What’s new in prostate cancer screening and prevention?
ABSTRACTProstate cancer is extremely common but causes death in only a minority of men in whom it develops, facts that raise issues regarding screening and treatment morbidity. Two large trials of screening with prostate-specific antigen (PSA) measurements came to seemingly opposite conclusions. Furthermore, a large trial of selenium and vitamin E found that these agents have no value as preventive agents.
KEY POINTS
- An elevated PSA level lacks specificity as a test for prostate cancer, but PSA measurements can be useful in combination with clinical risk factors or to measure changes in PSA over time.
- Rather than relying on PSA screening alone, we should stratify the risk of prostate cancer on the basis of race, age, PSA level, family history, findings on digital rectal examination, whether the patient has ever undergone a prostate biopsy, and whether the patient is taking finasteride (Proscar). A simple online tool is available to do this.
- There is no PSA level below which the risk of cancer is zero.
- Finasteride has been found in a randomized trial to decrease the risk of prostate cancer, but vitamin E and selenium supplements have failed to show a benefit.
Findings of trials of prevention
Selenium and vitamin E do not prevent prostate cancer, lung cancer, colorectal cancer, other primary cancers, or deaths. The Selenium and Vitamin E Cancer Prevention Trial (SELECT)3 involved 35,533 men 55 years of age or older (or 50 and older if they were African American). They were randomized to receive one of four treatments: selenium 200 μg/day plus vitamin E placebo, vitamin E 400 IU/day plus selenium placebo, selenium plus vitamin E, or double placebo. At a median follow-up of 5.46 years, compared with the placebo group, the hazard ratio for prostate cancer was 1.04 in the selenium-only group, 1.13 in the vitamin E-only group, and 1.05 in the selenium-plus-vitamin E group. None of the differences was statistically significant.
The Physician’s Health Study18 also found that vitamin E at the same dose given every other day does not prevent prostate cancer.
Finasteride prevents prostate cancer. The PCPT19 included 18,882 men, 55 years of age or older, who had PSA levels of 3.0 ng/mL or less and normal findings on digital rectal examination. Treatment was with finasteride 5 mg/day or placebo. At 7 years, prostate cancer had been discovered in 18.4% of the finasteride group vs 24.4% of the placebo group, a 24.8% reduction (95% CI 18.6–30.6, P < .001). Sexual side effects were more common in the men who received finasteride, while urinary symptoms were more common in the placebo group.
At the time of the original PCPT report in 2003,19 tumors of Gleason grade 7 or higher were more common in the finasteride group, accounting for 37.0% of the tumors discovered, than in the placebo group (22.2%), creating concern that finasteride might somehow cause the tumors that occurred to be more aggressive. However, a subsequent analysis20 found the opposite to be true, ie, that finasteride decreases the risk of high-grade cancers. A companion quality-of-life study showed that chronic use of finasteride had clinically insignificant effects on sexual function, and the PCPT and other studies have shown benefits of finasteride in reducing lower urinary tract symptoms due to benign prostatic hyperplasia (BPH), reducing the risk of acute urinary retention and the need for surgical intervention for BPH, and reducing the risk of prostatitis.
Dutasteride also prevents prostate cancer. A large-scale trial of another 5-alpha reductase inhibitor, dutasteride (Avodart), was reported by Andriole at the annual meeting of the American Urological Association in April 2009.21 The Reduction by Dutasteride of Prostate Events (REDUCE) trial included men who were 50 to 75 years old, inclusively, and who had PSA levels between 2.5 and 10 ng/mL, prostate volume less than 80 cc, and one prior negative prostate biopsy within 6 months of enrollment, representing a group at high risk for cancer on a subsequent biopsy. The trial accrued 8,231 men. At 4 years, prostate cancer had occurred in 659 men in the dutasteride group vs 857 in the placebo group, a 23% reduction (P < .0001). Interestingly, no significant increase in Gleason grade 8 to grade 10 tumors was observed in the study.
Preliminary analyses also suggest that dutasteride enhanced the utility of PSA as a diagnostic test for prostate cancer, had beneficial effects on BPH, and was generally well tolerated. The fact that the results of REDUCE were congruent with those of the PCPT with respect to the magnitude of risk reduction, beneficial effects on benign prostatic hypertrophy, minimal toxicity, and no issues related to tumor grade suggests a class effect for 5-alpha reductase inhibitors, and suggests that these agents should be used more liberally for the prevention of prostate cancer.
There is current debate about whether 5-alpha reductase inhibitors should be used by all men at risk of prostate cancer or only by those at high risk. However, the American Urological Association and the American Society of Clinical Oncology have issued guidelines stating that men at risk should consider this intervention.22
