Chemoprevention of esophageal and gastric cancers

Gastroesophageal cancers include cancer of the stomach, gastroesophageal junction, and esophagus, which differ markedly in their molecular and biologic characteristics and epidemiologic profiles. Gastric cancer is the second leading cause of cancer-related deaths worldwide and has been associated with environmental factors including diets high in fatty, pickled, smoked, or salty foods; diets low in fresh fruits and vegetables; and gastric mucosal infection with Helicobacter pylori. Recently, a study evaluated the potential benefits of antioxidant supplements and/or H. pylori eradication for 630 high-risk individuals with gastric dysplasia in Narino, Columbia. Participants were randomly assigned to receive anti-H pylori triple therapy and/or ascorbic acid, beta-carotene, or corresponding placebos for six years. Marked histopathologic improvement occurred for patients who received ascorbic acid, beta-carotene, or antibiotic therapy (compared with placebo), suggesting that these agents may be useful for reducing the risk of gastric cancer. Observational and laboratory data suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) may have a preventive effect for gastric cancer, but this has not been definitely proven in human trials. Until the mid-1970s, the most common type of esophageal cancer in the United States was squamous cell cancer, which remains common in parts of Asia and Africa. The major risk factors for squamous cell esophagus cancer are tobacco and alcohol consumption and certain dietary deficiencies; by contrast, the major risk factor for esophageal adenocarcinoma is gastroesophageal reflux. Both cancer types are associated with dysplastic precursors identifiable by cytologic or histopathologic analysis. Most esophageal cancer prevention trials have been conducted in the Linxian region of China, which has one of the highest rates of squamous cell esophageal cancer in the world. One large, randomized trial involving a complex fractional factorial design and nearly 30,000 men and women found that the combination of selenium, beta-carotene and vitamin E supplements resulted in a significant reduction in total cancer deaths (13 percent), a significant reduction in gastric cancer deaths (21 percent), and an insignificant reduction in esophageal cancer deaths (4 percent), when compared with placebo. These results suggest a modest role for one or more of these antioxidants for prevention of esophageal squamous cell cancer in this high-risk population.

As with gastric cancer, observational data suggest that NSAIDs may reduce the risk of esophageal cancer by 40 -70 percent. This hypothesis has yet to be tested in definitive, randomnized clinical trials. Esophageal adenocarcinoma, which arises from a metaplastic or dysplastic precursor called Barrett’s esophagus, has one of the fastest rising incidence rates among cancers in Western counries. Until recently, intervention for Barrett’s esophagus, both medical and surgical, primarily targeted acid exposure or acid reflux to improve symptoms, but there was no consistent evidence of disease regression or lower rates of progression to invasive cancer.

Although Barrett’s esophagus does not progress to cancer for most patients, there is currently no accurate way to distinguish between patients who will or will not have disease progression. Moreover, the vast majority of patients with gastro-esophageal cancer do not have a prior diagnosis of Barrett‘s esophagus. Molecular markers for esophageal carcinogenesis are urgently needed to facilitate early cancer detection and to serve as preventive targets for pharmacologic and/or dietary intervention. In August 2003, the US Food and Drug Administration (FDA) granted orphan drug designation to photodynamic therapy with a photosensitizing porphyrin mixture (porfimer sodium) for the ablation of high-grade dysplasia in patients with Barrett’s esophagus who cannot or choose not to have esophagectomy. The multicenter, controlled, partially masked trial leading to this approval involved 138 patients randomly assigned to receive photodynamic therapy plus omeprazole and 70 patients assigned to receive omeprazole alone. Follow-up ranged from two to 3.6 years. A complete and sustained eradication of high-grade dysplasia occurred for 77 percent of the patients treated with omeprazole alone (p<0.0001). Photodynamic therapy porfimer sodium involved intravenous injection of the porphyrin, which is activated 40-50 hours later by nonthermal endoscopic application of red light at 630 nanometers (a maxmum of three courses of treatment, as indicated) The proposed mechanisms for the photodynamic therapy include tissue necrosis from free radical damage, anoxia induced by vascular thrombosis, and inflammatory responses. The FDA approval of this approach provides an important option for patients with high-grade esophageal dysplasia and sets a precedent for the development of less invasive and less toxic strategies. Data from phase II trials evaluating the merits of eflornithine, celecoxib, or selenium for patients at risk for esophagical cancer are expected in the near future.