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Aspirin and other NSAIDs, Including COX-2 Inhibitors

Among other effects, aspirin and other NSAIDs inhibit cyclooxygenases. COX-1 is constitutively expressed in the GI tract. COX-2 expression is generally not observed in normal GI mucosa, but is induced in multiple epithelial malignancies, including gastric cancer.261,262 COX-2 expression is associated with aggressive cell growth in both human and mouse models of cancer263-266 and has been found to be overexpressed in 70% of gastric cancers.267 In this setting, COX-2 could potentially promote the growth of tumors, inhibit apoptosis, and increase angiogenesis. COX-2 expression has been reported to be elevated in preneoplastic lesions, including both intestinal metaplasia and dysplasia, and COX-2 expression appears to diminish after Hp eradication.268

Multiple epidemiologic studies have demonstrated a consistent association between NSAID use and reduced risk of gastric cancer.269-272 In a case-control study from Los Angeles County, NSAID use for more than 5 years was associated with a reduced risk of noncardia gastric cancer (odds ratio, 0.61), and there was a significant NSAID dose-related effect.270 A nested case-control study using the General Practitioners Research Database in the United Kingdom found that longterm users of non-aspirin NSAIDs decreased the risk of gastric cancer (odds ratio, 0.65), although there was no effect of aspirin use on the risk of gastric cancer.272 A meta-analysis reported a significant association between any NSAID use and reduced risk of gastric cancer (odds ratio, 0.78), with similar findings for both ASA and non-ASA NSAIDs.271

In a randomized controlled trial of Hp-negative patients with intestinal metaplasia, there was no difference in the rate of regression of intestinal metaplasia after 2 years between patients receiving the COX-2 selective inhibitor rofecoxib and placebo.273 This trial was limited by the relatively short follow-up period and use of premalignant endpoints. In a separate randomized controlled trial in patients with Hp and histology showing chronic atrophic gastritis (or worse), both Hp eradication and 24 months of the COX-2 selective inhibitor celecoxib resulted in histologic regression, although no additive effect was observed.274In a summary analysis of randomized trials of aspirin versus no aspirin for various outcomes, those studies with 10 to 20 years’ follow-up reported a reduced risk of gastric cancer in those assigned to aspirin (odds ratio, 0.42).275 Further trials in high-risk patients are warranted to determine if NSAIDs are effective for gastric cancer prevention.