Chemoprevention of prostate cancer

Abstract

Prostate cancer is an attractive target for chemoprevention because of its ubiquity, treatment-related morbidity, long latency between premalignant lesions and clinically evident cancer, and defined molecular pathogenesis. Prevention of this disease would have a major impact on disease-associated cost, morbidity, and mortality for a large segment of the population. A major advance in prevention of prostate cancer came in 2003 with the publication of the Prostate Cancer Prevention Trial (PCPT). This overview summarizes the results of that trial, the design of other large-scale trials, and advances in understanding of the molecular mechanisms underlying the effect of other promising agents, including dutasteride, selenium, Vitamin E, Vitamin D, COX-2 inhibitors, lycopene, and green tea.

Introduction

Prostate cancer is an attractive and appropriate target for primary prevention because of its incidence, prevalence, and disease-related mortality (Table 1). Although mortality from prostate cancer is decreasing, in the last 5 years alone more than 1 million men in the U.S. have been newly diagnosed with this disease [1]. Despite prostate-specific antigen (PSA)-induced stage migration, a high cure rate for localized disease, and improved understanding of prostate cancer biology, most men who develop metastatic disease are still destined to die of prostate cancer, with almost half a million deaths in the U.S. between 1989 and 2001 [1]. The burden of prostate cancer can also be measured in other terms. A recent study of complications after surgical therapy for localized disease in an unselected population-based cohort reported that at >18 months following radical prostatectomy, 8.4% of men were incontinent and 41.9% reported that their sexual performance was a moderate-to-large problem [2]. In a similarly designed study comparing outcomes after radiation to those after surgery, the radiation cohort reported an impotence rate of 61.5% and a significantly higher incidence of bowel problems [3]. Although many single-institution studies have reported better results in highly selected cohorts of treated patients, it is clear that the majority of men treated for localized disease in the community pay a substantial price to be cured. It seems self-evident that an effective prevention strategy would spare many men this burden of diagnosis and cure.

The molecular pathogenesis of prostate cancer also lends itself to a primary prevention strategy. Several histologic lesions including atypical small acinar proliferation (ASAP), proliferative inflammatory atrophy (PIA), and prostatic intraepithelial neoplasia (PIN) that contain both genetic and epigenetic changes intermediate between normal prostatic epithelium and prostate cancer have been described. The prevalence of PIN is similar in populations at much different risks of developing clinically evident cancer, suggesting that external environmental influences are important and potentially modifiable. Furthermore, the discrepancy between the cumulative clinical incidence of prostate cancer and much lower lifetime risk of death from prostate cancer suggests a long latency period during which an effective intervention may be used [4].

There are numerous observations in the epidemiologic literature suggesting associations between various dietary, lifestyle, genetic and non-traditional factors and the risk of developing prostate cancer. In general, it is recognized that it will not be practicable to quantitate all of these factors in the conduct of a prevention trial, but if the trial is large enough these effects are likely to be equally and randomly distributed in all of the study arms. In addition, most trials are designed to collect data relevant to these factors for secondary analysis and analysis of how they may confound the results. Several large-scale, population-based trials examining the effects of various agents on prostate cancer prevention have recently been launched or reported and will be reviewed, along with epidemiologic and molecular observations on other agents not yet in clinical trials.