Lifetime consumption of alcoholic beverages, tea and coffee and exocrine carcinoma of the pancreas: A population-based case-control study in The Netherlands

Int. J. Cancer: 50,5 14-522 (1992) 0 1992 Wiley-Liss, Inc.

Publication of the International Union Against Cancer Publication de I'Union lnternationale Contre le Cancer

LIFETIME CONSUMPTION OF ALCOHOLIC BEVERAGES, TEA AND COFFEE AND EXOCRINE CARCINOMA OF THE PANCREAS: A POPULATION-BASED CASE-CONTROL STUDY IN THE NETHERLANDS H.B. BUENO DE MESQUITA''4, P. MAISONNEUVE', C.J. MOERMAN', S. RUNIA3 and P. BOYLE' 'Department of Epidemiology, National Institute of Public Health and Environmental Protection, Postbus I , 3720 BA Bilthoven, The Netherlands; 'Unit of Analytical Epidemiology, International Agency for Research on Cancer, 150 Cours Albert-Thomas, 69372 Lyon, France; and 3Depatlment of Dietetics, University Hospital, University of Utrecht, PO Box 85500, 3508 GA Utrecht, The Netherlands.

From 1984 to 1988 a population-based case-control study was carried out in the Netherlands. in collaboration with the International Agency for Research on Cancer, to examine the possible relationship between the habitual lifetime consumption of alcohol, coffee and tea and exocrine pancreatic carcinoma in 176 cases and 487 controls. An interviewer-administered questionnaire was used to ascertain major life events and obtain estimates of consumption (ever-never) and frequency of consumption throughout life. Logistic regression analyses yielded odds ratios adjusted for age, sex, response status, smoking, dietary intake of energy and vegetables and of alcoholic or non-alcoholic drinks. When compared with data from non- drinkers, the cumulative lifetime consumption of all types of alcohol in grams of ethanol (ORs I .OO, 0.97, 0.93, I .25, p trend 0.55), beer, spirits, red wine and fortified wine was not related to risk. The consumption of white wine was inversely associated with risk (OR 0.4 I, 95% CI 0.24-0.70). The uniformly reduced risk estimates for the lifetime number of drinks of white wine were based on small numbers (ORs 1.00, 0.44, 0.25, 0.40, p trend 0.00 I). When compared with data from non-drinkers, our findings suggest an inverse dose-response relationship for the lifetime consumption of coffee (ORs 1.00, 0.72, 0.37, 0.58, p trend 0.06), whereas lifetime consumption of tea and of ground, instant and decaffeinated coffee was not associated with risk. The absence of an effect of lifetime consumption of decaffeinated coffee may be due to the small numbers of subjects. These results further strengthen existing evidence against a positive association between consumption as well as lifetime consumption of (sources of) alcohol, tea or coffee and the development of exocrine pancreatic cancer.

The majority of epidemiological investigations have indicated that smoking plays a role in the etiology of cancer of the exocrine pancreas (IARC, 1986). The results of studies on the effect of drinking alcoholic beverages have been less consistent. Although the majority of case-control and cohort studies could not show a relationship with pancreatic cancer, 4 case-control studies (Burch and Ansari, 1968; Durbec et al., 1983; Cuzick and Babiker, 1989; Olsen et al., 1989) and 2 cohort studies (Hirayama, 1981; Heuch et al., 1983) demon- strated positive associations with total alcohol consumption. A number of studies examined the relationship with specific types of alcoholic beverage. Findings on the effects of beer and wine appear inconsistent (Lin and Kessler, 1981; Durbecet at., 1983; Gold et al., 1985; Mack et al., 1986; Raymond et al., 1987; Hiatt et al., 1988; Falk et al., 1988; Cuzick and Babiker, 1989; Farrow and Davis, 1990). Therefore, evidence of an association with alcohol, which was considered insufficient in a review published in 1986 (Velema et al., 1986), still exists.

Although several case-control and cohort studies did not observe an association with the consumption of tea, one case-control study reported a significant positive relationship (Kinlen and McPherson, 1984), while a significant inverse association with regular tea consumption at the time of a college physical examination was found in a cohort study (Whittemore et al., 1983). Despite an initial report on the possible relationship between coffee and pancreatic cancer (MacMahon et al., 1981), the body of evidence derived from later case-control and cohort studies does not support in-

creased risk. Few studies have evaluated the possible effect of caffeine.

Evaluation of the dose-response effects of alcoholic or non-alcoholic beverages in most of the above-mentioned case-control studies was based on one question on normal consumption 1 to 3 years prior to diagnosis or interview. An assessment of consumption integrated over time and in relation to major life-events may, however, provide better estimate of exposure.

Recently, we reported a positive association between pancreatic cancer and the lifetime consumption of cigarettes with an odds ratio of 1.00 for never-smokers and 1.38, 1.46 and 2.18 for tertiles of smokers (Bueno de Mesquita et al., 1991a) and between pancreatic cancer and quintiles of total dietary intake of energy with odds ratios of 1.00, 1.71, 1.54, 1.65 and 3.44 (Bueno de Mesquita et a f , 1990); in contrast, an inverse relationship with quintiles of consumption of vegetables was observed with odds ratios of 1.00, 0.92, 0.59, 0.48 and 0.34 (Bueno de Mesquita et al., 1991b). Since the consumption of beverages, alcoholic or otherwise, may be correlated with smoking and the intake of energy and vegetables, it appears worthwhile to include these factors in an evaluation of such beverages.

During the period 1984-88 a population-based case-control study was carried out in the Netherlands to explore further the possible relationship between life-style factors, including diet, and pancreatic and biliary cancer. The study is part of the SEARCH (Surveillance of Environmental Aspects Related to Cancer) program of the International Agency for Research on Cancer. This report presents the findings of the Dutch study on the relation between lifetime consumption of alcohol (ethanol), beer, spirits, red wine, white wine, fortified wine, tea and different varieties of coffee and exocrine pancreatic carcinoma.

MATERIAL AND METHODS Study population

The study population and methods used have been de- scribed in detail (Bueno de Mesquita et al., 1990). In brief, the study was conducted in the central part of the Netherlands. Cases were defined as all individuals, alive or dead, 35 to 79 years of age, newly diagnosed between January 1984 and March 1987 and living in the study area at the time of diagnosis of cancer of the exocrine pancreas. The disease was defined as a clinical diagnosis of exocrine cancer of the pancreas. Histolog- ical verification of the diagnosis was obtained in 68% of cases. Multiple sources, such as clinicians (physicians and surgeons), records of pathology laboratories, hospital medical registries and the newly-formed cancer registry of the "Midden Neder-

4T0 whom correspondence and reprint requests should be sent.

Received: May 27, 1991 and in revised form September 27,1991

BEVERAGES A N D PANCREATIC CANCER 515

land” Comprehensive Cancer Center were used to trace eligible cases.

Controls from the general population, who were 35 to 79 years of age and had lived in the study area at some point during the period 1984-1987, were obtained from municipal population registries (CBS, 1983, 1985, 1986). The so-called index controls, who were interviewed directly, represented a stratified random sample of the general population of the study area, frequency matched to the age-and-sex distribution of the cases. The control-case ratio was at least 2 to 1 for those under age 60 and 1 to 1 for ages 60 and above. During the first 2 years of the study, however, about 39% of the eligible patients with pancreatic cancer could not be interviewed directly, mainly due to early death, and it was necessary to assign a proxy (a family member in most cases) for the interview. For comparison, a stratified random sample of proxy controls, frequency-matched for age and sex to the patients who were represented by proxies, was also formed. The sampling plan was similar to that adopted for index controls.

During the study period, 189 eligible patients with cancer of the pancreas were identified (100 males and 89 females). The study population further consisted of 702 controls, i.e. 487 population-based eligible index controls (216 males and 271 females) and 215 eligible proxies for living controls (103 males and 112 females). Among men, the response rates were 94.0% for cases and 73.7% for controls (75.5% for index and 68.0%

for proxy controls). Among women, the corresponding response rates were 92.1% for cases and 65.8% for controls (67.9% for index and 53.6% for proxy controls). Two male and 8 female index controls who were interviewed through proxies were included in the indirect group. Among male participants, 55.3% of the patients responded directly compared with 69.4% of the controls; for female participants the corresponding percentages were 61.0% and 73.0% (Table I). Among indirectly responding subjects, the proxy was a spouse for 78.6% of the male cases vs. 80.6% of the male controls and 40.7% of the female cases vs. 60.3% of the female controls. When a son or daughter acted as proxy, the corresponding percentages were 35.8% and 6.9% for men and 40.7% and 27.9% for women, respectively; for other persons, they were 16.8% and 16.7% for men and 50.1% and 20.6% for women, respectively. Percent- ages may add up to more than 100% because in some cases more than 1 type of proxy was present.

Thirteen patients did not participate for the following reasons: 7 were identified more than 1 year after death (53.9%), 3 refused (23.1%), in 2 cases the physician refused consent (15.4%) and in 1 case a suitable proxy could not be found (7.7%). The reasons for non-response of 130 index and 85 proxy controls were as follows: 120 (92.3%) index and 71 (83.5%) proxy controls refused, a suitable proxy could not be found for 12 proxy controls (14.1%), and 10 index (7.7%) and 2 proxy (2.4%) controls could not be contacted. As a result, 663

TABLE I - SELECTED CHARACTERISTICS OF 116 CASES AND 487 CONTROLS ACCORDING TO TYPE OF INTERVIEW THE SEARCH PANCREATIC CANCER STUDY. UTRECHT. 1984-1988 ~ ~

Cases Controls Direct’ Indirect‘ Direct’ Indirect’

Number (%) Number (%) Number (%) Number (%)

Participants Age in years

35-49 50-59 60-69 70 + Male Female

Non-smokers Less than 10

20 or more Smokers’

Never 046 ,s 10

184,901+ Smokers’

Sex

Lifetime average daily number of cigarettes’

10-19

Cumulative lifetime number of cigarettes4

46,811-184,900

Total caloric intake in cal/day4 0-1,665 1,666-1,938 1,939-2,247 2,248-2,612 2,613+ Unknown

0-164.5 164.6-200.7

Consumption of vegetables in g/day4

200.8-237.8 237.9-284.3 284.4+

102

6 13 44 39

52 50

28 35 18 10 11

28 19 20 24 11

12 22 17 16 27 8

24 26 18 16 10

(100.0)

38.2

(10.8

27.5 18.6

10.8

11.8

26.5 (7.8

74 (100.0)

3 15 27 29 39.2

16 (21.6 5 3 4

46 (62.2

16 (21.6 4 5.4 2 6

46 (62.2

12 14 10 13

4 (5.4

18 12 13 11 16

14.9 21.6

4 (5.4

347

38 57

119 133

163 184

117 116 73 27 14

117 72 72 72 14

78 69 71 70 55

4

63 72 70 70 68 4

(100.0)

(4.0

33.7

22.5

20.2 15.9 (1.2

18.2

20.2 19.6 (1.2

140 (100.0)

46 12 I!%/ 37 26.4 45

6 5

55 (39.3

12 (40.01 (8.6

30 21.4 26 18.6 3 (2.1

24 (17.1)

Unknown 8 ‘Direct and indirect (proxy) interviews on smoking and beverages.-zNon-filter + filter ~igarettes.-~Incornplete lifetime number of cigarettes smoked.-‘Categories

based on distribution among cases and controls combined.

516 BUENO DE MESQUITA ET AL.

subjects, i.e. 176 cases and 487 controls, were available for analysis.

Data collection and statistical analysis An interviewer-administered questionnaire covered se-

lected socio-economic items, lifetime consumption of tobacco and various beverages and other factors including medical history. After listing major life events, participants were asked to estimate the lifetime frequency of the consumption of specific beverages in terms of number of drinks and cigarettes per age period.

The cumulative intake of beverages, alcoholic or otherwise, was calculated up to age at diagnosis for cases and age at interview for controls. If the age at initial consumption was missing, assuming only marginal loss of ranking ability, consumption associated with the first period was excluded from the calculation of cumulative consumption. If, however, information was missing for any of the remaining periods, the cumulative consumption was defined as “unknown”.

For descriptive purposes the information on lifetime consumption of drinks of specific alcoholic beverages, tea and coffee was converted into a lifetime average weekly or daily number of drinks without taking standard volumes into ac- count (Table 11). For analytical purposes the cumulative lifetime consumption of specific beverages was calculated in liters using standard volumes. The lifetime consumption of all types of alcohol represents the cumulative intake of ethanol in grams. The ethanol content is based on the Dutch Nutrition Table of 1985, i.e. for beer 4g per 100 ml, for spirits 28g per 100 ml, for red and white wine log per 100 ml and for fortified wine 14g per 100 ml (Kommissie Uniforme Codering Voedingsmid- delen Tabel, 1985). The “total coffee” variable represents the cumulative quantity (in liters) of ground caffeinated, ground decaffeinated, instant caffeinated and instant decaffeinated coffee and espresso consumed. Four subgroups were formed, i.e. (1) ground coffee, representing the cumulative lifetime consumption of ground caffeinated, ground decaffeinated and espresso; (2) instant coffee, representing instant caffeinated

TABLE I1 - LIFETIME AVERAGE CONSUMPTION OF BEVERAGES AMONG 176 CASES AND 487 CONTROLS ACCORDING TO TYPE OF INTERVIEW. THE SEARCH PANCREATIC CANCER STUDY, UTRECHT, 19861988

Participants Number of drinks of beer per week

Never’ 51 >1 and 1 7 > 7 Users’

Never* < 1 31 and 1 7 > 7 Users’

Never’ 51 >1 and 5 7 > 7 Users3

Never2 < 1 51 and 1 7 > 7 Users3

Never2 < 1 31 and 1 7 > 7 Users’

Neve? < 2 72and 1 3 > 3 Users’

Never2 < 3 7 3 and 1 4 > 4 Users3

Number of drinks of spirits per week

Number of drinks of red wine per week

Number of drinks of white wine per week

Number of drinks of fortified wine per week

Number of cups of tea per day

Number of cups of total coffee per day4

Number

102

59 11 20 11 1

38 13 30 17 4

72 15 11 3 1

88 8 3 0 3

69 13 12 6 2

1 28 20 36 17

1 25 28 27

Number

74

36 7 5 2

24

23 14 11 6

20

46 13 8 2 5

61 5 2 2 4

49 7

10 4 4

4 2 2 6

60

2 2 1 4

(%)

(100.0)

(48.7

(32.4

31.1

(27.0

62.2

6.8

(82.4

(66.2

(13.5

5.4

(81.1

Number

347

194 60 57 33 3

147 64 85 47 4

240 56 41 8 2

259 55 27 4 2

24 1 53 31 22 0

9 108 91

102 37

5 93 90

126

Cases Controls Direct’ Indirect‘ Direct‘ Indirect‘

Number (%)

140 (100.0)

77 (55.0 13 8 4

38 (27.1

53 37.9 26 17 10 34 (24.3

18 (12.9

14 (10.0 3

18 12.9 4

98 (70.0

14 (10.0 12

1 8 3 4 (2.9

124 (88.6

2 9 5 6

LI (20.62 65 (87.82 33 ‘(9.52 118 (84.32 - ‘Direct and indirect interviews on smoking and beverages.-*Never or less than one drink a month. -‘Consumers with incomplete reports of lifetime consumption.

-4Ground caffeinated + ground decaffeinated + instant caffeinated + instant + expresso.

BEVERAGES AND PANCREATIC CANCER 517

and instant decaffeinated; (3) caffeinated coffee, representing ground caffeinated, instant caffeinated and espresso; and (4) decaffeinated coffee, representing ground decaffeinated and instant decaffeinated coffee.

For the evaluation of lifetime consumption, the continuous variables were categorized according to 5 levels of consumption. Categorization of subjects was based on the distribution of cases and controls. If there were fewer than 20% non- consumers, as was the case for tea and total (ground and caffeinated) coffee, all subjects with a known consumption level were separated into quartiles. If there were 20% or more non-consumers, as was the case for alcohol, beer, spirits, red wine, white wine, fortified wine and instant and decaffeinated coffee, non-consumers were grouped in the lowest reference category and consumers with a known frequency of consumption in tertiles. Consumers with an unknown consumption level were grouped in the 5th (highest) category.

Logistic regression analysis (Breslow and Day, 1980), using the GLIM statistical package (Baker and Nelder, 1985), provided point and interval estimates of the odds ratios. For analysis of specific alcoholic beverages, all the components were fitted simultaneously into the same model. Since tea and coffee are often interchanged, the consumption of total coffee as well as varieties of coffee was also adjusted for tea. Thus, 3 models were constructed, i.e. (1) for tea and total coffee; (2) for ground and instant coffee; and (3) for caffeinated and decaffeinated coffee. Risk estimates were adjusted for the age at diagnosis for cases and age at interview for controls (0-49; 50-59; 60-69; 70+), sex, response status (direct; indirect interviews), lifetime smoking of all, i.e. non-filter + filter, cigarettes (non-smokers; tertiles of smokers; smokers with an unknown frequency of consumption) and dietary intake of energy and vegetables (quintiles). In view of the large number of indirectly interviewed subjects, the imbalance in the proportion of cases to controls and possible differences in responses obtained in direct and indirect interviews, we followed the strategy advocated by Walker et al. (1988), i.e., separating the 2 types of interview and, assuming no interaction between exposure and response status, adjusting overall point estimates for response status, i.e. direct and indirect interviews. The test of heterogeneity over response status was applied to the trend rather than the point estimates. Whenever the numbers were sufficient, the results for selected beverages of interest are presented according to type of interview.

RESULTS Selected characteristics

Table I presents selected characteristics of cases and controls according to type of interview. Indirect interviews often yielded incomplete information on life-time number of cigarettes smoked, i.e. in 62.2% of cases and 39.2% of controls. Compared to controls, the distribution of quintiles of total dietary energy intake among cases shifted to higher levels, whereas the distribution of vegetable consumption shifted to lower levels.

Lifetime average consumption Lifetime average weekly or daily consumption of specific

beverages for direct and indirect responders is presented in Table 11. Among direct responders, the proportion of subjects classified as consumers with an incomplete lifetime consumption ranged from relatively low (tea and total coffee) to negligible (alcoholic beverages). Among indirect responders, a substantial proportion of the subjects fell into the category of incomplete lifetime consumption of beer and spirits; for tea and total coffee, the majority were classified as consumers with unknown lifetime consumption.

Alcoholic beverages After adjustment for age, sex, response status, lifetime

consumption of cigarettes and dietary intake of energy and vegetables and comparison with non-drinkers, it appeared that the drinking of alcohol was not related to risk (OR = 1.01; 95% CI 0.61-1.68). After additional adjustment for other alcoholic drinks (never vs. ever), the drinking of beer (OR = 0.92; 95% CI 0.56-1.48), spirits (OR = 1.09; 95% CI 0.70-1.70) and red wine (OR = 1.16; 95% CI 0.75-1.79) was also not associated with risk. However, the drinking of white wine was significantly and inversely associated with risk (OR = 0.41; 95% CI 0.24-0.70), whereas the consumption of fortified wine exhibited a significant positive relationship with risk (OR = 1.57; 95% CI 1.00-2.47). Tests for heterogeneity over response status were never statistically significant (p values 0.50 or more).

Cumulative lifetime intake of alcohol in grams of ethanol was not related to risk (Table 111). A stratified analysis according to type of interview also revealed no effects (ORs for direct responses 1.00, 0.81, 0.89, 1.21, p-value trend 0.61; for indirect responses 1.00, 1.11,0.73, 1.38,~-value trend 0.82).

Lifetime consumption of beer, spirits and fortified wine was also not associated with risk. Relative risk estimates for red wine did not indicate a relationship with disease. No effect was seen among direct or indirect responders (ORs direct 1.00, 0.83, 1.17 and 0.93,~-value trend 0.98; ORs indirect 1.00, 1.42, 2.81 and 1.23,~-value trend 0.33). Although the test for trend of lifetime number of drinks of white wine indicated a significant inverse dose-response relationship, point estimates showed a uniformly reduced risk pattern (ORs 1.00,0.44,0.25, 0.40, p-value trend 0.01). A significant inverse dose-response relationship was consistently found for direct and indirect responders (ORs direct 1.00,0.55,0.25 and 0.46,~-value trend 0.02; ORs indirect 1.00,0.33,0.15 and 0.31,~-value trend 0.04).

A substantial number of subjects were classified as drinkers with unknown lifetime consumption of alcohol-containing beverages. However, none of the related risk estimates was significantly different from unity (ORs for unknown consumption of alcohol 0.99,95% CI 0.48-2.05; for beer 0.77,0.33-1.77; for spirits 1.38, 0.61-3.15; red wine 0.60,0.16-2.25; white wine 1.25,0.33-4.67; fortified wine 1.22,0.31-4.85).

Tea Due to the small number of subjects who reported never

having consumed tea, i.e., 5 cases and 10 controls, the effect of ever having drunk tea could not be examined. Compared with the lowest level of consumption (including those who never drank tea), insignificantly reduced risks for all higher levels of lifetime consumption of tea were observed with no indication of a dose-response effect (Table IV). The relative risk estimate for the number of tea drinkers with unknown lifetime consumption was below unity but not significantly related to risk (OR 0.58, 95% CI 0.27-1.22). For direct responders, lifetime consumption of tea was not related to risk (ORs 1.00, 0.70, 0.92, 1.21,~-value trend 0.49).

Coffee The effect of ever drinking “total coffee” and the subgroups

“ground coffee” and “caffeinated coffee” could not be evaluated due to the very small number of non-users, i.e. 3 cases and 7 controls. After adjustment for age, sex, response status, lifetime consumption of cigarettes, dietary intake of energy and vegetables, tea (never vs. ever) and other coffee (never vs. ever) and comparison with non-drinkers, the drinking of instant coffee (OR 1.05,95% CI 0.71-1.54) and decaffeinated coffee (OR 0.82, 95% CI 0.49-1.38) was not related to pancreatic cancer. Tests for heterogeneity over response status were not statistically significant (p-values 0.23 and 0.52, respectively).


TABLE Il l - LIFETIME CONSUMPTION OF ALCOHOL-CONTAINING BEVERAGES AND PANCREATIC CANCER. THE SEARCH PANCREATIC CANCER STUDY, UTRECHT, 1984-1988

p value’ T3’ Users‘ N = 663 Never T1’ T2’

32 109

0.93 0.49 1.76

15 62 0.74 0.34 1.59

33 77

1.20 0.65 2.21

18 46

1.56 0.78 3.13

5 46 0.266 0.09 0.69

14 47

1.15 0.56 2.34

Total alcohol in grams of ethanol4 Cases Controls Odds ratio’ 95% CI

34 32 97 111 1.00 0.97

0.53 1.77

40 38 104 66

1.25 0.65 2.43

0.85 0.55

Beer in liters Cases Controls Odds ratio’ 95% CI

95 18 23 25 54 41

1.34 0.64 2.79

271 59 1.00 0.86 0.70 0.67

0.44 1.69

Spirits in liters Cases Controls Odds ratio’ 95% CI

61 29 88 0.96 0.54 1.69

29 84

1.13 0.58 2.20

24 38 200

1 .oo 0.82 0.63

Red wine in liters Cases Controls Odds ratio’ 95% CI

118 328

1.00

17 49

1.09 0.56 2.12

17 48

1.01 0.49 2.08

6 16

0.48 0.55

White wine in liters Cases Controls Odds ratio’ 95% CI

149 35 1

1.00

7 42 0.44 0.18 1.10

8 39 0.406 0.16 0.99

7 9

0.88 0.001

Fortified wine in liters Cases Controls

6 12

118 20 339 44

18 45

1.55 0.75 3.18

Odds ratio5 95% CI

1.00 2.51‘ 1.26 5.01

0.45 0.21

‘Tertiles relate to drinkers with known lifetime consumption; cut points for total alcohol 22,471 and 128,971 grams, for beer 276 and 1,779 liters, for spirits 47 and 288 liters, for red wine 47 and 174 liters, for white wine 32 and 101 liters and for fortified wine 35 and 166 liters.-’Drinkers with unknown lifetime consumption.-) values of x: for heterogeneity over response and x: for trend, excluding users with incomplete lifetime c~nsumption.-~Expressed as grams of ethanol of any of these types.-50dds ratios obtained by logistic regression analysis and adjusted for age, sex, response status, lifetime smoking of cigarettes and dietary intake of energy and vegetables; for beer, spirits, red wine, white wine and fortified wine an extra adjustment was made for lifetime consumption of other alcoholic drinks.-$ < 0.05.

The results for lifetime drinking of coffee indicated an inverse dose-response relationship with the test for trend approaching statistical significance (ORs 1.00, 0.72, 0.37,0.58, p-value trend 0.06) (Table IV). Among direct responders, no dose-response effect of total coffee was observed (ORs 1.00, 0.80,0.41,0.66,p-vaIue trend 0.15).

Compared with the lowest level of lifetime consumption, i.e. for ground coffee and caffeinated coffee, or non-drinkers, i.e. for instant coffee and decaffeinated coffee, the lifetime consumption of the 4 subgroups of coffee was not associated with disease. With the exception of instant coffee, the risk patterns for total coffee and the subgroups of coffee were generally below unity and were U-shaped. None of the odds ratios for the substantial number of consumers with an unknown frequency of consumption were significantly different from unity (OR for unknown lifetime consumption of total coffee 1.06, 95% CI 0.52-2.15; ground coffee 1.17,0.56-2.44, instant coffee 1.66, 0.74-3.70 and caffeinated coffee 1.25, 0.60-2.59). Again, formal tests for interaction did not suggest statistically significant differences between direct and indirect interviews.

inverse association with the drinking of white wine was observed. Compared with the lowest level of drinking, risk estimates for the various levels of lifetime consumption of white wine showed a uniformly reduced risk pattern that was consistent among direct and indirect responders. The sugges- tion of an inverse dose-response relationship with the lifetime consumption of coffee was not present in the analysis of direct responders only. Ever vs. never and the lifetime consumption of tea and ground, instant, caffeinated, decaffeinated and total coffee could not be related to risk.

Our study was specifically designed to assess, in an identical format, the effect of drinking alcoholic beverages, tea and coffee. The lifetime history of consumption in relation to major life events was chosen because of (1) lack of information about a possible latent period, (2) potential disease-related changes in pre-diagnostic consumption among cases which might intro- duce a recall bias, and (3) the assumption that higher-quality information is obtained when exposure assessment is related to major life events. In our study, however, differential or non-differential misclassification cannot be excluded.

For the less common habits, i.e. consumption of red, white and fortified wines and decaffeinated and instant coffee, the proportion of subjects classified as consumers with an unknown lifetime consumption was minimal, the related risks

DISCUSSION

Consumption of alcohol, beer, spirits, red wine and fortified wine could not be related to pancreatic cancer. A significant


TABLE N - LIFETIME CONSUMPTION OF TEA AND SUBGROUPS OF COFFEE AND PANCREATIC CANCER. THE SEARCH PANCREATIC CANCER STUDY, UTRECHT, 1984-1988

p value'

Yi Yi Users' N = 663 Q1 Q1' Q2' Q3'

Total tea in liters Cases Controls Odds ratio4 95% CI

Total coffee in liters Cases Controls Odds ratio4 95% CI

Ground coffee in liters Cases Controls Odds ratio4 95% CI

Instant coffee in liters Cases Controls Odds ratio4 95% CI

Caffeinated coffee in liters Cases Controls Odds ratio4 95% CI

Decaff. coffee in liters Cases Controls Odds ratio4 95% CI

29 16 76 90

1.00 0.54 0.26 1.13

26 23 79 84

1.00 0.72 0.36 1.43

25 28 82 80 1 .oo 0.99

0.51 1.95

None 107 14 288 63

1.00 0.71 0.36 1.39

24 26 82 81

1.00 0.96 0.48 1.92

None 150 6 393 32

1 .oo 0.54 0.21 1.39

25 82 0.82 0.41 1.63

17 90 0.37' 0.18 0.79

12 96 0.295 0.13 0.65

18 60

1.08 0.58 2.04

15 92 0.395 0.18 0.85

5 35 0.37 0.13 1.04

29 78 0.98 0.49 1.95

24 83 0.58 0.28 1.20

27 82 0.80 0.39 1.64

22 55 0.92 0.51 1.69

26 82 0.72 0.34 1.50

10 26

1.08 0.47 2.51

77 161

0.12

86 15 1

0.66

84 147

0.76

15 21

0.36

85 150

0.65

0.77

0.06

0.09

0.85

0.06

5 1

0.52 0.28

'Quartiles relate to subjects with known lifetime consumption; cut points for tea 3,597,6,430 and 9.930 liters, for total coffee 6,193,9,012 and 11,840 liters, ground coffee 5,731, 8,718 and 11,508 liters, instant coffee 0 136 and 618 liters, caffeinated coffee 6,098,8,962 and 11,769 liters and decaffeinated coffee 0, 107 and 476 liters. -'Drinkers with unknown lifetime consumption.-'p values of x: for heterogeneity over response and x: for trend, excluding users with incomplete lifetime consumption. -40dds ratios obtained hy logistic regression analysis and ad'usted for age, sex, response status, lifetime smoking of cigarettes, dietary intake of energy and vegetables and lifetime consumption of tea; for ground, instant, cadeinated and decaffeinated coffee an extra adjustment for other types of coffee was also included. -'p < 0.05.

were not different from unity and, with the exception of white wine, point estimates for lifetime consumption were probably influenced only marginally. For several more common habits, the proportion of unknowns was substantial, primarily among indirect responders. The highest proportion was observed for the most common habit of drinking tea and caffeinated or ground coffee, followed in decreasing order by alcohol, spirits and beer. This may be explained by the high level of detail in our questionnaire. Although unknown lifetime consumption for the more common habits was not associated with risk, the relatively high level of unknown consumption may have influenced our point estimates for lifetime consumption.

In our study, data on a considerable percentage of subjects, i.e. 42.0% of the cases and 28.7% of the controls, were obtained by interviewing, in decreasing order, spouses, chil- dren or others. This may have introduced differential or non-differential misclassification. However, our finding that none of the interaction terms was significantly different from unity may indicate reasonable agreement between direct and indirect interviews and further supports our results. Compari- son of the responses provided by index subjects and by proxies before the death of the index subject about the consumption of alcoholic or non-alcoholic beverages showed agreement to be high for the crude (yes/no) classification of alcohol consump-

tion and high or reasonable for the frequency of drinking specific alcoholic beverages, coffee and tea (Kolonel et al., 1977; Marshall et at., 1980; Herrmann, 1985; Metzner et al., 1989).

Neither consumption nor lifetime consumption of alcohol, based on a detailed history of the lifetime consumption of beer, spirits, red wine, white wine and fortified wine, was related to risk. This result adds to the growing body of evidence obtained in hospital-based (Wynder et al., 1973; MacMahon et al., 1981; Haineset al., 1982; Wynder et al., 1983; Gold et al., 1985; Hsieh et al., 1986; Mack et al., 1986; Falk et al., 1988; Ferraroni et al., 1989; Clavel et al., 1989), community- based (Gold et al., 1985) and population-based (Norell et al., 1986; Farrow and Davis, 1990) case-control and cohort studies (Klatsky et al., 1981; Hiatt et al., 1988) arguing against a role of alcohol in human pancreatic carcinogenesis. It is also in agreement with the absence of an effect of non-toxic levels of ethanol in animal research (Pour et al., 1983; Woutersen et al., 1989). Selection bias of cases and/or controls may have contributed to the positive associations with total alcohol consumption reported in 2 hospital-based (Burch and Ansari, 1968; Cuzick and Babiker, 1989) and 1 population-based case-control study using door-to-door controls (Durbec et al., 1983). After pooling the data from 2 negative hospital-based


case-control studies conducted in Paris (Clavel et al., 1989) and Greater Milan (Ferraroni et al., 1989) and the population- based case-control study conducted in Geneva (Raymond et al., 1987), no association with alcohol consumption was found (Bouchardy et al., 1990). The cohort study conducted in Japan found a significant dose-response effect for non-daily but not for daily alcohol drinkers (Hirayama, 1981). The positive relationship with heavy alcohol consumption, i.e. 4 or more drinks per day, observed in a Minnesota population-based case-control study using proxy respondents only (Olson et al., 1989) and the significant dose-response effect of alcohol (based on the frequency of consumption of beer and spirits) in the cohort study carried out in Norway (Heuch et al., 1983), which persisted after controlling for smoking of cigarettes in a subset of 18 cases with pancreatic cancer, however, remain of concern.

After adjustment for other sources of alcohol, no relationship was found with either beer drinking or the lifetime amount of beer consumed. Beer was positively associated with risk in 1 hospital-based (Cuzick and Babiker, 1989) and 2 population-based (Durbec et al., 1983; Raymond et al., 1987) case-control studies. The previously mentioned pooled analysis of 3 case-control studies (Bouchardy et al., 1990) which included 1 study in Paris (Clavel et al., 1989) and 1 in Greater Milan (Ferraroni et al., 1989), both without an effect of beer, and the study in Geneva (Raymond et al., 1987), which was positive, did not reveal any relationship with beer. However, in all 3 studies the consumption of beer was less frequent than that of wine; it was even uncommon in Greater Milan (Ferraroni et al., 1989). In contrast, in our population, beer drinking was quite common and certainly more so than wine drinking. Several other case-control studies using hospital (Falk et al., 1988), neighborhood (Mack et al., 1986) or population-based controls (Farrow and Davis, 1990) and one cohort study (Hiatt et al., 1988) also showed no association with beer. In brief, the weight of the evidence currently available does not support consumption of beer as a risk factor for pancreatic cancer.

The absence of a relationship with spirits, adjusted for other sources of alcohol, is consistent with the findings of other case-control studies, which reported on the effect of spirits using hospital (Falk et al., 1988), neighborhood (Mack et al., 1986) or population controls (Durbec et al., 1983; Raymond et al., 1987; Farrow and Davis, 1990). The cohort study conducted in California also revealed no association with liquor (Hiatt et al., 1988).

After adjustment for other sources of alcohol, neither the drinking nor the lifetime consumption of red wine was found to be related to risk. This is in agreement with the absence of an effect of red wine in the population-based case-control study in Geneva (Raymond et al., 1987) and the population-based case-control study among males in the state of Washington (Farrow and Davis, 1990). The observed risk pattern for the lifetime consumption of white wine-i.e. uniformly reduced odds ratios-was based on small numbers but may, if it is not accidental, either point to an unknown correlate of white wine, or suggest that drinking white wine above a critical threshold is protective, or reflect a true inverse association of white wine. Only one case-control study, which was conducted among males living in the state of Washington and-compared to our study-had a higher proportion of subjects who consumed white wine, has examined the effect of white wine and reported a non-significant inverse association (Farrow and Davis, 1990). If the differential effects of red and white wine are real, a biologically plausible explanation is not apparent. The inconsistent effects reported for wine as such may have been caused by the underlying difference in the effects of red and white wine or may be explained by the absence of adjustment for other sources of alcohol. Inverse relationships with wine were found

in 2 case-control studies in the USA using community (Gold et al., 1985) and neighborhood controls (Mack et al., 1986). The pooled analysis of the 3 case-control studies in Greater Milan, Paris and Geneva did not reveal a relationship with wine (Bouchardy et al., 1990), although the data from Paris did show a significant inverse dose-response effect. In contrast, a hospital- based case-control study in the US (Lin and Kessler, 1981, in men only) and a population-based case-control study in Marseille (Durbec et al., 1983) both observed positive associations with wine, whereas 2 hospital-based case-control studies in Louisiana, US (Falket al., 1988) and in England (Cuzick and Babiker, 1989) found no relationship. Although the consumption of fortified wine was significantly and positively associated with risk, the findings for the lifetime number of drinks did not support a dose-response effect, which is in agreement with the results of the case-control study in Los Angeles (Mack et al., 1986).

The absence of an association with the lifetime consumption of tea is in accordance with the findings of 5 case-control studies using hospital controls (MacMahon et al., 1981; Hsieh et al., 1986; La Vecchia et al., 1987; Cuzick and Babiker, 1989) or neighborhood controls (Mack et al., 1986) and 2 cohort studies, one in England in a population with a relatively high consumption of tea, i.e. 6.02 cups per day (KinIen et al., 1984) and the other in California with a relatively low level of consumption, i.e. 0.31 cups per day among all cases and 0.61 cups per day among controls (Hiatt et al., 1988). Although the significant positive association with tea found in a hospital- based case-control study in England was explained by the authors by the possibility of transient hyperglycemia causing compensatory thirst among cases (Kinlen and McPherson, 1984), the cohort study in California did not support this hypothesis since, after excluding diabetics, no relationship between blood glucose levels and pancreatic cancer cases diagnosed within 12 months of examination was observed (Hiatt et al., 1988). The significant inverse association with regular tea consumption at the time of a college physical examination, with no indication of the dose-response, observed in one cohort study (Whittemore et al., 1983) deserves further attention.

After adjustment for age, sex, response status, smoking, dietary intake of energy, vegetables and tea, an inverse dose-response effect of the lifetime consumption of total coffee was found, with the test of trend approaching statistical significance. However, the effect became weaker when only direct responders were analyzed. A true protective effect of drinking coffee does not really seem plausible and we wonder whether a disease-related decrease in the amount of coffee drunk could have influenced exposure estimates for cases. Our finding is consistent with animal, but not epidemiological, research. Long-term coffee consumption had an inhibitory effect on dietary-fat-promoted pancreatic carcinogenesis in rats and hamsters (Woutersen and van Garderen-Hoetmer, 1989). However, the majority of hospital-based (Wynder et al., 1983; Kinlen and McPherson, 1984; Hsieh et al., 1986; La Vecchia et al., 1987; Falk et al., 1988; Cuzick and Babiker, 1989) and population-based (Norell et al., 1986; Raymond et af., 1987; Olsen et al., 1989; Farrow and Davis, 1990) case- control studies and cohort studies (Whittemore et aL, 1983; Heuch et al., 1983; Kinlen et al., 1984; Snowdon and Phillips, 1984; Nomura et al., 1986; Jacobsen et al., 1986; Hiatt et al., 1988; Mills et al., 1988) did not indicate any relationship with risk. A recent review concluded that current epidemiological evidence does not suggest a significantly increased risk of pancreatic cancer associated with coffee consumption (Gordis, 1990). The significantly positive dose-response relationship with total coffee consumption observed in 2 hospital-based case-control studies (MacMahon et al., 1981; Clavel et al., 1989) and the insignificant dose-response effect seen among women compared with community controls (Gold et al., 1985)


may, if not due to chance, be related to the type of controls; this may also explain the weak effect of smoking (MacMahon et al., 1981; Gold et al., 1985) as well as the absence of any such effect (Clavel et al., 1989).

Simultaneous estimation of the effects of ground and instant coffee did not reveal any relationship with risk. Similarly, no effect of lifetime consumption of caffeinated and decaffeinated coffee was observed. These findings are in agreement with several hospital-based case-control studies which did not show any effect of consumption of normal (Hsieh et al., 1986) or decaffeinated coffee (Wynder et al., 1983; Hsieh et al., 1986; La Vecchia et al., 1987). The exclusion of 22% of eligible patients due to extreme morbidity and the inclusion of hospital controls with smoking-related conditions, i.e. 25% of male and 14% of female controls, in a hospital-based case-control study may have contributed to the significant positive relationships between decaffeinated coffee and male and female pancreatic cancer and the association with smoking among female subjects only (Lin and Kessler, 1981).

In summary, our findings do not suggest that the lifetime consumption of specific alcoholic beverages, tea or (de)caffeinated coffee positively influences the development of exocrine carcinoma of the pancreas. The inverse relationships with the

consumption and cumulative lifetime consumption of white wine deserve further investigation.

ACKNOWLEDGEMENTS

This project was supported by grant R 808 from the Ministry of Welfare, Health and Culture (formerly Ministry of Health and Environmental Hygiene) of The Netherlands. The authors thank F. de Waard, Department of Public Health and Epidemi- ology, State University of Utrecht, Utrecht (former head of the Department of Epidemiology, RIVM), F.C. Bourgeois and P.E. Steinberger, Computer Center, S.H. Heisterkamp, Center for Mathematical Methods, and W. Agterberg, P.W. Dols, G. Doornbos, J. Dorssers, J. van Gorp, M.C.A. Hofstee, A. Liesker, E. Rontgen-Pieper and M.C.E. Stam-Rademaker, Department of Epidemiology, National Institute of Public Health and Environmental Protection, Bilthoven, clinicians and pathologists of regional hospitals and the Comprehensive Cancer Center “Midden-Nederland” for their participation in this study. We are grateful to A.M. Walker, Harvard School of Public Health, for co-ordinating the international study and to R.J.J. Hermus, TNO-CIVO, D. Kromhout, F. Smeets and M. OckC, RIVM for evaluation of the draft of this report.

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Lifetime consumption of alcoholic beverages, tea and coffee and exocrine carcinoma of the pancreas: A population-based case-control study in The Netherlands