Background: Proton pump inhibitors (PPIs) are one of the most widely used drugs worldwide and are overprescribed in patients with cancer; there is increasing evidence of their effects on cancer development and survival. The objective of this narrative review is to comprehensively identify cancer medications that have clinically meaningful drug–drug interactions (DDIs) with PPIs, including loss of efficacy or adverse effects, and to explore the association between PPIs and cancer.Methods: A PubMed search of English language studies published from 1 January 2016, to 1 June 2021 was conducted. The search terms included “proton pump inhibitors,” “cancer,” “chemotherapy,” “immunotherapy,” “hormonotherapies,” “targeted therapies,” “tyrosine kinase inhibitors,” and “gut microbiome”. Recent and relevant clinical trials, meta-analyses, and reviews were included.Results: PPIs may have pro-tumor activity by increasing plasma gastrin levels or anti-tumor activity by inhibiting V-ATPases. However, their impact on cancer survival remains unclear. PPIs may decrease the efficacy of some antineoplastic agents through direct DDIs (e.g., some tyrosine kinase inhibitors, capecitabine, irinotecan, methotrexate). More complex DDIs seem to exist for immunotherapies with indirect interactions through the microbiome. PPIs worsen hypomagnesemia, bone loss, iron, and vitamin B12 deficiencies but may have a protective effect on the renal system.Discussion/Conclusions: PPIs may interact with the cancer microbiome and the efficacy of various antineoplastic agents, although only a few DDIs involving PPIs are clinically significant. Further pharmaco-epidemiological studies are warranted, but physicians should be aware of the potential consequences of PPI use, which should be dose appropriate and prescribed according to guidelines.

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Purpose: Proton pump inhibitors (PPIs) are one of the most widely used drugs worldwide and are involved in several drug interactions. Recently, several studies have suggested that PPIs may interfere with the efficacy of capecitabine. This study primarily aimed to investigate the effects of PPI intake on the pathological response rate of patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy with capecitabine. Method: A retrospective study was conducted at a French Comprehensive Cancer Center. Patients with locally advanced rectal cancer treated with neoadjuvant radiochemotherapy followed by surgery were included in the study. Demographic parameters, treatment characteristics, survival data, and PPI intake data were collected. Survival data were estimated using the Kaplan-Meier method and compared using the log-rank test.Results: In total, 215 patients were included, of whom 135 (62.8%) were men. The PPI intake frequency was 16.1%. The rate of complete histological response was lower in patients on PPIs than in those not on PPIs (8.7% vs. 19%, p=0.36). PPI intake was not associated with a statistically significant decrease in recurrence-free survival (hazard ratio [HR]=1.26, 95% confidence interval [CI] 0.61–2.60, p=0.54) or overall survival (HR=0.95, 95% CI 0.33–2.76, p=0.93).Conclusion: There is a trend to a lower complete histological response with PPI co-medication in patients treated for locally advanced rectal cancer. However, the safety of PPIs could not be confirmed. Further ancillary studies of prospective clinical trials or studies using the Health Data Hub are necessary to explore the effects of PPIs on rectal cancer more accurately.