AIMS: To study the association between long-term treatment with acid-suppressing drugs and risk of oesophageal or gastric adenocarcinoma.

PATIENTS: Persons registered in the General Practitioners Research Database in the United Kingdom and aged 40-84 years during the period 1994 through 2001.

METHODS: Population-based nested case-control study. Multivariable unconditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs).

RESULTS: In 4,340,207 person-years of follow-up 287 patients with oesophageal adenocarcinoma, 195 with gastric cardia adenocarcinoma, and 327 with gastric non-cardia adenocarcinoma were identified, and 10,000 control persons were randomly sampled. "Oesophageal" indication for long-term acid suppression, i.e. reflux symptoms, oesophagitis, Barrett's oesophagus, or hiatal hernia, rendered a five-fold increased risk of oesophageal adenocarcinoma (OR 5.42, 95% CI 3.13 to 9.39), while no association was observed among users with a group of other indications including peptic ulcer and "gastroduodenal symptoms", i.e. gastritis, dyspepsia, indigestion, and epigastric pain (OR 1.74, 95% CI 0.90 to 3.34). "Peptic ulcer" indication, i.e. gastric ulcer, duodenal ulcer, or unspecified peptic ulcer was associated with a greater than four-fold increased risk of gastric non-cardia adenocarcinoma among long-term users (OR 4.66, 95% CI 2.42 to 8.97) but no such association was found in those treated for a group of other indications, i.e. "oesophageal" or "gastroduodenal symptoms" (OR 1.18, 95% CI 0.60 to 2.32).

CONCLUSIONS: Long-term pharmacological gastric acid suppression is a marker of increased risk of oesophageal and gastric adenocarcinoma. However, these associations are most likely explained by the underlying treatment indication being a risk factor for the cancer rather than an independent harmful effect of these agents per se.