Nonsteroidal Antiinflammatory Drugs and Bladder Cancer

A Pooled Analysis

Sarah E. Daugherty; Ruth M. Pfeiffer; Alice J. Sigurdson; Richard B. Hayes; Michael Leitzmann; Arthur Schatzkin; Albert R. Hollenbeck; Debra T. Silverman


Am J Epidemiol. 2011;173(7):721-730. 

In This Article

Abstract and Introduction


Case-control studies have shown that regular use of nonsteroidal antiinflammatory drugs (NSAIDs) decreases bladder cancer risk, but few cohort studies have evaluated this association. The authors investigated NSAID use and bladder cancer in 3 large prospective studies (NIH-AARP Diet and Health Study; Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; and U.S. Radiologic Technologists Study). Frequency of aspirin and nonaspirin NSAID use 1 year prior to baseline was ascertained using self-administered questionnaires. Study-specific hazard ratios and 95% confidence intervals were estimated using Cox regression models and were combined using a fixed-effects meta-analytic model. Data from all studies were aggregated, and aggregated hazard ratios were estimated. The analysis included 508,842 individuals, with 2,489 incident cases of bladder cancer. A reduction in risk was observed for individuals who reported regular use (>2 times/week) of nonaspirin NSAIDs compared with those who reported no use (hazard ratio (HR) = 0.92, 95% confidence interval (CI): 0.81, 1.04). The risk reduction was limited to nonsmokers (HR = 0.58, 95% CI: 0.41, 0.83) (P trend = 0.008) (P interaction = 0.02). No association was observed between regular aspirin use and bladder cancer risk (HR = 1.04, 95% CI: 0.94, 1.15). Results suggest that nonaspirin NSAIDs, but not aspirin, are associated with a reduction in risk of bladder cancer, particularly for nonsmokers.


Several case-control studies have reported an inverse association with bladder cancer risk for individuals who reported regular use of nonaspirin, nonsteroidal antiinflammatory drugs (NSAIDs).[1–3] The one known prospective cohort study published to date on nonaspirin NSAIDs[4] and a record linkage study in Denmark,[5] however, have not supported these findings. Three case-control studies[2,6,7] reported a protective association between aspirin and bladder cancer, while other case-control and cohort studies, as well as the Women's Health Study, have found no association with aspirin use[3,4,8–12] or an elevated association.[13,14]

NSAIDs inhibit cyclooxygenase-1 and cyclooxygenase-2, a rate-limiting enzyme induced by endogenous (growth factors or cytokines) and exogenous (tobacco carcinogens) stimuli, and are involved in prostaglandin synthesis and the inflammatory response. At high concentrations, NSAIDs have anticarcinogenic properties operating through cyclooxygenase-2-dependent and -independent pathways to inhibit cellular proliferation, inhibit angiogenesis, and induce apoptosis.[15,16] Although not expressed in normal urothelial tissue, cyclooxygenase-2 has been shown to be overexpressed in both transitional cell and squamous cell urothelial tumor tissue.[17–20] In vitro and in vivo research suggests that NSAIDs and selective cyclooxygenase-2 inhibitors hinder growth and survival of bladder cancer cells and nitrosamine-induced tumors.[21–24]

Because of the limited and conflicting epidemiologic reports, we investigated the association between NSAIDs and bladder cancer risk using 3 large, prospective cohort studies. Our large sample size enabled us to conduct subgroup analyses by gender and smoking status; previous studies have been underpowered to examine potential effect modification by these important bladder cancer risk factors.


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