Alcol e tumori con focus sulle basse dosi

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1 Alcol e tumori con focus sulle basse dosi Carlo La Vecchia Department of Epidemiology, Istituto Mario Negri Department of Clinical Sciences and Community Health, Università degli Studi di Milano 1

2 Cancers of the mouth, pharynx, oesophagus, and larynx i) Consumption of alcoholic beverages increases the risk of cancers of the mouth pharynx, oesophagus, and larynx (apart from cancers, of the salivary glands and nasopharynx) ii) The risk increases approximately in proportion to the amount drunk iii) In each case, alcoholic beverages act synergistically with smoking, each agent approximately multiplying the effects of the other, and iv) The main component of alcoholic beverages that determines the risk of cancer is ethanol. 2

3 Alcohol and oral cancer and pharyngeal cancer 3

4 Alcohol and oral and pharyngeal cancer: meta-analysis 4

5 Alcohol and SCC esophageal cancer 5

6 Alcohol and SCC esophageal cancer: meta-analysis 6

7 Alcohol and esophageal adenocarcinoma Alcohol drinking is unrelated to esophageal adenocarcinoma 7

8 Alcohol and esophageal adenocarcinoma (Bagnardi et al., in press) 8

9 Alcohol and laryngeal cancer 9

10 Alcohol and laryngeal cancer: meta-analysis 10

11 Oral cancer Alcohol tobacco interaction Table 2. Odds ratio (OR) and rations of Ors and 95% confidence intervals (CI)* of oral cancer and pharyngeal cancer according to alcohol drinking and smoking habit. Italy and Switzerland, Alcohol drinking (drinks/wk) Smoking habit (cig./day) 0-20 OR (95% CI) OR (95% CI) OR (95% CI) 77 OR (95% CI) Alcohol-adjusted OR (95% CI) Oral cavity Never ( ) 6.8 ( ) ( ) 8.3 ( ) 53.9 ( ) 92.2 ( ) 3.8 ( ) ( ) 25.3 ( ) 81.5 ( ) ( ) 7.6 ( ) ( ) 24.8 ( ) ( ) ( ) 10.3 ( ) Smokingadjusted ( ) 18.8 ( ) 39.4 ( ) Franceschi et al.,

12 Odds ratios Alcohol tobacco interaction H&N cancer (INHANCE) 14.2 (8.3, 24.4) (6.4, 15.5) 4.8 (3.2, 7.2) 4.2 (2.4, 7.1) (2.1, 4.5) 2.2 (1.6, 3.1) >20 cigarettes/day 1-20 cigarettes/day (1.3, 2.9) 1.0 (0.8, 1.3) 1.0 Never 0 3 drinks/day 1-2 drinks/day Never Alcohol drinking Hashibe et al.,

13 Effect in the absence of smoking In Europe and North America, all cancers of the upper respiratory and digestive tracts are rare in the absence of smoking and only very few studies have included enough cases to provide useful information about the effect of alcohol by itself. 13

14 Effect in the absence of smoking H&N cancer (INHANCE) Hashibe et al.,

15 Effect in the absence of smoking There is no reason to suppose that tobacco smoke is the only carcinogenic agent to which the human upper respiratory and digestive tracts are exposed, and ethanol may be facilitating the effect of some other unrecognized carcinogenic agents in nonsmokers. Acetaldehyde is a carcinogenic metabolite of alcohol. Doll et al., 1999; IARC 2007;

16 Interaction with nutrition There is now reason to believe that the risk from exposure to many carcinogenic agents can be reduced by the regular consumption of fruit and vegetables. Heavy drinking is commonly associated with poor nutrition and this increases the risk (particularly of pharyngeal and oesophageal, but also laryngeal cancers) in heavy drinkers. Doll et al., 1999; IARC

17 A. Moderate versus Non-/Occasional Drinkers, Men and Women Author, year Sex Site Ca Exp Co Exp Ca NExp Co NExp RR (95% CI) Cancer of the large bowel. Moderate vs non/occasional drinkers Fedirko et al., 2011 Case-control studies Potter, 1986 W CR Potter, 1986 M CR Kune, 1987 W CR Kune, 1987 M CR Peters, 1989 M CR Longnecker, 1990 M CR Choi, 1991 M CR Riboli, 1991 W CR Riboli, 1991 M CR Barra, 1992 MW CR Peters, 1992 MW C Gerhardsson de Verdier, 1993 MW CR Hoshiyama, 1993 MW CR Newcomb, 1993 W CR Boutron, 1995 M CR Chyou, 1996 M CR Murata, 1996 M CR Slattery, 1997 W C Slattery, 1997 M C Yamada, 1997 MW CR Tavani, 1998 MW CR Murata, 1999 W CR Murata, 1999 M CR Ji, 2002 W CR Ji, 2002 M CR Sharpe, 2002 M CR Kim, 2004 MW CR Murtaugh, 2004 M R Hu, 2007 W CR Hu, 2007 M CR Stern, 2007 MW CR Gao, 2008 M CR Lightfoot, 2008 MW CR Benedetti, 2009 M CR Kim, 2009 MW CR Morita, 2009 MW CR Wernli, 2009 W CR Yamamoto, 2010 MW CR All case-control studies (I-squared = 65.5%, p = ) ) Cohort studies Wu, 1987 W CR Wu, 1987 M CR Klatsky, 1988 MW CR Stemmermann, 1990 M CR Goldbohom, 1994 MW CR Flood, 2002 W CR Otani, 2003 M CR Pedersen, 2003 MW CR Shimizu, 2003 M CR Sanjoaquin, 2004 MW CR Su & Arab, 2004 MW C Wei, 2004 W CR Chen, 2005 MW CR Wakai, 2005 W CR Wakai, 2005 M CR Akhter, 2007 M CR Ferrari, 2007 MW CR Tsong, 2007 MW CR Bongaerts, 2008 MW CR Kabat, 2008 W CR Lim & Park, 2008 MW CR Thygesen, 2008 M CR Toriola, 2008 M CR Allen, 2009 W CR All cohort studies (I-squared = 49.2%, p = 0.004) 0.004) All studies (I-squared = 60.1%, p = 0.000) (0.96, 3.22) 0.76 (0.53, 1.07) 1.13 (0.79, 1.61) 1.20 (0.86, 1.67) 1.00 (0.53, 1.90) 1.39 (1.05, 1.85) 1.74 (1.02, 2.97) 1.65 (0.84, 3.23) 1.06 (0.26, 4.27) 1.39 (1.10, 1.75) 1.05 (0.76, 1.45) 0.91 (0.68, 1.23) 0.44 (0.26, 0.73) 1.20 (0.89, 1.62) 1.40 (0.71, 2.76) 1.41 (1.14, 1.73) 1.72 (0.86, 3.42) 1.00 (0.78, 1.27) 0.87 (0.75, 1.00) 1.00 (0.42, 2.37) 1.20 (1.03, 1.39) 0.96 (0.42, 2.16) 0.85 (0.55, 1.32) 0.90 (0.44, 1.81) 0.86 (0.61, 1.20) 1.39 (0.97, 2.00) 1.30 (0.82, 2.07) 1.04 (0.78, 1.38) 0.93 (0.70, 1.25) 1.29 (1.03, 1.62) 2.19 (1.32, 3.64) 2.25 (1.46, 3.46) 2.02 (1.51, 2.69) 1.31 (0.96, 1.80) 1.54 (1.21, 1.97) 1.01 (0.82, 1.25) 0.87 (0.67, 1.13) 2.31 (0.67, 7.94) 1.18 (1.07, 1.29) 1.45 (0.80, 2.61) 2.42 (1.30, 4.50) 2.03 (1.27, 3.25) 1.39 (1.10, 1.76) 0.97 (0.64, 1.47) 1.00 (0.70, 1.42) 1.30 (0.89, 1.89) 1.03 (0.83, 1.28) 1.40 (0.76, 2.56) 1.53 (0.87, 2.69) 1.69 (1.03, 2.78) 1.08 (0.92, 1.27) 1.11 (0.74, 1.67) 1.32 (0.61, 2.86) 1.55 (1.11, 2.17) 1.34 (0.88, 2.05) 1.13 (0.95, 1.34) 1.84 (1.31, 2.58) 1.10 (0.93, 1.29) 1.06 (0.88, 1.27) 1.13 (0.52, 2.45) 1.40 (1.08, 1.83) 3.50 (1.22, 10.00) 1.07 (1.01, 1.13) 1.24 (1.14, 1.34) 1.21 (1.13, 1.28) 17

18 Ca Co Ca Co Author, year Sex Site Exp Exp NExp NExp RR (95% CI) Case-control studies Peters, 1989 M CR (0.52, 1.51) Longnecker, 1990 M C R (1.05, 2.53) Choi, 1991 M C R (2.58, 4.82) Riboli, 1991 M C R (0.32, 4.59) Barra, 1992 MW C R (0.83, 1.23) Peters, 1992 MW C (1.13, 2.47) Boutron, 1995 M CR (0.59, 2.86) Cancer of the large bowel. Heavy vs non/occasional drinkers Murata, 1996 M C R Tavani, 1998 MW CR Murata, 1999 M CR Ji, 2002 M C R Sharpe, 2002 M C R All case-control studies (I-squared = 83.4%, p = ) Cohort studies Otani, 2003 M CR Pedersen, 2003 MW C R (0.84, 5.59) 0.95 (0.76, 1.18) 1.96 (1.20, 3.20) 1.17 (0.91, 1.50) 2.05 (1.28, 3.30) 1.49 (1.13, 1.96) 1.70 (1.20, 2.40) 1.18 (0.87, 1.60) Wakai, 2005 M C R (1.11, 2.19) Akhter, 2007 M CR (1.32, 2.77) Ferrari, 2007 MW CR (1.27, 2.16) Lim & Park, 2008 MW CR (0.40, 3.06) Thygesen, 2008 M CR (1.21, 2.53) All cohort studies (I-squared = 0.0%, p = 0.468) 1.57 (1.38, 1.80) All studies (I-squared = 76.4%, p = 0.000) 1.52 (1.27, 1.81) Fedirko et al.,

19 Cancer of the large bowel. Dose-risk relation. Fedirko et al., in press 19

20 Conclusions. Cancers of the large bowel. Cohort and case-control studies are consistent in suggesting some direct relation between alcohol consumption and colorectal cancer. The relation, however, is moderate, and a two-fold risk for both colon and rectum cancer can be excluded, even with high levels of alcohol consumption. Doll et al., 1999; IARC 2007,

21 Liver cancer Alcohol drinking is strongly related to cirrhosis. Alcohol drinking is associated with primary liver cancer, although the relation is difficult to investigate in epidemiological studies, since most alcohol-related liver cancers follow a cirrhotic degeneration, which may lead to a reduction of alcohol drinking. 21

22 Standardised rate per 100,000 Population Liters of pure alcohol per adult (15+) Alcohol and mortality from cirrhosis. Italy Italy, Year 22

23 Standardised rate per 100,000 Population Liters of pure alcohol per adult (15+) Alcohol and mortality from cirrhosis. France France, Year 23

24 Standardised rate per 100,000 Population Liters of pure alcohol per adult (15+) Alcohol and mortality from cirrhosis. Hungary Hungary, Year 24

25 Liver cancer Table II. Relation of hepatocellular carcinoma with smoking and drinking habits: Milan, Italy, Hepatocellulcar carcinoma Controls Relative risk estimates (95% CI) M-H MLR Total alcoholic beverage consumption (drinks per day) < ( ) 1.10 ( ) > ( ) 1.43 ( ) (p=0.15) 1.83 (p= 0.18) La Vecchia et al.,

26 Liver cancer (Bagnardi et al., in press) 26

27 Liver cancer Alcohol Cohort Case-Control Cancer site intake Pooled RR (95% CI) Pooled RR (95% CI) P a Liver Light 0.85 (0.74,0.97) 1.31 (0.97,1.78) Moderate 1.00 (0.87,1.17) 1.15 (0.97,1.35) Heavy 1.12 (1.02,1.23) 2.79 (2.00,3.87) (Bagnardi et al., in press) 27

28 Liver cancer Apparently moderate assocation, possibility underestimated. Turati et al, subm 28

29 Alcohol and pancreatic cancer Men and Women Tramacere et al.,

30 Alcohol and pancreatic cancer Tramacere et al.,

31 Alcohol and pancreatic cancer There is convincing evidence for the absence of a role of moderate drinking in pancreatic carcinogenesis, coupled to an increased risk for heavy alcohol drinking. Given the moderate increase in risk and the low prevalence of heavy drinkers in most populations, alcohol appears to be responsible only for a small fraction of all pancreatic cancers. Tramacere et al.,

32 Breast cancer Collaborative re-analysis Collaborative re-analysis,

33 Alcohol and breast cancer Meta-analysis (Bagnardi et al., in press) 33

34 Alcohol, kidney cancer and lymphomas No excess risk, and possible inverse relationships 34

35 Alcohol and kidney cancer (Bagnardi et al., in press) 35

36 Alcohol and lymphomas (Bagnardi et al., in press) 36

37 Alcohol and cancer Low doses We evaluated the association between light drinking (<1 drink day) and cancer of the colorectum, breast, larynx, liver, esophagus, oral cavity and pharynx, through a metaanalytic approach. We searched epidemiological studies using PubMed, ISI Web of Science and EMBASE, published before December Bagnardi et al.,

38 Alcohol and cancer Low doses Bagnardi et al.,

39 Alcohol and cancer Low doses We included 222 articles comprising light drinkers (<1 drink day) and non-drinkers with the cancer sites of interest. Bagnardi et al.,

40 Alcohol and cancer Low doses <1 drink/day Bagnardi et al.,

41 Alcohol and cancer Low doses Alcohol 1 drink day and cancer Low doses Bagnardi et al.,

42 Alcohol and cancer Low doses Light drinking was associated with the risk of oral and pharyngeal cancer [relative risk, RR = 1.17; 95% confidence interval (CI) ], esophageal squamous cell carcinoma (SCC) (RR = 1.30; 95% CI ) and female breast cancer (RR= 1.05; 95% CI ). Bagnardi et al.,

43 Low doses and ALDH2 in Asian populations Asian individuals with the ALDH2 Lys allele experience a marked elevation in blood acetaldehyde after alcohol ingestion. In a Japanese case-control study of oral cancer, the RR for intermediate alcohol drinking /low folate was 2.4 for ALDH2 Lys+ vs 1.2 for those with ALDH2 Glu/Glu, a compared with those with low alcohol/high folate (Matsuo et al, 2012). 43

44 Total mortality and ischemic heart disease The consumption of alcohol appeared to reduce the risk of ischaemic heart disease, largely irrespective of amount. Among regular drinkers, mortality from all causes combined increased progressively with amount drunk above 21 units a week. Alcohol-related causes, including cancers, increased above 14 units per week. Doll et al.,

45 Doll et al.,

46 Alcohol in Mediterranean countries Alcohol consumption was traditionally high in Mediterranean countries, particularly in France and Italy, but substantial declines have been observed over the last three decades. The pattern and problem of alcohol drinking is also peculiar in these countries, with regular (rather than binge) drinking at meals, and with wine being the most common type of alcoholic beverage in most regions. 46

47 Alcohol consumption in Italy Castro et al.,

48 Alcohol in Mediterranean countries Alcohol drinking has major implications for the risk of cirrhosis and a few cancer sites, including those of the upper digestive and respiratory tract, whose incidence and mortality were exceedingly high in the 1970 s and 1980 s in France, northern Italy and Spain. Now, the highest rates are in central and eastern Europe. 48

49 Conclusions 1 In terms of risk assessment, high levels of alcohol consumption (i.e., more than four drinks per day) result in a substantial risk of cancer at several sites. Lower levels of consumption result in a moderately increased risk for selected cancers. Moderate alcohol consumption can have protective effects against certain types of heart disease. 49

50 Conclusions 2 A substantial number of cancer cases and cancer deaths are attributable to alcohol drinking. Over 85% of these are avoidable by moderating consumption. 50

51 Conclusions 3 Taking into account favourable and unfavourable effects of alcohol on health, a sensible advice should be given as for recommended limits to alcohol drinking. These limits should not exceed 30 g of ethanol per day (i.e. about to two drinks of beer, wine or spirits a day, meals included) for men and 15 g (one drink) for women. 51

52 52