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Association between proton pump inhibitors use and risk of gastric cancer in patients with GERD
  1. Yen-Chun Peng1,2,
  2. Lam-Ru Huang3,
  3. Cheng-Li Lin4,5,
  4. Wan-Yun Hsu6,
  5. Chi-Sen Chang1,
  6. Hong-Zen Yeh1,2,
  7. Chia-Hung Kao7,8,9
  1. 1 Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
  2. 2 National Yang-Ming University, Taipei, Taiwan
  3. 3 Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, Taiwan
  4. 4 Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
  5. 5 College of Medicine, China Medical University, Taichung, Taiwan
  6. 6 Department of Nursing, Taichung Veterans General Hospital, Taichung, Taiwan
  7. 7 Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
  8. 8 Department of Nuclear Medicine and PET Center, China Medical University Hospital, Taichung, Taiwan
  9. 9 Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan
  1. Correspondence to Professor Chia-Hung Kao, Graduate Institute of Clinical Medicine Science and School of Medicine, College of Medicine, China Medical University,Taichung 404, Taiwan; d10040{at}

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We read with interest the study by Cheung et al confirming the risk of proton pump inhibitors (PPIs) for gastric cancer regarding the patients after Helicobacter pylori (H. pylori) eradication with long-term PPIs use.1 Most concerns about the safety of PPIs pertain to the increased risk for enteric infections, fractures and nutritional deficiencies.2 To date, the association of PPIs use and risk of gastric cancer is still controversial in patients with gastro-oesophageal reflux diseases (GERD).

For GERD, PPIs are the mainstay of treatment in the management of patients with acid-related disorders.3 Thus, patients with GERD usually take long-term PPIs,and possibly carry the risk of gastric cancer. In the present study, we performed a case–control study to investigate the association of PPIs use and risk of gastric cancer using data from a nationwide population database, the National Health Insurance Research Database (NHIRD) in Taiwan.4

This study also used a subdataset of the NHIRD, which comprises one million randomly sampled beneficiaries enrolled in the NHI programme in 2000 (Longitudinal Health Insurance Database 2000; LHID2000) and collected all records on these individuals from 1996 to 2011. We identified patients diagnosed with GERD (International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes 530.81, 530.11) who were treated at least two times between 1996 and 2011. Patients aged ≥20 years with newly diagnosed gastric cancer (ICD-9-CM code 151) between 1 January 2004 and 31 December 2011 from the Registry of Catastrophic Illness and NHI database were selected for the case group. The date of the first diagnosis date for gastric cancer was used as the index date. Patients were excluded if they had another malignancy (ICD-9-CM codes 140–208), had taken a PPI within 1 year before the index date or were <20 years of age. The comparison subject was randomly selected from the remaining patients with GERD without gastric cancer. For each patient in the case group, one comparison case was randomly selected, frequency matched by sex, age (every 20-year span) and the year of the index date. Finally, a total of 1061 cases with gastric cancer and 1061 controls without gastric cancer were included in this study (figure 1).

Figure 1

Flow chart of selection of cases and controls. GERD, gastro-oesophageal reflux disease; ICD-9-CM, International Classification of Diseases, Ninth Revision, Clinical Modification; PPI, proton pump inhibitor.

The crude and adjusted OR for the model fitted to examine the association between medication use and the development of gastric cancer. The adjusted OR for gastric cancer risk in patients who received a PPI compared with that in patients without PPI use was 2.48 (95% CI 1.92 to 3.20). Compared with controls, PPI users had risk for proximal gastric cancer (adjusted OR=2.58, 95% CI 1.38 to 4.83), distal gastric cancer (adjusted OR=3.33, 95% CI 1.97 to 7.45), unspecified gastric cancer (adjusted OR=2.64, 95% CI 1.92 to 3.63) and others (adjusted OR=2.66, 95% CI 1.95 to 3.63), respectively (table 1).

Table 1

ORs and 95% CIs of gastric cancer associated with PPI and covariates

As Cheung’s results, both studies demonstrated twofold risk of gastric cancer and PPIs use. In our results, PPIs are associated with all sites of gastric cancer and particularly significant in distal type of gastric cancer. However, the Cheung’s result showed that PPIs use was only found to be significantly associated with an increased risk of non-cardiac cancer. Besides, our results demonstrate that the use of PPIs are associated with a increased risk of gastric cancer, including greater risk by increased defined daily dose (data not shown).

This nationwide population-based case–control study, use of PPIs was associated with increased risk of gastric cancer in GERD.


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  • Y-CP and L-RH contributed equally.

  • Contributors Y-CP, C-LL and C-HK: conception and design; collection and assembly of data; data analysis and interpretation. C-HK: administrative support. All authors: manuscript writing; final approval of manuscript.

  • Funding This work was supported by grants from the Ministry of Health and Welfare, Taiwan(MOHW107-TDU-B-212-123004), China Medical University Hospital; Academia Sinica Stroke Biosignature Project (BM10701010021); MOST Clinical Trial Consortium for Stroke (MOST 106-2321-B-039-005-); Tseng-Lien Lin Foundation, Taichung, Taiwan; and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.

  • Competing interests None declared.

  • Patient consent Detail has been removed from this case description/these case descriptions to ensure anonymity. The editors and reviewers have seen the detailed information available and are satisfied that the information backs up the case the authors are making.

  • Ethics approval This study was exempted by the Institutional Review Board of China Medical University in Central Taiwan (CMUH104-REC2-115-CR2).

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Data sharing statement The dataset used in this study is held by the Taiwan Ministry of Health and Welfare (MOHW). The Ministry of Health and Welfare must approve our application to access this data. Any researcher interested in accessing this dataset can submit an application form to the ministry of health and welfare requesting access. Please contact the staff of MOHW (Email: for further assistance. Taiwan Ministry of Health and Welfare Address: No.488, Sec. 6, Zhongxiao E. Rd., Nangang Dist., Taipei City 115, Taiwan (R.O.C.). Phone: +886-2-8590-6848. All relevant data are within the paper.

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