Journal of Clinical Epidemiology 55 (2002) 637641

Alcohol drinking and bladder cancer

Claudio Pelucchia,*, Eva Negria, Silvia Franceschic, Renato Talaminid, Carlo La Vecchiaa,b
a Istituto di Ricerche Farmacologiche Mario Negri. 20157 Milan, Italy Istituto di Statistica Medica e Biometria, Universit degli Studi di Milano, 20133 Milan, Italy c Field and Intervention Studies Unit, International Agency for Research on Cancer, Lyon Cedex, France d Centro di Riferimento Oncologico, 33081 Aviano, PN, Italy Received 18 August 2001; received in revised form 10 December 2001; accepted 23 January 2002 b

Abstract
The relation between alcoholic beverage consumption and bladder cancer risk was investigated using data from a casecontrol study conducted between 1985 and 1992 in two areas of northern Italy. Cases were 727 patients with incident, histologically confirmed bladder cancer, and controls 1,067 patients admitted to the same network of hospitals for acute, non-neoplastic, nonurologic, or genital tract diseases. Compared to nondrinkers, the odds ratio (OR) was 0.79 (95% confidence interval, CI, 0.581.08) for drinkers, and 0.84 (95%CI, 0.581.22) for 6 drinks/day. The OR was 0.86 (95%CI, 0.601.23) for 5 wine drinks/day, 0.69 for beer, and 0.85 for spirits. No trend was observed with duration (OR 1.00 for 40 years). ORs were consistent across various strata of covariates including age, sex, and smoking habits. Our study, based on a population with high alcohol (mainly wine) intake, found no association between bladder cancer risk and alcohol intake, even at high levels of consumption. 2002 Elsevier Science Inc. All rights reserved.
Keywords: Alcohol; Bladder cancer; Casecontrol study; Coffee; Tobacco

1. Introduction The issue of alcohol and bladder cancer has been widely considered, but remains open to discussion. No association was found in a multicentric U.S. study including 2,982 cases and a comparable number of controls [1], as well as in most other cohort and casecontrol studies [2]. Although a strong association can now be excluded, a meta-analysis of 16 epidemiologic studies published up to 1999 [3] gave an overall relative risk (RR) for current drinkers vs. nondrinkers of 1.3, of borderline significance. In a more recent cohort study from The Netherlands [4], a significant direct trend in risk was observed in men, with a RR of 1.6 for drinkers of 30 g of ethanol per day in males, and of 1.0 in females. Residual confounding by tobacco smoking, which is positively correlated with alcohol, or other covariates, remains, however, possible [4,5]. In Italy, alcohol consumption is widespread, and heavy consumptionparticularly of wineis frequent [6,7], i.e., over 75% of Italian males and over 50% of females were daily drinkers, and about 25% of men drank over 50 g of alcohol per day [8]. This provides an optimal situation for investigating any potential relation between alcohol drinking

and bladder cancer risk. We considered, therefore, data from a large, multicentric casecontrol study of bladder cancer from northern Italy [9,10], where detailed information was available on tobacco smoking, hence permitting careful allowance for this variable, as well as on a large number of other covariates. 2. Materials and methods Between 1985 and 1992 we conducted a casecontrol study of bladder neoplasm in the greater Milan area and in the province of Pordenone, in the North-east of Italy [911]. Trained interviewers identified and questioned cases and controls admitted to the hospitals in the areas under surveillance for cancer of the bladder or for a wide spectrum of other conditions. 2.1. Cases A total of 727 histologically confirmed incident cases of invasive, transitional cell bladder cancer (617 males, 110 females), aged 2779 years (median age 63), were included in the study. They were recruited in the National Cancer Institute and a network including other major general hospitals and university clinics in the greater Milan area and the Pordenone Cancer Institute and General Hospital. Controls were 1,067 subjects (769 males, 298 females), ranging from 25 to 79 years (median age 60), admitted to

* Corresponding author. Tel.: 39-02-39014.541; fax: 33200231. E-mail address: pelucchi@marionegri.it (C. Pelucchi).

39-02-

0895-4356/02/$ see front matter 2002 Elsevier Science Inc. All rights reserved. PII: S0895-4356(02)00 3 9 7 - 9

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C. Pelucchi et al. / Journal of Clinical Epidemiology 55 (2002) 637641

Table 1 Distribution of 727 cases of bladder cancer and 1,067 controlsa according to age, sex, and selected characteristics and corresponding odds ratios (OR) and 95% confidence intervals (CI). Italy, 19851992 Cases No. % Age 50 5054 5559 6064 6569 70 Sex Males Females Education 7 711 12 Smoking habits Never Ex Current ( 15 cig/day) Current ( 15 cig/day) Coffee drinking (cups per day) 0 1 2 3 Tea drinking (cups per day) 0 1 Servings of green vegetables (per day) 1 1 to 2 2 Exposure to occupation at riskd No Yes 50 49 125 173 178 152 (6.9) (6.7) (17.2) (23.8) (24.5) (20.9) 182 150 171 209 183 172 (17.1) (14.1) (16.0) (19.6) (17.1) (16.1) Controls No. % ORb 95% CI

617 (84.9) 110 (15.1) 449 (61.8) 182 (25.0) 96 (13.2) 122 243 107 255 (16.8) (33.4) (14.7) (35.1)

769 (72.1) 298 (27.9)

lected foods, history of selected diseases, family history of urological cancers, reproductive and sexual habits, history of relevant occupational exposures and modalities of diagnosis. Questions on tobacco included smoking status (eversmokers being defined as subjects who had smoked at least one cigarette, or pipe or cigar, per day for at least a year; exsmokers those who had stopped at least a year previously). Smokers and ex-smokers were asked the total duration of the habit, the average quantity smoked per day, and the names of up to three cigarette brands they had smoked for the longest time. Information was collected on consumption of wine, beer, and spirits, including the number of drinks per dayand how many days per weekand the total duration of the habit, in years. 2.2. Data analysis Odds ratios (OR) of bladder cancer and the corresponding 95% confidence intervals (CI) according to various measures of alcoholic beverage consumption, were obtained using unconditional multiple logistic regression [12] to account simultaneously for the effect of potential confounders. The regression equations included terms for study centre, age, sex, plus factors a priori identified as relevant in bladder carcinogenesis [5], i.e., education, smoking (i.e., never-smokers, ex-smokers, smokers of 15, 15 to 24, and 25 cigarettes per day plus a continuous term, pipe, or cigar smokers), coffee and tea drinking, consumption of green vegetables, and occupation previously defined as related to bladder cancer (i.e., chemical industry, dyestuff, painting, pharmaceutical, coal, and gas [13]). The significance of the linear trends in risk was assessed by comparing the differences between the deviances of the models without and with a term for alcohol consumption to the 2 distribution with 1 degree of freedom [12]. 3. Results Table 1 shows the distribution of cases and controls according to age, sex, and other selected covariates. Cases were more frequently ex- (OR 1.9) or current smokers (OR 2.4 for 15 cig/day; OR 3.6 for 15), reported higher levels of coffee drinking (OR 1.7 for 3 per day), and were more often involved in occupations at risk for bladder cancer (OR 1.7). Cases consumed less frequently green vegetables than controls, with an OR of 0.6 for the highest category of intake. Table 2 considers various measures of alcohol drinking. Wine drinking was reported by 84% of cases and 86% of controls, and heavy wine drinking (5 or more drinks/day) by 31% of cases and 30% of controls. Beer (21%) and spirit (29%) drinking was less common. For total alcohol, the OR for drinkers vs. nondrinkers was 0.79 (95% CI, 0.581.08). The OR for the highest consumption level ( 6 drinks per day) was 0.84 (95% CI, 0.581.22); for drinking five or more glasses of wine per day, the OR was 0.86 (95% CI, 0.60 1.23). An inverse relation was found for beer drinking (OR

706 (66.3) 1c 223 (20.9) 1.45 (1.141.85) 136 (12.8) 1.16 (0.861.57) 395 316 134 222 (37.0) (29.6) (12.6) (20.8) 1c 1.93 2.43 3.60 (1.432.63) (1.723.45) (2.644.92)

86 167 217 256

(11.8) (23.0) (29.9) (35.3)

151 278 314 323

(14.2) (26.1) (29.5) (30.3)

1c 1.05 1.32 1.69

(0.751.47) (0.951.83) (1.222.33)

619 (85.1) 108 (14.9)

907 (85.1) 1c 159 (14.9) 1.03 (0.781.35)

278 (38.2) 279 (38.4) 170 (23.4)

296 (27.7) 1c 402 (37.7) 0.81 (0.641.02) 369 (34.6) 0.60 (0.460.77)

657 (90.4) 1011 (94.8) 1c 70 (9.6) 56 (5.2) 1.71 (1.172.49)

a In some cases the sum does not add up to the total because of some missing values. b Estimates from multiple logistic regression including terms for age and sex. c Reference category. d Chemical industry, dyestuff, painting, pharmaceutical, coal, and gas.

the same network of hospitals of cases for acute, non-neoplastic, nonurological or genital tract diseases (23% were admitted for surgical conditions, 29% for fractures and other traumatic conditions, 18% for nontraumatic orthopaedic disorders, and 30% for miscellaneous other illnesses, such as skin, nose, and throat conditions). Less than 3% of subjects approached (cases, 2.6%; controls, 2.2%) refused the interview. The structured questionnaire included socio-demographic questions, detailed information on smoking habits, coffee and tea consumption, frequency of use of a few se-

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Table 2 Distribution of 727 cases of bladder cancer and 1,067 controlsa according to consumption of alcoholic beverages and corresponding odds ratios (OR) and 95% confidence intervals (CI). Italy, 19851992 Cases Type of Beverage Total alcohol, drinks per day Nondrinkers Drinkers 3 3 to 6 6 Trend, 2 0.42 (P 0.52) Wine, drinks per day Non drinkers Drinkers 3 3 to 5 5 Trend, 2 0.81 (P 0.37) Beer Nondrinkers Drinkers Spirits Nondrinkers Drinkers Duration of alcohol drinking (years) Nondrinkers 124 2539 40 Trend, 2 0.18 (P 0.67)
a b

Controls % (16.2) (83.8) (26.5) (26.7) (30.7) No. 152 913 319 275 319 % (14.3) (85.7) (30.0) (25.8) (29.9) ORb 1c 0.79 0.80 0.77 0.84 95% CI (0.581.08) (0.571.11) (0.541.10) (0.581.22)

No. 117 607 192 193 222

126 599 207 175 217

(17.4) (82.6) (28.5) (24.1) (29.9)

172 894 329 261 304

(16.1) (83.9) (30.9) (24.5) (28.5)

1c 0.86 0.90 0.78 0.86

(0.641.16) (0.661.25) (0.551.11) (0.601.23)

608 118 538 189 117 65 199 342

(83.8) (16.2) (74.0) (26.0) (16.2) (9.0) (27.5) (47.3)

802 264 730 337 152 157 400 351

(75.2) (24.8) (68.4) (31.6) (14.3) (14.8) (37.7) (33.1)

1c 0.69 1c 0.85 1c 0.68 0.73 1.00

(0.520.92) (0.660.92) (0.451.05) (0.511.02) (0.711.41)

In some cases the sum does not add up to the total because of some missing values. Estimates from multiple logistic regression including terms for age, sex, study center, education, smoking habits, coffee, tea, green vegetable intake, and exposure to occupation at risk (chemical industry, dyestuff, painting, pharmaceutical, coal, and gas). c Reference category.

0.69, 95% CI 0.520.92), and, though nonsignificantly, for spirits (OR 0.85, 95% CI 0.661.09). With reference to duration, the OR was 0.68 for 25 years, 0.73 for 2539 years, and 1.00 for 40 years. All tests for trend were nonsignificant. Table 3 gives the ORs according to average drinks per day of total alcohol drinking, in separate strata of age, sex, smoking habit, occupation at risk, coffee and tea, and green vegetable intake. The ORs were below unity in most subgroups, and no appreciable heterogeneity emerged across various strata. None of the interaction terms was significant. 4. Discussion Epidemiologic findings on a possible relation between alcohol drinking and bladder cancer are compatible with no association or a moderate positive one [24]. The risk estimates for drinkers in the present study (OR 0.8, 95%CI, 0.61.1) are in broad agreement, and in any case not heterogeneous from those of a recent meta-analysis, where the overall OR was 1.2 (95% CI, 0.91.7) [3]. Minor apparent differences may be due to the fact that various populations have different drinking patterns. In particular, Italians, like other Mediterranean population, drink

mainly wine [68], whereas populations from North America and northern Europe, where most studies have been conducted, drink more beer and spirits [2]. Wine consumption in Italy is frequent and often substantial [8,14]. Consequently, this study provides information mainly on wine on the risk of bladder cancer: the RRs for wine were similar to these of total alcohol intake, and it was difficult to disentangle any potential separate effect of beer and spirits. Wine may be a relevant source of fluid intake, which has been inversely related to bladder cancer in the Health Professionals follow-up study [15], although epidemiological results on the issue are not totally consistent [1618], perhaps also because of the difficulties in measuring total fluid intake [5,19]. Another explanation for the inconsistent epidemiological results on alcohol drinking and bladder cancer is that there are different correlates (including coffee [20,21] and diet [22,23]) of alcohol drinking, and the prevalence of other risk factors or cofactors can vary substantially across populations. Alcohol drinking, in fact, may be related to cigarette smoking, to a poorer diet [2426], or other recognized risk factors (i.e., social or occupational [5,8]) for bladder cancer. This, however, may apply less to Italy, where alcohol drinking is widespread [6].

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Table 3 Odds ratios (OR) and 95% confidence intervals (CI) of bladder cancer according to average alcoholic drinks per day in separate strata of selected covariates. Italy, 19851992 ORa (95% CI) Covariate Age 60 60 Sex Male Female Smoking habits Never smokers Ex smokers Current smokers Exposure to occupation at risk No Yes Coffee drinking (cups per day) 0 1 2 3 Tea drinking (cups per day) 0 1 Green vegetables (servings per day) 1 1 to 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0.77 (0.441.35) 0.87 (0.571.32) 0.86 (0.561.32) Drinkers: 0.88 (0.511.52) 0.78 (0.451.37) 0.74 (0.361.51) 0.97 (0.561.69) 0.79 (0.561.12) Drinkers: 0.40 (0.101.62) 0.65 (0.251.66) 0.83 (0.411.70) 0.75 (0.391.44) 0.79 (0.441.42) 0.90 (0.631.29) 0.34 (0.130.90) 0.80 (0.471.37) 0.89 (0.531.49) 1.18 (0.433.26) 0.83 (0.461.48) 0.81 (0.511.27) 0.73 (0.481.11) 0.74 (0.401.36) 0.93 (0.571.50) 0.77 (0.501.19) Non drinkersb 3 drinks 3 to 6 drinks 6 drinks

0.85 (0.421.74) 0.56 (0.281.14) 1.01 (0.581.76) 0.82 (0.571.19)

0.99 (0.422.33) 0.81 (0.391.69) 0.81 (0.461.44) 0.86 (0.581.27)

1.93 (0.764.90) 0.80 (0.371.72) 0.44 (0.210.90) 0.82 (0.451.50) 0.83 (0.571.22) 0.39 (0.131.17) 0.66 (0.371.16) 1.10 (0.631.92) 0.84 (0.292.43)

0.96 (0.352.63) 0.91 (0.421.99) 0.48 (0.231.02) 1.01 (0.521.96) 0.91 (0.611.37) 0.42 (0.131.31) 0.78 (0.421.42) 0.96 (0.521.76) 0.86 (0.302.45)

a Estimates from multiple logistic regression including terms for age, sex, study center, education, smoking habits, coffee, tea, green vegetables intake, and exposure to occupation at risk (chemical industry, dyestuff, painting, pharmaceutical, coal, and gas). b Reference category.

This study was hospital-based, and is therefore open to criticisms, because drinking may be related to several conditions requiring hospital admission [14,27], and the use of hospital controls may overestimate the level of drinking in the reference group. However, we excluded from the comparison group patients admitted for chronic conditions, particularly those associated with smoking and alcohol drinking, for digestive tract diseases and alcohol-related traumas; thus, only acute conditions, unrelated to recognized risk factors to bladder cancer, were included in the comparison group. Moreover, the results were consistent when separate analysis was made by major diagnostic categories of controls. Again, with reference to possible selection bias, cases and controls were identified in the major teaching and general hospitals of the areas under surveillance, and participation was almost complete. Reproducibility of information on alcohol drinking was satisfactory [28], as was validity in a companion study of breast cancer conducted in Italy [29]. The large number of patients in this study allowed meaningful analysis of subgroups. No significant heterogeneity emerged across strata of age, sex, tobacco smoking, and other selected covariates. Moreover, the potential confounding effect of smoking, coffee, and occupation was allowed for in the analysis.

In conclusion, this study, one of the largest casecontrol investigations on the issue for a population with frequent and heavy alcohol consumption, showed no consistent association between alcohol (mainly wine) drinking and bladder cancer risk, the RRs being below unity also for six or more drinks of alcoholic beverages per day. This was the case for various measures of alcohol drinking, including not only amount, but also duration of the habit, and in various subgroups of patients, such as males and females, smokers, and coffee drinkers.

Acknowledgments This report was supported by the Italian Association for Research on Cancer, Milan, Italy. The authors thank Mrs. M. Paola Bonifacino for editorial assistance.

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