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Annals of Oncology Advance Access published online on January 10, 2008
Annals of Oncology, doi:10.1093/annonc/mdm590
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© 2008 European Society for Medical Oncology. For Permissions, please email: journals.permissions@oxfordjournals.org

Alcohol consumption and renal cell cancer risk in two Italian case–control studies

C. Pelucchi1,*, C. Galeone1, M. Montella2, J. Polesel3, A. Crispo2, R. Talamini3, E. Negri1, V. Ramazzotti4, M. Grimaldi2, S. Franceschi5 and C. La Vecchia1,6

1 Istituto di Ricerche Farmacologiche ‘Mario Negri’, 20157 Milan
2 Servizio di Epidemiologia, Istituto Nazionale Tumori ‘Fondazione G. Pascale’, 80100 Naples
3 S.O.C. Epidemiologia e Biostatistica, Centro di Riferimento Oncologico, 33081 Aviano
4 Servizio Integrato di Epidemiologia e Sistemi Informativi (SINTESI), Istituto Nazionale Tumori ‘Regina Elena’, 00144 Roma, Italy
5 International Agency for Research on Cancer, 69372 Lyon Cedex, France
6 Istituto di Statistica Medica e Biometria ‘G. A. Maccacaro’, Università degli Studi di Milano, 20133 Milan, Italy

* Correspondence to: Dr C. Pelucchi, Istituto di Ricerche Farmacologiche ‘Mario Negri’, Via La Masa 19, 20156 Milan, Italy. Tel: +39-02-39014577; Fax: +39-02-33200231; E-mail: pelucchi{at}marionegri.it


   Abstract
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 Abstract
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 patients and methods
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 References
 
Background: There is some evidence that alcohol consumption is inversely associated with renal cell cancer (RCC), but the issue is still unclear.

Patients and methods: We investigated the relation using data from two Italian multicentric case–control studies conducted from 1985 to 2004, including a total of 1115 incident, histologically confirmed cases and 2582 controls hospitalised with acute, non-neoplastic conditions.

Results: Compared with non-drinkers, the multivariate odds ratios (ORs) of RCC were 0.87 [95% confidence interval (CI) 0.73–1.04] for ≤4 drinks per day, 0.76 (95% CI 0.59–0.99) for >4 to ≤8 drinks per day and 0.70 (95% CI 0.50–0.97) for >8 drinks per day of alcoholic beverages, with a significant inverse trend in risk (P value = 0.01). The ORs were 0.85 (95% CI 0.71–1.02) for wine, 0.84 (95% CI 0.68–1.03) for beer and 0.86 (95% CI 0.70–1.05) for spirits consumption, as compared with abstainers. No trend in risk of RCC emerged with duration (P value = 0.94) and age at starting alcohol consumption (P value = 0.81). Results were consistent in men and women, as well as in strata of age, smoking and body mass index.

Conclusions: This pooled analysis found an inverse association between alcohol drinking and RCC. Risks continued to decrease even above eight drinks per day (i.e. >100 g/day) of alcohol intake, with no apparent levelling in risk.

alcohol drinking, alcoholic beverages, case–control studies, renal cell carcinoma, risk factors


   introduction
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 Abstract
 introduction
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Epidemiological studies showed a role of a few modifiable risk factors in the aetiology of renal cell cancer (RCC), namely tobacco smoking and obesity [1]. Alcohol drinking has been less extensively investigated, but there is some evidence that it might be inversely (rather than directly, as for upper aerodigestive tract, liver, colorectal and breast cancer [2, 3]) associated with RCC. In fact, various cohort studies recently found a reduced incidence of RCC in alcohol drinkers, with relative risks (RRs) of 0.5 [95% confidence interval (CI) 0.3–0.8] in Finland [4] and 0.7 (95% CI 0.4–1.0) in the United States [5] and in Sweden (95% CI 0.4–1.2) [6], by comparing subjects at the highest level of alcohol consumption with non-drinkers or occasional drinkers. A pooled analysis of these and other eight cohort studies conducted in the United States, Canada and the Netherlands, including a total of 1430 subjects with RCC, showed RRs of 0.97, 0.82 and 0.72 for subsequent levels of alcohol consumption (highest level ≥15 g/day) as compared with non-drinkers and a similar inverse association in men and women [7].

Case–control studies generally found null or, more frequently in women, inverse associations [8–16]. The largest retrospective investigations providing information on alcohol and RCC were the ‘International renal cell cancer study’, including 1185 cases and 1526 controls that found odds ratios (ORs) for high alcohol intake of 1.0 (95% CI 0.7–1.4) in men and 0.5 (95% CI 0.3–0.8) in women [13], and a Canadian study of 1279 cases, which reported an inverse trend in risk of RCC in both genders (P value < 0.01) [17]. A few smaller case–control studies were conducted in Southern European populations [11, 15, 18, 19], where wine is the most commonly consumed alcoholic beverage [20], and these found no significant associations. The role of different types of alcoholic beverages, amount and duration of consumption and the consequences of drinking cessation are other aspects of the relation between alcohol consumption and RCC that are still unclear.

Therefore, we analysed the association of alcohol with RCC in Italy, i.e. in a population where regular and relatively heavy alcohol (mainly wine) drinking is common, using data from two case–control studies of RCC conducted from 1985 to 2004.


   patients and methods
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 Abstract
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The general scheme and methods of the studies have been extensively described elsewhere [15, 21]. In the first study, data were collected from 1985 to 1992 in the greater Milan area and the province of Pordenone, in northern Italy, on 348 patients with RCC (236 men and 112 women) aged 25–77 years (median age 60 years) and 1048 controls (753 men and 295 women) aged 23–79 years (median age 60 years). The second study was conducted from 1992 to 2004 in four Italian areas, including the greater Milan area and the provinces of Udine and Pordenone in northern Italy, the province of Latina in central Italy and the urban area of Naples in southern Italy, on 767 patients with RCC (494 men and 273 women) aged 24–79 years (median age 62 years) and 1534 controls (988 men and 546 women) aged 22–79 years (median age 62 years), matched with cases by study centre, sex and quinquennia of age, with a case to control ratio of 1 : 2. In both studies, cases were patients with incident, histologically confirmed RCC, admitted to major teaching and general hospitals of the study areas. Cancers of the renal pelvis and ureter (International Classification of Diseases-9 189.1–189.2) were not included. Histological information from the second study included cancer cell type [22]. There were 416 clear-cell, 51 papillary and 11 chromophobic carcinomas, 88 other/unclassified subtypes and 201 unknown histology. Controls were admitted to the same hospitals as cases for a wide spectrum of acute, non-neoplastic conditions, unrelated to known risk factors for RCC. The distribution of control diagnoses was different in the two studies; overall, 24% of controls were admitted for traumas (mostly fractures and sprains), 30% for other orthopaedic disorders (such as low-back pain and disc disorders), 17% for surgical conditions and 29% for various other illnesses including eye, nose, ear or skin disorders. Less than 5% of both cases and controls contacted refused to participate. A total of 1115 cases and 2582 controls were included in the present analysis.

Cases and controls were interviewed during their hospital stay by trained interviewers, using structured questionnaires that included information on socio-demographic characteristics; anthropometric measures; lifestyle habits, such as tobacco smoking and coffee consumption; dietary habits; personal medical history and family history of cancer in first-degree relatives. The section on alcohol drinking of the first study included the number of days per week and drinks per day each alcoholic beverage (i.e. wine, beer and spirits) was consumed and the duration of the habit. The second study included questions on weekly number of drinks of wine, beer, grappa (a typical Italian spirit), amari and digestives (other types of Italian liquors drunk after meals) and spirits (whisky, cognac and brandy), age at first and last use of each alcoholic beverage and whether consumption occurred during or outside meals or both. In both studies, one drink corresponded ~ 125 ml of wine, 330 ml of beer and 30 ml of liquors and spirits (i.e. ~12–15 g of alcohol, on the basis of a specifically designed food and beverages composition database [23]). The period of drinking was investigated up to 1 year before diagnosis for cases or hospital admission for controls. The questionnaires were tested for reproducibility and validity, and a satisfactory level of both measures of the pattern of alcohol consumption was observed across different levels and types of alcoholic beverage intake [24, 25]. The reproducibility of wine and total alcohol intake showed r > 0.75, whereas the validity was somewhat higher for wine (r ~ 0.70) than for other alcoholic beverages and total alcohol.

We used a two-sided Wilcoxon rank sum test to compare cases and controls according to consumption of different types of alcoholic beverages. ORs and the corresponding 95% CIs were calculated using multiple logistic regression models [26], adjusted for study, sex, age, study centre, years of education, family history of renal cancer in first-degree relatives, tobacco smoking and body mass index (BMI). The OR for an increase of one drink per day was also estimated, including total alcohol (or wine) consumption in the model as a continuous variable. The dose–response relation between ethanol daily intake and risk of RCC was further investigated using logistic regression splines with appropriate pointwise CIs [27–29], adjusted for the same cofactors. The best-fitting model was selected minimising the Akaike information criterion [30].


   results
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The distribution of RCC cases and of the comparison group according to selected variables is presented in Table 1. As compared with controls, cases reported a higher educational level (P < 0.01), were more frequently heavy smokers (P < 0.05) and had more frequently a family history of kidney cancer in first-degree relatives (P < 0.01). Among drinkers of each type of alcoholic beverage, the mean numbers of daily drinks were 2.95 and 3.32 for cases and controls, respectively, for wine consumption (P < 0.01), 0.67 and 1.16 for beer consumption (P < 0.01) and 0.73 and 0.84 for spirits consumption (P < 0.05).


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  		Table 1. Distribution of 1115 cases of renal cell carcinoma and 2582 controls according to sex, age and selected covariates (Italy, 1985–2004)

 
Table 2 gives the frequency distribution of cases and controls, the multivariate ORs and corresponding 95% CIs according to various measures of alcohol consumption. Overall, 23.1% of cases and 19.2% of controls were non-drinkers, whereas 6.3% of cases and 9.2% of controls consumed more than eight drinks of alcoholic beverages per day. With reference to the distribution of consumption of different types of beverages, 75.4% of cases and 78.8% of controls reported wine consumption, 32.8% of cases and 33.3% of controls reported beer consumption and 33.2% of cases and 34.3% of controls reported spirits consumption. As compared with non-drinkers, the ORs were 0.87 (95% CI 0.73–1.04) for subjects consuming ≤4 drinks of alcoholic beverages per day, 0.76 (95% CI 0.59–0.99) for >4 to ≤8 drinks per day and 0.70 (95% CI 0.50–0.97) for >8 drinks per day. There was a significant inverse trend in risk with dose (P value = 0.01). The OR was 0.97 (95% CI 0.95–1.00) for an increase in consumption of one drink of alcoholic beverages per day. With reference to different alcoholic beverages, ORs were 0.85 (95% CI 0.71–1.02) for wine, 0.84 (95% CI 0.68–1.03) for beer and 0.86 (95% CI 0.70–1.05) for spirits, as compared with abstainers. When we examined the frequency of days per week of wine consumption, the ORs were 0.97 (95% CI 0.73–1.28) for discontinuous drinkers and 0.83 (95% CI 0.69–1.00) for regular daily drinkers, as compared with abstainers. Further adjustment of the latter estimates for amount of alcohol consumption did not materially change the results. There was no trend in risk of RCC with duration of the habit (P value = 0.94) and age at starting consumption (P value = 0.81), nor any difference emerged comparing ex-drinkers (63 cases and 114 controls) with never drinkers (OR = 0.98, 95% CI 0.68–1.41).


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  		Table 2. Distribution of 1115 cases of RCC and 2582 controls according to alcohol consumption (Italy, 1985–2004)

 
Table 3 gives the ORs for total alcohol consumption according to strata of selected covariates. Results were consistent for men and women (P value for heterogeneity, 0.67). Likewise, no significant heterogeneity was reported across strata of age (P value = 0.92), BMI (P value = 0.40) and smoking (P value = 0.51). The risk in drinkers versus non-drinkers was, if anything, lower for the subset of 416 cases classified as clear-cell carcinomas (OR = 0.80, 95% CI 0.61–1.04).


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  		Table 3. Relationship between alcohol consumption and risk of renal cell cancer in strata of selected covariates (Italy, 1985–2004)

 
Figure 1 shows the shape of the best-fitting regression spline (dose–response curve). The risk of RCC decreased throughout the range of alcohol consumption.


Figure 1
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  		Figure 1. Estimates of odds ratios (solid line) and 95% confidence intervals (dashed lines) of renal cell cancers using regression spline by total alcohol intake. Regression equations include terms for age, sex, study, study centre, education, smoking habits, body mass index and family history of renal cancer. Curves are shown for best-fitting splines according to Akaike information criterion.

 

   discussion
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 Abstract
 introduction
 patients and methods
 results
 discussion
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 Acknowledgements
 References
 
This uniquely large national investigation from a southern European population found an inverse association between alcohol drinking and RCC. Thus, this study confirmed the results of a recent pooled analysis of cohort studies [7]. Given the wide range of alcohol drinking in Italy, including a relatively common heavy wine consumption [31], this study, however, also allowed to evaluate the risk of RCC in heavy drinkers. We found that risks continued to decrease even above eight drinks of alcoholic beverages per day (i.e. >100 g/day of alcohol), with no apparent levelling in risk. The existence of an inverse dose–risk relation gave further support to the hypothesis of a protective effect of alcoholic beverages. The reduction in risk of RCC was consistent in men and women, as well as in strata of age, smoking habit and BMI.

Lee et al. [7] explained the inverse association between alcohol consumption and RCC through the effects of alcohol on insulin sensitivity [32]. Other possible mechanisms of protection are a role of fluid intake (by diluting carcinogenic substances) and/or of antioxidant compounds contained in alcoholic beverages. Nevertheless, we found no meaningful difference in risk among different alcoholic beverages.

Duration of the habit was not associated with RCC risk. Duration of alcohol consumption, however, showed no influence on cancer even in studies of the upper aerodigestive tract, i.e. sites that are strongly (directly) related with amount of alcohol intake [33–35]. In the second study only, we were also able to consider age at starting consumption of alcohol that showed no influence on the risk of developing RCC, too, and the effect of stopping drinking. Nevertheless, when we separated ex-drinkers from never drinkers, we found no difference in risk of RCC.

A few previous studies indicated a different effect of alcohol intake on RCC risk according to gender, with a protective outcome among women but not men [12–14]. We also had considered this issue in an earlier report using data from our first case–control study [15], and we did not find significant results in both men and women. This pooled analysis conducted on a larger number of subjects also showed no appreciable modification in risk by gender.

Hospital controls could differ from the general population with regard to alcohol consumption, but we carefully excluded from the study any patient admitted to the hospital for chronic conditions or digestive tract diseases. Underreporting of drinking may have occurred, but alcohol consumption is socially accepted in Italy and information on alcohol drinking from the questionnaire was satisfactorily reliable and valid [24, 25]. Further, the similar interview setting of cases and controls is reassuring against potential information bias. Among other strengths of this study are the almost complete participation of cases and controls, use of data from a population with a wide range of alcohol drinking and a peculiar pattern of consumption (i.e. mainly wine drinking, consumed regularly during meals by both men and women), availability of information on duration of alcohol drinking, of several potential covariates of alcohol consumption and of age at starting and stopping consumption of each beverage.


   funding
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 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
Acknowledgements
 References
 
Italian Association for Cancer Research; the Italian League against Cancer; the Italian Ministry of Education (PRIN 2005); Italian Foundation for Cancer Research to C.G.


   Acknowledgements
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 Abstract
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 Acknowledgements
References
 
The authors thank Mrs Ivana Garimoldi for editorial assistance.

Received for publication October 17, 2007. Revision received December 6, 2007. Accepted for publication December 6, 2007.


   References
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 Abstract
 introduction
 patients and methods
 results
 discussion
 funding
 Acknowledgements
 References
 
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