CONFERENCE ALCOHOL AND HEALTH Amsterdam, 23 September 2010 Alcohol drinking and cancer risk: what s new? Dr Paule LATINO-MARTEL UMR U 557 Inserm, U 1125 Inra, Cnam, Université Paris 13; CRNH-IdF, France French Network on Nutrition and Cancer Research (NACRe network)
Alcohol and cancer risk: the state of the art Many studies have been published on this topic: from 1950, 7600 studies including 2100 epidemiological studies evaluation by expert groups International working groups WHO International Agency for Research on Cancer Agents occurring in occupational and environnemental settings, or resulting from individual and cultural habits (smoking, dietary pratices) suspected to be carcinogenic World Cancer Research Fund and American Institute for Cancer Research Food, nutrition and associated factors susceptible to increase or decrease the risk of cancer Alcohol drinking has been recognized as carcinogenic to humans for more than 20 years
1. Evaluation by IARC working groups Methodology Exposure data Studies of cancer in humans Studies of cancer in experimental animals Mechanistic and other relevant data Evaluation of the strength of evidence http://monographs.iarc.fr Categorization of the agent Group 1 Group 2A Group 2B Group 3 Group 4 The agent is carcinogenic to humans The agent is probably carcinogenic to humans The agent is possibly carcinogenic to humans The agent is not classifiable as to its carcinogenicity to humans The agent is probably not carcinogenic to humans Until 2000 IARC working groups evaluation 1988: Alcohol drinking 1999: Acetaldehyde Classification of the agent Group 1 Group 1 Référence Monograph n 44 Monograph n 71 Recently 2007: Alcoholic beverages and ethanol in alcoholic beverages 2009: Acetaldehyde in alcoholic beverages Group 1* Group 1 Baan et al, 2007, Monograph n 96 to be published Secretan et al, 2009, Monograph n 100 to be published * Cancers of the oral cavity, pharynx, larynx, oesophagus, liver, colorectum and breast
2. Evaluation by the WCRF/AICR Evaluations by the WCRF/AICR Until 2000 Recently 1997: Food, nutrition, and the prevention of cancer: a global perspective (1 st Report) 2007: Food, nutrition, physical activity and the prevention of cancer: a global perspective (2 nd Report)
Methodology of the systematic review and evaluation by the WCRF/AICR (2 nd report) 6 years, more than 200 scientists 1. Systematic review of studies published until 2006 by 9 international centers (metaanalyses of 7000 selected studies) 2. Independent evaluation by a panel of 22 international experts Grading of the evidence - Epidemiological studies (quality, lack of heterogeneity, consistency) - Biological plausibility convincing Recommendations probable limited substantial effect on risk unlikely www.wcrf.org
Conclusion of the 2007 WCRF/AICR report 20 cancer sites examined In chapter 4.8. Alcoholic drinks, the panel concludes: «The evidence that alcoholic drinks are a cause of cancers of the mouth, pharynx, and larynx, the oesophagus, the colorectum (men), and the breast is convincing» «Alcoholic drinks are probably a cause of colorectal cancer in women, and of liver cancer»
2.1 Systematic review and meta- analyses of epidemiological studies Types of epidemiological studies Case-control study: in a selected population of subjects with the disease (cases) and of subjects without the disease (controls), retrospective study comparing the past exposure to a risk factor Cohort study: in a population without disease at the beginning of the study, prospective study measuring the occurrence of the disease in subjects exposed or not to a risk factor Meta-analyses: statistical approach combining results of several studies to give a quantified synthetic result with higher statistical power
2.1.1 Alcoholic beverages and risk of cancer of the upper aerodigestive tract (UADT): mouth,, pharynx, larynx and oesophagus
Alcoholic drinks and mouth, pharynx, and larynx cancers Cohort and case-control studies Highest versus lowest exposure category
Alcoholic drinks and mouth, pharynx, and larynx cancers Cohort and case-control studies Per drink per week
Alcoholic drinks and mouth, pharynx, and larynx Case-control studies cancers: dose-response Cohort studies
Alcoholic drinks and oesophagus cancer Cohort and case-control studies Per drink per week Case-control studies Dose-response
2.1.2 Ethanol and risk of colorectal Colon Cohort studies Ethanol per 10 g per day cancer Colon-rectum Cohort studies Ethanol per 10 g per day Standard drinks differ between countries Conversion of drinks in grams of alcohol (ex: France)
2.1.3 Ethanol and risk of breast cancer Cohort studies Ethanol per 10 g per day Case-control studies Ethanol per 10 g per day
2.1.4 Ethanol and risk of liver cancer Cohort studies Ethanol per 10 g per day
Summary of the 2007 WCRF/AICR evaluation of epidemiological studies Increase of the risk of several cancers: UADT (mouth, pharynx, larynx, oesophagus) Colon-rectum Breast Liver No threshold observed: «The evidence does not show a clear level of consumption of alcoholic drinks below which there is no increase in risk of the cancers it causes.» «The important factor is the amount of ethanol consumed»
All alcoholic beverages have the same effect The number of epidemiological studies providing evidence on a particular type of alcoholic beverage (wines, beers, spirits ) is lower For UADT cancers, available data are in favor of an increased risk whatever the type of alcoholic beverage «Data do not suggest any significant difference depending on the type of drink»
2.2 Biological mechanisms (in 2007 and update)
Metabolism of ethanol Alcohol deshydrogenase Aldehyde dehydrogenase Seitz et al., Nat Rev Cancer 2007;7:599-612
Carcinogenicity of ethanol and acetaldehyde in laboratory animals Ethanol in drinking water of rats and mice: Seitz et al., Nat Rev Cancer 2007;7:599-612 Acetaldehyde in drinking water of rats: Carcinogenic effect on different organs and tissues (mammary gland, oral cavity, lung, stomach, intestine...) Soffritti et al., Ann N Y Acad Sci 2002;982:87-105
Genetic polymorphisms Current data support a role of polymorphisms in genes for alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) combined with alcohol consumption in UADT cancers Ethanol Risk of head and neck cancer in individuals with the ALDH2 *1*2 versus *1*1 genotype ADH1B*1 (Europeans) Low activity ALDH2*2 (Asians) Inactivity ADH ALDH Acétaldéhyde Acétate For UADT cancers, drinkers with ADH1B*1 and/or ALDH2*2 alleles are at higher risk than carriers of the other alleles Druesne-Pecollo et al., Lancet Oncol 2009;10:173-180 Boccia et al., Cancer Epidemiol Biomarkers Prev 2009;18:248-254
Acetaldehyde directly provided by alcoholic beverages Alcoholic beverage Beers Wines Apple ciders Acetaldehyde concentration in the alcoholic beverage (mg/l) Residual acetaldehyde concentration in saliva after swallowing (µm) Spirits Fortified wines 9±7 34±34 50±41 66±101 118±120 195 734 ND 1387 2417 1555 alcoholic beverages tested The mutagenicity and carcinogenicity of acetaldehyde have been observed at 40 to 200 µm Lachenmeier et al., Food Chem Toxicol 2008;46:2903-2911
INCa/NACRe, Alcohol drinking and cancer risk 2008:59p Excessive alcohol consumption induces denutrition Seitz, Recent Dev Alcohol 1998;14:67-95 Lieber, Annu Rev Nutr 2000;20:395-430 Lieber, Alcohol Res Health 2003;27:220-231 Leo et al., Am J Clin Nutr 1999;69:1071-1085 Maillot et al., Pathol Biol 2001;49:683-688 Voigt, Clin Liver Dis 2005;9:151-169 Boffetta et al., Lancet Oncol 2006;7:149-156 Marshall et al., In Cancer epidemiology and prevention 3rd Ed Schottenfeld and Fraumeni 2006:243-258
Mechanisms specific to cancer sites UADT Liver High acetaldehyde concentration in saliva Irritation of the UADT mucosa Alcohol (solvent) favoring the passage of carcinogens through the mucosa (synergy between alcohol and tobacco) Boyle, Ann Oncol, 2003 Inflammatory reactions leading to hepatitis and cirrhosis Colorectum Interference with the metabolism of folates Breast Modification of the plasma level of sexual hormones
2.3 Level of evidence
3. Other data Results of cohort studies published between 2007 and 2010 Risk of a second primary cancer Risk of cancer after alcohol drinking cessation Risk of childhood cancer
Cohort studies published between 2007 and 2010 45 recent publications on various cancer sites Cancer sites for which the level of evidence is convincing or probable: UADT cancers: Yes (8/9) Breast cancer: Yes (7/8) Colorectal cancer: Yes (5/6) Liver cancer: Yes (1/1) These recent results support the WCRF/AICR conclusions
Alcohol and risk of a second primary cancer The review suggests that alcohol drinking increases the risk of a second primary cancer after a cancer of the UADT Reference Alcohol consumption Total cancers UADT cancers Schwartz (1994) Yes vs no 1,08 (p=0,119) Barbone (1996) 60 glass/week vs no 1,3 (0,5-3,3) 2,0 (0,5-7,1) Do (2003) Yes vs no 1,4 (0,9-2,2) Carvalho (2004) Yes vs no 3,3 (1,2-9,2) Lin (2005) Yes vs no 2,1 (1,4-3,3) Leon (2005) 80 g/day vs no 1,87 (1,01-3,50) Dikshit (2005) 121 g/day vs no 1,9 (1,1-3,2) 3,5 (1,1-11,2) Franco (1991) High/moderate vs no 2,2 (0,7-6,8) Day (1994) 30 glasses/week vs no 1,5 (0,5-4,5) Russo (1996) >90 g/day vs no 1,24 (0,50-3,11) Ajusted for several confounding factors including smoking, excepted Leon (2005)
Alcohol drinking cessation reduces the risk of UADT cancers Pooled analysis of 13 case-control studies Oesophageal cancer: decrease after 15 years of abstention UADT cancers: decrease after 10 years of abstention In both cases, after more than 20 years, the risks were no longer significantly different from the risk of never drinkers Rehm et al., Int J Cancer 2007;121:1132-7
Risk of childhood cancer (in utero exposure) The meta-analysis of all published case-control studies shows an association between maternal alcohol consumption during pregnancy (yes versus no) and risk of acute myeloid leukemia in children aged 0 to 4 years Latino-Martel et al., CEBP 2010;19:1238-60 Pregnancy: a short but critical period
Overall conclusion The IARC evaluation, the WCRF/AICR evaluation, and the update lead to the same conclusion: «For cancer prevention alcohol drinking is not recommended»
Alcohol drinking is the second avoidable risk factor after smoking New cases: 12.4 millions worldwide (2008), 3.2 millions in Europe (2006) Cancer etiology is multifactorial: genetic background, tobacco, alcohol, nutrition, physical activity, viruses, radiations, environment Alcohol consumption is common throughout the world. In 2003, the 10 countries with the highest alcohol consumption were all in Europe Fraction of cancers attributable to alcohol drinking in 2002: 389 100 cancer cases worldwide 150 000 cancer cases in Europe 232 900 cancer deaths worldwide Boffetta et al, Int J Cancer 2006;119:884-887 Preventability estimates in UK (%) Cancer site PE (range) Mouth, pharynx, larynx 41 (4-67) OEsophagus 51 (13-74) Liver 17 (0-79) Colorectal 7 (0-18) Breast 22 (10-35) WCRF/AICR, Policy report 2009
Recommendations for cancer prevention From WHO European Region, 2006: «Region-wide specific drinking guidelines are not advisable» WHO continues to promote the message «Lessisbetter» To Health professionals: do not incite non-drinkers to begin regular consumption of alcoholic beverages, even at a moderate level encourage drinkers to reduce the amount consumed and the frequency of consumption recommend children and pregnant women not to drink alcoholic beverages To Alcoholic beverage producers: reduce the amount of ethanol and acetaldehyde of alcoholic beverages