Japanese Journal of Clinical Oncology Advance Access originally published online on July 26, 2006
Japanese Journal of Clinical Oncology 2006 36(9):582-597; doi:10.1093/jjco/hyl069
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© 2006 Foundation for Promotion of Cancer Research
Alcohol Drinking and Colorectal Cancer Risk: an Evaluation Based on a Systematic Review of Epidemiologic Evidence among the Japanese Population
1 Department of Preventive Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 2 Department of Preventive Medicine, Saga Medical School, Faculty of Medicine, Saga University, Saga, 3 Division of Epidemiology, Department of Public Health and Forensic Medicine, Tohoku University Graduate School of Medicine, Sendai, 4 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, 5 Department of Epidemiology & Preventive Medicine, Gifu University School of Medicine, Gifu and 6 Epidemiology and Prevention Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
For reprints and all correspondence: Tetsuya Mizoue, MD, Department of Epidemiology, Research Institute, International Medical Center of Japan, 1-21-1 Toyama, Shijuku-ku, Tokyo 162-8555, Japan. E-mail: mizoue{at}ri.imcj.go.jp
* Members of the Research Group for the Development and Evaluation of Cancer Prevention Strategies in Japan: S.T. (Principal Investigator), M.I. Shizuka Sasazuki, Motoki Iwasaki, T.O. (National Cancer Center, Tokyo); I.T. (since 2004), Yoshitaka Tsubono (in 2003), Taichi Shimazu (Tohoku University, Sendai); K.W. (Aichi Cancer Center, Nagoya); C.N. (Gifu University, Gifu); T.M. (Kyushu University, Fukuoka); and K.T. (Saga University, Saga).
Received April 4, 2006; accepted May 26, 2006
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Abstract |
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 TOP Abstract INTRODUCTIONMETHODSMAIN FEATURES AND COMMENTSEVALUATION OF EVIDENCE ON...References |
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Background: It remains unclear whether alcohol drinking is causally associated with colorectal cancer. On the basis of a systematic review of epidemiological evidence, we evaluated this association among the Japanese population, who may be more susceptible to alcohol-related diseases than Western populations.
Methods: Original data were obtained from searches of MEDLINE using PubMed, complemented with manual searches. The evaluation of associations was based on the strength of evidence and the magnitude of association, together with biological plausibility as previously evaluated by the International Agency for Research on Cancer.
Results: We identified 5 cohort studies and 13 case–control studies. A moderate or strong positive association was observed between alcohol drinking and colon cancer risk in all large-scale cohort studies, with some showing a dose–response relation, and among several case–control studies. The risk of colon or colorectal cancer was increased even among moderate drinkers consuming <46 g of alcohol per day, levels at which no material increase in the risk was observed in a pooled analysis of Western studies. A positive association with rectal cancer was also reported, but it was less consistent, and the magnitude of the association was generally weaker compared with colon cancer.
Conclusion: We conclude that alcohol drinking probably increases the risk of colorectal cancer among the Japanese population. More specifically, the association for the colon is probable, whereas that for the rectum is possible.
Key Words: systematic review • epidemiology • alcohol drinking • colorectal cancer • Japanese
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INTRODUCTION |
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TOPAbstractINTRODUCTIONMETHODSMAIN FEATURES AND COMMENTSEVALUATION OF EVIDENCE ON...References |
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In Japan, colorectal cancer has markedly increased over the last several decades (1) and its incidence is now among the highest levels in the world (2). Such chronological trend in colorectal cancer may be attributable to collective changes in various aspects of lifestyles including diet and physical activity. However, the increasing male-to-female gap in colorectal cancer mortality since 1970 in Japan (1) is of note and the contribution of tobacco smoking or alcohol drinking, both of which are much more prevalent in men than in women (3), is suspected. In our previous work (4), however, we did not find consistent data suggesting a close link of colorectal cancer to smoking among the Japanese.
Although numerous studies reported a positive association between alcohol drinking and colorectal cancer risk, it remains unclear whether alcohol drinking is causally related to carcinogenesis of the colorectum. A report from the World Cancer Research Fund and American Institute for Cancer Research concluded that alcohol drinking ‘probably’ increases colorectal cancer risk (5), whereas a recent report of a Joint World Health Organization (WHO)/Food and Agriculture Organization (FAO) Expert Consultation did not include colorectal cancer in the list of alcohol-related malignancies (6). However, the influence of alcohol drinking is of particular concern for the Japanese because of their relatively high prevalence of the slow-metabolizing ALDH variant (7), associated with higher levels of acetaldehyde in alcohol drinkers.
The objective of the present study was thus to review epidemiological findings regarding the association between alcohol drinking and colorectal cancer among the Japanese population. This work is conducted as a systematic review of epidemiological evidence regarding lifestyles and major forms of cancer in Japan (4,8).
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METHODS |
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TOPAbstractINTRODUCTIONMETHODSMAIN FEATURES AND COMMENTSEVALUATION OF EVIDENCE ON...References |
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The original data for this review were identified by searches of MEDLINE using PubMed, complemented by manual searches of references from relevant articles where necessary. All epidemiological studies on the association between alcohol drinking and colorectal cancer incidence or mortality among Japanese published from 1965 to 2005 were identified using the search terms ‘alcohol’, ‘colorectal cancer’, ‘colon cancer’, ‘rectal cancer’, ‘cohort studies’, ‘case–control studies’, ‘Japan’, and ‘Japanese’ as keywords found in the abstract. Papers written in either English or Japanese were reviewed, and only studies on Japanese populations living in Japan were included. The individual results were summarized in the tables separately by a study design as cohort or case–control studies and, if available, by cancer site as colon, rectum or colorectum.
An evaluation was made on the basis of the magnitude of association and the strength of evidence. First, the relative risks in each epidemiological study were grouped by the magnitude of association, while considering statistical significance (SS) or no statistical significance (NS), as strong, <0.5 or >2.0 (SS); moderate, either (i) <0.5 or >2.0 (NS), (ii) >1.5 to 2.0 (SS), or (iii) 0.5 to <0.67 (SS); weak, either (i) >1.5 to 2.0 (NS), (ii) 0.5 to <0.67 (NS) or (iii) 0.67–1.5 (SS); or no association, 0.67–1.5 (NS). In the case of multiple publications of analyses of the same or overlapping data sets, only data from the largest or most updated results were included, and the incidence was given priority over mortality as an outcome measure. The incidence was also given priority in a single publication describing both incidence and mortality. After this process, the strength of evidence was evaluated in a similar manner to that used in the WHO/FAO Expert Consultation Report (6), in which evidence was classified as ‘convincing’, ‘probable’, ‘possible’ and ‘insufficient’. We assumed that biological plausibility, based on evidence in experimental animals and mechanistic and other relevant data, corresponded to the judgement of the most recent evaluations from the International Agency for Research on Cancer [IARC (9,10)]. Notwithstanding the use of this quantitative assessment rule, an arbitrary assessment cannot be avoided when considerable variation exists in the magnitude of association between the results of each study. The final judgement was therefore made on the basis of a consensus of the research group members, and it was therefore not necessarily objective.
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MAIN FEATURES AND COMMENTS |
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A total of 5 cohort studies (11–16) and 13 case–controls studies (17–29) were identified (Tables 1 and 2, respectively). As regards Hirayama's study, we referred to two sources; one contained results for the colon and rectum with some additional data for sigmoid colon (13), whereas the other included results of detailed analysis for the sigmoid colon (12). Among the cohort studies, four (12–16) presented results by gender, one (10) for men only. The respective numbers for the case–control studies are two (17,25) and four (19,20,26,29), and the remaining seven studies (18,21–24,27,28) presented results for men and women combined. A summary of the magnitude of association for these studies is shown in Tables 3 and 4 for the cohort studies and case–control studies, respectively.
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Four large-scale cohort studies (12–16) showed relative risks separately for colon and rectum. In men, three (14–16) of these studies found a moderate to strong positive association with colon cancer and one (12) reported a strong positive association with sigmoid colon cancer. In women, a moderate association was also observed for colon (14) or sigmoid colon (12). For rectal cancer, one study (15) found a strong positive association in men only, whereas three studies found a weak positive association either in men (13) or in women (14,16). Of the two cohort studies showing relative risk for colon and rectum combined, a nation-wide study (15) reported a strong positive association in men but not in women. A significant dose– or frequency–response relation was observed for cancer of the colon (14), rectum (12,16), or both (15).
Of the 13 case–control studies evaluated, 10 studies (17–21,23–25,28) provided odds ratios for the colon and rectum separately and 1 study presented data for the colon only (22). Among these studies, two studies (17,22) found a strong inverse association between alcohol drinking and colon cancer risk, whereas other three studies (22,26,29) showed a strong positive association for colon and another study (20) found a weak positive association for distal colon. Similar results were observed for rectal cancer, but the association for rectum was less clear than that for colon. Of the four case–control studies (22,27–29) reporting odds ratio for the colon and rectum combined, three (22,27,29) found a strong positive association with alcohol drinking and the remaining study (28) exhibited a weak positive association. All studies (22,26,27,29) showing a strong positive association also reported a significant dose–response relation.
We should mention methodological issues in general and specific to the Japanese studies reviewed here. Attention should be paid when interpreting the results of case–control studies. First, patient recall of lifestyles in the remote past may be influenced by recent lifestyles. Secondly, many diseases are potentially alcohol-related, and this may be a source of bias in case–control studies using patient group as the reference. Thirdly, colorectal cancer risk associated with ex-drinking may be overestimated because quitting drinking might be a result of cancer manifestation. Fourthly, since few case–control studies controlled for physical activity and obesity, identified factors predictive of colorectal cancer risk (6), confounding by these factors may account for the observed association between alcohol drinking and colorectal cancer. However, recent large-scale cohort studies (14–16) that controlled for known or suspected aetiologic factors of colorectal cancer demonstrated a moderate or strong association, a finding arguing against confounding as an explanation for the association. Cohort studies have also their inherent limitations. Since only baseline information on lifestyles was used in analysis of the relation to colorectal cancer risk, the effect of bias related to changes in alcohol drinking habit during the time course cannot be ruled out. Moreover, we identified methodological differences among cohort studies reviewed; alcohol drinking habit was determined using simple, not-validated questionnaire, and death was the study outcome in earlier cohort studies, whereas in recent ones alcohol consumption was quantitatively estimated on the basis of a detailed, validated questionnaire and incidence was the study outcome. In this regard, more emphasis should be placed on the results of recent studies.
In experimental animals, there is sufficient evidence for the carcinogenicity of acetaldehyde (10), a metabolite of alcohol, whereas there is inadequate evidence for the carcinogenicity of ethanol and of alcoholic beverages (9). Although specific mechanisms whereby alcohol drinking influences colorectal carcinogenesis remains unclear, alcohol or acetaldehyde may induce DNA hypomethylation, an early step in colonic carcinogenesis, through its anti-folate effects (30). Moreover, acetaldehyde generated by intestinal bacteria may also increase the risk of colorectal cancer via folate deficiency (31).
The magnitude of association between alcohol drinking and colorectal cancer among Japanese studies appears to differ from that among Western populations. In a pooled analysis of Western cohort studies (32), relative risk of colon cancer for heavy alcohol drinkers consuming 45 g of alcohol or over per day versus non-drinkers was 1.2. In recent cohort studies in Japan, however, relative risks for colon cancer versus non-drinker category were 2.7 (14), 2.1 (15) and 2.4 (16) for the highest category of alcohol consumption, whose cut-off values were 37, 43 and 69 g of alcohol per day, respectively. Moreover, moderate drinking (<45 g/day) was materially unrelated to colon cancer risk in Western populations (32), whereas corresponding levels of alcohol consumption were associated with 1.4- to 1.8-fold increased risk of colon cancer among Japanese populations (14–16). These findings suggest that Japanese drinkers are more likely to develop colon cancer than Western counterparts. This may be explained in part by the relatively high prevalence of the slow-metabolizing ALDH variant among Japanese (7,29). Non-genetic factors may also contribute to the heterogeneity of risk among populations. For instance, a dietary pattern typical of Japanese drinkers—low consumption of fruits and vegetables and dairy foods (33)—may enhance the carcinogenic effects of alcohol or acetaldehyde. Furthermore, lean alcohol drinkers may be more likely to develop colorectal cancer than non-lean counterparts (32), presumably because of a differential effect of alcohol on insulin metabolism according to body composition. This may also account for the stronger alcohol–colon cancer association among the Japanese, who are on average leaner than Western people.
We found a consistent, moderate to strong positive association between alcohol drinking and colon cancer among major cohort studies, with some showing a dose–response relation, and among several case–control studies. For rectal cancer, most cohort studies showed a positive association with alcohol drinking, but the association was generally weaker than that for colon cancer. However, a pooled analysis of Western studies (32) did not exhibit significant variation in the magnitude of association according to site within the large bowel, and a Japanese study of alcohol and colorectal adenoma, a precursor of cancer, found a stronger association in the rectum compared with other sites of the colorectum (34). Thus, random variation may be a reason for the apparent inconsistent association for rectal cancer among Japanese studies. Moreover, the stronger and more consistent association in men than in women among Japanese studies may be attributable to a greater proportion of heavy drinkers in men, and not to a sex difference in disease susceptibility. Unfortunately, published data to date do not allow us to conduct a meta-analysis to confirm these, because results were presented according to alcohol consumption (in grams, millilitres or go) in most cohort studies but in less than half of the case–control studies among Japanese populations, whereas only drinking frequency was asked in other Japanese studies. A meta-analysis using original data set of recent cohort studies in Japan is now under way to clarify whether the magnitude of association differs according to site of the large bowel or sex and to quantify the impact of alcohol drinking on colorectal cancer risk among the Japanese population.
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EVALUATION OF EVIDENCE ON ALCOHOL DRINKING AND COLORECTAL CANCER RISK IN JAPANESE |
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TOPAbstractINTRODUCTIONMETHODSMAIN FEATURES AND COMMENTSEVALUATION OF EVIDENCE ON...References |
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From these results and on the basis of assumed biological plausibility, we conclude that alcohol drinking probably increases the risk of colorectal cancer among the Japanese population. More specifically, the association for colon is probable, whereas that for rectum is possible.
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Acknowledgments |
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The authors gratefully acknowledge the assistance of Ms Tamami Hatano, Ms Izumi Suenega and Mr Tomohiro Shintani. This work was supported by the Third Term Comprehensive 10-year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare, Japan.
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