Concomitant Use of Proton Pump Inhibitors and Survival Outcomes in Patients Receiving Adjuvant Chemotherapy for Stage III Colon Cancer

ABSTRACT Proton pump inhibitors (PPIs) are commonly prescribed in patients with cancer. Prior studies suggest concomitant PPI use may reduce the efficacy of oral capecitabine through impaired absorption, with no interaction expected with intravenous 5‐fluorouracil (5‐FU). Using the Australian Comprehensive Cancer Outcomes and Research Database (ACCORD), we identified patients with Stage III colon cancer diagnosed between 1 January 2006 and 31 December 2023. Concomitant PPI use during adjuvant chemotherapy was determined by chart review. We evaluated the prevalence of PPI use with fluoropyrimidine‐containing adjuvant therapy and its association with recurrence‐free survival (RFS) and overall survival (OS). A total of 459 patients were included as follows: 63 (14%) received 5‐FU alone, 115 (25%) capecitabine alone, 148 (32%) FOLFOX and 133 (29%) CAPOX. High‐risk disease (T4 and/or N2) was present in 203 patients (44%). Overall, 142 patients (31%) received a PPI during adjuvant chemotherapy, with similar rates across treatment groups ( p = 0.952). Formal interaction testing did not demonstrate significant heterogeneity of PPI effect across treatment regimens (RFS: LR test p = 0.615; OS: LR test p = 0.143). However, in high‐risk patients receiving CAPOX, PPI use was associated with reduced RFS (HR 3.07, 95% CI 1.38–6.84, p = 0.006) and OS (HR 4.11, 95% CI 1.44–11.74, p = 0.008). No impact was observed with capecitabine monotherapy, 5‐FU, or FOLFOX. Concomitant PPI use is common in Australian patients with Stage III colon cancer. While formal interaction testing did not reach statistical significance, PPI use was associated with inferior survival outcomes in high‐risk patients receiving CAPOX.