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IARC Working Group on the Evaluation of Carcinogenic Risk to Humans. Alcohol Consumption and Ethyl Carbamate. Lyon (FR): International Agency for Research on Cancer; 2010. (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, No. 96.)

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2Studies of Cancer in Humans

The available knowledge on the relationship between the consumption of alcoholic beverages and a variety of human cancers is based primarily on epidemiological evidence. The cancers considered to be causally related to alcoholic beverage consumption in the previous IARC Monographs on alcohol drinking (IARC, 1988) included those of the upper aerodigestive tract (oral cancer and cancers of the oropharynx, hypopharynx, larynx and oesophagus), liver, colon, rectum and possibly breast. Since 1988, many cohort and case–control studies on the relationship between consumption of alcoholic beverages and these and other cancers have been conducted in many different countries. The most comprehensive evidence has been obtained from several large cohort studies that investigated different cancer sites and, when available, different types of alcoholic beverage consumed. These cohort studies are described briefly in Section 2.1. The case–control studies are described in the sections pertaining to particular cancer sites. Additionally, two meta-analyses (Bagnardi et al., 2001; Corrao et al., 2004) found significantly increased risks for cancer at all of the aforementioned sites associated with alcohol drinking. Meta odds ratios less than 1.00 were found for melanoma, cervical cancer and kidney cancer. A positive dose-response relationship was observed for most of these sites. [The Working Group noted that the Bagnardi et al., 2001 study appears to be more comprehensive than Corrao et al., 2004, although a detailed list of the studies included in both meta-analyses is not given].

In reviewing these epidemiological studies, the Working Group took particular note of those that adequately considered issues related to bias and confounding. In this respect, since much of the evidence relates to cancers known to be caused by tobacco smoking, confounding by the effects of tobacco smoking is critical for many sites. Thus, the few studies that considered the risks from alcoholic beverage consumption in lifelong nonsmokers are particularly important.

The terminology and methods used to characterize the combined effects of two or more agents have been poorly standardized. For the purposes of this monograph, interdependence of effects is called ‘effect modification’, and the terms ‘synergism’ and ‘antagonism’ are used to describe the consequences of the interdependence of disease when both risk factors are present (Rothman & Greenland, 1998).

The effect of a risk factor for a disease may be estimated on an absolute (additive) scale or a relative (multiplicative) scale. In general, epidemiological studies use the relative risk scale, and present ratio measures (e.g. the relative risk that compares risk in the exposed group to that in a referent, typically unexposed, group). In those studies in which the findings depart (in either direction) from this scale, lack of synergy in the multiplicative scale (i.e. similar relative risks in low and high incidence groups) can imply synergy in the additive scale, and thus have important public health implications.

The Working Group did not evaluate studies of precancerous lesions, e.g. adenomas and polyps of the rectum, precursor lesions of the oral cavity or intraepithelial neoplasia of the cervix uteri for several reasons: firstly, many studies considered invasive cancers, secondly, precancerous lesions do not necessarily progress to cancer during the subjects' lifetime and thirdly, the implications of studies on lesions that have a high propensity not to progress to invasive cancer are uncertain.

In this respect, the pooling of results from many small studies and meta-analyses provide an opportunity to evaluate sites for which relatively few cases accrue. The Working Group placed substantial weight on the findings for cancer sites for which studies had been pooled.

Assessment of alcoholic beverage intake in case–control and cohort studies

In cohort studies, it may be difficult to obtain lifetime estimates of exposure to alcoholic beverages, especially for those studies that only collected data at baseline, since there is a risk that individuals may change their drinking habits during the period of observation. Even in case–control studies, in which, theoretically, there is an opportunity to collect exposure data up to the date of interview, problems of recall, including difficulties in recollection and classical recall bias, may result in complications in the development of reliable estimates of cumulative exposure. In general, the Working Group felt that the classification of subjects as current drinkers (light and heavy), former drinkers and never drinkers is valid and that data on amounts drunk per day (or per week for light or occasional drinkers) are also sufficiently reliable. However, estimates of various patterns of exposure to alcoholic beverages, especially binge drinking, are not available in most studies. Nevertheless, in spite of the differences in the quality and reliability of data on exposure between cohort and case–control studies, when data were available that produce findings that are congruent from both types of study, the Working Group placed much weight upon such evidence.

Alcoholic beverage intake in epidemiological studies has usually been assessed by interviews or questionnaires regarding usual intake over a period of months or years. Two main methods have been used: semiquantitative questionnaires (e.g. how often on average do you consume a bottle of beer?) or frequency–quantity questionnaires (e.g. how many days per week do you drink beer? And, on the days you drink, how many bottles of beer do you drink?). These questions can refer to consumption of either alcoholic beverages in general or specific beverages (e.g. beer, wine and liquor), which can then be summed to compute total intake of alcohol. Total alcohol intake is calculated by assuming (based on knowledge of the contents in the population studied) a specific amount of alcohol for each type of beverage (e.g. 12 g of alcohol per glass of wine, 13 g per bottle of beer and 15 g for one glass of liquor). Alcoholic beverage consumption can also be assessed by diet diaries or 24-hour recalls, but multiple days of intake are usually required because intake in many populations can vary considerably from day to day or over a year. Because these methods impose a substantial burden on the participant and/or investigator, they have rarely been used in cohort studies and, in case–control studies, they are not appropriate because alcoholic beverage consumption may have changed due to the occurrence of disease. However, these methods provide a quantitative measure of intake that can serve as a criterion of validity in subsamples of a study population.

Multiple sources of error can contribute to imperfect measurement of alcoholic beverage consumption. These include errors in reporting the frequency of intake, which can be influenced by many factors including inaccurate memory, social norms of desirability and subtle indications of judgment by the interviewers. Also, serving size and alcohol content of the same serving size can vary over time for the same person and between people. However, some of these sources of variation are tempered by averaging over time; for example, although serving size may vary from drink to drink over time for an individual, the average intake for one person compared with that of another may vary to a much lesser degree. Also, the differences among individuals in alcoholic beverage intake are large, and errors in serving sizes are usually minor in relation to the overall range of alcoholic beverage intake.

The validity of alcoholic beverage intake as assessed in typical epidemiological studies has been evaluated by comparisons with daily diaries or recalls, by associations with biological variables that reflect alcoholic beverage intake and by their ability to predict well established relationships such as those between alcoholic beverage consumption and risks for cirrhosis. Correlations between alcoholic beverage intake assessed by standardized questionnaire and diaries or 24-hour recalls have been evaluated in many studies and are high, generally ranging from 0.7 to 0.9 (Kaaks et al., 1997; Willett, 1998; Lee et al., 2007). Although the mean reported intakes in these studies are usually well below that of the average population, based on production or sales of alcoholic beverages, these comparisons are misleading because a larger percentage of alcoholic beverages is consumed by a small group of heavy drinkers (Greenfield & Rogers, 1999), who are less likely to participate in epidemiological studies.

The relationship between alcoholic beverage intake assessed by a questionnaire and that assessed by detailed recording can be used to adjust relative risks for measurement error in epidemiological studies (Rosner, 1995; Willett, 1998); several variations of this approach have been used, but they basically consist of two steps: first a regression calibration is conducted by assessing intake using a detailed method in a sample of the study population; then the true intake (intake assessed by the detailed method) is regressed on the ‘surrogate method’ (intake assessed by the questionnaire). The relationship between surrogate intake and true intake, expressed by the regression slope, is then used to correct the observed relative risk for error. Refinements of this method allow the calculation of confidence intervals (CIs) and adjustment for errors in covariates (Rosner, 1995). This approach to measurement error has been used in large cohort studies of alcoholic beverages and cancer, and the adjustments have been small (less than 5% change in relative risks) (Smith-Warner et al., 1998; Cho et al., 2004; Lee et al., 2007).

Studies on biomarkers, such as HDL (Giovannucci et al., 1991), provided strong evidence that alcoholic beverage consumption assessed by questionnaire has high validity.

The evidence described above suggests that the questionnaires commonly used in epidemiological studies provide reasonably accurate quantitative assessments of alcoholic beverage intake over the time period considered, typically a few months or a year. In a cohort study with long follow-up, repeated measures of exposure over time may provide a more accurate measure of long-term intake and allow a more detailed examination of temporal relationships (Willett, 1998). In both case–control and cohort studies, it may be useful to ask about alcoholic beverage intake during past periods of life (for example between the ages 20 and 30 years) because, for some cancers, that may be the period of maximal susceptibility. Few data are available of the validity of reported remote intake.

In summary, evidence based on comparisons with detailed assessments of alcoholic beverage intake using diaries or recalls and non-specific biomarkers indicate that recent alcoholic beverage consumption assessed by the questionnaires typically used in epidemiological studies has a high degree of validity within the ranges of consumption in the general population, and that important associations will not be missed. Further, the results of correction analysis of measurement error suggest that estimates of quantitative dose–response relationships for recent intake are reasonably accurate. However, with long follow-up, repeated measures of intake may be useful. The assessment of intake at remote periods of life may be useful, but the validity of these measures has not been well quantified.

2.1. Description of cohort studies

Information on cohort studies of cancer and alcoholic beverage consumption in general populations and special populations is given in Tables 2.1a and 2.1b, respectively.

Table 2.1a. Cohort studies of cancer and alcoholic beverage consumption in general populations.

Table 2.1a

Cohort studies of cancer and alcoholic beverage consumption in general populations.

Table 2.1b. Cohort studies of cancer and alcoholic beverage consumption in special populations.

Table 2.1b

Cohort studies of cancer and alcoholic beverage consumption in special populations.

2.1.1. Studies in general populations (Table 2.1a)

These studies are classified by the country in which the study was conducted.

(a) Asia/Oceania

(i) Australia
Melbourne Collaborative Cohort Study

This cohort was recruited in 1990–94 from the Melbourne metropolitan area, using the electoral rolls, advertisements and community announcements in the local media. The cohort comprised 41 528 people (17 049 men) aged 27–75 years. A structured interview included alcoholic beverage consumption for those who had ever drunk 12 alcoholic drinks in a year. Cancer cases were ascertained from the Victoria Cancer Register through to 31 December 2003 (Baglietto et al., 2005, 2006).

(ii) China
Zoucheng/Shandong Study

A 12.5-year prospective cohort study was carried out in a rural area of Zoucheng city. A probabilistic sample from three townships, aged 20 years and older, was identified in 1982 and consisted of 7809 men and 7994 women. An individual case card was created for each of the villagers and their smoking and drinking habits were recorded. Data concerning their death and change in health were collected annually. Mortality follow-up was to 1994 (Zhang et al., 1997).

Lin Xian Nutrition Intervention trial Study

In the frame of an intervention trial for micronutrients, approximately 30 000 residents of the Lin Xian region, aged 40–69 years, were interviewed in 1985 to obtain information on usual dietary intake, tobacco use, alcoholic beverage consumption, family history of cancer and other factors. The cohort was followed-up from 1986 through to May 1991, with little loss to follow-up. Information on cause of death and incidence of cancer was collected from local hospitals or a study medical team. Relative risks were adjusted for potential confounders as well as the vitamin/mineral intervention group (Guo et al., 1994; Tran et al., 2005).

Shanghai Men's Study

A cohort of 18 244 male residents of four small geographically defined communities from a wide area of Shanghai, aged 45–64 years, were enrolled between January 1986 and September 1989 (80% of eligible subjects). A structured questionnaire was completed at a face-to-face interview. The information obtained included level of education, history of tobacco use and alcoholic beverage consumption, current diet and medical history. Cancer incidence was ascertained through the population-based Shanghai Cancer Registry and vital status was ascertained by inspection of the Shanghai death-certificate records. Only 108 subjects were lost to follow-up, which continued until February 1993 (Yuan et al., 1997).

Jiashan County Screening Study

Screening for colorectal cancer was initiated in May 1989–April 1990 when all residents, aged 30 years and over, in 10 small towns in Jiashan County, Zhejiang Province, China, were invited for screening and a face-to-face questionnaire was completed by professional interviewers including information on alcoholic beverage drinking and smoking habits. Of 75 842 eligible individuals, 31 087 men and 33 256 women responded, about 70% of whom were farmers. Subjects were followed through the Cancer Registration System and a rapid reporting system from the Colorectal Registry, that was documented to be 95% complete. Deaths were ascertained through the Jiashan County Death Registration System through to 2001. Out-migration was estimated to be less than 1% annually (Chen et al., 2005a).

Yunnan Tin Corporation Miners Cohort

A cohort of 7965 Yunnan Tin Corporation miners aged 40 years and over was established in 1992. Cumulative radon exposure for each subject was obtained by adding-up the estimated working level months, for each job held at the Yunnan Tin Corporation before baseline screening. A questionnaire was administered by interviewers at baseline which included data on alcoholic beverage consumption. Follow-up continued until 1997 (Lu et al., 2000a).

(iii) Japan
Japanese Physicians' Study

A survey of smoking habits and alcoholic beverage consumption among physicians in western Japan was carried out using self-administered questionnaires in 1965. From 6815 male respondents in nine prefectures (51% response rate), a cohort of 5477 male physicians was established. Vital status was followed until 1983 and was confirmed by various medical associations. Copies of death certificates were obtained from the District Legal Affairs Bureau and the cause of death was coded with the ICD-8. After exclusions, the analysies were performed on 5130 men. Statistical analysis was performed using the Cox proportional hazards model (Kono et al., 1985, 1986, 1987).

Six Prefecture Study

In 1965, 122 261 men and 142 857 women, aged 40–69 years (95% of the census population), in 29 health centre districts from six prefectures in Japan were interviewed. The six prefectures were selected as being representative of the entire country. The one-page questionnaire administered at baseline included questions on smoking, alcoholic beverage consumption and dietary habits, occupation and marital status. A record linkage system was established for the annual follow-up. During the 16-year follow-up period, 8% of the cohort migrated from the original health districts. Deaths among cohort members were monitored by linkage to vital statistics kept at each public health centre (Hirayama, 1989; 1992; Kinjo et al., 1998).

Life Span Study

The Life Span Study cohort originally consisted of 100 000 survivors [sex distribution not reported] of the atomic bomb blasts in Hiroshima and Nagasaki. The cohort was expanded in 1968 and 1985 by adding approximately 10 000 survivors each time. The total cohort included approximately 120 000 individuals, of whom approximately 27 000 were non-exposed controls. Information on smoking was obtained from three interview surveys conducted on a subgroup of the entire cohort in 1963–64, 1964–68 and 1968–70, and four postal surveys conducted on various subgroups in 1965, 1969, 1979 and 1980.

The cancer incidence in 61 505 survivors for whom smoking data were available was reported. For 42% of this group, information on smoking was available from at least two surveys. Information on cancer incidence and mortality was obtained from the Radiation Effects Research Foundation tumour registry and mortality database. Poisson regression models were used to fit log-linear relative risk and linear excess relative risk models (Akiba, 1994; Land et al., 1994; Goodman et al., 1995).

Chiba Center Association Study

The Chiba Center Association Study was a nested case–control study based on a cohort population of 17 200 male participants in a mass screening for gastric cancer by the Chiba Cancer Association in Japan in 1984. Cancer cases in cohort members were detected by record linkage to the Chiba Cancer Registry. The participants were followed from 1984 until 1993. For each cancer case, two controls were selected from the cohort population by matching on sex, birth year and area of residence (Murata et al., 1996).

Aichi Cancer Center Hospital Study

The relation of atrophic gastritis, other gastric lesions and lifestyle factors to stomach cancer risk was prospectively studied among 3,914 subjects who underwent gastroscopic examination and responded to a questionnaire survey at the Aichi Cancer Center Hospital. During 4.4 years of follow-up on average, 45 incident cases of stomach cancer were identified at least three months after the initial examination. If the baseline endoscopic findings indicated the presence of atrophic gastritis, the risk of developing stomach cancer was increased 5.73-fold, compared with no indication at the baseline. The risk further increased with advancing degree of atrophy and increasing extension of atrophy on the lesser curvature. These trends in the relative risks were statistically significant (P = 0.027 and P = 0.041, respectively). The risk for stomach cancer was statistically significantly increased among subjects with gastric polyps, but not among those with gastric ulcer. Stomach cancer cases tended to consume more cigarettes, alcohol, rice, pickles and salted fish gut/cod roe and less fruits and vegetables and to have more family histories of stomach cancer than noncases, although these differences were not statistically significant. The results of the present study provide additional evidence on the relation between atrophic gastritis and stomach cancer and suggest a need for intensive follow-up of patients with atrophic gastritis and gastric polyps (Kato et al., 1992a).

Aichi Prefecture Study

Stomach-cancer mortality was prospectively studied among 9753 Japanese men and women who first responded to a mailed questionnaire in 1985 and were then followed through May 31, 1991. During this follow-up period, 57 stomach-cancer deaths were identified. Current smokers had an increased risk of death from stomach cancer compared with never-smokers (relative risk (RR) = 2.29, 95% confidence interval (CI): 1.15–4.56), but there was no dose-response to number of cigarettes smoked. Daily alcohol drinkers who consumed 50 ml or more of alcohol per day also had a greater risk than nondrinkers (RR = 3.05, 95% CI: 1.35–6.91). There was no association between stomach-cancer mortality and individual food consumption except a positive association with fruit intake. However, frequent use (greater than or equal to 3–4/week) of meat broiling and traditional style Japanese salad preparation in their cooking procedures were positively associated with stomach-cancer mortality. The RR values compared with infrequent use (less than or equal to 1–2/month) were 2.27 (95% CI: 1.06–4.85) and 3.10 (95% CI: 1.40–6.85), respectively. A positive family history of cancer, especially stomach cancer, significantly increased the risk for stomach-cancer death (RR = 2.01, 95% CI: 1.12–3.63). The effects of these variables remained after adjustment for other variables (Kato et al., 1992b).

Japan Collaborative Cohort (JACC) Study for Evaluation of Cancer Risk

A baseline survey was conducted in 45 areas throughout Japan from 1988 through to 1990 by investigators from 25 centres. At the end of 1990, a total of 127 500 (125 760) inhabitants were enrolled in this cohort. Among them, 110 792 subjects (46 465 men, 64 327 women aged between 40 and 79 years at baseline) were followed-up through to the end of 1997 and subsequently to 1999. The baseline data, which included details on alcoholic beverage consumption and tobacco use were collected using a self-administered questionnaire. Population registers were used to identify subjects who had moved out of a study area. The date and cause of death were confirmed annually or biannually by reviewing death certificates with the approval of the Prime Minister's office. In one analysis of 38 600 women participants in the cohort, follow-up was to 31 December 1997 (Lin et al., 2002; 2005; Sakata et al., 2005; Wakai et al., 2005; Nishino et al., 2006).

The Hospital-based Epidemiological Research Program at the Aichi Cancer Center (HERPACC)

A database was established in 1988 in the Aichi Cancer Center that included all outpatients on a first visit who completed a self-administered questionnaire on life-style factors which included information on alcoholic beverage consumption. The data-base was routinely linked with the hospital cancer-registry to identify cases of cancer. Between January 1988 and December 1999, 78 755 subjects were included. Cases were frequency-matched by age to cancer-free subjects, selected at random from the data-base, and the study was analysed as a nested case–control study (Inoue et al., 2003).

The Japan Public Health Center Study Cohorts (I and II)

A population-based cohort of 27 063 men and 27 435 women was established in 1990 from subjects who registered their addresses in 14 administrative districts of four Public Health Center areas. All subjects were born between 1930 and 1949 (40–59 years of age at baseline). Subjects were asked to reply to a lifestyle questionnaire, which included information on alcoholic beverage consumption. A total of 43 149 subjects (20 665 men (76%), 22 484 women (82%)) returned their questionnaires. All subjects were followed from 1 January 1990 to 31 December 1999. All deaths of cohort subjects were based on death certificates from each Public Health Center. Newly diagnosed cases of cancer were reported by hospitals in and around the study areas when the birth date and residence fulfilled the criteria for inclusion into the cohort. (Sasazuki et al., 2002).

A second cohort was established in 1993, and included six Public Health Centers in six prefectures, which comprised all residents aged 40–69 years (except for Osaka, which included other ages and was excluded from this cohort). By combining the first with the second cohort and excluding subjects deemed to be ineligible, a study population of 42 540 men and 47 464 women was defined for analysis. Mortality data were obtained from the Ministry of Health, Labour and Welfare; those who moved to other areas were identified from residential registers; cancer cases were identified through local major hospitals and population-based cancer registries. Follow-up was until 31 December 1999 (Otani et al., 2003).

Takayama City Cohort

A cohort was established in September 1992 among 36 990 residents of Takayama City, aged 35 years or older, who were asked to complete a questionnaire that included data on alcoholic beverage consumption. A total of 34 018 (92%) subjects responded. Details on patients with colon and rectal cancer were obtained from the two major hospitals in Takayama City, which cover about 90% of the colorectal cases in the city. Details of subjects who moved away from the city during the study were obtained from the residential registers. Follow-up was until 31 December 2000. After excluding those with incomplete data and non-melanoma skin cancer, the analysis cohort comprised 13 392 men and 15 659 women (Shimizu et al., 2003).

(b) North America

(i) Canada
Nutrition Canada Survey Cohort

The Nutrition Canada Survey was conducted beween September 1970 and December 1972, and incorporated 12 795 people from all 10 provinces in Canada who responded to the invitation to participate (a 47% response rate), together with 3295 unsolicited volunteers who participated. A retrospective cohort study was performed by linking the records for those aged 50–84 years to the Canadian Cancer Registry and the Canadian National Mortality Data Base to the end of 1993. Data on alcoholic beverage consumption had been collected at baseline by a 24-hour diet recall and a 1-month food-frequency questionnaire (Ellison, 2000).

National Breast Screening Study

The National Breast Screening Study is a multicentre, randomized controlled trial of mammography screening for breast cancer. Between 1980 and 1985, 89 835 women aged 40–59 years were randomized. In 1982, a semiquantitative diet questionnaire, which included data on alcoholic beverage consumption, was distributed to new attendees and previously enrolled women returning to the screening centres for further screening. A total of 56 837 women returned the dietary questionnaires. Reports on the diet cohort are based mainly on a case–cohort analysis, with a 10% subsample selected at random from the cohort as controls. The National Breast Screening Study diet cohort is included in the Pooling Project (Friedenreich et al., 1993; Jain et al., 2000a,b; Rohan et al., 2000; Navarro Silvera et al., 2005).

(ii) USA
American Registry of Radiologic Technologists

The cohort was based upon 143 517 radiological technologists certified by the American Registry of Radiologic Technologists for at least 2 years during 1926–1982. A questionnaire was mailed to 132 519 who were known to be alive and data on cancers diagnosed were obtained from that questionnaire, with 79 016 female respondents. Thus, this study was essentially of factors associated with the prevalence of breast cancer among those still alive at the time of the questionnaire, and was analysed as a nested case–control study (Boice et al., 1995; Freedman et al., 2003).

University of Pennsylvania Alumni Study

Physical and social characteristics recorded at college physical examination and reported in subsequent questionnaires to alumni in 1962 or 1966 by 50,000 former students from Harvard University and the University of Pennsylvania were reviewed for their relationship to major site-specific cancer occurrence. The records of 1,359 subjects who died with a major site-specific cancer in a 16- to 50-year follow-up period and of 672 subjects who reported such a cancer by mail questionnaire in 1976 or 1977 were compared with those of 8,084 matched classmates who were known to be alive and free of cancer at the time subjects with cancer had died or had been diagnosed. Cigarette smoking, as reported both in student years and years as alumni, predicted increased risk for cancers of the respiratory tract, pancreas, and bladder. Student coffee consumption was associated with elevated risk for leukemia, but it was unrelated to cancers of the pancreas and bladder. Male students with a record of proteinuria at college physical examination experienced increased risk for kidney cancer, and those with a history of tonsillectomy experienced increased risk for prostate cancer. Students who at college entrance reported occasional vague abdominal pain were at elevated risk for pancreatic and colorectal cancers in later years. Increased body weight during college was associated with increased risks for kidney and bladder cancers, whereas for alumni this index was associated only with kidney cancer. Increased weight-for-height during college (but not in 1962 or 1966) predicted increased occurrence of female breast cancer. Jewish students experienced elevated risk for subsequent cancers of the female breast, colon, and combined colorectum. These and other findings are presented as clues deserving further exploration for any etiologic significance that they may hold for the cancer sites studied (Whittemore et al., 1985).

Minnesota Breast Cancer Family Study

A family study on breast cancer was initiated between 1944 and 1952, including a total of 544 families and data on 4418 family members. Information was obtained from interviews, medical history questionnaires and death certificates. Follow-up of this cohort was initiated in 1990; families in which the proband was diagnosed with breast cancer before 1940 were excluded. Telephone interviews were completed with 6194 living women and 2974 surrogates from 426 multigeneration families; after excluding those with missing data, data on 9032 women were available for analysis (Vachon et al., 2001).

US Army Veterans Study

A cohort of 4401 US Army service men hospitalized for chronic alcoholism in 1944–45 was drawn as a sample from records of the US Department of Defense and the Veterans' Administration. Of these, 98% were <40 years of age at the time of hospitalization. They were matched for age with an equal number of enlisted men hospitalized for acute nasopharyngitis during the same period. Deaths in these groups were ascertained through the Veterans' Administration Beneficiary Identification and Records Locator Subsystem, and death certificates were obtained to code for cause of death. Follow-up for death was estimated to be 90–98% complete. No information was available on the drinking habits of individual members of the cohort or on average consumption by the cohort members. It was noted that only 7.5% of the chronic alcoholics had been discharged from military service for medical disability, including alcoholism. The mortality experience of the cohort was compared with that of the matched cohort of nasopharyngitis patients, and the mortality of both cohorts was compared with that of US males for selected causes of death. Overall mortality was approximately 80% higher in the alcoholics group than in the nasopharyngitis group (SMR, 1.9) (Robinette et al., 1979).

Framingham Study and Framingham Offspring Study

The Framingham Study began in 1948. The original cohort included 5209 persons (2873 women) aged 28–62 years at the first examination, who were examined biennially thereafter. In 1971, examination was begun on many of the children of the original cohort and their spouses. Of 5124 subjects aged 12–60 years enrolled in the Framingham Offspring Study, 2641 were women, and have been followed at 4-year cycles. Information on alcoholic beverage consumption was obtained at the examinations. Cancer cases have been identified by self reports and, for non-respondents, by linkage with the National Death Index and a cancer registry, with confirmation of diagnosis by searching for medical records. The median follow-up was 34.3 years (range, 0.2–42.5 years) for the original cohort and 19.3 years (range, 0.2–22.6 years) for the offspring cohort (average for the total cohort of 9821 subjects, 27.3 years) (Gordon & Kannel, 1984; Zhang et al., 1999; Djoussé et al., 2002, 2004).

Western Electric Company Cohort Study

In 1957, 3102 men were randomly selected from the population of 5397 men aged 40–55 years who had been employed for at least 2 years at the Western Electric Company's Hawthorne Works in Chicago; 2080 (67.1%) agreed to participate in a long-term, prospective, epidemiological study (Western Electric Health Study). Another 27 men served as a pilot group, bringing to 2107 the total number initially examined from October, 1957 to December, 1958. Approximately 65% were first and second generation Americans, predominantly of German, Polish, or Bohemian ancestry; most of the others were descendants of earlier emigrants from the British Isles. The men worked at various occupations associated with the manufacture of telephones and related products (Garland et al., 1985).

American Cancer Society Cancer Prevention Study I (CPS-I)

Between October 1959 and February 1960, volunteers for the American Cancer Society in 25 states recruited more than one million subjects, aged 30 years and over, from among their friends, neighbours and acquaintances. Families were enrolled, with the condition that there be at least one person aged over 45 years in the family. All family members over 30 years of age were requested to fill out a detailed four-page questionnaire. Vital status was checked yearly to 1965 and again in 1971 and 1975. Death certificates of deceased participants were obtained from state health departments. For 581 321 women, deaths were ascertained for 12 years (Garfinkel et al., 1988). For 276 802 white men in the cohort aged 40–59 years, enrolled in 1959 and followed for 12 years, 9293 deaths from all cancers were observed and related to alcoholic beverage consumption obtained at baseline (Boffetta & Garfinkel, 1990).

Tecumseh Community Health Study

A community health study was initiated in the town of Tecumseh, MI, through interviews and medical examinations in 1959–60. Information on alcoholic beverage consumption was obtained by trained interviewers. Follow-up was for up to 28 years by mailed questionnaires, with review of death certificates to confirm cause of death. The cohort included in the analysis totalled 1954 women (Simon et al., 1991).

Harvard Alumni Study

A cohort of undergraduates who had entered the University of Harvard between the years of 1916 and 1950 was identified when they responded to a health questionnaire sent out in 1962 or 1966. Updated information was obtained from 13 905 cohort members from periodic surveys that assessed lifestyle habits and medical history. The questions asked for information on daily amount of cigarette smoking, age at start and cessation of cigarette smoking, weight, height and physical activity. In surveys conducted in 1988 and 1993, participants were asked whether a cancer had been diagnosed by a physician. Deaths that occurred up to 1992 were traced using information from the alumni office to obtain death certificates. The authors claimed that mortality follow-up was virtually complete (Whittemore et al., 1985; Sesso et al., 2001).

Kaiser Permanente Medical Care Program Study

The first cohort for this study was selected from 87 926 white or black men and women who underwent at least one multi-phasic health check-up within the Kaiser Permanente Medical Care Program from July 1964 and August 1968 and who were followed through to 1976. From data in the baseline questionnaire, four groups were extracted, each of 2015 persons, matched for age, race and cigarette smoking, according to the usual number of alcohol-containing drinks/day (0, ≤2, 3.5 and ≥6). Mortality was ascertained by a search of California death indexes (Klatsky et al., 1981).

An expansion of this cohort comprised 94 549 men and 110 425 women, aged 10–89 years at baseline in 1964–73, who underwent at least one multi-phasic health check-up within the Kaiser Permanente Medical Care Program and were followed through to 1997 (Iribarren et al., 2001). Cancer incidence was ascertained from the first health examination through the San Francisco–Oakland Surveillance, Epidemiology and End Result (SEER) programme and the Northern California Kaiser Permanente Medical Care Program. Attrition due to termination of health plan coverage and death was of the order of 2% per year; the median follow-up time was 19.9 years (range, <1–33 years) (Klatsky et al., 1981; Iribarren et al., 2001).

Between 1978 and 1985, a similar cohort was established, which included 122 894 (for one study 106 203) men and women who received a multi-phasic health examination during 1978–84. Cancer cases were ascertained as for the first cohort (see above). Follow-up was eventually to 31 March 1999 (Klatsky et al., 1988; Hiatt et al., 1988, 1994; Efird et al., 2004).

American Men of Japanese Ancestry Study and Honolulu Heart Study

A cohort of 8006 American men of Japanese ancestry, born during the years 1900–19 and who resided on the Hawaiian island of Oahu, were interviewed and examined clinically from 1965 to 1968. Information obtained at the interview included age, smoking history, usual occupation, type of housing, education and religion. A food-frequency questionnaire and a 24-hour dietary recall was also administered. Newly diagnosed cases of cancer were identified through continuous surveillance of Oahu hospitals and linkage with the Hawaii Tumor Registry through to 1994 (Pollack et al., 1984; Nomura et al., 1990, 1995; Stemmermann et al., 1990; Kato et al., 1992c; Chyou et al., 1993, 1995, 1996).

Lutheran Brotherhood Insurance Study

A cohort of 26 030 white male life insurance policy holders of the Lutheran Brotherhood Insurance Society was identified in 1966, of whom 17 633 responded to a mailed food-frequency questionnaire and were followed for 20 years. Little difference was observed between responders and non-responders with regard to age, urban or rural residence, policy status and cancer mortality at 11.5 years of follow-up. The questionnaire included questions on tobacco use and the longest held occupation, frequency of consumption of 35 food items and the consumption of coffee, beer and spirits. Death certificates were coded for underlying and contributory causes of death. Person–years were accumulated up to death, loss to follow-up or the end of the study in 1986. The age-adjusted relative risks for cancer mortality resulting from exposure to alcoholic beverages were computed using Poisson regression. Statistical interaction between smoking and other risk factors was also examined. About 23% of the cohort members were lost to follow-up due to maturation or lapse of their policies (Hsing et al., 1990, 1998a; Kneller et al., 1991; Chow et al., 1992; Zheng et al., 1993).

Hawaiian Cohort Study

In this study, the consumption of high-fat animal products, raw vegetables, and fresh fruits, as well as obesity, smoking, and drinking was evaluated in relation to subsequent occurrence of prostate cancer. Data from a cohort of 20,316 men of various ethnicities were collected between 1968–1989 in Hawaii. A total of 198 incident cases with invasive prostate cancer were identified by computer-assisted linkage of this cohort to the statewide Surveillance, Epidemiology, and End Results registry. Weight was not consistently associated with prostate cancer, but there was an association with height. These associations were stronger in men diagnosed before age 72.5 years. The risk estimates for raw vegetable and fresh fruit intakes were close to 1.0. Smoking and alcohol drinking appeared to be unrelated to risk (Le Marchand et al., 1994)

The National Health and Nutrition Examination Survey (NHANES) I Epidemiological Follow-up Study

The first NHANES was performed in 1971–75, based on a probability sample of the civilian non-institutionalized population of the USA. Follow-up surveys were conducted and, by the end of 1992, 96% of the cohort was traced, and death certificates were traced for 98% of decedents. The analytical cohort comprised 3968 men and 6100 women aged 25–74 years at baseline (Schatzkin et al., 1987; Yong et al., 1997; Breslow et al., 1999; Su & Arab, 2004).

Nurses' Health Study

In 1976, a cohort of 121 700 female registered nurses was assembled in the USA. At enrolment, the nurses completed a mailed questionnaire on risk factors for cancer and heart disease. Responses to food-frequency questionnaires were also collected in 1980, when 98 462 nurses responded, and in 1984, 1986 and 1990. The response rate to follow-up questionnaires was almost 96% through to 1990. Family members were the main source of information on vital status for non-respondents but the National Death Index was also used. Multiple logistic regression models were used to compute odds ratios, after controlling for age, total energy intake and other potentially confounding variables. A subset of 89 538 women who reported alcoholic beverage consumption in 1980 were assessed by follow-up questionnaires in 1982 and 1984, and cases of cancer were identified (Willett et al., 1987a). A subsequent report on 85 709 women who reported alcoholic beverage consumption in 1980 and were followed for 12 years considered mortality related to alcoholic beverage consumption (Fuchs et al., 1995). A second cohort of 116 671 women was established from women who completed a more detailed dietary questionnaire in 1989, and were followed by questionnaires every 2 years to 1995 (Garland et al., 1999). This study is included as two cohorts (those initially assembled and followed to 1986, and those who completed a more detailed dietary questionnaire in 1986 and were followed subsequently) in the Pooling Project (Willett et al., 1987b; Fuchs et al., 1995; Garland et al., 1999; Colditz & Rosner, 2000; Michaud et al., 2001; Chen WY et al., 2002a; Wei et al., 2004; Lee et al., 2006).

Breast Cancer Detection Demonstration Project (BCDDP)

A cohort was established based upon the participants in the US Breast Cancer Detection Demonstration Project, which was established between 1973 and 1980 at 29 screening centres in 27 cities and involved 283 222 women. A follow-up cohort was established in 1979 from a subset of the participants, which included 4275 women who had been diagnosed with breast cancer, 25 114 women who had biopsies indicating benign breast disease, 9628 women who were recommended for biopsy but did not have the procedure and an additional 25 165 women not recommended for biopsy, matched with the other subjects on age, time of entry into the programme, ethnicity, screening centre and length of participation in the Project and comprised a total of 64 182 women. Between 1979 and 1981, 61 433 of the women completed a baseline food-frequency questionnaire, which included questions related to alcoholic beverage consumption. A follow-up questionnaire was sent between 1993 and 1995 in which self-reports of cancer occurrence were made. Medical records confirmed the diagnosis for 80% of these. Non-respondents were contacted by telephone. Women with prevalent colorectal cancers (reported at baseline) were excluded. The final analytical cohort comprised 45 264 women, of whom 40 865 had complete follow-up through to 1995–98. This cohort is included in the Pooling Project (Flood et al., 2002).

The New York State Cohort

A 45-item food-frequency questionnaire was sent to 265 000 residentially stable subjects selected from a private sampling frame in New York State in 1980 and was returned by 57 968 (32 689 men, 25 279 women). Follow-up was passive through to December 1987 from the records of the New York State Department of Health's vital statistics section and cancer registry. A second questionnaire was sent to the subjects who responded in 1980 who were not listed as dead or diagnosed with cancer. Assessment of the validity of follow-up was conducted in a nested case–control study, with each case matched by age, race, gender and country of residence to one control subject randomly selected from a pool of controls alive at the time of diagnosis of the case. The analytical cohort comprised 27 544 men and 20 456 women (Bandera et al., 1997).

Leisure World Study

A detailed health questionnaire was mailed to all residents of a retirement community in California in 1981, and to new residents in 1982, 1983 and 1985. A response rate of 62% was achieved overall (11 888 participants initially, and 13 979 later). Almost all of the residents were Caucasians of the upper-middle class, about two-thirds were women, and 80% were aged 65–86 years. Histological diagnosis of cancer was obtained from local hospitals. All participants were sent a follow-up questionnaire every 2 years. The latest follow-up reported (Shibata et al., 1994) was to 30 June 1990 (Wu et al., 1987; Shibata et al., 1994).

American Cancer Society Cancer Prevention Study II (CPS-II)

The CPS-II is a nationwide prospective mortality cohort study of nearly 1.2 million adults, aged 30 years or more, enrolled by volunteers of the American Cancer Society in 1982. As in CPS-I, enrolment was based on families and excluded persons in institutions and military service and others who would be difficult to trace. Each participant completed a four-page postal questionnaire on tobacco and alcoholic beverage use and diet. Deaths were ascertained from the month of enrolment until 31 December 1996 through personal enquiries made by the volunteers in 1984, 1986 and 1988 and later through linkage with the National Death Index. In one analysis (Thun et al., 1997), 490 000 men and women were followed from 1982 through to 1991, after excluding those with unquantified smoking and alcoholic beverage use, those missing all data on wine, beer and spirit consumption, and former drinkers who were non-drinkers. In another analysis, 66 561 postmenopausal women were followed for mortality from 1992 to 1997–98 (Boffetta et al., 1989; Thun et al., 1997; Coughlin et al., 2000; Feigelson et al., 2003).

Iowa 65+ Rural Health Study

In late 1981 and 1982, 80 percent of the non-institutionalized residents aged 65 years and older who lived in Iowa and Washington counties, Iowa (US), were enrolled into the Iowa 65+ Rural Health Study (n = 3,673), which was one of the four Established Populations for Epidemiologic Studies of the Elderly (EPESE) sites. These two counties are primarily rural, with several small towns. Of the 1,420 men enrolled into the cohort, only the 1,155 men completing the full-form baseline interview were eligible for inclusion into this report. The full-form baseline interview was conducted in the respondent's home by a trained interviewer, and included data on a variety of demographic, health, and social characteristics (Cerhan et al., 1997).

Second Cancers Following Oral and Pharyngeal Cancers Study

The cohort comprised 1090 first primary cancers of the oral cavity and pharynx included in a multicentre population-based case–control study in four areas of the USA in 1984–85, and followed to 1989. Information on alcoholic beverage consumption and tobacco use was obtained at the time the subjects were originally enrolled, and was updated for 80 cases with second cancers and 189 sex-, study area- and survival-matched cancer patients free of second cancers, with analysis as a nested case–control study (Day et al., 1994a).

Iowa Women's Health Study

The Iowa Women's Health Study was conducted on a cohort of women selected randomly from the Iowa Department of Transportation Driver's License list of whom 41 837 completed a postal questionnaire (response rate, 42.7%) sent in 1986. The questionnaire covered information on age, smoking history, physical activity and level of education. The Harvard semiquantitative food-frequency questionnaire was used to assess diet and alcoholic beverage consumption. Incident cases of cancer were ascertained through the Health Registry of Iowa, which is a population-based cancer registry in the SEER Program of the National Cancer Institute. The Iowa Women's Health Study is included in the Pooling Project (Gapstur et al., 1992, 1993; Potter et al., 1992; Harnack et al., 1997, 2002; Chiu et al., 1999; Kushi et al., 1999; Folsom et al., 2003; Kelemen et al., 2004).

Cohort of Iowa men

A retrospective cohort was formed from the controls in a population-based case–control study of six cancer sites conducted 1986–89 in Iowa (Cantor et al., 1998). These controls were randomly selected from the Iowa population using driver's licence records for men aged 40–64 years and from the files of the US Health Care Financing administration for men aged 65 years and older. Of 1989 men invited, 1601 (81%) agreed to participate. Follow-up was through to 1995. Incident cases of cancer were identified by linkage with the Iowa State Cancer Registry (Putnam et al., 2000).

Health Professionals' Follow-up Study (HPFS)

In 1986, a cohort of 51 529 male dentists, optometrists, osteopaths, podiatrists, pharmacists and veterinarians in the USA were asked to respond to a mailed semi-quantitative food questionnaire. The questionnaire included questions on age, current and past tobacco use, marital status, height and weight, ancestry, medications, disease history, physical activity and diet. Only men who completed the diet questionnaire adequately at baseline and who reported no cancer other than non-melanoma skin cancer were included in the analysis. After all baseline exclusions, 47 931 men, 40–75 years old in 1986 and followed for 6 years comprised the first analysis cohort (Giovannucci et al., 1995); subsequently, follow-up was extended to 31 January 1998 (Platz et al., 2004). Follow-up questionnaires were sent in 1988, 1990 and 1992 to ascertain new cancer cases. Family members and the National Death Index were the main source of information on vital status of non-respondents. This study is included in the Pooling Project (Giovannucci et al., 1995; Michaud et al ., 2001; Platz et al., 2004; Wei et al., 2004; Lee et al., 2006).

Study of Osteoporotic Fractures

This cohort was based upon a multicentric prospective study of white women aged 65 years and over who were recruited from population-based listings and followed for the occurrence of osteoporotic fractures. One year after the baseline examination, participants completed a questionnaire. Incident cancers were identified by follow-up at year 3, and verified by perusal of medical records. Those who had died were excluded, leaving 8 015 for analysis (Lucas et al., 1998).

National Health Interview Survey (NHIS)

The 1987 National Health Interview Survey included a core questionnaire completed by 47 240 households containing 122 859 persons. One adult, aged 18 years and over, from each household who completed the core questionnaire was randomly selected to complete a cancer-control or cancer-epidemiology supplement, the latter comprising 22 080 individuals. The response rate for the core questionnaire was 95% and that for the cancer epidemiology supplement was 86%. Records from this cohort were linked to the National Death Index to provide a mortality follow-up through to 31 December 1995. Usable data were available for 20 195 participants (Breslow et al., 2000).

The β-Carotene and Retinol Efficacy Trial (CARET)

This trial of the potential chemopreventive effects of β-carotene and retinol began as a pilot study of 816 asbestos-exposed male workers and 1029 male and female heavy smokers and became a full-blown efficacy trial in 1988, with a total of 4060 male asbestos-exposed workers and 14 254 smokers (44% women) after 3 years of randomization. The trial was stopped 21 months before the planned cessation of the intervention; detailed results of associations with risk factors ascertained at baseline (including alcoholic beverage consumption) considered cancers ascertained through to 15 December 1995 (Omenn et al., 1996).

Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

A cohort of 25 400 women participated in a study that investigated the association between dietary folate, alcohol consumption, and postmenopausal breast cancer. Dietary data were collected at study enrollment between 1993 and 2001. Folate content was assigned on the basis of pre-fortification (i.e., pre-1998) databases. Of the 25 400 women participants with a baseline age of 55–74 years and with complete dietary and multivitamin information, 691 developed breast cancer between September 1993 and May 2003. Cox proportional hazard models with age as the underlying time metric were used to generate hazard ratios (HRs) and 95% CIs (Stolzenberg-Solomon et al., 2006).

California Teachers Study

This cohort was established in 1995–96 when 133 479 active and retired female teachers and administrators participating in the California State Retirement System returned a 16-page questionnaire that included data on alcoholic beverage consumption. Women who moved out of state or who died contributed person–months to the analysis up to the date of these events. Incident cancer cases are identified by annual linkage to the California Cancer Registry. Follow up was to January 2001 (Horn-Ross et al., 2004; Chang et al., 2007).

(c) Scandinavia

(i) Denmark
Pooled Copenhagen cohort studies

The data from three cohort studies—the Copenhagen City Heart Study, the Glostrup Population Study and the Copenhagen Male Study—were pooled. The Copenhagen City Heart study was initiated in 1976; participants were selected from 90 000 persons living in a defined area around the University Hospital of Copenhagen. An age-stratified sample of subjects aged 20 years or more was selected at random. Seventy-four per cent of those invited to participate (14 223 subjects) attended, and the subjects were followed-up until 1989. The Glostrup Population Studies Cohort (see above) comprised a total of 10 162 subjects (including men and women). The Copenhagen Male Study followed 5246 men, aged 40–59 years, from 14 large workplaces who were examined four times between 1970 and 1985. The combined study cohort included 18 602 men and 14 662 women. Information on smoking and intake of wine, beer and spirits was collected using self-administered questionnaires. Cancer cases were identified by record linkage to the Danish Cancer Register. Vital status was determined from the national Central Person Register. Cox regression was used to adjust for confounding by cigarette smoking, in a model that included six categories of current smoking and eight 10-year bands of duration of smoking. The cohort was eventually followed through to 1998, when 15 491 men and 13 641 women were included (Grønbaek et al., 1998; Prescott et al., 1999; Albertsen & Grønbaek, 2002; Pedersen et al., 2003). Details concerning the pooled results from these studies are not provided in the Table.

Glostrup Population Study

The Glostrup Population Study was established primarily to investigate cardiovascular disease, and comprised subjects from several birth cohorts (1897–1962) examined between 1964 and 1992, drawn from a study area Southwest of Copenhagen. A study population of 5207 women aged 30–80 years at baseline was considered for the analysis of breast cancer risk factors. Cases of cancer were identified by linkage to the Danish Cancer Register (Høyer & Engholm, 1992; Petri et al., 2004).

Danish Diet, Cancer and Health Study

Between December 1993 and May 1997, 79 729 women aged 50–64 years, who were born in Denmark and living in the greater Copenhagen and Aarhus area, were selected from the Central Population Register and invited to participate in this study. Participants completed a detailed 192-item food-frequency questionnaire that they received by mail before a visit to one of the two study clinics. Information was obtained on alcoholic beverage consumption from the food-frequency questionnaire and on drinking patterns from a lifestyle questionnaire completed at the clinic visit. The study cohort comprised 23 778 women whose records were linked to the Central Population Register for information on vital status and migration and to the Danish Cancer Register for diagnostic details of cancer. Follow-up was to 31 December 2000. This cohort was also included in the EPIC study (Tjønneland et al., 2003, 2004).

(ii) Finland
α-Tocopherol β-Carotene (ATBC) Cancer Prevention Study

A cohort of 29 133 white Finnish men, aged 50–69 years, who smoked five or more cigarettes per day and who participated in the ATBC randomized trial, were recruited beween 1985 and 1988 and followed for 5–8 years; 27 101 completed the baseline questionnaire. Incident cancers were identified by linkage with the Finnish Cancer Register. Alcoholic beverage consumption was ascertained through a food-use questionnaire administered before randomization in the trial. Deaths were identified from the Register of Causes of Death in Finland. Trial assignment was available [but does not seem to have been incorporated into the analysis] (Glynn et al., 1996; Woodson et al., 1999; Stolzenberg-Solomon et al., 2001; Mahabir et al., 2005; Lim et al., 2006).

(iii) Norway
Norwegian Cohort of Waitresses

The cohort consisted of 5,314 waitresses organized in the Restaurant Workers' Union between 1932 and 1978. The follow-up period was from 1959 to 1991. The standardized incidence ratio (SIR) for all causes of cancer was 1.0 (95 percent confidence interval [CI] = 0.9–1.1), based on 430 observed cases. Cancers of the tongue, mouth, pharynx, larynx, esophagus, and liver were grouped together as alcohol-associated cancers. SIR for these cancers combined was 1.1 (CI = 0.5–2.2). For lung cancer, SIR was 2.3 (CI = 1.6–3.1). Cervical cancer was also more frequent than expected, and breast cancer less frequent than expected. The larger excess of lung cancer and cervical cancer appeared in the sub-cohort working in restaurants with a license to serve alcohol. No excess risk of alcohol-associated cancers could be detected in this cohort of Norwegian waitresses (Kjaerheim & Andersen, 1994)

Norwegian Cohort Study

A cohort of Norwegian men born between 1883 and 1929, who completed a self-administered dietary questionnaire in 1967, was followed from 1968 (Heuch et al., 1983) through to 1992. The target population was initially drawn from three sources: approximately 19 000 persons randomly drawn from lists of residents of Norway from the 1960 population census, approximately 5200 drawn from four selected counties and approximately 13 000 from a cohort of Norwegians living in Norway who had siblings living in the USA (Kjaerheim et al., 1998). The study population for the Heuch et al. (1983) analysis comprised 16 713 men and women aged 45–74 years who responded to a questionnaire on dietary habits (which included alcoholic beverage consumption) and were followed to 31 December 1968. The study population for the Kjaerheim et al. (1998) analysis comprised 10 960 men who were alive and living in Norway on 1 January 1968, and who had no diagnosis of cancer before that date. Information on cancer incidence in both analyses was obtained through the population-based Norwegian Cancer Register (Heuch et al., 1983; Kjaerheim et al., 1998; Lund Nilsen et al., 2000).

HUNT-1 Cohort Study

All inhabitants of the county of Nord-Trondelag who were at least 20 years of age were invited by mail to participate in a health survey, ‘Helseundersokelsen i Nord Trondelag 1’ (HUNT-1), in 1984. Of 85 100 adults invited, 75 043 attended and were subsequently followed. Those who attended were examined and completed detailed questionnaires including information on alcoholic beverage consumption and tobacco smoking. After exclusions of persons followed for less than 3 years, 69 962 persons were included in the study. Follow-up to 2002 was by linkage to the Norwegian Cancer Register and the Norwegian Central Person Register (Sjödahl et al., 2007).

Norwegian Women and Cancer Study (NOWAC)

Between January 1991 and January 1997, 179 388 women aged 30–70 years, sampled according to birth years from the national population register at Statistics Norway, were invited to participate in a study. Mailing was conducted in 24 sets over 7 years; 102 443 women responded. The questionnaire included detailed information on alcoholic beverage consumption and diet. Cancer incidence was determined by linkage to the Norwegian Cancer Register (Dumeaux et al., 2004).

(iv) Sweden
Swedish Twin Register Study

A cohort of 12 889 twin pairs of the same sex, identified from the Swedish Twin Register, was asked to complete a questionnaire in 1961; 10 942 responded initially. Zygosity was based on questions of childhood similarity. In 1967, a 107-item questionnaire regarding lifestyle factors including alcoholic beverage consumption was mailed to registrees. Mortality in twins was followed-up by record linkage to the Swedish Cancer and Death Registers through to 1997. Information from death certificates and hospital records and other data were collected for the period up to 1981; the underlying cause of death was determined according to the ICD 8th revision. For the period after 1981, the underlying cause of death as stated on the death certificate was used (Grönberg et al., 1996; Terry et al., 1998, 1999; Isaksson et al., 2002).

Swedish Mammography Cohort

The Swedish Mammography Cohort was established between 1987 and 1990, when all women who were born between 1914 and 1948 and resided in Uppsala and Vastmanland counties in central Sweden were invited to undergo a mammography and complete a mailed questionnaire on diet (67 items), including alcoholic beverage consumption, weight, height and education. A total of 66 651 women (74% of those approached) who returned the questionnaire formed the cohort. A second 96-item questionnaire was mailed in 1997 and was returned by 39 227 women. Follow-up was by record linkage to the National Swedish Cancer Register, the Regional Cancer Register and the Swedish Death and Population registers at Statistics Sweden. An initial report was conducted as a nested case–control study and included cases detected at the first screen (Holmberg et al., 1995). After various exclusions, the final cohort for analysis comprised 61 433 women for the first questionnaire and 36 664 for the second. This cohort was included in the Pooling Project (Holmberg et al., 1995; Rashidkhani et al., 2005; Suzuki et al., 2005; Larsson et al., 2007).

Malmö Diet and Cancer Cohort

The population for this cohort was defined in 1991 as all persons who lived in the city of Malmö and were born during 1926–45, and was expanded in May 1995 to include all women born during 1923–50 and all men born during 1923–45. On completion of the baseline examinations in October 1996, 28 098 persons were regarded as the base cohort, with a subsample of 11 726 postmenopausal women. Exposure data on alcoholic beverage consumption were collected by an interview-based modified diet history, including a 7-day menu book that recorded details of alcoholic beverage consumption. Cancer cases were identified by linkage to the National Swedish Cancer Register and the Southern Swedish Tumour Register (Mattisson et al., 2004).

(d) Western Europe

(i) France
Supplémentation en Vitamines et Minéraux Antioxydants Study

The objective of the study was to evaluate the relation between antioxidant-rich beverages and the incidence of breast cancer. This prospective study consisted of 4396 women without a history of cancer who were participants in the French Supplémentation en Vitamines et Minéraux Antioxydants Study. Beverage consumption was estimated by using three nonconsecutive 24-hour recalls. Incident cancer cases were identified through clinical examinations performed every other year, including, e.g., a screening mammogram, and through a monthly health questionnaire. Participants were followed for a median 6.6 years (Hirvonen et al., 2006).

(ii) Netherlands
Netherlands Cohort Study

This cohort was based on 204 municipal population registries throughout the Netherlands, and comprised 58 279 men and 62 573 women, aged 55–69 years in 1986, who completed a self-administered questionnaire at baseline. Follow-up was by record linkage to cancer registries and the Dutch database of pathology reports, initially to 1989, and subsequently to 1992. The cohort was analysed as a case–cohort; a subcohort of 3500 subjects randomly sampled from the cohort after baseline exposure measurement was followed to 1992 to obtain information on vital status and was used as control (Goldbohm et al., 1994; Schuurman et al., 1999; Zeegers et al., 2001; Schouten et al., 2004; Balder et al., 2005; Loerbroks et al., 2007).

(iii) United Kingdom
British Doctors' Study

In 1951, a questionnaire was sent to all British doctors included in the Medical Registry; 34 440 men and 6194 women responded, representing 69% and 60%, respectively, of those doctors not known to have died at the time of the inquiry. Further questionnaires were sent in 1957, 1966, 1972, 1978 and 1990 to men and in 1961 and 1973 to women; on each occasion, at least 94% of those alive responded. Reports were published on cause-specific deaths after 10, 20 and 40 years for men and after 10 and 22 years for women; more than 99% of the subjects had been traced. Information on causes of death was obtained principally from the Registrars General of the United Kingdom or from the records of the general Medical Council, the British Medical Association, relatives or friends. Because the subjects in the study were themselves physicians, they were a reasonably uniform socioeconomic group and the causes of death were certified more accurately than might have been the case among a sample of the general population. Data on alcoholic beverage consumption were available for the last 23 years of the study (1978–2001) and, for this period, data by drinking habit, adjusted for smoking (adjusted for 5-year calendar periods), were available, and were considered for 12 321 male doctors who were alive in 1978 (Doll et al., 1994, 2005).

Oxford Vegetarian Study

This cohort included 11 140 vegetarians and non-vegetarians recruited in the United Kingdom between 1980 and 1984, who were contacted through the Vegetarian Society of the United Kingdom, media publicity and through other participants. Non-vegetarian participants were nominated by vegetarian participants from among their friends and relatives. Upon entry into the study, participants completed a food-frequency questionnaire and answered questions on other lifestyle factors including information on alcoholic beverage consumption. Participants were followed for information on cancer and death through the National Health Service central registry to 31 December 1999. The analysis cohort comprised 10 998 participants aged 16–89 years at entry (Sanjoaquin et al., 2004). This cohort is included in the European Prospective Investigation of Nutrition and Cancer (EPIC).

General Practitioner Research Database Study

The general practitioner research database contains longitudinal patient records, and totals >35 million patient–years of data on British primary care. The information was recorded by general practitioners during standard medical care, including patients' demographics, medical disorders, diagnoses from hospital referrals and drug prescriptions. Information on alcoholic beverage consumption was included when present in the records, but appears not to have been collected specifically; only information recorded at least 2 years before the index date was considered. The study period was from 1 January 1994 to 31 December 2001. The study was analysed as a nested case–control strudy; the index date was the date of diagnosis for cases, and was randomly selected for the 10 000 controls who were frequency-matched to the cases (Lindblad et al., 2005).

(iv) Multiple countries in Europe
Multicentric European Study of Second Primary Tumours

A cohort of 928 (876 male, 52 female) cases of laryngeal and hypopharyngeal cancer was identified between 1979 and 1982 from a multicentric population-based case–control study in Italy, Spain and Switzerland that was conducted to study the effects of tobacco, alcoholic beverage consumption, diet and occupation on the development of cancers. The cohort was followed until 2000 for the occurrence of second primary tumours using population, mortality and cancer-registry files. Exposure information was obtained through interviews. Approximately 7% of the cohort was lost to follow-up. Of the 876 men and 52 women, 145 men and six women developed second primary tumours during the follow-up period. The Cox proportional hazard model, adjusted for age, centre, occupation, smoking and site of first cancer, was used to estimate hazard ratios (Dikshit et al., 2005).

European Prospective Investigation into Cancer and Nutrition (EPIC)

A cohort of healthy adults was recruited from Denmark, France, Germany, Greece, Italy, Norway, Spain, Sweden, the Netherlands and the United Kingdom to study multiple exposures, including cigarette smoking, vegetable/fruit intake and alcoholic beverage consumption, on risks for various cancers. Recruitment was initiated in 1992, and active and passive follow-up is ongoing. Exposure information was obtained from mailed questionnaires. Relative risks were obtained using the proportional hazard model adjusting for follow-up time, sex, education, body mass index, vegetable and fruit consumption, tobacco smoking and energy intake (Boeing, 2002; Rohrmann et al., 2006; Tjønneland et al., 2007).

2.1.2. Studies in special populations (Table 2.1b)

This group of studies is characterized by the assumption that the study subjects have a pattern of consumption of alcoholic beverages that is different from that of the general population, e.g. alcoholics, brewery workers, members of a temperance organization. Because of the availability of national registries of populations, inpatients and cancer, most of these studies were performed in Scandinavian countries. The estimation of risk in these individuals is not based upon a comparison of exposed and unexposed subjects within the cohort, but with the expected rates of cancer in the general population.

(a) North America

(i) Canada
Canadian Alcoholics Study

The cohort consisted of 9889 men (79% middle-class; <1% nonwhite) who had been admitted to the main clinical services for alcoholics in Ontario between 1951 and 1970. No information on individual drinking or smoking habits was available, but investigations of samples of the cohort indicated an average daily consumption of 254 mL [∼ 200 g] ethanol and that >92% were still drinking ten years after admission. A total of 94% of cohort members were current smokers, who smoked an average of 28 cigarettes per day. Altogether, 1823 deaths occurred before 1972; 960.9 were expected. Vital status could not be determined for 3.5% of cohort members. Cause-specific mortality was compared with that of the Ontario male population. A further comparison was made with US veterans who smoked 21–39 cigarettes per day, in an indirect attempt to control for the effect of tobacco on the risk of alcohol-related cancers. Results were also reported for 1119 women followed up for 14 years, but only a few cancer deaths were observed (Schmidt & Popham, 1981).

(ii) United states
Massachusetts Cohort of Chronic Alcoholics

To test the hypothesis that there is a positive association between chronic alcoholism and carcinoma of the pancreas, the mortality experience of 1382 chronic alcoholics was studied. Analysis was limited to a comparison of observed and expected proportional mortality of different causes of death in the 894 whites who were known to have died. For carcinoma of the pancreas, 3 deaths were observed and 5.2 were expected. The observed/expected ratios for other causes of death, including other sites of cancer, were in accordance with prior studies (Monson & Lyon, 1975).

Seventh-day Adventist Study

The study population was identified in 1973 from 437 California Seventh-day Adventists churches. Adventists are a religious group who do not consume tobacco, alcoholic beverages or pork, and half adhere to a lacto-ovo-vegetarian lifestyle. The list of households was computerized in 1974: 63 530 were identified to which a census questionnaire was sent; 36 850 households returned a questionnaire listing 95 196 persons. Persons under 25 years of age were excluded from all analyses, and the study population analysed comprised 59 090 subjects. In 1976, a lifestyle questionnaire was sent to all living members (57 841); 40 398 participants returned the questionnaire; non-Hispanic whites had a response rate of 75%. Participant data was linked with data from two cancer registries, which were in operation in California. SIRs were calculated. The group of non-Hispanic members of the cohort was compared with an external population of Connecticut (93% whites) (Mills et al., 1994; Singh & Fraser, 1998).

(b) Scandinavia

(i) Denmark
Danish Brewery Workers Cohort

A total of 14 313 male members of the Danish Brewery Workers' Union who had been employed for six or more months in a brewery during the period 1939–63 were enrolled in this retrospective cohort study. The brewery workers had the right to consume six bottles (2.1 L) of light pilsener (lager) beer (alcohol content, 3.7 g [∼ 78 g ethanol] per 100 mL) on the premises of the brewery per working day; 1063 members of the cohort worked in a mineral-water factory, with no free ration of beer. No information was available on alcohol consumption or smoking habits of individual members of the cohort; but, on the basis of comparisons with alcohol statistics and population surveys, it was estimated that cohort members with employment in a brewery had a four times higher average beer consumption than the general population. Vital status was ascertained for 99.4% of the cohort members. There were 3550 deaths (SMR, 1.1) in the cohort, and 1303 incident cases of cancer were identified during the period 1943–72 by record linkage with the Danish Cancer Registry. Expected numbers of cancer cases and deaths were computed on the basis of age-, sex-, residence- and time-specific rates (Jensen 1979, 1980).

Danish Alcohol Abusers Study

The study was based on 18 307 alcoholics from Copenhagen who entered a public outpatient clinic for free treatment for alcoholism from 1954 to 1987. From 1968, cohort members had population identification numbers. Prior to that date, the 5969 cohort members without a number were sought by computer linkages with municipal and Danish population registries. The resultant cohort consisted of 15 214 men who were observed for 12.9 years on average and 3093 women who were observed for an average of 9.4 years. The records of these cohort members were linked to the Danish Cancer Register to obtain information on cancer morbidity through to December 1987. The observed cancer incidence was compared with that expected in the Danish population (Tønnesen et al., 1994).

Nationwide Study of Patients with Cirrhosis

In a study based upon the Danish National Register of Patients, persons who were registered between 1977 and 1989 were enrolled if they had been discharged with alcoholic cirrhosis (ICD-8 571.09), primary biliary cirrhosis (571.90), non-specified cirrhosis (571.92), chronic hepatitis (571.93) or ‘other types of cirrhosis, alcoholism not indicated’ (571.99). Cirrhosis was considered as a whole, but also as four separate types, largely following the ICD-8 codes given above, except that ‘non-specified cirrhosis’ and ‘cirrhosis, alcoholism not indicated’, were merged into one group termed ‘nonspecified cirrhosis’ (571.92 and 571.99). All members of the study cohort were linked through their personal identification number to the nationwide Danish Cancer Register and followed-up through to 1993. The cohort for this analysis consisted of 11 605 subjects (5079 men and 2086 women with alcoholic cirrhosis) who had survived for 1 year after registration. Expected numbers were computed from the rates in the Danish Cancer Register and compared with those observed (Sørensen et al., 1998).

(ii) Finland
Finnish Alcoholics

Between 1944 and 1959, male ‘alcohol misusers’ were registered by the Finnish State Alcohol Monopoly on the basis of conviction for drunkenness, sanctions imposed by the municipal social welfare boards, and various breaches against the regulations governing alcohol usage. No information was available on the amount of alcohol consumed by the cohort members, nor on types of beverage or smoking habits. The numbers of incident cases of cancer of the oesophagus, of the liver and of the colon among an estimated 205 000 men born 1881–1932 and alive in 1965–68 were obtained by a manual match between the files of the Finnish Cancer Register for these years and the files of the Alcohol Misusers Registry. Person-years at risk during the period 1965–68 were estimated from samples, and these formed the basis for computing expected numbers of cases. Lung cancer risk was determined in a similar fashion, but for only one-third of the group in 1968.

A second group of men more than 30 years of age, who in 1967–70 had been listed as chronic alcoholics by the Social Welfare Office of Helsinki, were also studied. The mean annual number of such men was estimated to be 4370. No information was available on type or amount of alcoholic beverages drunk or on tobacco smoking, but the persons in the group of chronic alcoholics were heavy alcohol drinkers, most of whom drank cheap, strong beverages, wines and denatured alcohols. Incident cases of cancer occurring during 1967–70 were identified by record linkage with the Finnish Cancer Register, and expected numbers were derived on the basis of national incidence rates and computed person-years (Hakulinen et al., 1974).

(iii) Norway
Norwegian Alcoholics Study

A total of 1 722 men discharged during 1925–39 from the Psychiatric Department of an Oslo hospital with a diagnosis of alcoholism were enrolled in the study and observed until the end of 1962. No information was available on drinking and smoking habits of individual cohort members or of the cohort as a whole, 408 were considered to be vagrant alcoholics. Evidence of persistent alcoholism was available for about 75% of the vagrants and for 50% of the remaining group. Follow-up was virtually complete, with 1 061 deaths. Death certificates were located for 1 028 of these, and information on cause of death was available for another 28 persons. The observed numbers of deaths were compared with expected numbers based on causes of deaths for all of Norway (496.9) and for Oslo (629.0). (Sundby, 1967).

International Organization of Good Templars Cohort

A cohort of 5332 members, aged 10 years and over, from the 200 larger and active lodges of the International Organization of Good Templars was followed for 10 years from 1980. Members of the Organization sign a statement that they will not drink alcoholic beverages. Cancer incidence and cause-specific mortality of the cohort was determined by linkage to the Cancer Register of Norway and was compared with that of the total Norwegian population (Kjaerheim et al., 1993).

(iv) Sweden
Temperance Boards Study

This cohort study comprised 15 508 Swedish women with a history of heavy alcoholic beverage consumption and 15 508 matched comparison subjects. The excessive alcoholic beverage users were ascertained through a review of the records of all Temperance Boards of Sweden, which operated between 1917 and 1977. During this time, 21 757 women were registered. Before 1947, personal identification numbers did not exist, so the cohort was limited to records after 1947. Linkages were made with the Swedish Cancer Register, which started in 1958 (Sigvardsson et al., 1996).

The Swedish Brewery Workers Study

This study was based upon the Cancer–Environment Register that links cancer incidence data from the Swedish Cancer Register for the period 1961–1979 with information on occupation, occupational status, industry and residence obtained in the 1960 population census. A group of 6230 men who were, according to the census, employed in the Swedish brewery industry in 1960, aged 20–69 years, was followed-up in 1961–79 by linkage to the Swedish Cancer Register. Person–years were computed by linkage with the Swedish Population Register. Relative risks were computed using all Swedish men as the reference group (Carstensen et al., 1990).

Swedish In-patient Register Study of Patients with Chronic Pancreatitis

This cohort was also based on the Swedish In-patient Register, and a very similar methodology to that of Boffetta et al. (2001) was used. Records of all patients with a diagnosis of acute, chronic or unspecified pancreatitis were identified, and linked to the Registries of Population, Death and Emigration held by Statistics Sweden. After exclusions of those who could not be identified in these registers and those with pancreatic or other cancers diagnosed at the index hospitalization, 29 530 subjects were included in the cohort. Incident cancers were identified by linkage with the [Swedish] National Cancer Register up to 31 December 1989 (Karlson et al., 1997). In a more recent report using the same database as above (Karlson et al., 1997; Boffetta et al., 2001), five cohorts were considered: 178 688 subjects admitted to hospital for alcoholism, 3500 admitted for chronic alcoholic pancreatitis, 4952 admitted for chronic non-alcoholic pancreatitis, 13 553 admitted for alcoholic liver cirrhosis and 7057 admitted for non-alcoholic liver cirrhosis. Follow-up was through to 1995 by linkage with national registers. Standardized incidence ratios (SIRs) were computed taking the Swedish population as a reference (Ye et al., 2002).

National Board of Health and Welfare Hospital Discharge Study of Alcoholism

From 1965 onwards, the National Board of Health and Welfare started collecting data on individual hospital discharges in the Inpatient Register. From 1987, the register attained complete nationwide coverage. All patients recorded in the Inpatient Register with a discharge diagnosis of alcoholism were initially selected for inclusion in the study. A total of 196 803 individually unique national registration numbers, assigned to all Swedish residents, were registered at least once with a diagnosis of alcoholism between 1965 and 1994. December 31, 1995 was the end of the observation period. Record linkage of the study cohort to the nationwide Registers of Causes of Death, Emigration and Cancer allowed the calculation of follow-up time, in person-years, of eligible persons at risk as described previously in detail (Adami et al, 1992a, b). From the total cohort 7790 records were excluded because of erroneous or incomplete national registration numbers, a further 3405 patients were excluded because they had prevalent cancers at the time observation began and another 2941 patients because of inconsistencies uncovered during record linkage. Thus a total of 182 667 patients with alcoholism remained eligible, and of these 36 856 were women (Kuper et al., 2000c).

National Board of Health and Welfare Study of Alcoholic Women

This study was essentially on the same female cohort as that considered by Boffetta et al. (2001). A total of 36 856 Swedish women (mean age, 42.7 years), who were hospitalized at least once in 1965–94 with a diagnosis of alcoholism and were residents in Sweden, were included in the study. SIRs were calculated by multiplying the number of person–years within 5-year age groups and calendar-year strata by the cancer incidence rates in Swedish women. Exclusions from observed and expected groups were secondary cancers and cancers found incidentally at autopsy. The person–time and events during the first year of follow-up were excluded to avoid increased likelihood of diagnosis of one disease following hospitalization for alcoholism in the presence of a yet undetected malignancy. The authors took co-morbidities into account (i.e. factors in the hospitalization record other than alcohol dependence) and assessed person–time within each co-morbidity stratum (Lagiou et al., 2001; Weiderpass et al., 2001a,b).

Swedish In-patient Register and the National Cancer Register Study

This cohort was based on the Swedish In-patient Register, a database provided by the National Board of Health and Welfare since 1964 that contains complete nationwide records since 1987, and is an expansion of the study of Adami et al. (1992a,b). Using the national identification number, which is a unique identifier for each citizen, the cohort was linked to the Registers of Population, Death and Emigration, and the National Cancer Register. The 196 803 persons aged ≥20 years who were identified had a hospital discharge-diagnosis of alcoholism during 1965–94 and a unique national registration number. After exclusions for various reasons, 173 665 persons were included in the analytical cohort (138 195 men, 35 470 women). Incident cancers after discharge were identified by linkage with the National Cancer Register up to 31 December 1995 (Boffetta et al., 2001).

Uppsala Alcoholics Study

A cohort of 10 350 individuals was selected from the Uppsala Inpatient Register (Sweden), with a discharge diagnosis that contained a diagnostic code for alcoholism (International Classification of Diseases [ICD] 7: 307, 322; ICD 8: 291, 303) during 1965–83. After exclusion of those who had an inconsistent registry number, 9353 (8340 men, 1013 women) patients were entered into the study. Follow-up was by record linkage to the nationwide Register of Causes of Death and the National Swedish Cancer Register through to 1984. Expected numbers of cancers were computed from cancer incidence in the Uppsala health-care region to compare with the observed cases (Adami et al., 1992a).

The Uppsala Alcoholics cohort, identified at the same time and followed for the same period, was also analysed as three population-based cohorts with mutually exclusive hospital discharge-diagnoses of alcoholism, cirrhosis or both. It comprised 8517 patients with a diagnosis of alcoholism, 3589 subjects with cirrhosis and 836 subjects with both diagnoses (Adami et al., 1992b).

(c) Western Europe

(i) Republic of Ireland
Dublin Brewers Study

A list of 1628 deaths during the period 1954–73 was provided by a large brewery in Dublin, Ireland. On the basis of death certificates for all but two of these men and of statistics for the population of employees and pensioners in 1957, 1960, 1967 and 1970, relative risks for specific causes of death were estimated employing both national and regional rates. The expected number of deaths was 1675.8 (regional rates). It was estimated from previous research that ethanol intake among the brewery workers was 58 g per day, compared with 16–33 g per day for other groups of the Irish population. Beer (stout) was consumed on the premises. No information was available on individual consumption of alcohol or tobacco; smoking was forbidden at the brewery for many years. [The Working Group noted that the cohort at risk was estimated indirectly as 2000–3000 men at any one time during follow-up, and no individual follow-up of cohort members was performed.] (Dean et al., 1979)

(ii) United Kingdom
Study of Patients Hospitalized for Alcohol-related Diseases

A series of 1110 patients seen at hospitals in the Birmingham Region between 1948 and 1971 for alcohol-related conditions were followed to 1981. By means of cohort analysis, the incidence of cancer in the series was compared with that in the West Midlands Region. In men the cancer risk was increased 1.7-fold: individual sites at risk were liver (8-fold), buccal cavity and throat (27-fold), respiratory system (2.4-fold), and oesophagus (4-fold). No excess of colorectal cancers was observed. Although in women there was no overall excess of cancers, the risk was high in the biliary system (15-fold) and was moderately increased for cervix uteri (4-fold) (Prior, 1988).

A total of 935 patients who had been discharged from four mental hospitals in or near London, UK, during the years 1953–57, or who had died during the key hospitalization and who had been given a primary or secondary diagnosis implicating abnormal drinking, were followed for 10–15 years. Of the total sample, 70 (7.5%) remained untraced and 233 men (34.4%) and 76 women (29.6%) had died; a total of 112.7 deaths was expected. The study was extended to all of England and Wales 1953–64 by Adelstein and White (1976), who covered a total of 1595 men and 475 women (Nicholls et al., 1974)

2.2. Cancer of the oral cavity and pharynx

The evidence for carcinogenic effects of alcoholic beverage consumption on the risk for cancers of the oral cavity and pharynx in humans was considered to be sufficient by a previous IARC Working Group (IARC, 1988). This section evaluates the evidence related to the risk for oral and pharyngeal cancer in humans based on relevant cohort and case-control studies published after 1988.

Exposure to alcoholic beverages is given in many different measurements. For comparability between studies, one drink is equivalent to 14 g, 18 mL or 0.49 oz of alcohol, which generally corresponds to 330 mL of beer, 150 mL of wine and 36 mL of hard liquor. Cancers of the oral cavity and pharynx are predominantly squamous-cell carcinomas. The histology of the tumours is given when available. Generally, studies on pharyngeal cancers are predominantly oropharyngeal and hypopharyngeal cancers, rather than nasopharyngeal cancer. Two case-control studies are, however, specifically focused on nasopharyngeal cancer, as noted in the Tables.

The risks for cancer of the oral cavity and pharynx in relation to total alcoholic beverage consumption are summarized in Tables 2.2-2.5. The effect of alcohol types are presented in Table 2.6, the combined or joint effects of alcohol drinking and tobacco smoking are shown in Table 2.7, and the effect of alcohol cessation and the association between alcoholic beverage consumption and risk for oral and pharyngeal cancers among nonsmokers are presented in Tables 2.8 and 2.9, respectively.

Table 2.2. Cohort studies of cancers of the oral cavity and pharynx combined.

Table 2.2

Cohort studies of cancers of the oral cavity and pharynx combined.

Table 2.5. Case–control studies of cancers of the oral cavity and pharynx combined and alcoholic beverage consumption.

Table 2.5

Case–control studies of cancers of the oral cavity and pharynx combined and alcoholic beverage consumption.

Table 2.6. Consumption of different types of alcoholic beverage and incidence of cancers of the oral cavity and pharynx.

Table 2.6

Consumption of different types of alcoholic beverage and incidence of cancers of the oral cavity and pharynx.

Table 2.7. Joint effects of alcoholic beverage consumption and tobacco smoking on cancers of the oral cavity and pharynx.

Table 2.7

Joint effects of alcoholic beverage consumption and tobacco smoking on cancers of the oral cavity and pharynx.

Table 2.8. Effect of cessation of alcoholic beverage consumption on the incidence of cancers of the oral cavity and pharynx.

Table 2.8

Effect of cessation of alcoholic beverage consumption on the incidence of cancers of the oral cavity and pharynx.

Table 2.9. Risk of consumption of alcoholic beverages for cancers of the oral cavity and pharynx among nonsmokers.

Table 2.9

Risk of consumption of alcoholic beverages for cancers of the oral cavity and pharynx among nonsmokers.

2.2.1. Cohort studies (Table 2.2)

Five cohort studies of the general population have been published since 1988 on the relationship between alcoholic beverage consumption and oral or pharyngeal cancer (Boffetta & Garfinkel, 1990; Chyou et al., 1995; Murata et al., 1996; Kjaerheim et al., 1998; Boeing, 2002), four of which reported smoking-adjusted relative risks but one did not (Murata et al., 1996). Increases in risk with consumption of alcoholic beverages were observed in all five cohort studies of populations from the USA, Europe and Asia, and heavy consumption was associated with a significantly increased risk. The adjusted relative risks were 9.22 (95% CI, 2.75–30.93) for more than 60 g (or more than four drinks) per day (Boeing, 2002), 6.2 (95% CI, 3.7–10.1) for more than 60 g (or more than four drinks per day) in the American Cancer Society Prospective Study (Boffetta & Garfinkel, 1990) and 3.9 (95% CI, 2.1–7.1) for consumption of alcoholic beverages four to seven times per week in a study in Norway (Kjaerheim et al., 1998). A strong dose-response relationship was reported in three studies (Murata et al., 1996; Kjaerheim et al., 1998; Boeing, 2002); however, two studies found a J-shaped relationship with an inverse association with low levels of alcoholic beverage consumption (Boffetta & Garfinkel, 1990; Chyou et al., 1995). In both studies, an increase in risk was observed with increasing levels of alcoholic beverage consumption thereafter.

Separating the effects of alcoholic beverages and tobacco smoking is generally very difficult. In most of these studies, however, smoking was controlled for in the analyses (Boffetta & Garfinkel, 1990; Chyou et al., 1995; Kjaerheim et al., 1998; Boeing, 2002). The increases in risk with consumption of alcoholic beverages were consistently seen in situations where smoking was controlled for as well as where smoking was not taken into account.

Five cohort studies were based on special populations (Adami et al., 1992a; Kjaerheim et al., 1993; Tønnesen et al., 1994; Sigvardsson et al., 1996; Sørensen et al., 1998). This type of study usually does not consider individual exposure levels. The point estimates were either the SIRs or standardized mortality ratios (SMRs) without adjusting for tobacco smoking. Among special cohorts of alcoholics, an increase in risk for cancers of the oral cavity and pharynx compared either with the local population rates (Adami et al., 1992a; Tønnesen et al., 1994; Sørensen et al., 1998) or with a population control group (Sigvardsson et al., 1996) has also been shown. Among Swedish alcoholics, Adami et al. (1992a) found a fourfold increase in risk (95% CI, 2.9–5.6) for oral cavity and pharyngeal cancers. Tønnesen et al. (1994) also found more than a 3.5-fold increase in risk (95% CI, 3.0–4.3) among men and a 17-fold increase (95% CI, 10.8–26.0) among women. In Danish 1-year survivors of cirrhosis, Sørensen et al. (1998) found a ninefold increase in risk (95% CI, 7.8–10.8) compared with national incidence rates. Furthermore, among alcoholic cirrhosis patients, the risk was increased more than 11.5-fold (95% CI, 9.6–14.0) compared with fourfold (95% CI, 1.8–8.2) among chronic hepatitis cirrhosis patients. By cancer site, Sigvardsson et al. (1996) found 8.5-fold (95% CI, 2.0–37), 12-fold (95% CI, 1.6–92), 11-fold (95% CI, 1.4–85) and ninefold (95% CI, 1.1–71) increases in risk for cancers of the tongue, mouth, tonsil and hypoharynx, respectively, in a Swedish population. Conversely, a cohort study among members of the International Organization of Good Templars in Norway, an organization for which members sign a statement that they will abstain from the consumption of alcoholic beverages, showed a 56% decrease in risk (SIR 0.44; 95% CI, 0.09–1.27) compared with the national incidence rates (Kjaerheim et al., 1993). Data on individual alcoholic beverage and tobacco consumption, however, were not obtained, which makes the separation of the protective effects of abstaining from either factor very difficult, especially since the two habits are usually correlated.

Alcoholic beverages have also been shown to be a risk factor for second primary cancers of the oral cavity and pharynx in two prospective studies of patients with a first primary cancer (Day et al., 1994a; Dikshit et al., 2005). Day et al. (1994a) and Dikshit et al. (2005) studied the risks for second primary cancers of the upper aerodigestive tract in relation to alcoholic beverage consumption among North Americans and Europeans (from Italy, Spain and Switzerland), respectively. In both studies, an increase in risk was found, although a more dramatic increase was found among Europeans (3–3.5-fold increase in risk among those who drank ≥81 g per day) than among North Americans (1.5–increase in risk among those who drank ≥15 drinks [≥210 g] per week or ≥30 g per day), which may be attributed to differences in categorization.

Results from prospective cohort studies of the general population provide sufficient evidence for the important role of alcoholic beverage consumption in the development of oral and pharyngeal cancer. The strength of the association is demonstrated by significantly increased relative risks that range from 3.5 to 9.2. A strong dose–response relationship was observed in almost all of the studies. Alcoholic beverage consumption was associated with an increase in risk for oral and pharyngeal cancer across different geographic regions and populations, which further supports the evidence.

2.2.2. Case–control studies

(a) Cancer of the oral cavity (Table 2.3)

All of the studies listed in Table 2.3 were hospital-based case–control studies (Franceschi et al., 1990; Zheng et al., 1990; Choi & Kahyo, 1991a; Zheng et al., 1997; Rao & Desai, 1998; Balaram et al., 2002; Znaor et al., 2003; De Stefani et al., 2007) and all but one (Rao & Desai, 1998) adjusted for tobacco smoking when evaluating the effect of alcoholic beverage consumption. All six studies of cancer of the oral cavity reported a positive association, with a dose-response relationship with alcoholic beverage consumption in different geographical areas of the world. A study of cancer of the tongue with a relatively large sample size reported increased risks for 20–30 years of alcoholic beverage consumption (odds ratio, 3.3; 95% CI, 1.4–8.9 for men; 2.0; 95% CI, 1.0–4.6 for women) (Rao & Desai, 1998). No obvious association was found in a study of cancer of the tongue with a limited sample size (Zheng et al., 1997).

Table 2.3. Case-control studies of cancer of the oral cavity and alcoholic beverage consumption.

Table 2.3

Case-control studies of cancer of the oral cavity and alcoholic beverage consumption.

Overall, the increase in risk for oral cancer associated with alcoholic beverage consumption is consistent, even after controlling for smoking. The strength of the association was shown by elevated adjusted odds ratios for heavy consumption that ranged from 3.0 to 14.8. Furthermore, a dose-response relationship was observed with elevated alcoholic beverage consumption and increased risk in most studies with multiple exposure levels when adjusted for tobacco smoking. The association has been observed across different geographical regions and populations, which further supports the key role of alcoholic beverage consumption in oral and pharyngeal carcinogenesis.

(b) Cancer of the pharynx (Table 2.4)

Table 2.4. Case–control studies of pharyngeal cancer and alcoholic beverage consumption.

Table 2.4

Case–control studies of pharyngeal cancer and alcoholic beverage consumption.

Among nine case–control studies of cancer of the pharynx, three were populationbased (Tuyns et al., 1988; Nam et al., 1992; Cheng et al., 1999) and six were hospital-based (Franceschi et al., 1990; Choi & Kahyo, 1991a; Maier et al., 1994; Znaor et al., 2003; De Stefani et al., 2004, 2007). All studies adjusted for or were stratified by tobacco smoking. Results from all of the studies showed a strong association with alcoholic beverage consumption, except for one study of nasopharyngeal cancer in Taiwan, China (Cheng et al., 1999).

Alcoholic beverage consumption was associated with an increase in risk for cancers of the oropharynx and hypopharynx across different geographical regions and populations and the point estimates of adjusted odds ratios ranged from 3.6 to 125.2. Furthermore, all studies but one (Cheng et al., 1999) observed a strong dose–response trend between alcoholic beverage consumption and risk for oro- and hypopharyngeal cancer. A possible explanation for the lack of association in the study from Taiwan may be the categorization of exposure: the highest exposure group contained people who consumed ≥15 g (equivalent to just over one drink) per day, which may be too low a level to detect an association.

(c) Cancer of the oral cavity and pharynx combined (Table 2.5)

A total of 19 studies of cancer of the oral cavity and pharyngeal cancer combined were identified (Blot et al., 1988; Merletti et al., 1989; Barra et al., 1990, 1991; Maier et al., 1992a; Marshall et al., 1992; Mashberg et al., 1993; Kabat et al., 1994; Sanderson et al., 1997; Hayes et al., 1999; Franceschi et al., 2000; Garrote et al., 2001; Schwartz et al., 2001; Altieri et al., 2004; Castellsagué et al., 2004; Llewellyn et al., 2004a,b; Rodriguez et al., 2004; Shiu & Chen, 2004). Six were population-based (Blot et al., 1988; Merletti et al., 1989; Marshall et al., 1992; Sanderson et al., 1997; Hayes et al., 1999; Schwartz et al., 2001) and the rest were hospital-based. Tobacco smoking was considered as a potential confounding factor in almost all of the studies. Seventeen studies reported a strong association, with a dose-response trend, between alcoholic beverage consumption and cancers of the oral cavity and pharynx and two reported an increased risk, but the 95% CIs included a null value (Merletti et al., 1989; Llewellyn et al., 2004b).

An increase in risk for cancers of the oral cavity and pharynx has been observed in most studies across different geographical regions and populations and the point estimates of adjusted odds ratios ranged from 4.1 to 8.8 for heavy consumption of alcoholic beverages when adjusted for tobacco smoking and other confounding factors. The lack of significant associations in two studies (Merletti et al., 1989; Llewellyn et al., 2004b) may be explained by small sample size (86 male and 36 female cases in the former and 65 male and 51 female cases in the latter), which limits the power to detect an association, as well as the inclusion of light drinkers in the baseline comparison group (1–20 g per day in the former and within the recommended level in the latter).

2.2.3. Types of alcoholic beverage (Table 2.6)

In a study not described previously, Schildt et al. (1998) investigated the effects of snuff, smoking and alcoholic beverage consumption on the risk for cancer of the oral cavity. Among 354 histologically confirmed cases reported to the Cancer Registry from Norrbotten, Vasterbotten, Jamtland and Vasternorrland, Sweden, between 1980 and 1989 and 354 individually matched population controls, beer and liquor were found to be the types of alcoholic beverage associated with a higher risk (odds ratio for beer, 1.5; 95% CI, 0.7–3.2; odds ratio for liquor, 1.5; 95% CI, 0.9–2.3) in a model that contained snuff, smoking and the other types of alcohol. Self-completed questionnaires were completed by proxies for 60% of the participants.

Assessment of risk associated with different types of alcoholic beverage is a difficult task; drinkers rarely consume only one type of alcoholic beverage, and isolating the effects of a single type in the presence of the other types is not easy to accomplish. Furthermore, heterogeneity of effects across different populations further complicates the interpretation of results. Overall, among studies in the USA, the ranking from highest to lowest risk by alcoholic beverage type is beer, hard liquor and wine (Blot et al., 1988; Mashberg et al., 1993; Day et al., 1994b; Kabat et al., 1994). Among the Italian studies, the highest risk was associated with wine consumption (Franceschi et al., 1990). In Latin America, hard liquor was associated with the highest risk among Cuban (Garrote et al., 2001) and Brazilian populations (Schlecht et al., 2001), and wine was associated with the highest risk among Uruguayans (De Stefani et al., 2004). In several studies, the other types of alcoholic beverage were not controlled for in the analyses which may distort the association under study. Generally, the types of alcoholic beverage that are the largest contributors to alcoholic beverage consumption are usually associated with the greatest increases in risk.

2.2.4. Joint effects (Table 2.7)

The joint effects of alcoholic beverage consumption and tobacco smoking on cancers of the oral cavity and pharynx have been assessed extensively. The studies varied in their methods and in the approaches used to assess effect modification, which ranged from descriptive to formal estimation of interaction in multivariate models.

For cancers of the oral cavity and pharynx, the evidence comes almost entirely from case-control studies carried out in Asia, Australia, Europe and the USA. Two prospective cohort studies have reported joint effects of alcoholic beverage consumption and tobacco smoking including the European Prospective Investigation into Cancer and Nutrition (EPIC) study (Boeing, 2002) and a cohort study of Japanese men (Chyou et al., 1995). The evaluation of effect modification was descriptive, without formal assessment of multiplicative interaction in most of studies.

Overall, a large majority of studies on joint exposure to alcoholic beverage and tobacco consumption demonstrated a synergistic effect. Many studies demonstrated a greater than multiplicative interaction (Tuyns et al., 1988; Merletti et al., 1989; Franceschi et al., 1990; Zheng et al., 1990; Mashberg et al., 1993; Kabat et al., 1994; Franceschi et al., 1999; Hayes et al., 1999; Schlecht et al., 1999; Garrote et al., 2001; Schwartz et al., 2001; Boeing, 2002; Castellsagué et al., 2004; De Stefani et al., 2007). In contrast, some other studies demonstrated a greater than additive but less than multiplicative interaction (Maier et al., 1992a; Chyou et al., 1995; Schildt et al., 1998). Among tobacco chewers in India, there appears to be no interaction between chewing and alcoholic beverage consumption (Balaram et al., 2002).

2.2.5. Effect of cessation of alcoholic beverage consumption (Table 2.8)

Studies of cessation of alcoholic beverage consumption may be confounded by the fact that precursors and early malignancies of the oral cavity and pharynx may lead to such cessation. Nevertheless, this type of confounding may result in underestimation of the effect of cessation. For recent quitters, the risk for oral and pharyngeal cancers increases above that of current drinkers; as the number of years since quitting increases, however, that elevated risk gradually drops to below that of current drinkers and near to the levels of non-drinkers in some studies. Hayes et al. (1999) observed that risk could drop to near the levels of non-drinkers after 20 years of quitting among men. Castellsagué et al. (2004) showed that risk can be reduced to near levels of never drinkers after 14 years and De Stefani et al. (2004) showed that this occurs after 10 years of quitting. In contrast, Franceschi et al. (2000) showed that a reduction in risk with quitting compared with current drinkers is not attained even 11 years after quitting.

2.2.6. Effect of alcoholic beverage consumption in nonsmokers (Table 2.9)

Because tobacco smoking is a major risk factor for oral and pharyngeal cancer, the study of nonsmoking subjects can avoid the strong confounding effect of tobacco smoking. Of the studies that focused on the effects of alcoholic beverage consumption in nonsmokers, an increase in risk in relation to alcoholic beverages was consistent. Talamini et al. (1990a) compared 27 nonsmoking cases identified between 1986 and 1989 in Milan and Pordenone and 572 nonsmoking hospital-based controls matched on age and area of residence. A significant dose–response relationship between alcoholic beverage consumption and cancer of the oral cavity and pharynx was observed (P=0.04). Ng et al. (1993) identified 173 white nonsmoking cases of oral and hypopharyngeal cancer between 1977 and 1991 in eight US cities and compared them with 613 hospital-based controls matched on age, sex and date of interview. A significant dose–response relationship was also observed in this study (P<0.001). Sixty nonsmoking cases from Pordenone, Rome, Latina (Italy) and Vaud (Switzerland) were identified from 1992 to 1997 and compared with 692 hospital-based controls (Talamini et al., 1998). Again, a dose–response relationship was seen between alcoholic beverage consumption and cancer of the oral cavity and pharynx (P=0.01). The Pooling Project, the International Head and Neck Cancer Epidemiology Consortium, reported associations between alcoholic beverage consumption and oral and pharyngeal cancer among nonsmokers (Hashibe et al., 2007a). The study included 384 cases of oral cancer, 369 oropharyngeal or hypopharyngeal cancers, 155 cases of oral and pharyngeal (not otherwise specified) cancer and 5775 controls. A significant dose–response relationship was observed for oro- and hypopharyngeal cancer for both frequency and duration of alcoholic beverage consumption. The adjusted odds ratios were 1.66 (95% CI, 1.18–2.34) for 1–2 drinks per day, 2.33 (95% CI, 1.37–3.98) for 3–4 drinks per day and 5.5 (95% CI, 2.26–13.36) for five or more drinks per day. The association was weaker for cancer of the oral cavity.

In addition, among 25 studies of effect modification listed in Table 2.7, the effect of alcoholic beverage consumption was presented in 17 (Blot et al., 1988; Franceschi et al., 1990; Zheng et al., 1990; Kabat et al., 1994; Chyou et al., 1995; Murata et al., 1996; Sanderson et al., 1997; Zheng et al., 1997; Schildt et al., 1998; Franceschi et al., 1999; Hayes et al., 1999; Schlecht et al., 1999; Garrote et al., 2001; Schwartz et al., 2001; Balaram et al., 2002; Boeing, 2002; Castellsagué et al., 2004). The majority of these studies found a strong association with alcoholic beverage consumption among nonsmokers with a dose–response relationship. A strong association and a dose–response relationship between alcoholic beverage consumption and the risk for oral and pharyngeal cancers demonstrated strong evidence for the carcinogenic effect of alcoholic beverage consumption.

2.3. Cancer of the larynx

The consumption of alcoholic beverages and tobacco smoking are the two major risk factors for laryngeal cancer (Austin & Reynolds, 1996; Doll et al., 1999). A relationship between the consumption of alcoholic beverages and cancer of the larynx was first suggested in the early 1900s by mortality statistics and clinical reports, and was subsequently supported by ecological studies that compared per-capita alcoholic beverage consumption and trends in the incidence of and mortality from laryngeal cancer (Wynder, 1952; Tuyns, 1982). However, the definition of alcoholic beverages as an independent etiological factor for laryngeal cancer and its quantification was not obtained until the late 1950s and early 1960s following ad-hoc epidemiological investigations (Schwartz et al., 1962; Wynder et al., 1976; Jensen, 1979).

Several case–control studies found an independent dose–risk relationship between alcoholic beverage consumption and the risk for laryngeal cancer, as well as a synergistic effect with tobacco smoking. Studies published up to 1988 were reviewed in a previous monograph (IARC, 1988). These included six prospective studies (Sundby, 1967; Hakulinen et al., 1974; Monson & Lyon, 1975; Robinette et al., 1979; Jensen, 1980; Schmidt & Popham, 1981) and 14 case–control studies conducted in North America and Europe (Wynder et al., 1956; Schwartz et al., 1962; Vincent & Marchetta, 1963; Wynder et al., 1976; Spalajkovic, 1976; Williams & Horm, 1977; Burch et al., 1981; Herity et al., 1982; Elwood et al., 1984; Olsen et al., 1985; Zagraniski et al., 1986; Brugère et al., 1986; Tuyns et al., 1988). Four of the six prospective studies showed significant increases in risk. Furthermore, all of the case–control studies showed an association with alcoholic beverage consumption, and a trend in risk for the amount consumed, but no indication of a difference in risk for various types of alcoholic beverage. The previous IARC Working Group concluded that the occurrence of malignant cancer of the larynx was causally related to the consumption of alcoholic beverages (IARC, 1988).

However, several important aspects of the relationship between alcoholic beverage consumption and the risk for laryngeal cancer remained unsolved. These included the role of time-related variables, such as duration of the habit, age at starting, time since cessation of consumption for former drinkers and the effect of different types of alcoholic beverage. Further, the risk may differ by anatomical subsite, such as the supra-glottis and the glottis/subglottis.

The epidemiological evidence for an association between alcoholic beverage consumption and the risk for laryngeal cancer includes at least four cohort and 18 case–control studies that have been published since 1988.

2.3.1. Cohort studies (Table 2.10)

Table 2.10. Selected prospective studies of laryngeal cancer and alcoholic beverage consumption.

Table 2.10

Selected prospective studies of laryngeal cancer and alcoholic beverage consumption.

Since 1988, six prospective studies have examined the relationship between alcohol beverage consumption and laryngeal cancer.

A study from Sweden (Adami et al., 1992b) of 9353 individuals discharged from care facilities with a diagnosis of alcoholism, including 11 cases of laryngeal cancer, showed an SIR of 3.3 for this cancer type. No information on individual consumption of alcoholic beverages was available, although the level of consumption of these subjects was presumably much higher and of longer duration than that of the general population. Moreover, no adjustment was available for tobacco consumption or for other potentially confounding factors such as socioeconomic status or diet, although an unfavourable risk pattern in alcoholics is probable. In the largest study of subjects who had a hospital discharge diagnosis of alcoholism in Sweden (Boffetta et al., 2001), the relative risk for laryngeal cancer was 4.21 (95% CI, 3.78–4.68; based on 347 cases).

The Honolulu Heart Program study (Chyou et al., 1995) was based on 7995 American men of Japanese ancestry who lived in Hawaii, and included 93 cases of cancers of the oral cavity and pharynx, oesophagus and larynx. A strong dose–risk relationship with alcoholic beverage consumption was found with a relative risk of 4.7 for ≥25 oz/month of total alcoholic beverage intake, compared with non-drinkers. In a prospective study of 10 960 Norwegian men followed from 1962 through to 1992 (Kjaerheim et al., 1998) that included 71 incident cases of upper digestive tract and respiratory neoplasms, the relative risk for the highest level of alcoholic beverage consumption (4–7 times/week) was 3.9 compared with never or occasional drinkers. These results were not confounded by marital status, occupational group or body-mass index. In the two latter prospective studies, no separate risk estimates were given for laryngeal cancer.

2.3.2. Case–control studies (Table 2.11)

Table 2.11. Case–control studies of laryngeal cancer and alcoholic beverage consumption.

Table 2.11

Case–control studies of laryngeal cancer and alcoholic beverage consumption.

Twenty case–control studies published since 1988 have included information on alcoholic beverage consumption and laryngeal cancer. All of these included overall allowance for tobacco use. Two additional case–control studies from China of 99 and 116 patients also found an excess risk in heavy alcoholic beverage drinkers, but did not allow for tobacco smoking.

The dose–risk relationship between alcoholic beverage consumption and major digestive and respiratory tract neoplasms was estimated from the data of a series of Italian case–control studies using regression spline models, and showed substantial increases in risk for laryngeal cancer with regular consumption of more than 50 g ethanol per day (Polesel et al., 2005).

A meta-analysis of 20 case–control studies (Bagnardi et al., 2001) included over 3500 cases of laryngeal cancer and reported a strong direct trend in risk, with multivariate relative risks of 1.38 (95% CI, 1.32–1.45) for 25 g alcohol per day, 1.94 (95% CI, 1.78–2.11) for 50 g per day and 3.95 (95% CI, 3.43–4.57) for 100 g per day, based on a dose–risk regression model. Corrao et al. (2004) found significantly increased risks for laryngeal cancer when comparing point-based and model-based relative risks to that of meta-pooled relative risks from studies that provided information on low doses (i.e., ≤ 25g of alcohol per day), thus confirming the evidence of an association for modest doses as well.

2.3.3. Subsites of the larynx (Table 2.12)

Table 2.12. Selected case–control studies of alcoholic beverage consumption and cancer of the larynx by anatomical subsite.

Table 2.12

Selected case–control studies of alcoholic beverage consumption and cancer of the larynx by anatomical subsite.

The larynx can be divided into the supraglottis (also called extrinsic larynx) and epilarynx, which border on the hypopharynx, and the glottis (also called intrinsic larynx) and subglottis, which lie wholly within the respiratory system (Spleissl et al., 1990). These various subsites of the larynx are exposed to potential carcinogens at different levels: the glottis and subglottis are more highly exposed to inhaled agents and the supraglottis to ingested agents, while the junctional area between the larynx and the pharynx is exposed to both inhaled and ingested agents. Thus, each site could react differently to different etiological factors.

At least seven case–control studies (Brugère et al., 1986; Guénel et al., 1988; Falk et al., 1989; Maier et al., 1992b; Muscat & Wynder, 1992; Talamini et al., 2002; Menvielle et al., 2004) and one meta-analysis (Bagnardi et al., 2001) suggested that the risk from alcoholic beverage consumption was stronger for cancer of the supraglottis than for cancer of the glottis/subglottis. Conversely, other studies reported similar risks for both supraglottis and glottis/subglottis (Flanders & Rothman, 1982; Tuyns et al., 1988; Hedberg et al., 1994). In a multicentric study in France, Italy, Spain and Switzerland (Tuyns et al., 1988) and in two French studies (Brugère et al., 1986; Menvielle et al., 2004), a stronger effect of alcoholic beverage consumption was found for the epilarynx.

The available evidence thus indicates that the highest risks related to the consumption of alcoholic beverages tend to occur in tissues that come into close contact with both alcoholic beverages and tobacco smoke. Thus, alcoholic beverage consumption may influence the risk for laryngeal cancer particularly through its direct contact or solvent action, perhaps by enhancing the effects of tobacco or other environmental carcinogens.

2.3.4. Types of alcoholic beverage (Table 2.13)

Table 2.13. Selected case–control studies of laryngeal cancer and consumption of different types of alcohol beverage.

Table 2.13

Selected case–control studies of laryngeal cancer and consumption of different types of alcohol beverage.

Several studies have investigated whether the risk for laryngeal cancer depends on the type of alcoholic beverage consumed. In a cohort study in Hawaii (Chyou et al., 1995) of 93 cancers of the upper digestive and respiratory tract, no substantial difference in risk was found between the highest levels of consumption of beer (relative risk, 3.7), wine (relative risk, 3.8) or spirits (relative risk, 3.6). Another prospective study in Norway (Kjaerheim et al., 1998) of upper digestive and respiratory tract cancers found a higher risk for elevated consumption of beer (relative risk, 4.4) compared with that of spirits (relative risk, 2.7). However, due to the limited number of cases, specific analysis of laryngeal cancer was not possible in these two cohort studies.

Among case–control studies, a Canadian study (Burch et al., 1981) found an increase in risk among heavy beer drinkers (odds ratio, 4.8), but no consistent increase for spirit (odds ratio, 1.3) or wine drinkers (odds ratio, 0.5). Similarly, a case–control study from Denmark (Olsen et al., 1985) of 326 cases of laryngeal cancer and 1134 controls reported a higher risk in drinkers who preferably consumed beer (odds ratio, 1.4) than in those who preferred wine (odds ratio, 0.6) or spirits (odds ratio, 1.0). A case–control study in Uruguay (De Stefani et al., 1987) of 107 cases of laryngeal cancer and 290 controls showed a higher risk for wine (odds ratio, 7.4) than for hard liquors (odds ratio, 4.0). In an Italian study (Franceschi et al., 1990), wine was associated with the highest risk (odds ratio, 4.2), whereas a lower risk was reported for beer (odds ratio, 1.5) and hard liquors (odds ratio, 0.8). In a case–control study conducted in the USA (Muscat & Wynder, 1992), based on 250 cases, an increased risk for laryngeal cancer was found for heavy drinkers of beer (odds ratio, 2.7) and hard liquors (odds ratio, 2.2), but not for wine drinkers (odds ratio, 1.1). No strong differences were seen between consumption of beer, hard liquors or wine in a case–control study in Brazil (Schlecht et al., 2001) that included 194 cases of laryngeal cancer: the relative risk was 1.8 for high consumption of hard liquors and beer and 1.5 for that of wine. Higher risks were observed for cachaça (relative risk, 9.9), a typical Brazilian hard liquor. In a case–control study in Italy and Switzerland (Talamini et al., 2002), the risk was slightly higher for wine drinkers than for beer and hard liquor drinkers (odds ratios, 5.2, 3.2 and 2.9, respectively). Case–control studies conducted in Italy between 1986 and 2000 (Franceschi etal., 1990; Talamini etal., 2002; Garavello et al., 2006) included 672 cases of laryngeal cancer and 3454 hospital controls, admitted for acute, non-neoplastic conditions that were unrelated to smoking or alcoholic beverage consumption. Significant trends in risk were found for total alcoholic beverage intake, with multivariate odds ratios of 1.12 for drinkers of 3–4 drinks per day, 2.43 for 5–7, 3.65 for 8–11 and 4.83 for >12 drinks per day compared with abstainers or light drinkers. Corresponding odds ratios for wine drinkers were 1.12, 2.45, 3.29 and 5.91. After allowance was made for wine intake, the odds ratios for beer drinkers were 1.65 for 1–2 drinks per day and 1.36 for ≥3 drinks per day compared with non-beer drinkers; corresponding values for spirit drinkers were 0.88 and 1.15. Thus, in the Italian population which is characterized by frequent wine consumption, wine is the beverage most strongly related to the risk for laryngeal cancer.

Taken together, these data suggest, however, that the most frequently consumed beverage in each population tends to be that which yields the highest risk, and that ethanol is the main component of alcoholic beverages that determines the risk for cancer.

2.3.5. Joint effects

Several investigations have considered the combined effect of tobacco smoking and alcoholic beverage consumption on the etiology of cancer of the larynx (Flanders & Rothman, 1982; Elwood et al., 1984; Olsen et al., 1985; De Stefani et al., 1987; Guénel et al., 1988; Franceschi et al., 1990; Choi & Kahyo, 1991a; Zatonski et al., 1991; Maier et al., 1992a; Zheng et al., 1992; Chyou et al., 1995; Dosemeci et al., 1997; Schlecht et al., 1999; Bagnardi et al., 2001; Talamini et al., 2002). These studies gave risk estimates for the highest level of consumption for both factors compared with the lowest level of between approximately 10 and over 100, and indicated that a multiplicative model rather than an additive model or risk could explain the level of risk from combined exposure to both factors. Separating the effects of alcoholic beverages and tobacco remains difficult, however, since heavy drinkers tend to be heavy smokers and vice versa. Furthermore, most studies included very few cases who neither smoked nor drank.

An example of the combined effect of alcoholic beverages and tobacco on laryngeal cancer was given by Talamini et al. (2002). Compared with never smokers/abstainers or light drinkers, the relative risk for laryngeal cancer increased with increasing alcoholic beverage consumption in each stratum of smoking habit to reach 177.2 in heavy drinkers and smokers compared with moderate drinkers and nonsmokers. Similar results were found for smoking within strata of alcoholic beverage intake. The odds ratio for the highest level of alcoholic beverage consumption and current smoking was 177.2. In a French study (Guénel et al., 1988), the relative risk for combined heavy alcoholic beverage and tobacco consumption was 289.4 (95% CI, 83.0–705.8) for glottic and 1094.2 (95% CI, 185.8–2970.7) for supraglottic cancers. In a case–control study in Taiwan, China, the odds ratio for users of alcoholic beverages, betel quid and cigarettes compared with non-users was 40.3 (95% CI, 14.8–123.6) (Lee et al., 2005).

2.3.6. Effect of cessation of alcoholic beverage consumption

The risk for laryngeal cancer declines steeply with time since stopping smoking (Olsen et al., 1985; Guénel et al., 1988; Tuyns et al., 1988; Franceschi et al., 1990; Freudenheim et al., 1992; Kjaerheim et al., 1993; Bosetti et al., 2006). Data exist from only one study on time since stopping alcoholic beverage consumption. In a case–control study in Italy (Altieri et al., 2002) that included a total of 59 former drinkers, the odds ratios were 1.24 for 1–5 years, 1.29 for 6–19 years and 0.53 for ≥20 years since cessation of drinking compared with current drinking. The risk approached that of never drinkers only after 20 years since cessation (odds ratio, 0.56).

Thus, while the favourable effect of stopping smoking is evident within a few years after cessation, that of stopping drinking becomes apparent only in the long term. Among current smokers that have stopped drinking, the persistence of exposure to tobacco may play an important role in limiting the benefits from cessation of drinking. These findings must, however, be interpreted with caution, since former drinkers may represent a select group of individuals whose average alcoholic beverage intake had exceeded that of current drinkers.

2.3.7. Effect of Alcoholic beverage consumption in nonsmokers (Table 2.14)

Table 2.14. Selected case–control studies of laryngeal cancer and alcoholic beverage consumption in nonsmokers.

Table 2.14

Selected case–control studies of laryngeal cancer and alcoholic beverage consumption in nonsmokers.

An independent role of alcoholic beverages on the incidence of laryngeal cancer has been suggested, but is difficult to quantify (Austin & Reynolds, 1996). In developed countries, cancer of the larynx is rare in nonsmokers, and only a few studies have included enough cases to provide useful information on the effect of alcoholic beverages in nonsmokers.

A case–control study form Canada (Burch et al., 1981) of 204 cases and 204 matched controls reported an increased risk for laryngeal cancer in relation to alcoholic beverage consumption (odds ratio, 7.7 for ≥26 000 oz ethanol in a lifetime) in never smokers based, however, on three case–control pairs only. A multicentric case–control study in France, Italy, Spain and Switzerland (Tuyns et al., 1988) reported odds ratios of 1.7 for ≥80 g per day of alcohol among nine never-smoker cases of cancer of the endolarynx and of 6.7 for ≥40 g per day of alcohol among 22 nonsmoking cases of cancer of the epilarynx/hypopharynx. In a case–control in Italy conducted on 40 never-smoking cases, an excess risk (odds ratio, 2.5) for ≥8 drinks per day was found (Bosetti et al., 2002).

A pooled analysis of never-tobacco users from 11 case–control studies, including 121 cases of laryngeal cancer and 4602 controls, showed an increased risk for laryngeal cancer with the consumption of ≥5 drinks per day (odds ratio, 2.98; 95% CI, 1.72–5.17) (Hashibe et al., 2007b).

Thus, these studies confirmed that, even in a population of never smokers, elevated alcoholic beverage consumption increases the risk for laryngeal cancer. There is, however, no reason to suppose that tobacco smoking is the only carcinogenic agent to which the human upper respiratory and digestive tract is exposed, and ethanol may facilitate the effect of other unrecognized carcinogenic agents in nonsmokers, just as it commonly facilitates the effect of tobacco smoking (Doll et al., 1999).

2.4. Cancer of the oesophagus

The evidence for the carcinogenic effects of alcoholic beverage consumption on the risk for oesophageal cancer was considered to be sufficient by a previous Working Group (IARC, 1988). Several epidemiological studies have been published since that time, and this section evaluates the risk for oesophageal cancer based on the relevant cohort and case–control studies after 1988.

The 18 cohort and 38 case–control studies conducted in Argentina, China, Denmark, Europe, India, Italy, Japan, Norway, Sweden, the United Kingdom, Uruguay and the USA summarized in this section are described in Tables 2.15, 2.16 (literature originally in the Chinese language) and 2.17.

Table 2.15. Cohort studies of oesophageal cancer and consumption of alcoholic beverages.

Table 2.15

Cohort studies of oesophageal cancer and consumption of alcoholic beverages.

Table 2.16. Analytical studies of oesophageal cancer and alcoholic beverage consumption published in the Chinese literature.

Table 2.16

Analytical studies of oesophageal cancer and alcoholic beverage consumption published in the Chinese literature.

Table 2.17. Case–control studies of oesophageal cancer and alcoholic beverage consumption.

Table 2.17

Case–control studies of oesophageal cancer and alcoholic beverage consumption.

2.4.1. Cohort studies (Table 2.15)

(a) Special populations

Five cohort studies were based on either individuals who had high exposure to alcoholic beverages, such as alcoholics or workers in the brewery industry, or who had lower alcoholic beverage consumption, such as teetotalers (Carstensen et al., 1990; Adami et al., 1992b; Kjaerheim et al., 1993; Tønnesen et al., 1994; Boffetta et al., 2001). This type of study does not usually consider individual exposure levels. The point estimates were either the SIRs or SMRs with no adjustment for tobacco smoking. The four studies of alcoholics or brewery workers reported a statistically significant association, and the point estimates of the SIR ranged from 2.5 to 5.5 (Carstensen et al., 1990; Adami et al., 1992b; Tønnesen et al., 1994; Boffetta et al., 2001); the point estimate was 0.26 for teetotalers (Kjaerheim et al., 1993).

(b) General population

Thirteen cohort studies of the general population have been published, including two in the Chinese literature (Table 2.16), most of which adjusted for tobacco smoking. Ten cohort studies reported a statistically significant association between alcoholic beverage consumption and the risk for oesophageal cancer after controlling for tobacco smoking. In addition, these studies were carried out in different geographical regions of the world. The adjusted relative risks ranged from 2.8 in the USA (Thun et al., 1997) to 14.5 in Japan (Kono et al., 1987) for two or more drinks per day after adjusting for tobacco smoking. One study (Lindblad et al., 2005) reported a positive association for adenocarcinoma of the oesophagus with a relative risk of 1.76 (95% CI, 1.16–2.66) for heavy drinkers.

The two cohort studies in Linxian County, China, based on the same population reported a null association (Guo et al., 1994; Tran et al., 2005). The null association between alcoholic beverage consumption and oesophageal cancer in rural high-risk areas of China is probably due to the relatively low consumption of alcoholic beverages in these areas or other strong risk factor(s) which may mask or highly confound the association between alcoholic beverage consumption and oesophageal cancer. Another study from the Chinese literature (Wang et al., 2005a; Table 2.16) reported that an increased risk for oesophageal cancer was associated with elevated alcoholic beverage consumption (relative risk, 5.08 for >70 g/day or 5 or more drinks/day) after adjusting for tobacco smoking; however, no 95% CI was provided.

In summary, the results of the majority of the prospective cohort studies support that alcoholic beverage consumption can cause cancer of oesophagus.

2.4.2. Case–control studies (Table 2.17)

Among the 38 case–control studies, 20 studies were published in the English literature and 18 in the Chinese literature. Of the 20 studies published in the English literature, 18 adjusted for tobacco smoking, 8 were population-based and 12 were hospital-based. Sixteen of the 20 studies in the English literature on alcoholic beverage consumption and the risk for oesophageal cancer reported a statistically significant association. The adjusted odds ratios ranged from 1.7 to 3.5 for ever drinkers and from 5.4 to 37.3 for heavy drinkers. Among the case–control studies identified in the Chinese literature (Table 2.16), the majority were hospital-based and 10 studies did not adjust for tobacco smoking (Chen et al., 2000; Lu et al., 2000b; Zhang et al., 2000; Ding et al., 2001a,b; Li et al., 2001; Mu et al., 2003; Wang B et al., 2003a; Wang et al., 2004; Yan et al., 2004; Zhao et al., 2005). Eight of these reported a positive association with alcoholic beverage consumption; the odds ratios ranged from 1.72 to 6.41 for ever drinkers of alcoholic beverages and from 3.1 to 23.4 for heavy drinkers. The evidence for alcoholic beverage consumption and the risk for oesophageal cancer in the Chinese literature are consistent with that in the English literature. In addition, the results from case-control studies are also consistent with those from prospective cohort studies.

2.4.3. Histological types (Tables 2.17 and 2.18)

Consumption of alcoholic beverages is an established cause of oesophageal cancer and is strongly associated with the risk for squamous-cell carcinoma of the oesophagus and, to a lesser degree, with the risk for oesophageal adenocarcinoma (Brown et al., 1994; Gammon et al., 1997; Lagergren et al., 2000; Wu et al., 2001; Lindblad et al., 2005; Hashibe et al., 2007a).

One prospective study of alcoholics (Boffetta et al., 2001), one nested case-control study (Lindblad et al., 2005) and eight case-control studies of adenocarcinoma of the oesophagus (Table 2.18) in relation to alcoholic beverage consumption have been published. A cohort study of alcoholics in Sweden (Boffetta et al., 2001) reported an SIR of 1.45 (95% CI, 0.96–2.11) for oesophageal adenocarcinoma and 6.76 (95% CI, 6.15–7.41) for oesophageal squamous-cell carcinoma. The nested case–control study on adenocarcinoma of the oesophagus observed a null association (Lindblad et al., 2005). Among the eight case–control studies, two reported a significant association between alcoholic beverage consumption and oesophageal adenocarcinoma. The increased risk for adenocarcinoma of oesophagus was associated with a higher level of alcoholic beverage consumption in two studies (Kabat et al., 1993; Vaughan et al., 1995), but not in the other six. Thus, the evidence for alcoholic beverage consumption and the risk for adenocarcinoma of the oesophagus was considered to be insufficient.

Table 2.18. Selected cohort and case–control studies of oesophageal cancer by histological type and alcoholic beverage intake.

Table 2.18

Selected cohort and case–control studies of oesophageal cancer by histological type and alcoholic beverage intake.

2.4.4. Type of alcoholic beverage (Table 2.19a and Table 2.19b)

Table 2.19a. Selected cohort studies of oesophageal cancer and consumption of different types of alcoholic beverages.

Table 2.19a

Selected cohort studies of oesophageal cancer and consumption of different types of alcoholic beverages.

Table 2.19b. Selected case–control studies of oesophageal cancer and consumption of different types of alcoholic beverages.

Table 2.19b

Selected case–control studies of oesophageal cancer and consumption of different types of alcoholic beverages.

The types of alcoholic beverage consumed were examined in several studies. Consumption of beer or hard liquor led to a higher relative risk than consumption of wine (Kato et al., 1992c; Brown et al., 1994; Gammon et al., 1997; Grønbaek et al., 1998; Kjaerheim et al., 1998; Lagergren et al., 2000), whereas two studies (Barra et al., 1990; Sakata et al., 2005) also found an excess risk for wine drinkers. Most of the studies that investigated types of alcoholic beverage showed no substantial difference in risk.

2.4.5. Evidence of a dose–response

The risk for oesophageal cancer was shown to increase with increasing number of drinks per day or the number of days per week on which alcoholic beverages were consumed in 10 cohort and 21 case–control studies. Some studies found a relationship between the duration of alcoholic beverage consumption in years and the risk for oesophageal cancer (Cheng et al., 1995; Zhang et al., 1998; Liu et al., 2000; Znaor et al., 2003; Sakata et al., 2005; Wu et al., 2006a; Hashibe et al., 2007a). Using non-drinkers as the baseline, the influence of the cumulative amount of alcoholic beverage consumed was apparent (Lagergren et al., 2000; Sakata et al., 2005; Wu et al., 2006a; Hashibe et al., 2007a). A dose-response relationship was found between the frequency of alcoholic beverage intake and the risk for oesophageal cancer (Grønbaek et al., 1998; Kinjo et al., 1998; Wu et al., 2006a; Hashibe et al., 2007a). In two studies (Yang et al., 2005; Wu et al., 2006a), the relative risks were lower in former drinkers than in current drinkers but remained significantly elevated.

2.4.6. Effect of cessation of alcoholic beverage consumption (Table 2.20)

Table 2.20. Case–control studies of oesophageal cancer and cessation of alcoholic beverage consumption.

Table 2.20

Case–control studies of oesophageal cancer and cessation of alcoholic beverage consumption.

Studies on the cessation of alcoholic beverage consumption may be confounded by the fact that the precursors and early malignancies of the oesophagus may lead to such cessation. Nevertheless, this type of confounding may result in an underestimation of the effect. For recent quitters, the risk for oesophageal cancer increased above that of current drinkers; as the number of years of having quit increased, however, the risk gradually decreased to below that of current drinkers or even to close to the levels of non-drinkers in some studies.

Cheng et al. (1995) observed that risk could decrease to nearly the levels of non-drinkers after more than 10 years of quitting. Castellsagué et al. (2000) showed that risk can be reduced to 50% of that of current drinkers after more than 10 years of cessation. Bosetti et al. (2000) observed an odds ratio of 0.37 (95% CI, 0.14–0.99) after 10 or more years of cessation. All three case–control studies suggested a reduction in risk after cessation of alcoholic beverate consumption for more than 10 years.

2.4.7. Effect modification

The combined effects of smoking and alcoholic beverage consumption on the development of cancer of the oesophagus have been examined in several studies (Tables 2.17 and 2.21), which varied in the methods and approaches used to assess effect modification, and ranged from being descriptive to giving a formal estimation of interaction terms in multivariate models. Eight case–control studies (Franceschi et al., 1990; Negri et al., 1992; Kabat et al., 1993; Lagergren et al., 2000; Gallus et al., 2001; Znaor et al., 2003; Wu et al., 2006a; Hashibe et al., 2007c) and two cohort studies (Kato et al., 1992c; Sakata et al., 2005) reported the joint effect of alcoholic beverage consumption and tobacco smoking on the risk for oesophageal cancer. Overall, the studies showed that the joint effects were multiplicative rather than additive, but, since multiple logistic regression models were used in the analyses in most of these studies, some also showed them to be additive rather than multiplicative.

Table 2.21. Selected cohort and case–control studies of oesophageal cancer in nonsmokers and smokers by level of alcoholic beverage intake.

Table 2.21

Selected cohort and case–control studies of oesophageal cancer in nonsmokers and smokers by level of alcoholic beverage intake.

Some studies investigated sex-specific effects (Table 2.22), and reported similar risks for both men and women (Negri et al., 1992; Kabat et al., 1993; Kinjo et al., 1998). Most studies found non-significantly increased relative risks among women with oesophageal cancer, but a significant risk among men who were classified as heavy drinkers, after controlling for tobacco smoking (DeStefani et al., 1990; Adami et al., 1992b; Kinjo et al., 1998). The studies from Japan and Italy found a significantly increased risk for oesophageal cancer among women (Gallus et al., 2001; Yokoyama et al., 2006).

Table 2.22. Selected cohort and case–control studies of oesophageal cancer in men and women by level of alcoholic beverage intake.

Table 2.22

Selected cohort and case–control studies of oesophageal cancer in men and women by level of alcoholic beverage intake.

2.5. Cancer of the liver

Hepatocellular carcinoma (HCC) is the third most common cause of mortality from cancer and the sixth most common cause of cancer incidence worldwide (Parkin et al., 2005). Although it is relatively rare in developed countries compared to the developing world, the incidence of primary liver cancer has increased during the last few decades in the USA (Howe et al., 2001) and in several European countries, although it has levelled off and subsequently declined in most of southern Europe over the last decade (La Vecchia et al., 2000).

In 1988, the IARC Monograph on alcohol drinking concluded that there was “sufficient evidence for the carcinogenicity of alcoholic beverages" and that "the occurrence of malignant tumours of the liver is causally related to consumption of alcoholic beverages” (IARC, 1988). Since that time, further evidence has been presented on the risk of liver cancer associated with prolonged alcoholic beverage consumption, the increased risk of associated liver cancer among cirrhotics and the modifying effects of the infectious agents hepatitis B virus (HBV) and hepatitis C virus (HCV).

2.5.1. Cohort studies

(a) Special populations (Table 2.23)

Most HCCs occur in cirrhotic livers, and cirrhosis is a pathogenic step in liver carcinogenesis (La Vecchia et al., 1998). In alcoholics, prolonged, excessive alcohol consumption results in alcoholic cirrhosis. The risk of HCC has been examined among alcoholic and cirrhotic subjects. In western countries, a few cohort studies have pro- vided information regarding these special populations. Results from these cohort stud- ies are presented in Table 2.23. Since 1988, two cohort studies conducted in Sweden have assessed the risk of primary liver cancer. One cohort comprised alcoholic and cirrhotic subjects (Adami et al., 1992a) and the other cohort included male and female alcoholics (Adami et al., 1992b). An additional cohort study in Denmark was con- ducted among patients with cirrhosis (Sørensen et al., 1998). The number of cases ranged from four to 182 within these three populations. Each of the three studies showed evidence of a strong association between alcoholism, cirrhosis and liver can- cer. Two of these studies reported statistically significant SIRs greater than 35 among alcoholics and cirrhotics (Adami et al., 1992a; Sørensen et al., 1998). The Swedish cohort, which included alcoholics and cirrhotics, was based on a total of 83 cases and the Danish cohort of cirrhotics was based on a total of 245 cases. In contrast, a cohort study of 5332 Norwegian teetotallers reported a SIR for liver cancer of 0.31. However, this was based on only one observed case (Kjaerheim et al., 1993).

Table 2.23. Cohort studies of liver cancer and alcoholic beverage consumption in special populations.

Table 2.23

Cohort studies of liver cancer and alcoholic beverage consumption in special populations.

(b) General population (Table 2.24)

Table 2.24. Cohort studies of liver cancer and alcoholic beverage consumption.

Table 2.24

Cohort studies of liver cancer and alcoholic beverage consumption.

Two cohort studies have been conducted among the general population since 1988 (Yuan et al., 1997; Wang et al., 2003b). Neither study observed an association between alcoholic beverage consumption and liver cancer. In a study of male residents from communities in Shanghai, Yuan et al. (1997) reported a non-statistically significant reduction in risk among moderate (relative risk 0.68) and heavy (relative risk 0.84) drinkers of alcohol compared with non-drinkers. Similarly, Wang et al. (2003b) found no significant associations with the risk for HCC among drinkers compared with non-drinkers in a study of male residents from Taiwan.

2.5.2. Case–control studies (Table 2.25)

Table 2.25. Case–control studies of liver cancer and alcoholic beverage consumption.

Table 2.25

Case–control studies of liver cancer and alcoholic beverage consumption.

Ten case-control studies published since the last evaluation (IARC, 1988) provide information related to alcoholic beverage consumption and liver cancer: four were conducted in Italy (La Vecchia et al., 1998; Donato et al., 2002; Gelatti et al., 2005; Franceschi et al., 2006), two in the USA (Yuan et al., 2004; Marrero et al., 2005), and one each in Greece (Kuper et al., 2000a), Japan (Tanaka et al., 1992), South Africa (Mohamed et al., 1992) and Spain (Vall Mayans et al., 1990). All of these studies, with the exception of Yuan et al. (2004), used hospital-based controls. Tanaka et al. (1992) used city residents who visited a local public health centre for a routine health examination. Significantly higher relative risks were reported among heavy drinkers compared with non-, light or moderate drinkers in nine studies (Vall Mayans et al., 1990; Mohamed et al., 1992; Tanaka et al., 1992; La Vecchia et al., 1998; Donato et al., 2002; Yuan et al., 2004; Gelatti et al., 2005; Marrero et al., 2005; Franceschi et al., 2006). In these studies, the magnitude of the association ranged from 2.6 for intake of more than 100 g/day compared with 60 g/day or less (Gelatti et al., 2005); to 24.9 for those who consumed more than four drinks per day compared to those who consumed no drinks per day (La Vecchia et al., 1998). Tanaka et al. (1992) found a significant 1.7-fold increase in risk among men whose cumulative alcohol consumption was greater than 76.6 drink–years. No significant associations were observed among women. However, despite the number of studies that have demonstrated evidence of an association between heavy alcoholic beverage consumption and liver cancer, a clear, consistent dose–response relationship between light or moderate drinking and HCC risk has not yet been established.

2.5.3. Meta-analyses (Table 2.26)

Table 2.26. Meta-analyses of liver cancer and alcoholic beverage consumption.

Table 2.26

Meta-analyses of liver cancer and alcoholic beverage consumption.

Two meta-analyses have examined the association between alcoholic beverage consumption and liver cancer. A meta-analysis of 229 studies that evaluated the association between alcohol drinking and risk for cancer included data from 17 case-control and three cohort studies and 2294 cases of HCC. These 20 studies reported a direct trend in risk for HCC with increasing alcoholic beverage consumption. The reported relative risks were 1.17 (95% CI, 1.11–1.23) for consumption of 25 g alcohol per day, 1.36 (95% CI, 1.23–1.51) for 50 g per day and 1.86 (95% CI, 1.53–2.27) for 100 g per day (Bagnardi et al., 2001). An additional review of the Chinese literature included a meta-analysis of 55 case-control studies that investigated the risk factors for primary liver cancer in China. Twenty-two of these 55 studies assessed the effect of exposure to alcohol. A total of 3207 cases of primary liver cancer and 3983 controls were identified (Luo et al., 2005). The combined odds ratio reported from these 22 studies was 1.88 (95% CI, 1.53–2.32) for alcoholic beverage drinkers versus non-drinkers. No information regarding the dose–risk relationship was given. [The Working Group could not determine whether there was possible overlap between the individual cohort and case–control studies listed and the studies included in the meta-analyses conducted by Bagnardi et al. (2001) and Luo et al. (2005), because the individual studies included in the meta-analyses were not identified.]

2.5.4. Interaction with hepatitis viral infection (Table 2.27)

Table 2.27. Selected cohort and case–control studies of liver cancer by alcoholic beverage consumption and infection with hepatitis B virus (HBV) and hepatitic C virus (HCV).

Table 2.27

Selected cohort and case–control studies of liver cancer by alcoholic beverage consumption and infection with hepatitis B virus (HBV) and hepatitic C virus (HCV).

The impact of alcohol on primary liver cancer is difficult to measure because of the existence of other factors, in particular chronic infection with HBV and HCV—which have already been shown to be important determinants for HCC worldwide, and may modify the relationship between alcoholic beverage consumption and liver cancer.

Chronic infections with HBV and HCV have been shown to increase the risk for HCC by approximately 20-fold (Parkin, 2006). Five studies examined the association between alcoholic beverage consumption and the risk for liver cancer among patients with chronic infection with HBV and HCV; one cohort study (Wang et al., 2003b) and four case–control studies (Kuper et al., 2000a; Donato et al., 2002; Yuan et al., 2004; Franceschi et al., 2006). The cohort study reported a relative risk of 13.12 among non-drinkers with chronic HBV infection. Light to moderate drinking and heavy drinking further increased the relative risk to 17.93. All four case-control studies showed an increased risk for HCC with increased alcoholic beverage consumption among subjects infected with HBV or HCV. Three of these studies showed a significant increase in risk. However, the study by Kuper et al. (2000a), based on 333 cases of HCC and 360 controls, did not indicate the same significant trend in increased risk for HCC.

2.5.5. Interaction with tobacco smoking

The interaction between alcoholic beverage consumption and tobacco smoking—another recognized risk factor for HCC (IARC, 2004)—was considered in case-control studies in Greece (Kuper et al., 2000a) and the USA (Yuan et al., 2004; Marrero et al., 2005). In the Greek study (Kuper et al., 2000a), the relative risk was 5.6 (95% CI, 1.70–19.0) for heavy drinkers and heavy smokers compared with never smokers and non- and light drinkers. In a US dataset (Marrero et al., 2005), the relative risk was 7.2 (95% CI, 2.2–14.1) for combined exposure to alcoholic beverages and tobacco compared with cirrhotic subjects. In another US dataset (Yuan et al., 2004), the corresponding relative risk for exposure to both factors was 5.9 (95% CI, 3.3–10.4).

2.6. Breast cancer

Overall, more than 100 epidemiological studies—two thirds case–control and one third cohort—have evaluated the association between the consumption of alcoholic beverages and the risk for breast cancer. In addition, two pooled analyses, the largest of which included data from more than 50 studies, have been conducted. For ease of presentation, the data from the individual studies that were included in this pooled analysis are not presented in Tables 2.28 or 2.29, except for studies that examined detailed exposure effects, such as duration of alcoholic beverage consumption, that were not considered in the pooled analysis.

Table 2.28. Pooled and meta-analyses of femal breast cancer and alcoholic beverage consumption.

Table 2.28

Pooled and meta-analyses of femal breast cancer and alcoholic beverage consumption.

Table 2.29. Cohort studies of breast cancer and alcoholic beverage consumption among special populations.

Table 2.29

Cohort studies of breast cancer and alcoholic beverage consumption among special populations.

2.6.1. Pooled and meta-analyses

The pooling of data from many epidemiological studies permits the use of uniform definitions across studies and reduces the inevitable statistical variability in the findings from one study to another. This is particularly important when the associated risks are relatively small and individual studies lack statistical power. Hamajima et al. (2002) (The Collaborative Group on Hormonal Factors on Breast Cancer) collated and re-analysed individual data from 53 studies on 58 515 women who had breast cancer, which constituted most of the evidence available worldwide at that time. Results from this pooled analysis showed a linear increase in risk for breast cancer with increasing levels of alcoholic beverage consumption, with a relative risk of 1.46 (95% CI, 1.34–1.60) for women who drank ≥ 45 g alcohol per day (median, 58 g per day) compared with non-drinkers. This corresponds to an increase of 7.1% (95% CI, 5.5–8.7%) per 10 g per day (Table 2.28; see Figure 2.1). The results were consistent across studies and between cohort and case–control studies included in the analysis (Figure 2.2).

Figure 2.1. Relative risk for breast cancer in relation to reported alcoholic beverage consumption (adjusted by study, age, parity, age at first birth and tobacco smoking). Pooled analysis of data from 53 studies that included 58 515 women with breast cancer.

Figure 2.1

Relative risk for breast cancer in relation to reported alcoholic beverage consumption (adjusted by study, age, parity, age at first birth and tobacco smoking). Pooled analysis of data from 53 studies that included 58 515 women with breast cancer.

Figure 2.2. Details of and results from studies on the relation between al- cohol consumption and breast cancer. Relative risks are stratified by age, parity, age at first birth and smoking history.

Figure 2.2

Details of and results from studies on the relation between al- cohol consumption and breast cancer. Relative risks are stratified by age, parity, age at first birth and smoking history.

A previous meta-analysis of 38 case–control and cohort studies (Longnecker, 1994), most of which were included in the Collaborative Group analysis, and a pooled analysis of six cohort studies, based on 4330 incident cases of breast cancer (Smith-Warner et al., 1998), reported results consistent with the findings of the Collaborative Group (Hamajima et al., 2002). The latter study showed a 9% increase in risk per 10 g intake of alcohol per day (8% after correction for measurement error), which was adjusted for a wide range of potential confounding factors (Smith-Warner et al., 1998).

2.6.2. Additional cohort studies

Two cohort studies were conducted among women who had a high intake of alco holic beverages; both were conducted in Sweden and reported a significant increase in incidence rates for breast cancer among alcoholics compared with national incidence rates (Sigvardsson et al., 1996; Kuper et al., 2000b) (Table 2.29). However, neither of these studies provided information on individual exposures, or adjusted for potential confounders.

The majority of the 21 additional cohort studies conducted in the general population also showed an increase in risk for breast cancer with increased alcoholic beverage consumption (Table 2.30). The largest of these studies, conducted by the European Prospective Investigation into Cancer and Nutrition (EPIC) and based on 4300 cases, reported a significant 13% increase in risk for breast cancer for intakes of ≥ 20 g alcohol per day, which corresponds to an increase in risk of 3% per 10 g intake of alcohol per day (95% CI, 1–5%) (Tjønneland et al., 2007).

Table 2.30. Cohort and nested case–control studies of breast cancer and alcoholic beverage consumption in the general population.

Table 2.30

Cohort and nested case–control studies of breast cancer and alcoholic beverage consumption in the general population.

2.6.3. Additional case–control studies

The majority of the 35 case–control studies that were not included in the pooled analyses have reported positive associations with increasing alcoholic beverage intake, which were statistically significant in 14 studies (Table 2.31).

Table 2.31. Case–control studies of breast cancer and alcoholic beverage consumption.

Table 2.31

Case–control studies of breast cancer and alcoholic beverage consumption.

2.6.4. Measurements of alcoholic beverage intake

Taken together, all of the results from these studies suggest that low to moderate alcoholic beverage intake (i.e. in the order of one drink per day) is associated with an increased risk for breast cancer, and that the risk increases with increasing intake (Figure 2.1). Hamajima et al. (2002) (The Collaborative Group on Hormonal Factors in Breast Cancer) found a significantly increased risk (relative risk, 1.13; 95% CI, 1.07–1.20) for an intake of 18 g alcohol per day. No single study was large enough to estimate reliably the risk for breast cancer at such low levels of intake.

Several studies have examined the effect of lifetime alcoholic beverage intake by total amount (Freudenheim et al., 1995; Longnecker et al., 1995; Kinney et al., 2000; Gammon et al., 2002) or by 10 g intake of alcohol per day (Longnecker et al., 1995; Smith-Warner et al., 1998; Hamajima et al. 2002; Tjønneland et al., 2003) on the risk for breast cancer. One large case-control study, based on more than 6000 cases, reported an increase in risk of 31% per 13 g intake of alcohol per day (Longnecker et al., 1995). In contrast, the EPIC cohort found no association with lifetime alcoholic beverage intake after adjustment was made for current alcoholic beverage intake (Tjønneland et al., 2007).

Most studies that examined the age at which a woman started to drink in relation to risk for breast cancer reported no association (Freudenheim et al., 1995; Holmberg et al., 1995; Lenz et al., 2002; Horn-Ross et al., 2004; Tjønneland et al., 2004; Lin et al., 2005; Terry et al., 2006; Tjønneland et al., 2007).

One large case-control study found that, among women who had not recently consumed alcoholic beverages, consumption before the age of 30 years was positively associated with risk for breast cancer, which suggests a continuing increased risk with past consumption (Longnecker et al., 1995). Overall, however, there is limited information on the association between cessation of drinking and subsequent risk for breast cancer, and therefore no firm conclusions can be drawn.

2.6.5. Tumour type

Three cohort (Table 2.32) and 12 case-control studies (Table 2.33) examined whether the association between alcoholic beverage intake and risk for breast cancer differed by estrogen receptor (ER) or progesterone receptor (PR) status.

Table 2.32. Cohort studies of alcoholic beverage intake and breast cancer by hormone-receptor status.

Table 2.32

Cohort studies of alcoholic beverage intake and breast cancer by hormone-receptor status.

Table 2.33. Case–control studies of alcoholic beverage intake and breast cancer by hormone-receptor status.

Table 2.33

Case–control studies of alcoholic beverage intake and breast cancer by hormone-receptor status.

Three cohort studies (Potter et al., 1995; Colditz et al., 2004; Suzuki et al., 2005) (see Table 2.32) evaluated the association of alcoholic beverage intake according to receptor status. All three studies reported a significant association between alcoholic beverage consumption and risk for breast cancer for the most common subgroup of ER+ tumours; the small number of cases in the other subgroups may limit the power to detect significant differences between different subgroups of tumours. The Iowa Women's Health Study (Gapstur et al., 1995; Potter et al., 1995; Sellers et al., 2002) reported a higher risk with increasing alcoholic beverage intake for ER–/PR–tumours and the Swedish Mammography Cohort Study found a higher risk for ER+/PR+ and ER+/PR– tumours (Suzuki et al., 2005); both studies found stronger associations for users of hormone replacement therapy compared with non-users, although these were based on small numbers of cases and should be interpreted with caution.

Of the case–control studies, only one reported a stronger association for ER+/PR+ tumours than for ER-/PR- tumours in premenopausal women (relative risks, 1.4 and 0.9, respectively, for >3.5 drinks per week versus non-drinkers), although no significant difference was found in postmenopausal women (Cotterchio et al., 2003).

2.6.6. Types of alcoholic beverage

Results from studies that have looked at the type of alcoholic beverage consumed and risk for breast cancer have suggested an increased risk with increasing alcoholic beverage consumption regardless of the beverage type. Estimates from a pooled analysis of six cohort studies showed risks of 11%, 5% and 5% per 10 g intake of beer, wine and spirits per day, respectively (Smith-Warner et al., 1998), which suggests that the effect is principally due to the presence of alcohol.

2.6.7. Subgroups of women

Evidence of whether the association of alcoholic beverage intake and risk for breast cancer varied by lifestyle and other factors was available in the study of Hamajima et al. (2002) (Collaborative Group on Hormonal Factors in Breast Cancer). This pooled analysis indicated that the association of alcoholic beverages with the risk for breast cancer was not modified by tobacco smoking, age at diagnosis, reproductive factors, having a mother or sister with a history of breast cancer, use of oral contraceptives or use of hormone replacement therapy (see Fig. 2.3).

Figure 2.3. Percentage increase in the relative risk for breast cancer per 10 g of alcoholic beverage consumption per day in various subgroups of women (adjusted by study, age, parity, age at first birth and tobacco smoking).

Figure 2.3

Percentage increase in the relative risk for breast cancer per 10 g of alcoholic beverage consumption per day in various subgroups of women (adjusted by study, age, parity, age at first birth and tobacco smoking). Pooled analysis of data from 53 studies (more...)

2.6.8. Male breast cancer

Overall, one cohort study (Table 2.34) and eight case-control studies (Table 2) have evaluated the association between consumption of alcoholic beverages and the risk for male breast cancer.

Table 2.34. Cohort study of male breast cancer and alcoholic beverage consumption.

Table 2.34

Cohort study of male breast cancer and alcoholic beverage consumption.

Table 2.35. Case–control studies of male breast cancer and alcoholic beverage consumption.

Table 2.35

Case–control studies of male breast cancer and alcoholic beverage consumption.

One cohort study of male alcoholics in Sweden has reported on the relationship with male breast cancer; this study found no difference in the rates of male breast cancer between alcoholics and the general population, based on 13 cases (Weiderpass et al., 2001c; Table 2.34).

Two case–control studies were based on a population of alcoholics as reported from hospital records. One study reported a significant twofold increased risk for alcoholics (Olsson & Ranstam, 1988) and the other found no association (Keller, 1967). [Both studies included small numbers of exposed cases, had a high proportion of cases for whom data were missing and, in Olsson and Ranstam (1988), different risk estimates were produced when different groups of controls were used.] A European case–control study, based on 74 cases, found a sixfold increase in risk in the highest category of alcoholic beverage consumption (>90 g alcohol per day) compared with light drinkers and non-drinkers, corresponding to an increase in risk per 10 g intake of alcohol per day of 17% for beer and wine, but not spirits (Guénel et al., 2004). All other studies have found no association (Mabuchi et al., 1985a; Casagrande et al., 1988; Hsing et al., 1998b; Rosenblatt et al., 1999; Petridou et al., 2000; Johnson et al., 2002).

2.7. Cancer of the stomach

A possible relationship between alcoholic beverage consumption and risk for stomach cancer has long been hypothesized, but epidemiological evidence has been considered uncertain (IARC, 1988). This section evaluates the human evidence related to the risk for stomach cancer based on relevant publications from cohort and case–control studies published since 1988. Because a large proportion of cases of stomach cancer occur in China (accounting for 38% throughout the world), papers published in the Chinese literature are also included in this review.

The effects of total alcoholic beverage consumption on the risk for stomach cancer are summarized in Table 2.36 (cohort studies), Table 2.37 (cohort studies in the Chinese literature), Table 2.38 (case–control studies) and Table 2.39 (case–control studies in the Chinese literature). The effects of alcoholic beverage consumption and risk for stomach cancer by anatomic subtypes (cardia and distal cancer) are shown in Table 2.40, the effects of alcoholic beverage types are presented in Table 2.41 and the effects of alcoholic beverage consumption and the risk for stomach cancer stratified by gender are given in Table 2.42.

Table 2.36. Cohort studies of stomach cancer and alcoholic beverage consumption.

Table 2.36

Cohort studies of stomach cancer and alcoholic beverage consumption.

Table 2.37. Cohort studies of stomach cancer and alcoholic beverage consumption published in the Chinese literaturea.

Table 2.37

Cohort studies of stomach cancer and alcoholic beverage consumption published in the Chinese literaturea.

Table 2.38. Case–control studies of stomach cancer and alcoholic beverage consumption.

Table 2.38

Case–control studies of stomach cancer and alcoholic beverage consumption.

Table 2.39. Case–control studies of stomach cancer and alcoholic beverage consumption in China (published in the Chinese literature).

Table 2.39

Case–control studies of stomach cancer and alcoholic beverage consumption in China (published in the Chinese literature).

Table 2.40. Selected cohort and case–control studies of cancer in subsites of the stomach and intake of alcoholic beverage.

Table 2.40

Selected cohort and case–control studies of cancer in subsites of the stomach and intake of alcoholic beverage.

Table 2.41. Selected cohort and case–control studies of stomach cancer and different types of alcoholic beverage.

Table 2.41

Selected cohort and case–control studies of stomach cancer and different types of alcoholic beverage.

Table 2.42. Cohort and case–control studies of stomach cancer and alcoholic beverage consumption in men and women.

Table 2.42

Cohort and case–control studies of stomach cancer and alcoholic beverage consumption in men and women.

2.7.1. Cohort studies

(a) Special populations (Table 2.36)

In the Danish cohort study of 18 368 alcohol abusers conducted in Copenhagen in 1954–87, 64 cases of stomach cancers occurred during follow-up (Tønnesen et al., 1994). The SIR for stomach cancer was slightly increased and marginally significant (SIR, 1.3; 95% CI, 1.0–1.7). In the Swedish cohort of alcoholics (Adami et al., 1992a), a total of 25 cases resulted in a null association and an SIR of 0.9 (95% CI, 0.6–1.4) for men and 0.7 (95% CI, 0.0–4.0) for women.

(b) General population (Tables 2.36 and 2.37)

A total of 12 cohort studies of the general population that were conducted in Japan, the USA, Sweden, China, Denmark and the United Kingdom have examined the association between alcoholic beverage consumption and stomach cancer; three studies reported a significant association. Two cohort studies reported a statistically significant association between alcoholic beverage consumption and the risk for stomach cancer (Kato et al., 1992b; Fan et al., 1996) and one study with a large sample size reported an inverse relationship (Tran et al., 2005). Nine studies reported either a non-statistically significant association or no association.

There was evidence of an association between alcohol consumption and an increased risk stomach cancer in the two cohort studies conducted in Japan (57 cases; Kato et al., 1992b) and China (128 cases; Fan et al., 1996). The relative risks for stomach cancer were 3.05 (95% CI, 1.35–.91) for 50 mL or more alcohol per day (three or more drinks per day) when adjusted for age and gender (Kato et al., 1992b) and 6.28 (95% CI, 1.11–2.97) for men who had a cumulative alcoholic beverage consumption of 500 kg or more (Fan et al., 1996). One cohort study in China with a large sample size (1089 cardia cancer and 363 non-cardia cancer) reported inverse associations with alcoholic beverage consumption, with relative risks of 0.84 (95% CI, 0.72–.97) for cardia cancer and 0.79 (95% CI, 0.61–.02) for non-cardia cancer (Tran et al., 2005). The two studies that reported a positive association (Kato et al., 1992b; Fan et al., 1996) adjusted for age and gender, but it is not clear what confounding factors were adjusted for in the study by .Tran et al.,(2005).

A positive, but not statistically significant, association was observed in five studies (Kono et al., 1987; Kato et al., 1992a; Yuan et al., 1997 Terry et al., 1998; Wang et al., 2005a) and null results were reported in three studies with relatively large sample sizes ranging from 75 to 493 cases (Kneller et al., 1991; Nomura et al., 1995; Murata et al., 1996; Sasazuki et al., 2002).

2.7.2. Case-control studies (Tables 2.38 and 2.39)

Several case-control studies have reported results on the influence of alcoholic beverage consumption on the risk for stomach cancer. More than 50% of the studies reported a positive association between alcoholic beverage consumption and stomach cancer: 60% of the studies that adjusted for confounding factors and 52% of the studies that did not also report a positive association. The proportion of positive associations was 71% in the Chinese literature and 44% in the English literature.

In more than half of the studies, the odds ratios were adjusted for variables such as sex, age, residence, education, diet, socioeconomic status and cigarette smoking. Odds ratios were adjusted for Helicobacter pylori status in one study (Kikuchi et al., 2002). In 25 case-control studies, of which 11 were published in English (Lee et al., 1990; Boeing et al., 1991; Jedrychowski et al., 1993; Falcao et al., 1994; Inoue et al., 1994; Ji et al., 1996; De Stefani et al., 1998a; Zaridze et al., 2000; Munoz et al., 2001; Kikuchi et al., 2002; Shen et al., 2004), an association was found between stomach cancer and alcoholic beverage consumption. The point estimates of adjusted odds ratios for an association between alcoholic beverage consumption and the risk for stomach cancer were between 2.4 and 2.8 for 2–drinks per day.

2.7.3. Anatomic subsite and histological type (Table 2.40)

Among 12 case-control studies of both cardia cancer and distal stomach cancer, eight demonstrated a stronger association for cardia cancer than for distal stomach cancer. In two studies of histological types, the intestinal type seemed to be more strongly associated with alcoholic beverage consumption (Jedrychowski et al., 1993).

(a) Gastric cardia cancer

Prospective cohort studies have reported an association between alcoholic beverage consumption and the risk for adenocarcinoma of the gastric cardia and distal stomach (Sasazuki et al., 2002; Lindblad et al., 2005; Tran et al., 2005). Sasazuki et al. (2002) reported an elevated risk for cardia cancer of all histological types with alcoholic beverage consumption, although the relationship failed to reach significance. Tran et al. (2005) reported inverse associations for cardia and non-cardia cancer with alcoholic beverage consumption. The relative risks were 0.84 (95% CI, 0.72–0.97) for cardia cancer and 0.79 (95% CI, 0.61–1.02) for non-cardia cancer.

Among 12 case–control studies that reported an association between alcoholic beverage consumption and cardia cancer, five studies reported a statistically significant association (Jedrychowski et al., 1993; Kabat et al., 1993; Inoue et al., 1994; Zaridze et al., 2000; Kikuchi et al., 2002). The adjusted odds ratios were between 2.3 and 3.9 for heavy drinkers and a strong dose–response relationship was demonstrated in four of the five studies.

Zaridze et al. (2000) reported that the effect of hard liquor (vodka) consumption was stronger for cancer of the cardia in men. Compared with non-drinkers, the adjusted odds ratios in men were 2.8 (95% CI, 0.9–9.2) for light drinkers, 3.6 (95% CI, 1.1–11.8) for medium drinkers and 3.9 (95% CI, 1.2–10.2) for heavy drinkers.

An elevated risk for cardia cancer was observed among heavy drinkers in two case–control studies, but the results were not statistically significant (Zhang et al., 1996; Wu et al., 2001). Five studies observed no association between alcoholic beverage consumption and cardia cancer (Ji et al., 1996; Gammon et al., 1997; De Stefani et al., 1998a; Ye et al., 1999; Lagergren et al., 2000). In a population-based case–control study of 90 cases of gastric cardia cancer, 260 and 164 cases of intestinal and diffuse types of distal gastric cancer, respectively, results from Ye et al., (1999) showed that intake of alcoholic beverages was not associated with an increased risk for any type of cardia or gastric cancer. In a case–control study in Shanghai, China, Ji et al. (1996) examined the role of alcoholic beverage drinking as a risk factor for carcinoma by anatomic subsite of the stomach. Alcoholic beverage consumption was associated with a moderately excess risk for distal stomach cancer (odds ratio, 1.55; 95% CI, 1.07–2.26), but was not related to the risk for cardia cancer.

(b) Distal stomach cancer

Among 11 studies of distal stomach cancer, six observed a positive association (Jedrychowski et al., 1993; Inoue et al., 1994; Ji et al., 1996; De Stefani et al., 1998a; Zaridze et al., 2000; Kikuchi et al., 2002). The relationship was not as strong as that for cardia cancer, but the dose–response relationship was just as clear.

2.7.4. Type of alcoholic beverage (Table 2.41)

Some investigators considered the role of different types of alcoholic beverage and reported that the consumption of beer, spirits or wine did not affect the incidence of stomach cancer (Hansson et al., 1994; Zhang et al., 1996; Ye et al., 1999; Wu et al., 2001). In northern Italy, where wine was the most frequently consumed alcoholic beverage and accounted for approximately 90% of all alcoholic beverage consumption in the population, D'Avanzo et al. (1994) reported that the risk estimates adjusted for age and sex were 1.1 for light-to-moderate wine drinkers, 1.3 for intermediate drinkers, 1.6 for heavy drinkers and 1.4 for very heavy drinkers (≥8 drinks per day). López-Carrillo et al. (1998) reported an assessment of alcoholic beverage consumption in Mexico, including the popular Mexican liquor tequila, in relation to the incidence of stomach cancer. After adjustment for known risk factors, wine consumption was positively associated with the risk for developing stomach cancer (odds ratio, 2.93; 95% CI, 1.27–6.75) in the highest category of wine consumption, which corresponded to at least 10 glasses of wine per month, with a significant trend (P=0.005).

In a multicentric hospital-based case–control study carried out in Poland, the relative risk for stomach cancer increased as the frequency and amount of vodka drunk increased. People who drank vodka at least once a week had an threefold higher risk compared with non-drinkers (relative risk, 3.06; 95% CI, 1.90–4.95) (Jedrychowski et al., 1993). Alcoholic beverage consumption, particularly that of vodka, was found to increase the risk for gastric cancer in a Russian study (Zaridze et al., 2000). A case–control study that included 331 cases and 622 controls conducted in Montevideo, Uruguay, found that alcoholic beverage consumption (particularly that of hard liquor and beer) was associated with an odds ratio of 2.4 (95% CI, 1.5–3.9), after controlling for the effect of tobacco, vegetables and other types of beverage (De Stefani et al., 1998a). In another multicentric, hospital-based case–control study conducted in Germany, increased consumption of beer showed a positive association with risk whereas increased consumption of wine and liquor showed a significantly negative association (Boeing et al., 1991).

2.7.5. Effect modification (Table 2.42)

Several studies reported on the joint effects of alcoholic beverage consumption and tobacco smoking (Kabat et al., 1993; Hansson et al., 1994; Inoue et al., 1994; Ji et al., 1996; De Stefani et al., 1998a; Zaridze et al., 2000). The results of a case–control study in Nagoya, Japan, showed that the joint effect of drinking and smoking may play an important role in the development of stomach cancer, especially that of cardia cancer (odds ratio, 4.7; 95% CI, 1.1–20.2) (Inoue et al., 1994). However, most studies did not evaluate potential effect modification between alcoholic beverage consumption and tobacco smoking.

When stratified by gender, the results for men were statistically significant while those for women showed similar point estimates but insignificant trends. Kato et al. (1992a) examined the risk for men and women separately in a clinical epidemiological study and observed an increased risk for stomach cancer in daily consumers of alcoholic beverages compared with non-drinkers, but this association was not statistically significant. In a case–control study conducted in Japan, light drinkers showed the lowest risk among both men and women, and heavy drinkers showed the highest risk among men. In other words, the association was J-shaped among men and U-shaped among women (Kikuchi et al., 2002).

2.8. Cancers of the colon and/or rectum

Most of the studies of alcoholic beverage consumption and colorectal cancer included in the previous Monograph (IARC, 1988) were based on information about heavy alcoholic beverage drinkers or alcoholics and persons employed in the brewery industry, or were case-control studies; only five cohort studies were reviewed. Since that time, several additional cohort studies, case–control studies, as well as meta-analyses and a pooling project, representing research from Asia, Australia, Europe, North and South America, have been published. In total, these provide important information on associations of alcoholic beverage consumption and the risk for colorectal cancer overall, risk for specific anatomical sites within the large bowel and relationships with specific alcoholic beverages. In addition, several studies carefully considered potential confounding factors such as sex, age, level of obesity and smoking status, and others also included diet and physical activity. Finally, this large body of evidence allows for international comparisons of the strength and consistency of associations between alcoholic beverage intake and risk for colorectal cancer.

2.8.1. Cohort studies

(a) Special populations (Table 2.43)

Table 2.43. Cohort studies of colon and rectal cancers and alcoholic beverage consumption in special populations.

Table 2.43

Cohort studies of colon and rectal cancers and alcoholic beverage consumption in special populations.

Nine studies examined the risk for colon cancer and eight studies examined the risk for rectal cancer among heavy alcoholic beverage drinkers, alcoholics or brewery workers (Sundby, 1967; Hakulinen et al., 1974; Monson & Lyon, 1975; Adelstein & White, 1976; Dean et al., 1979; Jensen, 1979; Robinette et al., 1979; Schmidt & Popham, 1981; Carstensen et al., 1990).

Among the nine studies on colon cancer, the number of observed deaths or incident cases ranged from three to 82. Six studies showed no evidence of an association. In two studies, there were non-statistically significant elevated risks (relative risk, 1.2–1.3) among brewery workers (Dean et al., 1979, Carstensen et al., 1990).

Among the eight studies of rectal cancer, the number of observed deaths or incident cases ranged from none to 85. While five reported no excess risk for rectal cancer, two found statistically significant 1.6–1.7-fold higher risks for men who had been employed in the brewery industry (Dean et al., 1979; Carstensen et al., 1990). Another study, based on six deaths, reported a non-significant 3.4-fold higher risk for rectal cancer mortality for chronic alcoholic male US veterans compared with US veterans hospitalized for nasopharyngitis (Robinette et al., 1979).

(b) General population (Table 2.44)

Seven studies provided results for colon and rectum combined, and four of these observed no association of alcoholic beverage consumption with mortality from (Garland et al., 1985; Kono et al., 1986) or incidence of (Flood et al., 2002; Sanjoaquin et al., 2004) colorectal cancer. Based on data from the large US Cancer Prevention Study, Thun et al. (1997) reported a non-significant (P=0.06) inverse trend for the relationship between alcoholic beverage intake and the risk for mortality from colorectal cancer in women and no association in men. In a study of residents of a US retirement community, Wu et al. (1987) found a significant 2.4-fold higher risk for colorectal cancer among men, but not among women, who consumed 30 mL alcohol per day. Similarly, in a study of Seventh Day Adventists, the relative risk for colorectal cancer was 2.0 (95% CI, 1.0–4.2) for those who consumed alcoholic beverages at least once a week compared with those who drank alcoholic beverages less than once a week (Singh & Fraser, 1998).

At least 16 prospective cohort studies reported on the relationship between alcoholic beverage intake and the risk for colon cancer in China, Japan, northern Europe, the United Kingdom and the USA. Six studies reported no association (Gordon & Kannel, 1984; Goldbohm et al., 1994; Harnack et al., 2002; Pedersen et al., 2003; Wei et al., 2004; Chen et al., 2005a). In the study of Klatsky et al. (1988), a significant association was observed in women but not in men. Of the nine studies that reported statistically significant positive associations between alcoholic beverage intake and risk for colon cancer, six were conducted in Japanese populations or in American men of Japanese descent (Hirayama, 1989; Chyou et al., 1996; Murata et al., 1996; Otani et al., 2003; Shimizu et al., 2003; Wakai et al., 2005). In these studies, the magnitude of association ranged from 1.4 to 5.4 for the highest compared with the lowest (i.e. none) level of alcoholic beverage intake. In studies in the USA (Su & Arab, 2004; Wei et al., 2004), the magnitude of risk was 1.6–1.7 for intake of approximately 1–2 drinks per day compared with non-drinkers. In the Finnish study of smokers, there was a 3.6-fold higher risk for colon cancer among those who consumed at least two drinks per day compared with those who consumed less than 0.5 drinks per day (Glynn et al., 1996). None of the prospective cohort studies reported significantly lower risks for colon cancer associated with alcoholic beverage intake. Most studies adjusted for the potential confounding effects of age, body-mass index, smoking status and socioeconomic status or education; some also adjusted for physical activity and/or specific dietary factors (as described in detail below).

Fourteen prospective cohort studies assessed associations of alcoholic beverage intake with the risk for rectal cancer. Eight of these found no association (Goldbohm et al., 1994; Glynn et al., 1996, Murata et al., 1996; Harnack et al., 2002; Wei et al., 2004; Chen et al., 2005a; Wakai et al., 2005). Similarly to colon cancer, most of the six studies that showed a positive association between alcoholic beverage consumption and rectal cancer were conducted in Japanese populations or men of Japanese descent (Hirayama, 1989; Chyou et al., 1996; Otani et al., 2003; Shimizu et al., 2003), although one study from the USA (Klatsky et al., 1988) and one from Denmark (Pedersen et al., 2003) also found significantly positive associations. In general, the magnitude of association for rectal cancer was similar to, although slightly lower than, that for colon cancer in most studies.

(c) Meta-analyses (Table 2.45)

Despite the large number of cohort studies that assessed associations of alcoholic beverage consumption with risk for colon and/or rectal cancer and the large sample sizes included in many of them, the available evidence from these studies is limited for several reasons. First, most studies had very few cases (>50) in the highest category of alcoholic beverage intake, which limits the power to obtain precise estimates of modest risks. Second, it is not clear whether associations might differ according to anatomical site within the colon (i.e. proximal versus distal colon) or by type of alcoholic beverage. Third, associations in some studies might be confounded or modified by gender, level of obesity, diet or other lifestyle factors. To address these issues, Cho et al. (2004) conducted a detailed analysis of the relationship between alcoholic beverage consumption and the risk for colorectal cancer using pooled data from eight large cohort studies conducted in Europe or North America. The criteria for study inclusion in the pooling project were: (a) prospective cohort; (b) inclusion of at least 50 cases of colorectal cancer; (c) assessment of long-term dietary intake; (d) a validation study of dietary assessment; and (e) measurement of alcoholic beverage intake. As described in Table 2.45, this analysis included more than 4600 cases among approximately 490 000 men and women, aged 15–107 years at baseline, and reported follow-up rates were between 94 and 100%. In multivariate analyses that adjusted for age, tobacco smoking, body-mass index, education, height, physical activity, family history of colorectal cancer, use of non-steroidal anti-inflammatory drugs, use of multivitamins, energy intake and intake of other dietary factors, the relative risks for colorectal cancer across the five increasing levels of intake were 0.94, 0.97, 1.01, 1.16 and 1.41 (p for trend=0.001) compared with non-drinkers. The strength of the associations did not differ between men and women (relative risks for the highest versus the lowest categories of intake were 1.41 for both). While the risk for colorectal cancer was slightly stronger for wine intake (relative risk, 1.82 for ≥30 g alcohol per day compared with 0 g of alcohol per day) than for beer (relative risk, 1.37) or liquor (relative risk, 1.21), the differences among types of alcoholic beverage were not statistically significant. In addition, associations were not significantly different among anatomical sites (i.e. total colon versus rectum, proximal versus distal colon), and associations of specific beverage types also did not differ by anatomical site. Finally, as described in detail below, only body-mass index appeared to modify significantly the relationship between alcoholic beverage consumption and risk for colorectal cancer in the cohort-pooling project. The interactions of alcoholic beverages with multivitamin use, total folate intake, methionine intake, tobacco smoking and, in postmenopausal women, use of hormone therapy were not statistically significant (P>0.2).

Table 2.45. Meta-analyses of colon, rectal and colorectal cancer and alcoholic beverage consumption.

Table 2.45

Meta-analyses of colon, rectal and colorectal cancer and alcoholic beverage consumption.

Moskal et al. (2007) conducted a large meta-analysis that included 16 prospective cohort studies published between 1990 and 2005. Inclusion criteria for that analysis are shown in Table 2.45. In the meta-analysis, the average relative risk associated with an increase in consumption of 100 g ethanol per week was 1.19 for colorectal cancer, 1.15 for colon cancer and 1.15 for rectal cancer. In general, associations were only slightly stronger for men than for women. There was no consistent pattern of differences in magnitude of associations among Asian, European, or US studies; however, there was evidence of geographical heterogeneity for colon cancer (P=0.003).

2.8.2. Case–control studies (Table 2.46)

Thirty-eight case–control studies have investigated alcoholic beverage consumption and the risk for colon, rectal or colorectal cancer. The total number of cases included ranged from as few as 25 to as many as 1225.

Nine of the 38 studies provided results for colon and rectum combined. Among these, there was no evidence of a statistically significant association in four studies (Higginson, 1966; Wynder et al., 1969; Manousos et al., 1983; Boutron et al., 1995) and a non-significant positive association in three others (Stocks, 1957; Pernu, 1960; Yamada et al., 1997). A strong positive association was found in the study of Munoz et al. (1998) in Argentina where there was a threefold higher risk for colorectal cancer associated with intake of >24 g alcohol per day compared with <24 g alcohol per day. Conversely, Olsen and Kronborg (1993) reported a lower risk for colorectal cancer associated with four or more Kcal of total energy from alcoholic beverage intake compared with 0 Kcal per day (relative risk, 0.4; 95% CI, 0.3–1.0).

Twenty-six case–control studies examined the relationship between alcoholic beverage consumption and the risk for colon cancer specifically. There was no evidence of a significant association in 15 of these (Wynder & Shigematsu, 1967; Graham et al., 1978; Tuyns et al., 1982; Miller et al., 1983; Tajima & Tominaga, 1985; Kune et al., 1987; Ferraroni et al., 1989; Peters et al., 1989; Slattery et al., 1990; Choi & Kahyo, 1991b; Riboli et al., 1991; Gerhardsson de Verdier et al., 1993; Newcomb et al., 1993; Tavani et al., 1998; Ji et al., 2002). One study reported a significant inverse relationship between alcoholic beverage consumption and the risk for colon cancer (Hoshiyama et al., 1993). In one study, a twofold higher risk for colon cancer was observed for >12.9 g alcohol per day in women (95% CI, 0.9–4.5) and no association in men (Potter & McMichael, 1986). In the nine studies that showed a significant positive association, the relative risks ranged from approximately 1.5 to 6.4 for the highest versus the lowest level of alcoholic beverage intake (Williams & Horm, 1977; Pickle et al., 1984; Longnecker, 1990; Hu et al., 1991; Meyer & White, 1993; Le Marchand et al., 1997; Sharpe et al., 2002; Ho et al., 2004; Kim et al., 2004). Overall, there were no consistent differences in associations between the proximal and distal colon among the case–control studies.

At least 28 case-control studies have investigated rectal cancer, 18 of which showed no statistically significant association with alcoholic beverage consumption (Wynder & Shigematsu, 1967; Graham et al., 1978; Tuyns et al., 1982; Manousos et al., 1983; Miller et al., 1983; Pickle et al., 1984; Tajima & Tominaga, 1985; Potter & McMichael, 1986; Kune et al., 1987; Ferraroni et al., 1989; Peters et al., 1989; Riboli et al., 1991; Gerhardsson de Verdier et al., 1993; Hoshiyama et al., 1993; Le Marchand et al., 1997; Tavani et al., 1998; Ji et al., 2002; Kim et al., 2004). In two other studies, the relative risk for heavy versus light drinkers was 1.3 (95% CI, 0.9–1.7) (Murtaugh et al., 2004) and that for current versus never drinkers was 1.5 (95% CI, 0.9–1.9) (Ho et al., 2004). Eight studies showed a positive association (Williams & Horm, 1977; Kabat et al., 1986; Freudenheim et al., 1990; Longnecker, 1990; Choi & Kahyo, 1991b; Hu et al., 1991; Newcomb et al., 1993; Sharpe et al., 2002).

The meta-analysis of Longnecker et al. (1990) included data from 22 case–control studies (Table 2.45). In that analysis, the relative risk for colorectal cancer associated with an intake of 24 g alcohol per day was 1.07 (95% CI, 1.02–1.12). It should be noted that the results for the five cohort studies were stronger (relative risk, 1.3) than those for case–control studies.

2.8.3. Potential confounding

Several studies assessed whether an association between alcoholic beverage consumption and risk for colorectal cancer might be confounded by obesity and/or other lifestyle factors. For heavy alcoholic beverage drinkers and alcoholics, it is reasonable to assume that poor diet in particular could contribute to an apparent association. However, based on studies of alcoholics or men who worked in the brewery industry, there is only limited evidence of an elevated risk for colon or rectal cancer. As noted in the Tables, nearly all of the cohort studies adjusted for sex, age and smoking status, and some included covariates for body-mass index, dietary factors and physical activity. In addition, as described previously, one of the criteria for inclusion of data into the cohort pooling project was available information on diet. This allowed for a detailed assessment of potential confounding by specific dietary factors including total energy, fat, meat, fibre and specific micronutrients. Even after adjustment for all of the dietary factors considered, the association of alcoholic beverage intake with colorectal cancer persisted.

2.8.4. Effect modification

Whether the association between alcoholic beverage consumption and the risk for colorectal cancer is modified by gender or lifestyle factors has been examined in some studies (see Tables 2.442.46 for details). Some data suggest that associations are stronger for men than for women; levels of alcoholic beverage intake are on average higher among men but, in some studies, the number of cases among women with a high alcoholic beverage intake was insufficient to conduct a detailed analysis. Overall, there is little evidence of a meaningful difference in the association of alcoholic beverage intake with risk for colorectal cancer between men and women.

Table 2.44. Cohort studies of colon and rectal cancer and alcoholic beverage consumption.

Table 2.44

Cohort studies of colon and rectal cancer and alcoholic beverage consumption.

Table 2.46. Case–control studies of colon and rectal cancer and alcoholic beverage consumption.

Table 2.46

Case–control studies of colon and rectal cancer and alcoholic beverage consumption.

A few studies examined effect modification by cigarette smoking. In one cohort study, the association of alcoholic beverage consumption with the risk for colorectal cancer was observed only among nonsmokers (Flood et al., 2002). However, at least three other cohort studies (Murata et al., 1996; Otani et al., 2003; Pedersen et al., 2003) and two case–control studies (Tavani et al., 1998; Ji et al., 2002) failed to demonstrate any significant effect modification by smoking.

There is growing interest in the potential effect modification of folate intake. Freudenheim et al. (1991) found a nearly fivefold higher risk for rectal cancer among men with a high alcoholic beverage/low folate intake compared with men with a low alcoholic beverage/high folate intake. Subsequently, these findings were supported by those of Giovannucci et al. (1995) who found no elevated risk for colon cancer associated with high alcoholic beverage intake among men with high folate intake. However, data from at least two other cohort studies (Flood et al., 2002; Harnack et al., 2002) failed to support a significant interaction between alcoholic beverage and folate intake. In many studies, the power to detect significant interactions might have been limited. Therefore, the modifying effects of folate on alcoholic beverages were also examined in the large cohort pooling project. While not statistically significant (P>0.2), the results indicated a slightly stronger association of alcoholic beverage consumption with colorectal cancer for those with low folate intake and essentially no association for those with high folate intake.

Whether the degree of obesity modifies the relationship between alcoholic beverage consumption and risk for colorectal cancer remains unclear since few studies to date have had adequate power to consider this interaction carefully. In the cohort pooling project, the positive association with alcohol consumption was slightly stronger in leaner individuals than in heavier individuals; the relative risk associated with >30 g ethanol per day compared with 0 g ethanol per day was 1.84 for persons whose body-mass index was <22 kg/m2 but 1.08 for persons with a body-mass index of >25 kg/m2(p for interaction=0.03).

2.8.5. Conclusion

In summary, there is little evidence of a higher than expected risk for colon or rectal cancer among heavy alcoholic beverage drinkers, alcoholics or brewery workers. However, a large body of evidence from prospective cohort studies reported a statistically significant positive association between alcoholic beverage intake and the risk for colon, rectal or colorectal cancer, and no study reported a significant inverse association. These findings are supported by those of a large cohort pooling project and a recent meta-analysis of cohort studies. Although the evidence from individual case–control studies is less consistent, a meta-analysis of 22 case–control studies also supported a positive association. In contrast, two individual case–control studies found an inverse association. The positive association of alcoholic beverage consumption with risk for colorectal cancer does not appear to be confounded by other lifestyle or socio-demographic factors, since most large cohort and case–control studies adjusted for the potential confounding effects of gender, race/ethnicity, age, body-mass index, smoking status and socioeconomic status or education; some of these also adjusted for physical activity and/or specific dietary factors.

Based on data from the pooling project and the most recent meta-analysis of prospective cohort studies, the strength of association appears to be modest with a relative risk of 1.4 for an intake of ≥45 g alcohol per day compared with 0 g per day. However, there is uncertainty regarding the dose–response relationship.

The association between alcoholic beverage consumption and the risk for colorectal cancer does not appear to vary according to anatomical site within the large bowel or type of alcoholic beverage. Similarly, based on the available information, there is no consistent evidence of effect modification by gender or smoking status. Whether degree of obesity or dietary factors such as folate intake modify the relationship is unclear, since only a few studies have examined these interactions.

2.9. Cancer of the pancreas

2.9.1. Cohort studies

(a) Special populations (Table 2.47)

Table 2.47. Cohort studies of pancreatic cancer in special populations.

Table 2.47

Cohort studies of pancreatic cancer in special populations.

Ten cohort studies of men and women with a high alcoholic beverage intake (i.e. among alcoholics or brewery workers) have reported on the risk for pancreatic cancer. Four studies (Carstensen et al., 1990; Tønnesen et al., 1994; Sigvardsson et al., 1996; Karlson et al., 1997) found a significant excess risk among heavy alcoholic beverage drinkers compared with the national population, although all of these studies were based on small numbers of cases (i.e. <50). One study of men employed in a brewery in Sweden (and who were allowed a ration of 1 L of beer per day) and who were followed-up for nearly 20 years reported a significant excess rate of pancreatic cancer. The authors noted that a large reduction in the number of breweries occurred during the follow-up period (1960–80), and that potential is classification of exposure is probable (Carstensen et al., 1990). Three cohort studies of alcoholics in Sweden and Denmark also reported significant excess rates of pancreatic cancer compared with national incidence rates (Tønnesen et al., 1994; Sigvardsson et al., 1996; Ye et al., 2002), matched by age, sex and calendar time.

None of these studies provided individual exposure data and thus dose-response relationships could not be examined and potential confounding factors such as cigarette smoking could not be taken into account. Finally, it must be noted that high alcoholic beverage consumption may induce chronic pancreatitis, a known risk factor for pancreatic cancer. One study based on hospital discharge records in Sweden found that the rate of pancreatic cancer among patients with pancreatitis associated with alcoholism was higher than that among the national population, but similar to the rates found among patients with chronic or recurrent pancreatitis as a whole (Karlson et al., 1997).

(b) General population (Table 2.48)

Table 2.48. Cohort/nested case–control studies of pancreatic cancer and alcoholic beverage consumption in the general population.

Table 2.48

Cohort/nested case–control studies of pancreatic cancer and alcoholic beverage consumption in the general population.

Twelve cohort studies examined alcoholic beverage consumption and the subsequent risk for pancreatic cancer in the general population. Three studies reported a significant excess risk with increased alcoholic beverage intake (Klatsky et al., 1981; Heuch et al., 1983; Zheng et al., 1993). An early report from the Kaiser-Permanente study found a significantly increased risk for men and women who drank >6 drinks per day compared with non-drinkers (Klatsky et al., 1981), although this was not confirmed in a subsequent follow-up (Hiatt et al., 1988; Friedman & van den Eeden, 1993). Another study reported an excess risk among those with a frequent intake (i.e. >14 times per month) compared with none or very limited use (Heuch et al., 1983). [Data on smoking history were only available for a subsample of the cohort (∼5000 men) and this relative risk estimate was therefore based on small numbers. Further, the excess risk appeared to be weaker among cases without histological confirmation, which suggests that some selection bias may have occurred.] A cohort study conducted among the Lutheran Brotherhood in the USA also reported a significant threefold excess risk for death from pancreatic cancer among men who drank 10 or more times per month compared with never drinkers after adjustment for age and smoking, based on 57 deaths (Zheng et al., 1993).

The majority of the studies, most of which were conducted in the USA and Japan among populations with low to moderate alcoholic beverage intake, have not found a significant association between alcoholic beverage intake and pancreatic cancer. One cohort study in Japan reported a significant excess risk among former drinkers compared with never drinkers (Inoue et al., 2003), which was seen in both men and women. [Former drinkers may have ceased drinking because they are ill, causing a spuriously high relative risk in this category.]

All of these cohort studies adjusted for cigarette smoking, and some incorporated adjustments for other potential confounders such as diet, diabetes and family history. However, where crude and multivariate data were presented together, adjustment for these factors appeared to make little difference to the estimates for alcoholic beverage intake.

There are very limited data on the effect of duration of alcoholic beverage drinking or cessation of drinking on the risk for pancreatic cancer; those studies that have reported risks for former drinkers compared with never drinkers have shown highly inconsistent results.

2.9.2. Case–control studies (Table 2.49)

Twenty-nine case–control studies have published quantitative data on the association of alcoholic beverage intake and the risk for pancreatic cancer. Most studies found no association (see Table 2.49). Several studies suggested that heavy alcoholic beverage consumption (≥15 drinks/week) may be associated with an increased risk for pancreatic cancer (Falk et al., 1988; Cuzick & Babiker, 1989; Ferraroni et al., 1989; Olsen et al., 1989; Silverman, 2001). Other studies have reported significant reductions in risk with increasing alcoholic beverage intake (Gold et al., 1985; Baghurst et al., 1991; Talamini et al., 1999).

Table 2.49. Case–control studies of pancreatic cancer and alcoholic beverage consumption.

Table 2.49

Case–control studies of pancreatic cancer and alcoholic beverage consumption.

There is no consistent evidence that intake of any specific type of beverage is associated with risk for pancreatic cancer.

The difference in findings may be partly due to differences in study design. In many of these case–control studies, a large proportion of cases were deceased, which resulted in interviews being conducted among the next of kin. Although some studies suggest that spouse proxies give reasonable estimates of alcoholic beverage intake, many interviews were conducted with a child, friend or other relative, which may result in substantial exposure misclassification and/or recall bias. Further, studies that only included cases that were histologically verified may not be representative of all cases and may lead to bias if high alcoholic beverage intake is associated with reduced access to medical care. In addition, selection bias due to low response rates, possible confounding by tobacco smoking, failure to exclude controls who had tobacco- and alcohol-related diseases and chance findings as a result of small sample size may also contribute to these discrepant results.

2.10. Cancer of the lung

A possible link between alcoholic beverage consumption and the risk for lung cancer has long been speculated; however, epidemiological evidence has been considered to be inconclusive. The data available to the previous lARC Working Group (IARC, 1988) did not allow the conclusion that the association between consumption of alcoholic beverages and lung cancer was causal.

Lung cancer is the most common and fatal cancer in the world. The major cause of lung cancer is tobacco smoking, to which 80–90% of cases are attributable. A high correlation has been identified between use of tobacco and consumption of alcohol in many populations. As such, careful adjustment for smoking is one of the most important requirements for a valid interpretation of the effects of alcohol.

Factors important for causal inference, such as strength of the association, dose–response relationship, histological types, types of alcoholic beverage, and potential confounding by and interactions with tobacco smoking are considered here. The risks for lung cancer in relation to total alcoholic beverage consumption are summarized in Tables 2.502.52; the effects of alcoholic beverage consumption and the risk for lung cancer by histological types are presented in Tables 2.53 and 2.54; the effects of types of alcoholic beverage are presented in Tables 2.552.60; the combined or joint effects or effect modification of alcoholic beverage consumption and tobacco smoking are shown in Tables 2.61 and 2.62; the relationships between alcoholic beverage consumption and the risk for lung cancer among nonsmokers are shown in Tables 2.63 and 2.64.

Table 2.50. Cohort studies of total alcoholic beverage consumption and lung cancer in special populations.

Table 2.50

Cohort studies of total alcoholic beverage consumption and lung cancer in special populations.

Table 2.52. Case–control studies of total alcoholic beverage consumption and lung cancer risk in the general population.

Table 2.52

Case–control studies of total alcoholic beverage consumption and lung cancer risk in the general population.

Table 2.53. Cohort studies of alcoholic beverage consumption and lung cancer by histological type.

Table 2.53

Cohort studies of alcoholic beverage consumption and lung cancer by histological type.

Table 2.54. Case–control studies of alcoholic beverage consumption and lung cancer by histological type.

Table 2.54

Case–control studies of alcoholic beverage consumption and lung cancer by histological type.

Table 2.55. Cohort studies of beer consumption and lung cancer.

Table 2.55

Cohort studies of beer consumption and lung cancer.

Table 2.60. Case–control studies of liquor consumption and lung cancer.

Table 2.60

Case–control studies of liquor consumption and lung cancer.

Table 2.61. Cohort studies of alcoholic beverage consumption and lung cancer stratified by smoking status.

Table 2.61

Cohort studies of alcoholic beverage consumption and lung cancer stratified by smoking status.

Table 2.62. Case–control studies of alcoholic beverage consumption and lung cancer stratified by smoking status.

Table 2.62

Case–control studies of alcoholic beverage consumption and lung cancer stratified by smoking status.

Table 2.63. Cohort studies of alcoholic beverage consumption and lung cancer among nonsmokers.

Table 2.63

Cohort studies of alcoholic beverage consumption and lung cancer among nonsmokers.

Table 2.64. Case–control studies of alcoholic beverage consumption and lung cancer among nonsmokers.

Table 2.64

Case–control studies of alcoholic beverage consumption and lung cancer among nonsmokers.

Table 2.51. Cohort studies of total alcoholic beverage consumption and lung cancer in the general population.

Table 2.51

Cohort studies of total alcoholic beverage consumption and lung cancer in the general population.

2.10.1. Total alcoholic beverage consumption

(a) Cohort studies of special populations (Table 2.50)

All six studies based on cohorts of alcoholics—populations that have excessive alcoholic beverage intake—reported elevated mortality from lung cancer (Schmidt & Popham, 1981; Adami et al., 1992a; Tønnesen et al., 1994; Sigvardsson et al., 1996; Sørensen et al., 1998; Boffetta et al., 2001). However, due to the lack of control for tobacco smoking in all studies, the possibility that the observed association might be largely explained by the confounding effect of tobacco smoking can not be ruled out.

(b) Cohort studies of the general population (Table 2.51)

Among 20 cohort studies of the general population that provided tobacco smoking-adjusted risk estimates for total alcoholic beverage use, 10 reported an elevated risk for lung cancer associated with alcoholic beverage consumption, although it was seldom significant. Of the studies that examined high levels of alcoholic beverage intake (≥3 or ≥5 drinks/day), some reported elevated risks that became statistically significant at the highest category of alcoholic beverage consumption, all in men (Prescott et al., 1999; Lu et al., 2000a; Balder et al., 2005). Studies that used low drinking levels (e.g. 1–2 drinks/day) as the highest category did not find a significant association between these relatively low exposures and risk for lung cancer (Kono et al., 1986; Stemmermann et al., 1990; Breslow et al., 2000; Freudenheim et al., 2005).

Most cohort studies that reported a positive association also demonstrated a significant dose-response relationship. Other studies observed no association between alcoholic beverages and the risk for lung cancer at the highest level of consumption for both genders (Korte et al., 2002 [Cancer Prevention Study, II]; Nishino et al., 2006; Rohrmann et al., 2006) and in women (Prescott et al., 1999).

A meta-analysis (Korte et al., 2002) found a significantly increased risk for lung cancer with an ethanol intake of at least 2000 g per month (≥5 drinks/day): the weighted odds ratio from case–control studies was 1.5 (95% CI, 1.0–2.3) and the weighted relative risk from cohort studies was 1.4 (95% CI, 1.2–1.6). [The weighted odds ratio for case–control studies was based on only one study and the relative risk for cohort studies on only three studies. These results should therefore be interpreted with some caution.]

It should be noted that most studies examined the effects of recent drinking patterns (case–control studies) or of the drinking patterns at baseline (cohort studies). The exposure studied most extensively was the frequency of drinking. Other parameters of exposure to alcoholic beverages, such as duration and age at initiation of drinking and the relevant exposure period, were not reported.

(c) Case-control studies (Table 2.52)

Twenty-one case–control studies reported tobacco smoking-adjusted odds ratios for total alcoholic beverage consumption and the risk for lung cancer. Four of the seven population-based studies (Carpenter et al., 1998; Hu et al., 2002; Freudenheim et al., 2003; Benedetti et al., 2006) reported no significant association between any level of alcoholic beverage consumption examined and the risk for lung cancer. However, most of them used categories that reflected a relatively low level of drinking (e.g. 1 drink/day or less often; highest level of drinking, >2 drinks per day, but the median frequency for this category was unclear). Three hospital-based studies (De Stefani et al., 1993; Dosemeci et al., 1997; Rachtan, 2002) that used non-drinkers as the baseline comparison group found a significant association between consumption of more than one drink per day and the risk for lung cancer. Dosemeci et al. (1997) found an elevated risk for lung cancer and a dose-response with increasing frequency of consumption, duration of drinking and cumulative measures in bottle-years. One hospital-based study (Zang & Wynder, 2001) did not find an association for cumulative alcoholic beverage intake (frequency×duration), or for ≥7 oz of ‘whiskey-equivalents’ of alcohol per day [approximately ≥68 g of ethanol per day] (odds ratio, 1.1; 95% CI, 1.0–1.4). [The Working Group noted that the baseline comparison group in this study included people who consumed less than one alcoholic beverage per day.] De Stefani et al. (2002) also reported a null association for adenocarcinoma of the lung.

In addition, among nine case–control studies of lung cancer published in the Chinese literature, five adjusted for or stratified by tobacco smoking. Five studies reported a positive association between alcoholic beverage consumption and the risk for lung cancer and point estimates that ranged from 1.5 to 6.6 but none reported the levels of consumption.

2.10.2. Histological type (Tables 2.53 and 2.54)

Two cohort studies, one pooled analysis and seven case–control studies presented smoking-adjusted risk estimates for alcoholic beverages by histological type of lung cancer. There appears to be no consistent pattern for the effect estimates of alcoholic beverages on the main lung cancer types: squamous-cell carcinoma, adenocarcinoma and small-cell lung cancer (Tables 2.53 and 2.54). A positive association with squamous-cell carcinoma was reported in three case–control studies (Dosemeci et al., 1997; Zang & Wynder, 2001; Rachtan, 2002). A positive relationship between alcoholic beverage consumption and adenocarcinoma was reported in four case–control studies (Carpenter et al., 1998; Zang & Wynder, 2001 [lifetime exposure]; Rachtan, 2002; Benedetti et al., 2006 [only in men]). In a study in which only the cases of adenocarcinoma were included (De Stefani et al., 2002), no association was observed between alcoholic beverage consumption and this histological type, despite the large number of cases.

In a pooled analysis of seven cohort studies (Freudenheim et al., 2005), some association was found for adenocarcinoma and small-cell lung cancer among men, and for adenocarcinoma among women. In a more recent study that was not included in the pooled analysis (Rohrmann et al., 2006), virtually no association was observed for any lung cancer type among both men and women. [Estimates for lung cancer subtype were mostly based on small numbers of cases, which leads to difficulties in interpreting results due to wide confidence intervals and the possibility of chance findings.] Currently available data do not provide any conclusive evidence for the risk of alcoholic beverage intake on lung cancer subtype.

2.10.3. Types of alcoholic beverage

Findings from studies examining risk estimates for the consumption of different types of alcoholic beverages (i.e. beer, wine, and hard liquor) indicate that they may have different effects on lung cancer risk.

(a) Beer (Tables 2.55 and 2.56)

Among the six cohort studies that examined the effects of beer drinking on risk for lung cancer, two found a positive association for drinking one serving of beer per day in women (Potter et al., 1992) or two or more servings per day in men (Prescott et al., 1999) (Table 2.55). In the latter study, the point estimate for women was of similar magnitude as that in men (relative risk, 1.4 for men and 1.5 for women), but the confidence interval was wide (95% CI, 0.7–3.1).

In a pooled analysis that combined data from seven prospective cohort studies (Freudenheim et al., 2005), a positive association with a significant dose-reponse relationship was found between beer drinking and the risk for lung cancer among women, but not among men. The risk almost doubled for women who consumed >15 g ethanol from beer per day (approximately ≥1 beer per day; odds ratio, 1.9; 95% CI, 1.5–2.4), but the relative risk was 0.8 (95% CI, 0.6–0.9) for those with the lowest level of beer consumption (<5 g ethanol/day). A null association was reported in three studies (Pollack et al., 1984; Chow et al., 1992; Woodson et al., 1999), all of which were restricted to men. Chow et al. (1992) reported a relative risk of 1.7 (95% CI, 1.0–2.9) for drinking beer 6–13 times per month, and of 1.1 (95% CI, 0.6–1.9) for drinking beer more than 13 times per month.

Among 11 case–control studies that presented tobacco smoking-adjusted odds ratios for beer drinking compared with non-drinkers, three reported a positive association for the highest level of beer drinking used in the analyses (Bandera et al., 1992; De Stefani et al., 1993; Benedetti et al., 2006, in the first study in men only (Table 2.56).

Table 2.56. Case–control studies of beer consumption and lung cancer.

Table 2.56

Case–control studies of beer consumption and lung cancer.

(b) Wine (Tables 2.57 and 2.58)

Among 10 case–control studies (Table 2.58) that provided tobacco smoking-adjusted risk estimates for wine intake, only one reported a positive association for white wine intake (relative risk, 1.5; 95% CI, 0.5–4.4) but not for red wine or rosé (Ruano-Ravina et al., 2004). In contrast, a significant inverse association was observed between red wine consumption and risk for lung cancer in this study. Six other case–control studies reported odds ratios below 1 for wine consumption, although these were not always statistically significant.

Table 2.58. Case–control studies of wine consumption and lung cancer.

Table 2.58

Case–control studies of wine consumption and lung cancer.

Among the three cohort studies that reported risk estimates for wine drinking (Table 2.57), two reported a significant inverse association in men (Prescott et al., 1999; Woodson et al., 1999 [trend test]). In another study, drinking ≥50 oz of wine per month (approximately ≥10 glasses of wine per month) was associated with a twofold increased risk for lung cancer compared with non-wine drinkers (Pollack et al., 1984).

Table 2.57. Cohort studies of wine consumption and lung cancer.

Table 2.57

Cohort studies of wine consumption and lung cancer.

In a pooled analysis based on seven cohort studies (Freudenheim et al., 2005), an inverse association was detected by the trend test for men, but not for women.

None of the cohort studies reported relative risk estimates adjusted for dietary factors such as vegetable/fruit intake. Confounding by dietary factors may explain to current observations.

(c) Liquor (Tables 2.59 and 2.60)

Two of five cohort studies reported a positive association between liquor drinking and risk for lung cancer, adjusted for tobacco smoking (Table 2.59) (Pollack et al., 1984; Prescott et al., 1999 in men only). The strongest association was identified by Pollack et al. (1984), in which men who consumed ≥1 measure of whiskey per day were found to have a relative risk of 2.6 [95% CI, 1.3–5.0]. Prescott et al. (1999) found a borderline significant 50% increase in risk among men who consumed at least two drinks of liquor per day; no association was observed among women.

Table 2.59. Cohort studies of liquor consumption and lung cancer.

Table 2.59

Cohort studies of liquor consumption and lung cancer.

In a pooled analysis (Freudenheim et al., 2005), a positive association was detected among men who drank one measure of liquor per day or more, with a significant dose–response relationship. No association was observed among women.

Liquor consumption was found to be positively associated with the risk for lung cancer in three (Carpenter et al., 1998; De Stefani et al., 2002; Rachtan, 2002) of 11 case–control studies that reported tobacco smoking-adjusted odds ratio estimates for liquor consumption (Table 2.60). The strongest association was found in the study by Rachtan (2002), in which Polish women who consumed ≥100 g alcohol from liquor per week (approximately one measure per day) had an eightfold greater risk for lung cancer than non-drinking women (95% CI, 2.9–21.2).

2.10.4. Studies stratified by tobacco-smoking status (Tables 2.61 and 2.62)

Studies based on never smokers may be the most valid approach to study the carcinogenicity of alcoholic beverages in the lung. In smokers, tobacco smoking may modify the effect of alcohol consumption and heterogeneity of risk may exist between populations with different smoking patterns. One of the proposed mechanisms for the carcinogenic effect of alcoholic beverages is that they may act as a solvent for tobacco-associated carcinogens. It is therefore important to examine the effect of alcoholic beverage consumption among both never smokers and smokers, and to study the interaction between these two risk factors. Tables 2.61 and 2.62 summarize the results from cohort and case–control studies that presented relative risks for alcoholic beverage use by smoking category.

Results from two cohort studies (Nishino et al., 2006; Rohrmann et al., 2006) did not seem to suggest an interaction between smoking status (never, former and current) and alcoholic beverage consumption, although a p-value for a formal test of interaction was not available. [These analyses may have the limitation that most of the cases of lung cancer were smokers.]

In a pooled analysis (Freudenheim et al., 2005), no obvious interaction was suggested following stratification by smoking status among women. A positive association was only found among male never smokers but not among male former or current smokers, which suggests a heterogeneity of the effect of alcoholic beverages by smoking status in men.

Since most cases of lung cancer are smokers, several cohort and case–control studies examined the effect of alcoholic beverages according to the amount smoked. Woodson et al. (1999) conducted a cohort study with detailed analyses of the effect of alcoholic beverage according to intake by smoking behaviour, characterized by the number of cigarettes per day, duration of smoking, frequency of inhaling and time since quitting. No obvious differences in the relative risks were found across these smoking categories. Most of the case–control studies reported significant positive associations only among smokers or greater risk estimates among heavier smokers than among lighter smokers (Herity et al., 1982; De Stefani et al., 1993; Dosemeci et al., 1997; Zang & Wynder, 2001; Benedetti et al., 2006 [men only]).

2.10.5. Studies among nonsmokers (Tables 2.63 and 2.64)

Residual confounding by tobacco smoking is a concern when interpreting the associations between alcoholic beverage intake and lung cancer. Restricting the analysis to never smokers appears to be an effective strategy to provide further insight on this topic, although secondhand tobacco smoke might still be a concern.

Korte et al. (2002) reported the unpublished data from the Cancer Prevention Study (CPS) I and II (Table 2.63). In CPS I, an increased risk for lung cancer was associated with drinking ≥500 g alcohol per month among both men and women who had never smoked. This association was not observed in CPS II.

A pooled study (Freudenheim et al., 2005), based on seven cohorts, found an elevated pooled relative risk for alcoholic beverage consumption among never-smoking men (a dose–response was also observed), but not among never-smoking women.

Two cohort studies published subsequently reported a null association among never smokers, with adjustment for dietary factors. Both studies examined higher levels of alcoholic beverage drinking than those studied previously (Nishino et al., 2006: ≥50 g of ethanol per day [∼4 drinks/day]; Rohrmann et al., 2006: ≥60 g of ethanol per day [∼5 drinks/day]), although the number of cases at these levels of drinking was small.

Seven case-control studies included never smokers only as the study subjects or stratified analyses to never smokers (Table 2.64). [Analyses stratified to never smokers often suffer from the small number of lung cancer cases that arise among never smokers and result in wide confidence intervals.] In the three studies based on populations of never smokers (Kabat & Wynder, 1984; Koo, 1988; Hu et al., 2002), no significant differences in alcoholic beverage intake were found between cases and controls. [One limitation of such a design is the lack of power to examine the risk associated with heavy drinking, as it is uncommon to find heavy drinkers among never smokers. For example, Hu et al. (2002) compared drinkers of 1 serving/week and >1 serving per week with non-drinkers which reflects the low drinking level in this group of women and which is likely to contribute to the null association observed in this study.] In contrast, Rachtan (2002) identified a significantly elevated risk associated with even a moderate level of alcoholic beverage intake among Polish women who never smoked (e.g. odds ratio, 8.8; 95% CI, 2.8–27.3 for 4–8 g alcohol per week [approximately 0.3–0.6 drinks/week]). A strong dose–response was also observed. [The magnitude of the risk estimates seems unlikely for these levels of alcoholic beverage drinking. This result may represent a chance finding, confounding or population/environmental characteristics that are specific to this study.]

2.10.6. Population characteristics

There are currently no sufficient data to examine whether the effect of alcoholic beverages differ among men and women and among populations of different ethnic origins. Studies that consisted of men only or women only are often not comparable due to the different levels of alcoholic beverage exposure in these studies. A few studies conducted analyses stratified by gender using the same exposure categories (Williams & Horm, 1977; Bandera et al., 1997; Prescott et al., 1999; Korte et al., 2002 [CPS I and CPS II]; Pacella-Norman et al., 2002; Freudenheim et al., 2005; Benedetti et al., 2006; Rohrmann et al., 2006). There was no obvious heterogeneity between genders based on results of total alcoholic beverage consumption and risk for lung cancer. However, heterogeneity may exist when level of smoking, type of alcoholic beverage and histological type of lung cancer are considered.

2.11. Cancer of the urinary bladder

Information on alcoholic beverage consumption and cancer of the urinary bladder was derived from five cohort (Table 2.65) and 18 case–control (Table 2.66) studies, which included more than 9000 cases in total.

Table 2.65. Cohort studies of alcoholic beverage consumption and cancer of the urinary bladder.

Table 2.65

Cohort studies of alcoholic beverage consumption and cancer of the urinary bladder.

Table 2.66. Case–control studies of alcoholic beverage consumption and cancer of the urinary bladder.

Table 2.66

Case–control studies of alcoholic beverage consumption and cancer of the urinary bladder.

Of the five cohort studies, one investigation in the Netherlands (Zeegers et al., 2001) found a relative risk of 1.6 in men who drank ≥30 g ethanol per day, but no trend in risk with dose. The corresponding value for women was 1.0. The other cohort studies, one among Danish brewery workers (Jensen, 1979) and three from selected populations in the USA (Mills et al., 1991; Chyou et al., 1993; Djoussé et al., 2004) found no association between various measures of alcoholic beverage consumption and risk for cancer of the urinary bladder.

In a multicentre case-control study conducted in 1978–79 in 10 areas of the USA (Thomas et al., 1983), which included 2982 incident cases, no association was found between urinary bladder cancer and total alcoholic beverage consumption (relative risk for ≥42 drinks per week, 0.99 in men and 0.66 in women) or consumption of beer (relative risk, 0.93 in both sexes combined), wine (relative risk, 0.60) or spirits (relative risk, 1.14). Of the subsequent case–control studies, nine showed some excess risk in (heavy) alcoholic beverage drinkers and eight showed no association. Moreover, the largest studies, conducted in Canada on 1125 cases (Band et al., 2005) and in Italy on 727 cases (Pelucchi et al., 2002a), also showed no association between various measures of alcoholic beverage consumption and risk for cancer of the urinary bladder.

An explanation for some apparently inconsistent epidemiological findings on alcoholic beverage consumption and cancer of the urinary bladder is that there are different correlates (including tobacco, coffee and diet) of alcoholic beverage drinking in various populations. Alcoholic beverage drinking, in part, may be positively correlated with cigarette smoking, a poorer diet or other recognized risk factors (i.e. social or occupational) for bladder cancer. Thus, residual confounding is possible.

A meta-analysis of 11 studies (two cohort and nine case–control) published between 1966 and 2000 (Bagnardi et al., 2001), which included a total of 5997 cases, found relative risks of 1.04 (95% CI, 0.99–1.09) for 25 g, 1.08 (95% CI, 0.98–1.19) for 50 g and 1.17 (95% CI, 0.97–1.41) for 100 g ethanol per day.

Given the likelihood of residual confounding and the absence of an association in large studies, there is no clear pattern of association between total alcoholic beverage consumption or consumption of various types of alcoholic beverage and the risk for cancer of the urinary bladder.

2.12. Cancer of the endometrium

2.12.1. Cohort studies (Tables 2.67 and 2.68)

Since 1988, three prospective cohort studies have examined the association between alcoholic beverage intake and the risk for endometrial cancer in special populations, namely women hospitalized or being treated for alcohol dependence (Adami et al., 1992a; Tønnesen et al., 1994, Sigvardsson et al., 1996; Weiderpass et al., 2001a; Table 2.67) and three have studied the association in the general population (Gapstur et al., 1993; Terry et al., 1999; Jain et al., 2000b; Folsom et al., 2003; Table 2.68) (see the Tables for overlapping study populations).

Table 2.67. Cohort studies of alcoholic beverage consumption and endometrial cancer in special populations.

Table 2.67

Cohort studies of alcoholic beverage consumption and endometrial cancer in special populations.

Table 2.68. Cohort studies of alcoholic beverage consumption and endometrial cancer in general populations.

Table 2.68

Cohort studies of alcoholic beverage consumption and endometrial cancer in general populations.

These studies were conducted in North America (Gapstur et al., 1993; Jain et al., 2000b; Folsom et al., 2003) and in Scandinavia (Adami et al., 1992a; Tønnesen et al., 1994; Sigvardsson et al., 1996; Terry et al., 1999; Weiderpass et al., 2001a).

Three studies (Gapstur et al., 1993, Terry et al., 1999; Jain et al., 2000b) presented risk estimates adjusted for multiple possible confounders (body size and reproductive factors), while only one (Jain et al., 2000b) adjusted the analysis of alcoholic beverages for smoking (ever/never). Smoking showed a non-significant protective effect in all of these studies.

In one study among alcoholics (Weiderpass et al., 2001a), there was an inverse association between alcoholic beverage consumption and endometrial cancer, but the analytical models did not include important covariates that may have confounded the association, such as cigarette smoking and body size. In the two other studies among alcohol-dependent populations, there was no evidence of an association. There was no evidence of an association between alcoholic beverage intake and the risk for endometrial cancer in the three cohort studies conducted in the general population (Gapstur et al., 1993; Terry et al., 1999; Jain et al., 2000b).

2.12.2. Case-control studies (Table 2.69)

Table 2.69. Case–control studies of alcoholic beverage consumption and endometrial cancer.

Table 2.69

Case–control studies of alcoholic beverage consumption and endometrial cancer.

Case–control studies that have investigated the relationship between alcoholic beverage consumption and the risk for endometrial cancer were carried out in Japan, North America and Europe.

Seven of these were hospital-based, particularly studies from southern Europe (La Vecchia et al., 1986; Shu et al., 1991; Austin et al., 1993; Levi et al., 1993; Parazzini et al., 1995a; Kalandidi et al., 1996; Petridou et al., 2002), two were based on cases and controls who were included in a cancer survey or registry database (Williams & Horm, 1977; Kato et al., 1989) and eight were population-based (Cusimano et al., 1989b; Webster et al., 1989; Swanson et al., 1993; Goodman et al., 1997b; Newcomb et al., 1997; Jain et al., 2000c; McCann et al., 2000; Weiderpass & Baron, 2001).

Ten studies (Cusimano et al., 1989b; Kato et al., 1989; Webster et al., 1989; Austin et al., 1993; Swanson et al., 1993; Parazzini et al., 1995a; Kalandidi et al., 1996; Newcomb et al., 1997; Weiderpass & Baron, 2001; Petridou et al., 2002) were designed to examine the association between alcoholic beverage intake, other lifestyle factors such as cigarette smoking, use of hormone-replacement therapy and other risk factors in the etiology of endometrial cancer. Six studies (La Vecchia et al., 1986; Shu et al., 1991; Levi et al., 1993; Goodman et al., 1997b; Jain et al., 2000c; McCann et al., 2000) were designed to evaluate nutritional factors in relation to the risk for endometrial cancer.

Confounding factors were considered in all of the above studies except for one (Cusimano et al., 1989b), although adjustment may have been incomplete in three studies (Williams & Horm, 1977 [age, race and smoking]; Shu et al., 1991 [pregnancies and weight]; Levi et al., 1993 [only adjusted for age and centre]). Interviews were conducted with or questionnaires were completed by the subjects in all studies.

The results of case–control studies were not consistent. Ten reported little or no association between alcoholic beverage consumption and the risk for endometrial cancer (Kato et al., 1989; Webster et al., 1989; Austin et al., 1993; Swanson et al., 1993; Kalandidi et al., 1996; Goodman et al., 1997b; Newcomb et al., 1997; McCann et al., 2000; Weiderpass & Baron, 2001; Petridou et al., 2002). Two found an inverse association (Williams & Horm, 1977; Jain et al., 2000c), which was significant in the latter study. Four studies reported an increased risk for endometrial cancer with higher alcoholic beverage consumption (La Vecchia et al., 1986; Cusimano et al., 1989b; Shu et al., 1991; Levi et al., 1993; Parazzini et al., 1995a); in two of these, the association was non-significant (Cusimano et al., 1989b; Shu et al., 1991), in one it was significant with a positive trend analysis (Parazzini et al., 1995a) and one (Levi et al., 1993) found a positive association relative to wine and liquor, but not to beer.

2.12.3. Evidence of a dose–response

There was no evidence of a trend of increasing risk for endometrial cancer with increasing alcoholic beverage consumption in the cohort studies.

In the case–control studies, there was no dose-response association between alcoholic beverage consumption and the risk for endometrial cancer in most studies. One study (Jain et al., 2000c) presented a negative dose-response association and one report showed a clear dose-response trend (Parazzini et al., 1995a). In another study, there was an indication of a dose-response in the association but no formal test for trend was presented (Webster et al., 1989).

2.12.4. Types of alcoholic beverage

Only one cohort study investigated the effect of specific types of alcoholic beverage (beer, wine, spirits) on the risk for endometrial cancer (Gapstur et al., 1993) and found no evidence of any association.

Seven case-control studies evaluated different alcoholic beverages in relation to risk for endometrial cancer (Williams & Horm, 1977; Austin et al., 1993; Levi et al., 1993; Swanson et al., 1993; Parazzini et al., 1995a; Goodman et al., 1997b; Weiderpass & Baron, 2001). The studies by Levi et al. (1993) and Parazzini et al. (1995a) showed an increased risk for endometrial cancer with increasing consumption of wine and hard liquor, but not beer. Overall, there were no consistent patterns of association between any specific type of alcoholic beverage and risk for endometrial cancer.

2.12.5. Interactions

Few studies presented information on possible interactions between alcoholic beverage intake and other variables. One cohort study investigated alcohol as an interacting factor with hormone-replacement therapy (Beral et al., 2005). A positive association was found for Tibolone and an inverse association for continuous combined hormone-replacement therapy among women who consumed less than one drink daily.

Among the case-control studies, there was no consistent evidence of an interaction between alcoholic beverage consumption and different variables known or suspected to be associated with endometrial cancer, such as use of hormone-replacement therapy, body size, age, tobacco smoking, parity, education, physical activity, calory intake and other dietary aspects, oral contraceptive use or menopausal status.

2.13. Cancer of the ovary

2.13.1. Cohort studies (Tables 2.70 and 2.71)

Since 1988, four prospective cohort studies have examined the association between alcoholic beverage intake and the risk for ovarian cancer in special populations, namely women hospitalized or being treated for alcohol dependence (Adami et al., 1992a; Tønnesen et al., 1994, Sigvardsson et al., 1996; Lagiou et al., 2001; Table 2.70) and four have examined the association in the general population (Kushi et al., 1999; Kelemen et al., 2004; Schouten et al., 2004; Chang et al., 2007; Table 2.71). The studies were conducted in Europe (Denmark, the Netherlands and Sweden) and the USA. The studies in special populations presented results adjusted for age and calendar period only, whereas the population-based cohort studies presented results adjusted for a large variety of factors.

Table 2.70. Cohort studies of ovarian cancer and alcoholic beverage consumption in special populations.

Table 2.70

Cohort studies of ovarian cancer and alcoholic beverage consumption in special populations.

Table 2.71. Cohort studies of ovarian cancer and alcoholic beverage consumption in the general population.

Table 2.71

Cohort studies of ovarian cancer and alcoholic beverage consumption in the general population.

There was no evidence of an overall association between alcoholic beverage intake and the risk for ovarian cancer in these cohort studies.

2.13.2. Case-control studies (Table 2.72)

Table 2.72. Case–control studies of ovarian cancer and alcoholic beverage consumption.

Table 2.72

Case–control studies of ovarian cancer and alcoholic beverage consumption.

Twenty-three case–control studies investigated the relationship between alcoholic beverage consumption and the risk for ovarian cancer in Australia, India, Japan, North America, Scandinavia and western Europe.

Twelve of these were hospital-based (West, 1966; Williams & Horm, 1977; Byers et al., 1983; Tzonou et al., 1984; Mori et al., 1988; Whittemore et al., 1988; Hartge et al., 1989; La Vecchia et al., 1992; Nandakumar et al., 1995; Tavani et al., 2001a; Yen et al., 2003; Pelucchi et al., 2005), one was based on cases and controls who were included in a cancer registry database (Kato et al., 1989) and 10 were population-based (Gwinn et al., 1986; Polychronopoulou et al., 1993; Kuper et al., 2000b; Goodman & Tung, 2003; McCann et al., 2003; Modugno et al., 2003; Riman et al., 2004; Webb et al., 2004; Peterson et al., 2006).

Confounding factors were considered in all studies, although adjustment was less extensive in studies published during the 1980s. Overall, the results of case–control studies do not suggest any association between alcoholic beverage consumption and the risk for ovarian cancer, although a few studies indicated either positive or negative associations.

2.13.3. Evidence for a dose-response

There was no consistent evidence of a trend of increasing risk for ovarian cancer with increasing alcoholic beverage consumption based on the cohort or case–control studies.

2.13.4. Types of alcoholic beverage

In two population-based cohort studies the association between types of alcoholic beverage was investigated (Schouten et al., 2004; Chang et al., 2007). Intake of wine during the year before baseline was associated with an increased risk for ovarian cancer in one study (Chang et al., 2007), but was not confirmed in the other (Schouten et al., 2004).

Seven case-control studies evaluated different alcoholic beverages in relation to the risk for ovarian cancer (Gwinn et al., 1986; La Vecchia et al., 1992; Tavani et al., 2001a; Goodman & Tung, 2003; Modugno et al., 2003; Webb et al., 2004; Peterson et al., 2006). Overall, there were no consistent patterns of association between any specific type of alcoholic beverage (beer, wine, spirits) and risk for ovarian cancer.

2.13.5. Interactions

Three of the cohort studies (Kelemen et al., 2004; Schouten et al., 2004; Chang et al., 2007) investigated possible interactions between alcoholic beverage intake and other variables. Some weak interactions were found by Chang et al. (2007) for women who drank more than one glass of wine daily and were over 50 years of age, post-menopausal, used estrogen only hormone therapy, belonged to a higher social class, were never smokers and had higher total folate intake. Among the case–control studies, there was no consistent evidence of interaction between alcoholic beverage consumption and different variables known or suspected to be associated with ovarian cancer, such as reproductive history, education, body size or diet.

2.14. Cancer of the uterine cervix

2.14.1. Cohort studies (Table 2.73)

Table 2.73. Cohort studies of alcoholic beverage consumption and cervical cancer in special populations.

Table 2.73

Cohort studies of alcoholic beverage consumption and cervical cancer in special populations.

A total of six prospective cohort studies have examined the association between alcoholic beverage intake and risk for cervical cancer, all of which were carried out in special populations, namely women who were treated for alcohol abuse or alchoholism (Prior, 1988; Adami et al., 1992a; Tønnesen et al., 1994; Sigvardsson et al., 1996; Weiderpass et al., 2001b) or worked as waitresses (Kjaerheim & Andersen, 1994).

These studies were conducted in Scandinavia (Adami et al., 1992a; Kjaerheim & Andersen, 1994; Tønnesen et al., 1994; Sigvardsson et al., 1996; Weiderpass et al., 2001b) and in the United Kingdom (Prior, 1988), and were all based on record linkages between existing databases, such as registries for hospitalizations and clinical care for alcoholism, and data from trade-union files. The cancer outcome was obtained by the respective cancer registries in each country/region. The comparison of incidence rates of cervical cancer was made between the special populations selected for the studies and women from the general population who were the same age as the study participants, during the same time periods.

All five studies conducted among women who were treated for alcohol abuse or alchoholism presented elevated risk estimates for invasive cervical cancer. However, none of them were able to adjust for known risk factors for cervical cancer, namely human papillomavirus (HPV) infections, number of sexual partners and tobacco smoking, or attendance of cervical cancer-screening programmes. It is possible that women who abuse alcohol have other behavioural patterns that may affect the risk for cervical cancer, such as non-compliance with screening, tobacco smoking and having a higher prevalence of HPV than the general populations in their respective countries.

2.14.2. Case–control studies (Table 2.74)

Table 2.74. Case–control studies of invasive cervical cancer and alcoholic beverage consumption.

Table 2.74

Case–control studies of invasive cervical cancer and alcoholic beverage consumption.

The association between alcoholic beverage intake and cervical cancer was evaluated in 12 case–control studies, seven of which were hospital-based (two from Italy, two from Thailand, one from Uganda and studies from United Kingdom and the USA), three were register- or cohort- based (from the USA and Zimbabwe), one was population-based (from Lesotho) and one was a large multicentre study from Latin America that included both hospital and population controls. Seven studies did not show any or any significant relative risk among alcoholic beverage drinkers (Harris et al., 1980; Marshall et al., 1983; Cusimano et al., 1989b; Licciardone et al., 1989; Thomas et al., 2001a; Chiaffarino et al., 2002). Significantly elevated relative risks emerged from two case–control studies from Africa, in which adjustment for confounding was incomplete (Martin & Hill, 1984; Parkin et al., 1994). In the study from Latin America, in which adjustment for possible confounders was adequate, there was an elevated risk for cervical cancer among occasional drinkers (confidence intervals not given) but no association with heavy drinking (Herrero et al., 1989). No consistent results with a higher risk among moderate drinkers were found in a study from Uganda (Newton et al., 2007).

2.14.3. Evidence of a dose–response

The cohort studies did not present convincing evidence of a dose-response between risk for cervical cancer and duration of alcoholic beverage consumption, which was roughly estimated as years since cohort enrolment (first hospitalization/clinical treatment for alcoholism).

Two case–control studies from the USA and Latin America (Herrero et al., 1989; Licciardone et al., 1989), in which at least smoking habits and number of sexual partners were adjusted for, showed no dose–response effect. In four other case–control studies in which there was some indication of a possible dose-response association (Harris et al., 1980; Marshall et al., 1983; Martin & Hill, 1984; Parkin et al., 1994), the adjustment for possible confounders was incomplete. In one study, such a trend was observed only among consumers of wine and other alcoholic beverages combined (Chiaffarino et al., 2002).

2.14.4. Types of alcoholic beverage

The cohort studies did not investigate the effect of specific types of alcoholic beverages (beer, wine, spirits) on risk for cervical cancer.

Almost all case-control studies that tried to evaluate specific types of alcoholic beverage (Marshall et al., 1983; Martin & Hill, 1984; Chiaffarino et al., 2002) did not find consistent differences in risk for cervical cancer. Only Williams and Horm (1977) found an elevated risk for cancer of the cervix among beer drinkers.

2.14.5. Interactions

None of the cohort or case-control studies presented information on possible interactions between alcoholic beverage intake and other variables in the causation of cervical cancer. Information for histological subtypes was not given.

2.15. Cancer of the prostate

2.15.1. Cohort studies

(a) Special populations (Table 2.75)

Table 2.75. Cohort studies of alcoholic beverage consumption and cancer of the prostate in special populations.

Table 2.75

Cohort studies of alcoholic beverage consumption and cancer of the prostate in special populations.

Only one of the eight studies of special populations showed an association between alcoholic beverage consumption and cancer of the prostate. In a Danish study of alcohol abusers, higher numbers of prostate cancers were observed compared with those expected from the general population (Tønnesen et al., 1994).

(b) General population (Table 2.76)

Studies of prostate cancer that were conducted more recently generated concern when no attempt was made to distinguish between cases that were detected by screening, with a possibility that many might not have presented clinically during the life-time of the individual in the absence of screening, and those that presented clinically and were more likely to be progressive. Among the 17 cohort studies, two specifically identified more advanced cases (Platz et. al., 2004; Baglietto et. al., 2006) but neither suggested any association between alcoholic beverage consumption and such cases of prostate cancer. A few of the other cohort studies that did not make this distinction suggested an increased risk for prostate cancer at elevated levels of alcoholic beverage consumption (Hirayama, 1992; Schuurman et al., 1999; Putnam et al., 2000; Sesso et al., 2001), but there was no consistent dose-response relationship and many other cohort studies showed no association.

2.15.2. Case–control studies (Table 2.77)

Five of the 33 case–control studies considered type of disease. Slattery and West (1993) considered ‘aggressive’ tumours, Hodge et al. (2004) studied ‘clinically important’ disease, Hayes et al. (1996) conducted stratified analyses by tumour grade and stage, Chang et al. (2005) considered localized and advanced disease and Schoonen et al. (2005) classified cases as less and more aggressive cancers. The remainder did not appear to make any distinction, although, in the study of Walker et al. (1992), 90% of the cases were advanced at presentation. The majority of the studies showed no association between alcoholic beverage consumption and prostate cancer. Of those that suggested a positive association, one (De Stefani et al., 1995) showed a borderline elevation of risk for high levels of consumption of beer, but the risk at high levels of total alcoholic beverage consumption was not significant; one (Hayes et al., 1996) showed significant elevations in risk for ‘heavy’ and ‘very heavy’ consumers of alcoholic beverages, with higher risks among those with poorly or undifferentiated tumours, or with regional or distant metastases; and another (Sharpe & Siemiatycki, 2001) reported an elevation in risk for those with long duration of drinking, and the greatest elevation in risk for those who started drinking at age <15 years.

2.15.3. Meta-analysis

A meta-analysis that included six cohort and 27 case–control studies that were reported before July 1998 resulted in an estimate of 1.05 (95% CI, 0.98–1.11) for ever consumption of alcoholic beverages (Dennis, 2000). There was a suggestion of a weak dose-response relationship for increasing levels of alcoholic beverage consumption (relative risk, 1.21; 95% CI, 1.05–1.39 for four drinks/day) when data from 15 of the studies were used. [Results for the six cohort studies and the 27 case–control studies are presented in Tables 2.76 and 2.77, respectively.]

Table 2.76. Cohort studies of alcoholic beverage consumption and cancer of the prostate in general populations.

Table 2.76

Cohort studies of alcoholic beverage consumption and cancer of the prostate in general populations.

Table 2.77. Case–control studies of alcoholic beverage consumption and cancer of the prostate.

Table 2.77

Case–control studies of alcoholic beverage consumption and cancer of the prostate.

2.16. Cancer of the kidney

Twenty cohort studies that assessed the relationship between alcoholic beverage intake and kidney cancer were identified; six of these were in special populations of heavy alcoholic beverage consumers whose rates of kidney cancer were compared with those of other populations, one was a mortality follow-up of a Japanese population, one was a study among cirrhotic patients and twelve were part of a pooled analysis. Twenty-one case-control studies that included information on alcoholic beverages and kidney cancer were identified.

2.16.1. Cohort studies (Tables 2.78 and 2.79)

Several of the five follow-up studies of heavy alcoholic beverage consumers (Pell & D'Alonzo, 1973; Jensen, 1979; Robinette et al., 1979; Adami et al., 1992a; Tønnesen et al., 1994; Table 2.78) were seriously limited by very small numbers of renal-cell cancer and an inability to control for confounding by smoking. Two of these had approximately 40 cases (Jensen, 1979; Tønnesen et al., 1994); the SIRs were 1.0 and 1.4, respectively.

Table 2.78. Cohort studies of alcoholic beverage consumption and cancer of the kidney in special populations.

Table 2.78

Cohort studies of alcoholic beverage consumption and cancer of the kidney in special populations.

Recently, a pooled analysis that was part of the Pooling Project of Prospective Studies of Diet and Cancer (Lee et al., 2007; Table 2.79) included 12 cohorts that found at least 25 incident cases of renal-cell carcinoma and consisted of 530 469 women and 229 575 men, with a maximum follow-up time of 7–20 years. Only four of these studies (Nicodemus et al. 2004; Mahabir et al., 2005; Rashidkhani et al., 2005; Lee et al., 2006) had previously published findings, which tended to show inverse or null associations between alcoholic beverage intake and the incidence of renal-cell cancer. In most of the other cohorts, the numbers of renal-cell cancers were relatively small and the results may have not been published. A total of 1430 incident cases of renal-cell cancer were identified. Alcoholic beverage consumption was inversely related to risk; compared with non-drinkers, the relative risk was 0.72 (95% CI, 0.60–0.86) for consumption of >15 g alcohol per day (p for trend <0.001). Although there was significant heterogeneity among studies, the inverse trends were similar and statistically significant in both men and women.

Table 2.79. Cohort studies of alcoholic beverage consumption and cancer of the kidney in the general population.

Table 2.79

Cohort studies of alcoholic beverage consumption and cancer of the kidney in the general population.

2.16.2. Case–control studies (Table 2.80)

Table 2.80. Case–control studies of alcoholic beverage consumption and cancer of the kidney.

Table 2.80

Case–control studies of alcoholic beverage consumption and cancer of the kidney.

The 21 case–control studies generally showed no or inverse associations (some of which were statistically significant), and no significantly positive associations. Four relatively recent, large case–control studies of renal-cell cancer are particularly informative. A multicentre case–control study conducted in Australia, Denmark, Sweden and the USA is notable because of the large number of cases (1185 of renal-cell cancer) and the detailed data collected on potentially confounding factors (Wolk et al., 1996). The relative risk in men for consumption of ≥15 drinks per week was 1.0 (95% CI, 0.70–1.4) and that in women for consumption of ≥10 drinks per week was 0.5 (95% CI, 0.3–0.8). In a large Italian case–control study of 348 cases, the relative risk was 0.8 (95% CI, 0.5–1.3) for six or more drinks per day (Pelucchi et al., 2002b) and, in a large case–control study from Canada conducted by mailed questionnaire (1279 cases), the relative risks for 18 or more servings of alcoholic beverage per week were 0.7 (95% CI, 0.5–0.9) for men and 0.6 (95% CI, 0.4–1.1) for women with significant inverse trends in both sexes (Hu et al., 2003). A multicentre hospital-based case–control study in eastern Europe (1065 cases) calculated average lifetime alcoholic beverage consumption (Hsu et al., 2007); the relative risk for those who drank more than 137.5 g alcohol per week was 0.83 (95% CI, 0.61–1.12) and that for the top decile of intake was 0.39 (95% CI, 0.24–.66).

All the large case–control studies and the pooled analysis of cohort studies were limited to renal-cell carcinomas. No studies of alcoholic beverage consumption in relation to cancer of the renal pelvis were identified.

2.16.3. Evidence of a dose–response

The best available evidence on dose-response comes from the pooled analysis of cohort studies (Lee et al., 2007). Relative risks were 0.97 (95% CI, 0.85–11) for 0.1–4.9 g/day, 0.82 (95% CI, 0.69–0.96) for 5.0–14.9 g/day and 0.72 (95% CI, 0.60–0.86) for 15 or more g/day (p for trend <0.001). A non-parametric regression curve was fit to the continuous data from these studies, and significant departure from linearity was suggested (P=0.02) with flattening of the curve above approximately 30 g/day.

The participating cohort studies had validated data for alcoholic beverage consumption; therefore, regression calibration was used to correct the observed associations for measurement error in alcoholic beverage intake, and limited this correction to the range of 0–30 g/day (94% of the data) because the relation appeared to be close to linear within this range. The uncorrected relative risk was 0.79 (95% CI, 0.70–0.89) for a 10-g/day increment within this range; after correction for measurement error, the relative risk was 0.81 (95% CI, 0.74–0.90).

The large case–control studies all found relative risks of 1.0 or below for the highest category of alcoholic beverage consumption and were generally consistent with the results of the pooled analysis, although no formal meta-analysis of these studies is available.

2.16.4. Type of alcohol

In the Pooling Project of cohort studies (Lee et al., 2007), inverse trends were seen for beer, wine and liquor, but only the trend for wine was statistically significant. However, the relative risks for different beverages did not differ significantly from each other.

The data from the case–control studies also did not provide clear evidence that the inverse association with kidney cancer was limited to a specific beverage.

2.16.5. Interactions

The associations between alcoholic beverage intake and kidney cancer did not vary appreciably by body mass index, history of hypertension, smoking status or age at diagnosis.

2.17. Cancers of the lymphatic and haematopoietic system

Lymphomas and haematopoietic malignancies comprise a heterogeneous group of malignancies and their etiology is not fully understood. There is a growing number of epidemiological studies that have examined the associations of alcoholic beverage consumption with the risk for these cancers.

2.17.1. Cohort studies

(a) Special populations (Table 2.81)

Table 2.81. Cohort studies of alcoholic beverage consumption and cancers of the lymphatic and haematopoietic system in special populations.

Table 2.81

Cohort studies of alcoholic beverage consumption and cancers of the lymphatic and haematopoietic system in special populations.

Five studies among heavy alcoholic beverage users or brewery workers have investigated the risk for lymphatic and/or haematopoietic cancers (Hakulinen et al., 1974; Jensen, 1979; Robinette et al., 1979; Schmidt & Popham, 1981; Carstensen et al., 1990). Among the three studies that examined lymphatic/haematopoietic cancers combined, one showed no significant differences between the observed number of cases among Danish brewery workers, compared with the expected number of cases computed from age-, sex- and area-specific rates (Jensen, 1979); one showed a slightly increased risk for these cancers among Swedish brewery workers compared with the expected number of cases calculated using age-, follow-up time- and area-standardized rates for the Swedish male population (Carstensen et al., 1990); and another showed a non-significant decreased risk among chronic alcoholic male US veterans compared with expected numbers computed from age- and time-specific rates for US men (Robinette et al., 1979).

In two studies, the observed number of cases of lymphoma among alcoholics was lower than that expected based on rates for the general population (Hakulinen et al., 1974; Schmidt & Popham, 1981).

In studies among alcoholics, the observed number of cases of leukaemia did not differ significantly from those expected in one study (Hakulinen et al., 1974), and was non-significantly lower in two other studies (Robinette et al., 1979; Schmidt & Popham, 1981). Among brewery workers, a Danish study found no significant difference between the observed and expected number of leukaemia deaths (Jensen, 1979), while a Swedish study found a 1.6-fold higher risk of mortality among brewery workers compared with that expected from the local population (Carstensen et al., 1990).

(b) General population (Table 2.82)

Table 2.82. Cohort studies of alcoholic beverage consumption and cancers of the lymphatic and haematopoietic system in general populations.

Table 2.82

Cohort studies of alcoholic beverage consumption and cancers of the lymphatic and haematopoietic system in general populations.

Four prospective cohort studies examined associations between alcohol intake and the risk for the lymphatic and/or haematopoietic cancers (Boffetta et al., 1989; Kato et al., 1992c; Chiu et al., 1999; Lim et al., 2006).

For non-Hodgkin lymphoma specifically, Chiu et al. (1999) found a non-significant inverse association with alcoholic beverage intake among postmenopausal women in the USA. This relationship persisted after adjustment for several potential confounding factors including age, total energy intake, residence (farm, no farm), education, marital status, history of transfusion and diabetes, and intake of red meat and fruit. [The Working Group noted that the level of alcohol intake was very low in this study.] In the only other cohort study of non-Hodgkin lymphoma and alcoholic beverage consumption, Lim et al. (2006) found weak evidence of an inverse association among male Finnish smokers in a multivariate analysis.

In a study among American men of Japanese ancestry that also considered several potential lifestyle, medical and dietary confounding factors, results were presented for lymphoma and leukaemia combined. A threefold higher risk for lymphoma/leukaemia was associated with consumption of ≥30 mL alcohol per day compared with non-drinkers (Kato et al., 1992c).

In the two prospective cohort studies that assessed the association between alcoholic beverage intake and the risk for multiple myeloma, one study found no association (Lim et al., 2006) and one found a lower risk among ever regular drinkers compared with never regular drinkers (Boffetta et al., 1989).

2.17.2. Case-control studies

(a) Lymphoma (Hodgkin disease, non-Hodgkin lymphoma and other lymphomas) (Table 2.83)

Table 2.83. Case–control studies of alcoholic beverage consumption and lymphomas.

Table 2.83

Case–control studies of alcoholic beverage consumption and lymphomas.

Sixteen published case–control studies examined associations between alcoholic beverage intake and the risk for lymphomas (Williams & Horm 1977; Cartwright et al., 1988; Brown et al., 1992; Nelson et al., 1997; Tavani et al., 1997; De Stefani et al., 1998b; Matsuo et al., 2001; Tavani et al., 2001b; Briggs et al., 2002; Chiu et al., 2002; Morton et al., 2003; Chang et al., 2004; Willett et al., 2004; Besson et al., 2006a,b; Nieters et al., 2006).

Most case–control studies of alcoholic beverage consumption and lymphoma focused specifically on non-Hodgkin lymphoma and/or its histological subtypes. In the study of Chang et al. (2004), a positive association was observed only for men and only for the histological subtype chronic lymphocytic leukaemia. In that study, all cases and controls were free of human immunodeficiency viral infection and careful consideration was given to several potential confounding factors including age, tobacco smoking and occupational exposure to pesticides. Most other studies of non-Hodgkin lymphoma observed an inverse association with alcoholic beverage intake. The largest of these studies (Briggs et al., 2002) included 960 male (living only) cases and more than 1700 population-based controls and found no difference in the risk for non-Hodgkin lymphoma between drinkers and non-drinkers after adjustment of age, ethnicity and smoking status.

Most individual studies of non-Hodgkin lymphoma had limited power to conduct detailed analyses of alcoholic beverages and risk for this disease, particularly for specific beverage types and histological subtypes. Therefore, data from nine case–control studies conducted in Italy, Sweden, the United Kingdom and the USA were pooled to include 6492 cases of non-Hodgkin lymphoma and 8683 controls (Morton et al., 2005). Results of that analysis showed a significantly lower risk for non-Hodgkin lymphoma for ever drinkers compared with non-drinkers; however, there was no consistent dose–response relationship between frequency of alcoholic beverage intake and risk for the disease. There was also no consistent evidence of an association with duration of alcoholic beverage drinking or with the age at starting drinking; moreover, the risk for non-Hodgkin lymphoma for current drinkers was lower than that for former drinkers in a subset of the pooled data. No difference in the association by alcoholic beverage type or a combination of beverage types consumed was observed. For specific subtypes of non-Hodgkin lymphoma, no significantly elevated risks were found. The lowest risk associated with ever drinking was that for Burkitt lymphoma (odds ratio, 0.51; 95% CI, 0.33–0.77 for ever versus non-drinker). Lower risks for diffuse B-cell, follicular and T-cell lymphomas were also associated with ever drinking. The authors noted that all disease misclassification was probably non-differential and therefore unlikely to explain a significant inverse association; findings were similar when analyses were restricted to studies that had a high response rate.

A multicentre case–control study of non-Hodgkin lymphoma and alcoholic beverage intake included data from five European countries and comprised 1742 cases and 2465 controls (Besson et al., 2006a). Overall, there were no associations observed for ever drinking, age at starting drinking, duration of drinking or monthly consumption with risk for all non-Hodgkin lymphomas or with any histological subtype; similarly, no associations with risk for non-Hodgkin lymphoma were found for any specific type of alcoholic beverage. However, a lower risk associated with regular alcoholic beverage intake was observed for men (odds ratio, 0.76; 95% CI, 0.62–0.93; 691 exposed cases) and for non-Mediterranean countries (odds ratio, 0.7; 95% CI, 0.6–0.9).

Among the four studies that examined Hodgkin lymphoma specifically (Williams & Horm, 1977; Tavani et al., 1997; Besson et al., 2006b; Nieters et al., 2006), there was a consistent inverse association. For example, in the large multicentre European study, the odds ratio for Hodgkin lymphoma associated with ever regular drinking compared with never regular drinking was 0.61 (95% CI, 0.43–0.87; 81 exposed cases); this association was consistent for younger and older adults (Besson et al., 2006b).

(b) Leukaemia (Table 2.84)

Table 2.84. Case–control studies of alcoholic beverage consumption and leukaemia.

Table 2.84

Case–control studies of alcoholic beverage consumption and leukaemia.

The association of alcoholic beverage intake with risk for adult leukaemia was examined in six epidemiological case–control studies (Williams & Horm, 1977; Brown et al., 1992; Wakabayashi et al., 1994; Pogoda et al., 2004; Rauscher et al., 2004; Gorini et al., 2007). No consistent patterns of association between total alcoholic beverage intake and risk for all leukaemias combined were observed. Two studies showed a non-significant two- to threefold higher risk for acute lymphocytic leukaemia associated with heavy drinking (Wakabayashi et al., 1994) or with any drinking (Brown et al., 1992), a third found no association of drinking with risk for this type of leukaemia (Gorini et al., 2007). Similarly, there was no consistent evidence of associations with acute non-lymphocytic, chronic lymphocytic or chronic myeloid leukaemias among studies. The available evidence also did not support an association for any specific alcoholic beverage type.

(c) Multiple myeloma (Table 2.85)

Table 2.85. Case–control studies of alcoholic beverage consumption and multiple myeloma.

Table 2.85

Case–control studies of alcoholic beverage consumption and multiple myeloma.

Five case–control studies (four in the USA and one in Canada) examined associations between alcoholic beverage intake and the risk for multiple myeloma (Williams & Horm, 1977; Gallagher et al., 1983; Linet et al., 1987; Brown et al., 1992, 1997). In the largest study, there was a lower risk for multiple myeloma among drinkers compared with non-drinkers in white men and to a lesser extent in black men and white women (Brown et al., 1997). There was a non-significant 2.8-fold higher risk for multiple myeloma for white women who consumed ≥22 drinks per week (Brown et al., 1997). Among the other case–control studies, no consistent patterns of association were observed. It should be noted that most studies collected data on alcoholic beverage consumption from proxy respondents, and that some included prevalent cases. In addition, not all studies controlled for the potential confounding effects of tobacco smoking, and only one controlled for other factors such as farming, family history of cancer and occupational exposure to high-risk chemicals (Brown et al., 1992).

2.17.3. Parental exposure and childhood cancers (Table 2.86)

Table 2.86. Case–control studies of parental alcoholic beverage consumption and childhood haematopoietic cancer.

Table 2.86

Case–control studies of parental alcoholic beverage consumption and childhood haematopoietic cancer.

Six case–control studies in Australia, Canada, Europe and the USA examined associations of paternal alcoholic beverage intake before pregnancy and/or maternal alcoholic beverage intake during pregnancy with risk for haematopoietic cancers in children (McKinney et al., 1987; van Duijn et al., 1994; Severson et al., 1993; Shu et al., 1996; Infante-Rivard et al., 2002; Menegaux et al., 2005). Three of four studies reported no association between paternal alcoholic beverage intake 1 month or 1 year before pregnancy and risk of any childhood leukaemia or lymphoma (van Duijn et al., 1994; Severson et al., 1993; Shu et al., 1996), whereas a positive association between a higher number of drinks per day and the risk for acute lymphocytic leukaemia was observed in the fourth study (Infante-Rivard et al., 2002). For maternal alcoholic beverage intake during pregnancy, one study showed no association with leukaemia or lymphoma (McKinney et al., 1987), while another showed a reduced risk for acute lymphocytic leukaemia when comparing any intake with no intake (Infante-Rivard et al., 2002). Statistically significant two- to 2.4-fold higher risks for acute non-lymphocytic leukaemia were associated with any maternal alcoholic beverage intake during pregnancy in two studies (van Duijn et al., 1994; Menegaux et al., 2005). Similarly, statistically significant positive associations between maternal alcoholic beverage intake and risk for acute lymphocytic (Shu et al., 1996; Menegaux et al., 2005) and acute myeloid (Severson et al., 1993; Shu et al., 1996) leukaemias were observed. The strongest associations observed in the studies of alcoholic beverages and acute myeloid leukaemia were for children diagnosed at 10 years of age or younger (Severson et al., 1993; Shu et al., 1996). Overall, there was no consistent evidence of dose–response relationships for maternal or paternal alcoholic beverage intake or for intake of any specific type of alcohol beverage and risk for any childhood haematopoietic cancer. Most studies adjusted for potential confounding factors including maternal age, maternal smoking and child's gender. Importantly, it is unclear whether any of the observed associations between maternal or paternal alcoholic beverage intake and risk for childhood haematopoietic cancers are attributed to recall bias.

2.18. Cancer at other sites

2.18.1. Testis (Table 2.87)

Table 2.87. Case–control studies of alcoholic beverage consumption and testicular cancer.

Table 2.87

Case–control studies of alcoholic beverage consumption and testicular cancer.

(a) Parental exposure

Among two cohort (Robinette et al., 1979; Jensen, 1980) and three case–control studies (Schwartz et al., 1962; Brown et al., 1986; Weir et al., 2000) conducted in the general population, only one case–control study suggested a possible association between testicular cancer in adults and maternal drinking during pregnancy (Brown et al., 1986). The association was of borderline significance for the consumption of more than one drink per week relative to no drinking (odds ratio, 2.3; 95% CI, 1.0–5.2), but no association was observed for one drink (odds ratio, 1.1; 95% CI, 0.6–2.2), and no clear trend was apparent with the amount of alcohol consumed.

One additional cohort study conducted among male and female cirrhotics in Denmark found a slightly increased risk for testicular cancer of all histological types (SIR, 2.3; 95% CI, 1.0–4.5) that varied little with type of cirrhosis and disappeared after 10 years of follow-up (Sørensen et al., 1998).

One case–control study investigated the association of childhood germ-cell tumours (seminoma, embryonal carcinoma, yolk-sac tumour, choriocarcinoma, immature teratoma and mixed germ-cell tumours) and parental alcohol drinking (Chen et al., 2005b). Results showed no association between germ-cell cancer overall and alcoholic beverage drinking by either parent before pregnancy, or during pregnancy or nursing; odds ratios were 0.9 (95% CI, 0.7–1.2) and 1.0 (95% CI, 0.8–1.3) for ever drinking, for mothers and fathers, respectively. Additional stratified analyses by sex, histological type and anatomical site did not show any association.

(b) Adult exposure

Two case–control studies in the United Kingdom investigated the association between alcoholic beverage drinking and testicular cancer. Swerdlow et al. (1989) found no association for regular alcoholic beverage drinking, duration of drinking or consumption of beer, cider or spirits; however, a significant association was found with regular consumption of wine, with an odds ratio of 1.71 (95% CI, 1.21–2.43), but no dose–response relation. The other case–control study found no association with alcohol intake at the time of diagnosis or at age 20 years (UK Testicular Cancer Study Group, 1994).

2.18.2. Cancer of the brain

(a) Parental exposure and childhood brain cancer (Table 2.88)

Table 2.88. Case–control studies of parental alcoholic beverage consumption and childhood brain tumours.

Table 2.88

Case–control studies of parental alcoholic beverage consumption and childhood brain tumours.

Only one cohort study found an association between alcoholic beverage consumption and brain cancer (Robinette et al., 1979). Three additional studies with suboptimal methodology did not provide evidence of an association between increased alcoholic beverage consumption and brain cancer (IARC, 1988). However, a descriptive study based on cancer registries and national mortality data in France (Remontet et al., 2003) showed a large increase in the incidence of and mortality from brain cancer between 1980 and 2000, during which time alcohol consumption decreased markedly.

Five case–control studies have assessed the association between alcoholic beverage consumption of parents and childhood brain cancer. Two of the studies were conducted in the USA and Canada (Bunin et al., 1994; Yang et al., 2000), one in China (Hu et al., 2000), one in Germany (Schüz et al., 2001) and one in the USA (Kramer et al., 1987). Three of the studies examined the association between neuroblastoma and parental alcoholic beverage consumption (Kramer et al., 1987; Yang et al., 2000; Schüz et al., 2001). Kramer et al. (1987) found a weak, non-significant association for any maternal alcoholic beverage drinking during pregnancy, with a suggestive increase in risk with amount and frequency. However, these results were based on very small numbers of controls. A case–control study based on the Children's Cancer Group and Paediatric Oncology Group institutions in the USA and Canada (Yang et al., 2000) found no associations between the risk for neuroblastoma and either maternal or paternal alcoholic beverage consumption, while the combined analysis of two case–control studies used in the German study observed no overall association between maternal alcoholic beverage consumption during pregnancy and neuroblastoma or stage I/II neuroblastoma. However, an association was observed between advanced stage (III/IV) neuroblastoma and high alcoholic beverage consumption either during lifetime or around the time of pregnancy (Schüz et al., 2001).

One study conducted in the USA and Canada found that maternal beer consumption during pregnancy was associated with primitive neuroectoderma tumours, but no association was found between alcoholic beverage consumption and astrocytoma (Bunin et al., 1994), while the Chinese study reported that paternal hard liquor consumption before the pregnancy was associated with brain cancer (Hu et al., 2000). [The Working Group considered that there was a possibility of recall bias in this study.]

(b) Adult brain cancers (Table 2.89)

One cohort study (Efird et al., 2004) assessed associations between cigarette smoking and other lifestyle factors, including alcohol, and the occurrence of glioma in adults. There was no association with consumption of alcoholic beverages, beer or wine in the past year, although a slight non-significant association was observed for liquor consumption in the past year.

Nine case–control studies assessed the association between alcoholic beverage consumption and brain cancer in adults (Table 2.89). In studies conducted in Australia (Ryan et al., 1992; Hurley et al., 1996), Germany (Boeing et al., 1993) and the USA (Preston-Martin et al., 1989; Hochberg et. al., 1990; Lee et al., 1997), no significant associations or trends were observed with the consumption of alcoholic beverages and the occurrence of glioma or meningioma. However, three studies, one conducted in Canada and two conducted in China, did find an association between the consumption of alcoholic beverages and brain cancer. The Canadian study found an elevated risk for ‘ever use’ of wine, but not of beer or spirits (Burch et al., 1987) and one Chinese study (Hu et al., 1998) found that consumption of liquor was associated with the occurrence of glioma in men with significant trends for the number of years of drinking, lifetime consumption and average consumption. However, no associations were seen for beer in adjusted analyses. In a separate report of the same study (Hu et al., 1999), higher levels of consumption of beer, liquor and total alcohol were all associated with brain cancer, with respective adjusted odds ratios of 2.9 (95% CI, 1.1–7.6), 3.8 (95% CI, 1.6–9.2) and 3.2 (95% CI, 1.5–7.0) in the third tertile of consumption.

Table 2.89. Case–control studies of alcoholic beverage consumption and adult brain cancer.

Table 2.89

Case–control studies of alcoholic beverage consumption and adult brain cancer.

2.18.3. Cancer of the thyroid

The association of alcoholic beverage consumption and thyroid cancer was examined in four cohort (Table 2.90) and six case–control (Tables 2.91). studies.

Table 2.90. Cohort studies of alcoholic beverage consumption and thyroid cancer.

Table 2.90

Cohort studies of alcoholic beverage consumption and thyroid cancer.

Table 2.91. Case–control studies of alcoholic beverage consumption and thyroid cancer.

Table 2.91

Case–control studies of alcoholic beverage consumption and thyroid cancer.

One cohort study among alcoholics in Sweden reported no signfiicant excess risk for thyroid cancer compared with the general population (Adami et al., 1992a). Two cohort studies conducted in the general population also reported no significant association of increasing alcohol consumption with risk for thyroid cancer (Iribarren et al., 2001; Navarro Silvera et al., 2005).

A pooled analysis of the case–control studies (Table 2.91), based on 1732 cases, found no association with increasing intake of beer and wine (relative risk, 0.9 (95% CI, 0.7–1.1) for more than 14 drinks per week) (Mack et al., 2003). No difference was found for wine or beer separately or between men or women.

No data were available on the effect of duration of alcoholic beverage drinking or cessation of drinking on the risk for thyroid cancer.

2.18.4. Melanoma

(a) Cohort studies (Table 2.92)

Table 2.92. Cohort studies of alcoholic beverage consumption and melanoma.

Table 2.92

Cohort studies of alcoholic beverage consumption and melanoma.

Two cohort studies, one in a group of radiological technologists exposed to ion- izing radiation in the USA (Freedman et al., 2003) and one in alcoholic women in Sweden (Sigvardsson et al., 1996), found no significant associations between the risk for melanoma and alcoholic beverage intake.

(b) Case–control studies (Table 2.93)

Table 2.93. Case–control studies of alcoholic beverage consumption and melanoma.

Table 2.93

Case–control studies of alcoholic beverage consumption and melanoma.

Six of nine case–control studies reported no significant association between alcoholic beverage intake and the risk for melanoma (Østerlind et al., 1988; Bain et al., 1993; Kirkpatrick et al., 1994; Westerdahl et al., 1996; Naldi et al., 2004; Vinceti et al., 2005). These studies were conducted in Australia, Italy, Denmark, Sweden and the USA.

Three case–control studies in the USA reported some increase in risk for melanoma associated with alcoholic beverage intake (Stryker et al., 1990; Millen et al., 2004; Le Marchand et al., 2006). None of these were adjusted for exposure to ultraviolet light and thus the possibility of confounding can not be excluded.

2.18.5. Other female cancers (vulva and vagina)

(a) Cohort studies (Table 2.94)

Table 2.94. Cohort studies of alcoholic beverage consumption and other female cancers.

Table 2.94

Cohort studies of alcoholic beverage consumption and other female cancers.

Two cohort studies have examined the association between alcoholic beverage intake and risk for other female cancers. These studies were carried out in special populations, namely women being treated for alcohol abuse or alcoholism in Sweden (Sigvardsson et al., 1996; Weiderpass et al., 2001b). One study indicated an elevated risk for vaginal cancer but not for vulvar cancer (Weiderpass et al., 2001b). The other study presented high relative risk estimates for both vulvar and vaginal cancers combined. The cohort studies could not adjust risk estimates for factors that may have confounded the association between alcoholic beverage and vulvar and vaginal cancers, such as HPV infections, number of sexual partners and tobacco smoking. It is possible that women who abuse alcohol have other behavioural patterns that may affect risks for vulvar and vaginal cancer.

(b) Case–control studies (Table 2.95)

Table 2.95. Case–control studies of alcoholic beverage consumption and other female cancers.

Table 2.95

Case–control studies of alcoholic beverage consumption and other female cancers.

Three case–control studies investigated the association between alcoholic beverage consumption and risk for vulvar cancer in Italy (Parazzini et al., 1995b) and in the USA (Mabuchi et al., 1985b; Sturgeon et al., 1991). Two of these were hospital-based (Mabuchi et al., 1985b; Parazzini et al., 1995b) and one was population-based (Sturgeon et al., 1991).

Confounding factors were considered in two studies (Sturgeon et al., 1991; Parazzini et al., 1995b), but only one provided risk estimates adjusted for smoking and sexual behaviour (Sturgeon et al., 1991), which are potential confounders.

The three case–control studies reported no association between alcoholic beverage consumption and risk for vulva cancer.

(c) Evidence of a dose–response

One case–control study (Parazzini et al., 1995b) and the cross-sectional study (Williams & Horm, 1977) presented information on dose–response for alcoholic beverage consumption and vulvar cancer. Neither study found evidence of a dose–response.

(d) Types of alcoholic beverage

Three studies (Williams & Horm, 1977; Mabuchi et al., 1985b; Sturgeon et al., 1991) investigated differences in risk according to the type of beverage and found no evidence of an effect.

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