Chemoprevention for prostate cancer (1995)

With prostate cancer representing the most common Male cancer and the second most common cause of cancer-related death in men in the United States, increasing attention is being directed at providing early detection, as well as improvement in therapy. The third option to decrease cancer-related deaths, decreasing the incidence, has only recently gained attention. If tumor promoters can be removed from the patient environment and/or agents administered that inhibit cancer progression, we may indeed be able to decrease the incidence of this most common neoplasm. The prostate is a suitable site for chemoprevention strategies. High-risk populations, including those men with a strong family history of prostate cancer, black men, and/or men with prostatic intraepithelial neoplasia, a putative premalignant change identified on prostate biopsy or simple prostatectomy, represent useful target populations. If a chemopreventive strategy could be developed that was free of toxicity and also simple, inexpensive, and readily administered, indeed all men could be targeted. Several potential agents are available for chemoprevention in the prostate. The retinoids moderate differentiation and proliferation in several prostate cell lines. Severe toxicity, however, may preclude their wide-spread application. Difluoromethylornithine has also been investigated. A chemopreventive trial directed against lung cancer showed that alpha-tocopherol is associated with a decreasing incidence of prostate cancer. The greatest interest in the chemopreventive strategies for prostate cancer, however, has focused on decreasing the male androgens. Although most agents, such as luteinizing hormone-releasing hormone agonists and antiandrogens, have severe toxicity, the 5-alpha reduce-tase inhibitors, because they do not, are thought to be excellent agents for a chemopreventive trial. The dependence of prostate epithelial differentiation and maintenance of transformed cells on circulating androgens is widely acknowledged. This is the impetus for the hypothesis that reduction of circulating androgens or blockage of testosterone to the more active metabolite dihydrotestosterone by agents such as finasteride or epristeride will reduce the incidence of prostate cancer. The National Cancer Institute Intergroup Prostate Cancer Prevention Trial, now underway, will randomize 18,000 men to receive 5 mg finasteride or a placebo daily for 7 years in a chemopreventive strategy. Entry requirements include a normal result of digital rectal examination and a serum prostate-specific antigen result less than 3.0 ng/ml. Abnormalities on digital rectal examination results or prostate-specific antigen level greater than 4.0 ng/ml on annual evaluation indicate the need for biopsies in the men receiving the placebo. An equal number of men will undergo biopsy in the active arm of the study. At the end of the 7-year study, all men will have biopsies. Although the primary endpoint is a reduction in prostate cancer incidence, additional benefits include long-term follow-up of the patients receiving finasteride, with potential salutary benefits with regard to symptoms of benign prostatic hyperplasia. This trial, which already has accrued more than 75% of the required participants, should resolve the issue of whether reduction in effective androgen level will prevent the development of prostate cancer. Cancer 1995; 75:1783–9.