S3106 Risk of Colon and Gastric Cancer Development After Long-Term Proton Pump Inhibitor Use: A Meta-Analysis

Introduction: Proton pump inhibitors (PPIs) are commonly prescribed for GERD, peptic ulcers, and other acid-related conditions. Though considered safe short-term, concerns exist about a possible link between long-term use and GI cancers, particularly colon and gastric. This meta-analysis examines whether extended PPI use is associated with an increased risk of colon or gastric cancer, focusing on cohort studies with ≥5 years of follow-up. Methods: A systematic PubMed search identified cohort studies reporting hazard ratios (HRs) for colorectal or gastric cancer in patients on PPIs for ≥5 years. Pooled HRs were calculated using a random-effects model with inverse variance weighting. Heterogeneity was assessed via I2. Tau2 was estimated with the DerSimonian-Laird method; its CIs were calculated using the Jackson approach. Results: Colorectal cancer: Three cohort studies (n = 717,907) showed a pooled HR of 1.31 (95% confidence interval [CI] 0.81-2.10; P = 0.2675), indicating no significant link with long-term PPI use. Heterogeneity was high (I2 = 88%; Q = 17.37, df = 2; P = 0.0002), likely due to variation in exposure, follow-up time, and study populations. Gastric cancer: Six studies (n = 707,706) yielded a pooled HR of 1.64 (95% CI 1.22-2.20; P = 0.001), showing a significant association. Heterogeneity was substantial (I2 = 90%; Q = 52.06, df = 5; P < 0.0001), with possible sources including H. pylori prevalence, inconsistent confounder adjustment (smoking, aspirin), and outcome definition differences. Most showed a consistent risk trend. Funnel plots suggested possible publication bias in the gastric data, while fewer colorectal studies limited conclusions. Conclusion: This meta-analysis found that long-term use of PPIs was associated with an increased risk of gastric cancer, based on pooled observational data (HR = 1.64; 95% CI 1.22-2.20). The reason for this association is unclear and could be due to the use of PPI in patients with conditions such as H. pylori or peptic ulcer disease which may increase their risks of gastric cancer. No significant association was seen with colorectal cancer (HR = 1.31; 95% CI 0.81-2.10). Variation across studies likely stemmed from differing definitions of exposure and outcome. Still, most gastric cancer studies showed a consistent direction of risk. Funnel plots suggested possible publication bias in the gastric cancer data. These findings underscore the need for larger, better-designed studies to clarify the long-term safety of chronic PPI use and its link to GI cancer.