Spotlight on PPIs and cancer

Recent studies focused on the interaction between proton-pump inhibitors (PPIs), colorectal cancer (CRC), and gastric cancer.

The first study found that any use of PPIs was not associated with an increased risk of CRC compared to histamine-2 receptor antagonists; however, prolonged durations of use may be associated with a modest increased risk of CRC. Researchers used the United Kingdom Clinical Practice Research Datalink, a database of longitudinal primary care records, to identify 1,293,749 and 292,387 patients who initiated PPIs (esomeprazole, lansoprazole, omeprazole, pantoprazole, or rabeprazole) and H2 blockers (cimetidine, famotidine, nizatidine, or ranitidine), respectively, from 1990 to 2018, with follow-up until 2019. Included patients were required to be at least age 18 years and have one or more years of medical information in the database. Results were published July 1 by Gut.

Over a median 4.9 years of follow-up, the use of PPIs was not associated with an overall increased risk of CRC (hazard ratio [HR], 1.02; 95% CI, 0.92 to 1.14). However, HRs increased with cumulative duration of PPI use (HRs, 0.93 [95% CI, 0.83 to 1.04] for <2 years, 1.45 [95% CI, 1.28 to 1.60] for 2 to 4 years, and 1.60 [95% CI, 1.42 to 1.80] for ≥4 years). Similar patterns occurred in analyses of cumulative dose and time since treatment initiation. The number needed to harm was 5,343 for five years of follow-up and 792 for 10 years of follow-up. Among other limitations, there could have been some exposure misclassification, the study authors noted, adding that they were unable to measure treatment adherence. “Though the absolute risk of colorectal cancer is low at the individual level, given the high prevalence of PPI use, this increased risk could translate to a significant excess number of colorectal cancer cases at the population level,” they concluded. “In light of this risk, PPIs should be deprescribed in patients for whom treatment is no longer indicated, and physicians should closely monitor patients that require long-term PPI treatment.”

In the second study, also published by Gut on July 5, the same research group found that compared to use of H2 blockers, use of PPIs was associated with a 45% increased risk of gastric cancer. The researchers used the U.K. Clinical Practice Research Datalink to identify 973,281 new users of PPIs and 193,306 new users of H2 blockers from Jan. 1, 1990, to April 30, 2018. At cohort entry, all patients were required to be at least age 40 years and have at least one year of medical information in the database.

Over a median 5.0 years of follow-up, the use of PPIs was associated with an increased risk of gastric cancer compared with the use of H2 blockers (HR, 1.45; 95% CI, 1.06 to 1.98). The HRs increased with cumulative duration, cumulative omeprazole equivalents, and time since treatment initiation. The number needed to harm was 2,121 for five years after treatment initiation and 1,191 for 10 years after treatment initiation. Limitations of the study included the potential for exposure misclassification and residual confounding, the authors noted. “While PPIs have established clinical benefits when used according to evidence-based guidelines, this study highlights the need for physicians to regularly reassess the necessity of ongoing treatment,” they concluded.

A third study found that PPI use after CRC diagnosis was associated with increased all-cause and CRC-specific mortality. Researchers looked at all patients registered in the Swedish Prescribed Drug Registry who were diagnosed with CRC between 2006 and 2012 (n=32,411; 54.9% with one or more PPI dispensations after diagnosis) and followed them through register linkage to the Swedish Causes of Death Registry until December 2013. Results were published July 12 by the British Journal of Cancer.

Overall, 4,746 (14.0%) patients died, with an adjusted HR of 1.38 (95% CI, 1.32 to 1.44) for all-cause mortality among PPI users compared with PPI nonusers. Stronger associations were found among men, patients with cancer stage 0 to 1, those with rectal cancer, and those receiving CRC surgery. The association was also more pronounced when comparing new users to nonusers (adjusted HR, 1.47; 95% CI, 1.40 to 1.55) than when comparing continuous users to nonusers (adjusted HR, 1.32; 95% CI, 1.24 to 1.39). Risk estimates for CRC-specific mortality were similar to those for all-cause mortality. The study was limited by potential misclassification of exposure and the relatively short duration of follow-up, the authors noted. “Whether PPI use is causally linked or contributory to an increased mortality risk of patients with CRC, findings of this study may have implications for improving PPIs prescribing practices,” they concluded.

The final study found no adverse pathologic or oncological outcomes with concurrent use of PPIs and capecitabine for the neoadjuvant chemoradiation treatment of patients with locally advanced rectal cancer. Researchers looked at all patients with locally advanced rectal cancer treated with neoadjuvant chemoradiation treatment at one Canadian center between 2010 and 2016, 304 and 204 who received treatment with fluorouracil- and capecitabine-based neoadjuvant chemoradiation treatment, respectively. Results were published July 19 by the American Journal of Clinical Oncology.

Overall, 31 patients in the fluorouracil group and 20 in the capecitabine group used concomitant PPIs. There was no difference in pathologic complete response rate between the two study arms with the concurrent use of PPIs (P=0.633) or with and without the use of PPIs in the capecitabine arm specifically (20.0% and 20.7%, respectively; P=0.945). At a median follow-up of five years, there was no statistical difference in local or distant control in the capecitabine patients, with or without concomitant PPI use (P=0.411 and P=0.264, respectively). Multivariate analysis showed no association between PPI use and neoadjuvant chemoradiation treatment with capecitabine in terms of local control (HR, 0.001; P=0.988) or overall survival (HR, 1.179 [95% CI, 0.249 to 5.579]; P=0.835). Limitations of the study included its retrospective design and the relatively low number of patients who received PPIs, the authors said. “We report that it may be safe to use PPIs if essential, in this clinical setting, although it would be wise to exercise caution,” they concluded.