## Abstract

Background: Whether an association between alcohol drinking and gastric cancer risk exists is an open question. In order to provide a definite quantification of the association between alcohol drinking and gastric cancer risk, we conducted a meta-analysis of available data.

Patients and methods: We carried out a PubMed search of articles published up to June 2010 and identified 44 case–control and 15 cohort studies, including a total of 34 557 gastric cancer cases. We derived meta-analytic estimates using random-effects models, taking into account correlation between estimates. We carried out a dose–risk analysis using nonlinear random-effects meta-regression models.

Results: Compared with nondrinkers, the pooled relative risk (RR) was 1.07 [95% confidence interval (CI) 1.01–1.13] for alcohol drinkers and 1.20 (95% CI 1.01–1.44) for heavy alcohol drinkers (≥4 drinks per day). The pooled estimates were apparently higher for gastric noncardia (RR for heavy drinkers = 1.17, 95% CI 0.78–1.75) than for gastric cardia (RR = 0.99, 95% CI 0.67–1.47) adenocarcinoma. The dose–risk model estimated a RR of 0.95 (95% CI 0.91–0.99) for 10 g/day and 1.14 (95% CI 1.08–1.21) for 50 g/day.

Conclusions: This meta-analysis provides definite evidence of a lack of association between moderate alcohol drinking and gastric cancer risk. There was, however, a positive association with heavy alcohol drinking.

## introduction

Whether an association between alcohol drinking and stomach cancer risk exists is an open question. In 1988, an International Agency for Research on Cancer (IARC) working group concluded that there was inadequate evidence for the carcinogenicity of alcohol on gastric cancer [1]. In 2007, in a reassessment of the carcinogenicity of alcoholic beverages, the IARC working group concluded that for stomach cancer ‘there were suggestions that alcohol consumption might be associated with an increased risk, but confounding by smoking and dietary habits could not be ruled out’ [2].

A relation between alcohol drinking and gastric cancer risk is biologically plausible. Heavy alcohol consumption could cause chronic gastritis, which could predispose to cancer [3, 4]. However, it is unclear whether any potential relation between large amounts of alcohol drinking and stomach cancer risk is real or due to residual confounding by smoking and other risk factors of gastric cancer. Moreover, it is not known whether alcohol exerts a different carcinogenic effect on different portions of the stomach, notably on the cardia.

To address these issues, we conducted a meta-analysis of studies published on alcohol consumption and the risk of stomach cancer.

## materials and methods

### identification of studies and data collection

We carried out a literature search, using PubMed, of all case–control and cohort studies published as original articles in English up to June 2010, using the MeSH terms ‘alcohol drinking’ or ‘alcoholic beverages’ and ‘stomach neoplasms’, following the Meta-analysis Of Observational Studies in Epidemiology guidelines [5]. Supplemental Figure S1 (available at Annals of Oncology online) provides the flowchart for the selection of articles. Three of the authors (FI, LS and IT) retrieved and assessed potentially relevant papers, and reviewed the reference list in the articles to identify additional publications of interest. When multiple reports were published on the same study, we considered in the meta-analysis only the most informative one (usually, the most recent report). We identified 87 publications, of which 27 were excluded because they did not fulfill the inclusion criteria [i.e. studies not reporting the odds ratio (OR) or relative risk (RR) and the corresponding 95% confidence intervals (CIs), or sufficient information to calculate them], and one was excluded for inconsistency of the ethanol content estimation (i.e. drinks of beverages and grams of ethanol per day were inconsistent) [6]. Thus, the present analyses were based on 59 studies, including 44 case–control [7–50] and 15 cohort [51–65] studies.

For each study, we extracted information on study design, country, number of subjects (cases, controls or cohort size), type of controls and period of enrollment for case–control studies, duration of follow-up for cohort studies, cancer site, sex distribution of the study population, variables adjusted for in the analysis, RR estimates and the corresponding CI and, when available, the number of cases and noncases or person-years for each category of alcohol consumption.

### statistical analyses

The measure of interest was the RR (or the OR in case–control studies). Whenever available, we used multivariate-adjusted risk estimates; otherwise, we utilized or computed from the exposure distributions given in the papers the unadjusted RRs. When studies reported adjusted RR estimates without CIs, we computed the standard error (SE) using the SE from the unadjusted RR estimate penalized by a factor of 1.5, consistently with our companion meta-analyses on alcohol drinking and oral/pharyngeal [66] and laryngeal [67] cancers.

Since different units were used to express alcohol intake, we converted alcohol consumption categories into grams of ethanol per day as a standard measure of alcohol intake. The dose associated to each RR estimate was computed as the midpoint of each exposure category, and, for the open-ended upper category, as 1.2 times its lower bound [68]. We defined a drink as 12.5 g of ethanol. When possible, we chose nondrinkers as the reference category; however, in several studies, occasional drinkers were included in the reference category. We defined heavy alcohol drinking as drinkers of ≥4 drinks per day. If in a particular study more than one category fell in the exposure level considered, we combined the corresponding estimates using the method proposed by Hamling et al. [69]. This method was used to combine estimates using the same reference category or the same set of controls (e.g. gastric cardia versus gastric noncardia), taking into account correlation between estimates. It uses the adjusted estimates and the number of exposed and nonexposed subjects to derive a corresponding set of pseudonumbers of cases and controls/subjects at risk consistent with the reported adjusted estimates.

We generated forest plots for alcohol drinkers versus nondrinkers, overall, by cancer subsite (cardia versus noncardia) and by geographic area (Asian versus non-Asian studies). We also calculated the corresponding RR estimates of gastric cancer for heavy alcohol drinking and the RRs for alcohol drinkers versus nondrinkers in strata of selected covariates. Moreover, we computed RRs of gastric cancer based on studies reporting estimates for nonsmokers only. All the meta-analytic estimates were derived using random-effects models [70]. We assessed the heterogeneity among studies using the chi-square test [70], defining a significant heterogeneity as a P value of <0.10 and quantified the inconsistency using the I-squared statistic [71].

We carried out a dose–response analysis using a random-effects meta-regression model in a nonlinear dose–response relationship framework, providing the best-fitting two-term fractional-polynomial model [72].

We also carried out a publication bias analysis through the contour-enhanced funnel plot [73] and the Egger’s test for funnel plot asymmetry [74].

## results

The main characteristics of the 59 studies [7–65] included in the meta-analysis are given in supplemental Table S1 (available at Annals of Oncology online). A total of 34 557 gastric cancer cases were included.

Figure 1 shows the RRs of gastric cancer and alcohol drinking (drinkers versus nondrinkers), overall, by anatomic subsite and by geographic area. The overall RR, based on 44 case–control and 15 cohort studies, was 1.07 (95% CI 1.01–1.13). The corresponding estimates were 1.08 (95% CI 1.00–1.18) for case–control and 1.04 (95% CI 0.97–1.11) for cohort studies (P for heterogeneity = 0.488). The summary RRs were 0.94 (95% CI 0.78–1.13) for gastric cardia and 1.07 (95% CI 0.91–1.26) for gastric noncardia (P for heterogeneity = 0.303), based on 11 (two cohorts) and 13 (three cohorts) studies, respectively. The RR for drinkers versus nondrinkers was 1.02 (95% CI 0.95–1.09) among Asian and 1.12 (95% CI 1.01–1.24) among non-Asian studies (P for heterogeneity = 0.138).

Figure 1.

Summary relative risks (RRs) of alcohol drinking (drinkers versus nondrinkers) and gastric cancer, overall (A), by anatomic subsite (B) and by geographic area (C). M, men; W, women; M + W, men and women considered together; PY, person years.

Figure 1.

Summary relative risks (RRs) of alcohol drinking (drinkers versus nondrinkers) and gastric cancer, overall (A), by anatomic subsite (B) and by geographic area (C). M, men; W, women; M + W, men and women considered together; PY, person years.

Figure 2 shows the forest plots for heavy alcohol drinking, overall, by anatomic subsite and by geographic area. The overall RR, based on 13 studies, was 1.20 (95% CI 1.01–1.44). The RR was somewhat weaker in cohort (RR = 1.12, 95% CI 0.85–1.48) than in case–control (RR = 1.22, 95% CI 0.98–1.52) studies. The estimates were 0.99 (95% CI 0.67–1.47) for gastric cardia and 1.17 (95% CI 0.78–1.75) for gastric noncardia (P for heterogeneity = 0.561), both based on five (all case–control) studies. The RR for heavy alcohol drinking was 0.90 (95% CI 0.65–1.25) among Asian and 1.39 (95% CI 1.14–1.69) among non-Asian studies (P for heterogeneity = 0.026).

Figure 2.

Summary relative risks (RRs) of heavy alcohol drinking (≥4 drinks per day) and gastric cancer, overall (A), by anatomic subsite (B) and by geographic area (C). M, men; W, women; M + W, men and women considered together.

Figure 2.

Summary relative risks (RRs) of heavy alcohol drinking (≥4 drinks per day) and gastric cancer, overall (A), by anatomic subsite (B) and by geographic area (C). M, men; W, women; M + W, men and women considered together.

Table 1 considers the association between alcohol and gastric cancer, in stratified analyses. No significant differences were found across strata of sex, geographic area or between studies with and without adjustment for smoking and fruit and vegetable consumption. Among nonsmokers, the summary RR for alcohol drinking was 1.06 (95% CI 0.96–1.17; I-squared = 0.0%, P = 0.520), based on four case–control and three cohort studies (data not shown).

Table 1.

Summary RRs of alcohol drinking (drinkers versus nondrinkers) and gastric cancer, in strata of selected covariates

 n RR (95% CI) $χ12$ Heterogeneity (P value) Total 59 1.07 (1.01–1.13) Sex Men 31 1.07 (0.91–1.26) 0.924 (0.336) Women 16 0.96 (0.83–1.12) Geographic area Asia 26 1.02 (0.95–1.09) 2.204 (0.138) Other countries 32 1.12 (1.01–1.24) Adjustment for smoking habit Unadjusted estimates 32 1.04 (0.96–1.11) 1.336 (0.248) Adjusted estimates 29 1.12 (1.01–1.24) Adjustment for fruit and vegetable consumption Unadjusted estimates 47 1.05 (1.00–1.12) 0.904 (0.342) Adjusted estimates 13 1.16 (0.95–1.41)
 n RR (95% CI) $χ12$ Heterogeneity (P value) Total 59 1.07 (1.01–1.13) Sex Men 31 1.07 (0.91–1.26) 0.924 (0.336) Women 16 0.96 (0.83–1.12) Geographic area Asia 26 1.02 (0.95–1.09) 2.204 (0.138) Other countries 32 1.12 (1.01–1.24) Adjustment for smoking habit Unadjusted estimates 32 1.04 (0.96–1.11) 1.336 (0.248) Adjusted estimates 29 1.12 (1.01–1.24) Adjustment for fruit and vegetable consumption Unadjusted estimates 47 1.05 (1.00–1.12) 0.904 (0.342) Adjusted estimates 13 1.16 (0.95–1.41)

RR, relative risk; CI, confidence interval.

Figure 3 shows the dose–response analysis, giving the RR function and the corresponding 95% CI for the best-fitting relationship between alcohol consumption and gastric cancer risk [i.e. ln(RR) = ln(dose) + dose1/2]. This function has a minimum at 10 g/day, and the estimated RRs are 0.95 (95% CI 0.91–0.99) for 10, 1.01 (95% CI 0.96–1.06) for 25, 1.14 (95% CI 1.08–1.21) for 50, 1.30 (95% CI 1.19–1.40) for 75, 1.45 (95% CI 1.31–1.62) for 100 and 1.62 (95% CI 1.42–1.85) for 125 grams of ethanol per day.

Figure 3.

Relative risk function and the corresponding 95% confidence interval, describing the best-fitting dose–response relationship between alcohol consumption and gastric cancer risk.

Figure 3.

Relative risk function and the corresponding 95% confidence interval, describing the best-fitting dose–response relationship between alcohol consumption and gastric cancer risk.

Supplemental Figure S2 (available at Annals of Oncology online) shows the contour-enhanced funnel plot of studies on the association between alcohol drinking and gastric cancer risk. The graph appears to be symmetrical, suggesting the absence of a publication bias. Likewise, we found no asymmetry according to the Egger’s test (P = 0.240).

## discussion

In the present meta-analysis, we found no association between moderate alcohol drinking and gastric cancer risk, but a positive association with heavy alcohol consumption. Our results provide, therefore, more precise and valid estimates of risk than previously available [11, 18, 22, 33, 38, 54, 63].

We found higher RRs for gastric noncardia than for gastric cardia adenocarcinoma, where there was no indication of any excess. Likewise, for esophageal adenocarcinoma, several studies failed to find a consistent association with alcohol [75]. Moreover, in a companion meta-analysis on alcohol consumption and esophageal and gastric cardia adenocarcinoma risk, we did not find any association even at higher doses.

We also found a significant heterogeneity for heavy alcohol drinking by geographic area, suggesting no excess risk among Asian studies. This can be related to a role of aldehyde dehydrogenase (ADH) and alcohol dehydrogenase (ALDH) polymorphisms, which have been related to excess head and neck, esophageal and gastric cancer risk in Japan [76–78]. In fact, subjects with the ADH and ALDH mutant alleles cannot be heavy drinkers, and this reduces the prevalence of heavy drinking in Asian population [76–78].

Our results are in accordance with those of a Chinese cohort study published in September 2010, and thus not included in the present meta-analysis, based on 18 244 men followed for 20 years and 391 incident gastric cancer cases, which found, compared with nondrinkers, hazard ratios of 1.03 (95% CI 0.83–1.26) for drinkers, 0.94 (95% CI 0.76–1.18) for moderate (<4 drinks per day) and 1.46 (95% CI 1.05–2.04) for heavy drinkers (≥4 drinks per day) [79].

Considering drinkers versus nondrinkers, we found no significant difference across strata of any selected covariates, including adjustment for smoking and fruit and vegetable consumption, indicating a lack of appreciable confounding effect due to these factors. Moreover, among nonsmokers, we found a RR similar to the overall estimate. However, a confounding effect due to dietary habits cannot be ruled out. In fact, heavy alcohol drinking is commonly associated with poor nutrition and this could increase the risk in heavy drinkers [80–82]. The dose–risk relation had a minimum at 10 g/day. This may be due to a favorable role of moderate alcohol consumption on Helicobacter pylori gastric infection, or, most likely, to the observation that moderate drinkers tend to have more favorable dietary patterns than both nondrinkers and heavy drinkers in several populations [80–82].

H. pylori is a major risk factor for gastric cancer [83, 84] and is present in most (if not all) cases. Adequate adjustment for H. pylori is therefore impossible. Thus, there was no study reporting RR for alcohol consumption and gastric cancer adjusted for H. pylori infection. Only one study [38] reported gastric cancer risk associated with vodka consumption among H. pylori-positive and H. pylori-negative subjects. Compared with H. pylori-negative subjects, H. pylori-positive subjects showed a slightly higher OR for vodka drinking (2.3 versus 2.0), in the absence, however, of a significant interaction between vodka and H. pylori infection (P = 0.51) [38].

With reference to possible limitations, in this meta-analysis there was no significant heterogeneity in several estimates. Furthermore, the use of the random-effects model to derive summary estimates allowed to account for heterogeneity among studies [70]. Moreover, the contour-enhanced funnel plot and the Egger’s test for funnel plot asymmetry did not support the presence of major publication bias, providing further indication of the robustness of our results. A more general issue is that alcohol drinking, and particularly heavy drinking, is underreported in observational studies. However, studies investigating reproducibility and validity of self-reported alcohol drinking in various populations found satisfactory correlation coefficients i.e. between 0.61 and 0.99 [85–90]. Moreover, estimates from cohort studies, which are less subject to bias (e.g. the differential reporting of alcohol consumption), were lower, but not significantly different, compared with case–control ones.

Thus, the present comprehensive meta-analysis provides evidence of a lack of appreciable association between moderate alcohol drinking and gastric cancer risk. There was, however, a positive association with heavy alcohol drinking, particularly for noncardia adenocarcinomas.

## funding

This work was conducted with the contribution of the Italian Association for Cancer Research (AIRC), project No. 10068 and 10258 My First AIRC Grant (MFAG), and the Flight Attendant Medical Research Institute (FAMRI) Center of Excellence Award, project No. 052460_CoE. IT was supported by a fellowship from the Italian Foundation for Cancer Research (FIRC).

## disclosure

The authors declare no conflict of interest.

The authors thank I. Garimoldi for editorial assistance.

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