Prostate Cancer: Science and Clinical Practice

0122869818-ch000-prelims.fm Page ix Tuesday, March 4, 2003 2:16 PM Foreword This book is a comprehensive approach to ...

Author: Jack Mydlo (Editor) | Ciril J. Godec (Editor)

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0122869818-ch000-prelims.fm Page ix Tuesday, March 4, 2003 2:16 PM

Foreword

This book is a comprehensive approach to the study of causes, detection, and the various treatment modalities of prostate cancer. It starts in the laboratory, takes us through the operating room, and finishes in clinics and doctors’ offices all over the world. The editors, Drs Jack Mydlo and Ciril Godec, have collected contributions from global leaders of their fields in an attempt to cover every aspect of this disease. As a survivor of prostate cancer, I know the devastation of first hearing about the diagnosis, and then the confusion of dealing with all the options, side-effects, and long-term outcomes. This book is written in a way that clinicians, researchers, and in parts lay people, will understand and appreciate. Not

only does it describe the standard radical surgery and radiation therapies, but also discusses the latest in laparoscopic surgery and cryoablation therapy. It is also unique in that it compares the differences in the theories of prostate cancer etiologies and therapies from various parts of the globe. Since this disease affects husbands, boyfriends, fathers, sons and uncles, it is of the utmost importance that not only all men over the age of 40 understand this disease, but women as well. Prostate Cancer: Science and Clinical Practice should be required reading for people who want to understand and help themselves and the male loved ones in their lives. Senator Bob Dole

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Preface

Prostate cancer has become one of the greatest health care challenges of the industrialized world; this is based upon numbers of patients and families affected and the demands this places on ever shrinking health care budgets. This text represents an up-to-date look at the issues and answers regarding present knowledge and innovative ideas for the future. The editors have assembled a stellar faculty to provide the latest information of an ever-changing disease. This includes tumor biology, biopsy techniques, heredity, dietary and environmental factors, prevention, nerve sparing surgery, sural

nerve grafting, laparoscopic surgery, radiation and hormonal therapies, sexual aspects, personal testimonials and future treatments of the disease on the horizon. Although this book is aimed at the clinician and scientist, we believe that even lay persons may appreciate certain sections of the text in order to help them understand and perhaps select their own treatment modality. Jack H. Mydlo Ciril J. Godec

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Contributors

Clément-Claude Abbou Service d’Urologie CHU Henri Mondor 51 Avenue Du M1. De Lattre de Tassigny 94010 Créteil-cedex France

Neil A. Abrahams Department of Anatomic Pathology 9500 Euclid Avenue Cleveland Clinic Foundation Cleveland OH 44195 USA

Bulent Akduman Department of Urology University of Colorado Health Science Center Campus Box F710 4200 E. Ninth Avenue Denver CO 80262 USA

Thomas Anderson, Jr. Office of Community Relations University Services Building Suite 302 Temple University 1601 N. Broad Street Philadelphia PA 19122 USA

Gerald L. Andriole Division of Urologic Surgery Washington University School of Medicine 4960 Children’s Place, Box 8242 St Louis MO 63110-1002 USA Ronald E. Anglade Department of Urology Boston University School of Medicine 720 Harrison Avenue Suite 606 Boston MA 02118 USA Seetharaman Ashok Department of Urology Rhode Island Hospital Brown Medical School 2 Dudley Street, Suite 174 Providence RI 02905 USA R. Joseph Babaian Department of Urology The University of Texas M.D. Anderson Cancer Center 1515 Holcombe Blvd. Box 446 Houston TX 77030 USA [email protected]

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Contributors

Richard K. Babayan Department of Urology Boston University School of Medicine 720 Harrison Avenue Suite 606 Boston MA 02118 USA

David Crawford Department of Urology University of Colorado Health Science Center Campus Box F710 4200 E. Ninth Avenue Denver CO 80262 USA

David G. Bostwick Bostwick Laboratories 2807 N. Parham Road Richmond VA 23294 USA [email protected]

Paul Crispen Department of Urology Temple University Hospital Suite 350, Parkinson Pavilion 3401 N. Broad Street Philadelphia PA 19140 USA

Simon R.J. Bott Institute of Urology and Nephrology University College London Royal Free and University College Medical School 3rd Floor, Charles Bell House 67 Riding House Street London W1W 7EY UK

Steven C. Campbell Department of Urology and The Cardinal Bernardin Cancer Center Loyola University Medical School 2160 S. 1st Avenue Building 54, Room 237 Maywood IL 60153 USA [email protected]

Eduardo Canto Scott Department of Urology Baylor College of Medicine Texas Medical Center 6560 Fannin, Suite 2100 Houston TX 77030 USA

Philipp Dahm Duke University Medical Center Division of Urology Department of Surgery, Box 2977 Durham NC 27710 USA John W. Davis Department of Urology and The Virginia Prostate Center of the Eastern Virginia Medical School and Sentara Cancer Institute Yoo West Bramblelon Avenue, Suite 100 Norfolk VA 23501 USA Frans M.J. Debruyne Department of Urology – 426 University Medical Center Nijmegen PO Box 9101 6500 HB Nijmegen The Netherlands Steven J. DiBiase Department of Radiation Oncology University of Maryland School of Medicine 22 S. Greene Street Baltimore MD 21201 USA

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Contributors

Bob Djavan Department of Urology University of Vienna Wahringer Gurtel 18-20 1090 Vienna Austria Ehab El-Gabry Department of Urology Kimmel Cancer Center Thomas Jefferson University 1025 Walnut Street Philadelphia PA 19107 USA Lars Ellison Johns Hopkins Hospital 600 North Wolfe Street Carnegie 298 Baltimore MD 21287 USA Paul F. Engstrom Department of Population Sciences Fox Chase Cancer Center Temple University School of Medicine 7701 Burholme Avenue Philadelphia PA 19111 USA Abelardo Errejon Department of Urology University of Colorado Health Science Center Campus Box F710 4200 E. Ninth Avenue Denver CO 80262 USA John M. Fitzpatrick Department of Surgery Mater Misericordiae Hospital Conway Institute University College Dublin 47 Eccles Street Dublin 7 Ireland

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Neil Fleshner Division of Urology Princess Margaret Hospital 610 University Avenue, Room 3-130 Toronto Ontario M5G 2M9 Canada Eduard J. Gamito Department of Urology University of Colorado Health Science Center Campus Box F710 4200 E. Ninth Avenue Denver CO 80262 USA Ellen Gaynor Department of Medicine Loyola University Medical School and The Cardinal Bernadin Cancer Center 2160 S. 1st Avenue Building 54, Room 237 Maywood IL 60153 USA Glen Gejerman Department of Radiation Oncology Hackensack University Medical Center 30 Prospect Avenue Hackensack NJ 07601 USA Inderbir S. Gill Section of Laparoscopic and Minimally Invasive Surgery Department of Urology, A-100 Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland OH 44195 USA Phillip C. Ginsberg Department of Surgery Division of Urology Albert Einstein Medical Center 5401 Old York Road, Suite 500 Philadelphia PA 19141 USA

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Contributors

Ciril J. Godec Department of Urology Long Island College Hospital 339 Hicks Street Brooklyn New York NY 11201 USA

Eric M. Horwitz Department of Radiation Oncology Fox Chase Cancer Center Temple University School of Medicine 7701 Burholme Avenue Philadelphia PA 19111 USA

Kazuo Gohji Department of Urology Osaka Medical College 2-7 Daigakumatchi Takatsuki 569–8686 Japan

András Hoznek Service d’Urologie CHU Henri Mondor 51 Avenue Du M1. De Lattre de Tassigny 94010 Créteil-cedex France

Leonard G. Gomella Department of Urology Kimmel Cancer Center Thomas Jefferson University 1025 Walnut Street Philadelphia PA 19107 USA Richard Greenberg Department of Urologic Oncology Fox Chase Cancer Center 7701 Burholme Avenue Philadelphia PA 19111 USA Richard C. Harkaway Department of Surgery Division of Urology Albert Einstein Medical Center 5401 Old York Road, Suite 500 Philadelphia PA 19141 USA Beth A. Hellerstedt University of Michigan, 7303 CCGC, Box 0946 1500 East Medical Center Drive Ann Arbor MI 48109 USA

William B. Isaacs Brady Urological Institute Johns Hopkins Hospital 600 North Wolfe Street Baltimore MD 21287 USA Jonathan Izawa Department of Surgery and Oncology Division of Urology The University of Western Ontario London Health Sciences Center South Street, Victoria Campus London Ontario NGA 4G5 Canada Stephen C. Jacobs Department of Surgery University of Maryland School of Medicine 22 S. Greene Street Baltimore MD 21201 USA [email protected] Matthew Karlovsky Department of Urology Temple University Hospital Suite 350, Parkinson Pavilion 3401 N. Broad Street Philadelphia PA 19140 USA

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Contributors

Michael Kattan Department of Urology Memorial Sloan–Kettering Cancer Center 1275 York Avenue New York NY 10021 USA [email protected]

Andre Konski Department of Radiation Oncology Fox Chase Cancer Center Temple University School of Medicine 7701 Burholme Avenue Philadelphia PA 19111 USA

Aaron E. Katz Department of Urology College of Physicians and Surgeons Columbia University Atchley Pavilion 11th Floor 161 Fort Washington Avenue New York NY 10032 USA

Richard E. Link Scott Department of Urology Baylor College of Medicine Texas Medical Center 6560 Fannin, Suite 2100 Houston TX 77030 USA

Roger S. Kirby Department of Urology St George’s Hospital Blackshaw Road London SW17 OQT UK

Stephan Madersbacher Department of Urology University of Vienna Warhinger Gurtel 18–20 1090 Austria

Sohei Kitazawa Department of Molecular Pathology Kobe University Graduate School of Medicine 7-5-1 Kusonoki-cho Chuo-ku, Kobe 650-0017 Japan Laurence Klotz Division of Urology Sunnybrook and Women’s College Health Sciences Centre University of Toronto 2075 Bayview Avenue # MG 408 Toronto Ontario M4N 3M5 Canada Vladimir Kolenko Department of Surgical/Urologic Oncology Fox Chase Cancer Center Temple University School of Medicine 7701 Burholme Avenue Philadelphia PA 19111 USA

S. Bruce Malkowicz Division of Urology Hospital of the University of Pennsylvania 3400 Spruce Street Philadelphia PA 19104 USA [email protected] Michael Marberger Department of Urology University of Vienna Wahringer Gurtel 18-20 1090 Vienna Austria Fray Marshall Department of Urology Emory University School of Medicine Building A, Rm 3225 Atlanta GA 30322 USA

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Contributors

T. Casey McCullough Department of Surgery Division of Urology Albert Einstein Medical Center 5401 Old York Road, Suite 500 Philadelphia PA 19141 USA Kevin McEleny Department of Surgery Mater Misericordiae Hospital Conway Institute University College Dublin 47 Eccles Street Dublin 7 Ireland

Mark A. Moyad University of Michigan Medical Center Department of Surgery (Section of Urology) 1500 East Medical Center Drive Ann Arbor MI 48109-0330 USA Jack H. Mydlo Department of Urology Temple University Hospital Suite 350, Parkinson Pavilion 3401 N. Broad Street Philadelphia PA 19140 USA

Liza McLornan Department of Surgery Mater Misericordiae Hospital Conway Institute University College Dublin 47 Eccles Street Dublin 7 Ireland

Charles Myers Department of Urology University of Virginia Health Science Center Box 422 Charlottesville VA 22908 USA

Anoop M. Meraney Department of Urology Cleveland Clinic Foundation 9500 Euclid Avenue Cleveland OH 44195 USA

Vivek Narain Department of Urology Wayne State University Harper Professional Building 4160 John R. Suite 1017 Detroit MI 48201–2020 USA

Ronald A. Morton Scott Department of Urology Baylor College of Medicine Texas Medical Center 6535 Fannin, MS FB403 Houston TX 77030 USA Judd Moul Uniformed Services University of the Health Sciences Center for Prostate Disease Research 1530 E. Jefferson Street Rockville MD 20852 USA

Don W.W. Newling VU Medical Center Department of Urology PO Box 7057 1007 MB Amsterdam The Netherlands Brian Nicholson Department of Urology University of Virginia Health Science Center PO Box 422 Charlottesville VA 22908 USA

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Contributors

Carl Olsson College of Physicians and Surgeons Columbia University 161 Fort Washington Avenue New York NY 10032-3702 USA David P. Paulson Division of Urology Department of Surgery Duke University Medical Center PO Box 2977 Durham NC 27710, USA Kenneth J. Pienta University of Michigan, 7303 CCGC Box 0946 1500 East Medical Center Drive Ann Arbor MI 48109 USA Alan Pollack Department of Radiation Oncology Fox Chase Cancer Center Temple University School of Medicine 7701 Burholme Avenue Philadelphia PA 19111 USA Isaac Powell Department of Urology Wayne State University Harper Professional Building 4160 John R. Suite 1017 Detroit MI 48201-2020 USA Timothy L. Ratliff Department of Urology University of Iowa University of Iowa Hospital/Clinic 200 Hawkins Drive, 3243 RCP Iowa City IA 52242-1089 USA

Mesut Remzi Department of Urology University of Vienna Wahringer Gurtel 18-20 1090 Vienna Austria Martin Resnick Department of Urology University Hospitals of Cleveland Case Western Reserve University School of Medicine 10900 Euclid Avenue Cleveland OH 44106 USA Vincent Ricchiuti NEO Urology Associates, Inc. 602 Parmalee Avenue, Suite #300 Youngstown OH 44510-1653 USA [email protected] Eric S. Rovner Division of Urology 1 Rhoads Hospital of the University of Pennsylvania 3400 Spruce Street Philadelphia PA 19104 USA Daniel B. Rukstalis Division of Surgery MCP Hahnemann University 3300 Henry Avenue Philadelphia PA 19129 USA Ihor C. Sawczuk Department of Urology 11th Floor, Columbia Presbyterian Medical Center 161 Ft. Washington Avenue NY 10032-3702 USA

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Contributors

Peter Scardino Department of Urology Memorial Sloan-Kettering Cancer Center 1275 York Avenue NY 10021 USA Paul F. Schellhammer Department of Urology and The Virginia Prostate Center of the Eastern Virginia Medical School and Sentara Cancer Institute Yoo West Bramblelon Avenue, Suite 100 Norfolk VA 23501 USA Claude C. Schulman Department of Urology Erasme Hospital University Clinics of Brussels 808 route de Lennik B-1070 Brussels Belgium Ahmad Shabsigh Department of Urology 11th Floor, Columbia Presbyterian Medical Center 161 Ft. Washington Avenue NY 10032-3702 USA Neil Sherman Department of Urology University of Medicine and Dentistry of New Jersey NJ USA D. Robert Siemens Department of Urology Queens University 76 Stuart Street Kingston Ontario K7L 2V7 Canada Kevin Slawin Scott Department of Urology 6560 Fannin, Suite 2100 Houston TX 77030 USA

Barry Stein Department of Urology Rhode Island Hospital Brown Medical School 2 Dudley Street, Suite 174 Providence RI 02905 USA Mitchell S. Steiner Department of Urology University of Tennessee Health Science Center 1211 Union Avenue, Suite 340 Memphis TN 38104 USA Chandru P. Sundaram Division of Urologic Surgery Washington University School of Medicine 4960 Children’s Place, Box 8242 St Louis MO 63110-1002 USA [email protected] Dan Theodorescu Department of Urology University of Virginia Health Science Center Box 422 Charlottesville VA 22908 USA Edouard J. Trabulsi Departments of Urology Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York NY 10021 USA Aubrey Turner Center for Human Genomics Medical Center Blvd Wake Forest University School of Medicine Winston-Salem NC 27157-1076 USA

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Contributors

Robert G. Uzzo Department of Surgical/Urologic Oncology Fox Chase Cancer Center Temple University School of Medicine 7701 Burholme Avenue Philadelphia PA 19111 USA Richard K. Valicenti Director of Clinical Affairs Thomas Jefferson University 111 S. 11th Street Philadelphia PA 19107 USA Michael R. Van Balken Department of Urology – 426 University Medical Center Nijmegen PO Box 9101 6500 HB Nijmegen The Netherlands Deborah Watkins-Bruner Department of Population Science Fox Chase Cancer Center Temple University School of Medicine 7701 Burholme Avenue Philadelphia PA 19111 USA R. William G. Watson Department of Surgery Mater Misericordiae Hospital Conway Institute University College Dublin 47 Eccles Street Dublin 7 Ireland [email protected] Alan J. Wein Division of Urology Department of Surgery University of Pennsylvania School of Medicine Hospital University of Pennsylvania Philadelphia PA 19104 USA

Magali Williamson Institute of Urology and Nephrology University College London Royal Free and University College Medical School 3rd Floor, Charles Bell House 67 Riding House Street London W1W 7EY UK

David Wood Department of Urology University of Michigan 1500 E. Medical Center Ann Arbor MI 48109 USA

Jianfeng Xu Center for Human Genomics Medical Center Blvd Wake Forest University School of Medicine Winston-Salem NC 27157-1076 USA

Paul Yonover Department of Urology Loyola University Medical Center 2160 S. 1st Avenue Building 54, Room 237 Maywood IL 60153 USA

A.R. Zlotta Department of Urology Erasme Hospital University Clinics of Brussels 808 route de Lennik B-1070 Brussels Belgium

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Population Screening for Prostate Cancer and Early Detection in High-risk African American Men*

Chapter

1

Judd W. Moul Urology Service, Department of Surgery, Walter Reed Army Medical Center, Washington, DC 20307-5001, and Center for Prostate Disease Research, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20814-4799, USA

Prostate cancer is the most common malignancy in American men, accounting for more than 29% of all diagnosed cancers and approximately 13% of all cancer deaths.1 Nearly one of every six men will be diagnosed with the disease at some time in their lives.1 In 2002 alone, an estimated 189 000 US men were diagnosed with prostate cancer, and more than 30 000 will die of the disease.1 Despite the fact that population-based screening for prostate cancer has yet to be definitively proven or disproved to affect the disease-specific mortality, this summary explores changes in the ‘PSA Era’ (defined as the time in the USA when the prostate specific antigen (PSA) screening test came into widespread clinical use) and the prospects for targeted screening of certain groups of individuals who may be at particular risk of developing prostate cancer, namely African American men.

PROS AND CONS OF POPULATIONBASED SCREENING IN GENERAL Early detection for prostate cancer has been practiced for many years in the form of the digital rectal examination (DRE). However, over the last 15 years with the advent of prostate specific antigen, or PSA, the topic of prostate cancer screening has become a hotly contested issue.2,3 Early detection may take the form of the population-based screening or case finding. In the early 1990s, the American Cancer Society (ACS), the American Urological Association (AUA) and other organiza-

tions advocated screening for the early detection of prostate cancer.4,5 These groups recommend a DRE and PSA test for men starting at age 50. Notably, however, other organizations had argued against screening, including the US Preventative Services Task Force, the American Academy of Family Physicians and the American College of Physicians.6,7 Several factors favor the use of screening for the early detection of prostate cancer. First, because patients do not experience symptoms during the early stages, they are unlikely to seek care until the disease has progressed. Second, improvements in detection methods have increased the prospects for identifying the disease in its early stages, when the cancer is still confined to the organ, and is more easily treatable and often curable. Third, early detection might mean the difference between life and death, as no cure has been found for the advanced disease. To be of value, screening must lead to treatment that has a favorable impact on prognosis. Catalona et al. were one of the first groups to examine this issue by comparing disease stages in patients with prostate cancer who had or had not undergone or had PSA screening.8 The screened group had a lower percentage of cases with advanced disease and no greater percentage with latent disease. The investigators concluded that screening reduces the incidence of advanced disease and implied that the death rate will ultimately decrease.8,9 Since these reports, there have been a multitude of studies documenting the changes in the epidemiology of prostate cancer in the ‘PSA-Era’.

*The opinion and assertions contained herein are the private views of the author and are not to be considered as reflecting the views of the US Army or the Department of Defense.


4

Prostate Cancer: Science and Clinical Practice

PSA-ERA CHANGES SUPPORTING GENERAL SCREENING When an effective screening tool is introduced into a population, the following events should occur. There should be a transient increase in incidence owing to labeling of prevalent cancers. The cancers should be diagnosed in patients of a younger age. The cancer should be diagnosed at lower stages and there should be an apparent increase in disease-specific survival.10,11 As of 2002, PSA testing has arguably fulfilled these criteria, and many clinicians practice screening. Regarding the change in prostate cancer incidence, the SEER (Surveillance, Epidemiology and End Results Program of the National Cancer Institute) data as well as data from the Mayo Clinic and other sites document the change.12–16 Specifically, starting in 1989 and peaking in 1992, there was a marked rise, with a subsequent decrease of approximately 30%. These trends exemplify the Cull effect, that is, with the introduction of any screening tool into a population, there will be a rise in incidence, with a subsequent fall. This fall is because of the depletion of the prevalence pool of previously undiagnosed cases. The steady-state incidence of prostate cancer in the PSA-Era will eventually be a reflection of both patients aging, and entering into the pool, and those being removed from the pool as a result of dying, or being diagnosed with prostate cancer.12 It is unclear whether the incidence will decrease to prescreening levels, or remain higher than previous years.16,17 Current statistics from the SEER data indicate that the steady-state incidence in the PSA-Era has yet to be reached.1 Others have suggested that the fall in incidence is influenced by less aggressive screening by primary care physicians in response to data in the scientific and lay media that screening for prostate cancer does not effect morbidity and mortality.18,19 In the Department of Defense Center for Prostate Disease Research (CPDR) program, the incidence of new cases continues to be above prescreening levels and appears to have leveled off.20 The mean and median age of men at diagnosis has decreased significantly in the PSA Era. The introduction of age-specific reference ranges for PSA screening, first by Osterling et al., and subsequently by race and age by Morgan et al., have shown that prostate cancer, detection and subsequent treatment is an age-dependent process.21,22 The younger the patient is at the time of diagnosis, presumably, the earlier they are in the course of their disease. If curative-intent treatment is rendered at an earlier age, the more likely cure would occur. Chodak et al. have shown that men under 61 years of age had a statistically significant improved disease-specific survival.23 Smith et al. from our group have also shown that younger age at diagnosis is an independent predictor of better prognosis.24 Age greater than 65 years has been demonstrated to be an independent predictor of distant metastasis.25 Carter et al. have recently suggested that detection of prostate cancer in younger men is likely to lead to a decrease in prostate cancer mortality.26 In summary, there is strong evidence that, if the diagnosis of prostate cancer is made at a younger age, disease-specific mortality can be significantly reduced, and it

is now demonstrated that, in the PSA-Era, the age at diagnosis had decreased significantly. The decline in the age at the time of diagnosis from 72 to 69.4 years of age from 1990 to 1994 has been shown by the SEER data.18 From the SEER data and other literature, a leadtime of between 3 and 5 years is derived.13,15,18,27 In other words, with the aid of PSA, we are detecting cancers 3–5 years earlier than prior to screening. Thus the increase in survival (time of diagnosis to time of death) in the PSA-Era must be at least 3–5 years longer that the previous expected survival time to show any benefit in disease-specific survival with PSA screening. There has also been a significant stage migration in the PSA-Era. Most strikingly, the percentage of patients presenting with metastatic disease decreased from 14.1% and 19.8% in 1988 and 1989, respectively, to 3.3% in 1998 from our CPDR database.20 Before a survival benefit, a decrease in metastatic disease should be evident, which is clearly being shown on a national level by several studies.12–14,28 These findings are more impressive in light of the fact that no curative treatment exists for patients with metastatic disease. Similarly, we have also shown a statistically significant decrease in the incidence of clinical T3 and T4 disease. Again, demonstrating a stage shift from disease that can merely be managed, to disease that is amenable to cure. These T3 and T4 tumors, as well as T2 tumors, are most likely being diagnosed several years prior to when they would previously become evident. The advent of PSA testing is reclassifying these tumors as T1c, which is associated with decreased recurrence rates, and increased disease-specific survival, when compared to other clinical stages.29–31 The level of PSA at the time of diagnosis is a general surrogate of tumor volume or cancer burden. A decline in PSA levels over time is further evidence of stage migration to support screening. In our CPDR studies, the median PSA at the time of diagnosis decreased from 11.8 ng/dl in 1990 to 6.3 ng/dl in 1998.20 This is consistent with the findings of Vijayakumar et al. who have recently demonstrated a statistically significant drop in the PSA level of African American patients presenting with prostate cancer.32 Partin et al. have shown that the lower the pretreatment PSA prior to prostatectomy, the lower the chance of extracapsular extension, seminal vesical involvement and lymph-node metastasis.33 Moul et al. and many other investigators have shown that the PSA level is a significant contributor in determining the risk of recurrence after treatment with radical prostatectomy.34 Similarly, in patients treated with external beam radiation, the lower the level of pretreatment PSA, the greater the disease-free survival.29,35 Hopefully, this continued decrease in PSA at the time of diagnosis portends more successful treatment outcomes in the future. Most of the tumors diagnosed in the PSA-Era are not indolent tumors by traditional grade and Gleason criteria. Multiple studies including SEER have shown that moderately differentiated or Gleason sum 5–7 tumors predominate in the PSA-Era.12,13,36,37 One reason for the decrease in welldifferentiated tumors is the decrease in the number of


Population Screening for Prostate Cancer

transurethreal resection of the prostate (TURP) performed. It is established that tumors arising in the transitional zone (area resected with a TURP) have a significantly higher incidence of tumors with lower Gleason sum than tumors discovered in the peripheral zones by needle biopsy.38,39 Smith and Catalona have shown that 97% of the tumors detected through PSA screening are medically important (defined as palpable, multifocal or diffuse, and moderately or poorly differentiated).31 Other recent studies confirm that moderately differentiated or mid-Gleason grade tumors are clinically significant, with higher recurrence and diseasespecific mortality that lower grade tumors.23,40–42 Regarding survival, Gilliland et al. showed improved survival during a period of PSA screening in New Mexico using the SEER data.43 The SEER 5-year relative cancer survival rates for patients diagnosed in the following years groups: 1974–1977, 1980–1982 and 1989–1995 were 67%, 73% and 92%, respectively; each of these changes were statistically significant (P < 0.05). Etzioni et al. have determined that the improved survival is not due simply to PSA testing, even if one considers a very short lead time of 3 years.44 It is probably related to screening and more aggressive treatment. Nevertheless, our own data from CPDR also shows significant improvements in 5-year prostate cancer specific survival rates as the PSA Era has progressed.45 Specifically, for patients diagnosed between 1988 and 1991 at the Walter Reed Army Medical Center, the cancer specific survival was 81.7% compared to 92.5% for men diagnosed between 1992 and 1994 and 98.3% for men diagnosed between 1995 and 1998. This was based on a cohort of 2042 men and the cause of death was determined prospectively using the National Death Index, direct deaths certificate review and choice point commercial service (Fig. 1.1). Aside from these population and database trends, screening studies by Labrie et al.46 and Bartsch et al.47 suggest a benefit to population-based screening. Most notably, Bartsch et al. recently reported early results of the Tyrolean prostate cancer screening study in Austria.47 By aggressively offering screening to all men in the Tyrolean state of Austria between 1993

100 1995–98

Survival rate (%)

95 90 1992–94 85

5

and 1997, and testing two-thirds of eligible men between the ages of 45 and 75, they report a 42% decline in the diseasespecific mortality for prostate cancer compared to the rest of the county where PSA testing was not commonly practiced.

ARGUMENTS AGAINST POPULATION SCREENING Opponents of screening point to the potential for side effects from treatment, the possibility that some men will be treated unnecessarily, the economic burden on the health care system and the lack of definitive scientific evidence that the screening will reduce overall disease-specific mortality.19 Indeed, many men with prostate cancer do not die of the disease, whereas many other patients die of the disease despite our best efforts. No foolproof markers are currently available to differentiate these two groups. Therefore, a key objection to screening is that such efforts may uncover many cancers that, if left undetected, would never have caused morbidity or mortality; conversely, some cancers will cause death despite being detected by screening. Some observers have further recommended that screening should be avoided in men older than 70 or 75 years of age so as to reduce the detection of such ‘incidental cancers’ that are unlikely to affect life expectancy. Aside from the ‘true’ screening, or population-based screening controversy, case finding for prostate cancer using PSA and DRE is widely practiced. Case finding is the process of evaluating men with symptoms where the testing is for differential diagnosis of urinary tract or other disease. In this setting, PSA and DRE are standard tools that physicians must have at their disposal.48 The process of targeted screening for prostate cancer in a higher risk group of men, such as Blacks and those with a family history, could arguably, in my opinion, be considered similar to case finding. Recognizing that population screening for prostate cancer using PSA and DRE remains disputed to reduce the morbidity and mortality of the disease, authorities currently recommend that physicians and health care organizations provide the pros and cons as outlined above and let the well-informed patient decide. Many would argue that it would be wrong to mandate screening; however, it would be just as wrong not to offer the option of early detection tests for prostate cancer, especially for high-risk targeted groups, especially in light of aforementioned positive trends in the PSA-Era. Recently, the ACS and AUA have updated their prostate cancer screening to this effect.49,50 Most notably, the recommendations call for testing if the patient is undecided.49

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SHOULD AFRICAN AMERICAN MEN UNDERGO SCREENING FOR PROSTATE CANCER?

1988–91

75 70 0

1

2

3

4

5

6

7

8

9

10

Time to death from prostate cancer (years) Fig. 1.1. Survival from prostate cancer by time period of diagnosis.

For African American men specifically, do we recommend population screening based on current knowledge of greater incidence, greater stages at diagnosis and worse outcome or do


6


we wait for more definitive screening efficacy studies? I believe we have reasonable basis to recommend routine testing now using screening guidelines optimized for Black men.

RACIAL DIFFERENCES It has been widely recognized that there are observed differences in prostate cancers in White and Black men51–53 and our own studies in the equal access US military health care system are no exception.54 In 1995, we were the first to show that Black men with newly diagnosed prostate cancer had higher PSA values than White men, even after adjustment for age at diagnosis and grade and clinical stages of cancer.55 This study also documented that, even within the traditional clinical stage categories at diagnosis, Black men had significantly greater cancer volumes. Considering that the Black men were, on average, about 3 years younger than the White men, this tumor volume disparity was striking. In a more recent update with 226 cases, the higher cancer volume stage-for-stage in Black men persisted.56 What is accounting for the greater cancer burden in these Black men, who seemingly have equal access to screening as the White men? It could be that the Black men are not availing themselves to testing, have greater delay in diagnosis and larger tumors. We know that, in general, there has been less awareness of prostate cancer and less screening in the African American community.57 Data from Prostate Cancer Awareness Week consistently show that only about 5% of participants are Black despite the fact that 12% of the population as a whole is Black.58 On the other hand, is there a biologic factor, or factors, such as testosterone, that is making these tumors grow bigger more quickly? Studies in younger men have shown that Blacks had testosterone levels 10–15% higher than age-matched Whites.59 Furthermore, a more recent study has found genetic variation in the androgen receptor (AR) gene that may make the receptor more active in African American men.60 Specifically, the CAG polymorphic repeat in exon 1 of AR is shorter in Black men and theoretically could potentiate the effect of testosterone in prostatic cells. Alternatively, is it a combination of behavior and biology that is responsible for the observed differences? Despite not knowing the exact cause, what can we do now?

RACE-ADJUSTED GUIDELINES Working with the US military health care systems patients, our group has shown that Black men with newly diagnosed prostate cancer have higher serum PSA values than do Whites, even after correction for stage grade and tumor volume.55 In view of these findings, our group has also studied the ability of PSA to detect prostate cancer in both Caucasian and African American men and developed age-adjusted PSA reference ranges for maximal cancer detection.22 In this study, between January 1991 and May 1995, serum PSA concentration was

determined for 3475 men without clinical evidence of prostate cancer (1802 Caucasians, 1673 African Americans) and 1783 men with this disease (1372 Caucasians, 411 African Americans). PSA concentration was analyzed as a function of age and race to determine operating characteristics of PSA for the diagnosis of prostate cancer. Serum PSA concentration correlated directly with age for both Black and White men (r = 0.40, P = 0.0001 for Blacks and r = 0.34, P = 0.0001 for Whites). African American men had significantly higher PSA concentrations than Caucasian men (P = 0.0001). When sensitivity was plotted against 1-specificity, the area under the receiver operator characteristic (ROC) curve was 0.91 for Black men and 0.94 for White men, indicating that the PSA test was an excellent early detection tool. For comparison, the Papanicolaou smear for cervical cancer, which is an accepted clinical screening test, has an ROC value of 0.70. When we calculated age-specific reference ranges using identical methodology to Oesterling and colleagues in their 1993 study of primarily Caucasian patients from Olmstead County, Minnesota,21 we found very similar values for White men but higher values for Black men. These ranges were 0–2.4 ng/ml for black men aged 40–49, 0–6.5 ng/ml for men aged 50–69, 0–11.3 ng/ml for men aged 60–69, and 0–12.5 ng/ml for men aged 70–79. We then tested these new ranges in our group of Black men with prostate cancer to determine how these ranges would have performed, if they had been used to detect their cancers. Unfortunately, these markedly higher ranges would have missed 41% of the cancer (only 59% sensitivity). The reason these traditionally derived ranges performed so poorly is because they are simply the 95th percentile of values in the Black controls. Because there is more variability of PSA results in Blacks without the evidence of cancer, there is more skewness, which pushes the 95th percentile farther to the right (higher). This higher range, however, is not clinically useful. We, therefore, developed age-adjusted reference ranges for Black men with prostate cancer, selecting PSA upper limits of normal by decade in the men with prostate cancer by using the 5th percentile of PSA values. Only the lowest 5% of prediagnosis PSA values in the Black men with cancer are ‘normal’ and the remainder (95%) are above the normal (95% sensitivity). We refer to these ranges as the Walter Reed/Center for Prostate Disease Research age-specific reference ranges for maximal cancer detection (Table 1.1). They maximize sensitivity (cancer detection) without undue loss of specificity [false-positive/unnecessary transrectal ultrasound (TRUS)/ biopsy]. Reference ranges have been controversial especially for older men because they raise the ‘normal’ above 4.0 ng/ml. Advocates of screening have been concerned that ‘important’ cancers will be missed in these ‘older’ men who may be perfectly healthy and physiologically younger. By the same logic, the race-specific reference ranges that we have proposed22 have been criticized in that many feel that it is inappropriate to raise the ‘normal’ above 4.0 ng/ml in a high-risk group regardless of age. Specifically, Littrup feels that our values are perhaps too complex and would favor only two PSA ‘normals’ >2.0 ng/ml for ‘high-risk men’ and >4.0 ng/ml for


Population Screening for Prostate Cancer

7

Table 1.1. Comparison of Walter Reed/Center for Prostate Disease Research PSA reference ranges for maximal prostate cancer detection vs. traditional age-adjusted and original normal PSA values.

WR/CPDR ASRRs for maximum detection22 (ng/ml) Age (years)

African American

40−49 50−59 60−69 70−79

0−2.0 0−4.0 0−4.5 0−5.5

Caucasian

Traditional PSA ‘normal’ for all men (ng/ml)

Traditional ASRRs based on Causcasian men Mayo Clinic21 (ng/ml)

0−2.5 0−3.5 0−3.5 0−3.5

0−4.0 0−4.0 0−4.0 0−4.0

0−2.5 0−3.5 0−4.5 0−6.5

WR/CPDR, Walter Reed/Center for Prostatic Disease Research; ASRR, age-specific PSA reference ranges.

the ‘general’ population.61 Furthermore, Powell et al. have similarly criticized our screening guidelines regarding the raising of the PSA screening threshold above that for Caucasian men.62 They reason that, for any given PSA level, the prognosis for African American men is likely worse than Caucasian men and by raising the screening threshold, we will likely lower prognosis in this high-risk group. The key point is that our traditional age-specific PSA reference ranges (ASRRs) and reference ranges for maximal cancer detection provide compelling data that a PSA of 4.0 ng/ml is too high for many patients.

A PSA OF 4.0 NG/ML IS TOO HIGH ESPECIALLY IN YOUNG MEN Despite the continuing controversy about the ‘exact’ proper PSA by age and race, the most important concept in my opinion is recognizing that a PSA of 4.0 ng/ml is too high a screening cut-point for younger men, particularly African American men between 40 and 49 years of age. Bullock et al. screened 214 Black men between 40 and 49 years of age and found a prevalence of prostate cancer of 0.9% (2 of 214) when a PSA of 4.0 ng/ml was used.63 Interestingly, this prevalence increased to 5.6% (2 of 36) when the Black men also had a family history of prostate cancer. Conversely, Catalona et al. from the same university, found that the cancer detection rate was 38% in a small group of 16 Black men who had biopsy for PSA values between 2.6 and 4.0 ng/ml.64 In a follow-up series, this same group found an even higher prevalence of 42% for African American men with a PSA between 2.6 and 4.0 ng/ml.65 Until further data are available, I believe that African American men with a PSA >2.0 ng/ml between 40 and 49 years of age should have further evaluation. In older Black men, particularly those who are healthy and in their 50s and 60s, a clinician may use our age-adjusted sensitivity-based ranges22 or may opt to be even more aggressive and use the 2.0 ng/ml advocated by Littrup61,66 or the 2.5 ng/ml recommended by Catalona and associates.64,65

LOWERED PSA REFERENCE RANGES FOR CURABLE CANCER The concept of developing PSA reference ranges not just for cancer but curable cancer is emerging. Reissigl et al. from Austria were the first group, to my knowledge, to define PSA cut-points by decade of age for curable prostate cancer.67 These PSA values ranged from 1.25 ng/ml for men in their 40s to 3.25 ng/ml for men in their 70s. Curability definitions are somewhat arbitrary unless one waits the required 10 years or more to know exactly which patients were, in fact, cured. Instead, pathologic stage and grade of radical prostatectomy patients is a reasonable surrogate of curability. To this end, Carter et al. in a large study from Johns Hopkins, defined ‘curability’ in their series as organ confined with any grade of cancer or specimen confined (negative margins, seminal vesicles, and lymph nodes) with a Gleason sum less than or equal to 6.68 I used this definition to show that only 45% of early PSA-Era Black men who underwent a radical prostatectomy at our hospital were ‘curable’.69 This compared to 74% for the predominantly White patients reported by Carter et al.68 Furthermore, by lowering the pretreatment PSA value, the curability for both Black men and White men is strikingly better. Specifically, at Johns Hopkins 94% of men with a PSA value ⭐4.0 ng/ml were curable and 83% of Black men from Walter Reed with this low PSA were curable.25 With this in mind, I have reported PSA reference ranges for curable prostate cancer in African American men who were considered cured and who had a pretreatment PSA value.70 Age-adjusted 5th, 10th and 25th percentile of pretreatment PSA was calculated to define cut-points for screening PSA values to optimize curable prostate cancer in African American men (Table 1.2). In other words, based on this preliminary study, one would biopsy Black men with a PSA value greater than approximately 1.0 ng/ml to have a 95% probability of diagnosing curable prostate cancer. Recognizing that lowering the PSA ‘normal’ is always a tradeoff of sensitivity versus specificity (unnecessary biopsies), the 90th or 75th percentile may be


8


Table 1.2. Age-adjusted PSA upper limits of normal to diagnose curable prostate cancer in African American men.

5th percentile (95% sens.) 10th percentile (90% sens.) 25th percentile (75% sens.)

40–59

60–79

0.9 1.7 3.2

1.0 2.7 5.1

a better compromise. Recognize that three of four of these values are less than the traditional normal of 4.0 ng/ml. Conversely, Carter et al. have most recently further examined the concept of PSA values and curable cancer.71 Unlike our concept of lowering the PSA, they feel that age is a more important determinant of curability and that the PSA threshold should remain at 4.0 ng/ml in younger men. They contend that simply by screening younger men, we will pick up a high proportion of curable disease.

WHAT IS THE ‘NORMAL’ PSA IN YOUNG MEN? Our Department of Defense-funded CPDR has recently conducted studies showing that a PSA of 4.0 ng/ml is significantly higher than normal for young men. In 750 Black and 750 White military members between the age of 15 and 45 who had serum banked in the Army and Navy Serum Repository (ANSR), the mean PSA values were 0.52 and 0.47 ng/ml, respectively.72 The 95th percentile ranged from 1.16 to 1.38 ng/ml for the Blacks stratified by decade of age (1.38 ng/ml in the 40–49 group); for the Whites, the corresponding values were 0.71–1.13 ng/ml. Based on these data, even using a PSA value of 2.0 ng/ml as a cut-point for both Black and White men is considerably higher than these 95th percentile values. Our second study was a prospective screening study of healthy officers enrolled in the US Army War College at Carlisle Barracks, PA, USA and is a collaboration between CPDR and the Armed Forces Physical Fitness Institute. Starting in 1997, approximately 225 matriculating officers entering the school have been offered PSA testing as part of a comprehensive executive health screen. Three years of data are available for this interim analysis on 602 men between 40 and 49 years of age.73 Only 10 of 602 (1.7%) had PSA ⭓2.5 ng/ml and only 3 (0.5%) had PSA ⭓4.0 ng /ml. One of 602 (0.17%) was diagnosed with prostate cancer (PSA of 15.5 ng/ml) and had pT3 disease at radical prostatectomy. This study was conducted in very healthy, primarily Caucasian, men and our conclusions to date suggest that screening below 50 in normalrisk individuals may not be needed. However, using a PSA screening normal cut-point of ⭓2.5 ng/ml, less than 2% of men required further evaluation. Furthermore, baseline PSA data were obtained to compare with future screens, which likely will be of clinical value. A similar study is being initiated in African American military members to determine if the yield of screening would be higher.

Aside from PSA-reference ranges, Presti et al. have proposed lowering the cut-off for PSA density to 0.1 to optimize prostate cancer detection in African American men.74 Even though it has recently been proposed that less than annual PSA screening may be appropriate for younger Caucasian men who start with a PSA 50 cm3), therefore, a repeat biopsy is needed, when initial biopsy yield showed no prostate cancer.


Prostate Biopsy: Who, How and When?

Table 9.1. Vienna nomogram: the number of cores needed per biopsy to ensure 90% certainty of cancer detection as a function of prostate gland size and age.

Age (years)

Size of prostate gland (cm3)

70

20–29 30–39 40–49 50–59 60–69 >70

8 12 14 16 — —

8 10 12 14 16 18

8 8 10 12 14 16

6 6 8 10 12 14

• Small volume cancers are more frequent in larger prostates. • Performing two sets of sextant biopsy, patients with greater prostates (>50 cm3) have twofold higher probability of detecting prostate cancer.

THE IMPACT OF PSA DERIVATES As we know from PSA-based screening studies, approximately 9% of all asymptomatic men will have elevated serum PSA values but only about a third will have cancer detected on initial biopsy.22,23 The question is whether the 66% men with an initially negative prostate biopsy have an elevated serum PSA value because of benign prostatic hyperplasia, prostatitis or undetected cancer in their peripheral or TZ of the prostate. Keetch et al. have previously shown that cancer detection rates at biopsies two or three were 19% and 8%, respectively. However, their patients underwent serial biopsies of the PZ only.24 In a recent study, the ability of % free PSA, PSAD and PSA-TZ to increase the sensitivity and specificity of PSA screening was evaluated prospectively.25 Of the 1051 men with a total PSA level of 4–10 ng/ml, the initial biopsy was positive for prostate cancer in 22% (231 out of 1051) of the subjects. All 820 subjects diagnosed with benign prostatic hyperplasia (BPH) after the initial biopsy underwent a repeat prostatic biopsy 6 weeks later. Prostate cancer was detected in 10% (83 out of 820) of these subjects. Compared to the 231 subjects in whom prostate cancer was detected from the initial biopsy, both total prostate volume and TZ volume were significantly higher (P < 0.001) in the 83 subjects with prostate cancer detected in the repeat biopsy sample. The majority of cancers (84%) were detected in PZ, compared to 16% detected in the TZ. Total PSA, PSAD and PSA-TZ were all significantly higher in subjects diagnosed with prostate cancer in initial and repeat biopsy (P < 0.01). Based on the results of a previous study,16 cut-off values improving specificity with a sufficiently high level of cancer detection (sensitivity) were selected. At a cut-off of 30% and 0.26 ng/ml per cm3, respectively, % free PSA and PSA-TZ

79

were the most accurate predictors of a positive repeat biopsy result. Although a similar number of unnecessary repeat biopsies would have been eliminated by either % free PSA or PSA-TZ (approximately 50%), prostate cancer detection was much lower for PSA-TZ (78%) compared to % free PSA (90%). In both the overall group (initial biopsy results plus repeat biopsy results) and the repeat biopsy group, % free PSA and PSA-TZ were the best predictors of prostate cancer (r = 0.2150, P < 0.001). The respective areas under curve (AUCs) for % free PSA and PSA-TZ were 74.2% and 82.7% in the overall group, and 74.5% and 69.1% in the repeat biopsy group (P < 0.001). Although Zlotta et al. previously reported that measurement of the TZ volume is accurate and reproducible,26 all TRUS measurements are operator dependent and, therefore, subject to possible variability. Furthermore, the measurement of the TZ in small or large prostates sometimes might be difficult. It was reported previously that PSA-TZ was not a significant predictor of biopsy results when the total prostate volume was 20% would have eliminated 45.5% of negative biopsies. When % free PSA was combined with a PSA-TZ density cut-off of >0.22 ng/ml per cm3, 54.2% of negative biopsies could have been avoided.29 Although some previous studies focused on repeat-biopsy results, most have been retrospective trials conducted in relatively small patient populations.24,30–39 In one study of 193 men with a negative initial biopsy, 51 (26%) were found to have prostate cancer on repeat biopsy. Total PSA and volumereferenced PSA had the highest sensitivity. Another retrospective study in 51 men with a total serum PSA level of 2–15 ng/ml demonstrated a lower median % free PSA value in patients with a positive repeat biopsy compared with those with a negative biopsy (15% vs. 19%, respectively; P = 0.05).30 A % free PSA cut-off of 22% yielded a sensitivity of 95% and a specificity of 44% for predicting repeat biopsy results. In a prospective study of 67 men with persistent total PSA elevations and normal DRE, a low % free PSA (50 cm3. If midlobar base

biopsies were omitted from the protocol, the resultant eight-biopsy PZ regimen detected 95% of tumors. The systematic sextant biopsy method, practiced for a decade now, is inadequate and more extensive biopsy protocols obtaining a minimum of eight tissue cores, particularly from the lateral PZs, should be performed. The detailed maps of consecutive radical prostatectomies have shown that prostate cancers expand mostly in the transverse direction across the posterior surface of the capsule, followed by the cephalocaudal direction.2 Directing the biopsies more lateral to the midparasagittal plane might enable sampling of the large group of cancers located more laterally in the PZ.2 The posterior and posterolateral border of compressed fibromuscular tissues caused by the expansion of transition zone hyperplastic nodules, observed on TRUS, serves as an excellent marker for placement of PZ biopsies where more than 70% of cancers originate.2 Based on a three-dimensional (3D) computer-assisted prostate biopsy simulator and mounted step-sectional radical prostatectomy specimens, Bauer et al. found that all the biopsy protocols that use laterally placed biopsies based on the five-region anatomic model are superior to the routinely used sextant prostate biopsy technique.9 Although the majority of tumors arise in the PZ, up to 24% of prostate cancers originate in the TZ.43 Other studies have reported rates significant lower than this. Of 847 men who underwent TRUS-guided systematic sextant and TZ biopsies, only eight (2.9%) patients (4.1% of only state T1c considered) had solitary TZ tumors.44 Terris noted that patients undergoing routine TZ biopsies, in addition to sextant biopsies, had positive biopsies involving the TZ alone in 1.8% of cases.45 In a similar study, isolated TZ cancer was found in only 2.6% of men biopsied.46 The Johns Hopkins group performed repeat sextant and TZ biopsies in 193 radical prostatectomy specimens. They found that the TZ biopsy by itself was positive in only 2.1% of cases, concluding that routine TZ biopsies are not justified in light of such low detection rates.47 The low diagnostic yield of systematic TZ biopsy at the time of initial biopsy argues strongly against their routine use for detection of early-stage prostate cancer. However, performing TZ biopsies as part of a protocol of repeat systematic biopsies in selected men with prior negative biopsies may sometimes provide important information, which is additional to that obtained by repeating sextant biopsies alone.


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To evaluate cancer location on initial and repeat biopsy in the EPCD, all cancers were entered in a 3D spatial model and areas of highest cancer density measured by means of a computer-based 3D image reconstruction.9 Whereas cancers detected on initial biopsy are distributed homogeneously over the entire prostate, cancers on repeat biopsy are found in a more apicodorsal location. A comparison of tumor density between both groups shows significant differences in apical tumor density (P = 0.001), in dorsal tumor density (P = 0.02) and especially in apicodorsal tumor density (P < 0.001). This may explain the lower cancer detection rate on repeat biopsies (biopsies are rarely directed apicodorsally) as well as the fact that these cancers are commonly missed on initial biopsy. Thus, upon repeat biopsy, the biopsy technique should be modified and needles should be directed to a more apicodorsal location.9 • A minimum of eight prostate cores (particularly from the lateral PZ zone) is needed. • The impact of systematic TZ zone biopsies is still unclear. • Repeat prostate biopsies should be directed in a more apicodorsal orientation.

PIN/ATYPIA AND PROSTATE BIOPSY High-grade prostatic intraepithelial neoplasia (PIN) is most likely a precursor of prostate cancer and is frequently associated with it, whereas the direct link between low-grade PIN and cancer is not established. The clinical evolution of isolated high-grade PIN has been the object of much concern because of the possibility of undiagnosed prostate cancer or the evolution of this premalignant lesion in invasive carcinoma. High-grade PIN has been identified in approximately 4–14% of prostate needle biopsies.48–50 Evaluation pathology trends show that, of 62 537 initial prostate needle-core biopsies submitted by office-based urologists, processed at a single pathology laboratory, isolated high-grade PIN was diagnosed in 4.1% of the biopsies, a number which probably reflects the real incidence of this entity in general practice as opposed to reference centres.47 According to Zlotta et al. and Raviv et al.,51–53 analyzing 93 patients with diagnosis of isolated PIN without concurrent carcinoma, the cancer detection rate on repeat biopsy or operated specimen increased with PIN grades. In each PSA subgroup (0–4, 4.1–10, >10 ng/ml) the subsequent cancer detection rate was higher for high-grade PIN than for low-grade PIN. Nearly 50% of patients with isolated high-grade PIN were found to have prostate cancer on repeat biopsy, whereas only 13% of patients with low-grade PIN did so. Weinstein and Epstein noted that serum PSA levels were elevated in 90% of patients with high-grade PIN and cancer compared to 50% of those with PIN without associated cancer at the time of initial diagnosis, suggesting that serum PSA may be useful in distinguishing patients with PIN who will have cancer detected on repeat biopsy.54 In the study by Raviv et al.,51,52 the group of patients that later developed cancer had

significantly higher PSA compared to patients without cancer on repeat biopsy. In high-grade PIN, the incidence of later cancer was 33% and 62%, respectively, when PSA was below 4 ng/ml or above 10 ng/ml.52 Therefore, all subgroups of patients with high-grade PIN, but especially those with elevated PSA, should undergo repeat biopsy. Low-grade PIN was associated with subsequent cancer in 42.8% of cases when PSA was above 10 ng/ml, in 10.7% when PSA was between 4 and 10 ng/ml and in none of the cases when PSA was ⭐4 ng/ml.52 Low grade should cause no further action unless other factors, such as an elevated PSA, increase the suspicion of prostate cancer and should prompt repeat biopsies. The high detection rate of later cancer when PSA is over 10 ng/ml in low-grade PIN is similar to Cooner’s report on the detection of prostate cancer without reference to PIN.53 When PSA is above 10 ng/ml and whatever PIN grade, it seems clear that the high detection rate is more a reflection of the undetected presence of cancer than of the presence of PIN. Most experts agree that high-grade PIN is clearly a preneoplastic lesion because it fulfils all requirements for such a lesion. Thus, high-grade PIN, especially when associated with high PSA or abnormal DRE or TRUS, should be taken as a signal of high to extremely high probability of prostate cancer and repeat biopsies should be performed.53 • High-grade PIN in first prostate biopsy requires repeat biopsy.

MORBIDITY OF PROSTATE BIOPSY Generally, TRUS-guided biopsies are considered safe and are commonly performed in an outpatient setting. Djavan et al. found only two major complications in 1871 biopsies performed.25 In contrast, minor complications were frequent with 69.7% of all patients experiencing at least one complication. Although these complications generally do not need intervention (neither conservative nor surgical), patients need to be informed adequately. When evaluating 81 patients undergoing TRUS-guided biopsy, Irani et al. reported a mean visual analog pain scale (VAS score) of 3.55 Nineteen per cent of patients refused a repeat biopsy without some sort of anesthesia, and the authors questioned the safety and morbidity of repeat biopsies.55 Except for moderate to severe vasovagal episodes (2.8% vs. 1.4%, P = 0.03), no differences were noted in pain apprehension (VAS score 2.4 vs. 2.6, P = 0.09), and patient discomfort (moderate to severe in 8% vs. 11%, P = 0.29) during first and repeat biopsy, respectively.25 In contrast, in series reported by Collins et al.56 and Clemens et al.,57 22% and 30% of patients, respectively, considered the procedure significantly painful. Djavan et al. found an age-dependent pattern in pain apprehension with the younger patient (age 80 years, respectively. Thus, younger patients need to be counselled



adequately, and local or topical anaesthesia used. Rodriguez et al. confirmed also a higher discomfort rate in the younger age group as well.58 A review of the literature shows that the majority of the studies evaluated infectious and bleeding complications only at first biopsy. Several studies have demonstrated a significant decrease in infectious complications when prophylactic antibiotics were used.25,59–63 Thompson et al. reported asymptomatic bacteraemia, commonly with Bacteroides species and Enterococcus.64 Symptomatic infections were most commonly caused by Escherichia coli and Enterococcus, suggesting the use of fluoroquinolones and metronidazole for antibiotic prophylaxis.60,64–66 Sieber et al. in a retrospective review of 4439 patients reported an infection rate of 0.1%.67 Infectious complications are rare and, when needed, oral therapy is sufficient. Thus, cost issues need to be taken into consideration when selecting the type of antibiotic prophylaxis to be used. Urinary tract infections with fever were seen in 2.1% and 1.9% (P = 0.02) of patients at first and repeat biopsy, respectively.25 In one case (0.1%), a patient had to be admitted for prolepsis and was managed with intravenous antibiotics and discharged on day 6. In the immediate postbiopsy period, rectal bleeding (2.1% vs. 2.4%, P = 0.13), mild hematuria (62 vs. 57%, P = 0.06) and severe hematuria (0.7 vs. 0.5%, P = 0.09) were reported for the first and repeat biopsy, respectively. Delayed hemorrhagic morbidity included hematospermia (9.8% vs. 10.2%, P = 0.1), recurrent mild hematuria (15.9 vs. 16.6%, P = 0.06), respectively. Again no difference was noted between first and repeat biopsy. The rate of persistent hematuria was lower than previously reported (30–50%).59 This may be due to the fact that we routinely performed sextant biopsies and two additional TZ biopsies, whereas others had various numbers and sites of biopsy cores. Hematospermia was obviously reported for those patients who had ejaculation prior to the biopsy procedure (n = 671). The lower rate in our population (as compared to 59% reported in the literature) was similar to that reported by Rodriguez et al.59 Transrectal ultrasound-guided biopsy of the prostate is generally well tolerated with minor pain and morbidity. Repeat biopsies can be performed 6 weeks later with no significant difference in pain apprehension, infectious or hemorrhagic complications. • • • •

The morbidity of prostate biopsy in general is very low. Prophylactic antibiotic decreases morbidity. A systematic repeat biopsy has no more morbidity. Younger patients less than 60 years need to be counselled with respect to a higher pain and discomfort level during repeat biopsy, and local or topical anaesthesia offered, if desired.

SUMMARY It seems that traditional sextant biopsies might become obsolete in future designed trials, since a body of evidence supports the findings that this technique is far from optimal in patients with large prostates. Whether the future lies in performing

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biopsies more laterally, increasing the number of biopsies to 10, 12, 15 or even 18, or simply repeating the sextant biopsy scheme still needs to be verified. Current data suggest that cancers detected on repeat biopsy have a similar stage and grade distribution and total PSA values compared to cancers found on initial biopsy. Moreover, specific biological determinants such as % Gleason grade 4/5, Gleason score and cancer volume were identical in both groups, suggesting similar biological properties and at least identical characteristics, thus, opting in favor of a repeat biopsy policy. Location and density measurements of cancers detected suggest that cancers missed on initial biopsy and subsequently detected on repeat biopsy are located in a more apicodorsal location. Repeat biopsies should thus be directed to this rather spared area in order to improve cancer detection rates. However, cancers detected on third and fourth systematic biopsy show characteristics of ‘insignificant’ cancers. Therefore, a systematic repeat biopsy after the second biopsy in a PSA range of 2.5–10 ng/ml is not indicated and PSA-based watchful waiting should be advocaded. Percentage free PSA and PSA-TZ are the best markers for repeat prostate biopsy, increasing sensitivity and specificity. In prostate cancer patients detected on repeat biopsy, PSAD and PSA-TZ levels were higher. In all patients with high-grade PIN a repeat biopsy should be performed. Repeat biopsies performed as early as 6 weeks after the initial biopsy were generally well tolerated with minor pain and morbidity. Vasovagal episodes were more frequent after the first biopsy. Antibiotic prophylaxis seems to be warranted and limited to 4 days at least. Younger patients less than 60 years need to be counselled with respect to a higher pain and discomfort level during repeat biopsy, and local or topical anesthesia offered, if desired.

REFERENCES 1. Djavan B, Susani M, Bursa B et al. Predictability and significance of multifocal prostate cancer in the radical prostatectomy specimen. Tech. Urol. 1999; 5:139–42. 2. Stamey TA. Making the most out of six systematic sextant biopsies. Urology 1995; 45:2–12. 3. Billebaud T, Villers A, Astier L et al. Advantage of systematic random ultrasound-guided biopsies, measurement of serum specific antigen levels and determination of prostate volume in the early diagnosis of prostate cancer. Eur. Urol. 1992; 21:6–14. 4. Vashi AR, Wojno KJ, Gillespie B et al. A model for the number of cores per prostate biopsy based on patient age and prostate gland volume. J. Urol. 1998; 159:920–4. 5. Karakiewicz PI, Aprikian AG, Meshref AW et al. Computerassisted comparative analysis of four-sector and six section biopsies of the prostate. Urology 1996; 48:747–50. 6. Karakiewicz PI, Hanley JA, Bazinet M. Three-dimensional computer-assisted analysis of sector biopsy of the prostate. Urology 1998; 52:208–12. 7. Ravery V, Billeband T, Toublanc M et al. Diagnostic value of the systematic trus-guided prostate biopsies. Eur. Urol. 1999; 35:298–303. 8. Eskew AL, Bare RL, Mc Cullongh DL. Systematic 5-region prostate biopsy is superior to sextant method for diagnosing carcinoma of the prostate. J. Urol. 1997; 157:199–202.


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9. Bauer JJ, Zeng J, Weir J et al. Three-dimensional computersimulated prostate models: lateral prostate biopsies increase the detection rate of prostate cancer. Urology 1999; 53:961–7. 10. Chang JJ, Shinohara K, Bhargava V et al. Prospective evaluation of lateral biopsies of the peripheral zone for prostate cancer detection. J. Urol. 1998; 160:2111–14. 11. Norberg M, Egevad L, Holmberg L et al. The sextant protocol for ultrasound-guided core biopsies of the prostate underestimates the presence of cancer. Urology 1997; 50:562–6. 12. Djavan B, Zlotta AR, Ekane S et al. Is onset of sextant biopsies enough to rule out prostate cancer? Influence of transition and total prostate volumes on prostate cancer yield. Eur. Urol. 2000; 38:218–24. 13. Uzzo RG, Wei JT, Waldbaum RS et al. The influence of prostatic size on cancer detection. Urology 1995; 46:831–6. 14. Chen ME, Troncoso P, Johnston DA et al. Optimization of prostate biopsy strategy using computer based analysis. J. Urol. 1997; 158:2168–75. 15. Djavan B, Zlotta AR, Remzi M et al. Total and transition zone prostate volume and age: How do they affect the utility of PSA based diagnostic parameters for early prostate cancer detection? Urology 1999; 54:846–52. 16. Djavan B, Zlotta AR, Byttebier G et al. Prostate specific antigen density of the TZ for early detection of prostate cancer. J. Urol. 1998; 160:411–18. 17. Zlotta AR, Djavan B, Marberger M et al. Prostate specific antigen density of the transition zone: a new effective parameter for prostate cancer prediction. J. Urol. 1997; 157:1315–21. 18. Levine 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; 159:471–6. 19. Letran JL, Meyer GE, Loberiza FR et al. The effect of prostate volume on the yield of needle biopsy. J. Urol. 1998; 160:1718–21. 20. Vashi AR, Wojno KJ, Gillespie B et al. A model for the number of cores per prostate biopsy based on patient age and prostate gland volume. J. Urol. 1998; 159:920–4. 21. Djavan B, Rovery V, Zlotta A et al. Prospective evaluation of prostate cancer on biopsies 1, 2, 3 and 4: when should we stop. J. Urol. 2001; 166:1673–83. 22. Catalona WJ, Smith DS, Ratliff TD et al. Measurement of prostate specific antigen in serum as a screening test for prostate cancer. N. Engl. J. Med. 1991; 324:1156–61. 23. Brawer MK, Chetner MP, Beatie J et al. Screening for prostatic carcinoma with prostate specific antigen. J. Urol. 1992; 147:841–5. 24. Keetch DW, Catalona WJ. Prostatic TZ biopsies in men with previous negative biopsies and persistently elevated serum prostate specific antigen values. J. Urol. 1995; 154:1795–7. 25. Djavan B, Zlotta AR, Remzi M et al. Optimal predictors of prostate cancer in repeat prostate biopsy: a prospective study in 1,051 men. J. Urol. 2000; 163:1144–8. 26. Zlotta AR, Djavan B, Roumeguere T et al. Transition zone volume on transrectal ultrasonography is more accurate and reproducible than the total prostate volume. Br. J. Urol. 1997; Suppl. 80:A926. 27. 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. 28. Chan DW, Sokoll LJ, Partin AW et al. The use of % free PSA to predict prostate cancer probabilities: an eleven center prospective study using an automated immunoassay system in a population with nonsuspicious DRE. J. Urol. 1999; 161 (Suppl. 4):A353. 29. Horninger W, Reissigl A, Klocker H et al. Improvement of specificity in PSA-based screening by using PSA transition zone density and percent free PSA in addition to total PSA levels. Prostate 1998; 37:133–9.

30. Ukimura O, Durrani O, Babaian J. Role of PSA and its indices in determining the need for repeat prostate biopsies. Urology 1997; 50:66–72. 31. Letran JL, Blasé AB, Loberiza FR et al. Repeat ultrasound guided prostate needle biopsy: use of free to total PSA ratio in predicting prostatic carcinoma. J. Urol. 1998; 60:426–9. 32. Morgan TO, McLeod DG, Leifer ES et al. Prospective use of free prostate-specific antigen to avoid repeat prostate biopsies in men with elevated total prostate-specific antigen. Urology 1996; 48:76–80. 33. Fleshner NE, O’Sullivan M, Fair WR. Prevalence and predictors of a positive repeat transrectal ultrasound guided needle biopsy of the prostate. J. Urol. 1997; 158:505–9. 34. Catalona WJ, Beiser JA, Smith DS. Serum free prostate specific antigen and prostate specific antigen density measurements for predicting cancer in men with prior negative prostatic biopsies. J. Urol. 1997; 158:2162–7. 35. Keetch DW, McMurtry JM et al. Prostate specific antigen density versus prostate specific antigen slope as predictors of prostate cancer in men with initially negative prostatic biopsies. J. Urol. 1996; 156:428–31. 36. Rietbergen JBW, Boeken Kruger AE, Hoedemaeker RF et al. Repeat screening for prostate cancer after 1-year followup in 984 biopsied men: clinical and pathological features of detected cancer. J. Urol. 1998; 160:2121–5. 37. Durkan GC, Greene DR. Elevated serum prostate specific antigen levels in conjunction with an initial prostatic biopsy negative for carcinoma: who should undergo a repeat biopsy? Br. J. Urol. Int. 1999; 83:34–8. 38. Noguchi M, Yahara J, Koga H et al. Necessity of repeat biopsies in men for suspected prostate cancer. Int. J. Urol. 1999; 6:7–12. 39. Keetch DW, Catalona WJ, Smith DS. Serial prostatic biopsies in men with persistently elevated serum prostate specific antigen values. J. Urol. 1994; 151:1571–4. 40. Stamey TA, McNeal JE, Yemoto CM et al. Biological determinants of cancer progression in men with prostate cancer. JAMA 1999; 281:1395–400. 41. Hodge KK, McNeal JE, Terris MK et al. Random systematic versus directed ultrasound guided transrectal core biopsies of the prostate. J. Urol. 1989; 142:71–4. 42. Presti JR, Chang JJ, Bhargava V et al. The optimal systematic prostate biopsy scheme should include 8 rather than 6 biopsies: results of a prospective clinical trial. J. Urol. 2000; 163:163–7. 43. McNeal JE, Redwine EA, Freiha FS et al. Zonal distribution of prostatic adenocarcinoma: correlation with histologic pattern and direction of spread. Am. J. Surg. Path. 1988; 12:897–906. 44. Bazinet M, Karakiewicz PI, Aprikian AG et al. Value of systematic TZ biopsies in the early detection of prostate cancer. J. Urol. 1996; 155:605–6. 45. Terris MK, Pham TQ, Issa MM et al. Routine TZ and seminal vesicle biopsies in all patients undergoing transrectal ultrasound giuded prostate biopsies are not indicated. J. Urol. 1997; 157:204–6. 46. Morote J, Lopes M, Encabo G, de Torres I. Value of routine TZ biopsies in patients undergoing ultrasound-guided sextant biopsies for the first time. Eur. Urol. 1999; 35:294–7. 47. Epstein JI, Walsh PC, Sauvageot J et al. Use of repeat sextant and transistion zone biopsies for assessing extent of prostate cancer. J. Urol. 1997; 158:1886–90. 48. Orozco R, O’Dowd GJ, Kunnel B et al. Observations on pathology trends in 62,537 protstate biopsies obtained from urology private practices in the United States. Urology 1998; 51:186–95. 49. Bostwick DG, Qian J, Frankel K. The incidence of high grade prostatic intraepithelial neoplasia in needle biopsies. J. Urol. 1995; 154:1791–4. 50. Green J, Feneley MR, Young M et al. The prevalence of prostatic intraepithelial neoplasia (PIN) in biopsies from hospital practice and pilot screening: clinical implications. J. Urol. 1996; 155(Suppl.):A1260.



51. Raviv G, Janssen TH, Zlotta AR et al. Prostatic intraepithelial neoplasia: influence of clinical and pathological data on the detection of invasive prostate cancer, in patients initially diagnosed on previous needle biopsy. J. Urol. 1996; 156:1050–5. 52. Raviv G, Zlotta AR, Janssen TH et al. Does prostate-specific antigen and prostate-specific antigen density enhance the detection of prostate cancer in patients initially diagnosed to have prostatic intraepithelial neoplasia? Cancer 1996; 77:2103–8. 53. Zlotta AR, Raviv G, Schulman CC. Clinical prognostic criteria for later diagnosis of prostate carcinoma in patients with initial isolated prostatic intraepithelial neoplasia. Eur. Urol. 1996; 30:249–55. 54. Weinstein MH, Epstein JI. Significance of high grade prostatic intraepithelial neoplasia on needle biopsy. Human Pathol. 1993; 24:624–9. 55. Irani J, Fournier F, Bon D et al. Patient tolerance of transrectal ultrasound-guided biopsy of the prostate. Br. J. Urol. 1997; 79:608–10. 56. Collins GN, Lloyd SN, Hehir M et al. Multiple transrectal ultrasound-guided prostatic biopsies – true morbidity and patient acceptance. Br. J. Urol. 1993; 71:460–3. 57. Clements R, Aideyan OU, Griffiths GJ et al. Side effects and patient acceptability of transrectal biopsy of the prostate. Clin. Radiol. 1993; 47:125–6. 58. Rodriguez LV, Terris MK. Risks and complications of transrectal ultrsound guided prostate needle biopsy: a prospective study and review of the literature. J. Urol. 1998; 160:2115–20.

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59. Cooner WH, Mosley BR, Rutherford CL et al. Prostate cancer detection in a clinical urological practice by ultrasonography, digital rectal examination and prostate specific antigen. J. Urol. 1990; 143:1146–52. 60. Crawford ED, Haynes AL Jr, Story MW et al. Prevention of urinary tract infection and sepsis following transrectal prostatic biopsy. J. Urol. 1982; 127:449–51. 61. Davison P, Malament M. Urinary contamination as a result of transrectal biopsy of the prostate. J. Urol. 1971; 105: 545–6. 62. Fawcett DP, Eykyn S, Bultidue MI. Urinary tract infection following trans-rectal biopsy of the prostate. Br. J. Urol. 1975; 47:679–81. 63. Ashby EC, Rees M, Dowding CH. Prophylaxis against systemic infection after transrectal biopsy for suspected prostatic carcinoma. Br. Med. J. 1978; 2:1263–4. 64. Thompson PM, Talbot Rw, Packham DA et al. Transrectal biopsy of the prostate and bacteremia. Br. J. Surg. 1980; 67:127–8. 65. Thompson PM, Prior JP, Williams JP et al. The problem of infection after prostatic biopsy: the case for the transperineal approach. Br. J. Urol. 1982; 54:736. 66. Gustafsson O, Norming U, Nyman CR et al. Complications following combined transrectal aspiration and core biopsy of the prostate. Scand. J. Urol. Nephrol. 1990; 24:249–51. 67. Sieber PR, Rommel FM, Agusta VE et al. Antibiotic prophylaxis in ultrasound guided transrectal prostate biopsy. J. Urol. 1997; 157:2199–200.


Prostate Cancer Prevention: Strategies and Realities

Chapter

10

Robert G. Uzzo*, Deborah Watkins-Bruner, Eric M. Horwitz, Andre Konski, Alan Pollack, Paul F. Engstrom and Vladimir Kolenko Department of Surgical/Urologic Oncology (RGU, VK), Department of Population Science (DWB, PFE), Department of Radiation Oncology (EMH, AK, AP), Fox Chase Cancer Center, Temple University School of Medicine, Philadelphia, PA, USA

INTRODUCTION The management of solid malignancies has evolved over the last half century. Historically, cancer treatments were administered only when patients presented with acute events or developed overt manifestations of their disease. This reactive approach has largely been supplanted by a proactive one, whereby the goal of clinical oncology is increasingly early detection and prevention of long-term negative outcomes. The point of first intervention has been pushed forward by the development of sophisticated imaging techniques, flexible fiber optics and increasingly sensitive biomarkers, allowing most malignancies to be detected much earlier in their natural history. Additionally, important advances in therapeutics, including infection control, blood banking, effective anesthesia and pain control, invasive monitoring and acute postsurgical care permit complex patient management. Prostate cancer represents a relevant case in point. Prior to the widespread use of prostate specific antigen (PSA), nearly three-quarters of prostate cancer patients presented with symptomatic locally advanced disease or metastases.1 In contrast, the most common presentation today is non-palpable asymptomatic disease detected due to elevation in the serum PSA level.2 Clinical evidence suggests this tendency toward early diagnosis and intervention will increase cancer-specific survival rates.3 Given the potential for improved outcomes, *To whom correspondence should be addressed.

oncologic interventions often begin with the diagnosis of asymptomatic microscopic disease, incipient disease or increasingly no disease at all. The practice of ‘proactive medicine’ in clinical oncology can be separated into cancer screening and prevention strategies.*Screening involves detection of established disease early in its course, whereas prevention relates to patients with no clinically identifiable disease. Preventative efforts have been classified as primary, secondary or tertiary, depending on the targeted population. Primary cancer prevention efforts involve interventions in otherwise healthy individuals so as to prevent disease occurrence. This means intervening prior to the initiating cellular or molecular events. Secondary prevention strategies involve intervention after the initiating cellular events have already occurred in an attempt to prevent the promotional phase of carcinogenesis. Since these patient may be difficult to identify, on a practical level, secondary cancer prevention targets patients ‘at risk’ for a given disease because of known inheritable characteristics such as germline mutations. Tertiary prevention strategies involve intervention in an attempt to alter the course of already established disease. These efforts target patients with ‘premalignant’ disease, such as in situ carcinoma, or in the case of prostate cancer, prostatic intraepithelial neoplasia (PIN).4 Most prevention strategies focus on the identification of risk factors, public education and reinforcement of avoidance


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behaviors. Non-cancer examples include the association between dietary fat and obesity with heart disease, alcohol abuse with liver disease and promiscuity with sexually transmitted diseases. The concept of prevention is relatively new in clinical oncology and has been patterned after these and other successful public health initiatives. Oncologic examples include smoking cessation to reduce the incidence of lung carcinoma, limiting sun exposure for patients at risk for melanoma, removing asbestos to limit mesothelioma risk and decreasing contact with other known industrial carcinogens. While early cancer prevention programs have stressed avoidance, more recent cancer prevention strategies include direct intervention with substances believed to inhibit one or more steps involved in malignant transformation. The administration of agents in this manner has been termed chemoprevention. To date, there have been relatively few well-controlled cancer chemoprevention studies. Examples include the Breast Cancer Prevention Trial (BCPT) randomizing over 13 000 women at risk for developing breast cancer to receive either tamoxifen or placebo,5 the α-tocopherol–β-carotene (ATBC) lung cancer prevention trial evaluating over 29 000 male smokers,6 the Prostate Cancer Prevention Trial (PCPT)7,8 and the SELECT9 trial following over 18 000 and 32 000 men, respectively, in an attempt to decrease the risk of developing prostate cancer with 5α-reductase inhibitors (PCPT) or selenium and/or vitamin E (SELECT). Trials of this magnitude require immense resources and intense collaboration to avoid confounding variables, which can limit data interpretation. The National Institutes of Health and the National Cancer Institute now recognize the importance of chemoprevention trials and are actively involved in their development and oversight. Successful preventative agents must be sufficiently effective, minimally invasive, offer a low side-effect profile and be administered early enough in the course of the disease to affect outcome. Implicit in the design of preventative strategies is an understanding of the natural history of the disease they are intended to prevent. Malignancies most likely to benefit from preventative measures must have early events associated with a slow progression to malignant transformation. It is in these types of tumors that the interaction between environmental influences and genetic ones are likely to be greatest and, therefore, potentially benefited by avoidance or interactive preventative techniques. This makes carcinoma of the prostate an ideal neoplasm for preventative efforts.

PROSTATE EVOLUTION, GROWTH AND DIFFERENTIATION Prostate cancer is the most common non-cutaneous malignancy in American men.10 It is also primarily a disease of men beyond their reproductive years, thereby severely limiting the evolutionary selective process against cancer.11 Observational data suggest that environment plays an important role in determining the risk of prostate cancer. First, there is tremendous species specificity of prostate cancer, with a significant incidence of

spontaneous prostate cancer observed only in humans and dogs.11 None of man’s closest primate relatives are susceptible to carcinoma of the prostate. Second, there is tissue specificity for cancer among men’s reproductive organs. Despite sharing similar genetics and microenvironments, the human vas deferens and seminal vesicle rarely undergo malignant transformation. In addition, ethnic and geographical variations exist in the incidence of prostate cancer. Compared to the USA, the risk of prostate cancer is as much as tenfold less in Asian countries, a tendency that is lost upon immigration and adoption of a Western diet.11,12 Lastly, there is a high incidence of early pathological changes in the prostate epithelium of both American and Asian men, suggesting that differences in molecular promotion and not initiation explain the observed variations in incidence and mortality.11,13 Taken together, these data support the influence of the environment and epigenetic events on the clinical progression of prostate cancer. The prostate originates from solid epithelial outgrowths that emerge from the endodermal urogenital sinus below the developing bladder at approximately 10 weeks gestation. The prostatic buds grow into the adjacent mesenchyme, lengthen to form ducts, arborize and canalize.14 By 13 weeks approximately 70 primary ducts exist, which exhibit secretory cytodifferentiation.15 Further embryonic growth involves ductal proliferation and the establishment of prostate zonal anatomy. Considerable cellular heterogeneity exists across the prostatic ductal epithelium (Fig. 10.1). Signals derived from the developing prostatic stroma are believed to control the rate and fate of proliferating prostate epithelial cells.16 The human prostate is known to undergo several growth phases: fetal growth, followed by limited regression after birth and growth cessation, then ultimately prostatic regrowth accompanying the androgen surge of puberty until adulthood at which time the process stops17 (Fig. 10.2). In man and dog, prostatic growth is reiterated during aging as part of benign or neoplastic proliferative processes. This has led McNeal to theorize a ‘reawakening’ of embryonic growth within the prostate.18 Studies of prostatic cellular proliferation demonstrate that prostate epithelial growth occurs early in a man’s life, peaking in men 30–40 years old when prostate doubling times are 4–5 years. However, clinical benign prostatic hyperplasia (BPH) and prostate cancer are much more common during the seventh and eighth decades of life, when prostate epithelial growth is minimal and doubling times are significantly longer.17,19 These data suggest that for chemopreventative strategies to be maximally effective, they must be applied to men much younger than those typically at risk for developing prostate cancer.

EPIDEMIOLOGY RISK FACTORS AND INITIATING EVENTS Pathological studies reveal that the development of prostate cancer is a near inevitable consequence of aging in men. Its prevalence is substantial in autopsies of men in their 50s and 60s (29%) and increases progressively with each succeeding



Proximal

Histology:

Basal cells:

Castration-induced changes: Number branch points Changes in cellular cytoskeleton Basal cell population Androgen stimulation after castration: Basal cell population DNA synthesis

Distal

Simple cuboidal non-secretory to transitional epithelium

Tall columnar with secretory cytologic features

Abundant

Sparse

↑

↑↑↑

↓ None Min. change

↓↓↓ None

Min. change ↑

↓↓ ↑↑

DNA synthesis during normal growth phases:

91

↑↑

Fig. 10.1. Considerable heterogeneity exists across the prostatic ductal epithelium that may provide valuable insight into clinical relevant mechanisms, such as cellular initiation, disease progression, and response or resistance to therapies. Adapted from Uzzo et al.14

# of prostate cells

decade.20 In autopsied males, 40–50% of men in their 70s and nearly 70% of men in their 80s have histologic evidence of the disease.21 More recent data suggest that 6% of Asian men in their 30s who died from unrelated causes had histologic changes

Birth

Childhood

Puberty

Adulthood

Senescence

Fig. 10.2. The human prostate undergoes several growth phases: fetal growth, followed by limited regression after birth and growth cessation, then ultimately prostatic regrowth accompanying the androgen surge of puberty until adulthood, at which time the process stops.17 Studies of prostatic epithelial doubling times demonstrate higher levels of cellular growth several decades before the appearance of clinical disease, suggesting that prostate cancer prevention efforts should be started early in patients at risk.

consistent with prostate cancer.22 Race and geographic area do not seem to influence this autopsy prevalence.23 In contrast to histologic evidence of latent prostate cancer, the age-adjusted incidence and death rates from prostate cancer vary dramatically between countries and ethnic groups with the highest rates in African Americans (149/100 000 person years), intermediate rates in USA Whites (107/100 000 person years) and the lowest rates in Japanese (39/100 000 person years) and Chinese (28/100 000 person years).24 It has been recognized for some time that there are at least two distinct populations of men with prostate cancer: those that will die with the disease and those that will die as a consequence of it. Understanding the genetic and epigenetic factors distinguishing these two groups is imperative and has immediate clinical implications. A number of modifiable and non-modifiable risk factors have been associated with the development of prostate cancer. The most well established of these are non-modifiable including age, race and family history.25 However, possible modifiable risk factors are beginning to emerge including intake of dietary fat, calcium, lycopene and soy, cigarette smoking, androgen levels and receptor expression.25 Many other potential risk factors have been reported but not validated. Each may offer a potential point of dietary or pharmacological intervention. Despite these associations, the etiology of prostate cancer remains elusive. A number of somatic genetic lesions have


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been identified in the DNA from prostate cancer cells using sophisticated molecular techniques, including comparative genome hybridization, microsatellite repeat polymorphism allelotyping and fluoresence in situ hybridization (FISH).26–29 These studies demonstrate that most cases of prostate cancer exhibit somatic genome abnormalities; however, there is striking heterogeneity in the patterns displayed.26 These differences reflect the variable clinical behavior of most prostate cancers. The basis of genetic heterogeneity is poorly understood but may represent an accumulation of multiple environmental assaults on the DNA. New and compelling data suggest hypermethylation of the GSTP1 ‘CpG island’ sequence in prostate epithelial cells may lead to increased susceptibility to genomic damage by inflammatory processes and dietary mutagens offering potential targets for chemopreventative agents.26 Unfortunately, the study of these early processes has been limited by the lack of good preclinical animal models of prostate cancer and surrogate end-points to measure progression.30 The natural history of prostate cancer extends over decades and existing parameters, including PSA, lack sufficient specificity for early progression. Additional clinical measures of local or advanced disease are notoriously difficult to ascertain by history, physical examination or conventional radiographic studies. Furthermore, prostate cancer does not typically grow as a focal mass lesion within the prostate, but rather is infiltrative, making isolation of prostate cancer epithelia difficult and subsequent purification of its DNA challenging. Proposed intermediate biomarkers to identify progression include measures of cellular proliferation (PCNA, Ki-67), angiogenesis [vascular endothelial growth factor (VEGF), microvessel density], differentiation (loss of high-molecularweight keratin), apoptosis (TUNEL assay, bcl-2/bax), genetic damage (cytogenetic changes such as on 8p, 9p or 16q) and regulatory molecular defects (c-erbB-2, TGF, p53, androgen receptor).30 Currently, none of these parameters exhibit sufficient specificity, making the efficacy of chemopreventative therapies difficult to ascertain. Ongoing Phase II trials may help establish appropriate intermediate measures as surrogate cancer end-points.30,31

MOLECULAR TARGETS AND CANDIDATE PROSTATE CANCER PREVENTION AGENTS Discoveries and technologies associated with the National Institute of Health Human Genome Project32 and the National Cancer Institute (NCI) Cancer Genome Anatomy Project (C-GAP)33 promise innovative molecular targets for prostate cancer prevention. When evaluating the role of potential new agents, several critical questions must be considered.34 For example, does the agent inhibit growth or cause regression in existing models of prostate cancer? What is the agent’s toxicity profile? Can it be given effectively in an oral dose? Is cost a factor? Have phase I trials in humans been conducted? Is the mechanism of action known and can its effects be ? Is there a suitable target population for testing? The answer to these and other pressing questions

regarding chemoprevention agents are critically important and can only be answered through systematic study. Existing putative prostate cancer prevention agents can be classified into those intended to inhibit ongoing cellular mechanisms, such as sex steroid signaling, differentiation or proliferation, pro-apoptosis and angiogenesis, and those intended to reverse or prevent progressive DNA damage, such as gene therapy, growth factor therapy or antioxidant therapy35 (Table 10.1). Observational data suggest that the hormonal milieu during early prostate development is an important determinant of subsequent cancer formation. Castration early in life nearly eliminates the risk of BPH and prostatic cancer in subsequent years. Additionally, because of the known hormone dependency that normal prostate epithelia and prostate cancer cells exhibit, sex steroid hormone signaling has been aggressively targeted for chemotherapeutic and chemopreventative strategies. Recent studies evaluating the role of 5α-reductase inhibition and androgen deprivation for patients with premalignant changes (PIN) are yet to be completed.36 Many ‘natural’ remedies for prostate cancer are believed to contain phytoestrogens that target sex steroid pathways.37 Several promising agents thought to affect cell differentiation and proliferation are also being explored including retinoids and vitamin D analogs.38 The goal of other novel strategies including inhibition of growth signaling and antiapoptotic pathways is to target transformed cells without adversely affecting normal cellular turnover. It remains to be seen if this is clinically feasible. Perhaps a more attainable strategy is to prevent initial or progressive DNA damage. Epidemiologic studies provide encouraging preliminary data suggesting antioxidant nutrients, such as selenium, vitamin E and lycopene, are associated with decreased prostate cancer risk.39–42 Oxidative stress has been implicated in the early events initiating prostate cancer and there is strong evidence that endogenous or exogenous reactive oxygen species (ROS) damage lipids, proteins and nucleic acids. Oxidative modifications are thought to be directly mutagenic and may alter gene function including p53, c-fos and c-jun.43,44 The effects of two antioxidants are actively being studied as part of the Selenium and Vitamin E Cancer Prevention Trial (SELECT), which aims to enrol over 32 000 men throughout the USA and Canada over 7–12 years.9 Further prostate cancer prevention approaches, including the use of gene therapy and/or growth factors, await more convincing proof of the principle in the adjuvant setting.

TARGET POPULATIONS Target populations appropriate for the study of prostate cancer prevention should be stratified based on their risk of developing the disease given current epidemiologic evidence.45 Populations can be divided into low-, intermediateand high-risk groups. Those at highest risk include patients with known premalignant changes in their prostate, such as PIN. This subgroup provides patients with the most immediate likelihood of progression to cancer; however, it represents



93

Table 10.1. Potential prostate cancer prevention agents (adapted from Lieberman et al.35).

Inhibiting ongoing cellular events Sex steroid signaling

5α-reductase inhibitors Antiandrogens (agonists)

Proliferation/differentiation

Vitamin D Retinoids Ornithine decarboxylase inhibitors

Angiogenesis

VEGF, PDGF, FGF receptor inhibition Farnesyl transferase inhibitors

Pro-apoptosis mechanisms

Cyclooxygenase inhibitors Other anti-inflammatory agents Apoptotic signal transduction (NFκB)

Reverse existing or progressing DNA damage Antioxidants

Selenium Vitamin E Carotenoids Polyphenols

Growth factors

Endothelin Metalloproteinases PSA proteases

Gene therapy

Vaccines Cytotoxicity or suicide genes Immunostimulatory genes (GM-CSF)

PDGF, Platelet-derived growth factor; FGF, Fibroblast growth factor.

a rather small percentage of men and there is considerable controversy among pathologists regarding the spectrum of abnormal early prostate epithelial histology.46 Those at intermediate risk include African Americans, patients with a strong family history and those who can be identified with hereditary prostate cancer gene mutations such as HPC-1 linkage.47 Lowrisk populations include the general public; however, recruitment requires large study groups and long follow-up intervals.45 Those at low, intermediate and high risk are candidates for primary, secondary and tertiary preventative strategies, respectively.

THE PROSTATE RISK ASSESSMENT PROGRAM Given the need to identify appropriate target populations for prevention and screening studies, many institutions have begun to establish registries for patients at risk. Here we review the findings from one of the first institutional programs designed to collect such information. The Fox Chase Cancer Center (FCCC) Prostate Cancer Risk Registry (PCRR) and Prostate Cancer Risk Assessment Program (PRAP) were founded in 1996. The FCCC is an NCI-designated Comprehensive Cancer Center committed to the support of cancer prevention and early detection. The PRAP has been developed building on the successful history

of the FCCC Family Risk Assessment Programs for breast and ovarian cancers. PRAP is a multidisciplinary effort that includes clinicians across multiple disciplines, basic and behavioral scientists, genetic counselors, health educators, biostatisticians and others. This team has developed a program for prostate cancer risk analysis, risk education, early detection, and testing of risk reduction and cancer prevention strategies.

Objectives and aims The primary objectives of the PCRR and PRAP are to establish a registry and screening clinic for families at high risk for prostate cancer, to further our understanding of the complex mechanisms of prostate carcinogenesis, and to provide prevention, early detection and psychosocial interventions to unaffected individuals at high risk. Secondary objectives include the study of prostate cancer genetics through the creation of a high-risk specimen bank, the development and testing of tools for intervention and prevention strategies, and the evaluation of behavioral interventions to assist in educating, processing and coping with risk-related information.

PRAP eligibility PRAP eligibility criteria for at-risk populations include African Americans, men with at least one first-degree relative or two or more second-degree relatives with prostate cancer on the same


94

Men/families at high risk for prostate cancer


Risk registry • Identification of those eligible • Recruitment • Informed consent • Database development – data files – data entry – data storage – data retrieval – confidentiality

Screening • Telephone registration • Consultation – Education Prostate anatomy Prostate cancer Risk factors Sporadic, familial, hereditary Possible risk modifiers DRE/PSA information – Assessment Sociodemographics Family history Health history Diet history Quality of life Risk perceptors Risk behaviors Coping skills – Clinical examination DRE PSA (free/total) Genetic test (when available) • 4–6 week follow-up – DRE/PSA results – Pedigree review – Results of genetic test (when available) – Genetic counseling – Dietary results and recommendations – Potential risk modifiers – F/U recommendations • Annual follow-up

Genetic research • Linkage analysis • Risk modeling • Breast–prostate phenotype • Genetic testing of oncogenes and tumor suppressor genes • Genetic markers • Protocols for assessments and counseling

Behavioral research • Risk comprehension • Risk adjustment • Risk reduction • Risk education tools

Early detection, risk reduction, cancer prevention strategies

Outcomes research • Cancers detected – stage, grade • Life years saved • Quality of life • Preferences/utilities • Cost effectiveness • Patient satisfaction

Fig. 10.3. The Fox Chase Cancer Center model for a unified multidisciplinary Prostate Risk Assessment Program (PRAP).49

side of the family, or men who have tested positive for the BRCA1 gene mutation. PRAP eligibility is limited to men aged 35–69 years of age. The lower bound age was based on reports of early age of onset for at-risk men and the upper bound age was based on the PRAP goal of targeting men at-risk prior to the mean age of onset of prostate cancer for the general population.48 The PCRR includes affected family members of PRAP participants. The logistics of the PRAP and PCRR, including recruitment, registration, the screening appointment, feedback and follow-up are outlined in Fig. 10.3 and are described in detail elsewhere.49 The program includes an extensive assessment of family history, pertinent medical history, dietary habits, preventive health care behaviors, risk perceptions, psychological status and quality of life. An educational session and interview with a genetic counselor is mandatory prior to screening and informed consent. Most importantly, the health educator and genetic counselor work to answer questions and keep concerns in perspective. Following education, the participant has blood drawn for PSA (total and % free) and research purposes after which the physician takes a targeted health history and performs the digital rectal examination (DRE). An appointment for the feedback of results is made for approximately 4 weeks

postscreening. In the interim, a pedigree is generated and reviewed, the PSA results are obtained, and a computer printout of nutritional intake is generated and analyzed. Men with abnormal results, particularly an elevated total or low percentage % PSA, are contacted by the physician for consultation and appropriate referrals for diagnostic follow-up are made. Participants with a normal PSA or DRE return to PRAP for their feedback visit where they meet with the genetic counselor to review their pedigree and receive the physician’s follow-up instructions, which generally consist of annual or, when appropriate, semiannual screening. Other familial or hereditary illnesses discovered on pedigree review are discussed along with appropriate follow-up and referral. Implications of the findings for the participant and family members are discussed in addition to dietary recommendations and potential preventive health behaviors, including prevention clinical trials when appropriate.

Preliminary results PRAP/PCRR accrual Since its inception in October 1996 through August 2001, PRAP accrual has accrued nearly 400 men at increased risk for



prostate cancer (mean age 48 years). Since African American men have the highest risk of prostate cancer, PRAP specifically targets recruitment efforts to this population. Our ongoing minority recruitment efforts have yielded a 57% accrual of African American men. This is over 40% greater than the 13.5% African American representation in the FCCC primary service area. This is of twofold significance, since African American men have the greatest risk of developing prostate cancer and are often difficult to recruit into screening programs and clinical trials.50 Preliminary PRAP screening results A total of 71 out of 323 (22%) at-risk men who were screened have had abnormal findings. Of these, 9 out of 71 (13%) had abnormal DREs, 25 out of 71 (35%) had PSAs >4 ng/ml (range 4.5–10.1 ng/ml), and another 37 out of 71 (52%) had PSAs between 2 and 4 ng/ml with % free PSA at 27% or lower. Compliance with biopsy recommendations has been approximately 70%. To date, 19 pathologically confirmed prostate cancers have been detected. All were clinically significant tumors with Gleason scores of 6 or higher. Twelve of the 19 men (63%) with pathologically confirmed cancers had both normal DREs and total PSAs, and were only detected based on their low % free PSA (60 years, 64% of young Blacks had a high-grade prostate cancer compared to 11% of young Caucasians, and the differences were statistically significant. Among older African Americans and Caucasians, 42% of African Americans had high-grade prostate cancer compared to 50% of Caucasians and this difference was not significant. They demonstrated a worse survival of young African Americans, with a median survival of 3.9 years as compared with a median survival of 6.0 years among young Caucasians. There was no difference in median survival between older African Americans and older Caucasians. The limiting factor, however, in this study was a small sample size. Again the total number of patients was 117, of which 56 were Caucasian and 61 African American.27 None the less, this study, in addition to the surgical study presented, does suggest that age should be considered when comparing African American and Caucasian patient prostate cancer outcomes.

SURVIVAL IN MEN WITH METASTATIC PROSTATE CANCER Results of Southwest Oncology Group (SWOG) study (8894), a randomized, prospective phase III trial comparing orchiectomy and anti-antigen with orchiectomy and placebo in men with metastatic prostate cancer provided an opportunity to analyze the difference in survival among men with metastatic disease by ethnic background in a rigidly controlled treatment regimen. The large sample size and the lack of uncontrolled variables made this trial a good setting for evaluating whether differences in survival between African American men and Caucasian men can be explained by differences in prognostic variables or whether there may be a difference in the biological activity of metastatic prostate cancer among African American men. Using data from 288 African American men and 975 White men in the trial, they conducted a proportional hazard regression analysis to determine if ethnicity was an independent predictor of survival. The study was double blinded and the primary end-point of the study was death from any cause, with the secondary end-point being progression-free survival. No differences were noted in treatment assignment by ethnicity: 49.3% African American men and 50.2% of White men were randomly assigned to receive flutamide. The results of the study show that, compared to White men in the study, African American men in the study were generally younger, had higher PSA levels, more extensive disease, higher Gleason scores, more frequent bone pain and a worse performance status. African American men in the study also had poorer survival than White men in the study, perhaps because of their later stage of diagnosis. Of the 198 African American and 719 White men for whom complete information about covariants was available at study entry, the median survival is 26 months and 35 months, respectively (a log rank test, P = 0.001). To determine whether the poorer survival among African American men relative to White men was a reflection of the poor prognostic factors, they controlled for the effect of these factors in a multivariable proportional hazard regression model. After adjustment for the potential confounding variables, the African American patients had a hazard ratio for death relative to White patients of 1.23 [95% confidence intervals (CI) = 1.042–1.47], and this increase risk was statistically significant (P = 0.018). The likelihood ratio test for the addition of the ethnicity to the model with other prognostic variables showed that the effect of ethnicity was statistically significant. The conclusion of this study was that African American men with metastatic prostate cancer have a statistically significant worse prognosis than White men that cannot be explained by the prognostic variable explored in this study. Further, they state that their data suggest that the existence of ethnic differences in the biology of the disease may be the cause for these outcomes and should be further investigated.28


Prostate Cancer Treatment Outcomes

SUMMARY We have analyzed prostate cancer outcomes after various treatments among African Americans compared to Caucasians. We have identified two factors that determined differences and similarities of outcomes between African Americans and Caucasians. One is the stage at diagnosis and treatment and the other is age. The earlier the stage at diagnosis and treatment, the greater will be the similarity in outcome. However, as prostate cancer advances in stage at diagnosis and treatment, the greater the differences in survival outcomes between African Americans and Caucasians become. This suggest that the natural history of prostate cancer may be more progressive among African American compared to Caucasians. This is a concept that has been promoted but the evidence to support it is early in its development, such as hormonal regulation and epigenetic factors, i.e. diet. The second factor is age at diagnosis and treatment. It has been reported that older Caucasians have more aggressive prostate cancer at diagnosis than younger Caucasians and that age is a predictor of poor outcome among this cohort. This has been consistent with our findings. However, among African Americans this finding is not apparent. In fact, young African Americans (1, including 1q24–25, 1q33–42, 4q26–27, 5p12–13, 7p21, 13q31–33 and Xq27–28. The highest LOD score was 2.75 at marker D1S218, which maps to the long arm of chromosome 1 (1q24–25). When the linkage peak at 1q24–25 was evaluated in detail with additional

genetic markers in a combined collection of 91 US and Swedish families, a LOD score of 5.43 was detected by accounting for heterogeneity under the assumption that 34% of families were linked to this region.23 The locus at chromosomal segment 1q24–25 has come to be known as HPC1. The impressive LOD scores reported by this study fueled optimism that a major hereditary prostate cancer gene would be identified in short order, and thus a large share of the efforts to detect such a gene have been focused on chromosome 1q24–25. However, follow-up linkage studies have provided mixed results. The second genomewide screen included 504 brothers from 230 multiplex sibships that were collected by Washington University School of Medicine in St Louis. This study employed non-parametric linkage analyses, free of specific inheritance models, to avoid the potential for misleading results due to genetic model mispecification. Their approach identified five regions with ‘nominal’ evidence for linkage, including 2q, 12p, 15q, 16q and 16p.24 Among these regions, the strongest evidence of linkage was a multipoint LOD of 3.15 on chromosome 16q23. Interestingly, the 16q23 region includes a putative tumor suppressor gene that may be involved in breast, ovarian and prostate cancer. Although this study reported linkage to 1q, they found no evidence of linkage at the HPC1 locus previously reported on 1q24–25. Instead, this study reported linkage to two regions that flank 1q24–25, and only when they stratified based on the Hopkins Criterion. Linkage was detected at 1q41–43 among sibships that met the Hopkins Criterion for HPC, and at 1q21–22 among familial prostate cancer sibships that did not meet the HPC Criterion. Goddard et al. published a genomewide study that expanded directly upon the study reported by Suarez et al.24,25 This study included a modest increase in the total number of study participants, to include 564 men from 254 families with both prostate cancer and available Gleason scores. However, this report was distinguished by a study design that included four covariates in the analyses: (1) the sum of the sibling-pair Gleason scores; (2) age at onset (family mean age at diagnosis); (3) presence or absence of male-to-male transmission in the nuclear family; and (4) the number of affected first-degree relatives in the nuclear family. They did not detect strong linkage to any region, except when they incorporated clinical and family history variables in the analyses. A chromosome 14 linkage of 2.74 LOD was identified based on age at onset, and this covariate also provided significant linkage to chromosomes 4, 6, 7 and 20. They detected a large and significant linkage peak of 3.25 LOD near HPC1 after they stratified by high Gleason score. Additional linkage regions identified in the Gleason score strata were reported on chromosomes 2, 5, 8, 16 and X. The use of male-to-male transmission as a covariate increased insignificant linkage at chromosome 21 to a LOD of 3.12, and also implicated chromosomes 1–5. The analyses yielded a LOD score of 2.84 at the 1q41–43 region of chromosome 1 when both low Gleason score and male-to-male transmission were included, supporting the linkage originally reported by Berthon (1998) as detailed under the heading of ‘PCAP’ later in this chapter.25


Hereditary Prostate Cancer

Shortly after the publication by Suarez,24 a group at Fred Hutchinson Cancer Center published the third genomewide screen for prostate cancer.27 Among 94 families, they found two-point LOD scores ⭓1.5 for several chromosomal regions. When an autosomal dominant model of inheritance was evaluated, loci on 10q, 12q and 14q were implicated. Chromosomal regions on 1q, 8q, 10q and 16p were suggested as the most likely regions to contain an HPC gene when a recessive model of inheritance was assessed. A late onset locus was suggested by a multipoint LOD score of 3.02 on chromosome 11 when families were stratified by age of diagnosis. This study did not confirm linkage to the locus at 1q24–25. However, a linkage result of 1.99 LOD was found at 1q41–43 in their total set of samples, thus moderately supporting the linkage originally reported by Berthon et al.,26 as detailed under the heading of ‘PCaP’ later in this chapter. The most recently reported genomewide linkage analysis included 98 families from the USA and Canada.28 Each family had at least three verified diagnoses of prostate cancer among first- and second-degree relatives. Positive linkage signals of ‘nominal’ statistical significance were found in the 5p–q and 12p regions. The strongest finding of this study was the LOD score of 2.87 at 19p. The 1q24–25 locus was not confirmed by their results, nor were any of the other proposed HPC loci from previous genomewide linkage screens. To summarize the genomewide linkage screens, among the findings with at least marginal significance, the regions at 5p and 12p were the only specific linkages reported by more than one genomewide linkage study, except when detailed covariate analyses were performed. It is worth noting that, to date, each of these linkage studies have provided a different overall result. Specifically, the strongest LOD score findings from each study were not replicated by any of the other linkage studies. However, many of the regions implicated by genomewide linkage studies have been observed commonly in loss of heterozygosity (LOH) studies, including 7p and 13q by Smith,26 16q by Suarez,24 10q and 8q by Gibbs27 and, finally, 5p–q by Hsieh,28 thus providing additional support for the existence of important prostate cancer genes within these linkage regions.

Linkage confirmation and fine mapping Each of the most significant findings from genomewide linkage studies has been followed by locus-specific studies that utilize dense DNA markers. The use of more markers within a limited interval allows for confirmation of initial genomewide linkage results, as well as additional refinement from a broad linkage region that might contain thousands of genes to a narrow region manageable for the study of each included gene. Interestingly, a review of the literature reveals that every chromosome in humans, except for the Y chromosome, has been implicated in prostate cancer, at least marginally, by linkage analyses. The regions that have received the most attention in detailed linkage and gene-mapping efforts include HPC1 at 1q24–25, PCaP at 1q42–43, CaPB at 1p36, HPCX at Xq27–28, HPC20 at 20q13, ELAC2/HPC2 on 17p, and also linkage at 8p22–23.

149

HPC1 The initial linkage result in the region of 1q24–25 stands as the highest LOD score among all published studies of hereditary prostate cancer. The locus was quickly termed HPC1. Following the original study, analysis of HPC1 linkage by other research groups has been variable. While several groups have published results ranging from nominal to strong evidence for linkage to this region, there have been no studies that quantitatively reproduce the very strong initial findings. In addition, based on linkage analyses limited to the HPC1 region, there have been no results that clearly narrow down this large region, and some studies have even suggested the HPC region extends beyond the bounds originally reported by Smith et al.23 Many genes lie within this interval and detailed study of each of these genes is a daunting task. In fact, four groups have reported no significant evidence for linkage of HPC1 in their study populations after detailed studies of the region. Among 49 high-risk prostate cancer families, McIndoe et al. found no evidence for linkage in this region when their data were evaluated with either a nonparametric analysis or a parametric LOD score approach.29 Stratified analysis of these families by age at diagnosis was performed, and the 18 families with early age at diagnosis (0.2 ng/ml. † Progression defined as serum PSA >0.4 ng/ml. ‡ Progression defined as serum PSA >0.6 ng/ml.


233

The Decision-making Process for Prostate Cancer

pre-PSA era in 1993,12 expanded in a multi-institutional study involving over 4000 patients in 199713 and updated on over 5000 patients from Hopkins in 2001.14 Partin et al. found that the combination of PSA, Gleason score and clinical stage together were more accurate in predicting the final pathologic stage than any one of these three parameters alone. The resulting tabulation is a categorization, stratified for preoperative PSA, biopsy Gleason score and clinical stage, giving the chance of organ-confined disease, extracapsular extension, seminal vesicle involvement and nodal involvement after RRP. This allowed the patient and clinician the opportunity to derive the percentage chance of postoperative pathologic findings based on the individual biopsy data of the patient. This data set was validated on an external prostate database and had a classification accuracy of 0.724 – within 0.10.13,15 However, one drawback of this analysis is that the end-point is final pathologic stage and not a clinical parameter, such as recurrence or survival, which limits its usefulness. Using a similar approach, Kattan et al. evaluated the Baylor RRP database to find independent predictors of both pathologic stage and PSA recurrence after RRP based on preoperative information.16 Using Cox proportional hazards regression analysis, the clinical information and outcomes for 983 men undergoing RRP were modeled and a nomogram was developed. Incorporating clinical data similar to Partin, including preoperative PSA, biopsy Gleason and clinical stage, a point system was devised to categorize individual patients, as shown in Fig 24.1. The number of points increase as the PSA, stage or

Points PSA

0

10

20

1

T1c

Local recurrence Local recurrence after radical prostatectomy is defined as recurrent prostate cancer present in the prostatic fossa or pelvis, and is diagnosed by radiographic documentation of pelvic disease on computed tomography (CT), magnetic resonance imaging (MRI) or nuclear imaging, or by a positive biopsy of the prostatic fossa. Rising PSA after surgical treatment alone is not diagnostic; distant disease, either in regional lymph nodes or distant metastasis must be ruled out. Determining true local recurrence from subclinical micrometastatic disease is difficult and the majority of patients with locally recurrent pelvic disease will have concomitant distant metastatic disease. Han et al. examined the Hopkins experience in men undergoing RRP, which included 2404 men operated on from 1982 to 1999, with a mean follow-up of 76.6 months (range 12–204 months).17 A total of 412 of 2404 men experienced disease recurrence (17%) during follow-up. Of these, only 40 of 2404 men had isolated local recurrence (1.6%); the remainder had distant disease ± local recurrence or PSA recurrence only. Thus isolated local recurrence represented only 9.8% of all men with

30

0.1 T2a

Clinical Stage

Gleason score increases, and the total points determine the 60-month recurrence-free probability. This model was validated with a separate cohort, giving a receiver operating characteristic curve (ROC), which is the comparison of predicted probability with the actual outcome, of 0.79. This approach allows the clinician and the individual patient a more rigorous prediction of recurrence based on the specific clinical scenario.

40

2 34 6 7

T2c

90% in a sequence-specific and dose-dependent manner, and Bcl-2 mRNA levels returned to pretreatment levels by 48 hours after discontinuing treatment. Athymic male mice bearing subcutaneous LNCaP tumors were castrated and injected with Bcl-2 ODN or controls; LNCaP tumor growth and serum PSA levels were 90% lower in mice treated with antisense Bcl-2 ODN compared with mismatch or reverse polarity ODN controls.175 Antisense Bcl-2 oligodeoxynucleotides after castration have been shown to decrease the progression to androgen independence in the mouse model and androgen-independent LNCaP tumor regression in mice occurred with a novel method of administering paclitaxel with antisense Bcl-2 oligodeoxynucleotide.176,177

NOVEL THERAPEUTIC DELIVERY SYSTEMS IN THE TREATMENT OF PROSTATE CANCER Gene therapy involves delivering recombinant genetic material, in the form of DNA or RNA to combat disease. Major strategies involve modifying gene expression to correct deficiencies or block inappropriate gene expression, inducing ‘suicide’ genes to promote cancer cell death and modulating the interactions of the immune system with cancer cells. This is performed either by removing tissue and genetically altering it ex vivo or delivering the genetic material in vivo. In vivo gene therapy has been limited largely by inefficient delivery systems and improvements in gene vectors, and delivery will

allow practical use of clinical gene therapy for a variety of conditions. The ideal delivery system would be non-toxic to normal cells, deliver the genetic information efficiently with specificity to the targeted system and be inexpensive yet easily administered. Tumor cell vaccines are a typical ex vivo gene therapy strategy for cancer and rely on the ability of cancer-specific antigens to elicit an immune response. An approach is to harvest tumor cells from the patient, genetically modify the cells (usually with retroviral transfection) so that they can stimulate the immune system, irradiate the cells so that they are nontumorigenic, and reinject the cells into the patient. The first tumor vaccine trial for prostate cancer began in 1994 when granulocyte-macrophage colony-stimulating factor (GM-CSF) was transfected using retrovirus into a patient’s prostate cancer cells in vitro. The cells were then injected subcutaneously and found to be safe in phase I trials.178 Data from this trial indicate vaccination activated new T-cell and B-cell immune responses against PCA antigens. T-cell responses, evaluated by assessing delayed-type hypersensitivity (DTH) reactions against untransduced autologous tumor cells, were evident in two of eight patients before vaccination and in seven of eight patients after treatment. These data are the first to suggest that both T-cell and B-cell immune responses to prostate cancer can be generated by treatment with irradiated, GM-CSF genetransduced prostate cancer vaccines. A limitation in the trial by Simons et al. was generating vaccine cells in culture. This group has embarked on a new trial to estimate the efficacy of using the ex vivo, GM-CSF-transduced, prostate cancer cell lines PC-3 and LNCaP as a vaccine. They reported results on 21 patients treated and one had a partial PSA response of greater than 7 months in duration, 14 had stable disease and six patients underwent progression. By 3 months PSA velocity or slope decreased in 71% of cases. Additionally, numerous new postvaccination IgG antibodies were identified in these patients, indicating that immune tolerance to prostate cancerassociated antigens may be broken.179 The first report to demonstrate anticancer activity of gene therapy in human prostate cancer, by Herman and colleagues, used intratumoral injection of replication-deficient adenovirus carrying the thymidine kinase gene from the herpes simplex virus, followed by parenteral administration of the prodrug gancyclovir. They report promising results with some patients with local recurrence after radiotherapy obtaining a greater than 50% decrease in PSA lasting 6 weeks to 1 year.180 These data support the usefulness of cytoreductive gene therapy, by ‘suicide’ genes, or by increasing tumor cell sensitivity to chemotherapeutics. Replication-deficient adenovirus containing the herpes simplex virus thymidine kinase (HSV-tk) gene (‘suicide’ gene therapy) has also been used in men with localized prostate cancer. Multiple and/or repeat intraprostatic injections was followed by intravenous ganciclovir or oral valaciclovir 14 days after injection. A total of 52 patients were treated, with a total of 76 gene therapy cycles; toxic events were recorded in 16 of 29 patients (55.2%) who were given multiple viral injections into the prostate, seven of 20 (35%) who received two cycles of ‘suicide’ gene therapy and three of four (75%) who received


Molecular Therapeutics in Prostate Cancer

a third course of gene therapy. All toxic events were mild (grades 1 to 2) and resolved completely once the therapy course was terminated. Mean follow-up was 12.8 months and preliminary results for 28 patients indicated a mean decrease of 44% in serum PSA in 43% of patients.181 A current study is evaluating the effect of p53 replacement therapy utilizing intraprostatic Ad5CMVp53 injection in men with localized prostate cancer prior to radical prostatectomy. Patients are followed for tumor volume response by transrectal ultrasound and magnetic resonance imaging (MRI) and injections are continued every 2 weeks until tumor shrinkage abates, after which time they undergo radical prostatectomy. Results are not available at this time as this trial is still open for enrollment.182 Logothetis et al. reported initial results using a similar gene replacement strategy of adenovirus containing wild-type p53 (AdCMVp53) driven by the CMV promoter before radical prostatectomy in 17 patients with locally advanced prostate cancer. AdCMVp53 was administered via a transperineal route under ultrasound guidance. In this phase I–II study, three patients who completed a repeat course of therapy had a greater than 25% decrease in tumor size, as measured by endorectal coil MRI after the initial treatment course and there was no grade 3 or 4 toxicity in the 14 evaluable patients. Further results on efficacy due to the apparent radiological responses, correlations with gene expression, pathological findings at prostatectomy and surgical outcomes are pending.183 Investigators have recently completed a phase I trial in 24 patients with locally advanced prostate cancer using gene-based immunotherapy. A functional DNA–lipid complex encoding the IL-2 gene was administered intraprostatically, under transrectal ultrasound guidance, into the hypoechoic tumor lesion. Patients were stratified into two groups: group 1 included patients who underwent radical prostatectomy after the completion of the treatment regimen; and group 2 consisted of patients who had failed a prior therapy. IL-2 gene therapy was well tolerated, with no grade 3 or 4 toxic reactions occurring. Post-treatment prostate specimens were attained and compared with the transrectal biopsies performed prior to therapy. Evidence of systemic immune activation after IL-2 gene therapy included an increase in the intensity of T-cell infiltration seen on immunohistochemistry of tissue samples from the injected tumor sites, and increased proliferation rates of peripheral blood lymphocytes that were cocultured with patient serum collected after treatment. Transient decreases in serum PSA were seen in 16 of 24 patients (67%) on day 1. Fourteen of the patients persisted in this decrease to day 8 (58%). However, in eight patients the PSA level rose after therapy. More patients (9–10) in group 2 responded to the IL-2 gene injections and six of the nine also had lower than baseline PSA levels at week 10 after treatment.184 This group has also reported on novel chimeric PSA enhancers that exhibit increased activity in prostate cancer gene therapy vectors. They addressed the problem of low transcriptionally active native PSA enhancer and promoter, which otherwise confers prostate-specific expression when inserted into adenovirus vectors. The investigators exploited the mechanism by which

509

androgen receptor molecules bind cooperatively to androgen response elements in the PSA enhancer core, and act synergistically with AR bound to the proximal PSA promoter to regulate transcriptional output. They generated chimeric enhancer constructs by inserting four tandem copies of the proximal AREI element, duplicating the enhancer core, or by removing intervening sequences between the enhancer and promoter. They obtained chimeric PSA enhancer constructs, which were highly androgen inducible and retained a high degree of tissue specificity even in an adenoviral vector (Ad-PSE-BC-luc). They also demonstrated that augmented activity of the chimeric constructs in vivo correlated with their ability to recruit AR and critical coactivators in vitro. Furthermore, systemic administration of Ad-PSE-BC-luc into SCID mice harboring the LAPC-9 human prostate cancer xenografts showed that this prostate-specific vector retained tissue discriminatory capability compared with a comparable cytomegalovirus (CMV) promoter driven vector.185 Kwon and colleagues have utilized regulation of T-lymphocyte proliferation by the stimulatory HLA-B7 family with T-cell surface inhibitory receptor CTLA4 in a transgenic mouse model of metastatic prostate cancer growth after tumor resection. They modified their tumor vaccine with the addition of anti-CTLA4 antibodies and showed metastatic relapse dropped from 97.4% in controls to 44% in animals treated immediately after tumor resection.186 Additionally, anti-CTLA4 antibody treatment can delay tumor growth in a transgenic mouse model.187 In vivo gene therapies for prostate cancer utilize vectors to deliver genetic information to tissues. Viruses are commonly used and types include adenovirus, retrovirus, adeno-associated virus, herpes virus and poxvirus. Non-viral vectors include liposomes, DNA-coated gold particles, plasmid DNA and polymer DNA complexes. Overcoming the obstacle for gene therapy vector inefficiency is being approached with development of less immunogenic viral vectors and ‘stealth liposomes,’ which evade the first-pass destruction by the reticular endothelial system. Furthermore, developing more specific therapies by targeting specific cell receptors or using prostatespecific gene promoters (e.g. prostate-specific membrane antigen and human kallekrein II) may allow for lower effective doses and perhaps decreasing the side effects commonly seen with viral vectors. Correction of genetic alterations of tumor suppressor genes and cancer-promoting oncogenes can target a multitude of genes in the pathways to cancer development or progression. Restoration of one of the tumor-suppressor genes (Rb, p53, p21, and p16) have been shown to alter malignant phenotype, but would have to be delivered to every cancer cell to eradicate the cancer. The retinoblastoma gene has been shown to be mutated in human prostate cancer specimens, and gene therapy has shown some effectiveness in model systems of neuroendocrine and lung tumors.188,189 Mutations in p53 are reported at a wide range of rates; however, p53 gene therapy suppressed tumorigenesis and induced apoptosis in vitro.190 Furthermore, in vivo studies have shown some benefit of p53 gene therapy in prostate tumor models.191 Similarly, p21 gene therapy has


510


been shown to suppress growth in prostate tumor cells in vitro and in vivo.192,193 A concept that is being expanded is restoration of genes that confer increased chemosensitivity or radiosensitivity to prostate cancer tumors. One study has looked at proliferation of tumor cells after incubation with various combinations of p53 adenovirus (p53 Ad) and chemotherapeutic drugs. The authors found p53 Ad combined with cisplatin, doxorubicin, 5-fluorouracil, methotrexate or etoposide inhibited cell proliferation more effectively than chemotherapy alone in multiple human tumor cell lines, including DU-145 prostate cells. Human tumor xenografts in SCID mice dosed with intraperitoneal or intratumoral p53 Ad with or without chemotherapeutic drugs showed greater anticancer efficacy with combination therapy in four human tumor xenograft models in vivo.194 Another study evaluated gene therapy enhancement of prodrugs and radiation therapy. Prostate tumor cells (PC-3) were transduced with adenovirus containing a fusion gene encoding the E. coli cytosine deaminase and herpes simplex virus type-1 thymidine kinase under the control of a cytomegalovirus promoter. PC-3 cells expressing this protein were sensitized to killing by the normally innocuous prodrugs 5-fluorocytosine and ganciclovir. In addition, radiation-induced killing was enhanced in virally infected cells in the presence of the prodrugs.195 Additionally, some evidence exists that gene therapy may be cooperative with androgen deprivation. Castration was combined with HSV-tk plus GCV using an androgen-sensitive mouse prostate cancer cell line, which led to markedly enhanced tumor growth suppression in both subcutaneous and orthotopic models compared with either treatment alone. An enhanced survival was also observed, in which combination-treated animals lived twice as long as controls in the subcutaneous model and over 50% longer than controls in the orthotopic model.196 A very interesting study utilized a constructed recombinant adenovirus containing E. coli cytosine deaminase and herpes simplex virus type 1 thymidine kinase fusion gene under the control of a human inducible heat shock protein 70 promotional sequence. Heating at 41°C for 1 hour induced strong expression of the fusion gene product. Heat-induced expression of the CD-TK protein significantly reduced the survival of PC-3 cells in the presence of both 5-fluorocytosine and ganciclovir prodrugs. These data represent a novel form of gene therapy involving the transduction and regulation of a double suicide gene in tumor cells and may provide a unique application for hyperthermia in cancer therapy.197 In the future, perhaps hsp promoters could be used in combination with thermal energy modalities. Gene transfer trials sponsored by the National Institutes of Health are listed on the World Wide Web at http:// www4.od.nih.gov/oba/rac/clinicaltrial.htm and currently list 40 trials.

CONCLUSIONS The observation of phenotypic differences between normal cells and cancer cells led to basic science experiments to

discover why these changes occur. A cascade of discoveries brought about some answers and many more questions. Utilization of the rapidly growing wealth of basic science knowledge leads to therapeutic intervention, first at the level of the test tube or Petri dish, then to animal experimentation and finally in clinical trials. The outlook for prostate cancer patients is promising. Better methods of screening and diagnosis, as well as recognition of tumor markers, are improving the survival of patients afflicted with prostate cancer. New treatments for advanced prostate cancer are being evaluated at an increasing rate and significant advances for the therapy of prostate cancer should come sooner rather than later. It is likely that a combination of the strategies reviewed in this chapter will provide the most effective weapon in the battle against prostate cancer.

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LNCaP prostate tumor model. Clin. Cancer Res. 1999; 5:2891–8. Miyake H, Tolcher A, Gleave ME. Antisense Bcl-2 oligodeoxynucleotides inhibit progression to androgen-independence after castration in the Shionogi tumor model. Cancer Res. 1999; 59:4030–4. Leung S, Miyake H, Zellweger T et al. Synergistic chemosensitization and inhibition of progression to androgen independence by antisense Bcl-2 oligodeoxynucleotide and paclitaxel in the LNCaP prostate tumor model. Int. J. Cancer 2001; 91:846–50. Simons JW, Mikhak B, Chang JF et al. Induction of immunity to prostate cancer antigens: results of a clinical trial of vaccination with irradiated autologous prostate tumor cells engineered to secrete granulocyte-macrophage colonystimulating factor using ex vivo gene transfer. Cancer Res. 1999; 59:5160–8. Simons JW, Mikhak B, Chang JF. Clinical activity and broken immunologic tolerance from ex vivo GM-CSF gene transduced prostate cancer vaccines. J. Urol. Suppl. 1999; 161:abstract 188. Herman JR, Adler HL, Aguilar-Cordova E et al. In situ gene therapy for adenocarcinoma of the prostate: a phase I clinical trial. Hum. Gene Ther. 1999; 10:1239–49. Shalev M, Kadmon D, Teh BS et al. Suicide gene therapy toxicity after multiple and repeat injections in patients with localized prostate cancer. J. Urol. 2000; 163:1747–50. Sweeney P. and Pisters LL. Ad5CMVp53 gene therapy for locally advanced prostate cancer – where do we stand? World J. Urol. 2000; 18:121–4. Logothetis CJ, Hossan E, Pettaway CA. AD-p53 intraprostatic gene therapy preceding radical prostatectomy (RP): an in vivo model for targeted therapy development. J. Urol. Suppl. 1999; 161:abstract 1142. Belldegrun A, Tso CL, Zisman A et al. Interleukin 2 gene therapy for prostate cancer: phase I clinical trial and basic biology. Hum. Gene Ther. 2001; 12:883–92. Wu L, Matherly J, Smallwood A et al. PSA enhancers exhibit augmented activity in prostate cancer gene therapy vectors. Gene Ther. 2001; 8:1416–26. Kwon ED, Foster BA, Hurwitz AA et al. Elimination of residual metastatic prostate cancer after surgery and adjunctive cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade immunotherapy. Proc. Natl Acad. Sci. USA 1999; 96:15074–9.

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187. Hurwitz AA, Foster BA, Kwon ED et al. Combination immunotherapy of primary prostate cancer in a transgenic mouse model using CTLA-4 blockade. Cancer Res. 2000; 60:2444–8. 188. Kubota Y, Fujinami K, Uemura H et al. Retinoblastoma gene mutations in primary human prostate cancer. Prostate 1995; 27:314–20. 189. Nikitin AY, Juarez-Perez MI, Li S et al. RB-mediated suppression of spontaneous multiple neuroendocrine neoplasia and lung metastases in Rb + /– mice. Proc. Natl Acad. Sci. USA 1999; 96:3916–21. 190. Yang C, Cirielli C, Capogrossi MC et al. Adenovirus-mediated wild-type p53 expression induces apoptosis and suppresses tumorigenesis of prostatic tumor cells. Cancer Res. 1995; 55:4210–13. 191. Eastham JA, Grafton W, Martin CM et al. Suppression of primary tumor growth and the progression to metastasis with p53 adenovirus in human prostate cancer. J. Urol. 2000; 164:814–19. 192. Eastham JA, Hall SJ, Sehgal I et al. In vivo gene therapy with p53 or p21 adenovirus for prostate cancer. Cancer Res. 1995; 55:5151–5. 193. Steiner MS, Zhang Y, Farooq F et al. Adenoviral vector containing wild-type p16 suppresses prostate cancer growth and prolongs survival by inducing cell senescence. Cancer Gene Ther. 2000; 7:360–72. 194. Gurnani M, Lipari P, Dell J et al. Adenovirus-mediated p53 gene therapy has greater efficacy when combined with chemotherapy against human head and neck, ovarian, prostate, and breast cancer. Cancer Chemother. Pharmacol. 1999; 44:143–51. 195. Blackburn RV, Galoforo SS, Corry PM et al. Adenoviral transduction of a cytosine deaminase/thymidine kinase fusion gene into prostate carcinoma cells enhances prodrug and radiation sensitivity. Int. J. Cancer 1999; 82:293–7. 196. Hall SJ, Mutchnik SE, Yang G et al. Cooperative therapeutic effects of androgen ablation and adenovirus-mediated herpes simplex virus thymidine kinase gene and ganciclovir therapy in experimental prostate cancer. Cancer Gene Ther. 1999; 6:54–63. 197. Blackburn RV, Galoforo SS, Corry PM et al. Adenoviralmediated transfer of a heat-inducible double suicide gene into prostate carcinoma cells. Cancer Res 1998; 58:1358–62.


Antioxidants and Phytotherapy

Chapter

55

Charles E. Myers and Dan Theodorescu Department of Urology, University of Virginia, Charlottesville, VA, USA

INTRODUCTION Patients with chronic diseases are increasingly seeking alternative medicine therapies. Thirty-four per cent of Americans surveyed by phone in 1991 and 42% in 1997 reported using at least one type of alternative medicine. In addition, in 1991 one-third of alternative medicine users consulted a provider of alternative medicine, while in 1997 this figure rose to 46%.1,2 Extrapolation to the US population suggested that the 629 million visits to providers of alternative medicine exceeded the 386 million visits to all US primary care physicians in 1997.2 Of the $13.7 billion spent on alternative medicine in 1990, three-quarters were paid out of pocket,1 while of the $21.2 billion spent in 1997, $12.2 billion was paid out of pocket.2 Increasing health insurance coverage of alternative therapies also supports increasing patients usage.3 Because of such consumer demand, the National Institutes of Health (NIH) created the National Center for Complementary and Alternative Medicine (NCCAM). This center is dedicated to exploring complementary and alternative healing practices in the context of rigorous science, training complementary and alternative medicine (CAM) researchers and disseminating authoritative information (http://nccam.nih.gov). Complementary and alternative healthcare and medical practices are those healthcare and medical practices that are not currently an integral part of conventional medicine.* The list of practices that are considered CAM changes continually as CAM practices and therapies that are proven safe and effective become accepted as ‘mainstream’ healthcare practices. Today, CAM practices may be grouped within five major domains:† (1) alternative medical systems; (2) mind–body interventions; (3) biologically-based treatments; (4) manipulative and bodybased methods; and (5) energy therapies. The individual systems and treatments comprising these categories are too

numerous to list in this document. Thus, only limited examples are provided within each. The ‘biologically-based treatments’ category of CAM includes natural and biologically-based practices, interventions and products, many of which overlap with conventional medicine’s use of dietary supplements. Included are herbal, special dietary, orthomolecular and individual biological therapies. Herbal therapies employ individual or mixtures of herbs for therapeutic value. A herb is a plant or plant part that produces and contains chemical substances that act upon the body. Orthomolecular therapies aim to treat disease with varying concentrations of chemicals, such as selenium, and megadoses of vitamins. Biological therapies include, for example, the use of laetrile and shark cartilage to treat cancer, and bee pollen to treat autoimmune and inflammatory diseases. In the current chapter, we will discuss several biologically-based therapies relevant to prostate cancer and highlight the relevant biology and epidemiology pertaining to these approaches.

USE OF COMPLEMENTARY AND ALTERNATIVE MEDICINE IN PROSTATE CANCER PATIENTS The use of alternative medicine therapies for cancer patients varies from 7% to 64% in published studies with an average prevalence of 31.4% [Ernst, 1998 #2103].7 Interestingly, it appears that up to 72% of those patients using alternative therapies do not inform their doctors.1 Many patients hold high expectations for their alternative medicines. Most patients who utilize complementary therapy expect it to improve the quality of their life, over 70% expect it to boost their immune system and 62% believe that it will prolong

*The term conventional medicine refers to medicine as practiced by holders of MD (medical doctor) or DO (doctor of osteopathy) degrees, some of whom may also practice complementary and alternative medicine. Other terms for conventional medicine are allopathy, Western, regular and mainstream medicine, and biomedicine (source: http://nccam.nih.gov). † These are the categories within which NCCAM has chosen to group the numerous CAM practices; others employ different broad groupings (source: http://nccam.nih.gov).


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their life. As many as 37% of CAM users anticipate that the therapy will cure their disorder.4 Lazar and O’Connor reported several factors influencing the use of complementary or alternative medicine including: the attempt to control side effects; the need to be involved and to have some control over their therapy; the desire to avoid toxicities of conventional medicines; and the diagnosis of a disease for which proper treatment is lacking.5 Those that choose not to use complementary medicine (CM) do so for a variety of reasons including satisfying results from conventional medicine and confidence in medical professionals.6 We have previously demonstrated that up to 43% of clinically localized prostate cancer patients treated with curative intent were found to use at least one form of CM. In this study, vitamins and herbal therapies were found to be among the most prevalent forms of complementary therapies. It was also demonstrated that higher pretreatment Gleason scores were associated with increased usage of CM.7 Other studies have shown a positive correlation with increased socioeconomic status and education.8 These data led us to carry out another study to query as to the specific complementary therapies being used, the time frame of this usage, and the major motivational aspects and sources of information involved in this decision. In this study, information from 238 patients with localized prostate cancer treated with curative intent by radical surgery or radiation, including brachytherapy, was included. A total of 37% of patients acknowledged using some type of complementary therapy. Our data indicate similar overall use of CM among the treatment groups. The most common CM type was vitamins, utilized by 35% of patients, followed by herbal products and dietary changes used by 12% of respondents. Vitamin E and lycopene were the most commonly used single items in each group, respectively, while the most common dietary change was decreased fat intake. A total of 43% of patients began using CM before starting conventional treatment, while 32% began after initiation of such treatment. The majority of patients who utilized CM indicated they would never discontinue these therapies. The most common reason for using CM was the patient’s impression that it made them feel better and, secondarily, that it helped cure their cancer. Physicians were listed as the most common source of information regarding CM. Surprisingly, almost twice as many patients identified physicians as being advocates of CM than critics of this type of care. Many patients felt that their urologist or radiation oncologist was neutral or chose not to discuss the topic of CM with patients. However, for those physicians that did discuss this topic with patients, more patients felt that their urologist or radiation oncologist encouraged the use of complementary therapies than discouraged their use. Since alternative therapies may alter results of standard cancer therapies,9 produce side effects and confound results of clinical trials, new patient evaluations should include questions concerning any herbal preparations or practice of any alternative methods of cancer treatment. The potential confounding effects due to alternative medicine use are

particularly relevant in a disease such as prostate cancer, whose status is assessed by biochemical markers (i.e. prostate specific antigen – PSA). The most compelling finding is that several of these botanical therapies have shown striking clinical effects on human prostate cancer9 as well as in experimental in vitro studies. This will be discussed in more detail below.

DIETARY SUPPLEMENT HEALTH AND EDUCATION ACT OF 1994 The past few years have witnessed a dramatic increase in the use of herbal products as well as other methods associated with alternative and complementary medicine. What has fueled this shift toward herbal and nutritional supplements? Many patients view herbal products as offering a gentler, more natural form of therapy with fewer side effects. While this may be true for some supplements, the side effects of many herbal products have simply not been publicized adequately. In addition, the use of herbal products also puts the patient in control of his treatment, since most do not require prescriptions. As the American public turned their attention to natural products, the political and legal environment also began to change. One key event was the passage by Congress of a major new law governing the marketing and sale of these products. This law, called the Dietary Supplement Health and Education Act of 1994 (Public Law No:103-417)10 (full text of legislation can be found at http://thomas.loc.gov), represents the result of a debate dating back to the early 1960s, between the Food and Drug Administration (FDA) and parties seeking to provide Americans with less restricted access to supplements. Key aspects of the Act represent a different philosophy than that which had dominated the FDA: 1. ‘There is a link between the ingestion of certain nutrients or dietary supplements and the prevention of chronic diseases such as cancer, heart disease, and osteoporosis’. 2. ‘Healthful diets may mitigate the need for expensive medical procedures, such as coronary bypass surgery or angioplasty’. 3. ‘Preventive health measures, including education, good nutrition, and appropriate use of safe nutritional supplements will limit the incidence of chronic diseases, and reduce long-term health expenditures’. 4. ‘There is a growing need for emphasis on the dissemination of information linking nutrition and long-term health’. 5. ‘Consumers should be empowered to make choices about preventative health care programs based on data from scientific studies on health benefits related to particular dietary supplements’. 6. ‘Studies indicate that consumers are placing increasing reliance on the use of nontraditional health care providers to avoid the excessive costs of traditional medical services and to obtain more holistic considerations of their needs’.



7. ‘Dietary supplements are safe within a broad range of intake, and safety problems with supplements are relatively rare’. 8. ‘Legislative action that protects the right of access of consumers to safe dietary supplements is necessary in order to promote wellness’. This Act declared dietary supplements were neither foods nor drugs. Instead, they created a new category of food by specifically defining dietary supplements to include dietary ingredients, such as vitamins, minerals, herbs or other botanicals, amino acids or other dietary supplements. A dietary supplement must be intended for ingestion, such as a tablet, capsule, powder, softgel, gelcap or liquid form. The Act also specifically states that customers can be provided with publications on supplements in connection with the sale of the dietary supplements. These publications must not be false or misleading, not promote a specific brand of supplement, and provide a balanced view of the available scientific literature. In the store, it must be physically separated from the supplement. The Act allowed supplements to carry claims that they help preserve general well-being. Additionally, they can claim that they help preserve the structure or function of parts of the body. However, they can not state that the supplements are effective treatment of disease, because this would be a drug claim. This section of the Act has been the subject of discussion and litigation between the FDA and representatives of the supplement industry. The Act specifically empowers the FDA to oversee quality control of supplements and they are given the power to remove unsafe supplements from the market. In practice, this process has not worked very well. The plain fact is that the quality of supplements on the market is very variable. Studies have shown that supplements from some manufacturers can contain 25% or less of the active ingredient than stated on the label (www.consumerlabs.com). It also appears that supplements on the market are not adequately monitored for hazardous contaminants (www.consumerlabs.com). Therefore, it would appear that there is a need for increased supervision of the supplement industry to ensure Americans of the potency and safety of the supplements they purchase. While we wait for these changes, there are some promising trends. Several major pharmaceutical firms have purchased supplement companies and this promises improvement in quality control and standardization. Additionally, several major supplement manufacturers are funding clinical trials that specifically document the value and side effects of their herbal extracts. In summary, there is no doubt that Americans now have much greater access to nutritional or herbal supplements as a result of this Act. Additionally, Americans have much greater access to literature on nutritional and herbal supplements. However, these supplements range radically in their value. Among these supplements are therapeutic agents with a strong scientific basis and proven clinical value. Most of these lack FDA approval because no company has been willing to take them through the expensive process the FDA mandates. In contrast, other herbal products have no scientific basis, no

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sound clinical trial documentation of efficacy and may pose serious health risks.

ORTHOMOLECULAR THERAPIES Antioxidants Antioxidants represent one of the most common supplement classes ingested by prostate cancer patients. Widely used examples include vitamin C, vitamin E, selenium and plant polyphenols, such as those from green tea, grape seed and pine bark. There is a growing body of scientific and clinical work supporting the use of these compounds by patients with cancer and other diseases. Antioxidant defense network Many biochemical reactions essential for life carry with them the threat of oxidative damage to the tissues of your body. For example, the process by which mitochondria produce the ATP that drives your muscles and other tissues creates side products, such as hydrogen peroxide, that can damage tissues by oxidation. Exposure to sunlight can enhance oxidative damage to skin cells. Chemicals that naturally occur in food can cause oxidative damage. We are able to eat these foods safely only because our bodies do such a great job defending us against oxidative damage. An example of this are fava beans, which can cause severe injury if consumed by people who lack the normal defenses against oxidative damage. We now know that the body has a comprehensive antioxidant defense network in which each component part has a role to play.11,12 What are the components of this antioxidant defense network? One group of enzymes function to destroy or detoxify common oxidants. For example, hydrogen peroxide is one oxidant commonly formed as a byproduct as the tissues in the body perform their daily tasks. There are several enzymes capable of detoxifying hydrogen peroxide. The enzyme, catalase, reacts two hydrogen peroxide molecules together to form oxygen and water. A second family of enzymes, called glutathione peroxidases, reduces hydrogen peroxide to water. Most of the known glutathione peroxidases require selenium. A second group of components are vitamins that act as antioxidants. Vitamin C and vitamin E are prominent members of this group. Vitamin C is soluble in water and acts as an antioxidant in the water phase of the cell. Vitamin E is soluble in body fat and other lipids, but not in water. For this reason, vitamin E acts as an antioxidant for body lipids. A third group of components are the dietary antioxidants. It is now apparent that most vegetables and grains contain antioxidants. Tomatoes contain the red pigment, lycopene. Green tea contains antioxidant polyphenols. Onions and garlic have large amounts of sulfur-containing chemicals that are strong antioxidants. Fruits, such as blueberries, strawberries and raspberries, are another rich source of antioxidants. It now appears that these plant antioxidants act to bolster the effectiveness of other members of the antioxidant network. The final component of the antioxidant defense network are


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a group of proteins that sequester iron and copper. This is important because free iron and copper can stimulate the conversion of peroxides into free radicals that rapidly react with and destroy normal tissues. Under normal conditions, this system is so effective that free iron and copper do not exist in body fluids or tissues. When sequestration of iron fails, it causes hemochromatosis and hemosiderosis. When sequestration of copper fails, it causes Wilson’s disease. When all four components of the antioxidant defense network are functioning optimally, the body can effectively handle attack by a wide range of oxidants without sustaining serious injury. Oxidative damage can include injury to DNA, the genetic material in a cell. This genetic damage can foster the development of cancer or promote the progression of cancer from a slow-growing local problem to one that grows and spreads rapidly. Thus, a fully functioning antioxidant network can lower the risk that cancer will develop. However, this network operates so that various components overlap in their function, so that a deficiency in one component can be compensated by the others. For example, a low level of vitamin E may not be of great consequence if selenium, vitamin C and dietary antioxidants are present at optimal levels. This is an important point to keep in mind when reading the results of clinical trials: any antioxidant can appear to have no impact if the subjects are taking in large amounts other antioxidants and/or are not exposed to significant oxidant stress. Conversely, if the people in the trial are all subject to some oxidative stress, antioxidants may prove more effective than they would be in normal subjects. For example, cigarette smoking subjects the body to increased oxidative stress and smokers may have a greater need for antioxidants than non-smokers. This will prove important when we discuss some of the clinical trials involving antioxidants and prostate cancer. Oxidants and the development of prostate cancer Why should antioxidants alter the risk of dying from prostate cancer? Several papers provide a possible answer to this question.13,14 These authors have shown that prostate cancer cells exposed to testosterone produce hydrogen peroxide and other oxidants. This led them to propose that testosterone exposure results in the production of oxidants that cause genetic damage. Genetic damage can play a role in the progression as well as the genesis of cancer. The implication of this line of research is that strengthening the antioxidant network may lessen the risk of developing prostate cancer. It may also slow the progression of this disease from a slow-growing cancer limited to the prostate gland to one that has spread throughout the body and become resistant to all therapies. There are several antioxidants that may alter the natural history of prostate cancer. Selenium Over the past few years, there has been a dramatic increase in our knowledge about selenium and its effects on living organisms. A search of the Library of Medicine’s online database, PubMed, show more than 1000 scientific articles published on selenium since January 1998. One major factor behind this

surge in interest about the health effects of selenium has been the publication, in 1996, of a large randomized controlled clinical trial that demonstrated a marked reduction in cancer deaths associated with increased selenium intake.15,16 This trial was initiated in 1983 as a randomized controlled trial testing the impact of supplementation with 200 µg of selenium yeast per day on the risk of skin cancer. This clinical trial enrolled 1300 individuals residing in the Mid-Atlantic Coastal Plain from Virginia to South Carolina, an area long known to have low soil and water selenium levels. After 10 years, the overall cancer death rate was 50% lower in the subjects on selenium as compared to the control group. The cancers responsible for this difference were carcinomas of the prostate, colon and lung; prostate cancer deaths were decreased by 64%, colon cancer by 40% and lung cancer by 30%. The four major causes of cancer death are those of the lung, prostate, colon and breast. Thus, selenium dramatically reduced the death rate of three of the four most common causes of cancer death in the USA. Furthermore, there were no cases of selenium toxicity among the people in this trial who took selenium supplements for years. Selenium and prostate cancer Since the publication of this randomized controlled trial, there has been one major study designed to expand on the validity of these findings to address one criticism, namely that serum selenium levels used were just a snapshot of selenium levels at one point in time, while the development of prostate cancer takes many years and is more likely to be influenced by the average selenium level during that time period. Since hair and nails are formed at the rate of about one millimeter per day and thus are a better estimate of average selenium level, a recent study has examined the selenium content of nail clippings from close to 34 000 men and found that the risk of developing metastatic prostate cancer decreased as the selenium content of the nail clippings increased.17 When men with the highest and lowest nail selenium content were compared, a 65% reduction in the risk of metastatic prostate cancer was found in the former group. What is the next step in this line of investigation? The National Cancer Institute (NCI) has just funded a large randomized controlled trial in which men will be randomized between control, vitamin E, selenium and vitamin E plus selenium. Selenium and the immune system in cancer There are a number of studies that suggest adequate selenium levels are necessary for proper function of the immune system. The most convincing study is a randomized double-blind controlled clinical trial in patients with head and neck cancer.18 Cytotoxic T cells and natural killer cells are the most important parts of the immune system in terms of resistance to cancer. Cytotoxic T-cell number and natural killer cell function is usually depressed in head and neck cancer patients. Patients in this study all had untreated squamous carcinoma of the head and neck, and were randomized to placebo or selenium at a dose of 200 µg per day for 8 weeks. Plasma selenium levels were measured at the start and during the trial to ensure patients took the selenium as



directed. During the 8 weeks, 88% of the patients took the selenium dose assigned. At the start of the trial the average selenium levels in the two groups were 91.3 and 94.4 µg/l of blood plasma. After 8 weeks of selenium supplementation, the average selenium level in the men on this mineral increased from 91.3 µg/l to 105.3 µg/l. Despite this minor increase in plasma selenium, there were major changes in the immune system. In the patients on placebo, cytotoxic T cells killed only 7% of the tumor cells. After 8 weeks of selenium supplementation, the T cells were able to kill 78% of the tumor cell targets. This is a rather remarkable shift given the short duration of treatment and small increase in selenium levels. To place these findings in perspective, in the Clarke study, prolonged administration of the same dose of selenium, 200 µg per day, eventually increases the selenium levels to close to 200 µg/l rather than the 105.3 µg/l after eight weeks reported in this paper on head and neck cancer. Selenium and heavy metals Metals such as arsenic, lead, mercury, cadmium and thallium are all quite poisonous. Furthermore, industrial uses of these metals have led to largescale environmental contamination. One of these, cadmium, has been specifically implicated as a cause of prostate cancer. Selenium alters the toxicity of heavy metal ions in several ways.19,20 It is important to note that selenium can bind these metal ions into complexes that are insoluble in water. To a certain extent, selenium can bind to these metal ions in the gastrointestinal tract, diminishing the absorption of both selenium and the toxic metals. Once selenium has been absorbed, it can form complexes with these metal ions, lessening or delaying the toxicity of these metal ions and potentially reducing the risk of cadmium induced prostate cancer. Vitamin E Vitamin E is soluble in lipids but not in water. As a result, it largely acts to prevent oxidative damage to the lipids in a cell. In laboratory studies, vitamin E has been shown to act in concert with antioxidants present in the cytosol, such as vitamin C, glutathione and selenium. The first evidence that vitamin E might alter the progression of prostate cancer came as an unexpected result of a clinical trial designed to test the role of this vitamin in the prevention of lung cancer in smokers. In this trial, close to 29 133 male cigarette smokers were randomized to placebo, β-carotene, vitamin E or β-carotene plus vitamin E.21 At the point where men had been on the trial for 5–8 years, death rates from prostate cancer were 40% less in the men on vitamin E alone compared to placebo. In contrast, the men on β-carotene experienced a 30% increase in mortality from this malignancy. The group on β-carotene plus vitamin E was not significantly different from the control group. Vitamin E is not a single chemical substance but a name given to a family of fat-soluble antioxidants. These compounds differ in their content in foods as well as their ability to act as antioxidants. While α-tocopherol is widely available and the form most commonly used in laboratory and clinical studies,

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it is not the most active antioxidant. Recently, several groups have reported that γ-tocopherol is more active against prostate cancer cells than is the α form of this vitamin.22 In contrast, other groups have found γ-tocopherol no more active than α-tocopherol as an anticancer agent.23–25 Instead, they have found the most active tocopherol is the δ-form. Additionally, tocotrienols are considerably more active than the corresponding tocopherols, with the most active preparation currently available commercially being concentrated palm oil tocotrienols. Finally, vitamin E succinate appears to exert anticancer activity equal to or greater than any of the naturally occurring tocopherols or tocotrienols. There is now evidence that vitamin E kills prostate cancer cells by a unique mechanism. All cells in the body have the capacity to commit suicide. There are several means by which this suicide can be triggered. One means of accomplishing this is by activating certain proteins, called ‘death receptors’ on the surface of cells. These death receptor proteins are designed so that when they are activated, the cell bearing them rapidly destroys itself. One of the most common of these proteins is called Fas. When vitamin E-like chemicals kill prostate cancer cells, Fas rapidly appears on the surface of the prostate cancer cells and appears to undergo activation, leading to cell death. These findings suggest that vitamin E does more than prevent genetic damage caused by oxidants released as a result of testosterone exposure. In fact, it may well be that vitamin E-like molecules may actually be orally active chemotherapeutic agents with low toxicity. This concept has led at least one group to synthesize analogs of vitamin E chemically with the hope of increasing the anticancer activity of this family of compounds.

Vitamin A Vitamin A and its derivatives seem to have a protective effect against various cancers. However, epidemiological data on prostate cancer and vitamin A intake are conflicting. Some studies demonstrate a significant trend of increased prostatic cancer risk associated with decreasing serum retinol levels,26 while others fail to show a protective value.27 Some epidemiological studies have even shown an increased risk of prostate cancer with supplemental vitamin A intake.28 A possible explanation for this discrepancy may be the source of dietary vitamin A. For example, in Asia and other areas with a low incidence of prostate cancer, vitamin A is largely obtained from vegetables, while the main source of vitamin A in the USA is fat. The positive correlation between vitamin A and prostate cancer may be due to higher dietary fat intake. In a recent placebo-controlled, randomized intervention trial, β-carotene caused an increase in prostate cancer incidence.21 As described above the ‘Alpha-Tocopherol Beta-Carotene Cancer Prevention Study’ included 29 133 eligible male cigarette smokers randomly assigned to receive 20 mg β-carotene, 50 mg tocopherol, β-carotene and tocopherol or placebo daily for 5–8 years.21 β-Carotene treatment did not result in a decrease in cancer at any of the major sites but rather an increase at several sites, notably the lungs, prostate and stomach. Lung cancer increased by 18% (474 vs. 402 cases, 95% confidence


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interval 3–36, P = 0.01), prostate cancer by 25% (138 vs. 112 cases) and stomach cancer by 25% (70 vs. 56). Interestingly, the increase in cancer incidence was most pronounced in men consuming alcohol. Another possibility is that the dose–response curve of chemopreventive agents may be bell shaped with excess administration reducing the efficacy or even promoting tumors with agents, such as alcohol shifting the dose–response curve. The biphasic effect of retinoic acid on LNCaP (a popular human prostate cancer cell line used in experimental laboratory studies) growth should be considered when designing in vivo studies to determine the impact of retinoic acid on solid prostatic tumor growth. In addition, the fact that retinoic acid increases PSA secretion may complicate the interpretation of serum PSA levels used for outcome assessment.29

Vitamin D Vitamin D is a general term given to antirachitic substances synthesized in the body in response to ultraviolet radiation and found in foods activated by ultraviolet radiation. Calcitriol (1,25-D3) is the active form of vitamin D. Because the body can synthesize vitamin D, it has been reclassified as a hormone.30 In 1990 it was first suggested that vitamin D3 deficiency might increase the risk of prostate cancer.31 Subsequent studies showed an inverse association between ultraviolet solar exposure and mortality rates for prostate cancer32 and a direct association between vitamin D levels and prostate cancer.33 Unfortunately, other similar studies were not able to demonstrate this association.34 Prostate cell division is influenced by two steroid hormones, testosterone and vitamin D, the action of each being mediated by its respective receptor. The first study examined genetic polymorphisms in the androgen receptor (AR) and the vitamin D receptor (VDR), in a case-control pilot study of prostate cancer where 57 non-Hispanic White case patients with prostate cancer and 169 non-Hispanic White control subjects were genotyped for a previously described microsatellite (CAG repeats) in the AR gene and for a newly discovered poly-A microsatellite in the 3′-untranslated region (3′UTR) of the VDR gene.35 Both the AR and the VDR polymorphisms were associated, individually with prostate cancer. Adjusted odds ratios (ORs) [95% confidence intervals (CIs)] for prostate cancer were 2.10 (95% CI = 1.11–3.99) for individuals carrying an AR CAG allele with fewer than 20 repeats versus an allele with 20 or more repeats and 4.61 (95% CI = 1.34–15.82) for individuals carrying at least one long (A18–A22) VDR poly-A allele versus two short (A14–A17) poly-A alleles. For both the AR and VDR genes, the at-risk genotypes were more strongly associated with advanced disease than with localized disease. Another study tested the hypothesis that vitamin D receptor gene polymorphisms are associated with prostate cancer risk using a case-control study of 108 men undergoing radical prostatectomy and 170 male urology clinic controls with no history of cancer.36 Among the Caucasian control group, 22% were homozygous for the presence of a TaqI RFLP at codon 352 (genotype tt), but only 8% of cases had this genotype

(P < 0.01). A similar trend was seen among the small number of African Americans in this study (13% for controls, 8% for cases), although the difference was not statistically significant. Race-adjusted combined analysis suggests that men who are homozygous for the t allele (shown to correlate with higher serum levels of the active form of vitamin D) have one-third the risk of developing prostate cancer requiring prostatectomy compared to men who are heterozygotes or homozygous for the T allele (odds ratio MH = 0.34; 95% CI 0.16–0.76; P < 0.01). Substantial experimental data indicate that 1,25-dihydroxyvitamin D3 (calcitriol) has potent antiproliferative effects on human prostate cancer cells.37 Because of this and the genetic alterations of the VDR outlined above, investigators carried out an open-label, non-randomized pilot trial to determine whether calcitriol therapy is safe and efficacious for early recurrent prostate cancer. Their hypothesis was that calcitriol therapy slows the rate of rise of PSA compared with the pretreatment rate. After primary treatment with radiation or surgery, cancer recurrence was indicated by rising serum PSA levels documented on at least three occasions. Seven subjects completed 6–15 months of calcitriol therapy, starting with 0.5 µg calcitriol daily and slowly increasing to a maximum dose of 2.5 µg daily depending on individual calciuric and calcemic responses. Each subject served as his own control, comparing the rate of PSA rise before and after calcitriol treatment. As determined by multiple regression analysis, the rate of PSA rise during versus before calcitriol therapy significantly decreased in six of seven patients, while in the remaining man a deceleration in the rate of PSA rise did not reach statistical significance. In conclusion, it would appear that variation of the VDR gene is associated with prostate cancer susceptibility and therapeutic exploitation of vitamin D biology is a potentially fruitful approach in prostate cancer. These results support recent ecological, population and in vitro studies, suggesting that vitamin D is an important determinant of prostate cancer risk and, if confirmed, suggest strategies for chemoprevention/ treatment of this common cancer.

Vitamin C Vitamin C is the major circulating water-soluble antioxidant, which acts as a free-radical scavenger, resulting in inhibition of malignant transformation in vitro38 and a decrease in carcinogen-induced chromosome damage.39 Despite the popularity of vitamin C as a cancer preventive, to date no consistent relationship between vitamin C levels and prostate cancer has been demonstrated.40 However, treatment of androgen independent (DU145) and dependent (LNCaP) human prostate cancer cell lines, while growing in culture dishes with vitamin C, resulted in a dose- and time-dependent decrease in cell survival and cell division. Vitamin C induced these changes through the production of hydrogen peroxide, which damages cells by generating free radicals. These results suggest that ascorbic acid could be a potent anticancer agent for prostate cancer cells.41



HERBAL THERAPIES EMPLOYING INDIVIDUAL OR MIXTURES OF HERBS Monophenols and polyphenols in green tea Plant phenols are one of the most potent groups of antioxidants. They can occur as monophenols or as clusters of monophenols, called polyphenols. The major polyphenols from green tea are epigallocatechin-3-gallate (EGCG), epigallocatechin and epicatechin-3 gallate. Together, these make up 30–40% of the solids extracted from green tea leaves during brewing. However, polyphenols are found in a wide range of plant products that also have health benefits and may make a welcome alternative to green tea. Green tea intake has been associated with a decreased risk of cancers of the prostate, colon, pancreas, skin and other organs.42–44 Seemingly, green tea prevents the damage caused by a large number of cancer-causing chemicals and even excessive sun exposure. It appears that green tea can not only prevent cancer, but is able to stop the growth or even kill human cancer cells. This ability was documented in human breast, lung, colon, pancreatic and prostate cancers in tissue culture and in animal models. The contents of green tea have been carefully examined to determine the chemical in the tea responsible for the anticancer activity. There is a growing consensus that most of the useful activity is caused by a polyphenol called epigallocatechin gallate or EGCG. This compound caused the rapid shrinkage of human prostate cancers growing in mouse xenograft models. However, there is no known mechanism by which an antioxidant can cause cancer cells to stop growing or cause rapid shrinkage of a tumor mass. For this reason, it is very likely EGCG exerts its anticancer activity by a mechanism independent of its antioxidant activity. EGCG and other green tea polyphenols are sensitive to light and air. EGCG and other tea polyphenols are most stable at a pH of less than 5.5 and when the tea is brewed at 180 °F or less. The amount of EGCG found in green tea appears to be effective as a cancer prevention agent. The amount needed to stop the growth of cancer cells or to cause the cancer to shrink rapidly in the mice is much larger – projecting from the animal experiments a dose equivalent to 10 or more cups per day would be necessary. Human clinical trials have progressed to phase I, where a dose of green tea extract of 1000 mg per day (equivalent to 10–12 cups per day) was well tolerated. At present, we are unaware of any published Phase II or III clinical trials in prostate cancer.

Saw palmetto Saw palmetto is a compound derived from the fruit extract of the American dwarf palm tree that is native to the Atlantic Coastal Plain from North Carolina south through Northern Florida. The common herbal preparation represents the extracted lipids and sterols. Recent clinical trials testing saw palmetto in the treatment of benign prostatic hyperplasia (BPH) were reviewed in the Journal of the American Medical Association in 1998.45 After critically evaluating the quality of the clinical trials and the consistency of the results, the

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authors concluded that saw palmetto was an effective treatment for BPH. This conclusion has been confirmed in two subsequent extensive literature reviews.46,47 One problem with these reviews are that they do not take into account that various commercially available saw palmetto products vary in their potency and quality. There are many different ways to extract these lipids and sterols, yielding products with differences in their biologic effects. Also, the different brands and preparations available with varying amount of extract per capsule. Consumer Labs, Inc. has tested 27 of the products on the market and found that only 17 contain an adequate amount of the specific fatty acids and sterols needed to produce a therapeutic effect. A list of the manufactures that passed this test is available at their website, www.consumerlabs.com. The only sure way of knowing whether a given saw palmetto extract is active is for the manufacturer to sponsor clinical trials that document its activity. Clinical trials are expensive and most herbal products companies have been reluctant to participate in such stringent tests of the value of their products. The economic justification was that the consumer did not demand this investment and the cost of such trials eroded the profitability their business. A few companies have been foresighted enough to take part in clinical testing of their herbal extracts. In those few situations, we have solid evidence of the value of a herbal product as well as sound information about the effective dose and possible side effects. The biochemical basis for the activity of saw palmetto against benign enlargement of the prostate almost certainly includes inhibition of the formation of dihydrotestosterone (DHT) within the prostate gland. Interestingly, saw palmetto inhibits formation of DHT in the prostate gland, but not in many other tissues and may not alter blood levels of this hormone.48,49 The action of testosterone and dihydrotestosterone on the prostate gland is markedly stimulated by the hormone, prolactin. Saw palmetto is reported to block the response of prostate cells to prolactin.50 Saw palmetto has also been reported to inhibit the enzyme, 5-lipoxygenase, the enzyme that converts arachidonic acid to the eicosanoid, 5-HETE. This eicosanoid is known to stimulate the growth of prostate cancer cells.51 In BPH, the increased size of the gland can arise from an increase in the number of cells lining the prostate ducts as well as an increase in the number of stromal cells in the space between the ducts. With this background, it is interesting to note that saw palmetto has been shown to cause the death of both the stromal cells and the cells lining the prostate ducts.52,53 This has been followed by one study showing that saw palmetto was able to slow the growth of prostate cancer cells and, at high enough concentrations, even kill these cancer cells. To date, there are no clinical trials testing saw palmetto in the treatment of prostate cancer, so it is difficult to know whether this observation is clinically relevant. In summary, specific saw palmetto extracts appear to have useful activity in the treatment of BPH. This product appears to alter prostate biology through a number of mechanisms, some of which might also be relevant to the treatment of


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prostate cancer. This is especially true if these are considered as part of a multiagent regimen such as PC-SPES when saw palmetto is combined with other agents. Unfortunately, clinical trial documentation of the activity of saw palmetto extract against prostate cancer is completely lacking.

Black cohosh root The alcoholic extract of black cohosh root is widely used by women in Europe and now the USA as a treatment for menopausal symptoms.54–56 Virtually all of the clinical studies have been done with one preparation, Remifemin, originally developed in Europe and now marketed in the USA. Many men with prostate cancer on hormonal therapy are using Remifemin or other black cohosh root preparations as treatment for their hot flashes and other symptoms of male menopause. Black cohosh was one of the medicinal plants widely used by various American Indian tribes and adapted by early European settlers as a treatment for rheumatism. The use of black cohosh for menopausal symptoms became widespread during the 1800s in both America and Europe. At present, virtually all significant clinical and laboratory investigation on black cohosh have been performed by European investigators. Numerous clinical trials, including randomized controlled trials, have compared Remifemin with placebo and a variety of estrogen preparations commonly used as hormone replacement therapy for women. It is now well documented that this herbal preparation effectively reduces hot flashes in women. Remifemin also appears to be effective in countering the depression, insomnia and other psychiatric complications of female menopause. In addition, this black cohosh extract appears to prevent bone loss in animals after surgical removal of the ovaries, raising the possibility that it might also ameliorate the development of osteoporosis. This possibility has yet to be tested in humans. Remifemin also appears to act on the female genitalia, where it has been reported to cause estrogen-like effects on the vaginal mucosa. The production of estrogen by the ovary is stimulated by luteinizing hormone (LH). When the brain senses that sufficient estrogen is present, it decreases the production of LH, shutting down the production of additional estrogen.57 During menopause in women, LH production increases because the brain senses the absence of estrogen. The magnitude of this LH rise has been reported to correlate with the severity of menopausal symptoms. A majority of the studies indicate that a dose of Remifemin sufficient to reverse menopausal symptoms also blocks the release of LH. As with most herbal preparations, Remifemin is composed of a mixture of different chemicals. Fractions have been identified that can bind to the estrogen receptor and appear to mimic the actions of estrogen. Another fraction can block LH release even though it has no estrogenic activity. These results suggest that it would be possible to prepare black cohosh extracts that selectively suppress the response of the brain to menopause, such as hot flashes, depression and insomnia, that lack any activity at the estrogen receptor. The most common side effect of Remifemin is transient gastric distress seen in approximately 7% of women. In fact, it

seems to be as well or better tolerated than the commonly used estrogenic medications. In particular, it appears to be much less likely to cause uterine bleeding. In standard test systems, it also does not cause mutations or stimulate the development of cancers. This is important because naturally occurring estrogens may promote the development of cancers of the breast and uterus. What about the use of Remifemin and other black cohosh extracts in men? There are no clinical trials in which Remifemin or other black cohosh extracts were administered to men. In men already on hormonal therapy, the estrogenic activity of this supplement may cause breast enlargement and other estrogen-dependent side effects. We have no information about the impact of Remifemin and other black cohosh preparations on prostate cancer growth and spread, and it is impossible to predict its impact on this disease. Therefore, its use in men is questionable at best until we have a better understanding of its impact on the physiology of the human male and its effects on prostate cancer.

Lycopene It has been long known that intake of fruits, vegetables and grains are associated with a decrease in the risk of many cancers, but the specific components of these foods responsible for this reduced risk remain a matter of controversy. Lycopene is a member of a broad group of plant pigments, called carotenoids, that includes β-carotene (orange color of carrots) and lutein (yellow color in many vegetables). Carotenoids, especially β-carotene, have long been thought to play an important role in cancer prevention.58 Lycopene is the red pigment found in tomatoes, pink grapefruit, watermelon and apricots, and is related to β-carotene and other carotinoids in structure. Evidence strongly indicates that intake of tomato products and lycopene offer protection against cancers of the stomach, lung and prostate. Lycopene also appears to reduce the risk of cancers of the oral cavity, esophagus, breast, pancreas, cervix and colon. What is more interesting is that none of the 72 studies reviewed in preparation of this chapter report a link between lycopene and an increase in the risk of any cancer. Furthermore, there are no reports of toxicity, regardless of dose. In a recent review, Giovannucci discussed study after study in which the intake of lycopene, but not other carotenoids, such as β-carotene, correlates with protection from cancer.59 This is consistent with a recent randomized controlled trial that found supplemental β-carotene actually increased the risk of death from prostate cancer. This is an important point, because many dietitians and alternative health practitioners are still recommending β-carotene to men with prostate cancer. It is important to stress that there is no evidence to support this practice. Lycopene is well absorbed from cooked tomato products, such as tomato sauce or tomato paste, but not from fresh tomatoes. Additionally, lycopene absorption is enhanced by the addition of oil.60 Why should lycopene reduce the risk of cancer? Carotenoids can act as antioxidants and as precursors to Vitamin A. Among the common carotenoids, lycopene is



the most effective antioxidant, and this property may be important given the activity of vitamin E and selenium against this cancer. Several observations instill confidence in the importance of lycopene. First, the studies that report a reduced risk of cancer associated with lycopene involved the USA, Italy, Netherlands, Spain, Sweden, Australia, Iran, China and Japan, indicating the protective effect persists despite widely different dietary patterns, lifestyles and racial background. Second, the protective effect extends to a wide range of human cancers, each of which has its own unique biology and is caused by different mechanisms. Third, in every country and with every cancer examined, lycopene intake never correlated with a significant increase in the risk of cancer. What is lacking? Final proof of lycopene’s importance will require a randomized controlled clinical trial in which large numbers of people take a placebo or a defined amount of lycopene over a prolonged period of time, and the impact on cancer frequency and cancer deaths measured. Since tomato products are often used in prepared foods in ways that are not obvious, this study will be difficult to conduct.

PC-SPES PC-SPES is a combination of seven Chinese medicinal herbs [Reishi (Ganoderma lucidum) spores, Balkal skullcap (Scutellaria baicalenesis) root, Rabdosia (Rabdosia rubescens) root, Dyer’s wood (Isatis indigotica) root, mum (Dendranthema morifolium) flower, san-qi ginseng (Panax notoginseng) bark and licorice (Glycyrrhiza glabra) root] with the addition of one North American herb, saw palmetto. This herbal product appeared a few years ago and is widely used by patients as a treatment for their prostate cancer. The story of this herbal product illustrates the positive and negative aspects of the current regulatory environment with regard to supplements. This product did not proceed through the standard process by which prescription drugs are approved by the FDA. Shortly after this product was introduced, many of us became aware that in some patients this product induced a significant decrease in tumor size. Physicians initially had no information about appropriate dosing, side effects and antitumor activity of this preparation. Physicians specializing in prostate cancer have gathered experience with the use of this herbal product, largely because patients decided on their own to try it. Reports about PCSPES then began to appear in medical literature. In one of the first clinical and experimental studies to evaluate the effect of PC-SPES in humans, DiPaola and associates61 tested the estrogenic activity of PC-SPES in yeast and mice, and in men with prostate cancer. In this study, they measured the estrogenic activity of PC-SPES with transcriptional-activation assays in yeast and a biologic assay in mice. The clinical activity of PCSPES was evaluated in eight patients with hormone-sensitive prostate cancer by measuring serum prostate-specific antigen and testosterone concentrations during and after treatment. In complementary yeast assays, a 1:200 dilution of an ethanol extract of PC-SPES had estrogenic activity similar to that of 1 nM estradiol, and in ovariectomized CD-1 mice, the herbal

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mixture increased uterine weights substantially. In six out of six men with hormone-sensitive prostate cancer, PC-SPES decreased serum testosterone concentrations and in eight out of eight patients it decreased serum concentrations of PSA. All eight patients had breast tenderness and loss of libido, and one had venous thrombosis. High-performance liquid chromatography, gas chromatography and mass spectrometry showed that PC-SPES contains estrogenic organic compounds that are distinct from diethylstilbestrol, estrone and estradiol. This exciting study was followed by several other recent studies which examined both in vitro and clinical effects of PC-SPES. At UCSF,62 33 patients with androgen-dependent prostate cancer (ADPCa) and 37 patients with androgenindependent prostate cancer (AIPCa) were treated with PC-SPES (nine capsules daily). All ADPCa patients experienced a PSA decline of >80%, with a median duration of 57+ weeks. No patient developed PSA progression. Almost all of these patients had declines of testosterone to the anorchid range. Nineteen (54%) of 35 AIPCa patients had a PSA decline of >50%, a commonly used surrogate index for a robust response in these clinical situations.62 Median time to PSA progression was 4 months. Of 25 patients with positive bone scans, two had improvement, seven had stable disease, 11 had progressive disease and five did not have a repeat bone scan because of PSA progression. Severe toxicities included thromboembolic events and allergic reactions. Other frequent toxicities included gynecomastia/gynecodynia, leg cramps and grade 1 or 2 diarrhea. The study at Columbia University evaluated 69 patients with prostate cancer treated with PC-SPES (three capsules daily).63 Serum PSA responses and side effects were evaluated. Of the patients with prostate cancer, 82% had decreased serum PSA 2 months, 78% 6 months and 88% 12 months after treatment with PC-SPES. Side effects in the treated patient population included nipple tenderness in 42% and phlebitis requiring heparinization in 2%. In a recent study from the Dana–Farber Cancer Institute, 23 patients with AIPCa were treated with PC-SPES (six capsules daily). With a median follow-up of 8 months, 20 patients experienced a post-therapy decline in PSA. Twelve patients (52%) had a >50% decline in PSA. The median duration of the PSA response was 2.5 months. Toxicity was mild and included nipple tenderness, nausea and diarrhea. In univariate analyses, older patients and those with a longer duration of initial androgen ablation therapy were more likely to respond to PC-SPES.64 In recent in vitro studies from Columbia University,63 PC-SPES was evaluated for its ability to induce apoptosis on human prostate cancer cell lines LNCaP (hormone sensitive), PC3 (hormone independent) and DU145 (hormone independent). The effect of oral PC-SPES on growth of PC3 tumors present in male immunodeficient mice was studied. All of the cultured prostate cancer cell lines had a significant dosedependent induction of apoptosis following exposure to PC-SPES. Immunodeficient mice xenografted with the PC3 cell line had reduced tumor volume compared with sham-treated controls when they were treated with a PC-SPES extract from


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the time of tumor cell implantation but not when the treatment was begun 1 week after tumor cell implantation.

a substitute for animal proteins, prompting the FDA to allow firms marketing soy protein to claim that these products have a favorable impact on the course of coronary heart disease.77

Soy and genistein Several reviews have suggested that soy food consumption may contribute to the relatively low rates of breast, colon and prostate cancers in countries such as China and Japan.65,66 Soy contains isoflavones, such as genistein and daidzein, which are thought to account for the health benefits of this legume. You will see these compounds alternatively referred to by their specific chemical name, such as genistein, as isoflavones or as phytoestrogens. The latter term arises from the fact that these isoflavones mimic some of the biological effects of the female sex hormone, estrogen. In the laboratory, genistein has well-documented activity against prostate cancer.67–71 High concentrations of genistein and other soy isoflavones cause the death of prostate cancer cells. At somewhat lower concentrations, these isoflavones arrest the growth of prostate cancer and block tumor cell invasiveness. Additionally, there are now several studies in which soy products or isolated soy isoflavones have been demonstrated to slow the growth of human prostate cancer cells in animal models.68,72,73 The mechanism by which soy isoflavones might slow the growth and/or spread of prostate cancer is unclear. Genistein, at concentrations obtainable in humans, can block the action of both the epidermal growth factor and Her-2/neu receptors. This means that genistein can theoretically block one of the major mechanisms by which prostate cancer cells become hormone-refractory. While these isoflavones act as estrogenic compounds in laboratory assays, men on soy-rich diets have only minor alterations in sex hormone levels. Finally, soy isoflavones appear to block tumor angiogenesis in laboratory models by inhibiting the growth of proliferating endothelial cells.74 There is also controversy on the best soy product to use in order to obtain high blood levels of genistein and other soy isoflavones. Genistein is absorbed much more effectively from fermented soy products such as miso, natto and tempeh than it is from soy beans, tofu or soy milk. Additionally, soy phytoestrogen or genistein tablets or capsules currently on the market would easily permit the ingestion of several grams of soy isoflavones per day. An additional complication is that blood levels of genistein may underestimate the levels in the prostate. When genistein levels are measured in prostatic fluid, the concentration is 5–10 times higher than in the blood. Despite these findings, use of soy isoflavones in the treatment or prevention of prostate cancer in men is questionable. While there are quite a few epidemiology studies that show a correlation between high soy intake and a reduced risk of prostate cancer, no randomized controlled clinical trial showing that these soy products prolong the life of men with this disease has yet been published.75,76 We even lack clinical trials that show soy products arrest or slow the growth of prostate cancer in men. We do not even know the dose and schedule for the administration of soy isoflavones most likely to affect human prostate cancer. On the other hand, there appear to be other health benefits associated with the use of soy protein as

SUMMARY AND CONCLUSIONS The ‘Dietary Supplement Health and Education Act of 1994’ guarantees Americans ready access to herbal products. While selected herbal products have impressive therapeutic activity in tissue culture and animal models, with few exceptions clinical trial documentation of activity is less than impressive. In fact, the common pattern is for initially promising laboratory findings to lead to widespread commercial availability without any intervening clinical investigation. An additional problem of great concern is that the commercially available herbal products vary widely in their quality. Nevertheless, the increasing number of clinical trials carried out with these materials combined with the advent of modern molecular biological drug-screening techniques promises to revolutionize drug discovery and lead to effective anticancer compounds in the next 5–10 years.

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What is the Newest Technology in Treating Prostate Cancer? Transrectal High-intensity Focused Ultrasound

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56

Stephan Madersbacher and Michael Marberger Department of Urology, University of Vienna, Austria

PHYSICAL PRINCIPLE As an ultrasound wave propagates through a medium, it is progressively adsorbed and the energy is converted to heat in any medium that is not ideally viscoelastic, such as biological tissue.1–4 In diagnostic ultrasound systems, the amount of heat generated is extremely small and has not been shown to have any harmful effect. For therapeutic purposes, the intensities exceed those of diagnostic systems by the factor 103–104, which induce tissue temperatures in the focal area of >80 °C; this technique is known as high-intensity focused ultrasound (HIFU).1–4 The sharp heat impulse leads to a coagulative necrosis of all cellular elements within this focal area.1–4 As the HIFU beam is emitted in a focused way, thermal damage to intervening tissue and areas in the vicinity of the focal zone can be avoided. Hence, HIFU is the only means currently available permitting contact- and irradiation-free in-depth tissue ablation in any solid organ accessible for ultrasound.1–4 The thermal effect of HIFU on tissue is dependent on a number of factors, such as: (1) the ultrasonic site intensity throughout the tissues; (2) the absorption coefficients of the tissues; (3) the temperature rise throughout the exposed tissues [for short time intervals ( 4.0 ng/ml

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suprapubic tube (average 29 days), and 33% needed a transurethral debris resection averaging 7g. It was clearly shown that, to be successful, treatment of the entire prostate is required (Table 56.2). Gelet et al. analysed outcome predictors in 102 patients.8 As expected, patients with lower baseline PSA (

Prostate Cancer: Science and Clinical Practice

Prostate Cancer-Science and Clinical Practice

Prostate Cancer Principles and Practice

Prostate Cancer: Principles and Practice

Prostate Cancer Principles and Practice

Prostate Cancer. Methods and Protocols

Prostate Cancer Screening (Current Clinical Urology)

Prostate Cancer: Diagnosis and Treatment

Cancer neurology in clinical practice

Cancer Chemotherapy in Clinical Practice

Thyroid Cancer in Clinical Practice

Thyroid Cancer in Clinical Practice

Metastasis of Prostate Cancer

Management of Prostate Cancer

Prostate Cancer (Contemporary Issues in Cancer Imaging)

Cancer: Basic Science and Clinical Aspects

Prostate Cancer (Recent Results in Cancer Research)

Androgen Action in Prostate Cancer

Prostate Cancer: Nursing Assessment, Management, and Care

The Prostate Cancer Treatment Book

Drug Management of Prostate Cancer

Prostate Cancer (Deadly Diseases and Epidemics)

Prostate Cancer (Deadly Diseases and Epidemics)

Gene Therapy in the Treatment of Cancer: Progress and Prospects (Cancer: Clinical Science in Practice)

Body Contouring: Art, Science, and Clinical Practice

Clinical Psychology: Integrating Science and Practice

Prostate Cancer: Science and Clinical Practice