Critique 095: Effects of alcohol on lymphoma, leukemia, and other types of hematological cancers —- 13 November 2012

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.

Authors’ Abstract

BACKGROUND: Previous research suggests associations of lower alcohol intake and higher tobacco consumption with increased risks of haematological malignancy.  The prospective Million Women Study provides sufficient power for reliable estimates of subtype-specific associations in women.

METHODS: Approximately 1.3 million middle-aged women were recruited in the United Kingdom during 1996–2001 and followed for death, emigration and cancer registration until 2009 (mean 10.3 years per woman); potential risk factors were assessed by questionnaire.  Adjusted relative risks were estimated by Cox regression.

RESULTS: During follow-up, 9,162 incident cases of haematological malignancy were recorded, including 7,047 lymphoid and 2,072 myeloid cancers.  Among predominantly moderate alcohol drinkers, higher intake was associated with lower risk of lymphoid malignancies, in particular diffuse large B-cell lymphoma [relative risk 0.85 per 10 g alcohol per day (95% confidence interval 0.75–0.96)], follicular lymphoma [0.86 (0.76–0.98)] and plasma cell neoplasms [0.86 (0.77–0.96)].  Among never- and current smokers, higher cigarette consumption was associated with increased risk of Hodgkin lymphoma [1.45 per 10 cigarettes per day (1.22–1.72)], mature T-cell malignancies [1.38 (1.10–1.73)] and myeloproliferative/myelodysplastic disease [1.42 (1.31–1.55)].

CONCLUSION: These findings confirm and extend existing evidence for associations of subtypes of haematological malignancy with two common exposures in women.

Forum Comments

While many observational epidemiologic studies have found an inverse association between alcohol consumption and hematological cancers (such as lymphoma and leukemia), the present study is large enough to permit an evaluation of associations with various types of such cancers.  The analyses are based on the Million Women’s Study in the UK.  They analyses take 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.

Specific comments on the paper:  Forum reviewers consider this to be a very well-done   analysis, one that provides important new data on the association of alcohol with cancer.  The authors used subjects reporting from ½ to 3 drinks/week as the referent group, and compared the risk of this group with non-drinkers and with those women who consumed more.  Follow up averaged more than 10 years, during which more than 9,000 cases of hematological cancer were detected.

None of the types of cancer showed an increase in risk with alcohol consumption.  Instead, in comparison with non-drinkers, the risk of lymphoid tumors was reduced among consumers of up to 3 drinks/week (the referent group), and reduced further among those consuming larger amounts of alcohol.  The risk of myeloid tumors was not affected by alcohol intake.  Tobacco use was associated with an increase in risk for most types of cancer.

Forum reviewer Lanzmann-Petithory commented on preliminary results (not yet published) from the Nancy study (COLOR: Nancy cohort with a Relative Risk for Death from Lymphoid, Haematopoietic and Related Tissue Cancer).  She reports that there have been 261 cases of these cancers among 35,292 men.  “Adjusted by Cox regression, there is a tendency for a lower risk (RR = 0.59, CI 0.34-1.03) among subjects reporting 3 drinks of alcohol/day.  There were no differences noted according to type of alcohol, suggesting that the effects on this type of cancer are probably related to pure alcohol and not wine.”  She concludes: “Further, it is still possible that there is a dose effect, because the estimated RR of all such tumors in the COLOR study (0.59) was even lower than that seen among the women in the present study, who consumed less alcohol.”

Opposite effects of smoking and drinking:  Forum member De Gaetano believed that the authors fail to present a clear picture of their results.  “I see a clear L-shaped curve for drinking doses, both by ICD-O-3 and ICD- 10 classifications: e.g., the RR for abstainers was 1.05; for 0.5-3 drinks/week, 1.00; for 3-7 drinks/week, 0.91; and for consumers of more than 7 drinks/week, 0.90.  In any case we are dealing with moderate alcohol amounts:  It is not what I immediately understand by reading that the beneficial effect is seen by increasing alcohol doses.  I also noticed that if you drink 10 g alcohol/day your RR is 0.92 but if you smoke 10 cigarettes/day your RR is 1.13.  This striking difference between drinking and smoking is not clearly expressed in the paper.  One cannot simply conclude that drinking and smoking are associated with hematological disease.”

Lack of a demonstrated mechanism:  Some Forum members pointed out that despite the epidemiological evidence, a mechanism for a protection of alcohol against lymphoid cancers had not been demonstrated.  Stated reviewer Finkel: “Despite the weight of the numbers and the assurance of the statistical analysis, I intuitively do not place a lot of weight on the apparent benefit of alcohol in reducing risk of the enumerated diseases.  We know too little about the details of consumption.  I agree that the work was competently done.”  Adds reviewer Skovenborg: “The big question is why?  Plausible biological mechanisms seem to be absent.  Is the association causal?  New hypotheses and new studies are sorely needed!”

On the other hand, Reviewer Waterhouse counters: “The lack of a mechanism doesn’t invalidate the observations, but I agree it raises a need for mechanistic understanding for the disease reduction.  Of note is that the lowered relative risk of cancers associated with moderate alcohol consumption is the same, or even lower, than that of other ‘healthy’ diets, such as high intake of fruits and vegetables.”

Lanzmann-Petithory adds: “As there are no postulated mechanisms to explain this inverse relationship with lymphoid cancers, which are very common, this subject seems very relevant.  It is important that this study had the power to separate the subgroups according to new coding parameters.  Everything is now ready to study the mechanism by which alcohol could protect against mature B cell lymphoid malignancies.”

Forum Summary

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.

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Comments for this review were provided by the following members of the International Scientific Forum on Alcohol Research:

Harvey Finkel, MD, Hematology/Oncology, Boston University Medical Center, Boston, MA, USA

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

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

Erik Skovenborg, MD, Scandinavian Medical Alcohol Board, Practitioner, Aarhus, Denmark

Giovanni de Gaetano, MD, PhD, Research Laboratories, Catholic University, Campobasso, Italy

Dominique Lanzmann-Petithory,MD, PhD, Nutrition/Cardiology, Praticien Hospitalier Hôpital Emile Roux, Paris, France

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