Proton pump inhibitors are detrimental to overall survival of patients with glioblastoma multiforme: results from a nationwide real-world evidence database

Abstract

AbstractBackgroundAldehyde dehydrogenase-1A1 (ALDH1A1) is a primary metabolic enzyme impacting outcome of chemotherapy, including temozolomide, the standard-of-care (SOC) for glioblastoma multiforme (GBM). High expression of ALDH1A1 is associated with poor prognosis in multiple cancers. Proton pump inhibitors (PPIs) are often prescribed to manage corticosteroid-induced gastrointestinal toxicity but were recently identified as strong inducers of ALDH1A1, suggesting a negative impact on survival.MethodsReal-world data on GBM patients was annotated from electronic medical records (EMR) according to the prospective observational study, XCELSIOR (NCT03793088). Patients withIDH1/2mutations were excluded. Causal effects on survival were analyzed using a multivariate, time-varying Cox Proportional Hazard (CPH) model with stratifications includingMGMTmethylation status, age, sex, duration of corticosteroid use, extent of resection, starting SOC, and PPI use.ResultsEMR data from 554 GBM patients across 225 cancer centers was collected, with 72% of patients receiving care from academic medical centers. Patients treated with PPIs had numerically lower median overall survival (mOS) and 2-year OS rates in the total population and across most strata, with the greatest difference for MGMT-methylated patients (mOS 29.2 mo vs. 40.1 mo). In a time-varying multivariate CPH analysis of the above strata, PPIs caused an adverse effect on survival (HR 1.67 [95% CI 1.15-2.44], p=0.007).ConclusionsEvidence from a nationwide cancer registry has suggested PPIs have a strong detrimental effect on OS for GBM patients, particularly those withMGMTpromoter methylation. This suggests PPIs should be avoided for prophylactic management of gastrointestinal toxicity in patients with GBM receiving SOC chemoradiotherapy.Key PointsNationwide glioblastoma study suggests hazardous effect of proton pump inhibitorsDiscretion advised when prescribing proton pump inhibitors to glioblastoma patientsProphylactic proton pump inhibitor use to limit chemo toxicity may increase riskImportance of the StudyRecent molecular evidence suggests off-target activity of proton pump inhibitors (PPIs) may counteract the activity of alkylating chemotherapy in glioblastoma clinical care. Utilizing a time-varying cox proportional hazard model and abstracted clinical data from medical records according to a nationwide observational research protocol, we found PPIs were significantly associated with greater risk of death, independent of corticosteroid use. Importantly, the detrimental effect was most impactful for patients with methylated MGMT promoters who gain the most benefit from standard-of-care temozolomide treatment and experience the best outcomes.