Proton Pump Inhibitor Use and the Efficacy of Chemotherapy in Metastatic Colorectal Cancer: A Post Hoc Analysis of a Randomized Phase III Trial (AXEPT)

Background Concomitant use of proton pump inhibitors (PPIs) with capecitabine was suggested to be associated with poor outcomes in gastrointestinal cancers. We analyzed the differential impact of PPI use on capecitabine and fluorouracil using the data set from the AXEPT trial, a phase III randomized trial that demonstrated the noninferiority of mXELIRI (modified XELIRI: capecitabine plus irinotecan) to FOLFIRI (leucovorin, fluorouracil, and irinotecan), either with or without bevacizumab in patients with metastatic colorectal cancer. Patients and Methods Out of the per-protocol set (n = 620), patients with information on concomitant medications (n = 482) were included in this post hoc analysis. PPI use was defined as concomitant exposure of capecitabine and the use of any PPI for 20% or more of the study period. The treatment-by-PPI-use interaction was examined after adjusting for stratification factors. Results Of the 482 patients, 49 (10.1%) used PPI. Among the PPI users, the mXELIRI group tended to have poorer overall survival compared with the FOLFIRI group. In contrast, among the nonusers, the overall survival of the mXELIRI group was significantly better than that of the FOLFIRI group. Similarly, a trend of worse progression-free survival with mXELIRI compared with FOLFIRI was observed in PPI users but not in nonusers. Treatment-by-PPI-use interaction was significant for overall survival and progression-free survival. Conclusion The significant interaction between PPI use and the type of fluoropyrimidine in terms of overall and progression-free survival suggests that fluorouracil could be a more favorable option than capecitabine for patients with metastatic colorectal cancer using PPIs. Implications for Practice This study showed a significant interaction between the use of proton pump inhibitors (PPIs) and the type of fluoropyrimidines. This interaction mainly comes from the positive impact of PPIs in the survival outcomes in the fluorouracil arm rather than a negative impact of PPIs in the capecitabine arm. The possible drug-drug interaction shown in this study suggests that fluorouracil, rather than capecitabine, could be a more appropriate choice of fluoropyrimidine for patients who are taking PPIs in the treatment of metastatic colorectal cancer.