in Uruguay Drinking, Alcohol, Tobacco, Diet, and ...

Mate Drinking, Alcohol, Tobacco, Diet, and Esophageal Cancer in Uruguay Eduardo De Stefani, Nubia Muñoz, Jacques Estève, et al. Cancer Res 1990;50:426-431. Published online January 1, 1990.

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[CANCER RESEARCH 50, 426-431, January 15, 1990]

Mate Drinking, Alcohol, Tobacco, Diet, and Esophageal Cancer in Uruguay Eduardo De Stefani, Nubia MuÃ±oz,1Jacques EstÃ¨ve,Alberto Vasallo, Cesar G. Victora, and Sibylle Teuchmann Department of Epidemiology, Oncology Institute, Avenida Brasil 308 dep 402, Montevideo, Uruguay [E. D. SJ; International Agency for Research on Cancer, ISO, Cours Albert Thomas, F-69372 Lyon cedex 08, France [N. A/., /. Â£., S. T.J; National Cancer Registry, Eduardo Acevedo No 1530, Montevideo, Uruguay [A. Y.J; and Departamento de Medicina Social, Faculdade de Medicina, Universidade Federal de Pelotas, Caixa Postale 464, 96100 Pelotas, RS Brazil [C. G. V.J

ABSTRACT A case-control study was conducted in Uruguay to investigate the role of mate drinking, alcohol, tobacco, and certain dietary factors in the etiology of esophageal cancer. The study included 261 patients with squamous cell carcinoma of the esophagus and 522 hospital controls matched by sex and age. A strong association with a clear dose-response relationship was observed with the amount of mate drunk daily and duration of the habit. The relative risk for those drinking over 2.5 liters of mate per day was 12.2 (95% confidence interval, 3.8-39.6) after adjusting for the effects of age, area of residence, alcohol, and tobacco. Strong associations were also observed with tobacco smoking and alcohol drinking which appear to act in a multiplicative way. The relative risk for those who smoke and drink heavily compared to that of light smokers and drinkers was 22.6. The risk associated with black tobacco was about three times higher than that associated with blond tobacco. A clear protective effect was found for the consumption of fruits and vegetables but a dose-response relationship was present only for fruits. Finally, an increased risk was also found for those eating barbecued meat daily.

INTRODUCTION Esophageal cancer is characterized by worldwide geographi cal variation in incidence and mortality rates, even within small areas (1). In South America, the highest rates have been re ported in Uruguay, a small country which shows large variation in the rates of esophageal cancer. The mortality rates for males range from 40 per IO5 in the northeast region, which borders Brazil, to 10 per 10s in the capital city of Montevideo (2). The

High risk areas in South America (southern region of Brazil, Uruguay, and Argentina) offer a unique opportunity to study this problem. This is due to the fact that their populations share the habit of drinking large quantities of a local tea, known by the folk name of mate. This beverage, an infusion of the herb Ilex paraguayensis, is drunk very hot through a metal straw. Despite the fact that the prevalence rate of exposure is over 80%, there remains a well-defined nonexposed group. A pre vious case-control study in Uruguay, in which routinely col lected information on mate drinking was extracted from the clinical records of patients with esophageal cancer and other cancers, showed a strong association with mate drinking (RR = 4.7, 95% CI = 1.9-12.1), after adjusting for the effects of age and alcohol and tobacco consumption (2). Although a subsequent case-control study in southern Brazil did not show a strong association between mate drinking and esophageal cancer, the moderate increase in risk and the high prevalence of mate drinking in this population could account for a considerable proportion of esophageal cancers occurring (4). This case-control study was designed to obtain further infor mation on the hypothesis that mate ingestion is associated with the risk of developing esophageal cancer. SUBJECTS

death rates are lower for females, with a male/female ratio of 3.8 for the whole country. Cancer of the esophagus can be divided into those cancers essentially due to alcohol and tobacco and those in which these two factors do not appear to play an important part. The joint effect of tobacco and alcohol exposures accounts for about 80% of the etiology of the disease in North America (3), South America (2, 4), Europe (5), South Africa (6), and some Asian countries (7). On the other hand, in areas with extremely high incidence such as Iran and China, alcohol and tobacco appear to play a minor role (8, 9) and the main risk factors remain to be identified. There is evidence suggesting that opium tar may be the major cause in Iran (10), and yV-nitroso compounds have been proposed as possible etiological candidates but convincing evidence is still lacking in China (11). Factors producing chronic injury to the esophagus, such as rough foods, hot beverages, and certain vitamin deficiencies, may increase susceptibility to carcinogens. Esophageal thermal injury resulting from drinking hot bev erages is a very difficult issue to study epidemiologically because of the widespread consumption of these drinks and the unreli ability of data on temperature obtained through interviews. Received 6/14/89; revised 9/29/89; accepted 10/16/89. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1To whom requests for reprints should be addressed, at International Agency for Research on Cancer, 150 Cours Albert-Thomas, 69372 Lyon, Cedex 08, France.

AND METHODS

The basic protocol utilized in the Brazilian study (4) was used in this study. The Brazilian questionnaire was adapted to the local situation of Uruguay, especially in relation to type of tobacco and diet. In the study period from July 1985 to September 1988, 283 cases with clinical and/or radiological diagnosis of esophageal cancer were admitted to the four main hospitals in Montevideo. These centers have a catchment area which covers 45% of the population of Montevideo and about 55% of the rest of the country. Patients treated in these hospitals are covered by Social Security medical care and have rather low incomes. Conditions for eligibility were: (a) to have histolÃ³gica! diagnosis of squamous cell carcinoma; (b) to have been diagnosed within the previous 4 months; (c) to have lived in the country for at least 5 years; () not to have a diagnosis of tobacco and/or alcohol-related diseases; (c) to have lived in the country for at least 5 years. The main diagnostic categories among the controls are listed in Table 1. The questionnaires were completed by four trained social workers. Information was collected on socioeconomic status (education, income, and occupation); on the lifetime habits of drinking mate, coffee, and tea (quantity, duration, and temperature); alcohol drinking (dose, ex pressed in milliliters of alcohol, duration, and type of alcoholic bever age); and tobacco smoking (type of tobacco, duration, intensity, and cessation periods). Dietary habits were assessed in two time periods:

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ESOPHAGEAL CANCER [N URUGUAY

Table 2 Distribution afeases and controls according to main risk factors Table 1 Diagnostic categories among control patients ICD-9550-553360-379574-575153-154600540-542174172-173454185200-208186-187730-731|690-698122240-541581-594210-229281-289DiagnosisInguinal MaleNumberAge10 years 0.46 (0.23-0.92), No cases or controls used pipes or cigars. nondrinkers and occasional drinkers 0.48 (0.29-0.81) (P = Dietary Factors. In the following analyses, all risk evaluations 0.001). were made after adjustment for age, sex, region, alcohol, dura Influence of the Type of Alcoholic Beverage. The distribution tion of cigarette smoking, and type of tobacco smoked. The of type of alcohol consumed by the study subjects changes with current and past frequencies of consumption of the 10 food their total consumption of alcohol; as a consequence, this groups were compared between cases and controls and no distribution differs between cases and controls. Light drinkers significant differences were found. Therefore the current con tend to drink more beer and wine and less spirits than heavy sumption was used in the analysis. The 10 food groups were drinkers. On the other hand, heavy drinkers tend to drink more fresh meat, preserved meat, barbecued meat, fat, dairy products, spirits than light drinkers. Since total alcohol consumption is eggs, cereals, potatoes, vegetables, and fresh fruits. Table 6 given by the sum of the three types of alcoholic beverages, the reports the results for those food groups which have been average linear increase for each of them separately was calcu suspected of influencing the risk of esophageal cancer. A clear lated adjusting for the others and considering each beverage as protective effect and a significant dose-response relationship a continuous variable. There was a significant difference of was found with the consumption of fresh fruits. A reduction in effect between beverages. Beer did not contribute to the risk, risk was also observed with the consumption of vegetables but whereas wine and hard liquor increased the risk by the same without significant dose response. A significant increase in risk amount for each milliliter of pure alcohol added. Therefore, in Table 5 Age, residence, and alcohol adjusted relative risks (95% Cl)Â°for this population, the sum of liquor and wine consumption is a duration of smoking and type of tobacco (males only) better indicator of the risk associated with alcohol consumption tobaccoMainly of (years) than total alcohol. adjusted for Duration of cigarette smoking type of Influence of Other Smoking Variables (Male Smokers Only). tobacco*1 blond1 black3.2 (years)1-2425-44 When adding to the multiplicative model including age, resi dence, and average cigarette and alcohol consumption, age at 2.5(1.1-5.7) 2.5 8.1 3.3(1.5-7.3) start (four categories), number of years since quitting (five 45+Type 4.4Mainly 9.0Duration 1 2.6(1.7-3.9) categories), and duration (five categories), no effect of age at Type of tobacco adjusted for duration start was found, but years since quitting smoking and duration " The estimation was carried out within the set of male smoker cases and were found to modify significantly the risk. The assessment of controls. "The x1 for interaction between the two factors is 1.15 with 2 df. tobacco exposure by duration gives a better fit than the average 428


ESOPHAGEAL CANCER IN URUGUAY

Table 6 Adjusted relative risks for the current consumption of certain food stuffs DISCUSSION limes/ once times/ Food0Fresh a week111111-3 week0.30(0.1-0.8)1.03(0.7-1.6)0.49(0.3-0.7)0.86(0.6-1.2)0.60(0.4-0.9)>3 week0.38(0.2-1.0)2.07(1.2-3.5)0.48(0.3-0.8)1.04(0.6-1.9)0.48(0.3-0.8)Daily0.61(0.2-1.5)1.44(1.0-2.2)0.56(0.3-1.0)2.66(1.3-5.5)0.33(0.2-0.5)Tren It is estimated that about 40% of all esophageal cancer cases

occurring in Uruguay during the study period were included in our study. However, the degree of representativeness of the study cases cannot be evaluated. With this limitation in mind we can say that our results indicate that 90% of the cases of esophageal cancer occurred over the age of 55 and that cases meatFruits< tended to live in rural areas and to have a lower socioeconomic status than the controls, which is in agreement with observa tions in other populations (4, 6). With regard to etiology, this " Adjusted for age, residence, smoking duration, type of tobacco, and alcohol study revealed that, as in similar studies carried out earlier in consumption. Uruguay (2) and in Brazil (4), alcohol and tobacco are the main risk factors for this cancer and that these two factors appear to Table 7 Adjusted relative risks for mate drinking0 act in a multiplicative way. The relative risk for those who both of of RR drink and smoke heavily (over 250 ml of alcohol/day and over controls48443179518623410423092Adjusted cases51113378347115810184Number Cl)12.52(0.8-8.4)3.60(1.3-9.9)6.07(2.1-17.3)12.21(3.8-39.6)13.67(1.1-11.8)4.44(1.7-11.4)2.65(1.1-6.5)6.40(2.5-16.4) (95% 25 cigarettes/day) was about 20, which was less than that Daily liters/day00.01-0.490.50-1.491.50-2.492.50+Duration amount reported from France (5). As regards tobacco, this population offers a special opportunity to compare the effects of the two types of tobacco, as approximately half smoke blond, flue-cured tobacco and the other half smoke black, air-cured tobacco. The risk for smokers of black tobacco cigarettes was increased almost threefold compared to that of smokers of blond tobacco cigarettes and it increased even more with duration than with the number of cigarettes smoked. These findings are in agree (years)0-1415-2930-4445-5960+Number ment with results from case-control studies on bladder cancer in Italy (14), Argentina (15), on laryngeal cancer in southern Europe (16) and previous studies on cancers of larynx and oropharynx in Uruguay (17, 18), suggesting that black tobacco is more carcinogenic than blond tobacco. Moreover, these ob servations are reinforced by laboratory results showing that the smoke of black tobacco cigarettes contained more aromatic " Adjusted for sex, age, residence, alcohol, smoking duration, and type of amines and tobacco-specific nitrosamines than that from blond tobacco. tobacco cigarettes (19) and that the urine of smokers of black tobacco contained about twice as much mutagenic activity as for those who eat barbecued meat daily was observed but did the urine of blond cigarette smokers (20). In relation to alcohol, the risk increases more with the without a significant dose-response relationship. However, the amount of alcohol consumed than with the number of cigarettes increase in risk for those who eat barbecued meat daily persisted after adjusting for meat consumption. No clear effect for fresh smoked, which is in agreement with the observations made in meat and fat and no significant associations with the other food the high risk areas for esophageal cancer in France (5). As in the French studies, the correlation is essentially with the groups were observed. amount of alcohol consumed and not with the type of alcoholic Mate Drinking. Mate drinking is very common in Uruguay. beverage. In Uruguay, the magnitude of the increase in risk Only 9% of controls and 2% of cases were nondrinkers. There associated with the consumption of spirits in males was similar was a clear dose-effect relationship between amount of mate drunk each day and the risk of esophageal cancer (Table 7). to that associated with wine drinking, which is not surprising There was also a less convincing but significant relation with considering that about 80% of the male drinkers are wine duration of use. The slope of the dose-effect relationship was drinkers and 60% are drinkers of spirits. However, no increased risk associated with the consumption of beer could be detected the same for both sexes in each alcohol consumption category because there are very few beer drinkers among the male drink and in all smoking categories. There was, however, a significant absence of effect among blond tobacco smokers (x2 = 8.3 on 2 ers (20%). In contrast with the epidemiological studies which show that alcohol clearly increases the risk for esophageal df). There was no significant interaction with any other available factor. The slope of the dose-effect plot was larger among the cancer even among nonsmokers (21), the laboratory studies have yielded negative results (22). It has long been suggested rural population, but not significantly so. that alcohol may act as a solvent facilitating the transport of Interaction terms for tobacco smoking, alcohol and mate carcinogens through the esophageal mucosa (23), but it may drinking, and socioeconomic status were calculated and found also act as a chronic irritant, raising the susceptibility to carcin nonsignificant as expected from the size of the study. ogens by accelerating cell turnover and thus favoring contact Influence of Temperature of Hot Beverages. The reported between the carcinogens and the dividing target cells (1). temperature of beverages other than mate was not associated Concerning dietary factors, a clear protective effect and a with the risk of esophageal cancer. The temperature of mate had a nonconsistent significant effect: the slope of the dose- dose-response relationship was observed for the consumption effect relationship was lower among people who reported hot of fruits, which is in agreement with observations made in other populations (3, 4, 8, 24, 25). Although a protective effect of mate drinking, and higher and identical among those who report vegetables was also detected, no dose-response relationship was warm or very hot. The effect of dose of mate was nevertheless significant in the three categories of drinkers. observed. Unfortunately, no distinction was made between raw meatFatVegetablesBarbecued

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and cooked vegetables. No clear effect of fresh meat was found. A protective effect was found in France (26), but an increased risk has been associated with fresh meat in Brazil (4). A clear increase in risk was observed for those eating barbecued food daily compared to those eating them less frequently, even after adjusting for meat consumption. This observation is contrary to the findings of a similar case-control study carried out in a neighboring area (4), but it is consistent with laboratory inves tigations showing the presence of animal carcinogens and mutagens in barbecued foods formed by the pyrolysis of proteins (27). The present study was designed to study further the associa tion with mate drinking. A strong association with a clear doseresponse relationship was observed with the amount of mate drunk daily. The RR for those drinking over 2.5 liters per day was 12.2 (95% CI, 3.8-39.6), after adjusting for age, tobacco, and alcohol. A less strong and less clear dose-response relation ship was observed with duration of the habit. The fact that the mate effect was present among nonsmokers and light smokers, and among smokers of black tobacco but not smokers of blond tobacco, is puzzling. The possibility that blond tobacco smokers were from a higher socioeconomic level and had a higher intake of fruit and vegetables was considered, especially in view of a greater effect of mate drinking among the rural population, but it was not confirmed. The finding of a significant but not consistent effect of the temperature at which mate is drunk is not surprising considering the subjectivity in the perception of temperature. To evaluate the degree of misclassification in the reported temperature at which mate is drunk, a validation study is being carried out in Southern Brazil and in Montevideo. There are two possible mechanisms through which mate drinking could increase the risk of esophageal cancer. First, the plant extract may contain carcinogenic or promoting sub stances. This possibility was raised in a previous study carried out in Uruguay (2), but laboratory studies have so far not demonstrated any promoting or mutagenic activity.3 Secondly, hot mate drinking may increase the susceptibility of the esophagus to carcinogens. Several epidemiological stud ies point towards a possible effect of hot drinks on esophageal cancer incidence. Ecological studies from Japan (28), the Soviet Union (29), and northern Iran (30) have suggested that inhab itants of high risk areas drink larger quantities of hot tea than those of low risk areas. Also in Iran, Singapore, and Puerto Rico case-control studies indicated similar differences (8, 31, 32). A prospective study carried out in Japan (25) also showed a higher risk among those drinking hot green tea. A possible effect of mate drinking on precancerous lesions of the esophagus has been demonstrated in an endoscopie survey carried out in Rio Grande do Sul (33). In addition, in a recent study on chronic esophagitis among young subjects in a high risk population for esophageal cancer in China, the strongest risk factor found for esophagitis was the consumption of bev erages at burning hot temperatures.4 Experimental animal data suggest that hot drinks may poten tiate the effect of esophageal carcinogens (34). The above ob servations, and in particular the finding that mate drinking increases the risks of esophagitis, suggest that mate itself may not contain specific carcinogens but that its effect may be due to chronic thermal injury of the esophagus increasing the sus* H. Yamasaki and H. Bartsch, personal communication. 4J. Chang-Claude. J. Wahrendorf, S. L. Qui, G. R. Young, N. MuÃ±oz.M. Crespi, R. Raedsch, D. Thurnham, and P. Correa. An epidemiologie study of chronic oesophagitis among young persons in Huixian county, Henan Province, a high-risk area for oesphageal cancer in China, submitted for publication.

ceptibility of the esophagus to carcinogens such as those con tained in tobacco tar. Results from the previous studies in Uruguay and Brazil and the present one support this possibility. A direct test of whether mate exerts its effect through direct carcinogens or through chronic thermal injury is being carried out in Paraguay, where the habit of drinking mate is also widespread. There it is mainly drunk cold and the esophageal cancer rates are lower than in Southern Brazil, Uruguay, and northeastern Argentina. Finally, since this study was hospital based, the possibility of selection bias should be considered. The possibility of this bias among cases cannot be evaluated but it was attempted among controls. The inclusion of patients with other cancers in the control group did not appear to affect the associations detected. ACKNOWLEDGMENTS We are grateful to S. Macadar and L. Torres for their assistance.

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