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Esophageal Sphincter-Relaxing Drugs Linked with Adenocarcinoma

The incidence of esophageal adenocarcinoma has increased dramatically in western countries, especially among white males. Results from a recent study demonstrated a relation between the duration, frequency, and severity of heartburn and esophageal adenocarcinoma (see N Engl J Med 1999; 130:825). In this Swedish population-based, case-control study, the same researchers assessed the relation between drugs that relax the lower esophageal sphinchter (LES) and adenocarcinoma among 618 incident case patients (younger than 80) with esophageal and gastric cardia adenocarcinoma from 1995 through 1997 and among 820 age- and sex-matched controls.

All participants were asked about the use of nitroglycerin, aminophylline, ß-receptor agonists, anticholinergics, and benzodiazepines. Estimated incidence rate ratios (IRR) were calculated using multivariate logistic regression adjusted for confounding variables. To avoid recall bias, medications used in the 5 years before the interview were disregarded, and only patients who could remember the precise names for prescribed medications were classified as users. A significant association was evident between past use of LES-relaxing drugs and risk for esophageal adenocarcinoma; the IRR among daily, long-term users of LES-relaxing drugs ( (greater than) 5 years) was 3.8 (95 percent CI, 2.2-6.4) compared with those who never used these drugs. However, the association disappeared after adjustment for reflux symptoms. The risk was highest among users of anticholinergics (IRR, 4.2; CI, 2.0-8.9) and lowest among benzodiazepine users (IRR, 0.8; CI, 0.2-3.6). Cardia and squamous cell cancers were not associated with use of these drugs. The authors estimated that 10 percent of esophageal adenocarcinoma cases in Sweden could be attributed to the use of LES-relaxing drugs, and that treatment of 15,490 men for 5 years would yield 1 case. This number fell to 5570 for men older than 60.

Comment: These results suggest that the widespread use of LES-relaxing drugs during the last few decades may have contributed to the increasing incidence of esophageal adenocarcinoma. However, it is premature to stop prescribing all medications that affect LES pressure; despite the millions of people receiving LES-relaxing drugs, adenocarcinoma remains a relatively rare cancer compared with other gastrointestinal cancers, such as colon cancer. Further, the data were not stratified for the possible paradoxical protective effect of Helicobacter pylori or gastroesophageal reflux disease treatments. There are experimental data to suggest that aggressive therapy for GERD may have value beyond symptom control. Therefore, it makes sense to continue to use the best medication to treat each disease state and to treat GERD symptoms when they develop (in most cases with a proton-pump inhibitor). It is unlikely that avoidance of LES-relaxing drugs will significantly (if at all) decrease the rising incidence of esophageal adenocarcinoma.

— DA Johnson

Published in Journal Watch Gastroenterology September 25, 2000

Citation(s):

Lagergren J et al. Association between medications that relax the lower esophageal sphincter and risks for esophageal adenocarcinoma. Ann Intern Med 2000 Aug 1 133 165-175.

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