Eur J Epidemiol (2008) 23:395–401 DOI 10.1007/s10654-008-9244-4
CANCER
Alcohol consumption and risk of colorectal cancer: the Findrink study Adetunji T. Toriola Æ Sudhir Kurl Æ Jari A. Laukanen Æ Charles Mazengo Æ Jussi Kauhanen
Received: 28 September 2007 / Accepted: 23 March 2008 / Published online: 12 April 2008 Ó Springer Science+Business Media B.V. 2008
Abstract We investigated the association between alcohol consumption and colorectal cancer because previous studies have yielded conflicting results. As part of the Findrink study, data from the Kuopio Ischaemic Heart Disease (KIHD) Risk Factor Study were analysed. The KIHD study is a cohort of 2,682 men from Eastern Finland with no history of cancer at baseline. The men were grouped into five groups according to their weekly alcohol intake in grams. Association between alcohol and colorectal cancer was examined using Cox proportional hazard models. There were 59 cases of colorectal cancer during an average follow up of 16.7 years. Men within the highest quintile of alcohol consumption had a median weekly alcohol intake of 198.8 g. Age and examination year adjusted risk ratio of colorectal cancer among men within the highest quintile of alcohol consumption was 4.4 (95% CI: 1.6–11.9, P-value = 0.004). After adjusting for potential confounders, such as vegetable consumption, fibre intake, smoking, family history of cancer, socioeconomic status, leisure time physical activity, men with the highest amount of alcohol consumption still had a 3.5fold (95% CI: 1.2–9.9, P-value = 0.021) increased risk of colorectal cancer. Exclusion of men diagnosed with colorectal cancer during the first 2 years of follow up from the analyses did not alter the risk increase. In conclusion, this study gives further evidence of a positive association A. T. Toriola (&) C. Mazengo J. Kauhanen School of Public Health and Clinical Nutrition, University of Kuopio, P.O. Box 1627, 70211 Kuopio, Finland e-mail:
[email protected] S. Kurl J. A. Laukanen J. Kauhanen Research Institute of Public Health, University of Kuopio, Kuopio, Finland
between alcohol consumption and the risk of colorectal cancer. Keywords
Alcohol Colorectal cancer Cohort study
Introduction Colorectal cancer accounts for 9.4% (about 1 million incident cases) of all new cancer cases worldwide each year [1] which makes it one of the most common incident cancers [1]. While alcohol is an established strong risk factor for upper aerodigestive tract cancers (oral cavity, pharynx, oesophagus and larynx) [2, 3], its association with colorectal cancer is not fully ascertained. A report in 2003 by an expert consultation between World Health Organization and Food and Agriculture Organization did not include colorectal cancer as an alcohol-related malignancy [4] but a more recent monograph by WHO International Agency for Research on Cancer Monograph Working Group stated that colorectal cancer is causally related to alcohol consumption [5]. While some studies have observed positive associations between alcohol and colorectal cancer [6–8], others have not [9, 10]. A meta-analysis of 27 studies conducted in the 1990s (5 follow up and 22 case–control) studies [11] observed an increased risk of 10% with consumption of more than two drinks a day and suggested that a causal role for alcohol in colorectal cancer was inconclusive. However, a more recent meta-analysis of eight cohort studies found an increased risk of colorectal with alcohol consumption but limited to consumption of more that 30 g/day [12]. Moskal et al. in a dose–response meta-analysis of cohort studies observed that high intake of alcohol was significantly associated with increased risk of colon and
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rectal cancers by anatomical subsites but analysis involving the whole colorectum, though positive, was not significant [13]. They noted that geographical area where study was conducted was a source of heterogeneity. Alcohol consumption is increasing in many parts of the world and its impact on disease burden is also predicted to increase likewise [14]. Because geographical location where the studies were conducted was noticed to be a source of heterogeneity in results [13], we believe that the association between alcohol consumption and colorectal cancer may differ in our population, hence, we decided to examine the risk of colorectal cancer according to the amount of pure alcohol consumed per week in our cohort of middle aged men from Eastern Finland.
Materials and methods Study population The present study is part of the Findrink study which was carried out among participants of a prospective cohort (KIHD Risk Factor Study) originally designed to investigate risk factors for cardiovascular diseases, and other health related outcomes in a population based sample of middle-aged men from Eastern Finland. Baseline examinations were conducted between March 1984 and December 1989. The study group is a representative sample of men living in Kuopio and its surrounding rural communities who were aged 42, 48, 54 and 60 years at the time of baseline examination. Of the 3,235 eligible men, 2,682 (83%) volunteered to participate and 198 were excluded because of death or serious disease. Of those, men who had a history of cancer at baseline were excluded from the present study series and complete data was available for 2,627 men. The study protocol was approved by the Research Ethics Committee of the University of Kuopio and each participant gave written informed consent. Alcohol consumption Alcohol consumption was assessed with a structured quantity-frequency method using the Nordic Alcohol Consumption Inventory [15, 16]. This assessed alcohol consumption over the preceding 12 months. Usual frequency of intake and usual dose per sitting (in glasses or bottles) were queried separately for each beverage (beer, wine, spirits) with a structured response form. Thus, we were able to assess both total alcohol use and the timing or pattern of drinking (usual number of drinks per occasion). The measure of average weekly use of all alcoholic beverages was computed on the basis of the known alcohol content of each type of drink and reported doses and
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frequencies of drinking sessions [17]. For example, a 1/3-l bottle or can of regular beer in Finland contains &12 g alcohol. Strong beer has &14 g of alcohol and one portion of hard liquor contains &14 g of alcohol. Serum gammaglutamyl transpeptidase (GGT) and mean corpuscular volume (MCV) were determined from baseline blood samples as biomarkers of excessive alcohol use. Outcome events Incident cases of colorectal cancer were derived from the population based Finnish Cancer Registry. Since 1953, every cancer case in the health care system has been reported in a countrywide and population based manner in Finland. Coverage of the national cancer registry is virtually complete [18]. Our study cohort was record linked with the cancer registry data by using the personal identification code. Every resident of Finland has a unique personal identifier that is used in registries. Follow up for cancer was done using the personal identifiers. All colorectal cancer diagnoses that occurred between the study entry (March 1984 to December 1989) and December 2005 were included. Due to complete follow up system of the Finnish population, there are no losses to follow up. Diet Food consumption was assessed at the time of blood sampling during the baseline phase of the study. Subjects were instructed on the use of household measures for quantitative recording of their food intake during the 4 days of data collection. A nutritionist gave the instructions and checked the completed food intake records. Dietary intake of foods and nutrients was calculated using NUTRICA software (version 2.5; National Public Health Institute, Turku). The software is compiled using mainly Finnish values of nutrient composition of foods, and takes into account losses of vitamins in food preparation. The nutrient composition of foods in the NUTRICA software used reflects data on vitamin contents of fruits and vegetables [19]. Other variables Leisure time physical activity was assessed from a 12-month history, modified from the Minnesota Leisure time physical activity questionnaire. For each activity performed, the subjects were asked to record the frequency (number of sessions per month), average duration (hours and minutes per session), and intensity which were expressed in metabolic equivalents (METS) [20]. Smoking: a subject was described as a smoker if he had ever smoked on a regular basis and had smoked cigarettes, cigars or pipes
Alcohol, colorectal cancer
within the past 30 days. Life-long exposure to smoking (cigarette pack years) was estimated as the product of the number of smoking years and the number of tobacco products smoked daily until the time of baseline examination [21]. Socio-economic status (SES) was measured as a summary index that combined measures of income, education, occupation, occupational prestige, material standard of living, and housing conditions [22]. A high value on the SES index indicated a low socio-economic state. Statistical analysis Descriptive data on alcohol are presented as median, 25th and 75th percentiles and range. The relation between alcohol consumption and risk of colorectal cancer was assessed using Cox proportional hazards model. Subjects were grouped into five quintiles based on the amount of pure alcohol consumed per week (i) 1st quintile; men who consume \3.3 g of alcohol; (ii) 2nd quintile, 3.3–17.2 g/week; (iii) 3rd quintile, 17.3–48.8 g/week; (iv) 4th quintile, 48.9–115.3 g/week; (v) 5th quintile, [115.3 g/week. Three sets of co-variates were used for the three models. In model 1, we adjusted for age and examination year. In model 2, we adjusted for age, examination year, vegetable consumption and fibre intake and in model 3, we adjusted for age, examination year, vegetable consumption, fibre intake, family history of cancer, smoking, socio-economic status and leisure time physical activity. Co-variates were selected on the basis of their previous roles as predictive factors on outcome event from previous evidence and available data. Statistical analyses were done using the SPSS version 14 for windows (SPSS, Inc., Chicago, IL).
Results Table 1 describes the characteristics of the study cohort according to their alcohol consumption categories at baseline. The mean age of the participants was 53 years and men within the highest quintile of alcohol consumption category were on the average the youngest, with a mean age of 52.2 years, compared with a mean age of 54.1 years for those within the lowest quintile of alcohol consumption. Men with the highest level of alcohol consumption had the highest mean BMI, highest serum gamma glutamyl transpeptidase, were more likely to be smokers and consumed less vegetables, fibres, milk, fruits and berries compared with others. Men within the highest quintile of alcohol consumption had a median weekly alcohol intake of 198.8 g/week which is almost twice the total median weekly alcohol consumption of men within the other four quintiles combined. In all the quintiles of alcohol consumption, alcohol from liquor
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accounted for over 50% of total weekly alcohol intake in grams while alcohol from beer accounted for about 25% of total weekly alcohol intake within the highest three quintiles (Table 2). Amount of pure alcohol consumed from wine, particularly light wine in this cohort was very low. A total of 59 colorectal cancer cases occurred during an average follow up period of 16.7 years corresponding to 43,608 person years. Age and examination year-adjusted increased risk among men in the highest quintile of alcohol consumption was 4.4 (95% CI: 1.6–11.9) (Table 3a). Inclusion of dietary habits such as vegetable consumption and fibre intake that have the potential to modify the risk of colorectal cancer into the model did not alter the risk much; there was still a 3.8-fold (95% CI: 1.3–10.7) increased risk among the highest quintile of alcohol consumption. Further adjustments for family history of cancer, smoking, leisure time physical activity and SES in the final model yielded a 3.5-fold (95% CI: 1.2–9.9) increased risk among people who consume more than 115 g of ethanol/week compared with the lowest quintile of alcohol consumption. Exclusion of people diagnosed with cancer within the first 2 years of follow did not alter the risk in the multivariate adjusted model (RR 3.5, 95% CI: 1.2–9.9, P-value 0.02) (Table 3b). In this analysis, men within the 4th quintile of alcohol consumption had the least non-significant risk increase compared with others (RR 1.4, 95% CI: 0.4–4.4, P-value 0.59).
Discussion This prospective population based study among middle aged men in Eastern Finland shows that men with the highest weekly alcohol consumption have an increased risk of colorectal cancer. The increase in risk with increasing alcohol consumption supports an association of colorectal cancer with alcohol intake that cannot be explained by the potential confounders we considered. Alcohol may increase the risk of colorectal cancer through various mechanisms but these have not been fully defined. Even though ethanol itself is thought to be more of a cocarcinogen, rather than a carcinogen, [23] there is evidence that its’ major metabolite, acetaldehyde is carcinogenic [24, 25]. Acetaldehyde causes widespread DNA damage by forming adducts, inducing crosslinkages, causing chromosomal abnormalities and inhibiting DNA repair enzymes [24, 25]. The reasons why some of the previous studies have often yielded different results may be due to some of the following: (a) Differences in genetic susceptibility in various population groups; (b) Differences in the main type of alcoholic beverage consumed in various populations; (c) Differences in study settings.
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Table 1 Baseline characteristics of study population Quintile groups of alcohol consumptiona
Age (years)
1st (n = 525) Mean (SD)
2nd (n = 526) Mean (SD)
3rd (n = 526) Mean (SD)
4th (n = 525) Mean (SD)
5th (n = 525) Mean (SD)
54.1 (4.5)
53.4 (4.9)
53 (5.2)
52.5 (5.1)
52.2 (5.6)
Percentage in age groups 42–43 years (12.6%) 48–49 years (13.5%) 54–55 years (59.3%) 60–61 years (14.6%) Family history of cancer (%)
25
24
23
24
25
BMI (kg/m2)
26.7 (3.5)
26.5 (3.4)
26.6 (3.6)
26.9 (3.4)
27.7 (4)
Energy expenditure, leisure time (kcal/day)
128.9 (176.2)
149.9 (189.6)
146.3 (188.1)
147.1 (157)
132.9 (157.7)
Vegetable sum in g, 4 day mean
284.5 (134.9)
291.8 (129.1)
283 (119.3)
295.3 (119.3)
279.9 (124.4)
Fruits and berries sum in g, 4 day mean
177.3 (146.5)
164.3 (138.2)
163.6 (152.5)
157.2 (137.8)
136.5 (142.5)
Fibre intake in g, 4 day mean
27.5 (9.9)
26.7 (8.6)
25.5 (8.8)
23.9 (7.4)
21.9 (7.8)
Milk intake, g, 4 day mean
495.5 (341.8)
437.6 (312.5)
403.1 (323.4)
394.6 (314.1)
388.5 (341.1)
Meat sum in g, 4 day mean
136.4 (75.4)
151.9 (75.1)
163.3 (88.1)
164.7 (73.9)
187.5 (94.3)
Socio-economic status
13.6 (4.6)
12.1 (5.1)
11.8 (5.2)
11.7 (5.4)
12.3 (5.2)
Smoking (%)
14
26
32
39
50
Number of cigarettes/day
3 (8)
4 (8)
5 (9)
7 (10)
10 (13)
Weekly alcohol consumption (g/week) s-gamma gt U/L
0.5 (1) 21.3 (18.4)
9.3 (3.9) 23.3 (18.4)
31.9 (9.3) 27 (23.7)
77.9 (18.7) 31.8 (41.9)
261.3 (217.5) 49.4 (61.2)
Mean corpuscular volume, fl
90.2
90.7
92
92.5
94.2
a
Quintile groups of alcohol consumption: (i) 1st quintile, \3.3 g/week; (ii) 2nd quintile, 3.3–17.2 g/week; (iii) 3rd quintile, 17.3–48.8 g/week; (iv) 4th quintile, 48.9–115.3 g/week; (v) 5th quintile, [115.3 g/week
The relationship between alcohol and colorectal cancer may be modified by polymorphisms in genes encoding for ethanol metabolism. Such gene–environment interaction has been previously documented with respect to alcohol and breast cancer [26]. Likewise, polymorphisms in ADH3 metabolism have been found to modify the association between alcohol and colorectal adenomas, which are precursors to colorectal cancers [27]. In the study, high alcohol consumption was found to markedly increase the risk of colorectal adenomas in subjects with ADH3*1/*1 genotype compared with other ADH3 genotypes. A number of the studies conducted among Western [7, 12, 28, 29] and Japanese subjects [6, 30, 31] have often reported positive associations between alcohol consumption and colorectal cancer whereas studies conducted among Chinese subjects have often times yielded no associations [9, 32–34]. Even among population groups where positive associations were found, the daily amount of ethanol consumption that is positively related to colorectal cancer differs substantially. A pooled analysis of studies among American and European subjects revealed that alcohol intake of [45 g/day increased the risk of colorectal cancer by 1.51-fold [12] whereas among Japanese subjects, similar weekly intake was associated with a 2.1-fold increased risk
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[30]. Thus, the daily/weekly volume of alcohol consumption that is positively associated with increased risk of colorectal cancer in a population group may be quite different from that of another population group due to interplay of different genetic, environmental and dietary modifications. In a dose–response meta-analysis of published cohort studies, Moskal and his colleagues found out that geographical area was a significant source of heterogeneity even after adjusting for level of alcohol intake [13]. The association of alcohol with colorectal cancer in different populations may depend on the type of alcoholic beverage consumed most in such populations. Even though acetaldehyde is believed to be the major carcinogen, other chemical constituents in the beverages may also contribute to the development of colorectal cancer. In the review by Kune and Vietta [35], beer was associated with an increased risk of colorectal cancer in over 50% of cohort studies reviewed while wine was not associated with an increased risk in the seven cohort studies in which it was separately examined. However, in two out of three studies in which all alcoholic beverages were examined together, increased risks were found. This pattern of risk increase mainly due to beer and liquor has been supported by other studies [3, 29, 36]. Two Danish studies [37, 38] have
Alcohol, colorectal cancer Table 2 Amount of alcohol consumed from different alcohol beverages by quintile groups in g/week
399
Quintile
Alcohol beverages Beer
Liquor
Strong wine
Light wine
All beverages
25th percentile
0
0
0
0
0
Median
0
0
0
0
0
75th percentile
0
0
0
0
0.6
Range
0–3
0–3.2
0–1.8
0–2.8
0–3.2
25th percentile
0
3.2
0
0
6.1
Median
1.3
4.8
0
0
8.8
75th percentile
3
8
1.4
1.4
12.2
Range
0–15
0–16
0–8.4
0–14
3.3–17.2
1st
2nd
3rd 25th percentile
1.5
8.8
0
0
23.4
Median
6.8
16
0
0.1
31.5
75th percentile
13.7
24
2.8
2.8
40
Range
0–45
0–48
0–24.5
0–35
17.3–48.8
25th percentile
4.5
24
0
0
61.1
Median
18
44
0.3
0.6
76
75th percentile
36
64
4.9
4.2
93.4
Range
0–108
0–112
0–84
0–84
48.9–115.2
25th percentile
16.9
64
0
0
152
Median
48.8
120
1.4
0
198.8
75th percentile
108
192
14
7
287
Range
0–1008
0–2016
0–756
0–588
115.5–2853.1
4th
5th
shown that when wine consumption accounts for more than 30% of the total alcohol intake, the risk of colorectal cancer [37] and overall cancer mortality [38] is attenuated suggesting that other alcoholic beverages contribute more to the risk of colorectal carcinogenesis. In our study population, weekly wine consumption within the high risk group was less than 15% of the total weekly alcohol consumption with light wine accounting for only 5.6% of total alcohol consumption which means that the possibility of any risk attenuation by wine among men in our cohort is small. This proportion of wine intake reflects that seen in the general Finnish population in which wine consumption accounts for only about 15% of the of total alcohol consumption [39]. A peculiar feature of our cohort is the fact that pure alcohol from liquor contributes to more than 50% of the total alcohol consumption. We are of the opinion that this high proportion of pure alcohol from liquor may be one of the reasons for the high risk estimates observed in this study but we are limited by the small number of cases from making more extensive analyses. A recent study observed an increased risk of breast cancer among women who binge drink [40] showing that drinking patterns may also be
associated with increased risk of cancer, however, the relationship between drinking pattern and other types of cancer has not been investigated in details. Study settings/protocols may also account for differences in previous studies. The review by Kune and Vitetta [35] revealed that an elevated risk between alcohol and colorectal cancer was found in 90% of studies where community based controls were used compared with 30% of studies where hospital based controls were used. Marked differences in the alcohol consumption levels between hospital controls and community based controls could most likely have accounted for the differences in results. In studies conducted among women, there are usually no associations between alcohol and colorectal cancer compared with studies among men [35]. Likewise, in population studies [25, 30, 31, 35] where the risks were assessed together in both sexes; inclusion of women in the analysis usually reduces or attenuates the risks. This is likely to be because alcohol consumption among men is usually heavier compared with women [25], however, the pooled analysis of cohort studies [12] reported an increased risk also among the smaller proportion of women who
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Table 3 Risk ratios and 95% CI of colorectal cancer by quintile of alcohol consumption (a) at baseline and (b) after excluding 1st 2 years of follow up Quintile Person- Incident years cases n
Incidence rate/ 100,000
(95% CI)
Model 1 Risk ratio
(95% CI)
Model 2 P-value
Risk ratio
(95% CI)
Model 3 P-value
Risk (95% CI) ratio
P-value
(a) At baseline 7.0 106.6 1a
1a
1a
1st
8802.4
5
56.8
2nd
9098.4
13
142.9
65.2 220.6
2.6
(0.9–7.3)
0.07
2.6
(0.9–7.2)
0.08
2.4
(0.9–6.8)
0.10
3rd
8758.0
13
148.4
67.7 229.1
2.9
(1.0–8.2)
0.04
2.7
(0.9–7.7)
0.07
2.5
(0.9–7.2)
0.09
4th
8867.5
11
124.0
50.7 197.4
2.4
(0.8–6.9)
0.11
2.4
(0.8–6.9)
0.11
2.2
(0.8–6.4)
0.15
5th
8081.5
17
210.4
110.4 310.4
4.4
(1.6–11.9) 0.004
3.8
(1.3–10.7) 0.01
3.5
(1.2–9.8)
0.02
(b) After excluding 1st 2 years of follow up
a
7.0 106.6 1a
1a
1a
1st
8802.4
5
56.8
2nd
9098.4
12
131.9
57.3 206.5
2.4
(0.8–6.8)
0.1
2.3
(0.8–6.6)
0.11
2.2
(0.8–6.3)
0.14
3rd
8758.0
13
148.5
67.7 229.1
2.9
(1.0–8.1)
0.05
2.7
(0.9–7.7)
0.07
2.5
(0.8–7.2)
0.09
4th
8893.0
7
78.7
20.5 137.4
1.5
(0.5–4.7)
0.49
1.5
(0.5–4.7)
0.48
1.4
(0.4–4.4)
0.59
5th
8081.5
17
210.4
110.4 310.4
4.4
(1.6–11.9) 0.004
3.8
(1.3–10.7) 0.01
3.5
(1.2–9.8)
0.02
Reference
Model 1: Adjusted for age and examination year Model 2: Adjusted for age, examination year, vegetable consumption, fibre intake Model 3: Adjusted for age, examination year, vegetable consumption, fibre intake, family history of cancer, smoking, socio-economic status and leisure time physical activity
consumed more than 30 g/day. In our study cohort, the median weekly alcohol intake among men who had an increased risk of colorectal cancer was 199 g/week. This may imply that the association between alcohol and colorectal cancer may not be evident in populations where alcohol consumption is low or moderate even though in our study, there were elevated risks for men in quintiles 2 and 3 but these did not attain statistical significance. These results however need to be interpreted cautiously because of the small number of cancer cases. Strengths of our study include its prospective population based design. Assessment of exposure took place at baseline before the subjects developed cancer thereby avoiding recall bias. Participation rate in our study was high, follow up was long and there were no losses to follow up because of the unique personal identifier number and record linkage. We also had detailed information on a range of possible confounding factors which we controlled for. Nevertheless, the following limitations in our study also need to be considered while interpreting the results. (i) Alcohol consumption was assessed based on a questionnaire, thus subject to underreporting or any other misclassification. There is however no reason to believe that any reporting bias is likely to be systematically differential across drinking groups [41]. The questionnaire had previously been validated using biochemical markers of excessive alcohol use such as MCV and GGT, but nevertheless, we cannot completely rule out misclassification. (ii) Alcohol
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consumption was assessed at baseline; hence we do not have information on changes in drinking habits afterwards. This can lead to misclassification of exposures if drinking habits change during follow up. This type of misclassification, if influential will most likely bias the estimates towards null but in our study there could have been misclassification between adjacent categories and as such the estimates could be biased in any direction. (iii) Because of the relatively small number of cancer cases, our findings could have been due to chance. The small number of incident cancer cases also prevented us from carrying out more extensive analyses. In conclusion, the risk of colorectal cancer is increased in men with the highest amount of alcohol intake. The extent of this relationship may vary in different groups depending on the amount and predominant type of alcoholic beverage consumed within that group. Nevertheless, studies which consider lifelong alcohol consumption will be needed to provide more detailed information regarding the risks associated with each specific alcoholic beverage especially liquor. Acknowledgements This study was supported by grants 118551 and 118584 awarded by the Academy of Finland. The funding sources had no role in the collection, analysis, or interpretation of data; in the writing of the report; or in the decision to submit the article for submission. We express gratitude to Kimmo Rainkonen of the Research Institute of Public Health, University of Kuopio, Kuopio, Finland for data management.
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