Importance Proton pump inhibitors (PPI) are often prescribed to prevent steroid-induced gastritis and peptic ulcer disease in patients with glioblastoma. Yet, these drugs may enhance the activity of aldehyde dehydrogenase 1 A1 (ALDH1A1), which has been linked to protection from oxidative stress, radiotherapy, and chemotherapy. Objective To explore the associations of the use of potent ALDH1A1-activating PPIs (PA-PPIs) and other antacid drugs with outcomes in patients with newly diagnosed glioblastoma. Design, Setting, and Participants This meta-analysis was a secondary analysis of individual prospectively captured patient data using a dataset of 5 randomized clinical trials conducted between 2008 and 2020. Participants included patients with a new diagnosis of glioblastoma. Data analysis was completed in November 2024. Exposure We assessed drug use at baseline and defined 3 landmarks: start of temozolomide maintenance cycles 1 (landmark 1) and 4 (landmark 2), and end of cycle 6 (landmark 3). Main Outcomes and Measures The primary outcome measures were progression-free survival (PFS) and overall survival (OS) from baseline and from the start of each corresponding landmark time. Results The study population included 2981 patients (1858 62.3% male; median range age, 58 18-85 years). On univariate analysis, patients treated with PA-PPI had worse PFS and OS at all 4 time points. The multivariate analysis accounting for age, sex, performance status, steroid use, extent of resection, and MGMT status confirmed a difference for PFS at landmarks 1 (hazard ratio HR, 1.14 95% CI, 1.01-1.28), 2 (HR, 1.26 95% CI, 1.09-1.44), and 3 (HR, 1.31 95% CI, 1.10-1.56), and for OS at landmarks 1 (HR, 1.34 95% CI, 1.08-1.66) and 2 (HR, 1.14 95% CI, 1.01-1.29). No such association was seen for the use of other antacid drugs. The negative association of PA-PPI use with PFS and OS was observed independently of MGMT promoter methylation and steroid use. Conclusions and Relevance In this meta-analysis of patients with newly diagnosed glioblastoma, PPI use was associated with inferior survival outcomes. These findings suggest that PA-PPI use should be discouraged in patients with glioblastoma, since alternative agents are available and a detrimental effect cannot be excluded. Translational research studies should explore whether PPI-induced activity of ALDH mediates the potential adverse effects of PPI in glioblastoma. .
Rhun et al. (Tue,) studied this question.