LES Relaxing Drugs and the Rise in Esophageal Cancer
September 1, 2000 4 minutes read
LES Relaxing Drugs and the Rise in Esophageal Cancer
ABSTRACT & COMMENTARY
Synopsis: There has been an increase in esophageal cancer in the past three decades and this may, in part, relate to an increase in the use of drugs that reduce lower esophageal sphincter tone. In this case control study from Sweden, a positive association between the long-term use of such drugs and esophageal adenocarcinoma (but not squamous cell carcinoma or gastric adenocarcinoma) was revealed. Thus, drugs that relax the lower esophageal sphincter, such as aminophyllins, nitroglycerin (long- and short-acting), and benzodiazepines must be considered risks for the development of this malignancy. Patients requiring the long-term use of any of these drugs should be watched carefully for signs of reflux esophagitis and treated early if they develop.
Source: Lagergren J, et al. Ann Intern Med 2000;133:
165-175.
The increase in esophageal cancer observed over the past several decades has not been satisfactorily explained.1 Reflux esophagitis has been shown to be a clinical antecedent, particularly for adenocarcinomas, and it has been proposed that one factor may be the increased use of prescribed medications that reduce the lower esophageal sphincter (LES) tone and thereby permit a reflux of gastric acid. To address this question, Lagergren and colleagues performed a nationwide (Sweden) population-based case-control study with in-person interviews. They identified 189 patients with newly diagnosed esophageal adenocarcinoma, 262 with adenocarcinoma of the gastric cardia and 167 with esophageal squamous-cell carcinoma. Their prescription history was compared with 820 matched controls. Using multivariate logistic regression analysis, estimated incidence rate ratio was calculated.
For this analysis, five groups of LES-relaxing drugs were considered. These were selected because these drugs were in common use during the two decades prior to diagnosis, a time period considered relevant in light of the current understanding of the time required for the pathogenesis of esophageal and gastric cancers. Newer drugs, such as calcium channel blockers, which are known to relax LES, were not included in this analysis. The five groups of drugs that were included were: nitroglycerines, anticholinergics, b-adrenergic agonists, aminophyllines, and benzodiazepines.
There was a significant positive association between the use of LES-relaxing drugs and risk for esophageal adenocarcinoma. Ever users of any of the drugs had an estimated adjusted incidence rate ratio (IRR) of 1.8 (95% CI, 1.3-2.7) compared with never users. Treatment with LES relaxing drugs for less than five years was associated with a moderate but not statistically significant excess risk (IRR, 1.3 [CI, 0.6-2.9]), but treatment of five or more years carried an adjusted IRR of 2.4 (CI, 1.5-3.8). Among the patients with esophageal adenocarcinoma, 17.5% reported daily use of at least one of the studied drugs for five years or more, compared to 6.6% of controls (adjusted IRR, 3.8 [CI, 2.2 to 6.4] for daily users compared with never users).
In contrast to the striking data for adenocarcinoma of the esophagus, squamous cell carcinoma of the esophagus and adenocarcinoma of the stomach were not significantly linked to prior use of these drugs. Furthermore, by using the multivariate model, there was no evidence of confounding by socioeconomic status, body mass index, tobacco smoking, alcohol use, or dietary intake of fruit and vegetables. However, the association of adenocarcinoma of the esophagus and LES-relaxing drugs was found to be tightly linked to experiencing symptoms of reflux esophagitis.
COMMENT by william b. ershler, md
Among white men in the United States, the incidence of adenocarcinoma of the esophagus is increasing more rapidly than any other tumor type.2 The reason for this has not been satisfactorily explained. However, reflux esophagitis is a known risk factor3 and it stands to reason that drugs associated with decreased LES tone would be potential risks for esophageal adenocarcinoma. This report supports that hypothesis. Commonly prescribed drugs that are known to have the untoward effect of lowering LES and producing reflux were found to be associated with a significant and dose-related increase in esophageal adenocarcinoma. These drugs, such as aminophyllin, nitroglycerin (short- and long-acting), the anticholinergics and the b-agonists have been commonly prescribed for decades in Sweden. Other drugs, such as calcium channel blockers, tricyclic antidepressants, a-adrenergic antagonists, nicotine derivatives, and chlorpromazines are also known to reduce LES and are now more commonly used in Sweden and the United States. With the expanded use of these agents, it is likely that the incidence of adenocarcinoma of the esophagus will continue to climb.
It is one thing to uncover an association and even propose a mechanism for increased cancer risk. It is another to actually do something about it. If, indeed, this association is true, then clinicians must be more vigilant to detect early symptoms and signs of reflux esophagitis in patients placed at higher risk for esophageal cancer on the basis of a prescribed drug. v
References
1. Pera M, et al. Gastroenterology 1993;104:510-513.
2. Blot WJ, et al. JAMA 1991;265:1287-1289.
3. Lagergren J, et al. N Engl J Med 1999;130:825-831.
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