Critique 221: The relation of alcohol intake to stomach cancer – 20 November 2018

Wang SM, Freedman ND, Loftfield E, Hua X, Abn CC. Alcohol consumption and risk of gastric cardia adenocarcinoma and gastric noncardia adenocarcinoma: A 16-year prospective analysis from the NIH-AARP diet and health cohort. Int J Cancer 2018; pre-publication.

Authors’ Abstract

Introduction: The role of alcoholic beverages in the etiology of gastric cancer is unclear. Recent summaries showed a positive association between higher alcohol intake and gastric cancer risk, but the magnitude of association is small, there is moderate heterogeneity among studies, and most cases were from Asian populations.

Methods: We prospectively investigated the associations of alcohol consumption with gastric cardia adenocarcinoma (GCA) and gastric noncardia adenocarcinoma (GNCA) in 490,605 adults, aged 50–71 years at baseline who participated in the NIH-AARP diet and health study. Alcohol consumption in the past year was assessed at baseline by questionnaire and defined as total grams of ethanol intake per day or as a categorical variable: nondrinker, up to or including one drink per day, one to three drinks per day and greater than three drinks per day. We used multivariable-adjusted Cox proportional hazards regression to calculate the hazard ratios (HR) and 95% confidence intervals (CI) for associations between alcohol intake and risk of gastric adenocarcinomas.

Results: Through 2011, 662 incident cases of GCA and 713 of GNCA occurred. We found no association between higher alcohol consumption and GCA or GNCA, when examined as total alcoholic beverage intake or individual beverage types of beer, wine and liquor. Furthermore, we observed no association by stratum of sex, ethnic group, educational level or smoking status. We did, however, observe lower risk of GNCA among participants who drank up to one drink per day (HR = 0.81, 95% CI: 0.67–0.97) compared to nondrinkers.

Conclusion: In conclusion, alcohol consumption was not associated with increased risk of GCA or GNCA in this large U.S. cohort.

Forum Comments

Forum members considered this to be important paper as it is based on a very large group of subjects, and especially since it is from a single culture. Subjects are from the USA, so the analyses do not mix Westerners with Asians (who have a very different diet, other cultural factors, and a higher risk of gastric cancer).

Background: Reviewer Stockley provided a very good review of previous research on this topic. “The literature has been conflicting concerning the relationship between the consumption of alcoholic beverages and risk of gastric cancer and few studies have distinguished between cancer sublocations and tumour morphologies. Five studies suggested that there was a positive association between wine, for example, and the risk of gastric cancers, in particular for heavy consumers of wine who displayed up to a six-fold increase in risk (Benedetti et al; Hoey et al; de Stefani, Correa et al; De Stefani, Boffetta et al; Falcao et al). Two studies saw an inverse relationship for wine consumption but not for beer and spirits and one study saw no association (Boeing et al; Gammon et al; Marron et al). Similar to cancers of the UADT, it has been suggested that the ethanol and other compounds present in alcoholic beverages such as nitrosamines such as NDMA found in beer and spirits damage the gastric mucosa initiating gastric carcinogenesis (Gonzales et al; de Stefani, Boffetta et al). In addition, the occurrence of alcohol-related cancers of the gastric mucosa appears to be amplified by concomitant tobacco use and may be influenced by the presence of Helicobacter pylori (HP) infection in the gastric mucosa (Hardbower et al). Accordingly, meta-analyses that have not differentiated between wine, beer and spirits have observed a lack of association between light to moderate alcohol consumption and gastric cancer risk but a potentially positive association with heavy alcohol drinking (Tramacere, Negri, et al; Tramacere, Pelucchi, et al; Bagnardi et al). This was also observed from the limited number of observational studies, albeit less consistently, for alcohol consumption.”

Kunzmann et al presented data from a population-based cohort study of almost 100,000 older subjects who were followed for the occurrence of death from cancer over a median of 8.9 years. There were large numbers of deaths (n=9,599) and incident cancers (n=12,763) diagnosed during follow up, which should lead to more precise estimates of effect. The authors report that light-to-moderate drinking was associated with lower total mortality, but the risk of incident cancer increased with greater alcohol consumption, especially the intake of beer or spirits. However, the analyses indicate that the slightly increased risk of cancer associated with moderate alcohol consumption was less than the beneficial effect on mortality.

Comments of Forum members on the present analyses: Reviewer Waterhouse noted: “This study does a fine job of implementing a good set of controls for potentially confounding variables, such a smoking, education, BMI, etc., and also has the size to help resolve small effects, and the varying results previously reported. It is interesting that there is very little effect of drinking on these cancers, but their explanation comparing this North American population to Asian ones is very logical. Those who have deficient acetaldehyde dehydrogenase, typical in Asian populations, accumulate some acetaldehyde, a well-known carcinogen, and the cause of flushing. Since the acetaldehyde circulates, we might also expect to see an increase in other cancers among drinkers of Asian heritage.”

Forum member Skovenborg wrote: “I agree with the comments from Waterhouse and especially the differences in risk of cancer in the upper aerodigestive tract between European and North American population compared to East Asian populations. About 40% of Japanese have the inactive ALDH2*2 allele (e.g., 7% are homozygous and 35% are heterozygous), which acts in a dominant manner. After drinking 0.1 g ethanol/kg body weight, homozygotes for inactive ALDH2 and heterozygotes for inactive ALDH2 had 18 times higher and 5 times higher peak blood acetaldehyde concentrations, respectively, than active ALDH2*1/*1 homozygotes who had consumed 0.8 g ethanol/kg body weight (Enomoto et al).
“The results of a multicenter case-control study of 234 esophageal SCC cases and 634 controls found that the OR of moderate drinkers (198–365 g ethanol/week) with the ALDH2*1/*2 genotype was 55.8 (15.4–202.5) when never/rare drinkers (< 22 g ethanol/week) were used as the reference group, and that far exceeded the OR of 10.4 (2.9–37.8) of heavy drinkers (≥ 396 g ethanol/week) with the ALDH2*1/*1 genotype (Yokoyama et al).

Reviewer Van Velden noted: “This paper demonstrates the importance of small genetic poplymorphisms in the reaction on alcohol consumption. Fortunately, people with deficient acetaldehide dehydrrogenase do not drink because they suffer from headaches due to this metabolic abnormality. Our genetic makeup is also becoming a confounder.” Forum member Ursini added: “I agree — differences among human beings matter.”

Relating alcohol consumption to cancer risk: Reviewer Ellison noted that there are a number of cancers, especially those of the upper aero-digestive track, that are markedly increased among alcohol use abusers and other heavy drinkers; most studies do not show increased risk for such cancers for light drinkers. For example, Breslow et al combined data from the 1988, 1990, 1991, and 1997-2004 administrations of the National Health Interview Survey (n = 323,354) and evaluated the association with alcohol consumption. They found that light drinkers did not show an increased risk for total or for any site-specific cancer.
As for the present paper, Forum Member Teissedre wrote: “I fully endorse the critique and support the different comments of our colleagues.” Forum member Finkel, an oncologist, stated: “I was happy to read this paper on gastric carcinoma’s risk relationship to drinking. I have no quarrel with the study. After an epidemic of alarmist papers declaiming that even the pronunciation of the word “alcohol” leads to cancer, this one feels refreshing.”

Effects according to the type of beverage consumed: Many studies have reported that the type of beverage usually consumed has significant effects on health outcomes. As early as 1995, Grønbaek, Deis et al found that total mortality risk increased with greater intake of spirits, did not change with beer, and showed a decrease with wine consumption. These authors also noted that the increased risk of upper aero-digestive cancers associated with larger amounts of alcohol varied across beverage types: increases for more than 1 drink/day were seen for beer and spirits, but no significant effect was seen for wine (Grønbaek, Becker et al). These authors concluded: “A moderate intake of wine probably does not increase the risk of upper digestive tract cancer, whereas a moderate intake of beer or spirits increases the risk considerably.” A report from Kunzmann et al showed similar results.

Reviewer Goldfinger notod: “The relationship between alcohol and cancer is complex. Alcohol, likely in moderate to large amounts is carcinogenic, however there are considerable experimental and epidemiologic data suggesting that wine balances this risk with the anti-neoplastic effects of its non-alcohol components.” However, the present study does not support additional benefits from wine in comparison with those from other beverages.

Under-reporting of alcohol intake: It should be realized that all studies of alcohol consumption are based on self-report, and under- or over-reporting should be taken into consideration. Using extensive data from the very large Kaiser-Permanente studies, Klatsky et al have found that subjects likely to be under-reporters of their alcohol intake can be reasonably well identified by evidence of alcohol misuse in their datasets, and show increased risk of cancer associated even with what they report as “moderate” alcohol intake.

In the Klatsky et al studies, among subjects reporting 1-2 drinks/day who had at some time been found to have health or social problems related to alcohol (e.g., diagnoses of alcoholic hepatitis, cirrhosis, absences from work from excessive drinking, etc.) were labeled as “likely under-reporters.” Other subjects who had adequate study records that provided no evidences of alcohol misuse were and labeled as “unlikely under-reporters”. When relating the risk of cancer from all subjects reporting 1-2 drinks/day, an increase in risk of cancer was seen only among the likely under-reporters (RR=1.22 for likely under-reporters; 0.98 for unlikely under-reporters; and 1.20 for those without adequate evidence to judge under-reporting). Such data indicate that a better estimate of self-reported alcohol intake can provide more accurate estimates of effect of alcohol on health.

Insights into the relation of alcohol to cancer from studies of alcohol and breast cancer: The question of alcohol as a cause of cancer has been widely touted by certain investigators and in the lay media. While everyone agrees that large amounts of alcohol contribute to the risk of many cancers, some scientists continually return to the finding that “even light drinking may increase the risk of breast cancer.” Indeed, consumers of as low as 1 drink/day have shown evidence of an increase in risk in most studies, although factoring in the intake of folate, binge drinking, concurrent use of hormone replacement therapy, etc. tend to significantly lower the risk.

It is interesting that a number of large studies indicate that mortality from breast cancer does not appear to be increased for light-to-moderate drinkers, including those who consume alcohol after the diagnosis of cancer. In a report from the very large Nurses’ Health Study, Fuchs et al found that the association between alcohol consumption and death from breast cancer was U-shaped, with a RR of 0.67 for light consumers in comparison with non-drinkers. Similarly, in a study of 3,146 women with invasive breast cancer, Harris et al found that women with invasive breast cancer who consumed 3.4-9.9 g per day of alcohol had a lower risk of deaths (also, a RR 0.67) compared with non-drinkers, while women reporting ≥10 g/d had an adjusted HR of 1.36 (95% CI 0.82-2.26) compared with non-drinkers.

Lowry et al reported alcohol use and breast cancer survival among participants in the Women’s Health Initiative. This study included 7,835 women from the Women’s Health Initiative observational study and randomized trial diagnosed with breast cancer. Women who were consuming alcohol prior to their breast cancer diagnosis had a non-statistically significant 24% (95% CI, 0.56–1.04) reduced risk of breast cancer mortality and a 26% (95% CI, 0.61–0.89) reduced risk of all-cause mortality. Post-diagnosis alcohol consumption, and change in consumption patterns after diagnosis, did not appear to be associated with all-cause or breast cancer mortality.

In another very large study, Alaa et al reported associations with alcohol intake for 29,239 cases with 4,839 deaths, available from the 11 case cohorts. Pre-diagnosis consumption was associated with better survival: HR 0.80 (95% CI 0.73-0.88), while moderate post-diagnosis alcohol consumption was not associated with overall survival: HR 0.95 (95% CI 0.85-1.05). These authors concluded that, considering the totality of the evidence, moderate post-diagnosis alcohol consumption is unlikely to have a major adverse effect on the survival of women with breast cancer.

In contrast to protective effects of small amounts of alcohol in these studies, Kwan et al reported on 1,897 LACE study women participants who were diagnosed with early-stage breast cancer. During 7.4 years of follow-up: 293 breast cancer recurrences and 273 overall deaths. 958 of the women were drinkers (> 0.5 g/d of alcohol); the majority drank wine (89%). Drinking ≥ 6 g/d of alcohol compared with no drinking was associated with an increased risk of breast cancer recurrence: HR 1.35 (95% CI 1.00-1.83) and death due to breast cancer: HR 1.51 (95% CI 1.00-2.29). However, alcohol intake was not associated with all-cause death: HR 0.98 (95% CI 0,74-1.31) and possibly associated with decreased risk of non-breast cancer death: HR 0.84 (95% CI 0.54-1.33).

Ligibel has commented on the relationship between potentially modifiable lifestyle factors and risk of a second primary contralateral breast cancer among women diagnosed with estrogen receptor-positive invasive breast cancer: “Although regular alcohol intake has been linked to risk of primary breast cancer, moderate alcohol intake may actually have beneficial health effects, such as lowering the risk of heart disease. Given the inconsistencies regarding the relationship between moderate alcohol use and adverse outcomes in patients with breast cancer, it would be premature to counsel survivors to avoid all alcohol, based on current evidence.”

Forum member Skovenborg provides an overview: “Newcomb et al provide reassurance that modest alcohol consumption is not adversely associated with breast cancer–specific mortality and may, in fact, be associated with reduction in deaths due to cardiovascular disease as well as overall mortality. As more and more women survive their breast cancers and remain at risk for other conditions, investigation of these issues is increasingly important. Based on the best available evidence it appears that modest alcohol consumption after breast cancer diagnosis, up to approximately one drink per day on average, may be associated with optimal overall survival, without compromising breast cancer–specific survival.” Forum members agreed that considering overall health and mortality is necessary when providing advice regarding alcohol consumption; as long as the intake is light, the net health effects are almost all positive.

References from Forum critique

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Bagnardi V, Rota M, Botteri E, Tramacere I, Islami F . . . Corrao G, Boffetta P, La Vecchia C, et al. Alcohol consumption and site-specific cancer risk: a comprehensive dose-response meta-analysis. Br J Cancer 2015;112:580-593.

Benedetti ME, Parent, Siemiatycki J. Lifetime consumption of alcoholic beverages and risk of 13 types of cancer in men: results from a case-control study in Montreal. Cancer Detect Prev 2009;32:352-362.

Boeing H, Frentzel-Beyme R, Berger M, et al. Case-control study on stomach cancer in Germany. Int J Cancer 1991;47:858-864.

Breslow RA, Chen CM, Graubard BI, Mukamal KJ. Prospective study of alcohol consumption quantity and frequency and cancer-specific mortality in the US population. Am J Epidemiol 2011;174:1044-1053.

De Stefani F, Correa P, Fierro L, Carzoglio J, Deneo-Pellegrini H, Zavala D. Alcohol drinking and tobacco smoking in gastric cancer. A case-control study. Rev Epidemiol Sante Publique 1990;38:297-307.

De Stefani E, Boffetta P, Carzoglio J, Mendilaharsu S, Deneo-Pellegrini H. Tobacco smoking and alcohol drinking as risk factors for stomach cancer: a case-control study in Uruguay. Cancer Causes Control 1998;9:321-329.

Enomoto N, Takase S, Yasuhara M, Takada A: Acetaldehyde metabolism in different aldehyde dehydrogenase-2 genotypes. Alcohol Clin Exp Res 1991;15:141–144.

Falcao JM, Dias JA, Miranda AC, Leitao CN, Lacerda MM, da Motta LC. Red wine consumption and gastric cancer in Portugal: a case-control study. Eur J Cancer Prev 1994;3:269-276.

Fuchs CS, Stampfer MJ, Colditz GA, Giovannucci EL, Manson JE, Kawachi I, Hunter DJ, Hankinson SE, Hennekens CH, Rosner B. Alcohol consumption and mortality among women. N Engl J Med 1995;332:1245-1250.

Gammon MD, J.B. Schoenberg, H. Ahsan H. Risch HA, Vaughan TL, Chow WH, Rotterdam H, West AB, Dubrow R, Stanford JL, Mayne ST, Farrow DC, Niwa S, Blot WJ, Fraumeni JF Jr. Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia. J Natl Cancer Inst 1997;89:1277-1284.

González CA, Agudo A, Montes J, Riboli E, Sanz JM. Tobacco and alcohol intake in relation to adenocarcinoma of the gastric cardia in Spain. Cancer Causes Control 1994;5:88-89.

Grønbæk M, Deis A, Sørensen TIA, Becker U, Schnohr P, Jensen G. Mortality associated with moderate intake of wine, beer, or spirits. BMJ 1995;310:1165–1169.

Grønbaek M, Becker U, Johansen D, Tønnesen H, Jensen G, Sørensen TI. Population based cohort study of the association between alcohol intake and cancer of the upper digestive tract. Br Med J 1998;317:844-847.

Hardbower DM, Peek RM Jr, Wilson KT. At the Bench: Helicobacter pylori, dysregulated host responses, DNA damage, and gastric cancer. J Leukoc Biol 2014;96:201-212.

Harris HR, Bergkvist L, Wolk A. Alcohol intake and mortality among women with invasive breast cancer. The Swedish Mammography Cohort. Br J Cancer 2012;106:592-595.

Hoey J, Montvernay C, Lambert R. Wine and tobacco: risk factors for gastric cancer in France. Am J Epidemiol 1981;113:668-674.

Klatsky AL, Udaltsova N, Li Y, Baer D, Tran HN, Friedman GD. Moderate alcohol intake and cancer: the role of underreporting. Cancer Causes Control 2014;25:693–699. DOI 10.1007/s10552-014-0372-8.

Kunzmann AT, Coleman HG, Huang W-Y, Berndt SI. The association of lifetime alcohol use with mortality and cancer risk in older adults: A cohort study. PLoS Med 2018;15:e1002585.

Kwan ML, Chen WY, Flatt SW, Weltzien EK, Nechuta SJ, Poole EM, Holmes MD, Patterson RE, Shu XO, Pierce JP, Caan BJ. Postdiagnosis alcohol consumption and breast cancer prognosis in the after breast cancer pooling project. Cancer Epidemiol Biomarkers Prev 2013;22:32-41

Ligibel JA. Could modification of lifestyle factors prevent second primary breast cancers? J Clin Oncol 2009;27:5301-5302.

Lowry SJ et al. Cancer Epidemiol Biomarkers Prev 1–6. Publ. online May 19, 2016.

Marron M, Boffetta P, H. Møller, Ahrens W, Pohlabeln H, Benhamou S, et al. Risk of upper aerodigestive tract cancer and type of alcoholic beverage: a European multicenter case-control study. Eur J Epidemiol 2012;27:499-517.

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Tramacere I, Negri E, Pelucchi C, Bagnardi V, Rota M, Scotti L, Islami F, Corrao G, La Vecchia C, Boffetta P. A meta-analysis on alcohol drinking and gastric cancer risk. Ann Oncol 2012;23:28-36.

Tramacere I, Pelucchi C, Bagnardi V, Rota M, Scotti L, Islami F, Corrao G, Boffetta P, La Vecchia C, Negri E. A meta-analysis on alcohol drinking and esophageal and gastric cardia adenocarcinoma risk. Ann Oncol 2012;23:287-297.

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Forum Summary

There have been conflicting results from studies of the association between alcohol intake and the risk of gastric cancer. Some of the differences among studies have related to mixing subjects from Western countries with those from Asia, where dietary patterns, lifestyle factors, drinking patterns, and types of alcohol consumed differ from those among Western populations. Overall, gastric cancer rates are higher among Asians than in Western populations.

The present study is based on almost 500,000 subjects from the USA with follow up for a median of 15.5 years. The investigators identified a total of more than 1,300 cases of gastric cancer, made up of cases of gastric cardia cancer (GCA) or gastric noncardia cancer (GNCA ). The authors report: “We found no association between higher alcohol consumption and GCA or GNCA, when examined as total alcoholic beverage intake or individual beverage types of beer, wine and liquor. Furthermore, we observed no association by stratum of sex, ethnic group, educational level or smoking status. We did, however, observe lower risk of GNCA among participants who drank up to one drink per day (HR = 0.81, 95% CI: 0.67–0.97) compared to nondrinkers.” They conclude: “Alcohol consumption was not associated with increased risk of GCA or GNCA in this large U.S. cohort.”

Forum members considered this to be a large, very well-done analysis; subjects were aged 50-71 years at baseline, appropriate for evaluating the risk of gastric cancer. Data on a large number of potential confounders were included in the analysis. Diagnosis of cancer was from state cancer registries, shown to be very accurate. The statistical analyses included restricted spine analysis to test for a dose-response curve (not found), and excluded the first two years after alcohol assessment to lower the risk of reverse causality. Further beverage-specific analyses were carried out, and did not show differences according to whether the consumption was of beer, wine, or spirits.

Weaknesses included only one assessment of alcohol intake, at baseline, and no data on binge drinking or other aspects of the pattern of drinking. Subjects were generally well-educated, white, and consumed alcohol moderately (75% reported one drink or less). Thus, these results may not pertain to other ethnic groups or to heavier consumers of alcohol.

Overall, these results provide further support for the lack of an association between light-to-moderate alcohol intake and the risk of gastric cancer. The significant decrease in risk of gastric non-cardia cancer associated with consumption of up to one drink/day should obviously be replicated, but the authors provide some potential mechanisms that could explain such a phenomenon. The study did not support previous data suggesting that wine consumption might have additional benefits to those of other beverages in terms of cancer risk.

Reference: Wang SM, Freedman ND, Loftfield E, Hua X, Abn CC. Alcohol consumption and risk of gastric cardia adenocarcinoma and gastric noncardia adenocarcinoma: A 16-year prospective analysis from the NIH-AARP diet and health cohort. Int J Cancer 2018; pre-publication.

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Comments on this critique by the International Scientific Forum on Alcohol Research have been provided by the following members:                

R. Curtis Ellison, MD, Professor of Medicine, Section of Preventive Medicine & Epidemiology, Boston University School of Medicine, Boston, MA, USA

Harvey Finkel, MD, Hematology/Oncology, Retired (Formerly, Clinical Professor of Medicine, Boston University Medical Center, Boston, MA, USA)

Tedd Goldfinger, DO, FACC, Desert Cardiology of Tucson Heart Center, University of Arizona School of Medicine, Tucson, AZ, USA

Fulvio Mattivi, MSc, CAFE – Center Agriculture Food Environment, University of Trento, via E. Mach 1, San Michele all’Adige, Italy

Erik Skovenborg, MD, specialized in family medicine, member of the Scandinavian Medical Alcohol Board, Aarhus, Denmark

Creina Stockley, PhD, MSc Clinical Pharmacology, MBA (Formerly, Health and Regulatory Information Manager, Australian Wine Research Institute, Glen Osmond, South Australia) Australia

Arne Svilaas, MD, PhD, general practice and lipidology, Oslo University Hospital, Oslo, Norway

Pierre-Louis Teissedre, PhD, Faculty of Oenology–ISVV, University Victor Segalen Bordeaux 2, Bordeaux, France

Fulvio Ursini, MD, Dept. of Biological Chemistry, University of Padova, Padova, Italy

David Van Velden, MD, Dept. of Pathology, Stellenbosch University, Stellenbosch, South Africa

Andrew L. Waterhouse, PhD, Department of Viticulture and Enology, University of California, Davis, USA