Proton Pump Inhibitors and Survival in Patients With Colorectal Cancer Receiving Fluoropyrimidine-Based Chemotherapy

Authors: Ganessan Kichenadasse MBBS, FRACP1,2, John O. Miners PhD1, Arduino A. Mangoni MBBS, PhD, FRACP1, Christos S. Karapetis MBBS, FRACP2, Ashley M. Hopkins PhD1, and Michael J. Sorich PhD1
View More View Less
  • 1 Department of Clinical Pharmacology, College of Medicine and Public Health, and
  • | 2 Department of Medical Oncology, Flinders Centre for Innovation in Cancer, Flinders Medical Centre/Flinders University, Bedford Park, South Australia, Australia.

Background: Concomitant use of proton pump inhibitors (PPIs) may negatively affect the efficacy of anticancer drugs such as fluoropyrimidines in patients with colorectal cancer (CRC). The primary objective of this study was to assess whether there is an association between concomitant PPI use and survival outcomes in patients with CRC treated with a fluoropyrimidine-based chemotherapy. Patients and Methods: A secondary analysis of 6 randomized controlled clinical trials in patients with advanced CRC was conducted using individual patient data through data-sharing platforms. The outcome measures were progression-free survival and overall survival in PPI users and nonusers. Subgroup analysis included the type of chemotherapy, capecitabine versus 5-FU, line of therapy, and addition of a vascular endothelial growth factor receptor inhibitor. Overall pooled hazard ratios (HRs) with 95% confidence intervals were calculated using a random effects model. Results: A total of 5,594 patients with advanced CRC across 6 trials and 11 trial arms were included; 902 patients were receiving a PPI at trial entry and initiation of chemotherapy. PPI use was significantly associated with worse overall survival (pooled HR, 1.20; 95% CI, 1.03–1.40; P=.02; I2 for heterogeneity = 69%) and progression-free survival (overall pooled HR, 1.20; 95% CI, 1.05–1.37; P=.009; I2 = 65%) after adjusting for clinical covariates. Furthermore, the association between concomitant PPI use and survival outcomes was similar across most treatment subgroups. Conclusions: We speculate that alterations in the gut microbiome, altered immune milieu within the tumor, and interactions through transporters are potential mechanisms behind this association between PPI use and chemotherapy in patients with CRC, which warrant further study. Concomitant use of PPIs is associated with worse survival outcomes in patients with CRC treated with fluoropyrimidine-based chemotherapy. Clinicians should cautiously consider the concomitant use of PPIs in such patients.

Submitted June 7, 2020; final revision received September 20, 2020; accepted for publication October 12, 2020.

Published online May 5, 2021.

Author contributions: Study concept and design: Kichenadasse, Hopkins, Sorich. Data acquisition: Hopkins, Sorich. Data analysis and interpretation: All authors. Statistical analysis: Kichenadasse. Funding acquisition: Hopkins, Sorich.Technical/Material support: Miners, Mangoni, Hopkins. Supervision: Miners, Mangoni, Hopkins, Sorich. Manuscript preparation: All authors. Critical revision for intellectual content: All authors.

Disclosures: Dr. Karapetis has reported serving on the advisory board of Merck Serono, MSD, Bristol Myers Squibb, Roche, and AstraZeneca. Dr. Sorich has reported receiving grant/research support from Pfizer. The remaining authors have reported that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: This work was supported by funding from Cancer Council South Australia (1159924 and 1127220 to M.J. Sorich) and from the National Breast Cancer Foundation (PF-17-007 to A.M. Hopkins).

Correspondence: Ganessan Kichenadasse, MBBS, FRACP, Department of Medical Oncology, Flinders Centre for Innovation in Cancer, Flinders Medical Centre/Flinders University, Bedford Park, South Australia 5042, Australia. Email: ganessan.kichenadasse@flinders.edu.au

Supplementary Materials

    • Supplemental Materials (PDF 1.02 MB)
  • 1.

    Smelick GS, Heffron TP, Chu L, et al. Prevalence of acid-reducing agents (ARA) in cancer populations and ARA drug-drug interaction potential for molecular targeted agents in clinical development. Mol Pharm 2013;10:40554062.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Schoenfeld AJ, Grady D. Adverse effects associated with proton pump inhibitors. JAMA Intern Med 2016;176:172174.

  • 3.

    Xie Y, Bowe B, Yan Y, et al. Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study. BMJ 2019;365:I1580.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Bellone M, Calcinotto A, Filipazzi P, et al. The acidity of the tumor microenvironment is a mechanism of immune escape that can be overcome by proton pump inhibitors. OncoImmunology 2013;2:e22058.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Ikemura K, Hiramatsu S, Okuda M. Drug repositioning of proton pump inhibitors for enhanced efficacy and safety of cancer chemotherapy. Front Pharmacol 2017;8:911.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Lugini L, Federici C, Borghi M, et al. Proton pump inhibitors while belonging to the same family of generic drugs show different anti-tumor effect. J Enzyme Inhib Med Chem 2016;31:538545.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Pilon-Thomas S, Kodumudi KN, El-Kenawi AE, et al. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res 2016;76:13811390.

  • 8.

    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;125:11551162.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    van Leeuwen RWF, Jansman FGA, Hunfeld NG, et al. Tyrosine kinase inhibitors and proton pump inhibitors: an evaluation of treatment options. Clin Pharmacokinet 2017;56:683688.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    van Leeuwen RW, van Gelder T, Mathijssen RH, et al. Drug-drug interactions with tyrosine-kinase inhibitors: a clinical perspective. Lancet Oncol 2014;15:e315326.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Hussaarts KGAM, Veerman GDM, Jansman FGA, et al. Clinically relevant drug interactions with multikinase inhibitors: a review. Ther Adv Med Oncol 2019;11:1758835918818347.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Wedemeyer RS, Blume H. Pharmacokinetic drug interaction profiles of proton pump inhibitors: an update. Drug Saf 2014;37:201211.

  • 13.

    Altundag K. Coadministration of proton pump inhibitors may decrease the efficacy of capecitabine in metastatic breast cancer patients. J BUON 2017;22:559560.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    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;3:767773.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Graham C, Orr C, Bricks CS, et al. A retrospective analysis of the role of proton pump inhibitors in colorectal cancer disease survival. Curr Oncol 2016;23:e583588.

  • 16.

    Rhinehart HE, Phillips MA, Wade N, et al. Evaluation of the clinical impact of concomitant acid suppression therapy in colorectal cancer patients treated with capecitabine monotherapy. J Oncol Pharm Pract 2019;25:18391845.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Sun J, Ilich AI, Kim CA, et al. Concomitant administration of proton pump inhibitors and capecitabine is associated with increased recurrence risk in early stage colorectal cancer patients. Clin Colorectal Cancer 2016;15:257263.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Wong GG, Ha V, Chu MP, et al. Effects of proton pump inhibitors on FOLFOX and CapeOx regimens in colorectal cancer. Clin Colorectal Cancer 2019;18:7279.

  • 19.

    Cheng V, Lemos M, Hunter N, et al. Concomitant use of capecitabine and proton pump inhibitors – is it safe? J Oncol Pharm Pract 2019;25:17051711.

  • 20.

    Project Data Sphere. Project Data Sphere’s Data Sharing Platform. Accessed December 20, 2019. Available at: https://www.projectdatasphere.org/projectdatasphere/html/home

    • Search Google Scholar
    • Export Citation
  • 21.

    ClinicalStudyDataRequest.com. Accessed December 20, 2019. Available at: https://www.clinicalstudydatarequest.com/Default.aspx

  • 22.

    Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:23352342.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Carrato A, Swieboda-Sadlej A, Staszewska-Skurczynska M, et al. Fluorouracil, leucovorin, and irinotecan plus either sunitinib or placebo in metastatic colorectal cancer: a randomized, phase III trial. J Clin Oncol 2013;31:13411347.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Schmoll HJ, Cunningham D, Sobrero A, et al. Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III). J Clin Oncol 2012;30:35883595.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Van Cutsem E, Tabernero J, Lakomy R, et al. Addition of aflibercept to fluorouracil, leucovorin, and irinotecan improves survival in a phase III randomized trial in patients with metastatic colorectal cancer previously treated with an oxaliplatin-based regimen. J Clin Oncol 2012;30:34993506.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Saltz LB, Clarke S, Díaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26:20132019.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Tabernero J, Yoshino T, Cohn AL, et al. Ramucirumab versus placebo in combination with second-line FOLFIRI in patients with metastatic colorectal carcinoma that progressed during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine (RAISE): a randomised, double-blind, multicentre, phase 3 study. Lancet Oncol 2015;16:499508.

    • Search Google Scholar
    • Export Citation
  • 28.

    Altundag K. Coadministration of proton pump inhibitors and the efficacy of capecitabine in patients with advanced adenocarcinoma of the small bowel or ampulla of vater [letter]. Cancer 2017;123:1074.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Wang X, Liu C, Wang J, et al. Proton pump inhibitors increase the chemosensitivity of patients with advanced colorectal cancer. Oncotarget 2017;8:5880158808.

  • 30.

    Duncan JR, Penman ID, Plumb J, et al. Omeprazole is not cytotoxic to colorectal cancer cells in vitro [abstract]. Gastroenterology 2000;118:Abstract A1386.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Nies AT, Hofmann U, Resch C, et al. Proton pump inhibitors inhibit metformin uptake by organic cation transporters (OCTs). PLoS One 2011;6:e22163.

  • 32.

    Han X, Quinney SK, Wang Z, et al. Identification and mechanistic investigation of drug-drug interactions associated with myopathy: a translational approach. Clin Pharmacol Ther 2015;98:321327.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Redzic ZB, Hasan FA, Al-Sarraf H. Effects of omeprazole treatment on nucleoside transporter expression and adenosine uptake in rat gastric mucosa. Can J Physiol Pharmacol 2009;87:402410.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Phua LC, Mal M, Koh PK, et al. Investigating the role of nucleoside transporters in the resistance of colorectal cancer to 5-fluorouracil therapy. Cancer Chemother Pharmacol 2013;71:817823.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Kobayashi K, Bouscarel B, Matsuzaki Y, et al. pH-dependent uptake of irinotecan and its active metabolite, SN-38, by intestinal cells. Int J Cancer 1999;83:491496.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    van der Bol JM, Loos WJ, de Jong FA, et al. Effect of omeprazole on the pharmacokinetics and toxicities of irinotecan in cancer patients: a prospective cross-over drug-drug interaction study. Eur J Cancer 2011;47:831838.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 37.

    Imhann F, Bonder MJ, Vich Vila A, et al. Proton pump inhibitors affect the gut microbiome. Gut 2016;65:740748.

  • 38.

    Biswas S, Benedict SH, Lynch SG, et al. Potential immunological consequences of pharmacological suppression of gastric acid production in patients with multiple sclerosis. BMC Med 2012;10:57.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Macke L, Schulz C, Koletzko L, et al. Systematic review: the effects of proton pump inhibitors on the microbiome of the digestive tract-evidence from next-generation sequencing studies. Aliment Pharmacol Ther 2020;51:505526.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Wong SH, Yu J. Gut microbiota in colorectal cancer: mechanisms of action and clinical applications. Nat Rev Gastroenterol Hepatol 2019;16:690704.

  • 41.

    Haller DG, Cassidy J, Clarke SJ, et al. Potential regional differences for the tolerability profiles of fluoropyrimidines. J Clin Oncol 2008;26:21182123.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 869 869 869
PDF Downloads 556 556 556
EPUB Downloads 0 0 0