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Lim NR, Chung WC. Increased risk of adenomatous colon polyps in patients with long-term use of proton pump inhibitors: a single-center retrospective study. JOURNAL OF YEUNGNAM MEDICAL SCIENCE 2025; 42:24. [PMID: 39837312 DOI: 10.12701/jyms.2025.42.24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Accepted: 01/10/2025] [Indexed: 01/23/2025]
Abstract
BACKGROUND It is unclear whether long-term use of proton pump inhibitors (PPIs) has a potential carcinogenic effect on the colorectum. METHODS We reviewed a consecutive series of neurosurgery outpatients who underwent two or more colonoscopies between January 2014 and April 2023. Patients in whom the timing of endoscopy was not in accordance with the guidelines and those without a history of previous endoscopy were excluded. In the second colonoscopy, the risk of adenomatous colon polyps was evaluated depending on whether the patient had taken a PPI. RESULTS In total, 520 patients were enrolled. In the multivariate analysis related to the risk of adenomatous colon polyps, age and aspirin use for >5 years were identified as significant factors. After excluding patients who had taken aspirin for >5 years, the patients were divided into three groups: those who had taken PPIs for >12 months, those who had taken PPIs for >3 months but <12 months, and those who had not taken PPIs. The risk of adenomatous colon polyps in these groups was 35.2%, 32.8%, and 22.8%, respectively (p=0.10). In the post-hoc analysis, there was a significant difference between patients who took PPIs and those who did not (p=0.03). In the multivariate analysis, a history of PPI use for >12 months was a significant risk factor for the development of advanced colon polyps (p=0.03). CONCLUSION Prolonged PPI use appears to increase the risk of developing adenomatous and advanced colon polyps.
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Affiliation(s)
- Na Rae Lim
- Department of Internal Medicine, St. Vincent Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Woo Chul Chung
- Department of Internal Medicine, St. Vincent Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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Oberholtzer S, Zhu X, Dedeaux A, Martin O, Gould EN. Retrospective evaluation of the effect of acid suppressant drugs on leukocyte ratios in dogs with mast cell tumors. J Vet Intern Med 2024; 38:2305-2315. [PMID: 38888250 PMCID: PMC11256160 DOI: 10.1111/jvim.17133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2023] [Accepted: 05/31/2024] [Indexed: 06/20/2024] Open
Abstract
BACKGROUND Acid suppressant drugs (ASDs) are commonly used to decrease gastric acid production, but some evidence exists that ASDs exert immunomodulatory effects. Such an effect has not been investigated in dogs for which ASDs are routinely prescribed. HYPOTHESIS Compared to naïve subjects, dogs treated with ASDs will exhibit differences in leukocyte ratios after treatment. ANIMALS Fifty-one dogs with mast cell tumors (MCTs). MATERIALS AND METHODS Dogs with MCT that were either AS naïve or treated with ASDs (i.e., histamine-2-receptor antagonists [H2RA] or proton pump inhibitors [PPI]) were included in this retrospective study. Subjects were categorized into 3 treatment groups (AS naïve, H2RA treated, and PPI treated), and leukocyte ratios (neutrophil:eosinophil, lymphocyte:monocyte, and neutrophil:lymphocyte [NLR]) were calculated before and after treatment. A mixed effects analysis of variance on ranks was used to assess differences in ratios between treatments, between pre- and post-treatment time points, and between pre- and post-time points for each treatment. Concurrent administration of antihistamines, corticosteroids, and chemotherapeutic drugs was assessed as a confounding factor. RESULTS Famotidine (n = 14/14) and omeprazole (n = 12/12) were the only H2RA and PPI used, respectively. Dogs receiving famotidine had a significant increase in median NLR from pre- to post-treatment (3.429; range, 1.417-15 to 5.631; range, 2.654-92; P < 0.01) compared to PPI treated or AS naïve dogs. No differences existed in chemotherapeutic drug or corticosteroid use between groups. CONCLUSIONS A significant difference in NLR was identified in famotidine treated dogs compared with omeprazole treated or AS naïve dogs.
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Affiliation(s)
- Sydney Oberholtzer
- Department of Small Animal Clinical SciencesSchool of Veterinary Medicine and Biomedical Sciences, Texas A&M UniversityCollege StationTexasUSA
- Department of Veterinary Clinical SciencesCollege of Veterinary Medicine, University of MinnesotaSaint PaulMinnesotaUSA
| | - Xiaojuan Zhu
- Office of Innovative TechnologiesThe University of Tennessee, KnoxvilleKnoxvileTennesseeUSA
| | - Andrea Dedeaux
- Department of Small Animal Clinical SciencesCollege of Veterinary Medicine, University of TennesseeKnoxvilleTennesseeUSA
| | - Olya Martin
- Department of Small Animal Clinical SciencesCollege of Veterinary Medicine, University of TennesseeKnoxvilleTennesseeUSA
| | - Emily N. Gould
- Gastrointestinal Laboratory, Department of Small Animal Clinical SciencesTexas A&M University, School of Veterinary Medicine and Biomedical SciencesCollege StationTexasUSA
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Cesca MG, Ruiz-Garcia E, Weschenfelder R, D’Agustini N, Iseas S, Luca R, O’Connor JM, D’Alpino R, Pereira AA, Mello CA, Aguiar S, e Silva VS, Riechelmann RP. Influence of proton pump inhibitors on the pathological response of rectal cancer: a multicentre study. Ecancermedicalscience 2023; 17:1586. [PMID: 37799958 PMCID: PMC10550299 DOI: 10.3332/ecancer.2023.1586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Indexed: 10/07/2023] Open
Abstract
Background The standard neoadjuvant therapy for rectal cancer involves fluoropyrimidines and radiotherapy and, most recently, total neoadjuvant therapy (TNT). A drug-drug interaction between fluoropyrimidines and proton-pump inhibitors (PPI) was suggested, with a negative impact on oncological outcomes in breast, colon and gastric cancers. Little is known about such an effect on rectal tumours. We aimed to evaluate the impact of PPI utilisation on the pathological response after chemoradiation for rectal cancer. Materials and methods Retrospective multicentre study of rectal cancer patients treated with neoadjuvant chemoradiotherapy with capecitabine (cohort 1) or 5-fluororuracil (5-FU) (cohort 2); TNT with oxaliplatin-based regimens was allowed. The pathological response was considered a complete (ypCR) or complete + partial (ypCR + ypPR) according to American Joint Committee on Cancer. PPI use was considered at any time during the neoadjuvant period if concomitant to fluoropyrimidines. Results From January 2007 to November 2020, 251 patients received capecitabine and 196 5-FU. The rates of PPI use in cohorts 1 and 2 were 20.3% and 26.5%, respectively. TNT was offered to 18.3% in cohort 1. PPI use did not influence ypCR in cohort 1 (yes versus no: 29.4% versus 19.5%; p = 0.13) or 2 (yes versus no: 25.0% versus 26.4%; p = 1.0). Similar ypCR + ypPR were observed in both cohorts 1 (76.5% versus 72.0%; p = 0.60) and 2 (86.5% versus 76.4%; p = 0.16). PPI use was not associated with pathological response in multivariable analysis. PPI users experienced more grade 3 or higher diarrhoea and infections. Conclusion PPI concomitant to capecitabine/5-FU chemoradiation did not influence the pathological response in rectal cancer but was associated with more treatment-related adverse events.
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Affiliation(s)
- Marcelle G Cesca
- A.C. Camargo Cancer Center, Antonio Prudente Street, 211, São Paulo, SP 10509001, Brazil
| | - Erika Ruiz-Garcia
- Instituto Nacional de Cancerología, San Fernando Avenue, 22, Mexico City 14080, Mexico
| | - Rui Weschenfelder
- Hospital Moinhos de Vento, Ramiro Barcelos Street, 910, Porto Alegre, RS 90035-000, Brazil
| | - Nathalia D’Agustini
- Hospital Moinhos de Vento, Ramiro Barcelos Street, 910, Porto Alegre, RS 90035-000, Brazil
| | - Soledad Iseas
- Hospital de Gastroenterología Dr. Carlos Bonorino Udaondo, Caseros Avenue, 2061, Buenos Aires C1264AAA CABA, Argentina
| | - Romina Luca
- Instituto Alexander Fleming, Crámer Street, 1180, Buenos Aires C1426ANZ, Argentina
| | - Juan Manuel O’Connor
- Instituto Alexander Fleming, Crámer Street, 1180, Buenos Aires C1426ANZ, Argentina
| | - Renata D’Alpino
- Hospital Alemão Oswaldo Cruz, Treze de Maio Street, 1815, São Paulo, SP 01323-020, Brazil
| | - Allan A Pereira
- Hospital Sírio Libanês Distrito Federal, SGAS 613 Street, Brasília 70200-730, Brazil
| | - Celso A Mello
- A.C. Camargo Cancer Center, Antonio Prudente Street, 211, São Paulo, SP 10509001, Brazil
| | - Samuel Aguiar
- A.C. Camargo Cancer Center, Antonio Prudente Street, 211, São Paulo, SP 10509001, Brazil
| | - Virgílio Souza e Silva
- A.C. Camargo Cancer Center, Antonio Prudente Street, 211, São Paulo, SP 10509001, Brazil
| | - Rachel P Riechelmann
- A.C. Camargo Cancer Center, Antonio Prudente Street, 211, São Paulo, SP 10509001, Brazil
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4
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Obeidat AE, Monti G, Choi H, Acoba J. The Effect of Proton Pump Inhibitor Use on Survival of Patients With Colorectal Cancer: A Study of a Racially Diverse Population. Cureus 2023; 15:e38707. [PMID: 37292522 PMCID: PMC10246923 DOI: 10.7759/cureus.38707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/07/2023] [Indexed: 06/10/2023] Open
Abstract
Introduction Proton pump inhibitor (PPI) use is increasing in the general population. Chronic PPI use can lead to hypergastrinemia, which has been purported to increase the risk of developing colorectal cancer (CRC). Several studies have failed to report any association between PPI use and the risk of CRC. However, little is known about the effect of PPI use on CRC survival. In this retrospective analysis, we studied the effect of PPI use on CRC survival in a racially diverse population. Methods Data were abstracted for 1050 consecutive patients diagnosed with CRC from January 2007 to December 2020. The Kaplan-Meier curve was created to study the effect of PPI exposure compared to no exposure on overall survival (OS). Univariate and multivariate analyses were performed to investigate predictors of survival. Results Complete data were available for 750 patients with CRC, 52.5% were males, 22.7% were Whites, 60.1% were Asians, and 17.2% were Pacific Islanders. A total of 25.6% of patients had a history of PPI use. Moreover, 79.2% had hypertension, 68.8% had hyperlipidemia, 38.0% had diabetes mellitus, and 30.2% had kidney disease. There was no difference in median OS among PPI users compared to non-users, p value=0.4. Age, grade, and stage were predictors of inferior OS. No significant association was noticed with gender, race, comorbidities, or treatment with chemotherapy. Conclusion In this retrospective analysis of a racially diverse population of CRC patients, we found that PPI use was not associated with worse OS. Until high-quality prospective data are available, physicians should not stop PPIs that are clinically indicated.
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Affiliation(s)
| | - Gabriel Monti
- Internal Medicine, Oregon Health & Science University, Portland, USA
| | - Horyun Choi
- Internal Medicine, University of Hawaii Internal Medicine Residency Program, Honolulu, USA
| | - Jared Acoba
- Hematology and Oncology, The Queen's Medical Center, Honolulu, USA
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Bridoux M, Simon N, Turpin A. Proton Pump Inhibitors and Cancer: Current State of Play. Front Pharmacol 2022; 13:798272. [PMID: 35359844 PMCID: PMC8963837 DOI: 10.3389/fphar.2022.798272] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 02/04/2022] [Indexed: 12/11/2022] Open
Abstract
Background: Proton pump inhibitors (PPIs) are one of the most widely used drugs worldwide and are overprescribed in patients with cancer; there is increasing evidence of their effects on cancer development and survival. The objective of this narrative review is to comprehensively identify cancer medications that have clinically meaningful drug–drug interactions (DDIs) with PPIs, including loss of efficacy or adverse effects, and to explore the association between PPIs and cancer.Methods: A PubMed search of English language studies published from 1 January 2016, to 1 June 2021 was conducted. The search terms included “proton pump inhibitors,” “cancer,” “chemotherapy,” “immunotherapy,” “hormonotherapies,” “targeted therapies,” “tyrosine kinase inhibitors,” and “gut microbiome”. Recent and relevant clinical trials, meta-analyses, and reviews were included.Results: PPIs may have pro-tumor activity by increasing plasma gastrin levels or anti-tumor activity by inhibiting V-ATPases. However, their impact on cancer survival remains unclear. PPIs may decrease the efficacy of some antineoplastic agents through direct DDIs (e.g., some tyrosine kinase inhibitors, capecitabine, irinotecan, methotrexate). More complex DDIs seem to exist for immunotherapies with indirect interactions through the microbiome. PPIs worsen hypomagnesemia, bone loss, iron, and vitamin B12 deficiencies but may have a protective effect on the renal system.Discussion/Conclusions: PPIs may interact with the cancer microbiome and the efficacy of various antineoplastic agents, although only a few DDIs involving PPIs are clinically significant. Further pharmaco-epidemiological studies are warranted, but physicians should be aware of the potential consequences of PPI use, which should be dose appropriate and prescribed according to guidelines.
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Affiliation(s)
- Marie Bridoux
- University of Lille, Lille, France
- Medical Oncology Department, Lille University Hospital, Lille, France
| | - Nicolas Simon
- CHU Lille, ULR 7365—GRITA—Groupe de Recherche sur les Formes Injectables et les Technologies Associées, University of Lille, Lille, France
| | - Anthony Turpin
- Medical Oncology Department, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, UMR9020—UMR-S 1277—CANTHER-Cancer Heterogeneity, Plasticity and Resistance to Therapies, CHU Lille, University of Lille, Lille, France
- *Correspondence: Anthony Turpin, , orcid.org/0000-0002-2282-0101
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Patel A, Spychalski P, Antoszewska M, Regula J, Kobiela J. Proton pump inhibitors and colorectal cancer: A systematic review. World J Gastroenterol 2021; 27:7716-7733. [PMID: 34908809 PMCID: PMC8641055 DOI: 10.3748/wjg.v27.i44.7716] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 07/14/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The use of proton pump inhibitors (PPI) is common worldwide, with reports suggesting that they may be overused. Several studies have found that PPI may affect colorectal cancer (CRC) risk.
AIM To summarize current knowledge on the relationship between PPI and CRC from basic research, epidemiological and clinical studies.
METHODS This systematic review was based on the patients, interventions, comparisons, outcome models and performed according to PRISMA guidelines. MEDLINE, EMBASE, Scopus, and Web of Science databases were searched from inception until May 17, 2021. The initial search returned 2591 articles, of which, 28 studies met the inclusion criteria for this review. The studies were categorized as basic research studies (n = 12), epidemiological studies (n = 11), and CRC treatment studies (n = 5). The quality of the included studies was assessed using the Newcastle-Ottawa Scale or Cochrane Risk of Bias 2.0 tool depending on the study design.
RESULTS Data from basic research indicates that PPI do not stimulate CRC development via the trophic effect of gastrin but instead may paradoxically inhibit it. These studies also suggest that PPI may have properties beneficial for CRC treatment. PPI appear to have anti-tumor properties (omeprazole, pantoprazole), and are potential T lymphokine-activated killer cell-originated protein kinase inhibitors (pantoprazole, ilaprazole), and chemosensitizing agents (pantoprazole). However, these mechanisms have not been confirmed in human trials. Current epidemiological studies suggest that there is no causal association between PPI use and increased CRC risk. Treatment studies show that concomitant PPI and capecitabine use may reduce the efficacy of chemotherapy resulting in poorer oncological outcomes, while also suggesting that pantoprazole may have a chemosensitizing effect with the fluorouracil, leucovorin, oxaliplatin (FOLFOX) regimen.
CONCLUSION An unexpected inhibitory effect of PPI on CRC carcinogenesis by way of several potential mechanisms is noted. This review identifies that different PPI agents may have differential effects on CRC treatment, with practical implications. Prospective studies are warranted to delineate this relationship and assess the role of individual PPI agents.
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Affiliation(s)
- Agastya Patel
- Department of General, Endocrine and Transplant Surgery, Medical University of Gdansk, Gdansk 80-210, Poland
| | - Piotr Spychalski
- 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
| | - Jarek Kobiela
- Department of General, Endocrine and Transplant Surgery, Medical University of Gdansk, Gdansk 80-210, Poland
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Madka V, Kumar G, Pathuri G, Panneerselvam J, Zhang Y, Ganta V, Lightfoot S, Lubet RA, Suen CS, Steele VE, Janakiram NB, Mohammed A, Rao CV. Proton pump inhibitor omeprazole suppresses carcinogen induced colonic adenoma progression to adenocarcinoma in F344 rat. Cancer Prev Res (Phila) 2021; 14:1009-1020. [PMID: 34341012 DOI: 10.1158/1940-6207.capr-21-0057] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 05/25/2021] [Accepted: 07/09/2021] [Indexed: 11/16/2022]
Abstract
Colorectal cancer (CRC) causes over 53,000 deaths annually in the United States. Its rising incidences worldwide and particularly in young adults is a major concern. Here, we evaluated the efficacy of omeprazole (OME) that is clinically approved for treating acid-reflux, to enable its repurposing for CRC prevention. In the azoxymethane (AOM)-induced rat CRC model, dietary OME (250 and 500 ppm) was administered at early adenoma stage (8 weeks after AOM) to assess the progression of early lesions to adenocarcinoma. Administration of OME at 250 ppm or 500 ppm doses led to suppression of total colon adenocarcinoma incidence by 15.7% and 32% (p<0.01), respectively. Importantly, invasive carcinoma incidence was reduced by 59% (p<0.0005) and 90% (p<0.0001) in OME administered rats in a dose-dependent manner. There was also a strong and dose-dependent inhibition in the adenocarcinoma multiplicity in rats exposed to OME. Administration of 250 and 500 ppm OME inhibited total colon adenocarcinoma multiplicity by ~49% and ~65% (p<0.0001), respectively. While non-invasive adenocarcinomas multiplicity was suppressed by ~34% to ~48% (p<0.02), the invasive carcinomas multiplicity was reduced by ~74% to ~94% (p<0.0001) in OME exposed rats in comparison to the untreated rats. Biomarker analysis results showed a decrease in cell proliferation and anti-apoptotic/pro-survival proteins with an increase in apoptosis. Transcriptome analysis of treated tumors revealed a significant increase in adenocarcinoma inhibitory genes (Olmf4; Spink4) expression and down regulation of progression promoting genes (SerpinA1, MMP21, IL6). In summary, OME showed significant protection against the progression of adenoma to adenocarcinoma.
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Affiliation(s)
- Venkateshwar Madka
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
| | - Gaurav Kumar
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
| | - Gopal Pathuri
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
| | - Janani Panneerselvam
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
| | - Yuting Zhang
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
| | - Vishal Ganta
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
| | - Stanley Lightfoot
- Pathology-Retired, Center for Cancer Prevention and Drug Development
| | - Ronald A Lubet
- Division of Cancer Prevention, National Cancer Institute
| | - Chen S Suen
- Cancer Prevention, National Cancer Institute
| | | | | | - Altaf Mohammed
- Division of Cancer Prevention, National Cancer Institute
| | - Chinthalapally V Rao
- Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
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Wang X, Liu Q, Halfdanarson ÓÖ, Zoega H, Sadr-Azodi O, Engstrand L, Fall K, Brusselaers N. Proton pump inhibitors and survival in patients with colorectal cancer: a Swedish population-based cohort study. Br J Cancer 2021; 125:893-900. [PMID: 34253872 DOI: 10.1038/s41416-021-01480-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 06/09/2021] [Accepted: 06/30/2021] [Indexed: 12/21/2022] Open
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.
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Affiliation(s)
- Xinchen Wang
- Centre for Translational Microbiome Research, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Qing Liu
- Centre for Translational Microbiome Research, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Óskar Ö Halfdanarson
- Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland
| | - Helga Zoega
- Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavík, Iceland.,Medicines Policy Research Unit, Centre for Big Data Research in Health, UNSW, Sydney, NSW, Australia
| | - Omid Sadr-Azodi
- Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Lars Engstrand
- Centre for Translational Microbiome Research, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - Katja Fall
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Solna, Sweden.,Clinical Epidemiology and Biostatistics, School of Medical Sciences, Örebro University, Örebro, Sweden
| | - Nele Brusselaers
- Centre for Translational Microbiome Research, Department of Microbiology, Tumour and Cell Biology, Karolinska Institutet, Stockholm, Sweden. .,Global Health Institute, Antwerp University, Antwerpen, Belgium. .,Department of Head and Skin, Ghent University, Ghent, Belgium.
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9
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Meriggi F. Controversial link between proton pump inhibitors and anticancer agents: review of the literature. TUMORI JOURNAL 2021; 108:204-212. [PMID: 34159850 DOI: 10.1177/03008916211025091] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Drug-drug interactions represent a topic of great interest, not only due to the risk of unexpected adverse events but also due to the possibility of altering the effectiveness of a specific treatment. Inappropriate or concomitant use of drugs can often lead to changes in the bioavailability of various compounds, resulting in pharmacokinetic alterations. A recent example is the concomitant administration of proton pump inhibitors (PPIs) and anticancer agents. PPIs are overused beyond their classic indications, resulting in a high risk of interactions with other drugs, such as anticancer agents, both PO and intravenous. However, the real clinical impact of concomitant acid suppression therapy and anticancer therapies remains controversial and is not yet fully understood. Certainly, the gut microbiota plays a key role in regulating the response of the immune system, and PPIs can significantly alter the gut microbiome, resulting in gut dysbiosis. Indeed, while the link sometimes appears to lead to negative outcomes, as in the case of immunotherapy, oral capecitabine, or tyrosine kinase inhibitors, in other cases, it seems to enhance the effectiveness of intravenous chemotherapy. In this review, I analyse the possible drug interactions between PPIs and the main classes of anticancer drugs.
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Affiliation(s)
- Fausto Meriggi
- Oncology Department, Fondazione Poliambulanza Istituto Ospedaliero, Brescia, Italy
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10
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Kichenadasse G, Miners JO, Mangoni AA, Karapetis CS, Hopkins AM, Sorich MJ. Proton Pump Inhibitors and Survival in Patients With Colorectal Cancer Receiving Fluoropyrimidine-Based Chemotherapy. J Natl Compr Canc Netw 2021; 19:1037-1044. [PMID: 33951613 DOI: 10.6004/jnccn.2020.7670] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Accepted: 10/12/2020] [Indexed: 12/30/2022]
Abstract
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.
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Affiliation(s)
- Ganessan Kichenadasse
- 1Department of Clinical Pharmacology, College of Medicine and Public Health, and.,2Department of Medical Oncology, Flinders Centre for Innovation in Cancer, Flinders Medical Centre/Flinders University, Bedford Park, South Australia, Australia
| | - John O Miners
- 1Department of Clinical Pharmacology, College of Medicine and Public Health, and
| | - Arduino A Mangoni
- 1Department of Clinical Pharmacology, College of Medicine and Public Health, and
| | - Christos S Karapetis
- 2Department of Medical Oncology, Flinders Centre for Innovation in Cancer, Flinders Medical Centre/Flinders University, Bedford Park, South Australia, Australia
| | - Ashley M Hopkins
- 1Department of Clinical Pharmacology, College of Medicine and Public Health, and
| | - Michael J Sorich
- 1Department of Clinical Pharmacology, College of Medicine and Public Health, and
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Matsuoka H, Ando K, Swayze EJ, Unan EC, Mathew J, Hu Q, Tsuda Y, Nakashima Y, Saeki H, Oki E, Bharti AK, Mori M. CTDSP1 inhibitor rabeprazole regulates DNA-PKcs dependent topoisomerase I degradation and irinotecan drug resistance in colorectal cancer. PLoS One 2020; 15:e0228002. [PMID: 32764831 PMCID: PMC7413750 DOI: 10.1371/journal.pone.0228002] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Accepted: 06/30/2020] [Indexed: 12/15/2022] Open
Abstract
Irinotecan specifically targets topoisomerase I (topoI), and is used to treat various solid tumors, but only 13–32% of patients respond to the therapy. Now, it is understood that the rapid rate of topoI degradation in response to irinotecan causes irinotecan resistance. We have published that the deregulated DNA-PKcs kinase cascade ensures rapid degradation of topoI and is at the core of the drug resistance mechanism of topoI inhibitors, including irinotecan. We also identified CTD small phosphatase 1 (CTDSP1) (a nuclear phosphatase) as a primary upstream regulator of DNA-PKcs in response to topoI inhibitors. Previous reports showed that rabeprazole, a proton pump inhibitor (PPI) inhibits CTDSP1 activity. The purpose of this study was to confirm the effects of rabeprazole on CTDSP1 activity and its impact on irinotecan-based therapy in colon cancer. Using differentially expressing CTDSP1 cells, we demonstrated that CTDSP1 contributes to the irinotecan sensitivity by preventing topoI degradation. Retrospective analysis of patients receiving irinotecan with or without rabeprazole has shown the effects of CTDSP1 on irinotecan response. These results indicate that CTDSP1 promotes sensitivity to irinotecan and rabeprazole prevents this effect, resulting in drug resistance. To ensure the best chance at effective treatment, rabeprazole may not be a suitable PPI for cancer patients treated with irinotecan.
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Affiliation(s)
- Hiroya Matsuoka
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Fukuoka, Japan
| | - Koji Ando
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Fukuoka, Japan
- * E-mail:
| | - Emma J. Swayze
- Division of Hematology and Medical Oncology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Elizabeth C. Unan
- Division of Hematology and Medical Oncology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Joseph Mathew
- Division of Hematology and Medical Oncology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Quingjiang Hu
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Fukuoka, Japan
| | - Yasuo Tsuda
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Fukuoka, Japan
| | - Yuichiro Nakashima
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Fukuoka, Japan
| | - Hiroshi Saeki
- Department of General Surgical Science, Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Fukuoka, Japan
| | - Ajit K. Bharti
- Division of Hematology and Medical Oncology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Masaki Mori
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka City, Fukuoka, Japan
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12
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Indini A, Petrelli F, Tomasello G, Rijavec E, Facciorusso A, Grossi F, Ghidini M. Impact of Use of Gastric-Acid Suppressants and Oral Anti-Cancer Agents on Survival Outcomes: A Systematic Review and Meta-Analysis. Cancers (Basel) 2020; 12:E998. [PMID: 32325628 PMCID: PMC7226385 DOI: 10.3390/cancers12040998] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 04/04/2020] [Accepted: 04/14/2020] [Indexed: 12/11/2022] Open
Abstract
We performed a systematic review and meta-analysis to evaluate the role of gastric acid suppressant use on outcomes of tyrosine kinase inhibitors (TKIs) and oral chemotherapy. We identified all research evaluating the effect of GAS (gastric acid suppressants) use on patients receiving oral chemotherapy or TKIs for solid tumors. The pooled hazard ratios (HRs) and 95% confidence interval (95%CI) for overall survival (OS) and progression-free survival (PFS) were calculated with a fixed-effects or a random effects model. The study population included n = 16 retrospective studies and 372,418 patients. The series concerned gastrointestinal tract tumors (n = 5 studies), renal cell carcinomas (RCC, n = 3 studies), non-small cell lung cancers (NSCLC, n = 5 studies), and soft tissue sarcomas or mixed histologies solid tumors in n = 3 studies. The pooled HRs for OS and PFS were 1.31 (95%CI: 1.20-1.43; p < 0.01) and 1.3 (95%CI 1.07-1.57; p < 0.01) for GAS and no GAS users, respectively. Only studies of EGFR (epidermal growth factor receptor) mutated NSCLC patients receiving TKIs and those with colorectal cancer receiving oral chemotherapy showed a significant correlation between GAS and poor survival. Our study supports the evidence of a possible negative impact of concomitant GAS therapy on survival outcomes of patients receiving oral anti-cancer drugs.
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Affiliation(s)
- Alice Indini
- Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.I.); (E.R.); (F.G.)
| | - Fausto Petrelli
- Oncology Unit, ASST Bergamo Ovest, 24047 Treviglio (BG), Italy;
| | - Gianluca Tomasello
- Oncology Unit, Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, 20121 Milan, Italy;
| | - Erika Rijavec
- Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.I.); (E.R.); (F.G.)
| | - Antonio Facciorusso
- Gastroenterology Unit, Università Degli Studi di Foggia, 71122 Foggia, Italy;
| | - Francesco Grossi
- Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.I.); (E.R.); (F.G.)
| | - Michele Ghidini
- Oncology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; (A.I.); (E.R.); (F.G.)
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13
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Murphy N, Moreno V, Hughes DJ, Vodicka L, Vodicka P, Aglago EK, Gunter MJ, Jenab M. Lifestyle and dietary environmental factors in colorectal cancer susceptibility. Mol Aspects Med 2019; 69:2-9. [PMID: 31233770 DOI: 10.1016/j.mam.2019.06.005] [Citation(s) in RCA: 163] [Impact Index Per Article: 27.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Revised: 06/19/2019] [Accepted: 06/20/2019] [Indexed: 12/24/2022]
Abstract
Colorectal cancer (CRC) incidence changes with time and by variations in diet and lifestyle, as evidenced historically by migrant studies and recently by extensive epidemiologic evidence. The worldwide heterogeneity in CRC incidence is strongly suggestive of etiological involvement of environmental exposures, particularly lifestyle and diet. It is established that physical inactivity, obesity and some dietary factors (red/processed meats, alcohol) are positively associated with CRC, while healthy lifestyle habits show inverse associations. Mechanistic evidence shows that lifestyle and dietary components that contribute to energy excess are linked with increased CRC via metabolic dysfunction, inflammation, oxidative stress, bacterial dysbiosis and breakdown of gut barrier integrity while the reverse is apparent for components associated with decreased risk. This chapter will review the available evidence on lifestyle and dietary factors in CRC etiology and their underlying mechanisms in CRC development. This short review will also touch upon available information on potential gene-environment interactions, molecular sub-types of CRC and anatomical sub-sites within the colorectum.
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Affiliation(s)
- Neil Murphy
- International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Victor Moreno
- Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program, Catalan Institute of Oncology (ICO). Hospitalet de Llobregat, Barcelona, Spain; Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL). Hospitalet de Llobregat, Barcelona, Spain; Consortium for Biomedical Research in Epidemiology and Public Health (CIBERESP), Spain; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - David J Hughes
- Cancer Biology and Therapeutics Group, School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland
| | - Ludmila Vodicka
- Department of the Molecular Biology of Cancer, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic; Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Pavel Vodicka
- Department of the Molecular Biology of Cancer, Institute of Experimental Medicine, Czech Academy of Sciences, Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic; Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic
| | - Elom K Aglago
- International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Marc J Gunter
- International Agency for Research on Cancer (IARC-WHO), Lyon, France
| | - Mazda Jenab
- International Agency for Research on Cancer (IARC-WHO), Lyon, France.
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14
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Effects of Proton Pump Inhibitors on FOLFOX and CapeOx Regimens in Colorectal Cancer. Clin Colorectal Cancer 2018; 18:72-79. [PMID: 30551953 DOI: 10.1016/j.clcc.2018.11.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Revised: 11/02/2018] [Accepted: 11/09/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND First-line adjuvant chemotherapy options for early-stage colorectal cancer (CRC) include CapeOx (capecitabine, intravenous oxaliplatin) and FOLFOX (intravenous 5-fluorouracil, leucovorin, oxaliplatin). Capecitabine is an oral prodrug analog of 5-fluorouracil, and recent studies have suggested that proton pump inhibitors (PPIs) may detrimentally affect capecitabine efficacy. Conversely, some literature suggests that PPIs may negatively affect CRC itself. To gain insight into the nature of PPIs' effect on capecitabine and CRC, we investigated their effects on effectiveness of CapeOx versus FOLFOX chemotherapy. PATIENTS AND METHODS We conducted a retrospective chart review of 389 patients with stage II-III CRC who received adjuvant CapeOx or FOLFOX from 2004 to 2013. Information regarding PPI receipt, chemotherapy, and patient outcomes from medical records was analyzed. RESULTS Three-year recurrence-free survival was significantly lower in CapeOx-treated PPI recipients than non-PPI recipients (69.5 vs. 82.6%; P = .029). Unadjusted analysis showed that CapeOx-treated PPI recipients were twice as likely to experience cancer recurrence or death as CapeOx-treated non-PPI recipients (hazard ratio = 2.03; 95% confidence interval, 1.06-3.88; P = .033). FOLFOX-treated PPI recipients had a non-statistically significant difference in 3-year recurrence-free survival versus non-PPI recipients (82.9 vs. 61.7%; P = .066) and a non-statistically significant difference in recurrence/death (hazard ratio = 0.51; 95% confidence interval, 0.25-1.06; P = .071). No significant differences were seen in overall survival between groups. CONCLUSION Our results suggest PPIs negatively affected recurrence-free survival in CapeOx-treated CRC patients and yielded no significant effects among FOLFOX-treated patients, potentially implicating a pharmacokinetic interaction between PPIs and capecitabine. No overall survival effects were seen. Given PPIs' widespread use, further studies are required to corroborate our findings.
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