Critique 253 – The relation of alcohol consumption to the risk of glioma tumors of the brain – 5 January 2022

Cote DJ, Samanic CM, Smith TR, Wang M, Smith‑Warner SA, Stampfer MJ, Egan KM.  Alcohol intake and risk of glioma: results from three prospective cohort studies.  Eur J Epidemiol 2021;36:965–974. https://doi.org/10.1007/s10654-021-00800-1

Authors’ Abstract

Purpose The association between alcohol intake and glioma remains unclear. We evaluated the association between alcohol intake and incidence of glioma in three large, prospective cohort studies with repeated alcohol assessments.

Methods We harnessed data from three studies with repeat alcohol assessment to compute hazard ratios (HR) and 95% confidence intervals (CI) for glioma by overall alcohol intake and intake from specific beverages using Cox proportional hazards regression, adjusted for age, cohort, body mass index, smoking status, and caloric intake. Analyses were conducted separately for glioma overall and for glioblastoma (GBM).

Results We confirmed 554 incident glioma cases (362 GBM) among 237,505 participants with 6,216,378 person-years of follow up. Cumulative average alcohol intake was associated with reduced risk of glioma: HR=0.75, 95% CI 0.56–0.99 comparing >8–15 to ≤ 0.5 g/d; HR=0.71, 95% CI 0.53–0.96; comparing >15 g/d to ≤0.5 g/d.  When stratified by sex, for the same comparisons, the HRs for men were 0.57 (95%CI: 0.36–0.89) and 0.79 (0.53–1.16), and for women 0.90 (95%CI: 0.62–1.30) and 0.62 (95%CI: 0.39–0.97). Results were consistent when examining cumulative average, baseline, and recent intake, and with a 4 year lag.

Conclusion These results provide evidence against a positive association between alcohol intake and glioma risk. Alcohol intake was associated with reduced risk of glioma in both men and women.

Forum Comments

There appears to be an increase in the risk of glioma tumors of the brain, at least it seems that a number of prominent people have died from these tumors in recent years.  The authors of this paper present the association between reported alcohol consumption from multiple assessments over decades and the diagnosis of such tumors.  Among the important strengths of this paper is the fact that the data were collected as part of a prospective study, difficult to do in cancer epidemiology except with very large cohorts (such as the three Harvard studies here).  All in all, this paper provides appropriate data and analytic techniques for evaluating a potential relation between alcohol consumption and glioma, the most common type of brain tumor

Comments from Individual Forum Members

Forum member Ellison noted: “The estimation of alcohol intake in this study is as good as you can get, based on repeated assessments over decades.  Also, the ascertainment of outcome is close to complete, with validation of the medical records of suspected cases.  Information on the potential confounders considered were updated at each exam, as well as alcohol intake, giving more reliable data.  Secondary analyses include evaluating for effects of the pattern of drinking, type of beverage, and a history of heavy drinking in early life

“While the present study had relatively few heavy drinkers or alcohol abusers within their cohorts, results from previous cohort studies (Braganza et al; Kuan et al; Baglietto et al) have shown an adverse effect on the risk of glioma from heavy drinking, although some also suggest a protective effect from moderate drinking (as was shown in this study).  The authors did not adjust for socio-economic status (SES), which is known to modify the effects of alcohol; however, it is assumed that the SES did not vary markedly among the subjects in these cohorts, as they consisted only of female nurses or male health care workers.  All in all, the results from these large cohort studies are believable, and provide evidence for a slight decrease in risk of glioma for moderate drinkers.” 

Forum member Skovenborg wrote: “This study of the association of alcohol intake and risk of glioma with cases from three renowned cohorts is a remarkably good study in almost every aspect. So instead of reeling off the many virtues of the study I will focus on two issues: (1) non-drinkers and (2) drinking pattern.

• The number of nondrinkers is surprisingly high: 31% of the NHS cohort, 42% of the NHS II cohort and 24% of the HPFS cohort. The large numbers of nondrinkers make it very unlikely that the nondrinkers are a very special population with a very different lifestyle compared with the drinkers. The often heard argument of an association of special low Socio-Economic-Status with lifelong abstaining from alcohol is a moot point in these cohorts consisting 100% of nurses (NHS + NHS II) or Health Professionals (HPFS).

• The categorization of alcohol intake was based on the distribution of responses observed in the cohorts. One limitation of the study is the relatively low level and narrow range of alcohol intake, particularly among women. Another limitation is what Genevieve Knupfer called “the daily light drinker fiction” due largely to the use of artificial classifications of drinking patterns as are common in cohort studies as well as surveys of drinking behavior, such as average “grams of alcohol per day” or “number of drinks per day”. Since the tables present categories of consumption in grams alcohol/day, and the consumption begins with 0.5 grams, it seems reasonable to assume that these are artificially constructed daily averages, not what respondents report about what they usually drink every day. (It would be hard to imagine people who habitually drink, for example, 0.5-2 grams of alcohol per day.  Instead, this might consist of subjects consuming one drink every week or two.

“The artificial character of intake categories of 0 – 0.5 g/day and 0.5 – 2 g/day is obvious in this study and no harm seems to be done regarding interpretation of study results. However, using such categories as the only evidence for setting drinking guidelines is difficult.  For example, the 2018 Continuous Update Project report of the World Cancer Research Fund/American Institute for Cancer Research concluded: ‘Consumption of alcoholic drinks is a convincing cause of postmenopausal breast cancer and a probable cause of premenopausal breast cancer. The dose-response meta-analysis showed a significant 5% increased risk per 10 grams of ethanol per day: RR 1.05 (1.02-1.08). The dose-response meta-analysis for postmenopausal breast cancer showed a significant 9% increased risk per 10 grams of ethanol per day: RR 1.09 (1.07-1.12)’ I would suspect that the intake category of 10 grams of ethanol per day is an artificially constructed daily average based on information about (mostly) weekly alcohol consumption.  

“Little information on drinking patterns is found in the evidence base for the Expert Report 2018, ‘Alcoholic drinks and risk of cancer’, and with the artificial ‘10 grams of ethanol per day’ category. Using only an average based on weekly consumption, women are kept in ignorance about the likely difference in breast cancer risk between drinking, for example, 70 grams of ethanol in a fasting state during a weekend binge compared with drinking a glass of wine or beer with your meal most days of the week, as described by Mørch et al.”

Forum member Mattivi noted that the choice of the referent category was ≤ 0.5 g/d, rather than 0 g/d.  “This may be appropriate since there is often ‘unintentional’ exposure to alcohol, even from ‘non-alcoholic’ beverages such as apple juice, grape juice, and orange juice, which have minute amounts of alcohol (Gorgus et al), and ‘alcohol-free’ beer may contain up to 0.5% ABV.  Thus, the choice of ≤ 0.5 g/d as the referent group would be preferred.”

Reviewer Skovenborg responded: “I agree, but point out that the referent category was based on the alcohol content of self-reported specified portions of beer, wine, and liquor, and not blood alcohol content.  I note further that the investigators collected data separately for ‘regular beer’ and ‘light beer,’ even though, as of a report in 1999 (Logan et al), the alcohol content of light beer was not very different from regular beer: 4.13%v/v vs. 5.32%v/v.”

Forum member de Gaetano wrote: “In particular, I agree with reviewer Skovenborg when he notes that the large number of nondrinkers in the three cohorts of this study makes it very unlikely that the nondrinkers are a very special population with a very different lifestyle as compared with the drinkers. Considering lifelong abstainers as a special, non-comparable group of individuals is often declared by researchers who only include drinkers in their analyses or do not accept the largely reported finding that lifelong abstainers have a higher mortality risk than moderate/regular drinkers.” 

In terms of evidence for an increase in risk of glioma, Forum member Mattivi commented: “Some global figures are provided in a paper from a Lancet Neurology paper (GBD 2016 Brain and Other CNS Cancer Collaborators).  They conclude that ‘glioma incidence increased between 1990 and 2016’.   On the other hand other authors have reported that data is insufficient.  For example, an article by de Robles et al reached the conclusion: “There is a need for more accurate and comparable incidence and prevalence estimates of primary brain tumors across the world.”

Mattivi continued: “This paper is interesting as it comments on previous results reporting the lack of evidence of strong environmental (and genetic) risk factors for CNS cancer.  As summarized in the paper by the GBD 2016 Brain and Other CNS Cancer Collaborators: ‘Few known risk factors are associated with CNS cancer.’ The only consistent associations that have resulted from epidemiological studies are positive associations with ionising radiation (atomic weapon radiation, previous therapeutic irradiation) and negative associations with atopic conditions (asthma, eczema, food allergies). A multitude of other risk factors have been considered, including cell phone radiation, aspirin use, hormonal factors, low-frequency magnetic fields, pesticides, dietary factors including alcohol consumption, and industrial exposures, none of which have consistently shown associations with the risk of CNS cancer.” 

Forum member Goldfinger agreed that this study provides important information on alcohol as a potential risk factor for glioma: “It has been apparent to me that we are seeing an increased incidence of glioma/glioblastoma among the general population.  The reasons for this apparent increase are unknown, but the widespread use of mobile phones and exposure to radiofrequency EMF’s have been suggested as possible risk factors.  Survival rates for these tumors are poor, and thus further investigation as to pathogenesis, and associations with lifestyle exposures, are critically important.”  Reviewer Ellison added: “While abusive alcohol consumption remains as a potential risk factor, this study certainly suggests that light to moderate alcohol consumption is not a risk factor for this deadly disease.”

Reviewer Finkel concluded: “I echo the erudite critiques of other Forum members.  This study is an exemplar of the genre, and a small counter, but one of objectivity and power, to the legion of cranky complaints, biased and weak, that even the reading of a wine advertisement causes all manner of cancers.”

References from Forum critique

Baglietto L, Giles GG, English DR, Karahalios A, Hopper JL, Severi G.  Alcohol consumption and risk of glioblastoma; evidence from the Melbourne Collaborative Cohort Study.  Int J Cancer 2011;128:1929–1934.

Braganza MZ, Rajaraman P, Park Y, Inskip PD, Freedman ND, Hollenbeck AR, et al. Cigarette smoking, alcohol intake, and risk of glioma in the NIH-AARP Diet and Health Study. Br J Cancer. 2014;110:242–248.

De Robles P, Fiest KM, Frolkis AD, et al.  The worldwide incidence and prevalence of primary brain tumors: a systematic review and meta-analysis.  Neuro-Oncology 2015;17:776-783.

GBD 2016 Brain and Other CNS Cancer Collaborators.  Global, regional, and national burden of brain and other CNS cancer, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.  Lancet Neurology 2019;18:376-393.

Gorgus E, Hittinger M, Schrenk D.  Estimates of Ethanol Exposure in Children from Food not Labeled as Alcohol-Containing. J Analytical Toxicology, 2016;40:537–542.  doi: 10.1093/jat/bkw046.

Knupfer G.  Drinking for health: the daily light drinker fiction.  Br J Addict 1987;82:547-555.

Kuan AS, Green J, Kitahara CM, De González AB, Key T, Gillian KR, et al.  Diet and risk of glioma combined analysis of 3 large prospective studies in the UK and USA. Neuro-oncology. 2019;21:944–952.

Logan BK, Case GA, Distefano.S.  Alcohol Content of Beer and Malt Beverages: Forensic Considerations.  J Forensic Sci 1999;44:1292-1295.

Mørch LS et al. Alcohol drinking, consumption patterns and breast cancer among Danish nurses: A cohort study. Eur J Public Health 2007;17:624–629.  

World Cancer Research Fund/American Institute for Cancer Research. Continuous Update Project Expert Report 2018. Diet, nutrition, physical activity and breast cancer. (Available at dietandcancerreport.org).

Forum Summary

There appears to be an increase in the risk of glioma tumors of the brain, yet very few lifestyle or genetic factors shown to be true “risk factors” for the disease have been identified.  The authors of this paper present the association between reported alcohol consumption from multiple assessments over decades and the diagnosis of such tumors, combining data from subjects in large cohort studies of nurses and male health care providers..  Among the important strengths of this paper is the fact that the data were collected as part of a prospective study, difficult to do in cancer epidemiology except with very large cohorts.  A total of 554 cases of glioma tumors were identified in these cohorts from a total sample of more than 200,000 subjects.

Forum reviewers agree with the conclusions of the authors that light-to-moderate alcohol consumption does not increase the risk of glioma; in fact, total alcohol consumption over many decades was found to reduce the risk.  For example, a cumulative average consumption of total alcohol of >8 to 15 g/d (approximately 0.5 to 1.0 drink/day) was associated with a 25% lower risk of glioma when compared with the lowest category of intake (0 to 0.5 g/day) for both men and women.  For consumers of  > 15 g/d (just over 1 typical drink/day) versus the referent group, the risk for women was further significantly reduced to HR = 0.61; for men, the HR estimate was  0.79, but not statistically significant. (Some previous cohort studies have suggested an increase in risk for heavy drinkers.)  There were no differences according to type of alcoholic beverage. For the subgroup of subjects with glioblastomas, findings were similar but less precise, due to smaller case counts.

The Forum concludes that light-to-moderate alcohol consumption, versus no alcohol intake or very occasional drinking, does not increase the risk; in this very well-done study, such consumption showed a significant reduction in the risk of glioma tumors of the brain.

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This critique by the International Scientific Forum on Alcohol Research is based on comments from the following Forum members:

Giovanni de Gaetano, MD, PhD, Department of Epidemiology and Prevention, IRCCS Istituto Neurologico Mediterraneo NEUROMED, Pozzilli, Italy

R. Curtis Ellison, MD, Professor of Medicine, Emeritus; 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

Dominique Lanzmann-Petithory, MD, PhD, Nutrition Geriatrics, Hôpital Emile Roux, APHP Paris, Limeil-Brévannes, France

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; Principal, Stockley Health and Regulatory Solutions; Adjunct Senior Lecturer, The University of Adelaide, Adelaide, 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 

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