NSAIDs May Protect Against Development of Prostate Cancer

ANAHEIM, California—Prostate cancer can now be added to the list of malignancies for which nonsteroidal anti-inflammatory agents (NSAIDs) may have a protective effect, according to experimental and clinical research presented at the American Urological Association annual meeting.

A study of 887 men in the Baltimore Longitudinal Study of Aging found a trend toward a protective effect of NSAIDs other than aspirin (abstract 259). While the differences were not significant, the relative risk was 0.76 for users of NSAIDs other than aspirin users, 0.85 for men using aspirin, and 1.15 for men using acetaminophen.

Each year of NSAID use was associated with a 6% reduction in risk, also supporting the existence of a dose-response effect, reported Jay D. Pearson, PhD, director of epidemiology, Merck Research Laboratories, West Point, Pennsylvania.

The study followed the men for a median of 9.4 years and found 96 histologically confirmed cases of prostate cancer. Time-dependent proportional hazards analyses were used to estimate the relative risk of prostate cancer associated with medication use (ever/never or length of exposure) adjusted for age, education, and calendar year. Calendar year was included as a covariate because of secular trends in the use of NSAIDs and PSA screening.

"These results from a prospective cohort study suggest a reduction (not statistically significant) in the risk of prostate cancer associated with the use of NSAIDs: 24% reduction for NSAIDs, 15% reduction for aspirin, and no reduction for acetaminophen," Dr. Pearson said. "The lack of an association with acetaminophen also suggests that these reductions are not likely to be due to confounding with pain medications in general."

COX-2 Inhibitors

Experimental studies reported at the AUA meeting provided some insight into NSAIDs’ possible protective effect. The expression of cyclooxygenase-2 (COX-2) has been shown to be increased in human prostate cancers, and treatment with COX-2 inhibitors suppressed this expression, according to researchers from Memorial Sloan-Kettering Cancer Center and Louisiana State University Health Science Center, Shreveport (abstract 1184).

James A. Eastham, MD, of Memorial Sloan-Kettering, reported that treatment with a selective COX-2 inhibitor (NS398) decreased the viability and growth rate of a prostate cancer cell line (PC-3).

Studies in nude mice also demonstrated the ability of these agents to suppress primary tumor growth and the progression to metastasis. The animals were injected with PC-3 cells intraprostatically, so that a primary tumor developed and also metastasized to the lymph nodes.

Treatment with the COX-2 inhibitor (in dosages comparable to standard human doses) resulted in less primary tumor growth and substantially less progression to metastatic disease, compared with control animals. In addition, control animals showed signs of physical stress, whereas most animals in the treated arm remained healthy, Dr. Eastham reported.

Primary tumor growth was 42 mm3 in the treated mice vs 243 mm³ in the untreated mice (P < .00001). Two of 10 treated mice progressed to metastatic disease vs 9 of 10 controls (P < .005).

"We did not look at survival, but had we, we would have seen a difference. These findings are certainly encouraging that aspirin or a modification of aspirin may have an important role in prostate cancer treatment," he said at a press briefing held at the meeting.

In Dr. Eastham’s opinion, the evidence for a protective effect is much stronger for COX-2 inhibitors than for aspirin, at least in standard dosages. COX-2 inhibitors may induce cell death and inhibit angiogenesis, but which exact pathways are most manipulated is as yet unknown. "We want to look downstream," he said.

He commented, tongue in cheek, that COX-2 inhibitors at this point "appear to be a good treatment for prostate cancer in mice." He said he would not yet recommend that every man at risk for prostate cancer begin taking these agents. "But I am absolutely enthusiastic about their potential," he said.