The Association between Baseline Proton Pump Inhibitors, Immune Checkpoint Inhibitors, and Chemotherapy: A Systematic Review with Network Meta-Analysis

Abstract

(1) Although emerging evidence suggests that proton pump inhibitor (PPI)-induced dysbiosis negatively alters treatment response to immune checkpoint inhibitors (ICIs) in cancer patients, no study systematically investigates the association between PPIs, ICIs, and chemotherapy; (2) Cochrane Library, Embase, Medline, and PubMed were searched from inception to 20 May 2022, to identify relevant studies involving patients receiving ICIs or chemotherapy and reporting survival outcome between PPI users and non-users. Survival outcomes included overall survival (OS) and progression-free survival (PFS). Network meta-analyses were performed using random-effects models. p-scores, with a value between 0 and 1, were calculated to quantify the treatment ranking, with a higher score suggesting a higher probability of greater effectiveness. We also conducted pairwise meta-analyses of observational studies to complement our network meta-analysis; (3) We identified 62 studies involving 26,484 patients (PPI = 8834; non-PPI = 17,650), including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC), melanoma, renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and squamous cell carcinoma (SCC) of the neck and head. Eight post-hoc analyses from 18 randomized–controlled trials were included in our network, which demonstrated that, in advanced NSCLC and UC, patients under ICI treatment with concomitant PPI (p-score: 0.2016) are associated with both poorer OS (HR, 1.49; 95% CI, 1.37 to 1.67) and poorer PFS (HR, 1.41; 95% CI, 1.25 to 1.61) than those without PPIs (p-score: 1.000). Patients under ICI treatment with concomitant PPI also had poorer OS (HR, 1.18; 95% CI, 1.07 to 1.31) and poorer PFS (HR, 1.30; 95% CI, 1.14 to 1.48) in comparison with those receiving chemotherapy (p-score: 0.6664), implying that PPIs may compromise ICI’s effectiveness, making it less effective than chemotherapy. Our pairwise meta-analyses also supported this association. Conversely, PPI has little effect on patients with advanced melanoma, RCC, HCC, and SCC of the neck and head who were treated with ICIs; (4) “PPI-induced dysbiosis” serves as a significant modifier of treatment response in both advanced NSCLC and UC that are treated with ICIs, compromising the effectiveness of ICIs to be less than that of chemotherapy. Thus, clinicians should avoid unnecessary PPI prescription in these patients. “PPI-induced dysbiosis”, on the other hand, does not alter the treatment response to ICIs in advanced melanoma, RCC, HCC, and SCC of the head and neck.

Proton Pump Inhibitors and Cancer Risk: A Comprehensive Review of Epidemiological and Mechanistic Evidence

“…Considering the inconsistent findings, the antitumor effect of PPIs is more likely to be derived from a combination of factors such as cancer type and stage, as well as concomitant drug therapy [48]. Thus, until a clear pattern emerges, caution should be applied when administering PPIs and systemic antitumor therapy.…”

Stress pathway outputs are encoded by pH-dependent phase separation of its components

“…More broadly, the hallmark inversion of the pH gradient in cancer cells suggest that inhibitors of proton pumps and exchangers may improve chemosensitivity of tumours 52 . However, trials have returned mixed results with adverse patient outcomes reported when proton pump inhibitors were combined with kinasetargeting drugs or immune-checkpoint inhibitors 53,54 . While this is in part due to drug-drug interactions 55 , an improved understanding of the association between increased pHi and kinase signal regulation of cancer progression appears to be necessary to optimize pHi targeting as a therapeutic strategy.…”

Prognostic and Predictive Biomarkers in the Era of Immunotherapy for Lung Cancer

“…In the past few years, drug-drug interaction between ICIs, antibiotics (ATB), and proton-pump inhibitors (PPI) have been raised. The majority of publications are retrospective studies, but a meta-analysis seems to demonstrate a negative impact of this medication on ICIs' outcomes [136,137]. The decrease in overall survival and progression-free survival by ATB and PPI would probably result from the balance between the gut microbiota and immune checkpoint inhibitors.…”