Rethinking Proton Pump Inhibitors in Glioblastoma Care

Proton pump inhibitors (PPIs) are a class of medications that reduce gastric acid secretion and include agents such as omeprazole, esomeprazole, pantoprazole, and lansoprazole, among others. They are a mainstay in the treatment of gastric and duodenal ulcers and gastroesophageal reflux disease (GERD). PPIs are also commonly used for prophylaxis against gastritis in patients receiving corticosteroids, anticoagulation, or treatment for coronary artery disease.¹

Oncology providers are often trained to view PPIs as a routine component of supportive care in patients receiving corticosteroids, particularly in glioblastoma, where corticosteroids are central to symptom management. However, emerging data suggest that PPIs may alter tumor biology, modify the tumor microenvironment, and potentially affect the efficacy of cancer therapies. As a result, their use in patients with glioblastoma is being scrutinized, raising questions about whether they are always safe as a routine supportive care medication.

Emerging evidence challenges routine PPI use in glioblastoma

A recent article by Dr. Le Rhun and colleagues in the Journal of the American Medical Association challenges the assumption that PPIs are a benign component of supportive care.² In this large meta-analysis of nearly 3,000 patients across five randomized clinical trials, PPI use, particularly those that strongly activate an enzyme called ALDH1A1, like omeprazole and pantoprazole, was consistently associated with worse progression-free and overall survival. Notably, these associations remained significant even after adjusting for key prognostic factors, including age, performance status, extent of resection, whether the tumor had a specific DNA modification called MGMT promoter methylation, and concurrent steroid use.

In contrast, other antacid therapies, such as H2 receptor antagonists like famotidine and locally acting antacids such as calcium carbonate, were not associated with worse outcomes, suggesting that the observed effect may be specific to certain PPIs rather than a result of gastric acid suppression in general. While patients receiving corticosteroids were more likely to also receive PPIs, the negative association between PPI use and survival remained independent of steroid exposure. Importantly, the effect was observed regardless of MGMT promoter methylation status. Since MGMT methylation typically predicts response to temozolomide, this indicates that the detrimental effect of PPIs is unlikely to result solely from reduced chemotherapy effectiveness, pointing instead to other mechanisms, such as changes in the tumor microenvironment.

Although preclinical studies suggested that PPIs may enhance sensitivity to chemotherapy, these findings did not translate into clinical benefit. In fact, the association between PPI use and worse outcomes was strongest during active treatment, raising concern that PPIs may interfere with therapy. Proposed mechanisms include activation of ALDH1A1, a pathway linked to cancer stemness and therapy resistance, changes in tumor pH, alterations in drug absorption, and shifts in the gut microbiome. Some PPIs can cross the blood-brain barrier, raising the possibility of direct effects on the tumor or its microenvironment.

While this study is limited by its retrospective design and potential confounding, since patients with more aggressive disease may be more likely to receive both steroids and PPIs, the consistency of findings across analyses strengthens the concern.

Nursing considerations

These findings have important implications for oncology nursing practice. They emphasize that supportive care medications, even those often considered benign, can meaningfully influence cancer outcomes. In this analysis, many patients appeared to receive PPIs prophylactically without any documented gastrointestinal symptoms such as heartburn, gastritis, or a history of ulcers, suggesting that routine prescribing may not always be necessary. For example, a patient with glioblastoma receiving high-dose corticosteroids for cerebral edema might be started on a PPI automatically, even if they have no prior gastrointestinal complaints. Given the emerging evidence linking certain PPIs to worse progression-free and overall survival, oncology nurses play a key role in reassessing the need for these medications. Routine PPI use for steroid-associated gastric protection should be carefully reconsidered with attention to each patient’s individual risk factors. When gastric prophylaxis is indicated, alternative options such as H2 receptor antagonists like famotidine or locally acting antacids may provide effective protection with potentially lower risk.

References

1. Shanika LGT, Reynolds A, Pattison S, Braund R. Proton pump inhibitor use: systematic review of global trends and practices. Eur J Clin Pharmacol. 2023;79(9):1159-1172. doi:10.1007/s00228-023-03534-z
2. Le Rhun E, Sain D, Erridge SC, et al. Proton Pump Inhibitor Use and Survival in Patients With Newly Diagnosed Glioblastoma. JAMA Netw Open. 2025;8(11):e2545578. Published 2025 Nov 3. doi:10.1001/jamanetworkopen.2025.45578