J Clin EpldemiolVol.45,No. 9,pp. 1025-1030, 1992 Printed in Great Britain
ALCOHOL
0895-4356/92 S5.00+0.00 Pcrgamon Press Ltd
AND EPITHELIAL
OVARIAN
CANCER
CARLO LA VECCHIA, I.* EVA NEGRI,’ SILVIA FRANCESCHI 3+4*FABIO PARAZZINI,’ ANTONELLA GENTILE’ ‘Institute of Pharmacological Preventive Medicine, University Cancer Centre, Aviano (PN), Epidemiology
and MONICA FASOLI’
Research “Mario Negri”, Milan, Italy, ‘Institut of Social and of Lausanne, Lausanne, Switzerland, ‘Epidemiology Unit, Aviano Italy and 4European Cancer Prevention Organization (ECP), and Cancer Working Group, Brussels, Belgium
(Received revised form I5 January 1992)
Abstract-The relationship between alcohol consumption ovarian cancer was analysed using data from a case-control
and the risk of epithelial study of 801 histologically
confirmed epithelial ovarian cancers and 2114 controls in hospital for acute, nonneoplastic, gynecological, or hormone-related conditions, admitted to a network of teaching and general hospitals in the greater Milan area, northern Italy, i.e. a region with comparatively frequent alcohol consumption by women. Compared to alcohol abstainers, the multivariate relative risks (RRs) were 1.O [9S% confidence interval (CI), 0.7 to 1.41 for less than one, 1.1. (95% CI 0.9 to 1.6) for one to two, 1.2 (95% CI 1.0 to 1.5) for two to three and 1.3 (95% CI 0.9 to 1.8) for three or more drinks per day. A significant direct trend in risk with dose emerged. This finding chiefly derived from
an association between ovarian cancer risk and consumption of wine (which accounts for over 90% of alcohol intake in this female population). Although no significant interaction between the effect of alcohol consumption and various women’s characteristics emerged, there was a hint that the adverse influence of alcohol consumption is more marked in middle-age and less educated women. Thus, the results of this study suggest that relatively elevated alcohol intake (of the order of 40 g per day or more) may cause a modest increase of epithelial ovarian cancer risk. Alcohol
Ovarian cancer
Case-control study
INTRODUCTION
There is suggestive, although indirect, evidence that dietary factors have a role in ovarian cancer risk. Among the factors considered, positive associations have been noted with indicators of fat and possibly meat intake, while some protection has been found related to consumption of a diet rich in vegetables, possibly due to the large intake of some (micro) nutrients [I]. A further component of diet which has been found protective in a large case-control study from the U.S. (the Cancer and Steroid Hormone *All correspondence should be addressed to: Silvia Frances&i, Epidemiology Unit, Aviano Cancer Centre, Via Pedemontana Oct., 33081 Aviano (PN), Italy.
Study) is ethanol [2]. That study found a plausible biological interpretation in the reduced gonadotropin levels caused by high doses of alcohol consumption, with consequent anovulation and hence protection against ovarian carcinogenesis [3,4]. The data of other studies are, however, largely inconsistent. Four studies from the U.S. [5--S] found no significant association, and in a Greek study [9] the relative risk for alcohol consumption was above unity, with a significant direct trend with duration. A similar suggestion of a direct association between alcohol and ovarian cancer emerged from a large American hospital-based study [IO]. Daily alcohol drinking by women during meals is very common and socially accepted in
1025
CARLOLA VECCHIAet al.
1026
Italy. In fact the Italian female population has a particularly elevated chronic alcohol consumption [l 11, thus providing a favourable setting to re-assess this hypothesis. In this article we have, therefore, considered the relationship between alcohol and ovarian cancer, using data from a large case-control study conducted in northern Italy. MATERIALS
AND METHODS
The data were derived from an ongoing casecontrol study of ovarian cancer, based on a network of hospitals including major teaching and general hospitals in the greater Milan area, whose design and methodology have been previously described [ 121. Briefly, between January 1983 and May 1990, 801 incident cases of histologically confirmed epithelial ovarian carcinoma (median age 54 years, range 22 to 74) were interviewed. The comparison group consisted of 2114 controls, age 24 to 74 (median age 54 years) who: (1) had been admitted to the same network of hospitals for a wide spectrum of acute, non-neoplastic, hormonal or gynecological conditions (33% traumas, 30% orthopaedic, 16% surgical, 21% other miscellaneous illnesses); (2) had been diagnosed within the year before the interview, and (3) had not undergone bilateral oophorectomy. Less than 3% of eligible subjects (cases and controls) refused to be interviewed. The catchment area of cases and controls was comparable: 87% of cases and 89% of controls resided in the same region, Lombardy; 91% of the cases and 94% of the controls came from northern Italy. A standarized questionnaire was used to obtain information on socio-demographic factors, personal characteristics and habits including selected dietary habits, related gynecological and medical histories, and history of lifetime use of oral contraceptives or female hormones for various reasons. Questions on alcohol included the number of days per week each type of alcoholic beverage (wine, beer and spirits) was consumed, the average numbers of drinks per day and the duration of the habit, in years. All questions referred to the year before the onset of the disease which led to the hospital admission during which the interview was performed. Data analysis
The total alcoholic beverage consumption was obtained assuming a comparable ethanol
content in each drink (i.e. 150 ml of wine = 330 ml of beer = 30 ml of spirits = approx. 12 ml of pure alcohol). Statistical analyses were based on standard methods for case-control studies [12], including point and confidence interval (CI) estimators of relative risk (RR) by adjustment for age [13] and by unconditional multiple logistic regression [14] fitted by the method of maximum likelihood [14]. Included in the regression equations were number of drinks of each alcoholic beverage per day (as continuous variables) and terms for age (in decades), marital status (ever, never married), education (< 7, 7-l 1, 2 12 years), smoking (non-smoker, ex-smoker, current smoker of < 5, 5-14, > 15 cigarettes/ day), age at menarche (< 12, > 13 years) and at menopause (~49, > 50 years), parity (0, 1-2, 23) oral contraceptive use (never/ ever), and indicators of consumption of fat and green vegetables (i.e. frequency consumption tertile) (as ordinal variables). For multiple levels of exposure, tests of significance were based on chi-square values for trend, computed firstly by means of Mantel’s extension test [16], secondly as the difference between the deviance of the model without and the deviance of the model including the variable of interest. RESULTS
Table 1 gives the distribution of ovarian cancer cases and controls according to age and other selected variables. No difference Table I. Distribution of 801 cases of epithelial ovarian cancer and 21 I4 controls according to age, education, marital status and parity Milan, Italy, 1983-1990 Ovarian cases
Age group (years)
ALCOHOL
0895-4356/92 S5.00+0.00 Pcrgamon Press Ltd
AND EPITHELIAL
OVARIAN
CANCER
CARLO LA VECCHIA, I.* EVA NEGRI,’ SILVIA FRANCESCHI 3+4*FABIO PARAZZINI,’ ANTONELLA GENTILE’ ‘Institute of Pharmacological Preventive Medicine, University Cancer Centre, Aviano (PN), Epidemiology
and MONICA FASOLI’
Research “Mario Negri”, Milan, Italy, ‘Institut of Social and of Lausanne, Lausanne, Switzerland, ‘Epidemiology Unit, Aviano Italy and 4European Cancer Prevention Organization (ECP), and Cancer Working Group, Brussels, Belgium
(Received revised form I5 January 1992)
Abstract-The relationship between alcohol consumption ovarian cancer was analysed using data from a case-control
and the risk of epithelial study of 801 histologically
confirmed epithelial ovarian cancers and 2114 controls in hospital for acute, nonneoplastic, gynecological, or hormone-related conditions, admitted to a network of teaching and general hospitals in the greater Milan area, northern Italy, i.e. a region with comparatively frequent alcohol consumption by women. Compared to alcohol abstainers, the multivariate relative risks (RRs) were 1.O [9S% confidence interval (CI), 0.7 to 1.41 for less than one, 1.1. (95% CI 0.9 to 1.6) for one to two, 1.2 (95% CI 1.0 to 1.5) for two to three and 1.3 (95% CI 0.9 to 1.8) for three or more drinks per day. A significant direct trend in risk with dose emerged. This finding chiefly derived from
an association between ovarian cancer risk and consumption of wine (which accounts for over 90% of alcohol intake in this female population). Although no significant interaction between the effect of alcohol consumption and various women’s characteristics emerged, there was a hint that the adverse influence of alcohol consumption is more marked in middle-age and less educated women. Thus, the results of this study suggest that relatively elevated alcohol intake (of the order of 40 g per day or more) may cause a modest increase of epithelial ovarian cancer risk. Alcohol
Ovarian cancer
Case-control study
INTRODUCTION
There is suggestive, although indirect, evidence that dietary factors have a role in ovarian cancer risk. Among the factors considered, positive associations have been noted with indicators of fat and possibly meat intake, while some protection has been found related to consumption of a diet rich in vegetables, possibly due to the large intake of some (micro) nutrients [I]. A further component of diet which has been found protective in a large case-control study from the U.S. (the Cancer and Steroid Hormone *All correspondence should be addressed to: Silvia Frances&i, Epidemiology Unit, Aviano Cancer Centre, Via Pedemontana Oct., 33081 Aviano (PN), Italy.
Study) is ethanol [2]. That study found a plausible biological interpretation in the reduced gonadotropin levels caused by high doses of alcohol consumption, with consequent anovulation and hence protection against ovarian carcinogenesis [3,4]. The data of other studies are, however, largely inconsistent. Four studies from the U.S. [5--S] found no significant association, and in a Greek study [9] the relative risk for alcohol consumption was above unity, with a significant direct trend with duration. A similar suggestion of a direct association between alcohol and ovarian cancer emerged from a large American hospital-based study [IO]. Daily alcohol drinking by women during meals is very common and socially accepted in
1025
CARLOLA VECCHIAet al.
1026
Italy. In fact the Italian female population has a particularly elevated chronic alcohol consumption [l 11, thus providing a favourable setting to re-assess this hypothesis. In this article we have, therefore, considered the relationship between alcohol and ovarian cancer, using data from a large case-control study conducted in northern Italy. MATERIALS
AND METHODS
The data were derived from an ongoing casecontrol study of ovarian cancer, based on a network of hospitals including major teaching and general hospitals in the greater Milan area, whose design and methodology have been previously described [ 121. Briefly, between January 1983 and May 1990, 801 incident cases of histologically confirmed epithelial ovarian carcinoma (median age 54 years, range 22 to 74) were interviewed. The comparison group consisted of 2114 controls, age 24 to 74 (median age 54 years) who: (1) had been admitted to the same network of hospitals for a wide spectrum of acute, non-neoplastic, hormonal or gynecological conditions (33% traumas, 30% orthopaedic, 16% surgical, 21% other miscellaneous illnesses); (2) had been diagnosed within the year before the interview, and (3) had not undergone bilateral oophorectomy. Less than 3% of eligible subjects (cases and controls) refused to be interviewed. The catchment area of cases and controls was comparable: 87% of cases and 89% of controls resided in the same region, Lombardy; 91% of the cases and 94% of the controls came from northern Italy. A standarized questionnaire was used to obtain information on socio-demographic factors, personal characteristics and habits including selected dietary habits, related gynecological and medical histories, and history of lifetime use of oral contraceptives or female hormones for various reasons. Questions on alcohol included the number of days per week each type of alcoholic beverage (wine, beer and spirits) was consumed, the average numbers of drinks per day and the duration of the habit, in years. All questions referred to the year before the onset of the disease which led to the hospital admission during which the interview was performed. Data analysis
The total alcoholic beverage consumption was obtained assuming a comparable ethanol
content in each drink (i.e. 150 ml of wine = 330 ml of beer = 30 ml of spirits = approx. 12 ml of pure alcohol). Statistical analyses were based on standard methods for case-control studies [12], including point and confidence interval (CI) estimators of relative risk (RR) by adjustment for age [13] and by unconditional multiple logistic regression [14] fitted by the method of maximum likelihood [14]. Included in the regression equations were number of drinks of each alcoholic beverage per day (as continuous variables) and terms for age (in decades), marital status (ever, never married), education (< 7, 7-l 1, 2 12 years), smoking (non-smoker, ex-smoker, current smoker of < 5, 5-14, > 15 cigarettes/ day), age at menarche (< 12, > 13 years) and at menopause (~49, > 50 years), parity (0, 1-2, 23) oral contraceptive use (never/ ever), and indicators of consumption of fat and green vegetables (i.e. frequency consumption tertile) (as ordinal variables). For multiple levels of exposure, tests of significance were based on chi-square values for trend, computed firstly by means of Mantel’s extension test [16], secondly as the difference between the deviance of the model without and the deviance of the model including the variable of interest. RESULTS
Table 1 gives the distribution of ovarian cancer cases and controls according to age and other selected variables. No difference Table I. Distribution of 801 cases of epithelial ovarian cancer and 21 I4 controls according to age, education, marital status and parity Milan, Italy, 1983-1990 Ovarian cases
Age group (years)
