New Guidelines Recommend 5-Alpha Reductase Inhibitors for Preventing Prostate Cancer

Roxanne Nelson

February 25, 2009

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February 25, 2009 — A new joint guideline produced by the American Society of Clinical Oncology (ASCO) and the American Urological Association (AUA) has recommended chemoprevention for prostate cancer in healthy men.

Specifically, it recommends that asymptomatic men with a prostate-specific antigen (PSA) of 3.0 ng/mL or lower and who receive regular screening consider using a 5-alpha reductase inhibitor (5-ARI), such as finasteride or dutasteride, to help prevent prostate cancer.

According to the new guideline, published online February 24 in the Journal of Clinical Oncology and scheduled to appear in the April issue of The Journal of Urology, men in this category might benefit from a discussion with their physicians about the benefits and risks of 5-ARIs for the prevention of prostate cancer.

In addition, patients currently using these agents to treat benign conditions, such as lower urinary tract symptoms, should discuss continuing this treatment to reduce their likelihood of developing cancer.

Chemoprevention a Reality

"The goal of developing a chemopreventive agent that can reduce the risk of prostate cancer has been achieved, and that is a major achievement in and of itself," said Barnett S. Kramer, MD, MPH, associate director for disease prevention at the National Institutes of Health, in Bethesda, Maryland, and cochair of the guideline panel. "However, very few prevention messages can be adequately delivered as a sound byte, and that is certainly the case here. Therefore, the principal focus of the panel was on shared decision making — that is, to let men who are considering chemoprevention for prostate cancer know what the known benefits are, and what the known harms and the remaining uncertainties are."

The ASCO/AUA recommendations resulted from a systematic review of the literature, and 15 randomized controlled trials met the inclusion criteria. "That body of evidence provided proof that 5-alpha reductase inhibitors will decrease the risk of prostate cancer, at least in men who are being regularly screened," said Dr. Kramer during a press briefing. "That is important to point out because all of the trials conducted to date were in men who were being regularly screened for prostate cancer."

"It has been well established that the screening process itself increases the risk of being diagnosed with prostate cancer by about 2-fold," he added.

The Prostate Cancer Prevention Trial (PCPT) is the largest and only completed randomized trial that was prospectively designed to show a reduction in period prevalence of prostate cancer in generally healthy men, and provided the bulk of the evidence for the guideline. Over half (57%) of all study subjects participated in the PCPT, and the PCPT was the only trial to report subgroup results by race/ethnicity, age, and family history of prostate cancer.

The vast majority of men participating in these trials were white (92%), so the results primarily apply to white males, explained Dr. Kramer. However, subgroup analyses did not reveal significant differences across any of the ethnic or racial groups.

Results of the PCPT showed a reduction in the cumulative incidence of prostate cancer, from 24.4% in the placebo group to 18.4% in the finasteride group, during the 7-year study period. The rate of prostate cancer during the 7-year period was 4.9% in the control group and 3.5% in the finasteride group, for an absolute risk reduction of 1.4%.

Increase in High-Grade Tumors?

A secondary analysis triggered concerns about harm, because finasteride was associated with an increase in higher-grade prostate cancers. Gleason scores of 7 to 10 were more common in men taking finasteride (37%, or280 of 757 tumors) than in men taking placebo (22.2%, or 237 of 1068 tumors). This finding raised critical questions about the effect of 5-ARIs on prostate cancer morbidity and mortality, and whether the increase in higher-grade prostate cancer was due to finasteride.

However, subsequent analyses of these data suggested that the finding was an artifact because finasteride decreased prostate volume and made these high-grade cancers easier to detect, as previously reported by Medscape Oncology.

In the guideline, the expert panel has "judged that plausible reasons could have led to a spurious increase in high-grade cancers." They note that it is unlikely for an agent to increase the incidence of high-grade tumors while simultaneously decreasing the incidence of low-grade tumors.

Although it is not definitive, the subsequent evidence suggests that the incidence of high-grade tumors is due to artifacts and not the drug, explained Dr. Kramer.

Paul F. Schellhammer, MD, past president of the AUA and cochair of the panel that developed the guideline, agrees. "It is reasonable to believe that the issue has been resolved," he told Medscape Oncology, "and high-grade tumors are not likely to be a concern. But it is important to tell the patient that the initial report did mention this."

Virtually all studies showed that 5-ARIs are associated with a consistently higher frequency of adverse events than placebo, although the incidence is low. A 2% to 4% increase in erectile dysfunction and gynecomastia has been reported, along with decreases in ejaculate volume and libido for men who received finasteride in clinical trials.

But overall, adverse effects are minimal, according to Dr. Schellhammer. "In 1 study, the degree of sexual dysfunction was less among men taking the drug than among the controls," he said. "The process of aging is a more important factor than the drug in that regard."

Physician–Patient Communication

Physician–patient communication is important, the guideline emphasizes, and it is essential that the available data are presented to the patient considering the use of these agents for prostate cancer prevention and that the uncertainty is highlighted.

What remains unknown is the effect of 5-ARIs on prostate-cancer-related mortality, and that can be difficult to determine. "It may take another 10 years to get an answer on that," said Dr. Schellhammer. "The length of time that 5-ARIs need to be taken is also undetermined. In the PCPT study, finasteride was used for 7 years, so that's a limitation of our data."

For men considering use of 5-alpha-reductase inhibitors for chemoprevention, physicians should explain that:

  • these agents do not completely eliminate the risk for prostate cancer;

  • the risk for high-grade cancer is still uncertain;

  • the long-term effects of 5-ARIs on prostate cancer incidence, beyond approximately 7 years, are unknown;

  • the effect on mortality is not known;

  • the patient may experience potential but reversible effects on sexual dysfunction;

  • there will likely be improvement in lower urinary tract symptoms.

How do physicians feel about it for their own use? Howard Sandler, MD, chair of radiation oncology at Cedars-Sinai Medical Center, in Los Angeles, California, and moderator of the press briefing, said that he would consider using finasteride as chemoprevention.

"If I was leaning toward taking [finasteride], I would try it for a month or 2 and see about side effects," he said. "If there were no significant side effects, I would continue it."

He also said that he might "sleep a little better at night," since he was reducing his risk for prostate cancer. However, when asked directly by a journalist if he was going to take it, he said, "I haven't made up my mind yet."

Coauthors Peter C. Albertsen, MD, from the University of Connecticut Health Center, in Farmington, and Paul A. Godley, MD, from the University of North Carolina at Chapel Hill, have served as consultants to GlaxoSmithKline; Janet Wittes, PhD, from Statistics Collaborative, in Washington, DC, has consulted for Merck. None of the other authors have disclosed any relevant financial relationships.

J Clin Oncol. Published online before print February 24, 2009.
J Urol. 2009;181:1642-1657.


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