Systematic Reviews
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 28, 2021; 27(44): 7716-7733
Published online Nov 28, 2021. doi: 10.3748/wjg.v27.i44.7716
Proton pump inhibitors and colorectal cancer: A systematic review
Agastya Patel, Piotr Spychalski, Magdalena Antoszewska, Jaroslaw Regula, Jarek Kobiela
Agastya Patel, Piotr Spychalski, Jarek Kobiela, Department of General, Endocrine and Transplant Surgery, Medical University of Gdansk, Gdansk 80-210, Poland
Magdalena Antoszewska, Department of Dermatology, Venereology and Allergology, Medical University of Gdansk, Gdansk 80-210, Poland
Jaroslaw Regula, Department of Gastroenterology, Hepatology and Oncology, Center of Postgraduate Medical Education, The Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw 01-813, Poland
Author contributions: Patel A, Spychalski P, Regula J and Kobiela J contributed to the conceptualization; Patel A, Spychalski P and Antoszewska M curated data; Patel A, Spychalski P and Kobiela J contributed to the methodology, visualization and writing the original draft; Spychalski P, Antoszewska M, Regula J and Kobiela J contributed to the validation; Spychalski P, Regula J and Kobiela J contributed to the supervision; Kobiela J administrated the project; and all authors contributed to the formal analysis, investigation, writing the review and editing.
Conflict-of-interest statement: All the authors declare that they have no competing interests.
PRISMA 2009 Checklist statement: The authors have read the PRISMA 2009 checklist, and the manuscript was prepared in accordance with the PRISMA guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Jarek Kobiela, MD, PhD, Assistant Professor, Department of General, Endocrine and Transplant Surgery, Medical University of Gdansk, Marii Skłodowskiej-Curie 3a, Gdansk 80-210, Poland.
Received: July 4, 2021
Peer-review started: July 4, 2021
First decision: July 13, 2021
Revised: July 14, 2021
Accepted: September 8, 2021
Article in press: September 8, 2021
Published online: November 28, 2021
Research background

Proton pump inhibitors (PPI) are one of the most widely used medications globally. Several reports have raised concerns that they may be inappropriately or even overused. Several adverse effects of PPI have been reported such as increased risk of gastrointestinal cancers including colorectal cancer (CRC).

Research motivation

There is no systematic review covering the entire body of evidence on the influence of PPI on CRC carcinogenesis. Previous reviews have primarily focused on the epidemiological aspect, in terms of CRC incidence, of their relationship. A comprehensive review analyzing the association between PPI use and CRC may yield findings, which may have practical implications. Therefore, this systematic review aimed to summarize evidence from basic research studies on potential mechanisms of PPI, as well as from human epidemiological and clinical studies assessing the influence of PPI use on survival and treatment outcomes of CRC patients.

Research objectives

To summarize evidence from basic research, epidemiological and clinical studies focusing on the relationship between PPI and CRC.

Research methods

This systematic review performed according to the PRISMA guidelines was based on patients, interventions, comparisons, and outcomes. Using a predetermined search strategy, MEDLINE, EMBASE, Scopus, and Web of Science electronic databases were searched from inception until May 17, 2021. The initial search returned 2591 articles. Twenty-eight studies were included in this review and categorized as basic research studies (n = 12), epidemiological studies (n = 11), and CRC treatment studies (n = 5). The Newcastle-Ottawa Scale or Cochrane Risk of Bias 2.0 tool were utilized to assess the quality of the included studies depending on the study design.

Research results

Basic research studies show that PPI may paradoxically inhibit the trophic effect of gastrin rather than stimulating CRC development through it. Additionally, PPI may possess several anti-tumor properties (omeprazole, pantoprazole) while also being potential T lymphokine-activated killer cell-originated protein kinase inhibitors (pantoprazole, ilaprazole) and chemosensitizing agents (pantoprazole). Based on data from epidemiological studies, it appears that no causal association between PPI use and increased CRC risk exists. Treatment studies suggest that concomitant use of PPI with capecitabine use may reduce the efficacy of chemotherapy and result in poorer oncological outcomes. These studies also suggest that pantoprazole may have a chemosensitizing effect with the FOLFOX regimen.

Research conclusions

This systematic review identifies an unexpected inhibitory effect on CRC carcinogenesis by way of several potential mechanisms. Moreover, it appears that different PPI agents may have differential effects on CRC treatment, which may have practical implications. Further prospective studies are warranted to delineate this relationship as well as assess the role of individual PPI agents.

Research perspectives

PPI do not appear to have a growth promoting effect on CRC, however, a cautious approach should be adopted while concomitantly administering PPI and capecitabine-based chemotherapy. Recent evidence suggests that individual PPI agents have a differential effect on CRC carcinogenesis, with newer agents such as pantoprazole, ilaprazole and rabeprazole possessing beneficial characteristics, which may have a role in the treatment of CRC.