COX-2 Inhibition and the Prevention of Gastric Cancer

In the light of the uncertainties of the effects of H. pylori eradication on gastric cancer prevention, and the increasing recognition that any benefit is likely to be limited, there is a clear need to investigate additional chemopreventive strategies. As for many gastrointestinal and other malignancies, a strong body of epidemiological evidence supports the notion that aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive effects in gastric cancer [3] . The mechanisms by which NSAIDs inhibit or prevent neoplastic growth are not fully elucidated but most likely they are related to their ability to reduce cyclooxygenase (COX) expression, to induce apoptosis, and to inhibit cell proliferation and angiogenesis. Elevated expression of COX-2 is frequently observed in cancer, including gastric cancer [4] , and selective COX-2 inhibitors have demonstrable antitumor effects in many model systems [5] . Because they are considered less gastrotoxic than nonselective NSAIDs, in recent years, COX-2 inhibitors have been investigated as chemopreventive agents in a variety of premalignant states, including two recent large randomized controlled studies of celecoxib that demonstrated efficacy in the prevention of colorectal adenoma recurrence [6, 7] . However, recent revelations regarding unexpected cardiovascular toxicity have severely dampened enthusiasm for the widespread use of COX-2 inhibitors in otherwise healthy patients [8] . Although the incidence of gastric cancer has recently decreased in many Western populations, it is still a highly prevalent disease and a major cause of death worldwide. Because gastric cancer usually presents late, the prognosis remains poor, and thus the main strategy for improving clinical outcomes is through prevention. The recognition that most gastric cancers develop consequent to chronic Helicobacter pylori infection, and the relative simplicity of eradicating H. pylori with combination antimicrobial chemotherapy have led to the hope that much gastric cancer can be prevented through H. pylori eradication. However, the evidence thus far from larger randomized controlled trials of gastric cancer prevention with H. pylori eradication in subjects at high gastric cancer risk has provided only limited optimism [1, 2] . In these studies the benefit of H. pylori eradication was confined almost entirely to subjects who had not progressed to the stage of intestinal metaplasia prior to receiving H. pylori eradication therapy. Unfortunately, all clinical studies of H. pylori eradication have been underpowered to demonstrate an effect on gastric cancer as an end point. The difficulties of conducting such large controlled studies over decades in patients in whom withholding H. pylori eradication can be regarded as unethical mean that more definitive data from H. pylori eradication trials in human subjects are unlikely to be forthcoming any time soon. Published online: March 6, 2007