CHEMOPREVENTION FOR PROSTATE-CANCER

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 dete ction, as well as improvement in therapy. The third option to decrease cancer-related deaths, decreasing the incidence, has only recently ga ined attention. If tumor promoters can be removed from the patient env ironment and/or agents administered that inhibit cancer progression, w e may indeed be able to decrease the incidence of this most common neo plasm. The prostate is a suitable site for chemoprevention strategies. High-risk populations, including those men with a strong family histo ry of prostate cancer, black men, and/or men with prostatic intraepith elial 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 toxi city and also simple, inexpensive. and readily administered, indeed al l men could be targeted. Several potential agents are available for ch emoprevention in the prostate. The retinoids moderate differentiation and proliferation in several prostate cell lines. Severe toxicity, how ever, may preclude their widespread application. Difluoromethylornithi ne has also been investigated. A chemopreventive trial directed agains t lung cancer showed that alpha-tocopherol is associated with a decrea sing incidence of prostate cancer. The greatest interest in the chemop reventive strategies for prostate cancer, however, has focused on decr easing the male androgens. Although most agents, such as luteinizing h ormone-releasing hormone agonists and antiandrogens, have severe toxic ity, the 5-alpha reductase inhibitors, because they do not, are though t to be excellent agents for a chemopreventive trial. The dependence o f prostate epithelial differentiation and maintenance of transformed c ells on circulating androgens is widely acknowledged. This is the impe tus for the hypothesis that reduction of circulating androgens or bloc kage of testosterone to the more active metabolite dihydrotestosterone by agents such as finasteride or epristeride will reduce the incidenc e of prostate cancer. The National Cancer Institute Intergroup Prostat e Cancer Prevention Trial, now underway, will randomize 18,000 men to receive 5 mg finasteride or a placebo daily for 7 years in a chemoprev entive 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 eval uation 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. Alt hough the primary endpoint is a reduction in prostate cancer incidence , additional benefits include long-term follow-up of the patients rece iving finasteride, with potential salutary benefits with regard to sym ptoms of benign prostatic hyperplasia. This trial, which already has a ccrued more than 75% of the required participants, should resolve the issue of whether reduction in effective androgen level will prevent th e development of prostate cancer.