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Table 1.  Demographic and Clinical Characteristics of Patients With Cancer by PPI Use
Demographic and Clinical Characteristics of Patients With Cancer by PPI Use
Table 2.  Prevalence of PPI Use per Treatment Most Frequently Received
Prevalence of PPI Use per Treatment Most Frequently Received
1.
Sharma  M, Holmes  HM, Mehta  HB,  et al.  The concomitant use of tyrosine kinase inhibitors and proton pump inhibitors: prevalence, predictors, and impact on survival and discontinuation of therapy in older adults with cancer.   Cancer. 2019;125(7):1155-1162. doi:10.1002/cncr.31917PubMedGoogle ScholarCrossref
2.
Mir  O, Touati  N, Lia  M,  et al.  Impact of concomitant administration of gastric acid-suppressive agents and pazopanib on outcomes in soft-tissue sarcoma patients treated within the EORTC 62043/62072 trials.   Clin Cancer Res. 2019;25(5):1479-1485. doi:10.1158/1078-0432.CCR-18-2748PubMedGoogle ScholarCrossref
3.
Chu  MP, Hecht  JR, Slamon  D,  et al.  Association of proton pump inhibitors and capecitabine efficacy in advanced gastroesophageal cancer: secondary analysis of the TRIO-013/LOGiC randomized clinical trial.   JAMA Oncol. 2017;3(6):767-773. doi:10.1001/jamaoncol.2016.3358PubMedGoogle ScholarCrossref
4.
Chalabi  M, Cardona  A, Nagarkar  DR,  et al; imCORE Working Group of Early Career Investigators.  Efficacy of chemotherapy and atezolizumab in patients with non-small-cell lung cancer receiving antibiotics and proton pump inhibitors: pooled post hoc analyses of the OAK and POPLAR trials.   Ann Oncol. 2020;31(4):525-531. doi:10.1016/j.annonc.2020.01.006PubMedGoogle ScholarCrossref
5.
Raoul  JL, Edeline  J, Gilabert  M, Senellart  H, Frenel  JS.  Proton pump inhibitors and cancers: a hazardous association? [in French].   Bull Cancer. 2020;107(4):458-464. doi:10.1016/j.bulcan.2019.12.009PubMedGoogle ScholarCrossref
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    Research Letter
    Oncology
    June 16, 2021

    Prevalence of Proton Pump Inhibitor Use Among Patients With Cancer

    Author Affiliations
    • 1Department of Medical Oncology, Institut de Cancérologie de l’Ouest, Saint-Herblain, France
    • 2Oncology Data Factory & Analytics, Institut de Cancérologie de l’Ouest, Saint-Herblain, France
    • 3Department of Medical Oncology, Institut Centre E. Maquis, Rennes, France
    • 4Department of Medical Oncology, Institut de Cancérologie de l’Ouest, Angers, France
    • 5Department of Medical Oncology, Institut Paoli-Calmettes, Marseille, France
    JAMA Netw Open. 2021;4(6):e2113739. doi:10.1001/jamanetworkopen.2021.13739
    Introduction

    The cancer armamentarium is evolving with evidence of the efficacy of oral treatments. Their mode of administration is simple and convenient, but absorption is influenced by diet and gastric pH. Moreover, the efficacy of checkpoint inhibitors (CPIs) depends on the gut microbiome. Proton pump inhibitors (PPIs), which are among the most widely prescribed drugs, decrease the bioavailability of oral cancer treatments, lowering their efficacy,1-4 and induce major microbial alterations in the gut.4 We conducted a study to evaluate the prevalence of PPI prescribing, to identify the factors associated with PPI prescription, and to focus on patients receiving tyrosine kinase inhibitors (TKIs), CPIs, and capecitabine.

    Methods

    This cross-sectional study was conducted in 4 French Comprehensive Cancer Centers from June 15 to 19 and from June 22 to 26, 2020. It was approved by the ethics committee of Angers University, which waived the need for informed consent in accordance with university policy. This study follows the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

    Volunteer physicians collected data from patients with cancer seen in consultation or in the Same Day Unit. An information sheet (explaining the goals of the study, that patients could refuse to participate, and that all data would be anonymized) was given to patients; those who accepted were included. The physicians then completed a form (with scrolling menu) based on the patient’s medical records and answers to a few questions.

    Parameters were compared using Welch t test, χ2 test, or Fisher exact test as appropriate. Significant parameters were entered into a multivariable logistic regression with a stepwise procedure. All P values were 2-sided with P < .05 considered significant. Statistical analyses were performed with R statistical software version 4.0.2 (R Project for Statistical Computing).

    Results

    In total, 872 complete and verified (data manager) forms corresponding to 566 women (64.9%) and 306 men (35.1%) (median [range] age, 63 [20-91] years) (Table 1) were recorded. Among these, 229 patients (26.3%) were taking PPIs on the day of inclusion. Most patients who used PPIs did so on a regular basis (163 patients [71.1%]), at normal dosage (154 patients [67.2%]), for epigastric pain (114 patients [50.0%]), retrosternal pain (32 patients [14.0%]), proven esophageal or gastric ulcer (18 patients [8.0%]), or gastroprotection (34 patients [15.0%]).

    In univariable and multivariable analyses, the factors associated with PPI use were age (odds ratio [OR], 1.02 [95% CI, 1.00-1.03]; P < .001), center (reference, Rennes; Angers: OR, 2.10 [95% CI, 1.04-4.23]; Nantes: OR, 1.51 [95% CI, 0.94-2.53]; Marseille: OR, 3.49 [95% CI, 1.71-7.22]; P < .001), Eastern Cooperative Oncology Group performance status (PS) (reference, PS 0; PS 1: OR, 1.92 [95% CI, 1.36-2.72]; PS 2: OR, 2.51 [95% CI, 1.41-4.45]; PS 3: OR, 2.33 [95% CI, 0.32-12.33]; P < .001), hormone treatment (OR, 0.59; 95% CI, 0.37-0.90; P = .01), metastatic stage (χ22 = 7.42; P = .03), and tumor site (P = .045, Fisher exact test). The prevalence of concomitant PPI use differed with the cancer treatments (Table 2). Among the 20 patients taking TKIs and PPIs, 16 reported the long-term use of PPIs, mainly for epigastric pain (11 patients). If we focus on the 134 patients receiving drugs known to decline in efficacy when given with PPIs, 39 (29%) had concomitant prescriptions: capecitabine (5 of 21 patients), sunitinib (5 of 9 patients), cabozantinib (2 of 3 patients), pazopanib (1 of 5 patients), gefitinib (1 of 1 patient), erlotinib (1 of 2 patients), and sorafenib (1 of 3 patients), as well as 23 of 90 patients (25.6%) receiving CPIs.

    Discussion

    In this cross-sectional study, more than one-quarter of the patients (predominantly older with poorer PS) used PPIs. Almost one-third of those treated with drugs suspected to have altered efficacy if taken concomitantly with PPIs received PPIs.

    This study has some limitations. Not all physicians agreed to participate and did not include all patients seen (data collection was time-consuming). However, the study was prospective, with no major bias, and included many patients (872 patients). The high frequency of PPI use in Marseille may be associated with the fact that the participating physicians were largely treating pancreatic adenocarcinomas.

    The long-term use of PPIs is a problem in the population of patients with cancer, who may have various comorbidities, such as kidney dysfunction, anemia, infection, or hypomagnesemia.5 Moreover, indirect drug-drug interactions (eg, lower absorption of TKIs and capecitabine and gut microbiome changes) are associated with a decrease in survival benefit for some of these drugs.1-4 PPIs should be actively identified and substituted. In the case of heartburn or epigastric pain, antacids should be used; H2 antagonists are another option. TKIs must be taken 2 hours before or 10 hours after H2 antagonists. If PPI use is mandatory, TKIs must be given in the morning 2 hours before PPIs, or with an acidic beverage (eg, cola). For patients taking CPIs, the use of antacids is the best option.

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    Article Information

    Accepted for Publication: April 16, 2021.

    Published: June 16, 2021. doi:10.1001/jamanetworkopen.2021.13739

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Raoul JL et al. JAMA Network Open.

    Corresponding Author: Jean-Luc Raoul, MD, PhD, Department of Medical Oncology, Institut de Cancérologie de l’Ouest, Bd J Monod, 44805 Saint-Herblain, France (jean-luc.raoul@ico.unicancer.fr).

    Author Contributions: Dr Raoul had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Raoul, Gilabert, Frenel.

    Acquisition, analysis, or interpretation of data: Guérin-Charbonnel, Edeline, Simmet, Gilabert, Frenel.

    Drafting of the manuscript: All authors.

    Critical revision of the manuscript for important intellectual content: Edeline, Simmet, Gilabert, Frenel.

    Statistical analysis: Guérin-Charbonnel, Frenel.

    Administrative, technical, or material support: Raoul.

    Supervision: Raoul, Simmet, Frenel.

    Conflict of Interest Disclosures: Dr Raoul reported receiving personal fees from Bayer, Merck, and Transgene. Dr Edeline reported receiving grants from Beigene and personal fees from BMS, MSD, AstraZeneca, Roche, Bayer, Eisai, Ipsen, and Boston Scientific outside the submitted work. Dr Gilabert reported receiving personal fees from Amgen, Roche, AstraZeneca, Bayer, Merck, and Celgene. Dr Frenel reported serving on the boards of Roche, AstraZeneca, Eli Lilly, Pfizer, Daiichi, Novartis, and GSK outside the submitted work. No other disclosures were reported.

    Additional Contributions: The physicians and dedicated nurses who helped collect data for this analysis include P. Augereau, MD, E. Boughalem, MD, and P. Trémolières (Institut de Cancérologie de l’Ouest, Angers site); B. Chanez, MD (Institut Paoli-Calmettes, Marseille); A.L. Bedel, MD, D. Berton, MD, C. Blonz, MD, E. Bompas, MD, E. Bourbouloux, MD, M. Campone, MD, PhD, C. Colliard, MD, L. Doucet, MD, C. Forestier, Mss, S. Hiret, MD, A. Hospital, MD, E. Jouglar, MD, S. Le Henaff, MD, C. Moreau-Bachelard, MD, L. Peuvrel, MD, F. Pineau, Mss, J. Raimbourg, MD, F. Rolland, MD, M. Saint-Jean, MD, H. Senellart, MD, and D. Vansteene, MD (Institut de Cancérologie de l’Ouest, Nantes–Saint-Herblain site); and H. Bourien, MD, B. Boutruche, MD, L. Crouzet, MD, V. Diéras, MD, F. Le Du, MD, M. Pracht, MD, PhD, and E. Vauléon, MD (Centre Eugène Marquis, Rennes). They were not compensated for their contributions beyond their normal salaries.

    References
    1.
    Sharma  M, Holmes  HM, Mehta  HB,  et al.  The concomitant use of tyrosine kinase inhibitors and proton pump inhibitors: prevalence, predictors, and impact on survival and discontinuation of therapy in older adults with cancer.   Cancer. 2019;125(7):1155-1162. doi:10.1002/cncr.31917PubMedGoogle ScholarCrossref
    2.
    Mir  O, Touati  N, Lia  M,  et al.  Impact of concomitant administration of gastric acid-suppressive agents and pazopanib on outcomes in soft-tissue sarcoma patients treated within the EORTC 62043/62072 trials.   Clin Cancer Res. 2019;25(5):1479-1485. doi:10.1158/1078-0432.CCR-18-2748PubMedGoogle ScholarCrossref
    3.
    Chu  MP, Hecht  JR, Slamon  D,  et al.  Association of proton pump inhibitors and capecitabine efficacy in advanced gastroesophageal cancer: secondary analysis of the TRIO-013/LOGiC randomized clinical trial.   JAMA Oncol. 2017;3(6):767-773. doi:10.1001/jamaoncol.2016.3358PubMedGoogle ScholarCrossref
    4.
    Chalabi  M, Cardona  A, Nagarkar  DR,  et al; imCORE Working Group of Early Career Investigators.  Efficacy of chemotherapy and atezolizumab in patients with non-small-cell lung cancer receiving antibiotics and proton pump inhibitors: pooled post hoc analyses of the OAK and POPLAR trials.   Ann Oncol. 2020;31(4):525-531. doi:10.1016/j.annonc.2020.01.006PubMedGoogle ScholarCrossref
    5.
    Raoul  JL, Edeline  J, Gilabert  M, Senellart  H, Frenel  JS.  Proton pump inhibitors and cancers: a hazardous association? [in French].   Bull Cancer. 2020;107(4):458-464. doi:10.1016/j.bulcan.2019.12.009PubMedGoogle ScholarCrossref
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