, an additional 30–60 minutes of operation room (OR) time may be added to the procedure. Another advantage afforded by pretreatment planning is the ability to know in advance whether pubic arch interference (PAI) will pose a problem, so that appropriate measures (e.g. hormonal downsizing or intraoperative positioning) may be taken in anticipation of the problem. Planning images and target definitions Both palladium and iodine implants are planned using images of the prostate gland that are taken at 5 mm intervals from the base through the apex. The patient is placed in the dorso-lithotomy position, as close as possible to the position that he will be in during the procedure. Care must be taken that the gland is not deformed by excessive probe pressure. The prostate is to remain centered on the image grid, while the posterior margin is aligned along a grid row. The most proximal image is the zero plane, or 0.0 plane. This plane is located by visualization of the most proximal image or base, which typically includes a portion of the seminal vesicles. Source positions and images are defined by their distance from the zero plane. Measured caudally, transverse planes are numbered by their distance in cm from the zero plane. The 1.0 plane, for example, is 1.0 cm caudal to the zero plane. The most caudal image, the apex is usually less distinct with transverse imaging but I find this to be easily confirmed with sagittal imaging. The sagittal view helps verify the base and apical planes, with the continuous contour of the gland visually extrapolated from the midsection of the prostate (Figure 16.9). The crucial importance of the zero plane and zero retraction point must be emphasized. The zero plane is determined by the preplan. Typically, we do not go back as much as 4–5 mm—it is generally less, but every case is different. We use 2–3 mm as a rough guideline. I will shoot a seed in and then determine if it really went into the reference place by visualizing that on ultrasound. Again, throughout the procedure, we constantly check to make sure that reference point has not changed, that the seeds

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Figure 16.9 The aero plane can be determined by moving the TRUS probe through the prostatic base. The 0.0 plane typically shows seminal vesicles blending into the prostate (top middle panel). The −0.5 plane shows seminal vesicles and bladder but not the prostate. The tissue plane between the seminal vesicle base and posterior bladder (*) can be useful landmark to identify the plane above the prostatic base (−0.5). the sagittal view (left) can be used to verify that you are at the

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base. (Adapted with permission from Wallner K, Brachytheraphy made complicated, 2nd ed. Seattle, WA: Smart Medicine Press, 201:8.15.) are being placed accurately using that reference guide. Typically, I do not do the procedure while resting my ultrasound at the reference point, but rather go back approximately 1.0 centimeter, a couple of clicks, or one click and a half, or possibly a half click, sometimes where there is a landmark like a stone or a cyst or some part of the gland contour that is easily recognizable. Treatment-planning definitions for brachytherapy were derived from ICRU-50 planning definitions for external beam radiation therapy (ICRU, Han31). The gross target volume (GTV) is visualized on TRUS images as the prostate margin itself. The clinical target volume (CTV) covers the gland and periprostatic regions of potential microscopic invasion. With external beam treatment planning, the planning target volume (PTV) delineates a margin around the CTV to allow for patient setup changes and prostatic motion, as well as for targeting periprostatic tissue. With the brachytherapy procedure, because the position of the prostate on the template does not change, the PTV is not applicable whereas the GTV and CTV parameters apply equally well to brachytherapy and to EBRT. The treatment margin (TM) refers to the perpendicular distance between the GTV and the prescription isodose. The treated volume (TV) refers to the area encompassed by the prescription dose. These treatment-planning parameters are crucial for determining the amount of tissue treated and the dose delivered to the prostate, rectum, urethra, and proximal penile tissues. It should be kept in mind that both 103Pd and 125I brachytherapy deliver doses that are much greater than the prescription dose, because of the use of treatment margins and the high dose regions in close proximity to the sources. Treatment planning and target volumes At the start of the treatment planning study, the GTV is identified using TRUS images and incorporated (digitized) into a treatment-planning program. Identifying the prostate margins can pose a challenge because they can be blurred, especially in the region of the apex, where the glandular tissue and pelvic floor musculature are difficult to distinguish. When there are doubts, it is wise to adopt a policy of being slightly more generous with margins at the apex. A retropubic urethrogram may be helpful since the prostate apex is 1.0–1.2 cm above the bulbar urethra. The margins can usually be visualized more clearly posteriorly near the rectum, where care must be taken to limit the dose. Additionally, the proximal penile tissues (PPT) which are thought to be important for preserving erectile function are within 1.0 cm of the apex.32 The steep radial dose fall-off of 103Pd should allow more generous coverage of the apex while sparing the PPT to a predictive degree when compared to 125I. On a case-by-case basis, our treatment planning studies utilize all available preimplant data, for example, stage, prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), Gleason score, perineural invasion as well as diagnostic studies (color-flow Doppler ultrasound, endorectal MRI, etc.). Depending on those preimplant parameters, I

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typically use 3–5 mm of margin and upwards of 1.0 cm as indicated. It should be noted that the margin may vary throughout the gland: L versus R, base versus apex, and the anterior margin. No additional margin is added posteriorly. Smaller gland volumes typically allow for and require larger margins, and extracapsular placement is utilized in all but the largest glands (≥50 cm3). The proximal portion of volume, especially when there is clinical or radiographic the seminal vesicles is commonly included in the target evidence of seminal vesicle involvement or when the tumor is at the junction of the base and the seminal vesicles. The most proximal portion of the seminal vesicles (between the bladder and prostatic base) can certainly receive a cancerocidal dose with brachytherapy.33 However, extensive seminal vesicle invasion into the distal aspect does not typically lend itself to treatment with brachytherapy. Using dose-volume histogram (DVH) analysis, Stock and colleagues reported that vesicle tissue above the top of the prostate receives less than 50% of the prescription dose.34 Additionally, extensive seminal vesicular invasion may be a harbinger of metastatic disease. As expected, drawing more generous target volumes will increase the volume irradiated and total 103Pd activity required per implant. Because of the steep radial dose falloff associated with 103Pd, sources are routinely placed in extracapsular locations as per TRUS planning to achieve satisfactory dose coverage as evaluated by postimplant CT based dosimetry.35 Tumors occur most frequently in the posterior-lateral regions, which is where extraprostatic extension (EPE) is most likely to occur.36,37 Consequently, larger treatment margins should be used where the likelihood of EPE is higher.38 McNeal and colleagues reported that prostatic carcinoma is multifocal in 50% to 80% of cases, which would suggest that the entire prostate be treated with the prescription dose.37 Ideally, an implant will deliver a cancerocidal dose not only to the entire gland, but with a target margin large enough to cover extracapsular extension. This extraprostatic coverage is especially appealing since a substantial number of patients may harbor unforeseen microscopic extracapsular disease extension. Prostatectomy specimen studies have shown that EPE is usually limited to a distance of 3 mm measured radially from the prostatic edge, and therefore a 3 mm target margin is a reasonable guideline.38,39 Setting aside source placement errors and implant-related edema, a preplanning margin of 3–5 mm will typically achieve a postimplant margin of 3–5 mm. In my practice, with enhanced visualization afforded by color-flow Doppler ultrasonography, I routinely place additional seeds intraprostatically, or extracapsular to a visualized lesion abutting or breaching the capsule (Figure 16.10). While it may not be practical to prescribe a higher dose to one portion of the gland, the prostatic margin closest to the tumor-bearing region can be drawn more generously during preplanning. These extra ‘ad hoc’ sources address high risk areas within the prostate, though care must be taken to keep seeds away from the rectum and urethra. Extras are typically placed laterally to minimize rectal and urethral doses. Perioperative steroid to control swelling A great deal of literature has been devoted to the inconsistencies between preimplant and postimplant target margins caused by implant-related swelling and prostatic volume

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changes.31,40,41 Han and colleagues reported that postimplant target margins (TM) correlated only loosely with preplanned TMs due to implant-related prostatic volume changes. Badiozamani and colleagues compared implant-related dimensional changes with preimplant clinical parameters, including volume, hormonal deprivation, and supplemental EBRT, concluding that no single factor can accurately predict the degree of implant-related swelling. The study reported that postimplant target volumes increased by an average factor of 1.7.27,28 In my practice, perioperative and postoperative steroids and nonsteroidal antiinflammatory agents (celecoxib or ibuprofen) are used to control swelling and to reduce urinary retention. Perioperative dexamethasone has been shown to reduce swelling up to four weeks after the implant.42–46

Figure 16.10 Tumor, as visualized on color-flow Doppler ultrasound, can be easily delineated and utilized for dose optimization/escalation. (a) Brachytheraphy and extracapsular seed placement for dose optimization. (b)

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Brachytheraphy dose optimization using extracapsular seeds. Speight and colleagues also reported an improved dosevolume histogram associated with perioperative dexamethasone. In addition, celecoxib (Celebrex) has been shown to significantly reduce edema following brachytherapy and also appears to decrease urinary retention.47 Dosimetry analysis and modified peripheral loading In a sizable patient population, I have evaluated gland size and seed motion from the day of implant, then every two weeks up to 3 to 4 months. There has been no substantial change in gland size when using perioperative and postoperative steroids and nonsteroidal antiinflammatory agents. Therefore, CT scanning and postimplant dosimetry analysis need not be delayed, and many patients even undergo CT scanning for postimplant dosimetry on postop day 1. Immediate postimplant analysis allows for any mistakes to be revealed as soon after the fact as possible, making for easier correction. Narayana and colleagues reported that limiting sources to the periphery allows for optimal treatment of prostatic margins without excessive central doses.48 Modified peripheral source placement patterns avoid the urethral dose extremes of homogeneous loading that places seeds in a uniform pattern throughout the prostate. Wallner and colleagues demonstrated that excessive urethral doses are correlated with urethral morbidity.49 Urethral doses should be kept within approximately 150% to 250% of the prescription dose. While in practice, it is often assumed that the urethra is located midline, at the time of the implant the urethra may turn out to be quite circuitous in its course through the prostate. Intraoperative adjustments can be made simply by moving needles several millimeters away from the urethra. The prescription isodose is generally 4–5 mm outside the most peripheral seeds, and therefore, achieving a 3–5 mm treatment margin around the prostatic edge requires that sources be placed very near the edge. I generally place sources around the periphery at 1.0 cm spacing and within 2–5 mm from the margin. Because seeds at the periphery do not provide adequate coverage of the entire volume, additional sources are placed more centrally and/or peripherally to achieve optimal target coverage, with acceptable central doses. With seeds limited to the periphery, the margins can receive adequate doses without central overdosing.48 Comprehensive peripheral loading is not practical because placing all the sources at the periphery may result in underdosing the central portion of the gland. Merrick and colleagues have reported on the rationale for modified peripheral loading.43– 46 With this technique, the central dose is generally kept below 200% of the prescription dose, thus minimizing the likelihood of urinary complications. Extraprostatic source placement I am an advocate of extraprostatic source placement, and typically place seeds 1–5 mm outside the prostatic capsule. It should be noted that the clinical target volume (CTV)

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extends anteriorly and laterally beyond the prostate margin (GTV), with the added target margin most marked at the apex and base. Extraprostatic seed placement, as assessed by CT-based postimplant dosimetry, achieves broader and more uniform coverage without escalating urethral or rectal doses (Figures 16.11 and 16.12). Placing sources outside the prostate has not resulted in increased clinical problems (e.g. RTOG grade 3 and 4 toxicity or increased erectile dys function). This consideration is especially appealing since urethral morbidity is the most severe side effect associated with 103Pd brachytherapy. It is also an important consideration for prior TURP patients since increased central doses may result in increased incontinence. In our experience, the immediate periprostatic tissues (1 mm to 1 cm beyond the capsule) allow for source placement without substantial concern for migration.35 The concave ends of 103Pd Theraseed® may contribute to source fixity. In contrast to the more convex-shaped seeds, Theraseed® sources tend to anchor themselves within the immediate periprostatic tissue. Placement of additional seeds peripheral to the ultrasound-defined GTV is necessary to achieve both optimal uniform coverage and the prescribed minimum peripheral dose. The steep radial dose fall-off with 103Pd tends to reduce the minimum peripheral dose even when using a modified peripheral seed loading pattern. When using our prostate dosimetry, an increased number of 103Pd sources placed outside the prostate volume bring us closer to our dosimetry objectives (minimum peripheral dose coverage of 80%), without increased toxicity. To achieve this degree of dose coverage on postimplant CT analysis, substantial increases in preimplant ultrasound target volumes have been necessary over the years when using a modified non-uniform peripheral seed loading pattern. While recognizing that the evaluation of implant quality is multifaceted and depends to a large extent on target identification and postimplant dosimetric methods, it nonetheless seems logical that improving uniformity throughout the gland and targeting extracapsular regions would not only result in diminished morbidity, but should also increase the likelihood of tumor eradication. Total activity and source strength The total activity required for 103Pd and 125I implants increases as the prostate volume increases. However, there is only a rough correspondence between activity and volume because the actual activity depends on a number of

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Figure 16.11 Preimplant TRUS and postimplant CT showing extracapsular seed placement. (Reproduced with permission from Wallner K, Brachytherapy made complicated, 2nd ed. Seattle, WA: Smart Medicine Press, 2001:6.25.)

Figure 16.12 Tumor delineation on postimplant CT for dosimetric analysis. Brachytherapy dose optimization. other factors including the shape of the gland, how large the treatment margins are and how many targeting adjustments have been made to limit the dose to the rectum and urethra. Prostate brachytherapy has utilized a wide variety of source strengths, with no evidence of any effect on clinical outcomes. 103Pd sources typically vary in strength from 1.4 mCi to 2.0 mCi, while 125I sources range from 0.2 mCi to 0.9 mCi (NIST-99). Modified peripheral loading with higher strength seeds should lower costs by reducing the number of sources required.50 Some investigators have argued that the use of higher activity sources could lead to increased complications and/or inadequate target coverage, but that argument is not supported by any clinical data or by common sense. Radiation-induced morbidity is related to the dose delivered rather than individual source strength. Newcomers to brachytherapy might be advised to use lower strength sources because there is greater margin for error and less risk of overdosing. The fact that a few seeds are misplaced is less of a concern when those errors are spread out among a greater number of lower strength sources.

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Hormonal downsizing Androgen deprivation therapy (ADT) decreases prostate volume by approximately 25% to 50%.51–53 When ADT is used prior to 103Pd brachytherapy, treatment planning is based on the reduced prostatic volume. Planning images are obtained after at least 12 weeks of ADT when maximal shrinkage has been achieved. Hormonal treatment is typically optional for patients having intermediate risk features but encouraged for patients having high risk features. High risk factors would include two or more of the following: PSA >10, Gleason ≥7, cancer stage >T2b, and an elevated PAP. With the low risk or mildly aggressive cancers, I do not usually prescribe conventional ADT, that is, combined hormonal blockade using an antiandrogen and a LH-RH (luteinizinghormone-releasing hormone) agonist, since this may result in unwanted side effects, such as impotence, hot flashes, myalgia, and anthralgia. I often prescribe a milder or modified version of hormones (antiandrogen ± Proscar/Avodart), a protocol that is just enough to arrest the can-cer and to allow the patient to make a decision about treatment without the rush and urgency often associated with it. It should be noted that my own data do not demonstrate a strong advantage to utilizing hormones in patients having high risk features, but I cannot ignore the fact that numerous multi-institutional studies both in the United States and abroad have demonstrated a benefit with the utilization of hormonal therapy. In addition, within my own data, the patients who received hormones had far more aggressive tumors and yet fared similarly to the other patients under study.54 Implant technique and evaluation Positioning the patient After induction of anesthesia (spinal, general, or local), the patient should be placed in the dorso-lithotomy position, making every effort to replicate the planning position. The patient’s legs are rotated symmetrically with extension at the hips and knees to avoid pelvis rotation on the longitudinal axis. Care is taken to make sure the patient is lined up at the middle of the table with the perineum near the table edge, allowing sufficient space to facilitate maneuvering the TRUS probe. Pubic arch interference (PAI) can usually be rectified by placing the patient in the extended lithotomy position, tilting back the pelvis in order to reorient the pubic bones away from the anterior of the prostate. The pelvis can be tipped back by adjusting the stirrups or by manually maneuvering the patient’s pelvis toward the end of the table. Care should also be taken to make sure the scrotum is kept away from the perineum. This can be accomplished by using tape, a wet cloth or towel to hold the scrotum to the abdominal wall.

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Urethral imaging The urethra is visualized during the procedure to avoid misplacement of seeds in those patients with asymmetrical urethras. Misplaced intraurethral sources will be expelled, lowering the planned dose. A catheter can be used to visualize the urethra and bladder neck; however, this technique creates an artificial enlargement of the gland (e.g. an 18French catheter is sizable when compared to a 20–30 cc gland). In my practice, I routinely utilize the catheter prior to starting the implant, administering 50 cc of 100% Renografin™ into the bladder and obtaining a lateral fluoroscopic cystogram, while additional dye is instilled into the catheter. Keeping the image on a second fluoroscopic screen during the procedure provides a reliable urethral reference. Information regarding the bladder can be obtained (e.g. a smooth bladder wall vs a heavy trabeculated wall), while an enlarged prostatic median lobe may also be appreciated (both may predict voiding problems, in which case postimplant medical management can be intensified). The catheter is removed after obtaining the reference image, but only after carefully identifying and recording the location of the urethra as it courses through the gland from base to apex. A small amount of dye (10–15cc) remains in the bladder throughout the procedure in order to visualize the bladder-prostate interface. Too much dye may distort the gland, making it difficult to replicate the preimplant gland contour. TRUS probe positioning Before placing needles, the imaging planes should closely match those of the planning images. The posterior margin of the mid-prostate should line up on the grid as it did on the planning images. Adjustments can be made by angling the probe slightly in various directions. Probe pressure should be gentle, as excessive pressure can cause image distortion and artifactual deformation of the gland. As discussed, the 0.0 plane is visualized by moving the TRUS probe through the confluence of seminal vesicles, bladder, and prostatic base. Once the TRUS images correspond to those of the preplan, seed-loading depth is determined (Figure 16.12). The needle-guide template is mounted on the stepping unit close to the perineum, with a 1–2 cm margin between the skin and template so that the needle direction can be adjusted manually if necessary. According to the preplan, each needle will typically carry 5–10 seeds. It should be noted that the Mick applicator® deposits seeds beyond the tip of the needle, and therefore, the needle tip should be retracted 2–5 mm before placing a seed at the zero plane. A common operator loading error occurs when the TRUS probe is retracted too far from the reference (> 1.0 cm). When this happens, the most posterior superior aspect of the base of the gland may be underloaded because the operator is under the mistaken impression that he is loading the gland as it appeared before the TRUS probe was pulled back. This problem can be avoided by constantly monitoring the position of the reference plane.

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A simple solution to prostatic motion Even without the pressures of needle insertion and the ultrasound probe, the prostate can be very mobile, as external beam studies have demonstrated.55 The degree of prostatic motion varies from patient to patient, with most occurring in the anterior-posterior direction. During implant needle insertion, there may be lateral and cephalad displacement up to 1 cm. In order to minimize prostatic motion and the potential for misplacement, I routinely insert two crossing needles through the posterior aspect of the prostate, thereby anchoring the gland in place.56 The needles are fixed in the pelvic floor musculature at an angle (Figure 16.13). Two 18-gauge stainless-steel needles (provided by Mick Nuclear Instruments, Inc) are inserted transperineally, obliquely into the prostate, using manual and fluoroscopic guidance. These needles are left in place during the procedure. In my experience, maximum lateral displacement is decreased from approximately 1 cm to 2.0 mm, while craniocaudal motion is virtually eliminated. Needle insertion Needles are inserted through the template holes to penetrate the perineal skin. After the skin is pierced, rapid advancement minimizes needle deviations. When needle deflection is detected, the needle may be withdrawn several centimeters and then reinserted, making sure the needle is exactly parallel to the TRUS probe. A twisting motion may enable the needle to penetrate obstructing tissue planes (e.g. due to intraprostatic calculi) with minimal deflection. Monitoring the needles fluoroscopically during insertion helps guard against misplacement (Figure 16.14). In addition, fluoroscopic monitoring minimizes urethral piercing. Sources can migrate into the retroperitoneum, the lungs or heart, but despite concerns often raised in this regard, loss is typically minimal and dosimetrically inconsequential. Merrick and colleagues reported a low incidence of source migration even with a large percentage of extraprostatic sources.43–46 Studies have reported that sources migrate to the pulmonary vasculature in 11% to 25% of patients.57,58 No morbidity has been described in cases of pulmonary migration. A good implant depends on accurately determining the depth of the needles and maintaining correct positioning in the transverse TRUS images. Inserting the needle while viewing the appropriate plane helps to ensure the proper depth is achieved. The insertion can also be viewed fluoroscopically. Landmarks, such as intraprostatic calculi, cysts, etc., may be valuable to assess current depth of needle placement throughout the procedure. It may help to measure the distance in centimeters that the needle should be

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Figure 16.13 Insertion of two crisscrossing needles to minimize prostatic motion, with two fluoroscopic view. (Reproduced with permission from Wallner K, brachytheraphy made complicated, 2 ed. seattle, WA: Smart Medicine Pres, 2001:8.25.)

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Figure 16.14 Needle depth checked on sagittal TRUS view (Reproduced with permission from Wallner K, Brachytherapy made complicated, 2nd ed. Seattle, WA: Smart Medicine Press, 2001:8.19.) distal to the template. Sagittal TRUS imaging can also be used to check needle depth. Because of the vacuum created when a needle is withdrawn, seeds may slide along the track as the needle is retracted. This type of source displacement can be avoided by removing the needles in a slow, steady motion, and with 103Pd Theraseeds, utilizing a rapid clockwise rotation of the needle after it releases the seeds from their concave ends. Newcomers to brachytherapy are advised to take special care to avoid the pubic bones, as a rapid thrust of the needle tip against the pubic arch can bend or even break a needle. After multiple sources have been inserted, there is typically some degree of image degradation. Visual obfuscation can be reduced by inserting the anterior needles before the more posterior needles. This anterior-posterior progression reduces the likelihood that the posterior needles will obscure the more anterior needles. Proper needle positioning can be verified on the TRUS images proximal to the template (caudal to the prostatic apex), where the image is less likely to be obscured by sources. Even in experienced hands, seeds can sometimes be misplaced or migrate into the perirectal region, the bladder or the lungs. While these errant seeds are not known to cause any clinically significant problems, excessive seed loss can lead to underdosing part of the prostatic target.39 Errant seeds in the urethra or bladder are unusual, and when they occur, they typically pass spontaneously. Such errors can be minimized by judicious use of intraoperative fluoroscopy and TRUS, and by continually checking that the reference has not changed. Regarding intraoperative planning, I am currently unsatisfied with the state of ‘dynamic dosimetry’, finding it to be unreliable while adding little value. Until this technique advances, I believe that experience with both TRUS and fluoroscopy is more than satisfactory, providing ample operator feedback as to the exact placement of seeds. I consider intraoperative modifications with physics support for dosimetric analysis to satisfy the definition of ‘dynamic dosimetry’. Between the TRUS and fluoroscopy

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modalities (and considerable experience and intraoperative dosimetry), I am confident that each patient has or approaches having the ‘perfect implant’. After all, you cannot teach experience. Pubic arch interference Pubic arch interference (PAI) can usually be circumvented by shifting the needle path in relation to the pubic arch. Tincher and colleagues have evaluated the effects of pelvic rotation and needle angle on PAL.59 Extending the lithotomy position rotates the pubic arch superiorly, allowing more space for maneuvering the needles underneath the arch (Figure 16.15). After changing the patient’s position, the template grid should be checked to be sure the prostate is aligned properly. Altering TRUS probe angulation or moving the probe tip away from the prostate may enable the needle to pass more readily under the prostate; however, care must be taken when altering the probe’s position not to shift the grid alignment. Another technique for circumventing PAI is to bend the tip of the needle slightly, at about 3–4 cm from the tip. The needle is then inserted approximately 0.5–1.0 cm medial and posterior to the intended grid position, with the needle tip angling away from the arch. As the insertion proceeds, the needle is rotated 180 degrees, thereby forcing the tip away from the probe after it passes the arch. This method should be used as a last resort, as it may increase tissue trauma and the likelihood of urinary retention.60 The various methods used to circumvent PAI can lead to underdosing, but fortunately, when this occurs, the underdosed portion of the gland is usually the most anterolateral, where cancer is less likely to be present and where minor deviations from the target plan are not likely to be of clinical significance.36,37 Postimplant evaluation Postimplant dosimetry and evaluation provide for essential quality assurance through precise and objective analysis of prostate brachytherapy results. Postimplant evaluation tells us whether an implant was good or suboptimal, and this finding can have potential legal as well as clinical ramifications. If a patient has serious complications and takes legal action, postimplant dosimetry will be central to the case on both sides. With more favorable outcomes, the dosimetry provides assurance for the patient, and many are anxious to hear the specifics of the report even in highly technical terms. Postimplant imaging and dosimetric analysis routinely compare isodose volumes with the prostate margin. The sources and margins are identified using TRUS, CT, and/or MRI, each with its advantages and disadvantages. While CT scans allow for easy source identification, the prostatic margins are frequently obscure, especially near the apex. MRI provides better images of the margins, but is less effective at source identification. TRUS allows for real-time dosimetry, though there is typically some degree of postprocedural image degradation caused by the placement of sources (not to mention the discomfort!). In my experience, CT is practical and effective, taking into account the tendency to derive slightly larger volumes from CT scans. It should also be noted that despite problems with interobserver variability, CT-based dosimetric studies have been fairly

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consistent between experienced brachytherapy teams, and CT-based dosimetry does correlate with biochemical control rates.61,62 Casual inspection of postimplant images may show whether or not sources have been placed too close to the urethra or rectum. Postimplant dosimetric results are most

Figure 16.15 Extending the lithotomy position can reduce pelvic arch interference. Note how in this patient the pubic arch (arrow) obstructed the needle at the C5 template position (*). The extended lithotomy position allows the right side of the pubic arch to move away from the TRUS probe, allowing insertion to the C5 position. (Reproduced with permission from Wallner K. Brachytherapy made complicated, 2nd ed. Seattle, WA: Smart Medicine Press, 2001:8.29.) effectively analyzed by visual evaluation of the isodoses overlaid on cross sections of the prostate (Figure 16.16). Dose distribution obtained from the overlays may reveal cold spots and misplacements. In cases of suboptimal prescription dose coverage, additional sources can be added to the underdosed portion of the gland, or in some cases supplemental external radiation (preferably IMRT) may be added. When adding sources after the original procedure, care must again be taken to avoid excessive rectal and urethral doses.

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Evaluating target coverage Current practice is to assess dose coverage of the entire gland, assuming it to be uniformly at risk for cancerous involvement. Isodose overlays are used to evaluate implants for individual patients, while summary dosimetric indices are used to analyze dose-related clinical effects across groups of patients. The dose-volume histogram (DVH) graphs the percent of target covered versus increasing doses and can be used to derive an array of dosimetric parameters (Figure 16.16 and Table 16.2). The V100 index measures the percent of target volume covered by the prescription dose. A study by Roy and colleagues reported V100 values of 80% using postimplant CT scans.63 This inadequate coverage was later attributed to implant-related swelling.38,39 The effect of swelling is not as great as might be suggested by reported volume changes. Willins and Wallner demonstrated that with an average volume change of 25%, target coverage fell only by an average of 5%, due to preplan treatment margins that allow for swelling, keeping most of the volume increase inside the prescription dose. I have avoided problems with postimplant swelling by using aggressive perioperative and postoperative steroid therapy, so that postimplant CT can be utilized at postimplant day 1 or even at 3 months. V100 and D90 correlate best with biochemical control, and both are commonly used. The minimum prostatic dose (Dmin) is not a useful index because it has proven too sensitive to minor source placement variations.62 It should be noted that inclusion of the levator ani musculature or the puborectalis in the target volume or drawing the apex too generously leads to falsely large prostate volumes and falsely low V100 values. Our current quality control criteria for an ‘adequate implant’ require that at least 80% of the CT-defined prostate is covered by the prescribed isodose surface (12 500 cGy minimum peripheral dose for palladium alone; 8000–9000 cGy minimum peripheral dose when combined with supplemental external radiation; IMRT). Most patients do in fact receive at least 90% minimum peripheral dose. Failure to obtain 80% dose coverage mandates either reimplantation or supplemental external radiation IMRT.

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Figure 16.16 (a) CT-based evaluation of 11 500 cGy 103Pd implant and (b) dose—volume histogram. (Reproduced with permission from Wallner K. Brachytheraphy made complicated, 2nd ed. Seattle, WA: Smart Medicine Press, 2001:9.10; 9.11.) ‘Hot’ spots Hot spots occur because tissue adjacent to the seeds receives extremely high doses, and therefore, a significant amount of the prostate receives far greater than the prescription dose. High dose regions near the urethra or rectum may increase the likelihood of morbidity, although serious complications (incontinence, rectal ulcers, or parenchymal necrosis) are uncommon. The lack of correlation between the magnitude of high dose regions and clinical outcomes is probably due to the fact that current modified peripheral loading patterns minimize variations in magnitude of high dose regions.63–67

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Urethral and rectal doses The maximum acceptable urethral dose for 103Pd is approximately 300 Gy. With a modified peripheral loading pattern, the central urethral dose is easily kept well below the guideline of 2.5 times the prescription dose. My implants commonly reduce the urethral dose to unity or less.35 Since the advent of peripheral loading patterns in the 1990s, no relationship between urethral doses and morbidity has been reported, probably due to the limited range of urethral doses seen in current practice.64–66 Serious rectal complications, such as ulcerations and fistulas, are uncommon with brachytherapy. There are

Table 16.2 Various indices for quantifying implant quality Percent of prostate volume receiving prescription dose or higher V100 Dose covering 100% of prostate volume D100 Dose covering 90% of prostate volume D90 Percent of prostate volume receiving twice the prescription dose or higher V200 V200/V100 The fraction of prostate volume receiving more than twice the prescription dose Minimum dose delivered to any part of the prostate Dmin

little clinical data with regard to rectal tolerance and how to minimize rectal morbidity. Han and colleagues reported that rectal surface and volume doses are correlated with postimplant proctitis and rectal bleeding.68 However, they also suggested that some patients may be predisposed to higher rectal doses because low levels of perirectal fat cause the rectum to be in closer proximity to the prostate. Wallner and colleagues reported only a loose correlation between rectal bleeding or ulceration with doses in excess of 100 Gy.49 Howard and colleagues reported no correlation between high dose regions and the likelihood of serious rectal complications.69 Bice and colleagues evaluated dosimetry from five experienced brachytherapy teams, with each reporting a low incidence of rectal morbidity. A rough guideline may be suggested by their maximum rectal wall doses, which were approximately twice the prescription dose.70 Newcomers to brachytherapy are advised to include urethral and rectal doses in their postimplant dosimetric analysis to be certain that implants fall within acceptable guidelines. With experience, dosimetric analysis can be limited to assessing the extent of prostate coverage, with urethral and rectal dose calculations restricted to those patients who later develop serious complications. In those cases, doses are calculated at the time the complication is discovered, usually long after the procedure. Complications Urinary morbidity Following both 103Pd and 125I brachytherapy, most patients temporarily experience some degree of implant-related prostatitis. Voiding symptoms may include frequency and

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urgency, a weakened stream, and occasionally, urinary burning. These symptoms are not debilitating, but rather a nuisance and patients are encouraged to continue their normal level of activity. While patients undergoing 103Pd brachytherapy do experience increased short-term side effects, the more long-term urinary morbidities have been demonstrated to be extremely favorable (Figure 16.17).71–74 In fact, Stone demonstrated that patients with marked symptoms (high American Urological Association (AUA) scores) prior to treatment derived statistically significant improvement in symptoms and quality of life (QOL) after brachytherapy. Merrick showed no significant difference (not even a trend) when comparing brachytherapy patients to an untreated control group at a median of 69 months. Because the half-life of palladium is 17 days, urinary symptoms typically last 10 to 12 weeks. By contrast, the halflife of iodine is 60 days, and symptoms may persist for 10 to 12 months. Other investigators using either 125I or both isotopes reported temporal resolution of urinal morbidity within 6 to 12 months.43–46,75 Most patients return to baseline AUA scores. Preimplant parameters, such as prostate volume, age, preimplant AUA scores, and urinary flow parameters do not appear to influence long term AUA scores. Postimplant urinary retention is the most common acute morbidity. Retention may occur in 5–10% of patients, but usually lasts only a few days.76,77 A very small percentage of patients may develop refractory retention. In my experience urinary incontinence is virtually nil. Superficial urethral necrosis (SUN) is uncommon since the widespread adoption of peripheral loading patterns.78 Urethral stricture is also uncommon, and may be related to excessive apical doses.79–81 I have never had a patient who required permanent urinary diversion because of damage to the urethra. It appears that while the urethra tends to play an important role with brachytherapy in terms of the side effect profile, the urethra generally is able to withstand the dose, and once the sources decay, the side effects resolve spontaneously. Transurethral resection of the prostate Patients who have previously undergone TURP are at higher risk for developing incontinence. Although incontinence is a very rare complication associated with brachytherapy in general—it is less than 1% in virtually all the series. However, patients who have undergone TURP may be at higher risk for incontinence, up to 50% in some early series (Blasko82). More recent series with peripheral loading patterns demonstrate a 3% or less risk of incontinence.78,83 The reason that incontinence risks may be higher in these patients is because the TURP typically removes the superior (or internal or proximal) sphincter, leaving only the distal (or external) sphincter. The high doses of radiation delivered by the implant may impair that remaining sphincter. Another factor to consider is how large the TURP is compared to the size of the prostate. There must be enough prostate tissue around the TURP to hold the seeds; in cases where the TURP is excessive, there may not be enough tissue to anchor the seeds, and that may be a contraindication.

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Figure 16.17 Late urinary function after permanent prostate brachytherapy. EBRT, external beam radiotherapy; IPSS, International Prostate Symptom Score.73 It is rare that I would dissuade a patient from undergoing brachytherapy because of a TURP, but if a patient has had a TURP, the implant procedure has to be mapped out very carefully and the seeds need to be arranged differently than with those patients with no prior TURP. Sources are positioned in a way that avoids the TURP itself (Figure 16.18); otherwise they will be deposited into the empty cavity where they will be urinated out, or potentially do damage. With prior TURP patients, there should be a rim of tissue at least 1.0 cm remaining around the defect, to ensure sufficient tissue to anchor the seeds. I use a

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highly peripheral seeding loading pattern in these patients, and take care to avoid the remaining sphincter.

Figure 16.18 Transurethral resection of the prostate (TURP). Brachytherapy and extracapsular seed placement. Rectal complications In my experience with the implant procedure, I do not have one patient who has had to have a colostomy or who has a persistent rectal ulceration. Rectal ulceration is much less common than proctitis.68 Rectal bleeding from radiation proctitis occurs in 2% to 10% of patients and usually manifests between 6 and 18 months of the implant.64–68 Rectal bleeding is typically painless, with minimal blood loss, and only rarely requires transfusion. Most patients who experience rectal bleeding do not progress to rectal fistula, and most appear to heal spontaneously over time.84–88 Erectile dysfunction Defined in practical terms as the inability to maintain an erection sufficient for intercourse, impotence is a potential side effect from any therapy used to treat the prostate. The definition has been criticized for being too imprecise and allowing too much latitude for interpretation by patients and investigators.89–90 Within the limitations of the definition, in regard to potency preservation, brachytherapy appears to offer an appealing advantage over both radical prostatectomy and conventional external radiation IMRT. Any large study of patients with a long term follow-up should take into account normal, age-related impotence, but all too often we forget that there is a linear curve showing a 1.5% spontaneous decrease in potency with each year after the age of 40, and this is without any type of prostate treatment.91 Evaluating the effect of treatment on potency is made all the more problematical by the fact that prostate cancer affects an age group for which there is a high incidence of sexual dysfunction prior to treatment.

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Approx imately 50% of prostate cancer patients are already impotent at the time they are diagnosed.89 My own data at six years show that 70% of those patients who are potent at the time of 103 Pd brachytherapy will maintain their potency. The numbers vary considerably even among experienced teams, and I am aware of other institutions reporting 59%,92 and 39%,73,74,79–81 without pharmacologic support (Table 16.3). I believe that the risk of impotence may be decreased with palladium since the radial dose fall-off and the amount of radiation actually delivered at any distance from the seed to the neurovascular bundles (NVB) or proximal penile tissues is less with 103Pd than with any other isotope. Therefore, a slightly higher potency rate might be expected with palladium than with other isotopes. The importance of the NVD in preserving potency was probably overstated in early studies at Johns Hopkins University Hospital.93 After Walsh and colleagues94 attributed postsurgical impotence to NVB trauma, it was assumed by many investigators that implant-induced impotence might be related to excessive radiation doses to the NVBs. Merrick and colleagues95 did not find a correlation between NVB dose and impotence with patients followed up to four years. More recent studies suggest that a more likely cause for radiation-related impotence may be venous insufficiency due to overdoses to the penile bulb

Table 16.3 Prostate brachytherapy and potency preservation Study

Potency preservation at 6 years

Dattoli (unpublished) 70% Stock62 59% 39% Merrick79

Box 16.1 Brachytherapy dose to neurovascular bundle (NVB) and erectile dysfunction (ED) Is it important? ‘No relationship between dose to NVB (mean 215% ±55% of prescription dose) and the development of brachytherapyinduced ED’ Merrick G-S, et al Int J Rad One 2000:4895 [Median f/u 37 months] Wallner K, et al Int J Cancer 2001:96122 [Median f/u 49 months] f/u=follow up and proximal penile tissues, especially the corpus cavernosum, which harbors the most erectile tissue (see Box 16.1 and Figure 16.19). The penile bulb typically has a volume of 5.0–7.0 cc and is situated approximately 0.5–1.0 cm below the prostatic apex. With brachytherapy, the bulb usually receives a maximum dose of about 50% of the prescription dose, depending on the treatment margins and the distance between the prostatic apex and bulb. Merrick and colleagues demonstrated a correlation between excessive penile bulb doses and posttreatment impotence.79–81 External beam studies have also shown a strong correlation between bulb doses and impotence.96–98 Revised NVB and penile bulb dose parameters are now

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typically incorporated into brachytherapy planning to maximize tumor eradication and minimize the likelihood of impotence. Brachytherapy does not appear to produce the steady decline of potency that we have seen with full course external beam radiation through the years. Rather, there appears to be a leveling off of the potency rate over time after implantation. Again, the patient is getting older and he may be taking hypertensive medications, diabetic medications, or have other comorbid medical problems which could interfere with his potency. Stock and colleagues have

Figure 16.19 Prostate and periprostatic anatomy. Coronal cross-section of prostate and periprostatic structures. shown that patients with substantial erectile dysfunction prior to treatment are at an increased risk for impotency than patients who are fully potent prior to treatment.92 For those men who lose potency, intracavernosal paparavine, prostaglandin 1 (PGE1) injection, and Viagra™ (sildenafil) are very effective.73–81,99,100 Viagra™ has altered the clinical situation considerably. For those men who are potent at the time of treatment, 92% of patients having brachytherapy (± supplemental external radiation) will maintain their potency (Figure 16.20).78 As of the time of writing, two additional oral erectile aids, Levitra (vardenafil) and Cialis (tadalafil) are now available. Like Viagra, both are PG1 inhibitors. With the majority of patients who retain potency, the major change reported is diminution in the volume of the ejaculate. Shortly after the implant there may also be a discoloring or a different consistency to the ejaculate.

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Figure 16.20 Potency preservation/recovery with sildenafil (brachytherapy± EBRT).80 Typically, it’s described as being clearer and thinner, but patients have no problem with that as long as they are able to maintain an erection and achieve orgasm. Dry ejaculate occurs in as many as 25% of patients. Between one third to one half of patients report painful ejaculations for 3 months or longer postimplant.73 Due to inflammation of the ejaculatory ducts and urethra, many patients experience burning with ejaculation (orgalmasia) 6–12 months after the procedure. Bloody ejaculate is common up to several weeks after the implant. Hematospermia appears to have little clinical significance. A patient can have normal sperm after the procedure. While there may be a short period of oligospermia, a patient may have a return of sperm. However, because of the diminished ejaculate and change in milieu that the sperm will encounter, the likelihood of successful impregnation should be greatly reduced. Nonetheless, we counsel our patients to be careful, because they cannot consider themselves to be sterile because of the procedure. Supplemental external radiation: a cautionary note When external radiation is combined with brachytherapy, the sequence is typically EBRT (preferably IMRT) followed by an implant boost, with the doses of each modality moderated to achieve optimal coverage while limiting rectal and urethral doses. The history of the combined approach suggests there may be considerable reason for concern that reversing the sequence (implant first followed by external radiation) may increase the risk of rectal complications, in part because there is a significant interval when patients are receiving simultaneous implant and external radiation IMRT. The true pioneer of modern transperineal implants for prostate cancer, Dr Hans Henrik Holm of the University of Copenhagen, utilized 125I seed implants first, followed by a higher dose per fraction of EBRT than is generally used in the United States. His complication rate of 44% required subsequent colostomies or surgical urethral repairs. This result, coupled with a high local recurrence rate of 40%, led him to abandon the procedure altogether, with great disappointment.101

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Dr Holm has since been faulted for using full dose 125I followed by higher dose per fraction EBRT. While this might account for many of the complications, it does not explain why 40% of his patients still had cancer of the prostate. Another group, Patel and colleagues followed a similar protocol,102 but used lower doses similar to those commonly used in the United States. This group encountered similar complications and recurrence rates. In both series, severe complications in most patients did not occur until four to seven years following the protocol. Even with shorter follow-up (mean: 33 months), Zeithin and colleagues reported early complication rates (incontinence, 2.8%; rectoprostate fistula, 2.4%; rectal wall breakdown, 0.5%; urethral stricture, 0.5%) with the simultaneous approach utilizing either 125I or 103Pd combined with EBRT.103 With seeds placed prior to external radiation, there is also concern for radiation interactions (e.g. the Photo Electric effect, the Compton effect, Bremsstrahlung) that occur with high energy photons striking metallic objects, such as stainless-steel, titanium, or gold seeds. These interactions may cause dose escalation and radiation scattering to adjacent structures, such as the bladder, rectum, and urethra. Moreover, these interactions make it virtually impossible to accurately calculate the dose levels delivered to relevant tissues and organs in the treatment field. Another issue of concern with the ‘seeds first’ method (with the exception of very early stage prostate cancer) is the potential for active cancer cells to be released into the bloodstream as a result of the implant procedure itself. This potential was first identified when prostate cancer patients who underwent TURP were discovered to have a high risk of developing metastatic disease.104 More recent data have demonstrated that patients undergoing radical prostatectomy are also at high risk for spreading active cancer cells into the normal circulation.105 This potential threat is eliminated with the sequential implant-boost approach, because the external radiation has sterilized the peripheral field prior to the insertion of implant needles. Our combined approach (namely, IMRT followed by brachytherapy), in addition to deactivating cancer cells prior to needle insertion, has resulted in minimal complications compared to the use of seeds followed by external radiation in the studies cited. Cure rates Summary of 10 year results During the last ten years, brachytherapy has progressed to the point that it has become the treatment of choice for the majority of patients with clinically localized prostate cancer. Medicare data indicate the number of brachytherapy procedures performed annually now exceeds the number of prostatectomies, which peaked in the early 1990s (Figure 16.21). The trend in favor of seeding has been encouraged by the growing body of literature regarding tumor control rates. The majority of the published series, including my own, have reported brachytherapy results equal to or superior to both radical surgery and conventional external radiation therapy, with significantly lower complication rates.

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As summarized here, my personal series dates from 1991 with 103Pd and supplemental external radiation, utilizing three-dimensional conformal radiation therapy (3D-CRT).54 A total of 175 consecutive patients with stage T2a-T3 prostate cancer were treated from 1991 through 1995. Each patient had at least one of the following adverse

Figure 16.21 CMS Medicare data: seeds vs radical prostatectomy (1996– 2001). (Reproduced courtesy of Theragenics Corporation.) risk factors: stage≥T2b (27 patients T2b, 83 patients T2c, 60 patients T3 as per the fourth edition of the American Joint Committee on Cancer Manual for Staging of Cancer); PSA≥15 ng/mL (74 patients); Gleason score 7–10 (68 patients); and/or elevated PAP (53 patients): 77% of patients had two or more high risk features. Enzymatic acid phosphatase was determined using the method of Roy and colleagues.106 Because interobserver variability in Gleason grading is a matter of concern, slides for the majority of patients were reviewed by a single, highly regarded pathologist (Dr Lawrence True at the University of Washington). Patients whose biopsy slides could not be reviewed were not included in the statistical analysis of Gleason score. Patients received median 4140 cGy 3D-CRT to a limited pelvic field followed by 103 Pd boost (minimum peripheral dose 8000–9000 cGy, median seed activity 1.4 mCi). The clinical target volume was drawn approximately 0.5–1.0cm anterolaterally to the TRUS prostate margin. Patients received neo-adjuvant or adjunctive hormones, median duration 4 months (maximum 6 months). Biochemical failure was defined as a serum PSA level greater than 0.2 ng/mL. Biochemical success was analyzed using a posttreatment PSA of ≤0.2 ng/mL. Patients whose PSA plateaued at greater than 0.2 were scored as failures. Freedom from failure was calculated by the method of Kaplan-Meier. The overall actuarial freedom from biochemical failure at 10 years was 79%. Median follow-up was 7.3 years. Using a log rank multivariate analysis, the strongest predictor of failure was elevated PAP (p=0.003), followed by PSA (p=0.06), Gleason score (p=0.08), and stage (p=0.14). Morbidity was limited to temporary RTOG grade 1–2 urinary symptoms. One patient who had both a TUIP and TURP posttreatment developed low volume stress incontinence. No patient developed rectal ulceration. No patient was documented to have local failure by prostatic biopsy at the time of PSA rise. Hormonal therapy conferred no

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significant advantage although those patients receiving hormones had the most adverse features.

Table 16.4 Long term outcomes after treatment with EBRT and 103Pd for patients with higher risk prostate carcinoma107 ■ Material and methods; 1991–1995 161 consecutive patients: clinical stage was not included in risk stratification to avoid clinician subjectivity, ■ Only one patient had a staging pelvic lymphadenectomy. ■ Patients were followed at 3, 6, and 12 months, and every 6–12 months thereafter, ■ Definition of biochemical success: PSA≤0.2 mg/mL ■ Follow-up prostatic biopsies were performed only on failing patients. ■ All data independently re-reviewed, including slides (single pathologist: Dr Lawrence True) at the University of Washington, Seattle. ■ Patient characteristics ■ Mean PSA: 18.3. ■ Median PSA: 14.1. ■ 51 patients had elevated enzymatic PAPs (>2.5 U). ■ Median age: 67 (range: 45–80). Other Follow-up: 7.3 years median (minimum 5 years). 118 patients followed beyond 5 years. 48 patients received a median of 4 months (range: 2–8 months) hormonal ablation. ■ Results ■ 79% overall actuarial freedom from biochemical progression at 10 years using strict PSA nadir of ≤0.2 mg/mL (Freedom from failure calculated by method of KaplanMeier. Differences between groups were determined by the log rank method.) ■ Treatment related morbidity was limited to temporary RTOG grade 1–2 symptoms. No patient experienced RTOG grade 3–4 toxicity. ■ All failing patients underwent prostatic biopsies: No pathologically documented local failure, nor any clinical evidence of local failure. ■ Androgen ablation did not affect the failure rate (p=0.48), although these patients had at least 2 out of 3 adverse features (excluding stage). ■ PAP was the strongest predictor of long term biochemical failure. (p=0.0001), followed by PSA (p=0,04) and Gleason score. (p=0.13) using a log rank multivariate regression method. EBRT, external beam radiotherapy; PSA, prostate-specific antigen; PAP, prostate phosphate acid phosphatase; RTOG, Radiation Therapy Oncology Group.

Biochemical freedom from failure using combined 3D-CRT or IMRT and 103Pd boost for clinically localized high risk prostate cancer is quite high even when using strict PSA nadirs. Morbidity has been very acceptable. Despite the aggressive nature of the study group, with follow-up prostate biopsies performed on all failing patients, there was no

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pathological documentation of local failure; nor was there clinical evidence of local failure. These results were consistent with those in my most recent published series (2003) (Table 16.4, Figures 16.22–16.24).107 Considering the increased likelihood of biochemical failure in patients with an elevated pretreatment PAP and other high risk features (eg Gleason 8–10, PSA>20), with these patients we have begun adding an additional 540 to 1440 cGy to the periprostatic tissue, blocking the implant to the 1000 cGy isodose line. At the time of writ-ing, we have data out to 12.5 years, with 8 year median follow-up and results are actually improving to a point in excess of 80% biochemical disease-free survival. Comparing modalities No modern randomized studies comparing brachyther-apy, radical surgery, and external radiation have been performed. Instead, we rely on uncontrolled retrospective comparisons using PSA categories to stratify patient groups and compare the effectiveness of the various modalities. This represents a fairly reasonable form of analysis, given the overall prognos-tic consistency between institutions since the advent of PSA (Zietman,108 Zagars109). It should be emphasized that we are evaluating reported data and not mere opinions. When comparing brachytherapy with radical surgery in the PSA era, findings have been consistent when grouping patients in low, intermediate, and high risk categories. With a follow-up of 10 years or longer, both prostatectomy and seeding appear to be effective in 80% to 90% of patients with low tumor burdens (low PSAs), as reported by teams from the leading specialty centers. It is probably fair to say that with low risk favorable tumors (PSA<10, Gleason score≤6, clinical stage T2a or less) the two modalities are essentially comparable. But with intermediate and high risk patients, the data now appear to favor brachytherapy markedly over both radical surgery and conformal radiation therapy (3DCRT). Patients with greater tumor burden (PSA>10) have a high risk for biochemical failure with either prostat-ectomy or 3D-CRT. Indeed, it is with the higher risk groups that the results obtained with surgery and con-ventional external radiation have deteriorated to the point of being woefully unacceptable. The lack of any plateau in the disease-free survival curves of surgery patients with a pretreatment PSA above 10 is especially striking coming from leading institutions like Johns Hopkins,110 the University of Pennsylvania,111 and Brigham (Figures 16.25–16.26).112,113 Conclusions With cure rates at 80% and higher, brachytherapy is proving to be the only reasonable choice for intermediate and high risk patients at whatever age they are treated. A able plateaux of disease-free survival with implants alone number of investigators have demonstrated highly favor-or when combining brachytherapy with supplemental EBRT.79–81,107,114–117 In addition, a prospective randomized multicenter trial comparing palladium-103 brachytherapy with or without supplemental beam radiation is reporting no increased bladder-urethral-rectal toxicities with the combined treatment group.118

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With the emergence of brachytherapy as the new gold standard treatment for clinically localized prostate cancer, there will continue to be naysayers in the surgical community who will want longer term follow-up before accepting the procedure as meeting that standard of care. As we are now arriving at the benchmark of 15 year followup, the argument appears to be on the verge of resolution, with a growing number of brachytherapy teams reporting remarkably effective tumor control rates and favorable morbidity. It is safe to say that as far as the foreseeable future, the procedure is here to stay and its quality assurance is destined to become even more reliable as more proficient operators join the field.

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Figure 16.22 (a, b) Freedom from biochemical progression for 161 patients with PSA>10 or Gleason

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score≥7 treated with 103Pd plus 41 Gy beam radiation.107

Figure 16.22 (c) Freedom from biochemical progression for 161 patients with PSA>10 or Gleason score≥7 treated with 103Pd plus 41 Gy beam radiation.107

Figure 16.23 Likelihood of biochemical failure (rising prostatespecific antigen) by preoperative serum PSA.110 (Data derived from the

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series by Dr Patrick Walsh, Johns Hopkins Hospital, 1982–2001.)

Figure 16.24 The likelihood of biochemical failure (rising prostatespecific antigen) by preoperative biopsy Gleason score (a) and by pathologic Gleason score (b). (Data derived from the series by Dr Patrick Walsh, Johns Hopkins Hospital, 1982– 2001.)

Figure 16.25 Likelihood of biochemical failure (rising prostatespecific antigen) by postoperative pathologic stage and margin status. EPE, extraprostatic extension. OC,

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organ confined; SM, surgical margins; SV, seminal vesicles; LN, lymph nodes. (Data derived from the series by Dr Patrick Walsh, Johns Hopkins Hospital, 1982–2001.)

Figure 16.26 Permanent prostate brachytherapy compared to prostatectomy.119 (a) Biochemical disease-free survival (bNED) for

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selected prostatectomy and brachytherapy series,120,121 stratified by pretreatment prostate-specific antigen level, (b) Biochemical disease-free survival (bNED) for selected prostatectomy,119 and brachytherapy series,120,121 stratified by Gleason score of at least 5. References 1. Peschel RE, Chen Z, Roberts K, Nath R. Long-term complications with prostate implants: iodine-125 vs. palladium-103. Radiat Oncol Investig 1999; 7(5):278–288. 2. Wallner K, Merrick G, True L, et al. 125I versus 103Pd for low-risk prostate cancer: morbidity outcomes from a prospective randomized multicenter trial. Cancer J 2002; 8(1):67–73. 3. Nag S, Sweeney PJ, Wienthjes MG. Dose response study of Iodine-125 and Palladium-103 brachytherapy in a rat prostate tumor (NbAl-1). Endocurie/Hypertherm Oncol 1997; 9:97–104. 4. Ling CC, Li WX, Anderson LL, The relative biological effectiveness of 125I and 103Pd. Int J Radiat Oncol Biol Phys 1995; 32:373–378. 5. Ling CC. Permanent implants using Au-198, 103Pd and 125I: radiobiological considerations based on the linear quadratic model. Int J Radiat Oncol Biol Phys 1992; 23(1):81–87. 6. Beyer D, Nath R, Butler W, et al. American Brachytherapy Society recommendations for clinical implementation of NIST-1999 standards for (103)palladium brachytherapy. The clinical research committee of the American Brachytherapy Society. Int J Radiat Oncol Biol Phys 2000; 47(2):273–275. 7. Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial brachytherapy sources: recommendations of the AAPM Radiation Therapy Committee Task Group No. 43. American Association of Physicists in Medicine. Med Phys 1995; 22(2):209–234. [Erratum in: Med Phys 1996; 23(9):1579.] 8. Yu Y, Anderson LL, Li Z, et al. Permanent prostate seed implant brachytherapy: report of the American Association of Physicists in Medicine Task Group No. 64. Med Phys 1999; 26(10):2054–2076. 9. Luse RW, Blasko J, Grimm P. A method for implementing the American Association of Physicists in Medicine Task Group-43 dosimetry recommendations for 125I transperineal prostate seed implants on commercial treatment planning systems. Int J Radiat Oncol Biol Phys 1997; 37(3):737–741. 10. Bice WS, Prestidge BR, Prete JJ, Dubois DE Clinical impact of implementing the recommendations of AAPM Task Group 43 on permanent prostate brachytherapy using 125I. American Association of Physicists in Medicine. Int J Radiat Oncol Biol Phys 1998; 40(5): 1237–1241. 11. Nath R, Meigooni AS, Melillo A. Some treatment planning consideration for 103Pd and 125I permanent interstitial implants. Int J Radiat Oncol Biol Phys 1992; 22:1131–1138. 12. Li Z, Palta JR, Fan JJ. Monte Carlo calculations and experimental measurements of dosimetry parameters of a new 103Pd source. Med Phys 2000; 27:1108–1112. 13. Meigooni AS, Sowards K, Soldano M. Dosimetric characteristics of the InterSource-103 palladium brachytherapy source. Med Phys 2000; 27:1093–1100.

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14. Dicker AP, Lin C-C, Leeper DB, Waterman FM. Isotope selection for permanent prostate implants? An evaluation of 103Pd versus 125I based on radiobiological effectiveness and dosimetry. Semin Urol Oncol 2000; 18(2):152–159. 15. Merkle W. [Colour Doppler transrectal 3D-sonography of the prostate—first experiences]. Aktuel Urol 2002; 33(1):53–57 [In German]. 16. Sauvain JL, Palascak P, Bourscheid D, et al. Value of power doppler and 3D vascular sonography as a method for diagnosis and staging of prostate cancer. Eur Urol 2003; 44(1):21– 30 [Discussion 30–1]. 17. Roy C, Buy X, Lang H, et al. Contrast enhanced color Doppler endorectal sonography of prostate: efficiency for detecting peripheral zone tumors and role for biopsy procedure. J Urol 2003; 170(1):69–72. 18. Cheng S, Rifkin MD. Color Doppler imaging of the prostate: important adjunct to endorectal ultrasound of the prostate in the diagnosis of prostate cancer. Ultrasound Q 2001; 17(3):185– 189. 19. Bates TS, Reynard JM, Peters TJ, Gingell JC. Determination of prostatic volume with transrectal ultrasound: A study of intra-observer and interobserver variation. J Urol 1996; 155(4): 1299–1300. 20. Bazinet M, Karakiewicz PI, Aprikian AG, et al. Reassessment of nonplanimetric transrectal ultrasound prostate volume estimates. Urology 1996; 47 (6):857–862. 21. Rahmouni A, Yang A, Tempany C, Frenkel T. Accuracy of in-vivo assessment of prostate volumes by MRI and transrectal ultrasonography. J Comput Assist Tomogr 1992; 16:935–940. 22. Bartsch G, Egender G, Hubscher H, Rohr H. Sonometrics of the prostate. J Urol 1982; 127:1119–1121. 23. Al-rimawi M, Griffiths DJ, Boake RC, et al. Transrectal ultrasound versus magnetic resonance imaging in the estimation of prostatic volume. Br J Urol 1994; 74(5):596–600. 24. Narayana V, Roberson PL, Winfield RJ, McLaughlin PW. Impact of ultrasound and computed tomography prostate volume registration on evaluation of permanent prostate implants. Int J Radiat Oncol Biol Phys 1997; 39(2):341–346. 25. Kagawa K, Lee WR, Schultheiss TE, et al. Initial clinical assessment of CT-MRI image fusion software in localization of the prostate for 3D conformal radiation therapy. Int J Radiat Oncol Biol Phys 1997; 38(2):319–325. 26. Wallner K, Blasko J, Dattoli MJ. Prostate brachytherapy made complicated, 2nd ed. Seattle, WA: Smart Medicine Press, 2001:4.6. 27. Badiozamani KR, Wallner K, Cavanagh W, Blasko J. Comparability of CT-based and TRUSbased prostate volumes. Int J Radiat Oncol Biol Phys 1999; 43(2):375–378. 28. Badiozamani KR, Wallner K, Sutlief S, et al. Anticipating prostatic volume changes due to prostate brachytherapy. Radiat Oncol Investig 1999; 7(6):360–364. 29. Zaider M, Zelefsky MJ, Lee EK, et al. Treatment planning for prostate implants using magnetic-resonance spectroscopy imaging. Int J Radiat Oncol Biol Phys 2000; 47(4): 1085– 1096. 30. Mizowaki T, Cohen GN, Fung AY, Zaider M. Towards integrating functional imaging in the treatment of prostate cancer with radiation: the registration of the MR spectroscopy imaging to ultrasound/CT images and its implementation in treatment planning. Int J Radiat Oncol Biol Phys 2002; 54(5):1558–1564. 31. Han B, Wallner K, Aggarwal S, et al. Treatment margins for prostate brachytherapy. Semin Urol Oncol 2000; 18(2):137–141. 32. Sethi A, Mohideen N, Leybovich L, Mulhall J. Role of IMRT in reducing penile doses in dose escalation for prostate cancer. Int J Radiat Oncol Biol Phys 2003; 55(4):970–978. 33. Davis BJ, Haddock MG, Wilson TM, et al. Treatment of extraprostatic cancer in clinically organ-confined prostate cancer by permanent interstitial brachytherapy: is extraprostatic seed placement necessary? Tech Urol 2000; 6(2):70–77.

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34. Stock RG, Lo YC, Gaildon M, Stone NN. Does prostate brachytherapy treat the seminal vesicles? A dose-volume histogram analysis of seminal vesicles in patients undergoing combined 103Pd prostate implantation and external beam irradiation. Int J Radiat Oncol Biol Phys 1999; 45(2):385–389. 35. Dattoli MJ, Wallner K, Sorace R, Ting J. Planned extracapsular seed placement using Palladium-103 for prostate brachytherapy. J Brachyther Int 2000; 16:35–43. 36. Rosen MA, Goldstone L, Lapin S, et al. Frequency and location of extracapsular extension and positive surgical margins in radical prostatectomy specimens. J Urol 1992; 148(2 Pt 1):331–337. 37. McNeal JE, Price. HM, Redwine EA, et al. Stage A versus stage B adenocarcinoma of the prostate: morphological comparison and biological significance. J Urol 1988; 139(1):61–65. 38. Sohayda C, Kepulian PA, Levin HS, Klein EA. Extent of extracapsular extension in localized prostate cancer. Urology 2000; 55(3):382–386. 39. Davis BJ, Pisansky TM, Wilson TM, et al. The radial distance of extracapsular extension of prostate carcinoma: implications for prostate brachytherapy. Cancer 1999; 85:2630–2637. 40. Willins J, Wallner K. Time dependent changes in CT-based dosimetry of 125I prostate brachytherapy. Radiat Oncol Invest 1998; 6:157–160. 41. Waterman FM, Yue N, Corn BW, Dicker AP. Edema associated with 125I or 103Pd prostate brachytherapy and its impact on post-implant dosimetry: an analysis based on serial CT acquisition. Int J Radiat Oncol Biol Phys 1998; 41(5):1069–1077. 42. Speight JL, Shinohara K, Pickett B, et al. Prostate volume change after radioactive seed implantation: possible benefit of improved dose volume histogram with perioperative steroid. Int J Radiat Oncol Biol Phys 2000; 48(5):1461–1467. 43. Merrick GS, Butler WM. Modified uniform seed loading for prostate brachytherapy; rationale, design, and evaluation [Review]. Tech Urol 2000; 6(2):78–84. 44. Merrick GS, Butler WM, Dorsey AT, et al. Seed fixity in the prostate/periprostatic region following brachytherapy. Int J Rad Oncol Biol Phys 2000; 46:215–220. 45. Merrick GS, Butler WM, Dorsey AT, et al. Influence of prophylactic dexamethasone on edema following prostate brachytherapy. Tech Urol 2000; 6(2):117–122. 46. Merrick GS, Butler WM, Lief JH, Dorsey AT. Temporal resolution of urinary morbidity following prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 47(1):121–128. 47. Feigenberg SJ, Wolk KL, Yang C-H, et al. Celecoxib to decrease urinary retention associated with prostate brachytherapy. Brachytherapy 2; 2003:103–107. 48. Narayana V, Roberson PL, Winfield RJ, Kessler ML. Optimal placement of radioisotopes for permanent prostate implants. Radiology 1996; 199(2): 457–460. 49. Wallner K, Roy J, Harrison L. Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal 125I prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995; 32(2):465–471. 50. Maguire PD, Waterman FM, Dicker AP. Can the cost of permanent prostate implants be reduced? An argument for peripheral loading with higher strength seeds. Tech Urol 2000; 6(2):85–88. 51. Shearer RJ, Davies JH, Gelister JS, Dearnaley DP. Hormonal cytoreduction and radiotherapy for carcinoma of the prostate. Br J Urol 1992; 69(5):521–524. 52. Forman JD, Kumar R, Haas G, Montie J. Neoadjuvant hormonal downsizing of localized carcinoma of the prostate: effects on the volume of normal tissue irradiation. Cancer Invest 1995; 13(1):8–15. 53. Zelefsky MJ, Leibel SA, Burman CM, Kutcher GJ. Neoadjuvant hormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys 1994; 29(4):755–761. 54. Dattoli MJ, Sorace RA, Cash J, Wallner K. Biochemical failure rates following combination external beam radiation and Palladium-103 boost for clinically localized high risk prostate cancer: 10 year results. Int J Rad Oncol Biol Phys 2002; 52(2)(suppl. 1):38.

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55. Lattanzi J, McNeely S, Hanlon A, et al. Daily CT localization for correcting portal errors in the treatment of prostate cancer. Int J Rad Oncol Biol Phys 1998; 41:1079–1086. 56. Dattoli MJ, Wallner K. A simple method to stabilize the prostate during transperineal prostate brachytherapy. Int J Rad Oncol Biol Phys 1997; 38:341–342. 57. Steinfeld AD, Donahue BR, Plaine L. Pulmonary embolization of iodine-125 seeds following prostate implantation. Urology 1991; 37:149–150. 58. Tapen EM, Blasko JC, Grimm PD, et al. Reduction of radioactive seed embolization to the lung following prostate brachytherapy. Int J Rad Oncol Biol Phys 1998; 42:1063–1067. 59. Tincher SA, Kim RY, Ezekiel MP, et al. Effects of pelvic rotation and needle angle on public arch interference during transperineal prostate implants. Int J Rad Oncol Biol Phys 2000; 47:361–363. 60. Wang H, Wallner K, Sutlief S, et al. Transperineal brachytherapy in patients with large prostate glands. Int J Cancer 2000; 90:199–205. 61. Stock RG, Stone NN, Tabert A, et al. A dose-response study for 125I implants. Int J Rad Oncol Biol Phys 1998; 41:101–108. 62. Stock RG, Stone NN, Kao J, et al. The effect of disease and treatmentrelated factors on biopsy results after prostate brachytherapy. Cancer 2000; 89:1829–1834. 63. Roy JN, Wallner K, Harrington PJ, et al. A CT-based evaluation method for permanent implants: Application to prostate. Int J Radiat Oncol Biol Phys 1993; 26:163–169. 64. Merrick GS, Butler WM, Dorsey AT, Lief JH. Potential role of various dosimetric quality indicators in prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999; 44:717–724. 65. Merrick GS, Butler WM, Dorsey AT, et al. Rectal dosimetric analysis following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999; 43(5):1021–1027. 66. Merrick GS, Butler WM, Lief JH, et al. Efficacy of sildenafil citrate in prostate brachytherapy patients with erectile dysfunction. Urology 1999; 53(6):1112–1116. 67. Gelblum DY, Potters L. Rectal complications associated with transperineal interstitial brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2000; 48(1):119–124. 68. Han B, Wallner K. Dosimetric and radiographic correlates to prostate brachytherapy-related rectal complications. Int J Cancer 2001; 96(6):372–378. 69. Howard A, Wallner K, Han B, et al. Clinical course and dosimetry of rectal fistulas after prostate brachytherapy. J Brachyther Int 2001; 17:37–42. 70. Bice WS, Prestidge BR, Grimm PD, et al. Centralized multiinstitu-tional postimplant analysis for interstitial prostate brachytherapy. Int J Rad Oncol Biol Phys 1998; 41:921–927. 71. Stone NN, Stock RG. Complications following permanent prostate brachytherapy. Eur Urol 2002; 41(4):427–433. 72. Kollmeier MA, Stock RG, Stone NN. Urinary symptomatology and incontinence following post-brachytherapy transurethral re-section of the prostate. Int J Radiat Oncol Biol Phys 2003; 57(2 suppl):S439-S440. 73. Merrick GS, Butler WM, Wallner KE, et al. Long-term urinary qual-ity of life after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2003; 56(2):454–461. 74. Merrick GS, Wallner K, Butler WM. Management of sexual dysfunc-tion after prostate brachytherapy [Discussion 62, 67–70, 73]. Oncology (Huntingt). 2003; 17(1):52–62. 75. Kleinberg L, Wallner K, Roy J, et al. Treatment-related symptoms during the first year following transperineal 125I prostate implanta-tion. Int J Radiat Oncol Biol Phys 1994; 28(4):985–990. 76. Landis D, Wallner K, Locke J, et al. Late urinary function after prostate brachytherapy. Brachytherapy 2002; 1:21–26. 77. Sherertz T, Wallner K, Wang H, Sutlief S, et al. Long-term urinary function after transperineal brachytherapy for patients with large prostate glands. Int J Radiat Oncol Biol Phys 2001; 51(5):1241–1245.

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78. Stone RG, Ratnow ER, Stock NN. Prior transurethral resection does not increase morbidity following real-time ultrasound-guided prostate seed implantation. Tech Urol 2000; 6(2): 123– 127. 79. 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. 80. Merrick GS, Butler WM, Tollenaar BG, et al. The dosimetry of prostate brachytherapy-induced urethral strictures. Int J Radiat Oncol Biol Phys 2002; 52(2):461–468. 81. Merrick GS, Butler WM, Wallner KE, et al. The importance of radi-ation doses to the penile bulb vs. crura in the development of postbrachytherapy erectile dysfunction. Int J Radiat Oncol Biol Phys 2002; 54(4):1055–1062. 82. Blasko JC, Ragde H, Grimm PD. Transperineal ultrasound-guided implantation of the prostate: morbidity and complications. Scand J Urol Nephrol Supply 1991; 137:113–118. 83. Wallner K, Lee H, Wasserman S, Dattoli M. Low risk of urinary incontinence following prostate brachytherapy in patients with a prior transurethral prostate resection. Int J Radiat Oncol Biol Phys 1997; 37(3):565–569. 84. 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(3):387–394. 85. Shipley WU, Zietman AL, Hanks GE, et al. Treatment related sequelae following external beam radiation for prostate cancer: a review with an update in patients with stages T1 and T2 tumor. J Urol 1994; 152(5 Pt 2):1799–1805. 86. Teshima T, Hanks GE, Hanlon AL, et al. Rectal bleeding after conformal 3D treatment of prostate cancer: time to occurrence, response to treatment and duration of morbidity. Int J Radiat Oncol Biol Phys 1997; 39(1):77–83. 87. Hu L, Wallner K. Clinical course of rectal bleeding following 125I prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998; 41(2):263–265. 88. Hu L, Wallner K. Urinary incontinence in patients who have a TURP/TUIP following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998; 40 (4):783–786. 89. Zinreich ES, Derogatis LR, Herpst J, et al. Pretreatment evaluation of sexual function in patients with adenocarcinoma of the prostate. Int J Radiat Oncol Biol Phys 1990; 19(4): 1001– 1004. 90. Banker RL. The preservation of potency after external beam irradiation for prostate cancer. Int J Radiat Oncol Biol Phys 1988; 15(1):219–220. 91. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151(1):54–61. 92. 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. 93. Kim HL, Stoffel DS, Mhoon DA, Brandler CB. A positive caver map response poorly predicts recovery of potency after radical prostatectomy. Urology 2000; 56(4):561–564. 94. Walsh PC, Donker PA. Impotence following radical prostatectomy: Insight into etiology and prevention. J Urol 1982; 167:1005–1010. 95. Merrick GS, Butler WM, Dorsey AT, et al. A comparison of radiation dose to the neurovascular bundles in men with and without prostate brachytherapy-induced erectile dysfunction. Int J Radiat Oncol Biol Phys 2000; 48:1069–1074. 96. Pickett B, Fisch BM, Weinberg V, Roach M. Dose of radiation received by the bulb of the penis correlates with risk of impotence after three-dimensional conformal radiotherapy for prostate cancer. Urology 2001; 57(5):955–959. 97. Roach M, Winter K, Michalski J, et al. Mean dose to the bulb of the penis correlates with risk of impotence at 24 months: preliminary analysis of Radiation Therapy Group (RTOG) phase I/II dose escalation trial 9406. Int J Radiat Oncol Biol Phys 2000; 48:2104. 98. Pickett B, Fisch BM, Wienberg V, Roach M. Dose to the bulb of the penis is associated with the risk of impotence following radiotherapy for prostate cancer. Int J Radiat Oncol Biol Phys 1999; 45(suppl):263.

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99. Pierce LJ, Whittington R, Hanno PM, et al. Pharmacologic erection with intracavernosal injection for men with sexual dysfunction following irradiation: a preliminary report. Int J Radiat Oncol Biol Phys 1991; 21(5):1311–1314. 100. Zelefsky MJ, McKee AB, Lee H, Leibel SA. Efficacy of oral sildenafil in patients with erectile dysfunction after radiotherapy for carcinoma of the prostate. Urology 1999; 53(4):775– 778. 101. Iversen P, Rasmussen F, Holm, HH, Scand J Urol Nephrol Suppl 1991; 138:109–115. 102. Patel J, Worthen R, Abadir R, et al. Late results of combined iodine-125 and external beam radiotheraphy in carcinoma of prostate. Urology 1999; 36:27–30. 103. Zeitlin SI, Sherman J, Raboy A, et al. High dose combination radio-therapy for the treatment of localized prostate cancer. J Urol 1998; 160:91–96. 104. McGowan DG. The adverse influence of prior transurethral resec-tion on prognosis in carcinoma prostate treated by radiation ther-apy. Int J Radiat Oncol Biol Phys 1980; 6:1121– 1126. 105. Ogawa O, Iinuma M, Sato K, et al. Circulating prostate-specific anti-gen mRNA during radical prostatectomy in patients with localized prostate cancer: with special reference to neoadjuvant hormonal therapy. Urol Res 1999; 27:291–296. 106. Roy AV, Brower ME, Hayden JE. Sodium thymolphthalein monphosphate: a new acid phosphatase substrate with greater specificity for the prostatic enzyme in serum. Clin Chem 1998; 17:1093–1102. 107. Dattoli MJ, Wallner K, True L, et al. Long-term outcomes after treatment with external beam radiation therapy and palladium 103 for patients with higher risk prostate carcinoma: influence of prostatic acid phosphatase. Cancer 2003; 97:979–983. 108. Zietman AL, Coen JJ, Dallow KC, Shipley WU. The treatment of prostate cancer by conventional radiation therapy: an analysis of long-term outcome. Int J Radiat Oncol Biol Phys 1995; 32:287–292. 109. Zagars GK. Prostate-specific antigen as an outcome variable for T1 and T2 prostate cancer treated by radiation therapy. J Urol 1994; 152:1786. 110. Khan MA, Partin AW. Management of high-risk populations with locally advanced prostate cancer. Oncologist 2003; 8(3):259–269. 111. D’Amico AV, Whittington R, Malcowicz BD, et al. Predicting prostate specific antigen outcome preoperatively in the prostate specific antigen era. J Urol 2001; 116:2185–2188. 112. D’Amico AV, Chen MH, Oh-Ung J, et al. Changing prostate-specific antigen outcome after surgery pr radiotheraphy for localized rostate cancer curing the prostate-specific antigen era. Int J Radiat oncol Biol Phys 2002; 54:436–441. 113. D’Amico AV, Whittington R, Malcowicz SB, et al. Biochemical outcome after radical prostatectomy or external beam radiation for patients with clinically localized prostate carcinoma in the prostate specific antigen era. Cancer 2002; 95:281–286. 114. Blasko JC, Mate T, Sylvester JE, et al. Brachytherapy for carcinoma of the prostate: techniques, patient selection, and clinical outcomes. Semin Radiat Oncol 2002; 12(1):81–94. 115. Sylvester JE, Blasko JC, Grimm PD, et al. Ten-year biochemical relapse-free survival after external beam radiation and brachytherapy for localized prostate cancer: the Seattle experience. Int J Radiat Oncol Biol Phys 2003; 57(4):944–952. 116. Martinez A, Gonzalez J, Spencer W, et al. Conformal high dose rate brachytherapy improves biochemical control and cause specific survival in patients with prostate cancer and poor prognostic factors. J Urol 2003; 169(3):974–979. 117. Ragde H, Grado GL, Nadir BS. Brachytherapy for clinically localized prostate cancer: thirteen-year disease-free survival of 769 consecutive prostate cancer patients treated with permanent implants alone. Arch Esp Urol 2001; 54(7):739–747. 118. Ghaly M, Wallner K, Merrick G, et al. The effect of supplemental beam radiation on prostate brachytherapy-related morbidity: morbidity outcomes from two prospective randomized multicenter trials. Int J Radiat Oncol Biol Phys 2003; 55:1288–1293.

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17 Ultrasound-guided 103Pd prostate brachytherapy Jerrold Sharkey, Zucel Solc, William Huff, Raymond J Behar, Stanley D Chovnick, Ramon Perez, Juan N Otheguy, and Richard I Rabinowitz Introduction In this chapter, we describe our improved and evolving techniques in palladium-103 (Theraseed®) brachytherapy for patients with stage T1 and T2 adenocarcinoma of the prostate. We began this system in 1991.1 With our technique, brachytherapy is an effective, low morbidity, cost effective treatment for adenocarcinoma of the prostate. While both iodine-125 (125I) and palladium103 (103Pd) have been used extensively over the last 14 years,2 our opinion is that 103Pd (Theraseed®) provides a more rapid initial dose and therefore may give better control of higher Gleason grade tumors. We have assessed and highly refined our methodology for 103Pd brachytherapy in patients with prostate cancer. Standard brachytherapy techniques3 were modified to include a combination of preplanning with real-time adjustment, placing all needles at the same time to minimize prostate movement, using monitored anesthesia control (MAC), sedation during preoperative volume study and cystoscopy, and several other small but important changes. At two and six years posttreatment, 91–98% of patients had not experienced prostate-specific antigen (PSA) failure, by the American Society of Therapeutic Radiology and Oncology (ASTRO) definition. Biopsies were negative in 91% at two years. In our practice we used 103Pa (Theraseed®) exclusively for stage T1 and T2 prostate cancer. Retrospective reviews of pathology grades have revealed undergrading of original Gleason scores, which makes the theoretical advantages of 103P’s higher initial dose even more significant. Blasko has reported that 103Pd is as effective as 125I in patients with lower Gleason scores, and no difference in patient outcomes (pers comm 1999). Using 103 Pd, a calculated dose of 13 500 cGy can be delivered to the periphery of the gland, while conventional external beam radiotherapy (EBRT), and even the newer intensity modulated radiotherapy (IMRT) technology delivers only 6600–7800 cGy to the prostate and surrounding tissues. The short range of palladium radiation reduces the serious bladder and bowel complications that can occur after EBRT, and the risks of incontinence and impotence are less than that of radical prostatectomy.4,5 Also, postoperative irritative symptoms appear to have a shorter duration when compared to 125I because of the shorter half-life of radioactivity.6

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Methods As part of our continuing efforts to improve results of 103Pd brachytherapy over the last several years, we have modified our techniques for seed implantation, seed activity, and total activity implanted. Our current procedure is a significant modification of techniques and treatment described by Blasko,3 and Stone et al 7–10 in that we combine preplanning with real-time adjustment, place all the needles at once to minimize prostate movement, and use monitored anesthesia control (MAC) sedation for the preoperative volume study and cytoscopy.11 Specifically, our revised methods include: 1. The use of anesthesia for the preplanning ultrasound volume study with cystoscopy at the same sitting 2 weeks prior to the implant. The patient is placed in precisely the same extended lithotomy position he will be in at the time of the actual implant. 2. Use of a biplanar probe for both the preoperative volume study and the implantation procedure itself. 3. Increased seed activity from 2.0 to 2.25 U/seed (NIST 2000 equivalent). 4. Increased number of seeds used by approximately 25–30% since 1992 (i.e. for a typical 35 cc gland, the number of seeds has increased from approximately 75 to 95 seeds). 5. Placement of all needles first, rather than one row or needle at a time before seed loading. 6. Use of additional seeds to the tumor area or if intraoperative volume changes occur during the implant procedure. 7. The presence of a team comprising: radiation physicist, radiation oncologist, specially trained prostate ultrasound technician and urologist in the operating room (OR) during the implant procedure. 8. Careful consideration of pubic arch interference (PAI) using a preoperative computed tomography (CT) scan of the pelvis if indicated. 9. Use of neo-adjuvant Lupron® with or without antiandrogen to downsize the gland when the volume is over 50 cc or PAI is demonstrated. 10. More extensive and careful preoperative evaluation of bladder outlet obstruction and treating it preoperatively rather than postoperatively is critical. 11. During the planning process placement of a foley catheter allows for better recognition of the urethra and transurethral resection of the prostate (TURP) defects to allow for ‘urethral sparing’. 12. Use of sharper, disposable needles for better visualization of needles and with less trauma to the prostate. 13. Use of a fixed stand to stabilize the ultrasound probe and grid during the procedure as well as for the preoperative volume study. From 1991 through March 2004 we have treated 1442 patients with 103Pd (Theraseed®) brachytherapy exclusively. The mean age of the patients was 72.0 years, and about one quarter (25.1%) had undergone TURP before receiving brachytherapy. This TURP might have been done years earlier for relief of bladder outlet obstruction before a diagnosis of cancer was made. The other reasons for preoperative TURP was if downsizing was not effective in getting the gland below 50 cc after 6–9 months or because of severe bladder

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outlet obstructive symptoms associated with residual urine. We do a modified TURP, carefully leaving tissue near the veru/sphincter area and not carrying resection down to the capsule. This leaves enough retained tissue to hold seeds without the obstruction remaining. We then wait three months for complete healing (confirmed visually by cystoscopy) and regrowth of a healthy lining in the prostatic urethra. The average preoperative PSA was 7.46 ng/mL. Gleason scores ranged from 2 to 10, although more than two thirds (71%) of the patients had scores <7. Standard pretreatment assessments Standard staging studies, digital rectal examinations, and PSA tests were used to confirm that the disease is organconfined. Prostate ultrasound was used to determine prostate size. Each patient had 12–16 prostate mapping biopsies and 2–4 seminal vesical biopsies (1–2 per side). Mapping means that each core is placed in a separate test tube and labeled for location in the prostate (i.e. left lateral base, left apex, etc.). Additionally, a bone scan and pelvic CT scan are done. Where prostate glands are larger than 50 cc, preoperative neoadjuvant hormonal therapy (NHT) is administered until the prostate size decreases to <45 cc, as determined by transrectal ultrasound (TRUs). In patients with any degree of bladder outlet obstruction, we consider it critical that this be addressed and resolved before, rather than after, seed implantation to avoid postoperative urinary retention, increased symptomatic irritation from radiation, and the need to do a TURP after seed implantation. The incidence of incontinence is much higher when a TURP is done postimplantation.12 Therefore, before seed implantation, we identify and correct any bladder outlet obstruction. American Urological Association (AUA) symptom score, residual urine, and uroflow are assessed, as are complex urodynamics when necessary. When significant obstruction is discovered, we perform a transurethral incision of the prostate (TUIP) or TURP (25.1% of the patients) and delay implantation for three months to allow time for healing. At the time of the preoperative volume study a cystoscopy is carried out, and mucosal healing must be complete (visually by cystoscopy) or the implant is delayed. If healing is not complete superficial urethral necrosis can occur several months later after radiation from the effects of the seeds on the newly formed and usually ischemic mucosa that follows TURP. We generally treat milder bladder outlet obstruction with alpha-blockers for several weeks before and after brachytherapy to avoid the need for TURP and to prevent postoperative voiding problems. Preoperative volume study An accurate preoperative volume study (by the urology ultrasound technician), is essential because it determines the geometric volume to be targeted. The seed pattern, which determines how successfully the gland is covered by the actual implantation, is based on this study. Patients have the preoperative prostate volume study in the operating room in the lithotomy position.

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Patients receive modified anesthesia control (MAC) with Diprivan® (propofol), Sublimaze® (fentanyl citrate), and Versed® (midazolam hydrochloride). We feel sedation is necessary because variations in apparent prostate shape and length have been observed between the day of the preoperative study and the intraoperative volume study in patients who have not been sedated. Such changes can be caused by varying degrees of pelvic muscle relaxation and a different lithotomy position; both of which occur when a patient is uncomfortable without sedation. A simultaneous cystoscopy to rule out bladder pathology and urethral strictures, and to determine the degree of bladder outlet obstruction is also performed. It is not uncommon for us to discover unsuspected bladder tumors or urethral strictures at this preimplant cystoscopy. A stepping and stabilizing device is used with the ultrasound probe in both the preoperative volume study and the actual implantation procedure to improve the stability and accuracy and decrease set-up time. Allen stirrups are calibrated for position setting of the patient’s lithotomy position and this is recorded so that the patient is placed in this exact position setting during both volume study and implantation procedure. Fleet® enemas are given the evening before and the morning of the study. The patient is placed in the lithotomy position with buttocks flat, horizontal, and parallel to the floor. A foley catheter is placed to define the urethra, and indicates the location of the bladder neck. A transrectal biplanar ultrasound probe is placed parallel to the anterior rectal wall and the longitudinal mode is used to check this alignment. This is important to prevent needles from passing through the rectal wall in order to reach the base of the gland. A longitudinal ultrasound image is obtained at the longest cephalad-caudal axis to determine the number of transverse slices of the prostate. Then transverse ultrasound images are recorded from the base to the apex of the gland at 5 mm intervals. We label each image so that maximum information is available to the physicist and radiation oncologist. The location of the positive biopsies, Gleason score, and PSA are also provided to both physicist and radiation oncologist. The prostate gland, the urethra, the bladder neck and any TURP defects are outlined in each slice, which enables the physicist to devise a seed pattern that avoids excessively high doses to these areas. Because pubic arch interference can prevent needles being placed anteriorly or laterally in men with large glands and narrow pelvic openings, we obtain pelvic CTs to evaluate this interference when the gland is >50 cc, or in any situation where we suspect a problem might occur. If the interference involves a major part of the gland, then implantation is not done and external radiation is offered to the patient. If this is a minor interference we can change the angle of the probe at the end of the procedure to implant the problem areas and avoid the obstruction to needle passage by the pelvic bones. Because of improved ultrasound techniques (i.e. the use of the longitudinal mode and a foley catheter), we can localize the bladder neck, the base of the gland and the urethra, without the need for fluoroscopy. As a result of accurate visualization, seeds are rarely retrieved in the postoperative cystoscopy, and, because of the disposable needles and rapid placement of all needles, there is minimal swelling due to hematoma in or around the prostate.

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Planning procedures based on the volume study 1. The planning process begins with the radiation physicist and the radiation oncologist reviewing both the transverse and the longitudinal images of the volume study, and the total number of cuts to be used are agreed on. 2. The prostate and the urethra are entered as structures in the planning program. 3. A three-dimensional (3D) modified peripheral loading philosophy is used to determine the seed pattern. It is recognized that the base and apex of the gland are part of the periphery, and therefore these planes are usually fully loaded. In addition, any needle, or portion of a needle, which is at the periphery of the gland is uniformly loaded with seeds. For 125I, the spacing is always 1 cm in these needles. However, because of the shorter range of the 103Pd photons, it is sometimes necessary to place the 103Pd seeds cm apart in order to maintain the desired margin around the gland. In general, the interior needles have a seed at base and apex, and just enough seeds within the gland to maintain the desired dose throughout the volume of the gland. The urethra as well as any TURP defect is welldefined and clearly marked in each cut. Therefore, it is a simple matter to avoid placing seeds near these radiationsensitive structures. 4. Williamson et al have published a detailed review of the NIST 1999 calibration standards as they apply to 103Pd dosimetric calculations.13 Based on that analysis, they concluded that prior to 1997,103Pd monotherapy patients were receiving a dose of 120 Gy, and after 1997 the dose was 135 Gy. When we converted all calculation parameters to conform to the new standard, we continued to calculate the dose to the gland at 135 Gy for monotherapy, and 105 Gy for patients who received external beam radiation. In recent years we have reimplanted 42 seed failures. The dose for these reseeds is calculated at 110 Gy. From 1991 to 1993, the activity per seed was 2.0 U (NIST 2000 equivalent), with total implanted activity as determined by the original Sloan-Kettering nomograms and a formula presented by Anderson et al.14 In October 1993, we increased the target seed count by 15% after a review of postoperative CTs revealed difficulty achieving consistently adequate coverage with the number of seeds predicted by this nomogram. In October 1996, we again increased the total target activity, by increasing the number of seeds and by using seeds of 2.25 U. For a typical gland of 35 cc, with an average dimension of 3.8 cm, this would correspond to an increase in an implanted activity from 150 U (NIST 1999 equivalent) in 1992, to 215 U in 1999. 5. The seed pattern for a particular patient is essentially independent of the prescribed dose. The desired dose is obtained by varying the seed activity from 2.25 U for monotherapy to 1.75 U for combined therapy, and 1.85 U for reseeds. 6. The evaluation of the final dose distribution is based first on a visual inspection of both the plane-by-plane isodose distribution, and the 3D rendering of the dose cloud to insure that the gland is covered with a suitable margin (3–5 mm) around the lateral lobes, and somewhat less on the rectal side. The final evaluation is based on the dose-volume histogram (DVH) with the following criteria:

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(a) The percentage of the gland receiving more than 150% of the prescribed dose (V150) should be between 60% and 70%. This high dose region should be confined mainly to the lateral lobes where the higher probability of cancer exists. (b) The V150 for the urethra and/or the TUR defect should be less than 0.5%. (c) For reseed patients, the V150 for the urethra should be less than 1%, if possible. This planning process could be done in real-time in the OR with little or no change in philosophy. Doing it approximately two weeks prior to the actual implant, however, allows the physicist to determine in advance the exact number of seeds that will be needed. As mentioned previously, three to five additional seeds are ordered for each patient, so that real-time adjustments to the plan can be made in any case where the geometry of the prostate encountered at the time of the implant is slightly different from that marked on the volume study. Implantation procedure 1. Seed implantation is performed in our outpatient surgery center using general or spinal anesthesia. 2. Once the entire team is present the ultrasound images are recreated and matched as closely as possible to the preoperative volume study ultrasound. 3. The urologist then places 2–3 needles in the preplan distribution nearest to the center of the gland. This helps to prevent the gland from rotating and distorting the implant volume. 4. Then all the needles are placed by the urologist in the pattern predetermined by the radiation physicist’s plan from the posterior (bottom) row to the anterior (top) row, rather than inserting one needle at a time. The previous fixation makes it possible to place the remaining needles more accurately than if they were inserted one needle or row at a time.

Figure 17.1 Diagram showing transverse (T) versus longitudinal (L) ultrasound images.

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5. Once all the needles are in place, we proceed to check the prostate in each transverse slice, making sure that the edges or periphery of the prostate align with the initial setup, then rotating to the longitudinal ultrasound, we count once more, the number of slices, and the position of the apex, the balloon and consequently the base of the prostate. We then discuss potential or real changes that will have to be made using the real-time ultrasonography. If we encounter pubic arch interference (PAI) causing an inability to place some of the needles in the periphery of the prostate we place these needles at the completion of the implant (Figure 17.1). 6. Ultrasound imaging is switched from the transverse to the longitudinal view by the radiation oncologist in order to visualize the prostate-bladder neck interface and to compensate for prostate motion as a result of the initial positioning of the needles. We start by checking the needles on a plane-by-plane basis, starting with the most anterior plane. This allows us to ensure that the needle is inserted in the same coordinate throughout the cephalad-caudal axis. It also ensures that it is located in the proper plane using the longitudinal view. 7. Careful attention is also given to the peripheral needles to ensure that they are located within the prostate (as opposed to within the extracapsular tissue) unless otherwise specified in the preplan. The seed placement is done needle-by-needle, from the base going caudally to the apex, following the preplan, keeping the spacing as planned. Likewise, if a TURP is present, we make sure that the tip of the needle approaches, but does not extend into the TURP cavity. 8. We ensure that the spacing between the seeds remains accurate as the needle is moved from base to apex. Additionally, even though the number of seeds to be placed in each needle and the spacing between seeds were determined by the preoperative plan, the plan can be modified intraoperatively when the size or

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shape of the gland is not exactly the same as it had been in the volume study. These changes can be caused by pressure from the foley balloon, the position of the balloon on the ultrasound probe in the rectum, the amount of fluid in the bladder, or even slight displacement of the needles from their intended position (Figure 17.2). 9. As the radiation oncologist places the seeds in each planned coordinate, using the MICK applicator, it is very important to ensure that the position of the seeds is within the coordinate plan. Occasionally, as the needle is retracted (from base to apex) the needle pulls the prostate caudally. If no correction is made for this, then the two seeds will be less than the intended distance apart. In certain cases, it is necessary to pull the needle caudally up to 1 cm more than the original plan, let the prostate go back to its initial, original position and then, push the needle cephalad back to its intended position, and thereafter place the seed. Likewise, as the needle is retracted caudally, it could create a vacuum, which will move or displace the seed caudally, sometimes up

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to 1 cm away from an intended placement (that vacuum also has been noted to be created by the action of retracting the plunger within the MICK applicator). 10. As the seeds are placed from the most anterior plane down towards the rectum, we have noticed that as we get to the posterior-most planes some debris has

Figure 17.3 (a) Longitudinal ultrasound image of the prostate showing foley catheter (F), which aids in seeds being placed away from

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urethra, and needles (N). (b) diagram of (a). accumulated in the MICK applicator. It is seen coming out of the needle as the plunger moves forward, to push the seed in place. That debris is hyperechoic, and it could be mistaken for a seed. Careful observation ensures this does not interfere with the proper placement of each seed. Furthermore, in the lower most planes, occasionally there has been some bleeding noted between the rectum and the posterior wall of

Figure 17.4 Diagram showing how the pubic arch can interfere with direct placement of needles into anterior and lateral prostate. Note also that the movement of the probe can be up or down and sideways to reach those areas. the prostate, especially towards the apex, after the placement of the initial needles and as we continue to place the seeds. Consequently, real-time adjustments of the needles to ensure placement within the prostate and not outside of it has to be done in these instances.

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11. Occurrences, such as viewing a needle in its longitudinal plane going through the catheter, the presence of an undetected subcervical lobe, realization that there is more prostate tissue (initially not visualized in the volumetric ultrasound) lateral to the most lateral needles, will make the real-time changes in the placement of the seeds necessary to assure good peripheral coverage. As mentioned above, we avoid placement of seeds too close to the urethra, and add extra seeds in prostate tissue that was unrecognized initially. These fine points are crucial to success (Figure 17.3). 12. There are occasional cases in which some of the peripheral needles cannot be placed, due to a PAI. Once all the seeds have been placed in the needles already placed in their proper coordinates, we proceed to move the probe slightly to the contralateral side and then angle the entire stand back toward the side we need to implant. The image on the TV monitor is set to the widest transverse prostate image. Next, a needle is placed at the part of the gland in the desired plane at an angle. The grid lettering is of no value in this distorted view, so the placement may take several trials before the needle hits the desired location in the gland (Figure 17.4). Once completed, the image is changed to the longitudinal mode, and the needle is assessed to make sure that it is located within the proper plane. Seeds are then placed starting at the base and moving caudally towards the apex, in that previously unreachable area of the prostate. 13. An extra 3–5 seeds are ordered for each case; they are used to adjust for differences between the volume study and the actual treatment geometry, or to add an extra dose to the areas of positive biopsy. This is done in the longitudinal mode by changing the number of seeds placed in each needle to cover the area of the prostate being treated. 14. This has the advantage of not using preloaded needles and using real-time control in two planes. The ability to visualize the catheter as well as the entire length of the gland in the longitudinal mode makes it possible to avoid implanting close to the urethra or to any TURP defects. It also ensures that the posterior plane of needles is entirely within the prostate and not in the anterior rectal wall. 15. When implantation is finished, the ultrasound probe is removed and a cystoscopy is performed on all patients to retrieve any seeds that may have migrated into the bladder or urethral lumen. This happens rarely since the newer ultrasound probes have improved visualization. Blood clots, if any, are evacuated before placing the foley catheter, which is left in place for one day after surgery. 16. A healthcare nurse visits the patient on the day of discharge from the surgery center, and again the following morning to remove the foley catheter.

Results PSA, dosimetry, biopsy Patients are evaluated by both the urologist and the radiation oncologist 2 weeks after the procedure and every 6 months thereafter. Multiple sextant biopsies (approximately seven per side) and mapping (labeling the location in the prostate each biopsy was taken from and placing each biopsy core in a separate tube) are performed at 1,2, and 5 years. For patients with negative biopsies, we evaluate PSA levels at 6 month intervals and perform

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another biopsy only when a change in PSA is observed. PSAs are recorded every 6 months for 5 years then yearly from the date of implantation. Over the last 12 years all patients had postimplant CT scans of the pelvis with Veriseed 5 mm steps through the prostate, 10 days postoperatively. These were used for postimplant dosimetry using the MMS planning system. Our current procedure is yielding a postoperative mean V100 of more than 90%, which means that 90% of the prostate volume is receiving the prescribed dose of 135 Gy. A separate review is planned on our pre- and postimplant dosimetry. Figure 17.5 shows a typical example of our postoperative DVH taken from postoperative CT scans. Evaluation of treatment outcomes was based on ASTRO definitions applied to Freedom from PSA recurrence, as well as biopsy data. In our latest paper1 we analyzed our results not only using initial PSA groups, but also low risk, intermediate risk and high risk groups, based on both PSA and Gleason scores. These results confirm 12 years of success illustrated in current tables. We also show improvement in results using supplemental Ext.Radiation Therapy and Hormonal Therapy in Intermediate and High Risk groups. We further

Figure 17.5 Dose-volume histogram taken from postoperative CT scans. Tissue volume (V) distribution irradiated by the implant, with respect to dose (D). The prostate (red line) gets 100% of prescribed dose throughout the gland (V100); 68% of prostate gets 150% of prescribed dose. Urethra (green line): 90% of urethra gets 100%

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of precribed dose; 0.4% of the urethra gets 150% of prescribed dose.

Figure 17.6 Postoperative computed tomographic (CT) scan. (a) Peripheral seed distribution. (b) Typical CT scan 2 weeks postimplant. (c) X-ray simulation of postoperative seed count and distribution. show outstanding results compared to Radical Prostatectomy in all risk groups using the techniques outlined in this chapter.1 Figure 17.6 shows an example of a postoperative CT scan (see also Tables 17.1 and 17.2). Complications All patients experience some degree of short-term bladder and bowel irritation, which requires only symptomatic treatment. Most patients became symptom-free by 3–6 weeks or less, as assessed by urinalysis, postvoid residual ultrasound readings, and AUA symptom scores, and careful history and physical examination. No patient had rectal ulceration, fistula, chronic proctitis, radiation cystitis, or readmission for sepsis or urinary

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retention. It is notable that the patients who had undergone TURP experience no postoperative irritative problems in the immediate postoperative period. During our follow-up, fewer than 5% of the patients experienced incontinence, and this side effect was limited to only those patients who had undergone previous TURP and had developed calcification in the prostatic fossa (superficial urethral necrosis), usually 1–2 years postimplant. Impotence occurred in fewer than 15% of patients by retrospective history, which we know is not precise. These numbers are approximate and we currently are carrying out a prospective study on all our brachytherapy and radical prostatectomy patients, using sexual questionnaires and penile Doppler studies, to more precisely determine the exact incidence of these complications. One patient died from disease related causes—this man had a high initial PSA (>20) and had probably been understaged despite negative preoperative CT and bone scans. There are several other possible complications of brachytherapy, which occur rarely if at all in our practice. To some extent this may reflect the meticulous attention to each detail of the procedure by every member of our team. Possible complications and suggested means for prevention and/or treatment are presented below.

Table 17.1 Proportion of patients (%) free of PSA failure (ASTRO definition) after seed implantation Initial PSA (ng/ML)

1 yr 2 yrs 3 yrs 4 yrs 5 yrs 6 yrs

Brachytherapy (103Pd) monotherapy 0–4.0 100% 100% 98% 98% 98% 92% 4.1–10.0 100% 98% 96% 94% 92% 88% 10.1–20.0 100% 93% 86% 86% 72% 72% >20.0 100% 100% 100% 100% 100% 100% Total 100% 98% 96% 95% 93% 89% Brachytherapy (103pd) plus hormone therapy 0–4.0 100% 99% 96% 96% 96% 96% 4.1–10.0 100% 98% 96% 94% 93% 93% 10.1–20.0 100% 96% 93% 93% 93% 87% >20.0 100% 91% 91% 91% 91% 91% Total 100% 98% 97% 96% 95% 93% All patients 0–4.0 100% 100% 98% 97% 97% 94% 4.1–10.0 100% 98% 97% 95% 93% 91% 10.1–20.0 100% 95% 91% 89% 89% 84% >20.0 100% 94% 94% 94% 94% 94% Total 100% 98% 96% 95% 94% 91% ASTRO, American Society of Therapeutic Radiology and Oncology.

• Perioperative bleeding in the perineum or bladder of significance is rare and preventable by leaving a foley catheter in place overnight and making certain anticoagulants (aspirin/NSAIDs) are stopped one week before. • Urinary retention can be prevented by careful preoperative evaluation of outlet obstructive symptoms (AUA symptom scores), postvoid residual urine determination, and flexible cystoscopy at the time of volume study. If significant bladder outlet

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obstruction is found it should be taken care of preoperatively, as should unsuspected bladder tumors or urethral strictures. • Urinary frequency is common and treated with Aleve (which decreases prostate swelling and inflammation) twice daily for 7–21 days. Pyridium, Urised®, and steroids can also be used. • Bladder outlet obstructive symptoms, if they develop early, should be treated with alpha-blockers, or intermittent catheterization if large residuals develop. Bladder ultrasound for residual urine should be done at the first postoperative visit if symptoms are present. • Proctitis may be treated with cortisone suppositories or enemas, sitz baths, stool softeners, and Metamucil®. • Persistent colorectal complications should be referred for consultation. • Superficial urethral necrosis in post-TURP patients can be treated with careful TUR debridement, electrohydrostatic lithotripsy (if needed), and care to avoid the sphincter area.

Discussion We have described a true collaboration and attention to small details by a urologist, radiation oncologist, and radiation physicist. We have periodically reviewed our results and complications with the goal of making our procedure more accurate and therefore more effective for our patients. Brachytherapy, with a seed-dosing emphasis on the peripheral zone and sparing of the periurethral area, may leave more viable (PSA-producing) prostate than external radiation to account for PSAs not falling to zero. Our urethral dose is maintained at less than 150% of the prescribed dose of the preplan and confirmed by postoperative dosimetry. This is especially true when seeds are used as monotherapy without external radiation added. In cases of enlarged prostate (>50 cc), neo-adjuvant therapy can reduce the volume of prostate tissue exposed to the radiation doses in most cases, thereby requiring the placement

Table 17.2 Patients with negative biopsy after seed implantation Initial PSA (ng/mL) 1 yr

2 yrs

Brachytherapy (103Pd) monotherapy 0–4.0 95/107 (92%) 50/55 (91%) 4.1–10.0 120/128(87%) 48/56 (86%) 10.1–20.0 13/18 (72%) 11/11 (100%) >20.0 5/6 (83%) 3/4 (75%) Total 238/271 (88%) 112/126(89%) Brachytherapy (103Pd) and hormone therapy 0–4.0 109/112(97%) 57/59(97%) 4.1–10.0 204/214 (.95%) 104/112 (93%) 10.1–20.0 53/57(93%) 26/30(87%)

Basic and advanced techniques in prostate brachytherapy >20.0 Total All patients 0–4.0 4.1–10.0 10,1–20.0 >20.0 Total

266

21/24 (88%) 6/8 (75%) 388/408 (95%) 193/209 (92%) 208/220 (95%) 107/114(94%) 325/353 (92%) 152/168 (90%) 67/76 (89%) 37/41 (90%) 26/30 (88%) 9/12 (75%) 626/679 (92%) 305/335 (91%)

of fewer needles and permitting fewer seeds to be implanted in the brachytherapy procedure.7 Early periodic biopsies during the first two years after implantation of 103Pd are critical to determine the efficacy of this treatment and to allow early salvage treatments such as reseeding any ‘cold’ areas to be instituted in patients who fail therapy before the disease becomes metastatic. We do ‘mapping’ biopsies of the prostate (14–16 individually labeled specimens) to tell us the exact area of the prostate sampled. We have ‘reseeded’ 41 patients primarily from our first two years of experience in whom CT scans showed ‘cold spots’ that corresponded to the area of positive biopsy. The response rate to reseeding has been about 91% in terms of PSA falling to less than 1.5 ng/mL at the six year point, with 62% and 69% of biopsies negative at one and two years, respectively. It is too early to comment on its routine use in patients that fail. With greater experience and improved dosimetry reseeding has rarely been needed. For optimal efficacy of brachytherapy, experience with the technique is critical. We believe that our learning curve has been shortened by carefully reviewing our failures, we now know that our initial ultrasound equipment was inferior compared with today’s improved equipment. Also, in terms of visualization as well as the precision of seed placement using transverse and longitudinal views, as compared to only the transverse view initially used dramatically improved our results. As mentioned earlier, we have also increased our seed activity to correspond with standards commonly used today and have not needed to use fluoroscopy, rapid strands (only available for 125I seeds), or fixation needles in our technique. As a consequence of meticulous care during the planning procedure to keep the dose of radiation to the urethra within acceptable limits (1% of the urethral volume receiving 150% of the prescribed dose), we have managed to avoid the high incidence of incontinence and superficial urethral necrosis reported by clinicians who used uniform loading techniques (e.g. 5% in our series compared with 12% reported by Blasko).3 Generally, an incontinence rate of 5–10% occurs with radical prostatectomy (RP) and about 5–10% with external beam radiotherapy (EBRT).3 In addition, sexual function has been maintained in approximately 85% of our patients; our 15% rate of impotence compares with an impotence rate of 20–50% for RP and 10–30 % for EBRT.3 We believe that technical improvements in brachytherapy will continue to advance its role in the treatment of localized prostate cancer. This is a relatively noninvasive, onetime outpatient procedure, especially valuable in the older patient who may be uncomfortable with watchful waiting. Brachytherapy eliminates technical radiation problems, such as target motion, daily set-up variations, and localization errors that are

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problems with 7 weeks of external radiation. We believe this represents the ‘ultimate’ in conformal radiation treatment of the prostate. Biopsy data have been and will continue to be included in our analyses, as this information is crucial to the understanding of PSA data and to initiate salvage therapy promptly. A negative biopsy with a rising PSA is indicative of excellent local control by the implant, but extraprostatic spread of the cancer. A positive biopsy at 18–24 months indicates the need for additional local treatment if possible. Very few studies are available with both biopsy and PSA results in the radiation literature.3 Additionally, we feel it is important to the long-term outcome of prostate cancer for the urologist to control all aspects of treatment of this disease. If these results stand the test of time then brachytherapy, which is a less morbid treatment, will be an important addition to the urologist’s armamentarium. Our patient selection, exclusions, and use of postoperative dosimetry over the years are in agreement with the recently published American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer.16 Intraoperative dosimetry (with immediate addition of seeds to ‘cold’ areas will be the next important advance in our procedure. When conducted with the care and attention to detail employed in our clinic, seed implantation takes only one hour of the physician’s time and one half-day of the patient’s and outpatient facility’s time. Despite the fact that a considerably higher radiation dose is delivered to the prostate, brachytherapy is associated with less morbidity than standard EBRT. We have described several changes in our implantation techniques, which we offer as a means to improve the precision of seed placement. Acknowledgments The authors acknowledge the outstanding help of Sandy Windham, RN, Susan Randall, RN and Marissa Young Administrative Assistant, for their organizing the procedure to be done in a cost-effective manner in our outpatient surgical center and for careful patient data collection and follow-up. We also recognize the expert prostate ultrasound volumes pre- and intraoperatively by James Steele and Chuck Webster, physician assistants. References 1. Sharkey J, Cantor, A, et al. Brachytherapy versus radical prostatectomy in patients with clinically localized prostate cancer. Current Urology Reports 2002; 3:250–257. 2. Porter AT, Blasko JC, Grimm PD, et al. Brachytherapy for prostate cancer. CA Cancer J Clin 1995; 45:165–178. 3. Blasko JC, Grimm PD, Ragde H. Brachytherapy and organ preservation in the management of carcinoma of the prostate. Semin Radiat Oncol 1993; 3:240–249. 4. Hendricks JG, Kaplan SA. What the literature reveals about the complications of radical retropublic prostatectomy. Contemp Urology 1997; 9:13–22. 5. Wallner K. Radiation safety parameters following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999; 45:397–399. 6. Peschel RE, Chen Z, Robert K, Nath R. Radiation oncology investigations: Clinical and basic research. 1999; 7:278–288.

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7. Stone NN, Forman JD, Sogani PC. Transrectal ultrasonography and 125I implantation in patients with prostate cancer. J Urol 1988; 139:604A. 8. Stock RG, Stone NN, Wesson MP, DeWyngaert JK. A modified technique allowing interactive ultrasound guided three-dimensional transperineal prostate implantation. Int J Radiat Oncol Biol Phys 1995; 32:219–225. 9. Stone NN, Ramin SA, Wesson MP, et al. Laparoscopic pelvic lymph node dissection combined with real-time interactive transrectal ultrasound guided transperineal radioactive seed implantation of the prostate. J Urol 1995; 153:1555–1560. 10. Stone NN, Stock RG, DeWyngaert JK, Tabert A. Prostate brachytherapy: improvements in prostate volume measurements and dose distribution using interactive ultrasound guided implantation and three-dimensional dosimetry. Radiat Oncol Investig 1995; 3:185–195. 11. Sharkey, J, Chovnick SD, Behar RJ, et al. A minimally invasive treatment for localized adenocarcinoma of the prostate: a review of 950 patients treated with ultrasound-guided palladium 103 brachytherapy. J Endourol 2000; 14:4. 12. Hu K, Wallner K. Urinary incontinence in patients who have a TURP/TUIP following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998; 40:4–783–786. 13. Williamson et al. Recommendations of the American Association of Physicists in Medicine on 103 Pd interstitial source calibration and dosimetry: Implications for dose specification and prescription. Med Phys 2000; 27:634–642. 14. Anderson LL, Moni JV, Harrison LB. A nomograph for permanent implants of palladium-103 seeds. Int J Radiat Oncol Biol Phys 1993; 27:129–135. 15. Wallner KE, Roy J, Harrison L. Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal 125I prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995; 32:465– 471. 16. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999; 44:789–799.

18 Optimizing real-time, interactive, ultrasoundguided prostate brachytherapy Glenn A Healey Introduction For treatment of localized prostate cancer, brachytherapy has come of age as the alternative to external beam radiation therapy and radical prostatectomy.1–5 Although improvements in ultrasound inspired the renaissance in brachytherapy,6 a major impediment to ultrasound-guided implant excellence continues to be difficulty visualizing conventional seeds in real-time.7 Historically, ultrasound-guided implant techniques took advantage of the state-of-theart equipment at the time. Early ultrasound units had poor sagittal imaging (or none at all). This prompted early users to develop the preloaded needle technique;8 there was reliance on hub-stylet measurement, hub-template measurement, and base plane identification, rather than real-time sagittal imaging.9 In the past five years, enhancements in ultrasound technology, in particular the development of dedicated probes, have dramatically improved the sagittal ultrasound image. The hardware and software advances are an impetus to optimize ultrasound-guided techniques. However, intraoperative detection of a conventional seed is critically dependent on the seed location relative to the plane of the ultrasound transducer. A conventional seed is apparent when it is in the transducer plane, but ‘disappears’ if it lies only slightly offaxis. Therefore, it has been rare to visualize every seed in a line of implanted seeds when viewing in sagittal section, because it is rare for all of the seeds to be precisely coincident with a single sagittal ultrasound axis angle. The recently approved EchoSeed™ (Amersham Health, Princeton, NJ) was the first seed specifically designed to be easier to visualize in sagittal section because it continues to be visible off-axis. The innovative grooved design of the external surface of the EchoSeed makes the seed more echogenic. This allows visualization even when the ultrasound axis plane is rotated off the axis of the seed. A line of implanted EchoSeeds is more likely to be visualized in its entirety because a Compromise’ sagittal axis can be identified that captures all of the seeds. The enhanced ability to visualize the implant has at least three obvious benefits that set apart EchoSeed implants from conventional seed implants: 1. As each individual seed is placed, the user can immediately evaluate the seed in place. The next seed in the line can then be placed in relation to the actual location of other seeds in the line, allowing ongoing adjustment for prostate gland motion, needle deflection, and seed drift.

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2. Once the entire line of seeds is in place, the user can evaluate the relationship of the entire line of seeds with respect to the base and apex of the prostate gland to ensure that coverage is according to plan. Unintended cold spots can be assessed and taken care of, if deemed necessary, before moving on. 3. Rotating the ultrasound probe cradle (‘rocking the cradle’) very slightly in sagittal section can capture the three-dimensional location of an individual seed. A seed becomes ‘highlighted’ (exhibits greatest signal intensity) when the axis plane of the ultrasound probe is aligned with the axis of the seed. The enhanced ability to discriminate the precise location of an individual seed will improve the performance of computer-assisted, real-time, seed-capture/dosebuilding programs. Intraoperative evaluation of the developing dose-cloud based on improved seed localization gives the user greater implant quality assurance.

Techniques to optimize EchoSeed visualization The benefit of improved visualization of the EchoSeed is real-time, interactive implant optimization to more closely align an implant with its intended plan. To fully realize the benefits, however, techniques to optimize the ultrasound image are needed that take advantage of the EchoSeed’s uniquely echogenic design: • Dim the operating room (OR) lights to improve ultrasound monitor performance. • Select the ultrasound frequency (usually 6.5–7.5 megahertz; MHz) that will optimize the prostate image. • Dial down the ultrasound gain to decrease extraneous echoes in order to bring out the EchoSeed signal. • Rock the cradle to realign the sagittal axis and recapture the seed signal. Dim the operating room lights During the procedure, the operating room should be as dark as possible to optimize the use of ultrasound. In a darkened operating room (OR), the user’s eyes become darkadapted, improving the ability to see the grayscale contrasts of ultrasound imagery. The darkened OR also minimizes extraneous light reflecting off the ultrasound monitor screen, which can degrade the image. However, a darkened OR poses procedural and safety challenges that must be reviewed before proceeding. Key locations for task lighting should be identified, including the surgical scrub table, the anesthesia station, the physics workstation, and the template itself. Lighted clipboards are helpful for critical paperwork. Select the ultrasound frequency that optimizes the prostate image Each brand and model of an ultrasound unit has an optimal working frequency for prostate gland visualization. In general, 6.5–7.5 MHz is the optimal range. The selection of frequency can vary from case to case based on the inherent echogenicity of the

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prostate. It is useful to scroll through the frequency options at the beginning of the case and chose a frequency that diminishes internal echoes within the prostate. This is an especially useful exercise in the highly calcified prostate gland. Once a frequency is selected, it is recommended that the setting be used throughout the case. Manipulation of the gain is a much more sensitive way to re-optimize the image during the procedure. Dial down the ultrasound gain to bring out the seed signal The ultrasound gain should be turned down to accentuate the difference between the dark prostate gland and the highly echogenic EchoSeed. The trick is to set the gain as low as possible, preserving seed visibility without sacrificing prostate gland imagery. Gain settings of 20% to 40% are usually optimal. As the user moves from seed to seed and from needle to needle, the inherent echogenicity of the ultrasound image will change. It is useful to manipulate the gain to appreciate the setting that re-optimizes the image. During the case, the prostate gland image can become increasingly echogenic due to the presence of seeds and introduced air. As the prostate image degrades, the gain can be turned down in order to bring out the seed signal. Rock the cradle to recapture the seed signal Implant needles are typically placed in axial section, using institution-specific standard procedures. Once the needles are placed, the ultrasound is switched to the sagittal view to visualize the needle along its entire length and to appreciate the relationship of the needle tip to the base of the prostate. Seeds are then placed under direct vision in sagittal section. This allows the operator to assess in real-time the location of the seeds in the gland as they are being placed (Figure 18.1). Advancing and retracting individual needles within the gland will cause undesirable yet somewhat predictable movement of the prostate gland.9 Insertion of the needle tends to cause rotation of the gland (Figure 18.2a). Despite a vigilant technique to relax any tension on the gland caused by needle insertion (Figure 18.2b), a seed can ultimately lie in a position away from the axis of the needle (Figure 18.2c). To recapture the seed signal, it is necessary to rock the cradle (rotate the ultrasound probe) very slightly (Figures 18.2d and 18.3). The echogenic tip of the needle is still easily seen even though the operator has now moved off of the axis of the needle tip and on to the axis of the seed. As the next seed is released along the needle track (Figure 18.2e), the process of rocking the cradle is repeated to maintain visualization of the seeds (Figure 18.2f). The technique is to drop a seed, rock the cradle to optimize the seed signal, retract the needle and rock the cradle to reoptimize the image, then drop the next seed. Once the seeds in a given line of seeds have been placed and the needle is out of the gland, the cradle is rocked to select the sagittal axis that lies between the axes of the first and subsequent seeds in order to see the entire line of EchoSeeds (Figure 18.4). The apex and base of the prostate are seen in relation to the seeds, which allows the physician to immediately determine if the seeds are positioned as planned before moving on to the next needle. If there is a

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Figure 18.1 Establishing anatomical reference from the sagittal view of prostate brachytherapy radioactive seed implant placement procedure. loss of seed signal at any time during the case, the signal can be recaptured by rocking the cradle and further optimized by turning the gain down. Conclusions Prostate brachytherapy has become an acceptable treatment option for the treatment of localized prostate cancer. However, despite recent improvements in ultrasoundguided radioactive seed placement technique and ultrasound technology, the ability to visualize seeds in real-time during implantation is limited by the physical properties of conventional seeds. Whereas intraoperative visualization of conventional seeds is critically dependent on the seed location in relation to the ultrasound transducer plane, the unique grooved structure of the newly designed and recently approved EchoSeed permits visualization even when the ultrasound plane is rotated off-axis. The unique design of the EchoSeed is capable of taking full advantage of the new state-of-the-art in ultrasound equipment. Minor modifications in intraoperative technique will optimize the echogenic advantages of the seed. Improved visualization allows the user to make intraoperative adjustments to more closely align the developing implant with the intended plan. The enhanced visualization is an asset for computer-assisted, real-time, intraoperative, seedcapture/dose-building programs. Acknowledgment

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The author thanks Amersham Health, Princeton, NJ for their help with preparation of the manuscript.

Figure 18.2 Principal steps for placing radioactive seeds, including key points of technique for sequential seed placement that allow for gland distortion and optimize seed signal capture and image visualization. US, ultrasound probe.

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Figure 18.3 Rocking the cradle, a technique for manipulating the ultrasound transducer to optimize the image and further guide seed placement.

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Figure 18.4 On- and off-axis ultrasound visualization of seed implant References 1. Stock RG, Stone NN, Tabert A, et al. A dose-response study for 125I prostate implants. Int J Radiat Oncol Biol Phys 1998; 41:101–108. 2. Zelefsky MJ, Wallner KE, Ling CC, et al. Comparison of the 5-year outcome and morbidity of three-dimensional conformal radiotherapy versus transperineal permanent iodine-125 implantation for earlystage prostatic cancer. J Clin Oncol 1999; 17:517–522. 3. Brachman DG, Thomas T, Hilbe J, et al. Failure-free survival following brachytherapy alone or external beam irradiation alone for T1–2 prostate tumors in 2222 patients: results from a single practice. Int J Radiat Oncol Biol Phys 2000; 48:111–117. 4. Grimm PD, Blasko JC, Sylvester JE, et al. 10-year biochemical (prostate specific antigen) control of prostate cancer with 125I brachytherapy. Int J Radiat Oncol Biol Phys 2001; 51:31–40.

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5. Merrick GS, Butler WM, Galbreath RW, et al. Relationship between percent positive biopsies and biochemical outcome after permanent interstitial brachytherapy for clinically organconfined carcinoma of the prostate gland. Int J Radiat Oncol Biol Phys 2002; 52:664–673. 6. Holm HH, Juul N, Pedersen JF, et al. Transperineal iodine-125 seed implantation in prostatic cancer guided by transrectal ultrasonography. J Urol 1983; 130:283–286. 7. Nag S, Ciezki JP, Cormack R, et al., for the Clinical Research Committee, American Brachytherapy Society. Intraoperative planning and evaluation of permanent prostate brachytherapy: Report of the American Brachytherapy Society. Int J Radiat Oncol Biol Phys 2001; 51(5):1422–1430. 8. Grimm PD, Blasko JC, Ragde H. Ultrasound guided transperineal implantation of iodine-125 and palladium-103 for the treatment of early stage prostate cancer. Technical concepts in planning, operative technique and evaluation. Atlas of the Urologic Clinics of North America 1994; 2(2):113–125. 9. Stock RG, Stone NN, Wesson MF, et al. A modified technique allowing interactive ultrasoundguided three-dimensional transperineal prostate implantation. Int J Radiat Oncol Biol Phys 1995; 32:219–225.

19 Real-time prostate brachytherapy: transition from intraoperative nomogram planning to virtual planning Nelson N Stone, Jeffrey H Chircus, and Richard G Stock Introduction The real-time implantation of permanent sources into the prostate was introduced at Mount Sinai Medical Center in New York in 1990. The desire to develop a real-time implant technique came from the concern that the preplan method would not adequately address gland motion and changes in patient set-up. While the concept that the use of low energy radioactive sources could prove attractive in the treatment of localized prostate cancer, attaining uniform good results has been more elusive. The transition from the open, retropubic technique to the transperineal approach with ultrasound guidance was a necessary step in ensuring dosimetric consistency.1–4 The initial transrectal ultrasound probes used in prostate brachytherapy were crude compared to today’s equipment. Problems with image quality and proper planning led to many false starts and even caused the initiator of this approach, Holm, to abandon it altogether.2 Ragde had visited Holm and decided to take the ultrasound approach back to America.5 Working in Seattle with Blasko and Grimm, he developed the preplanned implant in the mid 1980s. The two most significant contributions in prostate cancer for urologists in the last 15 years have been the introduction of prostate-specific antigen (PSA) and the biplanar transrectal ultrasound probe. Perhaps it was a coincidence that they were both introduced towards the end of the 1980s, but nonetheless, the diagnosis and treatment of prostate cancer radically changed once they became part of the typical urologic practice. Ultrasoundguided biopsy using the B&K model 8551 biplanar probe (Bruel & Kjaer; B&K, Wilmington, MA) along with the spring-loaded needle made this procedure a common event.6 It was the initial experience with this probe in 1988 that led to the concept of creating a real-time method for placing the radioactive sources in the prostate.7 The impetus to develop a real-time technique was based on the concern that one could preplan an implant and at some later date place the seeds according to this plan and expect the final result to be the same. The introduction of the biplanar ultrasound probe for prostate biopsy with its sagittal image of the gland provided a completely different perspective than the monoplanar axial imaging probe (B&K model 1850, B&K Medical Systems, Inc, Wilmington, MA) initially used for the preplan implant. Axial imaging provided important information in determining prostate size through step section planimetry, but sagittal imaging gave strategic information for sampling the prostate gland.8 The sagittal image allowed visualization from the base to apex of the gland, view

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of the bladder and seminal vesicles, and rectum all in one view. The prostate biopsy experience also demonstrated how mobile the prostate was. The small spring-loaded biopsy needles caused movement of the gland in several directions creating the potential for major gland movement with the use of many larger implant needles. Such movement has recently been demonstrated in a study that measured gland motion and position during the needle placement process.9 The introduction of the B&K biplanar probe generated the initial interest for the creation of the real-time implant. The implant needles could be placed using axial imaging and the seeds deposited with the aid of a sagittal transducer. The next step was to decide on how to place the seeds. Two methods were possible. The Seattle group favored preloaded needles. An applicator method was selected for the real-time approach. In keeping with the philosophy of the real-time method, control of the position of each individual seed as it was placed was critical. Preloaded needles unnecessarily compromised the inherent flexibility in individual seed insertion with an applicator (Mick TP 200, Mick Radio-Nuclear Instruments, Inc, Mount Vernon, New York). The same can be said for stranded seeds. Any inherent advantage to these products may be lost by the brachytherapist’s inability to control the placement of downstream sources. The next issue to be solved was the planning of the implant. In keeping with the philosophy of intraoperative planning a set of rules was developed to accomplish this. The total activity needed for the case would be determined prior to the implant by comparing the prostate size to a look-up table (nomogram). The prostate size was measured by the urologist who determined the three dimensions of the gland and multiplied them by 0.52.7 This, of course, required the prostate volume measurement to be accurate otherwise not enough seeds would be available for the implant in the operating room (OR).10 The nomogram was initially developed from the Anderson ‘tieline’ used for the open retropubic implant at Memorial SloanKettering Cancer Center.11 The tie-line was converted to a cc/mCi table. It was also decided to place the seeds equally throughout the gland following the pattern suggested by Quimby.12 The activity per seed was selected to allow equal spacing of seeds throughout the gland. Thus, a 35 cc gland would require 17 mCi of iodine-125 to deliver a dose of 160 Gy and seeds of 0.5 mCi would be used. In the OR the prostate volume was remeasured by step section planimetry and the amount of activity to place in the gland was recalculated. The peripheral needles were placed using a spacing of 1 cm between needles and arranging them just inside the capsule. The number of interior needles was determined by evaluating the distance from urethra to capsule and maintaining a distance of at least 5 mm from the urethra. The interior needles were not placed at this time. The total number of needles was summed and this number was divided into the total number of seeds to be placed according to the nomogram. After peripheral needle placement, the seeds were placed at the base, just under the capsule, the second midway, and the remaining seed at the apex. All seeds were individually placed, taking care to determine the position of the tip of the needle prior to seed insertion. Once the periphery was finished, the interior needles and seeds were inserted. The seed placement looked ideal on the anteriorposterior scout film. The seeds conformed to the shape of the gland with consistent spacing between themselves. One of the most significant advances that were made early on in this work was the development

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of a 3D, computed tomographic (CT)-based software program that allowed the postimplant determination of dose-volume histograms of the prostate, urethra, and rectum. Experience in the first year resulted in significant modifications of this early technique. In order to achieve the goal of 90–95% coverage of the gland by the prescription dose, the total activity placed in the prostate had to be increased several times and the distribution of the sources slowly evolved from 50/50 to 75/25 periphery/interior.10 This process took almost 5 years, but resulted in a more consistent target D90. The changes in postimplant dosimetry results from 1990 to 1995 reflect these changes. The nomogram changes from 1990 to 1995 also attest to the magnitude of the increase in activity required to achieve these dosimetry results.10 The next significant change occurred with the addition of the biplanar electronic (linear array) probe (B&K model 8558). This probe uses two non-overlapping transducers, the first, a curved pad occupying the distal anterior surface of the probe, and a 5 cm rectangular array just proximal to it. The difference in imaging between the new electronic probe and the older mechanical one was remarkable. While the axial image was only modestly improved, the linear or sagittal image was dramatically different. The probe was introduced in 1996 for cryoablation, because of its superior imaging of the prostatic-rectal interface. It was adapted for the real-time implant when its superior sagittal imaging qualities were recognized. After a trial year at Mount Sinai, B&K agreed to create hardware to accompany the probe for seed implantation. The advantage over the older probes was documented in a recent report on postimplant dosimetry results.13 In concert with the advances in the real-time method, preplan brachytherapists were rewarded with the introduction of computer planning software, which improved the efficiency and accuracy of the plan. Several companies released their versions of software that allowed archiving of the ultrasound images into a treatment-planning system permitting the physicist to plan the needle and seed arrangements in advance of the implant. Towards the end of 1995, Multimedia Medical Systems (MMS) (Varian Medical Systems, Inc, Varian BrachyTherapy, Charlottesville, VA) introduced their treatment-planning software (TherpacPlus 6.6 B3DTUI and TherpacPlus B3DTUI 6.7). While the real-time brachytherapist had no interest in preplan software, the technicians of MMS were interested in coming up with a solution that would be usable in the OR with this technique. They introduced a version of 6.7, which permitted movement of the planning needle off the grid points, allowing real-time needle placement with subsequent matching of treatment-planning needle positions. The modified software was introduced into the realtime technique in 1998.14 It is still widely used throughout the world in those centers that have been trained in this methodology. TherpacPlus 6.7 Technique The prostate volume is determined in the urologist’s office by measuring the height, width and length (in sagittal) of the gland and multiplying by 0.52. This volume is given to the radiation oncologist, who using the look-up table specific for the manufacturer’s

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source, orders the appropriate seed strength and total activity. The prostate volume determination is repeated in the OR using 5 mm stepsection planimetry. Implantation begins by insertion of needles into the periphery of the gland using the largest ultrasound (US) transverse diameter cut as a guide. Needles are inserted just interior to the capsule and placed no more than 1 centimeter from the surrounding needles. Determination of gland circumference at the largest transverse section yields the total number of needles required in the periphery. After all peripheral needles are placed the prostate is contoured using US, the urethra identified by an arrow, and each image is stored by the treatmentplanning system. On each acquired prostate slice, the prostate contour was copied and the urethral marker circled. In addition, the anterior rectum was segmented (perirectal fat and mucosa). The planning system created a 3D grid matrix with x, y, and z axes. The seeds are then implanted with a Mick applicator using sagittal US imaging as a guide to needle and seed location. The implant is started at the most lateral posterior (7 o’clock) needle. The needle is advanced to the base of the gland and the first seed placed while observing that the needle is just proximal to the prostate capsule at the base. The goal for each row is to place the first seed at the base, the last one at the apex, and intervening seeds (usually 2–4) evenly spaced between the two ends of the gland. The number of seeds placed through the peripheral needles is determined by taking 75% of the total number of seeds required for the implant and dividing by the number of peripheral needles. Longer length rows require more seeds, while the shorter rows fewer. The distance between seeds in the periphery is always less than 1 cm. After finishing the first needle, the probe is rotated a few degrees clockwise and the next lateral-anterior needle is located and implanted. The entire peripheral implant takes about 20 minutes. During this time, the physicist works to complete the dosimetric representation of the implant.14 The position of the needles in the treatment planning system is determined based on the acquired US images with the actual implant needles in place. Needle positions are identified by the echo-bright flash present on the acquired transverse images. The needle position is first identified by locating the nearest grid position to the needle. This point is then dragged to the spot corresponding to the image of the needle on the acquired ultrasound image. The location of the seeds in the planning matrix is determined manually by examining the path of the needle through the transverse captured prostate images. Seeds can be placed on any of the 5 mm slices or 2.5 mm above or below any slice. After placement of all of the peripheral seeds, the corresponding isodose lines are visualized. The next step involves placing the internal needles. The remaining 25% of the seeds are inserted via these needles. Typically, between 6 and 9 needles are inserted into the interior such that they encompassed the periphery of the base and apical slices and are 0.5–1 cm from the urethra. Three to 4 seeds are inserted into these needles with one seed at the base and apex of the gland. Once these needles are inserted, the best imaging transverse cut visualizing these needles is acquired by the planning system. The needle positions are located on the planning matrix. If the prostate has not moved or changed shape, then the new interior needle positions are marked using the newly acquired US image. If the prostate had shifted position, then the needle positions from the US image are shifted to match the position of the interior needles in relation to the prostate from the actual implant. The positions of the seeds deposited are then determined on the planning software in a similar fashion to those implanted by the peripheral needles. Once the

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interior seeds have been placed the final isodose distributions are visualized and dosevolume histograms (DVH) generated. The next advance required a change from working on intraoperative ‘archived’ images to an interactive system with live sagittal imaging. There was also more of a need to move in the direction of a preplan methodology, not because it was necessary to have a plan prior to needle insertion, but to be able to generate enough information for the team as quickly as possible. Once the plan had been generated, it needed to be instantaneously updated with every change occurring during needle and seed placement. Finally, the program had to generate a live sagittal image from which the physicist could track individual seed placement and advise the radiation oncologist about the number and location of each seed along with the corresponding isodose contours. The engineers and technicians at Varian built the software in parts, which were individually tested. The new version, VariSeed 7.0 (recent update 7.1) with implant view took over two years to develop. The program was released in the fall of 2001 and, after 3–4 months of testing was ready to be widely introduced into the brachytherapy community. The VariSeed 7.0 was not just introduced for the realtime treatment methodology. Many brachytherapists, whether using a preplan or real-time methodology will find its features an enhancement over the older version. In addition, several other companies have advanced their brachytherapy planning software to the point where the user may find greater advantages for their style of implantation over the Varian product. It is not the purpose of this study to compare or recommend the different treatmentplanning systems, but rather to describe how the real-time method evolved, which invariably included the use of the Varian software. VariSeed 7.1 Technique The prostate volume is determined in the office using a biplanar transducer by calculating the height, width, and

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Figure 19.1 Use of the Bard/ProSeed planning module to rapidly generate the needle and seed placement locations. Selecting this planning module within the image view module creates an instantaneous plan. The 3 longitudinal measurements, once entered, give the number of peripheral and interior needles along with the corresponding number of seeds. length of the gland on the largest transverse and sagittal images and multiplying by 0.52. The total activity needed is calculated from a nomogram and delivered already loaded in disposable cartridges. The patient is positioned and the probe is placed in the rectum. The prostate gland is contoured at 5 mm intervals from base to apex. The images are stored in the treatment-planning program. The physicist uses several new tools in the VariSeed 7.1 program to rapidly auto-contour the prostate and identify the urethra and rectum. Contained within special versions of the 7.1 program is a ‘Bard/ProSeed’ planning module which allows the physicist to create a full plan, following the rules established for real-time planning in a matter of a few minutes. In essence, once the urologist completes the planimetry study, leaves the room to scrub, returns to prep and drape the patient, the planning is complete (Figure 19.1). The urologist places the peripheral needles according to the plan by observing the computer monitor. The urologist looks at a live transverse image of the gland with the virtual image of the prostate, urethra, and rectum superimposed over the ultrasound

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image. Virtual needles also appear and the urologist places the applicator needles through the template (grid) so they end up at or near the intended positions. It is not necessary to get an exact match, because the physicist can drag the virtual needles to the ‘flash’ positions of the inserted needle (Figure 19.2). After all of the peripheral needles have been placed the prostate is recaptured into the planning system (Figure 19.3). This is a crucial step because the needle placement has significantly altered the original plan. The needles cause the prostate to move cranial, displace it off the rectum and distort its edges.15 The needles also do not end up in the exact same position as the plan called for. The physicist updates the plan by adjusting the contours and adding or deleting seeds for each needle (Figure 19.4). Once the plan has been updated, the radiotherapist can start placing the seeds with the Mick applicator. Starting at the 7 o’clock position, the first needle is identified and advanced to the base of the gland. The physicist is looking at the corresponding live image on the planning system with the virtual prostate image, needle, and seeds in front of him (Figure 19.5). He can direct the number of seeds to be implanted in each row after checking the isodose contours overlying that sagittal image as well as the dosing parameters that were previously set. Once the radiation oncologist starts placing the seeds, the physicists can track there positions and overlay the virtual seeds on top of the actual seeds in the gland (Figure 19.6). The isodose contour at each succeeding needle is representative of the composite dosimetry of all of the seeds already placed and

Figure 19.2 Live transverse image with 5 posterior needles placed. Arrow points to next intended needle position. The posterior needle placement has moved the prostate anterior,

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necessitating the recontouring of the prostate after all peripheral needles have been placed (see text).

Figure 19.3 Image recapture with all of the peripheral needles placed. The newer images are captured ‘on top’ of the initial planning images.

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Figure 19.4 The physicist updates the plan once all of the peripheral needles have been placed by adding or deleting seeds for these needles or by adjusting the needle and seeds for the interior needles (which have not been placed at this point). The 140,160, and 240 Gy isodose lines are displayed.

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Figure 19.5 Implantation of posterior needle in midline or ‘D’ position. The plan indicates 4 seeds from base to apex with the corresponding isodose contour. The 160 Gy line covers the entire posterior aspect of the prostate with little dose to the rectum.

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Figure 19.6 Seed placement of a posterior needle. The physicist has aligned the virtual seeds to the corresponding implanted ones. In this way the plan is continually updated after the seeds are placed. the seeds yet to be placed. In this way the physicist is continually updating and modifying the plan as the physicians work to complete it. After finishing the periphery, the probe is returned to axial and the interior needles are placed in a similar fashion to the peripheral ones. The fine-tuning of the interior needle positions and number of seeds to be placed in these needles is dependent on the number and positions of the peripheral seeds already placed. In many cases, it is not unusual to end with fewer seeds than originally recommended by the planning module. The dosing criteria adhered to are: dose to 90% of prostate (D90) 160–180 Gy, 30% of the urethral volume (UD30) <150% of prescription (160 Gy) and volume of rectum (rectal V100) covered by the prescription dose < 1.3 cc. Results Ten consecutive patients underwent iodine-125 (125I) seed implant between April and September 2003 using the VariSeed 7.1 with implant view and the Bard/ProSeed planning module. Mean intraoperative prostate volume was 49.8 cc (range: 32.6–98.1) compared to 54.9 cc (range: 33.4–113.5, p=0.019) as determined by the 30 day postimplant CT study. The mean intraoperative prostate D90 was 193 Gy (range: 184– 207) compared to 197 Gy (range: 177–229, p=0.417) from the postoperative study.

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Results for the prostate V100, V150, rectal V100 (in cc) and urethral dose (to 30% of volume) are shown in Table 19.1. The intraoperative and postplan values were compared by taking a ratio of the two. The mean D90 ratio was 0.98 (95% CI 0.92–1.03) and the mean V100 was 1.06 (0.98– 1.15). The other variables are shown in Table 19.2. The mean difference in D90 values (intraoperative minus postoperative results) was 411 cGy (range: –3041–1696 cGy). Discussion The ideal implant technique should yield results for target tissue dosimetry that closely match the planning study, regardless of the method used. Unfortunately, most studies, even from centers of excellence, have yielded less favorable results.16 We have advocated the real-time technique over the preplan method for the reasons stated above. Matzkin has compared the two-step preplant method (n=142) to the Varian 6.7 intraoperative method (n=214) described above and found only 58.4% achieved their target dose with the preplan method, compared to 95.2% with real-time.17 Newer technology in medicine does not always result in improved clinical outcomes. This is our first attempt to

Table 19.1 Mean values for intraoperative versus postplan (30 day CT-derived) for prostate D90 (dose to 90% of gland), V100 (% of volume of prostate covered by 160 Gy), V150 (% of volume of prostate covered by 240 Gy), rectal V100 (volume of rectum covered by 160 Gy) and urethra D30 (dose to 30% of urethral volume) Intraoperative Postimplant p-value Prostate volume (cc) 48.7 54.9 0.019 D90 (Gy) 193 197 0.417 V100 (%) 103 97.4 0.96 V150 (%) 52% 36% 0.015 Rectal V100(cc) 0.8 1.2 0.244 Urethra D30 (Gy)

194

250

<0.001

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Table 19.2 Mean ratio with 95% confidence interval (CI) of intraoperative to postplan studies Ratio 95% CI D90 0.98 V100 1.06 V150 1.67 Rectal V100 0.81 Urethra D30 0.77 Prostate volume 0.91

0.92–1.03 0.98–1.15 1.05–2.30 0.26–1.36 0.71–0.84 0.82–1.01

quantitate our dosimetry results in a small cohort of patients implanted with Varian 7.1 with implant view. While the initial results appear to be very good, the intraoperative to postimplant D90 ratio was 0.98, is it substantially better than what can be achieved with Varian 6.7 using the real-time method? In a study of 77 patients comparing the intraoperative D90 to the postimplant dose using 6.7, Stone also found a ratio of 0.98.18 These data suggest that there may be little advantage to switching to the newer method. However, a closer analysis of the 6.7 data in the 125I patients revealed a mean OR D90 of 178 Gy (range: 126–214) versus the postimplant D90 of 188 Gy (142–225). The current study (Varian 7.1) revealed a much tighter and closer match between the OR and postimplant data: 193 Gy versus 197 Gy, with a much smaller range of doses. These data also substantiate that the use of an intraoperative planning system, combined with the real-time implant yields very favorable postimplant dosimetry results. Attaining a postimplant prostate D90 of at least 140 Gy in patients receiving an 125I implant is necessary to insure a favorable disease-free (PSA) outcome.19 For local control, doses of 160 Gy may be more appropriate. Stock has shown that patients receiving a dose of at least 160 Gy had a 4% likelihood of local recurrence (as determined by biopsy) 2 years after implantation.20 Thus, consistency of implant results, above a certain threshold (either 140 Gy or 160 Gy) has significant implications on cancer-specific outcomes. Selecting the ‘ideal’ implant method as a means of assuring this consistency is controversial. Many believe that the preplan method is superior, while others would argue for some form of intraoperative or ‘real-time’ technique. Most brachytherapists have started to move toward more of an intraoperative methodology, either running the preplan in the OR or by performing the interactive technique described here. Intraoperative planning has the advantage of minimizing the discrepancies in repositioning the patient and saves time by eliminating the preplanning carried out in a different setting. However, pubic arch interference, prostate gland movement, and edge distortion from needle insertion can still cause plan deviation, which may adversely affect implant quality. Gewanter found a decrease in overall planning time with the intraoperative preplanning approach. There was no difference in dosimetry from their standard preplanning and their intraoperative technique (V145:80% vs 83%).21 The ratio of mean %D90 comparing the preimplant to postimplant dosimetry results was also quite high (1.34 and 1.54, respectively). The intraoperative planning ratio was much higher because of significant overplanning in the operating room (mean D90:131%) compared to the postimplant dosimetry results (mean D90:85%). Wilkinson performed a similar

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study and found comparable results.22 Messing et al reported on an optimized inverse planning system.23 Patients first had a computerized preplan performed >1 month prior to implantation. Planning was repeated in the operating room with three stabilizing needles in place. An average of 23% underdosing was demonstrated when the preplan dosimetry results were compared to the intraoperative replanning results. No postimplant dosimetry data were reported, so making any judgment as to whether this system is an improvement over standard preplanning is not possible. Beyer has also evaluated the application of intraoperative dosimetry. In a pilot study of 17 patients, 9 control patients (standard preplan) had a median V100 (145 Gy) of 97%, while 8 intraoperative planned patients had a median V100 of 94%.24 Beyer’s approach is similar to that reported by Gewanter with some modifications. A greater attempt was made to incorporate intraoperative deviations, such as pubic arch interference, within the planning system. This study, like the other two reports on intraoperative preplanning, did not find a dosimetric advantage over the standard preplan technique. In fact, Beyer found the postimplant dosimetry was somewhat inferior. Of the 9 patients, 3 (33%) had V100 < 100% of which 2 < 90%. No comparison was made between the intraoperative and the postoperative plans. Zelefsky treated 248 patients with an intraoperative computer-optimized technique.25 He used an in-house program to optimize seed positions after peripheral needle placement along with their own dosing constraints. Postimplant dosimetry was obtained 4 hours after seed insertion. Comparisons were made to 247 patients treated with the standard preplan technique before the institution of the computerized method. Median V100 improved from 88% to 96% (p<0.05) and D90 from 95% to 120% (prescription 145 Gy, p<0.05). While a decrease was also noted in urethral dose, both the V150 and rectal doses were higher in the intraoperative computer-optimized treated patients. This is in contrast to the current study, where postimplant urethral doses were noted to be higher than the doses generated in the OR (194 vs 250 Gy to 30% of the urethra). However, a catheter was not placed for the CT study and the urethral position was just estimated. The rectal doses were not increased and the V150 was substantially less than what was reported in the Zelefsky study (36% vs 74%) suggesting that the 7.1 method may give a more homogeneous implant. It is clear from this study and the one reported by Zelefsky that an intraoperative approach combined with an interactive planning system could improve the dosimetry outcomes of prostate brachytherapy. These techniques yield consistent prostate doses that are sufficient for eradicating the tumor and low enough at critical structures, urethra, and rectum to protect the patient from long-term morbidity. More centers should consider adopting similar methodologies in order to enhance their prostate brachytherapy program. References 1. Whitmore WF, Hilaris B, Grabstald H. Retropubic implantation of iodine 125 in the treatment of prostatic carcinoma. J Urol 1972; 108:918–920. 2. Holm HH, Pedersen JF, Hansen H, Stroyer I. Transperineal 125I iodine seed implantation in prostatic cancer guided by transrectal ultrasonography. J Urol 1983; 130:283–286.

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3. Blasko JC, Wallner K, Grimm PD, Ragde H. Prostate specific antigen based disease control following ultrasound guided 125Iodine implantation for stage T1/T2 prostatic carcinoma. J Urol 1995; 154:1096–1099. 4. Dawson JE, Wu T, Roy T, et al. Dose effects of seeds placement deviations from preplanned positions in ultrasound guided prostate implants. Radiother Oncol 1993; 32:268. 5. Blasko JC, Radge H, Schumacher D. Transperineal percutaneous Iodine-125 implantation for prostatic carcinoma using transrectal ultrasound and template guidance. Endocurie Hypertherm Oncol 1987; 3:131–139. 6. Cooner WH, Mosley BR, Rutherford CL, et al. Prostate cancer detection in a clinical practice by ultrasonography, digital rectal examination and prostate specific antigen. J Urol 1990; 143:1146. 7. Stone NN, Ramin SA, Wesson MF, et al. Laparoscopic pelvic lymph node dissection combined with real-time interactive transrectal ultrasound guided transperineal radioactive seed implantation of the prostate. J Urol 1995; 53:1555–1560. 8. Stone NN. Ultrasound determination of prostate volume: A comparison of transrectal (ellipsoid versus planimetry) and suprapubic methods. J Endourol 1991; 5:251–254. 9. Stone NN, Roy J, Hong S, et al. Prostate gland motion and deformation caused by needle placement during brachytherapy. Brachytherapy 2002; 1:154–160. 10. Stone NN, Stock RG, DeWyngaert JK, Tabert A. Prostate brachytherapy: improvements in prostate volume measurements and dose distribution using interactive ultrasound guided implantation and three-dimensional dosimetry. Radiat Oncol Investig 1995; 3:185–195. 11. Anderson LL. Spacing nomogram for interstitial implants of 125I seeds. Med Phys 1976; 386–7 12. Quimby EH. The grouping of radium tubes in packs and plaques to produce the desired distribution of radiation. Am J Roentgenol 1932; 27:18–36. 13. Stock RG, Stone NN, Lo YC, et al. Post-implant dosimetry for 125I prostate implants: definitions and factors affecting outcome. Int J Rad Oncol Biol Phys 2000; 48:899–906. 14. Stock RG, Stone NN, Lo YC. Intraoperative dosimetric representation of the real-time ultrasound guided prostate implant. Tech Urol 2000; 6:95–98. 15. Stone NN, Roy J, Hong S, Lo YC, et al. Prostate gland motion and deformation caused by needle placement during brachytherapy. Brachytherapy 2002; 1:154–160. 16. Bice WS, Prestidge BR, Grimm PD, et al. Centralized multiinstitu-tional postimplant analysis for interstitial prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998; 41:921. 17. Matzkin H, Kaver I, Bramante-Schreiber L, et al. Comparison between two 125I brachytherapy implant techniques: pre-planning and intra-operative by various dosimetry quality indicators. Radiat Oncol 2003; 68:289–294. 18. Stone NN, Hong S, Lo YC, et al. Comparison of intraoperative dosimetric implant representation to post-implant dosimetry in patients receiving prostate brachytherapy. Brachytherapy 2003; 2(1):17–25. 19. Stock RG, Stone NN, Tabert A, et al. A dose-response study for 125I prostate implants. Int J Radiat Oncol Biol Phys 1998; 41:101–108. 20. Stock RG, Stone NN, Kao J, et al. The effect of disease and treatmentrelated factors on biopsy results after prostate brachytherapy. Cancer 2000; 89:1829–1834. 21. Gewanter RM, Wuu CS, Laguna JL, et al. Intraoperative preplanning for transperineal ultrasound guided permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 48:377–380. 22. Wilkinson D, Lee, Ciezki J, et al. Dosimetric comparison of preplanned and OR planned prostate seed brachytherapy. Int J Radiat Oncol Biol Phys 2000; 48:1241–1244. 23. Messing EM, Zhang BY, Rubens DJ, et al. Intraoperative optimized inverse planning for prostate brachytherapy: early experience. Int J Radiat Oncol Biol Phys 1999; 44:801–808. 24. Beyer DC, Shapiro RH, Puente E Real-time optimized intraoperative dosimetry for prostate brachytherapy: a pilot study. Int J Radiat Oncol Biol Phys 2000; 48:1583–1589.

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25. Zelefsky MJ, Yomada Y, Marion C, et al. Improved conformality and decreased toxicity with intraoperative computer-optimized transperineal ultrasound-guided prostate brachytherapy. Int J Rad Oncol Biol Phys 2003; 55:956–963.

20 The ProSeed approach: a multicenter study of the results of brachytherapy training Nelson N Stone, Jeffrey H Chircus, Richard G Stock, Joseph Presser, and the ProSeed team Introduction Prostate brachytherapy has become an accepted means of treating localized prostate cancer. The ‘new’ brachytherapy is distinguished from prostate seed implantation performed prior to 1985 by the use of ultrasound guidance to plan and place the radioactive sources.1–3 The older brachytherapy techniques used a ‘free-hand’ method of seed placement, which resulted in inadequate coverage of the prostate gland by the intended radiation and a higher clinical failure rate than had been anticipated.4–5 While the ultrasound-guided implant technique is considered to be far superior to the older implant method, little data have emerged that documents that quality implants consistently result with its use. Implant quality directly relates to clinical outcome, yet significant data are lacking on postimplant dosimetry from most centers.6 Two issues are emerging that could be crucially important to patients as they search for what they consider to be their best choice for treating their localized prostate cancer: can a quality implant always be performed and has the physician been trained adequately to get consistent high quality results? Prostate brachytherapy is a highly technical procedure requiring extensive training and experience in order to gain proficiency. We set up a training program that offered classroom-style instruction along with on-site proctorship of the treating physicians until a sufficient level of proficiency was achieved. After completing training, the physicians were allowed to treat patients on their own. The results of the training were assessed by determining the quality of the implant while the proctor was present and after the physician had completed training. This is the first report that analyses this type of postgraduate (residency) training and the impact that it has on assuring patients that they can receive a new type of treatment without having to worry that their physician will have to go through a ‘learning curve’ by gaining sufficient experience on them. Materials and methods Technique The real-time technique of seed implantation was the method for prostate brachytherapy taught to the physicians. Prior to implantation, the prostate volume measurement was

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obtained using: height×width×length multiplied by 0.52. This ‘ellipsoid’ volume was given to the radiation oncologist, who used an activity nomogram ordered the appropriate amount of activity to bring to the opearting room (OR). Details of this technique for prostate brachytherapy have been previously reported.2,7 Patients with biopsy proven adenocarcinoma of the prostate who had a Gleason score ≤6 were implanted with 125iodine (125I) to a minimum dose of 140 Gy (TG-43). Patients were brought to the OR where the ultrasound probe [Bruel & Kjaer; B&K, model 8551 (prior to 1998) or model 8558] was placed into a special cradle and stepping device and attached to the base unit. The probe was next positioned in the rectum and using transverse imaging, serial contours of the prostate were measured at 5 mm intervals from prostate base to apex. This planimetry volume was used when calculating the amount of activity to implant. The total activity, as determined by a nomogram, was divided by the activity per seed (usually 0.3–0.5 mCi/seed for 125I) gives the total number of seeds to implant. After the volume measurements were completed, imaging was switched to longitudinal and measurements were made anterior and posterior to the urethra and posteriorly from base to apex. These longitudinal measurements were used to determine the spacing between the seeds. The implant was begun by first finding the largest transverse image of the prostate and by placing Mick needles (Mick Radionuclear Instruments) in the periphery of the gland. Starting posteriorly, and keeping at least 7 mm above the anterior rectal wall, individual applicator needles were placed approximately 1 cm apart. Working in a clockwise fashion, the entire periphery of the gland was implanted with the needles. The number of needles was summed and divided into the number of seeds to be implanted in the periphery. For iodine-125 and palladium103, 75% of the total activity was placed in the periphery. Spacing between seeds in each row was determined by calculating the average length of the prostate. The average length was determined from the three length measurements made in longitudinal imaging. The spacing between seeds was then calculated by: seeds per row/n-1, where n=average height of the prostate. The maximum space allowed between seeds in the periphery was no greater than 10 mm. Implantation of the seeds was accomplished with a Mick applicator (Mick TP-200, Mick Radionuclear Instruments). Imaging was switched to sagittal and the probe was advanced in a cephalad direction until the entire prostate was overlying the transducer head. The probe was then rotated to the left (counter clock-wise) and the most lateral needle was imaged. The tip of the needle was identified and brought to the base of the gland. The radiation oncologist then placed the radioactive sources using the Mick TP 200 applicator. Working from base to apex and keeping the tip of the needle under constant ultrasound monitoring, each individual seed was placed until the apex of the gland was reached. The interior needles were then placed using ultrasound to space the needles 10 mm from the periphery, at least 5 mm from the urethra and approximately 10 mm apart. The implant procedure was enhanced with the addition of the Varian 6.7 software (Varian, Palo Alto, CA) in 1999, Varian 7.0 in 2002 and 7.1 in 2003. The addition of the planning software allowed for intraoperative dose adjustment.8–9 The planning rules, as detailed above, remained consistent, even with the addition of the software.

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Training The training consisted of two phases, a didactic session and proctoring. All personnel who participated in the procedure were required to attend the didactic session, which lasted about four hours. This included urologists, radiation oncologists, medical physicists, dosimetrists, nurses, and all OR personnel involved in the procedure. A urologist, radiation oncologist, and nurse gave lectures. Materials handed out included a detailed procedure manual, a didactic book and videotape demonstrating the procedure. At the end of the didactic session the participants were trained on the use of the equipment using a phantom model. After completion of the didactic session, physicians scheduled cases in their own OR. A physician proctor (either radiation oncologist or urologist), with significant experience in this technique, attended all cases until both the provider radiation oncologist and urologist were proficient in the method. This usually required a minimum of five cases, but was not specifically limited to a case number. It was up to the judgment of the last physician proctor to determine if an individual provider could perform cases independently (post-proctor). Yearly updates were recommended and provided both a clinical review and procedure enhancement with additional OR training. Implant quality evaluation One month after implantation the patient returned to have the implant evaluated. Computed tomography (CT) images of the prostate were taken at 3 mm intervals from the base of the bladder to the sphincter to assess the quality of the implant. Initially, CT images were sent to a central site where all the dosimetry was performed. Transverse CT images were analyzed by one physician (RGS) who traced out the prostate, rectum, and bladder on each slice. The images and seed positions were then digitized by a commercially available brachytherapy software package (MMS TherpacPLUS, Multimedia Medical Systems, 700 Harris Street, Suite 109, Charlottesville, VA, 22903). The software models dose distributions with the new dosimetry formalisms adopted by the American Association of Physicists in Medicine (AAPM) Task Group 43. The output is a graphical depiction of the isodose distribution of each transverse slice. A dosevolume histogram (DVH) was also generated to provide volume information of the implanted dose. The dosimetry parameters Dn, Rectn, and Bladdn, which are the doses encompassing n% of the prostate, rectal wall, and bladder wall, respectively, were interpolated from the DVH. Results were reported as dose-volume histograms and dose surface histograms of the prostate, rectal wall, and base of bladder, respectively. The dose to 90% of the prostate volume (as determined by the CT) was calculated as was the percent of the gland covered by the target dose (140 Gy for 125I, 115 Gy for full 103Pd, and 83 Gy for partial 103Pd). The doses to 10% and 30% of the rectal and bladder volumes were also calculated. After 1999, hospitals that obtained the Varian planning software through ProSeed performed their own postimplant dosimetry and sent the data in for analysis. All data was entered into a centralized database. Comparisons were made for the entire group as well as for the proctored and post-proctored cases using student t test.

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Results The initial four ProSeed hospitals were started in 1996 and were: Northwest Hospital Center, Baltimore, MD,

Figure 20.1 Number of implants per hospital. There was a mean of 26 cases per hospital (range: 1–108). Holy Cross Hospital, Silver Spring, MD, Baptist Hospital, Nashville, TN, and Reston Hospital Center, Reston, VA. By the end of 1997 and 1998, 19 hospitals and 44 hospitals were performing the ProSeed implants. Over 120 hospitals throughout the United States, Europe, the Middle East, and Africa have performed ProSeed implants to date. From 1996 to February 2001, a total of 990 patients received a prostate implant at 35 centers (mean 26 cases/ center) of which 289 (29.1%) were proctored (group 1) and 701 were done by physicians who had been certified to perform the implants independent of a proctor (group 2) (Figure 20.1). There were 665 125I (target dose 140 Gy), 135 full dose 103 Pd (target dose 115 Gy) and 19 partial 103Pd (target dose 77 Gy) implants (Figure 20.2). Mean D90 for

Figure 20.2 Distribution of cases by teaching (proctor) and implant type (p103Pd is partial 103Pd).

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125

I for group 1 vs 2 were 164 Gy vs 162 Gy (p=0.4). Mean D90 for full 103Pd for group 1 (n=45) vs 2 (n=89) were 133 Gy vs 125 Gy (p=0.02). Mean D90 for partial 103Pd for group 1 (n=47) vs 2 (n=144) were 88 Gy vs 92 Gy (p=0.1). Additional prostate, rectal, bladder, and urethral dose comparisons are shown in Tables 20.1–20.3. Of the 665 125I implants, 9.1% (18/197) of group 1 and 8.3% (39/468) of group 2 had a D90 < 140 Gy and 1.5% vs 1.9% had a D90 < 120 Gy (Figure 20.3). In the full 103Pd patients, 13.3% of the proctored cases had a D90 < 115 Gy vs 23.6% of the trained physicians, while 0% of group 1 vs 2% of group 2 resulted in D90 < 100 Gy (Figure 20.4). For the partial 103Pd cases, 23% vs 13.2% were found with a D90 < 77 Gy, while 0% of each group had a D90 < 60 Gy (Figure 20.5).

Table 20.1 Comparison of proctor (n=197) to certified (n=468) 125I postimplant dosimetry doses. D50–100: dose covering percent of prostate volume; rectal 10 and 30: dose to 10% and 30% of rectal volume; same for bladder and urethra. Values are in gray and represent means Proctor Certified p-value D100 D95 D90 D80 D50 Rectal 10 Rectal 30 Bladder 10 Bladder 30 Urethra 10 Urethra 30

81 143 164 190 242 125 64 102 59 201 186

77 139 162 186 240 122 60 98 59 198 184

0.03 0.02 0.4 0.2 0.5 0.4 0.1 0.2 0.9 0.8 0.8

Table 20.2 Comparison of proctor (n=45) to certified (n=89) 103Pd postimplant dosimetry doses. D50–100: dose covering percent of prostate volume rectal 10 and 30: dose to 10% and 30% of rectal volume; same for bladder and urethra. Values are in Gy and represent means Proctor Certified p-value D100 D95 D90 D80 D50 Rectal 10

51 111 133 163 228 87

50 0.6 105 0.01 125 0.02 152 0.02 221 0.4 86 0.7

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37 87 45 184 170

298

34 0.3 75 0.06 39 0.12 183 0.9 167 0.6

Table 20.3 Comparison of proctor (n=47) to certified (n=144) partial 103Pd postimplant dosimetry doses. D50–100: dose covering percent of prostate volume; rectal 10 and 30: dose to 10% and 30% of rectal volume; same for bladder and urethra. Values are in gray and represent means Proctor Certified p-value D100 D95 D90 D80 D50 Rectal 10 Rectal 30 Bladder 10 Bladder 30 Urethra 10 Urethra 30

32 73 88 110 161 63 28 46 21 140 127

36 0.04 76 0.06 92 0.1 110 0.1 158 0.7 61 0.7 26 0.4 54 0.05 28 0.006 135 0.6 123 0.6

Discussion Prostate brachytherapy was first described almost 90 years ago and has evolved into a highly technical procedure.8,10 Ten year data suggest that prostate brachytherapy is equivalent to radical prostatectomy in biochemical cure.11 Other studies with shorter follow-up also suggest equivalent results to external beam irradiation and radical prostatectomy.12–2020 With these data now readily available to clini cians and their patients, brachytherapy is rapidly becoming a popular method of treating localized prostate cancer. Physician training in prostate brachytherapy has typically been limited to one or two day courses offering at most didactic laboratory sessions. In addition, newly graduated urologists and radiation oncologists are emerging from their residency programs with little to no training because most academic programs are just beginning their own brachytherapy programs. There are no formal

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Figure 20.3 Percent of patients with D90 (125I) values by dose cutoff point.

Figure 20.4 Percent of patients with D90 (103Pd) values by dose cutoff point. programs that also train the hospital staff. Because of the highly technical nature of prostate brachytherapy, adequate training would appear to be critically important in assuring patients of a successful and safe outcome. While clinical outcome (e.g. biochemical freedom from failure based on PSA), can be one measure of a successfully performed implant, it can take at least 5 years in a prostate cancer patient to know if the treatment has been successful. In addition, late radiation complications, such as proctitis, urethritis, and cystitis, can take 2 to 3 years before they manifest themselves. It is not reasonable to wait for such outcomes to know whether or not the treating physician is delivering proper therapy. Quality assessment of an implant can be determined shortly after the procedure by a dosimetric evaluation. Older systems relying on plain or orthogonal radiographs did not accurately identify the relationship between the radioactive sources and the soft tissue structures (prostate, rectum, and bladder). Stone described the use of CT scan transverse images, which were digitized with a software program that accurately reconstructed the position of the seeds and the prostate, urethra, rectum, and bladder. The dose covering 90% of the prostate was described as well as the dose to the surface area of the rectum.21 Willis and

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Figure 20.5 Percent of patients with D90 (partial 103Pd) values by dose cutoff point. Wallner reported on their experience with CT-based dosimetry in 20 unselected patients who had received an 125I implant.22 They reported an average of 84% of the target volume (prostate) receiving a dose of 140 Gy. They considered an implant to be adequate if 140 Gy covered 80% of the prostate. Stock, in a dose-response study of 125I, was the first to report that a D90 dose of 140 Gy was necessary in order to achieve a substantial PSA biochemical freedom from failure (93% vs 48% in those patients who received less than 140 Gy).6 Biopsy studies have demonstrated 98% local control with a D90 of at least 100 Gy (pre-NIST 1999) in patients who had received a 103Pd implant.12 Adequate dosing for permanent implants combined with external beam irradiation (EBRT) has been harder to define. Dattoli used 103Pd at a dose of 80 Gy with external beam irradiation in high risk patients and found a favorable outcome.23 Likewise, Blasko reported on a group of high risk patients who received the combination treatment and received a dose of 86 Gy of palladium.24 Finally, the American Brachytherapy Society recommends that the brachytherapy dose be reduced to 50–75% of the full dose (for palladium: 58–86 Gy) when combined with EBRT.25 The data from this study demonstrate two important points. One, that community hospitals, performing the ProSeed implant can achieve high quality results in the majority of their patients. And second, with a comprehensive training program, centers can quickly learn the realtime implant technique. The ProSeed training program was designed as a turnkey approach where the entire team, including nursing staff, physicists, urologists, radiation oncologist, and hospital administration were trained in their respective responsibilities. The training took place over several months until the physician team was confident enough to perform the cases independent of the proctor. The mean D90 for the 125I patients when the proctor was supervising the case was 164 Gy compared to 162 Gy when the case was performed after the physicians had received their certification. Radiation doses to the rectum, urethra and bladder were also no different for the two groups. In addition, a similar number of cases (9.1% vs 8.3%) fell below the recommended therapeutic dose of 140 Gy. Lee et al described a brachytherapy ‘learning curve’ in reporting the dosimetry results of the first 63 patients treated at their center.26 They reported a C90 (90% of the prostate receiving a percentage of the prescription dose: 144 Gy). The mean C90 for the first 30 patients was 79.9% vs 89.9% for the next 33 (p=0.00009). Conversion of these values to D90 in gray would yield 115

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Gy vs 127 Gy for the two groups. When compared to the D90s reported for the ProSeed implants, these values are substantially inferior. While a direct comparison of the data from Lee’s center to the ProSeed data is not appropriate, it is clear from the large dose discrepancy that some explanations are warranted. Lee chose to perform a preplanned technique, while all of the implants performed in the ProSeed centers were done by the real-time method. While there are no randomized trials evaluating a possible advantage of one method of seed implantation over another, studies are starting to emerge indicating a preference of the real-time method. Matzkin reported the dosimetric outcomes of 142 consecutive patients treated by the preplan method and compared these to 214 who were implanted using the real-time method (Sourasky, Tel Aviv, Israel is a ProSeed center). The V90 (prescription dose 160 Gy) for the preplanned method was 67.5% vs 97.9% (p<0.01) for the realtime method.27 The authors of this study discount any ‘learning curve’ effect and attribute the dosimetry differences solely to the differences in technique. Technique aside, it is clear from the data presented in this study, that an intensive formal training program in prostate brachytherapy is highly effective in providing physicians with enough skills to independently perform good quality implants. The data from the Lee study also suggest that without such a program, even a year of ‘practice’ may also not be enough to bring a center up to the level of expertise necessary to perform the implants uniformly well. References 1. Holm HH, Pedersen JF, Hansen H, Stroyer I. Transperineal I-125 iodine seed implantation in prostatic cancer guided by transrectal ultrasonography. J Urol 1983; 130:283–286. 2. Stock RG, Stone NN, Wesson MF, De Wyngaert JK. A modified technique allowing interactive ultrasound-guided three-dimensional transperineal prostate implantation. Int J Radiat Oncol Biol Phys 1995; 32:219–225. 3. Blasko JC, Wallner K, Grimm PD, Ragde H. PSA based disease control following ultrasound guided I-125 implantation for stage T1/T2 prostatic carcinoma. J Urol 1995; 154:1096–1099. 4. Kuban DA, El-Mahdi AM, Schellhammer PF. I-125 interstitial implantation for prostate cancer: What have we learned 10 years later? Cancer 1989; 63:2415–2420. 5. Fuks Z, Leibel SA, Wallner KE, et al. The effect of local control on metastatic dissemination in carcinoma of the prostate: Long-term results in patients treated with I-125 implantation. Int J Radiat Oncol Biol Phys 1991; 21:537–547. 6. Stock RG, Stone NN, Tabert A, et al. A dose response study for I-125 prostate implants. Int J Radiat Oncol Biol Phys 1998; 41:101. 7. Stone NN, Stock RG. Brachytherapy for prostate cancer: real-time three-dimensional interactive seed implantation. Tech Urol 1995; 1:72–80. 8. Stock RG, Stone NN, Lo YC. Intraoperative dosimetric representation of the real-time ultrasound guided prostate implant. Tech Urol 2000; 6:95–98. 9. Stone NN, Hong S, Lo YC, Howard V, Stock RG. Comparison of intraoperative dosimetric implant representation to post-implant dosimetry in patients receiving prostate brachytherapy. Brachytherapy 2003; 2(1):17–25. 10. Pasteau O, Degrais P. The radium treatment of cancer of the prostate. Journal d’Urol (Paris) 1913; 4:341–366. 11. Ragde H, Abdel-Aziz AE, Snow PB, et al. Ten-year disease free survival after transperineal sonography-guided Iodine-125 brachytherapy with or without 45-Gray external beam irradiation

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in the treatment of patients with clinically localized, low to high Gleason grade prostate carcinoma. Cancer 1998; 83:989–1001. 12. Stock RG, Stone NN, DeWyngaert JK, et al. Prostate specific antigen findings and biopsy results following interactive ultrasound guided transperineal brachytherapy for early stage prostate carcinoma. Cancer 1996; 77:2386–2392. 13. Stock RG, Stone NN. The effect of prognostic factors on therapeutic outcome following transperineal prostrate brachytherapy. Semin Surg Oncol 1997; 13:454–460. 14. Wallner K, Roy J, Harrison L. Tumor control and morbidity following transperineal iodine 125 implantation for stage T1/T2 prostatic carcinoma. J Clin Oncol 1996; 14:449–453. 15. Beyer DC, Priestley Jr JB. Biochemical disease-free survival following 125I prostate implantation. Int J Radiat Oncol Biol Phys 1997; 37:559–563. 16. Blasko JC, Ragde H, Luse RW, et al. Should brachytherapy be considered a therapeutic option in localized prostate cancer? Urol Clin North Am 1996; 23:633–650. 17. Grado GL, Larson TR, Balch CS, et al. Actuarial disease-free survival after prostate cancer brachytherapy using interactive techniques with biplane ultrasound and fluoroscopic guidance. Int J Radiat Oncol Biol Phys 1998; 42:289–298. 18. Kaye KW, Olson DJ, Payne JT. Detailed preliminary analysis of 125Iodine implantation for localized prostate cancer using percutaneous approach. J Urol 1995; 153:1020–1025. 19. Ragde H, Blasko JC, Grimm PD, et al. Interstitial Iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 1997; 80:442–453. 20. Sharkey J, Chovnick SD, Behar RJ, et al. Outpatient ultrasoundguided palladium 103 brachytherapy for localized adenocarcinoma of the prostate: A preliminary report of 434 patients. Urology 1998; 51:796–803. 21. Stone NN, Stock RG, DeWyngaert JK, Tabert A. Prostate brachytherapy: Improvements in prostate volume measurements and dose distribution using interactive ultrasound guided implantation and three-dimensional dosimetry. Radiat Oncol Investig 1995; 3:185–195. 22. Willins J, Wallner K. CT-based dosimetry for transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1997; 39:347–353. 23. Dattoli M, Wallner K, Sorace R, et al. 103Pd brachytherapy and external beam irradiation for clinically localized, high-risk prostatic carcinoma. Int J Radiat Oncol Biol Phys 1996; 35:875. 24. Blasko JC, Ragde H, Cavanagh W, Sylvester J, et al. Long-term outcomes of external beam irradiation and I-125/Pd-103 brachytherapy boost for prostate cancer. Int J Radiat Oncol Biol Phys 1996; 36:198. 25. Nag S, Baird M, Blasko J, et al. American Brachytherapy Society survey of current clinical practice for permanent brachytherapy of prostate cancer. J Brachyther Int 1997; 13:243–251. 26. Lee WR, De Guzman AF, Bare RL, et al. Postimplant analysis of transperineal interstitial permanent prostate brachytherapy: evi dence of a learning curve in the first year at a single institution. Int J Rad Oncol Biol Phys 2000; 46:83–88. 27. Matzkin H, Kaver I, Brmante-Schreiber L, et al. Comparison between two iodine-125 implant techniques: pre-planning and intra-operative by various dosimetry quality indicators. Radiother Oncol 2003; 68:289–294.

Contributing hospitals in brachytherapy training Avera McKennan Hospital, Sioux Falls, SD; Baptist Memorial East, Nashville, TN; Baptist Medical Center, Birmingham, Memphis, Alabama; Boulder Community, Boulder, CO; Columbia Greenview Medical Center, Bowling Green, KY, Columbia; Danbury Hospital, Danbury, CT; DCH Regional Medical Center, Tuscaloosa, AL; DePaul, Norfolk, VA; Geisinger Wyoming Valley Medical Center, Wilkes Barre, PA Glens Falls

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Hospital, Glens Falls, NY; Kalispell Regional Hospital, Kalispell, MT; Lewis-Gale Medical Center, Salem, VA; Los Gatos Hospital, Los Gatos, CA; Lucy Lee Health Care System, Poplar Bluff, MO; Mather Memorial, Port Jefferson, NY; Med Center One Hospital, Bismark, ND; Mills Peninsula Health Services, San Mateo, CA; Mount Carmel Regional Medical Center, Pittsburg, KS; Maryview Medical Center, Portsmouth, VA; Niagra Falls Memorial Medical Center, Niagra Falls, NY; Phelps County Regional Medical Center, Rolla, MO; Pinnacle Health System, Harrisburg, PA; Reading Hospital and Medical Center, West Reading, PA; Pulaski Community Hospital, Pulaski, VA; Rex Health Care, Raleigh, NC; River Parishes Hospital, LaPlace, LA; Riverside Medical Center, Kankakee, IL; Shadyside Hospital, Pittsburgh, PA; Silvercross Hospital, Joliet, IL; Saint Mary Mercy Hospital, Livonia, MI; Saint Ritas, Lima, OH; Saint Tammany Parish Hospital, Covington, LA; Tulare District Health Care System, Tulare, CA; WCA, Jamestown, NY; Virtua Health Memorial Hospital, Mount Holly, NJ; Nelson N.Stone MD, Jeffrey H.Chircus MD and Richard G.Stock MD were the original founders of ProSeed, LLC and have a financial interest in ProSeed, Inc, a subsidiary company of C.R.Bard. Joseph Presser is a consultant physicist, The ProSeed Team: Laura Tweett, Mike Krachon, Julie Darity, Russ Dean and Eric Brown work in the ProSeed Office at Bard Urologic Division, Covington, GA.

21 Functional image registration in brachytherapy Takashi Mizowaki and Marco Zaider Background Image-guided radiation therapy has become clinically important as a result of technical advances in both diagnostic imaging and radiation therapy. To conduct tumortargeted radiation therapy, the ability to detect and treat regions with aggressive tumor deposits that include radioresistant or hypermetabolic cells is indispensable. Ling et al proposed the term biological target volume (BTV) for the description of these regions.1 Malignant cells within the BTV are considered clinically significant cancer because, at least in radiobiological terms, it is these cells that quite likely determine the ultimate outcome of radiation therapy. Therefore, an ideal imaging tool for radiotherapy treatment planning (RTTP) should provide information on the location and the number of these cells.1 A number of new techniques have been developed to overcome the drawbacks of conventional imaging modalities. In comparison with conventional (so-called anatomical) imaging, they are classified as biological imaging because of the ability to provide information on the metabolic, functional, physiological, or biochemical status of the tumor.1 Essentially, they can help to improve the detectability of the BTV within the gross tumor volume. Interest in these new imaging modalities has increased in direct proportion to improvements in RTTP and in dose delivery, such as external-beam intensity-modulated radiation therapy, or image-guided intraoperative planning in brachytherapy,1–3 with the result that one has the ability to design and implement treatment plans that safely escalate the dose to the BTV within the target volume. As a functional-imaging tool for the treatment of localized prostate cancer, magnetic resonance spectroscopy (MRS) is considered to be most promising.4 It is based on the observation that a significant increase in choline and decrease in citrate levels are observed in regions harboring cancer.5–9 On biochemical grounds, choline/citrate ratio is expected to reflect an increased rate of cell proliferation. In addition, there is limited empirical evidence of a correlation between choline levels and histological grade indicated by Gleason’s scores.6 Our preliminary data further confirm that MRS can detect most of the regions containing cells with high Gleason score (8 or higher). MRS is currently in clinical use at our institution for prostate implant brachytherapy. Treatment planning performed intraoperatively, makes use of this information to escalate the dose at the MRS voxels identified as having increased choline/citrate ratios.2,10 The prostate as a whole is treated to 100% of the prescription dose (144 Gy for 125I seeds); however, MRS positive voxels (tumor burdens) are prescribed 200% of the prescription

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dose with no upper limit. For every treatment (with or without MRS dose escalation) the urethral dose is kept under 120% of the prescription dose (Figure 21.1). A key element in the implementation of the above technique is the ability to map the location of MRS-positive voxels to the corresponding ultrasound (US) images for RTTP. The reason for this is the fact that an endorectal coil is necessary to conduct magnetic resonance imaging (MRI) and MRS examinations, and this results in a deformation of the prostate volume. MRI and MRS of the prostate are obtained with the combination of an endorectal and a pelvic phased array receiver coil.5,6 The endorectal balloon probe (which supports the endorectal coil, see Figure 21.2) is inflated to a total volume of 100 cm3 of air and under these conditions the prostate gland is pushed anteriorly against the pubic bone, which causes a slight flattening of its shape (Figure 21.3). Because treatment planning in prostate implants is performed based on US images, where the deformation of the prostate by the US probe is minimal, it was necessary to devise a procedure for mapping points of interest from MRS to US images. In the present chapter, our method for image registration of the prostate from the MRI/MRS (MR) to the US space is described. Image registration algorithm The mapping algorithm described below is based on the assumption that points within the gland maintain the

Figure 21.1 An example of the dosedistribution for prostate implants that incorporates MRS information. This

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plan is optimized to give at least 200% of the prescription dose (144 Gy for 125 I seeds) to the registered MRSpositive area on a US image (included in an area shaded in yellow).

Figure 21.2 An endorectal balloon probe for MRI/MRS study.

Figure 21.3 Magnetic resonance spectroscopy (MRS) information superimposed on the corresponding T2-weighted fast spin-echo image (TR,

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5000 ms; effective TE, 102 ms) of a 54-year-old patient with Gleason grade 7, pretreatment prostate-specific antigen (PSA) level of 4.5 ng/mL A left-posterior voxel labeled ‘P’ is judged as ‘possible cancer’ by MRS. ‘R_B’ indicates the rectum inflated with the balloon probe. Deformation of the prostate by the inflated endorectal balloon probe is apparent (arrows). same relative position with respect to the axial contours of the prostate and are displaced along the z-axis (craniocaudal direction) in direct proportion to the cranio-caudal dimension of the gland with reference to the center-ofmass (COM) of the prostate. The algorithm is as follows (Figures 21.4 and 21.5): (a) Calculate the COM of the prostate in the MRI/MRS (MR) (C1) and US (C2) space. (b) For a particular point [A1:(x1, y1, z1)] in the MR space, obtain the z-coordinate of the corresponding point [A2:(x2y2, z2)] in the US space from:

(1) Here, zT1 and zT2 refer to the z-coordinate of the superior aspects of the prostate in the MR and US space, respectively, and zB1 and zB2 refer to the z-coordinate of the inferior aspects of the prostate in the MR and US space, respectively. zC1 and zC2 are the z-coordinate of the prostate COM in the MR space and US space, respectively. (c) With the z position thus calculated, map the (x1, y1) in the MR space on to the (x2, y2) in the US space as follows:

(2)

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Figure 21.4 Schematic drawing of the mapping method in the sagittal plane: the diagram indicates the registration of a point (A1) in the MRI/MRS space to the corresponding point (A2) in the US space. The z-axis is along the superior-inferior direction.

Figure 21.5 Schematic drawing of the mapping method in the axial plane: the diagram indicates the registration of a point (A1) in the MRI/MRS space to the corresponding point (A2) in the US space. The x-axis indicates right-left

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direction and the y-axis represents the anteriorposterior direction. Here, yA1 and yA2 are the y-coordinate of the anterior aspects of the prostate in the MR and US space, respectively; and yP1 and yP2 represent the ycoordinate of the posterior aspects of the prostate, respectively. It is understood that (x2, y2) are calculated in the axial slice that corresponds to the z2 position obtained from Eq. (1). Validation of the algorithm Phantom study The validity of the algorithm (Eqs 1,2) was verified with the aid of an anthropomorphic pelvic phantom (Figure 21.6) built to our specifications by Computerized Imaging Reference Systems, Inc (CIRS, Norfolk, VA). The phantom is made mainly of a proprietary material (Zerdine™, a water-based polymer developed by CIRS to be CT, US, and MRI/MRS compatible), which accurately mimics human tissues for MR, US, and CT imaging. The phantom contains simulated prostate, bladder, urethra, seminal vesicles, and rectum, all made of Zerdine, and pelvic bones made of epoxy. Background material, which occupies all regions outside the structures defined above, is also made of Zerdine. According to the manufacturer, Zerdine was made to simulate the ultrasound characteristics of human liver tissue. The speed of sound, acoustic attenuation, and backscatter properties of this material can be adjusted to simulate different tissues. Thus, the contrast for different structures (built by molding Zerdine into the respective shapes) in this phantom is such that they are visible using both ultrasound and CT (the prostate is darker than background material, urethra material is darker than prostate, etc.). Seventyfive ‘dummy’ seeds (physically identical to model 6711 125I seeds) were placed in the prostate in a quasi-regular pattern. The coordinates of these seeds could be exactly determined with a CT study, and thus they served as reference markers for studying ‘prostate’ deformation when a rectal probe was inflated inside the rectum of the phantom (Figure 21.7). Two series of CT scans of the phantom were obtained, one without the endorectal probe (CT-Series_A) and the other with the endorectal balloon probe inflated with 100 ml of air (CT-Series_B). Therefore, the CT-Series_A represents the status of US image acquisition, while the CT-Series_B represents the status of MRI/MRS acquisition (Figure 21.7). The slice thickness of the CT images was 3 mm. The actual coordinates of the center of each seed were determined by using appropriate computer software (Interplant® Post-implant Analysis System, Version 1.0: Burdette Medical Systems, Inc, Champaign, IL) for each CT series. This software can reconstruct axial CT images of 1 mm thickness for positional determination of the seeds and plan evaluations. Then, the previously described mapping method was applied for the registration of each seed position from the CT-Series_B to the CT-Series_A, which simulated the registration from MRI/MRS to US images. Thereafter, coordinates of each

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seed in CT-Series_A calculated by the registration algorithm were compared with the actual seed position directly defined with the CT data (seed

Figure 21.6 A custom-made phantom that simulates the male pelvis was used to evaluate the mappin accuracy of our algorithm. This phantom can simulate deformations and shifts in structures caused by the endorectal balloon probe inflated within the ‘rectum’ (R).

Figure 21.7 A computed tomography (CT) image of the phantom: its original configuration (without the endorectal

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balloon probe: left) and with the inflated endorectal probe (right). ‘R’ in the left image indicates the empty ‘rectum’ and ‘R_B’ in the right represents the ‘rectum’ with inflated balloon probe. Inside the ‘prostate’ of the phantom, 75 dummy seeds are implanted. The deformation of the ‘prostate’ and the positional displacement of the implanted seeds by the endorectal probe are evident.

Figure 21.8 A flowchart of the steps needed to evaluate the accuracy of the image registration algorithm. CT, computed tomography; US, ultrasound.

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Figure 21.9 A schematic representation of the location of seeds with a positional error of 4 mm or larger in 3D space (indicated by+). positions determined by the computer software as described above), and the magnitude of the positional displacement was evaluated for each seed (Figure 21.8). In this way, the accuracy of the mapping algorithm was directly verified. In the phantom study, the absolute value of the threedimensional (3D) positional displacements between the registered and actual seed positions was 2.2 mm ±1.2 mm (average ± standard deviation; SD). Only 6 of the 75 implanted seeds had 3D positional displacement larger than 4 mm (Figure 21.9). The maximum value of the 3D displacements was 4.9 mm. The absolute value of the 3D positional error in this method was significantly smaller than that of our earlier method (p<0.0001 by both paired t-test and Wilcoxon signed rank test) (Figure 21.10).11 Patient study To validate this algorithm in vivo we have evaluated changes in seed positions due to the edema resolution of

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Figure 21.10 The absolute value of the 3D registration errors resulting from the phantom study as obtained with the current method (with corrections in zcoordinates) or with an earlier method (without corrections in z-coordinates).2 Positional accuracy for mapping in the current method was significantly smaller than that in the earlier approach (p<0.0001).

Figure 21.11 The absolute value of the 3D errors in the registration method as estimated for 20 seeds in a patient who underwent permanent prostate implant.

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the prostate in a patient who received permanent seed implant for prostate cancer. Two series of CT scans were obtained on this particular patient: one immediately after the implant and the other 6 weeks after the procedure. On the CT images obtained immediately after the seed implant, the edema of the prostate caused by the invasive procedure was observed. Throughout the period of 6 weeks that separates the two CT studies, there was edema shrinkage of about 30% in volume of the prostate that caused changes in the relative position of the seeds. Using the same methodology as in the phantom study (Figure 21.8), the accuracy of the mapping algorithm was evaluated on 20 seeds within the prostate of this particular patient. The result was similar to the outcome from the phantom study. The absolute value of the 3D positional error between predicted and actual seed positions was 2.4 mm± 1.3 mm (average±SD) (Figure 21.11). Current problems and future directions At this time, magnetic resonance spectroscopy (MRS) appears to be the most promising biological imaging modality for localized prostate cancer.4 In recent studies it was reported that proton MRS can well distinguish cancer dominant regions within the prostate gland from the normal prostate tissue based on the finding of significant reduction in citrate levels and increase in choline levels relative to the normal peripheral zone.5–9 In addition, cancer-positive voxels detected by 3D MRS can be precisely mapped on the corresponding MR images, which thus provides positional information on the location of the lesions within the prostate.5,12 Although MRS has relatively poor sensitivity and specificity (0.76 and 0.57, respectively,12 an argument can be made based on tumor-control probability models that a clinical advantage in brachytherapy may be expected when dosimetric hot spots, which are unavoidable, are placed at MRS-positive voxels rather than at random locations in the gland.2 A major limitation in the use of MRS in radiotherapy treatment planning (RTTP) is the need to account for changes in the shape of the prostate during the MRI/MRS study.2 Therefore, a method for performing image registration for a deformable object (prostate) is indispensable. We have developed an empirical registration method using proportional corrections based on the external con tour of the prostate. Despite its simplicity, this method is sufficienty accurate (2.2 mm ±1.2 mm) when compared to both the MRS voxel size (6.25 mm×6.25 mm×3.0 mm) and the typical slice thickness (5 mm) of the ultrasound (US) study for prostate implant. Because the spectroscopic signal obtained from a voxel (6.25 mm×6.25 mm× 3.0 mm) reflects the averaged response of tissue in it, with 2.2 mm uncertainty, there is no reason to be concerned about misplacement of the voxel. When an MRS-positive voxel is located laterally and close to the posterior surface of the prostate one may encounter the situation where the predicted position of the voxel (usually a part of the voxel) in the US space locates outside the prostate. This is due to the fact that, in contrast to the ‘normal’ prostate, the ‘MRS prostate’ is a distinctly nonconvex object. The ad hoc solution we have adopted is to move the voxel anteriorly inside the prostate; this is quite acceptable in view of the relatively modest spatial

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resolution of the MRS study and the fact that low dose rate brachytherapy patients do not have extracapsular extension of the disease. Another possibility is to reverse the order of the calculation in Eq (2) of the algorithm, that is, calculate the xcoordinate first and then the y-coordinate, as shown in Figure 21.12 (originally, y-coordinates are calculated first followed by the calculation of x-coordinates as indicated in Figure 21.5). The mapping accuracy of this reversed method was also examined in the phantom study: the

Figure 21.12 Schematic explanation of the ‘reverse’ mapping method. If the voxel is located close to the posterior surface of the concave-shaped prostate, the original method may result in a registered point outside the prostate. One can avoid this by simply conducting the same proportional calculation in Eq (2) in reversed order (obtain the x2-coordinate first followed by the calculation of the y2coordinate).

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Figure 21.13 Absolute values of 3D registration errors in the original and reverse methods.

Figure 21.14 An example of automated registration of magnetic resonance spectroscopy (MRS) positive voxels in our treatmentplanning system. The table contains

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the proportions of Eqs (1,2), as evaluated in the MRS space. The coordinates of the positive MRS voxels are automatically mapped to the US images. absolute value of the 3D registration error was 2.2 mm ± 0.9 mm (average ± SD), which is almost the same as in the original method (Figure 21.13). Some of the problems examined here may be ameliorated with the imminent availability for clinical use of a new 3.0 tesla MR unit, which offers better resolution in both spatial and MRS spectral characteristics compared with the current 1.5 tesla unit, and thus allows the utilization of either a smaller endorectal coil that will cause less deformation of the prostate or pants-style coil that does not require any endorectal probe. A different kind of limitation of this study comes from possible differences in the response to deformations between pelvic organs and the phantom material. For instance, the cancer burdens may have elasticity properties different from the healthy prostate tissue, while the phantom is made of a uniform deformable material. Also, for in vivo validation edema shrinkage may not provide a realistic simulation of the actual treatment situation. A study to validate this method with CT scans (with/without endorectal balloon coil) of patients who underwent permanent prostate implant is under consideration. The mapping algorithm has been implemented in our RTTP system for US-based intraoperative optimization of prostate seed implants (Figure 21.14). Specifically, after the prostate is outlined on both MRS and US axial images, software specially developed for this purpose automatically finds the center-of-mass of the gland, calculates the positions of the MRS-positive voxels in the US frame of reference with the aid of Eqs (1,2), and inserts the coordinates of these points in the list of constraints used in treatment plan optimization. As already mentioned, these points are given at least 200% of the prescription dose with no upper limit. Conclusions In conclusion, the algorithm for image registration reported here has acceptable accuracy and is sufficiently practical for clinical implementation. It should be useful for patientspecific tumor-targeted seed implants for prostate cancer with the potential expectation of improved treatment outcome as well as reduction in treatment-associated morbidity. In addition, this registration scheme should be helpful for guiding the pathologist to those regions of the gland where MRS positive signals were detected. References 1. Ling CC, Humm J, Larson S, et al. Towards multidimensional radiotherapy (MD-CRT): biological imaging and biological conformality. Int J Radiat Oncol Biol Phys 2000; 47:551–560. 2. Zaider M, Zelefsky MJ, Lee EK, et al. Treatment planning for prostate implants using magneticresonance spectroscopy imaging. Int J Radiat Oncol Biol Phys 2000; 47:1085–1096.

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3. Rosenman J. Incorporating functional imaging information into radiation treatment. Semin Radiat Oncol 2001; 11:83–92. 4. Thornbury JR, Ornstein DK, Choyke PL, et al. Prostate cancer: what is the future role for imaging? Am J Roentgenol 2001; 176:17–22. 5. Kurhanewicz J, Vigneron DB, Hricak H, et al. Three-dimensional H1 MR spectroscopic imaging of the in situ human prostate with high (0.24–0.7-cm3) spatial resolution. Radiology 1996; 198:795–805. 6. Kurhanewicz J, Vigneron DB, Males RG, et al. The prostate: MR imaging and spectroscopy. Present and future. Radiol Clin North Am 2000; 38:115–138, viii–ix. 7. Kurhanewicz J, Vigneron DB, Nelson SJ, et al. Citrate as an in vivo marker to discriminate prostate cancer from benign prostatic hyperplasia and normal prostate peripheral zone: detection via localized proton spectroscopy. Urology 1995; 45:459–466. 8. Kurhanewicz J, Dahiya R, Macdonald JM, et al. Citrate alterations in primary and metastatic human prostatic adenocarcinomas: 1H magnetic resonance spectroscopy and biochemical study. Magn Reson Med 1993; 29:149–157. 9. Costello LC, Franklin RB, Narayan P. Citrate in the diagnosis of prostate cancer. Prostate 1999; 38:237–245. 10. Zelefsky MJ, Cohen G, Zakian KL, et al. Intraoperative conformal optimization for transperineal prostate implantation using magnetic resonance spectroscopic imaging. Cancer J 2000; 6:249–255. 11. Mizowaki T, Cohen GN, Fung AY, Zaider M. Towards integrating functional imaging in the treatment of prostate cancer with radiation: the registration of the MR spectroscopy imaging to ultrasound/CT images and its implementation in treatment planning. Int J Radiat Oncol Biol Phys 2002; 54(5):1558–1564. 12. Scheidler J, Hricak H, Vigneron DB, et al. Prostate cancer: localization with three-dimensional proton MR spectroscopic imaging—clinicopathologic study. Radiology 1999; 213:473–480.

22 A novel prostate brachytherapy technique: use of preloaded needles without spacers. The Frankford Hospital experience Eric L Gressen, Jinyu Xue, Frank M Waterman, and Jay Handler Introduction Multiple techniques have been utilized to perform permanent prostate brachytherapy. There are marked differences in pretreatment planning in terms of the distribution of radioactive seeds and the treatment margin, defined in ICRU-50 as the distance from the prostatic edge and the prescription isodose.1 This chapter will describe in detail the process at our institution in evaluating and managing patients with prostate cancer treated with radioactive seed implantation either alone or combined with another treatment modality. Special attention will be given to the technique used for planning and executing the seed implantation. Patient evaluation All patients undergo a complete history and physical examination. Key elements of the history include urinary, bowel, and sexual function. Patients who have undergone a transurethral resection of the prostate (TURP) for bladder outlet obstruction may not be a suitable implantation candidate due to the potential for increased urinary incontinence after the procedure compared to patients who have not received a TURP. Ragde et al reported a 12% incontinence rate for seed implantation patients with history of a prior TURP.2 Bladder outlet obstruction and pyuria remain urologic concerns for selection for seed implantation since postoperative urinary retention presents a troublesome and challenging dilemma. Any hip/pelvic injury or limitations are taken into account to ensure tolerance of the lithotomy position for implantation. A significant cardiac and/or respiratory history may preclude one from performing implantation under any form of anesthesia. Physical examination always includes a digital rectal exam ination (DRE) for staging purposes and for determining an approximate size of the prostate gland. A heme occult test is performed on the stool specimen after DRE with a gastrointestinal consultation requested for an unexplained heme-positive stool prior to seed implantation to rule out colorectal malignancy. The pathology slides are always reviewed at our institution. The Gleason score, the number and percentage of involvement of each specimen, and the presence of perineural invasion are all taken into account to assess the risk of extracapsular extension, seminal vesicle and lymph node involvement. Computed tomography (CT) of the abdomen and

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pelvis is performed on all patients to further define the prostate size and to assess for lymphadenopathy with the rare additional benefit of identifying a second malignancy in the genitourinary or gastrointestinal tract. Patients who are seed candidates with a gland size of greater than 50 grams as measured by CT or transrectal ultrasound (TRUS) at the time of their initial biopsy are offered androgen ablation to minimize pubic arch interference and the number of seeds necessary for implantation. Patients are deemed optimal candidates for seed implantation alone if they satisfy the following criteria: Gleason score<7, prostate-specific antigen (PSA)<10, T1c/T2a disease, prostate gland size ≤50 grams, absence of perineural invasion, cancer noted in ≤3 specimens, no history of TURP. The prescription dose for monotherapy with iodine-125 (I125) seeds is 145 Gy calculated based on the American Association of Physics and Medicine (AAPM) Task Group No. 43 (TG–43) recommendations.3 Combination treatment consisting of external beam radiotherapy (EBRT) followed by seed implantation is offered to patients with an increased risk of extracapsular extension but a low risk of pelvic lymph node involvement. Patients fitting these criteria are those with a PSA in the range of 10–20 and/or a Gleason score of 7. Also, perineural invasion signifies an increased risk of extracapsular invasion and is taken into account for combination treatment. Combination treatment consists of 45 Gy EBRT to the prostate, seminal vesicles and surrounding tissue followed by 108 Gy delivered by 125I seed implantation 3–6 weeks later. Ultrasound volume study All patients, once deemed medically to be candidates for seed implantation and preliminarily anatomical candidates for seed implantation, undergo a TRUS for treatment planning and to assess pubic arch interference. CT is no longer used to assess for interference since TRUS has been proven to be at least as effective in visualizing the pubic arch as CT.4,5 If androgen ablation has been instituted, TRUS is performed 3 months after instituting the hormonal agents to account for most of the prostate gland reduction. For patients treated with combination therapy consisting of EBRT and seed implantation, TRUS is performed prior to commencing the external beam treatment to insure that there is no anatomic limitation to performing seed implantation and to minimize the rectal irritation from the procedure. All patients take two preparations of Fleet Phospha Soda 45 mL orally separated by 3 hours the day prior to the procedure. In rare cases, diazepam is offered to patients to decrease anxiety attributed to undergoing the TRUS procedure. There is an overall high tolerance level for this procedure. A dedicated Hitachi EUB-6500 ultrasound unit equipped with a 7.5 MHz endorectal ultrasound probe (Hitachi Medical Corporation of America, Tarrytown, NY) combined with a stepping and stabilizing apparatus table mount Sure-Point II (Amertek Medical, Inc, Singer Island, FL) is used for the TRUS study. The prostate, rectal wall, and urethra are well visualized. The dedicated prostate brachytherapy ultrasound technologist outlines the prostate and the pubic arch for treatment planning and to assess for pubic arch interference. If necessary, a urethrogram using aerated gel is performed to identify the urethra. A radiologist, specializing in TRUS, verifies the lack of or the amount of pubic arch interference. If minimal to no pubic arch interference is appreciated on TRUS,

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patients are placed on alpha-1 blockers at least 2 weeks prior to undergoing seed implantation to further minimize the risk of urinary retention. Treatment planning Treatment planning is done using VariSeed™ planning system (Varian Oncology Systems, Milpitas, CA). The TRUS images from the volume study are digitally imported into the planning system. The contours of prostate, urethra, and rectum are drawn and a planning tumor volume (PTV), which includes the prostate with the prescribed treatment margin, is generated. We utilize a treatment margin that is varied from 3–5 mm dependent on a series of risk factors determining the probability of extracapsular extension. In a study of 396 patients status postradical retropubic prostatectomy at the Mayo Clinic, a 3–5 mm treatment margin by brachytherapy would encompass all known tumor in approximately 99% of the prostatectomy specimens.6 Sohayda and colleagues observed similar results at the Cleveland Clinic in 255 radical prostatectomy specimens with a 4 mm tumor margin encompassing all disease in 90% of the cases.7 Of the three types of seed distributions described by Task Group 64,8 uniform loading, modified peripheral loading, and peripheral loading, none has proven to have superior clinical outcomes. Technically, peripheral loading can reduce the dose to the urethra compared to the other types, since the seeds are further displaced from the urethra. In addition, the peripheral technique requires the least number of needles, reducing prostate trauma from needle placement and shortening the time of the procedure. There are two seeding patterns for the peripheral loading technique, linear source peripheral loading where seeds are abutting without a spacer between two adjacent seeds, and point source peripheral loading where seeds and spacers are alternated along each needle track. The latter approach requires approximately half the number of seeds per needle compared to linear source peripheral loading, but would require approximately doubling the seed strength to maintain the same total source strength. The use of fewer seeds of high strength was cited as a disadvantage to peripheral loading by Butler et al because it requires more precise placement of each seed to avoid inadvertently delivering a high dose to a critical structure.9 Our primary seeding approach is peripheral loading with a specific pattern of seed and spacer sequence for each needle track tailored to optimize dose coverage of the PTV. Figure 22.1 demonstrates the difference between our primary seeding approach compared to pure linear or point source seeding patterns. This modified loading pattern allows the use of medium strength seeds (~0.375–0.450 mCi). Compared to our seeding approach, the point source peripheral loading typically requires a higher activity seed and the linear source peripheral loading requires a large number of seeds. Our variation of peripheral loading effectively minimizes the dose to the adjacent critical structures without compromising dose to the PTV. The preloaded needle technique has proven to be an effective approach to optimize seed implantation. The 100% isodose line is planned to cover the PTV taking into account subtle variations in contouring the prostate secondary to patient movement and internal organ motion with a wide treatment margin at the prostatic apex due to

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Figure 22.1 Three peripheral seed loading patterns described in the context: point, linear, and hybrid (from top to bottom). Our variation of peripheral loading is a hybrid of point and linear source peripheral loading tailored to optimize dose coverage of the planning tumor volume (PTV). the inherent uncertainty of contouring the apical region. The objectives of treatment planning include the relative sparing of the urethra by maintaining the majority of the urethra outside the 150% isodose line. The planned D90 for the urethra is approximately 100% of prescribed dose to the prostate. Once a plan is optimized, an isodose plan is printed to review with the radiation oncologist, demarcating the prostate contour with the 100% and 150% isodose lines, as demonstrated in Figure 22.2.

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Preadmission testing All patients undergo a complete blood count, basic metabolic profile, international normalized ratio (INR), protime (PT), prothrombin time (PTT), urinalysis, and electrocardiogram prior to the seed implantation. If there is an unexplained electrocardiogram finding, the patient is sent to a cardiologist for cardiac clearance. All plateletinhibiting agents are stopped at least one week prior to implantation. Warfarin, an anticoagulant, is discontinued 5 days prior to the procedure with an INR, PT, and PTT taken the morning of the implant to ensure a return to normal values. Preparation of the needles and seeds for implantation The loading sequence of seeds and spacers for each needle is printed on a diagram for visualization of the seed pattern, and to facilitate the loading process. The needle tip is sealed with surgical bone wax of approximate 5 mm length. The length of the wax is accounted for when the seeds are deposited into the prostate. A rapid seed-loading device, Quick-Load (Prostate Services of America, Inc, Singer Island, FL) is used to significantly reduce the time for preloading the needles and to provide quick verification of the loading pattern. An extra spacer is added to the end of the last seed in each needle to minimize migration of the seeds during the depositing process. The preloaded needles for an individual patient are stored in a shielded box, and each needle is placed into a hole having an alphanumeric coordinate corresponding to the template hole for needle insertion into the prostate. Seed implantation Prior to arrival to the cystoscopy suite, patients are given intravenous antibiotics and are placed in thigh-high Ted stockings. The vast majority of patients are given general anesthesia. Spinal anesthesia is given at the discretion of the anesthesiologist based on the patient’s medical condition and medications. Patients are set up in the lithotomy position with careful attention to symmetry of the pelvis and the positioning level of the stirrups to maximize reproducibility with the preplan TRUS volume study. The implant procedure is guided by TRUS image. Before insertion of the needles, each image slice is carefully checked relative to the template grid and aligned against the position of the preoperatively planned contours for the prostate and the urethra. Agreement between two TRUS volume studies is expected within a couple of millimeters

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Figure 22.2 Source placement as planned on each axial slice of transrectal ultrasound (TRUS) image (green spot: 125I seed). The red line is the contour of prostate and the dark green line in the center of the prostate demarcates the urethra. The gray line is the planning tumor volume (PTV) contour generated by the expansion of prostate with an appropriate margin. Cyan and pink lines are the 100% and 150% prescription isodose lines, respectively. for the dimension of the prostate and the location of the urethra. Variations in volume and shape are common with subtle changes in needle placement performed during implantation to account for these differences. Beaulieu et al reported 63% of the volumes taken in the operating room differed from the pretreatment-planning volume in the 35 cases evaluated at his institution.10 If the alignment cannot duplicate the dimension of the prostate within the acceptable deviation for many image slices, an appropriate adjustment of the needle positions is necessary to ensure good dose coverage. Offsetting a few needles usually fulfills the adjustment, but adding extra needles or eliminating planned needles may be required to optimize the implant.

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Two stabilizing needles (MDTech®, Gainesville, FL) with a hook-type mechanism are placed into the gland symmetrically along the same grid row. 125I seeds (BrachySource™, Covington, GA) (0.375–0.450 mCi/ source, TG-43) are used for implantation. The preloaded implant needles are inserted through the template and perineum, and into the prostate, under direct visualization with the TRUS. All needles are guided by the preplan. Anterior lateral needles are placed first to assess the need for further elevation of the lower extremities in the lithotomy position to avoid pubic arch interference and to avoid poor visualization of the anterior portion of the prostate from ultrasound transmission interference from posterior placed seeds. The physicist instructs the radiation oncologist which needle to place based on the plan and any modifications necessary based on subtle differences between the preplanned ultrasound volume study and the ultrasound volume study in the cystoscopy suite. Prior to deposition, an urethrogram with aerated gel is performed to insure at least a 5 mm distance between the seeds and the urethra. Before inserting the posterior row of needles, the shift of the rectal wall is verified through all slices from the base to apex and the needles are placed at least 5 mm from the anterior rectal wall. When all the planned seeds have been placed, an anterior-posterior radiograph is taken to assess the general location of the seeds noting seed migration into the bladder or periprostatic tissue. In rare circumstances when a seed deficit is apparent in a portion of the prostate gland due to seed migration, additional seeds may be placed taking into account the pretreatment plan. Cystourethroscopy When the seed implantation is complete, the urologist performs a cystourethroscopy to evaluate the bladder and urethra postimplant. It is not uncommon for the urologist to retrieve radioactive seeds, inadvertently placed into the urethra or bladder. An indwelling urinary catheter is not routinely placed after this procedure. Patients are given prescriptions for oral antibiotics, analgesics and alpha-1 blockers upon discharge from the hospital. Urinary retention If patients are unable to void 4 to 6 hours after the implant, an indwelling urinary catheter is placed for acute urinary retention and remains in for several days to allow for reduction in prostatic edema. If urinary retention persists, multiple trials of either successively longer duration continuous indwelling catheters or intermittent self-catheterization via a clean technique is performed until patients are able to uri nate freely without intervention. In troublesome cases of urinary retention 8 to 10 months post seed implantation, further intervention is decided by our urologic consultants. Patients are given alpha-1 blockers as a preparative regimen at least two weeks prior to implantation to lessen urinary irritative symptoms postimplant, and maintained for 6–12 months.

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Radiation precautions All patients are instructed to utilize a condom during sexual intercourse for the first two weeks postoperatively in case a seed is released during ejaculation. Pregnant women or potentially pregnant women should avoid prolonged personal contact with the patient for the first 2 months after seed implantation with no limit to the length of time in the same room if she maintains a distance of at least 6 feet (2 meters) from the patient. Children are not allowed to sit on the lap of the patient during the first two months following the implant. Postimplantation evaluation Postimplant dosimetry and evaluation is desired on all patients to assess the quality of the implant. Axial CT

Figure 22.3 Postimplant dosimetry performed in approximately 30 days after implantation. Source is identified as green spots on the axial slice of computed tomography (CT) scan at 5 mm spacing. Red line is the contour of prostate. Cyan and pink lines are the

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100% and 150% isodose line of prescription, respectively. images at 5 mm intervals are acquired 4–6 weeks after implantation since most of the prostatic edema induced by brachytherapy resolves in one month.11,12 The radioactive sources and contoured images are entered into our treatment planning system using VariSeed 7.0 Software (Varian Medical Systems, Inc, Charlotteville, VA). An example of the resultant images is displayed in Figure 22.3. A redundancy check is performed on seed localization to prevent duplication of seeds. Based on the recommendations of the American Brachytherapy Society (ABS), the dose given to 90% of the postimplant prostate volume (D90) and the percent of postimplant prostate volume covered by the prescription dose (V100) are obtained from the dosevolume histograms (DVH) and reported.13 The D90 typically falls between 160 Gy and 180 Gy with the V100 in the range of 90% to 100%. Conclusions The process of seed implantation and evaluation postimplant are evolving. Improvements in ultrasonic technology has allowed for better visualization of the prostatic anatomy and surrounding structures to enhance treatment planning and seed placement. Reserving catheter placement for the minority of patients that develop urinary retention improves patient satisfaction by avoiding the common symptoms of pelvic and penile discomfort attributed to foley catheters. Peripheral loading with variations in the distribution of seeds and spacers optimizes dose coverage of the planning tumor volume while reducing the maximal urethral dose to below 150% of the prescribed dose. Careful attention to the entire seed implantation process has resulted in good patient satisfaction and high quality implants based on postimplant computed tomography (CT) dosimetry in the majority of cases. References 1. International Commission on Radiation Units and Medicine (ICRU). Prescribing, recording, and reporting photon beam therapy. ICRU Report 1993;1–8. 2. Ragde H, Blasko JC, Grimm PD, et al. Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 1997; 80:442–453. 3. Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial brachytherapy sources: recommendations of the AAPM Radiation Therapy Committee Task Group No. 43. American Association of Physicists in Medicine. Med Phys 1995; 22:209–234. 4. Strang JG, Rubens DJ, Brasacchio RA, et al. Real-time US versus CT determination of pubic arch interference for brachytherapy. Radiology 2001; 219:387–393. 5. Wallner K, Ellis W, Russell K, et al. Use of TRUS to predict pubic arch interference of prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999; 43:583–585. 6. Davis BJ, Pisansky TM, Wilson TM, et al. The radial distance of extraprostatic extension of prostate carcinoma: implications for prostate brachytherapy. Cancer 1999; 85:2630–2637.

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7. Sohayda C, Kupelian PA, Levin HS, et al. Extent of extracapsular extension in localized prostate cancer. Urology 2000; 55:382–386. 8. Yu Y, Anderson LL, Li Z, et al. Permanent prostate seed implant brachytherapy: report of the American Association of Physicists in Medicine Task Group No. 64. Med Phys 1999; 26:2054– 2076. 9. Butler WM, Merrick GS, Lief JH, et al. Comparison of seed loading approaches in prostate brachytherapy. Med Phys 2000; 27:381–392. 10. Beaulieu L, Aubin S, Taschereau R, et al. Dosimetric impact of the variation of the prostate volume and shape between pretreatment planning and treatment procedure. Int J Radiat Oncol Biol Phys 2002; 53:215–221. 11. Prestidge BR, Bice WS, Kiefer EJ, et al. Timing of computed tomography-based postimplant assessment following permanent transperineal prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998; 40:1111–1115. 12. Waterman FM, Yue N, Corn BW, et al. Edema associated with I-125 or Pd-103 prostate brachytherapy and its impact on post-implant dosimetry: an analysis based on serial CT acquisition. Int J Radiat Oncol Biol Phys 1998; 41:1069–1077. 13. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999; 44:789–799.

23 Radioimmunoguided prostate brachytherapy Rodney J Ellis Introduction Prostate brachytherapy has gained widespread acceptance as an alternative to external beam radiotherapy or surgery for patients with localized prostate adenocarcinoma. As the technique has evolved, significant advances have refined the procedure. Early attempts at brachytherapy with permanent radioisotopes in the 1970s were marked by unsatisfactory results due to inadequate technology for proper treatment planning. The widespread availability of improved imaging modalities and planning software in the 1980s led to the development of prostate brachytherapy as it is widely practiced today, with a lowmorbidity transperineal approach that can be performed on an outpatient basis.1 Despite these advances, there is still no accepted technique to plan an implant procedure based on the distribution of tumor within the gland, rather than on the size and shape of the prostate itself. Theoretically, therapy designed to target specific foci of disease within the prostate would yield better local disease control with decreased morbidity. Various imaging techniques including ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI), give information about the size and shape of the gland but lack the anatomical imaging sensitivity and specificity required to differentiate normal prostate tissue from malignancy. Of the three modalities available, MRI appears to delineate tumor from normal prostate tissue most effectively. Most of the reported literature on MRI evaluation of the prostate relies on either endorectal or whole body coil MRI techniques to determine capsular penetration or seminal vesicle invasion. This helps in selecting patients for prostatectomy, but does not help in planning brachytherapy. Whereas standard MRI may be able to help detect macroscopic disease, its ability to detect lesions less than 5 mm is limited.2–5 Magnetic resonance spectroscopy (MRS) relies on the metabolic activity of cancers and appears to increase the specificity of endorectal coil MRI.6 Its use in localizing intraprostatic disease for specific treatment approaches is currently being explored at other institutions.7–10 It may help identify regions of disease within the prostate but its utility in evaluating the pelvis or abdomen would be limited by the amount of time required to scan such large areas by spectroscopy. Although some groups have been using MRS to attempt to detect occult tumor foci, this modality is not widely available. The use of a radiolabled antibody, indium-111 (111In) capromab pendetide (ProstaScint®), specific for prostatespecific membrane antigen (PSMA) allows the use of immunoscintigraphy to detect metastatic disease beyond the prostate.11 When we began our prostate brachytherapy program in February 1997, we decided to use a ProstaScint® scan on all patients as part of the routine work-up in order to help us select appropriate candidates for the procedure. The concept of radioimmunoguided brachytherapy for

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colorectal carcinoma had already been explored,12,13 and we attempted to translate this technique to prostate brachytherapy. Although ProstaScint® imaging has been criticized for having false-positives beyond the prostate gland when used for evaluation of metastatic disease, coregistration to CT, or MRI has greatly improved the ability to interpret regions of increased antibody uptake in the pelvis, abdomen, or chest by determining the underlying anatomical structure. Once the co-registration is completed, the contrast is increased on the single-photon emission computed tomography (SPECT) images to remove any residual uptake seen outside of the prostate within the surrounding musculature. Regions within the prostate that persist to have visualized antibody concentration are selected as target lesions for radiotherapy either by brachytherapy seed placement within the region, or possibly by intensity modulated radiotherapy (IMRT)targeted dose escalation. PSMA is upregulated and overexpressed by both cancerous tissue and prostatic intraepithelial neoplasia (PIN), but not atypical adenomatous hyperplastic lesions (AAH) or benign prostatic hypertrophy (BPH).14 While the expression of PSMA in PIN may result in a false-positive reading for carcinoma within the prostate gland with the image fusion, we believe that PIN should be targeted and treated as cancer during brachytherapy or IMRT, as it has been shown to be a likely precursor of invasive carcinoma.15 At the beginning of our series, we explored the possibility of using the ProstaScint® scan to determine where the areas of highest tumor burden were located within the prostate gland. We theorized that by obtaining SPECT images through the region of the prostate gland, we would be able to improve our distribution of radioactive sources at the time of implantation. We planned to deliver a higher dose of radiation to regions with a higher tumor burden while sparing sensitive normal structures, such as the urethra, rectum, and bladder if there was low antibody uptake in the prostate tissue adjacent to these structures. Thus, immunoscintigraphy with ProstaScint would allow us to target the tumor within the prostate using dose escalation with the overall goals of reducing biochemical failure and toxicity. We present in this chapter the accuracy of this method and the acute and chronic toxicity and outcome data from the first 124 consecutive patients with prostate cancer treated with radioimmunoguided brachytherapy either alone or in combination with electron beam radiotherapy (EBRT). Methods and results Image fusion In order to evaluate the ability of the gamma camera to detect regions of indium 111 (111In) capromab concentration within the prostate, regions of interest (ROIs) were placed within the anterior and posterior portions of the gland. Counts were determined from each region during the patient’s second scan four days post injection with the radiolabeled antibody. The total counts for each ROI were divided by the background activity, as defined by the number of counts within a similarly placed control region within the external obturator muscle. We have demonstrated previously that these ROI prostate-tomuscle ratios (P/M ratios) appear to have a strong correlation with the prostate biopsy results using a ratio of 3.0 or greater as a cutoff to define regions suspicious for

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containing carcinoma.16 Image fusion was completed through manual alignment of anatomic structures common to both the CT scan and ProstaScint image, such as bone marrow and vessels. The contrast of the ProstaScint study was increased to remove background activity from all non-vascular structures. The remaining regions of high antibody concentration were identified as sites suspicious for adenocarcinoma. We were able to see clearly anatomical relationships between the areas of antibody concentration and the surrounding prostate gland. In our current program at University Hospitals of Cleveland, we utilize a preplanned ultrasound volume study and postoperative CT-based dosimetry using a Rosses treatment-planning computer (Rosses Medical, Columbia, MD). We target the regions containing high antibody concentrations within the V150 isodose line, or 150% of the prescribed dose. A modified peripheral loading pattern is utilized in all of our implants; however, the central loading is altered based on clinical, pathological, and radiographic findings. Additionally, we are now developing a technique to import the co-registered images into the treatment planning to allow 3D reconstruction and intraoperative dosimetry. This would then allow comparison of the preoperative plan with the postoperative CTbased dosimetry, improving our ability to report partial organ dosimetry within the prostate. Correlation of prostate cancer foci and fusion images Between June 1998 and March 1999, we evaluated the biopsy data from 7 patients to assess the accuracy of this imaging technique. Each patient underwent prostatic biopsies at 12 sites determined independently of the imaging studies prior to a prostate brachytherapy procedure. We used 18 gauge tru-cut needles to obtain samples of prostate tissue transperineally. The biopsies were obtained under ultrasound guidance through the standard template used for the transperineal implant prior to performing the procedure (Bruel & Kjaer; B&K Leopard ultrasound unit and template, Copenhagen, Denmark). Anterior and posterior sextant samples were taken from the base, mid, and apex of the gland 1 cm lateral to the midline of the gland and 1 cm above and below the transverse midplane. These sites were labeled as left/right, anterior/posterior, base/ mid/apex, and sent in separate containers to a pathologist blinded to the results of the imaging studies. The samples were each read by a pathologist and reported to have either adenocarcinoma of the prostate or benign tissue including: benign prostatic hypertrophy, prostatic parenchymal tissue, prostatic intraepithelial neoplasia (PIN), or atypical acinar proliferation. The image fusion studies were read by two clinical investigators to be either positive or negative for high antibody concentration within each anterior and posterior sextant region prior to reviewing the pathologic results. True-positives (TP) were defined as regions where both the image and pathology were read as having antibody concentration and positive pathology for adenocarcinoma. True-negatives (TN) were defined as regions where both the image and pathology were read as having low or no antibody concentration and negative pathology for adenocarcinoma. False-positives (FP) were defined as regions where the image and pathology were read as having high antibody concentration but negative pathology for adenocarcinoma. False-negatives (FN) were defined as regions where the image and pathology were read as having low or no antibody concentration

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Table 23.1 A comparison of biopsy and imaging results by anatomic site Patient

RAB RPB RAM RPM RAA RPA LAB LPB LAM LPM LAA LPA

1

Pathology (+) (−) (−) (−) (−) (−) (−) (+) (−) (−) (−) (−) Image (+) (−) (+) (+) (−) (−) (−) (+) (−) (−) (−) (+) 2 Pathology (+) (+) (+) (+) (+) (+) (−) (+) (−) (−) (−) (+) Image (−) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) (+) 3 Pathology (−) (−) (−) (+) (−) (+) (−) (+) (+) (+) (+) (+) Image (−) (−) (−) (+) (−) (−) (−) (+) (+) (+) (−) (+) 4 Pathology (+) (−) (+) (−) (+) (−) (−) (−) (−) (−) (−) (−) Image (−) (−) (+) (−) (+) (−) (−) (−) (+) (−) (−) (−) 5 Pathology (+) (−) (+) (+) (+) (+) (−) (−) (−) (−) (−) (−) Image (+) (−) (+) (+) (+) (+) (−) (−) (+) (−) (−) (−) 6 Pathology (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) Image (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) (−) (+) 7 Pathology (+) (+) (−) (−) (−) (+) (−) (−) (+) (−) (−) (−) Image (+) (+) (−) (−) (−) (−) (−) (+) (−) (−) (−) (−) RAB, right anterior base; RPB, right posterior base; RAM, right anterior mid; RPM, right posterior mid; RAA, right anterior apex; RPA, right posterior apex. LAB, left anterior base; LPB, left posterior base; LAM, left anterior mid; LPM, left posterior mid; LAA, left anterior apex; LPA, left posterior apex.

Table 23.2 True-positive—negatives (TP/TN) and false-positives—negatives (FT/TN) by location within the prostate RAB RPB RAM RPM RAA RPA LAB LPB LAM LPM LAA LPA TP 3 TN 2 FP 0 FN 2

2 5 0 0

3 3 1 0

3 3 1 0

3 4 0 0

2 3 0 2

0 6 1 0

3 3 1 0

1 2 3 1

1 5 1 0

0 5 1 1

2 3 2 0

but positive pathology for adenocarcinoma (Tables 23.1 and 23.2). Accuracy of ProstaScint For the 84 biopsies obtained from these seven patients, we had 23 TP, 44 TN, 11 FP, and 6 FN readings. There did not appear to be a strong correlation between anatomic site and TP/TN/FP/FN rate. Of note, the left anterior base, left posterior mid, and left anterior apex had a high TN rate and a low TP rate. When the anterior portion of the gland was compared with the posterior, the TP/TN/FP/FN rates were very similar. The anterior gland had 10 TP, 22 TN, 6 FP, and 4 FN values. The posterior gland had 13 TP, 22 TN, 5 FP, and 2 FN values (see Tables 23.1 and 23.2). After comparison of the scans with the pathologic results, our method yielded an overall accuracy of 80% (TP+TN/total number of samples). We had a sensitivity of 79% (TP/TP+FN) and a specificity of 80%

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(TN/TN+FP). The positive predictive value (PPV) for the study was 68% (TP/TP+FP) with a negative predictive value (NPV) of 88% (TN/TN+FN).19 These results were encouraging, but it is important to note that the multifocal nature of prostate cancer can create significant sampling error when evaluating prostatic biopsies. Standard anatomical imaging of the gland with ultrasound at the time of TRUS biopsy does not always visualize tumor foci well. These biopsies were obtained in a routine fashion, but even repeat sextant biopsies in patients with a known diagnosis of cancer may fail to detect disease in 20% of patients.17,18 A positive image for which pathology was negative could therefore represent a false-negative biopsy or a false-positive scan reading. Although these preliminary results were encouraging, a

Figure 23.1 (a) Whole-mounted prostate specimen. The lesion is 7 mm in maximal dimension in the left posterior mid region of the prostate gland, (b) The fusion image. The region of antibody concentration matching the location of the lesion. Uptake in the right anterior near midline matches a 3 mm foci of adenocarcinoma identified 4 mm superior to the displayed slice on serial whole-mounted histopathology. current study is underway to obtain a more detailed comparison utilizing whole-mounted specimens obtained after prostatectomy for correlation with preoperative diagnostic studies (Figure 23.1). Patients Between February 1997 and December 2000, 124 consecutive patients with prostate cancer underwent ultrasoundguided transperineal implantation with palladium-103

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(103Pd) or iodine-125 (125I) seeds either alone or in combination with external beam radiation therapy (EBRT) at MetroHealth Medical Center or University Hospitals of Cleveland, both in Cleveland, Ohio. Preoperative evaluation included a history and physical examination, a ProstaScint scan, a thin slice pelvic CT scan with intravenous contrast, a prostate volume study, a pubic arch study if indicated, and measurement of prostate-specific antigen (PSA), prostatic alkaline phosphatase (PAP), and alkaline phosphatase. Lymph node sampling was performed in appropriate patients at the discretion of their urologist. Patients ranged in age from 45 to 79 years (median: 67 years). The pretreatment PSA values ranged from 1.5 to 42 ng/mL (median: 8.1 ng/mL). TNM staging was based on the 1993 American Joint Committee on Cancer staging and the patients were stage T1c to T3b (median: T1C). Gleason scores ranged from 3 to 9 (median 6). Risk factors (RF) were defined by: PSA greater than 10 (38 patients, 30.6%), Stage T2b or greater (26 patients, 21%), and Gleason score 7 to 10 (39 patients, 31.5%). Generally, patients with lower risk factors underwent brachytherapy alone (seed implant; SI alone); while patients were treated with EBRT and a brachytherapy boost (EBRT plus SI) if they exhibited at least one of the risk factors. For the 80 patients that underwent SI alone, 60 patients were low RF (0 RF); 17 patients were intermediate RF (1 RF) and 3 were high RF (2 or 3 RF). For the 44 patients having EBRT plus SI, 1 patient was low RF (0 RF); 15 patients were intermediate RF (1 RF) and 28 were high RF (2 or 3 RF). Thirty-three patients received neoadjuvant hormone deprivation (Lupron or Casodex) prior to or during treatment at the discretion of their urologist, in conjunction either with SI alone (13 patients) or with EBRT plus SI (20 patients). For the 91 patients who did not receive hormonal therapy, 67 patients were SI alone and 24 patients were EBRT plus SI. If the patient received hormone therapy prior to implant, the pretreatment PSA was that recorded prior to the initiation of hormone therapy. Tables 23.3 and 23.4 summarize the patient characteristics of these 124 patients. Treatment For the 80 SI alone patients, 53 patients received 103Pd at a minimal peripheral dose of 80 to 125 Gy (median: 115 Gy) and 27 patients received 125I at a minimal peripheral dose of 140–160 Gy (median: 144 Gy). For the 44 patients treated with EBRT plus a brachytherapy boost, all patients were treated with 45 Gy of EBRT delivered to the prostate with a 1.5 cm margin around the prostate and seminal vesicles. The EBRT was delivered with four fields in a

Table 23.3 Patient characteristics Characteristic n Stage T1c T2a T2b T2c T3a T3b

46 27 6 0 1 0

SI alone Percent (%)

n 57.5 33.8 7.5 0 1.25 0

19 6 15 1 2 1

EBRT+SI Percent (%) 43.2 13.6 34.1 2.3 4.5 2.3

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Grade Gleason 5 18 22.5 3 6,8 Gleason 6 56 70 8 18.2 Gleason 7 3 3.75 28 63.6 Gleason 8 3 3.75 4 9.1 Gleason 9 0 0 1 2.3 PSA 2–4 13 16.3 2 4.5 4.1–10 56 70 15 34.1 10.1–15 7 8.75 10 22.7 15.1–20 3 3.75 11 25 20–40 1 1.25 3 6.8 >40 0 0 3 6.8 Hormone therapy Yes 13 16.3 20 45.5 No 67 83.7 24 54.5 SI, seed implant; EBRT, external beam radiotherapy; PSA, prostatespecific antigen.

1.8 Gy fraction per day over five weeks. Approximately one month after the completion of EBRT, an ultrasoundguided brachytherapy boost was performed. Forty-one patients received 103Pd at a minimal peripheral dose of 70–100 Gy (median: 90 Gy) and 3 patients received 125I at a minimal peripheral dose of 108 Gy (Table 23.4). The dose was escalated to 150% of the prescribed dose for regions with increased ProstaScint uptake. Toxicity study For the first 43 patients who underwent monotherapy from February 1997 to August 1998, we followed PSA outcomes and the acute and late complications of treatment. The median PSA value at 10 months postimplant was 0.7 ng/mL, with a median PSA in the patients with and without adjuvant hormonal therapy of 0.33 ng/mL and 0.7 ng/mL, respectively. Radiation Therapy Oncology Group (RTOG) grading criteria were applied to rank the patients’ symptoms. Acute complications within the first month following implantation included grade 1 urinary symptoms in 13 patients (30%) and grade 2 urinary symptoms in 24 patients (56%) requiring an alpha-blocker. Acute high grade complications include grade 3 complications in six patients (14% total, including one patient with rectal bleeding and five patients who required a foley catheter beyond the first week following the implant), and no patients with grade 4 complications. Beyond 4 months, late complications included grade 1 urinary symptoms in 12 patients (28%) and grade 2 urinary symptoms requiring an alpha-blocker in 17 patients (40%). High grade complications were limited to one grade 3 patient who required intermittent selfcatheterization which resolved at one year (2%), and one grade 4 patient who underwent a TURP to relieve urinary obstruction (2%). All acute symptoms were within expected tolerance. Minimal late complications were noted; there were no complaints of urinary incontinence.20

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Statistics Clinical evaluation, including digital rectal examination (DRE) and PSA determination, was performed one month following implant, every three months for the first two years after implant, biannually for two years, and yearly thereafter. PSA values were followed in all 124 patients to evaluate disease outcomes. If the patient did not continue to follow with one of the investigators, PSA values were obtained from the patient’s current physician. Follow-up was also obtained with self-administered questionnaires, phone calls, and chart review. Follow-up was calculated from the day of implantation. Chi-square (x2) or Fisher’s exact tests were used to examine the association between two categorical factors. The Wilcoxon rank sum test was used to examine the mean or median difference of continuous measures between two groups. Three biochemical disease-free survivals (bDFS) were estimated. One was defined by American Society of Therapeutic Radiology and Oncology (ASTRO), the other two were defined by serum PSA level. The disease-free survival time was measured from the date of implantation to the time of biochemical failure or last date of follow-up. The institution of any hormonal intervention posttherapy was defined as a biochemical failure event for all these three definitions. Patients were censored at the date of last follow-up, or the date of death by other disease, if biochemical failure had not occurred. The overall survival rate was measured from the date of implantation to the date of death and censored at the date of last followup for survivors. Survival distribution was estimated using Kaplan-Meier methods and difference between/ among groups was tested using log-rank test. All tests were two-sided.

Table 23.4 Additional patient characteristics Characteristic

n

Age (yrs) SI alone EBRT+SI Pretreatment PSA (ng/mL) SI alone EBRT +SI Gleason score SI alone EBRT +SI Follow-up (mths) SI alone EBRT+SI Stage SI alone EBRT+SI SI alone dosage (Gy) 125 I implant 103 Pd implant EBRT+SI dosage (Gy)

124 80 44 124 80 44 124 80 44 124 80 44 124 80 44

Mean 66 67 64 9.6 7.5 13.6 6.1 5.8 6.8 36 37 36

SD 8 8 8 7 4 9.3 1 0.9 0.8 15 15 15

Median 67 68 45 8,1 7.3 12 6 6 7 33 36 33 T1c T1c T2a

Range 45–79 45–79 49–77 1.5–42 1.5–27.3 2–42 3–9 3–8 5–9 11–61 11–61 11–59 T1c-T3b T1c-T3a T1c-T3b

27 53

145.5 110.6

4.6 10.0

144 115

140–160 80–125

p-value* 0.04

<0.00 1

<0.001

0.678

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EBRT dose 44 45 0 45 45 125 I implant 3 108 0 108 108 103 Pd implant 41 87.8 6.9 90 70–100 * The p-value was between two treatment groups. SD, standard devotion, See Table 23.3 for other abbreviations,

Survival analysis Table 23.5 shows a yearly overall and biochemical diseasefree survival (bDFS) rate for the whole cohort. The 4 year overall survival was 89.3%. The 4 year (bDFS) rate for the whole group was 93.1% by ASTRO consensus definition (Figure 23.2a), and it was 82.2% and 72.5% defined by PSA<1.0 and PSA<0.5, respectively (Figure 23.2b).

Table 23.5 Yearly survival rate (%) for the entire patient population Survival rate

n

1 year

3 year

4 year

5 year

p-value*

124 992 91.1 89.3 89.3 Overall survival SI alone 80 100 90.9 88.2 88.2 0.947 EBRT +SI 44 97.7 91.3 91.3 bDFS ASTRO 124 96.8 91.1 93.1 93.1 SI alone 80 100 97.4 97.4 97.4 0.015 EBRT+SI 44 90.9 85.5 85.5 PSA<1.0 124 94.5 82.2 82.2 82,2 SI alone 80 97.5 85.2 85.2 85.2 0.203 EBRT+SI 44 88.6 76.6 76.6 PSA<0.5 124 94.4 74.1 72.5 67.4 SI alone 80 97.5 78.1 75.9 75.9 0.18 EBRT+SI 44 88,6 66.2 66.2 * ASTRO; American Society of Therapeutic Radiology and Oncology; bDFS, biochemical diseasefree survival. See Table 23.3 for other abbreviations,

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Figure 23.2 (a) Kaplan-Meier biochemical disease-free survival (bDFS) defined by ASTRO consensus for all the 124 patients with a 95% confidence interval, (b) Kaplan-Meier

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bDFS defined by PSA<1.0 or PSA<0.5 for all the 124 patients. Table 23.6 Yearly survival rate (%) by American Society of Therapeutic Radiology and Oncology (ASTRO) grading bDPS rate

n 1 year 3 year 4 year 5 year p-value

Risk factor Low risk 61 100 100 100 100 Intermediate risk 32 100 93.3 93.3 93.3 0.002 High risk 31 87.1 79.6 79.6 Baseline PSA ≤10 86 100 95.9 95.9 95.9 0.04 >10 38 89.5 86.6 86.6 86.6 Hormonal status HT 33 97 89,6 89.6 0.483 No HT 91 96.7 94.4 94.4 94.4 bDFS, biochemical disease-free survival; HT, hormonal therapy.

When stratified by treatment group, for the 80 patients treated with SI alone, the 4 year bDFS rate was 97.4% by ASTRO consensus definition, bDFS was 85.2% and 75.9% defined by PSA<1.0 and PSA<0.5. For the 44 patients treated with EBRT plus seed implant (SI), bDFS was 85.5% by ASTRO, 76.6% and 66.2% by PSA<1.0 and PSA<0.5 definition, respectively. Table 23.6 shows a yearly survival rate by ASTRO consensus definition stratified by risk factor (RF), baseline PSA, or hormonal therapy (HT). The 4-year actuarial bDFS rate for the low risk group (0 RF) was 100%, for the intermediate risk group (1 RF) it was 93.3%, and for the high risk group it was 79.6% (2 or 3 RF) (Figure 23.3a). For the patients with baseline PSA≤10, bDFS was 95.9%, however, for those with PSA>10, bDFS was 86.6% (Figure 23.3b). For the patients with neoadjuvant hormones, bDFS was 83.3%, and for those without neoajuvant hormones, bDFS was 94.4% (Figure 23.3c). A plateau on the bDFS curve for all the groups by any of the definitions occurred by 3 years. For all the patients without HT, the median PSA nadir was 0.2 ng/mL. The median time to nadir was 19 months. Discussion The favorable results observed in the present study are likely attributable to the radioimmunoguided prostate brachytherapy technique. In a previous publication, we demonstrated a semi-quantitative correlation with prostate biopsy results utilizing prostate to muscle ROI ratios for specific regions of interest (ROIs) within the prostate gland compared to background muscle regions of interest placed over the external obturator muscle.16 A sensitivity of 91% and a specificity of 92% were demonstrated in the study. Although the study demonstrated a strong correla tion between transrectal

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ultrasound guided biopsy results and antibody concentration within the prostate gland, it has at least two methodologic weaknesses. First, it is difficult to determine the exact site of biopsy within the prostate gland by transrectal ultrasound upon review of a written pathology report. While the majority of the patient’s biopsies were reported in sextant fashion, several of the reports merely referenced right or left prostate gland. Second, the use of regions of interest within the prostate gland to determine counts rather than the use of the actual fused image between the computed tomography (CT) scan and a ProstaScint® scan made it difficult to translate this information to the operating room at the time of the interstitial brachytherapy procedure. We are now in the process of obtaining further data to validate the accuracy of the fusion study by correlating histopathologic findings with the computer images. Initially in our current series, a dynamic implant technique, dependent solely on prostate volume, was chosen using the Mick® applicator. As we have become more comfortable with the image fusion technique, we are now relying more heavily on preplanning. However, we still prefer to use free seeds placed with the Mick® applicator to allow for adaptation from the preplan at the time of implant. The role of radiolabeled antibodies in the diagnosis and treatment of cancer continues to expand. Indium-111 capromab pendetide (ProstaScint®) scanning is becoming widely available for staging patients with prostate cancer. We hope to demonstrate that it is useful not only to stage patients with prostate cancer and to help select appropriate patients for prostate brachytherapy, but also to tailor the implant itself based on histopathologic changes within the gland not readily apparent by anatomic imaging procedures. By doing so, we hope to increase control rates while reducing the toxicity of treatment. Fusion of the pelvic CT and ProstaScint® scans identifies regions within the prostate felt to be at high risk of local failure, which can then be targeted with additional seeds at the time of implantation. Peripheral loading is applied to avoid an excessive urethral dose. While the initial patients in this study were all implanted using a nomogram approach and 2D dosimetry, current patients are being treated using a 3D ultrasoundbased preplanning technique to help improve targeting of the high risk regions. The concept of targeting intraprostatic disease with higher concentrations of radiation is not a radical or novel one. We have previously presented data depicting the feasibility of radioimmunoguided prostate brachytherapy.20 Other groups have identified localized disease with endorectal MRI/MRS and designed external beam therapy to provide an enhanced dose to these particular areas.21 The advantage inherent in such an approach is the ability to provide an increased dose to areas of disease concentration while sparing disease-free areas around the radiosensitive tissues of the urethra and rectum. Our approach focuses on applications with brachytherapy, but our imaging technique may also be useful in other treatment modalities, such as 3D conformal radiotherapy with intensity modulated radiotherapy (IMRT) for localized dose escalation.

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Figure 23.3 Kaplan-Meier biochemical disease-free survival (bDFS) defined by ASTRO consensus, (a) Patients were stratified by risk factor (RF). There were 61 patients with 0 RF (low risk), 32 patients with

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1 RF (intermediate risk), and 31 patients with 2 or 3 RF (high risk). The p-value is 0.002 among the three groups, (b) Patients were stratified by pretreatment PSA. There were 86 patients with PSA≤10; 38 patients PSA >10. The p-value is 0.04.

(c) Patients were stratified by hormonal therapy (HT): 33 patients with HT; 91 patients without HT. The p-value is 0.483. References 1. Blasko J, Ragde H, Luse R, et al. Should brachytherapy be considered a therapeutic option in localized prostate cancer? Urol Clin North Am 1996; 23(4):633–650. 2. Bates TS, Gillatt TA, Cavanagh PM, et al. A comparison of endorectal magnetic resonance imaging and transrectal ultrasonography in the local staging of prostate cancer with histopathological correlation. Br J Urol 1997; 79(6):927–932. 3. Ikonen S, Karkkainen P, Kivisaari L, et al. Magnetic resonance imaging of clinically localized prostatic cancer. J Urol 1998; 159(3):915–919. 4. Deasy NP, Conry BG, Lewis JL, et al. Local staging of prostate cancer with 0.2 body coil MRI. Clin Radiol 1997; 52(12):933–937.

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5. Maio A, Rifkin MD. Magnetic resonance imaging of prostate cancer: update. Top Magn Reson Imaging 1995; 7(1):54–68. 6. Scheidler J, Hricak H, Vigneron D, et al. Prostate cancer: localization with three-dimensional proton MR spectroscopic imaging—clinico-pathologic study. Radiology 1999; 213:473–480. 7. Pickett B, Vigneault E, Kurhanewicz J, et al. Static field intensity mod-ulation to treat a dominant intra-prostatic lesion to 90 Gy compared to seven field 3-dimensional radiotherapy. Int J Radiat Oncol Biol Phys 1999; 43:921–929. 8. Ling CC, Humm J, Larson S, et al. Towards multidimensional radio-therapy (MD-CRT): biological imaging and biological conformality. Int J Radiat Oncol Biol Phys 2000; 47(3):551– 560. 9. Zaider M, Zelefsky MJ, Lee EK, et al. Treatment planning for prostate implants using magneticresonance spectroscopy imaging. Int J Radiat Oncol Biol Phys 2000; 47(4):1085–1096. 10. Kurhanewicz J, Vigneron D, Males R. The prostate: MR imaging and spectroscopy. Radiol Clin North Am 2000; 38:115–138, viii–ix. Review. 11. Kahn D, Williams RD, Haseman MJ, et al. 111 Indium-capromab pendetide in the evaluation of patients with residual or recurrent prostate cancer after radical prostatectomy, The ProstaScint Study Group. J Urol 1998; 159(6):2041–2046. 12. Nag S, Hinkle G, Mojzisik C, et al. Radioimmunoguided brachyther-apy (Rigby): A new technique for implantation of occult tumors. Antibody Immunoconj Radiopharmaceut 1993; 6(1):29–37. 13. Nag S, Ellis RJ, Martin EW, et al. Feasibility study of radioimmunoguided iodine-125 brachytherapy for metastatic colorectal cancer. Radiat Oncol Investig 1995; 2:230–236. 14. Chang SS, Reuter VE, Heston WD, et al. Short term noeadjuvant androgen deprovation therapy does not affect prostate specific membrane antigen expression in prostate tissues. Cancer 2000; 88(2):407–415. 15. Qian J, Wollan P, Bostwick DG. The extent and multicentricity of high-grade prostatic intraepithelial neoplasia in clinically localized prostatic adenocarcinoma. Hum Pathol 1997; 28(2): 143–148. 16. Sodee DB, Ellis RJ, Samuels MA, et al. Prostate cancer and prostate bed SPECT imaging with ProstaScint®: Semi-quantitative correlation with prostatic biopsy results. Prostate 1998; 37:140–148. 17. Donohue RE, Millere GJ. Adenocarcinoma of the prostate: biopsy to whole mount. Denver VA experience. Urol Clin North Am 1991; 18(3):449–452. 18. Stroumbakis N, Cookson MS, Reuter VE, Fair WR. Clinical significance of repeat sextant biopsies in prostate cancer patients. Urology 1997; 49(3 A suppl): 113–118. * 19. Ellis RJ, Kim EY, Conant R, et al. Radioimmunoguided imaging of prostate cancer foci with histopathological correlation. Int J Radiat Oncol Biol Phys 2001; 49(5):1281–1286. * 20. Ellis RJ, Sodee DB, Spirnak JP, et al. Feasibility and acute toxicities of radioimmunoguided prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 48(3):683–687. * Reprinted from these two papers with permission from Elsevier. 21. Pickett B, Vigneault E, Kurhanewicz J, et al. Static field intensity modulation to treat a dominant intra-prostatic lesion to 90 Gy compared to seven field 3-dimensional radiotherapy. Int J Radiat Oncol Biol Phys 1999; 43:921–929.

24 Prostate brachytherapy under local anesthesia Sandra Arthurs and Kent Wallner Introduction Since its reintroduction, transperineal prostate brachytherapy has been performed under spinal (epidural) or general anesthesia, similar to what is standard for more invasive procedures, such as transurethral resection of the prostate (TURP) and prostatectomy. In fact, performing an implant is less invasive than a prostate biopsy, since no tissue is taken with the former, and should not require more than the little or no anesthesia, as is customary for biopsies.1 Spinal or general anesthesia entails a substantial cost, some degree of health risk, and burdensome scheduling requirements. Switching to local anesthesia provides substantial practical advantages, including less cost, less physician time coordination (bypassing anesthesiologist), and avoidance of dependence on operating room time. Prostate brachytherapy under local anesthesia was first described by the late Dr Jean Roy, who performed over 100 procedures in a fully equipped operating room using intraprostatic lidocaine (lignocaine) injections, along with intravenous (IV) sedation.2 Local anesthesia was instituted at Puget Sound Health Care System, Seattle in 1999, performing the procedure in the simulator suite of the radiation oncology department, without anesthesia personnel in attendance. Technique3 An intravenous (IV) line is started in a clinic room, just prior to the procedure. At that time, a brief preoperative interview is conducted by the brachytherapist, noting medications and previous medical history. The patient is then brought into the simulator suite and positions himself on the simulator table. The patient has a cardiac monitor attached and a urinary catheter is inserted. He is then placed in the lithotomy position, using stirrups attached to the simulator table (Figure 24.1). A 6–8 cm patch of perineal skin and subcutaneous tissue is anesthetized by local infiltration of 1% lidocaine (lignocaine), using a 25 gauge 1.5 inch needle (Figure

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Figure 24.1 The patient is fully awake for an implant procedure in the simulator suite in the Veterans Affairs Puget Sound Health Care System. 24.2a). All parenteral lidocaine (lignocaine) is given in a 0.5% solution with epinephrine (adrenaline) (1:100000). The transrectal ultrasound (TRUS) probe is then inserted and positioned to reproduce the planning images. A 3.0 inch 22 gauge spinal needle is used to inject lidocaine (lignocaine) up to the prostatic apex, in a pattern around the periphery of the prostate (Figure 24.2b). Once the pelvic floor and prostatic apex are anesthetized, a 7.0 inch, 22 gauge spinal needle is inserted through an 18 gauge 3 inch spinal needle into the peripheral planned needle tracks, monitored by TRUS (Figure 24.2c, and Figure 24.3). As the needles are advanced to the prostatic base, about 1.0 cc of lidocaine (lignocaine) solution is injected in the intraprostatic track. At this point in the procedure, a total of approximately 200–400 mg of lidocaine (lignocaine) is injected (Figure 24.4). Not all tracks are necessarily injected, depending on the total number and how patients tolerate the injections. A limited number of central tracks are also injected. The total dose is limited to 500 mg (approx. 7 mg/kg).

Figure 24.2 (a) Injection of lidocaine (lignocaine) into perineal skin and subcutaneous tissue, (b) periapical

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region, and (c) deep prostatic tissue. The deeper injections are made with 22 gauge spinal needles inserted through the transrectal ultrasound (TRUS) template.

Figure 24.3 (a) Typical lidocaine (lignocaine) injection points (white dots) for periapical and prostatic sites. 22 gauge spinal needles visualize well on transrectal ultrasound (TRUS) (b). When using a Mick® applicator, a maximum of two needles are in the patient at any one time. During the implant procedure, additional lidocaine (lignocaine) is injected into one or more needle tracks if the patient experiences excessive discomfort. Neither an anesthetist nor a nurse is present for the implant procedure. Lidocaine (lignocaine) injections are generally carried out by a physician, but could easily be done by a trained nurse, physician assistant, or radiation therapist. The total time needed to position the patient, perform the lidocaine (lignocaine) injections, and implant the seeds is typically less than two hours.3 At the completion of the source placement, the TRUS probe is removed and plain orthogonal pelvic radiographs taken with the catheter in place. The catheter is removed, and the patient then has his postimplant CT taken. About a total of two hours after completing the implant, the patient is discharged. Patients are allowed to drive themselves home, providing no sedative was given.

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Figure 24.4 Approximate amounts of lidocaine (lignocaine) injected into four regions. The precise amount varies from patient to patient, according to individual tolerance. The pelvic floor is typically the least sensitive site to needle insertion and lidocaine (lignocaine) injections.4 Patient tolerance Patients tolerate brachytherapy under local anesthesia surprisingly well. Their heart rate and diastolic blood pressure usually show minimal changes, consistent with mild discomfort.5 Serum lidocaine (lignocaine) levels are typically below or at the low range of therapeutic.5 Postimplant CTdefined target coverage has ranged from 80% to 95%; well within published criteria for technical adequacy.3 Large prostate glands have not posed a particular problem in completing the procedure.3 Anesthesia, as described here, still allows for maneuvering in order to avoid pubic arch interference. The arch itself is not particularly pain-sensitive, and can be anesthesized if necessary. To evaluate comfort level, patients were interviewed by telephone and asked to rate their pain with their prostate biopsy versus their prostate implant on a scale of 0 to 10. Of 58 patients interviewed at a median of 6 months since implantation, the median biopsy pain score was 4.5 and the median implant pain score was 3.0 (Figure 24.5).6 In general, there has been little correlation of patients’ biopsy pain scores and their implant pain scores (Figure 24.6).3 Five of the 58 patients interviewed by Smathers and colleagues (9%) stated that they would have preferred to have the procedure under general anesthesia.6 Currently, however, we suspect that fewer than 9% would prefer general anesthesia if asked, now that we have gained experience with the use of local anesthesia.

Basic and advanced techniques in prostate brachytherapy

Figure 24.5 Median patient-reported pain scores related to their prostate biopsy versus implant procedure.6

Figure 24.6 Patient-reported pain scores from the administration of lidocaine (lignocaine) and seed placement, versus their biopsyrelated pain scores. Due to overlap of scores, some points represent more than one patient3

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As of October 2004, more than 1150 patients have received implants under local anesthesia at Puget Sound. Only one patient has been switched to general or spinal anesthesia since June 1999—after lying down on the simulator table he decided not to proceed, before letting us begin the local anesthesia process. Other than extreme patient apprehension, we have encountered no contraindication to local anesthesia, providing patients are medically stable. Nonetheless, there was a learning curve, and the procedure has become easier with increasing staff experience. Judging from the experience of visiting physicians, we estimate that performing local anesthesia for 10 patients would allow most practitioners to feel comfortable with the technique. Sedation In addition to local lidocaine (lignocaine) infiltration, we have used a variety of sedation techniques over the last three years, including oral agents (benzodiazepines), conscious sedation with midazolam/fentanyl, and nitrous oxide (laughing gas). After a series of patient acceptance quality studies, we have abandoned the routine use of sedation, and currently rely on local lidocaine (lignocaine) infiltration alone.6,7 Our reasoning has been that the local lidocaine (lignocaine) is the primary mode of pain control, and that patient anxiety is best allayed with personal contact/communication during the procedure. In cases of severe anxiety, IV midazolam is given. Problems Performing implants with local anesthesia can entail some problems. Patients are more likely to move, requiring some adjustments in positioning of the TRUS probe. But with an easily adjustable TRUS stand, this has not been a major problem. The procedure is facilitated by a light-hearted rapport between the patient and staff—dour personalities (patients or staff) make the experience less pleasant. Conclusions The fact that patients typically rate their implant procedure-related pain as being somewhat less unpleasant than their prostate biopsy (a very common procedure that is rarely done under anesthesia), should allay any ethical concerns about using local anesthesia for implants. While a small percentage of patients state in retrospect that they would have preferred general over local anesthesia, it is far more common for patients to express relief about not needing general or spinal anesthesia.6 We have no plans to substantially alter the procedure from that described here.

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References 1. Nash PA, Bruce JE, Indudhara R, et al. Transrectal ultrasound guided prostatic nerve blockade eases systematic needle biopsy of the prostate. J Urol 1996; 155:607–609. 2. Roy J, Pouliot J, Taschereau R. Permanent transperineal prostate implants performed under local anesthesia. Int J Rad Oncol Biol Phys 1998; 42(suppl):296. 3. Mueller A, Wallner K, Corriveau J, et al. A reappraisal of local anesthesia for prostate brachytherapy. Radiother Oncol 2003; 37(5):309–312. 4. Wallner K, Blasko J, Dattoli M. Patient preparation. In: Dattoli M, ed. Prostate brachytherapy made complicated, 2nd edn. Seattle: Smart Medicine Press, 2001; 7.1–7.18. 5. Wallner KE, Simpson C, Roof J, et al. Local anesthesia for prostate brachytherapy. Int J Rad Oncol Biol Phys 1999; 45:401–406. 6. Smathers S, Wallner K, Simpson C, et al. Patient perception of local anesthesia for prostate brachytherapy. Semin Urol Oncol 2000; 18:142–146. 7. Simpson C, Wallner K, Sanchez D, et al. Patient anxiety and tolerance of prostate brachytherapy under local anesthesia. J Brachyther Int 2001; 17:77–81. 8. Wallner K. Prostate brachytherapy under local anesthesia: lessons from the first 600 patients. Brachytherapy 2002; 1:145–148.

25 The impact of hormonal therapy on pubic arch interference Adam P Dicker, Christopher T Chen, JD Liu, Richard C Valicenti, and Frank M Waterman Introduction Prostate cancer is the most frequent cancer and the second most frequent cause of death for men in North America. Much attention has been focused on the early detection of disease and recent reports appear to indicate that a greater percentage of patients are now detected with early stage disease. Radical prostatectomy and radiotherapy are reported as having good five year survival rates in men with early stage disease (stage≤T2b, PSA<10 ng/mL, and Gleason score≤6), although the advantages and disadvantages are the subject of active debate. There has been a recent resurgence in using permanent interstitial radioactive seed implants for prostate cancer because of advances in transrectal ultrasound (TRUS) and in computed tomography (CT).1–5 Transperineal interstitial permanent prostate brachytherapy (TIPPB) requires an unobstructed access to the prostate. Pelvic bones defining the pubic arch can block access to the anterior aspect of the gland; commonly referred to as ‘pubic arch interference/ overlap’ (PAI/PAO) (Figure 25.1). Assessment of potential PAI is critical when deciding whether or not a patient can be a candidate for a transperineal prostate implant,6 and can be performed with either CT,7–9 or TRUS.10,11 An example of a TRUS image of the pubic arch is shown in Figure 25.2. Androgen suppression treatment can be used to reduce both the size of the gland and the degree of PAI in those patients with significant PAI, although no benefit to reduction in biochemical control has been noted.12 Most literature reports to date have evaluated androgen suppression therapy and its ability to downsize the overall prostate volume.13 To date, there is limited information that evaluates the degree of PAI/PAO prior to and after androgen suppression therapy in the context of TIPPB. To aid in this evaluation of PAI in the planning of permanent prostate implants, we adapted technology primarily developed for the treatment planning of external beam radiotherapy (EBRT). The potential for PAI/PAO was evaluated by displaying the prostate contours superimposed on the pubic arch from the perspective of the needle template (‘needles-eye-view’). We used this methodology to evaluate patients prior to and after androgen suppression therapy to assess pubic arch interference and other prostate dimensions. The software and hardware methodology described here should be applicable with most external beam treatment-planning software packages.

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Treatment Men with biopsy proven adenocarcinoma of the prostate were referred to the multidisciplinary prostate program at the Kimmel Cancer Center at Thomas Jefferson University. Patients believed to be appropriate candidates for brachytherapy were counseled. Patients at high risk for pubic arch interference (volume>60 cm3), or whose initial radiographic evaluation suggested pubic arch interference, received a three month course of either luteinizinghormone-releasing-hormone (LHRH) agonist alone (Zoladex™, Zeneca Pharmaceuticals, 3.6 mg subcutaneous depot, monthly or Lupron™, TAP Pharmaceuticals, 7.5 mg intramuscular, monthly) or total androgen suppression (LHRH agonist and Flutamide, Schering-Plough, 250 mg three times a day) or antiandrogen alone (Casodex™, Zeneca Pharmaceuticals, 50 mg, daily). The form of androgen suppression was by preference of the referring physician. No attempt was made to randomize patients to any form of hormonal therapy. Prior to the administration of androgen suppression therapy a CT scan was performed to evaluate PAO/PAI. Limited bowel prep was performed prior to the scan (either 5 ounces of magnesium citrate or a Fleets™ enema), to clear the lower colon and rectum. A pelvic CT scan was performed on a flatbed helical CT scanner (Picker PQ5000, Cleveland, OH) with the patient in the supine position, legs straight to evaluate pubic arch interference. The urethra was lubricated and anesthetized with 10 mL 2% lidocaine (lignocaine) hydrochloride jelly

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Figure 25.1 Three-dimensional rendering of the pelvic bones (white) and prostate (red). The AQuSim™ software allows for a ‘cube-cut’ view for greater appreciation of the relationship between the prostate and pubic arch, (a) Represents a view from the perineum and (b) an oblique view. (International Medication Systems, South El Monte, CA). A foley catheter was inserted and the balloon inflated with 7–10 mL of diluted (50% original concentration) diatrizoate meglumine (Renografen-60™, Mallinckrodt Corp, St Louis, MO). The bladder was instilled with 30 mL dilute diatrizoate meglumine (2% in saline). The dye was diluted to minimize artifact on the scan. The prostate was imaged using 2.0 mm slice thickness and 2.5 mm indexing from base to apex. Using the Picker AQuSim™ software program, the periphery of the prostate gland was contoured either by author APD or author CC, but all contours were reviewed by APD. After completion of the contours and the computation of the prostate volume, the virtual simulation module was activated. The image setting used was designed to

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emphasize the digital reconstructed radiograph (DRR) for smooth bone. To obtain a perspective from the needle template (‘needles-eye-view’) the gantry and table angle parameters were adjusted and the following settings were used in the virtual simulation module: Gantry 90°, Table 90°, Window 425, Level 225. For the purposes of statistical analysis, the difference between pre- and postandrogen suppression therapy for each patient was used with respect to a measurement, and was tested against a difference of 0 mm change. Median, range, and quartiles were calculated (25% and 75%). Means and standard deviations were not used because those measurements may not be distributed normally and the population sample was limited. The signed rank test was applied to test the hypothesis that the change was positive. The signed rank test was selected because it does not require the assumption of normal distribution for the change.

Figure 25.2 ‘Needles-eye-view’. Patient 5 (a) prior to and (b) after androgen suppression therapy. Potential for pubic arch interference is assessed by displaying the prostate contours superimposed on the pubic arch from the perspective of the template. Note the significant overlap of the prostate contours, with the anterior-lateral aspect of the pubic arch extending to the outer cortex. The calculated prostate volumes and measurements prior to and after androgen suppression therapy are

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detailed in Tables 25.1–25.4. (Reproduced courtesy of Dr Peter Grimm, Seattle Prostate Institute.) Results All men were compliant with their androgen suppression therapy as measured by followup prostate-specific antigen (PSA) and serum testosterone levels. Potential for pubic arch interference was evaluated by displaying the prostate contours superimposed on the pubic arch from the perspective of the needle template (Figure 25.3). This perspective was obtained by adjusting the AQuSim™ software parameters to display the gantry and table, and rotated 90° for a ‘template/needles-eye-view’. The degree of pubic arch overlap can be identified and measured. In our experience, pubic arch overlap extending to the outer cortex represents a serious impediment to a transperineal

Figure 25.3 Transrectal ultrasound (TRUS) image of pubic arch interference. The yellow line denotes the outline of the pubic arch, (a) PreLHRH monotherapy. (b) Post LHRH monotherapy. (Reproduced courtesy of Dr Peter Grimm, Seattle Prostate Institute.) implant, and androgen suppression therapy is one possible solution. In addition, prostate volume, length, anterioposterior and longitudinal measurements can be calculated easily from the treatment-planning software and can be used to verify information derived from a volume study from a different source (ultrasound, magnetic resonance imaging). Androgen suppression therapy can have a dramatic effect on the dimensions of the prostate (Tables 25.1–25.4). Of the three measured dimensions of the prostate,

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neoadjuvant hormonal therapy appears to have the greatest effect on the longitudinal measurement (median change: 10.0 mm, range: 0–32.4 mm, p<0.0001) as compared with the AP (median change: 8.1mm, range: 0.6–19.2 mm, p<0.0001) and with the lateral (median change: 5.2 mm, range: 0–28.2 mm, p<0.0001). Although this can be dependent on the interpretation of the base and apex as well as the CT slice thickness. Prostatic volume changed significantly after hormonal therapy, ranging from 1.4% to 61.8% (median change: 23.4 cm3, range: 7.8–47.0 cm3, p<0.0001). The small sample size of this pilot study precludes any conclusions about the method of androgen suppression and the degree of volume reduction. The most striking part of this study was the measurable change in PAI/PAO after three months of androgen suppression therapy. All patients demonstrated a decrease in PAI/PAO and more than half of the patients showed a 50% or greater change. The median change for the right and left pubic arches was 4.6 mm (range: 2.3–6.2 mm, p<0.0001) and 3.8mm (range: 1.6–11.6 mm, p<0.0001), respectively. The decrease in PAO usually was not symmetrical, with one side having the greater change. Large changes in prostatic volume did not always correspond with similar changes in PAI/PAO and vice versa. Discussion The role of hormonal therapy (HT) in the management of prostate cancer has evolved over the past decades. The initial use of HT was for the primary management of metastatic disease. During the past ten years its use for patients with localized disease in the neoadjuvant setting for both surgery and radiation therapy has increased. The role for neoadjuvant HT for patients being considered for interstitial permanent prostate brachytherapy (TIPPB) is limited to downsizing the gland to reducing the amount of pubic arch overlap, and to facilitating the technical placement of radioactive seeds. Although the concept of downstaging is attractive, and surgical data now demonstrate that it is possible to shift clinical stage T3c disease into a lower stage, there has been no associated patient benefit noted in freedom from biochemical recurrence.14–17 Whether hormonal downsizing will improve local tumor control with TIPPB by reducing tumor volume before radiation is delivered, can be answered only by properly designed studies. Until randomized prospective studies properly evaluate this effect for TIPPB, we suggest that neoadjuvant HT be used only for patients with early stage disease. Studies of the use of neoadjuvant HT with threedimensional conformal external beam radiotherapy (3DCRT) demonstrated that reduction in size of the prostate can be accompained by a concomitant reduction in radia-tion dose to normal surrounding organs.4,18,19 Downsizing of the prostate can result in decreased acute complication rates.20–23 This concept, however, is not readily transferable to TIPPB. The steep dose gradient achieved by brachy-therapy limits the amount of rectum and bladder receiving a significant radiation dose. This study was designed to investigate the effect of HT on the degree of pubic arch overlap. It uses a unique approach to quantitating PAI/PAO by utilizing ‘beameye-view’ technology to superimpose the contours of the prostate on the pubic arch. A similar approach was published by Tincher et al.24 Different methods of neoadjuvant HT were

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used, according to referring physician preference. A reduction of 33–55% in gland size and volume has been reported by others,25–33 and a similar reduction was observed in this study. Neoadjuvant hormonal therapy had a dramatic effect by decreasing the proportion of PAI/PAO. Although this study was not designed to evaluate how different methods of androgen ablation affect PAI/PAO, there may be a suggestion that total androgen ablation carries no significant benefit in reducing PAI/PAO when compared with an LHRH agonist alone. One concern arising from this study would be interobserver variation of contouring the prostate.21,22,34 User variation can be minimized by letting only two individuals perform contouring and by having all contours reviewed by one individual. Transrectal ultrasound (TRUS) also has been used for evaluating pubic arch interference (Figure 25.3). Usually, this is performed by imaging the apex region and by moving the probe caudally until the bright echoes of the pubic arch are noted and a hard copy is printed. The prostate then is imaged at its widest anterior dimension and a hard copy printed. The prostate outline is traced on paper noting the position of the coordinates. This tracing is superimposed on the pubic arch image and evaluated for overlapping regions. A CT scan performed for diagnostic purposes also can be used for this purpose. It has been suggested that if greater than one-third of the gland is blocked by the pubic arch, the patient should either select a different form of treatment or consider hormonal downsizing.6 Large changes in prostate volume are not always associated with corresponding changes in PAI/PAO. One explanation for this is that PAI/PAO reflects a combination of

Table 25.1 Effect of androgen suppression therpay on Ap (anteroposterior), lateral, and longitudinal measurements of the prostate, as measured using CT Patient Hormone Status 1 Pre Post 2 Pre Post 3 Pre Post 4 Pre Post 5 Pre Post 6 Pre Post 7 Pre Post 8 Pre Post

Androgen AP Lateral Longitudinal Volume Right Left suppression (mm) (mm) (mm) (cm3) arch arch (mm) (mm) Total LHRH LHRH Total Total LHRH LHRH Total

61.6 51.8 46.5 38.7 44.9 34.8 45.7 42.9 42.0 34.3 48.8 38.4 54.2 46.1 50.2 45.4

62.6 60.5 58.2 46.7 48.3 42.4 47.1 44.2 50.3 43.6 48.3 43.1 58.5 53.9 59.6 54.5

82.5 69,9 44.9 34.9 40.0 40.1 40.0 30.3 37.6 30.1 45.0 30.0 45.0 32.4 47.4 35.1

134.9 87.9 72.6 40.1 44.6 36.8 64.6 41.2 42.0 31.5 62.7 31.8 87.0 51 80.7 59

22.0 18,9 7.2 3.9 8.1 4.6 12.0 9.7 14.9 10.7 8.5 3.1 8.5 2.2 11.1 5.0

17.4 13.7 8.0 2.1 12.3 5.8 12.3 8.7 16.2 12.4 10.4 8.4 6.7 0.8 9.6 5.9

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9 Pre LHRH 41.6 50.2 33.1 31.2 6.22 2.18 Post 30.6 42.6 24.9 18.6 0 0 10 Pre Total 47.6 65.6 57.5 48.9 9.4 9.9 Post 28.4 37.4 25.1 18.7 4.8 6.03 11 Pre LHRH 38.4 47.8 44.9 51.1 7.4 8.5 Post 37.8 44.0 44.9 41.8 2.2 7.0 12 Pre LHRH 46.5 47.8 44.9 55.4 12.0 17.2 Post 31.1 47.8 29.9 31.1 7.6 5.6 13 Pre LHRH 43.2 58.9 37.6 48.4 13.1 13.7 Post 39.8 49.5 35.0 33.9 7.2 8.5 14 Pre Antiandrogen 41.0 51.4 47.5 47.2 8.2 12,4 Post 40.2 47.0 40.0 46.5 5.8 11.8 15 Pre Antiandrogen 46.6 63.4 35.1 54.2 7.5 9.7 Post 43.8 61.1 35.1 46.6 3.5 9.5 Change in prostate volume was calculated by the AQuSim™ software. Pubic arch interference was measured by displaying the prostate contours superimposed on the pubic arch from the perspective of the template and is listed as ‘right arch’ and ‘left arch’, respectively. LHRH, luteinizinghormone-releasing hormone.

Table 25.2 Calculated difference between pre- and postandrogen suppression therapy measurements Patient Suppression method 1 Total 2 LHRH 3 LHRH 4 Total 5 Total 6 LHRH 7 LHRH 8 Total 9 LHRH 10 Total 11 LHRH 12 LHRH 13 LHRH 14 Antiandrogen 15 Antiandrogen

∆ AP ∆ Lateral ∆ Longitudinal ∆ Volume ∆ Rarch ∆ Larch (mm) (mm) (mm). (mm) (mm) (cm3) 9.8 7.8 10.1 2.8 7.7 10.4 8.1 4.8 11 19.2 0.6 15.4 3.4 0.8 2.8

2.1 11.5 5.9 2.9 6.7 5.2 4.6 5.1 7.6 28.2 3.8 0 9.4 4.4 2.3

12.6 10.0 −0.1 9.7 7.5 15.0 12.6 12.3 8.2 32.4 0 15.0 2.6 7.5 0

47.0 32.5 7.8 23.4 10.5 30.9 36.0 21.7 12.6 30.2 9.3 24.3 14.5 0.7 7.6

3.1 3.3 3.5 2.3 4.2 5.4 6.2 6.1 6.2 4.6 5.2 36.5 5.9 2.4 4.0

3.7 5.9 6.5 3.6 3.7 2.0 6.0 3.8 2.2 3.9 1.6 11.6 5.3 0.6 0.2

glandular size, position within the pelvis and pelvic bone architecture. For example, two patients can have identical prostate volumes, yet one may have significant PAI/PAO and the other minimal PAI/PAO. This may be because the first patient’s prostate has a more anterior location within the pubic arch. The anterioposterior location of the prostate is not well understood but is believed to be a function of the muscle tone of the levator ani and puborectalis muscles, plus the volume of air in the rectum.

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This study was undertaken to evaluate the effect of androgen suppression on the dimensions of the prostate from the perspective of a physician considering a transperineal interstitial permanent implant for a patient with prostate cancer. No attempt was made to compare different methods of androgen suppression. Although ultrasound is frequently used to compute prostate volumes for radioactive seed implantation, this study did not attempt to address the differences in measuring prostate dimensions when comparing ultrasound with CT,35–37 but focused strictly on the subject of PAI/PAO. Software to aid the evaluation of pubic arch interference has been reported by Pathak et al.11 The importance of patient positioning has been addressed by Strang et al.9 Their initial observation was that at time of TRUS volume scanning, the pubic arch was readily visible in real-time. In addition, virtually every patient appeared to have some PAI at CT but not at subsequent TRUS. They chose to study this discrepancy and hypothesized that this was due to CT being performed with the patient in the supine position, whereas TRUS was performed with the patient in the dorsal lithotomy position. Nine patients underwent preplanning CT and TRUS within 21 days of each other and were not treated with hormonal therapy before or during that interval. Every patient appeared to have PAI at CT (overall range: 8–20 mm, mean: 12.2 mm±3.4). Four of the nine patients had overlap at TRUS; one had at least a 5 mm overlap. The range of overlap at TRUS was 5 mm clearance (the distance between the anterior prostate and posterior pubic arch when there is no overlap) to 7 mm overlap (mean: 0.4 mm±3.6). The sensitivity of CT for any PAI was 100% (95% CI: 40%, 100%), and the specificity was 0 (95% CI: 0%, 52%). CT thus resulted in overestimation of PAI by 11.8 mm, in comparison with TRUS performed with the patient in a dorsal lithotomy position as the reference standard. However, this is without any software manipulation of the image (alteration of gantry angle) to take into account the lack of dorsal lithotomy leg position. Our clinical practice has incorporated aspects of this study. We acknowledge that the patient position in the CT scanner does not mimic that of the operating room. We did try to construct a device that would place the patient’s legs in a limited lithotomy position, but found that this device did not place the legs in a satisfactory position, although Tincher et al have solved this technical problem.24

Table 25.3 Percent change pre- and postandrogen suppression therapy measurements Patient Suppression % ∆ AP 1 Total 2 LHRH 3 LHRH 4 Total 5 Total 6 LHRH 7 LHRH 8 Total 9 LHRH 10 Total 11 LHRH

15.9 16.8 22.5 6.1 18.3 21.3 14.9 9.6 26.4 40.3 1.6

%∆ Lateral 3.4 19.8 12.2 6.2 13.3 10.8 7.9 8.6 15.1 43.0 7.9

%∆ Longitudinal 15.3 22.3 –0.3 24.3 19.9 33.3 28.0 25.9 24.8 56.3 0.0

%∆ Volume 34.8 44.8 17.5 36.2 25.0 49.3 41.4 26.9 40.4 61.8 18.2

%∆R arch 14.2 45.4 43.7 19.1 28,4 63.8 73.5 55.5 100.0 48.9 69.9

%∆ Larch 21.5 73.9 52.8 29.1 23.1 19.4 88.8 39.0 100.0 39.0 18.2

Basic and advanced techniques in prostate brachytherapy 12 LHRH 13 LHRH 14 Antlandrogen 15 Antiandrogen

33.1 7.9 2.0 6.0

0 16.0 8.7 16

33.4 6.9 5.5 0

43.9 30.0 1.4 14.0

360 36.5 45.0 29.2 53.3

67.5 38.6 4.8 2.0

Table 25.4 Statistical analysis of the difference between pre- and postandrogen suppression therapy on prostatic dimensions (anteroposterior, lateral, longitudinal), volume, and right/left public arch overlap ∆ AP (mm) Lateral (mm) longitudinal (mm) Volume (cm3) Eight arch (mm) Left arch (mm)

Median Min Max 25% Q 75% Q Signed rank test p< 8.1 5.2 10.0 23.4 4.6 3.8

0.6 0.0 0.0 7.8 2.3 1.6

19.2 28.2 32.4 47.0 6.2 11.6

4.8 3.8 7.5 12.6 3.5 3.6

10.4 7.6 12.6 30.9 5.9 5.9

0.001 0.001 0.001 0.001 0.001 0.001

Because the patient in the CT scanner is not in the dorsal lithotomy position we have learned to make adjustments in the ‘gantry angle’ to simulate the lithotomy position. Our clinical operating experience has been that no PAI has been experienced when gantry angles ranging from 90° to 115° are used to demonstrate that no overlap with the prostate and pubic arch exists. When gantry angles greater than 25° are necessary, we find that extended lithotomy positions are necessary to avoid PAI, as has been suggested by Stone and Stock.38 Conclusion Androgen suppression therapy can have a significant effect on overall prostate dimensions and can reduce pubic arch interference. Software designed for external beam radiation therapy (EBRT) can be used in the evaluation of pubic arch interference for patients who are being considered for permanent transperineal prostate brachytherapy. The ‘needles-eye-view’ can be used as both a research and clinical tool for the evaluation of pubic arch interference prior to and after androgen suppression therapy. This does not require specialized software and the information obtained can be used to corroborate data obtained from other volume studies to aid in the planning for the prostate implant. References 1. Blasko JC, Wallner KE, Cavanagh W. Radiotherapeutic strategies in the management of clinically localized, ‘low-risk’ prostate cancer: selection, results, and the search for answers. Cancer J Sci Am 1998; 4(3):157–158.

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2. Stock RG, Stone NN, Wesson MF, et al. A modified technique allowing interactive ultrasoundguided three-dimensional transperineal prostate implantation. Int J Radiat Oncol Biol Phys 1995; 32(1):219–225. 3. Wallner K, Chiu-Tsao ST, Roy J, et al. An improved method for computerized tomographyplanned transperineal 125 iodine prostate implants. J Urol 1991; 146(1):90–95. 4. Tunn UW, Acar O, Goldschmidt AJ. Effects of androgen deprivation prior to radical prostatectomy in 375 patients. Urol Int 1996; 56(suppl 1):6–12. 5. Morgenbesser SD, Williams BO, Jacks T, et al. p53-dependent apoptosis produced by Rbdeficiency in the developing mouse lens [see comments]. Nature 1994; 371(6492):72–74. 6. Grimm PD, Blasko JC, Ragde H. Ultrasound-guided transperineal implantation of Iodine-125 and Palladium-103 for the treatment of early stage prostate cancer. Atlas of the Urologic Clinics of North America 1994; 2(2):113–125. 7. Bellon J, Wallner K, Ellis W, et al. Use of pelvic CT scanning to evaluate pubic arch interference of transperineal prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999; 43(3):579–581. 8. Haberman K, Pathak SD, Kim Y. Effects of video digitization in pubic arch interference assessment for prostate brachytherapy. IEEE Trans Technol Biomed 2003; 7(1):8–15. 9. Strang JG, Rubens DJ, Brasacchio RA, et al. Real-time US versus CT determination of pubic arch interference for brachytherapy. Radiology 2001; 219(2):387–393. 10. Wallner K, Ellis W, Russell K, et al. Use of TRUS to predict pubic arch interference of prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999; 43(3):583–585. 11. Pathak SD, Grimm PD, Chalana V, et al. Pubic arch detection in transrectal ultrasound guided prostate cancer therapy. IEEE Trans Med Imaging 1998; 17(5):762–771. 12. Potters L, Torre T, Ashley R, et al. Examining the role of neoadjuvant androgen deprivation in patients undergoing prostate brachytherapy. J Clin Oncol 2000; 18(6):1187–1192. 13. Kucway R, Vicini F, Huang R, et al. Prostate volume reduction with androgen deprivation therapy before interstitial brachytherapy. J Urol 2002; 167(6):2443–2447. 14. Gomella LG, Liberman SN, Mulholland SG, et al. Induction androgen deprivation plus prostatectomy for stage T3 disease: failure to achieve prostate-specific antigen-based freedom from disease status in a phase II trial. Urology 1996; 47(6):870–877. 15. Corn BW, Valicenti RK, Mulholland SG, et al. Stage T3 prostate cancer: a nonrandomized comparison between definitive irradiation and induction hormonal manipulation plus prostatectomy. Urology 1998;51(5):782–787. 16. Soloway MS, Sharifi R, Wajsman Z, et al. Randomized prospective study comparing radical prostatectomy alone versus radical prostatectomy preceded by androgen blockade in clinical stage B2 (T2bNxM0) prostate cancer. The Lupron Depot Neoadjuvant Prostate Cancer Study Group. J Urol 1995; 154(2 Pt 1):424–428. 17. Watson RB, Soloway MS. Neoadjuvant hormonal treatment before radical prostatectomy [Review] [59 refs]. Semin Urol Oncol 1996; 14(2 Suppl 2):48–55. 18. Forman JD, Kumar R, Haas G, et al. Neoadjuvant hormonal downsizing of localized carcinoma of the prostate: effects on the volume of normal tissue irradiation [See comments]. Cancer Investig 1995; 13(1):8–15. 19. Zelefsky MJ, Leibel SA, Burman CM, et al. Neoadjuvant hormonal therapy improves the therapeutic ratio in patients with bulky prostatic cancer treated with three-dimensional conformal radiation therapy. Int J Radiat Oncol Biol Phys 1994; 29(4):755–761. 20. Vijayakumar S, Awan A, Karrison T, et al. Acute toxicity during external-beam radiotherapy for localized prostate cancer: comparison of different techniques [See comments] [Review] [44 refs]. Int J Radiat Oncol Biol Phys 1993; 25(2):359–371. 21. Fiorino C, Reni M, Bolognesi A, et al. Intra- and inter-observer variability in contouring prostate and seminal vesicles—implications for conformal treatment planning. Radiother Oncol 1998; 47(3):285–292.

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22. Cazzaniga LF, Marinoni MA, Bossi A, et al. Interphysician variability in defining the planning target volume in the irradiation of prostate and seminal vesicles. Radiother Oncol 1998; 47(3):293–296. 23. Soffen EM, Hanks GE, Hunt MA, et al. Conformal static field radiation therapy treatment of early prostate cancer versus non-conformal techniques: a reduction in acute morbidity. Int J Radiat Oncol Biol Phys 1992; 24(3):485–488. 24. Tincher SA, Kim RY, Ezekiel MP, et al. Effects of pelvic rotation and needle angle on pubic arch interference during transperineal prostate implants. Int J Radiat Oncol Biol Phys 2000; 47(2):361–363. 25. Sassine AM, Schulman CC. Neoadjuvant hormonal deprivation before radical prostatectomy. Eur Urol 1993; 24(suppl 2):46–50. 26. Schulman CC, Sassine AM. Neoadjuvant hormonal deprivation before radical prostatectomy [Published erratum appears in Eur Urol 1994; 25(3):247]. Eur Urol 1993; 24(4):450–455. 27. Aus G, Brandstedt S, Haggman M, et al. Effects of 3 months’ neoadjuvant hormonal treatment with a GnRH analogue (triptorelin) prior to radical retropubic prostatectomy on prostatespecific antigen and tumour volume in prostate cancer. Eur Urol 1994; 26(1):22–28. 28. Chen M, Hricak H, Kalbhen CL, et al. Hormonal ablation of prostatic cancer: effects on prostate morphology, tumor detection, and staging by endorectal coil MR imaging. Am J Roentgenol 1996; 166(5):1157–1163. 29. Tunn UW. Neo-adjuvant hormonal therapy of prostate cancer. Urol Res 1997; 25(suppl 2):S57S62. 30. Stone NN, Clejan SJ. Response of prostate volume, prostate-specific antigen, and testosterone to flutamide in men with benign prostatic hyperplasia. J Androl 1991; 12(6):376–380. 31. Weiner KX, Ciesla J, Jaffe AB, et al. Chromosomal location and structural organization of the human deoxycytidylate deaminase gene. J Biol Chem 1995; 270(32):18727–18729. 32. Pinault S, Tetu B, Gagnon J, et al. Transrectal ultrasound evaluation of local prostate cancer in patients treated with LHRH agonist and in combination with flutamide. Urology 1992; 39(3):254–261. 33. Kojima M, Ohe H, Watanabe H. Kinetic analysis of prostatic volume in patients with stage D prostatic cancer treated with LHRH analogues in relation to prognosis. Br J Urol 1995; 75(4):492–497. 34. Dubois DF, Prestidge BR, Hotchkiss LA, et al. Intraobserver and interobserver variability of MR imaging- and CT-derived prostate volumes after transperineal interstitial permanent prostate brachytherapy [See comments]. Radiology 1998; 207(3):785–789. 35. Roach M, Faillace-Akazawa P, Malfatti, et al. Prostate volumes defined by magnetic resonance imaging and computerized tomographic scans for three-dimensional conformal radiotherapy. Int J Radiat Oncol Biol Phys 1996; 35(5):1011–1018. 36. Narayana V, Roberson PL, Pu AT, et al. Impact of differences in ultrasound and computed tomography volumes on treatment planning of permanent prostate implants. Int J Radiat Oncol Biol Phys 1997; 37(5):1181–1185. 37. Narayana V, Roberson PL, Winfield RJ, et al. Impact of ultrasound and computed tomography prostate volume registration on evalua tion of permanent prostate implants. Int J Radiat Oncol Biol Phys 1997; 39(2):341–346. 38. Stone NN, Stock RG. Prostate brachytherapy in patients with prostate volumes >/=50 cm3: dosimetic analysis of implant quality. Int J Radiat Oncol Biol Phys 2000; 46(5): 1199–1204.

26 Using the needle manipulation ruler Brian J Moran Introduction Prostate brachytherapy was initially performed using radium. However, there were many problems associated with its use, one of which was radiation exposure to the hands of the brachytherapist. In the 1970s, the use of iodine-125 (125I) was popularized at Memorial Sloan-Kettering Hospital using an open suprapubic approach. This technique was abandoned in the early 1980s, not because of radiation exposure risks, but rather, because of flaws of seed placement in the technique itself. With the development of transrectal ultrasound (TRUS) and the transperineal interstitial implant technique of the prostate, seed placement was dramatically improved. Currently, iodine-125 and palladium-103 are the radioactive isotopes of choice for this procedure. Both of these sources have low energies with subsequent dramatic fall-off of dose as distance increases (inverse square law E ∞ 1/d2). These sources therefore pose a very low exposure risk to the healthcare professional working with them. Most institutions utilize preloaded 18 gauge 20 cm needles to perform interstitial implant of the prostate. The radioactive sources (seeds) are placed into the needles prior to deposition in the patient’s prostate. The procedure is very well-tolerated and described in detail elsewhere in this book. It should be noted that use of a Mick applicator has dramatically lower exposure risk, at least initially, since the needles used with this technique do not contain seeds at the time of needle placement. It is only later that the actual seeds are deposited from the Mick applicator into the needles that are already within the prostate. Technique Using the preloaded technique, needles are inserted through a perineal template that is attached to the ultrasound device. The template has (x and y) coordinates to assist in accurate placement of the needles. Ideally, the needle tip will meet the designated coordinate on the ultrasound image. However, this is not always the case and the needle tip image may be off target. The implant needle at this time can be redirected intracorporeally using the bevel at the tip of the needle. Then again, the bevel may not be successful in redirecting the needle to the desired coordinate, and additional maneuvers must be undertaken. It is not infrequent that extracorporeal needle manipulation is required to direct the needle to its desired x- and y-axis coordinates. Frequently, the brachytherapist will redirect the needle by use of the index finger placed between the perineum and the template. Pressure exerted on the needle by the index finger in the

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desired direction will usually result in proper placement of the preloaded needle resulting in subsequent seed deposition. Although overall radiation exposure during this procedure is minimal, the radiation exposure on the surface of the preloaded needle is not negligible (Table 26.1). However, sporadic exposure to radioactive 125I and 103Pd in the setting of prostate brachytherapy is probably

Table 26.1 Exposure rates for 103Pd and 125I at the needle surface 103

No. seeds/needle

Pd (1.4 mCi/seed) (U/seed) Needle surface (mR/h)

125

I (0.333 mCi/seed) Needle surface (mR/h)

3 22 14.1 4 29 21 5 36 23 6 40 27 Exposure rates of the needles containing 3–6 seeds per needle were measured on the needle sjurface at the center of the active length using a Victoreen 450B Dosimeter Survey Meter.

negligible. As this procedure gains acceptance and the volume increases, one should practice good radiation safety in accordance with ALARA (as low as reasonably achievable). At our institution, with the large volume of prostate brachytherapy being performed using the preloaded needle technique, we developed the needle manipulation ruler. As one can see from Table 26.1, the needles themselves, when containing radioactive isotopes, exhibit significant radiation exposure at the surface of the needle and up to a distance of 6 cm. Therefore, if the brachytherapist’s hands or fingers come within a 6 cm radius of the needle, he or she will be exposed to radiation; obviously, such exposure is undesirable. In the past, a 15–20 cm stainless steel ruler was used to assess the depth of needle insertion into the prostate gland. This was a useful aid in exact implantation of the prostate. To control the direction of insertion of the needle once the needle is inside the patient, surgeons used their fingers to guide and manipulate the needle (Figure 26.1). However, significant exposure to radiation can result to the fingers and hands of the brachytherapist while touching the needle, which houses the radioactive seeds prior to deposition in the prostate gland. The needle manipulation ruler described here is a medical device for use in brachytherapy. It minimizes the brachytherapist’s exposure to radiation while still allowing the surgeon to properly guide and manipulate the needle inside the patient (Figure 26.2). With a series of needle engagers contained on the end of the ruler, it is possible to manipulate the needle into its proper location without physically touching the needle with fingers or hands. The needle engagers are shaped and positioned to allow the needle to be adjusted in any direction from any position relative to the manipulation ruler. The advantage of using the needle manipulation ruler is that radiation exposure is

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Figure 26.1 Finger used to guide the needle.

Figure 26.2 The needle manipulation ruler. Table 26.2 Exposure rates for 103P and 125I at a distance of 12cm 103

No. of seeds/needle

Pd (1.4 mCi/seed) (U/seed) 12 cm from needle surface (mR/h)

125

I (0.333 mCi/seed) 1 2 cm from needle surface (mR/h)

3 2.3 0.71 4 2.6 1.3 5 3.4 2.0 6 4.0 2.2 Exposure rates of the needles containing 3–6 seeds per needle were measured on the needle surface at the center of the active length using a Victoreen 450B Dosimeter Survey Meter.

greatly reduced when compared to using the finger to adjust the ruler (Table 26.2). By integrating a ruler into the needle manipulator, the surgeon has a single device that can be held in one hand and used to safely manipulate the needle and measure the depth of insertion of the needle into the prostate gland rather than having to work with two separate devices. The needle manipulation ruler is 15 cm in length and is composed entirely of stainless steel. There are three directional notches which act as needle engagers located at the distal end. These engagers allow the brachytherapist to direct the needle within the

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patient. This occurs as the result of pressure exerted on the needle in a specific direction to the desired coordinate. The contact point between the surface of the needle and the edge of the stainless steel notch is quite small, measuring less than 1 mm. This is a dramatic difference compared to the surface contact when the index finger directs an implant needle. We have found this device to be invaluable because it allows a 10-fold reduction in radiation exposure, while allowing very accurate placement of the needles used during the implant.

Figure 26.3 Perineal spacing.

Figure 26.4 Incorrect use of the needle manipulation ruler. Since the needle manipulation ruler is very thin, it can be utilized within a minimal space a few millimeters between the perineum and the template. This is in stark contrast to the amount of space required, usually a minimum of 25 mm (1 inch), to use the index finger for extracorporeal redirection of needles (Figure 26.3). While the manipulation component of this device is very practical and effective, there is a proper way to use it. One of the common errors is just placing the device on the needle and applying pressure (Figure 26.4). This will result in a bent needle as both the template and the perineum are securing each end of the needle. The ruler should never be

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applied to the needle unless it is firmly placed against the perineum. The correct amount of pres-

Figure 26.5 The correct use of the needle manipulation ruler.

Figure 26.6 (a and b) Measuring with the needle manipulation ruler.

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sure to direct the needle within the patient is surprisingly small (Figure 26.5). The ruler component of this device is utilized to ensure that the appropriate depth of needle insertion has occurred into the patient’s prostate and equally important, that the trocar has been properly positioned and secured prior to needle withdrawal and subsequent seed deposition (Figure 26.6). Conclusion The needle manipulation ruler allows one to have minimal exposure during prostate brachytherapy using a preloaded needle technique while assisting real-time quality assurance that the z-axis orientation of seed deposition is occurring as planned in the preimplant evaluation.

27 Using the perineal pressure applicator device Brian J Moran Introduction Hematomas are not uncommon sequelae of skin needle puncture sites. Not infrequently, hematomas are noted at intravenous sites or just after blood specimen draws. The prostate is surrounded by venous plexi and the perineum has a rich blood supply. These anatomic areas are necessarily violated for the purpose of prostate brachytherapy. Unfortunately to date, techniques of prostate brachytherapy have not evolved to avoid this side effect and most likely never will. Patients with perineal hematoma frequently complain of pain while sitting on hard surfaces. Bruising and discoloration may accompany a perineal hematoma, particularly on the perineum, scrotum, and medial aspects of the thighs. While bruising may take many weeks to resolve, a true perineal hematoma can take many months to resolve. Therefore, developing a perineal hematoma should be regarded as a real possibility when counseling patients prior to the actual procedure. While hematoma is a possibility, it may be limited or even preventable if topical pressure is applied to the needle puncture sites immediately after the prostate brachytherapy procedure. This is usually accomplished by applying pressure on a sterile towel to the perineum. However, radiation exposure is not negligible to the operator’s hand when placing the hand in such close proximity to the radiation emitted from the iodine-125/palladium-103 prostate implant. Naturally, if a high dose rate remote afterloader technique is utilized, the perineum is not radioactive and therefore there is no hazard by applying direct pressure to the needle sites on the needle removal. At our institution, it is our policy to implant the prostate with the perineal template snug to the patient’s perineum. This minimizes subcutaneous bleeding and subsequent perineal hematoma during the actual procedure. It has been our experience that patients who exhibit bright red blood draining through the perineal template needle holes are usually at increased risk for developing perineal hematoma (Figures 27.1 and 27.2). As a policy, we apply direct pressure to the perineum upon removal of the template. Initially, this was done by hand on a sterile towel (Figure 27.3) but now we use a modified device to apply pressure.

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Figure 27.1 Blood draining through the perineal template.

Figure 27.2 Blood draining through the perineum. This modified device has been named the ‘perineal pressure applicator device’ (PPAD) (Figure 27.4). The PPAD has a soft, flat rubber surface, 12.5 cm in diameter attached

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Figure 27.3 Perineal pressure using hand and sterile towel.

Figure 27.4 The perineal pressure applicator device (PPAD). to a 50 cm acrylic broomstick handle. The head portion of the plunger has been filled with a soft foam material that is malleable. Furthermore, the flat end of the head has a 3 mm lead surface. The flat, rubber surface of the PPAD is placed against a folded, sterile towel over the needle puncture sites immediately on completion of the implant prior to cystoscopy (Figure 27.5). This design takes into account the three principles of minimizing radiation exposure: time, distance, and shielding. This philosophy is consistent with ALARA (as low as reasonably achievable) principles. The study To better understand the actual impact this device has on minimizing radiation exposure to the operator’s hand, we designed a study. Ten consecutive 125I and ten consecutive

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Figure 27.5 The perineal pressure applicator device (PPAD) in use following implant procedure.

Figure 27.6 Resolution of hematoma following use of the perineal pressure applicator device (PPAD). 103

Pd prostate implant patients were evaluated in order to discover radiation exposure rates at the perineal surface and at a perpendicular distance of 50 cm. The heights and weights of all patients were recorded as well as the total number of seeds/implant, activity/seed, and total activity of each implant. On completion of the implant, pressure was applied to the perineum using the handle of the PPAD for 5 minutes. In each case, exposure rate measurements were obtained with a Victoreen 450B Dosimeter Survey Meter. The exposure rate at the center of the needle puncture field on the perineum was measured. Exposure rate was then obtained at the handle of the PPAD, 50 cm from the perineal surface. A right angle was employed to ensure a perpendicular orientation of the PPAD handle to the perineal exposure rate site of measurement. All rate

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Table 27.1 Exposure rates with and without the use of the PPAD for both 125I and 103Pd Isotope I125 Pd103

No. Av. patients height (in) 10 10

70.3 68.7

Av. weight (Ibs) 202.9 199.8

Av. no. seeds/ implant

A/seed A total Perineum PPAD (50 (mCi) (mCi) (mR/h) cm) mR/h

104.5 97

0.333 1.28

34.8 123.66

16.57 9.72

0.52 0.015

measurements were obtained for a minimum duration of 1 minute. Our results showed that of the 20 patients evaluated in this analysis, none developed perineal hematoma within 10 days after implant (Figure 27.6). There was a profound reduction in exposure rates obtained at the handle of the PPAD compared to those at the perineal surface (Table 27.1). Conclusion The perineal pressure applicator device (PPAD) is a simple way to reduce the incidence of perineal hematoma after transperineal prostate brachytherapy and greatly reduces radiation exposure to the operator’s hand by a factor of 32 for 125I and 648 for 103Pd.

28 Permanent prostate brachytherapy using sources embedded in absorbable vicryl suture and a preplanned, preloaded needle technique W Robert Lee and Brian J Davis Introduction The history of prostate brachytherapy extends nearly 100 years, beginning in the early years of the 20th century in Paris. Enthusiasm for the procedure waxed and waned over the years. A number of renowned urologists contributed to the history of prostate brachytherapy including Hugh Hampton Young, Benjamin Barringer, and Willett Whitmore.1–3 The technique has evolved from an intraurethral approach using radium capsules to an interstitial approach relying on radon capsules to an open procedure returning back to a closed transperineal approach. The present widespread acceptance of permanent prostate brachytherapy is the result of prostate screening and improved technology that currently allows for an outpatient procedure that generally can be accomplished in one to two hours.4 Coincident with the evolution of various techniques, the sources used in the procedure have evolved. In the first application of brachytherapy to prostate cancer, radium capsules were placed intraurethrally.2 Hugh Hampton Young would develop his own intracavitary technique but it was Benjamin Barringer at Memorial Hospital in New York that pioneered the interstitial approach.1 Barringer’s technique relied on the use of radon capsules. These capsules were far smaller than the radium capsules and allowed for easier placement. The next advance in radioactive source evolution was the ability to produce encapsulated iodine-125 (125I) sources on a large scale. Early 125I source designs possessed a single radiopaque marker and the 125I was adsorbed on two beads with ion exchange resin.5 Subsequent source modification adsorbed the radioactive 125I to the surface of a silver wire which resulted in increased radiopacity and more consistent calibration. Palladium-103 (103Pd) sources were introduced into clinical practice in the late 1980s. In the mid 1970s investigators began to experiment with placing radioactive sources into suture material.6–8 The early reports describe a number of different techniques to insert sources in suture material. These early investigators believed that sources embedded in suture would result in: (1) even distribution of sources; (2) easy and rapid placement; and (3) reduction of source migration. Sources in suture were used to treat a variety of neoplasms including prostate, head and neck, lung, and gynecologic cancers.6–8 In January 1995, the US Food and Drug Administration (FDA) approved the use of a new medical device, the RAPIDStrand™ (Amersham Health). This device consisted of

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125

I sources embedded in stiffened, absorbable suture. The primary use for this device is the treatment of prostate cancer but other uses have been described.9 At the time of publication a number of stranded source devices have been approved by the FDA, each with different polymer material and as yet unreported rates of absorption. RAPIDStrand™ is the only stranded product with years of clinical experience and results that are described in the peer-reviewed published literature. For that reason, this chapter will focus on RAPIDStrand™, in particular, its use with a preplanned, preloaded needle technique. For this chapter, RAPIDStrand™ will also be referred to as ‘stranded sources’ or ‘sources embedded in suture (SES)’. Description of RAPIDStrand™ RAPIDStrand™ (Amersham Health) consists of 10 Model 6711 OncoSeeds™ (Amersham Health) spaced at a fixed distance of 1 cm embedded within polyglactin 910 absorbable suture (Medi-Physics RAPIDStrand product information sheet). The sources are spaced 1 cm from center to center as shown in Fig 28.1. The usual activity ranges

Figure 28.1 Photograph of RAPIDStrand™ showing three seeds each 1 cm apart. from 0.191 mCi to 0.673 mCi/seed. All sources within each strand are within the same activity range. The suture material is stiffened and subsequently sterilized by ethylene oxide. The stiffened suture material holds the sources in place to minimize source movement and optimize the intended radiation dose distribution. Studies of intramuscular implantation in rats show that non-stiffened suture material containing 125I sources is minimally absorbed until about postoperative day 40 but absorption is essentially complete between 60 and 90 days postoperatively. Potential advantages of stranded sources Advantages in source preparation RAPIDStrand™ is shipped as sequences of 10 sources in a single suture. This arrangement allows the potential for a decrease in needle loading time and reduced errors in source and spacer count. To the authors’ knowledge, no published papers have

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explicitly examined needle loading time with loose sources versus sources embedded in vicryl suture. Practitioners with clinical experience using both loose sources and sources in vicryl suture confirm the observation that needle loading time is less with sources in vicryl suture as compared to loose sources. Loading of loose sources requires loading each source and spacer individually, whereas loading of sources in vicryl suture only requires cutting of the strands to the required lengths. The strands themselves contain the desired number of sources and spacers and thus only one contiguous object needs to be loaded in the needle. Reduced source migration Early investigators using the transperineal technique found that the closed approach resulted in better dosimetry but source migration continued to be a problem.10 In particular, Kumar noted that loose sources tended to migrate by way of three mechanisms: (1) sources could be pulled down along the needle track owing to suction created by the needle; (2) peripheral sources occasionally migrated cephalad via the venous system into the pelvic veins; and (3) in patients treated with transurethral resection of the prostate (TURP), sources would often be lost by way of the urethra. He developed a method to fix iodine sources in vicryl ‘carriers’. In the first 14 patients he treated he observed no source migration. The published rates of loose source migration to the pelvis or lungs range from 6% to 55%, with most series reporting migration rates of approximately 20%.11–15 The largest series examining the incidence of source migration comes from investigators at the Seattle Prostate Institute.16 In this report presented at the Sixth Annual Advanced Brachytherapy Conference (Seattle, April 2003), the rates of source migration for loose sources 103Pd and RAPIDStrand™ sources were compared in more than 1000 patients. The rate of source migration to the lungs was significantly less with stranded sources compared to loose sources (23% vs 2%, p<0.0001). The only other report examining the rate of migration according to source type (loose vs stranded) also found that migration was significantly less for sources embedded in suture compared to loose sources (0.7% vs 11%, p=0.0002).14 Although these patients were not randomized, the unique source delivery system makes it likely that this observation is consistent with clinical reality. To date, no clinical consequences of source migration to the lungs has been reported, although at least one case of probable radiationinduced rectal cancer has been reported.17 Furthermore, source migration to the myocardium and coronary arteries has been observed.18,19 Improved dosimetry with sources embedded in suture There is at least a theoretical argument that the fixed relationship of the sources in vicryl suture will result in a reduction in spacing errors leading to improved postimplantation dosimetry.20 In a large report examining the spatial distribution of dose within the prostate gland, the region of the prostate most likely to receive a dose below the prescription dose is the anterior base.21 Anecdotal experience indicates that the sources most likely to migrate are those placed on the periphery of the prostate or those placed anteriorly (near the dorsal venous plexus). Given that the use of stranded sources results

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in: (1) lower rates of source migration; and (2) perhaps more consistent source placement by decreasing spacing errors, it is plausible that the use of stranded sources may be associated with improved postimplant dosimetry.

Table 28.1 Dosimetric quantifiers for the entire study population stratified by source type Variable

Entire group (n=40)

LS(n=20)

SES (n=20)

p-value*

Mean (SD)V100 90.3 (5.1) 86.5 (3.7) 94.1 (2.9) <0.0001 Mean (SD)V90 93.5 (4.2) 90.4 (3.2) 96.6 (2.2.) <0.0001 Mean (SD)V80 96.3(3) 94.1 (2.6) 98.5 (1.3) <0.0001 Mean (SO) D90 148 (22) Gy 132 (11) Gy 164 (17) Gy <0.0001 D90> 140 Gy 27/40 (67%) 7/20 (35%) 20/20 (100%) <0.0001 LS, loose sources; SES, sources embedded in suture; SD, standard deviation. *p-value is two-sided; LS vs SES. Modified with permission from Lee et al Radiother Oncol 2002; 65(2):123–127.22

Lee and others at Wake Forest University have examined a small group of patients to determine if the use of sources embedded in suture (SES) is associated with improved postimplant dosimetry when compared to the use of loose sources.22 These clinicians had been performing prostate implants for approximately three years using exclusively loose sources. In May 2000, sources embedded in suture were incorporated into the treatment procedure. In this paper the investigators compared postimplant dosimetric quantifiers of the first 20 patients treated with SES to the last 20 patients treated with loose sources. The patient and treatment characteristics of the two groups were not different, with the exception that the mean prostate volume of the patients treated with SES was slightly smaller (33.74 vs 39.55, p=0.0474). The dosimetric quantifiers for each group are listed in Table 28.1. It is clear that the V100 and D90 are superior in the group treated with SES. Fagundes has reported a similar improvement in postimplant dosimetry with the use of SES. In work presented at the American Brachytherapy Society (ABS) meeting in 2003, Fagundes reported on 473 patients treated with loose sources and Mick applicator (n=337) or a novel afterloading approach using sources embedded in suture. The calculated V100 was superior for the patients treated with SES (92.5% vs 88.4%, p<0.005). This improvement was achieved without an increase in acute urinary morbidity. Given the retrospective nature of the comparisons, the result can only be considered hypothesis generating and definitive statements require a randomized trial. Such trials are ongoing.23 Improved ultrasound imaging with stranded sources Recent advances in treatment planning systems have led many investigators to develop techniques that incorporate some type of dosimetric feedback during the procedure in the hope of improving postimplant dosimetric outcome and reducing morbidity.24–26 To date, most intraoperative treatment planning has relied on the location of the needles rather than the individual sources. Dosimetrically accurate intraoperative treatment planning will require accurate source localization using ultrasound.

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In a study by Davis et al, comparing detectability rates of loose sources in vivo by computed tomography (CT), magnetic resonance imaging (MRI), or transrectal ultrasound (TRUS), it was determined that interpretation of TRUS images leads to detection of only an average of 50% (95% CI: 40–57.7%) of loose sources after they are deposited.27 In another study, investigating TRUS as a means of source detection, TRUS source detection was increased to 62% with advanced image-processing techniques.28 Although a number of investigators are examining methods of ultrasound (US)-based source identification for intraoperative applications, the shortcomings of conventional TRUS in identifying loose sources remains an impediment towards achieving convenient USbased intraoperative dosimetry. In this regard, sources in vicryl suture may offer improved US imaging in vivo for two reasons. In the first place, the vicryl suture material itself provides a surface from which ultrasound reflects and produces an image. Second, the vicryl strands are more likely to keep sources oriented in a parallel manner such that acoustic backscatter from the sources and suture to the TRUS probe is more pronounced than otherwise. As such, it can reasonably be expected that increased acoustic backscatter yields a more readily detected signal and, ultimately, a higher source detectability rate as compared to loose sources. Quantitative data on imaging of sources in vicryl suture material relative to standard loose sources are provided below. Quantitative data regarding source and strand orientation as compared to loose sources are not available, although it is clear from clinical observations that sources in strand appear more parallel under fluoroscopic imaging than do typical loose source implants. Examination of fluoroscopic images of the seed distribution following brachytherapy reveals that seeds do not

Table 28.2 Comparison of ultrasound backscatter signal strength between seeds in vicryl suture material and standard loose seeds in decibels (dB) as a function of angle of seed orientation. Data for two standard TRUS brachytherapy operating frequencies, 5 MHz and 7.5 MHz, are provided Seed orientation (degrees)

0

5

10

20

30

40

50

60

70

5 MHz

−2.30 1.94 3.35 4.13 3.63 0.63 −1.13 −9.39 −11.18 −1.09 3.59 7.52 7.36 5.58 2.86 1.27 −3.12 −6.14 7.5 MHz −0.48 1.93 6.71 5.91 4.76 1.29 −2.73 −7.83 −12.6 0.38 3.59 10.13 7.72 7.27 3.12 −0.99 −5.04 −10.05 Seed orientation is given relative to the transducer; zero degree orientation corresponds to seed position that is absolutely perpendicular to the incident US beam. The range of values is the upper and lower standard deviations. The shaded areas represent the seed orientations where seeds in suture material produce greater acoustic backscatter than loose seeds. (Adapted from Davis et al.30)

necessarily line up completely parallel, but rather may assume various non-parallel orientations. In a study by Leif et al,29 it was demonstrated that the orientation of loose seeds varies with respect to the TRUS probe and to one another frequently up to 40° and

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that a 10° variation in orientation is routine. Consequently, the US-imaging properties of sources as a function of their orientation is relevant. The acoustic-imaging properties of sources in vicryl suture as compared to loose standard sources have been measured as a function of angle of orientation of the US beam relative to source alignment (Table 28.2).30 Ultrasound backscatter from loose sources and sources in vicryl suture was measured from two parallel rows of 10 sources with ultrasound transducers operating at 5 MHz and 7.5 MHz. The angle of incidence of the scanning US beam was varied from perpendicular to 70° away from the perpendicular with 5 MHz and 7.5 MHz transducers. Ultrasound images were digitized with 12-bit pixel resolution with pixel dimension of 0.2 mm2. The signal was analyzed using the method of integrated optical density (IOD) as a measure of the overall magnitude of the signal and, consequently, relates to source detectability.31 The results, given as a decibel ratio of signal from sources in vicryl suture to standard sources, are that the sources in vicryl suture provide an increased backscatter signal from 4° to 45° incidence away from the perpendicular. A mean of 3.6 dB and maximum of 7.9 dB was found at 5.0 MHz, and a mean of 4.5 and maximum of 10.1 dB was found at 7.5 MHz over this range of angular orientations. To put this in perspective, a typical TRUS-imaging system has a dynamic range of 50 dB at an imaging plane of depth, often referred to as the ‘local’ dynamic range. Therefore, the improvement in ultrasound backscattered signal strength of 3.6 dB to 10.1 dB over this clinically relevant range of seed orientations represents a meaningful fraction of the physical capacity of the imaging system. Differences in the backscattered signal between the sources in the absorbable suture material and loose sources are expected because the suture material reflects and absorbs ultra sound. The acoustic interaction between the sources embedded in vicryl suture and the suture material itself are complex and involve a combination of reflection, refraction, scatter, and absorption. Measurements of relative acoustic backscatter beyond 45° incidence demonstrated that the sources in vicryl suture material produce less backscattered signal than standard sources. In those uncommon circumstances where the long axis of the sources in vicryl suture are oriented at greater than 45° away from an incident ultrasound beam, the vicryl suture material may serve to diminish the reflected signal in a manner greater than if the sources were loose. Representative images of five standard seeds and 5 SES at 5 MHz imaging frequency and angles of incidence from 0° (perpendicular) to 50° away from the perpendicular are shown in Figure 28.2. Of further note, ultrasound scatter and absorption are physical interactions which are generally more frequency-dependent than reflection or refraction, so the small differences in backscatter signal strength as a function of angle between 5 MHz and 7.5 MHz are not unexpected. Nevertheless, these data strongly suggest that seeds in vicryl suture will provide improved ultrasound imaging in vivo because of the ultrasound imaging properties of the strands and seeds acting in concert and the more parallel and uniform seed orientation exhibited by stranded seeds as compared to loose seeds. Summary Radioactive sources embedded in suture have been used for nearly three decades in the treatment of prostate, head and neck cancer, and gynecologic cancer. Advantages for the

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use of embedded sources include: decreased source migration, improved dosimetric outcome, and improved ultrasound visualization. Refinements in source design over the past century have led to significant improvements in prostate brachytherapy.

Figure 28.2 Ultrasound images of standard seeds compared to seeds embedded in suture material as a function of angle of orientation. The six panels show 5 standard seeds in the top row and 5 seeds embedded in suture material in the bottom row of each panel. Zero degree orientation corresponds to perpendicular incidence of the ultrasound beam. Images taken at 5 MHz. References 1. Aronowitz JN. Benjamin Barringer: originator of the transperineal prostate implant. Urology 2002; 60(4):731–734. 2. Aronowitz JN. Dawn of prostate brachytherapy: 1915–1930. Int J Radiat Oncol Biol Phys 2002; 54(3):712–718. 3. Whitmore WF Jr, Hilaris B, Grabstald H. Retropubic implantation of iodine 125 in the treatment of prostatic cancer. 1972. J Urol 2002; 167(2 Pt 2):981–983. 4. Blasko JC, Mate T, Sylvester JE, et al. Brachytherapy for carcinoma of the prostate: techniques, patient selection, and clinical outcomes. Semin Radiat Oncol 2002; 12(1):81–94. 5. Ling CC, Yorke ED, Spiro IJ, et al. Physical dosimetry of 125I seeds of a new design for interstitial implant. Int J Radiat Oncol Biol Phys 1983;9(11):1747–1752.

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6. Martinez A, Goffinet DR, Palos B, et al. Sterilization of 125 I seeds encased in vicryl sutures for permanent interstitial implantation. Int J Radiat Oncol Biol Phys 1979; 5(3):411–413. 7. Beach JL, Mendiondo OA. A simple device for loading radioactive seeds into absorbable sutures. Radiology 1983; 146(3):842–843. 8. Palos BB, Pooler D, Goffinet DR, Martinez A. A method for inserting I-125 seeds into absorbable sutures for permanent implantation in tissue. Int J Radiat Oncol Biol Phys 1980; 6(3):381–386. 9. Rogers CL, Theodore N, Dickman CA, et al. Surgery and permanent 125I seed paraspinal brachytherapy for malignant tumors with spinal cord compression. Int J Radiat Oncol Biol Phys 2002; 54(2):505–513. 10. Kumar PP, Good RR. Vicryl carrier for I-125 seeds: percutaneous transperineal insertion. Radiology 1986; 159(1):276. 11. Nag S, Vivekanandam S, Martinez-Monge R. Pulmonary embolization of permanently implanted radioactive palladium-103 seeds for carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1997; 39(3):667–670. 12. Ankem MK, DeCarvalho VS, Harangozo AM, et al. Implications of radioactive seed migration to the lungs after prostate brachytherapy. Urology 2002; 59(4):555–559. 13. Merrick GS, Butler WM, Dorsey AT, et al. Seed fixity in the prostate/periprostatic region following brachytherapy. Int J Radiat Oncol Biol Phys 2000; 46(1):215–220. 14. Tapen EM, Blasko JC, Grimm PD, et al. Reduction of radioactive seed embolization to the lung following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998; 42(5): 1063–1067. 15. Older RA, Synder B, Krupski TL, et al. Radioactive implant migration in patients treated for localized prostate cancer with interstitial brachytherapy. J Urol 2001; 165(5):1590–1592. 16. Grimm PD, Blasko JC, Sylvester JE. Seed migration: Linked versus loose seeds. Sixth Annual Prostate Brachytherapy Conference, Seattle, WA, April 2003. 17. Yurdakul G, de Reijke TM, Blank LE, Rauws EA. Rectal squamous cell carcinoma 11 years after brachytherapy for carcinoma of the prostate. J Urol 2003; 169(1):280. 18. Davis BJ, Bresnahan JF, Stafford SL, et al. Prostate brachytherapy seed migration to a coronary artery found during angiography. J Urol 2002; 168(3):1103. 19. Davis BJ, Pfeifer EA, Wilson TM, et al. Prostate brachytherapy seed migration to the right ventricle found at autopsy following acute cardiac dysrhythmia. J Urol 2000; 164(5):1661. 20. Roberson PL, Narayana V, McShan DL, et al. Source placement error for permanent implant of the prostate. Med Phys 1997; 24(2):251–257. 21. Sidhu S, Morris WJ, Spadinger I, et al. Prostate brachytherapy postimplant dosimetry: a comparison of prostate quadrants. Int J Radiat Oncol Biol Phys 2002; 52(2):544–552. 22. Lee WR, de Guzman AF, Tomlinson SK, McCullough DL. Radioactive sources embedded in suture are associated with improved postimplant dosimetry in men treated with prostate brachytherapy. Radiother Oncol 2002; 65(2): 123–127. 23. Fagundes HM, Keys RJ, Wojick MF, et al. Searching for a better prostate seed implant: a new rapid strand after-loading technique. Presented at American Brachytherapy Society Meeting, May 2003. 24. Nag S, Ciezki JP, Cormack R, et al. Intraoperative planning and evaluation of permanent prostate brachytherapy: report of the American Brachytherapy Society. Int J Radiat Oncol Biol Phys 2001; 51(5):1422–1430. 25. Stone NN, Stock RG. Brachytherapy for prostate cancer: real-time three-dimensional interactive seed implantation. Tech Urol 1995; 1(2):72–80. 26. Zelefsky MJ, Yamada Y, Marion C, et al. Improved conformality and decreased toxicity with intraoperative computer-optimized transperineal ultrasound-guided prostate brachytherapy. Int J Radiat Oncol Biol Phys 2003; 55(4):956–963. 27. Davis BJ, LaJoie WN, McGee KP, et al. Seed identification rates as a function of imaging modality in permanent prostate brachytherapy using CT-MR-TRUS image fusion. Proceedings of the American Brachytherapy Society, Orlando, FL, May 2002:42.

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28. Holmes DR, Davis BJ, Robb RA. 3D localization of implanted radioactive sources in the prostate using trans-urethral ultrasound. Stud Health Technol Inform 2001; 81:199–205. 29. Leif EP, Davis BJ, Kline RW, et al. Optimal CT slice spacing for postoperation seed localization in permanent interstitial implants. Optimal CT slice spacing vs. radioactive source orientation for postimplant dosimetry and quality control in permanent interstitial implants. Presented at the 9th International Brachytherapy Conference, Boston, MA, 1997:22. 30. Davis BJ, Kinnick RR, Fatemi M, Greenleaf JF. Experimental evaluation of ultrasound imaging and backscatter signal amplitude of standard seeds, echogenic seeds and seeds in suture material as a function of angle of incidence of the ultrasound beam: application to permanent prostate brachytherapy. Proceedings of the American Brachytherapy Society. Orlando, FL, May 2002:60. 31. Oberholzer M, Ostreicher M, Christen H, Bruhlmann M. Methods in quantitative image analysis. Histochem Cell Biol 1996; 105(5):333–355.

29 The Utrecht technique in RAPIDStrand TM afterloading Jan J Battermann, Ina M Schulz, Marinus A Moerland, and Marijke van Deursen Introduction The RAPIDStrand™ device (Amersham Health) comprising iodine-125 seeds embedded in a stiff polyglactin suture, has been available since June 1996 in Europe, and 1995 in the United States. Since 1996, we have used RAPIDStrand™ (strand) for our permanent prostate brachytherapy (PPB) procedures, except for patients treated with the Fully Integrated Radiotherapy Seed Treatment (FIRST) system, which we introduced in January 2002. Our previous technique was using a Mick applicator to insert single seeds into the prostate. We first positioned all the needles and then loaded each individual needle. With RAPIDStrand™, the needles can either be preloaded or manually afterloaded. At our center in Utrecht, we prefer to place all the needles first, and use customized ‘strand holders’ to facilitate the insertion of the strands into the prostate. In this chapter we describe our technique. (See also Chapter 32 on the FIRST system, for general information on our intraoperative treatment procedures. These are similar for strands and single seeds using the automated afterloading system.) Implantation technique Pretreatment evaluation and preparation are similar to the FIRST technique. The implant procedure begins with the introduction of two stabilization needles into the prostate and subsequent three-dimensional (3D) imaging acquisition. During contouring, the needles are introduced into the prostate prior to the autoplan. Using dose-volume histograms (DVH), the team decides whether extra needles have to be placed or removed. In addition, the number of seeds per needle is established, using differential loading of the more centrally located needles to lower the dose to the urethra. When the plan is approved, the strands can be prepared and placed into the strand holders for insertion into the

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Figure 29.1 The prepared strand is put into the strand holder. prostate. In the preparation room adjacent to our brachytherapy operating room (OR), strands are cut to lengths of 1, 2, 3, or more seeds. This can be done with a surgical knife or electrocoagulation. Any jamming of the strand in a needle can be avoided by electrocoagulating the strand. However, during the past two years we have used jamming. The strands are then put into a strand holder both methods of cutting and have rarely experienced any (Figure 29.1) and placed in containers that indicate the length on the strands. The containers are then taken to the OR. Typically, the loading is from periphery to central, so the shorter strands are loaded into the prostate first. The strand holder is placed on the hub of the needle, after retraction of the obturator (Figure 29.2). The same obturator is used to introduce the strand in the needle. The holder is removed and with the obturator the strand is placed at the tip of the needle. This can be identified by the marking on the obturator, but is also sensed when the strand is gently pushed to the tip of the needle. While retracting the needle over the obturator with the stopper (Figure 29.3), the placing of the strand can be

Figure 29.2 The strand holder is placed on the hub of the inserted

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needle to facilitate the introduction of the strand.

Figure 29.3 The stopper is placed at the end of the obturator and the needle retracted. viewed using sagittal transrectal ultrasound (TRUS). TRUS can also be used to fine tune the position of each individual needle just before loading with the strand. This takes more time, but improves the quality of the implant. Although we used peripheral loading for many years, only with the intraoperative planning system, we realized the better sparing of urethra and rectum when Using differential needle loading.2 With strands, this is possible by inserting one or two seeds at the prostate base and then retracting the needle for the required distance of 2–4 cm before placing the remaining seed(s). Currently, we usually cut the strands in parts with a maximum of 2 or 3 seeds. The radiographer can prepare an inventory of strands of different lengths beforehand, especially when more than one patient is implanted that day. To obtain a strand of 4 or 5 seeds, add a strand of 2 or 3 to another strand of 2. Jamming is no more of a problem than with a complete strand. Amersham Health recently introduced a new strand with thicker ‘spacers’ between the seeds to further reduce the risk of jamming. Another reason for having longer strands in two parts is that with swelling of the prostate because of the implant procedure, a complete strand is not moved in one direction. Seed migration rarely occurs in complete strands and the use of parts of a strand, even with one seed, does not increase the migration rate. Postimplant care and postplanning are the same as the FIRST technique (see Chapter 32). Discussion We have used RAPID Strands™ for more than seven years and found our technique (with strand holders) very reliable. During this period, we moved from using a nomogram for the calculation of the required number of seeds, via preplanning to intraoperative

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planning. In using intraoperative planning we have realized that in previous years the dose to urethra, and especially rectum, might have been too high in a substantial proportion of patients. Indeed, we did encounter some patients with rectal problems, bleeding, and also some ulceration. Although fewer than 10% of patients experienced problems, with intraoperative planning we expect to lower this figure substantially. Late urethral complications are rare, but we feel that any early reaction is less severe with intraoperative planning than in previous years, including the acute urine retention.

Figure 29.4 X-ray of seeds in strands. Note the ‘neater’ position of the seeds compared to those in Figure 33.12. On plain x-rays, the distribution of seeds over the prostate area looks ‘neater’ with strands than with single seeds (Figure 29.4).3 This also applies to loose parts as well as complete strands. However, the direction of each individual seed has little influence on the quality of the implant. Dosimetry parameters for RAPIDStrand and selectSeed implants were similar. Conclusion In our experience, the implant technique is similar for strands and single seeds, using the Mick applicator or automated afterloading with FIRST; however, we do not have any experience with preloaded needles. The total time required for the different techniques seems to be more or less the same, but OR time is substantially longer with intraoperative planning, as is described in Chapter 32 on the FIRST system. On the other hand, accuracy is certainly improved with intraoperative planning and should lead to better results with respect to postimplant dosimetry and biochemical control.

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References 1. Battermann JJ. Iodine-125 seed implantation for localized prostate cancer. J Brachyther Int 1998; 14:21–27. 2. Zelefsky MJ, Yamada Y, Marion C, et al. Improved conformality and decreased toxicity with intraoperative computer-optimized transperineal ultrasound-guided prostate brachymerapy. Int J Radiat Oncol Biol Phys 2003; 55:956–963. 3. Lee WR, deGuzman AF, Tomlinson SK, et al. Radioactive sources embedded in suture are associated with improved postimplant dosimetry in men treated with prostate brachytherapy. Radiother Oncol 2002; 65:123–127.

30 The PIPER prostate brachytherapy planning system Yan Yu Introduction PIPER (RTek Medical Systems, Pittsford, NY) is a commercial software system for preplanning, intraoperative planning, and postimplant dosimetry of permanent prostate brachytherapy. Its design goals were clearly aimed at real-time implant planning, guidance, and dosimetry, including: • simple, work flow-oriented graphical user interface that can be run by operating room personnel; • encapsulation of advanced technologies in image processing, feature recognition, and practical inverse planning. Figure 30.1 shows the Microsoft ‘Tab’ layout of the PIPER user interface. Each tab activates a unique window layout in which all of the functionalities required under that step of the procedure can be accessed without leaving the screen. TRUS/Contouring Tab This screen contains tools for acquiring ultrasound images and contouring various anatomical structures on the images. Image import may be via live video (e.g. direct connection to the ultrasound video output), in DICOM or a number of common image formats, such as JPEG, BMP. Auto-contouring is a unique technology available in PIPER to assist the user to rapidly define the prostate and anterior rectal wall in a series of ultrasound images. This completely automatic tool is based on a synergistic combination of sophisticated imageprocessing techniques and a trained knowledge set of the prostate morphology using advanced mathematical modeling.1 In addition to autocontouring, drawing and editing tools are provided in this screen to define the urethra, bladder, pubic arch, neurovascular bundles, and tumor focus. Figure 30.2 illustrates the TRUS/Contouring screen. The prostate and anterior rectal wall were drawn automatically using the Auto-Contour technology, while the urethra, pubic arch, neurovascular bundles (estimated), and tumor focus (for illustration only) were drawn manually.

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Treatment Plan Tab Under the Treatment Plan Tab, needle/seed placement plans and dosimetry can be optimized via PIPER’s unique Inverse Planning Engine, or by one of several geometrically based automatic planning options, such as uniform, modified uniform, and peripheral loading. Of course, complete manual planning or manual editing of plans is always available to the user. The PIPER Genetic Algorithm Inverse Planning Engine embodies unique designs to produce clinically relevant, optimized needle placement plans in 1–2 minutes. Successive

Figure 30.1 Tab layout of the PIPERuser interface. Each tab leads to a main screen in which all of the functionalities under a given procedural step can be accessed.

Figure 30.2 The TRUS/Contouring screen. The prostate and anterior rectal

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wall were drawn automatically using Auto-Contour technology. A crosshatch was activated to illustrate the effect of the pubic arch on delimiting the planning space. generations of the Inverse Planning Engine have evolved along with clinically oriented research and investigation to include: • specifying needle loading rules, such as back-to-back seed loading at the apex or base; • requiring a minimum number of seeds per needle (e.g. to avoid planning with ‘1seeders’); • multiobjective optimization taking into account the prescribed dose, dose uniformity, minimizing dose to the urethra, rectum, and/or neurovascular bundles (if defined); • dose-escalating to the tumor focus (if defined); • on-the-fly sensitivity analysis to assess the dosimetric impact of a given mean displacement of the seeds during optimization; • specifying a desired range of needles used. The end result is an automated dosimetry-planning system that generates practical, clinically acceptable implant plans in a 1–2 minute running time. Figure 30.3 shows isodose distribution and a dosevolume histogram (DVH) of a sample dosimetry plan generated under the Treatment Plan Tab. In addition to the typical dose conformity to the target volume and sparing of the critical structures, the Inverse Planning Engine also produces an island of escalated dose around the tumor focus (posterolateral aspect) automatically. OR Support Tab The preplan or intraoperative plan, electronically signed by the treating physician from the previous step, is used as the starting point in the OR Support Tab, from which the needle/seed placement positions can be refined, adjusted, reoptimized, or built up incrementally as the implant proceeds, that is, the OR Support Tab is an environment for dynamic implant tracking and real-time dosimetry (see Figure 30.4). The OR Support Tab consists of a main display window, which can be toggled between live video, isodose display, 3D, and DVH views. In addition, isodose display is always available in thumbnail images on the screen. All of these displays are updated in real-time during the brachytherapy procedure. The needle placement plan is tabulated in the Interactive Planning Worksheet, which can be sorted into one of several customary orders. This worksheet contains the needle coordinates, retraction distance, the number of seeds in each needle, and the seed patterns. The needle and/or seed patterns can be modified, added or deleted, upon which the dosimetry will be updated.

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Figure 30.3 The Treatment Plan Tab. (a) Isodose display mode, (b) Dosevolume histogram (DVH) mode. Note the relative high dose region around the tumor focus (for illustration only),

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which was automatically generated by PIPER’s Inverse Planning Engine, without sacrificing dose and sparing of the urethra and rectum.

Figure 30.4 OR Support Tab’s live video view. Needle Tracking is a unique method available in PIPER to achieve real-time dosimetry verification. It allows the user to use a single click on the live ultrasound view to define the trajectory and deflection of the needle as it is being inserted. As the needle tip appears on live transverse ultrasound as a hyperechoic spot, the user identifies its resting location by a single mouse click. PIPER will then report the lateral and anteroposterior deviations, ∆x and ∆y, and recalculate the dosimetry using a deflected needle track by 3D backprojection to the template coordinates. This practical and clinically relevant design was based on actual intraoperative experience and requirements. It uses the same ultrasound view as that during needle insertion, and requires the same needle tip identification as when the clinician performs visually, therefore there is no extra time added to the procedure. At the same time, this method of Needle Tracking delivers true image-guided therapy with quantitative feedback and dosimetry in real-time. Note that the above methodology can be used to examine the dosimetric consequence of any needle placement error before the seeds are actually deposited into tissue. If the needle deflection results in unacceptable dosimetry, the needle may be reinserted, and the new needle tip reidentified, before seeds are actually implanted. This is another quality assurance tool in PIPER designed to assist the physician to deliver optimal prostate brachytherapy.

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A running total seed count is automatically updated in the Interactive Planning Worksheet as each needle is placed. Figure 30.5 is a screen shot of an actual brachytherapy implant at the end of the planned needle/seed placements. The prescribed treatment was a palladium-103 boost of 100 Gy to the prostate. If the treating physician determines that supplemental seed insertions are necessary (e.g. in the posterior leftlateral aspect of the prostate in Figure 30.5), they can be added to the needle placement plan and the worksheet, before the real-time dosimetry is electronically signed by the physician. CT Contouring Tab and a Validation Tab The CT Contouring Tab contains tools to import DICOM images, manually contour the prostate and critical structures, automatically localize all the seeds, and display isodose distributions. The CT Validation Tab analyses the dose-volume histogram (DVH) data, and permits the ultrasound-based dosimetry to be compared to computed tomographic (CT)-based postimplant dosimetry. The Find Seeds function is a unique algorithm for automatically localizing all the implanted seeds in a postimplant CT series. The methodology involves statistical and feature analysis of CT intensities in both 2D and 3D. This ensures that redundancies (one seed exposed on two or more CT slices) are automatically recognized and assigned their true

Figure 30.5 OR Support Tab at the completion of brachytherapy seed placement.

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positions in 3D, that is, in contrast to other common methods of seed elimination, this algorithm does not require the user to assume that a certain number of seeds exists in the volume imaged.2 Furthermore, higher seed localization accuracy can be achieved with more closely spaced and thinner CT slices without requiring any additional user time. Calcification will be automatically eliminated rather than included as seeds, further ensuring dosimetric accuracy. The postimplant CT-based dosimetry can be compared with the ultrasound-based dosimetry (i.e. OR real-time dosimetry) in the CT Validation Tab. This tool provides another opportunity for the brachytherapy team to achieve Quality Assurance and Improvements. Summary PIPER is a full-featured brachytherapy planning system for interstitial seed implantation of the prostate, designed to support intraoperative planning and real-time dosimetry as well as conventional preplanning techniques. It contains a number of unique, state-of-theart technologies designed by practitioners for practitioners. These technologies make intraoperative planning, guidance, and dosimetry feasible and clinically practical, as well as eliminate much of the time spent by the planning personnel in the preplanning setting. It will also serve as a mature platform for other exciting technologies in the near future. References 1. Liu H, Cheng G, Rubens D, et al. Automatic segmentation of prostate boundaries in transrectal ultrasound (TRUS) imaging. Proc SPIE; 4684:412–423. 2. Liu H, Cheng G, Yu Y, et al. Automatic localization of implanted seeds from postimplant CT images. Phys Med Biol 2003; 48:1191–1203.

31 Robot-aided and 3D TRUS-guided intraoperative prostate brachytherapy Aaron Fenster, Lori Gardi, Zhouping Wei, Gang Wan, Chandima Edirisinghe, and Donal B Downey Introduction Although current prostate brachytherapy is widely accept-ed, it still suffers from limitations and variability that have limited its full potential. Progress in overcoming limitations is being made in a number of laboratories and companies by addressing factors such as: The patient’s anatomy. Pubic arch interference (PAI) with the implant path occurs in many patients with large pro-states (>60 cm3) and even in some patients with prostates <40 cm3. These patients cannot be treated with conven-tional brachytherapy with parallel needle trajectories guided by the conventional brachytherapy template, as the anterior and/or the anterolateral parts of the prostate are blocked by the pubic bone.1–3 In this chapter, we describe a robot-aided approach, which removes the paral-lel needle trajectory constraint of the template, allowing patients with PAI to be treated with brachytherapy without undergoing additional lengthy hormonal therapy to shrink the prostate. Needle placement accuracy using two-dimensional transrectal ultrasound (2D TRUS). Although needles are inserted with real-time 2D TRUS guidance, lateral deflection is not detected easily due to the poor elevational resolution of conventional 2D ultrasound (i.e. thick TRUS beam). However, 3D TRUS imaging provides views of the prostate not available using 2D TRUS, allowing the trajectory of the needle to be detected in a coronal section.4,5 In this chapter, we describe an automated technique to track the needle in 3D and guide it to the planned location in the prostate. Delay between preplan and treatment. Typically, a preplan is performed about 2 weeks prior to treatment. For a preplan, 2D transverse TRUS images are obtained at 5 mm intervals, the prostate contour is manually traced and the dose plan and seed locations are calculated based on prostate volume and location at that particular time. However, reports have shown that the prostate volume can change during the delay by as much as 50%.6 Below, we describe a technique for rapid acquisition of a 3D TRUS image of the prostate, followed immediately by prostate segmentation and dose planning, allowing planning and treatment in the same session to avoid the problem of volume change. Anatomical changes during the procedure. The implantation process itself induces trauma and causes the prostate to swell due to edema.7,8 Variation of prostate shape and volume during the procedure will result in ‘misplaced’ seeds and loss of proper dose coverage.9 Rapid 3D TRUS imaging, prostate segmentation, and dose planning will allow

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dynamic reoptimization of the procedure, intraoperatively, to take into account changes in the prostate during the procedure.10 Delay between treatment and postplan. Factors, such as prostate motion, bleeding and swelling during implantation,7,8 TRUS imaging artifacts, migration of the seeds in the needle tracks,11 and needle deflection, contribute to errors between the preplan and the actual prostate dose distribution.12 Thus, verification of the actual locations of the seeds relative to the prostate margin, rectal wall, and bladder is needed intraoperatively to allow adjustments to the plan to compensate for potential ‘cold spots’. Currently, TRUS is not used to localize seeds because they are too difficult to identify in 2D TRUS images, even with the use of the new ‘echo-seeds’. For this reason, seed location verification is typically done with computed tomography (CT) or fluoroscopy, which show the seeds well but the prostate margins poorly. Since this is performed after implantation, intraoperative corrections are not possible. The availability of high quality 3D TRUS images may provide the ability to identify the seed locations intraoperatively. Advances in 3D TRUS imaging, robotics, and segmentation approaches allows us to consider performing the procedure intraoperatively with dynamic reoptimization and without the constraints of the rectilinear template.13–17 This type of approach would permit planning and implantation at the same session thereby avoiding problems of repositioning, prostate motion, and prostate size/contour changes between the preplan and the implantation. This will also partially overcome the problem of pubic arch interference and permit the development of intraoperative postimplant verification, allowing immediate corrections of implantation errors. In the following, we describe our developments of the tools for use in this type of procedure. Key to these developments is the use of 3D TRUS imaging and robotic aids. Robotic aids in brachytherapy Reducing the effects of pubic arch interference (PAI) requires freeing needle insertions from parallel trajectory constraints, that is needle trajectories should be positioned with considerable flexibility, allowing oblique trajectories. Medical robotic systems are playing an increasing role in different image-guided surgical procedures,18,19 including urology,20–22 and CT-guided prostate brachytherapy.14 Although they introduce more complex instrumentation and increasing hardware costs, robotic approaches provide significant advantages and cost saving in some cases. The key potential advantages of robotic aids in brachytherapy relate to their ability to position, orient, and manipulate needles in 3D space accurately and consistently. These characteristics are important because they help to free parallel needle insertion constraints.23 In addition, they do not get tired, can be dynamically programed and controlled, and can be effectively integrated with real-time imaging systems. 3D TRUS in brachytherapy Our introduction of 3D TRUS has alleviated some technical limitations of 2D TRUS by allowing interactive viewing of the prostate in three dimensions for treatment planning, providing a more efficient and reproducible delineation of the prostate boundary in 3D

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for accurate treatment planning, and allowing the development of 3D monitoring of needle placement during implantation.5,15,24–27 In addition, recent advances in computer and visualization techniques have allowed real-time reconstruction and visualization of 3D ultrasound images and their manipulation on inexpensive desktop computers. These developments, coupled with efficient software tools, have the potential to allow the development of a system capable of dynamic reoptimization and intraoperative postplan verification. In the following sections, we describe the integration of robotic aids and 3D TRUS imaging in the development of a system for prostate brachytherapy. In our approach, a one-hole needle guide is attached to the arm of a robot so that the position and orientation of the needle targeting can be changed as the robot moves. At this phase of the project, we are using the robot as a dynamically movable needle guide, that is, the robot positions the needle, but the physician inserts the needle into the patient’s prostate. In a later phase of our work, we will include robot insertion. By integrating the coordinate systems of the robot, TRUS transducer, and 3D TRUS image, we can determine the position of the guidance hole in the 3D TRUS image so that the needle can be guided to target any point identified in the 3D TRUS image. In addition, we also developed a near real-time method for automatic segmentation and tracking of brachytherapy needles during oblique insertion when the needle exits the 2D TRUS image plane. System description A schematic diagram of our robot-aided and 3D TRUSguided system is shown in Figure 31.1 and a photograph in Figure. 31.2. The system consists of an A465 industrial robot system (Thermo-CRS, Burlington, Ontario, Canada) with 6 degrees of freedom and a 3D TRUS imaging system developed in our laboratory.15,24 A needle-guide is attached to the robot arm, and has only one hole to guide the brachytherapy needle. Since the needleguide is attached to

Figure 31.1 Schematic diagram of the robot-aided and 3D TRUS-guided brachytherapy procedure. The use of

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the robot will remove the constraints of the rectilinear template, allowing angulated needle insertion. The transducer is mounted in a rotational mechanism allowing rotation along its long axis for 3D TRUS imaging.

Figure 31.2 A photograph of the robot-aided and 3D TRUS-guided prostate brachytherapy system showing the ultrasound transducer inserted into a phantom and ready for 3D TRUS imaging. the robot arm, the position of the hole in the robot coordinate system is known. A software module transforms the robot coordinate system to the 3D TRUS coordinate system allowing the needle-guide hole, and hence the needle trajectory, to be displayed and coordinated with the 3D TRUS images. In the subsequent sections, we describe the 3D TRUS acquisition system, prostate segmentation approach, dosimetry, calibration procedure, and evaluation of the errors with the calibration, needle tracking and seed implantation. 3D TRUS imaging system Although our 3D TRUS system can be coupled to any ultrasound machine with a sidefiring transducer, our results described below were made using a B&K Medical 2102 Hawk ultrasound machine (B&K, Denmark) with a sidefiring 7.5 MHz transducer. In our 3D TRUS system, the side-firing linear array transducer is coupled to a rotational mover developed in our laboratory.15 The mover rotates the transducer around its long axis to generate a 3D image volume in the shape of a fan scan, with a rotation angle of about

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100°.24 As the transducer is rotated, 2D US images from the ultrasound machine are digitized at 0.7° intervals at 30 Hz for about 9 seconds by a frame grabber and stored in the computer. The 2D images are reconstructed into a 3D image (as the 2D images are acquired), which is immediately available for viewing using 3D visualization software.15 Figure 31.3 shows an example of the quality of 3D TRUS images that can be achieved. Prostate segmentation Outlining the prostate margins manually is time consuming and tedious. Thus, a semi- or fully automated prostate segmentation technique is required that is accurate, reproducible, and fast. Because 3D US images suffer from shadowing, speckle and poor contrast, fully automated segmentation procedures result, at times, in unacceptable errors. Our approach has been to develop a semiautomated prostate segmentation that allows the user to correct errors.28,29 In our approach, the prostate is segmented in a series of cross-sectional 2D image slices obtained from the 3D TRUS image, and the resulting set of boundaries is assembled into a single 3D prostate boundary. Our 3D prostate segmentation algorithm has been described in detail in previous publications,28,29 and consists of the following three-step procedure as shown in Figure 31.4. (1) The operator manually initializes the algorithm by selecting four or more points on the prostate boundary in one central prostate 2D slice. A curve passing through these points is then calculated and is used as the initial estimate of the prostate boundary (Figure 31.4a). (2) The curve is converted to a polygon with equally spaced points, which are then deformed using a Discrete Dynamic Contour algorithm until it reaches equilibrium (Figure 31.4b). If required, the polygon can be edited by manually repositioning selected vertices. (3) The 2D segmented prostate boundary in one slice is extended to 3D (Figure 31.4c) by propagating the contour to an adjacent slice and repeating the deformation process. This is accomplished by slicing the prostate in radial slices separated by a constant angle (e.g. 3°) intersecting along an axis approximately in the center of the prostate.29 The accuracy of the prostate segmentation algorithm was tested by comparing its results with manual planimetry. Using the prostate volume obtained by manual planimetry as a reference, the errors in the semi-automated approach ranged from an underestimate of 3.5% to an overestimate of 4.1%. The mean error was –1.7% with a standard deviation of 3.1%.29 Segmentation of the prostate requires about 5 seconds when implemented on a 1 GHz PC. Dosimetry We use the AAPM TG-43 formalism, which uses predetermined dosimetry data in dose rate evaluation.30 The dose can be calculated by either considering the sources oriented in a line in any trajectory, or as point sources where source orientation is ignored. After delineating the organs,

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Figure 31.3 Example of 3D TRUS image of the prostate. The 3D image has been sliced to show: (a) a transverse view; (b) a sagittal view; and (c) a coronal view. The coronal view cannot be obtained usuing conventional 2D ultrasound imaging. the user selects the type of source to be used and enters its calibration data. Considering pubic arch interference (PAI), the possible needle insertion area is outlined and the preplan is produced. The preplan consists of about 20 needles, which can be oriented in oblique trajectories to avoid PAI. The isodose curves are displayed in real-time on the 3D TRUS image as well as on a surface-rendered view with the needles and the seeds. Each needle can also be activated and deactivated individually and the modified isodose curves can be observed instantly. The user can evaluate the plan using dose-volume histograms (DVH) for each organ and make necessary modifications. Figure 31.5 shows an example of the use of the preplan software for oblique trajectory needle planning. During the live planning procedure in the operating room (OR), after inserting each needle, the actual needle location is determined and the isodose curves are modified and displayed in real-time. This helps the user to decide whether the needle position is

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satisfactory. After retracting the needle, the actual seed locations are determined (currently we use assumed positions) and the new isodose curves are displayed. At this time the user has the option to modify the rest of the plan according to the ‘real’ seed locations after the needle retraction. System calibration The aim of the calibration procedure is to determine the transformation between the 3D TRUS image-based coordinate system and the robot coordinate system. Our

Figure 31.4 Images showing the steps of the 3D prostate segmentation algorithm. The 3D TRUS image is first resliced into 2D slices, (a) The user initializes the algorithm by placing 4 or more points on the boundary as shown. A model-based interpolation approach is used to generate an initial contour, (b) A deformable dynamic contour (DDC) approach is used to refine the initial contour until it matches the prostate boundary, (c) The contour is propagated to adjacent 2D slices of the 3D TRUS image and refined using the DDC. The process is repeated until the complete prostate is segmented as shown.

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Figure 31.5 Display of a typical dose plan with oblique needle trajectories for use with 3D TRUS guidance and robotic aids. Our 3D visualization approach allows display of a texturemapped 3D view of the prostate, extracted planes, and graphical overlays of surfaces and contours, (a) Coronal view with delineated organs, needles, seeds, and isodose curves, (b) Sagittal view, (c) Transverse view, (d) Surface rendered view showing the organs and needles with seeds. approach involves two calibration steps: (a) 3D TRUS image to the transducer coordinate system calibration (image calibration), and (b) the transducer to the robot coordinate system calibration (robot calibration). The transformation between any two different coordinate systems is found by solving the orthogonal Procrustes problem as follows. Given two 3D point sets K={kj}, L={1j} for j=1,2,…,N, finding a rigid-body transformation F: lj=F (kj)=Rkj+T, where R is a 3×3 rotation matrix, T is a 3×1 translation vector, so that we minimize the cost function:

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(1) A unique solution to Eq (1) exists if, and only if, the point sets K and L contain at least four non-coplanar points.31 For image calibration, we designed a phantom comprised of 1 mm diameter nylon strings positioned in a Plexiglas box (Figure 31.6a). The nylon strings were immersed in agar and were placed in three layers 1 cm apart. The strings were arranged with known separations and forming non-coplanar intersections. The coordinates of these intersections in the transducer coordinate system were known from the phantom design, whereas their coordinates in the 3D TRUS coordinate system were determined by scanning these intersections (Figure 31.6b). The transformation linking the two coordinate systems was determined by solving Eq (1) using the coordinates of the string intersections in both coordinate systems. For robot calibration, we used two orthogonal plates mounted on the transducer holder and drilled with five hemispherical divots on each plate (Figure 31.7). Homologous points in the transducer and robot coordinate systems are provided by the centers of the hemispherical divots on these two plates. The coordinates of these divot centers in the transducer coordinate system are known from the plate design. The coordinates of these divot centers in the robot coordinate system were determined by moving the robot to sequentially touch the divots with a stylus tip that was attached to the robot arm. The transformation linking the two coordinate systems was determined by solving Eq (1) using the coordinates of the divots in the two coordinate systems. Needle segmentation Robot-assisted brachytherapy procedure allows needle implantation in a non-parallel approach. Thus, the needle may be inserted in an oblique trajectory, which will result in its image passing out of the real-time 2D US image (Figure 31.8). Visual tracking of the needle tip in an US image while being inserted into the prostate is necessary to ensure proper placement and to avoid implanting seeds outside the prostate. Thus, we developed a technique to track the needle as it is being inserted obliquely. In our approach, we use near real-time 3D US imaging to segment the needle in 3D and then display oblique

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Figure 31.6 (a) Photograph of the image calibration phantom with the transducer inserted into the simulated rectum, (b) A 3D TRUS image of the image calibration phantom showing the nylon strings as white lines. The string intersections were used as fiducials to determine the image transformation used to integrate the 3D TRUS and robot coordinate systems.

Figure 31.7 Photograph of the plates used for the robot calibration. The positions of the divots in the transducer coordinate system are all known through the phantom design. The positions of the divots in the robot

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coordinate system were determined by moving the robot to touch these divots as shown in this figure.

Figure 31.8 Schematic diagram showing the ultrasound transducer mounted on the rotational mover used to produce 3D TRUS images of the prostate. The diagram shows that when the needle is inserted at an oblique angle relative to the transducer’s axis, multiple 2D US images are needed to track its insertion trajectory. sagittal, coronal and transverse image views with the needle trajectory highlighted. Since the needle may be angled, at most, approximately 20° from the orientation of the 2D US plane, and 2D images may be acquired at 30 images per second, a new 3D image may be formed in less than 1 second. From these 3D images, the needle may be segmented automatically,32,33 and the three planes needed to visualize the needle insertion maybe displayed. Figure 31.9 shows the results of needle insertion tracking in a prostate using our near real-time oblique needle segmentation and viewing approach. System evaluation We evaluated the performance of the robot-aided and 3D TRUS-guided brachytherapy system in a controlled laboratory setting using precisely built test phantoms. This is described below.

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3D TRUS image and robot coordinate system integration Calibration methods Accuracy analysis of the image and robot calibration was performed via the method used for analyzing accuracy of point-based rigid-body registration.34 This method involves the analysis of three errors: (1) fiducial localization error (FLE); (2) fiducial registration error (FRE); and (3) target registration error (TRE). FLE. The FLE is defined as the error in locating the fiducial points used in the registration procedure.35 We assumed that the mean value of the error in locating the fiducial points is zero and calculated the root-mean-square (rms) distance between the exact and calculated fiducial positions, thus:36 (2) where and are the variances of the errors in locating the fiducial points along the three orthogonal axes. The terms in Eq (2) are calculated as: (3) where, j=1,2,3 represents the components (i.e. x, y, or z), xijk is the kth measurement for ith fiducial point (for image calibration, i=1, 2, 3, 4, and for robot calibration, i=1, 2, …, 6), k is the number of measurements for each fiducial point. For both image and robot calibrations, n=10, and, (4) is the mean measurement for the jth component of the ith fiducial point.

Figure 31.9 Example of the views displayed during oblique needle tracking in a patient’s prostate, (a)

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Oblique sagittal view showing the oblique plane with the needle, (b) Oblique coronal view showing the plane with the needle (this view cannot be obtained with a conventional US system), (c) The 3D TRUS image has been sliced in a transverse direction showing the segmented needle trajectory, (d) The 3D TRUS image has been sliced in an oblique sagittal direction showing the needle. FRE. We know the exact positions of N fiducials P={pj; j=1,…,N} in the transducer coordinate system for either the image calibration phantom (Figure 31.6) or the robot calibration plates (Figure 31.7). For image calibration, we measured the positions of N fiducials (intersection of nylon strings) in the 3D image coordinate system Q={qj; j=1,…,N}. For robot calibration, we measured the positions of N fiducials (small divots) Q={qj; j=1,…,N} in the robot coordinate system by moving the robot to touch those small divots. FRE is calculated as the rms distance between corresponding fiducial positions before and after registration: (5)

where F is the rigid body transformation that registers the exact fiducial positions P with the measured fiducial positions Q. TRE. TRE is defined as the distance between corresponding points other than fiducial points before and after registration and calculated using Eq (5). We used four targets in the image calibration phantom to determine the TRE for image calibration, and four other markers on the plates to determine the TRE for robot calibration. Calibration results Our ability to localize the intersections of the nylon strings in the 3D TRUS image for the image calibration was analyzed along the X, Y, and Z directions and tabulated in Table 31.1 as the average fiducial localization error (FLE). From Table 31.1 it can be seen that the FLE for localizing the intersection of the strings was similar in the X or Y

Table 31.1 Fiducial localization error (FLE) (mm) for both image and robot calibration Image calibration

Robot calibration

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Y

Z

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Y

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Z

Mean 0.05 0.06 0.11 0.17 0.21 0.20 SD (0.01) (0.02) (0.01) (0.07) (0.11) (0.10) SD, standard deviation.

Table 31.2 Fiducial registration error (FRE) and target registration error (TRE) (in mm) for image and robot calibration. These values were obtained after the coordinate systems of the robot and 3D TRUS image had been integrated Image Robot calibration calibration FRE TRE FRE THE Mean 0.12 0.23 0.52 0.68 SD (0.07) (0.11) (0.18) (0.29) SD, standard deviation

directions and larger in the Z direction. This is attributed to the fact that the measurement error in the Z direction corresponded to the elevation (i.e. out-of-plane) direction of the acquired 2D images, which has the poorest resolution in 3D TRUS images.15 Table 31.1 also shows the FLE for localizing the divots on the two orthogonal plates used for robot calibration. From Table 31.1, it can be seen that the FLE for the divot localization was approximately the same in the three directions. This error, caused by the flexibility of the robot arm and backlash in the robot arm joints, is greater than that for the string intersection localization, and will dominate the calibration errors, affecting the accuracy of the system. The FRE and TRE values for the robot calibration are shown in Table 31.2. The mean FRE for the robot calibration was 0.52mm±0.18mm, and the mean TRE was 0.68 mm±0.29 mm, greater than those for image calibration. This results from the greater FLE for robot calibration as discussed above. Since system errors will result from both the image and robot calibration, the errors in the robot calibration dominate the accuracy of integration of the two coordinate systems. Needle placement accuracy The first phase of our testing involved measuring the accuracy of needle placement and angulation by the robot at the ‘patient’s’ skin. Needle placement accuracy was determined by using the robot to move the needle tip to nine locations on a 5 cm×5 cm grid that represented the ‘patient’s’ skin, (i.e. 3×3 grid of targeting points). A threeaxis stage (Parker Hannifin Co, Irwin, PA) with a measuring accuracy of 2 µm was then used to locate the needle tip. The displacement εd between the measured and targeted position of the needle tip was found as follows: (6)

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where (x, y, z) are the coordinates for the targeted point, (xi, yi, zi) are the coordinates for the ith measured point. The mean needle placement error, and the standard deviation (SD) from 10 measurements at each position was found to be 0.15 mm±0.06 mm. Needle angulation accuracy To measure the accuracy of needle angulation using the robot, we attached a small plate to the needle holder and used the robot to tilt the plate in four angles vertically and laterally (0°, 5°, 10°, 15°). After each tilt, we measured the orientation of the plate using the three-axis stage and determined the angulation error by comparing the measured and planned plate angle. Table 31.3 shows the mean angle differences between the measured and planned angulation by the robot and their standard deviations. As seen in Table 31.3, all mean angle differences were less than 0.12° with a mean of 0.07°. Since the angulation error will cause an increasing displacement error with increasing needle insertion distances, we estimated the displacement error after an insertion of 10 cm from the needle guide. Using the mean and maximum angulation errors, the mean and maximum displacement errors for a 10 cm insertion will be ±0.13 mm and ±0.50 mm, respectively. Needle targeting accuracy We used tissue-mimicking phantoms made from agar37 and contained in a Plexiglas box to determine the needle insertion accuracy. One side of the box was removable, allowing the insertion of the needle (Figure 31.2). Each of two phantoms contained two rows of 0.8 mm diameter stainless beads as shown in Figure 31.10.38 This approach provided four different bead targeting configurations: two different needle insertion depths and two different distances from the ultrasound transducer. These bead configurations formed a 4×4×4 cm3 cube to simulate the approximate size of a prostate. The targeting experiments involved first producing a 3D TRUS image, identifying a bead to be targeted, choosing a trajectory, positioning the robot to allow insertion of the needle to the target, and then insertion of the needle to the target. These needle insertion experiments were carried out with a rigid rod to avoid needle deflection. The accuracy was calculated by determining the deviations of the needle tip from the preinsertion bead locations in the 3D TRUS image. By averaging the results from all targeting experiments, the mean error was found to be 0.74 mm ±0.24 mm. In addition, we also plotted the results of the needle targeting accuracy as a 3D scatter plot of the needle tips relative to

Table 31.3 Results of accuracy evaluation of needle angulation by the robot for vertical and lateral tilts Vertical angulation Targeted angles 5° 0.02° Mean angle difference Standard deviation (0.02°) Maximum angle difference 0.08°

10° 0.04° (0.06°) 0.22°

15° 5° 0.06° 0.07° (0.05°) (0.05°) a 18° 0.12°

Lateral angulation 10° 0.10° (0.03°) 0.15°

15° 0.12° (0.08°) 0.28°

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Figure 31.10 Schematic diagram of the prostate phantom used for evaluation of needle targeting accuracy. The four rows of circles represent the four different bead configurations. The needle entered the phantom from the front, parallel to the x-axis. TRIP, top row, long penetration; TRSP, top row, short penetration; BRLP, bottom row, long penetration, BRSP, bottom row, short penetration. the target. In Figure 31.11, we show these results as well as the ellipsoid encompassing 95% of the needle tip locations (relative to the targets). Accuracy of needle tracking We compared the oblique needle tracking results to those obtained from the parallel trajectory since the trajectory of needle insertion parallel to the US transducer axis can be verified by observing the needle insertion in the realtime 2D TRUS images. We used the robot to guide the insertion of a needle at different angles (±5°, ±10°, ±15°) with respect to the parallel insertion trajectory. For each oblique needle trajectory, the needle was tracked automatically using the algorithm described above, its insertion

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Figure 31.11 Needle targeting accuracy is displayed as the 95% confidence ellipsoid. The origin of the coordinate system represents the target and the needle tip positions after insertion (relative to the targets) are presented by the squares. The projections of the needle tip positions and the ellipsoid (on the three orthogonal planes) are also shown. These results are for the targets near the transducer and for a short penetration, as shown in Figure 31.10. angle determined automatically and compared with the parallel insertion angle. This test was carried out with agar and a chicken tissue phantom,39 and repeated five times for each angle to determine the mean tracking error and its standard deviation. Table 31.4 shows the results of the needle tracking algorithm evaluation. In the chicken tissue phantom, the average execution time was 0.13±0.01 seconds, and the average angulation error was 0.54°±0.16°. In agar phantoms, the average execution time was 0.12±0.01 seconds, and the average angulation error was 0.58°±0.36°. The results shown in Table 31.4 demonstrate that needle insertion can be tracked in near real-time and that the tracking error does not significantly depend on insertion angle. Figure 31.9 shows the views provided to the physician during needle tracking.

Table 31.4 Needle tracking results for chicken tissue (a) and agar (b) phantoms for needle insertions at different angles. The values are the segmentation times (seconds) and the angulation errors (degrees)

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Angle −15° −10° −5° 5° 10° 15° (a) Time (s) 0.13 0.11 0.12 0.12 0.12 0.14 Error 0.50° 0.51° 0.43° 0.37° 0.74° 0.74° (b) Time (s) 0.12 0.12 0.12 0.11 0.12 0.13 Error 0.31° 0.71° 0.48° 0.68° 0.42° 0.86°

Seed implantation accuracy We used a brachytherapy needle to implant 0.8 mm spherical steel beads instead of brachytherapy seeds to test the accuracy of seed implantation using robot aids and 3D TRUS guidance. These beads were implanted into agar phantoms at different predefined positions, and using different needle trajectories (0°, ±5°, ±10°, ±15° with respect to the TRUS probe axis). These tests were carried out by first choosing a trajectory and a targeted position in the 3D TRUS image. Then, the robot was used to guide the needle and a bead was implanted. By obtaining a 3D TRUS image after the implantation, identifying the bead in the 3D TRUS image, and comparing the actual position of the bead to the planned position, the error in implantation could be determined. The bead implantation accuracy is tabulated in Table 31.5, showing that the mean error was 2.59 mm ± 0.76 mm. The greatest error was observed in the Y direction (in vertical plane), corresponding to the bevel direction of the needle. Discussion and conclusions We have demonstrated the technical feasibility of a robotaided prostate brachytherapy procedure using 3D TRUS guidance. The experimental results indicate that, with robotic assistance, the brachytherapy needle can be guided accurately and consistently to target points in the 3D TRUS image along various trajectories, including oblique, as specified by a preplan. We expect that with the introduction of a robotic system and 3D TRUS tools for automatic needle detection for oblique insertion, localization of the implanted seeds, and monitoring of prostate changes, an effective intraoperative prostate brachytherapy procedure will be possible. While most of the tools to accomplish this goal have been developed, seed segmentation from 3D TRUS images, such as the one shown in Figure 31.12, has not yet been accomplished and is required for a complete intraoperative system. However, based on the work to date, we can draw the following conclusions. In registering the coordinate systems of the robot and the imaging system, fiducial points in the 3D TRUS image must be determined. Errors in locating these fiducial points occur due to the poorer resolution in the 3D scanning direction, and will be greater for the points further away from the TRUS transducer.15 These errors will propagate, and result in targeting errors, causing systematic errors. Calibrating the robot coordinate system and integrating it with the 3D TRUS image requires that fiducial points related to the robot be identified (see Figure 31.7). Comparing Table 31.2 with Table 31.1, it is apparent that the fiducial localization error (FLE) for the robot fiducials is greater

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Table 31.5 Results of the seed implantation accuracy evaluation. The values are the error (mm) components along the coordinate axis between the planned and actual implanted bead locations. The errors have been measured for a range of needle trajectories −20° −15° −10° −5° 0° 5° 10° 15° 20° X 0.62 0.33 Y 2.79 2.01 Z 0.89 0.61 Total error 2.99 2.13 Mean±SD SB, standard deviation

0.34 0.78 0.41 0.54 0.65 0.40 0.51 1.02 2.97 1.58 2.97 3.27 3.03 1.99 0.79 0.75 0.53 0.75 0.98 0.63 0.87 1.33 3.16 1.72 3.11 3.48 3.12 2.23 2.59 mm ±0.76 mm

Figure 31.12 (a) A 3D TRUS prostate image postimplantation slices to reveal a transverse plane, (b) 3D TRUS image of the same patient as in (a), but sliced in the transverse and longitudinal directions showing the seeds, (c) The same image sliced in the coronal plane, showing the seeds arranged along the needle path. This view cannot be obtained using

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conventional ultrasound (US) techniques. than that for the 3D TRUS fiducials. Therefore, errors in calibrating the robot coordinate system will dominate and will deteriorate the overall accuracy of the system. Comparing the results obtained in the evaluation of the needle targeting accuracy using a rigid rod with those obtained for the bead implantation accuracy with a brachytherapy needle, it is apparent that the errors observed in the latter are larger and dominate the overall performance of the system. The large implantation error was primarily caused by needle deflection from the planned trajectory due to the bevel at the needle tip. Solving this source of error will greatly improve the performance of the system. In our prototype robot-assisted and 3D TRUS-guided system, the robot and 3D TRUS image coordinate systems are registered through specially designed calibration phantoms so that the position of the needle guidance hole could be related to the 3D TRUS image. This approach has allowed us to remove the parallel needle trajectory constraints present in current prostate brachytherapy procedures. Mounting the needle guide on a robot arm, rather than having it fixed to the ultrasound transducer holder, provides greater flexibility over the needle’s trajectory reducing the effects of pubic arch interference. While needle deflection due to the needle bevel contributes significantly to the overall error, robotic aids and 3D visualization may allow us to compensate for this deflection. Acknowledgments The authors gratefully acknowledge the financial support provided by the Canadian Institute of Health Research and the Ontario R&D Challenge Fund. AF holds a Canada Research Chair in Biomedical Engineering, and acknowledges the support of the Canada Research Chair Program. ZW acknowledges partial funding provided by Ontario Graduate Scholarship in Science and Technology. References 1. Watson LR. Ultrasound anatomy for prostate brachytherapy. Semin Surg Oncol 1997; 13(6):391–398. 2. Pathak SD, Grimm PD, Chalana V, Kim Y. Pubic arch detection in transrectal ultrasound guided prostate cancer therapy. IEEE Trans Med Imaging 1998; 17(5):762–771. 3. Strang JG, Rubens DJ, Brasacchio RA, et al. Real-time US versus CT determination of pubic arch interference for brachytherapy. Radiology 2001; 219(2):387–393. 4. Chin JL, Downey DB, Onik G, Fenster A. Three-dimensional prostate ultrasound and its application to cryosurgery. Tech Urol 1996; 2(4):187–193. 5. Chin JL, Downey DB, Mulligan M, Fenster A. Three-dimensional transrectal ultrasound guided cryoablation for localized prostate cancer in nonsurgical candidates: a feasibility study and report of early results. J Urol 1998; 159(3):910–914. 6. Messing EM, Zhang JB, Rubens DJ, et al. Intraoperative optimized inverse planning for prostate brachytherapy: early experience. Int J Radiat Oncol Biol Phys 1999; 44(4):801–808.

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7. Waterman FM, Yue N, Corn BW, Dicker AP. Edema associated with I-125 or Pd-103 prostate brachytherapy and its impact on postimplant dosimetry: an analysis based on serial CT acquisition. Int J Radiat Oncol Biol Phys 1998; 41(5):1069–1077. 8. Badiozamani KR, Wallner K, Sutlief S, et al. Anticipating prostatic volume changes due to prostate brachytherapy. Radiat Oncol Investig 1999; 7(6):360–364. 9. Yu Y, Anderson LL, Li Z, et al. Permanent prostate seed implant brachytherapy: report of the American Association of Physicists in Medicine Task Group No. 64. Med Phys 1999; 26(10):2054–2076. 10. Beyer DC, Shapiro RH, Puente F. Real-time optimized intraoperative dosimetry for prostate brachytherapy: a pilot study. Int J Radiat Oncol Biol Phys 2000; 48(5):1583–1589. 11. Taschereau RP, Roy J, Tremblay J. Characterization of source seed migration in permanent prostate implants. 40th Annual Meeting of the AAPM, San Antonio, 9–13 August, 1998. 12. Pouliot JR, Taschereau J, Vachon R. Determination of post-implant edema from seed distribution of prostate implants. Int J Radiat Oncol Biol Phys 1998; 42:221. 13. Stock RG, Stone NN, Wesson MF, DeWyngaert JK. A modified technique allowing interactive ultrasound-guided three-dimensional transperineal prostate implantation. Int J Radiat Oncol Biol Phys 1995; 32(1):219–225. 14. Fichtinger G, DeWeese TL, Patriciu A, et al. System for robotically assisted prostate biopsy and therapy with intraoperative CT guidance. Acad Radiol 2002; 9(1):60–74. 15. Fenster A, Downey DB, Cardinal HN. Three-dimensional ultrasound imaging. Phys Med Biol 2001; 46(5):R67–99. 16. Fenster A, Surry K, Smith W, et al. 3D ultrasound imaging: applications in image-guided therapy and biopsy. Comput Graph 2002; 26(4);557–568. 17. Peters T, Fenster A, Slomka P. Imaging for radiation therapy planning (MRI, nuclear medicine, ultrasound). In: Van Dyk J, ed. The modern technology of radiation oncology: A compendium for medical physicists and radiation oncologists. Madison, Wisconsin: Medical Physics Publishing, 1999; 191–230. 18. Howe RD, Matsuoka Y. Robotics for surgery. Annu Rev Biomed Eng 1999; 1:211–240. 19. Taylor RF, Jensen G, Riviere P. Medical Robotics and computerintegrated surgery: information-driven systems for 21st century operating rooms. J Jpn Soc Comput Aided Surg 2000; 2:47. 20. Cadeddu JA, Bzostek A, Schreiner S, et al. A robotic system for percutaneous renal access. J Urol 1997; 158(4):1589–1593. 21. Stoianovici D. URobotics—Urology Robotics at Johns Hopkins. Comput Aided Surg 2001; 6(6):360–369. 22. Sung GT, Gill IS. Robotic laparoscopic surgery: a comparison of the DA Vinci and Zeus systems. Urology 2001; 58(6):893–898. 23. Wei Z, Wan G, Gardi L, et al. Robot-assisted 3D-TRUS guided prostate brachytherapy: system integration and validation. Med Phys 2004; 31(3):539–548. 24. Tong S, Downey DB, Cardinal HN, Fenster A. A three-dimensional ultrasound prostate imaging system. Ultrasound Med Biol 1996; 22(6):735–746. 25. Tong S, Cardinal HN, Downey DB, Fenster A. Analysis of linear, area and volume distortion in 3D ultrasound imaging. Ultrasound Med Biol 1998; 24(3):355–373. 26. Tong S, Cardinal HN, McLoughlin RF, et al. Intra- and interobserver variability and reliability of prostate volume measurement via two-dimensional and three-dimensional ultrasound imaging. Ultrasound Med Biol 1998; 24(5):673–681. 27. Downey DB, Fenster A, Williams JC. Clinical utility of threedimensional US. Radiographics 2000; 20(2):559–571. 28. Ladak HM, Mao F, Wang Y, et al. Prostate boundary segmentation from 2D ultrasound images. Med Phys 2000; 27(8): 1777–1788. 29. Wang Y, Cardinal HN, Downey DB, Fenster A. Semiautomatic threedimensional segmentation of the prostate using two-dimensional ultrasound images. Med Phys 2003; 30(5):887–897.

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30. Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial brachytherapy sources: recommendations of the AAPM Radiation Therapy Committee Task Group No. 43. American Association of Physicists in Medicine. Med Phys 1995; 22(2):209–234. 31. Arun KH, Huang TS, Blostein SD. Least-squares fitting of two 3-D point sets. IEEE Trans Pattern Anal Mach Intel 1987; 9:698–700. 32. Ding M, Cardinal HN, Fenster A. Automatic needle segmentation in three-dimensional ultrasound images using two orthogonal twodimensional image projections. Med Phys 2003; 30(2):222–234. 33. Ding M, Fenster A. A real-time biopsy needle segmentation technique using Hough transform. Med Phys 2003; 30(8):2222–2233. 34. Maurer CR Jr, Maciunas RJ, Fitzpatrick JM. Registration of head CT images to physical space using a weighted combination of points and surfaces. IEEE Trans Med Imaging 1998; 17(5):753–761. 35. Fitzpatrick JM, West JB, Maurer CR Jr. Predicting error in rigid-body point-based registration. IEEE Trans Med Imaging 1998; 17(5):694–702. 36. Maurer CM, Fitzpatrick R. Estimation of accuracy in localizing externally attached markers in multimodal volume head images. Proc SPIE 1993; 1898:43–53. 37. Rickey DW, Picot PA, Christopher DA, Fenster A. A wall-less vessel phantom for Doppler ultrasound studies. Ultrasound Med Biol 1995; 21(9):1163–1176. 38. Smith WL, Surry KJ, Mills GR, et al. Three-dimensional ultrasoundguided core needle breast biopsy. Ultrasound Med Biol 2001; 27(8):1025–1034. 39. Smith WL, Fenster A. Optimum scan spacing for three-dimensional ultrasound by speckle statistics. Ultrasound Med Biol 2000; 26(4):551–562.

32 Initial experience with the FIRST system in Utrecht Jan J Battermann, Ina Schulz, Marinus A Moerland, and Marijke van Deursen Introduction Permanent prostate brachytherapy is now performed in many centers world-wide and is well accepted in North America and Western Europe. Different techniques are employed with either single seeds or strands, using preloading as well as after-loading, and preplanning or intraoperative planning. A new device was recently introduced by Nucletron Inc, the FIRST system (Fully Integrated Radiotherapy Seed Treatment). In this system, both an intraoperative planning system (SPOT; Sonographic Planning of Oncology Treatment) and an automated seed afterloader (seedSelectron) are combined. This system is in routine use at the radiation oncology department at University Hospital Utrecht since January 2002. The FIRST system The FIRST system combines intraoperative planning (SPOT) and automated seed delivery (seedSelectron). The configuration of the seeds, calculated with the SPOT system, is automatically transferred to the seedSelectron steering software. Increasingly, treatment centers are using intraoperative planning with the advantages of exact patient position and real-time adjustments.1–6 SPOT is a three-dimensional (3D) planning system, using 3D imaging of the prostate by ultrasound with a special electronic ultrasound probe with a transversal and longitudinal array. With 3D imaging and contouring of the prostate, a first plan is made based on geometric rules, the so-called ‘autoplan’. At the discretion of the radiation oncologist and physicist, adding or deleting needles and seeds can modify this plan. The autoplan can be evaluated by dose-volume histograms (DVH)—both the cumulative and the natural DVH. The cumulative DVH assesses the placement of the dose distribution over the target volume and provides prostate volume and coverage. The natural DVH assesses the homogeneity of the implant according to the width of the peak. The natural prescription dose (NPD) for a given dose distribution is located at the base of the peak at the low dose side and is the optimal prescription dose for the implant. The ratio between the NPD and the prescribed dose (PD) (usually 144 Gy) is called the natural dose ratio (NDR) and should be around 1 for an optimal plan. The higher the

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value, the ‘hotter’ the implant. Without the use of the natural DVH, overdose easily escapes detection.7,8 With SPOT, a needle update can be made after insertion of the needles to their actual position with 3D reconstruction. Hence, a ‘live’ plan can be made before the seeds are placed and evaluated for further modification of seed distribution. The calculated needle and seed configuration is transferred to the seedSelectron user interface. Since the seedSelectron has separate cartridges with radioactive seeds and spacers, any combination of active seeds and spacers in one needle can be made. After a train of seeds and spacers is built up in the compose element, a drive wire pushes the complete train into the prostate to the tip of the needle. The needle is retracted automatically 7 mm beyond the proximal seed in the train with the drive wire still in position. The wire is then again retracted 7 mm to avoid any sticking of the proximal seed to the drive wire. Subsequently, the wire is completely retracted and the needle is removed manually. The cartridges can hold up to 100 active seeds. However, cartridges with 90, 80, 70, 60, 50, or 10 seeds are also available. Cartridges with spacers always contain 100 spacers. However, cartridges can only be used for one patient, since blood can be introduced into the cartridge and cause contamination in the next patient undergoing this procedure. Implantation technique Pretreatment evaluation All patients referred for permanent seed implantation are screened for their eligibility by ultrasound imaging at the urology department in our hospital. This procedure is performed as a combined examination by the urologist and radiation oncologist. The prostate is screened for extracapsular tumor extension, which is an exclusion criterion for brachytherapy, and the prostate volume is measured. Since intraoperative planning is performed, no complete volume study is made on this occasion. Prostate volumes with a maximum of 50 cc are accepted, knowing that, in general, the volume will be approximately 10–20% larger with 3D ultrasound imaging. Questionnaires for lower urinary tract symptoms (International Prostate Symptom Score; IPSS) and sexual activity will have been completed before this first visit. The urine flow is measured before the ultrasound procedure. Patients are seen by the anesthesiologist, who will estimate the patient’s eligibility for anesthesia and discuss the type of anesthesia. Most patients are treated under epidural anesthesia, although it is advisable to use general anesthesia in a center just starting this procedure. The patients receive instructions for bowel cleansing and a prescription for a laxative to be used for five days before treatment. Pretreatment preparation Patients are hospitalized some hours prior to the procedure to allow ample time for the nursing staff to prepare him for treatment. The perineum is shaved and a rectal enema is given about one hour before implantation.

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The actual implant is carried out in a dedicated operating room (OR), which is also used for other brachytherapy procedures. Prophylactic antibiotics are administered as an intravenous bolus. With the patient anesthetized, his legs are placed in the stirrups in the lithotomy position with the femurs in a vertical plane. A foley catheter is introduced to drain the bladder and visualize the urethra on ultrasound. The catheter balloon is filled with a solution of contrast medium to identify the bladder outlet during fluoroscopy. The scrotum is displaced upwards with adhesive dressing and the perineum is washed with an antiseptic solution. In order to perform fluoroscopy during the procedure, see Figure 32.1 for set-up of patient and equipment. After the transrectal ultrasound (TRUS) probe is inserted into the rectum and locked in the stepping unit the template is mounted on to the stepping unit. The stepping unit and support device are aligned in such a way that the dorsal contour of the prostate is at the lowest line of the template (row 1). The prostate contour should be symmetric

Figure 32.1 Patient set-up with legs in stirrups, stepping unit in place, Carm, TRUS system and planning system. in the template, usually with the urethra at the D-line of the grid. Implantation procedure Stabilization needles are mandatory in order to reduce movement of the prostate during insertion of the needles and 3D imaging acquisition. After insertion of these locking needles, routinely in the center of the prostate (Figure 33.3), a first 3D scan is taken using the sagittal mode of the probe. The prostate is contoured, first using a sagittal view to identify the base, apex, and thickness of the prostate in the mid-sagittal plane (Figure 32.2). Then, on transverse imaging at increments of 2.5 or 5 mm, the contour is depicted from base to apex (Figure 32.5).

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Following contouring of the prostate, the urethra is contoured, again using both sagittal and transverse imaging. The process of contouring takes about 15 minutes. From this contour a treatment plan is made in the autoplan mode. Needles and seeds are placed inside the prostate volume according to geometric rules, (e.g. seed placing in a line at 10 mm, between lines at 5 mm, and seed staggering). Note that an autoplan only places seeds homogeneously in the prostate volume and this would result in an overdose to the central part of the prostate, including the urethra (Figure 32.4). The DVH, as described above, is essential for evaluating and optimizing the plan. At the discretion of the radiation oncologist and physicist, needles can be added or removed, and the seed composition per needle can be adjusted. Centrally placed needles, in general, only need one seed at the base and one at the apex, resulting in a substantial reduction of the dose to the urethra. We aim at a prostate coverage of over

Figure 32.2 Contouring of prostate and urethra in transversal, sagittal and coronal planes, and 3D composition of these images. Note the position of the two locking needles as echos on the transversal and coronal planes.

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Figure 32.3 Contouring in transverse plane. 95%, a margin of 2–3 mm around the prostate volume, a urethral dose lower than 150%, and the volume receiving 150% and 200% of the prescribed dose less than two thirds and one third of the prostate volume, respectively. The natural dose ratio (NDR) is a simple and helpful tool for evaluating over- or underdosing of the target volume (Figure 32.4). In centers with experience in this technique, the insertion of needles is routinely started after 3D scanning, without waiting for the treatment plan. All needles are placed (Figure 32.5), using both transverse and sagittal imaging to determine the position of each needle in relation to the base and apex of the prostate, starting at the most ventral row to reduce image interference from other needles. The needle is navigated using the bevel direction to fine tune the final position of the needle. The special needles, necessary for the FIRST system, have an obturator 5 mm shorter than the needle length; hence the obturator does not

Figure 32.4 Autoplan based on geometric rules (left). Red line indicates the contoured outline of the prostate. The blue line is the 150% isodose line, covering the whole prostate. The purple line is the

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prescription dose of 145 Gy. Natural dose volume histogram (right) shows a narrow peak, indicating a very homogenous dose distribution due to the high dose that is received by the whole gland. This is also reflected by the high natural dose ratio of 1.70.

Figure 32.5 Situation with all needles, including two locking needles, in place. The needle position is adjusted for the correct position in relation to the base plan. have to be retracted while inserting the needle. After insertion and proper placement of all needles, fluoroscopy is performed to verify the relation of the needle tips with the catheter balloon in the bladder. On the x-ray, shown in Figure 32.6, note that the tip of the obturator is at a different level to the tips of the needles. A second 3D ultrasound scan is then made with all the needles in position. With SPOT, there is the option of a 3D reconstruction of the needle position to its actual position in the prostate and hence more accurate treatment plan

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Figure 32.6 Definitive needle and seed positions, according to final treatment plan in schematic view (upper part). Loading pattern per individual needle (lower part).

Figure 32.7 Updated treatment plan, showing reduced dose to urethral and rectum in transversal plane (left) and exact needle position on sagittal plane (right).

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(Figure 32.7). This second scan is helpful in deciding the final seed configuration. When the team has agreed on the plan, it is saved and printed out (Figure 32.8). Intraoperative planning parameters, such as V100 (percent

Figure 32.8 Definitive needle and seed positions, according to final treatment plan in schematic view (upper part). Loading pattern per individual needle (lower part). prostate volume covered by the prescription dose) and D90 (minimal dose in 90% of the prostate) can be obtained, as well as other data. The seedSelectron is mounted on the stepping unit and connected to the SPOT system. After a trial run, the compose element, two cartridges containing active seeds and spacers, and the drive wire element are inserted into the seedSelectron (Figures 32.9 and 32.10). The transfer tube of the seedSelectron is attached to a small container to release one seed for validation of the seed activity. A particular quality assessment (QA) feature of the seedSelectron is individual measurement of radioactivity per seed during seed composition. The transfer tube is first connected to one of the needles with the tip at the

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base plane, to ensure that all the subsequent needles are within the delivery range. If necessary, the position of the seedSelectron on the stepper can be adjusted. The hook of the seedSelectron has to be positioned at the flange on the transfer tube to ensure

Figure 32.9 Disposables used for the FIRST implant. Not shown are the locking and insertion needles. The lead pot will contain the disposed seed for verification of the seed activity to calibrate the system.

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Figure 32.10 Schematic view of seedSelectron with cartridges containing active seeds and spacers. that the seed train reaches the tip of the needle. The first train of seeds and spacers is composed, the activity of each seed checked as well as the composition of the train, and then the seed train is automatically transported to the tip of the needle. Seed delivery can be performed either in the automatic or manual mode. In the automatic mode, the tip

Figure 32.11 Seed distribution over prostate gland, directly after implant procedure. See also Figure 29.4. positions are automatically derived from the calibration of the first needle at the base plane and the retraction values of the respective needles in the treatment plan. In the manual mode, the hook has to be positioned for each needle. The manual mode has an advantage in that each needle position can be checked by sagittal ultrasound and, if necessary, adjusted before actual seed delivery. Usually, needles have to be pushed a few mm deeper to obtain optimal placement of seeds. With sagittal ultrasound in place, deposition of seeds can also be checked. The deposition of the seed trains begins, as described above, with a deeply positioned needle. After this first needle, all the remaining are delivered similarly, starting with the highest row and going from left to right.

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When all the needles have been removed, including the locking needles, a final 3D scan is made as well as fluoroscopy (Figure 32.11) to assess the number of implanted seeds. The perineum is draped with sterile gauze. Postimplant care In Utrecht, we hospitalize the patient for one night after implantation. The urinary catheter is left in situ overnight and removed the next day, after performing a computed tomography (CT) scan for postplanning and fluoroscopy for a second check on the number of seeds. Postoperative care is usually routine postanesthesia care. Patients receive naproxen 250 mg three times a day to reduce swelling of the prostate. Alphablockers are not routinely prescribed: only for those patients with large volumes or a high IPSS. The patient is discharged after being checked that he can void normally. In our total practice of almost 1000 patients we only once had to postpone hospital discharge for acute retention after removal of the catheter. Postplanning Postimplant dosimetry is either done after CT or magnetic resonance imaging (MRI) one month after treatment when swelling should have gone down.9–11 Although we prefer MRI, because of better contouring of the prostate, we do not use MRI for all patients due to costs and facility availability. MRI, CT, and X-ray data are matched to optimize prostate contouring and seed localization. DVH parameters are very useful indices in assessing the quality of the implant. The emergency tool An emergency kit (Figure 32.12) is included in the FIRST system so that the implant procedure can continue should the system break down. The implant needles, already in situ, can be used with this tool. The two cartridges with active seeds and spacers can be placed in the tool, and a seed train can be composed manually. This train is then manually inserted by placing the tool on the needle and pushing the seed train into the prostate. The needle is then retracted manually. However, at the time of writing, we have implanted more than 150 patients with the FIRST system and have had to use the emergency kit only twice. Modifications in the FIRST system during 2003 have made it very reliable. Discussion Different techniques are used in different centers around the world. Intraoperative planning is becoming increasingly popular and has the advantages of accurate patient position and real-time dosimetry, resulting in a better dose distribution.1–6 Although the total OR time is substantially longer than after preplanning, especially with preloaded needles, the total time is reduced because neither a complete volume study nor a preplan

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have to be made. Table 32.1 gives a summary of the treatment times for different implantation techniques. From our own experience,

Figure 32.12 Emergency kit to finish the implant procedure manually in case a of break-down of the FIRST system. The two cartridges are mounted together and with the knob, a composition of seeds and spacers can be made according the original plan. The small tube is connected to the individual needle to insert the train of seeds and spacers manually with the needle obturator we found that for a proper volume study approximately 20 minutes is required. For patients treated with intraoperative planning, an ultrasound examination will be repeated after referral from another urology department to confirm the eligibility of the particular patient and assess the prostate volume. One should take into account that the volume might be up to 20% larger with a complete volume study or 3D volume assessment. Preplanning with current available 2D-planning systems will take 15 to 20 minutes. The FIRST system combines intraoperative planning with automated seed afterloading. The advantages of this system include optimal radiation protection and a straightforward composition of seeds and spacers in any combination, especially when central needles can be loaded with just one active seed at the beginning and at the end. Checking radioactivity of each seed, automatic train composition, and check on composition, improve quality control and save time, compared to measuring the activity at random of loose seeds or some strands. Furthermore, it saves time (and personnel) in

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preparing seed trains, and a preparation station in a separate source room is unnecessary. The length of time needed to insert the needles is similar for all techniques. We prefer to insert all the needles first, as this has the advantage of a better fixation in the prostate, and optimal control of the position of the needles, using both sagittal ultrasound scanning and fluoroscopy. When individual

Table 32.1 Estimated treatment times for different implant techniques Technique

Preplan and preparation OR time Total time

Mick applicator 45 min Str Strands preloaded 45 min 4+30 rain Strands afterloaded Live plan FIRST Live plan

45 min 1 h 30 min 45 min 2h 1 h 45 min 1 h 45 min 1 h 45 min 1 h 45 min

needles are introduced, their position checked, and seeds placed into the prostate separately, the treatment time is longer. This is because the control of the needle positions is at the end of the procedure. The loading of seeds in the prostate takes a little longer than the placing of seeds from preloaded needles and about the same time as the loading of seeds in sutures (RAPID Strand). A disadvantage of the FIRST system could be cartridges, although these are available with 10, 50, 60, 70, 80, 90, and 100 seeds. Unused seeds from a cartridge cannot be used in another patient, because the cartridge may be contaminated with blood. If insufficient seeds are present in a cartridge, extra seeds can be used (e.g. from a 10 seed cartridge) or, if available, loose seeds or RAPIDStrand, but, in general, the needles in the FIRST system are not compatible to other delivery systems, such as the Mick applicator or the Utrecht strand holders for RAPID Strands. (See Chapter 29.). Another problem is seed loss and seed migration. With peripheral loading of the seeds over the prostate volume, seed loss is quite rare (Table 32.2), and seed migration hardly ever encountered. With selectSeeds and peripheral loading, we see a higher migration rate, mainly resulting in one or more seeds entering the lungs. Although no detrimental effect of this migration has been described so far, we should try to reduce any dose at locations not to be irradiated to the minimum. Postplanning Since SPOT offers the possibility of 3D reconstruction of the actual needle position, the modified plan can be regarded as a postplan. In general, seeds are not as neatly lined up as with RAPID Strands (see Figures 32.11 and 29.4), which may reduce the homogeneity of the implant, but in our experience this has little influence on prostate coverage. We tested the FIRST system by the insertion of half of the prostate with Strands, and half with selectSeeds. We controlled the position of selectSeeds and strands with fluoroscopy and sagittal ultrasound during the actual insertion of the seed in the gland. We found that selectSeeds came approximately 5 mm closer to the prostate base than seeds

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Table 32.2 Seed loss and migration after different implant techniques used at UMC Utrecht Single seed

Strands of seeds

FIRST

No. patients 101 536 70 No. seeds 4227 38 903 5095 Lost at discharge 129 16 6 Lost at 1 month 26 233 7 Lost at 1 year* 46 211 1 Total lost 216 (5.1%) 460 (1.2%) 14 (0.3%) Migration 11 (0.3%) 25 (<0.1%) 41 (0.8%) Excluded are patients with pre- or post- (<1 year) implant transurethral resection of the prostate (TURP); patients with combined strands and Selectseeds (total 19 patients). UMC, University Medical Hospital. *34 patients with Selectseeds have not yet completed 1 year follow-up, and 83 patients with strands.

in strands. This is due to a 2.5 mm vicryl coating on the first seed in a strand, but despite this, the FIRST system places seeds exactly at the end of the needle tip. These differences resulted in slightly better coverage with selectSeeds compared to strands.12–14 Nowadays, we introduce the needles for loading with strands a few millimeters deeper than we did originally. When different parameters for dosimetry are compared, we found hardly any differences between strand implants and selectSeed implants. Although the modified plan after the 3D needle position update shows a coverage of almost 100% in all patients, postplanning one day later with CT imaging often shows some reduced coverage to 85– 95%. This can be attributed to postimplant swelling of the gland. The V200 and V150, in general, are below one and two thirds of the total prostate volume, respectively. D90 values obtained 4 weeks postimplant are normally between 100 Gy and 160 Gy and improved with intraoperative planning.14 Conclusions The FIRST system is a reliable technique that offers intraoperative planning and automated seed afterloading. The total treatment time for an individual patient does not substantially differ from other techniques, but OR time is longer, mainly because of intraoperative planning. This requires more OR time, independent of the implantation technique. On the other hand, intraoperative planning is more accurate and results in better dosimetry parameters. Advantages of FIRST are the quality control of seed strength and seedspacer combination, the straightforward composition of a differential loading pattern per needle, and optimal radiation safety. Automatic composition of seedspacer combinations saves time, personnel, and time in the preparation room. Disadvantages include the disposal of unused seeds from a cartridge and the higher percent of seed migration. The follow-up time since the introduction of FIRST is too short to give any reliable information on biochemical control so far. However, as dosimetry parameters are similar, or even better than in other techniques, we expect similar biochemical control results.

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References 1. Cormack RA, Tempany CM, D’Amico AV. Optimizing target coverage by dosimetry feedback during prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 48:1245–1249. 2. Beyer DC, Shapiro RH, Puente E Real-time optimized intraoperative dosimetry for prostate brachytherapy: a pilot study. Int J Radiat Oncol Biol Phys 2000; 48:1583–1589. 3. Nag S, Ciezki JP, Cormack R, et al. Intraoperative planning and evaluation of permanent prostate brachytherapy: report of the American Brachytherapy Society. Int J Radiat Oncol Biol Phys 2001; 51:1422–1430. 4. Thompson SA, Fung AY, Zaider M. Optimal needle arrangement for intraoperative planning in permanent I-125 prostate implants. Phys Med Biol 2002; 47:N209–215. 5. Zelefsky MJ, Yamada Y, Marion C, et al. Improved conformality and decreased toxicity with intraoperative computer-optimized transperineal ultrasound-guided prostate brachytherapy. Int J Radiat Oncol Biol Phys 2003; 55:956–963. 6. Lee EK, Zaider M. Intraoperative dynamic dose optimization in permanent prostate implants. Int J Radiat Oncol Biol Phys 2003; 56:854–861. 7. Riet A van’t, Loo HJ te, Ypma AF, et al. Ultrasonically guided transperineal seed implantation of the prostate: modification of the technique and qualitative assessment of implants. Int J Radiat Oncol Biol Phys 1992; 24:555–558. 8. Moerland MA, Laarse R van der, Luthman RW, et al. The combined use of the natural and the cumulative dose-volume histograms in planning and evaluation of permanent prostatic seed implants. Radiother Oncol 2000; 57:279–284. 9. Moerland MA. The effect of edema on postimplant dosimetry of permanent Iodine-125 prostate implants: a simulation study. J Brachyther Int 1998; 14:225–231. 10. Yue N, Chen Z, Peschel R, et al. Optimum timing for image-based dose evaluation of 125I and 103PD prostate seed implants. Int J Radiat Oncol Biol Phys 1999; 45:1063–1072. 11. Gellekom MP van, Moerland MA, Kal HB, Battermann JJ. Biologically effective dose for permanent prostate brachytherapy taking into account postimplant edema. Int J Radiat Oncol Biol Phys 2002; 53:422–433. 12. Moerland MA, Wijrdeman HK, Beersma R, et al. Evaluation of permanent I-125 prostate implants using radiography and magnetic resonance imaging. Int J Radiat Oncol Biol Phys 1997; 37:927–933. 13. Nag S, Bice W, DeWyngaert K, et al. The American Brachytherapy Society recommendations for permanent prostate brachytherapy postimplant dosimetric analysis. Int J Radiat Oncol Biol Phys 2000; 46:221–230. 14. Gellekom MP Van, Moerland MA, Wrjrdeman HK, Battermann JJ. Quality of permanent prostate implants using automated delivery with seedSelectron versus manual insertion of RAPID Strands. Radiother Oncol 2004; 7:49–56.

Part IV Treatment planning and techniques for high dose rate prostate brachytherapy

High dose rate

192

33 Ir prostate brachytherapy

Kas R Badiozamani, Timothy P Mate, and James E Gottesman Introduction High dose rate (HDR) brachytherapy is an established and rapidly advancing technique used to deliver highly conformal doses of radiation in the treatment of prostate cancer. Remote afterloading devices using high activity iridium-192 (192Ir) sources are commonly used in a variety of centers throughout the world, making HDR prostate brachytherapy increasingly available to many patients. This chapter is intended to provide the reader with a basic understanding of HDR implants, including appropriate patient selection, implant techniques, and outcomes. The rationale for the use of HDR brachytherapy in prostate cancer is discussed, as are areas for future research and development. Background and rationale HDR brachytherapy was first used for prostate cancer in the mid 1980s in Kiel, Germany,1 and others soon developed pilot programs in the United States, but the relatively limited availability of afterloaders precluded early, widespread adoption of the technique. Nonetheless, several factors make HDR an attractive and promising approach to the treatment of prostate cancer. Conformal dose escalation has been the major theme in prostate irradiation for more than a decade. Advances in computer technology have allowed for the development of complex, three-dimensional (3D) treatment plans that allow greater precision in dose delivery to the prostate to spare the rectum and bladder. It is hoped that intensity modulated radiotherapy (IMRT) will further this cause. However, organ motion and daily variations in set-up have continued to pose challenges to external irradiation techniques. Although permanent seed implants avoid this problem, accurate placement of seeds within the gland is technically challenging, and significant deviations from the preoperative plan may occur.2 These difficulties potentially compromise accurate and reliable dose escalation with sparing of normal structures. Remote afterloading with high dose rate iridium-192 (192Ir) theoretically remedies some of the dosimetric uncertainties of seed implants and conformal external beam irradiation. This technology can precisely place a single, movable high activity 192Ir source anywhere inside an afterloading needle, and then vary the time spent at a particular location (dwell time) to control dose deposition. When used in the context of a prostate implant with multiple needles, one may deliver a highly conformal dose to the periphery of the prostate while minimizing bladder and rectal doses. Furthermore, doses maybe differentially delivered within the prostate gland as desired while sparing the centrally located urethra. Because dwell times may be adjusted after the needles have

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been placed, small inaccuracies in needle placement can be overcome. For these reasons, HDR brachytherapy is currently the most accurate method for delivery of conformal irradiation to the prostate.3 Studies of the radiobiology of prostate cancer provide further support for the use of HDR. Recently, there have been reports suggesting that prostate cancers may be more susceptible to large fraction sizes compared with standard fractionation.4,5 Based on the linear-quadratic model of clonogenic cell death in response to irradiation, Brenner and Hall have suggested that prostate cancers have an alphabeta ratio of approximately 1.5,4 and there have been clinical data to support this finding.5 Although a detailed discussion of the linear-quadratic model and its application to radiation dosing is outside the scope of this chapter, such findings have prompted radiation oncologists to consider hypofractionated regimens for prostate cancer.6 The potential for increased late morbidity with large fraction sizes remains a concern, however, and for this reason the precise dose control afforded by HDR makes it particularly useful for regimens incorporating hypofractionation. Patient selection and pretreatment evaluation All patients with clinically localized disease may be appropriate candidates for HDR therapy. At the Swedish Cancer Institute in Seattle, Washington, we have tended to treat those patients with a high tumor burden, based on the following criteria: sextant biopsies with two or more zones positive, Gleason scores of 7 or higher, and pretreatment prostate-specific antigen (PSA) values greater than 10 ng/mL. This relatively adverse selection has resulted from the local presence of a permanent seed program demonstrating successful monotherapy in patients with low risk disease, but there is little to suggest that HDR would be less effective in these patients. Martinez is currently investigating HDR monotherapy in patients with favorable characteristics, specifically those with stage T1-T2a disease, Gleason scores of 7 or less, and PSA values of 10 ng/mL or less. Preliminary results have been encouraging thus far.7 As more data regarding the efficacy and morbidity of this treatment become available, it is anticipated that more low risk patients will pursue HDR therapy. Patients with a prior history of transurethral resection of the prostate (TURP) should be cautioned about the potential risk of incontinence, but in our experience even these patients have faired well, likely owing to the modest doses that may be administered to the urethra without compromising peripheral zone coverage. Likewise, large gland size (e.g. >60 cc) is not a contraindication. Although pubic arch interference (PAI) may preclude needle placement in the anterior portions of large prostates, this ‘defect’ can be overcome by modifying source dwell times. We have implanted prostates over 100 cc with little difficulty. All patients who may be considering an HDR implant are required to undergo a complete pretreatment evaluation, including appropriate biopsy with Gleason scoring, serum PSA evaluation, and digital rectal examination (DRE). Bone scans are recommended for patients with PSA levels greater than 20 ng/mL, or Gleason scores >8. No pretreatment computed tomographic (CT) scan or transrectal ultrasound (TRUS) is required for planning, although exceptions are made if the brachytherapist discovers an

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exceptionally large gland on DRE, in which 2–3 months of neo-adjuvant androgen ablation therapy may be used for downsizing. Magnetic resonance imaging (MRI) has the potential to delineate areas of extracapsular extension or gross disease within the prostate, but this has not been standard in our practice. Implant technique Our technique at the Swedish Cancer Institute is the one described below. There are, however, variations on this method including the use of real-time dosimetry, as described by Martinez et al, and the interested reader is referred to the citations listed. (1,8–12) However, the various techniques all have in common several salient features, including transrectal ultrasound guidance to place after-loading needles into the prostate, with three-dimensional dose (3D) optimization based on the resulting needle distribution. Dose schedules have been highly variable across institutions, and our own practice patterns have also undergone significant evolution since our first report (Table 33.1). Preoperative bowel prep includes a low fiber diet for 2–3 days prior to the implant, with only clear liquids

Table 33.1 High dose rate (HDR) brachytherapy: variations in prescribed doses Institution

Pelvic EBRT* HDR boost

interdisciplinaryBrachytherapy Center, Kiel, Germany

50 Gy pelvis 40 Gy prostate

Timing of No, operative implant procedures boost

9 Gy×2 entire After 20 Gy 2 gland;15 Gy×2 and40 Gy of to peripheral EBRT zone Swedish Cancer Institute, Seattle, Initial report: Initial: 3.0–4.0 2 weeks 1 WA 50.4 Gy prostate Gy×4 Current 8 before Current 45–50 Gy×2 EBRT Gy prostate William Beaumont Hospital, Royal 46 Gy pelvis 5.5–6.6 Gy×3 or Weeks 1 2 Oak, MI 8.25–1 0.5 Gy×2 and 3 of EBRT * EBRT, External beam radiotherapy.

allowed after lunch until midnight on the evening before the procedure, followed by one Fleets enema in the morning. Occasionally, an intraoperative rectal lavage may be needed if TRUS visualization is compromised by persistent stool in the rectum. In the operating room, patients are prepped and draped in the lithotomy position under general or spinal anesthesia, but no foley catheter is inserted at this point. TRUS is performed to assess gland size and align the prostate with respect to the mounted template on the ultrasound probe. Generally, we have aligned the gland such that the 3D position of the template corresponds to the position of the urethra; aerated gel can be inserted into the urethra to assist with visualization but this is usually not necessary. Three radiopaque seeds are

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inserted at the apex under TRUS guidance to later assist with target localization. Afterloading needles, usually 15–20, are inserted into the prostate in a pattern that is designed to preferentially treat the peripheral zone. Relatively more needles are placed in the peripheral zone of the prostate compared to the anterior gland, since tight control of dosing is desired in this region, due to the proximity of the rectum and the propensity of cancers to arise there. Coordinate 3D of the template, corresponding to the path of the urethra, is typically not loaded. We continue to use metal needles to create tracks in the prostate and perineum through which flexible plastic needles are substituted to allow for CT planning as described later. After the plastic needles are completely inserted, the TRUS probe is removed and the plastic template with the needles is sutured to the patient’s perineum. A rectal examination is done to assess posterior placement of the needles and also to place a belladonna and opiate (‘B and O’) suppository to minimize bladder spasms. The patient is then prepared for a cystoscopy. This allows for visualization of the bladder neck while the transperineal needles are advanced. We attempt to place the superior portion of each needle such that some bulging of the bladder neck is seen on cystoscopy, without any sharp ‘tenting’ of the mucosa. This ensures that adequate coverage of the prostatic base can be obtained while minimizing bladder trauma. This precision in needle placement is one of the advantages of the HDR technique and has contributed to low rates of urinary retention in the acute setting. Once the cystoscope is removed, a foley catheter is placed and connected to bladder irrigation of normal saline, and the patient is transferred from the operating room. After discharge from the postanesthesia care unit, the patient undergoes a treatmentplanning CT scan with the plastic afterloading needles in place. First, a lateral scout view is obtained to verify that the needle tips are just beneath the bladder. Next, images are obtained from the base to the apex at 5 mm intervals perpendicular to the needle array to record needle position and identify the prostate borders, bladder, urethra, and rectum. The target volume is defined as the prostate’s peripheral margin as drawn on the postimplant CT scan, and 100% of the prescribed dose is delivered to this volume. Maximum urethral doses are kept to 120% of the prescription. In order to keep the urethral doses at this level, however, a small anterior portion of the prostate may be omitted from the high dose region. Given the low probability of disease in this location, we have continued with this compromise in dosing, although typically the dose received by this region is not lower than 80% of the planned prescription. (See Figures 33.1–33.9.) Once the plan is reviewed and approved, the patient is transferred to a shielded room for treatment. The afterloading device is then connected to the extraperineal portion of the interstitial catheters, which are color-coded at the time of CT scan to help ensure that they are matched with the appropriate source channels. The first treatment of 8 Gy to the prostate periphery is delivered on the afternoon of the operative procedure and typically lasts approximately 15 minutes, after which time the patient is transferred back to the hospital floor for overnight observation. We have maintained patients on a morphine patient-controlled analgesia (PCA), for comfort in addition to continuous bladder irrigation with saline via a foley catheter. The next morning, a second application of 8 Gy is delivered and the catheters and template are removed in unison. Before each dose application, plain radiographs are used to determine the position of the catheters with respect to the marker seeds placed at the prostatic apex intraoperatively. Occasionally,

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minor shifts in position are needed, but this is rare. Previously, we administered four applications of 3.0–4.0 Gy each, but the majority of patients have tolerated the more hypofractionated regimen of two applications, which offers patients the advantage of a shorter inpatient stay. Martinez and others have demonstrated success with fewer applications, and as discussed above this may be relatively advantageous from a radiobiologic standpoint.5 Perioperative morbidity has been limited to perineal bruising and mild discomfort that typically resolve in a few days. Acute urinary retention has been a rare event, occurring in 2% of patients. Patients are discharged from the hospital shortly after the second fraction after they have demonstrated the ability to urinate without the use of the foley catheter. Outcomes Outcomes with this technique have compared favorably with those from prostatectomy, external irradiation, and permanent seed implants performed in patients with similar stages of disease. At William Beaumont Hospital, Royal Oak, Michigan, patients with any of the following tumor characteristics were treated with external beam and HDR boost; Gleason score ≥7, T2b or T3 disease, or PSA levels ≥10.0 ng/mL. In this relatively high risk population, biochemical control was achieved in 67% of patients at five years using the American Society for Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure.13 Using the same endpoint, results from our institution have been comparable. In an early pilot report from our institution, patients with pretreatment PSA levels <20 ng/mL were found to have an 84% freedom from PSA progression at 5 years.14 Eulau recently updated this series and stratified patients according to observed risk factors: pretreatment PSA level >15 ng/mL; Gleason score > 6; and tumor stage >T2b. Outcomes were reported using the ASTRO criteria. At 10 years, patients with 0–1 risk factor showed biochemical control rates of 97% and 69%, respectively. Patients with more advanced disease did not fare as well, with significantly lower biochemical relapse-free rates. However, it is not known how many of these failures were due to isolated local progression, as only three patients had a biopsy-proven local recurrence.15 Biopsy proven local control at 18 months has been at least 90% in two studies that prospectively performed such evaluations.8,12 Interpretation of postirradiation biopsies is complicated,16 but these local control results have been encouraging and consistent with the favorable biochemical endpoints reported for early-to-intermediate stage patients thus far. Table 33.2 shows reported results from various institutions using HDR therapy. Acute and long term morbidity rates have been very low in the available reports on HDR boost techniques, although prospective quality of life assessments are still lacking. In our experience, acute urinary retention has developed in only 2–3% of patients and late urethral strictures were seen in only 6.7%.15 Investigators at William Beaumont Hospital found only 5% grade 3 acute toxicity, with no patients experiencing grade 4–5 complications. Late urinary toxicity was correspondingly low, and no patient developed any late grade 3 gastrointestinal morbidity.13 At 5 years, the actuarial rate of grade 3 complications was 9%. Of patients, 29% developed impotence at a median of nearly one

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year posttreatment. In the published series from Sweden, most patients experienced some mild diarrhea within 6 months of therapy, but only four patients reported persistent rectal symptoms severe enough to require treatment after that time.8 Urinary morbidity beyond 6 months was seen in only six of 50 patients, with only 8% suffering grade 3 uropathy. The Kiel group has the longest experience and has reported similarly low rates of severe late toxicity. In their experience, a TURP performed within 6 months of HDR implant led to markedly higher rates of urinary symptoms,1 but overall rates of grade 2–3 complications were less than 10% (Table 33.3). In general, the low complication rates reported in HDR series have been one of the more encouraging aspects of this form of local treatment. Acute and long term morbid ity have compared favorably with those reported from other forms of therapy. Most likely, this is due to the precise dose-control that HDR allows compared to external beam and permanent seed implants. The physical dose distributions produced with HDR strongly suggest that this treatment should offer the widest therapeutic window currently available with definitive radiation. However, as mentioned above, prospective quality of life data are still lacking and protocols are currently being developed to determine whether these seemingly low complication rates will withstand further scrutiny. Future directions Current data have established HDR brachytherapy as an effective form of local treatment for prostate cancer. However, several areas remain for further investigation. The optimal dosing regimen for HDR remains unclear. Initially, we used four applications over a 40 hour period, delivering 3.0–4.0 Gy with each fraction, followed by 50.4 Gy of external beam irradiation delivered with a four field technique. Martinez’s initial series was treated using three fractions of 5.5–6.0 Gy each in combination with 46 Gy of EBRT. Results from both series were encouraging and since those initial reports, both of our institutions have moved to using two fractions of HDR boost. We are currently using 8 Gy with each fraction, while the William Beaumont group has reported early results with dose escalation up to 21 Gy delivered in two implants.13 Dose inhomogeneities that occur with brachytherapy complicate assessment of optimal dosing. While prescriptions to the periphery of the gland can be standardized, the number of catheters placed and the variations in dwell times can produce highly variable doses within the target volume. Furthermore, definitions of the prostate periphery can be variable across experienced brachytherapists, often a result of personal preference.2 Although target definition for dosimetric analysis of permanent seed implants has been geared to minimizing inclusion of extraprostatic tissue,17 we have continued to use a more generous target volume in our HDR practice, and these differences may complicate direct comparisons of dose-dependent outcome. As more data are gathered, dose-volume histogram (DVH) analysis may help elucidate some of these issues. One of the limitations of current HDR techniques is that supplemental EBRT is generally recommended for all patients. However, there may exist a subgroup of favorable stage patients for whom monotherapy with HDR alone may be adequate, and Martinez is actively enrolling patients on such a protocol.7 Preliminary results have been

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published using four fractions of 9.5 Gy each, and as for boost techniques, optimal dosing strategies also remain uncertain for monotherapy. Publications have thus far suggested that morbidity from the procedure is fairly low, but detailed and prospective quality of life analysis with actuarial assessment and validated instruments is still lacking. As these data are generated, DVH analysis may allow for specific dosing guidelines to be made for optimal HDR techniques. Given the radiobiologic considerations described previously, coupled with the precision of dose application from HDR,

Figure 33.1 Intraoperative TRUS setup. Note how the mounted blue guidance template is attached to the perineal applicator (top showing) in the picture. Steel needles will be passed through the template and applicator in the desired loading pattern.

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Figure 33.2 Placement of flexible catheters. After metal needles are placed in the desired pattern, flexible catheters are inserted into the tracks created by the metal needles. Each of the flexible catheters contains a metal wire to maintain rigidity during placement. Since these catheters will hold the iridium source, their integrity must be ensured. it appears that this technique would provide a higher therapeutic ratio than other forms of radiation treatment. If HDR methods are able to convincingly demonstrate a significantly improved quality of life for the same degree of tumor control (or better) as other forms of therapy, the procedure is likely to be offered to increasing numbers of patients in the years to come.

Figure 33.3 The perineal applicator and flexible catheters are in place, with the ultrasound-mounted template removed. The applicator is stitched in position. A small screw beneath the surgeon’s index finger is used to tighten the applicator apertures around each catheter, but not before final adjustment of the needle position during cytoscopy.

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Figure 33.4 Cytoscopy. The patient is removed from lithotomy position, and a cytoscopy is performed. Irrigation is used to clear seminal fluid from the bladder for improved visualization of the bladder neck.

Figure 33.5 Cytoscopy image. The bladder neck with the cytoscope in the urethra is visualized while the needles are advanced. Some ‘bulging’ of the bladder neck is desired, but any sharp tenting of the mucosa is to be avoided. In this patient, median lobe hypertrophy obscures the urethral opening.

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Figure 33.6 Needles may be advanced up to 4 cm at the time of cytoscopy depending on initial placement.

Figure 33.7 Lateral CT scout view of the needles in place. Note the position of the needle tips in relation to the bladder (filled with contrast material). Precise placement of the source carriers at the prostatic base is one of the attractive features of the high dose rate (HDR) brachtherapy technique.

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Figure 33.8 Computed tomography (CT) image of prostate with catheters in place. A peripheral loading pattern is used, with some sparing of the anterior zone.

Figure 33.9 Example of treatment isodose plan. The urethra in the center of the gland is kept to less than 120% of the prescribed dose.

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Table 33.2 Reported biochemical outcomes from institutions performing high dose rate (HDR) boost Study Mate 199814

Median follow- 5 year bNEDa up

No. patients Median PSA (ng/mL)

iPSA<20; 84%b iPSA>20:50% 104 12,9 6.3 yrs Overall: 83% 5 yrs Euiau15 77% 10 yrs 161 9.9 2.5 yrs 83% Kestin 200013 Borghede 19978 50 NR 45 mths 84%:18 mthsc 144 12.15 8 yrs 74%:5 yrsd Galalae 20021 (mean: 25.6) 69%:8 yrs a bNED, biochemical with no evidence of disease. Based on the American Society of Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure, unless otherwise specified, b Results stratified by pretreatment prostate-specific antigen level (iPSA), in ng/mL. c Defined as patients with PSA level of <1.0 ng/mL, d Three consecutive rises in PSA, greater than 1.0 ng/mL. 104

12.9

45 mths

Table 33.3 Long-term morbidity* Study

Gastrointestinal

Genitourinary

Mate 199814 Kestin 200013 Galalae 20021

2% grade 2 proctitis 6.7% urethral stricture No grade 3 morbidity 4% stricture 4% grade 3 2% grade 3 (‘cystitis’) 7% grade 2 4% grade 2 10% grade 1 12% grade 1 Borghede 19978 8% grade 2 proctitis 12% grade 1–3 No grade 3 morbidity 0 urethral strictures * Based on the Radiation Therapy Oncology Group (RTOG) grading scale, occurring beyond 6 months after therapy.

References 1. Galalae RM, Kovacs G, Schultze J, et al. Long-term outcome after elective irradiation of the pelvic lymphatics and local dose escalation using high-dose-rate brachytherapy for locally advanced prostate cancer. Int J Radiat Oncol Biol Phys 2002; 52(1):81–90. 2. Wallner K, Blasko J, Dattoli MJ. Prostate brachytherapy made complicated, 2nd edn. Smart Medicine Press, 2001:6.1–6.42; 9.1–9.44. 3. Hsu IC, Pickett B, Shinohara K, et al. Normal tissue dosimetric comparison between HDR prostate implant boost and conformal external beam radiotherapy boost: potential for dose escalation. Int J Radiat Oncol Biol Phys 2000; 46(4):851–858. 4. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 1999; 43:1095–1101. 5. Brenner DJ, Martinez AA, Edmundson GK, et al. Direct evidence that prostate tumors show high sensitivity to fractionation (low α/β ratio), similar to late-responding normal tissue. Int J Radiat Oncol Biol Phys 2002; 52(1):6–13.

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6. Madsen B, Jones D, His RA, et al. Development of apparatus and phase I trial for stereotactic hypofractionated accurate radiotherapy of the prostate (SHARP). Proceedings of the 43rd Annual Meeting of the Association of Therapeutic Radiology and Oncology (ASTRO), 2001. 7. Martinez AA, Pataki I, Edmundson G, et al. Phase II study of the use of conformal high-doserate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: a feasibility report. Int J Radiat Oncol Biol Phys 2001; 49(1):61–69. 8. Borghede G, Hedelin H, Holmang S, et al. Combined treatment with temporary short-term high dose rate Iridium-192 brachytherapy and external beam radiotherapy for irradiation of localized prostatic carcinoma. Radiother Oncol 1997; 44:237–244. 9. Kini VR, Edmundson GK, Vicini FA, et al. Use of three-dimensional radiation therapy planning tools and intraoperative ultrasound to evaluate high-dose-rate prostate brachytherapy implants. Int J Radiat Oncol Biol Phys 1999; 43(3):571–578. 10. Demanes DJ, Rodriguez RR, Altieri GA. High dose rate prostate brachytherapy: the California Endocurietherapy (CET) method. Radiother Oncol 2000; 57(3):289–296. 11. Martinez AA, Kestin LL, Stromberg JS, et al. Interim report of image-guided conformal highdose-rate brachytherapy for patients with unfavorable prostate cancer: the William Beaumont phase II doseescalating trial. Int J Radiat Oncol Biol Phys 2000; 47(2):343–352. 12. Stromberg J, Martinez A, Gonzalez J, et al. Ultrasound-guided high dose rate conformal brachytherapy boost in prostate cancer: treatment description and preliminary results of a phase I/II clinical trial. Int J Radiat Oncol Biol Phys 1995; 33(1):161–171. 13. Kestin LL, Martinez AA, Stromberg JS, et al. Matched-pair analysis of conformal high-doserate brachytherapy boost versus external-beam radiation therapy alone for locally advanced prostate cancer. J Clin Oncol 2000; 18(15):2869–2880. 14. Mate TP, Gottesman JE, Hatton J, et al. High dose-rate afterloading Iridium-192 prostate brachytherapy: feasibility report. Int J Radiat Oncol Biol Phys 1997; 41(3):525–533. 15. Eulau SM, Mate TP, VanHollebeke L, et al. High dose rate Iridium192 brachytherapy in localized prostate cancer: results and toxicity with maximum follow-up of 10 years. Proceedings of the 42nd Annual Meeting of the Association of Therapeutic Radiology and Oncology (ASTRO), 2000. 16. Prestige B, Kaplan I, Cox RS, et al. Predictors of survival after a positive post-irradiation prostate biopsy. Int J Radiat Oncol Biol Phys 1993; 28:17–22. 17. Badiozamani KR, Wallner K, Cavanagh W, Blasko J. Comparability of CT-based and TRUSbased prostate volumes. Int J Radiat Oncol Biol Phys 1999; 43(2):375–378.

34 High dose rate prostate brachytherapy. Treatment planning and results from Memorial Sloan-Kettering Cancer Center Yoshiya Yamada Introduction Brachytherapy represents the earliest use of radiotherapy in the treatment of prostate cancer. Barringer described using radium needles to treat prostate cancer at Memorial Hospital as early as 1917.1 Today, the use of high dose rate (HDR) brachytherapy for the definitive treatment of prostate cancer remains a standard treatment option at Memorial Sloan-Kettering Cancer Center (MSKCC). There are both physical and radiobiologic rationale for the use of HDR brachytherapy which make it an excellent technique to treat prostate cancer. High dose rate brachytherapy catheters securely hold the prostate in a reliable treatment position. There is very little likelihood of target organ motion. Similarly, the position of critical normal tissue structures, such as urethra and rectum, can be accurately located with a high degree of confidence. Therefore, there is very little uncertainty regarding doses received by the target or normal tissue. The high degree of dosimetric certainty which HDR provides enables clinicians to prescribe large fractions of radiotherapy with assurance that the dose is delivered as prescribed. Elimination of such uncertainties gives HDR brachytherapy a distinct advantage over external beam radiotherapy (EBRT), which must account for organ motion by expanding the volume of irradiated tissue beyond the prostate to ensure that the intended dose is delivered to the target. Therefore, surrounding normal tissues adjacent to the prostate, such as the rectum, will receive radiation to a larger volume relative to HDR treatment. Treatment planning Treatment planning at MSKCC utilizes computeroptimized postimplant computed tomography (CT)based dosimetry. Each HDR catheter as well as the urethra, rectum, and bladder are readily visualized, making exact dosimetry possible without the worry of organ motion. With strategic catheter placement, postimplant dosimetry can readily boost areas of concern, including areas suspicious for extracapsular extension of disease as well as intraprostatic areas suspicious either by biopsy or MRI/MRI spectroscopy. Although HDR delivers inhomogeneous dosimetry, this is advantageous in the setting of prostate cancer. With computer optimization, structures, such as the urethra, can be made to be relatively ‘cold’ while areas of concern can be made ‘hot’ relative to the prescribed dose

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(see Figure 34.1). Thus, with proper catheter placement, the peripheral zone of the prostate or other tumor-bearing areas can easily receive over 150% of the prescribed dose while urethral doses are maintained at less than 120% of the prescribed dose. This phenomenon is due to the inverse square law of brachytherapy physics. Since radiation doses fall off in an inverse square relationship relative to distance, high doses of radiation can be given to the prostate, while the rectum receives a significantly lower dose of radiation. CT-based treatment planning was performed using software developed in-house. The target volume, urethra, rectum, as well as each brachytherapy catheter was contoured on each relevant CT slice. Computer-optimized inverse treatment planning was performed using software developed in-house. The main dose-constraint variables governing the optimization engine include 100% target volume coverage, urethra Dmax≤120%, dose uniformity points between 100% and 175%, and dose conformity index between 1 and 1.1. In cases of extracapsular extension, the areas identified on MRI scans were included in the target volume. Doses were prescribed to the isodose line which encompassed the target volume, except at the bladder neck, where lower dose coverage was accepted. In some cases, due to geometric and anatomic considerations, full dose was not given to the prostate adjacent to the

Figure 34.1 Computed tomography (CT)-based treatment planning. Each catheter is identified as an air pocket on CT. Different colored lines represent levels of radiation dose intensity (isodose lines). Extracapsular

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extension identified on magnetic resonance imaging (MRI) and implanted with high dose rate (HDR) catheters (circled in yellow). bladder neck and the superior anterior base of the prostate, where no glandular tissue exists and the likelihood of carcinoma is very low (see Table 34.1). Reported maximum doses were calculated voxel-by-voxel, and often represent a single voxel maximum. Thus, the extreme maximum doses calculated to the urethra may appear to be high, but typically represent doses to very small volumes. Overall, the mean urethra dose was less than 120% of the prescribed dose (see Table 34.2).

Table 34.1 Target dosimetry Median Range V150 (%} 41.3 V100 (%) 97.8 D90 (Gy) 19.2

23–70 94–100 17–22

At MSKCC, we undertook a detailed analysis of rectal doses given by HDR techniques compared to three-dimensional conformal external beam radiation (3D-CRT). A significantly lower dose of radiation was received by the rectum with the use of HDR relative to 3D-CRT. The HDR and 3D-CRT rectal volumes for each patient were not found to be significantly different. The mean rectal V50, V90, and V100 for HDR vs 3DCRT was found to be 6.3 cc

Table 34.2 Urethral dosimetry Median Range Urethral Dmax 138% Urethral av. dose 118% Urethral V100 (cc) 2,2 Urettel V150 (cc) 0

142–331% 50–145% 1–4 0–2

vs 40.6 cc, 0.6 cc vs 14.8 cc, and 0.3 cc vs 11.7 cc, respectively. The mean D50, D90, D100, and Dmax were found to be 5.1 Gy vs 35 Gy, 2.7 Gy vs 23.4 Gy, 2.4 Gy vs 15.1 Gy, and 20.7 Gy vs 53.4 Gy for HDR doses and 3D-CRT doses, respectively. Rectal doses relative to target prescription doses (50.4 Gy for 3D-CRT and 16.5 Gy for HDR) were found to be 11% vs 30%, 15% vs 47%, and 27% vs 71% (HDR vs 3D-CRT) for D100, D90, and D50, respectively. The p-values for all analyzed factors were found to be highly significant (p<0.00001). Similar findings have been reported by others.2 Currently, at MSKCC, a CT-based computeroptimized postimplant treatment-planning algorithm is utilized to provide a HDR ‘boost’ of 19.5 Gy to the periphery of the prostate given in three fractions (6.5 Gy each) at least 6 hours apart, with an additional 50.4 Gy given to the prostate and seminal vesicles in 28 fractions using 3D-CRT techniques. We are continuing a program of dose escalation with the HDR portion of treatment.

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Radiobiology Because of less treatment uncertainty and computeroptimized treatment planning providing lower doses to critical normal structures, HDR is ideally suited for hypofractionated therapy. Hypofraction refers to a fractionation schedule which prescribes larger doses of radiation (i.e. >2–2.5 Gy per fraction), while reducing the number of fractions given. Although the total cumulative dose of radiation is typically lower than with standard fractionation schedules, because of the greater impact of larger doses of radiation per fraction, the biologically effective dose achieved can be equal to or greater than that of standard fractionation schemes. One method of expressing the reaction of cells to radiation is expressed as an α/β ratio based on linear-quadratic formalism. Prostate cancers are thought to be on the extreme low end of the spectrum of α/β ratios (1.2–3.5 in vitro) of human malignancies.3–6 Furthermore, prostate cancer cells also exhibit a low labeling index (0.6–2.5%), and Tpot estimates range from 16 days to 64 days, all suggesting that prostate cancers proliferate slowly.5 Because a small α/β ratio implies a larger sensitivity to changes in fraction size, hypofractionated treatment schedules are more likely to be effective against prostate cancer cells. Also, tumor repopulation is an unlikely significant radiobiologic parameter.6 Table 34.3 illustrates calculated biologic effective doses (BED) for various HDR schedules based on an α/β of 10 compared to 1.5. The most extreme example of hypofractionation included in Table 34.3 is 9.5 Gy×4 (no EBRT), which also permits the most sparing of acute reacting tissues, but delivers the highest effect on late responding tissue, such as prostate cancer. As an example based on actual patients, an analysis of patients treated with HDR prostate brachytherapy as a boost found improved prostate-specific

Table 34.3 Baiologic effective doses (BED) compared BED10

BED1.5

8640 cGy/48 102.0 190 5040 cGy/28+: 59.5 111 10 Gy×2 100.0 264 6 Gy×3 88.5 201 5 Gy×4 89.5 198 8.5 Gy×2 91.0 224 9.5 Gy×4 74.0 279 Note: time corrections are not included in the calculations.

antigen (PSA) relapse-free survival when the number of fractions was reduced from 3 to 2. This clinical correlation suggests that prostate cancers do have low α/β ratios that are more sensitive to changes in fraction size.7 Table 34.3 also suggests that hypofractionation should confer sparing of early reactions relative to late reactions. Thus, there is a significant radiobiologic argument for the use of hypofractionated treatment schedules in the management of prostate cancer.

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Technique Patients underwent HDR implant prior to external beam radiotherapy. The brachytherapy is typically performed under a general anesthetic. Each catheter is placed transperineally under transrectal ultrasound (TRUS) guidance through a template which is attached to the perineum. A cystoscopy is performed after catheter placement to ensure that no catheters transgress the bladder mucosa or urethra. The patients are placed on strict bedrest while catheters are in place. A three-way catheter is placed at the end of the procedure, and bladder irrigation is performed on a PRN (as required) basis. Patients are given intravenous antibiotics. CT-based computer-optimized treatment planning is performed on patients after recovery from the anesthesia. Catheters are marked at the template with permanent ink as a quality control measure against catheter migration. Antiembolism inflating boots are prescribed. Patients are placed on strict bedrest while the catheters are in place. All patients are treated with a 192Ir source. The implant is removed at the bedside after the last fraction has been administered. Patients are usually discharged following several hours of observation. Outcomes A detailed analysis of 54 patients with localized prostate cancer who were treated with HDR boost and 3D-CRT to

Table 34.4 Clinical characteristics of high dose rate (HDR) patients Median

Range

Number of patients 54 Age (yrs) 65 45–75 Gleason score 7 6–9 Clinical stage T1c T1b–T3b Pretreatment PSA 9.2 1.2–60 Pretreatment IPSS 4 0–18 Pretreatment potency 74% Follow-up (mths) 18 12–38 PSA, prostate-specific antigen; IPSS, international prostate symptom

the prostate (3D-CRT) between 1998 and 2000 at MSKCC was undertaken. Of the patients, 50 were prescribed 550 cGy×3, and 4 patients were prescribed 600 cGy×3; 7 patients received 4500 cGy in 25 fractions and 47 patients received 5040 cGy in 28 fractions using a six beam 3D-CRT technique. All cases treated during this time interval were included in this analysis. All pathology was reviewed at our institution prior to initiating treatment. Clinical characteristics of the patients are summarized in Table 34.4. Typically, patients considered for HDR were not

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favorable patients, with either Gleason score ≥6, PSA >10, or >T2b. HDR brachytherapy was not encouraged as a treatment option if the patient presented with significant urinary symptoms (international prostate symptom score; IPSS >12), if the patient could not undergo CT-based treatment planning (i.e. bilateral hip replacements), could not tolerate anesthesia, or otherwise could not tolerate the procedure. If the patient was thought to have a prostate larger than 60 cc, hormonal therapy (HT) consisting of combined androgen blockage was administered for approximately 3 months prior to the implant. Patients with particularly high risk features (Gleason >8, PSA>10, T3 disease) were considered for HT prior to and in conjunction with radiation therapy. Follow-up was performed regularly at 3–6 month intervals, including the use of IPSS/quality of life questionnaires and Radiation Therapy Oncology Group (RTOG) toxicity grading. No patients were lost to follow-up. KaplanMeier statistics were used for analysis. The median follow up for the entire group was 24 months (16–44 months). Of the patients, 74% reported full potency (sufficient for vaginal intercourse) prior to initiating treatment; 41% of patients were given neo-adjuvant HT prior to treatment. The median pretreatment IPSS was 4 (0–18). The clinical characteristics of this cohort are summarized in Table 34.4. No grade 3 RTOG urinary toxicity has been reported. Three patients experienced urinary retention requiring a catheter at some time during their posttreatment course. In all cases, the use of catheters for urinary retention was temporary. Two of the three patients had traumatic catheterizations during the implant procedure (after cystoscopy). As illustrated in Figures 34.2 and 34.3, significant urinary toxicity after treatment was unusual. The mean pretreatment IPSS was 5.3. The IPSS score peaked at the time

Figure 34.2 Urinary toxicity following high dose rate (HDR) brachytherapy. RTOG, Radiation Therapy Oncology Group.

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Figure 34.3 Urinary toxicity following high dose rate (HDR) brachytherapy. International prostate symptom scores (IPSS) and quality of life (QOL) scores. of first follow-up (3 months), and subsequently settled near to pretreatment levels. The same pattern was noted for RTOG urinary toxicity scores. Of patients, 7% reported grade 2 toxicity prior to treatment, and peaked at 15% at the time of first follow-up; 9% of patients continued to report grade 2 toxicity in subsequent follow-up. These patients were still using alpha-blockers to assist urination. Potency (erections sufficient for vaginal penetration) was also relatively wellmaintained. Prior to treatment, 76% of patients reported full potency, 13% were able to achieve erections with the use of sildenafil citrate (Viagra) and 11% were not able to achieve erections with the use of sildenafil citrate. At the time of last follow-up, 58% were still potent without the use of medications, and 28% of patients reported erections sufficient for vaginal penetration with the use of sildenafil citrate. This represents a 15% increase in the use of sildenafil citrate. Overall, only one patient who was potent prior to treatment experienced loss of sufficient erectile function and did not respond to sildenafil citrate (see Tables 34.5 and 34.6). Patients were satisfied with their urinary quality of life (QOL). Urinary QOL was rated by each patient at each follow-up, using a scale of 0–6 (0, delighted; 1, pleased; 2, mostly satisfied; 3, mixed feelings; 4, mostly dissatisfied; 5, unhappy; 6, terrible). The mean pretreatment QOL was 1.5, peaked at 3 months with a mean value of 2, and at 12 months, the mean reported value was 1.2 (see Figure 34.2). Significant rectal toxicity was not seen in this cohort. No patients experienced RTOG acute or late rectal RTOG toxicity grade 2 or higher. No PSA failures (ASTRO definition8) have yet been observed in this cohort, although median follow-up is still

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Table 34.5 Potency rates of high dose rate (HDR) patients MSKCC HDR

Pre tx Last follow-up % Change

Full potency (%) Sildenafil citrate (%) Impotent (%) Pre tx, pretoxicity.

76 13 13

58 28 14

−24% 115% 7%

Table 34.6 Potency rates at two years postreatment compared to hormone-nanïve patients Hormone naïve

HDR

3D CRT

Full potency (%) 83 78 Potent including sildenafil citrate (%) 93 84 HDR, high dose rate; 3D-CRT, three-dimensional conformal external beam radiotherapy.

short. One of the longest HDR-based outcomes in the literature comes from Galalae et al.9 HDR was utilized to deliver two fractions of 15 Gy and 9 Gy to the prostate, while giving 50 Gy to the pelvis to 144 patients. The median follow-up for this group was 8.2 years (range: 5–14). Of the patients, 60% had a PSA>10 (mean PSA: 25.6) and

Table 34.7 Long term outcomes for patients treated with high dose rate (HDR) brachytherapy9 Prognostic groups

Mesian PSA (ng/mL)

Median grade (WHO- 5 year bNED 8 year bNED Mostofi) (%) (%)

PSA<10 ng/mL G1– 46 2 94.7 2 PSA 10–20 ng/mL 12.8 2 83.3 G1–2 PSA>20 ng/mL G1– 36 2 68 2 PSA<10 ng/mL G3 3.8 3 72 PSA 10–20 ng/mL 15.7 3 77 G3 PSA>20 ng/mL G3 40.4 3 38 G, RTOG (Radiation Therapy Oncology Group) grade. PSA, prostate-specific antigen; bNED, biochemical with no evidence of disease.

93 81 64 64 75 32

nearly one third of the patients were staged T3. The majority of patients were not low risk patients. The reported outcomes based on risk stratification are presented in Table 34.7. In this relatively high risk cohort with mature follow-up, HDR in conjunction with EBRT offers a high rate of disease control.

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Summary There is mounting evidence that prostate cancers tend to be relentless, but very slow in the progression through their clinical natural history, in comparison with most other human malignancies. Using linear-quadratic modeling, radiobiologists suggest that localized prostate cancers may have α/β ratios in the neighborhood of 1.2–1.5—the extreme low end of human malignancies, which are typically assigned α/β values ≥8. Such data would suggest that hypofractionationed schedules, for which high dose rate (HDR) brachytherapy is ideally suited, is the optimal approach for the treatment of prostate cancer. A low α/β would also suggest that at equivalent dose levels, the acute toxicity should be lower with hypofractionation. Our experience indicates that significant acute toxicity is infrequent. This is likely due to superior dosimetry provided by computer-optimized treatment planning and also the inherent relative sparing of early responding tissues afforded by hypofractionation. Grade 3 late rectal toxicity associated with HDR brachytherapy has been reported between 0–4%.9,10 The patients with significant late toxicity were treated when sophisticated computer optimized CT-based treatment planning was not available, and this complication is now extremely rare in current treatment planning. Our data indicate that computer optimization can successfully provide excellent target volume coverage while sparing rectum and urethra. Although the follow-up of our cohort is not long, the acute toxicity has been thus far very acceptable. Reports with long term follow-up utilizing HDR brachytherapy are now emerging. Although most of the papers describe relatively high risk patients, the biochemical with no evidence of disease (bNED) rate is surprisingly high.9–12 Thus the HDR hypofractionation paradigm appears to be well suited for the treatment of prostate cancer from all aspects of management—treatment planning, radiobiology, toxicity, as well as disease control. References 1. Barringer BS. Radium in the treatment of carcinoma of the bladder and prostate. JAMA 1917; 58:1227–1230. 2. Hsu IJ, Pickett B, Shinohara K, et al. Int J Radiat Oncol Biol Phys 2000; 46(4):851–858. 3. King CR, Fowler IF. A simple analytic derivation suggests that prostate cancer alpha/beta ratio is low. Int J Radiat Oncol Biol Phys 2001; 51(1):213–214. 4. Fowler J, Chappell R, Ritter M. Is alpha/beta for prostate tumors really low? Int J Radiat Oncol Biol Phys 2001; 50(4): 1021–1031. 5. Duschesne GM, Peters LI. What is the α/β ratio for prostate cancer? Rationale for hypofractionated high-dose rate brachytherapy. Int J Radiat Oncol Biol Phys 1999; 44(4):747– 748. 6. Brenner DJ, Hall EJ. Fractionation and protraction for radiotherapy of prostate carcinoma. Int J Radiat Oncol Biol Phys 1999; 43(5):1095–1101.

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7. Brenner DJ, Martinez AA, Edmundson GK, et al. Direct evidence that prostate tumors show high sensitivity to fractionation (low α/β Biol Phys 52(1):6–13. ratio), similar to late-responding normal tissue. Int J Radiat Oncol 8. American Society for Therapeutic Radiology and Oncology Consensus Panel. Consensus statement: guidelines for PSA following radiation therapy. Int J Radiat Oncol Biol Phys 1997; 37(5):1035–1041. 9. Galalae RM, Kovacs G, Schultze J, et al. Long-term outcome after elective irradiation of the pelvic lymphatics and local dose escalation using high-dose-rate brachytherapy for locally advanced prostate cancer. Int J Radiat Oncol Biol Phys 2002; 52(1):81–90. 10. Mate TP, Gottesman JE, Hatton J, et al. High dose-rate afterloading 192 Iridium prostate brachytherapy: feasibility report. Int J Radiat Oncol Biol Phys 1998; 41(3):525–533. 11. Deger S, Boehmer D, Turk I, et al. High dose rate brachytherapy of localized prostate cancer. Eur Urol 2002; 41(4):420–426. 12. Martinez AA, Gustafson G, Gonzalez J, et al. Dose escalation using conformal high-dose-rate brachytherapy improves outcome in unfavorable prostate cancer. Int J Radiat Oncol Biol Phys 2002; 53(2):316–327.

35 High dose rate afterloading 192Ir prostate brachytherapy Alvaro Martinez, Jeffrey Demanes, Razvan Galalae, Howard J Korman, Hågen Bertermann, Carlos Vargas, Jose Gonzalez, and Gary Gustafson Introduction During the last two decades, surgery and radiotherapy have been the treatment modalities most frequently used to treat patients with prostate cancer. However, the specific indications for the different surgical procedures and/or radiotherapy techniques available remain under debate. Although a thorough discussion of this general topic is outside the scope of this chapter, it is important to recognize the prominence brachytherapy treatments have achieved. To this respect, The American Urologic Society,1 and the American College of Radiology,2 patterns of care of utilization have reported the significant increase of utilization of brachytherapy during the last decade. We will limit the extent of our data analysis and comments to a type of radiotherapy called high dose rate (HDR) brachytherapy whether used as monotherapy or as a boost therapy combined with pelvic external beam with or without androgen deprivation therapy (ADT). Prostate brachytherapy has been performed using one of two treatment techniques, low dose rate (LDR) or HDR. LDR brachytherapy involves the permanent implantation of multiple radioactive seeds; typically iodine-125 (125I) or palladium-103 (103Pd) seeds, into the prostate in order to deliver a therapeutic dose of radiation to the prostate gland over several weeks to months. This signifies that the patient remains radioactive for a while and must comply with the state rules and regulations for patients harboring radioactive material. HDR brachytherapy, on the other hand, uses a single high intensity radioactive source stored in a ‘robotlike machine’ called a remote afterloader. The afterloader sends and retracts this single source sequentially into each implanted needle, and is able to deliver a therapeutic dose of radiation in a very short period of time, typically 10–15 minutes. Hence, the patients are no longer radioactive after the completion of treatment. Advantages of high dose rate brachytherapy HDR has a number of advantages over LDR, that are patient- and target-specific. They are summarized below: 1. The overall treatment time is reduced from many weeks with LDR to several minutes with HDR. This eliminates the uncertainties related to volume changes occurring over

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weeks (typical with LDR) due to trauma and swelling or subsequent shrinkage due to postradiation fibrosis. 2. HDR significantly improves the radiation dose distribution secondary to the ability to modulate and accurately control the spatial source position and vary the source dwell time during treatment. 3. The intraoperative (or real-time) optimization used with HDR allows ideal selection of needle placement on real-time and better source position targeting, hence modulating the intensity with the potential for limiting treatment toxicity. 4. HDR can significantly reduce the cost of treatment, because the radioactive sources are not purchased per case treated, as is done with LDR. 5. Advantages in radiation safety and protection since the patient is not radioactive when he returns home. The HDR single radiation source is retracted into the robot at the completion of treatment. 6. There are multiple radiobiological considerations favoring HDR since the treatment is given in several minutes for which repopulation, cell cycle, and recovery of sublethal damage cannot occur. For patients with early stage prostate cancer, radical prostatectomy, external beam radiotherapy, and brachytherapy are commonly used treatment modalities. These treatment options have been supported by the excellent biochemical outcomes reported during the last few years for patients with similar stage disease and favorable prognostic variables. Although the most appropriate definition of biochemical failure may be controversial, the Cleveland Clinic Foundation,3 and William Beaumont Hospital, Michigan,4 have reported similar outcomes for patients with favorable prognostic features undergoing either radical prostatectomy or external beam radiotherapy at a single institution. The multi-institutional report from D’Amico et al5 indicated similar biochemical outcomes were achieved for favorable patients after any of three treatment modalities, radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy. In addition, several other investigators have reported excellent results with interstitial prostate brachytherapy,6–11 with biochemical control rates comparable to those of patients treated with either radical prostatectomy or external beam irradiation. The above series have supported the rationale for the use of interstitial brachytherapy in the treatment of early stage prostate cancer. While most monotherapy series have utilized LDR technique with 125I seeds or 103Pd seeds, HDR brachytherapy with iridium-192 (192Ir) is gaining popularity.10–12 A wide variety of treatment approaches has been used for patients with unfavorable prostate cancer. However, treatment remains a challenge. Survival rates from series in which radical prostatectomy is performed for stage C or T3 disease,13,14 and/or low dose external beam radiation therapy are given remain suboptimal.15 To improve on these results three radiotherapeutic strategies have been tested, including the addition of hormonal ablation before standard radiotherapy,16,18 the addition of particle beam as a boost to external beam radiotherapy,19,20 and dose escalating conformal radiotherapy. Dose escalation has been accomplished by using 3-dimensional (3D) conformal external beam radiotherapy (EBRT),21,22 or brachytherapy using a conformal high dose rate boost.23 Tumor dose escalation should hypothetically overcome radioresistance of tumor clonogens seen at conventional dose levels. The question remains as to which of these two strategies best escalates the dose sufficiently to obtain a greater therapeutic gain.

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The 3D conformal radiotherapy EBRT trials incorpo rate certain drawbacks, such as systematic and random setup errors, internal organ motion and deformation, which have been well documented and may limit efficacy.24–26 Because of these drawbacks, we began a dose escalating prospective clinical trial in 1991 using transrectal ultrasound-guided 3D conformal modulated high dose rate brachytherapy to deliver the boost dose.23 A key component for 3D conformal high dose rate prostate brachytherapy was our development of an interactive online dose optimization program,27,28 which we called the ‘hypofractionated high dose rate smart seed technique’. This new approach allowed direct visualization of isodose curves with rectal and urethral doses (Figure 35.1a, b) in relation to real-time prostate images and computerized selection of ideal needle location with online identification of actual needle position (Figure 35.1c). In 1991, our prospective Human Investigation Committee (HIC) approved a clinical trial, which was designed to test the hypothesis that for patients with poor prognostic factors local failure is related to the large volume of cell mass and radioresistant cell clones, both of which require biologically higher radiation dosages, than those conventionally used. Thus, we selected a hypofractionated 3D conformal high dose rate brachytherapy boost as the method of dose escalation. In 2001, we reported the interim three year results of 145 patients enrolled in this trial.23 We have expanded the database, increased the number of patients to 207, and updated the follow-up (5 years) and data analysis, now focusing on patients with poor prognostic factors.29 More recently, we reported an update combining the data from Kiel University, using a similar treatment program,30 and also Table 35.1 with the data from the California Endocuritherapy Cancer Center (CET) (Table 35.1).31 Equally important to survival outcomes are the toxicity and side effects associated with any curative treatment modality, whether surgery, external beam irradiation, or brachytherapy. Both the physician recommending treatment and the patient receiving it must consider the potential for treatment-related morbidities and the impact they may have on a patient’s quality of life. As a general statement, it appears that prostatic brachytherapy is the most convenient treatment and may have the lowest rate of long term complications when compared to radical prostatectomy or external beam radiotherapy.32 During the last 5 years, these appear to be the primary reasons for a significant increase in the utilization of prostate brachytherapy as a primary and curative treatment approach for patients with early stage prostate cancer.1,2,32 Materials and methods Hypofractionated treatment program High dose rate brachytherapy as a boost Our treatment technique has been previously described.18,19 The pelvis was treated with an isocentric dose of 46 Gy in 23 fractions using a 4-field technique. All patients underwent pretreatment pelvic computed tomography (CT) with contrast to assist in defining the prostate and normal tissue volumes. Pelvic EBRT was interdigitated

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Figure 35.1 (a) Urethral doses in per cent at 5 mm apart with isodose lines at the reference plane. (b) Prostate boundaries contour with overlying outline of the prostatic urethra in depicted green cricles. (c) Computer selected ideal template needle coordinates (blue dots). with transrectal ultrasound (TRUS)-guided transperineal conformal interstitial 192Ir implants. The overall treatment time was compressed to only 5 weeks. No EBRT was given on the day of the outpatient implant. After we established enough experience with patients’ tolerance to HDR prostate brachytherapy and that their toxicity was acceptable, we decided to decrease the number of (conformal) C-HDR implants from three to two. From 1991 to 1995, all patients underwent three TRUS-guided C-HDR implants, during the first, second and third weeks of treatment. After October 1995, all patients underwent two HDR implants during the first and third weeks of pelvic EBRT. This change was implemented to eliminate administration of spinal anesthesia and the surgical trauma of a third implant. Patients with a prostate gland volume >65 cm3 or length of 5.5 cm were initially ineligible for the protocol. These patients underwent downsizing with a short course of hormonal therapy (<6 months) and were the subject of a separate analysis.34 Brachytherapy dosimetry was never done using preplanning TRUS performed before the actual HDR implant. Instead, using our ‘HDR smart seed technique program’ the dosimetry was done in real-time intraoperatively. The implant procedure was performed under spinal anesthesia with the patient in the lithotomy position with extreme pelvic

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flexion. A 7.5 MHz biplanar TRUS probe was fixed to the table to allow only longitudinal motion. The apex and base of the prostate gland were identified online using transverse and sagittal TRUS images. The probe was positioned as parallel as possible to the prostatic urethra (Figure 35.2). The length of the prostate and corresponding treatment length was considered the distance from the base to the apex. No margins were added. The prostate gland was scanned at 5 mm intervals from 1.0 cm above the base to 1.0 cm below the apex of the prostate gland on the transverse plane (only for intraoperatively planning purposes, not for treatment). The urethra was mapped on each 5 mm transverse image as well. The transverse image with the largest cross-sectional prostate area was considered the reference plane. This area was contoured with no planning margins added. Consequently, the clinical target volumes (CTV) and planning target volumes (PTV) were the same (Figure 35.3). The optimal needle positions within the reference plane were determined intraoperatively using our real-time, interactive optimization program. The computer planning software gave the physician the needle coordinates with reference to the perineal template.27–29 Under TRUS guidance, the needles were placed parallel to the TRUS probe using a template

Table 35.1 Patients’ characteristics for high dose rate (HDR) brachytherapy boost by institution KM (n=160)

WBH (n=315)

CET (n=459)

5–7 yrs 4.1 yrs 4,2 yrs Median Age 69 yrs 69 yrs 68 yrs PSA 14.8 ng/mL 8.9 ng/mL 9.6 ng/mL Treated volume 30.8 cc 35 cc 30 cc 33% 31% 55% Hormones Gleason score 2–6 14% 38% 40% 7 51% 42% 43% 8–10 35% 20% 17% Clinical stage T1c–T2a 19% 40% 46% T2b–T2c 49% 50% 42% ≥T3a 31% 10% 12% KM, Kiel University Hospital; Germany; WBH, William Beaumont Hospital, Michigan; CET, California Esdocurietherapy Cancer Center; PSA, prostate-specific antigen.

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Figure 35.2 Sagittal transrectal ultrasound (TRUS) view showing the foley catheter inside the urethra. mounted and fixed to the probe. After placement of all needles, cystoscopy was performed to reconfirm the prostate treatment length with adequate depth by virtue of bladder mucosa tenting (Figure 35.4). To reconfirm the gland apex during cystoscopy, the TRUS probe was placed in the sagittal plane at the apex. The veru montanum (1 cm behind) was used to correlate with the TRUS probe position in the longitudinal plane. After cystoscopy, contrast material was instilled into the bladder and fluoroscopy (by way of a C-arm) was performed before and after connecting the transfer tubes to verify and document the appropriate needle tip positions (Figure 35.5). Because the

Figure 35.3 Real-time transrectal ultrasound (TRUS) image showing no margins added to the prostate contour. Clinical target-volume (CTV); planning target volume (PTV).

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Figure 35.4 Cytoscopy performed by the urologists with the flexible cytoscope to minimize trauma and maximize exposure, especially with the retroverted view. needle positions may have shifted slightly during cystoscopy, the final TRUS needle positions, as well as the final urethral locations before treatment, were recaptured to determine the actual treatment dwell positions and times. Intraoperatively, all dosimetric calculations were performed using real-time interactive optimization software (Figure 35.6).27,29 The treatment was optimized using standard geometric optimization.27 On each transverse TRUS image, the 100% isodose line encompassed the contoured prostate volume (Figure 35.7). The urethra was limited to ≤125% of the treatment dose in each transverse plane, as seen in Figure 35.8. The rectal dose was calculated at the anterior edge of the TRUS probe within the reference plane and was limited to <75% of the treatment dose. For those patients who underwent three initial implants, the dose to this treatment volume was subsequently escalated from

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Figure 35.5 (a) C-arm for fluoroscopy after cytoscopy is performed. Contrast material instilled in the bladder, (b) Xray film documenting the relationship of gold seeds placed at the prostatic base with tip of the needles and bladder contrast. 5.5 Gy for each initial implant to 6.0 Gy, and finally to 6.5 Gy. This group constituted the low dose group. Patients who received two implants initially received 8.25 Gy during each implant, then 8.75 Gy, 9.50 Gy, 10.5 Gy, and 11.5 Gy. This was the high dose group (Table 35.2). When the trial began in 1991, the linear-quadratic formula was used to calculate the biologic effective dose (BED).35 The α/β value ratio for tumor control probability was 10 and 4 for normal tissue complications. The basic assumption was that EBRT of 46 Gy in 23 daily fractions to the pelvis followed by a prostate EBRT boost of 24 Gy in 12 fractions (total dose 70 Gy at 2 Gy increments) in 7 weeks will deliver a BED to 5.5 Gy×3 in weekly HDR fractions interdigitated with 23 pelvic EBRT doses in 5 weeks. The expected biologic effect was a decrease in tumor

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Figure 35.6 Immediately prior to treatment and after cytoscopy, the entire prostatic volume was imaged and final needle position recaptured prior to definitive dosimetric analysis.

Figure 35.7 Analysis of multiple plane transrectal ultrasound (TRUS) images demonstrating the dosimetry coverage with excellent conformality at the reference plane. Calculated rectal dose of 68% of the prostate dose. control probability of 5% for the EBRT+HDR regimen. Similarly, when we eliminated one implant in 1995, the same formulation and biologic assumptions (α/β of 10) were used. There is evidence now that the α/β ratio for prostate cancer is much lower.36–38 In 1998, we published the validation of this low α/β value. The value 1.2 was derived from this EBRT+HDR clinical trial.39 For comparison, we have listed the BEDs for all levels of our dose escalation trial using α/β ratio of 10 and 1.2 (Table 35.2). For this analysis, the LDR group receiving three implants using an α/β of 1.2 had a BED of <93 Gy, for the HDR group with two implants, the BED >93 Gy. With an HDR dose of 11.5 Gy×2, the

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BED using an α/β ratio of 1.2 was 136.3 Gy, a dose unlikely to be achieved with an EBRT delivery system.

Figure 35.8 Urethral and prostatic dose-volume histogram (DVH) using the ‘Nucletron Swift’ guidance system: 80% of the prostate is receiving 115% of the dose; <15% of the prostate is receiving ≥150% and 0% of the dose; the urethra is receiving ≥115% of the prostate dose. Table 35.2 High dose rate (HDR) boost characteristics for patients treated at William Beaumont Hospital MI Dose level No. patients Median follow-up BED×1.2 G Low dose group (3 HDR fractions) High dose rate group (2 HDR fractions)

5.5×3 6×3 6.5×3 8.25×2 8.75×2 9.5×2 10.5×2

19 15 27 26 26 39 103

10.3 yrs 9.8 yrs 8.4 yrs 5.5 yrs 6.1 yrs 5.8 yrs 3.4 yrs

80.2 86.1 92.5 94.2 99.9 108.9 122.0

Basic and advanced techniques in prostate brachytherapy 11.5×2 45 BED, biologic effective dose; LDR, low dose rate.

466

2.7 yrs

136.3

High dose rate brachytherapy as monotherapy The BED accelerated hypofractionated regime was selected based on HDR favorable radiobiological considerations described above and physical dose delivery advantages of TRUS guidance,10 with conformal intensity modulated real-time dosimetry of prostate HDR brachytherapy.11,22,24 Figure 35.9 depicts an HDR intraoperative implant using the Nucletron Swift guidance system. All patients had biopsy-proven adenocarcinoma of the prostate. They were staged with the 2003 American Joint Committee on Cancer (AJCC) clinical stage II

Figure 35.9 (a) Real time intraoperative ultrasound image from ‘Nucletron Swift’ showing the computer-selected ideal needle positions to guide urologists and radiation oncologists during needle placement, (b) Real-time intraoperative 3D rendition from executed needle placement depicting the prostate contour, urethra trajectory, and seminal vesicles. (T1c–T2a) disease, Gleason score ≤7, and pretreatment PSA≤12 ng/mL. The majority of patients presented with what would be considered low risk or favorable prostate cancer. Standard pretreatment work-up was performed for staging. Prior to gland implantation, and with the patient in the treatment position, a TRUS was performed with or without light sedation to determine the anatomical and geometrical suitability of the gland for brachytherapy; the criteria were: prostate gland volume 15–65 cc; length ≤5.5 cm; and adequate pubic arch separation. Once it was determined that the patient met all clinical

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and anatomical criteria for monotherapy, the HDR and LDR brachytherapy treatment options were discussed and then the patient selected the brachytherapy modality. A short course of neo-adjuvant androgen deprivation (≤6 months) was utilized for downsizing the gland volume in 31% of William Beaumont Hospital patients, in equal proportions between permanent seeds and HDR and in 30% of the California Endocuritherapy Cancer Center patients (Table 35.3). All procedures were done under spinal anesthesia. William Beaumont Hospital Experience All biopsy specimens were reviewed at our institution. The volume and length were based on TRUS performed in the department of radiation oncology, with the patient under light sedation in treatment position. Between January 1996 and December 2002, 253 patients with clinically localized prostate cancer, were treated with accelerated hypofractionated brachytherapy as the sole treatment modality. Of the patients, 92 were treated with high dose rate (HDR) brachytherapy alone using 92Ir, and 161 patients were treated with low dose rate (LDR) brachytherapy alone using 103Pd. The mean patient age in the HDR and LDR treatment groups was 64 and 66, respectively. The mean preimplant gland volume was 39 cc for both treatment groups. For the implant procedure as well as for pain control during the entire treatment time, spinal anesthesia was administered following placement of an epidural catheter. The patient was supine in the lithotomy position. A foley catheter was placed with the balloon containing 7 cc of contrast material, and the bladder filled with 150 cc of sterile water. A modification of our standard rigid perineal template was affixed to the biplanar 7.5 MHz ultrasound probe. The probe was then introduced into the rectum, positioned as parallel to the urethra as possible, and fixed to the table, allowing caudad-cephalad movement only. In the same manner as in the boost technique, using both transverse and sagittal views, the TRUS was used to visualize and identify the base and apex of the prostate, as well as normal structures, such as urethra, rectum, and bladder. Images were captured, and the urethra was mapped at each 5 mm transverse slice from base to apex. The transverse image with the largest cross-sectional area was considered the Reference plane’. The treatment volume was cylindrical in shape, extending from base to apex, with the crosssection corresponding to the reference plane. No margin was added around the prostate gland either at the reference plane or at the apex or prostatic base. Optimal needle positions were then generated intraoperatively using an online, interactive inhouse software program.16,19 Flexible plastic needles with metal stylets, either 20 cm or 23 cm long and

Table 35.3 Patients’ characteristics for high dose rate (192Ir) or low dose rate brachytherapy (103Pd) monotherapy by institution HDR brachytherapy WBH (n=92) Median follow- 25 mths up 65 yrs Mean age 6.0 Mean

LDR brachytheraphy WBH (n=161)

HDR bachytherapy CET (n=77)

40 mths

20 mths

66 yrs 5.3

63 yrs 7.9

Basic and advanced techniques in prostate brachytherapy pretreatment Mean gland volume

41 cc (16–93)

39 cc (15–111)

468

38 cc (9–1 34)

No, patients (%} No patients (%) No, patients (%) Clinical stage T1a–T1c 55 (60) 100 (62) 47(61) T2a 34 (37) 55 (34) 21 (27) T2b 2 (2) 4 (2) 9 (12) T2c 1 (1) 2 (1) − Pretreatmeat PSA ≤3.9 11 (12) 36 (22) 14 (18) 4.0–9.9 75 (82) 123 (77) 61 (79) ≥10.0 6 (6) 2 (1) 13 (17) Gleason score ≤5 5 (6) 22 (14) 14 (18) 6 80 (87) 131 (82) 61 (79) 7 6 (6} 6 (4) 2 (3) 8 1 (1) − − NAD 28 (30) 50 (31) 20 (26) WBH, William Beaumont Hospital, MI; CET, California Eadocuritherapy Cancer Center.

1.9 mm in diameter, were placed through the template under TRUS guidance (Figure 35.10). Location of the prostate base determined the depth of needle insertion. Dosimetry was continuously updated in real-time based on the actual location of needles to compensate for organ distortion and motion and to assure conformal coverage of the gland.19 Gold seed markers were then placed under TRUS guidance at the base and at the apex of the prostate to assess and measure possible interfraction needle displacement (Figure 35.5). Flexible cystoscopy was performed after placement of all needles to verify that the bladder and urethral mucosa were not perforated. Tenting of the bladder mucosa from the plastic needles was a requirement. Before delivery of the radiation, the entire prostate was imaged again, with final needle and urethral positions captured by TRUS and a final treatment plan created. The bladder was filled with 150 cc of contrast material, and fluoroscopy was performed to record the relationship of the tip of the needles to the bony anatomy and the bladder base. After removing the metal stylets, plastic collars were tightened around the needles to fix them to the template. This prevented any caudad-cephalad movement of the needles with respect to the template. The template was then sutured to the perineum (Figure 35.11). The treatment plan was geometrically optimized to determine dwell positions and times.19 The dose prescription was to a point of minimum dose in the implanted volume. The rectal dose was calculated at the anterior edge of the TRUS probe and was limited to ≤75% of the prescription dose. The dose to any segment of the urethra was limited to ≤125% of the prescription dose. The prescription dose was 950 cGy delivered four times for a total dose of 3800 cGy. Two fractions were delivered daily over 2 days, with at least 6 hours separating each fraction. The brachytherapy needles with the template were then removed as well as the epidural catheter. The patient was discharged home after voiding spontaneously, typically

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3–4 hours after completing treatment. Using the linear-quadratic formula,22 this dose fractionation is the equivalent of an external beam regimen of 76.4 Gy (50.4 Gy in 28 fractions plus a boost of 26 Gy in 13 fractions). This can be derived using an α/β value of 7 for estimating tumor control, a relatively conservative assumption.

Figure 35.10 Under transrectal ultrasound (TRUS) guidance, the flexible plastic catheters were placed transperineally following the computer-generated intraoperative plan. California Endocuritherapy Cancer Center Experience Between January 1996 and December 2002, 77 patients with clinically localized prostate cancer were treated with interstitial brachytherapy as the sole treatment modality. Patient characteristics are presented in Table 38.1. The mean patient age was 69 years and median prostate volume was between 30 and 35 cc. The California Endocurietherapy (CET) method of high dose rate brachytherapy is described as being prostate-specific accelerated HDR brachytherapy in Demanes et al.13 Either the Syed or CET type of perineal template was placed freehand on the perineum and not fixed to the hand-held biplanar transrectal ultrasound (TRVS) probe. A standard pattern consisting of 17 Flexiguide catheters with a metal wire (Best Industries) was inserted around the prostate

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anterior and lateral to the capsule and just within the posterior capsule at the ‘reference plane’, and into the prostate. Care was also taken to avoid the non-linear course of the prostate urethra. Cystoscopy was also performed to ensure that the catheters did not penetrate the urethra or bladder while adequately covering the prostate base. The template was sutured to the

Figure 35.11 Completed monotherapy implant with template sutured to the perineum. Plastic stifferners are used to prevent tube kinking, and secured with red caps. perineum, and after recovery the patient underwent a dual method of simulation radiography consisting of plain film localization for applicator adjustment and quality control and a computed tomography (CT) scan was performed. The images were downloaded to the ‘treatment-planning’ computer and a three-dimensional (3D) reconstruction was carried out. The dose was prescribed to a point 5–6 mm beyond the prostate capsule laterally and 3 mm posteriorly. Multiple point doses to the bladder neck, urethra, and anterior edge of the TRUS probe were calculated. A dose-volume histogram (DVH) and virtual images of the anatomy, clinical target volume (CTV), and planning target volume (PTV) were obtained. A series of six HDR fractions was administered twice a day in two separate procedures one week apart. Each fraction delivered 7 Gy for a total dose of 42 Gy. The dose to any segment of the urethra was limited to 103%, the bladder neck 80%, and the rectum 75% of the prescription dose. Postoperative management was similar to that described for the WBH experience. Results Treatment results are presented in two parts. First, the long term survival and toxicity results with HDR as a boost with or without adjuvant/concurrent hormonal therapy is discussed. Second, the monotherapy results are reviewed.

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High dose rate brachytherapy as a boost The cases were clinically staged. Considering the inaccuracies of clinical staging, if these cases had been pathologically

Figure 35.12 Outcome for all patients treated with high dose rate (HDR) boost at William Beaumont Hospital. CSS, cause specific survival; OS, overall survival; BC, biochemical control. staged (after prostatectomy) they would have been up staged by more than 60% in stage and Gleason categories. There was no difference in prostate gland volume based on different numbers of prognostic factors or brachytherapy dose level. Mean follow-up for the entire group (n=383) was 4.8 years (range: 0.4–12). Mean follow-up was 4.3 years (range: 0.4–10.3) for patients with one poor prognostic factor, 5.6 years (range: 1.5–12) for two, and 6 years (range: 1–11.3) for all three. Mean followup was 8.1 years (range: 2.0–12) for the low dose rate (LDR) group and 4.1 (range: 0.4– 8.2) for the high dose rate (HDR) group. The 5 and 10 year actuarial analysis of biochemical control, overall survival, diseasefree, and cause-specific survival for all WBH patients is shown in Figure 35.12. Based on the American Society of Therapeutic Radiology and Oncology (ASTRO) consensus panel definition of biochemical failure, the 5 year actuarial biochemical control rate was 52% for the LDR group versus 87% for the HDR group (p<0.001). In addition, the mean dose was 83.2 Gy for biochemically controlled cases versus 75.6 Gy for biochemical failures (t-test, p<0.001). The biochemical control in the collaborative group for the three institutions (n=934) is shown in Figure 35.13. The difference in biochemical control (p<0.001) is secondary to the difference in risk factors among the three institutions. Patients at CECC had a more favorable clinical stage (T) classification and Gleason score compared to the remaining two institutions. Figure 35.14 depicts the 5 year and 10 year biochemical control stratified by the use of hormonal therapy (HT). No difference in biochemical control was seen at 10 years. When

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patients with all three risk factors (n=177) were selected (≥T2b, PSA ≥ 10 ng/mL, and Gleason score ≥7), patients receiving HT had decreased cause-specific sur-

Figure 35.13 Biochemical control by institution (n=934). CET, California Endocuritherapy Cancer Center; WBH, William Beaumont Hospital, Michigan; Kiel, Kiel University Hospital, Germany.

Figure 35.14 Biochemical control stratified by the use of hormonal therapy (n=934). cmHDR, conformal modulated high dose rate (HDR); ADT, androgen deprivation therapy. vival, as seen in Figure 35.15 (p=0.02). The inferior outcome for the patients receiving neo-adjuvant/concurrent hormonal suppressive therapy with high dose radiotherapy raised the question about the benefit of HT when combined with optimal radiation doses. It is unclear if the deleterious effect of HT was due to its administration, duration, or timing.

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There was no difference in prostate gland volume based on the different prognostic factors or brachytherapy dose levels. The 5 year rates of local treatment failure by digital rectal examinations (DRE) were 8% and 6%, respectively. Median patient age was 69 years (range: 48–85), which is typical of radiotherapy series. Analysis of biochemical control, overall survival, disease-free survival, and causespecific survival at ages less than 65, 65–75 and greater than 75 years demonstrated no significant differences.

Figure 35.15 Cause-specific survival for patients with all three poor prognostic factors stratified by the use of hormonal therapy (HT) (n=177). cmHDR, conformal modulated high dose rate (HDR); ADT, androgen deprivation therapy. Whether analyzing by these subgroups or as a continuous variable, age was not a significant predictor of outcome, as younger and older patients benefited equally (biochemical control: p=0.633). The Radiation Therapy Oncology Group (RTOG) glossary was used to assess complications and expanded to include toxicity common to brachytherapy. RTOG grades 1–2 toxicity was seen at the level expected from the external beam component of the treatment program. No increases in percentage of grade 1 or 2 complications were seen as a consequence of the implants. Grade 2 late urinary complications, mostly urinary strictures, were seen in 7 of 58 patients treated with three separate implants or low dose, and 3 of 149 treated with two implants or high dose (Pearson Chi-square: p=0.006). Multivariate analysis of total urethral stricture, dose per fraction, segment of urethra, highest dose, length of follow-up, and number of implants (2 vs 3) revealed that only three implants correlated with increased risk of stricture. Median time was 2.0 years for late grade 3 genitourinary stricture, 2.7 for low dose, and 1.8 for high dose. The 5 year actuarial rate of RTOG late genitourinary complications was 8% for grade 3 and 0% for grade 4. Grade 3 urinary incontinence developed in only one patient following transurethral resection of the prostate performed 3.8 years after radiotherapy. The corresponding 5 year actuarial rate for RTOG gastrointestinal complications was 0.5% for grade 3 and 0.5% for grade 4 (an asymptomatic rectal ulcer developed in one patient).

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No patients experienced grade 5 acute or late toxicity. For patients claiming to be sexually potent the 5 year actuarial impotence rate was 51%, with impotence occurring at a median interval of 0.7 years (range: 0.0–5.2). No difference in impotence rate was observed based on dose level (p=0.897). High dose rate brachytherapy as monotherapy A total of 330 prostate cancer patients were treated with either high dose rate (HDR) 192Ir or low dose rate (LDR) 103Pd brachytherapy alone. The median follow-up for all patients was 32 months (range: 3–82). Data are presented for all patients, as well as for only those patients who did not receive hormonal manipulation for gland downsizing. Each toxicity event was censored as a separate event. In other words, the same patient who presented in followup with dysuria, hematuria and increase in urinary frequency was counted as 3 separate events. For chronic complications, the same patient was uncensored only once (Tables 35.4–35.6). Acute toxicity Table 35.4 shows the results for acute toxicity according to treatment technique with and without neo-adjuvant hormonal manipulation. HDR brachytherapy alone was associated with statistically significant reductions in the acute rates of dysuria, from 65% with 103Pd seeds to 38% with HDR monotherapy (p<0.001), as well as urinary frequency and/or urgency, from 94% (103Pd) to 53% (HDR, p<0.001) and urinary retention from 43% (103Pd) to 29% (HDR, p=0.012). In addition to reduced acute genitourinary symptoms, HDR was also associated with lower rates of rectal pain, 18% (LDR) versus 7% (HDR, p=0.025). Hormonal androgen ablation was given to 31% of patients in both groups. HDR monotherapy and permanent seeds were associated with similar rates of acute urinary incontinence, diarrhea, and rectal bleeding. Acute grade 1 urinary retention consisting of the use of a catheter for several days in the immediate postoperative period was seen more often after LDR permanent seeds implant, whereas the rates of more prolonged grade 2 retention treated with alphablockers was the same. The majority of acute toxicities in both groups were grade 1. Overall, however, there was a greater percentage of grade 3 acute genitourinary toxicities seen in LDR patients, 15%, compared to only 4% with HDR. There were no grade 4 toxicities in either treatment group. Chronic toxicity Table 35.5 shows the results for chronic toxicity according to treatment technique, with and without hormonal manipulation. Again, HDR brachytherapy alone was associated with reduced urinary frequency and urgency, 54% (103Pd) versus 32% (HDR) (p<0.001). As mentioned above, 31% of the patients in both groups received hormonal androgen deprivation. Again, the majority of toxicities were grade 1. There

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Table 35.4 Acute urinary toxicity for high dose rate (LDR) (192Ir) and low dose rate (HDR) (103Pd) brachytherapy as monotherapy Acute toxicity*

HDR alone with 192Ir (n=92) LDR alone with 103Pd (n=427) Grade Grade Grade All n Grade Grade Grade All n 1 2 3 toxicities 1 2 3 toxicities

Genitourinary Dysuria 30% 8% Incontinence 5% 1% Urinary retention 13% 16% Urinary frequency or 33% 15% urgency Hematuria 1% 2% Gastrointestinal Diarrhea 13% 1% Rectal pain 7% 0% Rectal bleeding 2% 0% * No grade 4 toxicities were observed.

0% 0% 2% 5%

38% 35 7% 6 32% 29 53% 49

48% 3% 24% 54%

14% 3% 12% 25%

3% 0% 1% 13%

1%

4% 4

1%

0%

0%

0% 0% 0%

14% 13 7% 6 2% 2

9% 15% 2%

2% 3% 0%

1% 0% 0%

65% 83 6% 8 36% 46 94% 119 1%

1

11% 14 18% 23 2% 2

Table 35.5 Chronic urinary toxicity for high dose rate (HDR) (192Ir) and low dose rate (LDR) (103Pd) brachytherapy as monotherapy Chronic toxicity*

HDR alone with 192Ir (n=92) LDR alone with 103Pd (n=127) Grade Grade Grade All n Grade Grade Grade All n 1 2 3 toxicities 1 2 3 toxicities

Genitourinary Dysuria 8% 6% Incontinence 7% 0% Urinary retention 4% 13% Urinary frequency or 13% 8% urgency Hematuria 6% 6% Gastrointestinal Diarrhea 4% 0% Rectal pain 4% 0% Rectal bleeding 9% 0% * No grade 4 toxicities were observed.

2% 0% 2% 0%

15% 14 7% 6 18% 17 32% 29

17% 8% 9% 39%

2% 2% 10% 14%

0% 0% 3% 1%

20% 25 9% 12 28% 35 54% 69

0%

11% 10

6%

0%

0%

6% 8

0% 0% 0%

4% 4 4% 4 9% 8

3% 5% 2%

0% 1% 1%

0% 0% 0%

3% 4 6% 7 2% 3

were no differences in the remaining chronic toxicity rates of urinary incontinence or retention, hematuria, diarrhea, rectal pain, or rectal bleeding between the two treatment groups. Considering the limitations of the current definition for urinary retention, all chronic retention cases were related to the usage of >6 months of alpha-blockers (no patient necessitated prolonged use of a catheter). The rate of urethral stricture requiring dilatation was 3% with HDR compared to 1% with 103Pd (p=0.3). The median time to

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development of urethral stricture was 17 months, with a range of 4–37 months. Figure 35.16 shows, the cumulative proportion of chronic grade 1 genitourinary toxicity by treatment modality and over time. Examining the area under the curve clearly demonstrates more toxicity for the 103P LDR group (p=0.028). No difference was noted between the two treatment types.

Table 35.6 Survival for high dose rate (HDR) (192Ir) and low dose rate (LDR) (103Pd) brachytherapy as monotherapy 4 year results

HDR brachytherapy LDR brachytherapy HDR brachytherapy pWBH (n=92) WBH (n=161) CET (n=77) value*

Over all survival 100% 93% 98% Cause-specific 100% 100% 100% survival Biochemical 99% 98% 96% control * Kaplan-Meier log rank, WBH, William Beaumont Hospital, MI: CET, California Endocurietherapy Cancer Center,

Figure 35.16 Cumulative incidence of chronic grade 1 genitourinary toxicity for high dose rate (HDR) 192lr and low dose rate (LDR) 103Pd brachytherapy as monotherapy.

0.345 – 0,602

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Potency Potency was evaluated only on those patients in whom the pretreatment potency status was known, and in whom posttreatment potency status was also evaluated. Hormonal manipulation for up to 6 months for gland volume downsizing was used equally in 30% of the LDR and HDR cases. Regardless of the use of adjuvant hormonal therapy all cases were included. This included 51 patients treated with HDR brachytherapy alone and 71 patients treated with permanent 103Pd. The 4 year probability of impotency was 38% for all patients with available data. As shown in Figure 35.17, the probability was 49% for LDR patients, and 21% for HDR patients (p=0.006). The mean times to impotency for the HDR and LDR treatments were 3.9 years and 3.2 years, respectively.

Figure 35.17 Cumulative incidence of impotency for high dose rate (HDR) (192lr) and low dose rate (LDR) (103Pd) brachytherapy as monotherapy. Conclusions Biochemical control Although this is an interim report, we have presented the 4 year survival analysis and biochemical control rates. Using the American Society of Therapeutic Radiology and Oncology (ASTRO) consensus panel definition of three consecutive rises above the nadir level, the 4 year biochemical control rate was the same for both brachytherapy treatment modalities. It was 98% at WBH and 96% at CET using HDR monotherapy, and 98% using 103Pd seeds. Table 35.6 depicts the survival outcome comparison of the three

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treatment groups. No statistical difference was noted in overall and/or cause-specific survival according to treatment technique or between centers. Cost analysis A cost analysis for both types of brachytherapy procedure was carried out. The technical (facility) cost analysis of both procedures showed HDR to be, on average, 23–29% lower in cost than LDR. This differential is related to the number of 103Pd seeds used. The professional (practitioner) total cost analysis revealed no significant difference in cost. References 1. Mettlin CJ, Murphy GP, McDonald CJ, Menck HR. The national Cancer Data Base Report on increased use of brachytherapy for the treatment of patients with prostate carcinoma in the USA. Cancer 1999; 86:1877–1882. 2. Lee WR, Moughan J, Owen JB, Zelefsky JM. The 1999 patterns of care study of radiotherapy in localized prostate carcinoma. A comprehensive survey of prostate brachytherapy in the United States. Cancer 2003; 98(9):1987–1994. 3. Kupelian P, Katcher J, Levin H, et al. External beam radiotherapy versus radical prostatectomy for clinical Stage T1-T2 prostate cancer: Therapeutic implications of stratification by pretreatment PSA levels and biopsy Gleason scores. Cancer J Sci Am 1997; 3:78–87. 4. Martinez AA, Gonzalez JA, Chung AK, et al. A comparison of external beam radiation therapy versus radical prostatectomy for patients with low risk prostate carcinoma diagnosed, staged and treated at a single institution. Cancer 2000; 88(2):425–432. 5. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280:969–974. 6. Blasko JC, Grimm PD, Sylvester JE, et al. Palladium-103 brachytherapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2000; 46:839–850. 7. Stock RG, Stone NN, Tabert A, et al. A dose-response study for I-125 prostate implants. Int J Radiat Oncol Biol Phys 1998; 41:101–108. 8. Wallner K, Merrick G, True L, et al. I-125 versus Pd-103 for low risk prostate cancer. Morbidity outcomes from a prospective randomized multicenter trial. Cancer J Sci Am 2002; 8:67–73. 9. Beyer DC, Priestley JB. Biochemical disease-free survival following I125 prostate implantation. Int J Radiat Oncol Biol Phys 1997; 37(3):559–563. 10. Martinez AA, Pataki I, Edmundson G, et al. Phase II prospective study of the use of conformal high-dose rate brachytherapy as monotherapy for the treatment of favorable stage prostate cancer: A feasibility report. Int J Radiat Oncol Biol Phys 2001; 49(1):61–69. 11. Grills IS, Martinez A, Hollander M, et al. High dose rate brachytherapy as prostate cancer monotherapy reduces toxicity compared to low dose rate Palladium seeds. J Urol 2004; 171:1098–1104. 12. Yoshioka Y, Nose T, Yoshida K, et al. High-dose-rate interstitial brachytherapy as monotherapy for localized prostate cancer: Treatment description and preliminary results of phase I/II clinical trial. Int J Radiat Oncol Biol Phys 2000; 48(1):675–681. 13. Demanes JD, Rodriguez RR, Altieri GA. High dose rate prostate brachytherapy: the California Endocurietherapy (CET) Method. Radiother Oncol 2000; 57:289–296. 14. Morgan WR, Bergstralh EJ, Zincke H. Long-term evaluation of radical prostatectomy as treatment for clinical stage C (T3) prostate cancer. Urology 1993; 41:113–120.

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15. Gerber GS, Thisted RA, Chodak GW, et al. Results of radical prostatectomy in men with locally advanced prostate cancer: Multiinstitutional pooled analysis. Eur Urol 1997; 32:385– 390. 16. Oefelein MG, Smith ND, Grayhack JT, et al. Long-term results of radical retropubic prostatectomy in men with high grade carcinoma of the prostate. J Urol 1997; 158:1460–1465. 17. Hanks GE, Diamond JJ, Krall JM, et al. A ten-year follow-up of 682 patients treated for prostate cancer with radiation therapy in the United States. Int J Radiat Oncol Biol Phys 1987; 13:499–505. 18. Pilepich MV, Caplan R, Byhardt CA, et al. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: Report of Radiation Therapy Oncology Group Protocol 85–35. J Clin Oncol 1997; 15:1013–1021. 19. Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997; 337:295–300. 20. Roach M, Lu J, Pilepich M, et al. Predicting survival and the role of androgen suppressive therapy (AST): Radiation Therapy Oncology Group (RTOG) phase III randomized prostate cancer trials. Int J Radiat Oncol Biol Phys 1998; 42:177. 21. Shipley WU, Verhey JJ, Munzenrider JE, et al. Advanced prostate cancer: The results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. Int J Radiat Oncol Biol Phys 1995; 32:3–12. 22. Forman JD, Duclos M, Sharma R, et al. Conformal mixed neutron and photon irradiation in localized and locally advanced prostate cancer: Preliminary estimates of the therapeutic ratio. Int J Radiat Oncol Biol Phys 1996; 35:259–266. 23. Zelefsky MJ, Fuks Z, Wolfe T, et al. Locally advanced prostate cancer: Long-term toxicity outcome after three-dimensional conformal radiation therapy—a dose escalation study. Radiology 1998; 209:169–174. 24. Hanks GE, Lee WR, Hanlon AL, et al. Conformal technique dose escalation for prostate cancer: Biochemical evidence of improved cancer control with higher doses in patients with pretreatment prostate-specific antigen >10ng/ml. Int J Radiat Oncol Biol Phys 1996; 35:861– 868. 25. Martinez AA, Kestin LL, Stromberg J, et al. Interim report of imageguided conformal high dose rate brachytherapy for patients with unfavorable prostate cancer: The William Beaumont phase II doseescalating trial. Int J Radiat Oncol Biol Phys 2000; 47:343–352. 26. Melian E, Magaeras GS, Fuks Z, et al. Variation in prostate position quantitation and implications for three-dimensional conformal treatment planning. Int J Radiat Oncol Biol Phys 1997; 38:73–81. 27. Yan D, Ziaja E, Jaffray D, et al. The use of adaptive radiation therapy to reduce setup error: A prospective clinical study. Int J Radiat Oncol Biol Phys 1998; 41:715–720. 28. Yan D, Jaffray DA, Wong JW. A model to accumulate fractionated dose in a deforming organ. Int J Radiat Oncol Biol Phys 1999; 44(3):665–675. 29. Edmundson GK, Rizzo N, Teahan M, et al. Concurrent treatment planning for outpatient high dose rate prostate template implants. Int J Radiat Oncol Biol Phys 1993; 27:1215–1223. 30. Edmundson GK, Yan D, Martinez A. Intraoperative optimization of needle placement and dwell times for conformal prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995; 33:1257– 1263. 31. Martinez AA, Gonzalez J, Spencer W, et al. Conformal high dose rate brachytherapy improves biochemical control and cause specific survival in patients with prostatic cancer and poor prognostic factors. J Urol 2003; 169:974–980. 32. Martinez AA, Galalae R, Gonzalez J, et al. No apparent benefit at 5 years from a course of neoadjuvant/concurrent androgen deprivation for prostate cancer patients treated to a high total radiation dose. J Urol 2003; 170(6):2296–2301.

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33. Martinez AA, Galalae R, Mitchell C, et al. Lack of benefit from a short course of androgen deprivation for unfavorable prostate cancer patients treated with an accelerated hypofractionated regime. Int J Radiat Oncol Biol Phys 2003; 57:S175. 34. Blasko JC, Grim PD, Sylvester JE, et al. Palladium-103 brachytherapy for prostate carcinoma. Int J Radiat Oncol Biol Phys 2000; 46(4):839–850. 35. Brenner DJ, Martinez AA, Edmundson GK, et al. Direct evidence that prostate tumors show high sensitivity to fraction (low α/β ratio) comparable to late-responding normal tissues. Int J Radiat Oncol Biol Phys 2002; 52(1):6–13. 36. Cox DR. Regression models and life-tables. J Roy Stat Soc 1972; B34:187–220. 37. Fuks Z, Leibel SA, Wallner KE, et al. The effect of local control on metastatic dissemination in carcinoma of the prostate: Long-term results in patients treated with 125-I implantation. Int J Radiat Oncol Biol Phys 1991; 21:537–547. 38. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280:969–974. 39. Mate TP, Gottesman JE, Hatton J, et al. High dose-rate afterloading iridium-192 prostate brachytherapy: Feasibility report. Int J Radiat Oncol Biol Phys 1998; 41:525–533. 40. Radge 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; 83:989–1001. 41. Edmundson GK, Rizzo NR, Teahan M, et al. Concurrent treatment planning for outpatient high dose rate prostate template implants. Int J Radiat Oncol Biol Phys 1993; 27:1215. 42. Edmundson GK, Yan D, Martinez AA. Intraoperative optimization of needle placement and dwell times for conformal prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995; 33:1257. 43. Nag S, Ciezski JP, Cormack R, et al. Intraoperative planning and evaluation of permanent prostate brachytherapy: Report of the American Brachytherapy Society. Int J Radiat Oncol Biol Phys 2001; 51(5):1422–1430. 44. Martinez AA, Gonzalez J, Spencer W, et al. Conformal high dose rate brachytherapy improves biochemical control and cause specific survival in patients with prostate cancer and poor prognostic factors. J Urol 2003; 169:974–980. 45. Blasko JC, Haakon R, Grimm P. Transperineal ultrasound-guided implantation of the prostate: Morbidity and complications. Scand J Urol Nephrol Suppl 1991; 137:113. 46. Zelefsky MJ, Wallner KE, Ling C, et al. Comparison of the 5-year outcome and morbidity of three-dimensional conformal radiotherapy versus transperineal permanent iodine-125 implantation for earlystage prostatic cancer. Oncology 1999; 17(2):517–522. 47. Zelefsky MJ, Hollister T, Raben A, et al. Five-year biochemical outcome and toxicity with transperineal CT-planned permanent I-125 prostate implantation for patients with localized prostate cancer. Int J Radiat Oncol Biol Phys 2000; 47(5):1261–1266. 48. Kang SK, Chou RH, Dodge RK, et al. Gastrointestinal toxicity of transperineal interstitial prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002; 55(1):99–103. 49. Gelbaum DY, Potters L. Rectal complications associated with transperineal interstitial brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2000; 48(1):119–124. 50. Merrick GS, Butler WM, Dorsey AT, et al. Rectal dosimetric analysis following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999; 43(5):1021–1027. 51. Wallner K, Roy J, Harrison L. Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995; 32(2):465–471.

36 High dose rate brachytherapy in patients with high IPSS, large glands, or with prior TURP Glen Gejerman Introduction Prostate cancer is the most common cancer diagnosed among men in the United States, with an estimated 230 110 new cases and 29 900 deaths in 2004.1 In the prostatespecific antigen (PSA) era, the majority of men are diagnosed at an early stage, and treatment options include surgery, external beam radiotherapy (EBRT), and interstitial brachytherapy. Because of the risks of impotence and incontinence associated with radical prostatectomy, many men opt for a non-surgical approach. During the past decade prostate brachytherapy has been increasingly used as monotherapy or in combination with EBRT.2–5 Exponential growth has been forecasted so that while only 4% of men diagnosed with prostate cancer in 1996 were treated with brachytherapy, it is estimated that approximately half of those diagnosed in 2006 will be implanted.6 A 1999 medicare utilization review demonstrated that brachytherapy may supplant prostatectomy as the treatment of choice for localized prostate cancer.7 The majority of prostate interstitial brachytherapy is performed with permanent seed implants with or without supplemental external beam radiotherapy. Ten year PSA-free survival rates of 80–90% have been achieved with acceptable rates of morbidity.2–5 The development of the high dose rate (HDR) iridium192 (192Ir) remote afterloader and its success in treating gynecologic, pulmonary, and head and neck cancers prompted interest in treating prostate cancer with temporary HDR interstitial brachytherapy. The initial experience with multifractionated HDR brachytherapy in conjunction with EBRT noted excellent tolerance with superior conformality and minimal morbidity (Table 36.1).8–14 Mate et al delivered four HDR treatments with a minimum peripheral dose ranging from 3 Gy to 4 Gy.8 Dwell times in the periurethral needles were reduced limiting the maximum urethral dose to 120% while achieving 6–7 Gy per fraction to the posterolateral prostate. Approximately 10% of patients developed late genitourinary toxicity. However, as the implant technique evolved and steel needles were replaced with plastic catheters the incidence of urethral strictures became uncommon. Galalae et al combined irradiation of the prostate and pelvic lymphatics with HDR implants interdigitated after 20 Gy and 40 Gy external beam dose.9 The clinical target volume (CTV) was divided so that 15 Gy was delivered to CTV1, defined as the peripheral zone and 9 Gy to CTV2, which included the entire prostate gland. At a median follow-up of 8 years, the disease-free survival was 83% with an acceptable toxicity profile. Of patients, 12% developed significant late genitourinary toxicity consisting of incontinence, urethral stricture, or bladder sphincter sclerosis. These patients had undergone a transurethral resection of the prostate (TURP) with a median interval to radiotherapy of less than 5

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months. In contrast, none of 10 patients who had undergone TURP with a median interval to radiotherapy greater than 6 months experienced incontinence. Martinez et al treated high risk prostate cancer patients with 46 Gy pelvic EBRT and increasing doses of HDR brachytherapy using from 5.5 Gy to 11.5 Gy per fraction.10 An improved cause-specific survival was noted in patients treated with higher biological effective doses (>93 Gy). Since HDR brachytherapy can mitigate the technical difficulties sometimes encountered during an implant procedure, it has several potential advantages over permanent seed brachytherapy. The success of a permanent seed implant is dependent on the correct delineation of the target volume and optimal placement of needles and seeds. Because treatment planning and dose optimization of HDR brachytherapy is performed after the implant, the risk that prostate movement, needle deflection, and seed migration will impair the intended dosimetry is avoided. Narrow pubic arch anatomy is less of an obstacle in HDR brachytherapy because the ability to optimize dwell positions and dwell times in the anterolateral catheters will allow adequate dosimetric coverage even if pubic arch interference prevents ideal needle placement. HDR optimization makes it possible to accurately cover the target

Table 36.1HBR/EBRT studies Author

Years Pat Stage EERT HDR ient no.

Tx Follow- DFS Acute Acute Chronic Chronic Plan up GU GI GU GU ning Toxi Toxi Toxi Toxi city>1 city>1 city>1 city>1

Galalae9

1986– 144 1992

Trus Median 83% NA based 96 months

NA

Pmges11

1992– 82 1994

8.50% 10%

4%

Mate8

1989– 104 1995

Sim Median 79% 11% based 24 months CT Median 84% NA based 45 months Sim NA NA NA based

NA

9%

NA

NA

NA

NA

70%

2%

8%

Demanes13 1991– 491 1998

Borghede12 1998– 50 1994

T1b 50Gy 15Gy −T3 inter ×2 dictated fract with ions HDR to to perip heral pros tate zone T2 45Gy 9–10 −T3 after Gy× HDR 2 fx T1b 50.4Gy 3–4 −T3 after Gy× HDR 4 fx T1c 36Gy 2 sep −T3b before arate or proce alter dures HDR 6Gy/fx T1 50Gy 2 sep −T3 split arate course proce dures

Trus Median 96% 8% /Sim 45 based months

6%

11%

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Martinez10 1991– 2000

Syed14

1996– 1999

10Gy/fx 207 T1c 46Gy 2–3 sep −T3c interdig arate itated proce with dures HDR 5.5–1

200 T1c 39.6– −T3b 45Gy before or after HDR

Real Mean time 4.4 Trus years based

483

74% NA

1.5Gy/fx 5.5 CT Mean 93% 10% –6.5 based 30 Gy× months 4 fx

NA

12%

NA

20%

2%

1.50%

volume while simultaneously setting tolerance constraints for the urethra and rectum. This differential dosing is particularly useful for patients at higher risk for postimplant uropathy, such as those with high international prostate symptom scores (IPSS) and those with a prior TURP.15–18 The dynamics of postimplant edema must be considered when evaluating prostate and urethral dose after permanent seed implantation.19,20 Since prostatic edema remains relatively stable during the immediate postoperative period, dosimetric measurements of HDR brachytherapy may be more reliable.21 HDR catheters can be placed in the periprostatic tissues so that patients at risk for seminal vesicle or extraprostatic disease can be adequately treated. The temporary duration of HDR implants and the use of remote afterloaders obviate the need for radiation precautions. This has been shown to be a significant factor in a patient’s decision when considering the different treatment modalities.21 Finally, recent calculations of a low α/β ratio for prostate cancer suggests that the use of hypofractionated HDR brachytherapy may increase the therapeutic ratio.22,23 Nonetheless, because of the durable 10 year PSA-free survival and low morbidity seen with permanent seed implants, choosing between permanent seeds and HDR brachytherapy can be difficult. In the absence of wellestablished criteria, at Hackensack University Medical Center, New Jersey, we have limited the use of HDR brachytherapy to those patients who are not ideal candidates for permanent seed brachytherapy, that is, those with large glands, high IPSS, and those with a prior TURP. An increased risk of urinary morbidity has been found for patients with large prostate glands. Prostate volumes greater than 35–40 cc have been associated with grade 2 urinary toxicity and acute urinary retention.24–27 Gelblum et al found that patients with prostate volumes greater than 35 cc had a 52.6% grade 2 urinary toxicity rate compared with 35% in those whose glands were smaller than 35 cc.24 Lee et al reported a 25% risk of retention for patients whose pretreatment planning ultrasound target volume measured more than 45 cc.26 Crook et al demonstrated that the prostate volume was a significant predictor of acute urinary retention and that the risk increased for any given size when downsizing with androgen suppression was used.27 IPSS is also highly predictive of postimplant uropathy.15,16,24 Terk found an association between the baseline IPSS score and the risk of urinary retention after seed implantation.15 IPSS scores <10, 10–19, and >20 correlated with retention rates of 2%, 11%, and 29%, respectively. Gelblum et al reported that men with a baseline score greater than 7 had a 59.2% rate of grade 2 urinary toxicity and a

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greater chance of having residual symptoms after one year.24 Bucci et al demonstrated that high IPSS score was predictive for the need for and the duration of catheterization.16 The mean IPSS values for the no catheter and catheter-requiring patients were 6 and 10 (p=0.004). Patients who have undergone a TURP prior to permanent seed implantation have a higher risk for urinary incontinence.28,29 While the risk of urethral injury is decreased when a peripheral loading technique is employed,18 most brachytherapists consider a prior TURP to be a relative contraindication. The Hackensack University experience Between 1998 and 2003, 235 patients with stage T1a–T2b were treated with intensity modulated radiotherapy (IMRT) in combination with HDR brachytherapy. Patients were staged clinically by history, physical exam, digital rectal exam, and serum PSA measurement. Additional studies including CT scan, bone scan, and endorectal MRI were obtained as clinically indicated. The median age was 70 (range: 52–80 years); median PSA was 7 (range: 1.2–116); median ultrasound volume 25 cc (range: 11–105); median erectile function index 15 (range: 0–25), and median IPSS 9 (range: 0–29). Of the patients, 45% had a prior TURP, 48% had significant lower urinary tract symptoms (IPSS>10), and 24% had large prostate volumes (>45 cc); 13% of patients had pretreatment incontinence; 72% of patients were androgen ablated. All patients received 50.4 Gy IMRT prior to HDR brachytherapy. Patients underwent treatment planning CT simulation in the supine position with vaclock immobilization. The gross target volume (GTV) included the prostate and proximal seminal vesicles with 3 mm margins around the prostate (except at the rectal interface). The planning target volume (PTV) was circumscribed by the Corvus planning system (NOMOS Corp) and was determined by combining the immobilization uncertainty with the localization uncertainty. The resultant total uncertainty allocated the following margins: anterior, 10.2 mm; posterior, 10.2 mm; right, 5.8 mm; left, 5.8 mm; superior, 10.2 mm; inferior, 10.2 mm—1.8 Gy daily fraction was prescribed for a total of 50.4 Gy over 28 treatments. Inverse treatment planning enabled dose optimization so that the prescription goal to the GTV could be met while constraining the normal tissue dose. The normal tissue dose was restricted allowing no more than 10% of the bladder volume to receive greater than 41.4 Gy and no more than 10% of the rectal volume to receive 50 Gy. Dose-volume histograms (DVH) were reviewed and only those plans with 100% coverage of the GTV and at least 90% of the PTV were approved. The dose was prescribed to 76–95% (median: 86%), the prostate maximum dose was 52–66 Gy (median: 60 Gy), the bladder maximum dose was 51–65 Gy (median: 58 Gy), and the rectal maximum was 48–59 Gy (median: 55 Gy). After completion of IMRT, a volumetric study was obtained to document the prostate volume and the extent of the tissue defect in patients with prior TURP. HDR brachytherapy was performed within 6 weeks of completing IMRT.

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Operating room technique Patient positioning and template Patients underwent a bowel prep consisting of a one day full liquid diet followed by Golytely on the evening before the implant. This regimen facilitates good ultrasound images and avoids abdominal cramping during the subsequent constipation from Lomotil and morphine. After induction of anesthesia, patients were placed in the dorsolithotomy position with the femurs at a 90 degree angle to the OR table. Improper positioning will not allow the template to be sutured to the perineum in a flush position (Figure 36.1). If pubic arch interference (PAI) required an extended lithotomy position, the legs were repositioned once the anterior catheters were placed. Prophylactic antibiotics began perioperatively and continued for 5 days after the implant. A 7.5 MHz biplanar ultrasound probe was attached to a floor-mounted stepping unit and inserted in to the rectum. A needle guide/perineal template (Figure 36.2) was attached to the stepping device and advanced until flush against the perineum. Over the years, several changes have been made to the template but the basic design has remained constant. A needle guide template with a detachable perineal portion is used. The needle guide has holes with 0.5 cm spacing and the perineal template contains a silicone insert which prevents catheter movement relative to the template. A foley catheter was placed in the distal urethra and 30 cc of an aerosolized

Figure 36.1 Perineal template. Note that the superior portion is not flush against the perineum.

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Figure 36.2 Needle guide/perineal template in the stepping device.

Figure 36.3 Cystoscopy demonstrating mucosal penetration. surgilube mixture was injected. The prostate was imaged in 5 mm transverse sections and the urethral (and TURP defect) location was delineated. Proper urethral visualization is important because the urethra may be more anterior or lateral than expected.30 TURP defect sizes and locations can vary, therefore proper delineation is critical. While mucosal penetration would be subsequently detected with flexible cystoscopy (Figure 36.3), identifying the offending catheter can be difficult and time consuming, and avoiding mucosal trauma is prudent. Flexiguide catheter placement and flexible cystoscopy Prior to flexiguide insertion, 18-gauge metal needles were placed through the template and advanced to the

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Figure 36.4 (a) Volumetric study with transurethral resection of the prostate (TURP) defect (b) Corresponding image during implant. mid-gland. The resultant needle tract prevents excessive pressure on the flexiguide tip while piercing the skin and template. Catheter deviation is less likely and a parallel array of catheters is facilitated. The order in which the needles were placed generally followed a typical sequence. The first two needles (1 and 2) were placed laterally to ensure proper placement at the capsule edge and to stabilize the gland. Needles 3 and 4 were placed at the anterior surface of the gland (11 and 1 o’clock positions) on either side of the urethra. In patients with TURP defects, these needles were moved posterior and laterally as judged by the urethrogram (Figure 36.4). Needle 5 was placed at the prostate-rectal interface. These needles were replaced by 6 French (inner diameter 1.65 mm) catheters with stylets and advanced to the base as seen on the transverse image. Using the sagittal view, the catheters were advanced 5 mm beyond the base (Figure 36.5). The subsequent needles and

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Figure 36.5 (a) Transverse ultrasound image, (b) Corresponding sagittal image. catheters were sequentially placed (Figure 36.6) and advanced to the previously determined depth. Typically, 18–25 catheters were implanted. The detachable perineal template was unscrewed from the needle guide (Figure 36.7) and the stepping unit and TRUS probe were removed. After the template was sutured, the patient was taken out of the lithotomy position and placed in a frog-legged position for flexible cystoscopy. Cystoscopy confirms that the catheters have been advanced to the base by checking for tenting of the bladder mucosa at the bladder neck (Figure 36.8). If any of the catheters had traversed the prostatic urethra or pierced the bladder mucosa, they were identified and withdrawn to a submucosal position with cystoscopic visualization. The catheters were covered during cystoscopy to prevent them from getting wet. At completion of the procedure, a three-way foley catheter was placed and the patient was transferred to recovery room.

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Figure 36.6 Sequence of needle insertion.

Figure 36.7 Detaching the needle guide from the perineal template.

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Figure 36.8 (a) Flexible cystoscopy without mucosal tenting; (b) with mucosal tenting. CT treatment planning Patients were transferred to a custom brachytherapy mattress and treatment planning began within 3 hours of the implant. A helical CT was taken with the gantry angle parallel to the perpendicular plane of the catheters. The patient’s position was checked with alignment lasers and triangulating BBs were placed. Each catheter-template interface was marked, a rectal marker was placed, the foley catheter was clamped, and 40 cc of contrast was injected in to the bladder. Anterior and lateral scout films confirmed that the patient had been properly positioned and that the catheters had been advanced superiorly enough in to the base of the gland (Figure 36.9). Transverse images of the implant volume (with 3 cm superior and inferior margins) were collected in 5 mm abutting slices. The CT films were printed and the clinical target volume, urethra, TURP defect (when applicable), and rectum were outlined and digitized into the Nucletron Brachytherapy Planning System (Figure 36.10). The catheters were digitized from the visible tips in the base of the gland until 5 mm below the apex. The first dwell position was offset 5 mm from the tip and all dwell positions outside of the target were disabled. The optimization procedure was performed with a dwell time gradient factor of 2.5 in order to minimize the number of dwell positions with negative times. Dose optimization was performed using a full polynomial fit to dose points placed on the surface of the target volume with a 10 mm distance between dose points. The relative weight for each dwell position was manually adjusted to enhance the target coverage while maintaining the urethral dose below 110% and the rectal dose at 100% (Figure 36.10). Once the target dose of 5 Gy to the clinical target volume (CTV) was achieved, dose-volume histogram analysis and secondary hand calculations were performed.

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Patients received 20 Gy in four fractions. The treatments were delivered over 24–28 hours with a minimum of 6 hours between each fraction. Prior to each brachytherapy treatment, the catheter-template interface was checked to rule out catheter displacement from the template (Figure 36.11).

Figure 36.9 Anterior (a) and lateral (b) scout films of catheters with stylets.

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Figure 36.10 (a, b) Computed tomography (CT) with corresponding dosimetry. Repeat CT catheter movement In order to investigate the constancy of the catheter position during the treatment period, serial CT scans were obtained for 30 patients. During the initial treatment planning, after the 5 mm slices were collected, a second set of CT images was obtained in 2 mm slices. These were transferred to the Voxelq workstation (Philips Medical Systems), the catheter tips were digitized, and anterior and lateral digitally reconstructed radiographs (DRR) were generated with rendering of the catheter tips, ischial tuberosity, and perineal

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template (Figure 36.12). The mean distance between the ischial tuberosity and the catheter tips was measured and recorded. The distance between the ischial tuberosity and a fixed point on the template was similarly measured. This 2 mm CT set was repeated

(c, d) Patient with prior transurethral resection of the prostate (TURP) in a patient with a prostate gland >100 cc. and analyzed at different intervals: one group had the CT repeated before the second fraction, a second group before the third fraction and a third group before the fourth fraction. After the catheters were digitized, DRR films were generated and the mean distance between the catheter tips and the ischial tuberosity was calculated and compared to the first measurement to assess catheter movement. Using the mean distance avoided the necessity to match corresponding catheters between the CT sets and potential errors

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associated with this process. A similar analysis was performed to assess template movement. We found no movement of the catheters relative to the template. The template and catheters were almost always displaced in a caudal direction. The amount of displacement was time-dependent. The average displacement before the second fraction was 2 mm, before the third 8 mm, and before the fourth 10 mm (Figure 36.13). Without a redress of this movement, significant dosimetric changes are encountered.31 When comparing the first HDR treatment with the third fraction, median decreases in the following dosimetric parameters were noted: dose to 90% of the prostate volume, 35% (range: 0–60%); minimal dose to the

Figure 36.11 The catheter-template interface is checked before each treatment. base, 35% (range: 17–65%); and maximal dose to 1 cc, 13% (range: 3–19%). The reduction in the D90, and more significantly in the Dbase, demonstrate the loss of dose at the prostate base that results from the unavailable dwell positions. Thus, the potential of HDR brachytherapy to provide ultimate conformality may be limited by the catheter displacement that occurs with multifractionated therapy. While some centers resolve this problem by restricting the brachytherapy application to one or two

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Figure 36.12 Digitally reconstructed radiographs (DRR) of template and catheters. fractions per implant, their patients are subjected to multiple implant procedures. Others continue to deliver three or four HDR treatments after one implant procedure but compensate by advancing the catheter under fluoroscopy prior to each treatment. Because of the potential to push the prostate superiorly as the catheters are adjusted, this measure may compound the dosimetric error. We currently obtain a repeat CT scan prior to the third fraction, evaluate catheter position at the base, and if displacement is noted, advance the catheters. A repeat CT scan accurately documents the extent of displacement and when catheter advancement is needed, repeat planning is necessary to ensure appropriate coverage of the target volume. Pain management Given the discomfort associated with interstitial brachytherapy, urethral catheterization, and bed confinement, aggressive pain management is vital to a successful procedure. Because of logistical delays between the time a patient reports pain and the time analgesic medications are administered, the anticipation of pain adds a subjective response to physiologic events. Since studies have shown lower levels of pain-related anxiety when patients are in control of their analgesic regimen,32 we have prescribed morphine delivered by patient-controlled analgesia (PCA) devices.32 With the use of PCA, a basal infusion rate

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Figure 36.13 Time dependence of catheter displacement. maintains a non-zero blood concentration so that selfadministration of small opioid doses sufficiently boosts drug concentration into the therapeutic range. Patients can therefore self-titrate the amount of medication needed for the intensity of the pain. In order to clarify the nature and intensity of pain experienced during brachytherapy, 102 patients were assessed with a validated visual analogue scale from 0 (no pain) to 10 (severe pain) before implant, 2 hours after, and before each of the four treatments. Patients were asked to rate their back pain and pain from the foley and perineal catheters as ‘worst’, ‘average’, and ‘now’. The type of PCA, number of perineal catheters, and the presence of diabetes, obesity, or arthritis were analyzed for association with pain severity. Overall, the reported worst pain was mild-to-moderate with the following means: back, 2.4; foley catheter, 3; perineal catheters, 2.7. On univariate analysis, back pain increased over time (p=0.001) while perineal catheter pain decreased over time (p=0.005), and increased with the number of catheters (p=0.001). Foley catheter pain was worse in those with arthritis (p=0.0025) and obesity (p=0.001). Multivariate analysis with catheter number, diabetes, arthritis, and obesity as covariates demonstrated that only the type of PCA was associated with pain intensity. Patients managed with bupivicaine-epidural PCA experienced significantly less ‘worst’ pain than those with morphineparenteral PCA (p<0.0001). In our experience, when a PCA is used, prostate HDR causes mild-to-moderate pain and an epidural administration significantly reduces the pain intensity (Table 36.2). Toxicity All patients underwent HDR implant after completion of external beam irradiation. The median interval between IMRT and HDR was 3 weeks (range: 0.5–6). Urethrography was used to delineate the urethral course and a

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Table 36.2 Visual analogue scale pain intensity by route of PCA administration Mean back pain Mean foley catheter pain Mean perineal catheter pain Epidural PCA 0.5 0.6 Parenteral PCA 2.7 3.4 PCA, patient-controlled analgesia.

0.7 3.0

median of 19 (range: 12–28) flexiguide catheters were placed. Cystoscopy confirmed mucosal penetration in 22% of patients—most of these were early in the series and in patients who had large TURP defects. HDR dosimetry was optimized to deliver 20 Gy to the prostate target volume while keeping the median urethral D50 to 91% (range: 60– 123%) and urethral Dmax to 112% (range: 90–140%) of the prescribed dose. Four fractions of 5 Gy were separated by at least 6 hours. RTOG and LENT/SOMA scores were used to quantify toxicity (Tables 36.3 and 36.4).33 Acute toxicity During IMRT, 19% of patients reported grade 1 acute gastrointestinal (GI) toxicity: 21% of patients experienced grade 1 acute genitourinary (GU) toxicity and 16% of patients grade 2 toxicity. Symptoms resolved within 3 weeks of completing radiotherapy in 66% of patients and all returned to baseline by 10 weeks. After removal of the interstitial implant grade 1, acute GU toxicity was noted in 26% and grade 2 acute GU toxicity in 18% of patients. These symptoms resolved within 4 weeks. No acute GI toxicity was encountered. The following parameters were tested for association with toxicity: IPSS, age, TURP, prostate size, androgen suppression, number of interstitial catheters, mucosal penetration, IMRT/HDR dose to prostate rectum and urethra, and TURP defect dose. On univariate analysis a prior TURP was associated with a lower incidence of acute GU toxicity >1 with toxicity seen in 13% of TURP patients versus 30% in those without (p=0.06). Continuous significant predictors of greater than grade 1 acute GU toxicity included maximum prostate and rectal IMRT dose (see Table 36.5). Late toxicity The median follow-up is 25 months (range: 6–60). Of the patients, 23% developed grade 1 chronic GI toxicity

Table 36.3 Modified RTOG grading criteria for acute radiation toxicity Grade 1

Grade 2

Gastrointestinal symptoms Increased frequency or change in bowel habits not requiring medication. Rectal discomfort not

Diarrhea requiring Diarrhea requiring IV Acute or subacute medication (eg, support. Severe mucous obstruction, Fistula or Lomotil). Mucous discharge requiring perforation. Rectal discharge infrequently extended use of pads. bleeding requiring requiring pads. Proctitis Abdominal distension. more than 1 requiring analgesics or Proctitis requiring frequent transfusion. Abdominal

Grade 3

Grade4

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498

occasional narcotics. Mild rectal bleeding.

narcotics. Rectal bleeding pain or tenesmus requiring 1 transfusion, requiring bowel diversion. Genitourinary Frequency or nocturia Frequency of nocturia Hematuria requiring symptoms Frequency less frequent than hourly or more, Dysuria more than 1 or nocturia twice the hourly. Dysuria or pain or spasm requiring transfusion. baseline. Dysuria not bladder spasm frequent narcotics. Gross Hospitalization for requiring medication. requiring medication hematuria requiring 1 sepsis due to (Pyridium). Infrequent transfusion. Prolonged obstruction and/or gross hematuria. urinary obstruction due to ulceration or necrosis Temporary prostate inflammation or of the bladder. catheterization. clots requiring catheterization, RTOG, Radiation Therapy Oncology Group; IV, intravenous.

Table 36.4 RTOG and LENT grading criteria for delayed radiation toxicity Grade 1

Grade 2

Gastrointestinal symptoms Excess bowel movements twice the baseline. Slight rectal discharge or blood.

More than 2 antidiarrheals/ week. 2 or fewer coagulations for rectal bleeding. Occasional steroids for ulceration. Occasional dilatation. Intermittent use of protective pads. Regular non-narcotic or occasional narcotic medication for pain. Genitourinary Moderate frequency. symptoms Nocturia Nocturia more than twice the baseline. twice the baseline, Microscopic Generalized hematuria. Light telangectasia. mucosal atrophy and Intermittent minor telangectasia. macroscopic hematuria. 2 or fewer coagulations, Intermittent use of pads. Regular non-narcotic or occasional narcotic medication for pain. LENT

Grade 3

Grade 4

More than 2 antidiarrheals/ day At least 1 transfusion or more than 2 coagulations for bleeding. Prolonged steroids per enema, Hyperbaric oxygen for bleeding/ulceration. Regular dilation. Persistent use of protective pads. Regular narcotic use for pain.

Dysfunction requiring surgery. Perforation. Lifethreatening bleeding.

Severe frequency and dysuria, Nocturia more frequent than every hour. Reduction in bladder capacity (150 cc). Frequent hematuria requiring at least 1 transfusion. More than 2 coagulations for hematuria. Hyperbaric oxygen for bleeding/ ulceration. n. Persistent use of protective pads. Regular narcotic use for pain.

Severe hemorrhagic cystitis or ulceration requiring urinary diversion and/or cystectomy

Table 36.5 Acute gastrointestinal (GI) and genitourinary (GU) toxicity Acute GI toxicity 0–1 Acute GU toxicity>1 p-value Mean prostate max Mean rectal max

59.25 Gy (SD 304) 54.96 Gy (SD 248)

60.43 Gy (SD 142) 55.83 Gy (SD 145)

0.02 0.06

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SEX standard deviation,

Table 36.6 Significant predictors of chronic genitourinary (GU) toxicity Chronic grade 2 GU toxicity p-value Mean prostate US volume 18 cc(SD 8) 0.04 Mean catheter number 18 (SD 3) 0.03 Mean rectal HDR max 311 cGy(SD 85) 0,04 US, ultrasound; HDR, high dose rate; SD, standard deviation.

consisting of a slight mucoid discharge and frequent bowel movements. No intervention was required and resolution was noted by the 1 year follow-up: 9% of patients experienced grade 2 chronic GU toxicity consisting of stress incontinence requiring intermittent use of protective pads. All but two of these patients had preexisting incontinence that resulted from a prior TURP. The following parameters were tested for association with late toxicity: IPSS, age, TURP, prostate size, androgen suppression, number of interstitial catheters, mucosal penetration, IMRT/HDR dose to prostate rectum and urethra, and TURP defect dose. On univariate analysis, postimplant incontinence was associated with a prior TURP (18% of patients with TURP vs 0% without TURP, p=0.002) and pretreatment incontinence (46% of patients with prior incontinence vs 2% without p=0.0001). Continuous significant predictors of chronic GU toxicity included prostate volume, number of interstitial catheters, and maximum rectal HDR dose to 1 cc (Table 36.6). The small number of patients with late grade 2 GU toxicity and the similarity of pretreatment variables did not allow for a stable multivariate model. Conclusion High dose rate (HDR) brachytherapy in combination with intensity modulated radiotherapy (IMRT) is a highly conformal treatment achieving significant dose to the prostate gland with minimal morbidity. Excellent long term prostate-specific antigen (PSA)-free survival rates have been reported with 10 year biochemical cure rates greater than 70%.34 The lack of toxicity found in patients considered at highest risk for sequelae is encouraging and raises the possibility of further dose escalation. Further study is needed to resolve the issue of interfraction catheter movement and to determine the optimal balance of IMRT dose and HDR fractionation. References 1. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics 2004. Cancer J Clin 2004; 54:8–29. 2. Ragde H, Abdel-Aziz AE, 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; 83:989–1001.

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3. Sylvester JE, Blasko JC, Grimm PD, et al. Ten year relapse free survival after external beam radiation and brachytherapy tor localized prostate cancer: the Seattle experience. Int J Radiat Oncol Biol Phys 2003; 57:944–952. 4. Dattoli M, Wallner K, True L, et al. Long term outcomes after treatment with external beam radiation therapy and palladium 103 for patients with higher risk prostate carcinoma. Cancer 2003; 97:979–983. 5. Critz FA, Williams H, Levinson KA, et al. Prostate specific antigen bounce after simultaneous irradiation for prostate cancer: the relationship to patient age. J Urol 2003; 170:1864–1867. 6. Nag S. Brachytherapy for prostate cancer: summary of American Brachytherapy Society recommendations. Semin Urol Oncol 2000; 18(2):133–136. 7. Hudson R. Brachytherapy treatments increasing among Medicare Population. Health policy brief of the American Urologic Association, Inc. 1999; 9:1–8. 8. Mate TP, Gottesman JE, Hatton J, et al. High dose rate afterloading 192Iridium prostate brachytherapy: feasibility report. Int J Radiat Oncol Biol Phys 1998; 41:525–533. 9. Galalae RM, Kovacs G, Schultze J, et al. Long term outcome after elective irradiation of the pelvic lymphatics and local dose escalation using high dose rate brachytherapy for locally advanced prostate cancer. Int J Radiat Oncol Biol Phys 2002; 52:81–90. 10. Martinez AA, Gustafson G, Gonzalez J, et al. Dose escalation using conformal high dose rate brachytherapy improves outcome in unfavorable prostate cancer. Int J Radiat Oncol Biol Phys 2002; 53:316–327. 11. Dinges S, Deger S, Koswig S, et al. High dose rate interstitial with external beam irradiation for localized prostate cancer—results of a prospective trial. Radiother Oncol 1998; 48:197–202. 12. Borghede G, Hedelin H, Holman S, et al. Combined treatment with temporary short-term high dose rate Iridium-192 brachytherapy and external beam radiotherapy for irradiation of localized prostatic carcinoma. Radiother Oncol 1991; 44:237–244. 13. Demanes DJ, Rodriguez RR, Altieri GA. High dose rate prostate brachytherapy: the California endocurietherapy (CET) method. Radiother Oncol 2000; 57:289–296. 14. Syed AMN, Puthawala A, Sharma A, et al. High dose rate prostate brachytherapy in the treatment of carcinoma of the prostate. Cancer Control 2001; 8:511–521. 15. Terk MD, Stock RG, Stone NN. Identification of patients at increased risk for prolonged urinary retention following radioactive seed implantation of the prostate. J Urol 1998; 160:1379–1382. 16. Bucci J, Morris WJ, Keyes M, et al. Predictive factors of urinary retention following prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002; 53:91–98. 17. Blasko J, Ragde H, Grimm PD. Transperineal ultrasound guided implantation of the prostate: morbidity and complications. Scand J Urol Nephrol 1991; 137:113–118. 18. Wallner K, Lee H, Wasserman S, Dattoli M. Low risk of urinary incontinence following brachytherapy in patients with a prior transurethral prostate resection. Int J Radiat Oncol Biol Phys 1997; 37:565–569. 19. Waterman FM, Dicker AP. The impact of post implant edema on the urethral dose in prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 47:661–664. 20. Gejerman G, Mullokandov EA, Saini AJ, et al. The effects of edema on urethral dose after palladium-103 brachytherapy. Med Dosim 2002; 27:221–225. 21. Martinez AA, Pataki I, Edmundson G, et al. Phase II prospective study of the use of conformal high dose rate brachytherapy as monotherapy for the treatment of unfavorable stage prostate cancer: a feasibility report. Int J Radiat Oncol Biol Phys 2001; 49:61–69. 22. Duchesne G, Peters L. What is the alpha/beta ratio for prostate cancer? Rationale for hypofractionated high dose rate brachytherapy. Int J Radiat Oncol Biol Phys 1999; 44:747–748. 23. Brenner DJ, Martinez AA, Edmundson GK, et al. Direct evidence that prostate tumors show high sensitivity to fraction (low α/β ratio) comparable to late responding normal tissue. Int J Radiat Oncol Biol Phys 2002; 52:6–13.

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24. Gelblum DY, Potters L, Ashley R, et al. Urinary morbidity following ultrasound guided transperineal seed implantation. Int J Radiat Oncol Biol Phys 1999; 45:59–67. 25. Han BH, Demel KC, Wallner K, et al. Patient reported short term complications after prostate brachytherapy. J Urol 2001; 166(3):953–957. 26. Lee N, Wuu C, Brody R, et al. Factors predicting for postimplantation urinary retention after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 48:1457–1460. 27. Crook J, McLean M, Catton C, et al. Factors influencing the risk of acute urinary retention after trus-guided permanent prostate seed implantation. Int J Radiat Oncol Biol Phys 2002; 52:453– 460. 28. Ragde H, Blasko JC, Grimm PD, et al. Interstitial I-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 1997; 80:442–453. 29. Wallner K, Blasko JC, Cavanagh W. Brachytherapy in the management of prostate cancer. In: D’Amico AV, Hanks GE (eds) Radiotherapeutic management of prostate adenocarcinoma. New York: Oxford University Press, 1999, 135–149. 30. Gejerman G, Richter F, Lanteri V, et al. Impact of urethral localization during transrectal ultrasonographically-guided transperineal prostate brachytherapy. J Brachyther Int 2000; 16:249–255. 31. Mullokandov E, Gejerman G. Analysis of serial CT scans to assess template and catheter movement in prostate HDR brachytherapy. Int J Radiat Oncol Biol Phys 2004; 58:1063–1071. 32. Upton RN, Semple TJ, Macintyre PE. Pharmacokinetic optimisation of opioid treatment in acute pain therapy. Clin Pharmacokinet 1997; 33:225–244. 33. Storey MR, Pollack A, Zagars G, et al. Complications from radiotherapy dose escalation in prostate cancer: preliminary results of a randomized trial. Int J Radiat Oncol Biol Phys 2000; 48:635–642. 34. Galalae RM, Martinez A, Mate T, et al. Long term outcome by risk factors using conformal high dose rate brachytherapy boost with or without neoadjuvant androgen suppression for localized prostate cancer. Int J Radiat Oncol Biol Phys 2004; 58:1048–1055.

Part V Combination of external beam radiotherapy and prostate brachytherapy

37 Combining external beam radiotherapy with prostate brachytherapy: issues and rationale Clarissa Febles and Richard K Valicenti Introduction The optimal treatment for clinically localized prostate cancer is controversial. For low risk prostate cancer patients (T1c/T2a, Gleason score <7, prostate-specific antigen (PSA) ≤10.0 ng/mL), monotherapy with either radical prostatectomy, three-dimensional conformal radiotherapy (3D-CRT), intensity modulated radiotherapy (IMRT), or prostate brachytherapy, result in similar biochemical relapse-free survival.1–3 Patient and physician preference usually influence treatment selection, based on critical assessment of relative side effect profiles, and quality of life evaluations. While brachytherapy alone in low risk patients can yield excellent disease control and a reported 93% 5 year freedom from biochemical failure, brachytherapy as monotherapy in intermediate and high risk disease (Gleason score >6, and/or PSA >10 ng/mL) is less than optimal.3 Kuban et al reported in the late 1980s the higher local failure rates observed in patients with stage B2 and C, moderately well, and poorly differentiated prostate cancer treated with brachytherapy alone, using the retropubic implant method.4 With the introduction and routine use of PSA follow-up, local control in intermediate and high risk patients is much lower than previously reported. Even with modern brachytherapy techniques, intermediate and high risk patients fair poorly with brachytherapy alone. In a recent report by Kwok et al, 5 year results with iodine-125 (125I) prostate brachytherapy as monotherapy was a disappointing 63% and 24% in intermediate and high risk patients, respectively.5 The combination of external beam radiotherapy (EBRT) and prostate brachytherapy has been used to improve outcomes in intermediate and high risk patients. This chapter focuses on the use of external beam radiotherapy with prostate seed implantation and provides a review of the rationale and available data in combining these modalities. Rationale for combined modality therapy Improved disease-free survival, freedom from distant metastasis and overall survival has been shown with delivery of high radiation doses to the prostate.5–8 Multiple approaches have been used to deliver dose escalation to the prostate: intensity modulated radiotherapy (IMRT), high energy neutrons, hyperfractionated radiation, and prostate brachytherapy boosts in conjunction with external beam radiotherapy (EBRT). The addition of EBRT provides a broader delivery of radiotherapy and the benefit of greater dose distribution and coverage of tumor that has extended beyond the prostate capsule. Brachytherapy alone, however, may be limited in its ability to deliver adequate doses to disease extending beyond the prostate. By combining brachytherapy and three-

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dimensional conformal radiotherapy (3D-CRT) one gains the benefit of higher dose delivery provided by brachytherapy along with coverage of disease that may extend outside of the prostate gland proper with the use of EBRT. Furthermore, if cancer cells have spread to the draining lymph nodes, brachytherapy will not address these areas of disease. An additional benefit of combined brachytherapy and EBRT is in patients who have received suboptimal implants. Combined modality may be justifiable in those patients who have received suboptimal implants and require supplemental doses of radiation to compensate for underdosed areas of disease. Achieving higher doses The importance of treating to higher radiation doses has been established by multiple dose-response studies.6–8 There are both 3D-CRT and prostate brachytherapy data supporting a dose-response in intermediate and high risk patients.7,9,10 The Radiation Therapy Oncology Group (RTOG) reported improved disease-specific and overall survival in patients with high Gleason scores who received higher doses of EBRT.9 Stone and Stock reported their experience with permanent 125I implants and found that dose was the most significant predictor of biochemical control.10 The benefit was greater for those patients presenting with PSA levels >10 ng/mL. The 4 year freedom from biochemical failure (PSA <1.0 ng/mL) was 51% and 100% in patients with a D90 (the dose covering 90% of the prostate) <140 Gy versus D90>40 Gy, respectively (p=0.009). Treatment of extrapriostatic extension cancer A second benefit of combining EBRT with brachytherapy is the added radiation doses to disease that has extended through the prostatic capsule and/or into the seminal vesicles. Both extracapsular extension (ECE) and seminal vesicle invasion (SVI) are adverse prognostic factors that can be estimated by PSA and Gleason scoring, using the following equations derived from Partin and described by Roach. 11–13 ECE=(3/2) PSA+[(GS−3)×10] SVI=PSA+[(GS−6)×10] The extent to which radioactive seeds placed within the prostate can adequately treat extracapsular disease has been debated. Patients at higher risk of ECE may benefit less from brachytherapy alone. Davis et al evaluated postprostatectomy patients and found that extraprostatic extension (EPE) measured on average 0.8 mm, with a range from 0.04 mm to 4.4 mm.14 Current brachytherapy techniques typically encompass 3–5 mm beyond the gland. However, postprostatectomy measurements of ECE may not represent in vivo distance of actual tumor spread. As the risk of EPE increases, the benefit of brachytherapy as monotherapy becomes less, and combined EBRT and brachytherapy or EBRT alone ought to be considered.

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Treatment of pelvic lymph nodes With increasing tumor (T) stage, PSA, and tumor grade, men with prostate cancer are at higher risk of lymph node spread. The estimated risk of lymph node metastasis can be estimated from the formula devised by Roach:13 +LN=(2/3) PSA+[(GS−6)×10] Often, men with >15% risk of lymph node involvement are treated with whole pelvis external beam irradiation. Clearly, if patients are at an increased risk of lymph nodal metastases that can be eradicated with radiotherapy, brachytherapy is not adequate treatment. Thus, the addition of EBRT can address both extracapsular disease as well as subclinical lymph nodal metastases. Results from the RTOG 9413 trial show a significant improvement in progression-free survival in men with prostate cancer treated with whole pelvis EBRT in conjunction with hormonal therapy, compared with men treated with hormones and radiation to the prostate only.15 These data strongly suggest pelvic irradiation benefits patients with intermediate-tohigh risk disease. Supplementation of prostate brachytherapy dose Adequate dose delivery with interstitial seed implantation is dependent on proper visualization of the prostate, dosimetric planning, correct placement of radioactive seeds, and ultimately physician expertise. Despite improvements in brachytherapy techniques and better visualization with transrectal ultrasound (TRUS), often the preplanned dosimetry does not match the actual doses delivered to the prostate at the time of postimplant evaluation. If on postimplant dosimetric analysis, subtherapeutic doses have been radiation-delivered to the prostate, a patient may be considered for seed reimplantation or supplemental EBRT to provide adequate doses and avoid treatment failure. Postimplant dosimetric analysis The American Brachytherapy Society (ABS) recognizes the need for adequate postimplant dosimetry in delivering optimal patient care and has established guidelines for postimplant dosimetric analysis based on an expert panel’s review of the literature. The ABS recommends that computed tomography (CT)-based postimplant dosimetry be performed on all patients undergoing permanent prostate brachytherapy. The enlargement of the prostate due to edema immediately postimplantation can result in a 10% mean decrease in dose delivered to the prostate compared to dosimetry obtained one month postimplantation.16 Generally, imaging is obtained one month post implant, however, the optimal timing of imaging remains unclear. The ABS recommends that postimplant dosimetry be performed at a consistent interval with documentation of the 50, 80, 90, 100, 150, and 200% isodose lines, dosevolume histograms (DVH) and the minimal dose covering 90% of the prostate volume (D90). The percent volume of the prostate receiving at least 100% or 150% of the prescribed minimal peripheral dose or V100 and V150 also

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are recommended as parameters to be measured. The rectal and urethral doses should be reported and correlated with clinical outcome. Ultimately, the earlier the postimplant dosimetry is performed, the earlier an underdosed implant can be identified and additional treatment provided with either reimplantation or additional external beam radiotherapy.17 Candidates for combined modality therapy As outlined by the ABS, brachytherapy is an option for patients with a life expectancy of 5 years or more, who are without distant metastasis and without large transurethral resection of the prostate (TURP) defects.18 In patients with a significant risk of disease outside the implant volume, the addition of EBRT or hormonal therapy is advised. The risk of lymph node and seminal vesicle involvement as well as the risk of extracapsular extension should be calculated for each patient with the use of Partin Tables or other risk stratification models. The recommended brachytherapy doses when used in combination with EBRT are shown in Table 37.1. Treatment outcomes with combined permanent seed implant and EBRT No randomized trials have been conducted to evaluate the benefit of combined brachytherapy and external beam irradiation.

Table 37.1 ABS recommended seed implant doses with combined EBRT Isotope

Brachytheraphy dose (Gy)

EBRT dose (Gy)

103

Pd 80–90 40–50 125 I 100–110 40–50 ABS, American Brachytherapy Society EBRT, external beam radiotherapy;

Dattoli et al, at the University Community Hospital in Tampa, provided the earliest data with combined EBRT and prostate brachytherapy. A total of 73 patients with T2a–T3 prostate cancer with one or more of the following risk factors: stage ≥T2b, Gleason score 7–10, PSA >15 ng/mL, or elevated prostatic acid phosphatase (PAP) received palladium103 (103Pd) implant followed by EBRT; 10 patients did, however, receive 2 months of hormonal therapy prior to radiation. With a median follow-up time of 2 years, actuarial freedom from biochemical failure (PSA<1.0 ng/mL) was 79% at 3 years.19 PAP was the only significant predictor of biochemical failure (p=0.04). After poor results with 125I interstitial implants alone, Frank Critz, at the Radiotherapy Clinics of Georgia began treating patients with combined brachytherapy and EBRT in the late 1970s. Critz’s experience with ‘simultaneous’ interstitial seed implant and EBRT is the largest to date. Over 1000 men with T1−T2 lymph node negative NO low to high risk adenocarcinoma of the prostate received 125I implant followed 21 days later by EBRT, thus being exposed ‘simultaneously’ to both the radioactive seeds and external beam

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irradiation.20 Despite variable implant doses, which are considered less than the current standard, excellent disease-free survival was achieved. With a median follow-up of 3 years, disease-free survival, defined as achieving and maintaining a PSA nadir of ≤0.5 ng/mL was 79% and 72% at 5 and 10 years, respectively. Median time to recurrence was 3.5 years. Of note, patients who underwent a retropubic 125I implant had a 73% 5 year DFS while those patients receiving the ultrasound-guided transperineal implant had a higher 5 year disease-free survival (DFS) of 92% (p=0.0001). Again, emphasizing the importance of technique and the benefit of the more modern ultrasound-guided transperineal approach. The second largest reported experience with combined permanent interstitial implant and EBRT comes from Seattle, Washington. Ragde et al reported their updated results of 229 patients with T1–T3 adenocarcinoma of the prostate treated with transrectal ultrasound (TRUS)guided 125I implant with or without EBRT:21 82 men considered at high risk of extracapsular extension (Gleason score >6 and/or stage >T2b) received a mean peripheral dose (MPD) of 120 Gy by implant following EBRT (see Table 37.2). Of note, this prescribed implant dose is higher than that recommended by the ABS and American Association of Physicists in Medicine (APPM) Task Group 43. Using the updated American Society for Therapeutic Radiology and Oncology (ASTRO) definition of biochemical failure (three consecutive rises in serum PSA level measured 6 months apart) the observed 10 year biochemical with no evidence of disease (bNED) for the monotherapy group was 66% and 79% in the combination therapy group. Four patients died from prostate cancer yielding a disease-specific 10 year survival rate of 98%. The higher

Table 37.2 Comparison of biochemical disease-free survival (DFS) with combined brachytherapy and EBRT Study

Critz20

No. EBRT Implant Median % patients 10 yr Definition 5 yr patients dose dose (f/u) receiving biochemical biochemical of PSA ts (Gy) (Gy), (mths) hormones DFS (%) DFS (%), failure source 1029

45

80, 125I

45

0

79

0 14

− 79b

Ragde21 Dattoli19

82 73

45 120, 125I 41 80, 103Pd

122 24

Grado24

72c

45 120, 125I

47

100, Pd 66 45 90, 125I 54 0 Merrick26 110, 103 pd 25 103 MSKCC 65 50.4 Pd 36 86 a three consecutive rises in PSA level measured 6 months apart 103

72° 88d

72 PSA 70.5 ng/ml 79a ASTROa PSA 1.0 ng/mll –2 successive rises in PSA

79.9a

– ASTROa

87b

– ASTROa

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b

3 year freedom from biochemical failure, hormone naïve group. d patients exposed to androgen deprivation. c

biochemical control rate observed in the combined modality group, although not significant, is nonetheless encouraging and further supports the notion that excellent disease control can be obtained in intermediate and high risk patients with combined modality therapy. The updated Ragde et al results are comparable to the earlier published data which used a PSA>0.5 ng/mL as the definition of biochemical failure. In their earlier published data, a benefit in tumor control in the combined group was noted when a PSA endpoint of ≤0.4 ng/mL was used. The disease free survival was 63% in the combined modality group versus 74.5% in the implant alone group (p=0.046).22 The authors suggest that combining EBRT with a brachytherapy implant might be the best modality for patients with clinically localized prostate cancer, with results comparable to prostatectomy. While some physicians, such as Critz, propose combined implant and EBRT for all locally confined prostate cancer patients, others, including Ragde et al, use the following criteria for implant alone therapy: PSA<10 ng/mL, clinical stage ≤T2a, and Gleason score <7.21 While the level of PSA nadir necessary for optimal treatment outcome is debated (<1.0 ng/mL or <0.5 ng/mL), a low posttreatment PSA nadir is a known predictor of DPS.23 Critz et al showed that 77% of patients treated with combined EBRT and prostate implant had a PSA of 0.5 ng/mL or less at 60 months. Posttreatment PSA values decreased most rapidly within the first 3 months postimplant, and more gradually thereafter, and by 24 months 52% of patients achieved a PSA nadir of 0.5 ng/mL or less.23 The rate of PSA decrease, however, was not a prognostic indicator. Grado et al published on their actuarial DFS after prostate cancer brachytherapy using interactive techniques with biplane ultrasound and fluoroscopic guidance. A total of 553 T1–T3c prostate cancer patients (with no PSA, Gleason score, or hormonal therapy restriction) were treated with 125I or 103Pd seed implantation. 490 patients were analyzed, of whom 70 were at risk of having capsular involvement (determined by digital rectal examination, TRUS, or biopsy) and received 45 Gy adjuvant EBRT. Two additional patients received EBRT after brachytherapy because of suboptimal dose delivery during the brachytherapy. Twenty six patients in the implant alone group and 10 patients in the combination-modility group received androgen deprivation therapy. There was no significant difference in disease-free survival between the group treated by implant alone versus the group undergoing implant plus x-ray therapy. For the hormone naïve group the 5-year disease free survival was 80% for the implant alone group and 72% for the combined-treated group, while those patients receiving hormonal therapy had a 5-year DFS of 83% vs 88%, respectively.24 The Memorial Sloan-Kettering Cancer Center (MSKCC) reported their early but favorable results with 103Pd permanent implant and 3D–CRT in intermediate and unfavorable risk prostate cancer patients. PSA relapse-free survival at 3 years was 87%.25 More recently, Merrick et al reported favorable results with combined EBRT and permanent seed implantation. Five year biochemical DFS in 66 hormone naive patients with high risk prostate cancer (Gleason score ≥7, PSA≥10 ng/mL, clinical stage ≥T2b) treated with supplemental EBRT and permanent seed implant was 79.9%.26 A summary

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of institutional experiences with combination EBRT and brachytherapy boost is provided in Table 37.2. Treatment-related side effects Rectal and urinary toxicity Morbidity from the combined approach appears to be comparable to high dose 3D-CRT or surgery for similar risk patients. The most commonly observed toxicity with combined 3D-CRT and brachytherapy boost are RTOG grade 1–2 rectal and urinary toxicity. In the study by Singh et al, 13% of patients experienced rectal bleeding and 8% experienced increased frequency of bowel movements, while no patients experienced grade 3 or 4 rectal toxicity.25 The most commonly reported urinary side effects are symptoms of frequency, urgency, and nocturia, which are easily managed with alpha-blockers.19,24 Less commonly observed are urinary obstructive symptoms requiring intervention. A 6% rate of temporary foley catheterization was observed by Singh et al,25 and less than 3% of men required a TURP postimplantation for persistent urinary obstructive symptoms in the study by Datoli et al.19 Observed rates of stress incontinence ranged from 1% to 5%.19,20,25 One patient in the study by Dattoli et al developed complete urinary incontinence.19 Although complications of urinary incontinence, obstruction, and urethral stricture (less than 3%) are rare with combined modality therapy, they are more likely to be seen in men with a prior history of urinary obstructive symptoms and prior TURP.19,20 In Critz’s review of 1000 men treated with combined implant and EBRT, all cases of urinary incontinence, urethral necrosis, and urethral occurred in men with a prior history of TURP.20 Similar to the urinary toxicity profile, rectal toxicity with combined modality therapy is most likely to be of grade 1 or 2 (RTOG). In the MSKCC experience, 13% of patients experienced rectal bleeding and 8% experienced increased frequency of bowel movements and no grade 3 or 4 rectal toxicities were observed.25 Grado et al reported a rare 1% occurrence of rectal fistula.24 A more recent report randomizing low risk patients to implant alone (125I or 103Pd) and intermediate risk patients to 103Pd implants (90 Gy vs 115 Gy) with supplemental EBRT (44 vs 20 Gy), reported higher American Urological Association (AUA) scores at one month in the groups receiving higher prescription doses of 103Pd (125 Gy 103Pd alone and 115 Gy 103Pd plus 20 Gy EBRT).36 Similarly, rectal morbidity was significantly higher in the combined modality group only at one month. Rectal morbidity consisted mostly of increased frequency and mucous passage and no cases of rectal ulceration or fistula were documented. The dose of EBRT received (20 Gy vs 44 Gy) did not correlate with urinary or rectal morbidity, suggesting that the addition of EBRT does not impact on overall treatment morbidity. Furthermore, at one year, little difference in morbidity was observed between all treatment groups.36 Longer follow-up, and additional randomized studies will help to clarify the effect of supplemental EBRT on rectal and urinary toxicity as well as elucidate its effect on other parameters such as potency preservation and quality of life.

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Potency preservation Rates of potency preservation greater than 80% have been reported with brachytherapy as monotherapy.28 Potency following EBRT, however, is less preserved with reported rates of only 50% at 6 years.3 From the limited data available on the effects of combined prostate brachytherapy and EBRT on sexual function, the rates of sexual potency, not surprisingly, fall between those reported for either modality alone. Dattoli et al reported sexual potency rates of 82% and 77% at 1 and 3 years, respectively.19 Similar rates of potency were observed by Singh et al, and a reported 26% of sexually potent men developed erectile dysfunction after combined modality treatment.25 No difference in the rate of erectile dysfunction was observed among those men receiving neo-adjuvant androgen deprivation and men who did not receive hormonal therapy.25 Age has been shown to play a role in preservation of sexual function. Critz et al showed that men younger than 65 had an 85% rate of potency preservation, while men older than 65 had a 65% rate of potency (p=0.05).27 Future trials including an ongoing RTOG phase II study for intermediate risk prostate cancer patients receiving combined EBRT and prostate will provide further data on treatment-related toxicity and the overall safety and efficacy of the combined approach. High dose rate brachytherapy boost The largest experience with temporary high dose rate (HDR) implants has been in Europe. This remote afterloading technique enables treatment planning to take place after needles have been securely placed into the prostate. The dose delivered to the prostate is then calculated and controlled by the dwell time of the radiation source at specified locations within each needle. Several institutions have reviewed their experience with EBRT in combination with HDR brachytherapy for locally advanced prostate cancer. Mate et al reported their prospective results of 144 men with T1b–T3 clinically nodenegative prostate cancer treated between 1986 and 1992 with whole pelvis EBRT combined with two fractions of HDR brachytherapy consisting of 15 Gy/fraction to the peripheral prostate and 9 Gy to the entire prostate. Overall survival and bNED survival at 5 years was 80.4% and 74%, respectively.29 A match pair analysis was performed by Keston et al to compare patients treated with external beam irradiation alone with combined EBRT and interstitial HDR brachytherapy boost. Five year biochemical control rates for EBRT +HDR was significantly higher than for EBRT alone (67% vs 44%, p<0.001). The combined modality group achieved a lower PSA nadir (0.4 ng/mL vs 1.1 ng/mL) and sustained longer intervals of PSA nadir (1.5 vs 1.0 years).30 On multivariate analysis, Gleason score, tumor (T) stage, and the use of EBRT were significantly associated with freedom from biochemical failure. A correlation between biochemical control and cause-specific survival was also demonstrated. Addition of hormonal therapy In addition to dose escalation, the use of hormonal therapy has also been used to achieve better disease control in intermediate and high risk prostate cancer patients. While the

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addition of hormonal therapy to EBRT or surgery has shown a benefit in disease-free and overall survival, the use of adjuvant hormonal therapy with brachytherapy has not been well established. Data supporting hormonal therapy (HT) in conjunction with brachytherapy are limited by retrospective design and small sample size. Multiple prospective randomized trials have shown a benefit from the addition of androgen ablation to EBRT in patients with locally advanced prostate cancer. Both RTOG 86–10 and RTOG 85–31 showed a benefit in local control and disease-free survival.31,32 The EORTC study, published in The New England Journal of Medicine, showed improvement in overall survival in addition to disease-free survival and local control with the addition of adjuvant HT to EBRT.33 Neo-adjuvant HT is routinely used for downsizing large prostate glands prior to brachytherapy with the goal of shrinking the prostate and allowing for greater ease of implant and a better dose distribution. The ABS recognizes the use of HT with brachytherapy and EBRT and recommends its use only in the context of downstaging large prostate glands (>60 cc) prior to seed implantation.17 Several institutions have reviewed their experiences with combined HT and brachytherapy, however, no prospective randomized trials exist to date. Stone and Stock reported their results with neoadjuvant HT and brachytherapy in 115 patient with intermediate risk prostate cancer treated with leuprolide and flutamide for 3 months prior to implant and an additional 3 months post implant.34 A benefit in local control is suggested in the group receiving neo-adjuvant HT with local control measured by routine prostate biopsy at 2 years (3.8% vs 7.7%, p=0.05). Two additional retrospective studies, both limited by number of patients and mean follow-up time have evaluated the addition of androgen ablation to combined EBRT and brachytherapy seed implant. Sylvester et al performed a matched pair subset analysis of 98 patients with intermediate-to-high risk prostate cancer of which 21 patients received combined implant and EBRT plus androgen ablation.35 The overall rate of freedom from biochemical failure at 5 years was 77% in the HT group and 58% in the non-HT group (p=0.08). In the Grado et al retrospective implant review: 36 of 490 patients with T1–T3c prostate cancer who underwent brachytherapy seed implantation had received prior androgen deprivation therapy for prebrachytherapy reduction of prostate volume or per patient request. Ten of the 36 patients at risk of extracapsular extension received combined brachytherapy with EBRT. The 5 year disease-free survival for the implant alone group and implant combined with EBRT were 83% and 88% respectively.24 No strong evidence exists for the addition of adjuvant or neo-adjuvant HT to prostate brachytherapy. The studies published thus far are limited both in patient size and duration of follow-up. The role of HT in addition to prostate brachytherapy remains unanswered and we await future prospective trials. The potential benefit of HT in combination with brachytherapy has not yet been thoroughly investigated and no consensus exists for the routine use of hormonal therapy with brachytherapy in intermediate-tohigh risk patients. Conclusions and future directions Prostate cancer remains the most common non-cutaneous cancer diagnosed in men, and the second leading cancer cause of death. With the widespread use of prostate-specific

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antigen (PSA) testing, more men are being detected with localized prostate cancer. Optimal therapy for organconfined prostate cancer remains an ongoing dilemma. There is abundant evidence showing the benefit of higher radiation doses in treatment outcomes in men with intermediate and high risk features. While favorable risk patients have excellent outcomes with monotherapy, combined external beam and brachytherapy is an excellent treatment option for men with intermediate to high risk prostate cancer. Combining three-dimensional conformal radiotherapy (3D−CRT) with brachytherapy boost is a safe and effective way of delivering high radiation doses to the prostate and can achieve results similar to favorable risk patients. Brachytherapy and combined EBRT has been shown to be both safe and effective, however, we await the results of recently completed and future prospective randomized trials to verify these findings. While the addition of hormonal therapy to external beam irradiation has proven beneficial, the use of hormonal therapy with brachytherapy remains less clear. Future prospective clinical trials will help better define the role of combined external beam radiotherapy and brachytherapy and the additional use of hormonal therapy. References 1. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998; 280:969–974. 2. Zelefsky MJ, Wallner K, Ling CC, et al. Comparison of the 5-year outcome and morbidity of three-dimensional conformal radiotherapy versus transperineal permanent iodine-125 implantation for earlystage prostatic cancer. J Clin Oncol 1999; 17(2):517–522. 3. Blasko JC, Wallner K, Grimm PD, et al. Prostate specific antigen based disease control following ultrasound guided 125 iodine implantation for stage T1/T2 prostatic carcinoma. J Urol 1995; 154(3):1096–1099. 4. Kuban DA, El-Mahdi AM, Schellhammer PF, et al. I-125 interstitial implantation for prostate cancer. What have we learned 10 years later? Cancer 1989; 63:2415–2420. 5. Kwok Y, DiBiase SJ, Amin PP, et al. Risk group stratification in patients undergoing permanent (125)I prostate brachytherapy as monotherapy. Int J Radiat Oncol Biol Phys 2002; 53(3):588– 594. 6. Hanks GE, Martz KL, Diamond JJ, et al. The effect of dose on local control of prostate cancer. Int J Radiat Oncol Biol Phys 1988; 15:1299–1305. 7. Hanks GE, Hanlon AL, Pinover WH, et al. Survival advantage for prostate cancer patients treated with high-dose three-dimensional conformal radiotherapy. Cancer J Sci Am 1999; 5:152–158. 8. Pollack A, Zagars GK, Starkschall G, et al. Prostate cancer radiation dose response: results of the M.D.Anderson phase II randomized trial. Int J Radiat Oncol Biol Phys 2002; 53(5):1097–1105. 9. Valicenti R, Lu J, Pilepich M, et al. Survival advantage from higherdose radiation therapy for clinically localized prostate cancer treated in the Radiation Therapy Oncology Group trial. J Clin Oncol 2000; 18:2740–2746. 10. Stock RG, Stone NN, Tabert A, et al. A dose-response study for iodine125 prostate implants. Int J Radiat Oncol Biol Phys 1998; 41:101–108. 11. Chen A, Roach M, Diaz A, et al. Using pre-treatment PSA and Gleason score to predict for extra capsular extension among patients with clinically staged organ confined prostate cancer. Int J Radiat Oncol Biol Phy 1995; 32(suppl 1):1020.

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12. Partin AW, Mangold LA, et al. Contemporary update of prostate cancer staging nomograms (Partin tables) for the new millennium. Urology 2001; 58:843–848. 13. Roach M. The use of prostate specific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 1993; 150:1923. 14. Davis BJ, Pisansky TM, Wilson TM, et al. The radial distance of extraprostatic extension of prostate carcinoma: implications for prostate brachytherapy. Cancer 1999; 85(12):2630–2637. 15. Roach M, Lu JD, Lawton C, et al. A Phase II trial comparing whole-pelvic (WP) to prostate only (PO) radiotherapy and neoadjuvant to adjuvant total androgen suppression (TAS): Preliminary analysis of RTOG 9413. Proceedings of the 43rd Annual ASTRO Meeting, 2001. 16. Waterman FM, Yue N, Corn BW, et al. Edema associated with I-125 or Pd-103 prostate brachytherapy and its impact on post-implant dosimetry: An analysis based on serial CT acquisition. Int J Radiat Oncol Biol Phys 1998; 41:1069–1077. 17. Nag S, Bice W, DeWyngaert K, et al. The American Brachytherapy Society recommendations for permanent prostate brachytherapy post-implant dosimetric analysis. Int J Radiat Oncol Biol Phys 2000; 46:221–230. 18. Nag S. Brachytherapy for prostate cancer: Summary of American Brachytherapy Society recommendations. Semin Urol Oncol 2000; 18(2):133–136. 19. Dattoli M, Wallner K, Sorace R, et al. 103PD brachytherapy and external beam irradiation for clinically localized, high-risk prostatic carcinoma. Int J Radiat Oncol Biol Phys 1996; 35(5):875–879. 20. Critz FA, Levinson AK, Williams WH, et al. Simultaneous radiotherapy for prostate cancer: 125I prostate implant followed by externalbeam radiation. Cancer J Sci Am 1998; 4(6):359– 363. 21. Ragde H, Leroy K, Abdel-Aziz E, et al. Prostate specific antigen results in 219 patients with up to 12 years of observed follow-up. Cancer 2000; 89(1):135–141. 22. 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. 23. Critz FA, Levinson K, Williams WH, et al. Prostate-specific antigen nadir of 0.5 ng/ml or less defines disease freedom for surgically staged men irradiated for prostate cancer. Urology 1997; 49:668–672. 24. Grado GL, Larson TR, Balch CS, et al. Actuarial disease-free survival after prostate cancer brachytherapy using interactive techniques with biplane ultrasound and fluoroscopic guidance. Int J Radiat Oncol Biol Phys 1998; 42:289–298. 25. Singh A, Zelefsky MJ, Raben A, et al. Combined 3-dimensional conformal radiotherapy and transperineal Pd-103 permanent implantation for patients with intermediate and unfavorable risk prostate cancer. Int J Radiat Oncol Biol Phys 2000; 90:275–280. 26. Merrick GS, Butler WM, Lief JH, et al. Biochemical outcome for hormone-naïve patients with high-risk prostate cancer managed with permanent interstitial brachytherapy and supplemental externalbeam radiation. Cancer J 2002; 8(4):322–327. 27. Critz FA, Tarlton RS, Holladay DA, et al. Prostate specific antigenmonitored combination radiotherapy for patients with prostate cancer: I-125 implant followed by external beam radiation. Cancer 1995; 75:2383–2391. 28. Wallner KE, Roy J, Zelefsky M, et al. Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal 125I prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995; 32:465–471. 29. Mate TP, Gotttesman JE, Hatton J, et al. High dose-rate after-loading iridium-192 prostate brachytherapy: Feasibility report. Int J Radiat Oncol Biol Phys 1998; 41:525–533. 30. Kestin LL, Martinez AA, Stromberg JS, et al. Matched-pair analysis of conformal high-doserate brachytherapy boost versus external-beam radiation therapy alone for locally advanced prostate cancer. J Clin Oncol 2000; 18:2869–2880.

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31. Pilepich MV, Winter K, John W, et al. Phase III Radiation Therapy Oncology Group (RTOG) trial 86–10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiat Oncol Biol Phys 2001; 50(5):1243–1252. 32. Pilepch MV, Caplan RW, Byhardt RW, et al. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: Report of Radiation Therapy Oncology Group Protocol 85–31. J Clin Oncol 1997; 15(3):1013–1021. 33. Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997; 337(5):295–300. 34. Stone NN, Stock RG, Unger P. Effects of neoadjuvant hormonal therapy on prostate biopsy results after 125I and 103Pd seed implantation. Mol Urol 2000; 4(3):163–168. 35. Sylvester J, Blasko JC, Grimm PD, et al. Short-course androgen ablation combined with external-beam radiation therapy and low-doserate permanent brachytherapy in early-stage prostate cancer: A matched subset analysis. Mol Urol 2000; 4(3):155–159.

38 The role of external beam radiotherapy and permanent prostate brachytherapy in patients with localized prostate cancer Louis Potters Introduction Permanent prostate brachytherapy (PPB) is an acceptable curative treatment modality for men with localized prostate cancer.1–6 However, as currently performed, it is used either as monotherapy or in conjunction with a short course of external beam radiotherapy (RTPPB). The reasons for combining therapy are multifactorial (Table 38.1). Without prospective data, it is difficult to ascertain which is the best indication. The most frequently used indication is based on the ‘statistical’ risk of extracapsular disease associated with Gleason score, prostate-specific antigen (PSA), and stage.1 An implant only provides dose to the prostate with a 3–5 mm margin and may extend to include just the base of the seminal vesicles.2 The ‘field’ effect of external radiation to encompass the seminal vesicles and a larger prostatic margin potentially are at risk for extracapsular disease not treated by the implant. This approach has continued without much change since originally suggested by Blasko et al during the initiation of the modern era of prostate brachytherapy. Doses of 45 Gy with 75% of the prescribed implant dose are considered standard when using combined therapy. The American Society of Brachytherapy (ABS) has published criteria for prostate brachytherapy and recommends

Table 38.1 Indications for combining external beam radiotherapy (EBRT) with permanent prostate brachytherapy (PPB) 1. Risk of extracapsular disease (a) LN risk (b) Seminal vesicle risk (c) Extracapsular penetration – established capsular penetration – focal capsular penetration 2. Dose escalation 3. ‘Smooth out’ inhomogeneities

monotherapy in patients who have stage T1c and T2a, Gleason scores of 2–6, and a PSA <10 ng/mL. Patients with stage T2b or Gleason score 8–10 or PSA >20 ng/mL are recommended to undergo RT-PPB.3

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When using combination therapy, there is no consensus by the ABS for the sequence of combined therapy. The advantages reported for initiating treatment with external beam radiotherapy (EBRT) include a decrease in toxicity and better tolerance of the entire treatment course. Those sequencing with the implant first believe that the seed outline assists in locating the prostate at simulation and that combined, or simultaneous treatments may be more beneficial.4 A review of the literature is not helpful in assessing the indications or advantages of combining external radiation and brachytherapy (Table 38.2). Therefore, we will review our experience with RT-PPB versus monotherapy PPB. Methods Potters et al recently reported on 1476 consecutive patients with clinically localized prostate cancer treated with PPB between September 1992 and September 2000.5 The treatment criteria for monotherapy or RT-PPB were based loosely on the ABS definitions.7 However, patient selfselection and preference allowed for an overlap of treatment methodologies and risk factors. Monotherapy used iodine-125 (125I) or palladium-103 (103Pd) prescribed to 144 Gy (TG–43) or 140 Gy (NIST-1999), respectively.6,7 RT-PPB consisted of radiation to 41.4 Gy or 45 Gy and a 125I or 103Pd implant to 108 Gy or 105 Gy, respectively. These delivered doses were kept constant, which means that the written prescription doses have changed to account for changes in the air-to-water kerma strength for 125I and a change in the calibration standard for 103Pd. A total of 276 patients received neo-adjuvant androgen deprivation (NAAD) to reduce the prostate volume or were

Table 38.2 Review of current brachytherapy literature for permanent prostate brachytherapy (PPB) performed as mono therapy or combined with external radiotherapy (CMT) Study

n Median f/u Biochemical Definition (maths) control

Grado18 CMT Monotherapy Ragde19 CMT Monotherapy Critz20 CMT Dattoli21 CMT Zekfsky22 Monotherapy

46 70 392

81% 85% 93

75 144 689 73

ASTRO

88%

ASTRO 71%

High risk patients treated with CMT: no analysis performed comparing groups

Nadir<0.2 PSA<1.0

79% 48

248

PSA<1 No selection criteria between ng/mL groups’ no analysis performed comparing groups

79% 66% 48 36

Comments

All high risk patients CT-based 125I implants. Includes patients with clinical

The role of external beam radiotherapy Low risk Monotherapy Intermediate risk Monotherapy High risk Monotherapy Lederman23 CMT Low risk CMT Intermediate risk Monotherapy High risk Monotherapy Blasko13 CMT Monotherapy Low risk CMT Monotherapy Intermediate risk CMT Monotherapy High risk. CMT Monotherapy Potters24

517 T3 disease

112

88%

92

77%

22

38% 48

PSA>1.0 PSA cutoff for risk at 20 ng/mL ng/mL

348

77%

165

88%

124

75%

59

59% 58

ASTRO

403 231

88% 79%

75 279

94% 79%

p=0.06

104 111

85% 84%

p=0.86

52 11

62% 54% 35

ASTRO (Kattan)

CMT 314 81.5% Monotherapy 1162 82.1% Low risk (matched); CMT 38 87.7% Monotherapy 40 93.4% Intermediate risk (matched): CMT 174 84.8% Monotherapy 191 79.7% High risk (matched): CMT 102 68.6% Monotherapy 84 60.5% f/u, follow-up; PSA, prostate-specific antigen; ASTRO, American Society of Therapeutic Radiology and Oncology; CT, computed tomography.

p=0.53 p=0.54

p=0.54

p=0.64

p=0.49

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treated as per the patient’s urologist. The implant was performed with peripheral seed loading. Postimplant analysis consisted of stereo shift X-ray films (n=468) and as of late 1994, patients underwent computed tomography (CT)-based dosimetry at 3 weeks postimplant (n=829). The D90% was used to assess implant quality in this study and is defined as the D90 dose determined by CT evaluation relative to the prescribed dose.8 The American Society for Therapeutic Radiology and Oncology (ASTRO) definition of PSA failure following EBRT was applied in this study.9 This definition marks failure at the midpoint in time between the posttreatment nadir and the first of three consecutive PSA rises with time zero the date of implant. However, two important conservative modifications were made.10 First, the requirement that the three rises have to be consecutive was relaxed. If three rises occurred with intervening stable PSA values, but the PSA never decreased, the patient was considered a fail ure, at the midpoint in time between his first rise and the PSA immediately prior to the first rise. Second, for patients whose most recent PSA values were rising at their last follow-up, but in whom failure had not occurred, follow-up time was truncated to the PSA immediately prior to the first rise. Results From the initial 1476 patients, 174 patients were excluded having only a single posttreatment PSA value. The remaining cohort characteristics are presented in Table 38.3. The median follow-up is 42.1 months with an overall and disease-specific survival at 72 months of 97% and 99%, respectively. A total of 89% of patients obtained a PSA value within the last year of follow-up, and the characteristics of

Table 38.3 Patient characteristics (from Potters et al)8 n a 1016 (%) Monotherapy n=1016 (%) RT-PPB n=281(%) p-value* Isotope

125

I Pd Mean No Yes

245 (24.1) 771 (75.9) 100 799 (79) 217 (21)

39 (13.9) 242 (86.1) 105 174 (61.9) 107 (38.1)

T1c T2a T2b 2 3 4 5 6 7

598 (58.9) 384 (37.8) 34 (3.3) 76 (0.6) 16 (1.6) 42 (4.8) 105 (10.3) 587 (57.8) 225 (27.1)

144 (45.9) 131 (41.7) 39 (12.1) 2 (0.7) 8 (2.8) 9 (3.2) 83 (29.5) 142 (50.5) 34 (12.1)

103

D90%a NAADa Stage

Gleason score

0.001 0.072 0.001 0.012

0.007

The role of external beam radiotherapy 8 Pretreatment PSA Mean Median Range Age Mean Median Range Follow-up Median Range * Mann-Whitney test. a D90 dose normalized to the prescription dose. b Neo-adjuvant androgen ablation.

27 (2.7) 9.4 10.6 0.2–112 69.6 70.2 43–90 35.1 7–91

519 3 (1.1) 14.0 13.5 0.8–85 67.6 68.8 48–84 33.0 6–85

0.014

0.082

Table 38.4 Evidence of failure information from the entire cohort (Potters et al)8 First evidence of failure

n=1297

Biochemical relapse Clinical relapse Hormonal therapy Salvage prostatectomy Death from disease None (censored) Median (maximum) months of follow-up for censored patients Total number of PSA values obtained at follow-up Percent of censored patients who did not have their PSA measured within 1 year of analysis

Table 38.5 Cox regression analysis on all 1297 patients to predict PSA freedom from recurrence based on Gleason sum, pretreatment PSA value, stage, NAAD, and RT-PPB Characteristic

p-value

Hazard ratio (95% CI)

Pretreatment PSA value 0.0001 * Gleason sum score 0.0001 * The addition of NAAD 0,0018 0.48 (0.31:0.76) Clinical stage 0.874 1.10 (0.78:1.55) T2a vs T1c 1.10 (0.78:1.55) T2b vs T1c 1.05 (0.58:1.90) The addition of EBRT 0.058 0.67(0.46:1.01) * Splines were used for continuous variables, NAAD, neo-adjuvant androgen deprivation: EBRT, external beam radiotherapy.

131 4 14 2 0 1146 35 (91) 8783 11

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Table 38.6 Cox regression analysis to predict for PSA freedom from recurrence based on pre- and posttreatment variables Characteristic

p-value Hazard ratio (95% CI)

Pretreatment PSA value 0.0001 * D90% <0.0001 * Gleason sum score 0.0008 * The addition of NAAD 0.086 0.55 (0.30:1.00) Clinical stage 0.366 T2a vs T1c 0.86 (0.49:1.50) T2b vs T1c 1.46 (0.64:3.32) The addition of EBRT 0.561 1.00 (055:1.85) * Splines were used for continuous variables EBRT, external beam radiotherapy.

recurrence are presented in Table 38.4. Of the patients, 35 (2.6%) are lost to follow-up and are censored based on their last PSA value. The PSA freedom from recurrence (FFR) for the entire cohort is 83.2%. The results of the Cox regression presented in Table 38.5 demonstrate that the results of the following variables and their impact on PSA-FFR: pretreatment PSA (0.0001); Gleason sum (0.0001); the use of neo-adjuvant androgen deprivation (NAAD) (0.0018); clinical stage (0.874); and the addition of EBRT (0.058). Table 38.6 presents the same analysis including the D90% variable as a continuous variable and changed the results as follows: pretreatment PSA (0.0001); D90% (<0.0001); Gleason sum (0.0008); the use of NAAD (0.086); clinical stage (0.366); and the addition of EBRT (0.561). Figure 38.1 illustrates the hazard ratio for the D90 dose that demonstrates a steep dose-response for a D90% of less than 100%, which then plateaus at a D90% above that. Kaplan-Meier PSA-FFR was performed with stratification of the D90% cutoff point at 90% of the prescribed dose based on the use of RT-PPB and is shown in Table 38.7. Discussion This retrospective study represents a large cohort of patients treated with modern prostate brachytherapy techniques and is the first such study that incorporates postimplant dosimetry to better address the role of RT-PPB.

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Figure 38.1 Hazard ratio plotted for a D90 dose. Table 38.7 PSA relapse-free survival (PSA-FFR) for patients stratified by the D90% variable (Potters et al)8 Treatment method (n) PSA-FFR p-value D90<90%a

0.057 Monotherapy (176) RT-PPBb (45)

72.1 % 85.6%

D90≥90%a

0.086 Monotherapy (437) 96.4% RT-PPB(171) 83.9% a D90% is the D90 dose normalized to the prescription dose. b Combined modality therapy.

Based on Cox modeling, there appears to be no advantage for RT-PPB over PPB as monotherapy. The most common rationale for combining external radiation and brachytherapy is based on the need to expand the sphere of radiation dose beyond the prostate capsule when patients exhibit a high risk for extracapsular disease. It is clear from several studies that pathologic analysis of prostate specimens has established the risk of extracapsular extension of tumor being associated with the pretreatment PSA value, Gleason sum, and clinical stage.1 Nonetheless, Davis et al were able to determine that focal extracapsular extension of disease was within 3.3 mm of the prostate capsule over 90% of the time and that the maximum distance of disease was 1.2 cm.2 With modern transperineal

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brachytherapy techniques, dosimetric evaluation identifies that this narrow extracapsular region is encompassed by a high radiation dose. In fact, modern planning systems will automatically place a desired margin around the prostate to account for extracapsular spread.11 Others have suggested that the need to combine external radiation and PPB is to account for suboptimal implants. This is the so-called ‘spackle’ effect where additional radiation will account for ‘cold’ or underdosed areas within the target or prostate. There are many reasons why

Figure 38.2 Acturial potency in patients that did not receive neoadjuvant androgen deprivation (NAD), comparing those treated with an implant as monotherapy or in combination with external beam radiotherapy (EBRT). the target dose may not be achieved and these include inexperience, difficulty with intraoperative visualization of the target, and seed movement through the needle tracks. Nonetheless, the Potters study appears to demonstrate that RT-PPB is not an independent variable to predict PSA-FFR, either with or without considering implant dosimetry (Tables 38.5 and 38.6). However, based on the hazard ratio plot (Figure 38.2) that examines the D90 dose (Figure 38.1), there does appear to be a steep dose-response that predicts for PSA-FFR. This dose effect, on its own, has a significant impact on clinical outcome for patients treated with monotherapy PPB, but not for patients treated with RT-

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PPB.8 Since the delivered implant dose (D90 dose) reflects the quality of the implant, and since the addition of external radiation does not appear to be an independent variable to predict PSA-FFR, it is appropriate to consider the need to maximize implant quality above the need to offer combination therapy, regardless of the inherent risk associated with the presenting PSA value and Gleason score. Therefore, the more relevant question is to ensure an acceptable implant on a consistent basis. One consideration for improving the skill of the surgical team is to use intraoperative dynamic dosimetry,12 which is beyond the discussion of this current subject. Nonetheless, even this may not guarantee an adequate implant in all cases. Therefore, consideration for the use of combined external radiation and PPB may best be reserved for cases with inadequate dosimetry. However, this will require further study. The combination of adding EBRT to brachytherapy remains a popular method for treating high risk patients. Some authors even have suggested that all patients undergoing brachytherapy should receive combined therapy. Unfortunately, a review of the current literature does not allow one to generate any firm conclusions on this subject (Table 38.8). Blasko et al have compared their patients treated with combination EBRT and brachytherapy verses brachytherapy monotherapy and identified an improvement in the biochemical freedom from failure for the monotherapy subset as compared to the combined therapy subset (88% vs 79% 8 year PSA-FFR, respectively).13 The stratification of risk factors in their series predicts for this outcome based on the pretreatment PSA values and Gleason sum for each treatment group. Further, when these authors stratified their patients into three basic risk categories, no difference in outcome was observed between the treatment groups within each category, respectively. Another study from Ragde et al that has been used to assert the need for combined therapy in all patients, presents 12 year crude biochemical control rates of 76% in the

Table 38.8 PSA freedom from recurrence for patients stratified by the addition of external beam radiotherapy (EBRT) to brachytherapy relative to postimplant dosimetric analysis Treatment Monotherapy Combined EBRT and brachytherapy

Study Ragde14 Blasko13(65) Potters8(14) (090 dose<90%)

Potters8(14) (D90 dose≥90%)

60% 76%

96.4% 83.9%

88% 79%

72.1% 85.6%

combined therapy group as compared to 60% for those treated with monotherapy.14 Although multivariate analysis was not performed in the Ragde study, it appears that the combined therapy patients had higher risk disease as compared with the monotherapy group. This counterintuitive result may be explained on the basis of not achieving a desired dosimetry in the monotherapy group of patients. When compared with the described study from Potters et al, the use of patient stratification based on a dosimetry cutoff point makes clear a possible explanation of both the intuitive and counterintuitive results of Blasko et al and Ragde et al, respectively (Table 38.8). This comparison

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suggests that implant quality may be a more important factor for predicting outcome than the actual need for combined therapy, even in high risk patients. Others have suggested that perhaps there is an additive effect of combining external radiation following an implant. While the results presented by Critz et al appear to indicate acceptable biochemical control rates in a large series of men treated with this approach,20 there is no clear evidence that their data are any better than the Potters et al or Blasko et al series. Further, comparison of their results is tainted by their use of an unconventional definition of fail ure using a strict PSA nadir, and their potential misuse of that definition. Further, the Critz group uses smaller daily fractions of external radiation than is standard. Another confounding factor associated with the prescribing of combination external radiation and brachytherapy is the type of external fields that are being used. Anecdotal evidence suggests that many centers that combine modalities are using three-dimensional (3D) or intensity modulated radiation techniques (IMRT), encompassing the prostate and seminal vesicle only. If one was to consider the field effect of combination therapy, a more likely approach would be that of the Radiation Therapy Oncology Group (RTOG) experience where true pelvic radiation fields are placed in order to encompass the potential spread of disease into lymph nodes, since it has already been shown that the implant covers the areas of extracapsular spread. Combining therapies may increase treatment toxicities. In a review of both urinary and rectal complications, Gelblum et al were unable to show that combined therapies are associated with higher treatment-related toxicity.15 However, a study from Zeitlin et al reported a rectoprostatic fistula rate of 2.3% when external radiation follows

Table 38.9 Data from 48 responders comparing quality of life (QOL) indices for patients treated with combined external beam radiotherapy and permanent prostate brachytherapy (RT-PPB) versus brachytherapy as monotherapy RAND: 36-item health survey

UCLA prostate index

Physical function n.s. Urinary function 0.01 Role limitations 0.02 Urinary bother 0.02 Bodily pain 0.03 Bowel function n.s. General health perceptions n.s. Bowel bother 0.02 Emotional well-being 0.02 Sexual function n.s. Role limitations n.s. Sexual bother 0.04 Social function 0.01 Cancer interference with life 0.03 Energy/Fatigue 0.03 Cancer interference with family 0.002 UCLA, University of California, Los Angeles: n,s., not significant.

PPB.16 While this degree of rectal toxicity has not been reported elsewhere, it remains a concern that combined therapy may impact on rectal injury. In a study on potency preservation following PPB, Potters et al identified that the addition of external beam radiation with PPB contributed to a drop in potency preservation of about 15–20% (Figure 38.2). In a study using quality of life (QOL) parameters that examined prostate

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cancer patients treated with either monotherapy or RT-PPB, Brandeis et al found that urinary function and bother, bowel bother, sexual function and bother, American Urological Association (AUA) symptom score, and cancer interference with life were all statistically worse in the RT-PPB group even when adjusting for baseline differences between groups (Table 38.9).17 Further study on toxicity is required and needs to be balanced against outcome. Conclusions The use of combined EBRT and permanent prostate brachytherapy (PPB) continues for definitive treatment of clinically localized prostate cancer. It is clear from the presented data that the role for combination therapy remains suspect, at best. Future studies are required to address the need for combined treatments in lieu of toxicity and expense. Until such time, efforts to maximize implant quality should assure the treating physician that monotherapy PPB offers acceptable prostate-specific antigen freedom from recurrence (PSA-FFR) and can be safely offered to all patients deemed eligible for PPB. References 1. Partin AW, Kattan MW, Subong EN, et al. Combination of prostatespecific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multiinstitutional update. JAMA 1997; 277(18):1445–1451. 2. Davis BJ, Pisansky TM, Meyers RP, et al. The radial distance of extraprostatic extension of prostate adenocarcinoma: Implications for prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998; 42(suppl 1):132–132. 3. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999; 44(4):789–799. 4. Critz FA, Levinson AK, Williams WH, et al. Simultaneous radiotherapy for prostate cancer: 125I prostate implant followed by external-beam radiation [See comments]. Cancer J Sci Am 1998; 4(6):359–363. 5. Fleming I, Cooper JS, Henson DE, et al. AJCC Cancer staging manual, 5th edn. Philadelphia: Lippincott-Raven, 1997. 6. Beyer D, Nath R, Butler W, et al. American Brachytherapy Society recommendations for clinical implementation of NIST-1999 standards for (103)palladium brachytherapy. Int J Radiat Oncol Biol Phys 2000; 47(2):273–275. 7. Nath R Roberts K, Ng M, et al. Correlation of medical dosimetry quality indicators to the local tumor control in patients with prostate cancer treated with iodine-125 interstitial implants. Med Phys 1998; 25(12):2293–2307. 8. Potters L, Cao Y, Calugaru E, et al. A comprehensive review of CT-based dosimetry parameters and biochemical control in patients treated with permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2001; 50(3):605–614. 9. Consensus statement: guidelines for PSA following radiation therapy. American Society for Therapeutic Radiology and Oncology Consensus Panel. Int J Radiat Oncol Biol Phys 1997; 37(5):1035–1041. 10. Kattan MW, Fearn PA, Leibel S, Potters L. The definition of biochemical failure in patients treated with definitive radiotherapy. Int J Radiat Oncol Biol Phys 2000; 48(5):1469–1474.

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11. Merrick GS, Butler WM. Modified uniform seed loading for prostate brachytherapy: rationale, design, and evaluation. Tech Urol 2000; 6(2):78–84. 12. Zelefsky MJ, Yamada Y, Cohen G, et al. Postimplantation dosimetric analysis of permanent transperineal prostate implantation: improved dose distributions with an intraoperative computer-optimized conformal planning technique. Int J Radiat Oncol Biol Phys 2000; 48(2):601–608. 13. Blasko JC, Grimm PD, Sylvester 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. 14. Ragde H, Korb LJ, Elgamal AA, et al. Modern prostate brachytherapy. Prostate specific antigen results in 219 patients with up to 12 years of observed follow-up. Cancer 2000; 89(1):135–141. 15. Gelblum DY, Potters L. Rectal complications associated with transperineal interstitial brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2000; 48(1):119–124. 16. Zeitlin SI, Sherman J, Raboy A, et al. High dose combination radiotherapy for the treatment of localized prostate cancer [Discussion: 95–96]. J Urol 1998; 160(1):91–95. 17. Brandeis JM, Litwin MS, Burnison CM, Reiter RE. Quality of life outcomes after brachytherapy for early stage prostate cancer. J Urol 2000; 163(3):851–857. 18. Grado GL, Larson TR, Balch CS, et al. Actuarial disease-free survival after prostate cancer brachytherapy using interactive techniques with biplane ultrasound and fluoroscopic guidance. Int J Radiat Oncol Biol Phys 1998; 42(2):289–298. 19. 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. 20. Critz FA, Williams WH, Levinson AK, et al. Simultaneous irradiation for prostate cancer: intermediate results with modern techniques [Discussion: 741–743]. J Urol 2000; 164(3 Pt 1):738–741. 21. Dattoli M, Wallner K, Sorace R, et al. 103Pd brachytherapy and external beam irradiation for clinically localized, high-risk prostatic carcinoma. Int J Radiat Oncol Biol Phys 1996; 35(5):875–879. 22. Zelefsky MJ, Hollister T, Raben A, et al. Five-year biochemical outcome and toxicity with transperineal CT-planned permanent I-125 prostate implantation for patients with localized prostate cancer. Int J Radiat Oncol Biol Phys 2000; 47(5):1261–1266. 23. Lederman GS, Cavanagh W, Albert PS, et al. Retrospective stratification of a consecutive cohort of prostate cancer patients treated with a combined regimen of external-beam radiotherapy and brachytherapy. Int J Radiat Oncol Biol Phys 2001; 49(5):1297–1303. 24. Potters L, Cha C, Ashley R, et al. The role of external beam irradiation in patients undergoing prostate brachytherapy. Urol Oncol 2000; 5:112–117.

39 Simultaneous irradiation for prostate cancer: disease-free survival rates Frank A Critz Introduction Simultaneous irradiation (SI) is defined by the initial performance of a radioactive iodine125 (125I) seed implant, which has a 60 day half-life, followed by external beam irradiation (EBRT). Since the external beam component is given 3 weeks postimplantation, intraprostatic malignant epithelium as well as benign prostate epithelium is irradiated simultaneously by two separate sources, which produces dose intensification. In addition, potential extracapsular disease is also treated by the follow-up external beam irradiation. Thus, integration of both methods of radiation should effectively treat clinically localized prostate cancer. Based on this theory of SI, a formal study of this treatment process began in January 1984 with prostate implantation performed by the obsolete retropubic implant method. In 1992, a transition was begun from the retropubic implant method to the ultrasoundguided transperineal implant approach. This study concerns only men implanted with the transperineal technique as a part of SI and updates a prior report on this subject.1 Materials and methods From August 1992 through to December 2000, 3007 consecutive men with clinical stage T1-T2, Nx, Mo prostate cancer who did not receive neo-adjuvant androgen deprivation (NAAD) were treated with SI employing the ultrasound-guided transperineal implant technique (median 12 000 cGy). The excluded men either received NAAD before consultation or it was initiated at this facility to downsize an enlarged prostate with severe obstructive symptoms. NAAD has not been given with SI to treat prostate cancer. The clinical characteristics of all the men are described in Table 39.1. Gleason score was taken from community pathology reports through 1998 without review. A review of prostate biopsies began in 1999. Staging was performed by the 1992 American Joint Committee on Cancer (AJCC) criteria. External beam irradiation to the prostate seminal vesicles and periprostatic

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Table 39.1 Clinical characteristics of all 3007 men; 14 of these did not have a Gleason score No

%

Pre Treatment PSA groups 0–4 272 9 4.01–10.0 2024 67 10.01–20.00 555 19 >20.00 156 5 Total 3007 100 Gleason score 2–4 168 6 5–6 2059 68 7 650 22 8–40 116 4 Total 2993 100 Stage T1a and T1b 25 1 T1c 1608 53 T2a 768 25 T2b 440 15 T2c 166 6 Total 3007 100 Risk groups Low 1577 52 Intermediate 884 30 High 532 18 Total 2993 100 Min Med Max 0.3 6.7 105.1 PrePSA 36.0 65.0 88.0 Age PSA, prostate-specific antigen.

tissue was begun 3 weeks postimplant at a daily dose of 150 cGy, fives days per week for a total of 4500 cGy. Men with adverse prognostic factors defined as Gleason score ≥7, PSA ≥10.1 ng/mL or prostatic base involvement by either biopsy or palpation received an additional 750 cGy to the seminal vesicles and prostatic base. All men were treated three or more years ago. Followup was performed 3 months postimplant (approximately 2 weeks after all treatment), 3 months later and then every 6 months thereafter. There was no change to annual followup. Median follow-up was 4 years (range: 3 mths–11 yrs). Disease freedom was defined as the achievement and maintenance of a prostate-specific antigen (PSA) 0.2 ng/mL or less, and failure was defined as PSA nadir >0.2 ng/mL or a subsequent PSA rise above this level. For men with less than 5 year follow-up and who had not yet achieved PSA nadir 0.2 ng/mL, disease freedom was defined by a falling PSA. Because of the higher probability of PSA

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bounce during the first 5 years postimplant, men were defined disease-free if they had not yet achieved PSA nadir 0.2 ng/mL but had a single PSA rise at last follow-up. Men were defined as having recurrence if there were two PSA rises. Disease-free survival rates were calculated by the Kaplan-Meier method and comparison of curves by the log rank test. Results PSA nadir and the definition of disease freedom A subset of the database, 1658 men treated five or more years ago (1992–1998), was used to correlate PSA nadir achieved with subsequent disease freedom defined by the American Society of Therapeutic Radiology and Oncology (ASTRO) definition of recurrence (Figure 39.1). Men who achieved PSA nadir ≤0.2 ng/mL had a 98% 10 year diseasefree survival (DFS) rate compared with an 8 year DFS rate of 26% for those men who achieved PSA nadir 0.3–0.5 ng/mL, a highly significant difference (p<0.0001). Men who achieved PSA nadir ≥0.6 ng/mL had an even worse outcome. Disease-free survival rates Figure 39.2 documents the overall 10 year disease-free survival (DFS) rate of 85% for all 3007 men in this study. For the 283 men who recurred, the median time to recurrence was 30 months (range: 3–96 mths). Outcome according to pretreatment PSA is documented in Figure 39.3. There was a highly significant difference between each of the four PSA groups analyzed. Disease freedom according to the Gleason score is documented in Figure 39.4. There was no difference in outcome between men with Gleason score 2–6, but there was a significant difference between men who had Gleason score ≤6 compared to 7, and between men who had Gleason score 7 compared with Gleason score 8–10. Figure 39.5 is an analysis of disease freedom by stage. Men were analyzed according to risk group with risk factors defined as PSA≥10.1 ng/mL, Gleason score ≥7 or stage T2b, T2c (Figure 39.6). Low risk was defined by none, intermediate risk by one, and high risk by two or more of

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Figure 39.1 Disease freedom according to prostate-specific antigen (PSA) nadir achieved for men treated 5 or more years ago with disease freedom defined by the American Society of Therapeutic Radiology and Oncology (ASTRO) definition of recurrence.

Figure 39.2 Overall disease-free survival (DFS) rate for the 3007 men in this study.

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Figure 39.3 Disease-free survival (DFS) rate according to pretreatment PSA group. There was a highly significant difference (p>/=<0.0001) between each of the groups.

Figure 39.4 Disease-free survival (DFS) according to the Gleason score. There was no significant difference between Gleason score 2–4 compared with 5–6, but there was a significant difference between Gleason score ≤6

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compared with 7 (p=0.0001), and between Gleason score 7 compared with 8–10 (p=0.03).

Figure 39.5 Disease-free survival (DFS) according to clinical stage: 25 men with stage T1a–T1b were excluded.

Figure 39.6 Disease-free survival (DFS) according to risk group. There

532

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was a significant difference (p=0.0001) between each of these groups. these factors. There was a highly significant 10 year DFS rate between each of these groups. On multivariate analysis, pretreatment PSA and Gleason score were significantly associated with disease freedom but not stage. Discussion Prior to evaluation of the outcomes of radiotherapy, disease freedom must be defined. Since 1987 when clinical use of the prostate-specific antigen (PSA) test began, a wide variety of definitions of disease freedom after irradiation for prostate cancer has been proposed.2 In an attempt to arrive at a consensus on this issue, the American Society of Therapeutic Radiation Oncology (ASTRO) definition of disease freedom was created in 1997.3 Since then, almost all reports on radiotherapy for prostate cancer have used the ASTRO definition, or some variant to evaluate outcomes of irradiation. However, significant flaws in the ASTRO definition of disease freedom have been described.3–5 Further, the ASTRO definition of recurrence was created for external beam irradiation of prostate cancer and not for brachytherapy. More importantly, studies after both radical prostatectomy and irradiation have documented that calculations with the ASTRO definition produce significantly better disease-free survival (DFS) rates than those calculated with an undetectable PSA.6–8 Thus, comparisons of outcomes between calculations performed with the ASTRO definition and those with an undetectable PSA are inaccurate and misleading. A standard definition of disease freedom from prostate cancer after all treatment methods is needed. In the first research paper published on SI from this program using men implanted by the obsolete retropubic technique, the PSA nadir achieved correlated with disease freedom.9 In a later report, a PSA cutoff point of 0.5 ng/mL was recommended as the definition of disease freedom for irradiation of prostate cancer.10 With better PSA assays and evaluation only of men treated with SI using the modern transperineal implant technique, a PSA cutoff point of 0.2 ng/mL was recommended as the definition of disease freedom for irradiation of prostate cancer.8 Figure 39.1 updates the association of PSA nadir and disease freedom. This evidence-based definition coincidentally is the identical definition determined by Freedland et al who correlated various PSA nadir levels with outcome after radical prostatectomy.11 Consequently, a PSA cutoff point of 0.2 ng/mL has been recommended as the standard definition of disease freedom from prostate cancer after both surgery and irradiation and is used to evaluate the results of SI in this report. The overall 10 year disease-free survival rate of men treated with SI using the modern transperineal ultrasound-guided implant technique is 85% (Figure 39.2). Subset analysis according to pretreatment PSA demonstrates a significant difference between each of the four standard PSA groups (Figure 39.3). Analysis according to the Gleason score and clinical stage is also documented (Figures 39.4 and 39.5) and according to risk group in Figure 39.6. The lower than usual percent of men with a Gleason score 7–10 in this report (Table 39.1) maybe related to a lack of biopsy review.12 A substantial number of men with Gleason score ≥7 may have been misclassified as Gleason score ≤6. This may have

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an adverse effect on evaluation of men with lower Gleason scores and low risk group (Figures 39.4 and 39.6). On multivariate analysis, both the pretreatment PSA and Gleason score are significantly related to disease freedom. These outcomes compare favorably with results reported from radical prostatectomy for prostate cancer performed in the PSA era. The 10 year disease free survival rate from Johns Hopkins with radical prostatectomy, calculated with a PSA cutoff point of 0.2 ng/mL, is 80% which is approximately the same result achieved by simultaneous irradiation (SI) (Figure 39.2). Additionally, the results of this report support the principles of dose intensification for intraprostatic disease and treatment of potential extraprostatic cancer by follow-up external beam irradiation. Furthermore, the same definition of disease freedom, PSA cutoff point of 0.2 ng/mL, for both SI and radical prostatectomy suggests destruction of not only all malignant but also all benign prostate epithelium by SI which could prevent the theoretical development of a second new prostate cancer in the future. Conclusions Simultaneous irradiation is a treatment process that logically integrates a radioactive 125I prostate implant with subsequent external beam irradiation. The theory of SI is supported by the overall 10 year disease-free survival rate of 85% calculated with an undetectable prostate-specific antigen. References 1. Critz FA, Williams WH, Levinson AK, et al. Simultaneous irradiation for prostate cancer: Intermediate results with modern techniques. J Urol 2000; 164:738–743. 2. Vicini FA, Kestin LL, Martinez AA. The correlation of serial prostate specific antigen measurements with clinical outcome after external beam radiation therapy of patients for prostate carcinoma. Cancer 2000; 88:2305–2318. 3. American Society For Therapeutic Radiology and Oncology Consensus Panel: Consensus Statement. Guidelines for PSA Following Radiation Therapy. Int J Radiat Oncol Biol Phys 1997; 37:1035–1041. 4. Horwitz EM, Uzzo RG, Hanlon AL, et al. Modifying the American Society for Therapeutic Radiology and Oncology definition of bio-chemical failure to minimize the influence of backdating in patients with prostate cancer treated with 3-dimensional conformal radiation therapy alone. J Urol, 2003; 169:2153–2159. 5. Pickles T, Kim-Sing C, Morris WJ, et al. Evaluation of the Houston biochemical relapse definition in men treated with prolonged neoadjuvant and adjuvant androgen ablation and assessment of follow-up lead-time Bias. Int J Rad Oncol Biol Phys 2003; 57:11–18. 6. Gretzer MB, Trock BJ, Han M, Walsh PC. A critical analysis of the interpretation of biochemical failure in surgically treated patients using the American Society for Therapeutic Radiation and Oncology criteria. J Urol 2002; 168:1419–1422. 7. Amling CL, Bergstralh EJ, Blute ML, et al. Defining prostate specific antigen progression after radical prostatectomy: What is the most appropriate cut point? J Urol 2001; 165:1146–1151.

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8. Critz FA. A standard definition of disease freedom is needed for prostate cancer: Undetectable prostate specific antigen compared with the American Society of Therapeutic Radiology and Oncology consensus definition. J Urol 2002; 167:1310–1313. 9. Critz FA, Tarlton RS, Holladay DA. Prostate specific antigen-monitored combination radiotherapy for patients with prostate cancer. Cancer 1995; 75:2383–2391. 10. Critz FA, Levinson AK, Williams WH, et al. Prostate-specific antigen nadir: The optimum level after irradiation for prostate cancer. J Clin One 1996; 14:2893–2900. 11. Freedland SJ, Sutter ME, Dorey F, Aronson WJ. Defining the Ideal cutpoint for determining PSA recurrence after radical prostatectomy. Urology 2003; 61:365–369. 12. Steinberg DM, Sauvageot J, Piantadosi S, Epstein JI. Correlation of prostate needle biopsy and radical prostatectomy Gleason grade in academic and community settings. Am J Surg Pathol 1997; 21:566–576. 13. Han M, Partin AW, Piantasodi S, et al. Era specific biochemical recurrence-free survival following radical prostatectomy for clinically localized prostate cancer. J Urol 2001; 166:416– 419.

Part VI Permanent radioactive seeds: issues and features

40 Radioactive sources for insterstitial brachytherapy Manny R Subramanian, Krishnan Suthanthiran, and Anatoly Dritschilo Introduction Brachytherapy is an established modality for treating cancer of the head and neck, breast, cervix, prostate, and soft tissue sarcomas.1,2 Although technically demanding, brachytherapy techniques offer substantial advantages in dose distributions by providing a conformal geometry to tumor volumes of interest. Recent interest in brachytherapy has been enhanced by applications to prostate cancer treatment and partial breast irradiation. Both permanent and temporary high dose rate (HDR) interstitial brachytherapy treatments are currently employed in the treatment of malignant and non-malignant diseases. Brachytherapy involves the placement of radioactive elements within or near the target tissue. The first use of brachytherapy was for the treatment of lupus,3 shortly after the discovery of radioactivity and the isolation of radium.4 Radium applications proved to be useful in the treatment of a variety of tumors and non-cancerous pathologies and led to the development and improvement of brachytherapy technology to its present form. Both temporary and permanent HDR interstitial brachytherapy treatments are currently used in the treatment of malignant and non-malignant diseases. (The treatment of cancer or other tissue pathologies by placement of radioactive elements within or near the target tissue is termed brachytherapy.) This form of radiation therapy was attempted soon after Becquerel discovered radioactivity (1896) and Curie isolated radium from pitchblend (1898).1 The first disease treated with brachytherapy was lupus.1 Following this there were an increasing number of reports outlining successful application of brachytherapy to a variety of forms of cancer.2,3 Since then a variety of tumors and some normal tissue pathologies have been successfully treated with brachytherapy.4 A normal tissue pathology is that which is successfully treated with brachytherapy as a consequence of atherosclerosis, namely vascular restenosis. Brachytherapy has been prescribed since the early 1900s. For example, Henchke et al reported the successful use of iridium-192 (192Ir) and iodine-125 (125I) sources for the treatment of prostate cancer.5,6 Recent developments and techniques developed by Blasko et al7 have resulted in the accurate placement of seeds in the prostate based on preplanned dosimetry and transrectal ultrasonography.7,8 Several groups have reported encouraging long term survival and biochemical outcomes comparable to radical prostatectomy.9 Studies are currently underway employing factors, such as quality of life, cost of

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procedure, and biochemical/survival outcome comparing different treatment modalities.10 In this chapter we will briefly look at different radioisotope-based devices that are available for brachytherapy applications. Iridium-192 An iridium-192 source has been available for brachytherapy applications since the early 1970s. A diagram of the Best® iridium-192 source is shown in Figure 40.1. Iridium192 has an energy of 375 keV and a half-life of 74 days. The commonly used isotopes in temporary interstitial brachytherapy are: iridium-192, aurum (gold)-198, iodine-125, and cesium-137. The energy of photons from 125I (average) is 28 keV and the energy from 192 Ir photons (average) is 375 keV.11 Isotopes, such as 125I and 103Pd, are used in permanent interstitial brachytherapy applications.12 In addition to 192Ir, a few other isotopes are also used for high and low dose rate brachytherapy applications, as shown in Table 40.1. Iridium-192 is normally provided in ribbons or as a platinum (Pt)-clad wire. The seeds are about 3 mm long and 0.5 mm in diameter. There are two types of 192Ir configurations currently available. One contains a 0.2 mm thick stainless steel wall and has a 0.1 mm diameter core of 30% Ir-70% Pt. The other design has a 0.3 mm diameter core of 10% Ir90% Pt clad in a 0.1 mm thick Pt wall.13 Best® 192Ir seeds are of the former type, and a schematic diagram of the Best® seed is shown in Figure 40. 1b. Strands or ribbons can be ordered from Best Medical (Springfield, VA) at a standard spacing of 1 cm. Customized spacings are also available. Medium-to-high activity 192Ir ribbons

Figure 40.1 Diagram of the Best® iridium-192 source, (a) 192lr seeds in nylon ribbon, (b) 125Ir seed dimensions.

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Table 40.1 Common isotopes used in brachytherapy Isotope 192

Ir

Energy 375 keV

Half-life

Applications

74.2 days

Oncology Cardiology 198 Au 420 keV 2.7 days Oncology 125 I 28 keV 59.6 days Oncology 103 Pd 21 keV 17 days Oncology Cardiology 32 p 690 keV 14 days Cardiology 90 Sr/90Y 970 keV 28 yrs Cardiology 137 Cs 662 keV 30 yrs Oncology 32 P, phosphous-32, 90Sr, strontium-90; 90Y, yttrmm-90;137Cs, cesium137.

(1–5 Ci) are used in intravascular applications using a manual afterloading device. A diagram of the manual afterloading device used in low dose rate (LDR) oncology applications, developed by Best Medical, is shown in Figure 40.2.14 Despite moderately good clinical outcomes using 192Ir seeds in a LDR form, it soon became apparent that the radiation exposure to hospital staff and others, along with the need for the patient to remain in hospital for 2–3 days, necessitated the development of high dose rate (HDR) devices.15 High dose rate iridium-192 devices Whereas in LDR, radioactive seeds are placed in ribbons with appropriate openings tailored to the preplanned dose estimates, in HDR, a single source with an activity of approximately 10 Ci is placed in a predetermined site for a period of time determined by the desired dose. Several manufacturers (Nucletron, Varian, Best), have developed radioactive source delivery systems for placement at the disease site. The HDR systems developed by Nucletron and Varian are used in the treatment of oncologic diseases, and use an automated delivery device. The manual device (Figure 40.2) has been used for the delivery of intermediate-to-high doses for non-malignant diseases, such as cardiovascular abnormalities and other oncology applications. Detailed descriptions of automated HDR 192 Ir devices have been provided in the literature.16 lodine-125 Laurence Soft X-Ray Corporation introduced 125I seeds in the 1970s, with initial clinical studies performed at the Memorial Sloan-Kettering Cancer Centre in New York. Over the last 30 years, radioactive seeds have been used in the treatment of localized cancers, such as prostate cancer.17 Currently, there are over 10 manufacturers supplying 125I sources for the brachytherapy community. Figure 40.3a shows the Best® Model 2301 125I source as a typical

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Figure 40.2 The 192Ir manual afterloading device. example.18 Other sources available include those from Amersham, Oncura, Bard, Mentor, NASI, IsoAid, etc. The sources currently available are described by Heintz et al,19 and in the American Association of Physicists in Medicine (AAPM)/Radiobiological Physics Center’s file.20 Detailed descriptions of these sources are beyond the scope of this review; however, most of the sources contain a portion consisting of a radiographic marker and a portion containing 125I. The configuration is encapsulated in a metal cylinder of a similar device to the seeded source. Iodine-125 seeds are mainly used in the treatment of localized prostate cancer. High activity seeds (>1 mCi/seed) are used in the treatment of ocular cancer, cancer of sarcomas, etc., in temporary implants. Palladium-103 Palladium-103 sources have been available since the 1970s. Henschke was one of the earliest researchers to suggest that 103Pd could be suitable for use in brachytherapy applications. There are at least three different 103Pd seeds that are currently available on the market. These include the seeds manufactured by Best, NASI, and Theragenics. Although radiobiologically it has been shown in vitro that 103Pd may be a better isotope than 125I for the treatment of prostate cancer, no conclusive multicenter clinical data are available to date.21 It has been suggested that some of the side effects, such as rectal bleeding and incontinence, disappear much

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Figure 40.3 (a) The double wall Best® Model 2301 iodine-125 source. (b) The double wall Best® Model 2335 palladium-103 source. earlier in patients treated with 103Pd than those treated with 125I seeds. A preliminary report comparing 125I versus 103Pd in a clinical trial set-up was recently published by Wallner et al.22 The purpose of this study was to test the hypothesis that the shorter halflife of 103Pd versus 125I results in a shorter duration of radiation-related symptoms after prostate brachytherapy. Delivery systems for prostate brachytherapy Iodine and palladium seeds are available loose, loaded in Mick™ cartridges, in needles, and in tissue-absorbable strands. Both 125I and 103Pd seeds can be delivered using prostate implant needles (a needle and stylet) with the help of tissue-absorbable spacers for creating appropriate spacing between the seeds. Also, one could use Mick disposable or reusable cartridges loaded with radioactive seeds, and implant the seeds using a Mick applicator.11 Needles and other accessories are available from several manufacturers for these procedures. Seeds loaded in tissue-absorbable materials with appropriate spacing have recently become available in a presterilized format. These convenient seed-containing strands are user-friendly and can be used in the operating room without any additional work-up. Seed

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migration, suggested as a potential problem with loose seeds, would also be avoided by using strands.23,24 Best® iodine-125 seed (model 2301) The Best® seed (model 2301) consists of a tungsten rod with absorbed 125I encapsulated in double-walled titanium. The source is laser-welded at one end. Laser welding leads to seeds that are precise in diameter and length. Furthermore, Best® seeds are doublewalled, and are therefore mechanically strong. The source contains a tungsten marker that almost covers the entire length of the seed, leading to superior image characteristics. Iodine is adsorbed uniformly onto tungsten rods, including the ends. Hence, the Best® seed is one of the most isotropic of all the 125I sources currently available.19 (See Figure 40.3.) Dosimetry In accordance with American Association of Physicists in Medicine (AAPM), Task Group 43 (TG-43)27 requirements, the dosimetry factors for Best® iodine-125 seeds were measured independently by two separate groups: Ali Meigooni at the University of Kentucky and Ravinder Nath at Yale University. The radial dose functions measured using micro lithium fluoride thermoluminescence dosimeters are provided in Table 40.2. For detailed descriptions of dosimetric parameters see Nath and Yue,27 and Meigooni et al.28 Dosimetry measurements Doses of radioactive seeds are normally measured using lithium fluoride thermoluminescent dosimeters (TLD). These TLDs are placed in shallow holes machined in a solid water phantom material (Radiation Measurements, Middletown, WI). TLD chips of varying dimensions are commercially available (Hershaw, Solon, OH). The polymer material used in the construction of the phantom material has been shown to have some effect on the experimental values.25 D90 is defined as the dose delivered to 90% of prostate volume. Stock et al have shown that a biochemical cure rate corresponds to the dose delivered (100–160 Gy).9 Hence, TG-43 recommends the measurement of the dosimetry parameters using certain established procedures. The dose distribution around a sealed source is determined using the formalism according to TG-43:

Table 40.2 Radial dose function values for Best® iodine 125 seeds Radial distance (cm) Nath27 (in Water) Meigooni28 (in Solid Water) 0.5 1.0 1.5 2.0

1.046 1.000 0.938 0.876

1.048 1.000 0.899 0.824

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2.5 0.773 – 3.0 0.693 0.683 3.5 0.596 – 4.0 0.528 0.522 4.5 0.458 – 5.0 0.406 0.358 5.5 0.371 – 6.0 0.331 0.287 6.5 0.286 – 7.0 0.240 0.208 8.0 – 0.159 9.0 – 0.115 10.0 – 0.083 Dashes indicate that radial dose function values have not been made.

(1) where SK is the air-kerma strength of the source, Λ is the dose rate constant, G(r, θ) is the geometry factor, g(r) is the radial dose function, F(r, θ) is the anisotropy function, and r0=1 cm. The dose rate constant is defined as the dose rate per unit air-kerma strength, and is provided in units of (Gy h−1 U−1) (U=unit of the air-kerma strength of the source). The other two parameters that are required for treatment-planning purposes are radial dose function, g(r) and anisotropy function, F(r, θ). Radial dose function represents the tissue attenuation of photons from the radioactive seeds. The formula for radial dose function is: (2) Further details about this function can be found in the literature.19,28 In Eq (2), the two D values are the dose rate constants measured at distances r and r0. r0, the reference distance is normally 1 cm. G(r, θ), the geometric factors, describes the effect of the distribution of radioactive material inside the source. Anisotropy function Anisotropy function F(r, θ) represents the variation of dose rate around the source at each distance. According to TG-43 formalism, the anisotropy function is: (3) Meigooni et al also recently published the Monte Carlo calculations for Best® 125I seeds.29 Recently, the AAPM sub-committee on Low Energy Interstitial Brachytherapy Dosimetry assembled the revised dosimetric data, based on TG-43 prerequisites, useful for medical physicists while planning for brachytherapy procedures. These data take into consideration all the available experimental information, theoretical calculations, etc. The

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revised recommendation from the subcommittee is that the dose calculation does not require the use of an anisotropy constant.30 The measured anisotropy factors and estimated anisotropy constant for Best® 125I seeds are provided in Table 40.3. The values reported by Nath and Yue and Meigooni et al are within experimental margin of error.27,28 The dose rate constants for Best® seeds were determined experimentally and theoretically by Nath and Yue,27 and Meigooni et al28 in independent measurements. These values are provided in Table 40.4 and correspond to the National Institute of Standards and Technology (NIST-1999) SK standard, revised in 2000. For values to be used in clinical studies, medical physicists and oncologists are urged to make informed decisions based on published data.30

Table 40.3 Anisotropy factors for Best® iodine-125 seeds Radial distance

Anisotropy factor Nath and Yue28 Meigoni et al29

2 cm 0.96 4 cm 0.94 5 cm – 6 cm 0.96 7 cm – Anisotropy constant 0.96

0.99 – 0.99 – 0.97 0.98

Table 40.4 Dose rate constants for Best® iodine125 seeds Dose rate constant (cGy h−1 U−1) 28

Meigooni et al 1.03 Nath and Yue27 1.02 1.01 Monte Carlo studies29 Note: values correspond to NIST 1999 SK standard, revised in 2000,

Table 40.5 Dosimetry parameters for Best® palladium-103 seeds Dose rate constant (cGy h−1 U−1)

Anisotropy constant*

24

Peterson and Thotmdsen Meigooni et al32

0.71 (TLD) 0.94 0.69 (TLD) 0.89 0.67 (MC) 0.88 * Simple average method TLD, thermoluminescent dosimeters; MC, Monte Carlo method. Experimental values obtained using TLD measurements.

Recently, Heintz et al compared different 125I sources used for permanent interstitial implants.20 The radial dose function values for Best® model 2301 substantially match Amersham’s 6711 sources. Furthermore, model 2301, Best® 125I seeds, emit pure 125I spectrum. Some of the other 123I seeds emit silver x-rays, thereby lowering the average energy.

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Best® palladium-103 seed (model 2335) The dimensions, double wall encapsulation, and other exterior aspects of Best® 103Pd seeds are similar to those of Best® 125I seeds described above (see Figure 40.3). The interior of the Best® 103Pd seed model 2335 consists of six polymer resin beads coated with 103Pd separated by a rectangular tungsten marker in the middle. The dosimetric parameters for the Best® 103Pd source were obtained by two independent groups of investigators, Peterson and Thomadsen (University of Wisconsin) and Meigooni et al (University of Kentucky).25,31 The Monte Carlo calculations were carried out by Meigooni et al. Some of the Peterson and Meigooni data are provided in Table 40.5. Conclusions The future of high and low dose rate brachytherapy looks promising. Accurate determination of disease sites using sophisticated imaging modalities, such as magnetic resonance imaging (MRI), positron emission tomography (PET) and PET/CT, real-time planning in the operating room employing optimized dosimetry, dose-sparing to critical organs using unique signal emitting devices, and combinations of brachytherapy with new treatment modalities,32,33 are some of the noval approaches that are currently under investigation. References 1. Hilaris BS, Mastoras DA, Shih LL, Bodner WR. History of brachytherapy. In: Nag S, ed. Principles and practice of brachytherapy. Armonk, NY: Futura Publishing, 1997:13. 2. Goldberg SW, London FS. Frage der Bezichungen Zaischen Bequerelstrahlen Hantuffectionen. Dermatologische Zeitschrift 1906; 10:457. 3. Abbe R. Radium in surgery. Journal of the American Medical Association 1906; 47:183. 4. American Heart Association. 2002 heart and stroke statistical uptake. Dallas, TX: American Heart Association, 2003. 5. Henschke UK, Hilaris BS, Mahan GD. Afterloading in interstitial and intracavitary radiation therapy. Am J Roentgenol 1963; 90:386–395. 6. Henschke UK. The treatment of cancer with small sources of radioactive iridium. In: Pack GT, Ariel IM, eds. Treatment of cancer and allied diseases, Vol I, 2nd edn. New York: Paul B Hoeber, Harper Books, 1958:431. 7. Blasko JC, Ragde H, Schumacher D. Transperineal percutaneous iodine-125 implantation for prostate carcinoma using transrectal ultrasound and template guidance. Endocurie/Hypertherm Oncol 1987; 3:131–139. 8. Grimm PD, Blasko JC, Ragde H. Ultrasound-guided transperineal implantation of iodine-125 and palladium-103 for the treatment of early-stage prostate cancer. Urol Clin North Am 1994; 2:113–116. 9. Merrick GS, Wallner KE, Butler WM. Permanent interstitial brachytherapy for the management of carcinoma of the prostate gland. J Urol 2003; 169:1643–1652. 10. Merrick GS, Butler WM, Lief JH, Dorsey AJ. Temporal resolution of urinary morbidity following prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 47:121. 11. Anderson LL, Nath R, Weaver KA, et al. Interstitial brachytherapy: Physical, biological and clinical considerations. New York: Raven, 1990:3–13.

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12. For further information, visit: http://isotopes.lbl.gov 13. Boutroux-Jaffré E In: Pierquin B, Marinello A, eds. A practical manual of brachytherapy. Madison, WI: Medical Physics Publishing, 1997:3. 14. Amols HI. In Intravascular brachytherapy. Wisconsin, WI: Medical Physics Publishing, 2002:289. 15. Kuske RR Jr. Breast brachytherapy. Brachytherapy 1999; 13(3):543–558. 16. AAPM Report No. 41. Remote afterloading technology. New York: American Institute Physics, 1993. 17. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1994; 44:789–799. 18. Nath R, Melillo A. Dosimetric characteristics of a double wall 125I source for interstitial brachytherapy. Med Phys 1998; 20:1475–1483. 19. Heinz BH, Wallace RE, Havezi JM. Comparison of I-125 sources used for permanent interstitial implants. Med Phys 2001; 28:671–682. 20. AAPM/Radiobiological Physics Center at: http://rpc.mdanderson. org and http://www.aapm.org 21. Ling CC. Permanent implants using Au-198, Pd-103, and I-125: Radiobiological considerations based on the linear quadratic model. Int J Radiat Oncol Biol Phys 1992; 23:81–87. 22. Wallner K, Merrick G, Cavanaugh W, et al. Cancer J 2002; 8:67–73. 23. Anderson LL, Nath R, Weaver KA, et al. Interstitial brachytherapy: Physical, biological and clinical considerations. New York: Raven, 1990:65–71. 24. Tapen EM, Blasko JC, Grimm PD, et al. Reduction of radioactive seed embolization to the lung following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998; 42:1063–1067. 25. Peterson SW, Thomadsen B. Measurements of the dosimetric constants for a new 103Pd brachytherapy source. Brachytherapy 2002; 1:110–119. 26. Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial brachytherapy sources: recommendations of the AAPM Radiation Therapy Committee Task Group 43. Med Phys 1995; 22:209–234. 27. Nath R, Yue N. Dosimetric characterization of an encapsulated interstitial brachytherapy source of 125I on a tungsten substrate. Brachytherapy 2002; 1:102–109. 28. Meigooni AS, Gearheart DM, Sowards K. Experimental determination of dosimetric characteristics of best 125I brachytherapy source. Med Phys 2000; 27:2168–2173. 29. Sowards KT, Meigooni AS. A Monte Carlo evaluation of the dosimetric characteristics of the Best Model 2301 125I brachytherapy source. Appl Radiat Isot 2002; 57:327–333. 30. Rivard MJ, Coursey BM, DeWerd LA, et al. Update of AAPM Task Group 43 Report: A revised AAPM protocol for brachytherapy dose calculations. Med Phys (in press). 31. Meigooni AS, Bharucha Z, Yoe-Sein M, Sowards SK. Dosimetric characteristics of the best double-wall 103 Pd brachytherapy source. Med Phys 2001; 28(12):2568–2575. 32. Ellis RJ, Sodee DB, Spirnak JP, et al. Feasibility and acute toxicities of radioimmuno-guided prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 48:683–687. 33. Jung M, Zhangy Y, Dimtchev A, et al. Interstitial gene delivery in human xenograph prostate tumors using titanium metal seeds, (submitted).

41 RADIOCOIL: a coiled wire brachytherapy source Piran Sioshansi Introduction Brachytherapy by seed implantation for the treatment of prostate cancer has been demonstrated to be a clinical success with long term follow-up data showing results similar to radical prostatectomy with minimal morbidity and lower rates of debilitating side effects of incontinence and impotence.1–2 Despite this success story, there are opportunities for improvement in current generation seeds that can and should be addressed. RADIOCOIL source is a second generation linear brachytherapy source designed with the motivation of addressing some of the imperfections and shortcomings in using seeds for brachytherapy with an eye on improving patient outcomes. Among the features of the RADIOCOIL linear source are: more homogeneous dose distribution, stability in tissue, the ability to place the source with extracapsular extension, elimination of source migration, visibility under ultrasound, and a smaller profile source. The smaller profile in turn, allows the use of smaller-gauge, sharper needles for source deployment, thus reducing edema and trauma to the patient. In addition to the enhancement in the source performance, the RADIOCOIL source is easier to produce, as it is manufactured by an automated batch process, minimizing the requirement for 100% inspection and assaying of the source. Manufacturing method of a typical palladium-103 seed The traditional method of making a 103Pd seed relies on bombarding a rhodium foil target with an internal beam in a high current cyclotron. During the course of irradiation, which typically takes a week or longer, a small fraction of the monoisotopic nuclei of rhodium103 (103Rh) are transmuted into 103Pd by a (p,n) reaction whereby a proton is absorbed in the nucleus of 103Rh and a neutron is emitted. The one week around the clock bombardment yields 103Pd with an abundance of less than 0.1% in the rhodium matrix. The 103Pd produced in this way is separated from rhodium by a chemical process. The purified 103Pd is then enriched and, typically, plated on to radiopaque cylinders. The radiopaque cylinder is placed inside a titanium shell, and the shell is laser-welded shut to construct a sealed source. The seeds produced by this method require extensive quality control and are 100% tested for sealed-source performance. They are individually assayed for determining the apparent activity. Figure 41.1 shows schematically the steps

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involved in manufacturing and testing a seed. The result of this design is a rigid cylindrical seed measuring 0.81 mm diameter and 4.5 mm in length. Sometimes, representative seeds are inserted in a phantom for dosimetry. The radial dose function and the directional activity of the seed is measured to establish the

Figure 41.1 Traditional manufacturing steps for 103Pd seeds. difference between the cylindrical geometry of the seed from a point source isotropic model that the seed is designed to emulate. It is not surprising that the anisotropy function of the seed may indicate variations on the order of 50%, as very little activity is emitted from the two ends of a cylindrical seed as compared to the mid-plane of the seed. Manufacturing method of the RADIOMED source The manufacturing of the RADIOMED source is based on direct bombardment of an extended length (typically more than a kilometer) of a fine rhodium wire wrapped on a drum by an external beam of a one-of-a-kind, high intensity, self-extracting cyclotron. The beam is raster scanned on the rotating drum, creating a highly uniform activation field. The rhodium wire activated by this method, after a typical one week of bombardment by the proton beam, contains in order of 100 parts per million 103Pd in a rhodium matrix and, thus, is classified inherently as a sealed source. The activated wire produced by this process is then coiled to a dimension of 0.35 mm and is laser cut to integer lengths from 1 to 6 centimeters. As described, the manufacturing process has very few steps and easily lends itself to automation and remote monitoring. By virtue of increased monitoring and built-in quality assurance (QA), the need for assaying and quality control (QC) of the product is sharply reduced. Figure 41.2 shows schemat-

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Figure 41.2 Manufacturing steps for the RADIOMED source. ically the few steps involved in manufacturing the RADIOCOIL source. The RADIOMED design The diameter of the coil in this design is a compromise between a desire to keep the source dimension as small as possible for flexibility and compliance with tissue, yet give it a dimension so that the source is visible to the naked eye and some mechanical integrity so that the source is easily handled. The 0.35 mm of the coiled wire design is such that, if the source is dropped, it can be found and, when found, it can be lifted with a soft-tipped tweezer. Source is with this dimension are inherently radiopaque and are visible under fluoroscopy, diagnostic X-ray, computed tomography (CT), and magnetic resonance imaging (MRI) scans. The coiled design and the extended nature of the source, serendipitously, contribute to the very important feature of making it highly echogenic, as every turn of the coil reflects the waves and is therefore visible under ultrasound. The ultrasound visibility of the source is an enabling feature of the RADIOCOIL source, as it allows the physician to see the source as it is being released in the presence of neighboring sources. This characteristic of the RADIOCOIL source allows the physician to correct any ‘cold’ spots or deficiencies in the source resting position compared to the treatment plan while the patient is being intraoperatively monitored by transrectal ultrasound (TRUS). Thus, in principle, the RADIOCOIL source allows the physician to perform, via ultrasound, a postoperative treatment verification in the same session during which the source is being implanted. In addition, this avoids the need for an additional visit to the hospital for a CT scan to complete postoperative verification. Efforts are under way to complete the ultrasound posttreatment planning of the source so that, before the patient is released from the operating room (OR), the physician/physicist team can

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evaluate the adequacy of the dose distribution and correct any cold spots or deficiencies in the plan and augment any deficiency in the plan. The coiled design, flexibility, and extended nature of the source make it conformal to the organ in which it is implanted, stable in tissue, and non-migrating. The source flexibility is shown in Figure 41.3. Repeated evaluation of the source in a canine prostate model has shown that the source is stable from the time of release, when placed intracapsular with or without an extracapsular extension. Radiographic examination of the source has shown that the source is stable in the prostate from the time of release. Furthermore, the examination of the source, after sacrificing the animals, has shown that tissue integrates into the coil and the source cannot be separated from the tissue in which it is embedded.

Figure 41.3 Flexible coiled wire RADIOMED source. RADIOCOIL source specification The RADIOCOIL source is a flexible helical coiled wire that is inherently a sealed source. It is made from a 0.05 mm× 0.200 mm cross-section ribbon coiled to an outer dimension of 0.35 mm. RADIOCOIL is initially supplied in integer lengths from 1 cm to 6 cm. (The intention is to supply the source, in the future, in a continuous length, allowing the physician/ dosimetrist to cut it to proper non-integer lengths in the OR.) The source activity range is 1–2.1 mCi/cm with uniformity of 3% over the length of the source (as measured by a detector placed at the distance of 10 mm from the axis of the source). The source specification is outlined in Table 41.1. The source calibration is traceable to National Institute of Standards and Technology (NIST) standards. NIST calibrated sources have been sent to ADCLs (accredited dosimetry calibration laboratories) for cross-calibration of their well chambers. Hospitals can, in turn, use the ADCLs for making their measurement traceable to NIST standards. Figure 41.4a shows the appearance of the RADIOCOIL source under 40×magnification and Figure 41.4b is a schematic drawing of the source. The source design lends itself to either a preloaded needle brachytherapy procedure or intraoperative loading technique. Thus, the RADIOCOIL source can accommodate the physician’s preference to work with a preplan design based on preoperative ultrasound determination of

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Table 41.1 The RADIOMED source specification Source diameter 0.35 mm Source lengths Integer lengths (1–6 cm) provided in color-coded cartridges Source activity 1.0–2.1 mCi/cm of coil Activity uniformity ±3% over the length of the source* * As measured by a detector placed 10 mm away from the axis of the the source.

the prostate volume, as measured during an earlier office visit, or an intraoperative approach to choose an appropriate length of the source to match the actual size of the prostate presented in the OR. The source is supplied in a sterile pouch ready for use. The source kit for performing a complete brachytherapy procedure comes with three 1 cm representative coils included in each pack for on-site source activity measurement, if necessary. Features and clinical benefits of the RADIOMED source The RADIOCOIL source has a number of enabling features and enhancement over traditional brachytherapy seeds. These features and the clinical advantages they provide are summarized in Table 41.2. Dosimetry The formal dosimetry for the RADIOMED source, based on the recommendation of the American Association of Physicists in Medicine (AAPM) Task Group (TG-43),3 was performed by Dr A.S.Meigooni and his team at the University of Kentucky. The dosimetry study, which includes measurements in solid water as well as Monte Carlo simulation and in both solid and liquid water, has been submitted for publication in Medical Physics.4 In addition to establishing a dose rate constant Λ of 0.64 cGy h−1 U−1 for a 0.5 cm active length (0.56 cGy h−1U−1 for a 0.1 cm active length), the highlights of the dosimetry study include the radial dose and anisotropy functions for 0.5, 1.0 cm coils and Monte Carlo simulation for all other lengths. Figures 41.5 and 41.6 show the radial dose function g(r) and anisotropy function f(θ) measured at a 2 cm distance from the source center for a 0.5 cm coil, respectively, and compare the results with a Monte Carlo simulation and, also, a commercially available Pd seed. It is important to point out that anisotropy function is not an appropriate description for the RADIOCOIL

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Figure 41.4 (a) Magnified view of the RADIOCOIL source, (b) Diagram of the source. Table 41.2 Features and clinical benefits of the RADIOMED Feature

Clinical benefits

Uniform distributed activity Coil echogenic design

Homogeneous dose distribution

Visible under ultrasound Controllable source release, easy postimplant dosimetry Natural stranded design Can be placed extracapsular Coil flexible design Stable in tissue and nonmigratory Inherently radiopaque Visible under fluoro, x-ray, CT, and MRI Small diameter Can be inserted by smaller diameter needles—less trauma CT, computed tomography; MRI, magnectic resonance imaging,

source. This term is a carryover from describing the variation of a radiation emission from a cylindrical seed with the isotropic emission of an ideal point source that the seed is designed to emulate. For the RADIOCOIL line source, there is a need for the AAPM to assign a new Task Group and establish new nomenclature appropriate for a line source. In a more practical consideration, the dose from a uniform linear source is represented by combining 1/r dependence, where r is distance of the tissue from the source axis, and attenuation in the intervening soft tissue. In contrast, the dose from a column of (n) seeds and spacers is represented by a combination:

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Figure 41.5 Comparison of Model 200 radial dose data with measured and Monte Carlo values obtained for 0.5 cm active length source model. where ri is the distance of tissue from source i and the attenuation of radiation in intervening distance in soft tissue from each source. The emulation algorithm to compare the linear source against a seed-spacer column is easy to set up and is remarkably accurate. Figure 41.7a shows a comparison of a 5 cm RADIOCOIL source and Figure 41.7b an equally spaced 5 seed-spacer column. The isodose lines for the two figures show that at distances larger than 5 mm from the source axis, the dose is identical and the tissue is incapable of distinguishing between an ideal (fixed spacing and isotropic point source emission) from a 5 seed-spacer column and a 5 cm equivalent RADIOCOIL source. At distances closer than 5 mm to the source axis, the RADIOCOIL source, as anticipated from a linear source, delivers a homogeneous dose as

Figure 41.6 Comparison of anisotropy function values for 0.5 cm source at 2 cm radial distance.

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compared to the heterogeneous dose characteristic of isolated point sources. Furthermore, for the equivalent volume receiving a 100%, V100, prescribed dose, the volume exposed to 150%, V150, of the prescribed dose is larger for the 5 seed-spacer column. In addition, the contact dose to the tissue abutting the RADIOCOIL source is lower when compared to an isolated seed. These attributes of the RADIOCOIL source may reduce the excessive dose delivered to the urethra, nerve bundles, or the rectum if, unintentionally, a source is placed at close proximity to these radiosensitive structures. Thus, the RADIOCOIL source may ameliorate toxicity to neighboring structures and reduce the undesirable radiation damage-related side effects, of brachytherapy—the primary complication of the procedure. Delivery system The small diameter of the RADIOMED source (0.35 mm) makes it suitable for use with a 22-gauge needle. However, the 22-gauge needle does not have the required rigidity for use in prostate applications. The 17- or 18-gauge needles currently used for brachytherapy (standard seeds are 0.81 mm diameter) are clearly oversized for the fine diameter RADIOCOIL source. To reach a compromise between smaller gauge, sharper needles and large-bore, rigid needles, a special 19-gauge (outer diameter 1.08 mm) thick wall needle has been designed. The thick wall of the needle allows for the design of a multifaceted needle tip with improved strength and sharpness ideal for perpendicular piercing of tissue, as measured by reduced penetration force. The thick wall also gives the needle the characteristic rigidity required for reaching the intended location within the prostate for source placement. The side bevel of the needle tip gives it the customary steerability while the fine tip bevel makes it ideal for piercing of the tough, yet mobile, prostate capsule. In addition, the needle cannula near the tip is roughened to make it echogenic and the shank of the needle is silicone-coated to lessen the tissue drag forces. Figure 41.8 shows the size and design of the New Dimension needle in comparison with the 18-gauge commercially available needles. Table 41.3 shows the force of penetration and factional force for the RADIOCOIL source as compared to three different commercially available needles. The source is delivered in a self-shielded cartridge, which doubles as a shipping container. The philosophy behind the design of the RADIOCOIL delivery system is to give the operating physician the option and freedom to make the final commitment for the length of the source to be deployed in a given needle position intraoperatively. Once the needle is inserted and the length of the prostate is measured under ultrasound guidance, the physician can decide on the source length and will choose it from the source (loaded in a cartridge) supply provided in the OR. The cartridge is readily attached to the hub of the needle; a special long stylet with centimeter demarcation lines is used to advance the source for deployment. The cartridge is color-coded to indicate the length of the source. Figure 41.9 shows the color-coded cartridge for the RADIOCOIL source. The template for the RADIOCOIL source is identical to the existing brachytherapy templates with the exception that the needle holes are for 19-gauge needles. The RADIOCOIL cartridges are supplied in a sterile pouch. In most cases, the source has been assayed and certified by an independent nuclear pharmacist. Additional 1 cm reference sources are supplied (in a non-sterile form) as part of the package for on-site

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source-activity measurement and verification, if necessary. The source cartridges, needles, stylets, and calibration sources are supplied together in a kit as an all-inclusive package. Source deployment procedure The flexible nature of the RADIOCOIL source requires special attention during source placement. The RADIOCOIL source should not be injected, as any attempt to inject the flexible source into soft tissue will cause the coil to bend. Instead, the RADIOCOIL source, when advanced by the stylet to the tip of the needle, must be released by holding the stylet steady while retracting the needle and thus carefully releasing the source in the track created by the needle.

Figure 41.7 Isodose line simulation from (a) an ideal 5 seed-spacer assembly as compared to (b) a 5 cm RADIOCOIL source. At distances

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larger than 5 mm from the source axis, the isodose lines are identical. At closer distances, the isolated point sources deliver a heterogeneous dose compared to the homogeneous dose for a linear source. Even though the RADIOCOIL source can be preloaded in a needle (by using customary wax at the needle tip), the preferred mode is to place the needle inside the prostate and, under ultrasound guidance, position the tip of the needle at the distal surface of the prostate (or 5 mm beyond the distal surface). Once the required source length based on the prostate size is determined, the brachytherapy practitioner chooses the appropriate cartridge containing the anatomically correct source length, attaches the cartridge to the needle hub, and advances the source to the tip of the needle by the long stylet supplied for this purpose. The centimeter demarcation on the stylet allows for accurate advancement of the source to the tip of the needle. (For example, a 4 cm long source is advanced to the

Figure 41.8 The comparison between the thick wall 19-gauge New Dimension needle (shown to left of figure) compared to three other commercially available 18-gauge needles. needle tip by stopping at the 4 cm mark between the stylet and the needle hub.) At this point, the source is ready to be released by carefully holding the stylet steady in one hand while withdrawing the needle with the other hand. Evaluation of the RADIOCOIL source in an animal host The RADIOCOIL source has been evaluated in a canine prostate model. The primary goal of the study was to evaluate the stability of the coiled wire design in prostate tissue.

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The secondary goals were to evaluate the tissue response and histology of the tissue surrounding the source and also to test the delivery system for the source and to obtain the radiographic features of the source to help design a source with optimal performance. The animal study was performed at Dartmouth College under the supervision of Dr Jack Hoopes at the Department of Neurosurgery and Radiation. In all cases, the sources were implanted with the animal under general anesthesia with an open laparotomy. Figure 41.10 shows the RADIOCOIL source placement in a dog’s prostate during open laparotomy. The dog’s prostate was isolated and RADIOCOIL sources of various lengths were implanted in the different prostate lobes such that 5 mm of the source were extended beyond the prostate gland. The dogs were x-rayed and CT images were taken immediately post implant, a week later, and at the time of sacrifice—21 days post implant. Figure 41.11 shows a series of CT scans comparing the position of the coiled wire source on day 1 and day 21. The position of the RADIOCOIL source when compared relative to each other, to the other anatomical landmarks and measured against the position of the fiducial markers showed the relative and absolute stability of the sources in tissue within the accuracy of the measurement reported to be in order of 1 mm.5 Clinical evaluation of RADIOMED While waiting for the infrastructure for the activation of the RADIOCOIL source to come on line, an attempt was

Table 41.3 Insertion force of the New Dimension 19-gauge needle compared to three other 18-gauge needles Needle insertion force (arbitrary units)

Point junction Heel Cannula New Dimension 19-gauge for RADIOCOIL ~0 Vendor 1:18-gauge 1.20 Vondor 2:18-gauge 2.49 Vendor 3:18-gauge 1.89. n.a., not available.

1.48 2.00 n.a. n.a.

1.15 2.16 2.84 2.11

0.06 1.64 2.16 2.24

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Figure 41.9 RADIOCOIL source in color-coded cartridges.

Figure 41.10 The position of RADIOCOIL sources (arrows) implanted inside an isolated canine

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prostate in an open laparotomy procedure.

Figure 41.11 Stability of the RADIOMED source in canine studies. Within the accuracy of the measurement, the RADIOMED source is stable and non-migratory in the prostate gland. made to evaluate the delivery system and the performance of the RADIOCOIL design in a clinical setting and to obtain in vivo information on the visibility of the source by various imaging modalities (ultrasound, x-ray, CT, etc.). Ten patients were implanted with the non-radioactive version of the RADIOCOIL source in their prostate using the transperineal approach. The non-radioactive version of the RADIOCOIL source, it turns out, is an excellent market that is visible under all imaging modalities including ultrasound, MRI, x-ray, CT, and fluoroscopy. The patients in this study were implanted with two coils of different lengths. One coil was placed in the base of the prostate with the distal end marking the basal extent of the prostate. The other coiled wire was placed at the apex of the prostate. The two coils helped to clearly mark the distal and proximal boundary of the prostate and were used as reference points throughout the brachytherapy procedures. Figure 41.12 shows the TRUS image of a typical RADIOCOIL marker in a patient in both longitudinal and axial orientations. The two images clearly demonstrate the echogenicity of the RADIOCOIL source. Note that there is minimum evidence of ghost echoes present in these images.

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Figures 41.13 and 41.14 show the fluoroscopic appearance and the x-ray image of the non-radioactive RADIO COIL marker, respectively. These images mani-fest the inherent radiopacity of the RADIOCOIL source. Figure 41.15 shows the CT scan of the RADIOCOIL marker in four adjacent slices 5 mm apart in a prostate patient designated for HDR treatment. (The dark spots in each slice show the footprint of the HDR catheters as they intersect each CT slice.) Noteworthy is the predictability of the location of the RADIOCOIL marker from one slice to the next, an inherent characteristic of a straightline source. This feature of RADIOCOIL will simplify the postimplant evaluation of implant quality as compared to treatment plan and, in the case of detecting ‘cold’ spots within the gland, facilitate the decision of considering supplemental external beam radiotherapy or a second implant procedure. At the three month patient follow-up, the markers proved to be well tolerated. Relative distance between the markers, when compared to anatomical landmarks, shows that the markers are stable and non-migratory. Conclusions The RADIOCOIL permanent implant linear source is designed to address some of the shortcomings of the

Figure 41.12 (a) Longitudinal and (b) axial ultrasound image of a RADIOCOIL source in the prostate. The absence of a ghost (echo) appearance in the longitudinal image is noteworthy.

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Figure 41.13 Fluoroscopic image of the non-radioactive RADIOCOIL sources in a typical prostate brachytherapy patient. traditional seeds. The source utilizes a fine coiled wire design that gives it some enabling features including visibility under ultrasound, homogeneous dose distribution that ensures the entire gland is treated with a homogeneous tumoricidal dose, the ability to place a portion of the source extracapsular for delivering adequate dose to the gland margins with a higher degree of accuracy, and an

Figure 41.14 Diagnostic x-ray of a non-radioactive RADIOCOIL source in a prostate patient in the presence of a foley catheter balloon filled with contrast media.

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easier method to assess the quality of implant dosimetry intraoperatively. Furthermore, the source is delivered with an improved delivery system suitable for either preloaded needles based on a preplanned volumetric measurement of the prostate or intraoperative treatment plan options. The culmination of improved clinical features of the RADIOCOIL source is expected to contribute to even better patient outcomes as compared to permanent seed implant brachytherapy. In addition to the improved features, the RADIOCOIL source is easier to produce and has a higher degree of built-in quality assurance/quality control, reliability, and reproducibility.

Figure 41.15 A CT scan of a high dose rate (HDR) prostate patient showing the footprint (white spot) of the nonradioactive source in various slices 5 mm apart. The dark spots are the intersection of the HDR catheters intersecting each slice. Acknowledgment The development of the RADIOCOIL source was supported, in part, by a NIH National Cancer Institute SBIR grant No. 2 R44 CA78005. References 1. Kupelian P, Potters L, Khuntia D, et al. Radical prostatectomy, external beam radiotherapy <72 Gy, external beam radiotherapy ≥72 Gy, permanent seed implantation, or combined seeds, external beam radiotherapy for state T1–T2 prostate cancer. Int J Radiat Oncol Biol Phys 2004; 58:25–33.

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2. Potters L, Perez CA, Beyer DC, et al, for the American College of Radiology. Permanent source brachytherapy for prostate cancer: ACR appropriateness criteria. Radiology 2000; 215(Suppl): 1383–1400. 3. Nath R, Anderson L, Luxton G, et al. Dosimetry of interstitial brachytherapy sources. Med Phys 1995; 22(2):209–234. 4. Meigooni AS, Zhang H, Clark JR, et al. Dosimetric characteristics of a new RADIOMED Pd103 wire line source for use in permanent brachytherapy implants. Med Phys (submitted). 5. Hoopes J. Tissue effect and post implant movement of Pd-103 brachytherapy wires and gold fiducial in the canine prostate. Internal report at Surgical Research Laboratories, Dartmouth Medical School, Hanover, NH, February 2004.

42 InterSource brachytherapy seeds ®

John Russell and Jaclyn Collins Introduction International Brachytherapy, sa (IBt) manufactures and markets world-wide two permanently implantable radiation sources, InterSource103 and InterSource125, utilizing palladium-103 and iodine-125, respectively* The unique hollow seed design provides a product line including individual loose seeds, seeds loaded in Mick™ cartridges, InterStrand103 and InterStrand125 seeds on a biodegradable suture at a standard 1 cm spacing, InterStrand Special™, in which seed spacing on the strand is customized to a doctor’s prescription, and EZ-Pak™, in which brachytherapy needles are preloaded to prescription, sterilized, and shipped ready to use. A cutaway view of the InterSource® brachytherapy source shows the hollow seed construction and the sealed toroidal space between the two titanium tubes comprising the capsule (Figure 42.1). The manufacture of tiny seeds with this complex geometry was made possible because of the invention and development of ink

Figure 42.1 The InterSource® brachytherapy source. (Reproduced with permission from International Brachytherapy.) jet printing of intensely radioactive liquids. The x-ray marker is a ring of platinum iridium. Iodine-125 sources are available from 0.2 mCi to 0.7 mCi (0.254–0.889 U) and palladium-103 sources are available from 0.5 mCi to 1.8 mCi (0.646–2.327 U). Because of the hollow tube design of the InterSource®, a hydraulic pressure cannot be supported that would move an implanted seed in the direction parallel to the long axis of

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the seed. As a result, there are very few reported cases of migration of implanted InterSource® seeds.1,2 Product descriptions InterSource® seeds Both InterSource103 palladium seeds and InterSource125 iodine seeds are calibrated based on the NIST Wide-Angle-Free-Air-Chamber (WAFAC) standard for air-kerma strength (U) in units of cGy cm2/hour. This calibration (National Institute of Standards and Technology; NIST-2000) is available at the Accredited Dosimetry Calibration Laboratories so that interested institutions may transfer that calibration to their dose measurement systems. Apparent activity can be computed, using the American Association of Physicists in Medicine (AAPM) subcommittee interim recommendation, from the formulas: For InterSource103: Air-kerma strength in cGy h−1 at 1 cm= 1.293×Apparent activity in mCi. For InterSource125: Air-kerma strength in cGy h−1 at 1 cm= 1.27×Apparent activity in mCi. The TG–43 parameters3 that describe the radiation distribution around implanted seeds have been measured and calculated by two independent institutions for both InterSource103 and InterSource125.3–7 The two sets of results for each isotope have been averaged, see Tables 42.1 and 42.2. *After this paper was finalized, manufacture of InterSource103 palladium-103 seeds encapsulated in titanium was discontinued in anticipation of an advanced plastic palladium seed being introduced to the market in the first quarter of 2005.

Table 42.1 TG–43 parameters for InterSource103 model 1031L brachytherapy source4,5 Anisotropy constant: a Dose rate constant: Λ2000=0.694 cGy h−1 U−1 Distance r(cm) Radial dose function g(r) 0.0b 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.5

1.207 1.231 1.239 1.213 1.187 1.148 1.097 1.047 1.000 0.782

Anisotropy factor

0.906

0.901

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2.0 0.600 0.885 2.5 0.453 3.0 0.340 0.886 3.5 0.256 4.0 0.191 0.889 4.5 0.143 5.0 0.105 0.889 53 0.080 6.0 0.058 6.5 0.044 7.0 0.033 7.5 0.022 8.0 0.017 8.5 0.013 9.0 0.010 9.5 0.007 10.0 0.005 a The dose me constant Λ, is based on the revised NIST-1999 calibration standard, which is generally referred to as NIST-2000. b The value of g(r) at 0.0 cm is indicated in italics, and was linearly extrapolated from the previous two calculated values.

InterStrand® InterStrand® consists of 10 InterSource® seeds strung on a biodegradable, 0.5 mm diameter, monofilament suture

Table 42.2 TG–43 parameters for InterSource125 model1 251L brachytherapy Source6,7 Anisotropy constant: a Dose rate constant: Λ2000=1.02 cGy h−1 U−1 Distance r(cm) Radial dose function g(r) 0.0b 0.3 0.4 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0

0.812 0.938 0.980 1.005 1.000 0.946 0.877 0.798 0.721 0.644 0.574 0.508 0.448

Anisotropy factor

0.972 0.951 0.944 0.965 0.943 0.947

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5.5 0.393 6.0 0.343 0.949 6.5 0.297 7.0 0.257 0.965 7.5 8.0c 0.206 a The dose rate constant, Λ, is based on the revised NIST-1999 calibration standard, which is generally referred to as NIST-2000. b The value of g(r) at 0.0 cm is indicated in italics, and was linearly extrapolated from the previous two calculated values, c The value of g(8.0) for iodine seeds is indicated in italics, and was determined with a sum of exponentials the previous data. (VariSeed™ Informational Notification from Varian Brachytherapy, 14 January 2000 release,)

(Figure 42.2) The seeds are spaced 1 cm center-to-center and fixed in place by slight deformations of the suture at sterile packaging in a stainless steel tube which shields the iodine or palladium radiation. The suture maintains seed spacing and minimizes seed migration. The column strength of the suture is sufficient to easily penetrate bone wax and the monofilament suture is not adversely affected by fluids. The excellent visibility of the InterSource® seed is maintained.

Figure 42.2 The InterStrand® comprises 10 InterSource® seeds strung on a monofilament suture. (Reproduced with permission from International Brachytherapy.) InterStrand® Special InterStrand® Special is a customized InterStrand® in which the seed spacing and number of seeds on a suture is customized to the treatment plan prescribed by the physician (Figure 42.3). This can reduce the number of needles per patient and provide excellent coverage of the base and apex of the gland. InterStrand® Special reduces prep time.

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EZ-Pak™ Preloaded Needle Program The EZ-Pak™ Preloaded Needle Program includes: • InterStrand®, InterStrand® Special, or InterSource® iodine or palladium seeds loaded into needles or cartridges.

Figure 42.3 The InterStrand Special™ is a customized InterStrand®. The seed spacing and number of seeds is prescribed by the physician. (Reproduced with permission from International Brachytherapy.)

Figure 42.4 The EZ-Pak™ Preloaded Needle Program. See text for details. (Reproduced with permission from International Brachytherapy.)

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• Radiograph to ensure accurate loading according to 10% source assay and certification. • the prescribed treatment plan. • The Needle Program is packaged, sterilized, and provided ready for use (Figure 42.4).

References 1. Chen Q, Blair H. Accurate and efficient detection of seed migration in prostate I-125 permanent implantation with a collimated gamma scintillation survey meter [Abstract]. Med Phys 2002; 29:1356. 2. Chen Q, Blair H. Detection and reduction of seed migration in prostate I-125 permanent implantation [Abstract]. Med Phys 2003; 30:1429. 3. Nath R, Anderson L, Luxton G, et al. Dosimetry of interstitial brachytherapy sources: Recommendations of the AAPM Radiation Therapy Committee Task Group No. 43. Med Phys 1995; 22:209–234. 4. Meigooni A, Sowards K, Soldano M. Dosimetric characteristics of the InterSource103 palladium brachytherapy source. Med Phys 2000; 27:1093–1100. 5. Reniers B, Vynckier S, Scalliet P. Dosimetric study of a new palladium seed. Appl Radiat Isot 2002; 57:805–811. 6. Reniers B, Vynckier S, Scalliet P. Dosimetric study of the new InterSource125 iodine seed. Med Phys 2001; 28:2285–2288. 7. Meigooni A, Yoe-Sein M, Al-Otoom A, Sowards K. Determination of the dosimetric characteristics of InterSource125 iodine brachytherapy source. Appl Radiat Isot 2002; 56:589– 599.

43 The customized monofilament: a new approach to permanent prostate brachytherapy Matthew Bouffard Introduction For the purpose of convenience, permanent prostate seed implants were first conceived in the familiar 1 cm grid: a 4.5 mm seed followed by a 5.5 mm spacer (JC Blasko pers comm). This standard spacing became the blueprint for all permanent implants, regardless of the specific conditions of a given patient. This led to some undesirable results, including high doses to sensitive and healthy tissue. Advances in treatmentplanning software (TPS) allowed for ‘special loading’—needles that were not bound by standard spacing. This aided in reducing healthy tissue doses and preserving quality of life by permitting sparing of the urethra and rectal wall, as well as the penile bulb and nerve bundles.1,2 However, the special loading needles still fit into the standard spacing format, as the larger spacing was planned in 5 mm increments, preserving the 1 cm grid. This attempted preservation of the 1 cm grid in the z-axis creates an inherent error in all special loading needles. Since standard 5.5 mm spacers are used in succession to create the special loads, all spacers after the first are 0.5 mm too long, as they do not directly follow a 4.5 mm seed and there is no need for the extra length. This results in a 10% error in the length of the spacing in all special loads as well as an error in the placement of the second source (Table 43.1). In general, if d is the intended sourcetosource distance in mm, the error in the placement of the second source is given by: (0.1−d−1)×100% For example, a special load calling for a 3.0 cm space from the center of one source to the center of the next would contain five consecutive spacers. While the extra 0.5 mm on the first would compensate for the adjacent 4.5 mm seed, the final four spacers would each be 0.5 mm too long. There is no need for the extra material here, resulting in 2.0 mm of extra space and a 6.67% error in the placement

Table 43.1 Percent error between intended source to source distance (d.) and actual source to source distance (da) associated with special loads di (cm) da(cm) Error (%) 1.50 2.00 2.50 3.00

1.55 2.10 2.65 3.20

3.33 5.00 6.00 6.67

The customized monofilament 3.50 4.00 4.50 5.00 5.50 6.00

3.75 4.30 4.85 5.40 5.95 6.50

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7.14 7.50 7.78 8.00 8.19 8.33

of the second source and all successive sources, adversely affecting dosimetric outcomes.3 By the same token, an inherent error is present for special loads containing consecutive seeds. With 4.5 mm seeds placed consecutively, there is no 0.5 mm space between seeds to preserve the 1 cm grid. Thus, the second seed is displaced by 0.5 mm, an error of 10% between the intended and actual source-to-source distance. Any additional consecutive seed will be displaced by a further 0.5 mm and have the same 10% error. Again, this deviation causes misplacement and a reduction in dosimetric quality and validity. As prostate brachytherapy progressed, strands were introduced to allow extracapsular implantation with a reduced risk of seed migration.4,5 This new technology improved implant quality and dosimetric results, but it was not without limitations.6 Early strands suffered from the ‘accordion effect’, causing an increase in needle jamming.7 Furthermore, these strands were also restricted in the spacing they were capable of having, being designed for standard spacing. Lastly, these strands were generally only suitable for use in the periphery of the gland. Description and application Recently, the custom monofilament, a new type of strand, was introduced: the ReadiStrand. This strand, due to its inherent design characteristics, does not suffer from the ‘accordion effect’ and can be constructed for any loading pattern, standard or not (Figure 43.1). It has the ability to have any number of sources placed consecutively, or any length of spacing between sources, thereby eliminating the inherent error of special loads. With these capabilities, the custom monofilament can be used for the entire implant, not just for extracapsular extension, possibly reducing the risk of migration and displacement for the entire implant. The customized monofilament’s ability to be constructed to any dosimetric pattern raises further possibilities. Infinite spacing in a reproducible product would offer an additional dimension for planning purposes (JC Blasko pers comm). Newer versions of some treatment planning software offer inverse optimization. This feature allows for an optimized, customized implant to be planned according to what best suits a patient’s needs without the restriction of the 1 cm grid, providing the opportunity for an implant to be fitted to the patient, rather than fitting the patient to a template. The evolution of the permanent seed implantation process has had a positive effect on the overall quality of the dosimetric results. In the early stages of the acceptance of permanent seed implants, where all needles contained sources with standard spacing, the aim was simply to kill the cancer. This generally resulted in an acceptable V100 and D90,

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but it came at the cost of an unreasonably high V150, as well as troublesome doses to the urethra, bladder, and rectal wall. The advancement of TPS addressed this problem. The V150 and the doses to the urethra, bladder, and rectal wall were lowered via special loading. This, however, resulted in a drop in the V100 and D90 values. The loss was acceptable, as the focus had shifted from killing the cancer to treating the cancer while maintaining quality of life. The development of strands for extracapsular extension further reduced doses that were once unreasonably high, with little or no detriment to the V100 or D90. The seemingly unique characteristics of the customized monofilament could be the next advancement in this process. The infinite dosimetric variability may allow further progress in the reduction of sensitive and healthy tissue dosage. ‘Hot’ spots or ‘cold’ spots can be created as necessitated by the patient’s condition. Tissue-adhering properties purported by the monofilament may lower the risk of migration and increase the accuracy of seed placement. These qualities may lead to a reduction in the number of seeds needed to ensure proper coverage. The reduced risk of migration will allow for more extracapsular sources to be placed, maintaining proper dose coverage while placing fewer interior sources, further reducing sensitive tissue dosage and better preserving quality of life.8,9

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Figure 43.1 Magnified photograph of the custom monofilament, exhibiting both standard and non-standard spacing lengths.

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Figure 43.2 Post-operative x-ray images of two implants performed by the same physician. The implant to the left was performed with loose loads. The implant to the right was done with the custom monofilament and exhibits increased linearity and reduced bunching. Additional benefits Greater visibility The customized monofilament seems to offer other application advantages. By keeping the sources linearly aligned and orthogonal to the ultrasound slices, the sources should appear with greater visibility during postoperative analysis (Figure 43.2). Furthermore, since some later TPS versions have the ability to perform dosimetry by treating the seeds as linear sources rather than point sources, maintaining the linear alignment of the sources would increase the ability to effectively validate the dosimetric results given by the postoperative analysis. When linearity is maintained, the dose clouds are aligned as prescribed by the treatment planning software, and the postimplant dosimetric calculations may more accurately reflect the actual values. This is especially beneficial when considering sensitive tissue doses, as linear dosimetric evaluations have shown sensitive tissue doses to be up to 35% higher than point source evaluation (WM Butler pers comm). Additionally, by eliminating the inherent error of special loads with loose sources and fixed length spacers, the customized monofilament should further validate the dosimetric results. None of these attributes should reduce the quality of the V100 and D90. On the contrary, the preservation of linearity and the apparent reduced risk of migration and displacement should actually improve the V100 and D90 values when customized monofilaments are used (Figure 43.3). Further, linear dosimetry should allow for more

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careful monitoring of sensitive tissue dose, helping preserve postimplant quality of life. These characteristics should allow for a ‘smarter’ implant with thought-out dose planning, specifically targeting problem areas while inten tionally protecting sensitive and healthy tissue, hopefully improving overall implant quality and maximizing preservation of quality of life. Preloaded strands The recent availability of strands that are preloaded and delivered in sterile surgical kits could also offer practical advantages. The customized monofilament comes preassayed and sterilized in preloaded, radiograph-verified, preplugged needles. This eliminates valuable on-site personnel hours spent loading needles, calibrating, and sterilizing sources, and should reduce the radiation exposure received by the staff.10,11 The customized monofilament is delivered in needles that can assist in improving implant quality. The monofilament needle is designed to cause minimal trauma. Unlike other needles, which bore into the perineum, the monofilament’s needle is designed to produce a flap when penetrating the perineum. The resulting flap should reduce edema and allow the body to heal more rapidly; improving patient recovery time. The needles are preplugged with a synthetic 1.5 mm, bioabsorbable plug, which unlike other plug materials, does not jam or lubricate the custom monofilament upon expulsion, and allows for precise location of the first source placement. The combination of the custom monofilament and its accompanying needle eliminates the ‘accordion effect’ that plagues other stranded source products. The synthetic plug offers an additional benefit. The use of bone wax by doctors in the clinical setting to plug the tip of seeding needles has been commonplace. Each needle

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Figure 43.3 Post-operative analysis of a custom monofilament case. Ultrasound determined the target value to be 93.1 cm3. 276 seeds were implanted, resulting in a V100 of 98.17%, a D90 of 111.41%, and D10 Urethra of 107.85%. (Images courtesy of Dr Donald B Fuller MD.) contains approximately 4–5 mm3 of bone wax at its tip resulting in the introduction of 100–300 mm3 of nonabsorbable bone wax into the prostate gland in a typical implant of 20–60 needles. While bone wax is approved for use as a hemostatic agent to control bleeding in orthopedic surgery, studies have shown the use or presence of bone wax in soft tissue can lead to the growth of sarcomal cancers.12 Conversely, synthetic materials have a long history of use in soft tissue. These synthetic materials are completely absorbed into the body via enzyme reaction. As the growth of this practice increases, care

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should be given to the selection of materials and instrumentation most suited for the intended use to protect patient outcome and quality of life. Unlike other stranded source products, the customized monofilament does not have to start and end with a seed. Any amount of spacing material can be added to either end of the monofilament. Not only does this allow for continued use of ‘trailing spacers’ to those accustomed to using them in loose loads, but it allows for baseline loading as well. In baseline loading, a monofilament that calls for its first source in the non-baseline plane is constructed with the appropriate amount of spacing material at its tip, allowing the needle to be inserted to the baseline and expelled at that depth, eliminating the need for the manual retraction of such needles. When using this method, there is no empty needle track before the first source, possibly reducing the chances for migration or displacement. Furthermore, by eliminating the process of manually retracting the needles, the time and motion for the procedure is reduced to approximately one minute per needle (P Sanchez, pers comm). This technique results in reductions in operating room time as well as allowing for shorter anesthesia sedation for the patient, improving throughput for the facility, and creating the opportunity for quicker patient recovery. Conclusions The customized monofilament may have much to offer to permanent prostate brachytherapy, assisting those practitioners who are entering the field of this practice and minimizing the learning curve of becoming proficient in seed implantation. It allows for customized spacing and special loading without being constrained by 5.5 mm spacing increments, and eliminates the inherent error associated with special loads. It does not suffer from the ‘accordion effect’, introduces no bone wax to the tissue, and can reduce the already low risk of migration and displacement associated with stranded sources. The customized monofilament may be the next step in dosimetric evolution, increasing the sparing of healthy and sensitive tissue while potentially improving implant quality and dosimetric outcomes. Furthermore, its linearity simplifies postimplant analysis, makes it ideal for linear dosimetry evaluations, and can help validate dosimetric outcomes while ensuring acceptable doses to sensitive and healthy tissue. The customized monofilament is also beneficial from a practical standpoint, coming preloaded, thereby saving time and possibly reducing exposure, and offering the capability for baseline loading, reducing time in motion for the procedure. As the field of permanent prostate brachytherapy continues to evolve, the customized monofilament can only become more advantageous. As advancements continue in treatment planning software, patient-specific, optimized, customized implants can be produced; in which each needle will contain a special load, custom-configured to best suit a given patient’s conditions. As prostate brachytherapy continues to vie with external beam radiotherapy (EBRT) and radical prostatectomy (RP) as the best means of treating prostate cancer while maintaining quality of life, it is innovations like the customized monofilament that will allow permanent prostate brachytherapy to continue to be a safe and effective choice for patients.

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References 1. Butler WM, Merrick GS, Lief JH, Dorsey AT. Comparison of seed loading approaches in prostate brachytherapy. Med Phys 2000; 27(2):381–392. 2. Merrick GS, Butler WM, Wallner KE, et al. The importance of radiation doses to the penile bulb vs. crura in the development of postbrachytherapy erectile dysfunction. Int J Radiat Oncol Biol Phys 2002; 54(4):1055–1062. 3. Roberson PL, Narayana V, McShan DL, et al. Source placement error for permanent implant of the prostate. Med Phys 1997; 24(2):251–257. 4. Merrick GS, Butler WM, Dorsey AT, et al. Seed fixity in the prostate/periprostatic region following brachytherapy. Int J Radiat Biol Phys 2000; 46(1):215–220. 5. Tapen EM, Blasko JC, Grimm PD, et al. Reduction of radioactive seed embolization to the lung following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998; 42(5):1063–1067. 6. Lee WR, deGuzman AF, Tomlinson SK, McCullough DL. Radioactive sources embedded in suture are associated with improved postimplant dosimetry in men treated with prostate brachytherapy. Radiother Oncol 2002; 65:123–127. 7. Friedland JL, Feygelman V, Haller EM, et al. Problems with rigid seed strand lodging during prostate implantation: a proposed mechanism and solution. Med Dosim 1997; 22(1):17–21. 8. Narayana V, Roberson PL, Winfield RJ, et al. Optimal placement of radioisotopes for permanent prostate implants. Radiology 1996; 199(2):457–460. 9. Brown D, Colonias A, Miller R, et al. Urinary morbidity with a modified peripheral loading technique of transperineal 125I prostate implantation. Int J Radiat Oncol Biol Phys 2000; 47(2):353–360. 10. Butler WM, Dorsey AT, Nelson KR, Merrick GS. Quality assurance calibration of 125I rapid strand in a sterile environment. Int J Radiat Oncol Biol Phys 1998; 41(1):217–222. 11. Bice WS Jr, Walker ES, Gearty S, et al. A comparative evaluation of loading times and exposures for permanent prostate brachytherapy. J Appl Clin Med Phys 2002; 3(4):263–272. 12. Morrison BA. Soft tissue sarcomas of the extremities. Baylor University Medical Proceedings 2003; 16:285–287.

Part VII Postimplant: analysis of postimplant dosimetry

44 Salvage of suboptimal prostate seed implantation: reimplantation of an underdosed region of the prostate base Lesley Hughes, Frank M Waterman, and Adam P Dicker Introduction Prostate cancer is one of the most common male cancers in the United States. The scope of the disease is far-reaching with estimates by the American Cancer Society for 2004 showing prostate cancer comprising 33% of all cancers in males, surpassing lung cancer incidence.1 The number of patients diagnosed with prostate cancer is increasing worldwide, through increased physician/patient awareness and screening efforts. Treatment options for the individual patient, depending on pretreatment characteristics, may include watchful waiting, prostate brachytherapy, external beam radiotherapy, or radical prostatectomy. Transperineal interstitial permanent prostate brachytherapy (TIPPB) for the treatment of prostate cancer has been increasingly utilized in the past decade. Single institution data have provided most information for outcome data and procedure technique. Prostate implant technology is a complex procedure with respect to treatment planning and technical delivery of the radioactive seeds. Prostate brachytherapy techniques are varied and continue to evolve with improvements in the ease and reliability of seed delivery. Institutions with a great deal of experience have developed short courses for instruction of clinicians in seed implantation. Experts in brachytherapy generally accept that there is a learning curve’ for the prostate implant technique.2 Lee and colleagues reported improvement of dosimetric delivery after 25–30 cases done by a single practitioner.3 Formal training programs in prostate brachytherapy, whether proctored or certified, significantly shorten or eliminate the ‘learning curve’ for individual practitioners.4 Unfortunately suboptimal implants do occur but currently there is little guidance in the literature as to how to deal with this difficulty. We will discuss one approach to salvage of a suboptimally dosed prostate implant. Materials and methods The patient was a 67-year-old male with a Stage II, T1cN0MO, adenocarcinoma (American Joint Committee on Cancer; AJCC, 1997) of the prostate with a Gleason score 6 (3+3) and prostate-specific antigen (PSA) of 7.7 with an American Urological Association (AUA) urinary symptom score of 5, who chose prostate brachytherapy as his treatment decision after full discussion of all treatment options available for his disease. His preimplant prostate volume was 36.7 cc and he did not receive hormonal therapy.

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The iodine-125 (125I) implant was preplanned to deliver a minimum dose of 150 Gy to the prostate based on the recommendations of American Association of Physicists in Medicine (AAPM) TG-43 for calculating dose.5 The seeds were peripherally loaded, which produced an isodose distribution characterized by a broad dose minimum in the central portion of the prostate encircled by a high dose region. The implant was planned so that the 150 Gy isodose line was approximately 3–5 mm beyond the prostate. The implant required 21 needles and 77 seeds using a 125I seed strength of 0.54 mCi/seed (National Institute of Standards and Technology; NIST-99). The preplan V100 and D90 were 100% and 212 Gy, respectively. Computed tomography (CT) scans for postimplant dosimetric evaluation were obtained on the day of the implant and 35 days later. These studies were obtained using the CT scanner (PQ5000, Picker, Cleveland, OH) in our department. Axial images were obtained at 2.5 mm intervals using a 2 mm slice thickness. The same individual (FW) did all the seed localization and contouring. The urethra and rectum were contoured beginning at the base of the prostate and extending to the last image that contained seeds, which in this case was 1.75 cm inferior to the apex. The postimplant CT scan obtained on the day of the implant revealed that the seeding began 1.5–2 cm inferior to the actual base of the gland, which left the superior aspect of the gland significantly underdosed. This also resulted in a large number of seeds being implanted in the proximity of the apex and extending 1.5 cm inferior to the apex. The patient was informed of the suboptimal seed placement immediately and after a full discussion of the options available, a re-implantation was planned. Planning the re-implantation presented several challenges. It is necessary to know the locations of the seeds already implanted and the dose distribution delivered by these seeds as a starting point for planning the reimplantation. Hence, the plan must be generated based on a postimplant imaging study in which all of the seeds can be localized. A transrectal ultrasound (TRUS) volume study is not suitable for this purpose because not all of the seeds can be visualized. Therefore, the plan was based on the postimplant CT scan obtained 35 days after the procedure. However, the use of a CT scan for planning presents another problem; namely, the treatment-planning system (Variseed, Varian, Palto Alto, CA) does not allow the plan to be generated from a CT scan. The treatment-planning system was developed to utilize TRUS images on which the template hole pattern was already superimposed. Both the prostate contours and the template corners must be digitized into the computer. This problem was overcome by superimposing a grid on the CT images and digitizing them into the treatment planning system as if they were TRUS images. A 1 cm×1 cm grid of points was first superimposed onto the CT images using a tool of the ACQsim CT simulator (Philips Medical Systems, the Netherlands). Hard copies of the CT study were then generated for digitization into the computer. First, it was necessary to define the corners of the template on the CT images. The template used to perform the implant measures 6 cm×6 cm. Thus, a 6 cm×6 cm template was drawn on the CT images based on the superimposed grid points. The exact alignment of the template relative to the prostate is unimportant at this stage of the planning process; therefore, the relative positions of the template and prostate were arbitrarily selected based on the available grid points. The treatment-planning software allows the alignment of the template and the prostate contours to be modified once the digitization process is

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completed. Thus, once the digitization was completed, the template was moved relative to the prostate so that the prostate was centered left to right. The template was also moved in the anterior-posterior direction so that the most posterior contour of the prostate was located on the first row of template holes. It was assumed that the prostate could be aligned with the template as planned at the time of the implant or, if not, the plan could be modified by relabeling the rows accordingly. Results Figure 44.1 shows the first nine images of the postimplant CT scan obtained 35 days after the initial implant. These images were acquired at 2.5 mm intervals and show the first 2 cm of the gland, beginning at the base. It is evident from these images that the first 1.5 cm of the gland is devoid of seeds. Adequate seeding only appears about 2 cm from the base. Thus, one would expect the dose coverage to be suboptimal. The top half of Figure 44.2 is a sagittal plane through the central axis of the prostate based on the CT scan shown in Figure 44.1 that graphically illustrates the underdosed region of the gland. The circles and triangles represent seeds implanted in this plane. As noted above, the seeding began 1.5–2 cm inferior to the base, which left the superior aspect of the gland significantly underdosed. It is also apparent that the seeds and the dose distribution extended well beyond the apex as a result of the inferior shift in the seed distribution. The second implant was preplanned to boost the dose to the superior portion of the gland. Figure 44.3 shows the dose-volume histograms (DVH) of the first and second implants. Note that V100 and D90 in the first implant were only 46% and 49 Gy, respectively. The DVH indicates that the entire prostate, including the underdosed region, would receive a dose of at least 35 Gy from the original implant. Thus, the second implant needed to deliver a maximum dose of only 115 Gy to the underdosed region. For this reason, the second implant was planned using a seed strength of 0.42 mCi instead of 0.54 mCi, to scale down the total dose that would be delivered by the second implant. The use of lower strength seeds allowed us to maintain the same seed spacing used in the initial implant; however, it is not necessary to use lower strength seeds. The second implant was performed 49 days after the initial implant. A total of 53 additional seeds were implanted using 16 needles. Figure 44.4 shows the first nine images of the CT scan obtained 34 days after the second implant (and 84 days after the first implant). The seeds added during the second implant can be identified by comparison of Figures 44.1 and 44.4. The improvement in dose coverage is shown graphically in the lower half of Figure 44.2 and by the DVH in Figure 44.3. The DVH, which is based on a postimplant CT scan shown in Figure 44.4, shows that the re-implantation increased V100 and D90 to 98% and 201 Gy, respectively. Figure 44.5 shows DVHs of the urethra following the first and second implants. The urethral dose was relatively high due to the clustering of seeds near the apex and beyond. This is evidenced by the fact that 25% of the urethra received a dose ≥400 Gy from the first implant. In the combined implant, 25% of the urethra received a dose ≥500 Gy. The apparent increase in the urethral dose

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Figure 44.1 Images from the computed tomographic (CT) scan obtained 35 days after the first implant showing the suboptimal seeding at the base of the prostate. largely reflects the fact that the superior 2 cm of the urethra (approximately one third of the contoured volume) received very little dose from the first implant. Thus, the DVH was shifted toward higher doses when the dose to this volume was increased by the second implant. Figure 44.6 shows dose-surface histograms (DSH) of the surface of the rectum following the first and second implants. The DSH indicates that 10% of the rectal surface received a dose equal to or greater than 150 Gy as a result of the first implant. This dose increased to about 200 Gy for the combined implants. This increase reflects the fact that a large fraction of the rectal surface received very little dose from the first implant. The patient at one month follow-up for the first implant had an AUA symptom score of 8 and was on no medication (alpha-blockers) for urinary problems. He was experiencing some erectile dysfunction and was started on sildenafil citrate (Viagra). He continued to have erectile dysfunction with little response to sildenafil citrate. His symptomatology remained stable with respect to his urinary symptoms until 6 months after the second implant when his AUA score increased to 13. He was tried on tamsulosin hydrochloride (Flomax) with some relief of his symptomatology. His PSA evaluation showed a steady decline from 7.7 to 0.2 ng/mL with the latest follow-up 37 months

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postimplant. Due to back pain, the patient was evaluated with a bone scan and plain films correlated to show degenerative disease of the spine. Discussion Transperineal prostate brachytherapy has been increasingly utilized in the treatment of prostate cancer. Due to the highly technical nature of the procedure there is operator variation due to the learning process or technical difficulties. Fluoroscopy during the procedure may assist in proper needle placement and seed delivery. Localizing seed placement in the base and apex of the gland may help to facilitate seed implantation.6 Seed fixity is also a problem with movement of seeds causing changes in the dosimetry.7

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Figure 44.2 Sagittal planes through the central axis of the prostate that show the isodose distribution and dose coverage following the first and second implants.

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Figure 44.3 Dose-volume histograms (DVH) that show the prostate dosimetry following the first and second implants.

Figure 44.4 Images from the computed tomography (CT) scan obtained 34 days after the second implant showing the reseeding of the underdosed region.

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Figure 44.5 Dose-volume histograms (DVH) that show the urethral dosimetry following the first and second implants.

Figure 44.6 Dose-surface histograms (DSH) that show the rectal dosimetry following the first and second implants.

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Embedded seeds in suture and preloaded needles are associated with improved postimplant dosimetry in a single institution study.8 The impact of source placement errors depends on the seed density. The misplacement of anterior seeds in implants with a lower anterior seed density has been shown to have a greater impact on the postimplant dosimetry than the misplacement of posterior seeds. Needle divergence of only small degrees (5–10 degrees) can cause up to 10–20% reduction of minimum target dose.10 Training of physicians, by proctoring or certification, in delivery of prostate brachytherapy shortens the learning curve and improves the quality of the dosimetric plans.4 Formal training programs for new practitioners would be of benefit in prostate brachytherapy delivery. There is little guidance in the literature on the salvage of suboptimal implants. Choices may include external beam radiotherapy (EBRT), high dose rate implantation, intensity modulated radiation therapy (IMRT), radical prostatectomy, and re-implantation. The case presented in this chapter describes re-implantation as a salvage procedure. We show that this is a feasible and tolerable procedure. References 1. Jemal A, Tiwari RC, Murray T, et al. Cancer Statistics, 2004. CA Cancer J Clin 2004; 54:8–29. 2. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999; 44:789–799. 3. Lee WR, deGuzman AF, Bare RL, et al. Post implant analysis of transperineal interstitial permanent prostate brachytherapy: evidence for a learning curve in the first year at a single institution. Int J Radiat Oncol Biol Phys 2000; 46:83–88. 4. Presser J, Stone NN, Chircus JH, et al. Multicenter experience with prostate brachytherapy training [Abstract]. Int J Radiat Oncol Biol Phys 2001; 51(suppl 1):199. 5. Nath R, Anderson LL, Luxton G, et al. Dosimetry of interstitial brachytherapy sources: Recommendations of the AAPM Radiation Therapy Committee Task Group No. 43. Med Phys 1995; 22:209–233. 6. Baird MC, Holt RW, Selby TL. Improvement of transperineal implant dosimetry by intraoperative cystoscopic confirmation of prostate anatomy. J Urol 2000; 164:406–410. 7. Merrick GS, Butler WM, Dorsey AT, et al. Seed fixity in the prostate/ periprostatic region following brachytherapy. Int J Radiat Oncol Biol Phys 2000; 46:215–220. 8. Lee WR, deGuzman AF, Tomlinson SK, McCullough DL. Radioactive sources embedded in suture are associated with improved post implant dosimetry in men treated with prostate brachytherapy. Radiother Oncol 2002; 65:123–127. 9. Sidhu S, Morris WJ, Spadinger I, et al. Prostate brachytherapy post implant dosimetry: a comparison of prostate quadrants. Int J Radiat Oncol Biol Phys 2002; 52:544–552. 10. Nath S, Chen Z, Yue N, et al. Dosimetric effects of needle divergence in prostate seed implant using 125I and 103Pd radioactive seeds. Med Phys 2000; 27:1058–1066.

45 Can prostate brachytherapy treat potential extraprostatic disease? Ashish Patel, Frank M Waterman, and Adam P Dicker Introduction Extraprostatic extension (EPE) is an unfavorable prognostic factor for prostate cancer patients with clinically organconfined disease. Growing evidence suggests that EPE may exist in a significant fraction of favorable risk clinical stage T1–T2 patients, with numbers reported between 10% and 50%.1,2 The extent of EPE has been the topic of several recent studies, with potential implications for prostate brachytherapy.3–5 The goal of brachytherapy is to deliver a uniform dose with an adequate margin for disease eradication. However, the steep dose gradient at the periphery of the prostate (up to 20 Gy/mm) brings into question the dose actually being delivered to potential EPE.6 As a result, the American Brachytherapy Society (ABS) currently recommends that patients with a high risk for EPE be treated with external beam radiotherapy (EBRT) with brachytherapy used as a boost.7 The radial extent of EPE has been the subject of several recent studies examining hematoxylin-eosin (H&E) stained post-prostatectomy specimens.3–5 Davis et al from the Mayo Clinic, reported that EPE was present in 28% of the specimens, with a median radial distance of 0.5 mm.4 A subset analysis of 107 patients, who meet the criteria for brachytherapy (PSA <10, Gleason <7, gland size <60 cc), showed EPE present in 11 cases, with a mean and maximum radial extent of 0.03 mm and 0.6 mm, respectively. Similar findings were described by Sohayda et al. This series found EPE to be within 3.3 mm in 90% of favorable risk cases (clinical stage T1–T2, PSA ≤10 ng/mL, Gleason ≤6).5 Both of these studies suggest that a 3–5 mm treatment margin from the prostatic capsule would encompass 95–100% of EPE in favorable risk patients. Treatment Investigators from Thomas Jefferson University have recently reported on the ability to consistently deliver the full prescription dose 3–5 mm outside the prostatic capsule using both iodine-125 (125I) and palladium-103 (103Pd) permanent prostate seed implants.8,9 In the report by Butzbach et al,8 22 favorable risk patients, who received 103Pd seeds as either monotherapy (5 patients) or as a boost following external beam radiation therapy (17 patients) were evaluated. The implants were prescribed to 120 Gy for monotherapy and 70–80 Gy for boost, and were planned with a margin of 3–5 mm from the edge of the prostate. All implants were conducted using a peripheral loading technique, with seeds averaging 1.5 mCi/seed in strength (Figure 45.1). All patients in this study underwent

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both pre- and postimplant computed tomography (CT) scans, with contouring conducted by a single individual (FW). The postimplant CT was obtained, on average, 36 days after the procedure. The radial distance between the prescription isodose line and the edge of the prostate contour was measured in five locations around the posterior aspect of the prostate for each transverse image (Figure 45.2). These locations were chosen based on previous reports demonstrating EPE to be most prevalent in the posterior half of the prostate gland.10–12 Results A summary of the Butzbach et al results is shown in Table 45.1. The average distance ranged from 4.0 mm to 6.3 mm for the five defined positions around the prostate. The 6 o’clock position received the smallest coverage, averaging 4.0 mm, which was an effort to minimize rectal toxicity. When the average distance in each location around the prostate was stratified to the apex, mid-gland, and base, the smallest margins were located at the base and 6 o’clock position. Based on these results, prostate brachytherapy using 103Pd is capable of delivering a prescription dose 3–5 mm beyond the gland using a peripheral loading technique. However, the margins did vary throughout the gland, ranging between 0 mm to 8 mm, which suggests

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Figure 45.1 Treatment planning: 103Pd. (a) Planned prescription isodose line (120 Gy outermost line). The plan used a 3–5 mm margin outside the prostatic gland (crosshatch). The implant was performed with either a 1.5 or 2.0 mCi seed. Representative pretreatment plans with both strengths are shown using the same 40 cc prostate, illustrating that the intended coverage is virtually identical. Note that fewer

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seeds are required when using a higher seed strength, (b) Transverse computed tomography (CT) image of prostate after prostate brachytherapy. Note the peripheral distribution of seeds. that implant quality is operator-dependent with excessive source placement error reducing or even eliminating margin over portions of the gland.13 A similar report by Patel et al studied 60 consecutive favorable risk patients, who received 125I prostate implants, to determine whether implants already planned with a 5 mm margin for source placement error were also capable of treating extraprostatic extension.9 In contrast to the Butzbach et al report,8 all 60 patients received 125I prostate implants as monotherapy. The prescribed dose in this series was 145 Gy. Similar techniques as described in the Butzbach et al study were employed to contour the prostate and implant the seeds. Previous studies indicate that planning a 3–5 mm margin outside the prostatic cap

Figure 45.2 Radial distance measurements in the posterior aspect of the prostate. Table 45.1 Mean preplan and postimplant extraprostatic margins (±standard deviation) (mm) at the base, mid-gland, and apex of the prostate Position

Gland Base Mid-gland Apex

Left lateral 4.9±0.4 3.1±0.4 Left posterolateral 5.2 ±0.4 3.4±0.5 Posterior 4.0±0.4 2.7±05 Right posterolateral 5.4±0.4 4.0±0.5 Right lateral 6.3±0.3 4.0±0.5

4.9±0.4 6.8±0.6 5.9±0.5 6.3±0.6 4.5±0.4 4.9±0.5 5.4±0.5 6.9±0.7 6.3±0.4 8.4±0.5

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sule allows for compensation for source placement errors, therefore a 5 mm margin was planned to allow for these errors that are inherent to prostate brachytherapy and not to treat EPE.14,15 As in the previous study, the radial distance between the prescription isodose line and the edge of the prostate contour was measured in five locations around the posterior aspect of the prostate for each transverse image (Figure 45.2). A summary of the Patel et al results is shown in Table 45.2. The mean postimplant margins ranged from 2.9 mm to 9.4 mm, with overall mean postimplant margins at the base, mid-gland, and apex of 3.8, 5.0, and 7.2 mm, respectively. When pre- and postimplant margins were compared, a statistically significant difference was found at the base (p=0.00003), but not at the apex (p= 0.6960) or mid-gland (p=0.31274). Therefore, the planned margins at the mid-gland and apex were not needed to compensate for source placement errors in these regions. However, this was not true at the base, where the plans were not executed as well as in the mid-gland and apex. Of the measurements, 38% at the base were <3 mm versus 15% and 12% at the mid-gland and apex, respec tively, which was approximately the same as planned. When an implant is planned with a dose margin that is intended to compensate for source placement error, any margin available to treat EPE depends on the degree of source placement error. Therefore, EPE can only be treated after compensating for source placement error. A third study investigating the extraprostatic dose distribution with permanent prostate brachytherapy was recently reported by investigators from the Schiffler Cancer Center.16 In this study, Merrick and associates examined 26 patients with low risk prostate carcinoma enrolled in a prospective, randomized phase III trial comparing 103Pd and 125I sources. Similar to the studies from Thomas Jefferson University, a 5 mm margin was planned around the prostate; however, a different implantation technique was utilized with the placement of additional seeds at the base of the seminal vesicles and periprostatic region. These extraprostatic implants accounted for approximately 40% of the total seeds placed during the procedure. The prescribed dose was 145 Gy for 125I and 115 Gy for 103Pd. None of the patients in this series received additional EBRT; however, 11 patients did receive 3–4 months of neo-adjuvant

Table 45.2 Mean preplan and postimplant extraprostatic margins (± standard deviation) (mm) at the base, midgland, and apex of the prostate Position Left lateral Left posterolateral Posterior Right posterolateral Right lateral

Base Mid-gland Apex Preplan Postimplant Preplan Postimplant Preplan Psotimplant 5.5±2.7 6.3±3.4 4.6±2.3 5.7±3.4 5.3±2.4

3.7±3.0 4.0±4.0 2.9±4.1 3.5±4.7 4.6±3.0

5.8±2.9 5.9±2.8 4.6±2.3 5.2±2.4 5.7±2.3

5.4±2.5 5.5±2.8 .5.1±2.5 5.3±3.0 6.5±2.7

9.4±4.5 6.6±2.7 4.1±2.2 6.0±2.6 9.0±3.5

8.1±3.6 7.2±4.2 4.9±3.7 6.9±4.7 9.0±3.5

hormonal therapy secondary to urinary obstruction or unfavorable geometry. Postimplant dosimetry was based on CT scans obtained within 2 hours of implantation on day 0, and the radial distance was measured from the center of the gland to the capsule, 100%, 90%, and 75% isodose lines along 72 radial lines at 5° increments.

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A comparison of 125I and 103Pd dosimetric characteristics yielded no clinically significant differences between the two isotopes. The greatest margins were found at lateral and posterolateral positions at the base and apex of the gland. Negative margins were found at the anterior of the base in both isotopes, which corresponds to the location of the bladder neck, a structure that was intentionally underdosed. A composite polar plot demonstrating the mean sagittal prostate dimensions and dosimetric margins is presented in Figure 45.3. The overall mean 100% isodose

Figure 45.3 Prescription isodose line measurements. Representative crosssection of mid-prostate detailing location of measurements taken along the periphery of the gland. margin was 6.5 mm ± 1.8 mm. No statistically significant differences were observed between the two isotopes at the 100% isodose margin; however, the margins for 103Pd were significantly smaller at the 90% and 75% isodose levels. This isotopic difference at lower isodoses is expected to be secondary to the sharp dose fall-off characteristic of 103 Pd. No statistically significant correlations were found between any dosimetric margin and factors, such as age, disease classification parameters, number of seeds, seed strength, or volumetric parameters.

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Conclusions These three studies confirm that prostate brachytherapy is capable of delivering a prescription dose margin 3 mm beyond the prostatic capsule; however, it is important to note that none of these studies attempt to address the biologic necessity or appropriate dose to treat EPE. Due to variability in implant quality and its operator dependence, it is not recommended to treat patients at high risk for EPE with implants alone. The role of prostate brachytherapy alone in intermediate-risk patients will be addressed in the recently activated Radiation Therapy Oncology Group clinical trial, RTOG 0232, which randomizes patients to two arms, EBRT with brachytherapy boost or brachytherapy alone. References 1. Epstein JI, Partin AW, Sauvageot J, Walsh PC. Prediction of progression following radical prostatectomy. A multivariate analysis of 721 men with long-term follow-up. Am J Surg Pathol 1996; 20(3):286–292. 2. Partin AW, Kattan MW, Subong EN, et al. Combination of prostatespecific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multiinstitutional update. JAMA 1997; 277(18):1445–1451. 3. Davis BJ, Pisansky TM, Wilson TM, et al. The radial distance of extraprostatic extension of prostate carcinoma: implications for prostate brachytherapy. Cancer 1999; 85(12):2630–2637. 4. Davis BJ, Haddock MG, Wilson TM, et al. Treatment of extraprostatic cancer in clinically organ-confined prostate cancer by permanent interstitial brachytherapy: is extraprostatic seed placement necessary? Tech Urol 2000; 6(2):70–77. 5. Sohayda C, Kupelian PA, Levin HS, Klein EA. Extent of extracapsular extension in localized prostate cancer. Urology 2000; 55(3):382–386. 6. Dawson JE, Wu T, Roy T, et al. Dose effects of seed placement deviations from preplanned positions in ultrasound guided prostate implants. Radiother Oncol 1994; 32:268–270. 7. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer [Review] [132 refs]. Int J Radiat Oncol Biol Phys 1999; 44(4):789–799. 8. Butzbach D, Waterman FM, Dicker AP. Can extraprostatic extension be treated by prostate brachytherapy? An analysis based on postimplant dosimetry. Int J Radiat Oncol Biol Phys 2001; 51(5):1196–1199. 9. A detailed examination of the difference between planned and treated margins in 125I permanent prostate brachytherapy. Brachytherapy 2003; 2:223–228. 10. Blasko JC, Wallner KE, Cavanagh W. Radiotherapeutic strategies in the management of clinically localized, ‘low-risk’ prostate cancer: selection, results, and the search for answers. Cancer J Sci Am 1998; 4(3):157–158. 11. Catalona WJ, Dresner SM. Nerve-sparing radical prostatectomy: extraprostatic tumor extension and preservation of erectile function. J Urol 1985; 134(6):1149–1151. 12. Catalona WJ, Bigg SW. Nerve-sparing radical prostatectomy: evaluation of results after 250 patients. J Urol 1990; 143(3):538–543.

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13. Waterman FM, Yue N, Corn BW, Dicker AP. Edema associated with I-125 or Pd-103 prostate brachytherapy and its impact on postimplant dosimetry: an analysis based on serial CT acquisition. Int J Radiat Oncol Biol Phys 1998; 41(5):1069–1077. 14. Yu Y, Waterman FM, Suntharalingam N, Schulsinger A. Limitations of the minimum peripheral dose as a parameter for dose specification in permanent 125I prostate implants. Int J Radiat Oncol Biol Phys 1996; 34(3):717–725. 15. Roberson PL, Narayana V, McShan DL, et al. Source placement error for permanent implant of the prostate. Med Phys 1997; 24(2):251–257. 16. Merrick GS, Butler WM, Wallner KE, et al. Extracapsular radiation dose distribution after permanent prostate brachytherapy. Am J Clin Oncol 2003; 25(5):e178-e189.

Part VIII Quality of life and posttreatment sequelae after prostate brachytherapy

46 Health-related quality of life following prostate brachytherapy W Robert Lee, Deborah Watkins-Bruner Prostate brachytherapy (PB) in the treatment of clinically localized prostate cancer is increasing dramatically worldwide. This resurgence in popularity is the result of improved technology and newer techniques that allow for an outpatient procedure. PB offers the potential advantage of convenience and decreased morbidity compared to radical prostatectomy (RP). There is also a widespread perception that PB is associated with a better quality of life compared with other treatments. Health-related quality of life (HRQOL) encompasses a wide range of human experience. Contemporary definitions of HRQOL are based on the World Health Organization’s categorization of health as a ‘state of complete physical, mental, and social wellbeing and not merely the absence of disease’.1 It is important to emphasize that HRQOL, in general, involves the perceptions of health and ability to function as reported by the patient involved. HRQOL research applies the principles of psychometric test theory, a discipline with which many clinicians are unfamiliar.2 Data are collected with HRQOL questionnaires (instruments) which, when possible, should be completed by the patients themselves. These instruments generally consist of a number of questions (items) that are organized into scales. Each scale is designed to measure a different aspect (domain) of HRQOL. HRQOL instruments may contain several dozen items addressing a number of domains. HRQOL instruments are generally categorized as generic or disease-specific. Generic HRQOL instruments measure overall well-being and at the very least should address the level of functioning in the physical, emotional and social domains. Examples of generic HRQOL instruments include the RAND Medical Outcomes Study 36-item Health Survey (SF-36),3 and the Sickness Impact Profile (SIP).4 Disease-specific HRQOL instruments focus on those domains that may be more clinically relevant for the population studied. Diseasespecific HRQOL tools have been developed for patients with cancer, AIDS, and many other conditions. A number of reliable, valid instruments to measure prostate cancer specific HRQOL in men with early stage prostate cancer are available. Examples include the Functional Assessment of Cancer Therapy-Prostate (FACT-P),5 the University of California, Los Angeles-Prostate Cancer Index (UCLAPCI),6 the Prostate Cancer Treatment Outcome Questionnaire (PCTO-Q),7 the Expanded Prostate cancer Index Composite (EPIC),8 and the prostate cancer module of the EORTC QLC-C30.9 Good HRQOL research requires instruments that have been tested and found to be reliable and valid. This review will be confined to those studies using reliable, valid instruments in men treated with PB. Studies will be classified according to the type of brachytherapy (low dose rate or permanent vs high dose rate or temporary).

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HRQOL following low dose rate prostate brachytherapy In one of the first analyses of HRQOL in men treated with PB, investigators at the University of California, Los Angeles compared generic and disease-specific HRQOL in men undergoing brachytherapy for early stage prostate cancer to those undergoing radical prostatectomy and age-matched health controls.10 The study incorporated the SF-36 and the UCLA-PCI questionnaires in a cross-sectional design. The men with prostate cancer completed the various questionnaires 3–17 (median: 7.5) months following treatment. The PB group included 48 men treated with PB—14 received external beam radiotherapy (EBRT) in addition to PB and 34 did not, and the RP group included 74 men. There were 134 men in the control group. Compared to men in the RP group, men treated with PB were older, less healthy, and had less formal education. Generic HRQOL did not differ greatly among the three groups. In fact, the only generic HRQOL domain in the SF36 that differed was physical function, with RP patients scoring higher than the PB or control groups. Disease specific HRQOL measures were very different between the groups. Urinary function (leakage) was worse in the PB group than in controls but better than in the RP group. The PB group had more irritative urinary symptoms and worse bowel function than controls. Sexual function and bother were worse in the PB group than controls, but no different from the RP group. Physical function, urinary function, and bother and the American Urological Association (AUA) symptom index scores improved with time after brachytherapy. The authors also divided the PB group according to whether EBRT was also given and found that men who received both EBRT and PB scored worse in all disease-specific HRQOL domains compared to those men treated with PB alone. Investigators from the University of Virginia have reported a cross-sectional analysis of 242 men with clinically localized prostate cancer.11 In this report, 138 men (57% response rate) completed and returned mailed questionnaires including the FACT-G, International Prostate Sympton Score (IPSS), and the Brief Sexual Function Inventory. Of these men, 27 had been treated with RP, 70 received PB combined with 8–9 months of androgen deprivation therapy (ADT), and 41 had been treated with a combination of PB, EBRT, and 8–9 months of ADT. When the age-adjusted FACT-G scores were compared between all three groups, the scores in the RP and PB groups were similar but the scores of men that had received EBRT in addition to PB were considerably lower (indicating decreased HRQOL). This paper is difficult to interpret as ADT was given in all men treated with PB. Recent reports indicate that even short-term ADT combined with PB can have significant effects on sexual function (see below). Davis and colleagues from Eastern Virginia Medical School have reported on a HRQOL in men treated with PB alone, EBRT, and RP for clinically localized prostate cancer.12 These investigators mailed the SF-36, the UCLA-PCI and the IPSS questionnaire to more than 600 men following definitive treatment. The response rate was greater than 80% in all groups. Important demographic differences between the treatment groups were identified. Men treated with RP tended to be younger, healthier, and less likely to receive neo-adjuvant androgen deprivation (NAAD) therapy compared to men treated with PB. The median time from treatment to survey completion was

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longer in the men treated with RP compared to the men treated with PB (37.9 months vs 22.4 months, p>0.05). The raw and adjusted SF-36 scores were not significantly different between men treated with RP and those treated with PB. Examination of the urinary, bowel and sexual domains of the PCI indicated that men treated with PB or EBRT had better sexual and urinary function than men treated with RP. Men treated with PB also reported less sexual bother than men treated with RP. Bacon et al have analyzed a subset of men being followed in the Health Professionals Follow-up Study.13 The authors reported on 842 men that had been diagnosed with clinically localized prostate cancer between 1993 and 1998. The study population had completed the SF-36 and UCLA-PCI questionnaires. These men received various treatments including: radical prostatectomy (n=421), external beam radiotherapy (n=221), brachytherapy (n=69), hormonal treatment (n=33), watchful waiting (n=31), and other (n=67). The authors provide no information as to whether some men included in the PB group also received EBRT. In addition, no information was provided concerning the use of ADT in combination with PB, RP, or EBRT. Age-adjusted generic HRQOL scores showed very small differences according to treatment group with the RP group having the highest scores. Significant differences were observed in sexual, urinary, and bowel HRQOL according to treatment group. Men treated with PB and EBRT reported higher sexual and urinary function as well as less sexual bother compared to men treated with RP. The men treated with PB or EBRT, however, also reported significantly worse bowel function, bowel bother, and urinary bother (in the case of PB) than men treated with RP. In a very recent report from investigators at the University of Michigan, Wei et al have provided a crosssectional analysis of more than 1000 men treated with RP, PB, or EBRT between 1995 and 1999.14 The PB group included an unreported percent of men treated with a combination of EBRT and PB. Additionally, compared to the RP group the PB group was more likely to be treated with ADT. The PB group had the shortest time between treatment and completion of the HRQOL questionnaires (median: 21 months, range: 4–52). These authors used a number of validated questionnaires including the EPIC instrument and compared the HRQOL in each group to a group of age-matched controls. The EPIC instrument was constructed by modifying the UCLA PCI instrument and adding items that address irritative urinary symptoms, irritative bowel symptoms, symptoms related to androgen deprivation, and items expanding the assessment of function-specific bother in each of these new domains. Measures of generic HRQOL (SF-36 and FACT-G) did not differ between controls and treatment groups. Using the EPIC instrument, however, the PB group was found to have significantly worse urinary, bowel, and sexual HRQOL compared to controls. A comparison of HRQOL scores in men at least one year from completion of therapy found that the PB group had significantly worse urinary irritative, bowel, and sexual symptoms than the RP or EBRT groups. By excluding the patients that received EBRT from the PB group sexual HRQOL was similar to the EBRT group and superior to the RP group, suggesting that the addition of EBRT to PB leads to decreased sexual function. In a recent report from the Michigan group, Hollenbeck et al have examined sexual HRQOL following PB.15 The authors compared the sexual HRQOL in 84 men treated with PB and a similar number of age-matched controls. The majority of men treated with PB received some form of ADT prior to PB and more than 40% of men received EBRT in addition to PB. Advanced age and the use of ADT were independently associated with

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sexual HRQOL following PB. In men under the age of 69, 33% reported at least fair sexual function following PB compared to 19% in men treated with ADT. For those men over the age of 69, at least fair sexual function was reported by 26% following PB but only 5% of these older men reported fair sexual function if ADT was used along with PB. Knowing the prevalence of erectile dysfunction after PB alone or in combination with EB and/or ADT is also critical to understanding the benefit of interventions to ameliorate this decrement in quality of life. A recent study by Potters et al documented a differential response to sildenafil (Viagra) by cancer treatment combination in a subanalysis of 84 patients (from a cohort of 1166 patients, median age: 68 years; median follow-up: 34 months) accepting treatment for ED.16 Of the 36 patients who never received ADT and were treated with either 50 mg or 100 mg of sildenafil as needed, 12/15 (80%) men treated with PB alone and 18/21 (86%) men treated with EBRT + PB were able to achieve erections satisfactory for intercourse. In contrast, of 48 patients who had been treated with neo-adjuvant ADT, 11/25 (44%) treated with PB alone and 11/23 (48%) treated with EBRT+PB were able to achieve success with sildenafil. Summarizing the results outlined above, several statements can be offered. First, when HRQOL is measured with a generic instrument (SF-36 for instance), there do not appear to be any large differences between men treated for prostate cancer and similarly aged men without cancer, or those with cancer who have yet to receive definitive treatment. Second, when HRQOL is measured with a symptom-specific instrument, there are often differences between men treated for prostate cancer and similarly aged men without cancer. Third, it appears that there are treatment-specific changes in HRQOL within the urinary, bowel, and sexual domains. Specifically, it appears that men treated with RP have more difficulty within the sexual and certain urinary domains compared to men treated with PB or EBRT. On the other hand, PB and EBRT are associated with more bowel dysfunction than RP, and PB is associated with more urinary bother than EBRT or RP. The strength of these conclusions is tempered by the cross-sectional nature of these reports. Litwin has demonstrated that age-matched men without prostate cancer report less than perfect sexual, bowel, and urinary HRQOL. In addition, without a control group it is difficult to understand the magnitude of the problem. Unlike urinary and bowel incontinence, which are abnormal at any age, but increase in prevalence with age due to functional impairments and concurrent medical disease, there is a high level of erectile dysfunction (ED) in the general population associated with ‘normal’ aging. A population study of physiologic erectile dysfunction among 1290 subjects between the ages 40 and 70 demonstrated age to be the most significant independent predictor of ED, although other factors were found to correlate with ED to lesser degrees (i.e. heart disease, hypertension, diabetes, cigarette smoking, etc.).17 Overall, 17.2% of subjects reported minimal ED, 25.2% reported moderate ED, and 9.6% reported complete ED. The probability of complete ED tripled from 5.1% to 15% in men between 40 and 70 years and the probability of moderate ED doubled from 17% to 34%. An estimated 40% of men aged 40 had either minimal, moderate, or complete ED, while that estimate rose to 67% by age 70. In sum, prospective data collection, including baseline values, are required to examine the net effect of any treatment on various HRQOL domains. In one of the few prospective reports, Lee and colleagues have described a prospective study examining HRQOL in a group of men treated with PB.18 In a pilot study reported in 2000, the authors studied 31 men who had completed the FACT-P questionnaire prior to

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PB and at several times (1, 3, 6, 12 months) following PB. All men were treated with PB alone, no EBRT was utilized. Clinically meaningful decreases in the FACT-P scores (indicating decreased HRQOL) were noted one month following PB with a return to baseline by 12 months. An examination of the domains of the FACT-P demonstrated that the HRQOL decreases occurred in the Functional Well-Being (FWB), Physical WellBeing (PWB), and Prostate Cancer Symptom (PCS) subscales. In a later report from the same group at Wake Forest University, Lee compared changes in HRQOL as measured by FACT-P in men treated with PB, RP, or EBRT.19 Ninety men were included (PB, 44; RP, 23; EBRT, 23). The study design did not use randomization, treatment was chosen based on the recommendation of the treating physicians and the wishes of the patient. The authors compared the HRQOL profiles in each of the treatment groups. After adjusting for baseline HRQOL there were significant differences in HRQOL at one month according to treatment group. Men treated with PB or RP experienced larger declines in HRQOL at one month than men treated with EBRT. Importantly, however, by one year there were no significant differences in HRQOL according to treatment group. In fact, the HRQOL scores for all groups at 12 months were not significantly different than baseline scores for any of the treatment groups. HRQOL following treatment with PB alone vs treatment with combination PB and EBRT In most of the cross-sectional reports above the prostate brachytherapy (PB) groups contained men treated with PB alone and men treated with a combination of PB and EBRT. In a few papers the HRQOL consequences associated with the use of EBRT combined with PB were analyzed. In the Brandeis et al paper, the addition of EBRT to PB predicted for poorer generic and disease-specific HRQOL along with higher IPSS scores (more urinary symptoms).10 In the Krupski et al paper the group receiving EBRT and PB had worse HRQOL compared to the group treated with PB alone.11 The Michigan paper did not specify what percent of men had received EBRT in the PB group but they reported that excluding those patients that received a combination of EBRT and PB improved sexual HRQOL in the PB group.14 The best way to determine whether the addition of EBRT to PB is associated with a decrease in HRQOL compared to treatment with PB alone is by way of a randomized trial. No trials have yet been accomplished although the Radiation Therapy Oncology Group (RTOG) has a trial ongoing. For the time being there is at least a suggestion that the addition of EBRT may decrease HRQOL. HRQOL following high dose rate prostate brachytherapy The number of reports addressing HRQOL following treatment with high dose rate (HDR) prostate brachytherapy is small. A literature search using PubMed found only two reports using a validated HRQOL instrument. In the first report, Joly et al analyzed 71 men with prostate cancer treated with a combination EBRT and HDR PB and compared them to 71 age-matched controls without cancer.20 In this retrospective, cross-sectional study all participants were mailed a generic

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HRQOL instrument (Nottingham Health Profile) and a prostate-cancer specific tool (EORTC QLC-C30). Generic HRQOL scores were similar between the two groups, but a comparison of EORTC QLC-C30 scores found differences in the urinary and sexual domains. Patients treated with EBRT and HDR PB were more likely to have urinary incontinence and to be inactive sexually compared to controls. In a very recent report Egawa and colleagues from Japan administered the SF-36 and a portion of the EORTC prostate questionnaire to 58 men treated with HDR PB and EB.21 The authors observed significant decreases in five domains of the SF-36 in the first month after HDR treatment but by 12 months, scores had returned to baseline in all generic HRQOL domains. A similar time course of decline and recovery was observed in the disease-specific domains measured. All disease-specific scores had returned to baseline 12 months following treatment. Future directions The study of health-related quality of life (HRQOL) in men with early stage prostate cancer is a relatively young discipline. Several reliable, validated instruments exist to measure HRQOL in men with prostate cancer. These tools have been applied to document HRQOL prior to treatment, to estimate the effects of treatment on HRQOL, and to explore relationships among changes in different domains of HRQOL. Most evidence to date suggests that there are important differences in sexual, urinary, and bowel HRQOL according to treatment received. This underscores the importance of completing randomized trials in men with clinically localized prostate cancer. References 1. World Health Organization (WHO). Constitution of the World Health Organization, basic documents. Geneva: WHO, 1948. 2. Tulsky DS. An introduction to test theory. Oncology 1990; 4:43–48. 3. Stewart AL, Hays RD, Ware JE. The MOS short-form general health survey: reliability and validity in a patient population. Med Care 1988; July:724–735. 4. Bergner M, Bobbitt RA, Carter WB, Gilson BS. The Sickness Impact Profile: development and final revision of a health status measure. Med Care 1981; Aug:787–805. 5. Esper P, Mo F, Chodal G, et al. Measuring quality of life in men with prostate cancer using the functional assessment of cancer therapyprostate instrument. Urology 1997; 50:920–928. 6. 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; 36:1002–1012. 7. Shrader-Bogen CL, Kjellberg JL, McPherson CP, Murray CL. Quality of life and treatment outcomes: prostate carcinoma patients’ perspectives after prostatectomy or radiation therapy. Cancer 1997; 79:1977–1986. 8. 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; 56:899–905. 9. 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 QLQC30. Qual Life Res 1996; 5:212–221.

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10. Brandeis JM, Litwin MS, Burnison CM, Reiter RE. Quality of life outcomes after brachytherapy for early stage prostate cancer. J Urol 2000; 163:851–857. 11. Krupski T, Petroni GR, Bissonette EA, Theodorescu D. Quality-of-life comparison of radical prostatectomy and interstitial brachytherapy in the treatment of clinically localized prostate cancer. Urology 2000; 55:736–742. 12. Davis JW, Kuban DA, Lynch DF, Schellhammer PF. Quality of life after treatment for localized prostate cancer: differences based on treatment modality. J Urol 2001; 166:947–952. 13. Bacon CG, Giovannucci E, Testa M, Kawachi I. The impact of cancer treatment on quality of life outcomes for patients with localized prostate cancer. J Urol 2001; 166:1804–1810. 14. 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; 20:557–566. 15. Hollenbeck BK, Dunn RL, Wei JT, et al. Neoadjuvant hormonal therapy and older age are associated with adverse sexual health-related quality-of-life outcome after prostate brachytherapy. Urology 2002; 59:480–484. 16. Potters L, Torre T, Fearn PA, et al. Potency after permanent prostate brachytherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2001; 50:1235–1242. 17. Feldman HA, Goldstein I, Hatzichristou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151:54–61. 18. 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 Radiat Oncol Biol Phys 2000; 46:77–81. 19. Lee WR, Hall MC, McQuellon RP, et al. A prospective quality-oflife study in men with clinically localized prostate carcinoma treated with radical prostatectomy, external beam radiotherapy, or interstitial brachytherapy. Int J Radiat Oncol Biol Phys 2001; 51:614–623. 20. Joly F, Brune D, Couette J-E, et al. Health-related quality of life and sequelae in patients treated with brachytherapy and external beam irradiation for localized prostate cancer. Ann Oncol 1998; 9:751–757. 21. Egawa S, Shimura S, Irie A, et al. Toxicity and health-related quality of life during and after high dose rate brachytherapy followed by external beam radiotherapy for prostate cancer. Jpn J Clin Oncol 2001; 31:541–547.

47 Rectal complications following permanent seed implants Louis Potters Introduction Ultrasound-guided permanent prostate brachytherapy (PPB) alone or in conjunction with external beam radiotherapy (EBRT) for adenocarcinoma of the prostate is quickly growing in popularity as a treatment option for patients with early stage, localized cancers. As experience with this technique has grown over the last several years, reports in the literature have presented the urinary morbidity from several centers.1–3 The rectal morbidity associated with PPB has been less well investigated and documented.4,5 As patients are asked to participate in the treatment decisions for early stage, localized prostate cancer, the morbidity of each treatment method plays an important role in the selection process for each patient. In the immediate postimplant period, a patient undergoing PPB may have some mild transient rectal discomfort and bleeding as a result of the ultrasound probe during the procedure. During the weeks following the implant, there may be changes in bowel habits in the form of diarrhea or constipation, tenesmus, and rectal pressure.6–8 These symptoms generally respond to conservative symptomatic management. Late injury includes proctitis, rectal ulceration, fistula formation, and incontinence.9 The most common of these is proctitis, which often presents as a painless hemorrhoidal type bleeding that is usually self-limited. Bleeding from proctitis presents late, about one to two years after implantation and may be exacerbated by constipation. Conservative management is recommended with stool softeners and local steroid creams or foams. Aggressive measures, such as biopsies and laser treatments, may precipitate ulceration and fistula formation and should be avoided whenever possible.7,10,11 Rectal injury following PPB fortunately occurs with low frequency. However, it remains the most severe complication that can occur and can be associated with malpractice litigation. This is due to the catastrophic nature of rectal injuries coupled with their delayed onset at a time when follow-up visits to the radiation oncologist are infrequent. The importance of understanding rectal injury cannot be understated. Appropriate management strategies must be explained to the patient. One question that arises frequently is whether there is a dose-effect that can explain or be responsible for rectal injury. Clearly, the proximity of the rectal mucosa to the posterior aspect of the prostate is associated with high radiation dose, even when an implant dose conforms tightly to the prostate itself. Further, there is little consensus as to what constitutes a high dose to the rectum. In addition, the definition of the rectum is ambiguous when describing a delivered dose to that structure. Authors have described various definitions of the rectum, either as a point or volume. Conforming our definition

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and how it is represented on postimplant dosimetric studies is required in order to establish dose criteria for the risk of rectal injury. In a recent review from Wallner et al, they examined several cases of severe rectal ulceration and were unable to distinguish dosimetric characteristics that would have identified a risk for developing such a complication. As an attempt to review this subject, the series from Gelblum and Potters will be reviewed. Materials The Gelblum and Potters series reported on 825 patients with biopsy proven adenocarcinoma of the prostate who were treated with PPB (Table 47.1). The treatment method for these patients has been previously reported.12 PPB was performed using realtime intraoperative transrectal ultrasound (TRUS) guidance with needles placed using the peripheral spacing technique. Both the sagittal and axial images on TRUS were used to confirm the proximity of needle placement to the posterior prostate margin. Patients who received PPB alone were treated to a minimum peripheral dose (MPD) of 136 Gy with palladium-103, and 144 Gy with iodine-125 (post TG–43

Table 47.1 Patient characteristics from the Gelblum and Potters series Variable Number of patients implanted Age (median) Median preimplant PSA <10 ng/mL 10–20 ng/mL >20 ng/mL Gleason score 2–4 5–6 7 8–9 Stage (1998 AJCC) T1c T2a T2b Prostate size (median) Isotope 125 I 103 Pd Neo-adjuvant anti-androgen therapy Preimplant irradiation Total activity (median) 103 Pd

No. 825 67 yrs (range: 52–89) 9.49 ng/mL (range: 0.6–56 ng/mL) 393 378 54 99 471 206 49 380 379 66 34.6 cc 240 685 173 140 116 mCi

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125

I 38.2 mCi PSA, prostate-specific antigen; AJCC, American Joint Committee on Cancer.

formalized).13,14 When external beam irradiation preceded PPB, a dose of 45 Gy at 180 cGy/fraction was prescribed and delivered via four-field technique. Anterior and lateral fields measured on average 12×12 cm and 11×12 cm, respectively. The MPD for 103Pd was 102 Gy and for 125I was 108 Gy (post TG-43 formalized) when combined modality treatment was used. At each follow-up appointment, patients were interviewed with respect to their bowel function. Bowel and rectal complaints were documented using a modified Radiation Therapy Oncology Group (RTOG) rectal symptom scoring scale (Table 47.2). Patients who complained of rectal irritation were treated with hydrocortisone acetate hemorrhoidal suppositories three times daily for a minimum of 3 weeks and advised to use sitz baths. Patients with persistent irritation or complaints were treated with hvdrocortisone retention enemas twice daily for 2 to

Table 47.2 Modified RTOG rectal toxicity scale used in the current study Modified RTOG rectal toxicity Grade 1 Tenesmus, dear mucous discharge Grade 2 Intermittent rectal bleeding, erythema of rectal lining on proctoscopy Grade 3 Rectal ulceration Grade 4 Bowel obstruction, fistula formation, blood transfusion required RTOG, Radiation Therapy Oncology Group.

4 weeks. Crude and actuarial analysis for the incidence of rectal morbidity was evaluated. Computed tomography (CT)-based post-PPB dosimetry was initiated in 1994–1995. The method of rectal dose calculation has varied considerably since this time (rectal point dose vs rectal volume) and thus meaningful data from the dose-volume histogram were not available for that study. Results With a median follow-up of 48 months (24–85 months), the crude incidence of rectal toxicity in this patient cohort peaked at 9.6% at 10 months with patients either experiencing grade 1 or 2 rectal toxicity. Of the patients, 58 (7%) had grade 1 complaints while 21 (2.5%) reported grade 2 complaints. During the entire follow-up period, 77 patients (9.4%) reported grade 1 toxicity while 54 patients (6.6%) reported grade 2 toxicity or rectal bleeding. The actuarial incidence of rectal toxicity for patients that underwent PPB alone versus PPB and external beam irradiation is shown in Table 47.3. The addition of external beam radiotherapy (EBRT) did not impact the incidence of rectal morbidity. Additionally there was no difference

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Table 47.3 Actuarial incidence of rectal toxicity for patients receiving combined external beam radiotherapy and PPB verses PPB alone PPB+EBRT (n=140)

PPB Alone (n=685)

Grade 1 10.5% Grade 2 7.1% Grade 3 0.7% PPB, transperineal interstitial permanent prostate brachytherapy; EBRT, external beam radiotherapy.

8.9% 6.5% 0.4%

Table 47.4 Univariate analysis of contributing factors for grade 1 and 2 rectal toxicity Characteristic

Grade 1 and 2 (p-value)

Isotope 0.634 Neo-adjuvant hormones 0.962 External beam radiotherapy 0,086 Case order 0.178

in the incidence of grade 1 or 2 rectal toxicity for the selection of isotope, the addition of hormone therapy, or case order (Table 47.4). By 3.5 years, no patients reported rectal complaints. Rectal ulceration reported as a grade 3 complication was not reported until 12 months following PPB (Table 47.5). Four cases of the 825 patients in this study (0.5%) reported a grade 3 rectal complication. Colonoscopy or proctoscopy documented all four patients with grade 3 toxicity. Two patients reported problems with rectal ulceration at 12 months post-PPB and one each at 18 and 23 months after the implant. Three of the four patients were implanted with 125I, while one patient was implanted with 103Pd. One of the three patients treated with 125I received external beam irradiation in combination with PPB and only one of these patients received neoadjuvant antiandrogen therapy as part of his treatment. Two of the four patients with rectal ulcers were biopsied at the time of routine colonoscopy for “anterior rectal proctitis”, with bleeding and ulceration subsequent to the biopsy. Bot h pathology reports identified inflammatory proctitis with neovascularization. The ulcerated regions were described as ranging in size from 2 cm to 4 cm in greatest dimension. All four ulcers resolved with conservative management. No patient has had a significant drop in hematocrit or required a blood transfusion. No grade 4 toxicities were reported in this study. Discussion A common method for assessing rectal toxicity after radiation therapy is the Radiation Therapy Oncology Group (RTOG) toxicity scale. In the Gelblum series, a modified scale was used and their results are similar to others who present an absolute rectal bleeding

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rate of approximately 6%. The overall incidence of proctitis in the literature following permanent brachytherapy has been reported to range from 1% to 12%.7,15 While the 12% proctitis rate reported by Wallner et al represents the early experience with CT-based implants, subsequent refinements of the technique indicate that proctitis rates have decreased to about 4–6% overall.5,7,16,17 Merrick et al report similar results of rectal toxicity in their small, retrospective series of patients treated with permanent prostate brachytherapy (PPB) alone.18 They report a rate of self-limited proctitis of 9% from a cohort of 45 patients. They calculate anterior rectal wall doses based on postimplant CT scans done with a rectal obturator in place on postoperative day 5 with a mean estimated dose exposure to the anterior portion of the rectum of 82.5% of the prescription dose from the implant. No correlation was found between the average rectal dose and prostatic volume. They also found no relationship of the isotope used for PPB and the incidence of proctitis. The addition of external beam radiotherapy (EBRT) to PPB was also not a contributing factor for the development of rectal toxicity. They conclude from their dosimetric calculations that permitting doses ≤85% of the prescribed dose to the anterior rectal wall, independent of isotope used is associated with a 9% incidence of proctitis. This is identical to the 9% quoted in the current study.

Table 47.5 Grade 3 rectal toxicities from the Gelbum series Patient Isotope EBRT Hormones Implant dose 1 2 3 4

125

I I 125 I 103 Pd 125

No Yes No No

No No Yes No

144 Gy 100 Gy 144 Gy 120 Gy

Time for ulcer formation (mths)

Time to resolution (mths)

Rectal biopsy

12 12 23 18

9 8 7 Still dealing at 8 mths

Yes Yes No No

EBRT, external beam radiotherapy,. radiotheraphy.

A second study evaluating rectal dosimetry in patients treated with PPB by Wallner et al reviewed 65 patients treated with T1/T2 prostate cancers treated with CTplanned prostate implants alone.19 They report a 10% incidence of proctitis. Further, a correlation was noted with reported grade 1 (rectal bleeding) and grade 2 (rectal ulceration) toxicity and a rectal surface dose greater than or less than 100 Gy for patients treated with 125I. There was no significant relationship for the onset of rectal toxicity for the total isotope activity implanted, the minimum permitted dose (MPD), or individual seed strength. An update of this series by Hu and Wallner reports a median time to rectal bleeding of 8 months postPPB.15 Of the patients from that study, 13 underwent sigmoidoscopy and 7 were found to have rectal ulceration while the remaining 6 had radiation proctitis. Rectal bleeding resolved spontaneously in that study as well. Synder et al reporting on grade 2 proctitis following 125I implants concluded that the incidence of proctitis was volume-dependent (Figure 47.1).20 In fact, the risk of proctitis was volume-dependent for each dose studied, 80, 140, 160, and 240 Gy, respectively. The 5 year actuarial risk of grade 2 proctitis was 5% if 1.3 cc or less of the rectal volume

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received the prescription dose of 160 Gy, and 17% for >1.3 cc (p=0.001). Others have tried to correlate the risk of proctitis relative to the delivered dose and volume of the rectum with less success.15,21 These studies of detailed dosimetric analysis identify higher rectal doses in patients with radiation proctitis, making it a potential method of identifying patients at higher risk of rectal injury. However, to date there has not been a single series that has identified an absolute radiation dose as a threshold for developing proctitis. While there is currently no specific recommendation on dose, intraoperative planning systems may allow the operator to measure and limit the rectal dose during the case.18,22 An earlier report from Blasko and colleagues reports a 2.6% incidence of proctitis following PPB with 71% resolving spontaneously.23 They suggested an increased risk of late proctitis following combined modality treatment (6%) verses PPB alone (1%). The addition of EBRT to permanent prostate brachytherapy may be a risk factor for increased rectal toxicity. While the Gelblum study was unable to demonstrate a difference in proctitis between patients treated with implant only versus combined external radiation and implant, a study from Staten Island University Hospital reported an alarmingly high percentage of 2.3% for fistula formation.9 While these data raise a concern that combination therapy may be associated with more rectal injury, to date no other series, whether monotherapy or combined therapy, has reported a fistula rate this high. Using the incidence of colostomy as a surrogate for fistulization, Benoit et al reported a rate of 0.3% in Medicare patients undergoing prostate brachytherapy.24

Figure 47.1 The crude Incidence of rectal toxicity in all 825 patients who received permanent prostate brachytherapy (PPB).7 Grades: (1) tenesmus, clear mucous discharge; (2) intermittent rectal bleeding, erythema,

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or rectal lining on proctoscopy; (3) rectal ulceration; (4) bowel obstruction, fistula formation, blood transfusion required. Nonetheless, the observation of increased rectal bother when PPB is combined with external radiation has been reported by Brandeis et al in a study comparing quality of life indicators between implant alone and when combined with external radiation.25 In that study, rectal bother was significantly higher in those patients treated with combination therapy. Recent series reporting on three-dimensional conformal external beam radiotherapy (3D-CRT) of the pro-state present much higher rates of rectal bleeding and discomfort.26,27 A report from the Fox Chase Cancer Center describes late rectal bleeding to be an expected complication of high dose treatment of prostate cancer.28 The cumulative incidence of grade 2 and grade 3 rectal toxicity at 12 months was approximately 40% and 25%, respectively. The median rectal dose delivered to the prostate gland in that study was 72 Gy, with a range of 62.11–80.74 Gy. Most rectal bleeding developed between 6 and 12 months following the treatment for a median duration of 3 months. The central dose to the prostate gland was the only treatment related factor found to be significant on Cox multivariate analysis. Others have reported a combined rate of acute grade 1 and 2 rectal toxicity of 14% in patients undergoing 3DCRT with the majority of the patients receiving 70.2 or 75.6 Gy to the prostate and early data with short follow-up indicate lower rates of rectal complications when intensity modulated radiotherapy (IMRT) is utilized. Diagnosis of radiation proctitis is usually made by sigmoid or colonoscopy. It is accepted that if areas of proctitis are identified in a previously irradiated field, surgical interventions, such as biopsies, may precipitate further erosion of the mucosa with the subsequent formation of an ulcer or fistula.29 This is illustrated in the Gelblum series where 50% of the patients that experienced grade 3 rectal toxicity had been biopsied prior to the development of the ulcer. These patients also appear to require a longer time to heal from their ulcers (8–9 months vs 3–4 months for patients not biopsied). No fistulas were reported in this series. The use of aggressive diagnostic measures, such as biopsies, should be avoided at all costs and it is paramount that patients be educated on this matter since follow-up with a gastroenterologist is generally not associated with communication back to the radiation oncologist. The mechanism of radiation proctitis appears related to edema and fibrosis of arterioles in the luminal crypts of the colonic mucosa.29,30 As fibrosis increases, the mucosal lining becomes more friable and is clinically associated with bleeding. The gastrointestinal literature has reported an increased risk of developing radiation proctitis in patients with underlying vascular changes associated with diabetes, hypertension, and chronic inflammatory bowel diseases. Nonetheless, Grann and Wallner have demonstrated that patients with inflammatory bowel diseases may not be at an increased risk of rectal injury when treated with PPB.31 Several medical interventions have been reviewed in the literature including sulcralfate enemas, systemic and per-rectum steroids, and argon laser coagulation for large ulcers.32–39 However, the optimal medical treatment for radiation proctitis has not

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yet been identified. In patients with significant bleeding, the use of 4% formalin appears to be an effective and non-invasive measure to control radiation proctitis. Counter et al have presented their data treating patients with radiation proctitis and identified that 100% had initial success with cessation of bleeding.39 Three patients out of 27 had recurrent bleeding; none required transfusion. One patient required repeat formalin instillation, with no further bleeding at 3 months follow-up. Another promising treatment for patients with persistent bleeding is the use of the argon-gas laser. Fantin et al have presented their experience with this technique and have shown that with a median of two treatment sessions (range: 2–4), complete symptom relief was achieved.35 All interventions were well tolerated without complications. During follow-up (median: 24 months, range: 18–24 months), there was no recurrence of symptoms (bleeding, tenesmus). Most importantly, with these two treatment approaches, no evidence of progression was identified in these studies. PPB is a now a standard option for most men seeking treatment of early stage, localized prostate cancer. A review of the literature shows a lack of information regarding the development of gastrointestinal toxicity after PPB. In fact, the recently reported guidelines by the American Brachytherapy Society (ABS) fail to consider rectal morbidity at this time.40 Fortunately, the incidence or rectal injury is not high following PPB relative to definitive external radiotherapy. Nonetheless, there is more to learn to prevent the one or two catastrophic injuries that can occur. Most important is that close follow-up and patient education is vital at the time of initial consultation and at each follow-up visit. Any symptoms should be treated conservatively without biopsy or surgical intervention unless the patient is bleeding enough to require transfusion. It is also vital that the urologist understand the significance of rectal injury as they may play a more important role during follow-up. Any referral to a gastroenterologist should be accompanied with information that the patient sustained radiation via a PPB and that it is likely that erythema and neovascularization will be visible on colonoscopy. However, a biopsy should not be performed. It is likely that with future study, the dose limitations of the rectum will be better delineated and that intraoperative techniques will be available to limit the rectal dose. However, it is likely that rectal injury will remain part of the management of patients undergoing PPB and that understanding the risks of incorrectly treating such patients will, it is hoped, limit bad outcomes. References 1. Gelblum D, Potters L, Ashley R, et al. Urinary morbidity following ultrasound-guided transperineal prostate seed implantation. Int J Radiat Oncol Biol Phys 1999; 45(1):59–67. 2. Terk MD, Stock RG, Stone NN. Identification of patients at increased risk for prolonged urinary retention following radioactive seed implantation of the prostate. J Urol 1998; 160(4):1379– 1382. 3. Nag S, Scaperoth DD, Badalament R, et al. Transperineal palladium 103 prostate brachytherapy: analysis of morbidity and seed migration. Urology 1995; 45(1):87–92.

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4. Vicini FA, Kini VR, Edmundson G, et al. A comprehensive review of prostate cancer brachytherapy: defining an optimal technique. Int J Radiat Oncol Biol Phys 1999; 44(3):483– 491. 5. Kleinberg L, Wallner K, Roy J, et al. Treatment-related symptoms during the first year following transperineal 125-I prostate implantation. Int J Radiat Oncol Biol Phys 1994; 28(4):985–990. 6. Blasko JC, Mate T, Sylvester JE, et al. Brachytherapy for carcinoma of the prostate: techniques, patient selection, and clinical outcomes. Semin Radiat Oncol 2002; 12(1):81–94. 7. Gelblum DY, Potters L. Rectal complications associated with transperineal interstitial brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2000; 48(1):119–124. 8. Merrick GS, Butler WM, Dorsey AT, Dorsey JT 3rd. The effect of constipation on rectal dosimetry following prostate brachytherapy. Med Dosim 2000; 25(4):237–241. 9. Zeitlin SI, Sherman J, Raboy A, et al. High dose combination radiotherapy for the treatment of localized prostate cancer [Discussion: 95–96.] J Urol 1998; 160(1):91–95. 10. Han BH, Wallner KE. Dosimetric and radiographic correlates to prostate brachytherapy-related rectal complications. Int J Cancer 2001; 96(6):372–378. 11. Wallner K, Roy J, Harrison L. Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995; 32(2):465–471. 12. Cha CM, Potters L, Ashley R, et al. Isotope selection for patients undergoing prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999; 45(2):391–395. 13. Beyer D, Nath R, Butler W, et al. American Brachytherapy Society recommendations for clinical implementation of NIST-1999 standards for (103)palladium brachytherapy. Int J Radiat Oncol Biol Phys 2000; 47(2):273–275. 14. Nath R, Roberts K, Ng M, et al. Correlation of medical dosimetry quality indicators to the local tumor control in patients with prostate cancer treated with iodine-125 interstitial implants. Med Phys 1998; 25(12):2293–2307. 15. Hu K, Wallner K. Clinical course of rectal bleeding following I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998; 41(2):263–265. 16. Merrick GS, Butler WM, Dorsey AT, et al. Rectal function following prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 48(3):667–674. 17. Battermann JJ. I-125 implantation for localized prostate cancer: the Utrecht University experience. Radiother Oncol 2000; 57(3):269–272. 18. Merrick GS, Butler WM, Dorsey AT, et al. Rectal dosimetric analysis following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1999; 43(5):1021–1027. 19. Wallner K, Roy J, Harrison L. Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995; 32(2):465–471. 20. Snyder KM, Stock RG, Hong SM, et al. Defining the risk of developing grade 2 proctitis following 125-I prostate brachytherapy using a rectal dose-volume histogram analysis. Int J Radiat Oncol Biol Phys 2001; 50(2):335–341. 21. Zelefsky MJ, Yamada Y, Cohen G, et al. Postimplantation dosimetric analysis of permanent transperineal prostate implantation: improved dose distributions with an intraoperative computer-optimized conformal planning technique. Int J Radiat Oncol Biol Phys 2000; 48(2):601–608. 22. Zelefsky MJ, Yamada Y, Cohen G, et al. Postimplantation dosimetric analysis of permanent transperineal prostate implantation: improved dose distributions with an intraoperative computer-optimized conformal planning technique. Int J Radiat Oncol Biol Phys 2000; 48(2):601–608. 23. Blasko JC, Ragde H, Grimm PD. Transperineal ultrasound-guided implantation of the prostate: morbidity and complications. Scand J Urol Nephrol Suppl 1991; 137:113–118.

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24. Benoit RM, Naslund MJ, Cohen JK. A comparison of complications between ultrasound-guided prostate brachytherapy and open prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 47(4):909–913. 25. Brandeis JM, Litwin MS, Burnison CM, Reiter RE. Quality of life outcomes after brachytherapy for early stage prostate cancer. J Urol 2000; 163(3):851–857. 26. Shipley WU, Zietman AL, Hanks GE, et al. Treatment related sequelae following external beam radiation for prostate cancer: a review with an update in patients with stages T1 and T2 tumor. J Urol 1994; 152(5 Pt 2):1799–1805. 27. Schultheiss TE, Lee WR, Hunt MA, et al. Late GI and GU complications in the treatment of prostate cancer. Int J Radiat Oncol Biol Phys 1997;37(1):3–11. 28. Teshima T, Hanks GE, Hanlon AL, et al. Rectal bleeding after conformal 3D treatment of prostate cancer: time to occurrence, response to treatment and duration of morbidity. Int J Radiat Oncol Biol Phys 1997; 39(1):77–83. 29. Rubin P, Cassarett GW. Clinical radiation pathology. Philadelphia: WB Saunders, 1968. 30. Donner CS. Pathophysiology and therapy of chronic radiationinduced injury to the colon. Dig Dis 1998; 16(4):253–261. 31. Grann A, Wallner K. Prostate brachytherapy in patients with inflammatory bowel disease. Int J Radiat Oncol Biol Phys 1998; 40(1):135–138. 32. Babb RR. Radiation proctitis: a review. Am J Gastroenterol 1996; 91(7):1309–1311. 33. Sasai T, Hiraishi H, Suzuki Y, et al. Treatment of chronic postradiation proctitis with oral administration of sucralfate. Am J Gastroenterol 1998; 93(9):1593–1595. 34. Grigsby PW, Pilepich MV, Parsons CL. Preliminary results of a phase I/II study of sodium pentosanpolysulfate in the treatment of chronic radiation-induced proctitis. Am J Clin Oncol 1990; 13(1):28–31. 35. Fantin AC, Binek J, Suter WR, Meyenberger C. Argon beam coagulation for treatment of symptomatic radiation-induced proctitis. Gastrointest Endosc 1999; 49(4 Pt 1):515–518. 36. Kochhar R, Sharma SC, Gupta BB, Mehta SK. Rectal sucralfate in radiation proctitis [Letter]. Lancet 1988; 2(8607):400. 37. Charneau J, Bouachour G, Person B, et al. Severe hemorrhagic radiation proctitis advancing to gradual cessation with hyperbaric oxygen. Dig Dis Sci 1991; 36(3):373–375. 38. Baum CA, Biddle WL, Miner PB Jr. Failure of 5-aminosalicylic acid enemas to improve chronic radiation proctitis. Dig Dis Sci 1989; 34(5):758–760. 39. Counter SF, Froese DP, Hart MJ. Prospective evaluation of formalin therapy for radiation proctitis. Am J Surg 1999; 177(5):396–398. 40. Nag S, Beyer D, Friedland J, et al. American Brachytherapy Society (ABS) recommendations for transperineal permanent brachytherapy of prostate cancer. Int J Radiat Oncol Biol Phys 1999; 44(4):789–799.

48 Sexual function following permanent prostate brachytherapy Gregory S Merrick and Wayne M Butler Introduction Erectile dysfunction (ED) has been estimated to affect up to 30 million American men, results in a deleterious effect on quality of life (QOL) including physical and emotional wellbeing, marital discord, and loss of self-esteem, and is a common sequela following treatment for prostate cancer.1–4 The National Institutes of Health (NIH) Consensus Conference defined ED as ‘the inability of attain and/or maintain penile erection sufficient for satisfactory sexual performance’, and recommended the development of reliable methods for assessing and evaluating treatment outcomes.1 Following potentially curative treatment for carcinoma of the prostate gland, potency preservation has generally been assumed to be most likely following brachytherapy, but longer followup has raised substantial doubts about the potency-sparing advantage of brachytherapy. 5–7 Following either palladium103 (103Pd) or iodine-125 (125I) brachytherapy with or without supplemental external beam radiotherapy (EBRT), ED has been reported in 6–87% of cases.5–18 With additional follow-up, continued deterioration in erectile function is expected due to the normal aging process.19 Radiation-related impotence likely represents a multifactorial process.20 In the case of brachytherapy, there is emerging evidence that ED is technique-related and may be minimized by careful attention to source placement.21 Accordingly, the documentation of sexual function and dose distributions following brachytherapy may result in refinement in treatment techniques, improved treatments for ED, and ultimately improved QOL outcomes. Quality of life instruments QOL instruments attempt to uniformly report lifestyle effects and to facilitate comparisons between different modalities. Investigators have increasingly quantified postimplant QOL with survey instruments much more detailed than previously published scales, such as those of the Radiation Therapy Oncology Group (RTOG).22 Unfortunately, none of the current QOL instruments adequately capture brachytherapyrelated sexual dysfunction. In fact, a variety of sexual symptomatology other than ED occurs following prostate brachytherapy.7,8 In a prospective randomized brachytherapy trial, brachytherapy-specific sexual changes were detailed by means of an in-depth survey of sexual function following

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therapy by blending the specific erectile questions of the International Index of Erectile Function (IIEF-5) with a number of more detailed topics (Table 48.1).8,23 Hematospermia, orgasmalgia (pain at the time of orgasm), and alteration in the intensity of orgasm were reported by 26%, 15%, and 38% of patients, respectively.8 Orgasmalgia normally occurs within the first year following implantation and is probably related to inflammation of the terminal portion of the ejaculatery ducts and the urethra.24 Hematospermia can occur as both an early and late phenomenon and probably is a result of radiation-induced capillary fragility with no apparent clinical significance.24 For most patients, the side effects are of limited duration. In addition, following brachytherapy, radiation therapy, and radical prostatectomy, Schover et al reported a significant incidence of difficulty reaching orgasm.7 Prostate brachytherapy does affect sexual function, and unfortunately, some of these changes are not addressed by standard survey tools. For QOL instruments to accurately reflect sexual function, new validated instruments with the inclusion of brachytherapyspecific symptomatology will be mandatory to accurately measure sexual QOL and to evaluate different brachytherapy techniques. The assessment of sexual potency following brachytherapy The wide ranges of ED after brachytherapy are in part a result of differences in followup, definitions of potency, and the mode of data collection. Litwin and colleagues

Table 48.1 Specific erectile function questions of the International Index of Erectile Function (IIEF) 1. How often are you able to get an erection 4. During sexual intercourse, how often were you able to maintain your erection after you had during sexual activity? penetrated (entered) your partner! 0=No sexual activity 1=Almost never/never 0=Did not attempt intercourse 2=A few times (much less than half the 1=Almost never/never time) 3=Sometimes (about half the time) 2=A few times (much less than half the time) 4=Most times (much more than half the 3=Sometimes (about half the time) time) 5=Almost always/always 4=Most times (much more than half the time) 5=Almost always/always 2. When you had erections with sexual stimulation, how often were your erections 5. During sexual intercourse, how difficult it to hard enough for penetration? maintain your erection to completion of 0=No sexual activity intercourse? 1=Almost never/never 0=Did riot attempt intercourse 2=A few times (much less than half the 1=Extremely difrtcult time) 3=Sometimes (about half the time) 2=Very difficult 4=Most times (much more than half the 3=Difficult time) 4=Slightly difficult . 5=Almost always/always

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5=Not difficult 3. When you attempted sexual intercourse, how often were you able to penetrate (enter) your 6. How do you rate your confidence that you could partner? get and keep an erection? 0=Did not attempt intercourse 1=Almost never/never 1=Very low 2=A few times (much less than half the 2=Low time) 3=Sometimes (about half the time) 3=Moderate 4=Most times (much more than half the 4=High time) 5=Almost always/always 5=Very high

reported that physician ratings of patient symptoms did not correlate well with patient self-assessment of QOL.25 To date, only two potency studies have exclusively utilized patient-administered validated instruments.6,7 The International Index of Erectile Function (IIEF-5 or IIEF-6) comprises 15 questions in 5 domains (erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction) and has been validated as a sensitive and specific tool for the evaluation of male sexual function.26,27 In contrast, Stock and colleagues formulated a four-tiered system where erectile function was graded on a 0–3 scale with erectile function primarily assigned by the physician at the time of patient interview (Table 48.2).5,10

Table 48.2 Mount Sinai four-tiered system for erectile function grading (from Stock et al5,10) Score Definition 0 1 2 3

No erections Ability to have erections but insufficient for vaginal penetration Erectile function sufficient for vaginal penetration but suboptimal Normal erectile function

The Mount Sinai scoring system is currently being utilized in two prospective randomized prostate brachytherapy trials.23,28 In the pretreatment evaluation of erectile function, the Mount Sinai scoring system has been demonstrated to closely correlate with IIEF scores (unpublished data). The remainder of the brachytherapy potency literature has either utilized a non-validated patient questionnaire,13,36 or has not utilized patient questionnaires, and has defined potency by either a subjective physician interpretation of erections sufficient for vaginal penetration,14–16,18 or without any defining criteria.9,17 Potency preservation Following brachytherapy, wide ranges of ED have been reported and may be the result of differences in patient follow-up, various definitions of ED, and the mode of data collection (Table 48.3). Data collection and QOL outcomes studies should be obtained by direct patient surveys for valid and reliable data/information.25 In general, series with longer follow-up and those that have used patient-administered instruments have reported

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lower rates of potency preservation. Using the IIEF-5 instrument, Merrick and colleagues reported a 6 year 39% rate of potency preservation for patients undergoing brachytherapy with or without supplemental EBRT and/or with or

Table 48.3 Potency preservation after permanent prostate brachytherapy Study

Year

No, patients

Potency Median f/u Definition of preservation (mths) potency

Stone9 1995 Stock10 19% Wallner15 1996

71 65 56

94% at 2 yrs 94% at 2 yrs 86% at 3 yrs

24 15 36

Sharkey17 1998 Dattoli14 1996

434 46

≥85% at 4 yrs 77% at 3 yrs

28 (m) 24

Zeitlin16

1998

100

62% at 5 yrs

33 (m)

Kiteley36 2002

50

60% at 4 yrs

34

Merrick8 2001

34

59% at 2 yrs

13

2001

313

59% at 6 yrs

31

Chaikin13 1996

27

55% at 2 yrs

18 (m)

Zeiefeky12 1999

132

47% at 5 yrs

24

Potters18

2001

482

53% at 5 yrs

34

Memck6

2002

Stock5

181 39% at 6 yrs 181 25% at 6 yrs Schover7 2002 138 19% at 4 yrs f/u, follow-up; MD, doctor; m, mean; Pt, patient.

41 41 24

? 0→3 Erection sufficient ? Erection sufficient Erection sufficient ‘Quite a bit’ ‘Very much’ IIEF-5≥11

Data collection method ? ? MD interview ? ? ? Pt administered

MD phone interview or Pt administered 0→3 2/3 MD interview, 1/3 Pt administered Erection MD phone interview sufficient Erection ? sufficient Erection MD interview sufficient IIEF-5≥11 Pt administered IIEF-5>21 Pt administered IIEF-6>22 Pt administered

without hormonal manipulation.6 In patients not receiving EBRT, a 52% rate of potency preservation was reported at 6 years.6 This finding is comparable to prior 5 and 6 year potency results from Mount Sinai and Memorial Sloan-Kettering for patients undergoing monotherapeutic brachytherapy.5,12 Using the IIEF-6, Schover et al reported that 19%, 13–18%, and 7–15% of patients undergoing brachytherapy, radical prostatectomy, or external beam radiation therapy did not develop any erectile dysfunction.7 In contrast, Potters and colleagues, utilizing physician interviews to assign potency, reported a 76% rate of potency preservation at 5 years for patients undergoing monotherapeutic brachytherapy.18 In addition, Potters et al reported that 80% of brachytherapy-induced ED was apparent by 24 months,18 while two other studies reported the median time to development of brachytherapy-induced ED was 17 months and 6 months, respectivel.6,12

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Because sexual function represents a spectrum of performance, reported rates of potency preservation are often divergent even when the same or comparable instruments are used due to various thresholds of success. For example, following brachytherapy, Merrick and colleagues defined potency preservation as an IIEF-5 score ≥11, which translates into the ability to successfully engage in sexual intercourse on almost one half of all encounters.6 In contrast, the Cleveland Clinic used an IIEF-6 score >22 out of 30 to select patients who did not develop any erectile dysfunction following potentially curative treatment. When an IIEF-5 score >21 out of 25 was utilized to define the absence of ED following brachytherapy, treatment success at the Schiffler Cancer Center was comparable to that of the Cleveland Clinic (25% vs 19%).6,7 Following potentially curative cancer treatment, it is questionable whether investigators should report potency preservation as the absence of any diminution of erectile function rather than the ability to successfully engage in sexual intercourse a certain percentage of the time. Using patient-administered validated instruments with longer follow-up, two factors regarding post-implant ED have become apparent. First, there is a significant incidence of immediate postimplant ED which is presumably related to needle trauma. Merrick and colleagues reported that 6 of 34 patients developed severe ED (IIEF-5<6 in the immediate postimplant period).8 Long-term potency in patients who experienced immediate postimplant ED has not been detailed, but spontaneous improvement has been noted with time. The second important factor is that ED increases with time after treatment. Series with longer follow-up have uniformly reported lower rates of potency preservation (Table 48.3). Potency preservation rates following all treatment approaches are significantly lower when patient-administered questionnaires are used in comparison to the collection of data by physician interview. The utilization of patientadministered questionnaires following radical prostatectomy has resulted in dramatically differing results.7,29–32 In four of those studies, a 7–44% rate of potency preservation following radical prostatectomy was reported.7,30–32 In contrast, however, a study of 64 patients using a validated patientadministered questionnaire and a definition of potency as ‘the ability to engage in unassisted intercourse with or without sildenafil’ reported that 86% of patients were potent following radical prostatectomy.29 Only 2 patients were exclusively sildenafildependent. A possible selection bias, however, may have been inherent to the study because only 38% of the 59 patients who agreed to participate returned all four questionnaires. A recent Cleveland Clinic study with a patient participation rate of 49% and a mean follow-up of 4.3 years reported a potency preservation rate of 13–18%.7 Factors affecting potency The mechanism of brachytherapy-induced ED has not been definitively proven. The etiology, however, likely represents a multifactorial process including neurogenic compromise, vascular insufficiency, local trauma, and psychogenic causes.20

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Preimplant erectile function Stock and colleagues reported preimplant erectile function to be the strongest predictor of posttreatment ED.5 Six years following brachytherapy, 70% of patients with normal preimplant erectile function maintain potency versus only 34% of patients with preimplant erections sufficient for intercourse, but considered suboptimal (Figure 48.1).

Figure 48.1 Potency preservation as a function of preimplant erectile function. These patients were scored by Stock et al as either normal (solid line), suboptimal, but capable of intercourse (dashed line), and no erections or erections inadequate for intercourse.5 Merrick and colleagues also reported that preimplant erectile function was predictive of 6 year potency preservation (50% for normal erections vs 13% for preimplant erections considered suboptimal). Patient age Patient age may influence the likelihood of brachytherapyinduced ED. Potters and colleagues reported that patients <60, 60–69, and ≥70 years of age had a 78%, 58%, and 50% potency preservation rate at 5 years following brachytherapy.18 Schover et al also reported that younger age was strongly associated with better sexual outcomes.7 In contrast, Merrick and colleagues reported that patient age was significant in univariate, but not multivariate analysis (Figure 48.2),6 while Stock et al reported no relationship between patient age and impotence.5

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Supplemental external beam radiotherapy The addition of supplemental external beam radiotherapy (EBRT) appears to increase the incidence of brachytherapyinduced ED. Merrick and colleagues reported that the addition of supplemental EBRT to brachytherapy decreased the 6 year actuarial rate of potency preservation from 52% to 26%.6 Potters et al reported a statistically nonsignificant reduction in potency when EBRT was added to brachytherapy (76% vs 56%, p=0.08).18

Figure 48.2 The effect of age at implant on potency preservation from Merrick et al.6 The population was stratified into age cohorts of (dotted line). <60 years (solid line), 60–69 years (dashed line), and 70+ years Neo-adjuvant hormonal manipulation Studies investigating the relationship between neoadjuvant hormonal manipulation and potency preservation have reported mixed results. With a median follow-up of 34 months, Potters et al18 reported the use of neo-adjuvant hormonal manipulation predicted for posttreatment ED. In patients undergoing monotherapeutic brachytherapy, 76% maintained potency whereas when neo-adjuvant hormonal manipulation was followed by brachytherapy without supplemental EBRT, the potency preservation rate was 52%. Schover et al also reported poor sexual outcomes with the use of neo-adjuvant hormonal therapy.7 In contrast, two other studies failed to reveal a relationship between hormonal therapy and ED.5,6 In univariate analysis, Stock et al reported a deleterious effect due to neo-adjuvant hormonal therapy (potency preservation rates of 54% vs 61%, p=0.04).5 In multivariate analysis, however, neo-adjuvant hormonal manipulation was not statistically significant (p=0.12). Merrick et al reported the utilization of hormonal manipulation did not statistically affect the ultimate rate of potency preservation (37% vs 46%, p=0.836).6

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Choice of isotope Of the multiple published brachytherapy potency studies, only two have evaluated the influence of choice of isotope on potency preservation.5,6 With 6 year results, neither study was able to discern a difference in potency preservation based on isotope. A current ongoing prospective study comparing palladium-103 (103Pd) with iodine-125 (125I) for patients with low risk prostate cancer (clinical stage T1b-T2a 1996 American Joint Committee on Cancer, prostate-specific antigen (AJCC, PSA) ≤10 ng/mL, Gleason score 5–6) will provide invaluable information regarding the ultimate effect of choice of isotope on potency preservation.23 Additional clinical and treatment parameters Of a multitude of additional clinical and treatment parameters evaluated, one study reported a strong correlation between diabetes mellitus and brachytherapy-induced ED. Patients without and with diabetes had potency preservation rates of 49% versus 0% at 2 years and 41.4% versus 0% at 6 years (p=0.017).6 Mechanism of brachytherapyinduced ED Radiation-related impotence likely represents a multifactorial process.20 In the case of brachytherapy, there is emerging evidence that ED is technique-related and may be minimized by careful attention to source placement. Radiation dose to the prostate gland Conflicting results have been reported regarding the relationship between radiation dose to the prostate gland and the development of brachytherapy-induced ED. Stock and colleagues reported that a D90 (radiation dose delivered to 90% of the prostate gland) >160 Gy for 125I or a D90 >100 Gy for 103Pd was predictive of brachytherapyinduced ED.5 Although statistically significant differences in potency preservation were reported, the absolute differences were minimal (58% vs 64%, p=0.02). In contrast, Merrick et al reported no correlation between the radiation dose delivered to the prostate gland in terms of the D90 and V100/150/200 (the percent volume of the prostate receiving 100%, 150%, and 200% of the prescription dose) and brachytherapy-induced ED.6 Neurovascular bundles Following radical prostatectomy, ED has been correlated with surgical trauma to the neurovascular bundles (NVB).33 Excessive radiation to the NVB represents a potential mechanism for brachytherapy-induced ED. DiBiase and colleagues reported that radiation doses to the neurovascular

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Figure 48.3 Schematic diagram of the location of the neurovascular bundles (NVB) which lie approximately 2 mm outside the posterolateral lobes of the prostate. Merrick et al. calculated additional points on a 4 mm wide ribbon to simulate the NVB plexus.35 bundles are in the range of 200% of the minimum prescribed dose (MPD).34 To date, studies have failed to establish a relationship between radiation doses to the NVB and brachytherapy-induced ED.8,35,36 Merrick and colleagues evaluated the radiation dose to the NVB by means of a two-dimensional geometric model based on day 0 computed tomography (CT)-based dosimetry (Figure 48.3).8,35 Because the exact location of the NVB is somewhat variable, represents a plexus and not a well-localized structure, and is not identifiable on CT, the delivered radiation dose to the region of the NVB was determined by both point dose measurements and dose-surface histograms with the conclusion that the radiation dose in the evaluated area is relatively homogeneic.8,35 With a median follow-up of 37 months, no relationship was discerned between radia tion doses to the NVB (mean dose: 217% MPD) and the development of brachytherapy-induced ED in both retrospective and prospective evaluations.8,35 Although initial reports have been negative, it is possible that with longer follow-up NVB doses may be found to contribute to brachytherapy-related ED. Penile erectile bodies There is an increasing body of data implicating excessive radiation doses to the proximal penis and radiationrelated ED.37–40 The penile erectile bodies (the paired corpora cavernosa and the midline corpus spongiosum) represent a potential candidate for sitespecific radiation doses related to ED (Figure 48.4).39 Followed posteriorly into the perineum, the corpora cavernosa separate and form the crura of the penis, which are attached to the inferior pubic rami. Between the two crura, the corpus spongiosum enlarges to form the bulb of the penis, which is attached superiorly to the inferior surface of the urogenital diaphragm. The penile bulb is best visualized on T2-weighted magnetic

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resonance imaging (MRI) and appears as an oval-shaped hyperdense midline structure located 10–15 mm inferior to the apex of the prostate gland (Figure 48.4).39 With day 0 CT-based dosimetric evaluation, the radiation dose delivered to 50% of the bulb of the penis (D50) was <50 Gy and the dose delivered to 95% of the bulb of the penis (D95) was <20 Gy for the majority of patients who maintained potency while the vast majority of men who became impotent exceeded these values.37,38 In contrast, Kiteley et al also evaluated radiation doses to the bulb of the penis and were unable to correlate proximal penile doses with posttreatment ED.36 Excessive radiation doses

Figure 48.4 Transverse computed tomography (CT) and magnetic resonance imaging (MRI) of the midbulbar region illustrating the corpora cavernosa, left and right crura, penile bulb, pubic arch, and rectum. to the bulb of the penis are the result of either poor planning and/or poor intraoperative technique. Refinements in implant technique, including preplanning and intraoperative seed placement with utilization of the sagittal ultrasound plane for the deposition of the apical/periapical seeds, will result in lower radiation doses to the proximal penis with potential improvement in potency preservation. Management of brachytherapyinduced erectile dysfunction Patients with radiation-related ED typically respond well to conventional erectile aids with improved erectile function and overall quality of life.41 Mulhall reported that a lack of erectile activity may be deleterious to erectile function and, as such, patients should be encouraged to develop regular erections with or without sexual relations.42 In the absence of routine penile erections, the corporal smooth muscle experiences chronic hypoxia with resultant loss of elasticity and distensibility which may lead to a venous leak. Based on the premise that erections enhance tissue oxygenation and suppress smooth muscle fibrosis, therapy to enhance nocturnal erections (night-time ‘physical therapy’ for the

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penis) might have a therapeutic benefit.43 Montorsi et al demonstrated that sildenafil (Viagra), but not placebo, taken at bedtime produced a significant improvement in nocturnal erectile activity.44 This concept of night-time ‘physical therapy’ could also potentially reduce brachytherapy-induced ED. The majority of patients with brachytherapy-induced ED respond favorably to sildenafil citrate.45 In a brachytherapy population, the 6 year actuarial rate of potency preservation was 92% when potent patients were grouped with ED patients who used sildenafil citrate (Figure 48.5).6 The postimplant response to sildenafil was highly dependent on preimplant potency.6 Patients with normal erections and erections sufficient for vaginal penetration but considered suboptimal responded favorably to sildenafil in 95% and 70% of cases, respectively.6 Potters et al reported that 83% of patients who underwent prostate brachytherapy with or without supplemental EBRT responded favorably to sildenafil, while only 46% of patients who received neo-adjuvant hormonal manipulation responded to such pharmacologic support. Radiation-induced ED also responds to vasoactive agents and penile implants.46,47 Conclusions Brachytherapy-induced erectile dysfunction (ED) is more common than initially reported. Although the etiology of brachytherapy-induced ED is likely multifactorial, the

Figure 48.5 Potency preservation in a brachytherapy cohort with and without the support of sildenafil citrate (Viagra). (Adapted from Merrick et al).6 available data strongly support the proximal penis as an important site-specific structure. Some, but not all studies have also reported preimplant potency, patient age, diabetes mellitus, the use of supplemental external beam radiotherapy, and radiation doses to the

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prostate gland to be predictive for the development of posttreatment ED. The majority of patients with brachytherapy-induced ED respond favorably to sildenafil. In order to obtain the most reliable quality of life information, potency data should be collected by validated patient-administered instruments. Continued attempts to refine patient selection, brachytherapy planning philosophies, intraoperative technique, and postimplant management may result in improved rates of potency preservation, improved treatments for ED and ultimately, better quality of life outcomes. References 1. NIH Consensus Development Panel on Impotence: Impotence. JAMA 1993; 270:83–90. 2. Day D, Ambegaonkar A, Harriot K, et al. A new tool for predicting erectile dysfunction. Adv Ther 2001; 18:131–139. 3. Burnett AL. Erectile dysfunction: a practical approach for primary care. Geriatrics 1998; 53:34– 48. 4. Laumann EO, Paik A, Rosen RC. Sexual dysfunction in the United States: prevalence and predictions. JAMA 1999; 281:537–544. 5. Stock RG, Kao J, Stone NN. Penile erectile function after permanent radioactive seed implantation for treatment of prostate cancer. J Urol 2001; 165:436–439. 6. Merrick GS, Butler WM, Galbreath RW, et al. Erectile function after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002; 52:893–902. 7. Schover LR, Fouladi RT, Warneke CL, et al. Defining sexual outcomes after treatment for localized prostate carcinoma. Cancer 2002; 95:1773–1785. 8. Merrick GS, Wallner K, Butler WM, et al. Short-term sexual function after prostate brachytherapy. Int J Cancer (Radiat Oncol Investig) 2001; 96:313–319. 9. Stone NN, Stock RG. Brachytherapy for prostate cancer: Real-time three-dimensional interactive seed implantation. Tech Urol 1995; 1:72–80. 10. Stock RG, Stone NN, lannuzzi C. Sexual potency following interactive ultrasound-guided brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 1996; 35:267–272. 11. Ragde H, Blasko JC, Grimm PD, et al. Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate cancer. Cancer 1997; 80:442–453. 12. Zelefsky MJ, Wallner KE, Ling CC, et al. Comparison of the 5-year outcome and morbidity of three-dimensional conformal radiotherapy versus transperineal permanent iodine-125 implantation for early stage prostate cancer. J Clin Oncol 1999; 17:517–522. 13. Chaikin DC, Broderick GA, Malloy TA, et al. Erectile dysfunction following minimally invasive treatments for prostate cancer. Urology 1996; 48:100–104. 14. Dattoli M, Wallner K, Sorace R, et al. 103Pd brachytherapy and external beam irradiation for clinically localized high-risk prostatic carcinoma. Int J Radiat Oncol Biol Phys 1996; 35:875– 879. 15. Wallner K, Roy J, Harrison L. Tumor control and morbidity following transperineal iodine 125 implantation for stage T1/T2 prostatic carcinoma. J Clin Oncol 1996; 14:449–453. 16. Zeitlin SI, Sherman J, Raboy A, et al. High dose combination radiotherapy for the treatment of localized prostate cancer. J Urol 1998; 160:91–96. 17. Sharkey J, Chovnick S, Behar R, et al. Outpatient ultrasound-guided palladium 103 brachytherapy for localized adenocarcinoma of the prostate: A preliminary report of 434 patients. Urology 1998; 51:796–803. 18. Potters L, Torre T, Fearn PA, et al. Potency after permanent prostate brachytherapy for localized prostate cancer. Int J Radiat Oncol Biol Phys 2001; 50:1235–1242.

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19. Feldman HA, Goldstein I, Hatzichriftou DG, et al. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. J Urol 1994; 151:54–61. 20. Zelefsky MJ, Eid JF. Elucidating the etiology of erectile dysfunction after definitive therapy for prostate cancer. Int J Radiat Oncol Biol Phys 1998; 40:129–133. 21. Merrick GS, Butler WM. The dosimetry of brachytherapy-induced erectile dysfunction. Med Dosm 2003; 28:271–274. 22. Lawton CA, Won M, Pilepich MV. Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: Analysis of RTOG studies 7506 and 7706. Int J Radiat Oncol Biol Phys 1991; 21:935–939. 23. Wallner K, Merrick GM, True L, et al. I-125 versus Pd-103 for low risk prostate cancer: Morbidity outcomes from a prospective randomized multicenter trial. Cancer J Sci Am 2002; 8:67–73. 24. Wallner K, Blasko J, Dattoli MJ, eds. Prostate brachytherapy made complicated, 2nd edn. Seattle: SmartMedicine Press, 2002:16.1–16.30. 25. 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; 159:1988–1992. 26. Blander DS, Sanchez-Ortiz RF, Broderick GA. Sex inventories: Can questionnaires replace erectile dysfunction testing? Urology 1999; 54:719–723. 27. Rosen RC, Riley A, Wagner G, et al. The International Index of Erectile Function (IIEF): A multidimensional scale for assessment of erectile dysfunction. Urology 1997; 49:822–830. 28. Wallner K, Merrick G, True L, et al. I-125 versus Pd-103 for low risk prostate cancer: Preliminary urinary functional outcomes from a prospective randomized trial. J Brachyther Int 2000; 16:151–155. 29. Walsh PC, Marschke P, Ricker D, et al. Patient-reported urinary continence and sexual function after anatomic radical prostatectomy. Urology 2000; 55:58–61. 30. Talcott JA, Rieker P, Clark JA, et al. Patient-reported symptoms after primary therapy for early prostate cancer: Results of a prospective cohort study. J Clin Oncol 1998; 16:275–283. 31. Talcott JA, Rieker P, Propert KJ, et al. Patient-reported impotence and incontinence after nervesparing radical prostatectomy. J Natl Cancer Inst 1997; 89:1117–1123. 32. Stanford JL, Feng Z, Hamilton AS, et al. Urinary and sexual function after radical prostatectomy for clinically localized prostate cancer. JAMA 2000; 283:354–360. 33. Lepor H, Gregerman M, Crosby R, et al. Precise localization of the autonomic nerves from the pelvic plexus to the corpora cavernosa: A detailed anatomical study of the adult male pelvis. J Urol 1985; 133:207–212. 34. DiBiase SJ, Wallner K, Tralins K, et al. Brachytherapy radiation doses to the neurovascular bundles. Int J Radiat Oncol Biol Phys 2000; 46:1301–1307. 35. Merrick GS, Butler WM, Dorsey AT, et al. A comparison of the radiation dose to the neurovascular bundles in men with and without prostate brachytherapy induced erectile dysfunction. Int J Radiat Oncol Biol Phys 2000; 46:1069–1074. 36. Kiteley RA, Lee WR, deGuzman AF, et al. Radiation dose to the neurovascular bundles or penile bulb does not predict erectile dysfunction after prostate brachytherapy. Brachytherapy 2002; 1:90–94. 37. Merrick GS, Wallner K, Butler WM, et al. A comparison of radiation dose to the bulb of the penis in men with and without prostate brachytherapy induced erectile dysfunction. Int J Radiat Oncol Biol Phys 2001; 50:597–604. 38. Merrick GS, Butler WM, Wallner KE, et al. The importance of radiation doses to the penile bulb versus crura in the development of postbrachytherapy erectile dysfunction. Int J Radiat Oncol Biol Phys 2002; 54:1055–1062. 39. Wallner KE, Merrick GS, Benson ML, et al. Penile bulb imaging. Int J Radiat Oncol Biol Phys 2002; 53:928–933.

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40. Mulhall JP, Yonover P, Sethi A, et al. Radiation exposure to the corporeal bodies during 3dimensional conformal radiation therapy for prostate cancer. J Urol 2002; 167:539–542. 41. Perez MA, Meyerowitz BE, Lieskovsky G, et al. Quality of life and sexuality following radical prostatectomy in patients with prostate cancer who use or do not use erectile aids. Urology 1997; 50:740–746. 42. Mulhall JP. Minimizing radiation-induced erectile dysfunction. J Brachyther Int 2001; 17:221– 227. 43. McCullough AR. Prevention and management of erectile dysfunction following radical prostatectomy. Urol Clin North Am 2001; 28:613–627. 44. Montorsi F, Maga T, Strambi LF, et al. Sildenafil taken at bedtime significantly increases nocturnal erections: Results of a placebo-controlled study. Urology 2000; 56:906–911. 45. Merrick GS, Butler WM, Lief JH, et al. Efficacy of sildenafil citrate in prostate brachytherapy patients with erectile dysfunction. Urology 1999; 53:1112–1116. 46. Pierce LJ, Whittington R, Hanno PM, et al. Pharmacologic erection with intracavernosal injection for men with sexual dysfunction following irradiation; A preliminary report. Int J Radiat Oncol Biol Phys 1991; 21:1311–1314. 47. Dubocq FM, Bianco FJ, Maralani SJ, et al. Outcome analysis of penile implant surgery after external beam radiation for prostate cancer. J Urol 1997; 158:1787–1790.

49 Prostate-specific antigen bounce following prostate brachytherapy Frank A Critz Introduction Prostate-specific antigen (PSA) bounce is an extremely interesting and very common phenomenon that has been recognized in men treated for prostate cancer with brachytherapy,1–5 as well as external beam irradiation alone.6,7 PSA bounce is defined by a temporary postirradiation PSA rise of benign etiology.1 PSA bounce causes two major issues: anxiety in men treated with irradiation for prostate cancer and a problem for physicians who must sort PSA bounce from treatment failure. In our experience, anxiety caused by bounce can be minimized by educating men about this issue before and after irradiation for prostate cancer. Consequently, all physicians who have contact with men given irradiation for prostate cancer should be aware of PSA bounce. This report describes PSA bounce after brachytherapy for prostate cancer. Materials and methods From 1992 to 1998, 1658 men with clinical stage T1–T2, Nx, M0 prostate cancer were treated with simultaneous irradiation (SI), a radioactive iodine-125 (125I) seed implant with the ultrasound-guided transperineal implant technique followed by external beam radiotherapy (EBRT). Men who received neo-adjuvant androgen deprivation were excluded from this analysis. The technique of irradiation has been previously described. PSA bounce is defined by a PSA increase of 0.1 ng/mL or more, above the PSA level before the bounce followed by a subsequent decrease to or below the prebounce nadir with PSA 0.2 ng/mL as the floor. PSA fluctuations below PSA 0.2 ng/mL are not considered a bounce. For example, a PSA change from 0.1 to 0.2 to 0.1 ng/mL is not a bounce; whereas, an increase from 0.2 to 0.3 ng/mL or more and back to 0.2 ng/mL is defined as a bounce. All men in this study were treated five or more years ago. Follow-up was performed three months postimplant, three months later, and every six months thereafter. Men were not changed to annual follow-up. Although PSAs were often obtained on a more frequent basis than every six months when trying to sort bounce from recurrence, only PSAs obtained at the above follow-up schedule were used in this study. PSA measurements were obtained from a variety of laboratories using several different PSA assay techniques.

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Results Figure 49.1 describes a hypothetical case of PSA bounce which is used to define various terms associated with bounce. Prebounce nadir means the lowest PSA achieved prior to onset of PSA bounce. The first PSA rise of 0.1 ng/mL or more above the prebounce nadir defines the onset of PSA bounce and duration of PSA bounce is defined by the time from onset to return of PSA to the prebounce nadir level or lower. PSA bounce peak means the highest PSA achieved during bounce and bounce height is defined by bounce peak less prebounce nadir. A second bounce is defined by a subsequent PSA rise after return to the initial PSA bounce nadir. Calculated at the time of onset, the overall incidence of PSA bounce in this study is 45% (746/1658) (Figure 49.2). Figure 49.3 demonstrates the incidence of bounce, calculated from the time of onset, according to age of men at implantation. Figure 49.4 evaluates the time to onset of bounce for the 746 men who experienced a bounce. Of bounce cases, 99% have an onset within 60 months of implantation. Only 1% (7/746) had a bounce onset at 66 months or more follow-up. Figure 49.5 documents the bounce height of all men who experienced a bounce in this study. The median height is 0.3 ng/mL (0.1– 11.8 ng/mL) and 17% had a bounce height of ≥1.1 ng/mL. Bounce duration is documented in Figure 49.6, including the median and range of bounce height according to duration. As noted, bounce duration is directly related to bounce

Figure 49.1 A hypothetical case of prostate-specific antigen (PSA) bounce used to define terms associated with PSA bounce called bounce characteristics.

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Figure 49.2 The time distribution of PSA bounce calculated at the time to onset of bounce based on evaluation of all 1658 men in this study.

Figure 49.3 The incidence of bounce, calculated from the time to onset, according to age of men at implantation. Younger men have a

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significantly higher frequency of PSA bounce than older men.

Figure 49.4 Of the 746 men who experienced a bounce, this histrogram documents the time to onset of bounce. As noted, 3% of men who have a bounce experience this phenomenon at the first PSA after treatment, 68% of bounces have an onset between 12 and 24 months postimplant and 99% of bounces have an onset within 60 months of implantation. Only 1% of men who had a bounce had an onset at 66 months or more following implantation.

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Figure 49.5 Bounce height for the 746 men in this study who had a PSA bounce. The median bounce height is 0.3 ng/mL (0.1–11.8 ng/mL).

Figure 49.6 Duration of PSA bounce for the 746 men who experienced a bounce based on PSA obtained at 6 month intervals from implantation, except for the initial PSA at 3 months postimplant. Additionally, the median and range of bounce heights is provided for bounce duration which

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shows a direct correlation between duration and median bounce height. height. The prebounce nadir is evaluated in Figure 49.7. The disease-free survival rate, calculated with PSA cutoff point of 0.2 ng/mL, is demonstrated in Figure 49.8. This information is inaccurate due to the bias caused by men who experience a bounce because men who have an early recurrence will not have the opportunity to bounce. Inherently, men who have a bounce should always have a significantly higher diseasefree survival rate. When adjustment is made for the bias caused by bounce men, disease freedom from prostate cancer is unrelated to bounce. Discussion To analyze prostate-specific antigen (PSA) bounce, only men treated five or more years ago should be evaluated.

Figure 49.7 Prebounce nadir for the 746 men who experienced a bounce. The median prebounce nadir was 0.7 ng/mL (0.1–8.9 ng/mL).

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Figure 49.8 Disease freedom according to whether or not men experienced a PSA bounce. Although calculated correctly, the findings in this figure are inaccurate and misleading due to bias caused by bounce men. Men who have an early recurrence will not have a chance to have a PSA bounce. Consequently, men who have a bounce will inherently have a better disease-free survival rate than men who do not experience a PSA bounce. After adjustments for the bias factor created by bounce, there is no significant difference in disease freedom between men who have a bounce and men who do not have a bounce. Also, the frequency of PSAs to be evaluated should be standardized. In this report, all men were treated 5 or more years ago and only PSAs obtained at 6 month intervals, based on the date of implantation, were evaluated except for the initial PSA three months postimplant. PSA bounce is a very common phenomenon. Overall, 45% of men experience a PSA bounce (Figure 49.2) with a peak time to onset at 18 months postimplantation (Figure 49.4) and 68% of men have a bounce onset between 12 and 24 months postimplant. Onset of PSA bounce is rare after 60 month follow-up and occurred in only 1% of men in

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this study. The frequency of PSA bounce is directly related to a man’s age at implantation (Figure 49.3) and is 58% for men aged ≤60 at implant compared to a bounce frequency of only 26% in men aged 71 or more. Sixty-five percent of men have a bounce duration of 6 months, a single PSA rise (Figure 49.6). However, 35% of men have a bounce duration between 12 and 30 months and bounce duration is directly related to bounce height. Consistent with the time to onset of PSA bounce, the median prebounce nadir is 0.7 ng/mL (Figure 49.7). Although the median prebounce height in this study is only 0.3 ng/mL (Figure 49.5) and does not appear impressive, a PSA rise of any magnitude can cause considerable anxiety in men who are expecting a fall in PSA after brachytherapy for prostate cancer. The peak bounce height in this study is 16.0 ng/mL and 15% of men have multiple PSA bounces. Various clinical factors have been evaluated to see if there is any relationship to PSA bounce. Neither pretreatment PSA, Gleason score, clinical stage, race, prostate size, nor implant dose is related to PSA bounce.2 The only clinical factor related to PSA bounce is patient age at implantation. In fact, age of men has a dramatic effect on PSA bounce. Although intuitively one might think that older men with enlarged prostates might have a higher frequency of PSA bounce, analysis of this database shows that PSA bounce is much more common in younger men. Of men aged ≤60, 58% had a bounce compared to 40% of men aged 61–70 and 26% of men aged ≥71. Additionally, young men have an earlier onset of bounce, the duration is longer, the bounce height is higher and have more multiple bounces than older men.2 In other words, most men aged ≤60 will have a PSA bounce and bounce characteristics are much worse in younger men than older men. The etiology of PSA bounce is unknown. We have noted a recurrence of urinary symptoms postimplantation that roughly corresponds to the time of onset of PSA bounce which may reflect delayed inflammation of the prostate. Additionally, we have noted a relationship of sexual function to the incidence of PSA bounce which may partially explain why young men have a higher bounce frequency than older men. However, the majority of cases of bounce are not related to any known factor. One of the most important issues of PSA bounce is the relationship to disease freedom. Based on previous analysis of our data,1,2 as well as other reports,3–5 PSA bounce is not related to treatment failure. Comparison of diseasefree survival (DFS) curves between bounce and no bounce men will inherently show that men who experience a bounce have a better DFS rate (Figure 49.8). However, this is due to the bias caused by PSA bounce and when adjustments are made for this bias, no difference is noted in DFS rate according to whether or not men have a bounce. In fact, all evidence indicates that PSA bounce is unrelated to prostate cancer but is due to an effect on benign prostate epithelium prior to destruction by SI. No pretreatment clinical factors of prostate cancer, except for patient age, are related to bounce.2 Additionally, PSA bounce is rare after 5 year follow-up. Only 1% of men who had a bounce have an onset after 5 year follow-up. This correlates with the finding that of the men who achieve PSA 0.2 ng/mL after SI, 99% will do so by 5 year follow-up.8 Achievement of PSA nadir 0.2 ng/mL suggests destruction of most, if not all, benign prostate epithelium for this is the same PSA goal for a successful radical prostatectomy. Distinguishing PSA bounce from recurrence of prostate cancer is another major issue. Except for close PSA followup, there is no known method to sort bounce from recurrence. Malignant epithelium may resolve slowly from a histological standpoint after

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irradiation, which may confound interpretation of prostate biopsy.9 Several cases of falsepositive prostate biopsies have been documented in men who have had a bounce.10 The characteristics of bounce (Figure 49.1) appear to be unrelated to monotherapy with either 125I or 103Pd implantation or EBRT before or after seed implant for prostate cancer.3 Variation in reporting of bounce characteristics may be due to different definitions of bounce, studies with less than a 5 year follow-up and variation in frequency of PSA follow-up. In this study, PSA bounce is defined as a rise of 0.1 ng/mL. Other investigators of brachytherapy have defined bounce by a rise of 0.2 ng/mL, 0.4 ng/mL, or a percent increase in PSA.3–5 Defining bounce by a rise of only 0.1 ng/mL could be criticized as being within the background noise of the PSA assay. However, the time distribution of men with a PSA rise of 0.1 ng/mL compared to 0.2 ng/mL or more is similar instead of a random event as one might expect if a PSA rise of 0.1 ng/mL was due to background noise.2 Conclusions Prostate-specific antigen (PSA) bounce is defined as a temporary PSA rise caused, it is believed, by an effect on benign epithelium and is unrelated to either the cure of prostate cancer nor any clinical factors except for age of men at implantation. Young men have a higher frequency and worse bounce characteristics than older men, which is particularly disconcerting because young men would be more favorable candidates for local salvage treatment should there be local recurrence. Except for close PSA follow-up, there is no known way to distinguish bounce from treatment failure. References 1. Critz FA, Williams WH, Benton JB, et al. Prostate specific antigen bounce after radioactive seed implantation followed by external beam radiation for prostate cancer. J Urol 2000; 163:1085– 1089. 2. Critz FA, Williams WH, Levinson AK, et al. Prostate specific antigen bounce after simultaneous irradiation for prostate cancer: The relationship to patient age. J Urol 2003; 170:1864–1867. 3. Cavanagh W, Blasko JC, Grimm PD, Sylvester JE. Transient elevation of serum prostate-specific antigen following 125I/103Pd brachytherapy for localized prostate cancer. Semin Urol Oncol 2000; 18:160–165. 4. Merrick GS, Butler WM, Wallner KE, et al. Prostate-specific antigen spikes after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002; 54:450–456. 5. Stock RG, Stone NN, Cesaretti JA. Prostate-specific antigen bounce after prostate seed implantation for localized prostate cancer: Descriptions and implications. Int J Radiat Oncol Biol Phys 2003; 56:448–453. 6. Hanlon AL, Pinover WH, Horwitz EM, Hanks GE. Patterns and fate of PSA bouncing following 3D-CRT. Int J Radiat Oncol 2001; 50:845–849. 7. Rosser CJ, Kuban DA, Levy LB, et al. The prostate specific antigen bounce phenomenon after external beam radiation for clinically localized prostate cancer. J Urol 2002; 168:2001–2005. 8. Critz FA. Time to achieve PSA nadir 0.2 ng/ml following simultaneous irradiation of prostate cancer. J Urol 2002; 168:2434–2438.

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9. Crook JM, Perry GA, Robertson S, et al. Routine prostate biopsies following radiotherapy for prostate cancer: results for 226 patients. Urology 1995; 624:45. 10. Smathers S, Wallner K, Sprouse J, True L. Temporary PSA rises and repeat prostate biopsies after brachytherapy. Int J Radiat Oncol Biol Phys 2001; 50:1207–1211.

50 Factors predicting for urinary incontinence following prostate brachytherapy Tracy L McElveen, Frank M Waterman, Hayeon Kim, and Adam P Dicker Introduction Permanent prostate brachytherapy has evolved over the last decade as a treatment option for early stage prostate cancer. Excellent five year biochemical control rates have been shown, suggesting that radical prostatectomy, threedimensional conformal radiation therapy, and brachytherapy are relatively equally effective for the treatment of favorable risk disease.1–9 Issues about quality of life are increasingly important to patients faced with choosing a treatment modality and to the physicians who counsel them. Quality of life issues often include rectal bleeding or diarrhea, sexual dysfunction, irritative urinary symptoms, and urinary incontinence. Although the majority of papers have focused on the obstructive urinary symptoms patients have experienced, little has been published regarding urinary incontinence. Urinary incontinence has been associated with radical prostatectomy and according to the National Medicare Experience over 47% of patients have reported some degree of incontinence following this procedure.10 Rates over a broad range of 0–40% following brachytherapy have been reported.4,5,11–15 Many reports however, contain physician-acquired information, which has been shown to correlate poorly with data collected with patient self-assessment questionnaires.10,16–20 Much of the published literature on this topic lacks dosimetric information and does not specifically include urinary incontinence in the grading scale. Attempts to establish widespread use of validated self-assessment questionnaires to adequately address incontinence have been unsuccessful to date. Although the incidence of incontinence after brachytherapy is likely less than after radical prostatectomy, it may not be as low as presently believed. We evaluated the incidence of urinary incontinence and attempted to determine predictive factors for this complication. Method Our study cohort consisted of 153 consecutive patients with early stage prostate cancer implanted by one physician (APD) at our institution from October 1996 through December 2001, giving a median follow-up of 47 months (range: 14–74). Patient characteristics included a prostatespecific antigen (PSA)≤10, Gleason score (GS)≤6, and stage≤T2b. Patients who received external beam radiotherapy (EBRT) and patients implanted with palladium103 (103Pd) were excluded. All patients were evaluated with a history and physical examination, baseline International Prostate Symptom Score (IPSS),

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and an internal pathologic review of biopsy specimens. Seven of these patients received approximately three months of androgen suppression for glandular downsizing and were included in our analysis. After obtaining institutional review board approval, a survey including a selfassessment questionnaire and an IPSS form was sent to each of the 153 patients. The American Brachytherapy Society (ABS) recommends that the IPSS be used for reporting urinary morbidity and that incontinence, dysuria, gross hematuria, and urinary retention be quantified using the National Cancer InstituteCommon Toxicity Criteria (NCICTC).21–23 ABS also recommends the use of patient-administered instruments that report actuarial and crude incidences of these toxicities. In an effort to comply with these recommendations we used the NCI-CTC version 2 to formulate a patient selfassessment questionnaire. For other adverse events some words were simplified, but for urinary incontinence, the scale appeared on the survey in the exact language used in the NCICTC version 2: grade 0 is no incontinence; grade 1 includes incontinence with coughing, sneezing, laughing; grade 2 includes spontaneous incontinence with some control; and grade 3 is no control. This is not a selfassessment tool, however; no self-assessment instrument currently exists to provide a measure of the incidence of incontinence in patients treated with brachytherapy. Because the exact language of the scale for incontinence was used in the survey, we believed that using the NCICTC version 2 was the best way to report a crude incidence of incontinence, while using the ABS recommended tool, and the recommended patient self-assessment format. Patients who reported any degree of incontinence were contacted by phone and interviewed to determine baseline urinary continence. Preimplant computed tomography (CT) scans were obtained with a foley catheter in place, which was used to assess prostate volume, to evaluate for pubic arch interference, and for treatment planning. The prostate and intraprostatic urethral volumes were contoured on each slice by the same individual (FMW). The implants were planned (Variseed, Varian, Palo Alto, CA) to deliver a minimum dose of 145 Gy to the gland plus a symmetric 3–5 mm margin. 125I seeds, 0.4–0.6 mCi, National Institute of Standards and Technology (NIST-99), were loaded peripherally keeping the seeds within the prostate except at the apex. This technique generated a broad dose minimum in the central portion of the prostate encircled by a high dose region to promote urethral sparing. Implants were performed under general anesthesia with a foley catheter in place to visualize the urethra. The earliest implants, which included approximately half of those in this study, were performed under template and fluoroscopic guidance using a technique similar to that described by Wallner et al.24 The more recent implants were performed with transrectal ultrasound and fluoroscopic guidance. Transperineal needles were placed according to the plan and seeds were implanted using a Mick® applicator (Mick RadioNuclear Instruments, Inc, Mount Vernon, NY). In earlier years, patients were admitted overnight for observation, but more recently, were discharged the day of the procedure with the foley catheter in place. Catheters were self-removed the following morning. Postoperative dosimetry was calculated in accordance with ABS guidelines from a CT scan performed approximately 30 days after the procedure to allow for resolution of prostatic edema (mean: 37.1±26.4 days; range: 0–195 days).25 The prostate and intraprostatic urethral volumes were contoured on each slice by the same individual (FMW) who also localized the implanted seeds. A urinary catheter was used for the

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preimplant CT scan, but not for most postimplant CT scans, which made the urethra more difficult to localize. At the time of the postimplant CT scan, most of the edema had resolved so that the pre- and postimplant volumes were similar. The urethra was localized as a 4–5 mm diameter circle based on its location in the preimplant CT scan. This localization was done on an image-by-image basis while viewing both studies simultaneously. A dose-volume histogram (DVH) of the volume defined by the contours was compiled to evaluate the urethral dose. We acknowledge that there is a certain degree of uncertainty in the location of the urethra and in the urethral dose because of the absence of a urinary catheter. However, we showed in a prior study that the urethral dose, defined as the D10, D25, or D50 is relatively insensitive to the location of the urethra when the 125I seeds are peripherally loaded so as to produce a broad dose minimum in the central portion of the prostate.26 In that study, the dose to the urethra identified by a foley catheter was compared with a surrogate urethra that was localized at the geometric center of the prostate. The surrogate urethral D10, D25, or D50 were higher by 3.5±5.5%, 1.0±6.0%, and 2.3±7.1%, respectively. Lee et al recently showed similar results with a surrogate urethra contoured on CT scans obtained 30 days postimplant.27 In this study, the urethra in the postimplant CT scan was localized at the approximate location of the urethra in the preimplant CT scan instead of at the geometric center of the prostate. Thus, we would expect the uncertainty in the postimplant urethral doses in this study to be even less than in the previous studies using surrogate urethras. Eight patients received their CT scan on day 0, the day of the procedure, instead of day 30. We showed previously that the urethral dose is significantly underestimated by day 0 dosimetry.28 More specifically, we reported that the urethral D10, D25, D50, D75, and D90 doses increased, on average, by 90, 81, 67, 49, and 40 Gy, respectively, between day 0 and day 46 postimplant. Therefore, the urethral doses of patients who received their CT scan on day 0 were normalized to those who received a later scan by increasing the urethral doses accordingly. Postimplant dose-volume histograms (DVHs) of the prostatic urethra were compiled for each patient and the D5, D10, D25, D50, D75, and D90 urethral doses were recorded. These are defined as the doses that encompass 5, 10, 25, 50, 75, and 90% of the volume of the urethra, respectively. Postimplant DVHs also were compiled for the prostate. The prostate dosimetric parameters recorded were V100, V200, and V300 the percentages of the prostate volume that received a dose equal to or greater than 100%, 200%, and 300% of the prescribed dose, respectively, and D90, the minimal dose delivered to 90% of the prostate volume. In addition, the prostate volume, total activity of the implant, number of needles, number of seeds, and seed activity also were recorded. Clinical characteristics recorded included age, stage, Gleason score, pretreatment PSA, preimplant IPSS, length of follow-up, and the most recent IPSS collected in the survey. Of the 153 patients surveyed, 4 patients died of other causes and 112 (75%) responded. Of these, 37 reported grade 1 or grade 2 and no patient reported grade 3 incontinence. Four patients indicated that they had some degree of incontinence prior to their implant and these patients

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Table 50.1 Univariate analysis of clinical parameters Parameter

All patients Grade 0 Grades 1,2 p-value (n=108) (n=75) (n=33) (t-test)

Age at implant (yrs) 65±6 65±6 65±7 0.759 Gleason score 5.9±0.8 5.8±0.9 6.0±0.8 0.136 PSA 6.2±1.8 6.4±1.7 5.8±2.0 0.200 Prostate volume (cc) 42.0±12.9 42.4 ±12.1 41.3+14.5 0.659 Follow-up (mths) 45±17 43±17 504±17 0.019 Preimplant IPSS 7.8±5.5 6.6±4.5 10.0±6.4 0.005 Postimplant IPSS IPSS 8.5±6.6 6.9±5.5 11.4±7.4 0.002 PSA, prostate-specific antigen; IPSS, International Prostate Symptom Score.

were deleted from the analysis leaving a total of 108 patients, 33 of whom stated that their leakage began after prostate brachytherapy. Of the 33 patients, 28 (26%) reported grade 1 incontinence and 5 (5%) reported grade 2. Because the number of patients who reported grade 2 was so small, the data for grades 1 and 2 were combined into a single group for univariate and multivariate analysis. The results of a univariate analysis of the clinical parameters of the patients that did and did not experience incontinence are listed in Table 50.1. The two groups were homogeneous for age, Gleason score, PSA, and prostate volume. In comparing patients with incontinence to patients without, there was a significant difference in the length of follow-up (p=0.019). However, as shown in this study, the incidence of incontinence decreased markedly between 1997 and 2001 as a result of a similar annual reduction in the urethral dose. Thus, we attribute the difference noted in the length of follow-up to the fact that the majority of patients reporting incontinence were implanted during the early years of our study when urethral doses were much higher. There also was a significant difference in the mean preimplant IPSS of the patients who did (10.0±6.4) and did not (6.6±4.5) experience incontinence (p=0.003). Mean postimplant IPSS is also listed in Table 50.1. The mean postimplant IPSS of the patients experiencing incontinence (11.4±7.4) not only remained significantly greater (p=0.002) than patients who did not (6.9±5.5), but no significant difference between the preand postimplant IPSS values was noted. This indicates that the patients in our study returned to their respective baseline IPSS within the varying lengths of follow-up. Table 50.2 lists the results of the univariate analysis of the dosimetric parameters. There was no significant difference in total activity implanted, number of needles used for implantation, and quality of the implant as defined by the prostate D90, V100, and V200 values. There was a significant difference however, in the value of V300, the percentage of the prostate volume that received at least 300% of the prescribed dose. This is consistent with the finding described below that patients experiencing incontinence received a significantly higher urethral dose. Table 50.2 also indicates that the difference in the number of seeds implanted was marginally significant (p=0.043). We attribute this to the fact that we used fewer high strength seeds to implant the same prostate volume during the early years of this study when the majority of the incidences of incontinence occurred. We noted a significant difference in the urethral doses of the patients who did

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and did not experience incontinence. The urethral D5, D10, D25, D50, D75, D90 doses of the patients experiencing incontinence all were significantly higher, as indicated by the pvalues in Table 50.2. In a multivariate analysis, the preimplant IPSS and the urethral D10 dose were the only parameters that remained significant (p=0.003 and p=0.002, respectively). Results Urethral dose The urethral dose-volume histograms (DVH) of the patients who did (grades 1, 2) and did not (grade 0) experience incontinence were separately averaged and are plotted in Figure 50.1. This figure shows that the patients experiencing incontinence received a significantly higher dose at all levels of coverage (Table 50.1). The most significant difference was noted at the D10 level where the mean urethral D10 dose of patients with grade 0 was 314± 78 Gy, compared with 394±147 Gy for patients who experienced incontinence (p=0.002). The incidence of incontinence is plotted in Figure 50.2 as a function of the urethral D10 dose. These data are listed

Table 50.2 Univariate analysis of dosimetric parameters Parameter

All patients Grade 0 Grades 1, 2 p-value (n=108) (n=75) (n=33) (t-test) Total activity (mCi) 47.4±10.3 47.3±10.1 47.6±10.8 0.891 No, needles 16.2±3.5 16.0±3.6 16.6±3.2 0.362 No. seeds 88.4±19.4 90.9±20.0 83.5±16.0 0.043 Prostate D90(Gy) 182.3±35.8 180.8±34.2 185.3±41.5 0.522 Prostate V100(%) 94.5±5.8 94,4 ±5.0 94.7 ±6.0 0.825 Prostate V200 (%) 51.6±16.4 49.5+16.5 55.4±13.9 0.075 Prostate V300 (%) 21.1±11.6 19.2±9.9 24.5±13.5 0,024 Urethral D5 (Gy) 351±122 325±83 411±170 0.003 Urethral D10 (Gy) 338±110 314±78 394±147 0.002 Uretrtral D25(Gy) 317±95 297±71 363±124 0.003 Urethral D50 (Gy) 282±76 267±58 317±98 0.004 Urethral D75 (Gy) 229±57 219±50 252±67 0,009 Urethral D90 (Gy) 180±49 171 ±43 199±59 0.010

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Figure 50.1 A plot of the averaged urethral dose-volume histograms (DVH) of patients who experienced grade 0 and grades 1, 2 urinary incontinence following permanent prostate brachytherapy.

Figure 50.2 The incidence of urinary incontinence as a function of the urethral D10 dose.

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Table 50.3 The incidence of incontinence as a function of the urethral D10 dose D10 (Gy) Grade 0 Grades 1, 2 Incidence (n=75) (n=33) (%) 150–249 250–349 350–449 ≥450

13 41 14 7

4 12 7 10

24±10 23±6 33±10 59±12

in Table 50.3. Figure 50.2 illustrates that the incidence of incontinence increased with the urethral D10 dose. Although there is no clear dose threshold, the incidence of incontinence increased noticeably when the D10 dose exceeded 350 Gy, increasing to nearly 60% when the dose exceeded 450 Gy. The first three bars in Figure 50.2 represent dose increments of 100 Gy. The last bar includes all of the patients who had a D10 dose ≥450 Gy and extends to 810 Gy, the highest D10 dose observed. These patients were grouped together because there were only 17 patients with a D10 dose ≥450 Gy. The error bars represent the standard deviation in the percentage of patients who experienced incontinence, which was calculated as σ=√pq/n where p and q were the percent of patients who did and did not experience incontinence, respectively, and n was the total number of patients in that dose interval. Preimplant IPPS The incidence of incontinence is plotted in Figure 50.3 as a function of the preimplant IPPS. These data are listed in Table 50.4. This figure indicates that the incidence of incontinence was relatively insensitive to the preimplant IPSS in the range of 0–14. When the IPPS is 15 or greater, however, the incidence of incontinence increased sharply to about 70%. These results show that patients with an IPSS≥15 are at a much higher risk of incontinence. The first three bars in Figure 50.3 represent an IPSS increment of 5. The last bar was extended to 15–24 because there were only 14 patients with an IPSS≥15. Multivariate analysis indicated that the urethral D10 dose and the preimplant IPSS are both predictive of postimplant incontinence. Figure 50.3 includes patients who may be incontinent as a result of the urethral D10 dose, and does not solely reflect the incontinence attributable to the IPSS. Similarly, the incidence of incontinence plotted in Figure 50.2 does not solely reflect the incontinence attributable to the D10 dose. Although we cannot completely separate the influence of these two variables, we can reduce the influence of the

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Figure 50.3 The incidence of urinary incontinence as a function of the preimplant IPSS: American Urological Association (AUA) score. Table 50.4 The incidence of incontinence as a function of the preimplant IPPS IPPS Grade 0 Grades 1, 2 Incidence (n=75) (n=32) (%) 0–4 5–9 10–14 15–24

30 26 15 4

9 23 ±7 8 24±7 5 25 ± 10 10 71+12

D10 dose by deleting patients with a D10 dose ≥350 Gy from Figure 50.3. As shown in Figure 50.4, this reduced the incidence of incontinence from about 25% to 12% for patients with an IPSS <10, but did not alter the incidence of incontinence for patients with an IPSS ≥15. This finding strongly suggests that patients with a preimplant IPSS ≥15 are at a high risk for incontinence regardless of the urethral dose, while patients with an IPSS < 10 are at minimal risk unless they receive a high urethral dose. Because only five patients reported grade 2 incontinence, there were insufficient data to differentiate between the risk factors for grade 1 and grade 2 incontinence. However, it is interesting to note that four of the five patients had either a very high urethral D10 dose or a high preimplant IPSS. Two patients had urethral D10 doses of 580 Gy and 810 Gy and two patients had preimplant IPSS of 17 and 20. The remaining patient had a D10 dose of 285 Gy and a preimplant IPSS of 10. These results suggest that the severity of incontinence is related to the urethral dose and the preimplant IPSS.

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A total of 41 patients did not respond to the survey. However, the preimplant clinical parameters and the postimplant dosimetry of these patients did not differ significantly (p≥0.3) from the patients that responded to the survey. Most notably, their mean urethral D10 dose was 346±91 Gy and their mean preimplant IPSS was 9.2±7.6. No incontinence was documented on the charts of these patients; however, until the findings of this study, we did not routinely ask about urinary leakage on follow-up visits. Incidence of incontinence vs year of implantation Figure 50.5a shows the incidence of incontinence in our patients as a function of the year that the implant was performed. We began our implant program in October 1996, and included this abbreviated year in the 1997 cohort. A high incidence of incontinence (52%) is noted in the patients implanted in 1997. The incidence of incontinence remained above 30% in 1998 and 1999 and then decreased

Figure 50.4 The incidence of urinary incontinence as a function of the preimplant IPSS (AUA score) in the patient population having a urethral D10 dose ≤350 Gy.

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markedly to an average of 12% for the years 2000 and 2001. The overall decrease in the incidence of incontinence is attributed primarily to the reduction in the average urethral D10 dose during these years, which is plotted in Figure 50.5b. The average D10 dose was approximately 450 Gy in 1997, but only half that value in 2001. Over the years a conscious effort was made to reduce the urethral dose, as more information became available that associated urethral dose with morbidity. Another contributing factor is the reduction in the fraction of patients with preimplant IPSS≥15. Figure 50.5c shows the percent of patients implanted each year who had an IPSS≥15. Approximately 25% of the patients in 1997 had a preimplant IPSS≥15, but only 5–7% of the patients met that criterion in 2000 and 2001. A marked decline in both risk factors, the urethral D10 dose and the IPSS was noted over the 5 years included in this study, resulting in a significant decline in the incidence of incontinence. Our clinical experience, as well as the results shown in Figures 50.2–50.4, indicate that the incidence of incontinence following brachytherapy can be minimized by patient selection and by keeping the urethral dose as low as possible. Prostate brachytherapy has evolved considerably since its inception and has demonstrated excellent clinical outcomes; comparable with radical prostatectomy and external beam radiotherapy (EBRT). Despite its success, a considerable amount of controversy continues to exist and long term data are now being recorded regarding morbidity, dosimetry, and quality of life. We generated a self-assessment questionnaire based on the National Cancer InstituteCommon Toxicity Criteria (NCI-CTC), version 2 to evaluate urinary incontinence in our patient population and found a 31% incidence of incontinence. We evaluated patient and dosimetric parameters to determine predictive factors for this complication and found that both the magnitude of the urethral D10 dose and the magnitude of the preimplant IPSS correlate directly with the incidence of urinary incontinence.

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Figure 50.5 (a)The incidence of incontinence in patients implanted during the years 1997, 1998, 1999, 2000, and 2001. (b) The mean urethral

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dose of the patients implanted each year, (c) The percentage of the patients implanted each year who had a preimplant IPSS≥15. To our knowledge, only the study by Merrick et al evaluated patients treated with brachytherapy alone and correlated urinary incontinence to dosimetric and clinical parameters.29 They found no significant difference in the EPIC scores (Expanded Prostate cancer Index Composite) of implanted patients compared with newly diagnosed controls.30 They reported a mean maximal urethral dose of only 130±18 Gy on day 0. Our results indicate that the incidence of incontinence would be low at this dose level. It is probable that their lack of an observed dose-response is because of the low urethral doses delivered to their patients. Several investigators have studied the relationship between the urethral dose and urethral morbidity, in which incontinence was not a specific endpoint.16,31–33 Wallner et al found that urinary morbidity was related to the maximum central urethral dose and to the length of the urethra that received a dose greater than 450 Gy.31 With intraoperative planning, Zelefsky et al were able to limit the median urethral dose to 201 Gy compared to 378 Gy with conventional planning and noted that acute urinary symptoms resolved more quickly with the lower doses.33 Desai et al reported increased urinary toxicity scores in patients receiving higher urethral doses.16 Merrick et al found that the mean membranous urethral dose was a predictive factor for urethral strictures.32 These reports suggest a dose-response for the urethra but to date no reported series has demonstrated an association between urethral dose and urinary incontinence. Our data clearly demonstrate a dose-response for the urethra and indicate that the urethral D10 dose is a predictive factor for urinary incontinence. We found on multivariate analysis that the preimplant IPSS also was predictive of urinary incontinence. Although the IPSS was developed initially by the American Urological Association in 1992 for evaluating patients with benign prostatic hypertrophy, it has become a useful tool for assessing patients for baseline urinary function and for tracking postradiation urinary symptoms.34,35 Using this score to stratify patients at higher risk for postimplant complications, however, is somewhat controversial.36,37 Several investigators have correlated preimplant IPSS with acute urinary toxicity and urethral strictures in implanted patients.12,34,38,39 Merrick et al did not find a relationship between the preimplant IPSS and incontinence with a mean antecedent IPSS of only 5.69.29 In our series, the mean preimplant IPSS also was low (7.8±5.5) but we noted a significant difference (p=0.003) between the scores of patients who did not report incontinence (6.6± 4.5) and those who did report incontinence (10±6.4). In our study population, 13% had an IPSS ≥15 and the incidence of incontinence increased dramatically in these patients. A higher baseline urinary function score appears to be predictive for those patients more likely to experience urinary incontinence. In addition to determining predictive factors for incontinence we sought to evaluate the incidence of this complication in our patient population. The risk of urinary incontinence following prostate brachytherapy has not been clearly defined with reported incontinence rates ranging from 0% to 40%.4,5,11–15,40 Available reports are limited and difficult to interpret because of differing implant techniques, the variety of tools used to

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assess this complication, the various definitions of incontinence, and the differences in the mode of data collection, such as physician grading or patient self-assessment. The techniques of prostate brachytherapy have evolved considerably over the last decade and a greater emphasis has been placed on urethral sparing. Talcott et al reported a 40% incidence of incontinence in patients with implants performed using a uniform seed distribution.11 Postimplant dosimetry was not obtained for these patients; however, this type of seed distribution produces high central doses within the prostate and likely resulted in high urethral doses similar to those delivered in our earlier implants when our incidence of incontinence ranged from 30% to 50%. At the other extreme, Merrick et al reported no difference in EPIC scores of patients following brachytherapy compared with newly diagnosed controls with implants carried out using a technique that limited the mean maximal urethral dose to 130 Gy.29 Our results reflect this evolution of technique in that our incidence of incontinence decreased significantly between 1997 and 2001 as we reduced the urethral doses delivered. Differences in implant technique that have an impact on the urethral dose likely contributed to the wide range of incontinence reported in the literature. The variety of tools used to assess incontinence also contributes to the confusing results reported in the literature and to the wide range of reported rates. Several investigators used the Radiation Therapy Oncology Group (RTOG) toxicity scale or a modification to grade morbidity and reported 0–5% incidence of incontinence.3,12–15 This scale, however, does not specifically include incontinence as an endpoint or detail its severity. It is not surprising then that the incidence of incontinence is generally low in studies that use this scale. The IPSS has been shown to be useful for monitoring urinary morbidity, but it also does not include incontinence. The EPIC is a frequently used selfassessment quality of life tool developed by expanding the University of California, Los Angeles-Prostate Cancer Index (UCLA-PCI) and asks four questions regarding urinary incontinence.20,30 Both the EPIC and the UCLA-PCI are scaled to standardized values from 0 to 100, with 100 being the most favorable outcome. This tool provides an evaluation of the impact of incontinence on the patient’s quality of life, but it does not describe the crude rates of incontinence in the patient population, making comparisons with studies using this scale difficult. Another reason for the controversy about the incidence of incontinence following prostate brachytherapy is the definition of ‘incontinence’. Incontinence is considered as any involuntary leakage of urine, but this general term encompasses occasional leakage of a few drops, to complete loss of the capacity to contain urine. Ragde et al, for example, reported the incidence of incontinence to be 0% in patients without a history of transurethral resection of the prostate (TURP).3 However, patients were only classified as incontinent if they required the use of a protective pad. Many patients who reported incontinence in our study would have been regarded as continent using these criteria, which would have resulted in a significantly lower incidence of incontinence. How investigators define incontinence has a significant effect on the incidence reported. Differences in the mode of data collection, be it physician grading or patient selfassessment, have also been shown to significantly affect results. Some reported studies are based on physician assessment of patient symptoms while others are based on selfassessment. In the CaPSURE database of more than 3900 patients, physicians rated patients in several areas, including urinary incontinence. These data were compared with

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patient-completed selfassessment questionnaires and significant differences were noted in all quality of life and clinical domains.18 The incidence of incontinence, then, varies with different modes of data collection and is likely to be an under-reported complication in studies based solely on physician assessment. When evaluating incontinence in brachytherapy patients, it is important to know the incidence of this problem in the general population. In studies of men without prostate cancer or patients who opted for observation of their cancer, the incidence of incontinence has not been as low as could be expected. In a population of normal older men, Litwin found that 33% had some degree of urinary leakage.41 Similarly, in a review of the literature including over 21 studies and 12 000 men, Thorn found the prevalence of incontinence among community-dwelling older men to be 11–34% with a median of 17%.42 Reports in the literature indicate that incontinence is not uncommon in the general population and highlights the fact that a portion of brachytherapy patients would be expected to experience some level of urinary leakage independent of their diagnosis or its treatment. Series that report extremely low incontinence rates may be underestimating this symptom for any of the reasons noted in this discussion. It is understandable, considering all of the above, that a wide variation exists in the incidence of incontinence following prostate brachytherapy as reported in the literature. More standardization is needed in the definition of incontinence, in the tools that are used to assess incontinence, and in the manner in which the urethral dose is calculated and reported. Investigators also need to report the urethral dose and preimplant IPSS when reporting the incidence of incontinence. Conclusions Similar to sexual dysfunction, urinary incontinence is a feared complication of prostate cancer treatment and is, therefore, an important endpoint to evaluate when investigating treatment outcomes and quality of life. There are several established types of incontinence including urge incontinence (detrusor overactivity), neurogenic incontinence (detrusor underactivity), overflow incontinence (urethral obstruction), and stress incontinence (urethral incompetence). The mechanism of incontinence in patients that have received prostate brachytherapy is not well defined. Our study does not attempt to speculate on the mechanisms of incontinence in our population nor does it indicate how incontinence may change with time, age, medication, or surgical intervention. An attempt to collect this information was made via telephone interviews; however, these details were difficult for patients to recall, precluding reliable conclusions. The data presented identify two risk factors for urinary incontinence, urethral D10 and the preimplant IPSS. These factors should be used to guide physicians recommendations but do not represent contraindications to implantation. In selecting patients for this procedure, a global picture including stage of disease, Gleason score, prostatespecific antigen (PSA), medical comorbidities, prior urological procedures, medications, urinary symptoms, and preimplant dosimetry should be evaluated. Limiting the urethral D10 dose and selecting patients with preimplant IPSS less than 15 will minimize the incidence of urinary incontinence in patients receiving prostate brachytherapy.

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References 1. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer [See comments]. JAMA 1998; 280(11):969–974. 2. Zelefsky MJ, Wallner KE, Ling CC, et al. Comparison of the 5-year outcome and morbidity of three-dimensional conformal radiotherapy versus transperineal permanent iodine-125 implantation for early-stage prostatic cancer. J Clin Oncol 1999; 17(2):517–522. 3. Ragde H, Blasko JC, Grimm PD, et al. Interstitial iodine-125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma [See comments]. Cancer 1997; 80(3):442–453. 4. Ragde H, Blasko JC, Grimm PD et al. Brachytherapy for clinically localized prostate cancer: results at 7- and 8-year follow-up. Semin Surg Oncol 1997; 13(6):438–443. 5. 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 [See comments] [Review] [49 refs]. Cancer 1998; 83(5):989–1001. 6. Wallner K, Roy J, Harrison L. Tumor control and morbidity following transperineal iodine 125 implantation for stage T1/T2 prostatic carcinoma. J Clin Oncol 1996; 14(2):449–453. 7. Eastham JA, Kattan MW, Groshen S, et al. Fifteen-year survival and recurrence rates after radiotherapy for localized prostate cancer. J Clin Oncol 1997; 15(10):3214–3222. 8. Gerber GS, Thisted RA, Chodak GW, et al. Results of radical prostatectomy in men with locally advanced prostate cancer: multi-institutional pooled analysis. Eur Urol 1997; 32(4):385–390. 9. Zincke H, Bergstralh EJ, Blute ML, et al. Radical prostatectomy for clinically localized prostate cancer: long-term results of 1,143 patients from a single institution. J Clin Oncol 1994; 12(11):2254–2263. 10. Fowler FJ Jr, Barry MJ, Lu-Yao G, et al. Patient-reported complications and follow-up treatment after radical prostatectomy. The National Medicare Experience: 1988–1990 (updated June 1993). Urology 1993; 42(6):622–629. 11. 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(2):494–499. 12. Gelblum DY, Potters L, Ashley R, et al. Urinary morbidity following ultrasound-guided transperineal prostate seed implantation. Int J Radiat Oncol Biol Phys 1999; 45(1):59–67. 13. Kaye KW, Olson DJ, Payne JT. Detailed preliminary analysis of 125iodine implantation for localized prostate cancer using percutaneous approach. J Urol 1995; 153(3 Pt 2):1020–1025. 14. Brown D, Colonias A, Miller R, et al. Urinary morbidity with a modified peripheral loading technique of transperineal (125)I prostate implantation. Int J Radiat Oncol Biol Phys 2000; 47(2):353–360. 15. Stokes SH, Real JD, Adams PW, et al. Transperineal ultrasoundguided radioactive seed implantation for organ-confined carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1997; 37(2):337–341. 16. Desai J, Stock RG, Stone NN, et al. Acute urinary morbidity following I-125 interstitial implantation of the prostate gland. Radiat Oncol Investig 1998; 6(3):135–141. 17. Litwin MS, Hays RD, Fink A, et al. Quality-of-life outcomes in men treated for localized prostate cancer. JAMA 1995; 273(2): 129–135. 18. 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(6):1988–1992. 19. Slevin ML, Plant H, Lynch D, et al. Who should measure quality of life, the doctor or the patient? Br J Cancer 1998; 57(1):109–112.

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20. 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(7):1002–1012. 21. Nag S, Ellis RJ, Merrick GS, et al. American Brachytherapy Society recommendations for reporting morbidity after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002; 54(2):462– 470. 22. Trotti A, Byhardt R, Stetz J, et al. Common toxicity criteria: version 2.0. an improved reference for grading the acute effects of cancer treatment: impact on radiotherapy. Int J Radiat Oncol Biol Phys 2000;47(1):13–47. 23. Trotti A. The evolution and application of toxicity criteria. Semin Radiat Oncol 2002; 12(1 suppl 1):1–3. 24. Roy JN, Wallner KE, Harrington PJ, et al. A CT-based evaluation method for permanent implants: application to prostate. Int J Radiat Oncol Biol Phys 1993; 26(1):163–169. 25. Nag S, Bice W, DeWyngaert K, et al. The American Brachytherapy Society recommendations for permanent prostate brachytherapy postimplant dosimetric analysis. Int J Radiat Oncol Biol Phys 2000; 46(1):221–230. 26. Waterman FM, Dicker AP. Determination of the urethral dose in prostate brachytherapy when the urethra cannot be visualized in the postimplant CT scan. Med Phys 2000; 27(3):448–451. 27. Lee HK, D’Souza WD, Yamal JM, et al. Dosimetric consequences of using a surrogate urethra to estimate urethral dose after brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 2003; 57(2):355–361. 28. Waterman FM, Dicker AP. The impact of postimplant edema on the urethral dose in prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 47(3):661–664. 29. Merrick GS, Butler WM, Wallner KE, et al. Long-term urinary quality of life after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys 2003; 56(2):454–461. 30. 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(6):899–905. 31. Wallner K, Roy J, Harrison L. Dosimetry guidelines to minimize urethral and rectal morbidity following transperineal I-125 prostate brachytherapy. Int J Radiat Oncol Biol Phys 1995; 32(2):465–471. 32. Merrick GS, Butler WM, Tollenaar BG, et al. The dosimetry of prostate brachytherapy-induced urethral strictures. Int J Radiat Oncol Biol Phys 2002; 52(2):461–468. 33. Zelefsky MJ, Yamada Y, Marion C, et al. Improved conformality and decreased toxicity with intraoperative computer-optimized transperineal, ultrasound-guided prostate brachytherapy. Int J Radiat Oncol Biol Phys 2003; 55(4):956–963. 34. Terk MD, Stock RG, Stone NN. Identification of patients at increased risk for prolonged urinary retention following radioactive seed implantation of the prostate. J Urol 1998; 160(4):1379–1382. 35. Barry MJ, Fowler FJ Jr, O’Leary MP, et al. The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992; 148(5):1549–1557. 36. Merrick GS, Butler WM, Wallner KE, et al. Prophylactic versus therapeutic alpha-blockers after permanent prostate brachytherapy. Urology 2002; 60(4):650–655. 37. Merrick GS, Butler WM, Lief JH, et al. Temporal resolution of urinary morbidity following prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000; 47(1):121–128. 38. Locke J, Ellis W, Wallner K, et al. Risk factors for acute urinary retention requiring temporary intermittent catheterization after prostate brachytherapy: a prospective study. Int J Radiat Oncol Biol Phys 2002; 52(3):712–719. 39. Bucci J, Morris WJ, Keyes M, et al. Predictive factors of urinary retention following prostate brachytherapy. Int J Radiat Oncol Biol Phys 2002;53(1):91–98. 40. Hu K, Wallner K. Urinary incontinence in patients who have a TURP/TUIP following prostate brachytherapy. Int J Radiat Oncol Biol Phys 1998; 40(4):783–786.

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41. Litwin MS. Health related quality of life in older men without prostate cancer. J Urol 1999; 161(4):1180–1184. 42. Thorn D. Variation in estimates of urinary incontinence prevalence in the community: effects of differences in definition, population characteristics, and study type. J Am Geriatr Soc 1998; 46(4):473–480.

Index

AAPM TG-56 113 acini 5, 7 ‘accordion effect’ 389 ACQsim (Philips) CT simulator 398 adenocarcinoma lymphoepithelioma-like prostatic 22 postradiation pathology 7–8, 9 and pubic arch interference 237 sonographic appearance 88, 91 adenoid cystic carcinoma 21 ADT see androgen deprivation therapy afterloading devices HDR brachytherapy remote 327 manual 368, 369 age and potency 429 and PSA bounce 435, 438 air kerma rate constant 100 ALARA principles, compliance with 248 American Association of Physicists in Medicine see AAPM American Brachytherapy Society (ABS) on modified uniform seed-loading 116, 120 on peripheral seed-loading 113 American College of Surgeons Oncology Group (ACOSOG) clinical trials 35, 36 American Society of Therapeutic Radiation Oncology (ASTRO) definition of disease freedom 363 analgesia 297, 336, 337 anatomy prostatic/periprostatic 158 see also prostate gland, anatomy androgen deprivation therapy (ADT) with brachytherapy 62 with EBRT/brachytherapy 346 and HRQOL 414, 415 before palladium-103 brachytherapy 149 with radiotherapy 11 androgen suppression therapy prostate gland measurements 241–2, 243 and pubic arch interference 237, 240

Index

660

anesthesia for HDR brachytherapy 317 local advantages 233 brachytherapy under 233–6 for palladium-103 brachytherapy 169, 170 preferred type 235 anisotropy function/constant 94, 142, 370, 371 and RADIOCOIL 374, 375, 377 anti-inflammatories 146 antiapoptosis genes 13 antibodies, radiolabeled see radioimmunoguided brachytherapy AQuSim (Picker) software 238 AQuSim (Picker) software 239 argon laser coagulation 423 Arizona Oncology Services 111 ASTRO definition of biochemical failure 76 basal cell carcinoma 21 basal cell cytokeratin see keratin 34_E12 basal cell hyperplasia 6, 7 ‘beak sign’ 83 beam-eye view imaging see needles-eye-view imaging benign prostatic hyperplasia anatomy 85–6, 87, 88, 89 cystic changes 86 benign tissue postradiation pathology 5–7 scoring radiation effect 11 Best iridium source 367, 368 Best seed systems model 2301 iodine-125 368, 369, 370 dose rate constants 371 radial dose function values 370 model 2335 palladium-103 369, 371 dosimetry parameters 371 biochemical control 319 biochemical disease-free survival (bDFS) 226–8, 230–1 biochemical failure, definition of 76 biochemical relapse-free survival (BRFS) EBRT with brachytherapy 346 palladium-103 brachytherapy 178 in Seattle approach 136–7 biopsies after 103Pd brachytherapy 178, 179 correlation with imaging data 222, 223, 228 in diagnosis 67, 68 interpretation postradiation 5 under/overgrading 18 needle

Index prognostic factors 17 tumor volume in 20 pain scores 235 positive, number of, as marker 20 site of 20 see also pathology biopsy/prostatectomy concordance studies 19 biplanar mechanical sector endocavitary probes 75 bladder outlet obstruction and iodine-125 brachytherapy 218 and palladium-103 brachytherapy 170 bNED rates after palladium-103 brachytherapy 165 after radical prostatectomy 60–1 bone wax 391–2 bowel function and HRQOL 414 BrachySource seeds 218 brachytherapy 127–8, 224–5 3D TRUS in 272 advantages 179–80 combined with EBRT 344 future directions 347–8 and hormonal therapy 347 HRQOL after 416 issues/rationale 343–9 for localized prostate cancer 351–8 comparative studies 79 complications/side effects 78–9 historical 75 Seattle approach 137 contraindications 79–80 delivery systems 369–70 dose 125–6 dose and relapse rate 61 dose supplementation 344 with EBRT/ADT 346 high dose rate (HDR) 77 historical perspective 75–6 timeline 75 history 367 and HRQOL 414–15 indications 64 internet information 68 inverse square law 303 isotope selection 126–7 isotopes 61, 76–7 limitations 271–2 under local anesthesia 233–6 pain scores 235 patient tolerance 235–6 problems 236 sedation 236

661

Index

662

technique 233–5 low dose rate (LDR) 77 patient’s view 68, 69 plus ADT 62 plus CHT 68 plus EBRT 77 history 75 and ProstaScint scan 52 prostate cancer mapping, implications of 27–33 PSA non-progression rates 61–2 quality of life issues 63–4 radioactive sources 367–72 calibration changes 141 comparisons 141–2 history 255 insertion 142 linear 373, 391 localization of potential positions 100–1 low vs high energy 99 selection 99–100 stranded 255–60 Utrecht technique 261–3 see also InterSource seeds; RADIOCOIL robot-aided/3D TRUS-guided 271–83 robotic aids in 272 time taken by different techniques 291 transperineal LDR temporary 124 treatment options 77–8 treatment-planning software 93–7 AAPM TG-43 formalism 94 auto-segmentation 95 dose-surface histogram 95, 399 dose-volume histogram 94–5, 102 image acquisition 93–4 image segmentation 94 intraoperative seed detection 96 inverse planning 95–6 isodose display 94 needle tracking 96, 268 post-implant CT dosimetry 95 treatment planning stages 93 treatment/target volume definition current standards 35–6 extraprostatic extension measurements 38–41 intraprostatic tumor volume 38 multifocality 38 from prostatectomy section evaluation 35–42 urethra-cancer distance 36–7 ultrasound-guided see also EchoSeed brachytherapy; under palladium-103 brachytherapy

Index

663

urologist’s view 75–82 vs surgery 59–65 brachytherapy training study 197–204 clinical outcomes 201 hospitals participating 197–204 implant quality evaluation 198, 201 results 198–202 technique 197–8 training 198 branch-and-bound algorithms 102, 103, 104–5 Brief Sexual Function Inventory 414 calcifications 86, 268 cancer grade see grade, cancer capromab pendetide 43 normal uptake distribution 45, 47 uptake due to inflammation 52 uptake with rising PSA 53 see also ProstaScint scans carcinoid tumors of prostate 21–2 catheter geometry/stopping positions 102 central zone glands 85 choline/citrate ratio 205 Cleveland Clinic Foundation intraoperative treatment planning 111 Cleveland Clinic trial on EPE radial distance 40 clinical target volume (CTV) 35, 145 HDR brachytherapy 313, 314, 327 and urethra-cancer distance 37 vs gross tumor volume 148 Columbia treatment planning technique 110 combination hormone therapy (CHT) 68, 69 computed tomography (CT) 43 catheter geometry/stopping positions 101 catheter trajectory calculation 111–12 co-registration of ProstaScint scan 54 CT-based treatment planning 303, 304 and dosimetric planning dosimetry, post-implant 95 extraprostatic source placement 148 HDR brachytherapy 299 in HDR brachytherapy 312 MR/MRS image registration phantom study 209 for needle positioning 77 palladium-103 brachytherapy 142, 143–4 ultrasound-guided 177 postoperative dose quantification 131, 147 implant quality evaluation 198 tumor delineation 149 for pubic arch interference 242 target coverage evaluation 154

Index treatment planning 333–4, 335 conformal dose escalation 295 Connecticut Tumor Registry 59 consultation, patient’s view of 67–9 Corvus planning system 329 counseling 64 cut-cube view 238 cystourethroscopy 218 cysts of prostate 86, 87–8 cytoscopy in HDR brachytherapy 299, 314, 318 HDR brachytherapy 331 mucosal penetration 330 mucosal testing 332 decay rates 99–100 delivery systems 369–70 RADIOCOIL 375, 377 digital rectal examination (DRE) in detailed tumor mapping 30 in diagnosis 67 in Partin Tables 17 disease-free survival definitions of 363 and PSA 363 and PSA bounce 436, 437, 438 simultaneous irradiation study 359–64 DNA ploidy, postradiation 8–9 Doppler ultrasound 142 color-flow palladium-103 brachytherapy 142–3 tumor delineation 147 pretreatment studies 144 prostate cancer 88, 89, 90 prostate gland 88–9, 90 dorso-lithotomy position 149 dose EBRT with brachytherapy 345 homogeneity/inhomogeneity seed implantation 124 Wheeling approach 119 iodine-125 seeds with EBRT 345 palladium-103 seeds with EBRT 345 received, with combination therapy 343–4 dose-distribution with MRI information 206 dose escalating conformal radiotherapy 77–8 dose optimization 147 dose prescription EBRT vs brachytherapy 140 HDR variations 295 standardization 124

664

Index

665

treatment planning 101–2 dose rate phenomenon 140 dose-surface histograms (DSH) 95 reimplantation of underdosed region 399, 402 dose-volume histograms (DVH) FIRST system 285, 286 HDR brachytherapy 298, 316 PIPER-generated 266, 267 reimplantation of underdosed region 398, 401, 402 in Seattle approach 127 stranded sources 261 in training 198 urethral dose, in incontinence study 442 US-guided 103Pd brachytherapy 176 in Wheeling approach 116, 117 dosimetric planning intraoperative 75–6 and intraoperative seed detection 96 Variseed 110 dosimetry 124–5, 370–1 anisotropy function 371 EBRT with brachytherapy 344–5 Frankford Hospital approach 219 intraoperative 195 measurements 370–1 modified uniform loading 125 palladium-103 dosimetry analysis 147–8 extraprostatic source placement 148 hormonal downsizing 149 source strength 149 total activity 148–9 peripheral vs uniform seed-loading 113, 125 RADIOCOIL 375, 376–7 Seattle approach 124, 127–8 post-implant 134, 136 stranded sources 256–7 urethral/rectal tolerance 113 in urinary incontinence study 442, 449 US-guided 103Pd brachytherapy 176 ductal carcinoma of prostate 22 ductal ectasia of seminal vesicles 86, 87 EBRT see external beam radiotherapy EchoSeed 181, 183 echogenic structure 181, 183 EchoSeed US-guided brachytherapy 181–6 US frequency selection 182 US gain control 182 US probe rotation 181, 182–3 visualization optimization 181–2

Index

666

endocavitary probes 75 endorectal balloon probe 205, 206 EPE see extraprostatic extension erectile dysfunction brachytherapy-induced management 431 mechanisms 429–31 needle trauma 428 neurovascular bundle trauma 429–30 penile erectile body damage 430–1 and radiation dose to prostate 429 time-related 428 and HRQOL 415 Mt Sinai four-tiered system 426 and palladium-103 brachytherapy 157–9 and quality of life 425 see also potency; sexual function/dysfunction extended lithotomy position 129, 243 and pubic arch interference 153 external beam radiotherapy (EBRT) combined with brachytherapy 75, 77 current literature 352 EBRT type 357 future directions 347–8 HDR 327, 328 as boost 346–7 and hormonal therapy 347 HRQOL after 416 indications 351 iodine-125 brachytherapy see simultaneous irradiation study issues/rationale 343–9 for localized prostate cancer 351–8 long-term outcomes 160 patient selection/characteristics 344–5, 351, 353 permanent seed implant 345–7 radioimmunoguided 224–5 rationale 355 results/discussion 355–8 sequence 351 side effects 346 vs PPB monotherapy 351, 357 actuarial potency 356 Wheeling approach 117 combined with hormonal therapy 78 combined with PPB 41 dose escalation with 312 early use 123 and HRQOL 414, 415 inverse planning 95 patient’s view 68, 69, 70 quality of life issues 63

Index

667

tumor eradication 8 extracapsular extension (ECE) 35 extracapsular seeds 147 extraprostatic extension (EPE) 35 combination therapy 344 in low-risk patients 405 potential, brachytherapy for 405–9 extraprostatic margins 405, 406, 407, 408, 409 isodose distribution 408 treatment 405 radial distance 38–40 radial extent studies 405 stranded sources for 390 and treatment margins 146 volume 40–1 EZ-Pak Preloaded Needle Program 387 FACT-G 414 FACT-P 415 family, informing 68 finger manipulation in needle insertion 247, 248 FIRST system 261 autoplan 285, 286, 287 emergency kit 290 implantation procedure 286–90 needles in position 287, 288 prostate/urethra contouring 286, 287 seed delivery 288–9 seed distribution 289 seed positions 288 postimplant care 290 postimplant imaging 289 postplanning 290, 291–2 pretreatment evaluation/preparation 286 seed loss/migration 291 Strands vs selectSeeds 292 system 285, 286 Utrecht experience 285–92 fluoroscopy in HDR brachytherapy 315 flutamide 69, 70, 237 foley catheter in HDR brachytherapy 314 US-guided 103Pd brachytherapy 174 Frankford Hospital experience 215–20 cystourethroscopy 218 evaluation patient 215–16 postimplantation 218–19 preadmission 217 needle preparation 217 radiation precautions 218

Index

668

seed implantation 217, 218 seed preparation 217 treatment planning 216 ultrasound volume study 216 urinary retention 218 Fully Integrated Radiotherapy Seed Treatment see FIRST system functional image registration algorithm 205–8 reversal 212–13 validation 208–11 automated 213 background 205 future directions 212–14 mapping MR/MRS to CT 205–14 mapping ProstaScint to CT/MR 221–32 patient study 210, 211 phantom study 208–10, 211 problems 212, 214 registration errors 211, 213 schematics of method 207, 208 genetic algorithms 102, 103 Gleason grade and brachytherapy efficacy 61–2 in diagnosis 68 of needle biopsy 17–20 non-concordance 18, 20 in Partin Tables 17 postradiation 8–9 and prostatectomy efficacy 60–1 and risk of death 59 under/overgrading 18 glutathione S-transferase pi (GST-π) 13 gold-198 75, 123 seed markers 315, 318 grade, cancer, postradiation 8–10 gross tumor/target volume (GTV) 35, 145 identification 146 half-life of palladium-103 vs iodine-125 140 Harvard University intraoperative treatment planning 111, 112 health-related quality of life (HRQOL) after brachytherapy 413–17 future directions 416 high dose rate 416 low dose rate 413–15 with/without EBRT 416 instruments 413, 414 after local therapy for prostate cancer 63 hematoma 251, 253 hematospermia 425

Index

669

high dose rate (HDR) brachytherapy 77, 100–1 advantages 311–12, 327, 329 afterloading 311 background/rationale 295, 327–9 biochemical control 324 biologic effective doses 305, 315, 316 as boost 305, 311, 312–15 characteristics 316 combined with EBRT 346–7 results 319–21 California Endocuritherapy Cancer Center experience 319 catheters digitally-reconstructed images 336 movement 337 for high IPSS/prior TURP patients 334, 335, 336 placement 319 for high IPSS/prior TURP patients 330, 331 clinical/planning target volumes 313, 314 combined with EBRT 327, 328 HRQOL after 416 complications/side effects 298, 300, 321–2, 323–4 cost 311, 324 cytoscopy 298, 314, 318 for high IPSS/prior TURP patients 331 mucosal penetration 330 mucosal testing 332 dose-constraint variables 303 dose prescription variations 295 dose regimens 297–8, 300, 301, 313, 314–15, 319 for high IPSS/prior TURP patients 333 dosimetric certainties 303 dosimetry 304, 318 coverage 315 for high IPSS/prior TURP patients 334, 335 dwell times 327 future directions 298, 299 for high IPSS/prior TURP patients 327–39 Hackensack University experience 329–30 operating room technique 330–6 HRQOL after 416 hypofractionated treatment program 312–17 imaging techniques 312–13 implant technique 296–9, 300 at MSKCC 305 iridium-192 295–301, 311–25, 368 limitations 298 margins, lack of 313, 314, 317 as monotherapy 312, 316, 317 completed implant 319 results 321 at MSKCC 303–9 needle/catheter placement 295, 296, 313, 315, 317

Index

670

outcomes 299, 300, 301 at MSKCC 305–8 pain management 336, 337 patient characteristics 306, 314, 318 patient positioning 330 patient selection/evaluation 296 perineal applicator/template 299 catheter interface check 336 detachable 330, 331, 332 digitally-reconstructed images 336 for high IPSS/prior TURP patients 330 postradiation care 305 prescription dose 318 radiobiology at MSKCC 305 results 319–21 survival 319–20, 323, 324 technique, basic 311 toxicity 306–7, 320 acute 321, 322, 337 chronic 321, 322 late 337, 339 treatment planning 100, 102 for high IPSS/prior TURP patients 333–4 at MSKCC 303–5 treatment time 311 TURP defect location 330 volumetric study with 331 William Beaumont Hospital experience 317–18 high dose rate (HDR) brachytherapy remote afterloader 327 homogeneity 119, 124 hormonal therapy 237–45 with EBRT/brachytherapy 347 plus brachytherapy 178 plus radiotherapy 78, 224 and pubic arch interference 237–45 see also androgen deprivation therapy; androgen suppression therapy ‘hot’ spots 154 HRQOL see health-related quality of life human antimouse antibody (HAMA) reaction 52 hyperplasia 6 hypofractionated treatment program 312–17, 329 imaging techniques/modalities biological 205 in palladium-103 brachytherapy 142–4 in treatment of EPE 41 immunohistochemistry after radiotherapy 11–13 immunoscintigraphy 43–4, 52, 54 see also capromab pendetide;

Index

671

ProstaScint scan implants background 123–7 technical breakthroughs 124 closed, first 123 evaluation 152–5, 353 indices 155 history 123 Seattle approach biochemical relapse-free survival (BRFS) 136–7 isotope selection 126–7 results 131, 136–7 side effects 137 technique 128–35 treatment planning 127 treatment planning/dosimetry 127–8 temporary 123, 124 see also brachytherapy incontinence, urinary see urinary incontinence indium-111 222, 228 inflammatory bowel disease 80 intensity modulated radiotherapy (IMRT) 93, 95, 221, 295 with HDR brachytherapy 329–30 International Commission on Radiation Units and Measurement (ICRU) 35 International Index of Erectile Function (IIEF) questions 425, 426 International Prostate Symptom Score (IPSS) high, HDR brachytherapy for 329 and late toxicity 339 and HRQOL 414 for urinary incontinence assessment 441, 449 preimplant, as factor 445–6, 447, 448 InterSource seeds 385–7 descriptions 385 on InterStrand 386–7 TG-43 parameters 385–6 InterStrand 386–7 InterStrand special 387 intraoperative dosimetric planning 75–6 intraprostatic tumor volume 38 inverse square law 303 iodine-125 61, 75, 76, 77, 386–7 activity 126–7 characteristics 99, 100, 126, 141, 142 radiation exposure of staff 251, 253 radiation exposure with preloaded needles 247, 248 radioactive sources 368–9, 385 stranded sources 255 vs palladium-103 139–42 radiobiology/dose rate phenomenon 139 source calibration changes 141 source comparisons 141–2

Index

672

source insertion 142 in vitro/in vivo studies 141 iodine-125 brachytherapy Best seed model 2301 368, 369, 370 dose rate constants 371 radial dose function values 370 dose in Wheeling approach 114, 116, 120 dose prescription 124 early use of seeds 123–4 with EBRT outcomes 345, 346 side effects 346 see also simultaneous irradiation study Frankford Hospital approach 215–20 with EBRT 215–16 low dose rate 77 for potential EPE 405, 406, 407, 408 results 407 real-time US-guided 187–96 iridium-192 75 characteristics 99, 100 radioactive sources 367–8 high dose rate devices 368 iridium-192 brachytherapy manual afterloading device 368, 369 see also HDR brachytherapy isodose display 312 isotopes 61, 76–7 selection, Seattle approach 126–7 used in brachytherapy 368 Joint Center for Radiation Therapy 111 Kaplan-Meier plots of biochemical relapse-free survival 228, 230–1 keratin 34_E12 11, 12 lidocaine (lignocaine) brachytherapy under 233–6 dose/administration 233–4, 235 linear energy transfer (LET) 140 low dose rate (LDR) brachytherapy 77 HRQOL after 413–15 patient characteristics 318 treatment planning 100 Lupron 69, 70, 170, 237 luteinizing hormone-releasing hormone (LHRH) agonist 237, 240 lymph node involvement 35 and ProstaScint scan 46–7, 48, 49 lymph node treatment 344 lymphoepithelioma-like prostatic adenocarcinoma 22

Index

673

magnetic resonance imaging (MRI) 43 endorectal balloon probe 205, 206 functional imaging 205 in intraoperative planning 112 mapping/registration in US space 205–14 algorithm 205–8 reversal 212–13 validation 208–11 schematics of method 207, 208 palladium-103 brachytherapy 142, 144 magnetic resonance spectroscopy imaging (MRSI) 144 endorectal balloon probe 205, 206 functional imaging 205 mapping/registration in US space 205–14 algorithm 205–8 reversal 212–13 validation 208–11 automated 213 limitations 211, 214 schematics of method 207, 208 malignant cell location 205 margins extraprostatic 405, 406, 407, 408, 409 lack of in HDR brachytherapy 313, 314, 317 periprostatic 120 treatment margin (TM) 145 treatment margin (TM) for 146 markers of postirradiation recurrence 11, 13 Mayo Clinic trial on EPE radial distance 40 Medical Outcomes Study 36-item Health Survey (SF-36) 413, 414 Memorial Sloan-Kettering Cancer Center (MSKCC) HDR brachytherapy at 303–9 intraoperative treatment planning 111–12 Metropolis algorithm 105 MIB (Ki-67) immunoreactivity 11, 13 Mick applicator 110, 369 in brachytherapy under local anesthesia 234 and preloaded needles 187 radiation exposure 247 in radioimmunoguided brachytherapy 228 seed placement 150 stranded sources 261 and TherapacPlus 188–9 in training 197, 198 US-guided 103Pd brachytherapy 173, 174 and VariSeed 190 microvessel density after radiotherapy 13 minimum peripheral dose (mPD) 101, 124 minimum prostatic dose (Dmin) 153 MMS planning software 110

Index

674

see also Variseed monoclonal antibodies 7E11 43, 52 J591 52 radiolabeled 43 uptake in ProstaScint scan 50–1 monofilament stranded sources customized 389–93 description/application 390 preloadability 391–2 standard/non-standard spacing 390 visibility 391 InterStrand 386–7 Monte Carlo annealing see simulated annealing algorithms MSKCC see Memorial Sloan-Kettering Cancer Center Müllerian duct cysts 86, 87–8 multifocality in target volume definition 38 National Cancer Institute Common Toxicity Criteria (CTC) 441–2 SEER database 60, 63, 64 natural dose ratio 285, 287 needle(s) depth assessment/adjustment 130, 133, 249 palladium-103 brachytherapy 150, 151 deviation 100 correction for 112 loading report, Seattle approach 126 placement/insertion accuracy of 271 FIRST system 288 HDR brachytherapy 297, 298, 331, 332 hematoma after 251 palladium-103 brachytherapy 150, 152 ultrasound-guided 169, 172 perineal spacing 249 PIPER-generated 266 radiation exposure 247–8 real-time US-guided brachytherapy 188, 189 Seattle approach 128, 131 training 197–8 in position, Seattle approach 130, 132 preloaded with seeds 129, 387 and Mick applicator 248 radiation exposure 247, 248 without spacers 215–20 preloaded with strands 387, 391–2 preparation, Frankford Hospital experience 217 reference depth establishment 130, 132 tracking 96 PIPER-generated 268

Index

675

Seattle approach 131 withdrawal 130, 134, 152 US-guided 103Pd brachytherapy 172 needle manipulation ruler 247–50 correct/incorrect use 249–50 description 248 needles(beam)-eye-view imaging 237, 238, 239, 240, 243–4 nomograms progression prediction 17 treatment planning 188 nuclear morphometry 13 Nucletron Swift planning system 316, 317 obesity and prostate cancer therapy 80 oncogenes after radiotherapy 13 orgasmalgia 425 overgrading 18 pain management 297, 336, 337 pain scores 235, 337 palladium-103 61, 76–7 activity 126–7 characteristics 99, 100, 126, 141–2 radioactive sources 369, 385 seed manufacture 373–4 see also RADIOCOIL palladium-103 brachytherapy ADT before 149 Best seed model 2335 369, 371 dosimetry parameters 371 combined with EBRT outcomes 345, 346 side effects 346 complications/side effects effects of TURP 155, 156 erectile dysfunction 157–9 rectal complications 157 with supplemental external radiation 159 urinary morbidity 155, 156 disadvantages 142 dose prescription 124, 169 in Wheeling approach 114, 116, 120 imaging techniques 142–4 color-flow Doppler ultrasound 142–3 computed tomography 142, 143–4 magnetic resonance imaging 142, 144 transrectal ultrasound 142, 143 implant evaluation ‘hot’ spots 154 postimplant 152, 153 target coverage 153–4

Index

676

urethral/rectal doses 154–5 implant technique needle insertion 150, 152 patient positioning 149 prostatic mobility 150 pubic arch interference 152 TRUS probe positioning 150 urethral visualization 149–50 in LDR brachytherapy 77 monotherapy vs combination 178 outcomes 10 year results 159–61 bNED rates 165 with EBRT 160 freedom from biochemical progression 162 likelihood of biochemical failure 163–4 vs other modalities 161 patient characteristics 318 for potential EPE 405, 407, 408 results 405–6 preimplant dosimetry/planning dosimetry analysis 147–8 extraprostatic source placement 148 hormonal downsizing 149 modified peripheral loading 147–8 perioperative steroids 146–7 planning images 144–5 source strength 149 target definitions 145 target volumes 146 total activity 148–9 treatment planning 146 radiation exposure with preloaded needles 247, 248 of staff 251, 253 in Seattle approach 127 seed numbers in Wheeling approach 115 stranded sources 255 ultrasound-guided 169–80 advantages 169 anesthesia 169, 170 complications 177–8 implantation procedure 172–6 longitudinal imaging 173, 174, 176 methods 169–70 modified peripheral loading 171 planning procedures 171–2 probe stabilizer 171 reseeding 179 results 176–7 sedation 169, 170 seed numbers/activity 169, 171–2

Index transverse vs longitudinal imaging 172 volume study preoperative 170–1 procedures based on 171–2 vs iodine-125 139–42, 169 dose rate phenomenon 140 radiobiology 139 source calibration changes 141 source comparisons 141–2 source insertion 142 in vitro/in vivo studies 141 Partin Tables 17–18 pathology interpretation 5 under/overgrading 18 postradiation adenocarcinoma 7–8, 9 benign tissue 5–7 clinical significance 9–10 interpretation 5 prostatic intraepithelial neoplasia (PIN) 7 radiotherapy plus androgen ablation 11 variability/reproducibility 10 see also biopsies patient characteristics/selection 344–5 EBRT with brachytherapy 344–5, 351, 353 HDR brachytherapy 296, 306, 314, 318 LDR brachytherapy 318 low vs high dose brachytherapy 318 PPB with EBRT 351, 353 palladium-103 318 rectal complications 420 radical prostatectomy 38 simultaneous irradiation study 359 patient-controlled analgesia 297, 336 patient positioning FIRST system 286 HDR brachytherapy 330 lithotomy position 233 extended 129, 153, 243 simulated in CT scanner 243 palladium-103 brachytherapy 149 ultrasound-guided 170, 171, 175 and pubic arch interference 153, 175, 242–3 pelvic bones and prostate, 3D view of 238 pelvic lymph node treatment 344 perineal hematoma 251, 253 perineal pressure applicator device (PPAD) 251–4 perineural invasion 21 peripheral zone 85 periprostatic anatomy 158

677

Index

678

periprostatic margins, seeds in 120 periurethral glands 85 permanent prostrate brachytherapy (PPB) 36 combined with EBRT 41 current literature 352 EBRT type 357 indications 351 iodine-125 brachytherapy see simultaneous irradiation study outcomes 345–6 patient selection/characteristics 351, 353 rationale 355 results/discussion 355–8 seed implant doses 345 sequence 351 side effects 346 vs PPB monotherapy 351, 357 actuarial potency 356 decay rates 100 dose prescription 102 and intraprostatic tumor volume 38 monotherapy 352 rectal complications 419–24 Seattle Prostate Institute approach 123–38 sources embedded in vicryl suture 255–60 Utrecht technique 261–3 and urethra-cancer distance 37 photon energy of palladium-103 vs iodine-125 140 planning target/tumor volume (PTV) 35, 36, 145 Frankford Hospital approach 216 HDRbrachytherapy 313, 314 Seattle approach 127 Wheeling approach 113–14 potency assessment after brachytherapy 425–6 factors affecting 428–9 age 428, 429 erectile function preimplant 428 hormonal manipulation 429 isotope choice 429 supplemental EBRT 428–9 preservation/recovery 157, 158 after brachytherapy 426–8 studies 427 with/without sildenafil 431 with EBRT/brachytherapy 346 HDRbrachytherapy 323 see also erectile dysfunction; sexual function/dysfunction PPB see permanent prostrate brachytherapy preloaded needles 129, 215–20 EZ-Pak Preloaded Needle Program 387 needle manipulation ruler 247–50

Index

679

radiation exposure 247, 248 with strands 387, 391–2 probabilistic hill climbing see simulated annealing algorithms proliferation markers 11, 13 primary transitional cell carcinoma of prostate 22–3 ProSeed brachytherapy training study 197–204 results 198–202 ProstaScint antibody, schematic of 45 ProstaScint scans 43 accuracy of 223–4 co-registration with CT scan 54 detection of disease 52 human antimouse antibody (HAMA) reaction 52 image fusion 229 indications 55 operator skill 52 prostate cancer metastases study 45–6 recurrent disease detection 53 staging 44–52, 54–5, 228–9 and brachytherapy 52, 53 limitations 51–2 preoperative staging 46–8, 49 recurrent disease detection 48, 50–1 tumor targeting 221, 222 see also capromab pendetide; radioimmunoguided brachytherapy prostate cancer α/β ratios 308, 315 anatomy, sonographic 88, 89, 90 brachytherapy vs surgery 59–65 detailed mapping 27–33 discussion 28, 30, 32 distribution and gland weight 31, 32 and Gleason grade 31, 32 peripheral zone 28, 29, 30 and PSA level 29, 32 summary 27, 29 transitional zone 28, 29, 30, 32 and tumor classification 29 and tumor volume 32 zonal 27, 28 materials/methods 27–8 results 28, 29–30, 31–2 diagnosis 67–8 differential diagnosis after radiotherapy 11 histologic variants 21–3 incidence in US 59 metastatic disease 45–6, 48 detection 48, 49 multifocality and biopsies 223

Index

680

natural history 59 quality of life after local therapy 62–4 radiotherapy modalities 139 recurrent disease classification 50 detection 50–1, 53 sonographic appearance 89–90, 91 staging 50–1 sonographic appearance 88, 89, 90, 91 post-treatment 89–90 treatment choices patient’s view 68–9 urologist’s view 59–65 Prostate Cancer Index (UCLA-PCI) 413, 414 Prostate Cancer Intervention Versus Observation Trial (PIVOT) 60 Prostate Cancer Outcomes Study 62–3 prostate gland 3D view with pelvic bones 238 anatomy benign prostatic hyperplasia 85–6, 87, 88, 89 cysts 85–6, 87–8 gross anatomy 83–5 sonographic 83–92 cancer 88, 89, 90 post-treatment 89–90 zonal anatomy 84, 85 see also anatomy, prostatic/periprostatic center-of-mass (COM) 206 dimensions with ADT 241–2, 243 mobility 150, 151 radial distance measurements 407 TRUS visualization 128, 131 prostate gland volume androgen suppression therapy 241–2, 243 change during procedure 271 CT measurement 144 in diagnosis 67 in FIRST system 286 HDRbrachytherapy 319 large, and HDR brachytherapy 329 and late toxicity 339 measurement training 197 MRI measurement 143 and pubic arch interference 240, 242 step section planimetry measurement 188 TRUS measurement 143, 144 Prostate Implant Planning Engine for Radiotherapy (PIPER) 110, 265–9 autocontouring 265 find seeds function 268 Genetic Algorithm Inverse Planning Engine 265, 266 needle tracking 268 seed count, running total 268

Index tabs CT Contouring tab 268 CT Validation tab 268, 269 layout 265 OR Support tab 266, 268, 269 Treatment Plan tab 265–6, 267 TRUS/Contouring tab 265, 266 prostate-specific antigen (PSA) in diagnosis 67, 68 and disease-free survival 363 introduction 187 nadir 360 nadir/cut-off point 360, 363, 364 non-progression rates after brachytherapy 61–2 after radical prostatectomy 60–1 in Partin Tables 17 post-treatment 70 screening early use 124 efficacy 60 impact of 76 after therapy 61–2 brachytherapy 178 radiotherapy 11, 12 and urethra-cancer distance 36, 37 after US-guided 103Pd brachytherapy 176 prostate-specific antigen (PSA) bounce 433–9 age at implant 435, 438 clinical factors 438 definition 433 disease-free survival rates 436, 437, 438 duration 433, 434, 436, 438 height 433, 434, 436, 438 incidence 433, 435, 438 peak 433, 434, 438 prebounce nadir 433, 434, 437, 438 sexual function/dysfunction 438 time distribution 434 time to onset 433, 434, 435, 438 and treatment type 438 vs recurrence of cancer 438 prostate-specific membrane antigen (PSMA) 43 antibody for 221 see also ProstaScint antibody assays in staging 43–4, 52 detection 44 expression/elevation 43–4 as prostate cancer marker 44 protein structure 44 prostatectomy, radical (RP) 60 and HRQOL 414, 415

681

Index

682

patient characteristics 38 post-treatment sonographic appearance 90 and ProstaScint scan 46–8 PSA non-progression rates 60–1 quality of life issues 63 prostatectomy specimens brachytherapy target volume definition from 35–42 whole-mount, serial sectioning of 36 prostatic acid phosphatase (PAP) 11, 43 prostatic anatomy 158 prostatic intraepithelial neoplasia (PIN) postradiation pathology 7 radiotherapy for 221 prostatic mobility 150, 151 pubic arch interference 95, 271 avoidance palladium-103 brachytherapy 144, 149, 152 ultrasound-guided 170, 171, 175 evaluation 238 and hormonal therapy 237–45 before/after 239, 240, 243 in robot-aided/3D TRUS-guided system 274 working around 175 quality of life with EBRT/brachytherapy vs monotherapy 357, 358 instruments 425 after local therapy for prostate cancer 62–4 see also health-related quality of life radial distance 38–40 measurements 407 radiation exposure perineal pressure application 251, 252–3 preloaded needles 247, 248 radiation-induced secondary malignancies 79 radiation interactions 159 radiation safety 248 Frankford Hospital experience 218 HDR brachytherapy 311, 329 Radiation Therapy Oncology Group (RTOG) clinical trials 35–6 hormonal therapy 78 morbidity scoring scheme 78 radiation toxicity 306–7, 320, 337 acute 321, 322, 337 gastrointestinal 337, 339 chronic 321, 322 with EBRT/brachytherapy 346, 357–8 genitourinary 337, 339 grading criteria

Index

683

CTC 441–2 modified RTOG 338, 420 RTOG/LENT 338 grading criteria, RTOG/LENT 338 late 337, 338, 339 NCI Common Toxicity Criteria (CTC) 441–2 radioimmunoguided brachytherapy 225 rectal 420–1, 422 urinary 306–7, 346 radical prostatectomy (RP) see prostatectomy, radical radioactive sources see under specific isotope or technique radiobiology 295 HDR brachytherapy 305 radiobiological effect and dose rate 140 RADIOCOIL 373–83 anisotropy function 374, 375, 377 calibration 375 color-coded cartridges 380 CT scan in prostate 381, 383 delivery systems 375, 377, 379 deployment procedure 377, 378, 379 insertion force 379 design 374 diagram 376 dosimetry 375, 376–7 echogenicity/radiopacity 374, 381 evaluation in animals 374, 379, 380–1 in humans 379, 381 features/clinical benefits 376–9, 382 fluoroscopic image 381, 382 isodose lines 376, 378 manufacture 374 specification 375 ultrasound image in prostate 381, 382 X-ray, diagnostic 381, 382 radioimmunoguided brachytherapy 221–32 cancer foci/fusion image correlation 222–3, 224 image fusion 222, 228, 229 patients 224, 225, 226 ProstaScint accuracy 223–4 statistics 225–8 survival analysis 226–8 toxicity study 225 treatment 224–5 RADIOMED source see RADIOCOIL radiotherapy ADT with 11 immunohistochemical findings after 11–13 modalities for prostate cancer 139 plus androgen ablation 11 radium 367

Index

684

intraurethral 123 RAND Medical Outcomes Study 36-item Health Survey (SF-36) 413, 414 RAPIDStrand advantages 256–8 description 255–6 in FIRST system 291 Utrecht technique 261–3 ReadiStrand description/application 390 preloaded needles with absorbable plugs 391–2 standard/non-standard spacing 390 ‘trailing spacers’ 392 visibility 391 rectal complications 419 with EBRT/brachytherapy 346 palladium-103 brachytherapy 157 after permanent prostrate brachytherapy 419–24 bother 423 discussion 421, 422–3 with EBRT 422, 423 fistulas 423 materials 419–20 patient characteristics 420 proctitis 421, 422, 423 rectal bleeding 422, 423 rectal toxicity 420–1 results 420–1 treatment 423 ulceration 421, 422, 423 in Seattle approach 137 rectal dose 113 HDR brachytherapy 304–5, 315 intraoperative vs postplan 194 palladium-103 brachytherapy 154–5 and rectal injury 419 reimplantation of underdosed region 402 in Wheeling approach 120 recurrence, postirradiation markers 11, 13 sonographic appearance 89–90, 91 reimplantation of underdosed region 397–403 initial implant 397 isodose distribution 400 operator variation 399 postimplant CT scan 398, 399 postreimplant CT scan 401 procedure 398 results 398 reseeding 179 reverse transcriptase polymerase chain reaction (RT-PCR) 43 in serum PSMA assay 44 Riverside Research Institute intraoperative treatment planning 112

Index

685

robot-aided/3D TRUS-guided brachytherapy 271–83 dose plan display 275 needle trajectories 275 procedure schematic 272 system 273, 277 system description 272 3D TRUS imaging 273, 274 calibration 274, 276 of robot 277 dosimetry 273, 274 needle segmentation 276–7 prostate segmentation 273, 275 system evaluation fiducial localization errors 277, 278, 279, 281–2 fiducial registration errors 278, 279 needle angulation/placement/targeting 279–80 needle tracking 278, 280–1 seed implantation 281 target registration errors 278 TRUS/robot integration calibration methods 277, 278 calibration results 278–9 US transducer mount 277 ‘rocking the cradle’ 181, 182–3 RP see prostatectomy, radical RT-PCR see reverse transcriptase polymerase chain reaction safety, radiation 248 salvage therapy 51, 55 Scandinavian Prostate Cancer Group Study 60 Scout image of HDR implant 101 Seattle approach biochemical relapse-free survival (BRFS) 136–7 dosimetry 124, 127–8 post-implant CT-based 135 implant technique 128–35 isotope selection 126–7 needle loading report 126 results 131, 136–7 side effects 137 target volumes 127–8 transrectal ultrasound volume study (TRUVS) 127, 128 treatment planning 127 secondary malignancies, radiation-induced 79 sedation brachytherapy under local anesthesia 236 palladium-103 brachytherapy 169, 170 seed(s) detection, intraoperative 96 distribution Frankford Hospital approach 216

Index

686

stranded sources 262, 263 identification, intraoperative 112 implantation advantages 179–80 evolution/expectations 390 Frankford Hospital experience 217, 218 permanent, rectal complications after 419–24 real-time 187 reimplantation see reimplantation suboptimal, salvage of see reimplantation training 198 loss 291 manufacture 373–4 migration 41, 124 comparison 291 in Frankford Hospital approach 218 stranded sources 256, 262 numbers 115 in Seattle approach 130, 133 US-guided 103Pd brachytherapy 169, 171 placement assessment 218 FIRST system 288–9 loading philosophies accepted 118 modified uniform loading 113–14, 118 misplacement and inverse planning 95–6 and reimplantation 399, 403 Wheeling approach 119 modified uniform loading 113, 115–17, 125 first/second modifications 116 parameters in Wheeling approach 115 pain scores 235 peripheral loading 125 combined PPB/EBRT 353 in Frankford Hospital approach 216–17 vs uniform loading 113 periprostatic margins 120 real-time US-guided brachytherapy 188, 189 training 197 reimplantation of underdosed region 399, 403 Seattle approach 130 spacers/special loads 389 in treatment of EPE 41 TRUS-guided 93 uniform loading 125 US-guided 103Pd brachytherapy 172–6 longitudinal imaging 173, 174 preparation, Frankford Hospital experience of 217 stranded see stranded sources seed redundancy test 220

Index

687

seed uncertainty 114 seedSelectron 285, 287–8 schematic 289 seminal vesicle involvement 35 seminal vesicles cysts 88 sectioning in target volume definition 36 sonographic appearance 83, 84, 86, 87 TRUS visualization 128, 131 sextant biopsy protocol 20 sexual function/dysfunction after brachytherapy 78–9, 323, 425–32 and EBRT 346 HDR 307 palladium-103 157–9 HRQOL 414–15 after local therapy for prostate cancer 63–4 quality of life instruments 425 see also erectile dysfunction; potency SF-36 413, 414 signet-ring carcinoma of prostate 22 sildenafil (Viagra) 431 simulated annealing algorithms 102, 103–4 simultaneous irradiation study discussion 363–4 disease-free survival rates 359–64 vs radical prostatectomy 364 materials/methods 359–60 patient characteristics 359 results definition of disease freedom 360 disease-free survival rates 360–3 PSA nadir 360 single-photon emission computed tomography (SPECT) 221, 222 small cell undifferentiated neuroendocrine carcinoma 22 ‘smart seed technique’ 77 software for brachytherapy 93–7 sonographic anatomy of prostate see under prostate gland Sonographic Planning of Oncology Treatment (SPOT) 285, 287 sources see radioactive sources ‘spackle’ effect 355 SPOT 285, 287 squamous cell carcinoma 22 staging future developments 52, 54 ProstaScint scan 44–52, 54–5 and brachytherapy 52, 53 limitations 51–2 preoperative staging 46–8, 49 recurrent disease detection 48, 50–1 serum PMSA assays 43–4

Index

688

and monoclonal antibodies 52 statistical analysis androgen suppression/prostate size 243 pubic arch interference 238 radioimmunoguided brachytherapy 225–8 statistical cooling see simulated annealing algorithms steroids for implant-related swelling 146 stochastic relaxation see simulated annealing algorithms stranded sources 187, 255–60, 369 ‘accordion effect’ 389 advantages 256–8 development 389 InterStrand 386–7 InterStrand special 387 preparation 256 seed distribution 262, 263 strand holders 262 strength 262, 263 Utrecht technique 261–3 surgery vs brachytherapy 59–65 see also prostatectomy, radical Surveillance Epidemiology and End Results (SEER) database 60, 63, 64 survival EBRT with brachytherapy 345 and Gleason grade 59 HDR brachytherapy 319–20, 323, 324 Kaplan-Meier plots 228, 230–1 after radical prostatectomy 61 radioimmunoguided brachytherapy 226–8 and Seattle approach 136–7 see also biochemical relapse-free survival; disease-free survival swelling, implant-related 146–7 target coverage evaluation 153–4 target volumes definition extraprostatic extension measurements in 38–41 intraprostatic tumor volume in 38 multifocality in 38 urethra-cancer distance measurement in 36–7 and implant-related swelling 146–7 Seattle approach 127–8 template guidance 75 with flexiguide tubes 101 permanent implants 100 TherapacPlus 188–9 Theraseed 141, 148, 152 ultrasound-guided brachytherapy 169–80 thermoluminescent dosimeters (TLD) 370

Index

689

three-dimensional histograms 27 toxicity see radiation toxicity training 197–204 brachytherapy under local anesthesia 236 transitional zone prominent 32 sonographic appearance 85 transperineal interstitial permanent prostate brachytherapy (TIPPB) 237, 240 reimplantation of underdosed region 397–403 transrectal ultrasound (TRUS) 2D and 3D 271–2 3D TRUS-guided brachytherapy see robot-aided brachytherapy automatic contouring 95 for brachytherapy 75 HDR 297, 313, 317 detection of stranded sources 257 early use 124 extraprostatic source placement 148 in FIRST system 286 in Frankford Hospital approach 216, 217 guidance for seed placement 93 needle tracking 96, 271 palladium-103 brachytherapy 142, 143, 150 probe angle 131, 135, 152 probe positioning 150 prostate visualization 131 pubic arch interference 95, 240, 242 palladium-103 brachytherapy 144, 149, 152 seminal vesicle visualization 131 target volume definition 35 urethra visualization 128, 130 volume study (TRUVS) 127, 128 transurethral resection of prostate (TURP) 75 complications/side effects 78 as contraindication to brachytherapy 79, 215 extraprostatic source placement 148, 157 HDR brachytherapy after 329 complications/side effects 337 early work 327 and late toxicity 339 and palladium-103 brachytherapy 155, 156, 170 and Seattle approach 127 treatment choices patient’s view 68–9 urologist’s view 59–65 treatment goals 35 treatment margin (TM) 145, 146 treatment planning 99–107, 124–5 algorithms branch-and-bound 102, 103, 104–5 genetic 102, 103 simulated annealing 102, 103–4

Index

690

design/verification 102–5 dose prescription 101–2 examples 105–6 Frankford Hospital approach 216 HDR brachytherapy 303–5 for high IPSS/prior TURP patients 333 imaging tool, ideal 205 intraoperative advantages 194–5 computer-optimized 195 dosimetric results 110–11 future directions 112 by needle position 111–12 real-time ultrasound-guided brachytherapy 187 time requirements 111 vs postplan studies 194 models 103 modified peripheral loading 147–8, 171 modified uniform loading 125 Mt Sinai approach 109 and needle deviation 100 optimized inverse planning 194–5 palladium-103 brachytherapy perioperative steroids 146–7 planning images 144–5 for potential EPE 406 target definitions 145 target volumes 146 treatment planning 146 preoperative 109–10 Mick applicator 110 volume study 109 Seattle approach 123–38 preoperative 109, 113 source position localization 100–1 source selection 99–100 in urinary incontinence study 442 Wheeling approach 113–21 dose homogeneity 119 modified uniform loading parameters 115 postimplant dosimetry 117–18 preimplant dosimetric evaluation 115, 117–18 preplanning dosimetry 114–17 preplanning philosophy 113–14 treatment-planning software 93–7 AAPM TG-43 formalism 94 auto-segmentation 95 Corvus planning system 329 dose-surface histogram 95 dose-volume histogram 94–5, 102 EBRT, adapted 237, 243 image acquisition 93–4

Index

691

image segmentation 94 intraoperative seed detection 96 inverse planning 95–6 isodose display 94, 266, 267 MMS 110 needle tracking 96, 268 PIPER 110, 265–9 post-implant CT dosimetry 95 Prostate Implant Planning Engine for Radiotherapy (PIPER) 110 in robot-aided/3D TRUS-guided system 274 TherapacPlus 188–9 in training 198 Variseed 110 tumor death/eradication brachytherapy vs external beam 8 time taken for 7 tumor suppressor genes 13 tumor volume in needle biopsy 20 UCLA Prostate Cancer Index (UCLA-PCI) 413, 414 ultrasound biplanar linear array endorectal probe 75, 188 biplanar transrectal probe 169, 171 introduction 187 mapping of MR/MRS images to 205–14 algorithm 205–8 reversal 212–13 validation 208–11 schematics of method 207, 208 stranded sources 257–8, 259 see also Doppler ultrasound ultrasound grids 130 ultrasound-guided brachytherapy history 181 real-time interactive see EchoSeed US-guided brachytherapy training study 197–204 see also palladium-103 brachytherapy, ultrasound-guided ultrasound volume study 216 undergrading 18 urethra sonographic appearance 83, 84 ultrasound visualization 128, 130, 149–50 urethra-cancer distance measurement 36–7 urethral dose 113 HDR brachytherapy 304, 313, 316 intraoperative vs postplan 194 with MRI/MRSI 205, 206 palladium-103 brachytherapy 147, 154–5 ultrasound-guided 170 reimplantation of underdosed region 398–9, 402 in Seattle approach 131, 135

Index

692

in urinary incontinence study 442 in Wheeling approach 116, 117, 119, 120 urinary incontinence assessment tools 449 definition 450 incidence 441 in general population 450 by preimplant IPPS 445–6, 447, 448 by urethral dose 443–5, 448, 449 by year of implantation 446–7, 448 after local therapy for prostate cancer 63 predictive factors study 441–51 method 442–3 patients 442–3 results 443–50 statistical analysis 443 in Seattle approach 137 urinary morbidity brachytherapy HDR 297–8, 306 palladium-103 155, 156, 177, 178 Frankford Hospital experience 218 and HRQOL 414 risk with large prostate glands 329 Utrecht technique 262 urinary toxicity 306–7, 346 US see ultrasound Utrecht technique in RAPIDStrand afterloading 261–3 utricular cysts 88 V100 index 153, 155 VariSeed 110, 189–93 Bard/ProSeed planning module 190 treatment results 193 in Frankford Hospital approach 220 image recapture 191 isodose contours 192 live transverse image 191 plan update 192 seed placement 190, 193 in urinary incontinence study 442 vasa deferentia 83, 87 Viagra (sildenafil) 431 vicryl sutures echogenic nature 257 embedded energy source 255–60 X-ray simulations of seed distribution 177 zero plane 144–5 Zoladex 237