Evidence of Benefit
Tobacco, Alcohol, and Dietary Factors
In the United States, squamous cell carcinoma of the esophagus is strongly associated with tobacco and alcohol abuse. The risk declines with smoking cessation. In China, esophageal cancer is associated with deficiencies of nutrients such as retinol, riboflavin, alpha-carotene and beta carotene, alpha-tocopherol, ascorbate, and zinc, and with exposure to specific carcinogens (e.g., N-nitroso compounds).Chemoprevention
A prospective, placebo-controlled, esophagus chemoprevention study randomly assigned 610 high-risk Chinese subjects. Subjects ranged in age from 35 to 64 years and received either placebo or combined low-dose retinol (15 mg or 50,000 IU) plus riboflavin (200 mg) and zinc gluconate (50 mg) for 13.5 months. Standard histological evaluations (including two endoscopic biopsies) were made of 93% of all entered subjects. Micronuclei from esophageal cells were obtained before therapy began and after the 13.5 months of treatment. Serum levels of vitamin A, beta carotene, riboflavin, and zinc were obtained at 0, 2, and 13.5 months.
The second report of this study presented micronuclei frequency results. A statistically significant reduction occurred in the mean percentage of micronucleated esophageal cells in the active-treatment group compared with the placebo group. The pattern of cell proliferation, another potential intermediate endpoint marker, also improved.
Two National Cancer Institute-sponsored phase III trials of combinations of multiple vitamins and minerals have been reported. Both were conducted in a high-risk area of China (Linxian). In one, a complex modified factorial design was used to study four different vitamin/mineral combinations administered for 5 years at doses one to two times the U.S. recommended daily allowances (RDA) to 29,584 subjects. The combination of beta carotene, alpha-tocopherol, and selenium was associated with a nonstatistically significant 4% reduction in the esophageal cancer mortality rate. The other trial included only higher-risk subjects with esophageal dysplasia  and had a two-arm design (26 vitamins and minerals, including beta carotene, alpha-tocopherol, and selenium, at two to three times the U.S. RDA in one arm versus placebo in the other). This 6-year intervention was associated with a nonsignificant change: a 16% reduction in the esophageal cancer mortality rate. Similar studies have not been conducted in the United States.Aspirin and nonsteroidal anti-inflammatory drugs
A systematic review and meta-analysis of the association of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) with esophageal cancer identified two cohort and seven case-control studies published between 1980 and 2001. Pooled results show a protective association between aspirin/NSAID use and esophageal cancer (odds ratio [OR] = 0.57; 95% confidence interval [CI], 0.47–0.71). Association with aspirin use was statistically significant (OR = 0.50; 95% CI, 0.38–0.66); association with NSAIDs was of borderline significance (OR = 0.75; 95% CI, 0.54–1.0). Aspirin/NSAID use was associated with lower risk of both adenocarcinoma (OR = 0.67; 95% CI, 0.51–0.87) and squamous cell carcinoma (OR = 0.58; 95% CI, 0.43–0.78).Radiofrequency Ablation in Dysplastic Barrett Esophagus
A randomized controlled trial  assessed whether, among persons with Barrett esophagus and dysplasia, radiofrequency ablation (vs. sham ablation) could eradicate dysplastic Barrett esophagus and decrease the rate of neoplastic progression. Among persons with low-grade dysplasia, eradication of dysplasia occurred in 90.5% of the treatment group compared to 22.7% in the control group; in the high-grade dysplasia group, rates were 81.0% compared to 19.0%. Additionally, 77.4% of persons in the ablation group had complete eradication of intestinal metaplasia, compared to 2.3% in the control group. Persons in the ablation group had less disease progression, and although cancer was not a primary outcome because expected numbers were small, there were fewer cancers in the ablation group (1.2% vs. 9.3%; P = .045). The complication rate was relatively low; among 84 treated persons, there was one upper gastrointestinal hemorrhage and five strictures that were easily treated.
This study suggests that treatment of Barrett with dysplasia may ablate Barrett esophagus and prevent disease progression, but the study provides only weak evidence (indeed, it was not designed to answer) about whether treatment reduces the outcome of esophageal cancer. Evidence from the study suggests that ablation does not simply coagulate and hide dangerous cells under the surface of the esophagus (those cells could later evolve to cancer). A question entirely separate from this study is whether patients should or should not be screened for Barrett esophagus (this study focused on treatment of persons with Barrett who had been identified as having dysplasia). Furthermore, the study does not discuss the net benefits and harms of an overall program of screening (e.g., of screening persons with gastroesophageal reflux disease (GERD) or certain GERD symptoms) and the surveillance of persons with Barrett. The potential for overdiagnosis and overtreatment may be considerable, if physicians used results of this study to treat persons with Barrett esophagus and no dysplasia.References
- Oesophagus. In: World Cancer Research Fund., American Institute for Cancer Research.: Food, Nutrition and the Prevention of Cancer: A Global Perspective. Washington, DC: The Institute, 1997, pp 118-129.
- Muñoz N, Wahrendorf J, Bang LJ, et al.: No effect of riboflavine, retinol, and zinc on prevalence of precancerous lesions of oesophagus. Randomised double-blind intervention study in high-risk population of China. Lancet 2 (8447): 111-4, 1985. [PUBMED Abstract]
- Muñoz N, Hayashi M, Bang LJ, et al.: Effect of riboflavin, retinol, and zinc on micronuclei of buccal mucosa and of esophagus: a randomized double-blind intervention study in China. J Natl Cancer Inst 79 (4): 687-91, 1987. [PUBMED Abstract]
- Yang GC, Lipkin M, Yang K, et al.: Proliferation of esophageal epithelial cells among residents of Linxian, People's Republic of China. J Natl Cancer Inst 79 (6): 1241-6, 1987. [PUBMED Abstract]
- Blot WJ, Li JY, Taylor PR, et al.: Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 85 (18): 1483-92, 1993. [PUBMED Abstract]
- Li JY, Taylor PR, Li B, et al.: Nutrition intervention trials in Linxian, China: multiple vitamin/mineral supplementation, cancer incidence, and disease-specific mortality among adults with esophageal dysplasia. J Natl Cancer Inst 85 (18): 1492-8, 1993. [PUBMED Abstract]
- Corley DA, Kerlikowske K, Verma R, et al.: Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis. Gastroenterology 124 (1): 47-56, 2003. [PUBMED Abstract]
- Shaheen NJ, Sharma P, Overholt BF, et al.: Radiofrequency ablation in Barrett's esophagus with dysplasia. N Engl J Med 360 (22): 2277-88, 2009. [PUBMED Abstract]