Advanced Therapy of Prostate Disease

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Advanced Therapy of Prostate Disease

Advanced Therapy of Prostate Disease Martin I. Resnick, MD Lester Persky Professor and Chair Department of Urology Case Western Reserve University University Hospitals of Cleveland Cleveland, Ohio

Ian M. Thompson, MD Chief, Department of Surgery University of Texas Health Sciences Center Uniformed Services University of Health Sciences Director of Urologic Oncology Brooke Army Medical Center San Antonio, Texas

2000

B.C. Decker Inc. Hamilton • London

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Notice: The authors and publisher have made every effort to ensure that the patient care recommended herein, including choice of drugs and drug dosages, is in accord with the accepted standard and practice at the time of publication. However, since research and regulation constantly change clinical standards, the reader is urged to check the product information sheet included in the package of each drug, which includes recommended doses, warnings, and contraindications. This is particularly important with new or infrequently used drugs.

CONTRIBUTORS

Paul Abrams, MD, FRCS Bristol Urological Institute Southmead Hospital Bristol, United Kingdom Peter C. Albertsen, MD, MS Division of Urology University of Connecticut School of Medicine University of Connecticut Health Center Farmington, Connecticut George A. Alexander, MD Office of Special Populations Research National Cancer Institute National Institutes of Health Bethesda, Maryland

John J. Bauer, MD Uniformed Services University of the Health Sciences Urology Telemedicine and Advanced Technology Walter Reed Army Medical Center Washington, DC

Peter R. Carroll, MD Department of Urology University of California San Francisco University of California San Francisco/Mt. Zion Cancer Center San Francisco, California

Ronald M. Benoit, MD Allegheny University of the Health Sciences Allegheny General Hospital Pittsburgh, Pennsylvania

Culley C. Carson, MD Department of Surgery University of North Carolina Chapel Hill, North Carolina

Gerald L. Andriole, MD Division of Urology Washington University School of Medicine

Mitchell C. Benson, MD Department of Urology Columbia University, College of Physicians and Surgeons Squier Urologic Clinic New York Presbyterian Hospital— Columbia Presbyterian Campus New York, New York

John G. Anema, MD Department of Urology Brooke Army Medical Center Fort Sam Houston, Texas

Michael L. Blute, MD Department of Urology Mayo Clinic Rochester, Minnesota

Christopher J. Austin, MD Department of Urology University of Iowa Iowa City, Iowa

Otis W. Brawley, MD Office of Special Populations Research National Cancer Institute National Institutes of Health National Institutes of Health Clinical Center and National Naval Medical Center Bethesda, Maryland

Chris H. Bangma, MD, PhD Academic Hospital Rotterdam Erasmus University Rotterdam Rotterdam, The Netherlands David M. Barrett, MD Mayo Medical School Department of Urology Mayo Clinic Rochester, Minnesota

Reginald C. Bruskewitz, MD Department of Surgery Division of Urology University of Wisconsin Hospital and Clinics Madison, Wisconsin

H. Ballentine Carter, MD Department of Urology The Johns Hopkins University School of Medicine The Johns Hopkins Hospital Baltimore, Maryland R. Duane Cespedes, MD University of Texas Health Sciences Center Female Urology and Urodynamics Wilford Hall Medical Center San Antonio, Texas Jeffrey K. Cohen, MD Allegheny University of the Health Sciences Allegheny General Hospital Pittsburgh, Pennsylvania Charles A. Coltman, MD The Cancer Therapy and Research Foundation of South Texas San Antonio, Texas E. David Crawford, MD University of Colorado Health Sciences Center University Hospital Denver, Colorado

vi / Contributors

Daniel J. Culkin, MD Department of Urology University of Oklahoma Health Science Center Oklahoma City, Oklahoma Rodney Davis, MD Section of Urologic Oncology Tulane University New Orleans, Louisiana Nancy A. Dawson, MD University of Chicago Cancer Research Center Chicago, Illinois Todd H. Doyle, MD Radiation Oncology Hospital of the University of Pennsylvania University of Pennsylvania Health System Philadelphia, Pennsylvania George W. Drach, MD Division of Urology University of Pennsylvania Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Mario A. Eisenberger, MD Professor of Oncology and Urology The Johns Hopkins University Baltimore, Maryland Daniel S. Elliott, MD Mayo Graduate School of Medicine Department of Urology Mayo Clinic Rochester, Minnesota Rod J. Ellis, MD Department of Radiation Oncology Case Western Reserve University School of Medicine Cleveland, Ohio L. Andrew Eskew, MD Piedmont Urological Association High Point Regional Hospital High Point, North Carolina

Scott A. Fengler, MD, FACS, FASCRS Department of Surgery, Uniformed Services University of the Health Sciences St. Francis Hospital Tulsa, Oklahoma

S. Larry Goldenberg, MD, FRCSC Department of Surgery University of British Columbia Prostate Centre at Vancouver General Hospital Vancouver, British Columbia

Robert C. Flanigan, MD Department of Urology Loyola University Medical Center Stritch School of Medicine Maywood, Illinois

Gary D. Grossfeld, MD Department of Urology University of California San Francisco University of California San Francisco/Mt. Zion Cancer Center San Francisco, California

John P. Foley, MD Division of Urology University of Texas Health Sciences Center at San Antonio Brooke Army Medical Center Fort Sam Houston, Texas Jack Geller, MD University of California San Diego Clinical Medicine Anticancer Inc. San Diego, California Valal George, MD, PhD Wayne State University Harper & Childrens Hospital of Detroit Detroit, Michigan Glenn S. Gerber, MD Department of Surgery University of Chicago Pritzker School of Medicine Chicago, Illinois Edward L. Gheiler, MD Wayne State University Harper Hospital Detroit, Michigan Cynthia J. Girman, Dr.PH Clinical Epidemiology Mayo Clinic Department of Epidemiology Merck Research Laboratories Blue Bell, Pennsylvania Frank E. Glover Jr, MD Memorial Hospital Bainbridge, Georgia

Gerald E. Hanks, MD Radiation Oncology Temple University School of Medicine Department of Radiation Oncology Fox Chase Cancer Center Philadelphia, Pennsylvania Javier Hernandez, MD Department of Surgery University of Texas Health Science Center San Antonio, Texas Celestia Higano, MD Division of Medical Oncology Department of Medicine University of Washington Seattle, Washington Eric M. Horwitz, MD Radiation Oncology Fox Chase Cancer Center Philadelphia, Pennsylvania Maha Hussain, MD, FACP Wayne State University Barbara Ann Karmanos Cancer Institute Harper Hospital Detroit, Michigan Christopher W. Johnson, MD Department of Urology Columbia University, College of Physicians and Surgeons Squier Urologic Clinic New York Presbyterian Hospital— Columbia Presbyterian Campus New York, New York

Contributors / vii

John N. Kabalin, MD, FACS Section of Urologic Surgery University of Nebraska College of Medicine Regional West Medical Center Scottsbluff, Nebraska Fernando J. Kim, MD Department of Urology Loyola University Medical Center Stritch School of Medicine Maywood, Illinois Hines Veterans Administration Hospital Hines, Illinois Eric A. Klein, MD Section of Urologic Oncology Department of Urology Cleveland Clinic Foundation Cleveland, Ohio Barnett S. Kramer, MD, MPH Uniformed Services University of the Health Sciences Division of Cancer Prevention National Cancer Institute Bethesda, Maryland John N. Krieger, MD Department of Urology University of Washington VA Puget Sound Health Care System Seattle, Washington Rasmus H. Krogh, MD Department of Surgery Division of Urology University of Wisconsin Hospital and Clinics Madison, Wisconsin Menachem Laufer, MD The Johns Hopkins University Baltimore, Maryland Tel Aviv Medical Center Tel Aviv, Israel Gary E. Leach, MD Department of Urology University of Southern California Tower Urology Institute for Continence Cedars-Sinai Medical Center Los Angeles, California

Wendy W. Leng, MD Department of Urology University of California San Francisco San Francisco, California

Brian J. Miles, MD Scott Department of Urology Baylor College of Medicine Houston, Texas

Mark R. Licht, MD Department of Urology Cleveland Clinic Florida Fort Lauderdale, Florida

David C. Miller, BS Division of Urology Washington University School of Medicine

Scott A. MacDiarmid, MD, FRCSC Department of Urology University of Arkansas for Medical Sciences Little Rock, Arkansas

Gary J. Miller, MD, PhD Professor of Pathology and Urology University of Colorado Health Sciences Center Denver, Colorado

Gregory T. MacLennan, MD Department of Pathology Case Western Reserve University University Hospitals of Cleveland Cleveland, Ohio

Ralph J. Miller Jr, MD Allegheny University of the Health Sciences Allegheny General Hospital Pittsburgh, Pennsylvania

Susan R. Marengo, PhD Urology Research Laboratory Case Western Reserve University Cleveland, Ohio

Allen F. Morey, MD, FACS Brooke Army Medical Center Fort Sam Houston, Texas

David L. McCullough, MD Department of Urology Wake Forest University School of Medicine North Carolina Baptist Hospital Wake Forest University Baptist Medical Center Winston-Salem, North Carolina Edward J. McGuire, MD Department of Urology University of Texas Houston Health Science Center Houston, Texas Winston K. Mebust, MD Section of Urology, Department of Surgery University of Kansas Medical Center Kansas City, Kansas Lori Merlotti Allegheny University of the Health Sciences Allegheny General Hospital Pittsburgh, Pennsylvania

Judd W. Moul, MD Department of Surgery Uniformed Services University of the Health Sciences Bethesda, Maryland Edward J. Mueller, MD University of Texas Health Science Center St. Luke’s Baptist Hospital San Antonio, Texas Perinchery Narayan, MD Division of Urology University of Florida Gainesville, Florida Durwood E. Neal Jr, MD Division of Urology Southern Illinois University School of Medicine Springfield, Illinois

viii / Contributors

Robert J. Nejat, MD Department of Urology Columbia University, College of Physicians and Surgeons Squier Urologic Clinic New York Presbyterian Hospital— Columbia Presbyterian Campus New York, New York Ajay Nehra, MD Department of Urology Mayo Clinic and Mayo Foundation Rochester, Minnesota Peter Nelson, MD Division of Medical Oncology Department of Medicine University of Washington Seattle, Washington Brian E. Nicholson, MD Department of Urology Loyola University Medical Center Stritch School of Medicine Maywood, Illinois Mark J. Noble, MD Department of Urology Cleveland Clinic Foundation Cleveland, Ohio Keith J. O’Reilly, MD Section of Urology Madigan Army Medical Center Tacoma, Washington David K. Ornstein, MD Urologic Oncology Branch National Cancer Institute Manoj Patel, MD Division of Urology University of Florida Gainesville, Florida Rashmi I. Patel, MD Case Western Reserve University University Hospitals of Cleveland Cleveland, Ohio David F. Paulson, MD Duke University Duke Medical Center Durham, North Carolina

Michael Perrotti, MD Robert Wood Johnson Medical School Cancer Institute of New Jersey Robert Wood Johnson University Hospital New Brunswick, New Jersey Paul K. Pietrow, MD Vanderbilt University Medical Center Nashville, Tennessee J. Edson Pontes, MD Wayne State University Harper Hospital Wertz Cancer Institute Detroit, Michigan Isaac J. Powell, MD Department of Urology Wayne State University Karmanos Cancer Institute Detroit, Michigan Theresa P. Pretlow, MD Departments of Pathology, Oncology, and Environmental Health Sciences Case Western Reserve University Medical Center Cleveland, Ohio Thomas G. Pretlow, MD Departments of Pathology, Urology, Oncology, and Environmental Health Sciences Case Western Reserve University Medical Center Cleveland, Ohio Farhang Rabbani, MD, FRCSC Urology Service Department of Surgery Memorial Sloan-Kettering Cancer Center New York, New York Martin I. Resnick, MD Department of Urology Case Western Reserve University University Hospitals of Cleveland Cleveland, Ohio

Jerome P. Richie, MD, FACS Harvard Medical School Harvard Program in Urology Brigham and Women’s Hospital Boston, Massachusetts Mack Roach III, MD Radiation Oncology, Medical Oncology and Urology University of California San Francisco San Francisco, California Andrew C. Roberts, BS, MD Department of Urology The University of Oklahoma Health Science Center Oklahoma City, Oklahoma Steven G. Roberts, MD Department of Urology Mayo Clinic Rochester, Minnesota Thomas A. Rozanski, MD Uniformed Services University of the Health Sciences Brooke Army Medical Center San Antonio, Texas Oliver Sartor, MD Louisiana State University Medical School Stanley S. Scott Cancer Center New Orleans, Louisiana Anthony J. Schaeffer, MD Department of Urology Northwestern University Medical School Northwestern Memorial Hospital Chicago, Illinois Richard A. Schoor, MD Department of Urology Northwestern University Medical School Northwestern Memorial Hospital Chicago, Illinois Fritz H. Schröder, MD, PhD Academic Hospital Rotterdam Erasmus University Rotterdam Rotterdam, The Netherlands

Contributors / ix

Claude C. Schulman, MD, PhD Department of Urology University Clinics of Brussels Brussels, Belgium Thomas M. Seay, MD, LTCOL, USAF, MC, FS Department of Urology Wilford Hall Medical Center Lackland AFB, Texas San Antonio Uniformed Services Health Education Consortium San Antonio, Texas Allen D. Seftel, MD Department of Urology Case Western Reserve University University Hospitals of Cleveland and Cleveland VA Medical Center Cleveland, Ohio Moshe Shalev, MD Scott Department of Urology Baylor College of Medicine Houston, Texas Joseph A. Smith Jr., MD Vanderbilt University Medical Center Nashville, Tennessee Graeme S. Steele, MBBCh, FCS Harvard Medical School Division of Urology Brigham and Women’s Hospital Boston, Massachusetts Marcos V. Tefilli, MD Wayne State University Karmanos Cancer Institute Detroit, Michigan Ashutosh Tewari, MD Division of Urology University of Florida Gainesville, Florida Alun W. Thomas, BSc, MBBS, FRCS Bristol Urological Institute Southmead Hospital Bristol, United Kingdom

Ian M. Thompson, MD Department of Surgery University of Texas Health Sciences Center Uniformed Services University of the Health Sciences Brooke Army Medical Center San Antonio, Texas J. Brantley Thrasher, MD, FACS University of Kansas Medical Center Kansas City, Kansas Eric Vigneault, MD Department of Radiation Oncology Laval University CHUQ, Pavillon L’Hôtel-Dieu de Québec Quebec City, Quebec Nicholas J. Vogelzang, MD University of Chicago Cancer Research Center Chicago, Illinois Joanne Waldstreicher, MD Clinical Research, Endocrinology, and Metabolism Merck Research Laboratories Rahway, New Jersey Patrick C. Walsh, MD Department of Urology The Johns Hopkins University School of Medicine The Johns Hopkins Hospital Baltimore, Maryland William Bedford Waters, MD Loyola University Medical Center Stritch School of Medicine Maywood, Illinois Hines Veterans Administration Hospital Hines, Illinois

John D. Wegryn, MD Department of Urology Case Western Reserve University University Hospitals of Cleveland and Cleveland VA Medical Center Cleveland, Ohio Richard Whittington, MD Department of Radiation Oncology Hospital of the University of Pennsylvania Philadelphia, Pennsylvania Richard D. Williams, MD Department of Urology The University of Iowa Iowa City, Iowa Timothy J. Wilt, MD, MPH Minneapolis VA Center for Chronic Diseases Outcomes Research Minneapolis VA Medical Center Minneapolis, Minnesota David P. Wood Jr, MD Department of Urology Wayne State University Department of Urologic Oncology Karmanos Cancer Institute Detroit, Michigan Ali M. Ziada, MD University of Colorado Health Sciences Center University Hospital Denver, Colorado Horst Zincke, MD, PhD Professor of Urology Mayo Clinic Rochester, Minnesota Alexandre R. Zlotta, MD Department of Urology University Clinics of Brussels Brussels, Belgium

PREFACE

It is well known that prostate cancer is the leading malignancy in aging men in the United States, and equally well known that it is the second leading cause of cancer-related death of American men. Benign prostatic hyperplasia is a common problem affecting the aging male; more than a third will experience symptoms requiring some form of therapy. Finally, prostatitis, another common disorder, occurs in younger men but is also seen in all ages, and both diagnosis and treatment can be problematic. Over the past decades, there have been many monographs, publications, and research efforts expended on these disorders and a marked increase has occurred in the 1990s. Why then is another book needed and what is its purpose? Because the diseases of the prostate are multi-faceted and because there have been significant changes over the past few years, an update by experts addressing the more controversial issues should be of value. For instance, there have been marked changes in the concepts regarding treatment modalities for patients with localized and regionally advanced carcinoma of the prostate. Additionally, the use of PSA and the wide introduction of screening and early detection though common remains controversial. We have also witnessed many changes in the management of benign prostatic hyperplasia in that past options related primarily to transurethral resection, while today many new less invasive techniques plus pharmacologic therapy are readily available. The field of prostatitis is also changing markedly with not only a redefinition of the disease itself, but reassessment of the treatment options available, as well. Our hope is that Advanced Therapy of Prostate Disease will address many of these issues. Experts in the field were chosen and in all instances the chapters are concise, to the point, and should provide the reader with practical, up-to-date information. We expect this text will be outdated in several years; hopefully, if it is well received and the many changes that we have seen in the past continue in the future, further editions will continue to update physicians in the latest evaluation-treatment trends of these disorders. MIR IMT

Dedicated to investigators throughout the world who are working tirelessly to prevent and cure prostate disease, and to our patients with prostate disease who have participated in studies to help develop those strategies for prevention and a cure. To our families, Laura, Ian III, and Donna, Vicki, Andy, Jeff, Missy, and Katelin, who have tolerated our absences and late nights at work with our patients. Martin I. Resnick, MD Ian M. Thompson, MD

CONTENTS

1

Epidemiology of Prostate Cancer: an Overview Peter C. Albertsen, MD, MS

1

2

Epidemiology of Prostate Cancer in African Americans Isaac J. Powell, MD

6

3

Epidemiology of Prostate Cancer in Africa George A. Alexander, MD, and Otis W. Brawley, MD

14

4

Prostate Cancer among the Chinese: Pathologic, Epidemiologic, and Nutritional Considerations Gary J. Miller, MD, PhD

18

5

Epidemiology of Prostate Cancer in Jamaicans Frank E. Glover Jr, MD, Patrick C. Walsh, MD, and H. Ballentine Carter, MD

28

6

Epidemiology of Prostate Cancer in Hispanic Americans Javier Hernandez, MD, and Ian M. Thompson, MD

31

7

Assessment of Risk of Prostate Cancer: Algorithms for Diagnosis, Staging, and Prognosis John J. Bauer, MD, and Judd W. Moul, MD

34

8

Molecular Factors in the Assessment of Prostate Cancer Risk Oliver Sartor, MD

44

9

Screening for Prostate Cancer: an Overview David C. Miller, BS, David K. Ornstein, MD, and Gerald L. Andriole, MD

50

10

The Optimal Diagnostic Tool: Assessment of Diagnostic Modalities to Detect Early Prostate Cancer Chris H. Bangma, MD, PhD, and Fritz H. Schröder, MD, PhD

60

11

Screening for Prostate Cancer: the Case for Screening Robert J. Nejat, MD, Christopher W. Johnson, MD, and Mitchell C. Benson, MD

73

12

Screening for Prostate Cancer: the Argument for Caution Barnett S. Kramer, MD, MPH, and Otis W. Brawley, MD

80

xiv / Contents

13

Natural History of Localized Adenocarcinoma of the Prostate John P. Foley, MD, and Ian M. Thompson, MD

86

14

Prostate Physiology and Regulation Susan R. Marengo, PhD

92

15

Pathobiology of Prostate Diseases: an Update Gregory T. MacLennan, MD

118

16

Models of Prostate Cancer Thomas G. Pretlow, MD, and Theresa P. Pretlow, MD

138

17

Diagnosis of Prostate Cancer L. Andrew Eskew, MD, and David L. McCullough, MD

154

18

Staging of Prostate Cancer Rashmi I. Patel, MD, and Martin I. Resnick, MD

159

19

Radical Prostatectomy: Patient Preparation Paul K. Pietrow, MD, and Joseph A. Smith Jr, MD

177

20

Stage T1a Prostate Cancer: the Case for Treatment Gary D. Grossfeld, MD, and Peter R. Carroll, MD

184

21

T1b-T2NxM0: the Case for Observation Fernando J. Kim, MD, and William Bedford Waters, MD

195

22

Radical Retropubic Prostatectomy for Clinical Stage T1b-T2 Prostate Cancer Moshe Shalev, MD, and Brian J. Miles, MD

202

23

Radical Perineal Prostatectomy David F. Paulson, MD

210

24

Continence-Enhancing Modifications for Radical Prostatectomy Mark R. Licht, MD, and Eric A. Klein, MD

219

25

T1-T2NxM0: the Case for External Radiotherapy Eric Vigneault, MD, and Mack Roach III, MD

229

26

Permanent Low-Dose-Rate Interstitial Brachytherapy Rod J. Ellis, MD

241

27

T1b-T2NxM0: a Case for Hormonal Therapy? Farhang Rabbani, MD, FRCSC, and S. Larry Goldenberg, MD, FRCSC

253

Contents / xv

28

Role of Cryosurgery in the Treatment of Prostate Cancer Ronald M. Benoit, MD, Jeffrey K. Cohen, MD, Ralph J. Miller Jr, MD, and Lori Merlotti

258

29

Should T1c Disease Be Treated Differently from T2 Disease? Keith J. O’Reilly, MD, and J. Brantley Thrasher, MD, FACS

267

30

T3-T4NxM0: the Case for Observation Thomas A. Rozanski, MD, and Rodney Davis, MD

275

31

T3-T4NxM0: the Case for Radiotherapy Eric M. Horwitz, MD, and Gerald E. Hanks, MD

284

32

Clinical-Pathologic T3NxM0 Prostate Cancer: the Case for Surgery Marcos V. Tefilli, MD, and David P. Wood Jr, MD

291

33

Node-Positive Prostate Cancer: the Case for Observation Daniel J. Culkin, MD, and Andrew C. Roberts, BS, MD

300

34

TxN+M0: the Case for Radiotherapy Richard Whittington, MD, and Todd H. Doyle, MD

304

35

TxN+M0 Disease: the Case for Early Hormonal Therapy and Surgery Thomas M. Seay, MD, LTCOL, USAF, MC, FS, and Horst Zincke, MD, PhD

311

36

TxNxM1: the Case for Monotherapy Menachem Laufer, MD, and Mario A. Eisenberger, MD

317

37

TxNxM1: the Case for Total Androgen Deprivation Ali M. Ziada, MD, and E. David Crawford, MD

324

38

Is Early Hormonal Therapy Preferable? Valal George, MD, PhD, and Maha Hussain, MD, FACP

332

39

Staging Failures of Initial Therapy J. Christopher Austin, MD, and Richard D. Williams, MD

340

40

Management of Prostate-Specific Antigen Failure after Definitive Therapy for Clinically Localized Prostate Cancer Marcos V. Tefilli, MD, Edward L. Gheiler, MD, and J. Edson Pontes, MD

353

41

Management of Local Failure following Treatment of Localized Prostate Cancer Graeme S. Steele, MBBCh, FCS, and Jerome P. Richie, MD, FACS

365

42

Secondary Hormonal Therapy Nancy A. Dawson, MD, and Nicholas J. Vogelzang, MD

378

xvi / Contents

43

Management of Hormone-Refractory Prostate Cancer: Chemotherapy and Immunotherapy Peter Nelson, MD, and Celestia Higano, MD

385

44

The Artificial Genitourinary Sphincter Daniel S. Elliott, MD, and David M. Barrett, MD

405

45

Collagen Therapy for Postprostatectomy Incontinence Wendy W. Leng, MD, R. Duane Cespedes, MD, and Edward J. McGuire, MD

410

46

Management of Complications of Therapy: Erectile Dysfunction Allen D. Seftel, MD, John D. Wegryn, MD, and Ajay Nehra, MD

416

47

Anorectal Complications of Prostate Surgery Scott A. Fengler, MD, FACS, FASCRS

423

48

Chemoprevention of Cancer of the Prostate Ian M. Thompson, MD, and Charles A. Coltman, MD

428

49

Prostate Cancer: Management of Complications of the Disease and Its Therapy Michael Perrotti, MD

446

50

Randomized Clinical Trials in Prostate Cancer Timothy J. Wilt, MD, MPH

452

51

Hormonal and Cellular Aspects of Benign Prostatic Hyperplasia R. Duane Cespedes, MD

463

52

Need for Urodynamics and Other Testing Gary E. Leach, MD, and Scott A. MacDiarmid, MD, FRCSC

471

53

Minimal Essential Diagnostic Testing Rasmus H. Krogh, MD, and Reginald C. Bruskewitz, MD

481

54

Pathophysiology of Bladder Outlet Obstruction and Voiding Dysfunction R. Duane Cespedes, MD

491

55

Prevention of the Progression and Long-Term Complications of Benign Prostatic Hyperplasia Cynthia J. Girman, Dr.PH, and Joanne Waldstreicher, MD

498

56

Benign Prostatic Hyperplasia: When to Intervene Steven G. Roberts, MD, and Michael L. Blute, MD

508

57

Preprocedural Evaluation/Preparation Alun W. Thomas, BSc, MBBS, FRCS, and Paul Abrams, MD, FRCS

515

Contents / xvii

58

Options for Treatment of Benign Prostatic Hyperplasia: Alpha-Blockers Perinchery Narayan, MD, Manoj Patel, MD, and Ashutosh Tewari, MD

531

59

5 Alpha-Reductase Inhibitors Jack Geller, MD

543

60

Transurethral Needle Ablation of the Prostate for Treatment of Benign Prostatic Hyperplasia Claude C. Schulman, MD, PhD, and Alexandre R. Zlotta, MD

552

61

Options for Treatment: Contact Edward J. Mueller, MD

562

62

Free Beam Laser Prostatectomy John N. Kabalin, MD, FACS

568

63

Transurethral Resection of the Prostate Mark J. Noble, MD, and Winston K. Mebust, MD

584

64

Transurethral Incision of the Prostate John G. Anema, MD, Allen F. Morey, MD, FACS, and John P. Foley, MD

593

65

Open Prostatectomy in the Management of Benign Prostatic Hyperplasia Fernando J. Kim, MD, Brian E. Nicholson, MD, and Robert C. Flanigan, MD

600

66

Phytotherapy in the Treatment of Benign Prostatic Hyperplasia Glenn S. Gerber, MD

607

67

Prostatitis: Pathophysiology George W. Drach, MD

615

68

Prostatitis: Diagnosis Culley C. Carson, MD

621

69

Prostatitis: Differential Diagnosis, Classification, and Conventional Treatment Strategies John N. Krieger, MD

627

70

Prostatitis: Factors Influencing Prognosis Richard A. Schoor, MD, and Anthony J. Schaeffer, MD

643

71

Prostatitis: Advanced Therapy Durwood E. Neal Jr, MD

650

Index

659

CHAPTER 1

EPIDEMIOLOGY OF PROSTATE CANCER: AN OVERVIEW PETER C. ALBERTSEN, MD, MS and four counties in the San Jose-Monterey region south of San Francisco, were added. Information concerning cancer deaths in the United States is derived from data provided by death certificates filed with state health departments and vital statistics offices. Each state collects mortality information that is processed and consolidated into a national database by the National Center for Health Statistics. The underlying cause of death is selected for tabulation following the procedures specified by the World Health Organization in the relevant Manual of the International Classification of Diseases, Injuries, and Causes of Death.

Adenocarcinoma of the prostate is the most common nonskin cancer among American men. The American Cancer Society estimates that 184,500 new cases of prostate cancer will be diagnosed in the United States in 1998 and that 39,200 men will die from the disease.1 The rate of new prostate cancer diagnoses has increased exponentially over the past three decades.2 During the 5 years preceding 1992, there has been an even more dramatic surge in prostate cancer incidence following the introduction of widespread testing for serum prostate-specific antigen (PSA).3 Since 1992, however, the annual incidence rate has declined by 11% and continues to decline.4 The mortality rate from prostate cancer has also changed during the past two decades. After increasing steadily from 1973 to 1990, the mortality rate from prostate cancer fell by 6.3% from 1991 to 1995.5 The rate for men under 75 years fell by 7.4% while the rate for men aged 75 years and older, a group accounting for twothirds of all prostate cancer deaths, fell by 3.8%. This is the first recorded fall in the mortality rate from this type of cancer since the 1930s when cancer statistics were first collected. Whether the decline in prostate cancer mortality can be attributed to early diagnosis and screening is the subject of much controversy and debate.

How Is Information Reported? Cancer incidence rates are often reported either as actual counts at a given point in time or are expressed as ageadjusted rates. Simply reporting the raw number of new cases annually provides some information concerning the magnitude of the disease incidence within a population. Unfortunately, this approach does not take into account the number of patients at risk for developing cancer. The age distribution of populations changes over time. Western countries, for example, generally have a greater number of elderly people compared to most developing nations. As more people live longer, the risk of developing prostate cancer increases. This will be especially true when the large “baby boom” generation enters its seventh and eighth decades. As a consequence, the absolute number of new cancer cases may increase but the relative incidence rate may increase, decrease, or remain constant. Epidemiologists often express incidence rates as an age-adjusted rate when they need to determine whether the number of new cases of prostate cancer is increasing faster or slower than the growing population at risk, or if they wish to make meaningful comparisons between different populations separated by geography or time. To correct for the age distribution of the population at risk, new cases must be weighted to reflect the pool of potential patients. Normally, the Bureau of Vital Statistics adjusts incidence rates to fit the United States population age distribution present during a census year. The standard used by the SEER program is the age distribution recorded in the 1970 census of the United States. The incidence and mortality data quoted earlier were adjusted

How Is Information Collected? Information concerning newly diagnosed cancer cases occurring in the United States is derived from data collected by the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program.5 The SEER program was created following passage of the National Cancer Act in 1971 and is mandated to collect, analyze, and disseminate information that is useful in preventing, diagnosing, and treating cancer. The geographic areas comprising the SEER program’s database include approximately 13.9% of the United States’ population. Nine population-based registries including five states (Connecticut, Hawaii, Iowa, New Mexico, and Utah) and four standard metropolitan statistical areas (Atlanta, Detroit, San Francisco-Oakland, and SeattlePuget Sound) comprise the core regions of the SEER program. In 1992, the SEER program was expanded to increase coverage of minority populations, especially Hispanics. Two new areas in California, Los Angeles County 1

2 / Advanced Therapy of Prostate Disease

to the 1970 United States standard population and are expressed as an age-adjusted rate per 100,000 men.

How Have the Incidence Rates of Prostate Cancer Changed during the Past Two Decades? During the two decades spanning 1973 to 1992, the ageadjusted prostate cancer incidence rate for all men increased dramatically (Figure 1–1).3 The rate increased linearly between 1973 and 1986 but accelerated between 1987 and 1992. During the 5 years preceding 1992, the age-adjusted incidence rate of prostate cancer increased 84% from 102.9 cases per 100,000 men to 189.4 cases per 100,000 men. The two largest increases were observed in 1990 and 1991. Since 1992, there has been a precipitous drop in the number of new cases so that by 1994, the most current year for which accurate data are available, the incidence rates appear to be returning to the rates present before the introduction of widespread testing for PSA4 (Figure 1–2). The shape of the incidence curves are similar for African Americans and Caucasians although the peak incidence for African Americans was 1 year later. The incidence of prostate cancer in African Americans continues at a rate almost double that among Caucasians.

How Do Incidence Rates Vary by Patient Age at Diagnosis? Despite widespread screening efforts targeted at men aged 50 to 65 years, the age-adjusted incidence rates still

FIGURE 1–1. Prostate cancer incidence by stage for all ages. Data are from four Surveillance, Epidemiology, and End Results areas. From Potosky AL, Miller BA, Albertsen PC, Kramer BS. The role of increasing detection in the rising incidence of prostate cancer. JAMA 1995;273:548–52.

suggest that prostate cancer is a disease of older men. For the two decades leading up to 1993, the age-adjusted incidence rates were highest for men aged 75 years and older, followed by that for men aged 65 to 74 years.5 Since 1993, the age-adjusted rate has decreased sharply among men aged 75 years and older, so that the highest age-adjusted rate of prostate cancer now occurs among men aged 65 to 74 years. Prostate cancer is still relatively uncommon among men under the age of 65, but the annual ageadjusted rate among this group has more than tripled between 1989 and 1992. The rate has decreased slightly since 1992. For much of the 1980s, the mean age of diagnosis was approximately 72 years for Caucasians and 70 years for African Americans.5 Since the introduction of PSA testing, the mean age at diagnosis has fallen. As of 1994, the mean age at diagnosis among Caucasians was 69 years and 67 years among African Americans. These statistics suggest that prostate cancer is being diagnosed in the late 1990s approximately 2.5 years earlier than it was a decade ago. Because of this abrupt increase in the lead time of diagnosis, patients can expect to live an additional 2.5 years after their diagnosis compared to reports from a decade ago. To attribute improvements in longevity to aggressive intervention with either surgery or radiation, researchers must allow for a 2.5-year lead time when making comparisons with historic series.

How Has the Stage of Incident Prostate Cancers Changed Over the Past Decade? Before 1986, the diagnosis of localized prostate cancer accounted for the majority of the increase in incident cases. Only modest increases were detected for regional and distant-stage cases. After 1986, the stage-specific incidence rates began to increase exponentially for all stages except distant-stage disease. From 1986 to 1991, the incidence of localized disease increased 75% while incidences of regional and unstaged disease rose 144% and 161%, respectively.3 The incidence of distant disease remained essentially unchanged. The age-adjusted incident rates for distant disease have fallen dramatically since 1991, and are now approximately half what they were at the beginning of the decade. Decreasing rates of distant disease most likely reflect widespread use of PSA testing. While decreasing rates of distant disease are a significant indicator that early detection may subsequently lead to decreased mortality, this fact alone is not sufficient to demonstrate the efficacy of aggressive prostate cancer screening and treatment. Currently available mortality estimates have not demonstrated a convincing decline in prostate cancer deaths. Given the long natural history of prostate cancer, increased treatment of localized disease will not yield large population-based improvements until early in the next century.

Epidemiology of Prostate Cancer: an Overview / 3

How Has the Grade of Incident Cases Changed Over the Past Decade? Since the introduction of widespread PSA testing, the number of new cases of moderately differentiated disease has increased dramatically. Between 1974 and 1984, the number of incident cases of well-, moderately, and poorly differentiated disease were roughly comparable. Between 1984 and 1989, the age-adjusted incidence of well- and poorly differentiated tumors continued to increase slowly while the age-adjusted incidence of moderately differentiated tumors grew more rapidly. After 1989, there was a dramatic increase in the number of moderately differentiated tumors, such that the number of these new cases was two to three times higher than the number of well- and poorly differentiated tumors. Since 1991, moderately differentiated tumors have represented over half of the newly diagnosed cases while well- and poorly differentiated tumors each accounted for approximately 20% of new cases. Coding rules utilized by the SEER program may explain some of these changes. According to SEER conventions, the most accurate pathology grade is utilized when recording the grade of newly diagnosed cancers. For patients undergoing radiation therapy or conservative management, the grade of their tumor is based on the needle biopsy or transurethral resection specimen that resulted in a diagnosis. For patients undergoing radical prostatectomy, the results of the surgical pathology report replace the results obtained on biopsy. As a result, some of

the well-differentiated tumors may be upgraded to moderately differentiated tumors. These changes, however, do not likely account for the majority of new cases of moderately differentiated disease.

How Are the American Cancer Society Projections of Cancer Incidence and Mortality Calculated? Every year the American Cancer Society (ACS) prepares estimates for all major cancers. They publish statistics concerning the number of newly-diagnosed cancer cases and the number of cancer deaths occurring within the United States.1 These widely quoted estimates are calculated from data available from the United States Bureau of the Census and the cancer incidence rates collected by the National Cancer Institute’s SEER program. Estimates of new cancer cases are calculated using a three-step procedure. First, the annual age-specific cancer incidence rates for a 15-year period are multiplied by the age-appropriate United States Census Bureau population projections for the same years to estimate the number of cancer cases diagnosed annually for a 15-year period. These annual cancer case estimates are then fitted to an autoregressive quadratic model. This model is used to predict the following year’s rate. Although the American Cancer Society projections are based on SEER data, the projections are extrapolated 3 to 4 years into the future. For example, the ACS estimates of new prostate cancer cases published for 1997 were based

FIGURE 1–2. Prostate cancer incidence rates by age group at diagnosis and race. Rates are age-adjusted to the 1990 United States standard population. From Merrill RM, Potosky AL, Feuer EJ. Changing trends in U.S. prostate cancer incidence rates. J Natl Cancer Inst 1996;88:1683–5.


on SEER public-use data available only through 1993. Because of the rapid rise in the number of incidence cases reported during the early 1990s, the ACS projections initially underestimated and then over-estimated the estimates derived from SEER data (Figure 1–3).6 As a consequence, the ACS published an adjustment to the 1997 estimates in the July/August issue of CA: A Cancer Journal for Clinicians that reduced the projected number of cases for 1997 from 334,500 to 209,900.4 These new estimates are based on an assumption that incidence rates will decline during the period 1993 to 1995 and will then resume the annual increase in incidence rates documented before the widespread use of prostate-specific antigen screening. Whether these assumptions are correct remains to be determined. The use of ACS projections has led to incorrect perceptions and inflated concern about prostate cancer trends in the PSA era. In hindsight, the recent changes in prostate cancer incidence rates do not appear to reflect an epidemic of new prostate cancers but rather a “cull” phenomenon that can result when a new, more sensitive test becomes available for disease detection. Such a cull phenomenon occurs when a large number of previously unsuspected cases are detected, resulting in fewer detectable cases in the remaining population. This cull effect should show the greatest declines in incidence among the men most extensively tested. This theory is supported by the observation that since 1992 incidence 350

Number of Cases (x 1,000)

300 American Cancer Society adjusts projection in July 1997 to n = 209,900

250

200

150 SEER Estimate 100 American Cancer Society Projection

50

0

81

83

85

87 89 91 Year of Diagnosis

93

95

97

FIGURE 1–3. United States men with prostate cancer: SEER estimates and American Cancer Society projections by year of diagnosis. SEER estimates obtained by multiplying the age-specific incidence for the SEER registries by the United States population. From Stephenson RA. Population-based prostate cancer trends in the PSA era: data from the Surveillance, Epidemiology, and End Results (SEER) program. Monogr Urol 1998;19:3–19.

rates for older men have fallen more rapidly than for younger men. Furthermore, Stephenson has reported that PSA testing appears to be related to age. The fraction of men undergoing PSA testing increases as a function of their age, from 17% of men in their fifth decade to 75% of men in their ninth decade.6

How Have Prostate Cancer Mortality Rates Changed during the Past Decade? Mortality from prostate cancer has gradually increased among both Caucasians and African Americans during the past two decades. In absolute terms, 33,565 men died of prostate cancer in 1991 and 34,901 men in 1994.5 When viewed in relative terms, however, the data suggest a different trend. Among Caucasian men, the ageadjusted mortality rate rose from 20.3 deaths per 100,000 men in 1973 to 24.7 deaths per 100,000 men in 1991. Rates among African Americans were more than twice as high. Since then the rates have declined. The National Cancer Institute recently reported data showing that the prostate cancer death rate in the United States fell between 1991 and 1995, from 26.5 to 17.3 deaths per 100,000 men in the overall population.7 The percentage decline was greatest for young Caucasion males and smallest for older men and African American men (Figure 1–4). The differences between absolute and relative age-adjusted rates are explained by the increasing number of men dying from prostate cancer but the even greater increase in the number of older men still alive in the United States population. The increase in the size of the population at risk (the denominator) has been proportionally more rapid than the increase in the number of men dying from prostate cancer (the numerator). This has resulted in a recent small age-adjusted decline during the past year.

What Is the Significance of the Recent Decline in Prostate Cancer Mortality Rates? Epidemiologists are uncertain how to explain the recent decline in prostate cancer mortality rates. It may be an All ages

50 ng per mL, 66% had microscopic lymph node invasion and 90% had seminal vesicle invasion. However, the majority of clinicians do not find the value of PSA alone sufficiently reliable for predicting the final pathologic stage for the individual patient. For example, Oesterling et al.16 found that the diagnostic accuracy of an elevated PSA value was 55% for capsular perforation and 50% for seminal vesicle invasion and lymph node involvement. Clinical stage determination by DRE is also notoriously inaccurate as a single staging marker. Zinke17 found in a large study that 40% of clinical stage C prostate cancer patients were understaged and had pathologic stage D1 disease, and 20% were overstaged with pathologic stage B2 disease. Kramer et al.18 found tumor grade to correlate with pathologic stage—93% of patients with biopsy Gleason score of 8 or higher had metastatic nodal disease and those patients with a score of 4 or less had no nodal disease. Despite this distinction between local and advanced disease at the lower and upper ends of Gleason scoring, the majority of patients are found to have a Gleason score between 5 and 7, making this a suboptimal marker when used alone. Kleer et al.19 at the Mayo Clinic evaluated the use of clinical stage and tumor grade in augmenting the predictive capability of pretreatment PSA. They found that the combination of clinical stage and tumor grade when used with pretreatment PSA significantly increased the predictive power of these pretreatment prognostic variables. Unfortunately, the Mayo Clinic tumor grading system used in this study is not a routinely employed pathologic grading system and therefore makes this model less useful for the community physician. Another example of the utility of combined predictive variables is a study by Wolf et al.20 that added TRUS findings to the algorithm of a grade-stratified PSA scale. With evidence from others describing the correlation of PSA to tumor grade,21 the authors stratified PSA values by grade to produce more accurate staging. The addition of TRUS to the staging algorithm, necessary only in patients with negative predictions using the grade-stratified PSA scale (46% of patients), increased sensitivity to 86% and the negative predictive value to 79%, while positive predictive value remained unchanged at 77%. Wolf found that this algorithm was especially useful in a subset of patients with a PSA < 4 ng per mL or > 15.9 ng per mL. The algorithm predicted an 85 and 88% likelihood of organconfined and nonorgan-confined disease, respectively. Wolf ’s evaluation of PSA-density grade-stratified method


did not demonstrate better predictive capability over the grade-stratified PSA scale. Unfortunately, TRUS is highly operator-dependent, and extensive experience with this technique is required to reproduce results reported by academic centers. Badalament et al.22 combined pretreatment PSA and results obtained from sextant core biopsies to develop an algorithm for predicting nonorgan-confined prostate cancer. Their technique had a sensitivity of 85.7%, specificity of 71.3%, positive predictive value of 72.9%, negative predictive value of 84.7%, and an area under the receiver operating characteristic curve of 85.9%. Data obtained from the sextant core biopsies included multiple variables: quantitative nuclear grade, total percent tumor involvement, number of positive sextant cores, biopsy Gleason score, involvement of more than 5% of a base and/or apex biopsy, and DNA ploidy. Both quantitative nuclear grade and DNA ploidy were determined using an image analysis system and computer software that is commercially available (Dr. Robert W. Veltri, UroCor Inc., Oklahoma City, OK). This computer assisted image analysis technique is able to calculate 38 quantitative nuclear grading descriptors including size, shape, DNA content, and Markovian chromatin texture features.23 The authors provide a cautionary note regarding the use of the quantitative nuclear descriptors to predict tumor stage or aggressiveness. Specifically, the tissue processing methods, cell analysis and sampling techniques, patient sample training set size and composition, and stringency parameters for statistical analysis or neural network configurations will affect any feature-based algorithm. Therefore, it is imperative to train and test such feature-based algorithms on different populations using the same criteria for sample selection and processing. There should be a prospective multicenter trial of this technology performed. This novel approach is commercially available and is called Uro-score.24 The nomograms developed by Partin et al.25 in 1993 represent a more practical approach incorporating commonly used clinically obtained variables. These nomograms have recently been added to the 1996 prostate cancer practice guidelines of the National Comprehensive Cancer Network.26 They use a combination of pretreatment PSA, clinical stage, and biopsy Gleason score to predict the pathologic stage for men with clinically localized prostate cancer undergoing radical prostatectomy. Specifically, probabilities of organ-confined disease, established capsular penetration, seminal vesicle involvement, and lymph node involvement are displayed in an easy-to-use tabular format. This original set of nomograms was evaluated at a separate institution on a different patient population by Kattan et al.27 Their results suggested that the nomograms did discriminate quite well between organconfined and nonorgan-confined disease but had difficulty predicting high probabilities of seminal vesicle invasion and lymph node metastasis, pathologic features

known to have the most profound impact on prognosis. For example, when the nomograms predicted a 75% chance of positive lymph nodes, less than 20% of the patients in the Kattan data set actually had pathologically confirmed lymphatic involvement. The performance of the nomograms in the low probability areas, especially for seminal vesicle invasion, was quite good. Kattan and colleagues concluded that despite the accuracy of the nomograms in the Johns Hopkins University data set they may not be applicable to general clinical practice until further validations and modifications are performed. Deficiencies in the earlier published nomograms led to a larger multi-institutional study of a combined cohort of 4133 men by Partin et al.28 published in 1997. In the validation analyses of this much larger multi-institutional study, the nomograms correctly predicted the probability of a pathologic stage 72.4% of the time to within 10% (organ-confined disease, 67.3%; isolated capsular penetration, 59.6%; seminal vesicle involvement, 79.6%; and pelvic lymph node involvement, 82.9%). These new nomograms also included the 95% confidence intervals for all predicted probabilities, items not included in the earlier 1993 study. Using the same preoperative variables of pretreatment PSA, clinical stage, and Gleason score, Bishoff et al.29 analyzed a cohort of 481 men to predict the probability of lymph node involvement. This study was conducted to identify patients at low risk for nodal involvement so that a perineal prostatectomy could be safely performed without pelvic lymph node sampling prior to the procedure. Depending on the estimated probability of positive lymph nodes ranging from 2 to 10%, pelvic lymphadenectomy could be omitted in 20 to 63% of patients. Similarly, Roach et al.,30 Harris et al.,31 Narayan et 32 al., and Bluestein et al.33 developed algorithms or modeling equations to predict the probability of positive lymph nodes. The models by Harris et al., Narayan et al., and Roach et al. are based strictly on PSA and Gleason score. These studies suggested little additional benefit of incorporating the clinical stage because of the difficulty in reproducibility.30–32 Conversely, Bluestein et al. found the clinical stage to be reproducible and included it in their model.33 Roach et al.30 developed an equation based on data from Partin et al. (1993 nomograms):25 N+ (risk of positive nodes) = 2/3 PSA + (Gleason score – 6) × 10

If N+ is less than 15%, the patient is identified as at low risk for lymph node metastasis. If N+ is 15% or greater, then the patient is considered at high risk and a staging pelvic lymphadenectomy is recommended. The model by Harris et al.31 is based on experience with 484 patients presenting for radical prostatectomy. Narayan et al.32 used records from eight medical centers, including 932 patients with presumed localized prostate cancer who

Assessment of Risk of Prostate Cancer: Algorithms for Diagnosis, Staging, and Prognosis / 39

had undergone lymphadenectomy. Limits of PSA to ≤ 10 ng per mL and a biopsy Gleason score ≤ 6 were used. The false negative rate was 1% and the 95% confidence interval raised this to 2%. The authors considered a falsenegative rate under 3% to be an acceptable risk. The model by Bluestein et al.,33 which included the clinical stage, was developed from a cohort of 1632 patients who had undergone lymph node dissections. The authors also accepted a false-negative rate of < 3%. Spevack et al.34 reviewed records of 214 patients with a 14% positive lymph node rate and compared the four models by Roach et al.,30 Harris et al.,31 Narayan et al.,32 and Bluestein et al.33 This study revealed the following results respectively: 78%, 50%, 76%, and 42% of the patients were identified as low risk and could be spared a pelvic lymph node dissection. The false-negative rates were 13 (7.8%), 5 (4.6%), 14 (8.6%), and 1 (1.1%). Sensitivities were 56.7, 83.3, 53.3, and 96.7%. This study identified the model by Bluestein et al.33 to be the most sensitive. While this model identified a smaller number of patients at low risk for nodal disease (42%), it had the highest negative predictive value (98.9%) and the lowest false negative rate.

Algorithms for Prognosis The prediction of preoperative pathologic stage is important in counseling a patient before proceeding with radical prostatectomy. Despite these predictions, many patients, even those without organ-confined disease, are long-term disease-free survivors and surgical therapy is appropriate. Once surgical intervention is completed, a new set of predictive algorithms and statistical equations predicting recurrence and progression are now available to adequately inform the patient of future expectations. Approximately 65% of prostate cancers are clinically localized at the time of diagnosis and despite improved preoperative pathologic stage prediction, between 40 to 60% of men are found to have extracapsular disease after radical prostatectomy.35–37 Of these patients, the reported 5-year progression-free survival rate is 93% for PSA between 4.1 to 9.9 ng per mL and 71% for patients with a PSA greater than 10.0 ng per mL.38 Overall, approximately 25 to 40% of patients will have evidence of biochemical recurrence 10 years after radical prostatectomy for clinically localized prostate cancer.39–41 Lerner et al.42 evaluated 904 patients with multivariate statistical analysis, using the variables of pretreatment PSA, clinical stage, pathologic grade (Gleason score), pathologic stage, and DNA ploidy. They found that PSA, pathologic grade, and DNA ploidy were independent predictors of disease progression. The authors then developed two prognostic scoring systems, one with DNA ploidy and one without, to identify five distinct patient risk groups. Those patients with the lowest score had a 92% progression-free survival rate at 5 years, compared to only 39% for those patients with the highest scores. The systems were defined as follows:

System 1—add 0.8 if PSA is greater than 10 ng per mL, and add 0.8, 1.2, or 1.9 if Gleason score is 6, 7, 8 or more, respectively. Progression-free survival rate for those with a score of “0” was 90%, whereas only 41% with a score greater than 2.0 were free of cancer at 5 years. System 2 included DNA ploidy—add 0.7 if PSA is greater than 10 ng per mL, add 0.7, 1.1, or 1.7 if Gleason score is 6, 7, 8 or more, respectively, and add 0.4 or 0.8 if DNA ploidy is tetraploid or aneuploid, respectively. For the patients with the lowest score of “0,” 92% were free of cancer at 5 years, compared to only 39% with prognostic scoring system scores of 2.0 or more. Similar discrete risk groups were identified with both systems. Both systems identified intermediate groups between 0 and 2.0 (0.1 to 0.9, and 1.0 to 1.9), with different statistically significant 5-year progression-free survival rates. Veltri et al.43 performed a similar study on 70 patients that combined postoperative Gleason score and a novel variable termed the Quantitative Nuclear Grade (QNG). Multivariate statistical analysis of age, clinical stage, capsular penetration, surgical margins, postoperative Gleason score, and the QNG revealed that with a stepwise backward elimination of nonsignificant variables at a high stringency (p = .05), only Gleason score and QNG remained in the final predictive model. Quantitative Nuclear Grade can be determined by using a commercially available product. The computer-generated QNG is an evaluation of 38 nuclear morphometric descriptors that develops a QNG based on those descriptors that are statistically significant in the proposed data set. In this data set, 11 nuclear morphometric descriptors were found to be independently significant at a cutoff point of p < .05. The combination of Gleason score and QNG separated these patients into three distinct risk groups with respect to progression-free survival: low, moderate, and high. The model showed a sensitivity of 89%, specificity of 84%, positive predictive value of 78%, negative predictive value of 92%, and a receiver operator characteristic area under the curve of 92%. Partin et al. 44 developed a simple biostatistical model equation that categorized 216 clinical stage B2 postradical prostatectomy patients into three risk groups for likelihood of serologic failure. Many preoperative and pathologic variables were analyzed but after multivariate regression analysis only three variables were included in the final model to adequately select for high-risk patients after surgery. These consisted of a sigmoidal transformation of PSA (PSAST), prostatectomy Gleason score, and specimen confinement (margin status), which were incorporated into an equation that calculated the log relative risk of recurrence (Rw) as follows: Rw = (0.061 × PSAST) + (0.54 × postop Gleason) + (1.87 × specimen confined)


The sigmoidal transformation of PSA was defined as follows: PSAST = 10/(1 + exp6.8704–0.9815 × PSA)

This transformation of PSA was used to decrease the weighting toward low and high PSA levels (< 4.0 ng per mL and > 10.0 ng per mL) and to increase the predictive value of the intermediate levels of PSA (4.0 to 10.0 ng per mL). The constants used in this transformation were chosen to compress the upper and lower ends of PSA. Levels less than 4.0 ng per mL (in which early PSA recurrence is rare) would yield PSAST values between 0 and 0.5, and PSA levels > 10.0 ng per mL (in which early PSA recurrence is most common) would yield PSAST values between 9.5 and 10.0. Depending upon the calculated value for Rw, these patients could be stratified into three risk groups. Recurrence risk categories were determined to be low risk if Rw was less than 4.0, intermediate risk if from 4.0 to < 5.75, and high risk if Rw was more than 5.75. This model was validated using a separate cohort of 214 men treated at another institution by multiple urologists. Traditional variables were employed that are commonly and accurately determined at most institutions, making this form of risk assessment a practical clinical tool that can be used in decisions concerning adjuvant therapy. This model allows those patients at high risk for recurrence to be identified shortly after surgery, while their tumor burden is minimal. These may be ideal patients to benefit from adjuvant therapy or investigational therapies. Despite the obvious clinical utility of this type of risk assessment modeling, the Johns Hopkins model did not evaluate race as a potential variable and included only patients with clinically-palpable stage B2 disease. Ethnicity has been shown to be a significant predictor of recurrence after radical prostatectomy.45 Unfortunately, Partin’s study included only 8.5% African American patients. Subsequently, the current authors and colleagues46 evaluated 378 patients who had undergone radical prostatectomy at their institution, and developed a modeling equation similar to Partin’s. All stages of clinically organ-confined prostate cancer (T1a, b, c and T2a, b, c) were incorporated and a race variable was added (African American versus non-African American) as the patient population was approximately 25% African American. In the analysis, age, race, prostatic acid phosphatase (PAP), and nuclear grade as well as the established prognostic variables of pretreatment PSA, postoperative Gleason score, and other various pathologically determined stage variables were evaluated. This study also included a validation cohort of 91 patients treated by multiple surgeons at a separate medical center. By expanding the patient base to include all patients that are likely candidates for curative radical surgery and by adding the race variable, a more representative model

was formulated to calculate the relative risk of recurrence after surgery. The final model calculated the relative risk of recurrence (Rr) as follows: Rr = exp[(0.51 × race) + (0.12 × PSAST) + (0.25 × postop Gleason score) + (0.89 × organ confinement)]

Race was defined as “1” if the patient was African American or “0” if Caucasian or other. The sigmoidal transformation of PSA (PSAST) is defined as: PSAST = 10/(1 + exp6.8704–0.9815 × PSA)

Postoperative Gleason score (2 to 10) was defined as a continuous integer value. The organ-confined term (no capsular penetration) was defined as “0” whereas the nonorganconfined term (capsular extension and/or positive margins) was defined as “1.” The Rr values allowed stratification of patients into low-, intermediate-, and high-risk groups. The men at lowest risk of serologic recurrence after a radical prostatectomy were those with an Rr less than 10.0 (86% 5-year Kaplan-Meier disease-free survival rate [KM-DFSR]), intermediate risk when Rr was between 10.0 and 30.0 (59.0% 5-year KM-DFSR), and at highest risk if the Rr was greater than 30.0 (30.3% 5-year KM-DFSR). These cut-off values were defined by natural breaks in the numerical listing of Rr for each patient. This equation is extremely useful in predicting postoperative risk of recurrence but requires information obtained only after the prostate has been removed and evaluated pathologically. The development of these relative risk equations by Partin et al.44 and the current authors and colleagues46 spurred interest in developing a similar equation that could predict both the probability of extracapsular extension and the relative risk of recurrence after surgery using only pretreatment variables. By using this type of equation, the clinician can more thoroughly counsel patients about the expected outcome after radical prostatectomy even before the surgery is completed. The current authors and colleagues47 collected data on 260 radical prostatectomy patients for whom data for the following variables were available: age, race, biopsy Gleason score, biopsy nuclear grade, biopsy glandular differentiation, and clinical stage. These pretreatment variables were analyzed to predict recurrence using a Cox regression model with backward elimination of nonstatistically significant variables (p > .20). The traditional variables that significantly correlated with recurrence were incorporated into a model equation that calculates the relative risk of recurrence (Rr) as follows: Rr = exp[(0.47 × Race) + (0.14 × PSAST) + (0.13 × worst biopsy Gleason score) + (1.03 × stage T1c) + (1.55 × stage T2b,c)]

Assessment of Risk of Prostate Cancer: Algorithms for Diagnosis, Staging, and Prognosis / 41

FIGURE 7–3. Preoperative nomogram for prostate cancer recurrence. From Kattan MW, Eastham JA, Stapleton AMF, et al. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 1998;90:766–71.

Race was defined as “1” if the patient was African American or “0” if Caucasian, Hispanic, or Asian. Sigmoidal transformation of PSA (PSAST) was calculated using the following equation: PSAST = 10/(1 + exp6.8704–0.9815 × PSA)

Biopsy Gleason score (2 to 10) was defined as a continuous integer value. Stage T1c and T2b,c were defined as “1” if that was the patient’s clinical stage and “0” if that was not the patient’s stage. If “0” in this equation, the variable is effectively dropped. The Rr values allowed stratification of patients into low-, intermediate-, and high-risk groups. The men at lowest risk of serologic recurrence after a radical prostatectomy were those with an Rr less than 8.0 (94.7% 3-year KM-DFSR), intermediate risk when Rr was between 8.0 and 40.0 (65.4% 3-year KM-DFSR), and at highest risk if the Rr was greater than 40.0 (0.0% 3-year KM-DFSR). These cutoff values were defined by natural breaks in the numerical listing of Rr for each patient. The same variables (race, clinical stage, biopsy Gleason score, and sigmoidal transformation of PSA [PSAST]) that were used in the relative risk of recurrence equation were then analyzed with respect to the capsular status, using logistic regression. The fitted regression equation

was used to estimate the probability of extracapsular extension (PECE) as follows: PECE = 1/[1+ exp (–Z)] where Z= –2.47 + 0.15 (PSAST) + 0.31 (worst biopsy × Gleason score) + 0.18 (Race) + 0.16 (stage T1c) + 0.38 (stage T2b,c)

The variables in this equation were defined in the same manner as the preoperative relative risk equation presented earlier. Three probability groups were formed (low PECE < 0.43, medium PECE = 0.43 to 0.77, high PECE > 0.77). These cut-off values were defined by natural breaks in the numerical listing of the PECE for each patient. Specificity for the high PECE group was 97.2% and the sensitivity for the low PECE group was 87.0%. This model equation was validated using a validation cohort from a separate institution. Within this validation cohort, the probability group of low PECE (p < .43), 4 of 11 patients (36.5%) actually had positive capsular penetration. Conversely, the high PECE (p > .77) group had 20 of 25 patients (80.0%) with positive capsular penetration. The current authors’ modeling equations47 for estimating the probability of extracapsular disease and the relative risk of recurrence after radical prostatectomy for clinically


confined prostate cancer are based on easily obtained and widely accepted traditional preoperative prognostic variables. The equations, despite their complexity, can be easily automated on a personal computer for simultaneous calculation of both the probability of extracapsular disease and the estimated outcome of surgical intervention. These attributes may make these model equations more practical for use by the community-based urologist. Kattan and colleagues have also recently developed an algorithm in the form of a nomogram employing preoperative variables to predict disease recurrence after radical prostatectomy48 (Figure 7–3). This nomogram uses pretreatment PSA, clinical stage, and biopsy Gleason score on a scale and assigns points that are used to determine the 60-month recurrence-free probability. This nomogram was developed based on 983 radical prostatectomy patients treated at Baylor University. The developers are careful to point out that it is only applicable to the patient who has selected radical prostatectomy. Similar algorithms to predict recurrence after radiation and/or brachytherapy will no doubt be developed over the next few years.

5.

6. 7.

8.

9.

10.

11.

Summary The use of algorithms to predict the likelihood, stage, and outcome of prostate cancer is still in its infancy. Over the last few years, however, investigators have used traditional statistical methods and neural network computer programs to develop nomograms, probability tables, and computer-based equations to improve patient care. The simplest algorithms such as age-specific reference ranges for PSA and the Partin nomograms for predicting pathologic stage are already in widespread clinical use. As researchers and clinicians become more sophisticated in this area, more complex equations and algorithms will be available on office computers, local area networks (LAN), and the Internet, and will be widely used. As with many other aspects of prostate cancer, prospective, multicenter trials are needed to determine the clinical utility of diagnostic, staging, and prognostic algorithms.

References 1. Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6630 men. J Urol 1994;151:1283–90. 2. Benson MC, Whang IS, Pantuck A, et al. Prostate-specific antigen density: a means of distinguishing benign prostatic hypertrophy and prostate cancer. J Urol 1992; 147:815–6. 3. Oesterling JE, Jacobson SJ, Chute CG, et al. Serum prostate specific antigen in a community based population of healthy men: establishment of age-specific reference ranges. JAMA 1993;270:860–4. 4. Morgan TO, Jacobson SJ, McCarthy WF, et al. Age-specific

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reference ranges for prostate-specific antigen in black men. N Engl J Med 1996;335:304–10. Optenberg SA, Clark JY, Brawer MK, et al. Development of a decision-making tool to predict risk of prostate cancer: the Cancer of the Prostate Risk Index (CAPRI) test. Urology 1997;50:665–72. Douglas TH, Moul JW. Applications of neural networks in urologic oncology. Semin Urol Oncol 1998;16(1):35–9. Snow PB, Smith DS, Catalona WJ. Artificial neural networks in the diagnosis and prognosis of prostate cancer: a pilot study. J Urol 1994;152:1923. Snow P, Crawford ED, DeAntoni EP, et al. Prostate cancer diagnosis from artificial neural networks using the Prostate Cancer Awareness Week (PCAW) database [abstract]. J Urol 1997;157:365. Stamey TA, Barnhill SD, Zhang Z, et al. Effectiveness of ProstAsure in detecting prostate cancer and benign prostatic hyperplasia in men age 50 and older [abstract]. J Urol 1996;155 Suppl 5:436A. Stamey TA, Barnhill SD, Zhang A, et al. A neural network (ProstAsure) with high sensitivity and specificity for diagnosing prostate cancer (Pca) in men with a PSA < 4.0 ng per mL [abstract]. J Urol 1997;157:364. Loch T, Leuschner I, Brüske T, et al. Neural network analysis of subvisual transrectal ultrasound data: improved prostate cancer detection [abstract]. J Urol 1997;157 Suppl 4:364. Moul JW, Snow PB, Fernandez EB, et al. Neural network analysis of quantitative histological factors to predict pathological stage in clinical stage I nonseminomatous testicular cancer. J Urol 1995;153:1574. Niederberger CS. Commentary on the use of neural networks in clinical urology. J Urol 1995;153:1362. Stamey TA, Kabalin JN. Prostate-specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. I. Untreated patients. J Urol 1989;141:1070–5. Stamey TA, Kabalin JN. Prostate-specific antigen in the diagnosis and treatment of adenocarcinoma of the prostate. II. Radical prostatectomy treated patients. J Urol 1989;141:1076–83. Oesterling JE, Chan DW, Epstein JI, et al. Prostate-specific antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostatectomy. J Urol 1988;139:766–72. Zinke H. Combined surgery and immediate adjuvant hormonal treatment for stage D1 adenocarcinoma of the prostate: Mayo Clinic experience. Semin Urol 1990;8: 175–83. Kramer SA, Sphar J, Brendler CB, et al. Experience with Gleason’s histopathology grading in prostatic cancer. J Urol 1980;124:223–5. Kleer E, Larson-Keller JJ, Zinke H, Oesterling JE. Ability of preoperative serum prostate-specific antigen value to predict pathological stage and DNA ploidy. Influence of clinical stage and tumor grade. Urology 1993;41: 207–16. Wolf JS, Shinohara K, Carroll PR, Narayan P. Combined role of transrectal ultrasonography, Gleason score, and prostate-specific antigen in predicting organ-confined prostate cancer. Urology 1993;42(2):131–7.

Assessment of Risk of Prostate Cancer: Algorithms for Diagnosis, Staging, and Prognosis / 43 21. Partin AW, Carter HB, Chan DW, et al. Prostate-specific antigen in the staging of localized prostate cancer: influence of tumor differentiation, tumor volume, and benign hyperplasia. J Urol 1990;143:747–52. 22. 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;156:1375–80. 23. Veltri RW, Partin AW, Epstein JI, et al. Quantitative nuclear morphometry, Markovian texture descriptors, and DNA content captured on a CAS-200 image analysis system, combined with PCNA and HER-2/neu immunohistochemistry for prediction of prostate cancer progression. J Cell Biochem 1994;Suppl 19:249. 24. Veltri RW. Algorithms vie for diagnostic role in prostate cancer. J Natl Cancer Inst 1997;89:13–5. 25. Partin AW, Yoo J, Carter HB, et al. The use of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 1993;150:110–4. 26. Baker LH, Hanks G, Gershenson D, et al. National Comprehensive Cancer Network prostate cancer guidelines. Oncology 1996;Suppl 11:265–88. 27. Kattan MW, Stapelton AM, Wheeler TM, Scardino PT. Evaluation of a nomogram used to predict the pathologic stage of clinically localized prostate cancer. Cancer 1997;79:528–37. 28. Partin AW, Katten MW, Eric NP, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage on localized prostate cancer. JAMA 1997;277:1445–51. 29. Bishoff JT, Reyes A, Thompson IM, et al. Pelvic lymphadenectomy can be omitted in selected patients with carcinoma of the prostate: development of a system of patient selection. Urology 1995;45:270–4. 30. Roach M, Marquez C, Hae-Sook Y, et al. Predicting the risk of lymph node involvement using pretreatment prostate-specific antigen and Gleason score in men with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1993;28:33–7. 31. Harris MJ, Bishoff JT, Reyes A, Thompson IM. Preoperative PSA and prostate biopsy Gleason’s grade predictive of benign pelvic lymph nodes in men with prostate cancer [abstract 340A]. J Urol 1994;151:451. 32. Narayan P, Fournier G, Gajendran V, et al. Utility of preoperative serum prostate-specific antigen concentration and biopsy Gleason score in predicting risk of pelvic lymph node metastasis in prostate cancer. Urology 1994;44:519–24. 33. Bluestein DL, Bostwick DG, Bergstralh EJ, Oesterling JE. Eliminating the need for bilateral pelvic lymphadenectomy in selected patients with prostate cancer. J Urol 1994;151:1315–20. 34. Spevack L, Killion LT, West JC, et al. Predicting the patient at low risk for lymph node metastasis with localized prostate cancer: an analysis of four statistical models. Int J Radiat Oncol Biol Phys 1996;34:543–7.

35. D’Amico AV, Whittington R, Malkowicz SB, et al. A multivariate analysis of clinical and pathological factors that predict for prostate-specific antigen failure after radical prostatectomy for prostate cancer. J Urol 1995;154: 131–8. 36. Partin AW, Oesterling JE. The clinical usefulness of prostate-specific antigen: update 1994. J Urol 1993;152: 1358–68. 37. Lu-Yao GL, Potosky AL, Albertsen PC, et al. Follow-up prostate cancer treatments after radical prostatectomy: a population-based study. J Natl Cancer Inst 1996;88: 166–72. 38. Catalona WJ, Smith DS. 5-year tumor recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994;152:1837–42. 39. Frazier A, Robertson JE, Humphrey PA, Paulson DF. Is prostate-specific antigen of clinical importance in evaluating outcome after radical prostatectomy? J Urol 1993;149:516–8. 40. Stein A, deKernion JB, Dorey F. Prostate-specific antigen related to clinical status 1 to 14 years after radical prostatectomy. Br J Urol 1991;67:626–31. 41. Epstein JI, Carmichael MJ, Pizov G, Walsh PC. Influence of capsular penetration on progression following radical prostatectomy: a study of 196 cases with long-term follow up. J Urol 1993;150:135–41. 42. Lerner SE, Blute ML, Bergstralh EJ, et al. Analysis of risk factors for progression in patients with pathologically confined prostate cancers after radical retropubic prostatectomy. J Urol 1996;156:137–43. 43. Veltri RW, Miller MC, Partin AW, et al. Ability to predict biochemical progression using Gleason score and a computer-generated quantitative nuclear grade derived from cancer cell nuclei. Urology 1996;48:685–91. 44. Partin AW, Piantadosi S, Sanda MG, et al. Selection of men at high risk for disease recurrence for experimental adjuvant therapy following radical prostatectomy. Urology 1995;45:831–8. 45. Moul JW, Douglas TH, McCarthy WF, McLeod DG. Black race is an adverse prognostic factor for prostate cancer recurrence following radical prostatectomy in an equalaccess health care system. J Urol 1996;155:1667–73. 46. Bauer JJ, Conelly RA, Sesterhenn IA, et al. Biostatistical modeling using traditional preoperative and pathological prognostic variables in the selection of men at high risk for prostate cancer recurrence after radical prostatectomy for prostate cancer. J Urol 1998;159: 929–33. 47. Bauer JJ, Conelly RA, Sesterhenn IA, et al. Statistical modeling using preoperative prognostic variables in predicting extracapsular extension and progression after radical prostatectomy for prostate cancer. Mil Med 1998;163:615–9. 48. Kattan MW, Eastham JA, Stapleton AMF, et al. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 1998;90:766–71.

CHAPTER 8

MOLECULAR FACTORS IN THE ASSESSMENT OF PROSTATE CANCER RISK OLIVER SARTOR, MD Adenocarcinoma of the prostate is by far the most common visceral malignancy in men. In the past, prediction of adenocarcinoma of the prostate was linked to wellestablished clinical risk factors such as age, race, and family history. Over the past several years, a series of studies have begun to address the molecular markers that might add additional insights into the understanding of prostate cancer risk. In the future, there is hope that clinicians can use these (as yet undiscovered) molecular measurements to more accurately predict prostate cancer risk in individual men. In this chapter, recent progress toward that goal will be reviewed. Any molecular risk factors for prostate cancer will be evaluated in concert with well-established clinical risk factors; thus, a brief discussion of clinical risk factors is warranted as part of the background discussion for this chapter (Table 8–1). Age is the most dramatic and least understood of the conventional factors implicated in prostate cancer risk. For reasons that are unknown, the risk of prostate cancer rises more than 1000-fold during the natural aging process. Prostate cancer is rare prior to the age of 40 years and common in 80-year-old men, regardless of their ethnic or geographic origin. Race is another poorly understood but well-described clinical risk factor. African Americans have both an increased incidence and mortality from prostate cancer as compared to other ethnic groups. Conversely, Asian Americans are at lower risk as compared to other ethnic groups, both in the United States and in Asia. Family history is also a well-described risk factor. Men with a first-degree relative with prostate cancer are at increased risk relative

to men without such a history, particularly if the firstdegree relative was diagnosed at less than 65 years of age. Several areas of molecular investigation are preliminarily linked to prostate cancer risk and warrant further discussion (see Table 8–1). First, a series of polymorphisms have been described in the molecules involved both in the signal transduction and metabolism of androgenic hormones (Table 8–2). Second, a collection of recent experiments have clearly implicated insulin-like growth factor-I (IGF-I) in prostate cancer risk. Third, the well-accepted tumor marker prostate-specific antigen (PSA) has many uses, one of which is the ability to predict future prostate cancer risk. Though the molecular genetics of hereditary prostate cancers are an increasingly important topic, this subject will not be emphasized secondary to coverage in other chapters. Prior to analyzing studies of risk factors for prostate cancer, it is prudent to discuss those factors that influence the probability of finding cancer and that are not risk factors in the usual sense of the term. First and foremost, it is essential to understand that the probability of finding cancer is dependent on the diligence of the search as well as the population under study. Any series in a comparable population which evaluates sextant biopsy results will find more cancer than a series which examines only single biopsy specimens. It is also critically important to understand that the probability of detecting prostate cancer is dependent on the population examined. Series performed in the pre-PSA era cannot readily be compared to studies in the post-PSA era, and cohorts of patients with advanced disease cannot readily be compared to cohorts with localized cancers. Similarly, comparisons of studies examining a high proportion of African American men cannot readily be compared to studies that virtually exclude this population. Concurrent control populations are preferable to historic controls. Thus, when reviewing studies of prostate cancer risk, one should evaluate both the methodology of cancer detection and the particular population examined prior to making definitive conclusions.

TABLE 8–1. Established Clinical and Putative Molecular Risk Factors for Prostate Cancer Established clinical factors Age Race Family history Putative molecular factors Androgen receptor polymorphisms Cytochrome P-450 promoter variants Insulin-like growth factor-I Prostate-specific antigen

Androgen Receptor CAG Repeats Surprisingly, consistent mutations in genes associated with the androgen signaling pathway have yet to be described as a risk factor for prostate cancer. However, 44

Molecular Factors in the Assessment of Prostate Cancer Risk / 45

several polymorphisms in this pathway have been described as potentially important in this regard, and this section will examine these issues in some detail. The androgen receptor is part of a highly conserved family of steroid hormone receptors. Each of these family members is a protein containing three structural regions, a hormone-binding domain, a deoxyribonucleic acid (DNA)-binding domain, and a transactivation domain that modulates transcriptional activity (Figure 8–1). The androgen receptor gene is located on the X chromosome (Xq11-q12); thus, only one allele is responsible for gene expression in males. The first exon of the androgen receptor gene contains a region of CAG repeats which encode for a series of glutamine residues located in the middle of the receptor’s transactivation domain.1 Several populationbased studies indicate that this region is highly variable. Normal men may have anywhere between 11 and 31 CAG repeats in the androgen receptor gene with a corresponding number of glutamines in the androgen receptor protein.2 Androgen receptor function has been linked to CAG repeat length. A marked increase in CAG repeat length (40 to 60 range) has been detected in patients with Kennedy’s syndrome,3 an X-linked neurodegenerative disease accompanied by varying degrees of androgen insensitivity. Men with Kennedy’s have a blunted luteinizing hormone (LH)- and follicle-stimulating hormone (FSH)-suppression response after androgen administration, indicating impairment of androgen-mediated action.4 In vitro studies demonstrate that androgen-induced transcriptional activity is dependent on the number of CAG repeats in exon one. Transfection experiments with a series of androgen receptor genes containing a variable number of CAG repeats indicate that lower ligand-induced transcriptional activity is present in receptors with an increased number of CAG repeats.5 Furthermore, deletion of the CAG repeat region results in increased transcriptional activity.5 Additional studies have indicated that a higher number of androgen receptor CAG repeats is associated with a reduction in cellular messenger ribonucleic acid (mRNA) and protein levels.6 Thus, multiple mechanisms may abrogate androgen-receptor-mediated signal transduction in men with an increased number of CAG repeats. Several studies indicate that prostate cancer risk may be linked to germline androgen receptor gene CAG repeat length. In a preliminary study, Ingles and colleagues7 noted approximately a twofold increased risk of prostate cancer in men having a CAG repeat length of less than 20. Giovannucci et al.8 reported that the risk for developing prostate cancer was inversely proportional to CAG repeat length. In this report, 587 prostate cancer patients and 588 controls from the Physician’s Health Study were examined using a nested case-control design. Men with a repeat length of less than 19 had a 1.5-fold relative risk of prostate cancer compared to men with a repeat length of greater than 25. In addition to being at higher risk for prostate cancer, men

TABLE 8–2. Selected Polymorphisms Potentially Linked to Prostate Cancer Risk Androgen receptor Exon one CAG repeat length Exon one GGC repeat length Cytochrome P-450 (CYP) CYP3A4 upstream promoter variant

with shorter CAG repeats were also more likely to have poor prognostic markers such as advanced stage and/or poorly differentiated disease. When examining the subset of men with low-grade or low-stage cancers, CAG repeat length was not noted to be a risk factor. In a study by Hakimi and colleagues9 examining only patients undergoing radical prostatectomy for clinical stage B prostate cancer, men with lymph-node-positive prostate cancer were more likely to have a CAG repeat length of less than 18 compared with (literature controls) men with no history of prostate cancer. The odds of having a CAG repeat length of less than 18 were eightfold higher in Caucasian men with lymph-node-positive cancer compared to men with lymph-node-negative cancer. Taken together both the Giovannucci and Hakimi studies are consistent in that men with a shorter CAG repeat length have increased risk of nonorgan-confined prostate cancer. Another study, published by Stanford et al.10 did not demonstrate a statistically significant correlation between CAG length and prostate cancer risk when analyzing all subjects but did find increased risk for men who had both a CAG repeat length of < 22 and a GGN (a distinct polymorphism) repeat length of ≤ 16. Detailed studies of the family history of patients with prostate cancer indicate the possibility of an X-linked component to prostate cancer risk.11 The age-adjusted

A

B FIGURE 8–1. A, A schematic of the androgen receptor protein showing the regions of amino acid variability and the functional domains common to all steroid receptors. B, A schematic of the androgen receptor gene showing the CAG and GGN repeats in the first exon as well as the regions encoding the various functional domains in the androgen receptor protein.


prostate cancer risk in those with affected brothers exceeds that of those men with affected fathers, a finding consistent with (but not diagnostic of) an X-linked disease. Whether or not this risk is related to androgen receptor CAG repeat length or other recently described X-linked loci12 is not clear. Hardy et al.13 analyzed data from 109 Caucasian men with prostate cancer and concluded from a multivariate analysis that age of onset was linked to CAG repeat length (shorter repeats were linked to earlier onset of disease). The Hardy et al. report examined primarily patients originally diagnosed with advanced-stage disease. The Hakimi et al.9 report specifically examined this question as well and did not find an age-related association with CAG repeat length. As noted above, however, only patients undergoing radical prostatectomy were used in their data set. Comparison of data is hampered because of differences in the patient populations under investigation. Racial variation in CAG repeat length has been noted in several studies examining men with no known prostate cancer.2,14 These studies and other studies indicate that African American men have a statistically significant shorter number of CAG repeats as compared to nonHispanic Caucasians (mean 19 versus 21). A recent study indicates that approximately 57% of African American men have < 20 CAG repeats as compared to only 28% of non-Hispanic Caucasians in the United States.15 These differences could potentially explain the increased risk and earlier onset of prostate cancer in African American men compared with other ethnic groups. Because African Americans are consistently diagnosed with more advanced disease, CAG repeat length could potentially be a contributory factor for this observation as well. Additional studies are currently being conducted to specifically examine this hypothesis.

Androgen Receptor GGC Repeats In addition to containing a polymorphic CAG repeat in the transactivation domain, exon one of the androgen receptor also contains a polymorphic GGC repeat. The GGC repeat encodes for a variable number of glycines and is located approximately 1.1 kilobases 3' of the CAG repeat. The variable GGC repeat (4 to 24 triplets) follows an invariant (GGT)3GGG(GGT)2 repeat that also encodes for six consecutive glycines. The median and mean GGC repeat length are both approximately 16.9,10 Unpublished observations by Barrack and colleagues indicate that the GGC repeat length is shorter in African Americans as compared to Caucasians. Functional consequences, if any, have yet to be ascertained for variations in androgen receptor GGC length. Hakimi and colleagues9 report that men with prostate cancer are 4.6-fold more likely to have GGC repeats of < 15. Stanford and colleagues,10 in a study of 281 cases and

266 controls, reported that men with < 17 repeats have a 1.6-fold relative risk of prostate cancer compared to men with 17 or more repeats. Platz et al.,16 in the largest reported study of 582 cases and 794 controls, presented data suggesting that both increases and decreases above the mean were associated with slight elevations of risk. Taken together, these studies suggest modest increases in risk for men with a less-than-average number of GGC repeats. Interactions between the two androgen receptor exon one polymorphisms have also been evaluated. Stanford and colleagues10 examined the interaction between the two polymorphisms and concluded that men with both GGC of < 17 and CAG repeats of < 22 were at increased risk compared with men having longer GGC and CAG repeats.

Polymorphisms in the 5 Alpha-Reductase Gene The 5 α-reduction of testosterone to the potent androgen dihydrotestosterone (DHT) is catalyzed by the 5 α-reductase enzymes. Two forms of the 5 α-reductase enzyme have been described; current nomenclature designates these as type I and type II enzymes. A TA repeat is present in the 31 untranslated region of the type II gene. After examination of appropriate data sets, Kantoff et al.17 concluded that there was no relationship between type II 5 αreductase TA repeat length and prostate cancer risk.

Hormone Levels The androgen sensitivity of prostate cancer has been well described over the past five decades. Androgen withdrawal is clearly recognized as one of the cornerstones of management in patients with advanced prostate cancer disease. In addition, androgens are necessary for normal prostatic growth and development during puberty. Interestingly, however, data suggesting that variations in serum testosterone or DHT are a risk factor for prostate cancer in normal men are minimal or contradictory. A variety of studies measuring these potent androgens in both typical case-control and prospective studies indicate no significant elevation in risk associated with alterations in circulating testosterone levels.18–21 Low DHT levels have been associated with elevations in prostate cancer risk in some19 but not all20,21 studies. Low DHT/testosterone ratios have also been implicated as a prostate cancer risk factor in some18 but not all studies. Taken together, studies of hormones and prostate cancer are more compatible with a model in which serum androgen levels play a permissive rather than causative role. It is also readily conceivable that serum hormonal measurements may or may not correlate with intraprostatic hormonal measurements.


Androgen Metabolism The cytochrome P-450 (CYP) enzyme system is involved in the metabolism of xenobiotics, pharmaceuticals, and a variety of endogenous and exogenous steroids including testosterone.22 The CYP3A enzyme subfamily is particularly important, being the predominant CYP expressed in both the liver and intestine.23 The CYP3 subfamily members catalyze the 2-, 6-, and 15-β hydroxylation of testosterone (in addition to a variety of other reactions). In liver microsomal preparations, the CYP3-dependent 6-β hydroxylation reaction accounts for 75 to 80% of testosterone’s oxidative metabolism.24 CYP3A activity is expressed in both normal and malignant prostatic tissue, however interindividual variation is high;25 only 61% of prostate cancers express the protein.26 This variability in expression has been hypothesized to result from a polymorphism within the 5' regulatory promoter.27 Approximately 14% of white men are heterozygotic and 3% homozygotic for an allele containing an A to G transition (CYP3A4-V) approximately 290 base pairs upstream from the CYP3A4 transcriptional start site in a region known to bind nuclear proteins and known to regulate CYP3A4 transcription rates.28 When examining a cohort of prostate cancer patients, men carrying a CYP3A4-V allele were more likely to present with advanced-stage disease as compared to men carrying the wild type (CYP3A4-W) allele.27 The authors of this study hypothesize that individuals expressing CYP3A4-V may have more bioavailable testosterone as a consequence of expressing less CYP3A4 enzyme. Whether or not men with or without this polymorphism are subject to an increased risk of prostate cancer awaits additional and appropriately controlled studies. Interestingly, this polymorphism in the CYP3A4 promoter region has also recently been linked to treatment-related leukemias.29

Insulin-Like Growth Factor-I Insulin-like growth factor-I has recently been linked to prostate cancer risk in a series of studies. The initial observation was a relatively small case-control study noting increased IGF-I in men with prostate cancer but not benign prostate hyperplasia.30 A much larger nested case-control study using data derived from the Physicians’ Health Study cohort has confirmed and extended this initial report.31 In the Chan et al.31 report, increasing plasma levels of IGF-I were directly linked to increasing prostate cancer risk. Importantly, this increased risk was detected in men with both normal and elevated PSA measurements, suggesting that these risk factors were independent of one another. When examining men with the highest quartile of IGF-I, the prospective risk of prostate cancer was increased 2.4-fold, relative to those with an IGF-I in the lowest quartile. In a multivariate

analysis adjusting for PSA and the major circulating IGF-I binding protein (IGFBP-3), men with a PSA ≤ 4 ng per mL and highest quartile PSA had a 4.3-fold prostate cancer risk. After a similar IGFBP-3 adjustment, men with a PSA > 4 ng per mL in combination with the highest quartile of IGF-I had a 17.5-fold risk of prostate cancer. On the basis of the findings of this study, a combination of PSA and IGF-I determinations could be used to construct a prospective risk-factor profile considerably more powerful than race or family history. Another large case-control study performed in Sweden has confirmed the association between IGF-I and prostate cancer32 and found this association to be particularly strong in men < 70 years old. In the Swedish study, no association was found between IGF-I level and stage at presentation, and no association was found between IGF-binding protein-3 (IGFBP-3) concentration and prostate cancer risk. The mechanism whereby IGF-I might contribute to prostate cancer risk may involve several potential pathways. Studies in prostatic tumor cell lines indicate that IGF-I can stimulate androgen-receptor-mediated gene transcription in the absence of exogenous androgen.33 Interestingly, this effect is blocked by antiandrogens. Experiments in animal models demonstrate that tumor growth can be inhibited by strategies designed to disrupt IGF-I signaling pathways. Overexpression of the inhibitory IGF-binding protein-4 (IGFBP-4) delays onset of prostate tumor formation.34 Furthermore, a dominant negative mutant of the IGF-I receptor inhibits prostate cancer growth in both soft-agar and animal models.35 Growth is stimulated by IGF-I in stromal as well as epithelial cells.36 These experiments indicate that disruption of IGF-I signaling pathways can inhibit prostatic tumor growth under a variety of modeled conditions. Interestingly, the secreted serine protease PSA can catalyze IGFBP-3 fragmentation.37 After PSA-induced cleavage, this binding protein has a markedly reduced IGF-I binding affinity. Thus, it is conceivable that PSA-secreting cells could increase “free” IGF-I concentrations in the local cellular microenvironment, thereby increasing the amount of IGF-I available to interact with its cell surface receptor. In the clinical setting, acromegalics have a marked increase in prostate volume that reverses with successful acromegalic treatment.38 Taken together, a variety of basic and clinical data support the concept that IGF-I can stimulate prostatic growth, and clinical studies clearly support the concept that increasing plasma IGF-I levels are associated with a substantially increased prostate cancer risk in men.

Prostate-Specific Antigen Prostate-specific antigen is a serine protease normally secreted by the prostatic epithelial cells during the ejaculatory process. Control of PSA transcription is, in part,


regulated by a typical androgen-response element located in the 5' regulatory region of the gene.39,40 Numerous studies indicate that PSA production is dependent on androgens. The role of PSA in the early detection and management of prostate cancer patients is well defined and well discussed in other aspects of this publication. Often overlooked, however, is the role of PSA in assessing the future risk of prostate cancer. In the provocative Physicians’ Health Study, serum and data were collected from 22,071 men (age 40 to 84 years) enrolled in the study beginning in 1982. After a decade of follow-up, 366 men diagnosed with prostate cancer were compared to 1098 age-matched controls for PSA measurements at the time of initial study enrollment.41 As anticipated, elevations in PSA (> 4.0 ng per mL) were associated with increased risk of prostate cancer (with a sensitivity and specificity of 73% and 91%, respectively). The estimated lead time between elevation of PSA and clinical diagnosis of prostate cancer was 5.5 years. These data support what numerous other publications have concluded: elevations in PSA are associated with individuals having an increased prostate cancer risk and PSA testing can lead to an earlier diagnosis of disease. Often overlooked in this study, however, is the fact that differences in PSA within the “normal” range were predictive of prostate cancer being diagnosed in the ensuing decade. This implies that PSA does not simply function as a tumor marker (as widely appreciated) but, rather, PSA can serve as a marker for future prostate cancer risk. In this study, men with a serum PSA between the range of 1.0 and 1.5 ng per mL had a 2.2-fold increased risk compared to men with a PSA of < 1.0 ng per mL. Men with a PSA in the 1.5 to 2.0 ng per mL range had a 3.4-fold risk and men with a PSA between 2.0 and 3.0 ng per mL had a 5.5-fold increased risk of prostate cancer (compared to men with a PSA of < 1.0 ng per mL). Though many interpretations of these data are possible, they are consistent with the hypothesis that PSA may function as a surrogate marker for androgen-mediated effects on prostatic gene transcription, which, in turn, is linked to prostate cancer risk. Alternatively, PSA, in and of itself, may have a procarcinogenic action. As noted above, interactions between PSA and IGF-I, a generally acknowledged prostatic growth factor, are consistent with the latter hypothesis.37 Clearly, more studies are warranted to explore both these hypotheses (and others) in more detail.

Summary Accumulated data over the past decade has considerably increased our understanding of molecular risk factors associated with prostate cancer. Many of these studies link alterations of androgen-signaling efficiency (or markers thereof) to prostate cancer risk. A series of polymorphisms in the androgen receptor (both CAG and

GGC repeat length) and androgen-metabolizing enzymes such as CYP3A4 are promising in terms of predicting future risk of prostate cancer; however, the levels of risk associated with these polymorphisms are considerably less than those associated with serum PSA and plasma IGF-I. Considerable future efforts are necessary to further define and explore these putative molecular risk factors and to devise methods of intervention that best capitalize on the information provided by their measurement.

References 1. Chang C, Kokontis J, Liao S. Molecular cloning of human and rat complementary DNA encoding androgen receptors. Science 1988;240:324–6. 2. Edwards A, Hammond HA, Jin L, et al. Genetic variation at five trimeric and tetrameric tandem repeat loci in four human populations. Genomics 1992;12:241–53. 3. La Spada AR, Wilson EM, Lubahn DB, et al. Androgen receptor gene mutations in X-linked spinal and bulbar muscular atrophy. Nature 1991;352:77–9. 4. Sobue G, Doyu M, Morishima T, et al. Aberrant androgen action and increased size of tandem CAG repeat in androgen receptor gene in X-linked recessive bulbospinal neuronopathy. J Neurol Sci 1994;121:167–71. 5. Chamberlain NL, Driver ED, Miesfeld RL. The length and location of CAG trinucleotide repeats in the androgen receptor N-terminal domain affect transactivation function. Nucleic Acids Res 1994;22:3181–6. 6. Choong CS, Kemppainen JA, Zhou ZX, Wilson EM. Reduced androgen receptor gene expresssion with first exon CAG repeat expansion. Mol Endocrinol 1996;10: 1527–35. 7. Ingles SA, Ross RK, Yu MC, et al. Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor. J Natl Cancer Inst 1997;89:166–70. 8. Giovannucci E, Stampfer MJ, Krithivas K, et al. The CAG repeat within the androgen receptor gene and its relationship to prostate cancer. Proc Natl Acad Sci U S A 1997;94:3320–3. 9. Hakimi JM, Schoenberg MP, Rondinelli RH, et al. Androgen receptor variants with short glutamine or glycine repeats may identify unique subpopulations of men with prostate cancer. Clin Cancer Res 1997;3:1599–608. 10. Stanford JL, Just JJ, Gibbs M, et al. Polymorphic repeats in the androgen receptor gene: molecular markers of prostate cancer risk. Cancer Res 1997;57:1194–8. 11. Monroe KR, Yu MC, Kolonel LN, et al. Evidence of an Xlinked or recessive component to prostate cancer risk. Nat Med 1995;1:827–9. 12. Xu J, Meyers D, Freije D, et al. Evidence for a prostate cancer susceptibility locus on the X chromosome. Nat Genet 1998;20:175–9. 13. Hardy DO, Scher HI, Bogenreider T, et al. Androgen receptor CAG repeat lengths in prostate cancer: correlation with age of onset. J Clin Endocrinol Metab 1996;81: 4400–5. 14. Irvine RA, Yu MC, Ross RK, Coetzee GA. The CAG and


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GGC microsatelilites of the androgen receptor gene are in linkage disequilibrium in men with prostate cancer. Cancer Res 1995;55:1937–40. Sartor O, Zheng Q, Eastham JA. Androgen receptor gene CAG repeat length varies in a race-specific fashion in men without prostate cancer. Urology. [In press] Platz EA, Giovannucci E, Dahl DM, et al. The androgen receptor gene GGN microsatellite and prostate cancer risk. Cancer Epidemiol Biomarkers Prev 1998;7:379–84. Kantoff PW, Febbo PG, Giovannucci E, et al. A polymorphism of the 5 alpha-reductase gene and its association with prostate cancer: a case-control analysis. Cancer Epidemiol Biomarkers Prev 1997;6:189–92. Hsing AW, Comstock GW. Serological precursors of cancer: serum hormones and risk of subsequent prostate cancer. Cancer Epidemiol Biomarkers Prev 1993;2:27–32. Signorello LB, Tzonou A, Mantzoros CS, et al. Serum steroids in relation to prostate cancer risk in a case-control study. Cancer Causes Control 1997;8:632–6. Gann PH, Hennekens CH, Ma J, et al. Prospective study of sex hormone levels and risk of prostate cancer. J Natl Cancer Inst 1996;88:1118–26. Dorgan JF, Albanes D, Virtamo J, et al. Relationships of serum androgens and estrogens to prostate cancer risk: results from a prospective study in Finland. Cancer Epidemiol Biomarkers Prev 1998;1069–74. Cupp MJ, Tracy TS. Cytochrome P450: new nomenclature and clinical implications. Am Fam Physician 1998;57: 107–16. Lown KS, Ghosh M, Watkins PB. Sequences of intestinal and hepatic cytochrome P450 3A4 cDNAs are identical. Drug Metab Dispos 1998;26:185–7. Draper AJ, Madan A, Smith K, Parkinson A. Development of a non-high pressure liquid chromatography assay to determine testosterone hydroxylase (CYP3A) activity in human liver microsomes. Drug Metab Dispos 1998;26: 299–304. Agundez JA, Martinez C, Olivera M, et al. Expression in human prostate of drug- and carcinogen-metabolizing enzymes: association with prostate cancer risk. Br J Cancer 1998;78:1361–7. Murray GI, Taylor VE, McKay JA, et al. The immunohistochemical localization of drug-metabolizing enzymes in prostate cancer. J Pathol 1995;177:147–52. Rebbeck TR, Jaffe JM, Walker AH, et al. Modification of clinical presentation of prostate tumors by a novel genetic variant in CYP3A4. J Natl Cancer Inst 1998;90:1225–9. Hashimoto H, Toide K, Kitamura R, et al. Gene structure of CYP3A4, an adult-specific form of cytochrome P450 in human livers, and its transcriptional control. Eur J Biochem 1993;218:585–95.

29. Felix CA, Walker AH, Lange BJ, et al. Association of CYP3A4 genotype with treatment-related leukemia. Proc Natl Acad Sci U S A 1998;95:13176–81. 30. Mantzoros CS, Tzonous A, Signorello LB, et al. Insulin-like growth factor-I in relation to prostate cancer and benign prostatic hyperplasia. Br J Cancer 1997;76:1115–8. 31. Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998;279:563–6. 32. Wolk A, Mantzoros CS, Andersson SO, et al. Insulin-like growth factor I and prostate cancer risk: a populationbased, case-control study. J Natl Cancer Inst 1998;90: 911–5. 33. Culig Z, Hobisch A, Cronauer MV, et al. Androgen receptor activation in prostatic tumor cell lines by insulinlike growth factor-I, keratinocyte growth factor, and epidermal growth factor. Cancer Res 1994;54: 5474–8. 34. Damon SE, Maddison L, Ware JL, Plymate SR. Overexpression of an inhibitory insulin-like growth factor binding protein (IGFBP), IGFBP-4, delays onset of prostate tumor formation. Endocrinology 1998;139: 3456–64. 35. Burfeind P, Chernicky CL, Rininsland F, et al. Antisense RNA to the type I insulin-like growth factor receptor suppresses tumor growth and prevents invasion by rat prostate cancer cell in vivo. Proc Natl Acad Sci U S A 1996;93:7263–8. 36. Grant ES, Ross MB, Ballard S, et al. The insulin-like growth factor type I receptor stimulates growth and suppresses apoptosis in prostatic stromal cells. J Clin Endocrinol Metab 1998;83:3252–7. 37. Cohen P, Graves HC, Peehl DM, et al. Prostate-specific antigen (PSA) is an insulin-like growth factor binding protein-3 protease found in seminal plasma. Clin Endocrinol Metab 1992;75:1046–53. 38. Colao A, Marzullo P, Ferone D, et al. Prostatic hyperplasia: an unknown feature of acromegaly. J Clin Endocrinol Metab 1998;83:775–9. 39. Cleutjens KB, van Eekelen CC, van der Korput HA, et al. Two androgen response regions cooperate in steroid hormone regulated activity of the prostate-specific antigen promoter. J Biol Chem 1996;271:6379–88. 40. Zhang J, Zhang S, Murtha PE, et al. Identification of two novel cis-elements in the promotor of the prostatespecific antigen gene that are required to enhance androgen receptor-mediated transactivation. Nucleic Acids Res 1997;25:3143–50. 41. Gann PH, Henneckens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostate cancer. JAMA 1995;273:289–94.

CHAPTER 9

SCREENING FOR PROSTATE CANCER: AN OVERVIEW DAVID C. MILLER, BS; DAVID K. ORNSTEIN, MD; GERALD L. ANDRIOLE, MD more slow growing or benign cancers.3 This occurs because tumors that grow rapidly and are more aggressive typically produce symptoms and are primarily identified by routine diagnostic procedures rather than screening tests. Length-time bias occurs when there is an impression of improved survival due to screening programs, based solely on the preferential detection of slowly progressive disease.6 These biases must be taken into account when assessing the value of any screening program.3

Prostate cancer is the most commonly diagnosed noncutaneous malignancy in American men and is exceeded only by lung cancer as a cause of cancer death among United States males.1 Estimates for 1998 indicated that over 180,000 men would be diagnosed with carcinoma of the prostate in the United States and more than 39,000 would die from this disease.1 In addition, a substantial fraction of United States health care dollars are allocated to diagnosis and treatment of this disease.2 The identification of serum prostate-specific antigen (PSA) measurements as a valuable tool for early diagnosis of prostate cancer has resulted in widespread implementation of early detection as a means to reduce the morbidity and mortality of this cancer. The importance of improving diagnosis and treatment for men with prostate cancer is unchallenged; however, the most efficient way of accomplishing this has been debated.

Screening for Prostate Cancer Proponents of widespread screening argue that current screening protocols result in detection of medically important prostate cancers while they are still organconfined and curable.5,7 To date, however, screening has not been proven to reduce morbidity and mortality.8 Critics of widespread screening therefore contend that the financial, emotional, and physical burdens of screening and subsequent diagnostic and therapeutic interventions may outweigh presumed benefits from screening.3 Given these conflicting viewpoints, it is not surprising that screening recommendations issued by various professional organizations have been highly variable and even contradictory. The American Cancer Society and the American Urological Association are in agreement in recommending that annual prostate cancer screening with digital rectal examinations (DRE) and PSA levels should be offered to all men starting at age 50 and for younger men who are at increased risk for prostate cancer.9 This protocol was approved by the Food and Drug Administration (FDA) in 1997.10 Recent recommendations from the American College of Physicians, however, do not endorse routine screening of all men but instead advocate an approach whereby physicians outline the potential benefits and known harms of screening, diagnosis, and treatment, discuss the patient’s concerns, and then allow the screening decision to be made on an individual basis.11 The United States Preventive Services Task Force does not currently recommend any routine screening for prostate cancer.9 Although disagreement on its appropriate use persists, screening for prostate cancer is widespread in the United States. Prostate Cancer Awareness Week, which was instituted in 1989, is now the largest cancer screening program in the nation and has attracted more than 3 million

General Principles of a Screening Test Screening tests are used to identify asymptomatic individuals with early stage, potentially curable disease. The ultimate goal of screening is to alter the prognosis of a given condition by identifying patients early and instituting effective therapy. For a screening program to be worthwhile, the disease of interest must fulfill a number of criteria including, but not limited to, the following: the disease must be common; it must be accompanied by significant morbidity and mortality if not treated; therapy must alter its natural history; and there must be some benefit in terms of outcome or associated morbidity when the disease is treated in the presymptomatic versus the symptomatic stage.3 Based on these criteria, prostate cancer screening is unquestionably appropriate,3 but the question of whether or not current screening programs have been successful in altering the natural history of this disease or improving outcomes for patients remains controversial.4,5 Two factors confounding interpretation regarding results of screening programs are “lead-time bias” and “length-time bias.” Lead-time bias may occur if early diagnosis results in patients living longer with a disease without ultimately affecting mortality.6 With lead-time bias, the apparent improvement in survival occurs only because of a shift in the date of diagnosis, and intervention produces no real prolongation of life. Length-bias sampling refers to the tendency of screening programs to preferentially detect 50

Screening for Prostate Cancer: an Overview / 51

participants.12 In addition, efforts are well underway to recruit over 300,000 men to participate in randomized, controlled trials in both the United States and Europe that may determine whether screening for prostate cancer improves mortality. The United States component of this international group, the National Cancer Institute’s Prostate, Lung, Colorectal, Ovarian (PLCO) screening trial, has already enrolled over 50,000 men.13 Given the highly promising data on screening currently available as well as the enormous public interest, it is clear that screening programs will remain prevalent for years to come.

Screening Tools Digital Rectal Examination Historically, the DRE was considered the first-line approach to screening for carcinoma of the prostate. Digital rectal examination has long been a component of routine health screening examinations for middle-aged and older men and is not associated with any additional risks or extra financial cost.11 Abnormalities on DRE associated with cancer and thereby indicating the need for prostate biopsy include induration, asymmetry, or nodules.14,15 While the true sensitivity and specificity of DRE remain undetermined, the positive predictive value of DRE for detecting prostate cancer has been estimated by various studies to be between 15 and 30%.11 Using the presence of nodules as criteria for biopsy, Thompson et al.16 reported a positive predictive value (PPV) of 26% while Chodak and associates detected 36 malignancies in 144 biopsies (PPV of 25%) that were performed based on detection of induration, asymmetry, or nodules on examination.14 In addition, DRE appears to have a low negative predictive value in that the absence of abnormalities on DRE does not appear to considerably reduce the patient’s odds of having a clinically significant cancer. Coley et al. suggest that this low negative predictive value is likely due to the low sensitivity of DRE for the detection of prostate cancer.11 Another confounding factor limiting widespread use of DRE alone as a screening tool is limited interexaminer reliability, even among urologists. This is demonstrated by a study by Smith and Catalona showing that DRE findings were disconcordant among examiners for half of cancers.17 Digital rectal examination by itself is a poor screening modality since cancers detected by DRE tend to be advanced and incurable.6 In a study by Thompson et al., 15 of 17 cancers detected by DRE revealed no evidence of metastases based on clinical staging; subsequent pathologic examination, however, resulted in upstaging to advanced, noncurable disease in 66% of cases.16 In addition, Chodak and associates reported that 50% of patients diagnosed with clinical stage B disease based on DRE findings were upgraded to stage C or D1 following pathologic examination of surgical specimens.14

There is a also a lack of data from controlled studies to indicate that screening with DRE alone alters survival from carcinoma of the prostate. In fact, when Gerber and associates examined prostate cancer mortality in men undergoing routine screening with DRE, they found that disease-specific survival was lower for men whose cancer was detected on a subsequent screening DRE than for men whose disease was diagnosed on the initial examination.18 Despite its ease of performance and low cost, therefore, DRE alone has limited, if any, utility in screening for prostate cancer. Recent data indicate that DRE may be complementary to PSA testing,3 however. When used together this combination represents the most effective screening tool for detecting prostate cancer in its earliest stages.15,19 In a community screening study, Bretton reported that 50% of men with both an abnormal DRE and PSA were found to have cancer at the time of biopsy. This represented a higher positive predictive value than for abnormalities in DRE or PSA alone.19 Similarly, Catalona et al. showed in a study of over 6000 men that the combination of PSA and DRE resulted in a greater than 80% improvement in cancer detection rates over DRE alone.15 More specifically, for patients with a PSA between 4.1 and 9.9 ng per mL, the presence of an abnormality on DRE increased the PPV of the PSA elevation to 49% from 24% with a normal DRE. Moreover, among patients with a total PSA higher than 10.0 ng per mL, the presence of a positive DRE resulted in a 69% PPV versus the 42% PPV seen in patients with a similar degree of PSA elevation but with normal physical exams.15 Similar findings were reported by Brawer and associates.20 In addition, a study by Babaian et al. reported a PPV of 75% for DRE and PSA in combination, compared to 59% and 51%, respectively, for PSA and DRE alone.21 These findings indicate that screening by digital rectal examinations enhances detection of early prostate cancer when performed in conjunction with PSA measurements. Prostate-Specific Antigen Prostate-specific antigen is the best single test for early diagnosis of prostate cancer and, along with DRE, has recently received FDA approval as an aid in the detection of prostate cancer in men 50 years of age and older.10 Since its introduction as a clinical marker nearly two decades ago, PSA has had a profoundly favorable impact on diagnosis and treatment of prostate cancer. The PSA produced by prostatic epithelial cells is not only secreted into prostatic fluid but enters the systemic circulation.3 In serum, PSA is primarily bound to the protease inhibitor α1-antichymotrypsin, and only a small fraction exists in an unbound or free form.22 Currently, the most frequently used assays measure total serum PSA, including both PSA bound to α1-antichymotrypsin and unbound PSA. The findings from six PSA-based prostate cancer screening studies15,20,23–26 are shown in Table 9–1. These results indicate that 8 to 15% of men who are older than


50 years of age will have an abnormal total serum PSA (> 4.0 ng per mL) on initial screening and that cancer will be detected in 1.5 to 4.1% of these patients. Based on followup biopsy results, the PPV of an elevated total PSA ranges from 11 to 34%. The false-positive elevations in serum PSA may have been due to one of a number of benign prostatic conditions or prostatic manipulations that have been shown or are speculated to produce elevations in total serum PSA to levels exceeding the threshold for suspicion of malignancy. Benign prostatic hyperplasia (BPH) is a common condition in men over 50 years of age and has been demonstrated in several studies to produce elevations in total serum PSA that overlap with levels associated with malignancy.27,28 In fact, Nadler et al. reported that prostate volume was the most important benign contributor to PSA elevation.28 The authors also reported that both acute and chronic prostatic inflammation accounted for some elevation in total PSA.28 Reports on the effects of ejaculation on PSA levels have been conflicting to date. Herschman et al. reported a statistically significant elevation in total PSA for up to 24 hours following ejaculation and concluded that PSA measurements within this interval may lead to inaccurate interpretation of both total and free PSA levels.29 In contrast, Stenner and associates found an initial postejaculation fall in PSA levels followed by a return to baseline over 12 hours. These authors concluded that ejaculation has no clinically significant impact on PSA levels and that patients need not abstain from sexual activities prior to PSA screening.30 The effect of finasteride on PSA levels is better defined, as several studies have shown that it lowers total serum PSA levels by 50% on average.31 Recently, Andriole et al. reported data demonstrating that doubling the total PSA level for men receiving finasteride preserves the sensitivity and specificity of PSA testing.32 Although false-positive results are possible, the risk of prostate cancer has been clearly and consistently shown to rise with total serum PSA levels, making this an efficacious test for prostate cancer screening.20,33 In a large multicenter trial reported by Catalona et al., the PPV for prostate cancer when the PSA was between 4.1 and 9.9 ng per mL was 26%

TABLE 9–1. Results from Prostate-Specific Antigen–Based Prostate Cancer Screening Trials Author Catalona23 Mettlin24 Brawer20 Labrie25 Catalona15 Catalona26

Initial PSA Elevation (%)

Cumulative Cancer Detection Rate (%)

8.34 14 15 12.4 9.4 15

2.2 1.5 2.6 4.1 3.1 3.3

Adapted from Arcangeli CG, Ornstein DK, Keetch DW, Andriole GL. Prostate-specific antigen as a screening test for prostate cancer: the United States experience. Urol Clin North Am 1997;24:299–306.

but this increased to over 50% when PSA levels were higher than 10.0 ng per mL.15 Although 4.0 ng per mL has traditionally been designated as the upper limit of normal, total PSA is not always above this level in men with clinically detectable and potentially dangerous prostate cancers. In a study by Brawer and Large, 32% of men with biopsyproven cancer had PSA levels of < 4.1 ng per mL.34 Further, Catalona et al. reported a cancer incidence of 18% in men with a “nonelevated PSA” who participated in a multicenter trial.15 In addition, a study by Gann et al. demonstrated that men with a baseline total PSA between 2.0 and 4.0 ng per mL have a 12-fold increased risk of prostate cancer after 10 years of follow-up when compared with patients whose baseline PSA was < 1.0 ng per mL.35 Smith et al. evaluated longitudinal data from a PSA-based screening program and found that men whose initial PSA was > 2.5 ng per mL had a 13-fold increased risk of being diagnosed with prostate cancer over 4 years of follow-up than those patients whose initial PSA was < 2.6 ng per mL.36 In a large prospective study by Catalona et al. of patients with a normal DRE and serum PSA between 2.6 and 4.0 ng per mL, 22% of the 322 men who underwent biopsy were found to have cancer and more than 80% of these lesions were pathologically localized and therefore potentially curable. Only 17% of surgically-staged tumors in this series were classified as clinically unimportant.37 Currently available evidence thus convincingly demonstrates that the risk of prostate cancer is minimal in patients whose total PSA is < 2.6 ng per mL but increases dramatically as PSA rises above 10.0 ng per mL. Given the sensitivity and specificity of these cutoffs for the detection of prostate cancer and the current practice of prostate biopsy for all patients whose PSA is > 10.0 ng per mL, it appears that measurement of total PSA alone may be sufficient to achieve optimal initial evaluation of these distinct cohorts. However, the apparent limitation in specificity of total PSA measurements in the “diagnostic gray zone” has led to the search for other tests to help stratify cancer risk among patients with total PSA levels of 2.5 to 10.0 ng per mL. Specifically, studies have evaluated the ability of selected PSA derivatives to improve the specificity of PSA screening. Several PSA transformations including PSA density, slope, age-specific PSA, and free PSA levels have been investigated. Prostate-Specific Antigen Density Prostate-specific antigen density is calculated by dividing the serum PSA level (in ng per mL) by the transrectal ultrasonography (TRUS)-determined prostate volume (in cubic centimeters). The PSA density has been promoted by some authors as a method of improving the specificity and PPV of PSA testing.38 Most studies that have evaluated PSA density report higher values in men with prostate cancer than in those without.38 Recommendations for PSA density cutoffs in men with total PSA levels between 4.0 and 10.0 ng per mL have ranged from 0.09 to 0.15 with


variable effects on sensitivity, specificity, and number of biopsies performed.39,40 The variability in these findings may be a reflection of the practical limitations involved in determining PSA density, including the invasive nature and limited reliability of TRUS-determined prostatic volumes.10 The utility of PSA density in early detection protocols and the appropriate cutoff for improvement of specificity have yet to be fully elucidated. Prostate-Specific Antigen Slope The rate of change in total serum PSA over time (PSA slope or velocity) has been reported to be higher among men with prostate cancer than those with benign prostatic enlargement or no prostatic pathology.41 Several investigators have proposed a PSA slope of 0.75 ng per mL per year as a cutoff to enhance specificity for prostate cancer detection in PSA-based screening programs.41,42 Accurate determination of PSA slope, however, requires measurements over an 18-month time period and is therefore not useful in the short term but may be helpful in determining the need for repeat biopsy. Age-Specific Prostate-Specific Antigen Reference Range Age-specific PSA reference ranges have been proposed in the past as a means of improving the sensitivity of cancer detection in younger men (who would most benefit from aggressive diagnosis and treatment) and to enhance specificity of PSA screening among older men. In two separate studies, Oesterling et al. defined a set of age-specific PSA reference ranges and reported that their use in PSA-based screening studies resulted in an increased specificity (11%) and PPV (5%) for cancer detection, associated with a 9% decrease in sensitivity. In addition, the authors classified 95% of the missed cancers as clinically unimportant.43,44 These results were not confirmed, however, in a prospective, multi-institutional trial by Catalona et al. showing that the use of age-specific reference ranges would have prevented detection.45 While the use of age-adjusted PSA reference ranges does improve specificity of cancer detection in elderly men, this occurs at the expense of missing a substantial number of medically important tumors. The clinical use of this reference range has fallen out of favor.

prospective, multicenter clinical trial by Catalona et al. suggest that a free PSA cutoff of 25% or less is optimal for patients with total PSA values between 4.0 and 10.0 ng per mL and a benign DRE, irrespective of their age or prostate size. Using this cutoff, improvement in specificity over total PSA alone was evident in that 20% of unnecessary biopsies were avoided. Moreover, there was only a minimal loss of sensitivity as 95% of cancers identified by total PSA alone were also detected when a free PSA cutoff of 25% was employed.48 Thus, free PSA measurements may prove highly effective in limiting the number of unnecessary biopsies in screening programs, while preserving the sensitivity of cancer detection (Table 9–2).48 The ProstAsure index has recently been introduced. This index represents the product of a neural networkderived, nonlinear algorithmic procedure that is based on input variables including age, total PSA, and serum creatine phosphokinase and prostatic acid phosphatase levels.49 Preliminary studies suggest that ProstAsure may have an improved sensitivity and specificity for cancer detection when compared with free PSA at a cutoff value of 15%.49 The authors, however, emphasize that these findings will require confirmation in prospective clinical trials.

Effects of Prostate-Specific Antigen–Based Early Detection on Prostate Cancer Incidence While the optimal use of PSA and its derivatives continues to evolve, it is undeniable that screening for cancer with prostate-specific antigen has had a profound impact on incidence patterns for carcinoma of the prostate in the United States. Based on data from the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute, the age-adjusted incidence rate of prostate cancer increased 84% between 1987 and 1992 from 102.9 cases per 100,000 to 189.4 cases per 100,000.50 Pototsky et al. also analyzed data collected by the SEER program and reported that the age-adjusted incidence rate of prostate cancer for men over 65 years of age in four SEER areas rose by 82% from 1986 to 1991, with the most dramatic annual increases occurring in 1990 (20%) and

Free Prostate-Specific Antigen Free PSA represents the small fraction of PSA that is unbound in serum. Several recent studies have shown that the percent serum free PSA (free PSA/total PSA × 100) is lower in patients with malignant prostatic disease than in those with benign prostates.45–47 These studies have demonstrated that free PSA measurements improve the specificity of prostate cancer detection in PSA-based screening trials without dramatically reducing sensitivity, and that the utility of free PSA may be greatest for patients whose total PSA falls in the diagnostic gray zone of 2.5 to 10.0 ng per mL. Results from a recently completed

TABLE 9–2. Probability of Prostate Cancer According to Free Prostate-Specific Antigen Cutoff* Free PSA Cutoff (%)

CaP (%)

0–10 10–15 15–20 20–25 > 25

56 28 20 16 8

*Among men with total PSA levels of 4.1 to 10.0 ng per mL and benign DRE. Adapted from Catalona WJ, Partin AW, Slawin KM, et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease. JAMA 1998;279:1542–7.


1991 (19%).51 When SEER sites in Connecticut and Minnesota were independently studied, changes in the incidence rates in these individual geographic locations were consistent with nationwide trends.52,53 The nearly universal explanation for the dramatic rise in the incidence of prostate cancer over this 5- to 10-year period is that it is a manifestation of widespread implementation of serum PSA testing.51,52 More specifically, Wingo et al. contend that when a screening test such as PSA is rapidly introduced and widely accepted by the population, the incidence rate for the disease of interest will invariably increase because cancers which would otherwise have been diagnosed at a later time will now be detected at an earlier stage, thereby increasing the incidence of the disease of interest.50 Moreover, Pototsky and colleagues commented that there is little evidence to suggest that the increased incidence of prostate cancer during this interval was linked to changes in the prevalence of theoretic risk factors such as prior vasectomy or increased consumption of dietary fat.51 While PSA-based screening did result in an initial rise in incident cases, subsequent epidemiologic data has revealed a decline in the age-adjusted incidence of prostate cancer since 1992. In his analysis of incidence data from the population-based Connecticut Tumor Registry, Polednak reported that for men in the age ranges 65 to 74, 75 to 84, and 85-plus years, the peak prostate cancer incidence in 1992 was followed by a decline such that in 1994 incidence rates in the 75 to 84 and 85-plus age groups had returned to or dropped below pre-PSA “baseline” rates dating from 1988.53 Significantly, this same study did not demonstrate a decline in prostate cancer incidence rates after 1992 in men between 45 to 54 and 55 to 64 years of age. The author hypothesized that the absence of such a decline in this population may be due to increased detection of cancers with long lead times.53 Stephenson et al., reporting on data from the Utah Cancer Registry, also described a decrease in the prostate cancer incidence rates from a peak of 236.2 cases per 100,000 in 1992 to 195.0 and 164.0 per 100,000 in 1993 and 1994, respectively.54 Merrill and associates reported similar declines after analyzing incidence data from eight different SEER locations.55 In addition, it was demonstrated in two large-scale studies that the cancer detection rate decreases to approximate the prostate cancer detection rate in the absence of screening after 3 to 4 years of serial PSA-based screening.36,56 Finally, evidence of this continued decline in the incidence of prostate cancer since 1992 led the American Cancer Society to make a midyear adjustment in their projections for the number of new cases in 1997, from 334,500 to fewer than 210,000 cases.50 Therefore, a more longitudinal evaluation of prostate cancer incidence in the PSA era indicates that the concern that widespread screening with PSA would lead to detection of a large number of possibly incidental carcinomas of the prostate was without foundation.

Effects of Prostate-Specific Antigen–Based Early Detection on Prostate Cancer Stage Prostate-specific antigen-based screening has also resulted in a dramatic stage migration among newly diagnosed prostate cancers and has increased the number of tumors that are organ-confined at the time of diagnosis twofold compared to the pre-PSA era. Historically, only 33% of cancers were pathologically organ-confined at the time of diagnosis.26,57 In contrast, cancers detected through PSAbased screening programs are much more likely to be organ-confined. In a study of 24,346 men by Smith and Catalona, 69% of tumors detected by initial PSA screening and 74% of those detected through serial screening were shown to be pathologically organ-confined when surgical staging was available.58 Similar findings were described by Catalona and associates who reported that pathologically organ-confined cancers were found in 63% and 71% of men undergoing initial or serial PSA-based screening, respectively.26 Mettlin et al. reported on a cohort of 2999 asymptomatic men between 55 and 70 years of age who participated in a multimodality early-detection program involving PSA, DRE, and TRUS; 64% of cancers detected in this series were proven to be pathologically organconfined.57 Finally, in the Hybritech study of 6630 men, the use of PSA in combination with DRE produced a 78% increase in the detection of organ-confined disease, and 71% of patients undergoing radical prostatectomy had prostate cancer that was pathologically organ confined.15

Characteristics of Prostate-Specific Antigen–Detected Cancers The preceding data demonstrates rather robustly that screening with PSA improves our ability to detect early, pathologically organ-confined carcinoma of the prostate. However, some have questioned whether this downward stage migration will improve mortality from prostate cancer and have suggested that many of the cancers detected through PSA screening are indolent and clinically unimportant. The controversy surrounding this question arises from the fact that, historically (in the pre-PSA era), there has been a discrepancy between the incidence of clinical prostate cancer and the high prevalence of the disease found at autopsy. Specifically, it has been reported that 30% of men over 50 years of age with no clinical evidence of disease are found to have adenocarcinoma of the prostate at the time of autopsy.59 To appropriately address this question, a number of studies have examined whether screening with PSA successfully detects cancer at an earlier stage without identifying an increased proportion of incidental or clinically insignificant cancer. The aggressiveness of a prostate carcinoma depends on its grade, volume, and PSA level, the latter of which


increases in proportion to tumor volume.60 Consequently, the criteria that have traditionally been associated with medically important cancer include such clinicopathologic features as palpable tumor, multifocal or diffuse involvement, and moderately or poorly differentiated histology (Gleason score [GS] 4 or higher). In contrast, features of tumors that are more likely to be medically unimportant include those that are microfocal or have well-differentiated histology.58,59 In a Washington University study, only 3% of men with PSA-detected prostate cancer who underwent surgical staging were determined to have clinically insignificant disease based on the findings of impalpable, pathologically confined, well-differentiated (GS ≤ 4), minimal (≤ 0.5 cc) tumors.58 Moreover, Ohori and colleagues examined radical prostatectomy (RP) specimens from 306 cancers detectable by PSA, DRE, or TRUS and compared these to 90 cancers that were detected incidentally in cystoprostatectomy specimens. In this series, only 9% of the clinically detected tumors were classified as clinically unimportant versus 78% of the incidental cancers from the cystoprostatectomy specimens. In this same study, PSAdetected cancer was no more likely to be clinically unimportant than cancers detected by abnormal findings on DRE.59 Humphrey et al. assessed the pathologic features of 100 consecutive RP specimens from men in PSA-based screening programs and found that 94% of carcinomas had a clinically significant Gleason score of 5 to 8 and that in 68% of cases the tumor volume exceeded the clinically significant threshold of 0.5 cc.61 In addition, in a study of patients with elevated PSA and no palpable abnormalities on DRE, 65% of carcinomas examined following RP had a tumor volume greater than 1.0 cc and were therefore considered medically important.62 Finally, in a recent study, Douglas et al. analyzed 67 patients with stage T1c disease who underwent RP. They found that multifocal disease was present in 96% of specimens and, by study criteria, insignificant tumors were reported in only 4 cases.7 It seems that an overwhelming majority of the evidence indicates that most carcinomas detected by PSA elevation are medically important tumors deserving of early diagnosis and treatment (Table 9–3).

Effects of Early Detection on Cancer Mortality Although PSA-based screening has not been proven to reduce mortality in a randomized prospective trial, several pieces of evidence are highly suggestive that it will. As described previously, implementation of PSA-based screening produced a downward shift in cancer stage, with an increased incidence of organ-confined disease at the time of diagnosis and a decrease in the number of newly detected advanced cases.56,58,61 Most investigators, in turn, view this stable stage migration as actual evidence for a

reduction in mortality based on the ability of currently available therapy, particularly radical prostatectomy, to cure organ-confined disease.6,63 It is argued, therefore, that continued detection of early-stage disease through PSA-based screening protocols is the most effective strategy for ultimately achieving decreased mortality.6 In addition, there is significant indirect epidemiologic evidence suggesting that screening may indeed have a profoundly beneficial effect on survival and mortality. For instance, data from the SEER program indicates that the 5-year relative survival rates from prostate carcinoma have improved from 66.7% between 1974 and 1976 to 79.6% in the interval from 1983 to 1990.64 In a separate analysis of SEER data, a 20% increase in relative survival from carcinoma of the prostate from 1985 to 1993 compared to the period 1973 to 1980 was revealed.65 In addition, a decision model developed by the American College of Physicians suggests that, with appropriate treatment, the use of screening to detect organ-confined cancers in men between the ages of 50 and 69 years may increase life expectancy by up to 3 years.11 Finally, in 1996, the National Center for Health Statistics reported an estimated 6.3% decrease in mortality from prostate cancer in the United States from 1991 to 1995.66 Therefore, while the results of prospective, randomized trials are not yet available, the initial interpretation of data from the PSA era is highly promising with regard to impact on long-term survival. There are, however, alternate interpretations of the above data. Consistent with a decrease in mortality from prostate cancer, for example, these data may represent a manifestation of the lead-time bias and length bias associated with screening.67 More specifically, the present author suggests that the improved survival data may simply be due to prolonged awareness of the cancer’s existence without actual prolongation of the patient’s life. Also screening may merely be detecting slow-growing, less aggressive cancers which are nonlethal and would never require treatment.67 Others question whether early-stage prostate cancer can be cured by any means, citing the absence of controlled trials.8 It is clear that while most of the evidence is favorable, some disagreement remains concerning the interpretation

TABLE 9–3. Comparison of the Clinical and Pathologic Features of Prostate Adenocarcinomas Discovered by Prostate-Specific Antigen Screening* Median tumor volume Mean Gleason score % extra-capsular % < 0.5 cc and Gleason score ≤ 4

Autopsy

Cystoprostatectomy

T1c

0.05–0.15 4.8 0

0.02–0.17 5.1 2

0.5–2.4 6.8 20–48

94

78

5–15

*In cystoprostatectomy specimens, and at autopsy. Adapted from Ohori et al.,59 Smith and Catalona,58 Humphrey et al.,61 Scaletscky et al.,62 Douglas et al.7


of survival data from PSA-based studies as well as the true impact of early detection on mortality from carcinoma of the prostate. However, there appears to be an unwavering consensus, both within the urologic and the greater medical community, that the question of whether screening actually reduces prostate cancer mortality can only be answered by prospective, randomized controlled studies such as the National Cancer Institute PLCO screening study13 and the European Randomized Study of Screening for Prostate Cancer,68 both currently underway. The already widespread dissemination of prostate cancer screening will hopefully not compromise the completion or validity of these landmark trials. In summary, total serum PSA is the best single screening test for detecting prostate cancer. It is prostatespecific but not cancer-specific, as it may be elevated by a number of benign prostatic conditions as well as physical or pharmacologic manipulation of the prostate gland. The overlap of PSA elevations occurring in these various conditions makes the specificity of PSA as a cancer screening tool less than ideal. Nevertheless, widespread implementation of PSA-based screening has resulted in a dramatic increase in the detection of medically important, organ-confined prostate cancer and has greatly enhanced the potential for curative intervention and decreased mortality in men with this disease.

Economics of Prostate Cancer Screening Since prostate cancer is the most common visceral neoplasm in American men, the costs associated with its diagnosis and treatment represent a not insignificant component of United States health care expenditures. In a 1990 analysis by Optenberg and Thompson, it was estimated that the annual cost for clinical management of prostate cancer for men between 50 and 70 years of age prior to the widespread implementation of PSA-based screening programs was $255 million.69 However, as screening with PSA has become widely accepted in the past decade, estimates of health care expenditures related to prostate cancer have increased dramatically. Numerous studies have attempted to predict the actual costs associated with a single year of screening for prostate cancer in men between the ages of 50 and 70 years. In an updated analysis, Lubke, Optenberg, and Thompson estimated that the first-year cost of screening with PSA and DRE would be $25.7 billion in a scenario where organ-confined disease was managed with radical prostatectomy and more advanced tumors were treated with either radiotherapy or bilateral orchiectomy.70 This estimate was reduced to $17.6 billion when no treatment was undertaken for low-grade (GS 2–4), high-grade (GS 8–10), or T3 and T4 disease and all intermediate-grade disease was treated with radical prostatectomy.70 Kramer and colleagues proposed a similar exponential cost increase when they estimated an $11.9 billion price tag for the first year of screening in men from 50 to 74 years of age.71 This figure

includes the cumulative costs of screening, diagnosis, treatment, and any associated complications. Although there is little disagreement that widespread screening for prostate cancer has driven a profound increase in the share of health care dollars devoted to this disease, many authors have argued convincingly that this is money well spent. For instance, in a model developed by Benoit and Naslund, the cost per year-of-life saved by screening with DRE and PSA was estimated to be under $5000, which is significantly lower than the figures assigned to other medical interventions including mammography, liver transplantation, and control of hypertension.72 However, critics of this study contend that the authors’ consideration of a number of factors was incomplete, possibly altering their results, including their failure to figure time lost from work and lost productivity into estimates of societal costs of disease.73 In a separate analysis, Littrup estimated the cost of prostate cancer screening per quality-adjusted life year to be $14,200 to $51,267. Thus, the author concluded that screening for prostate cancer was cost effective when compared with the cost per quality-adjusted life year for breast cancer screening ($20,000 to $50,000) and fecal occult-blood screening for colon cancer ($35,054).74 The validity of these figures is limited, however, because many of the variables contributing to the estimates are subjective. As yet there is no truly accurate method to quantify the cost of each year of life saved by early detection of prostate cancer. In the context of these conflicting data and opposing viewpoints, the dramatic rise in expenditures associated with aggressive screening for carcinoma of the prostate will only be validated when it has been unequivocally demonstrated in appropriately designed trials that early detection and treatment reduce morbidity and increase disease-specific survival from prostate cancer.

Summary Serum PSA-based screening has been extensively studied for the past several years. It appears that we can comment with some certainty on the relative performance of serum PSA and DRE in detecting early-stage prostate cancer. We can also state that initial screening clearly improves detection of pathologically organ-confined, clinically significant cancers and has decreased the incidence of advanced disease. Moreover, epidemiologic data strongly suggests that annual, serial screening does not overdetect incidental carcinomas. Further, the specificity of prostate cancer screening may be enhanced as the optimal use of such PSA derivatives as PSA density, PSA velocity, and percent-free PSA are better defined. As these advances in diagnostic capability are coupled with an increased ability to predict the behavior and clinical significance of individual tumors, the already powerful argument for widespread PSA-based screening will become even more compelling. Currently, both the American Cancer Society and the American Urological Association recommend that


annual DRE and total serum PSA measurements be offered to men older than 50 years of age and younger men at high risk for prostate cancer. The benefits of screening should be realized in men whose life expectancy exceeds 10 years and who are willing to undergo curative therapy for prostate cancer. Among younger men, PSA levels over 2.5 ng per mL should be considered suspicious and require further investigation. In men older than 65 years of age, a slightly higher PSA threshold of 4.0 ng per mL may be appropriate, and biopsy is indicated when total PSA exceeds this level. In addition, it appears that a free PSA cutoff of 25% improves specificity while maintaining sensitivity of PSA screening for patients whose total PSA is between 4.0 and 10.0 ng per mL. Finally, while the impact of prostate cancer screening on disease-specific mortality will not be fully defined until the completion of randomized, prospective clinical trials, PSA screening is undoubtedly the most effective current method for detecting organconfined disease, thereby affording patients a realistic chance to be cured of a potentially devastating disease.

References 1. Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin 1998;48:6–29. 2. Kramer BS, Brown ML, Prorok PC, et al. Prostate cancer screening: what we know and what we need to know. Ann Intern Med 1993;119:914–23. 3. Goldstein MM, Messing EM. Prostate and bladder cancer screening. J Am Coll Surg 1998;186:63–74. 4. Brawley OW. Prostate carcinoma incidence and patient mortality: the effects of screening and early detection. Cancer 1997;80:1857–63. 5. Smith DS, Catalona WJ. The nature of prostate cancer detected through prostate-specific antigen-based screening. J Urol 1994;152:1732–6. 6. Andriole GL, Catalona WJ. Using PSA to screen for prostate cancer: the Washington University experience. Urol Clin North Am 1993;20:647–51. 7. Douglas TH, McLeod DG, Mostofi FK, et al. Prostate-specific antigen-detected prostate cancer (stage T1c): an analysis of whole mount prostatectomy specimens. Prostate 1997;32:59–64. 8. Collins MM, Barry MJ. Controversies in prostate cancer screening: analogies to the early lung cancer screening debate. JAMA 1996;276:1976–9. 9. Stein B, Lindenmayer JM. Proposed prostate cancer screening recommendations. Med Health RI 1997;80:343–5. 10. Arcangeli CG, Ornstein DK, Keetch DW, Andriole GL. Prostate-specific antigen as a screening test for prostate cancer: the United States experience. Urol Clin North Am 1997;24:299–306. 11. Coley CM, Barry MJ, Mulley AG. Early detection of prostate cancer. Part III: screening for prostate cancer. Ann Intern Med 1997;126:480–4. 12. DeAntoni EP. Eight years of “Prostate Cancer Awareness Week”: lessons in screening and early detection. Cancer 1997;80:1845–51.

13. Vanchieri C. Prostate cancer screening trials: fending off critics to recruit men. J Natl Cancer Inst 1998;90:10–2. 14. Chodak GW, Keller P, Schoenberg HW. Assessment of screening for prostate cancer using the digital rectal examination. J Urol 1989;141:1136–8. 15. Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate-specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6630 men. J Urol 1994;151:1283–90. 16. Thompson IM, Ernst JJ, Gangai MP, Spencer CR. Adenocarcinoma of the prostate: results of routine urological screening. J Urol 1984;132:690–2. 17. Smith DS, Catalona WJ. Interexaminer variability of digital rectal examination in detecting prostate cancer. Urology 1995;45:70–4. 18. Gerber GS, Thompson IM, Thisted R, Chodak GW. Disease-specific survival following routine prostate cancer screening by digital rectal examination. JAMA 1993;269:61–4. 19. Bretton PR. Prostate-specific antigen and digital rectal examination in screening for prostate cancer: a community-based study. South Med J 1994;87:720–3. 20. Brawer MK, Chetner MP, Beatie J, et al. Screening for prostatic carcinoma with prostate-specific antigen. J Urol 1992;147:841–5. 21. Babaian RJ, Dinney CP, Ramirez EI, Evans RB. Diagnostic testing for prostate cancer detection: less is best. Urology 1993;41:421–5. 22. Christensson A, Laurell C, Lilja H. Enzymatic activity of the prostate-specific antigen and its relation with extracellular serine protease inhibitors. Eur J Biochem 1990;194:755–63. 23. Catalona WJ, Smith DS, Ratliff TL, et al. Measurement of prostate-specific antigen in serum as a screening test for prostate cancer. N Engl J Med 1991;324:1156–61. 24. Mettlin C, Lee F, Drago J, Murphy JP. Findings on the early detection of prostate cancer in 2425 men. Cancer 1991; 67:2949–58. 25. Labrie F, Dupont A, Suburu R, et al. Serum prostate-specific antigen as a pre-screening test for prostate cancer. J Urol 1992;147:846–52. 26. Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993;270:948–54. 27. Stamey TA, Yang N, Hay AR, et al. Prostate-specific antigen as a serum marker for adenocarcinoma of the prostate. N Engl J Med 1987;317:909–16. 28. Nadler RB, Humphrey PA, Smith DS, et al. Effect of inflammation and benign prostatic hyperplasia on elevated serum prostate-specific antigen levels. J Urol 1995;154:407–13. 29. Herschman JD, Smith DS, Catalona WJ. Effect of ejaculation on serum total and free prostate-specific antigen concentrations. Urology 1997;50:239–43. 30. Stenner J, Holthaus K, Mackenzie SH, Crawford ED. The effect of ejaculation on prostate-specific antigen in a prostate cancer-screening population. Urology 1998; 51:455–9.

58 / Advanced Therapy of Prostate Disease 31. Guess HA, Gormley GJ, Stoner E, Oesterling JE. The effect of finasteride on prostate-specific antigen: review of available data. J Urol 1996;155:3–9. 32. Andriole GL, Walsh PC, Epstein JI, et al. Treatment with finasteride preserves the usefulness of PSA in prostate cancer (CaP) detection. J Urol 1998;159 Suppl: 277. 33. Catalona WJ, Hudson MA, Scardino PT, et al. Selection of optimal prostate-specific antigen cutoffs for early detection of prostate cancer: receiver operating characteristic curves. J Urol 1994;152:2037–42. 34. Brawer MK, Lange PH. Prostate-specific antigen: its role in early detection, staging, and monitoring of prostatic carcinoma. J Endourol 1989;3:227–36. 35. Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostatic cancer. JAMA 1995;273:289–94. 36. Smith DS, Catalona WJ, Herschman JD. Longitudinal screening for prostate cancer with prostate-specific antigen. JAMA 1996;276:1309–15. 37. Catalona WJ, Smith DS, Ornstein DK. Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng per mL and benign prostate examination: enhancement of specificity with free PSA measurements. JAMA 1997;277:1452–5. 38. Benson MC, Whang IS, Olsson CA, et al. The use of prostate-specific antigen density to enhance the predictive value of intermediate levels of serum-prostate specific antigen. J Urol 1992;147:817–21. 39. Seaman E, Whang M, Olsson CA, et al. PSA density: role in patient evaluation and management. Urol Clin North Am 1993;20:653–63. 40. Smith DS, Catalona WJ, Keetch DW. Comparison of percent free PSA and PSA density as methods to enhance the specificity of PSA screening. J Urol 1996;155 Suppl: 422A. 41. Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of prostate-specific antigen levels in men with and without prostate disease. JAMA 1992;267:2215–20. 42. Smith DS, Catalona WJ. Rate of change of serum prostatespecific antigen levels as a method for prostate cancer detection. J Urol 1994;152:1163–7. 43. Oesterling JE, Jacobsen SJ, Cooner WH. The use of agespecific reference ranges for serum prostate-specific antigen in men 60 years old or older. J Urol 1995;153:1160–3. 44. Oesterling JE, Jacobsen SJ, Chute CG, et al. Serum prostate-specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges. JAMA 1993;270:860–4. 45. Catalona WJ, Smith DS, Wolfert RL, et al. Evaluation of percentage of free serum prostate-specific antigen to improve specificity of prostate cancer screening. JAMA 1995;274:1214–20. 46. Woodrum DL, Brawer MK, Partin AW, et al. Interpretation of free prostate-specific antigen clinical research studies for the detection of prostate cancer. J Urol 1998;159:5–12. 47. Luderer AA, Chen Y, Soriano TF, et al. Measurement of the proportion of free to total prostate-specific antigen improves diagnostic performance of prostate-specific

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Screening for Prostate Cancer: an Overview / 59 65. Smart CR. Prostate cancer facts and fiction. J Surg Oncol 1997;66:223–9. 66. Shalala DE. Cancer death rate decline for the first time ever in the 1990s [press release]. Bethesda (MD): National Cancer Institute; 1996. 67. Brawley OW. Prostate carcinoma incidence and patient mortality: the effects of screening and early detection. Cancer 1997;80:1857–63. 68. Standaert B, Denis L. The European randomized study of screening for prostate cancer: an update. Cancer 1997; 80:1830–4. 69. Optenberg SA, Thompson IM. Economics of screening for carcinoma of the prostate. Urol Clin North Am 1990; 17:719–37.

70. Lubke WL, Optenberg SA, Thompson IM. Analysis of the first-year cost of a prostate cancer screening and treatment program in the United States. J Natl Cancer Inst 1994;86:1790–2. 71. Kramer BS, Brown ML, Prorok PC, et al. Prostate cancer screening: what we know and what we need to know. Ann Intern Med 1993;119:914–23. 72. Benoit RM, Naslund MJ. The economics of prostate cancer screening. Oncology 1997;11:1533–43. 73. Chodak GM. The Benoit and Naslund article reviewed. Oncology 1997;11:1543. 74. Littrup PJ. Future benefits and cost-effectiveness of prostate carcinoma screening. Cancer 1997;80:1864– 70.

CHAPTER 10

THE OPTIMAL DIAGNOSTIC TOOL: ASSESSMENT OF DIAGNOSTIC MODALITIES TO DETECT EARLY PROSTATE CANCER CHRIS H. BANGMA, MD, PHD; FRITZ H. SCHRÖDER, MD, PHD Screening for prostate cancer (PCa) is feasible due to the availability of diagnostic tools to detect prostate malignancy at an early and asymptomatic stage. None of the current diagnostic modalities, however, will detect cancer at an initial stage in which only molecular changes have occurred, or a stage in which only a few cells show histologic features of malignancy. Histologic studies of whole mount sections of prostate glands at autopsy have shown that the true incidence of prostate cancer at death is far more common than any early detection study with current diagnostic tools has ever indicated.1 The incidence of histologic cancer increases with age, as shown in populationbased early detection studies. This illustrates the lack of sensitivity of current screening modalities. What defines an “optimal” diagnostic tool? In terms of detection, this could be the tool (or combination of tools) that maximizes the number of detected cancers. The biologic behavior of prostate cancer shows, however, that not all men detected with a cancer will become symptomatic, or even ultimately die of it. It may therefore be desirable to diagnose the majority of cancers as harmless, or not diagnose them at all. In this sense, the optimal diagnostic tool should be able to inform about the aggressiveness of the detected cancer. Even better, it should inform about the pathologic stage of the disease so that decisions can be made as to whether the patient should undergo radical resection or other forms of available curative treatment. Diagnostic tools currently lack these qualities. Ongoing analysis of detected cancers may in the future enable clinicians to correlate diagnostic tests to some of the histologic and molecular qualities expected to be of prognostic value. The optimal diagnostic tool might be further defined in terms of patient comfort and financial and time effectiveness. These aspects can be summarized for most detection programs as the lowest number of biopsies (Bx) needed to detect one cancer, or Bx per PCa. In line with this, minimalizing the complications caused by the application of the screening modalities should be another goal of the optimal tool. Within the sequence of events from selecting participants from the population to undergo the screening protocol until death of a participant, several diagnostic steps

may be taken (Figure 10–1). The application of the diagnostic tools can be related to each of these events. Several of these events have been analyzed in the literature, such as the relationship between diagnostic tools and the frequency of prostate biopsy or the detection rate of cancers. More recently, the relationship between diagnostic testing and the histologic characteristics of radical prostatectomy specimens has been reported. Future studies will likely reveal the relationship between diagnostic tools and the characteristics of cancers found at death. It is clear that no single answer is to be expected in seeking the optimal diagnostic tool. Various aspects of detection, prognosis, and nondisease-related efficacy need to be combined. The question becomes even more complicated on the level of statistical comparison. Studies describing different populations with regard to age, race, geography, and selection for participation must be examined, any number of which may be defective in the presentation of their material and use of statistical methods. The underlying impossibility of proper comparison might restrict this investigation to a mere description of study results. This, however, does not diminish the value of the individual studies, which will shed light on forthcoming analyses of diagnostic tools.

Statistical Aspects It is important to discuss some of the statistical terms and methods used in evaluating diagnostic tools before examining specific modalities. Comparing different methods as diagnostic tools requires reproducibility of each method and agreement between different methods on the same item of diagnosis. Reproducibility of a tool, or test, can be expressed in intraobserver or assay variability (by the same observer), or interobserver (by two or more observers) variability. When measuring prostate-specific antigen (PSA), for example, it is possible to relate the numeric values of various determinations of the same serum sample at different closely related time points, and calculate the coefficient of variation by the ratio of the mean and its standard variation. This variation is theoretically dependent on the batch of chemicals and stan60

The Optimal Diagnostic Tool: Assessment of Diagnostic Modalities to Detect Early Prostate Cancer / 61

dards used, for which the term “lot-to-lot” variation is used, calculated similarly. Determination of the variation between different assays (interassay variation) is not very current as it is not justifiable to use different assays within the concept of one study, for frequently discussed reasons of assay design and the presence of PSA isoforms. The determination of reproducibility is less easy for digital rectal examination (DRE). The observer is usually not blinded to the patient and examination performed, and the examination result is at best semiqualitative, for example, “normal,” “suspicious,” or “cancer.” Analysis of the quality of DRE can only be performed as interrater agreement, for which “kappa” is calculated.2 Total agreement corresponds with a kappa of 1.00; in practice, a kappa value of below 0.50 is associated with poor agreement. The value of kappa depends on the proportion of subjects (prevalence) in each category and the number of categories. This makes the already small number of studies even less likely to be comparable. To improve the methods of diagnosis, intense research has been carried out to compare different diagnostic tools or tests, or their combinations, and seek agreement on the outcome. Up to the level of diagnosis, the endpoints are usually straightforward and dichotomous: to biopsy (yes or no); having cancer (yes or no). When the test is designed in such a way that its result is dichotomous, DRE suspect/not suspect, for example, or PSA above or below the cutoff level, simple terms can be used to describe the test. The quality of such a test can be expressed in its sensitivity and specificity in illustrating the proportion of men positive or negative that are correctly diagnosed by the test. This assumes, however, that the true prevalence of the disease is known; in this case, the true prevalence of prostate cancer in the population. Since this value is unknown for PCa, the test’s ability to predict the diagnosis or biopsy result must be evaluated, rather than the patient’s true disease status. Terms such as sensitivity and specificity can therefore only be used in patient populations with an expected similar prevalence of disease. Such information in most geographic areas is unknown. As a result, only studies assuming that disease prevalence is somewhat comparable due to the similarity in the distribution of race, diet, and migration between those areas can be compared. With the progression of large-scale screening programs, the age-adjusted cancer incidence will probably decrease,3 which may change the relative value of screening tools. Second-round screening tools may differ from those used in the first round. The use of the screening result and diagnosis as the gold standard of tumor incidence has led to unrealistically high estimates of the sensitivity of diagnostic tests in screening, especially in those groups where not every man is subjected to a diagnostic biopsy. From the incidence of cancers diagnosed in groups of screening participants in

which all men underwent PSA-driven biopsies, the “a priori prevalence” was extrapolated for men with a PSA below the cutoff value.4 This method gives a more realistic outcome of sensitivity calculations for tests applied in that PSA range. In practice, it is often more useful to know the number of patients with positive and negative tests that are correctly diagnosed. This is described by the positive predictive and negative predictive values of the test, both of which illustrate its accuracy. These predictive values are also unfortunately dependant upon prevalence, and therefore cannot be universally employed. The statistical method becomes more complicated whenever the test or endpoint is based on continuous rather than dichotomous measurements. Predicting cancer by the level of serum PSA (without the use of a cutoff), or the free to total PSA ratio (FT ratio), requires discriminant analysis based on logistic regression to assess the test. For the simplest dichotomous outcome (cancer yes/no), this means that sensitivity and specificity are calculated for every value of the test. Put together in a graph, this defines a receiver operator characteristic curve (ROC), originally based on signal detection by radar. Since such curves are used frequently, several aspects of this type of graphic representation are described below. Receiver operator characteristic curves help illustrate cutoff values and compare different tests in identical populations. They do not prove superiority of a clinical test

FIGURE 10–1. Diagnostic events (in squares) in the sequence of screening and follow-up for prostate cancer. The size and darkness of the curved arrows indicate the current knowledge regarding diagnostic tools. Block arrows indicate the function of diagnostic modalities regarding the outcome of events.


method, as decisions on choosing a method are based on more than statistical differences. The most favorable outcome of a test is represented by the upper left corner of the graph, in which the sensitivity and specificity of the test are both 100%. There are no false-negatives and false-positives at that point, and the test completely correlates with the gold standard of the specific diagnosis. Fitting a curve through that point would follow the lines of the axes, and the area under that curve would comprise the whole surface of the square lined by the axes. Compromise is necessary with every other graph because of the chance of false test results. The line x = y represents “sensitivity = 1 – specificity,” or “sensitivity + specificity = 100%.” This line shows the test result as if a coin is being tossed: the outcome of the test is correct in 50% of cases and the area under the curve is 50% of the surface, comprising 100%. To do better than chance, the test characteristic curve must shift above this line. The area under the curve then illustrates how often the test will predict a true outcome, given any cutoff value. This information might not be relevant, as clinically the point with a 10% sensitivity is not interesting. Curves with a higher predictive value, however, are usually shifted to the left into the clinically interesting areas. This “area under the curve” information is used as an argument in favor of differing testing procedures. Any point of the curve can be considered as a cutoff value for the test. The test result will be predicted by reading the sensitivity and specificity of the test on the x and y axes. Such a curve will always have a confidence interval that is smaller if the number of results used is larger. Often the desired sensitivity is high, occasionally 90 to 95%. The interesting portion then lies in the upper right corner of the graph, where the curve is almost horizontal. In that area, only a small change in the sensitivity based on its confidence interval will result in a considerable variation of the specificity. Unless such confidence intervals are mentioned, reports on improved specificity may be misleading when comparing sets of tests. Studies based on a small number of participants result in considerable confidence intervals, since charateristics other than those tested for, such as age and race, will influence the prediction of the test outcome of the group. In such cases, as a rule of thumb the standard error (SE) of quoted sensitivity and specificity of a dichotomous system may be calculated by the square root of the product of the studied frequencies of each group, divided by the number of participants. The 95% confidence interval can be estimated by plus or minus two times the standard error. This can also be regarded as the minimum significant difference needed to distinguish one sensitivity value from that of another curve. For example, assume that 300 biopsies are being studied, 60 of which are malignant. The diagnostic tool used detects 55 cancers correctly, and 200 benign cases correctly; sensitivity = 55/60 = 92%, with SE = (SqrRt [60 × 55 × 5])/60 = 2.1%; specificity = 200/240 = 83%, with SE

= 5.8%. In this scenario, an over 11.6% (related to 28 individuals) reduction of biopsies is required to significantly improve on the specificity of this method at this level of sensitivity. The point on the ROC curve nearest to the upper lefthand corner is frequently indicated as the optimal value of sensitivity and specificity. This point indicates merely the cutoff value where it would “cost” as much to have a false negative result as it would cost to have a falsepositive result, equalizing sensitivity and specificity. As mentioned before, the optimal cutoff value is determined by clinical decision.

Diagnosis by Biopsy: the Gold Standard Biopsy represents the gold standard of prostate cancer diagnosis. There is no better proof of the presence of a cancer than the histologic evidence. It is clear that the incidence of PCa is influenced by the method of prostate sampling. The real incidence of prostate cancer is unknown, as is the natural history concerning size and location within the prostate. In a small series of radical cystoprostatectomy specimens, removed for urothelial carcinoma, small volume prostate cancers were found in the absence of clinical symptoms.5 Prostate biopsies on autopsy specimens could provide data on the accuracy of prostate biopsies, permitting some extrapolation to a younger screening group. The biopsy procedure is a sampling procedure, and therefore PCa cannot be excluded with complete certainty. To assess the qualities of the sampling procedures, several attempts have been made to relate the technical aspects of taking biopsies (such as number, location, and direction) with histologic outcome (cancer-core length, tumor volume and location). The chance of hitting a carcinoma by random sextant biopsy decreased with increasing prostate gland size in computer simulations of a series of imaginative prostate glands harboring various sizes of cancer.6 Directing the sextant biopsies especially toward the lateral parts of the peripheral zone improved cancer detection.7 Not surprisingly, more cancers were found when the number of biopsies was increased in a clinical series.8 In this study, sampling with 7 to 11 additional biopsies in newly defined lateral and midline regions more than doubled the total number of detected tumors from 49 to 119. It was found that 83% of the cancers had a Gleason score of 6 or more; remarkably, the tumors appeared to be the same size as those in a sextant biopsy series. Computerized biopsy simulations on a series of mapped whole mount sections of radical prostatectomy specimens with PCa showed that the chance of missing a cancer with random sextant biopsies is considerable, estimated at about 25%.9 In a population of men diagnosed with prostate cancer, a second set of biopsies did not show malignancy in 27% of cases.10 There is a question whether the performance of an increased number of prostate biopsies will not only


increase the number of cancers but also influence the qualities of the cancers. Will the number of larger cancers increase (as they are easier to detect), or will a larger number of minor and clinically insignificant cancers be detected? In Terris’ series of sextant biopsies of 442 cancers detected in 816 patients, 10% of cancers had a tumor volume of < 0.5 mL.11 This arbitrary tumor volume of 0.5 mL has become a commonly cited threshold over the years for minimal or insignificant disease, especially when combined with a well-differentiated histology. The location of tumors, for example close to the prostate capsule, and features such as microvessel density, were not taken into account. Roughly 10 to 15% of tumors detected in various other series had the features of those detected at autopsy.12 Chen calculated that 18% of tumors with a volume < 0.5 mL (incidence in that series of 18%) carried a more than 90% chance of being identified by biopsy while this number in larger tumors was at least 73% and proportional to tumor size.13 Similar computer simulations were performed in 59 mapped autopsy prostates (derived from a series of consecutive autopsies) with clinically undetectable prostate cancers, in 25% of which PCa was found. The detection of multifocal cancers and cancers of larger volume increased compared to low-volume cancers.14 More important, single foci of well-differentiated cancers smaller than 0.5 mL went undetected by random sextant biopsies in 80% of specimens. Such volumetric and histologic criteria are used to define the significance of cancers but are subject to discussion, and various groups will report differently. Crawford came to a definition of insignificant cancer having a tumor volume of ≤ 0.25 mL with a maximum Gleason score of 7.14 The model detected 58% of asymptomatic significant and 20% of insignificant cancers. In Chen’s computer biopsy series, the number of detected smallvolume cancers doubled when the number of biopsies increased to 10 while that of the larger tumors detected increased from 107 to 147 (from 73% to 96%).13 This means that the number of small-volume cancers in screening will likely increase proportionally to the number of larger cancers, if the distribution of cancers is comparable to the population described by Chen. The proof of this will be demonstrated in those screening studies in which an adjustment of the protocol regarding biopsy indications alters the number of smaller cancers found. The effect of performing repeated series of biopsies may be questioned. Will the chance of detecting a cancer by performing two sets of random sextant biopsies be different than obtaining 12 at one time? Will a second round of screening detect the larger cancers missed in the first round, or will it only detect the less important small volume cancers? Not surprisingly, there was a 10% increase in the number of cancers detected in a series of men from a screening population biopsied for an increased PSA over 4 ng per mL after one previous series of negative biop-

sies.15 In the Rotterdam series, a similar result in rescreening by PSA, DRE, and transrectal ultrasonography (TRUS) after 1 year was reported. This series showed that the cancers detected during the second round of screening had similar histologic characteristics as those found during the first round of screening.16 Tumor volume appeared smaller but not significantly so. The second-round tumors were detected predominantly in prostates of larger total gland volume, suggesting that these had been missed during the first-round screening. This indicates that the number of biopsies may need to be adjusted to gland volume. Likewise, adjustment to age to decrease the risk of finding clinically unimportant disease may be of benefit for the elderly subset of men.17 This once again stresses the sampling nature of the current method for prostate biopsies. Assuming a second or third set of biopsies is justifiable in certain men with persistent abnormal screening tests, various authors have sought a way to predict a positive outcome and restrict the number of men who undergo rebiopsy. When performed on the indication of an increased PSA, an increased PSA density or a decreased FT ratio correlated to finding prostate cancer.18,19 There are a minority of cancers diagnosed in the transition zone of the prostate. These cancers are often confined but of larger volume, thereby increasing serum PSA. To detect these cancers, sextant biopsies with two additional transition-zone biopsies have been advocated in the case of an elevated PSA after a negative set of sextant biopsies.15 Carcinoma was detected in 19 of 166 participants (12%), and in 10% of men with cancer these were found in the transition-zone biopsies only. Some of the transition-zone cancers may still escape diagnosis, presenting an argument that some urologists should consider a diagnostic transurethral resection in the case of persistently elevated PSA.20 In a screening setting, 340 men with normal DRE and elevated PSA levels (using age reference values) underwent a biopsy regimen that included two transitionzone biopsies in addition to sextant biopsies.21 In 28 of 98 diagnosed prostate carcinomas (29%), only the transitionzone biopsies were positive for PCa. In 20 men (71%), these cancers were pathologically organ-confined. We are restricted to the diagnosis made on biopsies as the gold standard. Screening by biopsy only may be the best diagnostic tool presenting minimal complications.22 This approach, however, is not feasible due to the enormous costs involved. Also, overdiagnosis and overtreatment of insignificant cancers is a major concern and presents an argument that biopsies should be performed only after prescreening by modalities discussed below. More than 90% of cancers detected in the first round of screening by PSA and DRE are pathologically localized,23–25 and 10 to 15% of these are well-differentiated cancers of small volume (< 0.5 mL).16,26 Only our limited understanding of their natural history, with the possibility that they could be or become aggressive, life-threaten-


ing cancers, provides a rationale in retrospect for active removal of even small tumors. Adequate tools to predict insignificant tumors are lacking. In general, series of ultrasound guided sextant biopsies demonstrate adequate sensitivity. It is clear that the number of biopsies influences the chance of detecting PCa, and thus a strict comparison with sextant biopsy is not possible when the number of cases is limited to four. In a series of sextant biopsies plus TRUS lesion biopsies (seven or eight biopsies in total) the value of the extra biopsies increased the detection frequency minimally by 5%.27 Transrectal ultrasonography appeared to be better than DRE as a tool to direct biopsies.6 In Rotterdam, Rietbergen confirmed that the seventh biopsy uniquely detected only 5% of visible cancers (DRE normal and PSA < 4 ng per mL), that is, 19 of 298 cancers in 6533 men.4 Transrectal ultrasonography, however, appeared to be an excellent guidance tool, as 79% of the biopsies directed at hypoechogenic lesions showed malignancy.

The Classic Three: Prostate-Specific Antigen, Digital Rectal Examination, Transrectal Ultrasonography Various diagnostic modalities are discussed below, starting with the “classic” three: PSA, DRE, and TRUS. Most early detection efforts focused on these modalities, and each of them was at some time thought to be useful as an independent screening tool. In these studies, younger age was excluded from analysis, based on the clinical presentation of prostate cancer. Age, however turned out to be a valuable tool, especially in relation to PSA, and will be discussed in the section on prostate volume and age-related PSA adjustments. Prostate-specific antigen isoforms are discussed as well as tools for repeat screening. Prostate-Specific Antigen Determination of PSA in serum has become a major part of current urologic practice. Its importance as an indicator for prostatic disease, especially malignancy, is illustrated by the tremendous volume of literature referring to it and the presence of over 40 commercially available biochemical assays worldwide. Rapidly increasing interest in comparable serum PSA determinations has streamlined efforts to develop international biochemical standards.28 This development has been slowed by discrepancies between assays based on the existence of PSA isoforms in the serum29 and lack of understanding the physiologic variation of PSA in the serum. Assays for determining total PSA, hereafter referred to as PSA, currently show a low variation within and between batches, expressed as the coefficient of variation (CV). This CV is minimally dependent on the PSA range but is usually around 5 to 6%. Even for “ultrasensitive” assays developed especially for PSA ranges below 0.1 ng per mL, a good CV is obtained.30 These assays will not be discussed in this

chapter as they have no value for PCa screening. The low CV and the relatively low costs have made serum PSA an attractive instrument for mass screening. Variation between PSA assays is based on the design of the individual tests, in which the antibodies used bind to the various epitopes of the PSA molecule are of predominant importance. The oft-quoted PSA values determined by the Hybritech assay as reference material are mainly of historic interest and are commercially driven. The high quality of the biochemical performance of PSA assays is in sharp contrast to the physiologic variation observed in various studies. The difference between individual PSA determinations of healthy persons may be as large as 30% within 1 month30 and up to 55% over 1 year.31 Comparison between studies analyzing PSA variation is difficult due to the influence of the number of determinations, the time period between them, and the population studied. The number of reports of screening populations showing time-based PSA variation have been limited. The PSA variation over time, often referred to in terms of PSA velocity, has so far not shown any benefit for detecting PCa at a follow-up or second-round screening visit. More reports are expected in coming years. Prostate-specific antigen is a physiologic product of normal prostatic epithelial cells and not a tumor marker in itself. Various studies have claimed a significant and independent effect of age (r = .37 to .43) and of prostate volume (r = .55 to .56) on the serum PSA level.33–35 Others showed age and prostate size to be dependent factors, likely due to the higher age of the men analyzed.36 Up to 5 to 6% of the variation of serum PSA could be explained by age, and 30 to 34% by prostate size.34,36 It soon became evident that serum PSA concentration is relatively higher in men with PCa compared to those without. This is most likely due to increased “leaking” of the PSA into the abundantly available tumor capillaries rather than into the lumen of prostatic ducts at the apical side of the epithelial cell. The tumor-related contribution of serum PSA appears to correlate to tumor volume and, to a lesser extent, to its degree of differentiation.37 To distinguish healthy individuals from those with prostatic disease, and to select men at risk for PCa to undergo prostate biopsies, it became necessary to define normal reference values. The overlapping distributions of PSA values for healthy men and for those with PCa did not allow for a single PSA value discriminating both groups, and the extent of overlap was dependent on the population analyzed. In most screening programs, the initial goal was to maximize the number of cancers detected at an acceptable cost and morbidity, determine the incidence and characteristics of these cancers, and treat them accordingly. Subsequently, in order not to miss detectable and treatable cancers, a relatively low cutoff value of 3 to 4 ng per mL was chosen. Gradually it became evident that in the intermediate PSA range of 4 to 10 ng per mL, five to six biopsy pro-


cedures were performed to detect one carcinoma.38–41 To reduce the number of negative biopsies for psychologic and financial reasons, methods were designed to correct the slightly elevated PSA values for influences other than malignancy. It was therefore logical to normalize these PSA values to the other most evident measurable factors of increase: age and prostatic size. Age-Related Prostate-Specific Antigen Reference Values The concept of age-related PSA reference values is similar to that of the initially recommended PSA cutoff value of 4 ng per mL, based on the distribution of PSA values in a subset of the general population. Age-related reference values were defined for 5- or 10-year intervals as those including the lower 95% range of PSA values in clinically healthy individuals (Table 10–1). These age-adjusted reference values were aimed at increasing the sensitivity of cancer detection for individuals aged less than 60 years and to increase specificity in the elderly age group. In the latter group, various agerelated factors such as prostate size, infarction, and subclinical inflammation increase the serum PSA. This concept would theoretically have worked well for screening populations, as it appeared to do for clinical populations, if the distribution of PSA values (their median value and standard deviation) of men with PCa had not overlapped considerably with benign values. Catalona compared the age-specific PSA reference values with the use of a uniform PSA cutoff value for all ages in a multicentered screening study of 6630 men aged 50 years or older.42 In the age group under 60 years, 48 tumors were found in 256 biopsies indicated by an abnormal DRE or PSA over 4 ng per mL. An extrapolated increase of 15% in cancer detection at the cost of a 45% increase in the number of biopsies was calculated. In the older age groups actual observations showed that 8% of pathologically organ-confined cancers would have been missed by application of reference values for men aged 60 to 69 years, and up to 47% for men older than 70 years of age. As the number of quadrant biopsies needed to detect one carcinoma (Bx/PCa) remained constant across age groups, a uniform PSA cutoff of 4.0 ng per mL was advocated. To improve specificity in the older age group, Oesterling applied his recommended reference ranges in 2988 men aged 60 years or older.43 He found that 92 (5.5%) of the 1686 biopsies could have been avoided, of which 19 (21%) harbored a malignancy. Only one of those 19 cancers was histologically advanced. Cancer was detected in 20% of the remaining 94% of biopsies. The Bx/PCa ratio would therefore have changed from 2.8 to 2.7, a very limited gain. In the Rotterdam section of the European Randomized Study of Screening for Prostate Cancer (ERSPC), Rietbergen reported that the application of these reference values as a prescreen test would have led to the loss of 22

(13%) of all detectable cancers while avoiding 138 (14%) of all biopsies.22 This analysis was performed in a subset of men aged 55 to 76 years, all of whom underwent biopsies because of an elevated PSA of 4 ng per mL or more. To improve sensitivity in the older age group, Reissigl performed a screening study based on the PSA reference values as an initial screening test in men aged 45 to 75 years.44 Of 11,595 men, 8% had a PSA level of 4 ng per mL or more while 9% had an elevated PSA based on age reference values. Impalpable tumors were found in 16 men under 60 years of age with a PSA < 4.0 ng per mL. The number of biopsies increased by 66 (8%), from 778 to 844, and the number of detected carcinomas increased by 16 (8%), from 197 to 213. The Bx/PCa ratio remained at 3.9. All 16 cancers in this younger age group were pathologically organ-confined and none was reported to be “insignificant.” Overall, the readily applicable age reference values as prescreen values appear to have minimal additional benefit for cancer detection in a screening setting; too many detectable cancers are missed in the older age groups. Conversely, in the younger age group, the sensitivity for detecting significant tumors appears to increase, but the number of biopsies needed to detect these tumors increases significantly. It would be appropriate in future studies to re-evaluate the characteristics of lost tumors. It is possible that the loss of detected but relatively less harmful cancers is worth the gain in the number of organ-confined cancers in the younger age group, while leaving the overall Bx/PCa ratio unchanged. Prostate-Specific Antigen Density To normalize PSA values to prostate size, TRUS volumetry has been used to calculate the mean serum level of PSA related to 1 mL of prostatic tissue, or the PSA density (PSAD).45 Of all volumetric methods, step-section planimetry appears to be the most accurate and reproducible,46 but calculating prolate spheroid volume using caliper measurements is more time efficient and automatically available on most ultrasonic equipment. The application of PSAD was intended to add value to PSA alone, especially in the intermediate PSA range in which a relative indication for PSA-driven biopsy existed. Various studies addressing PSAD in screening populations are referenced in Table 10–2.42,47,48 The choice of a cutoff value is based on two studies. In a clinical population, Benson used 0.15 ng per mL per cc of prostate tissue as a cutoff value to discriminate between benign and malignant disease.45 Lee et al. altered their iniTABLE 10–1. Age-Related PSA Cutoff Values (ng per mL) Author

PSA Correlation to Age

Oesterling34

0.43

PSA = prostate-specific antigen.

N

40–49 Years

50–59 Years

60–69 Years

70–79 Years

471

2.5

3.5

4.5

6.5

66 / Advanced Therapy of Prostate Disease TABLE 10–2. PSAD as Indicator for Biopsies in the Intermediate and High PSA Range Author, Year

PSA

N

Cutoff (ng/mL/cc)

Bx/PCa

Reduction in Number of Bx (%)

Missed PCa(%)

Littrup, 199447 Catalona, 199442

4–10 4–10

154 161 DRE negative 1202

0.12 0.10 0.15 0.10 0.12 0.15

2.3 2.5 2.3 2.8 2.6 2.3

12 58 75 19.6 28.6 40.7

0 21 48 5 8.6 14.1

Rietbergen, 199848

≥4

PSAD = prostate-specific antigen density; PSA = prostate-specific antigen; Bx = biopsy; PCa = prostate cancer; DRE = digital rectal examination.

tial cutoff of 0.20 to 0.12 ng per mL per cc as a result of their analysis of the screening population from the American Cancer Society–National Prostate Cancer Detection Project (ACS-NPCDP) study.49 In their subsequent analysis they argued for the use of PSAD and DRE as selection tools following the application of serum PSA, leading to a cost-effective biopsy protocol.47 Their analysis showed that among 2558 participants, 60 cancers in 154 biopsies would have been detected due to an elevated PSA level while PSAD required only 136 biopsies to yield the same number of cancers. The study, however, was marred by a low biopsy compliance, and its multicenter design does not guarantee high consistency in ultrasonic procedures and indications for biopsy. Catalona objected to the use of PSAD based on the data of his multicentered screening study of nearly 5000 men.42 Reasoning that PSAD would be used to detect unpalpable carcinomas in the PSA range between 4 and 10 ng per mL, Catalona analyzed PSAD in a group of 734 men, of whom 161 had a normal DRE and who consented to random quadrant biopsies. In these 161 participants, 33 cancers were detected. Using a PSAD of 0.150 ng per mL per cc or more, 16 of 33 impalpable cancers were missed, 9 of which were organ-confined. Reducing the number of biopsies performed by 75% obviously did not outweigh the loss of detectable and confined carcinomas, even when the PSAD cutoff level was lowered to 0.100. These numbers are less dramatic when related to the total number of biopsies performed for an elevated PSA of > 4 ng per mL. The number would be reduced from 464 (with 151 cancers) to 344 (with 135 cancers), improving the overall Bx/PCa ratio from 770/192 (= 4.0) to 650/176 (= 3.7). In a further attempt to correct for benign changes of prostate size and PSA elevations, the size of the ultrasonically visible transition zone representing benign prostatic hyperplasia was used to adjust serum PSA values. Some studies claim a higher correlation between the transition zone volume and PSA compared to that involving total prostate volume.50 The PSA transition zone density (PSAT) is calculated by the ratio of PSA and TRUSdetermined transition zone volume.51 These ultrasonic measurements are more susceptible to observer variation compared to volumetry of the entire prostate gland.46 Applied to a screening population, Rietbergen found no better performance of PSAT compared to PSAD in his

analysis of 1202 biopsied participants with a PSA of > 4 ng per mL.48 At a PSAT cutoff of 0.16 ng per mL per cc, a reduction of 20.0% of biopsies would have been obtained at the cost of missing 5.8% (21 of 361) of detectable cancers. Reissigl claimed in 380 screened men between 45 and 75 years of age with an elevated PSA according to age-reference values in the PSA range between 2.5 and 10 ng per mL, that 24% of negative biopsies (n = 77) could have been avoided without missing any of the 58 prostate cancers (Bx/PCa = 5.3), using a cutoff value for the PSAT of 0.22 ng per mL per cc.21 These results are impressive, but from the data published it is impossible to say whether this biopsy reduction occurred mainly in younger men in the screening population (aged 45 to 59 years [55%]). These men were healthy volunteers, 22% of whom had biopsies, resulting in a 0.9% cancer incidence. For some reason, PSAD was not analyzed. Although Reissigl announced a prospective study using PSAT, it seems reasonable to conclude at this time with available data that PSAT has limited value in reducing the number of unnecessary biopsies in screening programs. Digital Rectal Examination Although DRE was used as the sole screening tool up to only one decade ago, this concept belongs now to the urologic history books. Results of studies on DRE, often case finding series, relate the incidence of palpable tumors only to age. The average detection rate with DRE alone appeared to be 1.4% between 51 and 70 years of age. Bentvelsen and Schröder provide a worthwhile overview of an era when larger screening efforts by PSA and DRE had just been started.52 From the introduction of PSA onward, incidence analysis of tumors detected by DRE has been influenced by the higher biopsy frequency for men with a serum PSA above the cutoff level for prostate biopsies. The value of DRE should be considered separately for men with and for those without an additional biopsy indication but a suspicious finding on DRE. The value of DRE in men with an extra biopsy indication, such as an elevated PSA, is not for detection but for staging and prognosis. Digital Rectal Examination with Prostate-Specific Antigen Less than 4 ng per mL Several screening studies that employed DRE as the sole biopsy indicator in PSA ranges lower than 4 ng per mL


are summarized in Table 10–3. Early detection in a community setting, involving 148 clinical centers, found 322 cancers in almost 32,000 participants over 50 years of age screened by PSA and DRE in the first screening round.53 Unfortunately, 46% of men with suspicious findings refused further investigations by biopsy. In the Rotterdam screening program of the ERSPC for men between 55 and 70 years of age, a similar positive predictive value (PPV) of 13% was found for men with a suspicious DRE and a PSA < 4 ng per mL.4 Whole mount sectioning of 15 prostates of the men operated on showed that all of them had a tumor volume < 1 mL (median < 0.41 mL) and a Gleason score of 7 or less. Since biopsies are not performed in men with a normal DRE and a PSA < 4 ng per mL, a negative predictive value (NPV) for DRE cannot be adequately calculated. Only a few studies provide such information in a screening setting by performing a biopsy in all study participants. Smith compared two screening arms of a study involving 30,000 men over 50 years old, screened by DRE and PSA. Biopsies were performed in 2466 men on the indication of a suspicious DRE and/or a PSA > 4 ng per mL in the one arm, and in 198 men with a similar indication but a PSA of > 2.5 ng per mL in the other arm.25 Remarkably, the PPV of DRE in both groups was identical at 28%. Response rates of participants to undergo prostate biopsies were approximately 33% in the combined arm versus 80% in the second arm, a difference which may have influenced the results. The predictive value of DRE in the lower PSA ranges appears to be small and is correlated to the serum PSA level.4 The tumor characteristics of these DRE-detected cancers do not show aggressive features such as unfavorable tumor size or pathologic grade. The DRE-detected tumors were not larger compared to the size of tumors detected by ultrasonography, and had similar histologic features. The low PPV and restricted reproducibility of DRE suggest that the results of a digital examination are influenced by serendipity. The DRE indicated a tumor by chance alone in 20 to 30% of cases, as was calculated from the correlation between palpability and the location of a histologic tumor at the side of the palpable lesion.4 Studies analyzing DRE as an aid to direct prostate biopsy also showed that contralateral tumor detection often occurred in the biopsies remote to the palpable lesion (on the side), illustrating that no additional help was provided by DRE for this purpose.52 Therefore, in the low PSA range below 3 or 4 ng per mL, DRE appears to be a poor screening tool. Nevertheless, it would be unrealistic to say that DRE does not play any role at all in screening in the low PSA range. The DRE does detect a number of carcinomas that are almost always confined to the prostate and therefore curable. Tailoring a screening approach might be feasible.

In the ERSPC screening population of 8367 participants, only four cancers were found by DRE or TRUS in the 1702 (20%) men with a PSA of ≤ 1 ng per mL. These welldifferentiated cancers had a volume of < 0.5 mL. This means that 20% of the population can be safely screened by PSA only. Detection of cancers on the indication of DRE only with a PSA between 1 and 3 ng per mL showed 43 cancers in 4619 men (55% of the screening population) at the cost of a Bx/PCa ratio of 10.4 Above a value of 3 ng per mL, the PPV of DRE and PSA might be compared in groups in which the biopsies are driven by a PSA cutoff of 3 ng per mL. Lodding calculated a PPV of 19% for DRE between 3 and 4 ng per mL PSA in 243 men, all biopsied, among whom 32 cancers were found.55 Five of the tumors were palpable and their histology appeared similar to the T1c cancers. Digital Rectal Examination with ProstateSpecific Antigen Greater than 4 ng per mL In the PSA range indicating biopsies (usually 4 ng per mL Hybritech and higher) the value of DRE initially has been analyzed to restrict the number of biopsies indicated by PSA only. With the maturation of screening data, however, it has become clear that a large number of detectable cancers were impalpable and classified as T1c according to the 1992 TNM classification. In the PSA range of 4 to 10 ng per mL, DRE detected 115 of 249 cancers correctly (PPV = 45%) while 123 detectable cancers in the same group of 1095 screening participants were impalpable.4 These T1c cancers did not differ in their histologic features from palpable lesions classified as T2a-b in the intermediate PSA ranges, nor were they different in tumor volume.16 They may therefore be regarded as equally significant for prognosis. This implies that at present DRE is important mainly in the clinical staging of detected tumors. Transrectal Ultrasonography The value of TRUS for screening has not always been analyed from a purely scientific point of view. Transrectal ultraTABLE 10–3. Cancers Found by DRE Below a PSA Cutoff Value of 4 ng per mL Author, Year Crawford, 199653 Smith, 199725 Mettlin, 199341 Lodding, 199855 Schröder, 19984

PSA < 4

DRE+

PCa

PPV (%)

28,846

3032

78

14.6

16,926

1433

143

12.4

2999

260

29

11

243

55

11

20

7055

639

82

12.8

Remark Low biopsy compliance Low biopsy compliance DRE and/or TRUS positive PSA range 3.0–4.0 Mean tumor volume 0.5 mL

DRE = digital rectal examination; PCa = prostate cancer; PPV = positive predictive value; PSA = prostate-specific antigen; TRUS = transrectal ultrasonography.


sonography is time consuming and therefore of considerable cost; two adverse factors for a screening program. Furthermore, TRUS is operator-dependent, and its interpretation learning curve is considerable. Though studies for intra- and interobserver reproducibility have been limited to volumetry of the prostate gland, most experts on TRUS will agree that only larger lesions are readily recognizable. Cancers will be most frequently heralded by hypoechogenic lesions, and fewer than half the biopsied hypoechogenic lesions in clinical series will show histologic malignancy.56 Evaluation of TRUS for detection of PCa in a screening setting is limited to a small number of studies. Mettlin reported on the multicentered screening effort of the ACS-NPCDP, in which the use of TRUS led to twice the number of biopsies compared to DRE in the first screening round (14.1 versus 6.7%).57 The PPV of TRUS by itself was 6% compared to 7.8% for DRE only. In the Rotterdam component of the ERSPC, TRUS was performed on all 3963 participants during the period 1992 to 1997, independent of DRE or PSA results.4 As biopsies were indicated on abnormal DRE or a raised PSA level (> 4 ng per mL), the results of TRUS-driven biopsies differ among those with one or more biopsy indications. With TRUS as sole indicator (PSA < 4 ng per mL), a PPV of 6.7% was shown, to that of DRE (8.1%) as sole indicator, approximating Mettlin’s results. The number of biopsies required to detect one cancer was 11.2 for TRUS and 10.0 for DRE. Remarkably, biopsies indicated by a combination of an abnormal TRUS and DRE in this low PSA range showed cancer in approximately 20% of men biopsied, which is similar to biopsies indicated by an increased PSA of more than 4 ng per mL. The apparent efficacy of cancer detection by the TRUS/DRE combination, however, is flawed by the characteristics of the detected tumors, as the mean tumor volume was 0.5 mL while the mean tumor volume in the PSA range between 4 and 10 ng per mL was 1.22 mL. These results motivated the change of the Rotterdam screening protocol in 1996 to screening with PSA only. The TRUS procedure has always been regarded as an important adjunct in guiding prostate biopsy. In protocols in which TRUS was not incorporated as a primary screening tool, application of TRUS during the biopsy procedure revealed suspicious lesions that were biopsied in addition to or instead of the usual random biopsies. The value of these extra biopsies appeared to be minimal, as discussed above. Currently, TRUS is considered by few to be of additional value in staging prostate cancers. Ongoing efforts to establish automated interpretation of gray-scale images may improve its diagnostic performance. Intravenous administration of ultrasonic contrast agents for the application of color-Doppler ultrasonography enhances tumor recognition for experienced clinicians.57 In screening for prostate cancer, however, TRUS currently has no role apart from its value of visualizing the prostate gland.

Prostate-Specific Antigen Isoforms With the discovery of PSA isoforms in the serum, a new era in tumor markers began. Prostate-specific antigen was found to circulate as a free, uncomplexed molecule in the blood or to bind to a number of serum proteins, of which α-antichymotrypsin (ACT) and α2-macroglobulin appeared predominant.58 The complexing process influenced some of the normally available antigenic sites on the free PSA molecule in such a way that various antibodies could no longer detect the PSA molecule. This phenomenon offered the opportunity to measure free and complexed forms, as complexing differed in men with prostate malignancies compared to those without.29 No obvious metabolic explanation for this phenomenon has yet been found. As ACT is abundantly available in the circulation but ACT production is increased within some prostate cancer cells as well as in cells found in hyperplastic nodules,59 research is ongoing to find an intracellular mechanism for complex formation.60 New assays for determining different forms of complexed PSA and for other members of the kallikrein family, such as the human glandular kallikrein hK2, are on the horizon. The binding of PSA to ACT was the first complex studied. Assays were developed measuring the free fraction compared to the total serum PSA concentration. This was expressed as a percentage, or as the free-to-total ratio (FT ratio). The FT ratio of men with PCa was on average lower compared to those without PCa but a considerable overlap between the distribution of these values existed in clinical series.61 Further, it became evident that due to the specific affinity of antibodies for their antigenic site, the total PSA value could be influenced. Assays were reported to be equimolar when the affinity of the antibody used for total PSA determination was equal between free and complexed PSA forms, resulting in the same total PSA value for any FT ratio. Although total PSA determinations theoretically may decrease due to this “skewed response,” these alterations are most likely of minor importance compared to the previously discussed physiologic changes of PSA. The mean variation of the FT ratio appears to be 15% over several weeks and not influenced by age or total PSA level.62 The determination of a useful cutoff level for the FT ratio has remained an obstacle. Although the FT ratio does not change significantly with age,63 it does increase with prostate volume. An extensive review of primarily clinical studies analyzing the application of the FT ratio concluded that specificity can be increased by use of the FT ratio. It remains unclear, however, how to use it (for what patient group, at which cutoff level), necessitating extensive multicentered studies for further assessment.64 Initial optimism that the FT ratio would improve cancer detection and reduce the number of negative biopsies has thus been tempered. The above article shows a figure of Van Cangh illustrating the dependency of the cancer


probability predicted by the FT ratio in different populations with variable cancer prevalence.65 In a number of reports the improved specificity of a test is based on a significantly larger area under the ROC curve. This indicates an overall quality of the test while the curves may assist in illustrating and choosing a cutoff level. Unfortunately, the statistical significance does not imply a clinically important advantage. In well-defined subsets of men, the use of the FT ratio in addition to PSA might be safe and justified when it has been assessed ultimately in connection with the characteristics of the cancers detected. In screening settings, the application of the FT ratio appeared potentially valuable when used in the intermediate PSA range between 4 and 10 ng per mL although it remained unclear which cutoff value to use. The reduction of the number of biopsies, however, may not be outweighed by the loss of the number of detectable cancers. Moreover, the cancers lost for detection were all histologically confined to the prostate.66 In the lower PSA range, no study has been performed in which the FT ratio was used as an indication for biopsy in all participants. For the PSA range from 2.5 to 4 ng per mL, Catalona found enhanced cancer detection in 332 men with normal DRE when biopsies would be indicated by the FT ratio.67 Catalona recommended performing biopsies when the FT ratio was below the cutoff value of 27%. This suggests, however, that too many false-positive indications for biopsy would be indicated by the FT ratio.68 In the PSA range above 10 ng per mL, the FT ratio appears universally low, and its use to exclude men from biopsy with a high FT ratio does not seem to be justified due to the strong probability of cancer suggested by PSA alone. Only a few studies exist that attempt to compare the use of the FT ratio to other additional modalities, such as PSAD or age reference values. For the PSA range between 3 and 4 ng per mL, Lodding calculated that the use of the optimal combination of FT ratio and PSAD in men with normal DRE would have reduced the number of biopsies indicated by a PSA > 3 ng per mL by 21% (from 217 to 172), resulting in a sensitivity for PCa of 93%.55 This was better than use of a single modality, as they each reduced the number of biopsies 10 to 12% at the same level of sensitivity. Bangma reported that the combined use for men from a screening population with a PSA between 4 and 10 ng per mL would reduce the number of biopsies by 40% at a cost of missing 12% of cancers.66 Of the cancers detected by FT ratio, 85% were the same as those detected by PSAD. It remains an intriguing question whether there is a fundamental relationship between the different concepts of PSAD and the FT ratio. The effect of a decreased FT ratio or an elevated PSAD is theoretically higher when the partial tumor volume in the prostate is larger compared to that of the normal tissue. So far, reports about the improved specificity of the FT ratio for prostate cancer in specific volumetric ranges of the prostate gland are

clinically based and no additional value has been found in screening populations.

Sequential Screening The performance of diagnostic tests has thus far been highlighted for first-round screening only. Several largescale screening protocols have included follow-up visits for participants with negative results during initial evaluation. Some of these studies have reported on intermediate results.48,57,69 Clearly, the composition of the screened population changes after filtering out detectable cancers with each screening round.57 Therefore, subsequent results of the application of screening tools will change. One modality adequate for first-round screening might be worthless for further screening. On the other hand, newly applied tools may be useful. Prostate-specific antigen velocity might be such a tool. In small retrospective studies, an exponential increase in the PSA level was observed during the 5-year period previous to cancer diagnosis. This PSA change correlated roughly with the cancer stage at the time of diagnosis. Increase in PSA, often expressed for reasons of simplicity in ng per mL per yr (PSA velocity), has been analyzed in several screening settings.57,70,71 The cutoff value of 0.75 ng per mL per year, proposed by Carter and based on observations in a selected group of patients with PCa, did not have any discriminatory value over a study period of 1 year.71 In Mettlin’s study57 extending over 5 years, men with PCa appeared to have, in almost 50% of cases, a PSA increase of more than 0.5 ng per mL per year compared to 12% of men with benign prostates. It is not clear from this study how many observations were involved or the mean observation period until the diagnosis of cancer. It is obvious, however, that an increase of 0.5 ng per mL per year cannot be justified as a biopsy indication when 12% of participants without disease show the same increase. The correlation between the risk of carcinoma and an increasing serum PSA has been observed, but biologic variation of serum PSA is the main obstacle to the clinical application of these changes. Kadmon confirmed the considerable biologic variation of PSA in men without prostate cancer in a screening population. He advised at least three annual PSA measurements before an increase in PSA should be considered abnormal.72 In 327 men aged 50 years or older who had previous negative biopsies in a screening setting, PSAD or a PSA increase of more than 0.75 ng per mL annually (measured over a variable time period) in the presence of an elevated PSA or abnormal DRE could not stratify adequately between benign and malignant disease.73 In general, it should be expected that the cancer detection rate decreases after the first screening and levels off after several evaluations. Tumors may become smaller and more difficult to detect by palpation and ultrasonography unless they are of a fast-growing character. Further, some of the detected tumors will be those that had been


missed by previous biopsies due to sampling error. This general trend of decreasing incidence has been observed by Stephenson3 as well as by the ACS-NPCDP.57 In this multicentered study, the first round incidence of 2.8% decreased to a value of 1.1 to 2.1% during subsequent years. During the 5 years of follow-up, 203 cancers were detected with DRE, TRUS, and PSA in 2999 men aged 55 to 70 years, of which 1575 completed five visits. The PSA level, PSAD, and PSA change were all related to the presence of cancer, but due to the mixed screening designs of participating centers the exact value and optimal use of the various screening modalities is difficult to assess. It was reported that TRUS and DRE became less effective indicators for positive biopsies over time. In the primary screening round of the Rotterdam section of the ERSPC, 1875 of 8013 men had been biopsied for suspicious findings on DRE or TRUS or an elevated PSA, of which 374 (20%) harbored a malignancy.4 Those with negative biopsy results were screened again after 1 year, and 442 biopsy procedures were performed in 984 men. Prostate cancer was found in 49 men (11%). The pathologic tumor characteristics and tumor volumes after radical prostatectomy of 11 of these rescreened men were not significantly different from those found in the first screening round. The fraction of well-differentiated smaller sized tumors appeared to be equal in both screening rounds. The average size of the prostate glands in which they were detected, however, was significantly larger (53.4 mL versus 43.6 mL) than those in which PCa was diagnosed during the first screening. This suggests that they were the result of sampling error at the first biopsy, rather than the presence of a rapid growing or aggressive type of PCa.

Choosing the Best Screening Tools The choice of optimal screening tools depends on the population characteristics and attitudes toward participant comfort, scientific goals, local opportunities, and costs. These factors may differ worldwide and may change with maturation of screening data. Adjustments to screening protocols should be based firmly on data obtained from our own or comparative studies,22 rather than on gradual changes made by individual contributors within multicentered projects.57 Multivariate analysis of factors involved and subsequent statistical simulations based on significant risk factors are important steps in evaluating and redesigning screening strategies. Until screening endpoints in terms of mortality and quality of life are evaluable, intermediate endpoints such as tumor detection followed by pathologic and prognostic characteristics of detectable cancers should be used to evaluate and determine optimal screening modalities. Limitations of current screening tools may be summarized as follows:

• The drawbacks of the gold standard, which is a set of ultrasound-guided sextant prostate biopsies, are known, but it is not known whether a change of method or technique will be advantageous. • Simple and excellent serum tools (PSA and FT ratio) are available, but biologic variation limits their serial application. • Cancers can be identified much better than 10 years ago, but it is not known to what extent screening tools correlate with the clinical significance of the disease. • There may be enough information about the various screening tools to design nomograms to increase specificity in the prediction of prostate cancer, but their application is restricted due to considerable confidence ranges. It is likely that in the very near future, information will become available that will force project managers to tailor protocols to subgroups of specific age, race, or participants for follow-up. It has already become clear that positive family history, African American origin, or the histologic finding of prostatic intraepithelial neoplasia are conditions representing an increased risk of harboring or developing prostate cancer. One of the major goals for PCa detection programs is to distinguish the bad from the relatively benign cancers. Regardless of screening tools, numerous cancers are found, enough to determine the differences in mortality in screened and unscreened populations. Whenever randomized screening studies prove that prostate screening is at all justified, accurate current and future data will be indispensable to formulate optimal screening regimens.

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58. Lilja H, Cockett AT, Abrahamsson PA. Prostate-specific antigen predominantly forms a complex with alpha 1antichymotrypsin in blood. Implications for procedures to measure prostate-specific antigen in serum. Cancer 1992;70:230–4. 59. Bjork T, Bjartell A, Abrahamsson PA, et al. Alpha 1antichymotrypsin production in PSA-producing cells is common in prostate cancer but rare in benign prostatic hyperplasia. Urology 1994;43:427–34. 60. Bjartell A, Bjork T, Matikainen MT, et al. Production of alpha-1-antichymotrypsin by PSA-containing cells of human prostate epithelium. Urology 1993;42:502–10. 61. Christensson A, Bjork T, Nilsson O, et al. Serum prostatespecific antigen complexed to alpha 1-antichymotrypsin as an indicator of prostate cancer. J Urol 1993;150:100–5. 62. Ornstein DK, Smith DS, Rao GS, et al. Biological variation of total, free, and percent-free serum prostate-specific antigen levels in screening volunteers. J Urol 1997;157: 2179–82. 63. Oesterling JE, Jacobsen SJ, Klee GG, et al. Free, complexed, and total serum prostate-specific antigen: the establishment of appropriate reference ranges for their concentrations and ratios. J Urol 1995;154:1090–5. 64. Woodrum DL, Brawer MK, Partin AW, et al. Interpretation of free prostate-specific antigen clinical research studies for the detection of prostate cancer. J Urol 1998;159:5–12. 65. Van Cangh PJ, De Nayer P, De Vischer L, et al. Free-to-total prostate-specific antigen (PSA) ratio improves the discrimination between prostate cancer and benign prostatic hyperplasia (BPH) in the diagnostic gray zone of 1.8 to 10 ng per mL total PSA. Urology 1996;48:67–70. 66. Bangma CH, Rietbergen JB, Kranse R, et al. The free-tototal prostate-specific antigen ratio improves the specificity of prostate-specific antigen in screening for prostate cancer in the general population. J Urol 1997; 157:2191–6. 67. Catalona WJ, Smith DS, Ornstein DK. Prostate cancer detection in men with serum PSA concentrations of 2.6 to 4.0 ng per mL and benign prostate examination. Enhancement of specificity with free PSA measurements. JAMA 1997;277:1452–5. 68. Bangma CH, Kranse R, Blijenberg BG, Schröder FH. The value of screening tests in the detection of prostate cancer. Part II: Retrospective analysis of free/total prostate-specific analysis ratio, age-specific reference ranges, and PSA density. Urology 1995;46:779–84. 69. Smith DS, Catalona WJ, Herschman JD. Longitudinal screening for prostate cancer with prostate-specific antigen. JAMA 1996;276:1309–15. 70. Brawer MK, Beatie J, Wener MH, et al. Screening for prostatic carcinoma with prostate-specific antigen: results of the second year. J Urol 1993;150:106–9. 71. Carter HB, Epstein JI, Chan DW, et al. Recommended prostate-specific antigen testing intervals for the detection of curable prostate cancer. JAMA 1997;277: 1456–60. 72. Kadmon D, Weinberg AD, Williams RH, et al. Pitfalls in interpreting prostate-specific antigen velocity. J Urology 1996;155:1655–7. 73. Keetch DW, McMurtry JM, Smith DS, et al. Prostatespecific antigen density versus prostate-specific antigen slope as predictors of prostate cancer in men with initially negative prostatic biopsies. J Urol 1996;156: 428–31.

CHAPTER 11

SCREENING FOR PROSTATE CANCER: THE CASE FOR SCREENING ROBERT J. NEJAT, MD; CHRISTOPHER W. JOHNSON, MD; MITCHELL C. BENSON, MD The American Cancer Society (ACS) estimates that there will be 179,300 new cases of prostate cancer diagnosed in 1999, making it the most commonly diagnosed malignancy among men in the United States. In addition, a projected 37,000 men will die this year secondary to prostate cancer. As a result, the ACS and the American Urological Association (AUA) have put forth guidelines recommending that annual serum prostate-specific antigen (PSA) testing and digital rectal examination (DRE) be offered to men aged 50 and older who have at least a 10-year life expectancy. The PSA and DRE should also be offered to younger men at high risk for developing prostate cancer, such as African American men or men with a strong family predisposition to the disease (two or more affected first-degree relatives, e.g., father, brother). Information should be provided to patients regarding the risks and benefits of intervention.1 In order for prostate cancer screening to be deemed a successful and worthwhile endeavor, three separate and distinct goals must be satisfied. First, we have to demonstrate that screening increases the diagnosis of earlier stage prostate cancer. Second, we have to prove that patient survival is prolonged, and lastly, a decrease in the prostate cancer–specific mortality rate has to be demonstrated. There is a large body of evidence to support the theory that prostate cancer screening increases the diagnosis of earlier stage prostate cancer.2–5 The incidence of newly diagnosed, organ-confined prostate cancer has risen significantly since the introduction of PSA testing. Conversely, the diagnosis of previously untreated, metastatic prostate cancer has plummeted.4–6 To fulfill our second goal, we must provide evidence that patient survival is prolonged by screening. Earlier diagnosis leads to prolonged survival by definition. Leadtime bias is the expected increase in survival related to earlier diagnosis. If a patient undergoes screening for prostatic disease and is diagnosed 3 years before he would have presented clinically, the screening test would have increased the patient’s life from time of diagnosis to an endpoint (e.g., death) by 3 years, thereby prolonging survival. Gann and colleagues, in a prospective study of frozen serum samples, estimated that PSA testing pro-

vided an average 5.5-year lead time in the diagnosis of clinically significant prostate cancer.7 Therefore, the first two prerequisites of any screening program have been satisfied by the use of serum PSA and DRE. The last objective of screening is to decrease the prostate cancer death rate and this remains to be definitively proven. However, there is a body of evidence amassing that leads us to conclude that this prerequisite will be satisfied. Given current technology, screening for prostate cancer will always be associated with error. This is because the only way one can exclude a diagnosis of prostate cancer with 100% certainty is to remove the entire prostate and to step section the entire gland with histologic examination. This is clearly both impractical and excessively invasive. However, anything short of total evaluation of the entire prostate will have a reduced sensitivity, that is, some cancers will be missed owing to sampling error. The issue of whether or not to screen American men for prostate cancer has been a subject of debate.8–13 Opponents argue that screening only benefits a select group of patients with clinically aggressive, organconfined disease, and they believe that treatment of most cases of prostate cancer detected by screening is either ineffective (i.e., tumor not organ-confined) or unnecessary (i.e., tumor not biologically significant). They further maintain that screening results in substantial economic cost, morbidity, and anxiety that are not justified by an increased detection of disease. Finally, and the most valid argument, is the fact that no prostate cancer screening program has been demonstrated to decrease mortality in a prospective, randomized, controlled trial. Those in favor of screening, including the authors, argue that prostate cancer is a major illness killing about as many men as breast cancer kills women, and that only through screening can this disease be brought under control. Waiting until the benefits of screening have been definitively proven could cost thousands of men their lives. The morbidity of treating early disease is in many instances less than the morbidity of treating advanced disease. Lastly, the economic considerations of screening should not weigh against this endeavor unless screening is proven to be of no benefit. Given the current data, the economic onus is on those who are against, rather than those who are in favor of screening. 73


Screening by Digital Rectal Examination Before the widespread clinical use of PSA, DRE was the most common initial test for the diagnosis of prostate cancer. While several earlier reports have concluded that annual screening using DRE leads to improved early detection of disease and prolonged survival,14,15 other studies contradicted these findings.16,17 The limitation of DRE as a screening test appears to be its poor sensitivity in detecting curable (i.e., pathologically organ-confined) disease. In fact, approximately 40 to 60% of men with clinically localized prostate cancer detected by annual DRE have local or systemic spread of disease when pathologic staging is available.14,16,18 In addition, a study by Gerber and colleagues that evaluated disease-specific survival following routine screening by DRE in over 4000 men suggests that this approach will not decrease the mortality rate from prostate cancer.17 The investigators compared cancers diagnosed during the initial screen (prevalence group) with those identified during subsequent screens (the incidence group). It was hypothesized that the cancer-specific mortality would be lower in the incidence group. In fact, the cancer-specific mortality was significantly higher in this group. These findings led to the conclusion that routine screening by annual DRE may be insufficiently frequent and/or sensitive to prevent significant mortality from prostate cancer. The limitations of DRE as a sole screening modality have been further clarified by Flanigan and colleagues.19 In a multicenter study, more than 6000 men underwent screening by DRE and PSA. An abnormal result in either screening test led to a recommendation of transrectal ultrasonography (TRUS) with four-quadrant prostate biopsy. Of the 624 men who underwent biopsy, 1002 quadrants were suspicious by DRE, and 110 (11%) contained cancer. The positive biopsy rate for nonsuspicious quadrants was 9% (p = .97) and was statistically no different from that of a suspicious quadrant. In fact, 74% of cancers were diagnosed in prostate quadrants normal to palpation. In summary, it is clear that more clinically localized cancers can be detected through the use of annual screening by DRE. Unfortunately, a significant percentage of these tumors have already spread beyond the prostatic capsule at the time of diagnosis, rendering a cure unlikely. Therefore, although we are strongly in favor of prostate cancer screening and recognize that DRE is an extremely inexpensive screening tool, we do not believe that DRE alone will satisfy the three necessary prerequisites of successful screening.

Screening by Transrectal Ultrasound Following the introduction of transrectal ultrasonography of the prostate, there was a great deal of enthusiasm regarding its use in the early detection of prostate cancer. It was felt that TRUS would be able to detect many non-

palpable small tumors that were missed by DRE alone.20 However, studies have shown that TRUS has several limitations with regard to its use as a screening test for prostate cancer. Most importantly, TRUS has low positive and negative predictive values, which were reported to be 36 and 89%, respectively, in one study.21 Cooner and colleagues reported the positive predictive value of TRUS to be only 16% in men with a palpably benign prostate.22 This number drops to 9.8% when both DRE and PSA are normal. Additional limitations of TRUS as a screening tool include the procedure’s invasiveness, cost, and limited detection rate when the less invasive DRE and PSA are normal. It is the authors’ belief that the major value of TRUS is its ability to allow for anatomic sampling of the prostate when other screening tests are abnormal.

Screening by Prostate-Specific Antigen Since the late 1980s there has been an unquestionable increase in the detection of prostate cancer and the diagnosis of curable disease.4 Since DRE and TRUS have been shown to be ineffective screening tools, most epidemiologists relate this dramatic rise to PSA-based screening. Regarding PSA’s ability to improve detection of curable disease, one may compare stage at time of diagnosis. According to Jacobsen and colleagues, the incidence of clinically organ-confined prostate cancer increased from 61% in the pre-PSA era (i.e., DRE-detected cancers) to more than 90% in the post-PSA era.23 The incidence of pathologically organ-confined disease showed a similar upturn from an average of 33% before the widespread use of PSA testing, to as high as 70% following the introduction of PSA into community medical practice.3,16 In large PSA-based prostate screening trials involving thousands of men, cancer detection rates have ranged from 1.5% to 4%. The positive predictive value of PSA testing in these trials has varied between 11 and 34%. The false-negative PSA values were felt to be due to the relatively high incidences of benign prostatic hyperplasia (BPH) and subclinical prostatic inflammation in the screening population.24–27 Brawer and associates screened 1249 men over the age of 50 with serum PSA levels.25 Men with a PSA value greater than 4.0 ng per mL were further evaluated by DRE and TRUS-guided biopsy. A total of 187 men (15%) had an elevated PSA. In the 105 men who underwent biopsy, a total of 32 carcinomas were identified (31%). Mettlin and colleagues reported on a series of 2999 men aged 55 to 70 years who were screened for prostate cancer using PSA, DRE, and TRUS.28 Of the 164 patients that were found to have tumors, 103 underwent radical prostatectomy and 64 (62%) had pathologically organ-confined disease. In 1994, Catalona and colleagues published a multicenter study involving 6630 men aged 50 and above who underwent testing with serum PSA and DRE.27 Of the 14.8% of men

Screening for Prostate Cancer: the Case for Screening / 75

with a PSA greater than 4 ng/mL, 32% were found to have prostate cancer. Thus, the cancer detection rate for PSA was 4.6%. Again, PSA played a primary role in the diagnosis of pathologically localized disease. Of the 160 patients who underwent radical prostatectomy, 114 (71%) had pathologically organ-confined disease. In fact, the use of PSA and DRE in combination increased detection of organ-confined disease by 78% over DRE alone. In summary, it is the belief of the authors that PSA plays a vital role in the detection of early-stage curable prostate cancer. Serum PSA determinations should be the central modality of prostate cancer detection at this time. However, cancer detection rates, positive predictive value of PSA testing, and the possibility of false-positive results need to be discussed with patients prior to PSA-based screening.

PSA Derivatives The sensitivity of PSA has never been questioned. It is the test’s lack of specificity (i.e., the number of false-positives that result in invasive evaluations) that has caused most concern. In an attempt to improve specificity, several investigators have tried to modify the interpretation of PSA values. These modifications have been termed PSA derivatives. Numerous PSA derivatives have been developed and tested clinically with the purpose of optimizing the use of PSA as a screening tool. This can only be achieved by increasing the test’s specificity while preserving its sensitivity. PSA Density PSA density (PSAD) is one such variation and is defined mathematically as total PSA (ng/mL) divided by the volume of the prostate gland (cc). The concept of PSAD is based on the assumption that the PSAD calculation would standardize the amount of PSA produced per cubic centimeter of prostate tissue. A volume occupied by cancer will result in a higher serum PSA than a volume occupied by benign tissue. It was postulated that PSAD would be able to identify which patients had an elevated PSA secondary to benign enlargement, BPH, versus those with elevations secondary to prostate carcinoma.29 The concept of PSAD was introduced at ColumbiaPresbyterian Medical Center by the authors in collaboration with Dr. William Cooner of Mobile, Alabama. The objective was to derive a means of decreasing the number

TABLE 11–1. Age- and Race-Specific Reference Ranges for Prostate-Specific Antigen Serum PSA (ng/mL) Age 40–49 50–59 60–69 70–79

Caucasian

Japanese

African American

0–2.5 0–3.5 0–4.5 0–6.5

0–2.0 0–3.0 0–4.0 0–5.0

0–2.0 0–4.0 0–4.5 0–5.5

of false-positive PSA results and thus the number of unnecessary biopsies. An analysis of 773 patients with a normal DRE and a PSA between 4 to 10 ng per mL who subsequently underwent TRUS led to the proposal of a PSAD cutoff value of 0.15 mg per mL. In this preliminary study, only patients with an abnormal TRUS (hypoechoity or asymmetry) underwent an initial biopsy. The positive prostate biopsy rate in this group was 6% for patients with a PSAD less than 0.15 versus 18% for patients with a PSAD greater than 0.15.30 Another investigation by Bazinet and colleagues confirmed these findings.31 In their study, 142 patients with a negative DRE and a PSA between 4 to 10 ng per mL underwent prostate biopsy. They noted that only 2 patients who had a PSAD less than 0.15 biopsied positive, while 20 patients had positive biopsies with a PSAD greater than 0.15. Despite these encouraging initial data, other studies have failed to confirm improved cancer detection rates using PSAD compared with total serum PSA.32,33 Factors responsible for the conflicting results and conclusions may involve anatomic and technical difficulties in determining prostate volume, lack of uniformity regarding the statistical analysis applied to the different studies, and the fact that the epithelial-stromal ratio differs considerably from patient to patient. Differences in the amount of epithelium versus stroma in an individual’s prostate allow for a wide range of PSA production in prostates of similar volume. Because of these observations, PSAD as a means of increasing the specificity of serum PSA testing is not universally accepted. Age-Specific PSA An age-specific reference range for serum PSA is a variation of total PSA which was designed to increase sensitivity in younger men and to increase specificity in older men. The concept of age-specific PSA follows that as most men get older they develop BPH, with a resultant increase in their prostate size and an increase in their serum PSA. In a community-based study, Oesterling and colleagues enrolled 537 men aged 40 to 79 into a screening protocol that included serum PSA, DRE, and TRUS.34 Of the 537 men, 471 had all three tests performed without any evidence of prostate cancer. Utilizing this subset of patients, they correlated serum PSA with age and prostate volume. The results indicated that PSA increased by 0.04 ng per mL (3.2%) per year. From these data, using 95th percentile confidence limits, age-specific reference ranges for serum PSA were developed (Table 11–1). Several investigators have tested this hypothesis and examined its clinical usefulness in lowering the normal PSA value in younger men and raising the normal value in older men. It appears that lowering the normal range in younger men is valid and appropriate. In a multiinstitutional study, Catalona and colleagues utilized a patient population base consisting of 6630 men undergo-


ing PSA and DRE screening followed by TRUS, with prostate biopsy for those with abnormal results.35 They reported that a cutoff of 3.5 ng per mL in men 50 to 59 years old resulted in a 15% increase in cancer detection versus a cutoff of 4.0 ng per mL. Partin and colleagues studied a population of clinical stage T1c prostate cancer who had undergone radical prostatectomy.36 The authors concluded that in men younger than 60 years, a significant number of additional tumors would be detected by using age-specific ranges. Thus, it appears that the PSA cutoff of 4.0 ng per mL may be too high for younger men. However, it must be taken into consideration that the added sensitivity of a lower PSA cutoff would be at the cost of decreased specificity and the resultant added morbidity (more falsepositive results leading to more negative biopsies). The validity of increasing the normal PSA range in older men is less established. Had age-adjusted reference ranges been used in the Catalona study, men aged 60 to 69 would have undergone 15% fewer biopsies.35 However, 8% of organ-confined tumors would have been missed in this age group. In men older than 70, 44% fewer biopsies would have been performed with 47% of organconfined cancers missed. Partin and colleagues also made the observation that raising the PSA range for older men would result in decreased sensitivity, but they also raised the question of clinical significance and clinical consequence of the missed tumors.36 In summary, investigators support the theory that the use of age-specific reference ranges would improve the sensitivity of PSA in younger men, allowing for the diagnosis of more organ-confined prostate cancer. For now, most experts are unwilling to raise the upper limit of normal in older men. Race and Age-Specific PSA The database that led to the development of age-specific ranges for PSA was composed almost entirely of Caucasian men. It has been known for a long time that Asian men generally have smaller prostates and a lower incidence of prostate cancer than Caucasian or African American men. African American men have the highest incidence of prostate cancer in the world.37 These facts led investigators to evaluate the effect of race on age-specific ranges. Oesterling and colleagues performed a study similar to the one outlined above in an attempt to clarify age-specific reference ranges in Japanese men.38 The resulting age-specific ranges for Japanese men are posted in Table 11–1. Morgan and colleagues completed a study examining age-specific reference ranges in African American men.39 This study confirmed that the PSA concentration correlates with age, and that the upper limit of normal serum PSA should also be age dependent in African Americans. Morgan determined that if traditional age-specific reference ranges were used as outlined by Oesterling for Caucasian men, 41% of cancers in their African American

cohort would have been missed. The age-specific reference ranges for African Americans are also listed in Table 11–1. The differences appear minor, but they have tremendous clinical significance because it is in African Americans that prostate cancer is more prevalent; it occurs at an earlier age, and it has the highest mortality rate. PSA Velocity Another derivative used to improve PSA screening is known as PSA velocity (PSAV). Utilizing data and frozen serum from the Baltimore Longitudinal Study of Aging, Carter and colleagues were able to plot the PSA values of 73 men, aged 60 or older, over a 7-year period.40 They observed that men without prostate symptoms or prostate cancer had little change in their PSA value over time. Patients with BPH had a linear slope of PSA velocity, while patients with prostate cancer had an initial linear component that became exponential. Investigators calculated PSAV with an equation utilizing at least three separate points and suggested that a PSAV greater than 0.75 ng per mL per year was suspicious for prostate cancer. The “normal” PSAV was examined by several studies including one by Smith and Catalona, which prospectively enrolled 982 men to examine the efficacy and utility of PSAV.41 This study calculated that for patients with a PSA less than 4.0 ng per mL, the cutoff PSAV predictive of cancer was 0.75 ng per mL per year. However, for patients with PSA greater than 4.0 ng per mL, the cutoff point which predicts cancer was 0.4 ng per mL per year. The major question surrounding PSAV is how many serum measurements are required and how far apart they should be spaced. Carter and colleagues addressed these issues by retrospectively examining serial PSA measurements in 806 men.42 They focused on the number of PSA determinations, the time interval between PSA measurements, and the effect on the calculated PSAV. The authors concluded that three or more values with time intervals greater than 6 months between readings are necessary to determine velocity. This severely limits the clinical utility of PSAV, in that it is of greatest value retrospectively, and of least value when the PSA determinations occur within 1 year of each other. Therefore, at a minimum, 2 years of PSA determinations are required to accurately stratify patients by PSAV. With this lengthy time frame, patient anxiety and the possibility of disease progression become issues which push toward an early biopsy. As a result, PSAV would appear to be of greatest utility in men who have already undergone a biopsy which proved negative for cancer. Free to Total PSA Ratio One of the more recent PSA derivatives is the comparison of unbound (free) PSA to the total amount of PSA in the serum. The PSA can exist as free PSA and as PSA bound to α1-antichymotrypsin (ACT) or α2-macroglobulin

Screening for Prostate Cancer: the Case for Screening / 77

(A2M).43,44 The PSA bound to A2M (PSA-A2M) is antigenically shielded and not measurable by any PSA assay. The PSA-ACT complex, however, is immunoreactively unique and can be measured in the serum as a separate moiety. As a result, it is possible to compare the amount of free PSA to the total amount of PSA (free + PSAACT). Lilja and colleagues documented that the majority of PSA in the serum is complexed to ACT, accounting for approximately 85% of the total serum PSA.44 They later compared the ratio of free:total (FT) PSA in men with BPH to the FT PSA of men with prostate cancer. They found that the FT ratio was significantly lower in men with prostate cancer than men with BPH (18 versus 28%, respectively, p < .0001).45 Importantly, this difference was present for PSA values above and below 10 ng per mL. They concluded that the use of FT PSA ratio would allow for a differentiation of elevated PSA levels secondary to BPH and prostate cancer without decreasing the sensitivity of PSA. The explanation of why PSA secreted from BPH is less likely to be bound to ACT (higher FT ratio) may be found within prostate cancer cells. Bjork and colleagues found that prostate cancer cells produce not only PSA, but also ACT. This coexpression of PSA and ACT may allow for an increased likelihood of a PSA-ACT complex when PSA is expressed from a cancer cell as opposed to a benign cell.46 However, this is only speculative and the reason or reasons behind the observed FT differences remain unknown. Regardless of the explanation for the increased PSAACT complex in PSA expressed from prostate cancer cells (lower FT ratios), FT PSA ratios improve PSA specificity for patients with serum PSA levels in the 4 to 10 ng per mL range (Table 11–2). The use of Hybritech’s FT PSA has been granted approval from the Food and Drug Administration, and FT ratios from other companies are expected to be approved in the near future. However, FT PSA, like the other PSA derivatives, is not without controversy. A universal FT PSA cutoff has yet to be established, and it appears that like PSAD and age- and race-specific PSA, the resultant increases in specificity are at the cost of decreases in sensitivity.

The Status of Screening There are reports that support the notion that since the introduction of PSA in the late 1980s, PSA-based prostate cancer screening has led to dramatic changes in the epidemiology of the disease, which are suggestive of effective screening.4,23 Data supplied by the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database from 1973 to 1994 have shown a substantial increase in the number of newly diagnosed cases of prostate cancer. This trend accelerated when PSA use became widespread in the late 1980s. New prostate cancer

TABLE 11–2. Percent of Free to Total PSA Ratio and Cancer Probability Ratio (%) 0–10 10–15 15–20 20–25 > 25

Probability of Cancer (%) 56 28 20 16 8

cases peaked in 1992 and have since declined. However, the incidence has not fallen back to pre-PSA screening levels. In addition to the drastic changes in the number of cases of prostate cancer during the PSA-testing era, there has been a downward shift in the age at which the disease is diagnosed.4 Perhaps more significant, however, is the increased proportion of tumors that are organ-confined at the time of diagnosis.4 Tumors diagnosed by PSA have a 70 to 80% chance of being organ-confined compared to only 20 to 30% in the pre-PSA era.2–4 A trend toward the diagnosis of moderately differentiated tumors has also become apparent. Indeed, organ-confined moderately differentiated disease now comprises 36% of tumors being diagnosed today. This is a significant increase from 22% prior to the PSA era. Also consistent with, but not definite proof of, the introduction of effective screening is the reduction of mortality secondary to prostate cancer. In 1996, the National Center for Health Statistics reported a 6.3% decrease in prostate cancer mortality in the United States.47 This was the first time such a decline had been reported. Since then, the data coming out of Quebec and Canada have confirmed this trend.48 After 1991, prostate cancer mortality rates declined moderately until 1995, and then more dramatically in 1996. Age-standardized prostate cancer mortality rates declined by 23% in Quebec between 1991 and 1997, and by 9.6% in Canada between 1991 and 1996. There are currently large well-designed, randomized, controlled trials underway both in the United States and Europe. The National Cancer Institute is running the Prostate, Lung, Colorectal, Ovarian (PLCO) screening trial that will last 16 years and involve 74,000 men who will be screened for prostate cancer with PSA and DRE at more than 10 screening centers across the country.49 The European Randomized Study of Screening for Prostate Cancer (ERSPC) will follow 172,000 men over 15 years.50 Preliminary data from these studies will not be available for 10 years, but they are anxiously awaited. A recent study by Labrie and colleagues was the first prospective, randomized, controlled prostate cancer screening trial published to date.51 The study enrolled 46,193 male voters from Quebec City aged 45 to 80. Screening invitations were mailed by random selection to 30,956 (67%) men. The remaining one-third of patients served as nonscreened controls. Prostate cancer screening consisted of a


serum PSA determination and DRE at the patient’s first visit with subsequent annual PSA tests. The TRUS with prostate biopsy was performed if PSA exceeded 3.0 ng per mL or if DRE was suspicious. Appropriate treatment was initiated if prostate cancer was diagnosed. The prostate cancer death rates during the 8-year period were 48.7 and 15 per 100,000 man-years in the unscreened and screened groups, respectively (p < .01), a 69% difference in favor of screening and early treatment. The authors were criticized for selection bias because only 23% of men randomized to undergo screening actually agreed to undergo testing. A second point of contention was that the intent-to-screen analysis only revealed a 6% decrease of the prostate cancer death rate in favor of the group initially invited to be screened. These criticisms, however, do not completely invalidate the results of the study. The authors pointed out that there was a noncompliance rate of 77% in the original invited group and a contamination rate of 7% of the uninvited men. When statistical adjustments were made to account for these levels of noncompliance and contamination, the effect of screening was estimated to reduce the death rate from prostate cancer by 54 to 100%. Therefore, the authors felt the 69% benefit of screening shown in their report was consistent with the results of the intent-to-screen analysis. Randomized, controlled trials currently taking place will all certainly be subject to some degree of selection bias. Additionally, any potential lack of survival differences in these ongoing trials will undoubtedly be influenced by the penetration of PSA determinations into the control unscreened populations. It will be difficult, if not impossible, to prevent these men from having PSA determinations performed by their primary care practitioners. As a result, men undergoing PSA screening outside of the study will infiltrate the nonscreened arm in any of these studies to various degrees.

Conclusion The introduction of routine serum PSA determinations into the annual health physical of older men has dramatically influenced the demographics of prostate cancer diagnosis. In general, prostate cancer is being diagnosed in younger men with a normal DRE. They are often found to have clinically localized disease of lower grade. Many of these men are seeking the potentially curable therapies of radical prostatectomy and radiation therapy (external beam and brachytherapy). In the past, these patients would have escaped diagnosis owing to a lack of symptoms and a normal DRE. Accordingly, their tumors would have progressed to the advanced disease so common in the 1980s. Given these facts, it is impossible for the authors to conclude that PSA screening will not satisfy the three tenets of a successful screening modality. The decreased death rate for prostate cancer now being evidenced in

preliminary results and SEER studies will be validated. The naysayers who refuse to accept screening will be left to ponder how many lives could have been saved had the widespread use of PSA been universally accepted sooner.

References 1. von Eschenbach A, Ho R, Murphy GP, et al. American Cancer Society guideline for the early detection of prostate cancer: update 1997. CA Cancer J Clin 1997; 47:261–4. 2. Smith DS, Catalona WJ. The nature of prostate cancer detected through prostate specific antigen based screening. J Urol 1994;152:1732–6. 3. Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993;270:948–54. 4. Farkas A, Schneider D, Perrotti M, et al. National trends in the epidemiology of prostate cancer, 1973 to 1994: evidence for the effectiveness of prostate-specific antigen screening. Urology 1998;52:444–9. 5. Stephenson RA. Population-based prostate cancer trends in the PSA era: data from the Surveillance Epidemiology and End Results (SEER) program. Monogr Urol 1998;19:3–19. 6. Labrie J, Candas B, Cusan L, et al. Diagnosis of noncurable prostate cancer can be practically eliminated by prostate-specific antigen. Urology 1996;47:212–6. 7. Gann PH, Hennekens CH, Stampfer MJ. A prospective evaluation of plasma prostate-specific antigen for detection of prostate cancer. JAMA 1995;273:289–94. 8. Arcangeli CG, Ornstein DK, Keetch DW, Andriole GL. Prostate-specific antigen as a screening test for prostate cancer. Urol Clin North Am 1997;24:299–321. 9. Brawer MK. Screening and early detection of prostate cancer will decrease morbidity and mortality from prostate cancer: the argument for. Eur Urol 1996;29 Suppl 2:19–23. 10. Gerber GS, Chodak GW. Value of prostate cancer screening. Eur Urol 1993;24:161–5. 11. Denis LJ. To screen or not to screen? Prostate 1992;Suppl 4:63–70. 12. Jacobson JO. Can screening for early-stage prostate cancer be rationalized? Hematol Oncol Clin North Am 1996; 10:549–64. 13. Albertsen PC. Screening for prostate cancer is neither appropriate nor cost effective. Urol Clin North Am 1996;23:521–30. 14. Thompson IM, Rounder JB, Teague JL, et al. Impact of routine screening for adenocarcinoma of the prostate on stage distribution. J Urol 1987;137:424–6. 15. Jenson CB, Shahon DB, Wangensteen OH. Evaluation of annual examinations in the detection of cancer. Specific reference to cancer of the gastrointestinal tract, prostate, breast and female reproductive tract. JAMA 1960;174:1783–8. 16. Chodak GW, Keller P, Schoenberg HW. Assessment of screening for prostate cancer using the digital rectal examination. J Urol 1989;141:1136–8. 17. Gerber GS, Thompson IM, Thisted R, Chodak GW. Disease-specific survival following routine prostate cancer screening by digital rectal examination. JAMA 1993;269:61–4.

Screening for Prostate Cancer: the Case for Screening / 79 18. Mueller EJ, Crain TW, Thompson IM, Rodriguez FR. An evaluation of serial digital rectal examinations in screening for prostate cancer. J Urol 1988;140:1445–7. 19. Flanigan RC, Catalona WJ, Richie JP, et al. Accuracy of digital rectal examination and transrectal ultrasonography in localizing prostate cancer. J Urol 1994;152(5 Pt 1): 1506–9. 20. Lee F, Torp-Pedersen S, Littrup PJ, et al. Hypoechoic lesions of the prostate: clinical relevance of tumor size, digital rectal examination and prostate-specific antigen. Radiology 1989;170:29–32. 21. Chodak GW, Wald V, Palmer E, et al. Comparison of digital rectal examination and transrectal ultrasonography for the diagnosis of prostate cancer. J Urol 1986;135: 951–4. 22. Cooner WH, Mosley BR, Rutherford CL, et al. Prostate cancer detection in a clinical practice by ultrasonography, digital rectal examination and prostate specific antigen. J Urol 1990;143:1146–52. 23. Jacobsen SJ, Katusic SK, Bergstralh EJ, et al. Incidence of prostate cancer diagnosis in the eras before and after serum prostate-specific antigen testing. JAMA 1995; 274:1445–9. 24. Mettlin C, Lee F, Drago J, Murphy GP, and members of the American Cancer Society National Prostate Cancer Detection Project. Findings on the detection of early prostate cancer in 2,425 men. Cancer 1991;67:2949–58. 25. Brawer MK, Chetner MP, Beatie J, et al. Screening for prostate carcinoma with prostate-specific antigen. J Urol 1992;147:841–5. 26. Labrie F, Dupont A, Suburu R, et al. Serum prostate specific antigen as pre-screening test for prostate cancer. J Urol 1992;147:846–51. 27. Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol 1994;151:1283–90. 28. Mettlin C, Murphy GP, Lee F, et al. Characteristics of prostate cancer detected in the American Cancer Society-National Prostate Cancer Detection Project. J Urol 1994;152:1737–40. 29. Benson MC, Whang IA, Olsson CA, et al. The use of prostate specific antigen density to enhance the predictive value of intermediate levels of serum prostatespecific antigen. J Urol 1992;147:817–21. 30. Seaman E, Whang M, Olsson CA, et al. PSA density (PSAD): role in patient evaluation and managment. Urol Clin North Am 1993;20(4):653–63. 31. Bazinet M, Mashref AW, Trudel C, et al. Prospective evaluation of prostate-specific antigen density and systematic biopsies for early detection of prostatic carcinoma. Urology 1994;43:44–51. 32. Catalona WJ, Richie JP, DeKernion JB, et al. Comparison of prostate specific antigen concentration versus prostate-specific antigen density in the early detection of prostatic carcinoma: receiver operating characteristic curves. J Urol 1994;152:2031–6. 33. Brawer MK, Aramburu EAG, Chen GL, et al. The inability of prostate specific antigen index to enhance the predictive value of prostate-specific antigen in the diagnosis of prostate cancer. J Urol 1993;150:369–73.

34. Oesterling JE, Jacobsen SJ, Chute CG, et al. Serum prostate-specific antigen in a community based population of healthy men: establishment of age-specific reference ranges. JAMA 1993;270:860–4. 35. Catalona WJ, Hudson MA, Scardino PT, et al. Selection of optimal prostate-specific antigen cutoffs for early detection of prostate cancer: receiver operating characteristics curves. J Urol 1994;152(part 1);2037–42. 36. Partin AW, Criley SR, Subong EN, et al. Standard versus age-specific antigen reference ranges among men with clinically localized prostate cancer: a pathologic analysis. J Urology 1996;155:1336–9. 37. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics, 1997. CA Cancer J Clin 1997;47:5–27. 38. Oesterling JE, Kumamoto Y, Tsukamoto T, et al. Serum prostate-specific antigen in a community-based population of healthy Japanese men: lower values than for similarly aged white men. Br J Urol 1995;75:347–53. 39. Morgan TO, Jacobsen SJ, McCarthy WF, et al. Age specific reference ranges for prostate-specific antigen in black men. N Engl J Med 1996;335:304–10. 40. Carter HB, Pearson JD, Metter EJ, et al. Longitudinal evaluation of prostate-specific antigen in men with and without prostate disease. JAMA 1992;267:2215–20. 41. Smith DS, Catalona WJ. Rate of change in serum prostatespecific antigen levels as a method for prostate cancer detection. J Urol 1994;152:1163–7. 42. Carter HB, Pearson JD, Waclawiw Z, et al. Prostate-specific antigen variability in men without prostate cancer: effect of sampling interval on prostate-specific antigen velocity. Urology 1995;45:591–6. 43. Christensson A, Lilja H. Complex formation between protein C inhibitor and prostate-specific antigen in vitro and in human semen. Eur J Biochem 1994;220:45–53. 44. Lilja H. Structure, function, and regulation of the enzyme activity of prostate-specific antigen. World J Urol 1993; 11:188–91. 45. Prestagiacomo AF, Lilja H, Pettersson K, et al. A comparison of the free fraction of serum prostate-specific antigen in men with benign and cancerous prostates: the best case scenario. J Urol 1996;156:350–4. 46. Bjork T, Bjartell A, Abrahamsson PA, et al. Alpha 1-chymotrypsin production in PSA producing cells is common in prostate cancer but rare in benign prostatic hypertrophy. Urology 1994;43:427–34. 47. Smith CR. The results of prostate carcinomas screening in the U.S. as reflected in the Surveillance, Epidemiology, and End Result program. Cancer 1997;80:1835–44. 48. Meyer F, Moore L, Bairati I, Fradet Y. Downward trend in prostate cancer mortality in Quebec and Canada. J Urol 1999;161:1189–91. 49. Gohagan JK, Prorok PC, Kramer BS, et al. The prostate, lung, colorectal, and ovarian cancer screening trial of the National Cancer Institute. Cancer 1995;75:1869– 73. 50. Schroder FHG, Bangma CH. The European randomized study of screening for prostate cancer (ERSPC). Br J Urol 1997;79 Supp:68–71. 51. Labrie F, Candas B, Dupont A, et al. Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized controlled trial. Prostate 1999;38:83–91.

CHAPTER 12

SCREENING FOR PROSTATE CANCER: THE ARGUMENT FOR CAUTION BARNETT S. KRAMER, MD, MPH; OTIS W. BRAWLEY, MD For years, the public has been told that the key to curing cancer is early detection. This simplified soundbite has created, without rigorous evaluation, widespread support for screening efforts in a number of cancers. In fact, the public is not well prepared to accept negative results from randomized trials designed to rigorously test the efficacy of screening strategies such as chest radiography for lung cancer1 or breast self-examination for breast cancer.2 The medical community has not successfully conveyed the complexities of screening and the potential downside of widespread acceptance of screening without evidence of net benefit.3,4 The American medical community, more so than the medical communities of other developed countries and countries with organized health care systems, has recently embraced prostate cancer screening without rigorous evaluation. Indeed, prostate cancer screening may be done without the patient’s knowledge or consent and even more frequently is done without advising the patient of the uncertain efficacy of prostate cancer screening and treatment.5 In a real sense, the country has embarked upon a large uncontrolled clinical experiment.6 Though as yet unproven, screening for and aggressive treatment of localized prostate cancer may well be beneficial in that it may decrease prostate cancer mortality and save lives. However, it does have a definite cost of human suffering. At this point, we must weigh proven risks against unproven benefits. Ten years into the prostate-specific antigen (PSA) screening era, evidence shows that PSA screening still needs definitive evaluation. Many have concluded that an average increase in survival time after diagnosis and a shift toward lower stage disease at diagnosis will necessarily translate into saved lives. However, screening is capable of detecting disease of little or no medical significance (overdiagnosis), artificially increasing survival time after diagnosis, and triggering unnecessary treatment. While there has been a recent decline in prostate-cancer-specific mortality, it is not certain that the decline is due to screening. Indeed, there is evidence that screening is not causally related to the decline. Whether prostate cancer screening saves lives and at what human cost remains a cogent question. It is a question far more easily addressed by definitive randomized trials than by uncontrolled observations or

assumptions based on limited study design. The randomized prospective clinical trial ushered in the era of modern clinical medicine, and its power to answer pressing medical questions, cannot be overestimated.

Clinical Significance or Insignificance of Prostate Cancer Length bias is a well-described phenomenon associated with many tests used to screen asymptomatic individuals. It arises because asymptomatic disease processes, cancer included, are on average less biologically aggressive than symptomatic diseases. The phenomenon is illustrated in Figure 12–1, where, the length of each horizontal line represents the duration of the disease’s natural history in its recognizable states. Short lines represent a faster, more aggressive clinical behavior. A screening test is more likely to pick up prevalent indolent cases (left of Figure 12–1) than more life-threatening cases (right), thereby increasing the ratio of indolent to aggressive cancers in the pool of detected cases. The illustration shows that 5 of 5indolent cancers are picked up, compared with 1 of 5 aggressive cancers. Length bias has been documented in randomized trials of mammography for breast cancer and chest radiography with sputum cytology for lung cancer. More recently, it has been associated with digital rectal examination (DRE) screening for prostate cancer.7 There are consistently more cases detected in the screened group than in the control group. In the case of lung cancer, virtually all these excess cases of lung cancer were localized surgically operable lesions; yet, in the randomized screening trials for lung cancer, virtually identical numbers of lung cancer deaths were observed in the screened arms versus the controlled arms. In two of these studies, there was an increased but not statistically significant number of deaths in the screened group. This illustrates that length biases do exist and do matter in terms of quality of life. An extreme form of length bias, known as overdiagnosis, occurs when lesions are detected that never would have come to medical attention at all, were it not for screening. There are two forms of overdiagnosis: (1) detection of lesions with virtually no potential for progression, and (2) detection of indolent lesions with potential to progress but 80

Screening for Prostate Cancer: the Argument for Caution / 81

not within the remaining “natural” lifespan of the individual. The latter form of overdiagnosis can be substantial in a disease such as prostate cancer, in which the average age of diagnosis is in the eighth decade of life. The most significant question in a man with diagnosed prostate cancer is, “Is this specific cancer of clinical significance to this particular patient?” Half of all American men diagnosed with prostate cancer are 71 years of age or older and over 80% are 65 years or older. For years, it has been known that prostate cancer is unusual among malignancies in that more than a third of men over age 50 years dying of causes unrelated to prostate cancer are found at autopsy to have one or more foci of prostate cancer.8,9 A smaller but substantial proportion of men in their 30s and 40s also harbor prostate cancer.10 Many of these tumors fulfill the histologic and size criteria of clinically significant cancer. These criteria take into account tumor volume, differentiation, and capsular penetration.11,12 Such tumors by definition, however, did not contribute to the patient’s death. Studies of cystoprostatectomy specimens from men with bladder cancer also demonstrate that the reservoir of undetected slow-growing tumors is large. These studies suggest that the more we look for prostate cancer, the more we will find it. Reports of men diagnosed and treated with T1c prostate cancer should be interpreted in light of the fact that a number of tumors found at autopsy actually fulfill histologic criteria for clinically significant disease but are obviously not clinically significant.13 In one recent case series, pathologists estimated that 15% of men with T1c stage cancers had tumors that did not fulfill histologic criteria for clinically significant prostate cancer.14 The T1c tumors are those identified by needle biopsy after an elevated serum PSA. In other words, pathologists, looking at a group of men diagnosed through screening and treated with radical prostatectomy believe that at least 1 in 7 received unnecessary treatment based on histologic criteria for malignancy and aggressiveness. Given the additional considerations of competing causes of death in an elderly population, this is likely to be a minimum rather than maximum proportion. The autopsy data showing disease that is “histologically clinically significant” but not truly clinically significant would only raise this estimate. Several clinical observational studies have demonstrated that a number of diagnosed tumors can be observed and do not need definitive therapy.15–17 In a Swedish study of men diagnosed with clinically stage A and B prostate cancer, after 10 years of follow-up, only 8.5% had died of prostate cancer. Ultimately, only 15% of the deaths in the series were due to prostate cancer. Even clinical stage C disease can be indolent. In a series of 50 patients, Adolfsson reported that 12% had died at 5 years and 30% at 9 years with observation.15

FIGURE 12–1. The length bias phenomenon: length of horizontal lines depicts duration of disease natural history; a screening test, depicted by the vertical lines, enriches the sample for detection of biologically less aggressive tumors.

Effectiveness of Therapy for Localized Prostate Cancer Willet Whitmore’s famous statement “when cure is possible, is it necessary; when cure is necessary, is it possible?” is as pertinent today as when he first made it years ago. It is well established that survival after definitive treatment of organ-confined prostate cancer is relatively good. It is also clear that treatment cures some cancers that do not need to be cured. The efficacy of screening is a crucial but unresolved question. The American Urological Association convened the Prostate Cancer Clinical Guidelines Panel to analyze the literature regarding available methods for treating locally confined prostate cancer. The panel concluded that outcomes data are inadequate to make valid comparisons of treatment. In a similar literature review, Wasson et al.18 were unable to find definitive evidence concerning the efficacy of treatment of localized disease. Both groups cited the large number of weak study designs that allowed selection biases affecting choice of treatment and patient selection. Only one small randomized prospective trial has been completed assessing radical prostatectomy.18–20 This trial involved 111 men with early stage prostate cancer randomized to radical prostatectomy and placebo versus placebo alone. This trial with small size and low power showed a statistically indistinguishable life expectancy in both arms. Only recently has the question of treatment efficacy been re-addressed. The Prostate Intervention Versus Observation Trial, started in 1993, compares radical prostatectomy to palliative expectant management for clinically localized prostate cancer. The study will ultimately enroll approximately 1050 men, and is expected to have 90% power to detect a 15% reduction in all-cause mortality.19 Similar trials are underway in Europe, assessing the efficacy of radiation therapy as well as radical prostatectomy.21–26 Unfortunately, the results of these trials will not be available for several years.


Does treatment of localized prostate cancer save lives? Screening efficacy rests upon treatment efficacy. If treatment is ineffective at saving lives, screening will not save lives. But the very existence of such randomized trials with a “watchful waiting” control arm is evidence of the underlying uncertainties—uncertainties which are, oftentimes, not transmitted to men facing the decision regarding screening for prostate cancer.

Prostate Cancer Screening: Results of Screening Trials No randomized clinical trial in prostate cancer screening has been completed and analyzed on an intention-totreat or intention-to-screen (i.e., as randomized) basis. Recently, Labrie et al.27 have publicly presented interim results of a trial, but it was not analyzed on the basis of intention to treat. When analyzed by randomization allocation, the relative risk of death from prostate cancer in the screened group was 1.16 times greater than in the control group. Only about a third of men randomized to be screened were actually screened, and thus the inclusion of the unscreened men in the analysis of the group randomized to be screened would dilute any potential efficacy of screening. However, their inclusion should not have raised the risk of prostate cancer death above that of the control group if screening is truly efficacious. In the recent past, DRE of the prostate was assumed to be an effective screening technique, and many major health organizations recommended it be done as a prostate cancer screen. There are no completed clinical trials of DRE. However, DRE has been assessed in case-control studies that suggest no effect on preventing metastatic prostate cancer or disease-specific survival.28,29

Screening at the Population Level: Trends in Incidence and Mortality Prostate cancer screening, especially screening with serum PSA in the late 1980s and early 1990s, has profoundly increased the age-adjusted incidence of diagnosed prostate cancer in the United States. Steady rises in the 1970s and early l980s can be attributed to an increase in the number of transurethral resections of the prostate (TURPs) for benign prostatic hyperplasia.2 The subsequent acceleration of incidence can be attributed to increasing use of PSA.3 It should be noted that the use of TURP actually decreased during the late 1980s. A more recent decline in the incidence of prostate cancer may be due to a clearing of the prevalent cases. It may also be due to the fact that several organizations began recommending against prostate cancer screening in the early 1990s. By 1993, a number of American organizations that publish screening recommendations recommended against screening for prostate cancer or took the

position that it was unproven.4 Medicare data indicate that the rate of PSA testing in men aged 65 years and over rose 12-fold from 1988 to 1991, and the proportion of men getting a PSA for the first time peaked in 1991 and 1992. Incidence trends track with first-time PSA utilization rates.30,31 Prostate cancer mortality rates have increased over the past 20 years for both African American and Caucasian men although they have declined slightly during the past few years. From 1991 to 1995, there has been a 6.3% decrease in mortality rates. The Surveillance, Epidemiology, and End Results (SEER) mortality rate has not gone below the baseline mortality rate of the late 1970s and early 1980s. While mortality rates rose from 1973 to 1991, the increase is not as dramatic as those for prostate cancer incidence and provides some evidence of length bias (the diagnosis of tumors with relatively less life-threatening potential than symptomatic cancer). An increased rate of rise in prostate cancer mortality in the late 1980s may be related to the increase in incidence. As diagnostic abilities improved slightly, more deaths are attributed to the disease, a form of attribution bias. Curiously, at the very same time, when prostate cancer incidence in the United States began to fall so precipitously, prostate cancer mortality also began to fall slightly. Some have taken this mortality fall as a priori evidence of a benefit from nationwide screening.32 However, in addition to the fact that changes in treatment practice have occurred in recent years, shifts in mortality may also be due, at least in part, to fewer diagnoses of prostate cancer prior to death. If, in fact, the recent decrease in mortality is due to screening efficacy, it has occurred much more quickly than most would have guessed; and mortality benefits should occur much more quickly in the ongoing randomized screening trials in the United States and Europe than initially estimated. The data clearly demonstrate that length bias and overdiagnosis may be important confounders in analyzing prostate cancer incidence and mortality trends in the PSA screening era. Prostate cancer screening and treatment patterns vary widely throughout the United States. An assessment of the age-adjusted incidence patterns among Caucasian men in nine American populationbased cancer registries from the early 1970s to 1994 showed widely varying incidence of diagnosed cancers as well as use of radical prostatectomy. The regional data also suggest caution in attributing recent declines in mortality to screening. There is no geographic correlation between incidence and mortality rate (Figure 12–2). Indeed, the area with the greatest decrease in mortality, Connecticut, had the lowest rate of screening and lowest incidence during this period from 1973 to 1995. International comparisons of rates are also useful. Comparisons of age-adjusted prostate cancer rates in Caucasian men in the United States and United Kingdom show a widely varying incidence but similar mortality. Prostate

Screening for Prostate Cancer: the Argument for Caution / 83

cancer screening is not as widespread in the United Kingdom as it is in the United States. Moreover, a smaller proportion of men diagnosed with localized disease are treated with radical prostatectomy. Despite consistently higher incidence rates in the United States, with a more recent dramatic rise and fall in incidence, compared to the United Kingdom, mortality rates are extremely similar from the 1960s to the 1990s (Figure 12–3). This again suggests that greater detection efforts in the United States find a higher proportion of tumors that are not clinically significant.33 Likewise, the uncertainty about the efficacy of treatment of localized prostate cancer has led to a 20-fold difference in prostatectomy rates per 100,000 among Medicare beneficiaries in the states of Rhode Island versus Alaska.34 Nevertheless, the age-adjusted mortality rates for Caucasian males in the states of Rhode Island and Alaska are very similar.35

Potential Adverse Consequences of Treatment Morbidity Much of the enthusiasm for screening stems from the desire to avoid the suffering from advanced prostate cancer that screening and treatment could, in theory, prevent. Screening and subsequent treatment, however, cause considerable morbidity. All those who receive treatment are at risk for the morbidities of therapy, including those who are cured unnecessarily and those who need to be cured but are not. The men in these two categories experience all the morbidities of local therapy but none of the benefits. In fact, they experience them sooner and for a longer time since screening advances their date of diagnosis without extending lifespan. A recent study of Medicare beneficiaries36 notes that of 3173 undergoing radical prostatectomy from l985 to 1991, less than 60% were found to have organ-confined disease. Five years after surgery, the proportion of men receiving additional therapy for cancer recurrence or persistence was about 35%. Even in men with pathologically confined cancer after radical prostatectomy, the cumulative incidence of additional prostate cancer treatment at 5 years was 25%. The morbidities of prostate cancer treatment are better defined than the efficacy of the treatment itself. All forms of localized prostate cancer therapy have side effects but those for radical prostatectomy and external beam radiation are best described. Both are known to cause impotence, rectal injury, urinary incontinence, and urethral stricture. Literature reviews from physicians at major medical centers give impotence rates of 25 to 40%, rectal injury rates of 1 to 3%, urinary incontinence rates of 3 to 6%, and urethral stricture rates of 8 to 18%, with radiation therapy at the lower range compared to surgery.37 Morbidity is a highly subjective factor, and patientreported morbidities from surveys are substantially

higher than physician-reported morbidity rates. In a survey of Medicare patients38 undergoing radical prostatectomy from 1988 to 1992, 30% reported the chronic need for pads and urinary clamps. More than 60% reported a problem with wetting, 60% reported having no erections since surgery, and 90% reported no erections sufficient for intercourse in the month prior to answering the survey. Twenty-eight percent reported receiving follow-up treatment for recurrence of prostate cancer within 4 years of prostatectomy. It is not clear if the newer “nerve-sparing” or anatomic prostatectomy has solved the problem of postsurgical sexual impotence. In a study of patients treated with the newer procedure, the self-reported frequency of impotence and urinary incontinence was similar to that found in the survey of Medicare patients, even though the average age of those in the nerve-sparing study was younger than that in the Medicare survey.39 Although statistical power was limited, sexual dysfunction and urinary dysfunction did not seem to differ substantially between men who had undergone standard versus nerve-sparing radical prostatectomy. Radiation therapy also confers significant risk of morbidity.40 Clearly, more information is needed in this area. Prostatectomy incurs a higher risk of treatmentrelated death than radiation therapy.38 While individual surgeons have reported death rates of less than 0.5% depending on patient selection and the surgeon’s skill, the surgical mortality rate was 2% in a national sample of Medicare beneficiaries. Unfortunately this study included only men aged 65 years and over, but this age group does include more than 80% of all men with prostate cancer. In that same series, 8% of men suffered major cardiopulmonary complications after radical prostatectomy. Economic Costs It has been estimated that PSA screening for all men aged 50 to 74 years without pre-existing cardiac disease would add $12 to $26 billion in the first year of a nationwide screening campaign.41–43 Such a cost would divert the finite health care budget from interventions of proven and known effectiveness. If prostate cancer screening is not of substantial benefit, this would result in a net loss in the overall health of the nation. If screening is proven effective, therefore, it would be important to compare its

FIGURE 12–2. Prostate cancer incidence and mortality comparisons showing no correlations.Pcancer. JAMA 1995;273:548–52.


cost-effectiveness to that of other beneficial medical interventions in men.

Conclusion The medical community is in a very unfortunate position because it has taken so long to put its assumptions about prostate cancer screening and treatment to definitive testing. Lead-time bias and length bias cloud interpretation of previous prostate cancer screening data. Radical prostatectomy series demonstrate that a substantial number of men treated for localized disease ultimately relapse; autopsy, observation, and epidemiologic studies suggest that many men diagnosed with prostate cancer do not have clinically significant disease given their risk for competing causes of death. Indeed, if there is some benefit, it may be counterbalanced by harm to many more. The only way to demonstrate that screening saves lives and gauge the net benefits and harms is through a welldesigned randomized trial with an “intention-to-screen” analysis of men as randomized. A randomized trial of prostate cancer screening began in the United States in 1993.37 Several other trials are underway in Europe.44 In addition, trials of definitive surgery and radiation have also begun.19 If such trials had been launched just 5 years earlier, we would likely have results by now. The current state of knowledge does not permit a fully informed decision with regard to routine prostate cancer screening and subsequent management. Ongoing trials should inform the disagreements over screening effectiveness. Organizations taking a skeptical view of prostate cancer screening include the United States Preventive Ser-

FIGURE 12–3. Prostate cancer incidence and mortality trends in the United States and the United Kingdom (1968–1995).

vices Task Force, the American College of Physicians, and the Canadian Task Force on the Periodic Health Examination.45–49 While most organizations issuing screening recommendations have not advocated prostate cancer screening, recently the major American organizations that had previously suggested that men be screened evaluated the more recent data and moved away from a recommendation that “screening should be done” and toward informed education as to the benefits and risks of screening and patient choice. The National Cancer Institute does not have a position for or against prostate screening and is currently conducting a large prospective randomized trial testing the value of DRE and PSA testing in the screening setting. In the meantime, while results of this and other randomized trials are pending, health professionals should inform each man about the current state of knowledge, detail the known risks and theoretic benefits, encourage participation in clinical trials whenever possible, and reassure the individuals that for now there is no clear-cut right or wrong choice regarding their decision to be screened or not.

References 1. Eddy DM. Screening for lung cancer. Ann Intern Med 1989;111:232–7. 2. Thomas DB, Gao DL, Self SG, et al. Randomized trial of breast self-examination in Shanghai: methodology and preliminary results. J Natl Cancer Inst 1997;89:355–65. 3. Taube A. Screening with PSA (prostate specific antigen) raises ethical questions. Lakartidningen 1996;93:3341. 4. Brown V. Informed consent for PSA testing. J Fam Pract 1996;43:234–5. 5. Glode LM. Prostate cancer screening: a place for informed consent? Hosp Pract 1994;29:8,11–8. 6. Mandelson MT, Wagner EH, Thompson RS. PSA screening: a public health dilemma. Annu Rev Public Health 1995;16:283–306. 7. Gerber GS, Thompson IM, Thisted R, Chodak GW. Disease-specific survival following routine prostate cancer screening by digital rectal examinations. JAMA 1993;269:61–4. 8. Breslow N, Chan CW, Dhom G, et al. Latent carcinoma of prostate of autopsy in seven areas. Int J Cancer 1977; 20:680–8. 9. Stemmermann GN, Nomura AM, Chyou PH, Yatani R. A prospective comparison of prostate cancer at autopsy and as a clinical event: the Hawaii Japanese experience. Cancer Epidemiol Biomarkers Prev 1992;1:189–93. 10. Sakr WA, Haas GP, Cassin BF, et al. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 1993;150:379–85. 11. Sakr WA, Grignon DJ, Haas GP, et al. Epidemiology of high grade prostatic intraepithelial neoplasia. Pathol Res Pract 1995;191:838–41. 12. Albertsen PC. Screening for prostate cancer is neither appropriate nor cost-effective. Urol Clin North Am 1996;23:521–30.

Screening for Prostate Cancer: the Argument for Caution / 85 13. Saxena S, Mohanty NK, Jain AK. Screening of prostate cancer in males with prostatism. Indian J Pathol Microbiol 1997;40:441–50. 14. Albertsen PC. Defining clinically significant prostate cancer: pathologic criteria versus outcomes data. J Natl Cancer Inst 1996;88:1177–8. 15. Adolfsson J. Deferred treatment of low grade stage T3 prostate cancer without distant metastases. J Urol 1993;149:326–8. 16. Pontes JE. Issues on early diagnosis and treatment of localized prostate cancer. Urol Int 1996;56 Suppl 1:1–5. 17. Brawley OW. Prostate carcinoma incidence and patient mortality: the effects of screening and early detection. Cancer 1997;80:1857–63. 18. Wasson JH, Cushman CC, Bruskewitz RC, et al. A structured literature review of treatment for localized prostate cancer. Prostate Disease Patient Outcome Research Team. Arch Fam Med 1993;2:487–93. 19. Moon TD, Brawer MK, Wilt TJ. Prostate Intervention Versus Observation Trial (PIVOT): a randomized trial comparing radical prostatectomy with palliative expectant management for treatment of clinically localized prostate cancer. PIVOT Planning Committee. Monogr Natl Cancer Inst 1995;19:69–71. 20. Graversen PH, Nielsen KT, Gasser TC, et al. Radical prostatectomy versus expectant primary treatment in stages I and II prostatic cancer. A fifteen-year followup. Urology 1990;36:493–8. 21. Gann PH. Interpreting recent trends in prostate cancer incidence and mortality. Epidemiology 1997;8:117–20. 22. Chodak GW. Carcinoma of the prostate. Lancet 1997;350: 592. 23. Thompson IM, Coltman CAJ, Crowley J. Chemoprevention of prostate cancer: the Prostate Cancer Prevention Trial. Prostate 1997;33:217–21. 24. Nijs HG, Tordoir DM, Schuurman JH, et al. Randomised trial of prostate cancer screening in the Netherlands: assessment of acceptance and motives for attendance. J Med Screen 1997;4:102–6. 25. Wang TT, Sathyamoorthy N, Phang JM. Molecular effects of genistein on estrogen receptor mediated pathways. Carcinogenesis 1996;17:271–5. 26. Schröder FH. The European Screening Study for Prostate Cancer. Can J Oncol 1994;4 Suppl 1:102–9. 27. Labrie F, Candas B, Dupont A, et al. Screening decreases prostate cancer death: first analysis of the 1988 Quebec prospective randomized controlled trial [see comments]. Prostate 1999;38(2):83–91. 28. Friedman GD, Hiatt RA, Quesenberry CPJ, Selby JV. Casecontrol study of screening for prostatic cancer by digital rectal examinations. Lancet 1991;337:1526–9. 29. Gerber GS, Thisted R, Chodak GW, Thompson IM. Disease-specific survival following routine prostate cancer screening by digital rectal examination: corrected patient classification. JAMA 1993;270:2437. 30. Potosky AL, Miller BA, Albertsen PC, Kramer BS. The role of increasing detection in the rising incidence of prostate cancer. JAMA 1995;273:548–52. 31. Legler JM, Feuer EJ, Potosky AL, et al. The role of

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prostate-specific antigen (PSA) testing in the recent prostate cancer incidence decline in the U.S.A. Cancer Causes Control 1998;9:519–27. Smart CR. The results of prostate carcinoma screening in the U.S. as reflected in the Surveillance, Epidemiology, and End Results program. Cancer 1997;80:1835–44. Shibata A, Ma J, Whittemore AS. Prostate cancer incidence and mortality in the United States and the United Kingdom. J Natl Cancer Inst 1998;90:1230–1. Lu-Yao GL, McLerran D, Wasson J, Wennberg JE. An assessment of radical prostatectomy. Time trends, geographic variation, and outcomes. The Prostate Patient Outcomes Research Team. JAMA 1993;269:2633–6. Lu-Yao GL, Greenberg ER. Changes in prostate cancer incidence and treatment in USA. Lancet 1994;343:251–4. Lu-Yao GL, Potosky AL, Albertsen PC, et al. Follow-up prostate cancer treatments after radical prostatectomy: a population-based study. J Natl Cancer Inst 1996;88: 166–73. Kramer BS, Brown ML, Prorok PC, et al. Prostate cancer screening: what we know and what we need to know. Ann Intern Med 1993;119:914–23. Fowler FJJ, Barry MJ, Lu-Yao G, et al. Patient-reported complications and follow-up treatment after radical prostatectomy. The National Medicare Experience: 1988–1992. Urology 1993;42:622–9. Litwin MS, Hays RD, Fink A, et al. Quality-of-life outcomes in men treated for localized prostate cancer. JAMA 1995;273:129–35. Jonler M, Ritter MA, Brinkmann R, et al. Sequelae of definitive radiation therapy for prostate cancer localized to the pelvis. Urology 1994;44:876–82. Optenberg SA, Thompson IM. Economics of screening for carcinoma of the prostate. Urol Clin North Am 1990; 17:719–37. Lubke WL, Optenberg SA, Thompson IM. Analysis of the first-year cost of a prostate cancer screening and treatment program in the United States. J Natl Cancer Inst 1994;86:1790–2. Woolf SH. Public health perspective: the health policy implications of screening for prostate cancer. J Urol 1994;152:1685–8. Schröder FH, Bangma CH. The European Randomized Study of Screening for Prostate Cancer (ERSPC). Br J Urol 1997;79 Suppl 1:68–71. Rose VL. ACP issues guidelines on the early detection of prostate cancer and screening for prostate cancer. Am Fam Physician 1997;56:1674–5. Woolf SH. Should we screen for prostate cancer? BMJ 1997;314:989–90. Shröder FH, Damhuis RA, Kirkels WJ, et al. European randomized study of screening for prostate cancer—the Rotterdam pilot studies. Int J Cancer 1996;65:145–51. Denis LJ, Murphy GP, Schröder FH. Report of the consensus workshop on screening and global strategy for prostate cancer. Cancer 1995;75:1187–207. Ramsey EW. Early detection of prostate cancer. Recommendations from the Canadian Urological Association. Can J Oncol 1994;4 Suppl 1:82–5.

CHAPTER 13

NATURAL HISTORY OF LOCALIZED ADENOCARCINOMA OF THE PROSTATE JOHN P. FOLEY, MD; IAN M. THOMPSON, MD An intimate knowledge of the natural history of adenocarcinoma of the prostate is essential for any physician who treats patients with this disease. As prostate cancer can be a relatively slow-growing tumor associated with a long asymptomatic and latent period and usually occurs in men who are at risk of dying from other causes (effectively eliminating the “opportunity” of the tumor to manifest itself clinically), decision making by both clinicians and patients is often based on the disease’s natural history. In this chapter, we will examine the experience of published series of patients in whom no treatment was provided for localized disease to develop an understanding of what appears to be the natural history. We will further examine how the behavior of the disease has “changed” over time (as methods of detection, diagnosis, and staging have changed) as well as a number of tumor and host features that can modulate tumor behavior. Specifically excluded from this review are those studies that have reported the results of observation alone for patients with T1a (A1) prostate cancer—focal, low-volume, welldifferentiated disease diagnosed at the time of transurethral resection of the prostate. Evidence is substantial that except in rare circumstances (very young patients), the majority of these patients will have excellent outcomes without treatment.1

have other competing causes of death. These two factors tend to exaggerate the “efficacy” of surveillance. The other bias is that historically detected tumors may not be similar to tumors detected contemporarily. Examples of this phenomenon include the virtual disappearance of lowgrade tumors, currently constituting less than 15% of tumors, compared to over twice as many 10 years ago. A recent evaluation at our institution has found that this phenomenon is probably due to the dramatic fall-off in the number of transurethral resections of the prostate (TURPs), the method by which most well-differentiated tumors are detected.2 This change may have led to an increased detection of more biologically active tumors, making a comparison with historic surveillance series more problematic. Nevertheless, an understanding of the historic experience with surveillance remains key to the evaluation of the impact of treatment on the natural history of the disease. A total of 17 series of surveillance have been published in which some element of tumor staging has been presented. Table 13–1 displays the results of these series, in the order of the final date of patient accession (for example, the first series of Hanash3 included patients diagnosed between 1934 and 1942 while the second series of Cook4 included patients diagnosed between 1939 and 1961). This ordering of outcomes is important due to the phenomenon of “stage migration.” While it is indeed possible that the natural history of prostate cancer has changed in the last 30 years, this change is more likely to be due to improved staging. As such, 30 to 40 years ago, patients considered to have localized prostate cancer were staged only with skeletal surveys (radiography of long bones) and acid phosphatase while patients in more contemporary series have been staged by computed tomography, transrectal ultrasonography, and bone scans. Additionally, previous series of patients often were diagnosed on the basis of symptoms while patients in more recent series may have been diagnosed by digital rectal examination (DRE) screening. For these reasons, earlier series undoubtedly included patients with metastatic disease. As a result, their failure over time was likely to be much greater than current series of patients who were staged more assiduously and accurately.

Results of Surveillance for Localized Prostate Cancer Perhaps the best method to evaluate the natural history of carcinoma of the prostate is to review series of patients without treatment who were followed up. These results then become the “floor” for any treatment of the disease. For example, if 10-year data from a surveillance series finds that the risk of development of metastatic disease is 20%, the treatment series must improve upon that figure, and any cost and morbidity arising from treatment must be compared directly with gains in such outcomes. Unfortunately, such comparisons suffer greatly from patient selection biases. Two of these are extremely important. First is the bias that surveillance series have generally enrolled patients with low-risk (well-differentiated, lowvolume, low-stage) tumors as well as older patients who 86

Natural History of Localized Adenocarcinoma of the Prostate / 87

Perhaps the earliest series of note, a total of 1000 patients from the Mayo Clinic, suffered from serious problems with tumor staging.5 The first series with more reliable staging was that of Hanash and colleagues.3 This series of 200 patients included patients of all stages—A, B, C, and D. While staging did not include any of the currently available modalities, the authors made several important observations. First, the risk of death was inversely proportional to the age at diagnosis. As such, the relative survival (actual survival divided by the expected survival of a similar-aged man) of the 50- to 59-year-old cohort was less than that for the 60- to 69-year-old cohort. Of interest, men over age 80 diagnosed with prostate cancer actually had a better survival than expected for the population. The authors also observed that patients with higher-grade tumors had a substantially worse prognosis than those with low-grade tumors. Finally, they observed that controlling for tumor grade, a patient with clinical symptoms of his disease had a significantly worse prognosis. A small series of 20 untreated prostate cancer patients was found in Cook and Watson’s review of 367 prostate cancer patients at Ellis Fischel State Cancer Hospital between 1939 and 1961.4 In this population of patients, the mean age was 74 years; the mean age of all other patients was 67 years. While overall survival at 5 and 10 years was 36% and 20%, respective cancer-specific survivals were 55% and 52%. A substantial experience with 233 patients (118 with stage A and 115 with stage B disease) was reported by Barnes et al. in 1976.6 Unlike prior reports, the authors noted that the majority of patients had been treated hormonally (orchiectomy or estrogens) either immediately or on a delayed basis. Some patients also required transurethral resection of the prostate for symptoms but none were treated for cure. As can be seen in Table 13–1, the authors had the first group of patients with longer survivals at 10 and 15 years for both stage A and stage B disease. They made the additional observation that patients with focal and diffuse disease had different outcomes—an observation that would be made later with better estimates of tumor volume using whole mount techniques. For example, while focal stage A disease had 5-, 10-, and 15-year survivals of 58%, 56%, and 35%, the respective survivals for diffuse stage A disease were 58%, 26%, and 14%. The authors again found that tumor grade and outcome were intimately linked, finding 5-, 10-, and 15-year survivals in grades I and II stage B disease of 81%, 70%, and 42% compared with 53%, 43%, and 15% for grade III and IV disease. A most interesting study was published in its last iteration by Madsen et al. in 1988.7 This publication provided full 15-year follow-up on 142 patients with T1 or T2 prostate cancer, who were randomized to either undergo radical prostatectomy or to receive surveillance alone. Unfortunately, the study was much too small to reach any

conclusions regarding the relative efficacy of the two forms of disease management. (For example, the current PIVOT trial is expected to accrue 1000 patients to address the same question with sufficient statistical power.) Nevertheless, the outcomes of the patients randomized to observation are illustrative of the natural history of prostate cancer diagnosed between 1967 and 1975. As can be seen from Table 13–1, survivals of almost 40% were reported for patients with stage B disease. The authors also

TABLE 13–1. Results of Surveillance for Localized Prostate Cancer Reference Number (Year) Stage 3 (1942) 4 (1961) 6 (1970) 7 (1975) 8 (1976)

9 (1979) 11 (1982) 14 (1984) 15 (1984)

16 (1985) 17 (1985)

18 (1986)

19 (1986) 20 (1991)

A B B A B A B Gleason 2–4 Gleason 5–7 Gleason 8–10 T1b-T2 T1b-T2 T1-2 T1-2 T1-2 T1-2 TxNxM0† 55–59 yr, Gleason 2–4 55–59 yr, Gleason 2–4 55–59 yr, Gleason 7 55–59 yr, Gleason 7 70–74 yr, Gleason 7 70–74 yr, Gleason 7 55–59 yr, Gleason 8–10 T1-2 (75% of patients) T1a T1b T2 B1‡ B2‡ B3‡ TxM0 T1-4M0

Percent Survival No. of Patients 50 129 20 118 115 30 20 44 160 130 279 279 122 122 223 223 767

5 10 15 Years Years Years 86 19 36 62 71 59 85 100* 88* 63* 88 95* 82 99* NS NS 92 98* 70 75* 60 84* 58*

278 13 53 28 29 37 9 120 301

40 100* 93.7* 70* 95 86 86 70 90§ 80*

52 4 20 43 51 49 59 95* 75* 52* 61 80* 50 84* 40.8 85.6*

22 1 NS 27 28 15 39 92* 66* 47* NS NS NS NS 20.7 80.9*

84 96* 35 48* 24 48* 23*

72 95* 16 30* 9 60* 14*

NS NS NS NS 90 60 66

NS NS NS NS 62 36 66

NS 50*

NS 30*

NS = not stated. *Prostate-cancer-specific survival (likelihood of not dying of prostate cancer within time period). †Staging in this study was haphazard. Bone scans were performed on only 30% of patients, acid phosphatase was performed in 53%, and there was no testing for the presence of metastatic disease in between 15% (Gleason 8 to 10) and 33% (Gleason 2 to 4) of patients. Estimates of overall survival and cancer-specific survival are obtained from the figures in the text and are approximate. ‡See text for explanation of staging definitions. §90% represents cancer-specific survival including only those deaths that were definitely due to prostate cancer. Seventy percent represents cancer-specific survival, including those deaths that were possibly due to prostate cancer.


commented on the relationship of tumor grade and outcome. They found that the 10-year survival for Gleason score ≤ 4 (24 patients) was 76%, for Gleason score 5 to 6 (92 patients) 48%, and 26% for Gleason score ≥ 7. The first of two analyses of patients from the Connecticut Tumor Registry was performed by Albertsen et al. in 1995.8 An analysis of patients originally diagnosed between 1971 and 1976 identified 451 patients who (1) had no evidence of metastatic disease (using acid phosphatase, bone scan, or metastatic survey); (2) were untreated; (3) had histologic evidence of prostate cancer, independent of autopsy or in association with bladder cancer diagnosis (e.g., prostate cancer diagnosed at the time of radical cystoprostatectomy); and (4) had sufficient clinical information to compute a comorbidity index score. The mean age of these patients was 70.9 years, and 14% were stage A1 (T1a), 24% were A2 (T1b), 49% were stage B (T2), and 13% were classified as T1x (due to inadequate pathologic material to classify the tumor as either T1a or T1b). The authors did not report overall survival but, of much greater value, reported cumulative mortality from prostate cancer itself, on the basis of initial tumor grade. These data are noted in Table 13–1. As the authors classified the patients’ cause of death, they were able to determine the impact of prostate cancer on survival. For men ages 65 to 75 years, they found that a Gleason 2 to 4 prostate tumor had minimal to no impact on life expectancy. However, this same age group, diagnosed with a Gleason 5 to 7 tumor, had a 4- to 5-year reduction in life expectancy. For men unfortunate enough to have a poorly differentiated tumor, the reduction in life expectancy was 6 to 8 years. The authors also noted that in those patients with a higher comorbidity score (i.e., sicker patients), the impact of their tumor on life expectancy was, as would be expected, less. A novel review by Lerner et al. from Baylor College of Medicine analyzed a group of 360 patients with T1b-T3a prostate cancer who were treated with staging pelvic lymphadenectomy and a combination of interstitial radiotherapy with 198Au seeds and external beam radiotherapy.9 The authors’ purpose in the review was to investigate the risk of prostate cancer death among men treated with brachytherapy using open implantation techniques—a procedure that had lost favor because of poor seed placement and resultant poor dosimetry. This less-than-adequate treatment modality would then provide a window on the potential mortality from “contemporary” prostate cancer (1966 to 1979) left untreated. Two sets of results are displayed in Table 13–1, both overall survival as well as prostate-cancer-specific survival, only summarizing the 279 patients with T1-T2 disease. The large number of patients also allowed the authors to calculate the actuarial risk of cancer death by age group. At 5 years, the risk of cancer death in men < 60, 60 to 70, and > 70 years of age was 8%, 9%, and 5%, respectively. At 10 years, the respective rates were 25%, 31%, and 34%.

Adolfsson et al. from the Karolinska Hospital in Stockholm have presented two reviews of patients with localized prostate cancer followed up without therapy.10,11 The most recent update11 included 122 patients diagnosed between 1978 and 1982 with T1-T2 tumors, who had well- or moderately differentiated disease. All patients underwent bone scans and acid phosphatase determinations prior to study inclusion. The median patient age was 68 years and the median follow-up was 91 months. The majority (109) of patients were diagnosed with T2 disease. During follow-up, 55% of patients developed disease progression to T3, 14% developed metastatic disease, and 7% died due to prostate cancer (compared to 38% who died of other causes). Using lifetable analyses, the risk of developing metastatic disease at 5 and 10 years was 8% and 28%, respectively. During follow-up 45% of patients required subsequent treatment due to local and/or distant disease progression. Johansson et al. from the Orebro Medical Center in Orebro, Sweden, have updated a series of patients with clinically localized prostate cancer, at different periods.12–14 Their most recent update14 summarized 223 patients with tumor confined to the prostate (T0-T2) who received no initial treatment for their disease. The mean age of these patients was 72 years, and the average follow-up was 168 months. Of these patients, 13% developed metastatic disease, 11% died of prostate cancer, and in 2%, prostate cancer was a contributing cause of death. Prostate-cancerspecific survival (reported as corrected survival by the authors) at 10 and 15 years was 85.6% and 80.9%, respectively. The risk of disease progression was substantial— 45% at 10 years and 57% at 15 years of follow-up. Albertsen’s second review of the Connecticut Tumor Registry comprised 767 men with localized prostate cancer who were managed without treatment between the years 1971 and 1984.15 Although the series included men without evidence of metastases, the staging of the patients was relatively haphazard (see footnote to Table 13–1). Nevertheless, the authors’ review had a number of strengths, including long follow-up, complete re-review of pathology by Dr. Gleason, and assignment of cause of death. By doing so, the authors were able to create a series of figures that displayed the patients’ overall survival and disease-specific survival, on the basis of age at diagnosis and biopsy Gleason score. A report of 278 patients with prostate cancer managed by surveillance alone was presented by Handley et al. from Newcastle upon Tyne.16 Staging information was sparse at best in this report with no T-stage reported, no mention of use of bone scans, and no patient undergoing lymph node staging—all this despite the fact that the patients were diagnosed between 1978 and 1985. The follow-up period was short (mean 41 months) and the average patient age was 73.1 years. While 54 patients (19.4%) were known to have metastases, prostate cancer was cited as the cause of


death in 42% of the total number of patients. Additionally, 49% of patients required treatment during follow-up, of whom 83% received hormonal therapy. Although the authors reported that 75% of patients had T0-2 disease at diagnosis, the results of this series are distinctly different from almost all contemporary series of prostate cancer and probably reflect substantial understaging bias. Another series of patients from Scandinavia (the Norwegian Radium Hospital in Oslo) was the subject of the report of Waaler and Stenwig.17 Of 94 patients, 66 were T0NxM0, and 28 were T1-T2NxM0, with an average age of 73.3 and 74.5 years, respectively. Unfortunately, due to the short period of follow-up, only 5-year data were available regarding outcomes. One of the few United States series of untreated patients with localized prostate cancer hailed from Memorial Sloan-Kettering Cancer Center (MSKCC).18 Illustrating the degree of patient selection, the 75 patients reported in the series were a small fraction of the more than 4000 patients evaluated at MSKCC during that same period. Patients were staged in accordance with Whitmore’s staging system of that time (the same system used by the American Joint Commission on Cancer in their 4th edition of the staging manual): B1—palpable tumor ≤ 2 cm in diameter, B2—palpable unilateral tumor > 2cm in diameter, B3—palpable bilateral disease. The mean patient age for the three groups was somewhat lower than in previous series: 65, 67, and 69 years, respectively. The mean follow-up was extremely long— 133, 130, and 108 months. During follow-up, metastatic disease developed in 21% of patients with B1 disease, 46% of patients with B2 disease, and 22% of patients with B3 disease. Nevertheless, the median survival was substantial: > 200 months in B1 disease, > 125 months in B2 disease, and 190 months in B3 disease. Survival at 5, 10, and 15 years is displayed in Table 13–1. In a series of 120 patients without metastatic disease diagnosed between 1980 and 1986 from the University of South Manchester, United Kingdom, George noted a mean age of 74.8 years and had a follow-up of between 1 and 7 years.19 While palpable local progression was noted in 84% of patients, metastases developed in 11%, and death from prostate cancer was noted in 4% (compared with the rate of death from other causes of 40%). A unique study of a large number of patients from Göteborg, Sweden, was reported in 1995 by Aus et al.20 Of the 514 patients, 301 had no evidence of metastases at diagnosis. Unfortunately, it is difficult to determine the number of men who were T1-T2 as 158 of 301 were classified as T2b-T3 at diagnosis. Additionally, the authors selected patients who had prostate cancer and died between 1988 and 1991. As such, a death endpoint was reached in all patients. By using this methodology, the authors reported that they had completed the evaluation of cause of death in all patients and therefore could

report complete prostate-cancer-specific survival in all patients. A close evaluation of their Kaplan-Meier survival curves notes that all curves go to zero at 25 years of follow-up. From this projection, the authors concluded that ultimate cancer mortality rate in patients with M0 disease was 50% and among 65 patients who survived at least 10 years, mortality was 63%. The techniques of analysis used by the authors in this study have been called into question by a number of investigators. Of first concern is the attribution of prostate cancer death. We have demonstrated that such attribution is often extremely difficult and that survival curves can change dramatically, on the basis of individual interpretations of cause of death.21 Additionally, the act of censoring patients who die of other causes should prevent disease-specific survival curves from “going to zero,” as is seen in virtually all displays in Aus’ paper.20 As such, the accuracy of the authors’ estimates is of some concern.

Meta-analysis of Outcomes Data In 1994, Chodak published the results of a by-patient meta-analysis of six surveillance series comprising 828 patients.22 The principal conclusion of the authors was the impact of tumor grade on outcome. At 10 years, disease-specific survival for well-differentiated and moderately differentiated tumors was 87% and was 34% for poorly differentiated tumors. Of note, the authors also conducted an analysis of metastatic disease-specific survival, finding 10-year results of 81% for welldifferentiated tumors, 58% for moderately differentiated tumors, and 26% for poorly differentiated tumors. This second analysis is extremely important as it must be recalled that (1) the median age for most surveillance series is approximately 72 years, and (2) the evidence is compelling that the median survival for patients with metastatic prostate cancer is 2 years. Thus, if surveillance is offered to younger men, the likelihood of death from prostate cancer is extremely high within 10 to 12 years of follow-up.

Characteristics of Prostate Cancers Currently Detected It is well known that prostate cancer is a ubiquitous disease among older men if autopsy data are used for analysis. Data from these autopsy series suggest that prostate cancer can be found in 34% of men in the fifth decade of life and in as many as 54% of men in their eighth decade.23,24 From these data, some have suggested that prostate cancer screening will detect many of these indolent, “autopsy” tumors. Evidence suggests otherwise. In the American Cancer Society–National Prostate Cancer Detection Project, 2999 men aged 55 to 70 years underwent DRE, transrectal ultrasonography, and prostate-specific antigen (PSA) determi-


nations on an annual basis for up to 5 years.25 In these men, a total of 164 tumors were detected, with 83 found during the first year (the so-called “harvest effect”). During the subsequent years, 2 to 5 prostate cancers were found in 38, 16, 21, and 6 patients. Similar findings were published by Catalona in a series of 10,251 men who underwent prostate cancer screening.26 During the initial examination, 174 prostate cancers were detected, and during follow-up screens, 165 tumors were detected. Thus, during both initial and follow-up examinations, 339 tumors were detected in 10,251 men (a total of 2.3%), far different from the 30 to 60% rate of autopsy tumors. It thus appears likely that screening for prostate cancer with DRE and PSA will result in the detection of only a fraction of the “autopsy” tumors. It remains to be determined, however, if these screening programs will detect tumors that are of no clinical significance. Evidence is compelling from a number of studies that the tumors detected using current techniques of screening are truly of clinical significance. Ohori et al. conducted a study of 306 patients treated with radical prostatectomy for clinically localized prostate cancer and compared them with 90 patients who underwent cystoprostatectomy for invasive bladder cancer and who had no evidence of prostate cancer.27 The authors characterized radical prostatectomy specimens by tumor volume, grade, and pathologic stage and applied these criteria to all prostate tumors found in cystoprostatectomy specimens. Tumors were categorized as “unimportant” (less than 0.5 cm3, confined to the prostate, and no Gleason 4 or 5 component), “clinically important and curable” (> 0.5 cm3 or Gleason 4 to 5 and organ-confined), or “clinically important and advanced” (extraprostatic disease). These three categories proved to be reliable predictors of outcome with 5-year progression-free survivals of 100%, 86%, and 45%, respectively. When these categories were applied to cystectomy specimens, 78% were unimportant, 22% were important-curable, and none were advanced. Conversely, radical prostatectomy specimens included only 9% of unimportant tumors but had 62% important-curable tumors and 29% advanced tumors. Similar findings were reported by Smith and Catalona.28 In a series of 24,346 men undergoing screening, 1059 prostate cancers were detected. Of these men, 816 underwent surgical staging, allowing a determination of pathologic tumor stage. Of this group, only 25 (3%) were found to have microfocal, well-differentiated disease. A similar analysis by Dugan and colleagues using PSA doubling time estimates and tumor volumes in radical prostatectomy specimens estimated that clinically insignificant disease was treated with radical prostatectomy in between 0.3 and 14.5% of patients.29 These data thus suggest that the prostate tumors currently diagnosed with PSA screening and contemporary methods of prostate biopsy closely resemble those tumors

that have proved to be of significance over the years of experience as illustrated in Table 13–1. Optimistic data have been presented by Catalona et al. that with serial screening, the likelihood of organ-confined (and therefore, curable) disease increases.26 The combination of these observations suggests that intervention with serial screening may indeed alter the natural history of the disease if a curative treatment is imposed.

Decision Analyses While not specifically designed to determine the natural history of localized prostate cancer, several decision analyses have been published over the past 5 to 6 years that have addressed a similar question: the impact and utility of prostate cancer screening or treatment for localized disease. Many of the conclusions reached from these decision analyses are based on estimates of the natural history of the disease and therefore will be discussed in this chapter. The first such analysis was performed by Fleming et al.30 The authors developed a series of outcomes for men 60 to 75 years of age, using estimates of the disutility of complications of treatment and of the disease and concluded that only with the most optimistic assumptions regarding treatment efficacy would treatment for prostate cancer affect patient outcomes. Unfortunately, for reasons that are inexplicable, of the five natural history studies of prostate cancer that the authors used to estimate what would happen to patients if tumors were left untreated, four studies reported on results of T1a disease. (As stated above, T1a disease unquestionably behaves in an indolent fashion and is undeniably different from T1b-T2 disease in all respects.) Additionally, the disutility of a variety of complications is very much at odds with the experience of any clinician who manages prostate cancer. For example, treatment-related impotence and incontinence were given disutility factors of 95% and 70%, respectively. While these indeed may seem reasonable, how it can be appropriate to give hormonally responsive metastatic prostate cancer a disutility rate of 90% is hard to understand. With these issues in mind, it is not surprising that the authors came to the conclusion that treatment had little effect on the natural history of the disease. A similar analysis of prostate cancer screening was conducted by Krahn et al.31 The authors in this study used only one estimate for the natural history of the disease, that of Johansson. In addition to the problems inherent in using data from 70-year-old men to develop a decision analysis applied to men 50 to 70 years of age is the issue concerning the initial exclusion of men with poorly differentiated disease from Johansson’s study. As can be seen from Table 13–1, while Johansson’s study provides one estimate, there is considerable variation in the estimates of these outcomes. Of note, the authors did find that screening with PSA alone was relatively cost effective with an


incremental cost-utility ratio of $42,000 per qualityadjusted life-year gained in 50-year old men. While this may seem to be a relatively high cost, it is very much in line with other therapeutic and preventive interventions.

Conclusion With a change in how prostate cancer has been diagnosed and staged over the past five decades, a change in the anticipated natural history of the disease has been witnessed. Current data suggest that prostate cancer diagnosed in a man with a 10- to 15-year anticipated life expectancy places the patient at substantial risk for disease progression and metastatic disease as well as for death due to the disease. Outcome seems to be intimately related to tumor grade; while well-differentiated tumors have a small impact on life expectancy, moderately and poorly differentiated tumors may result in a 4- to 8-year reduction in a patient’s lifespan. The opinions expressed herein are those of the authors and do not necessarily reflect those of the Departments of the Army or Defense.

References 1. Sheldon CA, Williams RD, Fraley EE. Incidental carcinoma of the prostate: a review of the literature and critical reappraisal of classification. J Urol 1980;124:626–31. 2. Endrizzi J, Thompson IM. The disappearance of well-differentiated prostate cancer due to PSA screening and decrease in number of transurethral resections of the prostate. Proceedings of the Kimbrough Urological Seminar; San Antonio (TX): Society of Urologists: Government Service; 1998. 3. Hanash KA, Utz DC, Cook EN, et al. Carcinoma of the prostate: a 15-year followup. J Urol 1972;107:450–3. 4. Cook GB, Watson FR. Twenty single nodules of prostate cancer not treated by total prostatectomy. J Urol 1968; 100:672–4. 5. Bumpus HC. Carcinoma of the prostate: a comparative study of modes of treatment. J Urol 1940;44:169. 6. Barnes R, Hirst A, Rosenquist R. Early carcinoma of the prostate: comparison of stages A and B. J Urol 1976; 115:404–5. 7. Madsen PO, Graversen PH, Gasser TC, Corle DK. Treatment of localized prostatic cancer. Radical prostatectomy versus placebo. A 15-year followup. Scand J Urol Nephrol 1988;110 Suppl:95–100. 8. Albertsen PC, Fryback DG, Storer BE, et al. Long-term survival among men with conservatively treated localized prostate cancer. JAMA 1995;274:626–31. 9. Lerner SP, Seale-Hawkins C, Carlton CE, Scardino PT. The risk of dying of prostate cancer in patients with clinically localized disease. J Urol 1991;146:1040–5. 10. Adolfsson J, Carstensen J, Lowhagen T. Natural course of clinically localized prostate adenocarcinoma in men less than 70 years old. J Urol 1991;146:96–8. 11. Adolfsson J, Carstensen J. Deferred treatment in clinically localised prostatic carcinoma. Br J Urol 1992;69:183–7. 12. Johansson JE, Adami HO, Andersson SO, et al. Natural

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30.

31.

history of localised prostatic cancer. Lancet 1989;1: 799–803. Johansson JE, Adami HO, Andersson SO, et al. High 10year survival rate in patients with early, untreated prostatic cancer. JAMA 1992;267:2191–6. Johansson JE, Holmberg L, Johansson S, et al. Fifteen-year survival in prostate cancer. A prospective, populationbased study in Sweden. JAMA 1997;277:467–71. Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998;280:975–80. Handley R, Carr TW, Travis D, et al. Deferred treatment for prostate cancer. Br J Urol 1988;62:249–53. Waaler G, Stenwig AE. Prognosis of localised prostatic cancer managed by “Watch and Wait” policy. Br J Urol 1993;72:214–9. Whitmore WF, Warner JA, Thompson IM. Expectant management of localized prostatic cancer. Cancer 1991;67:1091–6. George NJR. Natural history of localised prostatic cancer managed by conservative therapy alone. Lancet 1988;1: 494–6. Aus G, Hugosson J, Norlen L. Long-term survival and mortality in prostate cancer treated with noncurative intent. J Urol 1995;154:460–5. Clark J, Lillis P, O’Rourke T, et al. Reliability of disease specific survival in prostate cancer trials. Mol Urol. [In press] Chodak GW, Thisted RA, Gerber GS, et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994;330:242–8. Woolf SH. Screening for prostate cancer with prostatespecific antigen: an examination of the evidence. N Engl J Med 1995;333:1401. Sakr WA, Haas GP, Cassin BF, et al. The frequency of carcinoma and intraepithelial neoplasia of the prostate in young male patients. J Urol 1993;150:379. Mettlin C, Murphy GP, Lee F, et al. Characteristics of prostate cancer detected in the American Cancer Society—National Prostate Cancer Detection Project. J Urol 1994;152:1737–40. Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993; 270:948–54. Ohori M, Wheeler TM, Dunn JK, et al. The pathological features and prognosis of prostate cancer detectable with current diagnostic tests. J Urol 1994;152:1714–20. Smith DS, Catalona WJ. The nature of prostate cancer detected through prostate specific antigen based screening. J Urol 1994;152:1732–6. Dugan JA, Bostwick DG, Myers RP, et al. The definition and preoperative prediction of clinically insignificant prostate cancer. JAMA 1996;275:288–94. Fleming C, Wasson JH, Albertsen PC, et al. A decision analysis of alternative treatment strategies for clinically localized prostate cancer. JAMA 1993;269:2650–8. Krahn MD, Mahoney JE, Eckman MH, et al. Screening for prostate cancer: a decision analytic view. JAMA 1994; 272:773–80.

CHAPTER 14

PROSTATE PHYSIOLOGY AND REGULATION SUSAN R. MARENGO, PHD ing by day 19.7,8 At birth, the rodent prostatic epithelium predominately expresses cytokeratins characteristic of basal cells.8,9 Differentiation of the basal epithelium into distinct luminal (cytokeratins 8, 18, 19) and basal epithelia (cytokeratins 5, 7, 14, and 19) begins during the first 7 to 10 days of life, concomitant with canalization of the prostatic ducts (proximal [urethra] then distal [acinus]).8,9 At birth, the mesenchyme is strongly androgen-receptor positive, with small amounts of androgen receptor being expressed in the basal epithelium.8,9 As differentiation proceeds, the luminal epithelial cells come to express the highest levels of androgen receptor, although some expression remains in the stroma.7–9 Five α-reductase types I and II are detectable in the undifferentiated urogenital sinus and in the developing prostate, with type I localized to the epithelium and type II to the mesenchyme.10,11 For a more detailed discussion of prostatic ductule development in the mouse, the reader is referred to a series of studies by Cunha and associates.11–13 The elegant studies of Cunha and Chung demonstrated that the urogenital sinus mesenchyme is responsible for the induction of a prostatic phenotype in the urogenital sinus.14 Subsequent studies demonstrated that this induction includes the induction of expressed prostatic proteins.15,16 In the fetal rat, the androgen receptors are largely localized in the stromal rather than the epithelial compartment, and a lack of androgen receptors in the mesenchyme, but not the epithelium, produces a vaginal rather than a prostatic phenotype (Figure 14–1).8,9,14,17 In the fetal human prostate, androgen receptors have been localized in the smooth muscle and epithelial cells by in situ hybridization and immunohistochemistry.3,18 Using the reconstituted prostate model, Hayward and associates19 demonstrated that stromal-epithelial crosstalk goes both ways, and that combining human epithelium with murine mesenchyme results in the development of a stroma phenotypically resembling the human prostatic stroma, with its high proportion and liberal distribution of smooth muscle fibers.

This chapter focuses on the normal physiology of the human prostate and its regulation. Because of the pronounced interspecies variation in the types of accessory sex glands present and the constitution of their secretions, this review cannot be considered a review of general prostatic physiology that can be extrapolated to other species. Since the rodent model (rats and mice) has been utilized extensively as a model for investigation of prostatic physiology and pathology, these species will be included where pertinent.

Development and Anatomy Development The prostate originates from five pairs of buds arising on the posterior side of the urogenital sinus on either side of the verumontanum, which then invade the mesenchyme of the urogenital sinus.1,2 The topmost buds arise from the inner mesoderm and eventually develop into the transition zone of the human prostate, while the lower buds arising from the endoderm ultimately form the peripheral zones of the prostate.1,2 Cannulation of ductules begins almost immediately.1 The period of development of the fetal prostate (10 to 12 weeks) roughly coincides with that of maximal testosterone production by the fetal testis (12 to 18 weeks). At about 17 weeks, prostatic acid phosphatase (PAP) can be detected within the fetal prostate. Androgen receptor protein can be detected in both the epithelium and stroma of the fetal prostate, while expression of 5 α-reductase protein is limited to the stroma.3 In humans, a distinct anterior lobe is present only until 16 weeks, after which it regresses totally.1 It has been postulated that the central zone arises from the wolffian ducts rather than from the urogenital sinus, which would make its origin mesodermal rather then endodermal.4 Anatomically, the central zone lies in close opposition to the ejaculatory ducts, and its epithelium more closely resembles that of the seminal vesicles than that of the peripheral and transition zones.4 Biochemically, the expression of lectins and pepsinogen II (which has an extremely limited distribution) in the central zone resembles that of the seminal vesicles rather than that of the peripheral zone.5,6 In mice, development of the urogenital structures begins at roughly day 14.7,8 There is a definitive urogenital sinus formed by day 17, with solid epithelial chords form-

Gross Anatomy The gross and microscopic anatomy of the human4,20–22 and rodent23–28 prostates have been described in detail and will be covered only briefly here. The gross anatomy of the human prostate is best described as a zonal arrangement consisting of the peripheral zone (70 to 92

Prostate Physiology and Regulation / 93

75%), central zone (20 to 25%), transitional zone (5 to 10%), and the periurethral zones (approximately 1%) (Figure 14–2).20,24,27 For a comparison of the original lobular nomenclature of prostatic anatomy with that of the currently used zonal nomenclature, the reader is referred to the 1980 work of McNeal.4 The human prostate has two unique features that contribute to the development of the obstructive symptoms of prostatic disease. First, the gland completely surrounds and envelops the urethra, which makes a 35-degree bend at the verumontanum. Second, a large fibrous capsule accounting for approximately one-third of the total prostatic mass covers the entire anterior and anterolateral surface of the gland.20 The capsule is composed primarily of smooth muscle fibers that infiltrate the parenchyma of the gland.20 Pathologically, the three zones have very different profiles. Prostatic cancer (PCa) is most common in the peripheral zone, followed by the transition zone (approximately 20%), and central zone (5 to 10%).20 Prostatic intraepithelial neoplasia (PIN) is limited to the peripheral and central zones in approximately two-thirds of cases.29 In the remaining third, PIN is distributed throughout the three zones.29 Traditionally, benign prostatic hyperplasia (BPH) has been considered a disease solely of the transitional and periurethral zones. Detailed studies, however, have revealed that a small proportion of BPH nodules are located in the peripheral and central zones.30 In contrast to the human prostate, the rodent prostate is clearly divided into three or four lobes26 (see Figure 14–2). The ventral lobe is the largest and rests on the ventral surface of the bladder. There has been discussion as to whether the dorsal and lateral lobes are actually one pair of lobes or two, although they are often harvested as one unit for dissection purposes.26 The final lobe is the coagulating gland or anterior prostate.26 Based largely on the observation that tumors induced in the rodent prostate generally arise in the dorsal-lateral lobe,31–33 it has been proposed that this lobe is analogous to the peripheral zone in the human. Definitive biochemical and anatomic evidence has not yet been obtained, however.

zone. The periurethral zone immediately surrounds the proximal urethra as a series of abortive, embryonic glands without their own periglandular muscularis.35 They do not invade the surrounding urethral muscularis. Although there is zonal variation in the anatomic details, the prototypical prostatic acinus is lined with a tall cuboidal or columnar epithelium connected by desmosomes at the apical pole (for a review of the comparative fine structure of the human and rodent prostate, see the studies by Brandes23 and Price24). The apical boarder is lined with highly variable numbers and sizes of microvilli. The Golgi apparatus and endoplasmic reticulum are located supranuclearly and are highly developed, as is consistent with the cells’ secretory function. Apocrine and merocrine (exocrine) secretion are widely observed in both species. Studies in rats suggest that the

Histology Histologically, the normal adult human prostate consists of three major compartments: stromal (45%), epithelial (21%), and acinar luminal (34%).34 The acini in the peripheral zone are compact and regularly shaped,35 lined by a uniform columnar epithelium, and surrounded by loose and irregularly arranged muscle bundles.35 In contrast, the acini of the central zone are heterogeneous in shape and size, are partially separated by intraluminal ridges, and are closely surrounded by compact stromal muscle bundles.35 The epithelium is crowded and of irregular height and nuclear placement. Surrounding the proximal urethra to the level of the verumontanum is the transitional zone, which histologically resembles the peripheral

FIGURE 14–1. Effects of tissue localization of the androgen receptor on differentiation of the urogenital sinus (UGS). Epithelium and stroma from the urogenital sinuses of wild-type (androgenreceptor positive) or Tfm (androgen-receptor negative) mice were recombined and grafted under the renal capsule. Prostatic epithelium was obtained when wild-type or Tfm epithelium was recombined with wild-type stroma. Recombination of wild-type or Tfm epithelium with Tfm stroma resulted in development of a vaginal morphology. Reproduced with permission from Cunha GR, Chung WK, Shannon JM, Reese BG. Stromal-epithelial interactions in sex differentiation. Biol Reprod 1980;22:19–42.


FIGURE 14–2. Comparison of the gross anatomy of the human (left) and rat (right) prostate. PZ = peripheral zone; CZ = central zone; TZ = transition zone; fm = anterior fibromuscular stroma; UD = distal urethra; UP = proximal urethral segment; E = ejaculatory ducts; bn = bladder neck; s = preprostatic and distal striated urethral sphincters; C = coronal plane; OC = oblique coronal plane; BL = bladder; SV = seminal vesicles; CG = coagulating gland; V = ventral lobe of the prostate; L = lateral lobe of the prostate; D = distal lobe of the prostate; Bur G = bulbourethral gland; UR = urethra; PU = pubis; vas deferens; CE = cauda epididymis. Reproduced with permission from Price D. Comparative aspects of development and structure in the prostate. In: Vollmer EP, editor. Biology of the prostate and related tissues. Vol. XII. Bethesda (MD): Dept. of Health, Education, and Welfare (US); 1963. p. 1–27; and Jesik CJ, Holland JM, Lee C. An anatomic and histologic study of the rat prostate. Prostate 1982;3:81–97.

distal/acinar tips actively undergo mitosis while few, if any, mitotic figures are observed in the intermediate to proximal portions of the ductules.27 In contrast to the tall columnar epithelium observed in the distal and intermediate regions, the epithelium in the proximal region is low cuboidal and contains frequent apoptotic figures.27 Basal cells lie between the luminal epithelium and the basement membrane and do not communicate with the lumen. It has been hypothesized that these cells serve as precursors to the luminal epithelial cells and to replenish the epithelium in the event of androgen withdrawal (e.g., in seasonal breeders).9,36,37 The prostatic stroma is separated from the epithelium by a dense acellular basal lamina. It is composed of smooth muscle cells, fibroblasts, and an extracellular matrix and contains the nerves and vasculature of the organ. The primary cell type in the prostatic stroma is smooth muscle cells, which closely surround the ductules. In humans, the stromal smooth muscle infiltrates the entire stroma and is a major component of the prostate, constituting 22% of the gland.38 There is far less smooth muscle in the rodent prostate, largely limited to thin sheaths of smooth muscle cells enveloping the ductules and acini.38 Fibroblasts are loosely interspersed between the cells of the smooth muscle sheath and the glandular units.38 In both rodents and humans, smooth muscle

cells express the expected markers and are androgenreceptor positive.38 Prostatic neuroendocrine (endocrine-paracrine, amine precursor uptake and decarboxylation [APUD]) cells are believed to differentiate from the prostatic stem cell population. Their presence in the epithelial compartment of normal, hypertrophic, and cancerous prostates has been well documented.39,40 Neuroendocrine cells have been identified in the peripheral zone, the periurethral glands, and the prostatic ducts.41 Immunohistochemical studies of paraffin-embedded tissues have not revealed neuroendocrine cells in rats,42 although neurosecretory granules have been described in the prostate tumors in transgenic mice expressing the Gγ/T-15 viral oncogene. 43 Neuroendocrine cells have two major morphologic phenotypes: open and closed.39,44 Open neuroendocrine cells extend slender processes to the tubule lumen. Closed neuroendocrine cells do not communicate with the lumen but rather extend dendritic-like processes amongst the adjacent exocrine epithelial cells. Ultrastructurally, neuroendocrine cells are distinguished from luminal epithelial cells by heterogeneous, dense-core granules (neurosecretory granules).39,40 Androgen receptors have been reported to be both present45 and absent46 from neuroendocrine cells, although the disappearance of neuroendocrine cells from the acini of newborns shortly after


birth and their reappearance at puberty41 argues for either direct or indirect (paracrine) androgen regulation. The function of neuroendocrine cells within the prostate is not known. Based on morphology, however, some type of secretion or monitoring of luminal contents by open neuroendocrine cells seems likely.39,40,44 The most common proteins identified within the cytoplasm granules are chromogranins A and B, secretogranin, neuron-specific enolase, and serotonin, although calcitonin, katacalin, somatostatin, and bombesin/gastrin-related peptide have also been detected.39,40 Frequently, a given tumor will express multiple peptides.40,47 Although neuroendocrine cells express a cytokeratin profile more characteristic of basal than luminal epithelial cells,39,48 both prostate-specific antigen (PSA) and prostatic acid phosphatase have been detected in neuroendocrine cells.47,49 Additionally, neuroendocrine cells have been observed to cluster around afferent and efferent nerves, posing the possibility that they may regulate this axis.44 Based on the frequent presence of neuroendocrine cells within clusters of proliferating cells in PCa and BPH, it is also possible that these cells are involved in paracrine regulation of prostatic growth.46,50 The neuroendocrine cells themselves are apparently postmitotic and do not express proliferation markers.51,52

Prostatic Function and Secretions Under natural mating conditions, the secretions of the accessory sex glands function to (1) dilute the caudal epididymal sperm to the appropriate concentration and volume; (2) remove urine and bacteria from the urethra; (3) provide appropriate buffering and energy sources for the sperm until they leave the site of deposition and begin their ascent up the female reproductive tract ; (4) remove the motility and capacitation inhibitors necessary in the epididymis to ensure a fresh product; and (5) in species exhibiting postejaculatory solidification of the semen, such as rats/mice and humans, provide the chemical components for solidification and, if appropriate, dissolution of the seminal clot. Sperm removed from the epididymis in humans and other species53,54 can fertilize ova, indicating that the secretions of the accessory sex glands are not essential for fertility, at least under laboratory conditions. However, under natural conditions fertility has not been optimized through genetics, management, or advanced reproductive technology and the secretions of the accessory sex glands are likely to play a larger role in maximizing the male’s fertility than is apparent under laboratory conditions. Ionic Composition The composition of human prostatic fluid and that of other mammalian species has been detailed in Aumuller2 and in Setchell et al.55 Little is known about the biochemical composition of rat prostatic fluid. In humans, the prostate contributes about 0.5 to 1 mL to the total

ejaculate (2 to 6 mL total ejaculate, 40 to 240 million sperm per mL).56,57 Due to the high concentration of citric acid (approximately 91 mM, range 45 to 176 mM), the pH is slightly acidic at 6.5. Compared to plasma and interstitial fluid, human prostate secretions contain extremely high levels of divalent cations, including Ca++, Zn++, and Mg++, roughly equivalent amounts of Na+, and relatively low amounts of Cl– and HCO3–. Protein averages about 24 mg per mL. The primary sugar present is inositol (8.2 mM), with low levels of glucose (0.9 mM) and virtually no fructose. Citrate In many species, the concentration of citrate in the semen (5 to 50 mM) greatly exceeds that of the blood (0.07 to 0.12 mM).21 In humans, the peripheral zone of the prostate is the primary source of seminal citrate, while in the rat, citrate is secreted by the lateral and ventral lobes of the prostate as well as by the seminal vesicles.21,55 Because of its key role in the tricarboxylic acid cycle (TCA) and in fatty-acid synthesis, citrate is conserved rather than secreted by most tissues. In contrast, the human prostate is able to concentrate citrate in the prostatic fluid to levels of 24 to 130 mM (making it the predominant anion), compared to plasma/extracellular concentrations of 0.1 mM.21 Mitochondrial aconitate hydratase activity (citrate catalyzed to isocitrate) is inhibited by chelation with Zn++; 21,58 the excess citrate then replaces Cl – as the primary anion utilized by the luminal sodium transporter (Figure 14–3).21,59 Replenishment of four carbon submits for the TCA cycle is accomplished by a citrate-stimulated sodium-aspartate pump on the basal surface of the epithelium and subsequent transamination of aspartate to oxaloacetate.59,60 Citrate is likely to act as a seminal buffering agent, a chelator of free Ca++ and Zn++,61,62 and possibly a scavenger of free radicals.63 Given the role of free Ca++ in inducing capacitation,64 it may be that citrate is acting to prevent premature capacitation in the female reproductive tract. Zinc Zinc is concentrated in the prostatic fluid and the apical and mitochondrial portions of the prostatic epithelium.65,66 Concentrations of Zn++ are highest in the lateral portions of the peripheral zone in humans65 and in the lateral lobes of the prostate of the rat, with little if any present in the dorsal and ventral lobes of the prostate.65,66 High levels of Zn++ in the prostatic fluid may inhibit the enzymatic activity of secreted proteases such as PSA.67 In semen, most of the Zn++ is bound to either citrate or metallothionein, both also secreted by the prostate.68,69 Zinc has been demonstrated to bind ejaculated sperm in its free and bound states70 and has been hypothesized to play roles in the inhibition of nuclear decondensation.68,71


FIGURE 14–3. Aspartate transport and citrate production in prostate luminal epithelial cells. The low affinity L-aspartate transporter Na+-K+ ATPase and a citrate transporter are represented at the apical membrane. The high affinity L-aspartate transporter and glucose transporters are represented in the basal membrane. Reproduced with permission from Lao L, Franklin RB, Costello LC. High-affinity L-aspartate transporter in prostate epithelial cells that is regulated by testosterone. Prostate 1993;22:53–63.

Inositol Human and rat prostates have relatively high concentrations of myo-inositol.72–74 In the rat, 3-hydro-myo-inositol injected systemically is concentrated in the prostate, especially in the coagulating gland and prostatic fluid,72,73 and synthesis of myo-inositol from glucose has been demonstrated in the ventral prostate.75 Ejaculated human sperm have not been demonstrated to metabolize inositol,76 and its function in the seminal plasma is unknown. Polyamines Humans and rats (but not mice) are unique in that their prostates have very high levels of ornithine decarboxylase (ODC) (EC 4.1.1.17) activity, with the prostatic fluid containing high levels of polyamines.77,78 In human semen, concentrations of spermine are 10 times greater than putrescine or spermidine,77,78 while in the rat ventral prostate spermidine is the most abundant, followed by putrescine and cadaverine.79 Expression of ODC is localized to the luminal epithelium.80 In the rat, regulation of ODC activity differs with the lobe involved. In pubertal rats or in testosterone-supplemented castrates, ODC activity in the dorsal lateral prostate parallels that of lobe proliferation.81 In contrast, such a correlation has not been detected in the ventral prostate,

suggesting a differential regulation of this enzyme between lobes and regions of the prostate. It is believed that the primary function of ODC in the ventral prostate is to synthesize and secrete the polyamines spermine and spermidine into the prostatic fluid.77,78,82 The role of polyamines in the semen is not known, although they have been speculated to play a role in seminal clot formation, to act as bactericides, and to be involved in sperm motility or metabolism.55,78 Ornithine decarboxylase is a 54-kDa cytosolic protein that functions as a homodimer to catalyze the first and rate-limiting step in the polyamine cascade.83,84 Polyamines play a crucial but poorly defined role in progression from the G1 to S phase of the cell cycle; not unexpectedly, ODC expression is very tightly regulated, with three pathways (regulation of transcription and translation, of mRNA, and of protein degradation) employed to keep activity in check.83,84 Epithelial proliferation in the normal prostate as judged by any one of a number of proliferation indices is very low at 0.14 to 1.7% (Ki-67: 0.2 to 1.5%),85,86 with the cellular turnover of the organ being estimated to be in the neighborhood of 1.5 to 2 years.87 The prostate would therefore not be expected to express constitutively high levels of ODC. The mechanism by which the prostate avoids polyamine-induced downregulation of ODC,83,84 or ODC-induced tumorigenesis,88 is not known.


Prostasomes Human prostatic secretions also contain 150 to 200 nm vesicles, typically coated with a trilaminar membrane and released by exocytosis from the prostatic epithelium.89 The prostasome membrane contains Mg++/Ca++ dependent adenosinetriphosphatase (ATPase), which may be responsible for the transport and concentration of Ca++ within the prostasome.89 Prostasomes have abundant enzymatic activity, including multiple ATPases,89 serine/ threonine kinase,89 alkaline phosphatase, 5'-nucleotidase, alkaline phosphodiesterase,90 and aminopeptidases.91 They also contain chromogranin B, neuropeptide Y, and vasoactive intestinal polypeptide.92 Prostasomes are unusual in that their membranes contain high levels of cholesterol and sphingomyelin and relatively low levels of phosphatidylcholine,93 resulting in a highly ordered, very fluid membrane.94 Sperm and prostasomes are able to fuse,94 and the transfer of lipids and proteins from prostasome to sperm has been reported.91,94,95 Prostasomes have been observed to stimulate sperm motility,89,96 increase sperm-membrane fluidity,94 and provide immunologic protection.95,97 Proteins Prostatic secretions include a variety of growth factors (epidermal growth factor [EGF]/transforming growth factor [TGF]-α;98 vascular endothelial growth factor;99 and hepatocyte growth factor/scatter factor100), proteases,101–104 phosphatases,105 and binding proteins.102,106–108 In humans, the primary secreted proteins are PSA, PAP, and βmicroseminoprotein (β-MSP or β-inhibin).102 In the rat, the primary secreted proteins are prostatic-binding protein (PBP) (30 to 50%)109and cystain-related protein (5 to 10%).107 Due to space limitations, discussion will be confined to those proteins that have been well characterized or exploited for diagnostic and experimental use. Prostatic-Binding Protein Prostatic-binding protein is secreted by both the rodent and human prostate and has been referred to variously as prostatein and estramustine-binding protein.110 It is a member of the uteroglobulin superfamily of proteins and is a serine protease.111 In the rat, PBP is the major secretory protein of the prostate, with its expression limited to the ventral lobe.16,112 In humans, PBP is a minor prostatic secretory product113 and is expressed in a variety of organs, including the liver and colon.114 Prostaticbinding/estramustine-binding protein has been detected in the normal and diseased human prostate.115,116 It is a tetramer with one subunit composed of C1-C3 submits and the other of C1-C2 submits.117 The function of PBP in vivo is not known. As well as binding estramustine, PBP binds lipids, steroids, and polyamines, and can prevent the androgen receptor from binding to deoxyribonucleic acid (DNA).112,118,119 It may

serve to traffic secretory products out of the cell, as 3-hydro-estramustine injected into rats is localized first in the prostate, then in the acinar lumens.120 The expression of PBP has been studied extensively, however, in gaining a better understanding of the regulation of the androgen-promoter and differentiation function of the ventral prostate.16,107,121 As radiolabeled PBP injected intraperitoneally has been shown to be taken up by the prostate,122 it is possible that PBP could act as a carrier for chemotherapeutic agents in PCa. Prostatic-binding/ estramustine-binding proteins act as a “ligand,” and estramustine phosphate is currently being investigated as neoadjuvant therapy in PCa,123,124 given its ability to arrest cells in the G2 to M phase of the cell cycle and its enhancement of the effectiveness of radiation therapy both in vitro and in vivo.125,126 Kallikreins The human kallikrein family of serine proteases currently consists of: (1) hK1, which is expressed in the pancreas, kidney, and submandibular salivary gland; (2) hK2, human glandular kallikrein; and (3) hK3, or PSA—the latter two are expressed by the prostatic epithelium.101,127,128 While the expression of PSA is highest in the prostate, it has been detected in a variety of tissues in both sexes, most notably in that of the normal and cancerous breast.101,128 Prostate-specific antigen is expressed by the prostates of other primates but has not yet been detected in the prostates of other genera.101 Rodent semen also coagulates, but the seminal clot forms a rigid copulatory plug which does not dissolve, thus preventing intercourse with rival males and backwash of the sperm out of the vagina.82 At ejaculation, enzymes secreted by the anterior prostate (coagulating gland) catalyze the crosslinking of proteins secreted by the seminal vesicles. Removal of the plug or coagulating glands substantially reduces the fertility of a given male. Prostate-specific antigen is a 33- to 34-kDa singlechain glycoprotein with chymotrypsin-like activity, as opposed to the trypsin-like activity displayed by the other human kallikreins.101,128 Like other proteases, PSA is initially secreted as a zymogen that is rapidly activated in the semen, possibly by a cascade including hK2.129 In the undiseased prostate, most if not all of the PSA is secreted luminally.101,128 At ejaculation, sperm are mixed with the secretions of the accessory sex glands (Figure 14–4). The major protein secreted by the seminal vesicles is semenogelin, which reversibly immobilizes the sperm and causes coagulation of the semen.130,131 Seminal coagulation is not required for sperm immobilization by semenogelin.131 Within 5 to 20 minutes of ejaculation, PSA enzymatically dissolves the clot,130 thus freeing the sperm to enter the cervical crypts and begin the ascent up the female reproductive tract. The purpose of the clot and sperm immobilization is not known. Indeed, immobile or


dead sperm are rapidly expelled from the vagina, leaving those sequestered within the cervical crypts to fertilize the ova.57 Prostate-specific antigen also activates seminal α2-macroglobulin, a nonspecific protease inhibitor, which by exposing its binding sites allows sperm to bind to it.132 In the normal prostate, the vast majority of PSA is secreted apically into the prostatic fluid; serum levels of PSA are negligible. However, in patients with BPH and prostate cancer, substantial amounts of PSA are secreted basely, allowing the protein to be detected in the blood and utilized for diagnostic and follow-up purposes. It has been demonstrated in vitro133,134 that PSA is able to degrade insulin-like growth factor binding protein 3 (IGFBP-3), thus liberating insulin-like growth factors (IGF-I, IGF-II) to bind to receptors on the prostate cell membrane and stimulate growth.134,135 If PSA also plays a substantial role in liberating growth factors from their binding proteins in situ, then the presence of PSA in the stromal compartment under either natural or pathologic conditions could be an important mechanism regulating prostatic growth. Prostatic Acid Phosphatase For a detailed review of the structure of PAP and its properties in the human prostate, the reader is referred to Moss and colleagues136 and Chu and colleagues.137 Prostatic acid phosphatase is a member of the nonspecific orthophosphate monoesterase family, of which there are four distinct types: those with widespread distribution (erythrocytic and lysosomal), those that are largely organ/cell specific, and those that are prostatic and macrophagic. Prostatic acid phosphatase is a glycopeptide

of about 41 to 50 kDa, although dimers and trimers (enzymatically active form) held together by noncovalent bonds are common. Enzymatic activity is maximal at pH 5.0. The specific substrate for PAP or its discrete function has not yet been determined. Prostatic acid phosphatase is a general phosphatase that can dephosphorylate serine, threonine, or tyrosine;138 recent evidence indicates that PAP may regulate the phosphorylation of transmembrane growth factor receptors.139 Variable sialization results in at least three isoenzymes, with 2a comprising the majority (approximately 95%) of the enzyme and being the isoform detected in the blood during screening for the resurgence of PCa. The specific function of PAP within the prostatic secretions is not known. Following the identification of PAP in the serum of patients with PCa140 and the discovery that expression of the patient’s protein is positively regulated by androgens,105 PAP was utilized for the detection of disseminated prostatic carcinoma (capsular extravasation, or metastasis) using enzymatic and later immunologic assays. However, due to methodologic difficulties and the inability to detect PAP in the serum until after dissemination of the disease, its usefulness as a marker for PCa has been limited.136 Recently, it has been proposed that PAP may negatively regulate phosphorylation of membrane tyrosine kinases such as P185erbB-2.139 The epithelium of the ventral prostate of the rat also produces an acid phosphatase (P150), which has an approximate 75% homology to human PAP, a short signal sequence, lacks a membrane anchoring sequence, and is regulated by androgens.141,142 Unlike human PAP, rat PAP is not inhibited by tartrate.136,141

FIGURE 14–4. Proposed functions of prostate-specific antigen (PSA). IGF-I = insulin-like growth factor I; IGFBP-3 = insulin-like growth factor binding protein 3; IGFR-I = insulin-like growth factor receptor I. Adapted from Jones et al.,184 Cohen et al.,134 Lilja,130 and Robert et al.67


Beta-Inhibin/Beta-Microseminoprotein Beta-Inhibin, or β-microseminoprotein, is a nonglycosylated heterodimer consisting of alpha and beta subunits of a roughly 18-kDa protein. It is related to the transforming growth factor/immunoglobulin-binding superfamilies143 and is expressed by the epithelia of both the rat and human prostates.102,144 In addition to its role as an ovarian/testicular-produced negative regulator of pituitary follicle-stimulating hormone (FSH) secretion,143 it is readily detected in the linings of the reproductive, respiratory, gastrointestinal, and urinary tracts, especially in the mucosal cells.145 It is also readily detected in human seminal fluid and binds to ejaculated sperm.146 Although one of the three major secretory proteins produced by the human prostate,102 the role of βinhibin/β-microseminoprotein in prostatic physiology and pathology has not been intensively researched. Probasin Probasin is a 20-kDa, single-chain, highly basic (pI approximately 11.5) nonhistone protein that localizes to the prostatic secretions, secretory granules, and epithelial nuclei.136,147 The differential localization appears to be due to multiple transcripts with and without a signal peptide for secretion.148 The primary site of expression is the dorsal lateral prostate, although small amounts are also expressed in the ventral prostate.149 Not surprisingly, the expression of probasin is regulated by androgens.147,149 Based on sequence homology, probasin is a member of the ligand-binding family,148 which includes retinol-binding protein and α2-macroglobulin.150 The function of probasin within the prostate is not known, although it is known to be a heparin-binding protein and to have little if any mitogenic effects on the prostatic epithelium in vitro.151 In research, it has been used as a marker of androgen-dependent differentiation of the dorsal lateral prostate,121,152 in elucidation of androgen regulation of gene expression,153,154and through its promoter to target androgen-dependent gene expression to the prostate.31

Regulation of Prostatic Function and Growth Although androgens play a key role in the regulation of prostatic growth, function, and disease, it is now clear that they act in concert with, or as a backdrop for, a host of other regulatory pathways. Prostatic growth and the development of differentiated function take place under the influence of increased expression of testosterone during puberty,1,2 although castration prior to puberty does not entirely prevent subsequent prostatic growth.155,156 Once its mature size is reached, however, the prostate and other accessory sex glands cease growing, even though testosterone levels remain elevated. Supraphysiologic doses of exogenous testosterone do not

stimulate additional growth.157,158 Withdrawal of testosterone results in massive involution of the gland, characterized by apoptosis of the secretory epithelium.105,159 At maturity, therefore, testosterone becomes responsible for survival of the prostate and maintenance of its differentiated functions. The mechanism for this switch from a growth stimulator to a maintenance factor is not known but could be of prime importance in understanding the renewal of testosterone’s ability to stimulate prostatic growth in PCa and BPH. From an evolutionary standpoint, the majority of mammals are seasonal breeders and show drastic decreases in testosterone levels during the nonbreeding season. Thus, there must be a mechanism to either maintain prostatic function during the nonbreeding season or reinitiate it during sexual recrudescence.36,37 It is not unreasonable to assume that vestiges of these mechanisms would be present in the prostates of nonseasonal breeders such as humans. It is not known if the androgen-independent cells of advanced prostatic carcinoma are originally derived from the stem cells that survive during the nonbreeding season or if they are androgen-dependent cells that have developed the capacity to utilize other mechanisms to support their growth in the absence of androgens. Endocrine Regulation Androgens The prostate is dependent on testicular-derived testosterone; despite the presence of the 3β-hydroxysteroid dehydrogenase-∆5-∆4 isomerase complex,160 the prostate has not been reported to synthesize testosterone de novo. It can reversibly metabolize testosterone to androstenedione (17β-hydroxysteroid dehydrogenase161) and, possibly irreversibly, to estrogens (see below). The prostate’s primary metabolite of testosterone is dihydrotestosterone (DHT), an irreversible reaction catalyzed by 5 α-reductase.162 This is a more potent ligand for the androgen receptor than is testosterone, as it binds the receptor with greater affinity, enhances translocation from the cytoplasm to the nucleus, and is more effective in activating many androgenresponse elements.163,164 Following 5 α-reduction, DHT and androstanedione are further metabolized by 3α/βhydroxysteroid dehydrogenase to 5 α-androstane-3α/β17β-diol and androsterone.165,166 The reader is referred to the work of Amann and colleagues167 for a review of nomenclature and metabolic pathways for androgens in the male. Two forms of 5 α-reductase have been cloned in humans and rats.162 Type I isozyme is active over a broad pH range on either side of neutral, while type II isozyme is active over a very narrow pH, centering at 4.5.162 The rat prostate expresses both isozymes, with type I being expressed by basal epithelial cells and type II predominating in the stroma of the regenerating ventral


prostate.168,169 In the human prostate, type II isozyme predominates,162 however type I expression and activity have recently been reported.170,171 Immunohistochemistry and in situ hybridization have detected both isozymes in basal, epithelial, and stromal cells, with lesser amounts being detected in the luminal epithelial cells.3,170–173 Interestingly, type I isozyme appears to be preferentially localized to the nucleus, while type II isozyme is localized to the cytoplasm.170 In culture, freshly isolated epithelial cells express type II isozyme. As the time in culture increases, however, type II activity decreases and type I activity becomes predominant.174 The androgen receptor is a member of the steroid/ thyroid hormone superfamily of nuclear receptors.163,164,175 The androgen receptor is 110 to 112 kDa (910 to 919 amino acids) and can be divided grossly into the N-terminus (amino acids 1 to 559), the DNA-binding region (amino acids 559 to 625), the hinge region (amino acids 625 to 671), and the ligand-binding region (amino acids 671 to 919) (Figure 14–5).163,164,175 The N-terminus contains a transactivation domain and three homopolymeric regions: Gln, Pro, and Gly.163 The Gln (CAG) polymorphism is of particular interest due to its role in X-linked spinal and bulbar muscular atrophy (Kennedy’s disease).176 Normal individuals have 17 to 29 CAG repeats, but affected males have > 40 repeats.176 Receptors with high numbers of repeats have decreased ligand binding and transcriptional activation.176 Investigations are ongoing to determine if variations in the length of N-terminus repeats the length CAG polymorphisms and are associated with increased risk for

PCa177,178 or fertility.179 The DNA-binding region contains domains involved with dimerization and nuclear localization, two zinc fingers, and the dimerization domain, which continues into the hinge region.163,164 The ligand-binding region contains two hydrophobic pockets for the ligand, nuclear localization, dimerization, and transactivation region, and the Hsp90 protein-binding site.163,164 The qualitative affinity of androgens for the androgen receptor follow the sequence DHT to testosterone to androstenedione to 5 α-androstane-3α/β-17βdiol androsterone.163,164 Following ligand binding, the androgen receptor undergoes conformational changes resulting in the dissociation of the heat shock/chaperone proteins and homodimerization, nuclear translocation, and eventual association with the androgen-response element on the DNA and the appropriate transcriptional regulatory cofactors.163,164,175 In rats and humans, the androgen receptor is localized primarily in the luminal epithelium, with heterogeneous expression in the prostatic stroma and little or none in the basal epithelial cells.180–182 In addition to the classic steroid-receptor mechanism described above, the androgen receptor is able to interact with several other regulatory pathways (see Figure 14–5). Although receptor phosphorylation is classically thought of as being part of the signaling pathway of membranebound receptors (e.g., the epidermal growth factor receptor [EGFR] family,183 IGFR,184 and TGFR),185 it is now known that steroid receptor activity is also regulated by phosphorylation.175 Androgen receptors are phosphorylated predominately on Ser residues, at least three of which

FIGURE 14–5. Schematic diagram of the human androgen receptor gene. Black areas = transactivation domains; P = proline directed phosphorylated Ser residues; HSP = heat shock protein; pKC = protein kinase C; pKA = protein kinase A; MAPK = mitogen-activated protein kinase; DNADep Kin = DNA-dependent kinase; Ser-Pro = serine-proline directed kinase; Cas-Kin II = casein kinase II. Adapted from Wiener et al.,164 MacLean et al.,176 Blok et al.,175 and Zhou et al.186


show Pro-directed phosphorylation.175,186 Unlike many of the membrane-bound receptors, steroid receptors cannot undergo autophosphorylation.175,187 This reliance on kinases not directly associated with the receptor provides a key opportunity for modulation of androgen-receptor activity by other signaling pathways. When exposed to androgens, the androgen receptor undergoes a two- to fourfold increase in apparent phosphorylation. This has been shown, however, to be due to increased receptor stabilization rather than to increased phosphorylation.188 While not essential for activity, phosphorylation increases androgenreceptor transcriptional activity and may affect ligand binding.175,186 The androgen-receptor ligand-binding domain also includes consensus recognition motifs for multiple protein kinases175 (see Figure 14–5), and both EGF and IGF-I increase transcriptional activation of the androgen receptor in the presence of ligand.189 Paradoxically, the androgen receptor can also be activated in the absence of ligand (as judged by reporter constructs) by several growth factors, including EGF, IGF, and keratinocyte growth factor (KGF).190 Protein kinase A agonists are also able to stimulate the androgen receptors in kidney and prostate cells cotransfected with androgen receptors and androgenresponsive reporter constructs.191 Recently, it has been reported that TGF-β1 is capable of inducing translocation of the androgen receptor from the nucleus to the cytoplasm in human and rat stromal cultures, by an as yet undetermined mechanism.192 The role played by phosphorylation in androgenreceptor function or its interactions with other signaling pathways is currently an emerging field. However, given the extensive use of phosphorylation/dephosphorylation cascades in membrane-bound receptor signaling and the fact that many key growth factors are tyrosine or serine/ threonine kinases (see below), androgen-receptor phosphorylation/dephosphorylation would appear to be an ideal mechanism for mutual regulation of paracrine factor–steroid hormone signaling pathways. The effects of androgens on the expression of paracrine factors and their receptors are listed in Table 14–1. Physiologically, DHT, rather than testosterone, is responsible for virilization of the urogenital sinus and external genitalia.162 Treatment of pregnant rats with 5 α-reductase inhibitors during differentiation of the reproductive tract inhibits prostate development, an effect that can be reversed by simultaneous treatment with DHT.193 In the human fetus, the type II isozyme is critical for differentiation of the male reproductive tract, as evidenced by the incomplete masculinization of infants and children with a type II 5 α-reductase deficiency.162 Individuals with a type I isozyme deficiency have not yet been detected.162 Underscoring the importance of DHT’s role in the prostate is the use of 5 α-reductase inhibitors (e.g., finasteride) in the treatment of BPH, resulting in a gradual decrease in prostate size and serum PSA levels.162 Chronic

finasteride use in rats also reduces prostatic size and DNA content and increases apoptosis, however these changes are neither as rapid nor as dramatic as those observed with castration.194 In contrast to the obvious superiority of DHT compared to testosterone in the development and maintenance of adult prostate morphology are the very modest differences in expression of messenger ribonucleic acid (mRNA)/protein in the prostates of rats treated with testosterone versus DHT or castration versus finasteride.195,196 Expression of most of the secretory products mentioned above and the growth factors listed below is regulated by androgens and is summarized in Table 14–1. In addition to upregulation, androgens frequently act as negative regulators of protein expression. Negative regulation falls into two categories: (1) an immediate and transient increase (hours to days) following castration, as exemplified by testosterrone-repressed prostate message (TRPM)-2 and TGFβ,197,198 which likely play a direct role in the regression process; and (2) a more gradual and sustained increase (weeks) in expression, exemplified by C-cell adhesion molecule (C-CAM) and cytokeratin 8.197,199 Additionally, androgen regulation of gene expression is to a degree organ-dependent, as has been shown for S-adenosylmethionine200 and EGFR; 201,202 these are clearly regulated by androgens in the prostate but are not necessarily regulated by androgens in the peripheral androgen-responsive tissues. Sensitivity to androgens also varies with the lobe of the prostate studied;197,203,204 presumably, this would also hold true for the different zones of the human prostate. Estrogens The ability of estrogens to induce prostatic dysplasia in rats205 and hyperplasia in dogs and cynomolgus monkeys206,207 has spurred the investigation of their role in prostatic physiology and disease in humans. As exogenous estrogens inhibit testosterone secretion via negative feedback at the hypothalamus-pituitary, most in vivo models include treatment with exogenous androgens. Estrogens have been reported to stimulate 3-hydro-thymidine incorporation208 and the expression of desmin in cultures of human prostatic stromal cells.209 Further, aromatase inhibitors have been reported to inhibit hyperplastic changes in animal models and patients with BPH.210,211 Aromatase activity has been reported in preparations of the ventral prostate in rats,212 and proteins immunoreactive with aromatase antibodies have been detected in the human prostate,213,214 although detection of aromatase activity has yielded mixed results.213–219 It is likely that the primary source of estrogens in sexually mature males is the testicular Leydig’s cells, which express substantial amounts of aromatase activity in many species, including rats and humans.220,221 In the human prostate, estrogen receptors are confined to the stromal elements (periacinar fibroblasts, myoblasts, smooth muscle cells).222,223 Per unit stroma,


estrogen receptors are highest in the zone of the prostate that is susceptible to BPH, the transition zone.224 The precedent for steroid hormones to affect epithelial function and development via paracrine factors secreted by the stroma has been well established,14,225 but such a pathway has not yet been studied for estrogens in the prostate. Estrogen receptors can be detected in the rat prostate by immunohistochemical methods during the prenatal period and puberty but not in the adult (45 days).226 Both the α and β forms of the estradiol receptor in the adult rat prostate are detected by reverse transcriptase–polymerase chain reaction (RT-PCR) and

in situ hybridization.227–229 The β estradiol receptor is the major estrogen receptor expressed in the rat prostate, with approximately equal expression being detected in the ventral, dorsal, and lateral lobes of the adult prostate.227–229 While labeling in the stroma is predominant in the prenatal animal, in the pubertal and adult rat, it is most intense over the epithelial compartment.229 Expression of the α-estrogen receptor is much lower than that of the β form, being highest in the lateral lobe and lowest in the ventral lobe.228 The physiologic significance of these two receptor isotypes is not known, and although they differ in their ability to bind to certain androgens

TABLE 14–1. Regulation by Androgens of Prostatic Secretory Products and Signaling Pathways* Substance

Level of Regulation Examined

Assay Method

Effect†

Reference

Citrate

Precursor uptake Key synthetic enzymes Uptake by mitochondria Key synthetic enzymes Key synthetic enzymes Protein mRNA Serum protein mRNA Protein Serum protein

Uptake assay Western blot Atomic absorption Enzyme activity Enzyme activity Immunohistochemistry Transcriptional regulation RIA Northern blot Immunohistochemistry Enzyme activity RIA; enzyme activity SDS-PAGE Promoter—receptor interactions RIA Northern blot, in situ hybridization Ligand binding immunohistochemistry Immunohistochemistry Northern blot Enzyme activity Immunohistochemistry PCR Immunohistochemistry Northern blot Binding assay RT-PCR RIA Northern blot RT-PCR Immunohistochemistry Northern blot Binding assay Northern blot Affinity labeling Northern blot Immunohistochemistry

Positive

Lao,59 Costello367

Positive Positive Positive Positive

Liu203 Hasagawa75 Fjosne368 Page,369 Aumuller370

Positive 4.9 kB—no change 2.3, 1.5 kB—positive Positive Positive Positive

Rittenhouse,101 Clements128 Huggins,105 Moss,136 Chu,137 Terracio,141 Porvari371

No change Negative (transient) Positive Negative Positive

Risbridger144 Banerjee,265 Kumar,372 Prins,373,375 Quarmby,374 Takeda,376 Bentvelsen377 Miyamoto,169 George378

No change Negative Positive Negative

Lau,228 Kruithof-Dekker379

Positive Positive Negative

Nishi,267 Hiramatsu380

Zinc Myo-inositol Polyamines PBP/estramustine-binding protein PSA (human) PAP (rat) PAP (human) Probasin Inhibin Androgen receptor 5 α-reductase

Protein Promoter activity Protein mRNA Protein Protein mRNA Protein

Estrogen receptor (rat) Estrogen receptor (human) Prolactin receptor EGF receptor

mRNA Protein mRNA Protein

EGF

Protein mRNA mRNA Protein mRNA Protein mRNA Binding mRNA Protein (BP-5) Protein (BP-3) mRNA Protein mRNA Protein

TGF-α TGF-β TGF-β receptor IGF-I IGFR-I IGFBP2–5 α1-adrenergic receptors β2-adrenergic receptors Muscarinic receptors

RT-PCR Ligand binding Northern blot Ligand binding

Matuo,149 Kasper153

Nevalainen233 Traish,202 St-Arnaud263

Banerjee,265 Liu381

Negative Negative Negative → positive Negative → positive Negative Negative

Kyprianou198 Kyprianou292 Nickerson382 Nickerson382 Nickerson,382 Thomas383

No change

Auger-Pourmarin384

Positive Positive

Collins358 Shapiro365

PBP = prostatic-binding protein; PSA = prostate-specific antigen; PAP = prostatic acid phosphatase; EGF = epidermal growth factor; TGF-β = transforming growth factor beta; IGF = insulin-like growth factor; IGFR-I = insulin-like growth factor receptor-I; IGFBP = insulin-like growth factor binding protein; BP = binding proteins; RIA = radioimmunoassay; PCR = polymerase chain reaction; RT-PCR = reverse transcriptase-polymerase chain reaction; SDS-PAGE = sodium dodecyl sulfate–polyacrylamide gel electrophoresis. *Unless otherwise noted, data were obtained from adult rodents. †Positive/negative: decreased/increased expression following castration, or increased/decreased expression with supplemental testosterone to intact or castrated males. Experiments using 5 α-reductase inhibitors instead of castration are not included.


and antiestrogens, both forms have similar affinities for the three common estrogens (estrone, estradiol-17β, and estrone).227 Androgens have not been reported to affect the expression of either receptor subtype.228 Recently, alternative mechanisms for estrogen stimulation of prostatic cells have been reported, raising the question whether estrogen receptors are even a requirement for estrogen-mediated action on the prostate. By binding to sex steroid–binding globulin (also known as androgen-binding protein), and interacting with receptors on the cell membrane, estradiol has been shown to stimulate cyclic adenosine monophosphate (cAMP) production and PSA secretion and arginine esterase in explants of human BPH tissue.230,231 Prolactin Prolactin receptors are present in the secretory epithelium of the human prostate232 and in the epithelium of the dorsal and lateral lobes of the rat prostate.233 The primary source of serum prolactin is probably the pituitary, however prolactin protein and message have been detected in the epithelium of the dorsal and lateral prostates of both rats234 and humans.232 Prolactin stimulates prostatic growth,21,235,236 mitochondrial zinc accumulation,203 and citrate metabolism.237,238 Although expression of prolactin protein234 and the message for its receptor233 are positively regulated by testosterone, at least some of prolactin’s effects are independent of testosterone’s effects on the prostate.236,238 In the rat, the lateral lobe of the prostate is the most sensitive to the mitogenic, transcriptional, and metabolic effects of prolactin.203,239 Paracrine and Autocrine Growth Factors In addition to hormonal regulation, the prostate is clearly under paracrine and autocrine regulation, as has been demonstrated by epithelial/mesenchymal recombination studies in vivo14,16,240,241 and coculture/conditioned media studies in vitro.242–244 Some growth factors such as nerve-growth factor (NGF)/trk and NGF-β receptors245,246 as well as hepatocyte growth factor/met receptors247–249 operate as classic paracrine mediators, with ligand produced by the prostatic stroma and the receptors present on the basal and/or luminal epithelial cells. In contrast, TGF-β250,251 and IGF-II134 have the necessary components to utilize both paracrine and autocrine (epithelial to epithelial or stromal to stromal) pathways. The role played by these growth factor pathways in prostatic physiology and disease as well as their integration into the other prostatic regulatory pathways are currently being actively researched. This review focuses on three of the better characterized systems in the prostate that represent two strictly local pathways: (1) EGFs (generally stimulatory to proliferation); (2) TGF-βs (generally inhibitory for proliferation); and (3) IGFs, which act by both endocrine and local pathways.

Epidermal Growth Factor Family Pathway The EGFR family of membrane-localized tyrosine kinases has to date four members: (1) erbB-1/EGFR (170 kDa); (2) erbB-2/neu/HER-2 (185 kDa); (3) erbB-3 (160 kDa); and (4) erbB-4 (170 kDa).183,252 Depending on the particular ligand bound and the complement of receptors present, homo- or heterodimers of receptor subunits are formed following ligand binding.183,252 To date, no ligand has been identified for P185erbB-2, and P60erbB-3 appears to not have an active tyrosine kinase domain.183 This forces these two receptors to form obligate heterodimers with other members of the EGFR family for ligand-directed intracellular signaling. In the human prostate, all four EGFR/erbB family members have been identified in the epithelial compartment, with all but P170erbB-4 being expressed primarily in the basal epithelium; P170erbB has been reported to be expressed in both the basal and secretory epithelium.253–257 There are also persistent reports of some EGFR expression in the prostatic stroma.258,259 Multiple ligands for the EGFR family have been detected in the normal human prostate, including EGF,260 and heparinbinding (HB)-EGF,261 which have been localized to the stroma. Immunoreactive TGF-α has been identified inconsistently in a small proportion of normal human prostatic epithelial cells.257,258 The presence or absence of TGF-α in the stroma of the normal human prostate is still uncertain.257,258 Together, these results suggest that the EGFR/erbB family acts as a paracrine pathway from the stroma to the epithelium. Unlike the other ligand of the EGFR/erbB family, neu differentiation factor (NDF/heregulin) has been localized in the stromal, basal, and secretory epithelium.254 In rats, EGFR P185erbB-2 and P160erbB-3 have been identified in normal prostates and cell lines.202,262,263 Both EGFR and TGF-α have been localized to the luminal epithelium of the ventral prostate in the rat; thus the EGFR–TGF-α axis may operate, unlike in the human prostate, as an autocrine rather than a paracrine pathway.264,265 There has been no TGF-α detected in the stroma of any of the three lobes.264 Epidermal growth factor is also expressed by the rat prostatic epithelium, with the highest levels of expression in the dorsal prostate, although some expression has also been detected in the ventral lobes.266,267 There has been no EGF detected in the rat prostatic stroma.266 Interest in EGF in relation to the prostate is in part due to its role in proliferation and its use as an additive to tissue-culture medium. Epidermal growth factor stimulates the proliferation of prostatic epithelial cells in vitro268,269 and following orthotopic injection.270 It has also been reported to stimulate the growth of fetal prostates and adult human fibroblasts.271 The EGFR family is also believed to play a role in PIN and PCa, as there are frequently changes in levels of expression and a shift of localization of expression with these conditions. Prob-


ably the best documented change is the dramatic increase in P185erbB-2 expression seen in PCa.253 The P185erbB-2 is able to form active heterodimers with all three other EGFR/erbB receptors, and it can be activated by a variety of ligands, including NDF, EGF, and TGF-α.183,272 An upregulation of this receptor would therefore dramatically increase the activation pathways available to the cell. Experiments with nontumorigenic epithelial cells from the rat ventral prostate have demonstrated that increased expression of P185erbB-2 can induce tumorigenesis and metastasis.262 Each of P185erbB-2 EGFR, P160erbB-3, and TGF-α has been reported, albeit inconsistently, to show increased expression in the luminal epithelium in PIN or PCa as well as in human prostate epithelial cell lines derived from PCa.255,256,273–276 It is possible that acquisition of an autocrine loop for the EGFR/erbB pathway may be a key event in the progression of PCa. The decreased expression of EGF in PCa compared to the normal prostate has also led to speculation that a shift in available ligands (e.g., decreased EGF, increased TGF-α) may also play a role in the progression of PCa.256,274 Transforming Growth Factor-β Inhibition of prostatic growth and the subsequent induction of either differentiation or apoptosis also appear to be regulated by paracrine factors.133,277–283 Of these pathways, the TGF-β family (TGF-β1, -2, and -3) has been the most intensively studied. The TGF-βs are classically thought of as inhibitors of epithelial growth and inducers of apoptosis in epithelial cells from several organs.185,284 They are secreted in a latent form that must subsequently be activated.185,246,284–286 Activation can occur through several mechanisms, including integrins αvβ1,285 IGFR-II,287 and extracellular proteases.185 Based on the localization of receptors and ligand, TGF-β, at least in the human prostate, should be able to act by both paracrine and autocrine pathways. The receptor is a transmembrane heterodimer with serine/threonine kinase activity.185,284 In the human prostate, both TGFR-I and TGFR-II are present in the glandular epithelial cells and colocalize with cells coexpressing smooth muscle α-actin in the stroma.251,288 Immunoreactivity of the ligand, TGF-β1, has also been localized to both the epithelial and stromal compartments.250 Immunoreactivity of TGF-β2 and -3 is preferentially localized in the epithelium, with TGF-β3 localized to the basal epithelial cells.289 Both receptors as well as TGF-β1 and -3 have been detected in the ventral prostate of the rat.286,290,291 The TGF-βs and their receptors were one of the first proteins shown to be negatively regulated by androgens, as their expression was dramatically upregulated immediately following castration and downregulated with subsequent androgen replacement.180,198,291,292 Continuous perfusion with TGF-β1 in vivo reduces wet weights of the ventral prostate without reducing serum testosterone,

implying that the effects of TGF-βs are downstream of those of testosterone.293 In vitro, exposure to TGF-β1 induces apoptosis in NRP-154 cells and primary cultures of prostatic epithelial cells as well as inhibiting the growth of primary cultures of epithelial cells from the rat ventral prostate.294,295 However, it should be noted that in both studies results were found to be highly dependent on culture conditions. The TGF-βs also inhibit the proliferation of prostatic stromal cells296,297 and induce differentiation of primary stromal cultures from a fibroblastic phenotype (expression of fibronectin and vimentin) to the smooth muscle phenotype (expression of α–smooth muscle actin).185,296 Epidermal growth factor can attenuate the TGF-βs’ induction of smooth muscle phenotype,269 their ability to induce apoptosis,295 and their inhibition of proliferation.298 The TGF-βs are able to inhibit androgen and EGF-stimulated growth; treatment of castrated rats with EGF increases the expression of TGF-β1 mRNA in prostatic stromal cells, suggesting a feedback loop between growth stimulators and inhibitors.192,290 Paradoxically, the overexpression of TGF-βs in tumorigenic prostate cell lines has been shown to induce greater tumor growth, be associated with induction of carcinomas and hyperplasia in the myc+ras transgenic mice prostate model, and to possibly induce hyperplasia in murine recombinant prostates.241,284,299 The phenotypic changes by which TGF-β promotes tumorigenesis are likely to be multiple, including alterations in the expression of extracellular matrix components, integrins, protease inhibitors, and metalloproteases.185,300–302 Insulin-Like Growth Factor The IGF pathway in the prostate differs from that of other growth factors in that it has both endocrine (IGF-I) and paracrine (IGF-II) components.184,303 IGFR-I, which is activated by IFG-I > IGF-II >>> insulin, is present on human prostatic epithelial cells and adenoma cell lines.135,304 As judged by in situ hybridization and RTPCR, IGFR-I is present at low levels in the prostatic stroma.135,305 The IGFR-II component has been less well characterized and has been reported to be present only on the adenoma cell line DU 145278 and on benign human stromal cells.305 The primary source of serum and presumably prostatic IGF-I is the liver.184,303 The IGF-I protein has not been identified in the conditioned media of primary cultures of human prostate fibroblasts or epithelial cells134,305,306 or in prostatic carcinoma cell lines.279,307 In the rat, however, IGF-I has been identified in the prostatic stroma308,309 and IGF-II has been detected in the prostatic epithelium,135 stroma,306 and in the conditioned media of prostatic stromal and epithelial cells.306 It thus may act as an autocrine (epithelial to epithelial) or paracrine (stromal to epithelial) regulator in the rat. The activity of the IGF pathway is also modulated by binding proteins, originating both in the sera and


locally.134,184 As judged by combinations of protein (immunohistochemistry, Western blot) and mRNA (Northern blot, in situ hybridization), both prostatic fibroblasts and epithelial cells express IGFBP-1 through IGFBP-7.134,306,310–314 The ability to liberate serumderived IGF-I from its carrier proteins (primarily IGFBP-3) is another mechanism by which this pathway is regulated. At least three prostatic enzymes—PSA,133 cathepsin D,315 and urokinase279—are capable of releasing IGF-I from IGFBP-3. Whether the basally secreted PSA or the increased expression of urokinase and cathepsin D in PCa101,128,316,317 actually liberate enough IGF-I to stimulate the growth of the tumor remains to be determined (see Figure 14–4). Several in vivo and in vitro experiments have demonstrated that the IGF pathway can have an effect on prostatic growth. The prostate is vestigial in IGF-I null mice,318 and systemic treatment of IGF-I in rats increases wet weight of the ventral and dorsal lateral prostate by increasing the proportion of epithelial cells.319 In vitro, both IGF-I and IGF-II increase growth of prostatic epithelial cells and PCa cell lines.134,320,321 Also, expression of antisense message to IGFR-I reduces tumor size and metastatic capabilities of the PA-III rat adenocarcinoma model.322 Using the Noble rat model, Wang and Wong308 reported that during the induction of adenoma, expression of IGF-I shifted from the prostatic stroma to the epithelium, suggesting, as has been demonstrated for EGFR/TGF-α, a shift from a paracrine to autocrine pathway for this growth factor during tumorigenesis. In contrast, IGFBPs are generally reported to inhibit growth in most but not all cases.133,278,279,323 Probably the best studied of the prostatic IGFBPs, IGFBP-3 has been reported to induce apoptosis of cell lines derived from PCa by both ligand-dependent and -independent pathways.282,324 Clinically, there has been a great deal of interest in determining if increased serum levels of IGF-I325,326 and altered IGFBP profiles327 can be used to predict, diagnose, or follow PCa. In vivo, IGF-I expression in the liver is regulated by growth hormone that acts at this level to increase IGF-I and somatostatin expression, both of which act at the anterior pituitary to inhibit the release of growth hormone. Similar to the use of luteinizing hormone–releasing hormone (LHRH) agonists to inhibit testosterone expression by the testis, somatostatin agonists are being explored as potential therapeutics for PCa.328,329 Neurogenic Regulation Traditionally, investigation of the role of neurogenic regulation in the prostate has been limited to the obstructive symptoms of BPH330,331and the addition of the prostatic secretions to the ejaculate.98,332 Its role in regulation of prostatic function has not been well studied, although evidence is accruing that it may play a broader role than previously suspected. The reader is referred to Walsh and

colleagues,333 Higgins and Gosling,334 and McVary and colleagues335 for descriptions of the gross distribution of nerves and ganglia within the human prostate. Synaptomenal complexes appear to be limited to the prostatic stroma.336,337 Alpha-adrenergic innervation predominates in both the rat and human prostate, although muscarinic335,338 and nonadrenergic noncholinergic pathways334,336,337,339–341 are also present. Alpha1-adrenergic receptors are localized primarily to the stromal compartment in both rats and humans.342–344 Alpha2-adrenergic receptors have also been identified in the prostate, particularly in the vicinity of blood vessels344 and in the prostatic capsule.345,346 Based on genetic and agonist/antagonist studies, three α1 subtypes have been identified: α1A (previously α1C), α1B, and α1D (previously α1A and α1A/D).347,348 Both RT-PCR and in situ hybridization studies have identified all three subtypes in the human prostate.349–351 Based on mRNA, protein expression, ligand-binding, and isometric contraction studies, the α1A subtype is by far the most predominant receptor in the human prostate.349,350,352–355 The role played by these receptors in prostatic contraction is illustrated by the clinical use of α1-adrenergic blockers in relieving the obstructive symptoms of BPH.330,331 The agonist/antagonist binding profile for prostatic α1A receptors differs from that found in several other tissues. It has been hypothesized that the prostatic α1A-receptor is a unique α1A subtype, another as yet uncharacterized receptor, or is subjected to unique regulatory pathways.352,354,355 The α1C-adrenergic receptors are localized predominantly, but not exclusively, within the stroma.349–351 Studies have found α1D (α1A/D) receptors in both the stromal and epithelial compartments.349,350 In contrast, the α1B receptors are predominately localized to the glandular epithelium.349 In addition to expelling the contents of the prostatic acini during ejaculation as has been found in the rat,98,332 the adrenergic pathway may also play a role in promoting prostatic smooth muscle differentiation356 and in survival of the prostate stroma and epithelium.335,357 Beta-adrenergic receptors are present in the prostatic capsule345,346 but, as judged by ligand-binding and contraction studies, are all but absent from the parenchyma of the human prostate.335,346 In contrast, β2 receptors are readily detectable in the rat ventral prostate.358 Beta2adrenergic agonists stimulate cAMP accumulation in epithelial-cell primary cultures359 and have been reported to upregulate the expression of PBP message and protein in denervated prostates and in recombinant prostatic graphs in the renal capsule.357,360 Unlike the α1-adrenergic agonists,98,332,361 β2-adrenergic agonists do not appear to regulate exocrine secretion.98 The muscarinic cholinergic receptor system is also present in both rats and humans species although this has been much less extensively studied.335,338 In human prostatic adenomas, the M1 subtype has been localized to the


prostatic epithelium and is the predominant muscarinic receptor detected by immunoprecipitation and ligandbinding studies.344,362 The presence of muscarinic receptors in the stroma is still a matter of controversy,344,362 but the M2-receptor subtype has been detected primarily on cultures of prostatic smooth muscle.363 In the ventral prostate, the M3 subtype predominates,364 although the M1 subtype has also been detected on the prostatic epithelium.365 In humans, muscarinic agonists stimulate the contraction of the prostatic capsule but not of the parenchyma.346 Muscarinic receptors (M3 subtype) have also been reported to stimulate proliferation of primary cultures of epithelial cells obtained from radical prostatectomies.366 In rats, muscarinic agonists induce a sustained release of prostatic secretory products, which appears to occur by mechanisms other than smooth muscle contraction.98,332

Conclusion Historically, the prostate has functioned to enhance fertility by secreting buffers and protective agents that help keep the sperm in a quiescent and undamaged state until they have reached the ampulla of the oviduct, as well as by secreting PSA that releases the ejaculated sperm from the semenogelin coagulate. In the past, few men lived long enough for PCa or BPH to become clinically relevant, much less life threatening. The dramatic increase in life expectancy during the twentieth century has altered the role of the prostate in men’s health. The prostate is the only organ in the body that demonstrates abnormal growth (PIN, BPH, or PCa) in nearly 100% of American males by their sixth decade. Further, unlike the epithelium of the skin and colon, the prostatic epithelium is relatively protected from environmental assault and has a very low rate of turnover. Is there a basic regulatory mechanism in the prostatic housekeeping machinery that goes awry as men age? What are the physiologic differences between the transitional zone and peripheral zone such that the former is highly predisposed to benign disease while the latter demonstrates almost no benign disease but cancer instead? Given the unique attributes of abnormal prostatic growth, whether benign or malignant, future research must be directed toward understanding the basic developmental and regulatory pathways of the prostate so that appropriate preemptive measures and therapies can be developed.

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Prostate Physiology and Regulation / 117 the pharmacological selectivity profile of alpha1 adrenoceptor antagonists at prostatic alpha1 adrenoceptors: binding, functional and in vivo studies. Br J Pharmacol 1996;118:871–8. 356. Smith P, Rhodes NP, Beesley C, et al. Prostatic stromal cell phenotype is directly modulated by norepinephrine. Urology 1998;51:663–70. 357. Thompson TC, Zhau HY, Chung LW. Catecholamines are involved in the growth and expression of prostatic binding protein by rat ventral prostatic tissues. Prog Clin Biol Res 1987;239:239–48. 358. Collins S, Quarmby VE, French FS, et al. Regulation of the beta2-adrenergic receptor and its mRNA in the rat ventral prostate by testosterone. FEBS Lett 1988; 233:173–6. 359. Carmena MJ, Hueso C, Recio MN, Prieto JC. Beta-adrenergic stimulation of cyclic AMP accumulation in rat prostate epithelial cells during sexual maturation. Mech Ageing Dev 1990;52:79–86. 360. Guthrie PD, Freeman MR, Liao ST, Chung LW. Regulation of gene expression in rat prostate by androgen and beta-adrenergic receptor pathways. Mol Endocrinol 1990;4:1343–53. 361. Steidle CP, Cohen ML, Hoover DM, Neubauer BL. Comparative contractile responses among ventral, dorsal, and lateral lobes of the rat prostate. Prostate 1989; 15:53–63. 362. Ruggieri MR, Colton MD, Wang P, et al. Human prostate muscarinic receptor subtypes. J Pharmacol Exp Ther 1995;274:976–82. 363. Yazawa H, Saita Y, Iida E, et al. Characterization of muscarinic cholinoceptor in primary culture of smooth muscle cells from human prostate. J Urol 1994;152: 2173–7. 364. Pontari MA, Luthin GR, Braverman AS, Ruggieri MR. Characterization of muscarinic cholinergic receptor subtypes in rat prostate. J Recept Signal Transduct Res 1998;18:151–66. 365. Shapiro E, Miller AR, Lepor H. Down regulation of the muscarinic cholinergic receptor of the rat prostate following castration. J Urol 1985;134:179–82. 366. Rayford W, Noble MJ, Austenfeld MA, et al. Muscarinic cholinergic receptors promote growth of human prostate cancer cells. Prostate 1997;30:160–6. 367. Costello LC, Liu Y, Franklin RB. Testosterone stimulates the biosynthesis of m-aconitase and citrate oxidation in prostate epithelial cells. Mol Cell Endocrinol 1995; 112:45–51. 368. Fjosne HE, Strand H, Ostensen M-A, Sunde A. Ornithine decarboxylase and S-adenosylmethionine decarboxylase activity in the accessory sex organs of intact, castrated, and androgen-stimulated castrated rats. Prostate 1988;320:309–20. 369. Page MJ, Parker MG. Effect of androgen on the transcription of rat prostatic binding protein genes. Mol Cell Endocrinol 1982;27:343–55. 370. Aumuller G, Seitz J, Heyns W, Flickinger CJ. Intracellular

localization of prostatic binding protein (PBP) in rat prostate by light and electron microscopic immunocytochemistry. Histochemistry 1982;76:497–516. 371. Porvari K, Kurkela R, Kivinen A, Vihko P. Differential androgen regulation of rat prostatic acid phosphatase transcripts. Biochem Biophys Res Commun 1995;213: 861–8. 372. Kumar VL, Majumder PK, Kumar V. Androgen deprivation causes up-regulation of androgen receptor transcript in the rat prostate. Mol Cell Biochem 1997;171: 133–8. 373. Prins GS, Woodham C. Autologous regulation of androgen receptor messenger ribonucleic acid in the separate lobes of the rat prostate gland. Biol Reprod 1995; 53:609–19. 374. Quarmby VE, Yarbrough WG, Lubahn DB, et al. Autologous down-regulation of androgen receptor messenger ribonucleic acid. Mol Endocrinol 1990;4:22–8. 375. Prins GS, Birch L. Immunocytochemical analysis of androgen receptor along the ducts of the separate rat prostate lobes after androgen withdrawal and replacement. Endocrinology 1993;132:169–78. 376. Takeda H, Nakamoto T, Kokontis J, et al. Autoregulation of androgen receptor expression in rodent prostate: immunohistochemical and in situ hybridization analysis. Biochem Biophys Res Commun 1991;177:488–96. 377. Bentvelsen FM, McPhaul MJ, Wilson CM, et al. Regulation of immunoreactive androgen receptor in the adrenal gland of the adult rat. Endocrinology 1996;137:2659–63. 378. George FW, Russell DW, Wilson JD. Feed-forward control of prostate growth: dihydrotestosterone induces expression of its own biosynthetic enzyme, steroid 5-alphareductase. Proc Natl Acad Sci U S A 1991;88:8044–7. 379. Kruithof-Dekker IG, Tetu B, Janssen PJ, Van-der-Kwast TH. Elevated estrogen receptor expression in human prostatic stromal cells by androgen ablation therapy. J Urol 1996;156:1194–7. 380. Hiramatsu M, Kashimata M, Minami N, et al. Androgenic regulation of epidermal growth factor in the mouse ventral prostate. Biochem Int 1988;17:311–7. 381. Liu X-H, Wiley S, Meikle W. Androgens regulate proliferation of human prostate cancer cells in culture by increasing transforming growth factor-alpha (TGFalpha) and epidermal growth factor (EGF)/TGF-alpha receptor. J Clin Endocrinol Metab 1993;77:1472–8. 382. Nickerson T, Pollak M, Huynh H. Castration-induced apoptosis in the rat prostate is associated with increased expression of genes encoding insulin-like growth factor binding proteins 2, 3, 4 and 5. Endocrinology 1998;139: 807–10. 383. Thomas LN, Cohen P, Douglas RC, et al. Insulin-like growth factor binding protein 5 is associated with involution of the ventral prostate in castrated and finasteride-treated rats. Prostate 1998;35:273–8. 384. Auger-Pourmarin L, Roubert P, Chabrier PE. Alpha1adrenoceptors in testosterone-induced prostatic hypertrophy. Eur J Pharmacol 1998;341:119–26.

CHAPTER 15

PATHOBIOLOGY OF PROSTATE DISEASES: AN UPDATE GREGORY T. MACLENNAN, MD

Prostatitis

spp. Another major grouping of rDNAs, found in 74% of patients, were distinct from previously reported sequences but were > 90% similar to known gram-negative bacteria. Minor rDNA groups showed similarities to Flavobacterium and Pseudomonas testosteroni; in addition, two patients had rDNAs < 70% similar to known rDNAs. The findings from these two studies suggest that microorganisms undetectable by traditional methods may be harbored within the prostate. In fact, most of these diverse sequences are not reported in environments outside the prostate; the sequences suggest the adaptation of limited groups of bacteria to the microenvironment of the prostate. The authors note that prostate tissue from asymptomatic volunteers also contained 16S rDNA sequences, although in a much lower percentage than that noted in the symptomatic patients reported in their studies. Their future studies will address such issues as the relationship between prostatitisassociated pain and the presence of rDNA sequences, and the question of whether the presence of infectious microorganisms may play a role in the development of prostate hyperplasia and/or prostate cancer.

Acute prostatitis and chronic recurrent prostatitis are clinical entities associated with readily documented single or multiple bacterial isolates. These entities are well accepted and relatively well understood. Chronic idiopathic prostatitis/prostatodynia, however, remains an enigma. A number of recent publications indicate that our knowledge of the processes underlying these difficult problems is increasing at an encouraging pace. Prokaryotic DNA Sequences in Prostate Tissue Krieger and colleagues evaluated 135 men with chronic prostatitis refractory to multiple previous courses of antibiotics.1 Standard investigations showed no evidence of lower urinary tract dysfunction or structural abnormalities, nor was there evidence of bacteriuria, bacterial prostatitis, urethritis, or urethral pathogens by optimal clinical and microbiologic techniques. Samples of prostate tissue from these patients were obtained, using double needle biopsy to limit skin contamination. Organismspecific and broad-spectrum polymerase chain reaction (PCR) assays were performed on these biopsies, taking precautions to ensure that their results could not represent contamination. Organism-specific assays detected Mycoplasma genitalium, Chlamydia trachomatis, or Trichomonas vaginalis in 8% of patients. The broad-spectrum assays detected sequences encoding 16S ribosomal ribonucleic acid (rRNA) in 77% of patients, about a third of whom also were noted to have tetracycline resistance–encoding genes (tetM-tetO-tetS). A strong correlation was noted between the presence of 16S rRNA sequences in prostate tissue and the presence of significant numbers of inflammatory cells in the patient’s expressed prostatic secretions (EPS). The prokaryotic gene sequences detected were distinct from those of common skin and gut flora. In a follow-up study reported by the same group of investigators, sequencing was carried out on 36 ribosomal deoxyribonucleic acid (rDNA) clones from 23 rDNApositive patients as well as phylogenetic studies comparing the detected sequences to those of known bacteria.2 Sequences from 35% of patients grouped with Aeromonas

Commensal and Difficult-to-Culture Bacteria Other lines of investigation have supported the notion that chronic idiopathic prostatitis may be caused by ascending infection of the prostate by bacteria, some of which are known uropathogens, and some of which are commensal organisms such as Staphylococcus epidermidis and Staphylococcus haemolyticus.3 It is postulated that such organisms possess virulence factors that become operative in the prostatic microenvironment, facilitating colonization. It is further postulated that these bacteria produce extracellular “slime substance,” which favors their persistence in spite of antibiotic therapy. A study by Berger and colleagues in 1997 addressed the relationship between genitourinary infection and inflammatory prostatitis in 85 patients without bacteriuria.4 Urine, urethral fluids, and transperineal prostate tissue samples were cultured, with particular emphasis on attempts to culture commensal and fastidious bacteria. Inflamed prostatic secretions were noted in 25 patients, and 60 patients had noninflamed prostatic secretions. The 118

Pathobiology of Prostate Diseases: an Update / 119

patients in the former group were found to have a significantly higher likelihood of any type of positive bacterial culture, positive culture for anaerobic bacteria, higher total bacteria counts, and more bacterial species isolated. A study by Domingue and colleagues in 1997 showed that careful microscopic examination and the use of enriched culture media could document the presence of difficult-to-culture coryneform bacteria in EPS, despite negative routine cultures, using blood agar.5 The organisms in question were identified as Corynebacterium group atrial natriuretic factor (ANF) and Corynebacterium minutissimum. A related study in 1995 by Riegel and colleagues reported the isolation of a newly described coryneform species, Corynebacterium seminale, from various sites (semen, urine, urethra, blood) in patients with genital infections.6 Further emphasis on the subject of difficult-toculture bacteria was placed by a report by Szoke and colleagues in 1998.7 These investigators isolated an average of 3.9 types of anaerobic bacteria from the urethral samples and EPS of 24 patients, using careful culture techniques. The roles of C. trachomatis and Ureaplasma urealyticum in the genesis of prostatitis remain controversial. Separate studies published in 1995 and 1996 produced opposing views of the significance of the former.8,9 One of the patients in the previously noted PCR assay study by Krieger and colleagues tested positive for C. trachomatis.1 Based on the results of their study of serum antichlamydial antibodies in groups of men with and without chronic prostatitis (subcategorized by the number of leukocytes in the EPS), Ostaszewska and colleagues concluded that C. trachomatis may be the causative organism in up to 30% of such cases.10 No studies supporting U. urealyticum as an etiologic agent in prostatitis have appeared since 1994.3 Granulomatous Prostatitis Several articles examining mycobacterial infection of the prostate were published in 1997. Galbis and colleagues described a patient suffering from acquired immunodeficiency syndrome (AIDS) who developed a tuberculous abscess of the prostate.11 LaFontaine and colleagues found granulomatous prostatitis in 9 of 12 radical cystoprostatectomy specimens from patients previously treated with intravesical bacillus Calmette-Guérin (BCG); in 7 of these cases, acid-fast bacilli (AFB) were identified with special stains.12 In 94 cases of granulomatous prostatitis diagnosed by needle biopsy in a study by Oppenheimer and colleagues, 18.1% were classified as infectious; in all cases in this subset, there was a history of intravesical BCG instillation.13 The remainder of the cases were categorized as nonspecific (77.7%) or indeterminate (4.3%) in etiology. An additional note of interest in the latter study was that two cases of nonspecific granulomatous prostatitis seen in consultation by the authors had previously been misdiagnosed as poorly differentiated carcinoma, resulting in radical prostatectomy and subsequent litigation.

Fungal Prostatitis Isolated reports of this rare entity have appeared in recent years. A case of Aspergillus prostatitis in a man immunosuppressed by corticosteroid therapy was reported in 1997.14 Two cases of Cryptococcus neoformans prostatitis, in a patient with AIDS and a patient with Behçet’s disease, respectively, were reported in 1994 and 1995.15,16 Viral Prostatitis Herpes simplex and cytomegalovirus have been documented as infrequent causative organisms in the genesis of prostatitis from reports early in this decade.17–19 In 1996, Monini and colleagues reported that, using PCR techniques, they had identified DNA sequences derived from a novel herpesvirus, Kaposi’s-associated herpesvirus (KHSV), from prostate tissue and ejaculates (as well as other sites) of a large proportion of healthy immunocompetent men.20 Their findings suggested that this virus is ubiquitously present in healthy adults and is probably transmitted by sexual contact. Subsequent studies by Corbellino and colleagues21 and Tasaka and colleagues22 failed to confirm the findings of Monini and colleagues.20 Those authors stressed that the results of assays based on PCR studies are easily compromised by contamination of materials and instruments used in performing the tests. An analysis by Anderson and colleagues of DNA samples of prostate tissue from 24 patients failed to detect evidence of human papillomavirus.23 Although this study was primarily aimed at unraveling the etiology of prostate cancer, the results provide no support for the notion that this virus is a likely cause of prostatitis. Bacterial Urovirulence Factors in Prostatitis Although the urovirulence properties of Escherichia coli strains which cause acute or chronic urinary tract infections in women have been well characterized, studies of these properties in E. coli causing prostatitis in men were not reported until 1997. Andreu and colleagues studied E. coli isolates from men with acute and chronic prostatitis and compared urovirulence characteristics in these organisms with those of E. coli isolates from women with pyelonephritis, acute cystitis, and complicated urinary tract infection (UTI).24 They concluded that encapsulation, hemolytic activity, and the ability to produce cytotoxic necrotizing factor (CNF)-1 were features of E. coli which may enable it to colonize prostatic tissue and produce chronic prostatitis. Their findings minimized the importance of pap-encoded fimbriae in producing invasive prostate infection. In general, the urovirulence profiles of E. coli producing prostatitis are similar to those of strains from women with acute uncomplicated pyelonephritis. Terai and colleagues, in a similar study of men with acute prostatitis, concluded that the strains of E. coli involved in this process require several virulence factors to overcome inherent male genitourinary tract defense mechanims.25


Chemical Prostatitis Pursuant to the theory that inflammation associated with nonbacterial prostatitis is initiated by reflux of urine into prostatic ducts, Persson and Ronquist demonstrated a statistical relationship between prostatitis-associated pain estimated by a scoring scale questionnaire and the content of white blood cells, urate, and creatinine in EPS.26 These investigators believe that urate and possibly other purine and pyrimidine base–containing nitrogen metabolites are prime suspects in the initiation of nonbacterial chronic prostate inflammation. Autoimmunity and Prostatitis Two recent articles from Cordoba, Argentina, have addressed autoimmunity as a cause for prostatitis. Studies from Argentina dating back as far as 1981 have demonstrated that the intraperitoneal instillation of a saline extract of rat male accessory gland protein associated with liposomes (RAG) into rats can elicit both primary and secondary cellular immune responses to RAG as well as prostatitis.27 The observations of Correa and colleagues suggest that special antigen-presenting cells known as peritoneal dendritic cells (PDC), which comprise only about 1% of the normal population of peritoneal cells, are of greater importance in initiating this process than the much more numerous peritoneal macrophages.28 In an article from the same institution in 1998, Donadio and colleagues described initial prostate infiltration by macrophages, followed by an influx of lymphocytes as a consequence of immunization against the male accessory sexual gland homogenate.27 The infiltrates appeared under the epithelium and around blood vessels. The study showed more advanced changes including interstitial fibrosis, acinar enlargement, and flattening of acinar epithelium. Adoptive transfer techniques confirmed the autoimmune nature of the process. Disease transfer was antigen specific and could be accomplished by cells, but not by serum. The authors speculate that the infiltrating inflammatory cells produce their destructive effects by direct contact with target cells and/or by secretion of harmful substances such as proteases, free radicals, or cytokines. Further support for the concept that chronic prostatitis/ chronic pelvic pain syndrome may have an autoimmune etiology was presented by Alexander and colleagues.29 These investigators showed a significant proliferative response of CD4+ peripheral helper T lymphocytes drawn from patients with a history of chronic prostatitis/chronic pelvic pain syndrome, following exposure to seminal plasma. No significant response to the same antigen was elicited in similar T cells drawn from historically asymptomatic men. Seminal Markers of Inflammation Further information regarding cytokines and other products of inflammation has been provided in two recent

articles. Ludwig and colleagues studied the levels of several markers of seminal plasma inflammation in men with chronic prostatitis, men with significant leukocytospermia, and men with no known prostatic inflammation.30 Their findings indicate that polymorphonuclear (PMN) elastase and complement C3 correlate significantly with prostatic inflammation. The levels of the following markers did not achieve statistical significance as markers of prostatic inflammation in this study: C-reactive protein, α-glucosidase, PSA, and prostatic secretory protein (PSP) 94. Alexander and colleagues found significant elevations of the mean levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in the semen of men with chronic prostatitis/pelvic pain syndrome as compared with levels in asymptomatic men.31 Levels of the noted cytokines did not correlate with the number of leukocytes per high power field in expressed prostatic secretions. The authors note that not all their symptomatic patients had elevated cytokine levels, in keeping with the notion that not all pelvic pain syndromes are secondary to prostatic inflammation. The diagnosis and treatment of prostatitis remains a difficult challenge for caregivers. In a recent survey of Canadian primary care physicians and urologists, prostatitis was perceived as being significantly more frustrating to treat than either benign prostatic hyperplasia (BPH) or prostate cancer, mainly due to a lack of confidence in accurately diagnosing and satisfactorily treating this condition.32

Benign Prostatic Hyperplasia Several excellent textbooks of urologic pathology have been published recently, and the reader is referred to them for comprehensive discussions of BPH and other aspects of prostate pathology.33–35 In the following sections, information which has become available since the publication of these fine textbooks will be reviewed. Recent studies have addressed such diverse topics as the role of estrogens in the induction of BPH and prostate cancer, the frequency of P53 mutations in BPH, the distribution of keratin 19 in benign and malignant prostate tissue, the role of peptide growth factors in the development of BPH and prostate cancer, the roles of different types of prostatic epithelial cells in the genesis of prostatic diseases, atypical adenomatous hyperplasia, prostatic atrophy, and prostatic crystalloids. Androgen Receptor Ligands in Prostate Tissue Previous studies have supported the concept that testosterone and dihydrotestosterone (DHT) function as ligands for androgen receptors (AR), which reside within the target cells in a nonactivated state. Binding of ligand to receptor results in a complex chain of events that ultimately influences the transcriptional apparatus of the cell with induction or repression of target gene expression. It is postulated that coactivators or corepressors may act as


regulators in this process. Yeh and colleagues have isolated an AR coactivator, ARA70, and shown that it enhances AR transcriptional activity six- to 10-fold in human prostate cancer cells.36 Further studies by these investigators demonstrate that this enhancement of AR activity is even more pronounced (> 30-fold) in the presence of 17βestradiol (E2), but not in the presence of diethylstilbestrol. The elucidation of this new E2-AR-ARA70 pathway for activation of androgen target genes may have implications in our understanding of the development of the male reproductive system, BPH, and prostate cancer. P53 Tumor Suppressor Gene Mutations in Benign Prostatic Hyperplasia Noting that mutations and/or loss of heterozygosity in the tumor suppressor gene P53 have been shown to be strongly associated with the genesis and advancement of prostatic carcinoma and that most carcinomas develop in BPHbearing prostates, Schlecte and colleagues initiated a search for P53 mutations in transurethrally resected BPH tissue, using nonhyperplastic prostate tissue and samples of prostatic adenocarcinoma as controls.37 The P53 mutations were identified in 29 of 153 BPH specimens (19%) and in 26.2% of the tissue specimens from patients known to have prostate cancer. Two patients with P53 mutations developed prostate cancer 2 to 3 years after transurethral resection of BPH tissue, and one developed bladder cancer. None of the 118 patients with nonmutated DNA developed urologic cancer during the period of follow-up. The authors conclude that P53 mutation in BPH tissue may be a risk factor for the subsequent development of prostate cancer. Distribution of Keratin 19 in Adult Human Prostate Tissue It has been observed that the luminal cells lining acini of nonlactating mammary epithelium show variable expression of cytokeratin 19. It has been proposed that keratin 19–negative cells are precursors of keratin 19–positive cells. This is of interest because all invasive breast cancers are keratin 19 positive; furthermore, there are structural and functional similarities between breast and prostate tissue. With this in mind, Peehl and colleagues used immunohistochemical and immunoblot techniques to evaluate the expression of keratin 19 in normal, benign hyperplastic, dysplastic, and malignant epithelia in adult prostate tissue.38 These investigators were unable to discern any uniform pattern of keratin 19 expression in the noted tissues or cell cultures. Keratin 19 was commonly found in both basal and luminal cells in histologic preparations. Keratin 19 expression was observed in a minority of cancer cells, in marked contrast to the findings in invasive breast cancer. In short, keratin 19 expression does not appear to correlate with any epithelial cell lineage or phenotype in the human adult prostate.

Autocrine/Paracrine Influences on Normal and Abnormal Prostate Growth In the human adult prostate, androgen receptor is demonstrable in occasional mature smooth muscle cells and is strongly expressed by the nuclei of secretory epithelial cells. Furthermore, there is evidence that ARnegative basal cells are the source of benign epithelial proliferations. Consequently, it is postulated that epithelial proliferation is driven by the elaboration from ARpositive smooth muscle cells of peptide growth factor signals that interact with cognate receptors in AR-negative basal cells.39,40 One such peptide growth factor is transforming growth factor alpha (TGF-α), which binds to and activates its receptor, epidermal growth factor receptor (EGFR). Leav and colleagues undertook an extensive analysis of the immunohistochemical localization of TGF-α and EGFR in fetal, neonatal, prepubertal, and young adult prostate glands, and compared the findings with those in samples of BPH, high-grade prostatic intraepithelial neoplasia (HGPIN), and prostate carcinoma.39 These investigators noted persistent expression of EGFR exclusively in the proliferation-competent basal cells through the entire spectrum from fetal life through adulthood. In contrast, the ligand, TGF-α, became increasingly localized to smooth muscle cells as maturation proceeded, a finding which suggests that TGF-α acts as a paracrine mediator of proliferative signals arising from prostatic stromal cells and interacting with EGFRpositive basal cells. It is believed by these and other investigators that the mitogenic interactions of TGF-α and EGFR in the adult prostate are mediated by androgens.39 In the pathogenesis of BPH, androgen continues to regulate the TGF-α/EGFR pathway through stromal/epithelial interactions, a paracrine process which is markedly enhanced, for reasons which are presently undefined, during the development of BPH. The onset of carcinogenesis involves an autocrine process, according to these investigators; this is discussed separately in the section on prostatic adenocarcinoma. Prostatic Epithelial Cell Compartments: Their Roles in Proliferative Disorders Bonkhoff and Remberger have provided an extensive review of the relative roles of various types of prostatic epithelium in normal and abnormal prostatic growth.41 Prostatic epithelium is composed of three cellular phenotypes: secretory luminal cells, basal cells, and neuroendocrine cells. Secretory luminal cells express nuclear AR and PSA and require the support of circulating androgens. Basal cells lack AR and PSA expression, and proliferate under estrogen stimulation. They express specific cytoplasmic high-molecular-weight cytokeratin 34βE12 and may express nuclear estrogen and progesterone receptors. Neuroendocrine cells comprise the third epithelial cell type in prostate tissue.


Although there is lack of consensus in this matter, it appears likely that the basal cell layer includes the prostatic stem cell population and that basal cells are pluripotential, capable of differentiating into secretory luminal cells and endocrine cells via intermediate phenotypes42,43 (Figure 15–1). The proliferation of basal cells is regulated by growth factor receptors (such as EGFR, p185, erbB-2 p180erbB-3) and is stimulated by estrogens. The protooncogene bcl-2 protects basal cells from apoptic cell death, and the telomerase gene imparts basal cells with immortality.44,45 The development of basal cell hyperplasia in response to estrogen stimulation suggests that estrogens block differentiation of basal cells to secretory luminal cells. This estrogen effect is balanced by androgens. Basal cells are “androgen independent,” in the sense that they are not induced to proliferate by androgen stimulation, and they do not require androgen for survival. Nevertheless, a proportion of basal cells are “androgen responsive”; it is believed that androgens are capable of inducing this population of basal cells to differentiate into an intermediate population of “amplifying cells.”45 These cells can undergo a limited number of doublings, ultimately generating a population of terminally differentiated, nonproliferating secretory luminal cells that require circulating androgens for their continued maintenance and undergo programmed cell death (apoptosis) when deprived of testosterone.44 Hence, the turnover (net gain versus stasis versus

net loss) of secretory epithelium is thought to be largely dependent on the proportion of androgen-responsive basal cells in the proliferative compartment. Previous studies have suggested that with aging, there is a diminution in 5 α-reductase activity and in DHT levels in prostatic epithelium; it is postulated that this results in increased AR gene expression in the basal cells, making them more responsive to the androgen effect. An alternative hypothesis is that growth factors elaborated by stromal cells increase the androgen sensitivity of basal cells. In either case, as the number of androgen-responsive basal cells increases, the net effect is an acceleration of differentiation to secretory luminal cells, that is, glandular hyperplasia. Cordon-Cardo and colleagues recently reported an apparent role for the P27KIP1 gene in the genesis of BPH.46 The protein product of this gene is a negative regulator of the cell cycle. Both P27KIP1 messenger RNA (mRNA) and P27 protein were found abundantly in stromal and epithelial cells of normal prostate tissue but both were virtually absent in BPH tissue, suggesting that the absence of this growth-suppressive protein may permit the development of BPH. In addition, mice genetically lacking the P27KIP1 gene were noted to develop hyperplastic glands. Because prostatic adenocarcinoma showed contrasting results when analyzed for the presence of P27KIP1 mRNA or P27 proteins, the authors believe that BPH is not a precursor to prostate cancer.

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INTERMEDIATE CELL

LUMINAL CELL

FIGURE 15–1. Prostatic epithelial cells and their inter-relationship: a stem cell model. Horizontal lines indicate basal keratin expression, vertical lines indicate luminal keratin expression, and crossed lines indicate the transition in keratin expression signifying the transition of basal cells to luminal cells via intermediate cells (for details see discussion). With permission from Xue Y, Verhofstad A, Lange W, et al. Prostatic neuroendocrine cells have a unique keratin expression pattern and do not express bcl-2. Am J Pathol 1997;151:1759–65.


The concept that BPH is not a precursor to prostate cancer was supported by De Marzo and colleagues, who noted that basal cells, which are the reservoir from which BPH is ultimately derived, express much higher levels of gene products that protect against genomic aberrations than do secretory cells (e.g., glutathione S-transferase PI [GSTPI], glyceraldehyde-3-phosphate dehydrogenase [GAPDH], and nuclear phosphoprotein 32 [pp32]). It is hypothesized that possession of these protective proteins prevents the acquisition of multiple genomic changes that result in neoplastic transformation.45 Neuroendocrine cells are capable of producing a wide assortment of regulatory peptides.41 They are distinctive by their expression of the neuroendocrine marker chromogranin A, and by their lack of detectable nuclear AR, an indication that they are androgen insensitive.47 These cells are considered terminally differentiated and nonproliferative, a concept supported by their lack of expression of bcl-2 (which protects against apoptosis) or MIB-1 (a proliferation marker).48 Despite their lack of bcl-2, they may be protected from apoptosis by other members of the same gene family, for example, MCL1.48 A study by Cockett and colleagues in 1993 suggested that neuroendocrine cells may play a role in the development of BPH.49 This hypothesis does not seem to have garnered further support. Atypical Adenomatous Hyperplasia of Prostate Atypical adenomatous hyperplasia (AAH) is an enigmatic small acinar proliferation reportedly observed in up to 23% of prostate specimens.50 Although the large majority of foci of AAH are confined to the transition zone, AAH may also be seen outside this region. It resembles well-differentiated prostatic adenocarcinoma in that it consists of aggregates of closely packed, uniform, smallto-medium-sized acini with variable degrees of circumscription.50,51 The age-peak incidence of AAH precedes that of adenocarcinoma, cells of AAH show increased nuclear area and diameter relative to benign epithelium, and there is a topographic relationship between AAH and small acinar carcinoma.51 In contrast to the findings in adenocarcinoma, however, prominent nucleoli and crystalloids are infrequent, and a patchy layer of basal cells can be identified either with routine hematoxylin and eosin stains or by employing immunohistochemical staining for 34βE12.51 The biologic behavior of AAH, specifically its potential as a precursor of prostatic adenocarcinoma, has been a subject of scrutiny and debate for some time.50,51 Grignon and Sakr reviewed all the available information in this regard in 1996.50 Atypical adenomatous hyperplasia has been reported to be more frequent in prostates with cancer than in the noncancerous glands. Intraluminal crystalloids are noted in up to 24% of AAH acini but are less common in AAH than in adenocarcinoma. Wispy intraluminal basophilic (acidic) mucin has been reported in acini of AAH with a fre-

quency comparable with that noted in adenocarcinoma. As noted above, AAH consistently shows varying degrees of disruption of the basal cell layer. Studies of the proliferation rate of the epithelial cells in AAH and the number of silver-staining nuclear organizing regions (AgNORs) in these cells have consistently shown values intermediate between BPH and adenocarcinoma. Studies of the DNA content of AAH epithelia have shown inconsistent results. Reports of increased expression of peanut agglutinin receptors and decreased expression of blood group isoantigens in AAH epithelia suggested a closer kinship to adenocarcinoma than to benign epithelium. Some findings were less supportive of the putative premalignant nature of AAH. In a study of the expression of the carbohydrate D-galactose-N-acetyl-D-galactosamine by the prostatic epithelium, no expression was noted in cases of AAH, in contrast to its expression in 95% of cases of adenocarcinoma. Attempts to identify chromosomal abnormalities using fluorescence in situ hybridization demonstrated a loss of chromosome 8 in 4% of cases. Allelic loss of 8p22 was noted in 6% of AAH compared with 56% of carcinoma cases. The cumulative findings were considered to be inconclusive. More recently, Cheng and colleagues reported the results of their search for allelic imbalances in five microsatellite polymorphic markers on chromosomes 7, 8, and 18, in 15 patients with AAH.51 Allelic imbalances were detected in 7 of 15 (47%) of AAH cases. More concisely, 47% of AAH foci included cells with genetic alterations characteristic of prostatic adenocarcinoma. These findings suggest that AAH may represent an early genetic phase in the evolution of prostatic adenocarcinoma. Morphologic Findings in Benign Prostates Two recent reports have examined prostatic atrophy (PA), a predominantly peripheral zone lesion sometimes mistaken for adenocarcinoma on histologic sections. It can be especially problematic in sections from needle biopsies. Billis studied step sections from the prostatic peripheral zone of 100 autopsies, noting that PA is present in 85% of men over 40 years of age, and that the incidence of PA increases with age.52 Morphologic observations suggested that the presence of PA correlates best with the presence of local atherosclerotic changes, suggesting ischemia as an etiologic factor. There appeared to be no consistent association with nodular prostatic hyperplasia, prostatitis, systemic atherosclerosis, HGPIN, or adenocarcinoma. Oppenheimer and colleagues reported 51 cases with a lesion which they designated partial atrophy, to denote foci of crowded benign glands lined by cells with relatively scant cytoplasm but lacking the distinctive acinar architecture and nuclear basophilia typically observed in atrophic foci at low magnification.53 Some lining cells contain readily visible nucleoli, and basal cells typically are difficult to identify without the use of an immunoperoxi-


dase stain for 34βE12. These lesions create diagnostic uncertainty because they may be difficult to distinguish from low-grade adenocarcinoma. The authors point out that in partial atrophy there is lack of nuclear enlargement, conspicuous nuclear atypia is uncommon, and the cells lining the acini of partial atrophy exhibit a high nuclear (N):cytoplasmic (C) ratio. The acini in the focus of concern tend not to have an infiltrative appearance and, in fact, may blend with adjacent acini that are clearly benign. Foci of partial atrophy may lie directly adjacent to foci of fully developed atrophy. None of the foci of partial atrophy described in this report contained blue tinged mucinous secretions or crystalloids. Intraluminal crystalloids are enigmatic eosinophilic structures that have been linked to prostatic adenocarcinoma in publications dating back to 1977. They have subsequently been reported to occur in acini of benign glands and in foci of AAH. It has been proposed that crystalloids identified in benign glands on needle biopsy are a harbinger of concurrent carcinoma and thereby constitute an indication for repeat biopsy. Henneberry and colleagues examined follow-up biopsies and serum PSA levels in 31 men whose only unusual finding on initial biopsy was the presence of intraluminal crystalloids within benign glands and compared these results with the findings in a control population of men with a benign first biopsy not showing crystalloids.54 The incidence of cancer on subsequent biopsy was not significantly different in the two groups. The authors concluded that the isolated finding of intraluminal crystalloids in benign glands is not associated with an increased risk of concurrent carcinoma and does not constitute an indication for repeat biopsy.

Prostatic Neoplasia Carcinogenesis Where do prostate cancer cells come from? Why do they behave as they do? In general, prostate cancer is the net result of alterations in the regulatory control of cell proliferation, cell DNA repair, apoptosis, cell differentiation, cell/matrix interactions, angiogenesis, and senescence. These functions are influenced by oncogenes, tumor suppressor genes, hormones, growth factors, and growth factor receptors. De Marzo and colleagues maintain that an understanding of carcinogenesis requires an appreciation of the numerous differences between basal cells and their derivatives—the epithelial cells found in normal prostatic glands, in BPH, in HGPIN, and in adenocarcinoma. The theories of these investigators are based on their own observations and those of numerous other investigators, and are summarized below.41–45 First, it is informative to consider the attributes of basal cells. A subset of these cells is considered to be stem cell progenitors of normal luminal secretory cells and neuro-

endocrine cells41 (Figure 15–2). Stem cells possess abundant protective proteins (GSTPI, GADPH, pp32) that prevent the permanent acquisition of carcinogenic genomic alterations. The growth suppressive influence of P27KIP1 is intact in these cells, as is the cell death suppressive effect of bcl-2. In addition, stem cells are immortalized by their ability to express telomerase. Telomerase is a reverse transcriptase that provides a template for the synthesis of DNA telomeres—DNA repeat sequences found at the ends of eukaryotic chromosomes. Cells which lack telomerase lose telomere segments with each round of replication, and their descendants ultimately undergo senescence. As previously noted, stem cells differentiate into a pool of transiently proliferating “amplifying cells,” which under normal circumstances simply renew the supply of terminally differentiated luminal secretory cells. In BPH, it appears that an expanded pool of activated stem cells produces more than the usual number of amplifying and terminally differentiated luminal secretory cells. These stem cell descendants are no longer pluripotential, nor are they immortal or protected from apoptosis. Of critical importance, however, is that they retain the genome protective influence of GSTPI and therefore do not usually undergo malignant transformation. The epithelial cells observed in HGPIN and adenocarcinoma demonstrate a different set of molecular characteristics (Figure 15–3). It is hypothesized that these cells are derivatives of transiently proliferating (amplifying) secretory cells that have not yet undergone terminal differentiation. It is further hypothesized that downregulation of the P27KIP1 gene in these cells allows them to linger in the cell cycle (rather than undergo terminal differentiation and eventual senescence) and that loss of genome protective influences results in their acquisition of neoplastic genomic alterations through the practice of “unsafe replication.” In support of this hypothesis, it has been shown by Cheville and colleagues that prostate cancers with downregulation of P27 are more likely to display aneuploidy, higher grade, and involvement of seminal vesicles and regional lymph nodes.55 Neoplastic cells activate or maintain telomerase expression, facilitating immortality, and their survival is further enhanced by their expression of bcl-2, which prevents apoptosis and allows cell survival despite DNA damage. Their proliferative capacity is enhanced by their abnormal expression of growth factor receptors, and by loss of tumor suppressor genes.41 As the “unsafe replication” continues, additional genomic alterations accumulate that impart invasive and metastatic properties to the neoplastic cells.45 As noted by Bonkhoff, the invasive and metastatic properties of prostatic carcinoma are marked by the production of distinctive periacinar and pericellular basement membrane material and associated laminin and collagen receptors, accompanied by the loss of normal basement membrane–associated adhesion proteins and receptors.42


Aspects of neuroendocrine differentiation in prostatic adenocarcinoma were also recently addressed by Bonkhoff and Remberger.41 Malignant cells expressing a neuroendocrine phenotype are believed to be descendents of the transiently proliferating “amplifying cells” derived from stem cells and are detectable in about 10% of all common adenocarcinomas.41,48 Surprisingly, these cells are not usually highly proliferative; in fact, neuroendocrine differentiation occurs exclusively in the G0 phase of cell proliferation. However, it is believed that neuroendocrine cells secrete growth-promoting peptides which enhance the proliferation of nearby malignant exocrine cells by a paracrine mechanism. It is further believed that these cells are intrinsically androgen insensitive and, thus, are refractory to hormonal therapy.47 Hence, they are triply troublesome: (1) they do not respond to hormonal manipulation themselves, (2) they are capable of promoting the growth of adjacent exocrine cells even in an androgendeprived milieu, and (3) their relative lack of proliferative activity suggests a probable resistance to radiation therapy and chemotherapy. Despite the troublesome nature of malignant neuroendocrine cells, a recent study indicates that focal neuroendocrine differentiation, which can be found by immunohistochemical studies in up to 25% of core needle biopsies of newly diagnosed prostate cancer, does not provide prognostic information independent of Gleason score or Ki-67 labelling index.56 Of considerable interest in this study was the finding of a significant increase in the frequency and density of neuroendocrine differentiation between the initial needle core biopsies and subsequent biopsy specimens taken from patients that had become refractory to hormonal therapy. This finding correlates nicely with the results of a study by Papandreou and colleagues concerning the loss of neutral endopeptidase 24.11 (NEP) by tumor cells of androgen-independent prostate cancers.57 Androgen-dependent prostate cancers express a cell-surface enzyme, NEP, which inactivates the neuropeptides involved in the growth of androgenindependent tumor cells. When antiandrogen therapy is instituted, with loss of androgen-dependent clones of tumor cells, there is a net loss of NEP, and a net gain in bioavailable neuropeptides. Androgen-independent tumor cells thus gain a growth advantage by using mitogenic neuropeptides as an alternate source of androgen in order to stimulate cell proliferation. The process of carcinogenesis appears to be dependent upon three cellular characteristics: (1) increased cell proliferation, (2) extended cell survival, and (3) diminished apoptosis. The role of apoptosis in carcinogenesis has been extensively clarified in recent years.58 It is known that prostate cancer typically is a mixture of androgendependent and androgen-independent clones. Upon androgen withdrawal, the androgen-dependent clones are induced to undergo apoptosis, whereas androgenindependent clones do not initiate this “cellular suicide.”

Even androgen-independent cells retain their apoptosis machinery and can be induced to undergo apoptosis by a wide spectrum of pharmacologic and biologic agents.58 Apoptosis is a complex event that is influenced by the relative effects of a host of cellular proteins, which can be characterized as proapoptotic (P53, Bax, Bad, Bak) or antiapoptotic (bcl-2, P21). Two roles are ascribed to P53: (1) arresting the cell cycle to allow DNA repair, and (2) triggering apoptosis to induce self-destruction of cells that

Normal Maturation Sequence

BASAL COMPARTMENT

Stem Stem Cell Features: Genome protection (e.g., GSTP1) Active proliferation capacity (e.g., decreased P27KIP1) Death suppression (e.g., bcl-2) Immortality (e.g., telomerase) Pluripotentiality

Other Features: Secretion Genetic instability Nuclear atypia Clonal Invasiveness Metastatic potential

Normal Stem

SECRETORY COMPARTMENT Transiently Proliferating Postmitotic

BPH

PIN

_

_

Cancer

_+/+

+

+

+ + +

_ /+ _ _

_ /+

+

_ _ _

+

_ _ _ _ _

_

+ +

+ + +

_/+

_/+

+ + +

+ + + + +

_ _

FIGURE 15–2. Stem cell model of BPH and cancer development. Although BPH and cancer develop often within the same patient, the target cells are different and the resultant abnormal cells retain or enhance different features of the normal stem cell and its maturing progeny. In BPH, there is an abnormal increase in the pool of basal cells with proliferative capacity. This basal TP cell maintains genome protection and, hence, resistance to transformation, which explains why BPH usually does not progress to cancer. Also, BPH partially retains the stem cell features of cell death capacity. In BHP, as in the normal epithelium, secretory cells become terminally differentiated (postmitotic). In high-grade prostatic intraepithelial neoplasia (PIN), the target TP cell is in the secretory compartment, which explains the lack of basal cell–specific marker expression (cytokeratins 5 and 14). Like other secretory compartment cells, these cells have lost genome protection activity, perhaps since they are normally programmed for the permanent exit of cell cycle terminal differentiation. These cells become blocked from full maturation, remaining in the cell cycle to a large degree by acquiring alterations in cell cycle control. Proliferating secretory type cells are subject to DNA damage from environmental factors and acquire genome alterations in oncogenes and tumor suppressor genes, resulting in clonal expansion. Cell immortality results from re-expression or increased expression of telomerase. Additional genetic changes in genes that control cell adhesion, angiogenesis induction, and motility result in invasion (carcinoma) and eventual metastasis. Dark nuclei = P27KIP1 positive; light nuclei = P27KIP1 negative. With permission from De Marzo AM, Nelson WG, Meeker AK, Coffey DS. Stem cell features of benign and malignant prostate epithelial cells. J Urol 1998;160:2381–92.


are beyond repair. The relative contributions of the apoptotic proteins to carcinogenesis were evaluated by Tang and colleagues in a study of the effects of growth-factor deprivation on the survival properties of cell-culture populations derived from normal and hyperplastic prostate tissue and from primary and metastatic prostate carcinomas.58 Growth-factor deprivation led to rapid apoptosis in non-neoplastic cell lines. In contrast, malignant cell lines demonstrated enhanced cell proliferation and decreased apoptosis. Further analysis revealed that nonneoplastic cells upregulate proapoptotic proteins (wildtype P53, Bax, Bad, Bak), show little or no bcl-2 expression, and either no change or a decrease in P21 expression. The results of growth-factor deprivation and molecular changes in normal cells are a halt in cell proliferation and apoptosis leading to decreased cell number (Figure 15–4). In contrast, neoplastic cells continue to proliferate despite growth factor deprivation, probably due to autocrine growth factor production. In addition, they evade apoptosis by refraining from P53 upregulation, by a diminution or deletion of the apoptosis-inducing proteins Bax/Bad/ Bak, by upregulating P21 (which halts the proliferative machinery at a time when cancer cells would be prone to “mitotic catastrophe”), by upregulating bcl-2 (an antiapoptosis mechanism), and possibly by aberrant expression of immunoglobulin molecules unique to cancer cells (P25, P54/55) whose role is unknown but which may, in

some way, extend the survival of cancer cells. Sustained proliferation and evasion of apoptosis allows the prolonged survival of cancer cells. Sustained proliferation and evasion of apoptosis allow the prolonged survival of neoplastic cell lines; in vivo, this would account for the production of the lesion we recognize as carcinoma. Much information has accumulated concerning the influence of growth factors on prostatic proliferation, and interest continues because growth factor manipulation may be a realm of therapeutic intervention. This topic was reviewed by Culig and colleagues.40 The growth factors operative in physiologic and nonphysiologic prostatic conditions are EGF, TGF-α and -β, fibroblast growth factors (FGFs), and insulin-like growth factors (IGFs). All are believed to be positive growth factors, with the exception of TGF-β, which inhibits prostatic growth and antagonizes growth-promoting factors. Under normal physiologic conditions, they act in a paracrine fashion. Transformation to a neoplastic state is accompanied by a shift from paracrine control of growth to an autocrine state. Leav and colleagues demonstrated a rather abrupt appearance of both TGF-α and EGFR in dysplastic luminal secretory cells; ordinarily, EGFR is restricted to basal cells, and its ligand, TGF-α, is restricted to smooth muscle cells.39 In addition, they noted that the co-localization of AR, TGF-α, and EGFR in dysplastic cells is identical to the pattern of expression of these molecules in invasive carcinoma. This

FIGURE 15–3. Loss of genome protective function in high-grade prostatic intraepithelial neoplasia (HGPIN) based on proliferation compartment infidelity. With permission from De Marzo AM, Nelson WG, Meeker AK, Coffey DS. Stem cell features of benign and malignant prostate epithelial cells. J Urol 1998;160:2381–92.


suggests two concepts: (1) that autocrine growth stimulation is an early phenomenon in carcinogenesis, and (2) that this autocrine loop is regulated by androgens during this phase of carcinogenesis. As carcinogenesis proceeds, the autocrine loop is believed to become progressively independent of androgen for continued growth.39 In addition, there is evidence to suggest that prostate carcinoma cells are also capable of endogenous production of FGFs.40,59 It is unclear whether neoplastic cells participate in endogenous IGF production. Studies on TGF-β support the concept that advanced prostate cancer escapes the inhibitory effects of TGF-β. A recent report by Cipriano and Chen offers an explanation for the lack of inhibition of prostate cancer cells by TFG-β.60 Normal progress of cell

A

replication through the G1 phase is permitted by several “cyclin-Cdk complexes.” When cyclin-Cdk complexes are associated with “cyclin-dependent kinase inhibitors” (CKIs), cell-cycle arrest occurs. The normal inhibitory effect of TGF-β is mediated through several CKIs. In prostate cancer cells, it appears that there is a failure of inhibition of Cdk2 activity by CKIs, and consequently cellcycle arrest is not accomplished. While much has been written about the importance of chromosomal alterations associated with carcinogenesis, less attention has been paid to the role of epithelial-stromal interactions in normal and abnormal prostatic growth. This subject was addressed in a recent review by Bonkhoff.61 It is well known that acinar structures har-

wt P53: P21: bcl-2: little/no bcl-XL: Bax/Bad/Bak:

wt P53: P21: bcl-2: little/no bcl-XL: Bax/Bad:

P53: null P21: wt P53: bcl-2: P21: bcl-XL: bcl-2: Bad/Bak: Bax: bcl-XL: Bax/Bad/Bak: P25/P54/55: yes

wt P53: P21: bcl-2: little/no bcl-XL: Bax/Bad/Bak: P25/P54/55: yes

P53: mutant P21: bcl-2: bcl-XL: Bad/Bak: Bax: deleted P25/P54/55: yes

Growth Apop +++

Growth Apop +++

Growth + Apop +++

Growth +++ Apop +

Growth +++ Apop +

BPH

NHP

LNCaP

Growth +++ Apop ++

PC3

PCA

DU 145

B Normal Prostate Epithelium Androgen dependence Growth factor dependence Long population doubling time Wild-type P53 Little/no bcl-2

Deprivation

Deprivation P53 upregulation P21: no change or decrease Bax/Bad/Bak upregulation bcl-2: little/no expression

No cell proliferation Apoptosis

Decreased cell number

Prostate Cancer Cells Androgen independence Autocrine growth factor production Short population doubling time Non-functional P53 High bcl-2 Low/no Bax

Deprivation

Cell proliferation

No P53 upregulation

Deprivation P21 upregulation

Bax/Bad/Bak: decrease or deletion bcl-2: upregulation Novel proteins: P25: P54/55(?)

Evasion of apoptosis

Extended survivability

FIGURE 15–4. A, The overall survivability of various prostate cells in the absence of trophic factors is presented: BPH < NHP < LNCaP < PCA < PC3 < PCA < DU 145. Shown above are changes in apoptosis proteins. (Refer to text for details.) No change; increase (upward arrowhead); decrease (downward arrowhead); little or no expression (little/no). Shown in the middle are the cell growth and apoptosis properties of various prostate cells in the absence of trophic factors, as deduced from preceding figures. (– = no growth;. + to +++ = different levels of apoptosis.) The BPH and NHP cells did not proliferate at all and demonstrated fast apoptotic kinetics. The LNCaP cells demonstrated a low level of proliferation and an intermediate level of apoptosis. The PC3 cells demonstrated very aggressive growth and intermediate levels of apoptosis. The PCA and DU 145 cells, in contrast, demonstrated a rapid cell proliferation as well as much delayed and decreased levels of apoptosis. B, Summary of molecular events leading to differential survivabilities of normal versus cancerous prostate epithelial cells in the absence of trophic factors. Note that there exist exceptions to this generalized scheme. For example, PCA cells possess wild-type P53 and express little/no bcl-2. With permission from Tang DG, Li L, Chopra DP, Porter AT. Extended survivability of prostate cancer cells in the absence of trophic factors: increased proliferation, evasion of apoptosis, and the role of apoptosis proteins. Cancer Res 1998;58:3466–79.


boring benign epithelium are surrounded by basement membrane (BM) material. Normal BM is mainly composed of type IV collagen, laminins, heparin sulfate proteoglycans, and entactin. Prostatic basal cells possess receptors for laminins, collagen subunits, and a receptor associated with hemidesmosome formation. It is believed that the adhesive interactions between the epithelial cells and BM are predominantly mediated by laminin receptors, that epithelial BM are produced predominantly by basal cells, and that prostatic epithelial cells require BM components for growth and differentiation. It has been shown that the cells of HGPIN exhibit increasing transcriptional activity of genes encoding BM components, raising speculation that this abnormal expression of BM-encoding genes may modify the structure of the underlying BM, which in turn may alter cell/matrix adhesive interaction. Furthermore, the cells of HGPIN lose hemidesmosomeforming proteins and a host of adhesive molecules normally found in prostatic epithelial cells; this is accompanied by a progressive loss of basal-cell differentiation. Invasive prostate carcinomas continue to produce BM and to express integrin receptors, which facilitates attachment of tumor cells to the adjacent BM. This BM-forming function is maintained through all stages of the disease and appears to increase as tumor progression and metastasis supervene. However, the BM produced by cancer cells is abnormal. These cells lose a variety of hemidesmosomeforming proteins and associated adhesive molecules. In many if not all instances, there is complete loss of certain types of collagen chains.62 Furthermore, as the tumor grade increases, the number of cell/matrix receptors progressively diminishes. It is postulated that de novo synthesis of BM and maintenance of adhesion molecules may facilitate extracellular matrix penetration during the processes of invasion and metastasis.61,62 Clearly, this is an avenue which will receive continued scientific attention in the coming years, since future therapeutic endeavors may revolve around prevention of stromal invasion and metastasis. The first documentation of malignant transformation of human prostatic epithelial cells by exposure to the chemical carcinogen N-nitroso-N-methylurea (NMU) was reported by Rhim and colleagues.63 The process of carcinogenesis was observed in prostatic cells immortalized by DNA transfection with the HPV-18 genome and subsequently exposed repeatedly to NMU. Multiple chromosomal losses or gains were observed, the most frequent of which were loss of the short arms of chromosomes 8 and 10 and gain of the long arm of chromosome 8. Prognostic Indicators in Prostate Cancer Because there is such a large disparity between the autopsy prevalence of histologic prostate cancer and its clinical incidence, it is readily apparent that the mere presence of prostate cancer in needle biopsy or transurethral resection of the prostate (TURP) specimens may or may not alter or

threaten the individual’s life. It is the acquisition of the ability to metastasize that characterizes a life-altering or life-threatening prostate cancer. It is for this reason that ongoing efforts are being made to identify molecular changes associated with metastatic potential. Metastasis is the result of a sequence of events, including growth, local invasion, and destruction of extracellular matrix, angiogenesis, angiolymphatic invasion, survival in the circulation, adhesion at a metastatic site, exit from the circulation, and proliferation at the metastatic site.64 It is well known that there is an inverse correlation between tumor size (the result of tumor growth) and long-term survival.65 Hence, it seems sensible to examine the factors that may influence tumor growth, in relation to their prognostic value. Studies of these factors are most commonly done using immunohistochemical or molecular biologic techniques. The studies are usually performed on archival tissue from patients whose long-term outcome is known, to allow correlation of the prognostic marker with subsequent tumor behavior. Stapleton and colleagues evaluated the prognostic value of P53, Ki-67, and apoptotic index in cancers removed by radical prostatectomy.66 Of the three markers, only apoptotic index (the number of apoptotic bodies per 100 cancer cells) provided prognostic information independent of other parameters, that is, clinical stage, serum PSA, and Gleason score. These investigators speculate that high apoptotic activity establishes the conditions for the selection of subsets of aggressive tumor cell clones, on the basis of compromised function of the apoptotic pathway. In a similar study of archival radical prostatectomy specimens, Kim and colleagues evaluated the association between the immunohistochemical expression of TGF-β membrane receptor type I (TGFβRI) and a variety of pathologic and clinical parameters.67 They report that loss of expression of TGF-βRI significantly correlated with higher Gleason score, advanced clinical stage, decreased 4-year survival rate, and increased serologic recurrence rate. Insulin-like growth factor binding protein-3 (IGFBP-3) was reported to provide no useful prognostic information in a comparable study by Hampel and colleagues.68 Before a carcinoma cell can metastasize, it must first break free of the adhesive molecular bonds that normally anchor it to its neighboring cells and to the underlying matrix. In prostate tissue, the major cell-to-cell adhesion molecules are cadherins. Cadherin molecules of neighboring cells bind to one another in the extracellular space. The cadherin molecule also traverses the cell membrane to bind with members of the catenin family, which, in turn, link to cytoskeletal microfilaments such as actin.69 Several studies analyzing radical prostatectomy or TURP tissue have shown that aberrant expression of E-cadherin and/or α-catenin correlates with poor outcome, in terms of disease progression and overall survival.69,70 A problem arises, however, when trying to use markers such as


E-cadherin or P53 to predict the prognosis, when the only tissue available is a prostate needle biopsy specimen. This difficulty was reported by Ruijter and colleagues, who found an alarmingly low sensitivity for detecting abnormal E-cadherin expression by needle biopsy, probably because of inherent sampling error but also because of the marked heterogeneity of all prostate cancers.71 After analyzing their results, these authors question the utility of E-cadherin and P53 expression as prognostic markers in needle biopsy specimens. Considerable research activity has centered recently on “metastasis regulation genes” such as KAI1, CD44, and thymosin (Figure 15–5). It has been observed that hybrid cancer cells derived from fusion of highly metastatic and nonmetastatic cells continue to be tumorigenic but demonstrate suppressed metastatic capability, provided they retain all the chromosomes from both parental cell lines. Subsequent chromosome loss re-establishes metastatic potential, suggesting that metastatic suppressor gene(s) have been inactivated by mutation, allelic loss, or biochemical inactivation.72 A gene on human chromosome 11, designated KAI1, has been isolated and has been shown to suppress metastatic capability when introduced into rat prostate cancer cells.73 Furthermore, diminished expression of KAI1 was consistently observed in metastatic human prostate cancer.73 Neither the exact manner in which metastasis is suppressed nor the mechanism of downregulation is known; downregulation in this case does not appear to involve either mutation or allelic loss. Also located on chromosome 11 is another metastasissuppressor gene, CD44, whose products are involved in cell-to-cell and cell-to-extracellular matrix interactions. Downregulation of CD44 expression appears to be involved in the progression of prostate cancer to metastasis.74,75 An additional factor which appears to be operative in allowing malignant cells to abandon their organ of origin is the apparent upregulation of thymosin β-15, a molecule which directly regulates cell motility in prostate cancer cells. According to Bao and colleagues, the expression of this gene product correlates with the Gleason score, and studies of its possible utility in predicting the metastatic potential of prostate cancer diagnosed by needle biopsy are underway.76

achieved with antibodies against PSA and prostatic acid phosphatase. The staining patterns were not prognostically useful. Their study confirms that hK2 is prostate localized, tumor associated, and expressed more intensely in high-grade carcinomas than PSA. Studies to evaluate the utility of serum hK2 as a marker for prostate cancer are planned; it is noted that this molecule may be useful as a target for reverse transcriptase–polymerase chain reaction (RT-PCR) in the detection of circulating cancer cells that express hK2. Sophisticated molecular techniques have been successfully employed to identify gene products that are unique to prostate cancer cells. A gene on chromosome 9, specific to prostate cancer cells, and its gene product have been identified by Bussemakers and colleagues.78 This gene has been designated DD3. A cell surface antigen uniquely produced by prostate cancer cells, labelled PTCA-1, has also been identified by Su and colleagues.79 Discovery of these unique genetic aberrations is tantalizing because they may be useful therapeutically, for example, in genetherapy regimens. Ornithine decarboxylase (ODC) is an enzyme involved in the biosynthesis of cellular polyamines. It has been observed that there is dysregulation of ODC activity in rodent tumors. It is known that the highest levels of ODC in humans are found in prostate tissue. Mohan and colleagues reported that ODC activity and protein expression are significantly higher in human prostate cancer than in paired benign prostate tissue controls. Furthermore, ODC activity in prostatic fluid obtained by digital rectal massage from prostate cancer patients was significantly higher than ODC levels in prostatic fluid from patients without prostate cancer.80 These authors suggest that measurement of ODC levels in prostatic fluid may be useful as a noninvasive test for prostate cancer and as a mechanism for monitoring the efficacy of treatment.

Thymosin β-15 (Activator) KAI1 (Suppressor) E-Cadherin

Recently Developed Molecular Diagnostic Modalities It is recognized that PSA has become the most important tumor marker for prostate cancer. However, the sensitivity and specificity of serum PSA leave room for improvement. Darson and colleagues reported their evaluation of human glandular kallikrein 2 (hK2) expression in a large series of pathologic stage T2 prostatic adenocarcinomas treated by radical prostatectomy.77 They found that the immunohistochemical expression of hK2 increased incrementally from benign epithelium to HGPIN to adenocarcinoma, and showed an inverse relationship to staining,

α-Catenin

MOTILITY

METASTASIS

Integrins

Extracellular Matrix FIGURE 15–5. Important steps in increasing tumor cell motility as part of the cascade to metastasis. With permission from Coffey DS. Prostate cancer metastasis: talking the walk. Nature Med 1996;2:1305–6.


Studies of the Morphology of Prostate Neoplasms High-Grade Prostatic Intraepithelial Neoplasia This entity, now well established as the most likely precursor of prostatic adenocarcinoma, continues to be a topic of much research interest, as noted in prior references. The ultrastructural features of HGPIN were described comprehensively by Bostwick and colleagues in a study comparing the benign epithelium, HGPIN, and adenocarcinoma.81 This study was unique in that the tissue analyzed was fresh and optimally fixed for ultrastructural assessment. The ultrastructural features of HGPIN were found to be intermediate between those of benign epithelium and adenocarcinoma, providing further support for the hypothesis that HGPIN is a premalignant lesion. Animal models may prove valuable in assessing the utility of chemoprevention in halting or reversing the progression of HGPIN to prostate cancer. In a report by Waters and Bostwick, it is noted that HGPIN occurs spontaneously in the canine prostate and that there are numerous similarities between canine and human HGPIN.82 Canine HGPIN displays marked cytologic atypia and basal-celllayer disruption as well as proliferative index and microvessel density parameters intermediate between those of benign epithelium and adenocarcinoma. Furthermore, HGPIN was identified in the majority (66%) of canine prostate cancers. Prevalence data confirmed that HGPIN is found in 55% of elderly, sexually intact dogs and is infrequently found in young, sexually intact dogs and elderly, castrated dogs. In short, the prevalence of HGPIN in dogs is strongly influenced by age and testicular androgens. These authors propose that the canine prostate may be a useful model in assessing prostate carcinogenesis. The possibility that HGPIN is the precursor of relatively aggressive prostate cancers but not of indolent well-differentiated cancers was raised by Dawson and colleagues in a study of the expression of the RET protooncogene product by benign prostatic epithelium, HGPIN, and a variety of grades of prostate cancer.83 Higher RET expression was observed in HGPIN and in tumors with poorer histologic differentiation; weak expression was noted in the benign epithelium and welldifferentiated tumors. Obviously, more study will be needed to resolve this question. Morphologic Features and Prognosis As previously noted, there is considerable research underway using molecular and immunohistochemical techniques to identify factors that can be used clinically in the management of prostate cancer patients. The histologic evaluation of routinely processed pathologic specimens continues to provide helpful prognostic information, as evidenced by the following studies. In a large series of radical prostatectomies, McNeal and Yemoto evaluated vascular invasion as a prognostic

indicator.84 Vascular invasion was found in 7% of cancers < 4 cc in volume, and in 24% of cancers > 4 cc in volume. Vascular invasion, cancer grade, and cancer volume were all found to be statistically significant independent predictors of cancer progression. The significance of perineural invasion noted on prostate needle biopsy continues to be a subject of debate. The results of comprehensive studies by Egan and Bostwick,85 and by Epstein,86 have led them to conclude that this finding does not independently influence the likelihood of PSA recurrence following radical prostatectomy, when preoperative Gleason score, serum PSA, and clinical stage are also taken into account. Epstein also notes that excising the neurovascular bundle in cases with perineural invasion reduces the incidence of positive surgical margins by 17.5%. A different viewpoint was expressed by Stone and colleagues.87 These investigators assessed the significance of “extensive” perineural invasion and seminal vesicle involvement by cancer on prostate needle biopsies in relation to lymph node metastasis. Their results indicate that both factors are independent predictors of lymph node metastasis; they recommend that lymph node dissection should precede definitive therapy if either of these findings is observed on prostate needle biopsies. It appears that this is one debate that will require more evaluation. A study of the significance of capsular invasion and extracapsular spread of prostate cancer by Wheeler and colleagues yielded several interesting findings.88 These investigators found a strong association between the level of invasion by the cancer into or through the prostatic capsule and the volume, grade, pathologic stage, and recurrence rate after radical prostatectomy. Tumors that did not invade the capsule did not metastasize in this patient cohort, regardless of tumor volume or grade. There was a linear relationship between degree of capsular invasion and the occurrence of adverse findings, such as seminal vesicle or lymph node involvement and postoperative recurrence of tumor. In a related report, Sanwick and colleagues compared the frequency of extracapsular tumor extension with preliminary needle biopsy findings.89 In patients with cancer of Gleason score 3 or lower on one side and no cancer in at least three needle cores from the opposite side, there was rarely any extracapsular extension of tumor on the side thought preoperatively to be free of tumor. Their findings suggest that the neurovascular bundle can safely be preserved on the side without evidence of cancer, given the conditions specified above. The problem of unwarranted optimism among pathologists was addressed by Iczkowski and Bostwick.90 Comparing their grading of over 1400 needle biopsies and TURP specimens sent for consultation with the grades assigned by the referring pathologists, these authors observed a 2% incidence of “well-differentiated” cancers (Gleason score 2 + 2 = 4 or less) in these cases. The referring pathologists had labelled 56% of the cases


as “well differentiated.” Steinberg and colleagues also noted a pronounced tendency on the part of pathologists in nonacademic settings to assign low Gleason scores (2 to 4) to cancers detected in needle biopsies.91 The point being made is that the common overdiagnosis of “welldifferentiated” cancer on needle biopsy may inadvertently (and inappropriately) influence choice of therapy to the patient’s detriment. Variants of Prostatic Adenocarcinoma Neoplastic glomeruloid structures exhibit a pattern of growth that mimics the renal glomerulus; these architectural oddities have been noted in Wilms’ tumor, gliomas, and, more recently, prostatic adenocarcinoma. Pacelli and colleagues noted glomerulus-like malignant epithelial aggregates in 9 of 202 radical prostatectomy specimens and in 3 of 100 needle biopsy cases.92 The finding is believed by these authors to be specific for malignancy since it was not observed in benign epithelia or in HGPIN. The significance of the entity is so far uncertain, although it seems most often to be a component of high-grade cancers that tend to exhibit extraprostatic extension. The cytoarchitectural changes in the morphology of prostatic adenocarcinoma induced by total androgen blockade therapy have been well characterized in numerous reports. Tran and colleagues have described an additional, previously unreported, alteration in prostate cancer morphology as a consequence of androgen ablation—the formation of lakes of extravasated mucin, with or without recognizable residual tumor.93 In 3 of 13 cases exhibiting this finding, no residual intact prostatic adenocarcinoma could be found; review of preoperative biopsies confirmed the diagnosis of adenocarcinoma. This study is important for at least two reasons. First, identification of these mucin lakes in a radical prostatectomy specimen may prompt the pathologist to search for the other more subtle findings that are typical of preoperative androgen ablation therapy. Secondly, pathologists need to be aware that these mucin lakes may be the only residual clue to the previous existence of adenocarcinoma in the gland to be examined. For several years, there has been controversy among pathologists concerning cytologically malignant solid, papillary, and cribriform cellular proliferations within prostatic ducts that retain a basal cell layer. The debate has centered on the question of whether such proliferations represent a premalignant lesion (HGPIN) or whether they represent intraductal extension of an established invasive cancer (intraductal carcinoma [IDCa]). Proponents of both viewpoints have presented compelling arguments.94–96 The practical difficulty of this uncertainty is that a pathologist confronted with these findings in a needle biopsy specimen must provide a guideline to the urologist for patient management. Most pathologists agree that intraductal comedo-necrosis is only seen in cases of established carcinoma. Wilcox and

colleagues have suggested that the debate may be unresolvable, that a cytologically malignant intraductal proliferation may represent either HGPIN or a fully established cancer invading the ductal spaces, and that there is presently no reliable way of distinguishing the two entities on needle biopsy specimens.97 Therefore, Wilcox and colleagues have proposed that aggregates of cytologically malignant cells within a duct with an intact basal cell layer and showing central comedo-necrosis should be considered to represent cancer; all other intraductal proliferations should be lumped together as HGPIN, with a recommendation to repeat biopsy. In an article closely related to the above discussion, Bock and Bostwick have questioned the existence of prostatic duct adenocarcinoma as a distinct pathologic entity with unique pathologic and clinical features.98 In 5% of 338 radical prostatectomy specimens, they found areas with microscopic features normally attributed to prostatic duct carcinoma within typical peripheral zone adenocarcinomas; the noted areas comprised up to 60% of total tumor volume. They believe that prostatic duct adenocarcinoma is simply a manifestation of typical adenocarcinoma with extension into accommodating large ducts. Diagnostic Pitfalls and Dilemmas in Prostate Pathology The problem of overdiagnosing prostate cancer has been discussed in a previous section. Several recent reports have described subtle alterations in prostatic adenocarcinoma morphology, which can be difficult to recognize as malignant. Foamy gland carcinoma, characterized by the presence of abundant xanthomatous cytoplasm within tumor cells, is a deceptively bland lesion described by Nelson and Epstein.99 Recognition of a malignant process is aided by the crowded and infiltrative architecture of the neoplastic glands and by the frequent presence of dense pink acellular secretions within smaller than normal acini (Figure 15–6). It is noteworthy that these neoplasms often do not display nucleomegaly or nucleolomegaly. The entity is considered by the authors to be of intermediate grade. Pseudohyperplastic prostatic adenocarcinoma, originally described by Epstein and revisited in a recent article by Humphrey and colleagues, can also be readily misinterpreted as a benign condition.100 The malignant glands in this condition can display nodular architecture, cystic change in larger acini, complex branching, luminal undulations, and true papillary projections with fibrovascular cores. The malignant epithelium is often columnar. Fortunately, the lining cells are cytologically malignant upon close inspection, with nucleomegaly and nucleolomegaly in all cases reported by Humphrey and colleagues; the diagnostic difficulty lies in the deceptively benign-looking architechture. Prostatic adenocarcinoma with atrophic features is a deceptively innocuous-looking lesion described by two groups of investigators in 1997.101,102


A

B

FIGURE 15–6. Foamy gland carcinoma. A, At low power, there are crowded acini with abundant dense secretions. The acini are clearly different from the normal adjacent acini. B, At high power, there is a single layer of epithelial cells without nucleomegaly or nucleolomegaly; the cytoplasm is copious and ”foamy.“ The diagnosis of malignancy in these cases is based on recognition of abnormal architecture.

The diagnostic problems in this entity are both architectural and cytologic. The lesion resembles acinar atrophy on scanning magnification. The acinar spaces are either dilated and round to oval, or small with an irregular distorted outline (Figure 15–7). The lining cells appear attenuated, with scant cytoplasm and a high nucleus-to-

cytoplasmic ratio. A diagnosis of malignancy is facilitated if the atypical glands display clear-cut infiltration between adjacent benign acinar structures. The diagnosis of adenocarcinoma with atrophic features should only be made when there is convincing cytologic evidence of malignancy (nuclear and nucleolar enlargement) and

A

B

C

D

FIGURE 15–7. Adenocarcinoma with atrophic features. At low power, malignant acini are small, distorted, and angular (A), or dilated and round to oval (B); in either case, they mimic atrophy. At higher magnification (C, D), the malignant acini are lined by cytologically malignant cells.


should be made with great caution when there is a background of inflammation. Cowper’s glands, normal residents of the urogenital diaphragm, may be sampled inadvertently during TURP, or occasionally in the course of prostate needle biopsy. They are composed of small tightly packed acini and can be misinterpreted as adenocarcinoma. Saboorian and colleagues addressed this problem and pointed out that the acinar epithelium of Cowper’s glands stains positively for mucin and negatively for PSA and PAP.103 The acinar units are lined by an attenuated layer of myoepitheial cells that show positive staining for smooth muscle actin but negative staining for protein S100 or 34βE12. The authors correctly emphasize that reliance on a negative 34βE12 stain for basal cells to diagnose cancer can be treacherous in instances such as this. The noted combination of staining characteristics helps to resolve the nature of the suspicious acinar units; however, the most critical factor is the initial recognition that the worrisome focus may be derived from a normal anatomic structure. Prostate needle biopsies often include atypical small acinar proliferations (ASAP) that are suspicious for but not diagnostic of malignancy because they lack the full complement of architectural and cytologic findings required for an unequivocal diagnosis of malignancy. The few atypical features they display may represent partial sampling of a host of “cancer mimics.” Considerable attention has been directed toward this problem recently, following assessment of the clinical significance of this biopsy finding.104,105 Factors that prevent a diagnosis of malignancy in these cases include paucity of abnormal acini for evaluation, disappearance of the worrisome focus on deeper levels, lack of convincing cytologic abnormality, crush artifact, associated inflammation, and nearby atrophic changes (Figure 15–8). Follow-up biopsies reveal adenocarcinoma in 45 to 60% of instances. Unlike HGPIN, ASAP is not a unique entity; however, it is a useful diagnostic category

A

that reflects the pathologist’s uncertainty but still reflects considerable risk of malignancy. Considering the high risk of subsequent detection of malignancy after an initial diagnosis of ASAP, routine follow-up needle biopsies in these cases would seem reasonable and prudent. Pathologists continue to refine existing techniques and develop new techniques designed to aid in resolving diagnostic dilemmas. The value of being able to demonstrate the presence of basal cells in a suspicious focus of prostatic acini is well recognized. In practice, however, it is widely acknowledged among pathologists that the immunohistochemical stain for 34βE12 is both temperamental and variable under routine conditions, despite considerable experience in its use. A substantial improvement in the use of 34βE12 to identify basal cells has been reported by Iczkowski and colleagues.106 Their technique involves the use of a combination of steam heat with EDTA buffer and protease digestion to enhance basal cell immunoreactivity in needle biopsy specimens. Furthermore, a new antibody has been developed for the immunohistochemical demonstration of A-80, a mucinous glycoprotein that is consistently and strongly upregulated in the overwhelming majority of cases of prostatic adenocarcinoma and HGPIN but not expressed by normal or hyperplastic prostatic epithelium.107 The anti–A-80 antibody has been employed to identify the relics of malignant acini in prostatic tissue examined after androgen ablation therapy and appears to be a very useful adjunct to routine diagnostic evaluation in this setting. Further studies are planned to evaluate the utility of this immunohistochemical stain in identifying residual malignancy following radiation therapy. Other Neoplasms of the Prostate Transitional cell carcinoma of the prostate in the absence of invasive bladder carcinoma was revisited by Cheville and colleagues, who reported the clinicopathologic features

B

FIGURE 15–8. An example of one of the entities that are included under the designation “atypical small acinar proliferation (ASAP)” at low and high power magnification (A, B). This single acinus is lined by cells with macronucleoli; however, one of the cells may be a basal cell. The acinus disappears in deeper levels. Because the focus raises concern for malignancy, but cannot be confidently diagnosed as adenocarcinoma, the appropriate appellation is “ASAP.”


and outcome of 50 patients with this lesion, treated by radical cystoprostatectomy over a 30-year period at the Mayo Clinic.108 Involvement of the bladder by transitional cell carcinoma in situ (CIS) was observed in 64% of the pathologic specimens, but patients with current or prior invasive bladder carcinoma were excluded from the series. The overall 5-year disease-specific survival was 52%. Patients whose disease was limited to CIS had a 100% 5-year survival; in patients with urethral submucosal/prostatic stromal invasion, the 5-year survival fell to 45%. Survival rates were even lower in patients with extraprostatic extension of tumor or with lymph node metastases, but the limited number of patients with these findings precluded meaningful statistical analysis. The authors noted that 20% of their patients later developed urethral CIS, a finding that supports the notion of prophylactic urethrectomy in this patient group. The specialized prostatic stroma can give rise to sarcomas and other stromal proliferations. A series of 22 such lesions was analyzed by Gaudin and colleagues, who believe that these lesions represent a spectrum of neoplasms that can be grouped into two clinicopathologic categories: prostatic stromal sarcoma (PSS), and prostatic stromal proliferations of uncertain malignant potential (PSPUMP).109 On the basis of their observations and an extensive literature review, they note that patients range in age from the 3rd to the 9th decade of life (peak incidence in the 6th and 7th decades), and present with urinary retention, hematuria, rectal pain, and/or a palpable abdominal mass. The lesions may become as large as 58 cm; most appear to arise posteriorly with basal extension and compression of other pelvic organs. Microscopically, all lesions display hypercellularity, which is most marked in the sarcomatous lesions. Stromal sarcomas demonstrate mitotic figures, necrosis, and stromal overgrowth. The PSPUMP lesions lack necrosis and significant mitotic activity and can be further subdivided into four categories

on the basis of the degree and extent of cytologic atypia, the presence or absence of benign prostatic glands, and the presence or absence of a “leaf-like” architecture resembling phyllodes tumor of the mammary gland. Immunohistochemically, PSS and PSPUMP commonly express vimentin, CD34, and progesterone receptor; however, the expression of muscle markers is distinctly different between the groups. It is noted that immunohistochemical results allow a distinction between PSS and other sarcomas such as leiomyosarcoma and rhabdomyosarcoma. Both PSS and PSPUMP are prone to local recurrence, and occasionally PSPUMP lesions have shown behavior that suggests progression to PSS. The authors acknowledge that it is still unclear whether all of these lesions are necessarily neoplastic since some are reportedly focal and without evidence of recurrence or progression. The cumulative experience with malignant lymphoma involving the prostate was greatly enhanced by a report by Bostwick and colleagues of 62 additional cases from two large institutions, bringing the reported total to 158 cases.110 Sixty cases were of non-Hodgkin’s type and two were Hodgkin’s lymphoma. Mean age at diagnosis was 62 years, with a range of 5 to 89 years. Patients presented with obstructive voiding symptoms. About half the patients had previous documentation of lymphoma involving other sites, a third presented with primary extranodal lymphoma, and it was indeterminate whether the remainder of lymphomas were primary or secondary. A wide variety of histologic subtypes were represented in both the primary and secondary groups; not surprisingly, the majority of small lymphocytic lymphomas were secondary in the prostate (Figure 15–9). There was no significant difference in median survival after diagnosis of prostatic involvement by lymphoma between primary and secondary lymphoma or between histologic subtypes. Lymphoma-specific survival was 64% at 1 year, 50% at 2 years, 33% at 5 and 10 years, and 16% at 15 years of follow-up.

FIGURE 15–9. Malignant lymphoma involving the prostate. A normal prostatic acinus is engulfed in a sea of small atypical cells. Immunohistochemical stains confirmed the lymphoid nature of the abnormal infiltrate.

Many of the uncertainties concerning idiopathic chronic prostatitis/pelvic pain syndrome are being aggressively unravelled. It appears from the content of recent publications that syndromes included under this designation probably encompass a spectrum of disorders of infectious, chemical, and autoimmune origin, all of which produce similar symptomatology. Studies of cytokine levels in seminal plasma may provide additional clinical measurements that may be helpful in triaging individual cases. The molecular and cytogenetic aberrations which culminate in the development of BPH and prostatic adenocarcinoma are being intensely investigated. The goal of many investigators is to develop a diagnostic method which could be readily employed in combination with well-established parameters such as Gleason score and serum PSA to accurately predict the behavior of an indi-

Summary


vidual cancer. Elucidation of molecular and cytogenetic pathways of disease will hopefully pave the way for innovative new preventive and therapeutic modalities. It appears that some promising advances have been made toward achieving these goals.

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Pathobiology of Prostate Diseases: an Update / 137 75. De Marzo AM, Bradshaw C, Sauvageot J, et al. CD44 and CD44v6 downregulation in clinical prostatic carcinoma: relation to Gleason grade and cytoarchitecture. Prostate 1998;34:162–8. 76. Bao L, Loda M, Janmey PA, et al. Thymosin β-15: a novel regulator of tumor cell motility upregulated in metastatic prostate cancer. Nature Med 1996;2:1322–8. 77. Darson MF, Pacelli A, Roche P, et al. Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: a novel prostate cancer marker. Urology 1997;49:857–62. 78. Bussemakers MJG, van Bokhoven A, Debruyne FMJ, Isaacs WB. A new prostate-specific marker, overexpressed in prostatic tumors [abstract]. J Urol 1997;157:21. 79. Su ZZ, Lin J, Shen R, et al. Surface-epitope masking and expression cloning identifies the human prostate carcinoma tumor antigen gene PTCA-1, a member of the galectin gene family. Proc Natl Acad Sci U S A 1996;93: 7252–7. 80. Mohan RR, Challa A, Gupta S, et al. Overexpression of ornithine decarboxylase in prostate cancer and prostatic fluid in humans. Clin Cancer Res 1999;5:143–7. 81. Bostwick DG, Pacelli A, Lopez-Beltran A. Ultrastructure of prostatic intraepithelial neoplasia. Prostate 1997;33:32–7. 82. Waters DJ, Bostwick DG. The canine prostate is a spontaneous model of intraepithelial neoplasia and prostate cancer progression. Anticancer Res 1997;17:1467–70. 83. Dawson DM, Lawrence EG, MacLennan GT, et al. Altered expression of RET proto-oncogene product in prostatic intraepithelial neoplasia and prostate cancer. J Natl Cancer Inst 1998;90:519–23. 84. McNeal JE, Yemoto CEM. Significance of demonstrable vascular space invasion for the progression of prostatic adenocarcinoma. Am J Surg Pathol 1996;20:1351–60. 85. 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;21:1496–500. 86. Epstein JI. The role of perineural invasion and other biopsy characteristics as prognostic markers for localized prostate cancer. Semin Urol Oncol 1998;16:124–8. 87. Stone NS, 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;160:1722–6. 88. Wheeler TM, Dillioglugil O, Kattan MW, et al. Clinical and pathological significance of the level and extent of capsular invasion in clinical stage T1-T2 prostate cancer. Hum Pathol 1998;29:856–62. 89. 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;52:814–9. 90. Iczkowski KA, Bostwick DG. The pathologist as optimist. Am J Surg Pathol 1998;22:1169–70. 91. Steinberg DM, Sauvageot J, Piantadosi S, Epstein JI. Correlation of prostate needle biopsy and radical prostatectomy Gleason grade in academic and community settings. Am J Surg Pathol 1997;21:566–76. 92. Pacelli A, Lopez-Beltran A, Egan AJM, Bostwick DG. Prostatic adenocarcinoma with glomeruloid features. Hum Pathol 1998;28:543–6.

93. Tran TA, Jennings TA, Ross JS, Nazeer T. Pseudomyxoma ovarii-like posttherapeutic alteration in prostatic adenocarcinoma. Am J Surg Pathol 1998;22:347–54. 94. Bostwick DG, Amin MB, Dundore P, et al. Architectural patterns of high-grade prostatic intraepithelial neoplasia. Hum Pathol 1993;24:298–310. 95. McNeal JE, Yemoto CE. Spread of adenocarcinoma within prostatic ducts and acini: morphologic and clinical correlations. Am J Surg Pathol 1996;20:802–14. 96. Rubin MA, de La Taille A, Bagiella E, et al. Cribriform carcinoma of the prostate and cribriform prostatic intraepithelial neoplasia. Am J Surg Pathol 1998;22:840–8. 97. Wilcox G, Soh S, Chakraborty S, et al. Patterns of highgrade prostatic intraepithelial neoplasia associated with clinically aggressive prostate cancer. Hum Pathol 1998;29:1119–23. 98. Bock BJ, Bostwick DG. Does prostatic duct adenocarcinoma exist? Am J Surg Pathol 1999. [In press] 99. Nelson RS, Epstein JI. Prostatic carcinoma with abundant xanthomatous cytoplasm. Am J Surg Pathol 1997;20: 419–26. 100. Humphrey PA, Kaleem Z, Swanson PE, Vollmer RT. Pseudohyperplastic prostatic adenocarcinoma. Am J Surg Pathol 1998;22:1239–46. 101. Cina SJ, Epstein JI. Adenocarcinoma of the prostate with atrophic features. Am J Surg Pathol 1997;21:289–95. 102. Egan AJM, Lopez-Beltran A, Bostwick DG. Prostatic adenocarcinoma with atrophic features: malignancy mimicking a benign process. Am J Surg Pathol 1997;21: 931–5. 103. Saboorian MH, Huffman H, Ashfaq R, et al. Distinguishing Cowper’s glands from neoplastic and pseudoneoplastic lesions of prostate: immunohistochemical and ultrastructural studies. Am J Surg Pathol 1997;21:1069–74. 104. Cheville JC, Reznicek MJ, Bostwick DG. The focus of “Atypical glands, suspicious for malignancy” in prostatic needle biopsy specimens. Am J Clin Pathol 1997; 108:633–40. 105. Iczkowski KA, MacLennan GT, Bostwick DG. Atypical small acinar proliferation suspicious for malignancy in prostate needle biopsies. Clinical significance of 33 cases. Am J Surg Pathol 1997;21:1489–95. 106. Iczkowski KA, Cheng L, Crawford BG, Bostwick DG. Steam-EDTA optimizes immunohistochemical expression of basal cell-specific anti-keratin 34βE12 to discriminate cancer in prostatic epithelium. Mod Pathol 1999. [In press] 107. Gould VE, Doljansakai V, Gooch GT, Bostwick DG. Stability of the glycoprotein A-80 in prostatic carcinoma subsequent to androgen deprivation therapy. Am J Surg Pathol 1997;21:319–26. 108. Cheville JC, Dundore PA, Bostwick DG, et al. Transitional cell carcinoma of the prostate. Clinicopathologic study of 50 cases. Cancer 1998;82:703–7. 109. Gaudin PB, Rosai J, Epstein JI. Sarcomas and related proliferative lesions of specialized prostatic stroma. A clinicopathologic study of 22 cases. Am J Surg Pathol 1998; 22:148–62. 110. Bostwick DG, Iczkowski KA, Amin MB, et al. Malignant lymphoma involving the prostate. Report of 62 cases. Cancer 1998;83:732–8.

CHAPTER 16

MODELS OF PROSTATE CANCER THOMAS G. PRETLOW, MD; THERESA P. PRETLOW, MD The authors define a “model of prostate cancer (PCa)” as a system that can be manipulated in the laboratory without the active participation of a patient to better understand human PCa. Many kinds of model systems have been used to investigate the biochemistry, physiology, molecular biology, and experimental therapy of PCa. Different approaches have used human tissue for biochemical analysis, organ culture, tissue culture, and xenografts as well as prostates from several different experimental animals, including rodents and dogs. Using these models of PCa has involved a wide range of techniques. Those models that seem most relevant to the biology and pathogenesis of human prostate cancer will be emphasized. The authors agree with Gleave and Hsieh1 that “An ideal model for the study of human prostate cancer does not exist.” While studying human prostate tissue requires much more effort and interdisciplinary organization than studying many other models, it seems that studying human tissue has been and will continue to be the most relevant and meaningful approach. All extant laboratory models of PCa have much larger proliferative fractions and more rapid rates of growth than do most human PCas. As reviewed previously,2 whether investigators studied proliferation of PCa cells with tritiated thymidine incorporated into prostate cells in vitro,3 the expression of Ki-67,3 incorporation of bromodeoxyuridine injected into patients immediately before prostatectomy4,5 or added to cultured prostates after prostatectomy,6 or the expression of other markers of cell proliferation, most found that the mean proportion of cells in the proliferative fraction in PCas ranged from 0.68%3 to 3.3%7 of cells. More than 90% of patients with clinically evident PCa, that is, not just latent PCa, had fewer than 6% of cells in the proliferative fraction. As discussed,2 this stands in sharp contrast to most other human cancers. For example, the mean proliferative fraction includes 22% of cells in gastric carcinoma8 and 38.7% of cells in colorectal carcinoma.9 The low proliferative fraction and slow rate of growth are characteristics of human PCa that greatly complicate the design of models accurately reflecting the biology of human PCa. Sakr et al.10 have carried out a detailed histopathologic analysis of the prostates of 525 men who died from trauma and found that invasive PCas can be identified in 8% of men in their twenties and 31% of men in their thirties. The small proliferative fraction in PCas

suggests a very slow rate for growth of most PCas, which is quite credible in view of the several decades between the times when these cancers can be detected histopathologically, become sufficiently advanced to be diagnosed clinically, and kill patients. Unfortunately, all models of PCa depending on tissue culture or life expectancies of laboratory animals will involve much briefer periods than the several decades during which most human PCas remain small and undiagnosed. Except for the very limited number and variety of PCa tissue culture cell lines, models of benign and malignant prostatic tissue and cells placed directly in culture are very limited in their life expectancies.

Human Models Models for studying benign prostates and PCa include fresh, human prostatic tissue; prostatic tissue fixed and embedded in paraffin or other embedding media; prostatic fluid obtained by prostatic massage; fresh tissue placed in organ culture or prepared for tissue culture; tissue culture lines; and xenografts. Human Prostatic Tissues Procuring prostatic tissue to be studied fresh, fixed, and embedded in paraffin, in organ culture, in tissue culture, or as xenografts requires much more careful attention than does procuring most other human tissues. Based on personal experience in running National Cancer Institute– sponsored human tissue procurement programs in two universities over a span of two decades, the authors have found that prostatic tissues are among the first of many studied human tissues to lose their biochemical integrity and viability after removal from patients. It is important that they immediately be put into cold saline or culture medium in the surgical suite so that they are cooled en route to the surgical pathologist. Enzymatic activities that the authors have studied11–22 as well as many other biologic properties, such as the ability to grow in culture19,23 or as xenografts,24,25 decline rapidly if prostatic tissues are not promptly cooled after interruption of the blood supply. Benign and malignant prostatic tissue can be obtained from total prostatectomies. Benign hyperplastic prostatic tissue is abundantly available in medical centers from transurethral resections of prostatic tissues (TURPs) when they are carried out without cautery. Tissue from PCa is much less readily available, except in those centers where 138

Models of Prostate Cancer / 139

large PCas and/or nodal metastases are resected. In many centers, total prostatectomies are performed only for those patients with low levels of circulating prostate-specific antigen (PSA); these cancers are small and often difficult to locate grossly. Small cancers are often needed in their entirety for histopathologic documentation. In the authors’ experience, if transurethrally resected prostatic tissue is immediately placed in cold saline in an ice bath in the operating room, biochemical and biologic functions are often more intact than when tissues are obtained from total prostatectomy. This difference may be related to the fact that transurethrally resected prostatic tissues can be placed in cold saline within seconds of interruption of the blood supply. The blood supplies of whole prostates will have been interrupted for longer periods of time before the tissue is removed from the patient and can be cooled in cold liquid. If sagittal sections of all resected fragments (“chips”) from all transurethrally resected prostates with a preoperative clinical diagnosis of benign prostatic hyperplasia (BPH) were examined by cryostat section, at least 10% of patients would be found to have unsuspected carcinomas,26,27 some of them extensive. Pacelli and Bostwick28 found that 18.3% of transurethral resections from 698 patients with the clinical diagnosis of BPH contained adenocarcinoma. The authors found PCa in the transurethrally resected prostates of 19 of 100 similar patients. Many investigators are well served if they receive one-tenth of a gram of PCa, and some transurethral resections (3 to 5% in the authors’ experience) contain sufficient cancer in excess of that required for diagnosis to make fresh and/or frozen tissue available to dozens of investigators. Histopathologic documentation of sagittal sections of each chip provides diagnostic information and essential quality control necessary for work with this histopathologically heterogeneous tissue. In the authors’ laboratory, resected chips weighing less than 0.1 g were often biochemically altered; chips weighing more than 0.1 g, as most chips from most surgeons do, were excellent. This approach makes the lateral halves of each piece of resected tissue available for research. Prostatic Fluid In the early 1970s, the authors became aware of the importance of prostatic fluid when Grayhack et al. presented some novel findings, reported subsequently.29–33 He demonstrated that the ratios of lactic dehydrogenase isoenzymes V/I were different in prostatic massage fluids obtained from patients with diagnosed PCa compared to fluids from patients without diagnosed PCa. Grayhack et al. found other chemical differences between fluids from patients with and without diagnosed PCa. With prostatic massage, one can obtain prostatic fluid cells from a large proportion29,30,33–37 of PCa patients without using a knife or needle. Both Koss and Bologna et al.34–36 concur that cytologically identifiable PCa cells in prostatic massage fluid are

sufficiently uncommon to make cytologic examination of prostatic fluid an impractical approach to diagnosing PCa for most patients. Importantly, however, Bologna et al.35,36 have concluded, that the relatively small number of PCa cells in prostatic massage fluid usually expands rapidly in culture, and that the presence of PCa cells in the fluid of PCa patients observed during culture provides the basis for a diagnostically useful screening test that permits identification of at least 80% of PCa patients. The authors do not yet have sufficient data to confirm Bologna et al.’s observations in detail, but preliminary data are consistent with his conclusions. Specifically, the authors37 obtained over 1 million cells from prostatic fluids of 11 of 16 patients who had rectal massage immediately prior to total prostatectomy for PCa. One was infected and the remaining 10 contained cells that grew in soft agar. The soft agar culture system of Hamburger and Salmon et al.,38–42 as used by the authors previously,43–45 results in the formation of colonies by malignant cells and failure of benign cells to grow from tumors. Except for the work of Bologna et al. and Koss,34–36 the authors are not aware of any detailed characterization of prostatic fluids for their content of PCa cells. With qualitatively different approaches, data from Grayhack et al.,30 Bologna et al.,36 and the authors’37 laboratory suggest that prostatic fluid deserves investigation as a valuable source of PCa cells. Organ Culture Organ culture represents potentially one of the most useful modalities for the short-term (4 to 8 weeks) propagation of benign human prostatic epithelial cells. It is a method unknown to many “modern” PCa researchers. The organ culture of human prostatic tissues has been reviewed in detail.23 Commencing in the early 1950s, Ilse Lasnitzki46 conducted studies related to carcinogenesis with the organ culture of mouse prostate. Following a sabbatical year with Laznitzki, Heidelberger in collaboration with Iype,47 used organ culture followed by tissue culture. They were the first investigators to induce carcinomas of any kind in vitro followed by proving their tumorigenicity in vivo. This work, along with Heidelberger’s design and synthesis of 5-fluorouracil, were reviewed in Heidelberger’s Clowes Memorial Lecture48 and elsewhere.49 Lasnitzki’s early work46,50–53 was related to the study of carcinogens as they affected rodent prostates in organ culture and to methods for reversing or antagonizing the carcinogenic process with vitamins and other approaches.51,52,54,55 Her group50–52,56,57 and Franks’ group58,59 also studied the effects of many steroid hormones on rodent prostates in organ culture. Lasnitzki’s collaborations with others60,61 demonstrated that testosterone and metabolites of testosterone stimulated rodent prostatic epithelium in organ culture and eventually led her to the conclusion that dihydrotestosterone was the “principal


intracellular androgen whether the hormone in the incubation medium was testosterone or dihydrotestosterone.”62 Work with the organ culture of human prostatic tissues closely resembled the work Lasnitzki conducted on the prostates of rodents. In 1971, two laboratories63,64 reported the successful maintenance of benign human prostatic tissue in organ culture. Stonington and Hemmingsen63 reported that small fragments of human prostatic tissue became “encapsulated” in 7 to 14 days with a layer of epithelial cells “in continuity with the glands on serial section,” that the supporting stromal cells were lost, and that the production of histochemically demonstrable acid phosphatase continued at 21 days in culture. They described the morphologic changes in these fragments in detail.65,66 Harbitz67 confirmed many of these findings. Stonington and Hemmingsen63 specifically mention that they initially fed their organ cultures so that “medium rises only half way up the explant mass.” This is an important point since growth is more vigorous and attachment and outgrowth of epithelial cells on plastic culture dishes are much more vigorous in shallow medium with the cultured tissue less than entirely submerged in medium. The best culture medium for this purpose contains supplements previously described by the authors et al.68 Encapsulation of the organ fragments by epithelial cells in their laboratory was seen in more than half of the fragments after 3 days in culture, 73% after 5 days, and 90% after 10 days in culture. While production of PSA and acid phosphatase remained significant at all time intervals examined, the contents of many other enzymes were rapidly modulated in organ culture.19,23 Incorporation of bromodeoxyuridine, assessed immunohistochemically, demonstrated continued vigorous growth of epithelial cells for more than a month and less vigorous growth for periods up to 2 months.23 Webber et al.69 noted the potential utility of organ culture as a step in purifying benign prostatic epithelial cells. Organ cultures of human prostates were used extensively to investigate the effects of different hormones on the prostate in organ culture.70–77 These studies often found small and inconsistent changes in organ cultures of prostates treated with different hormones. Ghanadian et al.70 have emphasized the enormous variability observed among samples of prostates obtained from different patients. Xenografts and Cell Lines in Culture Before separately addressing xenografts and cell lines in culture, two important differences between the results of the two techniques should be addressed. The first is illustrated in Table 1 of a 1996 paper by Ellis et al.78 The authors of this report stated that “At this time, only eight continuously passaged prostate cancer cell lines...and nine serially passable xenografts [sic] lines (both primary and metastatic)... currently exist (summarized in Table 1).” The authors then listed not 8 but 9 established

PCa cell lines in their table. While the most recently developed tissue culture cell lines and xenografts listed in the table were started in 1991, the table is important because the several other xenografts and tissue culture cell lines developed prior to publication of the paper, and subsequently, exemplify the generalizations flowing from the table. One of 9 listed culture lines and 6 of 9 listed xenografts resembled most human PCas in being sensitive to androgens. Similarly, 1 of the 9 culture lines produced PSA; another, designated ND-1, produced a “trace” of PSA. The other 7 listed cell lines produced none. The ND-1 culture line was originally described as producing “small amounts of prostate specific antigen” as assayed with the “Tandem PSA...assay.”79 In contrast, 4 of the 9 listed xenograft lines produced PSA, the largest single protein product of most benign and malignant prostatic epithelia in patients. Similarly, all the xenografts the authors started from three patients, (CWR31/91, CWR21, and CWR22) make both PSA and androgen receptors.25,44,80 In addition to the fact that most xenografts are more similar to PCas in patients than are tissue culture lines, initiating PCa xenografts has enjoyed a much higher success rate than initiation of tissue culture lines from PCas. In 1980, Gittes81 reviewed the attempts to establish PCa xenografts up to that time, and concluded that “the incidence of ‘take’ of prostate cancer has been close to zero.” It is not known with certainty why success rates have been higher recently. The authors, however, have established four xenografts from the primary PCas of 3 of 33 patients in their laboratory.25 Other laboratories have reported higher levels of success than those described by Gittes in 1980 in establishment of xenografts.81 Klein et al.82 obtained persistent growth of PCas as xenografts for more than 5 passages from 2 of 8 patients with metastatic PCa. One of these 2 xenografts resulted from transplantation of transurethrally resected prostatic tissue. One group83 from Europe has developed seven PCa xenografts. Based on currently available knowledge, the establishment of PCa xenografts appears to be much more readily feasible than direct establishment of tissue culture lines from PCas. In at least two instances, after being passaged several times as xenografts, cells from the xenografts have been used to establish PCa tissue culture lines.82,84 Human Prostate Cancers as Xenografts Xenografts as models of PCa have been reviewed in detail2,81,83,85 and summarized in the recent report of a workshop.86a In 1980, Mickey et al. reported growth of the DU 145 PCa tissue culture cell line as a xenograft.86b In 1980, Hoehn et al.87 reported establishment of the first human PCa xenograft to survive and continue to be used to the present time, PC-82, an androgen-dependent xenograft. Four years later, Hoehn et al.88 reported a


second androgen-dependent xenograft, PC-EW. Both these xenografts regressed after hormonal manipulations of several kinds over the longest periods of observation reported (7 and 9 weeks); interesting differences in the histologies during regression were described.88 In 1984 and subsequently, Ito et al.89,90 described the HONDA tumor, another androgen-dependent PCa xenograft. Ito and Nakazato90 reported that they could identify viral particles in the HONDA tumor; however, the significance of these particles is unknown. Evidence of viral infection has been found in human PCas from different continents;91,92 the biologic and clinical significance of these infections, however, is unclear. Studies of papillomavirus infections were reviewed with different conclusions in a recent characterization93 of several new patients. While the review of this area was well referenced, the subjects studied were very different ethnically from those studied in the two earlier reports.91,92 Another investigation94 with an excellent review of the recent literature leads to the conclusion that infection of human PCas with papillomavirus is unusual. In 1985, Graham et al.95 obtained the “479” xenograft from tissue taken from a bone biopsy from a patient who had been treated with androgen ablation and several kinds of chemotherapy; the tumor was described95 as “estrogen and androgen insensitive.” In 1986, Harper et al.96 described another androgen-dependent xenograft, TEN/12. In 1987, Pittman et al.97 started a xenograft from primary, small-cell PCa. Csapo et al.98 described the PCEG, androgen-dependent xenograft in 1988. In a study of PC-82, PC-EW, and PC-EG, they found that both PSA and prostatic acid phosphatase (PAP) in the blood of nude mice increased with increasing tumor size; however, “the indicator value of PSA was 20 to 50 times higher than that of PAP.…”28 In 1991, Gingrich et al.99 described the DU 5683 xenograft which was started from a metastasis to a lymph node of a patient who had been treated earlier with orchiectomy; DU 5683 grew equally well in male and female nude mice. In 1990, Kleinman and her collaborators100 reported that the use of Matrigel as a vehicle for injecting small-cell lung cancer cells and MCF7 breast cancer cells greatly enhanced their tumorigenicity. Matrigel is often described as a “basement membrane–like substance” derived from the extraction of the Engelbreth-Holm Swarm (EHS) tumor, a transplantable tumor that arose approximately four decades ago. Several additional reports from Kleinman et al. confirmed these results with different kinds of cells.101–103 One of these, from 1992,103 was entitled “Malignant transformation of NIH-3T3 cells after subcutaneous co-injection with a reconstituted basement membrane.” While there were certainly behavioral and phenotypic changes in 3T3 cells injected in Matrigel, that is, they formed sarcomas and acquired other different phenotypic properties, it is important to recognize that Boone104 had

demonstrated over a decade earlier that very small numbers of 3T3 cells formed sarcomas when attached to microspheres and injected into mice. The word “transformation” might be subject to several different interpretations since 3T3 cells can form sarcomas when injected in the absence of Matrigel. Many other reports24,25,80,105–107 on the use of Matrigel to enhance the tumorigenicity of cell lines have been published. More important, Mehta et al.108 used Matrigel to approach a much more difficult problem that had been very refractory to many other approaches. They digested 28 primary human breast cancers in a mixture of enzymes and injected the cells into nude mice in Matrigel. Seventeen of the 28 cancers grew in nude mice, and 7 of these tumors gave rise to distant metastases spontaneously from the subcutaneous injection sites. Prior to this approach, breast cancer had been exceptionally refractory to growing as primary xenografts in immunologically deprived rodents. Kleinman et al.’s report100 led the authors to inject three PCa cell lines, PC-3, DU 145, and LNCaP, into nude mice with and without Matrigel.24 The tumorigenicity of PC-3 increased 25,000-fold in Matrigel; that of DU 145, 7000-fold. Tumors were obtained from LNCaP only when cells were injected in Matrigel. The authors were also excited at that time because 6 of 10 primary human PCas, minced and suspended in Matrigel, survived until the mice were sacrificed 70 to 123 days after transplantation. Subsequently, the authors have developed several serially transplantable xenografts with this system.25,44,80 For newer xenografts, the authors have always injected minced tumor with Matrigel into some animals and minced tumor without Matrigel into others. All minced tumors that have grown with Matrigel have also grown without Matrigel. The same is true of serially transplanted xenografts. If instead of injecting minced tissue one obtains cell suspensions from these same xenografts by enzymatic digestion, tumorigenicities of all the xenografts examined are at least 1000-fold enhanced when cells are injected in Matrigel.2,44 The authors have also found no detectable differences in tumorigenicity or biologic behavior between tumors that have been passaged serially for 10 successive passages with the vehicles being either consistently Matrigel or consistently culture medium. In the laboratory, Matrigel has enhanced the tumorigenicity of PCa xenografts as cell suspensions. The tumorigenicities of minced tissue from the same PCa xenografts, however, have not been affected by Matrigel. Starting with PCas resected from 3 patients, the authors’ laboratory25 has developed 4 xenografts that are phenotypically significantly different. It was originally believed that the 4 xenografts came from 4 patients. Subsequently, it was found that 2 of these 4 serially transplanted xenografts, CWR31 and CWR91, were cytogenetically complex and identical. Unexpectedly, CWR31 and


CWR91, despite their cytogenetic identity, have several biologic properties that are different, that is, the number of cells required to transplant the tumors and the frequency of spontaneous pulmonary metastases. After the 20 patients from whom tumor was transplanted prior to the authors’ first report of these tumors,25 tissue from 13 additional patients has been transplanted without the development of additional xenografts. That is, based on a very small sample (33 patients), the authors have had a 9% success rate in starting new xenografts. One of the authors’ androgen-dependent xenografts, CWR22,80 regresses after animals are castrated but has been the source of four cytogenetically different relapsed xenografts, CWR22R.44 There are several important variables likely to enhance the rate of success in starting new xenografts. Using Matrigel for serial transplantation of cell suspensions, not minced tissues, seems very important. Despite the use of Matrigel, the authors have lost some xenografts after the first and second serial transplantations. The marked heterogeneity among nude mice with respect to their circulating levels of testosterone makes the use of sustainedrelease testosterone very important for the growth of androgen-dependent tumors. While the authors’ laboratory has generated a smaller body of data consistent with the data of van Steenbrugge,109 the latter remains the best study of levels of circulating androgen in nude mice. The van Steenbrugge study showed that “natural” levels of circulating androgen in nude mice vary enormously among mice from a level approaching zero to significantly higher levels than those found in human adult males. Consistent with van Steenbrugge’s work,109 the authors’ laboratory has found that sustained-release testosterone administered to nude mice can produce levels of androgen consistent with human adult male levels. Failure to use sustained-release testosterone would likely result in (1) a lower success rate in initiating new xenografts because of the failure of androgen-dependent tumors to grow, and (2) selection, in an androgen-deprived environment, of subpopulations of cells not optimally representative of patients’ tumors. The authors do not believe that there are adequate data to support van Weerden et al.’s opinion that “Although the number of animals is small, it seemed that tumor take and growth at onset did not relate to androgen levels in the host animal as tumors developed in either intact male mice or in male and female mice supplemented with testosterone....”83 Of the 7 tumors reviewed by van Weerden et al., only 4 failed to grow in females. Generalization about hormonal supplementation of animals based on these 4 tumors in the absence of data seems hard to defend. The authors’ work suggests that androgen level in the host is important for androgen-dependent tumors; more data, however are needed. Unequivocally, CWR2124 and CWR2244 tumors regressed in castrated animals, and some male nude mice had levels of circulating androgen in the

range of castrated mice both in the authors’ laboratory [unpublished observation] and in a much larger study.109 Schröder and collaborators have made enormous contributions to our understanding of xenografts of prostatic tissues in nude mice. In 1976, they reported that transplantation of 19 PCas into 84 nude mice resulted in histologically confirmed survival of PCa from 17 of 19 tumors 10 to 142 days after transplantation; “continuous passaging of transplants in ‘nude’ mice was not attempted.”110 Similarly, 6 prostatic adenomas were transplanted into 26 nude mice; tissue from 5 of the 6 adenomas could be identified histologically after an average of “57.3 days (range 17 to 132 days).” In 1974, Okada and Schröder111 reported establishing, from a primary human PCa, a “reproducibly” transplantable xenograft110 and a PCa cell line which was subsequently shown not to be altered by androgen withdrawal.112 Unfortunately, this cell line was contaminated with HeLa cells and lost.113 Work from Schröder and his collaborators over the next two decades contributed significantly to our knowledge of PCa xenografts. They write in a very informative review in 1994 that “During a period of more than 10 years (1977 to 1990), almost 200 clinical specimens were transplanted in Balb/c nude mice, resulting in a very low number of permanent tumor models: the hormonedependent PC-82 model; 2 hormone-independent tumors, PC-133 and PC-135; and, more recently, the PC295 tumor.”85 Establishing these 4 xenografts from “almost 200” human PCas would appear to represent a success rate of 2%; 2 of the 4serially transplantable lines were derived from lymph node resections from patients with metastatic disease. None were developed from transurethrally resected tissue. In contrast, they developed “permanent tumor [xenograft] lines” during the next 3 years, from “6 out of 19 transplants.”85 Several of their lines, PC-295, PC-310, PC-324, PC-329, PC-339, PC-346, and PC-347, were described in detail 2 years later.83 Three of these xenografts were derived from transurethrally resected tissues; 1, from a skin metastasis; and 2, from “primary prostate tumor.” Two of the 3 transurethrally resected PCas that formed xenografts were from tumors that had “relapsed”83 after hormonal therapy. van Steenbrugge et al.85 suggest that the change in their rate of success related to their use of NMRI nude mice for the 19 most recent xenografts; they had used Balb/c nude mice in the earlier work with “almost 200” PCas. Using NMRI mice may be advantageous; it is equally possible, however, that the strain of mice previously used in Schröder’s institution presented a disadvantage. In work currently in progress in the authors’ laboratory, several strains of immunologically defective mice have been compared: 2 strains of NMRI mice imported from Europe, NMRI and HAN-NMRI; 2 strains of severe combined immunodeficiency (SCID) mice; 2 strains of nude mice; and beige mice. The NMRI nude mice and an


unrelated strain of nude mice obtained from the genetics colony were similar in their ability to grow difficult xenografts. Surprisingly, SCID mice and beige mice offered no advantages. While the reported numbers of xenografts are too small to permit conclusions, the available data suggest that the success rate is highest when advanced PCas are transplanted. Klein et al.82 transplanted tissue from 8 patients with more advanced cancer (stages C and D disease). Two serially transplantable PCa xenografts were obtained, both from patients with stage D disease. One of these was from a metastasis; the other, from transurethrally resected tissue. All 3 of the xenografts in the authors’ laboratory originated from transurethrally resected tissue of patients with advanced disease. The PC-EW line from Hoehn et al.88 was from a metastasis. van Steenbrugge et al.85 identify the origins of the 10 xenografts started by their laboratories over two decades as follows: 4 are from metastases, 3 are from transurethrally resected prostatic tissues (2 after relapse following responses to hormonal therapy), and 3 are from “primary prostate tumor” (total prostatectomies?). That is, 6 (perhaps 7) of the 10 were from patients with advanced disease. Moreover, only 2 of the 3 from “primary prostate tumor” are described as being hormone dependent. There is a need for PCa xenografts that, like most PCas in patients, regress in response to castration of the host then subsequently relapse. There are a large number of human PCas that are androgen-sensitive, in that they respond to castration and/or pharmacologic attacks on their reactivities to androgen.114 These responses may last from a few months to a few years. The authors believe that the xenograft best exemplifying this pattern of hormonal responsiveness is the CWR22 androgen-dependent tumor and the CWR22R tumors, that is, tumors that developed in animals bearing CWR22 tumors that regressed after castration but subsequently recurred. For animals bearing 1-gram tumors, the tumors will disappear or almost disappear after castration of the host and PSA will disappear from the blood. This phenomenon, followed by relapse of the tumor in approximately half of animals 3 to 10 months after castration, has been reported.44 Data were also presented44 showing that some castrated animals could be free of measurable tumors and measurable serum PSA for more than a year and a half but experience recurrence when given sustained-release testosterone.44 Other xenografts have been suggested to be good models of hormonally responsive tumors. Concerning LNCaP, Gleave et al.115 remarked that “Following castration, PSA levels decreased rapidly up to 8-fold...no reduction in tumor volume occurred.” The LuCaP xenograft has responded to castration of the host116 by a two- to threefold decrease in circulating PSA and slight retardation of the growth rate of the tumor. van Steenbrugge et al.85 studied PC-346 and concluded that “Although not yet definite,

the PC-346 tumor might be the first established human xenograft model showing the clinically very important relapse phenomenon.” The graph they included to support this statement showed a slight shrinkage of tumor in 1 of 6 animals, with tumors in the other 5 animals showing a range of responses from no response to a slight retardation in rate of growth for a short period of time. Klein et al.82 felt “clearly...that LAPC-4 is an androgen-dependent xenograft” capable of “progression...to androgen independence” because it grows 4.3 weeks after transplantation in intact males but takes 13.4 weeks to grow in castrated males or females. It was subsequently reported117 that LAPC-4 expresses a newly discovered antigen, designated “prostate stem cell antigen,” that is reported to be a membrane antigen expressed by 88% of PCas. As described above, CWR22 tumors up to 1 gram in size routinely completely regress in castrated animals, recur in approximately half of animals, and often show > 1000-fold declines in circulating PSA after castration. Recently, Chen et al.118 described a very interesting study of the differences of several chemotherapeutic agents in CWR22, CWR22R, and CWR91 xenografts, leading them to conclude that these are “useful models for drug activity evaluation.” In 1992, Stephenson et al.119 reported that strains of PC-3 and LNCaP tumors grew more easily and metastasized more often when transplanted orthotopically in immunodeficient mice. Waters et al.120 subsequently raised serious questions about the specificity of the orthotopic location. In addition to following the lead of Stephenson et al.119 in injecting PC-3 cells orthotopically, Waters et al. injected PC-3 cells into the walls of the stomach and bladder and showed that these sites were as effective as the orthotopic site for the production of metastases. As reviewed previously,2 the current authors believe that there were weaknesses in the paper by Stephenson et al.119 and that their conclusions cannot be generalized generically to all PCa xenografts. For example, CWR22 does not grow well orthotopically. While neither LNCaP nor PC-3 metastasize frequently from the subcutaneous site, the 2272 strain of CWR22R, CWR21, and CWR91 all metastasize to lungs spontaneously from the subcutaneous site. There are many human prostate cancer cell lines that metastasize in nude mice. To the authors’ knowledge, Ware et al.121 was the first to report the metastasis of human prostate cancer cells in nude mice, a process that she characterized in detail and subsequently reviewed.122–124 Continuing studies of metastasis have been conducted on PC-3 tumors;125–127 this tumor has little in common phenotypically with most prostate cancers. With DU 145, Knox et al.128 found no differences between orthotopic and subcutaneous transplantation that affected biologic behavior, metastatic behavior, or the expression of several genes. They point out several experimental disadvantages of the orthotopic site, including urinary obstruction, increased animal mortality, and inac-


cessibility of the site to convenient measurements of the tumors. Orthotopic transplantation has become in vogue recently. Like the work of Knox et al. with DU 145, the authors’ work80 in comparing many sites for transplanting of CWR22 found that orthotopic transplantation offered no advantages. Waters et al.’s120 demonstration that the pattern of metastasis for PC-3 is similar whether cells are transplanted orthotopically or in several other sites, and studies of other cell lines, raise important questions about the advantages of orthotopic transplantation. To date, most studies of orthotopic transplantation have been limited to work with a very limited number of tissue culture cell lines. It makes sense that, if seeking “optimal microenvironments,” many sites for transplantation would be tested. Waters et al.120 did test many sites for the transplantation of PC-3; the authors tested many sites for the transplantation of CWR22.80 Most studies that have found the orthotopic transplantation of prostate cancer tissue culture cell lines “best” have tested only two sites for transplantation. No new xenografts have resulted from the orthotopic transplantation of resected human PCas. The common usage of “androgen-independent” must be questioned. Data from work in progress in the authors’ laboratory show that some relapsed PCas that grow in female mice can be stimulated in vivo to grow faster when hosts have been treated with sustained-release androgen. There are also data in the authors’ laboratory demonstrating that cells from tumors showing no detected responses to androgens in vivo may respond to growth factors in vitro in a fashion that is augmented by the presence of androgen. Mouse sarcomas can result from transplantation of some human PCas. Specifically, CWR21, 1 of the 4 xenografts (CWR21, CWR31, CWR91, and CWR22) the authors started from 3 patients and have transplanted serially in their laboratory has been replaced by mouse sarcomas in slightly less than 10% of transplantations. These mouse sarcomas have monoclonal cytogenetic aberrations that differ from one sarcoma to the next. Often when CWR21 is not replaced by sarcomas the 15 to 20% of cells from this tumor that are stromal cells will show similar monoclonal, cytogenetic aberrations, that is, they are probably neoplastic despite the fact that they do not grow fast enough to replace the CWR21 tumors. From CWR31, CWR91, CWR22, and several CWR22R (relapsed CWR22) tumors, the authors have obtained only normal, diploid mouse stromal cells and have never observed sarcomas. Replacement of xenografted human tumors by mouse neoplasms appears to be an uncommon event for most human tumors; from the authors’ discussion of this problem with other researchers, however, it would appear that some human PCas frequently give rise to mouse sarcomas. In 1978, the replacement of a colon cancer xenograft by neoplastic cells with mouse karyotypes was reported.129

Subsequently, Beattie et al.130 reported that 2 of 50 serially passaged human tumor xenografts had been replaced by mouse sarcomas; the original human tumors were a hepatoma and an undescribed adenocarcinoma. Sparrow et al.131 later reported that 2 of 30 human tumor xenografts in their laboratory had been replaced by mouse sarcomas; these tumors were a small-cell carcinoma of the lung and an ovarian carcinoma. In 1997, Pathak et al.132 reported a subline of LNCaP and, from the same group, Ozen et al.133 reported 3 advanced human PCas that were replaced by mouse sarcomas. The authors’ laboratory has had communications from investigators who had been working with PC-82 but were requesting CWR22 xenografts since as many as half of their transplantations of PC-82 had been replaced by sarcomas. The authors have had first-hand reports of other PCas causing the same problems. From the literature, conversations with others, and the authors’ experience in their own laboratory, it would appear that there is a specific subgroup of human PCas that are susceptible to being replaced by mouse sarcomas. The authors have never encountered this phenomenon in studies of CWR31, CWR91, CWR22, or any of the CWR22R lines. At least one other group carrying 7 human PCa xenografts has found that only a specific minority of tumors shows this phenomenon. To date, the mechanisms are unclear. Human Prostate Cancer Tissue Culture Cell Lines As the authors134 discussed in a review of methods for obtaining cell suspensions from solid tissues, the first step for working with cell suspensions is to evaluate different means of obtaining cells in suspension in a viable, functional form. If the cells are to be representative of the tissues from which they are obtained, one would like to know what proportions of the different kinds of cells available in the tissue were obtained in the suspensions of cells. In 1976, Stone et al.135 described the use of collagenase to obtain cells in suspension for culturing human prostatic tissues. Yields, that is, cells per gram of tissue, were not given. At approximately the same time, the authors’ laboratory compared physical disaggregation, collagenase, Pronase, and trypsin for the dissociation of benign and malignant prostatic tissues and found that collagenase gave the lowest yield of viable cells, by a wide margin.136,137 Peehl,138 in a review of prostatic epithelial cultures, states that she has described the “most comprehensive methodologies for the procurement and culture of adult human prostatic epithelial cells from normal, benign prostatic hyperplasia (BPH) and malignant tissues....” She advocates using collagenase and has never given a quantitative description of the number of cells obtained per gram of tissue with this approach. While Peehl may well be correct in stating that her descriptions have been the “most comprehensive” and that she has worked for over 15 years at Stanford, a major prostate


surgery center, with an excellent availability of human prostatic tissues,139,140 the question remains: are these not only the most comprehensively described but the most effective methods of the culturing of prostatic tissues? As reviewed below, Peehl has followed the lead of others in recent years in transforming prostate cells with a variety of vectors. In 15 years, however, her methods for culturing PCas and benign prostatic tissues in the absence of vectors has not resulted in a single cell line. The first of the PCa cell lines that are available today was described by a group at Duke University in 1977.141,142 This line was named DU 145 and was shown to grow both as a tissue culture line and a xenograft. In 1978 and subsequently, Kaighn and collaborators143,144 described the second PCa cell line, PC-3. These lines, and putative PCa cell lines that were subsequently lost, were reviewed in 1980.145 These two lines and LNCaP, a line described in 1980 and subsequently by Horoszewicz et al.,146,147 have been the basis for the overwhelming majority of work with PCa cell lines in the past two decades. If we exclude cell lines that have resulted from immortalization of prostate cells in tissue culture with various vectors, which to the authors’ knowledge is not related to any process that occurs in patients, DU 145, PC-3, and LNCaP are three of the four PCa cell lines that both (1) were derived from human tissues not altered by the introduction of foreign genes, and (2) are currently available from the American Type Culture Collection. The fourth, NCI-H660, is a neuroendocrine tumor that, according to the American Type Culture Collection, was established from metastatic tumor that was originally reported to be an extrapulmonary small-cell carcinoma of the lung.148 Recently, James Jacobberger’s laboratory84 has developed a cell line from a CWR22R strain. To our knowledge, this new CWR22R culture line, which Dr. Jacobberger makes available to anyone requesting it, and LNCaP are the only prostate cancer cell lines that make PSA, express androgen receptors, and respond to androgen to some degree. Having noted that most of the published work with PCa cell lines has been carried out with three cell lines, it should be pointed out that there are several other PCa cell lines, including the one from the authors’ institution (derived from the 2152 strain of CWR22R),84 that have been developed directly either from human PCas or PCa xenografts, and described with widely varying degrees of documentation. These include the ALVA lines,138,149–151 two of which, ALVA-31 and ALVA-41, show evidence of responsiveness to androgens.149–151 Other lines include EB-33,111,112 a line that became replaced by HeLa cells;113 DUPRO-1,99 JCA-1,152 ND-1,79 PC-93,153 and TSUPR1.154 As reviewed by Ellis et al.,78 LNCaP was the only one of these PCa cell lines available in 1996 that has been established to make both significant amounts of prostatespecific antigen and androgen receptors. The new line

from the Jacobberger laboratory84 from the relapsed CWR22R also makes both PSA and androgen receptors. In 1989, Kaighn et al.,155 the investigator in whose laboratory the PC-3 cell line was developed, reported the transformation of human neonatal prostatic epithelial cells by strontium phosphate transfection with a plasmid containing SV40 early-region genes. This was the first report of the transformation of human prostatic epithelial cells by the introduction of foreign genes into prostate cells. Numerous investigators have followed Kaighn et al.’s lead and developed a large and increasing number of PCa cell lines by the introduction of foreign or altered genetic material into cells.156–166 These lines have been used extensively in tissue culture and as xenografts; their relevance to naturally occurring PCa needs investigating.

Nonhuman Animal Models Animal models of PCa have been used widely and have influenced treatment of human prostatic diseases. In presenting their studies of the effects of castration on PCa and benign prostates both in man and dogs, Huggins et al.167–169 reviewed 19th and early-20th century studies in rodents and dogs in which the effect of castration on the prostate had been investigated. Huggin et al.’s work with man clearly indicated that androgens affect the behavior of both benign and malignant prostates in man. There has been extensive investigation of animal models since the work of Huggins et al., some relatively unique.170–172 Canine Model In 1916, Goodpasture and Wislocki173 reported that autopsies performed on 15 “very old” mongrel dogs showed that their prostates were “two or three times the normal size” and that 8 of 15 of the prostates contained “tumors” that were not further described. Later, Huggins and Clark167 described the functions of hyperplastic prostates in dogs. In 1968, Leav and Ling174 reviewed autopsies of 20 dogs that had died from PCa. They found that the cancers were found in older dogs, mean age of 10.1 years, and that the cancers commonly metastasized to the lung, urinary bladder, bone, mesentery, rectum, and pelvic muscle. Interestingly, in stark contrast to humans, PCa in 3 of the 10 dogs metastasized to their hearts. Leav and Ling174 cited a large number of papers reporting that PCa had not been found to be a common cancer in dogs at that time. Orgad et al.175 reported a detailed histochemical characterization of canine prostatic tissues, including 18 PCas with a variety of lectins. Canine PCa shared some features in common with PCa in man.176 More recently, Waters et al.177 reviewed the ages at death of 686 dogs that had died of PCa and concluded that the development of PCas in dogs is related to age. They have also described prostatic intraepithelial neopla-


sia in dogs with many similarities to prostatic intraepithelial neoplasia in man.178,179 Of particular interest, elderly dogs with PCa have a high incidence of prostatic intraepithelial neoplasia.178 Rodents Rodents have been used to study carcinogenesis in the prostate for many years.180,181 In a very interesting review of tumors in experimental animals (primarily rodents), Bosland182 stated that “spontaneously occurring prostate tumors are rare in most species” except in the dog, the “ACI/SegHapBR (or ACI/Seg)” rat, and man. Following the earlier work of Shain et al.,183 the lesions in these rats are described in great detail by Ward et al.184 They report that carcinomas occur in 35 to 40% of this strain of rat by the age of 33 months; they also note, however, that “the majority of human tumors are morphologically different.”184 In fact, the majority of human tumors diagnosed clinically are different in many other ways. These very careful investigators184 studied 201 rats and did not observe a single metastasis. While these tumors may be called “cancer,” this model seems very marginal as a model of human PCas. There is a very large body of literature addressing the use of rodents as models for prostate carcinogenesis.185 Unlike many organs (colon, liver, etc.), rodent prostates are quite different from human prostates grossly, histologically, biochemically, and functionally.186 Without reviewing this area comprehensively, it should be noted that PCas have been produced in rodents by radiation,187–189 chemical carcinogens,190–193 and hormonal manipulations.194 Each of these approaches has been reviewed in detail recently.182 There are no models of autochthonous PCa in rodents, excluding transgenic animals, that metastasize spontaneously to bone, the most common organ system to which PCa metastasizes in humans.195,196 In evaluating the literature related to prostate carcinogenesis in the rodent, it is important to ascertain that investigators identified the cancers in stages sufficiently early to permit distinction between carcinomas of the seminal vesicles and PCas, that is, before carcinomas envelope and become confluent with both the seminal vesicles and prostate. One of the authors (TG Pretlow) has performed or supervised over 1000 autopsies on humans and has attended pathology conferences for over three decades but has not seen a single cancer of the seminal vesicle in man. There is only one study197 in the literature prior to the current decade describing cancer of the seminal vesicles in rodents. It appears that many investigators assumed large adenocarcinomas in the lower pelves of rats, like most adenocarcinomas in the lower pelves of man, were likely to be prostatic in origin. In 1994, two laboratories disproved this assumption. Cohen et al.198 examined in detail a previously used model of PCa in the Lobund-Wistar rat. After treating these animals with

N-methyl-N-nitrosourea and testosterone, they reported that “Seventy-three percent of the tumors involved only the seminal vesicle, 22% involved other portions of the prostatic complex as well as the seminal vesicle, and 5% were located in the coagulating gland (anterior prostate).”198 In that same year and subsequently, investigators from Michael Sporn’s laboratory199 reported that PCas were slightly more frequent than carcinomas of the seminal vesicles in the Lobund-Wistar rat treated with a regimen similar to that used by Cohen et al. The same regimen had been used in many earlier publications from other laboratories, with PCas as the only described malignant products. While it is clear that PCas do occur spontaneously in some strains of rats200 (as reported earlier201–203), it is clear that many of the earlier studies that did not adequately examine the seminal vesicles and prostates histopathologically did not detect the fact that a considerable proportion of the tumors termed “prostate cancer” in rodent models are likely to have originated in the seminal vesicles. While different strains of rodents differ with respect to the relative frequencies of carcinomas of the prostate and seminal vesicles, most rodents studied develop both kinds of tumors in the appropriate experimental environments.170–172,199,204,205 Rodent models have recently been reviewed in a workshop.170 The summary statement for the symposium of which this workshop was a part stated: “Rodent models are easy and economical to use....”206 While these models have been biologically interesting, the critical, unanswered question is: since the work of Huggins and Clark167 with dogs in 1940, have we learned anything unique that is significantly relevant to human PCa from the study of PCas originating in rodents? The Dunning Tumor The Dunning tumor, often called the “Dunning prostate cancer,” was first described by Dunning207 in 1963, and was perhaps best described by Aumuller’s group in 1992.208 The original tumor “occupied a large part of the lower abdominal cavity...[and]...measured 5.0 × 4.5 × 4.0 cm.”207 The gross pathology was never seen by a pathologist; without any allusion to specific data, however, it was “histologically and histochemically” thought to have originated from the prostate of the rat. In the absence of specific data, it is difficult to imagine what kinds of evidence would allow this conclusion about a 5.0-cm tumor in the pelvis of a rat. Surprisingly for a PCa, “heart blood...showed an acid phosphatase level of 9.5, which was not as high as has been observed (14.4, 16.2, and 20.9) in some of the rats bearing the transplanted squamous cell carcinomas of the prostate.”207 This tumor was declared an outstanding model of PCa by the National Prostate Cancer Project of the National Cancer Institute in the 1970s, which announced subsequently over several years that these “hormone-responsive prostatic adenocarcinomas are available” to investigators.209 The Dunning


tumor continues to be used very widely without any convincing evidence that it was a PCa. In 1991, Aumuller et al.210 carried out immunohistochemical investigations refuting previous claims that basal cells might be found in the Dunning tumor. They also reported finding myoepithelial cells, cells that are foreign to rodent prostates. In 1992, Goebel et al.,208 in collaboration with Aumuller, reported new data and summarized several earlier papers from the Aumuller group that showed that the Dunning tumor has much more in common chemically with breast cancer than with PCa. It manufactures “milk fat globule membrane proteins, lactoperoxidase, and lactalbumin” while failing to manufacture proteins normally found in rat prostates.208 Transgenic Models The status of transgenic mice in the investigation of PCa was recently reviewed and will not be described in detail here.206,211 The authors would agree with Waters et al. and Green et al.206,211 that justified “concerns persist regarding the validation and correlation of these models with human prostate cancer.” On the other hand, the transgenic models represent a qualitatively different approach from the traditional approaches to the study of growth regulation in rodent PCas, and enjoy a high degree of interest because of this genetically and biologically different approach. In 1994, Maroulakou et al.212 reported observing both prostatic hyperplasia and PCa in transgenic mice. Since then, there have been several different heterologous genes used to develop transgenic models of PCa.213–218 This work was summarized in the report of a recent workshop.211

Summary There are many different ways of approaching the investigation of prostate cancer, a cancer which has increased markedly over the past three decades both in frequency of diagnosis and as a cause of death in men in the western world. Analyzing resected human tissues offers a unique opportunity to directly investigate human prostate cancer. Obtaining and preparing human prostatic tissue, however, is difficult because the chemical integrity of the tissue degrades rapidly if it is not promptly obtained and cooled in the operating room. Also, the tumors are often heavily mixed with benign tissue, making careful histopathologic control essential if data obtained from human prostatic tissues is to be interpreted accurately. The slow rates of growth and very small proportions of cells in the proliferative fractions in most human prostate cancers constitutes a very significant difference between most laboratory models and prostate cancers as they occur in humans. As discussed above, Sakr and colleagues10 have shown that prostate cancers can be found in relatively young men (for example, 8% of men in their twenties), and that many decades pass between the time when cancer can be detected in prostates and its clinical appearance. Except for resected human tissue, none of

the commonly employed models for the study of human prostatic carcinomas take decades to grow significantly. Tissue culture lines and xenografts represent two other approaches. There are limited numbers of cell culture lines established from human prostate cancers, and the overwhelming majority of these fail to make PSA, the most abundant protein product of human prostates. Many of the culture lines also fail to make androgen receptors. Much less than 1% of the prostate cancers that have been tested in culture have formed cell lines. In contrast, the majority of xenografts of prostate cancers make both PSA and androgen receptors. Approximately 5 to 10% of prostate cancers will grow as xenografts, given the knowledge that is currently available. Historically, much less effort has been devoted to establishing these xenografts than to tissue culture lines, and there is reason to speculate that improved technology in this area may facilitate a higher rate of success than the current 5 to 10%. The availability of serially transplantable xenografts makes a large amount of prostate cancer tissue available repeatedly over long periods of time. In some cases, this has aided the development of tissue culture lines from prostate cancer xenografts. Both rodents and dogs have been studied extensively as models for prostate cancer. Prostate cancers do not naturally occur in most rodents; there are some strains, however, from which some animals will develop prostate cancer when quite old. The literature in this area is a bit confusing because most of the work prior to the last decade was done under the assumption that most cancers in the pelves of rodents were prostate cancers. Many more recent studies have shown that many of the tumors previously viewed as prostate cancers were, in fact, cancers of seminal vesicles. Human prostates and rodent prostates are quite different with respect to their gross anatomy, histology, biochemistry, and function. An enormous amount of work has been done with carcinomas in rodents. It can only be speculated the extent to which carcinomas of the prostate or seminal vesicle in rodents will ever reveal important information about human prostatic carcinomas. The most recently developed models of prostate cancer are the transgenic models. In these models, exogenous genetic material is introduced into prostatic cells and facilitates their growth as cell lines, some of which are malignant. These models may be very useful for investigating biologic mechanisms of many kinds; the extent to which the products of such investigations will reveal anything important about human prostate cancers remains to be determined.

Acknowledgment This work was supported by grants CA57179 from the National Cancer Institute and DK51347 from the National Institute of Diabetes and Kidney and Digestive Diseases. The authors thank Dr. M. Edward Kaighn, Dr. Raymond B. Nagle, and Dr. Mark E. Stearns for their helpful comments and criticism.


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from prostatic carcinoma and benign prostatic hyperplasia. Int J Oncol 1998;12:257–63. 163. Jackson-Cook C, Bae V, Edelman W, et al. Cytogenetic characterization of the human prostate cancer cell line P69SV40T and its novel tumorigenic sublines M2182 and M15. Cancer Genet Cytogenet 1996;87:14–23. 164. Kremer R, Goltzman D, Amizuka N, et al. Ras activation of human prostate epithelial cells induces overexpression of parathyroid hormone-related peptide. Clin Cancer Res 1997;3:855–9. 165. Parda DS, Thraves PJ, Kuettel MR, et al. Neoplastic transformation of a human prostate epithelial cell line by the v-Ki-ras oncogene. Prostate 1993;23:91–8. 166. Rhim JS, Kung HF. Human prostate carcinogenesis. Crit Rev Oncog 1997;8:305–28. 167. Huggins C, Clark PJ. Quantitative studies of prostatic secretion. II. The effect of castration and of estrogen injection on normal and on the hyperplastic prostate glands of dogs. J Exp Med 1940;72:747–62. 168. Huggins C, Stevens RA. The effect of castration on benign hypertrophy of the prostate in man. J Urol 1940;43: 705–14. 169. Huggins C, Hodges CV. Studies on prostatic cancer: the effect of castration, of estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941;1:293–7. 170. Lucia MS, Bostwick DG, Bosland M, et al. Workgroup I: rodent models of prostate cancer. Prostate 1998;36: 49–55. 171. Tamano S, Rehm S, Waalkes MP, Ward JM. High incidence and histogenesis of seminal vesicle adenocarcinoma and lower incidence of prostate carcinomas in the LobundWistar prostate cancer rat model using n-nitrosomethylurea and testosterone. Vet Pathol 1996;33:557–67. 172. Tamura Y, Ono Y, Suzuki T, et al. Carcinogenesis in accessory sex organs of rats induced by 3,2’-dimethyl-4aminobiphenyl: response by androgen deprivation. Histochem Cell Biol 1997;108:505–12. 173. Goodpasture EW, Wislocki GB. Old age in relation to cellovergrowth and cancer. J Med Res 1916;33:455–74. 174. Leav I, Ling GV. Adenocarcinoma of the canine prostate. Cancer 1968;22:1329–45. 175. Orgad U, Alroy J, Ucci A, Merk FB. Histochemical studies of epithelial cell glycoconjugates in atrophic, metaplastic, hyperplastic, and neoplastic canine prostate. Lab Invest 1984;50:294–302. 176. Abel PD, Keane P, Leathem A, et al. Change in glycoconjugate for the binding site of the lectin Ulex europeus 1 following malignant transformation of prostatic epithelium. Br J Urol 1989;63:183–5. 177. Waters DJ, Patronek GJ, Bostwick DG, Glickman LT. Comparing the age at prostate cancer diagnosis in humans and dogs [letter]. J Natl Cancer Inst 1996;88: 1686–7. 178. Waters DJ, Hayden DW, Bell FW, et al. Prostatic intraepithelial neoplasia in dogs with spontaneous prostate cancer. Prostate 1997;30:92–7. 179. Waters DJ, Bostwick DG. Prostatic intraepithelial neoplasia occurs spontaneously in the canine prostate. J Urol 1997;157:713–6. 180. Moore RA, Melchionna RH. Production of tumors of the prostate of the white rat with 1:2-benzpyrene. Am J Cancer 1937;30:731–41.

Models of Prostate Cancer / 153 181. Horning ES, Dmochowski L. Induction of prostate tumors in mice. Br J Cancer 1947;1:59–63. 182. Bosland MC. Chemical and hormonal induction of prostate cancer in animal models. Urol Oncol 1996;2: 103–10. 183. Shain SA, McCullough B, Segaloff A. Spontaneous adenocarcinomas of the ventral prostate of aged A X C rats. J Natl Cancer Inst 1975;55:177–80. 184. Ward JM, Reznik G, Stinson SF, et al. Histogenesis and morphology of naturally occurring prostatic carcinoma in the ACI/segHapBR rat. Lab Invest 1980;43:517–22. 185. Bosland MC. Animal models for the study of prostate carcinogenesis. J Cell Biochem Suppl 1992;16H:89–98. 186. Boorman GA, Elwell MR, Mitsumori K. Male accessory sex glands, penis, and scrotum. In: Boorman GA, Eustis SL, Elwell MR, et al., editors. Pathology of the fischer rat. San Diego (CA): Academic Press; 1990. p. 419–28. 187. Takizawa S, Hirose F. Role of testosterone in the development of radiation-induced prostate carcinoma in rats. Jpn J Cancer Res 1978;69:723–36. 188. Hirose F, Takizawa S, Watanabe H, Takeichi N. Development of adenocarcinoma of the prostate in ICR mice locally irradiated X-rays. Jap J Cancer Res 1976;67:407–11. 189. Brown CE, Warren S. Carcinoma of the prostate in irradiated parabiotic rats. Cancer Res 1978;38:159–62. 190. Bosland MC, Prinsen MK, Dirksen TJM, Spit BJ. Characterization of adenocarcinomas of the dorsolateral prostate induced in Wistar rats by N-methyl-Nnitrosourea, 7,12-dimethylbenz(a)anthracene, and 3,2’-dimethyl-f-aminobiphenyl, following sequential treatment with cyproterone acetate and testosterone proprionate. Cancer Res 1990;50:700–9. 191. Pour PM. A new prostatic cancer model: systemic induction of prostatic cancer in rats by a nitrosamine. Cancer Lett 1981;13:303–8. 192. Pour PM, Groot K, Kazakoff K, et al. Effects of high-fat diet on the patterns of prostatic cancer induced in rats by N-nitrosobis(2-oxopropyl)amine and testosterone. Cancer Res 1991;51:4757–61. 193. Shirai T, Sakata T, Fukushima S, et al. Rat prostate as one of the target organs for 3,2’-dimethyl-4-aminobiphenyl-induced carcinogenesis: effects of dietary ethinyl estradiol and methyltestosterone. Jpn J Cancer Res 1984;76:803–8. 194. Brown CE, Warren S, Chute RN, et al. Hormonally induced tumors of the reproductive system of parabiosed male rats. Cancer Res 1979;39:3971–6. 195. Saitoh H, Hida M, Shimbo T, et al. Metastatic patterns of prostatic cancer. Correlation between sites and number of organs. Cancer 1984;54:3078–84. 196. Saitoh H, Yoshida K-I, Uchijima Y, et al. Two different lymph node metastatic patterns of a prostatic cancer. Cancer 1990;65:1843–6. 197. Bielschowsky F, Hall WH. Carcinogenesis in parabiotic rats. Tumors of liver and seminal vesicle induced by acetylaminofluorene in normal males joined to castrated males or females. Br J Cancer 1951;5:106–14. 198. Cohen MB, Heidger PM, Lubaroff DM. Gross and microscopic pathology of induced prostatic complex tumors arising in Lobund-Wistar rats. Cancer Res 1994; 54:626–8. 199. Slayter MV, Anzano MA, Kadomatsu K, et al. Histogenesis of induced prostate and seminal vesicle carcinoma in

Lobund-Wistar rats: a system for histological scoring and grading. Cancer Res 1994;54:1440–5. 200. Pugh TD, Chang C, Uemura H, Weindruch R. Prostatic localization of spontaneous early invasive carcinoma in Lobund-Wistar rats. Cancer Res 1994;54:5766–70. 201. Pollard M. Spontaneous prostate adenocarcinomas in aged germfree Wistar rats. J Natl Cancer Inst 1973; 51:1235–41. 202. Pollard M, Luckert PH. Transplantable metastasizing prostate adenocarcinomas in rats. J Natl Cancer Inst 1975;54:643–9. 203. Pollard M, Chang CF, Luckert PH. Investigations on prostatic adenocarcinomas in rats. Oncology 1977;34:129–32. 204. Tsukamoto S, Akaza H, Imada S, et al. Chemoprevention of rat prostate carcinogenesis by use of finasteride or casodex. J Natl Cancer Inst 1995;87:842–3. 205. Joseph IBJK, Vukanovic J, Isaacs JT. Antiangiogenic treatment with linomide as chemoprevention for prostate, seminal vesicle, and breast carcinogenesis in rodents. Cancer Res 1996;56:3404–8. 206. Waters DJ, Bostwick DG, Murphy GP. Conference summary: first international workshop on animal models of prostate cancer. Prostate 1998;36:47–8. 207. Dunning WF. Prostate cancer in the rat. Monogr Natl Cancer Inst 1963;12:351–70. 208. Goebel H-W, Rausch U, Steinhoff M, et al. Arguments against the prostatic origin of the R-3327 Dunning H tumor. Virchows Arch B Cell Pathol 1992;62:9–18. 209. Project NPC. Announcements. Prostate Cancer News 1981;8:6. 210. Aumuller G, Groschel-Stewart U, Altmannsberger M, et al. Basal cells of H-Dunning tumor are myoepithelial cells. A comparative immunohistochemical and ultrastructural study with male accessory sex glands and mammary gland. Histochemistry 1991;95:341–9. 211. Green JE, Greenberg NM, Ashendel CL, et al. Workgroup 3: transgenic and reconstitution models of prostate cancer. Prostate 1998;36:59–63. 212. Maroulakou IG, Anver M, Garrett L, Green JE. Prostate and mammary adenocarcinoma in transgenic mice carrying a rat C3(1) simian virus 40 large tumor antigen fusion gene. Proc Natl Acad Sci U S A 1994;91:11236–40. 213. Barrios R, Libovitz RM, Wiseman AL, et al. RasT24 driven by a probasin promoter induces prostatic hyperplasia in transgenic mice. Transgenics 1996;2:23–8. 214. Greenberg NM, DeMayo F, Finegold MJ, et al. Prostate cancer in a transgenic mouse. Proc Natl Acad Sci U S A 1995;92:3439–43. 215. Kasper S, Sheppard PC, Yan Y, et al. Development, progression, and androgen-dependence of prostate tumors in probasin-large T antigen transgenic mice: a model for prostate cancer [published erratum appears in Lab Invest 1998;78(6):i-xv]. Lab Invest 1998;78:319–33. 216. Perez-Stable C, Altman NH, Mehta PP, et al. Prostate cancer progression, metastasis, and gene expression in transgenic mice. Cancer Res 1997;57:900–6. 217. Tehranian A, Morris DW, Min BH, et al. Neoplastic transformation of prostatic and urogenital epithelium by the polyoma virus middle T gene. Am J Pathol 1996;149:1177–91. 218. Zhang X, Chen MW, Ng A, et al. Abnormal prostate development in C3(1)-bcl-2 transgenic mice. Prostate 1997; 32:16–26.

CHAPTER 17

DIAGNOSIS OF PROSTATE CANCER L. ANDREW ESKEW, MD; DAVID L. MCCULLOUGH, MD Historic Perspective

However, cancerous lesions can show up as hyperechoic, hypoechoic, or isoechoic lesions.4 Transrectal ultrasonography (TRUS) can show asymmetry of the gland, which may prompt a biopsy.

Diagnosing prostate cancer requires obtaining cancerous tissue from the prostate gland. The evolution of this now simple office-based procedure is interesting. Prostate biopsy began as an open transperineal aspiration of the prostate, originated by Ferguson around 1930.1 This method was refined until a prostate tissue recovery rate of 86% was attained. Over time, the open transperineal aspiration approach was abandoned for the transrectal aspiration approach. Transurethral resection of prostate was used to diagnose cancer of the prostate but proved to be less accurate than other forms of biopsy. With the advent of core biopsy needles, transperineal and transrectal digitally directed biopsies became a popular means of obtaining prostate tissue for diagnosis. Core biopsy needles also allowed for a histologic diagnosis as opposed to a cytologic diagnosis. The advent of transrectal ultrasound has revolutionized prostate biopsy and has greatly increased the diagnostic accuracy of this screening procedure. With over 200,000 cases of prostate cancer diagnosed every year in the United States and thousands of other men undergoing negative biopsies, the magnitude of this procedure can be appreciated.

Presence of High-Grade Prostatic Intraepithelial Neoplasia on Prior Biopsy While low-grade prostatic intraepithelial neoplasia (PIN) is not considered a precancerous lesion, high-grade PIN is considered a precancerous lesion of the prostate; approximately 35 to 38% of high-grade PIN eventually converts to prostate cancer.5,6 The current recommendation is to rebiopsy the prostate at 6-month intervals after a positive diagnosis of high-grade PIN has been established. Biopsy after Curative Therapy Palpable abnormality and/or rising PSA after curative therapy for cancer (radical prostatectomy, external beam radiation, or cryotherapy) is an indication for prostate biopsy. In this setting, a positive biopsy would dictate further treatment plans based on the individual clinical situation.

Indications for Prostate Biopsy

Patient Preparation

Elevated Prostate-Specific Antigen The most common current indication for prostate biopsy is an elevated serum prostate-specific antigen (PSA) level. The serum reference range is 0.0 to 4.0 ng per mL, with a level > 4.0 ng per mL considered elevated; age-adjusted normal PSA levels, however, have been established. Oesterling et al. demonstrated an 8% increase in the number of biopsies and organ-confined cancers detected in men aged 50 years or less (normal digital rectal examination) when agespecific PSA reference ranges were used (Table 17–1).2

Informed Consent Full, informed consent should be obtained from the patient prior to prostate biopsy, including alternatives, consequences, and complications of biopsy. Bowel Preparation Patients are started on a clear liquid diet at lunch time the day before biopsy. Laxatives are given the day prior to biopsy, followed by a cleansing enema before the biopsy session. Alternatively, a formal polyethylene glycol bowel preparation can be administered on the evening prior to the biopsy. The patient is given nothing by mouth on the day of biopsy.

Abnormal Digital Rectal Examination Abnormal or suspicious digital rectal examination of the prostate is an indication for prostate biopsy. If there is a prostate nodule, focal induration of the gland, or a diffusely hard prostate gland, biopsy should be promptly carried out regardless of PSA level.

Antibiotics There is a 3-day course of quinolone antibiotic administered commencing the day before biopsy and continued through to the day after biopsy. If preprocedure assessment reveals urinary tract infection, a longer course of antibiotics would be prescribed as indicated. Patients with valvular heart disease are administered parenteral

Abnormalities Seen on Transrectal Ultrasonography Classically, the echo pattern of prostate cancer seen on transrectal ultrasound was that of hypoechoic lesions.3 154

Diagnosis of Prostate Cancer / 155

antibiotics as outlined by the American Heart Association.7 Ampicillin 2 g and gentamicin 80 mg are administered intravenously or intramuscularly 30 minutes prior to biopsy, with amoxicillin 2 g given by mouth 6 hours after biopsy. Patients with penicillin allergies are given vancomycin 1 g intravenously in place of ampicillin. Due to the longer serum half-life of vancomycin, a delayed dose is not necessary. Discontinuation of Anticoagulants or Antiplatelet Drugs Patients are taken off anticoagulants or antiplatelet drugs prior to the biopsy session, if medically possible. Patients who require warfarin sodium for mechanical heart valves or heart arrhythmias are converted to heparin prior to procedure and are maintained on heparin following biopsy until adequately anticoagulated with warfarin. Aspirin and nonsteroidal anti-inflammatory drugs should be avoided prior to biopsy. Patients who have a recent history of using these drugs should have a bleedingtime preprocedure to rule out qualitative platelet defect. To reduce bleeding complications after biopsy, the biopsy session should be postponed until the bleeding time has normalized.

Technique of Transrectal Ultrasound-Guided Needle Biopsy Transrectal ultrasonography allows accurate imaging of the prostate and accurate biopsy needle placement. Transrectal ultrasound-guided needle biopsy of the prostate is an office procedure which can be accomplished quickly, without anesthesia, and is well tolerated by patients. Patient Positioning Patients are placed in either the knee-chest lateral decubitus position or the dorsal lithotomy position for biopsy, depending on the preference of the operator. Analgesia Transrectal ultrasound-guided needle biopsy can be performed without the use of anesthesia. Parenteral or oral analgesics may be administered, depending on operator and patient preferences. Anecdotally, intrarectal topical lidocaine jelly seems to reduce discomfort associated with prostate biopsy. Patient anxiety regarding biopsy can be reduced if patients are warned prior to the biopsy needle being inserted. This prepares the patient for the noise and discomfort associated with biopsy needle firing, which often will startle an unsuspecting patient. Imaging the Prostate and Obtaining Biopsies Once the patient has been positioned for biopsy, the lubricated transrectal ultrasound probe is inserted into the rectum. The probe is inserted with the tip aimed in a direction pointing toward the patient’s umbilicus until

TABLE 17–1. Age-Specific Reference Ranges for Serum PSA Concentration, Prostatic Volume, and PSA Density Age Group (Years) Parameter

40–49

50–59

60–69

70–79

Serum PSA concentration, ng/mL Prostatic volume, mL PSA density, ng/mL-cc

0.0–2.5

0.0–3.5

0.0–4.5

0.0–6.5

13–51 0.0–0.08

15–60 0.0–0.10

17–70 0.0–0.11

20–82 0.0–0.13

Reproduced with permission from Oesterling JE, Jacobsen SJ, Chute GG, et al. Serum prostate-specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges. JAMA 1993;270:860–4.

the probe tip is past the anal verge, then the probe is directed along the direction of the rectum. The prostate is imaged from the bladder neck down through the apex. The seminal vesicles and periprostatic tissue are imaged. Images are obtained in the transverse and sagittal planes. If present, contour abnormalities and abnormal or asymmetric echo patterns are noted. The volume of the prostate can be measured.8 Biopsies are then taken with ultrasound guidance to aim the biopsy needles accurately. The biopsy needle is a spring-loaded 18-gauge automatic device for singlepatient use. The needles obtain a core of prostate tissue 15 mm in length. It must be remembered that the beveled needle tip is usually 5 mm in length. The biopsy core will thus be taken 5 mm proximal to the needle tip. Core biopsy needles should be oriented so that the point of the beveled needle rather than the flat side of the bevel strikes the prostate surface initially. This will minimize deflection of the needle by the prostate, enabling more accurate core sampling (Figure 17–1). Use of a sagitally oriented transducer allows a needle guide to be projected on the ultrasound machine so that the entire course of the needle through the prostate can be observed (Figure 17–2). Once the core biopsies are obtained, they are sent in formalin for microscopic interpretation or sent fresh for frozen section if an immediate diagnosis is required. Postbiopsy Care Patients are kept on quinolone antibiotics for 48 hours after biopsy. Patients are instructed to force fluids, especially in cases where gross hematuria is encountered. Patients are encouraged to maintain a sedentary lifestyle and avoid aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) for 72 hours to minimize postbiopsy bleeding. Patients are counseled that hematuria, hematochezia, and hematospermia may occur as a result of the biopsy and should be short lived. Prolonged bleeding is reported by some patients. Patients are instructed to report prolonged bleeding, fevers, or voiding difficulty after a biopsy session. Hematospermia may occur up to a month postbiopsy.


FIGURE 17–1. Core biopsy needles should be oriented so that the point of the beveled needle rather than the flat side of the bevel strikes the prostate surface initially. This will minimize deflection of the needle by the prostate and more accurate core sampling is accomplished. Reproduced with permission from Cooner WM, Holt W. Needle biopsy of the prostate. In: Marshall F, editor. Textbook of operative urology. Philadelphia: WB Saunders; 1996.

Methods of Biopsy Sextant Prostate Biopsy Introduced by Hodge et al. in 1989, the sextant method of prostate biopsy is worldwide the “gold standard” method of prostate biopsy.9 As originally described, the sextant method of biopsy takes six biopsies of the prostate. The biopsies are obtained in the midlobe parasagittal plane at the apex, middle, and base of the prostate bilaterally (Figure 17–3). More recently, the sextant method of prostate biopsy has changed as originally described. The biopsies have been moved laterally instead of being located parasagitally.10

FIGURE 17–2. Transrectal ultrasound in sagittal plane shows angle of entry (arrows) of biopsy needles, allowing the entire course of the needle through the prostate to be observed. Reproduced with permission from Eskew LA, Bare RL, McCullough DL. Systematic fiveregion biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol 1997;157:199–203.

Five-Region Prostate Biopsy Concern arose that the standard sextant method of biopsy may not provide an adequate biopsy sample. Thus, a prospective study was performed comparing the sextant method of biopsy with a more extensive method called the five-region prostate biopsy.11 Using the five-region method, sextant biopsies as originally described are taken from the prostate gland. In addition, biopsies are taken from the far lateral aspects of the gland on each side and from the middle. There are a minimum of 13 biopsies routinely taken (Figure 17–4). By using the five-region biopsy, the diagnostic yield of prostate is increased by 35% over the standard sextant biopsy. In glands measuring over 50-cc volume, at least one additional core from each region is generally taken (total 18 cores). Prostate cancer diagnosed using the five-region technique has been shown to be significant in grade, volume, and ploidy, as has cancer diagnosed by the sextant technique.12 Other Forms of Biopsy Chen et al. analyzed prostate biopsy using a computergenerated biopsy model.13 Sectioned cancerous prostate specimens with tumor areas highlighted were digitized, and computer-simulated biopsy sessions were performed for 180 prostates. In this model, a biopsy scheme was reported which diagnosed cancers 96% of the time when cancer volume was > 0.5 cc.

Accuracy of Prostate Biopsy As with any screening test, prostate biopsy is not 100% accurate in identifying carcinoma when it is present. Several studies have investigated this phenomenon. Fleshner et al. repeated TRUS-guided needle biopsy of the prostate in 130 men and found 30% of these men to have cancer on repeat biopsy.14 Correlating risk factors including age, pathologic result of initial biopsy, interbiopsy interval, PSA, PSA density, and other factors, they concluded that baseline risk for positive repeat biopsy even in the lowest risk patients (PSA < 10 ng/mL) was sufficiently high to justify repeat biopsy in patients who continue to meet the criteria for biopsy in follow-up. Levin et al. performed a study in which patients underwent sextant prostate biopsy followed by a second sextant prostate biopsy at the same setting. They found a 30% discrepancy in biopsy results from the initial biopsy compared to final biopsy, indicating a potential 30% false-negative rate of sextant prostate biopsy.15 Authors often have reported significant rates of cancer detection after initial negative biopsies. Keetch et al. reported a 19% positive rebiopsy rate in a cohort with persistently elevated PSA.16 Ellis and Brawer reported a 20% positive rebiopsy rate in a cohort with negative initial TRUS-guided biopsy.17 Svetec et al. performed sextant biopsy of 90 prostates ex vivo immediately after these glands had been removed for clinically localized carci-

Diagnosis of Prostate Cancer / 157

der catheter insertion and continuous bladder irrigation until the bleeding subsides. Platelet count, bleeding time, and coagulation studies may be obtained to rule out medical causes of excessive hematuria after prostate biopsy. Hematochezia is encountered infrequently after prostate biopsy and is usually self-limited. Excessive or prolonged bleeding may be treated by first packing the rectum with lubricated gauze packing material. This usually stops the bleeding. If bleeding continues, anoscopy or rigid sigmoidoscopy is performed to localize the source of the bleeding. Once the bleeding point is localized on the anterior rectal wall, an absorbable suture may be placed to stop the bleeding. Patients with hemorrhoids or portal hypertension may be at increased risk for rectal bleeding after prostate biopsy. If an anterior rectal-wall hematoma develops after biopsy, expectant management with stool softeners and low-residue diet can be pursued.

FIGURE 17–3. Position of six biopsies in (A) transverse and (B) sagittal views. Biopsies are taken in midlobe parasagittal plane at apex, middle, and base of prostate bilaterally. TZ = transition zone; PZ = peripheral zone; CZ = central zone. Reproduced with permission from Terris MK, McNeal JE, Stamey TA. Detection of clinically significant prostate cancer by transrectal ultrasound-guided systematic biopsies. J Urol 1992;148:829–32.

noma of the prostate. All glands had pathologically confirmed adenocarcinoma. Using the sextant biopsy on the prostatectomy specimens, however, they found a 45.6% false-negative biopsy rate.18 Needless to say, a false-negative rate of sextant biopsy exists and most likely ranges from 20 to 30%, based on the above studies. These data suggest that some carcinomas exist at the time of intial biopsy but are undetected possibly due to inadequate sampling or operator-dependent error. The false-negative rate could possibly be reduced by a more thorough biopsy session. The optimal number of biopsies to take during a biopsy session is not known.

Complications of Prostate Biopsy Reported complications or consequences of prostate biopsies include hematuria, hematochezia, hematospermia, pain, urinary retention, prostate abscesses, urinary tract infections, tumor tracking of biopsy site, and anterior rectal-wall hematomas. Hematuria after prostate biopsy is usually self-limited and transient. Serious problems with hematuria are more likely to be encountered in patients who have a bleeding dyscrasia, or in patients who are on medication which would inhibit normal blood clotting mechanisms. Hematuria with clots after biopsy should be managed with blad-

FIGURE 17–4. Figure depicting cross-sectional and posterior view of prostate showing peripheral zone (PZ) and areas of biopsy (circles). Shaded areas represent additional regions of biopsy using 5-region method. Reproduced with permission from Eskew LA, Woodruff RD, Bare RL, McCullough DL. Prostate cancer diagnosed by the five-region biopsy method is significant disease. J Urol 1998;160:794–6.


Hematospermia is common after prostate biopsy and is self-limited but may persist for up to 30 days. Patients should be warned of this phenomenon prior to biopsy to prepare them for it. It has been the authors’ experience that patients with significant obstructive voiding symptoms prior to prostate biopsy may develop transient urinary retention after a biopsy session. This may be treated conservatively with a few days of catheter drainage and oral α-blocking agents. If the prostate biopsy is negative for cancer, the patient with urinary retention after biopsy may declare himself as a candidate for long-term medical treatment for benign prostatic hyperplasia or as a candidate for surgery to relieve bladder obstruction, should medical treatments fail. Patients with a positive biopsy for prostate cancer who are not candidates for radical prostatectomy may require androgen ablation with or without other surgical treatments to alleviate bladder outlet obstruction. Infectious complications after prostate biopsy can be minimized with careful prebiopsy preparation, including prophylactic antibiotics and bowel preparation or cleaning enemas. Gustafsson et al. report a urinary tract infection rate of 62% when prophylactic antibiotics were not used in patients undergoing transrectal prostate biopsy. One-half of these infections required hospitalization and parenteral antibiotics.19 Thompson et al. reported previously a 100% rate of bacteremia and an 87% rate of urinary tract infection in a cohort of patients biopsied without antibiotic prophylaxis.20 Besides preparing the patient for the biopsy to prevent infection, the equipment used for biopsy should be one-time use equipment as much as possible. Keizur et al. report iatrogenic urinary tract infection with Pseudomonas species in 8.2% of prepared patients undergoing transrectal biopsy. The source of the infection was found to be ultrasound transmission gel colonized with Pseudomonas species.21 The authors have had no serious septic events with a preoperative bowel cleansing (polyethylene glycol) and 3 days (6 doses) of a quinolone antibiotic.

Summary Transrectal ultrasound-guided needle biopsy of the prostate has become the gold standard method of obtaining prostate tissue to rule out malignancy. This is an office-based procedure which is readily available and is well tolerated by patients. The false-negative biopsy rate which exists seems to be inversely related to the number of core biopsies taken at the time of biopsy. Patient complications are rare and usually minor and self limited. Infectious complications may be minimized by careful patient preparation.

References 1. Ferguson RS. Prostatic neoplasms: their diagnosis by needle puncture and aspiration. Am J Surg 1930;9:507–11.

2. Oesterling JE, Jacobsen SJ, Chute GG, et al. Serum prostate-specific antigen in a community-based population of healthy men: establishment of age-specific reference ranges. JAMA 1993;270:860–4. 3. Lee F, Gray JM, McLeary RD, et al. Prostatic evaluation by transrectal sonography: criteria for diagnosis of early carcinoma. Radiology 1986;158:91. 4. Rifkin MD, McGlynn ET, Choi H. Echogenicity of prostate cancer correlated with histologic grade and stromal fibrosis: endorectal ultrasound studies. Radiology 1989;170:549–52. 5. Davidson D, Bostwick DG, Qian J, et al. Prostatic intraepithelial neoplasia is a risk factor for adenocarconoma: predictive accuracy in needle biopsies. J Urol 1995;154: 1295–9. 6. Bemer A, Danielsen HE, Pettersen EO, et al. DNA distribution in the prostate. Normal gland, benign and premalignant lesions, and subsequent adenocarcinomas. Anal Quant Cytol Histol 1993;15:247–52. 7. Danjani AS, Bisno AL, Ching KJ, et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. JAMA 1990;264:2919. 8. Terris MK, Stamey TA. Determination of prostate volume by transrectal ultrasound. J Urol 1991;145:984–7. 9. Hodge KK, McNeal JE, Terris MK, et al. Random systematic versus directed ultrasound-guided transrectal core biopsies of the prostate. J Urol 1989;142:71. 10. Stamey TA. Making the most of six systematic sextant biopsies. Urology 1995;45:2. 11. Eskew LA, Bare RL, McCullough DL. Systematic five-region biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J Urol 1997;157:199–203. 12. Eskew LA, Woodruff RD, Bare RL, McCullough DL. Prostate cancer diagnosed by the five-region biopsy method is significant disease. J Urol 1998;160:794–6. 13. Chen ME, Troncoso P, Johnston DA, et al. Optimization of prostate biopsy strategy using computer-based analysis. J Urol 1997;158:2168. 14. Fleshner NE, O’Sullivan M, Fair WR. Prevalence and predictors of a positive repeat transrectal ultrasoundguided needle biopsy of the prostate. J Urol 1997;158: 505. 15. Levin MA, Ittman M, Melamed J, et al. Two consecutive sets of transrectal ultrasound-guided sextant biopsies of the prostate for the detection of prostate cancer. J Urol 1998;159:471. 16. Keetch DW, Catalona WJ, Smith DS. Serial prostatic biopsies in men with persistently elevated serum prostate antigen values. J Urol 1994;151:1571. 17. Ellis WJ, Brawer MK. Repeat prostate needle biopsy: who needs it? J Urol 1995;153:1946. 18. Svetec D, McCabe K, Peretsman S, et al. Prostate rebiopsy is a poor surrogate of treatment efficacy in localized prostate cancer. J Urol 1998;159:1606. 19. Gustafsson O, Norming U, Nyman CR. Complications following combined transrectal aspiration and core biopsy of prostate. Scand J Urol Nephrol 1990;24:249. 20. Thompson PM, Pryor JP, Williams JP, et al. The problem of infection after prostate biopsy: the case for the transperineal approach. Br J Urol 1982;54:736. 21. Keizur JJ, Lavin B, Leidich RB. Iatrogenic urinary tract infection with Pseudomonas cepacia after transrectal ultrasound-guided needle biopsy of the prostate. J Urol 1993;149:523.

CHAPTER 18

STAGING OF PROSTATE CANCER RASHMI I. PATEL, MD; MARTIN I. RESNICK, MD As medical technology and diagnostic imaging techniques continue to advance and provide for increased longevity, a larger portion of the male population will be diagnosed with prostate carcinoma. An accurate assessment of the stage of prostate cancer (PCa) prior to definitive therapy represents a clinical challenge to the physician treating PCa. Ideally, staging should reliably reflect the natural history of cancer, describe the burden and extent of tumor at the time of diagnosis, and stratify patients into prognostically distinct groups. Pathologic staging is more useful than clinical staging for predicting prognosis because tumor volume and grade, surgical margin status, extent of extracapsular extension (ECE), and involvement of seminal vesicles and lymph nodes can be determined.1 Preoperative (clinical) stage should predict postoperative (pathologic) stage with a reasonable degree of accuracy, particularly when considering nonsurgical treatments such as radiation therapy that do not yield tissue for pathologic examination. From a practical standpoint, clinical stage is performed to distinguish those patients who would likely benefit from local ablative therapy, that is, radical prostatectomy, from those with more advanced cancer who are less likely to benefit from this type of treatment. Further, accurate tumor staging is essential to identify risk factors for ECE prior to radical surgery. It is well known that ECE often leads to positive surgical margins. This is clinically important in that the incidence of ECE tends to increase with advancing clinical stage and histologic tumor grade. For example, Van Den Ouden et al. showed that the incidence of positive surgical margins ranged from 15% (T1 disease) to 47% (T3 disease). High-grade lesions were associated with greater frequency of residual disease than were lowgrade lesions in radical prostatectomy specimens.2 Since the accurate assessment of clinical stage plays an integral role in choosing definitive treatment options and improving treatment outcomes, many new approaches have been developed to more accurately predict pathologic stage. Digital rectal examination (DRE), routine prostate-specific antigen (PSA) screening, and transrectal ultrasonography (TRUS) have been the traditional mainstays of detection, diagnosis, and noninvasive staging over the years. Similarly, both pelvic lymph node dissection and radionuclide bone scan play an important role in staging of many patients. New imaging modalities such as magnetic resonance imaging (MRI), positron emission

tomography (PET), and radioimmunoimaging are being evaluated as potential means of detecting and staging patients with asymptomatic disease. This chapter reviews different techniques and imaging modalities currently available for the preoperative staging of patients with prostate adenocarcinoma.

Current Staging Systems Several staging classification systems have been designed to categorize PCa with respect to location, size, degree of ECE, and presence or absence of metastatic disease. Whitmore developed one of the first staging classification systems, in 1956.3 This system was based on the results of DRE and radiographic studies and categorized the disease as: stage A, the presence of subclinical disease; stage B, organ-confined disease without evidence of metastases; stage C, local extraprostatic disease without metastases; and stage D, evidence of metastatic disease. This system was the most commonly used staging system in the United States until its modification by Jewett in 1975.4 Jewett subclassified stage A disease based on whether the disease was focal (A1) versus diffuse (A2) and on the histology of the cancer. Stage B disease was subclassified as B1, which identified focal unilateral involvement of the prostate (B1 nodule; “Jewett Nodule”) and B2, which diffusely involved both lobes, without capsular involvement.1 Stage C disease minimally involved the capsule (C1) as well as more extensive ECE-producing bladder outlet or ureteral obstruction (C2). Stage D implied metastatic disease. The tumor, node, metastasis (TNM) system developed in 1975 by the American Joint Committee for Staging and End Results Reporting (AJC), further subclassified PCa based on the amount of tumor burden from needle core biopsies (T1), palpable size of the lesion (T2), pathologic findings of capsular involvement (T3), as well as lymph node metastases (N4).5 In 1988, Whitmore et al., acting as the Organ Systems Coordinating Center (OSCC) of the National Institutes of Health, proposed a modified TNM staging system that would attempt to unify the clinical staging systems for PCa.6 Although this system did not achieve widespread acceptance, it did incorporate results from tumors detected by TRUS, serum PSA, and DRE. It also allowed for flexibility and adaptability to recent developments in evaluating patients with PCa by using MRI as well as radioimmunoimaging. 159


Finally, the International Union Against Cancer (UICC)/American Joint Committee on Cancer (AJCC) proposed in 1992 another unifying revision of the TNM system for staging PCa.7,8 First, a new category (T1c) was introduced to recognize nonpalpable, noninvasive tumors identified by random biopsy after detection of an elevated serum PSA level. Second, T2 palpably organconfined cancers were subdivided into three groups based on relative involvement of the prostate rather than simply absolute size determined by DRE. Third, cancers with ECE (T3) were subdivided into three groups based on laterality and seminal vesicle invasion. Recently, von Eschenbach et al. compared the utility and prognostic power of this revised TNM system to that of the Whitmore-Jewett system.9 This study conclusively proved that the UICC/AJCC system allows for designation of a greater number of meaningful tumor categories that are prognostically superior to the Whitmore-Jewett system. The UICC/AJCC system is therefore now considered the international standard; it is the most applicable staging system for PCa, and it has become the staging system most frequently used today. The AJCC system was updated in 1997, dividing both stage T2 and T3 disease into two stages: T2a and T2b (one or both lobes involved with organ-confined disease) and T3a and T3b (extracapsular extension and seminal vesical invasion) (Table 18–1).10

Limitations of Current Staging Systems There are a number of clinical factors which limit current PCa staging systems, including: (1) preoperative understaging with DRE; (2) preoperative understaging with transurethral resection of the prostate (TURP); (3) limitations of various imaging modalities to evaluate presence and extent of tumor; and (4) variability in pathologic staging.1 The DRE is one of the traditional methods used for staging PCa. It relies on palpation of the prostate to differentiate confined from nonconfined disease, unilateral from bilateral disease, and small from large tumors. Studies indicate, however, that detection rates based solely on DRE rarely exceed 2.2%; the accuracy of clinical staging based on DRE alone is approximately 50% in men with palpable disease.11–13 Further, Bostwick et al. identified clinical understaging in 59% and clinical overstaging in 5% of 311 cases of prostatectomy specimens.1 Also, DRE lacks specificity, and studies have demonstrated false-negative rates as high as 36% for lesions thought to be suspicious based soley on palpation.14 In a recent multicenter study by Flanigan et al. evaluating patients with PSA > 4 ng per mL or with a suspicious DRE in a patient who had undergone TRUS-guided biopsies, 74% of the biopsies containing cancer were not considered suspicious based on DRE alone.15 While traditionally DRE has been the mainstay of PCa detection, studies have proven conclusively that DRE alone lacks

sensitivity and specificity and is not a reliable sole means of evaluating a patient at risk for PCa. Clinical understaging with TURP is a well-recognized dilemma in early carcinoma of the prostate. Since the majority of tumors arise in the periphery of the prostate gland, TURP is not used as a staging modality in over 70% of early cancers. The sensitivity of TURP in detecting stage T1(A) cancers is only 28%, and up to 60% of patients with stage T1a(A1) tumors who have repeat TURP have residual tumor, with 26% of these being upstaged.1 Walsh et al. found that 26% of the patients studied with clinical T1b(A2) stage tumors had higher final pathologic stages and that they all had residual tumor.16 These are only a few studies demonstrating that examining TURP specimens is not a reliable method of PCa staging. Imaging modalities that could accurately access volume and extent of ECE would be invaluable to preoperative staging. However, as is discussed later in this chapter, even with recent advances in imaging technology (MRI, PET, radioimmunoimaging), no single imaging modality can provide all the necessary information needed to reliably and accurately predict clinical stage. The variability of pathologic staging also limits current PCa staging systems. For instance, the processing of TURP specimens is not standardized, and numerous methods have been developed to measure tumor volume and define substages T1a(A1) and T1b(A2). The pathologist’s “eyeball” estimation of tumor volume includes TURP chip counting (fewer or more than three chips involved), tumor area ratio estimation (percentage of specimen area), TURP chip ratio (ratio of benign-tomalignant chips), and cancer foci counting (fewer or more than three microscopic foci of cancer).1 Pathologic understaging can also be caused by variability in the processing of radical prostatectomy specimens. Haggman et al. examined the results of limited sectioning of specimens (sections through palpable tumor plus two random sections of apex and base) versus complete sectioning (whole organ sections).17 They found a significant increase in positive surgical margins (12% versus 59%, respectively) and pathologic stage with the complete sectioning approach. Currently, there does not seem to be a standardized approach for processing prostatic pathologic specimens. Further, standardized terminology to describe tumor invasion is lacking. For instance, localized ECE has been variously referred to as capsular “invasion,” “penetration,” or “perforation.” There are clearly limitations to the current staging systems, as has been shown by recent data describing a significant tendency toward tumor understaging and a limited ability to define the true extent of the disease. For example, a review of 17 recent studies comparing clinical and pathologic staging data of radical prostatectomy specimens demonstrated an overall clinical staging accuracy of 52.4%.18 This underscores the need for refinement in tech-

Staging of Prostate Cancer / 161 TABLE 18–1. Comparison of TNM and Whitmore-Jewett Staging Systems for Clinically Localized Prostate Cancer Stage TNM TX T0 T1a T1b T1c T2a T2b T3a T3b T4

Whitmore-Jewett * * A1 A2 * B1 B2 C1 C2 *

Description Primary tumor cannot be assessed No evidence of primary tumor Impalpable tumor, not visible by imaging in ≤ 5% of resected tissue Impalpable tumor, not visible by imaging in > 5% of resected tissue Impalpable tumor, not visible by imaging identified with needle biopsy (e.g., because of elevated PSA) Tumor confined within the prostate involving one lobe Tumor confined within the prostate involving both lobes Extracapsular extension of tumor Invasion of the seminal vesicle(s) Tumor is fixed or invades adjacent structures other than seminal vesicles (e.g., bladder neck, external sphincter, rectum, levator muscles, and/or pelvic floor)

*No corresponding stage. From American Joint Committee on Cancer. AJCC cancer staging manual. 5th ed. Philadelphia: Lippincott-Raven; 1997.

nologies and standardization of pathologic evaluation of specimens so that both prognosis and management plans can be based on solid clinical and pathologic data.

Prostate Cancer Staging Techniques An accurate clinical staging assessment is essential following diagnosis of PCa to enable the physician to assess the prognosis of the patient and design a rational treatment strategy. Preoperative evaluation of patients with PCa begins with its initial diagnosis, which is generally made using a combination of modalities to maximize the sensitivity and specificity of the diagnostic process.19 In general, the techniques currently available to evaluate clinical stage and grade of disease can be divided into clinical indicators and radiologic indicators. Clinical indicators used in assessing PCa include history and physical examination, laboratory survey, PCa serum markers, prostate needle biopsy, and pelvic lymph node dissection. Radiologic studies used to evaluate PCa include TRUS, plain radiography, computed tomography (CT), bone scintigraphy, MRI, radioimmunoimaging, PET, and, rarely, lymphangiography. Clinical Indicators History and Physical Examination The history and physical examination should elicit signs or symptoms suggesting either localized or extensive disease. Generally speaking, patients with low-volume, lowgrade, localized tumors are asymptomatic with respect to malignancy. For these patients, the most common symptom prompting evaluation is related to bladder outlet obstruction secondary to concurrent benign prostatic hyperplasia (BPH), rather than PCa. These complaints may include both obstructive and irritative voiding symptoms. Recognizing them may prompt further investigations leading to diagnosis of the underlying malignancy. Other symptoms elicited from the history, such as an acute change in voiding habits or hematuria, while

commonly attributed to BPH, may represent an extension of tumor into the bladder neck, trigone, or bladder base. Also, locally extensive disease can obstruct or invade the ejaculatory ducts leading to hematospermia and/or a decrease in ejaculate volume. Prostate cancer may at times involve the pelvic plexus, which innervates the corpora cavernosa and may lead to impotence.20 In addition, nonspecific complaints such as suprapubic, pelvic, lower extremity, and perineal pain have been described in 20 to 40% of patients diagnosed with PCa.21 Finally, constitutional symptoms such as weight loss, fatigue, and diffuse bone pain, while occurring in < 15% of patients at initial presentation, should prompt an exhaustive search for metastases prior to considering aggressive local therapy.21 Digital Rectal Examination As stated previously, DRE may estimate the local extension of disease, but it lacks the sensitivity and specificity to determine either tumor volume or ECE of PCa. Based on 17 radical prostatectomy studies, the false-negative rate of DRE for nonorgan-confined disease was approximately 48%.18 The overall specificity of DRE for organconfined disease staging in one study was only 9% while the overall accuracy was 57.7%.18 The positive predictive value (PPV) for DRE in several studies ranged from 21 to 53%.20 Conversely, the negative predictive value (NPV) of DRE for organ-confined disease ranged from 80 to 90%, indicating that when DRE suggests extraprostatic disease, it is usually correct.22,23 The DRE can therefore be a useful adjunct in the staging process by allowing evaluation of the peripheral architecture of the gland, assessing the site, location, and laterality of regions of induration which may reflect tumor. Cooner et al. found that the sensitivity of DRE increases significantly when used in combination with TRUS and serum PSA.24 In an elegant, multicenter study, Smith et al. performed both transrectal ultrasonography and DRE on 386 patients who were candidates for radical prostatectomy. The authors


used receiver operating characteristic curves (ROC) to compare the staging abilities of the two tests. An ideal test would have a ROC value of 1.0; that is, it would always be positive if the tumor was extraprostatic and would always be negative if the tumor was confined to the prostate. On the other hand, a coin toss would have a ROC value of 0.5. The ROC values for TRUS and DRE were 0.69 and 0.72 for predicting extracapsular tumor extension and 0.74 and 0.69 for predicting seminal vesicle invasion. Neither value was significantly different. This landmark study suggests that a well-performed DRE is as effective in local staging of prostate cancer as is transrectal ultrasound.25 Digital rectal examination is limited for several reasons, including failure to provide an accurate estimate of tumor volume and an inability to detect microscopic spread, which accounts for a large proportion of extraprostatic tumor sites. The findings on DRE may also be affected by some forms of benign prostatic diseases (chronic prostatitis, calculi) and after transurethral surgery or prior prostate needle biopsies. Nevertheless, DRE continues to remain an integral part of PCa staging, especially due to its low cost and ease of performance. Laboratory Survey The laboratory survey, including the complete blood count (CBC), serum electrolytes, blood urea nitrogen (BUN), and serum creatinine will be within normal limits for most patients. However, patients with advanced disease may show alterations in hematologic or renal function. For instance, an elevation in BUN and serum creatinine due to ureteral or bladder outlet obstruction secondary to invasive PCa and anemia, or from chronic disease caused by either bone marrow involvement by tumor or renal failure leading to decreased erythropoietin production, may be features of newly diagnosed disease. The serum alkaline phosphatase can also be useful in preoperative staging. Although not specific for PCa, an elevated serum alkaline phosphatase may be a harbinger of bony metastases. One study showed that approximately 90% of patients with PCa metastases to bone had an increased serum alkaline phosphatase.26 Prostate Cancer Serum Markers The role of PCa serum markers has changed tremendously in helping clinicians more accurately predict clinical/pathologic stage. These markers include prostatic acid phosphatase (PAP), PSA and its derivatives, and reverse transcriptase–polymerase chain reaction (RT-PCR) for PSA. Prostatic acid phosphatase and PSA are two FDAapproved serum tumor markers for PCa. The former was discovered to be a component of human ejaculate and has been found in high concentrations in patients with bony metastases from PCa. Elevations in PAP and the response of PAP to castration therapy were first documented in

metastatic PCa patients more than 50 years ago.18 However, early enthusiasm for PAP as a screening test for PCa waned when several studies concluded that men with organ-confined cancer often had normal PAP levels.27 Stamey et al. demonstrated that PAP does not correlate with PCa stage as well as does total serum PSA.28 Similarly, another study showed that only 21 of 460 men (4.6%) with PCa had an elevated PAP.29 Clearly, several limitations preclude PAP from being a valuable screening or clinical staging technique for PCa. These limitations include a relative insensitivity for distinguishing periprostatic invasion from disseminated disease, a substantial variation in PAP levels over time, lack of specificity for PCa, and an inability to distinguish soft tissue (i.e., lymph node) involvement from metastatic disease.19,21 Since a negative serum PAP is diagnostically trivial and an elevated PAP provides negligible information beyond serum PSA and clinical staging, potential application of serum PAP is outdated. Most clinicians, therefore, consider serum PAP to have no practical role in clinically evaluating newly diagnosed PCa.18 Although controversial, some clinicians use the enzymatic acid phosphatase instead of the radioimmunoassay for PAP to stage patients with PCa. Chybowski et al. showed that 90% of patients with an elevation in enzymatic acid phosphatase who had a negative bone scan at the time of diagnosis will have metastatic PCa within two years.30 Therefore, some clinicians still obtain a serum enzymatic acid phosphatase to evaluate patients with clinically localized PCa. If elevated, radical prostatectomy is not recommended. This last waning indication for PAP has been disputed by a recent study by Brawn et al. showing enzymatic PAP to be unreliable for predicting metastatic disease.31 Total serum PSA is prostate-gland specific but not PCa specific.22,32,33 It was first isolated from seminal plasma in 1971 by Hara et al., and 8 years later this protease was isolated from the prostate by Wang et al. who demonstrated its specificity to prostate tissue.34,35 It is a chymotrypsin-like serine protease that functions to hydrolyze the coagulum of the ejaculate, thus enhancing sperm mobility. Stamey et al. calculated the half-life of PSA to be 2.2 days,28 while Oesterling et al. calculated it to be 3.2 days.36 Total PSA is the sum of all immunologically detectable forms of serum PSA, which includes the free (unbound) form, plus the predominant complexed (bound) form. Serum PSA, coupled with DRE and TRUS-guided prostate needle biopsy, has revolutionized the detection of PCa as well as monitoring the response to treatment of patients with PCa. One of the earliest PSA studies screened 1653 asymptomatic healthy men over the age of 50 years and found 92% to have PSA < 4.0 ng per mL. Six percent of the men had values ranging from 4 to 9.9 ng per mL; 22% of these men proved to have cancer. Only 2% of the

Staging of Prostate Cancer / 163

total patient population had PSA levels > 10.0 ng per mL but the cancer detection rate among them was 67%.37 The conventional ranges of PSA levels optimizing detection of PCa while minimizing the false-positive rate are < 4.0 ng per mL for low probability of PCa, 4 to 10 ng per mL for intermediate, and > 10 ng per mL for high probability. Oesterling summarized several large studies showing a statistically significant difference in detection in these three ranges with organ-confined disease versus BPH38 (Table 18–2). Seventy-five percent of the patients with BPH had a PSA < 4 ng per mL while 57% of the patients with PSA > 4 ng per mL had organ-confined PCa. The level of serum PSA has also been shown to be predictive of metastatic PCa. Only 3 of 561 patients with PCa and a PSA < 10 ng per mL had an abnormal bone scan.39 The sensitivity of a preoperative serum PSA > 10 ng per mL in predicting ECE, seminal vesicle invasion, and nodal metastases has been found to be 20%, 61%, and 71%, respectively.36 Lange et al. determined the PPV of a PSA > 10 ng per mL to be 78% for ECE and the NPV to be 61%.40 Myrtle et al. found that serum PSA levels were elevated (> 4.0 ng per mL) in 81% of the patients they studied with PCa; moreover, the percentage of patients with a PSA value above the reference range increased progressively with advancing stage.41 In 1987, Stamey et al. found that the PSA level was elevated in all of the 115 patients they studied with advanced disease and that the elevation was proportional to the estimated volume of tumor.28 While extremely sensitive as a diagnostic screening tool and mechanism for identifying metastatic disease, the ability of serum PSA at levels < 20 ng per mL to discriminate localized versus locally extensive cancer and, therefore, to serve as a sole predictive staging modality, is limited. Specifically, Oesterling et al. showed that, while a strong correlation exists between increasing PSA levels and ECE of cancer, the sensitivity and specificity of this test across broad ranges of cutoff values (4 to 16 ng per mL) were inadequate to justify its use as sole predictor of locally advanced cancer.36 Lange et al. likewise concluded that PSA alone was not a sufficiently reliable tumor marker in staging PCa because of its poor predictive value.40 In 1994, Partin’s staging guidelines showed that a majority of men (70 to 80%) with a PSA < 4.0 ng per mL had pathologically organ-confined disease and that 50% with a PSA of > 10 ng per mL had ECE.42 Therefore, while the trend is clearly toward an increased risk of residual cancer after surgical treatment with higher levels of PSA, the relatively poor sensitivity and predictive value and the fact that almost one-quarter of the patients with positive surgical margins had a PSA level < 10 ng per mL suggest that PSA by itself cannot be used to define clinical stage or predict poor surgical outcomes.43 The reason for the inability of the serum PSA to predict locally advanced PCa appears to be threefold: (1) the lack of an accurate method of determining tumor volume

prior to surgery; (2) decreasing production of PSA by higher-grade tumors as a function of tumor volume; and (3) the relative contribution of benign conditions (BPH, prostatitis) in generating a leaky PSA syndrome, versus cancer-to-serum PSA level which renders the test unreliable in predicting clinical stage.44,45 To improve the predictive value of the serum PSA and enable better differentiation between BPH and PCa in patients with elevated PSA, several authors have studied PSA derivatives such as prostate-specific antigen density (PSAD), PSA velocity (PSAV), free versus complexed PSA, and age-specific PSA. Since PSA elevations from 4 to 10.0 ng per mL can be due to BPH in many men, Benson et al. suggested adjusting PSA for ultrasound-based prostate size by calculating PSAD, which represents the quotient of PSA and prostate volume.46,47 The focus on PSAD assumes that cancer results in a greater increase in serum PSA than does hyperplasia. It has been proposed that a PSAD of 0.15 or greater be the threshold for recommending prostate biopsies in men with PSA levels between 4 and 10 ng per mL and a normal DRE.48,49 Several studies, however, refute the usefulness of PSAD. Oesterling et al. showed that PSAD does not provide any additional clinical information over PSA when using age-specific reference ranges.50 Also, Catalona et al. found that in men with PSA levels between 4 and 10 ng per mL and a normal DRE and TRUS, 50% of cancers would have been missed using a PSAD of > 0.15 as a guide for biopsy.51 In a recent study, Presti et al. concluded that PSAD should not be used to determine the need for biopsy in men with normal DRE and/or TRUS due to the large number of missed clinically significant prostate cancers.52 Similarly, Lee and Oesterling concluded that “there is no significant role for PSAD in early detection of prostate cancer.”53 Prostate-specific antigen density seems to be an imperfect predictor of cancer primarily due to its poor reproducibility of volume determinations using TRUS and variations in normal prostate sizes. Prostate-specific antigen velocity, defined as the change in PSA over time, is another method developed to improve differentiation between benign and malignant prostate disease. Since PSA rises with increases in BPH and cancer volume, and it is assumed that welldifferentiated cancers produce more PSA than lessdifferentiated cancers, interpreting a single PSA value becomes difficult. Therefore, PSAV is the use of serial PSA levels to evaluate a patient, thus avoiding the interrelated variables of PSA concentration, BPH volume, cancer volume, and cancer differentiation.45 Carter et al. studied men with PCa, BPH, and normal prostates from the Baltimore Longitudinal Study of Aging. They found a significant difference in the ageadjusted rate of change in PSA among these groups, with PCa patients having the highest rate of change, followed

164 / Advanced Therapy of Prostate Disease TABLE 18–2. PSA Values for BPH versus Organ-Confined Prostate Cancer Percentage of Patients with PSA Values in Specified Range (No./Total) Number of Patients

0.0–4.0 ng/mL*

> 10.1 ng/mL*

Reference

BPH

Partin et al.45 Lange et al.40 Hudson et al.166

72 357 168

185 31 103

47 (34/72) 79 (282/357) 79 (133/168)

45 (83/185) 45 (14/31) 38 (39/103)

46 (33/72) 18 (64/357) 19 (32/168)

44 (82/185) 32 (10/32) 26 (27/103)

7 (5/72) 3 (11/357) 2 (3/168)

11 (20/185) 23 (7/31) 36 (37/103)

Totals

597

319

75 (449/597)

43 (136/319)

22 (129/597)

37 (119/319)

3 (19/597)

20 (64/319)

p value

BPH

Organ-Confined PCa

4.1–10.0 ng/mL*

Organ-Confined PCa

p < .0001

BPH

Organ-Confined PCa

BPH

Organ-Confined PCa

p < .0001

p < .0001

*Tandem-R PSA assay. Reproduced with permission from Oesterling JE. Prostate-specific antigen: a critical assessment of the most useful tumor marker for adenocarcinoma of the prostate. J Urol 1991;145:907–10.

by BPH and control patients, respectively. They determined that a PSAV greater than 0.75 ng per mL per year identified prostate cancer patients, with a sensitivity of 72% and a specificity of 90%.54 However, Smith and Catalona showed a cancer detection rate of only 47% among men with PSAV > 0.75 while Oesterling et al. found tremendous variation in PSAV across all age ranges.55,56 In two separate studies, the minimal length of follow-up time to calculate PSAV has been determined to be 18 months.55,57 Further, an average rate of change in PSA between three repeated PSA measurements has been shown to optimize the accuracy of PSAV in helping detect PCa.54,58 Although not widely accepted, PSAV can be a helpful adjunct to PCa detection. Recently, the discovery that PSA exists in bound and unbound forms sparked another test to help in the diagnosis of PCa. The PSA primarily exists in a complexed form, bound to either α1-chymotrypsin (ACT) or α2macroglobulin (AMG). However, current immunoassays can detect only the free PSA and PSA-ACT. The AMG covers the epitopes of the free PSA which are needed for detection. It has been shown that men with PCa have an increased level of serum PSA complexed to ACT than they do of free PSA. Conversely, more free PSA exists in men with BPH than with PCa.59 In one of the earliest reports, Lilja et al. found a median of 18% free PSA in PCa and 28% in BPH.60 Stenman et al. reported 40% free PSA in cancer patients versus 60% in BPH patients.61 Several studies have found that a free/total PSA cutoff ranging from 18 to 23% improved the ability to distinguish between cancer and noncancer patients with intermediate total PSA levels (4.0 to 10.0 ng per mL).59,62 Currently, the role of free and complexed forms of PSA remains undefined but has the potential to categorize men with intermediate levels of PSA into high-risk and low-risk groups for prostatic carcinoma. The normal aging prostate undergoes hyperplasia, resulting in increased prostate size and PSA production. It has been shown that 1 g of BPH gives rise to 0.2 ng per mL of PSA in serum.28 Accounting for this size increase with age, Oesterling et al. adjusted the serum PSA reference ranges, hoping to increase detection of cancer in younger

patients most likely to benefit from treatment and to minimize unnecessary evaluation in older patients who may be less likely to benefit.63 They established the following normal, age-specific PSA references ranges: age 40 to 50, 0 to 2.5 ng per mL; age 50 to 60, 0 to 3.5 ng per mL; age 60 to 70, 0 to 4.5 ng per mL; age 70 to 80, 0 to 6.5 ng per mL.63 Other studies have shown that the age adjustment of PSA provided no advantage in cancer detection over the traditional PSA cutoff of 4.0 ng per mL, primarily due to an increased risk of missing tumors in older men by increasing the PSA threshold.64–66 Current data suggest that a cutoff of 4.0 ng per mL is an effective threshold to maximize PCa detection and minimize undue biopsy in men between 50 and 70 years of age. The optimal PSA cutoff is not known. However, greater suspicion is warranted when evaluating younger patients with levels < 4.0 ng per mL as these patients have the most to gain from a diagnosis of PCa, especially with accompanying risk factors such as family history or black race. Higher thresholds may be appropriate in older men to avoid costly or unnecessary evaluations which may be unlikely to benefit the elderly patient.20 Currently, even though PSA is the most accurate, important, and clinically useful tumor marker for PCa, it is not without its shortcomings. Prostate-specific antigen assays, therefore, will continue to evolve to better distinguish patients with and without PCa. Further attempts to enhance the predictive value of serum PSA in detecting PCa have centered on the RT-PCR for PSA technique. Many authors have postulated that it may be possible to “molecularly stage” the patient using a technique relying on RT-PCR detection of messenger RNA for PSA in circulating cells. This hypothesizes that these circulating cells represent PCa cells and impending metastatic disease. Katz et al. found RT-PCR PSA analysis to have a sensitivity of 83%, specificity of 76%, and a PPV of 80% in predicting positive surgical margins.67 In this study, RT-PCR PSA was used to assess the presence of capsular penetration and seminal vesicle involvement, along with the demonstrated absence of RT-PCR PSA in women, and in men without PCa. In a later study by Cama et al., the PCR assay for PSA was a stronger predictor of


pathologic stage than a PCR assay for prostate-specific membrane antigen (PSMA), a prostate epithelial transmembrane glycoprotein.68 Thus, RT-PCR PSA appears to be PCa-cell-specific and directly correlates with pathologic stage.20 Unfortunately, about 25% of patients with localized prostate cancer will have a positive RT-PCR, which presents a major limitation to this study, especially when the majority of patients will be low stage at diagnosis. An additional limitation of the test is that this assay can potentially identify both malignant and benign PSAproducing cells and “PSA-like” cells in the circulation.69 Since the ability of these detected systematic cells to establish a metastatic site is not known and long-term followup results are not currently available, the RT-PCR PSA technique should be used with caution, especially in the patient with low-stage disease. Prostate Needle Biopsy The prostate needle biopsy, while not included in traditional clinical staging, can provide important information to help predict the pathologic stage of PCa. Factors such as histologic grade (Gleason score), neovascularity of the tumor, the number of positive biopsies, biopsy core tumor volume, laterality, and percent involvement of the positive lesions reflect the biologic potential and relative aggressiveness of the tumor. Other histopathologic parameters that can be helpful but are inconsistently available include perineural invasion, pericapsular fibroadipose tissue involvement, and bilaterality of the tumor.70 The most commonly used histologic grading system for PCa is the Gleason system.71 Several authors have shown that the presence of a Gleason 4 or 5 grade or a Gleason sum greater than 7 portends a poorer prognosis.72–76 Badalament et al. demonstrated that a Gleason score of 7 or greater had a 58% accuracy in predicting organ-confined disease.77 Partin et al. showed that PSA, Gleason score, and clinical stage could independently predict ECE and that the combination of these elements has the greatest prognostic potential78 (Table 18–3). Gleason grade is also useful in predicting the risk of lymph node metastases. McNeal et al. noted that a high Gleason score in combination with large tumor volume conferred a significantly increased risk of lymph node metastases.79 Stamey and Grossman et al. independently confirmed this observation.80,81 Moreover, Partin et al. determined that the combination of localized disease on DRE, serum PSA ≤ 10 ng per mL, and a Gleason score ≤ 6 reflects a low likelihood of nodal metastases.78 The Gleason scoring system, however, is not without its limitations. These include: (1) the finding that preoperative Gleason score does not always correlate with final pathologic grade after surgery (a phenomenon resulting from limited tumor sampling);82,83 (2) the relatively infrequent occurrence of well-differentiated (Gleason score 2 to 4) and poorly differentiated (Gleason score 8 to 10)

cancers on biopsy specimens (20% in most large series);82,84 (3) the fact that the majority of men with PCa have intermediate Gleason scores (5 to 7), but the correlation between Gleason score and prognosis is accurate mostly on the extreme ends of the scale;82 and (4) the fact that intermediate Gleason scores may have different staging implications depending on the presence and percentage of the Gleason 4 or 5 component.78,79 In an effort to improve accuracy in predicting pathologic stage, Ackerman et al. found that pretreatment PSA level and the number of positive core biopsies correlated well with the risk of positive surgical margins.85 In particular, 15% of the patients in this study with only one positive biopsy each had evidence of positive margins while 47% of men with multiple positive biopsies had residual disease after radical prostatectomy.85 Hammerer et al. calculated the sensitivity and specificity of the number of positive sextant cores and the total linear percent involvement for predicting lymph node metastases.86 In this study, using 280% as the total linear percent involvement cutoff point, the sensitivity, specificity, and accuracy of percent involvement were 66%, 93%, and 87%, respectively. Also, of the patients with fewer than five positive scores, only 5.6% had positive lymph nodes.86 Similarly, Bostwick et al. accurately predicted ECE using percent cancer on biopsy, PSA, and Gleason score.87 Another attempt to improve the predictive value of prostate needle biopsies was performed by Daniels et al., correlating bilaterality of neoplastic disease to subsequent pathologic stage. The study showed that patients with bilateral disease had, on biopsy, an increased risk of margin positive disease (32%) compared to those with only unilateral disease(19%).70 Also, the site of origin appears to be a significant prognostic factor. Cancer arising in the transition zone of the prostate appears to be clinically less aggressive than the more common peripheral zone cancers.88–91 In addition, there are data to suggest that tumor volumes may predict local tumor stage. Villers et al. demonstrated seminal vesicle invasion in 6% of tumors < 4 cc in volume, versus 82% for lesions > 12 cc in volume.92 Similarly, Stamey and McNeal reported that cancer volumes of 4 cc or less are generally associated with a good prognosis whereas tumors of 12 cc or more are surgically incurable.19 Another study showed capsular penetration in only 7% of tumors < 4 cc in volume but in 86% of those tumors > 12 cc in volume.93 In general, capsular penetration is uncommon in tumors < 5 cc while seminal vesicle invasion or lymph node metastases are uncommon in tumors < 4 cc in volume.94 Clearly, tumor volume is a strong indicator of clinical stage and disease outcome. Unfortunately, there are no reliable methods of calculating tumor volume within the prostate gland prior to therapy. Although some investigators have advocated the use of seminal vesicle biopsies to improve preoperative staging of PCa,95–97 others have not found them useful when routinely performed.98 Stone et al. reported that 47.8% of

166 / Advanced Therapy of Prostate Disease TABLE 18–3. Partin Nomogram for Prediction of Final Pathologic Stage* 0.0– 4.0 Clinical Stage

4.1–10 Clinical Stage

10.1–20 Clinical Stage

Greater than 20 Clinical Stage

T1a T1b T1c T2a T2b Tsc T3a




— — 42 — —

100 100 100 100 —

78 79 53 39 32

82 71 59 43 31

83 73 62 51 39

67 56 44 32 22

71 64 48 37 25

— 43 33 26 12

100 100 — — —

— 49 36 24 11

— 55 41 24 —

61 58 44 36 29

52 43 28 19 14

— 37 37 24 15

— 26 19 14 9

— — — — —

— 33 20 7 — — — 24 32 — 3 — — 22 14 11 4 5 — 7 18 4 5 3 — 3 3 1 2 2

Prediction of established capsular penetration 2–4 0 15 22 14 26 17 — 5 0 22 30 20 34 26 — 6 0 30 34 29 46 38 59 7 — 43 40 39 59 50 — 8–10 — — — 50 68 — —

0 0 0 0 —

22 29 45 58 64

29 34 38 44 48

19 28 38 49 59

34 45 56 68 77

27 34 49 59 71

— 58 68 75 87

0 0 — — —

— 49 62 73 87

— 40 45 52 —

40 43 56 64 70

49 58 73 81 86

— 61 59 73 82

— 75 82 86 92

— — — — —

— — — — —

— 97 96 95 97

— — 95 98 98

Prediction of seminal vesicle involvement 2–4 0 1 1 cm are not visualized by TRUS.112 Further, TRUS has demonstrated a 66% sensitivity and 46% specificity in its ability to correctly stage advanced and localized disease, in addition to identifying only 59% of tumors > 5 mm. The overall accuracy of TRUS in detecting extraprostatic PCa is only 58%.113 The ultrasono-

graphic finding suggestive for ECE is a large hypoechoic lesion with an overlying irregularity to the normal continuous hyperechoic boundary surrounding the prostate.114,115 To further confound the examination, several benign processes can also mimic the hypoechoic pattern of PCa, including hyperplastic nodules, cysts, inflammatory lesions, and postbiopsy hematomas. Clearly, TRUS alone is neither reliable nor accurate in the contemporary staging of PCa. It does, however, have significant value as an adjunctive study for evaluating patients with PCa, by guiding systematic sextant biopsies toward hypoechoic regions and directing accurate seminal vesicle biopsies.19 Radiography Bone radiography can also be a useful adjunct in clinically staging PCa, primarily in evaluating or confirming suspicious lesions found on bone scintigraphy. Plain radiographs are also useful in identifying osteoblastic (75% incidence) or mixed osteoblastic/osteolytic (15% incidence) lesions, which typify disseminated prostate metastases.21 The most common sites of prostatic bony metastases are the spine, followed by the femur, pelvis, rib cage, skull, and humerus. Computed Tomography The clinical utility of CT in PCa staging has generally been disappointing, with sensitivities ranging from 27% to 75% and specificities ranging from 66% to 100%.116–118 Although rarely seen, findings on CT suggestive of invasive disease include unilateral levator ani enlargement, rectal wall thickening, and loss of tissue fat planes between the prostate and seminal vesicle or bladder wall. Many of these findings will be noted on a properly performed DRE. One drawback of CT is its inability to distinguish between cancer and benign abnormalities of the prostate, and to demonstrate microscopic extracapsular involvement. Further, it can detect lymph node enlargement but cannot determine the cause of nodal enlargement (e.g., inflammation versus tumor). In clinical studies, the sensitivity of CT scanning for detecting pelvic lymphadenopathy varies from 25 to 93%119 (Figure 18–1). Because of this, Levran et al. concluded that given the current low incidence (3.7%) of positive nodes in a patient with a serum PSA ≤ 20 ng per mL and the resolution limits of the CT scan, this study is not indicated in the preoperative staging of these low-risk patients.120 Lee and Oesterling similarly do not recommend CT as a routine modality for staging newly diagnosed PCa in patients with PSA levels of 20 ng per mL or under.53 This very low risk of positive nodes along with the risk of a false-positive CT scan makes this test potentially more harmful than helpful as a staging test in a group of patients with newly diagnosed PCa.


Bone Scintigraphy Advanced PCa favors the axial skeleton for metastases; therefore, excluding bony involvement is essential in selecting appropriate treatment. The bone scintigram (radionuclide bone scan) is an extremely sensitive method to detect PCa metastases (0 to 8% false-negative rate),121 superior to bone radiographs, serum alkaline phosphatase level, and clinical evaluation122–124 (Figure 18–2). Of those men with negative bone radiographs, at least 25% will have skeletal metastases on bone scan.125 Unfortunately, the bone scan is so sensitive that it tends to have a high false-positive rate, detecting not only metastatic disease but also inflammatory lesions, Paget’s disease, healing fractures, degenerative bone disease, arthritis, and bony infections.21,124,126 In the past, the standard evaluation for a newly diagnosed PCa patient included a bone scan. It remains the gold standard for skeletal metastases detection since its development in 1963; recent data, however, call into question its routine use as a staging modality. For instance, Oesterling found that for patients with newly diagnosed PCa and a PSA ≤ 10 ng per mL, bone scans added little to pretreatment tumor staging.127 Further, Chybowski et al. showed that a PSA of < 20 ng per mL had a 99.7% NPV for finding metastatic lesions on the bone scan.30 The authors concluded that bone scans are unnecessary in staging untreated PCa patients who have no skeletal symptoms and a PSA value ≤ 10 ng per mL.30 Similarly, Vijayakumar et al. and Gleave et al. showed a 100% NPV for positive bone scans in patients with a PSA level ≤ 10 ng per mL and recommended ceasing bone scans for these patients.128,129 Although occasional exceptions to this rule will be seen, these studies suggest that PCa disseminated to bone may be accurately excluded in patients without bone pain and low PSA without incurring the added cost of bone scintigraphy. The role of bone scans in patients with known metastatic disease has also been studied with regard to the num-

FIGURE 18–1. Pelvic CT in a patient with stage T3 cancer of the prostate showing right-sided prostate cancer impinging on the bladder base (arrow).

ber and location of osseous metastases. Studies have shown that bone scintigraphy can provide prognostic information as well as predict the duration of response to hormonal ablative therapy. For instance, patients with metastases limited to the pelvis and lumbar spine, with few metastatic foci on bone scan, demonstrate a significantly better response to hormonal therapy and have a longer mean survival than patients with more extensive disease at presentation.130 These studies support the utility of bone scans in patients with metastatic disease found on presentation for staging and predicting response to therapy and overall survival. Although there are no absolute data on bone scan imaging in the patient with recurrent PCa following definitive therapy, Lee and Oesterling suggest that bone scans are unnecessary in postprostatectomy patients with a PSA level < 2.0 ng per mL.131 While bone scintigraphy is the most sensitive method of detecting bony involvement with PCa, current data suggest that it should be reserved for newly diagnosed PCa patients with symptomatic bone pain, a PSA level > 10 ng per mL, or evidence of local or distant metastases. If the bone scan is positive, especially in a weight-bearing location, or the patient has bone pain with a negative scan, plain radiographs of the area of interest are often indicated. If the plain films are equivocal or negative in the face of high clinical suspicion, an MRI of the area can help localize metastatic disease. Oesterling studied the economic implications of eliminating bone scans according to the above criteria and calculated a potential savings of $38 million annually.127 Magnetic Resonance Imaging Magnetic resonance imaging is an expensive imaging technique that produces images in all three planes without using ionizing radiation. Although it is not possible to discern the internal architecture of the prostate on T1-weighted images, PCa often appears as a high-intensity signal (Figure 18–3). The zonal anatomy of the prostate can be demonstrated on T2-weighted images.132 Prostate cancer appears as a low-intensity signal on T2-weighted images, contrasting sharply with the usual high intensity of the peripheral zone.133 Other abnormalities, however, such as adenoma, prostatitis, and corpora amylacea also produce low-intensity signals, making MRI not very accurate at identifying localized PCa. Unfortunately, MRI has proven to have an overall staging accuracy approximately equal to that of TRUS in local staging of PCa.132 Rifkin et al. compared body MRI to TRUS in staging of patients with early PCa and found that MRI correctly staged 77% of those with advanced disease and only 57% with localized disease, for an overall staging accuracy of 69%.113 It was able to identify only 60% of all malignant tumors measuring more than 5 mm on pathologic analysis.113 In an attempt to improve accuracy, a balloonmounted endorectal coil was developed to enhance imag-


ing details of the MRI scan for the prostate and periprostatic tissue. Tempany et al. performed MRI scans in patients using three different imaging techniques and compared the results of conventional body coil, body coil with fat suppression, and endorectal coil.134 The overall accuracy was 61%, 64%, and 54%, respectively, and the authors concluded that none of these techniques was sufficiently accurate for staging early PCa. Similarly, Perrotti et al. advised against the routine use of endorectal coil MRI to stage localized PCa.135 Further, contrast/gadolinium-enhanced MRI images did not improve overall staging accuracy for localized PCa.136,137 Some centers, though, are using MRI in patients with known PCa to confirm bony metastases on a routine basis. At the current time, due to the inaccuracy and high cost of the MRI, there is little justification for its use in the preoperative staging of PCa. Radioimmunoimaging The development of hybridoma technology in 1975 was an important breakthrough in monoclonal antibody (MoAb) technology, which revolutionized the field of immunoassays and in vitro diagnostics such as PSA testing.138 Radioimmunoimaging has contributed greatly to diagnosing and staging of both ovarian and colorectal carcinoma;139 the promise of MoAbs in the area of in vivo imaging for PCa, however, is just now being realized. Anatomic imaging modalities (CT, MRI, TRUS) are variously deficient in tumor detection, as stated earlier. Most of these modalities are organ-specific and may fail to recognize distant disease; radioimmunoimaging, however, localizes tumors using tumor-specific radiolabelled MoAbs. Consequently, functional imaging by radioimmunoscintigraphy can differentiate tumor recurrence from postoperative changes and can detect cancer in normal-sized lymph nodes. It can also evaluate the entire body in one session, thus allowing detection of distant metastases and local recurrences.139 Despite these advantages, immunoscintigraphy, as any imaging modality, does have its limitations. For instance, monoclonal scans are hampered by less spatial detail, making it less likely to detect ECE. While monoclonal antibodies have been found to be highly immunogenic, suggesting they cannot be used repeatedly,140 a recent study by Williams et al. concluded that the indium-111-labelled MoAb could be repeatedly administered without significant side effects.141 Previous antibody studies using radiolabelled antiPAP and antiPSA monoclonal antibodies have shown sites of metastases.142,143 These antigens are suboptimal, however, because elevated levels of antigens cross react with the antibody, reducing its availability to the target cells of interest. Also, these antigens have a propensity to be rapidly removed from the blood and subsequent sequestering by the liver.144,145 The most commonly used radiolabelled MoAb today is the indium-111 CYT-356 (ProstaScint, Cytogen

Corporation, Princeton, NJ) described by Horoszewicz et al., which is a murine immunoglobulin G monoclonal antibody to a glycoprotein localized on the cell membrane of benign and malignant prostate epithelium.145 This antibody is commercially available. Many recent preliminary studies using this MoAb have shown it to be superior to conventional imaging studies in detecting overt PCa metastases and recurrent PCa in post-therapy patients with rising PSA levels142,144–149 (Figures 18–4 and 18–5). Babaian et al., for instance, found indium-111 CYT-356 imaging to have a sensitivity of 44%, specificity of 86%, a PPV of 50%, and an NPV of 83%.150 Another study, by

FIGURE 18–2. Bone scan of a patient with stage T4 cancer of the prostate showing diffuse metastatic disease throughout the pelvic girdle and lumbar spine (arrow).


Positron Emission Tomography While many techniques use noninvasive cross-sectional imaging to detect oncologic processes, only PET uses noninvasive in vivo biochemical and/or physiologic reac-

tions to detect cancer (Figure 18–6). Although PET has been in existence since the 1960s, it has experienced a prolonged period in gaining clinical acceptance.153 The procedure was first used to detect recurrent brain tumors. Its use in urology is just now being recognized. The basis of PET technology is the radiotracer, which is a positron emitting analogue of glucose that provides a means of measuring in vivo biochemical functions. The most commonly used PET tracer is the glucose analogue 18-fluoro-2-deoxyglucose (FDG). Following intravenous injection, FDG accumulates in tissue with a high rate of glycolysis (i.e., malignant neoplasms). The radiotracer emits a positron which collides with a negatively charged electron to form photons, which are then detected by photon detectors. This procedure has been shown to detect tumors of the thyroid, breast, lung, colon, and ovaries.154 Also, PET scans have shown alterations in tumor metabolism prior to any changes shown on CT or MRI, and can identify metastases in the presence of other normal imaging studies.155–157 The amount of radiation the patient receives from an FDG PET scan is roughly equal to that of CT.158 The value of PET scanning in PCa is still under investigation. Several studies have demonstrated difficulty in imaging prostate lesions secondary to the intense adjacent bladder activity and the high uptake of FDG in BPH.159–161 Laubenbacher et al. and Effert et al. both concluded that there was no significant difference in the activity of FDG uptake between PCa and BPH.159,161 Shreve et al. confirmed that the uptake of FDG in PCa is low, which may reflect the characteristics of a slow-growing tumor.160 The study concluded that “FDG PET can help identify osseous and soft tissue metastasis of prostate cancer with a high positive predictive value (98%) but is much less sensitive (65%) than bone scintigram in the identification of osseous metabolism.”160 One study reported a sensitivity of only 20% for osseous metastases.162

FIGURE 18–4. ProstaScint scan showing metastatic right iliac node disease in a patient with stage D prostate cancer (arrows).

FIGURE 18–5. ProstaScint scan showing recurrence of prostate cancer in the prostatic bed of a patient who has undergone radical prostatectomy (arrow).

FIGURE 18–3. Prostatic carcinoma. A T1-weighted MRI scan showing an area of increased signal posterolaterally on the right lobe.

Sodee et al., showed residual or metastatic disease in 14 of 15 patients with rising PSA levels after radical prostatectomy.149 In addition, multicenter studies with this MoAb revealed that the smallest foci of tumor visualized are 3 to 5 mm in size, which is far below that of other imaging modalities.151,152 The ProstaScint scan has received FDA approval and will most likely be used in patients with newly diagnosed PCa who are deemed to be at high risk for having lymph node involvement and in those patients who have an elevated PSA level following radical prostatectomy.140 With further refinements, it may be used to define the local extent of the primary tumor and may prove to be an adjunct in the clinical evaluation of patients before radical therapy.


FIGURE 18–6. A PET scan showing metastatic prostatic carcinoma in the periaortic, retrocrural, and pulmonary regions.

There may be a more feasible application for PET scanning in the detection of lymph node metastases to the pelvis and retroperitoneum, where bladder activity is less of a problem. Investigations are currently underway examining the use of PET in patients with PSA relapse after primary local therapy. Preliminary results show that in patients with a high PSA level (> 4.0 ng per mL) or a high PSA velocity (greater than 1.3 at 6 months), PET may be more sensitive than CT for detecting lymph node metastases.154 Additional studies have shown that a decrease in FDG uptake following therapy is an early predictor of chemo- or radiosensitivity.163–165 This ability to evaluate treatment efficacy and determine the presence, extent, and metabolic activity of metastatic disease may be important in clinical management decisions when considering early versus late hormonal or experimental therapy. Although intense FDG uptake can be interpreted as highly suspicious for tumor, lesions with mild uptake are equivocal. Therefore, in addition to the high cost of a scanner, poor resolution of images, and the need of a cyclotron to generate positron emitting tracers, PET scans have only a complementary role with other imaging modalities in contemporary staging of PCa. Lymphangiography Historically, pedal lymphangiography was a popular technique for evaluating the status of pelvic lymph nodes. By examining the internal architecture of lymph nodes, images can be produced that cannot be duplicated by other techniques. However, the technique is invasive, uncomfortable, time-consuming, and carries the risk of pulmonary embolism due to the lipid-based contrast medium. Fur-

ther, metastases must be at least 5 mm in diameter to be detectable by this technique. Although good images can be obtained of the common iliac, external iliac, and paraaortic nodes, the images of the hypogastric and obturator nodes, which become involved earliest in PCa, are not as clear. In a study of 40 patients with PCa, lymphangiography has produced a false-positive rate of 59% and a false negative rate of 36%.130 Today, with the advent of newer imaging modalities, lymphangiography has become essentially obsolete and most clinicians consider this technique to be of little value in staging PCa.

Conclusion There has been little impact on the natural history of PCa in the past, despite aggressive intervention. This has likely been due to the inability to select and treat patients most likely to benefit from aggressive treatment. Through continued research efforts, however, new data have been reported that have influenced the approach to PCa. As these data accumulate, the group of patients thought to benefit from aggressive intervention will most likely be redefined. Until then, PSA determination, TRUS-guided biopsies, and assessment of tumor grade, along with appropriate imaging studies, will continue to be the mainstay of PCa staging.

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CHAPTER 19

RADICAL PROSTATECTOMY: PATIENT PREPARATION PAUL K. PIETROW, MD; JOSEPH A. SMITH JR, MD Patient Education

Successful treatment of localized carcinoma of the prostate is dependent upon appropriate patient selection and proper preparation. This not only influences ultimate treatment results but can have an impact on treatment and disease-related morbidity. Issues of patient preparation and perioperative management are often based more on custom and anecdotal experience than on solid, evidence-driven decision making. Nevertheless, growing data increasingly support various measures designed to produce the best outcome. This enabled construction of pathways for patient management that begin with patient preparation and can be carried through to discharge.

Patient preparation for treatment of prostate cancer often begins well before the doctor-patient relationship is established. Many patients present to a physician’s office with preconceived expectations developed from contact with friends, relatives, co-workers, literature, and, increasingly, the Internet. Therefore, by the time a diagnosis of prostate carcinoma is established, the patient may know a great deal about the various treatment options. Assuming that the patient has elected to undergo radical prostatectomy, it is important to help teach the patient what to expect in the various stages of his therapy. Each urologic surgeon should explain the basic course of the patient’s trip to the operating room and of the typical steps in his recovery. In the authors’ practice, every patient is seen by the Department of Anesthesia in the preoperative evaluation clinic, where a history and physical examination is performed to determine any increased anesthetic risks. There is no consensus in the anesthesia literature on the necessity of preoperative laboratory tests. For patients with no additional risk factors, however, a basic chemistry panel, including electrolytes and a complete blood count, are sufficient. Coagulation studies such as prothrombin time (PT) or partial thromboplastin time (PTT) are not required in the absence of an identified bleeding tendency. Chest radiographs are not ordered unless indicated by the patient’s medical history since only 0.1% of routine studies reveal an abnormality requiring a change in preoperative planning.5 Electrocardiograms are performed for all patients over the age of 50 years. Specific anesthetic risks should be explained to the patient at this point. At the authors’ clinic, patients are also instructed to discontinue all anticoagulants (aspirin, nonsteroidal antiinflammatory drugs, warfarin) for 7 days prior to operation. With the exception of diabetes medications, patients are instructed to continue all other routine morning medications on the day of their procedure, including antihypertensives. The nurse manager of the authors’ clinic also meets with each patient to arrange a scheduled date for the operation. This allows the nurse manager to reinforce important preparatory points brought up by the surgeon and anesthesiologist. In addition, each patient is given a

Selection of Therapy To achieve the greatest chance of therapeutic success, an appropriate course of action must be selected for each patient. The best treatment for localized prostate cancer is controversial and frequently debated in the medical literature. In addition, patients often form their own opinions based on information from multiple sources. The responsibility of the physician is to help guide the patient to a realistic plan by adequately assessing and synthesizing several factors, including tumor stage/grade, patient age and comorbidities, and patient preferences and expectations. The natural history of localized prostate cancer has led most clinicians to apply aggressive therapy to patients whose life expectancy is at least 10 to 15 years.1–3 The overall assessment of the patient and his coexisting medical condition is inherently subjective, based on physical examination, medical and family history, and clinical judgment. The authors assessed the accuracy of physician judgment of patient longevity by submitting the medical records of 261 consecutive radical prostatectomy patients to the actuarial division of a major life insurance company.4 By the insurance actuary’s projection, at least 80% of the patients had a life expectancy of greater than 10 years. Of note, 26 men were recognized preoperatively as having a projected life expectancy of under 10 years but underwent radical prostatectomy at their own insistence. It appears that even when compared to insurance actuaries, physicians select appropriate patients for treatment of localized prostate carcinoma in a highly practiced, if less structured, clinical manner. 177


printed instruction sheet describing preoperative diet restrictions (clear liquids the day before surgery with nothing by mouth after midnight), advice on what to bring to the hospital, and directions to the admitting office. The authors have not used a more extensive bowel preparation as the incidence of rectal injury is substantially less than 1%. This same pamphlet describes a typical postoperative course, including anticipated length of stay, dietary management, pain control, and the expected intravenous lines, drain, and Foley catheter. Discharge instructions are outlined as well as follow-up visit plans. In short, great efforts are taken to inform the patient of a typical hospital course and to help remove much of their anxiety about what will transpire. There is a great deal of overlap incorporated into this system as patients frequently have difficulty processing all the information presented at any one encounter.

Collaborative Care Pathways Patient education and preparation are critical in promoting a successful outcome of any surgical intervention. Collaborative care refers to the concept of delivery of care in an environment in which the goals are clearly defined.6 As such, it requires input and participation from all levels of the professional team, including the attending surgeons, operating room nurses, resident physicians, floor nurses, social workers, nurse specialists, and even ancillary staff. The tool of the collaborative care team is the creation of a clinical care pathway to help standardize patient management. The care pathway maps out goals and optimum daily care for the ideal patient (Figure 19–1). Practices considered wasteful or unsubstantiated in the medical literature are replaced by those supported by objective data. It is recognized, of course, that not all aspects of basic patient management have been scrutinized in current medical literature, but great efforts are taken to remove practices based purely on habit or custom. It is important to stress that each pathway is created to represent the course of an ideal patient. Care should be expanded as needed for more complex situations. The pathway should be developed with close supervision by the attending physician. The completed product should contain input of all members of the care team and address all steps of a patient’s stay, including preoperative, intraoperative, and postoperative care. Ideally, each institution, and each surgeon if feasible, should develop a unique pathway. Close observation of each patient while on the pathway is very important as the pathway assumes an ideal course. Deviation from the path is not considered a failure as long as such changes occur in response to an individual patient’s needs and not to a potential worst-case scenario. The impact of the pathway at the authors’ institution has been dramatic.7 While recognizing that nearly half of total patient costs are incurred in the operating room,

efforts were made to remove unnecessary supplies and equipment. Standardized trays and sutures were organized. The greatest savings in overall cost occurred in the operating room and in routine care. Operating room costs diminished as a result of a decrease in surgical supplies and surgical time, which decreased by an average of 52 minutes. Length of hospital stay also dropped to a median of 2.9 days (Figure 19–2). Total hospital costs and charges were reduced by 44% (Figure 19–3) while maintaining a high level of patient satisfaction. Overall, 99% of patients responding to a follow-up questionnaire were generally pleased with their hospital stay.

Bowel Preparation Rectal injury is a potential complication of pelvic surgery and can lead to significant morbidity and even mortality. Wound infection, fascial dehiscence, rectourethral fistula, and the need for a diverting colostomy are all acknowledged sequelae of rectal injury. While the reported incidence of rectal injury has ranged from 1 to 11%, most recent reports place the rate at the lower end of the spectrum.8–11 Several factors have been identified to predict those patients at increased risk for sustaining an injury, including previous transurethral surgery, prior pelvic radiation therapy, and a history of previous rectal surgery. High-stage local disease is another potential predisposing factor although the available data supporting this are inconsistent. In addition, the surgical approach influences injury rates. Radical perineal prostatectomy is associated with a higher incidence of rectal laceration than is retropubic surgery.9 To help prevent the serious sequelae of a rectal injury and reduce the need for diverting colostomy, many surgeons advocate using a preoperative bowel preparation. Mechanical bowel preparation can decrease the obvious soilage of the wound and may increase the success of a primary rectal closure. Indeed, several reports on the management of rectal injuries during radical prostatectomy state that primary closure without fecal diversion should not be attempted unless the patient has undergone some type of bowel preparation.8,10 Many variations on the standard Nichols-Condon preparation have been suggested, and multiple studies in the general surgical literature have searched for the ideal antibiotic regimen.12–16 None of these have proven superiority, however, and the “gold standard” remains a mechanical preparation combined with erythromycin and neomycin base, 1 g each given at 1:00 PM, 2:00 PM, and 11:00 PM the day before surgery. There are, however, drawbacks to bowel preparation. Many patients find a thorough mechanical preparation difficult and sometimes intolerable. Heavy preoperative use of antibiotics can lead to the development of resistant organisms, monilial overgrowth, diarrhea, or Clostridium difficile enterocolitis. The frequency with which rectal

Radical Prostatectomy: Patient Preparation / 179 Preop (Outpatient)

Day of Surgery (OR → Floor)

Postop: Day One (Floor)

Postop: Day Two (Floor → Home)

Postop: Day Three (Floor → Home)

F/U: 14 Days (Clinic)

Bowel sounds present, ± flatus Drain output < 100 cc/d Possible D/C if tolerate diet Remove drain if < 60 cc and D/C planned today

Bowel sounds present, passing flatus Follow up appt. w/MD D/C drain if < 60 cc/24° Discharge home with Foley catheter D/C teaching complete

Pt. to bring Depends undergarment to clinic visit

Goals

Preop testing completed WNL Patient/family teaching completed Consent signed

Bowel sounds present, no flatus Drain output < 150 cc/day UOP >150 cc over 4 hours

Labs

SMA 18 CBC w/plt T&S

Hct

Tests

H&P CXR EKG

Treatments

Consent signed

VS q4° x 24, then q8° I&O q4hr Foley catheter IMED Pump JP drain TED stockings Pulm. toilet: TCDB and IS q1hr WA

Activity

Ad lib

May be OOB tonight

Ambulate in hall TID

Diet

Clear liquid diet for supper, then NPO at 12 MN, night before surgery

NPO No ice chips

Full liquid evening meal

Consults

Anesthesia Case Manager

Equipment & Supplies

Meds/IV

OR supplies Anesthesia supplies IMED/IV tubing JP drain TED stockings Foley/Urine bag PCA pump 2 bisacodyl tabs PO in AM the day before surgery

Preop: Cefazolin IV 1 hr prior to surgery Postop: • IV (D5 1/2 NS with 20 mg KCL at 150 cc/hr • Ketorolac 30 mg IV in recovery, then 15 mg IVq6hr for 36 hr • PCA pain med • Promethazine IV q6hr PM nausea • Tylenol prn T >101° •

Teaching/ D/C Plan

Procedure Plan of care VUMC Orientation

Procedure Postop care Hospital routines

Patient Flow

Complete tests and labs

Admit EMA Usual surgery 1.5–2 hr Average blood loss 550 cc General anesthesia Lower abd. midline incision

D/C Possible D/C drain

D/C drain

Regular diet

Regular diet

Possible D/C drain

D/C drain

Hep-lock IV Dulcolax supp. if pt. hasn’t passed flatus

D/C Hep-lock

Foley remains in for 2 weeks after discharge

D/C IV fluid (decrease rate 100 cc/hr)

D/C D/C PCA Oxycodone and Tylenol pm pain

Begin home care instructions Instruct pt. in use of leg bag Complete home care instructions and give pt. HCI sheet Schedule F/U appt. w/attending MD in 14 d Pt. to bring urine protective (Depends undergarment) to follow-up appt.

FIGURE 19–1. Clinical care pathway for radical prostatectomy. OR = operating room; UOP = urine output; F/U = follow-up; ELOS = estimated length of stay.


While some urologists keep patients on oral antibiotics as long as an indwelling Foley catheter is in place, there does not appear to be a difference in the rate of clinically significant infections compared to those patients not maintained on antibiotics. It has therefore been the authors’ practice to not recommend antibiotics at the time of discharge although an oral antibiotic may be given for 24 to 48 hours following catheter removal. Consecutive Cases

FIGURE 19–2. Radical prostatectomy hospital stay.

injury occurs often does not justify the use of a full, standard bowel preparation. Rectal injury has not occurred in the authors’ series of over 600 consecutive radical retropubic prostatectomies. Therefore, we routinely use a modified preparation consisting of a clear liquid diet the day prior to surgery, bisacodyl (Dulcolax) 10 mg by mouth the morning prior to surgery, and nothing by mouth after midnight. The individual surgeon must use his or her own judgment in deciding which patients require bowel preparation. Factors such as prior rectal/prostatic surgery or previous radiation therapy as well as the surgeon’s own complication rate should influence the decision whether an individual patient requires a bowel preparation.

Antibiotics Radical prostatectomy is considered a “clean contaminated” surgical procedure because of entry into a hollow viscus.17 Wound infection rates can be lowered in this category by the use of preoperative antibiotics, provided they are delivered in such a manner that peak serum levels will be achieved at the time of incision.18 One to two additional postoperative doses may also be given although the data proving the benefit of this are less clear. Extended use of antibiotics has not proven to be of benefit and may promote emergence of resistant organisms. First- or second-generation cephalosporins are frequently used as they provide good gram-positive (skin) coverage as well as activity against some of the gram-negative organisms commonly found in the urinary tract.

Consecutive Cases

FIGURE 19–3. Radical prostatectomy total hospital charges.

Deep Venous Thrombosis Prophylaxis Deep venous thrombosis (DVT) and its potential complications remain the leading cause of major morbidity and mortality following radical prostatectomy. Clinically recognized DVT occurs in 3 to 5% of patients while pulmonary embolism is observed in roughly 1% of cases, with an associated mortality rate of 0.3%.19 There are probably an equal number of unrecognized thromboembolic events. In fact, pulmonary embolism is clinically suspected in only 20 to 30% of those cases where it is the cause of death as determined by autopsy.19 It is equally important to recognize the less drastic sequelae of a DVT such as postphlebitis syndrome, chronic venous insufficiency, or even predisposition to recurrent thromboembolism. The economic consequences are also significant due to factors such as increased length of hospitalization and lost wages. Finally, it is important to realize that most episodes of pulmonary embolism do not occur until after the patient has been discharged.20 There have been multiple studies examining techniques for the prophylaxis of DVT in surgical patients and specifically in prostatectomy patients. Systemic anticoagulation with warfarin has been proposed but has not gained widespread popularity due to concerns about increased intra- and postoperative hemorrhage and increased lymphatic leak and lymphocele formation. Various forms of heparin, particularly unfractionated (UFH) versus low-molecular-weight (LMWH) versions, have been studied and compared. In a recent meta-analysis comparing LMWH to UFH in general surgery patients, both were found to have similar rates of thromboembolic events, with no clear advantage for either form of prophylaxis.21 The only noted statistical difference was a small advantage for LMWH in the incidence of “minor bleeding events” (defined as wound hematomas not requiring evacuation and injection site hematomas). Low-molecular-weight heparin does offer the practical advantage of a more convenient dosing schedule and decreased incidence of thrombocytopenia. The authors evaluated the use of LMWH in radical retropubic prostatectomy patients and have found it to be a safe method of thromboembolic prophylaxis.22 While there was no increase in intraoperative blood loss or postoperative drain output, there was an increased incidence of scrotal and pelvic hematomas. For this reason, the authors

Radical Prostatectomy: Patient Preparation / 181

have now restricted the use of anticoagulants to those patients with a higher risk of thromboembolic events, such as obese patients or those with a previous history of DVT. Pneumatic sequential compression devices (SCD) are often used for DVT prophylaxis, especially among the general surgery and orthopedic patient populations. Several studies have proven their benefit in these settings in lowering the rate of DVT.23,24 The urologic literature has been less persuasive. Strup et al. found that the use of SCDs in their radical prostatectomy patients led to increased intraoperative blood loss, presumably because the SCDs promoted venous return from the lower extremities.25 The authors’ data have failed to confirm an association between SCD use and blood loss with radical prostatectomy.26 Cisek and Walsh examined a large, nonrandomized series of consecutive radical prostatectomy patients and were unable to prove that the rate of DVT decreased with the use of SCDs beyond the immediate perioperative period.20

Blood Management Intraoperative blood loss is a potential source of morbidity for individuals undergoing radical prostatectomy, and the possible necessity of blood transfusion should be discussed with each patient. Due to the potential for transmission of bloodborne diseases, many patients fear the use of homologous blood. With current screening methods, the risk of infection by the human immunodeficiency virus (HIV) is estimated to range from 1 in 450,000 to 1 in 660,000,27 the risk for hepatitis C is 1 in 100,000,28 and the risk of hepatitis B is 1 in 60,00027 (Table 19–1). In addition, hemolytic reactions can result from improperly crossmatched or administered blood at a rate of 1 in 4000. The most common immediate complications are circulatory overload (1 in 100 to 200) and febrile transfusion reaction, occurring in 1 out of every 200 transfusion recipients. To avoid some of these potential problems, many surgeons recommend preoperative banking of autologous blood.29 While the risks of clerical error (the most common cause of transfusion reactions), improper blood storage, and bacterial contamination still exist, banking eliminates the risk of acquiring a new viral infection. Concern has been raised, however, that lowering the hematocrit through preoperative blood donation increases the likelihood that a patient will require a transfusion. Again, the risk of clerical and contamination error still exist, perhaps creating a net increase in risk for the patient. After reviewing expected blood loss and the perception that the majority of patients would not require a transfusion, the authors initiated a prospective study in which autologous blood was not collected prior to radical retropubic prostatectomy. Intraoperative blood loss, length of hospital stay, and, most important, transfusion requirements were analyzed and compared to prestudy practices.30 Only 2.4% of patients required blood trans-

fusion (homologous), compared to the previous transfusion rate of 60% when predonated autologous units were available. The average blood loss was 579 cc while the mean postoperative serum hematocrit was 33% at the time of hospital discharge. With further experience, fewer than 1% of the authors’ patients have required transfusion of any blood products. When combined with the knowledge that homologous transfusion currently has a very low rate of viral transmission, the authors no longer recommend preoperative autologous blood donation prior to radical prostatectomy. The Cell-Saver suction can capture red cells lost during the course of the operation for later return to the patient. Concerns about the return of malignant cells dislodged during manipulation of the prostate seem to be obviated by the use of proper filters to capture all cells larger than an erythrocyte. While this device is used frequently in cardiac and orthopedic surgery, it is probably not necessary when dealing with the volume of blood loss encountered by most urologic surgeons during a typical prostatectomy. This is especially true in the more recent era of anatomic dissections and greater understanding of the periprostatic and deep dorsal vein complexes. In addition to the expense of the equipment, the cost of the trained technician required to operate the devices makes routine use of it prohibitive. Exogenous erythropoietin is available for use to aid in stimulating bone marrow to produce red blood cells. There is a small risk of allergic reaction associated with its use. Experience with the use of erythropoietin for radical prostatectomy is limited. However, several weeks of administration can increase serum hematocrit by several percentage points and decrease transfusion requirements in some groups.

Anesthesia The method of anesthesia used for radical retropubic prostatectomy is mostly a matter of surgeon, anesthesiologist, and patient preference. There is no conclusive eviTABLE 19–1. Frequency of Adverse Events of Red Blood Cell Transfusion Adverse Event

Estimated Frequency per Unit of Blood

Death 2° hemolytic reaction Febrile transfusion reaction Allergic transfusion reactions Acute anaphylaxis Acute hemolysis Transfusion-induced immunosuppression Bacterial contamination Cytomegalovirus Hepatitis B virus Hepatitis C virus Human immunodeficiency virus

1:633,000 1:200 1:333 1:20,000–50,000 1:4000 Unknown 1:1,000,000 3–12 per 100 1:60,000 1:100,000 1:450,000–660,000

Adapted from Simon TL, Alverson DC, AuBuchon J, et al. Practice parameter for the use of red blood cell transfusions. Arch Pathol Lab Med 1998;122:130–8.


dence for the superiority of one method over another for this particular procedure. While some studies suggest that the use of epidural anesthesia can reduce intraoperative blood loss via vasodilatation of the lower body vasculature, others have failed to confirm this finding.31 The authors prefer general anesthesia as no adverse effect on blood loss or other parameters has been observed. The selection of patients with at least a 10- to 15-year life expectancy for radical prostatectomy inherently produces healthier individuals than those undergoing various other oncologic operations. In addition, improved understanding of the local venous systems and refinement of anatomic dissection of the prostate have helped dampen the massive fluid shifts associated with radical prostatectomy in the past. The need for invasive monitoring therefore seems to be diminished. In addition, the use of invasive vascular catheters is associated with potential morbidity. Arterial catheters can cause infection, thrombosis, or even nerve injury during placement. Central venous catheter insertion can lead to pneumothorax, hemothorax, arterial injury, infection, or hematoma formation. With this in mind, the authors discontinued using invasive lines for patients as part of the collaborative pathway. In subsequent evaluations of the hospital course of 247 consecutive patients, the authors have found that none of these patients required intraoperative placement of an invasive line. 32 In addition, none of these patients suffered an adverse event that would have been more appropriately treated if a line had been in place at the time of the event. It can therefore be concluded that invasive monitoring is not necessary during radical prostatectomy.

Pain Management Many options are available for postoperative pain control, including intermittent narcotics, patient-controlled devices (PCA), epidural catheters, and adjuvant agents (e.g., ketorolac). Multiple studies have proven the effectiveness of epidural anesthesia or patient-controlled narcotics in surgical patients. Some studies have shown a more rapid resolution of postoperative ileus and improved gastric emptying when epidural catheters are used. In addition, other authors have shown improved patient comfort with epidural narcotics compared to parenteral narcotics.33 Shir et al. recently looked at the use of epidural catheters versus general anesthesia in radical prostatectomy patients for delivering intraoperative anesthesia and postoperative analgesia.34 Patients were randomized to either method. No differences were noted in complication rates, return of bowel function, or length of hospitalization. Nonsteroidal anti-inflammatory drugs (NSAIDs), in particular ketorolac, are being used increasingly for perioperative pain relief and have proven to be safe and effective in radical prostatectomy patients.35 Data suggest a role

for these and other drugs administered preoperatively to achieve preemptive effects.36,37 The need for narcotics can be decreased if NSAIDs are used, thereby reducing side effects such as ileus.35 This has enabled earlier resumption of oral feeding and more rapid discharge from hospital. The authors currently recommend a 30-mg intravenous dose of ketorolac administered 30 minutes before surgical incision. Postoperative doses of 15 mg are repeated every 6 hours for 36 hours, at which time the patient is converted from a morphine PCA to long-acting oral narcotics. It is very important to adhere to strict dosing regimens and avoid prolonged use of this medication.38 Older patients, or those with underlying renal insufficiency (atypical prostatectomy candidates), are at increased risk of suffering adverse consequences from the use of this medication. Increased risks of gastrointestinal and operative site hemorrhage from inappropriate use of ketorolac are well documented.

Discharge Planning Effective discharge planning begins before the patient enters the hospital. There should be a system for followup developed, and the patient should be instructed on how to access this system. Specific, detailed home-care instructions should be established and provided to the patient in verbal and written form. Instructing patients in the care of their Foley and legbag has become a routine part of postoperative care for surgical floor nurses. In addition, warning signs and symptoms of potential complications such as wound infection, DVT, and pulmonary embolism are reviewed. The nurse practitioner working at the authors’ clinic visits each patient and reviews much of the same information. Home health care nurses can be arranged if necessary. The nurse practitioner performs a follow-up phone call 1 to 2 days after discharge to help answer any questions and avert potential complications.

References 1. Warner J, Whitmore WF Jr. Expectant management of clinically localized prostate cancer. J Urol 1994;152 (5 Pt 2):1761–5. 2. Studer UE. Radical prostatectomy or deferred treatment? Semin Surg Oncol 1995;11:46–9. 3. Chodak GW, Thisted RA, Gerber GS, et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994;330:242–8. 4. Koch MO, Miller DA, Butler R, et al. Are we selecting the right patients for treatment of localized prostate cancer? Results of an actuarial analysis. Urology 1998;51(2): 197–202. 5. Archer C, Levy AE, McGregor M. Value of routine preoperative chest X-rays: a meta-analysis. Can J Anaesth 1993;40:1022–7. 6. Koch MO, Smith JA Jr, Hodge EM, et al. Prospective development of a cost-efficient program for radical retropubic prostatectomy. Urology 1994;44:311–8.

Radical Prostatectomy: Patient Preparation / 183 7. Smith JA Jr, Koch MO. Collaborative care pathways— impact on treatment costs and quality of care after radical prostatectomy. J Managed Care 1997;1:36–9. 8. McLaren RH, Barrett DM, Zincke H. Rectal injury occurring at radical retropubic prostatectomy for prostate cancer: etiology and treatment. Urology 1993;42:401–5. 9. Lassen PM, Kearse WS. Rectal injuries during radical perineal prostatectomy. Urology 1995;45(2):266–9. 10. Harpster LE, Rommel FM, Sieber PR, et al. The incidence and management of rectal injury associated with radical prostatectomy in a community based urology practice. J Urol 1995;154:1435–8. 11. Borland RN, Walsh PC. The management of rectal injury during radical retropubic prostatectomy. J Urol 1992; 147:905–7. 12. Condon RE, Bartlett JG, Greenlee H, et al. Efficacy of oral and systemic antibiotic prophylaxis in colorectal operations. Arch Surg 1983;118:496. 13. Khubchandani IT, Karamchandani MD, Sheeb JA, et al. Metronidazole versus erythromycin, neomycin, and cefazolin in prophylaxis for colonic surgery. Dis Colon Rectum 1989;32:17. 14. Groner JI, Edmiston CE Jr, Krepel C, et al. The efficacy of oral antimicrobials in reducing aerobic and anaerobic colonic mucosal flora. Arch Surg 1989;124:281. 15. Gottrup F, Diederich P, Sorensen K, et al. Prophylaxis with whole gut irrigation and antimicrobials in colorectalsurgery: a prospective randomized double-blind clinical trial. Am J Surg 1985;149:317–22. 16. Wolff BG, Beart RW Jr, Dozois RR, et al. A new bowel preparation for elective colon and rectal surgery: a prospective, randomized clinical trial. Arch Surg 1988;123:895–900. 17. Cluver DH, Horan TC, Gaynes RP. Surgical wound infection rates by wound class, operative procedure, and patient risk index. Am J Med 1991;91:1525. 18. Carson CC III. Antimicrobial prophylaxis in genitourinary surgery. In: Mulholland SG, editor. Antibiotic therapy in urology. Philadelphia: Lippincott-Raven Publishers; 1996. p. 221–36. 19. Clagett GP. Prevention of postoperative venous thromboembolism: an update. Am J Surg 1994;168:515–22. 20. Cisek LJ, Walsh PC. Thromboembolic complications following radical retropubic prostatectomy: influence of external sequential pneumatic compression devices. Urology 1993;42:406–8. 21. Palmer AJ, Schram W, Kirchof B, Bergemann R. Low molecular weight heparin an unfractionated heparin for prevention of thrombo-embolism in general surgery: a meta-analysis of randomised clinical trials. Haemostasis 1997;27:65–74. 22. Koch MO, Smith JA Jr. Low molecular weight heparin and radical prostatectomy: a prospective analysis of safety and side effects. Prostate Cancer Prostatic Dis 1997;1:101–4.

23. Hull RD, Hirsch J. Preventing venous thromboembolism. J Cardiovasc Med 1984;1:63–77. 24. Nicolaides AN, Fernandes E, Fernandes J, Pollock AV. Intermittent sequential compression of the legs in the prevention of venous stasis and postoperative deep venous thrombosis. Surgery 1980;87:69–76. 25. Strup SE, Gudziak M, Mulholland SG, Gomella LG. The effect of intermittent pneumatic compression devices on intraoperative blood loss during radical prostatectomy and radical cystectomy. J Urol 1993;150:1176. 26. Koch MO, Brandell RA, Lin D, Smith JA Jr. The effect of sequential compression devices on intraoperative blood loss during radical prostatectomy. J Urol 1994; 152:1178–9. 27. Simon TL, Alverson DC, AuBuchon J, et al. Practice parameter for the use of red blood cell transfusions. Arch Pathol Lab Med 1998;122:130–8. 28. Donahue JG, Munoz A, Ness PM, et al. The declining risk of post-transfusion hepatitis C virus infection. N Engl J Med 1992;327:369–73. 29. Toy PT, Menozzi D, Strauss RG, et al. Efficacy of preoperative donation of blood for autologous use in radical prostatectomy. Transfusion 1993;33:721–4. 30. Koch MO, Smith JA Jr. Blood loss during radical retropubic prostatectomy: is preoperative autologous blood donation indicated? J Urol 1996;156:1077–80. 31. Shir Y, Raja SN, Frank SM, Brendler SB. Intraoperative blood loss during radical retropubic prostatectomy: epidural versus general anesthesia. Urology 1995;45:993. 32. Ead DN, Koch MO, Smith JA Jr. Is invasive anesthetic monitoring necessary during radical prostatectomy? [Submitted] 33. Yeager MP, Glass DD, Nee RK, Brinck-Johnsen T. Epidural anesthesia and analgesia in high-risk surgical patients. Anesthesiology 1987;66:729–36. 34. Shir Y, Frank SM, Brendler CB, Raja SM. Postoperative morbidity is similar in patients anesthetized with epidural and general anesthesia for radical prostatectomy. Urology 1994;44:232–6. 35. Grass JA, Sakima NT, Valley M, et al. Assessment of ketorolac as an adjuvant to fentanyl patient-controlled epidural analgesia after radical retropubic prostatectomy. Anesthesiology 1993;78:642–8. 36. Gottschalk A, Smith DS, Jobes DR, et al. Preemptive epidural anesthesia and recovery from radical prostatectomy. JAMA 1998;279:1076–82. 37. Michaloliakou C, Chung F, Sharma S. Preoperative multimodal analgesia facilitates recovery after ambulatory laparoscopic cholecystectomy. Anesth Analg 1996; 82(1):44–51. 38. Strom BL, Berlin JA, Kinman JL, et al. Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. JAMA 1996;275:376–82.

CHAPTER 20

STAGE T1A PROSTATE CANCER: THE CASE FOR TREATMENT GARY D. GROSSFELD, MD; PETER R. CARROLL, MD Stage T1 prostate cancer is an incidentally discovered malignancy. The patient becomes aware that he has stage T1 prostate cancer following pathologic examination of tissue removed by transurethral resection or open enucleation for presumed benign prostatic hyperplasia (BPH). Approximately 10% (range 8 to 22%) of men undergoing such procedures will be diagnosed with incidental prostate cancer.1–6 This percentage has remained constant despite the introduction of serum prostate-specific antigen (PSA) screening for prostate cancer and the evolution of noninvasive treatment modalities for BPH. Monda et al. described the prevalence of stage T1 prostate cancer in 966 patients undergoing transurethral resection of the prostate (TURP) for presumed BPH.7 This population included 499 consecutive patients who underwent TURP prior to the introduction of serum PSA testing and 467 consecutive patients who underwent TURP after being screened for prostate cancer with serum PSA and transrectal ultrasound-guided biopsies. The prevalence of stage T1 prostate cancer was nearly equivalent in these two groups despite the use of PSA screening in the more recent cohort (stage T1 prostate cancer in 8.6% of unscreened patients versus 10.3% of screened patients). Since the diagnosis of stage T1 prostate cancer depends on tissue obtained at the time of surgery for BPH, the introduction of newer, less invasive treatment modalities would be expected to have a significant impact on the overall incidence of newly discovered stage T1 prostate cancers. This has indeed been the case. Many minimally invasive therapies for BPH, including medical treatment, intraurethral stenting, laser, and electrical or microwave ablation of the prostate, do not produce prostatic tissue for histologic diagnosis. As a result, the overall number of patients with stage T1 prostate cancer appears to have declined.3 Fowler et al. analyzed temporal trends in the diagnosis of stage T1 prostate cancer over a period of time that included the introduction of medical and minimally invasive treatments for BPH.3 While these authors found no change in the proportion of TURP patients diagnosed with stage T1 prostate cancer during this time period, they did find a marked decline in the absolute number of prostate cancers detected. This decline in prostate cancer detection closely paralleled the less frequent use of TURP in the treatment of BPH.

Stage T1 prostate cancers appear to represent a spectrum of disease. These tumors can be divided into two biologically meaningful groups based on tumor volume and grade. It is generally accepted that high-volume, high-grade disease possesses a significant risk for progression if left untreated.8 Low-volume, low-grade disease, however, (socalled stage T1a prostate cancer) may pursue an indolent course and therefore not require treatment. More recent studies describing the natural history of untreated stage T1a prostate cancer have challenged this long-held belief by reporting disease progression in patients with long-term follow-up. The appropriate treatment of patients with stage T1a prostate cancer has thus become a matter of debate in the literature. For younger patients diagnosed with stage T1a prostate cancer who have at least a 10-year life expectancy, some would recommend aggressive local treatment of the primary tumor to prevent disease progression. The purpose of this chapter is to provide evidence in support of an aggressive approach to the treatment of stage T1a prostate cancer. This will be accomplished by (1) defining stage T1a prostate cancer; (2) describing the pathologic findings associated with radical prostatectomy specimens removed for stage T1a prostate cancer; (3) summarizing recent literature concerning the biologic potential of untreated stage T1a prostate cancer; (4) describing the accuracy of clinical staging techniques used to define the risk of progression for patients with stage T1a prostate cancer; and (5) summarizing the results of definitive local treatment for patients with this stage of disease. Through the course of the chapter it will become increasingly obvious that select patients with untreated stage T1a prostate cancer may be at a substantial risk for disease progression. These patients should therefore be considered candidates for definitive local treatment of their disease.

Definition Stage T1 prostate tumors can be categorized into two separate groups based on tumor grade and stage. In 1975, Jewett proposed that stage T1 tumors be subdivided into those of low biologic potential that pursue an indolent course and rarely progress (low stage and low grade), and those with a more aggressive biologic potential and a high likelihood of progression if left untreated (high grade and/or high volume).9 Unfortunately, precise cut-points 184

Stage T1a Prostate Cancer: the Case for Treatment / 185

between low and high volume and low and high grade were not specified and have never been standardized. Consequently, the definition of focal (stage T1a) and diffuse (stage T1b) incidental prostate cancer has varied between different series in the literature. Low-volume disease has previously been defined based on the total number of chips involved with cancer (less than 3 or 5 chips containing cancer), the total volume of tumor resected (< 1 cm3 of cancer present in the specimen), and the percentage of the specimen involved with tumor (from < 5% involvement to < 50% involvement with cancer).6,10,11 Similarly, the distinction between low- and high-grade disease has varied between investigators. Some authors have included both well- and moderately differentiated tumors (Gleason 2 to 4 and 5 to 7) in the stage T1a category while others have included only well-differentiated tumors.6,10 Epstein and colleagues demonstrated that as long as the tumor occupied ≤ 5% of the TURP specimen, there was no difference in the progression rate at 8 years following diagnosis whether the tumor Gleason score was ≤ 4 or 5 to 6.12 The most recent American Joint Committee on Cancer staging system for prostate cancer categorizes stages T1a and T1b disease using a 5% volume cutoff without mention of tumor Gleason score.13 Percent of the TURP specimen involved with tumor is often estimated by circling all identifiable foci of carcinoma with a marking pen and then combining these foci to calculate the percentage of total tissue involvement with tumor.8,14,15 Although this seems to be a crude method of estimation which does not account for the total volume of resected tissue, it has been shown to be a reproducible technique. Cantrell et al. demonstrated that the pathologist’s estimate of tumor volume corresponded well with tumor progression, and that this estimate was an equally good predictor of progression when compared with the morphometrically determined percentage of tumor extent.8 Other measures of tumor burden, such as the total number of tumor foci present, were less accurate in predicting progression. Epstein and colleagues recently examined whether actual resected tumor volume was a better predictor of progression in stage T1 prostate cancer than percent involvement with tumor.14 These authors questioned whether 1% involvement of a 50-g specimen (0.5 g of tumor) would have a worse prognosis than 1% involvement of a 5-g specimen (0.05 g of tumor). This study demonstrated that while both actual tumor volume and percent involvement with tumor were highly associated with tumor progression, percent involvement with tumor had a stronger association with progression. Variability in the method by which TURP or open prostatectomy specimens are processed may potentially influence the distinction between stage T1a and T1b prostate cancer. Murphy et al. and Rohr have demonstrated that submission of eight cassettes of tissue (12 g) can detect nearly all stage T1b prostate cancers and approximately

90% of stage T1a tumors.16,17 Because high-grade tumors should extensively involve the TURP specimen, this method of analysis should not lead to mistaken classification of stage T1a versus T1b based on tumor grade. In contrast, Newman et al. reported a 65% increase in the occurrence of incidentally diagnosed prostate cancer when the total specimen was examined.18 In addition, areas of highgrade carcinoma were focally present in 7% of their stage T1b lesions. These foci may have been missed if the entire TURP specimen had not been submitted. McDowell et al. examined whether or not submission of remaining tissue after the initial processing of eight cassettes would change stage T1a prostate cancer to T1b or vice versa.15 In this study, the authors examined 34 cases of stage T1 prostate cancer in which the tumor involved ≤ 15% of the specimen and 10 or more cassettes were required for total submission. The first eight slides were initially reviewed then the remaining slides were reviewed to determine if the overall percent involvement or grade changed. It was interesting to note that review of the remaining slides did not result in restaging any of these cancers based on volume criteria. Thus, there appeared to be no benefit to resubmitting stage T1b tumors (≥ 5% involvement) because examination of the remaining tissue would not lower tumor stage. However, one T1a tumor was upstaged to T1b based on the discovery of a high-grade tumor focus in the remaining tissue after examination of the initial eight slides. Because of this finding, and the infrequency with which extra tissue would need to be submitted, these authors recommended resubmission of all remaining tissue in those few cases of stage T1a prostate cancer requiring more than eight cassettes for complete analysis.

Pathology Does stage T1a prostate cancer represent an incidental, low-volume, unifocal tumor with limited biologic potential, or does it actually represent the “tip of the iceberg” for a larger, peripherally based malignancy? To address this issue, several studies have examined radical prostatectomy specimens removed for clinical stage T1a prostate cancer and described the incidence and characteristics of any residual prostatic cancers (Table 20–1). Parfitt et al. analyzed radical prostatectomy specimens removed from 31 patients with clinical stage T1a prostate cancer.19 These authors reported that 52% of the specimens contained no evidence of residual tumor while focal residual disease (reclassified as stage T1a) was found in 35% of the remaining cases. Residual diffuse tumor was present in only 13% of these specimens. In contrast, Paulson et al. analyzed 18 radical prostatectomy specimens removed for clinical stage T1a disease and found no evidence of residual tumor in three specimens (17% only).20 Of the remaining cases, 22% demonstrated a


single microscopic focus of residual disease while 61% were upstaged to stage T1b or T3. At least 2 patients in this series demonstrated evidence of tumor extension into the seminal vesicles while 1 patient had evidence of bladder-neck invasion.20 Zincke et al. analyzed radical prostatectomy specimens obtained from 32 patients with clinical stage T1a disease and found no residual tumor in 25%, stage T1a disease in 41%, stage T1b disease in 22%, and extracapsular disease extension or pelvic lymph node involvement in 12% of cases.21 Two studies from the Johns Hopkins Hospital have also described the pathologic findings of radical prostatectomy specimens removed for clinical stage T1a prostate cancer.22,23 In their initial study, Epstein and colleagues analyzed radical prostatectomy specimens obtained from 21 such patients.22 In this series, 14% of patients had no residual tumor at the time of radical prostatectomy even though all of these specimens demonstrated histologic evidence of severe dysplasia on final pathologic analysis. Sixty-two percent of the remaining specimens demonstrated minimal residual disease while 24% demonstrated substantial residual tumor in the radical prostatectomy specimen. When minimal residual tumor was present, it was located at the prostatic apex or in the periphery of the gland, areas which are difficult to sample by repeat transurethral resection. Of the 5 cases with substantial residual tumor, 2 (40%) demonstrated focally positive surgical margins near the prostatic apex. Larsen et al. expanded on this initial study by analyzing radical prostatectomy specimens removed from 64 patients with clinical stage T1a disease.23 In this study, only 6% of specimens had no residual cancer while 74% had minimal and 20% had substantial residual cancer (defined as either >1 cm3 total tumor volume, capsular penetration, or high-grade tumor). Five cases (8%) demonstrated capsular penetration and 2 of these also had positive surgical margins. Residual tumors were distributed in a heterogeneous manner throughout the prostate, with 39% having a predominately apical location and 61% having a predominately peripheral location. Neither transurethral resection tumor volume, per-

cent involvement of the TURP specimen with tumor, nor tumor grade at TURP were significantly associated with radical prostatectomy tumor volume or the presence of minimal versus substantial residual disease.23 McNeal et al. compared the morphologic features of radical prostatectomy specimens obtained from 11 patients with clinical stage T1 prostate cancer to those of specimens obtained from 73 patients with clinical stage T2 disease.24 This study demonstrated that all stage T1 cancers were located anteromedially (commonly invading the anterior fibromuscular stroma) while most stage T2 cancers were located posteriorly. The stage T1 and T2 cancers were similar with respect to range of tumor volume and degree of differentiation. Both stages of tumor demonstrated progressive dedifferentiation with increasing tumor volume. These results strongly suggested that although differing in their sites of origin, stage T1 and T2 tumors were similar with respect to their biologic potentials. In a related study by Voges et al., morphometric analysis was performed on 44 radical prostatectomy specimens removed from patients with clinical stage T1 tumors (22 patients with stage T1a and 22 patients with stage T1b cancer).25 Six of the 22 specimens (27%) removed for clinical stage T1a disease demonstrated extracapsular disease extension on final pathologic analysis while 5 of the 22 specimens (23%) demonstrated positive surgical margins. Further, 90% of the specimens from patients with clinical stage T1a disease demonstrated unsuspected cancers apparently unrelated to the index tumor identified at the time of transurethral resection. Eighty-three percent of these unsuspected tumors were located outside of the transition zone and 26% measured > 0.2 cm3 in volume. Based on these morphometric studies, it was concluded that transurethral sampling cannot reliably predict total tumor volume, residual tumor volume, or cancer grade. Finally, Babaian et al. analyzed 8 stage T1a prostate cancers identified from 100 cystoprostatectomy specimens removed from patients with bladder cancer.26 Similar to the findings of Voges et al.,25 these authors demonstrated that 50% of the specimens with stage T1a prostate cancer demonstrated multifocal disease (3 specimens

TABLE 20–1. Analysis of Radical Prostatectomy Specimens from Patients with Clinical Stage T1a Prostate Cancer Author

N

Parfitt19 Paulson20

31 18

Epstein22 Larsen23 Zincke21 Voges25

21 64 32 22

No Residual Disease

Minimal Residual Disease

Substantial Residual Disease

52% 17%

35% 22%

13% 61%

14% 6% 25% 0

62% 74% 41% 14%*

24% 20% 34% 86%

ECE = extracapsular extension. *Total residual volume less than 0.2 cm3.

Comments 2 patients with seminal vesicle invasion, 1 patient with bladder neck invasion 10% margin positive 8% ECE, 3% margin positive 9% stage C, 3% positive lymph nodes 90% with unsuspected cancers


with 2 tumor foci and 1 specimen with 3 tumor foci). In addition, 62.5% of these specimens contained foci of grade 3 prostatic intraepithelial neoplasia (PIN) which were distinct from any overt focus of cancer. It is evident from these radical prostatectomy studies that a significant percentage of patients with clinical stage T1a prostate cancer will have substantial residual tumor present after the initial transurethral resection. In many instances, these tumors may be multifocal and exhibit adverse pathologic characteristics (including extracapsular disease extension and positive surgical margins). Unfortunately, resected tumor volume, percent of TURP specimen involved with tumor, and tumor grade cannot accurately predict which patients will continue to harbor substantial disease following TURP. It is clear that some patients with clinical stage T1a prostate cancer will be at risk for disease progression with longterm follow-up and expectant management. These are the patients who may benefit from aggressive local therapy of their prostate cancer.

Natural History of Untreated Stage T1a Prostate Cancer Stage T1a prostate cancer is an incidental finding. Any patient with this diagnosis, therefore, will have no signs or symptoms referable to his underlying malignancy. In addition, stage T1a prostate cancer, by definition, represents low-volume, low-grade disease which may possess a limited potential for progression. Because this stage of disease is often diagnosed in elderly men, several important issues must be addressed before a recommendation can be made regarding aggressive treatment for a newly diagnosed patient. These issues include: (1) the natural history of untreated stage T1a prostate cancer; (2) the overall life expectancy of the patient; (3) serious complications that may be associated with treatment; (4) the ability to distinguish stage T1a tumors with a high likelihood of progression from those with a low biologic potential; and (5) the effectiveness of local treatment in eradicating disease. Due to its seemingly low biologic potential, most early studies suggested that stage T1a prostate cancer had little impact on either overall or prostate cancer-specific survival. Generally, a 10-year mortality rate of less than 5% was associated with expectant management of such patients, likely due to a high prevalence of comorbid conditions in this patient population leading to death from intercurrent illness.6 In a study of 847 consecutive patients undergoing suprapubic prostatectomy for BPH, Bauer et al. found that 28 patients had well-differentiated prostate cancer at the time of surgery.27 Overall survival for these patients at 5 and 10 years following diagnosis was 75% and 47%, respectively. Consequently, these authors suggested that small, well-differentiated, incidentally discovered prostate cancers may require no further

treatment. Confirming these results, Hanash et al. reported disease specific outcomes for 21 patients with incidentally discovered, low-grade prostate cancers who were managed expectantly.28 Overall survival 5 years after diagnosis was reported to be 100% for these patients, and survival in this group of patients continued to be superior to expected survival (based on life-table analysis) for up to 15 years after diagnosis. The high rate of intercurrent illness in this patient population has resulted in disease progression replacing overall survival as the end point for measuring the biologic potential of stage T1a prostate cancer. In 1981, Cantrell et al. examined the rate of disease progression in 49 patients with stage T1a disease and at least 4 years of follow-up after diagnosis.8 Disease progression was reported in only one patient (2%) during this follow-up period (Table 20–2), confirming the low biologic potential of this stage of disease. Due to increasing life expectancy, patients with stage T1a prostate cancer who are managed expectantly will spend more time alive with their prostate cancer. Consequently, the policy of expectant management for these patients has recently been challenged. Several studies have demonstrated not only the potential for disease progression but also for death due to disease in these patients.5,12,29 More recent studies, with long-term follow-up, suggest that disease progression can occur in 10 to 27% of patients with stage T1a prostate cancer who are managed expectantly for 7 to 10 years after diagnosis (see Table 20–2). Epstein et al. reported the results of 50 men with stage T1a prostate cancer who were managed expectantly and followed for at least 8 years after diagnosis.12 In this study 8 patients (16%) experienced disease progression, and 6 of these 8 patients died of prostate cancer within an average of 2 years after progression. Neither tumor volume on the TURP specimen nor tumor grade predicted which patients would ultimately progress. Thompson and Zeidman followed 60 patients with stage T1a prostate cancer for an average of 7.5 years after diagnosis.5 Although the overall rate of disease progression was low in this groups of patients (5%), 8% of patients at risk for at least 7 years demonstrated progressive disease, and all 3 patients who progressed died of disease within 1 year of progression. Similar to the findings of Epstein et al., these authors reported no correlation between tumor volume at TURP and disease progression. Blute et al. reported progressive disease in 27% of men with stage T1a prostate cancer managed expectantly with the median time to progression being 10.2 years.30 Three of the 4 patients who progressed in this study did so with systemic disease. Finally, Ingerman et al. reported disease progression in 13% of patients with stage T1a prostate cancer presumed to be at low risk due to a negative staging TURP.31 Of the 3 patients who progressed, 1 did so with metastatic disease.


Additional evidence in support of the observation that stage T1a prostate cancer may progress over time is found in a study by Brawn.32 In this study, TURP specimens were examined from 54 patients with prostate cancer who required two separate transurethral resections. The second procedure was performed from 3 to 11 years after the initial TURP. Of 26 patients with grade 1 prostate cancer at the time of initial TURP, 19 (73%) had higher grade tumors at repeat resection. In addition, 75% of grade 2 lesions and 88% of grade 3 lesions dedifferentiated into a higher grade at repeat TURP. All 8 poorly differentiated tumors (grade 4) remained poorly differentiated on both resections. Grade was unchanged in only 10 (19%) patients, and only 1 lesion demonstrated a lower grade at repeat resection (from grade 2 to grade 1). The presence of metastases in this study was associated with tumor grade. While no grade 1 tumors demonstrated metastases, 19% of the grade 2 lesions, 55% of the grade 3 lesions, and 80% of the grade 4 lesions were associated with metastatic disease. These data suggest that low-grade prostate cancers may have the ability to dedifferentiate over time and that progression of the disease may be a consequence of such dedifferentiation. Similar to the data obtained from the radical prostatectomy studies described above, studies examining the natural history of untreated stage T1a prostate cancer strongly suggest that a significant percentage of these tumors have the potential for progression with long-term follow-up. Not only can these tumors progress locally, but there is also evidence to suggest that systemic progression, leading to death from disease, may be possible. It does not appear that the likelihood of progression can be reliably predicted from the findings at TURP, but the major risk factor for progression appears to be extended follow-up. Thus, for patients with stage T1a disease and a long life expectancy (greater than 10 years), some form of local treatment does appear warranted.

Risk Assessment Tumor volume and grade have been the traditional measures used to categorize incidental prostate cancers into stages T1a or T1b. It is also clear, however, that while some clinical stage T1a tumors will progress, others will pursue a more indolent course. The ability to distinguish those tumors with a high likelihood of subsequent progression from those that will not progress is of obvious clinical importance in selecting appropriate patients for definitive local therapy. Several staging modalities have been studied for this purpose, including repeat TURP, transrectal ultrasound and prostate biopsy, and serial PSA measurement. Repeat Transurethral Resection of the Prostate Repeat TURP has been proposed as a staging procedure for patients with stage T1a prostate cancer. It has been hypothesized that the presence of residual cancer at the time of repeat resection should be useful in upstaging patients from T1a to T1b disease, thus identifying patients who require early, aggressive local therapy. Studies examining the use of repeat TURP in these patients, however, have not clearly demonstrated the benefit of this staging procedure. These studies have reported diffuse residual disease (resulting in clinical upstaging to T1b disease) in only 3.5 to 26% of patients (Table 20–3). Conversely, 63 to 82% of patients have demonstrated no evidence of residual disease at the time of repeat TURP.1,19,33–37 While tumor volume on the initial TURP specimen does not appear to be associated with the finding of diffuse residual disease at repeat TURP,19 an association between tumor grade and upstaging has been reported.36 In a study by Sonda et al., none of 12 patients with Gleason score 2 to 4 cancer on the initial TURP were upstaged by repeat resection, compared to 3 of 19 patients (16%) with Gleason score 5 to 7 tumors.36

TABLE 20–2. Natural History of Untreated Stage T1a Prostate Cancer Author

Year

N

Number with Progression (%)

Heaney52 Correa53 Cantrell8 Blute30 Epstein12 Thompson5 Lowe34 Roy29 Zhang37 Ingerman31

1977 1974 1981 1986 1986 1989 1990 1990 1991 1993

50* 39* 49 15 50 60 80 19 132 24‡

3 (6%) 3 (8%) 1 (2%) 4 (27%) 8 (16%) 3 (5%) 12 (15%) 3 (16%) 13 (10%) 3 (13%)

N/A = not specified; TURP = transurethral resection of the prostate. *Some patients in these series treated with radical prostatectomy or hormonal therapy. †Median time to progression. ‡All patients without residual carcinoma on repeat TURP.

Follow-Up

Definition of Stage T1a (Volume, Grade)

N/A N/A At least 4 years 10.2 years† At least 8 years 7.5 years 8.4 years N/A 8.2 years 7 years

Small and focal, well differentiated Focal, none poorly differentiated ≤ 5% of TURP, none poorly differentiated < 1 cm3, well differentiated ≤ 5% of TURP, Gleason 2–7 < 5 foci on TURP, well differentiated ≤ 5% of TURP, none poorly differentiated Low volume and grade < 5% of TURP, Gleason ≤ 4 < 5% of TURP, Gleason < 5


While it is possible that residual disease at the time of repeat TURP may identify a subset of patients at a higher risk for disease progression, a negative repeat TURP does not appear to exclude this risk. Zhang et al. performed repeat TURP on 52 patients with clinical stage T1a disease.37 Fourteen patients (27%) demonstrated residual foci of well-differentiated disease, including 2 patients (4%) who were upstaged to T1b and underwent radical prostatectomy. Of the remaining 12 patients, progressive disease was eventually encountered in 3 patients (25%). Although the presence of residual disease did appear to identify a population of patients at increased risk for disease progression, a negative repeat TURP did not exclude the possibility of progression (8% of patients with a negative repeat TURP still progressed). These findings were confirmed in a study by Ingerman et al. in which 3 of 24 patients (13%) with clinical stage T1a prostate cancer and a negative repeat TURP developed progressive disease.31 This progression rate, which was similar to that reported for stage T1a patients not undergoing repeat TURP, caused these authors to conclude that repeat TURP does not effectively evaluate the risk of progression in these patients. The inability of repeat TURP to identify patients with a high likelihood of disease progression is not surprising given the anatomic location of residual prostate cancer. As described above, Epstein et al. reported that residual carcinoma in radical prostatectomy specimens removed for clinical stage T1a prostate cancer is often located at the prostatic apex or in the periphery of the gland, adjacent to the prostatic capsule.22 Tumor in these locations is usually not amenable to TURP. Further, Voges et al. reported that 90% of radical prostatectomy specimens removed for stage T1a disease contained unsuspected cancers and that 83% of these cancers were located in the peripheral zone.25 Repeat TURP therefore does not appear to be useful in distinguishing those patients with clinical stage T1a prostate cancer who require aggressive local therapy from those who can be managed expectantly. Transrectal Ultrasonography and Biopsy Although transrectal ultrasonography (TRUS) with ultrasound-guided biopsy of the prostate has been a welldescribed method of prostate cancer diagnosis and staging, few studies have examined the utility of TRUS and biopsy in risk assessment for patients previously diagnosed with stage T1a prostate cancer. Carroll et al. described the results of transperineal needle biopsy of the prostate in 26 patients with stage T1a prostate cancer, including 24 patients who had also undergone a staging TURP.33 Only 2 of these 26 patients (8%) had residual tumor identified by transperineal biopsy. Of the 24 patients undergoing both procedures, residual disease was identified in 6 patients on repeat TURP, with only 1 of these patients (17%) also demonstrating tumor by transperineal needle biopsy. These results suggest that

transperineal needle biopsy is not a reliable method for detection of residual disease following initial TURP. Several studies have examined the ability of TRUS to identify residual disease in patients with stage T1 prostate cancer following their initial TURP. Sheth et al. performed TRUS in 29 patients with stage T1 prostate cancer prior to radical prostatectomy.38 The sensitivity of TRUS for evaluating clinical stage T1 lesions was only 55%. The total extent of tumor was often underestimated by TRUS and was unreliable for detection of anterior cancers. The specificity of TRUS in this study was also low (37%), as 19 of the 30 hypoechoic lesions identified did not prove to be cancer. Egawa et al. performed TRUS in 38 patients with stage T1 prostate cancer approximately 3 weeks after initial TURP.39 The positive predictive value (PPV) of TRUS in this study ranged from 60 to 80%. The predictive ability of TRUS was correlated with both the amount and location of residual disease. Forty-seven percent of the hypoechoic lesions identified by TRUS and located in the transition zone, and 88% of those located in the peripheral zone, were positive for cancer on histologic examination. When considering stage T1a patients only, TRUS identified residual cancer in only 2 of 11 patients (18%). Zhang et al. examined the ability of TRUS and biopsy to correctly identify residual disease in 52 patients with stage T1a prostate cancer who had been followed for 1 to 15 years after initial TURP.40 Hypoechoic areas were identified in 29 patients (58%). All patients in the study subsequently underwent ultrasound-guided biopsies. Carcinoma was detected in 8 of the patients evaluated, including 7 who demonstrated abnormalities on ultrasound. The PPV for ultrasound for the early detection of prostate cancer in this series was 24% (7 of 29 patients). Terris et al. evaluated the ability of ultrasonography and biopsy to identify residual tumor in three groups of patients with stage T1 prostate cancer.41 The first group underwent ultrasound only. Of 37 patients with residual disease at the time of radical prostatectomy, only 9 (24%) demonstrated focal hypoechogenicity on ultrasonograTABLE 20–3. Results of Repeat TURP in Patients with Clinical Stage T1a Prostate Cancer

Author

N

No Residual Tumor

McMillen35 Bridges1 Lowe34 Carroll33 Sonda36 Zhang37 Parfitt19

27 40 44 40 31 52 55

63% 70% 84% 78% 71% 73% 82%

Minimal Residual Tumor (T1a)

Diffuse Residual Tumor (T1b)

11% 25% 16%* 15% 20% 23% 14.5%

26% 5% N/A 7%† 9% 4% 3.5%

*Amount of residual disease (minimal versus diffuse) not specified. †Patients upstaged based on increased tumor grade.


phy consistent with residual disease. The second group included 25 patients who underwent TRUS with routine sextant biopsy. Cancer detection was increased to 28% in this group. Finally, a third group of 47 patients underwent TRUS with modified systematic biopsies that included additional anterior transition-zone biopsies. This technique improved cancer detection to 47%. Because all patients in groups two and three did not undergo radical prostatectomy after ultrasonography and biopsy, the actual incidence and volume of residual cancer in these patients was unknown. These studies demonstrated that interpreting TRUS following TURP can be problematic. Prostate asymmetry secondary to prior resection, artifactual peripheral zone hypoechogenicity, and the natural hypoechogenicity of residual benign prostatic hyperplasia can make interpretation of TRUS challenging in this setting.41 Further, the anterior location of many incidental prostate cancers also makes accurate identification difficult. In an attempt to improve prostate imaging following TURP, Carroll et al. reported on the use of magnetic resonance imaging (MRI) following TURP.42 Although the sensitivity of MRI for detecting residual cancer in the peripheral zone was 81%, MRI was unable to detect any cancers confined to the transition zone. Serum Prostate-Specific Antigen Few studies have examined the ability of PSA to accurately predict residual disease or disease progression following initial TURP in patients with clinical stage T1a prostate cancer. Monitoring post-TURP PSA in these patients should prove useful given that: (1) PSA increases with increasing tumor volume; (2) the contribution of cancer to serum PSA is 10 times greater than that of BPH; (3) prostate cancer has a more rapid growth rate than BPH; and (4) removal of the hyperplastic epithelium by TURP might increase the correlation between PSA and tumor volume.2,43 In a study of 24 patients with clinical stage T1a disease and a negative repeat TURP, Ingerman et al. found that the mean serum PSA level in three patients with disease progression (7.1 ng per mL) was significantly higher than that of the 21 patients who did not have progressive disease (1.3 ng per mL).31 Voges et al. correlated post-TURP serum PSA levels with residual cancer volume in 44 patients undergoing radical prostatectomy for clinical stage T1 disease.25 They reported that post-TURP PSA levels increased with increasing residual cancer volumes. Nineteen of 20 patients (95%) with a residual cancer volume > 0.9 cm3 had a serum PSA level ≥ 2.5 ng per mL, while 7 of 8 patients (88%) with a residual cancer volume < 0.4 cm3 had a serum PSA level < 1.0 ng per mL. In patients with serum PSA levels between 1.0 and 2.5 ng per mL, residual volume varied between 0 and 1.88 cm3.25 Carter et al. also correlated serum PSA levels with residual tumor volume in 67 patients with stage T1

prostate cancer undergoing radical prostatectomy.43 Similar to the findings of Voges et al., this study demonstrated that serum PSA was able to reliably predict residual tumor volume only when levels were very low (< 1 ng per mL) or very high (> 10 ng per mL). All stage T1a patients with a serum PSA < 1 ng per mL following TURP had a residual tumor volume < 0.5 cm3, while all stage T1 patients with a serum PSA > 10 ng per mL had a residual tumor volume > 0.5 cm3. For the majority of patients with a serum PSA level between 1.0 and 10 ng per mL, however, there was no significant correlation between PSA level and tumor volume. More recently, Feneley et al. analyzed the use of serial PSA testing and TRUS in 48 patients with stage T1 prostate cancer who were followed for an average of 2.8 years.44 Thirty-six of these patients had stage T1a disease, including 11 (31%) who demonstrated evidence of residual disease. These authors examined whether absolute PSA level, PSA density, PSA velocity, or TRUS could accurately predict the presence of residual disease in those patients undergoing TRUS-guided biopsies 3 months after TURP. Serum PSA levels were significantly higher in those patients with residual disease than in those without residual disease. Using a cutoff of 4.0 ng per mL, the sensitivity of an elevated PSA in predicting residual disease in T1a patients was 82%. However, specificity using this cutoff was only 60%. Similarly, sensitivity and specificity for predicting residual disease using PSA density (cutoff 0.15 ng per mL per cm3) were 82 and 68%, respectively, while TRUS had the poorest sensitivity (56%) and specificity (52%). The best predictor of residual disease in this study was PSA velocity. An incremental rise in PSA of 20% per year in untreated stage T1a patients improved sensitivity to 86% and specificity to 80%. While these few studies have examined the ability of PSA to predict the presence of residual disease in stage T1a patients following initial TURP, no study has adequately addressed the predictive ability of serum PSA with respect to disease progression in this setting. Prostate-specific antigen velocity appears to be the most promising measure in this regard. Additional studies are needed, however, to define which value of PSA velocity would be most indicative of progressive disease and what threshold should be used to recommend treatment. In summary, although clinical stage T1 patients can be divided into those with a low risk for disease progression (T1a) and those with a high risk for disease progression (T1b) based on tumor volume and grade, it is clear that some patients with clinical stage T1a disease will progress over time. While repeat TURP, TRUS ultrasound-guided prostate biopsies, and post-TURP serum PSA monitoring may be useful in defining risk for some clinical stage T1a patients, these methods are neither sensitive nor specific enough to be used for routine clinical decision making. The ability to distinguish those clinical stage T1a patients


at high risk for disease progression from those at low risk awaits improvements in these clinical staging modalities. While it appears prudent to followup untreated clinical stage T1a patients with periodic rectal examinations and serum PSA levels, indications for intervention as well as the proper timing of intervention cannot be determined based on these techniques.

Local Treatment Options for Patients with Stage T1a Prostate Cancer Similar to other stages of prostate cancer, there have been no well-designed, randomized prospective trials comparing definitive local treatment versus observation for patients with stage T1a prostate cancer. In addition, no study to date has adequately compared one local treatment modality with another. In fact, few studies have been reported which describe disease-specific outcomes following local treatment for patients with stage T1a disease. For those studies which do describe such outcomes, the results of treatment for stage T1a patients are often combined with those of stage T1b patients, even though the biologic potential of these two tumor types are clearly different. In a study examining local treatment for stage T1 patients with a high probability of disease progression, Lowe and Listrom retrospectively compared disease-free survival in patients treated with aggressive local therapy (either radical prostatectomy or radiotherapy) with those managed expectantly.45 Even though patients in this study were not categorized as T1a or T1b, the results are of interest. For 17 stage T1 patients undergoing radical prostatectomy with at least 4.5 years of follow-up after surgery, survival free of disease was 93%. For 31 stage T1 patients treated with radiotherapy, survival free of disease was 84%. These results were compared to those of control patients who were managed expectantly in both a matched pair and an unmatched analysis. These analyses demonstrated that stage T1 patients treated with either radical prostatectomy or radiotherapy had significantly better disease-free survival than patients managed expectantly.45 Due to the small sample size, however, differences between the radical prostatectomy and radiotherapy groups were not statistically significant. Radical Prostatectomy Several large series have examined the efficacy of radical prostatectomy as definitive local therapy for prostate cancer (Table 20–4). Only a small percentage of patients in any of these studies, however, were stage T1a patients. Catalona and Smith reported 5-year tumor recurrence rates in 925 patients undergoing radical retropubic prostatectomy using serum PSA as an end point for treatment failure.46 Twentyone patients (2%) in this series had clinical stage T1a disease prior to surgery. Actuarial 5-year disease-free survival

(serum PSA ≤ 0.6 ng per mL) was 90% for all patients with clinical stage T1a or T1b disease. Gerber et al. reported the results of radical prostatectomy from a multi-institutional pooled analysis of 2758 men undergoing radical prostatectomy from eight university medical centers.47 For patients with clinical stage T1, grade 1 (well-differentiated) disease, 10-year actuarial disease-specific survival was 100% while 10-year actuarial metastasis-free survival was 99%. Finally, Pound et al. described their results with radical prostatectomy in 1621 men.48 Fifty-five (3%) of these patients had clinical stage T1a disease prior to surgery. Disease recurrence was defined as a detectable serum PSA level (> 0.2 ng per mL) following surgery. Five- and 10-year actuarial disease-free survival for these 55 stage T1a patients undergoing radical prostatectomy was 100%. There are two studies examining outcome following radical prostatectomy that have included only patients with stage T1 prostate cancer (see Table 20–4). Paulson et al. reported 76 patients who underwent radical prostatectomy for stage T1 disease.20 Eighteen of these 76 patients (24%) had stage T1a disease while the remaining patients had stage T1b disease prior to surgery. When analyzing their results, Paulson et al. stratified patients based on pathologic findings at prostatectomy (i.e., organ-confined, specimen-confined, margin-positive) and not by clinical disease stage. Overall, 10 patients failed, including 5 who failed locally and 5 who failed with distant disease. Of these 10 patients, 3 had Gleason score 8 or 9 tumors and therefore would have certainly been classified as T1b. For all 76 patients, 5- and 10-year actuarial disease-free survival was estimated at 85% and 75%, respectively. Zincke et al. also described the results of radical prostatectomy in 148 patients with clinical stage T1 disease.21 Of these patients, 32 (22%) had clinical stage T1a cancer prior to surgery. No patient in the T1a group died of disease with a mean follow-up of 4.6 years after surgery. One of the 32 stage T1a patients (3%) experienced disease progression (local progression 3 years after surgery, distant progression 4 years after surgery). Actuarial progression-free survival was approximately 95% for clinical stage T1a patients at 5, 10, and 15 years after surgery. This continued to be true even if a detectable serum PSA level (> 0.2 ng per mL) was considered evidence of disease progression. An improved understanding of the mechanisms and anatomy of urinary continence and erectile function has led to better operative techniques with respect to radical prostatectomy. Given the excellent results that are possible for clinical stage T1a patients with respect to disease-free and overall survival and the reduced morbidity associated with surgery, several authors have recommended that radical prostatectomy be a treatment option that is offered to patients with clinical stage T1a disease.21,22 This appears to be especially true for younger patients with at least a 10-year life expectancy since their

192 / Advanced Therapy of Prostate Disease TABLE 20–4. Results of Definitive Local Therapy for Patients with Clinical Stage T1a Prostate Cancer Author

Modality

Catalona46 Gerber47 Pound48 Paulson20 Zincke21 Zagars49 Ragde50 Critz51

RP RP RP RP RP XRT Brachy Brachy + XRT

N (T1a only) 21 101 55 18 32 23 5 10

Results 5-yr PSA-free survival 90% for T1a/T1b 100% actuarial disease specific, 99% actuarial metastasis-free survival at 10 years for T1, grade 1 100% 5- and 10-year actuarial PSA-free survival 85% 5-year and 75% 10-year actuarial disease-free survival for clinical T1a/T1b Approximately 95% actuarial progression-free survival at 5, 10, and 15 years (including PSA) 100% actuarial 5-year relapse-free survival No progression at median follow-up of 69 months Clinical recurrence in 1 patient at median follow-up of 45 months

RP = radical prostatectomy; XRT = external beam radiotherapy; Brachy = brachytherapy; PSA = prostate-specific antigen.

risk of disease progression may be as high as 10 to 25% (see Table 20–2). However, any benefit of radical prostatectomy over expectant management in these patients can only be confirmed by properly designed clinical trials. Therefore, the decision of whether or not to proceed with aggressive local treatment can only be made based on retrospective evidence and the consideration of clinical factors such as patient age and overall health status. Radiation Therapy Little data are available concerning outcomes following radiotherapy for stage T1a prostate cancer (see Table 20–4). Zagars et al. described disease outcome in 707 patients treated with external beam radiotherapy.49 Of these patients, 23 (3%) had clinical stage T1a disease. No patient in this study with stage T1a cancer experienced disease relapse or a rising PSA following radiotherapy. Because prior TURP is a risk factor for urinary incontinence after seed implantation, few clinical stage T1a patients have been included in brachytherapy series. Ragde et al. treated 5 patients with clinical stage T1a disease using iodine-125 seed implantation. 50 After a median follow-up of 69 months for the entire study group, no patient with stage T1a cancer had experienced disease recurrence. Critz et al. treated 10 patients with clinical stage T1a prostate cancer using iodine-125 seed implantation followed by postimplant external beam radiotherapy.51 Mean follow-up for patients in this study was 45 months. Of these 10 patients, 1 experienced a PSA recurrence associated with clinical recurrence of disease.

Stage T1a Prostate Cancer: the Case for Treatment Stage T1 prostate cancer is diagnosed in approximately 10% of men undergoing TURP for BPH. Although the incidence of such tumors has declined since the introduction of minimally invasive treatments for BPH, the percentage of men undergoing TURP who are found to have stage T1 prostate cancer has remained relatively constant despite routine preoperative PSA testing.

Many stage T1a prostate cancers will behave in an indolent fashion, leading most authors to continue recommending conservative treatment for elderly patients with this stage of disease. This is due to the high rate of death from intercurrent illness. Life expectancy of the general population continues to increase, however, and the definition of “elderly” has changed since earlier studies examining the natural history of stage T1a prostate cancer. Many patients who are currently in their 60s and early 70s are in excellent health and without significant comorbid conditions These patients can expect more than 10 additional years of life expectancy. The data presented in this review suggest the following considerations with respect to managing patients with stage T1a prostate cancer: (1) while most radical prostatectomy specimens removed for stage T1a disease show minimal tumor, at least 20 to 30% may show substantial residual cancer; (2) most of these specimens also demonstrate multifocal disease; (3) there appears to be an approximate 16 to 25% chance of disease progression in patients with stage T1a disease managed expectantly and followed up for 7 to 10 years; (4) there are currently no reliable diagnostic methods upon which to base treatment decisions for stage T1a patients; and (5) excellent results can be achieved with respect to disease-free and overall survival in these patients with definitive local treatment (either radical prostatectomy or radiotherapy). As with definitive local therapy for all early stages of prostate cancer, the dilemma is whether to overtreat some patients in order to potentially cure the others who may subsequently experience disease progression and die as a result of disease.11 The data presented herein suggest that definitive local treatment should be considered for those patients with stage T1a disease who are likely to have a long life expectancy. In these patients, the possibility of disease progression appears to be significant, and excellent results, with minimal morbidity, can be achieved with definitive local therapy. However, treatment must be individualized for all patients. Treatment decisions must take into account not only disease characteristics and life expectancy but also the wishes and expectations of the patient and his family.


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20. Paulson DF, Robertson JE, Daubert LM, Walther PJ. Radical prostatectomy in stage A prostatic adenocarcinoma. J Urol 1988;140:535–9. 21. Zincke H, Blute ML, Fallen MJ, Farrow GM. Radical prostatectomy for stage A adenocarcinoma of the prostate: staging errors and their implications for treatment recommendations and disease outcome. J Urol 1991;146:1053–8. 22. Epstein JI, Oesterling JE, Walsh PC. The volume and anatomical location of residual tumor in radical prostatectomy specimens removed for stage A1 prostate cancer. J Urol 1988;139:975–9. 23. Larsen MP, Carter HB, Epstein JI. Can stage A1 tumor extent be predicted by transurethral resection tumor volume, percent or grade? A study of 64 stage A1 radical prostatectomies with comparison to prostates removed for stages A2 and B disease. J Urol 1991;146:1059–63. 24. 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;139:61–5. 25. Voges GE, McNeal JE, Redwine EA, et al. The predictive significance of substaging stage A prostate cancer (A1 versus A2) for volume and grade of total cancer in the prostate. J Urol 1992;147:858–63. 26. Babaian RJ, Troncoso P, Ayala A. Transurethral-resection zone prostate cancer detected at cystoprostatectomy. A detailed histologic analysis and clinical implications. Cancer 1991;67:1418–22. 27. Bauer WC, McGavran MH, Carlin MR. Unsuspected carcinoma of the prostate in suprapubic prostatectomy specimens. Cancer 1960;13:370–8. 28. Hanash KA, Utz DC, Cook EN, et al. Carcinoma of the prostate: a 15-year follow-up. J Urol 1972;107:450–3. 29. Roy CR, Horne D, Raife M, Pienkos E. Incidental carcinoma of prostate. Long-term follow-up. Urology 1990;36: 210–3. 30. Blute ML, Zincke H, Farrow GM. Long-term follow-up of young patients with stage A adenocarcinoma of the prostate. J Urol 1986;136:840–3. 31. Ingerman A, Broderick G, Williams RD, Carroll PR. Negative repeat transurethral resection of prostate fails to identify patients with stage A1 prostatic carcinoma at lower risk of progression: a long-term study. Urology 1993;42:528–32. 32. Brawn PN. The dedifferentiation of prostate carcinoma. Cancer 1983;52:246–51. 33. Carroll PR, Leitner TC, Yen TS, et al. Incidental carcinoma of the prostate: significance of staging transurethral resection. J Urol 1985;133:811–4. 34. Lowe BA, Barry JM. The predictive accuracy of staging transurethral resection of the prostate in the management of stage A cancer of the prostate: a comparative evaluation. J Urol 1990;143:1142–5. 35. McMillen SM, Wettlaufer JN. The role of repeat transurethral biopsy in stage A carcinoma of the prostate. J Urol 1976;116:759–60. 36. Sonda LP, Grossman HB, MacGregor RJ, Gikas PW. Incidental adenocarcinoma of the prostate: the role of repeat transurethral resection in staging. Prostate 1984; 5:141–6. 37. Zhang G, Wasserman NF, Sidi AA, et al. Long-term followup results after expectant management of stage A1 prostatic cancer. J Urol 1991;146:99–103.

194 / Advanced Therapy of Prostate Disease 38. Sheth S, Hamper UM, Walsh PC, et al. Stage A adenocarcinoma of the prostate: transrectal US and sonographicpathologic correlation. Radiology 1991;179:35–9. 39. Egawa S, Greene DR, Flanagan WF, et al. Transrectal ultrasonography in stage A prostate cancer: detection of residual tumor after transurethral resection of prostate. J Urol 1991;146:366–71. 40. Zhang G, Wasserman NF, Kapoor DA, Reddy PK. Early detection of local disease progression from stage A1 prostate carcinoma by transrectal ultrasonography. Cancer 1992;69:2300–5. 41. Terris MK, McNeal JE, Stamey TA. Transrectal ultrasound imaging and ultrasound guided prostate biopsies in the detection of residual carcinoma in clinical stage A carcinoma of the prostate. J Urol 1992;147:864–9. 42. Carroll PR, Sugimura K, Cohen MB, Hricak H. Detection and staging of prostatic carcinoma after transurethral resection or open enucleation of the prostate: accuracy of magnetic resonance imaging. J Urol 1992;147:402–6. 43. Carter HB, Partin AW, Epstein JI, et al. The relationship of prostate-specific antigen levels and residual tumor volume in stage A prostate cancer. J Urol 1990;144:1167–71. 44. Feneley MR, Webb JA, McLean A, Kirby RS. Postoperative serial prostate-specific antigen and transrectal ultrasound for staging incidental carcinoma of the prostate. Br J Urol 1995;75:14–20. 45. Lowe BA, Listrom MB. Management of stage A prostate cancer with a high probability of progression. J Urol 1988;140:1345–7.

46. Catalona WJ, Smith DS. Five-year tumor recurrence rates after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994;152:1837–42. 47. Gerber GS, Thisted RA, Scardino PT, et al. Results of radical prostatectomy in men with clinically localized prostate cancer. JAMA 1996;276:615–9. 48. Pound CR, Partin AW, Epstein JI, Walsh PC. Prostate-specific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am 1997;24:395–406. 49. Zagars GK, Pollack A, Kavadi VS, von Eschenbach AC. Prostate-specific antigen and radiation therapy for clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1995;32:293–306. 50. Ragde H, Blasko JC, Grimm PD, et al. Interstitial iodine125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 1997;80:442–53. 51. Critz FA, Tarlton RS, Holladay DA. Prostate-specific antigenmonitored combination radiotherapy for patients with prostate cancer. I-125 implant followed by externalbeam radiation. Cancer 1995;75:2383–91. 52. Heaney JA, Chang HC, Daly JJ, Prout GR Jr. Prognosis of clinically undiagnosed prostatic carcinoma and the influence of endocrine therapy. J Urol 1977;118: 283–7. 53. Correa RJ, Anderson RG, Gibbons RP, Mason JT. Latent carcinoma of the prostate—why the controversy? J Urol 1974;111:644–646.

CHAPTER 21

T1B-T2NXM0: THE CASE FOR OBSERVATION FERNANDO J. KIM, MD; WILLIAM BEDFORD WATERS, MD Carcinoma of the prostate is “the” cancer of the 1990s. This disease has touched the lives of several high-profile public figures such as golfer Arnold Palmer, Senator Bob Dole, French President François Mitterrand, General Norman Schwarzkopf, and entertainers such as Frank Zappa and Bill Bixby.1 Prostate cancer (PCa) has become the most diagnosed cancer in America and the second leading killer of men.2–4 Moreover, deaths from PCa are increasing by 2 to 3% per year because men are living longer and fewer men are dying of other causes such as cardiovascular disease.5,6 The annual detection rate of PCa is increasing rapidly in the United States.5–9 This is largely due to widespread early detection of the disease using prostate-specific antigen (PSA), digital rectal examination (DRE), and prostate needle biopsy with transrectal ultrasonography (TRUS).10–19 Death from PCa is common. This year, over 184,500 men will be diagnosed with PCa and more than 39,200 men previously diagnosed will die because of it.5–7 Crucial questions arise as to whether it is possible to reduce the mortality of PCa with early diagnosis and aggressive treatment and whether localized PCa progresses at a rate fast enough to kill most men if left untreated. Studies have clearly demonstrated that PSA testing leads to increased detection of organ-confined tumors.13,20–23 Detection and treatment of such tumors may eventually lead to decreased mortality from PCa. Many authors, however, are concerned about aggressive early detection and treatment, particularly in older patients. In the United States, men diagnosed with early PCa are treated with curative intent using radiation therapy or radical prostatectomy.24–26 Conversely, elsewhere in the world watchful waiting or expectant observation with subsequent delayed hormonal therapy at disease progression is commonly recommended as a management strategy.27–31 Although efforts are being made to address the issues of early detection and treatment of clinically localized PCa (stages T1 and T2), these controversies are unlikely to be resolved in the near future. The role of expectant management is therefore likely to remain unsettled and prove one of the most important and controversial areas in genitourinary oncology. In this chapter, the published results of watchful waiting over the last decade are reviewed, and an attempt is made to place this approach in perspective in relation to men with clinically localized prostate cancer.

Natural History of Untreated Localized Prostate Cancer The long-term results of initial conservative management of clinically localized PCa have been investigated by a number of authors. Unfortunately, studies have been uncontrolled and retrospective or have suffered from questionable study design or methodologic problems. Results of Deferred Therapy In 1972, Byar and colleagues published the single clinical trial (VACURG) in which patients were randomized either to aggressive surgical therapy (radical prostatectomy) or observation alone.32 In this study, a total of 76 men with stage A disease and 66 men with stage B tumors were randomized although 22% (31 of 142) were omitted for a variety of reasons. The overall cancer progression rate was 14% (16 of 111), and there was no significant difference in survival or progression between the observation and surgically treated groups. The authors concluded that if radical prostatectomy has any value for patients with stage A or B PCa, it must not be very dramatic. Unfortunately, this study had a small number of patients and a median follow-up of only 7 years. To evaluate the differences in progression of the disease and especially survival rates, a minimum of 10 to 15 years of follow-up is required following diagnosis. Moreover, a disproportionate number of patients with stage A PCa were included; lacking complete information about the volume or grade of tumor, it is conceivable that these men had very low-grade localized disease that would not progress despite treatment. Finally, excluding the randomized patients omitted from the study from the group with palpable disease (stage B), only 30 men underwent radical prostatectomy, of which 20 men were observed. Moskovitz et al.33 reported on 101 men with clinical stages T1b to T3 PCa managed by subtotal prostatectomy. The actuarial 5-year survival rates were 91.3, 60.6, and 41.7% for stages T1b, T2, and T3 disease, respectively. Moskovitz and colleagues concluded that these survival rates “resemble those quoted in the literature” and that “these results justify a less aggressive approach to carcinoma of the prostate.” The mean age of the patients in this report was 72 years (range of 50 to 92 years), which is past the age at which most urologists in the United States would consider offering aggressive therapy. As in 195


most watchful waiting series, many of the patients had low-grade, well-differentiated (57.4%) or moderately differentiated (21.8%) disease. At a mean follow-up of 58 months, 29% of the men had died of PCa, 23% of other causes, and 43% had PCa. Only 6% of men were alive without clinical evidence of prostate cancer.33,34 Whitmore et al.31 retrospectively reviewed the records of 75 men with clinical stage T2 PCa who received no therapy for at least 1 year following diagnosis. Actuarial survival at 15 years was 67%, 39%, and 63% in men with T2a, T2b, and T2c lesions, respectively. This is not a true watchful waiting series because definitive therapy was offered to all patients at the time of local progression. Again, the histology was favorable, including well- and moderately differentiated tumors in 48 and 39% of cases, respectively. Despite these favorable clinical features, 64% had local progression, 33% had distant metastases, and 22% died of PCa.31,34 Jones35 reported on 233 men with clinically localized PCa who were followed up conservatively for up to 25 years. The author concluded that “the overall survival of patients was not statistically different from the United States life-tables probability for men of similar ages” and that “it appears prudent that all patients with localized PCa should have this management option (deferred therapy) as well as radical prostatectomy or external irradiation.” This study has several flaws that were identified by Steinberg et al.34 The series was described as a long-term study of watchful waiting. However, 52 of the patients survived less than 3 years. Only 233 of the 306 patients were included in the data analysis. The treatment and outcome of the remaining 73 patients were not stated. The mean patient age, duration of follow-up, and rate of development of metastatic disease were not reported. When the data are examined closely, only 80 of the 233 men were followed expectantly. Brachytherapy was administered in 44 cases (19%), but treatment of the remaining 109 (47%) was not specified. In addition, of the 80 men followed expectantly, only 14 had survived more than 6 years, and 8 more than 11 years when the study was published.34,35 Adolfsson et al.36 reported on 122 men with well- or moderately differentiated clinically localized PCa that was diagnosed by needle aspiration cytology and then followed up conservatively. The mean follow-up was 91 months. Local tumor progression occurred in 55% of the patients and metastatic disease developed in 14%. The patients were carefully selected. The mean age at diagnosis was 68 years and all had well-differentiated (77%) or moderately differentiated (23%) tumors. Patients with poorly differentiated tumors were excluded from the study. The diagnosis of PCa in this series was established by needle aspiration cytology, a technique associated with a high incidence of false-positive results. Patients were also treated at the time of rapid local progression or

development of metastatic disease. The 5- and 10-year actuarial rates of progression to clinical stage T3 disease were 52% and 69%, respectively. The respective rates for metastatic disease were 10 and 26%.34,36 Johansson et al.37 reported on 223 patients with clinical stage T1 and T2 PCa for expectant therapy with delayed treatment. From 1977 through 1979, only patients with well-differentiated tumors were included. From 1979 through 1984, patients younger than 75 years of age who had moderately or poorly differentiated tumors were randomly allocated to receive local radiation or no treatment. No data were given on the patients treated with radiation therapy. There was also a subgroup of 58 patients younger than 70 years of age who met current indications for radical prostatectomy and had clinical T1 or T2 disease with moderately differentiated tumors. Local progression was noted in 21 patients (36%), distant progression in 7 (12%), and death from PCa in 5 (9%). The actual progression-free survival rate was 60% and 50% at 5 and 10 years, respectively. In the entire group, local progression was reported in 50 patients (22%), distant progression in 26 (12%), and death from PCa in 19 (9%). The actuarial progression-free survival rate was 68% and 53% at 5 and 10 years, respectively. Of the 47% of patients who showed progression at 10 years, 84% had undergone orchiectomy or treatment with estrogens. It can be assumed that the progression and death rates from PCa were even higher than reported.38 Again, this study was biased to include older men with early-stage, low-grade tumors. Although only 9% of the men died of PCa, 48% died of other causes during observation. Because of the older age of many patients, there were a number of deaths from other causes. Approximately 50% of patients who are over 70 years of age will die of a noncancer-related death after 10 years of observation. It is possible that many of the patients in the study did not live long enough for their prostate malignancy to be the primary cause of death. Also, there are questions about the method used by Johansson to diagnose PCa, aspiration biopsy technique, in these patients. The Swedish registry mandates that patients with atypia on fine-needle aspiration biopsy be classified as having cancer. There is a possibility that patients without cancer were classified as having grade I disease. Few studies correlate aspiration cytology and punch biopsy. Nakamura et al. showed that in 77 cases out of 102 patients diagnosed with PCa by needle biopsy, 90% were concordant with findings of aspiration cytology. Moreover, grading on aspiration cytology revealed only 60% agreement compared to tissue obtained with the histologic method.39 Chodak et al.40 summarized the results of six nonrandomized studies in a meta-analysis of 828 men with clinically localized prostate cancer who were treated conservatively with observation and delayed hormonal therapy. The 10-year disease-specific actuarial survival rate was 87% for those with grade I disease, 58% for those with grade II, and

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34% for those with grade III. The 10-year metastasis-free survival rate was 81% for those with grade I disease, 58% for those with grade II, and only 26% for those with grade III. Forty-two percent of patients with grade II disease developed metastatic disease at 10 years and 70% at 15 years. Actuarial survival statistics demonstrated that grade was the most significant variable in predicting survival.38 The aforementioned studies and the meta-analysis summary by Chodak have been severely criticized for selection bias (predominance of low-grade, low-stage tumors), no central pathologic review of the cases to confirm the diagnoses and grades of prostate cancer, and a median age of 69 years, suggesting that many men in the series died of other causes before being at risk of death from PCa. Albertsen et al.41 reported on 451 men diagnosed with clinically localized PCa between 1971 and 1976. The patients received no treatment or immediate or delayed hormonal therapy. The mean follow-up was 15.5 years. The age-adjusted survival of men with Gleason score 2 to 4 tumors was not significantly different from that of the general population. The maximum estimated lost life expectancy of men with Gleason score 5 to 7 tumors, however, comprising 80% of the study, was 4 to 5 years, and 6 to 8 years for patients with Gleason score 8 to 10 tumors. The authors concluded that “compared with the general population, men aged 65 to 75 years with conservatively treated low-grade PCa incur no loss of life expectancy.” They also stated that “men with higher grade tumors (Gleason scores 5 to 10) experience a progressively increased loss of life expectancy.” The former statement received much publicity but the latter statement received much less.34,41 The Albertsen study41 supports the treatment philosophy that older men with well-differentiated tumors do well with conservative treatment. Only 44 (9.8%), however, had well-differentiated tumors, including more than half with clinical stage T1a disease. Only 6 men (1.3%) had palpable stage T2 well-differentiated tumors. Further, almost half of the patients received immediate hormonal therapy. The 10- and 15-year survival rates for men with Gleason grades 5 to 7 were 32% and 15%, respectively, and 15% and 5% for those with Gleason grade 8 to 10. This compares with 10- and 15-year survival rates of 58% and 32%, respectively, in a healthy population. This study illustrates that even men older than 70 years with moderately or poorly differentiated PCa are at risk of losing several years of life with conservative therapy.34 Johansson et al.42 reported in 1997 on 642 men with PCa of any stage diagnosed between 1977 and 1984 in Sweden. The mean age of the patients was 72 years. Among 300 patients with a diagnosis of localized disease (T0-T2), 33 (11%) died of PCa. The corrected 15-year survival rate was similar in 223 patients with deferred treatment (81%) and in 77 patients who received initial treatment (81%). Johansson and colleagues concluded that “patients with localized PCa have a favorable outlook following watchful

waiting, and the number of deaths potentially avoidable by radical initial treatment is limited. Without reliable prognostic indicators, an aggressive approach to all patients with early disease would entail substantial overtreatment.” This study, too, has problems common to other watchful waiting series. The mean age of the patients was 72 years, diagnosis was made by fine-needle aspiration, and the patients who progressed to symptomatic disease were treated with estrogens or orchiectomy. More important, PCa accounted for a higher proportion of all deaths in patients younger than 61 years (44%) than in those older than 80 years (25%) at diagnosis. More patients with poorly differentiated tumors also died of the disease. From these data, observation would not seem appropriate for younger men with moderate and/or poorly differentiated tumors who have a longer life expectancy. Albertsen et al.43 reported on 767 men with localized PCa diagnosed between 1971 and 1984 who were aged 55 to 74 years at diagnosis, either treated or not treated with immediate or delayed hormonal therapy, and followed for up to 10 to 20 years after diagnosis. The primary objective of the analysis was to estimate the probability of dying from PCa or other competing causes given a patient’s tumor histology (Gleason score) and age at diagnosis. Men with Gleason scores of 2 to 4, 5, 6, 7, and 8 to 10 face a 4 to 7%, 6 to 11%, 18 to 30%, 42 to 70%, and 60 to 80% chance, respectively, of dying from PCa within 15 years of diagnosis depending on their age at diagnosis. The majority of the younger men with Gleason scores of 2 to 4 were still alive but face a possibility of death from PCa in the future. Most of the older men with low Gleason scores died from competing medical hazards rather than from PCa. The men with Gleason scores 5 and 6 had a somewhat higher risk of death from PCa when managed with observation. In contrast, men with Gleason scores 7 and 8 to 10 experienced a very high rate of death from PCa regardless of their age at diagnosis. Very few of these men are still alive. The above study had several limitations, as Albertsen et al. point out: many men had inadequate staging evaluations, many were excluded because of incomplete or absent records, the majority of diagnoses were made by transurethral resection (60%), and there is a lack of rationale behind the timing of hormonal therapy (immediate or delayed). The study does make clear that younger men are at risk longer of dying from untreated PCa if their Gleason score is greater than 5.43 Another study addressing the role of watchful waiting compared to aggressive initial therapy was published by Fleming et al. from the Prostate Patient Outcomes Research Team (PPORT).44 In this study, a decision analysis model was used to compare the outcomes of radical prostatectomy, external beam radiation, and observation in men with clinically localized PCa. Probabilities and rates of development of progressive disease and death from PCa were calculated from a review of the


medical literature. The authors concluded that in patients with well-differentiated tumors, treatment provides limited benefit over watchful waiting in terms of “qualityadjusted life expectancy.” For those patients with moderately or poorly differentiated PCa, the results of the study indicated that surgery or radiation therapy may provide up to 3.5 additional years of quality-adjusted life. Finally, the PPORT group concluded that men over 75 years of age are not likely to benefit from aggressive treatment when compared with watchful waiting. Determination of quality-adjusted life expectancy is based on the anticipated morbidity associated with radical prostatectomy or radiation therapy. More important, the overall results of the decision analysis are based largely on the tumor grade-specific rates of progression to metastatic disease in men managed by observation, derived from five published studies of watchful waiting.45,46

rates in the observation group are not representative of modern series of men with clinically localized PCa. Marked changes in detection and treatment of PCa as well as changes in life expectancy and overall health care over the period of the studies have had the result that the men selected for observation have little relation to patients currently diagnosed with PCa. Further study is needed to adequately address these issues. The PIVOT trial should provide answers to these questions.

Prognostic Factors for Localized Disease Many factors and variables are used in making decisions on treatment options for patients with localized disease. These may be categorized as patient variables, tumor variables, and access to medical care.49

Current Studies of Deferred Therapy

Patient Variables

The Scandinavian Prostatic Cancer Group is conducting a study in which patients with stages Tlb, Tlc, T2a, and T2b tumors are randomized between observation and radical prostatectomy.47 All men must be under 75 years of age, preferably under 70, with diagnosis of well-differentiated or moderately differentiated tumors. Patients selected for radical prostatectomy initially undergo pelvic lymphadenectomy, and the prostate is removed only in the absence of nodal metastases. Men with positive pelvic lymph nodes are initially observed, and hormonal therapy is initiated if symptomatic disease manifests. Patients randomized to initial observation are managed by a similar strategy. In the United States, a similar ongoing study, the Prostate Cancer Intervention Versus Observation Trial (PIVOT),48 compares expectant management and radical prostatectomy. It is sponsored by the Veterans Administration Cooperative Studies Program, the National Cancer Institute, and the Agency for Health Care Policy and Research. It is expected that over 1000 men under the age of 75 years who are candidates for radical prostatectomy will be enrolled. The primary end point is all-cause mortality. Secondary outcomes include PCa and treatment-specific morbidity and mortality, health status, predictors of disease-specific outcomes, and cost effectiveness of care. In the first 3 years of enrollment, nearly 500 men have been randomized. Early results of participants’ baseline characteristics indicate that enrollees are representative of clinically localized PCa patients throughout the United States, allowing results from PIVOT to be generalized. This study is necessary to determine preferred therapy for localized prostate cancer.48 It is immediately evident that underestimating or overestimating the progression rate of untreated PCa will significantly bias results against or in favor of aggressive therapy. Unfortunately, the patients selected in these studies who have been used to determine progression

The age of the patient at diagnosis is of paramount importance. The studies noted above have shown that men with a relatively short natural life expectancy, that is, under 10 years, will have little risk of cancer-related death or morbidity from cancer progression.33,36,40,43,49 These risks, however, increase considerably after 10 years. Observation may not be appropriate for younger men. Age alone, however, is not an accurate predictor of life expectancy or treatment outcome.49,50 Family history, longevity, and coexisting illness such as hypertension, cardiovascular disease, pulmonary disease, diabetes, and other illnesses may add or subtract several years to the patient’s physiologic age. The psychologic characteristics of the patient are also important. Some men may not be emotionally equipped to tolerate an observation protocol. This must be assessed during the initial visit and in subsequent interactions with the patient and his family. The patient must be relied upon to return for follow-up if an observation course is selected. Tumor Variables The stage of the tumor at diagnosis is important. The volume of the tumor, location, evidence of extension beyond the gland, the initial serum level of prostate-specific antigen, Gleason score, deoxyribonucleic acid (DNA) ploidy, and the growth rate of the tumor are all important variables to be considered when deciding on active treatment or observation.49 Prostate volume may be determined by DRE or TRUS if the tumor is palpable or sonolucent; accurate measurement with these techniques, however, is not certain and is often inaccurate. More information may be gained from the location and extent of malignancy found on the ultrasound-guided biopsy specimens and the measurement of tumor length within the biopsy core.49,51,52 Several studies in recent years have focused on the use of PSA as an adjunct prognostic marker in patients with

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clinically localized PCa. Partin and colleagues have demonstrated the value of combined data analysis— including clinical stage, serum PSA level, and preoperative Gleason score—to predict pathologic stage in 4133 men who underwent radical prostatectomy with clinically localized PCa at three academic medical centers.53 Prostate-specific antigen levels at diagnosis and the subsequent rise in serial serum PSA levels provide useful information for estimating the rate of tumor growth.49,54 Increasing tumor volume is usually concomitant with development of higher tumor grade, extension beyond the confines of the prostate, and metastatic potential.49,51 Currently, tumor grade (Gleason score) remains the single most useful predictor of disease progression and cancer mortality. This was shown in the meta-analysis by Chodak et al.,40 and by Albertsen et al.43 Men with high-grade localized tumors managed by surveillance had a much higher chance of progression to metastatic disease and of death from PCa after 10 years of followup, regardless of age at diagnosis. The analysis of DNA ploidy has been evaluated as a tool to predict biologic PCa behavior.49,55–57 Adolfsson et al.55 prospectively analyzed DNA ploidy in correlation to tumor progression in men with grade I or grade II malignancy who opted for surveillance. Almost equal numbers of diploid and nondiploid tumors were found. The nondiploid tumors progressed more rapidly and frequently than did the diploid tumors.49,55 Access to Medical Care Managed care restrictions, lack of medical insurance, and the availability of adequate, modern treatment facilities with the technical expertise of physicians, radiation therapists, and urologists are all factors that must be taken into consideration when selecting treatment options. The results of radical prostatectomy and radiation therapy reported from academic medical centers seem to have less morbidity and mortality than those reported using Medicare and other data sources.49

Rationale for Watchful Waiting and Monitoring for Localized Prostate Cancer Over the past decade, there have been a number of major advances in diagnosing and treating PCa. It is now possible to diagnose the disease in more men at an earlier stage due to the use of DRE, PSA testing, and improved biopsy techniques.58 The rationale for observation of men with localized PCa is based on several premises. First, there has been no decline in the disease-specific mortality rate despite advances in surgical and medical therapy for PCa over the past 30 years. Second, since the prevalence of PCa far exceeds the clinical incidence of the disease, there

is concern that some detected malignancies are “indolent” or “latent” and will not be progressive during the patient’s lifetime. Treatment of such cancers not only exposes patients to the risks of therapy they will not benefit from but also favorably biases the results of uncontrolled clinical trials. Finally, an increasing number of largely retrospective, uncontrolled studies have suggested that untreated men with low-grade malignancies have limited progression rates and high survival figures with follow-up of 5 to 10 years.33,35,36,40 Long-term prospective, randomized trials comparing early diagnosis with active therapy versus no treatment (watchful waiting) are in progress, but data from these clinical trials will not be available for many years, long after most urologists currently practicing have retired. At the current time, clinicians counseling a patient on treatment options for clinically localized prostate cancer should assess the patient’s overall medical condition (including attitude, fear, and anxiety) and family history of longevity as well as his tumor status and access to medical care.49 Watchful waiting is probably the best treatment option for men with well- and perhaps moderately differentiated, low-volume prostate cancer who have a life expectancy less than 10 years, as estimated by chronologic age and general health status. The patient should be comfortable with the prospect of living with the presence of prostate malignancy and the almost certain prospect that progression (albeit usually slow) will occur. The physician and patient must agree on what follow-up tests will be performed, their frequency, and the treatment implications of test results, as outlined by Adolfsson et al.49 The physician should be knowledgeable concerning prostate cancer behavior, should be available to perform followup visits within a facility that is easily accessible to the patient, and should educate the patient as much as possible concerning the nuances of the disease and its treatment.49 Most men older than 70 years, particularly those with well-differentiated tumors, derive little survival benefit from radical prostatectomy. The morbidity of radical prostatectomy is greater in older men.34,59 Therefore, except for those in excellent health and those with poorly differentiated tumors, most men older than 70 years should probably be treated alternatively. The conclusions derived from watchful waiting studies in older men, however, cannot and should not be applied to younger, healthier men who face the possibility of death from prostate cancer in the future, or to those with more advanced or aggressive disease. These studies also demonstrate that, when treated ineffectively, many of these men die of prostate cancer. The actual survival benefit with aggressive treatment is unknown at the present time.34 Hopefully, these data will be forthcoming with the above-mentioned randomized trials. In the interim, the best treatment strategy for the individual patient can be chosen using the above recommendations.34,49


References 1. Marks S. Prostate cancer: a family guide to diagnosis, treatment, and survival. 5th ed. Tucson (AZ): Fisher Books; 1997. 2. Wingo PA, Landis S, Ries LA. An adjustment to the 1997 estimate for new PCa cases. Cancer 1997;47:239. 3. Silverberg E, Boring CC, Squires TS. Cancer statistics. Cancer 1990;40:9. 4. Majeed FA, Burgess NA. Trends in death rates and registration rates for PCa in England and Wales. Br J Urol 1994;73:377. 5. Brasso K, Friis S, Iverson P. Is prostate cancer incidence increasing? [abstract 199]. J Urol 1997;157(Pt 2):53. 6. Nomura AM, Kolonel LN. Prostate cancer: a current prospective. Am J Epidemiol 1991;13:200. 7. Mettlin C, Jones GW, Murphy GP. Trends in prostate cancer care in the United States, 1974–1990: observations from the patient care evaluation studies of the American College of Surgeons Commission on Cancer. Cancer 1993;43:83. 8. Whittemore AS, Wu AH, Kolonel LN, et al. Family history and prostate cancer risk in black, white, and Asian men in the United States and Canada. Am J Epidemiol 1995;141:732. 9. Moul JW, Douglas TH, McCarthy WF, McLeod DG. Black race is an adverse prognostic factor for PCa recurrence following radical prostatectomy in an equal access health care setting. J Urol 1996;155:1667. 10. Fracchia J, Straley H, Wennberg J, Smith R. Managed care clinical corner: prostate cancer screening. Am J Managed Care 1997;3:923–6. 11. Andriole GL, Coplen DE, Mikkelsen DJ, Catalona WJ. Sonographic and pathological staging of patients with clinically localized prostate cancer. J Urol 1989;142: 1259–61. 12. Babaian RJ, Fritsche HA, Evans RB. Prostate-specific antigen and prostate gland volume: correlation and clinical application. J Clin Lab Anal 1990;4:135–7. 13. Bazinet M, Meshref AW, Trudel C, et al. Prospective evaluation of prostate specific antigen density and systematic biopsies for early detection of prostatic carcinoma. Urology 1994;43:44–6. 14. Canadian Task Force on the Periodic Health Examination: periodic health examination, 1991 update III. Secondary prevention of PCa. Can Med Assoc J 1991;145: 413–28. 15. Carter HB, Hamper UM, Sheth S, et al. Evaluation of transrectal ultrasound in the diagnosis of PCa. J Urol 1989;142:1008–10. 16. Cooner WH, Mosley BR, Rutherford CL Jr, et al. Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination, and prostate-specific antigen. J Urol 1990;143:1146–54. 17. Crawford ED, Schutz MJ, Clejan S, et al. The effect of digital rectal examination on prostate-specific antigen levels. JAMA 1992;267:2227–8. 18. Flanigan RC, Catalona WJ, Richie JP, et al. Accuracy of digital rectal examination and transrectal ultrasonography in localizing prostate cancer. J Urol 1994;152:1506–9.

19. Helzlsouer KJ, Newby J, Comstock GW. Prostate-specific antigen levels and subsequent prostate cancer: potential for screening. Cancer Epidemiol Biomarkers Prev 1992;1:537–40. 20. Hudson MA, Bahnson RR, Catalona WJ. Clinical use of prostate-specific antigen in patients with PCa. J Urol 1989;142:1011–7. 21. Humphrey PA, Walther PJ, Curtin SM, Vollmer RT. Histologic grade, DNA ploidy, and intraglandular tumor extent as indicators of tumor progression of clinical stage B prostate carcinoma. Am J Surg Pathol 1991;15:1165–70. 22. Kleer E, Oesterling JE. Prostate-specific antigen and staging of localized prostate cancer. Urol Clin North Am 1993;20:675–704. 23. Komatsu K, Wehner N, Prestigiacomo AF, et al. Physiologic (intraindividual) variation of serum prostate-specific antigen in 814 men from a screening population. Urology 1996;47:343–6. 24. Oesterling JE, Chan DW, Epstein JI, et al. Prostate-specific antigen in the preoperative and postoperative evaluation of localized prostatic cancer treated with radical prostatectomy. J Urol 1988;139:766–72. 25. Jewett HJ. The present status of radical prostatectomy for stages A and B prostatic cancer. Urol Clin North Am 1975;2:105–24. 26. Epstein JI, Walsh PC, Brendler CB. Radical prostatectomy for impalpable PCa: the Johns Hopkins experience with tumors found on transurethral resection (stages Tla and Tlb) and on needle biopsy (stage Tlc). J Urol 1994;152:1721–9. 27. Bakke A, Grong K, Hoisaetre PA. Should we treat localized prostatic cancer? Proceedings of the 1985 Finnish Urological Club Meeting; 1985 March 1; 58–65. 28. Larsson A, Norlen BJ. Five-year follow-up of patients with localized prostatic carcinoma initially referred for expectant treatment. Scand J Urol Nephrol 1985;19 Suppl:30. 29. Orestano R. Problems of the wait-and-see policy in incidental carcinoma of the prostate. In: Altwein JE, Faul P, Schneider W, editors. Incidental carcinoma of the prostate. Berlin: Springer-Verlag; 1991. p. 163–6. 30. Jones GW. Prospective, conservative management of localized prostate cancer. Cancer 1992;70 Suppl:307–10. 31. Whitmore WF Jr, Warner JA, Thompson IM. Expectant management of localized prostatic cancer. Cancer 1991;67:1091–6. 32. Byar DP, Mostofi FK, Veterans Administration Cooperative Urological Research Group. Carcinoma of the prostate: prognostic evaluation of certain pathological features in 208 radical prostatectomies examined by step-section technique. Cancer 1972;30:5–13. 33. Moskovitz B, Nitecki S, Richter Levin D. Cancer of the prostate: is there a need for aggressive treatment? Urol Int 1987;42(1):49–52. 34. Steinberg GD, Bales GT, Brendler CB. An analysis of watchful waiting for clinically localized prostate cancer. J Urol 1998;159:1431–6. 35. Jones GW. Prospective, conservative management of localized prostate cancer. Cancer 1992;70(1 Suppl):307–10.

T1b-T2NxM0: the Case for Observation / 201 36. Adolfsson J, Carstensen J, Lowhagen T. Deferred treatment in clinically localized prostate cancer. Br J Urol 1992;69 183. 37. Johansson JE, Adami HO, Andersson SO, et al. High 10-year survival rate in patients with early, untreated prostatic cancer. JAMA 1992;267:2191–6. 38. Partin AW, Walsh PC. Surgical management of localized prostate cancer. In: Raghavan D, Scher HI, Leibel SA, Lange PH, editors. Principles and practice of genitourinary oncology. Philadelphia (PA): LippincottRaven; 1997. p. 499. 39. Nakamura T, Akimoto S, Shimazaki J. Usefulness of fine needle aspiration cytology in the diagnosis of prostate cancer. Jpn J Urol 1995;86:853–9. 40. Chodak GW, Thistad RA, Gerber, G, et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994;330:242. 41. Albertsen PC, Fryback DG, Storer BE, et al. Long-term survival among men with conservatively treated localized prostate cancer. JAMA 1995;274:626–31. 42. Johansson JE, Holmberg L, Johansson S, et al. Fifteen-year survival in prostate cancer. A prospective, populationbased study in Sweden. JAMA 1997;277:467–71. 43. Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998;280:975. 44. Fleming C, Wasson JH, Albertsen PC, et al. A decision analysis of alternative treatment strategies for clinically localized prostate cancer. J Urol 1993;269:2650–8. 45. Zhang G, Wasserman NF, Sidi AA, et al. Long-term followup results after expectant management of stage Al prostatic cancer. J Urol 1991;146:99–103. 46. Haapiainen R, Rannikko S, Makinen J, Alfthan O. To carcinoma of the prostate: influence of tumor extent and histologic grade on prognosis of untreated patients. Eur Urol 1986;12:16–20. 47. Chodak GW, Gerber, G. Treatment of early stage prostate cancer. Comprehensive textbook of genitourinary oncology. Baltimore (MD): Williams & Wilkins; 1996. p. 734–41. 48. Wilt TJ, Brawer MK. The Prostate Cancer Intervention Versus Observation Trial. VHSJ 1998;3:60.

49. Adolfsson J, Austenfeld M, Thompson IM. The case for conservative therapy for localized prostate cancer. In: Rashavan D, Scher HI, Leibel SA, Lange PH, editors. Principles and practice of genitourinary oncology. Philadelphia (PA): Lippincott-Raven; 1997. p. 468–72. 50. Corral DA, Bahnson RR. Survival of men with clinically localized prostate cancer detected in the eighth decade of life. J Urol 1994;151:1326–9. 51. Stamey TA, Freiha FS, McNeal JE, et al. Localized prostate cancer. Relationship of tumor volume to clinical significance for treatment of prostate cancer. Cancer 1993; 71(3 Suppl):933–8. 52. Terris MK, McNeal JE, Stamey TA. Estimation of prostate cancer volume by transrectal ultrasound imaging. J Urol 1992;147(3 Pt 2):855–7. 53. Partin AW, Kattan MW, Subong EN, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 1997;277: 1445–51. 54. Schmid HP, McNeal JE, Stamey TA. Observations on the doubling time of prostate cancer. The use of serial prostate-specific antigen in patients with untreated disease as a measure of increasing cancer volume. Cancer 1993;71:2031–40. 55. Adolfsson J, Ronstrom L, Hedlund PO, et al. The prognostic value of modal deoxyribonucleic acid in low-grade, low-stage untreated prostate cancer. J Urol 1991;144: 1404–6. 56. Montgomery BT, Nativ O, Blute ML, et al. Stage B prostate adenocarcinoma. Flow cytometric nuclear DNA ploidy analysis. Arch Surg 1990;125:327–31. 57. Greene DR, Rogers E, Wessels EC, et al. Some small prostate cancers are nondiploid by nuclear image analysis: correlation of deoxyribonucleic acid ploidy status and pathological features. J Urol 1994;151:1301–7. 58. Smart CR. The results of prostate carcinoma screening in the U.S. as reflected in the Surveillance, Epidemiology, and End Results program. Cancer 1997;80:1835–44. 59. Lu-Yao GL, McLerran D, Wasson J, Wennberg JE. An assessment of radical prostatectomy. Time trends, geographic variation, and outcomes. The Prostate Patient Outcomes Research Team. JAMA 1993;269:2633–6.

CHAPTER 22

RADICAL RETROPUBIC PROSTATECTOMY FOR CLINICAL STAGE T1B-T2 PROSTATE CANCER MOSHE SHALEV, MD; BRIAN J. MILES, MD

Radical prostatectomy is considered a very effective form of treatment for patients with localized prostate cancer and a life expectancy of 10 years or more. Until 1947, when Millin1 introduced the retropubic approach, this operation was performed perineally. The retropubic approach gained popularity in the late 1970s after the introduction by Walsh2 and associates of a series of technical modifications based on a precise definition of periprostatic anatomy. These modifications resulted in reduced blood loss and lower rates of incontinence and erectile dysfunction, transforming the radical retropubic prostatectomy into a safer operation with an acceptably low morbidity rate. However, radical prostatectomy is curative only if all cancer is removed. For this reason, only patients with clinically organ-confined disease should be selected for surgery. Due to the generalized use of prostate-specific antigen (PSA) testing and the growing public and physician awareness of this disease, more patients are diagnosed at an earlier stage than in the past, making more men eligible for this operation. In 1997, 52,000 men underwent a radical retropubic prostatectomy and a similar number of operations are estimated for 1998.3 The ideal candidates for surgery are men with biopsy Gleason scores of ≤ 7 and a PSA below 10 ng per mL, who therefore have a probability of lymph node involvement of less than 1% and seminal vesicle involvement of less than 3%.4,5

who have a greater than 10 years life expectancy, a clinical stage of T2a or less, a biopsy Gleason grade of < 4 (primary or secondary), or a Gleason score < 7 and PSA levels of less than or equal to 10 ng per mL.6–8 Carcinoma of the prostate invading the seminal vesicles (stage T3c) is recognized as a very poor prognostic feature. In general, radical prostatectomy is not indicated in these patients due to the poor long-term results. It is estimated that seminal vesicle invasion will be found in 14.6% of patients with clinically organ-confined cancer.9,10 The Kaplan-Meier actuarial likelihood of PSArecurrence-free survival 4 years after surgery in patients with localized prostate cancer and seminal vesicle invasion is less than 50%.11 Poorly differentiated tumors usually have significant extracapsular extension at the time of diagnosis but biopsy Gleason score should not be used alone for excluding patients from surgery as patients with poorly differentiated cancer confined to the prostate have been found to have an excellent prognosis, similar to those of lower-grade cancer. The 5-year nonprogression rates were 85 ± 18% and 92 ± 4%, respectively.12 In a multi-institutional study on a group of 4133 patients treated with radical prostatectomy, nomograms to predict pathologic stage were developed, which combined PSA level, clinical stage, and Gleason score. These nomograms correctly predicted the probability of a pathologic stage 72.4% of the time,8–10,13 and they can be used when counseling patients to make more informed treatment decisions. However, it is important to point out to patients that the final pathologic stage does not equate with ultimate prognosis, for example, a 50% chance of extracapsular extension does not equal a 50% chance of recurrence (especially if the margins are negative).

Preoperative Assessment Accurate preoperative staging requires digital rectal examination (DRE), measurement of serum PSA level, transrectal ultrasonography (TRUS), and ultrasoundguided biopsy of the prostate for histologic examination and assessment of biopsy Gleason grade and score. Staging of prostate cancer involves the judicious use of bone scan and computed tomography (CT)/magnetic resonance imaging (MRI) of the pelvis and/or abdomen to detect systemic or locoregional disease. The combination of these parameters can give a good prediction of tumor extent in the individual patient. The best long-term results in terms of PSA nonprogression rates and progression-free rates have been achieved in healthy patients

Technique Radical prostatectomy is generally preceded by modified bilateral pelvic lymph node dissection, encompassing the tissue located between the external iliac vein laterally, the obturator nerve medially, Cooper’s ligament distally, and the bifurcation of the common iliac vein proximally. These nodes are forwarded for gross evaluation by the patholo202

Radical Retropubic Prostatectomy for Clinical Stage T1b-T2 Prostate Cancer / 203

gist, who performs frozen section when there is suspicion of metastasis. At our institution, only 2% of patients have been found to have unsuspected nodal microscopic involvement. Some investigators have recently recommended abandoning routine pelvic lymph node dissection because of the increased ability to accurately predict the likelihood of lymphatic metastasis.14 The basis for this recommendation is to decrease costs and potential morbidity from this procedure. We, however, feel that this is an important part of a complete cancer operation. Carrying out lymph node dissection with radical prostatectomy allows the accurate assignment of final pathologic stage and helps in planning future management strategies should the patient develop a PSA recurrence. After the pelvic lymph node dissection is completed, the endopelvic fascia is identified and opened bilaterally. The levator ani muscle fibers that are invariably loosely adherent to the prostate are then gently swept laterally off the prostatic surface, exposing the apex of the prostate. We then minimally incise the puboprostatic ligaments, being careful not to carry the dissection of these ligaments distally under the pubis, where the chance of injuring the external sphincter and continence mechanism increases significantly. The dorsal vein complex must now be addressed. The work of Reiner and Walsh15 has greatly improved our understanding of the anatomy of dorsal vein and periprostatic venous complexes and, thus, our ability to manage it. Although back bleeding from these complexes has sometimes been minimal, we have found that it is usually significant and therefore warrants control. To this end, we place sutures of 0-Vicryl at the bladder neck, and midprostate (Figure 22–1A). The dorsal vein complex is then approached. An index finger is placed under the complex and the Foley catheter/urethra localized. With gentle pressure between the urethra and dorsal vein complex, against the underside of the contralateral symphysis pubis, the lateral pelvic fascia investing these structures is disrupted. One must be careful not to carry out this blunt manipulation excessively to avoid carrying the dissection distally into the sphincteric structures. A right-angle clamp is then passed under the dorsal vein complex, and a 22-gauge sternal wire is grasped and brought beneath it (Figure 22–1B). This wire pulls the complex into a very distinct bundle and serves as a guide for sharply transecting it while simultaneously minimizing the chances of inadvertently cutting into the anterior prostate (Figure 22–1C). Bleeding from the dorsal venous complex is then controlled by closing the edges of the lateral pelvic fascia over the complex with a running 2-0 Vicryl suture (Figure 22–1D). Finally, the divided portion of the dorsal vein complex on the surface of the prostate is oversewn with running sutures. It is important to not drift laterally over the surface of the prostate when controlling this back bleeding; the edges of the lateral pelvic fascia have to be

simply closed to control bleeding. Drifting further laterally will generally create bleeding from the venous plexus running laterally over the surface of the prostate. After gaining hemostasis of the dorsal venous complex, the pillars of the prostate must then be taken down to completely expose the apex of the prostate. Once this is accomplished, the lateral pelvic fascia over the neurovascular bundles is approached (Figure 22–2A). If a nerve-sparing procedure is being performed, the fascia is incised anterior to the neurovascular bundle; if not, it is incised posterior to the bundle (Figure 22–2B). During this dissection, the posterior layer of Denonvilliers’ fascia is incised to ensure that it is incorporated with the specimen. When the posterior layer of Denonvilliers’ fascia is included with the prostate, the anterior perirectal fat will be seen along the entire surface of the rectum and not the shiny white plane that is more comfortable for blunt dissection, and that is located between the leaves of the fascia (Figure 22–3A). If the bundles are being sacrificed, the distal end is ligated with 3-0 chromic ligatures for hemostasis. After appropriately handling the neurovascular bundles, the urethra is transected, and 6 sutures of 2-0 Monocryl are placed at the 1, 3, 5, 7, 9, and 11 o’clock positions, tagged, and draped for future placement in the corresponding positions of the bladder neck (see Figure 22–3A). In placing the posterior sutures, care must be exercised to ensure inclusion of the edge of the posterior layer of Denonvilliers’ fascia with the urethra and yet to avoid incorporating a portion of the neurovascular bundle in this suture. Once the sutures have been placed, the prostate is lifted off the anterior surface of the rectum, being certain to include both layers of Denonvilliers’ fascia (perirectal fat should be seen along the entire surface). Once the prostate is dissected to the level of the lateral pedicles of the seminal vesicles, the Foley catheter, which has been removed just prior to placement of the posterior urethral sutures, is reinserted, placing modest traction on the prostate. The lateral pedicles are then mobilized, clipped, and transected. The seminal vesicles are mobilized in the standard fashion, and the ampullae of the vasa identified and transected. The prostate is then removed by transecting the attachments to the bladder neck. Although some advocate a bladder neck-sparing approach, we believe the bladder neck should be widely resected to ensure clear margins at the base and easy, wide eversion of the bladder mucosa over the neobladder neck. Once the mucosa is everted with 3-0 Vicryl, a 2-0 figure-of-8 Vicryl is placed to define the inferior, 6 o’clock position of the bladder neck. The rest of the defect is closed in the standard tennis racket-fashion. At the end of bladder neck reconstruction, the new bladder neck should have a stoma-like appearance (Figure 22–3B). The urethral sutures are placed in the corresponding positions in the bladder neck, and the urethrovesical anastomosis completed.


A

B

C

D

FIGURE 22–1. Management of the dorsal venous complex.

Early Complications In the last decade, intraoperative complications and death secondary to radical retropubic prostatectomy have been significantly reduced. Major complications occur in 5.4 to 9.8% of the patients and death within 30 days from the operation in 0.3 to 0.4% of cases.16–18 The most frequent, major perioperative complications are hemorrhage, rectal injury, deep venous thrombosis, and pulmonary embolism (Table 22–1). Hemorrhage In 1979, after describing the anatomy of the male pelvis, Reiner and Walsh15 proposed the ligation of the dorsal vein complex early in the course of the operation to decrease

A

blood loss. Adopting this approach and by giving special attention to the major blood supply to the prostate and seminal vesicles, intraoperative blood loss can be reduced to 600 to 850 mL. For major control of prostatic vasculature, Mittemeyer19 proposed the antegrade (from bladder to prostatic apex) dissection of the prostate that, together with early dorsal vein ligation, has resulted in reduced intraoperative blood loss.18,20,21 Despite his success with this technique, it is infrequently used and not recommended by the authors. The reduced blood loss achieved in recent years has decreased the transfusion rate to 10% or less in patients who do not donate autologous blood.22 Because the transfusion rate is so low and the safety of the homologous blood pool has significantly improved, the preparation of autologous blood for transfusion is not cost effec-

B

FIGURE 22–2. Lateral approach to apex and neurovascular bundles.


A

B

FIGURE 22–3. Management of posterior layer of Denonvilliers’ fascia (A) and eversion of bladder neck (B).

tive and not recommended. Preoperative hemodilution is a less costly and more acceptable alternative to the autologous blood procurement technique for some patients, such as Jehovah’s Witnesses.23 Postoperative bleeding requiring acute transfusions is estimated to occur in 0.5% of the patients24 (Table 22–2). Rectal Injury Rectal injury is uncommon and estimated to occur in 0.6 to 1% of the patients.16,18,25 Factors predisposing patients to rectal injury during the operation are previous pelvic radiation therapy, rectal surgery, and transurethral resection of the prostate (TURP). Higher local tumor stage has not been associated with this complication.26 Injury to the rectal wall most often occurs during the apical dissection and division of the rectourethralis muscle. Rectal injury recognized during the operation can be successfully repaired after the prostatectomy has been completed by primary closure without a diverting colostomy. The injury is closed in two layers, and the anal sphincter is dilated. Some authors advocate the placement of the omentum between the rectum and the vesicourethral anastomosis to reduce the potential of fistula formation, although we have not found this necessary. Deep Venous Thrombosis and Pulmonary Embolism Deep venous thrombosis and pulmonary embolism are complications that frequently appear after patients are discharged from the hospital, with an incidence estimated to be approximately 2%.18,27,28 The inclusion of sequential pneumatic compression devices as a prophylactic measure during and after surgery are reported to have no influence on the incidence of this complication.29 Early ambulation is beneficial and essential, and should be encouraged in all patients. In a recent study, Heinzer and colleagues pointed out that lymphoceles and hematomas are important cofactors in the pathophysiology of thromboembolic complications after radical prostatectomy as

they compress the pelvic and lower extremity veins. Early diagnosis by pelvic ultrasonography and anticoagulant treatment can reduce the rate of this complication, especially in patients on heparin prophylaxis.28 The rate of venous thrombosis and pulmonary embolism can be effectively reduced after surgery by perioperative subcutaneous low-dose heparin injections but the increased risk of hemorrhage and lymphorrhea has decreased the frequency of its use in radical prostatectomy. The role of low-molecular-weight heparin as a prophylactic agent after radical prostatectomy, although not apparently associated with an increased risk of hemorrhage, has not been established.

Late Complications Anastomotic Strictures The cause (or causes) of anastomotic strictures is uncertain but is generally believed to be due to inadequate mucosa-to-mucosa apposition during urethrovesical reconstruction. Other contributing factors may be excessive intraoperative blood loss, prolonged anastomotic urine leakage, prior history of TURP, and excessive bladder neck reconstruction.30,31 The incidence of anastomotic contractures after radical retropubic prostatectomy has been reported to range from 1 to 22%.30 Preservation of the bladder neck reduced the incidence of strictures from 8.2 to 3.3% in Lowe’s study, with no statistically significant difference in the incidence of positive surgical margins when compared with a group of patients in whom the bladder neck was not preserved. We believe that wide eversion of the bladder neck mucosa and proper placement of the urethral sutures can further contribute to lower the rate of this complication31 (Table 22–3). Dribbling, weak urinary stream, or urinary overflow incontinence are suggestive of bladder neck contracture. The evaluation of these patients should include ultrasound measurement of postvoid residual urine and flexible cystoscopy to evaluate the anastomotic site. Treatment

206 / Advanced Therapy of Prostate Disease TABLE 22–1. Early Complications and Mortality Rate after Retropubic Radical Prostatectomy Complication

Zincke 199418 N = 1728

Hautmann 199432 N = 418

Gaylis 199816 N = 116

Andriole 199427 N = 1342

Dillioglugil 199717 N = 472

0.6 1.1 0.7 0

2.9 1.7 1.4 1.2

0.9 1.8 1.8 0

0.2 0.6 1.7 0.2

0.6 1.3 1 0.4

Rectal injury (%) Thrombophlebitis/deep vein thrombosis (%) Pulmonary embolism (%) Mortality within 30 days (%)

options include dilation, bladder neck incision, or bladder neck resection. Usually, one or two urethral dilations will suffice to eradicate the problem but for severe or persistent contractures, cold-knife incisions may be required. Correction of recalcitrant, excessively fibrotic contractures will infrequently require wide transurethral resection, and these are invariably associated with significant urinary incontinence. Incontinence Urinary incontinence is considered by many to be the complication with the most significant impact on quality of life following radical retropubic prostatectomy. There exists the belief in some quarters that fear of incontinence may cause many patients to seek alternative treatments. In the hands of surgeons with expertise in radical retropubic prostatectomy, incontinence requiring the use of pads is estimated to occur in less than 8% of cases. Fowler and associates, however, found that 31% of a Medicare population of patients reported some degree of wetness.37 These variations may be partially the result of patientreported versus physician-reported outcomes and the lack of a uniform definition of continence but they do point to a problem in interpreting published results describing quality-of-life changes due to radical prostatectomy. At our institution, physician-reported incontinence of any degree at 24 months after the operation is about 5%. Several modifications to the surgical technique have been proposed to enhance postoperative urinary control. Hollabaugh and colleagues have described techniques to avoid injury to the pelvic nerve and intrapelvic branch of the pudendal nerve, thereby achieving continence in 98% of patients, with a median time to “dryness” of 1 week and 95% of patients achieving dryness by 4 months.38 On the other hand, patients who are candidates for nervesparing surgery usually have a lower clinical stage and tend to be of a younger age. These parameters may have a

TABLE 22–2. Estimated Blood Loss (EBL) in Patients Undergoing Radical Retropubic Prostatectomy Series Meide et al.20 Zincke et al.18 Gaylis et al.16 Scardino33

No. of Patients

Mean EBL (mL)

Range (mL)

200 1728 116 100

748 600 872 850

340–1256 — 100–2500 250–2300

greater influence on the results than the nerve-sparing technique by itself. Others have suggested puboprostatic ligament sparing, bladder neck preservation, and proximal prostatic urethra and preprostatic sphincter preservation for improving continence and rapidity of return of urinary control.30,39,40 We believe that bladder neck sparing is not important and routinely employ wide resection to ensure clear margins at the base. Wide eversion of the bladder mucosa over the bladder neck is important, and the new bladder neck should have a stoma-like appearance after reconstruction. Not only does this reduce bladder neck contracture formation but also we believe that mucosal apposition at the new bladder neck created by this wide or exaggerated eversion contributes to continence, much as it does in the female urethra. Risk factors for postoperative incontinence include age over 65 years and bladder neck contracture. Incontinence may spontaneously improve in about 1 year after the operation; therefore, it is best to defer any invasive corrective treatment for at least this period. Impotence The most important factors which correlate with the return of erectile function after radical retropubic prostatectomy are age and preservation of the neurovascular bundles. Nerve-sparing surgery should be considered in relatively young patients at a low clinical stage, preferably stage T1c (in whom the nerves can be safely spared), with a Gleason score of ≤ 6 and normal sexual function before surgery. In one series, men under the age of 50 years preserved their potency in 90% of the cases if one or both neurovascular bundles were preserved but for older patients, sexual

TABLE 22–3. Incidence of Anastomotic Strictures (N) after Radical Retropubic Prostatectomy Series Shelfo et al.,30 1998 Tomschi et al.,34 1998 Popken et al.,35 1998 Lowe,31 1996 Lowe,31 1996 Eastham et al.,36 1996 * Series with bladder neck preservation.

No. of Patients

N (%)

365 239 340 91 99 360

5 (1)* 36 (15) 24 (7) 3 (3.3)* 8 (8.2) 23 (6)


function was better when both neurovascular bundles were preserved.41 Catalona reported retained potency in 63% and 41% when bilateral or unilateral neurovascular bundles were preserved, respectively42 (Table 22–4). In our institution, after November 1993 when a modified technique to the apical prostatic dissection was adopted (as described above), the postoperative potency rate is 71% at 17 months in men under the age of 65 years.

Positive Surgical Margins Positive surgical margins are defined as extension of the tumor to the inked surface of the resected specimen and suggests incomplete excision of the tumor. Positive margins may be a result of an inadvertent incision into the prostate or due to extraprostatic tumor extending beyond the prostatic capsule and the limits of resection. The overall rate of positive surgical margins in radical prostatectomy varies among surgeons and institutions but averages approximately 28%.43 In the last decade, there has been a shift in the patient population undergoing radical prostatectomy, with a distinct increase in patients with stage T1c disease. This fact, together with improved surgical technique, has led to a decrease in the rate of positive surgical margins at most centers with a broad expertise in radical prostatectomy. At Baylor College of Medicine, there has been a decline in positive surgical margins from 19% in the late 1980s to 8% after adopting the lateral approach to the neurovascular bundles.44 In general, the preservation of the neurovascular bundle by itself does not result in a higher rate of positive margins and does not adversely influence cancer control in carefully selected patients.45,46 The prostatic apex is a frequent site of positive surgical margins. It is estimated that up to 69% of the positive margins are found in the apical region of the prostate.47,48 This is attributed to the fact that the prostate apex is often a difficult area for exposure and dissection, leading to a higher rate of positive surgical margins. However, we have found that by using the lateral approach to the neurovascular bundles and the prostatic apex, the rate of surgical margins in this area can be significantly reduced. Klein and colleagues found this to be true and reported a decrease in positive margins from 37.4% to 15.8% using this technique.49 Positive surgical margins appear more frequently in patients with a PSA of 10 ng per mL or greater, biopsy Gleason score of ≥ 7, multiple positive biopsies, or clinical stages of T2b, T2c, or T3. TABLE 22–4. Potency Rate According to Age after Radical Retropubic Prostatectomy Age (Years)

Quinlan41

Catalona42

% of Patients

% of Patients

< 50 50–59 60–69 ≥ 70

90 82 69 22

60 84 57 33

In general, positive margins confer a significantly poorer prognosis. When combining Gleason score, pathologic stage, and surgical margin status, Walsh and colleagues2 demonstrated that positive margins did not significantly increase the recurrence rate in tumors with Gleason scores from 2 to 6 with focal capsular penetration.11 In contrast, positive surgical margins in tumors with established extracapsular penetration and/or a Gleason score of ≥ 7 had the same progression rate as tumors with seminal vesicle invasion. Neoadjuvant androgen ablation has been suggested to reduce the rate of positive surgical margins. Although this technique has been shown to reduce positive surgical margins, no benefit in progression rates or improved survival has been demonstrated.43,50

Surgical Efficacy Recently, the 10-year experience with radical retropubic prostatectomy was reviewed at Baylor College of Medicine. Using actuarial analysis at 5 and 10 years, the overall PSA nonprogression rate in this series of 1120 patients was 76% and 71%, respectively. These results are comparable with those from other centers of excellence (Table 22–5). The progression-free survival rate after radical retropubic prostatectomy is dependent on clinical stage, Gleason score, and preoperative PSA level. At our institution, PSA-based, 5-year nonprogression rates above 80% have been achieved in patients with clinical stage up to T2b, Gleason score up to 7, and preoperative PSA up to 10 ng per mL. However, the most powerful parameter in predicting progression is the pathologic stage of the cancer.45 In 92% of patients with pathologically organ-confined disease, PSA is undetectable and patients are clinically disease-free at 5 years of follow-up. The data collected from various institutions clearly show that radical prostatectomy can cure the majority of prostate cancer patients with acceptable morbidity.

Summary In the last decade, there have been several advances in the diagnosis and treatment of localized prostate cancer. These TABLE 22–5. Actuarial (PSA-based) 5- and 10-Year Nonprogression Rates in Patients after Radical Retropubic Prostatectomy for Clinical Stage T1 and T2 Prostate Cancer PSA Nonprogression Rate (%) Groups Johns Hopkins52 Washington University7 Mayo Clinic50 UCLA51 Baylor

No. of Patients

5 Years

10 Years

894 925 4774 610 1120

83 78 74 69 76

70 — — 47 71


have caused a shift toward a higher percentage of patients diagnosed at a low-stage disease who are candidates for surgery and who can be cured. The actuarial nonprogression rate at 10 years after surgery determined by an undetectable PSA level in patients at stage T1-T2 in modern series is approximately 70%46,53 (see Table 22–5). There are no other treatment options that have achieved these results, and therefore radical prostatectomy remains an ideal form of treatment for localized prostate cancer.

References 1. Millin T. Retropubic urinary surgery. London: Livingstone; 1947. 2. Walsh PC, Donker PJ. Impotence following radical prostatectomy: insight into etiology and prevention. J Urol 1982;128:492–7. 3. National Center for Health Statistics. Detailed diagnosis and procedures. National Hospital Discharge Survey. Hyattsville (MD): Center for Disease Control; 1997. 4. Terris MK, McNeal JE, Freiha FS, Stamey TA. Efficacy of transrectal ultrasound-guided seminal vesicle biopsies in the detection of seminal vesicle invasion by prostate cancer. J Urol 1993;149:1035–9. 5. Weldon VE, Tavel FR, Neuwirth H. Continence, potency and morbidity after radical perineal prostatectomy. J Urol 1997;158:1470–5. 6. Partin AW, Yoo J, Carter HB, et al. The use of prostatespecific antigen, clinical stage and Gleason score to predict pathological stage in men with localized prostate cancer. J Urol 1993;150:110–4. 7. Catalona WJ, Smith DS. 5-year tumor recurrence rate after anatomical radical retropubic prostatectomy for prostate cancer. J Urol 1994;152:1837–42. 8. Partin AW, Kattan MW, Subong EN, et al. Combination of prostate-specific antigen, clinical stage and Gleason score to predict pathological stage of localized prostate cancer. A multi-institutional update. JAMA 1997;277: 1445–51. 9. Stone NN, Stock RC, Unger P. Indications for seminal vesicle biopsy and laparoscopic pelvic lymph node dissection. J Urol 1995;154:1392–6. 10. O’Dowd GJ,Veltri RN, Orozco R, et al. Update on the appropriate staging evaluation for newly diagnosed prostate cancer. J Urol 1997;158:687–98. 11. Pound CR, Partin AW, Epstein JI, Walsh PC. Prostatespecific antigen after anatomic radical retropubic prostatectomy. Patterns of recurrence and cancer control. Urol Clin North Am 1997;24:395–406. 12. Ohori M, Goad JR, Wheeler TM, et al. Can radical prostatectomy alter the progression of poorly differentiated prostate cancer? J Urol 1994;152:1843–49. 13. Kattan MW, Eastham JA, Stapleton AM, et al. A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer. J Natl Cancer Inst 1998;90:766–71. 14. Bluestein DL, Bostwick DG, Bergstralh EJ, Oesterling JE. Eliminating the need for bilateral pelvic lymphadenectomy in select patients with prostate cancer. J Urol 1994;151:1315–20.

15. Reiner WG, Walsh PC. An anatomical approach to the surgical management of the dorsal vein and Santorini’s plexus during radical retropubic surgery. J Urol 1979; 121:198–200. 16. Gaylis FD, Friedel WE, Armas OA. Radical retropubic prostatectomy outcomes at a community hospital. J Urol 1998;159(1):167–71. 17. Dillioglugil O, Leibman BD, Leibman NS, et al. Risk factors for complications and morbidity after radical retropubic prostatectomy. J Urol 1997;157:1760–7. 18. Zincke H, Oesterling JE, Blute ML. Long-term (15 years) results after radical prostatectomy for clinically localized (stage T2c or lower) prostate cancer. J Urol 1994; 152:1850–7. 19. Mittemeyer BT, Cox HD. Modified radical retropubic prostatectomy. Urology 1978;12:313–20. 20. Meide G, Kleer GC, Kielczewski P, et al. Autologous blood donation prior to anatomical radical retropubic prostatectomy: is it necessary? Urology 1997;49:569–73. 21. Menon M, Voidyanathan S. The University of Massachusetts technique of radical prostatectomy. Eur J Surg Oncol 1995;21(1):66–8. 22. Goad JR, Scardino PT. Modifications in the technique of radical retropubic prostatectomy to minimize blood loss. Atlas Urol Clin North Am 1994;2:65–70. 23. Monk TG, Goodnough LT, Brecher ME, et al. Acute normovolemic hemodilution can replace preoperative autologous blood donation as a standard of care for autologous blood procurement in radical prostatectomy. Anesth Analg 1997;85:953–8. 24. Hedican SP, Walsh PC. Postoperative bleeding following radical retropubic prostatectomy. J Urol 1994;152: 1181–3. 25. Borland RN, Walsh PC. The management of rectal injury during radical retropubic prostatectomy. J Urol 1992; 147(3 Part 2):905–7. 26. McLaren RH, Barrett DM, Zincke H. Rectal injury occurring at radical retropubic prostatectomy for prostate cancer: etiology and treatments. Urology 1993;42:401–5. 27. Andriole GL, Smith DS, Rao G, et al. Early complications of contemporary anatomical radical retropubic prostatectomy. J Urol 1994;152:1858–60. 28. Heinzer H, Hammerer P, Graefen M, Huland H. Thromboembolic complication rate after radical retropubic prostatectomy. Impact of routine ultrasonography for the detection of pelvic lymphocele and hematomas. Eur Urol 1998;33(1):86–90. 29. Cisek LJ, Walsh PC. Thromboembolic complications following radical retropubic prostatectomy. Urology 1993;42:406–8. 30. Shelfo WS, Obek C, Soloway MS. Update on bladder neck preservation during radical retropubic prostatectomy: impact on pathologic outcome, anastomotic stricture and continence. Urology 1998;51(1):73–8. 31. Lowe BA. Comparison of bladder neck preservation to bladder neck resection in maintaining post prostatectomy urinary continence. Urology 1996;48:889–93. 32. Hautmann RE, Sauter TW, Wenderoth UK. Radical retropubic prostatectomy: moribidity and urinary continence in 418 consecutive cases. Urology 1994;43(2 Suppl):47–51.

Radical Retropubic Prostatectomy for Clinical Stage T1b-T2 Prostate Cancer / 209 33. Goad RJ, Eastham JA, Fitzgerald KB, et al. Radical retropubic prostatectomy: limited benefit of autologous blood donation. J Urol 1995;154:2103–9. 34. Tomschi W, Suster G, Holtl W. Bladder neck strictures after radical retropubic prostatectomy, still an unsolved problem. Br J Urol 1998;81:823–6. 35. Popken G, Sommerkamp H, Schultze-Seemann W, et al. Anastomotic stricture after radical prostatectomy. Incidence, findings and treatment. Eur Urol 1998; 33:382–6. 36. Eastham AJ, Kattan WM, Rogers E, et al. Risk factors for urinary incontinence after radical prostatectomy. J Urol 1996;156:1707–13. 37. Fowler FJ Jr, Barry MJ, Lu-yao G, et al. Effect of radical prostatectomy for prostate cancer on patient’s quality of life: results from a Medicare survey. Urology 1995; 45:1007–13. 38. Hollabaugh RS Jr, Dmochowski RR, Kneib TG, Steiner MS. Preservation of putative continence nerves during radical retropubic prostatectomy leads to more rapid return of urinary continence. Urology 1998;51:960–7. 39. Poore RE, McCullough DL, Jarow JP. Puboprostatic ligament sparing improves urinary continence after radical retropubic prostatectomy. Urology 1998;51(1): 67–72. 40. Kaye KW, Creed KE, Wilson GJ, et al. Urinary continence after radical retropubic prostatectomy. Analysis and synthesis of contributing factors: a unified concept. Br J Urol 1997;80:444–501. 41. Quinlan DM, Epstein JI, Carter BS, Walsh PC. Sexual function following radical prostatectomy: influence of preservation of neurovascular bundles. J Urol 1991; 145:998–1002. 42. Catalona WJ. Surgical management of prostate cancer. Cancer 1995;75:1903.

43. Wieder JA, Soloway MS. Incidence, etiology, location, prevention and treatment of positive surgical margins after radical prostatectomy for prostate cancer. J Urol 1998;160:299–315. 44. Ohori M, Wheeler TM, Kattan MW, et al. Prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 1995;154:1818–24. 45. Epstein JI, Pizov G, Walsh PC. Correlation of pathologic findings with progression after radical retropubic prostatectomy. Cancer 1993;71:3582–93. 46. Walsh PC, Partin AW, Epstein JI. Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. J Urol 1994;152:1831–6. 47. Stamey TA, Villers AA, McNeal JE, et al. Positive surgical margins at radical prostatectomy: importance of the apical dissection. J Urol 1990;143:1166–72. 48. Gomez CA, Soloway MS, Civantos F, Hachiya T. Bladder neck preservation and its impact on positive surgical margins during radical prostatectomy. Urology 1993;42:689–93. 49. Klein EF, Kupelian PA, Tuason L, Levin HS. Initial dissection of the lateral fascia reduces the positive margin rate in radical prostatectomy. Urology 1998;51:766–73. 50. Abbas F, Scardino PT. Why neoadjuvant androgen deprivation prior to radical prostatectomy is unnecessary. Urol Clin North Am 1996;23:587–604. 51. Amling CL, Blute ML, Lerner SE, et al. Influence of prostate-specific antigen testing on the spectrum of patients with prostate cancer undergoing radical prostatectomy at a large referral practice. Mayo Clin Proc 1998;73:401–6. 52. DeKernion JB, Franklin JR, Belldegrun A, Smith RB. Surgery from a US perspective. Cancer Surv 1995;23:315–20. 53. Partin AW, Pound CR, Clemens JQ, et al. Serum PSA after anatomic radical prostatectomy. Urol Clin North Am 1993;20:713–25.

CHAPTER 23

RADICAL PERINEAL PROSTATECTOMY DAVID F. PAULSON, MD Anatomy

approached posterior to the urogenital diaphragm.2 Continuing the dissection into the urogenital diaphragm may damage the external sphincteric mechanism accompanying the membranous urethra as it pierces the urogenital diaphragm (Figure 23–2).

Understanding the anatomy of the male perineum allows the perineal surgeon to make appropriate preoperative, postoperative, and intraoperative decisions in patients with prostatic cancer. The perineum is defined as that area which exists between the thighs and extends from the coccyx to the pubis.1 It is the most external aspect of the pelvic outlet; the superior boundary is the levator ani. The lower or perineal surface of the levator ani is felt to form the upper boundary of the perineum. Both the anal and urogenital canal exit the levator ani to appear on the perineal surface. The perineal region can be divided into anterior and posterior triangular segments by a transverse line passing just anterior to the ischial tuberosities and in front of the anal canal. This chapter deals only with the anterior perineal triangle, which can be the “urogenital triangle” (Figure 23–1). The anterior urogenital triangle contains a fibromuscular septum, the urogenital diaphragm, that extends across the anterior portion of the pelvic outlet below the levator ani. This is of anatomic importance to the perineal surgeon as the prostate and associated structures are

Anterior and Posterior Triangles The anal and urogenital triangle of the perineum have the levator ani in common, forming the perineum’s uppermost boundary. The musculature existing in the perineum inferior to the levator ani has a common attachment in the midline between the two regions, with a blending of the two sets of muscles forming a fibromuscular mass referred to as the central tendon of the perineum (Figure 23–3). The central tendon is interposed between the anterior surface of the anal canal and the posterior surface of the urethra. This central tendon must be severed in a perineal prostatectomy to allow for posterior displacement of the anus and rectum. The ischiorectal fossa is a potential space lying lateral to the anus between the skin of the anal region and the levator ani and posterior to the transverse perineal musculature. This fossa is filled with fibrofatty tissue and as a potential space must be developed to access the prostate (Figure 23–4). After incision through the skin overlying the perineum, the surgeon cannot pass a finger directly into this potential space. Entrance must be made by an incision through an outer condensation of the fibrofatty tissue, the superficial perineal fascia. This fascia is classically described as being contiguous with Camper’s fascia (the fibrofatty tissue extending onto the abdomen and across the pubis). If this fibrofatty tissue is entirely removed, a muscular diaphragm and a series of muscular bands are exposed. The external or voluntary anal sphincter surrounding the anal canal and rectum for a distance of approximately 2 cm from the lower surface levator ani to the anal canal can thereby be well visualized. Two bands of muscle arise from the coccyx, separate to pass the rectum, and converge anteriorly to insert on the perineal body. These form a portion of the anal sphincter. Some fibers of the external anal sphincter are circular; they are termed the subcutaneous external anal sphincter, as opposed to the superficial external anal sphincter (those fibers described above that sweep from posterior to anterior, from coccyx to perineal body) (Figure 23–5). The urologic surgeon is concerned only with that portion

FIGURE 23–1. The dotted line drawn between the ischial tuberosities separates the anterior and posterior perineal triangles. The dissection carried out during radical perineal prostatectomy is conducted in the anterior urogenital triangle. The urogenital diaphragm fills a portion of the anterior urogenital triangle. The intent of the surgeon should be to approach the prostate beneath the posterior aspect of the urogenital diaphragm. 210

Radical Perineal Prostatectomy / 211

tum itself. Some of the longitudinal smooth muscle fibers from the anterior surface of the rectum leave the rectal wall to run on the upper surface of the levator ani. There they pass forward to attach to the urethra. These constitute the rectourethralis muscle (Figure 23–6). In approaching the prostate from the perineum, the fibers of the rectourethralis must be divided or separated in the midline (after the attachments of the external anal sphincter to the central tendon have been divided) to access the prostate. The fibers of the rectourethralis become contiguous with the neurovascular fascia surrounding the prostate.

FIGURE 23–2. The dotted line indicates the incorrect line of dissection through the prostate. Note that the correct line of incision is beneath the anal sphincter and beneath the posterior margin of the urogenital diaphragm. Dissection through the urogenital diaphragm risks injury to the membranous urethra and distal urethral sphincter.

of the anal sphincter that is anterior to the rectum. The fibers incised to gain access to the prostate are identified in Figure 23–5. They are termed the central tendon and insert on the perineal body (or the midpoint of the transverse perineal diaphragm). These fibers are cut at the point of their insertion into the perineal body.

Membranous Urethra and Urogenital Diaphragm The perineal surgeon must recognize the posterior aspect of the urogenital diaphragm and understand that the correct approach to the prostate is posterior to the transverse perineal musculature. The apex of the prostate is beneath the posterior aspect of the urogenital diaphragm (see Figure 23–2). Continence after prostatectomy is largely dependent on the intrinsic urethral mechanism that exists within the membranous urethra as it exits through the urogenital diaphragm. An improper approach to the prostate may cause the surgeon to dissect within, rather than beneath, the urogenital diaphragm. In so doing, it is easy to fragment the membranous urethra. Leaving the patient with this portion of the sphincteric mechanism damaged contributes to urinary incontinence. The membranous urethra is the shortest subdivision of the male urethra. It lies largely within the deep perineal space and is surrounded by the fibers of the sphincteric urethra. It may be no more than 1 cm in length, begin-

The Rectourethralis The rectum, as it passes through the muscles of the pelvic floor, becomes confluent with some fibers of the levator ani, which actually blend with the muscular wall of the rec-

FIGURE 23–3. The central tendon of the perineum is schematically represented here. This lies just beneath the subcutaneous tissues of the perineum, anterior to the rectum. With the patient in the exaggerated lithotomy position, it is defined as a fanlike fibromuscular structure extending from the anterior surface of the rectum.

FIGURE 23–4. The parasagittal section through the ischiorectal fossa. The broken line separating the major part of the ischiorectal fossa from its anterior recess represents the part of the so-called roof membrane sometimes described as separating the two parts of the fossa. From Hollingshead WH, editor. Anatomy for surgeons. 2nd ed. New York: Harper & Row; 1971.


Summary An appreciation of each of these features of the perineal anatomy is important to properly carry out the perineal prostatectomy. The functional integrity of these structures must be preserved in reconstructive and extirpative procedures.

Radical Perineal Prostatectomy

FIGURE 23–5. Once the central tendon has been divided, the surgeon identifies the superficial and subcutaneous external anal sphincters. The superficial anal sphincter sweeps around the anus and inserts anteriorly. In the midportion of the perineum, beneath two muscle bundles, is a surgical space that is triangular in nature. By retracting the superficial external anal sphincter fibers superiorly and laterally, the surgeon may identify the glistening white fascia of the rectum and use this as a guide to the prostate.

ning above the urogenital diaphragm at the apex of the prostate and ending just below the diaphragm. Here, after exiting the perineum, it becomes continuous with the bulbar urethra. Fasciae of the Pelvis An understanding of the fascial sheaths in the perineum is important in properly conducted operative procedure in this area. The retrovesical septum is an important anatomic structure. It is attached to the peritoneum of the rectovesical pouch superiorly and has been called the “anterior layer” of Denonvilliers’ fascia. The anterior portion of the rectal fascia that is easily separable from the anterior layer of Denonvilliers’ fascia is commonly called the “posterior layer” of Denonvilliers’ fascia (Figure 23–7).3,4 The two layers of Denonvilliers’ fascia have been suggested to represent both anterior and posterior layers of the peritoneum of the rectovesical pouch, which, after development, has receded from its original contact with the pelvic floor. It is now felt, however, that the septum itself represents a local condensation of areolar tissue. The anterior surface of Denonvilliers’ or the rectovesical septum covers the posterior aspect of the prostate and the seminal vesicles. This must be incised if the seminal vesicles are to be approached from below (Figure 23–8). Similarly, the potential space between the posterior aspect of bladder and the seminal vesicles is sheathed by a fascial layer that must be incised if the seminal vesicles are to be approached anteriorly.

Radical perineal prostatectomy is growing in popularity as a surgical procedure. It has been used by few surgeons over the past three decades because most have been taught radical retropubic prostatectomy. Nevertheless, the procedure has recently become much more in vogue because of recognized advantages of the operative approach. The surgical conduct of perineal prostatectomy as originally described has been modified over the past 25 years. This chapter describes modifications in radical perineal prostatectomy developed by the author over the past two decades and compares them with modifications described by others. Patient Selection Surgical treatment of prostatic malignancy is appropriate only for those patients in whom the disease is confined to the prostate. Preoperative staging maneuvers should be designed to ensure that the disease is so confined. Most of the patients the author and colleagues currently operate on have had isotopic bone scanning to exclude metastatic skeletal disease at the time of initial consultation. Both preoperative bone scan and staging pelvic lymphadenectomy may be excluded, however, in patients who have Gleason scores of 7 or less and whose prostate-specific antigen (PSA) level is < 25 ng per mL. The incidence of metastatic disease is under 2% when these criteria are used. Preoperative Preparation The patient is provided an osmotic bowel preparation the day before surgery and nonabsorbable oral antibiotics the evening before the procedure. On the morning of surgery, a neomycin enema is given 2 to 3 hours before the scheduled operative procedure. Broad-spectrum antibiotics are given parenterally as required. Contraindications Patients with significant competing risks of death estimated to result in mortality 10 years from the projected date of surgery are not considered candidates for radical prostatectomy. In general, patients who have previously undergone an open transcapsular or transvesical prostatectomy should not be considered candidates for perineal prostatectomy since fixation of the prostatic capsule or bladder within the pelvis may compromise the urethrovesical anastomosis. The procedure may be safely carried out in these patients, however, if adequate care is


taken. Previous transurethral resection of the prostate is not a contraindication and does not increase the risk of intraoperative or postoperative complications, nor does it increase the risk of postoperative incontinence. The author and colleagues routinely delay radical prostatectomy for 6 to 8 weeks after transurethral resection to allow healing of the prostatic fossa. The author, however, has operated as early as 3 to 4 days after transurethral resection without adverse outcome. Patients who are massively obese may not tolerate the exaggerated lithotomy position since the intra-abdominal contents may compromise diaphragmatic excursion and prevent adequate respiration, even with increased ventilatory pressures. Previous pelvic radiation, other pelvic surgery, and abdominal-perineal resection are not contraindications for perineal prostatectomy, except when previous therapy has compromised the bladder neck. Operative Procedure The procedure may be accomplished on a standard operating table with adequate leg support. The author prefers to use candy-cane stirrups, wrapping the feet to insure that the straps do not place excessive pressure on bony prominences (Figure 23–9).5 There is no need to wrap the legs or place them in alternating pressure stockings. The patient is positioned far from the head of the table, the small of the back being brought to the edge of the table with the buttocks extending approximately 20 to 30 cm over the table and the feet then rotated toward the head. It is not necessary to use shoulder braces to stabilize the patient. With the patient properly positioned, the weight of the patient is borne across the shoulder blades, and sandbags or folded towels are placed beneath the sacrum and the small of the back to maintain elevation of the pelvis. When legs and feet are rotated toward the head and the patient has been properly positioned, the perineum is parallel to the floor. The ischial tuberosities can be palpated and should lie in a line just posterior to the anus.

Urethra

Rectourethralis

Rectum

FIGURE 23–6. The rectourethralis is a condensation of muscular fibers that run from the rectum to the urethra anteriorly. It is variable in a cephalad-caudad direction and is always in the midline. The surgeon may create a space on each side of the rectourethralis all the way to the prostate itself. The rectourethralis may then be sharply divided without fear of injury to the rectum.

Surgical Procedure The procedure commences with a skin incision made approximately 1.5 cm anterior to the anal verge, extended posterolaterally on either side of the anus medial to the ischial tuberosities, and continued behind the anus on each side.5 To open the ischiorectal space, a defect using cutting cautery is created in the superficial perineal fascia on either side of the central tendon. The surgical space in the ischiorectal fossa is developed by placing a finger in this defect perpendicular to the floor and medial to the ischial tuberosities themselves (Figure 23–10).6 The finger is curved toward the operating surgeon and the overlying fibrofatty tissue is incised with cutting cautery. The next maneuver is designed to isolate the central tendon. Allis clamps are placed on the mucosa of the anus and the distal rectal segment placed on tension. The surgeon passes a finger beneath the central tendon and palpates

FIGURE 23–7. Schema of the fascial sheaths of the pelvic viscera in the male in sagittal section. Although essentially tubular condensations of connective tissue around the viscera, they receive contributions from or are continuous with the neurovascular sheaths, largely visible in sagittal section but represented here by puboprostatic ligament of the umbilicovesical fascia; from the fascia of the upper surface of the levator ani; and in the male from the rectovesical septum. From Hollingshead WH, editor. Anatomy for surgeons. 2nd ed. New York: Harper & Row; 1971.


FIGURE 23–8. The central tendon is divided close to the skin margin.

the taut rectal surface. There is a defect just distal to the rectourethralis as it inserts on the rectum. The finger is passed just distal to the rectourethralis over the surface of the rectum and exits the contralateral side. The tissue superior to the finger represents the tissue of the central tendon. The central tendon itself is a fibromuscular tissue that arises on the tip of the coccyx, flows around the rectum, and inserts on the perineal body. This fibromuscular tissue must be divided so that the anus and rectum can be displaced posteriorly. Once the surgeon has passed a finger anterior to the rectum, distal to the rectourethralis, and beneath the central tendon, the central tendon is divided in its entirety with cautery. The line of incision is made close to the skin margin (see Figure 23–8). The rectum will drop posteriorly following division of the central tendon. With upper traction on the perineal

body, the rectourethralis is easily identified as is the glistening surface of the anterior rectal fascia. Using Metzenbaum scissors held so that the curve approximates the curve of the rectum, and by gently spreading the scissors on either side of the midline, with blunt dissection, the anterior surface of the rectum can be exposed and mobilized on either side of the rectourethralis to and beyond the level of the prostatic apex (Figure 23–11). The next maneuver is designed to place the rectourethralis under tension. To accomplish this, an examining finger is placed in the rectum to place downward pressure on it while an assistant elevates the perineal body in the opposite direction using the anterior retractor. The operating surgeon now places a finger on either side of the rectourethralis to further open the space by blunt dissection. Using Metzenbaum scissors, the rectourethralis is partially cut in the midline. As the tissue is divided with Metzenbaum scissors, the midportion of the rectourethralis is seen to be white and largely avascular. Gently spreading the Metzenbaum scissors in the midline will create a defect between the two lateral leaves of the rectourethralis. The rectourethralis can then be separated to the level of the prostate. To facilitate access to the prostate, an assistant can push the prostate into the operative field using the Lowsley retractor. This will immobilize the prostate while the surgeon separates the supporting fibers of the levator sling and the fibrofascial tissue surrounding the prostate, and through which the nerves of corporal innervation pass. Once identified in the midline, the next maneuver will fully expose the prostate posteriorly and laterally by dissecting beneath the neurovascular fascia. This is accomplished using either a sharp or blunt dissection lateral to the prostate. Once this fascia has been identified, the decision can be made to sacrifice the neurovascular fascia or maintain it. Baby Deaver retractors are then placed either medial or lateral to the neurovascular fascia, at the surgeon’s discretion (Figure 23–12). Attention is then focused on developing a plane between the rectum and prostate. After the prostate has been exposed in the manner described above, its posterior aspect will be covered with fibromuscular tissue that is seemingly continuous with the anterior rectal surface. By downward pressure on the rectum, easily maintained by use of a weighted vaginal speculum, the margin between the rectum and prostate can be identified. These fibers may be divided using Metzenbaum or Strully scissors. Once they have been divided, digital dissection is used to develop a surgical space between the prostate and seminal vesicles anteriorly, and the rectal surface posteriorly. Exposure of the Prostate Apex and Urethra

FIGURE 23–9. The patient is placed in exaggerated lithotomy.

Once the prostate has been exposed laterally and posteriorly, the next step is to expose the apex of the prostate and identify the urethra. With the prostate exposed and still


FIGURE 23–10. The ischial space is opened with cautery.

covered posteriorly at the apex with fibromuscular tissue, the surgeon may palpate the Lowsley retractor within the urethra at the apex of the prostate. With Strully scissors, the fibers overlying the apex of the prostate and the urethra are incised only in the midline. With blunt dissection using a bronchial dissector, the prostate apex is displaced inferiorly and the urethra exposed in the midline. The dissector may then be pushed on either side of the urethra medial to the vasculature exiting from the prostate.5 The lymphatics from the prostate flow in this tissue and apical disease may extend along this vasculature. This neurovascular tissue, however, is independent of the neural tissue providing innervation to the corpora and should be divided. These vascular structures are sharply incised, and the surgeon, with digital dissection to the right and left of the urethra, can separate prostatic substance from the overlying dorsal venous complex and carry this dissection to the detrusor musculature.

FIGURE 23–11. The rectourethralis is placed on tension.

FIGURE 23–12. The urethra is separated from the adjacent vascular tissue.

At this point, a right-angled clamp is placed around the urethra. The clamp is opened and the prostatic substance separated from the urethra at the apex of the prostate to establish as much urethral length as possible beneath the transverse perineal diaphragm (Figure 23–13). It is often possible to establish a urethral length of 1 to 1.5 cm beneath the transverse perineal diaphragm, and it is this portion of the urethra that is important in postoperative urinary control. (Having biopsied over 200 of the patient-side urethral segments and not identifying malignancy, the author does not believe this maneuver places the patient at increased risk for residual malignancy.) Once the urethra is fully mobilized, the Lowsley retractor is removed

FIGURE 23–13. The urethra is divided at the apex of the prostate.


FIGURE 23–14. The vasculature to the prostate lies lateral to the seminal vesicles.

and the urethra divided at the apex of the prostate, with the patient-side margin being tagged with 2-0 suture to permit easy identification during reconstruction.

FIGURE 23–15. A direct urethrovesical anastomosis is supported by modified Vest suture anterior and posterior to the urethra.

Following division of the urethra, a Young prostatic tractor (or a straight Lowsley retractor) is passed through the urethra into the bladder and the blades extended. These permit the surgeon to identify the bladder wall and also manipulate the operative specimen. Allis clamps or a tenaculum may be placed on the prostate to draw it into the operative field and permit identification of the plane between prostate and detrusor fibers. With blunt dissection, the plane between the prostate and detrusor can be developed to the right and left of the bladder neck and the latter identified in the midline. Investing fibrous tissue between prostate and bladder laterally can be also identified and sharply divided. There is no significant vasculature in this tissue and, if vasculature is identified, it is not of a size to cause significant bleeding. Cut vessels can be easily cauterized to establish hemostasis. With the prostate under tension, the tissue extending from the bladder neck into the prostate is easily identified. This is then sharply divided using curved Metzenbaum scissors, then a large curved clamp is passed through the prostatic urethra from apex to bladder neck and a loop of soft rubber catheter brought through and used for manipulation of the specimen. With traction on the catheter and the tenaculi, the prostate is further mobilized on either side of the posterior bladder neck. Once it is maximally mobilized but still adherent to the posterior bladder neck, curved Metzenbaum scissors are passed behind the bladder neck to sharply divide the posterior bladder neck. Before doing this, however, a tagging suture should be placed on the bladder neck as the bladder will retract into the pelvis, possibly making it difficult to identify the bladder neck after removal of the prostate. With traction on the prostate to bring it further into the operative field, the surgeon should use scissors to incise the fibromuscular tissue overlying the vas deferens and seminal vesicles in the midline. This is largely an avascular fascia and the tissue may be divided with impunity. Once the vasa deferentia have been identified in the midline and the seminal vesicles lateral to the vasa deferentia, the physician can mobilize the lateral vascular pedicles to the prostate. This is accomplished using a right-angled clamp, passing it just lateral to the seminal vesicles but medial to the vascular pedicle to the prostate (Figure 23–14). Once this space has been developed, the vascular pedicles can be controlled using surgical clips, or they can be sharply divided and bleeding points subsequently controlled by electrocoagulation. Using the seminal vesicles as an anatomic marker, the seminal vesicles can be entirely encircled at the base of the prostate, all investing tissue being sharply divided to mobilize the prostate. Once the fibromuscular tissue and vascular pedicles have been severed, the specimen is held in place only by the seminal vesicles and vas deferens and by the fascia overlying the seminal vesicles posteriorly. The specimen may be elevated in the operative field and the fascia


the pelvis, separating the prostate and seminal vesicles from the rectal surface to the apex of the seminal vesicles and then controlling them. This is the methodology espoused by Harris and Thompson.6 When the vesicles are initially exposed, the pedicles at the base of the prostate are ligated and divided before exposure of the anterior prostate. The choice of surgical approach to the seminal vesicles, whether positive initially or anteriorly after division of the urethra, is purely physician preference. The current author finds it technically easier to approach the seminal vesicles and vas deferens as described.

Management of the Bladder Neck FIGURE 23–16. Kaplan-Meier projection of time-to-cancer-associated-death for patients with organ-confined, specimen-confined, or margin-positive disease.

divided. With the seminal vesicles identified, each vasa deferentia is isolated in the midline, controlled with a surgical clip, and divided. The seminal vesicles may be exposed either in their entirety or for a distance of 2 to 3 cm. If the surgeon elects not to remove the seminal vesicles in their entirety, they can be controlled at a distance of 2 to 3 cm from the prostate with surgical clips before division and the specimen then removed. There is no enhanced disease control established by removing the seminal vesicles in their entirety. This can be done but may be technically difficult. Also, there is concern that dissection to the tips of the seminal vesicles may compromise the neural innervation of the bladder and increase the probability of postoperative detrusor dysfunction. Alternatively, after the prostate has been exposed posteriorly, the prostate may be completely elevated within

FIGURE 23–17. Time to PSA failure as a function of disease extent.

There is much discussion surrounding “bladder neck preservation” versus excision of the bladder neck.6 Harris and Thompson6 advocate preservation. The current author, however, widely excises tissue at the bladder neck to ensure that all prostatic tissue has been removed. Preservation of the bladder neck fibers does not, the author believes, improve postoperative continence as this depends largely on that segment of urethra preserved at the level of the transverse perineal diaphragm. Wide excision of the bladder neck is accomplished by grasping the posterior bladder neck with an Allis clamp at the 6 o’clock position and cutting away the bladder neck from the 6 through 8 to 12 o’clock positions, and from the 6 through 4 to 12 o’clock positions. The surgeon then places a traction suture in the bladder neck at the 6 o’clock position, maintaining tension on the posterior bladder neck by weight of a Kelly clamp. Attention is then turned to covering the raw detrusor from the 9 through 12 to 3 o’clock segments with bladder mucosa. This is accomplished with 0000 Monocryl. The 6 to 9 o’clock and 6 to 3 o’clock segments need not be covered with mucosa since this portion will be closed in the subsequent racket-handle closure. Once the anterior bladder neck has been covered with vesicle mucosa, 0-strength absorbable sutures are placed outside-inside and inside-outside approximately 0.5 cm to either side of the 12 o’clock midline (Figure 23–15).

FIGURE 23–18. Time to continence.


These will later be brought through the perineal body and tied beneath the skin to support the direct urethrovesical anastomosis. An 18F Foley catheter is passed through the urethra. The previously placed 0-0 suture is used to identify the urethra as it penetrates the transverse perineal diaphragm. The surgeon then places 0-0 absorbable sutures in the urethra at the 2, 4, 8, and 10 o’clock positions. The two sutures placed at the 4 and 8 o’clock positions are driven in the mucosa-covered bladder neck approximately 0.5 cm from the 12 o’clock midline. An 18F Foley catheter is passed through the urethra and into the bladder and the balloon inflated. The bladder neck is closed from the 6 to 12 o’clock position with interrupted 0-strength absorbable sutures, the closure being made tight around the 18F Foley catheter. The two 0-0 urethral sutures that were placed at the 10 and 2 o’clock positions in the urethra are then brought into the reconstructed bladder neck approximately 0.5 cm on either side of the racket-handle closure. These four 0-0 absorbable sutures are snugly tied. Once the four direct anastomotic sutures have been secured, the two 0-strength absorbable sutures previously placed in the bladder neck near the 12 o’clock midline and the last two 0 sutures used in the racket handle posteriorly are brought through the transverse perineal body on the right and left side of the urethra with a No. 8 surgeon’s needle. These are tied beneath the skin. The wound is drained with a Penrose drain and the central tendon reconstructed using absorbable 0-0 sutures. Skin margins are closed with 0-0 strength absorbable vertical mattress sutures.

Postoperative Care The patient is mobilized within 6 to 8 hours after surgery, and oral intake is initiated within 4 to 8 hours after surgery. The patient is administered oral antibiotics plus a stool softener. Patients are routinely discharged 48 hours after the day of surgery. The catheter is left in place for 14 to 18 days and then removed by either the operating or referring surgeon. Although it is possible to remove the catheter earlier, the author and colleagues have found that difficulties in voiding after catheter removal are markedly reduced if the catheter is left in place for a longer period. Disease Control Benefit of Perineal Prostatectomy Although proponents of both perineal prostatectomy and retropubic prostatectomy vigorously maintain that their respective procedure provides superior cancer control, a rational assessment of the impact of disease control would indicate that equivalent outcome is achieved by either method. In a series of over 1200 patients subjected to radical prostatectomy at Duke University (segregated by local extent of disease—organ confined, specimen confined [microscopic T3 with negative margins], or margin positive [microscopic T3 with positive margins]), the PSA failure rates and cancer-associated death rates were equiva-

lent to other large single institution series using either perineal or retropubic surgery (Figures 23–16 and 23–17). The postoperative urinary control rate appears similar for patients subjected to radical perineal prostatectomy, even at geographically diverse sites. Weldon et al.7 from the University of California at San Francisco have reported a continence curve in 220 consecutive patients that closely approximates that reported by Frazier et al.8 (Figure 23–18). In the Duke University experience, 54 of 122 patients in this particular segment of the study were dry at the time of catheter removal. With the modifications described in this review, approximately 70% are dry at the time of catheter removal. The cumulative postoperative potency rate in 50 selected patients demonstrates a rate of approximately 75% for the California group, which is quite similar to the 77% potency rate in the Duke University experience. All three investigators reported a potency rate of 70%.6–8 Most adherents of perineal prostatectomy argue there is much less blood loss with the perineal approach than with the retropubic approach because the perineal dissection is conducted beneath rather than through Santorini’s venous plexus. The average operative blood loss reported by the San Francisco group was 600 cc.7 The average blood loss reported by the Duke University group was 565 cc.8 Harris and Thompson6 also reported low blood loss, though their exact figure is indeterminate. This blood loss figure should be compared to the blood loss reported by retropubic surgeons, which ranges from 1200 to 2000 cc per patient.

Conclusion It appears that perineal prostatectomy offers significant advantages over retropubic surgery with respect to surgical outcome. It is usually well tolerated by patients and surgeons.

References 1. Hollingshead WH, editor. Anatomy for surgeons. 2nd ed. New York: Harper & Row; 1971. 2. Paulson DF. The surgical technique of radical perineal prostatectomy. AUA Update Series. Vol.5 (lesson 38). Houston (TX): American Urological Association, 1986. 3. Paulson DF. Perineal prostatectomy. In: Marshall FF, editor. Operative urology. Philadelphia: WB Saunders; 1991. 4. Little NA, Paulson DF. Perineal radical prostatectomy. In: Whitehead ED, editor. Current operative urology. Philadelphia: JB Lippincott; 1989. 5. Paulson DF. Radical perineal prostatectomy. In: Marshall FF, editor. Textbook of operative urology. Philadelphia: WB Saunders; 1996. p. 545–54. 6. Harris MJ, Thompson IM. The anatomic radical perineal prostatectomy: a contemporary and anatomic approach. Urology 1996;48:762–8. 7. Weldon VE, Tavel FR, Neuwirth H. Continence, potency, and morbidity after radical perineal prostatectomy. J Urol 1997;158:1470–5. 8. Frazier HA, Robertson JE, Paulson DF. Radical prostatectomy: the pros and cons of the perineal versus retropubic approach. J Urol 1992;147:888–90.

CHAPTER 24

CONTINENCE-ENHANCING MODIFICATIONS FOR RADICAL PROSTATECTOMY MARK R. LICHT, MD; ERIC A. KLEIN, MD the prostatic urethra to the level of the verumontanum. These fibers are innervated by the autonomic nervous system. The distal sphincter is composed of an inner smooth muscle urethral layer combined with an outer periurethral arrangement of striated muscle fibers. The distal sphincter is innervated by both the autonomic nervous system via the pelvic plexus and somatic nerve branches from the pudendal nerve.8,9 The striated muscle of the distal sphincter is arranged in an approximate omega shape over the membranous urethra and the prostatic apex, with the bulk of the tissue oriented anteriorly beneath the dorsal vein complex. The distal sphincter is supported by the pelvic fascia, the puboprostatic ligaments, and the posterior midline fibrous tissue raphe, which is intimately associated with Denonvilliers’ fascia and the rectourethralis muscle. The overlap of fibers of the proximal and distal sphincter zones and the coordinated activity of each has led Myers to consider one unified continence mechanism as a continuum from bladder neck to membranous urethra.10 He describes this anatomic distance as the sphincteric functional urethral length. This concept is helpful in understanding how technical aspects of radical prostatectomy may influence urinary control. Factors contributing to normal continence in the male are summarized in Table 24–1.

In presenting the case for radical prostatectomy to patients with newly diagnosed, clinically localized prostate cancer, a discussion of postoperative urinary continence is mandatory. Most patients are already aware of the potential impact of surgery on urinary control and have access to often conflicting information regarding the risk of urinary incontinence. These data are confusing and can cause individuals to be concerned about choosing surgery over other forms of therapy. The medical literature also yields highly divergent results regarding continence following radical prostatectomy depending on the definition of incontinence, the mechanism of data collection, and modifications in surgical technique. Large contemporary series of radical prostatectomy report complete continence rates of 88 to 94%1–3 while the national Medicare experience4 found that 40% of men complained of stress incontinence and 30% wore pads or clamps to control urine leakage. Defining incontinence strictly as any amount of urine passing through the distal sphincter with an increase in intravesical pressure, Rudy et al.5 demonstrated with video urodynamics that 87% of patients studied were incontinent 6 months after surgery. Since the development of the anatomic approach to radical prostatectomy by Walsh,6 there have been numerous advances in the understanding of pelvic anatomy as it relates to urinary control in men. The mechanisms for urine loss following radical prostatectomy are also better understood. This expanded knowledge has led to modifications in surgical technique directed toward improving overall urinary continence and earlier return of postoperative urinary control.

Mechanisms of Postprostatectomy Incontinence Removal of the prostate causes a disruption in the normal anatomic configuration of the continence mechanism and its associated support structures (Table 24–2). The bladder neck following prostatectomy is directly anastomosed to the membranous urethra, with the bladder filling the space of the prostate in the pelvis. This results in a loss of overall urethral length. Dissection of the prostatic apex can further compromise both urethral length and support tissue. Portions of the distal sphincter may be destroyed or excised during the apical dissection. Damage to the smooth muscle fibers of the bladder neck can occur during dissection and reconstruction of the bladder neck, leading to impairment of function by loss of elasticity or scar tissue formation. Nerves supplying the distal bladder and urethra are often cut or injured as a result of surgery.

Anatomy of Male Continence The continence mechanism in men is commonly divided into two separate zones.7 The bladder neck and preprostatic sphincter have been considered together as the proximal sphincter while the distal sphincter includes tissue from the prostatic apex to the perineal membrane encompassing the membranous urethra. Urinary control can be maintained solely by one intact, functioning sphincter site. The proximal sphincter is composed of the circular smooth muscle fibers of the bladder neck which extend into 219

220 / Advanced Therapy of Prostate Disease TABLE 24–1. Factors Contributing to Normal Continence Bladder Compliance Competence of vesical neck Urethra Functional length Maximum closing pressure Striated urethral (external) sphincter Anatomic integrity Innervation

Scar tissue formation leading to poor urethral coaptation can occur at the vesicourethral anastomosis due to devascularization or postoperative urine leak. While loss of functional urethral length and sufficient sphincter action are the likely mechanisms for incontinence following prostatectomy, there has been significant debate in the literature as to which is most important. O’Donnell et al.11 showed radiographically that the functional level of continence after prostatectomy was approximately 1 cm distal to the vesicourethral anastomosis. They found urine in the proximal urethra at rest, with evidence of loss of closure pressure in incontinent patients. They therefore concluded that continence was maintained by a more distal sphincter mechanism. Presti et al.12 compared urodynamic studies in 24 incontinent patients and 13 continent patients who had undergone radical prostatectomy. They found a statistically significant difference between continent and incontinent patients in mean functional profile length, maximal urethral closure pressure, and maximal urethral closure pressure during voluntary contraction of the external sphincter. Continent patients had both increased functional urethral length as well as intact distal sphincter function. Fluoroscopically, continent patients were found to have tubularization of the bladder neck and proximal urethra above the level of the striated distal sphincter while incontinent patients did not. In flourourodynamic studies recently performed on 37 incontinent patients following prostatectomy, Gudziak et al.13 found that lack of functional coaptation of an intact proximal urethra alone and not loss of distal striated sphincter action was the cause of incontinence in all but one patient. They concluded that the volitional sphincter is not primarily responsible for postoperative urinary control. Similarly,

TABLE 24–2. Anatomic Changes following Radical Prostatectomy Decreased urethral length Loss of vesicourethral continuity Decreased elasticity of vesical neck and urethra Loss of fascia investing urethra Interruption of pelvic plexus innervation Changes in bladder compliance

Desautel et al.14 showed that of 26 incontinent patients in whom urethral scarring and anastomotic stricture was cystoscopically and radiographically demonstrated, all had urodynamic evidence of sphincteric incontinence as measured by abdominal leak point pressure. The contribution of bladder dysfunction to postprostatectomy incontinence is controversial. Incontinence could result from a poorly compliant, high pressure bladder with uninhibited detrusor contractions despite intact urethral and sphincteric function. By performing urodynamic studies on 162 incontinent patients, Leach et al.15 discovered bladder dysfunction alone in 14% and combined bladder dysfunction and sphincteric incontinence in 36% of patients. Conversely, Chao and Mayo16 reported bladder dysfunction alone as the cause of incontinence in only 4% of 76 patients, with sphincteric incontinence alone seen in 57%. They did, however, find combined bladder and sphincteric dysfunction in 43% of patients. Similarly, Presti et al.12 found that urethral and detrusor instability on urodynamics correlated poorly with incontinence, and Gudziak et al.13 concluded that bladder dysfunction is rarely the sole cause of postprostatectomy incontinence. While this issue has not been completely resolved, it does have important ramifications on the treatment algorithm for postprostatectomy incontinence. Incontinence following radical prostatectomy can be a complex issue influenced by many factors. To have the best chance of complete return of continence after surgery, however, patients most likely require a stable, compliant bladder, a functioning proximal sphincter unit free of scar tissue, and an intact distal sphincter mechanism. Based on this knowledge, specific surgical modifications have been made in the standard radical prostatectomy procedure to attempt to preserve the bladder neck, functional urethral length and support, and the distal sphincter mechanism and its innervation.

Continence-Enhancing Modifications Apical Dissection The apical dissection is the most challenging aspect of a radical prostatectomy as the dorsal vein complex, neurovascular bundles, and distal sphincter share a close anatomic relationship. Clinical experience has shown that a careful apical dissection can limit operative blood loss, preserve potency, and improve rates of postoperative continence. Recent modifications in surgical technique during this portion of the procedure have had a significant impact on improving the return of urinary control. In a standard retropubic approach, the puboprostatic ligaments are routinely divided along the posterior aspect of the pubis after incision of the endopelvic fascia to better expose the dorsal vein complex. Steiner,17 however, recently used cadaver dissection to show that the

Continence-Enhancing Modifications for Radical Prostatectomy / 221

puboprostatic ligaments support the proximal pendulous urethra and attach the membranous urethra and striated sphincter to the underside of the pubis. He postulated that this urethral suspensory mechanism played an important role in maintaining effective distal sphincter function and advocated preserving most of the puboprostatic ligament during dissection. This is accomplished by dividing the ligament midway between the pubis and prostate for the shortest distance necessary to enable exposure. Myers8 has also advocated total preservation of the puboprostatic ligaments to improve urethral support and postoperative continence. Lowe18 recently prospectively compared the continence rates of 51 patients who underwent preservation of the puboprostatic ligaments to 138 patients who underwent a standard apical dissection. In the study group, 25.5% of patients had immediate control on removal of the catheter while 80.4% were dry at 3 months. Overall, 100% of patients achieved complete continence within 1 year. These results were statistically significantly better at each time interval than in the group of patients whose puboprostatic ligaments were divided (Table 24–3). The author also noted lower blood loss in the study group and no difference in positive margin location or rate among the two groups. Poore et al.19 demonstrated similar results by sparing the puboprostatic ligaments. While the overall 1-year continence rate did not differ from that of patients whose ligaments were cut, patients in the study group had a significantly shorter time to continence (see Table 24–3). The above authors also found no compromise in cancer control as evidenced by no difference in positive margin rate or location of positive margins using the puboprostatic ligament-sparing technique. Gaining control of the dorsal vein complex is critical for hemostasis as well as for exposure of the prostatic apex. Using standard prostatectomy technique, proximal control of the complex often entails separating the venous plexus from the urethra with a right-angle clamp distal to the prostatic apex prior to suture ligation. Anatomic studies, however, have shown that this maneuver risks significant injury to the fibers of the striated urethral sphincter. Myers20 first described a suture bunching technique for control of the dorsal vein complex in which the last of a row of sutures is placed close to the prostatic capsule, leaving the striated sphincter intact distal to the ligature. Walsh et al.21 recently modified their apical dissection to preserve the distal striated sphincter by leaving the dorsal vein complex attached to the anterior surface of the urethra. They describe removing any sutures initially used to control bleeding from the dorsal vein and then oversewing the edges of the complex transversely to form an anterior hood of tissue, which is later incorporated into the vesicourethral anastomosis. The authors noted a more consistent, earlier return of continence in

TABLE 24–3. Effect on Continence of Sparing Puboprostatic Ligaments % Continent Lowe18

Poore19

Time after Catheter Removal

Ligaments Divided*

Ligaments Spared

Ligaments Divided

Ligaments Spared

Immediate 1 mo 3 mo 6 mo 12 mo

0 15 51 79 89

26 49 80 96 100

11 15 51 75 94

28 39 82 94 100

*Best result achieved in nonligament-sparing groups. Adapted from Lowe18 and Poore et al.19

113 patients using this technique, with 73% of patients dry by 3 months compared to 47% using their earlier technique. Similarly, Eastham et al.22 described surgical modifications of the apical dissection, including less manipulation of the urethra, preservation of periurethral tissue distal to the prostatic apex, and control of the dorsal vein complex by vertical approximation of the edges of the lateral pelvic fascia into a hood over the urethra. The oversewn lateral pelvic fascia is later incorporated into the vesicourethral anastomosis. Compared to a standard apical dissection, the authors reported a decrease in median time to continence from 5.6 to 1.5 months using the modified technique. The overall rate of continence at 2 years also increased from 82 to 95%. Kaye et al.23 recently compared the effect of three types of apical dissection on urinary control (Table 24–4). In their study, 134 patients were operated on using the standard technique of right-angle clamp dissection of the dorsal vein complex followed by suture ligation and transection distal to the prostatic apex. In a second group of 76 patients the anterior hood modification described by Walsh et al.21 was performed, while 70 patients underwent the dorsal vein bunching technique described by Myers,20 in which a large portion of the striated sphincter is preserved intact. Sixty percent of patients in the latter group achieved continence within 1 month of surgery, compared to 41% using the Walsh modification and 33% using the standard technique. At

TABLE 24–4. Effect of Various Techniques of Dorsal Vein Control on Continence % Continent Modification Ligation and transection Creation of urethral hood Bunching technique

Immediate

1 mo

3 mo

12 mo

10 8 33

33 41 60

57 76 89

90 93 99

Adapted from Kaye KW, Creed KE, Wilson GJ, et al. Urinary continence after radical retropubic prostatectomy. Analysis and synthesis of contributing factors: a unified concept. Br J Urol 1997;80:444–501.


1 year, 99% of patients in the bunching group were dry compared to 93% using the Walsh modification and 90% using the standard apical dissection. These continence rates between groups were narrowly statistically significant (p < .05). The current authors’ modification of the bunching technique described by Myers and their preferred method for division and control of the dorsal vein are illustrated in Figures 24–1 and 24–2. Once the dorsal vein complex is controlled, the urethra is incised. An attempt should be made to preserve as long a segment of urethra as possible without leaving prostate tissue attached. Walsh et al.21 describe the tissue around the posterior aspect of the urethra as the lateral and posterior portions of the striated urethral sphincter at their attachment to Denonvilliers’ fascia. They describe passage of a right-angle clamp behind the striated

sphincter muscle and then sharply dividing the urethra, sphincter muscle, and midline rectourethralis muscle. The posterior component of the sphincter is incorporated into the vesicourethral anastomosis. Considering this modification in technique as an extension of the earlier described preservation of the thicker anterior segment of the sphincter, an earlier return of urinary continence is noted. Klein24 described a similar surgical approach to preserving the posterior attachments of the urethra. Without passing a clamp around the urethra, the anterior and then the posterior wall of the urethra is divided in situ with a knife blade while still attached to the underlying fascia. The fascia is incised distal to the cut edge of the urethra over a right-angle clamp. The divided fascia is then included in the anastomosis. Klein initially reported his results

A

B

C

D

FIGURE 24–1. Bunching technique for control of the dorsal venous complex. A, The endopelvic fascia is incised at the prostatic apex bilaterally. The puboprostatic ligaments are left intact. B, Turner-Babcock clamps are used to bunch together the branches of the dorsal vein covering the dorsal surface of the prostate. C, Two figure-of-eight sutures are used to ligate these branches, incorporating the cut edges of the endopelvic fascia. D, Appearance after both sutures have been placed.


using this technique in 60 patients and later updated the experience with 83 consecutive patients.25 Complete continence without need for pads was attained by 88% of patients. Seventeen percent of patients were dry by the first week after catheter removal while all continent patients were dry by 4 months. An extended experience in more than 600 patients has confirmed these results, with approximately 60% of patients dry within 4 weeks of catheter removal [unpublished observations]. The contribution of a nerve-sparing approach to urinary continence is controversial. O’Donnell and Finan26

showed an improved continence rate in patients whose neurovascular bundles were spared (94%) compared to those whose neurovascular bundles were sacrificed (71%). Eastham et al.,22 reporting the Baylor experience of 581 patients, found by multivariate analysis that preservation of both neurovascular bundles was independently associated with an increased chance of regaining urinary control following surgery. Steiner et al.2 noted a 94% continence rate in men who underwent a bilateral nerve-sparing procedure, compared to 92% if one bundle was spared and 81% if both bundles were resected. These

A

B

C

D

FIGURE 24–2. Division and control of the dorsal vein. A, A right-angled clamp is placed between the anterior surface of the urethra and posterior surface of the dorsal vein distal to the figure-of-eight sutures. B, The dorsal vein is divided sharply with a knife. C, The cut surface of the dorsal vein is suture-ligated for hemostasis. D, Appearance of the urethra after division and ligation of the dorsal vein.


differences, however, were not statistically significant. Klein24 also found no significant difference in continence rates related to the number of neurovascular bundles preserved at surgery. Similarly, Catalona and Basler3 found that postoperative continence in 409 patients was not related to nerve-sparing surgery. The debate continues as to whether it is the greater technical precision required during the apical dissection in a nerve-sparing procedure or the actual preservation of neural input to the sphincter itself which has led to some of the differences in reported continence rates. Recently, Narayan et al.8 identified sensory branches of the dorsal nerve of the penis which travel close to the apex of the prostate and innervate the external sphincter. The authors concluded that these fibers were essential for normal sphincter reflex activity and that damage to these nerves during the apical dissection could

explain some of the clinical features of postprostatectomy incontinence. Hollabaugh et al.9 also traced the innervation of the external sphincter during dissection of fresh cadavers. They found that both the pelvic and pudendal nerves contribute intrapelvic branches to the sphincter at the level of the prostatic apex and could be damaged during the apical dissection. Based on these observations, they suggest omitting passage of a rightangled clamp behind the urethra and avoiding placement of anastomotic sutures at the 5 and 7 o’clock positions to avoid damaging these nerves. Greater understanding of the neural innervation of the sphincter mechanism has brought forth further anatomic support for the continence-enhancing surgical modifications described above. The current authors have recently modified the technique for apical dissection and currently prefer to release the neurovascular bundles bilaterally prior to incising the urethra27 (Figures 24–3 and 24–4). This permits complete mobilization of the prostate (with all layers of Denonvilliers’ fascia intact) off the anterior surface of the rectum and improved visualization of the junction of the posterior prostatic apex and urethra. Division of the posterior urethra can then be performed under direct vision, averting the possibility of leaving a small amount of apical prostatic tissue attached to the urethra. This technique also preserves the posterior fascial attachments of the urethra, as previously described.24,25 Bladder Neck Dissection

A

B FIGURE 24–3. Release of the neurovascular bundles. A, A rightangled clamp is placed under the lateral pelvic fascia, which is incised longitudinally (dotted line) to expose the groove between the rectum and prostate. B, The bundles are swept laterally and released from the prostate from apex to base bilaterally. After release of both bundles, the prostate is lifted off the anterior surface of the rectum (inset).

During a radical prostatectomy, the prostate is traditionally removed with a cuff of bladder neck attached to the base, and the bladder neck defect is then reconstructed. Recently, attempts have been made to preserve an intact bladder neck to prevent injury to the smooth muscle fibers of the internal sphincter mechanism. Reported results of the effectiveness of this technique on improving urinary control have varied. Licht et al.1 reported on 206 patients who underwent a modified bladder neck dissection in which the anatomic integrity of the bladder neck was preserved, as much as possible, by sharp dissection of the bladder neck–prostate junction. The bladder neck was reconstructed in 75 patients in whom the resulting lumen was greater than 22F. By both univariate and multivariate statistical analysis, preservation of the bladder neck had no impact on return of continence but was associated with a trend to a lower incidence of bladder-neck contracture. Patients who experienced a bladder-neck contracture were less likely to achieve complete continence. The authors did show that the rate of local recurrence or prostate-specific antigen–only failure was independent of whether the bladder neck was preserved or resected and reconstructed. Shelfo et al.28 also found that bladder neck preservation could be achieved without compromising cancer control. They reported an 88% continence rate and a 1% rate of


anastomotic stricture in 365 patients in whom they had used their technique for carefully preserving the circular bladder neck fibers. Lowe29 recently prospectively compared 91 patients who underwent bladder neck preservation with 99 patients in whom the bladder neck was reconstructed. He found that the time to continence was earlier

after bladder neck preservation, with 23.3% of patients dry within 1 month of surgery compared to only 11.2% of patients who had undergone bladder neck reconstruction (Table 24–5). By 9 months, however, the difference in continence rates between the two groups was no longer statistically significant. Overall, bladder neck preservation had

A

B

C

D FIGURE 24–4. Urethral division and placement of urethral sutures. A, Release of both bundles (see Figure 24–3) allows complete mobilization of the prostate off the anterior rectal surface, preserving all layers of Denonvilliers’ fascia on the rectal surface of the prostate. This maneuver allows for complete apical visualization, including the posterior aspect of the urethroprostatic junction. B, The anterior urethra is next incised sharply from the 3 to 9 o’clock positions, exposing the Foley catheter. C, The Foley catheter is removed and two anterior urethral sutures are placed at the 2 and 11 o’clock positions. D, The posterior urethra is divided sharply under direct vision. E, Posterior urethral sutures are placed at the 4 and 8 o’clock positions.

E


no effect on the ultimate rate of return of continence. Bladder neck contractures were more common in patients following bladder neck reconstruction (8.2%) than following surgery that preserved the bladder neck (3.3%); these differences, however, were not statistically significant. Kaye et al.23 recently reported an improved time to continence (41 versus 121 days) with bladder neck preservation compared to reconstruction. Further analysis, however, failed to demonstrate a significant overall continence benefit from

bladder neck preservation (see Table 24–5). The authors did report a statistically significant lower anastomotic stricture rate in patients undergoing bladder neck preservation. Gaker et al.30 have described early results using a technique to preserve both the bladder neck and a significant portion of the prostatic urethra and its periurethral muscular tissue, representing the preprostatic sphincter mechanism. The authors reported an earlier return of continence in patients undergoing this procedure (see Table 24–5) compared retrospectively to patients who had undergone a standard nerve-sparing operation, without compromising cancer control. One group of patients for whom careful bladder neck preservation may be critical to postoperative continence are those with preoperative striated sphincter deficiency. Aboseif et al.31 performed preoperative urodynamics on men undergoing radical prostatectomy and found that patients with a weak sphincter mechanism before surgery had a higher incidence of postoperative incontinence.

A

B

C

D

TABLE 24–5. Effect of Bladder Neck Preservation on Continence Median Time to Continence (mo)

Kaye23 Lowe29 Gaker30

Bladder Neck Resected

Bladder Neck Preserved

3.3 4 2.1

1.4 0.07 ng per mL) PSA failure definitions following XRT vary widely. The uro-oncologic community has seen numerous publications over the past decade reporting the outcomes of XRT for localized prostate cancer using different biochemical failure definitions.14 Relatively high and low PSA failure definitions such as nadir values > 4.0 ng per mL or > 0.5 ng per mL have been used.14–18 The multitude of PSA definitions makes it difficult to compare outcomes from different series and different treatment modalities.19 Using three different 5-year actuarial PSA failure definitions (nadir > 1 ng per mL, > 1.5 ng per mL, > 4 ng per mL), the differences in biochemical control range from 5 to 53%.20 Since residual normal prostate tissue may survive after radiation, PSA may be produced. Detectable PSA does not necessarily reflect persistent disease.21 In one study, the median serum PSA value of men believed to be free of prostate cancer who had received pelvic irradiation for nonprostate cancer was 0.65 ng per mL.21 On the other hand, the higher the PSA nadir after external beam radiation therapy (EBRT), the higher the chance of subsequent PSA failure, positive biopsy, and clinical failure.22,23 The American Society for Therapeutic Radiology and Oncology sponsored a consensus conference to define PSA failure following external radiation therapy.24 Their recommended failure definition is three consecutive increases in PSA. The date of failure should be the midpoint between the nadir and the first of the three PSA rising values.23 They also recommended repeating PSA testing every 3 to 4 months and using a minimum follow-up period of 24 months.23 There are inherent conceptual problems with this definition, however. Neither the rate of PSA increase nor the maximum PSA nadir are specified. Therefore, a patient with a very low PSA inching upward by 0.1 ng per mL may be considered a failure while a stable high nadir may not be considered a failure. These extreme examples illustrate some of the weaknesses of the consensus definition. So far, there are few long-term results based on using this new definition. To date, separate independent studies do

support its use. For example, among 568 patients with clinically localized prostate cancer (504, T1-T2; 64, T3), the use of the consensus definition for biochemical failure was a multivariate factor affecting the rate of distant metastases, disease-free survival, and cause-specific survival at 5 years.25 The results of radical prostatectomy versus XRT are compared in Tables 25–4 and 25–5. Table 25–6 summarizes the biochemical control of T1-T2Nx treated with standard XRT.26 The 5- and 10-year biochemical control in these series varies from 29 to 75%, and 10 to 70%, respectively. This wide variation among series stems from the difference in pretreatment patient characteristics and failure definitions. Preliminary data suggest that 3DCRT may be better than conventional treatment.

Three-Dimensional Conformal Irradiation The higher than expected failure rate for many patients and the increased toxicity associated with higher doses have resulted in increasing enthusiasm for finding ways to safely increase the dose of radiation. The inherent unproven assumption is that higher doses can increase the cure rate. With the availability of 3D treatment plan-

FIGURE 25–2. Actuarial incidence of relapse or increasing PSA according to nadir PSA value. From Zagars GK. Prostate-specific antigen as an outcome variable for T1 and T2 prostate cancer treated by radiation therapy. J Urol 1994;152:1786–91.


FIGURE 25–3. Likelihood of freedom from failure by T stage according to whether pretreatment PSA was more or less than 15 ng/mL. Failure is defined biochemically as an increase in serum PSA > 10% within the first 2 years after irradiation or PSA level > 1.0 ng/mL after 2 years. From Zietman AL, Coen JJ, Shipley WU, et al. Radical radiation therapy in the management of prostatic adenocarcinoma: the initial prostate-specific antigen value as a predictor of treatment outcome. J Urol 1994;151:640–5.

ning software, 3DCRT has become one of the dominant strategies used to increase the therapeutic ratio in treating localized prostate cancer. Conformal therapy attempts to reduce normal toxicity while increasing the radiation dose and local control.26 Studies done prior to the availability of 3DCRT demonstrated that standard radiotherapy resulted in fewer clinical local recurrences in patients who received doses ≥ 70 Gy compared to those who received ≤ 60 Gy (14% versus 23%, p = .0001).27 Hanks et al. reported a dose response for 5-year BNED rates (defined as two consecutive rising PSA levels and PSA > 1.5 ng per mL) in 232 consecutive patients treated at the Fox Chase Cancer Center.28 There were 208 patients treated for T1-T2Nx (57 T1, 151 T2) and 24 for T3 disease.28 No dose response was observed in patients with pretreatment PSA levels < 10 ng per mL.28 In patients with PSA levels of 10 to 19.9 ng per mL, the 5-year BNED was 35% at 70 Gy and 75% at 76 Gy.28 Patients with pretreatment PSA levels ≥ 20 ng per mL faired poorly, with a 5-year BNED of 10% at 70 Gy and 32% at 76 Gy.28 More recently, the dose response of 501 patients irradiated for localized prostate cancer at the University of California at San Francisco (UCSF) between 1987 and 1995 was reported.29 In a multivariate analysis, patients with a Gleason score > 6 and PSA < 20 ng per mL benefitted from a radiation dose > 71.5 Gy compared to a dose of < 71.5 Gy (freedom from biochemical failure [FFBF] at 4 years 70% versus 35%, p < .05).29 Patients with a Gleason score of 2 to 5 and PSA < 20 ng per mL did not appear to benefit from a higher dose.29 The PSA failure was defined as an increase of > 1 ng per mL on at least two consecutive occasions, separated by at least 1 month, or as a PSA increase > 4 ng per mL 1 year after treatment, or a PSA increase > 2 ng per mL 2 years after treatment.29

There was a more dramatic dose-response benefit observed in high-grade patients (Gleason score 8 to 10). In 50 patients irradiated at UCSF for high-risk prostate cancer (Gleason score 8 to 10, PSA < 20 ng per mL), Roach et al. observed an 83% FFBF rate at 4 years in patients who received > 71 Gy compared to 0% with a dose of < 71 Gy (p = .03).30 As shown in Figure 25–4, the 18 patients who received < 71 Gy were treated with conventional RT while the 32 who received > 71 Gy were treated with 3DCRT.30 Prostate-specific antigen failure was defined by a nadir > 1 ng per mL or an increase of 0.5 ng per mL or more in 1 year.30 Results for patients with high Gleason scores (8 to 10) treated with 3D conformal therapy were recently updated and combined with other institutional experiences and presented at the 1998 meeting of the American Society for Therapeutic Radiology and Oncology (ASTRO).31 In 186 patients irradiated with 3D conformal therapy for GS 8 to 10 at the University of Michigan, UCSF, or Fox Chase Cancer Center, the 5-year FFBF using the ASTRO consensus definition was 62.5% for all patients and 85% in T1-T2Nx patients. On multivariate analysis, RT dose (< 70 Gy versus > 70 Gy) and pretreatment PSA were prognostic factors of 5-year FFBF but not of overall survival.31 Figure 25–5 shows the risk ratio for PSA failure at 5 years in T1-T2 patients to be lower with higher RT doses (< 70 versus > 70 Gy).31 None of the prognostic factors were statistically significant for 5-year FFBF or survival for T3-T4Nx patients.31 The MD Anderson experience for radiation therapy (standard and 3D conformal) in 938 patients treated for localized prostate cancer (T1-T4Nx) was recently reported.32 There was a significant dose response for 3-year FFBF (or rising PSA) found in patients with pretreatment PSA levels > 4 ng per mL.32 The 3-year actuarial FFBF was 61%, 74%, and 96% for patients treated with ≤ 67 Gy (N = 500), > 67 to 77 Gy (N = 356), and > 77 Gy (N = 82), respectively.32 Figure 25–6 illustrates the dose response observed for FFBF (< 67 versus > 67 Gy) when limited to T1-T2 disease.33 Further evidence of dose response for prostate cancer treated with radiotherapy comes from the Memorial Sloan-Kettering Cancer Center phase I dose-escalation study.34 This study followed 743 T1 to T3Nx patients (N = 153 T1, 259 T2, 195 T3) treated with 3DCRT, with tumor target dose increasing from 64.8 Gy to 81 Gy.34 As shown in Figure 25–7, a PSA nadir ≤ 1.0 ng per mL was achieved in 90% of the patients treated with doses 75.6 or 81 Gy, in 76% of those treated with 70.2 Gy, and in 56% of those treated with 64.8 Gy (p < .001).34 The 5year PSA relapse-free survival rate (three consecutive PSA increases above the nadir) was 85% for patients with a good prognosis (T1-T2, PSA ≤ 10 ng per mL, and GS ≤ 6), 65% for intermediate (one unfavorable prognostic factor), and 35% for unfavorable (two or more unfavor-

T1-T2NxM0: the Case for External Radiotherapy / 233 TABLE 25–4. Patient Characteristics from Selected Surgical and Radiation Therapy Series Prognostic Factor 0–4 4.1–10.0 10.1–20.0 10–30 > 20 > 30 2–4 5 6 7 8–10 T1a–T2a T2b–T2c T3/4 N1

Surgical Average % (Range)*

Radiation Therapy Average, % (Range)†

Major Differences

26 (1.5–4.3) 41 (3.5–5.2) 26 (16–32)

21 (11–33) 30 (27–32) 21 (18–22) 29 35 (18–50) 7 30 (23–42)‡ NA 20 (15–25) 22 (15–32) 20 (6–37) 36 (20–61) 39 (33–39) 25–48 0–?

PSA < 10 ng/mL 56–78% vs. 27–64%

Patients treated by surgery tend to have lower grade (Gleason score ≥7, ~ 27% vs. 42%) and lower T-stage tumors than patients included in radiation therapy series (~ 1/3 T3), and node-positive patients are frequently excluded.

GS > 7 21–29% vs. 21–55%

Larger percentages of surgical patients have lower PSAs (< 10 ng/mL, average 67% vs. 51%) and lower T stages than radiation therapy series (~ 1/3 T3), and node-positive patients are frequently excluded.

T2c 0–6% vs. 9% and T3 ~ 0% vs. to 52%

Larger percentages of surgical patients have lower PSAs (< 10 ng/mL, average 67% vs. 51%) and lower tumor grades (Gleason score > 7, 27% vs. 42%) ,and node-positive patients are frequently excluded.

13 (6–20) 22 (10–16) 25 36 (28–44) 17 (14–20) 10 (7–13) 53 (35–67) 47 (33–65) ~0 ~0

Comments

NA = not available; PSA = prostate-specific antigen. *Most surgical series exclude node-positive patients and PSA failures > 0.2–0.6 ng/mL. †Clinical staging includes node-positive T3/4 patients and PSA failures >1.0–4.0 ng/mL or rising. ‡With the exception of MD Anderson, other institutions have very few patients with Gleason scores of 2 to 4. Modified from Roach M, Wallner K. Prostate cancer. In: Leibel S, Phillips T, editors. Textbook of radiation oncology. 1st ed. Philadelphia: WB Saunders Company; 1998. p. 741–84.

able prognostic factors) (p < .001).34 Of 136 patients who had prostate sextant biopsies ≥ 2.5 years following RT, positive biopsies were found in 7% (1/7) treated to 81 Gy, 48% (12/25) of those treated to 75.6 Gy, 45% (19/42) of those treated to 70.2 Gy, and 575 of those treated to 64.8 Gy (p < .05).34 Table 25–7 summarizes the dose response observed for high-risk localized prostate adenocarcinoma.

These retrospective and phase I studies support the contention that there is better tumor control with a higher dose of radiation. The follow-up in these series is too short to detect a benefit in cause-specific and overall survival. Once again, the different failure definitions used, the different prognostic factor distributions, and the various selection biases inherent at single institution series preclude direct comparisons. There is a prospective

TABLE 25–5. Summary of PSA Results for Selected Surgical and Radiation Therapy Series Prognostic Factor 0–4 4.1–10.0 10.1–20.0 10–30 2–4 5–6 7 8–10 T1a T1b T1c T2a T2b/T2c T3/4

Surgical Series PSA NED, %* (5/10 yr)

RT Series PSA NED, %† (5/10 yr)

85–95/ 55–93/ 56–/

80–86 42–67/ 30–75/ 45/ 68–75/ 60/ 63§ || 10 –33/9

1 ng/mL or by a factor 1.5. ||PSA increase ≥ 2 ng/mL from the nadir to a level that exceeded the normal range (> 4 ng/mL). ¶PSA nadir < 1.0 ng/mL. **13 patients were treated with 3DCRT to a dose between 75 and 78 Gy. ††125 were treated with conventional RT (60–70Gy) and 62 with 3DRT (71–87 Gy). ‡‡PSA ≤ 1 ng/mL or PSA rise ≥ 0.5 ng/mL in 1 year. Adapted from Hanks GE, et al.,65 Zietman AL, et al.,13 Schellhammer PF, et al.,18 Zagars GK, Pollack A,66 Pisansky TM, et al.,12 Horwitz EM, et al.,20 Seung SK, et al.67

phase I-II RTOG 9406 study underway.35 Only a multiinstitutional randomized study would provide the definitive answer on dose escalation. Based on these early observations, it would appear that a higher dose RT may achieve improved cancer control.

Role of Hormonal Therapy in Patients with T1-T2 Disease Neoadjuvant androgenic suppression prior to XRT decreases prostate volume and can decrease the volume of normal tissue included in the high-dose area.36,37 In a small Canadian randomized study, neoadjuvant and adjuvant total androgenic suppression (TAS) decreased the number of positive biopsies at 24 months following XRT for localized prostate cancer compared to XRT alone (6% and 29%, respectively, versus 67%).38 An ongoing randomized trial (RTOG 9408) is evaluating the role of neoadjuvant TAS compared to XRT alone for early stage prostate cancer. Another ongoing randomized study (RTOG 9413) is presently assessing the time of TAS (neoadjuvant versus adjuvant) and the role of whole pelvis XRT for localized prostate cancer. For now, the UCSF policy is to use neoadjuvant TAS before XRT for selected patients with a large prostate gland and to use adjuvant TAS for high-grade or locally advanced prostate cancer.

Whole Pelvis versus Small Field for Localized Prostate Cancer The value of prophylactic irradiation of the pelvic lymph nodes continues to be controversial. The only randomized study published was completed before the PSA era.39 In it, 449 T1bN0 and T2N0 patients assessed based on lymphograms or lymph node dissection were randomized in RTOG 7706 to whole pelvis RT (45 Gy) or prostate RT only.39 At a median follow-up of 12 years, no differences in NED survival or overall survival were noted between the two groups.39 The patients were not stratified by their risk of occult lymph node metastases. Many of them were at a very low risk of occult disease and therefore would not have been expected to benefit from whole pelvis RT. Several retrospective studies have demonstrated a potential benefit for larger field RT in high-risk patients.40–44 One of these, a retrospective study conducted at UCSF, concluded that whole pelvis RT was associated with a significant benefit in FFBF in patients with a calculated risk of lymph node involvement greater than 15%.45,46 In the 117 patients treated with whole pelvis RT, the median progression-free survival rate was 34.2 months, compared to 21 months in the 84 patients who received RT only to the prostate (p = .001).46 This advantage was obtained even though the

T1-T2NxM0: the Case for External Radiotherapy / 235

low-risk (< 15%) or high-risk (> 35%) group.47 The ongoing randomized trial (RTOG 9413) should ultimately settle this question. Meanwhile, the UCSF policy is to include the pelvic nodes in the field, using a dose of 45 Gy when the risk of lymph node involvement is above 15%.

Role of Particle Radiotherapy

FIGURE 25–4. Actuarial probability of freedom from PSA failure for patients with pretreatment PSA less than 20 mg/mL. Irradiated for high-grade prostate cancer (Gleason scores 8 to 10) at doses > 71 Gy compared to < 71 Gy (p = .03). From Roach M, Meehan S, Kroll S, et al. Radiotherapy (XRT) for high-grade (HG) clinically localized adenocarcinoma of the prostate (CAP). J Urol 1996;156:1719–23.

whole pelvis RT patients had slightly higher Gleason scores and T stages.46 In a more recent analysis, patients at an intermediate risk for lymph node invasion seemed to benefit more from whole pelvis XRT than either the

FIGURE 25–5. PSA failure-free survival by RT dose. T1-T2 patients only. From Fiveash JB, Hank G, Roach M, et al. 3D conformal radiation therapy (3DCRT) for high-grade prostate cancer: a multiinstitutional review. In: Cox J, editor. Proceedings of the American Society for Therapeutic Radiology and Oncology, 40th Annual Meeting; Phoenix (AZ): Elsevier; 1996. p. 143.

Advances in alternative methods of delivering radiotherapy for prostate cancer have occurred in the last few years and are worthy of note. Early studies utilizing proton beam irradiation have demonstrated no disease-free survival advantage and caused a rectal complication rate characterized primarily by excessive bleeding.48,49 However, investigators from Loma Linda, using a synchrotron-based proton source, have described improved physical dose distribution characteristics compared to those reported by the Massachusetts General Hospital (MGH) proton facility. In theory, this system should allow an improved dose distribution compared to the technique used in the randomized trial conducted by investigators from MGH. The investigators from Loma Linda believe that they are likely to obtain better results by omitting the perineal field used in the MGH trial, due to beam energy constraints. However, until improved planning software for proton beam irradiation is available that is competitive with that available for 3D conformal intensely modulated x-rays, it is doubtful that the full potential of proton beam irradiation will be realized. There are potential dose distribution advantages associated with protons but a lack of conformity in planes perpendicular to the main axis of the beam limits its conformity. The extraordinarily high cost of proton facilities

FIGURE 25–6. Actuarial freedom from relapse or a rising PSA for patients treated with radiation doses of ≤ 67 Gy (open squares) versus > 67 Gy (filled circles). Inset: the number of patients at risk at 0, 24, 36, and 48 months post radiotherapy. From Pollack A, Zagars GK. External beam radiotherapy for stage T1/T2 prostate cancer: how does it stack up? Urology 1998;51:258–64.


FIGURE 25–7. Actuarial (Kaplan-Meier) probability of achieving a post-treatment PSA nadir ≤ 1.0 ng/mL by dose in 530 patients who did not receive neoadjuvant androgen deprivation therapy. Nadir values were assessed from serial PSA levels obtained at 3- to 6-month intervals throughout the post-treatment follow-up period. The date of achieving a PSA within the range of 0–1.0 ng/mL was defined as the exit date for analysis of patients, while the date of achieving a nadir PSA of ≥ 1.1 ng/mL was used as the date of failure. The numbers in parentheses indicate the number of patients.

($46 to $70 million dollars) will likely hamper widespread implementation of this technology. Preliminary results from the University of Washington in Seattle and more recently from Wayne State University in Detroit suggest that there may be some biologic advantages to the use of neutron-based radiotherapy. Lack of a dose distribution advantage and the increased complication rate associated with this modality suggest that it is not likely to be widely adopted.50–54 Hip fibrosis, rectal complications, lack of conformity, and high cost associated with this technology more than outweigh the minimal theoretic and biologic advantages for x-ray-based 3D conformal intensity modulated therapy. Heavy charged particle-based radiotherapy could have the biologic advantages of neutrons as well as the dose distributions of protons. As with protons, however, the appropriate software to take advantage of this technology is not yet available. Preliminary results using inadequate software have demonstrated increased complications with no obvious improvement in local control.

The Future: Intensity Modulation Radiotherapy At UCSF, we have used six-field intensity modulation since 1992 to generate partial transmission blocks that prevent the hot spots that can occur on the anterior rectal wall during conformal therapy. Using this approach, an approximate 5% reduction in the rectal dose while providing adequate coverage of the prostate has been

demonstrated. The IMRT is now accomplished using multileaf collimation. The next generation of 3D dose-escalation RT is based on IMRT.55 Recent studies supported by pathologic clinical correlation suggest that magnetic resonance spectroscopic imaging (MRSI) allows differentiation of normal prostate and cancer based on the choline and citrate ratio.56 Using MRSI to define a dominant intraprostatic lesion (DIL), the authors modified the standard UCSF 3D conformal technique to deliver 2.25 Gy per day to the DIL and 1.8 Gy per day to the prostate gland. The total dose is 80 to 90 Gy to the DIL and 73.8 to 75.6 Gy to the prostate gland.57 It is too early to discuss the impact of this new technology on clinical end points but we have demonstrated that it is feasible. Better target definition and a higher dose to the highest risk portions of the gland are promising.

Complications Standard XRT is well tolerated. Most patients experience mild diarrhea and dysuria during the treatment, which respond well to symptomatic treatment. These side effects are limited in time and disappear several weeks after the end of the treatment. Long-term follow-up from RTOG 7506 and 7706 revealed moderate to severe long-term urinary complications in 7.7% of patients.58 Only 3.3% of patients experienced any grade 3 to 5 intestinal toxicity.58 Although there was a higher risk of grade 3 urinary complications in patients who received greater than 70 Gy, this was not true for grade 4 or 5 urinary complications, nor was it the case for grade 3, 4, or 5 gastrointestinal (GI) complications. Urinary and/or fecal incontinence are uncommon following radiotherapy and are usually related to prior transurethral resection of the prostate (TURP). Rectal bleeding is not infrequent (10% of patients) but is usually mild, self-limited, and dose/volume related.49,59,60 The Fox Chase series reported < 1% RTOG late GI grade 3 to 4 toxicity (all doses) and 6% late grade 3 to 4 Fox Chase Late Effects Normal Tissue (FC-LENT) toxicity (75–76 Gy).28 The observed late genitourinary (GU) LENT grade 3 to 4 toxicity was 4% (all doses).28 These low GI toxicity rates were obtained when a special rectal block was used to limit the dose to the anterior rectal wall to 72 Gy while keeping the dose to the prostate at 76 Gy.28 Preliminary results of a phase III study comparing toxicity and treatment outcomes of patients with localized prostate cancer after 78 Gy 3D conformal versus 70 Gy standard RT revealed no differences in GU and GI acute toxicity or PSA at 3 and 6 months.35 Ninety-two percent of patients presented with less than grade 2 GU and GI toxicity, with only five cases of grade 3 to 4 toxicity (4/5 in the conventional arm).35 It is still too early to draw definitive conclusions from these preliminary results because of the short follow-up (median < 8 months) and small number of patients (N = 100 conventional, N = 100 3DCRT). Beard

T1-T2NxM0: the Case for External Radiotherapy / 237 TABLE 25–7. Evidences of Dose Response for Localized Prostate Cancer Author

Stage

Gleason Score

PSA Pre-Tx (ng/mL)

Dose (Gy)

N

FFBF

p Value

Roach*

T1T2T3T4Nx

>6

< 20

92

T1T2T3T4Nx

≥8

< 20

Fiveash‡

T1T2Nx

≥8

Median 17.1

T3T4Nx

≥8

50% (4y) 70% (4y) 0% (5y) 83% (5y) 68.5% (5y) 85% NS

.05

Roach†

Pollack§

T1T2T3T4Nx

2–10

Median 9

Pollack||

T1T2Nx

2–10

Median 7.9

Hanks¶

T1T2T3Nx

2–10

< 10

< 71.5 > 71.5 < 71 > 71 < 70 > 70 < 70 > 70 < 67 67–77 > 77 < 67 > 67 < 70 70–71.9 ≥ 72 < 70 70–71.9 ≥ 72 < 70 70–71.9 ≥ 72 64.8 70.2 75.6–81

10–19.9 > 20

Zelefsky**

T1T2T3Nx

2–10

Median 15

83 103 78 500 356 74 354 289 95

70

66

248 195 87

61% (3y) 74% (3y) 96% (3y) 67% (4y) 87% (4y) 86% (5y) 77% (5y) 84% (5y) 29% (5y) 57% (5y) 73% (5y) 8% (5y) 28% (5y) 30% (5y) 56% 76% 90%

.03 .03

.026 .007 < .0001 .85

.02 .008

< .001

NS = not significant. *Roach M, et al.29 3DRT and non-3DRT, failure = rise > 1 ng/mL X 2 or > 4 ng/mL at 1yr or > 2 ng/mL at 2 yr. †Roach M, et al.30 3DRT and non-3DRT, failure = 0.5 ng/mL rise per year or > 1.0 ng/mL or + biopsy. ‡Fiveash JB, et al.31 3DRT alone failure = consensus definition. §Pollack A, Zagars G.32 3DRT and non-3DRT, failure = 2 consecutive PSA rises. ||Pollack A, Zagars GK.33 3DRT and non-3DRT, failure = 2 consecutive PSA rises. ¶Hanks GE, et al.28 3DRT alone, failure = 2 consecutive PSA rises exceeding 1.5 ng/mL. **Zelefsky MJ, et al.34 3DRT alone, end point = probability to obtain a PSA nadir < 1.0 ng/mL.

et al. compared the quality of life (Profile of Mood States and Health Survey Short Form-36) before and after external beam irradiation with large field compared to smaller field (conventional and conformal). They found GI and GU side effects to be frequent at 3 months but substantially improved at 12 months.61 There was a trend toward a better quality of life and better sexual function with the smaller and conformal field.61 With 3DCRT at 5 years of follow-up, the Memorial Sloan-Kettering Cancer Center phase I dose-escalation study reported no late GI or GU toxicity in 80% and 77% of the cases, respectively. They observed 12% and 14% grade 1 GI and GU toxicity, 6% and 8% grade 2 toxicity, and 1.9% and 0.8% grade 3 to 4 GI and GU toxicity.34 At 5 years, there was a dose response for toxicity (≥ 75.6 Gy compared to ≤ 70.2 Gy) observed for grade 2 GI of 17% versus 6% and GU toxicity of 13.8% versus 8% (p = .002).34 In 707 patients (603 = T1-T2) treated with 3DCRT at the University of Michigan between 1987 and 1994, 3% showed late RTOG grade 3 to 4 GI toxicity and 1% showed RTOG grade 3 GU at 7 years.62 The median dose used in the study was 69 Gy (44 to 87 Gy).62 Despite the use of higher

doses, these complication rates at 7 years are lower than the expected late complications reported with standard RT.58 Sixty consecutive patients were treated with 3DCRT in a pilot survey at UCSF, with a median follow-up of 21 months (range of 7–40 months).63 Sexual function sufficient for intercourse was retained in 37/60 patients (62%) (median age 72.3 years).63 Conformal radiotherapy is also rationalized as a way of minimizing normal tissue toxicity, by using computerized tomography planning and 3D planning software to accurately design the multiple beams and blocks needed to cover the target and still protect the rectum and bladder. Toxicity with standard XRT is minimal. Early results are encouraging and support the prospect of a safe delivery of a higher dose to the prostate gland with 3DCRT.

Conclusion For T1-T2M0 prostate cancer, standard XRT and radical prostatectomy have similar long-term (15-year) survival rates. Clinical local control end points based on digital rectal examination underestimate the failure rate following external irradiation and radical prostatectomy. Prostate-


specific antigen is a sensitive tool for detecting failure years before clinical failure. The 5- and 10-year BNED rates obtained with XRT or radical prostatectomy are comparable, even if patient and tumor characteristics generally favor the surgical group. Based on long-term data the 10- and 15year survivals are virtually identical.64 With standard XRT, post-treatment morbidity is low. With 3DCRT it is possible to increase the dose to the prostate gland with minimal toxicity. There is evidence of a dose-response effect for intermediate and higher-risk T1-T2 prostate cancer patients. Hormonal therapy may further enhance the results of local radiotherapy. The IMRT technology is promising and should allow radiation oncologists to safely escalate the dose of radiation to the prostate. Future studies will tell whether IMRT, hormonal therapy, or other advances will enable an increase in the therapeutic ratio for localized prostate cancer. Until then, a strong case can be made for external beam radiotherapy in patients with T1-T2 prostate cancer.*

Acknowledgments The authors would like to thank Diane Raymond and Deborah Roach for their support and acknowledge Abby Bodden’s assistance in the editing of this chapter.

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CHAPTER 26

PERMANENT LOW-DOSE-RATE INTERSTITIAL BRACHYTHERAPY ROD J. ELLIS, MD The history of brachytherapy for the treatment of prostate carcinoma extends back to the turn of the century, shortly after Madame Curie discovered radium in 1898. The first published report of the use of brachytherapy for prostate carcinoma appeared in 1914 and was written by Pasteau and Degrais, who used a urethral catheter to place a silver tube containing a radium source.1 In 1917, Barringer described the use of a transperineal approach to place radium needles temporarily into the prostate, thereby achieving favorable results.2 However, this technique was not widely adopted and was largely replaced by either surgery or external beam radiotherapy. Other forms of radiotherapy were developed to replace the use of radium. External beam radiotherapy was initially limited because the low energy of the beams resulted in excessive skin doses when an adequate dose was provided to the prostate. In the early 1950s, radioactive gold implants using colloidal Au-198 were introduced by Flocks et al. in an effort to provide high doses of radiation to the prostate while limiting the dose to surrounding normal tissue.3 Colloidal gold was felt to be useful due to its short half-life of 2.7 days as well as to the combination of its high-energy gamma rays and beta emissions capable of treating to a short distance (3 mm). The fact that 10% of the injected material would be absorbed into the lymphatics also allowed treatment of early microscopic metastases. Again, this technique was not widely adopted, largely due to the radiation safety hazards involved with liquid radiopharmaceuticals and to radiation exposure to medical personnel and others who came into contact with the patient following the procedure. By the 1960s, linear accelerators had become available that were capable of providing a higher-energy external radiotherapy source more suitable for pelvic treatment.4 Permanent radioactive gold-198 (198Au) seed implants were performed in the early 1970s, using a retropubic approach. Typically, these 198Au seed implants were combined with external beam radiation, delivering 20 to 35 Gy via the implant, with results which were equivalent to external beam radiation alone. The radiation safety hazards of liquid radiopharmaceuticals were eliminated by using a sealed radioactive source, but the

high-energy photons produced by the isotope remained a radiation hazard. 4–6 In 1972, Whitmore and Hilaris at the Sloan-Kettering Cancer Center reported a retropubic approach that used iodine-125 (125I).7 Although preliminary reports appeared promising, long-term studies failed to sustain adequate results, and prostate brachytherapy again fell out of favor.4,8–13 The failure of the retropubic technique was most likely due to inadequate implants and poor patient selection. The limitations for placing the seeds properly resulted in poor dose distributions, and testing for prostatespecific antigen (PSA) was not available to improve the selection of favorable patients. Although the prostate could be directly visualized during the implantation, the pubic bones often made it difficult to place seeds adequately into the apex of the gland. Interseed distances were difficult to control, resulting in both hot and cold areas within the prostate.14,15 In the early 1980s, transperineal implant techniques began to gain popularity. The first published series was by Charyulu and appeared in 1980. Twenty-three patients with stage C disease received external beam radiation of 57.2 Gy in 31 fractions followed by transperineal implantation using radon (222Rn). The needles were placed through the use of a perineal template with holes 1 cm apart. The tips of the needles were advanced to the level of the bladder neck, guided by plain-film radiography and using a Foley balloon with contrast in the bulb as a marker. Of these 23 patients, 15 were disease-free at 2 years, with a local control of 96%.4,16 Kumar and Bartone, who used 125I, improved upon the transperineal technique by using a C-arm fluoroscope rather than plain-film radiography to direct the needles.17 The introduction by Holm et al. in 1983 of transrectal ultrasonographic guidance for needle placement in the prostate greatly improved this technique by allowing direct visualization of the gland during the implantation.18 Nag was the first to publish (in 1985) results of the combined use of both ultrasonography (US) and C-arm fluoroscopy. This new technique allowed three-dimensional visualization of the prostate during the implantation.19 Other more recent advances include postoperative computed tomography (CT)-based dosimetry and three-dimensional comput241


erized treatment planning. Some institutions have even used CT guidance or magnetic resonance imaging (MRI) to perform prostate implantations.20,21 Other institutions are evaluating alternative methods using a temporary implant with high-dose-rate iridium-192 (HDR 192Ir).22–28 This chapter will focus on the currently popular technique for permanent seed implantation using 125I or palladium-103 (103Pd).

Permanent Interstitial Implantation Using Iodine-125 or Palladium-103 Isotope Selection There are both advantages and disadvantages to any of the commercially available isotopes used for prostate brachytherapy. The two most commonly used isotopes, 103Pd and 125I, are becoming commercially available through numerous vendors and provide low-energy gamma rays of 21 and 28 keV, respectively. The initial dose rate for 103 Pd is 24 cGy per hour compared to that of 125I, which has a slower initial dose rate of 8 cGy per hour.14 Clinical studies have shown both isotopes to be effective for the treatment of prostate cancer, and theoretic advantages have been proposed for each isotope. Although the 125I implantations performed in the 1970s using a retropubic approach often resulted in local failure, this was most likely due to the inadequacy of the technique rather than to any inherent radiobiologic disadvantage of 125I over 103Pd.14,15 Theoretic arguments have been made that the higher dose rate for 103Pd may

be more advantageous for higher-grade, faster-growing tumors that have shorter doubling times.29 Additionally, the slightly lower average energy for 103Pd of 21 keV versus 28 keV for 125I results in a higher radiobiologic effect (RBE) for 103Pd over 125I. An in vitro study performed by Ling et al.30 in 1995 suggested that the RBE of 125I was 1.4 compared to 1.9 for 103Pd. However, there are no in vitro studies comparing both isotopes specifically against a prostate cancer cell line. In 1993, Nag et al. performed an in vivo comparison of both isotopes in transplantable Nb AI-1 prostate tumors in Noble rats.31 While this study did show favorable results for 103Pd versus 125I beyond what would be expected for the higher radiobiologic effect alone, it involved only a limited number of animals and may not be applicable to human prostate cancers. Based on the above suppositions, some clinicians have elected to use 103Pd for tumors with a Gleason score of 7 or greater and 125I for tumors in which the Gleason scores are 6 or lower.14 To date, there are no clinical data to confirm that one isotope is superior to the other. Potential disadvantages associated with 103Pd include the fact that due to its lower photon energy, cold spots may develop within the implanted volume if the seeds are placed too far apart, such that a greater number of sources may be required (compared to 125I) to cover a large prostate. Another drawback of 103Pd is its short shelf life due to its 17-day half-life. The short shelf life can be a problem if an implant is delayed or cancelled with short notice as the seeds may not be usable for another procedure unless it can be scheduled quickly. Until randomized human trials comparing isotopes are completed, the decision of which isotope is appropriate in any given situation remains with the treating physician (Figure 26–1).32 Technique

FIGURE 26–1. Loose 125I seeds and Mick® cartridge in carrier. Both iodine and palladium seeds have physical dimensions of 48 mm × 0.8 mm.

Various techniques for implantation have been described in the literature. The two most common techniques involve the use of either preloaded interstitial brachytherapy needles or a Mick® TP-200 applicator.4,14,15,33 Most techniques rely on a volume study performed prior to the implantation to determine needle placement as well as seed positioning within each needle. The volume study may be completed either on an outpatient basis or at the time of the surgical procedure. The 125I seeds are available as loose seeds or embedded in Vicryl suture (Rapid Strand®), which can be cut to any desired length and placed in a preloaded needle. Loose seeds require absorbable suture material to be placed between them as spacers in the needle to maintain proper positioning. Seeds embedded in Vicryl suture may be most useful in the periphery of the implant to avoid seed migration away from the prostate through the periprostatic venous plexus.33,34 One disadvantage of the seeds embedded in Vicryl suture is the fixed interseed spacing of 1 cm. Uniform 1-cm spacing may not be appropri-

Permanent Low-Dose-Rate Interstitial Brachytherapy / 243

FIGURE 26–2. Disposable interstitial brachytherapy needles for prostate implants. The top needle is for use with a Mick™ applicator, and the bottom needle is used for preloaded seeds. (Needles provided courtesy of Bard.)

ate in the periurethral region as it may result in an excess dose to the urethra. There have also been reports of the embedded Vicryl seeds sticking to the needle at the time of implantation, thus making the implants difficult to position properly. A description of a technique for addressing this problem by plugging the needle tips with Anusol-HC™ has been published.35 The 103Pd sources are only available as loose seeds and can be placed either through preloaded needles or individually by using a Mick applicator (Figures 26–2 and 26–3). Treatment Planning There are several ways to plan brachytherapy implantations of the prostate. Traditionally, implantations were planned based on a nomogram approach using either the average length of the prostate or the total volume as determined by US or CT to determine the required amount of radioactive material for the implant.The total number of millicuries (mCi) required for the implant can be derived from the nomogram, and the number of seeds needed is determined by dividing the number of millicuries required for the implant by the desired activity in millicuries per seed.7,15 Typically, seed strengths range between 0.2 to 0.9 mCi for 125I and 0.9 to 2.0 mCi for 103Pd.36 Although the nomogram technique provides good results with practice, the use of commercially available treatment planning systems designed for prostate brachytherapy may allow increased confidence in the results of the implantation and provide an excellent way to learn how various loading patterns affect the shape of the prescribed

radiation isodose cloud. Computer planning also allows increased control over the resultant doses to the surrounding organs, such as the urethra, rectum, and bladder. Great care must be taken to avoid excessive doses to the urethra and anterior rectal wall. Wallner et al. reported excess urethral toxicity for 125I implants delivering over 400 Gy to the urethra, and most institutions attempt to limit the urethral dose to less than 150 to 200% of the prescribed dose delivered to the periphery of the prostate.37 Additionally, seeds placed in the posterior portions of the gland should not be placed closer than 0.5 cm to the rectal wall mucosa. Needle positioning should be visualized in both the transverse and sagittal planes prior to depositing seeds in order to avoid placing them into the rectum.38 A dose above 100 Gy to the anterior rectal wall should be as limited in volume as possible.39 In the author’s practice, all patients evaluated for interstitial brachytherapy undergo a transrectal ultrasonographically-guided volume study in the dorsal lithotomy position, utilizing a Bruel & Kjaer (B&K) model 8558 multifrequency linear array biplanar ultrasound probe (Figure 26–4). After placement of a Foley catheter to allow urethral visualization, the patient is placed in the dorsal lithotomy position. The ultrasound probe is placed in the rectum, and the length of the prostate is determined on sagittal imaging. The prostate is then imaged in the transverse plane from base to apex to assess the presence of intraprostatic lesions or calcifications. The ultrasound probe is then attached to the stabilizing unit and stepping device (SURE-POINT) (Figure 26–5). The posi-

FIGURE 26–3. Mick™ TP-200 applicator for placing loose seeds in the prostate gland.


FIGURE 26–4. Bruel & Kjaer (B&K) model 8558 multifrequency linear array biplanar ultrasound probe.

tion of the probe is adjusted to visualize the entire prostate gland from base to apex, such that the entire volume of the prostate is visualized within the software grid coordinates corresponding to the holes of the perineal template used for needle guidance (Figure 26–6). The probe is then advanced into the rectum to visualize the most cephalad slice, revealing the base of the prostate. The image at the most cranial portion of the gland is designated the “0” plane. Next, the transverse ultrasonographic image at this point is captured or “frozen,” and the edges of the prostate are traced on the US screen to record its position. The physicist then captures this image on a portable treatment-planning computer (Figure 26–7). A live image is then visualized to confirm that the

position of the prostate has not shifted while the image was being recorded. The ultrasound probe is then repositioned, using the stepping unit in 0.5-cm increments, and the above process is repeated until the entire prostate gland has been imaged in 0.5-cm intervals from base to apex, allowing the computer to determine the total prostate volume. All planes beyond the “0” plane are referenced in 5-mm increments as the distance from the base. Additionally, the pubic arch can be assessed during the volume study for possible interference with needle placement. After completion of the volume study, the rectal probe and Foley catheter are removed. The physicist, using the ultrasonographic volume study images obtained as described above, completes treatment plan-

FIGURE 26–5. Stabilizing unit and stepping device (SURE-POINT).

FIGURE 26–6. Template for needle guidance. The labeled columns and rows correspond to the coordinates superimposed on the prostate gland in the transverse image by the ultrasound unit’s software package.


FIGURE 26–7. Two-dimensional image of prostate volume study on a portable treatmentplanning computer. Display shows the gland and urethral contours as well as an enlarged prostate treatment volume with needle and seed coordinates.

ning. The target volume for implantation includes the original prostate volume with 2-mm margins added laterally and anterior to the gland on each slice, with additional 5-mm margins to the base and apex. To avoid needle or seed placement within the rectum, no additional margins are placed in the posterior plane. Various institutions have elected to use larger or smaller volumes based on their experience. There is no set standard, and this can unfortunately make comparisons of each institution’s outcomes difficult, as the volume encompassed by the prescribed dose may vary despite the same dose being prescribed. This change in treatment volume may affect treatment outcomes as a result of the amount of tissue beyond the prostate that receives the prescribed dose. While expanding the margins may treat extracapsular tumor extension more adequately, treatment-related complications such as impotency might be increased due to higher doses received by the neurovascular bundles. As monotherapy, the prescribed dose is 144 Gy for 125I and 115 Gy for 103Pd, delivered to the target volume. Patients may be given either general or spinal anesthesia for the implantation procedure. After induction of anesthesia, the patient is prepped and draped in the usual sterile fashion in the dorsal lithotomy position. A Silastic Foley catheter is placed in the bladder to allow visualization of the urethra by US and to better identify the urethra on the postoperative CT scan. Dilute Hypaque (2 cc in 7 cc of water) is placed in the Foley balloon to allow fluoroscopic visualization of the bladder neck. The scrotum may be sutured to the anterior medial thigh if necessary to retract the testicles. A transrectal ultrasound probe

is placed in the rectum and is then attached to the stabilization device and stepping unit. The prostate is repositioned to match the preplanned volume study. A repeat volume study is performed as described above to confirm that the prostate volume has not changed as compared to the preplan. If there is a significant change in the size or position of the prostate, the planning process may be repeated intraoperatively. Stabilizing needles may be placed if necessary to help immobilize the prostate gland.37 A fluoroscope is positioned over the prostate in an anterior/posterior projection to allow better visualization of the needles and seeds as they are placed intraoperatively. Disposable interstitial brachytherapy needles (17 or 18 gauge) are used for the procedure, and the radioactive seeds are placed individually, using a Mick® TP-200 applicator (Figure 26–8). Needle positioning and seed positioning within each needle are determined by the three-dimensional computerized preplan. Each needle should be placed in the appropriate coordinates of the template and visualized entering the prostate gland in the transverse plane. The needle is then advanced to the “0” plane or specified coordinates under sagittal visualization by US. The Mick® applicator may then be attached to the needle, and individual seeds are placed along the needle tract as per plan under ultrasonographic and/or fluoroscopic guidance as necessary. The use of the Mick® applicator allows more freedom to adjust seed placement as needed during implantation to account for changes in the prostate’s position or size38 (Figure 26–9). After completion of the implantation, fluoroscopy may be used to identify any “cold spots” that may require additional nee-


FIGURE 26–8. Typical operating-room setup for prostate brachytherapy. The patient is in a lithotomy position with fluoroscope positioned above the pelvis, and the ultrasound unit and probe with stabilizer/stepping unit are in place.

dle and seed placement (Figure 26–10). If necessary, cystoscopy may be performed to recover any seeds inadvertently placed within the bladder. Postoperatively, the patient is taken to the recovery room. After recovering from the anesthetic, the patient is transported to the radiology oncology department for a CT scan of the pelvis and where CT-based computerized dosimetry is used to assess seed placement. The radiation oncologist is responsible for identifying the boundaries of the prostate on each slice of the CT scan from base to apex. Identification of the prostate boundaries can be difficult and can lead to discrepancies when comparing data from various institutions. A few millimeters of difference per slice can result in a large difference in the prostate volume, thereby changing the results of the postoperative dosimetry. Additionally, prostate edema is a common problem in the initial postoperative period, such that the dosimetry changes daily for a period following the procedure. Vari-

ous recommendations have been made as to the optimal time to access postoperative dosimetry, based on the average rate of resolution of edema and the half-life of the implanted isotope.39,40 It is recommended that the postoperative CT scan be obtained on the day of the procedure. A CT scan immediately after the implantation allows identification of the urethra while a catheter is present for postoperative dosimetry and provides immediate feedback on the quality of the implantation while the procedure is still fresh in mind. The physicist identifies the seeds within the implant volume to determine various dosimetric parameters. The author’s department reports the dose received by the entire prostate gland (D 100), the dose received by 90% of the prostate volume (D 90), the percent of prostate volume that received 100% of the prescribed dose (V 100), and the percent of prostate volume that received 150% of the prescribed dose (V 150). The bladder, urethra, and anterior rectal wall should be contoured on the postoperative CT scan to assess dose to these structures (Figure 26–11). A modified peripheral loading technique is used to avoid delivering more than 150 to 200% of the prescribed dose to the urethra. An acceptable implant should maintain a V 100 of at least 80%. Although D 100 is often below the prescribed dose because of the sharp decrease of the radiation dose at the edge of the implant, D 90 ideally, should be greater than or equal to the dose prescribed for the implant.39,41–43 A precise definition of an adequate implant is not available due to the variations in reporting the results and to differences in techniques at different institutions. Obviously, a radiation dose that is below the prescribed dose in an area unlikely to be involved by cancer in a low-risk patient (such as in the anterior base) may not be significant. Conversely, an underdose in a region such as the peripheral zone may likely result in a clinical failure.44 Better imaging methods are needed to determine what regions of the prostate are likely to contain occult tumor, beyond what can be found by transrectal ultrasonographic (TRUS) biopsy and digital rectal examination (DRE).45 Patient Selection

FIGURE 26–9. Mick™ applicator in use to place seeds during a prostate implantation.

Selecting patients for brachytherapy versus external beam radiation or surgery can be difficult. Brachytherapy may not be appropriate for all patients, depending on their clinical stage and symptoms. An 125I or 103Pd implant as monotherapy may be appropriate for patients with clinical stages T1c through T2a, Gleason scores of 6 or lower, and PSA levels lower than 10 ng per mL.46,47 A patient’s clinical status must also be evaluated prior to recommending brachytherapy. A patient should have a life expectancy of more than 10 years and no underlying comorbid illness that would contraindicate the surgical procedure. In general, age may not be an exclusion factor for either elderly or young patients. Elderly patients who require treatment for high-grade or advanced tumors tol-


erate implants with minimal difficulty and may not require daily trips to a radiotherapy center if treated by implantation. Alternately, younger patients who do not wish to have surgery may elect to have an implant due to the decreased risk of impotency or urinary incontinence.4,43 Patients with significant obstructive symptoms or a prostate volume greater than 60 cc should be advised of the increased risk of urinary obstruction following the procedure. Patients may also require either a CT scan or an ultrasound evaluation to rule out pubic arch interference caused by the pubic symphysis obstructing the required needle path into the prostate gland in the anterior or lateral portions of the prostate. Some patients without an enlarged prostate may still have pubic arch interference due to a narrow pubic arch. Pubic arch interference is uncommon in patients with total prostate volumes of 60 cc or less and can generally be overcome by placing the patient in an exaggerated lithotomy position or by using hormonal therapy to decrease the prostate volume. Hormonal therapy with a luteinizing hormone– releasing hormone (LHRH) antagonist can decrease the prostate volume by 30 to 60%.48–51 To avoid complications, patients with a prior history of transurethral resection of the prostate (TURP) should be carefully selected for the procedure. Such patients should not have large tissue defects that would preclude adequate placement of seeds in tissue to allow full coverage of the remaining prostate tissue. In these patients, a peripheral loading technique that places the majority of the sources away from the urethra should be employed to decrease the risk of incontinence as a result of implantation.4 Initial reports quoted an incontinence rate as high as 48% for brachytherapy following TURP; however, brachytherapists using peripheral loading have not experienced a greatly increased risk of incontinence with properly selected patients (< 5%).14,52–54 Generally, an interval of at least 2 to 3 months should be allowed following TURP prior to brachytherapy.4 High-Risk Patients Patients who are not appropriate for implantation alone based on the risk of extracapsular extension may be appropriate for a combined modality of conformal external beam radiation and implantation as a boost. The external beam radiation may be delivered either before or after the implantation, depending on the physician’s preference. Any patient with adenocarcinoma of the prostate with a minimal risk of extracapsular extension may qualify for combined external beam radiation and an interstitial implant using 103Pd or 125I. Generally, this category would include patients with a Gleason score of 7 or greater, a PSA level greater than 10 ng per mL, clinical stage T2b or minimal T3a, four or more positives out of six TRUS sextant biopsies, or positive perineural invasion as seen on biopsy. 4,14,46

FIGURE 26–10. Fluoroscopic view of seeds in prostate and Foley balloon with dilute contrast. Fluoroscopy allows identification of regions that may need additional seeds placed to prevent underdosing of the gland.

Following completion of the brachytherapy planning as detailed above, patients receiving combined therapy undergo CT in the supine position with a Vac Fix system

FIGURE 26–11. Three-dimensional (3D) reconstruction of pelvic anatomy from a CT scan following prostate implantation. Display shows the prostate with the bladder and the rectum above and below. The seeds and the surrounding prescribed isodose cloud are seen around the prostate. This information can be displayed as a 3D image with a color wash showing the relative dose to each structure or tabulated numerically as dose volume histograms (DVHs) to report the various dosimetric parameters described in the text, such as V 100, V 150, D 100, or D 90.


positioned beneath the legs between the distal thighs and proximal calves for immobilization. Prior to scanning, contrast is given intravenously and is allowed to fill the bladder to visualize any portion of the prostate protruding into the bladder. Urethrography is used to identify the prostate apex. A rectal marker (SHADOWFORM®) is placed to identify the rectum. The CT scan is then entered into a three-dimensional (3D) treatmentplanning computer. Although treatment may require individualization per patient, this will usually involve a four-field approach using anterior/posterior and right/left lateral fields. A uniform origin of 1.5 cm is used to encompass the prostate and seminal vesicles as indicated for the initial treatment volume. The beams are equally weighted, and the dose is prescribed to the isodose volume encompassing the target at the rate of 1.8 Gy daily for a total of 25 fractions. Two to 4 weeks after completion of external beam radiotherapy, the patient typically undergoes interstitial implantation as detailed above. The prescribed dose is 80 to 90 Gy using 103Pd or 100 to 110 Gy using 125I. Locally Recurrent Patients It is still controversial whether patients with locally recurrent prostate carcinoma following prior conventional radiotherapy are candidates for salvage radiotherapy using interstitial brachytherapy. Although some institutions have reported favorable results using salvage implants, the risk of late complications is still unknown; therefore, these patients should be selected carefully. Ideally, treatment should be initiated prior to their reaching a PSA level greater than 10 ng per mL. Adjuvant hormonal therapy has also been used in selected patients. These patients should undergo biopsy to confirm local recurrence prior to treatment.55,56 At the author’s institution, all patients being considered for salvage brachytherapy following conventional doses of prior external beam radiation therapy undergo a ProstaScint® scan and a CT scan of the pelvis for image fusion to assess the risk of metastatic disease beyond the prostate. The fused images from the CT scan and the ProstaScint ® scan may also allow improved planning of source placement within the prostate to regions showing a higher concentration of the monoclonal antibody suspicious for locally recurrent cancer.45 Additionally, positron emission tomography (PET) may also be warranted in select patients to help rule out metastatic disease [M. Resnick, personal communication]. If a patient shows no evidence of metastatic disease and is not felt to be at high risk for postoperative urinary obstruction or complications, treatment planning for prostate brachytherapy is completed as detailed above. These patients undergo implantation using 103Pd to deliver a dose of 90 to 100 Gy to the treatment volume.

Follow-Up Care of Patients Managing patients following brachytherapy requires cooperation between the urologist and the radiation oncologist. Although late complications such as urinary incontinence and impotency are fewer compared to those that directly follow surgery, the acute urinary morbidity can be substantial. Most patients experience mild to acute urinary symptoms of obstruction and dysuria in the immediate postoperative period and for several days. The acute phase is mostly due to the trauma of needle insertion and seed placement and to catheter irritation. Usually, the acute trauma resolves within a week, and most patients describe a “honeymoon” phase where the symptoms are relatively minor or absent for 1 to 2 weeks following implantation. The symptoms usually peak at 2 to 4 weeks and occur earlier for 103Pd than for 125I. As the energy from the seeds is released into the surrounding tissue, most patients notice some degree of urinary irritation as a result of radiation prostatitis. The irritation often results in urinary frequency and dysuria of varying degrees. Some patients also experience hematuria or describe rectal irritation resulting in more frequent bowel movements, flatulence, or mucus production. The rectal irritation generally improves prior to the onset of the urinary symptoms, which usually resolve gradually over a 4- to 12-month period. About half of the patients complain that the irritative symptoms require medical management, while others comment on the presence of the symptoms but do not require treatment for relief. Most patients are able to treat the associated discomfort without narcotic pain medication and are generally able to find relief with over-the-counter medications such as nonsteroidal anti-inflammatory drugs (NSAIDs). Approximately half of the patients require the addition of a selective α1-adrenergic blocker following implantation and for at least several months to decrease urinary obstruction and dysuria.4,53 Fortunately, significant morbidity is generally low. Although radiation proctitis is a common temporary side effect, rectal ulcer or bleeding occurs in less than 5% of patients and is usually self-limiting. Urethral strictures are also rare. Severe obstruction may occur in some patients and may require temporary catheterization or intermittent self-catheterization beyond the first week of the implantation procedure. Managing the patients who have repeated obstructions can be disheartening. Often, these patients can use self-catheterization as needed for a period of time or keep a temporary indwelling Foley catheter. Some institutions manage these patients with temporary suprapubic catheters that allow the urethra to heal without further irritation from catheter placement. Generally, an obstruction will resolve in time, but this may take up to a year in extreme cases. Although urinary incontinence is rare in patients without a history of TURP prior to implantation, the urge to relieve postimplantation urinary


obstruction by means of TURP or transurethral incision of the prostate (TUIP) should be resisted for as long as possible due to the greatly increased risk of urinary incontinence that can occur at any time for several years following the TURP/TUIP procedure.56,57 Impotency following implants was at first felt to be as low as 20%; however, with longer follow-up times, it appears to be as high as 40 to 60%. Impotency is increased if patients receive adjuvant hormonal therapy. Short courses of adjuvant hormones should not be routine unless they are used to relieve obstruction or to decrease prostate volume to avoid pubic arch interference prior to implantation. Potency also appears to decline more rapidly in older patients after implantation.58 Rectal bleeding can also occur as a result of interstitial brachytherapy. Fortunately, the bleeding is self-limiting in most cases and is best managed by conservative treatment such as steroid-containing enemas. With proper attention to implantation technique, the risk of a colostomy is very low.15 Clinical Follow-Up Routine follow-up after brachytherapy should be done by both the radiation oncologist and the urologist. Patients may elect to follow up mostly with either their urologist or their radiation oncologist; however, close communication between the two should be maintained or alternating follow-up appointments with each specialist should be arranged. Until more data are available on the long-term results and potential complications following brachytherapy, physicians practicing brachytherapy must remain aware of the results from their own patients to learn better methods of patient management and to improve upon their implantation technique. Patients should be aware that it may often take at least 2 years for the PSA level to reach a nadir value. They should also be aware that a rise in PSA level may occur in as many as one-third of patients between the first and second year following implantation. This rise in the PSA level, termed a “benign bump,” appears to be related to late tissue reactions to the radiation and does not translate into a greater risk of treatment failure. The urge to offer further treatment, such as surgery or hormonal therapy, should be avoided for at least 2 years following implantation. While some physicians have suggested not drawing a PSA level for the first 12 to 24 months following implantation (to avoid the PSA-related anxiety associated with this frequent benign rise in the PSA level), most patients request more frequent evaluation of the results of the therapy. The author generally obtains baseline values for PSA, prostatic acid phosphatase (PAP), and alkaline phosphatase prior to implantation; following implantation, PSA levels are drawn routinely at the first follow-up appointment 1 month postimplantation and then every 3 to 6 months for the first 2 years. After 2 years, a yearly PSA level is obtained at follow-up. Digital rectal

examinations are performed at the same interval following the PSA examination. Routine prostate biopsies are not recommended unless there is a rising PSA level or a new abnormal finding on DRE. Routine biopsies have been performed at several institutions and have shown residual carcinoma to be rare for patients with a low PSA nadir, with the highest risk being for patients with a rising PSA level or a palpable lesion on DRE. Additionally, due to the changes associated with radiation, interpreting biopsy results postimplantation can be difficult.59,60 It is also recommended that repeat localization films be obtained by the radiation oncologist 4 to 6 months following implantation to rule out significant seed migration. Seed migration can result in an inadequate dose to a region of the gland and may require further therapy if the area is likely to be involved with carcinoma. Localization films are obtained the day of the implantation for dosimetric analysis to confirm the number of seeds in the prostate; these films include anterior and lateral pelvic views as well as a chest x-ray film. By counting the number of seeds seen on the films in the treatment volume, the physicist is better able to identify the correct number of seeds on the treatment-planning CT scan. Seed migration away from the prostate can occur for several days after the procedure and usually results in seeds embolizing to the lungs.4 Although the seeds that migrate have not been known to cause any clinical symptoms, they could result in local failure if an area of the prostate is left undertreated. It is rare that a patient will require a second implant or external beam radiation to correct for seed loss if careful technique is used to provide adequate coverage of all regions of the prostate. Other imaging studies (such as plain films, bone scans, CT scans, MRI scans, ProstaScint® scans, or PET scans) should be obtained only as indicated by a rising PSA level, new onset of bone pain, or clinical symptoms worrisome for recurrent or metastatic disease. Published Results Several studies describing the clinical results of prostate brachytherapy are now available. Although long-term results are still pending from most institutions, most reports show that brachytherapy can be as effective as either surgery or external beam radiation. This section will review some of the more recently reported results. Grado et al.61 recently reported the results of 490 patients implanted as primary treatment at the Mayo Clinic in Scottsdale, Arizona. Four hundred and eightynine of the implantations were performed using a Mick® TP-200 applicator with a biplanar ultrasound probe and fluoroscopic guidance. Both iodine and palladium sources were used, without selection for tumor grade. Of the 490 patients surveyed, 418 patients received implant alone while 72 patients received a median dose of 45 Gy adjuvant external beam radiation for increased risk of extracapsular extension. Adjuvant hormonal therapy was given


to 35 patients (7%). The median follow-up time was 46.9 months. Failure of PSA was defined as two consecutive rises above the post-treatment nadir value or a PSA level greater than 1.0 ng per mL in the adjuvant hormonal therapy group. Among the 454 patients not given adjuvant hormonal therapy, the median pretreatment PSA value was 7.5 ng per mL. Clinical stages varied from T1 to T3c, with 32% with T2a and 50% with T2b. Tumor grade was well differentiated in 23% of the patients, moderate in 54%, and high in 23%. Actuarial disease-free survival at 5 years was 79%, with an actuarial 5-year local control rate of 98% for the entire group. On multivariate analysis, only lower values for pretreatment PSA and post-treatment PSA nadir were significantly predictive of disease-free survival (DFS). In the 60% of patients who achieved a posttreatment PSA nadir less than 0.5 ng per mL, DFS was 93% at 5 years, compared to 25% for a PSA nadir between 0.5 to 1.0 ng per mL and 15% for PSA nadir values greater than 1.0 ng per mL. Disease-free survival as stratified by initial pretreatment PSA levels at 5 years was 88% for PSA levels less than 10 ng per mL, 72% for PSA levels of 10 to 20 ng per mL, and 57% for PSA levels greater than 20 ng per mL. While most patients complained of acute urinary symptoms requiring an α1-blocker, late complications were low, with less than 1% obstruction beyond 1 month, 1% rectal fistula, 0.4% gross hematuria, 0.8% penile dysuria, and 0.4% proctitis.61 Dattoli et al.62 reported their results for patients at high risk of extracapsular disease treated with a combination of 103Pd brachytherapy and external beam radiation. Seventythree consecutive patients with clinical stage T2a-T2b disease were treated between 1991 and 1994 using the Mick® applicator. All patients had at least one of the following risk factors for extracapsular extension: stage T2b or greater (71 pts), Gleason score of 7 to 10 (40 pts), PSA level greater than 15 ng per mL (32 pts), or elevated PAP (17 pts). Treatment consisted of external radiation to a limited pelvic field of 41 Gy followed 4 weeks later by a 103Pd implant to an additional 80 Gy. Ten patients received adjuvant hormonal therapy for 2 months prior to treatment. Biochemical failure was defined as a PSA level greater than 1.0 ng per mL. Although follow-up was limited to 1 to 3 years (median 2 years), the overall actuarial freedom from biochemical failure was 79%, with no failure reported beyond 18 months. On multivariate analysis, the strongest predictor of failure was elevated PAP (p = .04) followed by PSA (p = .17) and stage (p = .23). Morbidity was minimal, with most patients having only Radiation Therapy Oncology Group (RTOG) grades 1 to 2 urinary symptoms, usually relieved with an α1-blocker. One patient who underwent both TUIP and postimplantation TURP developed low-volume urinary incontinence. Potency was maintained in 77% of these patients.62 The most frequently quoted series of prostate brachytherapy patients comes from the Seattle group.

Ragde et al.63 published the first 10-year follow-up report on the initial 152 patients implanted with 125I between January 1987 and June 1988 at Northwest Hospital in Seattle, Washington. Implantation alone was performed in 98 patients (64%) and 45-Gy external beam radiation plus implantation was performed in 54 patients (36%) who were at higher risk for extracapsular extension. No patients received hormonal therapy. The median followup period was 119 months. Overall survival at 10 years was 65%. Only 2% of these patients died of disease. Failure was defined as a PSA nadir greater than 0.5 ng per mL. Ninety-seven patients (64%) were clinically and biochemically disease-free at 10 years. Only 6% developed bone metastasis. Despite the increased risk factors for the group who received adjuvant external beam radiation, there was no statistical difference in outcome between the two groups. Overall, the results were felt to be equivalent to results published for prostatectomy series.63 Blasko64 recently presented an update for the entire group of 634 patients treated at Northwest Hospital. The initial PSA mean and median values were 11.0 and 7.7 ng per mL (0.2 to 138), respectively. PSA failure was defined as a value greater than 1.0 ng per mL. Actuarial data reveal the biochemical relapse-free survival for the group of patients who received either 125 I or 103Pd implants with or without external beam radiation as 85% at 10 years. The 354 patients with clinical stage T1 to T2 disease, a Gleason score of 6 or less, and an initial PSA level below 10 ng per mL had a PSA-progression-free survival of 87%, compared to 84% in the 215 patients with one risk factor of either T3 disease, a Gleason score of 7 or greater, or an initial PSA level greater than 10 ng per mL. Patients with two or more of these risk factors had a decreased progression-free survival of 60%.64

Conclusion Prostate brachytherapy appears to be gaining acceptance as a standard treatment option for patients with clinically localized carcinoma. Further studies are needed to help define the appropriate patients for implantation alone versus combined therapy with external beam radiation versus 3D conformal radiotherapy or intensity-modulated radiotherapy (IMRT). It also remains to be seen if the favorable results reported so far will be routinely reproducible in the community hospital setting. It is hoped that improvements made during the past several years to prostate brachytherapy equipment along with future developments will allow this technique to continue to produce favorable long-term results.

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19. Nag S. Transperineal iodine-125 implantation of the prostate under transrectal ultrasound and fluoroscopic control. Endocurie/Hypertherm Oncol 1985;1:207–11. 20. Koutrouvelis P. Three-dimensional steriotactic posterior ischiorectal space computerized tomography guided brachytherapy of prostate cancer: a preliminary report. J Urol 1998;159:142–5. 21. D’Amico AV, Cormack R, Tempany CM, et al. Real-time magnetic resonance image–guided interstitial brachytherapy in the treatment of select patients with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 1998;42:507–15. 22. Borghede G, Hedelin H, Holmang S, et al. Combined treatment with temporary short-term high dose rate iridium-192 brachytherapy and external beam radiotherapy for irradiation of localized prostatic carcinoma. Radiother Oncol 1997;44:237–44. 23. Mate TP, Gottesman JE, Hatton J, et al. High dose-rate afterloading 192iridium prostate brachytherapy: feasibility report. Int J Radiat Oncol Biol Phys 1998;41:525–33. 24. Martinez A, Gonzalez J, Stromberg J, et al. Conformal prostate brachytherapy: initial experience of a phase I/II dose-escalating trial. Int J Radiat Oncol Biol Phys 1995;33:1019–27. 25. Stromberg JS, Martinez AA, Horwitz EM, et al. Conformal high dose rate iridium-192 boost brachytherapy in locally advanced prostate cancer: superior prostatespecific antigen response compared with external beam treatment. Cancer J Sci Am 1997;3:346–52. 26. Dinges S, Deger S, Koswig S, et al. High-dose rate interstitial with external beam irradiation for localized prostate cancer—results of a prospective trial. Radiother Oncol 1998;48:197–202. 27. Kini VR, Edmundson GK, Vincini FA, et al. Use of threedimensional radiation therapy planning tools and intraoperative ultrasound to evaluate high dose rate prostate brachytherapy implants. Int J Radiat Oncol Biol Phys 1999;43:571–8. 28. Kovacs G, Galalae R, Loch T, et al. Prostate preservation by combined external beam and HDR brachytherapy in node negative prostate cancer. Strahlenther Onkol 1999;175:87–8. 29. Ling CC. Permanent implants using Au-198, Pd-103 and I-125: radiobiological considerations based on the linear quadratic model. Int J Radiat Oncol Biol Phys 1992;23:81–7. 30. Ling CC, Li WX, Anderson LL. The relative biological effectiveness of I-125 and Pd-103. Int J Radiat Oncol Biol Phys 1995;32:373–8. 31. Nag S, Sweeney PJ, Wienthjes MG. Dose-response study of iodine-125 and palladium-103 brachytherapy in a rat prostate tumor (Nb-Al-1). Endocurie/Hypertherm Oncol 1993;9:97–104. 32. Wallner K, Blasko J, Dattoli M. Radionuclides. In: Wallner K, Blasko J, Dattoli M, editors. Prostate brachytherapy made complicated. Seattle: SmartMedicine Press; 1997. p. 5.1–5.14. 33. Ragde H. Brachytherapy (seed implants) for clinically localized prostate cancer. J Surg Oncol 1997;64:79–81. 34. Tapen EM, Blasco JC, Grimm PD, et al. Reduction of


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CHAPTER 27

T1B-T2NXM0: A CASE FOR HORMONAL THERAPY? FARHANG RABBANI, MD, FRCSC; S. LARRY GOLDENBERG, MD, FRCSC The role of androgen withdrawal therapy (AWT) in hormone-naive, clinically localized prostate cancer has not been adequately or appropriately tested. Nevertheless, it is a concept that is a part of clinical practice worldwide. Several surveys have revealed disparities among urologists’ attitude toward treatment of localized prostate cancer and the actual patterns of care. This situation exists in both Europe and North America. While most urologists favor definitive local therapy, many patients receive AWT as first-line treatment. In a survey of 656 European urologists concerning treatment of moderately differentiated, localized prostate cancer in a 60-year-old man, 79.9% chose definitive local therapy in the form of radical prostatectomy, external beam radiotherapy, or brachytherapy, while 15.9% chose conservative therapy in the form of hormonal therapy or watchful waiting.1 Another study of 26 Italian urologic centers reported that during a 1-year recruitment period (June 1994 to June 1995), 16 of 31 (52%) stage A2 patients, 52 of 138 (38%) stage B1 patients, and 98 of 170 (58%) stage B2 patients received hormonal therapy as first-line treatment, compared to 8 of 31 (26%) stage A2 patients, 78 of 138 (57%) stage B1 patients, and 72 of 170 (42%) stage B2 patients who received definitive local therapy with or without hormonal therapy.2 Telephone interviews conducted by the Gallup Organization in August 1994 revealed that 95% of 514 randomly selected American urologists would recommend radical prostatectomy for men younger than 70 years with localized prostate cancer and that 13% considered hormonal therapy appropriate.3 Data from 1035 hospitals (of 2000 invited) in the United States reveal that in 1990, 9.0% of 4126 stage I patients and 12.6% of 6761 stage II patients were treated with hormonal therapy.4 Clearly, AWT is being used as primary therapy for apparently localized prostate cancer (ALCaP) on an ad hoc basis outside of clinical protocols. This chapter will review the available evidence to support such an approach in special circumstances.

demonstrating a benefit of one therapy over another. While series evaluating radical prostatectomy, external beam radiotherapy, and expectant management have reported good results in patients with localized disease,5 each is subject to selection bias, suggesting that any management strategies may be appropriate for select individuals. The difficulty in comparing these nonrandomized studies arises from differences in grading (cytologic versus histologic) between studies,6,7 differences in method of grading (biopsy versus prostate specimen), differences in staging with respect to nodal metastases, lack of data on pretreatment prostate-specific antigen (PSA) in studies with long-term follow-up, and differences in age or comorbidities which may artificially improve cancer-specific survival. Nonrandomized, retrospective, population-based studies have suggested that appropriate patient selection can yield results with conservative therapy similar to that yielded by definitive local therapy, keeping in mind differences in staging and grading.8 To clarify the role of androgen deprivation in treating stage T1b-T2 prostate cancer, there is a need to distinguish between those men who are at high risk for treatment failure with definitive local therapy and those who may be better served by early hormonal therapy. Also, some patients who refuse definitive local therapy would benefit from immediate hormonal therapy prior to progression. Recently, the Prostate Cancer Clinical Guidelines Panel reviewed the literature from 1966 to 1993 on stage T2 prostate cancer to make treatment policy recommendations.9 Because of differences in significant characteristics such as patient age, tumor grade, and pelvic lymph node status among the various treatment series, the panel ultimately listed radical prostatectomy, radiotherapy, and surveillance as treatment options. The choice of treatment depends on life expectancy, overall health status, and patient preference.9 In general, definitive local therapy is deemed more appropriate for patients with a life expectancy of at least 10 years. However, evidence to support this view is lacking since the greater age and comorbid factors of patients in the surveillance series limits comparison of crude survival as well as cancer-specific survival. Older patients or those with other comorbid factors would be less likely to die of prostate cancer and more likely to die of other causes. This would artificially improve cancerspecific survival in surveillance series. Due to the limited

Choice of Therapy for Localized Prostate Cancer The controversy over treatment of localized prostate cancer has arisen from the lack of well-designed randomized trials 253


body of literature on hormonal therapy alone for localized prostate cancer, this approach would have to be considered experimental until sufficient data are available from welldesigned randomized trials to demonstrate an outcome superior to that of surveillance or at least equivalent to that obtained with definitive local therapy.

Results of Hormonal Therapy for Localized Prostate Cancer Since the androgen dependence of prostate cancer was demonstrated by Huggins and Hodges,10 AWT has been used in treating advanced prostate cancer. In 1997, the Medical Research Council Prostate Cancer Working Party Investigators Group reported on the results of a trial randomizing 938 patients with locally advanced (clinical stage T2 to T4) or asymptomatic metastatic prostate cancer. Patients were treated with either immediate hormonal therapy with orchiectomy, a luteinizing hormone–releasing hormone (LHRH) analogue, or with deferred therapy.11 Randomization was performed with stratification for age, clinical stage, and metastatic status. Comparison of the patients with nonmetastatic disease (256 patients randomized to immediate therapy and 247 randomized to deferred therapy), revealed a greater freedom from distant progression or death due to prostate cancer in patients receiving immediate therapy (96 events in 256 patients) versus deferred therapy (144 events in 244 patients) (p < .001, log rank test). These patients had both an improved crude survival (p = .02, log rank test) and prostate cancer-specific survival (p = .0003, log rank test). There were 150 deaths in 256 patients in the immediate therapy arm, compared to 171 deaths in 244 patients in the deferred therapy arm. The corresponding number of prostate cancer deaths was 81 in the immediate and 119 in the deferred therapy arms. While this data on locally advanced nonmetastatic prostate cancer cannot be directly applied to ALCaP, it is reasonable to postulate that these patients would also benefit from early AWT. In 1979, Barnes et al. reported on 155 patients with clinical stage A or B prostate cancer diagnosed between 1930 and 1967 who were treated with either immediate or delayed AWT.12 In this retrospective study, there was no difference in the 15-year survival rate of patients receiving immediate (23 of 95 patients or 24%) versus delayed (16 of 50 patients or 32%) hormonal therapy. In a retrospective study of 100 cases of clinical stage A prostate cancer, Heaney et al. reported 10-year actuarial crude survival rates of 33% in 67 patients treated with endocrine therapy.13 These results, however, were clouded by the fact that many patients treated with hormonal therapy had less well-differentiated disease and that 25 men suffered cardiovascular deaths because of the use of diethylstilbestrol (DES) at doses of 3 to 30 mg daily. In patients not dying of prostate cancer, 25 of 49 (51%) patients receiving

hormonal therapy died of cardiovascular disease, compared to 9 of 32 (28%) patients receiving no therapy. Blackard and associates reported on 91 patients with stage I prostate cancer who received no further therapy (45 men, median age 71 years), hormonal therapy (22 men, median age 72 years), or radical prostatectomy with or without DES (24 men, median age 68 years).14 Pretreatment cardiovascular status was best in the surgically treated patients but otherwise similar in patients receiving hormonal or no therapy. Median follow-up was 62 months in the 30 living untreated patients, 42 months in the 12 living hormone-treated patients, and 78 months in the 14 living surgical patients. No significant differences in survival were reported among the three groups; actuarial curves, however, were not generated by the method developed by Kaplan and Meier. In the studies reported by Heaney et al.13 and Blackard et al.,14 bone scans were not performed to assess metastatic disease, and the volume of disease (clinical stage A1 versus A2) was not specified. All of these early studies12–14 demonstrate trends but suffer from significant selection bias, incomplete staging, and inadequate survival analysis, which preclude drawing meaningful conclusions from them. More recently, Egawa and associates performed a retrospective review of 107 patients with localized prostate cancer diagnosed between 1971 and 1984.15 Immediate endocrine therapy was given in 55 patients and the remaining 52 patients were managed expectantly. Mean follow-up was 6.2 years. Patient age, weight of resected tissue, grade and clinical stage were comparable in the two groups. No significant difference in cancer-specific survival rates were reported between patients receiving no initial therapy (75% at 10 years, 95% confidence interval [CI] 64 to 86%) and those receiving immediate hormonal therapy (68% at 10 years, 95% CI 59 to 77%), (p = .88). However, the power of this study is limited by the short follow-up and by the inclusion of 33 patients with clinical stage A1 disease in whom the 10-year cancer-specific survival of 96% (95% CI 88 to 100%) was significantly better than that of patients with clinical stage A2, B1, or B2 disease. On multivariate analysis with the Cox proportional hazards model, grade was the only significant predictor of progression (hazard ratio of 2.9, 95% CI 1.6 to 5.3) for G2 versus G1 and 8.4 (95% CI 2.6 to 28) for G3 versus G1 as well as being the only significant predictor of death. Two randomized studies have assessed immediate hormonal therapy in patients with localized prostate cancer and another study is currently in progress. Byar reported on 148 patients with clinical stage I disease enrolled in the Focal Carcinoma Study from 1964 to 1969.16 This study was designed to accommodate patients who were too old or too ill to undergo radical prostatectomy or who refused surgery. Thirty-nine patients were randomized to placebo, 36 to DES 5.0 mg daily, 38 to orchiectomy and placebo, and 35 to orchiectomy and DES 5.0 mg daily. Median

T1b-T2NxM0: a Case for Hormonal Therapy? / 255

follow-up was 5 years 7 months. No significant difference in crude survival was noted between the various treatment arms. None of the 72 deaths was attributed to prostate cancer, consistent with the high risk of dying of other causes among these elderly men. Residual carcinoma was found in only 1 of 22 prostates in men undergoing autopsy. Conclusions are difficult to draw from this study due to the limited power of the small sample sizes. The South Sweden Prostate Cancer Study Group reported on a randomized, open, multicenter trial comparing early and deferred endocrine therapy in men with clinical stage I to III (T0a to T3NxM0, 1978 TNM classification) well- or moderately well-differentiated prostate cancer.17 Two hundred eighty-five men were randomized, of whom 228 were evaluable: 66 in the polyestradiol phosphate plus ethinyl estradiol group, 74 in the estramustine phosphate group, and 88 in the deferred therapy group. Mean follow-up among the 100 patients alive in August 1993 was 144 months (range: 111 to 180 months). In this study, 51 of 228 (22%) patients were older than 75 years, 159 of 228 (70%) had well-differentiated disease, 53 of 228 (23%) had clinical stage T0a disease, and 22 of 228 (9%) had clinical stage T3 disease. While no significant difference in interval to metastases was noted among the three groups (p = .07), there was a tendency for a higher probability of metastases in the deferred therapy group: the 10-year metastasis-free survival rate was 89% for patients receiving estrogen, 78% for those receiving estramustine, and 66% for patients whose therapy was deferred. There was a significant difference in the 10-year cancer-specific survival rates (p = .03): 88% for patients receiving estrogen, 79% for those receiving estramustine, and 74% for those whose therapy was deferred. No significant difference in overall survival was noted: the 10-year crude survival rate was 53% for patients receiving estrogen, 52% for those receiving estramustine, and 49% for deferred therapy patients. Comparison of treatment arms revealed a significant difference in the risk of metastasis developing for the estrogen-treated group versus the delayed therapy group: risk ratio 0.48 (p = .044) for all patients and 0.30 (p = .04) for the patients with stage > T0a, well-differentiated disease. Prostate cancer was the cause of death in 8 of 66 (12%) estrogen-treated patients, 13 of 74 (18%) estramustine-treated patients, and 25 of 88 (28%) deferred therapy patients. The death rates from cardiovascular disease were not significantly different between the treatment groups: 14 of 66 (21%) estrogen-treated patients, 11 of 74 (15%) estramustine-treated patients, and 14 of 88 (16%) deferred therapy patients. Conclusions regarding differences between the two forms of endocrine therapy cannot be drawn, however, since the small number of events in these arms limits the power of the study. The probability of detecting a 50% increase in metastasis-free or cancer-specific survival was 15 to 25% and for crude survival, 40 to 50%. To achieve a

power of 80%, 95 events per treatment arm would be required. Further, the exclusion of 57 patients (14 incorrectly staged, 30 protocol violations, 13 randomized to a new treatment arm) introduces an imbalance in pretreatment characteristics, despite stratification for age, stage, and grade. The authors state, however, that addition of 43 of the nonevaluable patients for whom survival data were available did not alter the results reported for the 228 patients. The European Organization for Research on the Treatment of Cancer (EORTC) is currently performing a randomized study, EORTC study 30891, among patients deemed unsuitable for radical prostatectomy who are randomized to immediate or deferred hormonal therapy.18 The target number of patients for accrual is 750. While no randomized studies have been performed in localized prostate cancer comparing AWT to definitive local therapy, Fellows et al. have reported on 277 patients with clinical stage T2 to T4NxM0 disease randomized to radiotherapy (88 patients), orchiectomy (90 patients), and combination therapy (99 patients) between 1980 and 1985.19 The three groups were comparable regarding age, performance status, clinical stage, Gleason score, and duration of follow-up, despite absence of stratification at randomization. Only 119 of 277 (43%) had stage T2 disease. Median follow-up was at least 4 years in all of the treatment groups. Metastasis-free survival was lower in the group receiving radiotherapy alone than in either of the two groups having orchiectomy (p < .005). This difference remained significant after stratification for stage, Gleason score, and performance status. No statistically significant differences in overall survival were noted. The survival rates in studies evaluating AWT for apparently localized or locally advanced prostate cancer are summarized in Table 27–1. Recently, Bolla and associates reported on the results of a phase III EORTC trial.20 In the study, a total of 415 patients with locally advanced prostate cancer were randomized to radiation alone or radiation and goserelin starting on the first day of radiation and continuing for 3 years. Flare was blocked in the hormonal therapy arm by cyproterone acetate during the first month of treatment. Analysis was performed on 401 evaluable patients with a median follow-up of 45 months. Only 34 of 401 (8.5%) patients had clinical stage T1-T2 disease. The 5-year actuarial rates with and without hormonal therapy were 79 versus 62%, respectively, for overall survival (p = .001), 85 versus 48%, respectively, for disease-free survival (p < .001), and 97 versus 77%, respectively, for survival in the local control (p < .001). Since no arm was included for hormonal therapy alone, it is not possible to determine if this may also have an outcome superior to radiotherapy alone.

Quality-of-Life Issues: Intermittent Androgen Suppression The concept of intermittent androgen suppression (IAS) was devised in an attempt to delay progression to the


androgen-independent state by restoring apoptotic potential to cells surviving androgen ablation. Progression to the androgen-independent state is delayed threefold in the Shionogi and LNCaP tumor models.21,22 Reintroduction of androgens in IAS results in down-regulation of androgenrepressed alternate pathways of signal transduction in these tumor models.22 The close parallel between the serum PSA response following castration in the LNCaP tumor model and human prostate cancer suggests that IAS should delay progression to androgen independence in human prostate cancer.22 Continuous androgen deprivation causes loss of libido, impotence, and hot flushes, and has been associated with osteoporosis and subsequent pathologic bone fractures23–25 as well as anemia.26 The long-term adverse consequences of continuous androgen deprivation may be decreased by IAS and quality of life may be preserved during the periods off therapy. The first pilot study of IAS with DES demonstrated successful palliation of symptomatic, advanced prostate cancer, allowing return to sexual activity within months of cessation of treatment.27 Goldenberg et al. reported on 47 patients treated with intermittent androgen suppression.28 Patients were treated with total androgen blockade for a minimum of 6 months until a PSA nadir was observed. Therapy was then withdrawn until serum PSA increased to 10 to 20 ng per mL, at which time therapy was reinstituted. The cycle was continued until progression to androgen independence was achieved. For the first two cycles, the patients were off therapy a mean of 41% and 45% of the time, respectively. The patients recovered sexual functioning and had an improved sense of wellbeing off therapy. In this series, 3 patients had clinical

TABLE 27–1. Survival Rates in Patients with Localized or Locally Advanced Prostate Cancer Treated with Immediate Androgen Withdrawal Therapy Series

No. Patients Stage Follow-Up (Years)

Barnes12 Heaney13 Blackard14 Egawa15 Byar16 Lundgren17

95 67 22 55 109 140

A–B A I A1–B2 I T0A–T3

NA NA 3.5 (median)|| NA 5.6 (median) 12 (mean)*¶

Fellows19 MRC11

90 256

T2–T4 T2–T4

4.6 (median) NA

NA = not stated. *Actual survival. †Actuarial survival. ‡Crude survival. §Cancer-specific survival. ||For those who are alive. ¶Includes patients treated with deferred therapy.

Survival 24% 15-year*‡ 33% 10-year†‡ 55% 7-year*‡ 68% 10-year†§ 50% 7-year*‡ 88% 10-year†§ (estrogen) 79% 10-year†§ (estramustine) 38% 7-year†‡ 37% 10-year†§

stage T1b tumors and three had stage T2b tumors. These men range in age from 62 to 80 years (mean 72.5). To date, 2 men have been on protocol for over 4 years and are both in the third cycle. Two others are in the second cycle in their third year of treatment while the remaining 2 are still in first cycle, 70 weeks after beginning AWT. In all cases, the off-treatment time averaged 49%. One patient died of noncancer-related causes; all others remain alive and well and hormonally-responsive. Since this report, numerous other investigators have confirmed the feasibility of IAS for treatment of prostate cancer with improved quality of life.29–32 Recently, Grossfeld et al. evaluated the use of IAS in selected patients with clinically localized prostate cancer.32 Of the 47 patients studied retrospectively, 3 were stage T1c, 21 stage T2, 21 stage T3, 1 stage T4, and 1 had unknown stage cancer. The 27 patients who had received no prior therapy were treated with IAS after refusal of definitive local therapy. Average time spent off therapy was 47%. With a mean follow-up of 24 months (range 5 to 52 months), only 1 patient has failed to respond after restarting on androgen deprivation therapy; this patient had failed external beam radiotherapy given 4 years earlier for Gleason score 7 stage T2b prostate cancer. Given the short follow-up in this study, however, and the small number of patients with stage T2, the durability of IAS compared to continuous androgen deprivation therapy is unknown. Intermittent androgen suppression remains experimental since the benefit of continuous androgen deprivation therapy for localized prostate cancer has not been conclusively demonstrated and the durability of the response to IAS remains unknown. However, since it offers a superior quality of life compared to continuous androgen deprivation in patients who are otherwise asymptomatic, it may represent a viable alternative to prolonged, continuous androgen deprivation for ALCaP.

Summary Given the paucity of well-conducted randomized trials with adequate follow-up, the efficacy of hormonal therapy compared to the other modalities in apparently localized prostate cancer remains unknown. To be considered a viable treatment option in otherwise healthy patients with a long life expectancy, equivalent efficacy to definitive local therapy would need to be demonstrated in adequately powered randomized trials. In patients who have a limited life expectancy due to advanced age or other comorbid factors, hormonal therapy may be reasonable if a clinically significant advantage in survival can be demonstrated over surveillance. The data on intermittent androgen suppression for localized disease remains too limited to adequately define the role of this approach. However, intermittent androgen suppression may provide a means of limiting toxicity of hormonal therapy while preserving its potential therapeutic benefit.

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References 1. Hansen MV, Grönberg A. Attitudes of European urologists to early prostatic carcinoma. Eur Urol 1995;28:196–201. 2. Bono AV, Rocca Rossetti S, Vercelli M, Marcozzi L, members of the REICAP Group (Ricerca Epidemiologica Italiana sul Carcinoma Prostatico). REICAP: prospective epidemiologic study of prostate cancer in Italy. Eur Urol 1996;30 Suppl 1:2–6. 3. Gee WF, Holtgrewe HL, Albertsen PC, et al. Practice trends in the diagnosis and management of prostate cancer in the United States. J Urol 1995;154:207–8. 4. Jones GW, Mettlin C, Murphy GP, et al. Patterns of care for carcinoma of the prostate gland: results of a national survey of 1984 and 1990. J Am Coll Surg 1995;180: 545–54. 5. Adolfsson J, Steineck G, Whitmore WF Jr. Recent results of management of palpable clinically localized prostate cancer. Cancer 1993;72:310–22. 6. Chodak GW, Bibbi M, Straus FH, Wied GL. Transrectal aspiration biopsy versus transperineal core biopsy for the diagnosis of carcinoma of the prostate. J Urol 1984; 132:480–2. 7. Waisman J, Adolfsson J, Löwhagen T, Skoog L. Comparison of transrectal prostate digital aspiration and ultrasoundguided core biopsies in 99 men. Urology 1991;37:301–7. 8. Lu-Yao GL, Yao SL. Population-based study of long-term survival in patients with clinically localized prostate cancer. Lancet 1997;349:906–10. 9. Middleton RG, Thompson IM, Austenfeld MS, et al. Prostate Cancer Clinical Guidelines Panel summary report on the management of clinically localized prostate cancer. J Urol 1995;154:2144–8. 10. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen, and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941;1:293–7. 11. The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial. Br J Urol 1997; 79:235–46. 12. Barnes R, Hadley H, Axford P, Kronholm S. Conservative treatment of early carcinoma of prostate: comparison of patients less than seventy with those over 70 years of age. Urology 1979;14:359–62. 13. Heaney JA, Chang HC, Daly JJ, Prout GR Jr. Prognosis of clinically undiagnosed prostatic carcinoma and the influence of endocrine therapy. J Urol 1977;118:283–7. 14. Blackard CE, Mellinger GT, Gleason DF. Treatment of stage I carcinoma of the prostate: a preliminary report. J Urol 1971;106:729–33. 15. Egawa S, Go M, Kuwao S, et al. Long-term impact of conservative management on localized prostate cancer. Urology 1993;42:520–6. 16. Byar DP, Veterans Administration Cooperative Urological Research Group. Survival of patients with incidentally found microscopic cancer of the prostate: results of a clinical trial of conservative treatment. J Urol 1972; 108:908–13. 17. Lundgren R, Nordle Ö, Josefsson K, South Sweden Prostate Cancer Study Group. Immediate estrogen

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or estramustine phosphate therapy versus deferred endocrine treatment in nonmetastatic prostate cancer: a randomized multicenter study with 15 years of follow-up. J Urol 1995;153:1580–6. Newling DWW. The geography of prostate cancer and its treatment in Europe. Cancer Surv 1995;23:289–96. Fellows GJ, Clark PB, Beynon LL, et al. Treatment of advanced localized prostatic cancer by orchiectomy, radiotherapy, or combined treatment: a Medical Research Council study. Br J Urol 1992;70:304–9. Bolla M, Gonzalez D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997; 337:295–300. Akakura K, Bruchovsky N, Goldenberg SL, et al. Effects of intermittent androgen suppression on androgendependent tumors: apoptosis and serum prostatespecific antigen. Cancer 1993;71:2782–90. Sato N, Gleave ME, Bruchovsky N, et al. Intermittent androgen suppression delays progression to androgenindependent regulation of prostate-specific antigen gene in the LNCaP prostate tumor model. J Steroid Biochem Mol Biol 1996;58:139–46. Townsend MF, Sanders WH, Northway RO, Graham SD Jr. Bone fractures associated with luteinizing hormone– releasing hormone agonists used in the treatment of prostate carcinoma. Cancer 1997;79:545–50. Carlstrom K, Stege R, Henriksson P, Grande M. Possible bone-preserving capacity of high-dose intramuscular depot estrogen as compared to orchiectomy in the treatment of patients with prostatic carcinoma. Prostate 1997;31:193–7. Eriksson S, Eriksson A, Stege R, Carlstrom K. Bone mineral density in patients with prostatic cancer treated with orchiectomy and with estrogens. Calcif Tissue Int 1995;57:97–9. Strum SB, McDermed JE, Scholz MC, et al. Anemia associated with androgen deprivation in patients with prostate cancer receiving combined hormone blockade. Br J Urol 1997;79:933–41. Klotz LH, Herr HW, Morse MJ, Whitmore WF Jr. Intermittent endocrine therapy for advanced prostate cancer. Cancer 1986;58:2546–50. Goldenberg SL, Bruchovsky N, Gleave ME, et al. Intermittent androgen suppression in the treatment of prostate cancer: a preliminary report. Urology 1995;45: 839–44. Oliver RTD, Williams G, Paris AMI, Blandy JP. Intermittent androgen deprivation after PSA-complete response as a strategy to reduce induction of hormone-resistant prostate cancer. Urology 1997;49:79–82. Higano CS, Ellis W, Russell K, Lange PH. Intermittent androgen suppression with leuprolide and flutamide for prostate cancer: a pilot study. Urology 1996;48:800–4. Theyer G, Holub S, Dürer A, et al. Measurements of tissue polypeptide-specific antigen and prostate-specific antigen in prostate cancer patients under intermittent androgen suppression therapy. Br J Cancer 1997;75:1515–8. Grossfeld GD, Small EJ, Carroll PR. Intermittent androgen deprivation for clinically localized prostate cancer: initial experience. Urology 1998;51:137–44.

CHAPTER 28

ROLE OF CRYOSURGERY IN THE TREATMENT OF PROSTATE CANCER RONALD M. BENOIT, MD; JEFFREY K. COHEN, MD; RALPH J. MILLER JR, MD; LORI MERLOTTI tion of the prostate was first used for treating prostate cancer in the 1960s and 1970s.3 The original freezing process was poorly controlled and monitored by digital palpation. Urethral sloughing caused by freezing was a significant cause of morbidity, and rectourethral fistulas often occurred due to transmural rectal freezing. Cutaneous fistulas also occurred when a perineal approach was used. As a result of the high morbidity associated with this modality, the treatment fell into disfavor. Disease control as measured by 10-year survival, however, was similar to that of surgery and radiation.4 It is important to note that cryosurgery was abandoned not due to poor cancer control but because of unacceptably high morbidity. Recently, CSAP has been revisited and retooled to serve as a minimally invasive treatment option for men with clinically localized prostate cancer. This chapter discusses the factors responsible for the re-emergence of CSAP in the treatment of prostate cancer as well as the authors’ philosophy regarding ideal candidates for the procedure. The technique of CSAP and several innovations to potentially improve outcomes are then reviewed. Finally, a summary of outcomes and complications attributable to CSAP is provided.

The proper treatment of clinically localized adenocarcinoma of the prostate remains controversial. There has been no prospective randomized study comparing treatment versus no treatment for men with clinically localized prostate cancer. Patients who do choose active treatment for their disease will realize any potential benefit only many years after such treatment. Complications from such treatment, however, are generally experienced in the short term. The risk of immediate morbidity in exchange for only the possibility of benefit in the distant future have led many to advise against treatment for lowstage prostate cancer. If patients do elect to undergo treatment for early-stage disease, they then need to decide among the many available treatment alternatives. Several treatment options now exist for similar stage disease (clinical T1-T3N0M0) including radical prostatectomy, external beam radiation, prostate brachytherapy (PB), or cryosurgical ablation of the prostate (CSAP). Radical prostatectomy remains the “gold standard” for treatment of organ-confined prostate cancer.1 Despite the high rate of disease control associated with radical prostatectomy, however, the fear of complications resulting from this procedure has led many men diagnosed with clinically localized prostate cancer to search for alternatives. Historically, older men, men with comorbidities that make radical surgery untenable, and men with extensive local disease have undergone external beam radiotherapy. In the past, treatment failure after external beam radiation was defined as recurrence on digital rectal examination (DRE) or development of metastatic disease; it is currently defined as a rising prostate-specific antigen (PSA) level after treatment. This changing definition of treatment failure has led to the recognition of a much lower rate of cancer control by external beam radiation than was previously accepted.2 Cryosurgical ablation of the prostate experienced a resurgence in the early and mid-1990s among men seeking a minimally invasive treatment option for their prostate cancer with a lower risk of complications than radical prostatectomy, and who were discouraged by poor long-term results and the long treatment course associated with external beam radiotherapy. Cryosurgical abla-

Role of Cryosurgery in Treatment of Prostate Cancer Patient Factors For many years, men who desired a surgical option for treatment of their prostate cancer could choose either a retropubic or perineal prostatectomy. These procedures entail a 2- to 5-day hospital stay followed by a 6- to 12week period to full recovery. Historically, the risk of blood loss was significant and commonly necessitated transfusion of several units of blood.5 More recently, the need for transfusions has decreased markedly as surgeons have learned the anatomic approach to radical prostatectomy. Urinary incontinence, depending on its definition, has been reported to be as high as 40% after radical prostatectomy.6 Despite widespread use of the nerve-sparing approach to radical prostatectomy, impotence has been reported in up to 60% of patients undergo258

Role of Cryosurgery in the Treatment of Prostate Cancer / 259

ing radical prostatectomy.6 Fear of major surgery and the risk of urinary incontinence and/or impotence after radical prostatectomy, combined with the uncertain benefit from treatment of localized disease, have led many patients and their physicians to seek other treatment options. External beam radiotherapy has long been an alternative to surgery for men with clinically localized prostate cancer. The risk of incontinence and impotence after radiation is lower than for surgery.7 Many studies, however, have questioned the long-term cancer control provided by radiation therapy.2,8 Also, external beam radiotherapy is a time-consuming treatment which requires 7 to 8 weeks of daily treatments. Recently, prostate brachytherapy has received considerable attention from both prostate cancer patients and their physicians.9 It appears to offer both excellent cancer control (at least in the short term) for men with low-grade, low-volume (low PSA) prostate cancer, and a very acceptable side-effect profile.10 Long-term results for current techniques of prostate brachytherapy are not yet available. Cryosurgical ablation of the prostate is a minimally invasive surgical treatment for prostate cancer. Treatment requires only an overnight stay in hospital and a recovery time to full activity of approximately 2 weeks. Incontinence risks are minimal and comparable to external beam radiation therapy.11 Impotence, which in the best of circumstances is difficult to quantitate, is similar to that reported for radical prostatectomy.11 These characteristics appeal to the patient concerned to minimize morbidity and undergo a minimally invasive treatment for prostate cancer.

is similar regardless of treatment option selected, at least in the short term.10,13–15 However, short-term results of cancer control in men with favorable pretreatment characteristics are misleading in that the disease spans one to three decades. It is only after a minimum of 5 to 8 years (and usually 10 to 20 years following diagnosis) that cause-specific cancer deaths begin to occur in men with these favorable preoperative characteristics. 12 Given the difficulty of providing definitive data on treatment outcomes using survival data alone in such a slow-growing cancer, PSA and post-treatment biopsy results have become surrogate markers for long-term treatment outcomes. While cancer control appears to be relatively similar for surgery and radiation (extracorporeal or interstitial) in patients with low-grade and early-stage tumors (lowrisk prostate cancer), the optimal treatment option for higher-grade and later-stage (high-risk) prostate cancers is less clear. High-risk disease can be defined by tumors with a Gleason score ≥ 7 and/or a serum PSA > 10 ng per mL. Surgery or radiation as monotherapy offers an unacceptably low rate of cancer control.16,17 Many treatment combinations have been advanced for these high-risk cancers, including

Selection Characteristics

All of the these combination therapies are being studied at major centers around the world, with the goal of improving outcomes for men with high-grade, highvolume prostate cancers.

The optimal treatment modality for men with clinically localized prostate cancer depends on characteristics of both the tumor (grade, stage, and volume of disease) and the patient (age and comorbidities). Given the generally slow growth of prostate cancer, each patient’s concern regarding potential side effects from treatment should be critically evaluated.12 Some patients will accept higher risks of side effects for the possibility of improved cancer control while others may choose a treatment with unknown long-term cancer control rates that offers a more acceptable side-effect profile. Historically, younger, healthier men with low-grade and low-volume tumors have undergone surgery while older men with larger tumors have received external beam radiotherapy. As a result, comparison between surgery and radiation was complicated by the selection bias existing between these two modalities. Prostatespecific antigen has allowed for more precise pre- and post-treatment stratification of patients. This allows for more accurate comparisons between similar cohorts of prostate cancer patients. For patients with a PSA level < 10 ng per mL and a Gleason score ≤ 6, cancer control

• androgen deprivation therapy (ADT) prior to radical prostatectomy, external beam radiotherapy, or PB; • radical prostatectomy followed by adjuvant radiotherapy; • PB preceded or followed by external beam radiotherapy with or without ADT; and • CSAP with or without adjuvant radiotherapy.

Morbidity after Treatment of Clinically Localized Prostate Cancer Complications after treatment of prostate cancer are well documented. The major concerns for most patients center on urinary incontinence and impotence. The incidence of impotence following radical prostatectomy has been reported to be as high as 60%, depending on age, stage, competence of the surgeon, and the presence of comorbidities.6 Certainly, in the best of hands, impotence rates are much lower than 60%.13 Approximately 50% of men will develop erectile dysfunction following external beam radiotherapy7 while PB carries the lowest risk of impotence (30%) following active treatment of clinically localized disease.18 Cryosurgical ablation of the prostate has a risk of impotence similar to that reported for radical prostatectomy since the treatment will extend out past the capsule, thus freezing the neurovascular bundles. Recovery of erectile function is usually limited to the


younger population.11 Underlying all of these numbers is the inability to quantify erectile dysfunction as well as the demographics of the population undergoing treatment. Additionally, as treatment options for erectile dysfunction become more successful and less invasive, the pretreatment concerns of the patient regarding potential loss of erectile ability after treatment lessen. Given the successful treatments available for treating impotence, incontinence may be the more feared complication following treatment for localized prostate cancer. The published rate of urinary incontinence following prostatectomy ranges from 5 to 30%.6,19 Radiation therapy, delivered by external beam or by PB, has an incontinence risk of 2% in men without prior transurethral resection of the prostate (TURP).7,10 There is an incontinence risk of approximately 4% for CSAP when an adequate urethral warmer is employed.11

Candidates for Cryosurgical Ablation of the Prostate Patients must decide which modality is the most reasonable approach for treatment of their disease based on the characteristics of their tumor, their overall health (i.e., life expectancy), their desire for long-term cancer control, and their fear of complications from treatment. The patient’s desire to avoid invasive surgery and the time they can or are willing to commit to treatment and recovery must also be factored into this decision. The authors’ preference for men with low-risk disease (defined as PSA level < 10 ng per mL and a Gleason score ≤ 6) and who are aged 65 years or less and in good health (defined by having a reasonable chance at 10 years of survival) is radical prostatectomy. In the authors’ opinion, radical prostatectomy offers the best long-term cancer control of all the current treatments for prostate cancer. If the disease is pathologically confined and the organ is removed, the patient has a very high cure rate.13 If the disease is specimen confined without a component of Gleason grade 4 or 5, chance for cure by surgery alone is also very high.20 Men over the age of 65 are informed of the higher complication rates associated with surgery and the decreased need for long-term control of their cancer. This is based on the fact that the cause-specific survival for men with low-risk disease at 10 years is very high.12 In the authors’ opinion, men over the age of 65 with low-risk prostate cancer can expect excellent cause-specific survival from radiation therapy (extracorporeal or interstitial). Men with low-risk prostate cancer who seek a surgical treatment for their disease that is minimally invasive will undergo PB while men with lowrisk disease who wish to avoid the operating room and/or the obstructive and irritative voiding symptoms associated with PB will undergo external beam radiotherapy. The role of CSAP for men with newly diagnosed prostate cancer is therefore principally in the treatment of high-risk, clini-

cally localized prostate cancer (PSA level ≥ 10 ng per mL, Gleason score ≥ 7 or cT2b or higher). Cryosurgical ablation of the prostate appears to offer the best cancer control for these tumors when compared to other treatment options, including the various combination therapies previously discussed.21 Cryosurgery should also be the treatment of choice for men with local failure as diagnosed by a positive biopsy 2 years after completing radiation therapy.22 Radical prostatectomy after external beam radiotherapy has failed to achieve cure rates greater than 30% and is associated with an unacceptably high risk of morbidity.23,24 Cryosurgical ablation of the prostate is also a viable treatment option for men under age 65 years who may desire a minimally invasive treatment option, are not candidates for open surgery, and who are not candidates for radiotherapy due to previous pelvic radiation or rectal disorders.

Theory It is accepted that cell death and necrosis will be induced by rapidly bringing tissues to subzero temperatures. Cell death is an effect of ice formation and a spectrum of events secondary to hypothermia.25 Hypothermia begins the cascade of injury marked by decreased intracellular energy stores and a breakdown in the physical and physiologic functions of the cellular membrane. Rapid hypothermia leads to intracellular dehydration and cell shrinkage. When the temperature drops below −4°C, ice crystals form in the extracellular space and eventually cross the cell membrane gap junctions, leading to intracellular ice, membrane rupture, and cell death. On completion of the freezing process, microscopic ice crystals coalesce into sheets of ice, creating shearing forces that account for additional destruction. Any viable cells remaining are suddenly faced with a markedly hypotonic environment (from the thawing of pure water), resulting in a sudden influx of free water by osmotic forces (membrane function remains inactivated). This causes cell swelling, rupture, and death. Finally, the freezing process causes obstruction of the vasculature, leading to anoxia and thrombosis. This final injury completes the cytotoxic cascade of events. Tissue absorption following cryotherapy can take up to 3 months and is marked initially by inflammation and removal of cellular debris and later by deposition of collagen and the creation of organized scar tissue. Histologically aberrant glands can be seen following CSAP, including basal cell hyperplasia, squamous cell metaplasia, and transitional cell metaplasia.26 Recovery of neural function depends on the integrity of the neural sheath and may take 6 to 12 months.27 The ultrasonically impenetrable nature of ice crystals causes sound waves to reflect off the frozen/nonfrozen interface and appear on transrectal ultrasonography (TRUS) as an advancing hyperechoic line with an anechoic shadow behind it. Histologic studies have confirmed a pre-

Role of Cryosurgery in the Treatment of Prostate Cancer / 261

cise correlation of cell death and necrosis to this ultrasonically visualized lesion.28 It is this characteristic imaging that allows the surgeon to aggressively yet safely freeze the prostate. With preliminary studies completed, attention in this area was directed toward developing a freezing technique that would avoid the shortcomings of the previous era of cryosurgery. The most pressing problems were fistulization from a perineal incision and urethral sloughing. Fistulization is avoided by and depends on ultrasound guidance. The growth of the iceball can be monitored and stopped when it reaches the anterior rectal wall. Urethral sloughing is avoided by use of a catheter placed in the urethra which circulates a warm (48°C) saline solution and prevents destruction of the prostatic urothelium. Viable urothelium is then surrounded by necrotic prostate parenchyma which involutes and eventually becomes scar tissue after freezing.

Technique Preoperative Preparation Patients must be free of active lower urinary tract infection prior to treatment. Prostate volume should be less than 65 grams since glands larger than 65 grams may be difficult to adequately treat with a single procedure. Alternatives for glands larger than 65 grams include preoperative androgen deprivation therapy (ADT) to reduce the size of the gland or treating the prostate in stages. Evaluation of nodal status is done through a “mini-lap” pelvic lymph node dissection. At the authors’ institution, nodal evaluation is excluded for men with PSA levels < 10 ng per mL, men over the age of 70 years, or men who have had prior ADT. Patients are instructed to administer a Fleet (phosphate-soda) enema the night prior to surgery and again at 6 AM the morning of surgery. Ofloxacin (300 mg) is given orally the night prior to surgery and on arrival at the hospital the morning of surgery. Flagyl (750 mg) is also given orally on arrival at the hospital. Patients are admitted to the same-day surgery unit the morning of surgery. Spinal or general anesthetic is chosen, depending on the preference of the patient and anesthesiologist. Technique of Cryoablation Once anesthetized, the patient is placed in the dorsal lithotomy position. Flexible cystoscopy is performed, and a 10F Cope loop suprapubic tube (Cook Urological, Spencer, IN) is placed into the dome of the bladder. On cystoscopic examination, any bladder lesions, urethral obstructive lesions, or median lobe prostate tissue are noted since they may require further treatment postoperatively. The cystoscope is removed and a urethral warming catheter is inserted. The catheter is perfused throughout the procedure with a saline solution at 40°C to maintain the viability of the urethra.

The transrectal ultrasound probe is then placed into the rectum. A biplanar piezoelectric transducer should be used for CSAP. This allows crucial three-dimensional surveillance of the freezing process. In addition, the sagittal or longitudinal scanner must utilize a linear piezoelectric (7 MHz) crystal. The linear sagittal transducer provides better definition of the structures posterior to the prostate without volume averaging and refractory artifacts commonly seen with mechanical sector scanning transducers. Routine volumetric analysis is performed using the formula (L × W × H) × 0.52. All hypoechoic areas are noted, and any areas of suspected capsular penetration are carefully documented. The authors began using color flow Doppler ultrasound to monitor CSAP in March 1994. Graphic analysis of the vessels can distinguish arterial and venous waveforms. This information is used to detect areas of increased vascularity, which may act as heat sinks to prevent adequate freezing. Cryoprobe placement can then be modified so that these vessels are encompassed and ablated in the iceball, thus enhancing the cytotoxic effects of the cryotherapy. The authors have also recently begun injecting areas of increased arterial blood flow with a vasoconstrictor (epinephrine) to decrease blood flow in these vessels and subsequently the heat sink effect. The blood flow to the rectum can also be assessed with color flow Doppler during freezing to prevent fistula formation. The probe access ports are placed. Each port is similarly placed beginning with a percutaneous puncture of the perineum. With a diamond-tipped needle placed in a needle guide, TRUS (transverse transducer) is used to guide the needle into the appropriate position in the prostate. It is then advanced under visualization by the sagittal transducer to the cephalad capsule of the prostate. The needle is removed following placement of a stiff, 0.038-inch, J-tipped guidewire. Using ultrasound visualization, a modified Amplatz dilator (Cook Urological, Spencer, IN) and Teflon introducer sheath are then advanced over the wire. Once in position, the dilator and wire are removed. The sheath is irrigated with saline solution to remove air and debris (which would interfere with freezing and decrease image quality). All probe sites are subsequently placed. Integral to the selection of probe sites is the normal geometry of the iceball that forms at the probe tip. The iceballs generated by the Accuprobe system are symmetric and reproducible. The ice begins at the probe tip (≤ 5 mm growth past the tip in the completed iceball) and extends up the shaft for a total length of 5 cm. The maximum radius of the iceball is 2 cm, and the final iceball is egg shaped. In a multiple probe arrangement, iceballs augment the performance of any adjacent probes. Any recesses between adjacent iceballs (probes) will be filled in as a result of this augmentation so that the final contour is smooth (referred to as ice sculpting).


The typical template involves five individually controlled probes. Two probes are placed anteriorly and three are placed posteriorly. The two anterior probes are placed between 5 and 8 mm from the anterior capsule at the midpoint between the urethra and the lateral capsule. The two posterolateral probes are placed so that iceball growth will extend past the lateral capsule before reaching the rectum (the end point of the procedure). The posterolateral probes should also be placed as anteriorly as possible (but not beyond the 2-cm radius of the iceball) to let the iceball grow out laterally to encompass the neurovascular bundles as seen by color flow Doppler ultrasound and medially to augment the performance of the other probes. The fifth probe is placed in the midline posterior to the urethra. Additional access ports can be placed outside the prostate parallel to the neurovascular bundles to triangulate areas of extracapsular extension or seminal vesicle involvement. Once all access ports are established, the cryoprobes are placed into the sheaths. The preslit Teflon sheaths are withdrawn, and the machine is activated by circulating liquid nitrogen through the probes. This will create a small iceball at the tip of the probe, “sticking” the probe in place. The authors generally stick the probes at –70°C to –100°C. The probes are suspended with rubber straps from a Bookwalter retractor ring suspended above the perineum. Thermocouplers can be placed at this point to monitor the temperature of the advancing iceball. Because objects close to the transducer cause acoustic interference, all manipulation, probe placement, and freezing are performed from anterior to posterior. Once all probes are “stuck” in place, the system is activated to circulate pressurized, supercooled liquid nitrogen at full flow through the probes (–180° to –200°C). As the tissue temperature drops below –4°C, the tissue water changes from liquid to a solid. This interface reflects all sound waves and is interpreted as a hyperechoic line. The lack of sound wave transmission beyond this interface is referred to as acoustic shadowing; the iceball itself is anechoic. The early freezing process is monitored in both sagittal and transverse planes to provide a three-dimensional image. Once the advancing edge of the iceballs from the anterior probes has reached the posterior row of probes, the posterior probes are activated. The anterior probes continue to freeze until the iceballs reach the posterior prostatic capsule. This augments the performance of the posterior probes and ensures adequate anterior margins. Surveillance at this point is done with the sagittal transducer as it provides better delineation of the structures posterior to the prostate. Simultaneous visualization of the entire prostate is enabled by a 6-cm linear array sagittal transducer (the ice is widest at the probe tip). The contour of the rectum does not follow a straight line. At the apex and urogenital diaphragm, the rectum is anterior compared to its location at the base. The sagittal transducer will

accurately show the relationship of the iceball to the entire rectal wall. As the treatment continues, there is an increase in blood flow around the prostate. The signals from the neurovascular bundles increase as the iceball approaches the rectum, and portosystemic shunts through the rectum can be visualized. These vascular changes are believed to be caused by microvascular obstruction in the prostate. This increased peripheral flow has the potential to heat and preserve surrounding tissue. Because of this finding, the authors began double freezing the prostate to extinguish these signals by an encompassing iceball. The probes remain activated until the advancing edge of the iceball abuts the anterior rectal wall. Although the temperature of the probes is –195°C, the temperature at the edge of the iceball is approximately 0°C. Extracellular ice is seen at –15°C and intracellular necrosis begins at –20°C. However, complete freezing of the entire intracellular content is believed to occur at –40°C. This temperature occurs 2 mm inside the leading edge of the iceball. Therefore, the iceball must extend several millimeters beyond the posterior capsule to ensure complete destruction of the prostate. Some centers have used thermocouplers to monitor temperatures in and around the prostate to ensure adequate freezing is achieved. After the first freeze cycle, the prostate is allowed to thaw (passively), after which it is refrozen (double freeze). After the first freeze and subsequent thawing, surviving cells will be sensitized and become much more susceptible to a repeat freezing process.29,30 Most prostates are longer than 4 cm, which requires pulling back the probes to treat the apical prostate and trapezoidal area. The second freeze will encompass the apical prostate and the trapezoidal area and is generally brought through the urogenital diaphragm. With prostates shorter than 4 cm, the procedure is complete after the double freeze in the initial position. The second freeze is commenced once the prostate has thawed sufficiently that it is again completely visible on ultrasound (disappearance of the iceball). Once the freezing process is completed, the probes are thawed and removed. Manual pressure is applied to the perineum for hemostasis, and the probe insertion sites are closed with simple 3-0 chromic sutures. The urethral warming catheter is left activated until the entire prostate has thawed, generally for 20 minutes. The catheter is removed, the suprapubic tube placed to straight drain, and the patient is taken to the recovery room. Postoperative Care The usual hospital stay for patients undergoing CSAP is 1 day. During the morning of the first postoperative day, the suprapubic tube is capped and removed when postvoid residuals measure consistently < 100 cc. Postoperative discomfort is minimal. Scrotal edema can be dramatic but will resolve spontaneously, usually within 3 weeks. Normal activity can be resumed in 1 to 2 weeks. Oral antibiotics

Role of Cryosurgery in the Treatment of Prostate Cancer / 263 TABLE 28–1. Patient Information for Men Undergoing Cryosurgical Ablation of the Prostate (CSAP)* All patients Virgin Virgin + ADT XRT failures XRT failures + ADT Favorable Unfavorable

N

Median Age (yr)

Gleason Score 5–6

Gleason Score 7

Gleason Score 8–10

742 462 165 56 44

66.0 66.0 65.0 67.0 67.0

Median PSA (ng/mL) Gleason Score 2–4 9.9 8.8 12.0 12.0 13.7

145 123 30 6 0

305 211 66 14 10

142 79 30 12 17

108 38 29 23 13

267 475

65.0 66.0

6.1 13.4

98 63

162 143

0 142

0 108

ADT = androgen deprivation therapy; XRT = external beam radiation therapy. Virgin patients are defined as those who have received no prior treatment (local or systemic) for their prostate cancer. Virgin + ADT patients have not received any local therapy for their prostate cancer but have received androgen deprivation therapy prior to CSAP. Favorable patients are defined as those who have a PSA 10 ng per mL and/or Gleason score ≥ 7). The authors have rigorously followed patients with both serial PSA data and post-treatment biopsies. Patients are asked to undergo biopsies 3 months, 24 months, and 60 months after treatment. Protocol biopsies consist of 11 cores (sextant biopsies, bilateral seminal vesicle and neurovascular bundle biopsies, and an ejaculatory duct biopsy), as discussed earlier. Any positive core detected regardless of future biopsy results for that patient is recorded as a positive biopsy. Table 28–2 reports biopsy results. Prostate-specific antigen results appear in Figures 28–1 to 28–5. Five-year actual data is reported, except for those patients who underwent XRT after CSAP (for either a positive biopsy or rising PSA), where data are only available up to 4 years. Serial PSA determinations and prostatic core needle biopsies following therapy are short-term indicators of treatment success. Longer follow-up is necessary to determine the relationship between post-CSAP PSA and cause-specific survival. Patients with a low and nonrising PSA are likely to be cured of their disease. In the current series, a significant discrepancy exists between PSA and biopsy outcomes after treatment. For example, patients with a favorable presentation have a PSA < 0.4 ng per mL 5 years after treatment in 51.2% of cases, but these TABLE 28–2. Biopsy Results for Patients Undergoing CSAP*

Virgin XRT failures Favorable Unfavorable

N

Positive

Negative

No Biopsy Performed

565 79 244 408

155 (27.4%) 33 (41.8%) 48 (19.7%) 143 (35.0%)

410 (72.6%) 46 (58.2%) 196 (80.3%) 265 (65.0%)

62 21 23 67

N = number of patients who underwent at least one biopsy postprocedure; XRT = external beam radiation therapy. *At Allegheny General Hospital.

100

100

90

90

80

80

70

70

60

60

Percent

Percent


50 40

50 40

30

30

PSA < 1.0 ng/ml

20

PSA < 1.0 ng/ml

20

PSA < 0.4 ng/ml

10 0

PSA < 0.4 ng/ml

10 0 1

2

4

3

2

1

5

Years after CSAP

3

4

Years after CSAP

FIGURE 28–1. PSA results for men who underwent CSAP as primary treatment for prostate cancer.

FIGURE 28–3. PSA results for men who underwent CSAP followed by external beam radiotherapy (XRT).

patients will have a positive biopsy in only 19.7% of cases. This discrepancy exists for all cohorts in our series. Sampling error may explain this discrepancy, but it should have been minimized by the three separate biopsies taken with 11 cores at each biopsy. The more likely explanations are the presence of subclinical metastatic disease and production of PSA by these systemic cancer cells and/or regrowth of urothelium and subsequent PSA production.31 In either case, the presence of clinically significant tissue is unclear. Further follow-up of these cohorts will determine survival results.

imposed by the FDA. This explains the mixture of rates of urinary incontinence seen in this cohort. Men who have undergone CSAP without an adequate urethral warmer will have a rate of urinary incontinence of 24%. Urinary incontinence, defined as the need for two or more pads per day 6 months after CSAP, occurred in 5.9% of all patients who did not have prior radiotherapy, regardless of whether urethral warming was adequate or inadequate. Transurethral resection of the prostate prior to CSAP increases the risk of urinary incontinence to 7.6%. Urinary incontinence after CSAP appears to be largely an all or none phenomenon, as the risk of stress incontinence is only 0.3% and the risk of urge incontinence is 1.1%. The most prevalent complication following CSAP is urethral sloughing, which occurs in approximately 15% of patients not undergoing radiation and in 19.6% of patients who have had

Complications The rate of urinary incontinence in this study is 4.0% for men who undergo CSAP with an adequate urethral warmer used. Between June 1994 and June 1995, an inadequate warmer was used due to regulations

100

70

90 60

80 70 Percent

Percent

50 40 30

50 40 30

20 10 0

60

1

2

PSA < 1.0 ng/ml

20

PSA < 0.4 ng/ml

10 0

3

4

5

Years after CSAP

FIGURE 28–2. PSA results for men who underwent CSAP after failure of external beam radiotherapy (XRT). Lower line represents PSA < 0.4 ng/mL.

PSA < 1.0 ng/ml PSA < 0.4 ng/ml

1

2

3

4

5

Years after CSAP

FIGURE 28–4. PSA results for men with a favorable presentation who underwent CSAP. Favorable presentation is defined as a PSA ≤ 10 ng/mL and a Gleason ≤ 6.

Role of Cryosurgery in the Treatment of Prostate Cancer / 265 TABLE 28–3. Complications after CSAP*

100 90 80

Percent

70 60 50 40 30

PSA < 1.0 ng/ml

20

PSA < 0.4 ng/ml

10 0 1

2

3

4

5

Years after CSAP

FIGURE 28–5. PSA results for men with an unfavorable presentation who underwent CSAP. Unfavorable presentation is defined as a PSA > 10 ng/mL and/or a Gleason score ≥ 7.

radiotherapy as some part of their treatment. If an adequate urethral warmer is not used, urethral sloughing will occur in up to 50% of patients. Impotence is difficult to quantify after any treatment for localized prostate cancer. The theoretic advantage of cryosurgery is the ability of the ice ball to extend outside the prostate. The neurovascular bundles of the prostate should be frozen if the prostate and periprostatic tissue is adequately treated. Younger men may be able to recover from this nerve injury while older men may not. This is consistent with the authors’ findings that younger men (aged less than 65 years) will maintain their erections 33% of the time while men older than 65 years will maintain their erections in only 15% of cases. Urethrorectal fistula has occurred in only 2 of our 742 cases. There has only been 1reported death from cryosurgery, the result of emphysematous cystitis and necrotizing fasciitis in a diabetic patient. Patients who undergo cryosurgery as salvage therapy after failure of radiation therapy to control local disease appear to be at highest risk for complications after cryosurgery. Incontinence in our series has been 13.8% for men who have had radiotherapy prior to CSAP. Sloughing syndrome is also more common in this cohort, occurring in 19.9% of these patients. Table 28–3 provides a complete list of complications.

Conclusion No single treatment option will be acceptable for every grade, stage, and clinical presentation of prostate cancer. Cryosurgical ablation of the prostate has a role in the primary treatment of men with high-risk, clinically localized prostate cancer (defined as PSA > 10 ng per mL, Gleason score ≥ 7, or clinical stage ≥ cT2b). Cryosurgery (occasionally followed by external beam radiotherapy) appears

Sloughing syndrome Urinary incontinence with adequate urethral warmer without adequate urethral warmer Urethral stricture Bladder neck contracture Urinary retention Urge incontinence Sepsis Perineal pain Urethrorectal fistula Stress incontinence

Patients without XRT (%)

Patients with XRT (%)

15.6 5.9 4.0 24.0 4.9 3.2 1.2 1.1 0.8 0.6 0.3 0.3

19.9 13.8

6.6 2.2 3.3 1.1 0.6 1.1 0 2.2

XRT = external beam radiotherapy. *Stratified by men who did or did not have external beam radiotherapy as some component of their treatment either before or after CSAP.

to offer improved rates of cancer control over other types of single or combination therapies for this high-risk prostate cancer and is associated with a very acceptable side-effect profile. Cryosurgical ablation of the prostate should also be the treatment of choice for men with recurrent local disease following external beam radiotherapy when local therapy is deemed appropriate. This technique is effective in appropriate candidates as defined above, as measured by biopsy and PSA. Cryosurgical ablation of the prostate remains in its infancy and awaits further technologic developments to improve outcomes. Continued improvements in instrumentation and surgical technique should allow for improved cancer control and lower morbidity. Continued critical examination of all forms of therapy for localized prostate cancer, including CSAP, is necessary to provide the best treatment options for individual patients.

References 1. Gibbons RP, Correa RJ, Brannen GE, Weissman RM. Total prostatectomy for clinically localized prostatic cancer: long-term results. J Urol 1989;141:564–6. 2. Stamey TA, Ferrari MK, Schmid HP. The value of serial prostate-specific antigen determinations 5 years after radiotherapy: steeply increasing values characterize 80% of patients. J Urol 1993;150:1856–9. 3. Gondor MJ, Soanes WA, Shulman S. Cryosurgical treatment of the prostate. Invest Urol 1966;3:372–8. 4. Bonney WW, Fallon B, Gerber WL, et al. Cryosurgery in prostate cancer: survival. Urology 1982;14:37–42. 5. Haab F, Boccon-Gibod L, Demass V, Kemmis Toublan M. Perineal versus retropubic radical prostatectomy for T1, T2 prostate cancer. Br J Urol 1994;74:626–9. 6. Fowler FJ, Barry JJ, Lu-Yao G, et al. Patient-reported complications and follow-up treatment after radical prostatectomy. Urology 1993;42:622–9. 7. Shipley WU, Zietman AL, Hanks GE, et al. Treatment related sequelae following external beam radiation for


8.

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10.

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12. 13.

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15.

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17.

18.

19.

prostate cancer: a review with an update in patients with stages T1 and T2 tumor. J Urol 1994;152:1799–1805. Crook JM, Bahadur YA, Perry GA, et al. Radiotherapy for prostate cancer: results of systematic biopsies for 479 patients. J Urol 1998;159:239A. D’Amico AV, Coleman CN. Role of interstitial radiotherapy in the management of clinically organ-confined prostate cancer: the jury is still out. J Clin Oncol 1996;14:304–15. Blasko JC, Wallner K, Grimm PD, Ragde H. Prostatespecific antigen-based disease control following ultrasound guided 125iodine implantation for stage T1/T2 prostatic carcinoma. J Urol 1995;154:1096–9. Cohen JK, Rooker GM, Shuman BA, et al. Cryosurgical ablation: management alternative for localized prostate cancer. In: Smith AD, editor. Textbook of endourology. St. Louis: Quality Medical Publishing, Inc; 1996. p. 1217–33. Chodak G. The role of watchful waiting in the management of localized prostate cancer. J Urol 1994;152:1766–8. Walsh PC, Partin AW, Epstein JI. Cancer control and quality of life following anatomical radical retropubic prostatectomy: results at 10 years. J Urol 1994;152:1831–6. Leibel SA, Zelefsky MJ, Kutcher GJ, et al. Three-dimensional conformal radiation therapy in localized carcinoma of the prostate: interim report of a phase I dose-escalation study. J Urol 1994;152:1792–7. Cohen JK, Miller RJ Jr, Rooker GM, et al. Four-year PSA and biopsy results after cryosurgical ablation of the prostate (CSAP) for localized adenocarcinoma of the prostate. J Urol 1997;157:419A. Benson MC, Kaplan SA, Olsson CA. Prostate cancer in men less than 45 years old: influence of stage, grade, and therapy. J Urol 1987;137:888. Bagshaw MA, Cox RS, Hancock SL. Control of prostate cancer with radiotherapy: long-term results. J Urol 1994;152:1781–5. Stock RG, Stone NN, Iannuzzi BA. Sexual potency following interactive ultrasound-guided brachytherapy for prostate cancer. Int J Radiat Oncol Biol Phys 1996;35:267–72. Milam DF, Franke JT. Prevention and treatment of incon-

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tinence after radical prostatectomy. Semin Urol Oncol 1995;23:224–7. Epstein JI. Incidence and significance of positive margins in radical prostatectomy margins. Urol Clin North Am 1996;23:651–3. Miller RJ Jr, Cohen JK, Merlotti LA. Percutaneous transperineal cryosurgical ablation of the prostate for the primary treatment of stage C adenocarcinoma of the prostate. Urology 1994;44:170–4. Pisters LL, von Eschenbach AC. Technique, results, and complications of “modern” prostate cryotherapy. Am Urol Assoc Update Series 1996;15:297–304. Rogers E, Ohori M, Kassabian VS, et al. Salvage radical prostatectomy: outcome measured by serum prostatespecific antigen levels. J Urol 1995;153:104–10. Pontes JE, Montie J, Klein E, Huben R. Salvage surgery for radiation failure in prostate cancer. Cancer 1993;71: 976–80. Baust JG, Chang AH. Cryosurgery: underlying mechanisms of damage and new concepts in cryosurgical instrumentation. Proceedings from the Ninth World Congress of Cryosurgery; 1995 June. Masson D, Bidair M, Shabaik A, et al. Pathologic changes in prostate biopsies following cryoablation therapy. J Urol 1995;153:484A. Trumble TE, Whalen JT. The effects of cryosurgery and cryoprotectants on peripheral nerve function. J Reconstr Microsurg 1992;8:53–8. Littrup PJ, Mody A, Sparschu R, et al. Prostatic cryotherapy: ultrasonographic and pathologic correlation in the canine model. Urology 1994;44:175–84. Myers RS, Hammond WG, Ketcham AS. Cryosurgery of experimental tumor. J Cryosurgery 1969;2:225–8. Gill W, Fraser J, Carter DC. Repeated freeze-thaw cycles in cryosurgery. Nature 1968;219:410–3. Shuman BA, Cohen JK, Miller RJ Jr, et al. Histologic presence of viable prostatic glands on routine biopsy following cryosurgical ablation of the prostate. J Urol 1997;157:552–5.

CHAPTER 29

SHOULD T1C DISEASE BE TREATED DIFFERENTLY FROM T2 DISEASE? KEITH J. O’REILLY, MD; J. BRANTLEY THRASHER, MD, FACS examined, that stage T1c tumors represent a clinically significant group of cancers that are best treated aggressively.

Prostate cancer is unique among human malignancies. It is the most common male cancer in the United States and the second leading cause of cancer deaths.1 The overall lifetime risk of developing prostate cancer is about 16% (1 in 6);1 it is estimated that 40% of men over the age of 50 have histologic evidence of prostate cancer.2 Despite this high incidence, it is estimated that only 8% will develop clinically significant cancer and that only 3% will die of their disease.2 This discrepancy between the incidence of prostate cancer and the number of patients who will develop clinically apparent disease has created controversy in determining appropriate management of prostate cancer. Further, prostate cancer exhibits slow growth, with doubling times of approximately 3 years, making the decision of whether to treat aggressively or conservatively a very difficult one. Prostate-specific antigen (PSA), a serum protease produced by prostate epithelium and periurethral glands in men, has revolutionized diagnosis and management of prostate cancer. Since its introduction, there has been a rapid rise in the incidence of prostate cancer, increasing by 83.4% from 1988 to 1992.3 This increase has been unparalleled by any other human malignancy. Screening efforts have given rise to a new set of patients who are diagnosed with prostate cancer solely because of an elevated PSA level, despite having a palpably normal gland. In 1992, this new subset of incidental tumors was recognized by the establishment of a separate category within the tumor staging system for prostate cancer, designated as stage T1c tumors. The importance of this new stage of tumor and the controversy generated is only recently becoming evident, with a growing body of knowledge emerging about these tumors and their significance. Originally thought to represent incidental cancers, it is becoming evident that T1c tumors encompass a diverse group of tumors, ranging from insignificant to advanced and aggressive disease. This chapter examines the current clinical and pathologic characteristics of stage T1c tumors and assesses whether they should be treated and managed similarly to palpable tumors (stage T2). It will become apparent, once what constitutes a “significant” prostate tumor is defined and the results of contemporary prostatectomy series are

Staging Hugh Hampton Young first described the digital rectal examination (DRE) as the primary modality for diagnosing prostate cancer, which led to the original stage classification described by Whitmore in 1956.4,5 This classification was modified by Jewett in 1975 to produce the Whitmore-Jewett system.6 The tumor, nodal, and metastases (TNM) system was first introduced by the American Joint Committee on Cancer (AJCC) and the Union Internationale Contra Le Cancer (UICC) in 1978.1 A consensus conference was held in 1992 among the AJCC, UICC, and the European Organization for Research and Treatment of Cancer (EORTC) Genitourinary Group, resulting in a revised TNM classification in which the T1c stage was created. This stage represented a group of tumors diagnosed by random biopsy following detection of an elevated PSA in a palpably normal gland (these tumors can also be classified in the Whitmore-Jewett system as B0 disease). The definition of T1c tumors as described by the TNM system has created controversy in that those tumors seen on transrectal ultrasound (TRUS) and biopsy positive for adenocarcinoma are not addressed. Ohori et al.7 evaluated 42 nonpalpable lesions visualized by ultrasound. These tumors were similar in grade and volume to stage T1c lesions not seen on ultrasound. The lesions seen at the time of TRUS, however, were more likely to demonstrate extracapsular penetration, seminal vesicle invasion, and lymph node metastasis than those not seen on TRUS. The study examined both palpable and nonpalpable tumors, however, and its purpose was not to examine visible versus nonvisible T1c tumors. In contrast to this, Ferguson et al.8 found no difference in tumor volume or multifocality in 97 tumors identified at the time of TRUS compared to 97 tumors not identified at the time of ultrasonography. Also, Carter et al.9 demonstrated that TRUS was neither specific nor sensitive in diagnosing prostate cancer. Therefore, despite this controversy, many institutions still classify tumors as T1c whether or not they are visible at the time of TRUS.

267


The Prostate-Specific Antigen Era When T1c tumors were originally classified, they were thought to represent another group of incidental cancers. However, with increasing public awareness and widespread adoption of PSA in screening programs, T1c tumors have rapidly become the most common stage of the disease at the time of diagnosis. Several screening studies have shown that approximately 39 to 45% of newly detected cancers are stage T1c tumors.10,11 More recently, 78% of cancers detected in a PSA-based screening program were clinical stage T1c.12 There has also been a significant increase in the number of patients undergoing radical prostatectomy for stage T1c tumors. Memorial Sloan-Kettering Cancer Center (MSKCC) reported that in 1991 only 0.4% of radical prostatectomies were for T1c tumors, while in 1995 they accounted for nearly 50%.13 Oesterling et al. reported that in 1988 only 14 patients at the Mayo Clinic underwent radical prostatectomy for T1c tumors while 118 patients did in 1991, representing an eightfold increase. During this same time period, those undergoing prostatectomy strictly for palpable disease increased by 94%.14 To better understand this rapid change in disease presentation for prostate cancer, diagnostic trends over the past 15 years must be examined. Results from the Surveillance, Epidemiology, and End Results (SEER) program provide insight into this and illustrate the magnitude of change resulting from PSA-based detection of prostate cancer. The SEER data show a gradual increase in the incidence of prostate cancer from 1973 to 1988, which was followed by a precipitous increase from 1988 to 1993 and a decrease from 1993 to 1996 (Figure 29–1A). This rapid change has been attributed to widespread use of PSA screening. There has also been a change in the methods of diagnosing and treating prostate cancer during this period. Diagnosis has increasingly been made by needle biopsy while radical prostatectomy has become the most common treatment for local and regional disease15 (Figures 29–1B and 29–1D). Prostate-specific antigen screening has also led to significant changes in the grade of newly diagnosed prostate cancer. Compared to the pre-PSA era, there are an increasing number of moderately differentiated tumors being diagnosed without a concomitant increase in the number of well-differentiated tumors diagnosed.15 Common sense suggests that repeated screening should detect less aggressive cancers over a longer period of time, given length-time bias; SEER data, however, demonstrate that a large pool of well-differentiated latent carcinomas has not been uncovered. Instead, there has been a shift to tumors with moderate differentiation15 (Figure 29–1C). During this same period, there have been similar changes in presenting clinical stage of prostate cancer. Between 1990 and 1994, there was a 52% drop in the rate of dis-

tant and advanced-stage tumors with a corresponding increase in early-stage tumors15 (Figure 29–1E).

What Is a Significant Tumor? In 1954, Franks, after finding 69 cases of prostate cancer in 220 autopsies, suggested that there were two types of prostate cancer: a latent form and a lethal form.16 Leslie Foulds then introduced the concept that small tumors do not metastasize but that the probability of metastasis increases with the volume of the tumor.17 McNeal showed that cancers larger than 3.2 cm3 with an absolute Gleason grade 4 or 5 were associated with a 58% incidence of lymph node metastasis.18 Tumor volume and grade have been shown to be directly proportional in a linear fashion to the probability of progression, with the capacity for distant metastasis limited to those tumors with a volume greater than 1.0 cc and a high Gleason score.19 It is believed that the window for curability of prostate cancer is somewhere between a tumor volume of 0.5 cm3 and 6.0 cm3.20 Many autopsy studies revealing latent adenocarcinoma of the prostate have failed to adequately characterize histologic characteristics. Two studies have examined the clinical characteristics of prostate cancer found incidentally at the time of cystoprostatectomy.7,21 The characteristics of these tumors as described by Stamey et al.21 are shown in Table 29–1. Thirty-five (40%) cases of prostate cancer were found in 139 cystoprostatectomy specimens. The median tumor volume was 0.04 cm3 and 87% were organ confined. Given an 8% likelihood that a man in the United States will develop prostate cancer large enough to be clinically evident and that disease progression is directly related to cancer volume, the authors concluded that clinical significance began at 0.5 cm3 since the largest 8% of their cancers ranged from 0.5 to 6.1 cm3. [The arbitrariness of this definition is highlighted by the recent observation that the lifefree prostate cancer risk is now 16%.] They then examined the tumor volume of 408 radical prostatectomy specimens performed for clinical stage A and B disease. The authors found that only 9% of their specimens had a volume < 0.5 cm3. Epstein et al.22 performed a retrospective review of 157 radical prostatectomy specimens for T1c cancer and compared them to 64 patients with T1a cancer and 439 T2 cancers (Table 29–2). They divided the tumors into several categories: insignificant, minimal, moderate, and advanced. Insignificant tumors were defined as having a volume < 0.2 cm3, being organ confined, and having a Gleason score less than 7. None of these tumors showed capsular invasion or progression after a follow-up of 5 years. Even with this strict definition, only 26 (17%) of 157 cancers were deemed insignificant. Dugan et al.23 defined insignificant cancer according to cancer volume, grade, cancer doubling time, and life expectancy. Clinically insignificant tumors were defined

Should T1c Disease Be Treated Differently from T2 Disease? / 269

250

Rate per 100,000

200

150

Blacks 100

Whites

50

0 74

76

80

78

82

84

86

90

88

92

94

Year of Diagnosis

A Whites 140

Rate per 100,000

Rate per 100,000

100

120

Moderate

80

100 60

80 60

Biopsy 40

TURP

40

Well

20 0 83 84

Poor

20

Prostatectomy 85

86

B

87

88

89

90

Other 91

92

93

Unknown

94

0 74

Rate per 100,000 60

76

78

C

Year of Diagnosis

20

Radical Prostatectomy

80 82 84 86 Years of Diagnosis

88

90

92

94

Percent of Cases

50

15 Radiation Therapy

40 30

10

No Treatment

20

Other Treatments

0 88

D

5

Hormone Therapy

10

89

90

91

Year of Diagnosis

92

93

0 84

94

E

86

88 90 Year of Diagnosis

92

94

FIGURE 29–1. Summary of trends seen during the PSA-era. A, Incidence rates by race and year of diagnosis. B, Incidence by method of diagnosis. C, Incidence rates by grade. D, Treatment of localized disease. E, Incidence of distant disease. Reproduced with permission from Stephenson RA. Population-based prostate cancer trends in the PSA era: data from the Surveillance, Epidemiology, and End Results (SEER) program. Monogr Urol 1998;19:3–19.

270 / Advanced Therapy of Prostate Disease TABLE 29–1. Summary of Radical Prostatectomy Series for Impalpable and Incidental Prostate Cancer* Series (yr) Oesterling14 (1993) Epstein22 (1994) Ohori7 (1994) Scaletsky30 (1994) Matthews43 (1994) Cookson34 (1997) Humphrey12 (1996) Carter40 (1997) Douglas42 (1997) Stamey21 (1993)‡

Number Mean Age Mean PSA Cancer Volume of Patients (yr) (ng/mL) (cm3) 208 157 29 142 53 107 78 240 67 90

66 61 63.2 68 63 60 63 58 63 65

10.0 10.4 7.8 8.7 10 11.4 7.4 9.4 8.6 3.3

6.4 1.9 2.23 >1.0 in 65% Not given Not given 1.9 0.5–4 in 62% 2.37 0.04

Gleason Score

Organ Confined (%)

5–7 in 77% 6.3 4–5 in 48% 5–7 in 77% 6.4 5–7 in 70% 5.6 5–7 in 92% 5 4–5 in 11%

53 51 79 68 64 54 59 72 46 87

Positive Lymph Node Seminal Margins (%) + (%) Vesicle + (%) 34 17 9 28 Not given 35 35 8 46 0

3 4 4 1.4 Not given 3 0 9† 1 0

9 6 5 7 Not given Not given 3 9† 6 0

PSA = prostate-specific antigen. *Found at the time of cystoprostatectomy. †9% represents combined seminal vesicle and lymph node involvement. ‡Cystoprostatectomy series.

as not exceeding 20 cm3 within the projected life expectancy of the patient, using the 1990 life tables. Assuming cancer doubling times of 2, 3, 4, and 6 years, clinically insignificant cancer was identified in 0.3%, 3.9%, 7.4%, and 14.5% of 337 prostatectomy specimens, respectively. Although this is a theoretic model, it is interesting to note that with an assumed 4-year doubling time, the authors reported that 72% of the 25 insignificant cancers were clinically palpable. They also found that no tumor in a patient under 60 years of age was insignificant, and that no T3 lesion was insignificant even when the assumed doubling time was 6 years. This contrasted with the study by Epstein et al.22 in which all of the insignificant cancers were nonpalpable. Although there is controversy over what constitutes a significant prostate cancer, it appears that tumor volume, grade, patient age, and life expectancy are all important variables.

Characteristics of T1 Cancers Within the TNM classification system T1 tumors comprise a group of clinically occult tumors. Tumors classified as T1a are described as comprising < 5% of the tissue obtained at the time of transurethral resection and consist of low-grade tumor (Gleason score of 4 or less) while TABLE 29–2. Pathologic Findings at Radical Prostatectomy of Clinical Stage T1c Compared to Clinical Stage T1a and T2*

Organ confined (%) Capsular penetration (%) Positive seminal vesicles (%) Positive lymph nodes (%) Positive margins (%) Mean Gleason score Mean tumor volume (cm3) *In the Johns Hopkins series.22

Stage T1a (n=64)

Stage T1c (n=157)

Stage T2 (n=439)

92 6 0 0 3 4.79 .54

51 15 6 4 17 6.3 1.9

34 23 14 7 43 6.3 4.0

T1b tumors are defined as comprising > 5% of the tissue obtained by transurethral resection of the prostate (TURP) or high-grade tumors with a Gleason score of 5 and greater. In approximately 13 to 22% of TURPs performed for benign prostatic hyperplasia, incidental prostate cancer will be found.24 Epstein et al. found that 92% of T1a tumors were organ confined and had a mean Gleason score of 4.8 with a mean volume of 0.54 cm3.22 Several studies have demonstrated a progression rate for T1a of approximately 10%, but with longer follow-up the progression rate has been recorded to be as high as 27%.25,26 Cancers classified as T1b, on the other hand, show greater variation in grade, location, and volume. Epstein et al.27 found that in 39 radical prostatectomies performed for T1b disease there was a 26% incidence of extracapsular extension and a 10% incidence of seminal vesicle invasion. Also, these tumors were noted to be located in the more central regions of the prostate. These tumors, therefore, displayed a greater heterogeneity than T1a tumors, and given the location, were more difficult to detect. The progression rate for T1b tumors at 5 years has been reported to be as high as 37%.28 There is a growing body of knowledge about the clinical and pathologic features of T1c tumors and how they compare to the T2 lesions. Table 29–1 summarizes nine prostatectomy series and one cystoprostatectomy study that evaluated the clinical and pathologic features of T1c tumors. The cystoprostatectomy study is added to allow comparison of T1c tumors to latent or incidental prostate cancers. As seen in the table, stage T1c cancers display a great deal of variability. Some represent small-volume, low-grade lesions while others diffusely involve both lobes of the prostate gland. Why these larger tumors are not palpable is poorly understood. In general, a lesion is not palpable unless it causes a desmoplastic reaction in the overlying capsule. With PSA screening, these tumors may be detected earlier and perhaps have not had the time necessary to develop such a desmoplastic reaction.


Another possible explanation is that the tumor may not be palpable because it resides deep in a relatively large gland. Oesterling et al.14 found that the mean gland volume for the T1c tumors was 57 cm3 compared to 47 cm3 for the T2a-b tumors (p < .05). Similarly, Epstein et al.22 found that the tumor/gland volume was 0.056 for T1c disease and 0.075 in T2 lesions. It is also possible that these tumors are multifocal and may be located more anteriorly in the central or transitional zones.29 Scaletsky et al.30 found that 70% of T1c tumors had multifocal disease within the prostate, seeming to arise from the peripheral zone in 71% of tumors and from the transitional zone in 18%. Epstein et al.22 found that approximately 80% of the tumors were found in the peripheral zone while only 15% were found in the transitional zone. Transitional zone cancers have been thought to be similar to those cancers previously found at the time of TURP. Elgamal et al.31 presented a different view of the pathologic characteristics of T1c cancer. In their series of 100 consecutive radical prostatectomies for stage T1c disease, they found that the cancer developed in the transition zone 46% of the time and had a higher serum PSA and tumor volume than those arising in the peripheral zone. This difference may be due to the fact that transitional zone cancers produce 35% more PSA per gram of cancer than do peripheral zone cancers.32 The smaller peripheral tumors, however, had a similar Gleason score and incidence of locally advanced disease. Stamey et al.33 recently reported that approximately 25% of 277 prostatectomy specimens done for clinical stage T1c disease had transitional zone cancer and suggested that this was the reason for the increased PSA in this group.

Comparison of T1c and T2 Prostate Cancer Preoperative Clinical Characteristics Several studies comparing the clinical characteristics of T1c and T2 cancers are limited by the fact that they did not represent a screened population.14,34 The MSKCC series showed no statistically significant difference in patient age, mean PSA, and percentage of positive biopsies that were moderately differentiated between T1c and T2 tumors.34 The Mayo Clinic series found a higher mean PSA level in T1c tumors compared to T2 tumors (10.0 ng per mL versus 6.7 ng per mL) but no difference in patient age or tumor grade.14 This higher PSA level in T1c tumors may have been related to the larger gland volume in this group. Nevertheless, it appears that T1c and T2 cancers do not demonstrate significantly different preoperative clinical characteristics. Tumor Volume The tumor volume among T1c cancers encompasses small unifocal lesions from < 0.2 cm3 to very large and

potentially locally advanced disease. When compared to cancers identified in contemporary cystoprostatectomy series, T1c tumors have 50 times the volume. The definition of a clinically significant volume varies, but it is generally accepted that tumors with a volume of 0.5 cm3 and greater are considered clinically significant.2 Oesterling et al.14 found that the mean tumor volume in T1c cancers was actually larger than that found in T2 cancers (6.4 cm3 versus 5.2 cm3). Epstein et al.22 reported that in the Johns Hopkins series the tumor volume for T1a tumors was 0.54 cm3, 2.2 cm3 for T1c tumors, and 4.0 cm3 for T2 lesions (see Table 29–2). Using 0.5 cm3 as the cutoff for significant tumor, 26% of T1c tumors were insignificant while 58% of T1a and only 5% of T2 tumors were found to be insignificant. Ohori et al.7 reported that 87% of T1c tumors had a volume > 0.5 cm3. Scaletsky et al.30 also demonstrated that the mean tumor volume for stage T1c tumors was > 1.0 cm3 in 65% of cases. The composite picture these data present suggests that T1c cancers represent significant tumors and are much larger than those found incidentally. Gleason Score Further evidence highlighting the significance of these tumors has been their pathologic features. Most of the tumors are of an intermediate grade, with a Gleason score of 5, 6, or 7. Poorly differentiated tumors (Gleason score of 8, 9, or 10) are found in 10% of patients and welldifferentiated tumors (Gleason score of 2, 3, or 4) in fewer than 20% of cases.29 The Gleason score of T1c cancers has also been found to be similar to that for T2 cancers. In the Johns Hopkins series by Epstein et al.,22 the mean Gleason score for both T1c and T2 cancers was 6.3. The MSKCC series reported that 77% of T1c tumors were Gleason score 5 and above versus 81% for the T2 cancers.34 Humphrey et al.12 examined the pathologic features of prostate cancer detected in a serum PSA-based screening program and found that 94% had a Gleason score of 5 to 8 (mean of 5.7) and only 6% were well-differentiated (Gleason score of 4 or less). In one series from the Mayo Clinic, 82% of T1c tumors had a Gleason score of 5 to 7.14 Another series found that in patients with a PSA level < 20 ng per mL and stage T1c cancer, 85% had a Gleason score of 5 or more.30 These studies all demonstrate that T1c tumors are different from cancers found at autopsy and are more similar in grade to palpable tumors. Pathologic Extent of T1c Cancers The strongest evidence that T1c cancers are clinically significant and similar to palpable cancers comes from examining the pathologic staging from prostatectomy series. Several series have directly compared the pathologic extent of clinical stage T1c and T2 cancers.14,22,34 Epstein et al.22 found that the organ-confined rate for stage T1a tumors was 92%, 51% for T1c, and 34% for T2


tumors (see Table 29–2). The Mayo Clinic series14 reported organ confinement in 53% of T1c tumors and 55% of T2 tumors and seminal vesicle involvement in 9 and 7%, respectively. The MSKCC series34 demonstrated no difference between T1c and T2 cancers with respect to organ confinement and margin positivity. This trend is consistent across many of the prostatectomy series reporting organ-confined rates ranging from 46 to 79% and margin positivity of 9 to 46% (see Table 29–1). These results support the contention that T1c cancers are clinically significant and resemble T2 cancers. It is somewhat alarming, however, that despite having a tumor marker such as PSA, the detection rate of organconfined disease has not improved. The answer to this dilemma may be partially due to the fact that most of the prostatectomy series are retrospective and do not represent a screened population. Humphrey et al.12 examined 100 consecutive prostatectomy specimens from men who had participated in a screening program and reported a 61% organ-confined rate. Ohori et al.7 from the Baylor College of Medicine reported on a highly selected group of patients and found an organ-confined rate of 79%. In a prospective study by the American Cancer Society, the organ-confined rate of T1c cancers detected was approximately 75%.35 Catalona et al. reported a 71% rate of organ confinement in a group of PSA-screened patients who had undergone prostatectomy.36 There are also several studies demonstrating that organ confinement is greatest in those patients with a PSA level between 4 and 10 ng per mL. Oesterling et al.14 showed a 62% rate of organ confinement in T1c tumors with PSA levels between 4 and 10 ng per mL, decreasing to 42% when the PSA level was > 10 ng per mL. Cookson et al.34 showed a 72% organ-confined rate in those patients with PSA levels between 4 and 7 ng per mL. The goal of any screening program is to detect clinically significant cancers early enough to allow treatment that will improve disease-specific survival. Will these screening programs detect an increasing number of insignificant cancers? Current data do not suggest this. Geary and Stamey37 examined the pathologic characteristics of nonpalpable and palpable cancers with PSA levels between 4 and 10 ng per mL. They found that only 7% of T1c cancers had a volume < 0.5 cm3 and that the organ-confined rate was 67% among T1c cancers, compared to 44% for palpable tumors. They concluded that the T1c cancers detected within this PSA range were significant tumors and appeared to be more pathologically favorable than palpable cancers. In a prospective evaluation of prostatectomy specimens from patients participating in a screening program, Humphrey et al.12 reported that 68% had a tumor volume greater than 0.5 cm3 and 94% had a Gleason score between 5 and 8, again suggesting that the majority of those tumors were clinically significant.

Prognostic Indicators Stage T1c cancers are a disease of clinical significance but represent a heterogeneous population of tumors, covering the spectrum from small, organ-confined cancers to locally advanced cancers. The goal in this heterogeneous population of tumors is to identify clinically significant yet organconfined disease. This has led to attempts to predict the final pathology of T1c cancers from preoperative clinical characteristics. Evidence suggests a correlation between serum PSA concentration and the clinical stage of prostate cancer. It has been determined that 1.0 cm3 of prostate cancer elevates serum PSA by approximately 1.9 ng per mL using the Hybritech assay and by 3.5 ng per mL using the Yang assay.38 Therefore, preoperative serum PSA may be a useful predictor of final pathologic stage. In the MSKCC series, a multivariate regression model using patient age, tumor grade, palpability, and preoperative PSA level revealed that serum PSA was the best prognostic variable.34 The organ-confined rate was highest in those patients who presented with PSA levels between 4 and 10 ng per mL. Similarly, locally advanced disease was more common in T1c lesions with a PSA level >10 ng per mL. As previously mentioned, tumor volume is related to the probability of disease progression and therefore patient prognosis. Preoperative estimation of cancer volume has been attempted using linear relationships of volume to serum PSA and calculating the volume of the hypoechoic area on ultrasound, yet none of these parameters has proved to be reliable in predicting final tumor volume. It has been found, however, that a core cancer length of ≥ 3 mm in one or two needle biopsies reliably predicted cancer volume of more than 0.5 cm3.39 Conversely, in this same series, the presence of < 3 mm of tumor in the biopsy specimen did not accurately predict an insignificant tumor in the final prostatectomy specimen. Epstein and associates, in a review of clinical and pathologic features of 157 men with T1c prostate cancer, correlated these features with the final pathology following radical prostatectomy. Their criteria for predicting an insignificant tumor was PSA density 0.1 or less, no Gleason score 4 or 5 in the biopsy specimen, fewer than 3 biopsy cores involved, and no core with greater than 50% involvement with cancer.22 Using these parameters, the authors were able to correctly predict insignificant tumors in 73% of cases.22 Carter et al.40 then applied these parameters in a prospective manner to evaluate the ability of such preoperative characteristics to accurately predict tumor significance; they then compared them to a previous radical prostatectomy series done at the same institution. The authors were able to show that there was earlier detection of cancers and an improved organ confinement rate but no difference in the incidence of men who underwent radical prostatectomy and were found to have insignificant tumors (16% versus 17%).


Impact on Survival It has yet to be determined whether early treatment of prostate cancer will improve survival. The impact of PSA screening and early detection of prostate cancer is still evolving. However, a recent analysis of 257 patients with stage T1c prostate cancer treated with radical prostatectomy revealed a 5-year survival rate free of progression of 84%, similar to that for clinical stages T1a-T2a yet significantly better than that for clinical stage T2b-c.41

Conclusion Clinical stage T1c prostate cancer is now the most commonly diagnosed prostate cancer stage. Though a diverse group of tumors, they are approximately 50 times larger than incidental cancers and only 15 to 20% can be considered clinically insignificant based on tumor volume. They have a similar grade, volume, and pathologic extent to palpable clinically localized tumors. Patients with stage T1c prostate cancer should therefore be offered the same treatment options as those with stage T2 prostate cancers. With the use of widespread PSA screening, an increasing number of stage T1c cancers are being diagnosed. This will hopefully lead to a greater number of organ-confined and potentially curable cancers being detected. Unfortunately, it is still impossible to predict clinically insignificant tumors. The use of predictive models and molecular markers may solve this problem in the very near future.

11.

12.

13. 14.

15.

16. 17. 18.

19. 20. 21.

References 1. Bostwick, DG. Staging prostate cancer—1997: current methods and limitations. Eur Urol 1997;32 Suppl 3:2–14. 2. Stamey TA, Freiha FS, McNeal JE, et al. Localized prostate cancer: relationship of tumor volume to clinical significance for treatment of prostate cancer. Cancer 1993; 71:933–8. 3. Smart CR. The results of prostate carcinoma screening in the U.S. as reflected in the Surveillance, Epidemiology, and End Results program. Cancer 1997;80:1835–44. 4. Young HH, Davis DM. Young’s practice of urology. Vol I. Philadelphia: W.B. Saunders; 1926. p. 621. 5. Whitmore WF. Hormone therapy in prostate cancer. Am J Med 1956;21:697–713. 6. Jewett H. The present status of radical prostatectomy for stages A and B prostate cancer. Urol Clin North Am 1975;2:105–24. 7. Ohori M, Wheeler TM, Dunn K, et al. The pathological features and prognosis of prostate cancer detectable with current diagnostic tests. J Urol 1994;152:1714–20. 8. Ferguson JK, Bostwick DG, Suman V, et al. Prostatespecific antigen detected prostate cancer: pathologic characteristics of ultrasound visible versus ultrasound invisible tumors. Eur Urol 1995;27:8–12. 9. Carter HB, Hamper VM, Sheth S, et al. Evaluation of transrectal ultrasound in the early detection of prostate cancer. J Urol 1989;142:1008–10. 10. Smith DS, Catalona WJ. The nature of prostate cancer

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detected through prostate-specific antigen-based screening. J Urol 1994;152:1732–6. Catalona WJ, Smith DS, Ratliff TL, Basler JW. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993; 270:948–54. Humphrey PA, Keetch DW, Smith DS, et al. Prospective characterization of pathological features of prostatic carcinomas detected via serum prostate-specific antigen-based screening. J Urol 1996;155:816–20. Cookson, MS, Fair WR. Clinical T1c prostate cancer. AUA Update Series 1997;Vol. XVI, Lesson 14:106–11. Oesterling JE, Suman VJ, Zincke H, Bostwick DG. PSA detected (clinical stage T1c or B0) prostate cancer. Urol Clin North Am 1993;20:687–93. Stephenson RA. Population based prostate cancer trends in the PSA era: data from the Surveillance, Epidemiology, and End Results (SEER) program. Monogr Urol 1998; 19:3–19. Franks LM. Latent carcinoma of the prostate. J Pathol 1954;68:603–16. Foulds L. The experimental study of tumor progression: a review. Cancer Res 1954;14:327–9. McNeal JE. Cancer volume and site of origin of adenocarcinoma in the prostate: relationship to local and distant spread. Hum Pathol 1992;23:258–66. McNeal JE, Kindrachuk RA, Freiha FS, et al. Patterns of progression in prostate cancer. Lancet 1986;1:60–3. Stamey TA. Prostate cancer: who should be treated? Monogr Urol 1995;16(1):3–16. Stamey TA, Freiha FS, McNeal JE, et al. Localized prostate cancer: relationship of tumor volume to clinical significance for treatment of prostate cancer. Cancer 1993; 71:933–8. Epstein JL, Walsh PC, Carmichael M, Brendler CB. Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA 1994;271:368–74. Dugan JA, Bostwick DG, Myers RP, et al. The definitive and preoperative prediction of clinically insignificant prostate cancer. JAMA 1996;275:288–94. Newman AJ, Graham MA, Carlton CE, Lieman S. Incidental carcinoma of the prostate at the time of transurethral resection: importance of evaluating every chip. J Urol 1982;128:948–50. Blute ML, Zincke H, Farrow GM. Long term follow up of young patients with stage A adenocarcinomas of the prostate. J Urol 1986;136:840–3. Lowe BA, Listrom MB. Incidental carcinoma of the prostate: an analysis of the predictors of progression. J Urol 1988;140:1340–7. Epstein JI, Walsh PC, Brendler CB. Radical prostatectomy for impalpable prostate cancer. The Johns Hopkins experience with tumors found on transurethral resection (stages T1a and T1b) and on needle biopsy (stage T1c). J Urol 1994;152:1721–9. Zagars GK, Geara FB, Pollack A, von Eschenbach AC. The T classification of clinically localized prostate cancer. An appraisal based on disease outcome after radiation therapy. Cancer 1994;73:1904–12.

274 / Advanced Therapy of Prostate Disease 29. Smith JA. Stage T1c prostate cancer: perspective on clinical management. Semin Urol Oncol 1995;13:238–44. 30. Scaletsky R, Koch M, Echstein CW, et al. Tumor volume and stage in carcinoma of the prostate detected by elevations in prostate-specific antigen. J Urol 1994;152: 129–31. 31. Elgamal AA, VanPoppel HP, Van de Voorde WM, et al. Impalpable invisible stage T1c prostate cancer. Characteristics and clinical relevance in 100 radical prostatectomy specimens—a different view. J Urol 1997;157:244–50. 32. Noldus J, McNeal JE, Stamey TA. Prostate-specific antigen levels per gram of cancer volume determined by monoclonal assay. J Urol 1996;155:441–3. 33. Stamey TA, Sozen TS, Yemoto CM, McNeal JE. Classification of localized untreated prostate cancer based on 791 men treated only with radical prostatectomy: common ground for therapeutic trials and TNM subgroups. J Urol 1998;159:2009–12. 34. Cookson MS, Fleshner NE, Soloway SM, Fair WR. Prognostic significance of prostate-specific antigen in stage T1c prostate cancer treated by radical prostatectomy. Urology 1997;49:887–93. 35. Mettlin C, Murphy GP, Lee F, et al. Characteristics of prostate cancer detected in the American Cancer Society. National Prostate Cancer Detection Project. J Urol 1994;152:1737–40. 36. Catalona WJ, Richie JP, Ahman FR, et al. Comparison of

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digital rectal examination and serum prostate cancer: results of a multicenter clinical trial of 6630 men. J Urol 1994;151:1283–90. Geary ES, Stamey TA. Pathological characteristics and prognosis of nonpalpable and palpable prostate cancers with a Hybritech prostate-specific antigen 4 to 10 ng per mL. J Urol 1996;156:1056–8. Noldus J, Stamey TA. Histological characteristics of radical prostatectomy specimens in men with a serum prostate-specific antigen of 4 ng per mL or less. J Urol 1996;155:441–3. Dietrick DD, McNeal JE, Stamey TA. Core cancer length in ultrasound-guided systematic sextant biopsies: a preoperative evaluation of prostate cancer volume. Urology 1995;35:987–92. Carter HB, Sauvageot J, Walsh PC, Epstein JI. Prospective evaluation of men with stage T1c adenocarcinoma of the prostate. J Urol 1997;157:2206–9. Lerner SE, Seay TM, Blute ML, et al. Prostate-specific antigen-detected prostate cancer (clinical stage T1c): an interim analysis. J Urol 1996;155:821–6. Douglas TH, McLeod DG, Mostofi FK, et al. Prostatespecific antigen-detected prostate cancer (stage T1c): an analysis of whole-mount prostatectomy specimens. Prostate 1997;32:59–64. Matthews GJ, Fracchia JA. PSA-detected prostate cancer: contrasts with palpable disease. J Surg Oncol 1994;59: 28–30.

CHAPTER 30

T3-T4NXM0: THE CASE FOR OBSERVATION THOMAS A. ROZANSKI, MD; RODNEY DAVIS, MD the intent to cure. There is a distinct decrease in cancer control for cT3-cT4 disease compared to cT1-cT2 disease when similar treatments are applied. Despite many recent technologic advances available to urologists, the digital rectal examination (DRE) remains the single best modality for detecting extraprostatic disease. Evidence of induration beyond the lateral borders of the prostate, asymmetry, or induration above the prostatic base (in the region of the seminal vesicles), and pelvic sidewall fixation are indicative of T3-T4 disease. While historic data show that 22 to 30% of cT3 cancers were clinically overstaged and actually organ confined, recent studies suggest that the positive predictive value (PPV) of a DRE suspicious for T3-T4 is 91 to 94%.4,7–13 When a well-performed DRE is suspicious for gross extension beyond the prostatic capsule, the vast majority of those patients showing this will have at least pT3 disease. Radiologic imaging modalities are of little benefit when used to distinguish localized from locally advanced disease (Table 30–2).14,15 Transrectal ultrasonography (TRUS), computed tomography (CT) scanning, and magnetic resonance imaging (MRI) are no better than DRE and provide little benefit to the patient with a DRE suspicious for cT3-cT4 cancer. Attempts to increase the sensitivity and specificity of MRI using the endorectal coil have not proved helpful in staging, showing an overall diagnostic accuracy of 68%.16,17 Biochemical assays are not helpful in distinguishing T2 from T3 disease. Nomograms using prostate-specific antigen (PSA), Gleason score, and clinical stage predict nodal metastases with considerable accuracy.18,19 Prostate-specific antigen fails, however, to differentiate between local and locally advanced disease. Serum PSA values > 20 per ng/mL are associated with an 87% risk of T3 disease; PSA in the 10 to 20 per ng/mL range carries an 84% risk, and there is considerable overlap of T2 and T3 disease with PSA values < 10 per ng/mL.20 Free PSA

Primum Non Nocere (first do no harm) Advanced carcinoma of the prostate is defined as any tumor that is not organ confined. This chapter will deal with locally advanced disease, that is, stages T3 and T4, wherein the tumor extends beyond the confines of the prostate capsule, though it has not clinically metastasized to lymph nodes or bone (NxM0) (Table 30–1). Clinically detected locally advanced disease (cT3) must be distinguished from pathologic extraprostatic disease (pT3). The number of radical prostatectomies performed for clinically localized disease has increased markedly over the past decade. Despite optimal treatment for presumed localized carcinoma of the prostate, positive margins are found in 30 to 60% of cases.1,2 This explosion of pT3 disease is a separate entity from cT3 disease. Unfortunately, many reviews include both cT3 and pT3, making comparison of studies difficult. Clinically detected locally advanced prostate cancer is characterized by an aggressive tumor biology, highgrade disease, significant local and distant metastases, significant morbidity, and a poor long-term prognosis. The American College of Surgeons (ACS) Cancer Database shows that the incidence of T3 cancers was relatively stable between 1986 and 1993, representing 14 to 18% of prostate cancer at presentation.3 Similarly, 19% of men found to have prostate cancers in screening programs today will have T3 disease.2,4 Unfortunately, these statistics include both clinical bulky cT3-cT4 cancers and pathologic C disease (pT3). At Eastern Virginia Medical School, the incidence of clinical T3 disease among newly diagnosed prostate cancer cases decreased from 20% in 1985 to 10% in 1994.5 This stage migration was also reported by Walter Reed Army Medical Center; in 1989, clinical T3 disease accounted for 12.2% of new diagnoses while cT1c disease was not reported. An aggressive screening program more than doubled the number of new prostate cancers diagnosed in 1994, with cT1c accounting for 44% and cT3 disease falling to 3.5%.6

Staging

TABLE 30–1. American Joint Committee on Cancer (AJCC) Staging of Prostate Cancer, 1997

Accurate staging of prostate cancer assists in determining optimal treatment. Staging and patient selection are very important since excellent results are obtained when treating localized disease whereas outcomes are much less favorable when locally advanced disease is treated with

T3: tumor extends through the prostate capsule T3a: extracapsular extension (unilateral or bilateral) T3b: tumor invades seminal vesicle T4: tumor is fixed or invades adjacent structures other than seminal vesicles (bladder neck, external sphincter, rectum, levator muscles, pelvic sidewall)

275


and free:total PSA ratios are unable to distinguish T2 from T3 prostate cancers.21,22 The reverse transcriptase– polymerase chain reaction assay for detecting prostate cancer in the peripheral blood that expresses PSA, or prostate-specific membrane antigen (PSMA), is not helpful in differentiating localized from locally advanced disease.23 Prostatic acid phosphatase (PAP) is rarely used today for staging purposes. The specificity of PAP for extracapsular disease is high but sensitivity is very low; the majority of men with T3-T4 disease and an elevated PAP will have a suggestive DRE and very high PSA.24 Burnett concluded that PAP contributes unique information in less than 1% of men with prostate cancer.25 Seminal vesicle invasion by a tumor is associated with a poor prognosis. Accurate determination of T3b disease would likely alter the therapeutic regimen since a seminal vesicle tumor is associated with large prostate tumor volumes, a fourfold risk of positive margins, a threefold increase in capsular penetration, greater likelihood of local recurrence, and shorter interval to recurrence.26 Transrectal ultrasonography demonstrating seminal vesicle asymmetry and volumes above 15 cc suggests a tumor.27 Seminal vesicle biopsy has been advocated by some prior to radical prostatectomy in high-risk patients. Valiancien et al. reported a PPV of 100% and a negative predictive value (NPV) of 87.5% with seminal vesicle biopsy prior to prostatectomy.26 While overstaging of clinical T3-T4 disease is unusual, understaging is very common. Serum PSA values are not helpful in distinguishing patients with a locally advanced tumor from those with metastatic disease to the pelvic lymph nodes.28 Between 42 and 56% of men with clinical T3-T4 disease will have lymph node metastases when surgically staged.9,10,28–31 The consistent surgical finding that half of cT3-cT4 patients have nodal metastases may actually be an underestimate. Freeman et al. reanalyzed pelvic lymph nodes using immunocytochemistry for monoclonal antibodies to cytokeratins and PSA in 95 patients with pT3N0 disease and found that 16% had unsuspected metastases to the lymph nodes.32

Management Considerations The optimal management for locally advanced prostate cancer is poorly defined; a gold standard does not exist. In 1986, the ACS reported that among patients with clinical

TABLE 30–2. Sensitivity and Specificity of Imaging Modalities in T3 Disease Sensitivity Specificity

TRUS

CT Scan

MRI

66% 46%

55% 65%

77% 57%

TRUS = transrectal ultrasonography; CT = computed tomography; MRI = magnetic resonance imaging. From Rifkin HD, et al.14 and Hricak H, et al.15

T3 disease, 48% were treated with noncurative modalities while 52% were treated with a variety of treatments with the intent to cure.33 There was a significant increase in the percentage of patients treated with curative intent in a more recent ACS review in 1994. Radical prostatectomy (RP) was performed in 43%, external beam radiation therapy (XRT) in 23%, and combination RP and XRT in 10%. Only 23% of patients with clinical C disease were observed or treated with hormonal therapy alone.34 These data are both interesting and disturbing since the literature fails to support any treatment modality as likely to cure locally advanced disease. Treatments with the intent to cure T3-T4 disease are associated with poor outcomes. The bleak outlook for locally advanced disease is likely related to the aggressive biology of the cancer. Over half of T3-T4 tumors are poorly differentiated whereas only 16 to 24% of T1b-T2 tumors are high grade.5,34 Partin et al. showed that as the initial Gleason score rises, the tumor is less likely to be pathologically organ confined.20 Among patients with Gleason scores of 8 to 10 and clinically organ-confined disease, only 8% ended up pathologically staged as T2.35 Clinical T3 tumors are extensive, and tumor volumes are much greater than in localized disease (Table 30–3). Locally advanced disease is associated with four times the average tumor volume seen in T1c and T2a cancers and over double the tumor volume in T2b and T2c disease.12 Studies of deoxyribonucleic acid (DNA) ploidy show a greater malignant potential for locally advanced tumors. Aneuploid tumors are seen more frequently in T3-T4 disease compared to localized tumors.36,37 High-grade disease and extensive tumor volume predispose locally advanced disease to failure (local recurrence and metastatic disease) regardless of treatment modality. The efficacy of any treatment regimen employed with the intent to cure must be measured by its success in eradicating disease and preventing recurrence while preserving the patient’s quality and duration of life. Tumor and patient factors must be considered in selecting a form of therapy. Tumor factors include clinical stage, overall tumor burden, and Gleason score. Patient factors are age, estimated life expectancy, comorbidities, and quality of life issues (e.g., potency, expectations, stress). The efficacies of treatment options for cT3-cT4 disease are difficult to compare. True single modality studies are rare, and most regimens combine local and systemic therapies. Some regimens are applied with intent to cure while others are noncurative. Selection bias is always a concern when treatment options such as radical surgery are more invasive than modalities such as radiation therapy. Historic controls are inadequate since PSA and bone scan information is lacking in many studies. Complete staging is optimal only for patients undergoing surgery, making less invasive options difficult to compare in a direct fashion. Early biochemical failure was not recog-

T3-T4NxM0: the Case for Observation / 277

nized until recently with the routine use of PSA testing. In addition to these hurdles, the efficacies of various treatments are difficult to compare because of the wide array of reporting techniques used to describe success or failure. These include local recurrence/control, biochemical recurrence, overall survival, disease-specific survival, disease-free survival, metastatic-free survival, progression-free survival, etc. Not only are these rates difficult to compare, there is significant variability in how they are ascertained. Treatment options for locally advanced prostate cancer include observation, hormonal therapies, radical prostatectomy, external beam radiation, interstitial radiation, cryotherapy, and combinations thereof. Reviewing the literature leads to a single conclusion: any form of monotherapy has a low chance of cure.

Natural History The natural history of untreated cT3-cT4 disease will likely never be determined because of the standard use of hormonal therapy to treat symptomatic disease and rising PSA. Therefore, the natural history of this disease reflects treatment with hormone therapy at some point in the patient’s lifetime. Untreated disease equates with no intent to cure and incorporates early or deferred hormone therapy and symptomatic treatments. The overall survival for untreated locally advanced prostate cancer at 5 years is 42 to 64%, and 16 to 37% at 10 years (Table 30–4). In a large contemporary series, Adolfsson reported a 5-year cancer-specific and overall survival of 88% and 64%, respectively.38 At 9 years, cancer-specific survival was 70% and overall survival 37%. This series is criticized for its abundance of well- and moderately differentiated tumors (96%). The risk for distant metastases at 5 years was 24%. Twenty-two percent of patients underwent transurethral resection of the prostate (TURP) for obstructive symptoms during follow-up, 58% received some form of endocrine therapy, and 12% were treated with local radiation therapy. Johannson et al. followed 183 patients diagnosed with cT3-cT4 disease.39 These diagnoses accounted for 28% of new prostate cancers over a 7-year period in one county in Sweden, where screening is not performed. The mean age at diagnosis was 72 years, and 24% of the group ultimately died of prostate cancer. The majority were treated with hormone therapy. Progression-free survival and overall survival at 10 years were 57.5% and 25.1%, respectively. In the Veteran’s Administration Cooperative Urologic Research Group (VACURG) study of over 1000 patients, 5- and 10-year overall survival of patients with stage C disease was 50% and 20%, respectively.40 Only 17.2% of deaths were attributed to prostate cancer, however. In a series from Scotland, Rana et al. reported that 85% of 199 patients with cT2-T4NxM0 disease required immediate TURP for obstructive symptoms.41 This reflects the mean patient age of 72 years, the fact that

TABLE 30–3. Median Tumor Volume by Stage Stage

Median Tumor Volume (cm3)

T1c T2a T2b T2c T3

1.5 1.3 2.4 2.7 6.8

From Ohori M, Wheeler TM, Scardino PT. The New American Joint Committee on Cancer and International Union Against Cancer TNM classification of prostate cancer. Clinicopathologic correlations. Cancer 1994;74:104–14.

screening was not performed, and that the majority of patients presented with obstructive symptoms. With an average follow-up of 4.2 years, 26% had local failure requiring additional treatment for obstructive symptoms, and 46% developed metastatic disease. Cause-specific survival was 70% and 50% at 5 and 10 years, respectively. Despite disease progression, actuarial survival was only 17% less at 5 years and 15% less at 10 years compared to an age-matched population in Scotland. Aus et al. reviewed all regional prostate cancer deaths between 1988 and 1991.42 In those patients diagnosed with locally advanced disease who were treated with noncurative modalities and followed until death, the ultimate cancer mortality rate was 50%. In this Swedish series, two-thirds of patients received primary endocrine therapy and one-third were treated with deferred hormonal manipulation. Since competing mortality rates are equal to or greater than the prostate cancer mortality rate in T3-T4 disease (Table 30–5), treatment with the attempt to cure locally advanced disease will potentially improve survival in less than half of patients.

Hormone Therapy Endocrine manipulation can provide dramatic local response and prolonged symptomatic improvement in locally advanced prostate cancer.43 Prostate-specific antigen values are reduced up to 98% and tumor volume usually shrinks by 25 to 30%. Hormone therapy (HT) results in definitive, measurable tumor response but it does not seem to extend survival. Androgen deprivation can be initiated early or late as monotherapy or as one of a combination of therapies in an intermittent or continuous manner. The original VACURG studies concluded that although osseous metastases were delayed, overall survival was not altered by early androgen deprivation.40 Twenty years later, Blackard reviewed the VACURG data TABLE 30–4. Overall Survival for Untreated cT3Nx Adolfsson38 Johannson39 VACURG40 Rana41

5 Years

9/10 Years

64% 50% 50% 42%

37% 25% 20% 16%


and concluded that early HT did enhance quality of life by diminishing cancer pain, improving performance status, and delaying bony metastases.44 Rana et al. followed 199 consecutive patients with locally advanced disease and concluded that there was no difference between immediate and delayed HT with regard to metastatic progression, cancer-specific survival, or overall survival.41 The Medical Research Council Prostate Cancer Working Party compared the impact of immediate versus delayed HT in 938 patients with asymptomatic, advanced prostate cancer.45 They found that metastases, pain, bladder outlet obstruction, ureteral obstruction, and spinal cord compression developed more often with deferred treatment. At the time of study analysis, death occurred in 40.6% of patients treated with delayed HT while only 28.7% of patients in the immediate HT arm had died. The majority of reports comparing monotherapy to combination HT have been performed for advanced prostate cancer. The data is conflicting but there is a lack of strong evidence to support the use of maximum androgen blockade.46 Dupont et al. treated 115 nonrandomized patients with cT3 disease using combination HT (flutamide and leuprolide) and concluded that compared to monotherapy historic data, local control failure rates were three times lower with maximum androgen blockade.47 Further studies are needed to clarify the role of single or combination endocrine manipulation in patients with cT3-cT4 disease. Androgen deprivation variably affects quality of life in asymptomatic patients. Adverse effects include hot flashes, lethargy, loss of vigor, mood alteration, decreased libido, impotence, and abnormal weight distribution. These symptoms may lead to cessation of therapy if medical modalities were employed. Fleshner and Trachtenberg treated 10 potent men with advanced prostate cancer using an antiandrogen and finasteride.48 Eight patients retained potency while the mean PSA value was reduced 10-fold. Osteoporosis and fractures have recently been recognized as long-term morbidities in men treated with androgen suppression.49,50 Appropriate counseling and evaluation for osteoporosis should be standard for all men treated with HT. Intermittent HT has been introduced as a means of reducing the adverse effects of androgen deprivation and possibly enhancing the effectiveness of HT. Intermittent HT has the potential to restore serum testosterone levels, allowing for the possible return of sexual function and TABLE 30–5. Deaths Attributable to Prostate Cancer in Untreated T3-T4 Disease Adolfsson38 Johannson39 VACURG40 Rana41 Aus42

30% 24% 17% 50% 50%

altering the adverse effects attributed to androgen deprivation.51 Androgen deprivation induces apoptosis. Continuous HT reduces the proportion of androgen-dependent stem cells and results in proliferation of androgenindependent cells.52 Intermittent termination of HT may allow androgen-dependent stem cells to proliferate.53 Strong evidence that intermittent HT will dramatically improve survival does not exist but there is no evidence that intermittent HT is inferior to continuous androgen deprivation. Intermittent HT may improve quality of life and reduce costs. Further studies, including an ongoing phase 3 Southwest Oncology Group protocol (SWOG 9346), should help clarify the role of intermittent HT.

Radical Prostatectomy The ideal patient most likely to benefit from RP is the man with organ-confined disease, when complete excision of disease is possible. By definition, cT3-cT4 cancer is less than ideal. It is very difficult to determine the efficacy of RP alone since most RP series include adjuvant therapy. Many series do not differentiate pT3 from cT3 disease, confounding the utility of RP for clinically detected locally advanced disease. Comparing RP series with radiation or expectant management is difficult since there are a number of potential biases and limitations that can only be circumvented with prospective randomized trials. Uncontrolled RP series likely select patients with less bulky T3-T4 disease for surgery and relegate bulky and poorly differentiated tumors to nonsurgical therapies. Single institution reports have limited broad applicability due to variations in patient selection, treatment, and follow-up. Van de Ouden et al. treated 100 patients with clinical stage C disease with monotherapy RP.10 Pelvic lymph node metastases were found in 48; 39 had pathologic T3 tumors; 3 had pT4 cancer; and 9 were overstaged and actually had pathologic T2 disease. Within 4 years, only a third of operated patients were clinically free of disease; biochemical failures were not reported but, if assessed, would markedly reduce the disease-free numbers. Overall survival at 10 years was 34%. The Mayo clinic reports excellent survival following RP for cT3 disease, despite finding nodal metastases in 33 to 52% of those patients and Gleason scores of 7 or higher in over 60% of specimens.9,30,54 Despite large numbers, mean follow-up is under 5 years, and 60% of patients received adjuvant therapy.54 Yamada et al. reported on 57 patients treated with RP and radiation therapy for clinical C disease; in addition to combination therapy, many patients received early HT and/or chemotherapy.55 At a mean follow-up of 5.4 years, only 33% were alive without evidence of disease. In a multi-institutional study performed at eight centers in the United States and Europe, 298 men with cT3 tumors were treated with RP.13 Forty-one percent had nodal metastases or seminal vesicle tumor while only 9% had pathologic organ-confined dis-


ease. The conclusion drawn was that surgery is unlikely to achieve a significant long-term survival benefit. Though RP is feasible for locally advanced disease, the morbidity of surgery must be considered. Despite the occasional excellent single institution series, some report incontinence rates (need to wear pads) between 20 and 47%.56–58 When patients were queried about incontinence by independent investigators, over twice as many reported incontinence compared to surgeon-reported rates in the same population.59 An ACS survey reported that erectile function is preserved in less that 30% of potent RP patients.56 Mortality is less than 1% but rises to 1.3% in men older than 70.56,60 The literature on overall survival for patients with locally extensive prostate cancer treated by RP reveals 5-, 10-, and 15-year survival rates of 63%, 34%, and 20%, respectively. Pelvic exenteration for cT3-cT4 disease adds no efficacy but does add significant morbidity.61–63 Spaulding reported local control in 50% of patients and a 5-year survival of 35% following cystoprostatectomy.62 The use of neoadjuvant hormone therapy (NHT) in cT3-cT4 tumors has not proved beneficial in rendering patients free of disease. The amount of PSA reduction following NHT is not predictive of pathologic response.64,65 Neoadjuvant HT does not decrease the rate of PSA recurrences following RP.66 Despite clinical downsizing, pathologic downstaging does not occur.61,64,65,67 There are no firm data that RP is superior to observation and hormonal therapy in the treatment of locally advanced prostate cancer. Approximately half of patients with cT3-cT4 disease have nodal metastases, regardless of treatment regimen. The recommendation of radical surgery for cT3-cT4 prostate cancer is difficult to justify.

External Beam Radiation Therapy External beam radiation therapy has been the most utilized treatment modality applied with the intent to cure bulky locally extensive prostate cancer. This likely reflects the recognition that surgical extirpation for cure is rarely successful. Unfortunately, the local control and overall survival rates following XRT differ little from patients treated with observation and hormone therapy. Survival rates vary considerably, and it is difficult to compare the different measures of response (e.g., metastatic-free, cancer-specific, disease-free). The methods by which these rates are ascertained are variable, and older series do not include PSA data. Controversy continues as to which PSA level is indicative of local control or cure following XRT. Post-treatment prostate biopsy data is similarly controversial when evaluating the efficacy of XRT. Overall survival is the only readily comparable measure of success. Zagars et al. reported 5- and 10-year overall survival rates of 72 to 77% and 47 to 49%, respectively, following XRT.68,69 These numbers are significantly better than

those shown by meta-analyses in the literature. In a review of over 3000 patients in 21 series, 5-, 10-, and 15year survival rates of 63%, 39%, and 24%, respectively, were shown.61 Schellhammer and Lynch’s review of several large series revealed low overall survival at 10 and 15 years of 15 to 30%.5 These numbers do not differ from the overall survival figures for untreated cT3-cT4 disease (see Table 30–4). Local control rates vary among series and range between 29 and 82%.68,70–72 Unfortunately, local control does not correlate with metastatic-free, biochemical-free, or overall survival. Hanno found no difference in local progression or time to first evidence of distant metastases in cT3 patients randomly assigned to XRT or delayed hormone therapy.73 In a Finnish study with a short 4-year follow-up, no difference in disease progression was reported in patients with locally advanced tumors randomly assigned to orchiectomy or XRT plus estrogens.74 The men undergoing orchiectomy alone had fewer complications. When PSA criteria are applied to large series, biochemical failure rates are 80 to 94% at 10 years.5,75 External beam radiation is usually well tolerated and most complications are mild to moderate in severity. However, severe complications have been reported in 6 to 8% of patients, with 2 to 3% requiring diverting colostomy, cystectomy, or urinary diversion.68,70 Erectile dysfunction occurs in 30 to 64% of radiated patients.76,77 Given the poor results obtained with conventional radiation therapy, several modifications and innovations have been described in recent studies: conformal XRT, neutron beam therapy, and neoadjuvant hormonal therapy. Conformal radiation therapy (CRT) makes use of highly sophisticated planning techniques in an attempt to increase the radiation dose to the prostate while limiting radiation delivered to surrounding structures. The standard dose of 70 to 72 Gy can be increased to over 80 Gy using three-dimensional CRT (3DCRT).78,79 Higher energy delivery can be achieved using neutrons in place of standard photon-based radiotherapy.80,81 Early reports are encouraging; however, substantial long-term data showing greater survival using 3DCRT or neutron radiation is lacking. Early reports using NHT and XRT showed improved local control and delayed time to biochemical failure. The goal of NHT is to facilitate XRT by tumor shrinkage and induce apoptosis by potentially synergistic interaction.75,82 Despite improved local control, the addition of NHT to XRT has not had an impact on progression to distant metastases and overall survival.71,82,83 External beam radiotherapy is well tolerated, but the results of radiation-based treatment for locally advanced disease are not encouraging and long-term cure is unlikely. The literature does not support the efficacy and general utility of XRT in cT3-cT4 disease over results obtained with symptomatic and hormone therapies alone.


Brachytherapy Interstitial radiation therapy for prostate cancer was popularized in the 1950s using colloidal gold-198. Recent advances in transrectal ultrasonography have given rise to a resurgence of brachytherapy. Additional agents utilized for interstitial radiation include iodine-125, iridium-192, and, more recently, palladium-103. Long-term follow-up is not available using recent techniques and agents to treat locally advanced prostate cancer. The available literature demonstrates that local control and overall survival following brachytherapy are not as good as results seen with XRT.61,84 The morbidity of brachytherapy has been reported to be greater than the complications associated with XRT.85 The Board of Directors of the American Urological Association (AUA) revised their Health Policy Statement regarding brachytherapy in 1997, as follows: “The AUA believes that brachytherapy treatment of the prostate is one of the methods of urologic management of adenocarcinoma of the prostate. The long-term curative efficacy of this treatment modality has not been established. When used, appropriate disclosure of facts regarding all other treatments for prostate cancer should be made to the patient.” No study to date shows interstitial radiation therapy to have greater efficacy than XRT in locally advanced disease. Modern series have few data and short follow-up; brachytherapy is an unproven modality for treating cT3-cT4 prostate cancer.

Cryotherapy There has been a general lack of enthusiasm in the United States for cryoablation of the prostate. Cryotherapy was first described as a treatment for prostate cancer in 1964.86 Renewed interest in the procedure followed improvements in transrectal ultrasonography and urethral warming devices. Studies in canine prostates showed that iceball progression could be accurately monitored using ultrasound.87 Liquid nitrogen cryoprobes can generate intraprostatic temperatures of –180 to –190°C, causing cell lysis. Ultrasonic guidance of the probes lateral to the prostate and into the seminal vesicles made this technique theoretically attractive for locally advanced disease. Unfortunately, poor efficacy and high complication rates have limited the utility of cryotherapy in cT3-cT4 prostate cancer. Porter et al. reported a 20-year follow-up of 40 stage C patients treated with cryoablation.88 Median progression-free survival was 30 months and overall survival was 78.5 months. Porter concluded that cryotherapy was poorly effective for local control. Shinohara et al. treated 64 cT3-cT4 patients between 1993 and 1996.89 Eighteen months after cryotherapy, the biochemical failure rate was 56% and local failure was 30%. Neoadjuvant hormone therapy did not alter the PSA failure rate. Some series use early repeat biopsy data to claim efficacy; Svetec et al., however, clearly demonstrated the limited utility of

repeat biopsy. Sextant biopsies at the time of radical prostatectomy demonstrated cancer in only half of patients with documented disease.90 Complications clearly limit the use of cryotherapy. Incontinence rates vary between 2.5 and 30%,91,92 fistulas occur more frequently following cryoablation of extensive disease,92 and erectile dysfunction is significant. Shinohara et al. reported that 84% of potent men with cT1-cT4 disease lost erections following cryoablation of the prostate.93 Cox and Crawford reported a complication rate of 59% in 64 patients, 8% being severe (sepsis, fistula, ureteral obstruction).94 The Board of Directors of the American Urological Association revised their position on cryotherapy in 1996, as follows: “The AUA believes that cryosurgical treatment of the prostate is one of the methods of management of adenocarcinoma of the prostate. The longterm curative efficacy of this treatment modality has not been established. When used, appropriate disclosure of facts regarding all other treatments for prostate cancer should be made to the patient.” The significant risks and marginal efficacy of cryotherapy relegate this modality to investigational use only. Observation and hormone therapy are less morbid and less costly than cryotherapy for locally advanced prostate cancer.

Conclusion No single treatment modality and no current combination of therapies has proven effective in curing locally advanced adenocarcinoma of the prostate. Many patients with cT3-cT4 disease have occult metastases at presentation and cannot be cured by local therapies. Neoadjuvant hormone therapy has not proved beneficial prior to either surgery or radiation, and any short-term benefits can probably be achieved with androgen deprivation alone. The results of radical prostatectomy and radiation therapy for locally advanced disease differ little from those obtained with expectant management and hormone therapies.84 Tumor grade and stage, morbidities from treatment, patient comorbidity, cost, and the patient’s wishes and expectations should be carefully considered before any treatment regimen is prescribed for cT3-cT4 disease. Men with high-grade locally advanced disease will likely derive no long-term benefit from any treatment modality. Young patients with low-grade tumors might be considered for curative modality, probably radical prostatectomy. The optimal treatment for locally advanced prostate cancer has yet to be determined. The majority of patients with cT3-cT4 prostate cancer, however, are best served by expectant management and hormone therapy.

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19. Bluestein DL, Bostwick DG, Bergstralh EJ, Oesterling JE. Eliminating the need for bilateral pelvic lymphadenectomy in select patients with prostate cancer. J Urol 1994;151:1315–20. 20. Partin AW, Yoo J, Carter HB, et al. The use of prostatespecific antigen, clinical stage, and Gleason score to predict pathologic stage in men with localized prostate cancer. J Urol 1993;150:110–4. 21. Bangma CH, Kranse R, Blijenberg BG, Schröder FH. The free-to-total serum prostate-specific antigen ratio for staging prostate carcinoma. J Urol 1997;157:544–7. 22. Noldus J, Graefen M, Huland E, et al. The value of the ratio of free-to-total prostate-specific antigen for staging purposes in previously untreated prostate cancer. J Urol 1998;159:2004–8. 23. Ellis WJ, Vessella RL, Corey E, et al. The value of a reverse transcriptase polymerase chain reaction assay in preoperative staging and follow-up of patients with prostate cancer. J Urol 1998;159:1134–8. 24. Lowe FC, Trauzzi SJ. Prostate acid phosphatase in 1993. Its limited clinical utility. Urol Clin North Am 1993; 20:589–95. 25. Burnett AL, Chan DW, Brendler CB, Walsh PC. The value of serum enzymatic acid phosphatase in the staging of localized prostate cancer. J Urol 1992;148:1832–4. 26. Valiancien G, Bochereau G, Wetzel O, et al. Influence of preoperative positive seminal vesicle biopsy in the staging of prostate cancer. J Urol 1994;152:1152–6. 27. Cummings JM, Boullier JA, Sankari BR, Parra RO. Seminal vesicle volume as a sonographic predictor of prostate cancer stage. Urology 1994;44:206–10. 28. Greskovich FJ, Johnson DE, Tenney DM, Stephenson RA. Prostate-specific antigen in patients with clinical stage C prostate cancer: relation to lymph node status and grade. J Urol 1991;145:798–801. 29. Gervasi LA, Mata J, Easley JD, et al. Prognostic significance of lymph nodal metastases in prostate cancer. J Urol 1989;142:332–6. 30. Zincke H, Utz DC, Taylor WF. Bilateral pelvic lymphadenectomy and radical prostatectomy for clinical stage C prostate cancer: role of adjuvant treatment for residual cancer and in disease progression. J Urol 1986;135:1199–205. 31. Sands ME, Zagars GK, Pollack A, Von Eschenbach AC. Serum prostate-specific antigen, clinical stage, pathologic grade, and the incidence of nodal metastases in prostate cancer. Urology 1994;44:215–20. 32. Freeman JA, Esrig D, Grossfeld GD, et al. Incidence of occult lymph node metastases in pathologic stage C (pT3N0) prostate cancer. J Urol 1995;154:474–8. 33. Schmidt JD, Mettlin CJ, Natarajan N, et al. Trends in patient care for prostate cancer, 1974–1983: results of surveys by the American College of Surgeons. J Urol 1986;136:416–21. 34. Mettlin CJ, Murphy GP. Prostate cancer. In: Steele GD, Osteen RT, Winchester DP, editors. National Cancer Database. Annual review of patient care. 1994. Atlanta: American Cancer Society; 1994. 35. Partin AW, Lee BR, Carmichael M, et al. Radical prostatectomy for high-grade disease: a re-evaluation. J Urol 1994;151:1583–6.

282 / Advanced Therapy of Prostate Disease 36. Kucuk O, Demirer T, Gilman-Sachs A, et al. Intratumor heterogeneity of DNA ploidy and correlations with clinical stage and histologic grade in prostate cancer. J Surg Oncol 1993;54:171–4. 37. Stege R, Lundh B, Tribukait B, et al. Deoxyribonucleic acid ploidy and the direct assay of prostatic acid phosphatase and prostate-specific antigen in fine needle aspiration biopsies as diagnostic methods in prostate cancer. J Urol 1990;144:299–302. 38. Adolfsson J. Deferred treatment of low-grade, low-stage T3 prostate cancer without distant metastases. J Urol 1993;149:326–8. 39. Johannson JE, Holmberg L, Johansson S, et al. Fifteen-year survival in prostate cancer. A prospective, populationbased study in Sweden. JAMA 1997;227:467–71. 40. Byer DP. The Veteran’s Administration Cooperative Urological Research Group’s studies of cancer of the prostate. Cancer 1973;32:1126–30. 41. Rana A, Chisholm GD, Khan M, et al. Conservative management with symptomatic treatment and delayed hormonal manipulation is justified in men with locally advanced carcinoma of the prostate. Br J Urol 1994;74:637–41. 42. Aus G, Hugosson J, Norlen L. Long-term survival and mortality in prostate cancer treated with noncurative intent. J Urol 1995;154:460–5. 43. Rozanski TA, Faerber GJ. Massive locally extensive prostate cancer. Urology 1994;43:242–3. 44. Blackard CE. Re: deferred treatment of low-grade stage T3 prostate cancer without distant metastases [letter; comment]. J Urol 1994;151:436. 45. Kirk D. Hormone therapy in advanced prostate cancer— report of the Medical Research Council ‘Immediate’ versus ‘Deferred’ Treatment Study [abstract]. Br J Urol 1996;77:52. 46. Trachtenberg J. Androgen ablation therapy— where to next [editorial]? J Urol 1997;158:178. 47. Dupont A, Cusan L, Gomez JL, et al. Combination therapy with flutamide and the LHRH agonist LHRH ethylamide in stage C prostate carcinoma. Br J Urol 1993; 72:629–34. 48. Fleshner NE, Trachtenberg J. Treatment of advanced prostate cancer with the combination of finasteride plus flutamide: early results. Eur Urol 1993;2 Suppl:106–12. 49. Daniell HW. Osteoporosis after orchiectomy for prostate cancer. J Urol 1997;157:439–44. 50. Townsend MF, Sanders WH, Northway RO, Graham SD. Bone fractures associated with luteinizing hormone– releasing hormone agonists used in the treatment of prostate carcinoma. Cancer 1997;79:545–50. 51. Hernandez J, Thompson IM. Intermittent hormone therapy for carcinoma of the prostate: a review. Mol Urol 1998;2:19–22. 52. Bruchovsky N, Rennie PS, Coldman AJ, et al. Effects of androgen withdrawal on the stem cell composition of the Shionogi carcinoma. Cancer Res 1990;50:2275–82. 53. Akakura K, Bruchovsky N, Goldenberg SL, et al. Effects of intermittent androgen suppression on androgendependent tumors. Cancer 1993;71:2782–90. 54. Lerner SE, Blute ML, Zincke H. Extended experience with radical prostatectomy for clinical stage T3 prostate

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CHAPTER 31

T3-T4NXM0: THE CASE FOR RADIOTHERAPY ERIC M. HORWITZ, MD; GERALD E. HANKS, MD External beam radiation therapy (RT) has long been the mainstay of treatment for patients with T3 and T4 prostate cancer. For these stage groupings, particularly T3c and T4 disease, patients have a poor outcome with surgery and there is no established role for that treatment. Data from Partin et al. have demonstrated that tumor biology can exceed the limits of surgery, even in the most favorable subgroup T3a, and in the most highly selected patients. Data from this multi-institutional study have shown that the chance of having organ-confined disease ranged from 1 to 27% for patients with pretreatment prostate-specific antigen (PSA) levels > 4 ng per mL. The risk of pelvic lymph node involvement or seminal vesicle invasion was as high as 42% and 40%, respectively.1 New modalities and technologies have led to innovative treatments for patients with T3 and T4 prostate cancer. These include 3-dimensional conformal radiation therapy (3DCRT),2–5 adjuvant hormone and external beam radiation therapy (RT),6–8 particle beam therapy,9–11 and brachytherapy.12,13 Recently completed prospective trials are defining current treatment standards for these patients.

accurate identification of the target (tumor) in three dimensions. It accomplishes this by reducing day-to-day patient motion and positioning error by immobilizing the patient, reconstruction of the prostate (target) in three dimensions from a computerized tomography (CT) scan done with the patient in the treatment position, directing multiple beams at the target that are shaped to conform to the shape of the target from each beam’s-eye view (BEV), and using treatment planning computers with dosimetric algorithms which allow the calculation of dose in three dimensions. The dose to normal tissue is restricted while the dose to the target is maximized, thereby improving the therapeutic index by increasing tumor control while reducing normal tissue complications. The target is treated with a beam conforming to the target shape (the prostate in this case) as illustrated in Figures 31–1 and 31–2. Results of treatment with 3DCRT with long-term (> 5 years) PSA follow-up are becoming available and demonstrate superior bNED control rates over conventional radiation therapy. Because higher doses of radiation can be delivered to the prostate using 3DCRT (without substantially higher rates of normal tissue complications), bNED control rates are significantly improved. Data spanning 5 to 7 years from such institutions as Fox Chase Cancer Center, Memorial Sloan-Kettering Cancer Center, and the University of Michigan show increased rates of bNED control, especially for patients with pretreatment PSA levels >10 ng per mL which is the group that benefits most from higher radiation doses. For patients with pretreatment PSA levels between 10 and 20 ng per mL, the advantage of 3DCRT was evident with an almost 30% difference in bNED control at 5 years.2,3 The update from Fox Chase Cancer Center reporting 5-year results for the authors’ dose escalation study was recently reported. Two hundred thirty-two patients were treated with 3DCRT between June 1989 and October 1992. During this time, radiation dose to the prostate increased from 63 to 79 Gy. Median follow-up was 60 months and 24 patients had T3 disease. Dose responses were demonstrated for patients with pretreatment PSA levels between 10 and 20 ng per mL and >20 ng per mL (Table 31–1). Patients with pretreatment PSA levels between 10 and 20 ng per mL treated at 70 Gy showed

Conventional External Beam Radiation Multiple studies using serial post-treatment serum PSA levels to assess treatment outcome in patients with prostate cancer have demonstrated the biochemical disease-free survival (bNED control) for patients with stage T3 and T4 disease when conventional doses of radiation were used.14–17 Zietman et al. reported the outcome of 1044 men with stage T1-T4 prostate cancer treated at Massachusetts General Hospital. Five hundred and forty men had stage T3-T4 disease, and bNED control at 5 and 10 years was 32% and 10%, respectively.14 Similar results were reported by Horwitz et al. for 64 patients with T3 disease, who showed bNED control at 5 years of 26%.15 At MD Anderson Cancer Center, bNED failure was 47% at 5 years for 246 patients with T3 and T4 disease treated during the PSA era.16

Three-Dimensional Conformal External Beam Radiation Three-dimensional conformal radiation therapy is a new technology developed in the late 1980s that allows more 284

T3-T4NxM0: the Case for Radiotherapy / 285

bNED control of 35% versus 75% for patients treated at 76 Gy (p = .02). Patients with pretreatment PSA levels > 20 ng per mL showed bNED control of 10% at 70 Gy. At 76 Gy, bNED control was 32% for the same strata of patients (p = .02). Increasing palpation T stage was associated with decreased rates of cause-specific (p = .002) and distant metastases-free survival (p = .0004) on multivariate analysis. As radiation dose increases, toxicity to normal surrounding tissue becomes potentially more significant. With techniques learned from the above study, Radiation Therapy Oncology Group (RTOG) serious late morbidity (grade 3 and 4) was observed in < 2% of patients. Fukunaga-Johnson et al. reported the University of Michigan experience of treating patients with clinically localized prostate cancer with 3DCRT. Patients in this series were treated with RT alone. Dose in this study ranged from 49 to 80 Gy. No patient received hormones before, during, or after treatment unless biochemical or clinical failure was documented. The 5-year bNED control for the 98 patients with T3 and T4 disease was 23%. Pretreatment PSA, T stage, Gleason score, total dose, pelvic field treated, surgical status, and favorable grouping were all statistically significant on univariate analysis. Only pretreatment PSA, T stage, and Gleason score, however, remained independent predictors on multivariate analysis. The authors concluded that additional therapy was warranted for this unfavorable group of patients.4 The update of the Memorial Sloan-Kettering Cancer Center dose escalation trial was recently reported by Zelefsky et al.3 Of the 743 patients in the study, 195 had T3 disease. Ninety percent of all patients who received 75.6 or 81 Gy achieved a post-treatment PSA nadir ≤ 1 ng per mL, compared to 76% and 56% of patients who received 70.2 and 64.8 Gy, respectively. It is not possible to separate the results of T3 disease from the entire study population, but for patients with intermediate disease (defined as having one of T2c-T3 disease, pretreatment PSA level > 10 ng per mL, or Gleason score > 6), overall 5-year bNED control was 65%; it was 35% for high-risk patients (defined as having more than one of the above). Good-risk patients had 5-year bNED control rates of 85%. These differences were statistically significant (p = .001). Intermediate and poor prognosis patients treated with ≥ 75.6 Gy had improved bNED control rates. To evaluate treatment response, post-treatment nadir PSA levels were correlated with biopsy findings 2.5 years after treatment. Seven percent of all patients (good and poor grouping) receiving 81 Gy had a positive biopsy, versus 45% at 70.2 Gy and 57% after 64.8 Gy (p < .05). Using multivariate analysis, T stage was an independent predictor of achieving a PSA nadir ≤ 1 ng per mL.3 These data support the premise of a dose response in the treatment of prostate cancer and that more advanced disease requires more aggressive therapy. Roach et al. reported the University of California at San Francisco (UCSF) experience of treating 50 patients

FIGURE 31–1. Anterior treatment portal for 3DCRT (prostate: blue; seminal vesicles: green; bladder: yellow; treatment field edge: red).

with high-grade prostate cancer (Gleason score 8 to 10) using 3DCRT. Twenty-seven of these patients had T3 and T4 disease. The median dose delivered was 74 Gy (range 63 to 80 Gy). Patients treated with > 71 Gy had 4-year rates of bNED control of 83%, versus 0% for those patients treated with conventional doses of radiation (< 71 Gy). Ten patients received neoadjuvant hormones but there was no difference in bNED control when outcome was stratified by hormone use. Because of the small numbers of patients in this series, bNED control was not stratified by T stage.5 As with the data from Fox Chase, results from other institutions that treat patients with 3DCRT show similar reductions in morbidity at high doses compared to patients treated using conventional techniques. Sandler et al. reviewed the University of Michigan experience and analyzed 712 patients treated with 3DCRT for late gastrointestinal (GI) effects. The dose used in this study ranged from 59.5 to 80.4 Gy. Using the RTOG grading system, only 14 grade 3 or 4 complications were observed. Increasing dose was the only variable significantly predic-

FIGURE 31–2. Lateral treatment portal for 3DCRT (prostate: blue; seminal vesicles: green; bladder: yellow; treatment field edge: red).

286 / Advanced Therapy of Prostate Disease TABLE 31–1. Effectiveness of Dose Escalation with ThreeDimensional Conformal Radiation Therapy PSA Strata

@ 70 Gy

@ 76 Gy

% Improvement

10–20 ng/mL > 20 ng/mL

35% 10%

75% 32%

40% 22%

PSA = prostate-specific antigen. Adapted from Hanks GE, Hanlon AL, Schultheiss TE, et al. Dose escalation with 3D conformal treatment: five-year outcomes, treatment optimization, and future directions. Int J Radiat Oncol Biol Phys 1998;41:501–10.

tive of late GI effects on univariate and multivariate analysis (including treatment technique, boost technique, age, and T stage). The actuarial risk of a grade 3 or 4 complication at 5 years was 3%.18 Data from the phase I dose escalation study of 743 patients with clinically localized prostate cancer from Memorial Sloan-Kettering Cancer Center have shown 6% grade 2 and 1% chronic genitourinary (GU) toxicity. No grade 4 toxicities were noted. Forty percent of patients experienced acute grade 2 genitourinary toxicity. The risk of chronic grades 2 and 3 GI complications were 8% and 0.8%, respectively. One patient experienced chronic grade 4 GI complications.3

Adjuvant Hormones and External Beam Radiation The Radiation Therapy Oncology Group has reported results from two phase III randomized prospective studies, which investigated the role of hormonal therapy in conjunction with external beam RT for patients with unfavorable tumor characteristics. The RTOG 85-31 study randomized 977 patients (T1-2N1M0 or T3N0-1M0 or pT3N0-1M0, 945 analyzable). Arm I patients were given from 65 to 70 Gy external beam RT, with goserelin started during the last week of RT and continuing indefinitely. Arm II patients were given RT alone, with goserelin given at the time of relapse (Figure 31–3). Significant differences were observed between arms I and II in 5-year rates of local control (84% versus 71%, p < .0001), distant-metastases free survival (83% versus 70%, p < .001), and disease-free survival (60% versus 40%, p < .0001), favoring arm II, which included the adjuvant hormones. The definition of bNED survival was a post-treatment PSA level > 1.5 ng per mL. There was a statistically significant difference in bNED survival seen between arms I and II (53% versus 20%, p < .0001). No difference in overall survival was observed between the two groups; for patients with Gleason scores 8 to 10 whose pathology specimens were centrally reviewed, however, there was a significant difference in the overall survival rate (66% versus 55% for arms I and II, p = .03) (Figure 31–3). Results were not stratified by T stage although approximately 70% of patients in this study had T3 disease.6 The companion study, RTOG 86-10, examined the role of short-term total androgen blockade in 471 patients

(456 analyzable) with locally advanced prostate cancer (T2b-4N0-1M0 and T ≥ 25 cm2). In arm I, patients were randomized to receive goserelin and flutamide 2 months before and then during 65 to 70 Gy external beam RT. Patients in arm II were treated with RT alone. As with the previous RTOG study, a significant difference in local control was seen between arms I and II (54% versus 29%, p < .001) as well as an improvement in progression-free survival for arm I compared to arm II (36% versus 15%, p < .001). No difference was seen in overall survival. Results in this study were not stratified by T stage, although 70% of patients in both arms had T3 or T4 disease.7 The second trial using adjuvant hormones that has shown a survival advantage was reported by Bolla et al. The European Organization for Research and Treatment of Cancer (EORTC) trial randomized 415 patients between external beam RT alone (70 Gy) and external beam RT with goserelin starting the first day of treatment and continuing for 3 years post-treatment (see Figure 31–3). Although T1 and T2 patients with grade 3 disease were eligible and were included in this study, 91% of patients in both arms had T3 or T4 disease. The followup is still short at this time (median follow-up of 45 months, 27% of patients still using hormones posttreatment), but the authors report a statistically significant improvement in overall survival at 5 years for the arm receiving hormones over that receiving external beam RT alone (79% versus 67%, p < .001). Five-year disease free survival was 85% for the former group versus 48% for the latter at 5 years (p < .001) (Figure 31–4).8 In a Swedish phase III prospective trial from Umeå University, surgically staged patients (all patients underwent bilateral staging pelvic lymph node dissections) with T1-4N0-3M0 disease were randomized to radiotherapy alone or radiotherapy and orchiectomy. With a median follow-up of 9.3 years, disease-free survival was 39% in the RT alone arm versus 69% in the RT and hormone group. This difference was statistically significant (p = .005). Cause-specific survival was 56% for the RT alone group versus 73% for the RT and hormones group, respectively (p = .06). When results were stratified by lymph node status, no difference in survival was seen for the lymph node negative patients. The trial originally planned to accrue 500 patients; however, after an interim analysis revealed significant differences in survival, the study was halted prior to completion. Because of the few patients, outcome was not stratified by T stage, only by nodal status.19

Particle Beam Therapy The theoretic advantage of using other subatomic particles for treating locally advanced prostate cancer rests with the physical characteristics of the particles compared to photons. To this end, investigators have used neutrons and protons to treat prostate cancer. Neutrons have 1800 times the mass of an electron, with no charge. Their pri-

T3-T4NxM0: the Case for Radiotherapy / 287

mary interaction is with the atomic nucleus rather than with electrons, resulting in nuclear recoil and fragmentation. Protons are similar in size to neutrons but possess a charge. Their primary interaction is with electrons, and the majority of their energy is deposited in at the end of a linear track known as a Bragg peak. Although neutrons have been used to treat cancer since the 1930s, they were first used to treat prostate cancer in a large national randomized prospective trial beginning in the 1970s. Ninety-one patients with T4N0-N1M0 disease (78 analyzable) were randomized in RTOG 77-04 to photon alone versus mixed photon/neutron treatment. Clinical local control at 10 years was 58 versus 70% for the photon alone and mixed photon/neutron treatments, respectively (p = .03). Overall survival was also significantly different between the two arms. At 10 years, overall survival was 29% and 46% (p = .04), respectively, for the photon alone and mixed photon/neutron arms.9 Based on the results from this RTOG study, the Neutron Therapy Collaborative Working Group (NTCWG) was established to further test using neutrons in treating prostate cancer. One hundred seventy-eight patients (172 analyzable) with T3-T4N0-N1M0 disease or high-grade T2 disease were randomized between photon beam therapy alone (7000 to 7020 cGy) versus neutron beam therapy alone (2040 ncGy). Local regional control was 68% for the photon arm at 5 years, versus 89% for the neutron arm. This difference was statistically significant (p = .01). Causespecific survival at 5 years was 59% for the photon arm and 68% for the neutron arm. This difference was not statistically significant. Severe grade 3 and 4 late GI complications (11% versus 3%) were higher in the neutron arm.10 Several clinical trials have been conducted at Wayne State University using an isocentric cyclotron equipped with multileaf collimation. Forty-seven patients with locally advanced adenocarcinoma of the prostate defined as T3-T4N0-N1M0 and/or a Gleason score ≥ 8 were treated with 9 NGy (Neutron Gy) and 18 PhGy (Photon Gy) to the pelvis and an additional 15 NGy and 18 PhGy to the prostate. In a second protocol, 104 patients with earlier stage disease were treated. Patients in both groups showed bNED control of 92%, 85%, and 38% for patients with pretreatment PSA levels < 10 ng per mL, 10 to 20 ng per mL, or > 20 ng per mL, respectively. No acute grade 3 or 4 GI or GU toxicity was observed.20, 21 The proton is the other heavy particle that has been investigated in a randomized prospective trial for the treatment of prostate cancer. Massachusetts General Hospital conducted a prospective trial where 202 patients (189 analyzable) with T3-T4N0-N2M0 disease were randomized between photons only (5040 cGy to the pelvis with a 1680 cGy photon boost to the prostate) or mixed photon/proton treatment (5040 cGy to the pelvis with a 2520 Cobalt Gray Equivalent [CGE] proton boost to the prostate). At 8 years, a statistically significant dif-

ference in clinical local control was observed between the two arms. Local control was 84% versus 19% for the proton and photon-only arms, respectively (p = .0014). This statistically significant difference was seen in the highgrade (Gleason score 7 to 10) tumors only. No significant

Metastatic disease: patients with centrally reviewed Gleason score 8 to 10.

NED survival for patients with centrally reviewed Gleason score 8 to 10.

Survival for patients with centrally reviewed Gleason score 8 to 10.

FIGURE 31–3. Clinical outcome for patients with centrally reviewed Gleason score 8 to 10 treated in the RTOG 85-31 study.


differences in overall, disease-free, and cause-specific survival were observed between treatment arms.11 Although each series has shown a statistically significant improvement in local control using heavy particle therapy, this translated into a survival advantage in only one study. Results from these studies have been promising. Widespread adoption of this technology is uncertain, however, in these times of limited resources and facilities.

Brachytherapy Another treatment strategy seeking to deliver increased doses of radiation to the prostate while sparing normal surrounding tissue involves interstitial implantation of the prostate with either permanent or temporary radioactive sources. Permanent seed implants alone with either iodine 125 (I-125) or palladium 103 (Pd-103) are usually reserved for patients with good prognostic features, including pretreatment PSA levels < 10 ng per mL, clinical stage

FIGURE 31–4. Clinical outcome for patients treated in the EORTC study.

T1 or T2 disease, and Gleason scores ≤ 6. Multiple series have consistently shown bNED control rates between 80 to 95% for appropriately selected patients.22–24 Patients with poor risk factors, however, including T2c and T3 disease, pretreatment PSA levels > 10 ng per mL, and Gleason scores ≥ 7, have shown disappointing results with seed implantation alone. Several groups have examined the combination of external beam RT with interstitial brachytherapy, with either a permanent or temporary high-dose-rate (HDR) prostate implant. One series combined patients from Memorial SloanKettering Cancer Center and the University Community Hospital in Tampa, Florida, looking specifically at treatment results for patients with high-risk disease: ≥ T2b disease, pretreatment PSA levels > 15 ng per mL, Gleason scores ≥ 7, or elevated prostatic acid phosphatase. These patients were treated with combination external beam RT (41 Gy) followed by a palladium 103 (Pd-103) permanent implant (80 Gy). Thirty-six patients had T3 disease; bNED control for these patients at 3 years was approximately 70%.25 One novel strategy utilizing brachytherapy combines external beam RT with temporary HDR interstitial implants. Several groups have reported their experience with this technique; only two groups, however, have treated patients with locally advanced disease.12,13,26,27 Preliminary results from William Beaumont Hospital by Stromberg et al. have been reported on 76 patients with stages T2b through T3 disease who were treated between 1991 and 1995.12,28 Patients treated on this phase I dose escalation protocol received 46 Gy external beam RT to the pelvis along with three temporary HDR iridium 192 (Ir192) implant boosts of 5.5, 6.0, or 6.5 Gy each. The 3-year actuarial rate of bNED control for the entire group of patients was 83%. No difference in bNED control rates was seen when stratifying by pretreatment PSA, Gleason score, or T stage. Acute grade 3 urinary and gastrointestinal complications (2 cases of dysuria, 1 of urinary retention, and 1 of diarrhea) were seen in 5% (4 of 76) of patients. All other acute toxicities were grades 1 or 2. Chronic grade 3 urinary toxicity was seen in 8% (6 of 75) of patients (5 cases of urethral strictures and 1 of urinary incontinence). One asymptomatic patient developed a rectal ulcer, which resolved spontaneously. No patient experienced a grade 4 or 5 complication. Potency was maintained in 72% of men who were potent prior to the initiation of treatment with a minimum of 24 months follow-up.12 Kovács et al. reported the results of a prospective study from Christian-Albrechts University. One hundred seventy-one patients, including 59 with T3 disease, received 5000 cGy to the whole pelvis with two separate HDR boosts of 1500 cGy each to the prostate. Median followup in this study was 55 months. Fifteen percent of the T3 patients had clinical progression (local and distant failure) at 5 years. The mean time from biochemical to clin-

T3-T4NxM0: the Case for Radiotherapy / 289 TABLE 31–2. Evaluating the Evidence Quality of Evidence Class I Class II Class III

Well-designed randomized controlled clinical trial Well-designed clinical studies (case control or cohort) Expert opinion, nonrandomized or retrospective studies

ical failure was 21 months. Toxicity for the entire patient population was minimal—five patients developed grade 3 proctitis (one patient required a colostomy) and three patients developed dysuria/cystitis. As with other reported brachytherapy series, all nine patients who developed some degree of incontinence had previously received transurethral resection of the prostate (TURP). The authors concluded in this interim analysis that patients with locally advanced T3 disease treated with an HDR boost had minimal toxicity and improved rates of clinical control.13 Results utilizing HDR brachytherapy to boost the prostate have been promising, but at this time patient numbers treated in these series are small and follow-up is short. This procedure remains investigational.

dard of practice for patients with poor prognosis prostate cancers. Having a standard of practice, however, does not mean that alternate treatments are improper; it simply provides a benchmark against which innovative new treatments should be measured. Proponents of alternate treatment technologies or methods, whether surgery, protons, implants, or other combinations, are encouraged TABLE 31–4. RTOG 85-31 and EORTC Treatment Schema* RTOG 85-31 Schema S T R A T

Determining a standard of care for patients with T3 and T4 prostate cancer is a straightforward process. Three classes of information are used to determine clinical practice, each differing by their quality of evidence. Table 31–2 illustrates these three classes, where class I data represents the highest quality evidence-based data, obtained from randomized prospective trials. Class II data is intermediate in quality and comes from designed clinical trials, either case controlled or cohort, and class III data is of the poorest quality and comes from retrospective studies or expert opinions. The importance of evidence-based medicine is in its application to clinical practice. Table 31–3 illustrates that practice standards should be based on class I evidence while practice guidelines recommending patient management are based on class II evidence. Practice options are treatments available that represent the spectrum of care for a disease process where there is no conclusive evidence as to the best treatment. The prospective randomized clinical trials reported by the RTOG and EORTC and discussed in this chapter both show a survival benefit to combination therapy for T3 and T4 prostate cancers (Table 31–4). This is extremely important class I information that establishes the stan-

R

Radiation therapy† plus goserelin‡

A

vs.

N Nodal status None Below common iliacs Common iliacs Para-aortics

I

Radiation therapy† alone D O M

Acid phosphatase status Not elevated Elevated

F

Evidence-Based Medicine and Standards of Practice

Histologic differentiation 2–5 6–7 8–10

Y

I

Z Prior radical prostatectomy No E Yes

†Radiation

therapy: 44–46 Gy to the regional lymphatics, then 20–25 Gy boost to the prostate. ‡Goserelin: patients started during last week of radiotherapy and continued indefinitely or until sign of disease progression. Eligibility: • T1-2N1M0 • T3N0-1M0 • pT3N0-1M0

EORTC Schema S T

Clinical stage T1-2 T3-4

R

Extraperitoneal pelvic lymph node biopsy Negative Positive Irradiation technique 4 field boost 3 field boost Institution

N

Radiation therapy§ plus goserelin||

A vs.

R

A T I F Y

Radiation therapy§ alone D O M I Z E

§Radiation

therapy: 50 Gy to the regional lymphatics, then 20 Gy boost to the prostate. patients started during first day of radiotherapy and continued monthly for 3 years. 150 mg of cyproterone acetate (steroidal antiandrogen) was given orally for 1 month starting 1 week before the goserelin.

||Goserelin:

TABLE 31–3. Basis for Clinical Practice Standards

Generally accepted principles for patient management based on class I evidence or overwhelming class II evidence Guidelines Recommendations for patient management based on class II evidence or strong consensus of class III evidence Practice options Based on inconclusive or conflicting evidence

Eligibility: • T1-2N0-XM0 and grade 3 • T3-4N0-XM0 any grade *Randomized prospective trials of radiation therapy alone versus radiation therapy and adjuvant goserelin.


to conduct the necessary prospective trials designed to provide class I evidence of the advantage of a new technology over existing standards of care. In the authors’ opinion, any alternative to combined hormone and external beam radiation management of patients with T3 and T4 prostate cancer should be considered in the context of an Internal Review Board (IRB)-approved clinical trial, with the informed consent of patients.

References 1. Partin AW, Kattan MW, Subong ENP, et al. Combination of prostate-specific antigen, clinical stage, and Gleason score to predict pathological stage of localized prostate cancer: a multi-institutional update. JAMA 1997;277: 1445–51. 2. Hanks GE, Hanlon AL, Schultheiss TE, et al. Dose escalation with 3D conformal treatment: five-year outcomes, treatment optimization, and future directions. Int J Radiat Oncol Biol Phys 1998;41:501–10. 3. Zelefsky MJ, Leibel SA, Gaudin PB, et al. Dose escalation with three-dimensional conformal radiation therapy affects the outcome in prostate cancer. Int J Radiat Oncol Biol Phys 1998;41:491–500. 4. Fukunaga-Johnson N, Sandler HM, McLaughlin PW, et al. Results of 3D conformal radiotherapy in the treatment of localized prostate cancer. Int J Radiat Oncol Biol Phys 1997;38:311–7. 5. Roach M III, Meehan S, Kroll S, et al. Radiotherapy for high grade clinically localized adenocarcinoma of the prostate. J Urol 1996;156:1719–23. 6. Pilepich MV, Caplan R, Byhardt RW, et al. Phase III trial of androgen suppression using goserelin in unfavorableprognosis carcinoma of the prostate treated with definitive radiotherapy: report of RTOG Protocol 8531. J Clin Oncol 1997;15:1013–21. 7. Pilepich MV, Krall JM, Al-Sarraf M, et al. Androgen deprivation with radiation therapy compared with radiation therapy alone for locally advanced prostatic carcinoma: a randomized comparative trial of the Radiation Therapy Oncology Group. Urology 1995;45:616–23. 8. Bolla M, Gonzales D, Warde P, et al. Improved survival in patients with locally advanced prostate cancer treated with radiotherapy and goserelin. N Engl J Med 1997; 337:295–300. 9. Laramore GE, Krall JM, Thomas FJ, et al. Fast neutron radiotherapy for locally advanced prostate cancer. Final report of a Radiation Therapy Oncology Group randomized clinical trial. Am J Clin Oncol 1993;16:164–7. 10. Russell KJ, Caplan RJ, Laramore GE, et al. Photon versus fast neutron external beam radiotherapy in the treatment of locally advanced prostate cancer: results of a randomized prospective trial. Int J Radiat Oncol Biol Phys 1994;28:47–54. 11. Shipley WU, Verhey LJ, Munzenrider JE, et al. Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone. Int J Radiat Oncol Biol Phys 1995;32:3–12. 12. Stromberg JS, Martinez AA, Horwitz EM, et al. Conformal high dose rate iridium–192 boost brachytherapy in locally advanced prostate cancer: superior prostate specific antigen response compared to external beam treatment. Cancer J Sci Am 1997;3:346–52.

13. Kovács G, Wirth B, Bertermann H, et al. Prostate preservation by combined external beam and HDR brachytherapy at nodal negative prostate cancer patients—an intermediate analysis after 10 years’ experience. Int J Radiat Oncol Biol Phys 1996;36:198. 14. Zietman AL, Coen JJ, Dallow KC, Shipley WU. The treatment of prostate cancer by conventional radiation therapy: an analysis of long-term outcome. Int J Radiat Oncol Biol Phys 1995;32:287–92. 15. Horwitz EM, Vicini FA, Ziaja EL, et al. Assessing the variability of outcome for patients treated with localized prostate irradiation using different definitions of biochemical control. Int J Radiat Oncol Biol Phys 1996;36:565–71. 16. Zagars GK, Pollack A, von Eschenbach AC. Prostate cancer and radiation therapy—the message conveyed by serum prostate-specific antigen. Int J Radiat Oncol Biol Phys 1995;33:23–35. 17. Kaplan ID, Cox RS, Bagshaw MA. Prostate-specific antigen after external beam radiotherapy for prostatic cancer: follow-up. J Urol 1993;149:519–22. 18. Sandler HA, McLaughlin PW, TenHaken RK, et al. Threedimensional conformal radiotherapy for the treatment of prostate cancer: low risk of chronic rectal morbidity observed in a large series of patients. Int J Radiat Oncol Biol Phys 1995;33:797–801. 19. Granfors T, Modig H, Damber J-E, Tomic R. Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study. J Urol 1998;159:2030–4. 20. Forman JD, Duclos M, Sharma R, et al. Conformal mixed neutron and photon irradiation in localized and locally advanced prostate cancer: preliminary estimates of the therapeutic ratio. Int J Radiat Oncol Biol Phys 1996;35: 259–66. 21. Forman JD, Porter A. The experience with neutron irradiation in locally advanced adenocarcinoma of the prostate. Semin Urol Oncol 1997;15:239–43. 22. Ragde H, Blasko JC, Grimm PD, et al. Interstitial iodine125 radiation without adjuvant therapy in the treatment of clinically localized prostate carcinoma. Cancer 1997;80:442–53. 23. Wallner K, Roy J, Harrison L. Tumor control and morbidity following transperineal iodine 125 implantation for stage T1/T2 prostatic carcinoma. J Clin Oncol 1996;14: 449–53. 24. Beyer DC, Priestley JB. Biochemical disease-free survival following 125 I prostate implantation. Int J Radiat Oncol Biol Phys 1997;37:559–63. 25. Dattoli M, Wallner K, Sorace R, et al. 103Pd brachytherapy and external beam irradiation for clinically localized, high-risk prostatic carcinoma. Int J Radiat Oncol Biol Phys 1996;35:875–9. 26. Mate TP, Gottesman JE, Hatton J, et al. High dose-rate afterloading 192Iridium prostate brachytherapy: feasibility report. Int J Radiat Oncol Biol Phys 1998;41:525–33. 27. Borghede G, Hedelin H, Holmang S, et al. Combined treatment with temporary short-term high dose rate Iridium-192 brachytherapy and external beam radiotherapy for irradiation of localized prostate cancer. Radiother Oncol 1997;44:237–44. 28. Stromberg JS, Martinez AA, Gonzalez JA, et al. Ultrasound-guided high dose rate conformal brachytherapy boost in prostate cancer: treatment description and preliminary results of Phase I/II clinical trial. Int J Radiat Oncol Biol Phys 1995;33:161–71.

CHAPTER 32

CLINICAL-PATHOLOGIC T3NXM0 PROSTATE CANCER: THE CASE FOR SURGERY MARCOS V. TEFILLI, MD; DAVID P. WOOD JR, MD Recent statistics from the American Cancer Society demonstrate that the death rate from prostate cancer is declining despite the aging of the male population, possibly due to screening programs and early aggressive treatment.1 Radical prostatectomy and radiation therapy are the most common forms of definitive treatment used for clinically localized prostate cancer. Results of both curative therapies available for prostate cancer are extremely variable, with 3- to 5-year rates of biochemical control ranging from 20 to 92% for surgical patients and 10 to 90% for patients treated with radiotherapy, depending on Gleason score, pretreatment serum prostate-specific antigen (PSA) levels and clinicopathologic stage.2–4 Local recurrence after radical prostatectomy has been documented in 4 to 23% of patients with T2 disease and in as many as 43% of those with stage T3 prostate cancer.4–9 In this chapter, the authors review the literature and their own experience with the surgical treatment of clinicopathologic stages T3NxM0 prostate cancer.

in almost 15 years of radical prostatectomy in many institutions has shown that a significant proportion of patients with pathologic T3 prostate cancer can actually be cured by surgery as monotherapy.2,4,8–10 Positive Surgical Margins The absence of significant periprostatic tissue in the confines of the bony pelvis and the anatomic proximity to adjacent structures make surgical excision of additional uninvolved normal surrounding tissue difficult during radical prostatectomy. Surgical margins should be designated as negative if tumor is not present at the inked surgical margin and positive if tumor cells touch the ink at the margin.11 Cancer present at the inked surgical margin in a radical prostatectomy specimen implies that the tumor has not been completely resected. Stamey et al. described two categories of positive surgical margins: those associated with extraprostatic extension (EPE) and those caused by inadvertent surgical incision through the capsule into a

Surgical Management of pT3N0M0 Prostate Cancer

TABLE 32–1. Characteristics of Patients Undergoing Radical Prostatectomy* Patient Characteristic

Radical prostatectomy is an effective form of therapy for prostate cancer, especially when the tumor is organ confined at final pathologic analysis. Clinical staging of localized prostatic cancer is hampered by inaccuracy, leading to understaging in up to 60% of patients.2,4,5,7–9 Such pathologic stage T3 disease may include extraprostatic extension, positive surgical margins, or involvement of the seminal vesicle. Table 32–1 summarizes the clinicopathologic characteristics of patients who underwent radical prostatectomy as monotherapy for clinically localized prostate cancer at Wayne State University and the Barbara Ann Karmanos Cancer Institute–affiliated Harper Hospital between January 1991 to December 1995. In this series of 652 men, in whom clinical staging suggested organ-confined disease (cT-cT2), 47.8% had pathologically organ-confined disease, 31.7% had extraprostatic extension, and 20.5% had either seminal vesicle or lymph node involvement. Similarly, most series of radical prostatectomy reported in the literature contain a large number of specimens with tumor extending beyond the prostate.8,9 However, the experience acquired

Gleason Score 10 ng per mL (p = .009). There was no significant difference in biochemical recurrence between patients with organ-confined disease versus those with specimen-confined disease (p = .42). There was a statistically significant difference noted, however, between nonspecimen-confined disease versus organ-

confined and/or specimen-confined cancers (p = .03) (Figure 32–7). On multivariate analysis, only a preoperative PSA level ≤ 10 ng per mL (p = .02) and surgical margins status (p = .04) were significant predictors of disease-free survival. These findings suggest that early detection of prostate cancer in men with high Gleason score, especially in those with a preoperative PSA level ≤ 10 ng per mL, may have a favorable impact on survival. The study also showed the independent prognostic significance of surgical margin status on final pathologic specimen in patients with high Gleason score (8 to 10) cancers. In summary, better diseasefree survival rates can be obtained in patients with highgrade tumors if detected while still pathologically organ confined. When the anatomic barrier of the prostatic capsule is broken, the prognosis is worse although some patients may achieve prolonged disease-free survival if negative surgical margins are obtained, especially those patients with a serum PSA level ≤ 10 ng per mL.

FIGURE 32–5. Survival function estimates for organ-confined disease versus EPE alone (negative surgical margins) versus EPE with positive surgical margins in patients with Gleason score ≥ 8 prostate cancer (p = .003).


Although patients with positive surgical margins are more likely to experience recurrence, this finding does not mean that all of these patients will inevitably suffer a relapse following radical prostatectomy. There are three possibilities for the patient with respect to the biologic reality of a positive surgical margin: (1) residual viable tumor will result in future local and/or systemic disease; (2) residual tumor will not survive because it is within the zone of surgical tissue destruction or is destroyed by the ensuing inflammatory reaction; and (3) the tumor meets the pathologic resection margin but does not extend beyond it. Since some patients can be cured by radical prostatectomy despite the presence of positive margins, advocating adjuvant radiotherapy for this entire population would subject a significant percentage of patients to unnecessary treatment. The authors’ policy is to follow patients who have positive margins with serial PSA determinations and to offer salvage treatment after evidence of biochemical recurrence (PSA level > 0.4 ng per mL) before the disease is clinically apparent. This therapeutic window appears to be narrow (PSA level of 2 ng per mL or less at the time of salvage radiotherapy).15 Extraprostatic Extension Epstein et al. evaluated 196 radical prostatectomy specimens with pathologic stage T3 (excluding patients with SVI) with negative lymph nodes in order to evaluate the influence of EPE on progression following radical prostatectomy.16 Cases were stratified according to the extent of EPE, margin status, and Gleason score. The parameters were correlated with biochemical progression. Tumors extending out of the prostate into periprostatic soft tissue were considered EPE and subdivided into focal (< 2 or 3 neoplastic glands present exterior to the prostate) and extensive (established capsular penetration with > 2 or 3 glands beyond the prostatic capsule). The Gleason histologic grade had independent prognostic significance for

FIGURE 32–6. Kaplan-Meier curve for disease-free survival comparing Gleason score 6 or less, 7, and 8 or higher prostate cancer (p = .0001).

those men with EPE without SVI or lymph node involvement. Patients with EPE and Gleason score ≥ 7 tumors had significantly worse biochemical disease-free rates compared to patients with Gleason score ≤ 6 tumors. Focal EPE did not affect disease progression except in cases of high-grade tumors (Gleason score ≥ 7). Patients with extensive EPE had a higher risk of progression than those with focal EPE. Tumors with extensive EPE were stratified into three groups with statistically significant increasing risk of progression: (1) margins negative and low grade (6 or less); (2) margins positive or high grade (7 or more) but both features not present together; and (3) margins positive and high grade. These investigators also showed that patients with positive margins and focal capsular penetration are at low risk for progression. Ohori et al. analyzed 150 patients with EPE but without other advanced pathologic features such as SVI or lymph node metastases.13 These patients had a relatively favorable prognosis. At 5 years, 78% (± 10%) remained free of disease progression. Thirty-three (22%) of these patients, however, had positive surgical margins, and the prognosis was significantly worse than that for patients with EPE and negative margins, especially among those with Gleason score 7 or less. Therefore, patients with EPE whose cancers are not completely excised are significantly more likely to experience recurrence disease than those whose cancers are completely excised. Extensive EPE has been frequently reported in men with clinical stage T2 prostate cancer, mostly in the posterolateral region of the neurovascular bundles.17–21 The Johns Hopkins group reported on 107 patients with clinically localized prostate cancer in whom pathologic examination revealed extensive EPE in the region of the neurovascular bundles along the posterolateral border of the prostate.18,19 All patients had negative lymph nodes and the mean follow-up was 48 months. Wide excision of the neurovascular bundle(s) resulted in negative surgical margins in 58% of patients, compared to 45% of patients in whom the neurovascular bundles were left intact (p = .03). The probability of having an undetectable PSA level at 5 years was 47% in patients with negative margins versus 6% for those with positive surgical margins (p = .001). The Cox proportional hazards model showed that surgical margin status, resection of neurovascular bundle(s), and Gleason grade were independent predictors of disease recurrence. These studies strongly suggest that some patients with extensive EPE can be rendered free of disease with wide excision of the neurovascular bundle(s), and that disease-free survival for patients with extensive EPE and negative surgical margins is sustained on a longterm basis. The beneficial effect of a negative surgical margin in patients with extensive EPE was also noted by the authors and others.10,21 Because the perineural space penetration commonly occurs on the side of the nodule

Clinical-Pathologic T3NxM0 Prostate Cancer: the Case for Surgery / 295

in clinical stage T2 disease and surgical margin status does have impact on disease-free survival, nerve sparing prostatectomy should not be performed on the side of a palpable induration.10,19–21 Seminal Vesicle Invasion Seminal vesicle invasion has been associated with poor outcome following local treatment for prostate cancer. In a recent study from Wayne State University, the authors reviewed their experience with SVI following radical prostatectomy for clinically localized prostate cancer.22 One hundred fifty-nine patients with SVI were identified out of 910 patients on whom radical prostatectomies had been performed between January 1991 and December 1995. The authors excluded 24 patients undergoing neoadjuvant/adjuvant hormonal or radiation therapy from the final analysis, 1 patient with clinical stage T3 disease, and 41 patients with positive lymph nodes, leaving a final cohort of 93 patients. The presence of positive surgical margins (p = .001) and a Gleason score of 7 or higher from either the preoperative biopsies (p = .03) or from the radical prostatectomy specimen (p = .01) were significant predictors of disease-free survival. The authors noted that patients with preoperative PSA levels ≤ 10 ng per mL had a better disease-free survival rate (p = .07). On multivariate analysis (after adjusting for Gleason score and PSA), positive surgical margins remained a statistically significant predictor of disease progression (p = .002). For all cases with positive surgical margins, the site of involvement was subclassified into two groups. The first included those patients who had a positive margin at the location where histologic proof of spread outside the gland was absent. The second category included those cases with a positive margin at a site where the EPE was also present. There was a significant difference in the biochemical recurrence rate noted between patients with positive margins at the site of EPE compared to patients with negative

FIGURE 32–7. Kaplan-Meier curve for disease-free survival comparing patients with high Gleason score and organ-confined disease versus specimen-confined and nonspecimen-confined cancers (p = .03).

TABLE 32–2. Correlation Between Pathologic Findings and Disease-Free Survival*

Overall Organ-confined Nonorgan-confined EPE only Positive margins only EPE plus positive margins Seminal vesicle invasion Positive lymph nodes Specimen-confined† Nonspecimen-confined PSA ≤10 ng/mL PSA ≥10 ng/mL

Number of Patients

% of DFS

Univariate Multivariate p Value p Value

84 8 76 3 5

33.3 62.5 30.2 100 60

–

–

0.11 – –

– – –

18

22.2

–

–

29 21 20 64 32 52

24.1 28.6 55 26.6 56.2 19.2

– –

– –

0.009

0.04

0.009

0.02

EPE = extraprostatic extension; DFS = disease-free survival; PSA = prostate-specific antigen. *In patients with high Gleason score (8 to 10) prostate cancer. †Specimen-confined disease defined as a radical prostatectomy specimen with negative margins and negative lymph nodes.

margins or those with a positive margin remote from the site of EPE (p = .0001) (Figure 32–8). These findings have several clinical implications. The authors’ data show that there is a subgroup of patients with SVI, negative lymph nodes, and negative surgical margins who have a 65% chance of being biochemically free of disease after radical prostatectomy at a mean follow-up of 3.5 years. Before postoperative adjuvant treatment is given, consideration of the surgical margin status is important to select appropriate high-risk patients. Also, patients showing a preoperative serum PSA level ≥ 10 ng per mL, a biopsy Gleason score ≥ 7, or a positive seminal vesicle biopsy should be counseled regarding their high risk of disease relapse when treated with radical prostatectomy.

FIGURE 32–8. Progression-free survival function estimates versus time for negative margins versus positive margins at site of SVI or EPE (p = .0001) versus positive margins at other sites (p = .47).


Surgical Management of cT3NxM0 Prostate Cancer Clinical stage T3 disease denotes a prostate cancer that extends beyond the confines of the prostate capsule. Classically, it has been estimated that 12 to 28% of patients with newly diagnosed prostate carcinoma have clinically classified T3 disease.23–29 Several goals are pursued in treating patients with locally advanced prostate cancer. These include: improving local control to help prevent bladder outlet obstruction, pelvic pain, hematuria, and ureteral obstruction; reducing distant metastases that might originate from persistent local disease; increasing the interval to disease progression; and increasing survival. Treatment for patients with clinical stage T3 disease remains controversial. Therapeutic options in these cases include hormonal therapy, transurethral resection, or simple enucleation with or without hormonal manipulation, external beam radiotherapy (EBRT) with or without neoadjuvant/adjuvant hormones, and primary radical prostatectomy with or without neoadjuvant/adjuvant therapy. The majority of patients with clinical stage T3 prostate cancer have been treated with EBRT with or without neoadjuvant/adjuvant hormones.30–32 Overall and cancer-specific survival rates at a follow-up of 15 years are 20% and 33%, respectively.25,30 Also, postradiation biopsy results in patients with clinical stage T3 tumors treated with EBRT are positive in about 74% of patients, of whom 72% had cancer progression on subsequent follow-up.30 Local tumor progression following radiation failure is a source of significant morbidity and has an adverse impact on the patient’s quality of life.30–32 Patients with clinical stage T3 prostate cancer who are treated with hormonal therapy or orchiectomy can also anticipate a poor survival rate. Within 2 years, 35% of these patients show systemic progression and 22% will die of metastatic disease.33 Patients with clinical stage T3 cancers treated with transurethral resection or simple enucleation often sustain significant morbidity from symptomatic local recurrence from the in situ primary tumor. Transurethral resection or simple enucleation of the prostate combined with androgen ablation may best be reserved for elderly or unwell patients to relieve voiding symptoms. Surgery Alone Radical prostatectomy for patients with locally advanced prostate cancer can be performed with acceptable morbidity, but this has not been a widely accepted treatment.24,26–29 Van den Ouden et al. reviewed the outcome of 100 patients who had radical prostatectomy as monotherapy for stage T3 prostate cancer.25 In this series, no neoadjuvant or adjuvant treatment was given before the patients showed evidence of postoperative clinical progression. The overall incidence of positive lymph nodes was 45%. Thirty-nine patients were found to have

lymph node metastases on frozen section and did not undergo a radical prostatectomy. Two additional patients were judged to have T4 disease during the surgery and radical prostatectomy was not performed. The final cohort of 59 patients underwent radical prostatectomy and was included in the final analysis. With a mean followup of 3.7 years, 36% of patients had clinical recurrence and an additional 27% had biochemical evidence of progression. Twenty-two of 59 patients (37.3%) have shown no evidence of biochemical disease. In the same article, the investigators identified patients with a high risk of having disease recurrence at 3.7 years mean follow-up. These included patients with clinical T3 disease who had grade 3 tumors (Mostofi system), a PSA level > 20 ng per mL, a prostatic acid phosphatase (PAP) level greater than 2 µg per L, or positive lymph nodes. Cystoprostatectomy or pelvic exenteration for clinical stage T3-T4 prostate cancer is rarely curative. McCullough and Leadbetter reported on 19 patients with stage T3-T4 prostate cancer who were treated with pelvic exenteration over a 25-year period.27 Two patients underwent pelvic exenteration and 17 had cystoprostatectomy. Ninety percent of patients also received hormonal therapy. Of 16 survivors 8 died of prostate cancer in the postoperative period, 2 died of other causes, and only 2 patients were free of clinical recurrence at follow-ups of 6.5 and 10 years (PSA was not available at that time). In a recent review from Wayne State University regarding salvage surgery for radiorecurrent prostate cancer, the authors found that when extensive local recurrence necessitates a salvage cystoprostatectomy versus a radical prostatectomy, a lower biochemical disease-free survival should be anticipated.29 In the authors’ series, only 10% of salvage cystoprostatectomy specimens had organ-confined disease and only 30% of patients were free of biochemical recurrence with a mean 3.5 year followup. Therefore, in patients with bulky cT3 or cT4 disease, extensive pelvic exenterations, although technically feasible, should not be advocated as an effective curative treatment. Gerber et al. reported on 345 clinical T3 patients who were to be treated with radical prostatectomy.34 All patients were included in the study, irrespective of lymph node status or whether radical prostatectomy was in fact performed. There was no indication whether adjuvant treatment was given. The mean follow-up was 39 months. Organ-confined disease was present in 8% of patients and 29% had lymph node metastases. The projected 10-year metastases-free survival was 32% and disease-specific survival was 57%. Lerner et al. reported on 812 patients with clinical T3 disease who underwent radical prostatectomy between 1966 and 1992.26 Surgical mortality was 0.4%, rectal injury rate was 1.8%, and the transfusion rate was 50%. Seventeen percent of patients had pathologically organ-confined disease, 50% were margin positive, and 35% had positive lymph nodes. The median follow-up was 3.5 years and 60% of patients received adjuvant treatment

Clinical-Pathologic T3NxM0 Prostate Cancer: the Case for Surgery / 297

(androgen ablation with or without EBRT) within 3 months after surgery; an unreported percentage of patients received salvage EBRT. The investigators analyzed 270 patients who were followed for at least 5 years. During that interval, 10% died of prostate cancer, 11% developed local recurrence, and 42% had biochemical evidence of disease. The disease-free survival rate based on PSA determinations for patients with clinical T3 prostate cancer has been reported to range from 10 to 40% at an average follow-up of 3.5 to 5 years. Complications encountered during and after surgery are comparable in stage T3 and T2 disease.25 Patients with clinical stage T3 prostate cancer usually do poorly on a long-term basis when treated with surgery as monotherapy. Radical Prostatectomy with Adjuvant Radiotherapy Epstein et al. have reported a 34% 5-year actuarial local failure rate proven by biopsy in patients who had extensive positive surgical margins at the time of pathologic sectioning of the radical prostatectomy (excluding patients with SVI or lymph node metastases).35 Persistent disease following radical prostatectomy is not merely a marker for subsequent appearance of distant disease but may indeed be the cause. For this reason, and because local growth of persistent disease sometimes causes morbidity, adjuvant EBRT has been advocated in high-risk patients following radical prostatectomy. “Cytoreductive” surgery followed by adjuvant radiation could also offer a theoretic therapeutic advantage in treating patients with locally extensive prostatic carcinoma who have no evidence of distant metastasis. Patients at high risk for systemic disease are unlikely to benefit from adjuvant radiotherapy in terms of survival or biochemical disease-free survival. Many authors have explored methods of distinguishing local from distal recurrence to define the patients who may benefit from adjuvant radiation therapy. Partin et al. evaluated the time interval to reach a PSA level of 0.5 ng per mL following radical prostatectomy, in an attempt to distinguish local recurrence from distant metastasis.36 They found that 81% of all biopsy-proven local failures with concurrent negative bone scans occurred in patients whose postoperative PSA level reached 0.5 ng per mL more than 12 months postoperatively. Conversely, 65% of all patients with a bone scan showing distant failure had a PSA level increase to 0.5 ng per mL within 12 months postoperatively. These results suggest that early (less than 12 months) postoperative PSA failure is associated with distant failure as a site of first failure whereas delayed PSA failure (more than 12 months) indicates patients most likely to have a local failure as a site of first failure. D’Amico et al. have defined the set of clinical patient factors and pathologic tumor characteristics that are independent predictors of early and delayed postoperative PSA failure in patients with positive margins.37 Patients with these

clinical or pathologic characteristics and biochemical failure within the first postoperative year would be expected to correlate with distant failure. Conversely, patients without these clinical/pathologic factors would be the most likely to develop a local recurrence as the site of first failure. The study suggests that patients with positive surgical margins, a prostatectomy Gleason score of 6 or less, a preoperative PSA level < 20 ng per mL, absence of seminal vesicle invasion, and negative lymph nodes may benefit from adjuvant radiotherapy following radical prostatectomy. Most of the reported series of surgery with adjuvant radiation in patients with clinical-pathologic stage T3 prostate cancer have showed biochemical control between 57% and 75% with follow-up ranging from 60 to 120 months.38–42 To determine the role of adjuvant radiotherapy following radical prostatectomy in a group of patients with T3-T4 disease, Anscher et al. followed 159 patients for a median period of 10 years who had undergone radical prostatectomy.38 Forty-six received adjuvant radiotherapy and 112 did not. Patients were analyzed with respect to survival, disease-free survival, local control, and freedom from distant metastases. The actuarial survival rate at 10 and 15 years was 62% and 52%, respectively, for the adjuvant radiotherapy group, compared to 52% and 37% for the radical prostatectomy-only group (p = .18). The disease-free survival rate for the radiotherapy group was 55% and 48% at 10 and 15 years, respectively, compared to 37% and 33% for the radical prostatectomyonly group (p = .16). Similarly, there was no difference in the rate of distant metastases between the two groups. In contrast, the local relapse rate was significantly reduced by the addition of adjuvant radiotherapy. The actuarial local control rate at 10 and 15 years was 92% and 82%, respectively, for the radiotherapy group versus 60% and 53% for the radical prostatectomy-only group (p = .002). To summarize, postoperative radiotherapy significantly improves local control compared to radical prostatectomy alone for stage T3-T4 prostate cancer but has no impact on distant metastases and disease-free survival rates. These data are consistent with the conclusion that many patients with clinicopathologic stage T3-T4 prostate cancer have occult metastases at presentation and will not be cured by local therapies alone. Although radiotherapy following radical prostatectomy is well tolerated and results in excellent local disease control, new treatment strategies need to be developed for patients with clinical T3 tumors, especially those with high Gleason scores (8 to 10), those with high preoperative PSA levels (>20 ng per mL), those with seminal vesicle invasion, and those with lymph node metastases. Neoadjuvant Androgen Suppression Locally advanced adenocarcinoma of the prostate has been difficult to control by either EBRT or radical prostatectomy. The combination of local therapies with hormonal


manipulation is an innovative strategy to combat this form of the disease. The combination of EBRT and total androgen suppression has shown potential for improving outcomes in patients with clinical stage T3 prostate cancer.32,43,44 Both radiation and androgen ablation induce apoptosis through different mechanisms, and a synergistic interaction has been reported between the two modalities in vitro.43 It appears that irradiation combined with hormones is a superior treatment to radiotherapy alone.44 The results of trials comparing surgery alone to combinations of surgery and hormones have been less encouraging.44 In a multi-institutional study using primarily a gonadotropin-releasing hormone analogue agonist plus flutamide preoperatively for 3 months, 47% of the 30 patients in the study were clinically downsized to T2 but only 10% actually had organ-confined disease at the time of surgery.28 Morgan and Myers showed clinical tumor downsizing in 81% of patients treated with megestrol acetate plus estradiol with or without cyclophosphamide for 3 months prior to radical prostatectomy.45 Only 11% proved to have pathologic T2 disease; the investigators concluded that there was little evidence of pathologic downstaging by preoperative hormonal therapy in patients with clinical T3 prostate cancer. In reality, the benefit of neoadjuvant hormonal treatment in patients with clinical T3 tumors remains unsure. No decrease in the positive margin rate in patients with clinical T3 cancers has been shown.46 Radical Prostatectomy with Adjuvant Hormonal Therapy Cheng et al. presented a retrospective analysis of 1035 patients with pathologic stage C prostate cancer who had been treated with radical prostatectomy.47 Of these patients, 661 had received no adjuvant treatment, 131 had adjuvant radiotherapy only, and 103 had postoperative adjuvant orchiectomy only. Orchiectomy and radiation appeared to demonstrate similar efficacy in controlling local recurrence: 5-year local recurrence-free survival was 96% for both adjuvant treatments, compared to 84% for those patients without adjuvant treatment. The authors concluded that adjuvant treatment significantly decreased local, systemic, and overall progression but did not improve cause-specific survival. To summarize, radical prostatectomy as monotherapy for treating clinical stage T3 prostate cancer is generally inadequate, especially for patients with high-grade tumors, a preoperative PSA level higher than 20 ng per mL, those with positive lymph nodes, and those with seminal vesicle invasion. Outcomes may be improved when surgery is used with adjuvant hormone and/or EBRT but the long-term disease-free survival rate is lower than in patients with organ-confined disease. Neoadjuvant hormones or more radical excision have not improved recurrence rates. There is a strong role for surgery in local palliation of disease to prevent bladder outlet obstruction, ureteral obstruction, and

other local complications. An investigation into a multimodal approach, with neoadjuvant androgen blockade, radical prostatectomy, and adjuvant EBRT to improve diseasefree survival, should be conducted.

Conclusion An often repeated truism in urology is that once prostate cancer has spread outside the gland, the window of opportunity to cure the patient is lost. This supports the theory that extracapsular extension and even positive margins are merely surrogate markers for the presence of metastatic disease. However, if having positive margins adversely impacts on prognosis, it should be avoided. This position seems logical and is supported by this chapter. While it may be true that patients with clinically advanced disease are not ideal candidates for radical prostatectomy, men with clinically localized prostate cancer who have pathologically nonorgan-confined disease have a relatively good chance of cure, depending on Gleason score, margin status, preoperative PSA level, and degree of EPE. Nerve sparing surgery can be performed safely but the criteria must be stringently followed to minimize the risk of having positive surgical margins. It also seems doubtful that an extremely radical procedure, such as cystoprostatectomy, would further improve disease survival as patients with such extensive disease almost always have disseminated disease as well. The practice of monotherapy for patients with locally advanced prostate cancer should be abandoned. These patients probably benefit more from a multimodality therapy.

References 1. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics. CA Cancer J Clin 1997;47:5–27. 2. Vicini FA, Horwitz EM, Gonzalez J, Martinez AA. Treatment options for localized prostate cancer based on pretreatment serum prostate specific antigen levels. J Urol 1997;158:319–25. 3. Lee WR, Hanks GE, Schultheiss TE, et al. Localized prostate cancer treated by external beam radiotherapy alone: serum PSA-driven outcome analysis. J Clin Oncol 1995;13:464–9. 4. Partin AW, Pound CR, Clemens JQ, et al. Serum PSA after anatomic radical prostatectomy. The Johns Hopkins experience after 10 years. Urol Clin North Am 1993;20: 713–25. 5. Foster LS, Jajodia P, Fournier G, et al. The value of prostatespecific antigen and transrectal ultrasound-guided biopsy in detecting prostatic fossa recurrence following radical prostatectomy. J Urol 1993;149:1024–8. 6. American Joint Committee on Cancer. Cancer Staging Manual. Philadelphia: Lippincott Raven; 1977. p. 219–23. 7. Epstein JI, Pound CR, Partin AW, Walsh PC. Disease progression following radical prostatectomy in men with Gleason score 7 tumor. J Urol 1998;160:97–101. 8. Bostwick DG, Myers RP, Oesterling JE. Staging of prostate cancer. Semin Surg Oncol 1994;10:60–72. 9. Paulson DF. Impact of radical prostatectomy in the management of clinically localized prostate cancer. J Urol 1994;152:1826–30.

Clinical-Pathologic T3NxM0 Prostate Cancer: the Case for Surgery / 299 10. Tiguert R, Gheiler EL, Tefilli MV, et al. The role of radical prostatectomy in patients with high-grade prostate cancer [abstract 228]. J Urol 1998;Suppl 159:61. 11. Sakr WA, Wheeler TM, Blute M, et al. Staging and reporting of prostate cancer. Sampling of the radical prostatectomy specimen. Cancer 1996;78:366–8. 12. Stamey TA, Villers AA, McNeal JE, et al. Positive surgical margins at radical prostatectomy: importance of the apical dissection. J Urol 1990;143:1166–9. 13. Ohori M, Wheeler TM, Kattan MW, et al. Prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol 1955;154:1818–24. 14. Fesseha T, Sakr W, Grignon D, et al. Prognostic implications of positive apical margins in radical prostatectomy specimens. J Urol 1997;158:2176–9. 15. Forman JD, Meetze K, Pontes JE, et al. Therapeutic irradiation for patients with an elevated postprostatectomy prostate-specific antigen level. J Urol 1997;158:1436–9. 16. Epstein JI, Carmichael MJ, Pizov F, Walsh PC. Influence of capsular penetration on progression following radical prostatectomy: a study of 196 cases with long-term follow-up. J Urol 1993;150:135–41. 17. Catalona WJ, Bigg SW. Nerve-sparing radical prostatectomy: evaluation of results after 250 patients. J Urol 1990;143:538–43. 18. Partin AW, Borland RN, Epstein JI, Brendler CB. Influence of wide excision of the neurovascular bundle(s) on prognosis in men with clinically localized prostate cancer with established capsular penetration. J Urol 1993; 150:142–6. 19. Smith RC, Partin AW, Epstein JI, Brendler CB. Extended follow up of the influence of wide excision of the neurovascular bundle(s) on prognosis in men with clinically localized prostate cancer and extensive capsular penetration. J Urol 1996;156:454–8. 20. D’Amico AV, Whittington R, Malkowicz SB, et al. A multivariate analysis of clinical and pathological factors that predict for prostate-specific antigen failure after radical prostatectomy for prostate cancer. J Urol 1995;154:131–8. 21. Villers A, McNeal JE, Redwine EA, et al. The role of perineural space invasion in the local spread of prostatic adenocarcinoma. J Urol 1989;142:763–8. 22. Tefilli MV, Gheiler EL, Tiguert R, et al. Prognostic indicators in patients with seminal vesicle involvement following radical prostatectomy for clinically localized prostate cancer. J Urol 1998. [In press] 23. Stamey TA, McNeal JE. Adenocarcinoma of the prostate. In: Walsh PC, Retik AB, Stamey TA, Vaughn ED, editors. Campbell’s urology. 6th ed. Philadelphia: WB Saunders; 1992. p. 1159–221. 24. Petros JA, Catalona WJ. Lower incidence of unsuspected lymph node metastases in 521 consecutive patients with clinically localized prostate cancer. J Urol 1992; 147:1574–85. 25. Van den Ouden D, Davidson PJT, Hop W, et al. Radical prostatectomy as a monotherapy for locally advanced (stage T3) prostate cancer. J Urol 1994;151:646–51. 26. Lerner SE, Blute ML, Zincke H. Extended experience with radical prostatectomy for clinical stage T3 prostate cancer: outcome and contemporary morbidity. J Urol 1995;154:1447–52. 27. McCullough DK, Leadbetter WF. Radical pelvic surgery for locally extensive carcinoma of the prostate. J Urol 1972;108:939–43. 28. Narayan P, Lowe BA, Carroll PR, Thompson IM. Neoadjuvant hormonal therapy and radical prostatectomy for clinical stage C carcinoma of the prostate. Br J Urol 1994;73:544–8.

29. Gheiler EL, Tefilli MV, Tiguert R, et al. Predictors for maximal outcome in patients undergoing salvage surgery for radiorecurrent prostate cancer. Urology 1998;51:789–95. 30. Bagshaw MA, Cox RS, Ray GR. Status of radiation treatment of prostate cancer at Stanford University. Monogr Natl Cancer Inst 1988;7:47. 31. Zagars GK, von Eschenbach AC, Johnson DE, Oswald MJ. Stage C adenocarcinoma of the prostate. An analysis of 551 patients treated with external beam radiation. Cancer 1987;60:1489–99. 32. Roach M. Neoadjuvant total androgen suppression and radiotherapy in the management of locally advanced prostate cancer. Semin Urol Oncol 1996;14:32–7. 33. De Vere White R, Paulson DF, Glenn JF. The clinical spectrum of prostate cancer. J Urol 1977;117:323–6. 34. Gerber GS, Thisted RA, Chodak GW, et al. Results of radical prostatectomy in men with locally advanced (clinical stage T3) prostate cancer: multi-institutional analysis [abstract 1194]. J Urol 1996;155:609A. 35. Epstein JI, Pizov G, Walsh PC. Correlation of pathologic findings with progression after radical retropubic prostatectomy. Cancer 1993;71:3582–93. 36. Partin AW, Pearson JD, Landis PK, Walsh PC. Evaluation of serum prostate-specific velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology 1994;43:649–59. 37. D’Amico AV, Whittington R, Malkowicz SB, et al. An analysis of the time course of postoperative prostate-specific antigen failure in patients with positive surgical margins: implications on the use of adjuvant therapy. Urology 1996;47:538–47. 38. Anscher MS, Robertson CN, Prosnitz R. Adjuvant radiotherapy for pathologic stage T3/4 adenocarcinoma of the prostate: ten-year update. Int J Radiat Oncol Biol Phys 1995;33:37–43. 39. Bahnson RR, Garnett JE, Grayhack JT. Adjuvant radiation therapy in stages C and D1 prostatic adenocarcinoma: preliminary results. Urology 1986;27:403–6. 40. Petrovich Z, Lieskovsky G, Freeman J, et al. Surgery with adjuvant irradiation in patients with pathologic stage C adenocarcinoma of the prostate. Cancer 1995;33:37–43. 41. Schild SE, Wong WW, Grado GL, et al. The result of radical retropubic prostatectomy and adjuvant therapy for pathologic stage C prostate cancer. Int J Oncol Biol Phys 1996;34:535–41. 42. Petrovich Z, Lieskovsky G, Langholz B, et al. Radical prostatectomy and postoperative irradiation in patients with pathological stage C (T3) carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1998;40:139–47. 43. Roach M. Neoadjuvant total androgen suppression and radiotherapy in the management of locally advanced prostate cancer. Semin Urol Oncol 1996;14:32–7. 44. Eulau SM, Corn BW. Combination of hormones and local therapies in locally advanced prostate cancer. Oncology 1996;10:1193–202. 45. Morgan WR, Myers RP. Endocrine therapy prior to radical retropubic prostatectomy for clinical stage C prostate cancer: pathologic and biochemical relapse [abstract 414]. J Urol 1991;145:316A. 46. Witjes WPJ, Oosterhof GON, Schaafsma HE, Debruyne FMJ. Current status of neoadjuvant therapy in localized prostate cancer. Prostate 1995;27:297–303. 47. Cheng WS, Frydenberg M, Bergstralh EJ, et al. Radical prostatectomy for pathologic stage C prostate cancer: influence of pathologic variables and adjuvant treatment on disease outcome. Urology 1993;43:283–91.

CHAPTER 33

NODE-POSITIVE PROSTATE CANCER: THE CASE FOR OBSERVATION DANIEL J. CULKIN, MD; ANDREW C. ROBERTS, BS, MD There has been much progress made in the diagnosis and staging of prostate cancer in recent years. The advent of biochemical techniques (prostate-specific antigen [PSA] testing, reverse-transcriptase polymerase chain reaction) and imaging technologies (computerized tomography, radioisotape scans, magnetic resonance imaging) have greatly facilitated the diagnosis of TxN+ adenocarcinoma of the prostate. Surgical, radiotherapeutic, and hormonal treatments, either as monotherapy or in combination, have likewise progressed. The therapeutic dilemma in treating node-positive prostate cancer is compounded by a lack of prospective randomized trials pitting control populations against monotherapy, combinations of therapies, and observation or deferred treatment. This chapter summarizes the available treatments for node-positive prostate cancer and compares the results of monotherapy, combinations of therapies, and deferred treatment. The case for observation of node-positive prostate cancer (with or without deferred treatment) will then be made. The value of pelvic lymph node dissection in the face of node positive disease, the survival benefit associated with the various therapies, and the expected outcome associated with observation will be addressed. The authors will attempt to identify or stratify TxN+ patients so that a subset of patients benefitting from initial (early) intervention may be selected. The incidence of prostate cancer and the recent trend in stage migration of this disease are discussed elsewhere in this text. It is clear, however, that the incidence of TxN+ prostate cancer has decreased with the advent of biochemical tests and digital rectal examination coupled with ultrasonic techniques.1 Once the diagnosis of prostate cancer is made, then clinical staging becomes important in directing therapy and in establishing the patient’s prognosis regarding life expectancy and disease-free survival. The natural history of prostate cancer is less than clear. The median age at diagnosis has been stated to be 72 years. The average life expectancy from the age of 75 years in the United States remains approximately 11 years.2 These two figures should be kept in mind when planning therapy for patients with adenocarcinoma of the prostate, particularly when considering observation as a treatment for certain patients with node-positive prostate cancer.

Patients with TxN+ prostate cancer discovered incidentally at the time of surgical intervention as well as patients diagnosed through percutaneous biopsy are included in this group identified as candidates for observation as therapy (deferred treatment).

Treatment Options for TxN+ Prostate Cancer The treatment options that will be discussed for this subset of patients include surgical extirpation, radiation therapy, endocrine therapy, and observation (deferred treatment). The intricacies and execution of these types of treatment will be discussed elsewhere in the book but the expected outcome variables, including survival and quality-of-life issues, will be addressed here. Outcome variables in treating prostate cancer have traditionally included local progression (bladder outlet obstruction, ureteral obstruction, pathologic bone fracture, impotence, and incontinence), biochemical recurrence or progression, development of distant metastasis, and disease-free survival. More recently, the issue of quality of life has surfaced as an outcome measure and is being incorporated into research reports. The available data for and against each treatment option are examined below. Surgical Extirpation Surgery as a treatment for nonlocalized adenocarcinoma of the prostate is not considered effective. However, since a majority of patients are categorized as node positive postoperatively (historically), there are numerous reports of surgical intervention in this group of patients. The reported survival rate of stage D1 patients treated with surgery as monotherapy is generally below 50% at five years.3 There have been, however, reports of a small number of patients with low volume nodal metastasis with improved survival following surgery.4 Several of these studies have also employed adjuvant hormonal or radiation therapy. de Kernion et al. analyzed outcomes of patients who underwent radical prostatectomy with pelvic lymph node dissection for D1 prostate cancer, comparing results to those for patients who also received early endocrine therapy.5 The estimated cause-specific nine-year survival rate was 71% for those patients receiv300

Node-Positive Prostate Cancer: the Case for Observation / 301

ing no early endocrine therapy and 91% for those who received early postoperative hormonal therapy. Historically, the survival difference between these two groups of patients has not been statistically significant; the interval to progression (PSA), however, may be longer in the early adjuvant therapy group. In a recent review of data from the Mayo Clinic, an overall survival advantage was shown for patients treated with radical prostatectomy and early androgen deprivation (orchiectomy) versus orchiectomy alone.6 The nodepositive patients treated with extirpation and orchiectomy in this series demonstrated a 66% 10-year survival rate versus a 28% rate among patients treated with orchiectomy alone. Other institutions have corroborated the data supporting early adjuvant hormonal therapy in patients first treated surgically.7 The argument against radical prostatectomy in this setting is based on similar survival rates being obtained through early androgen ablation with or without surgical extirpation. Accepting the morbidity and mortality associated with surgery without clearly proven survival benefit seems unjustified. Previous reports have refuted the therapeutic value of pelvic node dissection.8 Patients treated with pelvic node dissection only who then received delayed treatment (consisting of any modality) have generally demonstrated 5-year survival rates under 50%. Pelvic node dissection is regarded as a staging procedure by the authors’ institution. Radiotherapy External beam radiotherapy as a treatment for nodepositive prostate cancer applied in an extended field technique has been evaluated. Patients with pathologically proven lymph node metastasis demonstrated a 50% 5-year survival rate in a large series of consecutive patients.9 In a more recent report, a slightly increased survival rate was noted in a similar group of patients treated with external beam radiation with a subsequent boost to the prostatic bed; not all patients in this report were staged surgically, however, therefore their exact pathologic stage may be in question.10 Gervasi et al. reported on a larger series of patients who underwent pelvic node dissection followed by radiation treatment.11 This series reported data that included node-positive and node-negative patients who received radioactive gold seed implantation and external beam radiotherapy. The cancer-specific survival rate for all N+ patients at 5 years was reported as 75% ± 7%, decreasing to 43% at 10 years. Endocrine Therapy and Observation Outcome variables in treating node-positive prostate cancer have traditionally included local progression (bladder outlet obstruction, ureteral obstruction, impotence), biochemical recurrence or progression, development of distant metastasis, and disease-specific survival. More recently, the issue of quality of life as an outcome measure

has surfaced. When reviewing the literature of immediate versus deferred hormonal therapy, that is, observation, for advanced prostate cancer, it is important to be aware of the specific outcome variables being measured and compared. Moul provides an excellent definition of this clinical scenario as well as a review of the hormonal management of advanced prostate cancer,12 employing data recently published in Britain by the Medical Research Council Prostate Cancer Working Party Investigators Group.13 The literature examined in Moul’s review clearly and unequivocally confirms that early hormonal therapy delays the time to progression (biochemical and symptomatic), a result that has been confirmed by several authors.14 The rates of pathologic bone fracture, spinal cord compression, and ureteral obstruction as well as the requirement for transurethral resection of the prostate (TURP) were all significantly higher in the deferred versus immediate hormonal therapy groups (Table 33–1). The Moul study also revealed that the cause of death from prostate cancer was higher in the deferred versus immediate therapy groups (71% versus 62%). Overall survival improvement with immediate hormonal therapy, however, is not clearly demonstrated. The review contains valuable data confirming the above-noted improvement in outcome variables related to disease progression. However, the study was not blinded, follow-up data regarding compliance in the immediate therapy group were not reported, and a high percentage of men in the deferred treatment group experienced mortality due to prostate cancer without receiving hormonal therapy at all. This suggests that the treatment groups were not uniformly managed. It is, therefore, not accurate to cite an improvement in survival in the patients treated with early endocrine therapy. The key issues in the debate over immediate versus deferred hormonal therapy then become disease-specific survival and quality of life while receiving or not receiving therapy. Quality-of-life issues have recently become incorporated into research studies addressing prostate cancer and are an important outcome variable in the case of nodepositive prostate cancer. Since no clinically significant benefits in quantitative survival can be demonstrated with immediate hormonal therapy over deferred treatment, the quality of the remaining years of life becomes paramount. TABLE 33–1. Complication Rates in Patients given Immediate versus Deferred Hormonal Therapy Complication Bone fracture Spinal compression Ureteral obstruction Distant metastases TURP

Immediate Therapy

Deferred Therapy

2.3% 1.9% 7.0% 7.9% 13.9%

4.5% 4.9% 11.8% 0.8% 30.3%

Adapted from Moul JW. Contemporary hormonal management of advanced prostate cancer. Oncology 1998;12(4):499–505.


Hormonal deprivation can be achieved through several methods, including castration, luteinizing hormone– releasing hormone analogues (LHRH-A), antiandrogens, or combinations of these therapies (maximum/combined androgen blockade, androgen withdrawal, and intermittent androgen blockade). The physiologic basis and mechanism of action of hormonal therapy is reviewed elsewhere. It has been established, however, that combined androgen blockade results in a better survival rate than LHRH-A or orchiectomy alone.15,16 The morbidity of hormonal therapy is outlined in Table 33–2. The incidence of these side effects varies. Most surgically castrated patients become impotent. The incidence of side effects with LHRH analogues are reported as similar to that of surgical castration, with 57% of patients experiencing hot flashes but approximately 5% reporting impotence.17 Gastrointestinal symptoms are reported in 21 to 46% of patients treated with antiandrogens and gynecomastia in 40%.18 The incidence and long-term sequelea of osteoporosis remain to be defined in this population but should be considered a potential adverse effect of androgen deprivation.

Discussion The goal of therapy in treating TxN+ adenocarcinoma of the prostate is palliation of symptoms.19 When treating node-positive (advanced) prostate cancer, the goal of the chosen therapy must be clearly defined and kept in mind. The goal of palliative therapy is to limit the extent and minimize the symptoms of an already established disease process. At this time, extended survival cannot be demonstrated with any of the current therapies for advanced prostate cancer. The clinician and patient in this setting must discuss the therapeutic options and their attendant risks and benefits. When comparing the therapies discussed in this chapter (observation, monotherapy, and combinations of therapy), it must be noted that frequently cited studies often compare noncongruent populations of patients. This fact and the sparseness of data regarding the true natural history of untreated node-positive prostate cancer TABLE 33–2. Morbidity of Hormonal Therapy Method of Hormonal Ablation Adverse Effects/Disadvantages Castration

Cosmesis, loss of libido with or without loss of potency Psychologic trauma, weight gain Anemia, decreased muscle mass

LHRH analogues

Asthenia, hot flashes, skin rash Respiratory disorders, flare phenomenon. Decreased libido

Antiandrogens

Hot flashes, decreased libido Gastrointestinal effects Gynecomastia, impotence

(D1 disease) makes comparing therapies for this group of patients problematic.20 Clearly, some subset of patients may benefit from early intervention for node-positive prostate cancer. This subset of patients has yet to be defined although the patient with microscopic, low-volume node disease appears to be a likely candidate. Recently, Messing et al. reported a survival benefit for N+ prostate cancer patients treated with early hormonal therapy (EHT) versus those for whom therapy was deferred.21 Their abstract, presented at the 1999 American Urological Association, showed an approximate three-toone survival benefit for EHT. The current authors anxiously await their full report. Each of the previously discussed treatment modalities has certain risks and benefits and each accomplish local disease control and biochemical regression to different extents. Early intervention of any sort uniformly results in side effects and will make an asymptomatic patient symptomatic. All of the therapies discussed, however, have immediate morbidity, with the exception of deferred treatment. The value of deferred treatment also becomes apparent when at the time of symptomatic progression the previously stated options then can be utilized. Deferred treatment for the patient with advanced prostate cancer is not resigning them to inevitable disease progression and mortality but is the art of maximizing their quality of life. Deferred therapy is not a passive process; it requires close and careful follow-up. Intervention must occur when the disease process progresses and begins to affect the patient’s health and quality of life.

References 1. Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6630 men. J Urol 1994;151:1283–90. 2. Maddox GL. The encyclopedia of aging. New York: Springer Publishing Company; 1987. 3. Stein A, de Kernion JB. Adjuvant endocrine therapy after radical prostatectomy for stage D1 prostate cancer. Semin Urol 1990;8:184–9. 4. Catalona WJ, Miller DR, Kavaussi LR. Intermediate term survival results in clinically understaged prostate cancer patients following radical prostatectomy. J Urol 1988;140:540. 5. de Kernion JB, Neuwirth H, Stein A, et al. Prognosis of patients with stage D1 prostate cancer following radical prostatectomy with and without early endocrine therapy. J Urol 1990;144:700–3. 6. Ghavamian R, Bergstralh EJ, Blute ML, et al. Radical retropubic prostatectomy plus orchiectomy versus orchiectomy alone for pTxN+ prostate cancer: a matched comparison. J Urol 1999;161:1223–8. 7. Frazier HA, Robertson JE, Paulson DF. Does radical prostatectomy in the presence of positive pelvic lymph nodes enhance survival? World J Urol 1994;12:308. 8. Paulson DF. The prognosis of lymphadenectomy in ade-

Node-Positive Prostate Cancer: the Case for Observation / 303

9.

10.

11.

12.

13.

14.

15.

nocarcinoma of the prostate. Urol Clin North Am 1980;7:625. Bagshaw MA. Radiation therapy for cancer of the prostate. In: Skinner DG, Lieskovsky G, editors. Management of genitourinary cancer. Philadelphia: WB Saunders Co.; 1988. p. 437. Lawton CA, Cox JD, Glisch C, et al. Is long-term survival possible with external beam irradiation for stage D1 adenocarcinoma of the prostate? Cancer 1992;69(11): 2761–6. Gervasi LA, Mata J, Easley JD, et al. Prognostic significance of lymph nodal metastases in prostate cancer. J Urol 1989;142:332–6. Moul JW. Contemporary hormonal management of advanced prostate cancer. Oncology 1998;12(4): 499–505. The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostate cancer: initial results of the Medical Research Council trial. Br J Urol 1997; 79:235–46. Zagars GK, Sands ME, Pollak A, vonEschenbach AC. Early androgen ablation for stage D1 (N1 to N3, M0) prostate cancer: prognostic variables and outcome. J Urol 1994;151:1330–3. Eisenberg MA, Blumestein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for

16.

17.

18.

19.

20. 21.

metastatic prostate cancer. N Engl J Med 1998; 339(15):1036–42. Schellhammer P, Sharifi R, Block N, et al. Maximal androgen blockade for patients with metastatic prostate cancer: outcome of a controlled trial of bicalutamide versus flutamide, each in combination with luteinizing hormone-releasing hormone analogue therapy, Casodex Combination Study Group. Urology 1996;47 Suppl 1A:54–60. Sharifi R, Soloway M. Leuprolide Study Group: clinical study of leuprolide depot formulation in the treatment of advanced prostate cancer. J Urol 1990;143:68–71. de Kernion JN, Murphy GP, Priore R. Comparison of flutamide and Emcyt in hormone-refractory metastatic prostate cancer. Urology 1988;31:312–7. Schröder FH. Endocrine treatment of prostate cancer. In: Walsh PC, Retik AB, Vaughn ED Jr, Wein AJ. Campbell’s urology. 7th ed. Vol. III. Philadelphia: WB Saunders Company; 1997. Austenfeld MS. Management of stage D1 prostate cancer. AUA Update Series 1991; Vol X, Lesson 24:186. Messing E, Manola J, Wilding J, et al. Immediate hormonal therapy vs. observation for node positive prostate cancer following radical prostatecomy and pelvic lymphadenectomy: a randomized phase III Eastern Cooperative Oncology Group/Inter Group trial. J Urol 1999;161 Suppl:175.

CHAPTER 34

TXN+M0: THE CASE FOR RADIOTHERAPY RICHARD WHITTINGTON, MD; TODD H. DOYLE, MD Anatomic Distribution of Lymph Nodes

The incidence of node-positive prostate cancer has decreased in recent years because of earlier diagnosis and treatment of men with prostate cancer. In the first large series of 100 men treated with curative intent with interstitial radiation accompanied by lymph node sampling, 41% were found to have positive lymph nodes.1 In a more recent series of similar men undergoing radical prostatectomy and pelvic lymph node dissection reported by Sgrignoli et al. from Johns Hopkins, the incidence of positive nodes has fallen to 7.5%.2 Men found to have lymph node involvement in the year 2000 may not be similar to men diagnosed with lymph node involvement in 1970. Prior to the recent emphasis on prostate health, men frequently presented with indolent but extensive prostate cancers that had grown through several years of inattention to become locally extensive, with regional disease. These men were generally older, had moderately differentiated tumors with a Gleason score of 5 to 7, and had clinical T3 tumors; they usually presented with chronic progressive bladder outlet obstruction. There was also a second group of men who initially developed very aggressive tumors that grew rapidly and were likely to disseminate much earlier in their course. This group consisted primarily of younger men with poorly differentiated tumors with Gleason scores of 8 to 10 and clinical stage T1b or T2 tumors. These men were more likely to present with perineal pain syndromes or acute urinary retention. They developed distant metastases quickly and had shorter survivals than the first group. Bazinet et al. retrospectively evaluated the grade of metastatic tumor found in the lymph nodes of men undergoing iodine-125 implant and found that three factors predicted a significantly shorter survival. These included the presence of a Gleason score 5 tumor in the lymph node, more than 25% of the tumor in the node not staining for prostate-specific antigen (PSA), and aneuploid lymph node metastases.3 Finally, men with bulky nodal disease found at presentation must be distinguished from those men with microscopic disease involving one or a few nodes obtained at the time of pelvic lymph node sampling prior to radical prostatectomy or radiation. The volume of extraprostatic tumor will be much greater in the former group than in the latter and will present a greater challenge if systemic therapy is attempted.

The nodes commonly removed prior to radical prostatectomy or external radiation include the obturator and hypogastric lymph nodes although Golimbu et al. have demonstrated that the risk of presacral and presciatic lymph node metastases is nearly as high as the risk of obturator lymph node metastases.4 In a series of 30 men (25 with T1-T2 tumors and 5 with T3 tumors) undergoing extended lymphadenectomy, 15 were found to have nodal metastases. Four patients had metastases confined to the obturator-iliac regions, two had metastases only in the presacral or lateral sciatic region, and nine had positive nodes in both areas. This would suggest that any local therapy directed at the lymph nodes should encompass the posterior nodes in the sacral region as well as the obturator-iliac nodes.

Staging Because the nodes that drain the prostate cannot be palpated, a number of investigators have used less invasive testing measures to detect nodal involvement. Liebner et al. reported on the use of lymphangiograms (LAG) but found this test to be relatively insensitive since it properly visualizes only the external iliac, common iliac, and paraaortic lymph nodes.5 The primary nodal drainage of the prostate is to the obturator, internal and external iliac, and presacral lymph nodes, therefore, most of the highrisk areas are not visualized by LAG. This would suggest that there is likely to be extensive pelvic nodal disease when a LAG is positive. In a review of five series, Liebner et al. found the test sensitivity to be highly variable, with an average of 51% (range 33 to 75%), and test specificity to be 81% (range 21 to 95%). Platt et al. carried out a similar evaluation of computerized tomography (CT) scanning for staging patients for lymph node involvement. They carried out a total of 64 CT readings in a series of 32 patients and found that the sensitivity and specificity were 0% and 96%, respectively.6 In a small unpublished series from the University of Pennsylvania, the current authors have identified nine patients with antecedent lymphoproliferative disorders who presented with isolated pelvic and para-aortic lym304

TxN+M0: the Case for Radiotherapy / 305

phadenopathy on staging CT scan. An additional six patients were found who had no prior diagnosis but showed asymptomatic pelvic or para-aortic adenopathy on the staging CT scan. All of these patients were biopsied and all were found to have new lymphoproliferative disorders. These 15 patients were biopsied during the period when the authors diagnosed metastatic prostate cancer in the nodes of 66 other men reported separately. The positive predictive value (PPV) of a positive CT is 81% in the authors’ experience. Hanks et al. have reviewed the results of two Radiation Therapy Oncology Group (RTOG) trials, 77-05 and 77-06.7 Both trials recommended surgical staging of the lymph nodes but would accept radiographic staging with LAG or CT. Both trials showed a significantly higher disease-free survival in pathologically node-negative patients compared to pathologically node-positive patients but no difference in survival between radiographically staged nodepositive and node-negative patients. Based on these results, the discussion in this chapter will be confined to patients with histologically confirmed lymph node metastases. Until better testing methods become available, surgical lymph node sampling, using either a laparoscopic or open approach, should be carried out when the results would affect treatment selection or goals.

Natural History of Node-Positive Prostate Cancer Several small series have followed men expectantly and then treated them with palliative therapies. Kramer et al. reported a group of 13 men treated with initial observation and hormones for palliation of symptoms.8 The median time to develop hormone refractory disease was 22.5 months, and all patients had progressive hormone refractory disease within 60 months. Paulson et al. randomized a group of 77 patients to delayed hormonal therapy or extended field radiation.9 The median survival of the 36 patients assigned to delayed hormonal therapy was 33.5 months. While most patients died of progressive metastatic disease, the patients treated with expectant management were more likely to have symptomatic primary tumors as well. Local progression is associated with bladder outlet obstruction, bleeding, urosepsis, pain, rectal dysfunction, and general debilitation that can affect both qualitative and quantitative survival. More recently, Davidson et al. reported on a group of 61 patients who received modern supportive care and close follow-up without treatment.10 The median time to symptomatic progression was 18 months, and patients with advanced primary tumors (T3 or T4) or poorly differentiated tumors were found to have shorter progressionfree intervals. The time to progression correlated well with the PSA doubling time. The first site of clinical progression in 19 of the 39 men was the prostate.

Results of Monotherapy: Early Hormonal Therapy One of the earliest attempts to improve the survival and quality of life of men with nodal metastases at diagnosis relied on hormone therapy initiated immediately at diagnosis. Several series using this therapy are summarized in Table 34–1. Direct comparison of the results to other therapies or expectant management is difficult because patients treated with early hormones had received better supportive care because of more regular medical contact. The initial report by van Aubel et al. described superior results with early androgen deprivation compared to patients treated expectantly.11 Schmeller and Lubos compared a group of men treated with hormonal therapy alone to a selected group of N+ patients undergoing radical prostatectomy.12 While there was no demonstrated benefit to prostatectomy, both patient groups had a longer time to the development of symptomatic hormone refractory disease than was shown in other reported series of delayed hormonal therapy. Zagars et al. have reported on the results of a series of 229 men treated with hormones alone or hormones with radiation.13 Three-quarters of these men underwent staging lymphadenectomy prior to treatment. The remaining men were explored for possible radical prostatectomy and were found to have nodal involvement. Among 185 men treated with hormonal therapy alone, the 5-year survival rate was 83%, clinical relapse-free survival was 55%, and the biochemical relapse-free survival rate was 43%. To settle the issue of when hormonal therapy should be initiated, the Medical Research Council (MRC) in Great Britain treated a group of 934 patients with immediate or deferred androgen ablation.14 This study included men thought to be incurable due to locally advanced or metastatic disease. Locally advanced disease included T3 and T4 Nx tumors as well as N+ tumors. In the subset of N+ patients without distant metastases, patients receiving immediate therapy took longer to develop distant metastases or die (7 years versus 4 years for T4-T4Nx patients, p < .0001), and had a lower risk of symptomatic bladder outlet or ureteric obstruction. There was also a trend toward a lower incidence of skeletal fractures and visceral metastases. Median survival was approximately 10 months longer in patients treated with immediate hormonal therapy (p < .02).

Results of Monotherapy: Surgery Several authors have examined the role of surgery in managing men with prostate cancer metastatic to regional lymph nodes. The poor outlook for men with nodal involvement who are undergoing radical prostatectomy was recognized many years ago. McCullough et al. reviewed a number of series and reported that the 15-year survival rate free of disease was “possibly less than 5%” although there were a substantial number of men who died of causes other

306 / Advanced Therapy of Prostate Disease TABLE 34–1. Results with Early Hormonal Therapy* Reference

Number of Patients

Hormonal Therapy

Median FU (Months)

Clinical Progression-Free Survival

Overall Survival

van Aubel11 Schmeller12 Zagars13 MRC (Kirk)14

30 37 185 256

Orchiectomy Orchiectomy or LHRH Orchiectomy or LHRH Orchiectomy or LHRH

25 44 70 50

> 45 months 49 months 55% 5 year NR

NR 66% 6 years 83% 5 years 60 months

LHRH = luteinizing hormone–releasing hormone agonist; FU = follow up; NR = not reported. *In men with N+ prostate cancer.

than prostate cancer.15 Smith and Middleton reported similar results, and both authors noted that the outcome was generally worse in men with bulky or bilateral adenopathy (N3) compared to those with more limited disease (N2) or a solitary microscopically involved node (N1).16 More recently, Sgrignoli et al. were able to identify selected patients with Gleason scores < 8 that were at a significantly lower risk of early distant metastases after radical prostatectomy.2 The overall biochemical disease-free survival rate was only 12% at 10 years and the distant metastases-free survival rate was 47%. The metastases-free survival rate was 82% among men with Gleason scores ≤ 7, compared to 15% among men with Gleason scores ≥ 8. The 5-year progression-free survival rate was 22% for the entire group. These data suggest that men with well- or moderately differentiated tumors may be more likely to have indolent recurrences in the prostate bed while men with poorly differentiated tumors are at higher risk for distant metastases. The group at the Mayo Clinic has reported that the 10-year biochemical disease-free survival rate was 19% among men treated with radical prostatectomy alone, and that the overall survival rate was 83% at 10 years and 49% at 15 years.17 The risk of local recurrence was 26%. At UCLA, de Kernion et al. observed similar results, reporting a 9-year disease-free survival rate of 32% and a cancer-specific survival rate of 71%, although the biochemical disease-free survival was 10%.18 Schmid et al. reported similar results in 132 patients.19 Node-positive patients in this series received adjuvant radiation not to improve disease-free survival but with the goal of reducing the risk of pelvic recurrence. Survival was related to the extent of nodal involvement: 73% in patients with a solitary node ≤ 5 mm and 30% in patients with a larger node or with multiple nodes. Kupelian et al. reported a 5-year clinical disease-free survival rate of 67% after radical prostatectomy alone but the biochemical disease-free survival rate was only 18%.20 Results of surgery without adjuvant hormonal therapy are summarized in Table 34–2.

Fowler et al. reported that all 60 patients treated with pelvic lymph node dissection and iodine-125 implant developed distant metastases within 7 years of implant.21 Similar results were achieved with lymph node dissection and limited pelvic radiation followed by a prostate implant using gold-198.22 The 10-year clinical disease-free survival rate was 7%, and 90% of the patients with recurrent tumor had distant metastases. The 10-year overall and cause-specific survival rates were 32% and 43%, respectively. More extensive external beam radiation has not produced better results. Hanks et al. reviewed an RTOG trial that randomized 90 men with pelvic lymph node metastases to conventional radiation to the pelvis and prostate compared to extended field radiation treating the paraaortic nodes in addition to the pelvic nodes and prostate.23 There was no benefit in treating the lymph nodes due to the high risk of distant metastases. The 10-year survival rate for the entire group was 29% with a clinical no evidence of disease (NED) survival of 7%. Only two of the five 10-year clinical NED survivors had PSA confirmation with a PSA level < 1.0 ng per mL. Lawton et al. reviewed a subsequent trial that randomized men including those with nodal metastases to radiation alone or radiation with androgen suppression.24 Among 75 men treated with radiation alone, the 5-year overall and cancer-specific survival rates were 65% and 77% but clinical and biochemical disease-free survival rates were 55% and 11%. Lawton et al. also reported a series from the Medical College of Wisconsin that showed somewhat better results.25 With a median follow-up of 9 years, the 10-year actuarial survival rate was 30% and the metastasis-free survival rate was 46%. In this series, local progression was seen in only 5 of 26 documented recurrences while distant metastases occurred in 19 patients. This series differs from others in that only 23 of the 56 patients had biopsy confirmation of nodal involvement.

Results of Monotherapy: Radiation Therapy

The results presented thus far in this chapter demonstrate that monotherapy does not provide reliable long-term control of node-positive prostate cancer. There appear to be two coexistent problems in managing these patients, similar to the issues addressed in women with breast cancer.

Several studies have evaluated radiation therapy as a single modality in men with nodal metastases (Table 34–3).

Rationale for Combined Modality Therapy

TxN+M0: the Case for Radiotherapy / 307 TABLE 34–2. Results with Radical Prostatectomy Alone* Number of Patients

Follow-up

Sgrignoli2 (Johns Hopkins) Myers17 (Mayo Clinic) de Kernion18 (UCLA) Schmid19 (Basel)

113 78 35 43

10 years 10 years 9 years 10 years

Kupelian20 (Cleveland Clinic)

21

5 years

Author (Institution)

Cancer-Specific Survival

Clinical Disease-Free Survival

Biochemical Disease-Free Survival

NR 65% 71% 73% N1 30% N2 NR

47% 0% 32% 37% N1 13% N2 65%

12% NR 10% NR 24%

NR = not reported. *In men with N+ prostate cancer.

Patients frequently have a locally extensive primary tumor that cannot be managed effectively with systemic therapy, along with a very high risk of subclinical distant metastases that can only be managed with systemic therapy. These tumors have very high initial response rates with hormonal therapy but long-term control of palpable disease is unusual. Additionally, the most common site of subsequent disease progression after hormonal therapy remains the site of the prior tumor. The same logic that supports the use of adjuvant endocrine therapy in women with postmenopausal breast cancer may also support using the same therapy in men with high-risk prostate cancer.

Experience with Combined Modality Therapy: Hormones and Surgery Three series have evaluated combined radical prostatectomy and hormonal therapy in patients with lymph node metastases found at the time of surgery. The earliest report was by Myers et al., who compared the results of radical prostatectomy with and without the use of adjuvant hormones.17 Adjuvant hormones reduced the risk of recurrence from 100% to 25% at 10 years. de Kernion et al. reported similar results in a group of 21 men treated with early endocrine therapy compared to those observed and treated for clinical and biochemical progression.18 The cancer-specific survival rate for the former group rose from 71 to 91%, the recurrence-free survival rate from 32 to 63%, and the biochemical disease-free survival rate rose from 10 to 33%. Schmeller and Lubos reported similar results in a group of 37 patients treated with early endocrine therapy. The cancer-specific survival rate was 60% and the clinical relapse-free survival rate was 24%.12

Table 34–4 displays the results of these trials of radical prostatectomy and hormonal therapy for prostate cancer. Without prospective randomized trials, however, it will not be possible to attribute statistical significance to the results. Some authors suggest, however, that the degree of improvement with combination therapy is so much better that randomized trials may not be necessary. These results also cannot be compared to results achieved with radiation as differences in patient selection or tumor characteristics may be the cause of differences in outcomes. Patients treated with radiation may present to institutions where radical prostatectomy is not offered to some or all men with nodal metastases, or they may be medically unresectable. Still other men are unresectable due to the extent of the primary tumor or the nodal disease. Conducting a randomized clinical trial of therapies in N+ disease is probably not feasible because N+ tumors are so infrequently seen; also preconceived notions among physicians regarding efficacy of treatment for these tumors make such trials unlikely. Nevertheless, results reported thus far suggest that the early addition of adjuvant hormonal therapy may be beneficial and should be considered for these patients.

Experience with Combined Modality Therapy: Hormones and Radiation There are three large series in which combined hormonal and radiation therapy was employed for patients with nodal metastases. Lawton et al. reported the results of a large randomized trial comparing radiation alone to radiation plus early continuous androgen ablation.25 Patients eligible for this study included those with clinical stage T3

TABLE 34–3. Results with Radiation Therapy Alone* Author (Institution) Fowler21 Gervasi22 Hanks23 Lawton24 (RTOG) Lawton25 (Med Coll Wisc) NR = not reported. *In men with N+ prostate cancer.

Number of Patients

Follow-up




60 152 90 75 56

7 years 10 years 10 years 5 years 10 years

NR 43% 29% 77% 30%

0% 7% 7% 55% 46%

NR NR NR 11% NR


tumors, men with positive surgical margins or seminal vesicle involvement at radical prostatectomy, and patients with positive nodes. There was little difference found in the 5-year cancer-specific survival rates, which increased from 77 to 82% with the addition of androgen ablation. However, a significant improvement in biochemical diseasefree survival was seen, increasing from 11 to 55%. The lack of a significant difference in survival may have been related to the short duration of follow-up. Zagars et al. reported on a series of 44 men treated with combined androgen ablation and radiation or androgen ablation monotherapy and found a similar survival rate at 5 years: 83% for androgen ablation alone and 91% for combined radiation therapy and androgen ablation.13 Combined therapy increased the 5-year clinical disease-free survival rate from 55 to 90% and the biochemical disease-free survival rate from 42 to 90%. Both Lawton et al.25 and Zagars et al.13 used androgen ablation without an antiandrogen (Table 34–5). The current authors reported results in 66 patients in 1997.26 Thirty-one patients were treated with androgen deprivation, either orchiectomy or leuprolide, and 35 were treated with combined androgen blockade. Five patients did not tolerate antiandrogens and received less than 6 months of antiandrogen therapy. These men continued on androgen deprivation alone. The authors’ institutional policy is to complete the surgery in younger men (< 65 years) if there is microscopic nodal involvement and to abort the procedure in older men or men with gross nodal involvement. Lymph node sampling is also routinely recommended in men with high-grade T2 or clinical T3 tumors or PSA > 30 ng per mL, skewing the series somewhat toward older men and those with radiographically evident lymph nodes. The most recent update of this series of patients who underwent both hormonal therapy and radiotherapy shows an 87% cancer-specific survival rate at 8 years, a clinical relapse-free survival rate of 71%, and a biochemical relapse-free survival rate of 66%. It is important to note that there have been three biochemical recurrences in “G3” men who elected to stop their hormones after 2 to 4 years; in these men, PSA fell to undetectable levels again when hormones were reinstituted. Four additional patients have elected to be treated with intermittent androgen ablation and each has had a rise in serum PSA to a level ≥ 1.5 ng per mL within 12 months of interrupting hormonal therapy. This would

suggest that even with combined modality therapy, sterilization of all tumor is infrequent.

Rationale for Radiation with Adjuvant Hormonal Therapy There is a high risk of local recurrence following radical prostatectomy in patients with T3 or T4 tumors. Radiation may treat the periprostatic tissues more effectively to sterilize peripheral tumor margins and may be a preferred method to achieve local control. Similarly, if the node dissection is not extensive enough to remove all involved nodes, there would be a risk of nodal recurrence. Radiation has the advantage of being able to treat all of the remaining nodal tissue and has a better chance of sterilizing extraprostatic pelvic tumor. Also, radiation acts through a mechanism independent of the hormones and so will deliver two active treatments to the entire pelvis where the only evident tumor is located. There are four postulated beneficial mechanisms for a hormone-radiation interaction in this setting, as discussed by Steele and Peckham.27 It is unlikely that hormones would be radioprotective for normal tissue or radiosensitizing for the androgen-independent cells. The two mechanisms that are more likely to be active are spatial cooperation and toxicity independence. Toxicity independence is the fundamental basis of multiagent chemotherapy but also applies to combined modality therapy. The tumor population is treated with two different agents, each acting in a manner that does not affect the normal tissue tolerance of the other agent. This produces a better response than could be achieved with either therapy alone. The current combined modality data for either surgery or radiation therapy and hormonal therapy demonstrate a reduced risk of local recurrence with combined modality therapy. Spatial cooperation occurs when two therapies are given in a complementary manner so that a component of the tumor population that is not effectively treated by one treatment can be effectively treated by the other. This model suggests that hormonal therapy cannot achieve long-term control of the bulk tumor in the pelvis but is able to effectively control extrapelvic micrometastases. Radiation directed at the pelvis has no effect on systemic micrometastases but can provide effective long-term control of the pelvic tumor. The result is a reduction in both local recurrences and distant metastases.

TABLE 34–4. Results with Radical Prostatectomy and Early Adjuvant Hormonal Therapy* Author (Institution)

Number of Patients

Follow-up




Myers17 (Mayo Clinic) de Kernion18 (UCLA) Schmeller12 (Munich)

32 21 37

10 years 10 years 10 years

89% 91% 60%

75% 63% 24%

NR 33% NR

NR = not reported. *In men with N+ prostate cancer.

TxN+M0: the Case for Radiotherapy / 309 TABLE 34–5. Results with Radiation Therapy and Hormonal Therapy* Author (Institution) Lawton24 (RTOG) Zagars13 (MD Anderson) Whittington26 (Penn)

Number of Patients

Follow-up




98 44 66

5 years 5 years 8 years

82% 91% 87%

69% 90% 71%

55% 90% 66%

*In men with N+ prostate cancer.

The current paradigm used to plan treatment for men with node-positive prostate cancer is to consider them all to have subclinical metastatic disease. This assumption is supported by the universal lack of success of local therapies in controlling the tumor. In such a context, radiation could be considered a debulking procedure similar to surgery; other therapy must then be directed against micrometastatic disease as well as any residual local tumor. The experience with immediate versus symptomatic hormonal therapy in these patients suggests that the difference in progression-free and overall survival is greater than can be explained by lead-time bias. These data indicate that hormones are more effective if administered when the tumor burden is least. Whether this advantage is related to decreased tumor sensitivity as the tumor population grows or to clonal evolution of the tumor is not clear. These trials have also demonstrated that the predominant site for development of hormone refractory disease is in the prior sites of measurable disease. The greater the number of tumor cells, the higher the likelihood that androgen independent cells will be present or develop at these sites. The high incidence of disease relapse when hormones are stopped also suggests that there is a spectrum of hormonal sensitivity. Androgen-sensitive and -insensitive prostate cancer cells are excellent models for studying apoptosis in tumors, but it appears that there is a spectrum of cellular hormone sensitivity. It is likely that the dominant population in these tumors, as in most prostate cancers, is androgen dependent. There is also clearly an androgen-independent population that grows through any hormonal therapy. This androgen-independent population is relatively small in hormone naive tumors but represents the dominant population at the time of relapse. Recurrences observed in the population treated with shorter course or intermittent androgen deprivation also suggest the existence of a population with intermediate androgen sensitivity. This population requires androgens for growth but is able to survive in a resting state (G0) for an extended period of time when androgens are removed. It appears that this population is present outside the pelvis and occurs in nearly all patients who present with nodal metastases. Based on this model, combined modality hormonal-radiation therapy would be significantly more effective if continued indefinitely after local therapy.

Quality of Life The quality of life of the patients treated is a major issue in treatment decision-making. There have been two studies evaluating the quality of life of patients. Van Andel et al. examined a group of 55 men with prostate cancer, of whom 37 received no initial therapy and 18 began immediate androgen deprivation.28 Patients were evaluated 2 to 5 years after diagnosis, revealing that the subjective measures of quality of life were better in patients who elected delayed androgen deprivation compared to those treated immediately. In a follow-up evaluation 1 year later, better physical function was demonstrated among patients who had elected deferred treatment. Whether this reflects an effect of the therapy and whether it persists given the shorter time to develop metastatic disease was not addressed; further follow-up of these patients is necessary. Frohmuller et al. conducted a similar study, comparing men treated with radical prostatectomy plus androgen deprivation to androgen deprivation alone.29 Sixtynine percent of the patients not receiving local therapy developed moderate to severe symptoms of bladder neck obstruction or bladder invasion. Only 2% of patients undergoing radical prostatectomy had similar symptoms. Results of quality-of-life studies may depend on which variable is studied and when the study is completed.

Conclusion Physicians and patients must discuss all treatment options to reach an informed decision concerning monotherapy or combined modality therapy. The decision should be based on the patient’s age and underlying health status as well as on tumor characteristics, including Gleason score, PSA level, clinical stage, and volume and distribution of nodal metastases. All of the current observations support a combination of hormonal therapy with local therapy as opposed to sequential monotherapies. For patients with stage T1 or T2 tumors there is no evident advantage for either radical prostatectomy or radiation; for T3 and T4 tumors, however, pelvic tumor control is superior with radiation. While cures with combined hormonal-radiation therapy may be infrequent, it appears that long-term symptom-free survival is achievable. In the population of men who present with N+ prostate cancer, the net effect may be the same.


References 1. Barzell W, Bean MA, Hilaris BS, Whitmore WF. Prostatic adenocarcinoma: relationship of grade and local extent to the pattern of metastases. J Urol 1977;118:278–82. 2. Sgrignoli AR, Walsh PC, Steinberg GD, et al. Prognostic factors in stage D1 prostate cancer: identification of patients less likely to have prolonged survival after radical prostatectomy. J Urol 1994;152:1077–81. 3. Bazinet M, Hamdy SM, Begin LR, et al. Prognostic significance of antigenic heterogeneity, Gleason grade, and ploidy of lymph node metastases in patients with prostate cancer. Prostate 1992;20:311–26. 4. Golimbu M, Morales P, al-Askari S, Brown J. Extended pelvic lymphadenectomy for prostatic cancer. J Urol 1979;121:617–20. 5. Leibner EJ, Stefani S, and the Uro-Oncology Research Group. An evaluation of lymphography with nodal biopsy in localized carcinoma of the prostate. Cancer 1980;45:728–34. 6. Platt JF, Bree RL, Schwab RE. The accuracy of CT in the staging of carcinoma of the prostate. AJR Am J Roentgenol 1980;149:315–8. 7. Hanks GE, Krall JM, Pilepich MV, et al. Comparison of pathologic and clinical evaluation of lymph nodes in prostate cancer: implications of RTOG data for patient management and trial design and stratification. Int J Radiat Oncol Biol Phys 1992;23:293–8. 8. Kramer SA, Cline WA, Farnham R, et al. Prognosis of patients with stage D1 prostatic adenocarcinoma. J Urol 1981;125:817–9. 9. Paulson DF, Cline WA, Koefoot RB, et al., and the UroOncology Research Group. Extended field radiation therapy versus delayed hormonal therapy in node positive prostate cancer. J Urol 1982;127:935–7. 10. Davidson PJT, Hop W, Kurth KH, et al., and the EORTC genitourinary group. Progression in untreated carcinoma of the prostate metastatic to regional lymph nodes (stage T0 to 4, N1 to 3, M0, D1). Urology 1995;154: 2118–22. 11. van Aubel GJM, Hoekstra WJ, Schröder FH. Early orchiectomy for patients with stage D1 prostatic carcinoma. Urology 1985;134:292–4. 12. Schmeller N, Lubos W. Early endocrine therapy versus radical prostatectomy combined with early endocrine therapy for stage D1 prostate cancer. Br J Urol 1997;79: 226–34. 13. Zagars GK, Pollack A, von Eschenbach AC. Management of unfavorable locoregional prostate carcinoma with radiation and androgen ablation. Cancer 1997;80:764–75. 14. Kirk D. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial. Br J Urol 1997;79:235–46. 15. McCullough DL, Prout GR, Daly JJ. Carcinoma of the prostate and lymphatic metastases. J Urol 1974;111: 65–71.

16. Smith JA, Middleton RG. Implications of the volume of nodal metastases in patients with adenocarcinoma of the prostate. J Urol 1985;133:617–9. 17. Myers RP, Zincke H, Fleming TR, et al. Hormonal treatment at the time of radical retropubic prostatectomy for stage D1 prostate cancer. J Urol 1983;130:99–101. 18. de Kernion JB, Neuwirth H, Stein A, et al. Prognosis of patients with stage D1 prostate carcinoma following radical prostatectomy with and without early endocrine therapy. J Urol 1990;144:700–3. 19. Schmid H-P, Mihatch MJ, Hering F, Rutishauer G. Impact of minimal lymph node metastasis on long-term prognosis after radical prostatectomy. Eur Urol 1997;31: 11–6. 20. Kupelian PA, Katcher J, Levin HS, Klein EA. Stage T1-2 prostate cancer: a multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy. Int J Radiat Oncol Biol Phys 1997;37:1043–52. 21. Fowler JE, Fischer HAG, Kaiser DL, Whitmore WF. Relationship of pretreatment transurethral resection of the prostate to survival without distant metastases in patients treated with 125-I implantation for localized prostate cancer. Cancer 1964;53:1857–63. 22. Gervasi LA, Mata J, Easley JD, et al. Prognostic significance of nodal metastases in prostate cancer. J Urol 1989;142: 332–6. 23. Hanks GE, Buzydlowski J, Sause WT, et al. Ten-year outcomes for pathologic node-positive patients treated in RTOG 75-06. Int J Radiat Oncol Biol Phys 1998;40: 765–8. 24. Lawton CA, Cox JD, Glisch C, et al. Is long-term survival possible with external beam irradiation for stage D1 adenocarcinoma of the prostate? Cancer 1992;69:2671–6. 25. Lawton CA, Winter K, Byhardt R, et al. Androgen suppression plus radiation versus radiation alone for patients with D1 (pN+) adenocarcinoma of the prostate (results based on a national prospective randomized trial, RTOG 85-31). Int J Radiat Oncol Biol Phys 1997; 38:931–9. 26. Whittington R, Malkowicz SB, Machtay M, et al. The use of combined radiation and hormonal therapy in the management of lymph node positive prostate cancer. Int J Radiat Oncol Biol Phys 1997;39:673–80. 27. Steele GG, Peckham MJ. Exploitable mechanisms in combined chemotherapy-radiotherapy: the concept of additivity. Int J Radiat Oncol Biol Phys 1979;5:85–91. 28. Van Andel G, Kurth KH, de Haes JCJM. Quality of life in patients with prostate carcinoma: a review of the results of a study of N+ disease—prostate-specific antigen as predictor of quality of life. Urol Res 1997;Suppl 2:S79–S88. 29. Frohmuller HGW, Theiss M, Manseck A, Wirth MP. Survival and quality of life of patients with stage D1 (T1-3 pN1-2 M0) prostate cancer: radical prostatectomy plus androgen deprivation versus androgen deprivation alone. Eur Urol 1995;27:202–6.

CHAPTER 35

TXN+M0 DISEASE: THE CASE FOR EARLY HORMONAL THERAPY AND SURGERY THOMAS M. SEAY, MD, LTCOL, USAF, MC, FS; HORST ZINCKE, MD, PHD agonists or orchiectomy with or without an antiandrogen), external beam radiation (EXRT), RP, or a combination of these modalities.

Decreased Incidence of N+ Disease The use of prostate-specific antigen (PSA) screening for prostate cancer by physicians and a greater awareness of the disease by the general public have enhanced disease detection so that prostate cancer is now the most commonly diagnosed malignancy in men. Remarkably, this screening has reduced the number of newly diagnosed cases as such cases have been culled out of the screened population. From 317,000 new cases anticipated in 1996, the 1997 estimates decreased to 209,900 and the 1998 estimates to 184,500.1 Along with this decrease, a leftward shift in presenting stage is being observed, with more cases being diagnosed at an earlier and perhaps more curable stage.1–3 This trend is further evidenced by series from the late 1970s and early 1980s that reported the incidence of nodal metastates in patients with presumed localized disease to range from 20 to 40%,4–6 while the corresponding incidence in more contemporary series is 10% or less.7–9 At the Mayo Clinic, the current incidence of nodal metastases is less than 5%. While this decrease is significant from an epidemiologic standpoint, it holds little comfort for the individual patient with nodal metastases. The outlook for such patients, if untreated, is usually death from the disease unless comorbidity intervenes.

Limitations of Monotherapy in Treating N+ Disease Observation consigns the patient to the dismal outlook described above; monotherapy in N+ disease has likewise been found wanting. Long-term follow-up of N+ patients treated hormonally or with EXRT alone has infrequently exceeded 5 years. Clinical disease-free survival rates with limited follow-up (series from the pre-PSA era) for patients receiving radiation have ranged from 32 to 51%. Patients receiving early androgen ablation monotherapy have shown 35 to 55% disease-free survival rates.11–15 The median time to progression in 179 patients treated with hormonal monotherapy by Zagars et al.14 was 67 months. Those patients treated with hormonal monotherapy can expect a delay in skeletal progression at a median time ranging from 4 to less than 6 years, with death following at a median 2 years later.11–13,16 Steinberg et al. observed that 80% of patients treated with RP had no local recurrence at 5 years (confidence interval [CI] 55 to 92%), which led them to conclude that RP provides excellent local control.17 Ominously, however, only 3 of 27 patients followed for 3 years or more had undetectable PSA levels. These progression-free figures compare favorably with those reported at the Mayo Clinic (41 and 24% at 5 and 10 years, respectively)18 and by the UCLA group (55 and 32% at 5 and 9 years, respectively).19 Of patients treated with RP alone at the Mayo Clinic, 66 ± 6.12% had local control at 10 years.20 Radical prostatectomy effectively controls the local lesion; the results of surgical monotherapy, however, become tempered when the PSA data is examined further. That a detectable PSA level is a reliable predictor of failure has been confirmed in patients treated with hormonal therapy alone by Zagars et al.14 as well as in the Mayo series of patients undergoing RP plus hormonal therapy.20,21 In the latter series, a PSA elevation preceded overt clinical failure by a median time of only 14 months. de Kernion et al. reported 5- and 9-year PSA progression-free survival rates of only 28 and 11%, respectively.19 Figures at the Mayo

Historic Management of N+ Disease Typically, the discovery of nodal disease during radical prostatectomy (RP) has resulted in that therapy being immediately abandoned, on the assumption that the patient had little to gain from removal of the primary tumor in the context of systemic disease. Such patients, left untreated, will have clinical systemic progression rates exceeding 70% at a median time of 12 to 24 months.10 The majority of these patients will experience local morbidity and up to half will succumb to their disease within 8 years. If it is assumed that metastatic disease cannot be cured, its progression only delayed, the goal then becomes to provide a therapy that will increase the duration of freedom from disease and prevent the related disability as long as possible. Options available to node positive (N+) patients include observation with treatment on symptomatic progression, immediate or delayed primary hormonal ablation (luteinizing hormone–releasing hormone 311


Clinic are 25 and 5% for 5 and 10 years, respectively, for deoxyribonucleic acid (DNA) nondiploid patients.22 Studies prior to the PSA era based on monotherapy using external beam radiation encompassing the whole pelvis revealed that perhaps less than one-third of patients are free of disease at 5 years,23 a figure confirmed by the above studies. With extended field radiotherapy, the median time to progression in another series was only 16 months.24 Bagshaw reported that the 10-year survival rate for patients with nodal disease who had undergone extended field radiotherapy was only 20%.25 In another series, 51% of patients suffered local morbidity due to progression, leading to the conclusion that external beam radiation therapy was ineffective in controlling the local lesion.26

Rationale for Radical Prostatectomy in the Setting of N+ Disease Theoretically, surgical cytoreduction will decrease the bulk of disease, rendering systemic therapies more effective.27,28 There is also the potential for the primary tumor to serve as a sanctuary where hormonally refractory clones may develop.14,17,20 Finally, local morbidity that may result for those N+ cases not treated with prostatectomy must be considered. For those cases treated with androgen ablation alone, Zagars et al. found that local progression occurred in 32 and 51% of patients at 5 and 8 years, respectively.14 Rates of intervention required for outlet obstruction due to local recurrence have been reported to be 0.5% for those who have undergone RP versus 2% for those treated with external beam radiation with androgen ablation.29 Smith et al., however, examining the role of EXRT as monotherapy for N+ disease, found that half the patients suffered symptomatic local progression within 5 years, compared to 65% of patients treated expectantly.26 Looking at the expectant management of prostate cancer in general (any stage), Aus et al. found that of the men dying of prostate cancer, 41% had undergone at least one transurethral resection of the prostate and 17% had undergone procedures to relieve upper urinary tract obstruction.30 These procedures, along with other complications, resulted in as many as four separate hospitalizations per patient and an average of 37 days of hospitalization prior to death. One series reporting on combination orchiectomy and EXRT demonstrated a 5-year clinical disease-free survival rate of 71% and a cause-specific survival rate of 84% in 97 patients.13 Similar results were reported in another study.31 In a more recent review, patients with N+ disease were case matched between those who had had orchiectomy plus RP versus those who had had orchiectomy alone (i.e., the tumor was left in situ). Patients were matched according to number of positive nodes, clinical grade and stage, age, year of surgery, and preoperative PSA (when available, after 1987). The overall survival advan-

tage in cause-specific survival in the orchiectomy plus RP group at 10 years was 66 ± 6%, compared to 28 ± 6% in the group receiving orchiectomy alone.32 Clearly, for patients with an otherwise long life-span, leaving the primary tumor in situ can lead to significant morbidity with resultant diminuation of quality of life; it also shortens the period of efficacy for hormonal ablative therapies. The literature on outcomes after observation, external beam radiation, hormonal therapy, radical prostatectomy, and combination therapies is summarized in Table 35–1.

Surgical Management of N+ Disease: the Mayo Clinic Experience At the Mayo Clinic, more than 800 men with N+ disease have been treated with either RP alone or RP and early androgen ablative therapy (EAAT), defined as androgen ablation beginning within 3 months of RP.22 Follow-up ranged from 1 to 25 years, for a mean of 6 years. Regardless of their DNA ploidy, those men receiving RP and EAAT had a probability of freedom from clinical disease progression exceeding 94% at 5 years, and 84% were projected to remain free of disease at 10 years. With PSA data included, the overall disease-free probability was 79% at 5 years. In contrast, those men receiving RP but not EAAT had a probability of freedom from any progression of only 56% at 5 years and 19% at 10 years. Those patients with nondiploid tumors who received RP alone (i.e., androgen ablation delayed until clinical progression) fared worse, with a probability of freedom from any progression of only 25% at 5 years and 5% at 10 years; the outcome for diploid patients treated with RP alone was 56% at 5 years and 19% at 10 years, respectively. Those patients with diploid tumors who received RP with or without androgen ablation showed essentially the same disease-specific survival at 5 years (94 and 97%, respectively). At 15 years, however, those receiving EAAT had a disease-specific survival probability of 83%, compared to 49% for those for whom androgen ablation was delayed until progression (p < .002). Early androgen ablation therapy seemed to have no effect on ultimate diseasespecific survival for N+ patients with nondiploid tumors but did significantly delay time to progression (see above). When outcomes following RP for N+ disease in the PSA era (1987 on, in a population of men also predominantly treated with EAAT) are compared to those for men with pathologically organ-confined disease (≤ pT2c), there is only a 10% difference, even when DNA ploidy classes are not considered (Figure 35–1). Also, there is essentially no difference in local control (Figure 35–2 and Table 35–2). Based on these data, the fact that approximately half of N+ men treated with monotherapy androgen ablation will experience local progression within 8 years,14 and that overall progression-free survival at 5 years ranges from 35 to 52%,11,15 and is 25% at 8 years,14

TxN+M0 Disease: the Case for Early Hormonal Therapy and Surgery / 313 TABLE 35–1. Outcomes for Node-Positive Prostate Cancer*

Reference

% Clinical Progression-Free (PSA)

% Local Recurrence-Free Survival 5 Yr

No. Pts.

5 Yr

No treatment Van den Ouden et al.11

34

Davidson et al.33

61

Median time to prog. 2 yrs. 24 (median time to prog. 18 mo.)

Cheng et al.13 Hanks34

Radiation only EXRT

Bagshaw25

34 43

38 (T2 or less)

10 Yr

15 Yr

10 Yr

15 Yr

84

45

20

99

% Cause-Specific Survival 5 Yr

10 Yr

15 Yr

60 (T2 or less, crude) 50 (crude)

24 (T2 or less, crude) 18 (crude)

2 (crude)

EXRT + Brachy Gervasi et al.35 Leibel et al.36

152 Au-198 I-125

345

32 ± 8† 17 ± 7† 48 ± 10 † 16 (1 node) 8 (1 node) 51 (1 node) 25 (≥ 2 nodes)† 9† 4†

14 ± 10

75 ± 7 43 ± 11 21 ± 7 87 (1 node)‡ 35 (1 node)‡ 9 (1 node)‡ 62 (≥ 2 nodes)‡ 22 (≥ 2 node)‡ 9 (≥ 2 nodes)‡

Hormone only Zagars et al.14

179

Cheng et al.13 Frohmuller et al.15

60 87

34.6

14.6

114 86 77 30 34 12 49 45 64 35

41 41 60 37 0 (55 ± 8.4) (25 ± 7.2) 83§ 55 (28)

22 24.3 ± 6.28 38

0

0 (18.6 ± 7.8) (5.4 ± 4.7) 80§ 32 (11) (9 yrs)

0

97 45

71 (6 yrs)

25 (at 8 yrs, med time to prog. 67 mo.)

68

85 (crude) 57 (crude)

66 61.8

39 32.1

60 85 88 90 83 90 97.4 ± 2.6 86.4 ± 5.7

25 (9 yrs) 68 71.4 ± 6.31 70 69

78

71 (9 yrs)

RP only Frazier et al.36 Zincke et al.18 Zincke et al.20

Seay et al.22

Diploid Tetraploid Aneuploid Diploid Nondiploid

Steinberg et al.17 de Kernion et al.19

66 ± 6.12

90.7 ± 5.1 73.8 ± 8.7 80 ± 6.4 67.7 ± 9.7

83.4 ± 7.8 68.3 ± 8.5

53

48.5 ± 13.7

46

EXRT + Hormone Cheng et al.13 Whittington et al.31

RP + Hormones de Kernion et al.19 21 Frohmuller et al.15 52 Zincke et al.20 293 Seay et al.22 Diploid 287 Nondiploid 382

87 61.5 80 (83.8 ± 2.5) (72.7 ± 2.5)

Frazier et al.37

RP + EXRT + Hormones 42

Freeman et al.38

RP + EXRT/Chemo/Hormones 76 71 (42)

84 82 (crude at 6 yrs) 67 (40) (9 yrs) 35.8 76.4 ± 3.57 (70.9 ± 4.5) (56.3 ± 3.9)

90.4 ± 2.5 96.1 ± 1.4 87.7 ± 3.8 90.1 ± 1.8 84.1 ± 3.2

38 (22)

Note: numbers in parentheses indicate inclusion of PSA follow-up. EXRT = external beam radiation therapy; RP = radical prostatectomy. *After observation, radiation, hormonal therapy, radical prostatectomy, and combination therapy (world literature review). †Distant metastases-free only. ‡Crude survival. §Only 3 of 27 patients followed for 3 years or greater have undetectable PSA. ||Symptomatic local recurrence.

91 88.9 90 93.6 ± 3.4 89.7 ± 1.8

91 (9 yrs) 70.7 80.1 ± 4.16 85.7 ± 3.4 76.8 ± 3.1

86

67 (9 yrs)

88

74

83.2 ± 4.1


FIGURE 35–1. Kaplan-Meier projection for systemic/local/PSA (0.2 ng/mL or less) progression-free survival for patients with pT2c versus pTxN+ stage cancer of the prostate. Numbers in parentheses represent number of patients still under observation at the time of writing.

FIGURE 35–2. Kaplan-Meier projection for local recurrence-free survival for patients with pT2c versus pTxN+ stage cancer of the prostate. Number in parentheses represent patients still under observation at the time of writing.

the authors continue to offer RP with EAAT to patients with low volume nodal disease. The above data demonstrate the value of EAAT in this population when combined with definitive local treatment in the form of RP.

radical prostatectomy.17 Those patients with only microscopic nodal disease have a higher percentage of DNA diploid disease (43% and higher) and clearly have a better prognosis overall than those with nondiploid cancer.20,21

N+ Disease: Metastatic Disease of the Lowest Volume

Long-Term Androgen Ablation Considerations

Nodal disease is the very back of the “firewall” between localized and gross systemic disease. It is assumed that no patient diagnosed preoperatively with metastatic disease that can be clearly documented would be offered local therapy alone. Thus, in past series most patients with nodal disease were diagnosed as such at the time of exploration immediately prior to RP. Finding a grossly positive node(s) before commencing RP tends to lead the surgeon to believe intervention has been undertaken too late. Today’s N+ patients, however, given current staging and imaging modalities, are not the same as the N+ population of a decade ago. Most patients today will be found to have microscopic nodal disease at permanent section, rather than it being discovered on frozen section. Indeed, Steinberg et al. found that a false negative frozen section was a favorable prognostic sign in N+ cases treated with

The data presented clearly demonstrate a delay in progression for those N+ patients treated with radical prostatectomy and early androgen ablative therapies compared to those for whom androgen ablation was delayed until clinical progression.22 The benefits of radical prostatectomy with androgen ablation in N+ disease over androgen ablation alone are also demonstrated.31 These conclusions are made that much more impressive by the fact that the above data are generated from N+ patients of decades past, representing patients with more advanced disease than one tends to see today with PSA screening. In the setting of N+ disease, local and systemic hormonal therapies are clearly synergistic. Also, radical prostatectomy provides somewhat better results than other modalities used to control the primary lesion.

TABLE 35–2. Clinical/Prostate-Specific Antigen* Progression-Free, Local Recurrence-Free, and Cause-Specific Survival†

p-Stage

No. of Patients

Adjuvant Hormonal Rx

10-Yr PSA (≤ 0.2) Recurrence-Free (Mean % ± SE)

10-Yr Local Recurrence-Free (Mean % ± SE)

Cause-Specific Survival (Mean % ± SE) 10 Yr

Cause-Specific Survival (Mean % ± SE) 15 Yr

63.3 ± 2.6 70.9 ± 4.5 18.6 ± 7.8 (p < .0001)‡ 56.3 ± 3.9 54.0 ± 4.7 NS

88.9 ± 1.6 87.7 ± 3.8 73.8 ± 8.7 (p < .04)‡ 84.1 ± 3.2 67.7 ± 9.7 (p < .08)

96.1 ± 1.1 85.7 ± 3.4 83.4 ± 7.8 NS‡ 76.8 ± 3.1 68.3 ± 8.5 NS

86.0 ± 3.1 83.2 ± 4.1 48.5 ± 13.7 (p < .002 after 10 years)‡

pT2c pTxN+ Diploid

2318 338

No Yes No

pTxN+ Nondiploid

427

Yes No

PSA = prostate-specific antigen; SE = standard error; NS = not significant. *0.2 ng/mL or less. †In patients undergoing radical prostatectomy for stage pT2c and pTxN+ prostate cancer according to adjuvant hormonal treatment and DNA ploidy. ‡pTxN+ diploid without adjuvant hormonal therapy compared with pTxN+ diploid with adjuvant hormonal therapy, and pT2c without adjuvant hormonal therapy.

TxN+M0 Disease: the Case for Early Hormonal Therapy and Surgery / 315

The impact of hormonal ablative therapies on the lives of patients still needs to be considered. The effects of hormonal ablation on sexual function and the common occurrence of vasomotor phenomena are well known. For those patients desiring to maintain libido, and perhaps potency, sequential androgen blockade using finasteride plus an antiandrogen may be considered.39,40 Hot flashes can be effectively controlled using regimens based upon Depo-Provera.41 More ominously, recent studies have linked osteoporosis with androgen ablation; the resultant disability is much higher in this population than previously thought.42 Men under continuous androgen ablation should be closely followed with bone densitometry, before a debilitating fracture occurs. Despite the side effects, it has been recently reported that patients with advanced disease who are on complete androgen ablation and are in remission have a quality of life that is “indistinguishable” from men without the disease, and that this quality of life is “significantly” better than it is for those with hormonally refractory disease.43 The primary goal for clinicians is to cure the disease if possible and palliate if not. In the great majority of patients with nodal disease, a prolonged disease-free interval can be gained with a combination RP and EAAT. It is acknowledged that a cure in such patients may be in many cases ultimately unattainable. The ideal “cure” for the typically presenting patient should not be the clinician’s single goal, however, to the exclusion of providing significant local and long-term systemic palliation. The opinions herein reflect those of the author and are not to be considered as those of the United States Air Force or Department of Defense.

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34.

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41.

42. 43.

Organization for Research and Treatment of Cancer Genitourinary Group. Progression in untreated carcinoma of the prostate metastatic to regional lymph nodes (stage T0 to 4, N1 to 3, M0 D1). J Urol 1995;154: 2118–22. Hanks GE. The challenge of treating node-positive prostate cancer: an approach to resolving the questions. Cancer 1993;71:1014–8. Gervasi LA, Mata J, Easley JD, et al. Prognostic significance of lymph nodal metastases in prostate cancer. J Urol 1989;142:332–6. Leibel SA, Fuks Z, Zelefsky MJ, Whitmore WF Jr. The effects of local and regional treatment on the metastatic outcome in prostate carcinoma with pelvic lymph node involvement. Int J Radiat Oncol Biol Phys 1994; 28:7–16. Frazier HA II, Robertson JE, Paulson DF. Does radical prostatectomy in the presence of positive pelvic lymph nodes enhance survival? World J Urol 1994;12: 308–12. Freeman JA, Lieskovsky G, Grossfeld G, et al. Adjuvant radiation, chemotherapy, and adjuvant androgen deprivation therapy for pathologic stage D1 adenocarcinoma of the prostate. Urology 1994;44:719–25. Fleshner NE, Trachtenberg J. Combination finasteride and flutamide in advanced carcinoma of the prostate: effective therapy with minimal side effects. Urol 1996;154: 1642–5. Ornstein DK, Rao GS, Johnson B, et al. Combination finasteride and flutamide in men with advanced prostate cancer. Urology 1996;48:901–5. Ellsworth JB, O’Reilly KJ, Thrasher JB. Depo-provera therapy for hot flushes associated with hormonal treatment of advanced carcinoma of the prostate. J Urol 1998;159:132A,498. Daniell HW. Osteoporosis after orchiectomy for prostate cancer. J Urol 1996;157:439–44. Albertsen PC, Aaronson NK, Muller MJ, et al. Healthrelated quality of life among patients with metastatic prostate cancer. Urology 1996;49:207–17.

CHAPTER 36

TXNXM1: THE CASE FOR MONOTHERAPY MENACHEM LAUFER, MD; MARIO A. EISENBERGER, MD tion, prostate cancer cells could adapt to very low (castrate) levels of testosterone, which would continue to induce a clinically significant tumor growth.21 It was therefore implied that blocking the residual androgens at the level of the cancer cells by androgen receptor antagonists would result in better control of tumor growth.22 However, the actual role of residual testosterone and adrenal androgens in disease progression following androgen ablation treatment has never been conclusively demonstrated. Tumor recurrence is an inevitable event with any type of endocrine manipulation and is believed to be associated primarily with progressive changes in the tumor cells and the development of a hormone refractory state.23 The scientific accuracy and significance of the concept of maximal androgen blockade has been challenged by many over the past 15 years and remains controversial. The consequences of CAB both in clinical research and in daily clinical care, however, have been substantial. There have been a large number of clinical trials launched to investigate the potential benefit of CAB, accruing almost 8000 patients over the past 15 years. This large body of data provides the critical test of the CAB hypothesis. Widespread use of expensive combined endocrine regimens has no doubt contributed significantly to the astronomic increase in medical care costs of patients with metastatic prostate cancer. Thus, in view of the important clinical, biologic, and economic implications of the concept behind combined endocrine regimens, it is critical to evaluate the extensive clinical data accumulated over the past several years from research in this area. The studies conducted thus far are reviewed in the following sections.

There has been a substantial increase in the incidence of prostate cancer recently, particularly in the proportion of patients presenting with early stages of the disease.1,2 Despite this shift toward early diagnosis, prostate cancer remains the second most common cause of death from cancer, with approximately 25% of all prostate cancer patients ultimately dying from metastatic disease.3 In contrast to organ-confined disease, there is still no curative treatment for metastatic prostate cancer. Moreover, in spite of better understanding of the clinical and biologic aspects of this disease, the median survival of patients with metastatic prostate cancer has not changed in the last five decades and ranges from 24 to 36 months.3–5 The first line of treatment for metastatic prostate cancer relies primarily on the suppression of gonadal androgens. While androgen deprivation represents an extremely effective palliative treatment for patients with metastatic disease, a survival benefit for this treatment has never been properly demonstrated in randomized trials. Current methods for gonadal androgen ablation involve either surgical castration or medical castration with gonadotropinreleasing hormone (Gn-RH) analogues. Orchiectomy and Gn-RH analogues have shown comparable efficacy in terms of subjective and objective response, time to progression, and survival.6–11 The major palliative effects of endocrine treatment in prostate cancer include decreased pain and urinary symptoms and improved performance status and quality of life.12–15 Unfortunately, almost all patients with metastatic disease treated with gonadal suppression eventually show disease progression. The median time to clinical progression of cohorts of patients treated in large clinical trials by different forms of hormonal therapy have ranged from 12 to 18 months.6,8,9,16,17 Following disease progression, the survival rates of cohorts of patients with metastatic prostate cancer entered in clinical trials have remained relatively stable, and no treatment has been shown to improve survival in this group of patients.18 Combined androgen blockade (CAB) involves the use of an antiandrogen in combination with any method of castration. The concept of CAB was derived from laboratory observations that following gonadal suppression, incorporation of androgens into prostatic cells remained significant due to continuous production of adrenal androgens and their conversion to dihydrotestosterone (DHT).19,20 Further, it was suggested that following castra-

Overview of Clinical Trials Twenty-seven randomized controlled trials involving 7987 patients compared the outcome of surgical or medical castration alone (monotherapy) to almost every possible combination of castration and antiandrogens (17 of the trials are shown in Table 36–1). The majority of trials used the nonsteroidal antiandrogen flutamide, along with nilutamide in the combination arm. Only seven trials used the steroidal antiandrogen cyproterone acetate (CPA). This review is organized to evaluate trials according to methods of gonadal ablation and class of antiandrogen (steroidal versus nonsteroidal). 317


lack of statistical power to appropriately test the primary hypothesis.24 Relative efficacy was assessed by comparing treatment arms with respect to survival, disease progression, and response. Overall survival (death from any

The vast majority of patients had metastatic disease, largely stage D2, but several trials included patients with nonmetastatic disease. Many trials included small numbers of patients and insufficient follow-up, resulting in a

TABLE 36–1. Large Randomized Trials Comparing Combined Androgen Blockade to Monotherapy* Gn-RH analogue + antiandrogen vs. Gn-RH analogue Crawford26 (INT-0036) Leuprolide + flutamide Leuprolide + placebo Bono30 Leuprolide + flutamide Leuprolide Fourcade32 Goserelin + flutamide Goserelin + placebo Tyrrel33 Goserelin + flutamide Goserelin Boccardo34 Goserelin + flutamide Goserelin Crawford31 Leuprolide + nilutamide Leuprolide + placebo DeVoogt35 Buserelin + CPA Buserelin DiSilvero36 Goserelin + CPA Goserelin Thorpe37 Goserelin + CPA Goserelin Orchiectomy + antiandrogen vs. orchiectomy Dijkman27 Orchiectomy + nilutamide Orchiectomy + placebo Eisenberger25 (INT-0105) Orchiectomy + flutamide Orchiectomy + placebo Zalcberg38 Orchiectomy + flutamide Orchiectomy + placebo Robinson39 Orchiectomy + CPA Orchiectomy Jorgensen40 Orchiectomy + CPA Orchiectomy Gn-RH analogue + antiandrogen vs. orchiectomy Denis28 (EORTC 30853) Goserelin + flutamide Orchiectomy Iversen46 Goserelin + flutamide Orchiectomy DeVoogt35 Buserelin + CPA Orchiectomy

N

%M

PFS

OS

Comments

303 300

100 100

17 14

35 29

p = .035

121 120

62 56

N/A N/A

30 30

No difference

120 125

81 84

12 12.8

N/A N/A

Short f/u

287 284

56 58

25 31.7

42.4 37.7

p = .14

187 186

62 68

24 18

34 32

Not significant Short f/u

209 202

100 100

25 24

28.6 27

Not significant Preliminary results

111 113

100 100

16 14

25 25

Not significant

159 156

100 100

22.1 24.8

23.8 30.1

Monotherapy better Short f/u

175 175

100 100

10.8 11.4

N/A N/A

Not significant

202 208

98 100

21.2 14.7

27.3 23.6

p = .032

697 685

100 100

20.4 18.8

33.5 29.9

Not significant

112 110

100 98

N/A N/A

23 31

Monotherapy better Short f/u

111 110

100 100

18.8 17.2

21.8 22.9

Not significant

137 136

100 100

23 21

33 33

No difference

163 163

100 100

30 20

34 27

129 133

93 89

16.5 16.8

22.7 27.6

Monotherapy better Not significant

111 118

100 100

16 18

29 33

Monotherapy better Not significant

p = .04

N = number of patients; %M = percentage of patients with established metastatic disease; PFS = progression-free survival; OS = overall survival; N/A = not available; f/u = follow-up; Gn-RH = gonadotropin-releasing hormone; CPA = cyproterone acetate. * > 100 patients/treatment arm.

TxNxM1: the Case for Monotherapy / 319

cause) is the most accurate and most commonly used outcome parameter and will be the focus of this discussion. Most authors also compared the results of progressionfree survival (PFS) between CAB and monotherapy. Most of the trials, including the largest one (INT0105),25 reported no significant difference in survival between CAB and monotherapy while only three studies showed a statistically significant advantage for the use of CAB.26–28 As is shown in Table 36–1, for every positive trial (CAB survival benefit) there are one to five identically or similarly designed studies with negative results. Gn-RH Analogue plus Antiandrogen versus Gn-RH Analogue Alone Twelve studies (N = 3733 patients) used Gn-RH analogues as the method of castration in both treatments arms. The first published large-scale, prospectively randomized, clinical trial was the National Cancer Institute (NCI)sponsored INT-0036, published by Crawford et al. in 1989.26 This trial compared daily subcutaneous 1 mg leuprolide injections plus flutamide versus leuprolide and placebo in 617 patients. The median overall survival for patients treated with CAB and monotherapy was 35 and 29 months, respectively (two-sided p = .03). While the results of INT-0036 supported significant survival advantage for the CAB arm, it remains possible that this result is due to factors not necessarily central to the CAB concept. One explanation is that the difference in outcome might be related to the effect of CAB on the flare phenomenon. This phenomenon represents the transient increase in gonadotropins and testosterone levels during the early stages of Gn-RH analogue treatment.16 Although of relatively short duration, and despite the lack of clinical evidence to support the hypothesis, this hormonal stimulatory phase could have resulted in acceleration of tumor growth with consequent long-term effects on progressionfree and overall survival rates. The clinical flare has been shown to be effectively counteracted by concomitant administration of antiandrogens.29 In support of this hypothesis is the evidence from INT-0036, which suggested that during the first 12 weeks of treatment there was a favorable trend in pain control, improvement in performance status, and changes in acid phosphatase in patients randomized to the CAB arm.26 In a recently published study by Bono et al.30 for the Italian Leuprorelin Group, administration of flutamide for 2 weeks in combination with leuprolide (to counteract the flare in the monotherapy arm) resulted in no difference in overall survival between treatment arms compared to standard CAB. Another explanation for the results of INT-0036 is related to possible compliance problems associated with the use of daily subcutaneous administration of leuprolide, the only preparation available at the time of the study. Significant compliance problems exist with daily injections, resulting in inadequate testicular suppression;

this could explain the advantage observed for those receiving leuprolide with flutamide over leuprolide alone. Since INT-0036 was not designed to include a routine evaluation of serum testosterone, this argument could not be effectively excluded. Table 36–1 also illustrates seven large studies comparing a Gn-RH analogue with and without an antiandrogen, including three studies employing CPA in the combined regimen.31–37 Two studies in this category deserve elaboration. Tyrell et al.33 randomized 557 patients between goserelin and flutamide versus goserelin alone. Crawford et al.31 compared leuprolide plus nilutamide versus leuprolide plus placebo (N = 411 patients). In both studies, there was no statistically significant difference in survival. None of the other studies demonstrated a survival advantage for the combination arm; interestingly, one of the studies36 actually showed shorter survival in the combination arm. Orchiectomy plus Antiandrogens versus Orchiectomy Alone Orchiectomy may still be considered the “gold standard” for gonadal ablation. The use of bilateral orchiectomy eliminates the possibility of a flare reaction and compliance problems as alternative explanations for the results observed with the Gn-RH analogues. Dijkman et al.27 reported on a multinational, prospectively randomized, placebo-controlled study comparing orchiectomy plus nilutamide to orchiectomy alone. The results showed a small but significant difference in median survival (27.3 versus 23.6 months, p = .032), observed at 8.5 years follow-up, in favor of the CAB regimen. All other large studies comparing orchiectomy and orchiectomy plus antiandrogen reported negative results.25,38–40 An Australian multicenter trial reported by Zalcberg et al.38 compared bilateral orchiectomy plus flutamide versus bilateral orchiectomy and placebo. This trial accrued 222 patients and was reported after a relatively short follow-up. Interestingly, the calculated median survival favored monotherapy over CAB (31 and 23 months, respectively) although the difference was not statistically significant (p = .21). Cyproterone acetate was used in two studies,39,40 demonstrating a benefit in the CAB arm. Eisenberger et al.25 reported on the largest trial conducted thus far to evaluate the CAB question (NCI INT0105). This study was a prospectively randomized, doubleblinded, placebo-controlled trial evaluating orchiectomy with or without flutamide in 1387 patients. It was conducted by the same investigators involved in INT-0036 and was planned to address the questions posed by its findings. The study was designed to have sufficient statistical power to detect a ≥ 25% survival advantage for the CAB arm, based on the results of the previous study (INT-0036).26 The follow-up period was approximately 50 months; 70% of patients were dead at the time of the final analysis. The study failed to confirm the initial findings of INT-0036 in


support of the CAB hypothesis. The median survival of patients on the CAB arm was 33 months compared to 30 months on the orchiectomy arm (two-sided stratified p = .14, hazard ratio = .91, 90% CI = 0.81–1.01).25 The only distinct differences between the two INT trials were the greater proportion of patients with minimal disease (13 versus 20%) and the younger age (median 67 versus 70 years) in the earlier trial. It is unlikely that these differences can explain the disparity in outcome between the studies. Similarly, the main differences between the multinational nilutamide trial27 and INT-0105 are the choice of nonsteroidal antiandrogen and the size of the studies, which again do not explain the difference in results. An important observation concerning the multinational nilutamide and INT-0105 studies is the differences in prostate-specific antigen (PSA) changes associated with treatment. Dijkman et al.27 observed that in 121 of 457 patients, PSA value normalized after 3 months of treatment and that early normalization corresponded to longer survival and time to progression (p < .0001). The percentage of patients with normal PSA at 3 months was significantly higher in the CAB group (p < .001). However, in INT-0105 there was a large difference in the proportion of PSA normalization (< 4.0 ng/mL) between CAB and monotherapy (74 versus 61%, p = .0002) without a concomitant difference in progression-free and overall survival. The observations of INT-0105 fail to support the role of PSA as a surrogate marker for survival in stage D2 patients and may reflect a separate effect on PSA expression mediated by antiandrogens, which is not associated with clinically significant changes in tumor growth.41 These findings once again underscore the complexity involved in the assessment of PSA for evaluation of therapeutic efficacy in patients with metastatic disease.42,43 Gn-RH Analogue plus Antiandrogens versus Orchiectomy Alone Orchiectomy was compared to a combination of Gn-RH analogue and antiandrogen in three trials. The selection of two different types of castration in the treatment arms prevents a double-blinded comparison of treatment arms. The European Organization for Research and Treatment of Cancer (EORTC) conducted a trial (30853) comparing goserelin plus flutamide to bilateral orchiectomy in 327 patients, most of whom had M1 disease. Preliminary analysis with a median follow-up of 30 months revealed no advantage for CAB.44 After a longer follow-up time, the investigators reported a 7 month benefit (p = .04) in median overall survival for the CAB arm.28,45 The Danish Prostatic Cancer Group (DAPROCA) conducted an identical study around the same time as EORTC 30853, which failed to confirm the survival advantage. The results showed longer overall survival for the monotherapy (leuprolide alone) arm although this was not statistically significant.46 An evaluation of DAPROCA and EORTC

30853 trials indicated comparable populations and study parameters. Combined analysis of both studies did not result in significant survival difference.47 Antiandrogens Most clinical trials evaluating nonsteroidal compounds employed primarily nilutamide and flutamide in the CAB treatment arm. Except for minor differences in the type and incidence of some adverse effects, CAB regimens with these compounds demonstrate comparable outcome figures.5 Bicalutamide, a widely used nonsteroidal antiandrogen, has not been evaluated in the context of CAB versus monotherapy in randomized controlled trials. Schellhammer et al.48 reported on a study comparing four CAB regimens: leuprolide plus flutamide, goserelin plus flutamide, leuprolide plus bicalutamide, and goserelin plus bicalutamide. The most recent analysis indicates no significant overall difference in survival between the four arms. Subset analysis suggests a trend only in survival benefit for leuprolide plus bicalutamide.49 In view of the nature of this evaluation (subset analysis) this observation should be considered preliminary. Another study from the Italian Prostate Cancer Group compared single-agent bicalutamide given at a dose of 150 mg to the combination of goserelin and flutamide. Very preliminary findings suggest a similar pattern of progression-free and overall survival for the two arms of treatment.50 The rationale for this comparison is not clear since previous trials showed that single agent bicalutamide was less active than castration alone in both 50- and 150-mg regimens.51,52 However, if future analysis of the mature data confirms the preliminary observation, the results of this trial will not be in favor of CAB. Seven studies35–37,39,40 (six are shown in Table 36–1) used CPA in combination with surgical or medical castration. Cyproterone acetate is a steroidal antiandrogen that has not been approved for this use in the United States. No trial using CPA reported a significant improvement in survival. In the PCTCG meta-analysis (see below), there appears to be a trend toward decreased survival in populations treated with CPA in the combined regimen.5 Future studies to evaluate the role of cyproterone acetate in the CAB setting are clearly not indicated.

Observations in Patient Subsets (Minimal Disease) Preliminary results of the INT-0036 trial suggested that the CAB effect could be more prominent in patients with minimal disease and good performance status.53 Minimal metastatic disease was defined as axial skeleton involvement (pelvis and spine) and/or nodal involvement whereas the extensive disease subset included patients with appendicular skeleton (extremities, skull, ribs) and/or visceral involvement. With a median follow-up of ≥ 60 months, the median progression-free survival was 19

TxNxM1: the Case for Monotherapy / 321

months for the leuprolide plus placebo arm and 48 months for the combination arm. The median survival was 42 and 61 months, respectively. Multivariate analysis of the INT-0036 data indicated that extent of disease represents an important prognostic factor in metastatic prostate cancer.53 The subset analysis on INT-0036 included only a limited number of patients and therefore should be reviewed as a hypothesis requiring confirmation in specifically designed prospective randomized trials. Data from EORTC 30853 also suggest that patients with good performance status and minimal disease may benefit the most from CAB.54 The definition of extent of disease in the EORTC trial is different from the NCI intergroup trials and involves counting the positive areas on bone scan and ignoring the status of visceral involvement. Once again, considering the very small number of patients in this subset category, no formal conclusion can be drawn. Following the findings in INT-0036 regarding the minimal disease subset, patients in the NCI INT-0105 trial were prospectively stratified by extent of disease. The advantage in progression-free and overall survival observed for the minimal disease subset in INT-0036 was not seen in INT-0105.25 Unfortunately, despite the large overall number of patients in INT-0105, the number of patients with minimal disease is still limited and prevents definitive statements. However, the Kaplan-Meier curve distributions of progression-free and overall survival in the minimal disease subset in INT-0105 suggest that the large differences seen in the earlier study are questionable. It is important to recognize that none of the studies conducted thus far were designed and sufficiently powered to address the question on the relative value of CAB in the various subsets.

Meta-analyses In 1995, the Prostate Cancer Trialists’ Collaborative Group (PCTCG) reported on the first meta-analysis conducted to increase the statistical power of individual prostate cancer trials. Their report included data from 22 randomized trials comparing CAB to castration monotherapy in 5710 patients.5 To achieve an intention-to-treat analysis, complete individual data on each randomized patient were requested from the investigators. Hazard ratio was calculated separately for every trial based on the raw data and then combined to all other trials using log rank statistics. The meta-analysis showed a 2.1% difference in mortality in favor of CAB treatment (6.4% reduction in annual odds of death), which is not statistically significant. The results were not influenced by separate analysis for the different antiandrogens (flutamide, nilutamide, or CPA) or by the different methods of gonadal ablation. Two separate meta-analyses evaluated the effects of flutamide and nilutamide in the context of CAB. Caubet et al.55 selected nine published trials with adequate information while Bertagna et al.56 included only trials that com-

pared orchiectomy plus nilutamide to orchiectomy alone (N = 7). While both reports suggest a significant survival advantage for the CAB approach, there are major concerns about these analyses regarding criteria for study selection, limited number of patients, short follow-up, and the use of published versus raw data analysis. Such methodologic problems reduce the significance of these reports.

Adverse Effects and Quality of Life Because hormonal treatment is primarily a palliative therapy and has not been shown to significantly affect survival in metastatic prostate cancer, it is important to evaluate quality-of-life (QOL) issues associated with CAB.57 Among the most common adverse reactions of androgen deprivation are hot flashes, gynecomastia (sometimes painful), anemia, diarrhea, and changes in liver function tests. Anemia and diarrhea, however, were significantly more prevalent in patients treated by castration combined with flutamide.25,26,28,49 Nilutamide has been associated with side effects such as pneumonitis, alcohol intolerance, and impaired adaptation to the dark.56,58 Bicalutamide as a single agent and in CAB was reported to cause breast tenderness and other adverse effects similar to flutamide although with lower incidence.49 Another way to evaluate treatment-related toxicity is to compare patient dropout from clinical trials. The INT0105 trial reported that 33 patients with CAB were removed from the study because of drug toxicity, compared to only 10 patients in the placebo arm (p = .003). Higher incidence of dropout was also reported with the use of nilutamide and bicalutamide in CAB regimens.27,49 Several authors claim that response rate was higher and symptoms were controlled earlier with CAB, which may suggest a more favorable QOL for this arm.58 No validated QOL assessment instrument was available during the time most CAB studies were conducted, however, and the information available on QOL parameters is quite limited in most trials. The only study that prospectively evaluated QOL in patients undergoing CAB treatment was recently reported by Moinpour et al.15 This randomized, doubleblind, placebo-controlled trial employed an evaluation of the Southwest Oncology Group (SWOG) QOL questionnaire during the initial 6 months of NCI INT-0105. Data were collected on three treatment-related adverse effects, on physical functioning, and on emotional functioning. Improvement in QOL over the baseline parameters was seen in both arms but was more pronounced in the placebo group (monotherapy). Patients in the CAB arm reported more diarrhea and worse emotional functioning that were both statistically significant.15 Thus, the QOL benefit from orchiectomy in metastatic prostate cancer patients appeared to diminish with the addition of flutamide, possibly because of increased incidence of adverse effects. Since metastatic prostate cancer is incurable by current therapeutic approaches, the higher incidence of


adverse events and reduced QOL coupled with factors such as cost of treatment should be balanced against an at best marginal overall clinical benefit resulting from this therapeutic approach.

Summary There has been a large body of data accumulated over the years on clinical trials evaluating the concept of CAB as the primary treatment for metastatic prostate cancer. There are significant differences in study design, size of trial, choice of agents, methods of evaluation, and, to a lesser extent, patient selection criteria. Of 27 trials involving approximately 8000 patients, three were reported to result in a statistically significant prolonged survival. The advantage in median survival represented in these three trials ranged from 3.7 to 7 months (12 to 25% improvement). Other clinical trials with similar design showed no significant improvements. Despite the differences between studies, data from a meta-analysis including all studies (PCTCG) indicate that the treatment effect of CAB is clinically negligible. Further, neither the type of gonadal ablation (surgical versus medical) nor the choice of nonsteroidal antiandrogen has an impact on outcome. Trials employing CPA, however, show a trend of worse survival in the CAB arm. The data outlined in this chapter demonstrate that CAB versus monotherapy trials have failed to show consistent and significant improvement in patient survival. Further, there is no evidence that CAB is associated with a favorable outcome in QOL.

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28.

results of the Veterans Administration Cooperative Urological Research Group studies. Monogr Natl Cancer Inst 1988;7;165–70. Peeling WB. Phase III studies to compare goserelin with orchiectomy and diethylstilbestrol in treatment of prostatic carcinoma. Urology 1989;33 Suppl 5:45–52. Soloway MS, Chodak G, Vogelzang NJ, et al. Zoladex versus orchiectomy in treatment of advanced prostate cancer: a randomized trial. Urology 1991;37:46–51. Huggins C, Stevens RE, Hodges CV. Studies on prostatic cancer. II. The effects of castration on advanced carcinoma of the prostate gland. Arch Surg 1941;43:209–22. Nesbit RM, Baum WC. Endocrine control of prostatic carcinoma. JAMA 1950;143:1317–20. Fleischmann JD, Catalona WJ. Endocrine therapy for bladder outlet obstruction from carcinoma of the prostate. J Urol 1985;134:498–500. Moinpour CM, Savage MJ, Troxel A, et al. Quality of life in advanced prostate cancer: results of a randomized therapeutic trial. J Natl Cancer Inst 1998;90:1537–44. Eisenberger MA, O’Dwyer PJ, Friedman MA. Gonadotropin hormone releasing hormone analogues: a new approach for prostate cancer. J Clin Oncol 1986;4:414–24. Mcleod D. Hormonal therapy in the treatment of carcinoma of the prostate. Cancer 1995;75:1914–9. Eisenberger MA, Simon R, O’Dwyer PJ, et al. A re-evaluation of nonhormonal cytotoxic chemotherapy in the treatment of prostatic carcinoma. J Clin Oncol 1985;3: 827–41. Belanger A, Brochu M, Cliche J. Levels of plasma steroid glucuronides in intact and castrated men with prostatic cancer. J Clin Endocrinol Metab 1986;62:812–5. Geller J, Albert JD. DHT in prostate cancer tissue: a guide to management and therapy. Prostate 1985;6:19–25. Labrie F, Veillux R, Fournier A. Low androgen levels induce the development of androgen-hypersensitive cell clones in shionogi mouse mammary carcinoma cells in culture. J Natl Cancer Inst 1988;80:1138–47. Labrie F, Dupont A, Belanger A, et al. Combination therapy with flutamide and castration (LHRH agonists or orchiectomy) in advanced prostatic cancer: a marked improvement in response and survival. J Steroid Biochem Mol Biol 1985;23:833–41. Isaacs JT, Wake N, Coffey DS, Sandberg AA. Genetic instability coupled to clonal selection as a mechanism for tumor progression in the Dunning R-3327 rat prostatic adenocarcinoma system. Cancer Res 1982;42:2353–71. Blumenstein BA. Some statistical considerations for the interpretations of trials of combined androgen therapy. Cancer 1993;72:3834–40. Eisenberger MA, Blumenstein BA, Crawford ED, et al. A randomized and double-blind comparison of bilateral orchiectomy with or without flutamide for the treatment of patients with stage D2 prostate cancer: results of NCI Intergroup Study 0105. N Engl J Med 1998;339:1036–42. Crawford ED, Eisenberger MA, Mcleod DG, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989;321:419–24. Dijkman GA, Janknegt RA, De Reijke TM, Debruyne FM. Long-term efficacy and safety of nilutamide plus castration in advanced prostate cancer and the significance of early prostate specific antigen normalization. J Urol 1997;158:160–3. Denis LJ, Keuppens F, Smith PH, et al. Maximal androgen blockade: final analysis of EORTC phase III trial 30853. Eur Urol 1998;33:144–51.

TxNxM1: the Case for Monotherapy / 323 29. Kuhn J-M, Billebaud T, Navratil H, et al. Prevention of the transient adverse effects of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide). N Engl J Med 1989;321:413–8. 30. Bono AV, DiSilverio F, Robustelli della Cuna G, et al. Complete androgen blockade versus chemical castration in advanced prostatic cancer: analysis of an Italian multicentre study. Urol Int 1998;60 Suppl 1:18–24. 31. Crawford ED, Kasimis BS, Gandara D, et al. A randomized controlled clinical trial of leuprolide and anandron vs. leuprolide and placebo for advanced prostate cancer. Proc Annu Meet Am Soc Clin Oncol 1990;9:A523. 32. Fourcade RO, Colombel P, Mangin M. Zoladex plus flutamide versus Zoladex plus placebo in advanced prostatic carcinoma. Extended follow-up of the French multicenter study. In: Murphy G, et al., editors. Proceedings of the 3rd International Symposium on Recent Advances in Urological Cancer; Jersey: SCI; 1992. p. 102–6. 33. Tyrell CJ, Altwein JE, Klippel F, et al. A multicenter randomized trial comparing the lutenizing hormonereleasing hormone analogue goserelin acetate alone and with flutamide in the treatment of advanced prostate cancer. J Urol 1991;146:1321–6. 34. Boccardo F, Pace M, Rubagotti A, et al. Goserelin acetate with or without flutamide in the treatment of patients with locally advanced or metastatic prostatic cancer. Eur J Cancer 1993;29A:1088–93. 35. de Voogt HJ, Studer U, Schroder FH, et al. Maximum androgen blockade using LHRH agonist buserelin in combination with short-term (two weeks) or long-term (continuous) cyproterone acetate is not superior to standard androgen deprivation in the treatment of advanced prostate cancer. Final analysis of EORTC GU Group Trial 30843. European Organization for Research and Treatment of Cancer (EORTC) Genito-Urinary Tract Cancer Cooperative Group. Eur Urol 1998;33:152–8. 36. DiSilvero F, Serio M, D’Eramo G, Sciarra F. Zoladex vs. Zoladex plus cyproterone acetate in the treatment of advanced prostatic cancer: a multicenter Italian study. Eur Urol 1990;18:54–61. 37. Thorpe SC, Azmatullah S, Fellows GJ, et al. A prospective randomized study to compare goserelin acetate versus cyproterone acetate versus a combination of the two in the treatment of metastatic prostatic carcinoma. Eur Urol 1996;29:47–54. 38. Zalcberg JR, Raghhaven D, Marshall V, Thompson PJ. Bilateral orchidectomy and flutamide versus orchidectomy alone in newly diagnosed patients with metastatic carcinoma of the prostate: an Australian multicentre trial. Br J Urol 1996;77:865–9. 39. Robinson MRG, Smith PH, Richards B, et al. The final analysis of the EORTC GU Group phase III clinical trial (protocol 30805) comparing orchidectomy, orchidectomy plus cyproterone acetate and low dose stilbestrol in the management of metastatic carcinoma of the prostate. Eur Urol 1995;28:273–83. 40. Jorgensen T, Tveter KJ, Jorgensn LH. Total androgen suppression: experience from the Scandinavian Prostatic Cancer Group Study No. 2. Eur Urol 1993;24:466–70. 41. Thalmann GN, Sikes RA, Chang SM, et al. Suramininduced decrease in prostate-specific antigen expression with no effect on tumor growth in the LNCaP model of human prostate cancer. J Natl Cancer Inst 1996;88:794–801.

42. Prentice RL. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med 1989;8:431–40. 43. Eisenberger MA, Nelson WG. How much we can rely on the level of prostate-specific antigen as an end point for evaluation of clinical trials? A word of caution. J Natl Cancer Inst 1996;88:779–81. 44. Keuppens F, Denis LJ, Smith PH, et al. Zoladex and flutamide versus bilateral orchiectomy. A randomized phase III EORTC 30853 study. Cancer 1990;66:1045–7. 45. Denis LJ, Carniero de Moura JL, Bono A, et al. Goserelin acetate and flutamide versus bilateral orchiectomy: a phase III EORTC trial (30853). Urology 1993;42:119–30. 46. Iversen P, Ramussen F, Klarskov P, Christensen IJ. Longterm results of Danish Prostatic Cancer Group Trial 86: goserelin acetate plus flutamide versus orchiectomy in advanced prostate cancer. Cancer 1993;72:3851–4. 47. Suciu S, Sylvester R, Iversen P, et al. Comparability of prostate trials. Cancer 1993;72:3841–6. 48. Schellhammer P, Sharifi R, Block N, et al. A controlled trial of bicalutamide versus flutamide each in combination with lutenizing hormone-releasing hormone analogue therapy in patients with advanced prostate cancer. Urology 1995;45:745–52. 49. Schellhammer P, Sharifi R, Block N, et al. Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind randomized multicenter trial. Urology 1997;50:330–6. 50. Boccardo F, Rubagotti A, Miglieta L, et al. Bicalutamide monotherapy versus flutamide plus goserelin in prostate cancer patients. Preliminary results of an Italian Prostate Cancer Group study. Proc Am Soc Clin Oncol 1997;16:A317. 51. Iversen P, Tveter K, Varenhorst E. Randomised study of Casodex 50 MG monotherapy vs. orchidectomy in the treatment of metastatic prostate cancer. The Scandinavian Casodex Cooperative Group. Scan J Urol Nephrol 1996;30:93–8. 52. Tyrrel CJ, Kaisary AV, Iversen P, et al. A randomized comparison of Casodex 150-mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer. Eur Urol 1998;33:447–56. 53. Eisenberger MA, Crawford ED, Wolf M, et al. Prognostic factors in stage D2 prostate cancer; important implication for future trials: results of a cooperative intergroup study (INT 0036). Semin Oncol 1994;21:613–9. 54. Sylvester R, Denis LJ, de Voogt HJ. The importance of prognostic factors in the interpretation of metastatic prostate cancer trials. Eur Urol 1998;33:134–43. 55. Caubet JF, Tosteson TD, Dong EW, et al. Maximum androgen blockade in advanced prostate cancer: a metaanalysis of published randomized controlled trials using nonsteroidal antiandrogens. Urology 1997;49:71–8. 56. Bertagna C, De Gery A, Hucher M, et al. Efficacy of the combination of nilutamide plus orchidectomy in patients with metastatic prostatic cancer. A metaanalysis of 7 randomized double-blind trials (1056 patients). Br J Urol 1994;73:396–402. 57. Altwein J, Ekman P, Barry M, et al. How is quality of life in prostate cancer patients influenced by modern treatment? The Wallenberg Symposium. Urology 1997;49S: 66–76. 58. Dijkman GA, Fernandez del Moral P, Debruyne FMJ, Janknegt RA. Improved subjective response to orchiectomy plus nilutamide in comparison to orchiectomy plus placebo in metastatic prostate cancer. Eur Urol 1995;27:196–201.

CHAPTER 37

TXNXM1: THE CASE FOR TOTAL ANDROGEN DEPRIVATION ALI M. ZIADA, MD; E. DAVID CRAWFORD, MD have different androgen requirements for maintaining function and growth. Conventional monotherapy with either orchiectomy or LHRH agonist only achieves ablation of testicular androgens. Suppression and destruction of the prostate cancer cells with high or moderate androgen dependence may occur initially, resulting in a response to therapy. The cells with low androgen requirements, however, will be maintained by androgens of adrenal origin. This population of cells will continue to grow and will later evolve into androgen-independent cells. The objective of combination therapy is to block androgens of testicular or adrenal origin and hence prevent overgrowth of androgen hypersensitive cells. Blocking the effect of androgens is achieved by both lowering levels of circulating hormone and by blocking the receptor site. As a result, interaction of DHT and testosterone with the receptor is prevented. Eliminating testicular androgens, either by orchiectomy or LHRH agonist, will reduce DHT within the prostate by 60%. As adrenal androgen accounts for 40% of DHT within the prostate, the value of combining an antiandrogen with orchiectomy or an LHRH agonist should be evident. The ideal antiandrogen should have high specificity and affinity for the receptor and should have intrinsic activity; it has not been developed yet.

Combined or maximum androgen blockade (CAB) involves administering a pure antiandrogen to the patient being treated for prostate cancer by surgical or medical castration, and is fast becoming the preferred treatment for advanced prostate cancer. The treatment targets all sources of androgen, with the intention of competitively inhibiting testosterone and dihydrotestosterone (DHT) binding at the androgen receptor level. An alternative method of achieving maximal androgen blockade employs finasteride, a 5 α-reductase type 2 inhibitor, to inhibit conversion of testosterone to the more potent androgen DHT. Monotherapy, with surgical castration or luteinizing hormone–releasing hormone (LHRH) agonists, addresses only the issue of testicular androgen, leaving the prostate open to stimulation by intraprostatic androgens that promote growth of androgen-hypersensitive cells. An initial report by Labrie et al.1 on the clinical use of combined androgen blockade with LHRH agonist plus flutamide created the enthusiasm for studying CAB and led to its widespread use. Although somewhat controversial, CAB has been shown to be valuable in many papers. The bulk of clinical evidence has demonstrated that there may be not only a benefit with regard to symptom control with combination therapy but also a survival benefit. Other studies failing to show a survival advantage have confirmed a benefit for symptoms.2 Many of the trials failing to show a therapeutic advantage either had too small a sample size and were too low power to detect clinical and statistical significant difference,3 or had too short a follow-up period to observe that difference. Meta-analysis has not been able to confirm or deny the therapeutic benefit of CAB4 because of the different characteristics of all trials included. Current analysis of the data supports the use of CAB since antiandrogen monotherapy has been shown to be neither equivalent nor superior to CAB, and surgical or medical castration alone is equal or inferior to the combination therapy.

Clinical Basis for Combined Androgen Blockade In 1941, Huggins and Hodges6 established the sensitivity of prostate cancer cells to androgens. Orchiectomy and/or high doses of estrogen became the standard therapy for metastatic prostate cancer until the mid-1980s with the advent of CAB. The use of orchiectomy as standard firstline treatment for metastatic prostate cancer has not shown a survival benefit and relapse is almost always inevitable.7 Both normal and neoplastic prostate cells are stimulated by androgens, most notably DHT. This androgen was previously thought to originate solely in the testes. It was then found that in men androgen formation also takes place in peripheral tissue, including the prostate, which contributes considerably to DHT formation. The greatest source of androgens in males are the testes, producing testosterone that is subsequently converted in peripheral tissue to DHT, the active metabolite.

Rationale for Combined Androgen Blockade The rationale for CAB is based on Labrie et al.’s hypothesis5 regarding mixed cell populations with a wide range of phenotypes in advanced tumors. According to this theory, the androgen-dependent cells contained within the tumor 324

TxNxM1: the Case for Total Androgen Deprivation / 325

The adrenals have also been shown to contribute to androgen production. Within the prostate, adrenal precursors as well as testosterone from the testes are transformed into the active androgen metabolite DHT, which stimulates cell growth. Testosterone, though less active than DHT, can also bind to the androgen receptor but with less affinity. Surgical castration by orchiectomy or medical castration using LHRH agonists results in reduction of serum testosterone concentration by 95%. The level of circulating serum testosterone, however, is insufficient to determine the level of active androgen available to the prostate because it does not take into account the intraprostatic level of DHT that is the result of adrenal precursors.

Defining Advanced Disease The best treatment available for advanced prostate cancer with metastasis beyond the prostate can provide major benefits in terms of disease-free survival, decreased pain, improved quality of life, and even prolongation of life; unfortunately, it cannot provide a cure. Major progress has been achieved in the areas of early diagnosis and management of early disease. Despite the most efficient diagnostic procedures available, however, prostate cancer has already spread beyond the prostate at the time of first diagnosis in 50% of patients. At histopathologic examination of radical prostatectomy specimens, the cancer is upstaged in 20 to 50% of cases as a result of finding nonorgan-confined disease.8–10 In one study, 17% of patients with stage T1c cancer were found to have positive margins at the time of surgery.11 In fact, about 50% of cancers are not confined to the prostate at the time of diagnosis, despite the best screening procedures.12 Prostate cancer outside the prostate should be considered advanced, indicating the need for an earlier and efficient management of micrometastasis. Crawford and Blumenstein13 have described a new classification system for advanced prostate cancer Table 37–1. This new staging system was proposed to identify the hormone refractory stage (D3) and to recognize those patients who fail primary therapy by manifesting a rising prostate-specific antigen (PSA) level (D1.5), or who present with a rising PSA level after nadir induced by initial hormonal therapy (D2.5). The importance of this staging is that stage D2 is no longer recognized as the most common reflection of prostate cancer. Rising PSA level after failed local therapy has become the most common presentation and may give a lead time of years before lesions develop on bone scans or in other organs.

Surgical Castration and Antiandrogens The combination of orchiectomy and nilutamide14 will lead to regression and stabilization of the disease for 78% of patients (64% with placebo), including subjective and objective responses. The median interval to objective pro-

gression in this large randomized trial was 20.8 months with nilutamide compared to 14.9 months with a placebo. Statistically significant differences in both response and progression rates were achieved with combination therapy over orchiectomy alone. The median survival time for combination therapy was 27.3 months compared to 24.2 with placebo, and the cancer-specific survival time was 37 months compared to 30 months with orchiectomy alone. Compared to monotherapy, the combination showed substantially better pain relief at 1, 3, and 6 months. Quality of life, measured by the Karnovsky score, was the same for both types of therapies. The best available data on the combination of orchiectomy and flutamide15 comes from the National Cancer Institute (NCI) sponsored trial INT0105 comparing orchiectomy plus flutamide to orchiectomy alone in the largest phase III study of metastatic prostate cancer ever conducted. This study demonstrated a PSA response rate of 81% in patients who received flutamide compared to 61% for patients who received orchiectomy alone. In the flutamide study arm, no treatment-related deaths occurred and the incidence of severe toxicity (grade 2/3) was low. The time to progression for patients treated with combination therapy was 21 months. When a subset of good-risk patients was analyzed (i.e., those with good performance status and minimal metastatic skeletal deposits), the time to progression was 49 months. Overall survival for patients treated with orchiectomy plus flutamide was 31 months but 52 months for the same subset of good-risk patients. There was no statistically significant advantage of combination therapy over orchiectomy alone in the overall time to progression and survival. Results of the effectiveness of combined orchiectomy and cyproterone acetate compared to orchiectomy alone have not been published. The European Organization for Research and Treatment of Cancer (EORTC) protocol 3085 is the largest clinical trial to report outcomes with the use of this combination. Initial results and a further survival analysis16,17 have shown that progression and survival rates for the combination arm were no different than for monotherapy. There are no data on response rate, median interval to progression, or duration of survival. Likewise, symptom improvement, quality of life, and advantages or disadvantages to the combination of the steroidal antiandrogen cyproterone acetate and orchiectomy were not addressed in these reports. At this time, no clinical trial has reported results of the combination of bicalutamide (Casodex) and orchiectomy versus orchiectomy as monotherapy. Overall, the combination of surgical castration and antiandrogens is more effective than orchiectomy alone in alleviating metastasis-related pain, normalizing tumor markers, increasing the objective response rate, and prolonging the interval to progression. Disadvantages include the side effects of adding an antiandrogen, long-


term cost of the drug, and the lack of evidence of a survival benefit in any published study.

Medical Castration (LHRH Agonists) and Antiandrogens In the largest trial of its kind, the overall response rate for patients treated with the LHRH agonist leuprolide in combination with the antiandrogen flutamide is 43.6%, compared to 35.3% for leuprolide and placebo.18 There was a complete response achieved in 7.9% of the patients on CAB, compared to 7.1% with leuprolide alone, and a partial response in 35.7% of patients receiving CAB, compared to 28.2% for orchiectomy and placebo. The median progression-free survival time was 16.5 months for the combination and 13.9 months for the patients treated with leuprolide alone (p = .039). The median length of survival was 35.5 months for the combination arm versus 28.3 months for the leuprolide and placebo group. Differences between the treatment arms in progression-free survival and overall survival were particularly evident for patients with minimal disease and better performance status (Southwest Oncology Group [SWOG] performance status 0 to 2). Neither quality of life nor symptomatic benefit for the patients treated in this trial was reported. The advantage of combination therapy was a 26% improvement in the overall survival rate. The disadvantages are side effects of the drugs, cost, and the requirement for indefinite administration of the LHRH agonist as well as the dosage regimen of the antiandrogen. New depot formulations have permitted longer intervals for administration of the LHRH analogues. The overall, complete, and partial response rates of the combination of the LHRH agonist (goserelin) and flutamide in a large phase III trial were each 60%.19 The biochemical response rate measured by acid phosphatase was 70% with CAB versus 57% for orchiectomy alone. There was a statistically significant difference seen in median time to subjective and objective progression. Median time to subjective progression was 21.75 months for the combination therapy compared to 13 months for patients treated with orchiectomy alone. The average time to objective progression was 33.25 months for those patients

TABLE 37–1. Stage D Prostate Cancer: Proposed New Staging D0 D1 D1.5 D2 D2.5 D3 D3S D3I

Elevated acid phosphatase Pelvic lymph nodes Rising PSA after failed local therapy Metastatic disease in bone and/or other organs Rising PSA after nadir level HRPC (hormone refractory prostate cancer) Hormonally sensitive Hormonally insensitive

From Crawford ED, Blumenstein BA. Proposed substages for metastatic prostate cancer. Urology 1997;50:1027–8.

treated with the LHRH analogue and flutamide and only 21.25 months for those treated with orchiectomy alone. The time to first objective or subjective progression was 17.75 months versus 11.5 months (p = .002) in favor of the combination. The median duration of survival was 27.1 months with orchiectomy and 34.4 months for CAB. Disease-specific survival for orchiectomy was 28.8 months and 43.9 months for CAB (p = .007). Patients with less severe disease had a tendency to benefit the most from this combination therapy. Symptomatic control and quality of life was better for combination therapy, when analyzed by the following subjective parameters: World Health Organization (WHO) performance status, pain score, weight loss, and urologic symptoms. Progression-free intervals (free of symptoms and better quality of life) were also better with combination therapy: 13 months for the orchiectomy group versus 21 months for CAB. The combination of goserelin acetate and flutamide clearly has a response rate, overall median time to progression, symptomatic control, and survival advantage over orchiectomy alone. The disadvantages are a higher incidence of side effects for the combination therapy and a 7% rate of flutamide discontinuation due to liver or gastrointestinal toxicity. There are no data related to response rate, time to progression, symptomatic benefit, or survival for the combination of an LHRH agonist plus bicalutamide (Casodex) compared to an LHRH agonist alone. In a trial comparing the former regimen to an LHRH agonist and flutamide,20 the bicalutamide-based regimen using flutamide was equally effective, with the advantages of having fewer side effects (most notably, diarrhea) and a more convenient daily dosing. The combination of buserelin acetate and cyproterone acetate has not shown a benefit when compared to orchiectomy alone or buserelin plus two weeks of cyproterone acetate to block the flare phenomenon. Although the published results are from a study with a very small sample size and immature data, the use of the steroidal antiandrogen with an LHRH agonist buserelin does not appear to confer any benefit. This form of CAB did not show any difference compared to monotherapy (either buserelin alone or orchiectomy) with respect to response rate, degree of pain relief, time to progression, or duration of survival.21 The addition of cyproterone acetate has been shown to eliminate the biologic and biochemical signs of exacerbation (the flare phenomenon, discussed later in the chapter) that occurs with the use of LHRH analogues.22

Estrogens and Antiandrogens Reducing the dose of estrogens and adding an antiandrogen has the theoretic advantages of decreasing the well-known complications of estrogens, blocking the effect of residual circulating androgens, and lowering the cost of combined androgen blockade.23 No large randomized clinical trial has been conducted to evaluate this alternative. Geller et al. pro-


posed this possibility in 1981.24 In an analysis of 23 stage D2 patients treated with the steroidal antiandrogen megestrol acetate and diethylstilbestrol no advantage to either surgical castration or estrogen alone was shown in median time to progression of disease.25 The combination of steroidal antiandrogens and low-dose estrogens has proved to be effective in reducing serum testosterone to castration levels.26 The efficacy and clinical benefit of this combination compared to monotherapy remains to be seen.

Other Combinations The clinical usefulness of LHRH antagonists in the treatment of advanced prostate cancer is beginning to be reported.27 These new agents seem to be useful as monotherapy in the treatment of metastatic prostate cancer. The use of the LHRH antagonists avoids the initial transient stimulation that occurs with the use of LHRH agonists in monotherapy. Use of these novel substances in combination with antiandrogens warrants controlled clinical trials. Finasteride, a 5 α-reductase type 2 inhibitor, has been shown to have a direct inhibitory effect on prostate cancer cell lines.28 Also, finasteride combined with flutamide has been shown to decrease the size of the ventral prostate in the rat.29 Clinical responses in the treatment of advanced prostate cancer with finasteride as monotherapy have not been dramatic.30 Since the drug simply blocks conversion of testosterone to dihydrotestosterone and does not lower serum or intraprostatic levels of testosterone, an escape is seen through continued binding of testosterone to the androgen receptor, resulting in continued stimulation of tumor growth. Theoretically, the combination of flutamide and finasteride could effectively control tumors while maintaining serum levels of testosterone and decreased side effects due to hormonal manipulation. In a very small, nonrandomized, clinical trial of flutamide and finasteride in stage C and D1 sexually active patients, a biochemical response (measured by PSA) and durable response (up to 24 months) was shown in 22 of the 23 treated patients. Eighty-six percent of the men in the study maintained their sexual function.31 In an uncontrolled clinical trial with finasteride (5 mg PO bid) and flutamide (125 mg PO bid), the current authors treated 61 patients with rising PSA levels indicating failed therapy for apparent clinically localized disease, whether radical prostatectomy, radiation therapy, or cryosurgery. The chemical response rate was 60% with undetectable serum PSA levels. With an average follow-up of 12 months, four patients have failed this treatment method, as indicated by a rise in PSA. All patients (five of five) who were sexually potent at the start of therapy remained so [unpublished observation]. The effectiveness of this combination therapy needs to be evaluated in a randomized, controlled, clinical trial with adequate follow-up. The treatment seems to have good tumor control while preserving sexual function on patients with low tumor burden (i.e., stage D1.5).

FIGURE 37–1. Diagram representing the prostatic cells intracrine activity and the effects of other organs (hypothalamus, pituitary, adrenals and gonads).

The Flare Phenomenon The use of LHRH agonists induces an initial LH or gonadotrophin hormone release, followed by an increase in the LH dependent production of androgens from the testes.32,33 The rise in serum androgen levels is coupled with an increase in serum levels of alkaline phosphatase and prostate-specific antigen.34 These biochemical manifestations of tumor activity are thought to result from a temporary rise in testosterone and can become serious, even life threatening,35 in symptomatic patients showing high tumor burden, neurologic manifestations of spinal cord compression by bony metastases, or uremia from urinary flow obstruction. The phenomenon was recognized early in the use of LHRH agonists36 and has been confirmed in several reports.37–42 The chemical and clinical disease flare appears in 4 to 33% of patients treated with LHRH agonists as monotherapy but clinical disease flare is seen in less than 10%.39 It is now clear that this biologic effect does not generate an acceleration of tumor growth that would impair the beneficial effect of these compounds. Qayum et al. showed that another possible explanation of this phenomenon is a direct stimulus of cancer cells by LHRH analogues.43 Prostate cancer cell lines and benign and malignant tumors may contain high affinity LHRH receptors.44,45 Animal studies have shown that the cellular activity of cancer induced with LHRH analogues occurs before testosterone production increases and can continue even in the absence of this and other androgens. An initial, simultaneous administration of either keto-


conazole, estrogens, steroidal antiandrogens (cyproterone acetate), or pure antiandrogens (flutamide, nilutamide, or bicalutamide), prevents the initial and temporary detrimental effect occasionally observed with LHRH agonist used as monotherapy.39 Early reports using the LHRH antagonists have not noted a flare phenomenon.43

Antiandrogen Withdrawal Syndrome The antiandrogen withdrawal syndrome (AAWS) is the characteristic biochemical and clinical response observed when an antiandrogen is discontinued after evidence of disease progression in those patients treated with combined androgen blockade. It was initially described with the use of flutamide,46 and has subsequently been observed with other steroidal antiandrogens, pure antiandrogens, progestational agents, and estrogens.47 Patients on monotherapy with antiandrogens do not seem to manifest this response. Whether this is a therapeutic advantage of CAB with antiandrogens or a major drawback of these drugs is not known. Some authors have postulated that AAWS is the factor responsible for differing survival rates for the combination arms of CAB trials.48 Other interim endpoints, however, such as time to progression, also differ. Antiandrogen withdrawal syndrome seems not to be the reason for the survival difference due to the fact that these other interim results, which are a reflection of the therapeutic intervention, are usually measured before antiandrogen is withdrawn. Researchers have focused on the molecular basis of this response, directed by the findings on the paradoxically stimulatory effect of flutamide on LNCaP prostate cancer cell line. It has been shown that LNCaP possesses a mutated androgen receptor that is stimulated by the antiandrogen in a dose-dependent fashion. This and other mutations of the androgen receptor have been documented in metastatic and hormonally independent prostate cancer tissue.49 Castration induces synthesis of androgen receptors.40 Amplification of these receptors has been observed in 30% of prostate cancer specimens.41 An amplified mutated androgen receptor stimulated by antiandrogens could explain the response observed from stopping the paradoxical stimulatory effect of these drugs. An over 50% decline in PSA levels from baseline is observed in 28 to 80% of patients treated with antiandrogen withdrawal after evidence of disease progression. Symptomatic improvement is seen in 25 to 56% of patients. The median exposure to CAB is 16 to 96 months, the median time to respond is less than 6 weeks, and the median duration of response is 4 to 14.5 months (range 2 to 30 months). The patients more likely to respond are those with longer exposure time to the antiandrogen and those with higher serum PSA values.

Timing There is still a great deal of controversy over when androgen ablation should be initiated, despite the known efficacy

of CAB. Symptomatic patients should obviously be treated immediately. Controversy remains concerning those patients diagnosed with advanced disease who are asymptomatic. Due to the known side effects and financial burden of the various hormonal options, the decision is not trivial for many of those men with a good performance status and an active sexual life, especially when cost is an issue. With the assumption of tumor doubling time of days to several months, by the time of diagnosis about 75% of the tumor’s life has elapsed, making the notion of “early” therapy a misnomer. Indeed, many patients may have a nearlethal tumor burden at the time of presentation.42 Hormonal therapy may be curative for at least 10% of these patients. Theoretically, waiting until the tumor burden is uncontrollable may exclude those patients from this option. Until now, there have been no randomized controlled trials addressing this issue although some inferences can be made based on existing data. Animal studies have demonstrated an inherent survival advantage for those animals receiving early androgen ablation or extirpation of the primary tumor coupled with prompt initiation of systemic therapy.50 Re-evaluating the survival data in the Veterans Administration Cooperative Urological Research Group (VACURG) study51 sheds light on this issue. Based on the evidence in this study, younger patients with highgrade tumors (Gleason score 7 to 10) and stage D disease appear to derive a survival benefit from the initiation of hormonal therapy at the time of diagnosis. Other retrospective analyses have shown that in surgically proven stage D1 patients the progression-free interval is prolonged with early hormonal manipulation and there is a trend toward longer survival.52,53 The NCI trial INT0036 with LHRH agonist plus flutamide15 showed a substantial benefit for those patients with good performance status and lower tumor burden treated with CAB at the time of diagnosis, suggesting that the best results are seen in patients treated early in the course of their disease. Also, patients with advanced prostate cancer may experience a long asymptomatic disease period with androgen ablation. Recently, the results of a trial conducted by the Medical Research Council Prostate Cancer Working Party Investigators Group in the United Kingdom clearly demonstrated an advantage of early hormonal manipulation. This study included 938 patients randomized to immediate versus delayed hormonal manipulation with orchiectomy or an LHRH analogue for most patients. Both groups had a similar distribution of M0, Mx, and M1 patients. Distant and local progression were significantly more common in the deferred treatment group. At the time of publication, 67% of the study population had died from prostate cancer. There was no significant difference in patients with Mx or M1 disease but a survival advantage was noted for M0 patients. These results support the contention that early hormonal therapy is superior to delayed therapy.54


Men die from development of an androgen insensitive cell population that is unaffected by hormonal manipulation. Aside from the potential side effects of CAB and its cost, the risk of this early therapy could, theoretically, encourage the development of androgen independent clones of prostate cancer cells and lead to disease for which there is no effective therapy. Further scientific investigation is required regarding the dynamics of these androgen-resistant tumors. Nevertheless, physicians and patients must play an active role in the decision-making process, weighing the risks and benefits of the alternative therapeutic options. Early CAB will delay the interval to disease progression, prolong the symptom-free interval, perhaps preserve the quality of life of patients, and may eventually permit simultaneous use of other systemic therapies in a time when the tumor burden is more likely to respond.

Intermittent Hormonal Manipulation Intermittent therapy involves initiating androgen deprivation and, when a predefined clinical response is achieved, halting treatment to allow the tumor to repopulate with androgen-sensitive cells. Continuous block of androgendependent growth may cause some of these tumor cells to become hormonally independent. Due to the reversible nature of medical castration, the use of intermittent therapy would allow the tumor cells to escape from this hormonal independent growth. In vitro and animal models of prostate cancer suggest that intermittent androgen suppression delays progression to the androgen independent state but does not prevent it.55 Goldenberg et al.,56 in a very heterogeneous group of prostate cancer patients treated with various forms of intermittent combinations of androgen blockade, reported that during the off-treatment period patients had an improved sense of well-being and near normal sexual function. The mean overall survival was 52 months for patients with D2 disease. Intermittent androgen suppression therapy has the theoretic advantage of reduced toxicity and cost. It remains to be proven in randomized, controlled trials whether there is a survival advantage.

Conclusion Hormonal treatment is the first line of defense for advanced and recurrent disease. Androgen blockade is the only treatment of prostate cancer that has been shown to prolong life at both localized and advanced levels of disease. Combined androgen blockade using an optimal dose of a pure antiandrogen in association with medical castration offers a unique oppurtunity to remove all androgenic stimulation of a prostate neoplasm. Although the controversy regarding the merit of combined androgen blockade will continue as metastatic disease is noted at lower disease burdens, this therapy will have increasingly important applications.

References 1. Labrie F, Dupont A, Belanger A, et al. Combination therapy with flutamide and castration (LHRH agonist or orchiectomy) in advanced prostate cancer: a marked improvement in response and survival. J Steroid Biochem 1985;23:833–42. 2. Schellhammer PF. Combined androgen blockade for the treatment of metastatic cancer of the prostate. Urology 1996;47:622–8. 3. Blumenstein BA. Some statistical considerations for the interpretation of trials of combined androgen therapy. Cancer 1993;72 Suppl 12:3834–6. 4. Prostate Cancer Trialists’ Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomized trials with 3283 deaths in 5710 patients. Lancet 1995;346:265–9. 5. Labrie F, Dupont A, Belanger A, et al. New approach in the treatment of prostate cancer: complete instead of partial withdrawal of androgens. Prostate 1983;4:579–94. 6. Huggins C, Hodges DV. Studies on prostate cancer. The effect of castration, of estrogen and androgen injection on serum phosphates in metastatic carcinoma of the prostate. Cancer Res 1941;1:293–7. 7. Paulson D, Howe GB Jr, Hinshaw W, et al. Radiation therapy versus delayed androgen deprivation for stage C carcinoma of the prostate. J Urol 1984;131:901–2. 8. Gibbons RP, Correa RJ Jr, Brannen GE, Weissman RM. Total prostatectomy for clinically localized prostate cancer: long-term results. J Urol 1989;141:564–6. 9. Lange PH, Narayan P. Understanding and undergrading of prostate cancer. Argument for postoperative radiation as adjuvant therapy. Urology 1983;21:113–8. 10. Catalona WJ, Stein AJ. Staging errors in clinically localized prostatic cancer. J Urol 1982;127:452–6. 11. Epstein JI, Walsh PC, Carmichael M, Brendler CB. Pathologic and clinical findings to predict tumor extent of nonpalpable (stage T1c) prostate cancer. JAMA 1994;271:368–74. 12. Labrie F, Candas B, Cusan L, et al. Diagnosis of advanced or noncurable prostate cancer can be practically eliminated by prostate-specific antigen. Urology 1996;47:212–7. 13. Crawford ED, Blumenstein BA. Proposed substages for metastatic prostate cancer. Urology 1997;50(6):1027–8. 14. Janknegt RA, Abbou CC, Bartoletti R, et al. Orchiectomy and nilutamide or placebo as treatment of metastatic prostatic cancer in a multinational double-blind randomized trial. J Urol 1993;149:77–83. 15. Crawford ED, Eisenberg MA, McLeod DG, et al. Comparison of bilateral orchiectomy with or without flutamide for the treatment of patients with stage D2 adenocarcinoma of the prostate: results of NCI intergroup study 0105 (SWOG and ECOG) [abstract 1311]. J Urol 1997;157:336. 16. Robinson MRG, Hetherington J. The EORTC studies: is there an optimal endocrine management for M1 prostatic cancer? World J Urol 1986;4:171–5. 17. Robinson MRG. A further analysis of European Organization for Research and Treatment of Cancer Protocol 30805. Orchiectomy versus orchiectomy plus


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33. Warner B, Worgul TJ, Drago J, et al. Effect of very high dose d-Leucine 6-gonadotropin-releasing hormone proethylamide on the hypothalamic-pituitary testicular axis in patients with prostatic cancer. J Clin Invest 1983;71:1842–53. 34. Schröeder FH, Lock TMTW, Chadha DR, et al. Metastatic cancer of the prostate managed with buserelin versus buserelin plus cyproterone acetate. J Urol 1987;137: 912–8. 35. Mahler C. Is disease flare a problem? Cancer 1993;72 Suppl 12:3799–802. 36. Faure N, Lemay A, Laroche B, et al. Preliminary results on the clinical efficacy and safety of androgen inhibition by an LHRH agonist alone or combined with an antiandrogen in the treatment of prostatic carcinoma. Prostate 1983;4:601–24. 37. Kelly WK, Scher HI. Prostate-specific antigen decline after antiandrogen withdrawal. J Urol 1993;149:607–9. 38. Scher HI, Zhang ZF, Nanus D, Kelly WK. Hormone and antihormone withdrawal: implications for the management of androgen-independent prostate cancer. Urology 1996;47 Suppl 1A:61–9. 39. Moul JW, Srivastava S, McLeod DG. Molecular implications of the antiandrogen withdrawal syndrome. Semin Urol 1995;13:157–63. 40. Hiipakka RA, Liao S. Androgen physiology. In: DeGroot LJ, editor. Endocrinology. 3rd ed. Philadelphia: WB Saunders; 1995. p. 2336–47. 41. Visakorpi T, Hytinen E, Koiviston P, et al. Amplification of androgen receptor gene associated with tumor recurrence in prostate cancer patients receiving androgen withdrawal therapy [abstract]. Basic and clinical aspects of prostate cancer. Philadelphia (PA): Proceedings of The American Association of Cancer Research; 1994. A-41. 42. Fair WR, Heston WDW. Overview of cancer biology and principles of oncology. In: Walsh PC, Retik AB, Stamey TA, Vaughan ED, editors. Procedures of The American Association of Cancer Reseach. Campbell’s Urology. 6th ed. Philadelphia: WB Saunders; 1992. p. 1031–52. 43. Qayum A, Gullick W, Clayton RC, et al. The effects of gonadotrophin-releasing hormone analogues in prostate cancer are mediated through specific tumor receptors. Br J Cancer 1990;62:96–9. 44. Limonta P, Dondi D, Moretti RM, et al. Antiproliferative effects of luteinizing hormone–releasing hormone agonist on the human prostatic cancer cell line LNCaP. J Clin Endocrinol Metab 1992;75:207–12. 45. Palyi I, Vincze B, Kalnay A, et al. Effect of Gonadotropinreleasing hormone analogues and their conjugates on gonadotropin-releasing hormone receptor-positive human cancer cell lines. Cancer Detect Prev 1996;20: 146–52. 46. Kelly WK, Scher HI. Prostate-specific antigen decline after antiandrogen withdrawal. J Urol 1993;149:607–9. 47. Scher HI, Zhang ZF, Nanus D, Kelly WK. Hormone and antihormone withdrawal: implications for the management of androgen-independent prostate cancer. Urology 1996;47 Suppl 1A:61–9.

TxNxM1: the Case for Total Androgen Deprivation / 331 48. Goodman A, Rall TW, editors. Murad ferid hormones and hormone antagonists. The pharmacological basis of therapeutics. 8th ed. Pergamon Press; 1990. p. 1332–60. 49. Moul JW, Srivastava S, McLeod DG. Molecular implications of the antiandrogen withdrawal syndrome. Semin Urology 1995;13:157–63. 50. Isaacs JT. The timing of androgen ablation therapy and/or chemotherapy in the treatment of prostatic cancer. Prostate 1984;5:1–7. 51. Byar DP, Corle D. Hormone therapy for prostate cancer. Results of the Veterans Administration Cooperative Urological Research Group’s studies of cancer of the prostate. Monogr Natl Cancer Inst 1988;7:165–70. 52. Zincke H, Bergstralh EJ, Larson-Keller JJ, et al. Stage D1 prostate cancer treated by radical prostatectomy and

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CHAPTER 38

IS EARLY HORMONAL THERAPY PREFERABLE? VALAL GEORGE, MD, PHD; MAHA HUSSAIN, MD, FACP Widespread clinical use of prostate-specific antigen (PSA) for the early detection and monitoring of treatment outcomes in prostate cancer has resulted in a significant stage migration. It has also helped alter the definition of advanced prostate cancer, with the spectrum ranging from patients with locally advanced stage disease to overt systemic metastases. The past two decades have also witnessed significant technical improvements in the delivery of both local and systemic therapy although several basic questions remain unanswered. One question which continues to be debated is the timing of hormonal therapy. Previously this question was relevant primarily for patients with newly diagnosed metastatic disease. Today, however, it also involves patients who have a high risk of systemic relapse at the time of diagnosis and the growing population of patients with rising PSA levels as the sole manifestation of disease recurrence following local therapy. In the absence of conclusive prospective randomized clinical trials, treatment decisions are at times driven by emotion rather than by reason. Although most clinicians in the United States currently treat at the first objective sign of systemic metastases, the approach is less certain when an increased PSA level is the only manifestation of progression. Further, practice patterns may vary in other countries. In considering early hormonal therapy, the high response rate, favorable side-effect profile, and availability of long-acting reversible androgen deprivation therapies must be weighed against the palliative nature of androgen deprivation, the predictable progression to androgen independence in virtually all patients treated with life-long androgen ablative therapy, and the documented adverse effects on quality of life and on various organ systems.

be the earliest point in time for hormonal therapy. This position could be justified by the current data indicating that despite a steady decline in the incidence of newly diagnosed metastatic disease1 and microscopic lymph node metastases (from 20% in 1972 to 1988 to 3.4% in 1988 to 1991),2 the risk of extraprostatic disease in patients with clinically organ-confined prostate cancer is still significant (40 to 60%).3–7 Depending on the local/regional extent and histologic grade of the disease, approximately 50% of patients with prostate cancer will progress despite definitive local therapy, verifying the presence of early but occult systemic disease.8–10 Prostate-Specific Antigen Relapse and Metastatic Disease Serial PSA measurements following definitive local therapy have proven that the rate of permanent prostate cancer eradication is not as high as previously believed.8,9,11–13,14 Current data suggest that in most cases a rising PSA level following local therapy heralds clinical progression.11,14 The number of patients with a rising PSA level after local therapy is increasing; the time of their failure represents the second point in time of relevance to early hormonal therapy. Earlier data suggested that lack of PSA normalization following local irradiation correlated with subsequent PSA failure and that up to 44% of patients with PSA failure would develop systemic metastases within 3 years.15 Subsequent reports indicated that in patients treated with local irradiation, a post-therapy PSA doubling time of less than 6 months is highly associated with systemic relapse. On average it takes 4.5 times PSA doubling time to clinical recurrence.16 In 100 patients with a rising PSA level after treatment, Pollack et al. calculated that the median time from PSA elevation to clinical relapse was 40 months.17 One report indicated that the PSA doubling time differed in the first 2 years following surgery or irradiation but became similar after 2 years.18 The authors concluded that the growth rate of recurrent cancer after radiation and radical prostatectomy is similar. Recent observations from Lee et al. shed more light on the natural history of this disease.14 Overall, the estimated rate of distant relapse is 47% at 5 years following PSA failure. Predictors of distant metastases in a multivariate analy-

Natural History of Metastatic Prostate Cancer Occult Metastases An important variable in “early hormonal” therapy is the definition of “early.” Since the intent is to treat systemic disease effectively to prolong survival and reduce morbidity, it could be argued that the start of adjuvant hormonal therapy in carefully selected high-risk patients will 332

Is Early Hormonal Therapy Preferable? / 333

sis were time to PSA elevation (0 to 11.9 months versus ≥ 12 months, p < .001) and post-treatment PSA doubling time (0 to 11.9 months versus ≥ 12 months, p = .01). Seventy-five percent of patients with an increasing PSA profile within 12 months of treatment developed distant metastases within 5 years from the time of PSA elevation as opposed to 25% of those having a PSA rise at least 12 months after treatment (p < .001). Among surgically treated patients, it has been reported that 50 to 100% of patients whose PSA becomes detectable within the first year following radical prostatectomy will progress rapidly, with either local recurrence or distant metastasis.7,19–21 The effects of PSA-induced stage migration have also been noted in patients with newly diagnosed metastatic prostate cancer. This is reflected by a decline in the percentage of patients presenting with metastatic disease1 and is illustrated by data from the Metropolitan Detroit Cancer Surveillance System (member of the National Cancer Institute [NCI] SEER Program). Trends in stagespecific incidence were evaluated during a 22-year period (1973 to 1994). Incidence rates for stage of local and regional prostate cancer reached a maximum in 1992 and 1993, and distant stage disease has declined steadily since 1989 (p < .001). Despite the decline in its incidence and the perceived shift toward a less severe form of disease at presentation, metastatic prostate cancer remains incurable despite the best available therapy.22,23 Biology of Hormonally Treated Prostate Cancer Prostate cancer is a slowly growing tumor with low cellular turnover. There is a trend toward increased heterogeneity and genetic instability as tumor volume increases, reflected by increased incidence of aneuploidy and molecular changes. The frequency of aneuploidy increases with stage.24 The aggressive nature of nondiploid tumors is illustrated by the higher mortality associated with them compared to diploid tumors, despite appropriate therapy.25–29 There have been a variety of chromosomal alterations and loss/mutations of tumor suppressor functions associated with the metastatic and androgen independent phenotype. These are summarized in Figure 38–1.30–35 Reviewing the issue of early hormonal therapy in 1991, Kozolowski et al. stated that “there is no experimental or clinical evidence that early androgen ablation is biologically deleterious.”36 Although early but limited exposure may not be deleterious, the long-term sequelae of early and life-long hormonal therapy are not well known. The androgen dependence of prostate cancer is well established, as is the inevitable and irreversible progression to androgen independence.37,38 The latter heralds the terminal step in the natural history of prostate cancer. Clear understanding of the mechanism of progression is crucial not only for the development of better systemic therapy but also for clinicians considering early, long-term hormonal therapy. The mechanisms characterizing progres-

sion from localized to metastatic to androgen-independent prostate cancer are unclear. Of increasing relevance to the issue of early hormonal therapy are the genetic alterations underlying progression to androgen independence (see Figure 38–1). Two theories have been proposed to explain the phenomenon: the adaptation model and the clonal selection model.39,40 Central to both is an androgendeprived environment that may foster development or expansion of the androgen-independent phenotype. Experimental observations in the Dunning rat prostatic adenocarcinoma model may support treatment by early hormonal therapy.41 Tumor regression and increased survival were more achievable if the tumor volume was relatively small at the time of castration.41,42 On the other hand, studies using poorly differentiated, fast growing tumors demonstrated a significant reduction in androgen sensitivity and lack of response to castration in the later transplant generations. These data suggest the potential for mutation selection and spontaneous progression to androgen independence and the possible role for early castration in preventing progression.43 Results in the Dunning rat model must be contrasted with the observations of Bruchovsky et al.38 in their use of the Shionogi androgen-dependent mammary carcinoma. In this tumor model, androgen withdrawal resulted in the elimination of differentiated cells and a decrease in the number of tumorogenic stem cells. Despite continued androgen deprivation, tumor progression ensued and was associated with a 20-fold increase in the proportion of stem cells as well as a massive 500-fold increase in androgenindependent stem cells. Progression was delayed but not prevented by periods of androgen exposure and deprivation.44 The authors suggested that progression in this model may be due to the activation and enhanced expression of androgen-repressed genes coding for autocrine and paracrine growth factors that replace androgens in maintaining the viability of tumor cells. Progression to androgen independence has been clinically and experimentally associated with multiple changes at basic levels of cellular control, including increased expression of bcl-2 and C-myc,45,46 TRPM-2,47 altered P53 status, and androgen receptor-gene amplification and mutations.30,47,48 The bcl-2, a negative regulator of apoptosis, may form a hetrodimer with a related protein bax, a positive regulator of programmed cell death. The ratio of bcl-2 and bax determines cell survival or death. Experimentally, bcl-2 overexpression protected human prostate cancer cells from apoptosis in vitro and conferred resistance to androgen deprivation in vivo.49 Further, expression of bcl-2 has been linked to the androgen-independent property of prostate cancer recurrences.50,51 Enhanced expression of C-myc proto-oncogenes is observed following castration;46 it is involved in the regulation of mitosis and apoptosis.52 In the presence of critical growth stimuli such as overexpression of bcl-2, C-myc capacity to induce apoptosis may be

334 / Advanced Therapy of Prostate Disease LOCALIZED PROSTATE CANCER

Germline mutation Methylation changes 8p-loss

ANDROGENDEPENDENT TUMOR (Metastatic)

Osteonectin/ thrombospondin (angiogenesis) Chromosomal alterations 10p23; 16q; 11p; 13q; 17p

REGRESSED TUMOR

RECURRENT TUMOR ANDROGEN INDEPENDENT

LOCALIZED PROSTATE CANCER

METASTATIC (Androgen Dependent)

METASTATIC (Androgen Independent)

Androgen receptor and mutations TRMP-2 ↑ bcl-2 ↑ E-cadherin ↓ P53 ↓ C-myc ↑

Germline mutation (e.g., hMSH2 gene)

Osteonectin/ ↑ thrombospondin ↑ (angiogenesis) Chromosomal alterations allelic loss: 10p23; 16q; 11p; 13q; 17p gains: 7p and 8q Aneuploid ↑ TGF-beta, FGF-2, IGF ↑

Androgen receptor and mutations TRMP-2 ↑ bcl-2 ↑ E-cadherin ↓ P53 ↓ C-myc ↑

Methylation changes 8p-loss Diploid

FIGURE 38–1. Molecular events in prostate cancer progression.

abrogated.53 Expression of C-myc oncogene is demonstrated in both LNCap cells (hormone sensitive) and DU 145 cells which are not dependent on hormones for survival.54 Elevated levels of C-myc are often associated with cell proliferation and metastases. The tumor suppressor gene Mxil located at chromosome 10q22.1 is related to C-myc activity; less of this suppressor may lead to C-myc activation.55 These observations may in part help explain the clinical experience with hormone therapy. They should raise concerns about the potential deleterious effects of long-term therapy. The Case for and against Early Hormonal Therapy There has been a debate regarding the timing of androgen deprivation since it was introduced.56 At issue is whether early androgen deprivation improves survival. This has not been resolved as no prospectively randomized studies are available to answer the question stage by stage. Support for early hormone therapy was originally based on several reports that invariably involved comparisons with historic controls.57–59 Historic data on untreated metastatic prostate cancer reflect a very high mortality, with a median survival of less than 10 months.58 Arguments for early hormonal therapy based on comparisons with historic data are flawed for several reasons, including the retrospective nature of these studies, lack of randomization, changing patient characteristics, impact of progress in medical care on comorbidities, and on the diagnosis and management of prostate cancer with leadtime bias offered by early diagnosis/improved staging. Studies in Early Stage Disease The bulk of the experience on “early” hormonal therapy is derived from studies conducted by the Veterans Administration Cooperative Urological Research Group (VACURG) (discussed in the next section) and adjuvant or neoadjuvant hormonal trials in conjunction with definitive local therapy. Data summarized below suggest that hormonal therapy as part of a multimodal approach in the ini-

tial management of localized prostate cancer resulted in an improvement in disease-free survival and delayed progression. Conclusive evidence for absolute improvement in survival is yet to be demonstrated. There was a significant disease-free survival advantage noted at 5, 10, and 15 years in favor of diethylstilbestrol (DES) plus radiation therapy compared to radiation therapy only in patients with locally advanced prostate cancer.60 The authors attributed the lack of an overall survival advantage to the greater intercurrent disease-related mortality in the DES-treated patients. Another study conducted by the National Prostate Cancer Project (NPCP) randomized patients following radical prostatectomy or radiation therapy to either observation, estramustine, or cyclophosphamide. Recent updates incorporating a 14.3-year follow-up indicate that patients treated with estramustine had improved progression-free survival (PFS), especially those with T3 or T4 or grade 3 tumors and in those patients with extensive nodal metastases who were treated with radiation.61 Both studies were limited by small sample sizes (78 patients in the former and a total of 437 patients in the latter). More contemporary data were generated by two trials utilizing long-acting reversible gonadal suppressing agents. Both studies were conducted in patients with locally advanced or node-positive prostate cancer, a subset that is specifically at high risk for occult metastases. The Radiation Therapy Oncology Group (RTOG)62 trial used lifelong (or until progression) androgen suppression with goserelin while the European Organization for Research and Treatment of Cancer (EORTC)63 trial tested 3 years of adjuvant goserelin plus 1 month of cyproterone acetate. With 945 evaluable patients in the former trial and 401 evaluable patients in the latter, combined modality therapy was superior with regard to disease-free survival in both trials. Overall survival superiority was observed only in the EORTC trial. For the subset of patients in the RTOG trial with centrally reviewed tumors with a Gleason score of 8 to 10, however, the difference in actuarial 5-year survival favored the adjuvant therapy arm (66 versus 55%, p = .03).


Of note is the finding that the experimental arms of both trials had comparable 5-year survival rates (75 and 79%, respectively); the control arm of the EORTC study appears to have had inferior survival by comparison (71 and 62%, respectively). Although speculative, the latter result may be attributed in part to different clinical practice between the United Kingdom and this country with regard to timing of hormonal therapy, suggesting that hormonal therapy introduced at a delayed but critical time (e.g., time of first asymptomatic relapse) may be equivalent to early therapy. Additional information on early hormonal treatment can be derived from randomized studies that have used neoadjuvant hormonal therapy. In patients with locally advanced prostate cancer treated with definitive irradiation, 4 months of hormonal therapy (2 months prior to and 2 concurrent with radiation) had a positive impact on local control and progression-free survival. To date, however, no survival advantage has been demonstrated for neoadjuvant hormonal therapy.64–66 Preliminary reports with short follow-up have suggested no difference in biochemical recurrence rates between patients treated with short-course neoadjuvant hormonal therapy and radical prostatectomy compared to radical prostatectomy alone.67 The reasons for a lack of objective benefit in the latter setting are unclear. One hypothesis is that a brief exposure to hormonal therapy is ineffective in eliminating/controlling occult metastases. This idea is supported by the proven need for a longer but finite period of hormonal therapy in the adjuvant treatment of breast cancer, another hormonally sensitive tumor.68 Further, the neoadjuvant surgical studies that have been conducted were designed with short follow-up to detect changes in pathologic stage but not differences in survival.69,70 There are no ongoing or completed studies to address the role of immediate hormonal therapy in the setting of biochemical (PSA) failure. Randomized studies in this area are extremely difficult to conduct in the United States due to patient and physician biases. Most of the available data are nonrandomized observational reports. In the Lee et al.14 series, 31 of 151 patients developing PSA elevation following radiotherapy received salvage androgen deprivation before clinical recurrence while 48 patients were treated for clinical recurrence. Seven and 20 patients, respectively, had developed a second PSA elevation at the time of reporting, with an actuarial rate of second PSA elevation of 50% at 5 years. Such recurrence signifies the development of androgen independence. The authors concluded that longterm androgen deprivation salvage therapy for patients with increasing PSA levels is not indicated due to the variability in the natural history of this phenomenon, competing causes of death in older men, lack of supporting data, cost, and side effects of therapy. This position is supported by others.17 In another report with short follow-up, androgen deprivation at the time of biochemical failure follow-

ing radical prostatectomy decreased the incidence of clinical relapse from 13 to 43%.8 The clinical dilemma posed by this phenomenon, coupled with the potential negative effects of long-term hormonal therapy for this group of patients, provided the rationale for the National Cancer Institute of Canada to sponsor an intergroup trial evaluating the role of intermittent hormonal therapy relative to standard androgen deprivation. The rationale for the experimental arm is based on data (previously alluded to) linking long-term androgen deprivation to progression to androgen independence. The study also sought to minimize the side effects of androgen deprivation. Unfortunately, this phase III study will not address the issue of timing of hormonal therapy. Studies in Metastatic Disease For half a century, systemic therapy of prostate cancer has centered on suppressing androgenic stimuli by either surgical or medical gonadal suppression.56,71 The hypothesis that a tumor clone may be or will become sensitive to lower androgen levels fostered attempts to eliminate all sources of androgens, including the adrenals. Numerous studies conducted during the 1980s and 1990s to resolve this issue produced conflicting outcomes.71 Irrespective of the type of androgen deprivation, however, median progressionfree and overall survival for patients with metastatic prostate cancer remain at 12 to 18 months and 24 to 33 months, respectively, with virtually all patients dying from hormone-refractory prostate cancer. Historically, several major studies conducted by VACURG laid the foundation for most contemporary hormonal therapies in prostate cancer.72,73 The first study demonstrated that delaying hormonal therapy did not appear to compromise overall survival. Patients treated with high doses of DES, however, suffered higher death rates from cardiovascular complications.72 The second study demonstrated that hormonal therapy delayed progression but did not have an impact on overall survival, suggesting there is no difference between early and delayed hormonal therapy.73 When these data were reanalyzed over a decade later, young patients with Gleason scores ≥ 7 and stage D disease appeared to derive a survival advantage if hormonal therapy was initiated at diagnosis.74 Analyses of this nature (reanalyzing data at some point in the future without prior plans in the original study design) are suggestive but not conclusive and must be approached with caution.75 Several uncontrolled trials and reports25,76,77 suggested improvements in the interval-to-disease progression and in survival of patients with D1 prostate cancer treated with early orchiectomy. The largest, reported by Zincke et al., included patients with pathologic stage D1 disease following radical prostatectomy who were treated with immediate bilateral orchiectomy, compared to those who received delayed orchiectomy or radiotherapy. Patients treated with immediate orchiectomy had signifi-


cantly decreased progression rates. The 5- and 10-year overall and local nonprogression rates for those who underwent immediate orchiectomy were 84 and 80%, respectively, compared to 48 and 38%, respectively, for patients who received delayed hormonal therapy.25 To prospectively address the role of adjuvant hormonal therapy in resected stage D1 prostate cancer patients, a phase III intergroup trial was conducted comparing hormonal therapy to observation following radical prostatectomy (Southwest Oncology Group [SWOG] study 8793/EST 3886). The study is closed and results are awaited. The Medical Research Council (MRC) of the United Kingdom recently conducted a study evaluating outcomes of patients treated for advanced prostate cancer, randomizing patients to early or delayed hormonal therapy.78 Patients with either locally advanced or asymptomatic metastatic prostate cancer were included in the trial. There was a total of 938 patients recruited, with results reported for 934 patients. The study design required a target accrual of 2000 patients. Despite no obvious differences from an interim analysis, the study had to close prematurely due to declining recruitment. An intent-to-treat analysis was conducted, the results of which are summarized in Table 38–1. Immediate therapy was associated with a delay in tumor progression and fewer cancer-related complications. Cancer progression (metastasis or death) was noted in 37.5% (96 of 256) of the M0 subset randomized to the immediate treatment group, compared to 59% (144 of 244) in the deferred treatment group (p < .001). There was no statistically significant difference between the two arms in survival of patients with M1 or Mx disease. The MRC study attempted to answer the important question of immediate versus delayed hormonal treatment. On close examination, however, it suffers from several flaws that limit applicability of the conclusions to patients with prostate cancer in the United States. For example, 174 patients were not adequately staged (no bone scans performed), and patients in the deferred arm were not treated until they were significantly symptomatic. These represent TABLE 38–1. Immediate versus Deferred Treatment for Advanced Prostate Cancer* Immediate Deferred All deaths Overall (n = 934) Immediate (n = 469) Deferred (n = 465) Deaths from prostate cancer Overall Immediate Deferred

M0 256 244

Mx 83 90

M1 130 131

321 150 171

144 67 77

224 111 113

200 (62)† 81 (54) 119 (70)

86 (60) 38 (57) 48 (62)

174 (78) 84 (76) 90 (80)

*The Medical Research Council (MRC) 1997 study. †Parenthetic figures represent percentages of all deaths.

Total 460 (67) 203 (62) 257 (71)

clear deviations from standard practice in the United States. The study closed with less than 50% of the target accrual, raising questions as to adequacy of the sample size to detect differences with a high degree of confidence. The finding that early therapy delayed progression and reduced complications is in line with clinical and published experience. The current authors believe this is a major therapeutic objective in patients with M1 disease. Changing trends in causes of death over the past two decades reflect the impact of improvements in health care on deaths from prostate cancer, with 67% of patients in the MRC study dying from prostate cancer compared to 41% in the VACURG studies.72,73 This has direct clinical implications with regard to a proactive approach to treating prostate cancer patients. Finally, several studies comparing combined hormonal therapy to monotherapy have demonstrated that the extent of metastatic disease at the time of treatment correlates with survival.79,80 Patients with minimal disease particularly those who received combined therapy, had survivals superior to patients with extensive disease; suggesting that early hormonal therapy may have contributed to these apparent differences. It must be emphasized, however, that these data are only suggestive, as the differences in survival may be a function of varying biologic characteristics and lead-time bias rather than as a result of direct benefit from early hormonal therapy. Risks of Early Hormonal Therapy Androgen deprivation therapy is generally very well tolerated but can be associated with several distressing side effects, including hot flashes in about 60% of patients and impotence in 75 to 100% of patients.76,79 Other side effects include the recently recognized accelerated osteoporosis,81 potential psychologic problems, gastrointestinal upset, gynecomastia, weight gain, leg edema, and liver dysfunction.79,80 Conventional hormone therapy is administered for life or until disease progression. In the setting of metastatic disease, treatment generally continues for less than 3 years due to high patient mortality. A similar approach is being empirically adopted for patients with lesser stage disease and in the adjuvant setting. This translates to many more years of therapy, with all the associated negative quality-of-life side effects, costs, and unknown risks of long-term androgen deprivation with regard to other body systems. For these reasons, the ideal treatment duration, especially in the adjuvant setting, must be prospectively determined.

Conclusion The issue of early hormonal therapy must be considered separately for different stages of prostate cancer as therapy objectives are different. In the setting of metastatic disease, the issue may not be as relevant since therapeutic objec-


tives revolve around providing better quality of life in general for these patients, who will have a short survival complicated by a protracted morbid course. In this setting, delaying progression even in the absence of an improvement in survival may be clinically relevant. Efforts for this stage of disease must be directed toward investigating new treatment strategies, with the goal of prolonging survival. In the setting of PSA failure, current data are limited but published series suggest it is unlikely that “early hormonal therapy” has a high curative potential. As a result, therapy decisions must be individualized; however, since the tumor burden is relatively lower, efforts focusing on investigating novel treatments are highly justified. In the adjuvant setting, therapy objectives must focus on increasing cure rates and/or survival. Data from contemporary trials in patients with locally advanced prostate cancer treated with radiotherapy plus hormonal therapy indicate a disease-free survival advantage, but data on overall survival are inconclusive. The reasons for the lack of a conclusive survival advantage are unclear; whether these data can be extrapolated to patients with smaller tumors is also unclear. Prospective studies are required that address the value of adjuvant therapy and the optimal duration of hormone therapy alone or in combination with other systemic treatment. These studies must incorporate contemporary definitions of risk and must target patients with localized prostate cancer who are undergoing local therapy. Ongoing RTOG trials will hopefully define the role of hormone therapy in clinically localized disease. Similar efforts are underway to investigate its role in patients treated surgically.

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CHAPTER 39

STAGING FAILURES OF INITIAL THERAPY J. CHRISTOPHER AUSTIN, MD; RICHARD D. WILLIAMS, MD Patients who fail initial therapy for clinically localized prostate cancer are commonly classified as failures due to a detectable and progressively increasing serum prostatespecific antigen (PSA) level. Patients who are successfully treated by radical prostatectomy should have an undetectable PSA within 1 month postoperatively; therefore, any persistently detectable PSA (> 0.1 ng/mL) implies residual or recurrent cancer. After therapies in which the prostate is not removed, such as external beam radiotherapy, brachytherapy, or cryosurgical ablation, glandular epithelial elements may persist and produce various levels of serum PSA. In these scenarios, PSA levels may range above undetectable in successfully treated patients, and thus therapy should be considered a failure only if PSA levels are increasing on at least two consecutive occasions. The ideal method of staging patients who have failed initial therapy is uncertain. Staging of these patients, who most often are classified as biochemical (PSA only) failures is as imprecise as pretreatment staging. There are a multitude of staging tools available to the practicing urologist. These modalities include both nonanatomic methods, such as pre- and post-treatment serum PSA levels, the time from treatment to biochemical recurrence, pathologic data from the surgical specimen or pretreatment biopsy, and anatomic methods, which include digital rectal examination (DRE), computed tomography (CT), magnetic resonance imaging (MRI), transrectal ultrasonography (TRUS), bone scans, radioimmunoscintigraphy (RIS), and positron emission tomography (PET). The effectiveness of a staging tool depends on the criteria or so-called “gold standard” against which these modalities are judged. For instance, detection of recurrent disease can be defined solely by an abnormal mass on an imaging study, by histologic confirmation of the mass, or by the ability of the staging tool to categorize patients who can be successfully treated by a certain therapy where others will fail. An example of the latter would be the ability to predict which patients with a detectable PSA postradical prostatectomy would have a complete response to salvage radiotherapy. The fact that the outcomes of these tests can be measured by gold standards which often differ from one report to the next and that the gold standards themselves are subject to sampling error adds additional uncertainty to the value of various staging modalities. In this chapter, we will review the uses and limitations of commonly available modalities for staging patients with

residual or recurrent prostate cancer. We will attempt to present an unbiased assessment of each and conclude with a brief description of the algorithm used at the University of Iowa for managing these patients. The rationale behind staging a patient with an early biochemical recurrence is to try to differentiate patients with incurable metastatic disease from those with a recurrence within the prostate or the prostatic fossa. The assumption is that second-line therapies such as salvage radical prostatectomy, cryosurgical ablation, or radiotherapy can be effective at treating locally recurrent disease. Given that patients who undergo these salvage therapies are at significant risk for treatment-related morbidity, careful consideration needs to be given to whether or not the patient is a candidate for the proposed treatment. If a patient is a candidate, and the patient desires that treatment, staging to evaluate for locally recurrent or metastatic prostate cancer is appropriate.

Use of Prostate-Specific Antigen in Staging Radical Prostatectomy Patients A detectable serum PSA following radical prostatectomy is the most sensitive indicator of residual or recurrent disease.1–3 The PSA elevation may precede clinically detectable recurrences by several months to years. The PSA may never fall to an undetectable range after radical prostatectomy (residual disease), or it may be initially undetectable for several months to years before it increases into the detectable range (recurrent disease). Although there are a few case reports of patients with a biopsy-proven clinical recurrence despite an undetectable PSA level, the vast majority of patients with recurrent prostate cancer will have detectable PSA levels.4,5 When serial PSA values are followed in patients whose PSA is elevated following treatment by radical prostatectomy, the values increase in an exponential fashion. However, the slope of the increase varies greatly.2,6–8 Serial PSA values over time can be fitted to a straight line using regression analysis or by using two serial values—the first value, which is elevated, and a second (also elevated), which must be obtained more than 12 weeks later, thus allowing for the calculation of the PSA doubling time (Figure 39–1). The importance of PSA doubling time is demonstrated in two reports which showed that patients with an elevated serum 340

Staging Failures of Initial Therapy / 341

PSA following radical prostatectomy who have a documented (biopsy-proven) local recurrence only, have a longer PSA doubling time than those patients with proven metastatic disease.7,8 It has also been speculated that since PSA values correlate with tumor volume in prostatectomy specimens, PSA doubling time approximates the growth rate of the cancer.9 The mean PSA doubling times and their ranges for patients with PSA only, and those with local or distant recurrences following radical prostatectomy are shown in Table 39–1.7 A general trend is that patients with metastatic disease have PSA doubling times of < 12 months. Unfortunately, there are some patients with local recurrence only who also fall into this range. Thus, patients with a long PSA doubling time are more likely to have a local recurrence in the pelvis. A single report from Duke University evaluated factors which could predict a successful response to salvage radiotherapy in a univariate and multivariate

20 Patient A Patient B

PSA (ng/mL)

15

10

5

0

0

5

10

A

PSA (ng/mL)

1000

15 20 TIME (Months)

slope of line = log PSA2 - log PSA1 time PSADT = log 2 slope

25

30

35

PSADT = 3.8 months

100

Patient A Patient B PSADT = 36.6 months

10

TABLE 39–1. PSA Doubling Time in Radical Prostatectomy Patients

1

B

analysis.10 They found that PSA doubling time was not predictive of success; however, the values for the groups were not published. The PSA velocity has also been studied as a predictor of local or distant recurrence.11 In a multivariate analysis of radical prostatectomy, patients from Johns Hopkins University, a PSA velocity of < 0.75 ng per mL per year measured at 1 year from surgery was present in 92% of those with a local recurrence, and 46% of those with distant metastases. While PSA velocity may be a predictor of local versus distant recurrence, it does not seem to be an accurate method to exclude patients who are likely to have or develop metastatic disease. While PSA kinetics may provide some information about the site of recurrence when there are two consecutive elevated levels for calculations, so can the time from radical prostatectomy to the development of a detectable PSA. There have been several studies which have examined how the time to biochemical recurrence factors into response rates to salvage pelvic radiotherapy (S-XRT).10,12–16 The majority of these studies suggest that patients whose PSA rise occurs less than 6 to 12 months following radical prostatectomy have higher S-XRT failure rates than those whose time to recurrence is a longer interval ( more than 12 months). Patients in whom the PSA nadirs to > 0.1 ng per mL (detectable) postoperatively have been considered to have metastatic disease and should therefore have a much lower response rate to S-XRT compared to those whose PSA initially decreased to < 0.1 ng per mL. These series used a variety of different PSA levels as cutoff for a detectable PSA (range 0.1 ng/mL to 0.6 ng/mL), and therefore the patient populations are not completely comparable. Recently, a series of patients treated for an elevated PSA with S-XRT at Wayne State University compared patients with a PSA nadir in the detectable range (> 0.1 ng/mL) versus those in the undetectable range following radical prostatectomy.16 There were no differences in the complete response rates for the two groups (68% versus 78%, respectively). A response was unlikely if the nadir was above 2.0 ng per mL, leading to the conclusion that patients with PSA nadirs between > 0.1 and 2.0 ng per mL following radical prostatectomy should be considered for S-XRT. Multiple conflicting reports regarding this topic are not easily explained.

0

5

10

20 15 25 TIME (Months)

30

35

FIGURE 39–1. A, Graphic depiction of the exponential increase of PSA over time in two patients following radical prostatectomy. Note the more rapid rise in patient A versus patient B. B, Graphic depiction of the log slope PSA and PSA doubling times (PSADT) for patients A and B, again showing the faster increase of PSA levels in patient A but the PSA scale has been transformed to a logarithmic scale to make the rise over time a linear relationship.

Biochemical recurrence Local recurrence Distant metastases

n

PSA Doubling Time (Months)*

22 21 7

19 ± 21 (2.1–90.1)† 39 ± 67 (4.1–300)† 4.7 ± 2.8 (3.7–10.7)

*Mean ± standard deviation and (range). †p ≤ .01 versus PSA doubling time for distant metastases. From Fowler JE, Pandey P, Branswell NT, Seaver L. Prostate-specific antigen progression rates after radical prostatectomy or radiation therapy for localized prostate cancer. Surgery 1994;116:302–6.

342 / Advanced Therapy of Prostate Disease TABLE 39–2. Serum PSA Values in Patients Receiving Salvage Radiotherapy for an Elevated PSA Following Radical Prostatectomy PSA (ng/mL) Author

n

Responders

Failures

Cadedeau et al.14 Wu et al.10 Lange et al.13 Garg et al.16

82 54 28 70

1.7 1.2* 5.0 ≤ 2.0†

3.0 7.6* 10.6 > 2.0†

* p = .01 in multivariate analysis. †p < .0001 in predicting success when patients are stratified by a PSA of ≤ 2.0 or > 2.0 (response rates of 73% versus 31%).

The absolute PSA level prior to S-XRT is another variable which has been studied. Given the usefulness of PSA in predicting pathologic stage and its correlation to cancer volume, it is not surprising that patients with higher PSA values prior to S-XRT are less likely to have a complete response.3,9 Table 39–2 shows the mean PSA values prior to S-XRT in patients with a complete response or failure and whether the difference was statistically significant. It is evident that there is a trend toward patients with higher PSA levels having a predilection to fail, and thus these patients are more likely to have metastatic disease outside the treatment field. External Beam Radiation Patients Following radiotherapy, there is a gradual decrease in the serum PSA which can require from nearly 12 months to more than 36 months before reaching a nadir.17–19 Once the nadir is reached, the PSA either remains stable or begins to increase. There is debate as to what value the PSA nadir following XRT should be to define a cure. Certainly, this value is below the upper limit of normal for men without prostate cancer (4.0 ng/mL for most assays) and has been proposed to be 0.5 to 1.0 ng per mL. More important is the trend of serial PSA values. A persistently rising PSA, as in the postprostatectomy patient, precedes clinical recurrences by a mean of approximately 7.5 months.17,20 The kinetics of serial PSA values over time in patients with recurrent prostate cancer following radiation therapy have been shown to follow an exponential increase, similar to those in radical prostatectomy patients.7,18 The PSA doubling time can be calculated using the same methods TABLE 39–3. Mean PSA Doubling Times (Months) in Patients Following Radiation Therapy Author

n

Biochemical Recurrence

Local Recurrence

Distant Metastases

Fowler et al.7

55

Crook et al.19

118

21 ± 14 (2.1–90.1)* 21.8

14 ± 8 (4.5–42.9) 12.6

6.2 ± 2.2 (3.7–10.7)† 5.2†

* Expressed as mean ± standard deviation and (range). †p < .01 for distant versus local or biochemical recurrence.

as illustrated in Figure 39–1. In patients with biochemical, local, or distant recurrences, PSA doubling times are similar in those who underwent radical prostatectomy and radiation-treated patients. In patients with metastatic disease, PSA doubling times are shorter when compared with those with local recurrence or biochemical failures. Table 39–3 shows the PSA doubling times when stratified by site of recurrence. D’Amico and Hanks correlated PSA doubling time and time from treatment to biochemical failure in patients who failed radiation therapy with the time to clinical progression (distant metastases in 14 of 17 patients). Using this information, they could predict the minimal time to clinical progression (based on the 95% confidence interval) from the time of PSA recurrence (Table 39–4).20 While PSA doubling correlates well with time to clinical progression, it is not known whether it can predict a favorable response to any salvage therapy. The timing of the PSA nadir is also important in the radiated patient. Patients who develop metastatic disease reach the nadir PSA value (usually at a high level, >1.0 ng per mL) sooner than those with local failure, biochemical failure, or no evidence of disease (mean time to nadir of 11, 21, 20, and 33 months, respectively).19 In another series, 75% of patients with distant failure reached their nadir in less than 12 months.21 Thus, it seems that patients who have high nadir PSA values and early (less than 12 months) recurrence are likely to have metastatic disease. The absolute PSA level is also a consideration in patients who fail radiation therapy. Salvage prostatectomy results have shown that when the preoperative PSA is >10 ng per mL, the chance of having organ-confined disease markedly decreases, and so does the chance for achieving an undetectable PSA.22 Prostate-Specific Antigen following Brachytherapy and Cryosurgical Ablation Prostate-specific antigen values and kinetics have not been as extensively studied in patients following brachytherapy or cryosurgical ablation of the prostate. As a general rule, a rising PSA following therapy for either should be considered a biochemical failure.23–25 Brachytherapy should be expected to cause similar trends in PSA levels as those seen in external beam radiotherapy—a slowly decreasing value over a period of several months to years. Cryosurgical ablation, unlike radiotherapy, exerts its destructive effects immediately, and the PSA should reach a nadir within 3 months as would be expected after treatment by radical prostatectomy. However, since cryosurgical ablation of the prostate does not necessarily destroy all the epithelial elements (particularly in the periurethral area), a PSA nadir above the undetectable range is probably acceptable. It has been noted in a large series of patients from the University of California at San Francisco that all patients with a nadir of > 0.5 ng per mL develop an increasing PSA with or without a positive post-treatment biopsy.25


Pathologic Predictors of Recurrence Radical Prostatectomy Patients A significant advantage when considering the staging of radical prostatectomy patients over those treated with other modalities is the information provided by the pathology report from the prostatectomy specimen. Features such as seminal vesicle invasion, extracapsular extension, positive margins, Gleason score, and lymph node metastases are significant predictors of biochemical relapse.26–28 Recurrence has been defined in terms of biochemical (PSA) recurrence, local recurrence only, and distant metastases with or without local recurrence. Epstein et al. showed in a multivariate analysis that Gleason score, positive surgical margins, and capsular penetration were all independent predictors of recurrence.26 A Gleason score of 8 to 10 indicates a rate of progression (biochemical, local, or distant) of 65% at 10 years versus 49% for Gleason score of 7 and 19% for Gleason score of 5 or 6. For patients with organ-confined disease, the rate of progression is 15% at 10 years versus 32% for patients with focal capsular penetration, and roughly 45% for those with established capsular penetration or a positive margin. Patients with seminal vesicle invasion had a 73% rate of progression at 10 years and patients with lymph node metastases had a progression rate of 100%. These data underscore the importance of pathologic features in predicting recurrence but, with the exception of patients with high grade tumors (Gleason score ≥ 8), lymph node metastases, or seminal vesicle invasion, a large number of patients with adverse pathologic features will have longterm PSA recurrence-free survival. These patients present a treatment dilemma as many may desire adjuvant therapy, but there is no way to predict whether they will have recurrences until their PSA becomes detectable. The pathologic data also appear to be useful when considering whether a patient is an acceptable candidate for S-XRT for recurrence following radical prostatectomy. The main features which have been identified as predictive of outcome are pelvic lymph node metastases, Gleason score, and seminal vesicle invasion. A summary of pathologic features relating to response to salvage radiotherapy for an elevated PSA following radical prostatectomy is presented in Table 39–5. Thus, it is reasonable to conclude that patients with lymph node metastases should not be treated with S-XRT. Patients with seminal vesicle invasion and/or high Gleason score (≥ 8) seem to have a less likely chance for cure and should be discouraged from this type of treatment.

Transrectal Ultrasonography and Biopsy Radical Prostatectomy Patients The value of transrectal ultrasonography and biopsy (TRUS/Bx) as well as DRE have been studied as methods

TABLE 39–4. Minimal Time to Clinical Progression (Months) from Time of PSA Recurrence Based on the Time to Biochemical Recurrence following Radiation Therapy Time to PSA Recurrence

Minimal Time to Clinical Progression

3.0 8.6 17.2 30.3 46.0

1.2 12.0 24.3 40.7 60.2

From D’Amico AV, Hanks GE. Linear regressive analysis using prostate-specific antigen doubling time for predicting tumor biology and clinical outcome in prostate cancer. Cancer 1993;72:2638–43.

to detect local recurrence of prostate cancer. The presence or absence of adenocarcinoma on biopsy is the gold standard against which TRUS and DRE are judged. In a series of 30 patients with undetectable PSA levels following radical prostatectomy, biopsy of the prostatic fossa was negative in all of them. 29 In patients with a detectable PSA, positive biopsy (digitally or TRUSguided) varies from 38 to 50% for a single biopsy, and up to 54 to 59% on repeat biopsy following a negative initial biopsy.30–35 These data demonstrate the power of PSA as a predictor of recurrent cancer. This biopsy data correlates showing that 80 to 89% of postradical prostatectomy patients (with both positive and negative biopsies) respond to S-XRT with a drop in serum PSA.13,16,36 This indicates a substantial sampling error (false negative) rate for postradical prostatectomy TRUS biopsies, suggesting that biopsy misses a certain percentage of locally recurrent prostate cancers. Another characteristic of patients with positive biopsies of the prostatic fossa is that they tend to have higher PSA values than those with negative biopsies (median PSA 2.3 ng/mL versus 0.6 ng/mL, respectively).33 A recent series of postradical prostatectomy patients with rising PSA levels showed that the positive biopsy rate was 8% for patients with a PSA ≤ 0.5 ng per mL, 24% if the PSA was ≤ 1.0 ng per mL, and 52% if the PSA was > 8.0 ng per mL.35 The histologic findings of biopsies taken from the prostatic fossa range from fibrosis, fibromuscular tissue, seminal vesicle epithelia, benign prostate tissue, and adenocarcinoma. In patients with benign prostatic epithelia, recurrent carcinoma cannot be excluded nor is it an indicator that the PSA will not continue to increase in an exponential fashion characteristic of recurrent prostate cancer.32 Transrectal ultrasonography can be used primarily for two purposes in the staging evaluation of the patient with a biochemical recurrence after radical prostatectomy: (1) detection of the site of local recurrence, or (2) guiding the biopsies of the prostatic fossa. The ultrasonographic findings of residual, recurrent prostate cancer on TRUS include a hypo- or isoechoic mass which may be located at the site of the urethrovesical anastomosis, the bladder

344 / Advanced Therapy of Prostate Disease TABLE 39–5. Pathologic Features which Suggest a Poor Long-Term Response to Salvage Radiotherapy for Elevated PSA following Radical Prostatectomy Author

Pathologic Features

Comments

Cadedeau et al.14

Gleason score ≥ 8, seminal vesicle invasion, lymph node metastases

Wu et al.10

Lymph node metastases

Garg et al.16

Higher Gleason score, seminal vesicle invasion, capsular penetration

No patient with one of these features had an undetectable PSA at 2 years Seminal vesicle invasion was not predictive. All 3 of 3 with lymph node metastases failed Trend toward poorer response was not statistically significant

neck, or retrovesical, in decreasing order of frequency.33 When compared to biopsy results, the sensitivity of TRUS varies from 52 to 96% and the specificity from 26 to 83%.33–35 Given this degree of variation, it is not surprising that while some feel that TRUS is a valuable tool to visualize recurrences, most feel that its main purpose is only to systematically guide the biopsies. The relative lack of specificity of TRUS dictates that it is not sufficient to be used alone for identifying tumors. Prior to the use of PSA, DRE was the primary method used to detect local recurrence. However, PSA is a much better predictor of recurrent carcinoma. Patients who have an abnormal DRE and an undetectable PSA have negative biopsies almost without exeption.4,5,29 In patients with elevated PSA and normal DRE, biopsies reveal recurrent carcinoma in 23 to 55%.30,33,35 In patients with abnormal DRE and elevated PSA, the positive biopsy rate increases to 61 to 100%.29,30,32,33 These studies seem to illustrate an important point. Local recurrence in a patient with elevated PSA is a common and frequent event. Both TRUS/Bx and DRE can provide information as to the presence of recurrent prostate cancer in the region of the urethrovesical anastomosis but neither of them seem to be capable of excluding it nor can they predict the presence of recurrence outside the prostatic fossa. Radiation Patients Radiotherapy results are revealed over a longer timeframe than radical prostatectomy. Just as the serum PSA slowly decreases over a period, which can be as long as 3 years, foci of adenocarcinoma may persist in a successfully treated patient during this time. The usefulness of DRE in evaluating patients following external beam radiotherapy has been shown, as in radical prostatectomy patients, to be an insensitive method to detect local recurrence.37 The sensitivity of DRE based on biopsy results is 41% with a specificity of 57%. Ultrasonographically, areas of adenocarcinoma commonly appear as hypoechoic regions in the prostate. Transurethral ultrasonography is useful in guiding biopsies of these regions. However, the sensitivity of TRUS in detecting areas of recurrent prostate cancer is approximately 50%, so all hypoechoic areas need to be confirmed with biopsy.

In patients with stable (< 2.0 ng/mL) or decreasing PSA values TRUS/Bx should not be obtained routinely.19,38–40 The natural history of the histologic changes in biopsies following treatment of prostate cancer with external beam radiotherapy has been studied in a series of over 300 patients.37 At 12 months following radiation therapy, 29% (89 of 305) of the patients had a positive biopsy. When followed up and monitored with repeat biopsies at 6-month intervals, 43% (38 of 89) converted to negative at a median of 25.8 months following radiotherapy. Those patients with marked radiation effects on their biopsies were less likely to have local failure than those with variable or less radiation effects (18% versus 41%, respectively). Local failure was defined as a rising serum PSA and a positive biopsy with negative CT (abdomen) and bone scans. Patients with marked radiation effects also had a lower nadir PSA value compared to those with variable effects (0.7 ng/mL versus 1.3 ng/mL, respectively). This study underscores the importance of knowing the PSA levels, the recent trend of the PSA level (increasing or decreasing), the time from treatment when the biopsy was taken, and the amount of radiation effects in the specimen when considering the significance of a postradiation therapy biopsy which demonstrates carcinoma. A valid criticism against defining treatment outcomes based on a positive biopsy reverting to negative over time is whether the negative biopsy is due to radiation effects on the tumor or falsely negative due to sampling error. The rate of sampling error has recently been estimated by performing repeat TRUS/Bx on patients with biopsyproven prostate cancer prior to radical prostatectomy.41,42 In this population, the false negative biopsy rate was 23 to 45%. The higher rate was determined in a mixed population where half the patients received neoadjuvant hormonal therapy, likely resulting in a smaller tumor volume, and thus for a population not receiving androgen blockade, the rate is likely closer to 23%. Given what is known about false negative biopsy rates in patients with localized prostate cancer prior to radical prostatectomy, the question arises as to what to do with a patient who has a rising PSA following radiation therapy, without evidence of metastatic disease, and a negative prostate biopsy. Since salvage radical prostatectomy carries a significant risk of treatment-related morbidity, repeat biopsy of the prostate is warranted. Salvage radical


prostatectomies should only be performed in the presence of a biopsy demonstrating recurrent carcinoma of the prostate.22,43 Brachytherapy Patients Routine biopsies in patients treated with brachytherapy, as in external beam radiation patients, is unnecessary if the serum PSA is decreasing or stable (< 2.0 ng/mL). One report of a large series of patients treated with radioiodine (125I) or radiopalladium (103Pd) had TRUS/Bx at 1 year or greater; follow-up to evaluate response showed 2% had positive biopsies, 20% had indeterminate (radiation effect) biopsies, and 78% had negative biopsies.23 While at first glance these are strikingly lower rates than for external beam radiotherapy, it must be noted that the patients were highly selected (Gleason score < 7 in 80%, PSA < 10 ng/mL in 75%, all patients stage T2a or below). As a trend, similar to external beam radiotherapy patients, indeterminate biopsy rates gradually decreased with longer followup to negative biopsies (33% at 12 to 18 months and 5% at ≥ 54 months). Additionally, patients with positive biopsies had higher PSA values, higher PSA nadir values, and shorter time to nadir. Cryosurgical Ablation Patients Following cryosurgical ablation of the prostate, a rapid destruction of the areas which were frozen should occur. Currently, the effects of freezing are monitored intraoperatively by TRUS. The iceball has a striking hypoechoic appearance that allows its size to be easily monitored.25 Whole mount examination of salvage prostatectomy specimens have shown that the iceball seen grossly underestimates the areas of destruction in at least some of the patients.44 Positive biopsy rates following cryosurgical ablation of the prostate are 14.5 to 23%. Additionally, benign epithelial elements can be present in up to 50% of biopsies.24 Multiple freeze/thaw cycles seem to improve cancer control.25 Unlike patients treated with radiotherapy, a positive biopsy following cryotherapy is definite evidence of recurrent carcinoma. Radioimmunoscintigraphy Radioimmunoscintigraphy (RIS) is a whole-body imaging scan which is performed by intravenously injecting a monoclonal antibody which has been labeled with a radionuclide. The antigen for which the antibody is specific determines which tissues are labeled and thus detectable with scanning. Capromab pendetide (CP) is an immunoconjugate of a linker chelator, which allows for radiolabeling with 111indium, and the monoclonal antibody 7E11-C5.3. This monoclonal antibody has also been called CYT-356 and is currently marketed under the trade name ProstaScint™. Capromab pendetide binds to prostate-specific membrane antigen (PSMA), which is expressed in both benign and malignant prostate epithe-

lial cells.45 It is expressed in higher levels in carcinoma versus normal prostate tissue and has been reported to be upregulated in hormone refractory carcinoma.46 Paradoxically, the antibody binds to an epitope on the cytoplasmic portion of this transmembrane protein.47 The exact mechanism of its binding in vivo is unknown. 111Indium-CP has been studied primarily in two patient populations: (1) patients with high risk of pelvic lymph node metastases prior to staging pelvic lymphadenectomy and radical prostatectomy (based on Gleason score, serum PSA level, and clinical stage), and (2) patients with recurrent prostate cancer following radical prostatectomy manifested by a detectable increasing serum PSA. In one study designed to understand the ability of 111In-CP to image lymph nodes with metastatic prostate cancer, patients were scanned prior to staging pelvic lymphadenectomy and radical prostatectomy.48 The pathologic correlation of a group of 217 patients at high risk for nodal disease revealed 85 with pathologic confirmation of metastatic prostate cancer. In this population, the scan demonstrated a sensitivity of 60% with a specificity of 80%. These values were consistent with most prior smaller series.49–51 When the pathologic data were compared with conventional cross-sectional imaging tests, the sensitivity of CT or MRI of the pelvis was 9 to 13%.48,50 These studies are important to consider because they demonstrated that 111In-CP can detect metastatic prostate cancer in lymph nodes too small to be detected by CT. The postradical prostatectomy studies in patients with detectable serum PSA levels of ≥ 0.5 ng per mL have had 111In-CP scans which demonstrate abnormal foci in the areas of the urethrovesical anastomosis as well as metastatic lesions in the iliac, para-aortic, mesenteric, and mediastinal lymph nodes.52–55 In the largest study, which reported the results of 181 men with interpretable scans, the most common sites detected were the prostatic fossa and abdominal and pelvic lymph nodes (Table 39–6).53 The majority of the abnormal sites detected by CP in these studies are not visualized by CT or MRI scanning. Only 14% of the abnormal foci could be correlated with an abnormal mass detected by a conventional imaging study. None of the lesions were confirmed histologically. The lack of correlative pathologic data raises questions as to what exactly an abnormal scan means. While there is direct evidence that CP can detect pelvic lymph nodes which contain metastatic prostate cancer, the true status of the intra-abdominal foci remains uncertain. Local recurrences can also be detected with 111In-CP. In single photon emission computed tomography (SPECT), images of the pelvis foci of radiotracer activity can be detected in the area of the prostatic fossa. When correlated with TRUS/Bx results, 58 of 158 patients (37%) had positive biopsies in one report.53 The sensitivity for CP in detecting a biopsy proven recurrence was 49% with a specificity of 70%. These data place its use-


fulness in predicting a local recurrence in terms of a positive biopsy near or below that of TRUS alone. The serum PSA level in postradical prostatectomy patients is not a significant predictor of scan findings. The ability to correlate scan findings is, however, associated with the serum PSMA levels, which can be measured by Western blot.56 This is not surprising, given that this is the actual antigen to which CP binds. In most published series evaluating CP in patients with an elevated PSA following radical prostatectomy, the serum PSA levels are >1.0 ng per mL in patients with positive scans; however, positive findings are reported with PSA levels as low as 0.2 ng per mL.54 The real value of CP is that it images the entire body with a single scan. This provides information about the presence of local recurrence as well as sites of distant soft tissue metastases in the abdomen and chest. It does not image bone metastases as well as does bone scintigraphy, only imaging approximately 55% of lesions detected by bone scan and therefore should not be used as a substitute for bone scan.49 The 111In-CP scan results were also shown to be a statistically significant predictor of response to salvage radiotherapy in a series of 32 patients from two institutions with rising PSA values following radical prostatectomy (≥ 0.4 ng/mL).57 The decision to give radiotherapy was made independent of the scan findings, and the responses were retrospectively reviewed and correlated with scan results. A durable complete response (PSA ≤ 0.3 ng/mL for greater than 6 months) was seen in 4 of 5 (80%) patients with a normal scan, 12 of 18 (67%) with a recurrence in prostatic fossa only, and in only 2 of 9 (22%) patients with abnormal foci detected outside of the prostatic fossa. The median follow-up was 13 months. Logistic regression analysis showed that only a positive scan outside the prostatic fossa was a significant predictor of response to radiation therapy. The odds ratio for a response in patients with a scan demonstrating disease outside the prostatic fossa was 0.125, indicating that these patients are only one-eighth as likely to achieve a durable complete response as other patients. A second series of 13 patients recently published also found the scan could stratify into groups patients who responded better to radi-

ation therapy when patients were stratified into those with disease within the field of radiation (5 of 7 or 71% complete response) versus patients with foci outside the field of radiation (2 of 6 or 33% complete response).58 The mean follow-up for the responders in this group was 17 months. Unlike the prior study, it was found that patients with pelvic lymph nodes detected by the scan were included in the group which had a favorable response. This is possibly explained by the fact that the patients in the latter series included the pelvic lymph nodes in the field of radiation and attempted to treat areas corresponding to the foci of abnormal activity in the pelvis. The Food and Drug Administration (FDA) has approved CP scanning for the staging of patients after radical prostatectomy with a rising PSA. It has only been studied in a small number of patients following radiation therapy. Given that it seems to have the ability to image sites of occult recurrences in postprostatectomy patients, it seems reasonable to use it for staging postradiotherapy patients as well. The scans are safe to perform and may be repeated at a later date.52 Human antimouse antibodies (HAMAs) can be formed in patients who are injected with murine monoclonal antibodies, and CP is no exception to this. The rate of HAMA formation is 8% for patients who have a single scan and 19% in patients who undergo a second scan.59 The scans are typically performed within 30 minutes of infusion, then repeated 2 to 5 days later to allow clearance from the blood pool. The scans are difficult to interpret without special training to distinguish areas of normal biodistribution, which includes the liver, spleen, bone marrow, vasculature, genitalia, and variable uptake in the bowel. Given the baseline binding of these areas which are in the regions where abnormal foci are detected on planar whole body scans (Figure 39–2), multiple other fields of view, including coronal and transverse SPECT images, need to be performed to confirm that the abnormal sites truly lie outside the field of normal distribution. Table 39–7 lists the advantages and disadvantages of using 111In-CP to stage patients with recurrent prostate cancer. Computed Tomography

TABLE 39–6. Sites of Abnormal Foci Detected in Postradical Prostatectomy Patients with Elevated PSA by Capromab Pendetide Scans Site of Localization Prostatic fossa Abdominal lymph nodes Retroperitoneal/periaortic Mesenteric Pelvic lymph nodes Cervical/supraclavicular lymph nodes Inguinal lymph nodes Mediastinal lymph nodes Bone

# of Patients (%)53 62 (34) 42 (23) 40 (22) 10 (6) 40 (22) 2 (1) 1 (0.6) 1 (0.6) 4 (4)

In many reported series of patients treated for prostate cancer by either radiation therapy or radical prostatectomy, those patients who develop a biochemical recurrence are staged with a CT scan of the abdomen and pelvis.14,21,40 However, the actual findings of the CT scans are rarely reported. Preoperative CT scans are now much less frequently performed, due to the useful information serum PSA levels, Gleason score, and DRE provide in terms of predicting risk for pelvic lymph node metastases. Correlation of CT findings with PSA levels in patients with clinically localized prostate cancer have shown that the chance of detecting lymph nodes with metastatic cancer in patients with a PSA of < 20 ng per mL is less than 1%.60


A

B

FIGURE 39–2. A, Normal biodistribution of 111In-CP is demonstrated in this whole body planar image of a patient with a rising serum PSA following radical prostatectomy. The scan shows normal activity in the bone marrow, liver, spleen, great vessels, and genitalia. B, Whole body planar images of a different patient with an increasing PSA following radical prostatectomy. In addition to the normal sites of distribution, there is abnormal uptake in the region of the para-aortic lymph nodes (arrow). The sites were confirmed to be in the para-aortic region in transverse SPECT images.

Computed tomography has been found to have a wide variation in its usefulness and ability to detect lymph node metastases in patients prior to radical prostatectomy with a sensitivity in the range of 0 to 77% and a specificity of 66 to 98%.61–63 These variations are likely due to different criteria for the size of nodes considered pathologic, and to improvements in CT technology over the past decade. Computed tomography is only capable of determining an increase in node size, with > 1.0 to 1.5 cm considered abnormal, and has no ability to determine intranodal architecture. The best results have been reported more recently where asymmetric nodes larger than 6 mm were considered positive and further evaluated with fine-needle aspiration to confirm findings. Although it is clear that CT can detect lymph node metastases in patients with prostate cancer, it is also clear that its routine use in staging patients with clinically localized prostate cancer prior to radical prostatectomy and in patients with PSA levels < 20 ng per mL is not

warranted.64 Unfortunately, this type of analysis has not been done for patients with recurrent prostate cancer following local treatment; however, the high rate of patients with biochemical or local failure in most series of patients found to have negative CT studies offers indirect evidence against the efficacy of detecting metastatic disease in patients with early biochemical recurrence. After evaluating their series of patients with recurrent prostate cancer following radiation therapy, D’Amico and Hanks recommended against using CT to stage recurrences unless the PSA was greater than 6 ng per mL.20 Computed tomography has also been evaluated for its ability to detect a biopsy-proven local recurrence at the prostatic fossa following radical prostatectomy. Characteristic findings of a local recurrence were an enhancing mass in the region of the anastomosis with or without infiltration or erosion of the surrounding soft tissue, bone, or muscle.65 Masses which were definitely visualized were

TABLE 39–7. Advantages and Disadvantages of Using Capromab Pendetide Scanning to Stage Patients with Recurrent Prostate Cancer following Radical Prostatectomy Advantages

Disadvantages

Can detect both local and distant recurrence sites in a single scan Detects lymph node metastases too small to be detected by CT or MRI Scan results were predictive of response to salvage radiation therapy in a recent retrospective study

Scans are difficult to interpret HAMAs Expensive Lack of histologic or radiologic confirmation of lesions imaged leads to uncertainty about what exactly is sensitivity and specificity Scans take 3 to 5 days to complete


≥ 2 cm. The sensitivity of CT was 36%, and the majority (41%) of scans showed no findings while 23% were indeterminate, showing that CT is not useful in detecting local recurrences. Teleologically, there is no reason to expect that CT will be any better able to detect local or lymph node positive disease in patients with a PSA < 20 ng per mL after definitive treatment than it was before treatment; thus CT is not recommended for these patients. Magnetic Resonance Imaging Magnetic resonance imaging can be used to detect areas of recurrent prostate cancer. Preoperative studies have shown that MRI detects abnormally enlarged lymph nodes with a similar sensitivity to CT.66 While it can be used as a substitute for CT of the abdomen and pelvis in patients with a contrast allergy, it has a distinct advantage over CT in its ability to detect local recurrence in the pelvis.67,68 Its advantage in the pelvis is due to the ability to use an endorectal coil rather than just a body surface coil, which improves the quality and accuracy of imaging local recurrences following radical prostatectomy. In the area of the urethrovesical anastomosis, MRI can detect soft tissue masses and differentiate them from fibrosis or scar tissue. Based on detection of biopsy-proven lesions, the masses of recurrent carcinoma appear hyperintense (compared to the levator and/or obturator internus muscles) on T2weighted images. On T1-weighted images, the lesions are isointense; however, they do get enhanced with the administration of gadolinium. The sensitivity reported for MRI in detecting local recurrence is 75 to 100%, with a specificity of 80 to 100%. In a series of 35 patients with a suspected local recurrence, 31 had biopsy-proven recurrences which were visualized on endorectal MRI.68 The mean PSA in the group was 1.4 ng per mL, and the masses visualized were, on average, 16 mm in diameter. Endorectal MRI has been studied as a predictor of pathologic stage in prostatectomy specimens. These studies have shown an accuracy of approximately 60%. No studies have reported its usefulness in assessing patients with recurrences following radiation therapy or brachytherapy; however, if its accuracy in predicting extracapsular extension or seminal vesicle invasion could be improved, it might be a valuable tool for assessing whether or not a patient is a good candidate for a salvage radical prostatectomy, as organconfined disease is a major predictor for biochemical relapse-free survival.22 While MRI can help define local recurrences, its ability to reliably determine that these recurrences are confined to the prostate fossa limits its overall usefulness in the post-treatment setting.

clinically localized prostate cancer.69–72 It has been found that in patients with a serum PSA < 10.0 ng per mL and in the absence of skeletal symptoms and alkaline phosphatase elevations a bone scan will be positive on only 0.5% of patients; therefore, it is not a useful staging tool in this situation. The use of bone scans in patients who fail local therapy is less well defined. Lee and Oesterling anecdotally reported a series of 94 patients with an elevated PSA following radical prostatectomy, and all patients with positive bone scans had a PSA > 2.0 ng per mL.71 A second series examined bone scan findings in patients following radical prostatectomy (89 patients) or radiation therapy with a rising PSA (13 patients).72 There were four patients with a positive bone scan following radical prostatectomy, and all of them had a PSA > 40 ng

Bone Scintigraphy Bone scintigraphy remains the most accurate method of detecting skeletal metastases in patients with prostate cancer. Bone scans have been thoroughly evaluated for their usefulness in staging patients with newly diagnosed,

FIGURE 39–3. Suggested staging evaluation for patients with a detectable PSA following radical prostatectomy.


FIGURE 39–4. Suggested staging evaluation for patients with a detectable PSA following external beam radiotherapy, cryotherapy, or brachytherapy.

per mL. Three of the radiated patients had a positive bone scan and had PSA levels of ≥ 6.0 ng per mL. As a general rule, since most patients who have a good response to salvage radiotherapy following radical prostatectomy have lower pretreatment PSA levels (usually ≤ 2.0 ng per mL), it seems that a bone scan is not a useful staging tool if the PSA is < 2.0 ng per mL. Postradiotherapy patients (external beam or brachytherapy) and probably cryosurgically treated patients may have a higher threshold at which bone scans can be eliminated, but the data is so sparse that a cutoff of 2.0 ng per mL would seem reasonable in these patients as well. Overall, it is reasonable to believe that the status of the patients with bone-positive disease after definitive local therapy will not be different from that before treatment; thus, if the PSA is less than 10 ng per mL a bone scan is unnecessary. The only caveat may be a patient who has a Gleason score of 8 to 10 without elevated PSA, and thus may have bone metastases, may benefit from a bone scan. Positron Emission Tomography Positron emission tomography scans are relatively new imaging tools for staging of recurrences of prostate cancer. Like RIS, PET uses, following administration of radiotracer,

tomographic and whole body images of patients to detect the distribution and relative activity of the radiotracer.73 The most commonly used radiopharmaceutical is 2-deoxy2-[fluorine-18]fluoro-D-glucose (FDG). On the basis of the observation that tumor cells have a higher rate of glycolysis than do nonmalignant cells, PET scans use this high metabolism to detect primary tumors and metastases. It has a sensitivity of 65% in detecting bone metastases in prostate cancer.74 It also has the ability to detect liver and lymph node metastases; however, there are no published studies detailing its accuracy in staging prostate cancer preoperatively, so there is little pathologic data regarding its ability to detect recurrent prostate cancer. Positron emission tomography has been examined in patients with newly diagnosed prostate cancer at different stages and compared with findings in patients with benign prostatic hyperplasia (BPH).75 Results have shown that PET could not differentiate malignant and benign conditions of the prostate. In a study of 14 patients (10 radical prostatectomy and 4 radiation-treated patients) FDG-PET was compared to RIS with capromab pendetide.55 In detecting recurrences in the prostatic fossa, PET was found to be less sensitive (17% versus 86%) and less specific (50% versus 93%). In detecting lymph node metastases, 57% had positive nodes by capromab pende-


tide scanning; however, none of these were detected by PET. A single patient had a lesion detected by PET, which had not been detected by capromab pendetide. All patients had CT scans which failed to confirm any of the abnormalities. It is impossible to conclude anything at present other than that there is poor correlation between PET and capromab pendetide scan findings. Hopefully, as these scans are further studied in this patient population, the role of PET in staging patients with recurrent prostate cancer can be better defined.

Recommendations for Staging of Failures There is no proven, accepted method for staging patients with biochemical failures following treatment for localized prostate cancer. The evaluation should be tailored to the clinician’s resources and the patient’s clinical scenario and treatment desires. Our approach to these patients relies heavily on information gained by 111In-CP scanning, pathologic data, and serum PSA. A suggested protocol to approach patients with a rising PSA following radical prostatectomy or radiation therapy is provided in Figures 39–3 and 39–4. Our reliance on 111In-CP scanning is based on our published experience.52,53,57 Other institutions have reported using PET or spiral CT for staging, two modalities which have been less helpful at our institution.76,77 There are no reports of staging with PET or CT being used to predict outcome of salvage therapy. One notable difference between Figures 39–3 and 39–4 is the inclusion of TRUS/Bx in the evaluation of those patients previously treated with radiation therapy. This is an important point, given the significantly increased morbidity of salvage prostatectomy and cryotherapy in these patients.22,25 One must ensure that tumor is present within the prostate prior to proceeding with either of those two therapies.

References 1. Partin AW, Pound CR, Clemens JQ, et al. Serum PSA after anatomic radical prostatectomy: the Johns Hopkins experience after 10 years. Urol Clin North Am 1993;20:713–25. 2. Stein A, de Kernion JB, Dorey F. Prostate specific antigen related to clinical status 1 to 14 years after radical prostatectomy. Br J Urol 1991;67:626–31. 3. Hudson MA, Bahnson RR, Catalona WJ. Clinical use of prostate specific antigen in patients with prostate cancer. J Urol 1989;142:1011–7. 4. Oefelein MG, Smith N, Carter M, et al. The incidence of prostate cancer progression with undetectable serum prostate specific antigen in a series of 394 radical prostatectomies. J Urol 1995;154:2128–31. 5. Goldrath DE, Messing EM. Prostate specific antigen: not detectable despite tumor progression after radical prostatectomy. J Urol 1989;142:1082–4.

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37. Egawa S, Wheeler TM, Greene DR, Scardino PT. Detection of residual prostate cancer after radiotherapy by sonographically guided needle biopsy. Urology 1992;39: 358–63. 38. Crook JM, Bahadur YA, Robertson SJ, et al. Evaluation of radiation effect, tumor differentiation, and prostate specific antigen staining in sequential prostate biopsies after external beam radiotherapy for prostate carcinoma. Cancer 1997;79:81–9. 39. Crook JM, Perry GA, Robertson S, Esche BA. Routine prostate biopsies following radiotherapy for prostate cancer: results for 226 patients. Urology 1995;45: 624–32. 40. Crook JM, Bahadur YA, Bociek RG, et al. Radiotherapy for localized prostate carcinoma: the correlation of pretreatment prostate specific antigen and nadir prostate specific antigen with outcome as assessed by systematic biopsy and serum prostate specific antigen. Cancer 1997;79:328–36. 41. Rabbani F, Stroumbakis N, Kava BR, et al. Incidence and clinical significance of false-negative sextant prostate biopsies. J Urol 1998;159:1247–50. 42. Svetec D, McCabe K, Peretsman S, et al. Prostate rebiopsy is a poor surrogate of treatment efficacy in localized prostate cancer. J Urol 1998;159:1606–8. 43. Gheiler EL, Tefilli MV, Tiguert R, et al. Predictors for maximal outcome in patients undergoing salvage surgery for radio-recurrent prostate cancer. Urology 1998;51: 789–95. 44. Grampas SA, Miller GJ, Crawford ED. Salvage prostatectomy after failed transperineal cryotherapy: histologic findings from prostate whole-mount specimens correlated with intraoperative transrectal ultrasound images. Urology 1995;45:936–41. 45. Maguire RT. 111In-capromab pendetide (ProstaScintTM) for presurgical staging of patients with prostate cancer. J Nucl Med 1995;29:10P. 46. Horoszewicz JS, Kawinski E, Murphy GP. Monoclonal antibodies to a new antigenic marker in epithelial prostate cells and serum of prostate cancer patients. Anticancer Res 1987;7:927–36. 47. Axelrod HR, Gilman SC, D’Aleo CJ, et al. Preclinical results and human immunohistochemical studies with 90Y-CYT-356. J Urol 1992;147 Suppl:361A. 48. Troyer J, Feng Q, Beckett M, Wright GL. Biochemical characterization and mapping of the 7E11-C5.3 epitope of the prostate specific membrane antigen. Urol Oncol 1995;1:29–37. 49. Abdel-Nabi H, Wright GL, Gulfo JV, et al. Monoclonal antibodies and radioimmunoconjugates in the diagnosis and treatment of prostate cancer. Semin Urol 1992;10:45–54. 50. Babaian RJ, Sayer J, Podoloff DA, et al. Radioimmuno scintigraphy of pelvic lymph nodes with 111Indium labeled monoclonal antibody CYT-356. J Urol 1994;152:1952–5. 51. Levesque P, Hirschorn M, Noiseux S, et al. Radiolabeled monoclonal antibody 111-In-Cyt-356 localizes extraprostatic recurrences after prostatectomy. J Urol 1995; 153 Suppl:519A.

352 / Advanced Therapy of Prostate Disease 52. Kahn D, Williams RD, Seldin DW, et al. Radioimmunoscintigraphy with 111Indium labeled CYT-356 for the detection of occult prostate cancer recurrence. J Urol 1994;152:1490–5. 53. Kahn D, Williams RD, Manyak M, et al. ProstaScint ™ study group. 111In-capromab pendetide in the evaluation of patients with residual or recurrent prostate cancer following radical prostatectomy. J Urol 1998; 159:2041–7. 54. Sodee DB, Conant R, Chalfant M, et al. Preliminary imaging results using In-111 labeled CYT-356 (ProstaScint™) in the detection of recurrent prostate cancer. Clin Nucl Med 1996;21:759–67. 55. Haseman MK, Reed NL, Rosenthal SA. Monoclonal antibody imaging of occult prostate cancer in patients with elevated prostate-specific antigen: positron emission tomography and biopsy correlation. Clin Nucl Med 1996;21:704–13. 56. Murphy GP, Maguire RT, Rogers B, et al. Comparison of serum PSMA, PSA levels with results of cytogen-356 ProstaScint® scanning in prostatic cancer patients. Prostate 1997;33:281–5. 57. 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;16:284–9. 58. Levesque PE, Nieh PT, Zinman LN, et al. Radiolabeled monoclonal antibody Indium 111-labeled CYT-356 localizes extraprostatic recurrent carcinoma after prostatectomy. Urology 1998;51:978–84. 59. ProstaScintTM Kit (Capromab Pendetide). FDA package insert. Cytogen Corporation, Princeton, NJ. 60. Huncharek M, Muscat J. Serum prostate-specific antigen as a predictor of staging abdominal/pelvic computed tomography in newly diagnosed prostate cancer. Abdom Imaging 1996;21:364–7. 61. Oyen RH, Van Poppel HP, Ameye FE, et al. Lymph node staging of localized prostate cancer with CT and CTguided fine-needle aspiration biopsy: prospective study of 285 patients. Radiology 1994;190:315–22. 62. Walsh JW, Amendola MA, Konerding KF, et al. Computed tomographic detection of pelvic and inguinal lymphnode metastases from primary and recurrent pelvic malignancies. Radiology 1980;137:157–66. 63. Platt JF, Bree RL, Schwab RE. Accuracy of CT in the staging of carcinoma of the prostate. AJR 1987;149:315–8. 64. Levran Z, Gonzalez JA, Diokno AC, et al. Are pelvic computed tomography, bone scan and pelvic lymphadenectomy necessary in the staging of prostate cancer? Br J Urol 1995;75:778–81.

65. Kramer S, Gorich J, Gottfried HW, et al. Sensitivity of computed tomography in detecting local recurrence of prostatic carcinoma following radical prostatectomy. Br J Radiol 1997;70:995–9. 66. Wolf JS Jr, Cher M, Dall’era M, et al. The use and accuracy of cross-sectional imaging and fine needle aspiration cytology for detection of pelvic lymph node metastases before radical prostatectomy. J Urol 1995;153:993–9. 67. Boni RAH, Meyenberger C, Lunquist JP, et al. Value of endorectal coil versus body coil MRI for diagnosis of recurrent pelvic malignancies. Abdom Imaging 1996; 21:345–52. 68. Silverman JM, Krebs TL. MR imaging evaluation with a transrectal surface coil of local recurrence of prostate cancer in men who have undergone radical prostatectomy. AJR 1997;168:379–85. 69. Chybowski FM, Keller JJ, Bergstrahl EJ, Oesterling JE. Predicting radionuclide bone scan findings in patients with newly diagnosed, untreated prostate cancer: prostate specific antigen is superior to all other clinical parameters. J Urol 1991;145:313–8. 70. Oesterling JE, Martin SK, Bergstahl EJ, Lowe FC. The use of prostate-specific antigen in staging patients with newly diagnosed prostate cancer. JAMA 1993;269:57–60. 71. Lee CT, Oesterling JE. Using prostate-specific antigen to eliminate the staging radionuclide bone scan. Urol Clin North Am 1997;24:389–94. 72. Sanders H, Smith E, Woodward M, Graham SD Jr. The use of PSA to predict bone metastases in recurrence after definitive local therapy for prostate cancer. J Urol 1995; 153 Suppl:238A. 73. Hoh CK, Schiepers C, Seltzer MA, et al. PET in oncology: will it replace the other modalities? Semin Nucl Med 1997;27:94–106. 74. Shreve PD, Grossman HB, Gross MD, Wahl RL. Metastatic prostate cancer: initial findings of PET with 2-deoxy2[F-18]fluoro-D-glucose. Radiology 1996;199:751–6. 75. Effert PJ, Bares R, Handt S, et al. Metabolic imaging of untreated prostate cancer by positron emission tomography with 18Fluorine-labeled deoxyglucose. J Urol 1996;155:994–8. 76. Carlin BI, Resnick MI, Faulhaber PF, Miraldi F. Alteration in PET scanning technique increases accuracy in detecting the lymphatic spread of prostate cancer. J Urol 1998; 159 Suppl:289A. 77. Seltzer M, Naitoh J, Cangiono T, et al. Comparison of computed tomography (CT), positron emission tomography (PET), and monoclonal antibody scan (MAB) for evaluation of lymph node (LN) metastases in patients with PSA relapse after treatment for localized prostate cancer (CAP). J Urol 1998;159:9.

CHAPTER 40

MANAGEMENT OF PROSTATE-SPECIFIC ANTIGEN FAILURE AFTER DEFINITIVE THERAPY FOR CLINICALLY LOCALIZED PROSTATE CANCER MARCOS V. TEFILLI, MD; EDWARD L. GHEILER, MD; J. EDSON PONTES, MD The widespread acceptance of prostate cancer (PCa) screening and the greater awareness of the disease by the general public has led to a dramatic increase in the number of men diagnosed with PCa. Although the merits of PCa screening are controversial, there is consensus among the urologic community that early detection and subsequent treatment of clinically localized PCa in men with a high probability for a 10-year life expectancy are beneficial.1–10 Results of radical prostatectomy (RP) and radiation therapy (RT) for clinically localized PCa are extremely variable, with 3- to 5-year rates of biochemical disease control, ranging from 20 to 92% for surgically treated patients and 8 to 90% for patients treated with RT (Table 40–1).2–13 The detection of a rise in serum prostate-specific antigen (PSA) level following definitive therapy presents the physician with a series of dilemmas: the necessity of additional treatment, what treatment to recommend, when to initiate treatment, and how to assess the impact of treatment on survival as well as on quality of life (QOL). With the current use of PCa screening, a large number of young, healthy patients with small volume tumors are being treated with curative intent. There will be a cohort of these patients who will fail locally and be candidates for second-line treatment. Others will fail systemically and be treated with hormones for palliation. This chapter presents a review of the contemporary management of biochemical recurrence following RP and RT for clinically localized PCa. Although biochemical disease-free survival rates will be analyzed as a treatment end point, other issues such as QOL, clinical disease recurrence rates, and survival will also be addressed.

it provides special information related to staging (anatomic extent of disease), it correlates with prognosis (predicting the natural history of the disease and response to treatment), it confirms an apparent complete elimination of the cancer by treatment, and it allows for earlier detection of treatment failure leading to early salvage treatment, which translates into better patient survival. The Ideal Tumor Marker It is remarkable how closely PSA approximates the perfect tumor marker. There is no better tool than PSA for monitoring PCa patients after treatment. It is sensitive in detecting persistent or recurrent disease after treatment. Prostate-specific antigen is probably the best tumor marker in oncology today and clearly has had a profound impact on all aspects of PCa patient care. The PSA molecule is a single-chain glycoprotein and a member of the human kallikrein family. Amino-acid sequencing and cDNA cloning techniques have set the peptide length at 237 amino acids. The molecular weight ranges from 26,000 to 34,000 daltons, depending on the method used for analysis. The gene coding for PSA is located on the long arm of chromosome 19 and is under androgen regulation.14 Prostate-specific antigen is a serine protease with chymotrypsin-like enzymatic activity. It is synthesized in the ductal epithelium and prostatic acini and is located within the cell in cytoplasmic granules and vesicles, rough endoplasmic reticulum, vacuoles, and secretory granules, including lysosomal dense bodies.15 The antigen is found in normal and hyperplastic prostate tissue as well as in prostate cancer cells. It is secreted into the lumen of prostatic ducts to become a component of seminal plasma, reaching the serum after diffusion from luminal cells. Despite initial assumptions that PSA was tissue and gender specific, immunohistochemical studies have detected PSA in females and in male periurethral glands, anal glands, apocrine sweat glands, salivary gland neoplasms, breast tissue, and in human breast milk.16

The Perfect Tumor Marker Tumor markers are substances produced by tumors, are measurable in body fluids, and are useful in diagnosing and managing cancer. The perfect tumor marker would fulfill the following criteria: it is produced exclusively by tumor cells, it is detectable in any patient with the disease, 353

354 / Advanced Therapy of Prostate Disease TABLE 40–1. Rates of Biochemical Control* % Biochemical Control EBRT

Preoperative PSA Level

3DRT

Brachytherapy

Surgery

Zeitman et al.5

Lee et al.6

Horwitz et al.7

Sandler et al.8

Blasko† et al.9

Partin et al.10

< 4 ng/mL 4–10 ng/mL 10–20 ng/mL > 20 ng/mL

82 44 30 8

85 81 59 35

90 54 27 14

90 85 56 20

90 90 89 80

92 83 56 45

PSA = prostate-specific antigen; EBRT = external beam radiation therapy; 3DRT = three-dimensional radiation therapy. *Stratified by pretreatment PSA for surgical and radiation series at 5-year follow-up. †Total 197 patients, median Gleason score 5, median follow-up 36 months, 5-year actuarial rate.

The perfect tumor marker, as noted above, should allow for earlier detection of treatment failures, leading to prompt institution of further treatments that improve disease-free survival (DFS). For example, in testis cancer, beta-human chorionic gonadotropin and alpha-fetoprotein are useful following orchiectomy to detect disease relapse prior to any radiographic abnormalities. Because disease progression from PCa without concurrent changes in serum PSA levels is rare, success following definitive therapy is now judged based on freedom from biochemical disease progression. An increase in serum PSA level following initial treatment triggers further therapy, and the fall in serum PSA level implies effective salvage treatment.

Biochemical Recurrence following Initial Treatment The widespread use of PSA in the follow-up of patients undergoing definitive treatment has allowed for earlier detection of recurrent disease. Monitoring serum PSA levels after definitive therapy has made it apparent that permanent eradication of clinically localized PCa is not achieved as frequently as previously believed. An increase in PSA level following definitive treatment results from local failure, metastatic disease, or both. Biochemical Recurrence following Radical Prostatectomy The use of serum PSA levels to monitor patients following RP has changed many concepts about persistent or recurrent disease. An undetectable serum PSA level is synonymous with tumor-free status in men following RP. The main advantage of utilizing serum PSA levels after RP is early detection of persistent or locally recurrent microscopic disease, sometimes preceding clinical symptoms by years. With the advent of more sensitive PSA assays, however, it becomes possible that an elevated PSA level could be due to factors other than persistent cancer. These factors include PSA production from normal prostate tissue or benign prostatic hyperplasia (BPH) remnants, other sources of PSA (i.e., periurethral glands, breast tissue, perianal glands), or cross-reacting substances in the serum.14–18 The exact frequency of retained BPH tissue

following RP is not known but is probably rare and should not cause progressively rising serum PSA levels. Extraprostatic sources of PSA production such as the male periurethral glands may also falsely elevate serum PSA. Most investigators have found that these glands are unlikely to produce enough PSA to make it detectable in serum.14,15,18 Immunohistochemical studies have revealed the presence of staining for PSA in the urine of male PCa patients who have had their prostates removed. The major sources of urinary PSA following RP are the periurethral glands themselves rather than residual PCa, making urinary concentrations not useful for monitoring patients following RP.14,15,17,18 The most important cross-reacting substance that could potentially limit the value of ultrasensitive PSA assays is human glandular kallikrein (hCK-1). To date, these substances have not been proven to significantly affect serum PSA levels following RP.3,10,17–19 Serum PSA levels should rapidly decrease to undetectable levels following RP. Lange et al. found that if the serum PSA was < 0.4 ng per mL at 6 months following RP, only 9% of patients experienced disease recurrence, while all men with a serum PSA of > 0.4 ng per mL recurred.17 Because the half-life of PSA is short (2.2 to 3.1 days), a serum PSA elevation of 0.4 ng per mL or more occurring 3 to 6 months after RP is consistent with persistent disease. Others have defined biochemical disease recurrence as a serum PSA in the range of 0.2 to 0.6 ng per mL.18 Partin et al. evaluated the time to biochemical failure in an attempt to distinguish local versus metastatic disease recurrence.19 They found that 81% of all biopsy-proven recurrences, with no evidence of metastasis on bone scan, occurred in patients with biochemical disease recurrence more than 12 months postoperatively. Conversely, 65% of all patients with metastatic disease had biochemical disease recurrence within 12 months following RP. These results suggest that early (less than 6 to 12 months following RP) PSA failure is associated with distant metastasis whereas delayed PSA failure (more than 6 to 12 months after RP) represents patients who most likely have isolated local disease recurrence as the site of failure. Ultrasound-guided biopsy of the bladder-urethra anastomosis is of limited value in diagnosing local disease recur-

Management of Prostate-Specific Antigen Failure after Definitive Therapy for Clinically Localized Prostate Cancer / 355

rence since significant sampling error exists. Disease recurrence cannot be ruled out by a negative biopsy, and a positive biopsy is not useful in excluding metastatic disease. Also, patients with detectable serum PSA levels and negative bladder-urethra anastomosis biopsies have been found to benefit from salvage RT, making the interpretation of a negative biopsy difficult in this group of patients.20 The current authors’ definition of local recurrence following RP is largely based on final pathologic findings. Patients with positive margins in the absence of positive lymph nodes and/or seminal vesicle invasion are at higher risk for local recurrence. In this population, an initially undetectable serum PSA level that shows an increase more than 6 months following therapy, with a negative metastatic evaluation, is most likely due to local disease recurrence. Biochemical Recurrence following Radiotherapy The serum PSA nadir indicative of long-term DFS in patients following RT is not known. Radiation therapy does not eradicate the tumor immediately, and fatally damaged malignant cells destined for a postmitotic death may survive for many months. The serum half-life for PSA in patients following RT has been estimated to be between 1.9 to 3 months. Most investigators agree that a nadir PSA level of < 1 or 1.5 ng per mL is associated with long-term disease control. The definition of biochemical disease control, however, varies significantly from institution to institution. Zeitman et al. require a patient to achieve or maintain a serum PSA nadir of ≤ 1 ng per mL for 2 or more years after treatment to be considered biochemically disease free. They also consider a patient as having biochemical failure if they have two consecutive rises in serum PSA level, irrespective of the absolute serum PSA level.5 Lee et al. define biochemical DFS as being achieved if the most recent serum PSA level is less than or equal to the previous value, or a nadir serum PSA level of ≤ 1.5 ng per mL is reached less than 1 year following treatment.6 Recently, the same group reported that patients who do not achieve a PSA nadir of ≤ 0.99 ng per mL are at high risk for recurrent disease.21 Liebel et al. define biochemical failure as two consecutive increases in serum PSA above normal levels (4 ng per mL).22 Pisansky et al. define biochemical failure as any increase in the serum PSA level following treatment after achieving nadir.23 Zagars and Pollack define biochemical failure as two or more consecutive increases in serum PSA level above nadir. If any subsequent PSA value increases by 1 ng per mL or by a factor of 1.5 times the last serum PSA level, the patient is also considered as having failed treatment.24 Depending on which definition of biochemical failure is used, significant differences in overall treatment outcomes are reported (Table 40–2). In an attempt to explain why the serum PSA level does not become undetectable following RT, Grob et al. performed immunoperoxidase staining for the expres-

sion of PSA on biopsy specimens obtained 12 months after RT.25 Results of this study showed that the benign glands identified from these biopsy specimens did not stain for PSA. Only glands that were histologically identified as malignant showed evidence of any PSA staining. These findings support the conclusion that elevated serum PSA levels following external beam RT are more likely due to persistent cancer rather than to residual prostate tissue. Willet et al. reported that the PSA levels from patients undergoing RT for rectal or bladder cancer, with no evidence of prostate cancer, in whom the prostate was included in the radiation field, was undetectable at a median follow-up of 10 years.26 The nadir serum PSA level indicative of long-term biochemical disease-free survival remains a point of controversy, with no accepted standard definition. The American Society of Radiation Oncology defines biochemical recurrence after RT as three consecutive rises above the nadir level. An absolute nadir level, although recognized as a risk factor, was not identified as an indicator of treatment success or failure.27 Some authors agree, however, that a nadir PSA of < 1 or 1.5 ng per mL is necessary to achieve long-term disease control following RT.5,6,21 Prostate biopsies following RT have prognostic significance. Several reports have demonstrated that patients failing RT with a positive biopsy have worse prognosis than those with negative biopsies.28,29 The rate of isolated local disease recurrence or persistence following RT for PCa is still unknown although biopsies of the prostate done 1 to 2 years after RT may show malignant cells in at least 20% of patients. In summary, PSA can be used to monitor responses to RT, and the combination of a rising serum PSA level and positive prostate biopsy are highly sensitive and specific indicators of disease recurrence. The current definition of local disease recurrence following RT is a positive needle biopsy in conjunction with an increasing PSA level in a patient with a negative metastatic workup, at least 1 year after RT. Additionally, patients who develop a rising serum PSA level subsequent to a normal nadir are more likely to have local disease recurrence whereas patients who do not reach a nadir serum PSA are at high risk of developing and succumbing to metastatic disease. TABLE 40–2. Actuarial 5-Year Rates of Biochemical Control* % Biochemical Control at Nadir PSA

Pretreatment PSA Level

< 1 ng/mL†

< 1.5 ng/mL‡

< 4 ng/mL§

< 4 ng/mL 4–10 ng/mL 10–20 ng/mL > 20 ng/mL

84 45 25 5

90 54 28 14

91 74 55 15

*Based on various definitions of disease-free survival following radiotherapy. †Zeitman et al.5 ‡Lee et al.6 §Prestigiacomo and Stamey.18


Biochemical Recurrence following Cryotherapy The biochemical criteria for locally recurrent PCa following cryotherapy are not well defined. The lack of longterm treatment outcomes and established definitions of biochemical disease failure as well as continued aggressive biopsy policies present the primary difficulties in evaluating the current efficacy of cryotherapy in treating of PCa. From the available data, it seems that patients with persistent disease have higher PSA nadirs (> 0.5 or 1 ng per mL) and a higher PSA velocity more than 3 months following treatment. An undetectable PSA level 3 months after treatment is associated with a favorable outcome. Long-term data regarding disease-free survival following cryoablation are unavailable at this time.11,28

Imaging Once disease recurrence has been diagnosed in patients with clinical or biochemical disease recurrence, evaluating the location and extent of the disease becomes crucial. In patients with clinical disease recurrence, a complete evaluation, including an abdomen and pelvic computed tomography (CT) scan and a radionucleotide bone scan, is conducted. The CT scan enables evaluation of the local extent of recurrence. The bone scan is useful in identifying patients with osseous metastasis. The real value of imaging studies for isolated biochemical recurrences following RP and RT has not been established. Imaging for Biochemical Recurrence following Radical Prostatectomy The use of imaging techniques in localizing metastatic disease in patients with biochemical failure is controversial. The current authors reviewed the results of bone scans in patients with isolated biochemical recurrence following RP at Wayne State University between January 1993 and December 1996. One hundred forty-four bone scans were contributed by 93 patients. In a univariate analysis, stage, grade, preoperative PSA level, and time to recurrence were not significant indicators of positive bone scan. In a multivariate analysis, trigger PSA (the PSA that prompted the clinician to obtain the bone scan) was the single most useful parameter to predict the bone scan result. The authors did not find any bone scans that were positive for osseous metastasis in patients with a serum PSA < 46 ng per mL.30 The sensitivity of CT scans of the abdomen and pelvis in detecting nodal metastases or locally recurrent tumors in men with a rising PSA after RP were also reviewed, between January 1991 and January 1997. Sixty-eight patients were enrolled in the study. Two groups were identified with biochemical recurrence following RP, those with and those without hormonal therapy. Each group was divided into two subgroups, trigger PSA ≥ 10 ng per mL and trigger PSA < 10 ng per mL. Ninety-eight CT scans were performed. Seventy-one

and 27 CT scans were obtained for the groups with and without hormonal therapy, respectively. Of the 71 CT scans in untreated patients, 6 (8%) were positive for distant metastases. Of the 27 CT scans performed in patients with hormonal therapy, 7 (26%) were positive for metastases. With a trigger PSA cutoff of 10 ng per mL, only patients with levels higher than 10 ng per mL were found to have metastases in both groups (p = .001 and p = .01, respectively). The detection of lymph node metastases with CT scans is very limited in patients with biochemical recurrence who have a serum PSA ≤ 10 ng per mL [unpublished observations]. Radioimmunoscintigraphy with indium (In)-111labeled monoclonal antibody to prostate-specific transmembrane glycoprotein (PSMA) can be potentially useful for predicting PCa response to salvage RT. This radioimmunoconjugate, derived from the murine monoclonal antibody 7E11, recognizes PSMA that is expressed only by prostatic epithelial cells. Seltzer et al. evaluated the usefulness of CT scan, positron emission tomography scanning (PET), and monoclonal antibody scans (ProstaScint™) in diagnosing lymph node metastases in patients with biochemical disease recurrence following RP. They found the CT scan and PET scan to be useful in patients with serum PSA levels > 4 ng per mL but did not feel that the monoclonal antibody scans added any useful information.31 Conversely, Kahn et al. have shown ProstaScint™ to be useful in identifying patients who will respond favorably to salvage radiotherapy.32 They demonstrated that salvage RT is more likely to lead to a durable complete response when a negative In-111-capromab pendetide scan outside the pelvis is obtained. These results, however, need further study. Imaging for Biochemical Recurrence following Radiation Therapy The role of radionucleotide bone scans in detecting osseous metastases in patients with biochemical disease recurrence following RT was evaluated at the current authors’ institution. The authors reviewed bone scans from December 1991 to September 1996 in patients with progressively rising PSA following RT. One hundred forty-four bone scans were contributed by 104 patients. Bone scans were found to be useful in patients with Gleason score 8 or higher tumors, Gleason score 6 tumors and a PSA increase of 10.8 ng per mL per year, and Gleason score 7 tumors and a PSA increase of 2.4 ng per mL per year [unpublished observations]. The usefulness of CT scans in patients failing RT needs to be evaluated in a study.

Radiotherapy Failure Salvage Surgery for Locally Radiorecurrent Prostate Cancer Disease recurrence following RT has an aggressive natural history. Although some patients have metastatic disease


beyond the reach of local therapy, others appear to have only local disease recurrence. This becomes apparent when one considers that a persistently undetectable serum PSA level is obtained in half of all patients following salvage prostatectomy.12,33,34 These data suggest that, besides providing excellent local tumor control, a subset of patients with recurrent cancer may be cured by further aggressive local treatment.33,34 In addition, eradicating the primary tumor in a patient showing no evidence of metastasis may decrease the likelihood of developing metastatic disease. The primary question to be addressed is whether PSA failure following RT represents isolated local disease recurrence, which will thus become amenable to treatment with salvage surgery. Salvage surgery is indicated only in patients who have isolated local disease recurrence. Candidates also need to have good performance status with a life expectancy of more than 10 years. The Ideal Candidate for Salvage Surgery Salvage RP should be offered only to highly motivated individuals who accept the higher morbidity associated with this treatment approach. In a recent study at the authors’ institution, patients undergoing salvage surgery for radiorecurrent PCa were reviewed to determine the ideal candidate for salvage prostatectomy.33 Preradiation and preoperative clinical staging factors as well as pathologic stage were analyzed as predictors of DFS. Clinical staging prior to salvage prostatectomy was unable to identify patients with pathologically organ-confined disease and was not predictive of DFS. It was, however, useful in identifying patients with obvious extraprostatic disease. The current authors found that patients with clinically localized PCa prior to RT had a significantly better DFS than those patients with locally advanced cancer before initial RT (p = .03). Preoperative PSA values did not correlate with pathologic stage or DFS but a trend was noted toward patients with a serum PSA level < 10 ng per mL having the best chance of being cured. Final pathologic stage was strongly predictive of DFS, with seminal vesicle invasion and positive lymph nodes being the worst pathologic prognostic factors. Conversely, all patients with pathologically organ-confined disease following salvage surgery were biochemically disease free (p = .02). The optimal candidate for salvage RP may be a patient with a “clinical T1c tumor” following RT. The authors analyzed eight such patients in a series, each of whom had PSAdetected PCa, a normal digital examination, and were diagnosed by sextant prostatic biopsies. Six of these eight patients (75%) are disease free, all of whom had pathologically organ-confined disease (p = .07). Radical prostatectomy is the primary surgical operation for recurrent PCa following RT. Cystoprostatectomy and complete pelvic exenterations are however indicated in patients with extensive local disease recurrence, a small,

contracted bladder, urinary incontinence, hemorrhagic cystitis, or a concomitant bladder tumor. Although pelvic exenterations yield acceptable local clinical disease control, the procedure is of questionable benefit, with only 20 to 30% of patients achieving biochemical DFS on a shortterm basis.12,33 The poorer results seen in these patients are due to more advanced disease at the time of surgery; in the current authors’ series, only 10% of salvage cystoprostatectomy specimens had organ-confined disease and only 30% of patients receiving this treatment were biochemically disease free after a mean follow-up of 36 months.33 Therefore, patients with clinically locally advanced disease, especially prior to radiotherapy, are highly likely to have pathologically extraprostatic disease. In these cases, although technically feasible, salvage surgery should not be widely advocated as an effective curative treatment. Ideal candidates for salvage surgery should have clinically organ-confined disease before radiation therapy and presalvage serum PSA level < 10 ng per mL. The use of serum PSA levels may lead to the earlier diagnosis of recurrent disease with earlier initiation of salvage surgery, leading to improved outcomes with salvage surgery. Technical Aspects of Salvage Surgery Candidates for salvage RP must undergo a complete endoscopic and urodynamic evaluation. Based on these evaluations, patients are selected to have either salvage prostatectomy or cystoprostatectomy. All patients, despite extensive preoperative evaluation, should be informed of the possibility that during surgery a cystoprostatectomy with urinary diversion rather than a radical prostatectomy may be necessary. Salvage RP can be performed through a retropubic, perineal, or abdominoperineal approach. The technique of salvage prostatectomy and cystoprostatectomy with urinary diversion used by the authors has been previously published and is essentially the same as standard RP or cystoprostatectomy, with several modifications.35,36 Opening the endopelvic fascia can be difficult but the prostate can often be quite easily bluntly dissected from the pelvic side wall. It is not uncommon to have to sharply dissect the prostate off the rectum. Blunt dissection in this plane can lead to rectal injury. In this case, despite bowel preparation, closure of the rectotomy and a diverting colostomy are appropriate. Outcome and Morbidity of Salvage Surgery The published salvage surgery series can be divided into two groups, the first consisting of patients diagnosed with clinical disease recurrence in the pre-PSA era and the second, a more recent group, consisting of patients diagnosed secondary to a progressive PSA elevation without clinical evidence of disease recurrence. That there has been a shift toward earlier detection is evidenced by a decrease in the number of pelvic exenterations performed and an increased percentage of patients with localized


disease.12,33,34 Table 40–3 summarizes the clinical information available in the literature regarding salvage surgical therapy for local failure following RT.12,33,34,37–44 Salvage surgery provides excellent local clinical disease control as well as biochemical DFS. An undetectable serum PSA level has been reported in 20 to 60% of patients undergoing salvage surgery.12,33,34,37–44 Salvage RP is technically challenging, with short-term and long-term complication rates exceeding those for standard RP. Intraoperative complications such as blood loss have been acceptable, with an average loss of 1000 mL. Rectal injury has been reported in 0 to 35% of cases, with ureteral injury occurring rarely. Postoperative urinary incontinence has been reported in 10 to 60% of cases and bladder-neck contracture in 17 to 25% of cases. Virtually all patients have erectile dysfunction following this procedure. Cryotherapy following Radiation Failure Although the re-emergence of cryotherapy as a local treatment option has been controversial, several centers have attempted to show the efficacy of cryoablation therapy for patients who fail RT.45–47 Long-term DFS data following salvage cryoablation therapy are not available. Results are hard to interpret due to complementary androgen deprivation therapy (ADT) in many of these patients.47 In three published salvage cryotherapy series, PSA levels of < 0.4 ng per mL were obtained in about 30% of cases.45–47 The salvage cryotherapy procedure itself is well tolerated but the complications are significant. In a series reported by Pisters et al., the main patient-reported complications were urinary incontinence (73%), impotence (72%), obstructive urinary symptoms (67%), perineal pain (18%), and passage of debris in the urine (22%).47 Overall, salvage cryotherapy has an impact on local tumor control in a small cohort of patients. Many patients who are not considered candidates for salvage prostatectomy because of significant comorbidities may be considered for salvage cryotherapy. Although a less invasive procedure, salvage cryotherapy causes significant morbidity and achieves disease control less often than does salvage prostatectomy. Androgen Deprivation Therapy following Radiation Failure An increase in PSA level following RT indicates recurrent disease and prompts the clinician to obtain biopsies of the prostate and imaging studies to detect the presence of metastases. For patients in whom significant comorbidity, advanced local disease recurrence, or metastatic disease preclude surgery, observation or treatment with ADT may be indicated. The latter may be administered as monotherapy with bilateral orchiectomy or a luteinizing hormone–releasing hormone (LHRH) agonist or as combined androgen blockade (CAB), the former in combination with a nonsteroidal antiandrogen. Combined andro-

gen blockade leads to simultaneous suppression of testicular and adrenal androgens. It is unclear whether it is superior to monotherapy in terms of improving patient survival and reducing complications from metastatic PCa. Another important issue regarding ADT is when to initiate hormonal treatment. In a recent European study from The Medical Research Council Prostate Cancer Working Party Investigators Group, the effect of the timing of initiation of ADT treatment on the clinical course of patients with advanced prostate cancer was investigated. Treatment was instituted at the time of diagnosis (early) or was deferred until clinically significant progression had occurred (delayed).48 Among 934 patients, pathologic fractures, spinal cord compression, ureteric obstruction, and development of extraskeletal metastases were twice as common in delayed patients as in those treated early. There was also an advantage found in terms of survival for the group treated early. Nevertheless, issues relating to the optimal method of ADT, CAB versus monotherapy, timing of ADT, treatment cost, quality of life, and improved survival have not been settled. Androgen deprivation therapy is probably the most frequently used intervention for local failure following RT. Schellhammer et al. reported on a group of patients treated with either immediate or delayed hormonal therapy for local failure following definitive external beam RT or interstitial seed implantation. They showed a median cancer-specific survival from time of disease recurrence of 70 and 87 months, respectively.49 Also, 60% of patients required transurethral resection of the prostate for bladder outlet obstruction due to local disease progression; others required ureteral diversion, colostomy, or suprapubic tube placement.12,49 The effect of ADT on control of locally recurrent tumor following RT is of limited duration. Consequently, patients with a life expectancy greater than 10 years are at substantial risk for the development of metastasis and significant local morbidity due to tumor progression. The current authors suggest early ADT for patients who are not candidates for salvage surgery or for those who have failed salvage surgery. Salvage Surgery for Locally Recurrent Prostate Cancer following Seed Implantation Radioactive seed implantation remains a treatment option for selected patients with clinically localized PCa. Improvements in preimplant planning with the use of computed tomography, intraoperative ultrasound, and a transperineal approach have made this form of treatment popular. Despite more accurate seed placement leading to improved dosimetry, and better patient selection, local recurrence can still be expected in 20 to 30% of patients within 5 years.50,51 Brenner et al. reported their experience with salvage prostatectomy in 10 patients with locally recurrent prostate cancer following 125-I implantation.52 All patients had palpable prostate abnormalities at the


time of disease recurrence, confirmed to be prostate cancer by subsequent needle biopsy. Only three patients (two with organ-confined and a third with extracapsular extension but negative surgical margins) had an undetectable serum PSA level at a mean 40-month follow-up. The investigators concluded that salvage prostatectomy should not be widely advocated as an effective treatment for recurrent disease following 125-I implantation. This series was limited in that all patients had palpable prostate abnormalities at time of surgery. Whether surgery at the time of biochemical recurrence (prior to palpable abnormalities developing) will improve treatment outcomes remains to be determined. The lack of a standard definition of biochemical treatment failure following radiotherapy in the form of external beam or seeds contributes to delays in diagnosing recurrent disease in these patients.

Salvage Surgery following Failed Cryotherapy Cryotherapy for prostate cancer has traditionally been used as an alternative therapy in poor surgical candidates or when RT is contraindicated. Over the past decade, cryotherapy has gained acceptance as a first-line treatment due to its low surgical morbidity and the fact that it does not limit therapeutic options if failure occurs. The incidence of histologically persistent PCa following cryotherapy is at least 20%. Salvage surgery is a treatment option for cryosurgical failures. Grampsas et al. reported 6 cases of salvage perineal prostatectomy following cryotherapy failure.11 The most significant problem was urinary incontinence. Mean follow-up ranged from 0.5 to 12 months, and 5 of 6 patients were biochemically disease free. Although technically feasible, the role of salvage prostatectomy following cryotherapy needs to be better defined.

Radical Prostatectomy Failure Observation for Rising Prostate-Specific Antigen Levels following Radical Prostatectomy Observation may be appropriate for selected patients with rising PSA levels following RP. Some authors have shown that a rising PSA level is not always associated with clinical disease recurrence at the time of biochemical treatment failure. It may take many years for some patients to develop clinical signs of disease recurrence. In a large series from Johns Hopkins Institute, a significant number of patients managed expectantly for an isolated PSA elevation remained clinically disease free for up to 30 months following biochemical failure.10 It is generally accepted that a persistently abnormal or rising serum PSA level are reliable signs of persistent disease following RP, occurring months to years prior to clinical disease recurrence developing. Kupelian et al. analyzed 124 patients who had isolated bio-

TABLE 40–3. Summary of Clinical Information in Contemporary Series of Salvage Surgery* % % % % No. of Rectal Bladder Neck Urinary DFS Patients Injury Contracture Incontinence (Months)

Reference

Thompson et al.37 Neehut et al.38 Moul and Paulson39 Link and Freiha40 Ahlering et al.41 Stein et al.42 Pontes et al.43 Rogers et al.34 Lerner† et al.12 Gheiler et al.33 Garzotto§ and Wajsman44

5

0

20

20

Not stated

16 22

20 35

25 Not stated

73 54

88 (20) 33 (50)

14

0

0

45

43 (9)

34 13 43

0 8 9

0 15 11

36 36 30

40 122 40 29

15 7 2.5 6.9

27.5 20.2 12.5 6.9

58 Not stated 49 66%

65 (114) Not stated 28 (12–120) 47 (39) Not stated 47 (36) 79‡ (60)

DFS = disease-free survival. *For locally radiorecurrent prostate cancer. †38 patients underwent cystoprostatectomy and 5 patients underwent total pelvic exenteration. This series included patients treated between 1966 and 1992. ‡In 21 of 29 (72%) patients hormonal therapy continued indefinitely after surgery. §24 patients underwent neoadjuvant hormonal therapy.

chemical disease recurrence following RP.53 Eighty-five patients were observed and 39 patients were treated with either RT or ADT. With a median follow-up of 32 months, the clinical disease-free survival rate was 79% for the treated patients compared to only 32% for patients receiving no treatment. This demonstrates that for some patients, treatment for isolated biochemical disease recurrence with second-line treatments such as salvage RT may be beneficial. Salvage RT offers, in addition to excellent local disease control, a second chance for cure in patients with isolated biochemical disease recurrence, especially if no risk factors for metastatic disease are present. Adjuvant or Salvage Radiotherapy following Radical Prostatectomy? The rationale for adjuvant or salvage RT in patients with pathologically advanced PCa lies in the belief that residual tumor cells locally confined to the pelvis following RP may serve as a source of local and distant disease recurrence if untreated. The optimal timing and choice of treatment of disease recurrence following RP remain uncertain.53–56 Treatment may be initiated without clinically proven disease recurrence (adjuvant RT) or on the basis of biochemical or clinical disease recurrence (salvage RT). The limitation of adjuvant RT is that only 30 to 40% of patients with focally positive surgical margins progress at 5 years.54 Therefore, depending on criteria used to determine the need for adjuvant treatment, 30 to 60% of patients may be exposed to the side effects of treatment without deriving any clinical benefit.


Salvage RT has had poor results in patients with clinically proven local disease recurrence.13 Forman et al. evaluated the possibility of a therapeutic window between adjuvant therapy (60% of patients receiving unnecessary treatment) and curative therapy for proven recurrence (70% of patients already incurable).56 This therapeutic window appears to be narrow; patients fared best if they received salvage RT before developing clinical signs of disease recurrence and if they had a serum PSA level ≤ 2 ng per mL. Accordingly, an optimal strategy following RP may be to observe patients postoperatively, regardless of pathologic risk factors, except for those patients with positive lymph nodes. If patients are found to have an elevated PSA level at least 6 months after surgery, preferentially with a PSA level at the time of salvage RT of ≤ 2 ng per mL or less and no signs of metastatic disease, a course of therapeutic irradiation should be implemented. Tables 40–4 and 40–5 summarize the clinical information available in contemporary series of salvage and adjuvant RT following RP.13,55–69 Salvage Radiotherapy following Radical Prostatectomy The Ideal Candidate for Salvage Radiotherapy Postprostatectomy serum PSA levels are a sensitive indicator of disease recurrence or persistence. The primary question to be addressed is whether PSA failure following RP represents local disease recurrence which is thus amenable for treatment with salvage RT, or whether it represents metastatic disease recurrence. Serum PSA levels that do not become undetectable following RP have been associated with metastatic disease recurrence while serum PSA levels that initially drop to undetectable levels and later begin to rise are usually associated with local disease recurrence. Cadeddu et al. reported that patients with high Gleason score (8 to 10) tumors, positive seminal vesicles or lymph nodes, or patients with isolated biochemical disease recurrence within the first 6 to 12 months following RP rarely benefit form salvage radiation treatment.13 Other authors have shown that patients with isolated biochemical disease recurrence who had low Gleason score tumors, low preoperative serum PSA levels, and low PSA velocity following surgery are more likely to benefit from salvage RT.53 Low rates of cure should be expected from salvage RT treatment in patients with positive lymph nodes, seminal vesicle invasion, high-grade prostate cancer, PSA recurrence within the first 6 to 12 months following RP, serum PSA levels higher than 2.0 ng per mL at the time of salvage RT, or clinical local disease recurrence.13,56,61,62 Patients whose PSA does not fall to an undetectable level following RP are also unlikely to benefit from salvage RT. Conversely, patients with an initially undetectable serum PSA level and with biochemical disease recurrence 6 months following RP should be

staged. If they are thought to have isolated local disease recurrence, they should be treated with salvage RT. Technical Aspects of Salvage Radiotherapy The current authors do not routinely perform a transrectal ultrasound or biopsy evaluation of the prostatic bed prior to administering salvage RT. All patients undergo computerized tomography simulation with oral, intravesical, and urethral contrast media. Axial and nonaxial radiation fields are designed to conform to the size, shape, and location of the three-dimensionally reconstructed preoperative prostate and seminal vesicles. Radiotherapy includes delivery of 50 to 74 Gy (median total dose of 66 Gy) in 1.8 to 2.0 Gy fractions. The treatment is delivered to the prostatic bed and no attempt is made to include the pelvic lymph nodes. Higher doses (64 Gy or more) seem to be associated with a better response rate to therapy than are lower doses.61 Outcome and Morbidity of Salvage Radiotherapy Prostate-specific antigen will return to an undetectable range in 30 to 80% of patients treated with salvage RT following RP, a response that appears to be durable in about 21 to 69% of cases.13,55–57,60–62 The difference in response rates may reflect patient selection. Response to salvage RT is gradual, taking 2 to 48 months (mean 12) to achieve undetectable PSA levels.61 To determine the role of RT following RP, Anscher et al. followed 159 patients undergoing RP with pathologic stage T3 PCa for a median period of 10 years.63 Forty-six patients received RT and 112 did not. There was no difference in actuarial survival, DFS, or rate of distant metastases between the two groups. The local relapse rate, however, was significantly reduced by the addition of RT. Radiotherapy following RP significantly improves local control but no improvement in overall survival has been confirmed so far. Most patients tolerate salvage RT, with all patients experiencing some acute side effects (fatigue, bladder and bowel irritation). These symptoms, however, usually resolve within 3 months in most patients. Van Cangh et al. analyzed the potential influence of RT on urinary continence following RP.70 Forty-eight patients received 60 Gy of RT 3 to 4 months after RP and 52 did not. All patients had pathologically confirmed advanced disease following RP. With a mean follow-up of 24 months, 77% of the irradiated group were continent compared to 83% of the nonradiated group. The investigators concluded that RT to a dose of 60 Gy administered 3 and 4 months after radical prostatectomy had no adverse effect on urinary continence. In a series by Vander Kooy et al., 43% of patients experienced one or more late RT-induced complication.62 The most frequently experienced complication was related to the intestine/rectum (26%); hematuria was noted in 9% of patients; 3% developed a urethral stricture; and 3% had lower extremity edema. Chronic complications resolved in all but 17% of the patients.

Management of Prostate-Specific Antigen Failure after Definitive Therapy for Clinically Localized Prostate Cancer / 361 TABLE 40–4. Summary of Clinical Information in Contemporary Series of Salvage Radiotherapy* % % % No. of Gastrointestinal Urinary % DFS§ Reference Patients Complications Incontinence Impotence (Months)

Zeitman et al.55 Forman et al.56 Morris et al.57 Syndikus et al.58 Medini et al.60 Cadeddu et al.13 Schild et al.61 Vander Kooy et al.62 Lange et al.64 Kaplan and Bagshaw65 Hudson and Catalona66 Link et al.67 Wu et al.68

84† 14‡ 47†

Not stated Not stated 13

0 0 4

Not stated Not stated Not stated

60 (60) 35 (60) 64 (38)

48† 26‡

8 4

32 53

56 100

69 (31) 69¶ (60)

40†

Not stated

Not stated

Not stated

30 (60)

57† 25‡ 46 35†

Not stated Not stated 100 26

Not stated Not stated 100§ Not stated

Not stated Not stated Not stated Not stated

26 (24) 8 (24) 50 (60) 56 (60)

29† 39†

13.8 Not severe

Not stated Not severe

Not stated Not stated

43 (23) 44 (26)

21†

3.5

3.5

Not stated

29 (24)

25† 53†

12 15.2

8 8.5

Not stated 1.7

32 (24) 30 (15)

option.71–75 The questions regarding early versus delayed endocrine treatment or CAB versus monotherapy as they relate to prolonging survival remain unanswered. Concerning the timing of androgen blockade, most of the data indicating that early endocrine treatment leads to better overall survival are methodologically flawed.73,74 The European Study Group showed a significant survival advantage in patients treated with ADT at the time of diagnosis of metastatic disease compared to patients in whom therapy was delayed until clinical symptoms of metastatic disease developed.48 In patients who are found to have lymph node metastases, most of the reported series have shown that early endocrine treatment significantly delays progression.74–77 Regarding CAB versus monotherapy with an LHRH agonist for metastatic PCa, currently available data do not consistently demonstrate a survival advantage.72 In summary, cure of PCa by means of endocrine treatment is highly unlikely. Although there is controversy regarding survival benefit with early therapy following RP, most patients who are not candidates for local salvage RT insist on some sort of treatment when faced with rapidly rising PSA levels.

Salvage Surgery or Salvage Radiotherapy for Locally Recurrent Prostate Cancer ?

DFS = disease-free survival. *Following radical prostatectomy for prostate cancer. †Biochemical failure only. ‡Palpable local recurrence. §One patient received an artificial sphincter. ||Undetectable serum PSA levels. ¶Actuarial local control rate.

Androgen Deprivation Therapy following Radical Prostatectomy Failure For patients with lymph node involvement or biochemical disease recurrence less than 6 months following RP, hormonal therapy may be the most appropriate treatment

As patients are being treated for prostate cancer at a younger age, a significant number will ultimately fail primary therapy and become candidates for potentially curative salvage therapy. The current authors recently reviewed their clinical experience in order to evaluate the efficacy of salvage RT versus surgery for biochemically or clinically locally recurrent PCa following initial treatment.78 Only patients who had clinically localized disease and a serum PSA level < 20 ng per mL prior to initial therapy and who

TABLE 40–5. Summary of Clinical Information in Contemporary Series of Adjuvant Radiotherapy* % % % No. of Gastrointestinal Urinary % DFS† Reference Patients Complications Incontinence Impotence (Months)

Morris et al.57 Syndikus et al.58 Schild et al.59 Anscher et al.63 Freeman et al.69

40

10

35

62

88 (31)

89

10

44

89

93‡ (60)

60

5

7

Not stated

57 (32)

46

Not stated

Not stated

95

35

25

DFS = disease-free survival. *Following radical prostatectomy for prostate cancer. †Undetectable serum PSA levels. ‡Actuarial local control rate.

Not stated 62 (120) 96

64 (48)

FIGURE 40–1. Kaplan-Meier survival estimates for patients undergoing salvage procedures for locally recurrent prostate cancer. Disease-free survival was calculated from the time of initial treatment versus time (p = .20). With permission from Tefilli MV, Gheiler EL, Tiguert R, et al. Salvage surgery or salvage radiotherapy for locally recurrent prostate cancer. Urology 1998;52(2):224–9.


subsequently developed a biochemical recurrence were included in the study. Seventy (of 105) patients treated between December 1989 and March 1995 met the inclusion criteria. Initial treatment consisted of RP in 43 patients and RT in 27 patients. Salvage therapy consisted of surgery in patients treated with RT, and RT in patients treated by surgery. Although the mean PSA levels were similar before initial treatment, at the time of salvage treatment the mean PSA levels were 9.1 and 1.1 ng per mL for the salvage surgery and salvage RT groups, respectively (p = .0001). The total time between the initial and the salvage procedure was significantly higher in salvage surgery patients than in salvage RT patients (mean 39.5 versus 16.9 months, respectively p = .0001). Although there was no statistical difference in the DFS rate (Figure 40–1, p = .20), a trend to better biochemical disease control in the salvage RT group over the salvage surgery group was evident (74.4 versus 44.4%, respectively). In the authors’ analysis, patients who fail RT for PCa receive salvage therapy at a later time and have significantly higher serum PSA levels at the time of salvage treatment than do patients who develop recurrent disease following RP. The delay in diagnosing recurrent disease following RT might be due to the lack of a standard definition of biochemical treatment failure following RT. Lee et al. evaluated 364 men with clinically localized PCa treated with RT to determine whether the PSA nadir could predict biochemical DFS.21 Multivariate analysis demonstrated that patients with a PSA nadir < 0.9 ng per mL experienced improved biochemical disease-free survival independent of clinical stage, Gleason score, and pretreatment PSA. In the authors’ analysis, patients in the salvage RP group had a higher presalvage serum PSA level than did the salvage RT patients. This almost certainly means that these patients had higher disease volumes at the time of the salvage surgery. This is clinically important because the authors have also previously shown that patients who fail RP and receive salvage RT do significantly better if irradiated when the serum PSA level is < 2 ng per mL, probably because of smaller tumor volume.56 Because patients undergoing salvage surgery had higher preoperative serum PSA levels and bulkier disease than patients treated with salvage RT, substantial differences will probably be seen in the outcomes of therapy. Early identification of disease recurrence might improve outcome following salvage therapy. Salvage Surgery versus Salvage Radiotherapy: Quality-of-Life Issues The authors evaluated QOL in patients undergoing salvage procedures for locally recurrent PCa. Only those patients with clinically localized disease prior to initial therapy and who subsequently developed biochemical disease recurrence without evidence of clinical recurrence were included in the study. Data were collected by mailing subjects a selfadministered questionnaire (General Functional Assess-

ment of Cancer Therapy [FACT-G] and a Prostate Cancer Treatment Outcome Questionnaire [FACT-P]). The salvage surgery patients fared significantly worse in areas of physical well-being and urinary continence rates (FAIT-U and TOI-U).79 The authors believe that salvage surgery should be performed earlier in patients who failed initial RT to possibly improve outcomes. More stringent criteria for biochemically detected disease recurrence following RT are required. It is possible that patients with clinically localized PCa who are at high risk for local disease recurrence may have an equal or superior biochemical and clinical DFS and better QOL if the primary treatment is RP rather than RT.

Conclusion The goal in treating clinically localized prostate cancer is to eliminate all malignant tissue in the gland and surrounding tissues, thereby achieving long-term biochemical control and potential cure of the disease. Widespread use of PSA to follow up patients undergoing definitive therapy has shown that permanent eradication of PCa is not achieved as frequently as previously believed. However, it has also made for earlier detection of recurrent disease. Better selection criteria for salvage therapy, based on biochemical rather than clinical criteria, can produce higher rates of disease control. Further investigation is necessary to determine whether improving long-term local control with more aggressive treatment translates into improved survival rates.

References 1. Parker SL, Tong T, Bolden S, Wingo PA. Cancer statistics. CA Cancer J Clin 1997;47:5–27. 2. Bonin SR, Hanbon AL, Lee WR, et al. Evidence of increased failure in the treatment of prostate carcinoma in patients who have perineural invasion treated with three-dimensional conformal radiation therapy. Cancer 1997;79:75–80. 3. Partin AW, Yoo J, Carter HB, et al. The use of prostatespecific antigen, clinical stage, and Gleason score to predict pathologic stage in men with clinically localized prostate cancer. J Urol 1993;151:110–4. 4. Vicini FA, Horwitz EM, Gonzalez J, Martinez AA. Treatment options for localized prostate cancer based on pretreatment serum prostate-specific antigen levels. J Urol 1997;158:319–25. 5. Zeitman AL, Coen JJ, Shipley WU, et al. Radical radiation therapy in the management of prostatic adenocarcinoma: the initial prostate-specific antigen value as predictor of treatment outcome. J Urol 1994;151:640–5. 6. Lee WR, Hanks GE, Schultheiss TE, et al. Localized prostate cancer treated by external beam radiotherapy alone: serum PSA-driven outcome analysis. J Clin Oncol 1995;13:464–9. 7. Horwitz EM, Vicini FA, Ziaja EL, et al. Assessing the variability of outcome for patients treated with localized prostate irradiation using different definitions of biochemical control. Int J Radiat Oncol Biol Phys 1996;36: 749–51.

Management of Prostate-Specific Antigen Failure after Definitive Therapy for Clinically Localized Prostate Cancer / 363 8. Sandler HM, McLaughlin PW, Kish KE, Lichter AS. Results of 3D conformal radiotherapy in the treatment of 707 patients with localized prostate cancer. Int J Radiat Oncol Biol Phys 1995;32:141–4. 9. Blasko JC, Wallner K, Grimm PD, Ragde H. Prostatespecific antigen-based disease control following ultrasound guided 125Iodine implantation for stage T1/T2 prostatic carcinoma. J Urol 1995;154:1096–9. 10. Partin AW, Pound CR, Clemens JQ, et al. Serum PSA after anatomic radical prostatectomy. The Johns Hopkins experience after 10 years. Urol Clin North Am 1993;20: 713–25. 11. Grampsas SA, Miller GJ, Crawford ED. Salvage radical prostatectomy after failure transperineal cryotherapy: histologic findings from prostate whole-mount specimens correlated with intraoperative transrectal ultrasound images. Urology 1995;45:936–41. 12. Lerner SE, Blute ML, Zinke H. Critical evaluation of salvage surgery for radiorecurrent/resistant prostate cancer. J Urol 1995;154:1103–9. 13. Cadeddu JA, Partin AW, DeWeese TL, Walsh P. Long-term results of radiation therapy for prostate cancer recurrence following radical prostatectomy. J Urol 1998;159:173–8. 14. Sokoll LJ, Chan DW. Prostate-specific antigen. Urol Clin North Am 1997;24:253–9. 15. Armbruster DA. Prostate-specific antigen: biochemistry, analytical methods, and clinical application. Clin Chem 1993;39:181–5. 16. Graves HCB. Nonprostatic sources of prostate-specific antigen: a steroid hormone-dependent phenomenon? Clin Chem 1995;41:7–9. 17. Lange PH, Ercole CJ, Lightner DJ, et al. The value of serum prostate-specific antigen determination before and after radical prostatectomy. J Urol 1989;141:873–9. 18. Prestigiacomo AF, Stamey TA. A comparison of four ultrasensitive prostate-specific antigen assays for early detection of residual cancer after radical prostatectomy. J Urol 1994;152:1515–9. 19. Partin AW, Pearson JD, Landis PK, Walsh PC. Evaluation of serum prostate-specific velocity after radical prostatectomy to distinguish local recurrence from distant metastases. Urology 1994;43:649–59. 20. Lange PH, Lightner DJ, Medini E, et al. The effect of radiation therapy after radical prostatectomy in patients with elevated prostate-specific antigen levels. J Urol 1990;144:927–32. 21. Lee WR, Hanbon AL, Hanks GE. Prostate-specific antigen nadir following external beam radiation therapy for clinically localized prostate cancer: the relationship between nadir level and disease-free survival. J Urol 1996;156:450–3. 22. Leibel SA, Zelefsky MJ, Kutcher GJ, et al. Three-dimensional conformal radiation therapy in localized carcinoma of the prostate: interim report of a phase 1 dose-escalation study. J Urol 1994;152(Pt 2):1792. 23. Pisansky TM, Cha SS, Earle JD, et al. Prostate-specific antigen as a pretherapy prognostic factor in patients treated with radiation therapy for clinically localized prostate cancer. J Clin Oncol 1993;11:2158–66. 24. Zagars GK, Pollack A. Radiation therapy for T1 and T2 prostate cancer: prostate-specific antigen and disease outcome. Urology 1995;45:476–83. 25. Grob BM, Schellhammer PF, Brassil D, Wright GL Jr. Changes in immunohistochemical staining of PSA, PAP, and TURP-27 following irradiation therapy for clinically localized prostate cancer. Urology 1994;44:525–9.

26. Willet CG, Zietman AL, Shipley WU. The effect of pelvic radiation therapy on serum levels of prostate-specific antigen. J Urol 1994;151:1579–81. 27. Schellhammer PF, El-Mahdi M, Kuban DA, Wright GL. Prostate-specific antigen after radiation therapy. Urol Clin North Am 1997;24:407–14. 28. Hanno P, Brandes S, Stern S, Seidom EJ. Persistence of histologically viable appearing prostate tissue after cryosurgery [abstract 1099]. J Urol 1995;153 Suppl: 503A. 29. Scardino PT, Frankel JEF, Wheeler TM. The prognostic significance of postirradiation biopsy results in patients with prostatic cancer. J Urol 1986;135:510–6. 30. Bianco FJ, Lam JS, Davis LP, et al. Limited role of radionuclide bone scan in patients with prostate cancer recurrence after radical prostatectomy [abstract 111]. J Urol 1998;159(5):288. 31. Seltzer M, Naitoh J, Cangiano T, et al. Comparison of computed tomography (CT), positron emission tomograph (PET), and monoclonal antibody scan (MAB) for evaluation of lymph node (LN) metastases in patients with PSA relapse after treatment for localized prostate cancer (CaP) [abstract 1109]. J Urol 1998;159(5):288. 32. 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;16:284–9. 33. Gheiler EL, Tefilli MV, Tiguert R, et al. Predictors for maximal outcome in patients undergoing salvage surgery for radiorecurrent prostate cancer. Urology 1998;51:789–95. 34. Rogers E, Ohori M, Kassabian VS, et al. Salvage radical prostatectomy: outcome measured by serum specific antigen levels. J Urol 1995;153:104–10. 35. Pontes JE, Montie JE. Surgical techniques for salvage prostatectomy. Urol Clin North Am 1994;2:107–11. 36. Gheiler EL, Wood DP Jr, Montie JE, Pontes JE. Orthotopic urinary diversion is a viable option in patients undergoing salvage cystoprostatectomy for recurrent prostate cancer after definitive radiation therapy. Urology 1997;50:580–4. 37. Thompson IM, Rounder JB, Spence CR, Rodrigues FR. Salvage radical prostatectomy for adenocarcinoma of the prostate. Cancer 1988;61:1464–6. 38. Neehut GJ, Wheeler T, Cantini M, Scardino PT. Salvage radical prostatectomy for radiorecurrent adenocarcinoma of the prostate. J Urol 1988;140:544–9. 39. Moul JW, Paulson DF. The role of radical surgery in the management of radiation recurrent and large volume prostate cancer. Cancer 1991;68:1265–71. 40. Link P, Freiha FS. Radical prostatectomy after definitive radiation therapy for prostate cancer. Urology 1991;37: 189–92. 41. Ahlering TE, Lieskovsky G, Skinner DG. Salvage surgery plus androgen deprivation for radioresistant prostatic adenocarcinoma. J Urol 1992;147:900–2. 42. Stein A, Smith RB, de Kernion JB. Salvage radical prostatectomy after failure of curative radiotherapy for adenocarcinoma of the prostate. Urology 1992;40:197–200. 43. Pontes JE, Montie J, Klein E, Huban R. Salvage surgery for radiation failure in prostate cancer. Cancer 1993;71: 976–80. 44. Garzotto M, Wajsman Z. Androgen deprivation with salvage surgery for radiorecurrent prostate cancer: results at 5-year follow-up. J Urol 1998;159:950–5.

364 / Advanced Therapy of Prostate Disease 45. Miller RJ, Cohen JK, Shuman B. Percutaneous, transperineal cryosurgery of the prostate as salvage therapy for postradiation recurrence of adenocarcinoma. Cancer 1995;77:1510–4. 46. Bales GT, Williams MJ, Sinner M. Short-term outcomes after cryosurgical ablation of the prostate in men with recurrent prostate carcinoma following radiation therapy. Urology 1995;46:676–80. 47. Pisters LL, von Eschenbach AC, Scott SM, et al. The efficacy and complications of salvage cryotherapy of the prostate. J Urol 1997;157:921–5. 48. The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. Br J Urol 1997; 79:235–46. 49. Schellhammer PF, Kuban DA, Eh-Mahdi AM. Treatment of clinical local failure after radiation therapy for prostate carcinoma. J Urol 1993;150:1851–5. 50. Weyrich TP, Kandzari SJ, Jain PR. 125Iodine seeds implants for prostatic carcinoma. Urology 1993;41:122–6. 51. Ritter MA, Messing EM, Shanahan TG, et al. Prostatespecific antigen as a predictor of radiotherapy response and patterns of failure in localized prostate cancer. J Clin Oncol 1992;10:1208–17. 52. Brenner PC, Russo P, Wood DP, et al. Salvage radical prostatectomy in the mangement of locally recurrent prostate cancer after 125 I implantation. Br J Urol 1994;74:44–7. 53. Kupelian PA, Katcher J, Levin HS, Klein EA. Stage T1-2 prostate cancer: a multivariate analysis of factors affecting biochemical and clinical failures after radical prostatectomy. Int J Radiat Oncol Biol Phys 1997;37: 1043–52. 54. Epstein JI. Surgical margins in patients with carcinoma of the prostate. Am Urol Assoc Update Series 1994;8 (Lesson 7):53. 55. Zeitman AL, Coen JJ, Shipley WU, Althausen AF. Adjuvant irradiation after radical prostatectomy for adenocarcinoma of the prostate: analysis of freedom of PSA failure. Urology 1993;42:292–8. 56. Forman JD, Meetze K, Pontes JE, et al. Therapeutic irradiation for patients with an elevated postprostatectomy specific antigen level. J Urol 1997;158:1436–40. 57. Morris MM, Dallow KC, Zietman AL, et al. Adjuvant and salvage irradiation following radical prostatectomy for prostate cancer. Int J Radiat Oncol Biol Phys 1997;38: 731–6. 58. Syndikus I, Pickles T, Kostashuk E, Sullivan LD. Postoperative radiotherapy for stage T3 carcinoma of the prostate: improved local control. J Urol 1996;155:1983–6. 59. Schild SE, Wong WW, Grado GL, et al. The results of radical retropubic prostatectomy and adjuvant therapy for pathologic stage C prostate cancer. Int J Radiat Oncol Biol Phys 1996;34:535–41. 60. Medini E, Medini I, Reddy PK, Levitt SH. Delayed/salvage radiation therapy in patients with elevated prostate specific antigen levels after radical prostatectomy. A long-term follow-up. Cancer 1996;78:1254–9. 61. Schild SE, Buskirk SJ, Wong WW, et al. The use of radiotherapy for patients with isolated elevation of serum prostate-specific antigen following radical prostatectomy. J Urol 1996;156:1725–9. 62. Vander Kooy MJ, Pisansky TM, Cha SS, Blute ML.

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Irradiation for locally recurrent carcinoma of the prostate following radical prostatectomy. Urology 1997;49:65–9. Anscher MS, Robertson CN, Prosnitz R. Adjuvant radiotherapy for pathologic stage T3/4 adenocarcinoma of the prostate: ten-year update. Int J Radiat Oncol Biol Phys 1995;33:37–43. Lange PH, Lightner DJ, Medini E, et al. The effect of radiation therapy after radical prostatectomy in patients with elevated prostate-specific antigen levels. J Urol 1990;144:927–33. Kaplan ID, Bagshaw MA. Serum prostate-specific antigen after postprostatectomy radiotherapy. Urology 1992;39:401–6. Hudson MA, Catalona WJ. Effect of adjuvant radiation therapy on prostate-specific antigen following radical prostatectomy. J Urol 1990;143:1174–6. Link P, Freiha FS, Stamey TA. Adjuvant radiation therapy in patients with detectable prostate-specific antigen following radical prostatectomy. J Urol 1991;145:532–6. Wu JJ, King SC, Montana GS, et al. The efficacy of postprostatectomy radiotherapy in patients with an isolated elevation of serum prostate-specific antigen. Int J Radiat Oncol Biol Phys 1995;32:317–23. Freeman JA, Lieskovsky G, Cook DW, et al. Radical prostatectomy and postoperative adjuvant radiation for pathologic stage C (PCN0) prostate cancer from 1976 to 1989: intermediate findings. J Urol 1993;149:1029–34. Van Cangh PJ, Richard F, Lorge F, et al. Adjuvant radiation therapy does not cause urinary incontinence after radical prostatectomy: results of a prospective randomized study. J Urol 1998;159:164–6. Reiner WG, Scott WW, Eggleston JC, Walsh PC. Longterm survival after hormonal therapy for stage D prostatic cancer. J Urol 1979;122:183–4. Dalesio O, Schröder FH, Peto R, and the Prostate Cancer Trialists’ Collaborative Group. Maximal androgen blockade in advanced prostate cancer: an overview of 22 randomized trials with 3289 deaths in 5710 patients. Lancet 1995;346:265–9. Kozlowski JM, Ellis WJ, Grayhack JT. Advanced prostatic carcinoma: early versus late endocrine therapy. Urol Clin North Am 1991;18:15–24. Walsh PC. Benign and malignant neoplasms of the prostate. J Urol 1989;142:1032–3. Zagars GK, Sands ME, Pollack A, von Eschenbach AC. Early androgen ablation for stage D1 (N1 to N3, M0) prostate cancer: prognostic variables and outcome. J Urol 1994;151:1330–3. Seay TM, Blute ML, Zincke H. Long-term outcome in patients with pTx N+ adenocarcinoma of prostate treated with radical prostatectomy and early androgen ablation. J Urol 1998;159:357–64. Smith TA Jr, Lange PH, Yanknegt RA, et al. Serum markers as a predictor of response duration and patient survival after hormonal therapy for metastatic carcinoma of the prostate. J Urol 1997;1329–34. Tefilli MV, Gheiler EL, Tiguert R, et al. Salvage surgery or salvage radiotherapy for locally recurrent prostate cancer. Urology 1998;52(2):224–9. Tefilli MV, Gheiler EL, Tiguert R, et al. Quality of life in patients undergoing salvage procedures for locally recurrent prostate cancer. J Surg Oncol 1998;69:156– 61.

CHAPTER 41

MANAGEMENT OF LOCAL FAILURE FOLLOWING TREATMENT OF LOCALIZED PROSTATE CANCER GRAEME S. STEELE, MBBCH, FCS; JEROME P. RICHIE, MD, FACS and ADT following local definitive treatment failure for prostate cancer, have generally proved to be disappointing with respect to increasing overall cure rates.5 In view of the high incidence of patients diagnosed with clinically localized prostate cancer, physicians will be confronted with increasing numbers of patients with disease progression who are perplexed by outcomes of adjuvant and second therapies that may not only add to existing morbidity but contribute little to overall survival. The optimal strategy for evaluation and treatment of patients with biochemical failure is unclear. In the United States, it has been estimated that approximately one in three to one in five patients undergo additional cancer therapy following RP (the incidence of second therapies is 34 and 88% higher following radiotherapy and cryotherapy, respectively ).6,7 Prospective randomized clinical trials to evaluate the efficacy of adjuvant and second therapies are required to improve patient selection, optimize survival, and minimize morbidity. Unfortunately, these clinical trials have not been carried out and consequently many patients are subjected to adjuvant and second therapies that have an unknown impact on the natural history of their disease. Within each group of patients who fail local therapy for prostate cancer, however, there does exist a subset of patients who may potentially benefit from adjuvant or second therapies. This chapter characterizes this subset of patients and makes recommendations for appropriate adjuvant and second therapies.

The increase in the number of patients diagnosed with prostate cancer from the late 1980s to the mid-1990s was larger than for any other solid malignancy. This increase is related to a variety of factors, including increased physician and patient awareness, development of the prostatespecific antigen (PSA) blood test, and the relative ease with which the prostate gland can be biopsied. The number of patients who underwent radical prostatectomy from 1982 to 1992 increased by 100%, while the number of patients presenting with advanced disease during this time period declined by 60%.1 The increase in the number of patients diagnosed with clinically localized disease has resulted in prostate cancer management assuming greater prominence among both physicians and the general public. Treatment options for patients with clinically localized prostate cancer, however, remain controversial. Radical prostatectomy (RP), radiotherapy in the form external beam radiotherapy or brachytherapy, androgen deprivation therapy (ADT), and watchful waiting are well-recognized and generally accepted forms of therapy. In addition, cryotherapy has been used to treat localized disease, albeit in a relatively small group of patients. Despite recent advances in surgical techniques as well as in radiotherapy and medical management for clinically localized prostate cancer, only a small decline in the disease-specific mortality rate has been reported.2 Moreover, both surgery and radiotherapy expose patients to a number of short- and long-term side effects. Not only can these side effects be difficult to treat, but local therapy for prostate cancer can be associated with significant failure rates, especially in those patients with poorly differentiated disease, high pretreatment PSA values, and clinically nonlocalized tumors.3,4 Further, persistence of prostate carcinoma cells following primary treatment in the pelvis may ultimately lead to both biochemical and subsequent clinical progression, despite all attempts at adjuvant therapy and second therapies. To date, both adjuvant (within 3 months) and second therapies (after 3 months), that is, salvage external beam radiotherapy, salvage brachytherapy, salvage prostatectomy, salvage cystoprostatectomy, salvage cryotherapy,

Defining Disease Recurrence Using Serum Prostate-Specific Antigen The biologic detection limit (BDL) for PSA is the lowest level of PSA measurable in the serum for which there is a high degree of confidence that PSA actually exists in the serum.8 Using the Tandem-R PSA assay (Hybritech, SanDiego, California), BDLs of < 0.1 to 0.4 ng per mL have been reported.9–11 Among men whose serum PSA values were < 0.4 ng per mL 3 to 6 months following RP, only 9% demonstrated recurrence within 6 to 50 months. 365


However, 100% of men with post-RP serum PSA levels > 0.4 ng per mL had evidence of recurrence within 6 to 49 months.10–12 Second- and third-generation serum PSA assays have detection thresholds ranging from 0.01 to 0.14 ng per mL and can detect disease recurrence 16 to 18 months earlier than conventional PSA assays.13–17 Other investigational assays may detect recurrence 2.5 to 12.7 months before conventional assays.14,18 However, not all men with serum PSA levels detectable by ultrasensitive assay develop clinical progression of disease, and for this reason the clinical relevance of these assays has yet to be determined. Further, very small amounts of serum PSA may be produced by periurethral glands, leading to false-positive ultrasensitive assay readings.17 There is no proof that very early adjuvant therapy offers superior results to adjuvant therapy in relation to serum PSA detected by conventional assays. It is also important to remember that nearly 40% of patients who eventually display progression have an initially undetectable serum PSA, underscoring the need for serial measurement over time.19 In certain instances, it may be appropriate to recheck an isolated serum PSA elevation since laboratory error may give rise to false-positive values.

Serum Prostate-Specific Antigen Failure following Radical Prostatectomy While serum PSA lacks the sensitivity and specificity to be used alone as a screening tool for prostate cancer, it is a remarkably good surveillance tool for patients who have undergone definitive management for prostate cancer. Success or failure of local therapy is determined by a simple blood test at periodic intervals. With the exception of several anecdotal reports of local recurrence following RP with undetectable levels of PSA, most men who recur following surgery, either locally or with distant metastases, show a detectable serum PSA.20 In general, serum PSA failure rates range from 5 to 40% and depend on length of follow-up, clinical (TNM) stage, preoperative PSA value, Gleason score, and pathologic stage (capsular involvement, specimen confinement, seminal vesicle, and lymph node involvement).21 In a significant percentage of cases, patients will eventually develop metastatic prostate cancer (Figures 41–1A to 41–1D).22 For this reason, it is important to first determine those patients with recurrent or persistent local disease versus metastatic prostate cancer and then, of those patients with local disease, which group will most likely benefit from adjuvant or second therapies.

Serum Prostate-Specific Antigen Failure following Radiotherapy The prostate gland remains in situ following radiotherapy, allowing researchers to investigate levels of serum PSA that

might be expected to be produced by benign prostatic glands. Immune peroxidase histochemistry for expression of PSA on biopsy specimens obtained 1 year after radiation therapy, however, revealed that the benign glands did not stain for PSA. These findings support the view that serum PSA levels following radiotherapy are more likely due to persistent cancer than to benign prostatic tissue.23,24 The definition of treatment failure following radiotherapy has only recently been clarified as three consecutive increases in serum PSA independent of the nadir value.25 Following radiotherapy, serum PSA levels decline with an average half-life of 1.9 months (range 0.5 to 9.2 months), with some patients not achieving nadir levels for up to 18 months.26–28 The serum PSA level necessary to confirm disease-free status following radiotherapy, however, remains controversial; reported serum PSA nadirs range from 0.5 to 4 ng per mL.24 One study reported that all patients whose serum PSA values did not fall below 4 ng per mL developed disease progression and 14% who did achieve an undetectable serum PSA, following radiotherapy progressed.29 On the other hand, a more recent report indicated that patients who achieve a serum PSA nadir of ≤ 0.5 ng per mL had a 5-year disease-free rate of 93%, while those patients with a PSA nadir of 0.6 to 1.0 ng per mL only achieved a 5-year disease-free rate of 26%.30–33 It is generally agreed, therefore, that following radiotherapy an optimal serum PSA nadir is ≤ 0.5 ng per mL.34

Serum Prostate-Specific Antigen Failure following Cryotherapy Following cryotherapy, a serum PSA nadir of ≤ 0.4 ng per mL should be achieved. Higher values are associated with a significant risk of continued PSA elevation and a high likelihood of residual disease detected on prostatic biopsy.35

Disease Progression: Defining Local Recurrence versus Distant Disease Approximately 30% of men with detectable serum PSA levels following RP have local recurences, while 70% are thought to have distant disease alone or in combination with local disease.11 The importance of localizing the site of disease recurrence is clearly fundamental to the decision-making process with respect to adjuvant and second therapies. In a recent international study, investigative modalities selected by physicians to evaluate serum PSA failure following RP were reported. Ninety-eight percent of respondents used digital rectal examination (DRE), 68% used bone scan, 54% used transrectal ultrasonography (TRUS) and biopsy, 36% used abdominal and pelvic computed tomography (CT) scan, 31% used TRUS without biopsy, 25% used prostatic acid phosphatase, 11% used monoclonal antibody scan, and 5% used abdominal or pelvic magnetic resonance

Management of Local Failure Following Treatment of Localized Prostate Cancer / 367

imaging (MRI).36 All of these modalities, however, have been shown to be unreliable in accurately determining disease location.37

a hard and irregular fibrotic prostate gland resulting from radiotherapy. Several studies have confirmed that DRE has a low positive predictive value following radiotherapy.41,42

The Role of Digital Rectal Examination Digital rectal examination is an important part of postRP follow-up because disease recurrence has been documented in the absence of a detectable serum PSA level.20 However, DRE findings may be normal in the presence of biopsy-proven local recurrence in 50% of patients; on the other hand, DRE may reveal induration due to scar tissue rather than to local disease progression.38,39 Digital rectal examination findings at a single examination are therefore insufficiently sensitive or specific to detect local recurrence. Serial examinations may, however, provide useful information in this regard.40 Evaluation of the irradiated prostate by DRE can be unreliable. Residual tumor can be indistinguishable from

The Role of Imaging Techniques Ultrasound Transrectal ultrasonography of the prostate is not generally helpful in determining local recurrence. Color Doppler imaging during TRUS, however, has been shown to improve the detection of early recurrent or residual prostate cancer compared to TRUS alone.43 Some studies have suggested that TRUS of the prostate is of value in patients who have undergone radiotherapy as radiation does not change the ultrasonographic pattern of the prostate. Other studies, however, have shown that TRUS is no better than DRE or PSA in predicting which patients are likely to have a positive biopsy after radiotherapy for localized prostate cancer.8

A

B

C

D

FIGURE 41–1. Seven-year probability of nonprogression following radical prostatectomy stratified by: (A) preoperative serum PSA, (B) clinical stage, (C) tumor grade, and (D) pathologic tumor stage. (Number of patients available for follow-up is shown above horizontal axis.) Reprinted with permission from Partin AW, Pound CR, Clemens JQ, et al. Serum PSA after anatomic radical prostectomy. Urol Clin North Am 1993;20:713–25.


Transrectal ultrasonography therefore seems to have limited value as a screening tool for early recurrence following RP and for persistent disease following radiotherapy. In a patient in whom recurrence is suspected, however, TRUS is useful for directing anastomotic or prostatic biopsy.43 Computed Tomography Scan In a recent study to evaluate the sensitivity of CT scan in detecting local recurrence of prostatic carcinoma following RP, the procedure was found to yield positive results in only 36% of cases; 41% of cases were understaged. Based on these results, there seems to be no reason to include pelvic CT scanning in the workup of an elevated serum PSA following RP.44 Nevertheless, CT scan is now the most widely used test to evaluate pelvic lymph nodes. Unfortunately, even with improved imaging techniques, CT scanning has a sensitivity of only 30 to 80%.45 Magnetic Resonance Imaging Endorectal imaging has been used to predict local recurrence after cryosurgery; a recent study indicated that MRI fared poorly in differentiating between viable and necrotic prostatic tissue.46 Magnetic resonance imaging with a transrectal coil was recently found to have a high sensitivity in detecting local recurrence. In this series, however, 22 of 31 men studied had a palpable abnormality at DRE, indicating a select group of patients.47 The accuracy of MRI for staging pelvic lymph nodes is no better than that of CT scan.45 Bone Scintigraphy Bone scans are the most reliable way of establishing the presence of skeletal matastases but are rarely positive until serum PSA exceeds 8 ng per mL.48 Often, a rising serum PSA leads to the performance of a bone scan, even though these scans are rarely positive. In a recent study, the probability of a positive scan was < 5% until serum PSA had increased to 40 to 45 ng per mL.49 For this reason, bone scintigraphy plays little role in determining disease location at the time of serum PSA failure. In addition, negative bone scans do not necessarily rule out skeletal metastases. However, a baseline scan at the time of PSA elevation may be useful for comparison with scans conducted later during disease progression.37 Immunoscintigraphy: ProstaScint™ 111-Indium-capromab pendetide is a conjugate of a monoclonal antibody, a linking chelator, and a gamma-emitting radioisotope. The antibody is directed toward a membraneassociated antigen (prostate-specific associated antigen) of prostate cells that is more highly expressed in malignant than in normal cells. In two recent studies, immunoscintigraphy with 111-Indium-capromab pendetide was shown to be useful in detecting local recurrence in the prostatic fossa and in determining the extent of disease in patients with a

rising serum PSA following RP.50,51 One hundred and eighty-three patients with serum PSA progression following RP underwent immunoscintigraphy, which revealed disease in 108 of 181 patients (60%) with interpretable scans. The antibody was localized most frequently to the prostatic fossa (34% of cases), abdominal lymph nodes (23%), and pelvic nodes (22%). One-half of the positive localizations in the prostatic fossa were confirmed by biopsy.50 However, background tracer accumulation and signal-to-noise ratio limit the practical usefulness of this test. As a result, ProstaScint scans are not widely used. The Role of Serum Prostate-Specific Antigen Serum Prostate-Specific Antigen Failure following Radical Prostatectomy Serum PSA has been used both on its own and in combination with other parameters to predict the site of disease recurrence. Prostate-specific antigen doubling time following RP has been shown to be indicative of local recurrence when the doubling time is > 6 months, while metastatic disease is more common when the doubling time is < 6 months.52,53 A multivariate analysis using Gleason score, pathologic stage, and serum PSA velocity 1 year after RP has been shown to accurately distinguish local from distant disease.54 Using these variables, tables were constructed that predict the probability of local recurrence. For example, a patient with a Gleason score 5 tumor, a normal DRE, negative bone scan, and a PSA velocity 1 year after surgery of < 0.75 ng per mL per year has a > 90% chance of his tumor having recurred locally. On the other hand, a patient with positive seminal vesicles and a serum PSA velocity of > 0.75 ng per mL per year has a > 90% chance of having distant disease.54 Timing of serum PSA recurrence has also been shown to have predictive value with respect to establishing the site of recurrence. In this regard, a patient with a Gleason score ≥ 7 and a serum PSA recurrence < 2 years following surgery, or with positive seminal vesicles, lymph nodes, or both, were most likely to have distant metastases.21 Therefore, while the clinical significance of an isolated serum PSA value may be ambiguous with respect to location of disease, serum PSA can be used in combination with other parameters to accurately predict location of disease. Persistently Detectable Serum Prostate-Specific Antigen following Radical Prostatectomy The finding of a serum PSA that does not decline to undetectable levels following RP suggests that either a significant volume of disease has been left behind at the time of the RP or that the patient has metastatic disease. It is important to note, however, that a persistent PSA following RP (PSA never becomes undetectable) suggests the


presence of metastatic disease. These patients would not be expected to have a durable response to radiotherpay. This impression is borne out by two studies that reported a durable response in only 8 to 26% of patients who underwent external beam radiotherapy due to a persistently elevated serum PSA following RP.55,56 Serum Prostate-Specific Antigen Failure following Radiotherapy There are conflicting data regarding “normal” serum PSA nadir levels following radiation and regarding the definition of disease progression, the need for prostate biopsy, and the meaning of a positive biopsy. Nevertheless, serum PSA nadir levels appear to be the most important predictor of eventual clinical failure following radiation therapy.37 Currently, nadir levels > 0.5 ng per mL should be viewed as suspicious for recurrent or persistent disease.37 This value does not necessarily predict the location of residual/recurrent disease; for this reason, patients for whom salvage therapy is planned should undergo restaging studies. The Role of Anastomotic Site and Prostate Needle Biopsy Anastomotic Biopsy The role of TRUS-guided anastomotic biopsy is controversial. In patients with elevated serum PSA values and unremarkable DRE findings, TRUS-guided anastomotic biopsies are positive in only 50% of cases.10,56,57 Moreover, biopsies are positive in up to one-third of patients who subsequently undergo a second or third biospy.58,59 In addition, ultrasonographic descriptions of the vesicourethral anastomosis indicate that this area has a hypoechoic appearance and is therefore not helpful in detecting residual or recurrent cancer. Because of the risk of false-negative results, anastomotic biopsies are not widely practiced.41 Prostate Biopsy Following Radiotherapy The clinical relevance of prostate biopsy following radiotherapy is unclear. While biopsy results have been shown to correlate strongly with serum PSA, prostate needle biopsy is associated with a large sampling error.60 In addition, it has been reported that 21 of 31 men who had a positive biopsy at 12 months were found to have a negative biopsy at 16 to 29 months.41 For this reason, prostate needle biopsy is not generally performed in the setting of PSA failure following radiotherapy.

Local Treatment Options for Local Recurrence following Radical Prostatectomy The three main scenarios under which adjuvant or salvage therapy is contemplated following RP are failure of serum PSA to reach nadir levels, serum PSA failure at some time

during the follow-up period, and poor prognostic features (e.g., pathologic T3 disease) at the time of the RP. Available treatment options include watchful waiting, with institution of therapy at a later date, if at all (bearing in mind that biochemical failure may precede clinical progression by several years); ADT; salvage radiotherapy (following delayed rise in serum PSA), or adjuvant radiotherapy (in patients with persistently elevated serum PSA values or adverse pathologic features at the time of RP).

Adjuvant and Salvage Radiotherapy Several studies have shown that while adjuvant and salvage radiotherapy can lower serum PSA to undetectable levels, their overall success rate is generally disappointing, ranging from approximately 20 to 66% (Table 41–1).5,55,61–65 The success or failure of adjuvant and salvage external beam radiotherapy depends on a number of factors, including Gleason score, pathologic stage, preradiation serum PSA levels, and time to serum PSA failure. Preradiation serum PSA levels < 1 ng per mL were associated with much higher disease-free rates at 36 months compared to patients whose pretreatment serum PSA levels were > 1 to 2.5 ng per mL.66 In a recent study, 82 patients with either biochemical failure or documented local recurrence were analyzed.5 Patients with Gleason score 8 tumors, seminal vesicle invasion, or lymph node metastases did not achieve durable responses to radiotherapy, nor did patients whose serum PSA became detectable within the first postoperative year.5 Although adjuvant radiotherapy for patients with Gleason score ≥ 8 and positive seminal vesicles may improve local control of disease, there appears to be little impact on later development of metastatic disease.64,67 This unsatisfactory experience with adjuvant and salvage external beam radiotherapy to the prostatic bed following RP is due to a combination of factors, including poor patient selection. It is apparent that patients with highgrade disease, early PSA recurrence, and serum PSA values >1 ng per mL at the time of treatment are unlikely to exhibit a durable response to adjuvant or salvage external beam radiotherapy.65 Nevertheless, even when patients with poor prognostic factors such as early serum PSA recurrence (within 1 year), Gleason score > 7, seminal vesicle invasion, and lymph node metastasis are excluded, overall response to radiotherapy remains disappointing at only 25%.5 Not all radiotherapy failures are due to distant disease. Several recent series have alluded to the fact that many patients who fail salvage radiotherapy based on serum PSA detection do so with local disease. In other words, the radiation dose may be insufficient to sterilize local disease, indicating that a higher dose may be required.5,63,65 Those patients who never achieve an undetectable serum PSA following RP respond poorly to adjuvant radiotherapy, with the majority failing with metastatic disease.10,68,69 In a recent report, only one of nine patients

370 / Advanced Therapy of Prostate Disease TABLE 41–1. Detectable Serum Prostate-Specific Antigen Levels Immediately or some time after Radical Prostatectomy* Study Hudson et al.61 Lange et al.55 Wu et al.62 Cadeddu et al.5

Number of Patients

Percent Achieving Undetectable Serum PSA Level

21 19 21 82

40† 53‡ 30§ 21||

* Who achieve undetectable levels with external beam therapy.37 †< 0.6 ng/mL. ‡< 0.4 ng/mL. §< 0.1 ng/mL. ||< 0.2 ng/mL 2 years after salvage radiotherapy.

with persistently elevated post-RP serum PSA achieved undetectable serum PSA levels following adjuvant radiotherapy.65 However, even in this subset of patients, durable responses are seen in only 20 to 30% of cases.5,63–65 It is therefore possible that salvage radiotherapy is given too late, and that better response rates could possibly be achieved by subjecting high-risk patients with undetectable serum PSA values to adjuvant external beam radiotherapy. The problem with this approach is that there is no reliable way to define this subset of high-risk patients, especially since 30 to 50% of patients with positive surgical margins (T3a-T3b) are cured with surgery alone.10 The role of adjuvant radiotherapy in pathologic T3 disease has been extensively evaluated, mainly because this subset of patients is recognized to be at risk for eventual biochemical and clinical failure. In a recent report, 53 men who underwent RP and experienced subsequent seminal vesicle invasion were evaluated for progression following salvage and adjuvant radiotherapy.68 Only 38% of patients whose serum PSA never fell to undetectable levels were free of disease at 3 years. On the other hand, 86% of patients who underwent early adjuvant radiotherapy (prior to serum PSA progression) were disease free at 3 years, while only 48% of a cohort of patients followed expectantly were free of disease at 3 years.69 These findings were confirmed in a recent study involving 210 RP patients with stage pT3a-T3c disease. Adjuvant external beam radiotherapy (median dose 48 Gy), was given 42 to 90 days postoperatively. Follow-up ranged from 3 to 15 years, with a median of 5 years, and the influence of multiple variables such as age, Gleason score, serum PSA, and clinical and pathologic stage was evaluated. Fiveand 10-year disease-free survival rates were 67 and 57%, respectively. Seminal vesicle invasion and Gleason score ≥ 8 carried the worst prognosis, and this subset of patients was predicted to have 7.2 times the risk of recurrence compared to Gleason score ≤ 7 and T3a-T3b disease.68 An ideal candidate for radiotherapy after RP is therefore a patient with organ-confined disease (T1-T2), Gleason score ≤ 7, and a serum PSA that is undetectable for 1 to 2 years postoperatively, then slowly begins to rise. In

this group of patients, the outcome is optimal if those with a life expectancy of at least 10 years receive salvage radiotherapy while the serum PSA is < 1 ng per mL (see Figure 41–1D). Despite the potentially serious side effects of radiotherapy, several reports indicate that salvage and adjuvant external beam radiotherapy are well tolerated. For this reason, adjuvant therapy in high-risk patients has been advocated on the basis that it may be beneficial to some patients and is devoid of significant morbidity in the majority of patients. In general, 10 to 15% of patients experience short-term complications of increased bowel and bladder irritability, but very few long-term complications are reported.68–70 Prospective studies have found that salvage and adjuvant external beam radiotherapy do not significantly compromise urinary continence.71 Diabetes mellitus however, has been shown to be an independent predictor for late genitourinary and gastrointestinal complications following external beam radiotherapy. Given the high frequency of diabetes in the elderly prostate cancer population, physicians may consider treatment modifications for this group of patients.72

Local Treatment Options for Local Recurrence following Radiotherapy Radiation therapy in the form of brachytherapy is a popular option for treating clinically confined prostate cancer, while external beam radiotherapy is frequently used to treat both clinically localized and locally invasive disease. As with RP for clinically localized disease, a significant number of these patients will experience biochemical and clinical failure.34 It has been shown in a number of studies that complete eradication of localized prostate cancer following radiotherapy is achieved less often than originally thought.73,74 The advent of serum PSA testing has shown that biochemical failure will eventually occur in > 50% of patients.75 Therapeutic options available to the patient at the time of biochemical failure following radiotherapy include salvage surgery, salvage brachytherapy, and salvage cryotherapy. There are no long-term prospective randomized trials comparing these three modalities (Figure 41–2). Local recurrence of prostate cancer following radiotherapy is frequently associated with the development of metastatic disease and death.76–78 Earlier studies suggested that the median survival following progression was only 33 months.79 Detection of a rising PSA following radiotherapy signals the presence of either local recurrence, distant disease, or both and mandates restaging the patient if some form of salvage therapy is contemplated.78 Although limited therapeutic options exist for locally recurrent prostate cancer following radiotherapy, patients presenting with biochemical failure pose a therapeutic challenge for the physician, who must balance prospects for cure with the possibility of significant morbidity.


Radical prostatectomy for clinically localized prostate cancer

Biochemical failure following RP (recheck serum PSA value)

Poor prognostic features: pT3a-c, NO; Gleason score ≥ 8

Good prognostic feaures: pT1-pT2, NO; Gleason score ≤ 7; serum PSA failure >1 year; serum PSA ≤ 1 ng/mL

Consider adjuvant radiation therapy

Salvage external beam radiotherapy Adverse prognostic features: pT3c, NO (seminal vesicle invasion); Gleason score ≥ 8; serum PSA failure 10 ng per mL), and who have clinically localized disease and preoperative serum PSA values < 10 ng per mL (Figure 41–3). In addition, the patient must be willing to accept the significant complications associated with salvage surgery. In short, the complication rate is 10fold higher than that for patients who do not undergo radiotherapy, and the probability of cure without major complications is < 20% (Table 41–2).89 Salvage Brachytherapy The advent during the past decade of improved imaging technology, treatment planning, and imaging techniques has renewed interest in brachytherapy as a viable therapeutic option for treating clinically localized prostate cancer. While brachytherapy is well tolerated and associated with few major side effects, long-term survival rates of patients who undergo brachytherapy for localized prostate cancer appear to be worse than for patients who undergo RP.90 In addition, patients with adverse prognostic factors (stage T2b-T2c, serum PSA > 10 ng per mL, or Gleason score ≥ 7) were recently reported to have worse 5-year disease-free survival rates with brachytherapy than those patients who underwent external beam radiotherapy and RP.34 Salvage brachytherapy for patients who have failed external beam radiotherapy for localized prostate cancer has recently been reported.75 Actuarial biochemical disease-free survival at 3 and 5 years was 89 and 79%, respectively. Post-treatment serum PSA nadir was found to be a significant predictor of biochemical disease-free survival, but only half of the patients achieved a serum PSA nadir of < 0.5 ng per mL.75 The reported incidence of serious complications was lower than for other salvage therapies. In this series of 49 patients, only one clinical local failure was detected, giving a local control rate of 98%.75 Although this study promotes brachytherapy as an attractive option, further studies with long-term data are clearly needed to confirm the efficacy of this form of salvage therapy. Salvage Cryotherapy Much like brachytherapy, cryotherapy has recently undergone a renaissance as a therapeutic option for clinically localized prostate cancer. Improvements in both cryotherapy technology as well as high resolution TRUS of the prostate have combined to permit precise control of the extent of freezing and tissue destruction.91,92 While cryoablation is not a suitable option for locally extensive disease due to bladder base and ureteric involvement, it may be appropriate in patients with extracapsular

extension, especially those patients for whom salvage surgery would run the risk of a positive surgical margin.78,93 Although cryotherapy is appealing for those patients who are unsuitable for salvage surgery, there are no long-term prospective randomized trials supporting its use. In a recent study involving 146 patients followed for a median of 21 months (range 3 to 47 months) following cryotherapy, a serum PSA nadir of ≤ 0.5 ng per mL was achieved in 59 patients (40%). However, six of these patients were subsequently found to have prostate biopsies positive for cancer. Positive prostate biopsies were reported in 18 of 49 patients (37%) who did not achieve an undetectable serum PSA following salvage cryosurgery.78,94 In another salvage cryotherapy trial, prostate biopsies performed 3 months after cryotherapy were negative for prostate cancer in 88% of patients, but cancer was detected in one-third of patients who subsequently underwent transurethral resection of the prostate (TURP).95 Salvage cryotherapy has been reported to be associated with significant morbidity.93 Only 29% of patients who completed a urinary continence survey following salvage cryotherapy reported complete urinary control; 21% reported no control, and one patient developed a urethrorectal fistula that subsequently closed spontaneously.78 Based on these data, cryotherapy has some way to go before becoming a widely accepted form of salvage therapy.

Clinical Local Recurrence following Radiotherapy for Localized Prostate Cancer Lower Urinary Tract Symptoms It is generally believed that TURP following external beam radiotherapy for prostate cancer is associated with a high incidence of postoperative urinary incontinence. Although a recent study reported the risk of urinary incontinence to be negligible, there are nevertheless a number of caveats in the management of these patients.96 Since voiding symptoms correlate poorly with bladder outlet obstruction, careful objective evaluation of lower urinary tract symptoms (LUTS) in patients who have undergone radiotherapy should be undertaken whenever TURP is contemplated.97 In this regard, irritative voiding symptoms such as urgency, urgency incontinence, and frequency may be due to changes in bladder compliance, cystometric capacity, and detrusor instability (DI) rather than changes in outlet resistance. Transurethral resection of the prostate should be avoided in nonobstructed patients, especially those with DI, as their urinary symptoms may worsen as a result of reduction in outlet resistance. An appropriate course of action in such obstructed patients would be to consider ADT prior to surgery. In this way, outlet resistance may be reduced without

Watchful waiting for ADT Proceed with salvage cystoprostatectomy and adjuvant ADT

Watchful waiting or ADT

Fully inform patient of morbidity related to salvage surgery

FIGURE 41–3. Algorithm for serum PSA nadir > 0.5 ng per mL and local clinical recurrence following radiotherapy for localized prostate cancer.

Proceed with salvage prostatectomy and adjuvant ADT

Biopsy-proven bladder neck involvement, seminal vesicle invasion, reduced bladder compliance and/or cystometric capacity, manifestations of radiation cystitis


Evaluation for possible salvage surgery

Fully inform patient of morbidity related to salvage surgery

Tumor limited to prostate

Life expectancy < 10 years

Life expectancy > 10 years

Good prognostic features: negative metastatic workup Gleason score ≤ 7, serum PSA ≤ 10 ng/mL

ADT and ureteric stenting or percutaneous nephrostomy drainage

Urodynamic evaluation to define nature of lower urinary tract symptoms


Poor prognostic features: Gleason score >7, serum PSA > 10 ng/mL

Detrusor instability: treat symptomatically

Ureteric obstruction

Clinical local recurrence

Bladder outlet obstruction

Treat bladder outlet obstruction initially with ADT, TURP as a last resort

Serum PSA nadir >0.5 ng/mL

Observation and serial serum PSA measurement

Serum PSA nadir ≤ 0.5 ng/mL

Radiotherapy for localized prostate cancer


374 / Advanced Therapy of Prostate Disease TABLE 41–2. Results of Salvage Surgery following Radiotherapy for Clinically Localized Prostate Cancer Series Moul et al.88 Ahlering et al.85 Lerner et al.81 Rogers et al.80

No. of Patients

Days of Hospitalization

% Rectal Injury

% Bladder Neck Contracture

% Total Urinary Incontinence

% Estimated Disease-Free Survival at 5 and 10 Years

22 34 132 40

22 10 12 10

10 0 2 15

0 0 27 28

100 36 3 42

60/40 95/76 70/53 55/33

worsening of symptoms, especially urinary incontinence. The TURP procedure can then be reserved for patients who fail to respond to ADT. Permanent urinary incontinence is common in patients who undergo TURP following brachytherapy.98 For this reason, TURP should be avoided in brachytherapy patients if at all possible. Ureteral Obstruction Androgen deprivation therapy should be considered for the patient with ureteral obstruction and no significant metabolic derangements. In addition, dexamethasone has also been shown to be effective in relieving bilateral ureteric obstruction in the acute phase of renal failure secondary to locally advanced disease.99 However, in the patient with significant sequelae of ureteral obstruction (e.g., significant hyperkalemia, congestive heart failure, etc.), percutaneous nephrostomy or ureteral shunt placement should be considered. Finally, palliative ureteroneocystostomy may be an option in some patients who fail to respond to more conservative measures, especially if they have a reasonable life expectancy.

Androgen Deprivation Therapy in Patients Failing Definitive Local Therapy There are a number of controversial issues regarding the role of ADT in patients who fail definitive local treatment for prostate cancer. These issues pertain to the questions of early versus late ADT, and combined androgen deprivation therapy (CAD) versus monotherapy. There is no good evidence to support early ADT in patients who fail definitive local therapy because most studies have evaluated patients with clinically more advanced disease (positive pelvic lymph nodes or skeletal metastates).78 Nevertheless, the most common current approach is to satisfy the patient’s concerns by treating the serum PSA value rather than the patient and his disease. For this reason, ADT represents a huge financial burden on health care systems throughout the United States, despite the lack of scientific data justifying its use. Studies to provide answers to these questions are underway. There is also no evidence that patients who receive CAD have a survival advantage over patients treated with ADT by orchiectomy alone. In a recent report, 1387 patients with metastatic prostate cancer were randomized to treatment with bilateral orchiectomy and placebo or bilateral orchiectomy and flutamide.100 There was no sig-

nificant difference between the two groups in terms of overall survival. These patients, however, all had documented metastatic disease, therefore these data may not apply to patients with local failure following local definitive therapy. Although orchiectomy was used as the primary form of ADT, orchiectomy has been shown to be equivalent to luteinizing hormone–releasing hormone (LHRH) agonists. The logical conclusion is that the unnecessary additional expense associated with CAD should be avoided. If early ADT is contemplated in local failure following definitive therapy for prostate cancer, treatment should consist of either bilateral simple orchiectomy or LHRH agonist as monotherapy.

Summary The management of local failure following definitive treatment for prostate cancer is challenging. In view of the significant failure rates associated with both RP and radiotherapy as primary treatments for prostate cancer, the management of patients failing primary therapy has become an important issue. Serum PSA failure rates after adjuvant and salvage therapy are > 50%, even in well-selected patients. Physicians should therefore be mindful of quality-of-life issues before embarking upon salvage therapies. It is also important to bear in mind that biochemical failure may precede clinical failure by up to 5 years; despite serum PSA failure, many patients die with and not of their disease.101 This once again emphasizes the need for careful patient selection with regard to adjuvant and salvage therapy. Patient selection will not only maximize survival in an appropriate subset of patients but avoid unnecessary morbidity in patients unlikely to respond to therapy. The data clearly show that patients with adverse prognostic features such as high pretreatment serum PSA values, poorly differentiated disease, and early serum PSA recurrence do poorly irrespective of their chosen therapy. Those carefully selected patients who are candidates for adjuvant or salvage therapy should be fully informed of the odds of success in the long term and the high complication rates associated with these therapies. The role of ADT in patients with local failure is not well defined. If early therapy is contemplated, however, monotherapy with orchiectomy or an LHRH agonist is probably adequate. Only prospective randomized trials will provide the answers we need to better manage this important subset of patients.


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67.

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Management of Local Failure Following Treatment of Localized Prostate Cancer / 377 68. Lieskovsky PZ, Langholz B, Formenti S, et al. Radical prostatectomy and postoperative irradiation in patients with pathological stage C (T3) carcinoma of the prostate. Int J Radiat Oncol Biol Phys 1998;40(1):139–47. 69. Valicenti RK, Gomella LG, Ismail M, et al. Pathologic seminal vesicle invasion after radical prostatectomy for patients with prostatic carcinoma: effect of early adjuvant radiation therapy on biochemical control. Cancer 1998;2(10):1909–14. 70. Formenti SC, Lieskovsky G, Simoneau AR, et al. Impact of moderate dose of postoperative radiation on urinary incontinence and potency in patients with prostate cancer treated with nerve sparing prostatectomy. J Urol 1996;155:616–9. 71. Van Cangh PJ, Richard F, Lorge F, et al. Adjuvant radiation therapy does not cause urinary incontinence after radical prostatectomy: results of a prospective randomized study. J Urol 1998;159(1):164–6. 72. Herold DM, Hanlon AL, Hanks GE. Diabetes mellitus: a predictor for late radiation morbidity. Int J Radiat Oncol Biol Phys 1999;43(3):475–9. 73. Kaplan ID, Cox RS, Bagshaw MA. Prostate specific antigen after external beam radiotherapy for prostatic cancer: follow-up. J Urol 1993;149:519–22. 74. Holzman M, Carlton C, Scardino PT. The frequency and morbidity of local tumor recurrence after definitive radiotherapy for stage C prostate cancer. J Urol 1991; 146:1578–82. 75. Gordon LG, Collins JM, Kriegshauser JS, et al. Salvage brachytherapy for localized prostate cancer after radiotherapy failure. Urology 1999;53(1):1–10. 76. Scardino PT, Frankel JEF, Wheeler TM, et al. The prognostic significance of post-irradiation biopsy results in patients with prostate cancer. J Urol 1986;135:510–6. 77. Zagars GK, von Eschenbach AC, Ayala AG, et al. The influence of local control on metastatic dissemination of prostate cancer treated with external beam megavoltage radiation therapy. Cancer 1991;68:2370–7. 78. Corral DA, Pisters LL, von Eschenbach AC. Treatment options for localized recurrence of prostate cancer following radiation therapy. Urol Clin North Am 1996; 23(4):677–84. 79. Hanks GE, Martz KL, Krall JM, Diamond JJ. Analysis of independent variables affecting survival after recurrece of prostate cancer. Int J Radiat Oncol Biol Phys 1989; 16:1431–5. 80. Rogers E, Ohori M, Kassabian VS, et al. Salvage radical prostatectomy: outcome measured by serum prostate specific antigen levels. J Urol 1995;153:104–10. 81. Lerner SE, Blute ML, Zincke H. Critical evaluation of salvage surgery for radio-recurrent/resistant prostate cancer. J Urol 1995;154:1103–9. 82. Link P, Freiha FS. Radical prostatectomy after definitive radiation therapy for prostate cancer. Urology 1991;27: 289–92. 83. Pontes JE, Montie J, Klein E, Huben R. Salvage surgery for radiation failure in prostate cancer. Cancer 1993;71: 976–80. 84. Brenner PC, Russo P, Wood DP, et al. Salvage radical prostatectomy in the management of locally recurrent prostate cancer after 125-I implantation. Br J Urol 1994;75:44–7.

85. Ahlering TE, Lieskovsky G, Skinner DG. Salvage surgery plus androgen deprivation for radioresistant prostatic adenocarcinoma. J Urol 1992;147:900–2. 86. Zincke H. Radical prostatectomy and exenterative procedures for local failure after radiotherapy with curative intent. Comparisons of outcome. J Urol 1992;147:894–9. 87. Pisters LL, Wajsman Z. Salvage surgery following full-dose radiation therapy for prostate cancer. In: Bland KI, Karakousis CO, Copeland EM III, editors. Atlas of surgical oncology. Philadelphia: WB Saunders; 1995. p. 605. 88. Moul JW, Paulson DF. The role of radical surgery in the management of radiation recurrent and large volume prostate cancer. Cancer 1991;68:1265–71. 89. Catalona WJ. Management of cancer of the prostate. N Engl J Med 1994;331:996–1004. 90. Polascik TJ, Pound CR, De Weese TL, Walsh PC. Comparison of radical prostatectomy iodine 125 interstitial radiotherapy for the treatment of clinically localized prostate cancer: a 7-year biochemical (PSA) progression analysis. Urology 1998;51(6):884–9. 91. Onik GM, Porterfield B, Rubinsky B. Percutaneous transperineal prostate cryosurgery using transrectal ultrasound guidance: animal model. Urology 1991;37:277–81. 92. Onik GM, Cohen JK, Reyes GD, Rubinsky B, et al. Transrectal ultrasound-guided percutaneous radical cryosurgical ablation of the prostate. Cancer 1993;72: 1291–9. 93. Pisters LL, von Eschenbach AC, Scott SM, et al. The efficacy and complications of salvage cryotherapy of the prostate. J Urol 1997;157(3):921–5. 94. Greene GF, Pisters LL, Scott SM, Von Eschenbach AC. Predictive value of prostate specific antigen after salvage cryotherapy. J Urol 1998;160(1):86–90. 95. Bales GT, Williams MJ, Sinner M, et al. Short-term outcomes after cryosurgical ablation of the prostate in men with recurrent prostate carcinoma following radiation therapy. Urology 1995;46:676–80. 96. Patel HH, Peddada AV, Zimmern PE, et al. Risk of incontinence with transurethral resection of the prostate after radiation therapy for prostate cancer. J Surg Oncol 1997;64(2):127–9. 97. Yalla SV, Sullivan MP, Lecamwasam HS, et al. Correlation of American Urological Association Symptom Index with obstructive and nonobstructive prostatism. J Urol 1995;153:674–80. 98. 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):783–6. 99. Hamdy FC, Williams JL. Use of dexamethasone for ureteric obstruction in advanced prostate cancer: percutaneous nephrostomies can be avoided. Br J Urol 1995;75(6):782–5. 100. Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 1998;339: 1036–42. 101. Eastham JA, Kattan MW, Groshen S, et al. Fifteen-year survival and recurrences after radiotherapy for localized prostate cancer. J Clin Oncol 1997;15(10):3214–22.

CHAPTER 42

SECONDARY HORMONAL THERAPY NANCY A. DAWSON, MD; NICHOLAS J. VOGELZANG, MD ment, significant declines of prostate-specific antigen (PSA) levels, and tumor regression. This paradoxical response was first documented in response to flutamide withdrawal.10,11 It has subsequently been shown to occur with the two other nonsteroidal antiandrogens in current clinical use, bicalutamide12,13 and nilutamide.14,15 This phenomenon has also been documented following withdrawal of two steroidal antiandrogens, megestrol acetate16 and chlormadinone acetate,17 as well as with discontinuation of estrogen.18 The largest number of reported patients have had flutamide withdrawn. In an overview of this topic, Scher et al. documented PSA level declines in 47% (95% CI, 38 to 54%) and measurable disease response in 22% (95% CI, 9 to 42%) of patients.19 The median duration of response was 4 months. Response usually occurred 2 to 4 weeks after cessation of flutamide but occurred 6 to 12 weeks after withdrawal of bicalutamide and nilutamide, presumably due to their longer half-lives.20 Although antiandrogen withdrawal responses usually occur in the setting of disease progression while on CAD, responses have been documented in patients progressing after only 2 months of single antiandrogen therapy.21 Response has been associated with longer duration of prior antiandrogen exposure10,22 and higher baseline PSA values.22 Relatively lower levels of dehydroepiandrosterone (DHEA), the primary adrenal androgen, have also been correlated with response to antiandrogen withdrawal.23 The mechanism(s) responsible for antiandrogen and hormonal withdrawal responses is (are) unknown. One proposed explanation is an altered response due to a mutation of the androgen receptor (AR). In the LNCaP prostate cancer cell line, there is a mutation in the hormonebinding region of the receptor at codon 868 (a threonine to alanine substitution). In vitro, this mutant receptor is activated by estrogen, progesterone, flutamide, nilutamide, and cyproterone acetate.24–28 In contrast, the antiandrogen bicalutamide remains an antagonist for the mutant AR.24 Although similar mutations have been identified in primary tumors, they are more frequent in androgen-independent prostate cancers.29 Functional studies on two mutant androgen receptors identified in human tumor specimens demonstrated strong activation by estrogen and progesterone, with only weak stimulation of the wild-type androgen receptor. Current studies are

Metastatic prostate cancer that progresses after initial androgen deprivation is most commonly referred to as hormone-refractory prostate cancer or androgen-independent prostate cancer. Both these labels are misleading, as Fowler and Whitmore et al.1 and Manni et al.2 proved in their findings that the disease flares when exogenous testosterone is given. Likewise, it becomes quiescent again on discontinuation of the exogenous androgen. These clinical observations strongly suggest that the disease is not refractory to or independent of growth stimulation by exogenous testosterone. Thus, there is debate about the role of low levels of endogenous adrenal androgens and that of continued suppression of testicular androgen production by means of luteinizing hormone–releasing hormone (LHRH) agonists. In two retrospective analyses, the question was asked whether androgen deprivation should be continued or maintained when the “hormone-refractory” state was reached. The hormone-refractory state was defined clinically as the need for chemotherapy. In a 341 patient cohort studied by the Eastern Cooperative Oncology Group (ECOG), 287 men who continued androgen suppression had a superior survival (median 3 months longer) than the 54 men who ceased androgen suppression.3 In contrast, the Southwest Oncology Group (SWOG) did not find any difference in survival in 172 men who underwent orchiectomy compared to 84 men who ceased androgen suppression.4 The SWOG study notwithstanding, older studies have suggested a benefit of secondary orchiectomy.5,6 Although the percentage of patients benefitting is modest (12%), the responses can occasionally be long term. Whether further “removal” or “blocking” of adrenal androgens will cause further regression of the “androgen-independent” cancers is also debated. The current authors and others have previously reviewed the abundant clinical evidence that continued manipulation of the androgen milieu is clinically beneficial.7–9 In this chapter, evidence to support this position is updated.

Antiandrogen Withdrawal Syndrome In patients initially progressing on combined androgen deprivation (CAD), usually with either orchiectomy or an LHRH analogue plus an antiandrogen, discontinuation of the antiandrogen may result in symptomatic improve378

Secondary Hormonal Therapy / 379

ongoing within the Cancer and Leukemia Group B (CALGB) to determine the frequency of bone marrow involvement by metastatic prostate cancer, and to determine the frequency and nature of AR mutations in those marrows involved with metastatic disease. To date, over 100 marrows have been analyzed, with roughly 30% being positive (CALGB trial 9666). Several different types of AR mutations have been detected [M.E. Taplin personal communication, June 1998]. The CALGB will attempt to correlate the presence of a mutated androgen receptor and response by linking study 9666 to CALGB 9583. In the latter, 250 patients are being randomized to antiandrogen withdrawal alone or antiandrogen withdrawal plus ketoconazole and hydrocortisone. The endpoints will be response rate and duration of response. These will be correlated with adrenal androgen levels, which are measured as part of the protocol. Androgen-induced apoptosis is a second proposed mechanism for clinical benefit of antiandrogen withdrawal. When certain clones of prostate cancer cell lines are grown for prolonged periods of time in the absence of androgens, apoptosis will ensue if low levels of androgens are added to the culture. When these cell lines are used to form tumors in castrated nude mice which are then treated with androgens, an initial surge in PSA and other indices of prostate cell growth occurs, followed by dramatic tumor regression and cure.30 The mechanism responsible for this effect is obscure but may be similar to the clinically beneficial effect seen when estrogen is used to treat breast cancer that is rich in estrogen receptors.31 It can be hypothesized that withdrawal of the antiandrogen allows recovery of low levels of endogenous androgens. Such androgens bind to the prostate cancer cells that are overexpressing AR leading to growth stimulation followed by apoptosis. Overexpression of AR has been demonstrated in tumor samples from men with progressive metastatic disease.32

Second-Line Antiandrogens The addition of flutamide at the time of progressive metastatic disease is associated with an objective response in 15% and disease stabilization in 20% of patients (Table 42–1).33–37 Patients treated on the placebo arm of the National Cancer Institute’s Intergroup protocol 0036 comparing leuprolide and flutamide versus leuprolide and placebo, however, showed no survival benefit when flutamide was added at the time of disease progression.34

TABLE 42–1. Secondary Hormonal Manipulation: Addition of Flutamide Inhibits uptake and binding of androgen to the androgen receptor 230 patients, five trials: 15% objective response, 20% stable disease No obvious survival benefit in one phase III trial Toxicities: diarrhea, gynecomastia, abnormal liver function tests

Recently, Fowler et al. reported an 80% PSA response rate in the same population.36 The role of flutamide in men progressing after treatment with another antiandrogen or its withdrawal has not been studied but is expected by many authorities to have some benefit. Bicalutamide is a second-generation antiandrogen that differs from flutamide in that it has a longer half-life, allowing once-a-day dosing, a fourfold greater affinity for the androgen receptor,20 the ability to inhibit both mutant and wild-type androgen receptors,37 and less gastrointestinal toxicity. Scher et al., using a bicalutamide dose of 200 mg per day (the usual dose is 50 mg per day) reported that 12 of 39 patients (31%) relapsing after only one prior hormonal therapy demonstrated a > 50% decrease in PSA level (Table 42–2).38 None of 12 patients with two or more prior hormone therapies responded to high-dose bicalutamide. Of those in first relapse, 10 of 26 (38%) patients with prior flutamide exposure responded, compared to 2 of 13 (15%) without. Side effects of highdose bicalutamide included loss of libido, impotence, hot flashes, gynecomastia, and breast tenderness, none of which were dose limiting. Joyce et al., using a 150 mg per day dose of bicalutamide, reported a PSA response rate of 22.5% in 31 patients.39 Six of seven responders had been on prior long-term flutamide. Although responses were demonstrated in patients with or without prior response to flutamide withdrawal, they were most dramatic in two patients in the former category. Overall response duration was 4 months. The Southwest Oncology Group also studied bicalutamide at 150 mg per day and reported no objective responses in 52 patients although pain decreased significantly between pretreatment and the third month after treatment.40 The median survival was surprisingly long at 15 months. The current authors believe that these data support the hypothesis that highdose bicalutamide and flutamide are not completely crossresistant. Whether the standard dose of bicalutamide (50 mg per day) is crossresistant cannot be determined from the current data. Secondary responses to the alternate antiandrogen, nilutamide, also deserve further investigation. Clinical trials should prospectively examine the role of TABLE 42–2. Secondary Hormonal Manipulation: Addition of High-Dose Bicalutamide No. of Patients with > 50% PSA Level Decrease

Study Scher et al.38 Joyce et al.39 Kucuk et al.40

No. of Dosage Patients (mg q.d.) 39* 31 52

200 150 150

Prior Flutamide Yes No

Prior Flutamide Withdrawal Yes No

10/26 (38%) 2/13 (15%) 5/10 6/14 (43%) 1/17 (6%) 2/6 N/A N/A N/A

*1 prior hormonal Rx; 0/12 patients with ≥ 2 prior Rx responded.

5/10 4/6 N/A

380 / Advanced Therapy of Prostate Disease TABLE 42–3. Secondary Hormonal Manipulation: Addition of Ketoconazole No. of Study

Patients

Dawson et al.7

245/12 trials

Gerber and Chodak44 Small et al.45

9

Small et al.46

48 (after AAWD) 20 (with AAWD)

Duration Response 47% subjective 16% objective 36% stable disease 0% > 50% PSA level decrease 63% > 50% PSA level decrease 55% > 50% PSA level decrease

TABLE 42–4. Secondary Hormonal Manipulation: Addition of Aminoglutethimide plus Hydrocortisone (Months) NR

NR 3.5 (range: 2–12+) 8.5

AAWD = antiandrogen withdrawal; NR = not reported.

these agents as second- or third-line therapies for hormonerefractory prostate cancer.

Inhibitors of P-450-Dependent Enzymes Ketoconazole is an antifungal agent that inhibits both sterol membrane synthesis and the cytochrome P-450dependent enzyme 17,20-lyase (CYP34A).41 At high doses, it effectively blocks both testicular and adrenal androgenesis.42 This suppressive effect on testosterone was first investigated based on the development of unexpected gynecomastia in early clinical trials for dermatomycoses.43 Multiple studies of ketoconazole without glucocorticoids done in the pre-PSA era (N=15), reviewed by Dawson,7 demonstrated objective responses in approximately 16% of patients and stable disease in an additional 30% (Table 42–3).5 In the PSA-era, Gerber and Chodak, again using ketoconazole alone, reported zero of nine patients to have a > 50% decline in PSA level, although two of nine had excellent clinical responses.44 Ketoconazole combined with hydrocortisone in men progressing after antiandrogen withdrawal produced a > 50% decline in PSA in 30 (62.5%) of 48 evaluable patients for a median 3.5 months.45 Response was not influenced by prior response to antiandrogen withdrawal. Small et al., also reported a 55% response in 20 patients when ketoconazole and hydrocortisone were initiated simultaneously with antiandrogen withdrawal. In the latter study, the median response duration was 8.5 months and the median survival 19 months.46 Ketoconazole requires an acidic environment for optimal gastric absorption. The avoidance of H2 blockers and antacids is therefore recommended. Ingesting ketoconazole with acidic drinks may enhance its absorption. In some studies, dosing with meals and pH-lowering medications was permitted, but the drug was spaced to avoid meals. Ketoconazole is given in combination with hydrocortisone due to the rare development of adrenal insufficiency. The improved response to ketoconazole in later trials may therefore be partially due to the addition of hydrocortisone.

Aromatase inhibitor; decreases estrogens and androgens Requires replacement glucocorticoids 583 patients, 13 trials (pre-PSA era): 11% objective response, 23% stable disease Toxicity: commonly lethargy, nausea, rash; less common: hypothyroidism, hepatitis, edema

In contrast to ketoconazole, aminoglutethimide irreversibly inhibits P-450-mediated hydroxylation of the cholesterol ring, an early step in testosterone biosynthesis.47 The resultant decrease in adrenal glucocorticoids, mineralocorticoids, estrogens, and androgens requires concomitant hydrocortisone (Table 42–4). Clinical trials in progressive metastatic disease were primarily conducted prior to the development of PSA-response criteria. An overall response rate of 32%, of which 23% was stable disease, was achieved in 583 patients treated in 13 clinical trials.7 Recent reports of aminoglutethimide with simultaneous flutamide withdrawal have suggested surprising activity (Table 42–5). In the initial trial by Sartor et al., 14 (48%) of 29 patients demonstrated a > 80% decline in PSA level with this simultaneous maneuver.22 The median time to disease progression for responding patients was 32 weeks. The primary side effects of aminoglutethimide are lethargy, nausea, and rash. Hypothyroidism and abnormal liver function tests are infrequently reported. Dupont et al. reported an 80% PSA response.11 Figg et al., in a report of patients progressing after a combination of leuprolide, flutamide, suramin, and hydrocortisone, found that discontinuing flutamide with concomitant initiation of aminoglutethimide caused a > 50% PSA decline in 11 of 17 (65%) patients.48 Of these responding patients, five of seven with abnormal bone scans showed significant improvement. No responding patient had measurable disease. Median response duration was 344 days (range 30 to 1393 days). Liarazole is an inhibitor of the P-450-dependent enzymes retinoic acid 4-hydroxylase and aromatase. Its antitumor activity is attributed to enhancement of retinoic acid levels and resultant cellular differentiation.49 In the Dunning rat prostate tumor model, liarazole inhibited growth of both androgen dependent and independent subTABLE 42–5. Flutamide Withdrawal with Aminoglutethimide and Hydrocortisone Study Dupont et al.11 Sartor et al.22 Figg et al.48 * > 50% PSA decline. > 80% PSA decline.

†

No. of Patients

Response

40 29 17

80%* 48%† 65%

Median Duration (Months) 12 7 11


lines.50 In a phase I/II dose escalation trial, a 30% response rate was achieved in unselected patients receiving liarazole as a second- or third-line treatment.51 Side effects were consistent with hypervitaminosis A: primarily nausea, vomiting, and rash. In a subsequent phase III trial, liarazole was found to be less effective than prednisone and was therefore not approved by the Food and Drug Administration for this indication [unpublished data, 1997].

Glucocorticoids Glucocorticoids suppress adrenocorticotropic hormone (ACTH) levels and thus production of the adrenal androgens, androstenedione, DHEA, and dehydroepiandrosterone sulfate. Following reports of improvement in patients treated with surgical adrenalectomy, Miller and Hinman documented in 1954 the benefit of medical adrenalectomy using high-dose cortisone. Subjective improvement was achieved in eight of ten men and objective response in six.52 In the PSA era, biochemical responses have been documented with hydrocortisone ranging from 0 to 53%.53–56 In two large randomized trials comparing mitoxantrone plus glucocorticoids to glucocorticoids alone (Table 42–6), a PSA response rate (> 50% decline) of 15 to 22% was achieved with glucocorticoids. In a suramin plus hydrocortisone versus hydrocortisone trial, the 230 patients on hydrocortisone showed a rate of subjective improvement of only 28% and a rate of PSA level decline (> 50%) of 16% for a median of 2 TABLE 42–6. Secondary Hormonal Manipulation: Addition of Glucocorticoids No. of Patients

Treatment

Miller and Hinman52 Harland and Duchesne53

Cortisone 50–100 mg Hydrocortisone 40 mg qd

10

80% subjective

15

Tannock et al.54

Prednisone 7.5–10 mg qd Hydrocortisone

37

80% subjective 6 53% > 50% PSA (range: 2–16) level decrease 38% subjective 4

?

?

?

Kelly et al.56

Hydrocortisone 40 mg qd

30

4

Tannock et al.57

Prednisone 10 mg qd

81

Kantoff et al.58


123


230

0% objective 20% > 50% PSA level decrease 12% subjective 22% > 50% PSA level decrease 8% symptomatic 18% > 50% PSA level decrease 28% subjective 16% > 50% PSA level decrease 63% subjective 61% > 50% PSA level decrease

Dawson et al.55

Small et al.59

Storlie et al.60

NR = not reported.

Dexamethasone 38 0.75 mg bid

Response

Duration (Months)

Study

3

2

months.59 Further, in a recent retrospective review of the Mayo Clinic experience,60 dexamethasone at a dose of 0.75 mg twice daily was palliative in 79% of 38 patients and resulted in declines in PSA levels in 23 (61%).

Progesterones and Estrogens Megestrol acetate has several mechanisms of action that suggest a potential beneficial role in treating progressive metastatic prostate cancer. It inhibits the release of luteinizing hormone, 5 α-reductase conversion of testosterone to dihydrotestosterone, binding of androgen to its receptor, and at high doses may be cytotoxic.61 Based on clinical reports that suggest a dose-response effect, Dawson et al. studied two doses for the CALGB (160 mg versus 640 mg). The PSA response was only 12%, however, with no dose effect and no association with prior response to antiandrogen withdrawal.62 An unexpected tumor flare was observed in some patients, suggesting that megestrol acetate had agonistic activity. There was a similar low response rate reported in a smaller retrospective study63 (Table 42–7). The palliative benefit of both estrogens and orchiectomy in the treatment of advanced prostate cancer was first reported in 1941, by Huggins and Hodges.64 In the setting of hormone-sensitive disease, the inhibitory effect of estrogen is due to suppression of pituitary gonadotropins and in turn testosterone. Additionally, estrogens have been shown experimentally to be cytotoxic in a hormone-resistant prostate model 65 and against the PC-3 and DU 145 prostate cancer cell lines.66 Estrogens, primarily in the form of diethylstilbestrol (DES) were used as the primary form of medical castration until the 1980s, when their thromboembolic and cardiac toxicities caused them to be generally abandoned in favor of the newer and equally efficacious LHRH-analogues.67 However, high-dose estrogen therapy retains a potential role in the therapy of androgen-insensitive disease. In 1952, Hertz first reported the beneficial effects of intravenously conjugated estrogens and DES sulfate in patients with hormone-refractory prostate cancer.68 Subsequently, Flocks et al. reported on 34 men with refractory disease treated with diethylstilbestrol diphosphate (DESDP, DES-P, Stilphostrol, Honvan, Fosfestrol).69 The DESDP is an inactive estrogen that is dephosphorylated in vivo to DES. It is water soluble and can therefore be administered intravenously in large doses. Using doses of 250 to

NR

TABLE 42–7. Secondary Hormonal Manipulation: Addition of Megestrol Acetate 2

8

Study

Dosage (mg q.d.)

No. of Patients

Dawson et al.62 Osborn et al.63

160–640 160–320

149 14

NR = not reported

Percentage of Patients with Duration > 50% PSA Decline (Months) 12 14

NR 7–8+

382 / Advanced Therapy of Prostate Disease TABLE 42–8. Oncologists First Choice of Second-Line Hormone Therapy*† Treatment

No. of Votes; N = 34

Ketoconazole ± steroids Steroids Aminoglutethimide ± steroids Antiandrogen None/experimental protocol DES Megestrol acetate Estramustine

9 (26.5%) 8 (23.5%) 5 (14.7%) 5 (14.7%) 3 (0.9%) 2 1 1

DES = diethylstilbestrol. *Based on the survey question: What is your first choice of second-line hormone therapy excluding antiandrogen withdrawal? †Adapted from Dawson NA. Eligibility and response criteria in hormone refractory prostate cancer (HRPC). A need for consensus. Proc Am Soc Clin Oncol 1997:16:317a.

1250 mg given daily as a short IV infusion for 5 to 20 days, subjective benefit was noted in 21 of 27 men with prior estrogen therapy and in 5 of 7 men with both previous estrogen therapy and orchiectomy. There were three objective responses. In 1993, Droz et al. reviewed the results of six subsequent phase II trials of DES-DP involving 139 patients (130 hormone-refractory) and found no measurable tumor responses.70 There was a > 50% reduction in prostatic acid phosphatase (PAP) in 37 of 99 assessed patients, and subjective benefit occurred in 74 men. The doses in these studies ranged from 0.5 to 4.0 grams per day administered intravenously for 7 to 10 days. The cardiovascular toxicity was 5%. The median survival was only 5 months. The apprehension in using estrogen therapy is primarily related to concerns about cardiovascular toxicity in an elderly population. In two trials by the European Organization for Research on Treatment of Cancer (EORTC) that used oral DES at a standard dose of 3 mg per day, there was lethal cardiovascular toxicity in 11% of 185 men.71 Risk factors were identified and included older age, weight > 75 kg, and prior cardiovascular disease. Although concomitant use of aspirin seems warranted as prophylaxis, in two randomized trials comparing goserelin to DES, aspirin apparently did not protect against the excess cardiovascular toxicity of DES.72,73 However, in these studies, aspirin was not evaluated in a randomized fashion. Other common side effects of estrogen therapy include nausea, vomiting, weight gain, edema, and gynecomastia. Abnormal liver function tests are less common.

Conclusion Many patients with “hormone-refractory” prostate cancer are actually somewhat hormone-sensitive. In 1997, Dawson described the practice patterns of 34 urologic oncologists who treated hormone refractory prostate cancer (Table 42–8).74 When asked about their first choice of second-line hormone therapy (excluding

antiandrogen withdrawal), 26.5% identified ketoconazole with or without a glucocorticoid, 24% a glucocorticoid alone, and approximately 15% used an alternative antiandrogen or aminoglutethimide. The current authors recommend a trial of antiandrogen withdrawal as the first choice of therapy in patients failing combined androgen blockade for metastatic disease. Subsequent progression should be documented before any new treatment is started. Sequential use of an alternate antiandrogen, a P-450 enzyme inhibitor, and a glucocorticoid may then be beneficial, with modest toxicity. Failure of these medications to suppress growth of prostate cancer defines the patient as truly hormone “refractory.” Further treatment should be administered with agents not acting primarily through androgenmediated cell growth.75

References 1. Fowler JE, Whitmore WF. The response of metastatic adenocarcinoma of the prostate to exogenous testosterone. J Urol 1981;126:372–5. 2. Manni A, Bartholomew M, Caplan R, et al. Androgen priming and chemotherapy in advanced prostate cancer: evaluation of determinants of clinical outcome. J Clin Oncol 1988;6(9):1456–66. 3. Taylor CD, Trump DL. Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol 1993;11:2167–72. 4. Hussain M, Wolf M, Marshall E, et al. Effects of continued androgen-deprivation therapy and other prognostic factors on response and survival in phase II chemotherapy trials for hormone-refractory prostate cancer: a Southwest Oncology Group report. J Clin Oncol 1994;12(9):1868–75. 5. Nesbitt RM, Baum WC. Endocrine control of prostatic carcinoma. JAMA 1950;143:1317–20. 6. Silver RI, Straus FH, Vogelzang NJ, et al. Response to orchiectomy following Zoladex therapy for metastatic prostate carcinoma. Urology 1991;37:17–21. 7. Dawson NA. Treatment of progressive metastatic prostate cancer. Oncology 1993;7:17–27. 8. Scher HI, Steineck G, Kelly WK. Hormone-refractory (D3) prostate cancer: refining the concept. Urology 1995;46:142–8. 9. Small EJ, Vogelzang NJ. Second line hormonal therapy for advanced prostate cancer: a shifting paradigm. J Clin Oncol 1997;15(1):382–8. 10. Scher HI, Kelly WK. Flutamide withdrawal syndrome: its impact on clinical trials in hormone-refractory prostate cancer. J Clin Oncol 1993;11:1566–72. 11. Dupont A, Gomez J, Cusan L, et al. Response to flutamide withdrawal in advanced prostate cancer in progression under combination therapy. J Urol 1993;150:908–13. 12. Small EJ, Carroll PR. Prostate-specific antigen decline after Casodex withdrawal: evidence for an antiandrogen withdrawal syndrome. Urology 1994;43:408–10. 13. Small EJ, Schellhammer P, Venner P, et al. A double-blind assessment of anti-androgen withdrawal from Casodex or Eulexin therapy while continuing luteinizing hormone releasing hormone analogue therapy for patients


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CHAPTER 43

MANAGEMENT OF HORMONE-REFRACTORY PROSTATE CANCER: CHEMOTHERAPY AND IMMUNOTHERAPY PETER NELSON, MD; CELESTIA HIGANO, MD

eral heterogeneity of clinical disease, a difficulty in obtaining objective indices of response, and the recruitment of end-stage patients for clinical trials. Until recently, there has been no convincing evidence of the extension of survival or of the improvement in patient quality of life (QOL) to support the routine use of any given chemotherapeutic agent or combination of agents over symptomatic treatment. However, continued research into the development and evaluation of therapeutic agents has produced significant areas of recent progress in the understanding and treatment of advanced prostate cancer. Basic research aimed at understanding the biology of prostate carcinogenesis has identified rational approaches for combining and scheduling the administration of chemotherapeutic agents, and has provided for therapeutics targeted at modulating diverse cellular processes such as differentiation, angiogenesis, signal transduction, apoptosis, and tumor-host immune interactions. In addition, improved methods for assessing disease response in terms of accurate, reproducible measures of pain response, QOL, and surrogate markers of tumor burden have aided in the evaluation of treatment benefit. This communication will review the aspects of advanced disease that are important for the evaluation of therapeutic agents in advanced prostate cancer, and will describe the past results as well as the present and future approaches using cytotoxic and alternative systemic treatments for managing HRPC.

The effective treatment of prostate cancer patients with advanced disease is a major challenge. Metastatic disease can initially be effectively managed using the relatively nontoxic intervention of androgen ablation, that is, orchiectomy, diethylstilbestrol (DES), and luteinizing hormone–releasing hormone (LHRH) analogues. As the response rate exceeds 80% and the approach affords little morbidity in comparison to the cytotoxic approaches necessary for the treatment of other epithelial malignancies, it is the therapy chosen by most patients and physicians. However, most patients eventually experience biochemical or clinical evidence of disease progression in a median time of 12 to 18 months.1 Second-line treatment options are then considered, and usually consist of additional hormonal manipulations. Despite this approach, progression is the norm with the development of androgenindependent or hormone-refractory prostate cancer (HRPC). For patients with HRPC, the prognosis is poor with a median survival of 9 months. Prostate cancer is the leading site for cancer incidence in men, with 179,300 new cases and 37,000 deaths predicted for 1999. Most of the deaths will be due to hormone-refractory disseminated disease.2 In addition, the widespread use of prostate-specific antigen (PSA) as an early marker of disease recurrence has identified a cohort of patients with presumed disseminated disease who are without signs or symptoms. While certainly posing a treatment dilemma by intervening with potentially toxic systemic agents in an asymptomatic patient, PSA relapses offer an opportunity of intervention at a point of minimal disease burden when treatments may have the greatest benefit. A standard effective approach to HRPC remains to be defined. Numerous early trials with cytotoxic chemotherapeutic agents in the setting of androgen-independent disease yielded disappointing results with a general lack of efficacy and often with considerable toxicity. As recently as 1989, a review of chemotherapy for prostate cancer concluded that there was no indication for the routine use of chemotherapeutic agents.3 Evaluating therapies in advanced prostate cancer has been hampered by the gen-

Heterogeneity of Advanced Prostate Cancer In order to evaluate the potential impact of any therapy for prostate cancer, one must consider and attempt to define the heterogeneity present in the cohort of patients said to have advanced disease. Tumor biology differs not only between individuals, but also between different stages of the disease within the same patient. Examples of tumor heterogeneity include the following: the histologic cancer grade; the representation of cellular 385


subpopulations including the cohort of androgen-independent cells; tumor growth kinetics; disease location (soft tissue vs. bone); and extent of disease.4,5 Such characteristics have previously been used to stratify patients with advanced prostate cancer into cohorts with widely differing median survival rates of 4 years for minimal disease to less than 1 year for extensive disease.6 In addition, molecular heterogeneity in terms of autocrine and paracrine growth mechanisms, telomerase activity, alterations in the androgen receptor (point mutations and CAG repeat length), and other genetic variations resulting in distinct molecular phenotypes may further define the heterogeneity of advanced disease into distinct disease categories. These distinctions may have important implications on the variability of therapeutic response in patients. Although the terms androgen-independent and hormone-refractory prostate cancer have been used to place patients with advanced prostate cancer into disease categories, the terms have not been rigorously defined, and thus these patient cohorts also manifest a heterogeneous spectrum of disease with variable clinical courses. The progression of disease following first-line androgen deprivation does not consistently indicate hormonerefractory status, as some of these cancers will still respond to second-line hormonal therapy. The identification of a tumor that is no longer responsive to androgens is critical for the accurate evaluation of further therapeutic interventions. Patients with supposed hormone-refractory disease may have persistent production of androgens from residual functional testicular tissue after orchiectomy, production of androgenic steroids by the adrenal glands, or compliance problems with medications such as estrogens or LHRH agonists.7 Thus, measuring a serum testosterone level should be performed before assuming androgenindependent cancer progression. An important clinical scenario involves a tumor response to the discontinuation of the antiandrogen flutamide, called flutamide-withdrawal phenomenon, and that may occur in up to 30% of patients.8 This paradoxical effect has also been observed with other antiandrogens, prompting a more broad description of the antiandrogen withdrawal syndrome.8 Thus, a false assessment of tumor response could be attributed to an agent if administered at the same time a hormonal agent is being withdrawn, or if it is administered with a new hormonal agent, such as a corticosteroid given to alleviate toxicities or side effects. If recognized, these issues can be addressed by designing carefully controlled clinical trials that require a strict definition of HRPC. This would require the documentation of objective disease progression or a consecutive series of increasing PSA levels following the discontinuation of agents that act via the steroid hormone receptors, or by randomizing between a study agent with a steroid versus the steroid alone.9

Evaluation of Treatment Response Traditional Endpoints Clinical trials in oncology have traditionally used the endpoints of tumor response and survival (median survival time) to determine the efficacy of a given treatment. Several problems arise when attempting to evaluate prostate cancer responses by these criteria. First, patients with bidimensionally measurable tumor masses in whom response or progression can be accurately assessed account for only 20% of patients with prostate cancer. The majority of patients have bone metastases that are difficult to quantitate accurately. These osseous lesions may exhibit a delayed treatment response and likely represent a biologically different disease than soft tissue metastases. Second, very active agents used in large randomized studies are required to demonstrate a small benefit in both androgen-dependent and androgen-independent disease. Third, survival figures have been difficult to interpret because many patients receive treatment with a series of therapies over a prolonged time interval as a result of relapses and disease progression. It is then difficult to attribute a survival benefit to one particular agent. Fourth, adequate controls for other concurrent therapeutic manipulations, such as the addition of corticosteroids to attenuate toxicities or the discontinuation of antiandrogens, often have not been incorporated into the study design. Fifth, the stringency with which the response criteria are applied can have a substantial impact on the reported trial outcome. For example, reports describing a prostate cancer response to doxorubicin (DOX) ranged from 5 to 85%, depending upon the criteria employed.10 Consequently, the appropriate endpoints for evaluating clinical trials of oncologic agents in prostate cancer continue to evolve and should be carefully evaluated when interpreting the results of a clinical trial. Prostate Specific Antigen as a Surrogate Marker Due to the difficulty in quantifying tumor response to therapy using conventional radiographic criteria, changes in the serum marker PSA have been proposed as a marker for the evaluation of therapeutic intervention.11 In the context of response marker, post-therapy decline in PSA was originally proposed as a way to rapidly evaluate promising therapeutic approaches, and was not designed to be a surrogate endpoint of response. The use of PSA as a clinical trial endpoint is problematic because PSA levels may vary independent of actual cellular response due to the finding that the production or secretion of PSA may be affected by the therapy without altering cell proliferation.12,13 Tumor cell heterogeneity in terms of their PSA secretion rate and production per volume of tumor may also influence measurements. Prostate-specific antigen changes do not consistently correlate with other measures of tumor activity, as there are well-documented examples of progressive disease associated with decreasing PSA val-

Management of Hormone-Refractory Prostate Cancer: Chemotherapy and Immunotherapy / 387

ues. Finally, there are no standardized response criteria that have been validated using an endpoint of patient survival, and using PSA as an outcome measure has yielded variable results.14 Despite these shortcomings, it has become clear that PSA levels can provide preliminary evidence of therapeutic efficacy if the patient population is selected based upon strict criteria and if the appropriate agents are chosen for evaluation. A PSA rise has been shown to precede signs of clinical or radiologic progression.15,16 In a trial of trimetrexate (TMTX), an elevation in PSA of 50% from baseline on two separate determinations was shown to correlate with measurable disease progression.13 A study of suramin indicated that PSA followed a similar pattern to that observed with hormonal therapy, in that a decline of 75% or greater over the first 8 weeks was correlated with a prolongation of survival.17 A multivariate analysis of prognostic factors for survival demonstrated that achieving a post-treatment decline in PSA was the most significant factor associated with survival.14,18 This finding has been confirmed by other independent studies.19,20 In summary, while PSA is not a perfect tool for quantifying treatment response, it can be a useful adjunct in defining the activity of a therapeutic agent. An increase or a decrease in serum PSA level probably indicates a corresponding change in disease activity, but may or may not correlate with an alteration in survival duration. A serial rise of PSA following androgen ablation is highly predictive of relapse, and the PSA rise frequently occurs before other signs of disease progression.21 Decreasing PSA values have weak or delayed correlation with radiographic disease regression. At this time, a consensus as to what constitutes a PSA response has not been reached.22 A reduction of 50 to 80% over two to three samplings may be a reasonable measure of response, or conversely, increasing PSA values documented on two or three consecutive determinations indicate progressive disease and failure of the treatment regimen. Before this methodology can be adopted uniformly, standardization of response criteria and reporting will be required.10,18,23 New measures. In the 1970s and 1980s, many studies of chemotherapeutic agents were performed in patients with end-stage prostate cancer. No single compound or combination regimen produced an impact on survival, and the response based upon reduction of measurable disease was less than 10%.14 This led to the evolution of alternative treatment goals and the development of nontraditional measurements of treatment responses. Given the absence of agents that are curative or that prolong survival, endpoints that include objective assessments of pain relief, analgesic use, and QOL have been evaluated. The term QOL generally describes overall patient wellbeing, and includes social factors, psychologic factors, emotional factors, satisfaction with treatment, future orientation, sexuality, employment, economic status, spiritual

issues, and a host of physical parameters including pain and functional status.24,25 Measurements of QOL have been developed that are reliable, valid, and sensitive, and thus are suitable for the evaluation of therapeutic interventions and outcomes.21,24 A variety of QOL assessments have been developed employing questionnaires that are completed by the patient.22 These include: the European Organization for Research and Treatment of Cancer General Core Questionnaire (EORTC QLQ-C30), which combines appropriate disease- and treatment-specific modules;17,22 the Functional Living Index-Cancer (FLIC) which has 22 specific questions answered on a visual analogue scale with seven equal intervals;26 and the Functional Assessment of Cancer Therapy (FACT) which is composed of a general scale (FACT-G) and nine tumor-specific scales.27 Improved patient QOL has become an important endpoint for clinical trials of patients with cancer, and the FDA has established guidelines to permit the approval of cancer therapies based on their ability to enhance patient QOL.22 Data from QOL assessments can be used to compare treatment arms, to stratify patients in clinical trials, or to make decisions about whether to continue or discontinue therapy.21 Employing QOL endpoints in chemotherapy trials of patients with HRPC have shown significant benefit, as described below in the discussion on chemotherapeutic agents. Thus, clinical trial endpoints may include an objective response in measurable disease, time-to-tumor progression, survival, biochemical markers such as PSA, and QOL.

Cytotoxic Chemotherapy Studies of cytotoxic chemotherapy for the treatment of advanced prostate cancer have rarely shown significant survival benefit. Less than 10 to 15% of patients in clinical trials show objective tumor regression, and the attainment of a complete response is rare. Several factors have contributed to the generally dismal treatment responses and the corresponding attitudes of patients and physicians. The most significant factor is that most of the chemotherapy studies were done in the pre-PSA era, when patients were not entered into clinical trials until they had symptomatic progression after failure of initial hormone therapy. By comparison, the initiation of therapy at the time of asymptomatic PSA progression antedates symptomatic progression by a median of 6 months. As discussed previously, prostate cancer represents a heterogeneous disease that does not lend itself to traditional response assessments such as the direct measure of tumor regression. Patients with prostate cancer are generally elderly (median age 70 years) and often have comorbid diseases and variable end-organ function with the inability to tolerate treatment-induced side effects. Since hormone manipulation offers excellent palliation in terms of response and side-effect profile, the use of chemotherapy is considered as a last resort after development of hor-


mone resistance, tumor progression to a more virulent, treatment-resistant phenotype, and worsening patient performance status. Finally, chemotherapeutic agents and administration regimens are generally those that have shown efficacy in other epithelial malignancies. However, prostate cancer is biologically unique in that the growth rate is low when measured by the percentage of cells in Sphase, with a failure in apoptosis rather than proliferation.28,29 The characteristic metastatic pattern of bonedominant osteoblastic disease may also represent uniquely resistant cellular targets. The development of new measures of therapeutic response, including the careful assessment of QOL and the use of serum PSA as a response marker, has led to a reevaluation of the role of cytotoxic therapy for advanced prostate cancer. Advances in molecular biology have provided investigators with a more detailed understanding of the molecular aspects of prostate cancer growth and allowed for the design of rational treatment regimens targeting the nuclear matrix and cell cycle. Further promise has been generated by the continued development of new compounds and combinations of agents suitable for trials in patients with advanced prostate cancer.

Single-Agent Chemotherapy A large number of trials evaluating the efficacy of single chemotherapeutic agents in advanced prostate cancer have been performed. These studies have been generally disappointing, with a small percentage of patients exhibiting a partial or complete response. Many of these trials were performed prior to the PSA era and therefore used the traditional endpoints of tumor regression of bidimensionally measurable disease. In addition, these trials often did not accurately evaluate palliative endpoints. Table 43–1 summarizes selected single-agent trials. Alkylating Agents Early National Prostate Cancer Project (NPCP) trials with cyclophosphamide (CY) demonstrated an overall response rate (complete response [CR] plus partial response [PR]) of 0 to 7%. Expanding the response criteria to include stabilization of disease (SD) increased the response rates to between 26 and 46%.30 Published reviews of these and other trials with CY report overall response rates of 2 to 10%.31–33 In early randomized studies, CY was found to be superior to 5-fluorouracil (5-FU), and it became the standard cytotoxic agent for advanced prostate cancer.31 However, a randomized study comparing CY against melphalan (ME) in patients with HRPC found no difference in response rates between these two agents.34 Other trials have not shown an advantage for using a combination of agents when compared with CY alone. Randomized trials comparing CY with the combination of CY, methotrexate (MTX), and 5-FU,35 and the combination of CY, 5-FU, and mitomycin C (MC), demonstrated no significant dif-

ferences in response rates or survival.30 Ifosfamide (IF), an analogue of CY, has been evaluated in a regimen of continuous infusion for 2 consecutive days each month. No remissions were observed in 14 adequately treated patients (95% CI, 0–20%).36 A phase II study of IF and mesna given daily for 5 days in 21-day cycles demonstrated a response rate of 7% in 29 evaluable patients (95% CI, 0.3–48%).37 Metal-Containing Agents Trials with single-agent cisplatin (CS) and carboplatin (CP) have demonstrated marginal-to-modest antitumor activity against HRPC. A phase II study comprised of 25 patients with objectively measurable disease involving lymph nodes and visceral metastases was conducted using an every-3-week administration schedule. A PR occurred in three patients (12%), with SD in one additional patient.38 A schedule of weekly doses of CS, 40 mg per m2, found a response rate similar to the every-3-week schedule, with a 10% response rate in 29 patients (95% CI, 0–21%).39 Carboplatin was evaluated in 30 patients at doses of 320 to 400 mg per m2.40 Of the adequately treated patients with measurable disease, one of five had a greater than 50% tumor regression without a corresponding decrease in the serum acid phosphatase level, and one of 24 had a greater than 50% improvement in bone disease, again without any change in biochemical parameters. Thus, no responses were documented. The median survival was 297 days (range, 6–1152 days). In another study, 25 patients with measurable or evaluable metastatic HRPC were treated with weekly CP at 150 mg per m2 intravenously (IV). This schedule allowed for a higher dose intensity compared to monthly cycles. Toxicity consisted primarily of myelosuppression. Four out of 24 evaluable patients (17%) had a PR and 12 (50%) had SD. The median response duration was 7 months. These results suggest that CP, administered on a weekly dosing schedule, possesses a moderate but definite activity in prostate cancer patients.41 Pyrimidines Trials with pyrimidine agents, primarily 5-FU, have consistently shown some marginal antitumor activity in HRPC. The older literature, consisting of 124 cases, found a response rate of 9% (95% CI, 4–14%).10,31,42 Several dose schedules have recently been evaluated. Using the rationale that a long-term infusion strategy may be the optimal administration method for this cell-cycle-specific agent, a protocol of 300 mg per m2 per day continuous infusion for 10 consecutive days followed by a 2-week rest period was used to treat 32 patients. Of 30 evaluable patients, three achieved a PR (10% [95% CI, 0–21%]) and 14 had SD.43 The PR was 27% among those with measurable disease. The median survival time was 179 days with mild toxicity. In another study, 20 patients with metastatic progressive


prostate cancer were treated with a continuous 5-FU infusion of 250 to 300 mg per m2 per day.41 Two of the 20 patients (10%) had PRs, nine (45%) had SD, and the remaining nine (45%) had progressive disease. The mean duration of benefit in responding and SD patients was 6 months. Improvements in pain and Eastern Cooperative Oncology Group (ECOG) performance status were seen in most of the patients in the responding and SD categories. Toxicities included stomatitis (30%), hand/foot syndrome (15%), and diarrhea (5%). In another study, a 5-day continuous infusion schedule at a dose of 1000 mg per m2 per day every 28 days was given to 25 patients who had progressive disease, elevated PSA, and bidimensionally measurable lesions or evaluable lesions on bone scan or radiograph. Objective responses were not observed with this regimen, but 12 patients experienced SD with a median duration of 4 months. Toxicities were severe and included one episode each of sudden death, cardiac dysrhythmias, congestive heart failure, and one case of severe stomatitis and diarrhea.44 Finally, a 24-hour infusion schedule using a dose of 4 g per m2 every 2 weeks was used to treat 32 patients with HRPC who had no prior chemotherapy. Of 27 patients evaluable for response, there were no CRs or PRs (95% CI, 0.0–12%); however, nine patients (33%) had SD. Again, side effects were significant, with two patients experiencing neurologic toxicities.45 Antifolate agents. A summary of early phase II trials evaluating MTX in the setting of HRPC described response rates of 10% in 82 patients (95% CI, 3–17%).46 A more recent NPCP randomized phase III trial produced less encouraging results. Methotrexate was given on day 1 at a dose of 40 mg per m2 followed by 60 mg per m2 on day 8 and every 2 weeks thereafter. One PR (2%) was demonstrated in 63 evaluable patients (95% CI, 0–6%), and SD occurred in 20% of patients.47 A relatively new antifolate agent, TMTX, was evaluated in two reported studies. In one study, TMTX was given to 31 patients with measurable soft-tissue disease in doses of 8 to 29 mg per m2. Five patients had a PR (17% [95% CI, 3–30%]); however, the median response duration was only 3 months, and myelosuppression was seen in more than 50% of patients.13 In the other trial, a phase II ECOG study, TMTX was administered at a dose of 12 mg per m2 per day for 5 days in 21-day cycles to 18 patients who had HRPC, bidimensionally measurable disease, and good performance and physiologic status.48 No response was seen in any patient, and the median time-to-treatment failure and median survival were 6 and 20 weeks, respectively. Myelosuppression was a frequent toxicity. Thus, TMTX is relatively toxic and appears to have little activity in advanced HRPC. Intercalating Agents Single-agent DOX therapy was evaluated in a heterogeneous cohort of patients with metastatic prostate cancer

that included patients receiving prior cytotoxic chemotherapy. In this study, 52 patients received 30 to 60 mg per m2 of DOX every 3 weeks. A PR was achieved in only two of 39 adequately treated patients with measurable disease (5% [95% CI, 0–12%]). Three minor responses and one SD were noted.49 A study employing a weekly dosing schedule of 20 mg per m2 of DOX achieved a better response with four of 12 patients (33%) with measurable disease responding, and performance status and pain control improvements of 50 and 67% respectively.50 An analysis of 99 patients randomized to receive either DOX or 5-FU demonstrated a DOX response rate of 25% in patients with measurable disease versus an 8% response with 5-FU. Epirubicin (EP), a newer anthracycline derivative available in Europe, has also been evaluated, albeit with conflicting results. In one study, EP produced no measurable soft-tissue response in 32 HRPC pretreated and unpretreated patients (95% CI, 0–8%), although four patients showed improvements in osseous disease.51 In contrast, a TABLE 43–1. Results of Single-Agent Cytotoxic Chemotherapy in Hormone-Refractory Prostate Cancer

Agent Amsacrine Carboplatin Cisplatin Cyclophosphamide

Doxorubicin

Epirubicin Estramustine Etoposide 5-FU Ifosfamide + mesna Methotrexate Mitoxantrone

Vinorelbine Paclitaxel Prednisone Trimetrexate Vinblastine

Patients Treated

% Response Rate: CR+PR (total #)

95% CI

References

39 29 29 15 16 17 12 25 39 32 33 32 42 44 20 22 79 14 29 63 35 38 14 47 23 81 31 39

0 (0) 6.8 (2) 10 (3) 53† (8) 6 (1) 0 (0) 33* (4) 84† (21) 5* (2) 12* (4) 12 (4) 28 (9) 9 (21) 9 (20) 5 (1) 9 (2) 5 (4) 0 (0) 7 (2) 2 (1) 6 (2) 50‡ (19) 43§ (6) 40§ (19) 4 (1) 12‡ (10) 17 (5) 21 (8)

0–6 N/A 0–21 N/A N/A N/A 10–60 67–98 0–16 1–32 1–25 N/A 9–34 N/A 0–12 N/A 1–10 0–20 0–23 0–6 N/A 34–66 0–35 N/A N/A 6–22 3–30 8–33

(155,156) (40) (39) (157) (158) (35) (50) (50) (49) (42) (52) (159) (64) (63) (58) (61) (45,92,93) (36) (37) (47) (160) (161) (56) (162) (163) (95) (13) (164)

*Measurable disease only. †NPCP response criteria including stable disease. ‡Palliative response based on a decrease in pain intensity with no increase in analgesic usage. §> 50% reduction in PSA.


low-dose regimen of EP (12 mg/m2/week) produced one CR and three PRs for an overall response rate of 13% in 33 adequately treated patients (95% CI, 1–25%); in addition, 14 patients (42%) had SD.52 An alternative dosing schedule was utilized in another study, such that EP was administered at 90 mg per m2 IV every 28 days to 29 patients with metastatic HRPC.53 Responses were assessed according to the NPCP criteria. Eleven patients (38%) achieved a PR with a median duration of response of 6 months and a median survival time of 9 months (range 2–27 months). Further, in another phase II study, 100 mg per m2 of EP every 3 weeks was given to 39 patients with bidimensionally measurable disease and produced nine PRs (24%) and 16 SDs (42%).54 Responses could not be correlated with PSA measurements. A recently reported randomized trial compared the addition of weekly EP, 25 mg per m2, to total androgen blockade with bilateral orchiectomy and flutamide.55 Untreated patients with either metastatic (N = 117) or locally advanced cancer (N = 28) were enrolled. Progression-free survival (PFS) and overall survival (OS) were significantly improved in the EP arm of the study with an increase of 6 months (p < .02) and 8 months (p < .12), respectively. For those patients with greater than five sites of metastatic disease, the PFS and OS were further enhanced at 5 months (p = .005) and 10 months (p = .06), respectively. No impairment of QOL was seen in the EP treatment arm. A phase II trial examines amonafide, administered as 225 mg per m2 per day for 5 days every 3 weeks to 47 patients with HRPC, bidimensionally measurable disease, and good performance status. Of 43 evaluable patients, none achieved a CR and only five PRs were attained for an overall response rate of 12% (95% CI, 4–25%). Mitoxantrone, an anthracenedione related to DOX, has not demonstrated significant efficacy when used as a single agent. A trial using a dosing schedule of 1 to 1.5 mg per m2 per day by a 14-day constant infusion showed only a modest reduction in PSA levels with seven of 13 patients showing any decrease after one cycle, and only two of 13 patients achieving a greater than 50% reduction in PSA for 1 to 7 or more months.56 Only one patient had bidimensionally measurable parameters and did not respond to treatment. Approximately 33% of patients were stated to have some evidence of symptomatic improvement. Trials employing a more standard dose of 12 to 14 mg per m2 IV every 3 weeks have been conducted, and also report minimal activity. No responses were seen in 50 patients in one trial, and only a 6% (2 of 35) PR rate was found in another trial that enrolled 10 patients with a poor performance status.5,57 The median survival times for both series were approximately 10 months. Trials using mitoxantrone in combination with other agents are discussed below.

Antimitotic Agents Etoposide (ET), a topoisomerase II inhibitor, has been evaluated in the setting of HRPC using a variety of dosing schedules including IV and oral formulations. Responses to IV schedules of ET have been poor, with studies showing PR in one of 22, zero of 19, and one of 36 patients for an overall response rate of 3% (95% CI, 0–7%).58–60 A study in 22 patients with HRPC used oral ET at a dose of 50 mg per m2 per day for 21 days in a 28day cycle. Two PRs of 6 and 14 months’ duration were noted, and two patients had SD disease. Median survival was 31 weeks, with an overall 1-year survival of 30%. This study concluded that single-agent oral ET exhibited minimal activity in patients with HRPC.61 Vinblastine (VLB), an inhibitor of tubulin, has been evaluated in older studies that described an overall response rate of 21% in 39 patients with HRPC (95% CI, 8–33%).31 A more recent trial employing a continuous infusion schedule administered VLB at a dose of 1.5 mg per m2 per day for 5 consecutive days every 4 weeks.62 A 21% PR among 39 patients (95% CI, 5–37%) was achieved. The median response duration was 28 weeks. These results are encouraging, as the overall response rates to VLB are significantly higher than those reported for other single agents; however, myelosuppression was significant. Estramustine phosphate (EMP) has undergone extensive evaluation over the years as treatment of HRPC. While early studies indicated little activity against advanced prostate cancer, a resurgence of interest has been sparked by a more detailed understanding of the molecular structure of prostate cells, a better understanding of the actions of EMP, and the demonstration of synergistic activity of EMP with other agents in regimens designed to exploit the pharmacologic mechanisms of action of the agents. Estramustine phosphate has been classified as a hormone, but the most likely mechanisms underlying cytotoxicity involve the binding of EMP to microtubule-associated proteins, tubulin, and proteins of the nuclear matrix leading to antimitotic properties. An EMP-binding protein has been reported in prostatic cells, and this binding protein, which may be related to a sterol receptor or to protein, may aid in determining specificity against prostate cancer. Four separate protocols designed by the NPCP evaluated single-agent EMP in a total of 163 patients, and reported dismal CR plus PR rates of 6, 4, 2, and 0%, and survival times of 26, 26, 43, and 38 weeks, respectively.46 Three separate trials evaluating EMP in combination with prednimustine, vincristine, or cisplatin (CDDP) were performed with no added benefit and CR plus PR rates of only 0 to 4%.31,42 A review of European studies employing single-agent EMP and less strict response criteria described a 19% overall response rate (95% CI, 16–23%) in 561 patients with advanced prostate cancer.42 One early United States trial using oral EMP at a dose of 15 mg per kg


per day found an objective response in seven of 32 patients with measurable soft-tissue disease sites for a PR of 22%.63 Further, subjective responses including relief of pain, weight gain, sense of well being, and improved performance status occurred in all objective responders and in seven other patients with SD (15 of 32 patients, 47%). A more recent phase II multi-institutional study evaluated EMP at 14 mg per kg in three daily divided doses in 48 patients with HRPC.64 Responses to treatment were assessed using PSA and serum acid phosphatase levels, Karnofsky performance status, and pain scale determinations. A PR was assigned to those evaluable patients in whom all parameters improved. Of 42 adequately treated patients, 31% had a pain-scale response, 41% improved or maintained their performance status, and 21 and 19% had a marker-detected PR for PSA and serum acid phosphatase levels, respectively. The final PR rate was 14% (95% CI, 0–30%) for a median of 8.4 months. Thus, this study confirmed that EMP does have modest antitumor activity against HRPC. Antitumor Antibiotics Mitomycin C has been evaluated in a randomized trial comparing orchiectomy alone versus orchiectomy and MC in 178 newly diagnosed metastatic prostate cancer patients.65 Of 148 evaluable patients, 75 were treated with orchiectomy alone and 73 received adjuvant IV MC. Mean time-to-progression was 15 months in the orchiectomy group versus 14 months in the MC group. Interim analysis did not demonstrate a favorable effect of the combination with this chemotherapeutic agent compared to orchiectomy alone (p = .45). Suramin (SU) is a potent antitrypanosomal agent that has been shown to inhibit the growth of malignant prostate carcinoma cells in vitro by binding to specific growth factors (epidermal growth factor, platelet-derived growth factor) and by other mechanisms including the inhibition of growth regulatory proteins and deoxyribonucleic acid (DNA) polymerases. Early studies in patients with HRPC generated great excitement as in vivo activity was also seen, although a broad spectrum of toxic effects and complex pharmacology were limiting factors. Several studies have subsequently evaluated SU as a single agent or in combination regimens, and widely varying responses have been noted, although no survival benefit has been documented.66 Two factors may have contributed to early reports of SU efficacy. Studies in animal models of prostate cancer have demonstrated that SU can reduce PSA secretion from tumors without a corresponding decrease in tumor growth.67 Thus, it has been suggested that changes in serum PSA levels may not accurately reflect actual tumor response. Also, corticosteriods administered to prevent SU-induced adrenal insufficiency may have contributed to the treatment benefit attributed to SU. Two recent

abstracts address these issues in a population of patients with advanced prostate cancer that were randomized to receive hydrocortisone (HC) with or without SU. This phase III randomized trial compared SU plus HC with placebo plus HC in a cohort of 460 patients and demonstrated a significant improvement in pain response (43 vs. 28%), PSA response (32 vs. 16%), and relative risk of progression (1 vs. 1.5) in the SU plus HC arm.68 Therapy was well tolerated, but a survival benefit could not be ascertained due to the crossover design of the study. A PSA response to therapy was also shown to be associated with progression-free and overall survival in these patients.69 Despite these results, the toxicity profile of SU remains of significant concern, and the FDA has declined to approve SU for the treatment of HRPC. Other agents. Mitoguazone is an inhibitor of Sadenosylmethionine decarboxylase, an enzyme involved in the conversion of putrescine to spermidine and spermine. A phase II trial of mitoguazone (500–600 mg/m2/ week) in a selected group of patients with soft-tissue lesions resulted in a PR in 24% of 25 patients (95% CI, 11–44%).70 However, the responses were seen only in softtissue (nodal and lung) masses and not in bone lesions, and these responses were not durable. Another trial using mitoguazone on a similar treatment schedule demonstrated no efficacy with 0% of patients responding (95% CI, 0–15%).71 Finally, no remissions (95% CI, 0–15%) were observed in two dose-finding limited phase I studies involving 19 patients treated with a combination of mitoguazone and difluoromethylornithine, a compound that blocks an additional enzyme in the polyamine synthesis pathway.67,72 Older single agents which have limited (< 10% CR plus PR rates) antitumor activity should be mentioned with the understanding that previous trials lacked many of the methods that are currently available to assess tumor response accurately, for example, PSA levels, computerized tomography (CT) scans, magnetic resonance imaging (MRI) scans, positron emission tomography (PET) scans, immunoisotope scans, and ultrasonography. Several agents previously dismissed as inactive may deserve a re-evaluation using these newer technologies. The list of agents with antitumor activity in < 10% of patients includes dacarbazine, ME, procarbazine, streptozotocin, and vincristine. Only MC and vindesine, in limited trials, demonstrated some activity; MC produced a response rate of 21% (10 of 48 patients [95% CI, 9–32%]), and vindesine produced a response in 19% of 27 patients (95% CI, 4–33%).10

Combination Chemotherapy With a few notable exceptions, reported combinations of cytotoxic chemotherapeutic agents have added little benefit to single-agent chemotherapy in the treatment of HRPC. It must be emphasized that early trials of combi-


nation chemotherapy were performed in the pre-PSA era with patients exhibiting very advanced and usually symptomatic HRPC. In addition, an understanding of basic prostate cancer biology has provided insights for the rational selection of drug combinations such as EMP and paclitaxel targeting the cytoskeleton and nuclear matrix. Cytoxan + Methotrexate + 5-Fluorouracil The regimen of cytoxan (Cy), MTX, and 5-FU (CMF) is a combination active in epithelial malignancies including breast carcinoma. This regimen was evaluated in 52 eligible patients with measurable (19 patients), evaluable (29 patients), or bone scan only (4 patients) metastatic prostate cancer using a dosing schedule of 100 mg per m2 per day by mouth of CY, 15 mg per m2 weekly IV MTX, and 300 mg per m2 weekly IV 5-FU.73 Two PRs (7%) were seen among the evaluable patients. A total of 10 patients had SD (six with measurable disease and four of the evaluable patients). Median time-to-progression was 3.2 months for patients with measurable disease and 2.8 months for patients with evaluable disease. The median survival times were 10.9 and 10.2 months, respectively. Toxicity consisted primarily of myelosuppression. The combination regimen of CMF was concluded to be minimally active in metastatic HRPC. Doxorubicin-Based Combinations A phase II clinical trial was performed to assess the antitumor activity and toxicity of ketoconazole in combination with DOX in patients with HRPC. Thirty-nine patients were treated with oral ketoconazole (1200 mg) daily and DOX (20 mg/m2 in a 24-hour infusion) once weekly.74 Antitumor activity was assessed by the level of PSA decline. Prostate-specific antigen levels decreased at least 50% from baseline in 21 of 38 evaluable patients (55% [95% CI, 38–71%]). Seven of 12 patients (58%) with measurable soft-tissue disease (in the lung, lymph nodes, and liver) achieved a PR. Toxicities included stomatitis, mucositis, neutropenia, sudden cardiac death, and adrenal insufficiency. Overall, 17 patients (45%) required hospitalization for complications. Thus, although active, this regimen is associated with significant toxicity. A randomized trial comparing DOX and DOX plus CS was performed involving 37 patients with HRPC.75 Measurable bidimensional tumors were present in 13 patients in the DOX arm and in 10 patients in the combination arm. Partial responses were seen in one of 13 patients in the DOX arm and two of 10 patients (20%) in the combination arm. Improvement in performance status of 20% or greater was rarely observed with either treatment (7% DOX versus 8% combination). Acid phosphatase levels normalized or improved by 50% in 39% of patients who received DOX and 27% of patients who received the combination. The overall response rate by NPCP criteria was 53% for DOX and 59% for DOX plus CS. Myelotoxicity and gastrointesti-

nal toxicity were severe, particularly in the combination arm, and required discontinuation of treatment in some patients who responded to treatment. Time-to-progression and survival were similar for the two treatment groups. In this small group of 37 patients, the combination of DOX plus CS showed no improvement over DOX alone in response, response duration, or survival, and the combination was difficult to administer in this patient population. A recently reported phase I study designed to evaluate the efficacy and maximum tolerated dose of SU combined with DOX was conducted in 24 patients with HRPC.76 Doxorubicin (20 mg/m2) was administered IV over 24 hours at weekly intervals. Suramin was given IV over 2 hours twice weekly to achieve targeted plasma concentrations until dose-limiting toxicity or disease progression was observed. Twelve of 24 evaluable patients (50% [95% CI, 28–71%]) and six of 10 evaluable patients (60% [95% CI, 26–88%]) had a greater than 50% decrease of PSA and measurable lesions, respectively; therefore, this appears to be an active regimen. Dose-limiting motor neuropathy developed in three patients (13%). Based on the toxicity profile, a targeted SU steady-state plasma concentration of 200 µg per mL was suggested for future studies. Epirubicin + Suramin Preclinical and clinical single-agent studies indicate that SU may be an active agent for treating HRPC, although significant antitumor responses were observed when plasma SU concentrations were maintained in excess of 250 µg per mL. On the basis of preclinical synergistic activity for combined SU/DOX in prostate cancer cell lines, a pilot study involving 10 patients with metastatic HRPC was performed.77 The treatment regimen consisted of a fixed dose of SU in combination with weekly EP at 25 mg per m2 given until dose-limiting toxicity or tumor progression was evident. No patient achieved a PSA reduction of more than 50% and no objective responses were observed in any patient. Dose-limiting toxicity was observed in four patients consisting of neurotoxicity and nephrotoxicity. Thus, despite encouraging preclinical results, this combination of EP and SU cannot be recommended for treatment of HRPC. Estramustine-Based Combinations Several trials have been conducted using a combined regimen of EMP and VLB with the rationale that both agents are mitotic inhibitors with at least additive antitumor effects in vitro, and that both possess modest single-agent activities, nonoverlapping toxicities, and apparent lack of cross-resistance. Three phase II trials have reported activity using EMP and VLB in HRPC. These trials total 83 patients, 17 with bidimensionally measurable disease. In the trials of Seidman and colleagues and Hudes, 8-week cycles consisted of weekly VLB times six at a dose of 4 mg per m2 by IV injection, with oral EMP at 10 mg per kg per


day or 600 mg per m2 per day.78,79 In the study of Amato and colleagues, VLB was given as a weekly IV injection at a dose of 6 mg per m2 with an EMP dosage of 420 mg per day.80 Objective responses occurred in 6 of the 17 patients (31%) with measurable disease, and PSA decreases of > 50% were observed in 35 of 83 patients (42%). These results led to randomized trials comparing the single agents with the EMP plus VLB combinations. Vinblastine was compared with VLB plus EMP in a phase III randomized trial in HRPC patients that resulted in better pain relief, PSA response, and measurable disease response in the combination arm compared with single agent VLB.81 However, there was no significant difference in overall survival. An EORTC sponsored phase III trial comparing EMP alone versus EMP plus VLB is in progress. Vinorelbine (VL), another agent with tubulin inhibitory activity, was combined with oral EMP in a recently reported trial of patients with HRPC. Of 24 patients with bone metastases, nine patients had a 65% or greater decline in pretreatment PSA level, SD was observed in 10 patients, and five patients progressed. Of five patients with measurable disease, none had an objective response. Toxicities were minimal.82 Although neither EMP nor ET alone is very effective in the treatment of advanced HRPC, their activity was shown to be enhanced when used together in preclinical assays. Both of these agents target components of the nuclear matrix and interact in a synergistic fashion to selectively inhibit new DNA synthesis.83 Based upon these findings, a phase II clinical trial using EMP 15 mg per kg per day and ET 50 mg per m2 per day administered orally for 21 of 28 days was conducted.19 Forty-two patients were evaluated of whom 18 had measurable softtissue disease. A CR was obtained in three patients, and six patients achieved a PR for longer than 2 months. Prostate-specific antigen levels decreased by greater than 75% in five patients (28%) and by more than 50% in nine patients (50%). Of 24 patients with osseous disease, six (25%) demonstrated improvement and nine (38%) demonstrated stability in their bone scans. Fourteen of these patients (58%) achieved at least a 50% PSA reduction. A subsequent phase II trial by the same group employed a lower dose of oral EMP (10 mg/kg/day) and expanded the study entry criteria to allow prior chemotherapy treatment. Sixty-two patients were enrolled of whom 15 had measurable soft-tissue disease. Eight patients (53%) in the latter group had a PR. Seven of these eight patients also demonstrated a decrease in baseline PSA of more than 50%. The median survival of all patients was 56 weeks. Of 47 patients with disease limited to the bone, 16 (34%) had a PR to therapy based on a decrease in pretreatment PSA of more than 50%. Overall, 24 of 62 patients (39%) demonstrated a decrease in pretreatment PSA levels of at least 50% from baseline.84 A third trial was conducted with EMP and ET using a

similar dosing schedule in 56 patients with HRPC. To control for the possible interference of an antiandrogen withdrawal effect, all patients discontinued antiandrogen therapy and were not enrolled in the study unless there was evidence of disease progression. Forty-five percent of 33 patients with measurable soft-tissue disease demonstrated an objective response, which included five CRs and 10 PRs. Among 52 patients with osseous disease, 17% showed improvement and 50% showed stability in their bone scans. Thirty patients (58%) demonstrated a decrease of more than 50% in pretreatment PSA levels. The median survival of all patients was 13 months.85 Again, based upon preclinical efficacy in model systems, these studies were expanded to include other agents with effects on the cell matrix. Paclitaxel, a microtubule inhibitor, was shown to interact with EMP and ET, and the combination of these three agents had significant preclinical activity against androgen-independent prostate cancer cell growth in vivo and in vitro.86 Preliminary results of a phase II clinical trial of combined paclitaxel, ET, and EMP demonstrated activity with 57% of patients responding to this regimen as measured by a decrease in pretreatment PSA levels of greater than 50%.87 Another study with a similar rationale combined VL, a semisynthetic vinca alkaloid with tubulin inhibitory activity, with oral EMP and EP. Twentyfive patients were enrolled including three with measurable soft-tissue disease and 23 with osseous disease. Two patients with measurable disease and six patients with bone disease had a PR for an overall response rate of 32% (95% CI, 15–53%). Seven patients had SD and 10 had progression of disease. Median duration of response was 3 months (range 2–5 months). Prostate-specific antigen in 14 patients (56%) decreased from baseline by at least 50%. The results of this study indicate that the schedule is active and well tolerated in HRPC patients.88 Thirty-four patients with advanced HRPC were enrolled in a phase II trial combining paclitaxel 120 mg per m2 by 96-hour IV infusion on days 1 through 4 of each 21day cycle, together with daily oral EMP 600 mg per m2 per day.89 The rationale for combining EMP, a drug that binds to microtubule-associated proteins, with paclitaxel and other tubulin-binding agents was based on the hypothesis that greater inhibition of microtubule function and cytotoxicity could be achieved using drugs that bind to different but complementary protein targets in the microtubule. Four of nine patients with measurable disease had objective responses (one CR and three PRs). Of 25 assessable patients with metastases limited to bone, 14 had a 50% or greater decline in pretreatment PSA levels that was sustained for at least 6 weeks and seven had an 80% or greater decline. Overall, 17 of 32 patients (53.1%) with elevated pretreatment PSA levels had a 50% or greater decline of PSA and nine (28.1%) had an 80% or greater decrease. Median time-to-progression, based on increasing PSA level and other clinical criteria, was 22.5 weeks. The estimated


median overall survival time was 69 weeks. The combination of EMP and paclitaxel is an active regimen for patients with HRPC. These results further support the therapeutic strategy of combining agents that impair microtubule function by complementary mechanisms. Docetaxel is a semisynthetic taxane derivative that binds to microtubules. In a phase I to II trial of 34 HRPC patients, the combination of EMP 280 mg TID and docetaxel at escalating doses of 40 to 80 mg per m2 on day 2 resulted in an overall 50% PSA response rate of 63%. Five of 18 patients with measurable disease achieved a PR, and 53% of symptomatic patients were able to discontinue narcotic analgesics. The median survival was 22.8 months. The recommended dose of docetaxel for patients with minimal prior therapy is 70 mg per m2 and for those with extensive prior therapy, 60 mg per m2.90 Twenty-four assessable patients with HRPC were treated with daily doses of oral EMP at 10 mg per kg, and intravenous EP at 100 mg per m2, every third week up to a cumulative dose of 500 mg per m2.91 Responses were determined using World Health Organization (WHO) criteria and a 50% or greater reduction in serum PSA levels. No objective tumor responses were observed, although 13 of 24 patients (54%) demonstrated a PSA response. Subjective improvement (pain score, performance status) occurred in seven of 24 patients, whereas nine patients progressed. Biochemical progression (defined as a 50% or greater increase after PSA nadir) occurred after a median of 12 weeks. All but two patients were alive after a median follow-up time of 8.7 months for surviving patients (range 3.3–13.2 months). Toxicities included leukopenia, cardiovascular toxicity, and angioedema. Based on this limited series, the combination of EP and EMP in patients with HRPC is tolerable and appears to be effective in terms of significant PSA reduction. Selected phase II studies of EMP combinations are reviewed in Table 43–2.

progression, and survival were evaluated. Both regimens led to a pain remission in nearly 70% of the patients. Mucosal side effects like diarrhea and stomatitis occurred more often in the combination arm, whereas leukopenias were more frequent in the monotherapy arm. No statistically significant difference was observed between the two treatment arms regarding time-to-progression and survival. While both regimens led to a pain remission, the side effects of diarrhea and stomatitis were significant. A multi-institutional phase II study also evaluated the combination 5-FU and FA. In this study, 38 patients with HRPC and bidimensionally measurable prostate carcinoma received leucovorin (20 mg/m2 IV) followed by 5-FU (425 mg/m2 IV) daily for 5 days, with cycles repeated every 28 days.93 Three patients (7.9%) had PRs to therapy and 20 (52.6%) had SD. Median survival was 11.6 months for all 38 patients and median time-to-progression was 4.4 months. Overall, 23 of 38 patients (60.5%) experienced at least one grade 3 or 4 treatment-related toxicity. The study concluded that the treatment of HRPC patients with 5-FU and leucovorin chemotherapy produced few responses at the cost of significant side effects. Similarly poor results were seen in a randomized trial combining 5-FU with alpha-interferon (α-IFN) used as an agent for enhancing the tumoricidal activity of 5-FU.94 Patients with HRPC were randomized to receive 5-FU or 5-FU with α-IFN. Only two of 17 patients (11.7%) treated with 5-FU alone and four of 23 patients (17%) treated with the combination showed a greater than 50% decrease in serum PSA (no significant difference). There was no difference in duration of response or duration of survival between the two groups. Both regimens caused significant toxicity; there were three treatment-related deaths. The study concluded that 5-FU alone and 5-FU with α-IFN, at the doses used, have minimal antitumor activity against androgen-independent prostate cancer.

5-Fluorouracil + Modulators The effect of 5-FU can be modulated by the addition of folinic acid (FA), and this combination of agents has shown clinical utility in the treatment of epithelial malignancies such as colorectal carcinomas. A randomized phase II trial comparing monotherapy with 5-FU versus the combination of 5-FU and high-dose FA was evaluated in patients with HRPC.92 Pain remission, toxicity, time-to-

Mitoxantrone + Prednisone As described above, the poor responses produced by cytotoxic chemotherapies in HRPC in terms of the traditional endpoints of tumor regression and prolongation of survival have prompted the development of alternative measures of response focusing on symptom control and palliation. A landmark phase III trial conducted in Canada was specifically designed to evaluate palliative endpoints. The combi-

TABLE 43–2. Results of Selected Phase II Trials of Estramustine-Based Combination for Hormone-Refractory Prostate Cancer Estramustine

Number of Patients

> 50% PSA Decline (%)

Number Partial Response/ Number Measured Disease

Improved Pain (%)

Median Survival (Months)

Docetaxel165 Paclitaxel81 Vinblastine78 Etoposide19 Epirubicin91

32 34 36 42 24

20/32 (63) 17/32 (53) 22/36 (61) 22/42 (52) 13/24 (54)

5/18 4/9 1/7 9/18 *

8/15 (53) * 12/28 (43) * 7/24(28)

22.8 17 11.5 10.5 *

*Not reported.


nation of mitoxantrone and prednisone was compared with prednisone alone in 161 HRPC patients with symptomatic disease.95 The primary endpoint was a palliative response defined as a 2-point decrease in pain as assessed on a 6point pain scale that was completed by patients. Secondary endpoints included the following: a decrease of at least 50% in the use of analgesic medication without an increase in pain; duration of response; and survival. A palliative response was observed in 23 of 80 patients (29% [95% CI, 19–40%]) who received mitoxantrone plus prednisone, and in 10 of 81 patients (12% [95% CI, 6–22%]) who received prednisone alone (p = .01). An additional seven patients in each group reduced analgesic medication by at least 50% without an increase in pain. The duration of palliation was longer in patients who received chemotherapy (median, 43 and 18 weeks; p < .0001, log-rank) (Figure 43–1). Eleven of 50 patients randomized to prednisone treatment responded after addition of mitoxantrone. Despite improved palliative effects in the mitoxantrone arm, there was no difference in overall survival (Figure 43–2). A subsequent analysis of the Canadian trial also demonstrated a significant slowing of progression for the mitoxantrone treated patients. Progression was defined as any symptomatic, laboratory (PSA or alkaline phosphatase), or diagnostic event (CT or bone scan). The median time-to-progression for the mitoxantrone and prednisone group was 131 days versus 69 days for the prednisone alone group (p = .0001)96 (Figure 43–3). The twenty-three responding patients, including 7 with initial ECOG performance status of 2 or 3, received a median of 10 cycles (range 3–18 cycles) of therapy. Fewer than 5% of patients treated with mitoxantrone experienced grade 3 or 4 hematologic toxicity and < 2% of 130 patients treated with mitoxantrone developed febrile neutropenia after 796 cycles of chemotherapy. Nausea and vomiting were rarely a problem, grade 3 or 4 toxicity occurring in 3 of 654 cycles of mitoxantrone (0.5%). There was no nausea or vomiting reported after 71% of the cycles. There was a 5.5% incidence of cardiac events in the 128 patients treated with mitoxantrone. Four patients had a decrease in left ventricular ejection

FIGURE 43–2. Canadian trial—actuarial survival.

fraction (LVEF) below normal, and three patients experienced congestive heart failure. A follow-up phase III trial conducted by the Cancer and Leukemia Group B (CALGB) confirmed the palliative benefits and survival results of the Canadian trial.97 The trial differed from the Canadian trial in that survival was the primary endpoint. Presence of pain was not required for study entry, and crossover to the mitoxantrone arm was not permitted. In addition, the mitoxantrone dose was somewhat higher (14 mg/m2), and hydrocortisone replaced prednisone as the corticosteriod. The economic costs of this intervention involving cytotoxic chemotherapy with a palliative endpoint were further evaluated using a detailed retrospective assessment of hospital admissions, outpatient visits, investigations, therapies (which included all chemotherapy and radiation), and palliative care.81 The mean total cost until death or last followup was less for the mitoxantrone prednisone arm versus the prednisone-only arm. The major proportion of cost for both arms was inpatient care. Initial therapy with mitoxantrone plus prednisone was consistently less expensive in whichever time period was used to compare costs. Costutility analysis showed mitoxantrone plus prednisone to be the preferred strategy, and this analysis showed that a 100

Mitoxantrone + Prednisone (n=23)

80

Prednisone alone (n=10)

60

Prednisone alone (n=81)

60

p=.27 (log rank)

40

p 10% decline and 13% of men experiencing a >25% decline.19 Anemia may be associated with symptoms such as dyspnea, fatigue, and weakness in over 10% of treated men. These symptoms have been shown to respond to administered recombinant human erythropoietin.19 Osseous Metastases Persistent bone pain in the back or hip region is one of the most common presenting symptoms of metastatic disease. The imaging modality of choice in this situation is the radionuclide bone scan. This will reveal the most common sites of spread to be the spine (74%, most commonly the lumbar and thoracic region), ribs (70%), pelvis (60%), femur (44%), and shoulder (41%). Demonstrable metastases are most commonly osteoblastic or mixed osteoblastic-osteolytic, with pure osteolytic comprising approximately 10% of lesions.20 Treatment of the prostate cancer patient who has osseous metastases is primarily palliative. The aim of therapy is to relieve pain, prevent pathologic fracture, and to improve mobility and functional status. This usually demands a multidisciplinary approach, involving a urologist, medical oncologist, radiotherapist, nurse, and pain control specialist. The mainstay of systemic treatment of the prostate cancer patient with osseous metastases is androgen deprivation. Approximately 80% of men with osseous metastases will have symptomatic improvement with androgen deprivation alone.21 Objective measurement of response constitutes decreased density in blastic lesions and sclerosis or recalcification of lytic lesions in sites corresponding to subjective improvement. Radiologic evidence of healing may not be evident for many months, making objective measurement difficult. Other indirect methods for evaluating response of osseous metastases to androgen deprivation may be more helpful. In a study of 57 men with osseous metastases receiving androgen deprivation for the first time, both the nadir level of PSA to within the normal range and a 90% or greater decline in PSA level were significant predictors of prolonged, progression-free survival.22 The average time to reach the nadir PSA level for those with more than a 90% decline was 5 months. Pretreatment predictors of favorable response include initial serum PSA level < 100 ng per mL, fewer than six metastatic deposits on bone scan, pretreatment testosterone level > 300 ng per dL, and serum alkaline phosphatase level < 115 IU.23,24 In a multivariate analysis of prognostic factors, patients with absence of bone pain, serum testosterone level > 8.6 nmol per L, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and alkaline phosphatase level < 115 IU, the 2-year survival rate was 84%, compared to 8% in the absence of these favorable parameters.24 The 2-year survival rate was 53% for patients with 1 or 2 favorable variables, an important observation since the majority of patients do not fit into either extreme.


Spinal Cord Compression and Other Complications of Osseous Metastases Complications of osseous metastases include spinal cord compression, seen ultimately in 10% of men with prostate cancer (which is second only to lung cancer as an etiologic cause), pathologic vertebral compression fracture, pathologic long bone fracture (most commonly of the femur and humerus), hypercalcemia, and bone marrow failure.25 Nearly all patients with complications of osseous metastases complain of pain.25,26 In the case of spinal cord and nerve root compression, decreased sensation usually precedes motor symptoms and may be detected on careful examination. Magnetic resonance imaging (MRI) is frequently used to evaluate spinal cord compression, due to its high sensitivity and ability to image the vertebral bodies and paraspinal and intraspinal soft tissues.27 On T1-weighted images, bone metastases tend to stand out as focal or diffuse hypointense (dark) lesions against a background of higher signal intensity marrow.27 Compared to myelography, MRI is noninvasive, directly visualizes cord compression, and can measure the extent of tumor outside the thecal sac along the entire cord. In the patient with spinal cord compression, outcome is most accurately determined by neurologic status at the time of presentation, making early diagnosis crucial. Of those patients who are ambulatory at presentation, the majority (60 to 100%) will remain so following therapy if it is instituted promptly.25,28 The recommended primary treatment in the setting of spinal cord compression remains controversial; radiation therapy appears preferable in most cases. Radiotherapy seems as beneficial as decompressive surgery, particularly in the individual with early spinal cord compression at a single level—both radiotherapy and laminectomy followed by radiotherapy show similar results.29,30 Surgery is generally reserved for selected patients who progress after initial treatment and for those with bone instability.31,32 Most often a direct posterior radiotherapy field is used, including a margin of one to two vertebral bodies above and below the area of compression. Conventionally, 20 to 30 Gy is delivered over 1 to 2 weeks, although single dose treatments delivering 10 to 15 Gy have been reported to show equivalent results.25,33 Radiation is preceded by corticosteroid administration, and a dexamethasone taper is frequently used.25 Corticosteroids have anti-inflammatory properties which reduce swelling and edema; they also suppress the pituitary production of ACTH, resulting in decreased adrenal steroid production (including the adrenal androgens androstenedione and dehydroepiandrosterone).34 Confirmation of the diagnosis of prostate cancer is ascertained. When necessary, needle biopsy of the prostate will provide a diagnosis, obviating the need for bone biopsy. In the patient who has not previously been treated with androgen deprivation, this is promptly

initiated. Bilateral scrotal orchiectomy is an attractive option due to its simplicity, relatively low cost, and uniform ability to achieve castrate levels of testosterone. In the rare patient who cannot undergo orchiectomy, ketoconazole, an imidazole antifungal agent, may be equivalent to orchiectomy in the acute period due to its rapid onset of action. Ketoconazole is administered orally 200 to 400 mg three times per day to inhibit both testicular and adrenal androgens. Its mechanism of action involves inhibition of the cytochrome P-450-dependent 14-demethylation step in the steroid synthesis pathway and may have a direct cytotoxic effect. Side effects of ketoconazole include hepatic dysfunction and gastrointestinal disturbances. The overall prognosis for the patient with spinal cord compression is poor. Reported median survival ranges from 6 to 12 months.35–37 In a recent report of 35 patients with suspected spinal cord compression, imaging studies in 26 demonstrated epidural spinal cord compression.25 Interestingly, in five patients this provided the first indication of prostate cancer. Ninety-six percent of patients presented with back pain; of twelve patients with back pain alone who were ambulatory, six had decreased sensation below the level of the lesion. Eleven patients were paraparetic, one was paraplegic, and one patient with a cervical lesion was quadriplegic. Nearly half the patients had varying degrees of urinary and bowel complaints. All patients were initially treated with steroids, androgen deprivation, and radiation therapy, and three ultimately underwent laminectomy. Radiation was found to be effective in all ambulatory patients and in 83% of paraparetic patients. Seven patients, however, experienced recurrent compression during the follow-up period. Of the patients presenting with paraplegia, only 20% regained function with radiation; despite surgical decompression, average survival was only 3.9 months in these patients.25 Similar poor results were reported in a study of 137 patients undergoing radiation therapy for advanced disease.38 In this cohort of men with hormone refractory prostate cancer, at a follow-up of 3 months, 29 had died of disease, and palliation was felt to be effective in only 25% of remaining patients.38 Pathologic fractures may involve the ribs, pelvis, scapula, and vertebrae, generally as a result of diffuse replacement of bone by tumor insufficient to bear applied loads. Long bone pathologic fracture occurs due to an osseous metastatic defect; when it involves the humerus or femur, it is most likely associated with an area of metastasis characterized by a 2.5 cm bone defect and > 50% destruction of cortex.39 Long bone fractures are best treated surgically when technically possible and appropriate. Predicting the pathologic risk of fracture at pain sites based on size of defect and cortical loss, followed by prompt administration of radiotherapy, may be an effective way of avoiding this debilitating complication. Pathologic fracture involving the vertebrae may result in neurologic symptoms and must be diagnosed

Prostate Cancer: Management of Complications of the Disease and Its Therapy / 449

and treated promptly, as previously discussed. As with all cases of spinal evaluation, MRI can reliably elucidate the cause of vertebral compression fracture.40 The appearance of the marrow of the involved vertebral body on T1-weighted imaging (i.e., complete replacement, incomplete replacement, complete preservation) and the pattern of abnormality can be used to distinguish benign and malignant compression fractures in most cases.40 In all cases involving neurologic symptoms, it is important to differentiate between disorders caused by bone infiltration and those caused by intrinsic brain metastases. In rare cases, bony skull base metastases will result in nerve entrapment and cranial nerve palsies.41,42 The most commonly involved nerves are the fifth, sixth, and seventh cranial nerves. Skull base irradiation may result in significant symptomatic improvement in select cases and symptom improvement in over 50% of patients, durable in 80% of respondents.43 Management of Pain from Osseous Metastases Radiation therapy is used to manage symptomatic bone metastases that are unresponsive to androgen deprivation. For the patient with one or a few sites of localized pain secondary to osseous metastases, local radiotherapy may be administered. The optimal dose/fractionation scheme is not clearly defined although local radiotherapy is most often administered in several fractions of 3 Gy each. If so treated, approximately 75% of treated patients will experience effective pain control for up to 6 months without serious hematologic or gastrointestinal side affects.44 Wide-field therapy may be administered for patients with multiple painful bony metastases. This is most frequently administered as hemibody radiotherapy, usually as a single dose (6 to 8 Gy). Pain relief will occur within a few days in up to 70% of patients.45,46 Fractionated hemibody radiotherapy (30 Gy per 10 fractions) has been evaluated in this application.47 In a phase II study, fractionated hemibody radiotherapy was associated with improved pain control at 1 year (70% versus 15%) and decreased requirement for retreatment (13% versus 71%).47 Alternatively, when multiple metastatic bony sites exist, administration of systemic bone-seeking isotope therapy such as strontium-89 (89Sr) may be employed.48 This is a radiopharmaceutical that localizes to bone following intravenous administration. As a beta-emitting isotope, 89Sr localizes to areas of increased mineral turnover and decays with an approximate 40-day half-life. Evidence of the effect of 89Sr comes from a double-blind placebo controlled trial.49 In this study, improvement in symptoms was observed in 75% of the patients treated with 89Sr. Pain relief occurred 2 to 4 weeks following administration and reached maximal effect at 4 to 12 weeks. Results with 89Sr appear to be similar to those obtained with hemibody radiotherapy. Hematologic toxicity is similar with both treatments although nausea, vomiting, and diarrhea are

generally not seen with 89Sr. Effectiveness of palliative radiotherapy appears to correlate with extent of disease at the time of treatment and is often difficult to measure due to problems in controlling for physician-based scoring systems, accounting for concurrent changes in analgesics, and controlling for simultaneous therapies. Conventional methods of pain control become increasingly important as the disease advances and the patient becomes hormone refractory. In such cases, maintenance of primary testicular androgen ablation should be continued despite the patient’s “hormone refractory status.”50 In patients treated with total androgen blockade, the antiandrogen should be withdrawn. This is based on the observation that up to 50% of patients will experience a decrease in serum PSA level and stabilization of disease.51,52 In patients not receiving an antiandrogen, such an agent may be added with the potential for objective response rate in 15 to 20% of patients.53 Despite these steps being taken, patients with hormone refractory disease will ultimately experience pain and require pain management. To address this, the World Health Organization has developed guidelines for pain treatment through use of a pain ladder.54 First-line therapy is with nonsteroidal agents. Nonsteroidal antiinflammatory agents (ibuprofen, 600 to 800 mg every 6 to 8 hours) may relieve symptoms of inflammation associated with tumor growth and fracture and may involve the prostaglandins pathway.54 When required, an opiate is added to the anti-inflammatory agent. Opioids are administered around the clock, with tolerance overcome by an increasing dose. Advances in transdermal application of opioids (i.e., fentanyl) have made this approach extremely useful. Antidepressants are often used in concert with opioid therapy for maximal effect, particularly in cases of neuropathic pain states. Antidepressants are also useful in relieving the anxiety and clinical depression experienced by many patients with advanced disease.55 Urinary Manifestations of Disease Urinary symptoms such as retention of urine and hematuria can result from local disease progression and may be treated with cystoscopy and transurethral resection or fulguration. Ureteral obstruction may be treated with either percutaneous nephrostomy or internal stenting, but these procedures are associated with discomfort, infection, and other tube-related problems (nephrostomy obstruction, dislodgement and bleeding, and the need for periodic tube change). Frequent visits to the emergency ward, hospitalization, and heightened patient anxiety may result and must be weighed when considering these treatments. Anemia In patients with diffuse osseous metastases, replaced marrow results in decreased blood-cell counts. This is aggravated by the myelosuppressive effects of radiotherapy, the


anemia of androgen deprivation, and in some cases, hematuria due to local progression. Anemia is generally not acute in most cases, and very low hemoglobin levels may be tolerated by the patient. The physician should remain astute to the potential role of transfusion, particularly in the symptomatic patient. Anorexia and Cachexia Anorexia and cachexia will affect over half of patients with advanced disease. Treatment often consists of a series of nutritional supplements and pharmacologic agents, most commonly megestrol acetate (800 mg per day) and dronabinol (2.5 mg twice to three times per day).55 Hospice Care The primary goal of hospice care is palliation of the cancer patient with a life expectancy under 6 months. One significant advantage of hospice care is that it can be delivered in the patient’s home. More than 200,000 Medicare beneficiaries enter hospice programs annually; in one recent review, prostate cancer patients comprised 7.4% of enrolled individuals.56 Among prostate cancer patients, median survival was 46 days, with 14% expiring within 7 days of enrollment and 13.7% living more than 180 days following enrollment.

Conclusion The clinician must bring a working knowledge of the anticipated progression of prostate cancer, available therapies, and potential complications of both the disease and its therapies to bear on decisions concerning treatment for patients with this disease.

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9. Partin AW, Yoo J, Carter HB, et al. The use of prostatespecific antigen, clinical stage, and Gleason score to predict pathologic stage in men with localized prostate cancer. J Urol 1993;150:110–4. 10. Chybowski FM, Keller JJL, Bergstralh EJ, Oesterling JE. Predicting radionuclide bone scan findings in patients with newly diagnosed, untreated prostate cancer: prostate-specific antigen is superior to all other clinical parameters. J Urol 1991;145:313–8. 11. The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council trial. Br J Urol 1997; 79:235–46. 12. Herr HW, Kornblith AB, Ofman U. A comparison of the quality of life of patients with metastatic prostate cancer who received or did not receive hormonal therapy. Cancer 1993;71:1143–50. 13. Daniell HW. Osteoporosis after orchiectomy for prostate cancer. J Urol 1997;157:439–44. 14. Levis S, Kim C, Roos BA, Krongrad A. Do estrogens protect against bone loss in men treated for prostate cancer? Proceedings of the 76th Annual Meeting of the Endocrine Society; Anaheim CA 1994. The Endocrine Society, Bethesda, MD p. 1565. 15. Stepan JJ, Lachman M, Zverina J, et al. Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling. J Clin Endocrinol Metab 1989;69:523–7. 16. Clarke NW, McClure J, George NJ. The effects of orchiectomy on skeletal metabolism in metastatic prostate cancer. Scand J Urol Nephrol 1993;27:475–83. 17. Weber JP, Walsh PC, Peters CA, Spivak JL. Effect of reversible androgen deprivation on hemoglobin and serum immunoreactive erythropoietin in men. Am J Hematol 1991;36:190–4. 18. Eri LM, Tveter KJ. Safety, side effects, and patient acceptance of the luteinizing hormone–releasing hormone agonist leuprolide in the treatment of benign prostatic hyperplasia. J Urol 1994;153:448–52. 19. Strum SB, McDermed JE, Scholz MC, et al. Anemia associated with androgen deprivation in patients with prostate cancer receiving combined hormonal blockade. Br J Urol 1997;79:933–41. 20. Wilner D. Radiology of bone tumors and allied disorders. Vol 4. Philadelphia: WB Saunders; 1982. 21. Denis L. Prostate cancer. Primary hormonal treatment. Cancer 1993;71:1050–8. 22. Matzkin H, Eber P, Todd B, et al. Prognostic significance of changes in prostate-specific markers after endocrine treatment of stage D2 prostatic cancer. Cancer 1992;70: 2302–9. 23. Matzkin H, Perito PE, Soloway MS. Prognostic factors in metastatic prostate cancer. Cancer 1993;72:3788–92. 24. Chodak GW, Vogelzang NJ, Caplan RJ, et al. Independent prognostic factors in patients with metastatic (stage D2) prostate cancer. JAMA 1991;265:618–21. 25. Hoskin PJ. Radiotherapy in the management of bone pain. Clin Orthop 1995;312:105–9. 26. Smith EM, Hampel N, Ruff RL, et al. Spinal cord compression secondary to prostate carcinoma: treatment and prognosis. J Urol 1993;149:330–3.

Prostate Cancer: Management of Complications of the Disease and Its Therapy / 451 27. Traill Z, Richards MA, Moore NR. Magnetic resonance imaging of metastatic bone disease. Clin Orthop 1995; 312:76–88. 28. Bruckman JE, Bloomer WD. Management of spinal cord compression. Semin Oncol 1978;5:135–40. 29. Findlay G. Adverse effects of the management of malignant spinal cord compression. J Neurol Neurosurg Psychiatry 1984;47:761–8. 30. Barcena A, Lobato RD, Rivas JJ, et al. Spinal metastatic disease: analysis of factors determining functional prognosis and the choice of treatment. Neurosurgery 1984;15:820–7. 31. Moore AJ, Uttley D. Anterior decompression and stabilization of the spine in malignant disease. Neurosurgery 1989;24:713–7. 32. Siegal T, Siegal T. Surgical decompression of anterior and posterior malignant epidural tumours compressing the spinal cord: a prospective study. Neurosurgery 1989;17: 424–32. 33. Makin WP. Management of spinal cord compression due to metastatic disease. First International Consensus Workshop on Radiation Therapy in the Treatment of Metastatic and Locally Advanced Cancer; 1990; Washington (DC); Abstract 3A-7. 34. Plowman PN, Perry LA, Chard T. Androgen suppression by hydrocortisone without aminoglutethimide in orchiectomized men with prostate cancer. Br J Urol 1987;59:255–7. 35. Kuban DA, El-Mahdi AM, Sigfred SV, et al. Characteristics of spinal cord compression in adenocarcinoma of prostate. Urology 1986;28:364–9. 36. Flynn DF, Shipley WU. Management of spinal cord compression secondary to metastatic prostatic carcinoma. Urol Clin North Am 1991;18:145–52. 37. Zelefsky JM, Scher HI, Krol G, et al. Spinal epidural tumor in patients with prostate cancer. Cancer 1992;70: 2319–25. 38. Fossa SD. Quality of life after palliative radiotherapy in patients with hormone-resistant prostate cancer: single institution experience. Br J Urol 1994;74:345–51. 39. Hipp JA, Springfield DS, Hayes WC. Predicting pathologic fracture risk in the management of metastatic bone defects. Clin Orthop 1995;312:120–35. 40. Yuh WT, Zachar CK, Barloon TJ, et al. Vertebral compression fractures: distinction between benign and malignant causes with MR imaging. Radiology 1989;172: 215–8. 41. Cousin GC, Ilankovan V. Mental nerve anaesthesia as a result of mandibular metastases of prostatic adenocarcinoma. Br Dent J 1994;177:382–4.

42. Ransom DT, Dinapoli RP, Richardson RL. Cranial nerve lesions due to base of the skull metastases in prostate carcinoma. Cancer 1990;65:586–9. 43. Vikram B, Chu F. Radiation therapy for metastases to the base of the skull. Radiology 1979;130:465–8. 44. Price P, Hoskin PJ, Easton D, et al. Prospective randomized trial of single and multifraction radiotherapy schedules in the treatment of painful bone metastases. Radiother Oncol 1986;6:247–55. 45. Hoskin P, Ford HT, Harmer CL. Hemibody irradiation (HBI) for metastatic bone pain in two histologically distinct groups of patients. Clin Oncol 1989;1:67–9. 46. Kuban D, Delbridge T, El-Mahdi AM, Schellhamer PF. Halfbody irradiation for treatment of widely metastatic adenocarcinoma of the prostate. J Urol 1989;141:572–4. 47. Zelefsky MJ, Scher HI, Forman JD, et al. Palliative hemiskeletal irradiation for widespread metastatic prostate cancer: a comparison of single dose and fractionated regimens. Int J Radiat Oncol Biol Phys 1989; 17:1281–5. 48. Crawford ED, Kozlowski JM, Debruyne FMJ, et al. The use of strontium-89 for the palliation of pain from bone metastases associated with hormone-refractory prostate cancer. Urology 1994;44:481–5. 49. Lewington VJ, McEwan AJ, Ackery DM, et al. A prospective, randomized double-blind crossover study to examine the efficacy of strontium-89 in pain palliation in patients with advanced prostate cancer metastatic to bone. Eur J Cancer 1991;27:954–8. 50. Taylor CD, Elson P, Trump DL. Importance of continued testicular suppression in hormone refractory prostate cancer. J Clin Oncol 1993;11:2167–72. 51. Dupont A, Gomez JL, Cusan L, et al. Response to flutamide withdrawal in advanced prostate cancer in progression under combination therapy. J Urol 1993;150: 908–13. 52. Kelly WK, Scher HI. Prostate-specific antigen decline after antiandrogen withdrawal: the flutamide withdrawal syndrome. J Urol 1993;149:607–9. 53. Labrie F, Dupont A, Giguere M, et al. Benefits of combination chemotherapy with flutamide in patients relapsing after castration. J Urol 1988;61:341–6. 54. Esper PS, Pienta KJ. Supportive care in the patient with hormone refractory prostate cancer. Semin Urol Oncol 1997;15:56–64. 55. Jacobsen PB, Breitbart W. Psychosocial aspects of palliative care. Cancer Causes Control 1996;3:214–21. 56. Christakis NA, Escarce JJ. Survival of medicare patients after enrollment in hospice programs. N Engl J Med 1996;335:172–8.

CHAPTER 50

RANDOMIZED CLINICAL TRIALS IN PROSTATE CANCER TIMOTHY J. WILT, MD, MPH Randomized clinical trials (RCTs) are considered the gold standard scientific design for evaluating medical interventions. More than any other methodology, RCT can have a powerful and immediate impact on patient care. These trials compare interventions that are assigned to participating patients, using a random process.1 Because allocation of subjects to the different intervention groups is without bias, the groups can be expected to be comparable in measured and unmeasured risk factors. Any differences in the outcomes between groups can be said to be due to the assigned intervention rather than other extraneous factors. Randomized clinical trials provide the unbiased information required for evidence-based prostate cancer prevention, detection, and treatment. Despite their clinical importance, conducting randomized trials in prostate cancer has proven difficult. Opponents of RCTs contend that such studies are unnecessary, unethical, unfeasible, and unlikely to provide reliable answers for practitioners,2 and that problems with design, execution, and analysis can threaten the validity of RCTs. Conducting RCT in prostate cancer is difficult but feasible and necessary. Enhancing awareness and participation in randomized trials can promote delivery of high-quality prostate cancer care. However, clinicians, researchers, and patients often have difficulty identifying and evaluating relevant prostate cancer trials in an efficient manner. In this chapter, methods to identify, conduct, report, and evaluate RCTs will be described and their importance along with systematic reviews will be highlighted. A summary of the principal trials that are ongoing or in planning is included as well as factors related to completion of RCTs.

pretation of the results of existing trials and encourage high standards in the design, conduct, and reporting of future trials.3 The CONSORT guidelines recommend that trialists report the hypotheses to be tested, the sample studied, and the process of randomization, account for and describe all randomly assigned participants, and provide information on either primary endpoints for binary outcomes or estimates of mean and variance for continuous data (Table 50–1). Secondary endpoints, subgroup analysis, or multiple evaluations of a primary endpoint should be identified. To account for multiple comparisons and reporting of subgroup outcomes that are statistically significant only due to chance, the traditional measure of significance (i.e., p < .05) should be adjusted to a more conservative estimate (e.g., p < .05 divided by the number of comparisons made). This is especially important in trials that have shown little or no benefit in the primary outcomes. “Intention-to-treat” rather than “treatment-received” analysis should be used because it minimizes bias and preserves the between-arm comparability created through the random assignment. Additionally, clinicians should determine if a small but statistically significant outcome difference is clinically meaningful and if a study reporting no statistically significant differences was of sufficient size or duration to exclude clinically meaningful differences. The CONSORT guidelines and requests for submission of results from completed but unpublished trials are important because many trials withhold negative findings (publication bias) leading to overestimation of treatment efficacy.4 Other trials fail to report clinically relevant data or highlight changes in intermediate endpoints that do not fulfill the definition of surrogate endpoints.5 A recent consensus conference of the American Urological Association (AUA) Treatment Guidelines Panel has recommended that phase III prostate cancer trials should use all-cause survival as the primary endpoint.5 Clinically relevant secondary endpoints include disease-specific survival, quality of life, and treatment-related morbidity (Table 50–2). Surrogate endpoints must capture all relationships, both beneficial and adverse, between the treatment and the survival endpoint. Additionally, standard definitions of disease progression should be used (Table 50–3).

Design, Analysis, and Reporting of Randomized Clinical Trials Randomized trials can only appropriately influence clinical practice if they are well designed and conducted and their results reported systematically and in adequate detail. The goal of the Consolidated Standards of Reporting Trials (CONSORT) guidelines is to improve the design, analysis, and reporting of clinical trials. These guidelines should enhance the identification and inter452

Randomized Clinical Trials in Prostate Cancer / 453 TABLE 50–1. Consolidated Standards of Reporting Trials: CONSORT Guidelines Heading Title Abstract Introduction Methods

Subheading

Protocol

Assignment

Masking (Blinding) Results

Comment

Participant flow and follow-up analysis

Descriptor Identify the study as a randomized trial. Use a structured format. State prospectively defined hypothesis, clinical objectives, and planned subgroup or covariate analyses. Describe: planned study population, together with inclusion/exclusion criteria, planned interventions and their timing, primary and secondary outcome measure(s), the minimum important difference(s) and indicate how the target sample size was projected, rationale and methods for statistical analyses, detailing main comparative analyses and whether they were completed on an intention-to-treat basis, prospectively defined stopping rules (if warranted). Describe: unit of randomization (e.g., individual, cluster, geographic), method used to generate the allocation schedule, method of allocation concealment and timing of assignment, method to separate the generator from the executor of assignment. Describe mechanism (e.g., capsules, tablets); similarity of treatment characteristics (e.g., appearance, taste); allocation schedule control (location of code during trial and when broken); and evidence for successful blinding among participants, person doing intervention, outcome assessors, and data analysts. Provide a trial profile summarizing participant flow, numbers and timing of randomization assignment, interventions, and measurements for each randomized group. State estimated effect of intervention on primary and secondary outcome measures, including a point estimate and measure of precision (confidence interval). State results in absolute numbers when feasible (e.g., 10 of 20, not 50%) Present summary data and appropriate descriptive and inferential statistics in sufficient detail to permit alternative analyses and replication. Describe prognostic variables by treatment group and any attempt to adjust for them. Describe protocol deviations from the study as planned, together with the reasons. State specific interpretation of study findings, including sources of bias and imprecision (internal validity) and discussion of external validity, including appropriate quantitative measures, when possible.

Many RCTs use intermediate endpoints such as prostate-specific antigen (PSA) response as a primary measure of treatment efficacy because disease progression in the absence of PSA progression is rare. However, considerable information demonstrates that PSA has no role as a surrogate marker for survival and is not ideal for evaluation of disease progression or persistence.5,6 Other RCTs report reduction in pain control requirements in men with metastatic prostate cancer without adequately addressing whether interventions improve quality of life and reduce treatment-related morbidity and costs. If widely implemented, the CONSORT and AUA Treatment Guidelines Panel recommendations should improve identification of ongoing and completed trials and provide the data required for interpretation of study findings.

Identifying Ongoing and Completed Randomized Clinical Trials Several sources are available to facilitate the identification of ongoing and completed RCTs (Table 50–4). The Clinical Trials Referral Resource of the National Cancer Institute is designed to serve as a ready reference for physicians to help identify and enhance accrual to ongoing trials that might be suitable for their patients.7 A recent review outlined important areas in prostate cancer prevention and

treatment8 and provided contact names and phone numbers of randomized and nonrandomized clinical trials. The Physicians Data Query (PDQ) is a computerized database service provided by the National Cancer Institute (NCI) that contains cancer information summaries, listings of ongoing treatment, supportive care, screening, and prevention clinical trials.9,10 It serves as a directory of physicians and organizations involved in cancer care. The summary includes the study title, objectives, and detailed eligibility criteria for trials that are actively accruing participants. Each clinical trial summary is indexed for the type of cancer (including stage), the interventions and drugs being used, and the study phase. The summary is augmented with a listing of organizations where the trial is taking place and its principal investigators. Clinical trials in PDQ are also searchable by state/province, city, postal code, or country. The PDQ Backfile (PDQ-B) is a valuable resource for identifying ongoing or completed trials that are no longer accepting patients. It also provides a list of publications related to these trials. However, it does not describe whether the trial has reached its accrual goal and is still following up patients or whether the follow-up has been discontinued. The National Institutes of Health (NIH) and the Food and Drug Administration are developing a registry of trials involving investigational drugs used to treat life-threatening conditions. This will provide an important source for iden-

454 / Advanced Therapy of Prostate Disease Table 50–2. Summary and Conclusions of the AUA Treatment Guidelines Panel • Overall survival is the simplest and most desired endpoint. • Overall survival should be reported in all randomized trials involving prostate cancer. • All randomized trials involving localized prostate cancer must be adequately powered to assess the effect of treatment on overall survival. • Randomized trials must include measures of efficacy, toxicity, and quality of life. • Standards for the ascertainment of cause of death should be established and validated. • Intermediate endpoints, including clinical and biochemical failure, may be used to assess treatment effect. • No intermediate endpoints are currently known to be valid surrogate endpoints for survival in localized prostate cancer. • The choice of trial endpoints should be tailored to the trial hypothesis.

tification of ongoing prostate cancer trials, especially small or industry-sponsored studies. These studies are frequently not registered during patient enrollment and follow-up. Additionally, studies are less likely to be reported if their results are not positive (i.e., publication bias).11 Any clinical trial listed in PDQ must first undergo review. All NCI- or NIH-funded trials are included. Clinical trials being conducted through the European Organization for the Research and Treatment of Cancer (EORTC) or the Cancer Research Campaign of the United Kingdom (UK-CRC) as well as phase II and phase III clinical trials that have been submitted to the Food TABLE 50–3. Definitions of Disease Progression • Asymptomatic local disease progression/persistence – New or enlarging mass on DRE, TRUS, or other imaging modality – Biopsy-proven tumor after RP or XRT • Symptomatic local disease progression – Hematuria secondary to prostate cancer progression – Bladder outlet obstruction due to prostate cancer progression • Asymptomatic regional disease progression – Hydronephrosis on imaging study. Creatinine elevation to twice baseline or secondary to regional progression • Symptomatic regional disease progression – Pelvic pain secondary to prostate cancer – Lymphedema secondary to prostate cancer • Asymptomatic metastatic disease progression – Changes in laboratory tests due to prostate cancer including Hgb < 10.0; abnormal AST, PAP, bilirubin – Radiologic evidence of metastatic disease including bone and chest radiographs or abdominal CT/MRT • Symptomatic metastatic disease progression – Bone pain secondary to prostate cancer – Decrease in functional status category due to prostate cancer – Other symptoms (e.g., weakness, nausea, confusion) that in the opinion of the investigator are judged to be due to metastatic CaP • Asymptomatic progression of tumor biomarkers – Increasing or persistent PSA – Abnormal prostatic acid phosphatase DRE = digital rectal examination; TRUS = transrectal ultrasonography; RP = radical prostatectomy; XRT = radiotherapy; Hgb = hemoglobin; AST = aspartate transaminase; PAP = prostatic acid phosphatase; CT = computed tomography; MRT = magnetic resonance tomograghy; CaP = prostate cancer; PSA = prostate-specific antigen.

and Drug Administration under the Investigational New Drug (IND) regulations have undergone peer review and are included. Studies not meeting these criteria can be submitted for review and possible inclusion. Access to PDQ can be obtained via its web site at: cancernet.nci.nih.gov/pdq.htm.9 The PDQ/CANCERLIT Service Center can provide customized searches at 1-800345-3300 or e-mail: [email protected]. Patients and families can obtain trial information by calling the NCI’s Cancer Information Service at 1-800-4-CANCER. As of December 1998, 96 clinical trials were listed in the PDQ related to prostate cancer including 28 phase III randomized trials. There were 78 phase III treatment RCTs listed in PDQ-B. Hopefully, these sources will stimulate the reporting of all initiated RCTs, regardless of funding source and results.

Role of Systematic Review of RCTs in Prostate Cancer Management Systematic reviews assemble the results of primary investigations, using strategies to limit bias and random error. They are useful for health care providers and consumers because they efficiently integrate unmanageable amounts of information and provide data for rational decision making.12 Systematic reviews establish whether scientific findings are consistent and can be generalized across populations, settings, and intervention variations, or whether findings vary significantly by particular subsets. Metaanalyses are quantitative summaries and statistic pooling from individual, comparable studies that enable the effect of an intervention to be determined as precisely as possible. By using predefined explicit methods, high-quality systematic reviews improve the reliability and accuracy of results compared with traditional narrative reviews. Systematic reviews are also helpful in identifying gaps in existing evidence and recommending future trials that are required to close these knowledge gaps. The Cochrane Collaboration is an international network of individuals and institutions committed to conducting, maintaining, and promoting the accessibility of systematic reviews of the effects of health care.13,14 The TABLE 50–4. Sources of Information regarding Ongoing or Completed Prostate Cancer Trials Physicians Data Query • Website: http://cancernet.nci.nih.gov/pdq.htm • Phone: 800-345-3300 • E-mail: [email protected] Cochrane Review Group in Prostate Diseases and Urologic Malignancies • Website: http://hiru.mcmaster.ca/cochrane/centres/sanant_1/default.htm • Phone: 612-725-2158 Ext. 1666 • E-mail: [email protected] Prostate Cancer Trialists Collaborative Group • Phone: (+31) 20-512 2665 • E-mail: [email protected]

Randomized Clinical Trials in Prostate Cancer / 455

Collaboration produces the Cochrane Library, a unique collection of databases providing reliable information, to guide effective health care decisions. It includes full text and graphs of original updated systematic reviews produced by the Cochrane Collaboration, structured abstracts of high-quality published reviews, the most complete register available of controlled trials (assembled in part by diligently searching the world’s literature), and a bibliography on the science of systematic reviews and critical appraisal. The VP Prostate Diseases and Urologic Malignancies Cochrane Review Group maintains a registry of controlled trials in prostate cancer and conducts and disseminates systematic reviews relevant to prostate cancer prevention, detection, treatment, and rehabilitation. An example of one systematic review is an evaluation of evidence from randomized clinical trials on the relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostate cancer.15 This review identified, evaluated, synthesized, and disseminated a vast amount of clinically relevant information from over 50 randomized trials. Three key issues were addressed: (1) the relative effectiveness of the available methods for monotherapy (orchiectomy, luteinizing hormone–releasing hormone [LHRH] agonists, and antiandrogens) (24 trials were included); (2) the effectiveness of combined androgen blockade compared to monotherapy (27 trials were included); and (3) the effectiveness of immediate compared with deferred androgen suppression in three patient populations: (a) androgen suppression initiated at PSA rise compared with androgen suppression deferred until clinical signs or symptoms of progression (no trials included); (b) androgen suppression initiated at diagnosis, with primary androgen suppression deferred until clinical progression (3 trials were included); and (c) adjuvant androgen suppression initiated with radiotherapy (4 trials were included). The results demonstrated that (a) survival after treatment with an LHRH agonist is equivalent to survival after orchiectomy and that no one LHRH agonist is superior to another; (b) there is no statistically significant difference in survival at 2 years between patients treated with combined androgen blockade or monotherapy; and (c) no evidence is yet available from randomized clinical trials of androgen suppression initiated at PSA rise after definitive therapy for clinically localized disease. The review provides clinicians, researchers, patients and policymakers with a concise evidence-based assessment of the effects of androgen suppression on advanced prostate cancer. It also identifies the gaps in knowledge and recommends steps for future investigation.

Why Randomized Trials in Prostate Cancer Are Difficult to Conduct Difficulty in conducting prostate cancer treatment trials may be due to factors related to the disease, physician,

patient, and trial design (Table 50–5).16–21 Not all are unique to trials in prostate cancer. For example, fewer than 3% of all newly diagnosed cancer patients participate in randomized trials. The lack of volunteers thwarts much of cancer research. A better understanding of factors associated with enrollment into cancer trials is required to ensure future success. Factors related to prostate cancer and its treatment include the fact that prostate cancer has a relatively indolent natural history. Trials of long duration are generally required. The primary treatments appear to have relatively small efficacy, at best, and so large sample sizes involving multiple research centers are required to evaluate this efficacy with any degree of confidence. Furthermore, the invasiveness and adverse events associated with treatment options (surgery, radiation, surveillance, and chemotherapy) are quite varied. Both patients and physicians have difficulty accepting treatment determination by random allocation. Several physician-based factors have been shown to hinder accrual and may explain recruitment difficulties.2,16–18 These include lack of awareness of or access to clinical trials; physician bias that the trial therapy is not as good as the “standard therapy,” physician concern about losing patients to follow-up, and complexity of clinical trials; lack of equitable compensation for physician’s time and effort; concern that the doctor-patient relationship would be affected by a randomized trial; difficulty with informed consent; dislike about open discussions involving uncertainty; insufficient training in recruitment and adherence techniques, and conflict between the roles of scientist and clinician. Investigators must also contend with the firmly held beliefs of physicians in their respective discipline, the economics related to prostate cancer detection and treatment, and the fact that training programs rely on large numbers of cases. In the absence of scientifically valid data, patients’ treatment decisions are heavily influenced by information provided by family members, friends, advocacy groups, print and electronic media, and industrysponsored programs. Eligible candidates develop strong treatment preferences, distrust the randomization process, and decline enrollment. Political, economic, legal, and interest group concerns as well as the use of military language, i.e., “war metaphors,” affect treatment decisions for prostate cancer and many malignancies.22 Factors affecting a patient’s decision to participate include the ability to retain control over their treatment decision; advice provided by family, friends, physicians, and men with prostate cancer (including study enrollees); opportunity to obtain new treatments; close monitoring by doctors with special interest in prostate cancer; opportunity to contribute to scientific knowledge; and potential benefit to others, especially family members.19,20


Enhancing Recruitment and Retention in Randomized Clinical Trials Enhancing recruitment and retention requires a cooperative effort and a shift in the perceptions of the public and the medical profession regarding RCTs. There must be an understanding that RCTs provide high-quality, evidencebased health care. Randomized clinical trials are ethical, necessary, and feasible. The only way to obtain reliable answers regarding treatment of prostate cancer is through completion of randomized trials. Recruitment and retention are improved if the physician is committed to the scientific and clinical equipoise of the study; emphasis is placed on the importance and benefits of study participation; training is provided in physician/coordinator-patient recruitment skills including discussion regarding treatment uncertainty; wide TABLE 50–5. Factors Affecting Conduct of Randomized Trials in Prostate Cancer Disease factors • Relatively indolent natural history • Treatments have relatively small efficacy at best • Difficulty in assessing objective responses to treatment • Invasiveness of treatment options vary (surgery, radiation, surveillance, chemotherapy) • Cancer stigmata (use of military metaphors in cancer treatment) • Reluctance to allow cancer treatment to be determined by randomization Physician factors • Lack of awareness of or access to clinical trials • Physician bias that the trial therapy is not as good as the “standard therapy” • Physician concern about losing patients to follow-up • Lack of equitable compensation for physician’s time and effort • Concern that the doctor-patient relationship would be affected by a randomized trial • Difficulty with informed consent • Dislike of open discussions involving uncertainty • Inadequate training provided in physician/coordinator-patient recruitment skills • Conflict between the roles of scientist and clinician • Economics related to prostate cancer detection and treatment • Training programs rely on large number of cases Patient factors • Ability to retain control over treatment • Advice from family, friends, physicians, and men with prostate cancer (including enrollees) • Opportunity to obtain new treatments • Close monitoring by doctors with special interest in prostate cancer • Opportunity to contribute to scientific knowledge • Potential benefit to others, especially family members Study factors • Complexity of trial design • Clarity and organization of study protocol • Use of European Community Good Clinical Practice Guidelines • Long trial duration required • Large sample sizes required • Adequate funding • Adequate and effective publicity • Complexity and importance of study question • Therapy selected by random allocation rather than “patient preference”

interdisciplinary awareness of and collaboration with the protocol exists; there is adequate time to inform patients and their families; funding is available to support study personnel; and trial chairpersons maintain the enthusiasm of the research personnel and participants during the study follow-up period. Recruitment is unlikely if the primary discussion about treatment and enrollment is provided by a non–study physician (e.g., a physician-intraining) or is delayed until a person has developed a strong treatment preference, or the patient is referred specifically to receive a particular therapy. A protocol that is overly complex, excludes large numbers of potential subjects, or offers multiple treatment options is also likely to hinder recruitment. Active recommendations should be made to men to participate in randomized trials. Encouraging enrollment provides high-quality medical care. Randomized trials include treatment options that are at least as good as standard practice and which the current evidence indicates are equally effective. The design, conduct, and interim results of randomized trials are under closer scrutiny regarding clinical necessity, safety, and ethics than medical care provided in a non–study setting. Choosing to join randomized trials offers participants the benefits of receiving personalized, state-of-the-art health care from experts in prostate cancer. Participants are providing valuable information for future generations, including their sons and grandsons, who may face similar decisions. Enrolling in a randomized trial is an excellent treatment choice and is recommended by many scientific and lay organizations. New but unproven treatments are frequently believed to be superior to existing alternatives. However, therapeutic decisions that rely on clinical judgment or anecdotal experience, rather than evidence from RCTs use information of uncertain validity.23 Therefore, treatment according to “preference” is similar to selecting treatment by a “best guess” or “flip-of-the-coin.” Preferences for treatments should be based on beliefs that are founded on reliable information. If presented in this fashion, the proportion of well-informed people who have no strong preferences and thus would be willing to participate in RCTs should increase.21 Similar to trials conducted in other cancers, results from prostate cancer trials are sometimes inconclusive and the relative benefits of different treatments are still unknown.24 Several factors related to the quality of planning, conduct, analysis, and reporting of trials and to the lack of orderly development in the evaluation of various treatment regimens may be responsible for this inconclusiveness. Trial directors and participating investigators must commit themselves to the time and effort these studies require. Directors of randomized trials should seek feedback from clinicians, patients, and medical organizations


so that randomized trials are designed to appropriately address questions and outcomes of greatest clinical interest.25–27 A carefully constructed protocol is essential. The available evidence regarding treatment outcomes should be incorporated to ensure that the investigated treatments are at least as good as standard therapy. In some instances, an untreated control arm should be used if there is lack of proof of active treatment efficacy. This helps to prevent the premature abandonment of potentially promising combinations or the unjustified testing of excessively complex or toxic treatments. The trials should be operationally simple to conduct and well publicized. Recruitment and adherence training and materials should be provided to investigators and coordinators. Focus groups can assist in developing trialspecific information brochures, videotapes, and computer websites, targeted to patients and their families. The results must be generalizable, and the study should be of adequate size and duration to assess clinically important differences in outcomes, including mortality and quality of life. Funding agencies need to provide sufficient resources for the time-intensive task of patient accrual and show patience with the duration of time required to recruit and follow prostate cancer patients.

Review of Ongoing Randomized Clinical Trials The PDQ and Cochrane Data Bases provide the most complete and up to date listings of ongoing and recently completed randomized trials. The reader is referred to these for a listing of prostate cancer trials. The PDQ also includes information regarding patient eligibility and contact details. Unfortunately, many industry-sponsored or smaller studies remain unreported and are not included on these databases. A summary of studies attempting to address important questions in areas of prostate cancer prevention, detection, and treatment will be provided. The recommendations of the AUA Practice Guidelines Panel for Prostate Cancer Trial for conduct and endpoint assessment should be incorporated5,28 (see Tables 50–2 and 50–3). Prostate Cancer Prevention An ideal method to reduce prostate cancer mortality and morbidity would be through primary prevention, either through a reduction in the number of life-threatening, clinically evident cases or through a reduced age-dependent rate of development of the disease. One attractive agent for prevention has been suggested by studies indicating that development and progression of prostate cancer is androgen dependent. Finasteride causes a reduction in dihydrotestosterone levels and inhibits growth of prostate cancer cells in vitro. The Prostate Cancer Prevention Trials (PCPT) is a 7-year chemoprevention trial sponsored by the NCI,

assessing finasteride in 24,000 men aged ≥ 55 with no prior history of prostate cancer.29 The primary endpoint of PCPT is to test the difference in the biopsy-proven prevalence of prostate cancer between participants treated with finasteride and those treated with placebo. However, diagnosis of early-stage disease may not be a clinically meaningful endpoint because many of these cancers are asymptomatic and do not cause future morbidity or mortality. This trial does not have sufficient power to evaluate whether finasteride reduces overall or disease-specific mortality. The study coordinators admit that a trial of sufficient size and duration (51,000 men followedup for 15 years) to detect clinically relevant reductions in mortality would have been superior to the approach taken. However, this was rejected because of size, complexity, and cost.29 Results are expected by the year 2004. Recent interest has developed regarding dietary interventions for prostate cancer prevention. In particular, selenium, vitamin E, and lycopenes have emerged as promising candidates. The PCPT II is a multifactorial-designed trial to evaluate selenium and vitamin E in healthy men age 55 years or older. This study, still in the planning phase, is scheduled to begin in 1999 and is a collaborative effort between the NCI and Veterans Affairs (VA) Cooperative Studies Program. Thirty-two thousand men ≥ age 55 years without evidence of prostate cancer by digital rectal examination (DRE) and PSA will be randomized to receive a daily placebo, 400 mg vitamin E, 200 µg of selenium, or a combination of the two, daily for 7 years. The primary endpoint is prostate cancer incidence. Like PCPT, it does not have sufficient power to evaluate mortality. Another phase III study is examining the effect of a diet low in fat and high in soy, fruits, vegetables, vitamin E, and fiber on PSA levels in men with evidence of disease recurrence or persistence following radical prostatectomy or radiation therapy. Prostate Cancer Screening Early detection of prostate cancer with PSA testing and DRE is one of the great controversies in medicine.30–34 The rationale for screening is that undetected and untreated prostate cancer may grow locally, metastasize, and cause death and that early detection and appropriate treatment will delay or prevent these events. These assumptions, while plausible, are unproved and require evaluations in randomized clinical trials.35 A recently completed study in 46,000 Canadian men claimed that annual PSA testing and DRE reduced prostate-cancer-specific mortality almost threefold.36 However, this study did not use valid methods for randomization, mortality ascertainment, or analysis by intention-to-treat. These methodologic flaws make the results inadequate to determine if early detection of prostate cancer reduces mortality. The NCI Prostate, Lung, Colon, and Ovarian Cancer Screening Study (PLCO)37 and the European Random-


ized Study of Screening for Prostate Cancer (ERSPC)38 are both investigating the effectiveness of PSA and DRE testing on prostate cancer mortality. The former is allocating 37,000 men age 60 to 74 years to usual medical care or an initial examination and three subsequent yearly visits. The total study duration is 16 years. The sample size will allow for detection of a disease-specific mortality reduction of 20%. Treatment recommendations for men with newly detected prostate cancer are left to the discretion of their primary physician. The ERSPC study is enrolling over 180,000 men between the ages of 50 and 74 years from five countries. This study is hoping to identify the best screening method and target population by selecting the most appropriate combination of available screening tests. Each participating country has differences in age groups of enrollees, screening tests used, criteria per screening test selected to classify participants suspected of malignancy, screening interval, and whether randomization occurs before or after participation consent is obtained. The total study duration is 10 years. Similar to the PLCO trial, ERSPC does not mandate specific therapy for detected prostate cancer and is targeted to detect a reduction of 20% in prostate cancer. Localized Prostate Cancer Theoretically, cancer confined to the prostate gland should be curable by definitive radiotherapy or with surgical removal of the entire gland.28,39–50 However, the available information is insufficient to determine if surgery or radiation improves survival or quality of life in men with clinically localized prostate cancer. Only one study has directly compared radical prostatectomy to expectant management and reported no difference in survival between surgery and expectant management after 23 years.51 This study was too small to have sufficient power to detect clinically important differences in survival and was conducted prior to widespread PSA testing and use of “nerve-sparing” surgery. Another trial comparing radiation therapy with surgery was also limited, in part, by a small sample size. However, the results indicated that disease recurrence was higher in men treated with radiation therapy than in men treated with radical surgery.52 Two ongoing studies provide hope that sufficiently large randomized treatment trials can be conducted and will provide definitive answers regarding survival and quality of life for the two most frequently recommended treatment options for early stage prostate cancer: surgery and expectant management.53,54 The Swedish Prostate Cancer Group Study #4 (SPCG4) has enrolled 700 men with well- or moderately differentiated, clinically localized prostate cancer. Interim analysis in 520 cases noted no statistical difference in mortality with a mean followup of 3.5 years. The Prostate Cancer Intervention Versus Observation Trial (PIVOT) by the United States Depart-

ment of Veterans Affairs, the Agency for Health Care Policy and Research, and the National Cancer Institute CSP#407 has enrolled half the scheduled 1000 men within the first 4 years of recruitment. Both studies have a total duration of 15 years. Men are eligible for PIVOT if they are ≤ 75 years of age, have biopsy-proven, clinically localized prostate cancer (T1-T2, NX, M0) of any histologic grade, are surgical candidates, and have a life expectancy of at least 10 years. The types and indications for follow-up interventions are at the discretion of the physician while still adhering to the primary study purpose. In contrast to PIVOT participants, few men enrolled in SPCG4 have had prostate cancer detected by PSA testing. Preliminary baseline results from PIVOT demonstrate that the enrollees are representative of men being diagnosed with early stage prostate cancer in the United States.54 The American College of Surgeons is planning a randomized trial to evaluate the effects of brachytherapy versus radical prostatectomy on survival and quality of life in 2000 men with well- or moderately differentiated T1 or T2 prostate cancer and a PSA less than 15 ng per mL. Another proposal still being considered is to compare surgery to brachytherapy plus external beam radiation in men with poorly differentiated prostate cancer. Because brachytherapy is being widely used, the results of this trial will be of great importance if PIVOT and SPCG4 demonstrate that radical prostatectomy improves survival compared with expectant management. A Canadian research group has recently initiated a randomized trial to evaluate the efficacy and safety of cryotherapy compared with external beam radiation therapy (68–70 Gy) in conjunction with neoadjuvant hormonal therapy for the treatment of localized prostate cancer (Stages T1-T3, N0M0, all histologic grades, PSA < 25 ng/mL). The primary study objective is to determine if cryotherapy is equivalent to radiotherapy in terms of the proportion of patients with no evidence of disease progression at 36 months after treatment. Definitions of disease progression include PSA levels, biopsy, and clinical examination. Additional endpoints include overall and disease-specific survival, acute and chronic complications, and impact of treatment of health-related quality of life. The study is scheduled to enroll 480 patients over 4 years and is not of a sufficient size or duration to detect survival differences. The results of a meta-analysis of recently completed randomized trials indicate that radiation therapy with adjuvant androgen suppression for locally advanced or asymptomatic metastatic disease improves survival compared to radiation therapy alone.15 Building on these results, the Radiation Therapy Oncology Group of the NCI is comparing overall and disease-specific survival as well as local and/or distant clinical relapse rates in 2000 men with locally confined prostate cancer and PSA ≤ 20 ng per mL


treated with goserelin/flutamide prior to definitive radiotherapy versus radiotherapy alone. This study will not be able to determine whether radiotherapy improves survival compared with androgen suppression alone. At least two other radiation therapy trials are evaluating treatment for localized prostate cancer. Unfortunately, neither is using placebo controls and cannot determine if radiation therapy is better than observation or delayed hormone therapy. One trial is comparing a standard versus shortened radiotherapy schedule to assess local control rates, toxicity, and economic aspects. Another study conducted by the Medical Research Council is comparing conformal standard radiotherapy versus conformal high-dose radiotherapy in addition to neoadjuvant androgen deprivation. Finally, Zeneca Pharmaceutical Corporation is sponsoring a randomized trial in 6000 men who are at high risk of disease recurrence following treatment with radical prostatectomy or radiation therapy to determine if early hormone therapy with Casodex® bicalutamide improves survival and quality of life. Locally Advanced Prostate Cancer Up to half of all patients undergoing radical prostatectomy have pathologic evidence of locally advanced (pT3) disease. This finding is associated with much higher 10-year treatment failure (12% versus 30 to 60%) and mortality rates than patients with pathologically localized disease.55 The optimal treatment for these men is not known but includes observation, adjuvant hormonal therapy, and radiation. Randomized trials of androgen suppression initiated at PSA rise of persistence have not been conducted. A randomized trial initiated by EORTC comparing immediate versus deferred combined androgen ablation was discontinued because of lack of accrual. Ongoing trials include neoadjuvant versus adjuvant hormonal therapy plus either radiotherapy or radical prostatectomy, increased doses of radiation (through hyperfractionation, the use of conformal therapy, or coned-down boost), and the addition of systemic agents to radiation. Many of these trials are evaluating intermediate endpoints such as progression-free survival, local control rates, and treatment toxicity. Two important trials from the Southwest Oncology Group (SWOG) and EORTC have completed accrual and are evaluating whether postoperative radiotherapy improves survival for patients with pT3 disease.55 Hormone-Sensitive Advanced Prostate Cancer Almost 80% of men treated with androgen suppression either as initial or adjuvant therapy have clinical evidence of response. The number of men who are potential candidates for long-term androgen suppression therapy is large. Up to 30% of patients with clinically localized prostate cancer treated with radiotherapy still have positive biopsies 2 to 3 years after treatment. Twice as many have biochem-

ical evidence of recurrence which may reflect distant or local recurrence.56,57 About one in three men who undergo radical prostatectomy with curative intent receive additional treatment during the 5 years after this procedure.47 As noted earlier, a recent meta-analysis of completed trials has demonstrated that combined androgen suppression does not improve survival compared with surgical or medical orchiectomy.15 Furthermore, there were no differences in survival between the types of monotherapy. However, ongoing hormone therapy trials were initiated prior to these conclusions and are using combined androgen suppression. While extrapolation of results must be done with caution, it is reasonable to assume that surgical orchiectomy and diethylstilbestrol would produce similar results at a much lower cost compared to the hormonal options being used in current studies. A Medical Research Council (MRC) study in men with locally advanced nonmetastatic disease demonstrated that early androgen suppression reduced adverse events and may improve survival.58 Clinicians often monitor blood levels of PSA and offer androgen deprivation therapy based on the theory that suppression of the PSA level before there is evidence of disease-related symptoms improves the outcome. Consequently, more men with biochemical (PSA) evidence of disease persistence or those selecting expectant management are being considered for androgen suppression. Treatment is being initiated earlier in the natural history of the disease than prior to PSA testing but has not yet been demonstrated to improve the outcome. Men who undergo earlier hormonal treatment will have a longer duration of costly therapy in which they experience the adverse effects of androgen suppression, including osteoporosis, weight gain, hot flashes, muscle mass loss, and decreased potency and libido. A randomized trial of androgen suppression initiated at PSA progression following primary therapy was initiated by EORTC but failed to recruit an adequate number of patients. A recently completed NCI intergroup trial evaluated whether early hormone therapy with either orchiectomy or goserelin acetate (Zoladex®) improves survival compared with placebo in 250 men with D1 prostate cancer. The results of this study in conjunction with the previously mentioned MRC trial58 will provide important information regarding early hormone therapy in men with asymptomatic metastatic disease. A randomized trial of 1700 patients was initiated by SWOG to evaluate the effectiveness of neoadjuvant androgen suppression in an attempt to downstage the tumor prior to surgery when the disease extends beyond the capsule. While results indicated that neoadjuvant hormonal therapy reduced the rate of pT3 disease, the follow-up data has not demonstrated an improvement in PSA recurrence or survival.59 Unfortunately, slow patient accrual led to study closure. Intermittent androgen suppression relies on the hypothesis that tumor cells that sur-


vive androgen suppression are forced into a normal pathway of differentiation by androgen replacement, resulting in restoration of apoptotic potential and possible delay of progression to androgen independence. Serial PSA measurements may allow monitoring of disease activity and serve as trigger points for starting and stopping therapy.60 In addition to improving survival, intermittent therapy has the potential to reduce costs and complications associated with long-term continuous androgen suppression. Both NCI-C and SWOG are evaluating androgen suppression begun at PSA rise after radiotherapy and discontinued when PSA returns to nadir. Another study is assessing intermittent versus constant combined androgen deprivation in 1500 men with stage D2 prostate cancer who are responsive to such therapy. The primary objective is to compare survival rates in the two groups. This study will also assess the role of PSA levels in predicting survival outcomes and compare treatment effects on quality of life, potency, and libido. Hormone-Refractory Metastatic Prostate Cancer Hormone-refractory prostate cancer (HRPC) usually is defined as a serial rise in PSA levels and/or objective evidence of progression in the presence of adequate androgen blockade, documented by castration levels of testosterone.26 Second-line hormonal therapy may provide palliation and/or reduction in PSA levels. However, there is no conclusive evidence that any single agent or combination chemotherapy (including antiandrogen withdrawal) improves survival in men who relapse after initial hormone therapy.27 Narcotics, nonsteroidal or steroidal antiinflammatory agents, and focal radiation therapy are effective and much less expensive options for palliative care. Prostate-specific antigen has been used as an indicator of disease activity and marker of response to therapy, especially in trials evaluating treatment of hormone refractory prostate cancer.26 However, it has no role as a surrogate marker for metastasis-free or overall survival in patients with metastatic disease.5 Results from a SWOG study demonstrated that men treated with orchiectomy plus flutamide had a significantly greater PSA response than men treated with orchiectomy alone but no difference in survival.6 An NCI cooperative group trial is comparing the time to progression and survival in men with metastatic or recurrent advanced adenocarcinoma treated with or without suramin and hydrocortisone in addition to combined androgen blockade. Numerous chemotherapeutic regimens and other methods to reduce pain control requirements and enhance quality of life are currently being evaluated. However, reduction of pain control requirements without an improvement in quality of life may not be a clinically relevant trial outcome. For example, because of the toxicity and costs of chemotherapeutic regimens, patients may have equivalent or improved quality of life at a lower

cost while still using more pain medications or palliative radiation therapy. One trial is comparing the response rate and duration of response of ketoconazole/hydrocortisone in addition to antiandrogen withdrawal. As previously mentioned, antiandrogen withdrawal, while providing modest symptomatic relief in some patients, does not improve survival. The EORTC study is comparing prednisone alone to prednisone plus BMS-182751 in 400 men. Their primary outcome is overall survival and time to pain progression. Several studies are evaluating the ability of the bisphosphonate, clodronate, either alone or in combination with mitoxantrone and prednisone to reduce bone pain, pathologic fractures, and mortality. Radiation and radioactive isotope therapy have been demonstrated to provide palliation in patients with painful osseous metastases. The EORTC study is comparing local radiotherapy with strontium-89. An NCI cooperative group study is evaluating whether single-fraction versus multiple-fraction radiation therapy improves pain control, quality of life, and pathologic fractures in men with bone metastases.

Summary Past experience has demonstrated that randomized trials in prostate cancer are feasible and necessary to provide evidence-based prostate cancer health care. New guidelines and resources exist to facilitate the identification, design, conduct, and reporting of high-quality clinical trials. This will enhance the completion of RCTs and systematic reviews that are useful for disseminating and updating unbiased critical reviews of the effects of health care interventions in prostate cancer. The opportunity and responsibility currently exist to complete critically important randomized clinical trials in prostate cancer. The fact that men with prostate cancer currently select from a wide range of treatment options emphasizes the need for valid information from randomized trials. Successful enrollment and adherence in ongoing trials demonstrate the feasibility and generalizability of such studies. Regardless of which strategy proves superior, the results will provide our patients and colleagues with important therapeutic information. Physicians, cancer support groups, lay individuals, and the media should encourage enrollment so that the preferred treatment in men with prostate cancer can be determined. Supported by the U.S. Department of Veterans Affairs Cooperative Studies Program and Health Services Research and Development Program, the National Cancer Institute and the Agency for Health Care Policy and Research.

References 1. Blumenstein BA. The randomized clinical trial. In: Oesterling JE, Richie JP, editors. Urologic oncology. Philadelphia, (PA): WB Saunders; 1997. p. 792–800.

Randomized Clinical Trials in Prostate Cancer / 461 2. Bryg RJ, Johns JP. Academic nihilism. Why don’t we practice what we preach? Chest 1994;5:1309–10. 3. Begg C, Cho M, Eastwood S, et al. Improving the quality of reporting and randomized controlled trials. JAMA 1996;276:637–9. 4. Freemantle N, Mason JM, Haines A, Eccles MP. CONSORT: an important step toward evidence-based health care. Ann Intern Med 1997;126:81–3. 5. Schellhammer P, Cockett A, Boccon-Gibod L, et al. Assessment of endpoints for clinical trials for localized prostate cancer. Urology 1997;49 Suppl 4A:27–38. 6. Eisenberger MA, Blumenstein BA, Crawford ED, et al. Bilateral orchiectomy with or without flutamide for metastatic prostate cancer. N Engl J Med 1998;339: 1036–42. 7. Cheson B, Abrams JS, Nelson AP. Clinical trials referral resource. Oncology 1997;11:2244. 8. Thompson IM, Seay TM. Will current trials answer the most important questions about prostate cancer? Oncology 1997;11:1109–17. 9. National Cancer Institute. Information resources. Questions and answers about submitting clinical trials to PDQ. Available at: http://cancernet.nci.nih.gov/clinpdq/. 10. pdqinfo/Questions_and_Answers_About_Submitting_ Clinical_Trials_to_PDQ.html. Accessed December 8, 1998. 11. Ioannidis JPA. Effect of the statistical significance of results on the time to completion and publication of randomized efficacy trials. JAMA 1998;279:281–6. 12. Mulrow CD. Rationale for systematic reviews. BMJ 1994; 309:597–9. 13. Bero L, Rennie D. The Cochrane Collaboration. Preparing, maintaining, and disseminating systematic reviews of the effects of health care. JAMA 1995;274:1935–8. 14. Jadad AR, Cook DJ, Jones A, et al. Methodology and reports of systematic reviews and meta-analyses. A comparison of Cochrane Reviews with articles published in paper-based journals. JAMA 1998;280:278–80. 15. Aronson N, Seidenfeld J, Samson DJ, et al. Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostatic cancer. Evidence Report/Technology Assessment No. 4 (Prepared by Blue Cross/Blue Shield Association, Evidence-based Practice Center under Contract no. 290-97-0015). AHCPR Publication No. 99-E0012. Rockville, MD: Agency for Health Care Policy Research, May, 1999. 16. Tannock IF. The recruitment of patients into clinical trials. Br J Cancer 1995;71:1134–5. 17. Mansour EG. Barriers to clinical trials. Cancer Suppl 1994;74:2672–5. 18. Taylor KM, Margolese RG, Soskolne CL. Physicians’ reasons for not entering eligible patients in a randomized clinical trial of surgery for breast cancer. N Engl J Med 1984; 310:1363–7. 19. Slevin M, Mossman J, Bowling A, et al. Volunteers or victims: patients’ views of randomized cancer clinical trials. Br J Cancer 1995;71:1270–4. 20. Cassileth BR, Lusk EJ, Miller DS, et al. Attitudes towards clinical trials among patients and the public. JAMA 1982;248:968–70.

21. McPherson K, Chalmers I. Information about patients’ preference must be obtained first. BMJ 1998;317:78. 22. Lerner BH. Fighting the war on breast cancer: debates over early detection, 1945 to the present. Ann Intern Med 1998;129:74–8. 23. American Cancer Society. Questionable methods of cancer treatment. Am Cancer Soc 1993;3023:4. 24. Nicolucci A, Grilli R, Alexanian A, et al. Quality, evolution, and clinical implications of randomized, controlled trials on the treatment of lung cancer. A lost opportunity for meta-analysis. JAMA 1989;262:2101–7. 25. Denis L, Norlen BJ, Holmberg L, et al. Planning controlled clinical trials. Urology 1997;4 Suppl 4A:15–26. 26. Vollgenzang NJ, Crawford ED, Zietman A. Current clinical trial design issues in hormone-refractory prostate carcinoma. Cancer 1998;82:2093–101. 27. Oh W, Kantoff PW. Management of hormone refractory prostate cancer: current standards and future prospects. J Urol 1998;160:1220–9. 28. Middleton RG, Thompson IM, Austenfeld MS, et al. Prostate cancer clinical guidelines panel summary report on the management of clinically localized prostate cancer. J Urol 1995;154:2144–8. 29. Feigl P, Blumenstein B, Thompson I, et al. Design of the Prostate Cancer Prevention Trial (PCPT). Control Clin Trials 1995;16:150–63. 30. U.S. Preventive Services Task Force. Guide to clinical preventive services. 2nd. ed. Baltimore: Williams & Wilkins; 1996. 31. Selly S, Donovan J, Faulkner A, et al. Diagnosis, management and screening of early localized prostate cancer. A systematic review. Bristol, England: Health Care Evaluation Unit, University of Bristol, UK publishers; 1996. 32. Feinstein AR, Sosin DM, Wells CK. The Will Rogers phenomenon. Stage migration and new diagnostic techniques as a source of misleading statistics for survival in cancer. N Engl J Med 1985;312:1604–8. 33. Wald N. Ethical issues in randomized prevention trials. BMJ 1993;306:563–5. 34. Walsh PC, Brooks JD. The Swedish prostate cancer paradox. JAMA 1997;277:497–8. 35. Coley CM, Barry MJ, Fleming C, et al. Early detection of prostate cancer. Part II. Estimating the risks, benefits, and costs. Ann Intern Med 1997;126:468–79. 36. Labrie F, Dupont A, Candas B, et al. Decrease of prostate cancer death by screening; first data from the Quebec Prospective and Randomized Study. Proc ASCO 1998;17:A4. 37. Gohagan JK, Prorok PC, Kramer BS, et al. Prostate cancer screening in the prostate, lung, colorectal, and ovarian cancer screening trial of the National Cancer Institute. J Urol 1994;152:1903–4. 38. Standaert B, Denis L. The European randomized study of screening for prostate cancer. Cancer 1997;80:1830–4. 39. Chodak GW, Thisted RA, Gerber GS, et al. Results of conservative management of clinically localized prostate cancer. N Engl J Med 1994;330:242–8. 40. Johansson JE, Holmberg L, Johansson S, et al. Fifteen year survival in prostate cancer. A prospective, populationbased study in Sweden. JAMA 1997;277:467–71.

462 / Advanced Therapy of Prostate Disease 41. Fleming C, Wasson JH, Albertsen PC, et al. for the Prostate Patient Outcomes Research Team. A decision analysis of alternative treatment strategies for clinically localized prostate cancer. JAMA 1993;269:2650–9. 42. Wasson JH, Cushman CC, Bruskewitz RC, et al. A structured literature review of treatment for localized prostate cancer. Arch Fam Med 1993;2:487–93. 43. Gerber GS, Thisted RA, Scardino PT, et al. Results of radical prostatectomy in men with clinically localized prostate cancer. Multi-institutional analysis. JAMA 1996; 276:615–9. 44. Litwin MS, Hays RD, Fink A, et al. Quality of life outcomes in men treated for localized prostate cancer. JAMA 1995;273:129–35. 45. Fowler FJ, Barry MJ, Lu-Yao G, et al. Patient-reported complications and follow-up treatment following radical prostatectomy: the national Medicare experience (1988-1990). Urology 1993;42:622–9. 46. Fowler FJ, Barry MJ, Lu-Yao G, et al. Outcomes of externalbeam radiation therapy for prostate cancer: a study of Medicare beneficiaries in three Surveillance, Epidemiology, and End Results areas. J Clin Oncol 1996; 14:2258–65. 47. Lu-Yao GL, Potosky AL, Albertsen PC, et al. Follow-up prostate cancer treatments after radical prostatectomy: a population-based study. J Nat Cancer Inst 1996;88(3-4): 166–73. 48. Albertsen PC, Hanley JA, Gleason DF, Barry MJ. Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 1998;280:975–80. 49. D’Amico AV, Whittington R, Malkowicz B, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA 1998;280:969–74. 50. Chodak GW. Comparing treatments for localized prostate

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cancer—persisting uncertainty. JAMA 1998;280: 1009–10. Iversen P, Madsen AP, Corle DK. Radical prostatectomy versus expectant treatment for early carcinoma of the prostate: twenty-three year follow-up of a prospective randomized study. Scand J Urol Nephrol 1995;172 Suppl:65–72. Paulsen DF, Lin GH, Hinshaw W, et al. The Uro-Oncology Group. Radical surgery versus radiotherapy for adenocarcinoma of the prostate. J Urol 1982;128:502–4. Norlen BJ. Swedish randomized trial of radical prostatectomy versus watchful waiting. Can J Oncol 1994;4 Suppl 1:38–42. Wilt TJ, Brawer MK. The Prostate Cancer Intervention Versus Observation Trial. Oncology 1997;11:1133–9. Thompson IM, Paradelo JC, Crawford ED, et al. An opportunity to determine optimal treatment of pT3 prostate cancer: the window may be closing. Urology 1994; 44:804–11. Hanks GE, Lee WR, Schulthesis TE. Clinical and biochemical evidence of control of prostate cancer at 5 years after external beam radiation. J Urol 1995;154(2 Pt 1): 456–9. Health Care Financing Administration. Medicare Claims Data, Calendar Year 1995. The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: the initial results of the Medical Research Council trial. BMJ 1997;79:235. Soloway MS, Sharifi R, Wajsman Z, et al. Randomized prospective study—radical prostatectomy alone versus radical prostatectomy preceded by androgen blockade in cT2b prostate cancer: initial results. J Urol 1996;155:555A. Theyer G, Hamilton G. Current status of intermittent androgen suppression in the treatment of prostate cancer. Urology 1998;52:353–9.

CHAPTER 51

HORMONAL AND CELLULAR ASPECTS OF BENIGN PROSTATIC HYPERPLASIA R. DUANE CESPEDES, MD primordial prostatic buds invade the mesenchyme to form primordial zones, with the inner zone consisting of primarily mesodermal tissue and the outer zone primarily endodermal tissue. Whether this plays a part in the characteristic development of BPH within the inner zone and carcinoma in the outer zone is unknown. For the ductal system to develop within the prostate, androgen must be present during fetal development.4 The adult prostate can be divided into five relatively distinct zones on the basis of its proximity to the prostatic urethra.5 The transition zone, which is embryologically located at the junction of the proximal and distal urethral segments, comprises only 5% of the mass of the prepubertal prostate and is the site of origin of BPH. The peripheral zone contains almost 70% of the glandular tissue of the prepubertal prostate and is the site of origin of most carcinomas. The prostate appears to have typical growth phases, starting with initial growth during fetal development, when higher levels of androgen are present, followed by a modest involution postnatally, and growth cessation until puberty. Growth begins again under the influence of increased androgen levels at puberty and continues until adulthood when all zones of the prostate, with the exception of the transition zone, stop growing. Why the transition zone continues to grow is unclear; however, McNeal6 has theorized that a clone of mesenchymal (stromal) cells within the transition zone spontaneously revert to an embryonic state (the so-called embryonic reawakening theory), with subsequent induction of glandular growth. This theory, and others, that attempt to explain the development of BPH will be evaluated later, but the heterogeneity and diverse embryologic origins of the prostate gland coupled with its dependence on hormones and growth factors underlie the great difficulty in understanding the origin of BPH. Although we do not totally understand these factors, it is clear that they do play an important role in the development of BPH in man.

Benign prostatic hyperplasia (BPH) is the most common neoplastic disease in men, seen histologically in more than 50% of those over 60 years of age; however, the basic hormonal and cellular processes which lead to its development are still unclear.1 In the last few decades, there has been a tremendous effort to understand these processes because in some cases, prostatic enlargement can cause bladder outlet obstruction leading to significant voiding dysfunction or even loss of renal function. For a number of years, surgical procedures were the only means available to relieve this obstruction. Although obstruction is but one possible cause of voiding dysfunction, if perhaps we knew why BPH occurred, we may be able to prevent or reverse the process with less invasive medical therapy. Although there has been limited success in this regard, research has led to the development of medical treatments such as 5 α-reductase inhibitors and alpha-adrenergic receptor blockers, both of which are helpful in select patients but are not universally efficacious.2,3 What has become clear is that complex interactions exist between the epithelial and stromal components of the prostate and that these interactions develop and are maintained by a particular hormonal milieu, including, most importantly, androgens and estrogens. More recently, growth factors that appear to play an important role in the pathogenesis of BPH have been identified; however, their exact role has not been clearly defined. This chapter will briefly review the current state of knowledge regarding the hormonal and cellular processes that play a role in the development and progression of BPH.

Embryology and Growth Patterns An understanding of the complex embryology of the prostate is necessary as it helps to explain some of the morphologic features of BPH found later in life. The accessory sex glands, including the vas, ejaculatory ducts, epididymis, and seminal vesicles, are derived from the mesoderm from the wolffian duct system and differentiate under the influence of testosterone. The bulbourethral glands and prostatic tissue develop from the endodermal urogenital sinus under the influence of dihydrotestosterone (DHT) converted from testosterone by the enzyme 5 α-reductase. The

Stromal and Epithelial Interactions Early studies based on pathologic evaluations theorized that stromal proliferation and particularly the stromal nodules appeared to be the initiating event in the forma463


tion of BPH, with glandular hyperplasia subsequently proliferating in response.7–9 The pathophysiology of this process was unclear until McNeal noted that the new glandular budding was not a true glandular hyperplasia but appeared similar to the glandular development that occurs during fetal development. He hypothesized that a clone of embryonic stromal cells secreted an embryonic growth factor causing new gland formation and the formation of benign nodular neoplasms.10 A study using a murine model found that the development of prostatic ducts and acini is dependent on the presence of urogenital sinus mesenchyme in intimate contact with the epithelial component.11 Induction of prostatic growth does not occur if the tissues are separated. Additionally, the final size of the organ is dependent on the amount of mesenchymal tissue present and is independent of the amount of urogenital sinus epithelial tissue present.12,13 Furthermore, transplantation of additional fetal urogenital sinus mesenchyme within the adult prostate induces additional prostatic growth.14 The ability to induce prostatic growth is specific to the urogenital sinus mesenchyme as other embryonic mesenchymal tissues have not been able to induce prostatic growth. Interestingly, urogenital sinus mesenchyme from the androgen-insensitive fetal mouse is not able to induce prostatic growth from the bladder epithelial cells derived from androgen-sensitive mice. Conversely, mesenchyme derived from androgen-sensitive mice can induce prostatic growth in epithelium derived from androgen-insensitive mice demonstrating that it is the mesenchymal component (stroma) that responds to the embryonic hormonal environment and ultimately induces the prostatic epithelium to proliferate using nonhormonal paracrine or autocrine signals.15–18 When these experiments are repeated in castrated animals, prostatic tissue does not develop, again demonstrating the importance of androgens for prostatic development.19 Indeed, Cooke and colleagues demonstrated that while androgen receptors are present in embryonic epithelium, they are not functional until later in life.20 The ratio of epithelium to stroma appears to be an important factor in the growth and overall potential size of the prostatic gland. Studies have found that accelerated prostatic growth occurs in the fetus, where the volume of stromal tissue greatly exceeds that of epithelial tissue and that stromal growth precedes epithelial growth in puberty.21 It is clear that epithelial growth continues until a favorable epithelial-to-stromal ratio is reached that causes proliferation to cease. Pathologic studies quantifying the relative amounts of stromal and glandular tissue have shown that stromal tissue predominates by a factor of 2 to 1 in normal prostates and increases to 5 to 1 in BPH patients.22 A large proportion of this stromal tissue is smooth muscle. This finding has some importance in explaining the possible etiology of dynamic obstruction and may be the basis for treatment of lower urinary tract

symptoms (LUTS) with α-receptor blockers.23 Additionally, in BPH, stromal cells appear to be more metabolically active than glandular cells and the 5 α-reductase enzyme is found in much higher concentrations in the stromal tissue.24,25 In summary, the prostatic stromal tissue appears to be intimately involved in the induction and proliferation of the glandular prostatic elements. Abnormalities in the regulation of this process during adulthood may develop into BPH. This complex process not only requires the presence of androgens but also that tissues be in close proximity for the incompletely elucidated paracrine and autocrine interactions to occur. The clinical significance of the predominance of the smooth muscle within the prostatic stroma awaits further investigation.

Hormonal Mechanisms Role of Androgens The importance of the testis in BPH has been well known since the 1890s when it was found that castration produced dramatic relief of obstructive BPH in approximately 80% of patients.26 Scott later noted that BPH development is uncommon if the patient is castrated prior to age 30 years.27 In murine models, the overall decrease in prostatic size after castration is approximately 80%, with a 93% decrease in the epithelial component and a 22% decrease in the stromal component.28,29 The development of BPH also appears to be dependent on the timing of hormonal exposure. A recent study by Jie-Ping and FangLiu with follow-up periods of up to 65 years demonstrated that most patients castrated before age 26 years rarely develop a palpable prostate.30 Interestingly, 85% of these patients with very small prostates had voiding symptoms, including nocturia of two to ten times per night, demonstrating that an enlarged prostate is not necessary for the development of voiding symptoms. Isaacs found that the timing of castration in young rats and dogs determined the ultimate size of the prostate in the mature animal.31 What is unclear, however, is whether testicular androgens are simply a maintenance factor for the prostatic tissue or whether elevated levels and/or prolonged exposure directly cause cellular hyperplasia. One study that demonstrated a correlation between hormonal levels and BPH is a report by Partin and colleagues who found a corresponding increase in the free serum testosterone, estriol, and estradiol with increasing BPH volume.32 Testosterone itself has little effect on prostatic growth; however, DHT, which is necessary for prostatic growth, is formed from testosterone by the intracellular enzyme 5 α-reductase. Men with molecular defects in either the 5 α-reductase enzyme or the androgen receptor do not develop BPH.33 Prostate biopsies of males with a 5 α-reductase deficiency (male pseudohermaphrodites) have yielded only stromal tissue whereas the

Hormonal and Cellular Aspects of Benign Prostatic Hyperplasia / 465

heterozygous fathers of these patients have prostates similar to age-matched control males.34 It has been observed, however, that the tissue level of 5 α-reductase is only slightly elevated or normal in patients with BPH. Walsh and colleagues found that the tissue concentration of DHT in normal controls and patients with BPH were similar.35 In this study, the prostatic tissue of three men without BPH was found to have a similar prostatic DHT concentration as older men with BPH. Bartsch and colleagues found similar concentrations of progesterone, estrone, estriol, and estradiol levels in surgically removed BPH tissue and normal prostatic tissue.36 Conversely, Krieg and associates reported increased estradiol levels and estrone levels in stromal tissue obtained by prostatectomy from patients with BPH as compared with the stromal tissue obtained from brain-dead kidney donors.37 The DHT and testosterone concentrations were similar within the stromal tissue of the patients; however, the DHT concentration was lower in the prostatic epithelium of patients with BPH as compared with prostatic epithelium from kidney donors. The exact significance of these findings is unclear but investigators theorize that this may represent an accumulation of precursor metabolites. Other studies have also confirmed a two- to three-fold greater 5 α-reductase enzyme activity within the stromal tissues.38,39 When the BPH tissue is stained with an antibody to 5 α-reductase isoenzyme 2 (the only isoenzyme found in the prostate), the predominant staining also appears to be within the prostatic stroma.40,41 Therefore, although the overall levels of 5 αreductase are comparable between normal and BPH patients, there appears to be an increased concentration of 5 α-reductase within the stromal tissue of patients with BPH. It is theorized that this increased enzyme level may shift steroid metabolism toward the production of DHT, causing initial stromal proliferation, with glandular proliferation occurring secondarily. Another important factor in prostatic hormonal metabolism is the androgen receptor. Studies of the androgen receptor have shown an increased number of nuclear androgen receptors in both human and canine BPH tissue when compared with normal controls.42 In a canine model, investigators found that the prostates of elderly dogs were almost twice as sensitive to circulating testosterone as were those of young dogs.43 This study did not identify the factors leading to this increased sensitivity but it did demonstrate the ability of the prostate to compensate for declining free testosterone levels by increasing hormonal sensitivity. Although the ductal epithelial cells need androgens for proliferation, the required levels vary within the duct. The distal cells near the tip of the duct require a much higher androgen level than do the proximal cells but when normal androgen levels are present, the cellular proliferation rate (measured by DNA synthesis) is at least 10 times higher in the distal ducts.44 A similar phenome-

non can also be found in other tissues with a branching duct architecture (such as the breast); however, the exact significance of this finding is uncertain at this time.45 Role of Estrogens and Nonandrogens The role of estrogens in the development of BPH is controversial. Although it is clear that androgens play an important role in the development of BPH, there is one aspect that remains paradoxical: why does BPH progress with increasing age, when the levels of free testosterone (the active form) are decreasing?46 While free testosterone decreases with age, circulating estrogen levels remain constant or increase, yielding an increased estrogen-totestosterone ratio.47 Observations such as these have led to the hypothesis that estrogen may have a stimulatory or synergistic effect with androgens to stimulate prostatic growth.48 An early study by Walsh and Wilson revealed that the simultaneous administration of exogenous estrogens and androgens in the canine model increased the growth rate of the prostate above that seen with androgens alone.49 This observation was later confirmed by other investigators.50 Of note, only the 5 α-reduced androgens have such synergism with estrogens to increase prostatic growth. Further evidence of the importance of estrogens was provided by Partin and colleagues who found that human BPH volume correlated with levels of free testosterone, 17β-estradiol, and estriol levels.32 In the dog, exogenous estrogen administration has been shown to increase the concentration of prostatic DHT, presumably by increasing DHT formation by an alteration in cellular metabolism.51 Estrogen receptors have been found within the cytosol and nucleus of prostatic cells. These receptors are in higher concentrations in the stromal tissues and are decreased in BPH tissue as compared with the normal prostatic tissue.52 Studies in the canine model have found an increased number of high-affinity estrogen receptors within BPH tissue; however, in human studies, the number of high-affinity estrogen receptors within BPH tissue was lower than in adjacent normal tissue.53,54 Therefore, the role played by the estrogen receptor in BPH is unclear but investigators who studied experimentally induced BPH in dogs using estrogen and DHT found an increased number of androgen receptors within prostatic stromal cells.53,55,56 The importance of this finding is that the response of prostatic tissues to circulating androgens would be greatly increased. An especially important discovery is that concurrent administration of estrogens and DHT appears to reduce the rate of prostatic cell death.57 In a canine BPH model where the prostate is up to 4 times larger than normal, the rate of DNA synthesis was 33% less than normal control prostates, demonstrating that cellular replication is not increased.58 Because the cell death rate is lowered without reduction in the intrinsic mitotic rate, paradoxical prostatic enlargement may


occur. This important finding is the basis for one of the etiologic theories of the formation of BPH, that is, BPH is not caused by an increased cellular replication rate but a decreased death rate allowing cellular accumulation and an overall increase in gland size.57 Finally, estrogens have been found to enhance aromatase enzyme activity predominately within the periurethral and transition zones of the prostate.59,60 Increased activity in the aromatase enzyme, which irreversibly converts testosterone to estrogen, would effectively increase the estrogen levels within these zones, possibly increasing the number of androgen receptors and thereby increasing the sensitivity of these tissues to circulating androgens. In clinical studies with canine BPH models where an aromatase enzyme inhibitor was used to reduce cellular estrogen, no change in the size of the prostate was noted.61 These results make the role of the aromatase enzyme unclear. Interestingly, the serum testosterone level increased 10-fold with this treatment, demonstrating that elevated testosterone alone, in the absence of cellular estrogen, does not appear to cause cellular proliferation.62 Estrogens also affect the developmental potential of the prostate. Estrogen exposure during the neonatal period can impede the growth of the prostate and reduce the potential size of the adult prostate.63 Long-term estrogen exposure has a direct stimulatory effect, causing profound squamous metaplasia in mature prostates. The mechanism is unknown but the effects are predominant on the stromal tissue as estrogen receptors have not been positively identified on epithelial cells. The studies above suggest that estrogens may have a direct regulatory role in the development of BPH. Some investigators believe that estrogens exert their effects by increasing the secretion of pituitary prolactin, an established growth factor for BPH. In hypophysectomized rats, exogenous estrogens do not increase the growth rate of the prostate.64 Whether a similar phenomenon occurs in humans is unclear. Progesterone receptors are found throughout the prostatic cell cytosol and perhaps within the nucleus. These receptors are found in higher concentrations in BPH tissue as compared with normal prostatic tissue; however, little work has been done in this area, and their importance in BPH remains unclear.36 Estrogens appear to play an important role in the development of the prostate and BPH. Under the influence of increasing estrogen levels, the aging prostate may become more sensitive to falling levels of circulating androgens by increasing the number of androgen receptors or by increasing cellular aromatase activity. It is also possible that estrogens simply increase circulating levels of prolactin. The exact mechanism by which estrogens influence the development of the prostate and BPH is unclear, and further study will be necessary to define the role of estrogens in the development of BPH.

Growth Factors The possible role of a nonandrogenic factor in the development of BPH has been suggested by the observation that as the testosterone levels decrease in most aging men, the prostate continues to grow in size. Additionally, the exogenous addition of androgens increase the growth of the prostate in vivo but androgens do not act as mitogens to prostatic epithelial cells in culture.65 When epithelial cells are cultured with stromal cells, however, androgens are able to induce epithelial cell proliferation.66 Therefore, some other factor(s) must act as the final step in stimulating prostatic growth. Studies involving irradiation of the testicles of beagle dogs found that these animals maintained a normal level of testosterone and estradiol but sustained a significant decrease in prostatic size and weight, suggesting that a nonandrogenic factor elaborated by the testis is necessary for prostatic growth.67 Additionally, the exogenous administration of DHT or testosterone to castrated dogs rarely produces significant BPH. On the other hand, if androgens are administered to dogs with an intact hormonal axis, a significant increase in the incidence of BPH is witnessed.68 A similar study involving castrated and noncastrated rats who received exogenous androgens revealed that the former group of rats rarely developed BPH while the latter had a significant increase in prostatic growth.69 More recently, Sutkowski and colleagues found that human spermatocele fluid causes an increased growth rate in prostatic epithelial and stromal cells in culture.70 These studies suggest the existence of growth factors that may be the final effector molecules acting on the prostate to carry out the functions thought to be due to androgens or other hormonal substances. Most growth factors are proteins that function to either stimulate or inhibit the cell of origin (autocrine) or adjacent cells (paracrine). The increase or decline in the activity of a tissue appears to be regulated by a delicate balance among various growth factors. Additionally, some growth factors appear to be secreted in an active form while others are bound by the extracellular matrix and are subsequently activated by unknown mechanisms. Epidermal growth factor (EGF), found in both prostatic secretions and within prostatic tissues, has been found to act as a mitogen for prostatic epithelial cells.71,72 In studies involving castrated adult mice, the level of secreted EGF decreases after castration and returns to normal after exogenous androgens are given.73 Additionally, prostatic cells grown in culture require EGF for proliferation.65 Conversely, the production of EGF and its receptor are not increased in BPH.74 The exact mechanism by which EGF functions in the normal human prostate and its relationship to the development of BPH remains unclear. Though EGF does appear to be a required factor for cellular growth, it is not involved in the develop-

Hormonal and Cellular Aspects of Benign Prostatic Hyperplasia / 467

ment of BPH. Interestingly, EGF and a related growth factor, transforming growth factor (TGF)-α, are overexpressed in human prostate cancer and therefore may be important in initiating and maintaining the abnormal cellular growth patterns seen in prostatic carcinoma.75–77 Another growth factor implicated in the development of BPH is basic fibroblast growth factor (bFGF).78 This factor is increased in BPH tissues and causes prostatic stromal cell (but not epithelial cell) proliferation.79–81 Transgenic mice genetically engineered to produce an excess amount of the embryonic protein int-2 (functionally similar to bFGF) develop prostatic hyperplasia producing a prostate 20 times the mass of normal controls.82 Importantly, growth factors similar to bFGF (and int-2) and corresponding messenger ribonucleic acid (mRNA) have been found in elevated levels in BPH, suggesting a possible clonal reversion of the prostatic stroma to an embryonic state.83 Of note, androgen ablation (but not 5 α-reductase inhibitors) causes regression of this cellular hyperplasia.84 Basic FGF does not appear to act directly on the prostatic epithelial cells and is believed to function along with other growth factors in the initiation of stromal hyperplasia, which may then lead to glandular proliferation. A growth factor related to bFGF also believed to play a role in the development of BPH is keratinocyte growth factor (KGF), which is produced solely by prostatic stromal cells in response to androgen stimulation and is only mitogenic for prostatic epithelial cells.85,86 Keratinocyte growth factor, which is elaborated by the stromal cells and responds to androgen stimulation, may be a paracrine regulator of epithelial growth. There is some evidence that suggests that both bFGF and KGF secretion may be regulated by TGF-β in an androgen-dependent manner.87,88 This factor, which is elevated in BPH, inhibits prostatic epithelial cell growth and stimulates the production of bFGF by the stromal prostatic cells.81 The overall effect of TGF-β on the prostate is to promote stromal growth and directly inhibit epithelial proliferation while stimulating epithelial growth by inducing the secretion of bFGF, suggesting that it may be an important regulator of the stromal to epithelial ratio.89 As certain immortal prostatic carcinoma cell lines are not inhibited or even appear to be stimulated in the presence of TGF-β it may also be an important factor in prostate cancer, suggesting that the functional loss of TGF-β may allow unregulated cellular proliferation.90,91 The insulin-like growth factors (IGFs) include a large family of different factors, receptors, and binding proteins that have recently been implicated in the development of BPH.92,93 The stromal cells of BPH produce an increased amount of IGF-I and especially IGF-II, both of which stimulate epithelial and stromal proliferation. Interestingly, IGF-II is considered to be an “embryonic” form of IGF because the highest levels are found in the

fetus and are rarely produced in the adult, giving credence to McNeal’s “embryonic reawakening” theory as a possible etiology for the development of BPH.94 Finally, the exact source of these growth factors is unclear. Many of the growth factors are probably derived from the prostatic stroma and epithelial cells but may also reach the prostate systemically or through the urine or semen. The recent finding that factors in semen act as mitogens for prostatic tissues in culture supports the hypothesis that growth factors from distant organs may influence the growth of the prostate.70 Several facts also support the basis for systemic growth factors. As is well known, BPH is almost universal in men in their ninth decade. The probability that a benign tumor of the prostate occurs spontaneously in the majority of males seems unlikely. Similarly, the maintenance of the size and weight of the accessory sex organs in the face of declining testosterone levels also suggests systemic factors.95 Realistically, it is probable that the development of BPH requires the presence of both local and systemically produced factors but further research will be needed to elucidate these mechanisms.

Etiologic Theories of BPH Development Multiple theories have been proposed to explain the development of BPH in man. The earliest theories suggested that endocrine derangements possibly leading to elevated local levels of androgens may be the cause of BPH. However, these simplistic theories do not appear to be relevant any more.96 The underpinning of the stem cell model is that in the stable, zero growth state, cell growth and death rates are in exact balance, preserving a stable organ size.31,96 An alteration in the development and regulation of the stem cells may lead to cells that produce or respond to cellular products in an altered fashion, leading to a cellular proliferation rate that is faster than the cell death rate, and resulting in a gradual increase in gland size over time. This model does not take into account the cause of this hyperplastic state that may result from a decreased cell death rate or an increased cellular mitotic rate. Additionally, the underlying causes such as altered hormonal state, alterations in the production or responsiveness to growth factors, or a combination of both are not clear. Another theory, proposed by Coffey and Walsh, is that the mitotic rate remains stable or even decreases but that the cell death rate is decreased due to hormonal interactions, probably due to increased estrogens, resulting in cell proliferation and a gradual increase in gland size. Essentially, a relative proliferative state is induced.57 A third theory, introduced by McNeal, is the “embryonic reawakening” theory that proposes that a clone of the mesenchyme-derived stromal cells within the prostate


reverts to an embryonic state, where stromal proliferation occurs initially, with subsequent proliferation of the epithelial component to maintain the proper stroma to epithelial ratio.10 There are several studies supporting this theory. As described above, Muller and colleagues produced glandular hyperplasia in transgenic mice by causing the overproduction of an embryonic protein functionally similar to bFGF, which suggests that an alteration in FGF metabolism may be the cause for BPH.82 Additionally, recent evidence suggests that a change in IGF factors from IGF-I (the “adult” form) to IGF-II (the “embryonic” form) may also be an important step in the development of BPH.92

Conclusion The initiation and maintenance of BPH appears to be a multifactorial process involving complex interactions between the stromal and epithelial tissues. These processes are regulated by androgens, estrogens, and various growth factors, which may act locally, systemically, or both. The global theories of BPH development allow for a framework to direct research, but none can adequately explain the genesis of BPH with conclusive supporting data at this time. Further research is needed to solve the many remaining questions regarding the enigmatic development of BPH. The opinions or assertions contained herein are the private views of the authors and are not to be construed as reflecting the views of the United States Air Force or Department of Defense.

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growth factor: a potent mediator of stromal growth in human prostate. Endocrinology 1992;130:2955. Story MT, Livingston B, Baeten L, et al. Cultured human prostate derived fibroblasts produce a factor that stimulates their growth with properties indistinguishable from basic fibroblast growth factor. Prostate 1989;15:355–65. Mori H, Maki M, Oishi K, et al. Increased expression of genes for basic fibroblast growth factor and transforming growth factor type β2 in human benign prostatic hyperplasia. Prostate 1990;16:71–80. Muller WJ, Lee FS, Dickson C, et al. The int-2 gene product acts as an epithelial growth factor in transgenic mice. EMBO J 1990;9:907. Mydlo JH, Michaeli J, Heston WD, et al. Expression of basic fibroblastic growth factor mRNA in benign prostatic hyperplasia and prostatic carcinoma. Prostate 1988;13: 241–7. Tutrone RF, Ball RA, Ornitz DM, et al. Benign prostatic hyperplasia in a transgenic mouse: a new hormonally sensitive investigatory model. J Urol 1993;149:633–9. Peehl DM Stamey TA, Ruben JS. Fibroblast growth factors can replace epidermal growth factor for clonal proliferation of human prostatic epithelial cells. J Urol 1991; 145:475–9. Yan G, Fukabori Y, Nikolaropoulos S, et al. Heparin binding keratinocyte growth factor is a candidate stromal to epithelial andromedin. Mol Cell Endocrinol 1992;6:2123–8. Story MT, Baeten LA, Molter MA, Lawson RK. Influence of androgen and transforming growth factor beta on basic fibroblast growth factor levels in human prostate derived fibroblast cell cultures. J Urol 1990;143:241A. Lawson RK. Etiology of benign prostatic hyperplasia. In: Lepor H, Lawson RK, editors. Prostate diseases. Philadelphia: WB Saunders; 1993. p. 92–3. Steiner MS. Role of peptide growth factors in the prostate: a review. Urology 1993;42:99–110. Wilding G, Zugmeier G, Knabbe C, et al. Differential effects of transforming growth factor β on human prostate cancer cells in vitro. Mol Cell Endocrinol 1989;62:79–87. Steiner MS, Barrack ER. Transforming growth factor β1 overproduction in prostate cancer: effects of growth in vivo and in vitro. Mol Cell Endocrinol 1992;6:15–25. Cohen P, Peehl DM, Lamson G, et al. Insulin-like growth factors (IGFs), IGF receptors and IGF binding proteins in primary cultures of prostate epithelial cells. J Clin Endocrinol Metab 1991;73:401–7. Cohen P, Peehl DM, Baker B, et al. Insulin-like growth factor axis abnormalities in prostatic stromal cells from patients with benign prostatic hyperplasia. J Clin Endocrinol Metab 1994;79:1410–5. Peehl DM. Basic biological studies of prostate disease: translation to clinical application. AUA Update Series 1996;15(29):230–5. Lee C, Kozlowski JM, Grayhack JT. Etiology of benign prostatic hyperplasia. Urol Clin North Am 1995;22:237–46. Isaacs JT, Coffey DS. Etiology and disease processes of benign prostatic hyperplasia. Prostate 1989;2 Suppl: 33–50.

CHAPTER 52

NEED FOR URODYNAMICS AND OTHER TESTING GARY E. LEACH, MD; SCOTT A. MACDIARMID, MD Approximately one in four men 50 years and older develop urinary symptoms secondary to benign prostatic hyperplasia (BPH), which in many cases adversely affects their quality of life. The diagnosis of BPH is primarily based on the presence of obstructive and/or irritative voiding symptoms in men of appropriate age in the absence of other causes. Unfortunately, the bladder and bladder outlet tends to be an unreliable witness, and many conditions produce the same lower urinary tract symptoms, commonly referred to as prostatism, or more recently, lower urinary tract symptoms (LUTS). In most cases, a thorough history and physical examination combined with basic laboratory tests and simple urodynamic evaluation is all that is required to diagnose BPH and differentiate it from other conditions. More sophisticated and invasive procedures, including formal urodynamics and cystoscopy, are reserved for complex cases, their usage being highly dependent upon physician experience, bias, and expertise. The primary focus of this chapter will be a discussion of the role of urodynamics and other testing procedures in evaluating and treating patients with benign prostatic hyperplasia and lower urinary tract symptoms. Use of these tests to diagnose BPH and differentiate it from other diseases will be discussed as well as treatment selection. The role of urodynamics as a predictive measure of outcome in treating men with BPH will be evaluated. The important aspects of the urologic history and physical examination and their relation to the urodynamic findings will also be included since without them the diagnostic potential of urodynamics is limited.

an adequate detrusor contraction during voiding. This condition may be caused by neurogenic, obstructive, myogenic, psychogenic, or pharmacologic factors. Hyperactive or overactive detrusor function refers to bladder instability and/or loss of bladder compliance. An unstable bladder may be secondary to bladder outlet obstruction or may result from other causes, including developmental, idiopathic, neurogenic, and intravesical disease process. Loss of bladder compliance in adult males is most often secondary to bladder outlet obstruction or neurogenic bladder dysfunction but other causes resulting in bladder inflammation or fibrosis should be sought. Both hyposensitive and hypersensitive bladder disorders may result in lower urinary tract symptoms. Bladder hyposensitivity may be neurogenic in origin, the most common cause being diabetes mellitus, or may be due to chronic bladder overdistention and inefficient bladder emptying secondary to bladder outlet obstruction or myogenic failure. Hypersensitive bladder function refers to patients with frequency urgency syndrome and stable bladders during cystometrogram, referred to as sensory urgency, as well as those with painful bladder disorders. Common causes of bladder hypersensitivity include urinary infection, interstitial cystitis, bladder carcinoma and carcinoma in situ, and radiation cystitis.

Patient Evaluation Important aspects of the entire evaluation (Table 52–2), especially urologic history, must be included when discussing the role of urodynamics and other tests in evaluating patients with lower urinary tract symptoms and BPH. Failure to do so severely limits the diagnostic potential of urodynamics. Integrating subtleties of the urologic history with nonspecific urodynamic findings and using urodynamic data appropriately is more of an art than a

Lower Urinary Tract Symptoms The clinician must possess a fundamental knowledge of the pathogenesis of LUTS to effectively evaluate and treat male patients with urinary symptoms and establish a diagnosis of BPH (Table 52–1). The most common non-BPH conditions resulting in bladder outlet obstruction in adult males include primary bladder neck obstruction, urethral stricture disease, bladder neck contracture, prostate cancer, and functional obstruction secondary to detrusor-sphincter dyssynergia (DSD). An underactive bladder fails to develop or sustain

TABLE 52–1. Pathogenesis of Male Lower Urinary Tract Symptoms Bladder outlet obstruction Benign prostatic hyperplasia Non-BPH conditions Underactive detrusor function Hyperactive detrusor function Sensory disorders of the bladder

471


science and can maximize the diagnostic capability of the test, which will influence treatment and outcome. History Men with BPH complain of both obstructive and irritative voiding symptoms. The former include decreased force of stream, urinary hesitancy, straining to urinate, a feeling of incomplete emptying, and urinary retention. Irritative voiding symptoms include frequency, nocturia, urgency, and urge incontinence. The American Urological Association (AUA) Symptom Index is a validated symptom score which quantitates symptom severity but is not specific for BPH (Table 52–3). Unfortunately, neither urinary symptoms nor the severity of the AUA symptom score correlates with the presence or absence of urodynamically proven bladder outlet obstruction.1,2 Men with primary bladder neck obstruction are usually diagnosed at an earlier age or date the onset of their symptoms to an age at which a diagnosis of BPH is unlikely. They similarly complain of both obstructive and irritative voiding symptoms; the degree of urinary hesitancy and reduced force of stream associated with stopping and starting is often impressive. These men are often misdiagnosed as having chronic prostatitis although their obstructive symptoms are more severe than those associated with prostatitis and they lack the associated perineal and scrotal pain. Patients with urethral stricture disease may complain of dysuria, urethral discharge or itch, recurrent hematuria, and urinary tract infections as well as obstructive and irritative voiding symptoms. Spraying during urination is more common with distal strictures located within the penile urethra. Risk factors for urethral stricture disease include previous sexually transmitted diseases, previous urethral instrumentation or catheterization, and urethral trauma. Bladder neck contractures should be considered in all patients who have voiding dysfunction and who have undergone previous prostatectomy. Detrusor-sphincter dyssynergia results in functional obstruction of the bladder at the level of the distal urethral sphincter mechanism. The presence of DSD urodynamically demonstrated is pathognomonic of neurogenic bladder dysfunction. It occurs in most patients with spinal cord injuries who have complete lesions above the level of

the conus, and should be considered a possibility in all patients with spinal cord injuries or other cord lesions accompanied by obstructive voiding symptoms. “Classic” DSD does not occur in patients with LUTS who do not already have a neurologic diagnosis. Patients with hyperactive detrusor function most commonly complain of irritative voiding symptoms, particularly urgency and urge incontinence. Patients with small volume frequency syndrome secondary to bladder instability may report reduced force of stream and urinary hesitancy in the absence of obstruction as a result of small volume voiding. Their flow will become normal if they are forced to delay urination for several hours to allow for adequate filling of their bladder. Nocturnal enuresis in adults most commonly results from bladder instability. Unconscious incontinence, especially when it is of significant volume or flooding, is usually due to bladder instability not perceived as urgency because of abnormal bladder sensation. This is especially common in elderly male patients who have had a stroke or suffer from dementia or other neurologic disorders. Risk factors for hyperactive detrusor function must be identified. Patients with neurogenic bladder dysfunction may also complain of changes in perineal or perirectal sensation, in motor or sensory symptoms involving the lower extremities, or of altered bowel and erectile function. They may give a history of previous stroke or transient ischemic attacks, lumbar disc disease, spinal cord injury or surgery, diabetes, or Parkinson’s disease. Patients who complain of a recent onset of primarily irritative voiding symptoms, especially smokers, must be evaluated for bladder cancer and carcinoma in situ. Patients with long-standing insulin-dependent diabetes may have a hyposensitive bladder and secondary reduced bladder contractility from chronic overdistention and inefficient emptying of their bladder. Patients with hypersensitive bladder disorders often will void frequently because of bladder pain and pressure, not because of urgency or fear of wetness. Sources of suprapubic and bladder pain include bladder cancer, carcinoma in situ, and various causes of cystitis. Carcinoma in situ must be carefully ruled out in all male patients diagnosed with interstitial cystitis as the latter is extremely rare in men. Physical Examination

TABLE 52–2. Diagnostic Evaluation of Lower Urinary Tract Symptoms History and AUA Symptom Index Physical examination Urinalysis and culture Serum creatinine and prostate-specific antigen Simple urodynamics Complex urodynamics Cystoscopy Radiographic imaging

All male patients aged 50 years and older with lower urinary tract symptoms should be given a digital rectal examination to detect for carcinoma of the prostate. The size of the gland does not correlate with symptoms nor does it predict the presence or absence of bladder outlet obstruction. An overdistended bladder may be percussed or palpable suprapubically, and urethral fibrosis may be palpable in patients with urethral stricture disease. All patients suspected of having neurogenic bladder dysfunction should be given a focused neurourologic examina-

Need for Urodynamics and Other Testing / 473 TABLE 52–3. American Urological Association Symptom Index Not At All

Less Than 1 Time in 5

Less Than Half the Time

Half the Time

More Than Half the Time

5 or More Times

1. During the last month or so, how often have you had a sensation of not emptying your bladder completely after you finish urinating?

0

1

2

3

4

5

2. During the last month or so, how often have you had to urinate again less than 2 hours after you finish urinating?

0

1

2

3

4

5

3. During the last month or so, how often have you found you stopped and started again several times when you urinated?

0

1

2

3

4

5

4. During the last month or so, how often have you found it difficult to postpone urination?

0

1

2

3

4

5

Question

5. During the last month or so, how often have you had a weak urinary stream?

0

1

2

3

4

5

6. During the last month or so, how often have you had to push or strain to begin urination?

0

1

2

3

4

5

7. During the last month, how many times did you most typically get up to urinate from time you went to bed at night until the time you got up in the morning?

0

1

2

3

4

5

Pleased 1

Mostly Satisfied 2

Mixed 3

Mostly Dissatisfied 4

Unhappy 5

Terrible 6

8. If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about it?

Delighted 0

tion that includes assessment of anal tone, voluntary control of the anal sphincter, and perirectal sensation, confirmation of the presence of the bulbospongiosus reflex, and examination of the lower back for dermatologic stigmata suggestive of myelomeningocele. Laboratory Tests All patients with voiding dysfunction should undergo a urinalysis, and a urine culture when necessary, to rule out urinary tract infection and detect for microscopic hematuria. The Agency for Health Care Policy and Research clinical practice guidelines recommends a serum creatinine in all patients with BPH to detect for obstructive uropathy and silent renal insufficiency, which occur in approximately 1 to 2% of men with benign prostatic hyperplasia.3 Renal function should be assessed in all male patients with voiding dysfunction who have a significantly elevated postvoid residual urine volume. It is beyond the scope of this chapter to discuss the controversies sur-

rounding the use of serum prostate-specific antigen (PSA) as a routine screening test in aging male patients. It is recommended for all patients suspected of having prostatic carcinoma, especially those with a positive family history.

Urodynamic Evaluation Urodynamics encompasses a number of complementary techniques of varying degrees of complexity, the application of which need to be tailored to meet the clinical requirements of each case. In male patients, urodynamics are primarily used to assess detrusor function during bladder filling, to evaluate voiding function, to determine the presence or absence of bladder outlet obstruction, and to diagnose and characterize neurogenic bladder dysfunction. Urodynamics is often classified as being either simple or complex. Simple urodynamics includes volume/frequency charts, uroflowmetry, and determination of postvoid residual urine volume. Complex urodynamics includes cystometry, multifunction pressure-flow studies, sphincter electromyography, videourodynamics, and ambulatory urodynamic monitoring.

mL

Volume/Frequency Charts

FIGURE 52–1. Normal uroflow pattern.

The volume/frequency chart is a simple, noninvasive tool used to evaluate patients with voiding dysfunction, particularly those with increased urinary frequency and incontinence. The chart, though generally underutilized, is most commonly used to evaluate females with urinary incontinence but can also provide useful information regarding males with lower urinary tract symptoms. Typically, the patient records fluid intake and time and volume of each void for 3 to 5 days. Episodes of inconti-

Uroflowmetry Uroflowmetry is the simplest and only noninvasive urodynamic investigation. When combined with measurement of the postvoid residual volume, it is an invaluable screening test for bladder outlet obstruction in male patients with voiding dysfunction. It is also useful in identifying those patients who might benefit from more extensive urodynamic evaluation. Uroflowmetry is routinely used by most urologists in assessing men with lower urinary tract symptoms. The voided volume is defined as the total volume voided. The maximum or peak urinary flow rate (Qmax) is the maximum measured flow rate. The average flow rate is the voided volume divided by the flow time, which is the time during which measurable flow occurs. Patients should present for uroflow with a comfortably full bladder. They should be asked to void normally, either sitting or standing, and be provided with as much privacy as possible to remove inhibitory effects of the testing environment. Individuals may show considerable variation in consecutive maximum flow rates, which may be related to a learning effect on part of the patient.4 Despite this phenomenon, it is generally agreed that a single flow rate measurement in men with BPH is sufficiently accurate as long as the voided volume is satisfactory and the patient reports that it reflects his normal voiding habit. Urinary flow rates are dependent on sex, age, and volume voided. In elderly men a maximum urinary flow rate

> 15 mL per second is generally considered normal. Most men with bladder outlet obstruction have maximum urinary flow rates < 12 mL per second. Flow rates measured with voided volumes < 120 to 150 mL may be erroneous and should be repeated. Nomograms designed to relate volume voided to maximum urinary flow rate may be useful in interpreting flow rates recorded at lower voided volumes.5,6 There is no universally accepted nomogram for flow rate correction and these tools are not commonly employed in clinical practice. The appearance of the flow curve must also be considered when interpreting uroflows. The normal flow rate pattern is bell-shaped and characterized by a rapid rise to maximum flow, with the time to maximum flow not exceeding one-third of the flow time (Figure 52–1). Obstructed patients generally have a low maximum flow rate, prolonged flow time, and a slow time to maximum flow (Figure 52–2). Patients with decompensated detrusors typically demonstrate a straining pattern characterized by irregular spiking on their flow curve (Figure 52–3). Patients with urethral stricture disease often have a low maximum flow rate which plateaus in a box-like fashion on their flow curve. It is generally agreed that urinary flow rate is not diminished in patients with stricture disease until the urethral caliber reaches 10F. Although some studies advocate the diagnostic potential of these standard patterns for patients with specific pathologic conditions, data to strongly justify use of flow curve patterns in the differential diagnosis of men with LUTS is lacking.7–9 The sensitivity of uroflowmetry to diagnose bladder outlet obstruction secondary to BPH and its specificity in excluding patients with other causes is limited. Shoukry et al. assessed the value of uroflowmetry in diagnosing prostatic obstruction in 173 patients with lower urinary tract symptoms.10 They found that symptoms of prostatic obstruction were commonly associated with reduced maximum urinary flow rate and concluded that uroflowmetry diagnosed bladder outlet obstruction with a reasonable degree of accuracy. The value of this study is limited by the authors’ assumption that a diagnosis of bladder outlet obstruction can be made by symptoms alone, excluding pressure-flow urodynamics.

mL

mL


nence and severity of urine loss and pad usage should also be recorded. The record of fluid intake helps identify an easily treatable cause of urinary frequency. The average maximum voided volume represents the patient’s functional capacity, knowledge of which is useful to prevent bladder overfilling during cystometry. The bladder normally fills to a volume approximating its functional capacity prior to urination; the chart records a series of fairly consistent and sizeable (300 to 500 mL) voided volumes. An unstable bladder contracts at variable levels of bladder filling, typically resulting in urinary frequency and low and variable voided volumes. Consistently high voided volumes (> 600 mL) may be indicative of patients with bladder hyposensitivity.

FIGURE 52–2. Obstructed uroflow pattern.

FIGURE 52–3. Straining uroflow pattern.

Siroky et al. analyzed 53 patients with lower urinary tract symptoms and found that nearly all patients had a maximum urinary flow rate below the 2nd standard deviation, improving to above the 2nd standard deviation in all cases following prostatectomy. The authors concluded that urowflowmetry is helpful in distinguishing normal from obstructed patients.11 Gleason et al. found that the maximum urinary flow rate distinguished 121 normal men from 463 patients with either BPH, urethral stricture disease, or prostatitis but that it did not differentiate the latter three diagnoses.12 This study was also flawed by the authors’ assumption that a diagnosis of bladder outlet obstruction can be made based solely on symptoms. Uroflow measurements are dependent on detrusor contractility, relaxation of the sphincter mechanism, and the presence or absence of bladder outlet obstruction. Reduced flow rate is not diagnostic of bladder outlet obstruction. Chancellor et al. and Gleason found in separate studies that uroflowmetry did not distinguish between impaired detrusor contractility and bladder outlet obstruction.12,13 Approximately 25% of men with LUTS and reduced maximum urinary flow rates have poor detrusor contractility rather than bladder outlet obstruction.4 Conversely, a normal maximum urinary flow rate does not exclude a diagnosis of obstruction. Seven percent of patients with normal flow rates are obstructed with high voiding pressures.14 Patients with lower urinary tract symptoms thought to have bladder outlet obstruction secondary to BPH but who also have maximum urinary flow rates > 15 mL per second should be evaluated with pressure-flow studies to reduce treatment failures prior to invasive therapies being undertaken. Several investigators have assessed the value of uroflowmetry for predicting surgical outcome prior to prostatectomy. Patients with a maximum urinary flow rate < 10 mL per second prior to prostatectomy had a statistically significant better symptomatic outcome relative to patients with high flow rates.15 Jensen et al. similarly showed that patients with a maximum urinary flow rate > 15 mL per second have somewhat poorer outcomes following transurethral resection of the prostate (TURP) than patients with lower flow rates.16 Abrams et al. found that their surgical failure rates decreased from 28 to 12% when flow rate determination was included with symptoms as opposed to symptoms alone as part of their preoperative evaluation.17 McLoughlin et al. studied 108 men and found that a maximum urinary flow rate of < 12 mL per second reduced the number of misdiagnosed patients undergoing a TURP.18 In spite of these studies, no cutoff for maximum urinary flow rate exists that reliably predicts bladder outlet obstruction and surgical outcome. Postvoid Residual Urine Determination of postvoid residual urine volume following spontaneous voiding or uroflowmetry provides useful

PdetQmax (cm H2O)

Need for Urodynamics and Other Testing / 475

FIGURE 52–4. The Abrams-Griffiths nomogram.

information for evaluating patients with lower urinary tract symptoms. Though the “gold standard” for measuring residual volume is properly performed urethral catheterization, accurate measurement may also be determined by transabdominal ultrasound. The BladderScan BVI 2500 is a compact ultrasound unit that automatically computes bladder volume from cross-sectional readings of the bladder. It is accurate in adult patients. Coombes and Millard compared ultrasound measurements to bladder volumes obtained by catheterization and fluoroscopic screening in 100 patients, showing an excellent correlation of 0.97 (r2 = 0.94) and a mean difference between the two measures of 24 mL.19 Normal postvoid residual urine volume is < 100 mL and ideally less than one-third the voided volume. It should be recognized that residual urine volumes vary in subsequent measures in the same patient taken on the same day.20 Bruskewitz et al. studied 49 patients with lower urinary tract symptoms selected for TURP and found wide variations in postvoid residual urine volume in individual patients.21 In the current authors’ opinion, elevated or borderline elevated residual urine volumes should be repeated. Having a normal postvoid residual urine volume, however, does not rule out the diagnosis of bladder outlet obstruction. Conversely, an elevated residual is not diagnostic of obstruction. Abrams et al.22 and TurnerWarwick23 believe that an elevated residual urine volume may reflect bladder dysfunction or bladder decompression rather than bladder outlet obstruction. Abrams et al. assessed 117 patients, 77 of whom (66%) had a residual urine volume ≥ 50 mL and a mean residual urine volume of 116 mL. They found that 11 of 21 patients (52%) who were unobstructed urodynamically had residual urine volumes ≥ 50 mL and an average volume of 74 mL and concluded that there was minimal association between residual urine volume and obstruction.22 Despite the lack of data regarding the diagnostic role of measuring postvoid residual urine volume in patients with lower urinary tract symptoms, it is clearly advantageous to do so. Residual urine volume is an excellent screening tool for detecting the 1 to 2% of patients with


BPH who often present with milder symptoms but have asymptomatic bilateral hydronephrosis and renal insufficiency secondary to obstructive uropathy. These patients typically show significantly elevated postvoid residuals. Although there is no recommended cutoff, all patients with significantly elevated residual urine volumes should undergo a renal ultrasound combined with a serum creatinine to rule out hydronephrosis. Without routine measurement of postvoid urine volumes, the majority of patients with obstructive uropathy could go undiagnosed, significantly affecting outcome. Patients presenting with “chronic retention,” reported urinary symptoms, and grossly elevated postvoid urine volumes in the range of 700 to 800 mL or greater not associated with suprapubic or abdominal pain, are similarly diagnosed by measurement of postvoid residuals. The majority of these patients have decompensated detrusors with or without bladder outlet obstruction. These patients should be managed aggressively, with the role of surgery defined by pressure-flow urodynamics. They should not be managed by watchful waiting or medical therapy alone. Most will require intermittent catheterization until their bladder contractility is seen to improve urodynamic evaluation. Patients with moderately elevated postvoids secondary to bladder outlet obstruction should be followed more carefully and possibly treated more aggressively than those patients who empty efficiently. Patients with elevated residual urine volumes may deteriorate with watchful waiting; data regarding its value in predicting outcome with medical therapy or surgery are limited. Increasing residual urine volumes over time is an indication for surgical intervention in patients with detrusor contractility and bladder outlet obstruction. Pressure-Flow Studies Uroflowmetry alone cannot differentiate between high pressure/low flow and low pressure/low flow in patients with lower urinary tract symptoms. Simultaneous measurement of subtracted detrusor pressure, maximum urinary flow rate, and sphincter electromyography allows the clinician to determine whether impaired voiding is due to abnormalities of detrusor contractility, failure of sphincter relaxation, or an obstructed bladder outlet. The location of the obstruction may be determined by fluoroscopic monitoring during voiding (video urodynamics). Pressure-flow studies may also be used to identify high-pressure obstruction in symptomatic men with normal flow rates. The study should attempt to approximate normal voiding, with interpretation of results taking into account the potential adverse effects of the testing environment. Many men with a “bashful bladder” are not able to void and generate a normal detrusor contraction without privacy. The inability to establish a detrusor contraction in the laboratory does not necessarily imply total

obstruction or detrusor acontractility. Further insight into this has been gained with increased use of ambulatory urodynamic monitoring. Detrusor pressure at maximum flow and the maximum detrusor pressure during flow are the two voiding pressures evaluated during pressure-flow urodynamics. On occasion, the maximum detrusor pressure exceeds the pressure at maximum flow when the bladder is contracting isometrically against a closed sphincter. Classically, the high-pressure, low-flow micturition profile is typical of obstruction. At what point pressure-flow should be considered obstructive, however, has not been clearly established. Obstruction is indicated by a maximum detrusor pressure in excess of 100 cm of water, regardless of flow rate. Many experts contend that a voiding pressure greater than 60 cm of water achieving a maximum urinary flow rate < 12 mL per second implies obstruction. Lower voiding pressures that are well sustained but associated with very low flow rates may also signify obstruction in some patients. The results of pressure and flow studies can be classified according to a number of nomograms, the most popular of which are the Abrams-Griffiths nomogram and the Schafer linear passive urethral resistance relation (LinPURR). Patients are conveniently classified as obstructed, unobstructed, or equivocally obstructed using the Abrams-Griffiths nomogram (Figure 52–4). The LinPURR grades detrusor contractility on a scale from very weak (VW) to strong (ST) and quantifies obstruction from grade 0 (no obstruction) to VI (severe obstruction) (Figure 52–5).24 The Abrams-Griffiths nomogram is more commonly used because of its simplicity. Many urologists make decisions regarding the treatment of patients with BPH based on symptoms alone. It has been shown, however, that lower urinary tract symptoms do not correlate well with the presence or absence of bladder outlet obstruction. Similarly, the severity of symptoms measured by the sum of the responses to the seven questions of the American Urological Association Symptom Index does not correlate with the grade of obstruction obtained by utilizing the Schafer Lin-PURR relation nomogram and maximum urinary flow rate.1,2 The International Continence Society (ICS) recently published data from the ICS-BPH

FIGURE 52–5. The Schafer nomogram.


study. This was a multicenter study that used the ICS-BPH questionnaire and urodynamic and pressure-flow studies to evaluate 933 patients with lower urinary tract symptoms. The new questionnaire was developed to incorporate all urinary symptoms, related problems, and quality-of-life issues that could be indicative of bladder outlet obstruction, detrusor instability, and detrusor underactivity. Each question concerning a specific symptom was correlated with maximum urinary flow rate, detrusor pressure and maximum flow, and with the degree of obstruction based on the Schafer nomogram. Little to no correlation was shown between the various symptoms and the results of free uroflowmetry and pressure-flow studies.25 Abrams and Griffiths classified 117 male patients with lower urinary tract symptoms as unobstructed or obstructed based on urodynamic parameters.26 Approximately 50% of patients could be appropriately classified based on maximum urinary flow rate alone. Pressureflow studies could satisfactorily assess obstruction in twothirds of cases. The remaining one-third of patients were assessed by pressure-flow plot, with many being diagnosed as low pressure/low flow secondary to reduced bladder contractility. The evidence supporting the usefulness of pressureflow studies to predict surgical outcome is equivocal. It remains debatable whether separating symptomatic patients with proven high pressure/low flow or obstruction from patients with low pressure/low flow affects treatment selection and therapeutic outcome. Kuo and Tsai studied 50 patients treated by TURP to assess the predictive value of preoperative urodynamics.27 The surgical success rate was statistically improved in patients with high pressure/low flow preoperatively compared to patients with low voiding pressures. Abrams found among 152 patients who had had prostatectomy that urodynamics included in the preoperative evaluation improved the subjective improvement rate from 72 to 88%.28 Using the Abrams-Griffiths nomogram and pressure-flow plot, Jensen et al. classified 130 patients as obstructed (87), unobstructed (36), or equivocal (7) prior to TURP.29 The surgical success rate for the obstructed versus unobstructed groups was 93% and 78%, respectively (p < .02). The authors concluded that pressure-flow studies were useful in predicting outcome in patients with BPH prior to surgery. In contrast, Bruskewitz et al. found no relation between outcome following TURP in patients classified preoperatively as obstructed versus unobstructed based on urethral resistance.30 The data regarding the usefulness of pressure-flow studies as a predictor of outcome following surgery are limited and at best of only modest value compared to symptoms and uroflowmetry. Because of their invasiveness, cost, and limited predictive value, pressure-flow studies are not routinely performed in evaluating patients with BPH. There are, however, still clear clinical situa-

tions in which pressure-flow determination is not only valuable but highly recommended. Patients presenting with chronic urinary retention should in many cases be evaluated with pressure-flow studies prior to surgery or invasive therapy. These patients typically present with voiding symptoms and high postvoid residual urine volumes (> 700 to 800 mL), not associated with suprapubic discomfort. They should also be screened for silent hydronephrosis and obstructive uropathy. These men usually have chronic bladder decompression and poor detrusor contractility, either primarily or secondary to long-standing bladder outlet obstruction. They are initially treated by urethral catheterization, often combined with a selective alpha-1 antagonist. Unfortunately, most continue to be in near urinary retention despite conservative therapy. Although data regarding the success rate of surgical therapy in this group are limited, most of these patients remain symptomatic and continue to have high residuals postoperatively, often requiring long-term intermittent catheterization. Pressure-flow studies help identify those patients with detrusor contractility and those more likely to do better postoperatively. In contrast, the patient with a significantly increased maximum cystometric capacity of > 800 mL associated with no or very poor sensation of fullness, and who is unable to generate an involuntary or voluntary detrusor contraction, is unlikely to improve significantly following surgery. Identification of these high- and lower-risk groups can only be made with urodynamics. This differentiation becomes particularly important in high surgical risk patients. In those patients who are considering surgery, the urodynamic information yields useful predictive information, allowing more realistic expectations for both the physician and patient. Patients with LUTS suspected of having neurogenic bladder dysfunction should be evaluated with urodynamics prior to therapy, especially surgery. Patients with spinal cord injuries are infrequently misdiagnosed as having BPH but many other groups of patients may not be identified as having neurogenic bladder dysfunction without a careful history, urodynamics, and a high degree of suspicion. Patients who have had a stroke, have diabetes, Parkinson’s disease, dementia, or a past history of back injury or surgery are among the many groups who should be suspected of having a neurogenic bladder. Their obstructive voiding symptoms may be secondary to external sphincter dyssynergia, detrusor areflexia, or may result from frequent small volume voiding; these possible causes may be distinguished by cystometry and pressure-flow urodynamics. Irritative voiding symptoms are similarly common in patients with neurogenic bladder dysfunction secondary to alterations in bladder sensation, detrusor hyperreflexia, or loss of bladder compliance. Video urodynamics can be very helpful in identifying the site of obstruction in patients with external sphincter dyssyner-


gia versus BPH and can also identify those with a highpressure, neurogenic, Christmas tree-shaped bladder. The subtle findings demonstrated on urodynamics, combined with the patient’s urologic history and a physical examination, make nonspecific urodynamic findings highly diagnostic. For example, detrusor acontractility associated with loss of bladder sensation, significant detrusor instability, or loss of compliance in a patient who has diminished perineal sensation and who reports two previous lumbar diskectomies is highly likely to have a neurogenic bladder that will not respond to surgery, rather than a bashful bladder and BPH. The cumulative significance of mild abnormalities and risk factors identified by a careful history, physical examination, and urodynamics should not be underestimated in differentiating patients with neurogenic bladder dysfunction from those with BPH. Younger men who report the onset of symptoms at an age that makes BPH unlikely should similarly be evaluated for other causes, including neurogenic bladder dysfunction, urethral stricture disease, and primary bladder neck obstruction. Symptomatic patients presumably with bladder outlet obstruction but with maximum urinary flow rates > 15 mL per second should also be considered for pressure-flow studies. Approximately 7% of these patients have bladder outlet obstruction;15 evidence suggests that patients with maximum flows > 15 mL per second have statistically lower symptomatic success rates following surgery.16 Cystometry The cystometrogram is able to demonstrate detrusor instability in BPH patients complaining of irritative voiding symptoms. Bladders that were previously stable often develop instability in association with bladder outlet obstruction. Secondary detrusor instability occurs in up to 75% of patients with obstructive BPH.31 There are a number of studies reporting that relief of obstruction leads to amelioration of bladder instability in roughly 75% of cases.23,32 Patients with persistent bladder instability following surgery tend to remain symptomatic.19 It is generally felt, however, that the presence of bladder instability prior to surgery is not predictive of detrusor hyperactivity postoperatively. In most cases, a cystometrogram is not performed in evaluating men with lower urinary tract symptoms. As is the case with pressure-flow studies, there are clearly select circumstances in which the cystometrogram plays an important role and is recommended. Patients with lower urinary tract symptoms suspected of having neurogenic bladder dysfunction should be evaluated with cystometry prior to invasive therapy and surgery. These patients often have significant abnormalities in bladder storage, including loss of bladder compliance, detrusor instability, and abnormal bladder sensation, all of which may significantly alter treatment selection and therapeutic outcome. Many patients have

risk factors and symptoms that suggest a neurologic etiology. These can only be identified by determining the patient’s voiding history, giving them a physical examination, and maintaining a high degree of suspicion. For example, an elderly male patient who has had a previous stroke and who complains of impressive irritative voiding symptoms including urgency or unconscious incontinence is highly likely to have a neurogenic unstable bladder. He should be investigated with urodynamics, regardless of the severity of his obstructive symptoms and his measured maximum urinary flow rate. The presence of high-pressure instability occurring at low bladder volumes associated with incontinence is highly suggestive of neurogenic bladder dysfunction in this instance, even if the patient is urodynamically obstructed. It is naive to generalize and assume that this patients’ overactive bladder has a 75% likelihood of normalizing following surgical relief of his obstruction, and that his preoperative urodynamics are not predictive of a poor surgical outcome. Not only might his symptoms persist postoperatively, but his urgency incontinence may worsen. It is much less likely that a patient’s unstable bladder will improve following surgery if his bladder hyperactivity is secondary to other disease processes. Urodynamics gives the urologist the best means of making this important distinction preoperatively. Failure to respond to selective α-1 blockade may tend to select patients who might not have bladder outlet obstruction, making urodynamics even more important to consider. Patients remaining symptomatic following prostatectomy should be evaluated with cystometry and pressureflow studies before being considered for resection of “residual adenoma.” Approximately 25% of men continue to be symptomatic following TURP, the majority experiencing either detrusor hyperactivity or low pressure/low flow. Repeat transurethral resection should be limited to those with urodynamic evidence of bladder outlet obstruction. Patients with BPH who have primarily irritative voiding symptoms and milder obstructive symptoms should be considered for urodynamics even in the absence of neurologic risk factors. Reported urgency incontinence or unconscious incontinence is highly suggestive of significant bladder instability originating in the bladder or secondary to obstruction. Carcinoma of the bladder must also be considered. It is very reasonable to investigate this group of patients urodynamically prior to invasive therapy, especially if they have failed prior α−blocker therapy. Finally, male patients with LUTS associated with urinary incontinence should be evaluated with urodynamics. Most incontinent men have either overflow incontinence secondary to inefficient bladder emptying, stress incontinence following prostatectomy, or unconscious or urgency incontinence due to bladder instability. Their bladder hyperactivity or high residual urine volume may be due to primary bladder dysfunction or may be secondary to bladder outlet obstruction; the distinction is of


obvious importance with regard to selecting therapy. Wrongly assuming that the majority of incontinent patients have BPH and bladder outlet obstruction without investigating them will result in a number of treatment failures and in unnecessary surgery. Video Urodynamics Video urodynamics combines fluoroscopic visualization of the bladder and urethra during cystometry and pressureflow studies. It adds an anatomic and often complementary aspect to urodynamics and carries with it unique advantages. The anatomic location of bladder outlet obstruction is most easily determined using fluoroscopy to identify obstruction at the bladder neck, prostate, external sphincter mechanism, or urethra. Patients suspected of primary bladder neck obstruction should be evaluated with video studies before the surgeon proceeds with transurethral incision of the bladder neck. External sphincter dyssynergia may be readily identified with fluoroscopy, with or without simultaneous electromyography. The presence of a Christmas tree-shaped bladder (that may be associated with vesicourethral reflux and an open decompensated bladder neck and proximal urethra) is highly suggestive of neurogenic bladder, particularly in patients without long-standing obstructive BPH. Video urodynamics is recommended for patients with known neurogenic bladder dysfunction, especially those with high filling pressures on cystometry. It enables the clinician to detect pressure-induced changes in bladder appearance (trabeculation, diverticula, reflux, etc.) that may precede deterioration in renal function and potentially influence patient surveillance and treatment. Video urodynamics also provides state-of-the-art evaluation of male patients with urinary incontinence. Despite these advantages, the role of video urodynamics in evaluating men with lower urinary tract symptoms is limited to select cases. Ambulatory Urodynamics Ambulatory urodynamic monitoring has gained increasing popularity as a way of evaluating lower urinary tract dysfunction. Advances in microprocessor technology have made ambulatory urodynamics equipment reasonably affordable, lightweight, and increasingly available to the urologist. Conventional urodynamics is not without potential drawbacks—the procedures involved lack privacy and utilize nonphysiologic fill-rates and media which may alter the behavior of the detrusor and urethra. Ambulatory monitoring overcomes several of these inherent problems although artifacts during the recording continue to be problematic. Ambulatory studies provide a much longer “physiologic” filling phase, which enhances the detection of detrusor instability and provides a more accurate recording of bladder capacity and pressure during filling. There is a question as to whether ambulatory urodynamic monitoring improves the diagnostic capability of

urodynamics and whether it influences evaluation of men with LUTS. Webb et al. compared voiding pressures in ambulatory and conventional urodynamics in 20 men awaiting prostatectomy. They found that the mean detrusor pressure was approximately 30 cm H2O higher in the former and suggested that the nonphysiologic nature of the conventional urodynamic evaluation may have adversely affected detrusor contractility, resulting in lower voiding pressures.33 The current authors have recently studied a similar group of 64 men and found no significant differences in maximum detrusor pressure and detrusor pressure at peak flow between the two urodynamic techniques. Roughly 50% of patients with symptoms highly suggestive of bladder instability have instability detected during conventional urodynamics. It appears from limited data that ambulatory monitoring is more sensitive in detecting detrusor instability than are conventional studies but the clinical usefulness of this finding has not been ascertained.34 Lower end filling pressures and improved bladder compliance have been demonstrated during ambulatory monitoring in patients with both chronic retention and neurogenic bladder and who have high filling pressures on conventional studies. In summary, ambulatory monitoring has demonstrated differences compared to conventional urodynamic studies in a limited number of studies. It offers theoretic advantages over conventional monitoring but is not routinely used in investigating men with LUTS. Cystoscopy Cystoscopy is not recommended as part of the routine evaluation of men with BPH.3 It provides little information regarding vesicourethral function and the presence or absence of bladder outlet obstruction. It has also been established that there is no correlation between prostate size and the presence or absence of outlet obstruction. Indications for cystoscopy include hematuria, suspicion of bladder calculi or carcinoma, and ruling out of urethral stricture or bladder neck contracture; younger men with primary bladder neck obstruction have no specific cystoscopic findings. The diagnosis is only reliably made with video urodynamics. Some urologists utilize cystoscopy in patients with large glands to determine the most appropriate surgical approach. The presence of bladder trabeculations, cellules, diverticula as well as the endoscopic appearance of the adenoma appear to have very little diagnostic or predictive value.

Conclusion There are limited data supporting the role of complex urodynamics in patients with benign prostate hyperplasia. In this population, cystometry and pressure-flow studies have very little predictive value. Although routine application of urodynamics is unnecessary, it does play a major diagnostic role in evaluating symptomatic patients and differenti-


ating men with BPH from those with other disease processes. Appropriate use of this information ultimately translates into proper treatment selection and improved therapeutic outcome. Combining subtleties elicited from the patient’s history and physical examination with nonspecific urodynamic and sometimes cystoscopic findings optimizes the diagnostic capability of urodynamics. This is the art of assessing patients with voiding dysfunction.

References 1. Barry MJ, Crockett ATK, Holtgrewe HL, et al. Relationship of symptoms of prostatism to commonly used physiological and anatomical measures of the severity of benign prostatic hyperplasia. J Urol 1993;150:351–8. 2. Ko DSC, Fenster HN, Chambers K, et al. The correlation of multichannel urodynamic pressure-flow studies and AUA symptom index in the evaluation of benign prostatic hyperplasia. J Urol 1995;154:396–8. 3. McConnell JD, Barry MJ, Bruskewitz RC, et al. Benign prostatic hyperplasia: diagnosis and treatment. Clinical Practice Guideline, Number 8. Rockville (MD): Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services; 1994. p. 15–7. AHCPR Publication No.: 94-0582. 4. Drach GW, Layton TN, Binard WJ. Male peak urinary flow-rate: relationship to volume voided and age. J Urol 1979;122:210–4. 5. Siroky MB, Olsson CA, Krane RJ. The flow rate nomogram. I. Development. J Urol 1979;122:665–8. 6. Haylen BT, Ashby D, Sutherst JR, et al. Maximum and average urine flow rates in normal male and female populations—the Liverpool nomograms. Br J Urol 1989;64:30–8. 7. Rollema HJ. Uroflowmetry. In: Krane RJ, Siroky MB, editors. Clinical neurourology, 2nd ed. Boston: Little, Brown & Co.; 1991. p. 201–44. 8. Tripathi VN, Sridhar M. Urodiagrams: a new method of uroflow pattern analysis. J Urol 1983;130:309–11. 9. Van de Beek C, Stoevelaar HJ, McDonnell J, et al. Interpretation of uroflowmetry curves by urologists. J Urol 1997;157:164–8. 10. Shoukry I, Susset JG, Elkilali MM, Dutartre D. Role of uroflowmetry in the assessment of lower urinary tract obstruction in adult males. Br J Urol 1975;47(Pt 2): 559–66. 11. Siroky MB, Olsson CA, Krane RJ. The flow rate nomogram. II. Clinical correlation. J Urol 1980;123:208–10. 12. Gleason DM, Bottaccini MR, Drach GW, Layton TN. Urinary flow velocity as an index of male voiding function. J Urol 1982;128:1363–7. 13. Chancellor MB, Blaivas JG, Kaplan SA, Axelrod S. Bladder outlet obstruction versus impaired detrusor contractility: the role of uroflow. J Urol 1991;145:810–2. 14. Gerstenberg TC, Andersen JT, Klarskov P. High flow intravesical obstruction in the male. J Urol 1982;127: 943–5. 15. Jensen KM-E, Bruskewitz RC, Iversen P, Madsen PO. Spontaneous uroflowmetry in prostatism. Urology 1984;24:403–9. 16. Jensen KM-E, Jorgensen JB, Morgensen P. Urodynamics in

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prostatism. I. Prognostic value of uroflowmetry. Scand J Nephrol 1988;22:109–17. Abrams PH, Farrar DJ, Turner-Warwick RT, et al. The results of prostatectomy: a symptomatic and urodynamic analysis of 152 patients. J Urol 1979;121:640–2. McLoughlin J, Gill KP, Abel PD, Williams G. Symptoms versus flow rates versus urodynamics in the selection of patients for prostatectomy. Br J Urol 1990;66:303–5. Coombes GM, Millard RJ. The accuracy of portable ultrasound scanning in the measurement of residual urine volume. J Urol 1994;152:2083–5. Birch NC, Hurst G, Doyle PT. Serial residual volumes in men with prostatic hypertrophy. Br J Urol 1988; 62:571–5. Bruskewitz RC, Iversen P, Madsen PO. Value of postvoid residual urine determination in evaluation of prostatism. Urology 1982;20:602–4. Abrams P, Blaivas JG, Stanton SL, Andersen JT. Standardization of terminology of lower urinary tract function. Neurourol Urodyn 1988;7:403–27. Turner-Warwick R. Observations on the function and dysfunction of the sphincter and detrusor mechanisms. Urol Clin North Am 1979;6:13–30. Schafer W, Rubben H, Noppeney R, Deutz F-J. Obstructed and unobstructed prostatic obstruction. A plea for urodynamic objectivation of bladder outflow obstruction in benign prostatic hyperplasia. World J Urol 1989;6:198–203. de la Rosette JJNCH, Witjes WPJ, Schafer W, et al. Relationships between lower urinary tract symptoms and bladder outlet obstruction: results from the ICS“BPH” study. Neurourol Urodyn 1998;17:99–108. Abrams PH, Griffiths DJ. The assessment of prostatic obstruction from urodynamic measurements and from residual urine. Br J Urol 1979;51:129–34. Kuo HC, Tsai TC. The predictive value of urine flow rate and voiding pressure in the operative outcome of benign prostatic hypertrophy. Taiwan I Hsueh Hui Tsa Chih 1988;87:323–30. Abrams PH. Prostatism and prostatectomy: the value of urine flow rate measurement in the preoperative assessment for operation. J Urol 1977;117:70–1. Jensen KM-E, Jorgensen JB, Morgensen P. Urodynamics in prostatism. II. Prognostic value of pressure-flow study combined with stop-flow test. Scand J Urol Nephrol Suppl 1988;114:72–7. Bruskewitz RC, Jensen KM-E, Iversen P, Madsen PO. The relevance of minimum urethral resistance in prostatism. J Urol 1983;129:769–71. Abrams PH. Detrusor instability and bladder outlet obstruction. Neurourol Urodyn 1985;4:317–28. Webb RJ, Griffiths CJ, Ramsden PD, Neal DE. Measurement of voiding pressure on ambulatory monitoring: comparison with conventional cystometry. Br J Urol 1990;65:152–4. Webb RJ, Ramsden PD, Neal DE. Ambulatory monitoring and electronic measurement of urinary leakage in the diagnosis of detrusor instability and incontinence. Br J Urol 1991;68:148–52. Webb RJ, Griffiths CJ, Ramsden PD, Neal DE. Ambulatory monitoring in low compliance neuropathic bladder function. J Urol 1992;148:1477–81.

CHAPTER 53

MINIMAL ESSENTIAL DIAGNOSTIC TESTING RASMUS H. KROGH, MD; REGINALD C. BRUSKEWITZ, MD The diagnostic objective is to elucidate the patient’s condition sufficiently to find the right treatment approach and rule out other pathology without exposing the patient to unnecessary testing. The diagnostic techniques will be evaluated in this chapter through a critique of the USA/WHO guidelines. Guideline recommendations are outlined in the BPH decision diagram (Figure 53–1).

Benign prostatic hyperplasia (BPH) is one of the most common causes of morbidity in elderly men. No single diagnostic criterion for BPH has gained wide clinical acceptance, however, and the prevalence estimates depend very much on the criteria used. The prevalence of moderate to severe lower urinary tract symptoms (LUTS) has been estimated at 8 to 31% among men in their fifties, increasing with age to 27 to 44% among men in their sixties and seventies.1 The prevalence of histologic BPH in these same age groups is higher.2 The increase in the elderly male population combined with an increase in treatment options suggest that BPH/LUTS will continue to keep urologists and primary care physicians busy. Official recommendations for managing BPH are presented comprehensively in the World Health Organization (WHO) International Guidelines (1996) and in the USA BPH Guidelines (1994) from the United States Agency for Health Care Policy and Research (AHCPR).3,4 Both guidelines apply to a typical male patient older than 50 years with LUTS suggestive of bladder outlet obstruction (BOO) with no other known conditions. The terminology of BPH has changed over the past decade. The term “prostatism” was formerly broadly used to describe urinary symptoms in elderly men. It was inaccurate in many cases since no set of urinary symptoms are diagnostic for BPH. That classic prostatism symptoms may not be caused by prostatic disease is clearly illustrated by the fact that they are not gender specific.5–7 Lower urinary tract symptoms has been proposed as a more adequate expression.8 Neither prostatism nor LUTS, however, recognizes that the symptoms may have originated in the upper urinary tract or outside the urinary tract (e.g., as a result of polyuria, secondary polydipsia, congestive heart failure, etc.) Currently, BPH is considered a histologic diagnosis, LUTS has replaced what was formerly termed prostatism, and BOO describes urodynamic findings. Because the three conditions may or may not coexist, each patient must be evaluated individually.

Initial Evaluation All patients should initially be evaluated as described below. Medical History It is essential that a thorough medical history be taken to determine whether the patient’s symptoms are consistent with prostatic disease. Medication history is important as many drugs can contribute to urinary symptoms. Such drugs include cold and allergy medications, diuretics, anticholinergics, and alpha sympathomimetics. Of special interest is any history of hematuria, urinary tract infection, neurologic disorders which might cause a neurogenic bladder, instrumentation possibly leading to urethral stricture, trauma, sexually transmitted disease, and urinary retention. The degree of bother to the patient is most important. Symptom and bother assessment are discussed below. Physical Examination Inspection of the patient may suggest uremia, anemia, or edema, all occasionally associated with BPH, as well as other medical conditions. Palpation of the abdomen and over the kidneys may suggest bladder distention or occasionally identify renal pathology; it is routine, if seldom helpful. The physical examination includes a digital rectal examination (DRE) and a focused neurologic examination. The former provides information on anal sphincter tone and prostate asymmetry or induration, which may indicate prostate or colorectal cancer. While DRE gives the physician some idea of prostate size, it does not correlate well with prostate size estimated by transrectal ultrasound (TRUS)9–11 or prostate weight.12 Further, prostate size assessed by DRE correlates poorly with the severity of LUTS.13 When determination of prostate size

Diagnostic Testing When a patient presents with LUTS suggesting BPH, the physician may choose from a variety of diagnostic tests. 481


is important in guiding treatment selection, TRUS or transabdominal ultrasound are the preferred technique. The WHO guidelines highly recommend that the focused neurologic examination include assessment of bulbocavernosal reflex and of the motor and sensory function of the lower extremities.4 Manifestations of neurologic disease arouse suspicion of a neurogenic bladder. Such patients often require more than just the standard workup (e.g., a pressure-flow study may be appropriate).

Urinalysis Both urinary tract infection (UTI) and bladder cancer may cause symptoms resembling BPH. Urinalysis is generally recommended to screen for UTI and hematuria in patients presenting with LUTS. Urine dipsticks, inexpensive and simple to use, have largely supplanted microscopic examination of the spun sediment for screening purposes. The value of this screening technique is in dispute but may be useful in this selected patient group despite the lack of evi-

FIGURE 53–1. Decision diagram. Recommended and optional tests in BPH management. Based on the USA Guidelines 1994,3 the WHO Guidelines 1996,4 and adapted from Claus G. Roehrborn 1995.108

Minimal Essential Diagnostic Testing / 483

dence to support it as a screening procedure for the general population.14 Urinary tract infection by itself is not an indication for treating BPH. Urinary symptoms should be reassessed once the infection has been treated. Asymptomatic hematuria is a common finding, occurring in approximately 13% of the population.15,16 The dipstick test has a low positive predictive value (PPV) for cancer or other serious urologic diseases, varying from 4 to 26% in the medical literature.15–19 Ezz el Din et al. evaluated 750 patients with symptomatic BPH, finding microscopic hematuria in one-third of the patients. Only three had cancer, indicating that dipstick testing is also of limited value in a selected group of BPH patients.20 The dipstick urine test can be said to be useful only in conjunction with other findings to select patients who require more than the standard workup. Urine cytology can be considered in patients with severe irritable symptoms and a history of smoking. Serum Creatinine Serum creatinine is measured to monitor renal insufficiency secondary to obstruction. It does not have any predictive value with regard to improvement of symptoms or patient bother following transurethral resection of the prostate (TURP).21,22 Renal insufficiency can be expected in over 10% of men presenting with LUTS.3,22 Diabetes or hypertension are often known causes of elevated serum creatinine in these patients. Studies suggest that morbidity associated with TURP increases in patients with advanced renal sufficiency,23–25 (25 versus 17%23) as does mortality (sixfold24). An elevated serum creatinine in a patient with BPH is an indication for conducting imaging studies of the upper urinary tract. Renal ultrasonography has replaced intravenous urography as the test of choice in looking for evidence of hydronephrosis.

years, if the diagnosis of prostate cancer would change the treatment plan.4 If screening for prostate cancer is chosen, the combined use of DRE and PSA is the most effective method.32–35 If prostate cancer is then suspected, the next diagnostic step is transrectal ultrasound–guided biopsy of the prostate. There have been a number of newer PSA assays proposed but their value has not yet been determined.

Indications for Surgery Some patients present with unequivocal indications for surgery and may require no more than the initial evaluation and perhaps urethrocystoscopy (infra vide) to plan the operative approach. Filling cystometry may be helpful if primary bladder disease is suspected. Both the WHO and USA guidelines recommend surgery if the patient has refractory urinary retention or any of the following conditions clearly secondary to BPH: recurrent or persistent gross hematuria, bladder stones, or renal insufficiency. Recurrent UTIs and large bladder diverticula are more controversial indications for surgery. Most patients, however, require further evaluation. Complications of Benign Prostatic Hyperplasia

Prostate-Specific Antigen

Other complications of BPH include hydronephrosis, overflow incontinence, and gross bladder trabeculation. The risk of BPH progression to hydronephrosis is unknown but seems to be an infrequent phenomenon. Lower urinary tract symptoms, depressed peak flow, enlarged prostate, and older age are associated with an increased risk of acute urinary retention.36 The risk of progression to complete urinary retention for men with an International Prostate Syptom Score (IPSS—see Symptom Scores section, below) > 7 is 0.3 to 3.5% per year and increases with age.36 The significance of bladder trabeculation is poorly understood. The low risk of hydronephrosis and the reversibility of urinary retention make routine early intervention or complicated urodynamic evaluation unnecessary.

Prostate-specific antigen (PSA) can be elevated by a number of conditions affecting the prostate, including BPH,26 and can show substantial intraindividual variability over time.27,28 Sershon et al. demonstrated that PSA discriminates poorly between BPH and localized prostate cancer.29 Further, it is unclear whether PSA screening of men with LUTS improves outcomes for patients (e.g., improved survival, reduced morbidity or mortality from prostate cancer). Patients treated with finasteride deserve special attention as this medication lowers serum PSA.30 Before initiating finasteride treatment it is important to obtain a baseline PSA measurement for the patient. Prostatespecific antigen levels should decrease by 50% on average after 6 to 12 months of treatment.31 Anything less raises the suspicion of prostate cancer. The WHO guidelines highly recommend PSA screening in patients with LUTS who have a life expectancy over 10

Traditionally symptoms of “prostatism” were divided into “obstructive” and “irritative” symptoms. More recently, LUTS have been classified into voiding and storage symptoms. Voiding symptoms include hesitancy, abdominal straining, intermittency, weak urinary stream, dribbling, sensation of incomplete emptying, dysuria, and increased diuria. Storage symptoms include frequency, nocturia, urgency, incontinence, and bladder pain. Cardinal symptoms in BPH include weak stream, hesitancy, frequency, and nocturia. Men with BPH often present with both voiding and storage symptoms, which tend to be slowly progressive over years. Young patients and patients primarily with storage symptoms or rapid onset of symptoms are more likely to suffer from other disorders. Age-related changes in the bladder and other bladder disorders are causes of

Symptom and Patient Bother


LUTS that deserve attention. In aging men, the bladder capacity decreases and the incidence of detrusor instability increases.37 The latter may be a physiologic energysaving device in BPH,38 and prostate surgery has been shown to dramatically decrease bladder instability.39,40 Improved bladder function resulting from surgery as well as pharmaceuticals may have more impact on patient well-being than other parameters such as urinary flow rates. Although less well studied, an age-related decrease in the compliance of the prostate41 is likely to contribute to decreased urinary flow in elderly men. Symptom Scores Although no symptom or symptom complex specific to BPH exists, measures of symptom frequency and intensity are the most basic health status measures in BPH. Several symptom indices have been developed to reliably quantify LUTS. The American Urological Association (AUA) symptom index was introduced in 1992 by Barry et al.42,43 It was later adopted by the WHO and with the addition of one quality-of-life question became the IPSS.4 The AUA/IPSS symptom index is currently the one most widely used. Symptom scores from IPSS and the AUA symptom index are identical but the IPSS includes the separate quality-of-life question. It consists of a selfadministered questionnaire (Table 53–1), with symptoms classified as mild (0 to 7 points), moderate (8 to 19 points), or severe (20 to 35 points). The IPSS index is reproducible, internally consistent, and sensitive to changes in symptoms.42–44 Nevertheless, its reliability has been questioned,45,46 and it has been criticized for not including other symptoms such as dribbling and incontinence.47 Also, questions have been raised as to whether patients are able to correctly quantify their own clinical status.48 Ezz el Din et al. found significant variability between symptom scores obtained at baseline and after 8 weeks.46 Symptom score variability has likewise been noted by Barry et al., who nevertheless concluded that outcomes for BPH patients followed for 4 years depend on the severity of initial symptoms.49 The poor correlation between symptoms and prostate size or urodynamic measurements has long been recognized,50–57 and regional and international differences in symptom prevalence or symptom reporting have been found.58–61 Most of the criticism of IPSS applies to the other symptom scores as well. It is important to bear in mind that IPSS is not specific to BPH,5,6,45 given the nonspecificity of LUTS. In BPH management, symptom indices are not designed as screening instruments.62 Symptoms alone are not an adequate indicator of the presence or severity of BPH but along with patient bother may be an indication for treatment. The IPSS index may be used to establish a baseline of symptom severity and frequency and to monitor treated or untreated BPH patients.

The physician must still consider the individual patient when using symptom scores. Patients with high baseline scores may require a larger numeric change in symptom score to appreciate improvement compared to patients with low baseline scores.63 Further, different patients with similar symptom scores are bothered to varying degrees. What is usually paramount to the individual patient is the degree of bother and the impact the condition has on his quality of life, rather than a symptom score or other numeric measures which result from testing. Accordingly, bother is the most important factor in therapeutic decision-making. The WHO guidelines suggest that the patient should be evaluated and treated based on his degree of bother due to his symptoms and not on the symptoms alone.4 Baseline bother has been shown to be more predictive of TURP outcome than symptom score.21 Bother Scores As a supplement to IPSS, Barry and co-workers developed The Symptom Problem Index (SPI) and the BPH Impact Index (BII).64 These indices have gained less popularity than IPSS but may be helpful in objectively assessing bother and quality of life in BPH patients. They can be criticized for being too focused on bother directly related to LUTS and not determining the consequences of other aspects of BPH, for example, worries about cancer, sexual functioning, and the effect of LUTS upon relationships.65 The fact that doctors and other health care professionals are unable to intuitively measure patient quality of life66 elucidates the need for a practical and widely-used tool for its objective assessment. Overall, in the practical management of patients presenting with LUTS, it is essential to carefully review symptoms to determine if they are consistent with prostatic disease. The most widely used quantitative tool for this is the IPSS index. There is no practical tool to assess the bother of the symptoms and their effect upon patient quality of life. Consequently, there are no standards for measuring improvement in quality of life. Generally, a 30 to 50% improvement in symptom score is considered meaningful, depending on the baseline score. The IPSS index is a very valuable tool in BPH research, especially when evaluating different treatment modalities. The use of symptom indices, however, is not necessary in the routine care of BPH patients. The current authors’ approach is to review symptoms thoroughly with the patient to ensure that the symptoms are consistent with prostatic disease, then simply ask him whether the symptoms are bothersome enough to warrant any of the available treatment options.

Differential Diagnosis Differential diagnoses of BPH are summarized in Table 53–2.


Optional Diagnostic Tests

At present, urologists internationally are divided over the importance of urodynamics in BPH. The current authors feel that urodynamics most often does not add to treatment planning and that it should be considered optional. Others contend that urodynamics is underutilized in light of the nonspecificity of LUTS.67

These tests are not mandatory in the routine workup of a standard BPH patient but some of them may be of value depending on the results of the initial evaluation. Voiding Diary Patients whose dominant symptom is nocturia should keep a voiding diary. It is a useful supplement to their medical history and may help identify patients with polyuria or other nonprostatic disorders.

Uroflowmetry Uroflowmetry may be helpful when the results of the initial evaluation are in conflict or when planning surgery. Uroflowmetry is noninvasive and simple to perform. The maximum flow rate (Qmax) is obtained with the patient in private, in a normal voiding position, and when he feels the urge to void. Patients with a voided volume below 150 mL should be excluded.68 The threshold used in most studies is

Urodynamics Urodynamics in the form of uroflowmetry, postvoid residual urine, pressure-flow study, or filling cystometry has traditionally been widely used in BPH management.

TABLE 53–1. International Prostate Symptom Score (IPSS)* International Prostate Symptom Score (IPSS)

1. Incomplete emptying† Over the past month, how often have you had a sensation of not emptying your bladder completely after you finished urinating? 2. Frequency‡ Over the past month, how often have you had to urinate again less than 2 hours after you finished urinating? 3. Intermittency† Over the past month, how often have you found you stopped and started again several times when you urinated? 4. Urgency‡ Over the past month, how often have you found it difficult to postpone urination? 5. Weak stream† Over the past month, how often have you had a weak urinary stream? 6. Straining† Over the past month, how often have you had to push or strain to begin urination?

7. Nocturia‡ Over the past month, how many times did you most typically get up to urinate from the time you went to bed at night until the time you got up in the morning?

Not at All

Less than 1 Time in 5

Less than About Half theTime Half theTime

More than Half the Time

Almost Always

0

1

2

3

4

5

0

1

2

3

4

5

0

1

2

3

4

5

0

1

2

3

4

5

0

1

2

3

4

5

0

1

2

3

4

5

None

1 Time

2 Times

3 Times

4 Times

5 or More Times

0

1

2

3

4

5

Total IPSS Score = Quality of Life Due to Urinary Symptoms

Quality of Life If you were to spend the rest of your life with your urinary condition just the way it is now, how would you feel about that ? *Adapted from the WHO Guidelines 1996.4 †Voiding symptom. ‡Storage symptom.

Delighted

Pleased

Mostly Satisfied

0

1

2

Mixed about Equally Satisfied and Dissatisfied

Mostly Dissatisfied

Unhappy

Terribly

3

4

5

6


15 mL per second. From 75 to 79% of patients with Qmax ≤ 15 mL per second are obstructed, and 24 to 25% of patients with Qmax > 15 mL per second are obstructed.69,70 Eighty-eight percent of patients with Qmax ≤ 10 mL per second are obstructed, and 54% of patients in the “equivocal” group with a Qmax > 10 and ≤ 15 mL per second are obstructed.70 Low Qmax may be caused by BOO, a hypotonic bladder, or a combination of the two. Similarly, a patient with a normal Qmax may still have BOO despite good detrusor compensation. The WHO guidelines recommend at least two independent flow-rate recordings4 because of the intraindividual variability of Qmax.71,72 Maximum flow rate decreases with age,68 from > 25 mL per second in young men to < 10 mL per second in 80-year-old men.73 It is possible to adjust the results according to age,68 voided volume,74,75 and other parameters71,76,77 but this is not currently recommended.78 The patient with a normal preoperative Qmax is at a somewhat increased risk of treatment failure.69 Postvoid Residual Urine Measurements of postvoid residual urine (PVR) show significant intraindividual variability regardless of the technique used79,80 and do not correlate well with symptoms or other signs of BPH.79,81–84 The clinical value of PVR is thus presumably low although it has shown some predictive value at baseline toward symptom improvement following treatment.21,85 Some urologists view PVR as a safety parameter86 when monitoring patients who elect nonsurgical therapy but it is not known whether a high PVR has an impact on the upper urinary tract. Transabdominal ultrasonography (noninvasive) has now replaced catheterization (invasive) as a routine method for PVR determination. Pressure-Flow Study Adding simultaneous measurement of intravesical pressure to flow-rate recordings gives an indication of detrusor function. Pressure-flow study is the best tool to differentiate between patients with BOO and those with impaired detrusor function, which may be particularly helpful in patients with neurologic diseases. Intravesical pressure is measured using a small suprapubic or urethral catheter, making pressure-flow study an invasive and more morbid procedure than uroflowmetry.87 The maximum flow rate and the maximum detrusor pressure at Qmax (Pdet at Qmax) is usually plotted on the Abrams-Griffiths nomogram to determine whether the patient is obstructed.84 There is, however, disagreement as to what value represents obstruction. Computer programs and other mathematical models have been proposed to analyze pressure-flow data but their clinical utility has yet to be defined.88 Further, pressure-flow studies have shown considerable intraindividual variability89–91 and the fate of untreated, obstructed men is not known.

Jensen evaluated the prognostic value of urodynamics in a prospective study.52 As with uroflowmetry, a normal preoperative pressure-flow study predicts a slightly increased risk of treatment failure.92 Pressure-flow study is good at predicting success as defined by the patient (following prostatic surgery) but is in fact only marginally better than uroflowmetry. The PPVs (“diagnostic specificity”) for successful outcome for the two procedures were found to be 93 and 91%, respectively.69,92 It seems, however, that uroflowmetry and pressure-flow study may not be predictive of outcome with medical treatment (alpha-blockers).93,94 The current authors do not feel that urodynamic screening serves the interest of this patient category. Urodynamics is indicated if the results would influence treatment decisions and when there are anomalies such as severe symptoms in younger patients, severe symptoms in patients with normal uroflow, patients with neurologic disease, or patients who do not respond to therapy. For men leaning toward surgical treatment such as TURP, uroflowmetry can be used to assess whether their success rate will be about 70% or about 90%.69 Pressure-flow studies are most often not warranted, considering the insignificant improvement in predictive value compared to uroflowmetry and the invasiveness of the procedure. Filling Cystometry Filling cystometry is an invasive test that provides information about bladder sensation, capacity, pressure, compliance, and detrusor contractions. Overactive bladder or involuntary detrusor contractions are known as detrusor hyperreflexia when a neurologic cause is known and detrusor instability (DI) when there is no neurologic abnormality. The latter occurs in about 60% of men with BPH with the prevalence reduced to about 26% following prostate surgery.39,40 The clinical significance and predictive value of DI, however, are uncertain. Pressure-flow studies provide more specific information95 and filling cystometry is usually not warranted. It may be conducted in patients with suspected primary bladder or neurologic dysfunction who are in urinary retention and cannot urinate for a pressure-flow study. TABLE 53–2. Differential Diagnoses of BPH Cancer of the prostate Cancer of the bladder Calculi in bladder and urethra Urethral stricture Bladder neck contracture Urethral foreign bodies Neurologic dysfunction of the urinary tract (e.g., Parkinson’s disease, diabetes, etc.) Cystitis Prostatitis Pelvic masses Congestive heart failure


Urethrocystoscopy Visualization of the lower urinary tract and the bladder have traditionally been considered helpful but this invasive procedure has only a limited role in the evaluation of BPH.96 Cystoscopy cannot be used to identify which BPH patients will require surgery and it has no predictive value concerning the outcome of surgery. The main role of the procedure is to rule out serious alternative pathology such as bladder cancer and urethral strictures. Cystoscopy may be performed prior to invasive therapy to guide the urologist in choosing an operative approach. Imaging of the Upper Urinary Tract Imaging of the upper urinary tract is not recommended in the routine evaluation of BPH patients even though compromised renal function is the most morbid and potentially fatal complication of BPH. Most patients with LUTS (67 to 74%) have a normal intravenous excretory urogram (IVU), hydronephrosis being the most common reported abnormality (8 to 13%).97–100 Ultrasonography (noninvasive) is better than IVU (invasive) to detect hydronephrosis, tumors, and stones101,102 and can safely replace IVU.98,99,101,103,104 Imaging of the upper urinary tract should probably be limited to BPH patients with elevated serum creatinine or other indications of disease in the upper urinary tract.99–101,105–107 Summary The diagnostic objective is to evaluate the patient sufficiently to determine the right treatment and rule out pathology other than BPH, without subjecting him to various unnecessary testing. All men presenting with LUTS should go through an initial evaluation, including medical history, physical examination and DRE, urinalysis, serum creatinine, and PSA screening. Some patients present with unequivocal indications for surgery and may not require more than the initial evaluation. Most patients, however, require further evaluation. The IPSS index is very valuable in BPH research. Somewhat controversial is the current authors’ contention that IPSS may not be necessary in the routine care of BPH patients. The important thing to the individual patient is the degree of bother and the impact of the condition on his quality of life rather than on a symptom score. Accordingly, patient bother is the most important factor in therapeutic decision-making. The current authors’ approach is to review symptoms thoroughly with the patient to ensure that they are consistent with prostatic disease. He is then asked whether the symptoms are bothersome enough to warrant the various specific treatments available. Most often urodynamics does not contribute to the management of these patients. Urodynamics is indicated when there are anomalies such as severe symptoms in younger patients, severe symptoms in patients with nor-

mal uroflow, patients with neurologic disease, or patients who do not respond to therapy. Imaging of the upper urinary tract should be limited to BPH patients with elevated serum creatinine or other indications of disease in the upper urinary tract. If indicated, ultrasonography can safely replace IVU.

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490 / Advanced Therapy of Prostate Disease 80. Birch NC, Hurst G, Doyle PT. Serial residual volumes in men with prostatic hypertrophy. Br J Urol 1988;62: 571–5. 81. Griffiths HJ, Castro J. An evaluation of the importance of residual urine. Br J Radiol 1970;43:409–13. 82. Shoukry I, Susset JG, Elhilali MM, Dutartre D. Role of uroflowmetry in the assessment of lower urinary tract obstruction in adult males. Br J Urol 1975;47:559–66. 83. Andersen JT, Jacobsen O, Standgaard L. The diagnostic value of intravenous pyelography in infravesical obstruction in males. Scand J Urol Nephrol 1977;11: 225–30. 84. Abrams PH, Griffiths DJ. The assessment of prostatic obstruction from urodynamic measurements and from residual urine. Br J Urol 1979;51:129–34. 85. Jensen KM, Jorgensen JB, Mogensen P. Urodynamics in prostatism. IV. Search for prognostic patterns as evaluated by linear discriminant analysis. Scand J Urol Nephrol 1988;114 Suppl:84–6. 86. McConnell JD. Epidemiology, etiology, pathophysiology, and diagnosis of benign prostatic hyperplasia. In: Campbell’s urology. 7th ed. 1997. p. 1429–52. 87. Klingler HC, Madersbacher S, Djavan B, et al. Morbidity of the evaluation of the lower urinary tract with transurethral multichannel pressure-flow studies. J Urol 1998;159:191–4. 88. Griffiths D, Hofner K, van Mastrigt R, et al. Standardization of terminology of lower urinary tract function: pressure-flow studies of voiding, urethral resistance, and urethral obstruction. International Continence Society Subcommittee on Standardization of Terminology of Pressure-Flow Studies. Neurourol Urodyn 1997;16:1–18. 89. Madsen FA, Rhodes PR, Bruskewitz RC. Reproducibility of pressure-flow variables in patients with symptomatic benign prostatic hyperplasia [comments]. Urology 1995;46:816–20. 90. Rosier PF, de la Rosette JJ, Koldewijn EL, et al. Variability of pressure-flow analysis parameters in repeated cystometry in patients with benign prostatic hyperplasia [comments]. J Urol 1995;153:1520–5. 91. Witjes WP, de Wildt MJ, Rosier PF, et al. Variability of clinical and pressure-flow study variables after 6 months of watchful waiting in patients with lower urinary tract symptoms and benign prostatic enlargement J Urol 1996;156:1026–34. 92. Jensen KM, Jorgensen JB, Mogensen P. Urodynamics in prostatism. II. Prognostic value of pressure-flow study combined with stop-flow test. Scand J Urol Nephrol 1988;114 Suppl:72–7. 93. Witjes WP, Rosier PF, Caris CT, et al. Urodynamic and clinical effects of terazosin therapy in symptomatic patients with and without bladder outlet obstruction: a stratified analysis. Urology 1997;49:197–206.

94. Lepor H, Nieder A, Feser J, et al. Effect of terazosin on prostatism in men with normal and abnormal peak urinary flow rates. Urology 1997;49:476–80. 95. Jensen KM, Jorgensen JB, Mogensen P. Urodynamics in prostatism. III. Prognostic value of medium-fill water cystometry. Scand J Urol Nephrol 1988;114 Suppl: 78–83. 96. Madsen FA, Bruskewitz RC. Cystoscopy in the evaluation of benign prostatic hyperplasia [review]. World J Urol 1995;13:14–6. 97. Donker PJ, Kakiailatu F. Preoperative evaluation of patients with bladder outlet obstruction with particular regard to excretory urography. J Urol 1978;120: 685–6. 98. Matthews PN, Quayle JB, Joseph AE, et al. The use of ultrasound in the investigation of prostatism. Br J Urol 1982;54:536–8. 99. Juul N, Torp-Pedersen S, Nielsen H. Abdominal ultrasound versus intravenous urography in the evaluation of infravesically obstructed males. Scand J Urol Nephrol 1989;23:89–92. 100. Roehrborn CG, McConnell JD. Is routine imaging of the urinary tract prior to prostatectomy a justifiable practice? [abstract]. J Urol 1991;145:266A. 101. Cascione CJ, Bartone FF, Hussain MB. Transabdominal ultrasound versus excretory urography in preoperative evaluation of patients with prostatism. J Urol 1987; 137: 883–5. 102. Roehrborn CG, Chinn HK, Fulgham PF, et al. The role of transabdominal ultrasound in the preoperative evaluation of patients with benign prostatic hypertrophy. J Urol 1986;135:1190–3. 103. Reisman EM, Kennedy TJ, Roehrborn CG, McConnell JD. A prospective study of urologist-performed sonographic evaluation of the urinary tract in patients with prostatism. J Urol 1991;145:1186–91. 104. Hendrikx AJ, Doesburg WH, Reintjes AG, et al. Effectiveness of ultrasound in the preoperative evaluation of patients with prostatism. Prostate 1988;13: 199–208. 105. Wasserman NF, Lapointe S, Eckmann DR, Rosel PR. Assessment of prostatism: role of intravenous urography. Radiology 1987;165:831–5. 106. Wilkinson AG, Wild SR. Is preoperative imaging of the urinary tract worthwhile in the assessment of prostatism? Br J Urol 1992;70:53–7. 107. Koch WF, Ezz el Din K, de Wildt MJ, et al. The outcome of renal ultrasound in the assessment of 556 consecutive patients with benign prostatic hyperplasia [comments]. J Urol 1996;155:186–9. 108. Roehrborn CG. The Agency for Health Care Policy and Research. Clinical guidelines for the diagnosis and treatment of benign prostatic hyperplasia. Urol Clin North Am 1995;22:445–53.

CHAPTER 54

PATHOPHYSIOLOGY OF BLADDER OUTLET OBSTRUCTION AND VOIDING DYSFUNCTION R. DUANE CESPEDES, MD

Bladder Outlet Obstruction

The last two decades have seen a dramatic change in the thinking of urologists regarding benign prostatic hyperplasia (BPH) and the development of lower urinary tract symptoms. The common belief that the symptom complex called “prostatism” is secondary to bladder outlet obstruction and is simply a clinical manifestation of BPH appears unfounded. More recently, the term “lower urinary tract symptoms” (LUTS) has been used to describe the symptom complex previously termed prostatism, in an attempt to disassociate the symptoms from the perceived etiology: an obstructing prostate.1 It has become clear that the interrelationships between bladder function, outlet obstruction, and abnormal voiding symptoms are much more complex than originally believed. Lower urinary tract symptoms can be caused by a number of isolated or coexisting conditions, including bladder outlet obstruction, impaired detrusor contractility, sensory urgency, and detrusor instability. When BPH does cause bladder outlet obstruction, it may do so simply by protruding into the prostatic urethra, effectively narrowing the lumen. This has been called “static obstruction.” An additional, or perhaps coexisting, mechanism of obstruction is through an alteration in the response of the bladder neck and prostatic smooth muscle, causing inappropriate muscular contraction or nonrelaxation to occur. This has been termed “dynamic obstruction.” The response of the bladder is variable once obstruction has occurred. Although several adaptive response stages have been described, including irritability, compensation, and decompensation, the individual patient rarely follows these stages in a definable pattern and treatment is usually based on presenting symptoms. The mechanism(s) by which BPH develops as well as methods to prevent it remain unknown after a century of study. Recently, research efforts have focused on hormonal or growth factor abnormalities based on global etiologic theories of altered cell death rates or the possibility of “embryonic cell reawakening.” Current thinking regarding the possible mechanisms by which bladder outlet obstruction can occur, the etiology of voiding dysfunction, and the effects of bladder outlet obstruction on the bladder are reviewed in this chapter.

Quantification of Voiding Symptoms Traditionally, voiding symptoms associated with BPH have been classified as irritative, which includes dysuria, frequency, urgency, urge incontinence, and nocturia or obstructive, which includes dribbling, hesitancy, intermittency, straining, and weak force of stream. Although these symptoms are what usually bring the patient to the physician, most studies have shown that voiding symptoms and total symptom scores do not correlate well with urodynamic signs of obstruction.2–5 Prospective studies have demonstrated that lower urinary tract symptoms wax and wane over time and that the incidence of symptoms varies with the patient’s age and gender. Sommer and colleagues found in a nonselected male population that voiding symptoms increased progressively from the fifth to the seventh decades and that the incidence of voiding symptoms in the group diagnosed with “prostatism” was similar to asymptomatic patients in their sixth and seventh decades.6 The only symptoms more prevalent in the “prostatism” patients were nocturia and urge incontinence. Correlating these results with a modified Madsen-Iversen score, the authors found that 20% of asymptomatic men in their sixth and seventh decades had symptom scores equal in severity to those men undergoing prostatectomy for BPH. More recently, Barry and colleagues developed the seven-item American Urological Association (AUA) symptom index, which includes the following symptoms: incomplete emptying, frequency, intermittency, urgency, weak stream, hesitancy, and nocturia; a measurement of bother symptoms is also included.7 Patients were divided into mild (0 to 7), moderate (8 to 19), and severe (20 to 35), depending on the overall score. The AUA symptom score was found to be valid with respect to patients’ rating of urinary difficulty and in its differentiation of BPH patients and normal controls. In patients with voiding symptoms, however, it has never been shown to be predictive of the underlying disease. Recently, Yalla and colleagues demonstrated that the AUA symptom score could not distinguish between obstructed and nonobstructed voiding.8 Therefore, the AUA symptom score is not useful or recommended as a 491


screening tool for BPH. It may, however, be useful for measuring both changes in symptoms over time and improvements following therapeutic interventions. Identifying and Quantifying Obstruction Benign prostatic hyperplasia describes the pathologic condition of prostatic enlargement secondary to variable degrees of cellular proliferation within the stromal and glandular elements of the periurethral and transition zones of the prostate.9 This enlargement may be entirely asymptomatic and require no therapy. Bladder outlet obstruction is a urodynamic diagnosis that generally does require treatment to relieve the obstruction. The disparity between prostate size and symptoms is well known and illustrated by the common scenario in which patients with large prostates secondary to BPH may have minimal voiding symptoms while others with small or normal prostates may have severe symptoms and be severely obstructed.10,11 Also, “silent” obstructive uropathy with severe upper tract damage may occur without significant voiding symptoms. Carefully performed studies have shown that between 25 and 50% of patients undergoing urodynamics for “prostatism” may not be urodynamically obstructed.12–14 This is underscored by the results of a retrospective review of 787 patients with symptomatic “prostatism” evaluated with videourodynamics in which 23% had isolated prostatic obstruction and 39% had both bladder outlet obstruction and detrusor instability.15 Importantly, only 64% had evidence of bladder outlet obstruction, 17% had impaired detrusor contractility, and 1% had sensory urgency. These studies support the belief that “prostatism” may include multiple conditions that may exist singly or together. These include: (1) prostatic obstruction, (2) detrusor instability, (3) impaired detrusor contractility, (4) sensory urgency, and (5) primary bladder neck obstruction.16–19 There is good evidence that the diagnosis of bladder outlet obstruction due to BPH cannot be based on symptoms alone. For example, the AUA symptom score, while providing a reasonably reliable method of assessing voiding symptom severity and progression, cannot reliably differentiate between obstructive and nonobstructive conditions.20 Similar symptoms and worse AUA symptom scores are often found in elderly females in whom obstruction is not present.21 An additional confounding problem in correlating symptoms to disease process is the documented waxing and waning of lower urinary tract symptoms. Clark found that symptomatic improvement occurred in 25 of 36 patients with LUTS followed longterm, with improvement lasting a mean 1.9 years.22 In a prospective study using subjective and objective criteria, Birkhoff and colleagues found that 8 of 26 patients with obstructive uropathy due to BPH were subjectively improved at 3 years and that 4 of 26 were objectively improved.23 In another study of patients with LUTS evaluated with urodynamics, after 5 years only 20% of overtly

obstructed patients had undergone surgery; of the entire group, only 10% required surgery.24 The poor correlation between the patient’s symptoms and objective evidence of obstruction has led to the use of urodynamic tests, including uroflowmetry, postvoid urine determinations, and pressure-flow studies, which many believe to be the tests of choice in this group of patients.25–27 Although the need for urodynamic tests in diagnosing and selecting patients for treatment of BPH may appear intuitively obvious, the role of urodynamics remains controversial. This is in part due to differences in philosophy among investigators. Some believe that bothersome symptoms in and of themselves justify surgical or medical treatment whereas other investigators feel that obstruction should be documented in all cases, thereby avoiding surgery or indefinite medical therapy in unobstructed patients.28,29 An important concern in these cost-conscious times is whether the unequivocal diagnosis of obstruction improves the outcome of treatment sufficiently to justify the increased cost and invasiveness of a urodynamic evaluation. Abrams found that including pressure-flow studies in the preoperative evaluation significantly reduced the symptomatic failure rate of transurethral resection of the prostate (TURP) from 28 to 12%.30 Bruskewitz and colleagues performed a prospective analysis on 46 patients with symptoms of prostatism.31 Patients were urodynamically categorized as obstructed or unobstructed then treated surgically with TURP. Postoperatively, 89% of unobstructed patients had symptomatic improvement whereas 92% of obstructed patients were subjectively improved. In a recent review of the English language literature, a median 88% subjective improvement was found following TURP for LUTS symptoms (not urodynamically proven).32 Based in part on these last two studies, the routine use of urodynamics in the preoperative assessment has been questioned.28 The argument against the routine use of urodynamics identifies the inherent problems with interpreting urodynamic studies, such as the equivocal diagnosis of obstruction (“even the experts don’t agree”), the variable techniques used, different equipment utilized, differing treatment philosophies, the nature of the patient population, and test reproducibility. 33,34 These arguments, however, ignore the fact that a large number of patients will improve spontaneously without treatment and that TURP is generally considered a treatment for prostatic obstruction, not for unobstructed voiding symptoms. Nevertheless, the recently released BPH guidelines have classified pressure-flow studies as an optional study based on the physician’s judgment. 32 Pathophysiology of Bladder Outlet Obstruction Traditionally, the diagnosis of bladder obstruction by the prostate has focused on the severely symptomatic older male patient who in many cases did have an enlarged prostate and was visually obstructed on cystoscopy. Fre-

Pathophysiology of Bladder Outlet Obstruction and Voiding Dysfunction / 493

quent treatment success further reinforced the concept of a mechanical obstruction as responsible for voiding symptoms. The reason for the rare treatment failure or the symptomatic patient with a small prostate was unclear. More recently, studies have shown that voiding symptoms can and often do occur in unobstructed patients; in fact, older women often have voiding symptoms as severe as those of men diagnosed with “prostatism.”35,36 Also, the pathophysiology of obstruction has become more complicated. It is well known, that the use of sympathomimetic agents such as those found in cold remedies may cause acute urinary retention in symptomatic males. Caine and colleagues reported on the effectiveness of alpha-receptor blockers in prostatic obstruction based on the premise that increased tone in the smooth muscle of the prostate and capsule represented a significant obstructive component.37 Obstruction caused by the heightened muscular tone has been termed “dynamic” obstruction while obstruction caused by the mechanical obstruction of an enlarged prostate impinging on the lumen has been termed “static” obstruction. The dynamic component has been estimated to contribute up to 40% of the overall obstruction seen in prostatism; the proportion, however, depends heavily on gland size and capsular integrity and may vary over time in the same patient.38

Compensatory Responses of the Bladder to Obstruction Compensatory Stages The events transpiring after infravesical obstruction occurs have traditionally been divided into three sequential phases. According to the “theory of compensation,” the bladder goes through three distinct and sequential phases of “compensation” once obstruction occurs.39 Initially, the bladder becomes “irritable,” with the patient experiencing a decreased force of stream and urgency or even urge incontinence. In animal models, this stage is associated with a tremendous increase in bladder mass (both smooth muscle and collagen), with an initial decrease in bladder contraction strength that within 2 weeks increases to 70 to 80% of preobstruction strength.40 In humans, however, pathologic changes can rarely be identified in this clinical stage. It is important to note that patients present to the urologist because of symptoms, not obstruction, and that these voiding symptoms may simply be a manifestation of the aging bladder.4,41 The identification of this stage in the human, if it truly exists, may therefore be very difficult because obstruction would need to be proven urodynamically. In the second stage, the detrusor theoretically “compensates” for the obstruction by muscular hypertrophy and collagen deposition, presumably leading to an increased ability to generate pressure. Traditionally, this

stage is associated with the formation of cellules and trabeculation and a small postvoid residual. Teleologically, this response is understandable since the bladder must increase its strength in response to the increased outlet resistance. In reality, the bladder’s ability to generate pressure is decreased, although it may remain at 70 to 80% of normal for some time. The continuing morphologic changes in the smooth muscle and collagen may lead to a decreased ability to sustain pressure, which may be associated with an increasing postvoid residual. In animal models, if the obstruction is relieved during this stage, full recovery is common. Bladder trabeculation and cellules are often associated with obstruction. They are, however, often seen in females with unobstructed unstable bladders. The presence of trabeculation is therefore not specific for obstruction.42 In the third and final stage, compensation yields to detrusor decompensation, traditionally described as a progressively larger residual urine with endstage total decompensation ultimately leading to urinary retention, overflow incontinence, and upper tract changes. In animal models, the “trigger” causing the bladder to decompensate is unclear. When this stage is reached, however, bladder mass rapidly increases due to collagen deposition.40 Secondarily, the response to stimulation and bladder contraction strength and sustainability are rapidly impaired. Additionally, bladder denervation affecting both the afferent and efferent pathways has been observed and may play a role in dysfunction.43,44 In this stage, only partial recoverability of bladder function is possible, depending on the degree of decompensation. It has been shown in human studies that men in urinary retention have a higher incidence of inability to void following a prostatectomy than patients with small postvoid residuals.45 One recent study found that only 87% of patients in acute urinary retention were able to void following prostatectomy.46 Although most patients do not go through these stages in any definable manner and certainly most patients do not progress to urinary retention, these stages have been documented in animal studies.47,48 Some investigators question whether these stages exist at all in humans since in many cases patients do not progress to the next stage and may even improve and “go down” a stage without treatment.49 Also, it has never been established that “watchful waiting” of the obstructed patient invariably leads to detrusor decompensation. One prospective urodynamic study followed 25 patients with bladder outlet obstruction and large postvoid residuals over a 4-year period.50 Ten patients developed hypocontractility and underwent a prostatectomy; moderate symptomatic improvement was shown by most patients. Interestingly, urodynamic studies did not document significant changes in those patients with symptomatic improvement. More important was the finding that many of the patients with documented obstruction and an abnormal


flow rate had no evidence of detrusor decompensation after 4 years of chronic obstruction. What differentiates these patients from the others who developed hypocontractility is unknown. There appears to be a lack of human data supporting the “stages of compensation” in bladder outlet obstruction. Perhaps the animal model is correct, however, suggesting that many of the “obstructed” patients simply have a nonobstructive voiding dysfunction which may wax and wane with time. Perhaps it is only the patients with progressive symptoms or those who present with endstage sequelae who are truly obstructed. Without performing urodynamics on all symptomatic patients, it is unlikely that this will ever be known with certainty. It is also possible that the human experience does not correlate with the animal model because the animal model of obstruction is incorrect. Bladder outlet obstruction is often classified into two main types: compressive and constrictive. The slow, gradual obstruction characterizing prostatic obstruction is called “compressive” obstruction. In this type of obstruction, the opening pressure (the detrusor pressure when urine flow begins) is elevated, but little additional pressure is necessary to increase the flow rate. The prototype for constrictive obstruction is urethral stricture disease. In constrictive obstruction the opening pressure is normal, but increasing pressure is required to increase the flow rate. Therefore, the graphic plot of compressive obstruction is essentially horizontal while constrictive obstruction has an upward curve. The importance of these descriptions is that almost all animal models of obstruction are constrictive while obstruction in the adult male is almost always compressive. Additionally, most animal models cannot duplicate the micturition behavior found in humans as the anatomic relationships of the bladder, prostate, and intrinsic neurologic systems are different. Therefore, although the animal models used so far have helped immensely in understanding bladder outlet obstruction, they may not exactly reflect obstruction in the human. Changes in Bladder Collagen and Smooth Muscle In all animal models studied, a universal response of the bladder to partial obstruction is a profound increase in mass. Much of the focus in these studies has been on the deposition of collagen both between and within the hyperplastic muscle bundles. In the human, the individual muscle cells may be displaced away from each other by intervening collagen.42 The collagen is thought to be secreted by the smooth muscle cells. The reason for the excess collagen being produced is not known but it may be part of a general response to tissue ischemia.51 Elbadawi and colleagues suggest that the initial effect of obstruction is tissue ischemia followed by a compensatory bladder response that may include neovascularization, smooth muscle hypertrophy, collagen deposition,

and perhaps neural changes.51 The excess collagen deposition can lead to the problems seen in the endstage obstructed bladder: poor compliance, decreased contractile force, impairment of a sustained contraction leading to upper tract changes, and urinary retention. One group has astutely noted that although the collagen content is greatly increased, the actual proportion of collagen in the bladder is slightly decreased due to an even greater increase in smooth muscle growth.52 The collagen deposited in human bladders with poor compliance is predominately type III although the significance of this finding remains unclear.53,54 After the obstruction is relieved, the deposited collagen does not always recede completely and usually does not change appreciably until after 6 months.55 The smooth muscle appears to undergo both cellular hyperplasia and hypertrophy as a response to obstruction, although the hypertrophic component appears to predominate. The increase in smooth muscle mass has traditionally been thought of as a way of the bladder increasing its ability to contract; this, however, has been disproven. The ability of the bladder to contract usually decreases with an increase in smooth muscle mass in most animal models. Elbadawi and colleagues believe that the hyperplastic cells are impaired by cellular disorganization, leading to inefficient transmission of force to contiguous smooth muscle cells.42 The exuberant collagen deposition also leads to poor alignment of collagen fibrils, which impairs a coordinated contraction. Both of these altered conditions may lead to an overall impairment of contractile ability. An additional potential reason for impaired contractility in the obstructed bladder is a change in cellular metabolism. The detrusor muscle, like other smooth muscles, derives most of its energy from aerobic metabolism. The relative ischemia occurring with obstruction has been theorized to impair aerobic metabolism and shift metabolism toward anaerobic metabolism, which is much less efficient. Laboratory induced ischemia and obstruction have both been found to impair detrusor adenosine triphosphate (ATP) production, hypothesized to be a result of mitochondrial dysfunction.56 Kato and colleagues have also noted a decrease in aerobic metabolism in obstructed bladders, although no change in ATP production was noted.57 Metabolic alterations have also been described in the cellular regulation of calcium from the sarcoplasmic reticulum. Since smooth muscle contractions depend on the release of calcium, dysfunction of the sarcoplasmic reticulum may lead to impaired contractility. Indeed, recent studies have found abnormalities in detrusor contractility secondary to impaired calcium release by the sarcoplasmic reticulum.58,59 The etiology of impaired contractility in the obstructed bladder appears to be multifactorial, involving altered smooth muscle and collagen anatomy and changes in the

Pathophysiology of Bladder Outlet Obstruction and Voiding Dysfunction / 495

cellular metabolism of glycolysis and calcium release. Also, the importance of changes in bladder innervation (discussed below) in the development of impaired contractility is unclear. Further study is necessary to fully elucidate the mechanisms of impaired contractility resulting from obstruction. Development of Detrusor Instability Alterations in smooth muscle anatomy have also been proposed as a reason for the development of detrusor instability. Whereas detrusor instability was previously attributed to probable denervation supersensitivity (to circulating neurotransmitters), changes in smooth muscle gap junctions and cellular abutments have been identified by Elbadawi and colleagues in obstructed but not in normal bladders.42,43 Investigators believe these anatomic cellular changes play a role in the development of detrusor instability. More recently, increased activity in the Na+, K+ membrane pump of obstructed smooth muscle has also been identified as a possible source of detrusor instability.60 Therefore, changes in cellular depolarization characteristics and altered intercellular communication may also help explain the common finding of detrusor instability in obstructed bladders. The role of the nervous system in the development of instability is discussed below. Clinically, detrusor instability is present in up to 60% of patients with LUTS. No correlation between the severity of instability and severity of obstruction has been found, however.27,61,62 Instability resolves or is greatly improved in up to 70% of patients following prostatectomy, although up to 12 months may be required for full resolution.63,64 Changes in Detrusor Innervation The changes in innervation as a result of obstruction appear to be somewhat species specific. Whereas obstruction in rabbits and humans usually causes neural degeneration, obstruction in rats commonly causes neural proliferation.42,65,66 In the rat model, the voiding reflex appears to be augmented in the obstructed bladder, with facilitation localized to the spinal cord segment of the reflex.4 The search for a bladder-derived trophic factor eventually led to the discovery that secretion of nerve growth factor (NGF) increases in response to bladder obstruction. Additional proof of the importance of NGF was provided when antibodies to NGF prevented the typical increased neural proliferation in rats whose bladders were obstructed.67,68 If NGF is ultimately found to play a significant role in the development of voiding dysfunction in obstructed bladders, alteration of this response may prove useful in preventing detrusor instability and perhaps even altered sensation and hypocontractility. Changes in the innervation of the obstructed bladder have also been suggested as a possible etiology for the detrusor instability affecting many of these patients. In

the rat, the micturition reflex was altered by detrusor obstruction such that the sacral reflex arc in the obstructed rats was much faster than in most of the unobstructed rats. Although this phenomenon has not been demonstrated in humans, it is reasonable to surmise that a similar neural plasticity exists in humans and that facilitation of the voiding reflex may cause or exacerbate detrusor instability. At the present time, it is unclear whether intrinsic smooth muscle changes or neural changes (or both) are responsible for detrusor instability. Role of Smooth Muscle and Alpha-Receptors in the Treatment of Lower Urinary Tract Symptoms The increased density of smooth muscle tissue in response to obstruction has led some to speculate that dynamic obstruction may be an important component of obstruction in these patients. One theory suggests adrenergic receptor upregulation as a possible etiology. In this scenario, either the affinity or the absolute number of receptors would be increased. Studies by Gup et al. have shown, however, that the α1-receptor density was equivalent in transition-zone tissue specimens from men with symptomatic and asymptomatic histologic BPH.69 Further studies also revealed that the contractile response of the smooth muscle to α1-receptor agonists was similar between the symptomatic and asymptomatic BPH groups.70 Another mechanism proposed as a source of increased dynamic obstruction is a general state of increased catecholamine levels. This mechanism has been refuted by Lepor and colleagues who noted that patient catecholamine levels and AUA symptom scores were inversely related in men who underwent a prostatic biopsy for an elevated prostate-specific antigen or had an abnormal rectal examination.71 It is therefore unlikely that receptor upregulation or that an increased level of circulating catecholamines plays a significant role in dynamic obstruction. Alternatively, the percentage of prostatic smooth muscle has been found to correlate with peak urinary flow rate but not with the degree of patient symptoms. Subsequently, when these patients were treated with α1-receptor antagonists, the degree of improvement correlated with the amount of smooth muscle in the patient’s prostate. These studies suggest that α1-receptor antagonists improve patient symptoms by relaxing prostatic smooth muscle, but this hypothesis remains controversial.

Conclusion Although the exact initiating circumstances remain unclear, it is believed that bladder outlet obstruction causes a relative tissue ischemia which then induces the bladder to adapt in a multitude of ways, including smooth muscle hypertrophy, collagen deposition, and alterations in the innervation and metabolism of the bladder. These adaptations usually result in a progressive


impairment of function, which may be reversible if the obstruction is relieved before permanent detrusor changes have occurred. Although many advances have been made in understanding the pathophysiology of LUTS and bladder obstruction, many questions remain. Do the compensatory changes and relatively distinct stages seen in animal models of obstruction apply to humans? Are the current animal models of obstruction truly representative of urinary obstruction in man? What are the mechanisms for smooth muscle hypertrophy and collagen deposition? Why does detrusor instability occur with obstruction and what causes it to go away when the obstruction is relieved? The answers to these and many other related questions await further study.

References 1. Abrams P. New words for old: lower urinary tract symptoms for “prostatism.” BMJ 1994;308:929–30. 2. Abrams PH, Griffiths BJ. The assessment of prostatic obstruction from urodynamic measurements and from residual urine. Br J Urol 1979;151:129–34. 3. Andersen JT. Prostatism: clinical, radiological and urodynamic aspects. Neurourol Urodyn 1982;1:241–93. 4. Coolsaet BRLA, Elbadawi A. Urodynamics in the management of benign prostatic hypertrophy. World J Urol 1989;6:215–24. 5. McGuire EJ. The role of urodynamic investigation in the assessment of benign prostatic hypertrophy. J Urol 1992;148:1133–6. 6. Sommer P, Nielsen KK, Bauer T, et al. Voiding patterns in men evaluated by a questionnaire survey. Br J Urol 1990;65:155–60. 7. Barry MJ, Fowler FJ, O’Leary MP, et al. The American Urological Association symptom score for benign prostatic hyperplasia. J Urol 1992;148:1549–57. 8. Yalla SV, Sullivan MP, Lecamwasam HF, et al. Correlation of the American Urological Association symptom index with obstructive and non-obstructive prostatism. J Urol 1995;153:674–80. 9. McNeal JE. The prostate gland: morphology and pathobiology. Monogr Urol 1988;9. 10. Ashley DJ. Observations on the epidemiology of prostatic hyperplasia in males. Br J Urol 1966;38:567–9. 11. Christensen MM, Bruskewitz RC. Clinical manifestations of benign prostatic hyperplasia and indications for therapeutic intervention. Urol Clin North Am 1990;17: 509–16. 12. Coolsaet BRLA, Blok C. Detrusor properties related to prostatism. Neurourol Urodyn 1986;5:435–9. 13. Dean GE, Kaplan SA, Blaivas JG. The differential diagnosis of prostatism: a urodynamic survey [abstract 207]. J Urol 1991;145:264A. 14. Hellstrom P, Lukkarinen O, Kontturi M. Bladder neck incision or transurethral electroresection for the treatment of urinary obstruction caused by a small benign prostate? A randomized urodynamic study. Scand J Urol Nephrol 1986;20:187–92. 15. Kaplan SA, Te AE. Uroflowmetry and urodynamics. Urol Clin North Am 1995;22:309–20.

16. Abrams PH, Farrar DJ, Turner-Warwick RT, et al. The results of prostatectomy: a symptomatic and urodynamic urinalysis of 142 patients. J Urol 1979;121:640–2. 17. Andersen JT. Detrusor hyperreflexia in benign intravesical obstruction. J Urol 1976;115:532–4. 18. Norlen LJ, Blaivas JG. Unsuspected proximal urethral obstruction in young and middle aged men. J Urol 1986;135:972–6. 19. Kaplan SA, Te AE, Jacobs BZ. Urodynamic evidence of vesical neck obstruction in men with misdiagnosed chronic non-bacterial prostatitis and the therapeutic role of endoscopic incision of the bladder neck. J Urol 1994;152:2063–5. 20. Ko DSC, Fenster HN, Chambers K, et al. The correlation of multichannel urodynamic pressure flow studies and the American Urological Association symptom index in the evaluation of benign prostatic hyperplasia. J Urol 1995;54:396–8. 21. Chancellor MB, Rivas DA. The American Urological Association symptom index for women with voiding symptoms: lack of index specificity for benign prostatic hyperplasia. J Urol 1993;150:1706–9. 22. Clark R. The prostate and the endocrine. A controlled series. Br J Urol 1937;9:254–7. 23. Birkhoff TD, Widerhorn AR, Hamilton ML, Zinsser HH. Natural history of benign prostatic hypertrophy and urinary retention. Urology 1976;7:48–52. 24. Bell AJ, Finnelly RCL, Abrams PH. The natural history of untreated “prostatism.” Br J Urol 1981;53:613–6. 25. Griffiths HJL, Castro J. An evaluation of the importance of residual urine. Br J Radiol 1970;43:409–13. 26. Bruskewitz RC, Iversen P, Madsen PO. Value of postvoid residual urine determination in evaluation of prostatism. Urology 1982;20:602–4. 27. Andersen JT, Nordling J, Walter S. Prostatism. I. The correlation between symptoms, cystometric and urodynamic findings. Scand J Urol Nephrol 1979;13:229–36. 28. McConnell JD. Why pressure flow studies should be optional and not mandatory studies for evaluating men with benign prostatic hyperplasia. Urology 1994;44:156–8. 29. Abrams PH. In support of pressure flow studies for evaluating men with lower urinary tract symptoms. Urology 1994;44:153–5. 30. Abrams PH. Prostatism and prostatectomy: the value of urine flow rate measurements in the preoperative assessment for operation. J Urol 1979;117:70–1. 31. Bruskewitz R, Jensen KM, Iversen P, Madsen PO. The relevance of minimum urethral resistance in prostatism. J Urol 1983;129:769–71. 32. McConnell JD, Barry MJ, Bruskewitz RC. Benign prostatic hyperplasia: diagnosis and treatment. Dept. of Health and Human Services (US), Public Health Service, Agency for Health Care Policy and Research; 1994: Clinical Practice Guideline Number 8. p. 1–17. 33. Donovan JL, Abrams P, Schafer W. The international continence society study on BPH: urodynamic quality control and data analysis [abstract 268]. J Urol 1994;151: 294A. 34. Kirchner-Hermanns R, Thorner M, Schafer W, et al. Reproducibility of urodynamic data in BPH: influence of patient and investigator on data quality and analysis [abstract 269]. J Urol 1994;151:295A. 35. Girman CJ, Jacobsen SJ, Guess HA, et al. Natural history of

Pathophysiology of Bladder Outlet Obstruction and Voiding Dysfunction / 497 prostatism: relationship among symptoms, prostate volume, and peak urinary flow rate. J Urol 1995;153:1510–5. 36. Lepor H, Machi G. Comparison of the AUA symptom index in unselected males and females between 55 and 79 years of age. Urol 1993;42:36–40. 37. Caine M, Pfau A, Perlberg S. The use of alpha-adrenergic blockers in benign prostatic obstruction. Br J Urol 1976;48:255–8. 38. Caine M. Alpha adrenergic blockers for the treatment of benign prostatic hyperplasia. Urol Clin North Am 1990;17:641–9. 39. Smith JB, Pierce JM. Sequential events in prostatic obstruction. In: Hinman F Jr, editor. Benign prostatic hypertrophy. New York: Springer Verlag; 1983. p. 693–9. 40. Levin RM, Monson FC, Haugaard N, et al. Genetic and cellular characteristics of bladder outlet obstruction. Urol Clin North Am 1995;22:263–83. 41. Lutzeyer W, Hannappel J, Schafer W. Sequential events in prostatic obstruction. In: Hinman F Jr, editor. Benign prostatic hypertrophy. New York: Springer Verlag; 1983. p. 682–8. 42. Elbadawi A, Yalla SV, Resnick NM. Structural basis of geriatric voiding dysfunction. IV. Bladder outlet obstruction. J Urol 1993;150:1681–95. 43. Speakman MJ, Brading AF, Gilpin CJ, et al. Bladder outflow obstruction: a cause of denervation supersensitivity. J Urol 1987;138:1461. 44. Steers WD, DeGroat WC. Effect of bladder outlet obstruction on micturition reflex pathways in the rat. J Urol 1988;140:864. 45. Mebust WK, Holtgrewe HL, Cockett ATK, et al. Transurethral prostatectomy: immediate and postoperative complications. A cooperative study of 13 institutions evaluating 3,885 patients. J Urol 1989;141:243–7. 46. Djavan B, Madersbacher S, Klinger C, et al. Urodynamic assessment of patients with acute urinary retention: is treatment failure predictable? J Urol 1997;158:1829–33. 47. Levin RM, Longhurst PA, Monson FC, et al. Effect of bladder outlet obstruction on the morphology, physiology, and pharmacology of the bladder. Prostate 1990;3 Suppl:9. 48. Saito M, Longhurst PA, Tammela TL, et al. Effects of partial outlet obstruction of the rat urinary bladder on micturition characteristics, DNA synthesis, and the contractile response to field stimulation and pharmacologic agents. J Urol 1993;150:1045–51. 49. Elbadawi A. What role for the prostate in BPH-associated voiding dysfunction? Contemp Urol 1994;Aug:29–40. 50. George NJR, Fenely RCL, Robert JBM. Identification of the poor risk patient with “prostatism” and detrusor failure. Br J Urol 1986;58:290–5. 51. Elbadawi A, Meyer S, Regnier CH. Role of ischemia in structural changes in the rabbit detrusor following partial bladder obstruction: a working hypothesis and a biochemical structural model proposed. Neurourol Urodyn 1989;8:151–62. 52. Uvelius B, Mattiasson A. Collagen content in the rat urinary bladder subjected to infravesical outflow obstruction. J Urol 1984;132:587–90. 53. Baskin LS, Howard PS, Macarak EJ. Effect of physiological forces on bladder smooth muscle and urothelium. J Urol 1993;150:601–7.

54. Kaplan EP, Richier JC, Howard PS, et al. Type 3 collagen messenger RNA is modulated in non-compliant human bladder tissue. J Urol 1997;57:2366–9. 55. Kato K, Monson FC, Longhurst PA, et al. The functional effects of long term outlet obstruction on the rabbit urinary bladder. J Urol 1990;143:600–6. 56. Lin ATL, Chen MT, Yang CH. Blood flow of the urinary bladder: effects of outlet obstruction and correlation with bioenergetic metabolism. Neurourol Urodyn 1995;14:285–92. 57. Kato K, Lin ATL, Haugaard N, et al. Effects of outlet obstruction on glucose metabolism of the rabbit urinary bladder. J Urol 1990;143:844–7. 58. Levin RM, Yu HJ, Kim KB, et al. Etiology of bladder dysfunction secondary to partial outlet obstruction. Calcium disregulation in bladder power generation and the ability to perform work. Scand J Urol Nephrol 1997;184 Suppl:43–50. 59. Saito M, Hypolite JA, Wein AJ, et al. Effect of partial outflow obstruction on rat detrusor contractility and intracellular free calcium concentration. Neurourol Urodyn 1994;13:297–305. 60. Seki N, Karim OM, Mostwin J. The effect of experimental urethral obstruction and its reversal on changes in passive electrical properties of detrusor muscle. J Urol 1992;148:1957–61. 61. Dorflinger T, Frimodt-Moller PC, Bruskewitz RC, et al. The significance of uninhibited contractions in prostatism. J Urol 1985;133:819–122. 62. Abrams P. Detrusor instability and bladder outlet obstruction. Neurourol Urodyn 1985;4:317–20. 63. Andersen JT. Prostatism. III. Detrusor hyperreflexia and residual urine: clinical and urodynamic aspects and influence of surgery on the prostate. Scand J Urol Nephrol 1982;16:25–30. 64. Abrams P, Farrar DJ, Turner-Warwick RT, et al. The results of symptomatic and urodynamic analysis of 152 patients. J Urol 1979;121:640–2. 65. Gosling JA, Gilpin SA, Dixon JS, et al. Decrease in the autonomic innervation of human detrusor muscle in outflow obstruction. J Urol 1986;136:501–4. 66. Steers WD, Ciambotti J, Erdman S, et al. Morphologic plasticity in efferent pathways to the urinary bladder of the rat following urethral obstruction. J Neurosci 1990; 10:1943–51. 67. DuPont MC, Persson K, Spitskergent D, et al. The neuronal response to bladder outlet obstruction, a role for NGF. Adv Exp Med Biol 1995;385:41–54. 68. Steers WD, Creedon DJ, Tuttle JB. Immunity to nerve growth factor prevents afferent plasticity following urinary bladder hypertrophy. J Urol 1996;155:379–85. 69. Gup DI, Shapiro E, Baumann M, et al. The contractile properties of human prostate adenomas and the development of infravesical obstruction. Prostate 1989;15: 105–14. 70. Gup DI, Shapiro E, Baumann M, Lepor H. Autonomic receptors in asymptomatic and symptomatic BPH. J Urol 1990;143:179–85. 71. Lepor H, Shapiro E, Browsher R, Henry D. Tissue norepinephrine in prostate adenomas from men with symptomatic and asymptomatic BPH. J Urol 1990;144: 1263–6.

CHAPTER 55

PREVENTION OF THE PROGRESSION AND LONG-TERM COMPLICATIONS OF BENIGN PROSTATIC HYPERPLASIA CYNTHIA J. GIRMAN DR.PH; JOANNE WALDSTREICHER, MD Benign prostatic hyperplasia (BPH) is a common condition in men, second only to cataract surgery as the most common reason for a surgical procedure among elderly men. In 1995, over 5.5 million men in the United States above the age of 50 years were estimated to meet criteria proposed for discussing therapy1 for BPH according to treatment and diagnostic guidelines.2 The lifetime risk for medical or surgical intervention for BPH in a 50year-old man has been estimated at 40%.3 Benign prostatic hyperplasia represents a significant burden on health care, particularly in light of the aging of the general population. The three components of BPH, namely palpable enlargement of the prostate, lower urinary tract symptoms (LUTS), and obstruction, overlap to varying degrees in individual patients.4 Despite the high prevalence of BPH, standard clinical diagnostic criteria are yet to be developed. This limits the ability to characterize the natural history in untreated patients, and to identify risk factors for the disease or its progression.5 Since urinary symptoms can stem from other disease entities such as bladder disorders, the terms “lower urinary tract dysfunction” (LUTD) and LUTS have been proposed to describe symptoms that are not necessarily prostate-specific.6,7 Likewise, benign prostatic enlargement (BPE) refers to glandular enlargement, whether or not accompanied by LUTS. In this chapter, BPH refers to benign prostatic enlargement with associated LUTS. Although the high prevalence and chronic nature of BPH are established, therapeutic decision-making has previously been difficult because of the lack of documentation from well-designed long-term studies on the progression of BPH and its associated long-term risks if left untreated.5,8–10 This chapter reviews available data from community studies and clinical trials that document the long-term progressive nature of the disease. Recent evidence that progression and long-term complications of the disease may be preventable will be discussed.

Progression of Benign Prostatic Hyperplasia in Untreated Men Cross-sectional studies based on community samples have consistently shown age-dependent increases in symptom severity associated with BPH11,12 and declines in peak flow rate.13,14 Such studies have also documented an increase in prostatic volume with age.15–17 However, cross-sectional relationships with age do not necessarily characterize aging effects that occur over time in individual patients. Long-term longitudinal studies following individual patients over time provide better estimates of the progression of the disease. Until recently, few studies of this nature had been conducted and such information was lacking in the urologic literature. Recent longitudinal community studies have provided documentation of the progression of untreated BPH over periods of up to 7 years. In addition, data from long-term controlled clinical trials of medical therapy can also be examined for progression of BPH in placebo-treated men. Data from clinical trials, however, should be interpreted cautiously, given the selective nature of the trial population and the documented placebo effects which often occur in such studies.18 It is well known that clinical trial populations constitute a select population of men with the disease in question; rates of progression may depend on the entry criteria for the particular trial. In addition, the protocol-driven schedule of clinic visits and procedures may not always follow what might occur with the natural history of the disease. Placebo effects in blinded randomized clinical trials of BPH can be strong, in part due to psychologic factors in the blinded setting, positive expectations and anticipation of patients, providers, and caregivers toward treatment, clinic effects, compliance, and regression to the mean.18,19 This is particularly applicable to measures such as symptoms and urinary flow rate but is less so for measures of prostate volume and occurrence of spontaneous acute urinary retention. Placebo arms of clinical trials may therefore 498

Prevention of the Progression and Long-Term Complications of Benign Prostatic Hyperplasia / 499

not be generalizable to all men,19,20,21 reflecting only part of the natural history disease process.10 Randomized controlled clinical trials are the “gold standard,” however, by which to judge evidence regarding therapeutic effects on clinical measurements and long-term complications of untreated disease. In this chapter, crosssectional data from community and urologic studies as well as longitudinal data from both community-based studies and clinical trials will be examined to evaluate evidence for progression of BPH and the potential for its prevention.

Findings from Community Studies and Clinical Trials Symptoms It is well known that the prevalence of urinary symptoms increases with age. Based on cross-sectional communitybased studies, age-related increases in the prevalence of LUTS have been consistently found in numerous countries in studies using similar questionnaires, despite cross-cultural differences in the prevalence of moderate to severe symptoms.11,12,22–32 Few longitudinal studies have explored the progression of LUTS by following untreated men over time. Recent longitudinal findings from the community-based Olmsted County Study of Urinary Symptoms and Health Status Among Men suggest a measurable progression in symptom severity, on average, over 3.5 to 4 years accompanied by high intraindividual variability.20 The age-related changes found in this study were consistent with autopsy prevalence studies relating prostate volume to age.15 Another community study has also documented symptom progression over 3 years.33 Continued follow-up of such community-based cohorts of men should better characterize the rate of progression of urinary symptoms over longer time periods among untreated men in the community. In addition to the longitudinal community data from Olmsted County, 4-year longitudinal data are also available from a selected population of 500 patients with BPH who were considered candidates for elective prostatectomy or watchful waiting at five North American urology practices.34 Although variability in symptoms within individuals was high, progression was dependent on initial symptom severity. Of those with mild symptoms at baseline, a high proportion had progressed to moderate (50%), severe (7%), or had undergone surgery (10%) at 4 years. For those with moderate baseline symptoms, 17% had progressed to severe symptoms by 4 years and 24% had undergone surgery. The majority of patients with severe symptoms at baseline either still had severe symptoms (38%) by 4 years or had undergone surgery (39%).34 There have been long-term, placebo-controlled trials conducted in men with BPH that evaluated symptoms over periods of 1 to 4 years. Heterogeneity in the popula-

tions studied, entry criteria, number and frequency of clinic visits, symptom questionnaires used, and, especially, the magnitude of the placebo effects, however, limit the interpretation of such data from placebo arms of clinical trials in terms of natural progression of symptom frequency and severity. Placebo-controlled finasteride, terazosin, and tamsulosin studies in men with symptomatic BPH have shown symptom-score improvements varying from 1 to 6 units in placebo-treated patients treated for 1 or more years.35–40 The magnitude of placebo effect appears to diminish somewhat with longer-term controlled followup.41,42 In general, the degree of symptomatic improvement with placebo in this type of clinical trial setting is related to baseline symptom severity and may involve a regression to the mean phenomenon.18,43 In the 4-year placebo-controlled clinical trial known as the Proscar Long-term Efficacy and Safety Study (PLESS),40 however, a predefined slope analysis, which purposely evaluated the change in symptom score with placebo after the first year of the study, did show slight worsening (approximately 0.25 units per year) over years 2 through 4 of the study,44 consistent with the longitudinal data in untreated men. Urinary Flow Rate In cross-sectional studies, peak urinary flow rate has been shown to decline with age although intraindividual variability is high.13,45 Based on cross-sectional data collected from men randomly selected from the community, median peak flow rate declined from 20.3 mL per second for men aged 40 to 44 years to about 11.5 mL per second for men aged 75 to 79 years.13 Peak flow rate is dependent on voided volume and age, typically in a nonlinear manner; there have been various techniques proposed to construct nomograms.13,46–50 Single void peak flow rates have relatively low test-retest reliability in the same patients,51 and can be affected by medication and other extraneous factors, including diurnal variability and learning effects.45,52,53 Relatively little longitudinal data are available on the rate of deterioration in peak flow rates over time in representative cohorts of men. The longitudinal aspect of the Olmsted County community study recently reported that the decline in peak flow rate with age is supported by longitudinal data in individual untreated patients followed for approximately 5 years.54 The estimated rate of decline over 5 years in randomly selected men was approximately 2.4% per year. The rate of decline was greater in older men and in men with prostatic enlargement. Although urinary flow rates are often thought to be objective measurements, placebo effects in clinical trials, even beyond the initial “learning” effects, are common with such measurements. In general, placebo-treated patients have typically shown slight improvement or no deterioration over time, depending on the study. Most


alpha-blocker trials have been of limited duration, ranging from 3 weeks to 3 months of double-blind therapy, and have shown mean improvements for peak urinary flow rate as high as 2.2 mL per second in placebo groups at the end of study.35,36,55 In two trials of 1-year duration involving terazosin, the mean change for the placebo group ranged from 0.8 to 1.4 mL per second for peak urinary flow rate.37,40 Longer term finasteride trials have shown minimal change for peak urinary flow rates in placebo-treated patients over 1 to 4 years,41,56 and a 2-year study showed slight worsening for the placebo group.42 Prostate Size Autopsy studies, which by their very nature are crosssectional, have documented a steady increase in prostate volume with increasing age.15 Community-based crosssectional studies using transrectal ultrasonography or magnetic resonance imaging in men also suggest a steady increase in prostate size with increasing age.14,16,17,57,58 Jakobsen studied 115 men randomly selected from a population registry and another 60 men about to have a vasectomy. He noted slight increases in prostate volume with age but most of the men in his sample were aged 30 to 50 years.16 Bosch studied men aged 55 to 75 years recruited from a Rotterdam community to participate in a randomized trial of prostate cancer screening. He found much steeper age-dependent increases in overall prostate size and an age-related increase in the central hypoechoic volume.57 Garraway and Collins reported on prostate volume in men in a community setting selected on the basis of symptoms and low flow rate. Although the sample may not be representative of the general community, the agerelated increase in prostate volume corresponded well with that found in the autopsy series by Berry.15,23,58 Community-based longitudinal data are now available from the Olmsted County study, based on 5-year followup of randomly selected men aged 40 to 79 years.59 Prostate volume, as measured by ultrasound, increased an average of 1.6% per year consistently across all age groups. Interestingly, the rate of growth for individual patients was highly dependent on baseline prostate volume.59 Men with larger prostate volumes at baseline had larger growth rates than men with smaller prostates at baseline. The growth spurt around the sixth decade of life which had been postulated based on a small longitudinal study of 16 men followed for up to 7 years60 could be reflective of the typically larger prostate size for men in their sixties. Further research should confirm these findings. Although earlier clinical trials suggested potential placebo effects on prostate volume measurements,56 careful methodologic attention and blinding procedures can reduce or eliminate such effects in clinical studies.61 Long-term prostate growth has been documented in placebo-treated patients from the PLESS trial.41,62 In this 4-year study of 3040 men with symptomatic BPH and

enlarged prostates (determined by digital rectal examination [DRE]), prostate volume was obtained annually by magnetic resonance imaging in a subset of 155 men treated with placebo. All films were read at the end of the trial by a single radiologist blinded to treatment group as well as to patient identifiers, age, and year of measurement. Placebo-treated men experienced an average increase in prostate volume of approximately 3% per year. By the end of the study, men treated with placebo had a 14% increase in prostate volume over 4 years.41 Increases in prostate volume were documented in 80% of the placebo-treated men.44 The growth rates estimated in PLESS placebo patients are supported by estimates from 2-year trials.19,42 As it is known that men with increased prostate volume are at increased risk of BPH-related outcomes (e.g., developing acute urinary retention, BPHrelated surgery),21,63–65 prostate volume growth over time may put untreated men with symptomatic BPH at increased risk of long-term complications.

Long-Term Complications Untreated, BPH may lead to complications such as acute or chronic urinary retention, renal failure, serious or recurrent urinary tract infections (UTIs), bladder decompensation, hydronephrosis, and calculi, particularly bladder calculi.2,5,8,66–68 Few studies, however, have quantified the long-term risk of these complications. Several authors have reviewed the available literature on the incidence and risk of such complications in detail.2,5,8,10 Acute Urinary Retention and Associated Risk Factors Bladder outlet obstruction may progress to acute urinary retention (AUR), a painful, sudden inability to urinate. Many patients consider this to be the most serious outcome of untreated BPH,68 and it often requires emergency medical attention.69 Some clinicians considered AUR to be an absolute indication for surgical intervention67 while others have proposed catheterization and a voiding trial.66,69 The recurrence of AUR within 1 week of catheterization is high, however.69–71 The etiology of AUR is not well understood.5 Based on previous studies, it has been thought to occur unpredictably.72,73 The incidence-rate estimates for AUR vary dramatically by study. Estimates of AUR occurrence have ranged from 4 to 130 per 1000 person-years.72,74,75 More recently, Barry estimated the incidence of AUR at 2.5% per year of men with clinically diagnosed BPH followed for 4 years in North American urology practices.34 In a recent analysis based on a review of 3- to 4-year data from men participating in the Olmsted County longitudinal community study, age, symptoms, urinary flow rate, and prostate volume were significant risk factors for the occurrence of AUR.21 Incidence rates of AUR in symptomatic men varied by age, ranging from 3.0 per 1000 per-


son-years for men 40 to 49 years to 34.7 per 1000 personyears for men aged 70 to 79 years.21 Approximately half of the cases of retention were spontaneous while the rest were precipitated by factors such as preceding surgery, anesthesia, or medication.21 The risk of retention for men with prostates above 30 mL was elevated three-fold (95% CI: 1.0, 9.0) relative to men with smaller prostates and fourfold for men with low peak flow rate (< 12 mL per second). Rates of AUR in placebo-controlled patients have varied across clinical trial settings with different entry criteria, particularly when follow-up data were not diligently collected or there was a high discontinuation rate. Since men who deteriorate often discontinue clinical trials and are not followed up, adequate information on those most at risk is lost if detailed follow-up on discontinued patients is not obtained. In addition, short studies, especially those that enrolled men with smaller prostate volumes, have typically not had high enough rates of AUR for reliable analysis.76 Estimates have been surprisingly consistent, however, from four studies of sufficient duration (at least 1 year) and with adequate follow-up of discontinued patients, with data collected in a systematic fashion based on predefined criteria. The first, a randomized trial of transurethral resection of the prostate (TURP) versus watchful waiting in men over 54 years of age with moderate to severe symptoms and average baseline peak flow rate of approximately 12 mL per second, had a rate of “intractable urinary retention” of 2.9% for the watchful waiting group over 3 years.77 In the multinational, randomized, placebo-controlled Hytrin Community Assessment Trial (HYCAT) study, which evaluated patients over 55 years with AUA symptom index above 12 who were bothered and had a peak flow rate of 15 mL per second or below, the rate of spontaneous AUR in the placebo group was 1.3% in 1 year.40,78 In the pooled analysis of three multinational 2-year finasteride trials, the incidence of acute urinary retention was 2.7% over 2 years for placebo-treated patients with moderate to severe symptoms and prostatic enlargement.79 Finally, in the 4-year PLESS study, based in the United States, the incidence of spontaneous AUR in men with moderately to severely symptomatic BPH was 4% over 4 years.41 Thus, in the clinical trial setting, the incidence of spontaneous AUR in placebo-treated men is approximately 1% per year. The incidence of precipitated AUR was also documented in PLESS and was found to be 3% over 4 years. As in the community-based Olmsted County longitudinal study, the incidence of spontaneous and precipitated retention appears to be approximately equivalent.21,41 Surgical Intervention and Minimally Invasive Procedures The most common surgical procedure for BPH is TURP, with open prostatectomy typically reserved for men with very large prostates or for those in whom the lithotomy

position is problematic or who require additional procedures. Minimally invasive procedures have been introduced more recently although long-term data on efficacy, complications, and recurrence are only recently accumulating. The indications for surgery vary widely and are not universally accepted.67 Older patients and those with renal insufficiency are at higher operative risk80 for complications and mortality due to increased comorbidity and may not be good candidates for surgical intervention.68,81 Based on the Normative Aging Study, a man aged 50 years has been estimated to have a one in three chance of prostatectomy if he survives to the age of 80 years.82 Characterizing the risk for surgery is complex, however, due to the changing incidence of surgical intervention with time, the introduction of new surgical and medical alternatives, cost containment strategies, widely varying referral and geographic patterns, and lack of consensus on indications for surgery.67,83,84 The decision to proceed to surgery relies heavily on patient attitudes and values, which in turn can be influenced by the surgeon. Some patients avoid the trauma of surgery despite severe and bothersome symptomatology while others seek surgery for the mildest of symptoms. Although these factors make characterization of surgical risk complex, several epidemiologic studies and clinical trials have shed light on the rate of surgery and associated risk factors. Several studies have found that severity of urinary symptoms was predictive of surgical intervention85–87 although individual symptoms found to be predictive have varied by study. Other factors include prior clinical diagnosis of BPH, higher socioeconomic status, low body mass, Jewish religion, and nonsmoking status.82,87,88 One study based on up to 30 years of follow-up of over 1000 men found that increased age, prostate size (as estimated by DRE), and urinary symptoms were predictive of prostatectomy.89 This is consistent with the finding that men with prostatic enlargement, moderate to severe symptoms, or low peak flow rate are more likely to seek medical care.90 In the Veterans Administration trial of TURP versus watchful waiting, 24% of the men assigned to the watchful waiting group underwent surgery within 3 years and 2.9% had urinary retention.77 In the study mentioned above of 500 men with BPH who were followed in five North American urology practices,34 10% of those with mild symptoms at baseline underwent prostatectomy during the 4-year follow-up. The percentage of men proceeding to surgery was higher for men with moderate (24.1%) and severe (39.4%) symptoms at baseline.34 Placebo-treated patients from alpha-blocker trials provide little information on the rate of surgery in untreated men due to the typically brief duration of the controlled portion of the study and the lack of adequate follow-up, as mentioned above. The HYCAT study, however, which recruited men aged 55 years or older with moderate to severe symptoms (AUA symptom index


greater than 12) who were bothered and had reduced urinary flow rate (peak flow rate ≤ 15 mL per second), reported a prostatectomy rate of 5% for placebo-treated patients during the 1-year study.40 Placebo-controlled data from clinical trials of 5 αreductase inhibitors ranging in duration from 2 to 4 years are available and provide data from the clinical trial setting. In a combined analysis of three 2-year multinational studies, Andersen et al. reported that 6.5% of the placebo patients with moderate to severe symptoms and prostatic enlargement underwent prostatectomy over the 2-year follow-up.79 Similarly, in the 4-year PLESS trial, approximately 10% of placebo-treated patients with moderately to severely symptomatic BPH underwent surgical intervention over the 4-year period.41 Because participants in clinical trials may be encouraged to stay in the study and the studies were designed to be long-term, these rates may reflect an underestimate of rates of surgery in men with symptomatic BPH.41 It is therefore not surprising that the rates are lower than those reported over a similar period in the urologic practice setting.34 Rates for repeat prostatectomy following TURP or minimally invasive procedures have been reported but range in magnitude depending on the study. The Veterans Administration Cooperative trial of TURP versus watchful waiting had an estimated re-TURP rate for BPH of 2% over 3 years77,91 although earlier studies suggested a rate as high as 10%.81 One French study of TURP showed a 6.3% reoperation rate at less than 1 year and 6.5% of patients experiencing urethral stricture.92 The likelihood of reoperation within 6 years from 1980 to 1987 was 15.1% in a study of 330 Rochester, Minnesota men who were undergoing their first prostatectomy for BPH.93 In a recent study by Lu-Yao et al., based on a 20% random sample of Medicare claims, a recurrence rate of TURP for BPH of approximately 2.9% over 3 years and 5.5% over 7 years was reported,94 with the risk of recurrence dependent on age. Avoidance of surgery is important from a public health standpoint, partly because of the associated morbidity that occasionally occurs, and also because of the potential need for reoperation. Rare complications associated with surgical intervention include dilutional hyponatremia, perioperative infection such as epididymitis and UTI, fever, urinary retention, hemorrhage requiring transfusion, myocardial infarction, stroke, incisional complications,2,55,77,81 retrograde ejaculation, impotence, and urinary incontinence.81 The need for recatheterization, and hyponatremia presumably associated with fluid absorption, have also been reported.92 Minimally invasive procedures such as laser prostatectomy, transurethral incision of the prostate, prostatic stents, and transurethral microwave thermotherapy have been purportedly associated with lower morbidity than TURP or open prostatectomy but have potentially higher reoperative rates.95–100 Sufficiently long-term data in large

samples of men from multiple institutions are lacking, however. Effects of thermotherapy have been studied for periods as long as 3 to 4 years95,101 and appear to be durable in patients consenting to continued follow-up although various studies report high rates of complications such as urinary retention requiring catheterization. Retreatment rates vary from 0.6 to 14%.95,97,101,102

Pharmacologic Strategies for Prevention Alpha-Blockers Alpha-adrenergic blockers have been shown to rapidly alleviate symptoms and improve urinary flow rates in men with LUTS but do not appear to alter the disease process in such a way as to prevent progression. Alpha-blockers may induce apoptosis in the prostate gland103 but longitudinal data do not show a measurable effect on prostate volume.37 Alpha-blockers have not been typically studied in long-term controlled trials, and there are therefore only limited data available on long-term effects on outcomes. Only two controlled studies longer than 3 months have reported on outcomes such as AUR or BPH-related surgery; only one of these, the 1-year placebo-controlled HYCAT study, had a predefined objective of evaluating resource utilization although the high proportion of patients who discontinued the study (42%) and had no follow-up information limits interpretation.40 In HYCAT, no significant difference was found in the number of patients who underwent prostatectomy during the 1-year trial (48 in the placebo and 41 in the terazosin group). Likewise, no difference between active and placebo groups was found in the rate of AUR during the 1-year trial (1.3% in both groups).78 In a 6-month trial of alfuzosin, 7 patients in the placebo group and one patient in the alfuzosin group discontinued due to AUR. Thirty-one percent of the enrolled men dropped out of the study, however, despite its short length, and follow-up information was not obtained on these patients. Although long-term extension data are available for terazosin, doxazosin, tamsulosin, and alfuzosin that show a continuing symptomatic benefit, the lack of control group, high dropout rate, and responder enrichment typical for extension data make these results difficult to interpret. Five α-Reductase Inhibitors Finasteride, a highly specific type II 5 α-reductase inhibitor, has been shown to reduce prostate volume, decrease symptoms of BPH, and improve urinary flow rate.41,42,56,79 Recent data from the PLESS trial now confirm that finasteride alters the natural history BPH and may prevent progression of the disease.41,42,79 The 4-year, placebo-controlled PLESS trial randomized 3040 men with moderate to severe urinary symp-


FIGURE 55–1. Change in prostate volume over time by treatment group. Values reflect mean (±SE) percent change from baseline at each year. Adapted with permission from McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338:557–63. ©1998 Massachusetts Medical Society. All rights reserved.

toms and prostatic enlargement by DRE to either finasteride or placebo and assessed symptom scores, urinary flow rates, prostate volume (in a 10% subset of men), and the rates of BPH-related outcomes, including AUR and BPH-related surgery,41 over time. As has been shown in several prior studies, finasteride had a modest but durable effect on urinary symptoms and flow rate over the 4-year period compared to placebo. Additionally, finasteride decreased prostate volume by approximately 18% during the first year of the study,41 with prevention of further growth of the prostate over time. In contrast to the 80% of placebotreated patients who had growth of the prostate over the 4-year study period, 90% of finasteride-treated patients had decreases in prostate volume, with an overall mean decrease of 18% at the end of 4 years, and a 32% between-group difference in mean prostate volume between the finasteride and placebo groups at the end of the study (Figure 55–1). The most important contribution of the PLESS trial was its careful documentation of BPH-related outcomes, including AUR and the need for BPH-related surgery in patients over the 4-year study period.41 As part of the study, investigators contacted patients 6 months after discontinuation and at the end of the 4-year trial. Four-year data, including follow-up on discontinued patients, were available on 92% of the men randomized into the study. In addition, an Endpoint Committee, blinded to treatment group, reviewed all study-related documents on outcomes. Over the 4-year period, 13% of the men assigned to the placebo group underwent BPH-related surgery or experienced AUR (Figures 55–2 and 55–3). In

contrast, men in the finasteride group had a 55% reduction in the risk of BPH-related surgery (5% incidence over 4 years versus 10% for placebo) and a 57% reduction in the risk of AUR (4% incidence over 4 years versus 7% for placebo). These approximately 50% reductions in the risk of BPH-related outcomes were seen as early as 4 months into the study and continued throughout the 4year trial period.41 As men enrolled in the trial were symptomatic and had enlarged prostate glands at baseline, these data may not be generalizable to men without prostatic enlargement or symptoms. Subgroup analyses of the data from the study, however, demonstrated reductions in the risk of BPH-related outcomes of similar magnitude in all subsets of men based on baseline symptom severity and demographic factors.64 These data suggest that by reducing the volume of the prostate and preventing further growth over time, finasteride reduces the long-term risk of BPH-related outcomes and may prevent long-term progression of the disease.

Discussion Progression of urinary symptoms, prostate volume growth, and deterioration of urinary flow rate over time have been documented in a number of studies. Both cross-sectional and longitudinal community studies have consistently demonstrated worsening of urinary symptoms and flow rate, as well as prostatic growth, in men over 50 years of age. In addition, newly available data from placebo groups of men with BPH in controlled clinical trials have documented measurable prostatic growth in individual selected patients over time. With the accumulation of knowledge about BPH in recent years, the International Consultation on BPH Committee for Regulation of Prostatic Growth has recommended greater emphasis on possible intervention initiatives that could lead to the prevention of BPH.105 Clinical trials have now documented that disease progression can be altered.41,42,79 This is supported by findings from long-term studies demonstrating that finasteride leads to durable improvements in urinary symptoms and flow rates as well as a reduction of prostate gland size and prevention of further growth over time41,42,79 in men with symptomatic BPH.105 Multiple studies provided even stronger evidence in showing that finasteride reduces the risk of long-term outcomes of BPH, including development of AUR and the need for BPH-related surgery.41,79 No therapeutic agents other than finasteride have been shown to affect long-term complications or sequelae of BPH. The men recruited into most of the finasteride BPH trials were older (generally in their sixties) with moderate to severe BPH symptoms and an enlarged prostate on DRE. It is unknown what effect introduction of finasteride earlier in the disease process would have had. To study such effects and the effects on rarer complications,


FIGURE 55–2. Probability of acute urinary retention during the 4year study period in the placebo and finasteride groups. Figure shows life-table analyses; men who died, were given a diagnosis of prostate cancer, or were lost to follow-up were censored at the time of death, diagnosis of prostate cancer, or discontinuation of study therapy. Adapted with permission from McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338:557–63. ©1998 Massachusetts Medical Society. All rights reserved.

FIGURE 55–3. Probability of undergoing surgery for benign prostatic hyperplasia during the 4-year study period in the placebo and finasteride groups. Figure shows life-table analyses; men who died, were given a diagnosis of prostate cancer, or were lost to follow-up were censored at the time of death, diagnosis of prostate cancer, or discontinuation of study therapy. Adapted with permission from McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338:557–63. ©1998 Massachusetts Medical Society. All rights reserved.

a much larger patient population and even longer-term follow-up is necessary. The 7-year trial of finasteride, doxazosin, their combination, and placebo currently being conducted by the National Institutes of Health will hopefully answer some of these questions. Likewise, the National Cancer Institute trial being conducted in 18,000 men to assess finasteride as a potential prostate cancer chemopreventive agent will also greatly supplement the available long-term evidence on prevention of BPH upon its completion in 2003. Finally, long-term follow-up of young men currently being treated with finasteride 1 mg for male pattern hair loss may also shed light on this area.

References

Conclusion The past decade has introduced many new alternatives for treating BPH through minimally invasive procedures and medical therapy. Surgery and minimally invasive procedures may be employed later in the disease process and produce symptomatic relief but may have associated reoperative rates, while alpha-blockers rapidly alleviate symptoms. None of these strategies, however, have been shown to definitively alter the long-term progression of the actual disease process. The 5 α-reductase inhibitor finasteride has been shown to provide modest but durable symptomatic relief. It is the only available medical therapy which may prevent progression of BPH by shrinking the prostate gland and reducing the risk of long-term complications such as acute urinary retention and BPH-related surgical intervention.

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measures of prostate volume in a community-based sample: 5.5 year follow-up in the Olmsted County Study of Urinary Symptoms and Health Status Among Men. Urology 1999;161:1174–9. Ohnishi K, Watanabe H, Ohe H. Development of benign prostatic hypertrophy estimated from ultrasonic measurements with long-term follow-up. Tohoku J Exp Med 1987;151:51–5. Bonilla J, Stoner E, Grino P, et al. Intra and interobserver variability of MRI prostate volume measurements. Prostate 1997;31:98–102. Bonilla J, Roehrborn CG, McConnell JD, et al. Patterns of prostate growth observed in placebo-treated patients in the PLESS trial over four years. J Urol 1998;159:333. Lieber M, Fowler J, Castellanos R, et al. PSA is the strongest predictor of BPH-related outcomes: results of a 4-year placebo-controlled trial. J Urol 1998;159:107. McConnell J, Malek G, Bruskewitz R, et al. Acute urinary retention and BPH-related surgery: predicting those at highest risk and prevention with finasteride. J Urol 1998;159:255. Roehrborn CG, McConnell JD, Lieber M, et al. for the PLESS Study Group. Serum prostate-specific antigen concentration is a powerful predictor of acute urinary retention and need for surgery in men with clinical benign prostatic hyperplasia. Urology 1999;53:581–9. Christiansen MM, Bruskewitz RC. Clinical manifestations of benign prostatic hyperplasia and indications for therapeutic intervention. Urol Clin North Am 1990;17: 509. Graversen PH, Gasser TC, Wasson JH, et al. Controversies about indications for transurethral resection of the prostate. J Urol 1989;141:75. McConnell JD, Roehrborn CG. Patient selection and symptom evaluation. In: Chisholm GD, editor. Handbook on benign prostatic hyperplasia. Whitehouse Station (NJ): Merck & Co., Inc; 1994. Hastie KJ, Dickinson AJ, Ahmad R, Moisey CU. Acute urinary retention of urine: is trial without catheter justified? J R Coll Surg Edinb 1990;35:225–7. Breum L, Klarskov P, Munck LK, et al. Significance of acute urinary retention due to infravesical obstruction. Scand J Urol Nephrol 1982;16:21–4. Klarskov P, Andersen JT, Asmussen CF, et al. Symptoms and signs predictive of the voiding pattern after acute urinary retention in men. Scand J Urol Nephrol 1987; 21:23–8. Birkhoff JD, Wiederhorn AR, Hamilton ML, Zinsser HH. Natural history of benign prostatic hypertrophy and acute urinary retention. Urology 1976;7:48–52. Powell PH, Smith PJB, Feneley RCL. The identification of patients at risk for acute retention. Br J Urol 1980;53: 520–2. Ball AJ, Feneley RCL, Abrams PH. The natural history of untreated “prostatism.” Br J Urol 1981;53:613–6. Craigen AA, Hickling JB, Saunders CRG, Carpenter RG. Natural history of prostatic obstruction. J Roy Coll Gen Pract 1969;18:226–32. Jardin A, Bensadoun H, Delauche-Cavallier MC, et al., and the BPH-ALF Group. Alfuzosin for treatment of benign prostatic hypertrophy. Lancet 1991;337:1457–61. Wasson J, Reda D, Bruskewitz R, et al., for the Veterans


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Affairs Cooperative Study Group on Transurethral Resection of the Prostate. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. N Engl J Med 1994;332:75–9. Somers WJ, Mora MJ, Mason MF, Padley RJ for the HYCAT Investigators Group. The natural history of benign prostatic hypertrophy: incidence of urinary retention and significance of AUA symptom score. J Urol 1996;155:586. Andersen JT, Nickel JC, Marshall VR, et al. Finasteride significantly reduces acute urinary retention and need for surgery in patients with symptomatic benign prostatic hyperplasia. Urology 1997;49:839–45. DuBeau CE, Resnick NM. Controversies in the diagnosis and management of benign prostatic hypertrophy. Adv Intern Med 1991;37:55–83. Mebust WK, Holtgrewe HL, Cockett ATK, Peters PC. Transurethral prostatectomy: immediate and postoperative complications: a cooperative study of 13 participating institutions evaluating 3885 patients. J Urol 1989;141:243. Glynn RJ, Campion EW, Bouchard GR, et al. The development of benign prostatic hyperplasia among volunteers in the Normative Aging Study. Am J Epidemiol 1985;121:78–90. McPherson K, Wennberg J, Hovind O, Clifford P. Small area variations in the use of common surgical procedures: an international comparison of New England, England, and Norway. N Engl J Med 1982;307:1310–4. Wennberg JE, Mulley AGJ, Hanley D, et al. An assessment of prostatectomy for benign urinary tract obstruction: geographic variations and the evaluation of medical care outcomes. JAMA 1988;259:3027–30. Diokno A, Brown M, Goldstein N, Herzog A. Epidemiology of bladder emptying symptoms in elderly men. J Urol 1992;148:1817–21. Epstein R, Lydick E, DeLabry L, Vokonas P. Age-related differences in risk factors for prostatectomy for benign prostatic hyperplasia: the VA Normative Aging Study. Urology 1991;38:59–62. Sidney S, Quesenberry CP, Sadler MC, et al. Incidence of surgically treated benign prostatic hypertrophy and of prostate cancer among blacks and whites in a prepaid health care plan. Am J Epidemiol 1991;134:825–9. Morrison AS. Risk factors for surgery for prostatic hypertrophy. Am J Epidemiol 1978;135:974. Arrighi HM, Guess HA, Metter EJ, Fozard JL. Symptoms and signs of prostatism as risk factors for prostatectomy. Prostate 1990;16:253–61. Jacobsen SJ, Girman CJ, Guess HA, et al. Do prostate size and urinary flow rates predict health care seeking behavior for urinary symptoms in men? Urology 1995;45:64–9. Gibbons RP, Altwein JE, Bruskewitz RC, et al. Surgical and laser treatment. In: Denis L, Griffith K, Khoury S, et al., editors. Proceedings of the 3rd International Consultation on Benign Prostatic Hyperplasia (BPH). Plymouth, (UK): Health Publication Ltd; 1998.

92. Bruskewitz R, Fourcade R, Koshiba K, et al. Surgery. In: Denis L, Griffiths K, Khoury S, et al., editors. Proceedings of the 4th International Consultation on Benign Prostatic Hyperplasia (BPH). Plymouth (UK): Health Publication Ltd; 1998. 93. Stephenson WP, Chute CG, Guess HA, et al. Incidence and outcome of surgery for benign prostatic hyperplasia among residents of Rochester, Minnesota: 1980–1987. Urology 1991;38 Suppl:32–42. 94. Lu-Yao GL, Barry MJ, Chang C-H, et al., and the Prostate Patient Outcomes Research Team (PORT). Transurethral resection of the prostate among Medicare beneficiaries in the United States: time trends and outcomes. Urology 1994;44:692–8. 95. Blute M, Devonec M, de la Rosette J, et al. Thermotherapie. In: Dennis L, Griffiths K, Khoury S, et al., editors. Proceedings of the 4th International Consultation on Benign Prostatic Hyperplasia (BPH). Plymouth (UK): Health Publication Ltd; 1998. 96. Kaplan S, Baba S. Electrovaporisation of the prostate. In: Denis L, Griffiths K, Khour y S, et al., editors. Proceedings of the 4th International Consultation on Benign Prostatic Hyperplasia (BPH). Plymouth (UK): Health Publication Ltd; 1998. 97. Oesterling JE. Benign prostatic hyperplasia: medical and minimally invasive treatment options. N Engl J Med 1995;332:99–109. 98. Schulman CC, Prezioso D, Zlotta AR. Transurethral needle ablation of the prostate (TUNA). In: Denis L, Griffiths K, Khoury S, et al., editors. Proceedings of the 4th International Consultation on Benign Prostatic Hyperplasia (BPH). Plymouth (UK): Health Publication Ltd; 1998. 99. Stein BS, Altwein JE, Bruschter R, et al. Laser prostatectomy. In: Denis L, Griffiths K, Khoury S, et al., editors. Proceedings of the 4th International Consultation on Benign Prostatic Hyperplasia (BPH). Plymouth (UK): Health Publication Ltd; 1998. 100. Yachia D, Williams G. Stents. In: Denis L, Griffiths K, Khoury S, et al., editors. Proceedings of the 4th International Consultation on Benign Prostatic Hyperplasia (BPH). Plymouth (UK): Health Publication Ltd; 1998. 101. Blute ML, Patterson DE, Segura JW, et al. Transurethral microwave thermotherapy versus sham treatment: double-blind randomized study. J Endourol 1996;10: 565–73. 102. Hallin A, Berlin T. Transurethral microwave thermotherapy for benign prostatic hyperplasia: clinical outcome after 4 years. J Urol 1998;159:459–64. 103. Kyprianou N, Litvak JP, Borkowski A, et al. Induction of prostate apoptosis by doxazosin in benign prostatic hyperplasia. J Urol 1998;159:1810–5. 104. Griffiths K, Cockett ATK, Coffey D, et al. Regulation of prostatic growth. In: Denis L, Griffiths K, Khoury S, et al., editors. Proceedings of the 4th International Consultation on Benign Prostatic Hyperplasia (BPH). Plymouth (UK): Health Publication Ltd; 1998. 105. Boyle P, Gould AG, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 1996;48:398–405.

CHAPTER 56

BENIGN PROSTATIC HYPERPLASIA: WHEN TO INTERVENE STEVEN G. ROBERTS, MD; MICHAEL L. BLUTE, MD

When to Initiate Therapy

Over the past decade, there has been increasing debate over when to intervene for benign prostatic hyperplasia (BPH). The debate has been fueled by a number of variables, including how to define and identify this condition. Descriptive terms such as prostatism, lower urinary tract symptoms (LUTS), bladder outlet obstruction, and prostatic hypertrophy and hyperplasia have all been used in discussions regarding management of BPH. Some of these terms, however, have clouded the discussion and are no longer considered clinically useful. Currently, symptoms and signs related to BPH are discussed in terms of LUTS and bladder outlet obstruction. The presentation of BPH varies among individuals, another difficulty in identifying and defining the problem. Patients may present with isolated voiding symptoms with no objective evidence of obstruction, obstruction without symptoms, or benign growth of the prostate with or without symptoms or obstruction. Patients most often present with overlap of these conditions to varying degrees. There is also variability in terms of bother among patients with a similar constellation of symptoms. With this in mind, one of the most difficult decisions for the clinician caring for the patient with BPH is when to intervene with either medical or surgical therapy. There has been increasing emphasis placed on how a person's quality of life is affected by both symptoms resulting from BPH as well as by morbidity from BPH therapy. Further complicating the issue is the variability in the natural history of BPH among individuals. Cohort studies have shown that in men with symptomatic BPH followed over 3 years without therapy, over one-third of men will have an improvement in their symptoms, over one-third will have no significant change, and less than one-third will have progression in their condition.1,2 These data indicate that therapy is appropriate in many men with BPH. Observation should be considered a management option for others, however. Further, the management of BPH is in transition with regard to treatment modalities. Medical and minimally invasive therapies have assumed increasing importance as well as potentially changing the timing of intervention for BPH therapy. The aim of this chapter, therefore, is to determine the appropriate timing of initiation of therapy for BPH.

The pathophysiology of LUTS and bladder outlet obstruction is related to a static component resulting from the development and growth of nodules in the periurethral glandular tissue of the prostate, and a dynamic component from increased muscle tone of the bladder neck and prostate.3 Physiologic changes not directly related to the size or configuration of the prostate but that contribute to lower urinary tract symptoms include decreasing bladder capacity and compliance with age,4 changes in compliance of the prostate and prostatic urethra,5,6 and the high prevalence of detrusor instability in older men.7 These conditions will also influence the success of a particular therapy. Prior to intervention for this presumed condition, however, other conditions of the lower urinary tract that may influence voiding function must be excluded. The differential diagnosis in a patient with obstructive or irritative symptoms should include urethral stricture disease, urinary tract infection, bladder dysfunction secondary to neurologic disease, and malignant conditions of the lower urinary tract. This is particularly true for therapy instituted independent of a urologist. Once nonprostatic causes of LUTS have been excluded, appropriate therapy needs to be initiated, bearing in mind that BPH is a multifactorial disease and that no single therapy should be universally applied.

Quality of Life and Symptom Severity Maintaining the quality of life (QOL) of the individual patient should be an integral component of the decisionmaking process when initiating therapy for BPH. For example, nocturia two to three times per night may be terribly bothersome for one man but of little concern to another. Therefore, observation and regular checkups for the individual whose QOL is not altered would be appropriate. Similarly, the adverse impact that a particular therapy has on an individual's QOL with respect to side effects must be carefully considered prior to initiating therapy. These variables become relevant only after consultation between physician and patient. 508

Benign Prostatic Hyperplasia: When to Intervene / 509

As the resistance to bladder outflow increases, patients may experience obstructive LUTS such as hesitancy, intermittency, decreased force of stream, straining to urinate, postvoid dribbling, nocturia, a sense of incomplete emptying, and incontinence. Irritative symptoms including mainly frequency and urgency may also develop. Attempts at quantifying the severity of these symptoms have resulted in symptom score questionnaires. One commonly used symptom score questionnaire is that used by the American Urological Association (AUA) (Figure 56–1). All questions are referable to the effect of the symptom on the patient's QOL. More important than the absolute AUA symptom score is that the recommendation to initiate therapy should be based on the degree of bother the patient is experiencing.8 The success of a therapy should also be based on improvement of symptoms and the degree to which a patient's QOL is ameliorated. That the physician should not rely solely on the symptom score when deciding to institute therapy is illustrated by the example of a patient whose LUTS have remained stable over the past several years. His AUA symptom score of 15 would indicate that he has moderate LUTS (see Figure 56–1) although from his point of view the degree of bother is minimal. In fact, this risk-averse patient expressed dread about having to be burdened with another daily medication that would have to be taken indefinitely, stating that a surgical procedure would have to be the last resort. This illustration underscores that reliance on the patient's severity of symptoms is important but not always sufficient in making the decision to institute therapy. The Olmstead County population-based study9 evaluated the potential impact in the United States of the clini-

FIGURE 56–1. AUA symptom score questionnaire.

cal practice guidelines for the diagnosis and treatment of BPH set forth by the Agency for Health Care Policy and Research.10 It was projected in the study that nearly 30% of men aged 60 to 69 years and over 30% of men aged 70 to 79 years were eligible to discuss treatment options for BPH based on an AUA symptom score > 7. The number of men who actually seek out medical attention with at least moderate obstructive symptoms is far less. Only 13% of men with moderate to severe symptoms had sought out medical attention over the previous year, indicating that the degree to which QOL is affected by such symptoms may not be enough of an incentive to seek therapy.11

Optional Diagnostic Tests When symptoms are severe enough to adversely affect a patient's QOL, the use of objective data is often helpful to confirm bladder outlet obstruction and motivate the practitioner to discuss treatment options with the patient. These optional diagnostic tests include assessing urinary flow rate, measuring postvoid residual urine volume, and pressure-flow studies. Such tests are recommended based on the fact that men with altered voiding parameters are more likely to benefit from therapeutic interventions. Uroflowmetry is a widely used test that measures average and peak urine flow. Caution should be exercised when interpreting this test as there is significant variability among individuals with BPH. It has been observed that in a group of men with LUTS, nearly half had a > 2 standard deviation difference between two consecutive peak flow measurements.12 The other limitation of uroflow measurement is its low specificity; false positive results can be


obtained from a poorly contractile bladder, urethral stricture disease, bladder calculi, etc. Given the limitations of uroflowmetry, pressure-flow studies have been advocated to at least theoretically measure bladder outlet obstruction. These studies are performed by recording detrusor pressure and urinary flow simultaneously. The data can then be plotted on an Abrams-Griffiths nomogram. Results are plotted as showing evidence of obstruction, equivocal, and no evidence of obstruction.13,14 Using these results as a basis for treatment is controversial. There is still disagreement as to the delineation between obstruction and no obstruction interpreting an equivocal nomogram result. Even more difficult is how to reliably correlate the pressure-flow results with the patient's symptom score and degree of bother. In a prospective BPH study looking at preoperative uroflow versus pressure-flow studies in predicting success from prostatectomy as defined by the patient, sensitivity and positive predictive value (PPV) for uroflowmetry were 64% and 92%, respectively, and 75% and 94% for pressureflow studies.15,16 No difference was found in predictive value between uroflowmetry and the pressure-flow study after being followed for eight years.17 It was suggested that pressure-flow studies add little to uroflowmetry in men with LUTS being considered for therapy. Prostate configuration and tissue volume are important parameters in predicting success from a particular therapy being considered. Despite the belief commonly held by patients and physicians, a large gland in the absence of other subjective and objective criteria suggesting bladder outlet obstruction is not an indication for therapy. Cystourethroscopy can add valuable information when selecting which therapy is appropriate but findings on urethroscopy should not be the basis for instituting therapy. Numerous studies have evaluated the relationship between LUTS and prostate volume. Barry et al. found no correlation between symptom severity and prostate size in 189 men presenting with symptoms suggestive of BPH.18 All patients underwent self-assessment of symptom severity using the AUA symptom index, digital rectal examination, serum creatinine measurement, uroflowmetry, ultrasonography, and cystourethroscopy. The authors concluded that prostate enlargement is an attribute of BPH but is not the critical factor in the production of symptoms or physiologic outlet obstruction. This discrepancy is explained by the fact that a small degree of strategically placed hyperplasia in the periurethral area may cause considerable obstruction in some individuals, while in others a very large hyperplastic prostate may produce no obstruction.19

Watchful Waiting As mentioned above, the natural history of BPH suggests that at least two-thirds of patients followed over time for LUTS will experience either stabilization of their symptoms or even symptomatic improvement. Most interventions for

BPH are initiated after the onset of symptoms. The variable natural history would, however, justify at least a brief period of watchful waiting in individuals whose symptoms are relatively mild.10 At each office visit, usually annually, the patient's symptoms should be reassessed and compared to his baseline symptom index. Figure 56–2 shows the decision diagram for BPH management recommended by the Agency for Health Care Policy and Research.10 There is a physical examination and laboratory analysis performed, which should include a urinalysis and culture if indicated as well as a serum creatinine to monitor renal function. Optional studies such as measuring uroflow and postvoid residual urine volume may also be considered. The Olmstead County Natural History Study of LUTS reported on 2115 men followed over a 42-month period.20 Of the 1288 men who reported mild symptoms at baseline, 73% also reported mild symptoms at 42 months. Only 22% of these intially reporting mild symptoms had progression in their symptoms at 42 months. Overall, there was a slight decrease in symptom severity as measured by the AUA symptom index at 18 months; at 42 months, there was an increase in symptom severity across all age groups. Overall, the symptom score index increased by 0.18 but not consistently across all age groups. The symptom score increased by 0.05 points per year among men in their forties compared to 0.44 points per year for men in their sixties. There was variability in individual symptoms. Longitudinal changes in daytime frequency, dysuria, straining, urgency, and the sensation of incomplete emptying did not consistently show an increase with time among the different age groups. Double voiding, hesitancy, terminal and postvoid dribbling, nocturia, and weak stream showed consistent increases with time among all age groups. Nocturia and weak stream showed the greatest increase in symptom severity over time. Men in their sixties showed the most rapid increase in symptom severity. It was concluded that since there is so much variability in symptom severity, symptoms should be assessed at several intervals to understand the trend in symptom progression. Watchful waiting is a safe option for patients whose symptoms are not terribly bothersome. Craigen et al.21 reported on a prospective study of 123 patients with LUTS followed for 5 years. In the observation period, 6.5% developed acute urinary retention and 39% underwent prostate therapy. Of the men who did not have surgery, nearly half became asymptomatic during followup. The surgical and nonsurgical groups did not differ with respect to general health or baseline symptoms. Efficacy of watchful waiting versus transurethral resection of the prostate (TURP) were compared in a Veterans Affairs Cooperative Study.22 Men were randomized to surgery (280 patients) or watchful waiting (276 patients). There was no significant difference between the groups at baseline in terms of symptom score or degree of bother. As expected, the surgery group showed improvement in


FIGURE 56–2. Decision diagram for the diagnosis and treatment of BPH according to the Agency for Health Care Policy and Research clinical practice guideline. DRE = digital rectal examination; PE = physical examination; PSA = prostate-specific antigen; BPH = benign prostatic hyperplasia; TURP = transurethral resection of the prostate; TUIP = transurethral incision of the prostate. From McConnell JD, Barry MJ, Bruskewitz RC, et al. Benign prostatic hyperplasia: diagnosis and treatment. Clinical practice guideline, No. 8. Rockville (MD): Agency for Health Care Policy and Research, Public Health Service, U.S. Dept. of Health and Human Services; 1994 AHCPR publication 94-0582.

uroflow whereas flow rate in the other group remained steady over 3 years. The volume of residual urine decreased in both groups, being most pronounced in the surgery group, as would be expected. Both groups improved with respect to symptoms and degree of bother. There was no difference in changes of well-being measures between the two groups. After 3 years of follow-up, “treatment failures” in the watchful waiting group included urinary retention (3%), postvoid residual urine volume greater than 350 mL (6%), renal azotemia (0.4%), and high symptom score (5%). The authors concluded that roughly 80% of men receiving watchful waiting will not fail from this “treatment” strategy during a 3 year period.

medical therapies such as 5 α-reductase inhibitors and alpha-adrenergic antagonist drugs have made BPH therapy accessible to the primary care physician and at times has altered the timing of its initiation. By the time a patient sees a urologist they may have already had a trial of medical therapy and are facing a decision as to when to consider surgical therapy. These medical therapies are well tolerated and associated with low toxicity and are therefore often offered to the patient earlier in the course of the disease, when symptoms are less severe. The development of minimally invasive therapies has had a similar impact on the timing of intervention as medical therapy. These therapies are usually easy to perform, safe, and are associated with minimal convalescence.

Timing of Intervention

Indications for Therapeutic Intervention

The timing of intervention for BPH therapy has changed over the years for several reasons. First, the morbidity and mortality of prostatectomy has been reduced by better perioperative care and anesthesia as well as improvements in surgical technique and instrumentation. Following its introduction, TURP was often reserved for serious conditions such as obstructive uropathy, urosepsis, and hemorrhage because of a high associated morbidity and mortality. Currently, however, estimated mortality from this surgery is 0.2%; as a result it is more widely offered.23 Although surgical therapies will continue to be widely used, the advent of

The indications for therapeutic intervention for BPH are relative (Figure 56–3) but there are strong indications that are fairly easy to define. These are usually treated with surgery to provide reliable and rapid relief of bladder outlet obstruction. Severe Gross Hematuria Mild degrees of hematuria, especially microscopic hematuria, are common in men with BPH and are not an indication for therapy. Gross hematuria leading to blood clot


formation and urinary retention or anemia requiring replacement with blood products, on the other hand, is a strong indication for prostatectomy. Benign prostatic hyperplasia often coexists with other lesions of the urinary tract that may be responsible for the hematuria. Other etiologies, therefore, need to be excluded through an excretory urogram and cystoscopic evaluation. Bladder Calculi The association between bladder outlet obstruction and bladder calculi is well known. In a review of 100 cases of bladder calculi, the etiology was bladder outlet obstruction secondary to BPH in 80% of patients.24 These men required resection of the prostatic adenoma and extraction of calculi. Two-thirds of cases were managed transurethrally, with the remainder managed by open prostatectomy and stone extraction. The average amount of tissue resected was 35 g. There was no correlation between the degree of obstruction and the size of the prostate; nearly half the men had < 20 g of tissue resected. Infection was present simultaneously in nearly one-third of patients, and nearly half the patients experienced hematuria. There was a surprising discrepancy between the degree of symptom severity and the size of the calculi; patients with a very large stone burden often had few symptoms. The symptom profile of patients with bladder calculi in order of decreasing frequency was as follows: urinary frequency, nocturia, dysuria, hematuria, urgency, retention, poor urinary stream, and intermittency. Obstructive Uropathy As depicted in the decision diagram in Figure 56–2, it is recommended that serum creatinine be measured in all patients with LUTS.10 The justification for this is that a small but significant number of men presenting with LUTS will have renal insufficiency. Upper tract obstruction with azotemia is a dreaded complication of bladder outlet obstruction due to BPH. The interaction between an active, contractile detrusor and fixed bladder outlet obstruction will bring about alterations in bladder compliance and voiding pressures that can interfere directly with urine transport and glomerular function. The obvious indication for treatment is to preserve and prevent further deterioration of renal function. The BPH Guideline panel reviewed all literature between 1983 and 1990 regarding BPH and renal insufficiency. Renal insufficiency ranged from 3 to 30% with a mean of 13%. This likely represents an overestimation of the prevalence of renal insufficiency in a population presenting with LUTS as the men in the database (over 12,000) eventually received treatment. Further, men with renal insufficiency are at decreased risk of postoperative complications.23,25,26 Refractory Urinary Retention For obvious reasons, acute urinary retention (AUR) is particularly troubling to patients, so much so that many

will push for immediate definitive treatment to avoid a second episode. It is estimated that urinary retention is the indication for transurethral prostatectomy in nearly one-third of patients.23 The estimated 10-year risk of AUR in men with BPH varies widely, from as low as 4%2 to as high as 70%.1 A prospective cohort study designed to evaluate the natural history of BPH and LUTS described the occurrence of AUR.27 In 2115 men with LUTS followed for 50 months, 57 men developed AUR. Urinary retention in approximately half these men was associated with a surgical procedure and an anesthetic. Only 8 men who developed retention underwent TURP in the 6 months following the episode of retention. Only 1 of the 57 men experienced subsequent episodes of retention during the follow-up period. Overall, the risk of retention was 6.8 events per 1000 person-years of follow-up. The incidence of AUR varied by age and symptom severity. The cumulative incidence in men in their seventies was approximately 10% at 4 years whereas men in their forties and fifties had an incidence of between 2% and 3%. Rates of retention were higher among men with moderate to severe symptoms. Symptoms associated with an increased risk of a retention episode included repeat urination (having to urinate within 10 minutes of urinating), intermittency, and a weak stream. This last was the symptom most strongly associated with the occurrence of AUR. Peak urinary flow single episode) Symptoms (severe > moderate) Increased postvoiding residual urine (volume not specified)

FIGURE 56–3. Indications for BPH therapy.


retention, approximately 70% of patients either had an unsuccessful voiding trial after catheter removal or experienced recurrent retention within 1 week.28,29 Bladder Decompensation/Increasing Postvoid Residual/Overflow Incontinence Persistent or progressive bladder outflow obstruction can lead to high postvoid residual urine volumes and ultimately to overflow incontinence, representing a clear-cut indication for therapy. The bladder commonly shows evidence of both gross and microscopic changes in response to chronic obstruction. Grossly, the bladder often becomes trabeculated with hypertrophied detrusor muscle; microscopically, there is deposition of dense connective tissue.30 There is a chance that untreated obstruction will lead to irreversible changes, representing a missed opportunity for a cure. Clinical studies have shown, however, that even in the face of severe bladder decompensation with markedly elevated residual volumes, most men will demonstrate improved voiding dynamics after prostatectomy.31 Irritative Voiding Symptoms and Detrusor Instability The coexistence of bladder outlet obstruction and detrusor instability has been well-described. Uninhibited detrusor contractions no doubt contribute to irritative symptoms such as urgency, frequency, and urge incontinence, which are commonly seen in men with BPH. The etiology of this instability is assumed to be bladder outlet obstruction although irritative symptoms and instability are not necessarily specific to BPH.32 The fact that the instability disappears in many patients after the bladder outlet obstruction is relieved has been used as the argument that obstruction leads to instability. It is thought that infravesical obstruction leads to compensatory detrusor hypertrophy, resulting in a lowered threshold of the bladder wall stretch reflex, which produces urgency and cystometrically demonstrable uninhibited detrusor contractions.33 Of all men presenting with LUTS due to bladder outlet obstruction, as many as 60% will have detrusor instability by cystometric analysis prior to any therapy.7,33 It is disappointing that as many as one-third of patients will have persistent irritative symptoms and bladder instability following prostatectomy.32 The observation that detrusor instability may become fixed with ongoing bladder outlet obstruction raises the question whether an opportunity for instability reversal has been missed. It is unclear whether earlier intervention could prevent the development of the pathophysiologic changes leading to detrusor instability in this subgroup of patients.

Conclusion Benign prostatic hyperplasia is essentially universal in aging males. Lower urinary tract symptoms and bladder outlet obstruction secondary to BPH, however, vary in

their prevalence, presentation, and course. Natural history data and watchful waiting trials demonstrate that the former wax and wane over time, making it difficult to make concrete recommendations regarding the timing of therapeutic intervention. What is now recognized as being of utmost importance in deciding when to intervene for symptomatic BPH is the extent to which an individual's lifestyle is affected or altered by his symptoms and to what degree these symptoms and lifestyle alterations produce bother. These subjective parameters can only be ascertained at the time of patient-physician consultation. The timing of therapeutic intervention has been influenced by medical therapies developed for BPH, new minimally invasive therapies, and a reduction in morbidity and mortality from prostatectomy. Indications for therapeutic intervention of BPH can be divided into relative and categoric indications. The strong or categoric indications are fairly straightforward and usually require prostatectomy to provide rapid and reliable relief of infravesical obstruction. They include the following: (1) obstructive uropathy, exemplified by either progressive renal insufficiency or hydronephrosis; (2) development of bladder calculi; (3) refractory urinary retention; (4) severe bleeding from the prostatic urethra or bladder neck overlying prostatic adenoma; and (5) bladder decompensation, resulting in increased postvoid residual urine and overflow incontinence. Relative indications for therapy are less precisely defined. Moderate to severe LUTS quantified by an American Urological Association symptom score > 7 in association with a significant degree of bother reported by the patient would be an indication to at least discuss and offer medical or minimally invasive therapies. In the absence of a categoric indication for intervention, the patient's perspective on the impact of LUTS and bladder outlet obstruction on his life should ultimately dictate the timing of intervention. The type of intervention he receives will be influenced by the information he receives from his physician, including the risks and benefits of each therapy. This will enable him to decide if his symptom severity and quality-of-life alteration from his symptoms are at least as great as the possible side effects a particular therapy would have on his quality of life.

References 1. Birkoff J, Widerorn A, Hamilton M, Zinsser H. Natural history of benign prostatic hypertrophy and acute urinary retention. Urology 1976;7:45–52. 2. Ball A, Feneley R, Abrams P. The natural history of untreated “prostatism.” Br J Urol 1981;53:613–6. 3. Caine M. The present role of alpha-adrenergic blockers in the treatment of benign prostatic hypertrophy. J Urol 1986;136:1–4. 4. Homma Y, Imajo C, Takahashi S, et al. Urinary symptoms and urodynamics in a normal elderly population. Scand J Urol Nephrol 1994;157:27–30.

514 / Advanced Therapy of Prostate Disease 5. Bagi P, Vejborg I, Colstrup H, Kristensen JK. Pressure/ cross-sectional area relations in the proximal urethra of healthy males. I. Elastance and estimated pressure in the uninstrumented urethra. Eur Urol 1995;28:51–7. 6. Bagi P, Vejborg I, Colstrup H, Kristensen JK. Pressure/ cross-sectional area relations in the proximal urethra of healthy males. II. Power generation during voluntary contraction. Eur Urol 1995;28:58–63. 7. Abrams PH, Farrar DJ, Turner-Warwick RT, et al. The results of prostatectomy: a symptomatic and urodynamic analysis of 152 patients. J Urol 1979;121:640–2. 8. Cockett ATK, Aso Y, Denis L, et al. The 3rd International Consultation on BPH. Recommendations of the International Consensus Committee. In: Cockett ATK, Khoury S, Aso Y, et al. Proceedings from the 3rd International Consultation in Benign Prostatic Hyperplasia. Jersey (UK): Scientific Communication International Ltd; 1996. 9. Jacobsen SJ, Girman CJ, Guess HA, et al. New diagnostic and treatment guidelines for benign prostatic hyperplasia: potential impact in the United States. Arch Intern Med 1995;155:477–81. 10. McConnell JD, Barry MJ, Bruskewitz RC, et al. Benign prostatic hyperplasia: diagnosis and treatment. Clinical practice guideline, No. 8. Rockville (MD): Agency for Health Care Policy and Research, Public Health Service, U.S. Dept. of Health and Human Services; 1994 AHCPR publication 94-0582. 11. Jacobsen SJ, Guess HA, Panser L, et al. A population-based study of health care-seeking behavior for treatment of urinary symptoms: the Olmstead County Study of urinary symptoms and health status among men. Arch Fam Med 1993;2:729–35. 12. Golomb J, Linder A, Siegel Y, Korczak D. Variability and circadian changes in home uroflowmetry in patients with benign prostatic hyperplasia compared to normal controls. J Urol 1992;147:1044–7. 13. Abrams PH, Griffiths DJ. The assessment of prostatic obstruction from urodynamic measurements and from residual urine. Br J Urol 1979;51:129. 14. Abrams PH. The diagnosis of bladder outlet obstruction: urodynamics. In: Cockett ATK, Khoury S, Aso Y, et al. Proceedings from the 3rd International Consultation in Benign Prostatic Hyperplasia. Jersey (UK): Scientific Communication International Ltd; 1996. p. 299–354. 15. Jensen KME, Jorgensen JB, Mogensen P. Urodynamics in prostatism. I. Prognostic value of uroflowmetry. Scan J Urol Nephrol 1988;22:109–17. 16. Jensen KME, Jorgensen JB, Mogensen P. Urodynamics in prostatism. II. Prognostic value of pressure-flow study combined with stop-flow test. Scan J Urol Nephrol 1988;114:72–7. 17. Jensen KME, Jorgensen JB, Mogensen P. Long-term prognostic role of urodynamics: an 8-year follow-up of

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prostatic surgery for lower urinary tract symptoms. Br J Urol 1996;78:213–8. Barry MJ, Cockett AT, Holtgrewe HL, et al. Relationship of symptoms of prostatism to commonly used physiological and anatomical measures of the severity of benign prostatic hyperplasia. J Urol 1993;150:351–8. Christensen MM, Bruskewitz RC. Clinical manifestations of benign prostatic hyperplasia and indications for therapeutic interventions. Urol Clin North Am 1990; 17:509–16. Jacobsen SJ, Girman CJ, Guess HA, et al. Natural history of prostatism: longitudinal changes in voiding symptoms in community dwelling men. J Urol 1996;155:595–600. Craigen A, Hickling J, Saunders C, Carpenter R. The natural history of prostatic obstruction: a prospective survey. J R Coll Gen Pract 1969;18:226–32. Wasson J, Reda D, Bruskewitz R, et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. N Engl J Med 1994;332:75–9. Mebust WK, Holtgrewe HL, Cockett ATK, et al. Transurethral prostatectomy: immediate and postoperative complications. A cooperative study of participating institutions evaluating 3885 patients. J Urol 1989;141: 243–7. Douenias R, Rich M, Badlani G, et al. Predisposing factors in bladder calculi: review of 100 cases. Urology 1991; 37(3):240–3. Holtgrewe HL, Valk WL. Factors influencing the mortality and morbidity of transurethral prostatectomy: a study of 2015 cases. J Urol 1962;87:450–9. Melchior J, Valk WL, Foret JD, Mebust WK. Transurethral prostatectomy in the azotemic patient. J Urol 1974;112: 643–6. Jacobsen SJ, Jacobsen DJ, Girman CJ, et al. Natural history of prostatism: risk factors for acute urinary retention. J Urol 1997;158:481–7. Breum L, Klarkskov P, Munck L, et al. Significance of acute urinary retention due to infravesical obstruction. Scand J Urol Nephrol 1982;16:21–4. Taube M, Gajra H. Trial without catheter following acute retention of urine. Br J Urol 1989;63:180–2. Gilpin S, Gosling J, Barnard J. Morphologic and morphometric studies of the human, obstructed, trabeculated urinary bladder. Br J Urol 1985;57:525–9. Jones D, Gilpin S, Holden D, et al. Relationship between bladder morphology and long-term outcome of treatment in patients with high pressure chronic retention of urine. Br J Urol 1991;67:280–5. McGuire EJ. The role of urodynamic investigation in the assessment of benign prostatic hypertrophy. J Urol 1992;148:1133–6. Andersen JT. Detrusor hyperreflexia in benign infravesical obstruction. A cystometric study. J Urol 1976;115:532–4.

CHAPTER 57

PREPROCEDURAL EVALUATION/PREPARATION ALUN W. THOMAS, BSC, MBBS, FRCS; PAUL ABRAMS, MD, FRCS tom levels. Evaluation of the degree to which men are bothered by their symptoms is therefore an important part of the assessment. To complicate matters further, LUTS and their treatments can affect other aspects of the patient’s life, notably continence and sexual function. The impact of these domains on a patient’s life require careful evaluation when considering treatment options. Objective measures of LUTS are now routinely used in clinical research, and their use in clinical practice is increasing.1,2 Symptom indices have been developed for assessing severity of symptoms and evaluating temporal changes with or without treatment. Within the setting of urology, such tools have been developed principally to evaluate men with LUTS suggestive of BPO. Recent efforts, however, have concentrated on evaluating women with urinary incontinence. Symptom indices are scientifically validated and reliable instruments that allow an objective measurement of the severity of a patient’s symptoms. Reliable symptom scores (a numeric value produced by a patient having completed a symptom index) allow observation of disease progression in individual patients. They offer a consistent way of assessing patients, allowing them to be compared, and treatment decisions to be formulated. Efficacies of different treatments can be compared using valid symptom scores, and their inclusion in clinical trials can give important information.

The clinician must be meticulous in assessing and preparing patients for surgery. This will ensure the correct procedure is performed, improve the chances of a successful outcome, and reduce the risk of morbidity and mortality. An adequate preoperative appraisal of baseline symptoms, against which final outcome can be measured, exclusion of differential diagnoses, and assessment of the patient’s suitability for the intended operation are important. Correcting risk factors and implementing preventative measures as prophylaxis against commonly occurring perioperative complications are also vital. In this chapter, the options available for preprocedural management of men with lower urinary tract symptoms (LUTS) suggestive of benign prostatic obstruction (BPO), will systematically be explored. Much of the discussion will be considered standard practice. Certain aspects, however, such as the role of pressure-flow urodynamics, are still debated and their use dictated by local policy and urologist preference. The recent World Health Organization (WHO) International Consultation on benign prostatic hyperplasia (BPH) (Paris, 1997) reviewed all current data on the assessment and treatment of benign prostatic disease. The guidelines emerging from this consultation will be summarized in the appropriate sections.

Preprocedural Management

Measurement of Lower Urinary Tract Symptoms At present, there are at least seven questionnaires available to clinicians wishing to measure severity of LUTS suggestive of BPO. Their major aim has been to quantify urinary symptoms. Symptom scores derived from questionnaires currently available for use in clinical studies of men with symptoms include:

Symptom and Quality-of-Life Assessment The mechanisms by which BPH, a histologic process, causes LUTS are not fully understood. It is known that BPH gives rise to benign prostatic enlargement (BPE), with the possible subsequent complication of BPO. There are, however, poor correlations between the presence and severity of LUTS and anatomic and urodynamic measures of the severity of BPE and BPO, suggesting a more complex process. Still, symptoms are what bring the patient to the clinician, and reliable methods of measuring LUTS are important in understanding the impact of BPO and evaluating the efficacy of treatments for these symptoms. The presence and degree of symptoms constitute only one component in evaluating the impact of LUTS on men’s lives. Patients respond differently to similar symp-

1. Boyarsky3 2. Madsen-Iversen4 3. Maine Medical Assessment Programme (MMAP) instrument5 4. Danish Symptom Score (DAN-PSS-1)6 5. American Urological Association (AUA) Symptom Score7 6. International Prostate Symptom Score (IPSS)8 7. Bolognese (adapted from the Boyarsky schedule)9 515


These questionnaires seek information on many different symptoms (Figure 57–1), the selection of which is largely arbitrary. Such variability can be explained by the fact that there is little evidence suggesting which individual symptoms are related to BPH, BPE, or BPO. There is also no clear consensus on which symptoms should be used to identify or measure patients with these conditions. There are also important differences in the way the questionnaires are completed. The Boyarsky and Madsen-Iversen questionnaires were designed to be completed by the clinician. The MMAP, DAN-PSS-1, AUA, IPSS, and Bolognese were all designed to be completed by the patient. Questionnaires completed by the patient have several advantages over those completed by the clinician. They are more likely to accurately represent the patient’s perception rather than the doctor’s interpretation of particular symptoms. They also make it easier for patients to report the prevalence and severity of embarrassing symptoms. The most commonly used symptoms scores, with the best scientifically validated indices for patients with symptomatic BPO, are the AUA and the IPSS (Figure 57–2). Both are very similar in content. Recent studies, however, suggest that there are problems with these questionnaires. The main criticisms are that they cannot discriminate between symptoms due to BPO and those resulting from other forms of lower urinary tract dysfunction,10 and that they are unable to differentiate

between men and women with LUTS.11 Also, continence is not covered by these questionnaires. In a recent attempt to understand the pathophysiology of LUTS, The International Continence Society Benign Prostatic Hyperplasia Study12 developed an extensive questionnaire, which has been validated. The ICSmale questionnaire contains inquiries about 20 symptoms, including storage symptoms, voiding symptoms, and a range of others associated with the lower urinary tract, including various types of incontinence. It is self-completed and contains questions concerning the degree of “bother” of each symptom. This allows respondents to consider their experience of each symptom and then identify with some precision how much it bothers them. Symptom prevalence alone does not necessarily reflect the degree to which patients are affected by LUTS; it is therefore important to account for their degree of bother.13 The ICSmale questionnaire also contains a number of inquiries regarding quality of life and sexual function. At the 4th International Consultation on Benign Prostatic Hyperplasia (1997), recommendations for clinical practice in assessment of patients with LUTS suggestive of BPO included “the use of a short self-administered questionnaire.” The seven symptom questions from the IPSS remain the recommended instrument. Other validated instruments for objective measurement of symptom occurrence include the DAN-PSS-1 and the ICSmale questionnaires.

FIGURE 57–1. Symptoms inquired about in BPO symptom questionnaires

Preprocedural Evaluation/Preparation / 517

FIGURE 57–2. The International Prostate Symptom Score (IPSS)


Measurement of Sexual Function and Continence Assessment of sexual function is complicated and difficult to accomplish with a limited set of questions. Inquiries about sexual drive, erections, ejaculation, and overall satisfaction with sex life must all be made. Research suggests that men with severe LUTS also have poorer sexual function.14 Sexual function may improve with treatment that improves symptoms,15 but it is well documented that BPH treatments may adversely affect it as well. Neither the AUA/IPSS nor the DAN-PSS-1 questionnaires inquire about sexual function. Several indices exist for evaluation of sexual function. The BPH-Specific Health Related Quality of Life Instruments (BPHQOL20 and BPHQOL9) inquire about sexual function and its impact on health status.16 The validated Brief Sexual Function Inventory (11 items) inquires about all aspects of sexual function.17 The developers of the ICSmale questionnaire have produced an ICSsex questionnaire, the psychometric performance of which has not yet been reported.18 There are also several sexual function questionnaires that have been produced for use in prostate cancer research. The ICSmale and the DAN-PSS-1 questionnaires cover aspects of urinary incontinence and the patient bother it causes whereas the AUA/IPSS do not. There are also several questionnaires used in prostate cancer research that cover incontinence, none of which have been evaluated for use in BPH patients. Measuring Health Status Impact Overall “generic” health status can be easily measured using one of many validated questionnaires. These do not focus on the impact of, or symptoms associated with, one disease process. Principal examples include the EuroQol19 and the Short-Form Health Survey (SF-36)20 instruments. Such questionnaires can be invaluable, especially in the research setting, as they not only allow assessment of the impact of a disease process and the side effects associated with its treatment, but also allow for comparison with other disease processes. Generic instruments alone, however, may be insensitive to the impact of a particular disease process. To allow for this, inquiries about the bother associated with individual symptoms allow assessment of disease-specific health status. The ICSmale and the DAN-PSS-1 questionnaires accomplish this. Alternatively, assessment of LUTS on health can be performed with global inquiries on the effect of the overall urinary condition on different aspects of the patient’s health. Questionnaires incorporating this include the IPSS, the BPH-specific HRQol questionnaire,16 the BPH Impact Index,21 the BPH-Specific Interference with Activities Index,22 and the ICSQol Index.23 Recommendations from the 4th International Consultation on Benign Prostatic Hyperplasia (1997) state that

“at a minimum, clinicians are encouraged to ask the single global question in the IPSS to begin engaging their patients in a discussion about the impact of symptoms on their lives. Clinicians may want to consider using other question sets in their practices to assess in more detail issues of continence, sexual function, and impact of symptoms on health.” Recommendations for clinical research include more extensive use of the instruments summarized in the above section. Voiding Diaries Every clinician with urodynamic experience will testify as to the unreliability of LUTS in making a diagnosis of BPO, which is one of the reasons for urodynamic testing; any approach lending objectivity to the diagnosis becomes invaluable. Frequency-volume charts have an important role to play in objectively recording patient symptoms and are widely used by clinicians interested in lower urinary tract function. They allow an objective assessment of the severity of important symptoms (frequency, nocturia, incontinence) as well as the use of incontinence pads. Fluid intake is assessed by recording voided volumes. The current authors have gained considerable experience in the use of patient-completed frequency-volume charts over the past 20 years and find them essential to investigating the function of male and female lower urinary tracts. They were first produced in a simple form as part of a research project to assist in evaluating response to treatment24 and have developed to what the current authors now use (Figures 57–3A and 57–3B). They can be used in conjunction with urinary diaries, wherein a more detailed account of LUTS is recorded, if additional information is required. Patients are sent the charts with comprehensive instructions and asked to fill them in for a full 7 days prior to their appointment. The chart is split into daytime and nighttime periods to differentiate between daytime frequency and nocturia. Episodes of urinary incontinence and the number of pads used in a 24-hour period are also recorded. Patients are asked to make a crude assessment of their fluid intake (number of cups drunk). No effort is made to make this a precise measurement as this would make the chart too complex. Further, assessment of fluid intake is very difficult given that food contains a significant quantity of fluid. Patients on diets including large amounts of fruit and vegetables are often mystified by their high urine output when they appear to be drinking relatively little. Very few patients are unable to complete the charts; elderly people cope admirably, often providing the most accurate infrmation.25 The chart allows accurate history taking, preventing exaggeration of symptoms by the patient. It also allows the clinician to determine the maximum and average voided volumes of urine and thus estimate the average functional bladder capacity. This


A

B

FIGURE 57–3. Bristol Urological Institute departmental frequencyvolume chart. A, Instructions, chart for completion by patient.


becomes important when deciding to what volume a patient’s bladder should be filled during cystometry. Recommendations from the 4th International Consultation on Benign Prostatic Hyperplasia (1997) include the use of a frequency volume chart as a guideline to the severity of important LUTS. Medical History As with all patients presenting to a clinician, a comprehensive medical history is mandatory and remains the cornerstone of patient assessment. In assessing men with LUTS suggestive of BPO, certain aspects require particular attention. These include: • Precise definition of the presenting symptoms. • Family history of prostate diseases. Recent data provides evidence that BPH is inherited by some.26,27 • Confounding factors that may account for LUTS, including – other known diseases of the genital or urinary tracts; – previous surgery on the genital or urinary tracts; – previous trauma on the genital or urinary tracts; – concurrent medications which may affect lower urinary tract function (Table 57–1). • Sexual function. This may be affected by LUTS and should be assessed as a baseline before intervention. • Fitness for possible surgical intervention. Inquiries about concurrent medical problems are vital when considering intervention. • Smoking status. This is a possible anesthetic risk but has also been recently linked to LUTS.28 Physical Examination The urologist should conduct a full general physical examination, concentrating on those areas that might relate to urinary tract pathophysiology. The examination is usually unrevealing but should still be meticulously performed. The following components are of special relevance to the lower urinary tract. Abdominal Examination Palpation of the lower abdomen should be performed in an attempt to detect the bladder. Patients with significant urinary retention will have a bladder that is palpable or percussable above the symphysis pubis. Patients may be unaware of their bladder distention as is true of most cases of urinary retention seen in the urology department. Pressure applied in the suprapubic area creating a desire to void is a good indicator of an enlarged bladder. Palpation in the loin areas may identify an enlarged kidney. The degree of obesity of the patient should be noted as it may have a bearing on surgery. Also, recent reports have linked abdominal obesity with an increasing incidence and severity of LUTS and an increased likelihood of having to undergo a prostatectomy.29

External Genitalia Examination The external genitalia should be examined for any anatomic anomalies at or around the external meatus. The urethra should be felt for any thickening that might be indicative of inflammation or strictures. Rectal Examination Several aspects of the rectal examination are important to the urologist. On inspection, if the orifice begins to open with lateral traction of the perineal skin on either side of the anus, it is indicative of poor anal function. Loss or alteration of perineal sensation is a potential indicator of bladder/urethral dysfunction as they have common spinal nerve root origins (S2-S4). Assessment of anal tone and the presence of an anal reflex are useful in evaluating those with neurologic deficits. Pelvic floor function can be further assessed by asking the patient to tighten the anal sphincter. This can also be useful in teaching pelvic floor exercises. Fecal impaction should be noted as excess rectal distension could inhibit bladder function. Digital rectal examination (DRE) also serves to exclude rectal pathology. Rectal examination has a vital role in prostate evaluation. Crudely, it allows assessment of the size and shape of the prostate. The literature reports widely varying sensitivity and specificity of DRE in detecting prostate cancer, from 69 to 89% and 84 to 98%, respectively,30–33 in asymptomatic men in screening studies. This is associated with a positive predictive value of roughly 30% in men with a suspicious DRE. This figure is likely higher in men presenting with LUTS as they tend to be older and are therefore at increased risk of developing cancer. Neurologic Examination The urologist should be skilled in the performance of neurologic examination as many neurologic disorders lead to lower urinary tract dysfunction. All patients must undergo at least a simple neurologic evaluation to include a gross assessment of sensation, reflexes, and muscle function in the legs, and perineal assessment as described above. There should be a full examination performed in patients with known neurologic problems. Urinalysis Urinalysis is usually performed in men with LUTS suggestive of BPO, either in the form of dipstick analysis or urine microscopy, or both. Exclusion of a urinary tract infection is important as it may be causing the patient’s symptoms. The recommendations from the 4th International Consultation on Benign Prostatic Hyperplasia (1997) concerning urinalysis state that “If a dipstick test is utilized, it is recommended to choose a test that includes field for leukocyte esterase and nitrite tests for the detection of bacteriuria and urinary tract infection, beside the usual test parameters.” There has been a positive predictive value of 26% for urologic disease, includ-


ing cancer, reported in elderly men with microscopic hematuria.34 Such a simple, inexpensive investigation therefore has obvious advantages for this group of men. Blood Tests Biochemistry Renal function assessment is recommended not only as a preprocedural evaluation but to provide a baseline in men presenting with LUTS suggestive of BPO. The International recommendations (1997) are: 1. Renal function assessment is recommended as a guideline test. 2. Compromised renal function, documented by elevated serum creatinine (or other test), should prompt the use of appropriate optional imaging studies. 3. The diagnostic yield of such studies is significantly higher in this group of men than in men with LUTS and normal renal function. Studies that led to these recommendations included demonstrations that 10 to 15% of men with LUTS have some element of renal insufficiency,35,36 with approximately 20% of these showing upper tract dilatation on renal ultrasound.36 It is also well known that men with compromised renal function demonstrate an increased morbidity and mortality rate following transrectal resection of the prostate.37,38 Prostate-Specific Antigen It is beyond the scope of this chapter to fully discuss the merits of prostate-specific antigen (PSA) screening in evaluating men with LUTS suggestive of BPO. Several important points, however, will be addressed in the following section. Prostate-specific antigen is not specific to prostate cancer. Studies have demonstrated that a quarter of men with BPH have PSA levels above the normal range and that over 40% of patients with prostate cancer have PSA levels within the normal range.39–41 Good tumor markers TABLE 57–1. Examples of Drugs with Activity on the Urinary Tract Reducing outlet resistance Alpha-blockers: alfuzosin, doxazosin, indoramin, prazosin, tamsulosin 5 α-reductase inhibitors: finasteride Increasing outlet resistance Alpha/beta-blockers: labetalol Alpha agonists: amphetamine, clonidine, dextroamphetamine sulphate, ephedrine, epinephrine, methyldopa, phenylephrine, phenylpropanolamine Reducing bladder contractility Anticholinerics/anticholineric activity: amitriptyline, atropine, chlorpheniramine, chlorpromazine, haloperidol, isopropamide, oxybutynin, tolterodine, prochlorperazine, procyclidine, terfenadine Increasing bladder contractility Cholinergics: bethanechol, carbechol, neostigmine, pyridostigmine

must have high sensitivity and specificity as well as high positive and negative predictive values. Current evidence, however, demonstrates that the positive predictive value of PSA for organ-confined prostate cancer is 49% for levels > 4 ng per mL and 75% for levels >10 ng per mL. These figures can be improved if combined with an abnormal DRE or age-specific reference ranges for PSA.42 Despite these limitations, PSA testing does add value in many cases and should be considered another piece in the puzzle of assessing men with LUTS. Attempts have been made to account for the contribution of BPE to the serum PSA level. Prostate-specific antigen density, which is PSA level divided by prostate volume determined by transrectal ultrasound (TRUS), has been shown to have limited value. In the difficult diagnostic zone of PSA values ranging from 4 to 10 ng per mL, the few studies performed have failed to show any significant value of PSA density over PSA measurements in differentiating benign and malignant disease.43,44 Serial PSA measurements may be useful as patients with increases in PSA of > 0.75 ng per mL per annum have an increased likelihood of developing prostate cancer.45 Prostate-specific antigen velocity, the change in PSA levels over a 1-year period, has also failed to stratify patients into benign and malignant disease.46 In attempts to improve the PSA assay process, various isoforms of PSA have been identified. This has led to the concepts of free (nonprotein-bound) PSA and complexed PSA, with a free/total PSA index for the diagnosis of prostatic carcinoma. Early results suggest an improved specificity in diagnosing malignancy.47 The role of PSA testing in assessing men with LUTS suggestive of BPO remains controversial. The following are the International guidelines: 1. PSA should be offered to men with LUTS and a life expectancy of over 10 years, in whom the diagnosis of prostate cancer, once established, would change the treatment plan. 2. The benefits and risks, including the likelihood for a false-positive or false-negative PSA test and the potential need for a TRUS-guided biopsy, should be discussed with the patient. 3. Newer concepts such as PSA density, PSA velocity, and age-specific reference ranges have been suggested to enhance the statistical performance of PSA as a cancer screening test. Until definite studies are available, physicians have to use clinical judgement in determining which patients should, or should not, undergo TRUS and TRUS-guided biopsy. 4. New assays separating free and complexed PSA are being developed and are believed to enhance the statistical performance of PSA as a cancer screening test in the critical range of total PSA values between 2.0 and 10.0 ng per mL.


Endoscopy Several studies have sought a correlation between the appearance of the lower urinary tract on cystourethroscopy and LUTS or urodynamic findings. None has convincingly demonstrated an association between such findings as bladder trabeculation or diverticulae, and symptoms or objective measurements of urinary tract dysfunction.48–50 The diagnosis of bladder outlet obstruction (BOO) cannot be made by cystoscopic means. Preoperative cystourethroscopy can therefore be said to be of limited value and should not be used to diagnose BOO. Detection of bladder stones is an important issue. Detection of large bladder stones, which may dictate an open procedure and thereby avoid lengthy endoscopic extraction, should be mostly possible through preoperative radiography. Stones that are small on kidney, ureter, and bladder radiography (KUB) or too small to be visualized can be easily removed at transurethral resection of the prostate (TURP). Cystourethroscopy is therefore not recommended as part of the routine preoperative workup for prostate surgery. Other bladder pathologies such as tumors are best detected and dealt with by endoscopic means; full cystoscopic evaluation of the bladder is recommended prior to commencing prostate resection. Patients with bladder carcinoma often have microscopic hematuria that will have been detected on preoperative urinalysis. This would indicate a different course of investigation, including cystourethroscopy. Current international guidelines for endoscopic evaluation of men with LUTS suggestive of BPO include the following: 1. Diagnostic endoscopy of the lower urinary tract is an optional test in the standard patient with LUTS. 2. Endoscopy is recommended at the time of surgical treatment to rule out other pathology and to assess the size and shape of the prostate, which might have an impact on the treatment modality chosen. Urodynamic Investigations Flow Studies Uroflowmetry and postvoid residual (PVR) estimation with ultrasound are excellent noninvasive screening tests and should be performed in any individual complaining of symptoms of LUTS. These procedures do, however, have diagnostic limitations, and the clinician often has to proceed to pressure-flow studies to clarify the etiology of the bladder or urethral dysfunction. Flow studies should be performed both before and after procedures designed to modify the outflow tract so that the outcome of the treatment, such as surgery for urethral strictures and BPO, can be objectively assessed.

Flow studies are the screening test of choice in all men complaining of LUTS suggestive of BPO. Studies have demonstrated that the majority of men with significantly reduced flows have a demonstrable BOO on pressure-flow evaluation (Table 57–2).51 Many men with symptoms and higher flow rates, however, are unobstructed. Clinicians should therefore consider confirming the diagnosis of obstruction by performing pressure-flow studies in men with maximum flows >10 mL per second before undertaking invasive therapies. Flow rates are a reproducible way of quantifying the strength of the urinary stream. There does seem to be a learning curve associated with the test, however, with an initial void producing poorer results than subsequent attempts.52 To improve the validity of the test, it has been recommended that treatment decisions be based on a minimum of at least two flow-rate recordings, each with a voided volume >150 mL. Pressure-Flow Studies Suspicion of BOO is the usual reason for performing urodynamics in men. As mentioned above, all men with LUTS should be screened at least with urine flow studies and ultrasound assessment of PVR urine volume. The introduction of pressure-flow studies (pQs) has allowed a more objective evaluation of symptoms and a better understanding of the common disorders. There is a poor correlation between LUTS and urodynamic findings, the only symptoms with reasonable urodynamic associations being urgency and urge incontinence with detrusor instability (DI). Many urologists currently use symptoms as a basis for their decision to treat. Since the rationale behind the treatment of BOO due to BPH is to reduce or remove the obstruction caused by prostatic disease, the correlation between symptoms and objective measures of outlet obstruction is important. Over the past few years, several indices have been developed to measure subjective symptoms in men with LUTS (these indices are described above). There have been a considerable number of earlier and more recent studies, however, that have demonstrated LUTS’ poor diagnostic specificity for BOO.53–57 The original aim of producing a symptom score able to define obstruction and thus avoid invasive urodynamic investigation can now be considered to have failed. Therefore, symptoms alone should not be used as the major indication for invasive therapy. The pathophysiology of LUTS, their association with urodynamic findings, and their predictive value in diagnosis and treatment need to be better understood. The International Continence Society “Benign Prostatic Hyperplasia” Study (ICS-“BPH”),12 involving 1271 men in a prospective multicenter investigation is beginning to answer some of these questions. Other possible investigations in the diagnosis of BOO have not had better success. Prostate size,58–59 prostate transition zone volume,60 and radiologic findings61 corre-

Preprocedural Evaluation/Preparation / 523 TABLE 57–2. Results of Uroflowmetry in Relation to Pressure-Flow Diagnosis of Obstruction Maximum Flow Rates (mL/s) Obstructed (%) Unobstructed ( %)

< 10

10–14

>14

88 12

57 43

33 67

From Nielsen K, Nordling J, Hald T. Critical review of the diagnosis of prostatic obstruction. Neurourol Urodyn 1994;13:201–17.

lated poorly with both LUTS and the presence or grade of BOO proven by pQs. The same can be said for the diagnosis of BOO endoscopically62 although a recent study reports significant correlation between trabeculation and grade of outlet obstruction.50 As suggested above, uroflowmetry and PVR estimation62 give evidence of urinary dysfunction and as such are good screening tests but their shortcomings are becoming more known.51,63 Poor correlation has also been reported between LUTS and Urodynamic findings (UFS).50 More recent efforts have tried to determine the presence of obstruction by using other noninvasive64,65 and invasive66 methods. At present, only pQs reliably and conclusively identify patients with obstruction. The question of whether older men with LUTS should be given pQs has proved very controversial in recent years. The current authors believe that this should depend on the treatment intentions of the clinician. If conservative treatment is planned, then basic urologic evaluation is indicated but no urodynamic tests would be required at that point. If the patient wishes to have invasive treatment for BPO, a strong case can be made for preoperative pressure-flow assessment. It has been demonstrated that up to one-third of men with LUTS do not have BOO67 and are therefore unlikely to benefit from surgery, representing a significant potential saving in cost and morbidity. Also, despite improvements in surgery and anesthesia enhancing the safety of the operation,68 TURP is still associated with a significant complication rate.69 Finally, it has been demonstrated (with considerable ongoing controversy) that better patient selection through preoperative pQs improves outcome and that unobstructed patients undergoing TURP do less well symptomatically than obstructed patients.70–74 Most of these studies, however, have involved relatively small numbers and have not employed uniform definitions for obstruction or symptomatic outcomes. To absolutely demonstrate that preoperative pQs have a clinical prognostic value, larger studies are required with blinded preoperative urodynamics analyzed in a standard way and compared using carefully defined symptomatic outcomes. Such studies may be difficult to carry out since many regard them as unethical. Another important issue in preoperative pQs analysis is the presence of DI. The prognostic significance of preoperative DI is disputed but general agreement seems to exist as to the association between persistent postopera-

tive DI and an unsatisfactory outcome of prostate surgery. Therefore, the role of filling cystometry before surgery and the significance of DI in predicting longterm outcome require further investigation. One recent study suggested that men with BOO with DI associated with decreased bladder compliance are at increased risk of renal insufficiency compared to men with similar pQs findings but normal compliance.75 Various methods have been proposed in the recent past to aid in the diagnosis of BOO. The following nomograms are used to analyze pressure-flow results: AbramsGriffiths,76 LPURR,77 and URA.78 Excellent concordance between these methods of analysis has been demonstrated,62 which is not surprising given that they share the same theoretic background. After studying the existing nomograms, the ICS now recommends the use of the ICS provisional nomogram (Figure 57–4) for the diagnosis of BOO and provides three grades: obstructed, equivocal, and unobstructed.79 The Abrams-Griffiths number is derived by a simple calculation (pdetQmax-2Qmax). Values > 40 place the patient in the obstructed area of the ICS nomogram; values of 20 to 40 are equivocal; values < 20 are unobstructed.76 More complex methods of interpreting pressure-flow results involve computer analysis of data and examine the complete pressure-flow plot. It is not clear whether these provide additional information but results appear comparable in diagnosing obstruction.80 The standardization committee of the ICS is currently conducting a comparative study of the different methods used to analyze pQs,79 using high-quality data from many centers worldwide. It is hoped that this will lead to the development of new and better methods of analysis. The clinician must consider which urodynamic tests are appropriate for investigation for men presenting with LUTS. The older the patient, the more likely it is that BPO

FIGURE 57–4. The ICS provisional nomogram for defining bladder outlet obstruction. Points on the schematic demonstrate voids in each class. From Griffiths D, Hoffner K, van Mastright R, et al. Standardization of terminology of urinary tract function: pressureflow studies of voiding, urethral resistance, and urethral obstruction. Neurourol Urodyn 1997;16:1–18.


is the source of the problem. In younger men (under 50 years old) with poor flow, there is a higher likelihood that either bladder neck obstruction or detrusor underactivity is the cause, making videourodynamic assessment the investigation of choice. Ambulatory urodynamics are rarely indicated. For most male patients, that is, the group of older men with LUTS suggestive of BPO, conventional pressure-flow studies should be used. There is a well-established age-related decrease in maximum flow rate and voided volume in patients with LUTS, which cannot be attributed to an increase in BOO or impaired detrusor function.81 Very little is known regarding the cause of this phenomenon. Reduced Qmax of 10 to 15 mL per second was not found to be associated with obstruction in 60% of men older than 80 years with moderate to severe LUTS. The age-related decrease in such parameters in the elderly population could be associated with the observed increased incidence of DI, which would lead to greater voiding frequency, reduced voided volume, and, since flow is related to voided volume, a lower Qmax. In this age group, therefore, invasive urodynamic investigation is recommended prior to surgical intervention.81 Postprostatectomy problems are common. As many as 16% of men will undergo repeat prostatectomy within 7 years of TURP.82 It is often assumed that these patients have undergone an incomplete operation and will therefore benefit from a further procedure. The role of pressure-flow studies has been emphasized when there are persistent postoperative symptoms. Postoperative voiding symptoms may be caused by either persistent obstruction or poor detrusor function. Other patients have storage symptoms, possibly caused by obstruction or DI. Urethral strictures or bladder neck stenoses can also impair outcome. Nitti and co-workers demonstrated that symptoms post-TURP were unreliable in predicting the etiology of voiding dysfunction.56 Of the 50 men studied, only 16% had residual obstruction after surgery. This demonstrates that those who remain symptomatic after surgery are not commonly obstructed and should be urodynamically investigated with pressure-flow studies to determine the cause of their voiding dysfunction before TURP is repeated. As suggested above, detrusor underactivity is responsible for LUTS in a significant minority of patients, the symptomatology being indistinguishable from those with BOO. The International Continence Society defines this condition as “a detrusor contraction of inadequate magnitude and/or duration to affect complete bladder emptying in the absence of urethral obstruction. Both magnitude and duration should be considered in the evaluation of detrusor contractility.”79 Detrusor underactivity cannot be diagnosed with certainty from the flow trace and is usually indistinguishable from a flow trace exhibiting BOO. An irregular flow with the maximum flow in the lat-

ter half of the trace is suggestive of detrusor underactivity, however. Detrusor underactivity is diagnosed based on pressure-flow investigation, with a low sustained or wavelike contraction and associated poor flow. The current authors believe that men electing invasive treatment should undergo urine-flow studies and PVR volume estimation. If the patient’s maximum flow rate is < 10 mL per second, the chance of them having BOO is almost 90% (see Table 57–2). If the maximum flow rate is between 10 to 15 mL per second, however, the incidence of BOO falls to 57%. Therefore, as just under half of these patients will not have demonstrable BOO, the authors believe that all patients with a maximum flow rate of 10 mL per second or more should have pressure-flow investigation before invasive therapy. Current International Committee recommendations for the use of pQs include: 1. Pressure-flow studies are considered an optional test for the routine patient with LUTS, since the outcomes of the intervention are not sufficiently well known to permit its recommendation as a guideline. 2. The most useful parameters of the pressure-flow study is the detrusor pressure at maximum flow (pdetQmax). 3. Pressure-flow studies should be presented and reported in an easy to understand format (preferably the ICS nomogram). 4. Computer analysis of pQs may aid in their interpretation. At present, however, no single computer program can be recommended as the standard way of analyzing and reporting results. 5. Pressure-flow studies are not necessary prior to treatment in uncomplicated LUTS patients amenable to pharmacologic therapy. 6. Pressure-flow studies are not necessary prior to surgery in patients with uncomplicated LUTS, BPH, and Qmax flow rates < 12 mL per second. 7. Pressure-flow studies are recommended in LUTS patients with BPH who are young (under 50 years old) or have flow rates > 12 mL per second, in patients with neurologic disorders, or in men who failed symptomatically following standard surgical treatments. Urethral Function Studies Reports have contended that there is no association between maximum urethral closure pressure and the size of the prostate, and that prostatic length measured by urethral pressure profilometry consistently overestimates the length of the prostatic urethra measured by cystoscopy.83 In postprostatectomy incontinence, however, there is a close association between sphincter damage and reduced maximum urethral closure pressure. Based on this, urethral function studies can be said to have a role in assessing postprostatectomy problems but not in preoperative assessment of patients with suspected BPO.


Neurophysiologic Studies There have been no studies to evaluate the diagnostic or prognostic value of preoperative sphincter electromyography (EMG) in men with suspected BPO. Its use in this setting is therefore not recommended. Imaging Techniques Preoperative KUB radiography is a useful, simple investigation for men with LUTS. It aids detection of urinary tract calcification that may be contributing to the patient’s symptoms, soft tissue anomalies, and boney abnormalities such as prostatic carcinoma metastases. More extensive urinary tract imaging, such as intravenous pyelography or ultrasonography, cannot be recommended in men with uncomplicated BPO. These latter modalities, however, should be recommended in cases of urinary tract infection, hematuria, chronic urinary retention, a history of (or KUB demonstrating) urolithiasis, previous urinary tract surgery, or abnormal renal function tests. Prostate size and shape are of special interest when surgery is being contemplated. Size and configuration have a bearing on whether minimally invasive techniques or standard surgical modalities should be applied. Also, the presence of carcinoma could certainly alter management decisions. The advent of ultrasound has provided a breakthrough in assessing such features in the prostate. Transrectal ultrasonography is far superior at demonstrating the internal anatomy of the prostate compared to the transabdominal approach and is by far the most important imaging modality in assessing the prostate. Neither computerized tomography (CT), magnetic resonance imaging (MRI), nor positron emission tomography (PET) imaging has been demonstrated to be superior to TRUS in assessing men with LUTS. It is also cheap, relatively easy to perform, and does not involve exposure to ionizing radiation. The role of TRUS in assessing various prostatic features is examined below. Prostate Size Assessment of prostatic size by DRE is known to be notoriously inaccurate. Out of all the imaging modalities, measurement by TRUS is the most accurate method. Prostatic volume, however, should not be used as a criterion for treatment of LUTS. There is no evidence in the literature that prostate size is correlated with the presence of bladder outlet obstruction or that size is related to a successful outcome when TURP or a minimally invasive procedure is performed.84–86 Nevertheless, there are reports that those with larger prostates have a better outcome with high energy thermotherapy87 and that complications associated with transurethral incision of the prostate (TUIP) can be limited by operating on prostates under 30 g.88

Prostate Shape The presence of a median lobe may preclude a patient from treatment by some of the minimally invasive techniques. The use of TRUS in diagnosing the presence of a median lobe has been advocated by some workers89 but is easily performed by cystoscopic means prior to treatment. Prostate Carcinoma Digital rectal examination and PSA screening are the main methods of screening for carcinoma of the prostate in men with LUTS. If there is an abnormality in either, TRUS and biopsy of the prostate facilitate detection of cancer, allowing a more radical management plan where appropriate. The International Committee recommends the following for diagnostic imaging in men with LUTS: 1. No imaging is recommended in baseline assessment of men with LUTS. 2. Upper urinary tract imaging in patients with a history of UTIs, hematuria, urinary retention, urolithiasis, urinary tract surgery, and/or renal insufficiency. 3. TRUS pretreatment biopsy for occult carcinoma in patients with high risk factors. Suggestions for optional imaging include: 1. TRUS and biopsy prior to pharmacotherapy. 2. Pretreatment volume measurement by TRUS, prior to transurethral electrovaporization, TUIP, laser ablation, or high-energy thermotherapy. 3. TRUS prior to pharmacotherapy to serve as a baseline for follow-up.

Other Preprocedural and Anesthetic Considerations There is an increasing trend toward shorter admission times prior to operation in current practice. In the United Kingdom, this is primarily due to financial constraints placed on hospitals, with the implication that a patient’s preoperative “workup” is performed on an outpatient basis. This would be more efficiently performed in joint preoperative clinics with the urologists’ anesthesiology colleagues but unfortunately this is not the practice in most centers. Preoperative Risk Assessment Assessment of risk is obviously important. It allows measures to be taken in the pre-, peri-, and postoperative periods to minimize complications. It also enables clinicians to counsel patients as to what they might expect. This may lead to the decision not to perform the operation if the risks outweigh the perceived benefits. Assessment of concurrent medical problems, particularly those relating to the cardiovascular and respiratory systems, may have an impact on both the patient's fitness for surgery and on the


eventual outcome. The magnitude of the procedure, the underlying pathology, the type of anesthetic, and the technical competence of both the surgeon and anesthesiologist also have a bearing on the outcome. Increasing interest in risk assessment has led to prognostic scoring systems being developed (i.e., the Apache System) but these are mostly for evaluating critically ill patients and are not necessarily useful in the preoperative assessment of patients for elective procedures. Several important aspects of preoperative assessment are outlined in the following sections. Nutritional Assessment There is a considerable body of evidence suggesting that those with poor nutritional status are at high risk for postoperative problems. Those unable to eat for a period following surgery, for example in bowel operations, are obviously at even higher risk. All malnourished elective surgical patients will have a greater morbidity rate following surgery. In assessment of risk, various parameters have been used to assess the state of nutrition, with low plasma protein levels being consistently associated with poor wound healing, development of sepsis, and increased mortality. Cardiovascular Assessment Men undergoing prostate surgery for benign disease tend to be elderly and hence have a higher prevalence of ischemic heart disease (IHD). The presence and identification of patients with IHD are important considerations. Recent myocardial infarction (MI) and heart failure are proven risk factors for perioperative cardiac morbidity but evidence is not as clear for other factors such as arrhythmias. Well-controlled hypertension does not appear to be an adverse risk factor but previously undiagnosed hypertensives should probably be controlled prior to elective surgery. One-third of patients undergoing surgery within 3 months of an MI will have a further attack, reducing to 10% between 3 and 6 months, and 5% after this. Operating under a spinal as opposed to a general anesthesia does not alter these figures. Elective surgery should clearly be avoided until the risk is minimal. The presence of IHD can be identified by a clear medical history, and discussion about risk factors can provide clues about possible “silent” disease. The principal risk factors for IHD include smoking, diabetes, hypertension, family history, high cholesterol, poor fitness, and the presence of other arterial problems such as peripheral vascular disease. Further evidence can be found on physical examination and on ECG changes. Exercise ECG can be useful in those with significant IHD but more advanced techniques such as echocardiography and radionucleotide imaging are not for routine use and are unproven in assessing anesthetic risk. Respiratory Assessment It is important to identify individuals with compromised respiratory reserve preoperatively as this will exaggerate

postoperative complications. The most common concomitant problems are chronic obstructive airways disease (COAD) and asthma. Efforts should be made to correct any reversible component of the pulmonary disease prior to surgery. Patients should be advised to stop smoking preferably 2 to 3 months before elective surgery, and bronchodilators and physiotherapy should be used where appropriate. When it is anticipated there may be postoperative respiratory problems, the patient should be educated preoperatively on the importance and technique of chest physiotherapy. Anemia Bleeding is expected during TURP and the procedure is associated with a significant transfusion rate. Any preoperative anemia should be corrected, and patients should be counseled regarding the possible need for a transfusion and the implications. Obesity Obesity is a significant risk factor for peri- and postoperative problems. It increases the risk of developing IHD, with all its ramifications. Anesthetic problems include difficulty with intubation and ventilation, alveolar hypoventilation with CO2 retention, and esophageal reflux made worse by increased volumes of gastric acid secretions. Postoperative problems include an increased incidence of deep venous thrombosis (DVT) with subsequent embolism, and wound infection. Obviously, weight loss in the obese prior to surgery is desired. Renal Disease Renal disease secondary to prostate disease has been discussed above. It is essential that uremia and electrolyte disturbances are corrected prior to surgery. For those with irreversibly reduced kidney function, the main priority is to avoid further deterioration. This is accomplished through prevention of hypovolemia and strict fluid balancing. Diabetes As well as being at risk for IHD, cerebrovascular disease, and renal disease, diabetics require control of blood sugars during the peri- and postoperative phase. Insulindependent diabetics require a stable sliding scale prior to surgery and are best scheduled for the beginning of the surgical day. Drugs The patient’s full drug history is mandatory. Certain drugs affect bladder function (see Table 57–1) and others have important implications for the procedure itself as well as the anesthetic. For example, lithium, tricyclic antidepressants, and phenothiazines interfere with the anesthetic, and steroids and anticoagulants have implications with regard to the procedure itself.

Preprocedural Evaluation/Preparation / 527 TABLE 57–3. Risk Factors for Deep Venous Thrombosis Patient Factors

Disease or Procedural Factors

Age Obesity

Trauma or surgery Malignancy, especially pelvic, abdominal, metastatic Heart failure Recent myocardial infarction Paralysis of lower limb(s) Infection Inflammatory bowel disease Nephrotic syndrome Polycythemia Paraproteinema Paroxysmal nocturnal hemoglobinuria Behçet’s disease Homocystinemia

Varicose veins Immobility (bed rest > 4 days) Previous DVT/pulmonary embolism Thrombophilia Deficiency of antithrombin III, protein C, or protein S Antiphospholipid antibody or lupus anticoagulant

Routine Preoperative Testing Chest Radiography Abnormalities on chest roentgenogram occur in 35% of preoperative elective patients over the age of 60. Despite the fact that most of these patients proceed to surgery, preoperative radiography can probably be justified in this group. Obviously, in those with existing respiratory problems, a preoperative film can help define the problem and act as a baseline when postoperative complications arise. Regional policies will always differ. Electrocardiograms Abnormalities on an electrocardiogram (ECG) are not uncommon. The incidence increases from 10% at 40 years of age to 25% at 60 years of age. Local policies differ but those under the age of 40 with a normal physical examination and no risk factors for IHD would not warrant an ECG. Hematology As mentioned above, preoperative anemia needs to be corrected. Since blood loss during TURP is expected, a preoperative full blood count acts as a baseline. Preventive Measures Deep Venous Thrombosis The THRIFT consensus group90 has laid down guidelines for thromboembolic prophylaxis, the pertinent features of which are summarized here: 1. All hospital inpatients should be assessed for clinical risk factors and overall risk of thromboembolism. 2. Such patients should receive prophylaxis, according to degree of risk, at least until discharge from hospital. Low-risk patients require early mobilization only whereas moderate/high-risk patients require specific prophylactic measures.

Low risk for developing thromboembolic problems is defined as minor surgery (< 30 minutes) with no other risk factors other than age, or major surgery (> 30 minutes) with age under 40 years and no other risk factors. There must also be no significant concurrent medical problems.91 All other characteristics place the patient in the moderate or high-risk group. From this, it is clear that the majority of TURP patients are of moderate/high risk and warrant specific thromboembolic prophylactic measures. Risk factors for developing thrombosis are summarized in Table 57–3. Prophylaxis for DVT includes mechanical and pharmacologic methods. These are extensively covered in other texts and will not be discussed further here. Sepsis Transurethral surgery in a patient with sterile urine does not require prophylactic antibiotics. All urinary tract infections should be treated prior to surgery, and all patients having a TURP for acute retention who have had a catheter in preoperatively will need to have their surgery covered with antibiotics. Consent The procedure and its risks should be explained prior to the operation. Informed written consent should then be obtained. This should be done by the performing surgeon rather than the most junior member of the team, who may not appreciate the finer intricacies of the procedure. Problems specific to transurethral prostate surgery that require emphasis include: • • • • •

Risk of impotence Risk of retrograde ejaculation Risk of incontinence Failure rate/reoperation rate Risk of hemorrhage and possible need for transfusion

Conclusion In this chapter, the authors have endeavored to cover all aspects of management prior to intervention in patients with LUTS suggestive of BPO. Clinical practice varies from center to center and country to country. The recommendations from the recent International Consultation on BPH, which provide a consensus opinion on the research to date, have therefore been highlighted.

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55. Sirls LT, Kirkemo AK, Jay J. Lack of correlation of the American Urological Association Symptom 7 Index with urodynamic bladder outlet obstruction. Neurourol Urodyn 1996;15:447–57. 56. Nitti VW, Kim Y, Combs AJ. Voiding dysfunction following transurethral resection of the prostate: symptoms and urodynamic findings. J Urol 1997;157:600–3. 57. Ezz el Din K, Kiemeney LALM, de Wildt MJAM. The correlation between bladder outlet obstruction and lower urinary tract symptoms are measured by the International Prostate Symptom Score. J Urol 1996;156:1020–5. 58. Simpson RJ, Fisher W, Lee AJ, et al. Benign prostatic hyperplasia in an unselected community-based population: a survey of urinary symptoms, bothersomeness, and prostatic enlargement. Br J Urol 1996;77(2):186–91. 59. Ezz el Din K, Kiemeney LALM, de wildt MJAM. Correlation between uroflowmetry, prostate volume, postvoid residue, and lower urinary tract symptoms as measured by the International Prostate Symptoms Score. Urology 1996;48:393–7. 60. Lepor H, Nieder A, Feser J, et al. Total prostate and transition zone volumes, and transition zone index are poorly correlated with objective measures of clinical benign prostatic hyperplasia. J Urol 1997;158:85–8. 61. Abrams P, Feneley RCL, Roylance JR. Excretion urography in the investigation of prostatism. Br J Urol 1976; 48:681–4. 62. Abrams P. Objective evaluation of bladder outlet obstruction. Br J Urol 1995;76 Suppl:11–5. 63. Van de Beek C, Stoevelaar HJ, McDonnell J, et al. Interpretation of uroflowmetry curves by urologists. J Urol 1997;157:164–8. 64. Madersbacher S, Klingler HC, Djavan B, et al. Is obstruction predictable by clinical evaluation in patients with lower urinary tract symptoms? Br J Urol 1997;80:72–7. 65. Schacterle RS, Sullivan MP, Yalla SV. Combinations of maximum urinary flow rate and American Urological Association Index that are more specific for identifying obstructive and nonobstructive prostatism. Neurourol Urodyn 1996;15:459–72. 66. Comiter CV, Sullivan MP, Schacterle RS, Yalla SV. Prediction of prostatic obstruction with a combination of isometric detrusor contraction pressure and maximum urinary flow rate. Urology 1996;48:723–30. 67. Jensen KME. Clinical evaluation of routine urodynamic investigations in prostatism. Neurourol Urodyn 1989;8:545–78. 68. Boyle P, Maisonneuve P, Steg A. Decrease in mortality from benign prostatic hyperplasia: a major unheralded triumph. J Urol 1996;156:176–80. 69. Schatzl G, Madervascher S, Lang T, Marberger M. The early postoperative morbidity of transurethral resection of the prostate and of 4 minimally invasive treatment alternatives. J Urol 1997;158:105–10. 70. Abrams P, Farrar DJ, Turner-Warwick RT, et al. The results of prostatectomy: a symptomatic and urodynamic analysis of 152 patients. J Urol 1979;121:640–2. 71. Javle P, Jenkins SA, West C, Parsons KF. Quantification of voiding dysfunction in patients awaiting transurethral prostatectomy. J Urol 1996;156:1014–9.

530 / Advanced Therapy of Prostate Disease 72. Robertson AS, Griffiths C, Neal DE. Conventional urodynamics and ambulatory monitoring in the definition and management of bladder outflow obstruction. J Urol 1996;155:506–11. 73. Jensen KM-E, Jorgensen JB, Mogensen P. Long-term predictive role of urodynamics: an 8-year follow-up of prostatic surgery for lower urinary tract symptoms. Br J Urol 1996;78:213–8. 74. van Vernooig GE, Boon TA, de Gier TP. International Prostate Symptom Score and quality of life assessment versus urodynamic parameters in men with benign prostatic hyperplasia symptoms. J Urol 1995;153:1516–9. 75. Comiter CV, Sullivan MP, Schacterle RS, et al. Urodynamic risk factors for renal dysfunction in men with obstructive and nonobstructive voiding dysfunction. J Urol 1997;158:181–5. 76. Lim CS, Abrams P. The Abrams-Griffiths Nomogram. World J Urol 1995;13:34–9. 77. Schafer W. Analysis of bladder-outlet function with the linearized passive urethral resistance relaxation, linPURR, and a disease-specific approach for grading obstruction: from complex to simple. World J Urol 1995;13:47–58. 78. Van Mastright R, Kranse M. Analysis of pressure-flow data in terms of computer-derived urethral resistance parameters. World J Urol 1995;13:40–6. 79. Griffiths D, Hofner K, van Mastrigt R, et al. Standardization of terminology of urinary tract function: pressure-flow studies of voiding, urethral resistance, and urethral obstruction. Neurourol Urodyn 1997;16:1–18. 80. Trucchi A, Franco G, Manieri C, et al. Manual versus computer methods for diagnosing obstruction from pressure-flow tracings in patients with benign prostatic hyperplasia. J Urol 1997;157:871–5. 81. Madersbacher S, Klingler HC, Schatzl G, et al. Age related urodynamic changes in patients with benign prostatic hyperplasia. J Urol 1996;156:1662–7.

82. Neilsen K, Christensen MM, Po M, et al. Symptom analysis and uroflowmetry 7 years after transurethral resection of the prostate. J Urol 1989;142:1251–3. 83. Chapple CR, Coppinger SW, Turner-Warwick RT. Is urethral pressure profilometry useful in the pre-operative assessment of BPH. Br J Urol 1992;70(3):280–4. 84. Narayan P, Tewari A, Fournier G, Toke A. Impact of prostate size on the outcome of transurethral laser evaporation of the prostate for benign prostatic hyperplasia. Urology 1995;45:776–82. 85. Netto NR, de Lima ML, Claro J de A, de Andrade EF. The importance of prostate weight in transurethral microwave therapy. Arch Esp Urol 1995;48:413–7. 86. De la Rosette JJMCH, de Wildt MJAM, Hofner K, et al. High energy thermotherapy in the treatment of benign prostatic hyperplasia. Results of the European BPH study group. J Urol 1996;156:97–101. 87. De la Rosette JJMCH, D’Ancona FCH, Debruyne FMJ. Current status of thermotherapy of the prostate. J Urol 1997;157:430–8. 88. Christensen MM, Aagard J, Madsen PO. Transurethral resection transurethral incision of the prostate: a prospective randomized study. Urol Clin North Am 1990;17:621. 89. Guazzoni G, Montorsi F, Coulange C, et al. A modified prostatic urolume wallstent for healthy patients with symptomatic benign prostatic hyperplasia: a European multicenter study. Urology 1994;44:364–70. 90. Thromboembolic Risk Factors (THRIFT) Consensus Group. Risk of and prophylaxis for venous thromboembolism in hospital patients. BMJ 1992;305:567–74. 91. Salzman EW, Hirsh J. Prevention of venous thromboembolism. In: Colman RW, Hirsh J, Marder V, Salzman EW, editors. Hemostasis and thrombosis: basic principles and clinical practice. New York: Lippincott; 1982. p. 986.

CHAPTER 58

OPTIONS FOR TREATMENT OF BENIGN PROSTATIC HYPERPLASIA: ALPHA-BLOCKERS PERINCHERY NARAYAN, MD; MANOJ PATEL, MD; ASHUTOSH TEWARI, MD Pharmacophysiologic Rationale for the use of Alpha-Blocker Drugs

Benign prostatic hyperplasia (BPH) is one of the most common benign tumors affecting men over 40 years of age. The mean age at which patients develop symptoms is between 60 to 65 years. Ninety percent of men in their eighties exhibit histologic evidence of disease,1 81% will experience symptoms due to BPH,2 and 10% will develop acute urinary retention. The aging of the population also increases the number of men at risk for BPH. In the past year, more than 1.7 million men have made an office visit to the urologist3,4 and these numbers continue to increase. In the last 10 years, there has been a major shift in both the physician’s and patient’s perception of BPH. From being considered a disease of aging, requiring intervention only to prevent potential complications, an emphasis shift has occurred. Today, BPH is considered more a disease that affects quality of life; therefore, both evaluations and treatments are currently designed to relieve symptoms and reduce side effects. In this context, the use of medical therapies has become the primary first-line management option for patients initially presenting with symptoms. It has also been well established that patients with mild symptoms (International Prostate Symptom Score [IPSS < 7]) do not need therapy since a majority of the normal population older than 50 years will have mild symptoms. Secondly, there is currently adequate clinical data that medical management options can alleviate symptoms for up to 5 years in longterm trials, with excellent patient satisfaction and low incidence of long-term complications. Finally, there has been a perceptible shift from urologists to primary care physicians as the front-line managers in treating BPH. Alpha-blockers as a class are the most commonly used first line of agents in managing symptomatic BPH. Approximately 80% of the patients receiving medical management are prescribed alpha-blockers by their primary care physician.5 This chapter will focus on the evaluation of alpha-blockers in treating symptoms of BPH and the current status of their utility in the United States.

The prostate gland is often referred to as being composed of five distinct lobes during fetal development—anterior, posterior, median, and two lateral lobes. In the adult prostate, this distinction is usually abolished and the prostate is considered to be composed of three concentric layers: the outer layer (the external prostate gland proper) and the two inner layers (the periurethral glands). Prostate cancer tends to arise in the outer layers of the glands while BPH starts in the inner periurethral glands. Benign prostatic hyperplasia is believed to arise from fibrostromal proliferation in the periurethral glands. As the gland progresses in size, patients will present with lateral and/or median prostatic lobe(s) enlargement. This latter will result in (a) compression, narrowing, and elongation of the prostatic urethra; (b) growth of the median lobe into the bladder, causing a ball-valve effect and possibly an increase in irritative symptoms; (c) a bladder response to obstruction that may result initially in hypertrophy and subsequently in decompensation, stasis of urine, and upper tract damage; and (d) a host of related complications, including hematuria, urinary tract infections, and calculi formation. Pathophysiology of this common disease is far from clear. There is no direct cause and effect relationship between presence of glandular enlargement, physiologic presence of obstruction on urodynamic studies, and symptoms of “prostatism” experienced by the patient. Prostatism encompasses both obstructive and irritative symptoms. The obstructive symptoms cause a weak force of urine stream and are believed to be due to increased outflow resistance in the urethra (especially near the prostatic segment) while the irritative symptoms, such as frequency, hesitancy, urgency, and nocturia, are secondary to bladder response to obstruction as well as median lobe hyperplasia. The exact cause of symptoms in BPH is far from clear, and no one hypothesis can explain all of the symptoms. 531


While obstructive features are the key to the cause of BPH symptoms, irritative symptoms can occur without them. Also, diseases other than BPH can result in symptoms identical to that produced by BPH. The realization of this relationship has resulted in recent re-evaluations of the term “prostatism.” Many urologists now prefer to use the designation “lower urinary tract symptoms” (LUTS) rather than prostatism. This designation comprises not only patients with BPH but also those with chronic nonbacterial prostatitis, bladder dysfunction, sphincter dysfunction, symptoms due to age-related changes, and symptoms related to multiple medications, among others. Recent data showing that women have IPSS scores similar to men also suggest that the bladder and urethra may be the cause of symptoms, rather than BPH. The scientific rationale for using alpha-blocker therapy for BPH is based on the following observations: (1) prostatic smooth muscle contraction is the result of alpha-receptor mediated sympathetic stimulation; (2) contraction of smooth muscles in the prostatic capsule, adenoma, and bladder neck results in decreased bladder outflow; (3) several drugs are now available which can block alpha-receptor activity and cause relaxation of the prostatic smooth muscle; and (4) there is also evidence that alpha-receptors present in the anterior horn of the spinal cord may modulate both autonomic and somatic nerve response in the lower urinary tract. Evidence for predominant alpha-receptor activity in the prostate comes from the studies of Caine and Raz published in 1975. They used isometric measurements on tissue strips to demonstrate that human prostatic smooth muscles contract under the influence of sympathetic innervation and that their effects were mediated through the alphaadrenergic receptors.6 It has further been reported by several authors that BPH patients with a predominant stromal component have a greater degree of dynamic obstruction.7 Dynamic closure due to contraction of smooth muscles of adenoma, capsule, stroma, and bladder neck has been confirmed by the urodynamic studies of intraurethral pressure. In these in vivo studies, it has been revealed that approximately 40% of bladder outlet obstruction may be the result of smooth muscle contraction.8,9 Alpha-blocking drugs have been shown to both bind and relax the prostatic smooth muscle. Drugs such as phenoxybenzamine, prazosin, terazosin, doxazosin, alfuzosin, and tamsulosin, which are known alpha-receptor antagonists, bind extensively to prostatic alpha-receptors and relieve smooth muscle contractions (Figure 58–1).

Alpha-Adrenergic Receptors: Structure and Classification Adrenergic receptors are classified as alpha and beta receptors on the basis of their distribution, structure, mecha-

nism of action, and effect on the target organ. Beta receptors are found in the heart, juxtaglomerular renal cells, pancreatic beta cells, smooth muscle cells of vascular, respiratory, and uterine organs, hepatic cells, and somatic motor nerve terminals for voluntary skeletal muscle contraction. Alpha receptors are found in most vascular smooth muscle cells, especially the eye and the prostate gland. Essentially, all of these receptors are transmembrane proteins made up of seven helices that are structurally arranged to form an extracellular domain (the site of the norepinephrine-receptor complex) and an intracellular domain (the site of the G protein) (Figure 58–2). The alpha receptors are subdivided into two subgroups—alpha-1 and alpha-2. Alpha-1 receptors are postsynaptic in location and mediate contractions of smooth muscle in the prostate. Alpha-2 receptors are presynaptic in location and serve to regulate the amount of neurotransmitter transmission across the synaptic cleft. Stimulation of the alpha-2 receptors causes feedback inhibition of the ongoing release of norepinephrine from the stimulated adrenergic neuron; this inhibitory action decreases further output from the adrenergic neuron and serves as a local modulating mechanism for reducing sympathetic neurotransmission across the synaptic cleft. Blockage of these alpha-2 receptors results in a variety of systemic and cardiovascular effects due to their wide distribution. Similar to alpha-1 receptors, alpha-2 receptors are transmembrane proteins linked to a G-inhibitory protein on the intracellular surface. Activation of the alpha-2 receptor causes activation of the Gs protein which, in turn, leads to deactivation of the adenyl cyclase system and decreased production of cyclic adenosine monophosphate (AMP) production. The alpha-1 receptors are mediated primarily by the coupling protein Gq; this leads to activation of the phosphoinositide cascade and liberates inositol-1,4,5-triphosphate (IP-3) and diacylglycerol (DAG). The former opens the gated calcium channels in the cell membrane to increase the intracellular concentration of calcium while the latter activates the protein kinase enzyme to bring about an intracellular response, leading to smooth muscle relaxation. Various studies have demonstrated that alpha-1 receptors predominate in the normal prostate. Other than in smooth muscles, they are also present on the prostatic blood vessels. The prostatic-specific subtype is alpha-1a, an adrenergic receptor that constitutes 70% of all prostatic alpha-1 receptors. Since alpha-1 receptors are also present at various nonprostatic smooth muscles, they are not entirely uroselective. Blockade of these receptors causes few additional unwanted systemic side effects. Recently, however, a prostate-specific subtype of alpha-1 receptor has been identified by radioligand binding studies. Alpha receptors can either be native (denoted by capital suffix) or cloned (denoted by small case suffix). The true native alpha-receptors are called alpha-1A, alpha-1B, and alpha1D in a recent classification proposed by the international

Options for Treatment of Benign Prostatic Hyperplasia: Alpha-Blockers / 533

FIGURE 58–1. Mechanism of action of alpha-receptor antagonists at the synaptic junction. Reprinted with permission from Narayan P, editor. Benign prostate hyperplasia. Churchill-Livingston. London, England. [In press].

union of pharmacology (IUPHAR). Their cloned counterparts are called alpha-1a, alpha-1b, and alpha-1d. In an older classification, the cloned alpha-1A was called alpha1c, alpha-1b was called alpha-1b, and alpha-1D was called alpha-1a/d. Recently, a new alpha-1 receptor subtype was identified that has affinity for prazosin (alpha-1L); the importance of this receptor is still unexplained. Recognition of cloned prostate-specific smooth muscle adrenergic receptors (alpha-1a, previously called alpha-1c) have major therapeutic implications since blockade spares all other kinds of adrenergic receptors.

Alpha-1 Adrenoceptor Antagonists Short-Acting Antagonists Phenoxybenzamine Phenoxybenzamine was the initial alpha-adrenergic blocking drug used for management of BPH; however, it was a nonselective alpha-1 and alpha-2 receptor irreversible antagonist that produced many side effects. It did improve prostatic symptoms but had significant cardiovascular side effects in 30% of patients. It has also been shown to have mutagenic properties in animal studies.10,11 This drug is therefore no longer used in managing BPH. Prazosin Prazosin was the next selective alpha-1-blocker used to manage BPH, at which time it was already being used for

treating hypertension. Prazosin had fewer side effects and responded better than phenoxybenzamine. This drug, however, did have its setbacks; it was dispensed twice daily, which caused significant first-dose effect and vascular side effects during the morning dosage. In long-term studies, > 32% of patients discontinued use of prazosin due to various adverse effects. Prazosin must be given three times per day to be effective for BPH. In 1983, Hedlund and co-workers published results of a double-blind, placebo-controlled, crossover study with prazosin for the treatment of BPH in 20 patients.12 The maximum and mean urinary flow rates were improved significantly with prazosin. Postvoid residual urine volumes decreased significantly during treatment as well. Although obstructive symptoms improved during treatment, there was no effect on irritative symptoms. The investigators concluded that prazosin was an effective treatment for patients with symptomatic BPH.12 In 1987, Kirby and associates described 80 patients who were evaluated in a double-blind, placebo-controlled study using prazosin. The peak urinary flow rates increased significantly from a mean of 8 mL per second to 13 mL per second. There was no observed increase for the placebo cohort. The investigators also showed a decrease in the patients’ urinary frequency in the treatment group compared to the placebo cohort.13 Although the study was flawed by a high drop-out rate of 25 patients, the investigators concluded that prazosin could be useful for treating BPH. Other double-blind, placebo-controlled studies evaluating prazosin also showed statistically significant increases in urinary flow rate as well as improved “prostatism” symptoms.14–16 Alfuzosin Alfuzosin has been studied extensively in Europe. In 1985, Ramsay and co-workers evaluated 31 patients in a double-blind, placebo-controlled clinical trial; of the 31 patients, 20 were randomized to receive treatment.17 Although there was a significant improvement in frequency, there was no significant increase in peak urinary flow rates. Jardin and associates reported a large, randomized, double-blind controlled study of 518 men treated with alfuzosin for BPH.18–20 There was a significant decrease in obstructive and irritative symptoms, a significant increase in mean urinary flow rate, and a decrease in postvoid residual urine volume. This study had several weaknesses, however, including the fact that 55% of the men entered the study without a urinary flow rate evaluation and only 39% of the patients were evaluated with measurement of postvoid urine volume. There was also variation among the treatment centers in terms of dose titration and outcome measures. Current literature advocates continued use of alfuzosin for its effectiveness to be maintained in treating BPH symptoms. In a recent study, however, Kaplan et al.21 examined


FIGURE 58–2. Second messenger system associated with alpha and beta receptors. Reprinted with permission from Narayan P, editor. Benign prostate hyperplasia. Churchill-Livingston. London, England. [In press].

the potential of intermittent dosing of alfuzosin. This study was a prospective open-label, parallel, randomized trial involving two phases. The first phase of the study involved 111 men taking 2.5 mg three times daily for 3 months. After this 3-month period, patients who responded to alfuzosin (defined as a 40% decrease in the IPSS and a 30% increase in measurement of uroflow [Qmax]) were enrolled into the 6-month dosing/phase II of the study; a total of 79 men were enrolled. These phase II participants were then randomized into one of three groups; group 1 continued alfuzosin 2.5 mg three times daily every day, group 2 received alfuzosin 2.5 mg three times daily every other day, and group 3 discontinued alfuzosin. Measurement of uroflow (Qmax) and completion of the IPSS were used to evaluate efficacy. Results during the phase II trial were interesting; the IPSS was 7.1 and 6.5 for group 1; 6.5 and 6.7 for the group taking alfuzosin every other day (group 2); and 11.4 and 12.3 for group 3, at 3 months and 6 months, respectively. The Qmax was 12.7 mL per second and 11.7 mL per second for group 1; 12.2 mL per second and 11.9 mL per second for group 2; and 9.7 mL per second and 9.3 mL per second for group 3 at 3 months and 6 months, respectively. There were no differences among group 1, patients taking alfuzosin every day, and group 2, patients taking alfuzosin every other day (p = .43). However, groups 1 and 2 performed better than group 3 (p < .02 and p < .015, respectively). The data clearly indicate that patients who took alfuzosin daily (group 1) did not have better results than men who took alfuzosin every other day.21 The authors further stated that complete cessation of alfuzosin resulted in recurrence of symptoms and impaired urinary flow. These data provide evidence that intermittent alfuzosin therapy may be a reasonable therapeutic regimen in responding patients. 21

Long-Acting Antagonists Terazosin Terazosin, an antihypertensive drug, is a selective alpha-1 adrenergic antagonist that has been studied extensively and is currently approved by the FDA for treatment of BPH. This long-acting agent allows a once-a-day dosing schedule. Lepor and associates published the first randomized, placebo-controlled, phase II trial of terazosin, the largest experience to date with terazosin in the treatment of BPH. 22,23 This multicenter study included 285 men with symptomatic BPH who were randomly assigned in equal proportions to receive placebo or 2, 5, or 10 mg of terazosin administered once daily. Of the 285 men, 237 patients completed the 4-week, single-blind, placebo leadin period and the 12-week, double-blind treatment period. All terazosin treatment groups exhibited a significantly greater decrease in total Boyarsky symptom scores compared with the placebo cohort (p < .001). The increase in peak urinary flow rate for the 10 mg group was 3.0 mL per second, a significant change compared to baseline (p < .001). This change was also significantly larger than the placebo group (p = .009). The improvements in symptom scores and urinary flow rates did not reach a plateau within the dose ranges evaluated, suggesting that further efficacy may be achieved with doses of terazosin exceeding 10 mg. The investigators concluded that these findings demonstrated that terazosin is efficacious in treating symptomatic BPH. Further, Lepor and colleagues reported that the adverse effects of using terazosin were minimal.22–24 In the 2, 5, and 10 mg study groups, the incidence of postural hypotension was 2.7%, 8.3%, and 5.7%, respectively. The 8.3% for the 5 mg group was the only measurement statistically different from the placebo


cohort. Other reported adverse events include headache (5.8%), asthenia (2.9%), dizziness (2.9%), flu syndrome (1.4%), urinary tract infection (UTI) (1.4%), and syncope (1.4%). No other side effects were reported. Other phase II studies have shown similar results to those obtained by Lepor. One such study was conducted by Fabricius and Hannaford. They collected data from a randomized, placebo-controlled, double-blind study of oncea-day dosing of terazosin (10 mg per day) in 57 patients with symptomatic BPH.25 The study began with a 4-week placebo lead-in period followed by a single-blind 24-week treatment period. At the conclusion of the treatment period, 30 patients who responded to terazosin were randomly assigned to receive either terazosin or placebo (the double-blind study period). During the single-blind treatment period, peak urinary flow rate increased 54%, mean flow rate increased 55%, and residual volume decreased 56%. The mean obstructive symptom score, irritative symptom score, and physician global assessment score improved by 68%, 34%, and 27%, respectively. All of these changes were significant when compared with the baseline placebo group. Further, during the 12-week double-blind treatment period, the improvement in all efficacy variables was sustained in the terazosin group. Fabricius and Hannaford reported that the most frequent adverse events experienced by the patients in this study were headache, asthenia, and hypotension. When Lepor combined the data from this study with that of other terazosin studies, he found a 50% increase in peak urinary flow rates (p < .001), a 46% increase in the mean urinary flow rate (p < .001), a 67% decrease in obstructive symptoms (p < .001), and a 35% decrease in irritative-symptom scores (p < .001).23 Even though there are many successful clinical trial studies regarding terazosin in the United States, the same cannot be said about European clinical trials. Two studies in particular in Europe have not shown results from the terazosin group that are superior statistically or clinically to those in the placebo-treated groups. One study, conducted by Di Silverio from Italy, was a clinical trial using terazosin in 137 patients who were randomized to receive placebo or 2, 5, or 10 mg of terazosin. There were statistically significant differences between the placebo and active treatment groups when using the least square method (p = .012) but there were no statistically significant differences when percent changes from baseline were compared.26 In another study conducted in the United Kingdom, 86 patients with symptomatic bladder outflow obstruction were randomized to receive terazosin or placebo. All terazosin-treated men showed improvement in obstructive symptoms when compared with placebo-controlled patients but these differences were not statistically significant because of the small number of patients enrolled in the study. Further, improvements in uroflowmetry measurements were seen in both placebo-treated and terazosin-treated groups.

Of the total of 163 patients from four investigations, 14% complained of dizziness, 10% suffered headaches, 7% had asthenia, 4% had hypotension, and 4% complained of impotence.27 Less than 1% complained of syncope or decreased libido. These symptoms may be exaggerated as these studies included titration to maximum doses. No placebo group data were available for comparison. Doxazosin Holme and associates presented early results on the use of doxazosin in treating patients with symptomatic BPH. This double-blind, placebo-controlled study involved 47 patients who received 4 mg of doxazosin daily for 9 weeks and 44 patients who received placebo. The results of treatment were monitored by a symptom questionnaire, urodynamic studies, and voiding charts. The reduction in the degree of irritative symptoms was 80% for the treatment group and 45% for the placebo group (p < .05). Obstructive symptoms decreased by 63% for the treatment group and 31% for the placebo group (p < .05). Subjectively, 81% of the treatment group felt considerably much better, compared to 39% of the placebo group. The peak urinary flow rate increased by 25% in the doxazosin group but there was no change in the placebo cohort (p = .07).28 Very few side effects occurred in both groups, and no patient dropped out because of untoward events. Chapple and associates presented the results of a 3-month, double-blind, placebo-controlled study of doxazosin for the treatment of benign prostatic bladder outlet obstruction. In this study, 67 patients received doxazosin 4 mg daily and 68 patients received a placebo. Patients were monitored throughout the study for symptoms, flow rates, incidence of adverse events, and blood pressure when supine and erect. Patients treated with doxazosin experienced a statistically significant improvement in nearly all symptoms compared to placebo-treated patients: frequency, 44% versus 27% (p = .06); nocturia, 39% versus 19% (p = .02); urgency, 60% versus 38% (p = .004); and premicturition delay, 56% versus 26% (p = .003).29 The increase in peak urinary flow rate was 2.6 mL per second in the treatment group, compared with 1.1 mL per second for the placebo cohort. This improvement was not statistically significant (p = .09). There was, however, a statistically significant improvement in the mean urinary flow rate (1 mL per second for the treatment group versus 0.2 mL per second for the placebo cohort [p = .04]).29 Chapple and associates reported only 1 patient who withdrew from the study secondary to drug-related events. They reported no clinically significant changes in sexual function or blood pressure. 29 In 1995, Fawzy and associates conducted a 16-week, double-blind, placebo-controlled study of 100 normotensive men to evaluate the role of doxazosin in the treatment of BPH. In this study, the subjects were titrated to a maximally efficacious or tolerated dose of 8 mg; 87.8% of the


participants tolerated up to 8 mg. In the mean analysis, patients taking doxazosin showed a significant improvement in maximum urinary flow rate compared to patients taking placebo. According to Fawzy et al.’s report, this significant effect of doxazosin was noted as early as week two and was sustained throughout the study. The proportion of patients with a clinically meaningful increase in peak flow rate of at least 3 mL per second was significantly greater in the doxazosin group (39%) than in the placebo group (17%). The severity of obstructive symptoms, irritative symptoms, and total symptoms decreased significantly with doxazosin compared to placebo; this change was evident within 4 weeks of initiation of therapy and was sustained for the duration of the study. 30 The second United States study was conducted by Gillenwater et al. and was also a multicenter, double-blind, placebo-controlled, dose-response study in 248 hypertensive men who had BPH; 161 of these patients completed the study and were randomized to receive placebo or 2, 4, 8, or 12 mg of doxazosin. This study revealed that the maximum flow rate increased significantly in the doxazosin groups, by up to 3.6 mL per second, compared to an increase of 0.1 mL per second in the placebo group. The proportion of patients with a ≥ 3 mL per second increase in peak flow rate was significantly larger in the 8 mg and 12 mg doxazosin groups compared to the placebo group; there was less of a change in peak flow rate in patients taking 2 mg or 4 mg of doxazosin compared to placebo but a rate of at least 3 mL per second was noted. In the endpoint analysis of symptoms, 4 mg of doxazosin was superior to placebo in decreasing the severity of obstructive symptoms, irritative symptoms, and total symptoms.31 The severity of total and obstructive symptoms also decreased significantly with 8 mg of doxazosin. Adverse events were reported by 48% of the men taking doxazosin and 35% of the placebo-treated patients. The side effects most frequently reported were dizziness, headache, and fatigue. Only 2.5% of the doxazosin-treated men experienced hypotension. The authors noted that the incidence of adverse events did not increase with increasing dose or duration of treatment.31 Alpha-1A Subtype Selective Alpha-Adrenergic Antagonist Tamsulosin Tamsulosin is a newly developed member of this class of drugs, is suitable for once-a-day dosing schedule, and is currently being studied extensively in the treatment of BPH. Tamsulosin is a (-)-S-[2-[[2-(o-ethoxyphenoxy) ethyl] amino] propyl]-2-methoxybenzenesulfonamide HCl, a sulphamoylphenethylamine derivative which possesses potent and selective alpha-1A receptor antagonism. In preclinical trials, tamsulosin has been shown to have 13 times more efficacy for prostatic smooth muscle as compared to urethral smooth muscles. Other studies have

revealed a 10 to 12 times higher affinity for prostatic receptors as opposed to vascular and extraprostatic tissue. Recent changes in nomenclature of alpha-blockers reveal the alpha-1A receptors to predominate in the prostate while alpha-1B and alpha-1D receptors predominate in the vascular smooth muscle. Tamsulosin belongs to a class of alpha-1A-receptor antagonists that have preferred selectivity for prostatic smooth muscle although it does have some binding to vascular smooth muscle receptors as well. Tamsulosin binding is remarkable for its significantly lower degree of nonspecific binding compared to other alpha-receptor antagonists.32–45 Two 12-week, double-blind, placebo-controlled studies of tamsulosin 0.4 mg once daily have been conducted in Europe.42,43 More than 300 patients with symptomatic BPH were enrolled in each study. In a recent meta-analysis of data from 575 patients (tamsulosin 382, placebo 193), a small improvement in peak flow rate was shown with tamsulosin (+1.6 mL per second) that was statistically significant when compared with placebo (+0.6 mL per second; p = .002).39 Tamsulosin also significantly improved the mean total Boyarsky symptom score compared with placebo (–3.3 and –2.2 points; p = .002). Long-term, open-label follow-up of these studies showed that about 70% of the patients receiving tamsulosin achieved a clinically significant improvement in BPH symptoms and that the benefits were maintained over 12 months.40 Although tamsulosin is reported to have modest uroselectivity,45 dizziness considered to be possibly or probably related to study medication was experienced by 5% of the patients in this long-term study. Tamsulosin was recently approved in the U.S. as Flomax (by Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield [CT]) for treatment of patients with symptomatic BPH. The drug is available at a dosage of 0.4 mg given once per day, one-half hour after breakfast. The reasons for administering after food are that this administration allows a smoothing of the plasma levels and prevents rapid peaks in the blood, which may be beneficial in avoiding side effects. In a recent multicenter, randomized, double-blind, placebo-controlled, parallel group phase III clinical trial in the United States, Narayan and Tewari reporting for the Tamsulosin Investigator Group46 analyzed 735 patients randomized to double-blind therapy. Results revealed that tamsulosin at doses of 0.4 mg and 0.8 mg was clinically and statistically superior to placebo in relieving symptoms of BPH in men with baseline moderate to severe symptoms. Secondly, tamsulosin had a safety profile that was superior to other currently available alpha-receptor antagonists with no evidence of first dose effects and no clinically significant orthostatic hypotension. The only two side effects noted with the 0.4 mg dose were a higher incidence of dizziness and abnormal ejaculation. In this study, tamsulosin (0.4 mg and 0.8 mg) resulted in a reduction in total American Urological


Association (AUA) symptom score compared to placebo (p < .05). The percentage and number of patients who showed an improvement or reduction in the total AUA symptom score that was ≥ 25% from baseline to endpoint was 56% (134 of 238), 55% (133 of 244), and 40% (95 of 235) in the groups of 0.8 mg once daily, 0.4 mg once daily, and placebo, respectively (p < .05). In another pivotal study, Lepor reporting for the Tamsulosin Investigator Group analyzed a multicenter phase III, randomized, parallel-designed, double-blind clinical comparison of three treatment groups: tamsulosin 0.4 mg per day, tamsulosin 0.8 mg per day, and placebo. All patients were evaluated prior to the study for eligibility on the basis of the AUA symptom score, uroflowmetry and PSA levels. Patients were evaluated for study eligibility during a 4-week single-blind placebo lead-in period before entry into the double-blind treatment period; 618 patients qualified for the study. The double-blind treatment phase lasted a total of 13 weeks. The results of this study confirmed the effectiveness of tamsulosin in treating BPH at both the 0.4mg per day and 0.8 mg per day dosages. The effects of tamsulosin treatment were observed soon after initiation of therapy. Significant differences versus placebo in the total AUA symptom score were apparent after 1 week of treatment with tamsulosin 0.4 mg per day. Changes in uroflow demonstrated that tamsulosin has rapid onset of action, according to Lepor’s study. There was a statistically significant difference relative to baseline observed after the first dose of 0.4 mg per day tamsulosin versus placebo (p < .001). Further, the mean change from baseline to endpoint was significantly greater in both tamsulosin treatment groups than in the placebo group (p < .001). Additionally, statistically significant differences in uroflow compared with placebo occurred within 4 to 8 hours after a single dose of tamsulosin 0.4 mg.47 Overall, tamsulosin was well tolerated at dosages of 0.4 and 0.8 mg per day. Adverse events occurring more frequently in tamsulosin-treated patients included rhinitis, abnormal ejaculation, infection, and dizziness. Asthenia was minimal with tamsulosin. The incidence and severity of abnormal ejaculation were shown to be dose dependent. There was a higher overall incidence of discontinuation due to adverse events in the 0.8 mg per day tamsulosin group (13%) compared to the 0.4 mg per day tamsulosin group and placebo group (7% and 9%, respectively, p = .115).47 The higher incidence of discontinuation in the 0.8 mg per day tamsulosin group was reflected by a higher incidence of abnormal ejaculation, dizziness, chest pain, and hypotension than in the other two groups. On completion of the previously discussed 13-week double-blind phase, the investigators continued the study by giving the patients an option to continue the doubleblind treatment for up to 40 additional weeks. This extension study was designed to determine the long-term safety of tamsulosin and to identify whether response to tamsu-

losin is sustained, increased, or decreased during maintenance therapy. Of the 618 patients from the 13-week initial study, 418 (68%) continued into the extension phase of the same double-blind medication and dose. 48 The parameters measured in this study were the AUA symptom score and maximum urinary flow rate. Statistically significant improvements were observed in all treatment groups (p < .001), even the placebo group. The improvements in the AUA symptom scores, however, were greater in each of the tamsulosin groups (0.4 and 0.8 mg per day) than in the placebo group and were comparable in the two tamsulosin treatment groups. Seventy-eight percent (103 of 132) of the patients treated with tamsulosin 0.8 mg per day demonstrated a decrease in total AUA symptom score of ≥ 25% from baseline; 81% (111 of 137) of patients in the 0.4 mg per day tamsulosin group responded similarly; and 59% (72 of 123) of the patients in the placebo group responded similarly. Further, the mean changes in maximum urinary flow relative to baseline within the two tamsulosin groups were statistically significant (p < .001); the placebo group did not achieve a change of statistical significance. In the 0.8 mg per day tamsulosin group, 38% of the patients had a ≥ 30% increase in Qmax from baseline; 40% achieved the same in the 0.4 mg per day tamsulosin group; and 22% achieved the same in the placebo group. 48 It is interesting to note that when comparing efficacy parameters obtained at the end of the total 53 weeks to that of the first 13 weeks of the study, the results showed a greater reduction in the tamsulosin groups than in the placebo group at all visits. At the end of the extension phase, the mean change in Qmax relative to baseline was 0.43 mL per second in the placebo group, 1.69 mL per second in the tamsulosin 0.4 mL per day group, and 2.10 mL per second in the tamsulosin 0.8 mL per day group. This increase from baseline was statistically significant for both of the tamsulosin groups but the change was not significant for the placebo group. Further, in the tamsulosin 0.4 mg per day group, the percentage of nonresponders (patients who had less than a 25% decrease in the total AUA symptom score from baseline) who became responders (patients who had demonstrated a decrease in the total AUA symptom score of 25% or more from baseline) was 43%; this was significantly higher than that for responders who became nonresponders (6%). In contrast, in the placebo group the percentage of nonresponders at the end of the phase III trial who became responders (21%) at the end of the extension phase was lower than the percentage of responders who became nonresponders (23%).48 In this same study, over the combined 53 weeks of the double-blind treatment, there was an overall higher incidence of adverse events in the tamsulosin 0.8 mg per day group than in the 0.4 mg per day tamsulosin and placebo groups. The overall incidence of adverse events in the 0.4 mg per day tamsulosin and placebo groups was similar. The most commonly reported treatment-emergent side


effect for all three groups was infection (colds and upper respiratory infections). The overall incidence of cardiovascular side effects was indistinguishable between the three groups; 14%, 10%, and 14% for the placebo group, 0.4 mg per day tamsulosin group, and 0.8 mg per day tamsulosin group, respectively. Another adverse event, abnormal ejaculation, occurred in 26% of the 0.8 mg per day tamsulosin group compared to 10% and 0% in the 0.4 mg per day tamsulosin and placebo group, respectively. 48 From these data, it can be concluded that continued exposure to tamsulosin beyond the initial 13 weeks is not accompanied by enhanced risk for adverse events; the adverse events seen at the end of the 53-week trial period were similar to those seen at the end of the initial 13-week trial period. Adverse Events of Alpha-1 Adrenergic Antagonists The most important side effects of the alpha-1 blocking drugs are simply reflections of their alpha-blocking effects. The main manifestations are cardiovascular effects, which may cause orthostatic hypotension leading to dizziness, reflex tachycardia, and angina in patients with coronary artery disease. Another common side effect seen with the use of alpha-blockers is sexual dysfunction, mainly erectile dysfunction and retrograde ejaculation. Sexual Dysfunction Few studies have investigated the prevalence of sexual dysfunction among patients with symptomatic BPH. Preliminary analysis of baseline data obtained from the Prospective European Doxazosin and Combination Trial (PRFDIGT), however, suggests that there is a large burden of sexual dysfunction in patients with BPH. In addition, the Treatment of Mild Hypertension Study (TOMHS) provided an opportunity to examine the prevalence of sexual problems in a population of hypertensive men.49 At initial screening, 14% of men reported sexual problems, mostly erectile dysfunction (12%). The proportion of men experiencing problems in obtaining and/or maintaining erection increased substantially after 60 years of age. Since BPH and sexual dysfunction are both age-related disorders, it might be expected that a large proportion of elderly men with symptomatic BPH will also experience sexual problems. Although sexual dysfunction is traditionally thought to be related to antihypertensive agents, favorable effects were seen with doxazosin in the 24-month data from the TOMHS study.50 Doxazosin was significantly less likely to cause erectile dysfunction compared to the placebo and other antihypertensive therapy (p = ~.01 among all groups). In the 505 men treated with antihypertensive therapy, difficulties in maintaining erections occurred in only 1.3% of the doxazosin group, compared to 3.8% in the placebo, 4.6% in the beta-blocker, 6.1% in the ACEinhibitor, 9.0% in the calcium antagonist, and 14.1% in the diuretic groups.

In the U.S. tamsulosin study, the incidence of abnormal ejaculation was greater in patients receiving tamsulosin than in those receiving placebo (0.8 mg, 18%; 0.4 mg, 11%; and placebo, < 1%; p < .05). The abnormal ejaculation could be a combination of retrograde ejaculation secondary to bladder neck incompetence or could be due to anejaculation as a result of blockade of receptors on the vas deferens, seminal vesicles, and prostate. This hypothesis needs further study. Cardiovascular Effects By blocking the alpha-1 adrenoceptor, these drugs cause peripheral vasodilation, which reduces total peripheral vascular resistance and thereby lowers high blood pressure. Indeed, reduction in blood pressure was the primary indication for which alpha-1 adrenoceptor antagonists were developed. The effects of selective alpha-1 blockade on the blood pressure of patients with BPH are important in terms of the risk of adverse effects related to hypotension, both in normotensive patients and in those treated with other antihypertensives. Given that both BPH and hypertension become more prevalent with increasing age, and that one would expect to find that a large proportion of older men have both conditions, these are very real concerns. Clinicians are often faced with the dilemma of what to do when treating a patient with BPH who already has hypertension controlled by an agent other than alphablockers. Should the existing antihypertensive agent be withdrawn or the alpha-blockers be given in addition to existing medication? In a small pilot study, Kaplan et al. investigated the effects of doxazosin on the blood pressures of 32 pharmacologically normotensive patients (patients in whom blood pressure was controlled by antihypertensive medication) with BPH and 31 physiologically normotensive patients with BPH.51 The results showed that doxazosin-induced reductions in blood pressure were small and clinically insignificant in both groups (no differences between groups). Further evidence is available from the Hytrin Community Assessment Trial (HYCAT), a community-based, double-blind, randomized trial of the treatment of symptomatic BPH with terazosin versus placebo; 524 of the patients enrolled (274 were given terazosin and 250 were given placebo) were also treated with concurrent single or combination antihypertensive therapy. There were no significant differences between the terazosin and placebo patients in the incidence of blood pressure-related adverse events. These studies indicate that doxazosin or terazosin may be introduced for treating BPH in hypertensive men whose blood pressure is already adequately controlled by other antihypertensive agents, without fear of a further clinical reduction in blood pressure. Monitoring of blood pressure is recommended, at least initially, however, when alphablockers are given in addition to any other existing antihypertensive medication.


In terms of cost-effectiveness, the most logical approach in patients with concomitant hypertension and BPH is to replace the existing antihypertensive medication with an alpha-1 adrenoceptor antagonist. There is controversy over this approach, however. Hypertension often coexists with other risk factors for coronary heart disease, for example abnormal lipid profile and insulin resistance/glucose intolerance. Proponents of alpha-blockers for treatment of both diseases cite favorable effects of drugs such as doxazosin on these metabolic variables.52,53 Benefits include reduction in high blood pressure and serum lipids, an increase in fibrinolysis, inhibition of platelet aggregation, attenuation of the adverse hemodynamic and homeostatic effects of smoking, and regression of cardiac hypertrophy. Alpha-blockers are also reported to improve insulin sensitivity and glucose intolerance, both in hypertensive patients with insulin resistance and in noninsulin-dependent diabetic patients.54 Such benefits provide further rationale for choosing alpha1 adrenoceptor blockade for treating men with BPH who have one or more of these risk factors. Those opposed to the use of alpha-blockers for hypertension have equally powerful arguments. The Joint National Commission on Hypertension recommends

lifestyle modifications, diuretics, calcium-channel blockers, ACE (angiotension converting enzyme) inhibitors, and beta-blockers as first-line management for hypertension.55,56 The rationale for this is the fact that these agents have proven efficacy in reducing the risk of myocardial infarction, cerebrovascular accidents, and transient ischemic attack (TIA) in such patients. Alpha-blockers for hypertension are used mostly as additional rather than primary agents for treatment of hypertension. The second major objection to using alpha-blockers is the spontaneous incidence of postural hypotension with aging. The Shep Study,57 for example, reported the incidence of spontaneous postural hypotension (a fall in systolic BP of ≥ 20 mm Hg after 1 minute of quiet standing); it was reported that 20% of patients older than 65 years have postural hypotension, of which one-half are symptomatic. This study concluded further that the incidence of postural hypotension among the elderly increases with prolonged standing; 10.4% experienced hypotension after 1 minute of standing, 12% at 1 to 3 minutes of standing, and 17.3% at 3 minutes. One major cause of morbidity in elderly patients is falling due to spontaneous postural hypotension, resulting in hip fracture. Adding an

TABLE 58–1. Summary of Alpha-Blockers Drug Agent

Mechanism of Action

Phenoxybenzamine • α-1 and α-2 adrenoceptor antagonist • Short acting • Irreversible antagonist • Increases blood flow to skin, mucosa, and abdominal viscera Prazosin • α-1 adrenoceptor antagonist • Short acting • Reversible antagonist • Severely decreases diasystolic BP Alfuzosin • α-1 adrenoceptor antagonist • Reversible antagonist • Short acting Terazosin • α-1 adrenoceptor antagonist • Reversible antagonist • Long acting

Doxazosin

• α-1 adrenoceptor antagonist • Reversible antagonist • Long acting

Tamsulosin

• α-1 adrenoceptor antagonist • Reversible antagonist • Long acting

Pharmacokinetics

Dosing/Administration

Adverse Reactions

• IV T1/2: 24 hours • Duration of action: 3–4 days; the effects of daily administration are cumulative for nearly 1 week • Hepatic metabolism

• 5–10 mg bid orally

Postural hypotension, inhibited ejaculation with retrograde ejaculation, nasal congestion, nausea/vomiting, tachycardia, miosis

• High first-pass hepatic • 1–5 mg bid orally metabolism with bile excretion • After oral administration, peak plasma concentration is reached in 3 hours • T1/2:2–3 hours • 3–4 mg tid orally

Syncope, postural hypotension, dizziness, nasal congestion, fluid retention

• Hepatic metabolism with metabolite excreted in urine (40%) and bile/feces (60%) • Minimal first-pass effect • After oral administration, peak plasma concentration is reached in 40 minutes • T1/2:12 hours • High first-pass hepatic metabolism with enterohepatic recycling • After oral dose, peak plasma concentration is reached in 2–3 hours • T1/2:22 hours • Hepatic metabolism with metabolite excreted in urine • After oral administration, peak plasma concentration is reached in 5 days • T1/2:9–13 hours

• 2–10 mg bid orally • Treatment would be initiated with a 1 mg dose given at bedtime

Syncope, postural hypotension, dizziness, asthenia, impotence, flu-like syndrome, headache

• 4–8 mg O.D. orally

Syncope, postural hypotension, dizziness, headache

• 0.4–0.8 mg O.D. orally • Should be given 1/2 hour after breakfast

Postural hypotension, syncope, dizziness, abnormal ejaculation (includes ejaculation failure, ejaculation disorder, retrograde ejaculation, and ejaculation decrease)

Reprinted with permission from Narayan P. (ed). Benign prostate hyperplasia. Churchill-Livingston. London, England. [In press].

540 / Advanced Therapy of Prostate Disease TABLE 58–2. Cardiovascular Side Effects of Terazosin, Doxazosin, and Tamsulosin*

Side Effect Asthenia/fatigue Postural hypotension Dizziness Discontinued due to side effects

Terazosin†

Doxazosin‡

Percentage Percentage with with Terazosin Placebo

Percentage Percentage with with Doxazosin Placebo

7.4 3.9 9.1 20

3.3 0.8 4.2 1.2

p Value < .05 < .05 < .05 NS

8.8 — 15.6 12

1.7 — 9.0 4.0

Tamsulosin§

p Value

Percentage with Tamsulosin

Percentage with Placebo

p Value

< .05 — < .05 NS

11 1 20 9

9.0 1.0 15.0 8

NS NS NS NS

*In the USA. †From the package drug insert of terazosin. ‡From the package drug insert of doxazosin. §Data from the use of FDA approved dose of tamsulosin (0.4 mg in US93.01 Study). Reprinted with permission from Narayan P, editor. Benign prostate hyperplasia. Churchill-Livingston. London, England. [In press].

alpha-blocker exacerbates this problem. Conversely, this does not happen when elderly patients are given calciumchannel blockers or ACE inhibitors. Finally, patients already on antihypertensives may need to be watched more carefully when alpha-blockers are added. With time constraints, the physician may prefer to simply use an alpha-1 receptor subtype selective agent to eliminate the need to counsel patients periodically about postural hypotension and its sequelae. In the American tamsulosin studies, dizziness occurred in a small percentage of patients (8-mg dose caused dizziness in 23% of patients; 4 mg, 20%; and placebo, 15%; p = .039 between 0.8 mg and placebo). Since dizziness was not associated with postural hypotension, it could be due to the binding of the drug to baroreceptors in the central or peripheral nervous system. This incidence of dizziness, however, is comparable to terazosin and doxazosin studies.30,31,43,51,58–65 The lack of significant cardiovascular effects and hypotension with tamsulosin was also noted in the European studies. In the meta-analysis of the European trial, treatment-emergent adverse effects occurred in 36% of the tamsulosin group and in 32% of the placebo group (p = .802). During the 60 weeks of tamsulosin treatment, 60% of the patients experienced at least one treatmentemergent adverse event. Fifty-one (21%) of the patients experienced adverse events considered by the investigator to be probably or possibly related to tamsulosin.38–40,43,66 Tables 58–1 and 58–2 provide a summary of alphaantagonists and their incidence of adverse events caused at doses used for treating BPH.

Conclusion To be an effective treatment for BPH, medical therapy must not only improve the patient’s ability to urinate but must also have minimal side effects. It should be noted that currently available medical therapies must be continued indefinitely to maintain a therapeutic response. Medical therapies must also be cost-effective. The man who develops BPH at 50 years of age may need therapy for 20 to 40 years. The total cost of such treatment could be signif-

icant. As with any medication or treatment regimen, it is important to determine which patients are candidates for a trial of medical therapy for BPH. Any patient who is suffering from clinically significant BPH symptoms and is not in urinary retention is a potential beneficiary from treatment with an alpha-1 adrenergic blocker or 5 αreductase inhibitor (discussed elsewhere in the book). These therapies are not limited to the poor surgical candidate but can be useful for any patient with bothersome symptoms. Even in patients with moderate to severe symptoms, 85% remain satisfied with alpha-blocker therapy for a period of up to 1 year after treatment.67 Symptoms of a more severe nature and urinary retention, however, are contraindications to medical therapy. Patients with a history of orthostatic hypotension should not be treated with alpha-blockers. In the decision to use an alpha-1 adrenergic antagonist, the preferences of both the physician and the individual patient are important. To help with this decision, the advantages and disadvantages of each medication must be understood. The alpha-1 adrenergic antagonists have several advantages. The long-acting drugs allow for once-a-day dosing. The therapeutic effect, as indicated by a > 30% increase in peak urinary flow rate, is realized in > 50% of patients receiving this therapy. The beneficial effect from treatment is realized as soon as 1 week with tamsulosin or 2 to 3 weeks after reaching the maximum dose with other agents. The major disadvantage of these medications in treating BPH is the 10% incidence of untoward effects related to the cardiovascular system as well as titration to achieve maximum benefit. Some of these disadvantages have been solved by the use of subtype selective alpha-blockers.

References 1. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostate hyperplasia with aging. J Urol 1984;132(3):474–9. 2. Sagnier PP, Richard F, Botto H, et al. Adaptation and validation in the French language of the International Score of


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Symptoms of Benign Prostatic Hypertophy. Prog Urol 1994;4(4): 532–8. Barry MJ, Fowler FJ Jr, Bin L, Oesterling J. A nationwide survey of practicing urologists: current management of benign prostatic hyperplasia and clinically localized prostate cancer. J Urol 1997;158:488–91. Barry MJ, Roehrborn C. Management of benign prostate hyperplasia. Annu Rev Med 1997;48:177–89. Collins MM, Barry MJ, Bin L, et al. Diagnosis and treatment of benign prostate hyperplasia: practice patterns of primary care physicians. J Gen Intern Med 1997; 12:224–9. Caine M, Raz S. Some clinical implications of adrenergic receptors in the urinary tract. Arch Surg 1975;110: 247–50. Chapple CR, Aubry ML, James S, et al. Characterization of human prostate adenoreceptors using pharmacology receptor binding localization. Br J Urol 1989;63:487–96. Furuya S, Kumamoto Y, Yokoyama E, et al. Alpha adrenergic activity and urethral pressure in prostatic zone in benign prostate hypertrophy. J Urology 1982;128:836–9. Chapple CR, Aubry ML, James S, et al. Characterization of human prostate adrenoreceptors using pharmacology receptor binding localization. Br J Urol 1989;63:487–96. Abrams PH, Shah PJR, Stone R, Choa RG. Bladder outflow obstruction treated with phenoxybenzamine. Br J Urol 1982;54:527–30. Caine M, Perlberg S, Shapiro A. Phenoxybenzamine for benign prostate obstruction: review of 200 cases. Urology 1981;17:542–6. Hedlund H, Andersson KE, Ek A. Effects of prazosin in patients with benign prostatic obstruction. J Urol 1983;130:275–8. Kirby RS, Coppinger SW, Corcoran MO, et al. Prazosin in the treatment of prostatic obstruction: a placebocontrolled study. Br J Urol 1987;60:136–42. Shapiro A, Mazouz B, Caine M. The alpha-adrenergic blocking effect of prazosin on the human prostate. Urol Res 1981;9:17–20. Dutkiewicz S, Filipek M. Prazosin concentration monitoring in the treatment of prostatic adenoma. Int Urol Nephrol 1991;23:143–50. Chapple CR, Noble JG, Milroy EJ. Comparative study of selective alpha-1 adrenoceptor blockade versus surgery in the treatment of prostatic obstruction. Br J Urol 1993;72:822–5. Ramsay JW, Scott GI, Whitfield HN. A double-blind controlled trial of a new alpha-1 blocking drug in the treatment of bladder outflow obstruction. Br J Urol 1985;57:657–9. Jardin A. Efficacy of an alpha-blocker, alfuzosin, on urinary disorders in men with prostatic adenoma: intermediate results of a European multicenter study. Ann Urol (Paris) 1988;22:333–40. Jardin A, Bensadoun H, Delauche Cavallier MC, Attali P. Alfuzosin for treatment of benign prostatic hypertrophy: the BPH-ALF Group. Lancet 1991;337:1457–61. Jardin A, Bensadoun H, Delauche Cavallier MC, et al. Long-term treatment of benign prostatic hyperplasia with alfuzosin: a 24–30 month survey, BPH-ALF Group. Br J Urol 1994;74:579–84. Kaplan SA, Reis RB, Cologna A, et al. Intermittent alpha-

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blocker therapy in the treatment of men with lower urinary tract symptoms. Urology 1998;52:12–6. Lepor H, Auerbach S, Puras Baez A, et al. A randomized, placebo-controlled multicenter study of the efficacy and safety of terazosin in the treatment of benign prostatic hyperplasia. J Urol 1992;148:1467–74. Lepor H. Long-term efficacy and safety of terazosin in patients with benign prostatic hyperplasia: Terazosin Research Group. Urology 1995;45:406–13. Lepor H, Henry D, Laddu AR. The efficacy and safety of terazosin for the treatment of symptomatic BPH. Prostate 1991;18:345–55. Fabricius PG, Hannaford JM. Placebo-controlled study of terazosin in the treatment of benign prostatic hyperplasia with 2-year follow-up. Br J Urol 1992;70 Suppl 1:10–6. Di Silverio F. Use of terazosin in the medical treatment of benign prostatic hyperplasia: experience in Italy. Br J Urol 1992;70 Suppl 1:22–6. Lloyd SN, Buckley JF, Chilton CP, et al. Terazosin in the treatment of benign prostatic hyperplasia: a multicenter, placebo-controlled trial. Br J Urol 1992;70 Suppl 1:17–21. Holme JB, Christensen MM, Rasmussen PC. 29-weeks doxazosin treatment in patients with symptomatic benign prostatic hyperplasia. Scand J Urol Nephrol 1994;28:77–82. Chapple CR, Carter P, Christmas TJ. A three-month, double-blind study of doxazosin as treatment for benign prostatic bladder outlet obstruction. Br J Urol 1994;74:50–6. Fawzy A, Braun K, Lewis GP, et al. Doxazosin in the treatment of benign prostatic hyperplasia in normotensive patients: a multicenter study. J Urol 1995;154:105–9. Gillenwater JY, Conn RL, Chrysant SG, et al., for the Multicenter Study Group. Doxazosin for the treatment of benign prostatic hyperplasia in patents with mild to moderate essential hypertension: a double blind, placebo-controlled, dose-response multicenter study. J Urol 1995;154:110–5. Chapple CR. Selective alpha-1-adrenoceptor antagonists in benign prostatic hyperplasia. Rationale and clinical experience. Eur Urol 1996;29:129–144. Foglar R, Shibata K, Horie K, Hirasawa A, Tsujimoto G. Use of recombinant alpha-adrenoceptors to characterize subtype selectivity of drugs for the treatment of prostatic hypertrophy. Eur J Pharm 1995;288: 210–20. Garcia Sainz JA, Romero Avila MT, Villalobos Molina R, Minneman KP. Alpha-1-adrenoceptor subtype selectivity of tamsulosin: studies using livers from different species. Eur J Pharmacol 1995;289:1–7. Takenaka T, Fujikura T, Honda K. Discovery and development of tamsulosin hydrochloride, a new alpha-1adrenoceptor antagonist. Yakugaku Zasshi 1995; 155:773–89. Soeishi Y, Matsushima H, Watanabe T. Absorption, metabolism, and excretion of tamsulosin hydrochloride in man. Xenobiotica 1996;26:637–45. Soeishi Y, Matsushima H, Teraya Y. Metabolism of tamsulosin in rat and dog. Xenobiotica 1996;26:355–65. Chapple CR. Selective alpha-1-adrenoceptor antagonists


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in benign prostatic hyperplasia: rationale and clinical experience. Eur Urol 1996;29:129–44. Chapple CR, Wyndaele JJ, Nordling J, et al., for the European Tamsulosin Study Group. Tamsulosin, the first prostate-selective alpha-1A-adrenoceptor antagonist: a meta-analysis of two randomized, placebocontrolled, multicenter studies in patients with benign prostatic obstruction (symptomatic BPH). Eur Urol 1996;29:155–67. Schulman CC, Cortvriend J, Jonas U, et al., for the European Tamsulosin Study Group. Tamsulosin, the first prostate-selective alpha-1A-adrenoceptor antagonist: analysis of a multinational, multicenter, openlabel study assessing the long-term efficacy and safety in patients with benign prostatic obstruction (symptomatic BPH). Eur Urol 1996;29:145–54. Leonardi A, Hieble JP, Guarneri L, et al. Pharmacological characterization of the uroselective alpha-1-antagonist Rec 15/2739 (SB 216469): role of the alpha-1Ladrenoceptor in tissue selectivity. I. J Pharmacol Exp Ther 1997;281:1272–83. Abrams P, Schulman CC, Vaage S. Tamsulosin, a selective alpha-1c-adrenoceptor antagonist: a randomized, controlled trial I patients with benign prostatic “obstruction” (symptomatic BPH): the European Tamsulosin Study Group. Br J Urol 1995;76:325–36. Kawabe K. Efficacy and safety of tamsulosin in the treatment of benign prostatic hyperplasia. Br J Urol 1995;76 Suppl 1:63–7. Yamada S, Tanaka C, Kimura R, Kawabe K. Alpha-1adrenoeptors in human prostate: characterization and binding characteristics of alpha-1 antagonists. Life Sci 1994;54:1845–54. Yamada S, Tanaka C, Ohkura T, et al. High-affinity specific (3H) tamsulosin binding to alpha-1-adrenoceptors in human prostates with benign prostatic hypertrophy. Urol Res 1994;22:273–8. Narayan P, Tewari A, for the Tamsulosin Investigator Group. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. J Urol. [In press] Lepor H, for the Tamsulosin Investigator Group. Phase III multicenter placebo-controlled study of tamsulosin in benign prostatic hyperplasia. Urology 1998;51:892–900. Lepor H, for the Tamsulosin Investigator Group. Longterm evaluation of tamsulosin in benign prostatic hyperplasia: placebo-controlled, double-blind extension of phase III trial. Urology 1998;51:901–6. Grimm RH, Grandits GA, Svendsen K, for the TOMHS Research Group. Incidence and disappearance of erectile problems in men treated for stage I hypertension: the Treatment of Mild Hypertension Study (TOMHS). Eur Urol 1996;30 Suppl 2:26–38. Neaton JD, Grimm RH, Prineas RJ. Treatment of mild hypertension study: final results. JAMA 1993;270: 713–24. Kaplan SA, Meade D, Alisera P, et al. Doxazosin in physiologically and pharmacologically normotensive men with benign prostatic hyperplasia. Urology 1995;46: 512–7. Pool JL. Effects of doxazosin on serum lipids: a review of

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the clinical data and molecular basis for altered lipid metabolism. Am Heart J 1991;121:251–60. Pool JL. Effects of doxazosin on coronary heart disease risk factors in the hypertensive patient. Br J Clin Pract 1994;74:8–12. Fulton B, Wagstaff AJ, Sorkin EG. Doxazosin, an update of its clinical pharmacology and therapeutic applications in hypertension and benign prostatic hyperplasia. Drugs 1995;49:295–320. Chalmers J. The place of combination therapy in the treatment of hypertension in 1993. J Clin Exp Hypertens 1993;15(6):1299–313. Jerome M, Xakellis GC, Angstman G, Patchin W. Initial medication selection for treatment of hypertension in an open-panel HMO. J Am Board Fam Pract 1995; 8(1):1–6. Labarthe DR, Blaufox MD, Smith WM, et al. Systolic Hypertension in the Elderly Program (SHEP). Part 5: baseline blood pressure and pulse rate measurements. Hypertension 1991;17 Suppl 3:1162–76. Witjes WP, Rosier PF, Caris CT, et al. Urodynamic and clinical effects of terazosin therapy in symptomatic patients with and without bladder outlet obstruction: a stratified analysis. Urology 1997;49:197–205. Frankel S. Measures of Proscar, Hytrin and Cardura side effects. Neurourol Urodyn 1997;16:63–6. Lepor H, Nieder A, Feser J, et al. Effect of terazosin on prostatism in men with normal and abnormal peak urinary flow rates. Urology 1997;49:476–80. Lepor H, Kaplan SA, Klimberg I, et al. Doxazosin for benign prostatic hyperplasia: long-term efficacy and safety in hypertensive and normotensive patients. J Urol 1997;157:525–30. Kawachi I, Barry MJ, Giovanucci E, et al. The impact of different therapies on symptoms of benign prostatic hyperplasia: a prospective study. Clin Ther 1996;18(6): 1118–27. Debruyne FM, Witjes WP, Fitzpatrick J. The international terazosin trial: a multicentre study of the long-term efficacy and safety of terazosin in the treatment of benign prostatic hyperplasia—The ITT Group. Eur Urol 1996;30:369–76. Lepor H, Williford WO, Barry MJ, et al., for the VA Cooperative Studies Benign Prostatic Hyperplasia Study Group. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 1996;335(8): 533–9. Roehrborn CG, Oesterling JE, Auerbach S, et al., for the HYCAT Investigator Group. The Hytrin Community Assessment Trial study: a one-year study of terazosin versus placebo in the treatment of men with symptomatic benign prostatic hyperplasia. Urology 1996;47:159–68. Okada H, Kawaida N, Ogawa T, et al. Tamsulosin and chlormadinone for the treatment of benign prostatic hyperplasia—The Kobe University YM617 Study Group. Scand J Urol Nephrol 1996;30:379–85. Kaplan SA, Goluboff ET, Olsson CA, et al. Effect of demographic factors, urinary peak flow rates, and Boyarsky symptom scores on patient treatment choice in benign prostatic hyperplasia. Urology 1995;45:398–405.

CHAPTER 59

5 ALPHA-REDUCTASE INHIBITORS JACK GELLER, MD ical therapy for BPH. Finasteride (Proscar) did not bind to the androgen receptor and decreased plasma and prostate DHT levels by approximately 70%4,5 and 90%,6 respectively, when given in a dosage of 5 mg daily. Finasteride is a competitive inhibitor of 5 α-reductase NADPH complex, with a KIC50 of 10–8 M; its mechanism of action is shown in Figure 59–1. Dihydrotestosterone in prostate tissue is significantly lower in finasteridetreated patients than in castrates.7 The residual circulating DHT (approximately 30%) was shown to be due to another isoenzyme of 5 α-reductase called isoenzyme 1,8 and subsequent studies show that Proscar primarily inhibited isoenzyme 2,9 the predominant isoform of 5 α-reductase in the prostate. Genetic mutations of isoenzyme 1 have not been described in humans. There are other 5 α-reductase inhibitors in early clinical trials in the United States of America that have not yet been approved by the FDA, including SKF105657 and GI198745. This chapter will focus exclusively on finasteride.

Background and History of 5 α-Reductase Isoenzymes and Inhibitors Male pseudohermaphroditism due to 5 α-reductase deficiency was first described by Imperato-McGinley et al. and Walsh et al. in 1974.1,2 In this syndrome, which was phenotypically called pseudovaginal perineoscrotal hypospadius, probands had small prostates, femaleappearing external genitalia with clitoral enlargement, normal plasma testosterone levels, low plasma dihydrotestosterone (DHT) levels, and normal male XY chromosome pattern. Patients were eventually shown to have point mutations in the 5 α-reductase gene on chromosome 2, resulting in severe DHT deficiency and the clinical syndrome.3 This observation provided the stimulus for development of 5 α-reductase inhibitors to clinically treat symptomatic benign prostatic hyperplasia (BPH) since such inhibitors reduce prostate size with minimal effects on plasma testosterone, the prime regulator of male sexuality. In 1987, Merck began their first clinical trials with a 5 α-reductase inhibitor, finasteride, which culminated in FDA approval in 1992 for use of the drug as the first med-

Results and Significance of Major Clinical Trials with Finasteride Phase III Clinical Trial of Finasteride versus Placebo An international multicenter phase III trial to compare finasteride to placebo for 1 year10 followed by open extension for 4 years11 was initiated in 1989. Criteria for entry into this study were large prostates, maximum flow rates of < 15 mL per second, and moderate to severe symptom scores. In the first year of this large study of 1084 patients, finasteride-treated patients showed significant decreases in prostate volume of approximately 20% and significant increases in maximum flow rate of 1.5 mL per second compared to placebo values of +0.5 mL per second. They also showed significant decreases in symptom scores of approximately 3.3 units compared to –1.8 units in placebo patients.10 These changes were sustained or slightly improved in finasteride-treated patients over the subsequent 4 years in open extension (Figures 59–2, 59–3, 59–4).11 This arrest of prostate growth has been observed by the current author to continue for at least 8 years (unpublished observation). Confirmation of the major findings published in the New England Journal of Medicine10 for the phase III studies was also noted in the SCARP study,12 Prospect study,13 and Early Intervention Trials.13

FIGURE 59–1. Mechanism of finasteride (NK-906) action. Finasteride has high affinity binding to the NADPH-5 α-reductase enzyme complex, making it unavailable for testosterone conversion to DHT. 543


Veterans Administration Study* In 1996, results of a large Veterans Administration (VA) study comparing finasteride, terazosin, and the combination of both drugs to placebo in patients with BPH was published.14 This study showed no difference between finasteride and placebo with regard to changes in maximum flow rate and symptom score although gland size did decrease in finasteride-treated patients. In the same study, terazosin therapy resulted in significant improvement in both flow rates and symptom score. Finasteride plus terazosin was not different from terazosin alone. It was noted subsequently that this study differed from the five previously reported studies with regard to average prostate size.14 Average prostate size was only 37.5 g on entry into the VA study, compared to sizes in the five previous studies ranging from 41 to 59 g, with a mean of 47 g, and in which finasteride significantly reduced clinical symptoms and improved flow rates. Meta-Analysis of the Clinical Effects of Finasteride on Prostate Volume Because of the smaller-sized prostates of patients in the VA study, Boyle et al.13 undertook a meta-analysis of the five previous studies plus the VA study to determine if there was any relationship between changes in symptom score and maximum flow rate and baseline prostate size measured by magnetic resonance imaging (MRI) or transrectal ultrasonography (TRUS). In this meta-analysis, the investigators showed that there was significant improvement in both symptom scores and maximum flow rates in patients treated with finasteride compared to placebo if prostate size was > 40 g (Figures 59–5, 59–6). These benefits appeared to increase with prostate size > 40 g. At volumes < 40 g, the effects of finasteride on maximum flow and symptom score were not different from placebo with regard to these major parameters. The conclusion from Boyle’s meta-analysis was that finasteride should only be used in patients with large prostates of approximately 40 g or more. SCARP Clinical Trial Another major clinical trial that improved the understanding of the role of finasteride as medical therapy for BPH was the SCARP Scandinavian trial,12 a 2-year study of the effect of finasteride versus placebo in the natural history of BPH. In this study, significantly increased numbers of patients in the placebo group compared to the finasteride group underwent surgery for progression of disease and acute urinary retention (AUR). This study provided the first evidence that finasteride altered the natural history of BPH. * The study compared the effect on American Urological Association symptom scores and peak urinary flow rates of finasteride alone, terazosin alone, and finasteride plus terazosin to placebo in 1229 patients with BPH treated for 1 year.

FIGURE 59–2. Results of MRI measurements of prostate size during 5 years of treatment with finasteride is shown for the large phase III study in this figure in solid squares. During the first year only, changes in placebo size are shown in closed circles. Statistically significant decreases in prostate size of finasteride-treated patients versus placebo-treated patients is noted.

PLESS Clinical Trial More recently, results of the Proscar Long-term Efficacy and Safety Study (PLESS) have been published. The study compared finasteride to placebo in a 4-year, doubleblind, placebo-controlled trial, with regard to the effect on clinical symptoms, flow rate, and prostate sizes in patients with BPH.15 In this large study of over 3000 patients, finasteride reduced the cumulative need for surgery due to progression of BPH by > 50% and also reduced the incidence of AUR by > 50% (Figures 59–7, 59–8). The study meticulously accounted for greater than 90% of the patients over the 4-year period. This was one of the few studies in which a placebo group was maintained for 4 years. It proved to be exceedingly important and useful in showing the effectiveness of finasteride in reducing the need for surgery and occurrence of AUR.15 Following the PLESS study, it was possible to say that finasteride is not only effective in treating BPH in patients with prostates > 40 g but favorably alters the natural history of this disease process. The study also showed that prostate-specific antigen (PSA) levels correlated well with prostate volume and indicated that increasing baseline levels of PSA could be used to identify patients at increased risk for AUR or surgical intervention.16,17 Other important data from PLESS15 indicated that: side effects related to sexual dysfunction were significantly greater in the finasteride group in the first year only (Table 59–1); breast tenderness due to gynecomastia was rare but higher in finasteride-treated patients; and prostate cancer was detected equally in both groups, using a corrected

5 α-Reductase Inhibitors / 545

Practical Application of Clinical Trials: When and How to Use Finasteride for Treating Benign Prostatic Hyperplasia Once the diagnosis of BPH has been established by appropriate history, physical examination, and tests, medical therapy is appropriate if the patient has a progressing American Urological Association (AUA) symptom score in the range of 12 to 26. Values of 20 and above are staged as severe disease. Results of PLESS indicated that the best protective effects of finasteride against AUR and need for surgery were actually in the severe disease category with a mean symptom score of 23 (Table 59–2).19 In the current author’s 5-year experience, however,20 patients with symptom score values in the high “severe” category were invariably dissatisfied with medical therapy and required surgery. Therefore, patients with symptom score values of greater than 26 should probably go directly to surgery. Initiating Treatment and Selecting Patients Selection of patients for medical therapy of BPH is best accomplished by determining the extent and rate of progression of prostatism with a validated AUA symptom score questionnaire filled out by the patient.21 The AUA symptom score is also very useful for following the progression of BPH and triggering a decision to start medical therapy.21 Seven symptoms of prostatism are evaluated to determine the symptom score. Each symptom is given a value of one to five points with five representing the severe; the highest possible score, therefore, is 35.21 Mild BPH is indicated by a total of 0 to 8 points. Patients with such a score should be followed annually but do not usually require treatment. Moderate disease is signified by a score of 9 to 19 points. Scores above 20 represent advanced stage BPH.21 The ideal time to start medical therapy for BPH would be when the symptom score increases into the 9 to 19 range. In untreated mild or moderate BPH, the natural history of disease is for symptoms to increase to advanced stage disease and require surgery in approximately 20 to 30% of patients over 5 years.22–27 If medical therapy is appropriate, then the best results with finasteride therapy would be in patients with prostates ≥ 40 g and/or PSA levels > 2.5 ng per mL,16 while alpha1-adrenergic blockers would be appropriate for smaller glands. Roehrborn et al. have recently shown that 66% of patients with BPH and PSA levels > 1.3 ng per mL show significantly more improvement on finasteride than placebo.28 Finasteride,

4.0

Controlled

Extension

S.E.

(n=135) 3.0

+ Mean Change

PSA in finasteride-treated patients, with PSA values multiplied by 2 after the first year for comparison to normal range. When corrected PSA values were compared to raw placebo values on a receiver operating characteristics curve, a stringent criterion of sensitivity for the diagnosis of prostate cancer, similar values were noted.18

2.0

(n=270)

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Placebo Finasteride 5 mg (n=281) 3 6 9 12

18

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30 36 Months

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60

FIGURE 59–3. Changes from baseline in maximum urinary flow rate in mL per second during 5 years of treatment with finasteride are shown for phase III study in this figure by closed squares. Data for placebo group for the first year only is shown by closed circles. Statistically significant improvements in urinary flow rate were seen during the first year in finasteride-treated patients and sustained thereafter for 5 years.

because of its sustained effectiveness in reducing the size of the prostate and improving clinical symptoms of BPH as previously described, has now been shown by the PLESS trial15 to also have a significant effect on decreasing the occurrence of AUR as well as the ultimate need for surgical therapy for BPH. Finasteride should be given once

FIGURE 59–4. Results of total symptom score improvement in patients treated with finasteride for 5 years in the phase III study are shown by black connected squares. Placebo patient changes are shown for the first year only by closed circles. Statistically significant decreases are noted in symptom scores in patients treated with finasteride as compared to placebo and are sustained for 5 years.

Changes in Mean Baseline (ml/sec)


2.0 1.8

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< 20mL

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Prostate Size FIGURE 59–5. Meta-analysis of relationship of prostate size to changes in baseline maximum urinary flow rate in finasteride and placebo-treated patients is shown in this figure. At ≥ 40 g but not below, statistically significant increases are noted in maximum flow rates in finasteride compared to placebo-treated patients.13

daily in a 5-mg dose; no effect of food on absorption is noted.29,30 There is no modification of dosage required for age or renal insufficiency.29,30 The drug arrests the disease process by shrinking the prostate, which then remains stable at the reduced size for at least 5 years, according to the longest published follow-up information available.11 Roughly 40 to 50% of patients treated with 5 mg of finasteride show significant clinical improvement approximately 6 to 12 months following initiation of therapy.

Other patients show lesser degrees of clinical improvement, or none, although most prostates shrink in size. In the current author’s 5-year experience20 and in the PLESS data,15 symptoms of prostatism progress in only a small percentage of patients following initiation of therapy. Certain patients are unlikely to benefit from therapy. These include patients with advanced disease with symptom scores > 26, or patients who have either elevated residual urines, bladder stones, repeated gross hematuria, a history

Changes in Quasi-IPSS

3.0

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Prostate Size FIGURE 59–6. Meta-analysis of the relationship of prostate size to differences in change in International Prostate Symptom Score (IPSS) in patients treated with finasteride versus placebo. Statistically significant decreases in IPSS symptom score were noted in finasteride-treated patients at prostate volumes > 40 g but not below.13

5 α-Reductase Inhibitors / 547

Does finasteride mask prostate cancer? In a large double-blind phase III study10 as well as in the PLESS trial,15 prostate cancer was discovered as frequently in patients on finasteride as in those on placebo. If an undiagnosable early prostate cancer is present in a patient placed on finasteride therapy, however, the PSA level may indeed decrease; finasteride, an inhibitor of androgenmediated action, has been shown to cause a significant decrease in PSA, an androgen-dependent protein, in advanced prostate cancer in a small double-blind study.32 Since PSA is a good tumor marker for prostate cancer and predicts tumor mass, a small, undiagnosable early prostate cancer present at initiation of finasteride therapy would not become inoperable if the instructions outlined in the previous section on monitoring PSA are followed. Routine monitoring of hormonal steroids or gland size measurements is not required as these do not correlate with clinical response. FIGURE 59–7. Cumulative percent difference in need for surgical intervention during 4 years of either finasteride or placebo treatment during the PLESS trial is shown in this figure. Patients treated with finasteride showed a highly significant decrease > 50% in the need for prostate surgery compared to placebo-treated patients during the 4-year trial.

of repeated urinary tract infections related to obstruction, or denervation hypersensitivity of the bladder with inability to void more than 100 to 125 mL of bladder urine accompanied usually by severe urgency. These patients should be advised to undergo surgery. Patients who develop an elevated corrected PSA level of 4 ng per mL or more on finasteride (corrected PSA = PSA × 2 in patients after 1 or more years of finasteride therapy)31 should be referred to a urologist to rule out prostate cancer.

Side Effects As previously stated, no side effects associated with administration of 5 mg of finasteride were noted on any organ system, plasma lipids, electrolytes, or chemistries.10 Common complaints such as constipation, headache, or fatigue did not differ for finasteride or placebo-treated patients in over 300 patients studied in each group in a phase III double-blind trial.10 In the phase III study, however, a statistically significant increase in sexual side

Monitoring Patients should be seen at 3-month intervals for re-evaluation of symptoms during the first year of therapy; measurement of maximum urinary flow rate is optional and, if available, should be repeated at 6-month intervals. Digital rectal examination (DRE) to estimate prostate size and detect nodules as well as plasma PSA determination (blood test should be done prior to DRE) should be performed every 6 months for the first year. The same laboratory technique should be utilized for all PSA levels. No quantitative measurement of gland size is necessary. The baseline PSA level usually decreases by 40 to 50% after 1 year of finasteride treatment31 (the expected decrease as noted in a large phase III study). The frequency of PSA testing and DRE should then be extended to annual testing using the corrected PSA.31 If the corrected PSA rises to above upper normal test limits, it is advisable to refer the patient for transrectal ultrasound and biopsy to rule out prostate cancer.

FIGURE 59–8. Cumulative percent differences in occurrence of acute urinary retention during the 4-year follow-up of patients treated with finasteride or placebo shown in the PLESS study is shown in this figure. Patients treated with finasteride show the highly significant decrease in the occurrence of acute urinary retention of > 50% compared to placebo-treated patients.


effects was noted in the first year in the finasteride-treated group compared to the placebo group.10 This included decreased libido in 4.7% of the patients given finasteride compared to 1.3% of the placebo group, decreased ejaculate in 4.4% of the finasteride group compared to 1.7% of the placebo group, and impotence in 3.4% of the treated patients compared to 1.7% of the controls.10 In the PLESS trial, significant adverse events in sexual function in finasteride compared to placebo-treated patients were noted in the first year only (see Table 59–1). The decrease in ejaculate volume was anticipated as a side effect as the 5 α-reductase inhibitor blocks androgen-dependent functions, including production of seminal fluid. Duration of Therapy Initial therapy should be given to all patients for at least 6 months, the time it takes for a significant decrease in prostate size to occur. Improvement in obstructive and irritative symptoms of BPH is seen in 50% of patients with several months or more following size reduction. If therapy is effective in either improving symptoms or arresting disease, it should be continued indefinitely as the gland will regrow if therapy is discontinued. Drug Interactions Finasteride has shown no effect on drug levels or pharmacologic actions of propranolol, digoxin, theophylline, or warfarin.29 In addition, finasteride was used during large clinical trials in conjunction with a variety of commonly used drugs, including angiotensin-converting enzyme inhibitors, analgesics, HMG-CoA reductase inhibitors, nonsteroidal anti-inflammatory drugs, benzodiazepine compounds, H2-antagonists, and quinolone antibiotics, without any clinically significant adverse actions. Blood levels of these drugs, however, were not studied. Contraindications Pregnant women should not be exposed to the drug because development of external genitalia in the male fetus may be affected. Men interested in reproduction should not be given finasteride since the effects of chronic administration of the drug on fertility are unknown. Also, the drug is found in semen and theoretically could contaminate pregnant females and cause defects in the male fetus although drug levels in semen are minuscule.

Advantages and Disadvantages of Treatment Anticipated Clinical Response As previously noted, about 40 to 50% of patients in a large phase III double-blind controlled study showed unequivocal improvement in obstructive and irritative symptoms of prostatism. Based on a large phase III trial of approximately 200 patients given the 5-mg dose for 1

year and who have been followed in open extension for 4 years, stability in 50% or improvement in clinical symptoms (50%), with decreased prostate size, is maintained for most patients. For the 50 to 60% of patients who, in spite of reduction in prostate size, have only modest or no clinical improvement following therapy, the author suggests the following: if the patient has BPH with annoying but not quality-of-life-threatening symptoms, the outlook is good for stability at whatever level of prostatism exists as long as the patient continues taking the drug. If the patient is not satisfied with the result, he may elect to undergo surgery or add an alpha-adrenergic blocker such as terazosin (Hytrin) or doxazosin (Cardura) or tamsulosin to the regimen. No data are available regarding the effect of increasing the dosage of finasteride in patients unresponsive to the 5-mg dose. Comparison of Finasteride with Alpha1-Adrenergic Blockers The meta-analysis of Boyle et al. clearly showed finasteride to be clinically effective only in patients with prostates of approximately 40 or more grams.13 Recently, Roehrborn et al. demonstrated a very strong correlation between serum PSA and prostate volume and suggested that values of 2.5 ng per mL of PSA could be a proxy for

TABLE 59–1. Drug-Related Adverse Events* % of patients Adverse Event and Study Group Decreased libido Placebo Finasteride Impotence Placebo Finasteride Decreased ejaculate Volume Placebo Finasteride Ejaculation disorder Placebo Finasteride Breast enlargement Placebo Finasteride Breast tenderness Placebo Finasteride Rash Placebo Finasteride

Yr 1

Yr 2–4

3.4‡ 6.4

2.6 2.6

3.7‡ 8.1

5.1 5.1

p Value† .002

< .001

< .001 0.8‡ 3.7

0.5‡ 1.5

0.1§ 0.8

1.1 0.2

0.1|| 0.5

1.1 1.8

0.1 0.4

0.3 0.7

0.2 0.5

0.1 0.5

.002

.03

.03

.04

*Occurred in 1 % or more of men in year 1 and years 2 through 4 of the study and whose incidence differed significantly between groups. †p values are for the comparison of the overall (4-year) incidence of each event between the groups. ‡p < .001 for the comparison with the finasteride group. §p = .003 for the comparison with the finasteride group. ||p = .04 for the comparison with the finasteride group.

5 α-Reductase Inhibitors / 549 TABLE 59–2. Change in Quasi-IPSS Symptom Score Over 4 Years Finasteride Baseline Symptoms Mild (mean = 5) Moderate–low (mean = 10) Moderate–high (mean = 16) Severe (mean = 23)

Placebo

Difference

N

Mean + SD

N

Mean + SD

Mean

71 290 432 207

1.4 ± 4.4 –0.8 ± 4.5 –3.6 ± 5.7 –7.7 ± 6.8

90 227 403 163

3.4 ± 4.5 0.7 ± 5.0 –1.4 ± 5.3 –5.3 ± 7.0

–2.0* –1.5† –2.2† –2.4†

SD = standard deviation; IPSS = International Prostate Symptom Score. *p < .010. †p < .001.

enlargement to approximately 40 or more grams.28 Therefore, for patients with clinical symptoms of BPH and prostates of an estimated 40 or more grams and/or PSA levels of ≥ 2.5 ng per mL, finasteride appears to be the treatment of choice. According to Roehrborn, even patients with PSA levels > 1.3 ng per mL show significant clinical benefit from finasteride.28 Since clinical responses to finasteride may take up to 6 months, a combination of finasteride with alpha1-adrenergic blockers would be appropriate in selected patients for whom a 6-month wait for clinical results might be a concern. For patients with glands < 40 g, alpha1-adrenergic blockers would be the drug of choice. These are also effective in larger glands but there are no studies to indicate that their effectiveness is durable (5 years or longer), especially since many large prostates continue to grow. One distinct advantage of alpha1-adrenergic blockers is their clinical effectiveness within 5 to 10 days, compared to 6 months or longer for finasteride. In regard to durability of the effect, it has been shown in the literature that finasteride decreases prostate size by approximately 20% and that this reduced size is then stable for up to 5 years. Data from unpublished studies indicate that the prostate

remains unchanged in size for at least 8 years following the 20% initial reduction. The clinical effects of finasteride have also been shown to be durable for at least 5 years. In the case of alpha1-adrenergic blockers, the longest reported studies are those of Lepor et al., which have been carried out to 4 years with terazosin.14 At 4 years, only approximately 10% of the starting patients remained in the study, compared to 40% of finasteride-treated patients at 5 years (Figure 59–9). These high dropout rates for terazosin compared to finasteride suggest either more severe side effects or loss of effectiveness of terazosin. As demonstrated in the PLESS trial, particularly in the case of patients with large prostates, prostates may continue to grow and did so in placebo-treated patients at the rate of about 3 mL per year over the 4-year period.33 Thus, the increasing size of the prostate may override the benefits of alpha1-adrenergic blockers, which exert their clinical effects through smooth muscle relaxation and not a decrease in prostate size. In the PLESS trial, finasteride significantly reduced the need for surgery and the occurrence of AUR by > 50% compared to placebo. These effects signify that finasteride is a definitive therapy in and of itself for clinical BPH,

600 Proscar Hytrin

Number of Patients

500 400 300 200 100 0

0

6

12

18

24

30

36

42

48

54

60

Months FIGURE 59–9. Comparison of number of patients remaining in open extension of clinical trials of finasteride (Proscar) compared to terazosin (Hytrin) over 5 years for the treatment of BPH.


with a strong likelihood of being effective throughout the patient’s life. In the case of alpha1-adrenergic blockers, no controlled studies of drug effects on AUR and the need for surgery have been done. There are a limited number of studies on the combined use of alpha-blockers with finasteride. The VA study showed no effectiveness of finasteride but this can now be explained by the small average prostate size of patients in the study. In prostate glands of ≥ 40 g, it is likely that combined therapy would be useful in selective patients for whom speed of clinical onset of the drug's effectiveness is an important factor. Since alpha1-adrenergic blockers and finasteride work through different mechanisms, this combination should be very appropriate in such patients. The alpha1-adrenergic blockers should be discontinued after 6 months to see whether the decrease in prostate size has occurred to a point where symptoms are controlled with finasteride alone. In patients with small glands there is no role for finasteride, and alpha1adrenergic blockers should be used alone.

Comparison of Transurethral Resection of the Prostate with 5 α-Reductase Inhibitors Transurethral resection of the prostate (TURP) removes variable and usually large amounts of the periurethral adenoma and is a very effective therapy in patients with advanced stage BPH and symptom scores > 26. Finasteride actually works through a similar mechanism, that is, removal of the periurethral adenoma. Both Tempany et al.34 and Tewari et al.35 have shown that the primary effect of finasteride is on the reduction in size of the periurethral adenoma. It is estimated that three-quarters of the reduction in prostate size with finasteride occurs in the periurethral adenoma while finasteride is clinically effective in patients with large prostates and symptom scores up to 23.19 It is obvious from the limited capability of finasteride to reduce prostate size that it is inappropriate therapy in patients requiring aggressive removal of the periurethral adenoma based on the severity of their symptoms.

5.

6.

7. 8.

9. 10.

11. 12.

13.

14.

15.

16.

17.

18.

References 1. Imperato-McGinley J, Guerrero L, Gautier T, Peterson RE. Steroid 5 α-reductase deficiency in man: an inherited form of male pseudohermaphroditism. Science 1974; 186:1213–5. 2. Walsh PC, Madden JD, Harrod MJ, et al. Familial incomplete male pseudohermaphroditism, type 2: decreased dihydrotestosterone formation in pseudovaginal perineoscrotal hypospadias. N Engl J Med 1974;291:944–9. 3. Thigpen AE, Davis DL, Milatovich A, et al. Molecular genetics of steroid 5 alpha-reductase 2 deficiency. J Clin Invest 1992;90:799–809. 4. Rittmaster RS, Stoner E, Thompson DL, et al. Effect of

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22.

MK-906, a specific 5 α-reductase inhibitor, androgens, and androgen conjugates in normal men. J Androl 1989;10:259–62. Vermeulen A, Giagulli VA, Schepper PD, et al. Hormonal effects of an orally active 4-azasteroid inhibitor or 5 αreductase in humans. Prostate 1989;14:45–53. McConnell JD, Wilson JD, George FW, et al. Finasteride, an inhibitor of 5 α-reductase, suppresses prostatic dihydrotestosterone in men with benign prostatic hyplerplasia. J Clin Endocrinol Metab 1992;74:505–8. Geller J. Basis for hormonal management of advanced prostate cancer. Cancer 1993;71:1039–45. Thigpen AE, Silver RI, Guileyardo JM, et al. Tissue distribution and ontogeny of steroid 5 α-reductase isozyme expression. J Clin Invest 1993;92:903–10. McConnell JD. Benign prostatic hyperplasia. Hormonal treatment. Urol Clinic North Am 1995;22:387–400. Gormley GJ, Stoner E, Bruskewitz RC, et al., for the Finasteride Study Group. The effect of finasteride in men with benign prostatic hyperplasia. N Engl J Med 1992;327:1185–91. Moore E, Bracken B, Bremner W, et al. Proscar: five-year experience. Eur Urol 1995;28:304–9. Andersen JT, Ekman P, Wolf H, et al., and the Scandinavian BPH Study Group. Can finasteride reverse the progress of benign prostatic hyperplasia? A two-year placebocontrolled study. Urology 1995;46:631–7. Boyle P, Gould AL, Roehrborn CG. Prostate volume predicts outcome of treatment of benign prostatic hyperplasia with finasteride: meta-analysis of randomized clinical trials. Urology 1996;48:398–405. Lepor H, Williford WO, Barry MJ, et al. The efficacy of terazosin, finasteride, or both in benign prostatic hyperplasia. N Engl J Med 1996;335:533–8. McConnell JD, Bruskewitz R, Walsh P, et al. The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. N Engl J Med 1998;338:557–63. Roehrborn CG, Girman CJ, Rhodes T, et al. Correlation between prostate size estimated by digital rectal examination and measured by transrectal ultrasound. Urology 1997;49:548–57. Roehrborn CG, Boyle P, Waldstreicher J, Wang D. Urinary retention in the PLESS study population: characterization of patients and ultimate outcomes. J Urol 1998; 159:333. Andriole GL, Walsh PC, Epstein JI, et al. Treatment with finasteride preserves the usefulness of PSA in prostate cancer (CaP) detection. J Urol 1998;159:73. Kaplan S, Melman A, Fowler J, et al. Baseline symptom severity and its relationship to long-term response to finasteride. J Urol 1998;159:254. Geller J. Five-year follow-up of patients with benign prostatic hyperplasia treated with finasteride. Eur Urol 1995;27:267–73. Barry MJ, Fowler FJ Jr, O'Leary MP, et al. The American Urological Association symptom index for benign prostatic hyperplasia. J Urol 1992;148:1549–57. Birkhoff JD. Natural history of benign prostatic hypertrophy. In: Hinman F Jr, Boyarski S, editors. Benign prostatic hypertrophy. New York: Springer; 1983. p. 5.

5 α-Reductase Inhibitors / 551 23. Clarke R. The prostate and the endocrines: a control series. Br J Urol 1937;9:254–71. 24. Craigen AA, Hickling JB, Saunders CRG, Carpenter RG. Natural history of prostatic obstruction. J R Coll Gen Pract 1969;18:226–32. 25. Barnes RW, Marsh C. Progression of obstruction and symptoms. In: Hinman F Jr, Boyarski S, editors. Benign prostatic hypertrophy. New York: Springer; 1983. p. 711–3. 26. Ball AJ, Feneley RC, Abrams PH. The natural history of untreated “prostatism.” Br J Urol 1981;53:613–6. 27. Wasson JH, Reda DJ, Bruskewitz RC, et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. N Engl J Med 1995;332:75–9. 28. Roehrborn C, Boyle P, Waldstreicher J, et al. Baseline serum PSA and prostate volume predict long-term symptomatic response to finasteride: results of a fouryear placebo-controlled trial [abstract]. Presented at AUA Meeting; 1998; San Diego, CA. 29. Geller J. Benign prostatic hypertrophy. Curr Ther Endocrinol Metab 1998. [In press]

30. Peters DH, Sorkin EM. Finasteride: a review of its potential in the treatment of benign prostatic hyperplasia. Drugs 1993;46:177–208. 31. Guess HA, Gormley GJ, Stoner E, Oesterling JE. The effect of finasteride on prostate specific antigen: review of available data. J Urol 1996;155:3–9. 32. Andriole GL. 5 α-reductase inhibitors after radical prostatectomy. Prospectives 1995;5:1–8. 33. Holtgrewe L, Bruskew itz R, Glickman S, et al. Observations on the natural history of BPH in men followed in a four-year placebo-controlled trial [abstract]. Presented at AUA Meeting; 1998 May; San Diego, CA. 34. Tempany CMC, Partin AW, Zerhouni EA, et al. The influence of finasteride on the volume of the peripheral and periurethral zones of the prostate in men with benign prostatic hyperplasia. Prostate 1993;22:39–42. 35. Tewari A, Shinohara K, Narayan P. Transition zone volume and transition zone ratio: predictor of uroflow response to finasteride therapy in benign prostatic hyperplasia patients. Urology 1995;45:258–65.

CHAPTER 60

TRANSURETHRAL NEEDLE ABLATION OF THE PROSTATE FOR TREATMENT OF BENIGN PROSTATIC HYPERPLASIA CLAUDE C. SCHULMAN, MD, PHD; ALEXANDRE R. ZLOTTA, MD The efficacy and associated complications of surgical interventions for managing symptoms due to BPH, especially transurethral resection of the prostate (TURP) as the “gold standard,” have been under critical review. The advent of less invasive therapies such as pharmacotherapy or minimally invasive procedures have prompted a reassessment of the results and complications of surgical treatment for relief of prostatic obstruction. A recent meta-analysis estimates that between 5.2% and 30.7% of all patients undergoing TURP suffer from some morbidity and complications.1 The need for more simple, less morbid, and alternative surgical therapies has lead to the emergence of minimally invasive therapies. Patients are usually eager to choose a treatment which will relieve their symptoms without significant side effects. Since not all patients will subjectively experience symptomatic improvement with medical therapy and others are reluctant to take medications for a long period of time, minimally invasive therapies (among which thermotherapies play an important role) have gathered much interest over the past few years. All thermotherapies, whatever the form of energy used, aim to achieve sufficiently therapeutic temperatures (> 60°C) to produce necrosis of prostatic tissue. This is true for transurethral needle ablation of the prostate (TUNA) as well. In this procedure, low level radiofrequency (RF) energy is delivered directly into the prostate, producing reproducible and localized controlled necrotic lesions. The use of radiofrequency thermoablation in medicine is not new. It has already been used in cardiology to ablate aberrant bundles in WolffParkinson-White disease,2 to accurately destroy neoplastic tissue,3,4 and to treat chronic zygapophyseal joint pain.5 This type of energy has been evaluated for treatment of hypertrophic benign prostatic tissue because of the precision of RF delivery and the lesion created.

independent needles are deployed within the prostate; the base of these needles may be covered by a protective teflon shield. The generator produces a monopolar 490 kHz RF signal. This frequency allows greater penetration and a more uniform temperature distribution than is the case with microwaves (300 to 3000 MHz).6 The current passes through the prostatic tissue in the direction of a grounding pad placed on the sacrum of the patient. Radiofrequency produces ionic or molecular agitation and a collision of particles in accordance with the frequency of the generated wave of energy, resulting in a central, periurethral hot core. The nature of the RF signal is such that it can only be applied into the tissue through direct contact, with limited distance dissipation, which reinforces the safety of this wavelength (heat generated is directly proportional to 1/radius4). If the power is too high, it will cause rapid desiccation of the tissue, an increase in impedance, and prevent the desired effects.6 Therefore, a balance must be found between the appropriate energy level to continue to drive the lesion and an excess of energy that will cause elevation of the impedance and charring of the tissue around the needle. The dimensions of the thermal lesion will correspond to three factors: (1) the geometry of the active needles; (2) time during which the hot core is maintained; and (3) tissue impedance.6–8 The tissue effects of RF and the size of the lesions are extremely localized and very much depend on the heat loss due to convection, that is, vascularity.6 Radiofrequency is extremely vulnerable to vascular flow and has virtually no effect on vessels > 2 to 3 mm in diameter.9

Animal and Human Ex Vivo Studies Prior to human treatment, Goldwasser et al. demonstrated that 1 cm necrotic lesions could be created in the dog prostate using the TUNA system with no resultant damage to the rectum, bladder base, or distal prostatic urethra.10 Similar lesions were observed by the same authors in an ex vivo human prostate study.11

The TUNA System: Radiofrequency Energy Principles The TUNA system consists of a special TUNA catheter connected to a low-level radiofrequency generator.6 Two 552

Transurethral Needle Ablation of the Prostate for Treatment of Benign Prostatic Hyperplasia / 553

Human Pathologic and Radiologic Studies In initial studies on 25 patients aiming to assess the tolerance, safety, and the characteristics of lesions produced by TUNA, patients were treated with the procedure prior to scheduled retropubic prostatectomy.6 Three to 5 minutes of treatment per lesion were performed. Macroscopic examination of the surgical specimens recovered from 1 day to 3 months after TUNA demonstrated localized controlled necrotic lesions sharply delineated from the untreated areas.6,7 In specimens recovered within 48 hours after treatment with TUNA, hemorrhagic lesions were observed only, with slightly discolored tissue surrounding the active needle path. Necrotic lesions were maximal at 7 days post-TUNA.7 Fifteen days after TUNA, fibrosis was already observed in the recovered surgical specimens.6 Maximal lesion size ranged from 10 × 7 to 20 × 10 mm.2 Specific immunohistochemical staining showed destruction of all tissue components. Absence of staining for PSA, smooth muscle actin, neural tissue, alpha-adrenergic and nitrinergic receptors was evident in the ablated area.6,7,12 Analyzing histologic sections from 10 open prostatectomy specimens recovered 1 to 46 days after TUNA, in contrast with the glandular and muscle cells no positively stained nerve cells (using S100 antibodies) were noted in the treated areas, even in specimens recovered 24 hours after the ablation.7 Issa et al. have shown that the nitric oxide synthase (NOS) receptors seemed to be the most vulnerable to thermal damage whereas thermal damage to alpha-adrenergic receptors was more pronounced 1 to 2 weeks later.12 The extent of the lesions depends on: (1) the length of the deployed needles; (2) the wattage used; (3) the duration of the treatment; (4) the duration of the hold time (the time needed to maintain the target temperature); and (5) the temperature recorded at the shield. Indeed, when temperatures at the shield (thus the lowest temperatures of the lesion) were below 47°C, the size of the lesions was dramatically reduced.7 Temperatures Achieved at the Core of the Lesion and its Periphery Using an infrared temperature monitor in an ex vivo animal model, and therefore without blood flow (which is of utmost importance), Rasor et al. showed that the central core of the lesion around the tip of the needle reached 90 to 100°C.13 In a thermal mapping study using a specially designed catheter outfitted with additional thermosensors for temperature monitoring in men treated with TUNA prior to retropubic prostatectomy, temperatures of 50°C observed at the shield corresponded to core temperatures of 85 to 100°C.7

TUNA Catheter The TUNA catheter design has evolved over the past few years. The basic principles, however, remain the same. The TUNA catheter is a specially designed cystoscopic instrument, plastic moulded, and connected to the RF generator (Figure 60–1). Two needles which diverge at a 40 degree angle emerge perpendicular to the bulletshaped catheter tip (Figure 60–2). The specificities of this catheter and needle are the two protective Teflon shields that can be deployed independently to cover a certain amount of needle, thus protecting this area from thermal ablation. The flexible needles and covering shields can be advanced and retracted by moving calibrated controls on the catheter handle. Thermosensors at the end of the shield and on the tip of the catheter monitor prostatic and urethral temperatures during TUNA. An optical path within the catheter allows the introduction of a fiber optic viewing system to precisely position the catheter within the prostate under guidance similar to that used in simple cystoscopic procedure. There has been constant evolution in the design of the TUNA catheters. The most current version is the ProVu system (Figure 60–1). In contrast to previous versions, part of the device is reusable. Also, the optics have dramatically improved with the use of standard fiberoptics. Further, the needles are visible when they enter the prostatic tissue, which was not the case previously (Figure 60–3). Indeed, using the former TUNA catheters, needles were introduced somewhat blindly as the emergence of the needles at a 90 degree angle with the catheter itself could not be controlled. The procedure was performed introducing the needle blindly, the operator judging placement of the needles with respect to visualization of the catheter tip. In contrast to the previous catheters, where the catheter tip had to be rotated for the needles to point out toward the right and left lobes, the whole ProVu catheter is rotated as with any cystoscopic device as opposed to rotating the shaft only, as in the older versions. Finally, the angle between the catheter and the needles is no longer fixed. Needles can be deployed under visual control in front of the catheter and can therefore be used to treat a bladder neck hypertrophy or median lobes. The inability to treat these particular zones of the prostate with the older TUNA catheters contraindicated prostates with such characteristics.

Preservation of the Prostatic Urethra The preservation of the prostatic urethra is a major feature of the TUNA treatment. Indeed, destruction of the urethral mucosa can cause significant postoperative voiding symptoms and increase the retention rate following thermal treatments. Further, urethral preservation may omit the need for spinal or general anesthesia because the painsensitive region of the prostatic urothelium is preserved.


up to 6 mm beyond the deployed needle, measurements of the transverse diameter of the prostate (in the base, midprostate, and apex) are mandatory to avoid undesired necrosis.

TUNA Treatment A

B FIGURE 60–1. A, ProVu catheter and B, generator.

Clear differences in nerve ending distribution within the prostate are usually observed with the TUNA procedure.7 There is a higher density of innervation in the connective stromal parts of the prostate, just under the prostatic urethral mucosa, under the capsule, and around the prostatic hypertrophic nodules. There are a limited number of nerve endings seen in the glandular areas of the prostate. Overall, the nerve density of the adenomatous gland is clearly decreased. Since very few nerve endings are present in the deepest part of the transition zone, rapid destruction of the submucosal nerve endings with preservation of those located 2 to 3 mm beneath the urothelium may account for the absence of significant discomfort experienced by patients during the TUNA treatment.

Transurethral needle ablation of the prostate treatment is performed similarly to cystoscopy, with 2% intraurethral local xylocaine anesthesia (Figures 60–3 to 60–7).14–18 The current authors often use a penile clamp for 10 minutes. Local anesthesia can be supplemented with intravenous sedation when necessary. Patients also receive intravenous antibiotics prior to the procedure. There is no general or spinal anesthesia required for TUNA treatment and it can be performed as an outpatient procedure. In some cases, physicians may choose to use a prostatic bloc, either transperineal or, as in the authors' clinics, transrectal, using a lidocaine-Marcaine mixture. Patients are arousable and conversant during the procedure. The TUNA catheter is advanced and positioned in the prostate using direct fiberoptic vision (see Figure 60–2). The length of the needle deployed within the prostate is calculated based on measurement of the prostate by ultrasound. Indeed, pathologic studies have demonstrated that the thermal injury may occur up to 5 to 6 mm beyond the deployed needle, transverse with lesions up to 20 × 10 mm2.7 Therefore the needle should not be deployed more than 6 mm less than half the diameter of the prostate. At the same time, shields are deployed 5 to 6 mm inside the prostate, thus protecting the prostatic urothelium. Urothelium protection is one of the major characteristics of the TUNA procedure (see Figure 60–5). When both needles are adequately positioned in the prostate, RF energy between 2 to 15 watts is delivered for 5 minutes per lesion. The number of lesions depends on the size of the prostate. One pair of lesions (because there are 2 needles) is usually performed per 20 g of prostate. The current authors previously began with low power, to avoid quickly

Preoperative Evaluation Transrectal ultrasound as well as cystoscopy are helpful prior to TUNA therapy. Cystoscopy may point out situations where TUNA is not the best option (e.g., large median lobes or bladder neck contractures). Transrectal ultrasound, in addition to its role in diagnosis and evaluation of benign prostatic hyperplasia (BPH), is used to plan the needle deployment. Indeed, as anatomicopathologic studies have demonstrated that lesions may extend

FIGURE 60–2. Tip of TUNA catheter with adjustable shields (arrows).


A

B

FIGURE 60–3. Endoscopic view of needle placement with the new ProVu catheter; needles are now visible at endoscopy. Note that no part of the needle is uncovered. Treatment close to bladder neck (A) and in the midportion of the prostate (B).

desiccating the tissue around the needles. This led to needle charring and would hamper the propagation of RF energy. The energy, therefore, must be delivered continuously and slowly to achieve a minimum temperature of 50°C at the thermocouple on the shield after 4 minutes of treatment. The temperature at the end of the active needle tip is much higher with as much as a 40°C higher temperature than that achieved at the shield. This has been clearly demonstrated by several studies using infrared thermalmapping and a specially designed catheter.7 Temperatures at the tip of the needle may vary from 80 to 100°C. The generator has a cutoff safety feature that is activated when the urethral temperature is > 46°C, thus protecting the urothelium from thermal injury. Several drops of irrigation are often all that is necessary to cool the urethra. Previously, power had to be manually adjusted based on the temperatures achieved and impedance recorded. Currently, a new type of generator automatically adapts

FIGURE 60–4. TUNA procedure (1): advancement of TUNA catheter into prostatic urethra.

the power delivered into the prostate for each needle to achieve the best ablation possible, thereby reaching a minimum temperature of 50°C at the shield (nearly 100°C in the core of the lesion) and maintaining it for at least 1.5 to 2 minutes. This ensures the lesions are as large as possible. Heating is often unequal for each needle as the tissue impedance may differ around each of the active needles, depending on the histologic characteristics of the surrounding prostate tissue. Bladder emptying is sometimes necessary once several lesions have been created due to the use of irrigation. The bladder should be emptied periodically, depending on how much irrigant has been introduced, to prevent overdistension.

FIGURE 60–5. TUNA procedure (2): TUNA catheter is positioned 1 cm under the bladder neck for treating the first lesion. The shaft of the catheter is rotated toward the lateral lobe and needles are deployed. The extent of the lesion is indicated and corresponds to the combination of the lesions produced by each needle separately.


To date, several thousand patients have been treated in clinical trials. Early published results in 20 patients with a 6 month follow-up showed TUNA to be a promising, anesthesia-free alternative treatment that shows clear improvement in peak urine flow and improved International Prostate Symptom Score (IPSS) and quality of life after six months.19 The initial United States clinical trial on 12 patients20 confirmed a 70% improvement in both peak flow rates and quality of life, with maximum detrusor pressures and detrusor opening pressures decreasing significantly. Since these early results, several groups have reported long-term follow-up of 2 to 3 years (Table 60–1).21–24 Twelve month results from a prospective multicenter American study including 130 patients demonstrated that the American Urological Association (AUA) symptom score decreased from 23.7 to 11.9 points following TUNA whereas the peak flow rate improved from 8.7 mL per second at baseline to 14.6 mL per second at 1 year.25 The majority of patients showed improvements in both AUA symptom index (SI) and flow rate. For instance, approximately 50% of patients at 6 and 12 months experienced an

improvement of ≥ 4 mL per second, 30% experienced improvements of ≥ 6 mL per second, and 20% > 8 mL per second (see Table 60–1). The prospective multicenter collaborative study of 76 patients from 7 different centers in Europe and Israel demonstrated that TUNA produced significant improvements in IPSS, urinary flow rate, and quality of life at 1-year follow-up.26 The TUNA procedure was compared with TURP for treatment of BPH in a large-scale prospective randomized American study.27 Fifty-six men were treated with TURP and 65 with TUNA. In this trial, TUNA was equal to TURP in terms of AUA symptom score and quality of life. In terms of adverse events, TUNA was far superior to TURP. In terms of peak urinary flow rate and postvoid residual volume, TURP was superior to TUNA, with peak urinary flow rates at 12 months of 20.8 mL in the TURP group versus 15.0 mL in the TUNA group (both groups had 8.8 mL per second mean pretreatment uroflow values). Similar results were shown in a nonrandomized prospective study in Italy comparing TUNA with TURP.28 Most series confirm that 70 to 80% of patients are objectively and subjectively improved following TUNA (see Table 60–1). Mid- and long-term follow-up data are now available. Steele and Sleep showed in 47 patients studied prospectively that TUNA produced sustained subjective and objective improvements (assessment included 2-year follow-up with pressure flow studies).21 With an 18-month follow-up, Campo et al. reported similar findings.22 At 3 year's follow-up, the improvement in flow was similar to that reported after 1 year.23,24 Patient selection for TUNA is important as this procedure appears to be very effective in patients with mild to moderate obstruction23 and less satisfactory for patients with more severe obstruction.29 Several reports have shown from pressure-flow studies that maximum detrusor

FIGURE 60–6. Endoscopic view immediately after TUNA. Note the hyperemic lesions corresponding to the treatment (arrows).

FIGURE 60–7. TUNA procedure (3): four lesions have been completed.

The TUNA procedure is perfectly well tolerated with the use of local anesthetic, supplemented if necessary with intravenous sedation. Patients rarely complain of pain due to heat but often note urgency or a desire to void. This usually occurs when the first lesion is created close to the bladder neck. For lesions performed into the midportions of the transition zone of the prostate, patients rarely note discomfort. After the procedure, hyperemic areas where needles were introduced are often visible endoscopically (see Figure 60–6). No catheter is left in patients following the procedure. Once they have voided, patients are allowed to return home, with several days' worth of anti-inflammatory agents and antibiotics.

Clinical Results

Transurethral Needle Ablation of the Prostate for Treatment of Benign Prostatic Hyperplasia / 557 TABLE 60–1. Recent TUNA Clinical Results Symptom Score Study Group

Peak Flow Rate (mL/sec)

No. Patients/No. Starting

Follow-up (Months)

Baseline

Post-TUNA

Baseline

Post-TUNA

12 65 93/130

6 12 12

25.6 24.7 23.7

9.8 11.1 11.9

7.8 8.7 8.7

13.5 15 14.6

41/60 38/60 72/120 42/120 36/48 17/48 58/71 60/76 50 71 36

12 24 12 18 12 36 12 12 12 36 12

22.4 22.4 20.8 20.8 21.6 21.6 23.0 22.0 22.4 22.3 16.7

7.0 9.5 6.2 6.7 7.8 7.6 10.6 7.5 9.1 7.4 5.1

6.6 6.6 8.2 8.2 9.9 9.9 9.0 8.7 7.6 7.0 12.9

10.2 11.0 15.9 14.1 16.8 16.2 11.3 11.6 16.8 14.2 16.1

Issa20 (U.S. Pilot Study) Bruskewitz et al.27 (U.S. Randomized Study) Roehrborn et al.25 (US Prospective Multicenter Study) Steele and Sleep21 Campo et al.22 Schulman and Zlotta23 Rosario et al.29 Ramon et al.26 (European Multicenter Study) Giannakopoulos et al.35 Virdi et al.24 Bergamaschi et al.28 (Nonrandomized Prospective Study TUNA vs TURP)

TUNA = transurethral needle ablation of the prostate; TURP = transurethral resection of the prostate.

pressure and detrusor opening pressures decrease significantly after TUNA (Table 60–2). The number of patients with complete relief of obstruction after TUNA by urodynamic criteria may vary but seems to average 50%.22,28,29

TUNA Treatment for Patients in Retention Several studies have demonstrated that TUNA is highly effective in relieving patients in urinary retention due to BPH and that it seems particularly suitable for treating patients with greater risk during surgery.30 Analyzing 38 poor-risk patients in urinary retention who were treated with TUNA, nearly 80% of these patients resumed voiding within a mean of 8.7 days after the procedure. Complications were minimal and none of the patients developed any

Issa20 (U.S. Pilot Study) Steele and Sleep21

Campo et al.22

Rosario et al.29 Millard et al.31

Mean Detrusor Pressure No. Follow-up (cm H2O)/Maximum Flow Rate Patients (Months) Baseline Post-TUNA 9 (9)* 41/60 39/60 34/60 29/60 12/60 108/120 86/120 72/120 42/120 70/71 45/71 11/20

6 (6)* 1 3 6 12 24 3 6 12 18 3 12 6

TUNA = transurethral needle ablation of the prostate. *Indicated detrusor opening pressure.

Treatment for Patients with Nonbacterial Prostatitis In a very limited number of patients and with very short follow-up, Chiang et al. suggested that TUNA could be used to improve symptoms in patients with nonbacterial prostatitis.33 Additional studies on this topic are warranted.

Adverse Events

TABLE 60–2. Urodynamic Studies

Study Group

further retention during follow-up. Since the publication of this report, more than 80 patients in retention and severe comorbidity have been treated and showed the same voiding recovery rate [Zlotta AR, unpublished observation]. Similarly, Millard et al. reported a success rate of 75% (17 of 20).31,32 The TUNA procedure therefore seems to be particularly suitable for treating patients who are at greater risk during surgery, especially when in urinary retention.

91.8 (74.5)* 92.4 92.4 92.4 92.4 92.4 85.3 85.3 85.3 85.3 97.0 97.0 70.7

70.9 (56.3)* 77.0 68.5 54.8 72.9 58.9 53.2 61.3 63.7 67.8 79.0 82.0 59.9

Reports of morbidity following TUNA usually include the following: 1. Urinary retention is observed in 13.3 to 41.6% of cases.8,15,18,27 This retention is transient (1 to 3 days) in most patients but will last longer than 1 week on rare occasions. It is usually easily treated by suprapubic tube or by urethral catheterization for several days. 2. Hematuria is noted in most patients for 2 days but never requires transfusion. Patients with significant coagulopathy may experience more pronounced hematuria and should be counseled preoperatively. Rosario et al. reported no problem with bleeding in patients on warfarin at the time of the TUNA, however.29 3. Irritative voiding symptoms, dysuria, and increased urinary frequency may develop during the first few days after treatment and are usually treated with antiinflammatory agents.

558 / Advanced Therapy of Prostate Disease TABLE 60–3a. Cost Estimate: Transurethral Resection of the Prostate Hospital Urologist Anesthesia Total

$4127* $1034† $606† $5767

*Average charge on 3074 TURPs. †RBVS fee schedule in Maryland— 1995.

TABLE 60–3b. Cost Estimate: Transurethral Needle Ablation of the Prostate*

FIGURE 60–8. Endoscopic view 3 months after TUNA. Note the retraction of the lateral lobes at the bladder neck (arrows).

4. Urinary infection and epididymitis are very rare. 5. Sexual dysfunction is minimal. Whereas most series found no retrograde ejaculation or impotence at all after TUNA, the prospective multicenter United States trial found retrograde ejaculation and impotence of less than 1 and 2%, respectively.25 6. Urethral strictures have been described in < 1% of cases.19,21,22,25,27 7. No urinary incontinence has ever been reported following TUNA.

Reoperation Rate Reoperation rates are low as reported up to now. The current authors report that 14% of patients treated by TUNA in their series have subsequently required surgery due to absence of clinical improvement during 2 years of followup. Steele and Sleep noted a 12.7% reoperation rate in 47 patients followed for 2 years.21 In the multicenter collaborative study in Europe and Israel, there were 9 failures out of 76 patients as assessed by the absence of improvement in Qmax, eight of whom reported no symptomatic improvement but only five of whom reported no improvement in quality of life.26

Disposables: catheter other Facility Personnel Amortization Physician Total *Cost estimate of 50 consecutive cases.

reported his limited experience with prostates as big as 140 g. Successful treatment could be achieved provided that treatment was performed at 1 cm intervals in each lateral lobe (up to seven treatments per lobe in some cases). For median lobes, treatments have been successfully performed by either manipulating the TUNA catheter so that the needles point out inferiorly (taking care to measure the height of the tissue to be treated), entering the midportion of the median lobe, or using the new ProVu catheter. In some cases,14 the median lobe has shrunk significantly [unpublished observation]. Patients should be counseled about the possible risk of retrograde ejaculation if the bladder neck is treated during the TUNA procedure.

Possible Mechanisms of Action on BPH Symptoms Severe thermal damage to the intraprostatic nerve fibers in areas treated by TUNA has been demonstrated by ana-

TABLE 60–4. Quintiles Medical Technology Consultance (United Kingdom) Cost Analysis

Indications and Limits Patients with prostate glands >100 g or with a large median lobe or isolated bladder neck hypertrophy are not the best candidates for TUNA treatment. The new version of the TUNA catheter (ProVu) is currently under investigation for treatment of bladder neck or median lobes. As noted by Naslund, the ideal patient for the TUNA procedure is a man with obstructive BPH who has a prostate gland of ≤ 60 g with predominantly lateral lobe enlargement.14 For large glands, the same author

$795 $185 $635 $100 $163 $1500 $3378

Preoperative tests Anesthetic consumables Theater consumables Personnel costs OR charges Ward/recovery costs Cost of complications Total costs

TUNA

TURP (3 Days)

TURP (4 Days)

TURP (5 Days)

£ 155.48 £ 4.48 £ 444.64 £ 33.99 £ 93.33 £ 100.00 £– £ 831.92

£ 175.48 £ 52.02 £ 89.69 £ 88.29 £ 241.67 £ 561.00 £ 12.00 £ 1220.15

£ 175.48 £ 52.02 £ 89.69 £ 88.29 £ 241.67 £ 748.00 £ 12.00 £ 1407.15

£ 175.45 £ 52.02 £ 89.69 £ 88.29 £ 241.67 £ 935.00 £ 12.00 £ 1594.15

TUNA = transurethral needle ablation of the prostate; TURP = transurethral resection of the prostate.


lyzing histologic sections from 10 open prostatectomy specimens recovered after TUNA.7,12 The NOS receptors seemed to be the most vulnerable to thermal damage, as evidenced by the complete lack of immunohistochemical staining within the initial hours after TUNA. The clinical effects of TUNA can possibly be explained by an impairment of the alpha-receptor fraction and/or sensory nerves. Further, the distribution of the intraprostatic nerves may explain the excellent tolerance of this procedure under local anesthesia only. Tissue ablation from necrosis probably accounts for some of the clinical improvements observed after TUNA as well (Figure 60–9). Several groups have demonstrated the absence of a significant decrease in prostate size after TUNA.6,15,18–20,27 Little evidence of prostatic cavitation on TRUS after TUNA has been observed (Figure 60–10). Follow-up cystoscopy after TUNA shows scarring, prostatic defects, or lateral lobe retraction in fewer than half the patients (Figure 60–8). In many cases, no specific prostate defects are noted.14 The combination of the destruction of intraprostatic nerves with a moderate decrease in the transition zone volume of the prostate may partially explain the observed clinical efficacy of TUNA.

Cost Comparisons of cost estimates of TUNA versus TURP have been addressed in studies from the United States and the United Kingdom. In a study by Naslund and Stitcher (Table 60–3a and 60–3b), the cost estimate for TUNA reached $3378 while in Maryland in 1995 TURP averaged $5767.34 Most of the costs associated with TURP were related to the hospital stay; the disposable catheter was responsible for a major part of the TUNA costs. Hospital charges may sometimes be difficult to obtain and analyze, however. Without referring to long-term complications, TUNA appears to be less costly than TURP. In a published economic evaluation of TUNA versus TURP and drug therapy by Quintiles Medical Technology Consultance in the United Kingdom (Table 60–4) that analyzed reimbursement and price from a purchaser perspective, total management costs for patients reached £970.38 for TUNA versus £1372 for TURP. Much of the cost differential could be explained by the difference in length of hospital stay. Indeed, from a provider perspective, if a 3-day stay for TURP costs £1220 it may reach up to £1594 for 5 days for TURP. Again, most of the costs associated with TUNA came from the disposable catheter while most of the costs associated with TURP came from the hospitalization stay. Another study performed in the United Kingdom compared the costs of various drug therapies, including prazosin, terazosin, alfuzosin, tamsulosin, and finasteride. For the TUNA procedure, the study provided a direct comparison to TURP, assuming that both treatment modalities are equally effective but ignoring drug treatment failure and reoperation rates. With an annual average cost of TUNA at

FIGURE 60–9. TUNA lesion on microscopic examination (arrows). Note the clear delineation with untreated prostate (hematoxylin and eosin stain, original magnification ×100).

£800 most medical treatments after 2 years reached a cost higher than the price for TUNA. Again, it should be noted that no reoperation rates were taken into account and that long-term effectiveness of the treatment was not evaluated. In conclusion, it appears that TUNA is currently more cost effective than TURP and drugs. Long-term results, especially with respect to reoperation rates are required to be able to draw definitive conclusions on the final cost estimates of TUNA.

Current Place of TUNA in Benign Prostatic Hyperplasia Therapy The TUNA procedure has been approved by the FDA for use in the United States. The treatment may fill the gap between medical therapies and surgical therapies for BPH. As with all other minimally invasive therapies, it is important to take into account not just end results but the advantages of such therapies, despite the fact that the

FIGURE 60–10. Transrectal ultrasonography after TUNA (2 weeks). Note the hypoechoic lesion (white arrow).


degree of efficacy of TURP is not achieved. There is definitively a place and a need for such therapies as not all patients need or want an operation. Since this procedure can be performed in the typical office setting and adverse events from it are negligable, it perhaps does not need to be equivalent to TURP to find an important role as secondary therapy for medical failures or as primary therapy for symptomatic BPH.

Conclusion The TUNA procedure appears to be a very attractive treatment option for men with obstructive BPH. It seems to be a patient- and operator-friendly therapy since it is an outpatient procedure, does not require anesthesia, and provides a clear symptomatic and objective improvement of BPH symptom in most cases. Also, TUNA is much less morbid than TURP and is performed at a lower cost. Finally, for elderly patients with a high surgical risk, TUNA could become a treatment of choice for BPH symptoms. Long-term (5 year) follow-up is still required, however, to definitively establish this therapy as an effective treatment for BPH.

References 1. McConnel JD, Barry MJ, Bruskewitz RC, et al. Benign prostatic hyperplasia: diagnosis and treatment. Clinical practice guidelines, number 8. Rockville (MD): Agency for Health Care Policy and Research, Public Health Service, U.S. Department of Health and Human Services; 1994 Feb. AHCPR publication No: 94-0583. 2. Calkins H, Langberg J, Sousa J, et al. Radiofrequency catheter ablation of accessory atrioventricular connections in 250 patients. Circulation 1992;85:1337–46. 3. Rossi S, Di Stasi M, Buscarini, E et al. Percutaneous radiofrequency interstitial thermal ablation in the treatment of small hepatocellular carcinoma. Cancer J Sci Am 1995;1:73–81. 4. Zlotta AR, Kiss R, De Decker R, Schulman CC. MXT mammary tumor treatment with a high temperature radiofrequency ablation device. Int J Oncol 1995;7: 863–9. 5. Lord SM, Barnsley L, Wahis BJ, et al. Percutaneous radiofrequency neurotomy for chronic cervical zygapophyseal-joint pain. N Engl J Med 1996;336:1721–6. 6. Schulman CC, Zlotta AR, Rasor JS, et al. Transurethral needle ablation (TUNA): safety, feasibility, and tolerance of a new office procedure for treatment of benign prostatic hyperplasia. Eur Urol 1993;24:415. 7. Zlotta AR, Raviv G, Peny MO, et al. Possible mechanisms of action of transurethral needle ablation of the prostate on benign prostatic hyperplasia symptoms: a neurohistochemical study. J Urol 1997;157:894–9. 8. Schulman CC, Zlotta AR. Transurethral needle ablation of the prostate (TUNA): pathological, radiological and clinical study of a new office procedure for treatment of benign prostatic hyperplasia using low-level radiofrequency energy. Semin Urol 1994;13:205.

9. Organ LW. Electrophysiologic principles of radiofrequency lesion making. Appl Neurophysiol 1976;39:69–76. 10. Goldwasser B, Ramon J, Engelberg S, et al. Transurethral needle ablation (TUNA) of the prostate using low-level radiofrequency energy: an animal experimental study. Eur Urol 1993;24:400. 11. Ramon J, Goldwasser B, Stenfeld B, et al. Needle ablation using radiofrequency current as a treatment for benign prostatic hyperplasia: experimental results in ex vivo human prostate. Eur Urol 1993;24:406–10. 12. Issa MM, Wojno KJ, Oesterling JE, et al. Histopathologic and biochemical study of the prostate following transurethral needle ablation (TUNA): insight into the mechanism of improvement in BPH symptoms. J Endourol 1996;10:109. 13. Rasor JS, Zlotta AR, Edwards SD, Schulman CC. Transurethral needle ablation (TUNA): thermal gradient mapping and comparison of lesion size in a tissue model and in patients with benign prostatic hyperplasia. Eur Urol 1993;24:411. 14. Naslund MJ. Transurethral needle ablation of the prostate. Urology 1997;50(2):167–72. 15. Schulman CC, Zlotta AR. Transurethral needle ablation of the prostate: a new treatment of benign prostatic hyperplasia using interstitial low-level radiofrequency energy. Curr Opin Urol 1995;5:35. 16. Heaton JPW. Radiofrequency thermal ablation of the prostate: the TUNA technique. Techniques Urol 1995;1:3. 17. Dixon CM. Transurethral needle ablation for the treatment of benign prostatic hyperplasia. Urol Clin North Am 1995;22:441. 18. Issa MM, Oesterling JE. Transurethral needle ablation (TUNA): an overview of radiofrequency thermal therapy for the treatment of benign prostatic hyperplasia. Curr Opin Urol 1996;6:20–7. 19. Schulman CC, Zlotta AR. Transurethral needle ablation of the prostate for treatment of benign prostatic hyperplasia: early clinical experience. Urology 1995;45:8. 20. Issa MM. Transurethral needle ablation of the prostate: report of initial United States clinical trial. J Urol 1996; 156:413–9. 21. Steele GS, Sleep DJ. Transurethral needle ablation of the prostate: a urodynamic based study with 2-year followup. J Urol 1997;158:1834–8. 22. Campo B, Bergamaschi F, Corrada P, Ordesi G. Transurethral needle ablation (TUNA) of the prostate: a clinical and urodynamic evaluation. Urology 1997;49:847–50. 23. Schulman CC, Zlotta AR. Transurethral needle ablation of the prostate (TUNA) of the prostate: clinical experience with three years follow-up in patients with benign prostatic hyperplasia (BPH). Eur Urol 1993;33 Suppl 1:A586. 24. Virdi J, Pandit A, Sriram R. Transurethral needle ablation of the prostate (TUNA). A prospective study, threeyear follow-up. Eur Urol 1998;33 Suppl:A9. 25. Roehrborn CG, Issa MM, Bruskewitz RC, et al. Transurethral needle ablation for benign prostatic hyperplasia: 12-month results of a prospective, multicenter U.S. study. Urology 1998;51:415–21.

Transurethral Needle Ablation of the Prostate for Treatment of Benign Prostatic Hyperplasia / 561 26. Ramon J, Lynch TH, Eardley I, et al. Transurethral needle ablation of the prostate for the treatment of benign prostatic hyperplasia: a collaborative multicenter study. Br J Urol 1997;80:128–35. 27. Bruskewitz R, Issa MM, Roehrborn CG, et al. A prospective, randomized 1-year clinical trial comparing transurethral needle ablation to transurethral resection of the prostate for the treatment of symptomatic benign prostatic hyperplasia. J Urol 1998;159:1588–94. 28. Bergamaschi F, Campo B, Ordesi G, Torelli T. Prospective not-randomized study of TUNA versus TURP for patients with BPH demonstrating moderately high detrusor pressures and elevated symptom score. Eur Urol 1996;30 Suppl:A984. 29. Rosario DJ, Woo H, Potts KL, et al. Safety and efficacy of transurethral needle ablation of the prostate for symptomatic outlet obstruction. Br J Urol 1997;80:579–86. 30. Zlotta AR, Peny M-O, Matos C, Schulman CC. Transurethral needle ablation of the prostate: clinical experience in patients in urinary retention. Br J Urol 1996;77:391.

31. Millard RJ, Harewood LM, Tamaddou K. A study of the efficacy and safety of transurethral needle ablation (TUNA) for benign prostatic hyperplasia. Neurol Urodyn 1996;15:916–29. 32. Harewood L, Cleeve LK, O’Connel HE, et al. Transurethral needle ablation of the prostate (TUNA): clinical results and ultrasound, endoscopic, and histologic findings in pilot study of patients in urinary retention. J Endourol 1995;9:407–12. 33. Chiang PH, Tsai EM, Chiang CP. Pilot study of transurethral needle ablation (TUNA) in treatment of nonbacterial prostatitis. J Endourol 1997;11(5):367–70. 34. Naslund MJ, Stitcher MF. A cost comparison of TUNA versus TURP. J Urol 1997;157:A610. 35. Giannakopoulos X, Grammeniatis E, Gartzios A, Pappas G. Transurethral needle ablation (TUNA) of the prostate: preliminary results using the new generation TUNA III catheter on patients with symptomatic BPH controlled by a series of 50 patients using the TUNA II device. Eur Urol 1996;30 Suppl:A986.

CHAPTER 61

OPTIONS FOR TREATMENT: CONTACT EDWARD J. MUELLER, MD Since the electrocautery transurethral resection of the prostate (TURP) was popularized by Dr. Nesbit in 1943,1 TURP has been considered the “gold standard” treatment for bladder outlet obstructive symptoms secondary to benign prostatic hyperplasia (BPH). Recently, a wide variety of medical and less invasive surgical procedures have surfaced as alternative therapies for BPH. One of these new alternative therapies is contact laser vaporization of the prostate using the Surgical Laser Technologies neodymium: yttrium-aluminum-garnet (Nd:YAG) laser (SLT; Montgomeryville [PA]). This laser actually vaporizes the prostatic adenoma at the time of surgery, producing a surgical defect in the prostate similar to that produced by standard electrocautery TURP. The prostatic defect is produced with minimal bleeding, short catheter and hospitalization time, and rapid return to full, unrestricted, and normal activity. This significantly reduces the morbidity associated with BPH therapy while still producing excellent relief of the bladder outlet obstructive symptoms. Since no tissue is obtained while performing contact laser vaporization of the prostate, it is imperative to insure that there is no evidence of adenocarcinoma of the prostate prior to the procedure. Therefore, any patient with an elevated serum prostate-specific antigen or suspicious digital rectal examination of the prostate should undergo a transrectal ultrasound and prostate biopsy prior to the procedure. If the biopsy is negative, then contact laser vaporization of the prostate can be scheduled and performed. It is also helpful to perform preoperative cystoscopy to rule out other causes of the patient's bladder outlet obstructive symptoms and to define the lobar anatomy of the prostate prior to surgery. This helps in planning the operative procedure.

shell. Since that atom is unstable in this excited state, the electron will return, almost immediately, to its resting lowest energy state. When this occurs, a small bundle of energy, called a photon, is spontaneously released or emitted. If the photon is close to another atom still in the excited state, the photon will trigger the excited second atom to return to its resting state. The process of stimulated emission thus occurs and laser energy is formed. These two photons of identical energy and frequency will then travel together in perfect harmony. The process continues until there are more atoms in the excited state than in the resting state. This is called a population inversion of the lasing medium, allowing laser energy to be discharged. Laser light has three main characteristics: it is monochromatic, collimated, and coherent. Laser light is composed of photons that are all the same wavelength; it is thus monochromatic. Its collimated characteristic refers to the fact that the waves are parallel to each other and do not diverge significantly as they travel outward. This property of laser light is extremely important because it minimizes loss of power. When the collimated laser energy passes through a lens, the beam can be focused into a tiny spot that concentrates the energy to allow for excellent precision. Finally, laser light is coherent in that the waves travel in phase and in the same direction. This is extremely important in generating laser power.2,3 The degree of thermal damage to tissue from laser light depends on the temperature to which the laser energy heats the tissue. There is a warming of the tissues from 0 to 60°C. From 60 to 100°C, a process called coagulation occurs. This refers to protein denaturation and structural alteration of the blood, resulting in a change in consistency and slowing or stoppage of flow. Tissue dehydration and shrinkage then follow. Above 100°C, vaporization of tissue occurs, the conversion of liquid or solid components of tissue to vapor. The vaporized tissue is immediately removed.4 The Nd:YAG laser is the most frequently used laser in urologic surgery. The active medium consists of neodymium atoms contained within an yttrium-aluminumgarnet lattice. The Nd:YAG laser emits invisible infrared 1064 nm wavelength light. The laser energy is transmitted down a 600 micron semirigid endoscopic fiber (SREF), which is a fiberoptic fiber that delivers the laser energy to the end of the fiber, where the contact tip is screwed. These tips are reusable, fused-silica glass probes with a special

Contact Laser Physiology The acronym LASER stands for Light Amplification by Stimulated Emission of Radiation. In this process, light energy is converted into thermal energy. Light is released as a photon that travels in waves. Laser light differs from ordinary light in that it is organized light of all the same wavelength. Laser energy is generated when a negatively charged electron resting in its ground state is excited by an outside source of energy and jumps to a higher, less stable orbital 562

Options for Treatment: Contact / 563

wavelength conversion effect surface treatment that gives the appearance of a black coating on the tip of the probe. The wavelength conversion effect-treated tips function by absorbing a predetermined amount of laser energy at the tissue-tip interface. This raises the temperature at the tissue-tip interface proportional to the amount of absorbing treatment. The temperature at the tissue-tip interface is thereby raised above 100°C and can effectively vaporize and ablate the tissue. These surface-treated tips, unlike their untreated counterparts, exert an effect that is relatively independent of the tip's orientation with respect to the tissue. The tip, however, must be in contact with the tissue to have an effect.

Surgical Technique The first decision that must be made is which cystoscope to use. The Wolf continuous flow scope (Figure 61–1) has offset optics and a straight working channel that facilitates movement of the laser fiber. The SREF-15 laser fiber (Figure 61–2) is so thin and flexible (2.9 mm outside diameter), however, that almost any appropriate cystoscope and bridge can be used during the procedure. One such instrument that works extremely well is a standard 22F cystoscope and bridge with the single working channel coming straight back and angled downward approximately 15 degrees (Figure 61–3). The laser fiber can easily slide forward and backward without much resistance using this cystoscope. The laser fiber is then calibrated to insure good fiber transmission of the laser energy. If the fiber transmission is above 80%, the machine will automatically boost the energy to achieve 100% energy transmission at the set energy level. The fiber is then inserted through the working channel of the cystoscope and out the end. Only then can the laser tip be screwed onto the laser fiber. At the present time, there are two round laser tips appropriate for contact laser vaporization of the prostate, the MTRL-6 (3.5 mm OD) and the MTRL-10 (10 mm OD) tip (Figure 61–4). The lens and bridge is then inserted into the sheath of the cystoscope and the procedure is ready to begin. The laser (Figure 61–5) is then set at 50 to 60 watts of energy. The MTRL-6 tip will vaporize tissue more quickly since more energy is concentrated over a smaller surface area but will vaporize a smaller channel. The MTRL-10, on the other hand, will vaporize a larger channel but will do so more slowly since the available energy is spread over a larger surface area and visualization is less optimal as the tip takes up a large portion of the viewing area. In performing a contact laser vaporization of the prostate, it is vital that the urologist maintain a threedimensional image of the prostate and the anatomic landmarks throughout the case. These landmarks include the ureteral orifices, the bladder neck, the length of the prostatic fossa, and the position of the verumontanum and external sphincter. These must be kept foremost in the surgeon's mind since in contact laser vaporization of

FIGURE 61–1. Wolff offset optics cystoscope.

the prostate the laser fiber is pushed through the prostate, vaporizing the tissue it stays in contact with, instead of the usual pulling of the loop through the prostatic adenoma during electrocautery resection of the prostate. Following inspection of the bladder and identification of the landmarks, the procedure can begin. The first area to be vaporized, as in most electrocautery TURPs, is the bladder neck and any median lobe tissue. If a large median lobe is present, the surgeon should commence the procedure by vaporizing the median lobe. The first channel should be vaporized at the 12 o’clock position or at the very top of the median lobe. Working laterally, rows of tissue to the left and right of the midline are vaporized until the median lobe is removed down to capsular fibers. This is accomplished by pulling the cystoscope back to the midprostate area just beyond the median lobe. The laser fiber is then pushed forward until it comes into contact with the median lobe tissue and the laser is activated by pushing the foot pedal. The silicone tip should glow red when activated. The tip is slowly advanced by pushing it forward as the resistance on the tip of the fiber lessens. The tip must always be kept in contact with the tissue to heat and vaporize it. At the bladder neck, the resistance on the tip will disappear as it advances into the bladder. Once the tip advances into the bladder, the laser is deactivated by the surgeon. The laser fiber is withdrawn to beyond the median lobe and the procedure repeated adjacent to the initial channel. This procedure is repeated until the median lobe has been totally vaporized and the capsular fibers of the bladder neck have been identified.

FIGURE 61–2. SREF-15, semirigid endoscopic fiber.


FIGURE 61–3. Standard cystoscope with single working channel bridge for passage of the SREF-15 fiber.

The bladder neck tissue is then vaporized bilaterally as far as possible, to completely open the bladder neck. The ureteral orifices must always be visualized to insure that they are not vaporized. Sometimes a large median lobe will protrude well into the bladder and near the ureteral orifices. If this is the case, the procedure is initially carried out as above until the median lobe has been vaporized down to capsular fibers. Then the Vapormax (Figure 61–6), which has a right-angled tip, is substituted for the MTRL tip. The Vapormax is used to hook the posterior lip of tissue and pull it forward. The laser is then activated and the Vapormax is pulled toward the bladder neck, thus vaporizing the last of the median lobe tissue. The scope is then pulled back to the verumontanum and the prostate once again inspected. The left and right lateral lobes are vaporized from the verumontanum on into the bladder neck. The procedure starts on either side by positioning the cystoscope at the verumontanum and bringing the laser tip into contact with the prostatic adenoma at the 1 or 11 o’clock position. The laser is then activated and is slowly pushed forward, vaporizing the

FIGURE 61–4. Left: MTRL-6 tip; right: MTRL-10 tip.

tissue into the bladder neck, with tip-tissue contact maintained during all vaporization. When the pressure on the tip of the laser fiber begins to decrease, the fiber should be advanced. This vaporizes a channel through the lateral lobe. The tip is then pulled back to the verumontanum and successive parallel channels are vaporized down to the floor of the prostate. This series of vaporized channels is repeated until the entire lateral lobe is vaporized and the surgical capsule visualized. Long prostatic fossas with very long and bulbous lateral lobes may need to be vaporized with two passes of the laser tip. The inner half of the adenoma is vaporized first as far laterally as possible by serially vaporizing channels from the 1 o’clock and 11 o’clock positions down to the floor of the prostate until the surgical capsule is identified. The most distal adenoma is then vaporized in a similar fashion, vaporizing the entire lateral lobe and opening the prostatic fossa. Attention is then turned to the anterior tissue between 11 and 1 o’clock. Extreme care is required to preserve the urethral smooth muscle between the verumontanum and the external sphincter. This smooth muscle has been described as an important factor in passive continence, especially following TURP. This tissue is vaporized in a similar fashion by positioning the cystoscope at the distal end of the verumontanum and advancing the tip beyond the cystoscope to vaporize the anterior and apical tissue from the verumontanum into the bladder neck. This creates a wide-open prostatic fossa similar to that created in electrocautery TURP (Figure 61–7). At the end of the procedure, there are usually numerous tags of tissue protruding into the prostatic fossa. These tags are usually necrotic coagulated tissue and will

FIGURE 61–5. Surgical Laser Technologies (SLT) contact laser.


FIGURE 61–6. Vapormax right angle contact tip.

eventually slough and leave a smooth fossa that will reepithelialize in time. While these tags are necrosing and sloughing, however, they can cause urgency and frequency of urination. It is therefore imperative to vaporize as many of these tags as possible to create as smooth a fossa as possible. The best way to accomplish this is by bringing the tip into contact with the tag of tissue and energizing the laser. As the tip heats up, the tissue will adhere to the laser tip. By rotating the tip of the laser the tissue tag is pulled into the center of the tip and is vaporized. By moving around the prostatic fossa and vaporizing the tissue tags in this manner, a smooth, open prostatic fossa is produced. This will markedly decrease the urgency and frequency experienced by the patient in the immediate postoperative period. One of the major benefits of performing a contact laser vaporization of the prostate is the lack of bleeding during the procedure. The extremely high temperature at the tip-tissue interface vaporizes any vessels in front of the laser tip and cauterizes vessels in the near proximity

of the tip. Only rarely during the actual procedure of vaporizing the adenoma does bleeding develop. Gomella et al.5 documented a mean hemoglobin preoperatively of 14.4 (± 1.5) and postoperatively of 12.9 (± 1.5). The mean change in hemoglobin was –1.5 g per dL (± 0.8). When there is bleeding, it is usually very easy to identify the bleeding vessel and cauterize it by touching the vessel with the silicone tip. Most of the procedure is therefore carried out in a relatively bloodless environment, giving excellent visualization of the tissue during the procedure. Since there is a zone of coagulation that surrounds the laser tip due to the high temperature, these vessels are cauterized for some distance and rarely rebleed. Another major benefit of contact laser vaporization of the prostate is the fact that electricity is not used to resect the adenoma. Since the laser energy is converted into heat, normal saline can be used as the fluid medium for the procedure. In performing well over 200 contact laser vaporization procedures, the current author has never encountered a patient with transurethral resection syndrome due to fluid absorption during the case, nor has there been a case reported in the literature. In the study by Gomella et. al.,5 the mean preoperative serum sodium level was 138.4 mmol per liter (± 3.6) and postoperative levels were 135.6 mmol per liter (± 5.0). Once the procedure has been completed, a Foley catheter is inserted until the patient fully recovers from anesthesia. Since there is very little chance of significant bleeding and clots developing in the bladder, an 18F Foley with a 30 cc balloon can be inserted. Normally, a threeway Foley is used with the saline irrigation running at a slow drip for a short time after the procedure. This will insure adequate irrigation of the bladder since the large raw surface of the prostatic fossa does not bleed but may ooze a small amount of blood for several hours. The

FIGURE 61–7. Left, Preoperative view from the verumontanum; right, postoperative view from the verumontanum showing lateral lobe tissue completely vaporized and prostatic fossa wide open.


catheter is left in place for 6 to 8 hours to insure that the patient has fully recovered from the anesthetic agents administered during the case and that detrusor muscle tone has fully returned. Alternatively, the catheter can be left in overnight, depending on patient preferences and his proximity to the hospital. Most patients who wish to return home the night of surgery, however, can have the Foley catheter removed after approximately 6 to 8 hours, void without difficulty, and are discharged catheter-free and allowed to return to normal unrestricted activity the following morning. Patients who wish to stay overnight in the hospital have the Foley catheter removed at 6 AM the following morning and are discharged after they urinate. They are allowed to return to full unrestricted activity that same day.

Complications Complications from contact laser vaporization of the prostate are minor and rare. Although most of the time bleeding both during and following the procedure is minimal, if a venous sinus is entered there can be significant bleeding that is very difficult to control, as occurs with electrocautery TURP. Once the procedure is completed, the Foley catheter can be placed on traction, and the bleeding generally stops within a short period of time. With the use of traction immediately after the procedure and continuous bladder irrigation overnight, the drainage is usually crystal clear the morning after surgery. The catheter can then be removed and the patient discharged without undue worry. The problem of urgency and frequency of urination was a frequent and sometimes quite severe problem early on with contact laser vaporization of the prostate. It was initially thought that it was not necessary to vaporize all tissue tags remaining after completion of the procedure. These tags were coagulated and the theory was that they would necrose, slough, and eventually pass, creating a wide-open, smooth prostatic fossa. This did happen but while these tissue tags were sloughing and passing, patients frequently experienced urgency and frequency that was not well controlled with anticholinergic medications. These symptoms actually seemed to decrease and finally abate when the tissue passed and the fossa re-epithelialized. It is now realized that it is important to vaporize these tags of tissue, as described above, to prevent urgency and frequency. The urgency and frequency are now uncommon postoperative problems. Postoperative infection is also a possible complication. With a single preoperative intravenous dose of a fluoroquinalone, however, followed by three doses postoperatively, infectious complications are rarely encountered. As with electrocautery TURP, most men have the bladder neck vaporized to totally open the prostatic fossa. Therefore, most men develop retrograde ejaculation fol-

lowing surgery. All are counseled preoperatively regarding the development of retrograde ejaculation and rarely does the patient voice concern.

Discussion The urologist has been presented with a multitude of new therapies for BPH in the 1990s, both surgical and medical. Contact laser vaporization of the prostatic adenoma gives the urologist a surgical alternative that can remove the obstructing adenoma as efficiently as the gold standard electrocautery TURP and return the patient to full, normal unrestricted activity within 24 to 48 hours. The procedure is performed in same-day surgery or 23-hour observation with minimal side effects and/or complications. In Mueller’s series of 50 consecutive contact laser vaporization cases,6 18 of the patients had the Foley catheter removed approximately 6 hours following surgery, voided without difficulty, and were discharged from the hospital. Thirty of the remaining 32 patients had the Foley catheter removed the morning after surgery, voided without difficulty, and were discharged. In two patients, the Foley catheter was left indwelling as the patients remained in the hospital to be evaluated for coexistent medical problems. All patients were allowed to return to full, unrestricted physical activity within 24 hours of discharge. The 1993 Diagnosis Related Groups handbook lists the average length of stay for TURP patients without comorbidities to be 3.82 days and 5.79 days for patients with comorbidities.7 Seventy-eight percent of the patients in the Mebust et al. series,8 and 91% of the patients in the Holtgrewe et al. series9 were discharged by day five. This has changed somewhat in 1998 in that more patients are being discharged earlier, many, however, are going home with a catheter and leg bag and all must still refrain from strenuous activity for a variable length of time due to the risk of bleeding. In the Brooke Army Medical Center series,10 113 of 119 patients had their Foley catheters removed the morning after a standard electrocautery TURP and were successfully discharged from the hospital. All were cautioned to refrain from strenuous activity, however, until seen at their 1-month postoperative visit, due to the risk of postoperative bleeding. The most common criticism of the contact laser procedure is that vaporization of the tissue is very slow and the procedure takes too long to perform, especially on large glands. It must be remembered, however, that the entire operative time must be taken into account when operative time is considered. With standard electrocautery TURP, the operative time consists of the actual resection of the tissue, obtaining adequate hemostasis, evacuation of the chips, final inspection of the bladder and prostatic fossa for chips and bleeding sites, and placement of the Foley catheter. With the contact laser procedure, once the adenoma is adequately vaporized and the fossa is open, the Foley is placed. In the previously men-


tioned review of 50 consecutive cases, the operative times on the anesthesia record for the 50 cases were compared to 35 consecutive electrocautery TURPs performed by private practice staff physicians at a community hospital. To differentiate the size of the prostates, which definitely affected operative times, it was assumed that a 3 cm prostatic fossa was equal to 20 grams of resectable tissue. The electrocautery TURP required 3.11 minutes per gram of resectable tissue while contact laser vaporization took 22.80 minutes per cm of prostatic fossa. Thus, an average 3 cm prostatic fossa with an estimated 20 grams of resectable tissue would average 62.2 minutes with the elecrocautery TURP and 68.4 minutes with the contact laser vaporization.6 Gomella et al.11 have reported a unique approach to the large gland, suggesting that contact laser vaporization of the prostate as described above is best for prostates of 20 to 30 grams. For prostates > 30 grams, they describe a procedure they call coagulation and hemostatic resection of the prostate (CHRP). The goal of CHRP is to combine the speed of the noncontact free beam technique with immediate tissue removal and the early catheter removal of the contact method. Gomella et al. use the noncontact technique described by Kabalin12 to initially coagulate the prostatic adenoma. The laser tip is then changed to the MTRL-6 or MTRL-10 to vaporize a channel from the verumontanum into the bladder neck to allow for early catheter removal and voiding. The patient's obstructive symptoms will continue to improve as the necrotic tissue sloughs. Another major benefit of the contact laser procedure is the ability to perform the procedure on patients who are on aspirin or fully anticoagulated on warfarin. The contact laser will vaporize the vessels, and the area of tissue coagulation directly adjacent to the contact tip effectively coagulates any small vessels in this tissue. Thus, there is minimal bleeding both during the procedure and in the immediate postoperative period. The procedure has been successfully performed in seven patients fully anticoagulated on warfarin, without significant bleeding complications during or after the procedure. All patients experienced marked relief of their bladder outlet obstructive symptoms, were discharged the morning after the day of the procedure, and returned to full, normal unrestricted activity within 48 hours.13 Contact laser vaporization of the prostate removes tissue and allows immediate relief of symptoms comparable to electrocautery TURP. In the 34 patient series reported by Gomella et al.,5 the average peak flow rate increased from 6.2 mL per second preoperatively to 17.3 mL per second postoperatively, with average residual urine decreasing from 188 mL preoperatively to 22 mL postoperatively. The American Urological Association (AUA) symptom scores improved from an average 15.4 preoperatively to 5.6 postoperatively at 3 months. In Mueller’s series of 50 patients, the AUA symptom score decreased

from an average 22.9 (range 14 to 30) preoperatively to an average 2.1 (range 0 to 8) postoperatively.6 In summary, contact laser vaporization of the prostate immediately removes the obstructing adenoma comparable to the gold standard, electrocautery TURP, with excellent relief of bladder outlet obstructive symptoms. The main benefit of the procedure compared to TURP is minimal bleeding, both during the procedure and in the immediate postoperative period. This allows for earlier discharge from the hospital and a return to full, normal unrestricted activity within 24 to 48 hours of the surgery. The effective coagulation of vessels within the prostatic fossa by the contact laser also allows the surgery to be performed on patients fully anticoagulated or on aspirin. This represents a significant percentage of patients in the population requiring surgical relief of their symptoms, and definitely decreases the risk of complications both during and after the procedure.

References 1. Nesbit RM. Transurethral prostatectomy. Springfield (IL): Thomas Publ; 1943. 2. Stein BS. Laser physics and tissue interaction. In: Smith JA, editor. The urologic clinics of North America. Vol 13, No. 3. Philadelphia: WB Saunders; 1986. 3. Ball KA. Lasers: the perioperative challenge. St. Louis (MO): Mosby Year Book, Inc; 1995. 4. Fuller TA. Thermal surgical lasers. Oaks (PA): Surgical Laser Technologies Inc; 1993. 5. Gomella LG, Lofti MA, Reagan GN. Laboratory parameters following contact laser ablation of the prostate for benign prostatic hypertrophy. Techniques Urol 1995; 1:168–71. 6. Mueller EJ. Contact laser vaporization of the prostate: one surgeon's experience with 50 consecutive cases. Techniques Urol 1996;2:136–41. 7. The DRG handbook. Baltimore (MD): HCIA Inc./Ernst and Young; 1993. p. 211–6. 8. Mebust WK, Holtgrewe HL, Cockett ATK, et al. Transurethral prostatectomy: immediate and postoperative complications. A cooperative study of 13 participating institutions evaluating 3885 patients. J Urol 1989;141: 243–7. 9. Holtgrewe HL, Mebust WK, Dowd JB, et al. Transurethral prostatectomy: practice aspects of the dominant operation in American urology. J Urol 1989;141:248–53. 10. Mueller EJ, Zeidman EJ, Desmond PM, et al. Impact of early postprostate transurethral resection catheter removal [abstract]. J Urol 1993;149:433A. 11. Gomella LG, Lofti MA, Rivas DA, Chancellor MB. Contact laser vaporization techniques for benign prostatic hyperplasia. J Endourol 1995;9:117–23. 12. Kabalin JN. Laser prostatectomy performed with a right angle firing neodymium:YAG laser fiber at 40 watts per setting. J Urol 1993;150:95. 13. Mueller EJ. Contact laser vaporization of the prostate in patients on chronic anticoagulant therapy. Techniques Urol 1999;4:156–9.

CHAPTER 62

FREE BEAM LASER PROSTATECTOMY JOHN N. KABALIN, MD, FACS Lasers have been studied as potentially useful instruments for surgery of the prostate almost since the first lasers were brought into urologic operating rooms. In the 1990s, lasers have emerged as important and versatile tools for transurethral prostatectomy. The appeal of free beam lasers for prostatic surgery is based on several defining characteristics. Lasers offer a potentially convenient way to administer very large doses of energy to the prostate in a precise and controlled fashion and with an atraumatic, minimally invasive, no-touch technique—via a beam of light. Today, an increasing variety of laser wavelengths are becoming available for endourologic application, each with a unique range of tissue effects, allowing new and improved approaches to prostate surgery. In particular, free beam laser prostatectomy, relying primarily on either coagulation or vaporization effects produced by laser light, has proven a safe and effective surgical means to alleviate lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH).

Free beam laser coagulation of the prostate is greatly facilitated by the use of one of many versions of side-firing laser fibers with divergent beam emission (Figure 62–1). While these fibers vary in design and in a variety of more minor features, the most important operative variable is the configuration of the emitted laser beam. Laser coagulation of the prostate is optimally achieved with a wider angle beam, having a divergence of at least 30 degrees and thus relatively low energy density. Johnson et al. first reported the use of a flexible, side-firing Nd:YAG laser delivery fiber that could be positioned in the prostatic urethra under direct vision through a standard cystoscope.2 Canine studies have demonstrated the ability of a divergent beam Nd:YAG laser to create a large volume lesion in the prostate by causing extensive thermal injury, coagulation necrosis, and subsequent tissue slough.2–8 These results have been reiterated and confirmed in detailed histopathologic studies in human prostates treated in vivo (Figure 62–2).9–14

Free Beam Laser Coagulation of the Prostate

Operative Technique With the patient placed in a standard dorsal lithotomy position under general or regional anesthesia, free beam laser coagulation of the prostate can be performed under direct vision through a standard operating cystoscope. While special “laser cystoscopes” have been specifically developed for laser prostatectomy that incorporate such features as continuous flow irrigation, various means of fixating the laser fiber, and specialized beak designs, the current author has found that none of these offer any great advantage over a standard 20F cystoscope. Any available irrigation fluid will transmit Nd:YAG or KTP laser light. Because of the lack of fluid absorption, sterile water may be safely used. Room temperature irrigation provides necessary cooling of the laser fiber and helps prevent premature thermal deterioration of the distal side-firing reflector mechanism. Maximal depth and volume of prostatic transition zone coagulation is created with a fixed spot, continuous, long duration Nd:YAG laser application with a widely divergent, relatively low-energy density beam.4,5,7,8,11,12,14 Using a side-firing delivery fiber with 30 degree Nd:YAG laser beam divergence, maximal tissue coagulation has been demonstrated to occur at a moderate power setting of 40 watts and continuous fixed spot application times

Perhaps the most ubiquitous of operating room lasers, and the first to be used for transurethral prostate surgery,1 is the neodymium: yttrium-aluminum-garnet (Nd:YAG) laser wavelength (1064 nanometers). It offers several specific advantages for prostatectomy in addition to its widespread availability. It is easily transmitted by means of flexible delivery fibers, which facilitates endoscopic use. Its minimal absorption by water allows it to be used in a fluid medium without diminution in laser energy. The Nd:YAG laser penetrates deeply through tissue and produces superb coagulation and hence hemostasis. The potassium-titanyl-phosphate:YAG (KTP) laser wavelength (532 nanometers) offers almost identical technical features and tissue effects, with perhaps only slightly lesser tissue penetration, compared to the Nd:YAG laser. The KTP laser has been used by a minority of surgeons in a similar fashion to the Nd:YAG laser to perform prostatectomy. Free beam laser coagulation of the prostate—often referred to as visual laser ablation of the prostate (VLAP)—performed with either the Nd:YAG or KTP lasers, has been the most common laser operation utilized in the treatment of BPH. 568

Free Beam Laser Prostatectomy / 569

A

B

FIGURE 62–1. A, Distal, working end of side-firing Nd:YAG laser delivery fiber used for free beam laser coagulation of the prostate. B, Demonstration of lateral deflection and divergence of emitted laser beam from side-firing fiber.

of at least 90 seconds duration.4,5,7,8,14,15 There is a relative lack of visual feedback during free beam laser coagulation of the prostate since large volumes of tissue are not acutely removed and the eventual transurethral resection (TUR) defect that will be created after slough of coagulated transition zone tissue is not seen intraoperatively. Therefore, a systematic approach is recommended to avoid areas of nontreatment of obstructive BPH tissue. The key to successful voiding outcomes is to thoroughly treat all obstructing tissue elements, spacing laser applications no more than 1.5 to 2.0 cm apart. Aggressive, systematic laser treatment, with total Nd:YAG laser energy administration in excess of 1500 joules per gram of excess BPH tissue, is recommended. Treatment typically commences with the lateral lobes of the prostate, placing initial laser spot applications approximately 1 cm outside the bladder neck. Two, three, or more spot laser applications are made to each lateral

A

lobe in this initial transverse plane of the prostate, depending on the size of the gland (Figure 62–3). The side-firing fiber is held near the tissue surface with a stand-off distance of approximately 1 mm and directed so that the emitted laser beam strikes the tissue perpendicularly. Treatment in a single transverse plane may be sufficient in a small gland measuring perhaps 2 cm from the bladder neck to the verumontanum. In a larger prostate gland with longer lateral lobes, spot applications are repeated every 1.5 to 2.0 cm along the length of the lateral lobes until all obstructing BPH tissue is treated (Figure 62–4). By working from the bladder neck outward and using the beak of the cystoscope as well as the irrigation flow to separate the prostatic lateral lobes, treatment can be completed in even the largest and most occlusive prostate under direct vision and without burying the fiber tip in tissue. The latter may cause premature thermal degradation of the fiber and limit the efficacy of therapy.

B

FIGURE 62–2. A, Transverse section through a human prostate removed immediately after free beam Nd:YAG laser coagulation of the transition zone. B, Transverse section through a human prostate removed 1 year following free beam Nd:YAG laser coagulation prostatectomy, demonstrating large resulting TUR defect. From Kabalin JN. Laser prostatectomy—free beam. In: Resnick MI, Thompson IM, editors. Surgery of the prostate. New York: Churchill Livingstone; 1998. p. 267–82.


The same principles apply to free beam laser coagulation of the median lobe of the prostate. Spot laser applications are spaced every 1.5 to 2.0 cm across the breadth of the median lobe; in a small prostate, a single posterior midline application may be made to an elevated median bar (Figure 62–5). With a larger median lobe, spot laser applications are made to the most cephalad or intravesical extension of the median lobe and repeated at 1.5 to 2.0 cm intervals along the length of the lobe until all obstructing tissue is treated (Figure 62–6). Alternatives to these multiple fixed spot laser applications have been proposed. Such techniques mainly

attempt to optimize tissue effects achievable with those side-firing fibers that produce a narrow beam divergence (an approximate 15 degree angle of divergence is typical) and also represent the more common operative approaches using the KTP laser wavelength to perform prostatectomy. Unlike fixed spot laser applications, continuous linear laser applications are performed by slowly dragging a side-firing fiber along the length of the prostate from the bladder neck to the verumontanum. This maneuver is repeated circumferentially until all lateral lobe and median lobe tissue is treated. Very slow drag rates produce the best results, with rates of no more than

FIGURE 62–3. Operative approach for free beam Nd:YAG laser coagulation (VLAP) of the prostatic lateral lobes, shown in transverse section, with multiple fixed spot laser applications encompassing both lateral lobes in this transverse plane. From Kabalin JN. Laser prostatectomy—free beam. In: Resnick MI, Thompson IM, editors. Surgery of the prostate. New York: Churchill Livingstone; 1998. p. 267–82.


A

B

C

D

E

F

FIGURE 62–4. A–F, Operative approach for free beam Nd:YAG laser coagulation (VLAP) of the prostatic lateral lobes, shown in coronal sections, repeating fixed spot laser applications in multiple transverse planes (see Figure 62–3) along the length of the lateral lobes sequentially from the bladder neck to the verumontanum. From Kabalin JN. Laser prostatectomy—free beam. In: Resnick MI, Thompson IM, editors. Surgery of the prostate. New York: Churchill Livingstone; 1998. p. 267–82.


2 to 3 cm per minute suggested.16 Continuous linear laser applications use a minimum Nd:YAG laser power setting of 60 watts, with some surgeons preferring power settings up to 80 watts or more, although this causes side-firing laser fibers to deteriorate faster. Postoperative Management On completion of free beam laser coagulation of the prostate, a 16F, 5 cc Foley urethral catheter is inserted and placed to gravity drainage. Because of the superb hemostasis attained with free beam laser coagulation, postoperative catheter irrigation is not needed. The lack of bleeding or fluid absorption—the overall lack of physiologic stress to the patient—allows this form of laser prostatectomy to be easily performed on an outpatient basis. Catheter drainage is maintained for several days postoperatively (typically 1 week) to allow acute edema from the laser burns to subside, after which the catheter can be removed in the surgeon's office. Patients with poor detrusor function and chronic preoperative urinary retention may benefit from longer postoperative catheterization. All patients will require several weeks to achieve

final voiding outcomes after laser coagulation of the prostate. This period corresponds with that of ongoing dissolution and passage in the urinary stream of the lasercoagulated, necrotic BPH tissue. Clinical Outcomes The acute operative morbidity of Nd:YAG laser coagulation of the prostate is negligible and much less than that associated with electrocautery resection techniques. Significant bleeding or transfusion have been distinctly rare, and TUR-syndrome has never been reported. This may be explained by the physical mechanism of interaction of the Nd:YAG laser with prostate tissue, coagulating and sealing blood vessels through several millimeters depth. Cummings et al. used a quantitative breath ethanol technique to demonstrate the complete absence of fluid absorption during Nd:YAG laser prostatectomy.17 Even patients systemically anticoagulated for a variety of reasons or with other bleeding diatheses at the time of surgery have been safely treated with Nd:YAG laser coagulation of the prostate.18–20 Morbidity of Nd:YAG laser coagulation of the prostate was compared to standard electrocautery transurethral resection

FIGURE 62–5. Operative approach for free beam Nd:YAG laser coagulation (VLAP) of the prostatic median lobe, shown in transverse section, with multiple fixed spot laser applications encompassing the entire breadth of the median lobe. From Kabalin JN. Laser prostatectomy—free beam. In: Resnick MI, Thompson IM, editors. Surgery of the prostate. New York: Churchill Livingstone; 1998. p. 267–82.


of the prostate (TURP) in randomized prospective trials in two studies in the United States and the United Kingdom.21–24 The TURP was associated with serious treatment-related complications in more than one-third of men—35.6% and 33.3%, respectively, in the United States and the United Kingdom—during 1-year postoperative follow-up, including blood transfusions required in 14 of 134 men undergoing TURP in both series. In contrast, Nd:YAG laser coagulation of the prostate was associated with serious treatment-related complications in only 10.7% and 6.6% of men, respectively, in the United States and the United Kingdom studies, with no transfusion required in 132 laser cases. In an Australian, single institution trial, Costello et al. randomized 71 men in a prospective comparison of Nd:YAG laser prostatectomy and TURP.23,24 Serious treatment-related complications occurred in 35.1% followed up to 3 years after TURP, with blood transfusions required in 3 of 37 men. In 3 years of postoperative follow-up, serious treatment-related complications occurred in only 11.8% of laser-treated men, with no blood transfusions required. These findings are remarkably similar to the United States and the United Kingdom multicenter reports. In the most detailed analysis to date of acute and longterm complications following Nd:YAG laser coagulation of the prostate, a Stanford University study reported a 14.3% total complication rate in 230 men with minimum postoperative follow-up of 12 months and median followup of 35 months was documented (Table 62–1).15,25 No significant bleeding, transfusion requirement, TURsyndrome, or prostatic perforations were observed. Postoperative prostatitis occurred in 2.6% of men undergoing Nd:YAG laser prostatectomy. This syndrome, in which the laser-coagulated, necrotic prostate tissue mass becomes infected, causes significant dysuric symptoms and required multiple weeks of oral antibiotic therapy to resolve in each case. Greater care in insuring preoperative sterile urine and adequate perioperative antibiotic prophylaxis is perhaps required with Nd:YAG laser prostatectomy than with electrocautery resection techniques to avoid this unique prostatitis syndrome. It is also suggested that preoperative documentation of chronic or recurrent bacterial prostatitis represents a contraindication for Nd:YAG laser coagulation of the prostate.25 Stress urinary incontinence was not observed in these 230 cases and has been a very rare complication worldwide with Nd:YAG laser prostatectomy. Urethral stricture and bladder neck contracture occurred in 1.7% and 4.3% of patients, respectively, followed over the long term. The incidence of urethral stricture, in particular, is much less than that observed in long-term studies of patients undergoing TURP, probably due to shorter operative times during Nd:YAG laser treatment and use of smaller caliber endoscopes with less intraoperative manipulation required. The reoperation rate of 5.7% with median follow-up of

35 months translates to a 2% annual overall retreatment rate in this series of Nd:YAG laser prostatectomy, durability equivalent to that reported for TURP. Impotence has been documented in multiple published series to occur only rarely following Nd:YAG laser coagulation of the prostate. Although many initial papers reported very low rates of retrograde ejaculation following Nd:YAG laser coagulation, in more recent series utilizing current aggressive treatment approaches, retrograde ejaculation has occurred in as many as 36% to 47% of men treated.25,26 Large numbers of patients have been treated worldwide with Nd:YAG laser coagulation of the prostate, and numerous reports exist to document the efficacy of this operation

FIGURE 62–6. Operative approach for free beam Nd:YAG laser coagulation (VLAP) of the prostatic median lobe, shown in sagittal section, repeating fixed spot laser applications in multiple transverse planes (see Figure 62–5) along the length of the median lobe sequentially from the bladder neck to the verumontanum. From Kabalin JN. Laser prostatectomy—free beam. In: Resnick MI, Thompson IM, editors. Surgery of the prostate. New York: Churchill Livingstone; 1998. p. 267–82.

574 / Advanced Therapy of Prostate Disease TABLE 62–1. Complications of Free Beam Nd:YAG Laser Coagulation of the Prostate* Acute complications Significant hemorrhage/transfusion TUR-syndrome Prostatic perforation/extravasation Postoperative prostatitis Long-term complications Stress urinary incontinence Urethral stricture Bladder neck contracture Reoperation for residual tissue

n

Incidence

0 0 0 6

– – – 2.6%

0 4 10 13

– 1.7% 4.3% 5.7%

*Observed in 230 men with 1 year minimum postoperative follow-up (median 35 months of follow-up in this series) treated in a single institution.15,25

in relieving voiding symptoms due to BPH (Table 62–2).15,21,22,25–43 Overall, these outcomes are equivalent to standard TURP. In a large, carefully documented series, 87% of men experienced symptomatic improvement following Nd:YAG laser prostatectomy.25 At 1 year postoperative follow-up, 85% of patients exhibited at least a 50% improvement in peak urinary flow rate or symptom score. The versatility of Nd:YAG laser coagulation of the prostate is also similar to TURP, with demonstrated ability to treat median lobe configurations, large prostates, and men in urinary retention.25,44–46 Several detailed studies have documented the ability of Nd:YAG laser prostatectomy to improve simple and complex urodynamic measures of bladder outflow obstruction (Table 62–3).26,29,34,46–51 In addition to relatively standard pressure-flow studies, Cannon et al., de Wildt et al., and te Slaa et al. examined multiple complex and derived urodynamic measures of bladder outlet obstruction, determining that up to 95% of patients undergoing Nd:YAG laser coagulation of the prostate were rendered unobstructed after 6 months of postoperative follow-up.48–50 Mean prostatic volume losses of 28%,16 34%,29 and 37%47 have been documented by transrectal ultrasound following Nd:YAG laser coagulation of the prostate in three published reports. Long-term follow-up of patients treated with Nd:YAG laser coagulation of the prostate has shown that voiding improvement is stable and durable for at least 3 years TABLE 62–2. Voiding Outcomes Reported for Free Beam Nd:YAG Laser Coagulation of the Prostate* Postoperative Preoperative 3 Months Peak flow rate (mL/s) Postvoid residual (mL) AUA symptom index (n = 1851)

8.0 (n = 1765) 189 (n = 1295) 21.3 (n = 1851)

16.2 (n = 1306) 63 (n = 1104) 8.4 (n = 1308)

6 Months 12 Months 16.2 (n = 1433) 61 (n = 1044) 7.4 (n = 1466)

17.2 (n = 600) 72 (n = 576) 7.0 (n = 618)

*From 20 combined series with 3 to 12 months of postoperative follow-up.15,21,22,25–43

(Table 62–4).15,36 In a small series of men reported from Stanford University with 4- and 5-year continuous followup after Nd:YAG laser coagulation of the prostate for BPH, operative outcomes remained durable without symptomatic recurrence, measurable decrement in objective voiding parameters, or additional retreatments required.52

Free Beam Laser Vaporization and Resection of the Prostate Free beam laser coagulation of the prostate as described above, using either a divergent beam Nd:YAG or KTP laser, has provided a very safe and effective approach to transurethral prostatectomy. The deep thermal coagulation injury throughout the prostatic transition zone upon which these procedures rely for clinical efficacy, however, mandates a longer period of postoperative catheterization and a delay until realization of voiding improvement of weeks after the operation for most patients. Many view this as a distinct disadvantage of laser coagulation of the prostate compared to standard electrocautery TURP and some other surgical approaches. Acute laser vaporization of obstructing BPH tissue, with immediate intraoperative relief of bladder outlet obstruction, has thus been sought as an alternative. Attempts to use high power Nd:YAG (up to 100 watts) or KTP laser applications to acutely vaporize tissue have met with limited success, as might be predicted from the physics of these primarily coagulative laser wavelengths. Technologic developments leading to the production of very high powered Nd:YAG or KTP lasers in the future may make tissue vaporization with these wavelengths more efficient and reasonable. The Nd:YAG contact laser is capable of vaporizing tissue but is inefficient in bulk tissue removal, which is needed for all but the smallest prostates; it is also less hemostatic than free beam laser approaches. The carbon dioxide laser wavelength (10,600 nanometers) is readily capable of tissue vaporization but significant technical problems in adapting this common laser for endoscopic use have not yet been solved. The recent availability of the holmium:YAG (Ho:YAG) laser wavelength (2140 nanometers) for endosurgical applications, combined with the development of effective operative techniques appropriate to this unique laser, have allowed the realization of an efficient free beam laser vaporization prostatectomy procedure. In contrast to the Nd:YAG and KTP wavelengths, the Ho:YAG laser is highly absorbed by tissue water and causes rapid vaporization of exposed soft tissues. It is the first and only true vaporizing laser wavelength now available for endosurgical use. The pulsed Ho:YAG laser sources (as opposed to continuous wave lasers) currently available further maximize tissue vaporization effects. Like both the Nd:YAG and KTP laser wavelengths, Ho:YAG laser light can be transmitted through thin flexible delivery fibers and can be used in the endoscopic


fluid environment. The ability of the Ho:YAG laser to incise and vaporize prostatic tissue bulk was first demonstrated in canine models.53,54 These initial studies were subsequently repeated ex vivo and then in vivo in human radical prostatectomy specimens, confirming the ability of the Ho:YAG laser to ablate prostate tissue effectively, safely, and immediately (Figure 62–7).55,56 In addition to tissue vaporization, at relatively high power settings (> 50 watts) the Ho:YAG laser also produces significant subsurface tissue coagulation up to a depth of 3 to 4 mm. This is important as it allows hemostatic vaporization and resection of the prostate, effectively sealing tissue planes throughout the course of prostatectomy to stop bleeding and prevent systemic absorption of irrigation fluid.

TABLE 62–3. Effect of Free Beam Nd:YAG Laser Coagulation of the Prostate on Detrusor Voiding Pressures* PdetQmax (cm H2O) Series

n

Preoperative

Postoperative

te Slaa, et al.26 Van Erps, et al.29 Choe and Sirls46 Kabalin, et al.47 Cannon, et al.48 de Wildt, et al.49 James, et al.51

98 30 17 10 75 40 72

77.8 76.0 66.4 91.3 79.8 76.7 74.0

40.4 44.0 41.9 54.6 40.1 39.3 54.2

Total/Mean

342

76.9

43.9 (net change: –43%)

*Measured at peak flow (PdetQmax) in 7 selected series reporting urodynamic pressureflow studies.26,29,46–49,51

Operative Technique Incision, vaporization, and resection of the prostate by Ho:YAG laser requires a high energy laser source capable of emitting Ho:YAG laser energy of at least 2.0 to 2.5 joules per pulse. Pulse rates of 20 hertz or more are used. Minimum power outputs of 50 watts or more are generally desirable to produce adequate prostatic tissue vaporization and operative efficiency. Both 550 micron end-firing and 1000 micron side-firing flexible holmium laser delivery fibers are now available for prostatectomy. The 1000 micron side-firing fiber may enable simple vaporization of obstructing BPH tissue. The 550 micron end-firing fiber is preferred for Ho:YAG laser incision and resection of the prostate; it is also reusable and more cost-effective than side-firing devices. An end-firing fiber will maximize laser energy density at the point of application. Although any cystoscope may be used for Ho:YAG laser prostatectomy, a rigid endoscope providing distal fixation of the laser fiber greatly assists in this operation since considerable vibration of the fiber occurs during high energy pulsed Ho:YAG laser application. There are now several "laser resectoscope" designs available that meet this need, most also incorporating continuous irrigation flow. The patient is placed in a standard dorsal lithotomy position under general or regional anesthesia for Ho:YAG laser prostatectomy. Since the Ho:YAG laser wavelength is absorbed to some degree by the irrigation fluid, the laser fiber is kept in contact or near contact with the tissue to be treated to maximize effect. Any irrigation fluid may be used but sterile saline solution is most commonly utilized. In performing free beam laser vaporization and resection of the prostate, the endpoint of operation is the observation of a significant TUR defect in the prostatic fossa with no remaining obstructive tissue, as it is in TURP. In a smaller prostate gland, circumferential complete vaporization of all obstructing BPH tissue with the free beam Ho:YAG laser may be both feasible and efficient. The side-firing holmium laser fiber, directed laterally into the prostate and creating a more divergent beam with a wider swath of tissue vaporization, may offer some

advantage over a simple end-firing delivery fiber in implementing this technique. Obstructing tissue elements are simply painted with the Ho:YAG laser until they are vaporized and visibly disappear. For larger prostate glands, the technique of Ho:YAG laser resection of the prostate (HoLRP) has proven much more efficient in bulk removal of all BPH tissue and is the preferred approach, rather than directly vaporizing all obstructing tissue elements. In this systematic operative approach, treatment is begun by deeply incising the bladder neck posteriorly at the 5 and 7 o'clock positions with the Ho:YAG laser, using a 550 micron end-firing fiber. These incisions are continued from the bladder neck to the level of the verumontanum and then connected in the midline just cephalad to the verumontanum (Figure 62–8). The median lobe is then gradually undermined with this vaporizing laser, working in a retrograde fashion from the verumontanum back to the bladder neck. Before completely freeing the mass of median lobe tissue, the Ho:YAG laser is used to make additional incisions to divide the median lobe into fragments or "chips" than can be easily evacuated from the bladder. Liberation of a large median lobe in its entirety into the bladder is to be avoided when using standard tissue removal techniques (e.g., Ellik evacuator). The Ho:YAG laser resection of the prostatic lateral lobes is then begun by creating deep template incisions in TABLE 62–4. Long-Term Voiding Outcomes after Free Beam Nd:YAG Laser Coagulation of the Prostate* Postoperative Peak flow rate (mL/s) Postvoid residual (mL) AUA symptom index

Preoperative

1 Year

2 Years

3 Years

7.7 (n = 290) 334 (n = 273) 19.9 (n = 289)

16.9 (n = 193) 120 (n = 175) 7.8 (n = 218)

17.1 (n = 84) 117 (n = 84) 8.8 (n = 101)

19.7 (n = 18) 111 (n = 17) 5.7 (n = 20)

*As reported in the combined series of Kabalin and Costello, et al.15,36


the prostate above the lateral lobes bilaterally at the 1 and 11 o'clock positions (Figure 62–9). These incisions are deepened to the level of the prostatic capsule and continued along the length of each lateral lobe from the bladder neck to the verumontanum. For each lateral lobe, this resection is then carried posteriorly along the plane of the prostatic capsule, gradually freeing the lateral lobe from the capsule laterally. Additional longitudinal incisions directed upward and anteriorly from the previously resected floor of the prostatic fossa are then made, further undermining the lateral lobe and eventually connecting with the prior anterior incisions at the distal apex of the lateral lobe. Finally, working from the apex to the bladder neck with the Ho:YAG laser, the lateral lobe is gradually completely freed from the prostatic capsule laterally. Before releasing the entire lateral lobe of the prostate into the bladder, the Ho:YAG laser is again used to incise the lobe, creating smaller fragments or “chips” which will be easily evacuated from the bladder. Upon conclusion of this laser resection a small amount of anterior BPH tissue will occasionally be left between the 1 and 11 o'clock positions. It may be vaporized or undermined and resected with the Ho:YAG laser at this time to complete the resection. This systematic resection technique using the Ho:YAG laser thus combines multiple anatomically planned laser incisions to free median and lateral lobes from the prostatic capsule and divide each into manageable pieces for removal from the bladder. Unlike in other laser techniques, prostatic tissue chips are produced by this procedure which may be submitted for histologic evaluation. Using this vaporizing laser wavelength at very high energy outputs to create multiple incisions, however, also results in a very considerable volume of BPH tissue ablation by immediate vaporization. In fact, it has been estimated that well over half of all obstructing BPH tissue elements are completely vaporized during HoLRP, leaving less than half for removal as specimen.57

FIGURE 62–7. Transverse section through a human prostate removed immediately after free beam Ho:YAG laser vaporization of the transition zone, producing acute transurethral resection defect.

As an alternative, Gilling et al. have now developed a transurethral mechanical tissue morcellator for use in conjunction with HoLRP and have reported its safe application in over 70 prostatectomy procedures, without complication.58 This device eliminates the time and effort spent during HoLRP dividing the median and lateral lobe BPH segments into smaller pieces to enable later evacuation from the bladder. When this device is to be used, Ho:YAG laser resection of the entire median and lateral lobes of the prostate is performed relatively rapidly, without subdivision of the lobes, and the entire lobes pushed back into the bladder. This leaves only three large BPH fragments in the bladder that are then efficiently removed with the tissue morcellator and its suction evacuator. This operation has been described as transurethral enucleation of the entire prostatic adenoma and is anatomically comparable to open enucleation performed during simple open prostatectomy for BPH. Performing HoLRP in conjunction with the use of the tissue morcellator allows efficient treatment of even very large prostates, glands that might otherwise be considered for open prostatectomy. The morcellated prostate fragments have also proven adequate for histologic evaluation following these operations. During the course of Ho:YAG laser vaporization or resection of the prostate, tissue planes are continuously sealed by the laser, with coagulation demonstrable to a depth of 2 to 3 mm or more beyond the level of vaporization.54,56 This eliminates the constant oozing blood loss and irrigation fluid absorption typically observed throughout electroresection of the prostate. Larger bleeding vessels that are exposed can often be sealed simply by increasing the tissue standoff distance of the Ho:YAG laser fiber to approximately 1 mm, thus defocusing the beam and increasing its tissue coagulation properties. Alternatively and more effectively when dealing with larger bleeding vessels, the Nd:YAG laser wavelength can be used at a 40 to 60 watt power setting to secure hemostasis. Rather than aiming directly at the point of bleeding, the Nd:YAG laser should be focused on tissue immediately adjacent to the vessel, with laser energy continuously applied for 5 to 10 seconds—at least 2 to 3 seconds beyond the instant when cessation of bleeding is observed. This provides deep coagulation of the vessel and prevents any incidence of late postoperative rebleeding. There is a dual wavelength laser source currently available that permits instantaneous switching between Ho:YAG and Nd:YAG lasers via the surgeon's foot pedal control, allowing this step to proceed smoothly without interrupting the flow of the operation. This alternating use of the Ho:YAG and Nd:YAG wavelengths for vaporization/resection and coagulation, respectively, bears obvious similarity to the alternating use of cutting and coagulation currents during electrocautery resection. In practice, however, the Ho:YAG laser alone provides much greater tissue coagulation than any electrocautery device;


FIGURE 62–8. Operative approach for free beam Ho:YAG laser resection (HoLRP) of the prostatic median lobe. From Kabalin JN. Laser prostatectomy—free beam. In: Resnick MI, Thompson IM, editors. Surgery of the prostate. New York: Churchill Livingstone; 1998. p. 267–82.


FIGURE 62–9. Operative approach for free beam Ho:YAG laser resection (HoLRP) of the prostatic lateral lobes. From Kabalin JN. Laser prostatectomy—free beam. In: Resnick MI, Thompson IM, editors. Surgery of the prostate. New York: Churchill Livingstone; 1998. p. 267–82.


in the majority of Ho:YAG laser prostatectomy cases, the Nd:YAG laser is not used. In a significant minority of transurethral prostatectomies performed with the Ho:YAG laser, however, the Nd:YAG wavelength does prove advantageous in providing supplemental control (particularly of larger bleeding vessels) to produce an immaculately hemostatic operative field. Postoperative Management At the conclusion of Ho:YAG laser prostatectomy, a 20F, 30 cc Foley urethral catheter is inserted and placed to gravity drainage. Because of the superb hemostasis achieved with Ho:YAG laser vaporization or resection of the prostate, postoperative catheter irrigation is not required. Catheter drainage is typically maintained overnight. The hemostasis achieved during laser vaporization procedures and the overall minimal physiologic stress to the patient allow this operation to be performed on an outpatient basis if desired. It is often a more practical option to hospitalize the patient overnight to facilitate catheter removal and voiding trial on the first postoperative morning, rather than have the patient travel back to the office. This minimal care, overnight hospital stay is easily accommodated by a 23-hour inpatient observation unit, if available. The overnight catheterization involved is actually significantly shorter than the average postoperative catheterization following TURP and is made possible by the superior hemostasis achieved by laser vaporization. Since all obstructing BPH tissue has been acutely vaporized or resected intraoperatively, patients should expect immediate improvement in voiding following catheter removal—like standard TURP and unlike laser coagulation of the prostate. In a randomized prospective study of acute postoperative voiding symptoms occurring during the first 21 postoperative days following HoLRP or TURP, no difference was found between the two treatments.59 Clinical Outcomes The initial clinical pilot study using the Ho:YAG laser to relieve bladder outlet obstruction due to BPH was undertaken in Palo Alto, California.60 Clinical results of HoLRP to treat BPH have subsequently been reported from several centers worldwide (Table 62–5).57–75 The objective voiding outcomes measured after HoLRP are directly comparable to those expected following TURP. In an extended series of men treated with HoLRP,71 84% have experienced a > 50% improvement in peak flow rate, 83% have a postoperative peak flow rate > 15 mL per second, 90% have experienced a > 50% reduction in their American Urological Association (AUA) symptom index, and 86% have a total postoperative AUA symptom index score of < 7. There have been two randomized prospective studies directly comparing outcomes of Ho:YAG laser prostatectomy and TURP. Gilling et al. randomized 120 men undergoing surgery for BPH.72 On average, TURP proce-

dures were 17 minutes shorter than the HoLRP operation. However, TURP was associated with a 6.8% incidence of blood transfusion compared to zero for HoLRP and significantly longer postoperative catheterization and hospitalization requirements (approximately 2 days for TURP versus 1 day for HoLRP). Objective urodynamic outcomes, including pressure-flow studies, showed no difference between the two treatment arms at 3 weeks, 3 months, and 6 months of follow-up (Table 62–6). At a follow-up of 6 months, mean prostatic volume losses of 34% and 39% (not statistically different) for HoLRP and TURP, respectively, were documented by transrectal ultrasound. Mottet et al. randomized 34 men between TURP and Ho:YAG laser prostatectomy.73 On average, treatment with the Ho:YAG laser required 19 minutes longer than TURP in this series. Mean postoperative catheterization and hospitalization times, however, were again longer for TURP, which was also associated with more complications. No differences were observed in objective voiding outcomes of the two operations at followups of 3 months, 6 months, and 12 months. The HoLRP procedure has also been demonstrated to provide an effective and nonmorbid surgical intervention for those patients with BPH who present with urinary retention. In a recently published series of 36 patients presenting with urinary retention and treated with HoLRP, over 90% were rendered catheter-free within 24 hours following surgery.74 Only 2 of 36 men (5.6%) failed therapy, in both cases because of underlying detrusor failure that did not recover in spite of successful relief of bladder outlet obstruction by HoLRP. One randomized prospective study has been reported that compares HoLRP with free beam laser coagulation (VLAP) performed with the Nd:YAG laser for relief of BPH symptoms.75 A total of 44 men were treated in this study. The mean total operative time was 52 minutes for HoLRP versus 41 minutes for VLAP. Both surgical approaches provided significant improvement in voiding, and no significant differences in AUA symptom index scores or peak urinary flow rates were observed between the two treatment arms through 12 months of postoperative follow-up. Perioperative complications were minimal for both operations. Mean postoperative catheterization, however, was significantly longer for VLAP (> 1 week) than for HoLRP (only 1.4 days). Most men treated with VLAP continued to experience significant voiding symptoms assessed during the first 10 days after catheter removal, unlike the immediate voiding improvement observed after HoLRP. In ongoing clinical trials performed since 1993 in Palo Alto and Tauranga, more than 1200 men have undergone HoLRP for treatment of symptomatic BPH.71 More than 90% have had their catheters removed and have successfully voided within 24 hours after the operation. The mean overall postoperative catheterization time after HoLRP has been only 1.5 days (median 1 day), including

580 / Advanced Therapy of Prostate Disease TABLE 62–5. Voiding Outcomes Reported for Free Beam Ho:YAG Laser Resection of the Prostate (HoLRP) AUA Symptom Index Series

Peak Flow Rate (mL/s)

n

Preoperative

Postoperative

Preoperative

Postoperative

Postoperative Follow-up

Palo Alto/Tauranga63,64 Winnipeg65 Los Angeles66 Paris67 Japan68 China69 London70

381 70 70 48 45 18 17

20.7 23.0 23.6 18.0 24.0 24.6 19.0

4.9 9.0 5.0 6.0 2.3 9.0 9.0

8.6 7.8 5.8 9.0 6.6 9.4 11.0

22.8 20.0 20.5 17.0 16.5 20.0 17.0

6 mos 3 mos 12 mos 3 mos 12 mos 3 mos 3 mos

Total/Mean

649

21.4 \

5.5 /

8.2 \

21.2 /

–

–74%

men with preoperative urinary retention, many with poor detrusor function. There have been two cases of complications requiring blood transfusion (< 0.2% incidence), one of which was also associated with prostatic perforation. The total combined incidence of postoperative bladder neck contractures and urethral strictures in this series has been < 5%. The overall retreatment rate for residual BPH tissue has been approximately 0.5%. This incidence is actually less than that reported for TURP. Median followup for all patients in this series is not significantly greater than 1 year at this time, however, and this retreatment number may increase with longer follow-up.

Free Beam Laser Incision of the Prostate In smaller prostates, simple transurethral incision through the bladder neck, prostate, and prostatic capsule (transurethral incision of the prostate, or TUIP) can provide effective relief of bladder outlet obstruction with greater operative efficiency and less morbidity than standard TURP. The Ho:YAG laser has been used to perform free beam laser incision of the bladder neck and prostate rapidly and hemostatically.53,62,76 Operative Technique The free beam Ho:YAG laser is used at high power settings to incise the prostate and bladder neck—at least 2 joules per pulse and a pulse rate of at least 30 hertz—equivalent to 60 watts power or greater. In this procedure, a 550 micron

+159%

end-firing or side-firing holmium laser fiber is applied directly to the bladder neck and, with the laser activated, slowly pulled antegrade along the length of the prostate to the verumontanum. Paired posterolateral incisions (5 and 7 o’clock or 4 and 8 o’clock) are most commonly used but lateral (3 and 9 o’clock) incisions, more anterior incisions, or a single posterior (6 o'clock) incision seem equally effective. These incisions are deepened until periprostatic fat is visualized. Incision through the prostatic capsule seems to be the key to operative success, regardless of the location of the incision(s). Similar but shorter incisions may be used to incise the symptomatic hypertrophic or contracted bladder neck. This will be observed to gape open as the incisions are appropriately deepened. Postoperative Management Following free beam laser incision of the bladder neck and prostate, a 20F, 30 cc Foley urethral catheter is typically left indwelling overnight. This operation has also been performed without postoperative catheterization in selected patients, with reported success. The Ho:YAG laser provides superior intraoperative and postoperative hemostasis compared to electrocautery or cold knife techniques, making outpatient surgical treatment safe and feasible. Clinical Outcomes Gilling et al. performed TUIP with the free beam Ho:YAG laser in 69 men, reporting no complications and success-

TABLE 62–6. Comparison of Urodynamic Outcomes* Qmax (mL/s)

PdetQmax (cm H2O)

Schäfer Grade

n

Preoperative

Postoperative

Preoperative

Postoperative

Preoperative

Postoperative

HoLRP

61

TURP

59

8.9 p = ns 9.1

23.9 p = ns 22.4

75.9 p = ns 83.4

35.2 p = ns 39.2

3.5 p = ns 3.8

0.7 p = ns 1.2

HoLRP = Ho:YAG laser resection of the prostate; TURP = transurethral resection of the prostate; ns = not significant. *Including peak flow rate (Qmax), detrusor voiding pressure at peak flow (PdetQmax), and Schäfer grade for urethral obstruction. Measured preoperatively and 6 months postoperatively in patients undergoing either HoLRP or TURP in the randomized prospective trial reported by Gilling et al.72 No statistical difference was found between treatment arms for any measurement.

Free Beam Laser Prostatectomy / 581 TABLE 62–7. Reported Voiding Outcomes from Two Clinical Trials of Free Beam Ho:YAG Laser Incision of the Prostate62,76 AUA Symptom Index Series

Peak Flow Rate (mL/s)

n

Preoperative

Postoperative

Preoperative

Postoperative

Postoperative Follow-up

Tauranga, Cheshire, U.K.76

69 100

22.3 19.2

8.1 3.7

7.9 9.8

19.0 19.2

3 mos 6 wks

Total/Mean

169

20.5

5.5

9.0

19.1

–

/

\

N.Z.62

\ –73%

ful voiding in all 69 cases after only overnight catheterization.62 Cornford et al. published their experience with 100 cases of TUIP performed with the Ho:YAG laser.76 Ninetyseven patients were managed successfully without any catheter postoperatively, with no significant complications observed. Reported voiding outcomes following Ho:YAG laser TUIP in both series were excellent (Table 62–7). For the small but symptomatic prostate, TUIP is a very simple, easily performed, safe and effective surgical approach.

Summary Free beam laser prostatectomy techniques offer a safer, more hemostatic, and significantly less morbid transurethral approach for removal of obstructive BPH tissue compared to standard electrocautery resection techniques, including both classic TURP and the more recently described “electrovaporization” procedures. In addition, free beam laser prostatectomy operations have been demonstrated to produce clinical improvement in voiding comparable to the “gold standard” TURP data and far superior to many newer, minimally invasive surgical approaches to treatment of BPH. The latest techniques of free beam laser vaporization and resection of the prostate are associated with only overnight catheterization (shorter duration than the typical TURP) and immediate improvement in voiding, without the delay associated with thermal coagulating treatments for BPH (including older free beam laser coagulation operations, interstitial laser application, interstitial radiofrequency therapy, microwave thermotherapy, and high intensity focused ultrasound treatment). Free beam laser prostatectomy is also far more versatile than many newer treatments and surgical devices available for treatment of LUTS and BPH. Being highly operator-dependent, free beam laser prostatectomy allows for modifications of the surgical approach to accommodate any configuration of median or lateral lobe enlargement, massive intravesical median lobe formations, and asymmetric BPH growth. This versatility is similar to classic TURP and differs from many computer-driven technologies that allow for only certain fixed treatment protocols. The ability to treat even very large prostates, accommodating longer operative times if necessary without increased morbidity, surpasses the range of glands safely treated with TURP. Older, sicker

/ +112%

men, particularly those with severe underlying cardiac disease or failure and those who are actively anticoagulated, for whom TURP represents a significant and often prohibitive risk for morbidity or even mortality, can be safely treated with free beam laser prostatectomy techniques. Thus, in many ways free beam laser technology has shown greater versatility than standard TURP. The main drawbacks of free beam laser technology at this time are the necessity of acquiring new laser equipment and providing training. Proper equipment is essential, particularly in the case of laser vaporization and resection techniques. This equipment is not yet available in most operating rooms and will require a significant capital outlay to acquire ($100,000 to $200,000 for a new laser and all associated peripherals). Providing proper training in these new laser techniques represents an equally important and perhaps even more formidable hurdle. Most currently practicing urologists have not received extensive education or background in laser science and medical application of lasers during their original training and must therefore make a personal effort to acquire the knowledge and experience necessary to perform laser prostatectomy. Unfortunately, only a few centers and programs currently offer training in the latest techniques for laser prostatectomy. As noted above, these are highly operator-dependent procedures. This quality makes free beam laser prostatectomy among the most versatile and effective surgical techniques for treatment of BPH. This same quality—the dependence on a skilled operating surgeon familiar with both laser technology and the specific details of laser prostatectomy—may result in reduced clinical efficacy in less experienced hands.

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41.

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52.

53.

54. 55.

56. 57.

58.

urethral evaporation of prostate in the management of benign prostatic hyperplasia. J Urol 1995;154: 2083–8. Gottfried HW, Krautschick A, Hefty R, et al. Transurethral laser ablation of the prostate (TULAP). Preliminary results in 188 patients. Urologe A 1995;34:132–7. Malek RS, Barrett DM, Dilworth JP. Visual laser ablation of the prostate: a preliminary report. Mayo Clin Proc 1995;70:28–32. Kabalin JN, Gill HS, Leach GE, et al. Prospective multicenter ProLase II trial of neodymium:YAG laser prostatectomy. Urology 1997;50:63–5. Kabalin JN. Effect of prostate size on outcome of laser prostatectomy at six months. J Urol 1994;151:230A. Kabalin JN. Neodymium:YAG laser coagulation prostatectomy for patients in urinary retention. J Endourol 1997;11:207–9. Choe JM, Sirls LT. High-energy visual laser ablation of the prostate in men with urinary retention: pressure-flow analysis. Urology 1996;48:584–8. Kabalin JN, Gill HS, Bite G, Wolfe V. Comparative study of laser versus electrocautery prostatic resection: 18month follow-up with complex urodynamic assessment. J Urol 1995;153:94–8. Cannon A, de Wildt M, Abrams PH, de la Rosette JJMCH. Urodynamics and laser prostatectomy. World J Urol 1995;13:134–6. de Wildt MJAM, te Slaa E, Rosier PFWM, et al. Urodynamic results of laser treatment in patients with benign prostatic hyperplasia. Can outlet obstruction be relieved? J Urol 1995;154:174–80. te Slaa E, de Wildt MJAM, Rosier PFWM, et al. Urodynamic assessment in the laser treatment of benign prostatic enlargement. Br J Urol 1995;76:604–10. James MJ, Harriss DR, Ceccherini A, et al. A urodynamic study of laser ablation of the prostate and a comparison of techniques. Br J Urol 1995;76:179–83. Kabalin JN, Bite G. Laser prostatectomy performed with a right-angle firing neodymium:YAG laser fiber at 40 watts power setting. J Urol 1997;158:1923. Johnson DE, Cromeens DM, Price RE. Transurethral incision of the prostate using the holmium:YAG laser. Lasers Surg Med 1992;12:364–9. Kabalin JN. Holmium:YAG laser prostatectomy canine feasibility study. Lasers Surg Med 1996;18:221–4. Conrad S, Henke R-P, Reek C, Huland H. Effects of holmium:YAG laser energy on human benign prostatic hyperplasia tissue: a histologic ex vivo study. J Urol 1996;155:704A. Kabalin JN. Clinical development of holmium:YAG laser prostatectomy. SPIE Proc 1996;2671:292–9. Gilling PJ, Cass CB, Cresswell MD, Fraundorfer MR. Holmium laser resection of the prostate: preliminary results of a new method for the treatment of benign prostatic hyperplasia. Urology 1996;47:48–51. Gilling PJ, Kennett K, Fraundorfer MR. Holmium laser enucleation of the prostate (HoLEP) combined with intracavitary morcellation: early results. J Urol 1998;159 Suppl:303.

59. Gilling PJ, Mackey M, Cresswell MD, et al. The perioperative care of patients undergoing holmium laser resection of the prostate (HoLRP) compared with transurethral resection of the prostate. SPIE Proc 1998. [In press] 60. Kabalin JN. Holmium:YAG laser prostatectomy: results of U.S. pilot study. J Endourol 1996;10:453–7. 61. Gilling PJ, Cass CB, Malcolm AR, Fraundorfer MR. Combination holmium and Nd:YAG laser ablation of the prostate: initial clinical experience. J Endourol 1995; 9:151–3. 62. Gilling PJ, Cass CB, Cresswell MD, et al. The use of the holmium laser in the treatment of benign prostatic hyperplasia. J Endourol 1996;10:459–61. 63. Fraundorfer MR, Cass CB, Gilling PJ, Kabalin JN. The holmium laser in the treatment of benign prostatic hyperplasia. Eur Urol 1996;30 Suppl 2:105. 64. Gilling PJ, Cass CB, Cresswell MD, et al. The evolution of the use of the holmium laser for the treatment of benign prostatic hyperplasia. SPIE Proc 1997;2970:448–51. 65. Krahn HP. Holmium laser transurethral resection of the prostate (TURP) for benign prostatic hyperplasia (BPH). J Urol 1997;157 Suppl:40. 66. David RD, Fuchs GJ, Patel A. Holmium laser resection of the prostate. J Urol 1998;159 Suppl:247. 67. LeDuc A, Anidjar M, Teillac P, Desgrandchamps F. The holmium laser in the transurethral resection of prostate. Br J Urol 1997;80 Suppl 2:198. 68. Matsuoka K, Iida S, Tomiyasu K, et al. Transurethral prostatectomy using the holmium laser. J Urol 1997; 157 Suppl:41. 69. Wu KJ. Several alternative therapies for the treatment of BPH: comparison to the standard TURP. Br J Urol 1997;80 Suppl 2:213. 70. Denstedt JD, Wollin TA, Morton TJ, Nott L. Holmium laser prostatectomy for patients with symptomatic benign prostatic hyperplasia. J Endourol 1997;11:S158. 71. Kabalin JN, Gilling PJ, Fraundorfer MR. Application of the holmium:YAG laser for prostatectomy. J Clin Laser Med Surg 1998;16:21–7. 72. Gilling PJ, Kennett K, Fraundorfer MR, Kabalin JN. Holmium laser resection of the prostate (HoLRP) versus transurethral resection of the prostate (TURP): follow-up at 1 year. J Urol 1998;159 Suppl:249. 73. Mottet N, Anidjar M, Costa P, et al. A randomized study comparing the holmium-YAG vaporization and the transurethral resection of symptomatic BPH. J Endourol 1997;11:S160. 74. Kabalin JN, Mackey MJ, Cresswell MD, et al. Holmium:YAG laser resection of prostate (HoLRP) for patients in urinary retention. J Endourol 1997;11:291–3. 75. Gilling PJ, Cass CB, Malcolm A, et al. Holmium laser resection of the prostate versus neodymium:yttriumaluminum-garnet visual laser ablation of the prostate: a randomized prospective comparison of two techniques for laser prostatectomy. Urology 1998;51:573–7. 76. Cornford PA, Biyani CS, Brough SJ, Powell CS. Daycase transurethral incision of the prostate using the holmium:YAG laser: initial experience. Br J Urol 1997; 79:383–4.

CHAPTER 63

TRANSURETHRAL RESECTION OF THE PROSTATE MARK J. NOBLE, MD; WINSTON K. MEBUST, MD tically validated as to overall validity, test-retest reliability, and internal consistency. While the AUA symptom index is not disease-specific (it has been used in a slightly modified format for female voiding symptoms, for example), it does enable the treating physician to objectively evaluate the severity or frequency of a patient’s voiding symptoms. Because the AUA symptom index does not assess the degree of “bother” or impact of bladder outlet obstruction on a patient’s quality of life, the International Prostate Symptom Score (IPSS) was developed; it comprises the AUA symptom index, with one question added to address the quality-of-life issue. Barry and associates then put together a four-item questionnaire to assess the bother or impact of BPH on quality of life; this was introduced in 1993, and it has undergone a separate statistical validation process.4

History Transurethral resection of the prostate (TURP) can trace its origin to the introduction of the resectoscope by Joseph F. McCarthy in 1932.1 However, development of the resectoscope was made possible by other important inventions. One such invention was the incandescent lamp (Thomas Edison, 1879), which enabled direct visualization of the prostate. Another was the vacuum tube (Lee deForest, 1908), a key component of the electrosurgical generator used for the coagulation and cutting of tissue. A third was the fenestrated tube that permitted transurethral access to the prostate. Further refinements such as the Hopkins rod lens system and fiberoptics for lighting have improved transurethral image quality, and the addition of a compact television camera and video viewing system have facilitated the teaching of the operation to urology residents. Although TURP remains the most common operation performed for benign enlargement of the prostate, there has recently been a marked decrease in its use. One estimate suggests a 52% reduction in TURPs from 1989 to 1995.2 Such a decrease likely reflects the impact of nonsurgical options like alpha-blockers, 5α-reductase inhibitors, and watchful waiting as well as that of interventions like laser therapy, transurethral needle ablation, microwave therapy, and hyperthermia. It is likely that patients’ concerns regarding the low but still-present mortality and morbidity of TURP is driving the selection of one of the above alternative treatments. An alternative treatment may be less effective in relieving urinary symptoms but may minimize the complications and side effects that are nearly always associated with TURP (e.g., bleeding and retrograde ejaculation).

Preparation for Surgery Medical ethics dictate that patients should be fully informed of the risks, complications, advantages, and disadvantages of any form of treatment they are considering. They should also be aware of the alternatives (including the risks and benefits of the alternatives). For the patient considering TURP, informed consent implies a thorough discussion of medical treatment options (including any that were previously tried that failed to adequately help the patient’s symptoms) and a review of minimally invasive interventions as well as various surgical options. While discussion of every detail about each possible treatment is neither desirable nor necessary— whole books have been devoted to this subject, and there is not sufficient time in the office to review everything— there should certainly be discussion adequate enough that the patient may make an informed choice of therapy. At the conclusion of the discussion, the patient should be aware of general improvement rates for the various treatment modalities. The patient should not be given unrealistic expectations; then, if he decides on surgery, he is much less likely to be disappointed with any perceived minor imperfections following surgery (e.g., a small amount of postvoid dribbling). Once informed consent is complete and documented, it is important to prepare the patient for surgery to optimize the result and to minimize complications. A urinary

Indications for Prostatectomy Urinary symptoms constitute the most common reason for intervention in patients with bladder outlet obstruction due to benign prostate enlargement. Of the several methodologies for scoring a patient’s voiding symptoms, the American Urological Association (AUA) symptom index has received the greatest worldwide acceptance. This scoring system for urinary symptoms was developed by Michael Barry and colleagues as part of the AUA guideline on evaluation and management of benign prostatic hyperplasia (BPH).3 It has been statis584

Transurethral Resection of the Prostate / 585

tract infection must be cleared prior to surgery to reduce the chance of perioperative urosepsis. In the absence of infection, the use of prophylactic antibiotics is controversial. There are studies showing no discernible benefit to preoperative, systemic antibiotics,5 and there are also reports suggesting that antibacterial prophylaxis is beneficial.6,7 It has been our practice to administer systemic antibiotics prior to the commencement of surgery, and we maintain patients on oral antibiotics for a minimum of 5 days after removal of the Foley catheter. If a patient takes aspirin or aspirinlike compounds, they should be stopped at least 72 hours prior to surgery. Any systemic anticoagulants such as warfarin sodium (Coumadin) should be stopped sufficiently in advance of surgery to permit normalization of the prothrombin time or INR. If the patient must be anticoagulated until just before surgery, he should be converted to heparin several days preoperatively, and the heparin should be either temporarily halted for surgery or maintained at “minidose” levels for surgery. Low-molecular-weight heparin is another option that may protect against thromboembolic phenomena while lowering the chance of bleeding as compared to ordinary heparin. Despite some studies showing no significant increase in morbidity with certain regimens, we believe that a patient taking an anticoagulant (or antiplatelet drug) has a significantly increased risk of postoperative bleeding compared to an individual on no anticoagulant.8 Although there are exceptional circumstances where a TURP is to be performed on a man younger than 50 years of age and in which certain tests may be waived by the anesthesiologist, preoperative chemistries (including creatinine and electrolytes), complete blood counts (CBCs), urinalyses, electrocardiograms (EKGs), and chest radiographs will be needed for nearly all patients. There is some controversy regarding the need for routine coagulation tests on all patients, but it is still our practice to obtain a prothrombin time (PT), a partial thromboplastin time (PTT), and a platelet count before surgery. Since the majority of patients undergoing TURP have other medical problems, it is important to perform a complete medical evaluation prior to surgery.9 There are some preoperative tests that may be considered optional. For example, it might seem reasonable to obtain a voiding flow rate preoperatively; it is noninvasive, relatively inexpensive, easy to perform, and it yields additional information. Although uroflowmetry can provide a baseline for comparison with the postoperative result, it does not quantitatively correlate with a patient’s symptom score nor is there any specific rate of flow that acts as a definite indicator of bladder outlet obstruction. Further, uroflowmetry does not enable one to distinguish between detrusor impairment and bladder outlet obstruction. Therefore, its preoperative use should be individualized to the patient and may be left to the judgment of the urologist. A pressure-flow study, on the other hand, should

relate much more closely to the patient’s voiding physiology and can provide helpful information in rare situations where the clinical picture is otherwise unclear. Another optional preoperative test is the intravenous pyelogram (IVP). It can provide information if the patient has had prior urinary tract surgery, nephrolithiasis, or chronic infection. It is also important to study the upper urinary tract if there is a history of hematuria. In the absence of these indications, the chance of finding something on an IVP that would alter the course of treatment or affect the planned transurethral surgery is not significantly different from surveying the general population. Thus, imaging prior to TURP should not be routine.10

Anesthesia A variety of anesthetic techniques have been employed for TURP. Spinal, epidural, and general anesthesia are the most commonly used. However, there are reports that TURP may be successfully performed under local anesthesia alone, local anesthesia with intravenous sedation, acupuncture, or even hypnosis. In general, unconventional anesthetic methods have been used for glands less than 40 g in size. We feel that the choice of anesthetic should be tailored to each patient, based on his medical status, anatomy, and other relevant factors. The anesthesiologist should monitor standard parameters during surgery, such as the patient’s electrocardiogram, oxygen saturation, body temperature, and vital signs. In addition, it can be critical to keep track of hematocrit and serum sodium at times, particularly for procedures lasting more than 90 minutes or procedures that are especially bloody (suggesting that a venous sinus was entered at an early stage of the surgery). One might suppose that sympathetic blockade and peripheral vasodilation induced by a spinal anesthetic might risk greater blood loss or other problems during TURP. Interestingly, no significant difference has been seen in blood loss, postoperative morbidity, or mortality in several studies comparing type of anesthesia (spinal vs. general, epidural vs. general) used for TURP.

Surgical Technique Despite a variety of methods for performing TURP, the authors continue to use a methodology that closely follows that described by Nesbit in 1943.10 This technique follows an orderly plan that progressively results in a complete resection of the obstructing, adenomatous tissue. Before describing this technique in detail, we will first summarize our standard preparation in the operating room. Water can be used safely as an irrigating fluid, but for transurethral resection lasting more than 30 minutes, the danger that the patient might suffer hemolysis from absorption of irrigating fluid increases significantly. Hemolytic complications have been recognized for many years and are not trivial.11 Our custom is to use a nonhemolytic irrigating solution such as 1.5% glycine


although mannitol or cytol (a combination of mannitol and sorbitol) may also be used. While such fluids are not isotonic, they are nonhemolytic and have an osmolarity of roughly 200 mOsm/L. We place the patient in the lithotomy position, with his buttocks barely extending off the end of the table. We prefer Alcock leg holders to knee crutches for leg support. The perineum does not need shaving but receives a 5-minute scrub with germicidal soap (Betadine scrub or Hibiclens scrub or the equivalent). An O’Connor rectal sheath facilitates elevation of the floor of the prostate during surgery and maintains an aseptic surgical field. We begin by calibrating the urethra with bougies à boules. Most patients calibrate at 28F, but some patients have a narrower urethral caliber; in such cases, a 24F or 26F resectoscope sheath should be used. If the distal urethra is narrow, a perineal urethrostomy may be performed, enabling direct insertion of the resectoscope through the usually wider bulbar urethra. This can also minimize urethral abrasion when the prostate is very large and the transurethral resection prolonged. The technique for perineal urethrostomy is fairly standard and will not be repeated here. If the only area of distal narrowing is the fossa navicularis, dilation or dorsal internal urethrotomy may be performed. Ventral incision through the meatus most commonly results in spraying or severe deviation of the urinary stream and is best avoided. Some feel that the newer, continuous-flow resectoscopes may enable more rapid tissue removal (although several studies contradict this feeling). These may at least provide better visibility, as the bladder can be maintained in a partially distended state during continuous-flow resection, with partial distention countering venous pressure and reducing apparent bleeding. There may be a theoretic negative side to this if a venous sinus is opened up early in the resection; constant pressure might increase intravenous flow of irrigant into the patient’s vascular bed and thus might cause transurethral resection (TUR)-

FIGURE 63–1. First stage of resection of the prostate. Note that the resection begins at 12 o’clock and that the tissue at the bladder neck and adjacent adenoma is resected in quadrants. (Modified with permission of the Mayo Foundation.)

syndrome more quickly (see below, Intraoperative Problems). Intraoperative electrolyte monitoring should obviate any surprises in this regard. The continuous-flow resectoscopes are usually of larger diameter than noncontinuous-flow instruments and are best used in patients with no restriction of urethral caliber. When beginning the actual resection of prostatic adenoma, one’s choice of method should enable adequate visualization of anatomy, good control of bleeding, and efficient removal of tissue to minimize resection time (which we feel reduces the risk of complications). Most published techniques for TURP describe the resection as proceding initially from the anterior prostate (or “roof ” of the prostatic urethra) down toward the posterior prostate (or “floor”). There are times when a large median lobe obstructs the flow of irrigant such that visibility is reduced; in such cases, initial resection of part or all of the median lobe is probably best. Our custom is to follow the basic Nesbit technique,12 which is divided into three stages. Stage 1: After initial cystoscopy and urethral calibration, the bladder is filled with approximately 150 mL of nonhemolytic irrigation solution such as 1.5% glycine. The resection begins at the bladder neck and starts at the anterior or 12-o’clock position (Figure 63–1). Resection is carried down to the 9-o’clock position in stepwise fashion (the patient’s right lateral prostate lobe). The adenoma is trimmed down to the level where the apparent circular fibers of the bladder neck become visible. Over-resection or cauterization of the bladder neck may result in contracture and should be avoided. The opposite anterior quadrant is then resected in similar fashion from 12 o’clock to 3 o’clock. The posterior quadrants are then individually resected down to the 6-o’clock position. Hemostasis is maintained with spot application of electrocautery; the bladder neck is often an area where brisk bleeding occurs, and a shortcut here may lead to problems with poor visibility during the later phases of the resection. Stage 2: The resectoscope is brought back into a more distal position, such that the end is just proximal to the verumontanum. Resection again begins at 12 o’clock, which permits the lateral lobe tissue to fall into the midfossa. Resection is carried down to the prostatic capsule, which is recognized by its fibrous appearance compared to the granular or fluffy appearance of prostatic adenoma (Figures 63–2 and 63–3). After trimming right and left lateral lobes and with the remaining lateral lobe tissue falling to the floor, resection of fallen lateral lobe tissue is carried out at 3 o’clock and posteriorly for the patient’s left lobe and at 9 o’clock and posteriorly for the patient’s right lobe (Figure 63–4). When removing this posterior tissue, care must be taken not to extend proximally and undermine the trigone. Periodic rechecking of landmarks (such as the bladder neck and the verumontanum) should be performed so that the surgeon remains properly oriented


FIGURE 63–2. The second stage of resection of the prostate begins in the midgland at 12 o’clock and is carried down to the 9-o’clock position. (Modified with permission of the Mayo Foundation.)

FIGURE 63–4. The second stage of resection of the prostate is resected further from 9 o’clock and is carried down to the 6-o’clock position to remove posterior tissue. (Modified with permission of the Mayo Foundation.)

during the resection. Most urologists utilize the Iglesias modification of the Nesbit resectoscope (rather than the Stern McCarthy unit), which enables one hand to remain free for palpation and manipulation of the prostate through the O’Connor rectal sheath.1 By elevating the floor of the prostate through the O’Connor sheath, one can completely resect the remaining lateral lobe tissue in the majority of cases. Such elevation and palpation also allow one a tactile sense of how deeply one is resecting and may help avoid perforation of the posterior prostatic capsule, where fibers are less distinct. When the prostate is fairly small (15 g or less), it is not uncommon for experienced transurethral surgeons to combine the first and second stages of resection into a single phase. Stage 3: This involves trimming apical tissue just proximal to the external sphincter mechanism (Figures 63–5, 63–6, and 63–7). The verumontanum, which denotes the beginning of the external sphincter musculature, should be preserved as a landmark. Should the patient ever require repeat TURP for any reason, this landmark will help the surgeon to remain anatomically oriented. Some term the apical resection at the location of the verumon-

tanum “grooving the veru,” as it usually causes the verumontanum to be more pronounced as the trimming between verumontanum and urethral sidewall is akin to creating a groove. One must be careful not to cut into the fibers of the sphincter during this final trimming; doing so can lead to varying degrees of stress incontinence and to an unhappy patient. It is the experience of the authors that superficial smoothing of actual adenomatous apical prostate tissue does not cause incontinence. But deep resection or extensive coagulation in the region of the verumontanum may pose some risk therein. An additional consideration is that the plane of the urogenital diaphragm is often tilted rather than perpendicular to the longitudinal axis of the prostate. The sphincter mechanism begins more proximally on the roof than on the floor, due to this tilt. This is the likely reason that the most common area of damage to the external sphincter during TURP is at the 12-o’clock position; thus, apical tissue at 12 o’clock should not be resected as distally as at 6 o’clock. In some instances, it may be safer to leave small amounts of apical adenoma rather than risk sphinc-

FIGURE 63–3. The second stage of resection of the prostate continues in the midgland at 12 o’clock and is carried down to the 3-o’clock position. (Modified with permission of the Mayo Foundation.)

FIGURE 63–5. The third stage of resection of the prostate begins at the verumontanum. Apical tissue is resected toward 12 o’clock. (Modified with permission of the Mayo Foundation.)


FIGURE 63–6. Residual apical tissue has been cleared on the patient’s right side in this view while apical tissue on the patient’s left remains to be resected. (Modified with permission of the Mayo Foundation.)

ter injury. The surgeon can spot-coagulate small flaps of urothelium or tiny areas of loose tissue (a process that will cause harmless sloughing and disappearance during the healing phase postoperatively) rather than attempt resection of these flaps, which might result in cutting into sphincter tissue. The experience and judgment of the operator usually enables proper decision making at this phase. After completion of the third stage of resection, it should be possible to place the tip of the resectoscope just distal to the verumontanum and observe a clear pathway into the bladder with no visible obstructing mounds of lateral or median lobe tissue (see Figure 63–7). If the bladder neck appears to be significantly obstructing at this point (often true when the prostate is smaller than 20 g), we advise incising the bladder neck with a Collings knife electrode at the 6-o’clock position. Prior to this vesical neck incision, it is best to remove all prostate tissue fragments (“chips”) from the bladder, using the Ellik evacuator, and to be certain of complete hemostasis, using the resection loop for electrocauterization. This avoids repeated switching of the

FIGURE 63–7. Remaining apical tissue has been cleared from the patient’s left side, leaving an unobstructed view from the verumontanum through the bladder neck to the bladder. (Modified with permission of the Mayo Foundation.)

working element from the Collings knife back to the resection loop. Once the bladder neck is incised, we spotcauterize any small arteries in the incision line and then immediately remove the resectoscope. Although there is not perfect correlation with postoperative successful voiding, use of a Credé method on the mostly full bladder after removal of the scope should produce a strong stream (since the external sphincter is relaxed under anesthesia). Lack of good flow might indicate a retained piece of prostate tissue plugging the urethra or some other mechanical problem and, depending on circumstances, might be cause for endoscopic re-inspection. A three-way catheter, 22F or larger, is then inserted (this may require a stylet for guidance if it does not pass the bladder neck), the balloon is inflated with 30 to 50 mL, and irrigation with a bulb syringe is carried out. If the return is clear or light pink or clears to a light pink color on the second or third irrigation, one may feel comfortable with the level of hemostasis.

Intraoperative Problems Hemostasis If the irrigant does not return clear to pink when the Foley catheter is inserted at the completion of TURP, one may place the catheter on traction (the balloon should have 45 to 50 mL inflation for this) and irrigate again with the bulb syringe. If three or fewer irrigations result in a clear or pink return, the bleeding is venous and the catheter may be placed on traction (taped securely to the thigh on tension) to control postoperative bleeding. It can remain so for a variable length of time, 6 to 24 hours, depending on the clinical situation. Continuous bladder irrigation with normal saline or 1.5% glycine can be employed via the irrigation port of the catheter to help prevent blood clots that might plug the catheter from forming. If traction fails to control the bleeding, then a significant component of the bleeding must be arterial, and the resectoscope should be re-inserted and all bleeders meticulously coagulated. If this subsequently fails to result in a clear-to-pink return (even with traction), then other causes of bleeding, such as coagulopathy, should be considered. Instances in which major prostatic bleeding cannot be controlled endoscopically or with traction and that are not due to coagulation disorders are exceedingly rare in the experience of the authors. Embolization by an interventional radiologist or open surgical packing of the prostate represent extreme measures, but these can help control bleeding if conservative methods fail. Extravasation During or after the TURP, leakage of irrigant and/or urine through the prostatic capsule is rare (< 2% complication rate). This can occur if there is perforation of the prostate capsule during the resection. Symptoms include nausea, vomiting, mental confusion, restlessness, and


pelvic, back, or lower abdominal pain despite spinal anesthesia. Management consists of completion of the TURP as rapidly as possible (with good hemostasis), followed by catheter drainage. More than 90% of patients will heal without further intervention simply by rapid institution of catheter drainage at the first sign of this complication. If there is doubt, cystography can be performed to confirm the diagnosis, but we reserve this test primarily for patients who do not improve with catheter drainage and for whom open drainage of the retropubic space is contemplated. Because patients may become symptomatic with extravasation through the prostatic capsule, we prefer that incision of the vesical neck (for improvement of the bladder outlet) be performed only after all prostatic tissue resection is complete and after all tissue has been fully evacuated from the bladder. Bladder neck incision is essentially a controlled perforation, and without prompt catheter drainage after it is performed, one risks the same symptoms in the patient as inadvertent extravasation early in the TURP. Transurethral Resection Syndrome It is believed that the symptoms of nausea, vomiting, hypertension, bradycardia, mental confusion, and visual abnormalities (including abrupt blindness) occur secondary to rapid dilution of serum sodium when transurethral irrigating solution quickly enters the intravascular space, most commonly through a venous sinus. Water will diffuse into cells (especially those of the central nervous system), and there will be acute cell swelling which can be quite serious. Almost always, the patient will not experience significant symptoms unless the serum sodium falls below 125 mEq/L. Because the sodium concentration has been diluted over a short time course (1 to 2 hours), the best treatment is to rapidly correct this abnormality while it is still in an early phase. Such treatment consists of intravenous furosemide to induce diuresis of salt and water while at the same time administering a small volume of hypertonic (3% or 5%) saline solution. The amount of hypertonic saline to be given initially is one-third to one-half the amount calculated to raise the extracellular sodium concentration to the preoperative level. For example, suppose a 70-kg patient has a sodium level of 138 mEq/L prior to surgery and 113 mEq/L in the recovery room. In a 70-kg male, the extracellular fluid (ECF) volume is approximately 11.5 L (one can adjust this proportionately for a patient of a different body mass). The difference between the preoperative and postoperative sodium concentration may be multiplied by the ECF (25 × 11.5) to yield 287.5 mEq of sodium, and this amount of sodium is contained in approximately 600 mL of 3% normal saline. We would administer one-third of this amount (200 mL of 3% normal saline) fairly rapidly (30 to 60 minutes), and ordinarily, the diuresis induced by furosemide will prevent congestive heart failure. If there is improve-

ment but not sufficient improvement, another 100 mL of 3% normal saline may be given over another 30 minutes. Frequent monitoring of electrolytes (especially serum sodium) is essential during this phase. In our experience, patients recover quickly with rapid correction of the serum sodium concentration. Priapism On occasion, a complete erection may occur, which makes it difficult if not impossible to introduce the resectoscope. The simplest management of this is intracorporal injection of a direct-acting alpha-adrenergic agonist such as phenylephrine at a dose of 20 to 40 µg (0.2 to 0.4 mL of a 1:1000 solution). Alternatively, epinephrine may be used (0.4 mL of a 1:1000 solution), but this may risk more cardiac side effects. The erection should begin to subside after 10 minutes.

Postoperative Short- and Long-Term Complications For the purpose of this discussion, “short-term complications” refers to those occurring during the first 30 days after surgery. (This includes death.) Mortality is a rare short-term outcome following TURP and has steadily decreased during the operation’s approximately 60-year history. As recently as 1976, the mortality rate for TURP was in the 5% range in at least one major study by Perrin et al.,13 but this rate has dropped to 0.2% in a recent study by Mebust and associates.9 One epidemiologic review demonstrated no meaningful difference in mortality during the first 30 postoperative days after TURP compared to the general population in the same age and medical risk categories.14 There were some who found that open prostatectomy was a lower-mortality procedure than TURP, but more recent studies have strongly suggested that any mortality increase for the TURP group most probably reflects the generally poorer cardiopulmonary status of patients in the TURP group.15 In addition to mortality, other complications have been seen with some frequency in the first 30 days after TURP. The most common were failure to void (6.5%), bleeding requiring transfusion (3.9%), and urinary clot retention (3.3%).9 In an interesting study comparing the first 30 days after TURP to no surgery at all, the complication rate for the two groups was identical!16 In fact, the two groups had virtually identical rates of incontinence and impotence, two of the reasons cited by many patients and nonurologists for avoiding TURP altogether. There are only a few studies regarding long-term complications following TURP. Urethral stricture or vesical neck contracture has an incidence of 3 to 11% with 1 to 3 years follow-up, depending on the study one reviews.9,17,18 Retrograde ejaculation is common and ranges from 25 to 99% in incididence, again depending


on the study. Long-term incontinence rates are 0.68 to 1.4%, and long-term impotence rates are 3.3 to 34.8% (studies with preoperative and postoperative comparisons of impotence have found no significant difference).

Success Compared to Other Interventions The ideal method for treatment of BPH is one that is low in risk, affordable, highly successful, durable in response, and not likely to produce side effects. The ideal treatment does not yet exist, but TURP comes close to the ideal and is still considered the “gold standard” by which other treatments are judged. The statistical chance of symptom improvement for patients who have had TURP is 88% (75 to 96%). The degree of symptom improvement is approximately 85%.3 In a contemporary review, Meyhoff and Nordling found that 90% of their patients after TURP had satisfactory results after 5 years, with flow rates remaining significantly improved compared to preoperative flow rates.19 The re-resection rate was 8%, but very little tissue was resected, suggesting that at least some patients may have actually had bladder neck contractures. In two other recent comprehensive studies, patient satisfaction regarding general outcome was 92 to 95% with a follow-up of 5 to 6 years.20,21 Medical therapy as an intervention for BPH currently includes the choice of alpha-blocker medication and/or 5α-reductase inhibition. Both treatments are initially much less expensive than invasive therapy although their long-term true economic costs can approach that of TURP.22,23 They are usually well tolerated, with minor side effects in the majority of cases, and their use does not preclude the later use of invasive treatment(s). Clinical experience convincingly demonstrates that their efficacy lags far behind that of TURP with regard to improvement in symptom scores and flow rates.24–29 If one compares newer minimally invasive interventions (transurethral microwave therapy,30–38 transurethral needle ablation,39–43 interstitial laser coagulation,44–49 urethral stents,50,51 visual or ultrasonographically-guided laser ablation of the prostate,39,52–59 and hyperthermia60) to TURP, one invariably finds that TURP provides the overall best improvement in symptom score assessment and in urinary flow rates.61 Contact laser ablation,39,62 transurethral electrovaporization,63–70 and transurethral incision71–73 of the prostate can provide comparable improvement to TURP in symptom score and flow rate, with reduced blood loss (and the possibility of same-day surgery); but these modalities are not practical, or they lose efficacy when prostate size approaches or exceeds 40 g. Cost assessment studies point out that the initial cost of therapy for BPH (i.e., the first 2 years) is lower with medical therapy or with minimally invasive technology than with TURP; but when longer-term outcomes are

considered and the true economic costs are included (e.g., a significant percentage of those patients on medical therapy and some treated with minimally-invasive procedures still need TURP eventually), TURP compares very favorably.22,23,74 As some authors have recently pointed out, one should not consign the resectoscope to the history books just yet.61,75

References 1. Reuter HJ. Atlas of urologic endoscopic surger y. Philadelphia and Stuttgart: WB Saunders and Georg Thieme Verlag; 1982. 2. Holtgrewe HL. Health Care Financing Administration (US) data. 1997. 3. Barr y MJ, Fowler FJ, O’Lear y MP, et al., and the Measurement Committee of the American Urological Association. The American Urological Association symptom index for benign prostatic hyperplasia. J Urol 1992;148:1549–57. 4. Barry MJ, Fowler FJ, O’Leary MP, et al. Measuring diseasespecific health status in men with benign prostatic hyperplasia. Med Care 1995;33:AS145–55. 5. Gibbons RP, Stark RA, Correa RJ Jr, et al. The prophylactic use—or misuse—of antibiotics in transurethral prostatectomy. J Urol 1978;119:381–2. 6. Leroy A, Humbert G, Fillastre JP, et al. Penetration of lomefloxacin into human prostatic tissue. Am J Med 1992;92 Suppl 4A:12S–4S. 7. Viitanen J, Talja M, Jussila M, et al. Transurethral resection of the prostate and related topics. Randomized controlled study of chemoprophylaxis in transurethral prostatectomy. J Urol 1993;150:1715–7. 8. Chakravarti A, MacDermott S. Transurethral resection of the prostate in the anticoagulated patient. Br J Urol 1998;81(4):520–2. 9. Mebust WK, Holtgrewe HL, Cockett ATK, et al. Transurethral prostatectomy: immediate and postoperative complications. A cooperative study of thirteen participating institutions evaluating 3885 patients. J Urol 1989;141:243–7. 10. Mebust WK. Transurethral surgery. In: Campbell’s urology. Vol. 2. Philadelphia (PA): WB Saunders Co; 1998. 11. Creevy CD, Webb EA. A fatal hemolytic reaction following transurethral resection of the prostate gland: a discussion of its prevention and treatment. Surgery 1947;21:56–66. 12. Nesbit RM. Transurethral prostatectomy. Springfield (IL): Charles C. Thomas; 1943. 13. Perrin P, Barnes R, Hadley H, et al. Forty years of transurethral prostatic resections. J Urol 1976;116:757–8. 14. Chute CG, Stephenson WP, Guess HA, et al. Benign prostatic hyperplasia: a population-based study. Eur Urol 1991;20 Suppl 2:11–7. 15. Malenka DJ, Roos N, Fisher ES, et al. Further study of the increased mortality following transurethral prostatectomy: a chart-based analysis. J Urol 1990;144:224–8. 16. Wasson JH, Reda DJ, Bruskewitz RC, et al. A comparison of transurethral surgery with watchful waiting for moderate symptoms of benign prostatic hyperplasia. N Engl J Med 1995;332:75–9.

Transurethral Resection of the Prostate / 591 17. Bruskewitz RC, Larsen EH, Madsen PO, et al. 3-year followup of urinary symptoms after transurethral resection of the prostate. J Urol 1986;136:613–5. 18. Balbay MD, Ergen A, Sahin A, et al. Development of urethral stricture after transurethral prostatectomy: a retrospective study. Int Urol Nephrol 1992;24(1):49–53. 19. Meyhoff HH, Nordling J. Long term results of transurethral and transvesical prostatectomy: a randomized study. Scand J Urol Nephrol 1986;20:27–33. 20. Montorsi F, Guazzoni G, Bergamaschi F, et al. Long-term clinical reliability of transurethral and open prostatectomy for benign prostatic obstruction: a term of comparison for nonsurgical procedures. Eur Urol 1993;23:262–6. 21. Ala-Opas MY, Aitola PT, Metsola TEJ. Evaluation of immediate and late results of transurethral resection of the prostate. Scand J Nephrol 1993;27:235–9. 22. Ilker Y, Tarcan T, Akdas A. Economics of different treatment options of benign prostatic hyperplasia in Turkey. Int Urol Nephrol 1996;28(4):525–8. 23. Blomqvist P, Ekbom A, Carlsson P, et al. Benign prostatic hyperplasia in Sweden 1987 to 1994: changing patterns of treatment, changing patterns of costs. Urology 1997;50(2):214–20. 24. Beduschi MC, Beduschi R, Oesterling JE. Alpha-blockade therapy for benign prostatic hyperplasia: from a nonselective to a more selective alpha 1A-adrenergic antagonist. Urology 1998;51(6):861–72. 25. Cooper KL, McKiernan JM, Kaplan SA. Alpha-adrenoceptor antagonists in the treatment of benign prostatic hyperplasia. Drugs 1999;57(1):9–17. 26. Hansen BJ, Flyger H, Mortensen S, et al. Symptomatic outcome of transurethral prostatectomy, alpha-blockade and placebo in the treatment of benign prostatic hyperplasia. Evaluation of treatment with the Danish Prostatic Symptom Score (DAN-PSS-1) system. The ALFECH Study Group. Scand J Urol Nephrol 1996;30(2):103–7. 27. Kaplan SA, Olsson CA. Patient satisfaction with finasteride in the treatment of symptomatic benign prostatic hyperplasia. Clin Ther 1996;18(1):73–83. 28. Lowe FC, McDaniel RL, Chmiel JJ, et al. Economic modeling to assess the costs of treatment with finasteride, terazosin, and transurethral resection of the prostate for men with moderate to severe symptoms of benign prostatic hyperplasia. Urology 1995;46(4):477–83. 29. Woods AL. The management of symptomatic benign prostatic hyperplasia with the once-daily alpha 1 blocker, terazosin. Mil Med 1992;157(7):361–4. 30. Ahmed M, Bell T, Lawrence WT, et al. Transurethral microwave thermotherapy (Prostatron version 2.5) compared with transurethral resection of the prostate for the treatment of benign prostatic hyperplasia: a randomized, controlled, parallel study. Br J Urol 1997;79(2):181–5. 31. Dahlstrand C, Walden M, Geirsson G, et al. Transurethral microwave thermotherapy versus transurethral resection for symptomatic benign prostatic obstruction: a prospective randomized study with a 2-year follow-up. Br J Urol 1995;76(5):614–8. 32. Kirby RS, Williams G, Witherow R, et al. The prostatron transurethral microwave device in the treatment of bladder outflow obstruction due to benign prostatic hyperplasia. Br J Urol 1993;72(2):190–4.

33. Lee KT, Tan HH, Li MK, et al. Transurethral microwave thermotherapy (TUMT) for benign prostatic hyperplasia (BPH)—our first 100 cases. Singapore Med J 1995;36(2):181–4. 34. Mompo Sanchis JA, Paya Navarro JJ, Prosper Rovira F. Transurethral thermotherapy with microwaves in patients with benign prostatic hypertrophy and urinary retention: comparative study between high energy (25) and standard energy (2.0). Arch Esp Urol 1996; 49(4):337–46. 35. Netto NR JR, et al. The importance of the prostate weight in transurethral microwave thermotherapy. Arch Esp Urol 1995;48(4):413–7. 36. Tazaki H, Deguchi N, Baba S, et al. Magnetic resonance imaging following microwave thermotherapy, laser ablation and transurethral resection in patients with BPH. Urologe A 1995;34(2):105–9. 37. Walden M, Acosta S, Carlsson P, et al. A cost-effectiveness analysis of transurethral resection of the prostate and transurethral microwave thermotherapy for treatment of benign prostatic hyperplasia: two-year follow-up. Scand J Urol Nephrol 1998;32(3):204–10. 38. Wu YA. Transurethral microwave irradiation and resection of prostate. Chung Hua Wai Ko Tsa Chih 1993;31(3):164–6. 39. Schulman CC, Zlotta AR. Transurethral needle ablation of the prostate for treatment of benign prostatic hyperplasia: early clinical experience. Urology 1995;45(1):28–33. 40. Rosario DJ, Woo H, Potts KL, et al. Safety and efficacy of transurethral needle ablation of the prostate for symptomatic outlet obstruction. Br J Urol 1997;80(4):579–86. 41. Rodrigo Aliaga M, Lopez Alcina E, Monserrat Monfort JJ, et al. Treatment of benign hyperplasia of the prostate using thermal transurethral needle ablation (TUNA). Actas Urol Esp 1997;21(7):649–54. 42. Millard RJ, Harewood LM, Tamaddon K. A study of the efficacy and safety of transurethral needle ablation (TUNA) treatment for benign prostatic hyperplasia. Neurourol Urodyn 1996;15(6):619–28. 43. Dixon CM. Transurethral needle ablation for the treatment of benign prostatic hyperplasia. Urol Clin North Am 1995;22(2):441–4. 44. Muschter R, Whitfield H. Interstitial laser therapy of benign prostatic hyperplasia. Eur Urol 1999;35(2):147–54. 45. Horninger W, Janetschek G, Watson G, et al. Are contact laser, interstitial laser, and transurethral ultrasoundguided laser-induced prostatectomy superior to transurethral prostatectomy? Prostate 1997;31(4):255–63. 46. Baldassari M, Galosi AB, Cristalli AF, et al. Interstitial laser coagulation of the prostate in patients with prostatic hypertrophy: preliminary results with medium-term follow-up. Arch Ital Urol Androl 1998;70 (3 Suppl):31–5. 47. Muschter R, Hofstetter A. Interstitial laser therapy outcomes in benign prostatic hyperplasia. J Endourol 1995;9:129–35. 48. Muschter R, de la Rosette JJ, Whitfield H, et al. Initial human clinical experience with diode laser interstitial treatment of benign prostatic hyperplasia. Urology 1996;48:223–8. 49. Williams JC. Interstitial laser coagulation of the prostate: introduction of a volume-based treatment formula with 12-month follow up. World J Urol 1998;16:392–5.

592 / Advanced Therapy of Prostate Disease 50. Oesterling JE. The UroLume endoprosthesis: a summary of the European and North American experience. Prog Clin Biol Res 1994;386:561–75. 51. Yachia D. Long-term temporary prosthesis in prostatic obstruction. ProstaCoil, an expanding, self-fixating implant of large caliber. J Urol 1993;99(6):328–31. 52. Chatzopoulos C, Lorge FJ, Opsomer RJ, et al. Transurethral ultrasound-guided laser-induced prostatectomy: a critical evaluation. J Endourol 1996;10(5):463–7. 53. Schulze H, Martin W, Engelmann U, et al. TULIP— transurethral ultrasound-controlled laser-induced prostatectomy: an alternative to TURP? Urologe A 1993;32(3):225–31. 54. Schulze H, Martin W, Hoch P, et al. TULIP (transurethral ultrasound-controlled laser-induced prostatectomy)— experiences with over 80 patients. Urologe A 1995; 34(2):84–9. 55. Schulze H, Martin W, Hoch P, et al. Transurethral ultrasound-guided laser-induced prostatectomy: clinical outcome and data analysis. Urology 1995;45(2):241–7. 56. Cowles RS 3rd, Kabalin JN, Childs S, et al. A prospective randomized comparison of transurethral resection to visual laser ablation of the prostate for the treatment of benign prostatic hyperplasia. Urology 1995;46(2):155–60. 57. Jung P, Matteber P, Wolff JM, et al. Visual laser ablation of the prostate: efficacy evaluated by urodynamics and compared to TURP. Eur Urol 1996;30(4):418–23. 58. Uchida T, Egawa S, Iwamura M, et al. A non-randomized comparative study of visual laser ablation and transurethral resection of the prostate in benign prostatic hyperplasia. Int J Urol 1996;3(2):108–12. 59. Kabalin JN, Gill HS, Leach GE, et al. Prospective multicenter ProLase II clinical trial of neodymium:yttriumaluminum-garnet laser prostatectomy. Urology 1997; 50:63–5. 60. Petrovich Z, Pike MC, Boyd SD, et al. Transurethral hyperthermia for benign prostatic hyperplasia: long term results. Int J Hyperthermia 1996;12(5):595–606. 61. Holtgrewe HL. Current trends in management of men with lower urinary tract symptoms and benign prostatic hyperplasia. Urology 1998;51(4A Suppl):1–7. 62. Cresswell M, Cass CB, Fraundorfer MR, Gilling PJ. Holmium:YAG laser resection of the prostate: preliminary experience with the first 400 cases. N Z Med J 1997;110:76–8. 63. Gallucci M, Puppo P, Fortunato P, et al. Transurethral electrovaporization of the prostate with the Vaportrode VE-B. Preliminary results. Eur Urol 1996;29(4):450–5.

64. Gallucci M, Puppo P, Perachino M, et al. Transurethral electrovaporization of the prostate vs. transurethral resection. Results of a multicentric, randomized clinical study on 150 patients. Eur Urol 1998;33(4):359–64. 65. Hammadeh MY, Madaan S, Singh M, et al. Two-year follow-up of a prospective randomised trial of electrovaporization versus resection of prostate. Eur Urol 1998;34(3):188–92. 66. Hammadeh MY, Fowlis GA, Singh M, et al. Transurethral electrovaporization of the prostate—a possible alternative to transurethral resection: a one-year follow-up of a prospective randomized trial. Br J Urol 1998;81(5): 721–5. 67. Kupeli B, Yalcinkaya F, Topaloglu H, et al. Efficacy of transurethral electrovaporization of the prostate with respect to standard transurethral resection. J Endourol 1998;12(6):591–4. 68. Meade WM, McLoughlin MG. Endoscopic rollerball electrovaporization of the prostate—the sandwich technique: evaluation of the initial efficacy and morbidity in the treatment of benign prostatic obstruction. Br J Urol 1996;77(5):696–700. 69. Moreno JG, Hirsch IH, Gomella LG, et al. New prostatectomy technique: transurethral electrovaporization of the prostate. Technol Urol 1995;1(2):62–6. 70. Shokeir AA, al-Sisi H, Farage YM, et al. Transurethral prostatectomy: a prospective randomized study of conventional resection and electrovaporization in benign prostatic hyperplasia. Br J Urol 1997;80(4):570–4. 71. Di Silverio F, D’Eramo G, Flammia GP, et al. Comparative effects of transurethral incision (TUIP) and the combination of TUIP and LHRH agonists in the treatment of benign prostatic hypertrophy. J Urol 1996;102(3): 111–6. 72. Kletscher BA, Oesterling JE. Transurethral incision of the prostate: a viable alternative to transurethral resection. Semin Urol 1992;10(4):265–72. 73. Saporta L, Aridogan IA, Erlich N, et al. Objective and subjective comparison of transurethral resection, transurethral incision and balloon dilatation of the prostate. A prospective study. Eur Urol 1996;29(4): 439–45. 74. Ahlstrand C, Carlsson P, Jonsson B. An estimate of the lifetime cost of surgical treatment of patients with benign prostatic hyperplasia in Sweden. Scand J Urol Nephrol 1996;30(1):37–43. 75. Holtgrewe HL. Transurethral prostatectomy. Urol Clin North Am 1995;22(2):357–68.

CHAPTER 64

TRANSURETHRAL INCISION OF THE PROSTATE JOHN G. ANEMA, MD; ALLEN F. MOREY, MD, FACS; JOHN P. FOLEY, MD Transurethral incision of the prostate (TUIP) is increasingly recognized as an effective operative treatment for bladder outlet obstruction. Multiple studies over the past 25 years have confirmed the safety and effectiveness of TUIP, especially as an alternative to traditional transurethral resection of the prostate (TURP) for treatment of smaller prostate glands. New treatments promoted for the alleviation of bladder outlet obstruction (BOO) symptoms must not only be compared with the safety and efficacy of standard TURP but also with TUIP, the seminal minimally invasive treatment of BOO.

described making incisions in the bladder neck and prostate, Orandi was the first to describe this procedure as an incision of the prostate.6 He was therefore successful in setting forth TUIP as an effective treatment for BOO in patients who were not candidates for TURP. Orandi has reported results of TUIP performed on 846 patients.7 Orandi began performing TUIP in 1969 and first reported on this series in 1973.6,8 While Kietzer first published his data in 1961, Orandi credits his inspiration to Aboulker’s report of a series of 218 patients who had undergone divulsion of the prostate.9 This procedure entailed rupturing the anterior and posterior commissures of the prostate using an expandable sound. While improving voiding function in 75% of patients, this procedure was accompanied by an unacceptably high significant complication rate, including hemorrhage, incontinence, and phlegmon of the space of Retzius. Orandi surmised that controlled incisions in the prostate performed under endoscopic vision would yield effective results without significant complications in men who did not need TURP.7 While Orandi coined the term TUIP and published the first significant series, he recognized that others had been performing variations of his TUIP for some time. He does credit Keitzer and Turner-Warwick with previous descriptions of endoscopic incisions in and near the bladder neck. Turner-Warwick reported on 70 patients the same year that Orandi first published his series, both having begun bladder neck/prostate incisions in the late 1960s.10 British and European authors persisted in reporting this technique as transurethral incision of the bladder neck until about 1990. Over the past 25 years, different investigators have reported series of TUIP in both retrospective and prospective studies. Most have shown low complication rates and short- and long-term effectiveness comparable to TURP in men with prostate glands < 30 grams.

History Incisions of the lower urinary tract have been employed since the sixteenth century when Ambroise Paré designed an instrument for excising “carnosities” or strictures of the urinary tract.1 William Blizzard is credited with the first incision of the prostate, performed in 1806 with the use of a double gorget, or knife, introduced through a perineal urethrotomy. Significant complications, however, including hemorrhage, infection, incontinence, and operative mortality prevented general acceptance of this technique.2 Guthrie improved this procedure in 1834 by fabricating a small knife that could be extended beyond the tip of a metal catheter. Mercier further advanced these ideas in 1836 by developing an instrument to incise the bladder neck. In 1874, Bottini introduced a galvanocautery device comprised of two blades that allowed for passage of a galvanic current producing heat and thus cautery. This allowed some control of the hemorrhaging that had plagued previous techniques and instruments.3 The birth of modern urology with the advent of the cystoscope and diathermy enabled Beer in 1933 to significantly improve on techniques for incising the bladder neck.3 Keitzer published a series in 1961 and 1969 describing an incision of the bladder neck for “median bar” or “bladder neck contracture.” This was done blindly initially, using an Otis urethrotome to make incisions in the bladder neck at the 6 o’clock and 12 o’clock positions. Keitzer later developed a cold knife device that allowed direct visual incision of the bladder neck from the trigone to the verumontanum down to the capsule of the prostate.4,5 Orandi stands as the recognized pioneer and promoter of the modern TUIP procedure. While others had

Indications Indications for TUIP are similar to those for TURP, including recurrent urinary tract infections, urinary retention, and BOO symptoms—both obstructive (straining, weak stream, hesitancy, incomplete emptying, intermittency, and dribbling) and irritative (frequency, nocturia, and urgency). Patients with significant comorbid conditions or with a need for anticoagulation (e.g., 593


patients with a prosthetic heart valve) who may not tolerate TURP may better tolerate TUIP. Orandi originally proposed TUIP for men who were not candidates for TURP based primarily on a small prostate. He later extended his indications to all men with BOO with prostates of up to 40 grams.7 Prostate Size Most authors have proposed a prostate size cutoff for TUIP of < 30 grams while some suggest < 20 grams. Prostate size can be estimated by digital rectal examination (DRE) or transrectal ultrasound (TRUS). Some authors have used estimates derived in this manner for size cutoff while others use estimated “resectable” weight. Of note, of the 3500 patients reported by Mebust who had undergone TURP, 81% had resected specimens of < 30 grams.11 This suggests that the number of potential TUIP patients currently undergoing TURP is vast. Jansen’s recent prospective randomized trial, however, including patients with larger prostate glands of 20 to 40 grams (estimated by TRUS), found a significant benefit of TURP versus TUIP in patients followed more than 2 years. Nearly 25% of the TUIP patients in this study required a second operative procedure within 2 years. At follow-up cystoscopy, many of the TUIP patients showed adhesions between the prostatic lobes and “excessive healing” of the incisions.12 Riehman, on the other hand, reported no difference between TUIP and TURP outcomes in patients with prostate glands < 20 grams (resectable weight estimated by cystoscopy and DRE).13 Endoscopic Appearance Orandi described the importance of the endoscopic appearance of the prostate in addition to a size cutoff. He described the ideal TUIP patient as having a short prostatic urethra and an elevated bladder neck, without significant lateral lobe obstruction (Figure 64–1).7 Others have described this constellation of findings as primary vesical neck contracture, median bar, or sclerosis du col.14 Candidates with minimal lateral lobe hypertrophy can still be considered for TUIP, but patients with substantial lateral lobe hypertrophy have been shown to be poor candidates.12 For patients who have not had preoperative cystoscopy, the current authors obtain operative consent for both TUIP and TURP and make the final determination at the time of surgery. Prostate-Specific Antigen In the current prostate-specific antigen (PSA) era, all potential TUIP candidates should have a normal preoperative PSA level and DRE, and/or negative prostate biopsy. Unlike TURP, no tissue is resected with TUIP, therefore patients having occult carcinoma of the prostate presumably could be diagnosed by TURP rather than TUIP. Given the high sensitivity of preoperative PSA

measurement, it is unlikely that TUIP patients would harbor significant undetected occult carcinomas. Urodynamics At a minimum, urodynamic studies should include uroflometry documenting a decreased maximal flow rate. Along with flow rate, International Prostate Symptom Score (IPSS) is helpful and is increasingly required for approval of surgical treatment by managed care organizations. Some managed care companies also require documentation of a failure of α-blocker therapy. Despite these requirements, all patients must be fully advised of all treatment options, including medical therapy. Pressureflow studies should be considered in all patients with previous bladder neck surgery or with concurrent neurologic diagnoses. These urodynamic studies do not designate indication for TUIP over TURP but simply confirm BOO.

Technical Aspects Location of Incision The TUIP procedure can be performed with either one or two incisions. Double incisions have been described at the 3 and 9, 4 and 8, and 5 and 7 o’clock positions (Table 64–1). Proponents of a single incision have described doing so at the 5, 6, 7, or 12 o’clock positions. An incision at the 12 o’clock position involves the potential risk of entering the dorsal vein complex, with the resultant potential for massive hemorrhage.14 The incision is started 1 cm distal to the ureteral orifice (at the ureteric ridge for 6 o’clock incisions) and carried lateral to or just proximal to, the verumontanum. Making the incision at 5 or 7 o’clock decreases the risk of rectal injury; lateral incisions, however, may cause injury to the neurovascular bundle. Single Versus Double Incision No study has directly compared the benefits of two incisions versus a single incision. Series using a single incision report similar results as those with bilateral incision. Turner-Warwick did report a 10% lowering of the incidence (15 to 5%) of retrograde ejaculation in patients having only one incision but this has not been consistently confirmed by other investigators.10 A single incision approach has the advantage of less potential morbidity and shorter operative time. The current authors prefer a single incision at 6 o’clock, from the distal trigone to the verumontanum (Figure 64–2). Depth of Incision Most have reported making the incision(s) through the prostatic capsule down to the periprostatic fat. The rationale for this lies in the belief that the increased outflow resistance of the bladder in smaller prostates is due to the α-adrenergic–sensitive prostatic stroma forming the capsule.15 Incising through the capsule ensures interruption

Transurethral Incision of the Prostate / 595

of any residual tone. Orandi recommends in his later series incising only down to the prostatic capsule and preserving the bladder neck.8 The argument against incising through the capsule stems from concern over preventing significant hemorrhage and potentially increasing the risk of retrograde ejaculation. Collins Knife versus Loop The current authors routinely use a Collins knife with the diathermy in the coagulation mode. Others have espoused using a resectoscope loop to provide tissue for ruling out occult carcinoma.16 The loop can be used to “groove” the prostate at the 5, 6, or 7 o’clock positions. The use of the loop can also help visualization at the depth of the incision/resection, which is often difficult. Lin has recommended resecting the median lobe tissue between a 4 and 8 o’clock position.17 This technique should be more accurately described as a limited TURP but has shown good results and seems especially appropriate when a large median lobe remains following bilateral incisions. Method of Anesthesia Orandi first reported successful use of local anesthesia for performing TUIP and other transurethral procedures in 1984.18 He described a technique in which he injected local anesthetic transurethrally in and around the bladder neck. Since that time, several other investigators have reported successful variations of Orandi’s technique.19,20 Perineal injection of local anesthetic has also been described.21 The current authors routinely employ regional (spinal) anesthesia for TUIP.

Laser Transurethral Incision of the Prostate The neodymium:yttrium-aluminum-garnet (Nd:YAG) laser was first successfully used for visual laser ablation of the prostate (VLAP), the first laser technique for treating BOO.22 The use of this laser to perform TUIP has also been described using both contact tips and side-firing free-beam lasers.2 Because of the virtual absence of hemorrhage, the use of the laser TUIP has been especially effective in treating high-risk patients and those requiring anticoagulation. In a series of 12 patients on Coumadin treated with Nd:YAG laser TUIP, no hemorrhagic complications occurred (Morey A, personal communication, 1998). The free-beam Nd:YAG laser (1064 nm wavelength), however, penetrates approximately 5 mm into the prostate tissue and is more suited for creating zones of coagulation necrosis. This laser must be used in conjunction with an energy absorbing contact fiber tip to vaporize tissue, effectively eliminating tissue absorption of the laser energy. The holmium:YAG (Ho:YAG) laser (214 nm wavelength) by comparison has only a 0.4 mm absorption

length. Because it is a pulsed laser it has excellent tissue vaporization characteristics.23 As a pulsed laser, each laser pulse delivers power in the kilowatt range, which is much higher than the average power reading of 60 to 80 watts. This high power gives precise, char-free incising capability. Holmium YAG TUIP produces a 2 to 3 mm zone of coagulation necrosis seen histologically, which accounts for the near bloodless field.24 Cornford has espoused a catheterless Ho:YAG TUIP based on the excellent control and hemostasis associated with this technique.25 The current authors have found in their experience that this modality has shown an excellent ability to create a bloodless incision into the prostate. An open tip ureteral catheter is inserted through the electrode guide of a standard resectoscope and a 375 or 550 micron laser fiber is passed through it. The actual incision is made exactly as would be done for a standard TUIP. Reported results and complications are similar to those for TUIP performed with a Collins knife.25

Results Treatment outcome is generally measured by improvements in symptom score and maximal urinary flow rates. Madsen and Bruskewitz produced an excellent summary of the multiple studies reporting the outcome of TUIP; most showed efficacy roughly equivalent to TURP (Figure 64–3).26 Orandi published his nonrandomized, uncontrolled series of 646 patients followed over 15 years in 1985. Only 10% of his patients reported outcomes as poor, with the remainder reporting either complete symptom relief (79%) or improved symptoms (11%) following TUIP. Ten percent of Orandi’s TUIP patients eventually required TURP but half had continued symptoms despite a second operation.8 The largest series comparing TURP to TUIP in a randomized prospective study, with 220 patients, was reported

FIGURE 64–1. Endoscopic appearance from the verumontanum of an ideal candidate for TUIP. The prostatic fossa is short, and a high bladder neck is noted with minimal lateral lobe prostatic tissue.

596 / Advanced Therapy of Prostate Disease TABLE 64–1. Location of Incision* Unilateral

Bilateral

Both

Position of Incision

12, 10, 8, 6, 5, or 7o’clock

4 and 8, 9 and 3, 4 or 5 and 7 or 8, 5 and 7 o’clock

4 and/or 8, 5 and/or 7 o’clock

Reference

Jenkins 197827 Moisey 198228 Edwards 1982, 198529,30 Graversen 198731 Dorflinger 198732 Mobb 198833 Nielsen 198834 Kelly 198935 Waymont 198936 Bruskewitz 199037 D’Ancona 199038 Katz 199039 Christensen 199040 Soonawalla 199241 Simsek 199316 Riehmann 199513 Irani 199619 Cornford 1997, 1998†25,42 Gilling 1998†24

Orandi 1973, 1987, 19906,7,43 Turner-Warwick 197310 Andersen 198044 Dalaere 198345 Christensen 198546 Li 198747 Loughlin 198748 Drago 199121 Lin 199217 Jahnson 199812

Hedlund 19852 Hellstrom 198649

*Adapted from Riehmann M, Bruskewitz R. Transurethral incision of the prostate and bladder neck. J Androl 1991;12(6):415–22. †Transurethral incision of the prostate (TUIP).

by Soonawalla and Pardanani in 1992. They showed that for treatment of prostates less than 30 grams, TUIP was associated with significantly shorter operating times and a decreased need for transfusions (38 patients with TURP required blood transfusions versus none for TUIP). Followup at 3 months and 1 year showed significant improvement in symptoms and flow rates for both TUIP and TURP groups but no significant difference between the groups.41 Riehman presented a prospective randomized trial of TUIP versus TURP of prostates < 20 grams in 120 patients with an average follow-up of 34 months. Again, no significant difference was demonstrated between the procedures in terms of improved flow rates and symptom scores. Sixteen

A

percent of the TURP patients and 23% of the TUIP patients required additional treatments for their symptoms but this difference was not significant.13 Dorflinger presented 60 patients randomized to TUIP or TURP and showed significantly shorter operative time, decreased blood loss, and decreased need for transfusion with TUIP. He did, however, show a slightly better flow rate following TURP.50 The only study showing a significant difference between the results of TUIP versus TURP was Jahnson’s series, which included glands of up to 40 grams (see Indications section, above).12 The Benign Prostatic Hyperplasia (BPH) Guideline Panel reviewed all of the literature from 1983 to 1990 reporting results of TUIP and TURP studies. The panel showed that

B

FIGURE 64–2. A, The incision is produced with a Collins knife at the 6 o’clock position from the distal trigone to verumontanum. B, The incision is deepened roughly to the level of the circular prostatic capsular fibers.

Transurethral Incision of the Prostate / 597

the chance for improving symptoms was slightly better for TURP (75 to 96%) than TUIP (78 to 83%).51 The lower complication rate of TUIP, however, makes it an attractive alternative in suitable patients.

Complications Minimizing complications associated with standard TURP, especially in younger men, was one of the initial goals proposed by Orandi in 1973 for doing TUIP.6 In Mebust’s cooperative study of the immediate and postoperative complications of TURP, a low mortality rate of 0.2% was shown in 3885 patients but a significant postoperative morbidity rate of 18% was also found. Intraoperative complications included bleeding requiring transfusion (2.5%), transurethral resection syndrome (2%), and arrhythmias (1.1%). Postoperative morbidity included a 6.5% urinary retention rate, 3.9% transfusion rate, 3.3% clot retention rate, and a urinary tract infection rate of 2.3%.11 Specific complications of TURP and TUIP include bleeding requiring blood transfusion, sexual dysfunction (erectile dysfunction and retrograde ejaculation), bladder neck contracture/urethral stricture, total urinary incontinence, and death. The risk of blood transfusion associated with a TURP was 12.5% but only 1.2% with TUIP.51 Earlier series of TURP show higher transfusion rates; later surgeons were likely influenced by the risk of HIV infection and thus may have been more reluctant to transfuse. Sexual Dysfunction In the studies reviewed by the BPH Panel, the risk of erectile dysfunction following TURP and TUIP was 3.3 to 34.8% and 3.9 to 24.4%, respectively. Cornford reported that in his series of unilateral 7 o’clock Ho:YAG TUIP patients, all 77 patients who had normal erections preoperatively maintained normal erections postoperatively, with 8 to 10% developing retrograde ejaculation.25 Riehman showed, in a randomized prospective study involving 120 patients, a retrograde ejaculation rate of 68 and 35% for 22 TURP and 23 TUIP patients, respectively, who had been potent preoperatively (see Table 64–2).13 Soonawalla showed in his prospective randomized trial of 220 TURP and TUIP patients that no patients lost potency postoperatively. The retrograde ejaculation rates for 60 potent patients undergoing unilateral TUIP (through the bladder neck extending down to the fat) and 49 potent patients undergoing TURP were 33 and 36%, respectively.41 Most studies do, however, show a decreased risk of retrograde ejaculation following TUIP (6 to 55%) versus TURP (25 to 99%). Bladder Neck Contracture Many authors have noted an increased risk of bladder neck contracture in men with small prostate glands (< 20 g) undergoing TURP.56 Bladder neck incision fol-

FIGURE 64–3. Final endoscopic appearance from the verumontanum following single-incision TUIP reveals wide open bladder outlet and excellent hemostasis.

lowing TURP of a small gland has been shown to decrease the rate of bladder neck contracture.57 Orandi showed no instances of bladder neck contracture in his series of 846 TUIP patients. This compares with a reported rate of between 0.14 and 20% for TURP.

Conclusion Transurethral incision of the prostate is a safe and effective treatment for BOO, especially in men with small prostate glands and minimal lateral lobe hyperplasia. The proceTABLE 64–2. Comparison of Retrograde Ejaculation Following TUIP and TURP* TUIP Reference Windle52 Turner-Warwick53 Edwards29 Orandi8 Hedlund2 Hellstrom49 Dorflinger32 Larsen54 Orandi43 Mobb33 Kelly35 Christensen40 D’Ancona38 Katz39 Soonawalla41 Sirls55 Riehman13

%

N

15† nr 5‡ nr 20 20 47 114 5 61 0 7 0 17 28 9 31 17 15 40 45 11 13 23 0 22 17 42 33 60 11 36 35 23

Follow-Up nr nr 3 mos 3 mos–15 yr 6 mos 6 mos 3 mos 3–12 mos 1.5–36 mos 2–3 mos 6–34 mos 3–48 mos 3 mos 1.5–64 mos 3–24 mos 12–96 mos 1–82 mos

TURP %

N

51

49 6 mos–2.5 yr

Follow-Up

100

21 3 mos

62 45 100 25

13 21 8 12

6 mos 3 3–12 mos 1.5–36 mos

37 63

19 3–48 mos 19 3 mos

36

49 3–24 mos

68

22 1–82 mos

TUIP = transurethral incision of the prostate; TURP = transurethral resection of the prostate; nr = not reported. *Adapted from Riehmann M, Bruskewitz R. Transurethral incision of the prostate and bladder neck. J Androl 1991;12(6):415–22. †Bilateral. ‡Unilateral.


dure should be considered for men with small glands, medical problems precluding standard TURP, and for men desiring continued fertility. Holmium laser TUIP as a modification of standard TUIP is similarly effective and shows promise as an outpatient TUIP procedure, and for those on anticoagulation therapy.

References 1. Nation RF. Evolution of knife-punch resectoscope. Urology 1976;7:417–27. 2. Riemann M, Bruskewitz R. Transurethral incision of the prostate and bladder neck. J Androl 1991;12:415–22. 3. Hedlund H, Ek A. Ejaculation and sexual dysfunction after endoscopic bladder neck incision. Br J Urol 1985;57:164–7. 4. Keitzer WA, Cervantes L, Demaculangan A, Cruz B. Transurethral incision of the bladder neck for contracture in male patients. J Urol 1961;86:242–6. 5. Keitzer WA, Tandon B, Allen J, et al. Urethrotomy visualized for bladder neck contracture in male patients. J Urol 1969;102:577–80. 6. Orandi A. Transurethral incision of the prostate. J Urol 1973;110:229–31. 7. Orandi A. Transurethral resection versus transurethral incision of the prostate. Urol Clin North Am 1990;17: 601–12. 8. Orandi A. Transurethral incision of the prostate (TUIP): 646 cases in 15 years—a chronological appraisal. Br J Urol 1985;57:703–7. 9. Aboulker P, Steg A. La divulsion de la prostate d’apres 218 observations personnelles. J Urol Nephrol 1964;70:337. 10. Turner-Warwick RT, Whiteside CG, Worth PH, et al. A urodynamic view of the clinical problems associated with bladder neck dysfunction and its treatment by endoscopic incision and transtrigonal posterior prostatectomy. Br J Urol 1973;45:45–9. 11. Mebust WK, Hotgrewe HL, Cockett PC, Peters PC. Transurethral prostatectomy: immediate and postoperative complications. A cooperative study of 13 participating institutions evaluating 3885 patients. J Urol 1989;141:243–7. 12. Jahnson S, Dalen M, Gustavsson G, Pedersen J. Transurethral incision versus resection of the prostate for small to medium benign prostatic hyperplasia. Br J Urol 1998;81:276–81. 13. Riehmann M, Knes JM, Heissey D, et al. Transurethral resection versus incision of the prostate: a randomized controlled, prospective study. Urol 1995;45:768–75. 14. Mebust WK. Transurethral resection and excision of the prostate. In: Lepor H, Lawson RK, editors. Prostate diseases. Philadelphia (PA): WB Saunders; 1993. p. 150–63. 15. Hutch JA, Rambo ON Jr. A study of the prostate, prostatic urethra and the urinary sphincter system. J Urol 1970; 104:443. 16. Simsek F, Turkeri LN, Ilker YN, Akdas A. Transurethral grooving of the prostate in the treatment of patients with benign prostatic hyperplasia. An alternative to transurethral incision. Br J Urol 1993;72:84–7.

17. Lin C. Transurethral incision and posterior resection of prostate (TUI-PRP) for selected patients with benign obstructive prostatic disease. Urol 1992;39:508–11. 18. Orandi A. Urological endoscopic surgery under local anesthesia: a cost reducing idea. J Urol 1984;132: 1146–7. 19. Irani I, Bon D, Fournier F, et al. Patient acceptability of transurethral incision of the prostate under local anesthesia. Br J Urol 1996;78:904–6. 20. Hugosson J, Bergdahl S, Norlen L, Ortengren T. Outpatient transurethral incision of the prostate under local anesthesia: operative results, patient security and cost effectiveness. Scand J Urol Nephrol 1993;27:381–5. 21. Drago JR. Transurethral incision of prostate. Urol 1991; 38:305–6. 22. Costello AJ, Bowsher WG, Bolton KG. Laser ablation of the prostate in patients with benign prostatic hypertrophy. Br J Urol 1992;69:603–8. 23. Gilling PJ, Cass CB, Malcolm AR, Fraundorfer MA. Combination holmium and Nd:YAG laser ablation of the prostate: initial clinical experience. J Endourol 1995;9:151–3. 24. Gilling PJ, Fraundorfer MR. Holmium laser prostatectomy: a technique in evolution. Curr Opin Urol 1998;8:11–5. 25. Cornford PA, Biyani CS, Powell CS. Transurethral incision of the prostate using the holmium:YAG laser: a catheterless procedure. J Urol 1998;159:1229–31. 26. Madsen FA, Bruskewitz RC. Transurethral incision of the prostate. Urol Clin North Am 1995;22:369–73. 27. Jenkins JD, Allen NH. Bladder neck incision: a treatment for retention with overflow in the absence of adenoma. Br. J Urol 1978:50:395–397. 28. Moisey CU, Stephenson TP, Evans C. A subjective and urodynamic assessment of unilateral bladder neck incision for bladder neck obstruction. Br J Urol 1982;54:114–117. 29. Edwards L, Powell C. An objective comparison of transurethral resection and bladder neck incision in the treatment of prostatic hypertrophy. J Urol 1982;128: 325–327. 30. Edwards LE, Bucknall TE, Pittam MR, et al. Transurethral resection of the prostate and bladder neck incision: a review of 700 cases. Br J Urol 1985;57:168–171. 31. Graversen PH, Gasser TC, Larsen EH, et al. Transurethral incisions of the prostate under local anaesthesia in high-risk patients: a pilot study. Scand J Urol Nephrol 1987;106:87–90. 32. Dorflinger T, Oster M, Larsen JF, et al. Transurethral prostatectomy or incision of the prostate in the treatment of prostatism caused by small benign prostates. Scand J Urol Nephrol 1987;104:77–81. 33. Mobb GE, Moisey CU. Long-term follow-up of unilateral bladder neck incision. Br J Urol 1988;62:160–162. 34. Nielson HO. Transurethral prostatotomy versus transurethral prostatectomy in benign prostatic hypertrophy: a prospective randomized study. Br J Urol 1988; 61:435–438. 35. Kelly MJ, Roskamp D, Leach GE. Transurethral incision of the prostate: a preoperative and postoperative analysis of symptoms and urodynamic findings. J Urol 1989; 142:1507–1509.

Transurethral Incision of the Prostate / 599 36. Waymont B, Ward JP, Perry KC. Long-term assessment of 107 patients undergoing bladder neck incision. Br J Urol 1989;64:280–282. 37. Bruskewitz RC, Christensen MM. Critical evaluation of transurethral resection and incision of the prostate. Prostate (Suppl) 1990;3:27–28. 38. D’Ancona CAL, Netto NR Jr, Cara AM, Ikari O. Internal urethrotomy of the prostatic urethra or transurethral resection in benign prostatic hyperplasia. J Urol 1990; 144:918–920. 39. Katz PG, Greenstein A, Ratliff JE, et al. Transurethral incision of the bladder neck and prostate. J Urol 1990;144: 694–696. 40. Christensen MM, Aagaard J, Madsen PO. Transurethral resection versus transurethral incision of the prostate. Urol Clin North Am 1990;17:621–630. 41. Soonawalla PF, Pardanani DS. Transurethral incision versus transurethral resection of the prostate. A subjective and objective analysis. Br J Urol 1992;70:174–7. 42. Cornford PA, Biyani CS, Brough SJ, Powell CS. Daycase transurethral incision of the prostate using the holmium:YAG laser: initial experience. Br J Urol 1997; 79:383. 43. Orandi A. Transurethral incision of the prostate compared with transurethral resection of prostate in 132 matching cases. J Urol 1987;138:810–815. 44. Andersen JT, Nordling J, Meyhoff HH, et al. Functional bladder neck obstruction: late results after endoscopic bladder neck incision. Scand J Urol Nephrol 1980;14: 17–22. 45. Delaere KPJ, Debruyne FMJ, Moonen WA. Extended bladder neck incision for outflow obstruction in male patients. Br J Urol 1983;55:225–228. 46. Christensen MG, Nordling J, Andersen JT, Hald T. Functional bladder neck obstruction: results of endoscopic bladder neck incision in 131 consecutive patients. Br J Urol 1985;57:60–62.

47. Li MK, Ng SM. Bladder neck resection and transurethral resection of the prostate: a randomized prospective trial. J Urol 1987;138:807–809. 48. Loughlin KR, Yalla SV, Belldegrun A, Berstein GT. Transurethral incisions and resections under local anesthesia. Br J Urol 1987;60:185. 49. Hellstrom P, Lukkarinen O, Kontturi M. Bladder neck incision or transurethral electroresection for the treatment of urinary obstruction caused by a small benign prostate?: a randomized urodynamic study. Scand J Urol Nephrol 1986;20:187–192. 50. Dorflinger T, Jensen FS, Krarup T. Transurethral prostatectomy compared with incision of the prostate in the treatment of prostatism caused by small benign prostate glands. Scand J Urol Nephrol 1992;26:333–8. 51. McConnell JD, Barry MJ, Bruskewitz RC, et al. Benign prostatic hyperplasia: diagnosis and treatment. Clinical Practice Guideline, No. 8. Rockville (MD): Agency for Health Care Policy and Research, Public Health Service (US), AHCPR publication No: 94-0582. 52. Windle R, Roberts JB. Ejaculatory function after prostatectomy. Proc R Soc Med 1974;67:46–48. 53. Turner-Warwick R. A urodynamic review of bladder outlet obstruction in the male and its clinical implications. Urol Clin North Am 1979;6:171–192. 54. Larsen EH, Dorflinger T, Gasser TC, et al. Transurethral incision versus transurethral resection of the prostate for the treatment of benign prostatic hypertrophy: a preliminary report. Scand J Urol Nephrol 1987;104:83–86. 55. Sirls LT, Ganabathi K, Zimmern PE, et al. Transurethral incision of the prostate: an objective and subjective evaluation of long-term efficacy. J Urol 1993;150:1615. 56. Uhle CAW, Kohler FP. Postoperative vesical neck contracture. J Urol 1969;101:302. 57. Kulb TB, Kamer M, Lingeman JE, Foster RS. Prevention of postprostatectomy vesical neck contracture by prophylactic vesical neck incision. J Urol 137:230–1.

CHAPTER 65

OPEN PROSTATECTOMY IN THE MANAGEMENT OF BENIGN PROSTATIC HYPERPLASIA FERNANDO J. KIM, MD; BRIAN E. NICHOLSON, MD; ROBERT C. FLANIGAN, MD

Benign Prostatic Hyperplasia: Overview

Advances in medical treatment have drastically reduced the number of surgical interventions for BPH. In 1983, a total of 321,000 TURPs were performed in the United States, dropping to 229,000 in 1994.10 Despite new surgical techniques and instruments (i.e., laser TURPs, transurethral microwave treatment) to manage BPH, open prostatectomy remains the treatment of choice for the large-size prostate or when prostate obstruction is associated with other bladder pathology requiring treatment, such as nonendoscopically treatable bladder stones or bladder diverticula.

Benign prostatic hyperplasia (BPH) is the most common benign tumor in men aged > 60 years.1,2 The disease has stromal and glandular components and affects the transition (periurethral) zone rather than the peripheral zone, which is more commonly affected by prostate cancer.3 Autopsy data has revealed that approximately 25 to 50% of men with microscopic evidence of BPH have clinical manifestations during their lifetime. The number of patients who seek and receive treatment is even less due to variation in the perceived symptoms. In this chapter, the open surgical procedures available for the treatment of BPH will be discussed, specifically suprapubic and retropubic prostatectomy.

Indications and Patient Selection Open prostatectomy, whether retropubic or suprapubic (Table 65–2), is indicated for prostate glands > 50 to 75 g.11 Indications for the surgical treatment of men with BPH include the following:

Surgical Treatment Options Open prostatectomy is the oldest, most invasive, and most efficient treatment for BPH and produces a reported 98% improvement in symptoms. Compared with transurethral resection of the prostate (TURP) and transurethral incision of the prostate (TUIP), strictures and retrograde ejaculations are more common after open prostatectomy. Initially, open prostatectomy may offer higher cost than other types of treatment; the longterm cost, however, is lower (Table 65–1).4 Other surgical techniques available for treating BPH include transurethral vaporization, laser therapy, transurethral microwave therapy, transurethral needle ablation, and high-intensity focused ultrasound.

• Refractory urinary retention (after at least one attempt to remove the catheter) • Recurrent urinary tract infections, gross hematuria, or renal insufficiency due to BPH • Bladder stones due to BPH which are not amenable to endoscopic treatment • Large bladder diverticula(e) due to BPH • Severe musculoskeletal disease (e.g., ankylosis, scoliosis, or severe lordosis) that may present difficulty in positioning for TURP Chronic urinary outlet obstruction due to BPH often coexists with unilateral or bilateral inguinal hernia, and the surgeon may accomplish a successful preperitoneal approach herniography using the same midline incision as for the prostatectomy.12 Finally, the relative contraindications to this surgery include prostate cancer, previous pelvic or prostate manipulation (surgery or radiation) preventing safe access to the prostate gland, or small glands that can be resected endoscopically (the exact volume cutoff is dependent on the operator’s endoscopic abilities).

History In 1890, Bellfield in the United Kingdom first described the open enucleation of the prostate for treatment of BPH.5 In 1895, Fuller described the first six cases in the United States, performed at the New York Hospital.6 Several years later, this procedure was popularized by Freyer7 and his name has been attached to this particular suprapubic approach. The retropubic approach was first described by van Stockum8 but was popularized by Millin in 1945.9 600

Open Prostatectomy in the Management of Benign Prostatic Hyperplasia / 601 TABLE 65–1. Treatment Outcomes % reduction in symptom score Morbidity† Mortality† (30–90 days of treatment) Risk of total urinary incontinence† Surgical treatment due to complication† Risk of impotence† Retrograde ejaculation (% of patients) Loss of work days Hospital stay (days) Treatment cost & 1st year follow-up ($) Cost for 2nd year ($)

OPSU

TURP

TUIP

Medical*

79

85

73

31–51

7–42.7 1–4.5

5.2–30.7 0.5–3.3

2.2–33.3 0.2–1.5

3–43.3

0.3–0.7

0.7–1.4

0–1.1

0.3–14.1

0.6–10.1

1.3

4.7–39.2 36–95

3.3–34.8 25–99

3.9–24.5 6–55

2.5–5.3 0–11

21–28 5–10 12,788

7–21 3–5 8606

7–21 1–3

69

360

1.5–3.5 0 up to 1395 Up to 845

OPSU = open prostatectomy; TURP = transurethral resection of the prostate; TUIP = transurethral incision of the prostate. *Medical = α-blocker/finasteride. †90% confidence interval. Adapted from Narayan P, Tewari A. Optimal treatment for BPH [monograph]. Scientific Exchange; 1998; p. 10–1.

Preoperative Considerations and Evaluation The initial evaluation of patients presenting with symptoms related to the lower urinary tract includes a detailed medical history, including symptom assessment using the American Urological Association symptom score (AUASS); special attention should be directed to the patient’s degree of bother. Physical examination should be directed to the neurologic exam to detect any possible voiding dysfunction due to neurologic pathologies. The digital rectal exam is a pivotal tool to the urologist to estimate the prostate size and to detect palpable abnormal lesions. The urologist should obtain a careful past medical and surgical history, with special attention paid to factors contributing to lower urinary tract symptoms. Any history of prior instrumentation, prostatic surgery, trauma, or ure-

thritis may suggest urethral stricture. Pain in the bladder or penis may indicate the presence of a bladder stone or prostatitis, whether as a cause of symptoms or as a complication of obstruction. Hematuria may also indicate bladder or upper urinary tract malignancy and should be further evaluated using intravenous urography and cystoscopy. Patients should be asked not to take any medication that can cause abnormal bleeding, such as aspirin or NSAIDs (nonsteroidal anti-inflammatory drugs), for at least 3 to 5 days prior to surgery. Patients on Coumadin or similar drugs may be admitted at least 24 hours in advance for continuous intravenous heparin if necessary, which must be stopped at least 6 hours before surgery. Most patients will require evaluation and management of cardiovascular and other medical conditions (hypertension, diabetes mellitus, coagulopathy, etc.) prior to the surgery. Regional or general anesthesia is typically recommended after the patient is carefully evaluated and individualized according to risks and comorbidities of the procedure. Laboratory Assessment Blood Appropriate laboratory tests include blood count and differential, coagulogram, type and screen, and comprehensive metabolic panel, including electrolytes, blood urea, nitrogen, and creatinine, to evaluate for renal insufficiency. Prostate-specific antigen (PSA) levels should be obtained in men > 50 years of age or at age 45 years when the patient has a family history of prostate cancer or is African American. Role of Prostate-Specific Antigen in Benign Prostatic Hyperplasia Although an increase in serum PSA can be associated with BPH, PSA is useful in differentiating patients with BPH from those with prostate cancer. It may not be useful, however, in distinguishing stage Tla prostate cancer from BPH. Studies have shown that the median PSA value for patients with stages Tla and Tlb cancers was 3.8 ng per mL versus 3.4 ng per mL for those with BPH. Several subtypes of PSA

TABLE 65–2. Comparison of Surgical Techniques Suprapubic Prostatectomy

Retropubic Prostatectomy

Position

Supine, with slight Trendelenburg

Same

Skin incision

Midline–from the umbilicus to the symphysis pubis; or Pfannenstiel–transverse lower abdominal incision

Same

Bladder

Midline cystotomy (5 to 8 cm in length) extending inferiorly nearly to the prostatovesical junction

No cystotomy is performed

Prostate

Enucleation of adenoma through open bladder

Enucleation of adenoma through prostate capsule

Urinary catheter

Urethral catheter–Foley catheter, two or three-way (22 or 24F) with a 30 cc balloon Suprapubic catheter–Foley catheter (24F) with a 5 cc balloon

Urethral catheter–Foley catheter, three- way (22 or 24F) with a 30 cc balloon

Drain

Jackson-Pratt or Penrose drain is left in the perivesical space

Same


evaluation may be more useful, including PSA density, free and complexed PSA, and PSA velocity. Percent-free PSA may be used to enhance specificity of PSA and aid in differentiating benign from malignant prostatic diseases when PSA is mildly elevated (4 to 10 ng per mL).13 Urine Urine should be sent for urinalysis and urine culture and sensitivity (if urinary tract infection is suspected). Urinary tract infection and neurogenic bladder dysfunction can cause irritative symptoms similar to those caused by BPH. Uroflowmetry Uroflowmetry is noninvasive and easy to perform, and is the most frequently used method of diagnosing bladder neck obstruction. The maximum-flow rate is an informative measurement but is nonspecific because decreased flow may be due to impaired detrusor contraction as well as stricture. Maximum-flow rate > 15 mL per second usually excludes obstruction. Patients who have an equivocal flow rate of 10 to 15 mL per second may require further urodynamic testing. Patients with a flow rate < 10 mL per second are usually considered to have infravesical obstruction. There must be an adequate volume of urine passed to produce a valid peak-flow rate. Postvoid Residual Urine Postvoid residual urine is the measurement of the urine volume remaining in the bladder immediately after completion of micturition. According to the BPH Guidelines Panel, no conclusions on treatment should be based on this test alone. However, it is a helpful tool that can be used for follow-up and evaluation of response to therapy.14 Pressure-Flow Studies Pressure-flow studies measure the pressure in the bladder during voiding but do not predict response to surgical therapy. These studies should be limited to patients with normal peak-flow rates and symptoms suggestive of infravesical obstruction, or patients with a history of bladder voiding dysfunction, for example, patients with neurologic disease or diabetes mellitus. Clinically, men with lower urinary tract symptoms suggestive of BPH who are obstructed on pressure flow studies respond better to surgery than those who are unobstructed. Imaging/Endoscopic Studies The indications for intravenous pyelography (IVP) and cystoscopy are those common to any prostatectomy procedure, for example, hematuria, suprapubic pain, abnormal renal function, etc. If suspicion of prostatic malignancy exists, transrectal ultrasound and prostate biopsy should be performed prior to elective surgery.

Suprapubic Prostatectomy This procedure15 allows the surgeon to enucleate the adenoma from the rest of the prostate through a cystostomy, which can be helpful in managing concurrent bladder pathologies (e.g., bladder stones and bladder divertuculi). Position of Patient The patient should be placed in the supine position, with the anterior superior iliac spine over the break in the operating table, in a slight Trendelenburg position. They should then be prepped and draped from the xiphoid to midthigh, following standard sterile surgical technique. A sterile Foley catheter should be used to fill the bladder with sterile saline (200 to 300 cc). Skin Incision Two types of incision may be considered, depending on the surgeon’s experience and preference: (1) a midline incision from the umbilicus to the symphysis pubis, or (2) a transverse Pfannenstiel lower abdominal incision. Both incisions offer good exposure. Dissection is taken down to the linea alba of the rectus fascia, which is sharply divided, separating the rectus muscles for lateral retraction. The extraperitoneal space is entered after the transversalis fascia is opened sharply. The bladder is usually easily identified. After minimal dissection, a self-retaining retractor is placed. Bladder Before opening the bladder, intravenous indigo carmin may be administered by the anesthesiologist to enable prompt identification of the ureters. Electrocautery is used to create a midline cystotomy (5 to 8 cm in length) extending inferiorly nearly to the prostatovesical junction. Exposure may be aided by a single full-thickness stay suture (2.0 or 3.0) placed on each side of the cystotomy. Retractors may then be placed in the bladder to facilitate exposure. The bladder mucosa should be protected at all times from the retractor blades, with moist laps packed in the lateral and superior aspects of the bladder. At this time, the surgeon must examine and identify any bladder lesions, diverticula or calculi. The ureteral orifices must be identified before further intervention. Following bladder neck identification, the mucosa should be incised (sharply or with electrocautery) circumferentially around the bladder outlet and urethral catheter, distal to the trigone and ureteral orifices (Figure 65–1). Prostate Enucleation of the prostatic adenoma can be achieved with blunt finger dissection (Figure 65–2). Pressure is applied in the anterior midline to release the anterior commissure of the prostate. Enucleation is then accomplished by sweeping laterally along the surgical capsule plane, curving posteri-

Open Prostatectomy in the Management of Benign Prostatic Hyperplasia / 603

FIGURE 65–1. Placement of stay sutures at the vesical neck. Bladder incision is performed with electrocautery and simultaneous suctioning. Reprinted with permission from Hinman F Jr. Atlas of urologic surgery. Philadelphia: WB Saunders; 1989.

orly toward the midline. Each lateral lobe and a separate median lobe, if present, may be removed individually in this fashion. Alternatively, after the bladder mucosa incision is made around the bladder neck, a sharp dissection may be made with Metzenbaum scissors, starting at the 6 o’clock position. The surgeon then develops a plane between the adenoma and the surgical capsule. Further enucleation is performed in the same manner as in the previous method. The adenoma will then be tethered only by the urethra at the prostatic apex, which is divided sharply with scissors (Figure 65–3). Residual adenoma should be removed after examining the prostatic fossa.

FIGURE 65–2. Insertion of index finger into bladder and prostatic urethra. Begin enucleation laterally, then posteriorly, then free the vesical neck. Reprinted with permission from Hinman F Jr. Atlas of urologic surgery. Philadelphia: WB Saunders; 1989.

Hemostasis Prostatic fossa packing with gauze to tamponade capsular bleeding may be performed. Bleeding must be well controlled, and hemostatic sutures (figure-eight sutures of 2-0 chromic) may be placed at the 5 and 7 o’clock positions, where the prostatic vasculature enters the gland. The posterior bladder neck should be grasped with an Allis clamp to facilitate placement of these sutures. The posterior bladder neck can be approximated to the prostatic capsule using a running suture (2-0 chromic); this will also help with hemostasis and minimize bladder neck contracture. The gauze pack should be removed from the prostatic fossa and final hemostasis should be carefully performed with electrocautery (Table 65–3). Urethral and Suprapubic Catheter After a two or three-way Foley catheter (22 or 24F) is passed per urethra and positioned in the bladder, the balloon is inflated to 50 to 60 cc and pulled under traction to aid in hemostasis. Then a second 24F Foley suprapubic catheter is generally brought out through a separate stab incision lateral to the midline cystotomy. Finally, the bladder should be irrigated with sterile water to ascertain that the catheters are free of obstruction, particularly blood clots. Closure Cystotomy closure is performed in two layers, using running chromic sutures to achieve watertight seal. The first layer (3 or 4.0) incorporates the mucosa and the second (2.0) includes the detrusor muscle and the serosa. Both catheters are then irrigated to ensure patency and demonstrate the integrity of the bladder closure. There is a drain (Penrose or Jackson-Pratt) left in the perivesical

FIGURE 65–3. Prostatic apex excision under direct vision. Reprinted with permission from Hinman F Jr. Atlas of urologic surgery. Philadelphia: WB Saunders; 1989.

604 / Advanced Therapy of Prostate Disease TABLE 65–3. Potential Operative Maneuvers for Control of Bleeding Before Gland Enucleation

During Gland Enucleation

After Gland Enucleation

Ligation of dorsal venous complex Suture ligation of the prostatic pedicles

Traction stitch placed in the median lobe of the gland Finger pressure applied against the prostate surface during enucleation

Nasal speculum used to improved exposure of the prostatic fossa Running stitches at the 5 and 7 o’clock positions of the proximal prostatic fossa Malament stitch (1-0 nylon) to compress bleeding surfaces of the prostatic fossa

space and brought out through a separate stab incision. After the wound is irrigated, the fascia is approximated with interrupted figure-eight synthetic absorbable suture and the skin is closed with staples. The suprapubic catheter and drain are secured to the skin with nylon sutures and a sterile dressing applied. Postoperative Care Foley catheter traction generally remains for 12 to 24 hours postoperatively. Bladder irrigation is weaned off when the urine has become clear, usually between postoperative days 2 and 3. The retropubic drain is generally removed after the urethral catheter is removed. If a suprapubic catheter has been used, it may be clamped prior to discharge or left to continue drainage. Suprapubic catheter care instructions are given before the patient is discharged home. In addition to prophylactic antibiotics, medication (e.g., pain killers, Ditropan, and Pyridium) may be given for pain and bladder irritative symptoms. Follow-up Staples may be removed 1 week postoperatively and the suprapubic catheter (if left to drainage) may be plugged. If the patient has no other complications, a voiding trial can be attempted; if successful, the suprapubic catheter is removed.

control venous bleeding from the ventral side of the prostate. Thereafter, the capsule is incised in a transverse orientation with electrocautery. The incision is carried deep enough to extend through the surgical capsule to the adenoma. It is essential that the surgical capsule (i.e., the junction between the peripheral zone and the adenomatous tissue [transition zone]) be correctly identified to facilitate enucleation of the adenoma. The surgical plane between the capsule and the adenomatous tissue can be developed either sharply with curved scissors or bluntly with the index finger of the dominant hand (Figure 65–5). Finally, the adenoma can be enucleated and shelled out from the capsule. Of note, once the distal (apical) aspect of the adenoma is developed, it is possible to lift the adenoma out of the prostatic capsule with the help of ringed forceps or Babcock clamps, facilitating dissection and transection of the adenoma at the bladder neck. Care should be taken to avoid getting too close to the ureteral orifices. The mucosa proximal to the bladder neck can be, if necessary, sutured to the floor of the prostatic capsule to effectively cover and regenerate the raw area of the bladder neck, facilitating hemostasis and passage of the urethral catheter.

Retropubic Prostatectomy The objective of this operation is to remove the adenomatous tissue through an incision in the surgical capsule of the prostate, rather than through an opening in the bladder (Figure 65–4).16,17 This obviates the need for suprapubic catheter drainage in most cases. The incision in the capsule allows improved exposure and inspection of the prostatic fossa to control bleeding. The offset is an increased risk of intraoperative bleeding from the dorsal vein complex of Santorini secondary to dissection. Positioning of the patient, Foley catheter insertion, and skin incision is identical to that described for suprapubic prostatectomy. No cystostomy is performed. Use of a self-retaining retractor will allow exposure of the anterior surface of the prostate. The dorsal vein complex may be suture ligated (2.0 chromic) and divided to enhance exposure, if necessary. Placement of two overlapping rows of sutures (2.0 chromic) approximately 5 mm apart, in a transverse orientation, may help

FIGURE 65–4. Capsular incision with the electrocautery after placement of sutures 1 and 2 cm below the vesical neck. Reprinted with permission from Hinman F Jr. Atlas of urologic surgery. Philadelphia: WB Saunders; 1989.

Open Prostatectomy in the Management of Benign Prostatic Hyperplasia / 605

FIGURE 65–5. Dissection of plane between the adenoma and capsule using Metzenbaum scissors. Reprinted with permission from Hinman F Jr. Atlas of urologic surgery. Philadelphia: WB Saunders; 1989.

Hemostasis The remaining bleeders in the prostatic fossa can be controlled either by electrocautery or by figure of eight suture ligatures (2-0 chromic), usually at the 5 and 7 o’clock positions. Urethral Catheter At this time, a 22 or 24F three-way Foley catheter is inserted through the urethra into the bladder and the balloon inflated and placed on traction. Closure The transverse incision of the capsule is closed with one or two layers of 2.0 chromic or vicryl suture. It is recommended that the transverse capsular hemostatic sutures be left long and that the capsular closure be reinforced by tying knots over the running capsular closure suture line (Figure 65–6). Care should be taken not to puncture the balloon at this stage. If excessive bleeding is noted, it may be advantageous to place a suprapubic tube through a separate stab wound. Finally, a drain (Penrose or JacksonPratt) is placed in the retropubic space and brought out through a separate stab wound and secured to the skin with nylon sutures. After the wound is irrigated with sterile water, the fascia is approximated with interrupted single or figure-eight synthetic absorbable suture and the skin closed with staples. Bladder irrigation should be performed to ascertain urethral catheter patency. Postoperative Care Foley catheter traction remains for 12 to 24 hours postoperatively. The patient may require bladder irrigation. The Foley catheter is removed when the urine is clear and

FIGURE 65–6. Closure of the capsule with interrupted sutures. Reprinted with permission from Hinman F Jr. Atlas of urologic surgery. Philadelphia: WB Saunders; 1989.

patient is ambulating, between postoperative days 2 and 5. Retropubic drain should be removed after the urethral catheter is removed. As with suprapubic prostatectomy, prophylactic antibiotics and medication for pain and bladder irritative symptoms should be given when the patient is discharged home. Follow-up Staples may be removed 1 week postoperatively and voiding complaints reassessed.

Complications Secondary to Open Prostatectomy Patients should be informed of the potential risks of the procedure, including bleeding that requires transfusion, urinary incontinence, erectile dysfunction, retrograde ejaculation, urinary tract infection, and other possible organ injuries (such as to the rectum) (Table 65– 4). Capsular laceration must be repaired during enucleation. Injury to the ureteral orifice may be managed with placement of ureteral stents or by reimplantation in severe cases. TABLE 65–4. Potential Complications of Open Prostatectomy Intraoperative

Postoperative

Bleeding that requires blood transfusion Capsular laceration during enucleation Adjacent organ injuries (e.g., rectum and major blood vessels) Injury to ureteral orifice

Urinary incontinence Erectile dysfunction Retrograde ejaculation Urinary tract infection Vesicocutaneous fistula due to suprapubic catheter


Treatment Outcome Benign prostatic hyperplasia is a disease that affects millions of men and will continue to do so as life expectancy increases. When evaluating different surgical treatment modalities for BPH, it appears that open surgery may offer good to excellent results12 at comparable morbidity and mortality rates, resulting in a high level of patient satisfaction. It is expected that more men will seek treatment for obstructive lower urinary tract symptoms prompting researchers to try to find an ideal minimally invasive therapy for managing BPH and thereby improving the patient’s quality of life. Open prostatectomy is the ideal method for treating large size BPH, or when concomitant bladder diseases such as bladder calculi or diverticula dictate an open surgical procedure.

References 1. Barry MJ. Epidemiology and natural history of benign prostatic hyperplasia. AUA Update series, vol. 12, lesson 2. Houston: AVA Office of Education, 1993. 2. Ekman P. BPH epidemiology and risk factors. Prostate 1989;2 Suppl:23–31. 3. Porta M, Fernandez E, Alonso J, et al. Risk factors for benign prostatic hyperplasia. Am J Epidemiol 1994; 139:114–5. 4. Concato J, Horwitz RI, Feinstein AR. Problems of comorbidity in mortality after prostatectomy. JAMA 1992;267:1077–82. 5. Bellfield WT. Operations on the enlarged prostate with a tabulated summary of cases. Am J Med Sci 1890;100:439.

6. Fuller E. Six successful and successive cases of prostatectomy. J Cutan Genitourin 1895;13:229. 7. Freyer P. A new method of performing prostatectomy. Lancet 1900;1:774. 8. van Stockum WJV. Prostatectomia suprapubic extravesicales. Zentralbl Chir 1909;36:41–4. 9. Millin T. Retropubic prostatectomy: new extravesical technique. Report on 20 cases. Lancet 1945;2:693. 10. Rutkow I M. Surgical operations in the United States. Arch Surg 1997;132:983–90. 11. Edwards LE, Bucknall TE, Pittam MR, et al. Transurethral resection of the prostate and bladder neck incision: a review of 700 cases. Br J Urol 1985;57:168–71. 12. McConnell JD, Barry MJ, Bruskewitz RC, et al. Benign prostatic hyperplasia: diagnosis and treatment. Rockville (MD): Dept. of Health and Human Services (US), Agency for Health Care Policy and Research, Public Health Service; 1994 Feb. AHCPR Publication No. 94-0582. 13. Stamey T. Second conference on international standardization of PSA immunoassays. September 1 and 2. Urology 1995;45:173–84. 14. Hald T. Urodynamics in BPH: a survey. Prostate 1989;2 Suppl:69–77. 15. O’Connor VJ Jr. Suprapubic prostatectomy. In: Glenn JF, editor. Urologic surgery. Philadelphia: JB Lippincott; 1983. p. 853–60. 16. Walsh PC, Oesterling JE. Improved hemostasis during simple retropubic prostatectomy. J Urol 1990;143:1203. 17. Malament M. Maximal hemostasis in suprapubic prostatectomy. Surg Gynecol Obstet 1965;120:1307.

CHAPTER 66

PHYTOTHERAPY IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA GLENN S. GERBER, MD The use of plants or plant extracts for a variety of medicinal purposes (phytotherapy), including the treatment of voiding disorders, dates from ancient times. There is currently wide variation in the use of phytotherapeutic agents in men with lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) in different parts of the world. In some European countries, for example France and Germany, plant extracts are among the most commonly recommended initial treatment options in men with voiding symptoms. These agents are available by prescription in many cases and patients may be reimbursed for their cost by health ministries or insurance companies. Although many Americans use phytotherapeutic products, few physicians in the United States recommend such therapy for men with BPH, and all costs associated with such treatment are borne by the patient. Despite the lack of reimbursement by thirdparty payers for medicinal botanicals, it is estimated that $500 million to $1 billion is spent annually in the United States for such products.1 While it is widely perceived by many patients that it is advantageous to treat a variety of chronic medical conditions, such as LUTS, with “natural” remedies, there is limited scientific evidence to support the use of these agents in most cases. Phytotherapeutic agents used for treating men with LUTS have not generally been subjected to the same rigorous testing standards as other more commonly accepted therapies, such as alpha-blockers and 5 α-reductase inhibitors. This situation has changed somewhat in recent years as several European companies that market phytotherapeutic products have responded to this criticism and sponsored multicenter clinical trials. In contrast, medicinal botanicals are generally categorized as food additives in the United States and are therefore not eligible for patent protection. This is a significant financial disincentive for American companies to support clinical research into these products. In addition, most European companies have elected not to pursue approval of their phytotherapeutic products in the United States due to a variety of economic and other factors. Most medicinal botanicals contain multiple chemical components and it is generally unclear which, if any, of these ingredients are responsible for clinical activity.

There is also a lack of standardization of phytotherapeutic agents in the United States, potentially leading to marked variability in the chemical composition of natural products sold by different companies. Saw palmetto, the most popular plant extract used for treating LUTS, is sold in one form or another by 30 or more companies in the United States. In some cases, these products include saw palmetto alone while others contain a mixture of herbal products, vitamins, and minerals. In Europe, saw palmetto is most commonly marketed as a prescribable agent (Permixon), which is manufactured in France. Permixon is the most extensively studied form of saw palmetto but it is not clear that similar results reported with this specific agent will be seen with other forms of saw palmetto available in the United States. Most patients are not aware of the vast potential differences that may exist between the chemical composition and efficacy of products with similar or identical names.

Proposed Mechanisms of Action of Phytotherapeutic Agents There have been a wide variety of plant extracts recommended for patients with LUTS and BPH (Table 66–1). The most common components of these agents include phytosterols, fatty acids, terpenoids, and plant oils.1 The improvement in voiding symptoms and BPH are most often attributed to phytosterols, a class of compounds related to cholesterol.2 Beta-sitosterol is felt to be the most important phytosterol, and a variety of forms are present in most plant extracts used for treating BPH. There have been a number of suggested mechanisms of action associated with phytosterols, including antiandrogenic effects, direct inhibition of prostatic growth, and anti-inflammatory effects (Table 66–2).1,2 These actions have been most commonly demonstrated using in vitro studies and experimental models in which supraphysiologic doses are frequently utilized. While these studies may suggest important mechanisms, it is difficult to assess the clinical relevance of these actions in some cases. The most important example of this discrepancy concerns the evidence that saw palmetto acts as a 5 αreductase inhibitor. Although this action has been 607


demonstrated in a variety of in vitro studies,3,4 clinical studies performed among men receiving saw palmetto have generally failed to show significant enzyme inhibition (based on changes in prostate size and serum prostate-specific antigen [PSA] levels).5,6 In addition to concerns regarding mechanisms of phytotherapeutic agents, there is limited available information concerning bioavailability, and some plant extracts have been shown to be poorly absorbed from the gastrointestinal tract. Finally, in many cases scant information regarding pharmacodynamics is available.

Saw Palmetto The most popular plant extract used for treating LUTS is derived from the berry of the American dwarf palm tree (saw palmetto [Serenoa repens]), which is found in Florida and other areas of the southeastern United States. As described above, saw palmetto is sold under a variety of trade names in the United States and Europe. Permixon, the most extensively studied form of saw palmetto, is a liposterolic extract of the berry that contains a complex mixture of free fatty acids, phytosterols, and other compounds and is available in parts of Europe.5 In animal studies, some components of Permixon have been demonstrated to accumulate in normal and hyperplastic prostatic cells.7 In addition, bioavailability studies in humans have shown that at least some of the compounds contained in Permixon are absorbed through the intestinal tract.8 Mechanisms of Action Many mechanisms of action of saw palmetto have been proposed, including anti-inflammatory effects, antiandrogenic effects (mediated via androgen-receptor blockade), antiestrogenic effects, growth factor inhibition, and others.1–4,9,10 Popular belief, however, centers on the action of saw palmetto as an inhibitor of the conversion of testosterone (T) to dihydrotestosterone (DHT) by the enzyme, 5 α-reductase.1–4 There have been a variety of in vitro studies performed with Permixon using human skin fibroblasts, primary cultures of human BPH, and other models.3,4,9,10 These studies have generally demonstrated inhibition of type 1 and type 2 5 α-reductase activity, leading to a decrease in DHT production. In many cases, these studies have used supraphysiologic

TABLE 66–1. Plant Extracts Available for the Treatment of Benign Prostatic Hyperplasia Saw palmetto (Serenoa repens) African plum (Pygeum africanum) β-sitosterol (Harzol) Pollen extract (Cernilton) Stinging nettles South African star grass (Hypoxis rooperi)

TABLE 66–2. Suggested Mechanisms of Action of Phytotherapeutic Agents Used to Treat Benign Prostatic Hyperplasia Inhibition of 5 α-reductase Anti-inflammatory effects Antiandrogenic effects (via androgen-receptor blockage) Antiestrogenic effects Growth factor inhibition Protection or improvement in bladder (detrusor) function Effects on cholesterol metabolism Reduction in sex hormone-binding globulin

doses of Permixon, which raises concern regarding the true clinical effect of this agent. Clinical studies in humans have included a 3-month trial in 33 men awaiting suprapubic prostatectomy.11 These patients were randomized to receive finasteride, flutamide, placebo, or Permixon for 2 to 3 months prior to surgery. Following removal of the prostate, T, DHT, and growth factor levels were measured in the removed tissue. In the control group, regional distribution of all three measured factors was highest in the periurethral area and lowest in the subcapsular zone. After treatment with Permixon or finasteride, DHT and growth factor levels decreased significantly, with no difference in the intraprostatic distribution as was seen in those patients receiving placebo. In men treated with flutamide, there was no change in T or DHT levels although growth factor levels decreased throughout the prostate. The authors concluded that both finasteride and Permixon led to important changes in androgen support, primarily within the periurethral zone of the prostate. Rhodes et al. have also compared the effects of finasteride and Permixon using in vivo and in vitro studies.12 In rats stimulated with T or DHT, finasteride inhibited prostate growth while there was no change with Permixon. In a 7-day trial in 32 healthy male volunteers, finasteride led to decreased DHT levels while no significant change was seen in those men receiving Permixon. Strauch et al. have also demonstrated that Permixon does not lead to any significant change in serum DHT levels in men treated with this agent.13 Further evidence against clinically relevant 5 α-reductase activity associated with saw palmetto includes a lack of effect on serum PSA levels noted in several studies, and a minimal reduction in prostate size seen among men treated with Permixon for 6 months in one large clinical trial in Europe.5,6,14 In vitro studies have also suggested alternative mechanisms of action associated with saw palmetto. Using human foreskin fibroblasts, Sultan et al. found that this agent inhibits receptor binding of androgens.9 As has been noted for 5 α-reductase inhibition, evidence of clinically significant antiandrogenic activity has not been presented to date. Studies using Permixon have also suggested possible antiestrogenic effects.15 In a placebo-controlled trial

Phytotherapy in the Treatment of Benign Prostatic Hyperplasia / 609

in 35 men with BPH who underwent surgery after treatment for 3 months, a significant decrease in estrogen receptor activity was noted in the Permixon-treated patients compared to those receiving placebo.15 The authors concluded that this antiestrogenic effect was likely mediated by competitive blocking of the translocation of cystosolic estrogen receptors to the nucleus, which may lead to inhibition of estrogen-mediated prostatic growth. Finally, German investigators have found evidence that saw palmetto has anti-inflammatory effects in patients with BPH.16 Among a small group of men who subsequently underwent open prostatectomy, those receiving saw palmetto showed a significant reduction in periglandular stromal edema, intraglandular congestion, and congestive prostatitis compared to controls. Clinical Studies In the mid-1980s, several placebo-controlled clinical trials were performed in Europe with saw palmetto in men with symptomatic BPH.17–21 Champault et al. studied 110 men and reported a significant improvement in dysuria and nocturia in patients treated with saw palmetto compared to those receiving placebo.17 The mean urinary flow rate increased significantly in the saw palmetto group and was unchanged among the controls. Limitations of this study included the short duration of only 1 month and the absence of standardized assessment of subjective symptoms since validated instruments such as the American Urological Association (AUA) symptom score were not then available. Smith et al. performed a similar controlled trial using saw palmetto in 80 men with voiding symptoms and BPH.22 Although an improvement in the subjective assessment of symptoms and urinary flow rate were seen in both the placebo group and among those men treated with saw palmetto, there was no significant difference between the results of treatment in either group. In general, the early trials concerning saw palmetto are limited by small numbers of patients and brief, one- to two-month treatment intervals. More recent, larger scale clinical trials using saw palmetto in men with LUTS have also been reported. In an open-label study conducted in Belgium, 505 men with mild to moderate symptoms were treated with saw palmetto for 3 months.14 The mean peak flow rate improved from 9.8 mL per second to 12.2 mL per second, and the mean AUA symptom score decreased from 19.0 to 12.4. Overall, 88% of patients and physicians considered the therapy to be effective for relieving urinary symptoms. There was also a small but statistically significant decrease in prostate volume assessed by transrectal ultrasound, of 9.2% noted in men treated with saw palmetto. While saw palmetto appeared to lead to subjective and objective improvement in men with BPH, the lack of placebo controls in this trial limits drawing conclusions from it. In a 6-month open-label study conducted at the University of

Chicago that incorporated urodynamic evaluation of patients treated with saw palmetto, the current author and colleagues found that the mean AUA symptom score improved from 19.5 to 12.3 (p < .001).6 No improvements in urodynamic parameters such as peak flow rate, detrusor pressure, or postvoid residual were demonstrated, however. Men receiving saw palmetto reported no adverse effects, and there were no changes in routine serum chemistries or PSA levels noted. Finally, in a meta-analysis of 2794 men treated with Permixon, information on changes in peak urinary flow rate and nocturia were available and compared to placebo groups.23 Based on this analysis, the estimated effect of Permixon on peak flow rate beyond the placebo effect is 1.87 mL per second, and frequency of nocturia is decreased by a mean of 0.55 over placebo. In the largest randomized trial concerning saw palmetto reported to date, 1098 men with moderate symptoms received Permixon or finasteride for 6 months.5 The study was conducted at 87 centers in Europe and did not include a placebo control group. There was a significant improvement in the mean symptom score from 15.7 to approximately 9.5 noted in both groups. While both groups demonstrated a significant increase in the mean peak urinary flow rate, the improvement was statistically better in those men treated with finasteride. There were few adverse effects noted in either group although there was less evidence of sexual dysfunction among the men receiving Permixon. Prostate volume was measured by transrectal ultrasound and showed a significant decline in both groups. Patients treated with finasteride, however, had an 18% decrease compared to only 6% in those treated with Permixon (p < .001). In addition, there was a 41% decrease in serum PSA levels and a 3% increase in those patients treated with finasteride and Permixon, respectively. These findings appear to indicate that saw palmetto leads to no or minimal clinically relevant 5 α-reductase inhibition. In a separate analysis of these results, the investigators demonstrated that the response to finasteride and Permixon was independent of pretreatment prostate size.24 The results of the Veterans Administration (VA) Cooperative Trial in the United States,25 in which men were randomized to receive finasteride, terazosin, both drugs, or placebo, must be taken into account when assessing the results of this large European trial of Permixon versus finasteride. Since the findings of the VA trial suggested that finasteride was no more effective than placebo, it is possible that the results of the European study may largely indicate a placebo effect in patients receiving Permixon as well as in those treated with finasteride. Summary Saw palmetto is a well-tolerated plant extract that appears to lead to few, if any, significant adverse effects. While much attention has focused on the action of saw palmetto


as a 5 α-reductase inhibitor, there is little evidence to suggest that it has a significant, clinically relevant effect on prostate size or serum PSA levels. Therefore, it seems unlikely that saw palmetto can be considered to have a similar efficacy as finasteride. Alternative proposed mechanisms of action may play a role in improving urinary symptoms although further study is necessary concerning possible effects on prostatic inflammation, edema, and others. Overall, while a number of clinical trials have suggested that saw palmetto leads to significant improvement in voiding symptoms and urodynamic measures of obstruction, there is a need for properly conducted, placebo-controlled trials to determine whether this agent is truly effective in treating men with BPH.

Pygeum africanum The African plum tree, Pygeum africanum, is the source of another popular phytotherapeutic agent. The medicinal portion of the plant comes from the deeply fissured bark, which has been used by natives of southern Africa for many centuries. The primary components of Pygeum that are felt to be active in alleviating voiding symptoms secondary to BPH are phytosterols, linear alcohols, and triterpenoids.1,2 In vitro studies have demonstrated that Pygeum is a potent inhibitor of prostatic fibroblast proliferation in response to direct activators of protein kinase C and to a variety of growth factors.26,27 These actions are felt to lead to anti-inflammatory effects within the prostate. Also, it appears that phytosterols have an inhibitory effect on the production of prostaglandin E2 and F2 alpha, which may help relieve vascular congestion and local hyperemia. Although most research concerning Pygeum has focused on anti-inflammatory actions, the salutary effects of this agent may also be attributed to effects on the detrusor. Using Tadenan, an extract of Pygeum marketed by a French pharmaceutical company, Levin and his colleagues have conducted a series of investigations on bladder physiology.28,29 The initial response of the detrusor muscle to bladder outlet obstruction is smooth muscle hypertrophy and an increase in bladder mass. These changes in the detrusor may lead to reduced bladder capacity, hypercontractility, and other effects leading to a variety of voiding symptoms. In rabbits, the experimental creation of partial bladder outlet obstruction rapidly results in urothelial hyperplasia, smooth muscle hypertrophy, and increased collagen synthesis and deposition within the bladder.29 These changes lead to a decrease in the contractile response of the detrusor to stimulation and biochemical evidence of bladder dysfunction, with a reduction in the activities of citrate synthase and calcium ATPase.28 Among the first responses to bladder outlet obstruction is fibroblast hyperplasia induced by an increase in basic fibroblast growth factor activity.28 It has been demonstrated that Tadenan inhibits fibroblast hyperpro-

liferaton caused by growth factors, giving rise to the suggestion that this plant extract may improve bladder function in patients with prostatic obstruction. In their initial study, Levin et al. randomized rabbits to receive Tadenan at various doses for 3 weeks or to a control group.29 Partial bladder outlet obstruction was then experimentally created to simulate the effects of BPH; the animals were sacrificed 2 weeks later. Pretreatment with Tadenan led to a significant protective effect on the contractile response of the detrusor to a variety of forms of stimulation while having no measurable effect on the overall increase in bladder mass. Subsequently, these same investigators reported that pretreatment of rabbits with Tadenan had a beneficial effect on metabolic dysfunction seen in the partially obstructed bladder.28 While both control and treated animals had an initial decrease in citrate synthase and calcium ATPase levels, only those rabbits receiving Tadenan had a return of both enzymes to near normal levels within 7 to 14 days after the obstruction was created. The clinical relevance of these effects is unclear, however, since the dosages utilized in the study were well above physiologic levels.1 In addition, pretreatment of patients prior to the development of bladder outlet obstruction is rarely feasible. Therefore, it is unclear what effect Tadenan might have on detrusor function and physiology if administered after a prolonged period of obstruction, as typically occurs in patients with BPH. Clinical Studies There has been only limited study of the effectiveness of Pygeum in men with symptomatic BPH. Similar to the situation with other phytotherapeutic agents, most of these studies involved short treatment intervals and lacked standard means of assessing therapeutic outcome. In a placebo-controlled French study of 120 men treated for 6 weeks, patients receiving Pygeum had a significant improvement in symptoms of nocturia, hesitancy, and sense of incomplete bladder emptying compared to controls.30 Barlet et al. studied 263 patients treated with Pygeum or placebo for 2 months and found that the percentage of patients with symptomatic improvement was significantly greater among those men receiving Pygeum (66% versus 31%).31 Overall, the efficacy of Pygeum in men with BPH remains unproven and further study of this agent is required.

Phytosterols Phytosterols are a class of compounds that have been suggested to be the most important component of several phytotherapeutic products used for treating BPH. Phytosterols are derived from a number of plants, including Hypoxis rooperi (South African star grass). There have been a variety of mechanisms proposed by which phytosterols may improve voiding symptoms,

Phytotherapy in the Treatment of Benign Prostatic Hyperplasia / 611

including 5 α-reductase inhibition, anti-inflammatory effects, antiandrogenic actions, growth factor inhibition, antiestrogenic effects, and others.1,32 Beta-sitosterol has been suggested to be the most important phytosterol in treating voiding symptoms secondary to BPH.32,33 Harzol is a prescribable phytotherapeutic product manufactured in Germany. This agent is composed of a mixture of phytosterols that include primarily beta-sitosterol as well as smaller amounts of campesterol, stigmasterol, and other compounds.32 Although it has been suggested that beta-sitosterol is the most important active component of Harzol, it is not known which compounds are responsible for its effect on men with BPH. Following initial study suggesting an improvement in urinary symptoms and flow rates in patients with BPH treated with Harzol,34 Berges et al. published the results of a randomized, multicenter, placebo-controlled trial.32 In this study, 200 men with symptomatic BPH were treated with Harzol or placebo three times per day for 6 months. Among men receiving Harzol, the International Prostate Symptom Score (IPSS) improved from a mean of 14.9 to 7.5 while those treated with placebo showed a mean symptom score improvement from 15.1 to 12.8 (p < .01). Similarly, mean peak urinary flow rate increased from 9.9 to 15.2 cc per second in the Harzol group, compared to 10.2 to 11.4 cc per second among controls (p < .01). There was also a significant decrease in postvoid residual urine volume seen in men treated with Harzol compared to controls. No severe adverse effects were noted secondary to Harzol, and there was no significant change in prostate volume. Other studies concerning the use of phytosterol preparations composed primarily of beta-sitosterol have also been presented.35 Klippel et al. randomized 177 men with BPH to receive Azuprostat, a phytosterol preparation marketed in Europe, or placebo for 6 months.35,36 In results presented at the 4th International Consultation on BPH in 1997, there was a significant difference in IPSS improvement between men receiving Azuprostat and those receiving placebo (5.4 points, p < .01). In addition, the difference in peak urinary flow rate improvement (4.5 cc per second) and reduction in postvoid residual volume (33.5 cc) also indicated a significantly better response to the plant extract than to placebo.

Pollen Extract Studies have suggested that a number of phytotherapeutic products derived from the pollen extract of a variety of plants are of value in treating men with BPH.1,37 Most of these studies have used Cernilton, a pharmaceutical product composed of the pollen extract from several plants grown in Sweden. The two principal active constituents of Cernilton are a water soluble fraction and an acetone soluble fraction containing three betasterols.37 Animal studies using Cernilton have demonstrated a significant decrease in the size of the prostate associated with epithe-

lial cell atrophy, a decline in total and prostatic acid phosphatase levels, and an increase in zinc concentrations within the prostate.38 In addition, the water soluble fraction of Cernilton has been shown to inhibit the immortal human cell line growth in culture derived from prostate carcinoma.39 Finally, it has been shown that the hormonestimulated growth of BPH tissue transplanted into nude mice is significantly inhibited by Cernilton extract.37 Clinical studies with Cernilton have included a doubleblind, randomized trial in which 60 men awaiting surgery for BPH were randomized to receive Cernilton or placebo for 6 months.37 No adverse effects or changes in hematologic parameters were seen in patients treated with this plant extract. Based on a modified Boyarsky symptom score, men treated with Cernilton showed statistically significant improvement in subjective symptoms compared to men in the control group (69% versus 29%, respectively, p < .009). When analyzed by individual voiding symptoms, only nocturia and a sense of incomplete emptying significantly improved in the men treated with Cernilton compared to those receiving placebo. Although no change in peak urinary flow rate or voided volume was noted in either group of patients, residual urine volume declined significantly in those men treated with Cernilton (mean 145 cc to 102 cc after 6 months) compared to controls (p = .025). Finally, based on transrectal ultrasound measurements performed prior to treatment and after 6 months, a small but statistically significant decrease in prostate size in patients receiving Cernilton was noted compared to those in the placebo group (p = .025). The use of Cernilton has also been studied in men with chronic prostatitis and prostatodynia.40 In a nonrandomized, open-label investigation, 90 men who had had symptoms for 1 year or more and had no evidence of bacterial infection received the pollen extract for 6 months.40 Subjective assessment of perineal pain, frequency, and dysuria were assessed as well as the results of digital rectal examination, white blood cell counts in expressed prostatic secretions, complement levels in the seminal fluid, and uroflowmetry. There was a favorable response seen in 78% (56 of 72) of those without complicating factors such as urethral strictures or bladder neck contracture, and complete resolution of all symptoms and signs of prostatitis was noted in 36% (26 of 72). Results were poor in those with complicating factors, with only 1 of 18 (6%) showing any significant improvement in subjective or objective outcome measures. Although these results suggest that there may be a role for Cernilton in men with nonbacterial prostatitis and pelvic pain syndromes, the lack of placebo controls in this study makes it difficult to draw conclusions regarding the efficacy of this agent. Finally, the results of a study comparing Cernilton with the Pygeum extract Tadenan in men with symptomatic BPH have been reported.41 Superior improvements in


voiding symptoms, urine flow rate, and postvoid residual volume were noted among men treated with Cernilton.

Mepartricin Although Mepartricin is not truly a plant extract, it is best grouped with other phytotherapeutic agents used for treating symptomatic BPH. Mepartricin is a semisynthetic polyene derived from a Streptomyces strain. It appears to have favorable effects in men with BPH by selective binding activity with estrogens. This agent is produced in Italy and is marketed under the trade name Ipertrofan. Mepartricin binds to estrogen in the intestine, thus inhibiting its reabsorption.42 Since most estrogens are reabsorbed in the intestine after excretion into the bile, a decrease in reabsorption leads to a reduction in circulating serum levels. This leads to a decline in estrogeninduced stimulation of prostatic growth.42 In animal experiments, Mepartricin has been demonstrated to increase fecal excretion of estrogen and reduce blood and prostate estrogen concentrations as well as estrogen receptor levels within the ventral prostatic lobes.43 In patients with BPH, treatment with Mepartricin has led to a significant decrease in the serum concentration of estrone, estradiol, and estriol.44 In a multicenter trial conducted in several European countries, 198 men with untreated symptoms secondary to BPH with an IPSS of 12 to 24 were randomized to receive Mepartricin or placebo for 24 weeks.45 Patients also were required to have a peak urinary flow rate of 6 to 15 cc per second to be enrolled in the study. The patients treated with Mepartricin had a significantly greater reduction in symptom score and increase in urinary flow rate compared to controls as well as an improved qualityof-life measure. No significant differences were seen in the two groups with regard to changes in prostate size, PSA level, or postvoid residual urine volume. No serious adverse events were noted among men in either group. Mepartricin appears to be a promising treatment option, with a unique mechanism of action, for men with symptomatic BPH. Further study of this agent is planned.

Other Plant Extracts In addition to the phytotherapeutic agents discussed above, a variety of other plant extracts have been investigated in men with symptomatic BPH. Bazoton is the trade name of an extract from the plant Radix urticae and has a steroid-glycoside composition.46 This product has been tested in Hungary and appears to be an inhibitor of intracellular sex hormone–binding globulin receptors.46 In a limited, nonrandomized study, treatment with Bazoton led to symptomatic improvement as well as improvements in urinary flow rate and postvoid residual volume.46 In Germany, extracts from the roots of Urtica dioica (stinging nettles) are widely used for treating men with BPH. The suggested mechanisms of nettles include sup-

pression of prostatic cell growth and metabolism, inhibition of a variety of prostatic growth factor interactions, and blockage of the attachment of sex hormone–binding globulins to prostatic membrane receptors.47,48 Although randomized, placebo-controlled trials demonstrating subjective and objective benefit using nettles have been reported in Germany, these studies have generally included small numbers of patients treated for intervals of only 1 to 3 months.49 The value of stinging nettles in men with BPH therefore remains unclear. Other studies have investigated combination products incorporating two or more phytotherapeutic agents that have been used in men with BPH.50,51 These trials have frequently demonstrated subjective and objective benefit in treated patients compared to controls. The value of these studies, however, has generally been limited by small numbers of patients and short treatment intervals. Finally, therapeutic benefit has been suggested for other plant extracts such as those from pumpkin seeds, unicorn root, and rye pollen. No recognized studies using these agents in men with BPH have been presented to date.

Summary There is growing interest in the United States in the use of “natural remedies” to treat patients with chronic medical conditions such as BPH. Most American physicians have limited knowledge concerning these treatments and are unable to advise patients regarding their use. Due to the proliferation of health food and vitamin stores, the growing popularity of the Internet, and aggressive direct marketing to consumers, there has been a significant increase in the overall use of medicinal botanicals. Unlike therapies such as alpha-blockers and 5 α-reductase inhibitors, there have been few properly conducted trials of plant extracts in men with BPH. One of the primary reasons for the lack of scientific study of these agents is the absence of significant financial incentive for American companies marketing phytotherapeutic products to support such research, given that such products are generally not eligible for patent protection. Additional difficulties in assessing the efficacy of plant extracts in men with BPH include the lack of standardization of these agents. Vast differences are likely to exist between similar products sold by different manufacturers. This issue is further confused by the widespread availability of combination products that often contain vitamins and minerals as well as a variety of plant extracts. There is a clear need for randomized, controlled trials of phytotherapeutic products in men with BPH to ascertain the true value of these agents.

References 1. Lowe FC, Ku JC. Phytotherapy in treatment of benign prostatic hyperplasia: a critical review. Urology 1996; 48:12–20.

Phytotherapy in the Treatment of Benign Prostatic Hyperplasia / 613 2. Mowrey DB. Herbal tonic therapies. New Canaan: Keats Publishing Inc; 1993. 3. Delos S, Iehle C, Martin PM. Inhibition of the activity of basic 5 alpha-reductase (type 1) detected in DU 145 cells and expressed in insect cells. J Steroid Biochem Mol Biol 1994;48:347–52. 4. Bayne CW, Grant ES, Chapman K, Habib FK. Characterisation of a new coculture model for BPH which expresses 5 alpha-reductase types 1 and 2: the effects of Permixon on DHT formation [abstract]. J Urol 1997;157 Suppl 4:755. 5. Carraro JC, Raynaud JP, Koch G, et al. Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1098 patients. Prostate 1996;29:231–40. 6. Gerber GS, Zagaja GP, Bales GT, et al. Saw palmetto (Serenoa repens) in men with lower urinary tract symptoms: effects on urodynamic parameters and voiding symptoms. Urology 1998;51:1003–7. 7. Chevalier G, Benard P, Cousse H, Bengone T. Distribution study of radioactivity in rats after oral administration of the lipido/sterolic extract of Serenoa repens (Permixon) supplemented with (1-14C)-lauric acid or (4-14C)-sitosterol. Eur J Drug Metab Pharmacokinet 1997;22:73–83. 8. De Bernardi di Valserra M, Tripodi AS, Contos S, Germogli M. Serenoa repens capsules: a bioequivalent study. Acta Toxicol Ther 1994;15(1):21–39. 9. Sultan C, Terraza A, Devillier C, et al. Inhibition of androgen metabolism and binding by a liposterolic extract of “Serenoa repens B” in human foreskin fibroblasts. J Steroid Biochem 1984;20:515–9. 10. Carilla E, Briley M, Fauran F, et al. Binding of Permixon, a new treatment for prostatic benign hyperplasia, to the cytosolic androgen receptor in the rat prostate. J Steroid Biochem 1984;20:521–3. 11. Silverio F, Sciarra A, D’Eramo G, et al. Response to tissue androgen and epidermal growth factor concentrations to the administration of finasteride, flutamide, and Serenoa repens in patients with BPH [abstract]. Eur Urol 1996;30 Suppl 2:317. 12. Rhodes L, Primka RL, Berman C, et al. Comparison of finasteride (Proscar), a 5 alpha-reductase inhibitor, and various commercial plant extracts in in vitro and in vivo. 5 alpha-reductase inhibition. Prostate 1993;22: 43–51. 13. Strauch G, Perles P, Vergult G, et al. Comparison of finasteride (Proscar) and Serenoa repens (Permixon) in the inhibition of 5 alpha-reductase in healthy male volunteers. Eur Urol 1994;26:247–52. 14. Braeckman J. The extract of Serenoa repens in the treatment of benign prostatic hyperplasia: a multicenter open study. Curr Ther Res 1994;55:776–85. 15. Di Silverio F, D’Eramo G, Lubrano C, et al. Evidence that Serenoa repens extract displays an antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy patients. Eur Urol 1992;21:309–14. 16. Helpap B, Oehler U, Weisser H, et al. Morphology of benign prostatic hyperplasia after treatment with sabal extract IDS 89 or placebo. J Urol Pathol 1995;3:175–82. 17. Champault G, Patel JC, Bonnard AM. A double-blind trial

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prostatic hyperplasia with phytosterols. Br J Urol 1987; 66:639–41. Dreikorn K, Richter R, Schonhofer PS. Konservative, nicht-hormonelle Behandlung der benignen Prostatahyperplasia. Urologe A 1990;29:8–16. Klippel KF, Schipp B. A placebo-controlled, double-blind clinical trial of B-sitosterol (phytosterol) for the treatment of benign prostatic hyperplasia [abstract 5]. 4th International Consultation on BPH; 1997 July 2–5; Paris, France. Klippel KF, Hiltl DM, Schipp B. Randomized, double-blinded placebo-controlled trial to evaluate the efficacy of B-sitosterol (phytosterol) in patients with obstructive and irritative symptoms due to BPH [abstract 42]. 4th International Consultation on BPH; 1997 July 2–5; Paris, France. Buck AC, Cox R, Rees WM, et al. Treatment of outflow tract obstruction due to benign prostatic hyperplasia with the pollen extract, Cernilton. A double-blind, placebo-controlled study. Br J Urol 1990;66:398–404. Ito R, Ishii M, Yamashita S. Cernitin pollen-extract (Cernilton): antiprostatic hypertrophic action of Cernitin pollen-extract (Cernilton). Pharmacometrics 1986;31:1–11. Habib FK, Buck AC, Ross M. In vitro valuation of the pollen extract, Cernitin T-60, in the regulation of prostate cell growth. Br J Urol 1990;66:393–7. Rugendorff EW, Weidner W, Ebeling L, Buck AC. Results of treatment with pollen extract (Cernilton N) in chronic prostatitis and prostatodynia. Br J Urol 1993; 71:433–8. Dutkiewicz S. Usefulness of Cernilton in the treatment of benign prostatic hyperplasia. Int Urol Nephrol 1996; 28:49–53. Ghelfi R, Croce A, Mangiagalli M. Pharmacokinetics of

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Mepartricin. Absorption and excretion of its insoluble form. Terap Antib Chemioter 1978;28:3–6. Del Vecchio S, Ulissi A, Delle Monache M, et al. Faecal elimination of steroids in rats after oral absorption of Mepartricin. J Int Med Res 1990;18:468–72. Lotti T, Mirone V, Prezioso D, et al. Observations on some hormone fractions in patients with BPH treated with Mepartricin. Curr Ther Res 1988;44:402–6. Denis LJ, Pagano F, Robertson C, et al. Double-blind, randomized, placebo-controlled trial of Mepartricin in the treatment of BPH: final results after 6 months followup [abstract 532]. J Urol 1997;157 Suppl 4:136. Romics I. Observations with Bazoton in the management of prostatic hyperplasia. Int Urol Nephrol 1987;19: 293–7. Hryb DJ, Khan MS, Romas NA, Rosner W. The effects of extracts of the roots of the stinging nettle (Urtica dioica) on the interaction of SHBG with its receptor on human prostatic membranes. Planta Med 1995;61:31–2. Wagner W, Willer F, Samtleben R, Boos G. Search for the antiprostatic principle of stinging nettle (Urtica dioica) roots. Phytomedicine 1994;1:213–24. Vontobel HP, Herzog R, Rutishauser GH. Ergebnisse einer Doppelblind studie uber die Wirksamkeit von ERUKapseln in der konservativen Behandlung der benignen Prostatahyperplasie. Urologe A 1985;24:49–51. Carbin BE, Larsson B, Lindahl O. Treatment of benign prostatic hyperplasia with phytosterols. Br J Urol 1990;66:639–41. Metzker H, Martin C. Efficacy and safety of the Sabal Urtica combination PRO 160/120 in the treatment of patients with benign prostatic hyperplasia (a placebocontrolled double-blind long term clinical trial) [abstract 15]. 4th International Consensus on BPH; 1997 July 2–5; Paris, France.

CHAPTER 67

PROSTATITIS: PATHOPHYSIOLOGY GEORGE W. DRACH, MD medical etymologists cringe. For the purposes of this chapter, the terminology in Table 67–3 will be used. The most current concepts of gross and histologic anatomy of the prostate will now be examined.7 Human prostate tissue arises from two embryologic anlage and is a combination of fibromuscular tissue related to the urethra and of parenchymal glandular tissue. It contains approximately 60 tortuous apocrine glands. These secrete elements that are components of the ejaculate. Of the elements, prostatic zinc probably plays a major role in the antibacterial defense mechanism of the male urethra.8 Zinc has a remarkable effect on prostatic macrophages that may be important in prostatitis.9 “Lipid-laden macrophages” are a common component of inflamed prostatic secretions. The histology of the prostate has been studied extensively over the past two decades, primarily because of interest in prostatic carcinoma.7 Fortunately, this has led to associated observations on prostatitis. Anatomic and histologic zones of the prostate have been reviewed elsewhere in the book (see Chapter 15, Pathology of the Prostate.) For practical purposes, most authorities accept the definitions of McNeal,7 who separates the glandular prostate into peripheral, central, and transitional zones. The most proximal portion of the prostate is subdivided further into the transition zone (from which BPH arises) and the periurethral region. Prostatic carcinoma and prostatitis seem to occur primarily in the peripheral prostate rather than in the central or transitional portions.

The current author and colleagues proposed a possible classification of the syndromes of benign but annoying prostatic pain a number of years ago (Table 67–1).1 Some investigators accepted this method over the ensuing years; more recently, a reclassification emerged from a National Institutes of Health (NIH) Consensus Conference.2 This classification will be discussed further in a following chapter but is presented for purposes of terminology in Table 67–2. Prostatitis confuses and frustrates patients and physicians.3 This has been reiterated recently and is captured by Meares’ comment that “many (patients) are generally unhappy with the results of treatment.”4 Physicians, especially urologists, prefer to function on the basis of confirmed diagnoses. Since patients with nebulous prostatitis syndromes create insecure diagnostic ground, there is “the tendency for the clinician to refer the patient elsewhere.”4 One reason for such insecurity relates to urologists' inability to connect the anatomic disease conditions found in the prostate to the clinical syndromes seen in everyday practice. Perhaps no rational correlation can be made at this time. Most studies on the incidence of prostatitis syndromes report on surveys of lists of diagnoses obtained from institutional records.5 Other authors report on physician responses to questionnaires.6 In both cases, reporting physicians use mostly clinical judgment rather than objective data in making their diagnoses. Hence, “prostatitis” becomes a collection of symptoms without a concomitant pathophysiologic basis. This diagnosis by symptoms has led to the present national consensus classification. Assignment of the suffix “-itis,” however, connoting inflammation, to a syndrome such as prostatodynia that may have no inflammation associated with it, creates a pathologic misnomer that makes

Prostatitis This analysis of prostatitis will consider those conditions associated with histologic inflammation and bacterial infection, including abscess, inflammations for which bacteria seem unlikely causative factors, mycotic granulomatous infections, and granulomatous inflammation of uncertain etiology.

TABLE 67–1. Original Drach et al. Classification of Painful Benign Diseases of the Prostate* Type of Prostatitis Acute Chronic bacterial Chronic nonbacterial Prostatodynia

Cells in EPS

Bacterial Culture

Abnormal Voiding

> 10/HPF > 10/HPF > 10/HPF < 10/HPF

Positive Positive Negative Negative

Yes Perhaps Perhaps Usually

Histologic Abnormalities Inflammation of the prostate is a common histologic finding. In one study, Kohnen and Drach10 found that significant proportions of prostate adenoma tissue obtained from transurethral removal or enucleation showed evidence of inflammation. This study used cross-sectional area techniques to quantify proportions of inflamed prostate tissue. Men with no history of prostatitis had a

EPS = expressed prostatic secretions; HPF = high-power field. *Drach GW, Fair WR, Meares EM, Stamey TA. Classification of benign disease associated with prostatic pain: prostatitis or prostatodynia? J Urol 1978;120:266.

615

616 / Advanced Therapy of Prostate Disease TABLE 67–2. National Institutes of Health Consensus Classification of Chronic Painful Prostatitis Syndromes NIH Classification†

Definition

Category I. Acute bacterial prostatitis Category II. Chronic bacterial prostatitis Category III. Chronic abacterial prostatitis/CPPS Category IIIA. Inflammatory CPPS Category IIIB. Noninflammatory CPPS Category IV. Asymptomatic inflammatory

Acute infection of the prostate gland Recurrent infection of the prostate No demonstrable infection White cells in semen/EPS/voided bladder urine-3 (VB3 or postprostatic massage) No white cells in semen/EPS/VB3 No subjective symptoms detected prostatitis either by prostate biopsy or the presence of white cells in EPS/semen during evaluation for other disorders

EPS = expressed prostatic secretions; CPPS = chronic pelvic pain syndrome; NIDDK = National Institute of Diabetes and Digestive and Kidney Diseases; NIH = National Institutes of Health; VB3 = voided bladder - 3. †This classification system has become the NIDDK reference standard for research studies on these diseases and disorders. From Nickel JC. Prostatitis: myths and realities. Urology 1998;51:362–6.

mean 12.4 percent of cross-sectional area of the prostate revealing inflammation compared to 17 percent in men with a history of prostatitis. This finding was interpreted to mean that prostatic inflammation could be found in many men with no symptoms or signs of prostatitis. On the other hand, more inflammation was found in prostatic tissue of men who had complaints and findings of prostatitis. Nevertheless, it was surprising that only a 5 percent difference was found between the two groups. This same study defined several types of prostatic inflammation: acute intraglandular, abscess, chronic intraglandular, acute or chronic periglandular, or granulomatous. Acute prostatitis (Figure 67–1) occurs with classic intraglandular inflammation, multiple polymorphonuclear cells, thick mucoid exudate, and apparent inspissation of secretions in the lumen. Acute prostatitis may progress to microscopic or gross abscess. Chronic inflammation of the intra- and periglandular spaces is shown in Figure 67–2. There are many round cells and several large, fatladen macrophages; histologic findings consistent with chronic prostatitis. It seems likely that massage of such a prostate would result in expressed prostatic secretions that would contain chronic inflammatory cells and correlate with “chronic prostatitis.” Figure 67–3 shows typical granulomatous inflammation in a patient with known coccidioidomycosis. Fibrosis and giant cells are prominent. As emphasized in this study, the best definition of “prostatitis” includes the requirement that there is demonstrable inflammation in the prostate. To establish the presence of inflammation, tissue secretions or samples must be evaluated. Expressed prostatic secretions represent one such sample and prostatic biopsies another. Both sources have been extensively evaluated. Unfortunately, studies defining causative agents of inflammation have been inconclusive in most cases. Some microbiologic investigations, however, have contributed to the body of knowledge concerning prostatitis. Bacterial Prostatitis To correlate findings of abnormal cells in expressed prostatic secretions (EPS) with bacteria in prostate tissue, Berger

et al.11 extended the observations of Doble et al.,12 Nickel and Costerton,13 and Weidner et al.14 on microorganisms cultured directly from prostatic tissue obtained by perineal prostatic needle biopsy. Men with 500 or more inflammatory cells per mm3 in expressed prostatic secretions more often had positive biopsy cultures (p = .01), positive cultures for any bacteria (p = .01), positive cultures for any anaerobic species (p = .03), higher total bacterial counts (p = .02), and more bacterial species isolated from prostatic biopsies than men with fewer than 500 leukocytes per mm3. Some of the bacteria cultured from the prostate were skin bacteria or anaerobic organisms. The authors cautiously suggest that there is a possible etiologic relationship between these commensal and anaerobic bacteria and prostatic inflammation. They also point out that there is a correlation between increased numbers of inflammatory cells in prostatic secretions and the finding of some type of microorganism in prostatic tissue. If it is accepted that prostatic infection and inflammation are necessary to establish a diagnosis of prostatitis, then progress will have been made in defining the clinical syndrome of prostatitis. The authors of the above study found 7 aerobic and 14 anaerobic species of microorganisms (a total of 58 isolates) in the biopsies of 85 men. Many of the anaerobes were slow growing, fastidious organisms that would be missed by usual bacterial culture techniques. Some of the patients who carried the diagnosis of “nonbacterial” prostatitis, then, in fact had bacterial prostatitis. This may explain why many TABLE 67–3. Classification of Benign Painful Diseases of the Prostate* Prostatic Disease Category Acute prostatitis Chronic bacterial prostatitis Chronic nonbacterial prostatitis Prostatodynia

Cells in EPS

Positive Culture for Microorganism

Pathologic Inflammation in Prostate

> 10/HPF > 10/HPF > 10/HPF

Yes Yes No

Yes Yes Yes

< 10/HPF

No

No

EPS = expressed prostatic secretions; HPF = high-power field. *Used in this chapter.

Prostatitis: Pathophysiology / 617

FIGURE 67–1. Acute prostatitis occurs with classic intraglandular inflammation, multiple polymorphonuclear cells, thick mucoid exudate, and apparent inspissation of secretions in the lumen.

such patients who are treated with antibiotics in the absence of positive culture results benefit from such therapy.5 It is recognized, therefore, that some patients who have chronic nonbacterial prostatitis have localized prostatic inflammation due to bacteria that are not discovered through usual diagnostic testing. Many investigators have searched diligently for additional unusual causative microorganisms such as pleuropneumonia-like organisms (PPLO), mycoplasma, chlamydia, or viruses. According to Meares,4 multiple studies confirm only occasional causation of prostatitis by such microorganisms. Some patients may nevertheless have prostatitis in the absence of bacteria.

but are not infected by any of the microorganisms that appear to be related to their syndrome. The NIH consensus classification correctly places these patients into category IIIA, chronic abacterial prostatitis, inflammatory chronic pelvic pain syndrome (CPPS). Nickel15 points out, however, that even this abacterial group may only reflect an inability to define the infecting agent. He reaches this conclusion from reviewing studies of perineal biopsies such as those by Berger et al.11 noted above, reports of serum antibody responses to pathogens or bacterial deoxyribonucleic acid (DNA) in culture negative tissues, and from identifications of “cryptic” bacteria. Another potential explanation of prostatic inflammation in patients with abacterial prostatitis could be reflux of urine and its chemical irritants into prostatic ducts during abnormal voiding. Persson et al.16 studied 56 patients with nonbacterial prostatitis and came to the conclusion that reflux of urine into prostatic ducts might initiate a chemical inflammatory reaction. They deduced that urate might be the chemical agent responsible for the inflammation. Subsequently, they treated such patients with allopurinol and concluded that it “has a significant positive effect on nonbacterial prostatitis.”17

Nonbacterial (or Abacterial) Prostatitis After excluding the diagnoses discussed previously, the clinician is left with a category of patients who have symptoms of prostatitis and inflammation of the prostate (assessed by analysis of expressed prostatic secretions)

Granulomatous Prostatitis Prostatitis of the granulomatous type represents one of the proven infectious etiologies and is shown in the specimen in Figure 67–3, obtained from a patient with known coccidioidal fungal prostatitis. This patient presented with irritative voiding symptoms and microhematuria. Urinary tract imaging was unremarkable but calcified granulomas were seen on chest film. Cystoscopy revealed only an inflamed prostatic urethra. Prostate digital examination demonstrated firmness and irregularity on the left with some enlargement (ultrasound size 53 cc). Most revealingly, expressed prostatic secretions contained many round cells and “endosporulating spherules,” which are

FIGURE 67–2. Chronic inflammation of the intra- and periglandular spaces, showing many round cells and several large, fat-laden macrophages; histologic findings consistent with chronic prostatitis.

FIGURE 67–3. Typical granulomatous inflammation in a patient with known coccidioidomycosis. Fibrosis and giant cells are prominent.


pathognomonic of coccidioidomycosis (sometimes known as “Valley Fever”). Coccidioidal organisms were grown from a small portion of this secretion on culture. The tissue shown in Figure 67–3 was obtained by transperineal core biopsy because the patient had significant elevation of prostate-specific antigen (PSA) levels. No cancer was found. The patient improved quickly after he was placed on antifungal therapy. Unfortunately, fungal prostatitis and cancer may coexist. In the presence of elevated PSA levels, biopsy is advisable even if the cause of prostatitis clearly seems to be fungal.18 Treatment of recurrent superficial bladder carcinoma with bacille Calmette-Guérin (BCG) creates another potential for granulomatous prostatitis, as summarized by Roberts et al.19 In these patients, a history of prior BCG therapy may be a causative factor. The incidence of granulomatous prostatitis in these patients may approach 75 percent.20

The NIH classification shown in Table 67–2 places this type of patient in category IIIB, Noninflammatory CPPS. This category is distinguished from category IIIA (inflammatory CPPS or abacterial prostatitis) by the absence of inflammatory cells in semen, EPS, or the postprostatic massage-voided urine specimen. This classification seems out of place as it includes an inflammatory (i.e., prostatitis) group with a noninflammatory group. This is the reason the current author’s earlier classification1 used a designation that did not connotate inflam-

mation, that is, “prostatodynia.” Perhaps the designation “prostatalgia” would have been equally useful since both these words can be found in the medical dictionary and both refer to prostatic pain. Therefore, the current author’s preferred “blended” classification in Table 67–3 includes this term. It is prostatic pain or discomfort that accounts for much of the symptomatology expressed by CPPS patients. It is important to recognize that patients with category IIIB CPPS or prostatodynia do not demonstrate any prostatic inflammation or infection. Patients showing these conditions do not have prostatodynia; they have prostatitis.25 Patients with prostatodynia report perineal, abdominal, testicular, penile, and ejaculatory pain similar to that of patients with nonbacterial prostatitis. There is, however, no associated demonstrable inflammation.26 As to the cause of this syndrome, Wesselmann and Reich27 state that “...more often, despite an exhaustive evaluation, no etiology is found and...the cause of the pain remains enigmatic.” Some authors have implicated urodynamic irregularities in such pain syndromes. Reports include findings of abnormal bladder neck configuration28 or increased maximum urethral closure pressures at the distal prostatic or membranous urethral segments.29 This last study also noted a “synchronous decrease in urinary flow rate (peak and average flow) in the majority of patients.” The author suggests that the diagnosis of these patients should be “painful urethral syndrome,” not prostatodynia. If it is accepted that prostatodynia is equivalent to NIH category IIIB, CPPS in the absence of inflammation, patients with the “painful urethral syndrome” then meet this definition of CPPS. One characteristic pattern of the urethral flow that can be seen in some patients with prostatodynia has a “sawtooth” pattern on a urethral flow tracing (Figure 67–4). Patients who show this pattern may respond to treatment with alpha-sympathetic blocking drugs such as terazosin.30,31 The “sawtooth pattern” and the symptoms often disappear following terazosin treatment. This observation illustrates that one potential cause of prostatodynia may be abnormal bladder neck/prostatic urethral function that may be ameliorated by alpha-blocking drugs.

FIGURE 67–4. Urinary flow rate tracing from left to right. Peak urinary flow rate is adequate at 31 mL per second but the pattern is jagged, resembling “sawtooths.”

Patients with CPPS undergo extensive evaluations testing for infection or urodynamic problems. One test which may be helpful is transrectal ultrasound.32,33 While not indicated for prostate cancer screening, it will on occasion demonstrate a lesion that is subsequently demonstrated to be prostate cancer.34 If any suspicious benign anatomic findings are encountered during the ultrasound examination, further and more precise studies may be performed. In patients with decreased urinary flow rates, it should not be assumed that the cause is bladder neck dysfunction.

Granulomatous Inflammation of Uncertain Etiology Occasionally, granulomatous prostatitis may be present histologically without specific fungal or mycotic etiology.21 Allergy22 or autoimmune23 diseases have been implicated as possible etiologies for these granulomas. Perhaps the greatest problem associated with granulomatous prostatitis of unknown etiology is associated PSA level elevation24 and its similarity to carcinoma upon physical examination. Prostate biopsy is the most efficient method of distinguishing granulomatous prostatitis from prostatic cancer.

Neuromuscular Perineal Pain Syndromes

Anatomic Abnormalities

Prostatitis: Pathophysiology / 619

A FIGURE 67–5. A, Radiograph after bilateral seminal vesiculograms, with contrast remaining in cyst of the right prostate area. B, Voiding cystourethrogram after unroofing of cyst and conversion to a prostatic urethral diverticulum.

Urethral or meatal strictures may be present and may (as a result of high pressure voiding) lead to symptoms of prostatitis. In other words, at some point in the evaluation and management of the patient with prostatitis or prostatodynia who has failed several trials of therapy, imaging of the genitourinary anatomy is indicated. Figure 67–5 shows images of one such patient, a 46year-old man who had “prostatitis” for many years. He was treated with multiple antibiotics, alpha-blocking drugs, anti-inflammatory drugs, etc. without benefit. Transrectal ultrasound revealed a prostatic cyst. Ultimately, right vasography showed a diverticulum of the right ejaculatory duct (see Figure 67–5A). This diverticulum was unroofed transurethrally and converted to a prostatic urethral diverticulum (see Figure 67–5B). The patient’s symptoms and occasional urinary tract infections ceased completely. Similar cases have been reported previously.35

Nonprostatic Symptom Mimics Since symptoms now form the basis of most diagnostic schemes for prostatitis (see Table 67–2), at least two conditions that are not related to prostatic pathophysiology but may nevertheless cause symptoms that mimic prostatitis must be discussed: interstitial cystitis and transitional cell carcinoma. Meares4 identifies interstitial cystitis as one prostatitislike syndrome. Miller et al.36 have similarly suggested that prostatodynia symptoms may be a manifestation of interstitial cystitis. They reported on 12 of 20 patients who had bladder findings consistent with interstitial cystitis. Nine of the 12 improved following bladder dilation. Subse-

B quently, they performed a prospective study of 60 men with CPPS by performing bladder examination and dilation. Thirty-five of the men (58%) had moderate to severe petechiae following dilation.37 Again, 19 of the men showed some improvement after the treatment. It thus appears that the possibility of interstitial cystitis must be considered in the patient with CPPS. Finally, patients with transitional cell carcinoma of the bladder neck area may present with CPPS symptoms. Microscopic hematuria will usually also be present. Once again, bladder examination with cystoscopy is warranted in such patients.

Conclusion As noted at the beginning of this chapter, little correlation exists between those chronic pelvic pain syndromes diagnosed by physicians and the pathophysiologic conditions observed in the prostate. Our knowledge of prostatitis and prostatodynia will perhaps advance significantly when greater correlation is achieved.

References 1. Drach GW, Fair WR, Meares EM, Stamey TA. Classification of benign disease associated with prostatic pain: prostatitis or prostatodynia? J Urol 1978;120:266. 2. Chronic Prostatitis Workshop; 1995 Dec 7–8; Bethesda (MD). National Institutes of Health. 3. Drach G. Prostatitis: man's hidden infection. Urol Clin North Am 1975;2:499–520. 4. Meares EM Jr. Prostatitis. In: Walsh PC, Retik AB, Vaughn ED Jr, Wein AJ, editors. Campbell's urology. 7th ed. Philadelphia: WB Saunders; 1998. p. 615.

620 / Advanced Therapy of Prostate Disease 5. Collins MM, Stafford RS, O'Leary MP, Barry MJ. How common is prostatitis? A national survey of physician visits. J Urol 1998;159:1224–8. 6. Roberts RO, Jacobsen SJ, Rhodes T, et al. A communitybased study on the prevalence of prostatitis. J Urol 1997;157:242A. 7. McNeal JE. The prostate gland: morphology and pathobiology. Monogr Urol 1988;36–54. 8. Fair WR, Couch J, Wehner N. Prostatic antibacterial factor. Identity and significance. Urology 1976;7:169–77. 9. Stankova L, Drach GW, Hicks T, et al. Regulation of some functions of granulocytes by zinc of the prostatic fluid and prostatic tissue. J Lab Clin Med 1976;88:640–8. 10. Kohnen PW, Drach GW. Patterns of inflammation in prostatic hyperplasia: a histologic and bacteriologic study. J Urol 1979;121:755–60. 11. Berger RE, Kreiger JN, Rothman I, et al. Bacteria in the prostate tissue of men with idiopathic prostatic inflammation. J Urol 1997;157:863–5. 12. Doble A, Thomas BJ, Furr PM, et al. A search for infectious agents in chronic bacterial prostatitis using ultrasoundguided prostatic biopsy. Br J Urol 1989;64:297–301. 13. Nickel JC, Costerton JW. Coagulase-negative staphylococcus in chronic prostatitis. J Urol 1992;147:398–400. 14. Weidner W, Schiefer HG, Krauss H, et al. Chronic prostatitis: a thorough search for etiologically involved microorganisms in 1461 patients. Infection 1991;19 Suppl 3: S119–25. 15. Nickel JC. Prostatitis: myths and realities. Urology 1998; 51:362–6. 16. Persson BE, Ronquist G, Ekblom M. Evidence for a mechanistic association between nonbacterial prostatitis and levels of urate and creatinine in expressed prostatic secretion. J Urol 1996;155:958–60. 17. Persson BE, Ronquist G, Ekblom M. Ameliorative effect of allopurinol in nonbacterial prostatitis: a parallel double-blind controlled study. J Urol 1996;155:961–4. 18. Niku SD, Dalgliesh G, Devendra G. Coccidioidomycosis of the prostate gland. Urology 1998;52:127. 19. Roberts RO, Lieber MM, Bostwick DG, Jacobsen SJ. A review of clinical and pathological prostatitis syndromes. Urology 1997;49:809–21. 20. LaFontaine PD, Middleman BR, Graham SD Jr, Sanders WH. Incidence of granulomatous prostatitis and acidfast bacilli after intravesical BCG therapy. Urology 1997;49:363–6. 21. Lopez-Plaza I, Bostwick DG. Prostatitis. In: Bostwick DG, editor. Pathology of the prostate. New York: Churchill Livingstone; 1990. p. 15–30.

22. Epstein JI, Hutchins GM. Granulomatous prostatitis: distinction among allergic, nonspecific, and posttransurethral resections lesions. Hum Pathol 1984;15: 818–25. 23. Alexander RB, Brady F, Ponniah S. Autoimmune prostatitis: evidence of T cell reactivity with normal prostatic proteins. Urology 1997;50:893–9. 24. Speights VO Jr, Brawn PN. Serum prostate-specific antigen levels in nonspecific granulomatous prostatitis. Br J Urol 1996;77:408–10. 25. Lowentritt JE, Kawahara K, Human LG, et al. Bacterial infection in prostatodynia. J Urol 1995;154:1378–81. 26. Kreiger JN, Berger RE, Ross SO, et al. Seminal fluid findings in men with nonbacterial prostatitis and prostatodynia. J Androl 1996;17:310–8. 27. Wesselmann U, Reich SG. The dynias. Semin Neurol 1996; 16:63–74. 28. Di Trapani D, Pavone C, Serretta V, et al. Chronic prostatitis and prostatodynia: ultrasonographic alterations in the prostate, bladder neck, seminal vesicles, and periprostatic venous plexus. Eur Urol 1988;15:230–4. 29. Barbalias GA. Prostatodynia or painful male urethral syndrome. Urology 1990;36:146–53. 30. Neal DE Jr, Moon TD. Use of terazosin in prostatodynia and validation of a symptom score questionnaire. Urology 1994;43:460–5. 31. Drabick JJ, Gambel JM, Mackey JF. Prostatodynia in United Nations peacekeeping forces in Haiti. Mil Med 1997;162:380–3. 32. Veneziano S, Pavlica P, Mannini D. Color Doppler ultrasonographic scanning in prostatitis: clinical correlation. Eur Urol 1995;28:6–9. 33. de la Rosette JJ, Geisen RJ, Huynen AL, et al. Automated analysis and interpretation of transrectal ultrasonography images in patients with prostatitis. Eur Urol 1995; 27:47–53. 34. Newman JS, Bree RL, Newman JM. Prostate cancer: diagnosis with color Doppler sonography with histologic correlation of each biopsy site. Radiology 1995;195:86–90. 35. Fowler JE Jr, Peters JJ, Hamrick-Turner J. Mullerian duct cyst masquerading as chronic prostatitis: diagnosis with magnetic resonance imaging using a phased array surface coil. Urology 1995;45:676–8. 36. Miller JL, Rothman I, Bavendam TG, Berger RE. Prostatodynia and interstitial cystitis: one and the same? Urology 1995;45:587–90. 37. Berger RE, Miller JE, Rothman I, et al. Bladder petechiae after cystoscopy and hydrodistension in men diagnosed with prostatic pain. J Urol 1998;159:83–5.

CHAPTER 68

PROSTATITIS: DIAGNOSIS CULLEY C. CARSON, MD Diagnosis and treatment of prostatitis requires diligence and persistence on the part of both the physician and the patient. Although diagnosis of acute bacterial prostatitis is easily made and its treatment straightforward, chronic bacterial prostatitis and other inflammatory prostatic syndromes are more difficult to define and differentiate. Diagnosis and documentation of specific infection is often elusive, despite careful evaluation. Clinical evaluation and diagnosis of prostatitis is variable. Family practice physicians and urologists do not routinely utilize a standard diagnosis protocol to evaluate patients with symptoms of prostatitis. Moon reviewed a questionnaire completed by primary care physicians and urologists diagnosing and treating prostatitis in Wisconsin.1 His study demonstrated that fewer than 50% of urologists and only 11% of primary care providers evaluated expressed prostatic secretions to differentiate prostatic diseases. Similarly, few urologists or primary care physicians suggested nonantibacterial therapy to patients with prostatitis. While the nomenclature for prostatitis classification continues to be controversial, diagnosis is best separated into acute bacterial prostatitis and other nonacute inflammatory and bacterial syndromes.

whelming prostatic infections in acute bacterial prostatitis are usually associated with positive urine cultures; bacteria enter the bladder and the infecting organism is often cultured from the midstream urine collection. The most common uropathogens found in acute bacterial prostatitis are those most commonly seen in urinary tract infections, including: Escherichia coli, Proteus, members of the Klebsiella-Enterobacter group, and Enterococci. Once a history, physical examination, and Gram’s stain of the urine has established an acute urinary infection and blood and urine cultures have been collected, therapy can be begun empirically until specific culture and sensitivity information is available. Broad spectrum antibiotics, most of which usually penetrate the acutely infected prostate more efficiently than the chronically infected prostate, can be used until antibiotic therapy is tailored to the offending organism, based on definitive blood and urine culture sensitivity reports. These antibiotics should be targeted at gram-negative pathogens. Since acute bacterial prostatitis may progress to prostatic abscess, this possibility should be explored when patients show continued systemic signs and unabated symptoms while on appropriate antibiotic treatment, bed rest, and fluids. These abscesses may be multiple and are often associated with painful prostatic enlargement and fluctuance on rectal examination.2 Patients with further acute prostatitis who have other associated risk factors such as diabetes, chronic renal failure on maintenance dialysis, and other causes of immune compromise (especially if associated with urethral instrumentation or indwelling Foley catheters) are at highest risk for prostatic abscess.3 The signs and symptoms of prostatic abscess are variable. They were reviewed by Weinberger et al. in 1988 and included prostatic enlargement in 75% of patients, prostatic tenderness in 35%, and palpable fluctuance in 16%.3 Meares reviewed 213 men with prostatic abscesses and reported acute urinary retention in 34%, fever in 33%, dysuria in 27%, urinary frequency in 23%, and perineal pain in 23%. An additional 7% had hematuria or urethral discharge.4 Definitive diagnosis of a prostatic abscess may require more sophisticated imaging studies. Once a prostatic abscess has drained, a retrograde cystourethrogram or voiding cystourethrogram may demonstrate contrast filling of the abscess cavity. Initial diagnostic investigation with transrectal ultrasound (TRUS) is the most simple and effective method of identifying a prostatic abscess. Abscess cavities are clearly hypoechoic but contain some internal echoes

Acute Bacterial Prostatitis The diagnosis of acute bacterial prostatitis is usually straightforward and readily apparent on physical examination. Patients are frequently febrile and toxic with severe rigors, back pain, perineal pain, dysuria, urgency, and frequency with associated mild to moderate obstructive urinary symptoms. As many as one-third of patients with acute bacterial prostatitis will present in acute urinary retention as a result of prostatic edema and enlargement secondary to acute inflammation of an already enlarged and partially obstructed urethra.2 Once a diagnosis is presumed by history, physical examination usually supports the diagnosis, with a rectal examination demonstrating a severely swollen, extremely tender prostate. Expression of prostatic secretions in acute bacterial prostatitis should not be performed because of the potential for systemic spread of prostatic infection. If prostatic fluid is available for microscopic examination, multiple polymorphonuclear leukocytes, both singularly and in clumps, are demonstrated. Urine culture as well as prostatic fluid culture will reveal the infectious pathogen, which is also frequently seen on Gram’s stain of both urine and prostatic fluid. Massage of an acutely infected prostate should be proscribed as bacteremia and septicemia may result. Over621


that differentiate them from simple cysts. Central abscess debris produces these internal echoes. Similarly, prostatic abscesses, while frequently unilocular, may be complex, communicating, or multilocular in appearance. When multiple small cystic areas are present on TRUS, confirmation of cavity communication is usually not possible. An abscess that is significant may extend into the seminal vesicles, producing unilateral or bilateral seminal vesicle dilatation, thickening, and asymmetry.5 Computed tomography (CT) scan imaging may also be helpful in identifying prostatic abscesses, demonstrating low attenuation areas of the prostate with associated prostatic enlargement and asymmetry. Seminal vesicle enlargement and asymmetry may be also identified, with internal loculations of the seminal vesicles associated with seminal vesicle septal thickening. Computed tomography scanning may assist the urologist in identifying an optimal method for treating a prostatic abscess by defining the extent of the abscess and suggesting an appropriate surgical approach and subsequent management. Once a prostatic abscess has drained either spontaneously or surgically, the resultant cavity may fill with contrast administered either by retrograde urethrogram or voiding cystourethrogram, may epithelialize, or may remain indefinitely as open diverticuli. These cavities may produce a nidus for continued bacterial prostatitis or urinary infections. An abscess limited to the prostate may be drained transurethrally. An abscess that is multilocular or extends to the seminal vesicles may require more aggressive treatment with open surgical intervention. Radiographic imaging of acute bacterial prostatitis without abscess is usually nonspecific. While voiding studies may demonstrate prostatic urethral narrowing during the acute phase with large residual urine volumes, such findings are nonspecific and are similar to those associated with benign prostatic enlargement and bladder outlet obstruction. Similarly, intravenous urogram (IVU) or plain radiographs, while occasionally demonstrating associated prostatic calcifications, are nonspecific in patients with acute bacterial prostatitis or prostatic abscess. Cystoscopy as a diagnostic tool for prostatic abscess and acute bacterial prostatitis is usually nonspecific, with findings including elongation of the prostatic urethra and trigonal elevation or elongation.6 Thus, transrectal ultrasound and CT scan imaging are the best diagnostic tools and will be of assistance in differentiating acute prostatitis from prostatic abscess as well as in identifying appropriate treatment and guiding percutaneous drainage.

Diagnosis of Chronic Bacterial, Nonbacterial Prostatitis and Associated Inflammatory Prostatic Syndromes Inflammatory prostatic syndromes are some of the most common genitourinary complaints of men. Lipsky reported in 1989 that 76 of 1000 primary care physician office visits

for men were for genitourinary tract problems, of which 25% were for prostatitis.7 While chronic bacterial prostatitis accounts for a relatively small number of these patients, more than 90% of men with prostatitis-type symptoms are eventually diagnosed with nonbacterial prostatitis or other inflammatory syndromes such as prostatodynia.8,9 While the usual uropathogens associated with chronic bacterial prostatitis are the same as those associated with urinary tract infections and acute bacterial prostatitis, gram-positive organisms, especially Enterococci and Staphylococcus saprophyticus may also cause chronic inflammation in the prostate.10,11 Other unusual bacteria may be associated with the prostatic infections, especially in immune-compromised patients. These unusual bacteria include Mycobacterium tuberculosis, Neisseria gonorrhoeae, and fungi. Ureaplasma urealyticum (T-strain mycoplasma) and Chlamydia trachomatis have been widely studied as potential pathogens responsible for prostatitis; a variety of techniques, including antigen-specific immunoglobulins and immunoflourescent stains in patients with nonbacterial prostatitis, have been used. The results of these studies continue to be inconclusive, and both these agents continue to be unproven pathogens in chronic prostatic infectious disease.12,13

Symptoms and Signs Most patients with nonacute inflammatory and infectious diseases of the prostate present with similar symptoms, including bladder inflammation with irritative voiding symptoms such as urinary frequency, urgency, and dysuria. Referred pain can occur to the low back, genitalia, suprapubic area, and lower extremities; frequently perineal pain, scrotalgia, and postejaculatory discomfort occur alone or in combination in these patients. Obstructive symptoms are uncommon without coexistent prostatic hyperplasia. Obstructive symptoms may, however, occur in patients with associated bladder neck spasm and inflammatory prostatic conditions such as prostatodynia. Krieger and colleagues investigated the standardized evaluation of symptoms associated with chronic prostatitis.14 They compared a symptom index in 50 patients with prostatitis and 75 control patients. It was useful, reproducible, and helped in identifying symptoms. In their series, patients with prostatitis were more likely than control patients to complain of perineal, lower abdominal, testicular, penile, and postejaculatory pain as well as sexual dysfunction. Since prostatitis is frequently associated with significant psychologic abnormalities, investigation of associated psychologic diagnoses, stress, and depression should be undertaken in selected patients presenting for treatment of chronic prostatitis. Many patients may require psychologic or psychiatric referral for these conditions. Use of depression inventories and other psychologic questionnaires or structured psychologic interviews may be helpful in patients suspected of having significant depression stress syndromes or associated conditions.15,16

Prostatitis: Diagnosis / 623

Differentiating the etiologies of inflammatory diseases of the prostate is difficult, time consuming, expensive, and, at best, only partially accurate. Identifying prostatic inflammation through inflammatory expressed prostatic secretions may be helpful. Clearly, the microscopic examination of expressed prostatic secretions (EPS) can easily be done in a cost-effective fashion in most clinicians’ offices. This simple technique has been demonstrated to improve the diagnosis of prostatic inflammatory diseases. The definition of prostatic inflammation in expressed prostatic secretions is usually agreed upon as 10 or more white blood cells by high-power field with multiple lipid-laden macrophages. Wright et al. reviewed the diagnostic accuracy of leukocytosis in expressed prostatic secretions and found that 10 white blood cells by high-power field was diagnostic of prostatic inflammation and correlated well with leukocytes demonstrated in a spun-down postprostatic massage urinary specimen.17 These findings have been confirmed in a careful analysis by Weidner and Ebner.18 With these careful microscopic examinations and evaluations, patients with noninfectious prostatic inflammatory syndromes such as prostatodynia will demonstrate clear expressed prostatic secretions with few white cells on microscopic examination. These correlate well with patients who have negative selective prostatic cultures. Since many patients with chronic prostatitis have been on multiple antibiotics and are taking antibiotics when seen and examined, expressed prostatic secretions may be more accurate in these patients than selective cultures, which are difficult and quite expensive to obtain. More accurate methods of quantifying leukocytes in prostatic fluid specimens using a Fuchs-Rosenthal chamber have been suggested. Using this technique, 1000 polymorphonuclear leukocytes per micrometer has been suggested as an indication of chronic bacterial prostatitis.19 Other alterations in the composition of prostatic secretions have been suggested as diagnostic alternatives to leukocyte counts in evaluating chronic prostatitis. Weidner et al. have suggested that changes in EPS acidity may correlate with chronic bacterial prostatitis and suggest that those patients most likely to respond successfully to antibiotic treatment have a high pH. His study suggests that an EPS alkaline pH > 8.0 associated with chronic bacterial prostatitis significantly decreases the therapeutic success of antibiotics used in treating chronic bacterial prostatitis.20 The presence of lipid-laden macrophages (oval fat bodies) on microscopic examination of EPS has been the subject of some controversy. Both Meares and Stamey have reported that they rarely, if ever, occur in the prostatic secretions of men without prostatic inflammation and are absent from men whose urinary tract infections are caused by anterior urethritis. Lipid-laden macrophages in patients with prostatitis are increased as much as eightfold over those in patients without bacterial prostatitis.21,22 The position diagnosis of chronic bacterial prostatitis must be confirmed by quantitative, selected bacteriologic localization

studies. These studies, first described by Meares and Stamey in 1968, continue to be the standard for bacteriologic localization, and standardized pharmacologic treatment studies, and are helpful in resolving diagnostic dilemmas associated with clinical prostatic infection.23 Since these studies are frequently expensive, difficult to perform, uncomfortable, and not always reproducible, controversy has continued about their value and of all quantitative localization techniques in patients with prostatitis. De la Rossette and colleagues evaluated 409 patients with prostatitis syndromes. Their evaluation included urinalysis, renal ultrasonograms, plain films of the abdomen, and basic urodynamics.24 Urine cytology was not helpful in any patients while uroflometry was abnormal in 30% of patients investigated. Positive bacterial cultures were found in 10.4% of patients while urethral cultures were positive in 14.3% of patients. Prostatic fluid cultures did not provide significant additional information and semen cultures correlated poorly with either prostatic fluid or urine cultures. Since < 15% of most patients have bacterial prostatitis, the cost-effectiveness of this series of culture studies in all patients remains controversial.25,26 The technique for collecting urine specimens and prostatic fluid is simple and can be performed in any clinical setting or private office. Patients are instructed to present with a full bladder and void 10 mL of urine into a sterile container. This specimen is the voided bladder #1 (VB1) specimen. The patient then voids 100 mL of urine, which is discarded and voids 10 mL of urine into a sterile container that is labeled VB2. The patient is instructed to cease voiding and a prostatic massage is undertaken. Prostatic secretions are collected, if possible, in a sterile container and labeled EPS (expressed prostatic secretions). These secretions can be used for culture or microscopic examination. The patient then voids the remaining urine into a fourth aliquot labeled VB3. These specimens are immediately inoculated onto culture media. The VB1 specimen represents those bacteria present in the urethra while the VB2 specimen is the classic midstream specimen reflecting bladder bacteria. The EPS and VB3 specimens reflect the prostatic fluid and prostatic pathogens. For significant bacterial infection to be present, colony counts in the VB3 or EPS specimens must be at least 10 times greater (one log) than those in the VB1 or VB2 specimens. If all three specimens reflect large numbers of bacteria, a urinary antiseptic such as Macrodantin may be administered for 3 to 5 days and the studies repeated to confirm prostatic bacterial colonization. Because these studies are expensive, time consuming, and difficult, Nickel has suggested a pre- and postmassage test (PPMT). The pre- and postmassage test includes only the classic VB2 and VB3 specimens with the EPS used for microscopic evaluation. Nickel compared a personal series of 53 patients with 59 patients reported in the literature, investigating for the accuracy of the two-culture technique, and found that sensitivity and specificity of the


PPMT was 91%.27 Comparing the PPMT with the threeculture test, there was little difference in the additional (VB1 and EPS) cultures in making the diagnosis of chronic bacterial prostatitis. Bacterial evaluation of seminal ejaculate specimens has also been suggested for differentiating locations and causes of bacterial prostatitis. These ejaculate specimens do not appear to significantly improve the diagnostic accuracy and may be misleading in the absence of examination of EPS and selective cultures. Since seminal fluid contains not only prostatic fluid but also seminal vesical, urethral, and accessory sex gland fluid, it produces a misleading mixture of fluids for study. Microscopic examination of this fluid is also misleading since the differentiation of leukocytes from immature sperm without specific selective staining techniques is difficult. While these results may suggest generalized infection of many of the male accessory glands, localization using ejaculate cultures is difficult.28 Krieger and colleagues investigated seminal fluid specimens and EPS results in a group of men with and without chronic bacterial prostatitis.29 They demonstrated a poor correlation between inflammation in prostatic secretions as an endpoint for the definition of prostatitis and semen changes. Similarly, sperm motility, clumping, and other parameters of inflammation in semen specimens did not correlate well with prostatic inflammatory conditions. Thus, ejaculate cultures are infrequently helpful in differentiating chronic bacterial prostatitis from other prostatitis syndromes. Transperineal biopsy of the prostate for identifying prostatic infection has also been suggested. Since typical inflammation and infection of the prostate is not a global disease but only focal, these random biopsies are usually inaccurate.30 Currently, transrectal or perineal needle biopsy in diagnosing prostatitis remains controversial.28,31

Measurement of Immune Response Changes in human prostatic fluid immunoglobulins (IgG and IgA) in prostatitis has suggested chemical methods for differentiating prostatic infection and inflammatory disease. Shortliffe and associates used solid phase radioimmunoassay to evaluate the immune response of patients with acute and chronic bacterial prostatitis.32 There was a prostatic fluid secretory IgA elevation observed in chronic bacterial prostatitis patients independent of serum responses. In patients with acute bacterial prostatitis, antigen-specific IgG levels in both serum and prostatic fluids were found to be elevated, with a slow decline for 6 to 12 months following curative antibiotic therapy. Prostatic fluid IgA levels, in contrast, became elevated following infection and began to decline approximately 1 year following successful treatment. Serum IgA levels, however, declined and disappeared within 4 weeks of successful treatment. Patients with chronic bacterial prostatitis had elevations in prostatic fluid IgA and IgG levels without associated serum IgA or IgG elevation. When

chronic bacterial prostatitis was successfully treated with antibiotics, the prostatic fluid IgA levels remained elevated at 24 months while the IgG levels remained elevated for 6 months before decline. In patients inadequately treated with antibiotics, prostatic fluid IgA and IgG levels remained elevated.33 These same investigators were unable to document antigen-specific IgG or IgA elevations in prostatic fluid against Ureaplasma urealyticum or Chlamydia trachomatis in patients with nonbacterial prostatitis.34 These results clearly reflect the controversy surrounding the contention that these pathogens cause prostatitis. Other prostatic seminal agents have been shown to change in the presence of chronic bacterial prostatitis. These include changes in the ratio of lactate dehydrogenase (LDH) isoezyme 5 to isoezyme 1, prostatic antibacterial factor (PAF) (which probably represents zinc concentration), citric acid concentration, cholesterol concentration, spermine concentration, and acid phosphatase concentration.35 While each of these has been demonstrated to change in chronic bacterial prostatitis studies, their use as diagnostic tools continues to be uncertain.

Radiographic Examination Radiographic examination of patients with chronic bacterial prostatitis and prostatitis inflammatory syndromes is usually unnecessary and findings are nondiagnostic.36 While patients with tuberculosis prostatitis and granulomatous prostatitis may undergo radiographic examination with diagnostic findings, the majority of patients can be evaluated and treated without imaging studies. In patients who have chronic bacterial prostatitis and are undergoing TRUS for elevated prostate-specific antigen (PSA) levels, lesions may be identified, including prostatic calcifications, hypoechoic lesions in the peripheral zone, periprostatic venous engorgement, and abnormalities in size, symmetry, and consistency of the seminal vesicles. Hypoechoic lesions are frequently multifocal, often occurring in the peripheral zone and usually without changes in the overlying prostatic capsule.37–39 Prostatic calcifications are a more common abnormality in imaging studies of patients with recurrent chronic bacterial prostatitis. These calcifications are visible on TRUS as multifocal or unifocal, with or without acoustical shadowing, and are often associated with calcifications throughout the prostate and verumontanum. Such calculi can also be seen on plain pelvic film, IVP, or CT scan. Prostatic calculi are more common in patients with chronic bacterial prostatitis than in those with other inflammatory conditions of the prostate.37 Perisprostatic venous engorgement on TRUS has been associated with the diagnosis of chronic bacterial prostatitis as well as of benign prostatic hyperplasia (BPH). 5 Thin reported eight patients in whom TRUS for symptoms of prostatitis revealed prostatic cysts. The prostatic cyst aspiration was associated with relief of symptoms in

Prostatitis: Diagnosis / 625

the small group of patients.35 Seminal vesicles may also be abnormal, with engorgement, obstructive appearance, or calcifications. Christiansen and Purvis suggest that unilateral seminal vesicle dilatation, loculation and septal thickening of seminal vesicle, and calcifications of the seminal vesicle are more common in patients with chronic bacterial prostatitis.38 Seminal vesicle asymmetry occurs more than twice as often in patients with chronic bacterial prostatitis than in those with prostastodynia.37 The use of color Doppler flow techniques in differentiating normal prostates from chronic bacterial prostatitis has been suggested but the nonspecific nature of findings of increased blood flow has not been reproducible.40 The value of color Doppler flow in distinguishing prostatitis from prostatic malignancy or normal tissue warrants further investigation.41 While CT scan may demonstrate prostatic calcifications, its use in differentiating benign prostatic diseases is neither cost effective nor accurate. Computed tomography scanning appears to be an inappropriate method for evaluating patients with chronic bacterial prostatitis. Magnetic resonance imaging may be helpful in some rare conditions where TRUS and CT are not diagnostic.42 Elevations in PSA levels are frequently associated with chronic bacterial prostatitis.43–45 Differentiation of patients with PSA level elevations caused by prostatitis or other benign disease must be considered. If PSA level elevations are persistent, TRUS and biopsy for suspicion of prostatic malignancy must be carried out.46 Patients with elevated PSA levels who are in the younger age group or in whom acute elevation of PSA level is associated with tender prostates should be treated with antibiotics. Their PSA level should be determined again to eliminate the possibility of prostatic inflammation as a cause. The use of a fluoroquinolone for 2 to 3 weeks prior to repeat PSA screening will help differentiate those patients with benign and malignant disease. Similarly, free and total PSA ratios may be helpful to further pinpoint those patients who have benign inflammatory prostatic disease. The use of videourodynamics in evaluating patients who fail standard treatment algorithms for prostatitis has been suggested by Kaplan and associates.47 Using videourodynamics studies in 43 men aged 23 to 50 who had chronic voiding dysfunction associated with prostatitis, pseudodyssynergia was diagnosed based on brief intermittent closing of the membranous urethra during voiding in the absence of obstructive uropathy or abdominal straining. No patients had positive EPS or bacteruria. Alpha-adrenergic blocking agents were unsuccessful in these patients and many of them had elevated American Urological Association symptom scores suggestive of lower urinary tract symptoms (LUTS). Eighty-three percent of patients so diagnosed responded successfully to behavior modification and biofeedback techniques.

Granulomatous Prostatitis Granulomatous prostatitis is an uncommon chronic inflammatory condition of the prostate whose incidence is increasing with the use of intravesicle bacillus Calmette-Guérin (BCG) for superficial transitional cell carcinoma of the bladder.48–50 Patients frequently present with an abnormal prostatic examination characterized by significant prostatic induration and nodularity. In addition to BCG therapy, immune compromise such as human immunodeficiency virus infection may be associated with granulomatous prostatitis caused by tuberculosis, syphilis, brucellosis, viruses, fungi, eosinophilic changes, and Wegener’s granulomatosis.48 Granulomatous prostatitis is frequently a sequela of a urinary tract infection. Presenting symptoms are similar to acute prostatitis, with recurrent febrile episodes, rigors, irritative and even obstructive urinary symptoms.49 The patient’s PSA level is usually elevated with granulomatous prostatitis but normal levels have also been reported.51 Many of these patients will have hypoechoic lesions and prostatic calculi on TRUS. In a study of 668 urologic patients biopsied for abnormal prostatic examination, 19 had granulomatous prostatitis (2.8%). Ultrasound abnormalities of these 19 patients included a hypoechoic peripheral zone nodule in nine patients, multiple nodular foci in two, and a diffuse abnormal ultrasound pattern in seven. One patient had an isoechoic bulging peripheral zone nodule.5 These abnormalities on TRUS are indistinguishable from those of prostatic carcinoma, and biopsy is essential to eliminate the possibility of prostatic malignancy. Once the diagnosis of granulomatous prostatitis is confirmed, however, resolution is usually spontaneous and there may be no specific therapy required.

References 1. Moon TD. Questionnaire survey of urologists and primary care physicians’ diagnostic and treating practices for prostatitis. Urology 1997;50:543–7. 2. Granados EA, Riley G, Salvador J, Vincente J. Prostatic abscess: diagnosis and treatment. J Urol 1992;148:80. 3. Weinberger M, Cytron S, Servadio C, et al. Prostatic abscess in the antibiotic era. Rev Infect Dis 1988;10:239. 4. Meares EM. Prostatic abscess. J Urol 1986;136:1281. 5. Wasserman NF. Imaging of benign prostatic disease. I. Prostatitis and male infertility. Contemp Urol. [In press] 6. Cytron S, Weinberger M, Pitlik SD, Servadio C. Value of transrectal ultrasound for diagnosis and treatment of prostatic abscess. Urology 1988;32:454. 7. Lipsky BA. Urinary tract infections in men. Ann Intern Med 1989;110:138. 8. Brunner H, Weidner W, Schiefer HG. Studies on the role of Ureaplasma urealyticum, and Mycoplasma hominis in prostatitis. J Infect Dis 1983;147:807. 9. Krieger JN, Egan KJ. Comprehensive evaluation and treatment of 75 men referred to chronic prostatitis clinic. Urology 1991;38:11. 10. Carson CC, McGraw VD, Zwadiyk P. Bacterial prostatitis caused by Staphylococcus saprophyticus. Urology 1982; 19:576–8.

626 / Advanced Therapy of Prostate Disease 11. Nickel JC, Costerton JW. Coagulase negative Staphylococcus in chronic prostatitis. J Urol 1992;147:398–400. 12. Meares EM. Prostatitis. Med Clin North Am 1991;75:405. 13. Weidner W, Shieffer HG, Ringert RH. New concepts in the pathogenesis and treatment of prostatitis. Curr Opin Urol 1993;3:30–5. 14. Krieger JN, Egan KJ, Ross SO, et al. Chronic pelvic pains represent the most prominent urogenital symptoms of chronic prostatitis. Urology 1996;48:715–21. 15. Egan KJ, Krieger JN. Psychological problems and chronic prostatitis with pain. Clin J Pain 1994;10:218–26. 16. de la Rosette JJ, Ruijgrok NC, Jeuken JM. Personality variables involved in chronic prostatitis. Urology 1993;42: 654–62. 17. Wright ET, Chmiel JS, Grayhack JT, Schaeffer AJ. Prostatic fluid inflammation in prostatitis. J Urol 1994;152: 2300–3. 18. Weidner W, Ebner H. Cytological analysis of urine after prostatic massage (VB-3): a new technique for discriminating the diagnosis of prostatitis. In: Brunner H, Krause W, Rothauge CF, Weidner W, editors. Chronic prostatitis: clinical, microbiological, cytological and immunological aspects of inflammation. Stuttgart: FK Schattauer; 1985. p.141–51. 19. Anderson RU, Weller C. Prostatic secretion leukocyte studies in nonbacterial prostatitis (prostatosis). J Urol 1979;121:292–4. 20. Weidner W, Schieffer HG, Brahler E. Refractory chronic bacterial prostatitis: a re-evaluation of ciprofloxacin treatment after a median follow-up of 30 months. J Urol 1991;146:350–2. 21. Meares EM. Prostatitis syndromes: new perspectives about old woes. J Urol 1980;123:141–4. 22. Stamey TA. Prostatitis. J R Soc Med 1981;74:22–6. 23. Meares EM, Stamey TA. Bacteriologic localization patterns in bacterial prostatitis and urethritis. Invest Urol 1968;5:492–6. 24. de la Rosette JJ, Hubregtse MR, Meuleman EJ, et al. Diagnosis and treatment of 409 patients with prostatitis syndromes. Urology 1993;41:301–7. 25. Weidner W, Schieffer HG, Krauss H, Jantos C, et al. Chronic prostatitis: a thorough search for etiologically involved microorganisms in 461 patients. Infection 1991;19:119–25. 26. Krieger JN, McGonagle LA. Diagnosis considerations and interpretation of microbiological findings for evaluation of chronic prostatitis. J Clin Microbiol 1989;27:2240–4. 27. Nickel JC. The pre- and post-massage test (PPMT): a simple screen for prostatitis. Tech Urol 1997;3:38–43. 28. Weidner W, Jantos C, Schieffer HG, et al. Semen parameters in men with and without proven chronic prostatitis. Arch Androl 1991;26:173–83. 29. Krieger JN, Berger RE, Ross SO, et al. Seminal fluid findings in men with nonbacterial prostatitis and prostastodynia. J Androl 1996;17:310–8. 30. Berger RE, Krieger JN, Rothman I, et al. Bacteria in the prostate tissue of men with idiopathic prostatic inflammation. J Urol 1997;157:863–5. 31. Doble A, Thomas BJ, Walker MM, et al. The role of Chlamydia trachomatis in chronic abacterial prostatitis: a study using ultrasound guided biopsy. J Urol 1989; 141:332–3. 32. Shortliffe LMD, Wehner N, Stamey TA. Use of solid phase radioimmunoassay and formalin fixed whole bacterial antigen in the detection of antigen specific immunoglobulin in prostatic fluid. J Clin Invest 1991;67:790–9.

33. Shortliffe LMD, Webner N, Stamey TA. The detection of local prostatic immunologic response in bacterial prostatitis. J Urol 1981;125:509–15. 34. Shortliffe LMD, Wehner N. The characterization of bacterial and nonbacterial prostatitis by prostatic immunoglobulins. Medicine 1986;65:399–411. 35. Thin RN. Diagnosis of chronic prostatitis: overview and update. Int J STD AIDS 1996;8:475–81. 36. de la Rosette JJ, Karthaus HF, Debruyne FM. Ultrasonic findings in patients with nonbacterial prostatitis. Urol Int 1992;48:323–6. 37. Ludwig M, Weidner W, Schroeder-Printzen I, et al. Transrectal prostatic sonography as a useful diagnostic means for patients with chronic prostatitis or prostastodynia. Br J Urol 1994;73:664–8. 38. Christiansen E, Purvis K. Diagnosis of chronic abacterial prostatovesiculitis by rectal ultrasonography in relation to symptoms and findings. Br J Urol 1991;67:173–6. 39. de la Rosette JJ, Giesen RJ, Huynen AL, et al. Automated analysis in interpretation of transrectal ultrasonography images in patients with prostatitis. Eur Urol 1995; 27:47–53. 40. Veneziano S, Pavlica P, Mannini D. Color Doppler ultrasonic scanning and prostatitis: clinical correlation. Eur Urol 1995;28:6–9. 41. Patel U, Rickards D. The diagnostic value of color Doppler flow in the peripheral zone of the prostate with histologic correlation. Br J Urol 1994;74:590–5. 42. Fowler JE, Peters JJ, Hamrick-Turner J. Mularian duct cyst mass parading as chronic prostatitis: diagnosis with magnetic resonance imaging using a phased array surface coil. Urology 1995;45:676–8. 43. Neal DE, Clejan S, Sarma D, Moon TD. Prostate-specific antigen and prostatitis. I. Effect of prostatitis on serum PSA in the human and non-human primate. Prostate 1992;20:105–8. 44. Irani J, Levillain P, Goujon JM, et al. Inflammation in benign prostatic hyperplasia: correlation with prostatespecific antigen value. J Urol 1997;157:1301–3. 45. Bare R, Hart L, McCullough DL. Correlation of prostatespecific antigen and prostate antigen density with the outcome of prostate biopsy. Urology 1994;43:191–6. 46. Tchetgen MD, Oesterling JE. Effect of prostatitis urinary retention and ejaculation and ambulation on the serum prostate-specific antigen concentration. Urol Clin North Am 1997;24:283–91. 47. Kaplan SA, Santa Rosa RP, D’Alisera PM, et al. Pseudodyssynergia (contraction of the external sphincter during voiding) misdiagnosed as chronic nonbacterial prostatitis and the role of biofeedback as a therapeutic option. J Urol 1997;157:2234–7. 48. Stillwell TJ, Engen DE, Farrow GM. The clinical spectrum of granulomatous prostatitis: a report of 200 cases. J Urol 1987;138:320–7. 49. Miyashita H, Trancoso P, Babaian RJ. BCG induced granulomatous prostatitis: a comparative ultrasound and pathologic study. Urology 1992;39:364–71. 50. LaFontaine PD, Middleman BR, Graham SD, Sanders WH. Incidence of granulomatous prostatitis and acid fast bacilli after intravesical BCG therapy. Urology 1997;49:363–6. 51. Clements R, Thomas KG, Griffiths GJ, Peeling WB. Transrectal ultrasound appearances of granulomatous prostatitis. Clin Radiol 1993;47:174–7.

CHAPTER 69

PROSTATITIS: DIFFERENTIAL DIAGNOSIS, CLASSIFICATION, AND CONVENTIONAL TREATMENT STRATEGIES JOHN N. KRIEGER, MD

50% of adult men experience such symptoms at some point in their lives.2 National Health Center for Health Statistics data show 76 office visits per 1000 men per year for genitourinary problems, with prostatitis accounting for approximately 25% of these visits.4,5 Patients may experience symptoms for prolonged periods, and many relate the onset of their condition to sexual activity, commonly to an episode of acute urethritis.6,7 Antimicrobial therapy often results in transient relief of symptoms. Based on these observations, standard clinical practice is to use multiple courses of antibacterial therapy in the frequently vain hope that patients will experience lasting relief.2,8–11 In the author’s report of 75 patients with chronic prostatitis, the average patient had received 10 weeks of unsuccessful antimicrobial treatment during the 3 months prior to evaluation.6 Clinical characteristics of patients with prostatitis have not been carefully correlated with pathologic findings.2,11 Pathologic studies have not included sufficient clinical or microbiologic data. In contrast, clinical studies rarely found pathologic specimens to be helpful, likely reflecting the focal nature of prostatic inflammation in many patients.12–14

History Urology evolved because of the need to treat prostate diseases. Prostate inflammation, stones, and obstruction were well described in antiquity. The Ebers Papyrus considers prostatitis, urethritis, urinary retention, incontinence, and cystitis.1 Bladder stones, often due to prostatic or urethral obstruction, were found in Egyptian mummies. The ancient Egyptian physicians treated urinary retention due to bladder stones and prostate disease using reeds, copper and silver tubes, and rolled palm leaves. Physicians who used these instruments most became known as lithologists, the first specialists in Western medicine. Prostate disease was also well known in Eastern medicine. Hindu Vedas describe procedures for treating obstruction caused by prostatic disease and bladder stones that may be 4000 to 5000 years old. The Vedas also describe cannulas of wood and metal for urethral catheterization. Uroscopy, or examination of the urine, was highly developed and considered an art before the time of Hippocrates (460 to 377 BC), who also paid much attention to uroscopy. Herophilus of Chalcedonia, a well-known lithotomist, is credited with the first anatomic description of the prostate. Rufus of Ephesus described the “parastatus glandulus,” meaning “standing before,” the likely origin of the term prostate. Aristotle described the “varicose parastatae,” the likely origin of the term seminal vesicles. At the start of the Christian era, Celsus (25 BC to 50 AD) described urethral catheterization and urethrotomy. By 1500, cystostomy, usually by the perineal approach, was in widespread use for removing bladder stones. On occasion, portions of the prostate were excised to obtain access to the stone.1 Thus, the earliest prostatic surgery was probably unintentional.

The First Clinical Question From a practical standpoint, the first clinical issue is to distinguish patients with lower urinary tract complaints associated with bacteriuria from the larger number of men without bacteriuria.11 Most patients can be classified into one of four diagnostic groups: acute bacterial prostatitis, chronic bacterial prostatitis, chronic prostatitis/ chronic pelvic pain syndrome, and asymptomatic inflammatory prostatitis.15 Granulomatous prostatitis is a fifth category. This uncommon syndrome represents a characteristic histologic reaction of the prostate to a variety of irritants. Chronic prostatitis/chronic pelvic pain syndrome is by far the largest category. Because of considerable pathophysiologic progress, rational approaches to treating patients with acute and chronic bacterial prostatitis are possible.2,16 Treatment of

Overview and Clinical Consequences Prostatitis has been termed, “a wastebasket of ignorance.”2 This diagnosis is given to a large population of men presenting with varied complaints referable to the lower urogenital tract and perineum.2,3 By one estimate, 627


granulomatous prostatitis depends on accurate etiologic diagnosis. In contrast to bacterial and granulomatous prostatitis, there are few reliable data on the etiology of chronic prostatitis/chronic pelvic pain syndrome. Thus, current therapy is unsatisfactory for most men with prostatitis syndromes. Developing an effective treatment plan requires accurate diagnosis. The following sections summarize the author’s current approach to diagnosis of prostatitis syndromes.

History and Physical Examination The duration and severity of complaints associated with prostatitis should be documented in the patient’s history, possibly with the use of a standardized questionnaire (Table 69–1). The history should also concentrate on eliciting factors that may provide insight into the specific prostatitis syndrome. Especially important is a history of bacteriuria or an acute onset of a “flu-like” syndrome with systemic symptoms. These factors support the possibility of bacterial prostatitis (acute or chronic). Any history of previous genitourinary tract trauma, urinary tract stones, chemical exposure, or previous genitourinary tract cancer (especially transitional cell) suggests the need for imaging studies and cystoscopy. Similarly, a history of gross hematuria, chemotherapy, or painful voiding symptoms point to the possibility of conditions such as transitional cell carcinoma in situ or interstitial cystitis. Recent urinary catheterization, instrumentation, or urologic surgery may also be associated with an increased risk for bacteriuria and bacterial prostatitis. An accurate sexual history may reveal risk factors for sexually transmitted diseases, such as onset after an episode of urethritis or intercourse with a new partner.

This should include specific questions concerning the number of partners in the last month and lifetime, contraception (especially use of condoms), particular behaviors (especially anal intercourse), and genitourinary tract symptoms in the sexual partner. The presence of symptoms such as arthritis or conjunctivitis raises the possibility of rheumatiod disease associated with urinary tract symptoms (e.g., Reiter’s syndrome or Wegener’s granulomatosis). The review of systems should also elicit possible conditions associated with urolithiasis since a distal ureteral calculus may be associated with lower genitourinary tract symptoms. Neurologic symptoms should also suggest possible neuropathy, sacral cord disorders, or other conditions associated with urologic symptoms. Presence of gastrointestinal symptoms suggests the possibility of active bowel disease possibly associated with genitourinary tract symptoms (e.g., fissure, fistula, or inflammatory bowel disease). The physical examination should include careful examination of the genital skin for presence of lesions, evaluation of the urethra for discharge or stricture, and the scrotal contents for epididymitis or other abnormalities. The prostate should be evaluated for abnormalities suggesting presence of stones, infarction, induration, or enlargement. Conducting a limited neurologic examination may reveal findings that merit further evaluation. Urinalysis may show hematuria, bacteriuria, pyuria, or crystalluria associated with the symptoms of prostatitis. Role of Lower Urinary Tract Localization Studies Lower urinary tract localization studies may help resolve the critical clinical need to distinguish patients with complaints associated with bacterial urinary tract infections,

TABLE 69–1. University of Washington Symptom Score for Evaluation of Patients with Chronic Prostatitis 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

Pain in lower back Pain between the testicles and the anus Pain in the lower abdomen Pain in the rectal area Pain in the testicles Pain in the penis Pain during urination Bladder does not feel completely empty right after urinating Need to urinate again less than 2 hours after urinating Stopping and starting several times while urinating Difficulty postponing urination, hard to hold it Weak urinary stream Difficulty getting stream started Getting up to urinate at night Difficulty maintaining an erection Pain with ejaculation Difficulty getting an erection Blood in your semen Lack of interest in sexual activity Premature ejaculation Difficulty in reaching ejaculation

Not At All

A Little Bit

Moderately

Quite a Bit

Extremely

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2

3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4

Prostatitis: Differential Diagnosis, Classification, and Conventional Treatment Strategies / 629

that is, patients who may have bacterial prostatitis, from the larger number of patients without bacteriuria.2,17 Careful studies have shown that 20 leukocytes per high-power field indicate significant inflammation. Most recent reports use a criterion of ≥ 10 leukocytes per high-power microscopic field.3,17,25,28 There appears to be little value in determining leukocytes in the EPS of men with objective urethral inflammation, especially among men at risk for sexually transmitted diseases.11 Therefore, the author examines a urethral smear before proceeding with the lower urinary tract localization study.6,16 Differential Diagnosis of Prostatitis Syndromes Localization studies make classification of most men with prostatitis syndromes into four diagnostic groups possible: acute bacterial prostatitis, chronic bacterial prostatitis, chronic prostatitis/chronic pelvic pain syndrome, or asymptomatic prostatitis (Table 69–3).15 The great majority of men given the diagnosis of “prostatitis” are patients with pain complaints, sexual dysfunction, and voiding symptoms.15 Most have no history of bacteriuria and little evidence of bacterial infection of the prostate. Thus, most patients with “prostatitis” may be classified in the chronic prostatitis/chronic pelvic pain category: some have objective evidence of inflammation in their prostatic secretions, semen, or postprostate massage urine (inflammatory subgroup) while others have no objective evidence of inflammation (noninflammatory subgroup). Granulomatous prostatitis is a fifth category. This uncommon syndrome represents a characteristic histologic reaction of the prostate to a variety of insults.

Clinical Presentation, Complications, and Management Acute Bacterial Prostatitis Presentation Diagnosis of acute bacterial prostatitis is usually straightforward.2,17,19 Characteristic symptoms are those associated with acute urinary tract infection, especially urinary frequency, urgency, and dysuria. Patients may experience

bladder outflow obstruction due to acute edema of the prostate. Signs of systemic toxicity are also common, such as fever, malaise, and myalgias. On physical examination the patient may exhibit a high temperature, lower abdominal or suprapubic discomfort due to bladder infection, or urinary retention. Rectal examination is often impressive, revealing an extremely tender, tense, “hot” prostate. Urinalysis demonstrates pyuria, and cultures will be positive for uropathogenic bacteria, especially Escherichia coli, other gram-negative enterics, Pseudomonas species, and occasionally gram-positive organisms such as Enterococcus or Staphylococcus species. An elevated leukocyte count is common, with increased numbers of segmented cells. Bacteremia may occur spontaneously or as a result of vigorous rectal examinations. Management For the great majority of patients, appropriate antimicrobial therapy produces dramatic improvement. Many drugs that do not penetrate into the uninflammed prostate have proved to be effective for acute bacterial prostatitis.2,17 Thus, appropriate therapy for bacteremia caused by Enterobacteriaceae or Pseudomonas or Enterococcus species should be initiated once urine and blood cultures have been obtained. For patients requiring hospitalization, conventional therapy consists of a combination of an aminoglycoside plus a beta-lactam drug.4,11 This is the author’s choice, however, newer fluoroquinolones or third-generation cephalosporins are attractive alternatives for monotherapy.29 For outpatient therapy, the conventional choice consists of a combination of trimethoprim and sulfamethoxazole.2,17 Beta-lactam drugs and the new fluoroquinolones are also useful as oral therapy for patients with acute bacterial prostatitis who do not require hospitalization. The author usually prescribes one of the newer quinolones for outpatient management. Patients with urinary retention require bladder drainage. In this situation, the author prefers suprapubic cystostomy, either through the use of a percutaneous trocar or by open surgery. An indwelling transurethral catheter would pass through and obstruct drainage of the acutely infected prostate, increasing the risk of bacteremia and prostatic abscess.2,11 General therapeutic measures include hydration, analgesics, and bed rest.2,11,17,19 Complications Complications occasionally occur in patients with acute bacterial prostatitis, particularly if treatment is delayed or inappropriate.2,11,29–32 Chronic bacterial prostatitis occasionally follows an episode of acute bacterial prostatitis. Men with chronic bacterial prostatitis often remain asymptomatic between acute episodes of bacteriuria.2,4 Prostatic abscess occurs occasionally in patients receiving appropriate antimicrobial therapy for acute

Prostatitis: Differential Diagnosis, Classification, and Conventional Treatment Strategies / 631 TABLE 69–3. National Institutes of Health Consensus Classification of Prostatitis Syndromes Category

Characteristic Clinical Features

I. Acute bacterial II. Chronic bacterial III. Chronic prostatitis/chronic pelvic pain syndrome A. Inflammatory subtype† B. Noninflammatory subtype‡ IV. Asymptomatic

Acute UTI Recurrent UTI caused by the same organism Primarily pain complaints. Also voiding complaints and sexual dysfunction

Diagnosed during evaluation of other GU complaints

Bacteriuria

Inflammation*

+ +

+ +

– – –

+ – +

UTI = urinary tract infection; GU = genitourinary. *Objective evidence of an inflammatory response in expressed prostatic secretions, postprostate massage urine, semen, or by histology. †Formerly termed “nonbacterial prostatitis.” ‡Formerly termed “prostatodynia.”

bacterial prostatitis.11,30,31,33–39 This complication is especially common in diabetics, immunosuppressed patients, or in patients requiring long-term transurethral catheterization. Classically, the abscess presents as a fluctuant area in the prostate noted during rectal examination.31–33 Many patients, however, have more subtle findings. Transrectal ultrasound and computerized tomography are valuable for diagnosis in patients with such subtle findings.30,35–37 Treatment includes perineal, percutaneous, or transurethral drainage of the abscess as well as appropriate antimicrobial therapy.30,37 The author considers the transurethral approach to be optimal. The critical clinical issue with prostatic abscess is to consider this diagnostic possibility in patients with risk factors or in those who do not respond to therapy. Granulomatous prostatitis may occur during resolution of acute bacterial prostatitis.2,40 Most patients are asymptomatic but may have prostatic induration noted during rectal examination. The clinical findings often raise the question of carcinoma. Prostatic infarction may also complicate acute bacterial prostatitis. Such areas usually present as firm portions of the prostate. Their primary importance lies in the differential diagnosis of carcinoma. Chronic Bacterial Prostatitis Presentation The key to diagnosis of chronic bacterial prostatitis is documentation of recurrent episodes of bacteriuria caused by the same organism.2,16 Chronic bacterial prostatitis is an important cause of bacterial persistence in the male lower urinary tract.2,17,19 Persistence of small numbers of bacteria in the prostate is the most common cause of relapsing urinary tract infections in adult men.2 Patients with chronic bacterial prostatitis are often asymptomatic between episodes of bladder bacteriuria. The prostate is usually normal on both rectal and endoscopic evaluation. Diagnosis therefore depends on careful lower urinary tract localization studies as described above.18 Diagnosis based solely on symptoms, number of leukocytes in EPS or semen, or prostate biopsy is inaccurate.

Chronic bacterial prostatitis may occasionally present as a systemic illness. Small numbers of bacteria in the prostate do not cause the systemic illness but with acute exacerbations, bladder bacteriuria and secondary sepsis may result from the prostatic focus. This is especially likely among older men who have both prostatic obstruction and infection. Gram-negative bacilli, Enterobacteriaceae, and pseudomonads are by far the most important pathogens.2,16,17 Gram-positive cocci such as Streptococcus faecalis or Staphylococcus saprophyticus may be etiologic organisms in occasional cases.17,41 Reports implicating many other organisms are difficult to evaluate because of problems with case definitions, lack of documentation of bacteriuria caused by the alleged pathogen, or lack of an immunologic response by the prostate.11,42,43 Chronic bacterial prostatitis is associated with a profound secretory dysfunction.17 Alterations include higher EPS pH, changes in the ratio of lactate dehydrogenase (LDH) isozymes, and secretion of immunoglobulins. Other changes include decreased specific gravity of the following: prostatic secretions, prostatic antibacterial factor, cation concentrations (zinc, magnesium, and calcium), citric acid, spermine, cholesterol, acid phosphatase, and lysozyme. Characteristically, patients with chronic bacterial prostatitis have episodes of symptomatic bladder bacteriuria caused by the same organism. These acute episodes are separated by asymptomatic intervals of varying length.2,17 Lower tract localization studies during episodes of bladder bacteriuria are of no value since all the specimens have high colony counts.2,17 The key to accurate diagnosis is to evaluate patients when their midstream urine is sterile. It may occasionally be necessary to eradicate organisms present in the bladder urine and urethra with drugs such as penicillin G or nitrofurantoin to obtain diagnostic localization.2 Management Medical and surgical approaches have been recommended for management of chronic bacterial prostatitis. In the great majority of patients, medical treatment is effective in curing or suppressing bacterial prostatitis.2 4,29 In contrast, surgical procedures appear to have a limited role in managing these patients.


Antimicrobial Therapy To assure effective antimicrobial therapy for a localized bacterial infection such as chronic bacterial prostatitis, sufficient levels of an appropriate drug must be provided at the infected site. Unfortunately, many drugs have poor penetration of prostatic parenchyma.44,45 Other antimicrobials, such as erythromycin, that achieve good tissue levels have an inappropriate profile for common pathogens in prostatitis.2 Trimethoprim-sulfamethoxazole is the traditional “gold standard” for treating chronic bacterial prostatitis. Trimethoprim achieves adequate levels in prostatic parenchyma and is effective against the most common pathogens, both critical characteristics.2,46 Long-term therapy with trimethoprim (160 mg) plus sulfamethoxazole (800 mg), taken orally twice daily for 4 to 16 weeks, is superior to shorter courses.47,48 Such long courses result in symptomatic and bacteriologic cure in approximately one-third of patients, symptomatic improvement during therapy in approximately one-third of patients (who relapse after stopping treatment), and no improvement in the remaining patients.17,47–50 Trimethoprim alone has been studied less well. In theory, single agent trimethoprim should produce comparable results to combination therapy since sulfamethoxazole diffuses poorly into the prostatic parenchyma.2 During the past decade, the new fluoroquinolones proved useful for treating chronic bacterial prostatitis. In contrast to the beta-lactam drugs, concentrations of many fluoroquinolones are relatively high in prostatic fluid, prostatic tissue, and seminal fluid compared to plasma levels.51–55 Good results were reported for chronic bacterial prostatitis, including patients who failed therapy with trimethoprim-sulfamethoxazole.51–55 Promising agents include norfloxacin, ciprofloxacin, ofloxacin, and enoxacin.52–57 It is difficult to compare available studies because of varying diagnostic criteria and the considerable range in duration of treatment and length of follow-up. Because relapse rate is the critical criterion for evaluating treatment of prostatitis, patients cannot be considered cured without long-term follow-up. Further investigations, especially controlled clinical trials, are needed to determine the relative merits of the newer quinolones. Many other oral antimicrobials have been used to treat chronic bacterial prostatitis. Most reports are hampered by imprecise case definitions, lack of sufficient microbiologic data or follow-up, or an abundance of patients “infected” with organisms generally considered urethral contaminants. Although it is difficult to draw definitive conclusions, the indanyl ester of carbenicillin,58,59 doxycycline,60 rosamicin,61 erythromycin plus urinary alkalization with bicarbonate, 62,63 and combinations employing rifampicin plus trimethoprim64 may prove useful in selected patients. Some investigators report that aminoglycosides administered parenterally2

or by local injection into the prostate65,66 can cure patients who failed oral therapy. Bacteria cultured from patients with chronic bacterial prostatitis are generally antimicrobial-sensitive strains, even after multiple episodes and prolonged courses of therapy.2,11,17 While antimicrobial resistance is seldom a problem, an infected prostate may become the focus of a persistent infection, with recurrent bouts of bacteriuria and a risk of blood stream infection. Although often identified in the prostates of asymptomatic men,67,68 some studies suggest that prostatic calculi occur more often among men with chronic prostatitis. Infection of such stones may serve as a persistent focus for bacteria that is difficult to eradicate with antimicrobial agents.4,56,69–72 Patients with infected prostatic calculi, however, are exceedingly rare in the author’s practice. Other reasons offered for the difficulty in curing chronic bacterial prostatitis include difficulties in achieving high drug levels in localized areas of infection within the prostate, changes in prostatic fluid pH associated with infection limit diffusion of drugs into the prostate,73–75 and the presence of biofilms76,77 that protect bacteria from antimicrobial agents. Patients who are not cured may be rendered asymptomatic by long-term, low-dose suppressive therapy.2,17 Since most patients remain asymptomatic between episodes of bacteriuria, the goal of suppressive therapy is to prevent symptomatic episodes despite the persistence of bacteria within the prostate. Very low doses of drugs that are excreted in the urine are remarkably effective for this. Available agents include penicillin G, tetracycline, nitrofurantoin, nalidixic acid, cephalexin, trimethoprimsulfamethoxazole, and the fluoroquinolones. Clinical Approach The observations described above support a straightforward therapeutic approach for managing chronic bacterial prostatitis. It is important to document a prostatic source of organisms causing bacteriuria by careful lower urinary tract cultures. If cultures support the diagnosis of chronic bacterial prostatitis, then a prolonged course of therapy should be employed in an effort to cure the infection using an appropriate drug that achieves good levels in the prostate. The author’s preference is to recommend a fluoroquinolone at full dose for at least 3 months. As an alternative, a trimethoprim-sulfamethoxazole is recommended, one double-strength tablet twice daily for at least 3 months. Following therapy, lower urinary tract studies should be repeated to evaluate the response. A second course of treatment may be indicated for men with a persistent focus of prostatic infection, using a drug with a different mechanism of action. Patients who are not cured may be treated with long-term, low-dose, suppressive medication to prevent colonization of the bladder and urethra with organisms from the infected prostate.


Surgical Therapy Surgery has a limited role in treating patients with chronic bacterial prostatitis. Complete removal of the prostate by radical prostatectomy or cystoprostatectomy will cure bacterial prostatitis.2 Such surgery is a major undertaking, however, and is associated with significant complications; radical surgery is best reserved for patients with localized prostate cancer. For the rare men who have the combination of carcinoma of the prostate and chronic bacterial prostatitis, radical prostatectomy may cure both problems. Subtotal prostatectomy procedures (transurethral, retropubic, suprapubic, visual laser ablation, transurethral needle ablation, etc.) represent the most common operations for benign prostate disorders. These procedures remove periurethral adenomatous tissue, leaving the surgical capsule. The observation that most inflammation and infection appear to be located in the peripheral prostatic tissue may explain why subtotal prostatectomy cures only about one-third of patients.2,17,48 Therefore transurethral or open surgical procedures for removal of prostatic adenomas are best reserved for patients with symptoms of bladder outflow obstruction that persist after sterilization of the midstream urine. Occasional studies report higher cure rates using transurethral resection to remove infected prostatic calculi and periurethral adenoma.78–80 “Radical” transurethral resection is necessary to remove all infected stones because the peripheral prostate contains the most foci of infection and stones.13,72 Patient populations in most of these reports were poorly defined, and bacteriologic evaluation and follow-up were often inadequate to document the conclusion that 70 to 100% of patients were “cured.” Rare patients with chronic bacterial prostatitis have other obstructive lesions such as urethral stricture disease. Such patients may benefit from the combination of surgery and antimicrobial therapy. Before recommending surgery, it is essential to document the functional significance of obstructive lesions by appropriate studies when the patient is not bacteriuric. Chronic Prostatitis/Chronic Pelvic Pain Syndrome Presentation Bacterial prostatitis is a common clinical diagnosis and a frequent indication for antimicrobial therapy. Welldocumented bacterial infections of the prostate, however, whether acute or chronic, are uncommon.16,81 In the author’s prostatitis clinic, such infections account for < 10% of men presenting with prostatitis.6 More than 90% of patients given the diagnosis of “prostatitis” are patients with pain complaints, sexual dysfunction, and voiding symptoms.15 Most have no history of bacteriuria. In the traditional classification, these patients were con-

sidered to have “nonbacterial” prostatitis or “prostatodynia,” conditions about which there are few firm data supporting rational therapeutic decisions. The new National Institutes of Health (NIH) consensus terminology classifies these patients in the “chronic prostatitis/chronic pelvic pain syndrome” category. There are two subgroups, an “inflammatory subtype” and a “noninflammatory subtype,” depending on the presence or absence of leukocytes.15 Systemic symptoms and signs are absent. Genital examination is usually unremarkable, and the prostate is normal on rectal examination. Causes The etiology of chronic prostatitis/chronic pelvic pain syndrome is unclear. Many investigators have examined microbiologic, urodynamic, and psychologic aspects.2,4,11 No study has been completely satisfactory, however, with careful definition of the disease, adequate microbiologic evaluation, and psychologic assessment. Evidence for infectious causes is summarized below. Most of these agents are classified as bacteria from a microbiologic standpoint. The terms, “nonbacterial” and “abacterial,” therefore, should be avoided. The following sections consider the evidence for infectious agents that have been implicated in the etiology of this syndrome. Treatment of these agents relies primarily on antimicrobial therapy. Other chapters consider the various noninfectious causes and recommended treatments for this syndrome. Chlamydia trachomatis. Chlamydia trachomatis may be the most controversial organism implicated in chronic prostatitis/ chronic pelvic pain syndrome. Mårdh and Colleen82 evaluated urethral samples from 78 patients with “nonacute prostatitis” and from 20 normal men. One-third of the patients with prostatitis had antibodies to C. trachomatis, compared to 3% of controls. Tetracycline treatment was superior to placebo in resolving symptoms. Follow-up studies employing cultures and serology by the same investigators did not implicate C. trachomatis, however, as an etiologic agent in prostatitis.83–86 Similarly, the author and colleagues could not culture C. trachomatis from the urethras of men with chronic prostatitis,87 nor could a serologic or local immune response to C. trachomatis be demonstrated in a smaller number of such patients. Doble and associates evaluated 60 men with the diagnosis of “chronic abacterial prostatitis” using transrectal prostatic ultrasound with transperineal biopsy of abnormal areas.88 Chlamydiae were not cultured nor were these organisms detected by immunofluorescence. In addition, no patient had serum antibodies against C. trachomatis. Different conclusions were reported by Bruce et al.89 These investigators examined early-morning urine, prostatic fluid, or semen from 70 men with “subacute or chronic prostatitis.” Of these 70 subjects, 39 (56%) were infected


with C. trachomatis. Criticisms were directed against the methods and the high rate of positive cultures among controls: 9 (17%) of 54 men undergoing elective vasectomy were positive for C. trachomatis.90 In follow-up studies, Bruce and Reid91 evaluated 55 patients with “prostatitis,” including 31 men “believed to have chlamydial prostatitis.” Only six cases met strict criteria for chlamydial prostatitis based on identification of the organisms by culture or immunofluorescence techniques. These conclusions were supported by Kuroda et al., who identified C.trachomatis in the urethras of 20% of men with prostatitis.92 Other investigators have reached similar conclusions.38,93,94 Other data support an etiologic role for C. trachomatis in prostatitis. Poletti and associates isolated C. trachomatis from prostate cells obtained by transrectal aspiration biopsy of men with “nonacute abacterial prostatitis.”95 Abdelatif et al. used in situ hybridization to evaluate transurethral prostate chips from patients with histologic evidence of “chronic abacterial prostatitis,”96 detecting intracellular chlamydiae in 7 (30%) of 23 cases. Shurbaji and associates demonstrated C. trachomatis in paraffinembedded sections from 5 (31%) of 16 patients with histologic evidence of prostatitis, compared to none of 19 men with BPH without inflammation.97 Kobayashi and Araki identified peroxidase-antiperoxidase staining for chlamydiae in prostate biopsy tissue following therapy.98 Other investigators detected anti-C. trachomatis-specific IgA in EPS from 20 (29%) of 69 men with chronic nonbacterial prostatitis.99 These studies suggest that chlamydiae may invade the prostate, that chlamydial antigen can persist after therapy, and that the presence of such an antigen might be related to prostatitis. Criticisms of previous studies include absent or inappropriate controls and use of urethral specimens that may not reflect prostatic infection. Prostate tissue and secretions inhibit culture methods for C. trachomatis and other microorganisms. Other reservations are that methods such as microscopy, immunofluorescence, or in situ hybridization may lack sensitivity for identification of defective organisms or organisms present in small numbers. The recent demonstration of chlamydial DNA and ribonucleic acid (RNA) by polymerase chain reaction (PCR)-based assays in culture-negative cases of trachoma (a chronic eye disease caused by C. trachomatis) suggests that “Live Chlamydiae may remain at a site of infection and produce inflammation beyond the time at which microbial techniques are able to detect them.”100 Similar events may occur in chronic prostatitis. Another problem is that biopsies sampled abnormal areas only. The possibility that C. trachomatis may be important in some cases is supported by recent demonstration of C. trachomatis DNA in patients with chronic prostatitis/chronic pelvic pain syndrome despite negative urethral cultures.24 The precise role of C. trachomatis in chronic prostatitis/chronic pelvic pain syndrome clearly deserves further study.

In the author’s clinic, culture is the preferred diagnostic test for C. trachomatis, although molecular diagnostic techniques are being investigated. Doxycycline is currently prescribed as the preferred treatment, for at least 3 to 6 weeks. Ureaplasma urealyticum. Ureaplasma urealyticum is the genital mycoplasma that has been most strongly associated with chronic prostatitis/chronic pelvic pain syndrome. Other genital mycoplasmas (Mycoplasma hominis and Mycoplasma genitalium) have also been associated with urogenital tract complaints, including prostatitis and urethritis, but the supporting data are less conclusive. Weidner et al.101 suggested that U. urealyticum causes “chronic prostatitis.” In their study of > 700 patients, isolation of high concentrations of U. urealyticum (> 103 colony forming units [cfu] per mL) in prostatic fluid, semen, or postmassage urine was associated with signs and symptoms of “prostatitis.” “Significant” concentrations of U. urealyticum were found in 18 (13%) of 143 men with prostatitis in a recent report.102 Treatment with either ofloxacin or minocycline cleared the organisms in all cases and resolved symptoms in 10 men (71%). Isaacs cultured U. urealyticum from prostatic secretions of 11 (8%) of 131 patients with chronic nonbacterial prostatitis at concentrations >103 cfu per mL, suggesting an etiologic role.103 In contrast, other investigators were unable to implicate the genital mycoplasmas in nonbacterial prostatitis.82,104 Additional studies employing carefully defined populations and methods for isolation of multiple pathogens would be useful to assess the purported role of U. urealyticum in prostatitis. In the author’s setting, semiquantitative culture is the preferred method for detecting U. urealyticum. Although ureaplasmas have been isolated from the urethras of men with chronic prostatitis/chronic pelvic pain syndrome, they have also been isolated from healthy controls.87 Mycoplasma genitalium has been identified in prostate tissue samples from some patients with chronic prostatitis/ chronic pelvic pain syndrome.24 There was no evidence of U. urealyticum in these patients. The practice of the author and colleagues is to offer treatment to patients with high counts of ureaplasmas. Because methods of antimicrobial sensitivity testing are not well established for U. urealyticum, the patient and his sexual partners are treated with either doxycycline or enteric coated erythromycin, with a test-of-cure culture obtained following completion of therapy. Trichomonas vaginalis. Trichomonas vaginalis is a protozoan pathogen that has been proposed as one cause of varied urologic conditions including prostatitis. The protozoa cause nongonococcal, nonchlamydial urethritis and persistent infection. The author and colleagues isolated T. vaginalis and C. trachomatis with comparable frequencies from the urethras of men with chronic pro-


statitis syndromes.6 Trichomonas vaginalis has been identified in urinary sediment, prostatic secretions, and prostatic parenchyma. In some studies, the prevalence of trichomoniasis exceeded 85% among patients with symptoms of prostatitis persisting despite antibacterial therapy.105,106 These findings support previous reports of an association between T. vaginalis and prostatitis.105–110 Some suggest that the highest prevalence is in men with long-term symptoms and in those who have not responded to standard antibacterial therapy.106 The precise role of T. vaginalis as a cause of nonbacterial prostatitis, however, remains undefined. Recent support for a role for T. vaginalis in some patients was provided by identification of the protozoa in prostate biopsies from patients with chronic prostatitis despite negative urethral cultures for these organisms.24 Specific diagnosis is necessary since treatment of trichomoniasis requires antimicrobials seldom prescribed for urogenital infections in men. The author and colleagues consider culture to be the preferred diagnostic method although we are also evaluating immunologic and molecular methods of diagnosis.111–113 Cultures of multiple urogenital specimens (urethra, first-void urine, and semen), however, are necessary for optimal diagnosis.111,114,115 The treatment of choice is metronidazole, as either a single oral dose or a 1-week course. The author and colleauges use single-dose therapy for patients with urethritis and recommend at least 1 week of treatment for patients with symptoms of prostatitis. Other organisms. Many other organisms are potential causes of chronic prostatitis and urethritis syndromes, including viruses, fungi, and anaerobic and gram-positive bacteria. In two Scandinavian studies, men with “chronic nonbacterial” prostatitis had prostate biopsies that were cultured for aerobic bacteria, anaerobic bacteria, and viruses.116,117 Neither study demonstrated an etiologic role for such organisms. Gram-positive bacteria are the most controversial proposed microbial causes of nonbacterial prostatitis. Although the significance of gram-positive cocci has been debated for over 20 years, the consensus until recently was that these organisms are seldom, if ever, causative.11,16,17,118 Nickel and Costerton revived this debate by localizing coagulase-negative staphylococci in the prostates of three men with refractory “chronic prostatitis.”77 The bacteria were isolated in culture from prostate tissue. Electron microscopy demonstrated “sparse and focal microcolonies adherent to the prostatic ductal walls,” suggesting sequestration of resistant staphylococci within intraprostatic biofilms. In contrast, other investigators found that such organisms disappeared without treatment in all cases.119 In the preantibiotic era, Neisseria gonorrhoeae was a common cause of prostatitis and of prostatic abscess.39

Gonococcal prostatitis has seldom been reported in the postantibiotic era, however. Two studies have demonstrated anti-N. gonorrhoeae antibodies in prostatic fluid of men whose cultures were negative.85,120 Other studies have seldom identified N. gonorrhoeae in patients with prostatitis.4,16,87 Anaerobes were suggested as important but controlled studies showed no significant differences between cases and controls.119 These studies employed outdated bacteriologic methods, however. Of genitourinary viruses, herpes viruses types 1 and 2121–123 and cytomegalovirus124–126 are the most likely causes of prostatitis, based on case reports. Recent Studies Empiric observations support the concept that genitourinary tract infections may cause chronic prostatitis. Patients often relate the onset of their condition (often an episode of acute urethritis) to sexual activity.7 Antimicrobial therapy frequently relieves symptoms. Based on these observations, standard clinical practice is to use multiple courses of antibacterial drugs in the hope that patients will experience lasting benefit.10,11,127 For example, in a report of 75 subjects by the author and colleagues, the average patient received 10 weeks of antimicrobial treatment during the 3 months before evaluation.6 Unfortunately, standard uropathogens (that is, organisms that cause bacteriuria, such as Escherichia coli, Pseudomonas species, or Enterococcus) are identified in few cases. The great majority of studies described above used culture or antigen detection in samples such as urine, urethral swabs, and EPS. Interpretation of results may be complicated as specimens can acquire organisms during passage through the urethra. These considerations led the author and colleagues to directly evaluate both the urethra and prostate biopsies in patients with chronic prostatitis. Findings in prostate tissue were compared to the inflammatory response in prostate secretions. First, urethra, urine, and transperineal prostate biopsies were cultured for commensal and fastidious organisms. Leukocytes were counted in EPS from 85 men with chronic prostatitis/chronic pelvic pain syndrome.128 Patients with inflamed EPS were more likely to have any bacterial isolation (p = .01), positive cultures for anaerobic bacteria (p = .03), higher total bacterial counts (p = .02), and more bacterial species isolated (p = .02) in prostate biopsy cultures than men without EPS inflammation. These findings support the concept that bacterial colonization/invasion of the prostate may be associated with inflammatory prostatitis. Follow-up studies employed molecular approaches. The reasoning was that culture of urogenital microorganisms in men with chronic prostatitis constitutes a challenging clinical microbiology problem because of inhibitory substances129,130 and multiple prior courses of antimicrobials.131 Many microorganisms cannot be cultivated under


the most refined conditions.132 Environmental studies suggest that most microorganisms do not multiply on conventional media.133–143 Compared to environmental bacteria, a higher percentage of bacteria infecting or inhabiting human sites are known species but this source also contains a large number of uncharacterized species.134 This 5-year study by the author and colleagues combined optimal clinical, cultural, and molecular methods to evaluate a well-defined population of 135 men with chronic prostatitis/chronic pelvic pain syndrome.24 Microbiologic studies evaluated fastidious organisms, lower urinary tract localization cultures, and chamber counts of EPS leukocytes. Potential subjects were excluded if they had bacteriuria, bacterial prostatitis, urethritis, or a positive urethral culture for urogenital pathogens. Thus, patients were evaluated who could not be diagnosed using optimal clinical and microbiologic methods. This protocol included over 1000 physician visits, representing four or more visits for each of the 260 men evaluated to select the 135 study subjects. Prostate biopsies were obtained using a double-needle method to limit contamination and evaluated using molecular assays for C. trachomatis, T. vaginalis, genital mycoplasmas, herpes simplex viruses, and cytomegalovirus. Broad-spectrum assays were also conducted for both tetracycline resistance and 16S (bacterial) rRNA. After amplification, the polymerase chain reaction assay products were cloned and sequenced.24 Homology searches were completed followed by extensive phylogenetic analyses. Ten (8%) of the 135 subjects had positive assays for one or more specific microorganisms, including Mycoplasma genitalium (4 subjects), C. trachomatis (3 subjects), and T. vaginalis (2 subjects); one man was positive for both M. genitalium and C. trachomatis. These findings support previous studies indicating that both C. trachomatis95–97 and T. vaginalis109 may be identified in prostate tissue. To the knowledge of the investigators, this is the first demonstration of M. genitalium in prostate tissue. These observations suggest that C. trachomatis, T. vaginalis, and M. genitalium may be associated with some cases of chronic prostatitis/chronic pelvic pain syndrome, even among men who have no evidence of urethritis and in men with negative urethral cultures. The overwhelming majority of assays were negative, including 2541 (99.5%) of 2552 assays for specific pathogens. There were no positives for either the general mycoplasma assay or the U. urealyticum assay. Thus, M. genitalium was the only genital mycoplasma identified in patients with chronic prostatitis/chronic pelvic pain syndrome. Earlier reports suggesting an important role for M. hominis and U. urealyticum may reflect contamination with urethral organisms in less selected populations.101,144–146 No patient had a positive PCR for herpes simplex virus types 1 and 2, or cytomegalovirus.

The broad-spectrum molecular assays provided provocative findings. Tetracycline-resistance was detected in 25% of subjects and 16S rRNAs were detected in 77% of subjects. Although the tetracycline resistance and 16S rRNA assays were done in different laboratories by personnel who were blinded to other clinical and microbiologic findings, the results were highly correlated, with the tetracycline resistance-positives constituting a subset of the 16S rRNA-positive patients. There was a strong correlation between EPS inflammation and detection of 16S rRNA in prostatic tissue (p < .001). While there was no statistical correlation between EPS inflammation and tetracycline resistance, there was a 15% higher rate of inflammation among men whose prostate biopsies contained tetracycline-resistance sequences. Lack of statistical significance may reflect the relatively low number of subjects exhibiting tetracycline resistance. While it is impossible to determine cause-and-effect using a casecontrol design, these findings suggest that fastidious or noncultivable microorganisms may be important in the etiology of the inflammatory subtype of chronic prostatitis/chronic pelvic pain syndrome. Identification of bacterial rRNA and tetracyclineresistance sequences in prostate tissue from patients with chronic prostatitis does not establish that bacteria cause this syndrome. However, none of Koch’s postulates holds for every infectious agent.134 Establishing a role for bacteria in chronic prostatitis/chronic pelvic pain syndrome will likely involve multiple steps. Detecting bacteria in prostate tissue represents an important step in determining the etiology of these syndromes. The DNA sequence data obtained by the author and colleagues strongly suggest that the 16S rRNA-positives were from a source separate from known gut, skin, and laboratory contaminants. The correlation between 16S rRNA and tetracycline resistance is also consistent with the clinical observation that antibiotic therapy provides transitory, if any, relief for many patients. These findings suggest that identification, cloning, and sequencing of bacterial DNA in prostate tissue may help elucidate the causes of chronic prostatitis/chronic pelvic pain syndrome. Differential Diagnosis Three important conditions should be considered in the differential diagnosis of chronic prostatitis/chronic pelvic pain syndrome: interstitial cystitis, carcinoma in situ of the bladder,2,4 and prostate cancer. These disorders may present with irritative lower urinary tract symptoms that may mimic chronic prostatitis/chronic pelvic pain syndrome. Thus, for selected patients it may be reasonable to obtain urine specimens for cytology and to perform endoscopic examination under anesthesia, including hydrodistension, and to obtain appropriate bladder biopsies. It is also reasonable to recommend prostate-specific antigen (PSA) testing; during acute symptomatic exacer-


bations, however, that may be associated with acute elevation of serum PSA. Asymptomatic Inflammatory Prostatitis Prostatitis may occasionally be diagnosed in patients who have no genitourinary tract symptoms. This diagnosis includes a number of patients with evidence of prostatic inflammation but with none of the usual symptoms associated with other prostatitis syndromes. One common scenario occurs among patients who have an elevated PSA noted during routine screening. These patients undergo prostate biopsy to evaluate the possibility of prostate cancer. The most common benign pathologic diagnosis is “prostatitis,” based on histologic findings of inflammatory infiltrates in the prostatic parenchyma. Some clinicians recommend a course of antimicrobial or anti-inflammatory therapy in this situation. These recommendations are based on the observations that acute bacterial prostatitis and exacerbations of chronic bacterial prostatitis are associated with elevation of both serum PSA and acid phosphatase. Whether antimicrobial therapy is beneficial for asymptomatic patients with histologic evidence of prostatitis, however, remains uncertain. Another clinical scenario where asymptomatic inflammatory prostatitis may be diagnosed occurs among men undergoing evaluation for infertility.23 Many of these men have no genitourinary tract symptoms. On semen analyses, increased numbers of “round cells” may prompt diagnosis of prostatitis. Other diagnoses include “asymptomatic male genital tract infection,” “male accessory gland infection,” “prostato-seminal vesiculitis,” “leukocytospermia,” and “pyosemia.” Some infertility specialists recommend antimicrobial therapy but the proportion of patients who have active genital tract infections is poorly defined.81,147–150 Granulomatous Prostatitis The overwhelming majority of men with prostatitis may be classified in the four syndromes considered above. Some unusual patients have granulomatous prostatitis, however, a fifth category. This diagnosis is important because specific therapy is necessary to treat its infectious causes. Granulomatous prostatitis is a characteristic reaction of the prostate to a variety of irritants. Patients may present with firmness of the prostate on rectal examination, suggesting prostate cancer.151 Others present with symptoms of a systemic illness or lower urinary tract obstruction due to prostatic enlargement. Historically, tuberculosis caused most cases of granulomatous prostatitis. Tuberculosis remains an important consideration in patients from developing countries and among human immunodeficiency virus (HIV)-seropositive men.152–154 Other opportunistic agents may be associated with granulomatous prostatitis, especially among HIVseropositive men. These include cryptococcosis, coccidioidomycosis, blastomycosis, and atypical mycobacte-

ria.11,155–157 Granulomatous prostatitis may also occur in association with rheumatoid diseases, particular Wegener’s granulomatosis.158–161 Biopsy with appropriate cultures and specialized stains is often necessary for diagnosis. Thus, granulomatous prostatitis represents a characteristic histologic diagnosis that does not correspond to a discrete clinical syndrome. Pathology Grossly, the prostate appears indurated, and on rectal examination it is frequently nodular. Histologic examination demonstrates a granulomatous reaction with lipidladen histiocytes, plasma cells, and scattered giant cells. In some cases, prominent infiltrates containing many eosinophilic infiltrates are apparent. Recent reports suggest that histologic findings range from a localized appearance, resembling rheumatoid nodules, often associated with a history of previous transurethral surgery, to a more diffuse appearance associated with systemic illness or idiopathic etiology.162,163 Specific stains or cultures are usually necessary to establish an etiologic diagnosis. Etiology Granulomatous prostatitis is considered “specific” when associated with particular granulomatous infections and “nonspecific” in other cases. Recognized causes of nonspecific granulomatous prostatitis include acute bacterial prostatitis, prostatic surgery, and rheumatoid diseases. Many cases of granulomatous prostatitis follow episodes of acute bacterial prostatitis or previous prostatic surgery.2,40 Nonspecific granulomatous prostatitis. One theory is that nonspecific granulomatous prostatitis represents a tissue response of the foreign body type to extravasated prostatic fluid.40 Clinically, patients present with acute symptoms and signs of bladder outlet obstruction, associated with an enlarged, firm prostate that feels malignant. Fever and irritative voiding symptoms may occur. Nonspecific granulomatous prostatitis occurs in two forms, eosinophilic and noneosinophilic. Neither variety is common in clinical practice; the eosinophilic variety is especially rare. Eosinophilic and noneosinophilic granulomatous prostatitis are both clinically important as they may be confused with prostate cancer. On occasion, eosinophilic granulomatous prostatitis presents as a systemic illness associated with fibrinoid necrosis and generalized vasculitis.164 Because it occurs almost exclusively in patients with allergies, especially asthmatics, this entity is also known as “allergic granuloma of the prostate.”118 Granulomatous prostatitis has also been associated with other rheumatoid disorders, particularly Wegener’s granulomatosis.158–161 Specific granulomatous prostatitis. There are a number of specific granulomatous infections that may involve the


prostate. Tuberculous prostatitis is usually secondary to tuberculosis elsewhere in the genital tract.165,166 Most patients lack symptoms referable to prostatic infection. Biopsy demonstrates granulomas that frequently contain Langhans’ giant cells and that may exhibit caseous necrosis. Such infections are caused most often by Mycobacterium tuberculosis but have also been associated with atypical mycobacteria.167,168 Mycotic prostatitis may be secondary to systemic infection with many of the deep mycoses.169,170 Most cases have been reported to be associated with blastomycosis,169,171 coccidioidomycosis,156,172,173 and cryptococcosis.174,175 On occasion, histoplasmosis and paracoccidioidomycosis involve the prostate.169,176 Cases of prostatitis due to candidiasis or aspergillosis have also been described.177–179 Mycotic prostatitis is usually a manifestation of a systemic hematogenous dissemination. This process may involve any organs of the genitourinary tract. Mycotic involvement of the prostate is likely more common than is generally appreciated, since such infection is frequently asymptomatic and the prostate is often not specifically evaluated in autopsy protocols.169 Rare infectious causes of granulomatous prostatitis include actinomycosis, candidiasis, syphilis, and brucellosis [F. Mantz, personal communication, 1984].180,181 Granulomatous prostatitis may also complicate bacille Calmette-Guérin (BCG) therapy for bladder cancer.182 Recent reports suggest that acquired immunodeficiency syndrome and HIV infection may be associated with an increased risk for granulomatous prostatitis,155 and that the etiology may include pathogens such as Mycobacterium avium complex.157 Diagnosis and Management Granulomatous prostatitis is often most important in the differential diagnosis of an indurated, firm, or nodular prostate. Rectal examination raises the suspicion of prostatic carcinoma. Other causes of a nodular prostate include prostatic infarction, nodular benign prostatic hypertrophy, or a prostatic calculus. Prostate biopsy is often necessary for diagnosis. Use of appropriate stains and cultures to detect specific agents is important in cases where granulomatous prostatitis is a consideration. Treatment of granulomatous prostatitis involves specific treatment of the primary disease. Patients occasionally have symptoms directly referable to the prostate. Such men usually complain of obstructive voiding symptoms. In most cases, the symptoms resolve with systemic therapy. Patients with urinary retention are best managed by percutaneous placement of a suprapubic cystostomy tube. Prostatectomy may be necessary if symptoms persist after an appropriate course of antimicrobial therapy.

Conclusion Common, poorly understood prostatitis syndromes cause considerable morbidity in many men. Specific ther-

apy leads to cure or improvement for men with infectious causes of prostatitis. Treatment is frequently empiric and unsatisfactory, however, because of general limited understanding of the causes and pathophysiology of these neglected disease syndromes. Cryptic microorganisms may be important in some cases. Defining the precise role for such organisms will require better diagnostic algorithms and methods to elucidate the microbiology of the prostate in health and disease. If cryptic infection is associated with chronic prostatitis/chronic pelvic pain syndrome, it must be determined whether this represents the residue of prior infection or an ongoing active infection. The pathogenesis of infection and the role of antimicrobial agents and other therapies can then be defined.

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CHAPTER 70

PROSTATITIS: FACTORS INFLUENCING PROGNOSIS RICHARD A. SCHOOR, MD; ANTHONY J. SCHAEFFER, MD Prostatitis is a poorly understood syndrome. This lack of understanding may adversely affect outcomes in patients with all forms of prostatitis. To improve on the prognosis of prostatitis, the clinician requires an excellent understanding of its epidemiology, evaluation, etiology, pathophysiology, and therapy. The goal of this chapter is to illustrate some common misconceptions concerning prostatitis and provide an up-to-date review of prostatitis syndromes, with special emphasis on factors affecting prognosis. The term prostatitis implies prostatic inflammation. Prostatitis, however, represents a number of disorders related to symptoms and/or signs referable to the lower urinary tract.1 Acute bacterial prostatitis, chronic bacterial prostatitis, nonbacterial prostatitis, and prostatodynia—or pelviperineal pain syndrome—represent the four categories of prostatitis. There is currently an emphasis on standardizing and reclassifying the various forms of the disorder to enhance physician understanding.2 The incidence of nonbacterial forms of the disease predominate—approximately 60% in the form of nonbacterial prostatitis (NBP) and 30% as prostatodynia.3 With the exception of acute bacterial prostatitis, the various forms of prostatitis can not be distinguished solely on the basis of clinical symptomatology.

bacteria are responsible for the minority of cases, approximately 5 to 10%.5 These misconceptions no doubt affect physician’s diagnostic and therapeutic decision making, possibly impacting negatively on the disease.

Evaluation The classic categorization of prostatitis into four main groups evolved in the 1960s and 1970s and has remained the standard.8 Patients don’t always fit neatly into one category or another, however, and guidelines for treating such patients do not exist. What should be done, for instance, with the patient whose prostatic fluid culture is positive for an atypical organism or with the asymptomatic patient with leukocytes in their prostatic fluid? What treatment type would most likely benefit the patient with perineal pain but no voiding symptoms? The National Institutes of Health Consensus Conference on Prostatitis has devised a new prostatitis classification system to help solve these types of problems.2 Category I and II refer to acute and chronic bacterial prostatitis. Category III refers to chronic pelvic pain syndrome in the presence of negative prostatic fluid cultures. Category IIIA identifies patients with significant inflammation in the prostatic fluid, that is nonbacterial prostatitis, and category IIIB identifies patients without significant prostatic fluid inflammation, that is, prostatodynia. Category IV defines asymptomatic patients with inflammatory cells in the prostatic fluid.2 The new system has yet to be clinically validated but it is currently the standard reference in research settings. Its goal is to promote a better understanding of the disease, with improvements in diagnosis, treatment, and ultimately prognosis.

Epidemiology Many physicians underestimate the prevalence of prostatitis. It is, in fact, a very common disorder. Prostatitis will affect approximately 50% of men at some point in their lives; in autopsy series, histologic evidence of inflammation is found in up to 44% of cases.3–6 In 1985, more men visited urologists for prostatitis than for prostate cancer or benign prostatic hypertrophy (BPH).2 The current estimate of its incidence is 5 to 8%; for men < 50 years of age, it is the most common urologic problem.2 For men older than 50 years of age, it is third in frequency.2 Prostatitis syndromes account for one-quarter of office visits to the average urologist.3 In a recent poll of primary care physicians and urologists, a significant over-estimation of the prevalence of bacterial forms of the disease was demonstrated,7 with seventy-five percent of primary care physicians and 50% of urologists believing that bacterial prostatitis represents 70 to 90% of cases.7 The truth is that

Bacterial Prostatitis Microbiologic etiologies are responsible for approximately 5 to 10% of cases of prostatitis. The term “bacterial prostatitis” refers to causative organisms cultured by routine methods. Currently, this definition is restricted to typical urinary pathogens, such as gram-negative bacilli, not fastidious organisms that would require advanced techniques, such as antibody immunofluorescence or polymerase chain reaction, to detect. The same bacteria infect the bladder and the prostate. Escherichia coli is the 643


most common, followed by Klebsiella, Proteus, Serratia, Pseudomonas, and Enterobacter.3,5 The pathologic role of gram-positive species is controversial since most grampositive isolates probably represent urethral flora. However, Enterococcus faecalis, Staphylococcus aureus, and Staphylococcus saprophyticus are all less common but definite pathogens.9 Diphtheroids, coagulase-negative Staphylococcus, and Streptococcus species are not believed to be pathogenic at this time.9 Chlamydia and Ureaplasma have been linked to prostatitis and are the subjects of ongoing investigations. Recent data, however, suggest these organisms are not responsible.10,11

counts are normal. Prostatic fluid usually contains white blood cells and cultures localize uropathogens to the prostate. The outlook for complete recovery of patients with chronic bacterial prostatitis is good—with proper antimicrobials of appropriate duration, approximately 70% of patients may experience complete recovery.3,14

Category I: Acute Bacterial Prostatitis Acute prostatitis is the most dramatic and life threatening form of the disease. Acute prostatitis is easily diagnosed and readily distinguishable from the other forms of prostatitis on clinical grounds. Patients present acutely to a health care provider with abrupt onset of chills, fever, and associated irritative and/or obstructive voiding difficulty. Common additional complaints include perineal pain, especially when defecating, arthralgias, and myalgias. Patients will sometimes experience a prodrome of constitutional symptoms. Patients often appear toxic or septic and are generally febrile. The prostate is warm, swollen, and extremely tender. Prostate massage is absolutely contraindicated, as this maneuver can promote bacteremia.3 On laboratory analyses, a leukocytosis is common and urinalysis is suggestive of infection. Urine and blood cultures are usually positive for gram-negative organisms such as Escherichia coli.3 Acute bacterial prostatitis demands prompt evaluation and initiation of treatment to prevent serious morbidity or mortality. If adequately treated, however, most patients recover fully and have no long-term disability.

Category IIIA: nonbacterial prostatitis. Nonbacterial prostatitis (NBP) is the most common form of the prostatitis syndromes, accounting for approximately 60% of cases. It is the most common reason for patient visits to the urologist’s office and is eight times more common than either of the bacterial prostatidities.3 Despite continuous investigation, its etiology remains elusive. Several investigators have proposed that fastidious organisms such as Ureaplasma urealyticum and Chlamydia trachomatis, among others, are responsible but this has yet to be demonstrated.3,11 Prostate examination and microscopic analyses of urine and prostatic fluid from NBP and CBP patients are indistinguishable but urine and prostatic fluid cultures in NBP are continuously negative, characterizing the disorder. Like CBP, nonbacterial prostatitis has a relatively low morbidity; unlike CBP, it carries with it a high likelihood of inadequate treatment and longterm disability.

Category II: Chronic Bacterial Prostatitis Chronic bacterial prostatitis (CBP) appears to be the least common variety of prostatitis.1 While it has lower associated mortality and morbidity than does acute bacterial prostatitis, it is more difficult to adequately treat. The distinguishing characteristic of CBP is recurrent bouts of bacteriuria or symptomatic cystitis with the same bacterial pathogen. In fact, the most common cause of recurrent urinary tract infection in men is chronic bacterial prostatitis.3 Ten percent of men are infected with more than one organism.1,9 Some patients will have histories of antecedent acute prostatitis but most will not. Between active infections, the bacteria survive dormant in prostatic ducts and calculi.3,12,13 The physical examination is much different from that for acute bacterial prostatitis. The patient will not appear septic or even in severe discomfort, and the general medical examination should be normal in the absence of other medical conditions. Digital rectal examination (DRE) will usually reveal a normal or slightly indurated prostate. Blood chemistry and cell

Category III Category III prostatitis accounts for approximately 90% of all cases of prostatitis and is a very challenging disorder to treat. With current treatment modalities, patients may expect dismal cure rates and high relapse rates.

Category IIIB: prostatodynia. Prostatodynia (PD) may be said to occupy one end of the prostatitis continuum, opposite NBP. It is a chronic pelvic pain syndrome and an all-too-common disorder, accounting for approximately 30% of prostatitis syndrome cases. History and physical examination are essentially identical as in men with NBP, except that some of these men complain of extreme pain on DRE, despite normal findings. These men are often young to early middle age and their symptoms are localized to the perineum, prostate, scrotum, penis, rectum, anus, groin, and lower back.3 Pain is the most common complaint, followed by frequency and decreased stream.15 Pain is the sole complaint of a significant percentage of patients.7,15 There is often a marked psychiatric component to the disease. Some investigators have even referred to it as stress prostatitis.16 Forty percent of general physicians and 65% of urologists described a psychosomatic component to their NBP/PD patients.17 Sixty percent of PD patients are clinically depressed and suffer from anxiety disorder, and 50% exhibit clinical hypochondriasis and sexual dysfunction.17 These psychiatric diagnoses persist over time in roughly 40% of cases.17,18 Whether psychiatric issues are a cause or a

Prostatitis: Factors Influencing Prognosis / 645

function of the disease is not known. Urodynamic evaluation of some of these men has revealed low flow rates with elevated urethral closing pressure distal to the bladder neck and incomplete funneling of the bladder neck on videofluoroscopy.19–21 The implications of these findings are unclear but they may suggest a form of pelvic floor myalgia.22 The sine qua non of diagnosis rests in normal microscopic urine and prostatic fluid analyses with negative cultures. Treatments for the disorder have been nonspecific and often anecdotal. The prognosis for these patients often involves long-term disability.

Localization The localization method is the most accurate and efficient method of distinguishing between urethral, bladder, and prostate sources of inflammation or infection. The localization technique was initially described by Meares and Stamey et al. in 1968 and has become the standard for a thorough and methodic evaluation of prostatitis syndromes.8 Surprisingly, few primary care physicians and only about 50% of urologists perform localization evaluations on patients.7 In fact, one study revealed that only 33 to 45% of urologists even cultured urine or prostatic fluid as part of their evaluation.7 Physicians cite several reasons for not performing this basic and important diagnostic measure: it is cumbersome, perceived to have a low yield, and perceived to possess high false negative and false positive rates with low predictive value.2 Such a low percentage of physicians utilizing these basic diagnostic measures may impact adversely on treatment outcomes. Localization culture techniques have been described in detail elsewhere and will be briefly described here. The procedure involves analyzing aliquots of urine and prostatic fluid microscopically. The VB1, VB2, EPS, and VB3 specimens refer to the initial 10 mL voided, the midstream urine, the expressed prostatic secretions, and the first 10 mL of urine after a prostate massage, respectively. The VB1 represents the urethral specimen, the VB2 the bladder specimen, and the EPS and VB3 the prostatic specimens. The urethra may contain gram-positive bacteria in 95% of men and gram-negative bacteria in 5%.1,11 Since the VB2, EPS, and VB3 also must traverse the urethra, the possibility of contaminating theses specimens exists. The EPS is especially susceptible to contamination by urethral flora.1 Expressed prostatic secretions in most normal men will have low numbers of white blood cells (WBCs), that is, < 4.22. The exact upper limit of normal for EPS WBCs has been somewhat controversial but 90 to 95% will have < 10 WBC per high-power field (HPF).23 Certain subsets of normal men will have somewhat elevated levels (10 to 20 WBC per HPF), including men with BPH or infertility. Ten percent of volunteers without any genitourinary complaints will have > 10 WBC per HPF.23 Lipid-laden macrophages in EPS are relatively sensitive indicators of prostatic inflammation.1,23

Algorithm of Diagnosis When patients are first seen in the office, they should undergo an initial localization routine. One cost-effective, quick approach entails obtaining a VB1, VB2, and EPS on the first visit for analysis. If VB1 or VB2 shows inflammation or bacteriuria, patients should be cultured and treated empirically with an antimicrobial that achieves good urinary levels without penetrating the prostate and thus masking any prostatic microbiology. Nitrofurantoin, penicillin, and tetracycline all achieve adequate urinary bactericidal levels without entering the prostate. Fluoroquinolones, trimethoprim (TMP), or TMP/sulfamethoxazole inhibit prostatic growth as well as urinary growth and should be avoided during the initial diagnostic evaluation. Treating the patients in this fashion prior to their second visit will amplify any difference between VB1 and EPS. If VB1 or VB2 are negative on their first visit, quantitative culture of VB1, VB2, and EPS should be obtained; a negative VB1 and VB2 and positive EPS or >10-fold difference in VB1 and EPS bacterial counts indicate prostatic inflammation. Seminal fluid analysis has been used in the past but has since been abandoned due to its lack of sensitivity or specificity. It is not advocated at this time in the evaluation of prostatitis or lower urinary tract symptoms. Radiographic Imaging Unfortunately, there are currently no reliable radiographic modalities available to distinguish between the various forms of prostatitis. There are, however, techniques that can identify prostate pathology that may contribute to prostatitis. Approximately 75% of men older than 20 years of age and 100% older than 30 years of age will have prostatic stones.24 It is felt that these stones harbor the infectious agents from antimicrobials and the prostate’s own natural defense mechanisms.12 Plain radiography will detect stones in approximately 14% of patients, and ultrasound will detect them in 70% of patients.12,24 Except for imaging stones, ultrasound contributes little to the evaluation of the patient with prostatitis, despite initial reports of success.24,25 Similarly, computed tomography (CT) cannot distinguish between the various forms of prostatitis, although it is sensitive, like ultrasound, in detecting prostatic abscess. Magnetic resonance imaging is currently under investigation for its utility in men with prostatitis but anecdotal reports suggest it is no more effective than CT scan. Immunologic Molecular Diagnosis The search for etiologies of NBP has led researchers to develop antibodies to common bacterial and fastidious organisms such as Ureaplasma and Chlamydia. The basis of this rests in findings of increased prostate IgA and IgG levels in men with both chronic bacterial prostatitis and nonbacterial prostatitis compared to men without genitourinary (GU) complaints.1,9,11 Moreover, men ade-


quately treated for their CBP respond with decreased IgA and IgG levels compared to untreated or inadequately treated men.1 Shortliffe et al. examined prostatic fluid with antibodies against common epitopes of Ureaplasma and Chlamydia trachomatis as well as fastidious gram-negative organisms.11 No difference in antibody levels was found between men with and without prostate symptomatology. Investigations are currently underway using polymerase chain reaction (PCR) technology on prostate tissue to search for messenger ribonucleic acid (MRNA) specific to various organisms. Lactate Dehydrogenase Lactate dehydrogenase (LDH) is an enzyme responsible for reversibly catalyzing the conversion of pyruvate to lactate. It has five isotypes and it is felt that epithelial damage results in an increased ratio of the various isotypes. Isotype 5 resides in the prostate. Schaeffer et al. demonstrated an increased LDH and LDH5/LDH1 ratio in men with prostatitis compared to men without a GU history.23 LDH was not specific for CBP versus NBP. Prostate-Specific Antigen Prostate-specific antigen (PSA) levels have been extensively evaluated in prostatitis, mostly in an effort to distinguish prostate cancer from benign disorders. Whether or not prostatitis causes changes in PSA levels is controversial. Several investigators have noted a decrease in PSA levels in bacterial prostatitis compared to NBP or prostatodynia. They hypothesized a decrease in PSA production to account for the finding.11 In general, however, it does not appear that PSA can reliably differentiate between the various forms of prostatitis. Tissue Microbiologic Culture Attempts have been made to obtain prostate tissue for microbial culture. This has met with limited success for several reasons. First, most biopsies are done transrectally or transurethrally and promote contamination of specimens. Cultures performed on radical prostatectomy specimens may also suffer contamination since these prostates would all have been biopsied prior to surgery to establish the diagnosis of cancer. Second, chronic bacterial prostatitis represents focal infections. As such, a high false negative culture rate is to be expected. In summary, prostate biopsy is seldom indicated in the diagnosis of prostatitis.1,5,11,26

Pathogenesis and Pharmacodynamics There appear to be three major mechanisms of infection in the prostate. Reflux of urine into intraprostatic ducts is the most common proposed mechanism and is supported by indirect and direct evidence. The indirect evidence comes from the chemical composition of some prostatic stones removed from men treated for CBP. While prostate stones are typically composed of tricalcium

phosphate, the composition of some stones is similar to urinary stones, namely calcium oxalate, which suggests urinary reflux into the prostate.12,27 Persson and Ronquist demonstrated elevated prostate fluid creatinine and urate levels, adding more indirect evidence for the role of sterile reflux in pathogenesis.28 Reflux-induced prostatitis also has been demonstrated in animal models.29,30 Another mechanism of infection includes prior urinary instrumentation, although the majority of afflicted men have no such history.1 Finally, typical prostate stones are frequently felt to harbor pathogens within their matrix, out of reach of antimicrobials.26 For pathogens to cause infection once inside the prostate, they must elude the prostate’s own natural defenses. Bacteria do this by forming microcolonies enclosed in a protective glycocalyx envelope. They are inaccessible to antimicrobials inside this envelope.26 In addition, zinc levels—a major component of prostatic antibacterial factor—are low in men with CBP.1 Prostatic antibacterial factor is postulated to inhibit viral growth as well as growth of gram-negative rods, yeast, and fastidious organisms.1 Other host factors include an undefined role of immunoglobulins, interleukins, and the influence of androgen.1,9,11,29–31 There is recent evidence that autoimmune phenomena may play a role in chronic pelvic pain syndrome.32

Therapy and Prognosis Antimicrobial Therapy For an antimicrobial agent to be effective against prostatic infection, several properties of the agent must be met. First, the drug must achieve adequate bactericidal levels in both urine and prostate. Most commonly used agents today attain 50- to 100-fold greater urinary concentrations than serum concentration.1 Second, to enter the prostate under noninflammatory conditions, the agent should be lipid soluble and exist in the nonionized form. Once inside the prostate, the ideal agent should exist as a basic ion to trap itself within the prostate.1,13,26,30 The fluoroquinolones meet most of the above criteria and are the first agents of choice in treating bacterial prostatitis. Some have questioned whether an inflamed prostate represents a similar environment to the uninflamed prostate with respect to pharmacodynamics. To address this question, a group of investigators induced prostatitis in rats and then treated the animals with norfloxacin, followed by assays for intraprostatic norfloxacin levels.26 The authors found no difference in levels or efficacy of the antimicrobial and concluded that the pathophysiology of the inflamed prostate does not adversely affect pharmacodynamics. They concluded that the protective bacterial glycocalyx, rather than altered pharmacodynamics, was probably responsible for most antimicrobial treatment failures. In addition, there is ample evidence that the inflamed prostate is more penetrable by antimicrobials


than the uninflamed prostate.1,9,26 This explains why certain agents such as ampicillin and gentamicin are excellent choices for acute prostatitis but not for chronic bacterial prostatitis. Finally, the agent should have adequate activity against the offending pathogen. Most susceptibility panels reported in hospital laboratories note minimal inhibitory concentrations (MIC) for serum drug levels. As previously stated, most agents achieve a much higher urinary than serum concentration and should be interpreted according to urinary concentration. Acute Bacterial Prostatitis Patients with acute prostatitis are usually systemically ill. Treatment should be instituted rapidly after diagnosis. For the medically stable patient, an oral fluoroquinolone should be used. This class of antimicrobials achieves good penetration into the inflamed prostate and covers most urinary pathogens. Response to treatment should be rapid and sustained; otherwise, complications such as prostatic abscess should be considered. The more severely ill patient, or the patient not tolerating an oral regimen, should be admitted to the hospital for intravenous antimicrobials and hydration. Ampicillin and gentamicin or vancomycin with gentamicin are excellent choices. These agents achieve excellent serum, urinary, and prostate levels and are effective against the vast majority of urinary pathogens. Fluoroquinolones are again a good choice but the intravenous forms offer little advantage to the oral forms in terms of bioavailability. In addition to antimicrobials, patients suffering acute prostatitis should receive appropriate pain relief. Additional reports suggest that sitz baths, nonsteroidal anti-inflammatory drugs, and stool softeners may provide symptomatic relief.3 In the patient with urinary retention, bladder drainage with a suprapubic cystostomy may be preferable to using a urethral catheter to avoid the risk of bacteremia. Chronic Bacterial Prostatitis Chronic bacterial prostatis does not carry the mortality or morbidity of acute prostatitis. It is considered an outpatient treatment. With current antimicrobials, most patients will respond to therapy, and cure rates of 50 to 90% can be expected.14,33 The antimicrobial selected must be efficacious against the pathogen isolated in EPS and/or VB3 cultures. There have been a multitude of antimicrobials used in the past. Currently, fluoroquinolones are the preferred agents. Their broad spectrum against the majority of urinary pathogens, high lipid solubility, and low protein binding make them ideally suited for prostate penetration and antibacterial activity. Remarkably, only 25% of physicians use fluoroquinolones to treat prostatitis.7 The duration of therapy may be directly related to cure rates. Norfloxacin for 28 to 42 days cured 92% of CBP patients, compared to 75% of patients treated with the same drug at 14 days.34 Results

with the other fluoroquinolones are similar and are superior to all other antimicrobial classes, including intraprostatic antimicrobial injection.14,34,35 In comparison, TMP/sulfamethoxazole has been associated with maximal cure rates of 40 to 67% after 2 to 4 weeks of treatment.14 Only 53% of urologists and 37% of primary care physicians treat patients with therapy lasting longer than 4 weeks.7 After selecting an appropriate agent and duration of therapy, effectiveness should be monitored with repeat localization cultures after approximately 1 month. Ultimately, proof of success rests with an asymptomatic patient with no recurrent episodes of prostatitis. Suppressive Therapy Several options exist for the significant group of individuals who fail antimicrobial therapy. The goal of suppressive therapy is to decrease the number of symptomatic urinary infections by preventing bacteriuria in spite of persistent infection in the prostate. Trimethoprim, TMP/sulfamethoxazole, tetracycline, and nitrofurantoin are excellent choices for suppressive antimicrobial therapy. Each agent achieves excellent urinary levels, is inexpensive, and is well tolerated. In addition, these agents tend not to alter fecal flora, thus minimizing gastrointestinal problems associated with antimicrobials. The ultimate choice of antimicrobial, however, is governed by bacteria identification and antibiotic sensitivity panels from EPS and VB3. Surgical Therapy Transurethral resection of the prostate (TURP) has been used for men who are refractory to more conventional therapy. Standard TURP resects only the transition zone, yet anatomic analyses have shown that the majority of infectious foci are peripheral.5,12,30 Therefore, a radical TURP with a much more extensive peripheral and distal resection is required. Improvements in cure have at best been moderate but at the cost of much higher rates of incontinence. Cure rates with this modality have approached 40 to 50%.9,36 Radical prostatectomy, a therapy that would probably result in cure, is not indicated for treatment of this disease except in extremely limited circumstances. Nonbacterial Prostatitis and Prostatodynia Predictably, effective treatment for NBP and prostatodynia does not exist. While it is reasonable to try a course of antimicrobial therapy with activity against usual uropathogens as well as C. trachomatis and Ureaplasma, chronic antimicrobial therapy is not justified at this time. While some patients report benefit from sitz baths, prostate massage, anticholinergic agents, anxiolytics, anti-inflammatory agents, and zinc, no large scale, randomized controlled studies demonstrating their utility exist. Anecdotal reports suggest disappointing therapeutic benefit. Some small, nonrandomized investigations of alpha-blocker therapy suggest moderate improvement in


symptoms in as many as 50% of patients.20,37–39 No large, randomized controlled investigations for alpha-blockers exists. However, a trial of alpha-blocker therapy is probably warranted. Some recent studies have shown a beneficial effect of transurethral microwave thermotherapy, demonstrating improvement in 50 to 70% of patients.40,41 Long-term follow-up data are lacking and this procedure is considered investigational at this time. Since NBP and prostatodynia have such pervasive psychiatric components, perhaps the best opportunity for long-term impact on prognosis rests with psychotherapy, psychopharmacy, and biofeedback. Indeed, several authors have shown a benefit of psychotherapy and biofeedback training.17,19 Berguis et al. recommended antidepressant medication to treat men who had prostatodynia combined with a major depressive component.17 Despite all available treatment options, however, the prognosis for these patients is poor. Several investigators recently performed sickness impact profile assessments on NBP and PD patients.42 They revealed a level of disability in these unfortunate patients tantamount to that of patients suffering myocardial infarction, angina pectoris, or Crohn’s disease. An improved outlook for these patients may be gained by a multidisciplinary approach, eliciting advice and service from mental health providers.

Conclusion Prostatitis syndromes are a common occurrence for both patients and physicians and represent a diagnostic and therapeutic challenge to positively influence the lives of millions of people. While prognosis for patients with bacterial prostatitis is excellent with modern diagnostic methods and antimicrobial agents, these patients represent the minority of those with the syndrome. Unfortunately, the majority of patients suffer from nonbacterial prostatitis and prostatodynia. It is in these patients that improvements in diagnostic and therapeutic approaches will have the greatest impact on prognosis. The therapies discussed all play a role; if utilized in a rational, methodic, and analytic fashion, patients will likely benefit. Current research on prostatitis is exciting and hopefully the outlook for all patients suffering from prostatitis will improve.

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echo patterns in gray scale prostatic echocardiography. J Urol 1980;124:216. Nickel JC, Downey J, Clark J, et al. Antibiotic pharmacokinetics in the inflamed prostate. J Urol 1995;153:527–9. Sutor DJ, Wooley SE. The chrystollographic composition of prostate stones. Br J Urol 1974;46:533. Persson B, Ronquist G. Evidence for a mechanistic association between nonbacterial prostatitis and levels of urate and creatinine in expressed prostatic secretion. J Urol 1996;155:958–60. Jantos C, Altmannsberger M, Weidner W, Schiefer HG. Acute and chronic bacterial prostatitis due to E. coli: description of an animal model. Urol Res 1990;18: 207–11. Nickel JC, Olson E, Barabas A, et al. Pathogenesis of chronic bacterial prostatitis in an animal model. Br J Urol 1990;66:47. Naslund MJ, Stranberg JD, Coffey DS. The role of androgens and estrogens in the pathogenesis of experimental nonbacterial prostatitis. J Urol 1988;140(5): 1049–53. Alexander RB, Brady F, Donniah S. Autoimmune prostatitis: evidence of T cell reactivity with normal prostatic proteins. Urology 1997;50(6):893–9. Schaeffer AJ, Darras FS. The efficacy of norfloxacin in the treatment of chronic bacterial prostatitis refractory to trimethoprim-sulfamethoxazole and/or carbenicillin. J Urol 1990;144(3):690–3. Baert L, Leonard A. Chronic bacterial prostatitis: 10 years

35.

36. 37.

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of experience with local antibiotics. J Urol 1988;140: 755–7. Yamamoto M, Hibi H, Satoshi K, Miyaki K. Chronic bacterial prostatitis treated with intraprostatic injection of antibiotics. Scand J Urol Nephrol 1996;30:199–202. Smart CJ, Jenkins JD. The role of transurethral resection in chronic prostatitis. Br J Urol 1978;54:330. Barbalias GA, Nikifordis G, Liatsikos EN. Alpha-blockers for the treatment of chronic prostatitis in combination with antibiotics. J Urol 1998;159(3):883–7. Drabick JJ, Gambel JM, Mackey JF. Prostatodynia in United Nations peace keeping forces in Haiti. Mil Med 1997;162(6):380–3. Neal DE Jr, Moon TD. Use of terazosin in prostatodynia and validation of a symptom score questionnaire. Urology 1994;43(4):460–5. Baert L, Ameye F, Petrovich Z. Microwave hyperthermia for chronic prostatitis and prostatodynia. In: Weider W, Madsen PO, Scheifer HG, editors. Prostatitis: etiopathology, diagnosis, and therapy. Berlin: SpringerVerlag; 1994. Nickel JC, Sorensen R. Transurethral microwave thermotherapy for nonbacterial prostatitis: a randomized double-blind sham controlled study using new prostatitis specific assessment questionnaires. J Urol 1996; 155:1950–5. Wenninger K, Heiman JR, Rothman I, et al. Sickness impact of chronic nonbacterial prostatitis and its correlates. J Urol 1996;155(3):965–8.

CHAPTER 71

PROSTATITIS: ADVANCED THERAPY DURWOOD E. NEAL JR, MD Prostatitis is one of the most perplexing disease entities with which the practicing urologist must contend. Also, the treatment of this disease is the least gratifying in that the patients often are labeled as “crazy” and have a poor response. In many ways, there are some significant similarities with interstitial cystitis (IC), and perhaps some of the patients with complaints of prostatitis actually have IC, as has been suggested.1 Indeed, many of the symptoms and physical findings are similar and are outlined in Table 71–1. As in the case of IC, prostatitis has also been difficult to study, being a disease that lacked a formal and specific definition. Therefore, the National Institute for Diabetes, Digestive, and Kidney Diseases (NIDDKD) convened a consensus group to define prostatitis, expressly for the purpose of describing the different prostatitis syndromes in such a way that they could be investigated, and ultimately treated, in a more efficacious fashion. These are listed in Table 71–2. These new definitions, while not being radically different from the old criteria, serve the purpose of enabling urologists and primary care physicians to discuss and treat this disease in an organized way. Most of the controversy, with respect to treatment, centers on category III prostatitis. Category I and II are of bacterial origin, and the therapy is largely antimicrobial. Some of the ancillary treatments are not as widely accepted but most of the different regimens used for category III will also have efficacy in category II with respect to relieving the pain symptoms. As several authors have reported that category III constitutes the majority of patients suffering from this disorder,2,3 this chapter will focus on this group.

as well. Carbenicillin indanyl sodium (Geocillin-Roche) was probably the first antibiotic to have a specific indication for the treatment of prostatitis. It has an excellent spectrum of activity but it is cumbersome for patients as it is dosed four times a day. The tetracyclines as a group have an appropriately broad spectrum and also have the ability to penetrate the prostate well.9,10 More specifically, the derivatives doxycycline and minocycline have been shown to be efficacious and also have the added benefit of covering the more fastidious organisms such as Mycoplasma, Ureaplasma, and Chlamydia.6,9,11 It is not clear as to whether these organisms have a role in the etiology of category IIIA prostatitis as ample opinion exists for either side of the argument. They are, however, pathogenic for the urinary tract and may cause infections that are confused with category III prostatitis. The disadvantage with this class is that they are bacteriostatic and therefore rely, at least in part, on host defenses for bacterial clearance. Since the advent of the fluoroquinolones, the treatment of prostatitis of a known bacterial etiology has been simplified. These drugs freely penetrate into the prostate and may be found in the glandular tissue as well as the prostatic secretions.12–14 Their dissociation constant (pKa) and lipid solubility facilitates this bioavailability but may also contribute to the neurologic side effects. This class of antibiotic is becoming the medication used most commonly either in the period after the initial physician visit but prior to receipt of the culture results or as empiric therapy. If the culture is negative, most clinicians still continue to treat for their prescribed time interval. Perhaps the most commonly employed agent worldwide for the treatment of “chronic”

Antibiotics Most urologists will treat prostatitis empirically with a course of antibiotics prior to receiving the results of any bacteriologic studies that are performed. Furthermore, most would continue the antibiotic for a full course (2 to 12 weeks), irrespective of the culture results. The only change, typically, would be considered if the antibiogram indicated that a particular organism was resistant to the antibiotic employed. The time course for treatment is highly variable. Most authors and research indicate that a period of 30 days is adequate4–6 but literature exists to support as long as 3 to 6 months of therapy.7,8 A number of antibiotics have been touted as the most appropriate for the treatment of classic chronic bacterial prostatitis (CBP) or category II; these drugs should be used in category IIIA

TABLE 71–1. Common Symptoms in Prostatitis and Interstitial Cystitis 1. Voiding dysfunction • Frequency • Urgency • Dysuria • Pain 2. Pelvic pain • Ill-defined • Difficult to locate • Often associated with bladder filling 3. Dyspareunia 4. Associated inflammatory findings 5. Paucity of characteristic physical examination findings 6. Emotional overlay

650

Prostatitis: Advanced Therapy / 651

prostatitis is the sulfamethoxazole-trimethoprim combination. There are numerous references to support the theoretic reasons that these agents should be efficacious in these patients.7,15,16 Most of the work in this area has used animal models, which may not be completely applicable to humans. On the other hand, many years of employing this combination in patients has lent credence to its efficacy.16 There is some concern regarding delivery of certain antimicrobials to the prostate gland itself. Since bacteria may potentially be harbored in prostatic stones,4 prostatic ducts that are obstructed with inspissated secretions,17 or in their own protective glycoprotein matrix,18 it may be difficult to consolidate an agent in the prostate at a concentration sufficient to penetrate these adaptive defenses and eradicate the bacteria. There does not appear to be an appreciable difference between intravenous or oral routes of administration in the levels achieved, especially with the quinolones, which can dramatically affect the cost of therapy.19,20 Common prostatitis antibiotics are listed in Table 71–3. Some authors have administered the antibiotics directly into the prostate.21–23 The secretory dysfunction of infected prostates has popularized this method. The results are variable for this method but there is potential for development of granulomatous prostatitis, using this route. The theoretic advantages appear to be superceded by the complexity of administration and the cost, not to mention potential adverse events. The evidence for bacteria as an etiologic agent in category IIIA prostatitis is slowly accumulating, which, in turn, lends credence to empiric antibiotic therapy.4–6,15,24,25 Since it was recognized that bacteria may construct a glycoprotein matrix in which they grow at a metabolically slowed rate while being relatively protected from the host defense mechanisms and antimicrobial agents,26,27 interest has increased in searching for bacteria that may be difficult to detect with conventional methodologies. This state may hamper the microbiologists’ efforts to isolate organisms using standard culture techniques. This holds true for the cell-wall-deficient/defective organisms like Mycoplasma, Chlamydia, and Ureaplasma, as well as L-forms. Where extended culture techniques are employed, unusual organisms have been isolated; the isolates are bacteria that so far had been assumed to be commensals and not actually involved in the infection itself.28 It remains to be seen whether these are the etiologic agents or not but this may explain why patients who have bacteriologically negative prostates may respond to antimicrobial therapy. The use of more sophisticated molecular biologic techniques has shown the presence of bacterial genetic material in many of these patients.29,30 Several problems exist with the use of molecular biologic techniques in the establishment of a bacterial diagnosis. First, they are so sensitive that very small amounts of contaminating bacteria may significantly affect the results. Second, the genes used occasionally make it daunting to identify the specific organism,

TABLE 71–2. Categorization of Prostatitis Category I – Category II – Category IIIA –

Category IIIB

Category IV

Acute bacterial prostatitis Chronic bacterial prostatitis Pelvic or prostatic pain, associated with inflammatory changes in prostatic secretions but absence of a microbial etiologic agent – Similar to IIIA but largely comprising pelvic floor spasm and absence of inflammatory changes in the prostatic secretions – Prostatic inflammation discovered by histopathologic examination of the prostate that is otherwise asymptomatic for other causes (biopsy, prostatectomy)

and furthermore, information regarding sensitivity to antibiotics is little more than an empiric guess. The 16s ribosomal ribonucleic acid (rRNA) subunit has been found in a surprisingly large number of cases as has the m-Tet gene, which is a genetic sequence that is found in a modest number of uropathogens.29,30 In one study, bacteria were actually visualized in the prostate glands, using electron microscopy.31 The mere presence of bacterial genetic material (RNA or deoxyribonucleic acid [DNA]) or even organisms themselves does not prove unequivocally that the etiologic agents have been identified. It does, though, give a plausible explanation as to why a percentage of these patients respond to antibiotics and should suggest that further studies on a bacteriologic etiology for category III prostatitis should be conducted. Clinical Trials Few studies exist with respect to the use of antibiotics in category IIIA or chronic abacterial prostatitis. One of the problems is that this classification has only been adopted into use a short time ago, and its acceptance is not complete. Second, the degree to which the diagnosis is made differs from study to study. Last, patient accrual is difficult, owing to the fact that the great majority of patients, who come to the urologist with complaints similar to prostatitis, have usually already been treated with not one but several antibiotics, usually for a protracted time period. Most of these patients are actually seen by their primary care physician at the onset and are referred only after antibiotic failure. In attempting therapy with empiric antibiotics, prior to knowing whether one is treating category II or category IIIA, it would seem prudent to use an agent that is best suited for penetration into the prostatic parenchyma. In general, the agent must be highly lipid soluble; it must

TABLE 71–3. Antibiotics in the Treatment of Prostatitis Sulfamethoxazole-trimethoprim: most widely used Carbenicillin indanyl sodium: first approved for prostatitis Doxycycline and minocycline: broad spectrum, bacteriostatic Fluoroquinolones: broad spectrum, and excellent prostatic penetration


have low protein binding, and have a high pKa, specifically on the order of 8.6.32–34 The spectrum of activity should be sufficiently broad while retaining a high degree of activity against gram-negative organisms as well as the known gram-positive uropathogens (group D streptococci, certain coagulase negative staphylococci, and others). No single antibiotic fits this description perfectly. As previously mentioned, the most widely used agent is the combination sulfamethoxazole-trimethoprim (SMX-TMP). It is inexpensive, has fair prostatic levels, and the spectrum of activity is excellent for the pathogens most commonly found.16 There have even been a few studies using SMX-TMP in documented bacterial prostatitis with good results. Some questions, however, have arisen as to antibiotic levels in the human prostate.15,35,36 The tetracycline group, specifically doxycycline and minocycline, has shown promise in the treatment of category II prostatitis.9–11 These drugs are more lipid soluble than tetracycline itself, and prostatic parenchymal levels are established.11 These drugs have been used extensively in the fertility literature as empiric treatment of leukocytospermia.35,37,38 This condition, in fact, possibly represents category IV prostatitis or perhaps category IIIA. It has been shown, in uncontrolled studies, to reduce leukocytes in both the semen and prostatic fluid. It does have the significant adverse effect of gonadotoxicity, which is, at least in part, reversible.39 Macrolide antibiotics such as azithromycin and clarithromycin are well concentrated in the prostate gland and are excreted slowly, enabling excellent levels of drug to be present for an extended period of time.40,41 The spectrum, however, does not include gramnegative organisms to a significant degree.37,38,42 The 5-fluoroquinolones, such as ciprofloxacin, norfloxacin, and ofloxacin, are perhaps the agents of choice in category II prostatitis. This has led to clinicians using this drug as empiric therapy for category IIIA disease. These drugs reach abundant levels in the prostate and have a broad spectrum of activity.14 There are potential problems with theophylline toxicity, photosensitivity, and neurologic side effects as well as fertility concerns with ofloxacin.39 Lastly, as this group is more expensive than most other agents when therapy may take several weeks to complete, the cost may be substantial.

Endocrine Therapy Hormonal therapy for prostatitis has recently undergone a resurgence of interest. It was used many years ago in the treatment of abacterial prostatitis, especially using estrogens.43,44 The sex steroid, 17-beta estradiol, has been shown in certain species of rats to cause abacterial prostatitis. Wistar rats are more susceptible than SpragueDawley, indicating a genetic predisposition within the genus. This inflammation is known to occur spontaneously in the aging rat and has even been reported to be an autoimmune phenomenon.45 Furthermore, it appears

that prolactin plays a role in the induction and propagation of this inflammatory reaction. The possible autoimmune nature of this entity was also studied in humans, and prostatic plasma proteins are implicated as the antigen.46 A few reports exist in the literature stating that estrogen reduced the symptoms of abacterial prostatitis;43,44 however, side effects such as vasomotor instability, painful gynecomastia, and erectile dysfunction limit the usefulness. The increased incidence of cardiovascular side effects is obviated by the fact that most therapeutic interventions for prostatitis are of short duration. Most recently, finasteride (Proscar, MSD) has been suggested in the treatment of category IIIA prostatitis. It has shown efficacy in limited studies.47 Because of its limited adverse events, this would be a logical alternative to the use of estrogen. As yet, no controlled studies on hormones in prostatitis exist but the preponderance of clinical reports support the initiation of a placebo-controlled trial. Since it is not yet widely used in this condition, patient accrual should not be a problem. The efficacy may be attributed to size reduction, the reported diminution of prostatic blood flow, or other mechanisms. Antiestrogens have not shown efficacy in prostatitis, and one report actually implicates clomiphene citrate in the induction of prostatic inflammation.48

Alpha-Blockade Therapy Several authors have suggested that the use of alphablockade therapy benefits patients with all forms of prostatitis49–53 as well as patients with benign prostatic hypertrophy (BPH).54–57 There has been use of nonselective agents such as phenoxybenzamine55 as well as the more selective, long-acting alpha-1 receptor antagonists50,53 such as prazosin, terazosin, and doxazosin. The theoretic reason that these agents would be beneficial is that there is an increase in the urethral resistance and tone in patients who have symptoms of prostatitis.52 The resultant increase in pressure causes turbulent urine flow. Since the prostatic urethra, bladder neck, and proximal urethra are richly innervated with alpha-receptors, and they, in turn, respond to alpha-blockade, it is reasonable to use these agents to lower the urethral resistance. The etiology of pain in this disease process is postulated to be not only prostatic or urethral spasm but also reflux of urinary products into the ejaculatory and prostatic ducts, thereby initiating a selfperpetuating inflammatory process. The turbulent flow of urine that results may also be contributory to the pain syndrome. The manifestations in a given patient may not be a diminished urinary flow rate or an elevated postvoid residual, as these findings imply some degree of decompensation, as seen in patients with BPH. Another potential method of action for drugs of this nature in this disease is to diminish afferent stimulation. The alpha-adrenergic blockade not only decreases the smooth muscle contraction but also decreases sensory input traveling in the same


neurons, thereby relieving symptoms. Additionally, since category IIIB (similar to prostatodynia) has been treated with alpha-blockade with some degree of success, there is precedent for this form of therapy.50 As there have been no completed studies that employed a randomized, placebocontrolled double-blind methodology, work remains to be completed. However, it does not appear that there is potential merit in their use. More recently, one group of researchers has used alpha-blockade in conjunction with antibiotics and showed that there was a positive response in both bacterial and nonbacterial prostatitis.53 Clearly, there is a dearth of good studies in the literature, not only for treatment but also for etiology. An instrument is needed to measure prostatitis symptoms and is under development at this time by an National Institutes of Health (NIH) committee.

Other Medications Many of the drugs that have been used in this disease have anti-inflammatory properties. Nonsteroidal antiinflammatory agents are some of the most common agents used anecdotally. These agents block prostaglandin synthesis and are able to reduce not only the inflammatory component but also the pain associated with prostatitis. Since pain is the primary manifestation of category IIIA prostatitis, these agents are highly likely to be efficacious.58,59 These medications also have a strong antispasmodic effect on smooth muscle.60,61 This would reduce the voiding pain and also presumably ameliorate the voiding dysfunction that is evident in this group of patients. These agents have been used extensively in the treatment of ureteral colic for the same reasons, and they have been shown to have this antispasmodic effect on the ureter.60,61 Another type of anti-inflammatory agent that has been used in abacterial prostatitis is the free-radical scavenger, allopurinol.62–64 It is the most widely used agent in this class. The mechanism of action involves the reduction of urate in the urine and prostatic secretions. The theory is predicated on the assumption that there is urine reflux into the prostatic ducts, where the urate creates a nonspecific inflammation. The pain is correlated with the amount of urate in the urine and, potentially, this could be relieved by urate reduction. There is controversy in the literature with respect to the efficacy of this treatment.62 The results are mixed across a population but in individual patients that are well selected, there appears to be a good response. Antihistamines may play a special role on the basis that there are many similarities between prostatitis and IC. These agents (hydroxyzine, in particular) have shown efficacy in the treatment of IC owing to their ability to stabilize most cell membranes.65,66 They also have sedative properties and may serve in an anxiolytic capacity as well as contribute anticholinergic effects, similar in their action are the tricyclic antidepressants. For those patients in whom there is a significant voiding dysfunction (specifi-

cally, obstruction), the anticholinergic effects coupled with the result of peripheral adrenergic stimulation might actually exacerbate the symptoms of voiding dysfunction and, therefore, pain. If depression is a significant part of this disease complex, other agents should probably be explored. A variety of other medications have been sought but none has been sufficiently studied to ascertain whether they may be beneficial. They include pentosan polysulfonic acid (Elmiron®),67 which is one agent mentioned in upcoming clinical trials. As yet, there is no information on this or other heparinoids of glycosaminoglycan surrogates. Numerous other medications have been suggested anecdotally. Capsaicin, or pepper extract, has been used effectively by the intravesical route in patients with neurogenic bladders to reduce sensory input. Its action is on the C-fibers that transmit afferent information and on substance P.68,69 They are involved in pain transmission and are affected by capsaicin. Pressures are reduced and there is less uninhibited contraction. There is anecdotal information on the use of this agent in IC but there are no long-term studies. Recently, attention has turned to so-called alternative therapies. One such touted for the treatment of BPH is phytotherapy, also referred to as “plant extracts.”70,71 These substances are classified by the Food and Drug Administration as food additives and as such are not well regulated as to their potency, bioavailability, or other quality control issues. The method of action has not been clearly elucidated and has variously been ascribed to an estrogen effect (some of the agents are phytoestrogen compounds), five alpha-reductase inhibitors, inhibition of testosterone binding, and antiinflammatory, and others. There is little consensus amid a plethora of hyperbole. There are, however, a few studies that suggest that they are beneficial in relieving the symptoms of “prostatism” and BPH.72–75 These studies are mostly from Europe, where there is prescription availability of “saw palmetto.” The magnitude of its use in the United States for BPH is currently unknown, and there is no information on its use in prostatitis although there is some interest. Several compounds are available in addition to saw palmetto, including Pygeum africanum, Echinaceae purpurea and a host of others. Since pain is a major component of prostatitis syndromes, interest is being generated in the long-term use of pain medications and pain-modulating agents. Some that are being considered are gabapentin, tizanidine, and others. These are typically used with methadone or other long-acting narcotics. The investigational drugs are listed in Table 71–4.

Prostatic Massage Urologists have used prostatic massage for many years in the management of prostatic congestion. It was thought that this relieved this condition and ameliorated symptoms. Little attention was given to this modality, and it was largely relegated to a historic role. More recently, interest

654 / Advanced Therapy of Prostate Disease TABLE 71–4. Investigation Agents 1. Nonsteroidal anti-inflammatory drugs • Nonspecific pain and inflammation modulators 2. Allopurinol • Free-radical scavenger • Urate reduction 3. Antihistamines • Anti-inflammatory • Sedating and anxiolytic 4. Tricyclic antidepressants • Helpful in coexisting depression • May exacerbate voiding dysfunction • Some anti-inflammatory properties 5. Heparinoids • Pentosan polysulfate sodium • Heparin and glycosaminoglycan substitutes 6. Capsaicin • Pain modulation via C-fibers 7. Phytotherapy • Popular food additives 8. Alpha-blockade therapy • Proven efficacy in some cases • Ameliorates voiding dysfunction 9. Pain modulating agents 10. Hormone manipulation • Finasteride • Others

in this area has surged, largely generated by the Internet and the mushrooming prostate/prostatitis websites. The most well-known institution for this treatment being Dr. Feliciano’s clinic in the Philippines. Dr. Feliciano indicates that repeated prostatic massage is indicated for the treatment of a wide array of prostate or pelvic floor symptoms.17 The theoretic effectiveness of this method is predicated on the presence of inspissated prostatic secretions, causing congested glands and ducts. This would further lead to a microenvironment that would be supportive of an infectious process. The regular prostatic massage, usually combined with an oral antibiotic, allows for manual drainage of the obstructed ducts, facilitating drainage of the infection that may be present. Relief of congestion would allow for greater penetration of antibiotics into the prostate and, possibly better antimicrobial activity. To date, there has been no other published report regarding the efficacy of this treatment. Until there is more information, claims of efficacy should be tempered. Furthermore, before widespread implementation of this method, more data analysis should be undertaken. A treatment modality that has been offered for urge incontinence and the frequency/urgency syndrome in females is biofeedback. Considering its relative efficacy in these women, attention has turned to patients with prostatitis. Whereas no controlled trials exist, there are scattered reports of efficacy. It is an attractive alternative, largely because this technology is available in many urologists’ offices already and can be easily used. As they are

as yet unproven there are concerns with respect to reimbursement with this and other treatments.

Surgery The oldest surgical therapy for chronic prostatitis is the so-called radical transurethral resection of the prostate (TURP).76,77 There are reports of “cures” using this therapy but little has been reported lately. In fact, in most urology circles, there are only a handful of practitioners who have ever actually performed one of these surgeries for this indication. It is suggested that the entire transition zone, including the usual prostatic calculi seen at the junction of the peripheral zone, be resected, to remove all infected tissue. Another way of accomplishing this would be radical prostatectomy. Few urologists would suggest this therapy but theoretically it would remove all involved tissue. Since most patients do not have a demonstrable infection, this therapy should see very little use. Other less invasive procedures have been touted as therapy for chronic prostatitis as well. The first, and best studied is transurethral microwave thermotherapy.78,79 This method uses heat energy transmitted to the prostate gland by a special catheter. There are at least two of these devices available in the United States, where it is currently approved for the treatment of BPH. Its efficacy in the latter condition has been documented to be satisfactory, if not as durable as TURP.80 For prostatitis, the advantages are less well studied. There are reports of improvement of pain in these patients but very few exist on following them up over a period. The mechanisms by which this method would work are not known. Theories exist about these reasons but most are speculation. Microwave energy is clearly bactericidal at temperatures greater than 42°C, which are easily achieved in this form of treatment. The afferent neurons supplying the prostate would be affected in a similar fashion as the rest of the gland. The tissues are heated to the point of protein and DNA degeneration. This effectively causes prostatic cell death in the treatment area. Involution and some sloughing of tissue occur and cause the potentially infected tissue to be removed. Whether symptom relief is achieved by the bacterial killing, the tissue removal, or differentiation remains obscure.81 More research in this area will be necessary before these issues are resolved.

Conclusion The treatment of chronic prostatitis will continue to be as varied as the symptoms in the patients who suffer from this condition. In part, this is due to the fact that our understanding of the disease remains limited. It may be that the symptoms of category IIIA are the final outcome of a variety of processes, some infectious, some autoimmune, some of a nonspecific inflammatory nature, and others. Thus, treatment might depend on the precipitating event and the coincident etiology rather than the symptoms that are


apparent at the outset. On the other hand, etiology may not be important at all, and symptom relief may be the only area of pertinence. Category IIIB may be the most illdefined, so far, as there are no defining physical findings, laboratory tests, imaging studies, or even symptoms. If this is truly not a prostatic problem, as most would suggest, then the pelvic floor and its physiology must be explored. It also may be true that categories IIA and IIIB have no relationship to one another. One step in the right direction has been the attempt by the NIH to study this disease in a rational manner: first, to define the entities; second, to establish guidelines to standardize the study; and last, to begin an attempt at understanding the natural history. Only with these beginnings can we hope to gain an understanding of this disease. Future treatments of this disease will depend on the success of these ventures. One of the first advances will be a prostatitis symptom score sheet which will probably be similar to the BPH scoring instrument. This will give everyone a common ground to begin to assess treatment efficacy by examining a common outcome. Perhaps when we understand the natural history, more effective treatments will be forthcoming.

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fibres: similarities with the effect of capsaicin. Br J Pharmacol 1998;124:259–66. Rugendorff EW, Weidner W, Ebeling L, Buck AC. Results of treatment with pollen extract (Cernilton N) in chronic prostatitis and prostatodynia. Br J Urol 1993;71:433–8. Buck AC, Rees RW, Ebeling L. Treatment of chronic prostatitis and prostatodynia with pollen extract. Br J Urol 1989;64:496–9. Buck AC. Phytotherapy for the prostate. Br J Urol 1996;78: 325–6. Carraro JC, Raynaud JP, Koch G, et al. Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients. Prostate 1996;29:231–42. Gerber GS, Zagaja GP, Bales GT, et al. Saw palmetto (Serenoa repens) in men with lower urinary tract symptoms: effects on urodynamic parameters and voiding symptoms. Urology 1998;51:1003–7. Wilt TJ, Ishani A, Stark G, et al. Saw palmetto extracts for treatment of benign prostatic hyperplasia: a systematic review. JAMA 1998;280:1604–9.

76. Barnes RW, Hadley HL, O’Donoghue EP. Transurethral resection of the prostate for chronic bacterial prostatitis. Prostate 1982;3:215–9. 77. Dik P, Lock TM, Schrier BP, et al. Transurethral marsupialization of a medial prostatic cyst in patients with prostatitis-like symptoms. J Urol 1996;155:1301–4. 78. Nickel JC, Sorensen R. Transurethral microwave thermotherapy for nonbacterial prostatitis: a randomized double-blind sham controlled study using new prostatitis specific assessment questionnaires [comments]. J Urol 1996;155:1950–5. 79. Suzuki T, Kurokawa K, Suzuki K, et al. Transurethral balloon laser hyperthermia for chronic non-bacterial prostatitis: a clinical trial. Int J Urol 1995;2:29–32. 80. FC DA, Francisca EA, Witjes WP, et al. Transurethral resection of the prostate vs high-energy thermotherapy of the prostate in patients with benign prostatic hyperplasia: long-term results. Br J Urol 1998;81:259–64. 81. Sugiyama T, Park YC, Hanai T, et al. Why is transurethral microwave thermotherapy (TUMT) positively effective? Int Urol Nephrol 1998;30:293–300.

INDEX

Abdominal examination, in evaluation of BPH, 520 Abscess, prostatic, 621–622 Acute urinary retention, as complication of BPH, 500–501, 512–513 Africa, prostate cancer in, 14–16 African Americans, prostate cancer in, 6–10 Age and incidence of prostate cancer, 2 PSA levels and, 65 Alfuzosin, 533–534, 539t Algorithm(s) for local clinical recurrence following radiation therapy, 373f for prostate cancer detection, 34 for prostate cancer prognosis, 39–42 for prostate cancer staging, 37–39 Alkylating agents, 388 Alpha-adrenergic receptors, structure and classification, 532–533 Alpha-blocker drugs. See also names of specific drugs adverse effects of, 538–540 cardiovascular side effects of, 540t long-acting, 534–536 pharmocophysiologic rationale in BPH, 531–532 in prevention of BPH, 502 in prostatitis, 652–653 selective, 536–538 short-acting, 533–534 5 Alpha-reductase inhibitors, 543. See also Finasteride polymorphisms in, 46 in prostate cancer, 22 Alprostadil, 418 American Urological Association Symptom Score comparison to other questionnaires, 516, 516f in evaluation of BPH, 509f in evaluation of lower urinary tract symptoms, 473t Aminoglutethimide, 380 Amonafide, 390 Anastomotic strictures, as complication of radical prostatectomy, 205 Androgen deprivation therapy. See also Combined androgen blockade biology of, 333–334

clinical trials, 318t combined with radiation therapy, 234, 286 combined with radical prostatectomy, 297–298 complications of, 336, 418, 447 early, 334–336 erectile dysfunction during, 418 intermittent, 329 following local treatment failure, 374 in localized prostate cancer, 254–255 quality-of-life issues, 255–256 in metastatic prostate cancer, 317–322, 326–327, 335–336 quality-of-life issues, 321–322 in node-positive prostate cancer, 301–302, 305, 307–308, 314–315 following radiation therapy failure, 358 secondary, 378–382 for stages T1-T2 prostate cancer, 234 for stages T3-T4 prostate cancer, 277–278 Androgen(s) in BPH, 464–465 metabolism, 47 in prostatic function, 99–100, 102t receptors biochemical properties and functions of, 100–101 BPH and, 120 role in prostate cancer, 22, 45–46 tissue localization of, 93f regulation of, 102t relation to prostate cancer risk, 434–436 Anemia, as complication of prostate cancer, 449–450 Angiogenesis inhibitors, 398–399 Anorectal injuries, during prostate surgery, 423–426 Anorexia, as complication of prostate cancer, 450 Antiandrogen(s). See also Combined androgen blockade; Hormonal therapy in combined androgen blockade, 319–320 and medical castration, 326–327 and orchiectomy, 325–326 second-line, 379–388 withdrawal syndrome, 328, 378–379 Antifolate agents, 389 Anti-inflammatory drugs in prostate cancer, 432–433

659

660 / Index

in prostatitis, 653 Antimetastatic agents, 398 Antimitotic agents, 390 Antitumor antibiotics, 391 Apical dissection, in radical prostatectomy, 220–221 Artificial genitourinary sphincter indications for, 405 operative technique, 405–406 postoperative considerations, 408–409 preoperative considerations, 405–406 Asians BPH in, 19 prostate cancer in, 18–19 Atypical adenomatous hyperplasia, 123 Atypical small acinar proliferations, 133, 133f AUA Symptom Score. See American Urological Association Symptom Score Autocrine growth factors, in prostatic disease, 103 Autoimmunity, and prostatitis, 120 Bacteria commensal, 118–119 difficult-to-culture, 118–119 Basic fibroblast growth factor, in BPH, 467 Benign prostatic hyperplasia (BPH) acute urinary retention in, 500–501 alpha-blocker drugs for. See Alpha-blocker drugs androgen receptor ligands and, 120 in Asians, 19 AUA Symptom Score in, 509f, 516f bladder outlet obstruction in, 491–496 blood tests in, 411 clinical trials in, 499 complications of, 483, 500–501 contact laser treatment of, 562–567 diagnosis and treatment algorithm, 511f diagnosis of, 471–473, 481–483, 482f, 486t, 509–510 endoscopy in evaluation of, 522 epithelial-to-stromal ratio in, 464 etiologic theories of, 467–468 finasteride for. See Finasteride growth factors in, 466–467 histologic appearance of, 430f imaging studies for, 525 indications for intervention, 483, 508, 511–513, 512f IPSS in, 485f, 517f medical history in, 520 morphologic findings in, 123–124 open prostatectomy for. See Open prostatectomy P53 tumor suppressor gene mutations in, 121 physical examination in, 520–521 phytotherapy in, 607–612 preoperative assessment of, 525–527 prevention of, 502–504 progression of, 498–499

and prostate cancer, stem cell model of, 125f prostate size in, 500 quality-of-life assessment in, 508–509, 515 role of androgens in, 464–465 role of estrogens in, 465–466 role of nonandrogens in, 465–466 stromal proliferation in, 463–464 surgical intervention for, 501–502 symptom measurement, 484, 485f, 508–509, 515–520 timing of intervention, 511 transurethral needle ablation of the prostate (TUNA) for, 558–560 transurethral resection of the prostate (TURP) for, 501 urinary flow rate in, 499 urodynamic testing for, 473–480, 485–487, 522–525 watchful waiting, 510–511 Benign prostatic obstruction. See Benign prostatic hyperplasia (BPH); Chronic pelvic pain syndrome; Lower urinary tract symptoms; Prostatitis Beta-inhibin, 99 Beta-microseminoprotein, 99 Bicalutamide, 379 Biophosphonates, 399 Biopsy, prostate. See Prostate biopsy Bladder calculi, 512 decompensation, 513 responses to obstruction, 493–495 Bladder neck contracture, 597 excision, 217–218 preservation, 224–227, 225f, 226f Bladder outlet obstruction in BPH, 491–496 pathophysiology of, 492–493 responses of bladder to, 493–495 Blood tests, in evaluation of BPH, 521 Bone fractures, 448–449 Bone pain, 447 Bone scintigraphy in prostate cancer staging, 168, 169f following radiation therapy, 356 following radical prostatectomy, 356 in recurrent prostate cancer, 348–349, 368 BPH. See Benign prostatic hyperplasia Brachytherapy. See also Radiation therapy failure of, 358–359 history of, 241 interstitial follow-up care, 248–249 isotope selection for, 242 patient selection for, 246–248 published results, 249–250 technique for, 242–243 treatment planning for, 243–246

Index / 661

perineal implant, 241–242 salvage, 372 for stages T3-T4 prostate cancer, 280, 288–289 Bulbourethral sling procedure, 412 CAB. See Combined androgen blockade Cachexia, as complication of prostate cancer, 450 Cancer, prostate. See Prostate cancer Cancer deaths, 5f Cancer of the Prostate Risk Index (CAPRI), 34, 36f Carboplatin, 388 Carcinogenesis, of prostatic neoplasia, 124–128 Castration. See Androgen deprivation therapy; Combined androgen blockade; Orchiectomy Chemical prostatitis, 120. See also Prostatitis, nonbacterial Chemotherapy combination, 391–395 cytotoxic, 387–388 single-agent, 388–391, 389t China, histologic definitions of prostate cancer in, 20 Chlamydia trachomatis, in chronic prostatitis, 633–634 Chromosomal alterations, racial patterns of, 9 Chronic pelvic pain syndrome, 618–619, 644–645. See also Lower urinary tract symptoms; Prostatitis, chronic Cisplatin, 388 Citrate, 95 Clinical trials androgen deprivation therapy, 318t BPH, 499 finasteride, 543–545 prostate cancer design, analysis, and reporting of, 452–453 difficulties in conducting, 455–456 factors affecting conduct of, 456t identification of, 453–454, 454t recruitment and retention in, 456–457 review of ongoing, 458–460 standards for, 453t systematic reviews of, 454–455 prostate cancer prevention, review of ongoing, 457 prostate cancer screening, review of ongoing, 457–458 Collaborative care pathways, radical prostatectomy, 178, 179f Collagen injection therapy, for postprostatectomy incontinence complications, 414 patient evaluation, 410 results, 414 technique, 412–414 Colostomy, 424–426 Combined androgen blockade (CAB). See also Androgen deprivation therapy; Hormonal therapy; Orchiectomy antiandrogen withdrawal syndrome in, 327–328, 378–379 antiandrogens in, 319–320

in metastatic prostate cancer clinical trials for, 317–320 quality-of-life issues in, 321–322 rationale for, 324–325 in node-positive prostate cancer, 307–308 following radiation therapy failure, 358 timing of, 328–329 Computed tomography in prostate cancer staging, 167, 168f following radical prostatectomy, 356 in recurrent prostate cancer, 346–348, 368 Conformal radiation therapy. See Radiation therapy, three-dimensional conformal Connecticut Tumor Registry, 88 Contact laser vaporization of the prostate complications of, 566–567 physiology of, 562–563 surgical technique for, 563–566 Continence. See also Incontinence anatomy of, 219 factors contributing to, 220t measurement of, 518 Cowper’s glands, 133 Cryosurgery candidates for, 260 complications of, 264–265 erectile dysfunction following, 418 morbidity, 259–260 patient selection, 258–259 postoperative care, 262–263 following radiation therapy failure, 358 recurrence following, 345 results, 263–264 salvage, 372 for stages T3-T4 prostate cancer, 280 technique, 261–262 theory of, 260 Cryotherapy. See Cryosurgery Cyclophosphamide, 388 CYP3A enzyme, in prostate cancer, 47 Cystitis, resemblance to prostatitis, 619 Cystometry, in evaluation of lower urinary tract symptoms, 478 Cystoprostatectomy, following radiation therapy failure, 371–372 Cystoscopy, in evaluation of lower urinary tract symptoms, 479 Cytotoxan, 392 Decision models, for prostate cancer detection, 34 Deep venous thrombosis following radical prostatectomy, 180–181, 205 risk factors for, 527 Dendritic cell therapies, 397 Density, PSA. See Prostate-specific antigen (PSA), density

662 / Index

Detrusor innervation, 495 Detrusor instability, 495, 513 Diet, in prevention of prostate cancer, 10, 22, 438–439 Digital rectal examination in assessment of prostate size, 525 combined with PSA, 66–67 in evaluation of BPH, 520 as indication for prostate biopsy, 154 in prostate cancer screening, 51, 66, 74 in prostate cancer staging, 37, 160–161, 161–162, 267, 275 in radical prostatectomy follow-up, 367 Discharge planning, radical prostatectomy, 182 Dorsal vein control, effect on continence, 221t Doxazosin, 535–536, 539t Docetaxel, 394 Doxorubicin, 389, 392 Dunning tumor, 146–147 Ejaculation effect on PSA levels, 52 retrograde, 597t Endoscopy, in evaluation of BPH, 522 Environmental factors, in prostate cancer, 10 Epidemiology, of prostate cancer, 1–5 Epidermal growth factor in BPH, 466–467 role in prostatic disease, 103–104 Epirubicin, 389–390, 392 Epithelial cell compartments, prostatic, 121–122 Erectile dysfunction following cryosurgery, 418 evaluation of, 418 during hormonal therapy, 256, 418 pharmacologic treatment of, 418 following radiation therapy, 249, 417 following radical prostatectomy, 206, 207t, 416–417 as side effect of alpha-blocker drugs, 538 as side effect of finasteride, 547–548 surgical treatment of, 420 following TUIP, 597 following TURP, 589–590 Escherichia coli, role in prostatitis, 119 Estramustine phosphate, 390–391, 392–393, 394t Estrogens and antiandrogens, 326–327 in BPH, 465–466 in prostatic dysplasia, 101–103 in secondary hormonal therapy, 381 Etoposide, 390 External beam radiation therapy. See Radiation therapy, external beam Fecal diversion, 424–426 Fecal incontinence, 425–426 Filling cystometry, in evaluation of BPH, 486

Finasteride advantages and disadvantages of treatment with, 548–550 clinical trials of, 543–545 comparison with α-blocker drugs, 548 comparison with TURP, 550 effect on PSA levels, 51 in metastatic prostate cancer, 327 monitoring of patients on, 547 in prostate cancer prevention, 436 selection of patients for, 545–546 side effects of, 547–548 symptom improvement in, 545f, 546f in treatment of BPH, 502–503, 503f, 504f Five-region prostate biopsy, 156. See also Prostate biopsy Flare phenomenon, with LHRH agonists, 327 Fluid, prostatic. See Prostatic fluid 5-Fluorouracil, 388, 392, 394 Flutamide. See also Combined androgen blockade clinical trials with, 318t in secondary hormonal therapy, 379–380 Foamy gland carcinoma, 131, 132f Free beam laser prostatectomy coagulation clinical outcomes, 572–574 operative technique for, 568–572, 569f, 570f, 571f, 572f, 573f postoperative management, 572 comparison of outcomes, 580t incision, 580–581 vaporization and resection clinical outcomes, 579–580 operative technique for, 575–579, 577f, 578f postoperative management, 579 Free-to-total (FT) ratio, PSA. See Prostate-specific antigen (PSA) Fungal prostatitis, 119. See also Prostatitis, nonbacterial Gene therapy, 397–398 Genitourinary sphincter, artificial. See Artificial genitourinary sphincter Genome protective function, loss of, 126f Gleason grading system, 165 Glucocorticoids, 381 Gn-RH analogue, 319–320. See also Combined androgen blockade Granulomatous prostatitis. See Prostatitis, granulomatous Growth factors, in BPH, 466–467 Health care barriers, and outcome of prostate cancer, 9, 32 Health status, measurement of, 518 Hematuria, in BPH, 511–512 Hispanic Americans, prostate cancer in, 31–33 Histology of prostate, 93 of prostate cancer, racial differences, 8

Index / 663

HONDA tumor, 141 Hormonal therapy. See also Androgen deprivation therapy; Combined androgen blockade secondary, 378–382 Hospice care, in prostate cancer, 450 Hydrocortisone, 380 Hyperplasia atypical adenomatous, 123 benign prostatic. See Benign prostatic hyperplasia (BPH) ICSmale questionnaire, 516 Imaging studies, in evaluation of BPH, 525 Immunoscintigraphy, in recurrent prostate cancer, 368 Impotence. See Erectile dysfunction Incidence rates, prostate cancer in Asians, 18, 19t effects of early detection by PSA on, 53 in Hispanic Americans, 31 in Jamaicans, 28–30 in Nigeria, 6 projections of, 3 trends in, 82, 84t variance by age, 2, 3f Incontinence artificial urinary sphincter for, 411–412 bulbourethral sling procedure for, 412 collagen injection therapy for, 410–414 following cryosurgery, 264–265 fecal. See Fecal incontinence mechanisms of, 219–220 following radical perineal prostatectomy, 217f, 217–218 following radical retropubic prostatectomy, 206 following TURP, 589–590 Inflammation, seminal markers of, 120 Inositol, 96 Insulin-like growth factor in BPH, 467 in prostate cancer, 47 in prostatic disease, 104 Intercalating agents, 389 Interferons, 396–397 International Prostate Symptom Score (IPSS), 485f, 517f comparison to other questionnaires, 516, 516t Interstitial brachytherapy. See Brachytherapy Interstitial cystitis, resemblance to prostatitis, 619 Intraluminal crystalloids, 124 IPSS. See International Prostate Symptom Score Irritative voiding symptoms, as indication for treatment of BPH, 513 Isoflavins, role in prevention of prostate cancer, 433–434 Isotopes, for interstitial brachytherapy, 242 Jamaicans, prostate cancer in, 28–30

Kallikreins in diagnosis of prostate cancer, 129 in prostatic fluid, 97 Keratin 19, distribution in prostate tissue, 121 Ketoconazole, 380 Length bias, in screening tests, 80–82 LHRH agonists, 326–327 flare phenomenon, 327 LHRH antagonists, in metastatic prostate cancer, 327–328 Lignans, role in prevention of prostate cancer, 433–434 Lower urinary tract symptoms, 471–473. See also Chronic pelvic pain syndrome; Prostatitis, chronic AUA symptom index for, 473t evaluation of, 471–473 urodynamic testing for, 473–480 following radiation therapy, 372 measurement of, 515–520 prostate-specific antigen (PSA) levels in, 483 Lymph nodes distribution of, 304 in prostate cancer staging, 166–167 radiotherapy of, 234–235 Lymphangiography, 171 Magnetic resonance imaging in evaluation of spinal cord compression, 448 in prostate cancer staging, 168–169, 170f in recurrent prostate cancer, 346–348, 368 Malignant lymphoma, involving the prostate, 134, 134f Matrigel, use in tissue cultures, 141–142 Mepartricin, in treatment of BPH, 612 Metal-containing agents, 388 Methotrexate, 389, 392 Mitoguazone, 391 Mitomycin C, 391 Mitoxantrone, 394–395 Mortality rates, prostate cancer, 1 in African Americans, 6–7 in Asians, 18, 19t changes in, 4–5 National Cancer Institute, SEER program, 1, 82, 269t Needle biopsy. See Prostate biopsy, needle Neoplasia, prostatic intraepithelial. See Prostatic intraepithelial neoplasia Neural networks, for prostate cancer detection, 34–37 Neuromuscular perineal pain syndrome, 618–619. See also Chronic pelvic pain syndrome; Lower urinary tract symptoms Nigeria, prostate cancer incidence, 6 Node-positive prostate cancer. See Prostate cancer, node-positive Nonandrogens, role in BPH, 465–466

Index / 665

Prostate cancer advanced chemotherapy for, 387–388, 388–391, 389t, 391–395 definition of, 325–326 future directions in treatment for, 397–399 heterogeneity of, 385–386 immunotherapy for, 396–397 androgen deprivation therapy for. See Androgen deprivation therapy; Combined androgen blockade androgen metabolism in, 21, 45–47 animal models, 145–147 AUA treatment guidelines, 454t BPH and, 125f canine model, 145–146 carcinogenesis of, 124–128 cell culture of, 138–144 characteristics of, 89–90 chemoprevention of, 428–429. See also Prostate cancer, prevention of clinical significance of, 80–81 clinical trials, 452–460 complications of anorexia, 450 cachexia, 450 osseous metastases, 447–449 urinary, 449 conventional radiotherapy for. See Radiation therapy cryosurgery for. See Cryosurgery CYP3A enzyme in, 47 deferred therapy for, 195–198, 366t diagnosis of, 34, 55, 80–82, 154–158, 525 dietary factors in, 10, 21–22, 438–439 digital rectal examination as screening tool for, 51, 66, 74 disease progression definitions, 454t Dunning tumor, 146–147 early detection of, 55 epidemiology of, 1–5, 6–8, 14–16, 18–19, 28–29, 31–32 extraprostatic extension of, 294–295 Gleason grading system, 165 high-grade prostatic intraepithelial neoplasia, 130 histology of, 431f racial differences in, 8 hormonal prevention of, 434–436 hormonal treatment of. See Androgen deprivation therapy; Combined androgen blockade hormone levels in, 46–47 hormone-refractory, 385–386, 460 hormone-sensitive, 459–460 hospice care in, 450 human models, 138–145 imaging studies for, 525 impact of tumor grade on outcome, 89 incidence rates in Africa, 14, 15t in African Americans, 6

in Hispanic Americans, 31–33 in Jamaicans, 28–30 in Nigeria, 6 effects of PSA early detection on, 53 latent, 20, 21t localized. See also Prostate cancer, stage T1a characteristics of, 270–271 choice of therapy for, 253–254 clinical trials for, 458–459 early hormonal therapy of, 334–335 evidence of dose response for, 237t prognostic factors, 198–199 surveillance of, 86–89 location of, racial differences in, 8 metastatic androgen deprivation therapy of, 317 clinical trials for, 460 early hormonal therapy of, 335–336 natural history of, 332 PSA relapse and, 332–333 staging of, 325, 326t models of, 138 molecular diagnostic modalities, 129–130 morphology of, 130 mortality rates, 1, 84t in Africa, 16 in African Americans, 6–7 in Asians, 18, 19t changes in, 4 effects of early detection on, 55 trends in, 82 natural history of, 86–89, 446 neuroendocrine differentiation in, 125 node-positive combined therapy for, 306–309, 308t, 309t historic management of, 311 hormonal therapy for, 305, 314–315 incidence of, 311 natural history of, 305 outcomes for, 313t radiation therapy for, 306 staging of, 304–305 surgery for, 305–306, 312–314 survival rates for, 314t treatment options, 300–302 orchiectomy in. See Orchiectomy overdiagnosis of, 80–82 pathology of, 131–134 preoperative nomogram for recurrence of, 41f prevention of, 433–434 anti-inflammatory drugs, 432–433 clinical trials for, 457 retinoids, 437–438 soy, 428–429 tea, 23–24

668 / Index

nonbacterial, 617, 644, 647–648 pathobiology of, 118–120 pathogenesis, 646 patient examination in, 628–629 pharmacodynamics, 646 phytotherapy of, 653 prostatic massage in, 653–654 radiographic imaging in, 624–625, 645 suppressive therapy of, 647 surgical therapy of, 647, 654 symptoms of, 628t, 650t viral, 119 Prostatodynia, 618–619, 644–645 treatment of, 647–648 Prosthesis, penile, 407–408, 420 PSA. See Prostate-specific antigen Pseudohyperplastic prostatic adenocarcinoma, 131 Puboprostatic ligaments, preservation of, 221, 221t Pulmonary embolism, as complication of prostatectomy, 205 Pygeum africanum, in treatment of BPH, 610 Pyrimidines, 388 Quantitative Nuclear Grade (QNG), 39 Radiation therapy adjuvant, 369–370 combined with androgen deprivation therapy, 234, 286 conventional complications of, 236–237 long-term results, 229–232 digital rectal examination following, 344 dose response, 237t erectile dysfunction following, 417 external beam in node-positive prostate cancer, 301 following radical prostatectomy, 297 for stages T3-T4 prostate cancer, 279, 284 failure of algorithm for, 373f androgen deprivation therapy following, 358 PSA levels in, 344–345, 366 radical prostatectomy following, 356–359 salvage surgery following, 374t treatment options for, 370–371 TRUS following, 344–345 intensity modulation, 236 lower urinary tract symptoms following, 372 in node-positive prostate cancer, 306–308 particle, 235–236 PSA levels following, 233t, 342, 342t, 343t, 355–356 salvage, 360–361, 361t following radical prostatectomy, 359–360, 369–370 vs salvage radical prostatectomy, 361–362 in stage T1a prostate cancer, 192

three-dimensional conformal (3DCRT) for stages T1-T2 prostate cancer, 231–234 for stages T3-T4 prostate cancer, 279, 284–286 whole pelvis vs. small field, 234–235 Radical perineal prostatectomy. See Radical prostatectomy, perineal Radical prostatectomy anatomic changes following, 220t anesthesia for, 181–182 apical dissection in, 220–221 bladder neck dissection during, 217–218, 224–227, 225f, 226f blood management, 181 bowel preparation, 178 collaborative care pathways, 178, 179f combined with androgen deprivation therapy, 297–298 combined with radiotherapy, 297 continence-enhancing modifications for, 219–227 deep venous thrombosis prophylaxis, 180–181 discharge planning, 182 dorsal vein control during, 221t, 221–223, 222f, 223f erectile dysfunction following, 416–417 extraprostatic extension in, 294–295 failure of, 343–344, 359–361 PSA levels in, 340–341, 366 treatment options for, 369–370 hospital stay, 180f incontinence following, 206, 217f, 217–220, 410–414 nerve-sparing, 222–224 neurovascular bundle release during, 224, 224f in node-positive prostate cancer, 300–301, 305–307, 308t pain management, 182 pathologic findings in, 270t patient education, 177 perineal anatomic considerations, 210–212 incontinence following, 217t, 218 management of bladder neck during, 217–218 patient selection, 212 postoperative care, 217–218 surgical procedure, 213–217 positive surgical margins in, 291–293 PSA levels following, 340–341, 341f, 341t, 354–355 puboprostatic ligaments preservation in, 221, 221t retropubic complications, 204–207, 206t positive surgical margins in, 207 preoperative assessment for, 202 surgical efficacy of, 207, 207t technique, 202–203, 204f, 205f salvage following cryotherapy failure, 359 following radiation therapy failure, 356–359 vs. salvage radiation therapy, 361–362 in stage T3 prostate cancer, 296–297

Index / 669

in stage T1a prostate cancer, 191 in stages T3-T4 prostate cancer, 278–279 summary of series of, 270t vesicourethral anastomosis, 227, 227f Radical retropubic prostatectomy. See Radical prostatectomy, retropubic Radioimmunoimaging, in prostate cancer staging, 169 Radioimmunoscintigraphy following radical prostatectomy, 356 in recurrent prostate cancer, 345–346, 346t, 347t Radiotherapy. See Radiation therapy Rectal injury as complication of radical retropubic prostatectomy, 205 during prostate surgery, 424–426 Reference values, PSA, 64–65 Retinoids, role in prevention of prostate cancer, 437–438 Retrograde ejaculation, 597t Retropubic prostatectomy. See Open prostatectomy; Radical prostatectomy Reverse transcriptase–polymerase chain reaction (RT-PCR), 164–165 Sarcomas, 134 Saw palmetto, 608–610 SCARP trial, 544 Schafer nomogram, 476f Screening, prostate cancer, 50–57 decision analyses, 90 economics of, 56 effectiveness of, 73, 80–84 length bias in, 80–82 recommendations for, 50, 73 selection of tools for, 70 status of, 77 trials for, 52t, 82, 457–458 SEER (Surveillance, Epidemiology, and End Results) program, 1, 82, 269t Selenium, 430–432 Seminal vesicle, in prostate cancer, 276, 295–296 Serum alkaline phosphatase, in prostate cancer staging, 162 Serum androgen levels, in prostate cancer, 21. See also Androgen(s) Serum creatinine, in diagnosis of BPH, 483 Sextant prostate biopsy, 156. See also Prostate biopsy Sexual function, measurement of, 518 Signal transduction modulators, 397–398 Sling procedure, 412 Soy, 23 Sphincter deficiency. See also Artificial genitourinary sphincter artificial urinary sphincter for, 411–412 bulbourethral sling procedure for, 412 collagen injection therapy for, 410–414 Spinal cord compression, as complication of prostate cancer, 448

Staging of metastatic prostate cancer, 325, 326t of prostate cancer nomogram for, 166t systems for, 159–161, 161t Stem cell model, of development of BPH, 467 Suprapubic prostatectomy. See Open prostatectomy Suramin, 391, 392 Tamsulosin, 536–537, 539t Tea, chemopreventive actions of, 23–24 Telomerase inhibitors, 398 Terazosin, 534–535, 539t Testosterone, and prostate cell division, 10 Three-dimensional conformal irradiation (3DCRT). See Radiation therapy, three-dimensional conformal Tissue, prostatic. See Prostatic tissue Tissue culture cell lines, in prostate cancer cultures, 144–145 TMTX, 389 TNM staging system, for prostate cancer, 159–160, 161t Transforming growth factor α, 121 Transforming growth factor β, 104 Transgenic models, prostate cancer, 147 Transitional cell carcinoma, 133–134 resemblance to prostatitis, 619 Transrectal prostate biopsy, 155–156. See also Prostate biopsy Transrectal ultrasonography (TRUS) in assessment of prostate size, 525 color Doppler, 367–368 in evaluation of BPH, 125 as indication for prostate biopsy, 154 in prostate cancer screening, 68, 74 in prostate cancer staging, 167 in prostatitis, 624–625 in recurrent prostate cancer, 367 in stage T1a prostate cancer, 189 Transurethral incision of the prostate (TUIP) complications, 597 history, 593 indications, 593–594 laser, 595 results, 595–597 technique, 594–595 Transurethral needle ablation of the prostate (TUNA) catheters for, 553, 554f clinical results, 556f, 556–558, 557t cost, 558 human pathologic and radiologic studies, 553 preoperative evaluation for, 554 preservation of the prostatic urethra in, 554 radiofrequency energy principles for, 552 technique, 554–556 Transurethral resection of the prostate (TURP) anesthesia for, 585

670 / Index

comparison to other interventions, 590 complications, 589–590 history of, 584 indications for, 584 intraoperative problems, 588–589 patient preparation, 584–585 in prostate cancer staging, 160 repeat, 188–189, 189t selection of patients for, 501 technique, 585–588, 586f, 587f, 588f Trichomonas vaginalis, in chronic prostatitis, 634–635 TRUS. See Transrectal ultrasonography (TRUS) TUIP. See Transurethral incision of the prostate (TUIP) Tumor cell motility, 129f Tumor grade, impact on outcome, 89 Tumor volume as prognostic factor, 198 racial differences in, 8 stage T1c compared to stage T2, 271 TUNA. See Transurethral needle ablation of the prostate (TUNA) TURP. See Transurethral resection of the prostate (TURP) UICC/AJCC (International Union Against Cancer/ American Joint Committee on Cancer) staging system, prostate cancer, 160 Ureaplasma urealyticum, in chronic prostatitis, 634 Ureteral obstruction, androgen deprivation therapy for, 374 Urethral cuff, 406–407 Urethral function studies, in evaluation of BPH, 524–525 Urethrocystoscopy, in evaluation of BPH, 487 Urinalysis in evaluation of BPH, 482–483, 520

in evaluation of prostatitis, 629 Urinary flow rate, in evaluation of BPH, 499 Urinary tract, inflammation, localization of, 645 Urodynamic tests in evaluation of BPH, 485–487, 522–525 in evaluation of lower urinary tract symptoms, 473–480 in evaluation of postprostatectomy incontinence, 410 in evaluation of prostatitis, 625 following transurethral needle ablation of the prostate (TUNA), 557t Uroflowmetry in evaluation of BPH, 485, 522, 523t in evaluation of lower urinary tract symptoms, 474–475 Vesicourethral anastomosis, during radical prostatectomy, 227, 227f Video urodynamics, in evaluation of lower urinary tract symptoms, 479 Vinblastine, 390 Viral prostatitis, 119 Vitamin D, in prostate cancer prevention, 22, 436–437, 437f Vitamin E, in prostate cancer prevention, 429–430 Voiding diaries, in evaluation of lower urinary tract symptoms, 518, 519f Voiding symptoms, in evaluation of BPH, 491–492 Volume/frequency charts, in evaluation of lower urinary tract symptoms, 473–474 Whitmore-Jewett staging system, prostate cancer, 160, 161t Xenografts, as models of prostate cancer, 140–144 Zinc, 95

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