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

329

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

502

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

659

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

Basic and advanced techniques in prostate brachytherapy

2

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

7

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.


8

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


9

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


10

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 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


11

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 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


12

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


15

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


16

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.


17

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%) (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 (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 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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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 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 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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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 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

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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.


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,


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.


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)

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