Currently, the strongest evidence of chemoprevention effectiveness is related to the use of tamoxifen and raloxifene (Evista) in breast cancer, and the 5-alpha reductase inhibitor finasteride (Propecia) in prostate cancer. The PCPT (Prostate Cancer Prevention Trial) is the only prospective, randomized trial to show a reduction in prostate cancer prevalence with finasteride. However, the PCPT also showed an increase in Gleason scores 7 to 10 in those taking finasteride versus placebo, which prompted concerns about harm and complicated the decision-making process regarding prostate cancer chemoprevention. The American Society of Clinical Oncology (ASCO) and American Urological Association (AUA) developed a practice guideline on the benefits and harms of 5-alpha reductase inhibitors for prevention of prostate cancer.

Recommendations

Symptomatic men with a prostate-specific antigen (PSA) level of 3 ng per mL (3 mcg per L) or lower who regularly receive PSA screening, as well as men taking 5-alpha reductase inhibitors for benign conditions, may benefit from a conversation about the benefits and risks of treatment with 5-alpha reductase inhibitors.

IMPACT ON RISK AND MORTALITY

5-alpha reductase inhibitors decrease the period prevalence of for-cause (clinically suspected during the study) prostate cancer by about 26 percent (relative risk [RR] = 0.74; 95% confidence interval [CI], 0.67 to 0.83). The absolute risk reduction is approximately 1.4 percent, but it may vary with age. Compared with those in the control groups, the men taking 5-alpha reductase inhibitors had an RR of any prostate cancer of 0.74 (95% CI, 0.56 to 0.98), making the absolute risk reduction 2.9 percent.

No trials were large enough to identify clinically important differences in mortality. Nevertheless, the ASCO/AUA concluded that even if treatment with 5-alpha reductase inhibitors never results in reduced mortality, risk reduction of prostate cancer diagnosis with the consequent morbidity of treatment is a clinically beneficial end point.

EFFECT ON HISTOLOGIC GRADES AND STAGES

The PCPT reported a statistically significant reduction in the seven-year prevalence of prostate cancer with finasteride versus placebo. A secondary analysis found a statistically significant increase in high-grade cancer with finasteride, causing concern that there might be a causal relationship between finasteride and high-grade cancer. Several analyses have addressed this concern, and the ASCO/AUA determined that it is unlikely for a medication to increase the incidence of high-grade cancer while, at the same time, decreasing the incidence of low-grade cancer. However, it cannot be proven that finasteride would not increase the true incidence of high-grade cancers, and the uncertainty about the relationship between finasteride and high-grade cancer should be explained to patients.

BENIGN PROSTATIC HYPERPLASIA

5-alpha reductase inhibitors are approved by the U.S. Food and Drug Administration for treatment of symptomatic benign prostatic hyperplasia, and a systematic review confirmed their effectiveness. In the PCPT, the incidence of acute urinary retention was decreased by approximately one third with finasteride (RR = 0.67; 95% CI, 0.59 to 0.76). The incidence of transurethral resection of the prostate was 1.9 percent with placebo versus 1 percent with finasteride, which is a statistically significant decrease in the risk of surgical interventions.

BENEFITS

Studies of 5-alpha reductase inhibitors have not assessed quality of life using traditional measures; instead, most studies have included measures of urinary symptoms, sexual functioning, or endocrine effects. Studies of finasteride and dutasteride (Avodart) lasting at least six months and a meta-analysis of studies in men with lower urinary tract obstructive symptoms demonstrated a reduction in acute urinary retention risk (from 5.6 to 3.3 percent) and a reduction in the need for surgical intervention (from 3.3 to 1.7 percent). The largest benefits were seen in men with baseline PSA levels greater than 4 ng per mL (4 mcg per L).

ADVERSE EVENTS

5-alpha reductase inhibitors have a higher rate of adverse events than placebo. Almost all randomized controlled trials show a 2 to 4 percent increase in erectile dysfunction and gynecomastia, and a decrease in ejaculate volume and libido with 5-alpha reductase inhibitors. When all studies are combined, the overall rates of discontinuation or loss to follow-up were about 15 percent for 5-alpha reductase inhibitors and placebo. The rate of combined discontinuation and loss to follow-up secondary to adverse events was approximately 6 to 7 percent with 5-alpha reductase inhibitors and placebo.

EFFECT ON PSA LEVELS

The decrease in PSA levels by 5-alpha reductase inhibitors should be noted when determining the importance of PSA level. However, a consistently uniform scale multiplier does not exist because of inter- and intraindividual variability of PSA levels, laboratory variables, variable compliance of patients with regard to drug schedule, and paucity of data relating change of PSA level to duration of therapy. No specific cut point or change in PSA level has been prospectively validated in men taking 5-alpha reductase inhibitors.

TREATMENT DURATION

No trials have directly compared treatment durations of 5-alpha reductase inhibitors for prostate cancer prevention. The PCPT was the only reported trial designed to test 5-alpha reductase inhibitor effectiveness for prevention of prostate cancer, and was the most reliable trial for comparing the benefits and harms of finasteride in the most likely target population. Because finasteride was administered for a planned seven years, the ACSO/AUA determined that finasteride should be given for seven years if used for primary prevention, until additional information is available.

Physician-Patient Communication

Physicians should provide available information to patients about treatment with 5-alpha reductase inhibitors. Patients should be informed that these medications do not eliminate the risk of prostate cancer entirely, but they do reduce the clinical incidence. 5-alpha reductase inhibitors are also beneficial in reducing benign prostatic hyperplasia. Until risks are clarified, physicians should be clear about the uncertainties regarding whether increased high-grade cancer is related to finasteride. Patients should also be informed that there are no data on the long-term effects of 5-alpha reductase inhibitors beyond seven years, and it is unknown if the reduction in prostate cancer incidence will result in reduced prostate cancer mortality or longer life expectancy. Physicians should provide information about possible but reversible sexual adverse effects, such as lowered libido. It has been suggested that the ideal candidates for treatment with 5-alpha reductase inhibitors would be those who are concerned about prostate cancer, have a high risk of prostate cancer, have urinary symptoms that may be relieved by finasteride, and are not sexually active.