Introduction

Bladder cancer is among the most widespread neo-plasms in the world, and tobacco smoking, somechemicals and industrial processes and chronicinfections with Schistosoma haemathobium havebeen recognized as bladder carcinogens in humans[1].

Coffee drinking has been classified as a ‘possiblehuman carcinogen’ (group 2B) by IARC [2], basedon a weak, positive association between coffeedrinking and bladder cancer found in some but notall epidemiological studies. These inconsistentfindings may be due to either residual confoundingby tobacco smoking or other carcinogens, or todifferences in the genetic background of variouspopulations. In addition, they may, at least partly, bedue to the different type of coffee consumed invarious parts of the world. In particular the ‘espresso’and ‘mocca’ coffee usually drunk in Italy are verydifferent from the boiled type (‘infusion’) or instantcoffee consumed in North Europe and the USA [2].The case-control studies carried out in Italy alsoshowed contradictory results: in one, an associationbetween bladder cancer and coffee drinking wasfound in the absence of a dose-risk relationship [3];an increased risk was found among non-smokers but

not among smokers in another study on men [4],while the highest risk for coffee drinking was foundamong ex-smokers in a third study [5]. A role ofalcohol drinking for bladder cancer has been sug-gested, but no consistent evidence for a causal rela-tionship exists as yet [6].

The aim of this study was to investigate the roleof tobacco smoking, coffee and alcohol drinking asrisk factors for bladder cancer in the Brescia area innorthern Italy. Results on occupational risk factors inan expanded series of 172 incident plus 181 preva-lent cases have been reported separately [7].

Subjects and methods

All the subjects with bladder cancer admitted to theUrology Department at the main hospital in Brescia(hospital A) in 1991–1992 for diagnosis, treatmentor follow-up were enrolled in the study and inter-viewed. A total of 172 incident cases (135 men and37 women) diagnosed during 1990–1992 wereenrolled. All the cases but one were histologicallyconfirmed, and pathological stage and histologicaltype were available for all but 19 cases (11.0%).

We selected as controls people hospitalised withprostate adenoma (International Classification of

European Journal of Epidemiology 13: 795–800, 1997. 1997 Kluwer Academic Publishers. Printed in the Netherlands.

Bladder cancer, tobacco smoking, coffee and alcohol drinking in Brescia,northern Italy

Francesco Donato1, Paolo Boffetta2, Raffaella Fazioli3, Vito Aulenti4, Umberto Gelatti1 &Stefano Porru3

1 Institute of Hygiene, 3 Institute of Occupational Health and 4 Institute of Urology, University of Brescia, Brescia,Italy; 2 Unit of Environmental Cancer Epidemiology, International Agency for Research on Cancer, Lyon, France

Accepted in revised form 6 June 1997

Abstract. The association between tobacco smoking,the consumption of coffee and alcohol and bladdercancer was investigated in a hospital-based case-control study in Brescia, northern Italy. A total of 172incident cases (135 men and 37 women) and 578controls (398 men and 180 women) were enrolled.As expected, cigarette smoking was strongly associ-ated with bladder cancer. The odds ratios (OR) forcoffee drinking adjusted for age, education, residenceand cigarette smoking in current drinkers were 2.6(95% confidence interval, CI: 1.1–6.1) in men and5.2 (95% CI: 1.0–30.4) in women. A dose-responserelationship was found in men, with the highest risk

Key words: Alcohol drinking, Bladder cancer, Coffee drinking, Tobacco smoking

in the highest category of exposure: drinkers of morethan 5 cups per day had an OR of 4.5 (95% CI:1.2–16.8). The ORs for current alcohol drinkers were2.1 (95% CI: 1.0–4.8) in men and 3.4 (95% CI:1.2–9.7) in women; according to grams of ethanoldrunk per day (grams/day, g/d) the ORs were: 1.7(1–20 g/d), 1.6 (21–40 g/d), 4.3 (41–60 g/d) and 4.6(61+ g/d) in men and 3.1 (1–20 g/d) and 3.9 (21+g/d) in women. These results suggest that regularconsumption of both coffee and alcohol can beindependently associated with an increased bladdercancer risk.

Diseases, 10th revision: N40), urolithiasis (N20–N23) or obstructive uropathy (N13) [8], since thesediseases are unrelated to the exposures under study.The controls were recruited at random among thosehospitalised on the same week as the cases. Malesubjects were age-matched with cases (± 5 years)while for women it was not possible to reach acomplete match. Due to the relatively small numberof the incident cases in the study period, about 4controls for each case were enrolled to estimate anOR of at least 2 with a statistical power of 0.90 anda proportion of controls exposed to each risk factorinvestigated of at least 20% (one-sided test). Thecontrols were enrolled in the three town hospitalswith an Urology Department (hospital A, B and C),including the one where the cases were recruited(hospital A). This choice was due to the definitionof the ‘secondary’ study base, according toWacholder et al. [9], which mostly overlaps withthe population resident in the Brescia province(1,049,000 inhabitants in 1991). Of the base, mostsubjects suffering from bladder cancer were admittedfor diagnosis, treatment or follow-up to hospital A,while most people affected by benign urologicdiseases were admitted to hospitals A, B or C. Ineffect, data on hospital discharges of subjects residingin Brescia province in 1989–1990 showed that 50%of the bladder cancer cases were admitted at leastonce to hospital A and 62% people with benignurologic disease were admitted to hospitals A, B orC. The rest of both cancer and benign disease caseswere admitted only to smaller hospitals, in andoutside the town (less than 5% for each hospital).

Controls were group-matched with cases withrespect to sex and age. A total of 578 controls wereinterviewed. Among 398 male controls, 40.1% hadprostate adenoma, 47.9% urolithiasis, 6.3% hydro-nephrosis and the rest a combination of thesediseases; among the 180 women, 84.6% had urolithi-asis, 13.2% hydronephrosis and 2.2% both.

Information on age, place of residence, education,history of cigarette smoking and coffee and alcoholconsumption was collected via a structured ques-tionnaire. Coffee drinking was investigated by askinghow many cups of coffee the subject drank in atypical day. Ex-coffee drinkers were asked how longhad passed since they had stopped drinking.Similarly, alcohol drinking was investigated byasking how many glasses of wine, cans of beer ormeasures of spirits the subject drank in a typical day.People who drank coffee or alcoholic beverages lessthan daily were considered as non-drinkers. Totalalcohol consumption was computed according toapproximate average ethanol content of wine (12%in volume), beer (5%) and spirits (40%) [10]. Theaverage number of cigarettes smoked per day and thetime since ex-smokers had stopped smoking werealso asked. Among cases, exposures were truncatedat the date of diagnosis.

The odds ratios (OR) of cigarette smoking, coffeeand alcohol drinking, adjusted for age, residence,education and date of interview, were computed byunconditional logistic regression analysis using themaximum likelihood method [11]. The followingvariables were included in the logistic regressionmodels: age, place of residence, education, smokinghabit, coffee and alcohol drinking. The date of inter-view was also included as a categorical independentvariable at three tertiles. Smoking habit was includedas the total number of cigarettes smoked in thelifetime, since the latter variable showed the highest,both statistical and epidemiological, association withbladder cancer risk. Linear trends were assessed byfitting an ordinal exposure variable as a continuousterm and omitting the zero level. Interaction termsbetween cigarette smoking and coffee and alcoholdrinking were forced into the models and theirstatistical contribution was evaluated using the like-lihood ratio test. However, the epidemiologic inter-action between these exposures was assessed bystratified analysis whenever possible.

The reliability of the data collected on smokingand coffee drinking was assessed by re-interviewinga sample of cases and controls by telephone, usingthe test-retest method as suggested [12]. All thestatistical analyses were performed using theBMDP/Dynamic computer programme for personalcomputer [13]. When the asymptotic maximum like-lihood estimates of the parameters of the logisticregression models failed, exact inference methodswere performed using the LogXact statistical pro-gramme [14].

Results

The distribution of cases and controls according tosociodemographic characteristics is shown in Table1. Among women, cases were older than controls anda lower proportion of them resided outside theprovince of Brescia.

Cigarette smoking, coffee and alcohol drinkingwere both independently associated with bladdercancer (Table 2). Some categories of exposure werecollapsed with those immediately below in women,due to the smaller number of cases and/or controlsexposed. Cigarette smoking was confirmed as animportant risk factor for bladder cancer, with a strongdose-response relationship in men. The risk seem tobe higher in females than males, for each level ofexposure. A relatively high risk was found for coffeeconsumption in current drinkers, and the ORincreased with the number of cups usually drunk perday in men, where a linear trend was suggestedalthough not statistically significant. Likewise, ahighly significant linear increase of risk was foundaccording to the quantity of alcohol consumed perday in men.

No differences were observed in the OR estimates

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Table 1. Distribution of cases and controls according to sociodemographic characteristics and sex

Sociodemographic Men Womencharacteristic

Cases Controls Cases ControlsN (%) N (%) N (%) N (%)

Age (years)< 55 027 (20.0) 138 (34.7) 06 (16.2) 091 (50.6)55–64 041 (30.4) 093 (23.4) 07 (18.9) 049 (27.2)65+ 067 (49.6) 167 (42.0) 24 (64.9) 040 (22.2)

ResidenceProvince of Brescia 124 (91.9) 321 (80.7) 35 (94.6) 125 (69.4)Other provinces 011 0(8.1) 077 (19.3) 02 0(5.4) 055 (30.6)

Education (years)0–5 082 (60.7) 224 (56.3) 26 (70.3) 110 (61.1)6–8 030 (22.2) 091 (22.9) 05 (13.5) 037 (20.6)9+ 023 (17.0) 083 (20.9) 06 (16.2) 033 (18.3)

Total 135 (100.0) 398 (100.0) 37 (100.0) 180 (100.0)

Table 2. Odds ratios (OR) and 95% confidence interval (95% CI) of bladder cancer for cigarette smoking, coffee drinkingand alcohol drinking

Variable Man Women

Ca/Co ORa (95% CI) Ca/Co ORa (95% CI)

Smoking habitNon-smoker 008/123 Reference 19/132 ReferenceEx-smoker 061/161 4.8 (2.2–10.7) 03/12 2.4 (0.4–14.7)Current smoker 066/114 8.4 (3.7–19) 15/36 12.0 (3.3–44.1)

Lifetime smoking: N of cigarettes smoked (/1000)Non-smoker 008/123 Reference 19/132 Reference1–99 010/86 1.8 (0.6–4.9) 08/33 6.6 (1.8–24.7)100–199 032/71 5.7 (2.4–13.7) 05/9 7.1 (1.4–36.9)200–299 026/55 7.2 (2.9–17.8) 05/6c 12.6c (2.0–77)300+ 057/61 11.1 (4.7–26.4)Chi square for linear trendb (current smokers) p < 0.001 p < 0.05

Coffee drinkingNon-drinker 007/72 Reference 02/27 ReferenceEx-drinker 006/17 2.7 (0.7–10.3) 00/8 –Current drinker 122/309 2.6 (1.1–6.1) 35/145 5.2 (1.0–30.4)

1–2 cups/day 066/203 2.3 (0.9–5.6) 27/98 4.3 (0.8–23.9)3–4 cups/day 044/89 2.8 (1.1–7.4) 08/47d 4.9d (0.7–33.0)5+ cups/day 011/17 4.5 (1.2–16.8)

Chi square for linear trendb (current drinkers) p > 0.1

Alcohol drinkingNon-drinker 010/64 Reference 12/90 ReferenceEx-drinker 016/62 1.0 (0.4–2.7) 00/18 –Current drinker 109/272 2.1 (1.0–4.8) 25/72 3.4 (1.2–9.7)

1–20 g/day 018/68 1.7 (0.6–4.7) 14/49 3.1 (1.0–9.3)21–40 g/day 033/126 1.6 (0.6–3.8) 11/23e 3.9e (1.1–13.7)41–60 g/day 036/55 4.3 (1.7–11.0)61+ g/day 022/23 4.6 (1.6–13.4)

Chi square for linear trendb (current drinkers) p < 0.001

Ca/Co = Case/Controls. No information was available on the number of cups of coffee drunk per day for one male case.a Adjusted for age, residence, education, date of interview, smoking, coffee and alcohol.b No linear trend was estimated in women due to the reduce number of categories of exposure.c 200,000+ cigarettes smoked in lifetime.d 3+ cups/day of coffee.e 21+ g/day of alcohol.

when the analyses were restricted to either subjectsresident in the Brescia province or to those aged 65years and over. for instance, the ORs among thoseaged 65 and over for current drinking of coffee andalcohol only where 2.5 and 5.5 among men and 5.3and 3.0 in women, respectively.

Separate analyses were also performed for coffeeand alcohol drinking according to smoking status. Inmen, increased risks were found for daily consump-tion of both coffee and alcohol in all subgroups, andthe highest category of consumption (3+ cups/dayof coffee, 41+g/day of alcohol) always showed ahigher OR than the lowest (Table 3). The relation-ship of coffee drinking with cancer risk seems to bestronger among non-smokers than smokers. On theother hand, the increased risks for alcohol drinkingwere not found to vary according to smoking status.The same analysis in women was performed usingexact statistical methods, due to the small numberof cases who never drank coffee (n = 2), who repre-sented the reference category (data not shown). Inwomen, too, the ORs for coffee drinking weresomewhat higher among non-smokers than currentsmokers, although the confidence intervals wereextremely large, while the ORs for alcohol drinkingdid not vary according to smoking status.

Discussion

These findings support the positive associationbetween bladder cancer and tobacco smoking, coffeeand alcohol drinking found in other investigations.As regards tobacco smoking, these data confirmprevious research showing a dose-response relation-ship between cigarette smoking and bladder cancerrisk [1].

We observed an increased risk of bladder cancer

with coffee drinking in both sexes, which seems tobe dose-related and was evident in all categories ofsmoking status, though stronger in non-smokers.These findings are in opposition to the conclusionof no evidence of association in a recent review [15].Since this review, however, three new case-controlstudies carried out in Spain, France and Western NewYork showed an association of coffee drinking withbladder cancer, at least in non-smokers [16–18].Furthermore, a recent prospective study in Hawaiifound a relative risk of 2 in men [19], although nodose-response trend was observed, and another inNorway found a relative risk of 1.5 in men and 2.4in women in the highest category of consumptionwith respect to the lowest, although these associa-tions were not statistically significant [20].

Among the factors which might explain thesecontradictory results is the type of coffee usuallyconsumed. In Italy, most people consume caffeinatedground coffee, and most daily drinkers in our studyusually had mocca or espresso caffeinated coffee. Anincreased risk for coffee drinking has been foundmore frequently in countries where regular groundcaffeinated coffee is usually consumed, such as Italy[3–5], France [17, 21] and Spain [16], although someof these studies observed an increased risk in non-smokers only [4, 16], and others found no cleardose-response relationship [4, 5]. Furthermore, in astudy in Western New York the consumption ofregular percolated coffee was associated with ahigher risk than the consumption of instant or decaf-feinated coffee [18].

Finally, the different findings from studies carriedout in different populations may, at least partly, bedue to variability in the susceptibility to bladdercarcinogens. Some studies have found that peoplewith low activity of the N-acetyltrasferase enzyme

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Table 3. Odds ratios (OR) and 95% confidence interval (95% CI) of bladder cancer for coffee consumption and alcoholdrinking according to smoking status in males

Non-smoker Ex-smoker Current smoker

Ca/Co ORa (95% CI) Ca/Co ORa (95% CI) Ca/Co ORa (95% CI)

Coffee drinkingNon-drinker 1/38 Reference 03/23 Reference 03/11 ReferenceEx-drinker 0/5 – 05/8 6.3 (1.0–36.8) 01/4 1.0 (0.1–15.8)Current drinker 7/80 2.8 (0.3–27.4) 53/130 2.6 (0.7–9.6) 62/99 2.4 (0.6–10.0)

1–2 cups/day 5/62 1.9 (0.2–21.9) 30/89 2.5 (0.6–9.6) 31/52 1.4 (0.3–6.6)3–4 cups/day 2/18 7.6 (0.4–146) 23/41 4.2 (1.0–17.2) 30/47 2.0 (0.4–9.2)

Alcohol drinkingNon-drinker 1/27 Reference 05/14 Reference 04/23 ReferenceEx-drinker 1/12 2.6 (0.1–55.4) 07/31 0.6 (0.1–2.6) 08/19 1.9 (0.4–8.0)Current drinker 6/84 2.5 (0.3–25.0) 49/116 1.2 (0.4–3.9) 54/72 3.6 (1.1–11.7)

1–40 g/day 3/61 2.6 (0.2–36.5) 28/84 1.1 (0.3–3.6) 20/49 1.8 (0.5–6.6)41+ g/day 3/23 5.9 (0.4–93.5) 21/32 2.2 (0.6–8.1) 34/23 8.6 (2.3–31.8)

Ca/Co = Case/Controls.a Adjusted for age, residence, education and date of interview.

(‘slow acetylators’), which is involved in detoxifi-cation of potent bladder carcinogens such as ary-lamines, may be at increased risk of bladder cancer,especially when they are exposed to low doses of car-cinogens [22]. Furthermore, an increased risk forbladder cancer has recently been found in subjectswith the Glutathione S-transferase M1 (GSTM1) 0/0genotype [23].

The possible role of alcohol consumption asregards bladder cancer risk is not clear. Most epi-demiologic studies do not suggest an associationbetween alcohol drinking and bladder cancer [6, 10].A significant increase in risk was found for heavyintake of beer but not wine in some studies inGermany [24, 25] whereas no association was foundin a large population-based case-control study in 10geographic areas in the USA [26] and in other studies[3, 9, 27]. Some authors have suggested that residualconfounding due to tobacco smoking could explainthe increased risk for alcohol drinking found in somestudies but not in many others. We found a positiveassociation with alcohol drinking – mainly derivedfrom wine, which was dose-dependent in males andwas not confounded or modified by age, tobaccosmoking or coffee drinking; since the increased riskwas found also among those who claimed to havenever smoked in their life, it can not be explainedby residual confounding due to tobacco smoking.These results are in agreement with those from arecent case-control study in France [17], where wineis the most common alcohol beverage, as in Italy.

Although the findings of increased risk for bothcoffee and alcohol consumption are fairly consistentin this study, some possible flaws should be takeninto account.

The reliability of data on coffee drinking andcigarette smoking was assessed by re-interviewing arandom sample of cases and controls by telephoneafter 2–3 years [30]. A fair to good agreement forcoffee drinking was found between the first and thesecond interview (percent agreement: 89.2%, Kappa= 0.65), while agreement was very good for cigarettesmoking (percent agreement: 94.4%, Kappa = 0.92).The differences regarding coffee drinking are moreprobably due to irregular habits than to referral bias:for instance, many people who claimed in the firstinterview to drink 1–2 cups of coffee daily reporteda somewhat higher consumption in the second (2–3cups/day), and vice-versa. No systematic differencesbetween cases and controls were observed in agree-ment between the 2 interviews.

Possible confounding by occupation, cigarettesmoking and other factors should be taken intoaccount. No confounding by job titles or industry wasevident in a separate analysis of these data [7].Tobacco smoking can confound the effect of coffeedrinking, since these two factors are often associated.Although we took into account cigarette smokingassessed through broad categories of exposure,

residual confounding by smoking may still bepresent. However, this appears unlikely to explain theassociation found, since the ORs for coffee drinkingwere high in non-smokers, too. The pattern of riskfor coffee drinking according to smoking statussuggests that non-smokers may be at a higher riskthan smokers, in agreement with others [4, 16]. Aswell as from tobacco smoking, confounding bycorrelates of coffee drinking such as dietary factorshas been suggested. Some dietary factors have beenfound to be associated with bladder cancer [3, 17,19]. In this study no information on diet was col-lected. However, the association between dietaryfactors and coffee, which is essential in producingconfounding, was not found in a study in Italy [3]and the increased risk for coffee consumption wasfound to be independent of dietary factors in otherstudies [18, 24].

Finally, the use of hospital controls has beencriticised due to possible associations between thecontrols’ exposure and disease. Higher risks forcoffee drinking were found when using data fromhospital rather than population controls in a recentcase-control study on bladder cancer in Spain [16].However, the authors argued that the inclusion amongthe controls of people with diet-altering conditionssuch as gastrointestinal disorders may have led to anunderestimation of the consumption in the studybase, and, hence, an overestimation of the risk. Onthe other hand, coffee drinking may be even morecommon among hospital than population controls,since several diseases are associated with coffeeconsumption, as found in a French study [28], sug-gesting that a hospital-based case-control study mayalso underestimate the ‘true’ risk for coffee. Anyway,we followed a strict application of the exclusionprinciple in choosing controls admitted to hospitalsby excluding patients diagnosed with any diseaserelated to exposure, which has been confirmedrecently [9, 29]. Since a high number of pathologieshas been found to be associated with tobaccosmoking, alcohol drinking or coffee consumption, wepreferred to enrol controls among patients affectedby a relatively small number of diseases, such asbenign urinary diseases, which have never beenfound to be associated with any of the exposuresinvestigated. Furthermore, in a German case-controlstudy that found an increased risk of cancer of thelower urinary bladder for drinking coffee and fordrinking alcohol beverages, no substantial differenceswere observed when the controls with prostatediseases were removed from the analysis [25], and,accordingly, in a French case-control study whichfound an association between coffee consumptionand bladder cancer no differences were evident whenconsidering controls with different pathologies [21].Therefore, a possible bias in selecting as controlspeople with a lower consumption of both coffee andalcohol than the general population due to their

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diseases is likely to be weak, although it can not beexcluded completely.

In conclusion, the results of this case-control studysuggest that regular consumption of both coffee andalcohol can be independently associated withincreased bladder cancer risk, with a dose-effectrelationship, and that these associations are notconfounded by tobacco smoking.

Acknowledgments

The study was partly supported by the Lega Italianaper la Lotta Contro i Tumori.

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Address for correspondence: Francesco Donato, MD,Cattedra di Igiene, University of Brescia, via Valsabbina19, I-25123 Brescia, ItalyPhone: +39 30 3994401; Fax: +39 30 370 1404E-mail: nardi@master.cci.unibs.it

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