Nonsteroidal anti-inflammatory drugs and prostate cancer risk in the VITamins And Lifestyle (VITAL) cohort.

Introduction: Chronic inflammation may be important in prostate carcinogenesis. Several epidemiologic studies have reported inverse associations between nonsteroidal anti-inflammatory drugs (NSAIDs) and prostate cancer risk, although many studies are limited by assessment of short-term use only. Methods: Participants were male members of the VITamins And Lifestyle cohort, comprised 34,132 men, aged 50–76 years, living in western Washington State. Cox proportional hazards models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) of 10-year average use of individual NSAIDs with total prostate cancer (n = 1,550) and prostate cancer by grade. Results: Low-dose aspirin, regular-strength aspirin, ibuprofen, and any nonaspirin NSAID (ibuprofen, naproxen, and COX-2 inhibitors) were not associated with prostate cancer risk. There was a suggestion that regular-strength aspirin was inversely associated with risk of high-grade cancer (HR 0.73, 95% CI: 0.53–1.02). Conclusion: NSAID use was not associated with prostate cancer risk in the VITAL cohort. Impact: Our findings do not support the use of NSAIDs for chemoprevention of prostate cancer. Cancer Epidemiol Biomarkers Prev; 19(12); 3185–8. ©2010 AACR.


Introduction
There is increasing evidence which suggests that chronic inflammation is important in prostate carcinogenesis (1,2). Prostatitis has been associated with prostate cancer risk and proliferative inflammatory atrophy of the prostate, a condition marked by chronic inflammation, may be an early precursor lesion for prostate cancer (1,2). Non-steroidal anti-inflammatory drugs (NSAIDs) have anti-cancer properties in vitro and in vivo (3,4), in support of epidemiologic studies which have shown reductions in prostate cancer risk for aspirin use in particular (5). Many epidemiologic studies of NSAID use and prostate cancer risk, however, are limited by short-term measurement of NSAID use and most do not adjust for indications of use.
Here we examine the association of long-term NSAID use with prostate cancer risk in the VITamins And Lifestyle (VITAL) cohort study.

Study Population
Participants were male members of the VITAL cohort (6)

Statistical Analysis
We estimated hazard ratios (HR) and 95% confidence intervals (95% CI) for total prostate cancer and prostate cancer by grade in relation to NSAID use with Cox proportional hazards regression models, using participants' age as the time metric. Prostate cancer risk factors as well as potential indications for NSAID use were identified a priori for adjustment in multivariable models (see footnote b of Table 1). P-values for trend were calculated by treating categorical variables as ordinal in the models. We calculated minimum detectable risks (MDR) given 80% power (7). For comparisons of use to non-use of each NSAID, we had an MDR of Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Copyright © 2010 American Association for Cancer Research 0.85; for comparisons of high 10-year average use to non-use, the MDR was 0.80 for low-dose and regular strength aspirin, 0.69 for ibuprofen, and 0.73 for non-aspirin NSAIDs.

Results
Use of NSAIDs was not associated with total prostate cancer risk (Table 1). When the analysis was stratified by prostate cancer grade ( Table 2), use of regular-strength aspirin was suggestive of an inverse association with high-(HR 0.73, 95% CI: 0.53-1.02) but not low-grade (HR 1.04, 95% CI: 0.89-1.23) prostate cancer. No differences were observed for the remaining NSAIDs by grade or by stage (local vs. regional/distant; data not shown).

Discussion
We observed no association of use of individual NSAIDs with total prostate cancer risk in this cohort. In contrast to our findings, two recent meta-analyses reported 11% (HR 0.89, 95% CI: 0.77-1.03) (8) and 17% (HR 0.83, 95% CI: 0.76-0.91) (5) reductions in total prostate cancer risk among six and nine prospective studies of aspirin use, respectively. It may be that the null result we observed with aspirin use and total prostate cancer risk is due to residual confounding by PSA testing, as we only collected data on PSA testing at baseline. If aspirin use is positively associated with subsequent prostate cancer screening, a small reduction in risk would be negatively confounded towards 1.0.
One meta-analysis reported on the association of NSAID use with advanced prostate cancer; in it aspirin use was associated with a 17% (HR 0.83, 95% CI: 0.73-0.95) reduction in risk among six prospective studies (5). Our finding of a 27% statistically non-significant lower risk of high-grade prostate cancer among users of regular-strength aspirin is consistent with this estimate (5). In support of our findings, the meta-analyses did not find a reduction in risk of total (5,8) or advanced (5) prostate cancer among prospective studies of non-aspirin NSAIDs.
Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Copyright © 2010 American Association for Cancer Research   Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited.