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Adenocarcinoma of the Esophagus: Risk Factors and Prevention

Adenocarcinoma of the Esophagus: Risk Factors and Prevention

Esophageal cancer is a relatively rare but deadly cancer in the United States. Even in patients with limited locoregional disease at the time of diagnosis, who have received aggressive multimodality therapies as part of clinical protocols, median survival is only 17 months and 3-year survival, only 30%.[1,2] Patients with metastatic disease have a 6-month median survival, which is not improved by the administration of chemotherapy.

Given these statistics, the identification of risk factors and preventive strategies for esophageal cancer represents a promising alternative approach to a disease that has been relatively resistant to treatment. Dr. Forastiere and colleagues have prepared an excellent, comprehensive review of current data regarding the potential identification of individuals at risk for developing esophageal cancer and the few preventive measures that may be taken in such persons.

Barrett’s Esophagus

As the authors point out, Barrett’s esophagus is the risk factor that has the strongest association with esophageal adenocarcinoma, and patients with Barrett’s warrant scheduled surveillance endoscopies at recommended intervals. Identification of high-grade dysplasia in these patients requires either frequent endoscopic follow-up or surgery.

At the University of Michigan, we recommend surgical resection for patients with high-grade dysplasia, and have found cancer in more than 50% of these surgical specimens. However, surgeons at our medical center perform a very high volume of esophageal surgeries, and such surgeries are associated with very low operative morbidity and mortality. As Forastiere et al point out, other centers may opt to perform endoscopy every 3 months and initiate rigorous use of histamine blockers and proton-pump inhibitors in patients with high-grade dysplasia.

Ongoing research is attempting to identify biomarkers that may help assess cancer risk in patients with Barrett’s esophagus, which will allow more frequent surveillance of patients at higher risk. Possible biomarkers include Ki-67, p53 abnormalities, and ornithine decarboxylase activity. These markers can be abnormal in patients with squamous metaplasia and normal in those with completely reversed metaplasia, as well as normal squamous epithelium.[3]

Gastroesophageal Reflux Disease

Gastroesophageal reflux disease (GERD) is another clinical problem that predates esophageal adenocarcinoma in a large number of patients. Of interest, the authors point out that GERD, in addition to its relationship to the evolution of Barrett’s esophagus, has been identified as an independent risk factor.

Lagergren et al reported that the association between the risk of esophageal cancer and severe, longstanding symptoms of reflux was of the same magnitude in patients with or without Barrett’s esophagus. However, it is possible that Barrett’s may not have been diagnosed in some specimens because of tumor overgrowth or sampling error.[4] Letters to the editor in response to that manuscript noted that other factors may be associated with GERD, such as long-term acid suppression secondary to therapy with histamine blockers and proton-pump inhibitors (although this hypothesis is currently unsubstantiated).[5] Other letters suggested that undiagnosed short-segment Barrett’s esophagus may be an intermediary step between GERD and cancer.[6]

The implications of the possible association between GERD and adenocarcinoma cause one to consider whether patients with GERD should undergo endoscopic screening, rather than limiting surveillance to patients with Barrett’s esophagus. Forastiere et al correctly point out that a “rigorous evaluation” of the benefits and risks of such an approach is needed, because of the tremendous implications for medical costs and resource utilization.

Avoidable Risk Factors

Patients can be educated to avoid or control some of the most important risk factors for esophageal cancer identified in the article, such as tobacco, alcohol, and obesity, and these efforts may result in an eventual decline in the incidence of the disease. Avoidance of excessive alcohol and tobacco can lead to a decrease in squamous cell cancer, and a decrease in smoking and control of obesity may diminish the incidence of adenocarcinoma. Of course, the issue of obesity is complicated because of the possible risks and benefits contributed by such foods as vegetables, nitrates, fiber, and fats, as well as the increased incidence of GERD with obesity.

Education regarding these risks must start at a very early age, since the length of time between exposure to a carcinogen and the development of esophageal cancer itself may be quite a few years. Although it is laudable for any patient to stop smoking or drinking or to lose weight, the greatest impact on the disease will occur only if young people can be convinced to avoid or limit their use of “risky” foods or substances.


Forastiere and colleagues have done an extraordinary job of summarizing a difficult topic. Because risk and prevention are harder to quantify than the results of treatments, interpretation of the available data regarding these issues requires judgment and experience.

The authors include a discussion of factors that confer minimal or no risk (eg, breast cancer, prostate cancer, calcium channel blockers, histamine-2-blockers, asbestos, silica, and dusts) to clarify some of the more commonly asked questions about possible risk factors. However, they appropriately concentrate their discussion on the more pertinent issues influencing esophageal cancer: Barrett’s esophagus, GERD, tobacco, alcohol, obesity, and diet. It is exciting to learn from the research in these areas, so that we may continually refine our ability to predict who is at risk for this deadly disease and how we can possibly prevent its development.


1. Walsh TN, Noonan N, Hollywood D, et al: A comparison of multimodality therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335:462-467, 1996.

2. Urba S, Orringer M, Turrisi A, et al: A randomized trial comparing surgery to preoperative concomitant chemoradiation plus surgery in patients with respectable esophageal cancer: Updated analysis (abstract). Proc Am Soc Clin Oncol 16:983, 1997.

3. Garewal H, Ramsey L, Sharma P, et al: Biomarker studies in reversed Barrett’s esophagus. Am J Gastroenterol 94:2829-2833, 1999.

4. Lagergren J, Bergstrom R, Lindgren A, et al: Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma. N Engl J Med 340:825-831, 1999.

5. Marcus G: Gastroesophageal reflux and adenocarcinoma of the esophagus (letter). N Engl J Med 341:537, 1999.

6. Nandurkar S, Talley N: Gastroesophageal reflux and adenocarcinoma of the esophagus (letter). N Engl J Med 341:536, 1999.

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