Meta-Analysis Open Access
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World J Gastroenterol. Apr 28, 2013; 19(16): 2560-2568
Published online Apr 28, 2013. doi: 10.3748/wjg.v19.i16.2560
Acid suppressive drugs and gastric cancer: A meta-analysis of observational studies
Jeong Soo Ahn, Chun-Sick Eom, Christie Y Jeon, Sang Min Park
Jeong Soo Ahn, Sang Min Park, Department of Family Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul 110-744, South Korea
Chun-Sick Eom, Department of Family Medicine, Hallym University Chuncheon Sacred Heart Hospital, Chuncheon 200-702, South Korea
Christie Y Jeon, Center for Cancer Prevention and Control Research, UCLA Fielding School of Public Health, Los Angeles, CA 90095, United States
Author contributions: Ahn JS and Park SM had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis; Ahn JS and Park SM designed the study; Ahn JS, Park SM and Eom CS performed the data acquisition; Ahn JS and Jeon CY analyzed the data; Ahn JS, Park SM and Jeon CY wrote the paper; all the authors have approved the final submitted manuscript.
Supported by A National Research Foundation of Korea Grant funded by the Korean Government, No. 2010-0004429
Correspondence to: Dr. Sang Min Park, Department of Family Medicine, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehangno, Jongno-gu, Seoul 110-744, South Korea. sangmin.park.snuh@gmail.com
Telephone: +82-2-20723331 Fax: +82-2-7663276
Received: August 17, 2012
Revised: March 4, 2013
Accepted: March 8, 2013
Published online: April 28, 2013

Abstract

AIM: To evaluate the association between acid suppressive drug use and the development of gastric cancer.

METHODS: A systematic search of relevant studies that were published through June 2012 was conducted using the MEDLINE (PubMed), EMBASE, and Cochrane Library databases. The search included observational studies on the use of histamine 2-receptor antagonists (H2RAs) or proton pump inhibitors and the associated risk of gastric cancer, which was measured using the adjusted odds ratio (OR) or the relative risk and 95%CI. An independent extraction was performed by two of the authors, and a consensus was reached.

RESULTS: Of 4595 screened articles, 11 observational studies (n = 94558) with 5980 gastric cancer patients were included in the final analyses. When all the studies were pooled, acid suppressive drug use was associated with an increased risk of gastric cancer risk (adjusted OR = 1.42; 95%CI: 1.29-1.56, I2 = 48.9%, P = 0.034). The overall risk of gastric cancer increased among H2RA users (adjusted OR = 1.40; 95%CI: 1.24-1.59, I2 = 59.5%, P = 0.008) and PPI users (adjusted OR = 1.39; 95%CI: 1.19-1.64, I2 = 0.0%, P = 0.377).

CONCLUSION: Acid suppressive drugs are associated with an increased risk of gastric cancer. Further studies are needed to test the effect of acid suppressive drugs on gastric cancer.

Key Words: H2-receptor antagonists, Proton pump inhibitors, Gastric cancer, Meta-analysis



INTRODUCTION

Acid suppressive drugs were the second most prescribed medication worldwide in 2005. Histamine 2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) were widely used for the treatment of peptic ulcers, gastroesophageal reflux disease (GERD), and other benign conditions of the stomach, esophagus, and duodenum[1-4]. PPIs were one of the most commonly prescribed medications by primary physicians and are frequently used over the long term.

The safety of these drugs and their potential adverse effects is of great importance to public health. Several case reports suggested that acid suppressive drugs may increase the occurrence of gastric polyps or cancer[5-13], and several epidemiological studies have evaluated the association between long-term gastric acid suppression and the risk of gastrointestinal neoplasms. Several researchers have proposed that acid suppressive drugs may suppress gastric acid secretion and interfere with bacterial growth and nitrosamine formation[14-16]. In addition, the reduction of gastric acid secretion with acid suppressive drugs can lead to hypergastrinemia[17,18], which has been identified as a possible risk factor for gastric polyps and gastric and colonic carcinomas[19-22]. However, those findings are contradictory: several studies have found an increased risk of gastric cancer among acid suppressive drug users[23-25], whereas other studies found no evidence of an increased risk[26-28]. To date, no systematic meta-analysis has been published on this topic.

Therefore, in this study, we sought to investigate the association between the use of acid suppressive drugs and the risk of gastric cancer via a meta-analysis of cohort studies and case-control studies.

MATERIALS AND METHODS
Data sources and searches

Our review followed the Meta-analysis of Observational Studies in Epidemiology guidelines[29]. We performed our search in MEDLINE (PubMed) (inception to June 2012), EMBASE (inception to June 2012), and the Cochrane Library (inception to June 2012) using common key words regarding acid suppression and gastric cancer in case-control studies, cohort studies, and randomized controlled trials (RCTs). However, there were no RCTs among the search results that satisfied our inclusion criteria.

In addition, we searched the bibliographies of relevant articles to identify additional studies of interest. For the studies that did not directly report the association between the use of acid suppressive drugs and gastric cancer incidence, we contacted the authors in the field for any unpublished data. However, the authors did not have any available data to use in our meta-analysis. We used the following keywords in the literature search: “histamine receptor antagonist”, “H2 receptor antagonist”, “cimetidine”, “ranitidine”, “famotidine”, “nizatidine”, “proton pump inhibitor”, “proton pumps”, “omeprazole”, “nexium”, “lansoprazole”, “rabeprazole”, “pantoprazole”, or “esomeprazole” for the exposure factors and “stomach cancer”, “stomach neoplasia”, “gastric cancer”, “gastric neoplasia”, “stomach neoplasm” or “gastric neoplasm” for the outcome factors.

Study selection and data extraction

We included case-control studies and cohort studies that investigated the association between acid suppressive drug use and gastric cancer risk, which reported an adjusted odds ratio (OR) or relative risk (RR) and the corresponding 95%CI. We only selected articles that were written in English and excluded studies with no available data for outcome measures.

All the studies that were retrieved from the databases and bibliographies were independently evaluated by two authors of this paper (Ahn JS and Eom CS). Of the articles that were found in the three databases, duplicate articles and articles that did not meet the selection criteria were excluded. We extracted the following data from the remaining studies: the study names (first author), the year of publication, the country of publication, the study design, the study period, the population characteristics, the type of drugs, the adjusted OR or RR with a 95%CI:the study quality, and the adjustment. The data abstraction and the study selection were performed in duplicate.

Quality assessment

We assessed the methodological quality of the included studies using the Newcastle-Ottawa Scale (NOS) for the case-control and cohort studies in the meta-analysis[30]. The NOS is comprehensive and has been partially validated for assessing the quality of non-randomized studies in meta-analyses. The NOS is based on the following three broad subscales: the selection of the study groups (4 items), the comparability of the groups (1 item), and the ascertainment of the exposure and the outcome of interest for case-control studies and cohort studies, respectively (3 items). A “star system” (a score range from 0-9) has been developed for quality assessment. Each study can be awarded a maximum of one star for each numbered item within the selection and exposure categories, whereas a maximum of two stars can be assigned for comparability. In this study, we considered a study that was awarded 7 or more stars as a high-quality study because standard criteria have not been established.

Statistical analysis

The outcome of the meta-analysis was the risk of gastric cancer. We used the adjusted data (adjusted OR or RR with a 95%CI) for the meta-analysis. In addition, we conducted subgroup analyses by type of study design (case-control studies vs cohort studies), type of acid suppressive drugs (H2RAs vs PPIs), duration of acid suppressive drug use (within 5 years vs more than 5 years), location of gastric cancer (gastroesophageal junction, cardia, or non-cardia), and study quality (high-quality vs low-quality).

We pooled the adjusted ORs, RRs and 95%CIs based on both fixed-effects and random-effects models. Because the incidence of gastric cancer was low (< 5%), as evidenced in the cohort studies, we concluded that the outcome was sufficiently rare to assume that the OR could be used to approximate the RR. Heterogeneity was assessed using the Higgins I2 value, which measures the percentage of total variance across studies, which is attributable to heterogeneity rather than chance. Negative I2 values were set at zero to ensure that I2 fell between 0% (no observed heterogeneity) and 100% (maximal heterogeneity)[31,32]. We considered an I2 value greater than 50% to represent substantial heterogeneity. When the heterogeneity was substantial, we conducted sensitivity analyses: the changes in the I2 values were examined by removing each study from the analysis to determine which studies contributed most significantly to the heterogeneity. We assessed between-group heterogeneity using analysis of variance. When heterogeneity was found, we performed a meta-regression using the subgroup categories.

We used the Woolf method (inverse variance method) for a fixed-effects analysis[33,34], and we used the DerSimonian and Laird method for a random-effects analysis[35]. Begg’s funnel plot and Egger’s test were used to identify publication bias. Publication bias was detected in studies when the funnel plot was asymmetrical or the P-value was less than 0.05 using Egger’s test. We used the Stata/SE version 10.1 software program (StataCorp, College Station, TX, United States) for the statistical analysis.

RESULTS
Identification of relevant studies

Figure 1 shows a flow diagram of the study selection. A total of 4595 articles were identified by searching the three databases and relevant bibliographies. We excluded 824 duplicate articles and 3737 articles that did not satisfy the selection criteria. After the full texts of the remaining 34 articles were reviewed, the following 23 articles were excluded: one article from a study that shared an identical population[36]; 6 articles that were case reports[5-10]; 2 articles that included data on precancerous lesions, such as gastric polyps[37,38]; one article that described a study protocol without results[39]; 2 articles that only included mortality data[40,41]; 2 articles that were reviews or correspondence[25,42]; and 9 articles that were included totally or partially in another article[43-51]. As a result, we included 11 observational studies (9 case-control studies and 2 cohort studies), which ultimately met our inclusion criteria.

Figure 1
Figure 1 Flow diagram for identification of relevant studies.
Characteristics of the studies included in the final analysis

Table 1 shows the main characteristics of the 11 reviewed studies. Five studies were published in the 1990s[23-27], and 6 studies were published in the 2000s[52-57]. The countries where the studies had been conducted were as follows: the United States (n = 5), the United Kingdom (n = 2), Denmark (n = 2), Canada (n = 1), and Italy (n = 1). We identified a total of 94558 participants, which included 5980 cases and 88578 controls from the following articles: 1 article on a medical record-based case-control study, 3 articles on nested case-control studies, 2 articles on population-based case-control studies, and 2 articles on prospective cohort studies. Seven studies evaluated the association between H2RA use and the risk of gastric cancer, and 4 studies assessed the association between the use of H2RAs or PPIs and the risk of gastric cancer. The mean value for the methodological quality of the 11 studies was 6.64 stars according to the NOS (Table 1).

Table 1 Characteristics of observational studies on acid suppressive drugs and gastric cancer.
Ref.CountryDesignStudy periodRange of age (yr)PopulationDrugsAdjusted OR or RR (95%CI)Study quality1Adjustment for covariates
La Vecchiaet al[23]ItalyCC1985-198927-74563 cases and 1501 controlsCimetidine, Ranitidine1.80 (1.20 -2.70)5Age, sex, education, smoking, alcohol, coffee
Johnson et al[24]United StatesCC1988-1992NA113 cases and 452 matched controlsCimetidine, Ranitidine2.00 (1.00 -3.90)5Age, sex, first pharmacy use
Møller et al[25]DenmarkPCC1977-1990NA134 cases among 16739Cimetidine2.30 (1.60-3.10)6Age, sex, diagnosis, method of diagnosis
Schumacher et al[26]United StatesCC1981-198717-9499 cases and 365 controlsCimetidine2.30 (0.80 -6.90)6Age, sex, date of first pharmacy use
Chow et al[27]United StatesMCC1986-1992NA196 cases and 200 controlsCimetidine, Ranitidine, Famotidine, Nizatidine0.60 (0.30-1.30)6Race, smoking, BMI, number of composite conditions2
Farrow et al[52]United StatesPBCC1993-199530-79293 esophageal adenoca, 221 esophageal SCC, 261 gastric cardia adenoca, 368 non-cardia gastric adenoca and 695 controlsCimetidine, Ranitidine, Famotidine, Nizatidine1.00 (0.60-1.90)7Age, sex, study center, smoking, BMI, history of gastric or duodenal ulcer, GERD symptom frequency, alcohol
Suleiman et al[53]United KingdomNCC1990-1992NA231 cases among 9876 controlsCimetidine, Ranitidine2.56 (0.17-38.09)7Age, sex, MI, antacid, steroid, smoking, alcohol, social class, height, weight
García Rodríguez et al[54]United KingdomNCC1994-200140-84287 esophageal adenoca, 195 gastric cardiac adenoca, 327 gastric non-cardia adenoca and 10000 controlsH2RAs, PPIs1.24 (0.88-1.75)8Age, sex, calendar year, smoking, alcohol, BMI, UGI disorder, hiatal hernia, GU, DU, dyspepsia
Tamim et al[55]CanadaNCC1995-2003NA1589 cases and 12991 controlsH2RAs, PPIs1.37 (1.22-1.53)8Age, sex number of prescriptions to any drug, total length of hospitalizations and number of visit to GPs, specialist, emergency rooms
Duan et al[56]United StatesPBCC1992-1997NA220 esophageal adenoca, 277 gastric cardiac adenoca, 441 distal gastric adenoca and 1356 controlsH2RAs, PPIs1.15 (0.58 -2.29)7Age, sex, race, birthplace, education, smoking, BMI, history of UGI symptom
Poulsen et al[57]DenmarkPCC1990-2003NA161 cases among users of 18790 PPIs or 17478 H2RAsOmeprazole, Lanzoprazole, Esomeprazole, Pantoprazole, Rabeprazole, Cimetidine, Ranitidine, Nizatidine, Famotidine1.30 (0.70-2.30)8Age, sex, calendar period, history of H.pylori, gastroscopy year, COPD, alcohol, NSAID
Overall use of acid suppressive drugs and the risk of gastric cancer

Figure 2 shows the association between the use of acid suppressive drugs and gastric cancer risk. The overall use of H2RAs and PPIs was associated with an increased risk of gastric cancer in 9 case-control studies [adjusted OR = 1.36; 95%CI: 1.23-1.50, n = 9, I2 = 24.5% (range, 0.0%-64.0%)] and in 2 cohort studies [adjusted RR, 2.01; 95%CI: 1.51-2.68, n = 2, I2 = 63.0% (not available)] using a fixed-effects model, and this association was observed in a combined study [adjusted OR and RR, 1.42; 95%CI: 1.29-1.56, n = 11, I2 = 48.9% (range, 0.0%-74.0%)]. As shown in Table 2, an increased risk of gastric cancer was found with H2RA use [adjusted OR = 1.40; [95%CI: 1.24-1.59, n = 10, I2 = 59.5% (range, 19.0%-80.0%)] and with PPI use [adjusted OR = 1.39; 95%CI: 1.19-1.64, n = 3, I2 = 0.0% (range, 0.0%-90.0%)]. In a sensitivity analysis, when the study by Møller et al[25] was removed, the I2 values of the H2RA studies decreased from 59.5% to 34.3%, but the effect remained significant. In addition, when stratified by the study design, H2RA use was positively associated with gastric cancer in both case-control [adjusted OR = 1.30; 95%CI: 1.13-1.49, n = 8, I2 = 42.0% (range, 0.0%-74.0%)] and cohort [adjusted RR, 1.84; 95%CI: 1.41-2.41, n = 2, I2 = 80.4% (not available)] studies. The use of PPIs was associated with an increased risk of gastric cancer in case-control studies [adjusted OR = 1.44; 95%CI: 1.21-1.71, n = 2, I2 = 23.5% (not available)], whereas only one cohort study was conducted to evaluate the use of PPIs (adjusted RR, 1.20; 95%CI: 0.80-1.80) (data were not shown).

Table 2 Association between acid suppressive drugs use and gastric cancer risk in subgroup meta-analysis.
CategoryNo. of studiesAdjusted OR/RR (95%CI)Heterogeneity, I2 % (95%CI)Model usedHeterogeneity between groups
Type of drugsP = 0.01
H2RAs10[23-27,52-55,57]1.40 (1.24-1.59)59.5 (19.0-80.0)1Fixed-effects
PPIs3[54,55,57]1.39 (1.19-1.64)0.0 (0.0-90.0)Fixed-effects
Location of gastric cancerP = 0.03
GE junction2[24,26]2.28 (0.97-5.35)0.0 (NA)Fixed-effects
Gastric cardia4[52,54-56]0.88 (0.63-1.24)9.2 (0.0-86.0)Fixed-effects
Non-cardia6[24,26,52,54-56]1.42 (1.12-1.79)0.0 (0.0-75.0)Fixed-effects
Duration of drugs useP = 0.27
Within 5 yr7[23,24,26,27,52,55,57]1.58 (1.35-1.81)60.2 (9.0-83.0)1Fixed-effects
Over 5 yr6[23,24,26,27,52,57]1.24 (0.84-1.84)25.4 (0.0-69.0)Fixed-effects
Study qualityP = 0.01
High-quality26[52,53,54,55-57]1.34 (1.21-1.48)0.0 (0.0-75.0)Fixed-effects
Low-quality5[23-27]1.86 (1.49-2.32)63.5 (4.0-86.0)1Fixed-effects
Figure 2
Figure 2 Meta-analysis results of individual and pooled adjusted odds ratio or relative risk of gastric cancer. The size of each square is proportional to the study’s weight. Diamonds are the summary estimate from the pooled studies with 95%CI. OR: Odds ratio; RR: Relative risk.
Subgroup meta-analysis

In a subgroup meta-analysis, acid suppressive drugs were associated with an increased gastric cancer risk within 5 years of use [adjusted OR = 1.58; 95%CI: 1.35-1.81, n = 7, I2 = 60.2% (not available)]. In a sensitivity analysis, when the study by La Vecchia et al[23] was removed, the I2 values decreased from 60.2% to 41.4%; however, the summary estimate indicated an elevated risk of gastric cancer. Additionally, a positive association was observed in patients with more than 5 years of acid suppressive drug use. However, there was no statistical significance [adjusted OR = 1.24; 95%CI: 0.84-1.84, n = 6, I2 = 25.4% (not available)] (Table 2). The between-group differences in the effect estimates for within 5 years of exposure vs more than 5 years of exposure were not significant (P = 0.27).

Regarding the location of gastric cancer, a significant positive association was observed between the use of acid suppressive drugs and non-cardia cancer risk [adjusted OR = 1.42; 95%CI: 1.12-1.79, n = 6, I2 = 0.0% (not available)], whereas a marginal significance was observed in gastroesophageal junction cancer and the use of acid suppressive drugs [adjusted OR = 2.28; 95%CI: 0.97-5.35, n = 2, I2 = 0.0% (not available)]. However, there was no significant association between the use of acid suppressive drugs and gastric cardia cancer [adjusted OR = 0.88; 95%CI: 0.63-1.24, n = 4, I2 = 9.2% (0.0%-86.0%)]. The between-group differences in the effect estimates for non-cardia cancer vs gastroesophageal junction cancer vs gastric cardia cancer were significant (P = 0.03). The meta-regression according to the site of cancer indicated that the effect estimates for non-cardia cancers were significantly higher than those for cardia cancers (P = 0.02), and the effect estimates for gastroesophageal junction cancers were significantly different from those of cardia cancers (P = 0.04).

There was an increased risk of gastric cancer that was associated with the use of acid suppressive drugs in both high-quality [adjusted OR = 1.34; 95%CI: 1.21-1.48, n = 6, I2 = 0.0% (range, 0.0%-75.0%)] and low-quality [adjusted OR = 1.86; 95%CI: 1.49-2.32, n = 5, I2 = 63.5% (range, 4.0%-86.0%)] studies. No publication bias was observed in the selected studies (Figure 3, Begg’s funnel plot was symmetrical; Egger’s test, P for bias = 0.857).

Figure 3
Figure 3 Begg’s funnel plots and Egger’s test for identifying publication bias (P = 0. 857) in a meta-analysis of observational studies (n = 11). OR: Odds ratio.
DISCUSSION

In this meta-analysis of 11 observational studies, we found that both H2-receptor antagonist use and proton pump inhibitor use were associated with an increased risk of gastric cancer. In site-specific analyses, an increased risk of non-cardia gastric cancer was observed in patients who used acid suppressive drugs, whereas acid suppressive drug use was not associated with the risk of gastric cardia cancer.

Our meta-analysis has several strengths. This systemic review was the most comprehensive meta-analysis to date of observational studies that addressed the association between the use of acid suppressive drugs and the risk of gastric cancer, which included a large number of studies and participants. We performed a detailed analysis by stratifying the type of drugs (H2RAs or PPIs), the location of gastric cancer (gastroesophageal junction, cardia, or non-cardia), the duration of acid suppressive drug use, and the study quality.

Previous studies suggested that long-term H2RA use may increase gastric cancer[11-13], and long-term PPI treatment induced gastric fundic polyps, which led to the development of precancerous lesions[5-8]. There is biological evidence of the effect of acid suppressive drug use on the risk of gastric cancer. First, PPIs and H2RAs can reduce gastric acidity by modulating H(+)-K(+)-ATPase or competitive inhibitors of histamine binding sites in gastric parietal cells. Decreased gastric acidity, whether caused by gastric atrophy or acid suppressive drug-induced hypochlorhydria, may result in increased bacterial colonization and a greater number of bacteria that can produce nitrosamines[16,58], which are compounds that are associated with an increased risk of gastric adenocarcinoma[59]. Second, the reduction of gastric acid secretion by acid-suppressive drugs switches on the positive feedback of a gastric acid-producing cascade, which leads to hypergastrinemia[19]. This condition is a possible cause of carcinoids, gastric polyps, and gastric and colonic carcinomas because elevated serum gastrin could have a trophic effect on neoplastic growth in the gastrointestinal tract[60]. The use of long-term PPIs can cause hyperplasia in enterochromaffin-like cells and increase the incidence of atrophic gastritis and gastric polyps, which are a precursor to gastric cancer[37,38,43-46].

We found that acid suppressive drugs increased the risk of non-cardia gastric cancer, whereas acid suppressive drug use was not associated with a risk of gastric cardia cancer. One possible mechanism may be associated with the augmented effects of acid suppressive drugs and other risk factors of non-cardia gastric cancer, such as gastric atrophy and Helicobacter pylori (H. pylori) infection[61,62]. Several authors suggested that omeprazole treatment was associated with an elevated incidence of gastric corpus mucosal atrophy[63], and long-term PPI treatment in H. pylori infected patients could accelerate the development of corpus atrophic gastritis[64,65]. In addition, recent studies suggested that a history of H. pylori eradication prior to long-term PPI therapy could prevent the development of atrophic gastritis[57,66,67]. Considering this knowledge, further studies are needed to clarify the association between acid suppressive drug use and the risk of non-cardia gastric cancer, especially for patients with gastric atrophy and H. pylori infection.

We found that within 5 years of use, acid suppressive drugs increased the risk of gastric cancer, whereas there was a non-significant increased risk of gastric cancer among users of acid suppressive drugs for more than 5 years. Our meta-analysis was underpowered to detect statistically significant differences between the studies according to the duration of exposure; however, the qualitative differences were noteworthy. Early gastric symptoms of stomach cancer are typically similar to those of benign conditions, such as peptic ulcers, GERD, or functional gastrointestinal disease[23], which could lead to the use of acid suppressive drugs. Therefore, we could not exclude the possibility of misspecification and the protopathic bias of gastric cancer, especially among 5-year acid suppressive drug users. We found that two of the earliest studies (Møller et al[25] and La Vecchia et al[23]) contributed most significantly to the heterogeneity in the studies of H2RAs and in the studies that examined exposure within 5 years of the incidence of cancer. These studies may have been influenced by misspecification because endoscopic tools that would have detected early stage cancer were not readily available when the studies were conducted. There could be bias due to existing gastric conditions; however, we recommend that future studies carefully consider the appropriate control of previous gastric conditions.

Our meta-analysis has several limitations. First, most of the studies in our meta-analysis were observational studies. Observational studies, even when well-controlled, are susceptible to various biases, which may reduce the quality of the analysis. Second, most of the studies in our meta-analysis came from Western countries. The occurrence of gastric cancer is rapidly increasing in the United States and in Western Europe[68]; however, this disease is a more significant public health problem in Asia. Third, we did not have access to individual data on dose-response relationships that may have affected gastric acid production. Finally, we could not evaluate the effect of underlying gastric conditions, e.g., H. pylori infection, because these data were not presented in each study.

Our meta-analysis demonstrated that the use of acid suppressive drugs was associated with an increased risk of gastric cancer. Our findings should be confirmed by more prospective cohort studies that are designed with larger sample sizes and longer follow-up durations to test the effect of acid suppressive drugs on the risk of gastric cancer. These studies should focus on previous underlying gastric conditions for which acid suppressive drugs are prescribed and the dose response of acid suppressive drugs use.

COMMENTS
Background

The widespread use of acid suppressive drugs has led to concern about the development of adverse effects owing to prolonged gastric acid suppression, particularly the development of gastric polyps or gastric neoplasms. Authors performed a meta-analysis of cohort studies and case-control studies to determine whether the use of acid suppressive drugs, such as histamine 2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs), can increase the risk for gastric cancer.

Research frontiers

Several case reports suggested that antacids may increase the risk of gastric polyps or cancer. Several epidemiological studies have evaluated the association between long-term gastric acid suppression and the risk of gastrointestinal neoplasms. However, epidemiological studies have reported inconsistent findings regarding the association between the use of acid suppressive drugs and gastric cancer risk. To date, no systematic meta-analysis has been published on the use of acid suppressive drugs and the risk of gastric cancer.

Innovations and breakthroughs

In this meta-analysis of case-control and cohort studies, the authors found that both H2RA and PPI use were associated with an increased risk of gastric cancer. In site-specific analyses, an increased risk of non-cardia gastric cancer was observed in patients who used acid suppressive drugs, whereas acid suppressive drug use was not associated with a risk of gastric cardia cancer.

Applications

The use of acid suppressive drugs is associated with an increased risk of gastric cancer. However, authors could not exclude the possibility of misspecification and the protopathic bias of gastric cancer. The early gastric symptoms of stomach cancer are typically similar to those of benign conditions, such as peptic ulcers, gastroesophageal reflux disease, or functional gastrointestinal disease, which could lead to the use of acid suppressive drugs. There could be bias due to existing gastric conditions; therefore, they recommend that future studies carefully consider the appropriate control of previous gastric conditions.

Terminology

Acid suppressive drugs can reduce gastric acidity by modulating H(+)-K(+)-ATPase or competitive inhibitors of histamine binding sites in gastric parietal cells, which leads to hypergastrinemia. This condition is a possible cause of carcinoids, gastric polyps, and gastric and colonic carcinomas because elevated serum gastrin could have a trophic effect on neoplastic growth in the gastrointestinal tract.

Peer review

This study may lead conclusion that acid suppressive drugs such as H2R blocker or PPI may act as a stimulator for gastric cancer. It is difficult to obtain a substantial conclusion from 11 studies adopted by this paper because all 11 papers were observational study and no information on Helicobacter pylori infection. This paper is good for publication.

Footnotes

P- Reviewer Nagahara H S- Editor Wen LL L- Editor A E- Editor Xiong L

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