Research mounts on options for preventing prostate cancer

"That is daunting. The agent must be extremely safe and low-cost, and the net benefit will be far greater in high-risk populations," said Dr. Gann, professor of medicine at Northwestern University, Chicago. "The cost-benefit ratio of prostate cancer prevention will therefore improve in direct relation to our ability to improve risk prediction."

Nevertheless, prostate cancer prevention is an area of active research, and promising preventive agents include 5-alpha-reductase inhibitors and antioxidants such as selenium, vitamin E, lycopene, green tea, and soy. Weight control should be encouraged in men and warrants further study, as do other critical lifestyle choices, the committee said.

"Elevated PSA with negative biopsy results is a terrific opportunity for testing and applying preventive intervention," he said, adding that men with localized, non-aggressive cancer represent another potential population for preventive therapy.

Prevention trials

Prostate cancer prevention trials range from small studies using healthy volunteers, phase II trials of pre-prostatectomy and repeat biopsy patients to watchful waiting trials. Phase III studies with prostate cancer diagnosis as the endpoint can be carried out in high-risk men with elevated PSA levels and family history of the disease, but the number of participants available for study will be limited. To study the benefits and risks of prevention in low- or average-risk men, 15,000 to 30,000 subjects followed for 7 to 10 years would be required, making costs so high that interventions and dosages must be chosen very carefully.

Currently, four agents are being studied in large prostate cancer prevention trials: selenium, vitamin E, the 5-alpha-reductase inhibitor dutasteride (Avodart), and the anti-estrogen agent toremifene (Acopodene).

Particularly noteworthy is the large-scale Prostate Cancer Prevention Trial (PCPT), a randomized, double-blind, placebo-controlled trial of the 5-alpha-reductase inhibitor finasteride (Proscar) for the prevention of prostate cancer, which was completed in 2004. PCPT investigators reported a 25% reduction in the number of prostate cancers detected in the finasteride group compared with placebo. However, they also reported a nearly 25% increase in the detection of higher-grade cancers in the finasteride group. Researchers are concerned that these results could have arisen because finasteride inhibited the growth of less aggressive, more innocuous cancers, while actually promoting the growth of more aggressive, higher-grade ones.

"We in the committee feel that proper interpretation of the PCPT is the most important thing in the entire field of prostate cancer prevention," Dr. Gann said. "This trial is unprecedented in the type of challenges it presented to the designers. Here we have a situation where drugs of interest affect PSA, the primary means with which cancers are detected. Therefore, conventional incidence rates are very sensitive to artifactual differences in biopsy rates."

Furthermore, because 5-alpha-reductase inhibitors shrink the prostate, biopsy sampling density is increased and, therefore, the probability of detecting a prostate cancer is increased, especially, perhaps, a high-grade cancer. Normally, a decrease in PSA levels would be expected in patients treated with finasteride. Another explanation for this apparent conflict in the PCPT results could be that subjects harboring higher-grade cancers at the outset failed to achieve a normal drop in PSA, making them more susceptible to detection, especially in the early years of follow-up, Dr. Gann said.

"Although the full interpretation of this trial is quite complex, the apparent biological effect of finasteride in retarding cancer growth is a landmark finding," he said.