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

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.

Authors’ Abstract

Background: While current research is largely consistent as to the harms of heavy drinking in terms of both cancer incidence and mortality, there are disparate messages regarding the safety of light-moderate alcohol consumption, which may confuse public health messages. We aimed to evaluate the association between average lifetime alcohol intakes and risk of both cancer incidence and mortality.

Methods and findings: We report a population-based cohort study using data from 99,654 adults (68.7% female), aged 55-74 years, participating in the U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Cox proportional hazards models assessed the risk of overall and cause-specific mortality, cancer incidence (excluding nonmelanoma skin cancer), and combined risk of cancer and death across categories of self-reported average lifetime alcohol intakes, with adjustment for potential confounders. During 836,740 person-years of followup (median 8.9 years), 9,599 deaths and 12,763 primary cancers occurred. Positive linear associations were observed between lifetime alcohol consumption and cancer-related mortality and total cancer incidence. J-shaped associations were observed between average lifetime alcohol consumption and overall mortality, cardiovascular-related mortality, and combined risk of death or cancer. In comparison to lifetime light alcohol drinkers (1 – 3 drinks per week), lifetime never or infrequent drinkers (<1 drink/week), as well as heavy (2 -<3 drinks/day) and very heavy drinkers (3+ drinks/day) had increased overall mortality and combined risk of cancer or death. Corresponding hazard ratios (HRs) and 95% confidence intervals (CIs) for combined risk of cancer or death, respectively, were 1.09 (1.01-1.13) for never drinkers, 1.08 (1.03-1.13) for infrequent drinkers, 1.10 (1.02-1.18) for heavy drinkers, and 1.21 (1.13-1.30) for very heavy drinkers. This analysis is limited to older adults, and residual confounding by socioeconomic factors is possible.

Conclusions: The study supports a J-shaped association between alcohol and mortality in older adults, which remains after adjustment for cancer risk. The results indicate that intakes below 1 drink per day were associated with the lowest risk of death.

Forum Comments

Scientific data are clear: 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 cancer death. While much has been made of the risk of cancer associated with alcohol intake, few studies have focused on the total risk of death or cancer with varying levels of drinking.  The present report is a based on a population-based cohort study with 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 12,763 incident cancers diagnosed during follow up, so rather firm estimates of alcohol effects were possible. Results show a J-shaped association between alcohol and total mortality, and a slight linear increase in cancer incidence with increasing alcohol consumption (seen at or above about 1 ½ drinks per day for spirits and at or above about 2 drinks/day for beer; no increase in cancer risk was noted for wine consumption).  The conclusion of the authors is that there is a J-shaped association between alcohol and mortality in older adults, which remains after adjustment for cancer risk.

Specific comments from Forum members: Forum members were unanimous in considering this to be a well-done study of a large data set, with good ascertainment of outcomes, from older adults over a median follow-up period of 8.9 years; there were 9,599 deaths and 12,763 incident cancers.  The investigators used as outcomes (1) the incidence of any cancer, (2) total mortality, and (3) incidence of any cancer or death from any cause.  The investigators reviewed each subject’s medical records to confirm pathology of cancers.  The exposure was the “life-time” alcohol intake, using self-estimates of consumption in 4 time periods of life, multiplied by the number of years in each period.  Reviewer Ellison noted: “Personally, I am never too comfortable with this measure, as people usually have more difficulty in estimating much earlier alcoholic intake than more recent intake.  Adding all of the estimates together may obscure the actual intake during periods of life when effects on cancer and mortality are most important.  Nevertheless, the results of these analyses strongly support those of most earlier epidemiologic studies.”

Appropriate analytic methods were used in this study. The authors had data on a very extensive list of potential confounders, including a number related to the socio-economic status (SES) of subjects; this is important as SES is a strong modifying factor for the relation of alcohol intake to health, for both beneficial and harmful effects.  Further, the investigators used lifetime light drinkers (1-3/week) as the referent group in their main analyses for mortality.  Forum members noted that there large numbers of never drinkers in these cohorts (about one third of men and two thirds of women), certainly adequate numbers to use never drinkers as a referent group as well.  (Data in the supplemental material provided in the journal indicate similar or even more marked effects when “never drinkers” were used as the referent group: higher mortality among non-drinkers and heavy drinkers, lower risk among light-to-moderate drinkers.)

Reviewer Ellison also noted that the investigators tested for different effects according to the type of beverage consumed, but do not give results in the text. However, in the supplemental material provided, it is noted that there were more favorable results associated with wine consumption, especially for cancer incidence.  Specifically, cancer incidence increased rather linearly with the intake of beer and spirits, with significant increases in cancer rates appearing at intakes at or above about 1 ½ drinks per day for spirits and 2 drinks per day for beer.  However, their supplemental data show no significant increase in risk for wine consumption, regardless of the amount of intake reported.  For all alcoholic beverages combined, there is a J-shaped curve for total mortality.

Reviewer Goldfinger noted: “This review assumes the challenge of addressing cancer risk and mortality with alcohol consumption. There is a very large enrollment, however one-third are lost to follow up, were diagnosed with a priori malignancy, or died sometime after enrollment, quite possibly from cancer, and were not included. This may be a limitation of this study.

“The extent of their lifestyle and habit analysis for potential confounding is impressive. Putting their findings in perspective with cardiovascular benefit, also seen in this analysis, is quite laudable.  There are few studies, if any I can recall, looking at cancer risk that also acknowledge the offsetting benefit of reduced cardiovascular events.  Cardiovascular disease kills more human beings than all cancers put together.”  Reviewer Goldfinger concluded: ““I like this paper, and their review of the subject.  Again (and again), it was interesting to tease out beer and spirit drinkers from wine drinkers (excluding those consuming wine coolers), where there has been a reported  paradoxical reduced risk of cancers in subjects who are exclusively, or almost  exclusively, wine drinkers.”  This study confirms such findings.

Forum member Stockley wrote: “Given that cardiovascular disease and cancers have multiple risk factors which accumulate with age, including present and past alcohol consumption, measurement of average lifetime alcohol consumption avoids the bias that occurs when separating former drinkers from current drinkers, which Fillmore et al and Stockwell et al have alleged invalidates the J-shaped relationship between alcohol consumption and risk of death from cardiovascular disease and from all causes. In the present study, there was still a J-shaped relationship between alcohol consumption and cardiovascular mortality and all-cause mortality, irrespective of reference category (never drinkers versus light drinkers).”

Several Forum members noted that the present study supports the findings of Ford et al and of a number of other studies, including a very recent large study by Li et al in 2018. These studies have revealed that moderate alcohol consumption adds to the beneficial effects of other lifestyle components.  Li et al reported that among subjects in the Nurses’ Health Study and Health Professional Study, there were more than 42,000 deaths during follow-up periods extending up to 34 years. The effects of five healthy lifestyle factors (never smoking, lack of obesity, physical activity, moderate alcohol intake, and a good diet) on subsequent risk of mortality were striking: for subjects meeting criteria for all five factors versus none, there was an 84% reduction in all-cause mortality, 65% less cancer mortality, and 82% less cardiovascular disease mortality. The overall effect was associated with 12 to 14 additional years of life after age 50 for subjects meeting criteria for all five factors. In these studies, when moderate alcohol use was removed from the calculations, the mortality risk for those who also consumed alcohol was significantly lower than for those having only the other lifestyle factors.

Reviewer de Gaetano stated: “This study confirms the well documented J shaped curve for overall mortality and cardio-vascular mortality. It also confirms that cancer risk and cancer mortality are not favorably influenced by alcohol drinking, although the increased cancer risk observed at light consumption (0.5 – 2 drinks /day) remains very low.

“The most interesting data derives from the analysis of the combined risk of death and cancer incidence: indeed, the J-shaped association and mortality risk reduction observed for light alcohol intake remained, though slightly attenuated. Moreover, when assessing deaths for any cause within cancer patients, higher risk of death was observed in never drinkers and very heavy drinkers, in respect to light drinkers, confirming a J-shaped curve also in this population.  The data show that light drinking is associated with an overall advantage for health.  This conclusion is also supported by the observation that the relative benefit against cardiovascular disease is consistently higher than the increased risk for cancer.  Further, the J shaped curve they observed for all three different types of alcoholic beverages confirms previous data from our group (Di Castelnuovo et al) and by others on the J-shaped protection of alcohol tout court against total (all-cause) mortality.  Differences of different alcohol sources in respect to cancer remain to be confirmed.  In our studies, we could not find any significant difference between wine and beer on cardiovascular risk (Costanzo et al).”

Forum member Finkel stated: “I agree that this is is a worthwhile study, because of its breadth and length.  It does seem well done, and it addresses useful details often glossed over.  In real life terms, are the slight increases in risk among light drinkers of appreciable impact, or just playing with numbers?  I fear media and anti-alcohol people will pick at that one facet, and, as so often, suppress the overarching benefits of moderate drinking.”  All Forum members noted that the risk of the combined outcome, death or incident cancer, showed that the risk for light-to-moderate drinkers was considerably lower than that of non-drinkers, while there was a higher risk for heavy drinkers.  As the authors state, “The study supports a J-shaped association between alcohol and mortality in older adults, which remains after adjustment for cancer risk.”

References from Forum critique

Di Castelnuovo A, Costanzo S, Bagnardi V, Donati MB, Iacoviello L, de Gaetano G. Alcohol dosing and total mortality in men and women: an updated meta-analysis of 34 prospective studies.  Arch Intern Med 2006;166:2437-2445.

Costanzo S, Di Castelnuovo A, Donati MB, Iacoviello L, de Gaetano G. Wine, beer or spirit drinking in relation to fatal and non-fatal cardiovascular events: a meta-analysis.  Eur J Epidemiol 2011;26:833-850. doi: 10.1007/s10654-011-9631-0.

Fillmore KM, Stockwell T, Chikritzhs T, Bostrom A, Kerr W. Moderate alcohol use and reduced mortality risk: systematic error in prospective studies and new hypotheses.  Ann Epidemiol 2007;17(5 Suppl):S16–S23.

Ford ES, Zhao G, Tsai K, Li C. Low-risk lifestyle behaviors and all-cause mortality: findings from the National Health and Nutrition Examination Survey III Mortality Study. Am J Pub Health 2011;101:1922–1929.

Li Y, Pan A, Wang DD, Liu X, Dhana K, Franco OH, Kaptoge S, Di Angelantonio E, Stampfer M, Willett WC. Hu FB. Impact of Healthy Lifestyle Factors on Life Expectancies in the US Population.  Circulation 2018;137:00–00. (Pre-publication).  DOI: 10.1161/CIRCULATIONAHA.117.032047.

Stockwell T, Zhao J, Panwar S, Roemer A, Naimi T, Chikritzhs T. Do “Moderate”  Drinkers Have Reduced Mortality Risk? A Systematic Review and Meta-Analysis of Alcohol Consumption and All-Cause Mortality. J Stud Alcohol Drugs 2016;77:185-198.

Forum Summary

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.

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

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

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

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

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

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

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

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