Strategies for chemoprevention of prostate cancer

Abstract

Because prostate cancer has a long latency and high incidence, it is a good target for chemoprevention by agents such as retinoids, antiandrogens, antiestrogens, and vitamin D analogs. Phase II chemoprevention trials are frequently conducted on cohorts of patients with previous cancers or premalignant lesions who are scheduled for prostate cancer surgery; such trials are currently in progress with several agents. Prostatic intraepithelial neoplasia (PIN) can be used as a surrogate endpoint biomarker for prostate cancer incidence. Studies of men with highgrade PIN (HGPIN) are particularly useful in that they require a much smaller cohort of 200±400 patients instead of the 18 000 patients required for typical Phase III trials. Even with a smaller sample size, statistically signi®cant evidence of cancer prevention is achieved due to the high probability of HGPIN progressing to cancer (35±55%). A Bayesian sequential monitoring system allows interim analysis of biomarker modulation as early as the completion of 30 patients. Putting all these strategies together will help inhibit, delay, or modulate the natural history of prostate carcinogenesis.

Progress in Chemoprevention Drug Development: The Promise of Molecular Biomarkers for Prevention of Intraepithelial Neoplasia and Cancer—A Plan to Move Forward

“…Because prostate cancer incidence can be estimated in cohorts of patients with HGPIN, PSA abnormalities, and other risk factors, phase III placebo-controlled trials that have prostate cancer incidence as the primary end point can be conducted with 300 to 500 patients per arm, with the control group having an expected 40% prostate cancer incidence over 3 years. This trial design will more definitively evaluate prostate cancer risk-reduction candidates and will validate extent of HGPIN as a suitable efficacy end point (1,133,151,152). A 30% reduction in prostate cancer incidence in the HGPIN patients who are safely treated with the new agent compared with control patients should likely constitute clinical benefit.…”

“…However, the limitations of prostate biopsy sampling preclude repeated monitoring of PIN lesions to assess their natural history (138). When a diagnosis of HGPIN is combined with other risk factors, such as serum PSA, age, race, and/or family history, cohorts of men at very high risk for developing prostate cancer are identified who have prostate cancer incidence rates of 40% over 3 years and 80% over 10 years (151,152). Because extent of PIN cannot be reliably measured by serial sampling, a decrease in the extent of PIN with treatment is not a conclusive efficacy end point.…”

A Phase II Randomized, Placebo-Controlled Clinical Trial of Purified Isoflavones in Modulating Steroid Hormones in Men Diagnosed With Localized Prostate Cancer

“…The initiation and progression of prostate cancer is a multistep process including several intermediate steps and may involve a complex series of both exogenous and endogenous factors (2)(3)(4)(5). Although it is clear that clinical prostate cancer incidence and mortality vary greatly between populations, the frequency of latent prostate cancer is evenly distributed among populations, suggesting that external factors such as diet and other lifestyle factors are important in the transformation from latent into more aggressive, clinical cancer (4)(5)(6).…”

“…The initiation and progression of prostate cancer is a multistep process including several intermediate steps and may involve a complex series of both exogenous and endogenous factors (2)(3)(4)(5). Although it is clear that clinical prostate cancer incidence and mortality vary greatly between populations, the frequency of latent prostate cancer is evenly distributed among populations, suggesting that external factors such as diet and other lifestyle factors are important in the transformation from latent into more aggressive, clinical cancer (4)(5)(6). These specific features of prostate cancer, namely, high prevalence, long latency between lesions and clinically evident cancer, treatment related morbidity, significant mortality, and morbidity provide the most opportunistic and promising approach for evaluating agents for chemoprevention in men with early stage disease or those who are at high risk for prostate cancer to prevent disease progression and shifting the time of diagnosis to invasive disease.…”

Prostate Cancer Precursor Diseases

“…b. Differentiation Factors. Retinoids and vitamin D analog are known to improve differentiation of epithelial cells, including prostate epithelium.The development of invasiveness, as seen in HGPIN, is characterized by loss of adhesion facility and dedifferentiation with aneuploid nuclear characteristics; these processes may be sensitive to retinoids or vitamin D analogs Banach-Petrosky et al, 2006;Kelloff et al, 1999). Gene therapy and immunotherapy are still experimental in prostate cancer and HGPIN.…”