Introduction

INTRODUCTION Prostate Cancer: Progression, Risk Reduction, and Future Options Eric A. Klein, MD Supplement Editor, Prostate Cancer: Progression, Risk Reduction, and Future Options Section of Urologic Oncology, Urological Institute, Cleveland Clinic Foundation, Cleveland, OH [Rev Urol. 2002;4(suppl 5):S1–S2] © 2002 MedReviews, LLC rostate disease, either symptomatic benign prostatic hyperplasia (BPH) or cancer, is a significant health problem. The estimated prevalence of symptomatic BPH from community-based studies is 40% for men in their 70s, and histological evidence of BPH in autopsy studies is found in 60%–80% of men aged 60–69 years.1–3 Prostate cancer has been the most common visceral malignancy in U.S. men for more than 10 years. The estimated lifetime risk of disease is 16.6% for Caucasians and 18.1% for African Americans, with a lifetime risk of death of 3.5% and 4.3%, respectively.4 The prevention of either or both of these diseases could have a significant impact on the quality of life of a very large at-risk population. This supplement, based on a symposium presented at the 2002 Annual Meeting of the American Urological Association, summarizes the current state of scientific and clinical knowledge on the etiology and prevention of these diseases. “Benign prostatic hyperplasia" consists of three entities: microscopic BPH, seen histologically on prostate biopsies of asymptomatic men; macroscopic BPH, or palpable enlargement associated with aging; and symptomatic BPH, leading to lower urinary tract symptoms (LUTS) or bladder outlet obstruction (BOO). Clinical efforts have focused on prevention of symptomatic BPH, both LUTS and BOO. In this supplement, Dr. Roehrborn reviews the theoretical basis and clinical results of the Proscar Long-Term Efficacy and Safety Study (PLESS). In this study of more than 3000 men with symptomatic BPH, finasteride was shown to reduce the risk of both acute urinary retention and the need for surgical intervention in men with moderately severe symptoms. Recent data derived from the Medical Therapy of Prostatic Symptoms (MTOPS) study further demonstrate that early initiation of therapy with -blockers and finasteride can further reduce these risks. P VOL. 4 SUPPL. 5 2002 REVIEWS IN UROLOGY S1 Reducing the Risk of BPH Progression continued Recently the National Cancer Institute reported a reduction in overall cancer mortality between 1990 and 1997, including a reduction of approximately 6% in prostate cancer mortality.4 Furthermore, Tarone and colleagues reported that the mortality rate for prostate cancer in U.S. Caucasians has declined to a level lower than that observed prior to the introduction of PSA-based screening in 1987.5 These improvements in mortality have been variously ascribed to screening, improvements in therapeutic modalities, earlier and more aggressive therapy, and more appropriate application of hormone manipulation. However, there remain marked disparities in prostate cancer incidence and mortality among various ethnicities in the United States and around the world, which highlights the relatively poor state of knowledge regarding genetic, environmental, nutritional, and biologic variables important to this disease. Furthermore, despite these advances, most men who develop metastatic disease are still destined to die of prostate cancer. An ideal method to reduce the mortality and morbidity of carcinoma of the prostate would be through primary prevention, either through a reduction in the number of life-threatening, clinically evident cases or through a reduced, agedependent rate of development, so that tumors would become evident later in life. The development of effective strategies for chemoprevention requires a clear understanding of the molecular events underlying progression from normal epithelium to preinvasive lesions to cancer and the identification, development, and testing of agents that inhibit this sequence of events. Dr. Gann’s article reviews what is known about the molecular risk profile for prostate cancer and S2 VOL. 4 SUPPL. 5 2002 summarizes promising areas for more focused research on etiology and progression. The recognition that the androgenic milieu of the prostate was important in the development of prostate cancer led to the first wide-scale effort at prostate cancer prevention, the Prostate Cancer Prevention Trial (PCPT, SWOG-9217) with finasteride. Finasteride is a testosterone analogue that competitively inhibits the enzyme 5 reductase (type 2), which converts testosterone to dihydrotestosterone (DHT) in the prostate, and causes a profound reduction in circulating and cellular DHT. Finasteride inhibits growth of prostate cancer cells in vitro and is an active preventive agent in certain prostate-carcinogenesis animal models. The PCPT is an ongoing, phase III, double-blind, placebo-controlled, randomized trial to determine the efficacy of finasteride in the reduction of the period prevalence of prostate cancer. This trial opened in 1993 and easily exceeded the accrual goal of 18,000 men. Participants in PCPT are currently undergoing end-of-study prostate biopsies, and results are expected in 2004. In addition to determining if finasteride prevents prostate cancer, PCPT will also yield a wealth of information on the effectiveness of PSA screening and on the natural history of BPH. The use of nontraditional dietary supplements is widespread amongst men with prostate cancer and those who perceive themselves to be at risk, and the willingness to use such agents provides a ripe opportunity for their use in well-controlled clinical trials to determine if they are as effective as generally perceived. The Selenium and Vitamin E Cancer Prevention Trial (SELECT) will test the hypothesis that selenium or vitamin E alone or in combination may prevent REVIEWS IN UROLOGY prostate cancer. SELECT opened in July 2001 and has already enrolled more than 12,000 men, with a total accrual goal of 32,400. Both PCPT and SELECT include serum and tissue biorepositories, which will serve as substrates for biological investigation of the molecular events associated with observed clinical outcomes and should yield important insights into the biology of prostate cancer. Dr. Brawley’s article reviews the rationale and detailed designs of PCPT and SELECT. PCPT and SELECT include men at risk by virtue of their age and race. The recent identification of several prostate cancer susceptibility genes suggests that in the near future we will be able to identify a group of individuals at higher risk than the general population and focus our screening and prevention efforts on those most in need. Such an approach will permit more rapid and less costly clinical trials of potential chemopreventive agents and their use in highly targeted populations. My article reviews the current sate of knowledge on these genes and suggests some new strategies for incorporating their use into screening and prevention paradigms. On behalf of the authors, I extend the hope that you will find the information herein timely and useful. References 1. 2. 3. 4. 5. Garraway WM, Collins GN, Lee RJ. High prevalence of benign prostatic hypertrophy in the community. Lancet. 1991;338:469–471. Jacobsen SJ, Girman CJ, Guess HA, et al. New diagnostic and treatment guidelines for benign prostatic hyperplasia. Potential impact in the United States. Arch Intern Med. 1995: 155:477–481. Berry SJ, Coffey DS, Walsh PC, Ewing LL. The development of human benign prostatic hyperplasia with age. J Urol. 1984;132:474–479. Ries LA, Wingo PA, Miller DS, et al. The annual report to the nation on the status of cancer, 1973–1997, with a special section on colorectal cancer. Cancer. 2000;88:2398–2424. Tarone RE, Chu KC, Brawley OW. Implications of stage-specific survival rates in assessing recent declines in prostate cancer mortality rates. Epidemiology. 2000;11:167–170.