Alcohol and Cancer
Critique 246: Light to moderate alcohol intake and the risk of cancer — 8 February 2021
Reference: Rovira P, Rehm J. Estimation of cancers caused by light to moderate alcohol consumption in the European Union. European Journal of Public Health 2021; pre-publication. doi:10.1093/eurpub/ckaa236.
The present paper attempts to use alcohol-attributable data, based on combining average alcohol intake from diverse European populations, to judge the effects of moderate alcohol consumption on the risk of cancer for all populations. It is based on earlier calculations of risk, extensively covered in previous publications by the senior author. The investigators conclude that the risk of a number of types of cancer are increased even among subjects reporting no more than 20 grams of alcohol per day (up to about 2 typical drinks), an amount they state to be within recommended levels of consumption (but exceed current US Drinking Guidelines for women of no more than 1 drink/day). The largest contribution to their calculated effects of alcohol was from breast cancer in women (which made up “68.7% of all alcohol attributable cancer for both sexes”). Breast cancer is a condition for which many factors other than just average alcohol intake are important: factors such as pattern of drinking, type of beverage, folate intake, smoking, obesity, physical activity, etc., all of which tend to confound the association.
Forum members had real concerns about their methodology of using an estimate of “alcohol-attributable cancer” based on reported average intake from 28 separate countries, including the large countries in western Europe (e.g., Germany, France, UK, Italy, Spain, Sweden), East-European countries (such as Poland and Hungary), and many smaller countries (e.g., Malta, Cyprus, Luxembourg, Latvia). Given the marked variation in culture and drinking patterns among these countries, it was considered that there are a large number of confounders and modifiers of alcohol effects that vary by country, and make it impossible to simply take the average alcohol intake from such diverse cultures to estimate causality of alcohol and cancer for everyone. By lumping data from all of these countries, the analyses end up with values that relate to a non-existent hypothetical population; different countries have different risk relationships, so the estimates of effect described in the paper apply to no single country.
Further, the investigators do not report rates of other outcomes, especially total mortality, associated with drinking. Taking only one outcome condition, without at least noting that moderate drinking has almost uniformly been found to decrease all-cause mortality, limits the usefulness of their results for setting alcohol guidelines. Heavy alcohol use is recognized by all as a serious impediment to the health of individuals, and to society at large. However, recommending lowering the intake of alcohol for everyone does not take into consideration that light drinkers might be more likely than heavy drinkers to follow such advice and might decrease their consumption to zero. Because of moderate drinking’s almost uniformly demonstrated beneficial effect on cardiovascular disease, if many light drinkers stopped drinking completely it would be expected to increase, rather than decrease, total mortality rates and the health of the population.
In their conclusions, the authors only mention the results of their actual analyses briefly, then start the usual chant of the need for extensive public health measures (warning labels, public information campaigns, increasing alcohol taxes, etc.) which tend to emphasize the dangers of any alcohol consumption. However, the analyses in this paper do not provide the data that are needed if one is to set appropriate drinking guidelines, which should be age-specific, sex-specific, and population-specific. Such factors would include not only the alcohol-disease relation but the particular characteristics of the population, the objective of guidelines (to influence and change behavior among target populations), the behavior that is thought to be in need of change, the culture and mindset of the target population, and the kind of message that is likely to be effective. Forum members realize that there are tensions between advice intended only to reduce the prevalence of misuse versus advice that takes into account the well demonstrated beneficial health effects of light-to-moderate consumption. When setting guidelines, it is important to take into account the prevailing drinking culture of a country or population, because only in that way is it possible to produce a public health message that is likely to be respected and regarded.
For the full critique of this paper by the International Scientific Forum on Alcohol Research, please click here.
Critique 242: The relation of light alcohol consumption to the risk of common cancers – 1 October 2020
Reference: Caprio GG, Picascia D, Dallio M, Vitiello PP, Giunta EF, De Falco V, et al. Light Alcohol Drinking and the Risk of Cancer Development: A Controversial Relationship. Reviews on Recent Clinical Trials 2020;15:164-177
In an attempt to assess the relation between light alcohol consumption (<12.5g per day) and the risk of a number of types of cancer, the authors carried out a review of meta-analyses published within the past 15 years. Using as keywords “light alcohol drinking,” “light alcohol consumption” and “cancer”, they found 29 meta-analyses on the subject. They report their results as indicating that “Light alcohol drinking was not associated with an increased risk of cancer occurrence, with the exception of breast and prostate cancer and melanoma. Furthermore, a possible protective role of light alcohol consumption on the development of bladder, kidney and ovarian cancer and Non Hodgkin Lymphoma was observed.”
Forum reviewers found a number of weaknesses in the paper. While their title focuses on “light alcohol drinking,” most of their reports of results and their discussion deal with harmful effects of heavier drinking; however, by not including papers on ‘heavy drinking’ in their original search, they may have left out many relevant papers. Further, the very brief reviews of each common cancer that they comment upon are sometimes based on only one or two meta-analyses, leaving out a huge amount of key data, especially that from single, well-done, long-term cohort studies with important information on the relation of alcohol to cancer; potential confounding by many factors could not be taken into consideration.
In the analyses in the present paper, the reported average level of alcohol consumed is used, but there is insufficient evaluation of possibly more important indices of alcohol exposure: the pattern of drinking (e.g., type of beverage consumed, in binges or on a regular basis, consumption with or without food, etc.). Further, there is probably inadequate control for important confounders or consideration of the effects of under-reporting, which may have been seen in single studies but not apparent in meta-analyses. In addition, a number of errors are present within the report, such as conflicting statements that may misrepresent the numeric data given. These problems make these results of limited use to professionals in health policy who are developing guidelines for alcohol use in the general public.
Critique 241: A Mendelian randomization study of alcohol consumption and the risk of breast cancer and ovarian cancer reveals no significant associations — 22 July 2020
Reference: Zhu J, Jiang X, Niu Z. Alcohol consumption and risk of breast and ovarian cancer: A Mendelian randomization study. Cancer Genetics 2020;245:35–41
The authors of this ambitious study used a Mendelian Randomization (MR) approach in an attempt to determine if alcohol consumption is causally associated with the risk of female hormone-dependent cancers. They used summary level genetic data from the hitherto largest genome-wide association study (GWAS) conducted on alcohol consumption (N = ~1.5 million individuals), breast cancer (N cases = 122,977) and ovarian cancer (N cases = 25,509). They examined three different alcohol intake exposures: drinks per week, alcohol use disorder (AUD) and age-adjusted alcohol use disorder identification test (AUDIT-C), to reflect general and harmful drinking behavior. For instrumental variables (IVs), they constructed updated and stronger genetic instruments using 99 SNPs related to drinks/week, 9 SNPs related to AUD, and 13 AUDIT-C-related SNPs, and estimated the causal relationship applying several two-sample MR methods.
The key result of these analyses was that the investigators did not find any evidence that alcohol intake increased the risk of breast cancer. For ovarian cancer, an initial inverse association with alcohol intake became null when adjustments were made for confounders. While members of our Forum agreed with the overall conclusions of the authors, who stated that they did not find “any compelling evidence in support for a causal relationship between genetically predicted alcohol consumption and risk of breast or ovarian cancer, consistent across three different alcohol-related exposures,” Forum members identified a number of weaknesses of the analyses. For example, there were very limited data on the pattern of drinking or the type of beverage consumed, and no data on smoking and other lifestyle habits, diet, and many other environmental factors that relate to the effects of alcohol consumption. Further, much of the data utilized to generate the IVs of alcohol exposure were from men, rather than women, although the two conditions being studied are present only in women.
Forum members agreed with the authors about the need to combine data from MR analyses with data from observational and experimental studies before making conclusions about the relation of alcohol consumption to health and disease. Given the rapid expansion of genetic studies, it is likely that MR analyses will be increasingly important in our research efforts, but we agree that the consideration of a combination of data from observational studies, clinical trials, animal experiments, and MR analyses will be needed as we seek to improve our knowledge on the relation of alcohol intake to health and disease; it is, and will remain, a continuing challenge.
For the full critique of this paper by the International Scientific Forum on Alcohol Research, please click here.
Critique 236. Reasons for apparently diverse results from epidemiologic studies relating alcohol consumption to the risk of breast cancer – 19 February 2020
Reference: Chu L Ioannidis J PA, Egilman AC Vasiliou V, Ross JS, Wallach JD. Vibration of effects in epidemiologic studies of alcohol consumption and breast cancer risk. Inter J Epidemiol 2020;10:1–11. doi: 10.1093/ije/dyz271
The relation of alcohol consumption to the risk of breast of cancer has been the subject of innumerable epidemiologic studies over many decades, with most showing a slight increase in risk even for light drinking. However, it has been shown that this relation is attenuated when certain potential confounders are adjusted for, including folate levels, frequency of binge drinking, and the use of post-menopausal hormonal therapy. The present paper took the results of a recent large-scale meta-analysis and sought to try and explain why there is a large variability of results when the 97 studies included in that analysis were compared. The authors attempted to judge to what degree differences in exposure definitions, contrast levels, different study populations, different adjustment covariates, and different model approaches affected estimates of the effect of alcohol on cancer risk. The key factor the authors used in their analyses was the ratio between the most harmful and the most protective effects of estimated risk within each study.
All of the contrasts studied (different measures of alcohol consumption, different populations, different analytic approaches, etc.) had some effect on the estimates of effect of alcohol on the risk of cancer. As stated by the authors, “These findings suggest that whereas certain analytical and modelling choices, reflecting different types of alcohol and/or doses, can result in genuine differences, it is possible that many different analytical options, with different results, are pursued and selectively reported. Therefore, individual reported relative risk estimates from observational studies should be interpreted with caution.” Some Forum members disagreed with this conclusion, suggesting that due to marked variation in population, type of alcohol, analytic approaches, adjustment for confounding, etc., considerable error may be built in when combining data from heterogeneous studies. They felt that single large, long-term, well-done individual prospective studies may be preferable for judging the true effect of alcohol on the risk of breast cancer.
Thus, while Forum reviewers appreciated the attempt to explain differences in results of studies to get a more valid estimate of the true relation of alcohol consumption to the risk of breast cancer, and the analyses presented were done appropriately, some considered the approach described as not being a useful or valid one. Finding large differences in effects among sub-groups may not provide a reliable measure. Alternative approaches to scrutinize findings from observational studies, including Mendelian randomization or discussion centered on E-value (which assesses how strong an unmeasured confounder would have be to eliminate observed effect estimates), may be preferable. While such methods are imperfect, their use would be more interesting in informing the public and advancing scientific knowledge.
For the full critique of this paper by the International Scientific Forum on Alcohol Research, please click here.
Critique 229: A J-shaped curve for the relation of alcohol consumption to the risk of colorectal cancer — 10 July 2019
Reference: McNabb S, Harrison TA, Albanes, Berndt S, Brenner H, Caan BJ, et al. Meta-analysis of 16 studies of the association of alcohol with colorectal cancer. Int J Cancer. 2019 Apr 29. doi: 10.1002/ijc.32377. [Epub ahead of print]While heavy alcohol consumption is recognized as a contributor to the development of colorectal cancer (CRC), an increasing number of studies suggest that moderate alcohol consumption may not have an adverse effect on the risk of CRC, or even decrease the risk.
The present paper, a meta-analysis of 16 studies on the relation of alcohol consumption to invasive CRC, was conducted by leading investigators in the field. Forum members consider this to be a well-done study, with a large number of subjects, the ability to use individual level data in their meta-analysis, and the use of appropriate and complete analytic techniques.
The key finding of their study was that there was a J-shaped curve evident in all of their analytic approaches; their results strongly support a J-shaped association for the relation of alcohol intake to CRC: a slightly lower risk of cancer for light to moderate drinkers and an increased risk for subjects reporting an average of 3 or more drinks/day. Further, they found that their results did not vary by age, obesity, smoking, or family history of CRC. Overall, the effects of benefits/harms were somewhat more striking for cancers in the distal colon than in the proximal colon.
Potential mechanisms for heavy alcohol consumption being related to an increase in risk were discussed by the authors. As for moderate drinking decreasing the risk, potential mechanisms are discussed by a Forum member in this critique. He describes active, beverage-specific metabolites other than ethanol that reach the intestine. In particular, our attention goes to the several microbial catabolites which can be formed via our host microbiota in the colon.
The finding of a J-shaped curve between alcohol and CRC is similar to the relation seen for a number of other diseases, including coronary artery disease, ischemic stroke, dementia, and total mortality. While a linear relation between heavy drinking and certain upper aero-digestive tract cancers has been shown, for certain cancers there may be a J-shaped curve of effect, with reductions in risk for light-to-moderate drinkers.
Critique 226: Consumption of red wine may lower the risk of lethal prostate cancer – 16 May 2019
In an analysis from the Health Professionals Follow-up Study, the investigators evaluated the relation of alcohol consumption in their more than 45,000 study participants to the development of lethal prostate cancer. They related alcohol first to the overall risk of prostate cancer among all subjects, and then focused on the 5,182 men who developed non-metastatic prostate cancer to judge their risk of developing lethal prostate cancer or mortality. They judged the alcohol intake both prior to the diagnosis and after a diagnosis of prostate cancer. For reported alcohol consumption among subjects prior to the initial diagnosis of prostate cancer, there was a small (16%) but significant reduction in the risk of lethal prostate cancer among subjects reporting any alcohol consumption, but no significant effects of specific beverages on the risk of lethal prostate cancer. However, total mortality was lower for consumers of total alcohol intake and for most categories of intake for all types of beverage.
When they then related post-diagnosis alcohol intake (after the diagnosis of non-metastatic prostate cancer), the investigators found that red wine consumption was associated with a 50% reduction in the risk of developing lethal prostate cancer or mortality. There were no significant relations between total alcohol consumption or between the intake of other specific beverages and lethal disease.
The authors describe a number of hypotheses by which red wine, with its combination of high levels of polyphenols in addition to alcohol, may have lowered the risk of lethal prostate cancer. And there are numerous basic science experiments that have shown how polyphenols impede the development and growth of cancer cells. Presumably, it was not due to the alcohol in red wine, as similar amounts of alcohol in other beverages did not show a protective effect. While the effects of various polyphenols may play a role, at present the mechanisms of such an effect are not known.
Forum reviewers considered this to be a very well-done study and analysis, with repeated assessments of alcohol intake and essentially complete ascertainment of lethal prostate cancer and mortality. Forum members agree with the conclusions of the authors: “Our results indicate that moderate alcohol intake among men with prostate cancer is not associated with a higher risk of progression to lethal disease or overall mortality. The potential benefit of red wine on prostate cancer progression merits additional research.”
Reference: Downer MK, Kenfield SA, Stampfer MJ, Wilson KM, Dickerman BA, Giovannucci, EL, et al. Alcohol Intake and Risk of Lethal Prostate Cancer in the Health Professionals Follow-Up Study abstract. J Clin Oncology 2019 Pre-publication: DOI: 10.1200/JCO.18. 02462
Critique 221: The relation of alcohol intake to stomach cancer – 20 November 2018
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.
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. Results usually differ between Asian and 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 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.
For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.
Critique 217: Alcohol, cancer, and mortality: Further affirmation of the J-shaped curve for mortality and increase in incidence of cancer with larger intake of alcohol – 9 July 2018
Reference: 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. https://doi.org/10.1371/journal.pmed.1002585.
Scientific studies have shown consistently that that the consumption of small amounts of alcohol on a regular basis is associated with a lower risk of total mortality, while consumption of large amounts is associated with an increased risk of certain cancers and mortality. The present report is from a population-based cohort study of almost 100,000 older subjects who were followed for 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.
Specifically, in comparison with never drinkers or very light (< 1 drink/week) drinkers, the study shows lower mortality for “light-to-moderate” alcohol consumers (up to 2 drinks/day) but greater mortality among subjects classified as “heavy” (2 to < 3) or “very heavy” (3+ drinks/day) consumers. In beverage-specific analyses, there was a slight increase in total mortality for reported intake of spirits starting at the consumption of about 1 ½ drinks/day and for beer at or above about 2 drinks/day; no significant increase in cancer risk was associated with wine consumption, regardless of the amount. The authors conclude that “there is a J-shaped association between alcohol and mortality in older adults, which remains after adjustment for cancer risk.”
Forum member considered this to be a well-done analysis, and shows, essentially for the first time in a single study, how the beneficial effects of light and moderate drinking on cardiovascular disease and total mortality exceed the slight increase in cancer risk for alcohol consumption at this level. In other words, while even light-to-moderate drinking may be associated with a slight increase in the risk of certain cancers, such drinking still favorably affects the overall risk of mortality.
For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.
Critique 211: Effects of alcohol and aldehydes on DNA and risk of cancer; potential implications from a study in mice — 22 January 2018
Reference: Garaycoechea JI, Crossan GP, Langevin F, Mulderrig L, Louzada S, Yang F, Guilbaud G, Park N, Roerink S, Nik-Zainal S, Stratton MR, Patel1 KJ. Alcohol and endogenous aldehydes damage chromosomes and mature stem cells. Nature 2017;553:171-177. doi:10.1038/nature25154.
The authors of this paper, based on an extensive basic scientific experiment in mice, describe the features and mutational landscape of DNA damage caused by acetaldehyde, an endogenous and alcohol-derived metabolite. This damage results in DNA double-stranded breaks that, despite stimulating recombination repair, also cause chromosome rearrangements. Furthermore, the authors identify how the choice of DNA-repair pathway and a stringent p53 response limit the transmission of aldehyde-induced mutations in stem cells.
Forum members considered this to be a well-done series of experiments that add additional data on the effects of aldehyde on cellular damage, which could potentially lead to an increased risk of cancer. While interesting, these results in mice have limited applicability to the effects of alcohol in humans, as the study conditions do not correspond to that found in real life. For example, the levels of ethanol used to elicit the DNA changes were high and alcohol was directly injected into the animals, whereas in humans alcohol is orally absorbed and undergoes several types of metabolism that reduce maximum blood alcohol concentrations achieved. Further, the animal model was based on mice that had been genetically manipulated in that particular genes had been selectively ‘knocked out’ to make them unable to metabolize aldehyde or to repair DNA damage; while this was necessary to study the effects in a basic scientific experiment, it is in contrast to what would occur under non-manipulated conditions of alcohol consumption in humans
The damages shown in this experiment were to hematologic cells, and epidemiologic studies have generally not found an increase in the risk of hematologic cancers in humans to be associated with alcohol, especially from the moderate intake of alcohol (and many studies show instead a decrease in risk among drinkers). Thus, studies in humans have not provided support for these reported results from mice. Further, Forum members conclude that the polyphenols that are present in wine may play an important role in blocking a carcinogenic effect associated with alcohol intake.
For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here.
Critique 210: Beer, wine, and spirits consumption and risk of gastric cancer – 8 January 2018
Reference: Wang P-L, Xiao F-T, Gong B-C, Liu F-N. Alcohol drinking and gastric cancer risk: a meta-analysis of observational studies. Oncotarget 2017;8:99013-99023.
While heavy alcohol intake has been regularly found to increase the risk of upper aero-digestive tract (UADT) cancers (mouth, tongue, pharynx, larynx, etc.), results are less clear for gastric cancer. The present study is notable because it is based on a large number of subjects, uses appropriate analytic methods, and provides dose-dependent results according to type of beverage.
For total alcohol, the dose-response results in this meta-analysis show a curvilinear relation between alcohol intake and gastric cancer, with a minimal (4%) but significant increase per typical drink (12.5 g/alcohol). However, there were varying responses for different beverages. In beverage-specific analyses, for beer, a non-linear relation was found with a significant increase of 7%/drink (CI 1.01, 1.13); for liquor, there was a linear association, with RR=1.03 (CI 0.98, 109); and for wine, the RR was 0.99 (CI 0.93, 1.06).
While the authors show a figure of the dose-response curves for each beverage using a non-linear approach, they do not provide the specific values in a table or in the text; this makes it difficult to clearly determine threshold effects of beverages. The figures suggest that the risk associated with beer consumption shows a slight decrease for 1 to 2 drinks/day, then an increase; for spirits, no decrease with lighter intake is seen; for wine, the curve is continuously downward. The authors do state that “light, moderate, and wine drinking would not increase gastric cancer risk,” so it is presumed that significant increased risk was not noted for moderate drinking for any specific beverage when non-linear effects were evaluated. Thus, overall, it appears that this large meta-analysis shows no significant increases in risk for light to moderate consumption of an alcoholic beverage, but a slight increase in risk associated with greater intake of beer and spirits. For wine, no increase in the risk of gastric cancer was seen for any level of consumption.
In a number of sensitivity analyses, the authors found tendencies for a lower gastric cancer risk associated with alcohol for cohort versus case-control studies, for studies with larger numbers of subjects, for studies judged to be of higher quality, and for studies adjusting for confounding by SES & income; these types of studies would be expected to yield more precise estimates of effect. These results led the authors to state these sensitivity analyses “ . . . indicate that our results may be exaggerated to some degree, but it should be noted that the pooled risk estimates of high-quality studies yielded similar results to the original analysis.”
Overall, Forum members considered this to be a well-done analysis, and the data support an increase in gastric cancer risk for heavier drinking (of beer or spirits) but no significant effects for light or moderate drinking of any alcoholic beverage. Forum members considered that if the lack of increase in cancer risk from wine consumption seen in this analysis proves to be true, it might relate to the polyphenols in wine that block any adverse effects of alcohol on gastric cancer risk.
Critique 208: A statement on alcohol and cancer that ignores the net health effects of moderate drinking, such as increasing longevity of life — 16 November 2017
Reference: LoConte NK, Brewster AM, Kaur JS, Merrill JK, Alberg AJ. Alcohol and Cancer: A Statement of the American Society of Clinical Oncology. J Clin Oncol 2017;35:pre-publication. DOI: https://doi.org/10.1200/JCO.2017. 76.1155
The present publication is an attempt by the American Society of Clinical Oncology to describe the relation between alcohol consumption and cancer, including the effects on the risk of developing cancer and effects among subjects currently being treated for cancer. It came to the conclusion that there is a need for the public to be warned about the use of alcohol because of its effects on cancer, and describes numerous approaches for decreasing alcohol use in the population.
Forum members considered this paper to markedly distort the associations between alcohol consumption, especially light drinking, and health outcomes. The authors were particularly remiss in not describing the net health effects of light to moderate consumption: longer longevity of life. Their long discussion of policy implications, and ways of decreasing alcohol use in the population, were unrelated to the data they presented, and failed to describe how complex and culturally specific such recommendations are. The authors describe many ways of decreasing alcohol consumption in the population, but do not provide any data about whether or not the measures they propose are successful.
While all Forum members agree that heavy alcohol consumption increases the risk of several cancers (information that oncologists should be aware of), light drinking has generally been associated only with a slight increase in breast cancer, but not with other types of cancer (especially when under-reporting of intake is considered). Further, factors such as dietary folate intake, patterns of drinking such as binge versus regular moderate drinking, and type of beverage generally consumed have been shown to modify even this relation. Also, regular light or moderate drinking has been consistently shown to decrease the risk of cardiovascular disease (the leading cause of death), diabetes, dementia, and even total mortality, associations largely ignored in this paper.
Our Forum considers that this publication from the American Society of Clinical Oncology misses an opportunity to provide, for oncologists and for the public, up-to-date and balanced information of the true relations of alcohol consumption to the risk of cancer and other health outcomes. They have especially ignored the effects of moderate drinking on the risk of total mortality.
Reference: LoConte NK, Brewster AM, Kaur JS, Merrill JK, Alberg AJ. Alcohol and Cancer: A Statement of the American Society of Clinical Oncology. J Clin Oncol 2017;35:pre-publication. DOI: https://doi.org/10.1200/JCO.2017. 76.1155
For the full critique of this paper by members of the International Scientific Forum on Alcohol Research, please click here
Critique 202: Importance of folate intake for reducing breast cancer risk from alcohol consumption, especially for women with a positive family history of breast cancer – 17 July 2017
The strongest factor associated with the risk of a woman developing breast cancer appears to be a positive family history of such a diagnosis in a sibling or mother. Among environmental factors, almost all studies have shown that alcohol consumption relates to increased risk; a slight increase is often seen even among women who report only light drinking, e.g., an average of less than one drink per day. The present study evaluates how a positive family history of breast cancer in a first-degree relative and folate intake may modify the association between alcohol intake and breast cancer; the analysis is based on data from a large number of young women, aged 27-44 years at baseline, over a follow-up period of 20 years.
Forum members considered that this was a very well-done analysis from the large Nurses’ Health Study II, which followed young women for two decades. Alcohol consumption in total drinks/week was based on repeated assessments (but the pattern of drinking, binge versus regular drinking, was not evaluated). Repeated dietary questionnaires were used to estimate folate input. More than 2,800 incident invasive breast cancers were detected, essentially all being validated by a review of medical records.
The main results of this study were that without a positive family history of breast cancer, there was no significant increase in cancer risk for any level of alcohol intake. With a positive family history, however, there was a tendency for higher risk with increasing alcohol intake; this increase was not statistically significant for those with high folate, but a significant positive association (HR=1.82, 95% CI 1.06, 3.12; P-trend = 0.08) with cancer was seen for subjects with the highest level of alcohol intake plus low levels of folate.
Forum members conclude that the results from the present study should greatly relieve anxiety about breast cancer for women without a positive family history of breast cancer who choose to consume light-to-moderate amounts of alcohol. For women with a first-degree relative with breast cancer, the data indicate that if they maintain a high level of folate intake, it may attenuate an increase in risk associated with alcohol intake.
Reference: Kim HJ, Jung S, Eliassen AH, Chen WY, Willett WC, Cho E. Alcohol consumption and breast cancer risk by family history of breast cancer and folate intake in younger women. Am J Epidemiol 2017: pre-publication.
Critique 200: Does Light Drinking Increase the Risk of Cancer? — 8 June 2017
Reference: Choi Y-J, Myung S-K, Lee J-H. Light Alcohol Drinking and Risk of Cancer: A Meta-analysis of Cohort Studies. Cancer Research and Treatment 2017; pre-publication release.
The association between the consumption of alcohol and the risk of cancer has been of great interest for many decades. There are a number of types of cancer, especially those of the upper aero-digestive tract (such as mouth, tongue, pharynx, etc.) that are clearly increased among heavy drinkers, especially among subjects who are also heavy smokers. Cancer of the liver can be a result of alcoholic liver cirrhosis, related to long-term heavy drinking. Further, an increased risk for many other cancers have been shown for heavy drinkers, but generally not for light or moderate drinkers.
The risk of breast cancer in women, however, is usually found to be slightly higher in even light drinkers than it is among non-drinkers. This has been a common finding, although some studies suggest that the pattern of drinking, the estimated level of underreporting of alcohol intake, use of hormone replacement therapy, and level of folate intake may all affect this association. For colorectal cancer, some studies suggest an increase in risk even among light-to-moderate drinkers. This has led some to proclaim that no alcohol consumption is preferable for the prevention of cancer. Others suggest that it is important to consider not only cancer, but other diseases; for example, coronary heart disease, ischemic stroke, diabetes, and dementia (all of which are important causes of disability and death) occur less frequently among moderate drinkers than among non-drinkers. Further, the risk of total mortality is almost always found to be lower among light to moderate drinkers than among abstainers.
The present analysis was designed to help determine the association of light or moderate drinking with the risk of cancer. It consisted of a meta-analysis based on a total of 60 studies from 135 articles and included only cohort studies of high quality. The analysis focused on the association between very light (≤0.5 drink/day), light (≤1 drink/day), or moderate drinking (1-2 drinks/day) and the risk of cancer incidence and mortality.
The authors found that very-light drinking was not associated with the incidence of most cancers except for female breast cancer and male colorectal cancer, and was associated with a decreased incidence of both female and male lung cancer and both female and male thyroid cancer. Moderate drinking significantly increased the incidence of male colorectal cancer and female breast cancer, whereas it decreased the incidence of both female and male hematologic malignancy.
Forum members considered this to be a well-done meta-analysis, based on a large number of studies. The main weaknesses of the study related to the lack of ability of the authors to evaluate a number of known confounders: underreporting of alcohol intake, the pattern of drinking or the type of beverage consumed, socio-economic status, and folate intake or other dietary factors. Further, the authors did not describe the effects of alcohol consumption on total mortality.
The results of this study, obviously, support most previous epidemiologic evidence on the association between alcohol consumption and cancer. Larger amounts of alcohol are associated with increased risk of a number of cancers, and even light consumption is associated with the risk of breast cancer, and possibly colorectal cancer. However, given the inability to adjust for many confounders in this study, and lack of data on the net effects in terms of total mortality, it remains difficult for scientists to provide scientifically sound and balanced guidelines regarding the health consequences of alcohol consumption that are applicable to everyone in the population.
Critique 192: The association of alcohol consumption with the risk of prostate cancer – 12 September 2016
Reference: Dickerman BA, Markt SC, Koskenvuo M, Pukkala E, Muccil LA, Kaprio J. Alcohol intake, drinking patterns, and prostate cancer risk and mortality: a 30-year prospective cohort study of Finnish twins. Cancer Causes Control 2016;27:1049–1058. DOI 10.1007/s10552-016-0778-6
Scientific data are mixed on the association of alcohol consumption with the risk of prostate cancer. In the present paper, the authors have used data from 11, 372 subjects in the Older Finnish Twin Cohort who provided data on alcohol intake on two occasions. They were followed for the development of prostate cancer from 1981 to 2012, during which 601 incident cases of prostate cancer and 110 deaths from prostate cancer occurred. The authors relate reported average alcohol intake, and whether or not the subject reported binge drinking, to the risk of prostate cancer and prostate cancer-specific death. They also evaluated the risks of prostate cancer among alcohol-discordant twins. The authors used current abstainers and ex-drinkers as the referent group in their main analyses, but did sensitivity analyses using never drinkers as an alternative referent group.
The type of beverage consumed was not known, so whether or not wine or beer consumption may have a different relation with prostate cancer than spirits intake cannot be determined. However, overall the data indicated a higher risk of prostate cancer from heavy intake and binge drinking, but also a high risk among abstainers. The number of discordant twins (for alcohol consumption) was too small for definitive results in terms of the risk of prostate cancer among subjects with the same or a similar genetic background , but the lowest risk was among light drinkers who did not binge drink. Even among this subset of the population, abstainers had higher risk than light drinkers.
Thus, the results of this well-done study suggest that there may be a J-shaped relation between alcohol consumption and prostate cancer risk. Light drinkers appear to have the most favorable results for both incident prostate cancer and prostate cancer-specific mortality. The risk for subjects reporting heavy drinking and binge drinking was higher for both incidence and mortality than the risk of light drinkers; for unexplained reasons, abstainers also tended to have higher risk of prostate cancer and mortality.
Critique 188: Alcohol-attributable cancer in New Zealand – 28 June 2016
Reference: Connor J, Kydd R, Maclennan B, Shield K, Rehm J. Alcohol-attributable cancer deaths under 80 years of age in New Zealand. Drug and Alcohol Review 2016; pre-publication. DOI: 10.1111/dar.12443
Previous scientific research has shown that heavy alcohol consumption is a major risk factor for upper aero-digestive cancers, and even light drinking increases slightly the risk of breast cancer in women. The present study is based on a very small number of cases of cancer in New Zealand, tabulated separately for Māori and non-Māori subjects, and applies estimates of alcohol effects from other population-based studies. Besides having so few cases, the investigators had no individual data (on the pattern of alcohol consumption, type of beverage, smoking or other lifestyle habits, socio-economic status, etc.) on subjects who did, or did not, develop these cancers. It is not even known whether or not the specific subjects who developed these cancers consumed alcohol.
It has repeatedly been emphasized that disease-specific death rates must be interpreted in light of the effects of the exposure (in this case, alcohol consumption) on other causes of death as well, especially on total mortality risk. The large majority of studies have shown that moderate drinking clearly reduces the risk of most cardiovascular diseases, diabetes, and other of the diseases of ageing, as well as the risk of total mortality. However, the estimated effects of alcohol on total mortality are not included in this paper.
The very long Discussion in this paper is primarily a treatise on how the public must be told of the dangers of cancer from any alcohol consumption; it focuses on health policy recommendations and very little on the limitations of the data and the study. The authors end up making very broad recommendations based on very small numbers of subjects. Limitations to this study suggest that it adds little to our current understanding of the relation of alcohol consumption to the risk of cancer and other diseases.
Critique 187: Alcohol and squamous cell carcinoma of the skin — 14 June 2016
Reference: Siiskonen S, Han J, Li T, Cho E, Nijsten T, Qureshi A, Alcohol intake is associated with increased risk of squamous cell carcinoma of the skin: three US prospective cohort studies. Nutrition and Cancer 2016;68:545-553.
Skin cancers, whether melanoma, basal cell, or squamous cell, are all increased by ultra-violet rays of the sun, and such cancers are much more common in areas of the world with more sun exposure. Further, the risk of such cancers is higher among individuals reporting excessive tanning (either from the sun or from tanning salons). The present study was undertaken to judge the relation between alcohol consumption and the risk of cutaneous squamous cell carcinoma (cSCC), an association that is unclear from earlier research. Determining the relation between alcohol and skin cancer is made difficult by the fact that excessive sun exposure has been shown to be greater among consumers of alcohol than among abstainers, thus the potential for confounding.
In the present analyses, combined data from three cohorts of subjects in the US, who had repeated assessments of alcohol intake over many years, were evaluated tor the relation of alcohol to the development of verified cSCC. Subjects included women in two cohorts of the Nurses’ Health Study and men in the Health Professionals’ Follow-up Study. Among subjects providing a total of more than 4 million person-years of follow up, 2,938 cases of cSCC were identified.
The results varied somewhat among the different cohorts, but in the meta-analysis of the three studies using continuous measures of alcohol, there was an increase in risk of cSCC with alcohol intake. Among women, there was a steep increase in risk of cancer for low levels of intake (up to 5 grams of alcohol/day, slightly less than ½ of a typical drink), then a gradual increase in risk thereafter, whereas among men there was more of a gradual increase in risk with larger reported alcohol intake.
Overall, the authors report an increase in risk per typical drink per day of 22% for invasive cSCC and 14% for in situ cSCC. In beverage-specific analyses, white wine consumption of >/= 5 times/week was associated with an increased risk of cSCC (RR 1.31, 95% confidence interval: 1.09-1.59), but an increased risk of cSCC was not seen for other alcoholic beverages. The population-attributable risk associated with alcohol intake of ≥ 20 grams/day (about 1 ½ typical drinks) was 3% of cSCCs.
Forum members considered that the analyses were well done, and the results of the study are consistent with increases in risk associated with alcohol consumption for other types of skin cancer. Given that sun exposure is by far the primary risk factor for skin cancer, and consumers of alcohol tend to have greater number of sunburns (also shown in this study), it is always difficult to determine if residual confounding by sun exposure is playing a role. The authors of this paper attempted to adjust for sun exposure by including in their analyses the typical exposure values in the area of the world where the subjects resided, by recording the frequency that subjects reported 5 or more severe sunburns, and several other measures. As expected, there were reductions in the estimated RR for invasive cSCC when going from age-adjusted RR (1.34) to multivariable-adjusted estimates (1.22) of risk. However, the magnitude of decrease in risk estimates when only those adjustments for sun-exposure were added to the equation cannot be determined from the data presented.
Forum reviewers consider that these analyses support results from many previous studies and indicate that consumers of alcohol have a greater risk than non-drinkers of all types of skin cancer. Attempts to judge how much of this association may be due to residual confounding related to sun exposure are less than conclusive. Various hypotheses have been raised for possible interactions between sun exposure and alcohol, but currently there are no experimental data to test these theories. While the authors conclude that “physicians may consider counseling their patients about the association between alcohol consumption and risk for cSCC,” it might be more advantageous for physicians to focus more on the much greater protection against this disease that would occur if they were able to limit their patient’s exposure to ultra-violet radiation.
Critique 186: Changes in alcohol and effects on risk of breast cancer and heart disease — 19 May 2016
Reference: Dam MK, Hvidtfeldt UA, Tjønneland A, Overvad K, Grønbæk M, Tolstrup JS. Five year change in alcohol intake and risk of breast cancer and coronary heart disease among postmenopausal women: prospective cohort study. BMJ 2016;353:i2314. http://dx.doi.org/10.1136/bmj.i2314
This large study from Denmark was designed to test the hypothesis that women who increase their alcohol intake over a five year period have a higher risk of breast cancer and a lower risk of coronary heart disease (CHD) compared with women who exhibit a stable alcohol intake. It consisted of more than 20.000 postmenopausal women who had two assessments of alcohol intake, about 5 years apart; changes during that period were related to their subsequent risk of developing breast cancer or CHD, or dying, during the subsequent follow-up period that averaged 8 years.
For the risk of breast cancer, the baseline alcohol consumption reported by the women showed that higher alcohol intake was associated with a greater risk of developing breast cancer during follow up, but a lower risk of developing CHD and for total mortality. For relating changes in alcohol intake in the 5 years between the two alcohol assessments, those who increased their reported alcohol intake showed an increased risk of subsequent breast cancer, while those who decreased their intake also had a tendency for greater breast cancer. In terms of CHD and total mortality, the data were consistent with an increase in consumption lowering risk, while there was a tendency for a decrease in consumption to increase risk. Hence, the directionality for risk from changes in intake reflected the risks associated with baseline risk, and the authors conclude that their results “ . . .support the hypotheses that alcohol intake is associated with increased risk of breast cancer and decreased risk of coronary heart disease.”
Forum reviewers considered this to be a very well-done study. They, and the authors, appreciated the innate difficulty in separating effects on health of usual alcohol intake over time and changes over a limited period of time. Reviewers were also concerned by these problems, suggesting that some of the reported changes in alcohol consumption in this study may have just reflected individuals replying differently to questions regarding their drinking at different points of time. Further, the reason why some women may have actually increased or decreased their intake are not known.
Nevertheless, Forum members applaud the attempt of the authors to judge if changes in alcohol intake relate to cancer, CHD, and total mortality. This is a difficult task given that baseline and life-time alcohol consumption clearly relate to these outcomes. Further, data on the pattern of drinking (regular versus binge), any estimate of underreporting of alcohol, the type of beverage consumed and, as stated by the authors, certain known risk factors of breast cancer, were not available to be included in their analyses. Thus while the results of this study add important information on the relation of alcohol to disease, there remain questions about the specific relevance of changes in intake for such outcomes.
Critique 184: A major new meta-analysis on alcohol consumption and the risk of pancreatic cancer — 4 April 2016
Reference: Wang Y-T, Gou Y-W, Jin WW, Xiao M, Fang H-Y. Association between alcohol intake and the risk of pancreatic cancer: a dose–response meta-analysis of cohort studies. BMC Cancer 2016;16:212. DOI 10.1186/s12885-016-2241-1
The present meta-analysis was based on data from more than four million subjects in prospective cohort studies, among whom 11,846 incident cases of pancreatic cancer were diagnosed. With the lowest intake group (non-drinkers or occasional drinkers) as the referent group, the authors defined “light” consumption as up to 12 grams/day (essentially one typical drink); 12-24 g/day as “moderate”; and ≥24 g/day as “heavy” drinking. The key results of the study were that, overall, neither light drinkers (RR = 0.97) nor moderate drinkers (RR = 0.98) showed an increase in risk of pancreatic cancer, while subjects classified as heavy drinkers had a slight increase (RR= 1.15, 95% CI 1.06 – 1.25). The increase in risk was due to heavy drinkers of liquor, as there was no significant increase in risk even for heavy drinkers of beer (RR = 1.08, CI 0.90 – 1.30) or wine (RR = 1.09, CI 0.79 -1.49).
Forum members considered this to be an excellent paper on the association between alcohol consumption and pancreatic cancer. The authors used appropriate methods and limited subjects to those in prospective cohort studies, which would tend to limit bias. The paper shows that the significant increase in risk occurred only among men, with no significant effect of alcohol being found among women. Among the weaknesses of the study were that there was a mixture of lifetime abstainers and ex-drinkers included in the referent group, and the same cut-points for category of alcohol intake was used for both men and women, whereas drinking guidelines are generally lower for women than for men. Further, data on the pattern of drinking (regular versus binge) were not available.
To summarize, this study showed no significant association with cancer risk for any level of consumption of beer or wine, which could relate to their lower concentration of alcohol per volume of the beverage, to non-alcoholic substances (such as polyphenols, present in wine and beer), or even to different drinking practices among subjects consuming different beverages. Thus, Forum members agree with the conclusions of the authors that heavy alcohol consumption, especially of liquor, increases the risk of pancreatic cancer, but the intake of beer or wine may not be associated with an increased risk.
Critique 175: An update on the association of alcohol consumption with breast cancer: Effects of BMI — 24 November 2015
Reference: Shin A, Sandin S, Lof M, Margolis KL, Kim K, Couto E, Adami HO, Weiderpass E. Alcohol consumption, body mass index and breast cancer risk by hormone receptor status: Women’ Lifestyle and Health Study. BMC Cancer 2015;15:881 (DOI 10.1186/s12885-015-1896-3)
Most observational epidemiologic studies have shown a slight increase in the risk of breast cancer for women who consume alcohol; the degree of increase is usually small for light-to-moderate drinkers (between 5% and 15% increase for consumers of no more than one drink/day), but the risk may be higher for women consuming greater amounts of alcohol. However, there are a number of factors that affect this relationship, including the type of study (cohort or case-control), the pattern of drinking (regular versus binge), the type of beverage consumed, folate intake, use of hormone replacement therapy, as well as genetic factors. It has also been shown that the risk of breast cancer among obese women tends to be higher than among non-obese women, but there are limited data on how obesity interacts with alcohol in affecting the risk of breast cancer. It is clear that alcohol consumption cannot be evaluated in isolation, without considering other factors that relate to the development of breast cancer.
The present study is based on a large cohort of Swedish women who were examined as part of the Women’s Lifestyle and Health Study in 1991 – 1992, then followed through 2009 for the development of breast cancer: 1,385 cases were ascertained among the more than 45,000 women in the study. Alcohol was assessed at baseline and again at the follow-up examination, and the diagnosis of breast cancer was gleaned through linkage to the nationwide health registries in Sweden. Almost all of the women were pre-menopausal at baseline.
Forum members considered this to be a very well-done study, with almost complete ascertainment of cancer cases. There were some concerns, however, including the fact that the height and weight of subjects was not measured but self-reported, perhaps resulting in less accurate estimates of BMI. Further there may have been residual confounding from other factors related to breast cancer that were not assessed. Finally, the reported levels of alcohol consumption among the women in this study were very low (72% of the cohort drank either zero alcohol or below 5 g per day), but it cannot be determined if these are indeed the levels in this population or whether there may have been under-reporting of consumption.
The key findings as reported by the authors were that, overall, there was “no statistically significant association between alcohol intake and breast cancer risk after adjustment for confounders.” While this is indeed supported by their data, Forum members warned that readers should also note that there was an increase in risk found in less-obese women (BMI ≤ 25 kg/m2), among whom there was a step-wise increase in the risk ratio for cancer from 1.0, to 1.05, to 1.19, to 1.32 with increasing category of alcohol intake. This association was not seen in the more obese women for total cancer or for any of the sub-categories of cancer.
While the overall results did not show an increase in risk from alcohol intake, the results among non-obese women are similar to those seen in many other studies, and suggest a slight increase in the risk of breast cancer associated with alcohol for at least some women. The differences in effect according to BMI reported by the investigators are interesting and add to our understanding of the association of alcohol with breast cancer which, however, remains unclear.
Critique 170: An update on the association of alcohol consumption with the risk of cancer — 1 September 2015
Reference: Cao Y, Willett WC, Rimm EB, Stampfer MJ, Giovannucci EL. Light to moderate intake of alcohol, drinking patterns, and risk of cancer: results from two prospective US cohort studies. BMJ 2015;351:h4238; doi: 10.1136/bmj.h4238
This well-done analysis based on data from two very large cohort studies, the Nurses’ Health Study and the Health Professionals’ Follow-up Study, evaluated the association of alcohol consumption over many years with the risk of cancer. The authors conclude that men reporting an average intake of more than 15 grams of alcohol per day, but not less, have a significant increase in risk of alcohol-related cancers. In women, however, even the consumption of an average of 5.0 – 14.9 grams of alcohol per day (the equivalent of between ½ and 1 ½ typical drinks) was associated with a slight increase in total cancer risk, stated to be primarily from an increase in the risk of breast cancer. For both genders, there seemed to be a dose-response increase in risk of cancer with larger amounts of alcohol. At the same time, smoking was identified as an even more important risk factor than alcohol for these cancers.
Forum members considered this to be an important study presenting data that are of relevance to individuals and agencies providing advice regarding alcohol consumption. There is little question that heavy drinking markedly increases the risk of upper aero-digestive cancers, and no physician or agency advises people to consume in excess of the typical limits of no more than one or two drinks/day. Hence the finding in this study of an increase in some cancers among women (especially breast cancer) even for lighter drinking has implications for alcohol policy.
The Forum was disappointed that all dietary and other lifestyle factors that have been shown to increase the risk of cancer (data that are known to be available to these investigators) were not included in their report. Members were especially concerned that the net effects on health and mortality of light-to-moderate alcohol consumption were not commented upon in the paper. Given that the risk of the most common causes of death, especially cardiovascular diseases, are reduced by moderate drinking, it seems that the authors should have included data, or at least mentioned, the effects of alcohol on cancer mortality and, especially, on total mortality. It has recently been emphasized that cohort studies that report on only one outcome (in this case, cancer) but do not mention other outcomes that are affected by the same exposure, especially total mortality, do not present the full picture, and can lead to biased recommendations. The inclusion of such information from these cohorts could provide even more valuable data upon which to develop appropriate guidelines for alcohol use by individual patients and the public.
Critique 165: Fiber intake may modify the association of alcohol consumption with certain hormone-dependent cancers — 4 June 2015
Reference: Chhim A-S, Fassier P, Latino-Martel P, Druesne-Pecollo N, Zelek L, Duverger L, Hercberg S, Galan P, Deschasaux M, Touvier M. Prospective association between alcohol intake and hormone dependent cancer risk: modulation by dietary fiber intake. Amer J Clin Nutr 2015; pre-publication. Doi: 10.3945/ajcn.114.098418.
The positive association between alcohol intake and certain hormone-dependent cancers (especially breast cancer) noted in many studies has been attributed to an effect of alcohol through an increase in levels of estrogen and other hormones. The present study had extensive dietary data on more than 5,000 men and women in France, among whom comparisons were made between the sex-specific tertile of alcohol intake and the risk of hormone-related cancers (breast, prostate, ovarian, endometrial, and testicular).
The study found that, overall, the risk of some cancers (e.g., breast) but not others (e.g., prostate) were positively related to reported alcohol intake. The key results reported by the authors are that when the risks of cancer were related to alcohol while adjusting for fiber intake, subjects whose fiber intake was below the median value showed higher risks of cancer related to alcohol, but not subjects with higher fiber intake. For example, when the risk of breast cancer in women was related to the tertile of their alcohol intake, the 2nd tertile showed a HR of 1.55 (1.01 – 2.38) and the 3rd tertile (HR 1.70, CI 1.11 – 2.61), when compared with women in the lowest tertile.
For prostate cancer in men, however, the 2nd tertile showed a HR of 1.28 (CI 0.82 – 2.00) and the 3rd tertile a HR of 0.89 (CI 0.55 – 1.45). The interaction terms between alcohol intake and cancer were not significant for all hormone-dependent cancers or for breast cancer. Only the interaction term for prostate cancer reached statistical significance, but here the relationship between tertile of alcohol intake even among subjects with low dietary fiber did not show a clear dose-response relation.
Forum members had concerns about the large number of potential confounders in these analyses (e.g., different effects for different types of fiber, the intake of fiber being just a marker for folate intake or for other dietary or lifestyle factors), that made it difficult for the authors to reach firm conclusions. Unfortunately, the numbers of tumors for each of the sub-groups were often too small to give meaningful results. And there was no data on alcohol drinking pattern (regular moderate versus binge drinking) or type of beverage consumed. Thus, while this study indicates that alcohol intake may relate to certain hormone-dependent cancers, the analyses do not present a clear demonstration as to whether it is fiber intake or some other related factor that may modify the association.
Critique 162: What is the association between alcohol consumption and cancer? – 13 April 2015
- Klatsky AL, Li Y, Tran HN, Baer D, Udaltsova N, Armstrong MA, Friedman GD. Alcohol Intake, Beverage Choice, and Cancer: A Cohort Study in a Large Kaiser Permanente Population. Perm J 2015;19:March 1, 2015. http//dx.doi.org/10.7812/TPP/14-189
- Bagnardi V, Rota M, Botteri E, et al. Alcohol consumption and site-specific cancer risk: a comprehensive dose–response meta-analysis. British Journal of Cancer 2015;112:580–593. doi: 10.1038/bjc.2014.579
- Wienecke A, Barnes B, Neuhauser H, Kraywinkel K. Incident cancers attributable to alcohol consumption in Germany, 2010. Cancer Causes Control 2015;[Epub ahead of print].
Three major papers on the association of alcohol consumption and cancer have recently been published. Forum members considered that all were well-done, and presented valuable new information on the topic. While the key findings in each study are similar, each brings specific information on how alcohol relates to the risk of developing cancer. In this critique, we present the authors’ abstracts of each paper, our comments on the paper, and then an overall discussion of the topic.
Problems can occur when combing case-control studies with prospective cohort studies, as was done in one of the papers reviewed, as risk estimates are usually higher in the former type of study and potential confounding may be less complete. Further, it is especially important to consider the interaction between alcohol consumption and smoking for upper aero-digestive tract cancer, as was not always done. And none of the studies covered in this critique emphasized the net effects of alcohol that, because of protective effects against cardiovascular disease, is almost always associated with lower total mortality among moderate drinkers than among abstainers.
In summary, the Forum considers that the three papers reviewed provide important data on one of very few lifestyle factors that have been shown to relate to the risk of cancer. And cumulative research data clearly show that heavy alcohol intake increases the risk of upper aero-digestive tract cancers and some other cancers. Further, in these and many previous reports, even light alcohol consumption was associated with an increase in risk of breast cancer in women. Unfortunately, the threshold level of drinking associated with an increase in risk is not clearly defined for most cancers.
Forum members agree with the conclusions of Klatsky et al, who stated: “At present, a possible increased cancer risk at moderate intake should enter into individual estimation of the overall risk-benefit equation for alcohol drinking, especially for young persons. For most persons older than age 50 years, the overall benefits of lighter drinking, especially the reduced risk of atherothrombotic disease, outweigh possible cancer risk.”
For the full critique of these papers, and general comments on alcohol and cancer, by members of the International Scientific Forum on Alcohol Research, please click here.
Critique 149: The association of alcohol consumption with the risk of death from colorectal cancer — 28 October 2014
Reference: Cai S, Li Y, Ding Y, Chen K, Jin M. Alcohol drinking and the risk of colorectal cancer death: a meta-analysis. European Journal of Cancer Prevention 2014;23:532–539.
Data from prospective cohort studies on the association between alcohol consumption and the occurrence of colorectal cancer (CRC) are conflicting, with some suggesting an increase in risk while others failing to show such an effect. There are little data on the effects of alcohol consumption on the risk of mortality from CRC. The present study is based on a meta-analysis of data from nine cohort studies (with a total of more than two million subjects) to judge how the level of alcohol intake relates to CRC mortality. A total of almost 4,000 deaths from CRC were recorded. The conclusions of the authors are that the consumption of ≥ 50 grams of alcohol (about 4 typical drinks or more) per day increases the risk of death from CRC modestly [RR 1.21 (95% CI 1.01, 1.46)], but “light” drinking (≤ 12.5 g/day) or “moderate” drinking (12.6-49.9 g/day) do not increase the risk of CRC death. In fact, they state that their data support a “J-shaped” relation between alcohol intake and CRC mortality (i.e., a slight decrease in mortality associated with light drinking but an increased risk with heavier drinking).
Forum members considered this to be a well-done analysis. They noted the inability of the authors to evaluate differences in effect according to type of beverage consumed, the pattern of drinking, or the underlying folate levels of subject, all of which probably modify such a relation. The results are in line with earlier reports on alcohol and breast cancer, where alcohol appears to increase the incidence of the disease but does not increase mortality. For most diseases, including colorectal cancer, there may a J-shaped effect on mortality: a reduction in risk for light-to-moderate drinking but an increase with heavier drinking.
Overall, the present meta-analysis supports a finding of increased risk of death from colorectal cancer from heavy drinking. However, it shows rather convincingly that light to moderate amounts of alcohol do not increase the risk of death from this disease, probably because of the protective effects of moderate drinking on cardiovascular disease, a more common cause of mortality.
Critique 148: Alcohol and liver cancer — 24 September 2014
Reference: F. Turati, C. Galeone, M. Rota, C. Pelucchi, E. Negri, V. Bagnardi, G. Corrao, P. Boffetta, C. La Vecchia. Alcohol and liver cancer: a systematic review and meta-analysis of prospective studies. Annals of Oncology 2014; advance publication; doi:10.1093/annonc/mdu020
Hepatic cirrhosis frequently precedes the development of liver cancer, and excessive alcohol consumption is known to be one cause of cirrhosis. The investigators in the present study carried out a meta-analysis to evaluate the association of alcohol consumption with liver cancer. They used data from 19 prospectively studied cohorts with a large total number of cases: 4,445 incident cases and 5,550 deaths from liver cancer.
The analysis from this large study indicates that liver cancer is related to heavier alcohol intake, but not to light-to-moderate drinking (with the latter defined in this study as < 3 typical drinks per day). The authors conclude: “This systematic review suggests a moderate detrimental role of consumption of 3 or more alcoholic drinks per day on liver cancer, and a lack of association with moderate drinking.”
Forum reviewers considered this to be a well-done analysis with appropriate statistical methodology. While the authors were unable to test the potential effects of pattern of drinking (regular moderate versus binge drinking), the type of beverage (wine or other beverages), or potential effects of obesity (with the latter being a key factor associated with the most common type of liver disease in the US, non-alcoholic fatty liver disease), the results of this study support most other research indicating that more than moderate drinking increases the risk of cirrhosis and liver cancer. However, the findings of no effect from what the authors considered “moderate” drinking (< 3 drinks/day, which exceeds the guidelines for most countries), also fits with another recent meta-analysis showing no increase in risk of liver cancer to be associated with light drinking.
There are many adverse health effects of heavy alcohol consumption. Liver cirrhosis, which frequently precedes the development of liver cancer, is one such potential outcome. On the other hand, this study suggests that moderate alcohol intake does not increase the risk of liver cancer.
Critique 147: Association of alcohol intake with different types of breast cancer — 11 September 2014
Reference: Falk RT, Maas P, Schairer C, Chatterjee N, Mabie JE, Cunningham C, Buys SS, Isaacs C, Ziegler RG. Alcohol and Risk of Breast Cancer in Postmenopausal Women: An Analysis of Etiological Heterogeneity by Multiple Tumor Characteristics. Am J Epidemiol 2014; advance access; DOI: 10.1093/aje/kwu189.
The present study was based on a large number of women participating in a clinical trial (enhanced screening for certain cancers versus routine care) focusing on prostate, lung, colorectal, and ovarian cancer. During a follow-up period averaging about 9 years, a total of 1,905 women were diagnosed with invasive breast cancer. The analyses showed that an increase in cancer risk was associated with alcohol intake for estrogen and progestin positive (ER+/PR+) tumors, but not for other histologic types of breast cancer. The increased risk was predominantly seen among PR+ cancers, as there was no evidence of an increase in risk from alcohol for women with ER+/PR- tumors. An association with the highest category of alcohol intake was noted for ductal (the most prominent type), lobular, and mixed ductal/lobular tumors, but a clear dose-response curve was not present. The authors conclude that alcohol consumption is not associated with all breast cancer subtypes, and that future research should include precise definition of subtypes of cancer.
Forum reviewers considered this to be a well-done analysis. There were some questions about the characteristics of the participants in the study that could affect generalizability of the results. For example, the cohort of women in this study were more highly educated, more likely to have a positive family history of breast cancer, to be smokers, and perhaps more obese that the general population. Of more concern, however, was the lack of ability to evaluate a number of other potential risk factors for breast cancer: folate levels and other dietary factors, the pattern of drinking (regular versus binge), potential changes in drinking after the baseline measurement, type of beverage, or the HER2 status of tumors. The finding in the paper of an increase in breast cancer risk, in comparison with non-drinkers, even for women reporting less than ½ drink per week (RR 1.15, CI 0.97, 1.39) and 0.5 – < 1 drink per week (RR 1.25, CI 1.03, 1.53), suggests that residual confounding must also be considered; it is unlikely that such small amounts of alcohol would have a physiological effect.
Overall, the present study shows a significant increase in the risk of breast cancer among women in a cancer prevention trial who, at baseline, indicated that they were consuming even less than 1 drink/week. The increase was exclusively in ER+/PR+ tumors, but not in ER+/PR- or ER-/PR- tumors.
In future research on this association, information on folate levels and drinking pattern, and especially on type of beverage consumed and on evidence of under-reporting of alcohol intake, will be important in better defining how alcohol consumption relates to the risk of breast cancer. While the results of this study are important in studying the etiology of breast cancer (as alcohol appears to relate only to hormone receptor positive tumors), the findings may not necessarily help individual women know how their alcohol consumption by itself may relate to their overall risk of the disease.
Critique 144: Alcohol consumption and risk of endometrial cancer — 18 August 2014
Reference: Je Y, DeVivo I, Giovannucci E. Long-term alcohol intake and risk of endometrial cancer in the Nurses’ Health Study, 1980–2010. British Journal of Cancer 2014;111:186–194; doi: 10.1038/bjc.2014.257.
Most epidemiologic studies have shown that moderate alcohol consumption does not increase the risk of uterine cancer, and some have suggested an inverse or J-shaped relation. In a new analysis from the Nurses’ Health Study, with 68,067 female participants aged 34–59 years in 1980, investigators have related repeatedly assessed long-term alcohol intake, and related the cumulative average intake over time to the risk of invasive uterine cancer. A total of 794 cases of invasive endometrial adenocarcinoma were identified over a 30 year follow-up period.
The authors report an inverse association among alcohol drinkers (multivariable RR=0.81; 95% CI: 0.68–0.96) compared with nondrinkers. Women with an intake of <5 g per day (an average of approximately one-half drink per day) had a 22% lower risk of endometrial cancer (multivariable RR=0.78; 95% CI: 0.66–0.94), with no further decrease evident from larger amounts of alcohol. In comparison with non-drinkers, the relative risk was similarly reduced for consumers of more than 30 grams of alcohol per day, but the number of subjects in this category was small, and a potential increase in risk from heavy drinking could not be adequately assessed in this study.
Forum members considered this to be a very well-done prospective study, with clear and biologically plausible results. By having repeated assessments of alcohol, an estimate of long-term average consumption was possible. The approximately 20% lower risk of uterine cancer among subjects with light alcohol intake remained statistically significant after multivariate adjustments for known potential confounders. Reviewers agreed with the authors that a potential mechanism for the association could be a reduction in insulin concentrations and improved insulin sensitivity that have been shown to occur with moderate alcohol consumption. Further, the frequently demonstrated inverse relation for alcohol with obesity may also play a mechanistic role. Overall, this study adds to accumulating scientific data showing that moderate drinking does not increase the risk of uterine cancer, and probably is associated with a reduction in risk
Critique 138: Underreporting of alcohol intake affects the relation of alcohol to the risk of cancer — 23 April 2014
Reference: 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; on-line publication; DOI 10.1007/s10552-014-0372-8 2014.
Epidemiologists are often faced with reported adverse health effects of alcohol among subjects reporting very low levels of consumption, levels that physiologically should not cause diseases such as cancer. It is often assumed that at least some of the subjects reporting low levels of intake may be underreporting their actual intake, but heretofore it has been difficult to judge this.
In the present study, the authors used each subject’s computer-based data on conditions and diseases (including laboratory and social factors), related to alcohol misuse, collected over many years to identify subjects reporting “light-to-moderate” alcohol intake who were likely, or unlikely, to be underreporting their intake at a baseline examination. Overall, 18.4% of subjects were suspected of being underreporters while 46.5% had adequate data that suggested that they were not underreporters. (The remaining 35.1% of subjects had inadequate data stored in the computer to be classified.)
Among their cohort of more than 100,000 subjects, 14,880 developed cancer during an average follow-up period of 18 years. There were 23,363 subjects who reported that they were light (up to 1 drink/day) or moderate (1 to 2 drinks/day) drinkers. In all comparisons, subjects suspected of being underreporters of their alcohol intake had a higher risk of cancer than those not categorized as being underreporters. For example, among subjects reporting 1 to 2 drinks/day, in comparison with non-drinkers, the risk ratio of any type of cancer among those considered to not be underreporters was 0.98 (95% CI 0.87-1.09); in other words, no effect on cancer risk from alcohol. For those categorized underreporters, however, the relative risk of any cancer was 1.33 (95% CI 1.21–1.45). Similar results were seen for alcohol-related cancers as for any cancer. Also, the risk of breast cancer among women was less than one-half as high among moderate drinkers who were unlikely to be underreporters of their alcohol intake as among those considered likely to be underreporting their drinking.
Adjusting for confounding in prospective studies is an ever-present challenge for epidemiologists. One factor that has often been considered probable, but difficult to adjust for, is the underreporting of actual alcohol intake by subjects. Being able to adjust for such unerreporting would greatly improve studies relating alcohol consumption to the risk of cancer (and other chronic diseases). For epidemiologic studies that have extensive longitudinal data on all medical conditions (such as the Kaiser-Permanente Study, the basis for these analyses), the approach described in this paper could be an extremely valuable way of seeking the true relation between light-to-moderate alcohol intake and cancer as well as with a variety of other health outcomes. Based on the present study, an increase in the risk of cancer among light-to-moderate drinkers may occur primarily among those who underreport their alcohol intake.
Critique 129: Association of alcohol consumption with skin cancer; A report from the Women’s Health Initiative — 20 November 2013
Reference: Kubo JT, Henderson MT, Desai M, Wactawski-Wende J, Stefanick ML, Tang JY. Alcohol consumption and risk of melanoma and non-melanoma skin cancer in the Women’s Health Initiative. Cancer Causes Control 2013 (pre-publication) DOI 10.1007/s10552-013-0280-3
A report from more than 59,000 women in the Women’s Health Initiative related reported alcohol consumption to the risk of melanoma (MM) and non-melanoma skin cancer (NMSC). This was a fairly large study, with 532 cases of melanoma and 9,593 cases of NMSC occurring over approximately 10 years of follow up. The key reported results were for a higher hazard of MM (HR 1.64) and NMSC (OR 1.23) for drinkers of 7 or more drinks/week, compared with non-drinkers. Lifetime alcohol consumption was also positively associated with hazard of MM and risk of NMSC, with the only significant increases for MM according to type of beverage being seen for women with a preference for white wine or liquor. As shown in many previous studies, the risk of these skin cancers was lower among smokers than among non-smokers.
Forum reviewers thought that this was a very well-done analysis. They did note that there were large decreases in the estimates of HRs related to alcohol consumption when adjustments were made for sun exposure and other known confounders. For example, the HR for MM decreased for total wine from 1.30 to 1.06 when adjusted; for red wine:1.71 to 1.34; for white wine: 1.93 to 1.52; for liquor: 1.87 to 1.65; for beer: 1.34 to 1.18. The magnitude of these changes, as well as the very different baseline characteristics of the women according to their drinking habits, raises the possibility that there may be residual confounding affecting the results. In addition, reviewer Zhang points out that by including subjects with these skin cancers prior to baseline in their main analyses, there could be a problems with bias in their results.
Forum member Klatsky has recently reported on this topic using several decades of follow-up data from the Kaiser-Permanente study, with more than 300,000 subjects and more than 1,000 cases of MM. In that study, he and his colleagues found that among persons preferring wine, the HR for MM at 3+ drinks per day was 1.7 (95% CI 1.2-2.5), while it was 1.2, 1.3, and 1.1 in persons with preference for liquor, beer, and no beverage type. However, at 1-2 drinks per day, wine drinkers had a HR of 0.9. Klatsky states “So maybe too much should not be made of the beverage type data in these analyses. However, the association with alcohol seems statistically solid.”
A previous study by Mukamal, with data from 300,000 subjects participating in a risk factor surveillance survey reports: “Approximately 33.5% of respondents reported a sunburn within the past year. Heavier average alcohol use and binge drinking were both positively associated with prevalence and number of sunburns within the past year. The adjusted odds ratios for prevalence and number of sunburns among binge drinkers were 1.39 (1.31-1.48) and 1.29 (1.20-1.38), respectively.” Klatsky wonders whether “possible confounding by sun is not only an artifact of SES and tropical vacations, but whether heavy imbibers at the beach may fall asleep when exposed or simply do not notice their sunburn until it is severe.” Other Forum reviewers also worry that there may be residual confounding in the present study from sun and ultraviolet exposure.
Klatsky adds: “However, even if the alcohol-melanoma association is due to confounding by sun exposure, the same explanation seems less plausible for the inverse association between smoking and melanoma. While there is obviously no public health utility in any ‘protective’ effects of smoking, that association is scientifically interesting and could be a clue to mechanisms.”
The bottom line is that there are considerable observational epidemiologic data suggesting that alcohol consumption may relate to an increase in the risk of MM and NMSCs. As mechanisms are not known, there is still concern that much of this relation may relate to residual confounding by ultraviolet sun exposure, the most important environmental factor for these diseases.
Critique 128: Little effect of alcohol consumption on breast cancer risk found among African-American women — 14 November 2013
Reference: Chandran U, Zirpoli G, Ciupak G, McCann SE, Gong Z, Pawlish K, Lin Y, Demissie K, Ambrosone CB, Bandera EV. Does alcohol increase breast cancer risk in African-American women? Findings from a case–control study. British J Cancer 2013;109:1945–1953 | doi: 10.1038/bjc.2013.513.
Alcohol is known to be a risk factor for breast cancer in Caucasian women, but the evidence in African-American (AA) women is limited and results from previous studies are inconclusive. The present case-control study, based on 803 cases of breast cancer among African American women in the northeastern part of the USA, evaluated associations between recent and lifetime drinking and breast cancer risk. The authors report that there was no association between recent drinking and breast cancer risk, even when stratified by menopausal status or by hormone receptor status. Further, their analyses suggested a slight decrease in cancer risk with alcohol consumption among women who drank when under 20 years of age (OR = 0.65; 95% CI: 0.47–0.89), regardless of menopausal or hormone receptor status.
Forum reviewers point out that this was a case-control study of breast cancer, which always presents an opportunity for recall bias, and the number of cases was not large. Further, AA women generally drink very little, so it may be difficult to determine if larger amounts of alcohol may increase breast cancer risk.
On the other hand, the results were based on a very well-done and complete analysis, with appropriate control for known risk factors, similar results were obtained when recent (in last year) alcohol intake and long-term alcohol consumption were considered, and their finding of increased risk of breast cancer among subjects with a family history of breast cancer, a personal history of benign breast disease, and HRT use strengthen the results.
The results of this study are consistent with those from many previous studies showing little effect of alcohol consumption on breast cancer risk among AA women. However, given that few AA women in the USA drink alcohol, and those that do typically consume only small amounts, the study cannot estimate the potential effect on breast cancer among heavier drinkers. Further, Forum members believed that the decrease in the risk of breast cancer found in this study for drinking early in life (before age 20 years) may be due to residual confounding by socio-economic factors.
Overall, the present study supports previous research suggesting that the light alcohol consumption typically seen among AA women in the USA is not an important factor in their risk of breast cancer. On the other hand, this paper reports similar null results between alcohol and cancer risk among Caucasian women in their study. Current data do not necessarily indicate that there are ethnic differences in alcohol metabolism that may lead to differences between Caucasian and AA women in the association of alcohol consumption with breast cancer, and this study alone cannot be used to support such a premise.
Critique 125: Effects of alcohol consumption on risk of colorectal cancer; potential modification by folate intake — 25 September 2013
Reference: Nan H, Lee JE, Rimm EB, Fuchs CS, Giovannucci EL, Cho E. Prospective study of alcohol consumption and the risk of colorectal cancer before and after folic acid fortification in the United States. Annals of Epidemiology 2013;23:558-563.
Many epidemiologic studies have shown a small increase in the risk of breast cancer and colorectal cancer to be associated with alcohol consumption. Some have found that higher intakes of folic acid may attenuate such an increase in risk. The present study was designed to evaluate the influence of alcohol consumption on the risk of colorectal cancer according to folic acid fortification period in the United States. The relation of alcohol intake to colorectal cancer in two prospective studies (the Nurses’ Health Study and the Health Professionals Follow-up Study) was compared for a prefortification period (before 1998) with such risk estimates during the postfortification period, which began in 1998. A total of 2,793 cases of invasive colorectal cancer were documented.
The authors concluded that their data support an increase in colorectal cancer with high alcohol intake, and suggest that the risk may be lower in the postfortification period due to a higher folate intake in the US population. Forum reviewers had some concerns about these conclusions, as they point out that no dose-response relation between alcohol and colorectal cancer was shown in either period, and in data since 1998 no significant relation is seen between alcohol and such cancers. In fact, the authors of the present study state: “We also examined drinking pattern in relation to colorectal cancer risk; neither frequency of drinking nor quantity of drinking was associated with the risk of colorectal cancer;” they do not report their data upon which that statement is based.
Overall, the present paper does not answer the question as to the extent to which alcohol may relate to the risk of colorectal cancer, or if folate intake may modify any relation that may exist. Given that colorectal cancer (and breast cancer in women) are so common, it is important to evaluate how dietary folate and other nutrients may relate to such cancers. Further research on the relation of alcohol to these cancers, and potentially modifying factors, is greatly needed.
Critique 123: Alcohol consumption and lymphoid and myeloid neoplasms — 5 September 2013
Reference: Heinen MM, Verhage BAJ, Schouten LJ, Goldbohm RA, Schouten HC, van den Brandt PA. Alcohol consumption and risk of lymphoid and myeloid neoplasms: Results of the Netherlands cohort study. Int J Cancer 2013l133:1701–1713.
Many prospective studies have shown that moderate drinkers are at lower risk of certain types of lymphoid cancer. For example, a report in 2009 from the Million Women’s Study in the UK found that alcohol consumption showed a significant inverse association with the occurrence of non-Hodgkin lymphoma (NHL). Further, a 2012 paper from that study based on 9,162 incident cases of haematological malignancy, including 7,047 lymphoid and 2,072 myeloid cancers, concluded: “Among predominantly moderate alcohol drinkers, higher intake was associated with lower risk of lymphoid malignancies.” Those investigators did not find a significant effect of alcohol on the risk of myeloid tumors, such as acute myeloid leukemia. Another 2012 paper based on almost 2,000 cases of Non-Hodgkin Lymphoma concluded: “In summary, findings from the prospective study presented here support the hypothesis that alcohol intake might be associated with a reduced risk of NHL.”
The authors of the present paper from the Netherlands, based on 17.3 years of follow up with 1,375 cases of lymphoid and 245 cases of myeloid neoplasms, did not find a statistically significant reduction in the risk of lymphoid cancers, and the authors suggest: “If any association between alcohol consumption and lymphoid neoplasms exists, our study suggests an increased risk rather than a decreased risk.”
While reasons for this difference in results of this study when compared with other recent studies may be used to better understand the association between alcohol and such cancers, Forum reviewers were concerned about a number of aspects of this study. For example, the authors had data on alcohol consumption only at baseline for this very long (17+ year) follow up, so changes (either increases or decreases in intake) were not known. Further, the key relations reported were not adjusted for a large number of potentially confounding variables, such as a positive family history of hematological cancer. (The authors state that they carried out such multivariable analyses but do not present the data.) Of even more concern was the apparent inverse effect of alcohol on cancer risk for a number of types of tumors when dose-response relations were shown.
Given the rather consistent findings in other very large studies of hematological malignancies that the risk of many types of lymphoid cancer may be reduced by alcohol, and inconsistencies in the results of the present analyses, it is difficult to conclude that the present paper should change our current interpretation of the association between alcohol and these types of cancer.
Forum members look forward to reports from other prospective studies on this topic. For the present, however, the overwhelming scientific evidence suggests that moderate alcohol consumption is associated with a decrease in the risk of many types of lymphoid malignancies, but has little effect on myeloid cancers.
Critique 118: Clustering of alcohol consumption with socioeconomic and biologic risk factors for cancer — 30 July 2013
Reference: Touvier M, Druesne-Pecollo N, Kesse-Guyot E, Andreeva VA, Galan P, Hercberg S, Latino-Martel P. Demographic, socioeconomic, disease history, dietary and lifestyle cancer risk factors associated with alcohol consumption. Int J Cancer 2013;in press
It has been shown in most previous studies that moderate drinkers, especially those who generally consume wine, tend to have other “moderate” lifestyle factors. For example, they tend to be better educated, of higher socio-economic status, and generally are more active and eat a healthier diet than non-drinkers. An exception is cigarette smoking, which tends to be more common in drinkers than in abstainers. Epidemiologists studying alcohol and health are always striving to adjust appropriately for other lifestyle factors, attempting to assure that the difference in health outcomes among subjects relates to their drinking, and not to associated lifestyle factors.
In the present study, the investigators related alcohol consumption to a large number of socio-demographic and lifestyle factors that relate to the risk of cancer. They report that several factors were associated with alcohol consumption ≥10g/d in both genders: older age, smoking, higher socio-demographic category, higher income, and less healthy dietary intakes. Other factors were associated with alcohol consumption differently for men and women. The authors then report that the total number of such factors was higher among consumers of ≥10g/d of alcohol than among abstainers or lighter drinkers. They conclude: “The multiplicity of deleterious lifestyle behaviours combined with alcohol drinking must be taken into account in cancer prevention efforts. Gender-specific medical advice for people with personal or family history of alcohol-related diseases, including cancer, should be strengthened.”
While Forum reviewers found the data presented in this paper to be of interest, they did not believe that simply adding up all adverse risk factors provided useful information for the prevention of cancer. It is well known that smoking is a major risk factor for certain cancers, and in almost all studies alcohol consumers are more likely to be smokers; hence, drinkers should certainly be advised about the dangers of smoking. On the other hand, by simply summing the number of factors into a total score, the authors included a number of risk factors for which there is less of a scientific basis for their effect on cancer risk (e.g, the intake of supplements). Such factors should not be given the same weight as smoking as risk factors for cancer. Further, this study was carried out among computer-literate volunteers, so it may have limited relevance for the general population.
There have been extensive data showing that “healthy” and “unhealthy” lifestyle factors tend to cluster: for example, light-to-moderate drinkers tend to be leaner and eat a healthier diet than non-drinkers or heavy drinkers, as shown in this study. However, the prevention of chronic diseases relates to a large number of behaviors, and alcohol consumption cannot be considered as an isolated factor. Current epidemiologic data suggest that the combination of not smoking, being physically active, eating a healthy diet, avoiding obesity, and, unless contraindicated, regularly consuming small amounts of an alcoholic beverage, together make up what can be defined as a “healthy lifestyle.”
Critique 112: Relation of alcohol intake to risk of dying from cancer — 23 May 2013
Reference: Jin M, Cai S, Guo J, Zhu Y, Li M, Yu Y, Zhang S, Chen K. Alcohol drinking and all cancer mortality: a meta-analysis. Ann Oncol 2013;24:807-816. doi: 10.1093/annonc/mds508.
This paper presents a meta-analysis that related alcohol consumption to all-cancer mortality; it was based on almost 50,000 deaths reported in the literature from prospective cohort studies. Forum reviewers had some concerns about the conclusions of the paper, based on some discrepancies in the text, the lack of data on drinking pattern, no beverage-specific results, etc. Nevertheless, as expected, the reported average consumption of 50 or more grams of alcohol per day (equivalent to 4 or more typical drinks each day) was associated with an estimated 32% increased risk of dying from cancer.
However, there was no increase in the estimated risk of cancer death for subjects classified as “moderate” drinkers (defined by the authors using a wide range of intake: 12.6 to 49.9 grams/day, the equivalent of up to approximately 4 or more typical drinks). Further, Forum members were surprised that a slight but statistically significant decrease in cancer mortality risk was seen for “light” drinkers (those reporting an average of ≤ 12.5 grams/day, or about one typical drink). Forum members appreciated that misclassification of cause of death or residual confounding could have contributed to this latter result.
It is especially important that the only significant increase in risk in cancer mortality among the almost 50,000 cancer deaths reported in this meta-analysis was for consumers of 50 grams or more of alcohol. This suggests strongly that the overall risk of cancer mortality related to alcohol consumption is primarily (perhaps almost exclusively) from heavier drinking. Certainly, the findings from this study do not support the premise that “any amount of alcohol increases the overall risk of dying from cancer.”
Critique 109: In women developing breast cancer, moderate alcohol consumption before or after diagnosis does not increase breast cancer mortality and decreases total mortality — 16 April 2013
Reference: Newcomb PA, Kampman E, Trentham-Dietz A, Egan KM, Titus LJ, Baron JA, Hampton JM, Passarelli MN, Willett WC. Alcohol consumption before and after breast cancer diagnosis: Associations with survival from breast cancer, cardiovascular disease, and other causes. J Clin Oncol 2013; pre-publication. Available at jco.ascopubs.org/cgi/doi/10.1200/JCO.2012.46.5765
Most previous research has shown a slight increase in the risk of breast cancer (BrCa) among women who consume alcohol (versus nondrinkers), even among those whose average is only one drink/day. The association with death due to breast cancer is less clear, although overall total mortality among moderate drinkers is almost always lower than among non-drinkers; this reduction is generally attributed to a lower risk of cardiovascular disease.
The present study related alcohol consumption, both prior to the diagnosis of BrCa and after the diagnosis, with survival; deaths from BrCa and from cardiovascular disease, as well as total mortality, were related to alcohol intake. Specifically, in this study the authors assessed alcohol intake in a cohort of 22,890 women with incident invasive breast cancer (BrCa) who were residents of one of four US states and diagnosed at ages 20 to 79 years. During a median follow-up period of 11.3 years after diagnosis of BrCa, 7,780 deaths occurred, including 3,484 attributed to breast cancer.
Based on a quadratic analysis, moderate alcohol consumption before diagnosis showed a tendency towards lower risk of death from BrCa, and a significantly greater reduction in the risk of cardiovascular disease mortality and total mortality. Alcohol consumption after diagnosis was not associated with disease-specific survival, but was associated with a lower risk of total mortality. For women consuming alcohol prior to the diagnosis of BrCa, those who decreased their intake showed little effect on mortality, while those who increased their intake showed further lowering of their risk of cardiovascular and total mortality.
Forum reviewers considered this to be an excellent paper providing important new data on the association of alcohol consumption with survival after a diagnosis of invasive breast cancer. They thought that the statements of the authors accurately reflected their data, as they concluded: “Overall alcohol consumption before diagnosis was not associated with disease-specific survival, but we found a suggestion favoring moderate consumption. There was no evidence for an association with postdiagnosis alcohol intake and breast cancer survival. This study, however, does provide support for a benefit of limited alcohol intake for cardiovascular and overall survival in women with breast cancer.”
An accompanying editorial* agreed with the conclusions of the authors. The editorial stated, “Based on the best available evidence, including [the present report], 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.”
*Demark-Wahnefried W. To your health: How does the latest research on alcohol and breast cancer inform clinical practice? jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.490466),
Critique 099: Alcohol and survival after postmenopausal diagnosis of breast cancer — 20 December 2012
Reference: Vrieling A, Buck K, Heinz J, Obi N, Benner A, Flesch-Janys D, Chang-Claude J. Pre-diagnostic alcohol consumption and postmenopausal breast cancer survival: a prospective patient cohort study. Breast Cancer Res Treat 2012;136:195–207. DOI 10.1007/s10549-012-2230-2
This paper assessed the association of pre-diagnostic alcohol consumption with disease recurrence and survival in a prospective cohort study in Germany based on 2,522 postmenopausal breast cancer patients, aged 50–74 years. The authors report that alcohol consumption was non-linearly associated with increased breast cancer-specific mortality, but not with breast cancer recurrence. Results were independent of estrogen receptor status. The authors also report a non-significantly decreased risk of mortality due to other causes.
Forum reviewers considered this to be a well-done analysis that was limited, however, by the lack of data on drinking patterns prior to breast cancer diagnosis and because no data were available on drinking after the diagnosis (the latter limits the applicability of its results to women who have already developed breast cancer). The comparisons were primarily between non-drinkers/light drinkers and women in the highest alcohol category; the authors state that when ex-drinkers were removed from the referent category, their results regarding breast cancer-specific mortality were no longer statistically significant. The authors do not describe the potential effects on their main results that could result from what is known as “index event bias,” which may occur when an exposure (e.g., alcohol) relates to the development of a disease, breast cancer in this study, and may also relate to sequelae (e.g., recurrence or death) from the same disease.
Forum reviewers conclude that current scientific data show that alcohol consumption may increase the risk of developing breast cancer. However, they believe that the effects on subsequent survival after such a diagnosis remain unclear.
Critique 095: Effects of alcohol on lymphoma, leukemia, and other types of hematological cancers — 13 November 2012
Reference: Kroll ME, Murphy F, Pirie K, Reeves GK, Green J, Beral V, for the Million Women Study Collaborators. Alcohol drinking, tobacco smoking and subtypes of haematological malignancy in the UK Million Women Study. British Journal of Cancer 2012;107:879–887.
Many observational epidemiologic studies have found an inverse association between alcohol consumption and hematological cancers (such as lymphoma and leukemia). This study, based on the Million Women’s Study in the UK, is large enough to permit an evaluation of associations with various types of such cancers. Further, it takes into account newer coding systems for morphology so that diseases associated with the lymphatic system can be separated from those of the myeloid system.
The key findings are that alcohol consumption appears to lower the risk of several types of lymphoma and plasma cell neoplasms, but has little effect on the risk of myeloid tumors such as acute myeloid leukemia. Smoking is associated with an increase in risk for most such cancers.
Forum reviewers considered this to be a very well-done analysis, and the ability of the authors to separate the effects on lymphoid and myeloid cancers is important. Forum members emphasize the strong differences in effect of smoking (an increase) and alcohol consumption (a decrease) on the risk of these cancers. They support future research to discover the mechanisms by which moderate drinking may lower such risk.
Critique 094: The complex association between moderate alcohol consumption and breast cancer — 23 October 2012
Reference: Brooks PJ, Zakhari S. Moderate alcohol consumption and breast cancer in women: From epidemiology to mechanisms and interventions. Alcohol Clin Exp Res 2012; pre-publication: DOI: 10.1111/j.1530-0277.2012.01888.x.
An excellent review article from two scientists at the National Institue on Alcohol Abuse and Alcoholism describes the epidemiologic and basic scientific evidence linking alcohol consumption to the risk of breast cancer. The authors point out deficiencies in the epidemiologic data, especially that the pattern of drinking (regular moderate versus binge drinking) has generally not been taken into consideration (and the latter pattern can be associated with much higher blood alcohol concentrations). Further, epidemiologic studies usually provide data for only a short period of time, while the development of cancer may relate to exposures over many decades. The authors also comment upon the effect that under-reporting of alcohol by study participants could exaggerate effects on cancer risk from light drinking. They discuss two hypotheses that could relate alcohol to breast cancer risk: alcohol as a breast tumor promoter, and alcohol as a weak cumulative breast carcinogen, and present evidence from epidemiology and basic science that would relate to each hypothesis.
Overall, Forum reviewers were enthusiastic about this review paper, considering that it clearly outlined some of the difficulties scientists have in determining the causes of cancer. They agreed with the authors’ statements regarding the necessity to consider the overall net effects of moderate drinking, including reductions in the risk of cardiovascular disease and total mortality. They also agreed that future epidemiologic studies should focus on the pattern of drinking (and not just the average weekly amount of alcohol), and with their suggestions for future animal studies. One Forum reviewer cautioned that our understanding of the causes of breast cancer is still very incomplete, limiting our ability to provide well-founded recommendations to the public regarding moderate drinking as it relates to breast cancer risk.
For the full critique of this article by members of the International Scientific Forum on Alcohol Research, please click here.
Critique 092: The association of alcohol and tobacco with age at diagnosis among subjects with pancreatic cancer — 2 October 2012
Reference: Anderson MA; Zolotarevsky E; Cooper KL; Sherman S; Shats O; Whitcomb DC; Lynch HT; et al. Alcohol and tobacco lower the age of presentation in sporadic pancreatic cancer in a dose-dependent manner: A multicenter study. Am J Gastroenterol 2012; advance online publication, doi: 10.1038/ajg.2012.288
This analysis from a group of distinguished scientists supports previous research showing that smoking is associated with an earlier onset of pancreatic adenocarcinoma. Other research has shown that smoking may also be a causative factor in the development of this type of cancer. For alcohol, this study shows that heavy drinking also appears to be associated with earlier diagnosis; previous research from some epidemiologic studies has suggested further that heavy intake of alcohol may be associated with the development of pancreatic cancer.
Forum reviewers were concerned, however, about potential bias in regards to the time of diagnosis of such cancer, and about many other limitations of the study. For example, the inability to separate drinkers by the pattern of drinking (binge drinking versus regular, moderate intake), by the socioeconomic status of subjects, and by a lack of information on chronic pancreatitis, a known risk factor, weaken the implications of this paper. Forum members do not think that the results of this study will have a large impact on clinical practice, or on measures for the prevention of pancreatic cancer.
Critique 091: Light drinking may relate to increase in risk for certain cancers — 18 September 2012
Reference: Bagnardi V, Rota M, Botteri E, Tramacere I, Islami F, Fedirko V, Scotti L, Jenab M, Turati F, Pasquali E, Pelucchi C, Bellocco R, Negri E, Corrao G, Rehm J, Boffetta P, La Vecchia C. Light alcohol drinking and cancer: a meta-analysis. Pre-publication: Annals of Oncology 2012; doi:10.1093/annonc/mds337
A meta-analysis by a distinguished group of scientists was designed to determine if “light drinking” (defined as an average of up to 1 drink per day) was associated with the risk of certain cancers that have been shown in previous studies to be associated with the risk of cancer. The authors concluded that while the risk of these cancers was only slightly increased from such drinking, there were detectable increases in cancers of the oral cavity and pharynx, esophagus and female breast. They report no increase in the risk of cancers of the colorectum, liver, and larynx to be associated with such drinking.
Forum reviewers were concerned about a number of aspects of this study. While the statistical methodology was correct and done appropriately, the fact that the investigators (1) included both ex-drinkers and never drinkers in the reference group; (2) could not separate the effects of regular light drinking from binge drinking; (3) had no data on the duration of alcohol consumption at different levels; (4) did not adjust their analyses according to geographic region or type of study (both of which had large estimated effects on cancer risk); and (5) did not adjust their estimates of effect by other lifestyle habits, including smoking. All of these factors tend to weaken the implications of their results.
Forum reviewers were also concerned that despite the acknowledged limitations of their data, the authors present conclusions indicating that even light drinking increases the risk of certain cancers without commenting on the net health effects. They present only the effects on cancer (which was the topic of the meta-analysis) but do not comment on the overall or net health effects of light drinking: a marked reduction in the risk of much more common diseases, especially cardiovascular diseases, and a longer lifespan. Further, the lack of data on genetic patterns, folate intake, and other lifestyle factors makes it difficult to apply their findings to individual subjects. The Forum considers that while their analyses may be helpful in understanding associations between alcohol and cancer, the many limitations of this study indicate that it can provide only incomplete information on light alcohol consumption to be used as a basis for making recommendations to the public.
Critique 090: Effects of stopping alcohol consumption on subsequent risk of esophageal cancer — 13 September 2012
Reference: Jarl J, Gerdtham Ulf-G. Time pattern of reduction in risk of oesophageal cancer following alcohol cessation — a meta-analysis. Addiction, 107, 1234–1243. doi:10.1111/j.1360-0443.2011.03772.x
This paper provides an evaluation of the time following cessation of alcohol consumption that the risk of esophageal cancer returns to that of non-drinkers; it is based on 17 studies providing such information, 9 of which provided data for a meta-analysis. The authors conclude that an alcohol-related increased risk of esophageal cancer is reversible following drinking cessation, most likely requiring up to 16 years. The authors estimate that about one-half of the reduction in risk of cancer may occur within in a much shorter time, perhaps within about 4 or 5 years.
Forum reviewers considered this to be a well-done analysis. Forum members emphasized, as did the authors, a number of limitations of the study. Adjustments for smoking may not have been adequate: most upper aero-digestive cancers show a strong interaction between smoking and alcohol consumption in relation to cancer risk. (For many “alcohol-related” cancers, there is little effect of alcohol consumption among non-smokers.)
Further, large differences in the alcohol-cancer association were shown in this study for different geographical regions (some associations being much higher in Asia than in Europe or North America), but such differences were not adjusted for in the main analyses. The fact that the authors of this paper did not have data permitting the separation of ex-drinkers and never drinkers (both groups being included in the “non-drinker” category), and their inability to judge the effects of the baseline pattern of drinking (regular versus binge drinking), may also be limitations to the interpretation of their results. Adjustment for such factors may have influenced the effects of stopping drinking on subsequent cancer risk, and markedly changed the calculated effects on the numbers of cancers prevented worldwide.
In any case, the fact that cessation of drinking may reduce the risk of esophageal cancer is of importance. Other studies suggest further that just reducing the amount of alcohol consumed, rather than the complete cessation of drinking, may be associated with lowering of cancer risk, and low-level alcohol intake has been shown to have beneficial health effects on cardiovascular disease, diabetes, and other medical conditions.
Critique 089: Combination of hormone treatments and alcohol consumption influences the risk of breast cancer in women — 29 August 2012
Reference: Horn-Ross PL, Canchola AJ, Bernstein L, Clarke CA, Lacey JV, Neuhausen SL, Reynolds P, Ursin G. Alcohol consumption and breast cancer risk among postmenopausal women following the cessation of hormone therapy use: the California Teachers Study. Cancer Epidemiol Biomarkers Prev 2012.
An analysis among more than 40,000 postmenopausal women who were in the California Teachers Study was carried out to determine if there were differences in risk of breast cancer among women consuming alcohol according to their previous or current use of hormone therapy (HT). In the cohort, 660 women were diagnosed with invasive breast cancer during follow up.
Results from multivariate Cox proportional hazards regression models showed an increase in risk of breast cancer among alcohol consumers of more than 20 grams of alcohol per day (about 1 ½ to 2 typical drinks) who were current users of HT but not among those who were ex-users of HT. The authors conclude: “Following the cessation of HT use, alcohol consumption is not significantly associated with breast cancer risk, although a non-significant increased risk was observed among women who never used HT. Our findings confirm that concurrent exposure to HT and alcohol has a substantial adverse impact on breast cancer risk. However, after HT cessation, this risk is reduced.”
Forum reviewers considered this to be a very well-done analysis on a large group of post-menopausal women with repeated assessments of alcohol consumption and HT use. However, results from even very large studies on the relation between alcohol, HT, and breast cancer risk have often been conflicting. Even with numerous studies on this topic, we still have very poor predictors of which women will develop breast cancer. There is some increase in risk for women with a family history of such cancers and those who are obese. However, the percentage increases in risk associated with HT, alcohol consumption, and other environmental factors are generally small (unlike the many-fold increase in the risk of lung cancer among smokers in comparison with never smokers). This may explain why the results of individual studies may reach apparently conflicting conclusions. While the present study suggests that women who consume alcohol may have a decrease in their risk of breast cancer if they stop taking hormone replacement therapy, our current understanding of factors affecting breast cancer risk remains quite inadequate.
Critique 085: Moderate alcohol intake is associated with a lower risk of kidney cancer — 19 July 2012
Reference: Song DY, Song S, Song Y, Lee JE. Alcohol intake and renal cell cancer risk: a meta-analysis. British Journal of Cancer 2012;106:1881–1890.
A majority of previous epidemiologic studies have shown that moderate drinking is associated with a lower risk of kidney cancer, which may affect about 1% of the general population. In published prospective cohort studies, the risk for such cancer among moderate drinkers is usually about 25% less than the risk seen among non-drinkers.
This well-done meta-analysis supports these findings: for the more-reliable prospective cohort studies (rather than case-control studies) the current study finds a 29% lower risk for subjects in the highest category of alcohol consumption in comparison with subjects in the lowest alcohol category. The findings suggest similar effects among men and women, and for all types of alcohol beverages. The effects are seen at a level of about one drink/day, with little further reduction in risk for greater alcohol consumption.
Critique 078: An update on the association of alcohol consumption with risk of breast cancer — 10 April 2012
Reference: Seitz HK, Pelucchi C, Bagnardi V, La Vecchia C. Epidemiology and Pathophysiology of Alcohol and Breast Cancer: Update 2012. Alcohol and Alcoholism 2012; doi: 10.1093/alcalc/ags011
An excellent review paper on the relation of alcohol consumption to the risk of breast cancer concludes that, overall, there is a positive dose-response relation between alcohol drinking and the risk of breast cancer. The analysis shows that an increase in risk is seen even among women reporting an average of only about one drink/day. Given the high prevalence of such light drinking in most female populations, the authors estimate that up to 1 to 2% of breast cancers in Europe and North America may be attributable to light drinking alone. Thus, while alcohol appears to be a risk factor for breast cancer, it does not explain a very high percentage of cases.
Forum members considered this to be a well-done analysis, with a good review not only of epidemiologic studies but of potential mechanisms of effect of alcohol on breast cancer risk. An increase in estrogen levels from alcohol seems to be the physiologic mechanism most commonly suggested for the increase in risk.
The meta-analysis is noteworthy in presenting risks specifically for women who consume up to one drink/day, which is the common pattern for a high proportion of women in western cultures. On the other hand, the authors herefailed to discuss the potential modification of alcohol effects on cancer risk from folate in the diet; in many studies, high folate levels tend to diminish or eliminate an increase in risk from alcohol. Further, the paper does not provide a discussion of the net effects of moderate drinking on mortality. In older women, the decrease in the risk of cardiovascular disease (a much more common cause of death than breast cancer), greatly exceeds the potential increase in risk of death from breast cancer.
Critique 077: Swedish study supports a “U-shaped” association of alcohol consumption with risk of pre-diabetes and diabetes mellitus — 29 March 2012
Reference: Cullmann M, Hilding A, Östenson CG. Alcohol consumption and risk of pre-diabetes and type 2 diabetes development in a Swedish population. Diabet Med 2012;29:441–452. DOI: 10.1111/j.1464-5491.2011.03450.x
Subjects in a cohort in Sweden, some of whom had been exposed to a community intervention program to prevent diabetes, were evaluated 8-10 years after baseline for the presence of diabetes mellitus or impaired glucose metabolism (“pre-diabetes”) in relation to a baseline report of alcohol consumption. Approximately 2,000 men and 3,000 women had a normal glucose tolerance test at baseline; of these 105 men and 57 women developed type II diabetes. Of subjects with pre-diabetes at baseline, 175 men and 98 women progressed to diabetes. The authors report that total alcohol consumption and binge drinking increased the risk of pre-diabetes and diabetes in men, while low consumption decreased diabetes risk in women. However, the authors did not discuss the fact that in essentially all comparisons, the highest risk of diabetes or pre-diabetes was among abstainers.
Forum reviewers had some concerns about the study. For example, the study included some subjects who had been exposed to an intervention trial to prevent diabetes, yet no information is given on potential effects of the intervention. It was not a population-based group. Also, the sample was “enriched” with subjects who had a positive family history of diabetes, which may make it more difficult to judge the effects of environmental factors. Ex-drinkers and never drinkers were included in the abstainer group.
It appears that the authors focused only on the “statistically significant” results rather than commenting on the overall pattern of association (lower risk of developing diabetes for moderate drinkers than for abstainers and heavier drinkers). Further, the number of subjects in many of the sub-groups was very small, making it difficult to define specific cut-points for effects of alcohol on risk.
Nevertheless, reviewers considered that, overall, these analyses support the usual findings from previous research of a “U-shaped curve” for alcohol and diabetes for both men and women. There appears to be a reduction in risk with moderate alcohol intake and possibly an increased risk for heavier drinking.
Critique 068. Heavier alcohol consumption may increase risk of colon cancer in people with a family history of such cancer — 30 January 2012
Reference: Cho E, Lee JE, Rimm EB, Fuchs CS, Giovannucci EL. Alcohol consumption and the risk of colon cancer by family history of colorectal cancer. Am J Clin Nutr 2012;95:413–419.
An analysis based on a large number of subjects being followed in the Nurses’ Health Study and the Health Professionals Follow-up Study, relates alcohol consumption to the risk of colon cancer according to whether or not the subjects had a positive family history of colon cancer. Their results indicate that subjects with a family history whose average alcohol intake was 30 or more grams per day (about 2 ½ typical drinks by US standards) have an increase in their risk of colon cancer; there was not a significant association between alcohol and colon cancer among subjects without a positive family history.
Forum reviewers were somewhat concerned that the pattern of drinking (regularly or binge drinking) was not assessed, and that there was not a clear dose-response curve between the level of alcohol consumption and the risk of cancer (i.e., there was not a consistent increase in risk of cancer with greater alcohol intake). Further, folate intake was found to modify the association, with the highest risk for subjects with a positive family history of colon cancer, low levels of folate, and in the highest category of alcohol consumption.
The present study provides some support for an association between higher levels of alcohol intake and the risk of colon cancer among subjects with a positive family history of such cancer. However, there have been changes in the guidelines for screening for cancer (by endoscopy, with removal of pre-malignant tumors) and other preventive measures for people with a positive family history of colon cancer. Such measures could modify the effects of all risk factors for colon cancer in future analyses.
Click here for the full critique of this paper by the International Scientific Forum on Alcohol Research.
Critique 067: Comparison of effects of red wine versus white wine on hormones related to breast cancer risk 19 January 2012
Reference: Shufelt C, Bairey Merz CN, Yang YC, Kirschner J, Polk D, Stanczyk F, Paul-Labrador M, Braunstein GD. Red versus white wine as a nutritional aromatase inhibitor in premenopausal women. J Women’s Health, 2011;DOI: 10.1089/jwh.2011.3001
Aromatase inhibitors (AIs) prevent the conversion of androgens to estrogens, and could play a role in the development of breast cancer. This study of 36 pre-menopausal women consisted of a cross-over intervention trial to determine if there were differences between red wine and white wine in their effects on AIs. Subjects sequentially consumed eight ounces of red wine, followed by white wine (or vice versa), each beverage for a one-month period. The investigators concluded that red wine, but not white wine, was associated with significant effects on some indices of estrogen metabolism; free testosterone and luteinizing hormone were increased, but no significant differences were noted in estrogen levels.
Forum reviewers considered the results interesting and that they contribute to our understanding of the relation of wine to hormonal levels. On the other hand, they were concerned about methodological problems, including a lack of baseline data and variations in the timing during the menstrual period of blood sampling (which could affect estrogen levels). Also, no significant effect of the interventions was seen on blood levels of estradiol.
Further, the Forum thought that it should be pointed out that data are inconsistent on the relation of red wine consumption to the risk of breast cancer; many studies do not show beverage-specific effects on risk. More research will be needed to determine if the polyphenols in red wine can play a role in lowering the risk of breast cancer.
Click here for the full critique of this paper by members of the International Scientific Forum on Alcohol Research.
Critique 064: Association of lifestyle and environmental factors with the risk of cancer — 13 December 2011
Reference: Parkin DM, Boyd L, Walker LC. The fraction of cancer attributable to lifestyle and environmental factors in the UK in 2010. Summary and conclusions. British Journal of Cancer 2011;105:S77 – S81.
It has been well established that certain lifestyle habits relate to the risk of certain cancers (e.g., smoking and lung cancer). In a well-done analysis, the authors estimate the proportion of cancer in the population associated with a variety of lifestyle and environmental factors. They find that smoking has, by far, the largest effect on the risk of cancer, with 19.4% of cancer cases in the UK attributable to tobacco use. A poor diet (less intake of fruits and vegetables and fiber and greater intake of meat and salt), obesity, and alcohol are the next most important factors that relate to cancer, with alcohol being calculated to relate to 4.0% of cancer cases in the UK.
Forum reviewers considered this to be a well-done paper that used epidemiologic methods that are preferable to those used in some previous such analyses. Generally, they disagreed with the authors that no alcohol consumption was the theoretical “optimum exposure level,” as the risk of certain cancers seems to increase primarily from heavy drinking. Further, they found reason to believe that the purported effects related to diet may have been over-estimated.
Nevertheless, this paper provides considerable new information on lifestyle and environmental factors that may relate to the risk of cancer. It puts into perspective the importance of targeting certain behaviors for the potential reduction in the risk of cancer.
Critique 060: A new analysis from the Nurses’ Health Study on the association of alcohol with risk of breast cancer 3 November 2011
Reference: Chen WY, Rosner B, Hankinson SE, Colditz GA, Willett WC. Moderate alcohol consumption during adult life, drinking patterns, and breast cancer risk. JAMA 2011;306:1884-1890.
In a well-done analysis using prospectively collected data from the Nurses’ Health Study, the risk of breast cancer was found to be modestly increased among consumers of alcohol, even those whose total alcohol consumption was reported to be in the range of 3 to 6 drinks/week. Similar small increases in the risk of breast cancer have been found from alcohol consumption in the majority of previous studies observational studies. A strength of this study was the very large number of subjects, permitting the investigators to attempt to determine if both the amount of alcohol and the frequency of consumption were important in this association; strong effects were not found for either. A weakness is the failure to report the effects of folate intake on the association between alcohol and cancer; the same investigators have previously shown that folate is a potential moderator of the effects of alcohol on breast cancer risk.
The authors describe well the dilemma that women face regarding alcohol intake, which may increase slightly the risk of breast cancer but markedly decrease the risk of other more common diseases, especially cardiovascular conditions. For example, the authors state that regarding breast cancer, “We did find an increased risk at low levels of use, but the risk was quite small.” Forum members agree with the statement of the authors that “An individual will need to weigh the modest risks of light to moderate alcohol use on breast cancer development against the beneficial effects on cardiovascular disease to make the best personal choice regarding alcohol consumption.”
Critique 059: Association of quantity of alcohol and frequency of consumption with cancer mortality – 20 October 2011
Reference: Rosalind A. 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; DOI: 10.1093/aje/kwr210.
A paper from the National Institutes of Health in the United States attempts to evaluate the separate and combined effects of the frequency of alcohol consumption and the average quantity of alcohol per occasion as they relate to the risk of mortality from all cancers, as well as cancer-specific mortality. It is based on repeated administrations of the National Health Interview Survey in the United States, with a total of more than 300,000 subjects and over 8,000 deaths from cancer, and reports on total cancer deaths and deaths from lung, colorectal, prostate, and breast cancers.
For total alcohol consumption (frequency x quantity), the data indicate a significant reduction in the risk of all-site cancers (RR=0.87, CI 0.80-0.94) which, interestingly, is not emphasized by the authors and is not included in their abstract. Moderate drinking consistently shows no effect, and only heavier drinking is associated with an increase in all-site cancer risk. For site-specific cancers, an increase in risk of lung cancer was seen only for heavier drinkers, with a tendency for less cancer among light drinkers. There was no evidence of an effect of total alcohol consumption on colorectal, prostate, or breast cancer.
The authors excluded non-drinkers in a second analysis in which they used categories of usual daily quantity and of frequency of consumption in an attempt to investigate their separate effects. For all-site cancer and for lung cancer, these results again show an increase in risk only for drinkers reporting greater amounts of alcohol. The data also show an increase in cancer risk from more frequent drinking among women but not among men. For colorectal, prostate, and breast cancer, there is no clear pattern of an increase in risk from quantity of alcohol consumed. For frequency of drinking, again there is a suggestion of an increase in risk with more frequent drinking, although the trends are not statistically significant.
The overall message of this analysis is that light to moderate alcohol intake does not appear to increase the risk of all-site cancer (and light drinking was shown in this study to be associated with a significant decrease in risk). Similarly, light to moderate consumption was not associated with site-specific cancers of the lung, colorectum, breast, or prostate. Heavier drinking is known to be associated with a large number of adverse health effects, including certain cancers, as was shown in this study.
When considering cancer, alcohol consumption should not be considered in isolation, but in conjunction with, other lifestyle behaviors (especially smoking). We agree with the authors that both quantity and frequency of consumption need to be considered when evaluating the relation of alcohol to cancer; further, beverage-specific effects need to be further evaluated.
Critique 056: Relation of alcohol consumption to colorectal cancer 13 September 2011
Reference: FedirkoV, Tramacere I, Bagnardi V, Rota M, Scotti L, Islami F, et al. Alcohol drinking and colorectal cancer risk: an overall and dose–response meta-analysis of published studies. Annals of Oncology 22: 1958–1972, 2011, doi:10.1093/annonc/mdq653
A meta-analysis of case-control and cohort studies on the association of alcohol consumption with colorectal cancer was carried out, based on 22 studies from Asia, 2 from Australia, 13 from Western Europe, and 24 from North America. The paper provides evidence that alcohol, at least at higher levels of consumption, is associated with an increase in the risk of colorectal cancer. Overall, there was no increase in the risk for consumers reporting an average intake of up to 1 drink per day, but a modest increase (of 21%) for what the authors defined as “moderate drinking” (averaging up to 49.9 g of alcohol, or about 4 typical drinks, per day). The increase in risk was greater (52%) for consumers of 50 or more grams of alcohol per day.
Forum reviewers thought that this was, in general, a very well-done study that used appropriate statistical techniques for meta-analysis. There were some key concerns, however, including the following: (1) the authors’ definition of “moderate drinking” extended well above the usual recommended limits for sensible drinking; effects of consumption in categories of 1 to 2 drinks/day, 2 to 3 drinks/day, etc., were not given; (2) no results were provided according to type of beverage even though many previous studies have shown differences between health effects for consumers of wine, or wine/beer, and other beverages; and (3) no data were available on the pattern of drinking. Many studies have shown that regular, moderate drinking on most days of the week has very different health outcomes than drinking only on week-ends or binge drinking.
Despite these concerns, Forum members agreed that current data indicate that alcohol intake, especially heavier drinking, is associated with an increase in the risk of colorectal cancers. Future studies are needed to help determine if there is a threshold level of alcohol that increases the risk, if there are differences by type of beverage, and if the pattern of drinking (regular versus binge drinking) affects the risk.
Critique 054. Role of alcohol intake and smoking on upper aerodigestive cancers – 6 September 2011
Reference: Anantharaman D, Marron M, Lagiou P, Samoli E, Ahrens W, Pohlabeln H, et al. Population attributable risk of tobacco and alcohol for upper aerodigestive tract cancer. Oral Oncology 2011;47:725–731.
This paper provies an extensive analysis of the proportion of the risk of upper aero-digestive tract (UADT) cancers in the population (the population attributable risk) may be due to alcohol consumption and/or smoking. The analyses provide strong evidence that smoking is the most important factor in the risk of these cancers, and the risk is enhanced among those who also consume 2 or more drinks per day. Alcohol alone (i.e., among non-smokers) has little effect on the risk.
The authors state that their observations “are consistent with the hypothesis that alcohol acts as a carcinogen primarily because of its promoting effect on tobacco smoke.” In terms of the population-attributable risk, the authors conclude that “Our findings confirm that tobacco and alcohol together explain 73% of total UADT cancer burden in Europe.” Overall, tobacco use alone explained 28.7%, the combination of smoking and drinking 43.9%, and alcohol use alone only 0.4% of the population attributable risk. Among women, the risk of these cancers was higher among smokers than among those who both smoked and consumed alcohol; this perhaps suggests that the moderate intake of wine, the most common beverage among European women, may play a role in reducing the risk associated with smoking.
Forum reviewers thought that this was a very good paper, but hoped that in the future we would have more studies that evaluated the effects on risk of varying levels of alcohol consumption, differential effects of various beverages, and even differential effects according to subjects’ genetically determined differences in alcohol metabolizing enzymes.
Critique 049: Effects of smoking and alcohol use on risk of upper aero-digestive cancers 1 August 2011
Reference: Szymańska K, Hung RJ, Wűnsch-Filho V, Eluf-Neto J, Curado MP, Koifman S, Matos E, Menezes A, Fernandez L, Daudt AW, Boffetta P, Brennan P. Alcohol and tobacco, and the risk of cancers of the upper aerodigestive tract in Latin America: a case–control study. Cancer Causes Control (2011) 22:1037–1046. DOI 10.1007/s10552-011-9779-7
A case-control analysis from subjects living in areas of South America with high rates of upper aero-digestive tract cancers showed that both alcohol consumption and smoking tended to increase the risk of such cancers. However, the predominant cause of these cancers was the combination of smoking and alcohol consumption, with much higher risk than either exposure alone. The effects on risk were greater for smoking than for alcohol: for non-smokers, there was little effect of alcohol on risk. For non-drinkers, the risk of cancer associated with smoking was still increased, but was lower than it was for current drinkers.
An especially important finding in this study was that, among ex-drinkers and former smokers, the increased risks associated with alcohol and tobacco use decreased steadily as the time since quitting increased. As stated by the authors, most of these cancers “could be prevented by quitting the use of either of these two agents.”
Critique 048: A new report on drinking guidelines and the association of alcohol with risk of cancer. 18 July 2011
Reference: Latino-Martel P, Arwidson P, Ancellin R, Druesne-Pecollo N, Hercberg S, Le Quellec-Nathan M, Le-Luong T, Maraninchi D. Alcohol consumption and cancer risk: revisiting guidelines for sensible drinking. CMAJ 2011. DOI:10.1503. /cmaj.110363
The Canadian Medical Association Journal has published a commentary by some French scientists relating drinking guidelines to the association between alcohol and cancer. They conclude that the current guidelines for sensible drinking for the general population are not adequate for the prevention of cancer, and revisions and eventual exclusion of such guidelines are needed.
Forum reviewers agree that alcohol consumption, especially heavy intake, increases the risk of certain types of cancer. However, they consider that the opinions of the authors in the paper (labeled as an “Analysis” rather than an editorial or comments) do not reflect current sound scientific data, that the report is highly selective in citing a small number of papers that support their opinions, and that the authors have ignored a huge amount of recent data from more scientifically sound research that have largely discredited such studies. Further, the report provides no mention of the consistent finding from studies around the world that moderate drinkers tend to have lower all-cause mortality risk than do abstainers.
Scientific data over many decades have shown that excessive or irresponsible alcohol use has severe adverse health effects, including an increase in the risk of certain cancers. On the other hand, moderate drinking is associated with lower risk of cardiovascular disease and many other diseases of ageing and with all-cause mortality. A very large number of experimental studies, including results from human trials, have described biological mechanisms for the protective effects of alcoholic beverages against such diseases. A number of comprehensive meta-analyses provide much more accurate, up to date, and scientifically balanced views than does the current paper; such documents may be better sources of data upon which guidelines to the public regarding alcohol consumption should be based.
Critique 042: An increase in risk of certain types of gastric cancer from heavy drinking, but no increase from moderate alcohol consumption – 17 May 2011
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 Oncology 2011;doi:10.1093/annonc/mdr135
This well-done meta-analysis supports other data generated on the risk of alcohol consumption and gastric cancer – that is – that the risk may be real for heavy alcohol consumption but not for moderate intake. The type of gastric cancer relating to heavier alcohol intake in this study tended to be tumors involving the noncardia, but differences between the association with tumors of the cardia were not significant.
There was no increased risk of gastric cancer from alcohol among Asians; this may be due to lower alcohol intake; there is a greater prevalence among Asians of the inactive ALDH2 genotype that is associated with flushing and other adverse effects of alcohol, and such subjects tend to drink less alcohol. However, a number of studies have shown higher risk for upper aero-digestive cancers for subjects with this ALDH2 genotype, so the overall reason for the lower risk among Asians in this study remains unclear. The main outcome of the study is that there is no increase in the risk of gastric cancer associated with the moderate intake of alcohol.
Critique 039. The role that alcohol drinking may play in the risk of cancer. 17 April 2011
Reference: Schűtze M, Boeing H, Pischon T, et al, Alcohol attributable burden of incidence of cancer in eight European countries based on results from prospective cohort study. BMJ 2011; 342:d1584 doi: 10.1136/bmj.d1584 (Published 7 April 2011)
A large group of distinguished scientists have published a very detailed and rather complex paper describing the association between alcohol consumption and cancer. It is based on data from the EPIC study in Europe, with a mean follow up of 8.8 years for more than 300,000 subjects. The authors describe an increase in risk of many cancers from alcohol intake, but do not give data permitting the detection of a threshold of intake for an adverse effect on cancer risk. The investigators conclude that “In western Europe, an important proportion of cases of cancer can be attributable to alcohol consumption, especially consumption higher than the recommended upper limits.”
Members of the Forum were concerned that the authors did not separate moderate consumption from heavy consumption for their main analyses, ignored the demonstrated benefits of moderate drinking on total mortality, and did not point out other environmental influences (such as smoking, diet, obesity, etc.) that often have much larger effects on the risk of many cancers than does alcohol consumption. The authors make statements such as alcohol has negative effects on total mortality that are not supported by the data presented in their paper, and are contradicted by most large-scale population-based studies. Overall, while this paper supports the well-known association between heavy drinking and an increased risk of upper aero-digestive and certain other cancers, it adds little information useful for the prevention of most types of cancer.
Critique 018. Alcohol consumption following diagnosis of early-stage breast cancer may increase risk of recurrence of cancer but not total mortality risk – 14 September 2010
Reference: Kwan ML, Kushi LH, Weltzien E, Tam EK, Castillo A, Sweeney C, Caan BJ. Alcohol consumption and breast cancer recurrence and survival among women with early-stage breast cancer: The Life After Cancer Epidemiology Study. J Clin Oncol 2010;28 (published ahead of print, 10.1200/JCO.2010.29.2730).
In the Life After Cancer Epidemiology (LACE) study, 1,897 participants diagnosed with early-stage breast cancer between 1997 and 2000 and recruited on average 2 years post-breast cancer diagnosis were evaluated for the association between alcohol intake and breast cancer recurrence and death. The women, who were generally light drinkers, were followed for an average of 7.4 years. The study reported an increase in risk of breast cancer recurrence and breast cancer death, but no effect on total mortality, to be associated with consumption of 3 to 4 or more drinks per week when compared with women not drinking following their cancer diagnosis.
Previous research has been mixed on this topic. Almost all large studies have shown no increase in all-cause mortality for women who drink moderately following a diagnosis of breast cancer (as does this study). As for recurrence of breast cancer, most have shown no increase in risk, although one previous study of women with estrogen-receptor + tumors found an increased risk of a primary cancer developing in the contralateral breast to be associated with alcohol intake of more than 7 drinks per week.
Because of conflicting results among studies on this topic, further research will be needed to determine the extent to which alcohol following a diagnosis of breast cancer may relate to subsequent disease and death.
Critique 016. Association of alcohol with breast cancer risk varies according to subtype of tumor. 29 August 2010
Reference Li CI, Chlebowski RT, Freiberg M, Johnson KC, Kuller L, Lane D, Lessin L, O’Sullivan MJ, Wactawski-Wende J, Yasmeen S, Prentice R. Alcohol consumption and risk of postmenopausal breast cancer by subtype: the Women’s Health Initiative Observational Study. J Natl Cancer Inst 2010 Aug 23. [Epub ahead of print].
Most studies show a slight increase in the risk of breast cancer for women who consume alcohol. The association is thought to relate to alcohol’s effects on hormones, and alcohol use tends to be more strongly associated with hormonally sensitive breast cancers than tumors not sensitive to hormones. Few studies have evaluated how alcohol-related risk varies by breast cancer subtype. In the present study, follow-up data from 87,724 women in the Women’s Health Initiative Observational Study prospective cohort were evaluated for the relation of baseline alcohol consumption with subsequent breast cancer.
A total of 2,944 invasive breast cancer patients were diagnosed during follow up. In multivariable-adjusted analyses alcohol consumption was associated with an increase in the risk of lobular carcinoma (which makes up approximately 15-20% of breast cancers), but there was not a statistically significant association with the more-common ductal type of carcinoma. Hormone + cancers showed an association with alcohol intake, but not hormone – cancers. The findings support the importance of hormonal mechanisms in mediating the relation between alcohol use and breast cancer risk.
Critique 015. Moderate drinking does not appear to increase risk of breast cancer among women with a BRCA gene mutation. 22 August 2010
Reference: Dennis J, Ghadirian P, Little J, et al: The Hereditary Breast Cancer Clinical Study Group. Alcohol consumption and the risk of breast cancer among BRCA1 and BRCA2 mutation carriers. The Breast 2010; e-pub.
A large study was carried out to assess the effects of alcohol consumption on breast cancer risk among women with a BRCA1 or a BRCA2 gene mutation, both of which markedly increase the risk of breast cancer. Comparisons were made between women with a gene mutation who had developed invasive breast cancer matched with women with the same gene mutation who had not developed breast cancer. After a number of appropriate exclusions, there were 1,480 matched pairs with BRCA1 mutations and 445 pairs with BRCA2 mutations.
Data from the study support an earlier report suggesting no increase in breast cancer risk from alcohol intake for women with either gene mutation. In the previous study on this topic, a slight lowering of breast cancer risk was noted with light drinking among women with the BRCA2 mutation but not among those with the BRCA1 mutation. In the present study, a possible reduction in risk of breast cancer was seen for moderately drinking women with the BRCA1 mutation, but not the BRCA2 mutation. Further, in the present study, the reduction is risk of breast cancer was seen only for wine consumers. While one should not over-interpret epidemiologic data in the absence of identified biologic mechanisms, there have been a very large number of experimental studies showing that certain polyphenols present in wine actively impede the initiation and growth of cancer cells.
Overall, current scientific data suggest that alcohol in moderation does not increase the risk of breast cancer among women with a BRCA mutation, and wine may be somewhat protective. If this is indeed the case and given the high risk associated with these genetic mutations, it would be important to inform women with such a mutation that moderate alcohol does not appear to increase their risk of breast cancer.
Critique 001. Genetic effects on alcohol metabolism modify the relation of alcohol to breast cancer – 24 April 2010
Reference: Larsen SB, Vogel U, Christensen J, Hansen RD, Wallin H, Overvad K, Tjønneland A, Tolstrup I. Interaction between ADH1C Arg272Gln and alcohol intake in relation to breast cancer risk suggests that ethanol is the causal factor in alcohol related breast cancer. Cancer Letters, 2010, in press.
A study from Germany compared the association between alcohol and breast cancer risk according to genetic variations affecting levels of alcohol dehydrogenase, an enzyme that clears alcohol from the blood stream. The authors conclude that genetic factors associated with the slow clearance of alcohol are associated with increased risk of breast cancer for drinkers; an increase in cancer risk was not seen for drinkers with genetic factors leading to fast clearance of alcohol. Such a finding would suggest that alcohol itself is the cause of an increase in breast cancer risk among drinkers.
Unfortunately, some previous studies have shown the opposite, that an increase in breast cancer risk occurs only among women who have genes associated with fast, rather than slow, alcohol metabolism. Overall, current scientific data indicate that breast cancer’s relation to drinking is not resolved, remaining murky and conflicted, and perhaps overemphasized. This facet of that murkiness is itself also conflicted. As of now, it is unclear the degree to which genes affecting alcohol dehydrogenase modify the association between alcohol and the risk of breast cancer and other diseases.