The Prevention of Prostate Cancer — The Dilemma Continues

Abstract

Prostate cancer is the most common non-skin cancer in the United States, the second leading cause of death from cancer among U.S. men, and the seventh leading cause of death in the United States. The number of new cases of prostate cancer, now estimated at more than 220,000 per year, is expected to increase to more than 380,000 by 2025 because of the aging male population. The incidence of prostate cancer and the rate of death due to the disease increase exponentially with age. The other major risk factors for prostate cancer include a family history of prostate cancer, black race, and a high-fat diet. There is no proven method of prevention.Finasteride inhibits the conversion of testosterone to dihydrotestosterone by the enzyme 5 areductase, reducing the level of dihydrotestosterone, the most active androgen in the prostate, by 90 percent. Approved by the Food and Drug Administration as an oral medication for the treatment of symptoms of benign prostatic hyperplasia, finasteride shrinks the prostate by 20 to 30 percent and improves urinary flow rates and symptom scores. In long-term, placebo-controlled trials, finasteride has significantly reduced the risk of acute urinary retention and the need for surgical intervention for benign prostatic hyperplasia from about 10 percent to 5 percent. 1 Because of its beneficial effect on benign prostatic hyperplasia, finasteride was tested, in short-term, placebo-controlled trials, as a treatment for prostate cancer, but it had little effect, reducing serum levels of prostate-specific antigen (PSA) slightly but effecting no commensurate change in the measurable tumor burden. 2 Nevertheless, in the early 1990s, it seemed reasonable to postulate that finasteride might prevent prostate cancer by reducing androgenic stimulation. The Prostate Cancer Prevention Trial (PCPT) was initiated to test this hypothesis and is the first major trial of chemoprevention for prostate cancer. In this issue of the Journal, Thompson et al. 3 report the results of this seven-year trial involving more than 18,000 men. At entry, eligible men were considered to have a low risk of prostate cancer (as indicated by a normal digital rectal examination and a serum PSA level of no more than 3.0 ng per milliliter). The men were randomly assigned to 5 mg of finasteride per day or placebo and were monitored annually with a digital rectal examination and measurement of serum PSA. "Systematic" needle-biopsy samples were obtained either "for cause" (if the digital rectal examination or PSA level became abnormal) or at the end of the study, when all men who were still alive and had not received a diagnosis of prostate cancer were given a recommendation to have a biopsy. The end point of the study was the rate of detection of biopsy-confirmed prostate cancer. The study was designed to detect a relative reduction of 25 percent or more in the cancer-detection rate in the treatment group from the expected 6 percent rate in the placebo group.Contrary to the expectations of many experts, there was a substantial effec...

Finasteride Does Not Increase the Risk of High-Grade Prostate Cancer: A Bias-Adjusted Modeling Approach

“…Concurrently, finasteride apparently had increased the risk of high-grade disease. Although high-grade tumors were a relatively small proportion of all detected tumors in the finasteride group, the potentially increased risk of aggressive disease and an unfavorable editorial accompanying the initial publication led to a general lack of acceptance of finasteride for cancer prevention (5). In the United States, early detection and treatment remain the primary focus for controlling this disease.…”

“…We now know that finasteride enhances the detection of prostate cancer through the following effects on the performance characteristics of for-cause biopsies (see "Materials and Methods" section for definition): (a) improved sensitivity of prostate-specific antigen (PSA) for overall and high-grade cancer detection, (b) improved sensitivity of digital rectal examination (DRE) for cancer detection, and (c) more accurate grading of high-grade prostate cancer (5,6). Although these three detection biases would be expected to lead to cancer overdetection in study subjects receiving finasteride, there was a counteracting bias for greater cancer detection in the placebo group because these men more commonly underwent biopsy.…”

Long-term Consequences of Finasteride vs Placebo in the Prostate Cancer Prevention Trial

“…The results, published in 2003, showed that finasteride reduced the period prevalence of prostate cancer by 25% (5). However, the study results were criticized because of an observed increase in the risk of high-grade cancers (6). Subsequent studies have shown that this increase was likely an artifact of the detection process (7); a later report showed equivalent overall survival in the two study arms (8).…”

Antigua/Barbuda Cancer Mortality Study

“…The mortality/incidence ratios are given in Tables 4 and 5. It Increased mortality from prostate cancer represents the most significant change over this time period, and may be reflective of an ageing population, inadequate treatment, late clinical stage at diagnosis, or a combination of the three (7,8). This cancer ranks highest among the causes of cancer mortality in Antigua and Barbuda, and in the region (9,10).…”