The role of chemoprevention in Barrett esophagus and esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is a highly lethal cancer and is the most rapidly increasing cancer in the Western countries. In the United States, the incidence of EAC has increased 6-fold and despite recent advances, the 5-year survival is appalling. The high proportion of patients presenting with advanced disease, the poor response to therapy, and low survival rates warrants identification of potential agents for chemoprevention. Barrett esophagus (BE) is a well-established premalignant condition for the development of EAC. A better understanding of the pathogenesis and development of strategies to halt progression along the metaplasia-dysplasia-carcinoma sequence are desirable. The utility of rigorous acid inhibition with proton pump inhibitors (PPIs) as chemopreventive agents has been contested. Acid exposure increases cell proliferation and decreases apoptosis in BE and EAC. Therefore, preventing exposure of the esophageal mucosa to gastric acid by potent antisecretory agents may decrease cancer risk in BE patients. Studies have shown that PPI therapy does not lead to reliable regression of BE. Although, recent studies suggest decreased risk of dysplasia with PPIs, the effect of PPIs on progression of BE is unclear. There is epidemiologic and experimental evidence to suggest that chemoprevention using nonsteroidal anti-inflammatory drugs, aspirin, and selective cyclo-oxygenase-2 (COX-2) inhibitors may reduce the risk of cancer in BE patients. Their chemopreventive action is mediated by inhibition of COX-2 and resultant decrease in eicosanoid-prostaglandin E-2 production. Increased COX-2 expression has been demonstrated in BE including a progressive increase along the metaplasia-dysplasia-carcinoma sequence contributing to increased cell proliferation, decreased apoptosis, and increased angiogenesis. Increased cardiovascular toxicity associated with prolonged use of selective COX-2 inhibitors tempers enthusiasm for any further investigation of this agent class in this context. Results of ongoing studies investigating effect of aspirin with PPI therapy on neoplastic progression in BE are awaited. Other agents that have shown promising initial results include troglitazone, a peroxisome proliferators-activated receptor gamma ligand that reduces ornithine decarboxylase activity; telomerase inhibitors that induce apoptosis; and all transretinoic acid that induces apoptosis as well. Large randomized controlled prospective clinical studies are needed to validate the effect of chemopreventive strategies in high-risk populations; results of which could profoundly change the natural history and management of this disease.