Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Epidemiology

Proton pump inhibitors and survival in patients with colorectal cancer: a Swedish population-based cohort study

Abstract

Background

Proton pump inhibitors (PPIs) are associated with microbiome changes of the gut, which in turn may affect the progression of colorectal cancer (CRC). This study aims to assess the associations between PPI use and all-cause and CRC-specific mortality.

Methods

We selected all patients registered in the Swedish Prescribed Drug Registry who were diagnosed with CRC between 2006 and 2012 (N = 32,411, 54.9% PPI users) and subsequently followed them through register linkage to the Swedish Causes of Death Registry until December 2013. PPI users were patients with ≥1 post-diagnosis PPI dispensation. Time-dependent Cox-regression models were performed with PPI use as time-varying exposure.

Results

Overall 4746 (14.0%) patients died, with an aHR of 1.38 (95% CI 1.32–1.44) for all-cause mortality comparing PPI users with PPI nonusers. Higher-magnitude associations were observed among male, cancer stage 0−I, rectal cancer and patients receiving CRC surgery. The PPI-all-cause mortality association was also more pronounced comparing new users to non-users (aHR = 1.47, 95%CI 1.40–1.55) than comparing continuous users to non-users (aHR = 1.32, 95%CI 1.24–1.39). The risk estimates for CRC-specific mortality comparing PPI users to PPI nonusers were similar to those for all-cause mortality.

Conclusion

PPI use after the CRC diagnosis was associated with increased all-cause and CRC-specific mortality.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Timing of the use of proton pump inhibitors (PPIs) in relation to the diagnosis of colorectal cancer (CRC).

Data availability

Data used for this study cannot be shared, but the original data from the registries can be obtained by application to Swedish National Board of Health and Welfare.

References

  1. 1.

    Hálfdánarson ÓÖ, Pottegård A, Björnsson ES, Lund SH, Ogmundsdottir MH, Steingrímsson E, et al. Proton-pump inhibitors among adults: a nationwide drug-utilization study. Ther Adv Gastroenterol. 2018;11:175628481877794.

    Article  CAS  Google Scholar 

  2. 2.

    Lassalle M, Le Tri T, Bardou M, Biour M, Kirchgesner J, Rouby F, et al. Use of proton pump inhibitors in adults in France: a nationwide drug utilization study. Eur J Clin Pharmacol. 2020;76:449–57.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Daniels B, Pearson S-A, Buckley NA, Bruno C, Zoega H. Long-term use of proton-pump inhibitors: whole-of-population patterns in Australia 2013–2016. Ther Adv Gastroenterol. 2020;13:175628482091374.

    Article  CAS  Google Scholar 

  4. 4.

    Savarino V, Dulbecco P, de Bortoli N, Ottonello A, Savarino E. The appropriate use of proton pump inhibitors (PPIs): Need for a reappraisal. Eur J Intern Med. 2017;37:19–24.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Freedberg DE, Kim LS, Yang Y-X. The risks and benefits of long-term use of proton pump inhibitors: expert review and best practice advice from the American Gastroenterological Association. Gastroenterology. 2017;152:706–15.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Imhann F, Bonder MJ, Vich Vila A, Fu J, Mujagic Z, Vork L, et al. Proton pump inhibitors affect the gut microbiome. Gut. 2016;65:740–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Saus E, Iraola-Guzmán S, Willis JR, Brunet-Vega A, Gabaldón T. Microbiome and colorectal cancer: roles in carcinogenesis and clinical potential. Mol Asp Med. 2019;69:93–106.

    CAS  Article  Google Scholar 

  8. 8.

    Robertson DJ, Larsson H, Friis S, Pedersen L, Baron JA, Sørensen HT. Proton pump inhibitor use and risk of colorectal cancer: a population-based, case–control study. Gastroenterology. 2007;133:755–60.

    PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Lei W-Y, Wang J-H, Yi C-H, Liu T-T, Hung J-S, Wong M-W, et al. Association between use of proton pump inhibitors and colorectal cancer: a nationwide population-based study. Clin Res Hepatol Gastroenterol. 2021;45:101397.

  10. 10.

    Hwang IC, Chang J, Park SM. Emerging hazard effects of proton pump inhibitor on the risk of colorectal cancer in low-risk populations: a Korean nationwide prospective cohort study. PLoS ONE. 2017;12:e0189114.

  11. 11.

    Chubak J, Boudreau DM, Rulyak SJ, Mandelson MT. Colorectal cancer risk in relation to use of acid suppressive medications. Pharmacoepidemiol Drug Saf. 2009;18:540–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Siersema PD, Yu S, Sahbaie P, Steyerberg EW, Simpson PW, Kuipers EJ, et al. Colorectal neoplasia in veterans is associated with Barrett’s esophagus but not with proton-pump inhibitor or aspirin/NSAID use. Gastrointest Endosc. 2006;63:581–6.

    PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Yang Y, Hennessy S, Propert K, Hwang W, Sedarat A, Lewis JD. Chronic proton pump inhibitor therapy and the risk of colorectal cancer. Gastroenterology. 2007;133:748–54.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Lee JK, Merchant SA, Schneider JL, Jensen CD, Fireman BH, Quesenberry CP, et al. Proton pump inhibitor use and risk of gastric, colorectal, liver, and pancreatic cancers in a community-based population. Am J Gastroenterol. 2020;115:706–15.

  15. 15.

    van Soest EM, van Rossum LGM, Dieleman JP, van Oijen MGH, Siersema PD, Sturkenboom MCJM, et al. Proton pump inhibitors and the risk of colorectal cancer. Am J Gastroenterol. 2008;103:966–73.

    PubMed  Article  PubMed Central  Google Scholar 

  16. 16.

    Graham C, Orr C, Bricks CS, Hopman WM, Hammad N, Ramjeesingh R. A retrospective analysis of the role of proton pump inhibitors in colorectal cancer disease survival. Curr Oncol. 2016;23:583.

    Article  Google Scholar 

  17. 17.

    Tvingsholm SA, Dehlendorff C, Østerlind K, Friis S, Jäättelä M. Proton pump inhibitor use and cancer mortality. Int J Cancer. 2018;143:1315–26.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Brusselaers N, Wahlin K, Engstrand L, Lagergren J. Maintenance therapy with proton pump inhibitors and risk of gastric cancer: a nationwide population-based cohort study in Sweden. BMJ Open. 2017;7:e017739.

    PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Brusselaers N, Tamimi RM, Konings P, Rosner B, Adami H-O, Lagergren J. Different menopausal hormone regimens and risk of breast cancer. Ann Oncol. 2018;29:1771–6.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Ma Y, Brusselaers N. Maintenance use of aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs) and prostate cancer risk. Prostate Cancer Prostatic Dis. 2018;21:147–52.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Doorakkers E, Lagergren J, Engstrand L, Brusselaers N. Helicobacter pylori eradication treatment and the risk of gastric adenocarcinoma in a Western population. Gut. 2018;67:2092–6.

    PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Brusselaers N, Lagergren J, Engstrand L. Duration of use of proton pump inhibitors and the risk of gastric and oesophageal cancer. Cancer Epidemiol. 2019;62:101585.

    PubMed  Article  PubMed Central  Google Scholar 

  23. 23.

    Loikas D, Wettermark B, von Euler M, Bergman U, Schenck-Gustafsson K. Differences in drug utilisation between men and women: a cross-sectional analysis of all dispensed drugs in Sweden. BMJ Open. 2013;3:e002378.

    PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Suissa S. Immortal time bias in pharmacoepidemiology. Am J Epidemiol. 2008;167:492–9. 7

    PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Pottegård A, Friis S, Stürmer T, Hallas J, Bahmanyar S. Considerations for pharmacoepidemiological studies of drug-cancer associations. Basic Clin Pharm Toxicol. 2018;122:451–9.

    Article  CAS  Google Scholar 

  26. 26.

    Pottegård A, Hallas J. New use of prescription drugs prior to a cancer diagnosis: use of prescription drugs prior to cancer diagnosis. Pharmacoepidemiol Drug Saf. 2017;26:223–7.

    PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Tamim H, Monfared AAT, LeLorier J. Application of lag-time into exposure definitions to control for protopathic bias. Pharmacoepidemiol Drug Saf. 2007;16:250–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Brooke HL, Talbäck M, Hörnblad J, Johansson LA, Ludvigsson JF, Druid H, et al. The Swedish cause of death register. Eur J Epidemiol. 2017;32:765–73.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Barlow L, Westergren K, Holmberg L, Talbäck M. The completeness of the Swedish Cancer Register—a sample survey for year 1998. Acta Oncol. 2009;48:27–33.

    PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    Greene FL, Page DL, Fleming ID, Fritz A, Balch CM, Haller DG, et al. AJCC cancer staging manual. 6th. American Joint Committee on Cancer. 2002.

  31. 31.

    Nordic Medico-Statistical Committee. NOMESCO classification of surgical procedures (NCSP). Copenhagen: Nordic Medico-Statistical Committee, 2011.

  32. 32.

    Bastiaannet E, Sampieri K, Dekkers OM, de Craen AJM, van Herk-Sukel MPP, Lemmens V, et al. Use of Aspirin postdiagnosis improves survival for colon cancer patients. Br J Cancer 2012;106:1564–70.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Din FVN, Theodoratou E, Farrington SM, Tenesa A, Barnetson RA, Cetnarskyj R, et al. Effect of aspirin and NSAIDs on risk and survival from colorectal cancer. Gut. 2010;59:1670–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Flossmann E, Rothwell PM. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet 2007;369:1603–13.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40:373–83.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Sadr-Azodi O, Oskarsson V, Discacciati A, Videhult P, Askling J, Ekbom A. Pancreatic cancer following acute pancreatitis: a population-based Matched Cohort Study. Am J Gastroenterol. 2018;113:1711–9.

  37. 37.

    Tamim H, Monfared AT, LeLorier J. Application of lag‐time into exposure definitions to control for protopathic bias. Pharmacoepidemiol. Drug Saf. 2007;16:250–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    Kearns MD, Boursi B, Yang Y-X. Proton pump inhibitors on pancreatic cancer risk and survival. Cancer Epidemiol. 2017;46:80–4.

    PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Ayyagari S, Tan MC, Liu Y, El-Serag HB, Thrift AP. Use of acid-suppressant medications after diagnosis increases mortality in a subset of gastrointestinal cancer patients. Dig. Dis. Sci. 2020;65:2691–9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  40. 40.

    Xie Y, Bowe B, Yan Y, Xian H, Li T, Al-Aly Z. Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study. BMJ. 2019;29:l1580.

    Article  Google Scholar 

  41. 41.

    Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB. Colorectal cancer. Lancet 2019;394:1467–80.

    PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of colorectal cancer. JAMA. 2009;302:649–58.

  43. 43.

    Freedberg DE, Toussaint NC, Chen SP, Ratner AJ, Whittier S, Wang TC, et al. Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial. Gastroenterology. 2015;149:883–885.e9.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol. 2014;12:661–72.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  45. 45.

    Chu MP, Hecht JR, Slamon D, Wainberg ZA, Bang Y-J, Hoff PM, 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;3:767.

    PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Sun J, Ilich AI, Kim CA, Chu MP, Wong GG, Ghosh S, 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;15:257–63.

    PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Lundell L, Vieth M, Gibson F, Nagy P, Kahrilas PJ. Systematic review: the effects of long-term proton pump inhibitor use on serum gastrin levels and gastric histology. Aliment Pharm Ther. 2015;42:649–63.

    CAS  Article  Google Scholar 

  48. 48.

    Watson SA, Smith AM. Hypergastrinemia promotes adenoma progression in the APC(Min−/+) mouse model of familial adenomatous polyposis. Cancer Res. 2001;61:625–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Colucci R, Blandizzi C, Tanini M, Vassalle C, Breschi MC, Tacca MD. Gastrin promotes human colon cancer cell growth via CCK-2 receptor-mediated cyclooxygenase-2 induction and prostaglandin E2 production: Gastrin, cyclooxygenase-2 and colon cancer growth. Br J Pharmacol. 2005;144:338–48.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Yepuri G, Sukhovershin R, Nazari-Shafti TZ, Petrascheck M, Ghebre YT, Cooke JP. Proton pump inhibitors accelerate endothelial senescence. Circ Res. 2016;118:e36-42.

  51. 51.

    FASS (Farmacevtiska specialiteter i Sverige/ Farmaceutical specialities in Sweden). http://www.fass.se. Accessed 21 August 2020.

  52. 52.

    Team AP. Early Stage Colon Cancer-Clinical Practice Guideline GI-004. Alberta Health Services, Alberta. 2008.

  53. 53.

    Wong GG, Ha V, Chu MP, Dersch-Mills D, Ghosh S, Chambers CR, et al. Effects of proton pump inhibitors on FOLFOX and CapeOx regimens in colorectal cancer. Clin Colorectal Cancer. 2019;18:72–9.

    PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Zhang J-L, Liu M, Yang Q, Lin S-Y, Shan H-B, Wang H-Y, et al. Effects of omeprazole in improving concurrent chemoradiotherapy efficacy in rectal cancer. World J Gastroenterol. 2017;23:2575.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

Download references

Acknowledgements

We thank all the patients, healthcare workers and the Swedish National Board of Health and Welfare for their contributions to data collection.

Funding

This work was supported by Svenska Läkaresallskapet (SLS-788731, SLS-788751 SLS-783091) and The Swedish Research Council/Vetenskapsrådet (2020-01058). HZ was supported by a UNSW Scientia Fellowship. None of these sponsors had any role in the study design, the collection, analysis and interpretation of data.

Author information

Affiliations

Authors

Contributions

Study design: all authors. Data acquisition: NB. Statistical analysis: XW under supervision of NB. Data interpretation: all authors. Drafting of the manuscript: XW. Revising manuscript critically for important intellectual content and approving the final version of manuscript: all authors. Obtained funding: NB. Study supervision: NB. NB takes responsibility for the integrity of the data analysis.

Corresponding author

Correspondence to Nele Brusselaers.

Ethics declarations

Competing interests

The authors report no conflict of interest. HZ works at the Centre for Big Data Research in Health, UNSW Sydney, which has received funding from AbbVie Australia to conduct research, unrelated to the present study. AbbVie did not have any knowledge of, or involvement in, the present study.

Ethics approval and consent to participate

Individual consent from the participants was waived for this register-based study. Ethical approval of the study has been obtained from the Regional Ethical Review Board in Stockholm (reference number: 2014/129 - 31/4).

Consent to publish

Not applicable.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, X., Liu, Q., Halfdanarson, Ó.Ö. et al. Proton pump inhibitors and survival in patients with colorectal cancer: a Swedish population-based cohort study. Br J Cancer 125, 893–900 (2021). https://doi.org/10.1038/s41416-021-01480-0

Download citation

Search

Quick links