Int. J . Cancer: 46, 435-444 (1990) 0 1990 Wiley-Liss, Inc.
Publication of the International Union Againsi Cancer Publication de I‘Union lnternatlonale Contre le Cancer
ARE ENERGY AND ENERGY-PROVIDING NUTRIENTS RELATED TO EXOCRINE CARCINOMA OF THE PANCREAS? H.B. BUENODE MESQUITA1’4,C.J. MOEFMAN’, s. R U N I Aand ~ P. MAlSONNEUVE3 ’Department of Epidemiology, National Institute of Public Health and Environmental Protection, PO Box 1 , 3720 BA Bilthoven, The Netherlands; 2Department of Dietetics, The Utrecht University Hospital, PO Box 85500, 3508 GA Utrecht, The Netherlands (formerly Department of Epidemiology, National Institute of Public Health and Environmental Protection, Bilthoven, Netherlands); and 3Unit of Analytical Epidemiology, International Agency for Research on Cancer, 150 C o w s Albert-Thomas, 69372 Lyon Cedex 08, France. During 1984-68 a population-based case-control study was carried out in The Netherlands in collaboration with the International Agency for Research on Cancer in order t o further explore the possible relationship between diet and exocrine pancreatic carcinoma. Past habitual dietary intake was assessed in 164 cases and 480 controls. This is the first series of population-based studies of pancreas cancer to perform a comprehensive assessment of diet. The results of logistic regression analysis, controlled for age, gender and total cigarette consumption, suggested a positive association with past habitual intake of energy in directly interviewed patients (OR highest versus lowest quintile 3.35; 95% confidence interval 1.51-7.18). No indication of an effect of Quetelet index was found. When maximum-weight-ever-achieved was used, nonsignificantly reduced risks were observed for the upper 4 quintiles of “maximum” Quetelet index. After controlling for age, gender, response status and total cigarette consumption, a positive relationship with habitual past intake of total carbohydrates was observed (OR 2.40; 95% confidence interval I.44-3.99). The effect decreased considerably when the analysis was restricted to subjects who reported stable long-term dietary intake. After controlling for age, gender, total cigarette consumption and response status, a significant, positive association between pancreatic cancer and past habitual intake of simple sugars was found (OR 1.95; 95% confidence interval 1.24-3.07). Among those who reported stable longterm dietary intake, no effect was seen. The positive effect of simple sugars was present in males only (OR 1.15; 95% confidence interval 1.16-3.93) and was smaller in men who reported long-term stable dietary intake. Our findings suggest that the development of exocrine pancreatic carcinoma is positively related t o past habitual intake of total energy, total carbohydrates and simple sugars, whereas no relationship with body-mass index was observed.
intake have been reported so far and the question arose whether energy as such andlor specific energy-providing nutrients were responsible for these findings. Before mentioned observations in international correlation and analytic epidemiologic studies, however, may also suggest that a potential effect of diet depends on the origin of fat, protein and carbohydrates. Animal experiments support this view, as corn oil, fish oil, raw soy bean protein and casein were shown to influence pancreatic carcinogenesis in rats and hamsters (Birt etal., 1981; O’Connor et al., 1985; Roebuck et al., 1987; Pour et al., 1983; Pour and Birt, 1983). During 1984-88 a population-based case-control study was carried out in Utrecht, The Netherlands, to further explore a possible relationship between lifestyle factors, including diet, and pancreatic and biliary cancer. The study is incorporated in the SEARCH (Surveillance of Environmental Aspects Related to Cancer) programme of the International Agency for Research on Cancer (IARC) of the WHO, Lyon, France, which is designed to generate, formulate and test by epidemiological methods, and on an international basis, hypotheses on environmental hazards and lifestyle practices involved in cancer. We report here findings of the Utrecht study on the relation between habitual past intake of total energy (including energy derived from alcoholic beverages), total fat, saturated, monoand poly-unsaturated fatty acids, total, animal and vegetable protein, total carbohydrates, mono- and disaccharides (simple sugars), polysaccharides (complex sugars) and body mass index to exocrine pancreatic carcinoma.
On an international level, positive correlations have been demonstrated between the incidence andlor mortality of pancreas cancer and estimates of per capita consumption of energy-providing foods and nutrients, i.e. fats and oils, animal protein, sugar and meat (Lea, 1967; Armstrong and Doll, 1975; Maruchi et al., 1977; Yanai et al., 1979). Animal research has suggested dietary factors, i.e. intake of energy and of the energy-providing nutrients fat and protein, as likely contributory causes in pancreatic cancer induced by nitrosamines (hamsters) (Birt et al., 1981) or azaserine (rats) (Roebuck et al., 1981). Several epidemiologic studies have focused on the relationship between diet and pancreatic cancer. Results also point to specific energy-providing foods as promoting pancreatic cancer in humans, e.g. meat (Hirayama, 1975; Norell et al., 1986), white bread (Gold et al., 1985; Raymond et al., 1987; Olson et al., 1989) butter and pastry (Raymond et al., 1987) and rice (Falk et al., 1988). Other energy-providing foods however, like whole-grain bread (Mack el al., 1986, Olson et al., 1989) may protect against pancreatic cancer. Only one study was published on energy-providing nutrients, and suggested that fat increases and carbohydrates reduce the risk of pancreatic cancer (Durbec et al., 1983). Except for one study showing a negative association with energy intake (Durbec et al., 1983), no other studies on the effect of total energy
Study population The study area was situated in the central part of The Netherlands. In 1983 the population, living in 70 municipalities, numbered 1.13 million. A detailed description of subjects and methods has been published by Bueno de Mesquita et al. (1989). Cases were defined as all persons, alive or dead, aged 35-79, 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. Cases were identified as early as possible in the diagnostic period. The disease was defined as a clinical diagnosis of exocrine cancer of the pancreas. Microscopic verification of diagnosis was present in 68% of cases. Multiple sources, such as clinicians (physicians and surgeons), records of pathology laboratories, hospital diagnostic lists and the cancer registry of the beginning Comprehensive Cancer Centre “Midden Nederland” were used to trace eligible cases. From a comparison of observed with expected number of cases
MATERIAL AND METHODS
4T0 whom correspondence and reprint requests should be sent. Received: February 13, 1990 and in revised form June 22, 1990.
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BUENO DE MESQUITA ET AL.
based on incidence data from the neighbouring Dutch SOOZ Cancer Registry and of the histological verification rates in our study and the SOOZ registry (Bakker et al., 1987), we cannot exclude the possibility that up to 15% of eligible cases were not identified. General population controls, aged 35-79 and living in the study area at some point during 1984-1987, were sampled from the municipal population registries (C .B .S ., 1983, 1985 and 1986). The system of population registries has been in operation since the beginning of the last century. Submission of data on birth, death and change of residence is mandated by law. Consequently, the municipal population registries are considered almost 100% complete. Although in 1983 it was anticipated that a certain number of cases had to be interviewed indirectly, selecting deceased controls with causes of death which were entirely unrelated to any of the possible aetiologies under consideration was considered almost impossible. It was therefore decided that an acceptable control must have been alive at some point during the study period. Index controls, who were asked to respond directly, were a stratified random sample of the general population of the study area, frequency matched to the age- and sex-distribution of cases, using a control-case ratio of at least 2 to 1 for those under age 60 and 1 to 1 for ages 60 and above. After the first 2 years of the study, however, about 39% of eligible patients with pancreatic cancer could not be interviewed directly, mainly due to early death, and were replaced by suitable proxies. As this figure exceeded the proportion envisaged at the time the study was designed, during 1986 and 1987 an additional control group was asked to let suitable surrogates answer the questions on their behalf (proxy controls). Proxy controls, like index controls, were identified from population registers and frequency-matched to the age- and sex-distribution of indirectly responding patients, with a similar control-case ratio to that observed among index controls. During the study period 189 eligible patients with cancer of the pancreas were identified (100 males and 89 females) (Table I). 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 of living controls (103 males and 112 females). Among men, response rates for a dietary interview with complete information on dietary intake were 90.0% in cases and 72.7% in controls. Among women the corresponding response rates were 83.2% in cases and 64.8%in controls. A direct response was defined as an interview which was conducted in the presence of the index person, who was often assisted by one or more family members or other persons. An indirect response was defined as an interview in which the index person was absent and was replaced by one or more proxies, who were likely to be informative about the index person. Among male participants, 50.0% of the patients responded directly compared to 66.4% of the controls, while in females the corresponding percentages were 54.1% and 73.4%.Among indirectly responding subjects, for men the
proxy was a spouse in 76.1%of cases versus 84.6%in controls and for women in 45.9% of cases vs. 58.8% in controls. Twenty-five cases did not participate for the following reasons, incomplete data on food frequency (32%), identification more than 1 year after death (28%),refusal of case or proxy (20%), refusal by physician (16%), lack of suitable proxy (4%). The reasons for non-response among the 222 non-responding controls were as follows: refusal (88%), no suitable proxy (5%), no traceable proxies (5%) and incomplete food frequency data (2%).As a result 644 subjects, i.e. 164 cases and 480 controls, were available for analysis of the effect of usual dietary intake. Data collection The data were collected during 2 interviews. During the first an interviewer-administered questionnaire covered selected socio-economic topics, height, weight 2 years previously and maximum weight ever attained, lifetime consumption of tobacco and other factors including medical history. During the second interview a dietary questionnaire was administered by a dietitian. The time period of reference for living or deceased cases was approximately 1 year prior to diagnosis in order to discern typical pre-morbid dietary patterns and for living controls approximately 1 year prior to the date of interview. A large part of the dietary questionnaire consisted of a semiquantitative food frequency method and was developed in cooperation with the Department of Human Nutrition of the TNO-CIVO Toxicology and Nutrition Institute at Zeist. The semi-quantitative food frequency method was aimed at comprehensively assessing diet by estimating usual individual intake of 116 commonly used food items and food groups in order to rank subjects according to level of intake approximately 1 year earlier. After some introductory questions, first information was sought about meal patterns during a representative week about 1 year previously. Seasonal variation in consumption of certain products was taken into account. Standard portions in household measures were used to estimate usual amounts. Samples of crockery and table ware and colour photographs of about full-sized meals were used to clarify standard portions. At the end of the dietary interview, in order to gather information about long-term stability of food habits, questions were asked about the food pattern 10 years previously in comparison with the period about 1 year previously. Statistical methods Frequency and portion size of usual intake of food items were converted into average daily intake of foods and nutrients. Analyses of nutrients were based on the Dutch food table of 1985 (Bureau of Nutrition Education, 1985). In order to obtain odds ratios, related 95% confidence intervals and tests for trend for current degree of urbanity, educational level attained, personal income one year earlier and current marital status, adjusted for the possible confounding effect of 10-year age-groups, response status and total smoking, logistic regression analysis (Breslow and Day, 1980) was per-
TABLE I - PARTICIPATION AND MEAN AGE BY GENDER AND RESPONSE STATUS. THE SEARCH PANCREATIC CANCER STUDY, UTRECHT (1984-88)
Males
Total
Eligible Response Participants' Response status* Mean age
100 90.0% 90
89 1 72.3%
644
65.4
Females
cases
controls
cases
cnntrolr
319 72.7% 232
89 83.2% 74
383 64.8% 248
Direct
Indirect
Direct
Indirect
Direct
Indirect
Direct
Indirect
45 50.0% 66.0
45 50.0% 66.8
154 66.4% 65.0
78 33.6% 63.5
40 54.1% 67.2
34 45.9% 68.0
182 73.4% 66.1
66 26.6% 62.5
'Subjects with complete information on habitual dietary intake.-*lf the index person was willing to participate, a direct interview was conducted in the presence of the index person, who was often assisted by one or more family members and/or other persons. If the index person could not participate, an indirect interview was conducted in the presence of one or more family members and/or other persons.
437
ENERGY-PROVIDING NUTRIENTS AND PANCREATIC CANCER
formed. The total smoking variable represented the cumulative (lifetime) consumption of plain, hand-rolled, low-tar and other filtered cigarettes. To permit testing for trend across the 4 levels of smoking, i.e. non-smokers and 3 categories of smokers with known lifetime consumption, smokers with one or more unknown frequencies of consumption were grouped in the 5th, highest level of smoking. Usual daily intake of energy and nutrients by cases and controls was summarized by means and related standard deviations. The continuous variables on energy and nutrient intake were categorized into quintiles according to the distribution of cases and controls. Logistic regression analysis using the GLIM statistical package (Baker and Nelder, 1985) provided point and interval estimates of relative risks (Breslow and Day, 1980) for the different nutrients adjusted for 10-year agegroups, response status and total smoking. Tests for trend were based on giving scores 1-5 to the 5 stratum-specific odds ratios. The response status variable indicated a direct response or an indirect response during the dietary interview. Thereafter, an analysis of the variables as continuous was performed. After adjustment for 10-year age-groups, response status and total smoking, the regression coefficient and the 95% confidence interval were multiplied by the difference in the medians of the extreme quintiles and converted to an odds ratio and the related 95% confidence interval. The odds ratios therefore represent estimates of relative risks for the median of the highest quintile of intake using the median of the lowest quintile as reference category. Intake of energy and energy-providing nutrients are often highly correlated. To examine associations with nutrients, which contribute to energy intake, we therefore followed the strategy advocated by Howe (1989). First, the association between risk of disease and total energy intake was evaluated, using total energy (including energy from ethanol) alone in a model. If there was an association with total energy alone, the difference between each energy-providing nutrient and energy from other sources was tested using the “Willett-Stampfer” approach (model a) (Willett and Stampfer, 1986). If there was a difference between the effect of the nutrient and that of energy from other sources, the separate effect of the nutrient independent of other energy was tested using the Howe’s approach (model b) (Howe et al., 1986). If there was an association between the nutrient and risk independent of other en-
ergy, but no association between other energy and risk, the risk estimate was expressed using a model containing only the nutrient (model c). The absence of 2-way interaction between response status and total energy intake was tested by adding an interaction term for response status and energy, which provides a direct estimate of bias due to misclassification in the proxy stratum, with confidence intervals obtained directly from the associated standard error (Walker et d . , 1988). For energy-providing nutrients which were significantly related to risk, the absence of 2-way interaction with response status was evaluated by adding 2 interaction terms, one for the interaction between response status and the nutrient of interest and another for the interaction between response status and other sources of energy. The difference in the deviance obtained for the models including or excluding the interaction terms provides an estimate of heterogeneity across response status. However, as both tests of interaction have relatively low power, if an interaction term was substantial in relation to the main effect, interpretation was based on separate analysis for direct and indirect interviews as well. Finally, a similar analysis was carried out excluding 29 cases and 64 controls who reported that their diet 1 year previously was very different from that of 10 years previously. RESULTS
Effect of selected characteristics Categorical analysis of educational level attained, personal income, marital status and degree of urbanity adjusted for age, gender, smoking and response status did not suggest significant differences between cases and controls. The effect of total cigarette consumption by gender is shown in Table 11. Although, in both sexes, after excluding smokers with unknown lifetime consumption the test for trend was not significant, compared to never-smokers, odds ratios for several levels of total cigarette consumption suggest a positive relationship in both men and women. After adjustment for gender, compared to non-smokers, odds ratios for those who reported a lifetime consumption of 300,000 cigarettes or more (OR 2.62; 95% CI 1.15-5.96) and for smokers with unknown lifetime consumption (OR 3.69; 95% CI 2.006.80) were signif-
TABLE n - ODDS RATIOS AND 95% CONFIDENCE LIMITS FOR PANCREATIC CANCER FOR SELECTED CHARACTERISTICS BY GENDER. THE SEARCH PANCREATIC CANCER STUDY, UTRECHT ( 1 9 8 G 8 8 ) Males CdCO
n
OR‘
Females (95%CI)
941235
Lifetime consumption of cigarettes2 (unit = lo00 cigarettes) 7/33 1 .oo None
0.50
371140 23/80 8/17 214 12/11
1.00 1.28 2.11 2.30 4.397 2.61
12/50 17/50 18/44 17/49 15/54 315
1.00
1.37 1.75 1.28 1.13 1.91 0.01
(0.70-2.35) (0.79-5.63) (0.37-14.16) (1.60-12.03) p > 0.10 (0.563.37) (0.714.29) (0.52-3.13) (0.46-2.80) (0.32-11.52) p > 0.90
‘Odds ratios are obtained by logistic regression.-*Adjusted for 10-year age-group and response status. Cut-off levels were based on the distribution of total cigarette consumption in cases and controls in the international study.-’Smokers with unknown lifetime number of cigarettes con~umed.-~Adjustedfor 10-year age-group, response status and total smoking. Quintile boundaries for Quetelet index were based on the distribution in cases and controls and amounted to 23.0, 24.3, 26.0 27.9 in men and 21.6, 24.2, 25.9, 28.7 in women.-’Excludes smokers with unknown lifetime consum tion of cigarettes.-’Excludes the unknown category, i.e. subjects with incomplete data for computing the Quetelet index.- Pp < 0.05.
438
BUENO DE MESQUITA ET AL.
icantly raised. Excluding smokers with unknown consumption, a monotonic increase in risk was observed (OR 1.00, 1.36, 1.86,2.62) with a significant dose-response effect (p < 0.05). After controlling for age, response status and total smoking, the data on Quetelet index (weight 2 years previously divided by height squared) by gender suggest non-significant, opposite effects for males and females (Table 11). In contrast “maximum” Quetelet index, with maximum weight ever attained instead of weight 2 years earlier, showed nonsignificant, reduced risks for males (OR 1.00, 0.53, 0.45, 0.53,0.72) and females (OR 1.OO, 0.80,1.30, 0.56,0.89) for most of the quintiles without a significant dose-response effect. After controlling for age, gender, response status and total smoking, Quetelet index did not appear to be related to risk (OR 1.OO, 1.17, 1.05, 0.92, 0.99), but maximum Quetelet index suggested non-significant, reduced risks for the upper 4 quintiles (OR 1.00, 0.59, 0.62, 0.68, 0.64). Effect of energy and energy-providing nutrients Table 111 shows the mean and standard deviation of past daily intake of total energy and energy-providing nutrients. Compared to controls, male cases reported a significantly higher mean intake of mono- and disaccharides. Female cases reported a significantly higher mean intake of total energy, total and saturated fats and total and complex carbohydrates. Taking the quintile of lowest intake as reference and after adjustment for age, total smoking and response status, findings of the categorical analysis for males and females diverged considerably and further analyses were done for both sexes as well (Table IV). In men, compared to the lowest quintile of energy intake, none of the odds ratios for the upper 4 quintiles of usual intake of energy was significantly different from unity and no significant trend was observed. In females, the upper 4 quintiles of usual intake of total energy showed elevated risks with a significant test for trend; however, the trend did not appear to be linear. After adjustment for gender the upper 4 levels of energy intake showed raised risks (OR 1.OO, 1.71, 1.54,1.65, 3.44) and the test for trend for energy intake became highly significant (p < 0.005). Subjects in the highest quintile of intake experienced a 3- to 4-fold, significantly elevated risk (OR 3.44; 95% CI 1.73-6.86). Among males the tests for trend for past habitual intake of total carbohydrates and mono- and disaccharides were significant, but not clearly linear, while none of the other energyproviding nutrients showed a relationship with risk (Table IV). In women, significantly raised odds ratios for higher levels of daily intake of several nutrients, i.e. animal protein, total fat,
saturated and mono-unsaturated fatty acids, total carbohydrates and polysaccharides, were observed. Significant, positive tests for trend were seen for animal protein, mono-unsaturated fatty acids and polysaccharides; however, none of the risks showed a linear trend. After adjustment for gender (data not shown) elevated risk estimates and significant tests for trend emerged for past habitual intake of total protein, animal protein, polyunsaturated fatty acids, total carbohydrates, mono- and disaccharides and polysaccharides. Linear analysis and the eflect of long-term stability of the dietary pattern Next, a linear analysis of usual intake of total energy and energy-providing nutrients was performed, taking into account the confounding effect of total energy intake (Tables V and VI). After adjustment for age, total smoking and response status, both males and females showed a positive relationship with total energy (Table V). After adjustment for gender, an increase in usual energy intake of 1,457 kcal/day (i.e. from the median of the lowest quintile of 1,506 kcaYday to the median of the highest quintile of 2,963 kcallday) was associated with a significant, approximately 2.5-fold increase in risk of pancreatic cancer (OR 2.69; 95% CI 1.50-4.75). The exclusion of those who reported long-term instability of dietary pattern yielded a similar risk estimate (OR 2.50; 95% CI 1.34-4.68). Total carbohydrates and mono- and di-saccharides in males were the only energy-providing nutrients, which showed differences with energy from other sources approaching significance (models A, Tables V and VI), as well as significant effects independent of other sources of energy (models B in Tables V and VI), without significant effects of other sources of energy (data not shown). Consequently, the best risk estimates were obtained by using model C with the nutrient alone. Compared to the median of the lowest quintile, i . e . 169 glday, an increase in daily intake of total carbohydrates up to the median of the highest quintile, i.e. 350 glday, was associated with a significant, more than 2-fold increase in risk of male pancreatic cancer (OR 2.22; 95% CI 1.09-4.53). An increase in past usual intake of mono- and disaccharides from 75 up to 176 g/day was associated with a significant increase in male risk of about equal strength (OR 2.15; 95% CI 1.18-3.93). A similar, though somewhat weaker, risk pattern was observed when excluding males who reported instability in long-term dietary intake (data not shown). After adjustment for gender, carbohydrates and mono- and disaccharides were the only energy-providing nutrients which showed elevated risks for the difference with energy from other
TABLE 111 - MEAN AND STAKDARI) DEVIATIOY OF PAXI’ DAILY INTAKE OF ENERGY-PROVIDING YUTRIEKIS FOR CASES ASD COS1‘ROI.S BY GENDER TIIII SEARCH PAKCRCATIC CANCER STUDY, CTRECIIT ~1983-88)
Males
Total energy, kcall Total protein, g Vegetable, g Animal, g Total fats, g Saturated, g Mono-unsatur., g Poly-unsatur., g Total carbohydr., g Mono- anddissach., g Polysacch., g
Females
cases
controls
cases
controls
n = 90
n = 232
n = 74
n = 248
Mean
SD
Mean
SD
Mean
SD
Mean
SD
2518 82 28 54 110 47 42 18 264
570 19 8 15 31 16
2430 79 28 52 110 47 42 19 252 120 131
504 17 7 14 28 12 12 8 64 40 36
19792 70 23 46 89’ 392 34 15 215‘ 106, 108
494 16 7 12 25 12 10 7 68 47 34
1827 66 22 44 82 36 32 13 197 98 98
435 14 6
131’
131
13
7 72 47 38
11
22 10 9 6 60
44 26
’Includes calories obtained from alcohol.-*Mean daily intake of cases is significantly different from that of controls (95% confidence limits of mean difference do not include zero).
439
ENERGY-PROVIDING NUTRIENTS A N D PANCREATIC CANCER TABLE IV - ODDS RATIOS’ FOR PANCREATIC CANCER FOR QUINTILES OF INTAKE OF ENERGY-PROVIDWG NUTRIENTS ADJUSTED FOR AGE, TOTAL SMOKING AND RESPONSE STATUS BY GENDER. THE SEARCH PANCREATIC CANCER STUDY, UTRECHT (1984-88)
Nutrients
1
2
1.00 1 .oo 1.00 1 .oo 1.00 1.00
1 .oo 1 .oo 1.00 1.00 1 .oo
0.87 1.25 0.99 1.30 0.97 0.56 1.15 1.54 0.69 1.04 1.06
1.00 1.00 1.00 1 .oo 1 .oo 1 .oo 1 .oo 1.00 1 .oo 1.00 1.00
2.72’ 0.84 0.55 1.15 2.00 1.99 1.73 0.45 1.72 0.98 0.69
Quintiles* 3
x2 for 4
5
trend3
0.54 0.88 0.89 1.60 0.43 0.47 0.38’ 1.06 1.93 2.13 0.82
1.59 1.49 1.76 1.42 0.94 0.75 0.72 1.42 1.11 1.84 1.18
1.37 1.67 0.92 2.00 1.10 0.86 1.41 1.13 2.02 2.28 1.01
1.66 1.61 0.25 2.34 0.04 0.01 0.16 0.04 4.0S 5.445 0.03
2.16 1.08 0.71 1.00 2.87’ 2.05 1.78 0.79 2.28 1.48 0.80
2.02 1.14 0.52 1.54 2.35 1.16 3.585 1.15 1.56 1.55 1.37
4.51’ 1.98 1.67 2.65’ 2.49 3.21’ 2.22 1.39 2.805 1.46 2.64’
5.95’ 2.83 1.17 5.035 2.84 2.95 4. 185 2.85 3.62 1.36 6.69’
Males
Total energy, kca14 Total protein, g Vegetable, g Animal, g
Total fat, g Saturated, g Mono-unsaturated, g Poly-unsaturated, g Total carbohydrates, g Mono- and disacch., g Polysaccharides, g Females
Total energy, kca14 Total protein, g Vegetable, g Animal, g
Total fat, g Saturated, g Mono-unsaturated, g Poly-unsaturated, g Total carbohydrates, g Mono- and disacch. Polysaccharides
’Odds ratios are obtained by logistic regression analysis.-’Quintile boundaries in men for energy 1987, 2288, 2517, 2918; total protein 66.5, 74.2, 82.7, 93.8; vegetable protein 21.1, 25.1, 29.0, 33.7; animal protein 42.6, 48.0, 54.0, 62.4; total fat 85.5,99.7, 113.7, 132.0; saturatedfat 35.7,42.0,48.1,56.3;mono-unsatur. fattyacids 33,38,44,52; ply-unsatur. fattyacids 12, 16, 19, 25; total carbohydrates 198.2, 231.2, 260.8, 315.9; mono- and disaccharides 85.5, 105.6, 128.0, 157.9; polysaccharides 98.5, 118.4, 135.5, 158.1; in women 1514, 1713, 1903, 2178; total protein 54.7, 61.6, 69.1, 77.2; vegetable protein 17.6, 20.3.22.7, 25.9; animal protein 35.1,40.7, 45.8.53.3; total fat 64.8.76.0.86.5, 100.5; saturated fat 27.4, 33.0, 36.8, 44.5; mono-unsatur. fatty acids 24,28,34, 39; ply-UnSaNI. fatty acids 8, 1 1 , 14, 18; total carbohydrates 155.4, 177.2,205.7. 240.9; mono- and disaccharides 66.0, 82.7, 105.2, 124.7; plysaccharides 77.6, 89.5, 103.8, 120.3.-3Test for trend excludes unknown c~nsumption.-~Includescalories obtained from al~ohol.-~p < 0.05.
sources (model A), as well as significant effects independent of other sources of energy without an effect of other sources of energy (model B) (Table VII). Best risk estimates were obtained by including variables for the nutrients alone (model C). An increase in daily intake of total carbohydrates of 173 glday, i.e. the difference in medians of the extreme quintiles, was associated with a significant, 2- to 3-fold increase in risk for pancreatic cancer (OR 2.40; 95% CI 1.44-3.99). An increase of 107 glday in mono- and disaccharides was associated with a 2-fold increase in risk (OR 1.95; 95% CI 1.24-3.07). After restricting the analysis to those who reported long-term stable dietary intake, and after adjustment for other sources of energy (model B), the effect estimates for carbohydrates and monoand disaccharides were reduced in strength and no sevarate effects, independent of other sources of energy, were observed (Table VII). Effect of response status A stratified categorical analysis of quintiles of Quetelet index and maximum Quetelet index by response status and gender did not indicate an association with risk in any of the strata examined (data not shown). Interaction between response status and total energy consumption among males was not significant but was substantial. In directly interviewed men, dietary intake of total energy was significantly associated with disease (OR 2.65; 95% CI 1.04-6.71), a finding which was not affected by excluding those who reported that their diet 1 year earlier was “very different” from 10 years previously (OR 2.63; 95%CI 0.93-7.46). Indirectly interviewed male subjects showed no relationship between disease and total energy (OR
1.18; 95% CI 0.41-3.41). The response status-exposure interaction term among females was neither significant nor substantial in relation to the main effect of energy intake. After adjustment for gender, a significant interaction with response status was observed. A stratified analysis by response status showed that an increase in reported intake of 1,389 kcallday in directly interviewed subjects was associated with a more than 3-fold increase in risk (OR 3.35; 95% CI 1.56-7.18). ‘This excess in risk was still present after excluding those who reported long-term instability of dietary intake (OR 2.96; 9 5 8 CI 1.23-7.11). Indirectly interviewed subjects did not show a relationship with energy intake. In both sexes and in the sex-adjusted analysis, none of the differences in deviance between models with and without interaction terms for response status and intake of total carbohydrates and other energy were significant. Results on mono- and disaccharides also did not show a significant effect of interaction with response status. DISCUSSION
The results of logistic regression analysis adjusted for age, gender and response status pointed to a dose-response effect for life-time consumption of cigarettes. After adjustment for age, gender, total cigarette consumption and response status, our findings suggested that, compared to population-based controls, past habitual intake of total energy was significantly higher in patients with exocrine pancreatic carcinoma. However, a statistically significant interaction with response status was present. The analysis stratified by response status showed
440
BUENO DE MESQUITA ET AL.
Males Odds
rati"2
Total energy, kcallday' Total protein, g/day A
B C
1.88
(95%
Females
a
Odds
rafio2
(95%CI)
(0.97-3.66)
2.473 (1.32-4.56)
1.43 (0.54-3.79) 1.47 (0.61-3.55) 1.71 (0.91-3.19)
0.88 (0.32-2.47) 1.01 (0.4G2.55) 1.943 (1.01-3.75)
Total fat, q Y
0.153 (0.03-0.75) 1.36 (0.31-6.02) B 0.46 (0.18-1.13) 1.90 (0.72-5.00) C 1 . 1 1 (0.58-2.12) 2.623 (1.26-5.45) Total carbohydrates,
Y:lg B C
4.21 (0.93-19.13) 0.80 (0.17-3.73) 2.923 (1.17-7.26) 1.50 (0.65-3.45) 2.223 (1.09-4.53) 2.213 (1.17-4.19)
'Including calories from alcoholic beverages.-'Odds ratios represent estimates of relative risks associated with an increase in the variable examined equal to the difference in the medians of the extreme quintiles, i.e. in men for total energy 1310 kcallday, total protein 43 @day, total fat 72 g/day, total carbohydrates 181 g/day; in women for total energy 961 kcaYday, total protein 33 g/day, total fat 56 g/day, total carbohydrates 142 g / d a ~ . - ~
Publication of the International Union Againsi Cancer Publication de I‘Union lnternatlonale Contre le Cancer
ARE ENERGY AND ENERGY-PROVIDING NUTRIENTS RELATED TO EXOCRINE CARCINOMA OF THE PANCREAS? H.B. BUENODE MESQUITA1’4,C.J. MOEFMAN’, s. R U N I Aand ~ P. MAlSONNEUVE3 ’Department of Epidemiology, National Institute of Public Health and Environmental Protection, PO Box 1 , 3720 BA Bilthoven, The Netherlands; 2Department of Dietetics, The Utrecht University Hospital, PO Box 85500, 3508 GA Utrecht, The Netherlands (formerly Department of Epidemiology, National Institute of Public Health and Environmental Protection, Bilthoven, Netherlands); and 3Unit of Analytical Epidemiology, International Agency for Research on Cancer, 150 C o w s Albert-Thomas, 69372 Lyon Cedex 08, France. During 1984-68 a population-based case-control study was carried out in The Netherlands in collaboration with the International Agency for Research on Cancer in order t o further explore the possible relationship between diet and exocrine pancreatic carcinoma. Past habitual dietary intake was assessed in 164 cases and 480 controls. This is the first series of population-based studies of pancreas cancer to perform a comprehensive assessment of diet. The results of logistic regression analysis, controlled for age, gender and total cigarette consumption, suggested a positive association with past habitual intake of energy in directly interviewed patients (OR highest versus lowest quintile 3.35; 95% confidence interval 1.51-7.18). No indication of an effect of Quetelet index was found. When maximum-weight-ever-achieved was used, nonsignificantly reduced risks were observed for the upper 4 quintiles of “maximum” Quetelet index. After controlling for age, gender, response status and total cigarette consumption, a positive relationship with habitual past intake of total carbohydrates was observed (OR 2.40; 95% confidence interval I.44-3.99). The effect decreased considerably when the analysis was restricted to subjects who reported stable long-term dietary intake. After controlling for age, gender, total cigarette consumption and response status, a significant, positive association between pancreatic cancer and past habitual intake of simple sugars was found (OR 1.95; 95% confidence interval 1.24-3.07). Among those who reported stable longterm dietary intake, no effect was seen. The positive effect of simple sugars was present in males only (OR 1.15; 95% confidence interval 1.16-3.93) and was smaller in men who reported long-term stable dietary intake. Our findings suggest that the development of exocrine pancreatic carcinoma is positively related t o past habitual intake of total energy, total carbohydrates and simple sugars, whereas no relationship with body-mass index was observed.
intake have been reported so far and the question arose whether energy as such andlor specific energy-providing nutrients were responsible for these findings. Before mentioned observations in international correlation and analytic epidemiologic studies, however, may also suggest that a potential effect of diet depends on the origin of fat, protein and carbohydrates. Animal experiments support this view, as corn oil, fish oil, raw soy bean protein and casein were shown to influence pancreatic carcinogenesis in rats and hamsters (Birt etal., 1981; O’Connor et al., 1985; Roebuck et al., 1987; Pour et al., 1983; Pour and Birt, 1983). During 1984-88 a population-based case-control study was carried out in Utrecht, The Netherlands, to further explore a possible relationship between lifestyle factors, including diet, and pancreatic and biliary cancer. The study is incorporated in the SEARCH (Surveillance of Environmental Aspects Related to Cancer) programme of the International Agency for Research on Cancer (IARC) of the WHO, Lyon, France, which is designed to generate, formulate and test by epidemiological methods, and on an international basis, hypotheses on environmental hazards and lifestyle practices involved in cancer. We report here findings of the Utrecht study on the relation between habitual past intake of total energy (including energy derived from alcoholic beverages), total fat, saturated, monoand poly-unsaturated fatty acids, total, animal and vegetable protein, total carbohydrates, mono- and disaccharides (simple sugars), polysaccharides (complex sugars) and body mass index to exocrine pancreatic carcinoma.
On an international level, positive correlations have been demonstrated between the incidence andlor mortality of pancreas cancer and estimates of per capita consumption of energy-providing foods and nutrients, i.e. fats and oils, animal protein, sugar and meat (Lea, 1967; Armstrong and Doll, 1975; Maruchi et al., 1977; Yanai et al., 1979). Animal research has suggested dietary factors, i.e. intake of energy and of the energy-providing nutrients fat and protein, as likely contributory causes in pancreatic cancer induced by nitrosamines (hamsters) (Birt et al., 1981) or azaserine (rats) (Roebuck et al., 1981). Several epidemiologic studies have focused on the relationship between diet and pancreatic cancer. Results also point to specific energy-providing foods as promoting pancreatic cancer in humans, e.g. meat (Hirayama, 1975; Norell et al., 1986), white bread (Gold et al., 1985; Raymond et al., 1987; Olson et al., 1989) butter and pastry (Raymond et al., 1987) and rice (Falk et al., 1988). Other energy-providing foods however, like whole-grain bread (Mack el al., 1986, Olson et al., 1989) may protect against pancreatic cancer. Only one study was published on energy-providing nutrients, and suggested that fat increases and carbohydrates reduce the risk of pancreatic cancer (Durbec et al., 1983). Except for one study showing a negative association with energy intake (Durbec et al., 1983), no other studies on the effect of total energy
Study population The study area was situated in the central part of The Netherlands. In 1983 the population, living in 70 municipalities, numbered 1.13 million. A detailed description of subjects and methods has been published by Bueno de Mesquita et al. (1989). Cases were defined as all persons, alive or dead, aged 35-79, 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. Cases were identified as early as possible in the diagnostic period. The disease was defined as a clinical diagnosis of exocrine cancer of the pancreas. Microscopic verification of diagnosis was present in 68% of cases. Multiple sources, such as clinicians (physicians and surgeons), records of pathology laboratories, hospital diagnostic lists and the cancer registry of the beginning Comprehensive Cancer Centre “Midden Nederland” were used to trace eligible cases. From a comparison of observed with expected number of cases
MATERIAL AND METHODS
4T0 whom correspondence and reprint requests should be sent. Received: February 13, 1990 and in revised form June 22, 1990.
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BUENO DE MESQUITA ET AL.
based on incidence data from the neighbouring Dutch SOOZ Cancer Registry and of the histological verification rates in our study and the SOOZ registry (Bakker et al., 1987), we cannot exclude the possibility that up to 15% of eligible cases were not identified. General population controls, aged 35-79 and living in the study area at some point during 1984-1987, were sampled from the municipal population registries (C .B .S ., 1983, 1985 and 1986). The system of population registries has been in operation since the beginning of the last century. Submission of data on birth, death and change of residence is mandated by law. Consequently, the municipal population registries are considered almost 100% complete. Although in 1983 it was anticipated that a certain number of cases had to be interviewed indirectly, selecting deceased controls with causes of death which were entirely unrelated to any of the possible aetiologies under consideration was considered almost impossible. It was therefore decided that an acceptable control must have been alive at some point during the study period. Index controls, who were asked to respond directly, were a stratified random sample of the general population of the study area, frequency matched to the age- and sex-distribution of cases, using a control-case ratio of at least 2 to 1 for those under age 60 and 1 to 1 for ages 60 and above. After the first 2 years of the study, however, about 39% of eligible patients with pancreatic cancer could not be interviewed directly, mainly due to early death, and were replaced by suitable proxies. As this figure exceeded the proportion envisaged at the time the study was designed, during 1986 and 1987 an additional control group was asked to let suitable surrogates answer the questions on their behalf (proxy controls). Proxy controls, like index controls, were identified from population registers and frequency-matched to the age- and sex-distribution of indirectly responding patients, with a similar control-case ratio to that observed among index controls. During the study period 189 eligible patients with cancer of the pancreas were identified (100 males and 89 females) (Table I). 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 of living controls (103 males and 112 females). Among men, response rates for a dietary interview with complete information on dietary intake were 90.0% in cases and 72.7% in controls. Among women the corresponding response rates were 83.2% in cases and 64.8%in controls. A direct response was defined as an interview which was conducted in the presence of the index person, who was often assisted by one or more family members or other persons. An indirect response was defined as an interview in which the index person was absent and was replaced by one or more proxies, who were likely to be informative about the index person. Among male participants, 50.0% of the patients responded directly compared to 66.4% of the controls, while in females the corresponding percentages were 54.1% and 73.4%.Among indirectly responding subjects, for men the
proxy was a spouse in 76.1%of cases versus 84.6%in controls and for women in 45.9% of cases vs. 58.8% in controls. Twenty-five cases did not participate for the following reasons, incomplete data on food frequency (32%), identification more than 1 year after death (28%),refusal of case or proxy (20%), refusal by physician (16%), lack of suitable proxy (4%). The reasons for non-response among the 222 non-responding controls were as follows: refusal (88%), no suitable proxy (5%), no traceable proxies (5%) and incomplete food frequency data (2%).As a result 644 subjects, i.e. 164 cases and 480 controls, were available for analysis of the effect of usual dietary intake. Data collection The data were collected during 2 interviews. During the first an interviewer-administered questionnaire covered selected socio-economic topics, height, weight 2 years previously and maximum weight ever attained, lifetime consumption of tobacco and other factors including medical history. During the second interview a dietary questionnaire was administered by a dietitian. The time period of reference for living or deceased cases was approximately 1 year prior to diagnosis in order to discern typical pre-morbid dietary patterns and for living controls approximately 1 year prior to the date of interview. A large part of the dietary questionnaire consisted of a semiquantitative food frequency method and was developed in cooperation with the Department of Human Nutrition of the TNO-CIVO Toxicology and Nutrition Institute at Zeist. The semi-quantitative food frequency method was aimed at comprehensively assessing diet by estimating usual individual intake of 116 commonly used food items and food groups in order to rank subjects according to level of intake approximately 1 year earlier. After some introductory questions, first information was sought about meal patterns during a representative week about 1 year previously. Seasonal variation in consumption of certain products was taken into account. Standard portions in household measures were used to estimate usual amounts. Samples of crockery and table ware and colour photographs of about full-sized meals were used to clarify standard portions. At the end of the dietary interview, in order to gather information about long-term stability of food habits, questions were asked about the food pattern 10 years previously in comparison with the period about 1 year previously. Statistical methods Frequency and portion size of usual intake of food items were converted into average daily intake of foods and nutrients. Analyses of nutrients were based on the Dutch food table of 1985 (Bureau of Nutrition Education, 1985). In order to obtain odds ratios, related 95% confidence intervals and tests for trend for current degree of urbanity, educational level attained, personal income one year earlier and current marital status, adjusted for the possible confounding effect of 10-year age-groups, response status and total smoking, logistic regression analysis (Breslow and Day, 1980) was per-
TABLE I - PARTICIPATION AND MEAN AGE BY GENDER AND RESPONSE STATUS. THE SEARCH PANCREATIC CANCER STUDY, UTRECHT (1984-88)
Males
Total
Eligible Response Participants' Response status* Mean age
100 90.0% 90
89 1 72.3%
644
65.4
Females
cases
controls
cases
cnntrolr
319 72.7% 232
89 83.2% 74
383 64.8% 248
Direct
Indirect
Direct
Indirect
Direct
Indirect
Direct
Indirect
45 50.0% 66.0
45 50.0% 66.8
154 66.4% 65.0
78 33.6% 63.5
40 54.1% 67.2
34 45.9% 68.0
182 73.4% 66.1
66 26.6% 62.5
'Subjects with complete information on habitual dietary intake.-*lf the index person was willing to participate, a direct interview was conducted in the presence of the index person, who was often assisted by one or more family members and/or other persons. If the index person could not participate, an indirect interview was conducted in the presence of one or more family members and/or other persons.
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ENERGY-PROVIDING NUTRIENTS AND PANCREATIC CANCER
formed. The total smoking variable represented the cumulative (lifetime) consumption of plain, hand-rolled, low-tar and other filtered cigarettes. To permit testing for trend across the 4 levels of smoking, i.e. non-smokers and 3 categories of smokers with known lifetime consumption, smokers with one or more unknown frequencies of consumption were grouped in the 5th, highest level of smoking. Usual daily intake of energy and nutrients by cases and controls was summarized by means and related standard deviations. The continuous variables on energy and nutrient intake were categorized into quintiles according to the distribution of cases and controls. Logistic regression analysis using the GLIM statistical package (Baker and Nelder, 1985) provided point and interval estimates of relative risks (Breslow and Day, 1980) for the different nutrients adjusted for 10-year agegroups, response status and total smoking. Tests for trend were based on giving scores 1-5 to the 5 stratum-specific odds ratios. The response status variable indicated a direct response or an indirect response during the dietary interview. Thereafter, an analysis of the variables as continuous was performed. After adjustment for 10-year age-groups, response status and total smoking, the regression coefficient and the 95% confidence interval were multiplied by the difference in the medians of the extreme quintiles and converted to an odds ratio and the related 95% confidence interval. The odds ratios therefore represent estimates of relative risks for the median of the highest quintile of intake using the median of the lowest quintile as reference category. Intake of energy and energy-providing nutrients are often highly correlated. To examine associations with nutrients, which contribute to energy intake, we therefore followed the strategy advocated by Howe (1989). First, the association between risk of disease and total energy intake was evaluated, using total energy (including energy from ethanol) alone in a model. If there was an association with total energy alone, the difference between each energy-providing nutrient and energy from other sources was tested using the “Willett-Stampfer” approach (model a) (Willett and Stampfer, 1986). If there was a difference between the effect of the nutrient and that of energy from other sources, the separate effect of the nutrient independent of other energy was tested using the Howe’s approach (model b) (Howe et al., 1986). If there was an association between the nutrient and risk independent of other en-
ergy, but no association between other energy and risk, the risk estimate was expressed using a model containing only the nutrient (model c). The absence of 2-way interaction between response status and total energy intake was tested by adding an interaction term for response status and energy, which provides a direct estimate of bias due to misclassification in the proxy stratum, with confidence intervals obtained directly from the associated standard error (Walker et d . , 1988). For energy-providing nutrients which were significantly related to risk, the absence of 2-way interaction with response status was evaluated by adding 2 interaction terms, one for the interaction between response status and the nutrient of interest and another for the interaction between response status and other sources of energy. The difference in the deviance obtained for the models including or excluding the interaction terms provides an estimate of heterogeneity across response status. However, as both tests of interaction have relatively low power, if an interaction term was substantial in relation to the main effect, interpretation was based on separate analysis for direct and indirect interviews as well. Finally, a similar analysis was carried out excluding 29 cases and 64 controls who reported that their diet 1 year previously was very different from that of 10 years previously. RESULTS
Effect of selected characteristics Categorical analysis of educational level attained, personal income, marital status and degree of urbanity adjusted for age, gender, smoking and response status did not suggest significant differences between cases and controls. The effect of total cigarette consumption by gender is shown in Table 11. Although, in both sexes, after excluding smokers with unknown lifetime consumption the test for trend was not significant, compared to never-smokers, odds ratios for several levels of total cigarette consumption suggest a positive relationship in both men and women. After adjustment for gender, compared to non-smokers, odds ratios for those who reported a lifetime consumption of 300,000 cigarettes or more (OR 2.62; 95% CI 1.15-5.96) and for smokers with unknown lifetime consumption (OR 3.69; 95% CI 2.006.80) were signif-
TABLE n - ODDS RATIOS AND 95% CONFIDENCE LIMITS FOR PANCREATIC CANCER FOR SELECTED CHARACTERISTICS BY GENDER. THE SEARCH PANCREATIC CANCER STUDY, UTRECHT ( 1 9 8 G 8 8 ) Males CdCO
n
OR‘
Females (95%CI)
941235
Lifetime consumption of cigarettes2 (unit = lo00 cigarettes) 7/33 1 .oo None
0.50
371140 23/80 8/17 214 12/11
1.00 1.28 2.11 2.30 4.397 2.61
12/50 17/50 18/44 17/49 15/54 315
1.00
1.37 1.75 1.28 1.13 1.91 0.01
(0.70-2.35) (0.79-5.63) (0.37-14.16) (1.60-12.03) p > 0.10 (0.563.37) (0.714.29) (0.52-3.13) (0.46-2.80) (0.32-11.52) p > 0.90
‘Odds ratios are obtained by logistic regression.-*Adjusted for 10-year age-group and response status. Cut-off levels were based on the distribution of total cigarette consumption in cases and controls in the international study.-’Smokers with unknown lifetime number of cigarettes con~umed.-~Adjustedfor 10-year age-group, response status and total smoking. Quintile boundaries for Quetelet index were based on the distribution in cases and controls and amounted to 23.0, 24.3, 26.0 27.9 in men and 21.6, 24.2, 25.9, 28.7 in women.-’Excludes smokers with unknown lifetime consum tion of cigarettes.-’Excludes the unknown category, i.e. subjects with incomplete data for computing the Quetelet index.- Pp < 0.05.
438
BUENO DE MESQUITA ET AL.
icantly raised. Excluding smokers with unknown consumption, a monotonic increase in risk was observed (OR 1.00, 1.36, 1.86,2.62) with a significant dose-response effect (p < 0.05). After controlling for age, response status and total smoking, the data on Quetelet index (weight 2 years previously divided by height squared) by gender suggest non-significant, opposite effects for males and females (Table 11). In contrast “maximum” Quetelet index, with maximum weight ever attained instead of weight 2 years earlier, showed nonsignificant, reduced risks for males (OR 1.00, 0.53, 0.45, 0.53,0.72) and females (OR 1.OO, 0.80,1.30, 0.56,0.89) for most of the quintiles without a significant dose-response effect. After controlling for age, gender, response status and total smoking, Quetelet index did not appear to be related to risk (OR 1.OO, 1.17, 1.05, 0.92, 0.99), but maximum Quetelet index suggested non-significant, reduced risks for the upper 4 quintiles (OR 1.00, 0.59, 0.62, 0.68, 0.64). Effect of energy and energy-providing nutrients Table 111 shows the mean and standard deviation of past daily intake of total energy and energy-providing nutrients. Compared to controls, male cases reported a significantly higher mean intake of mono- and disaccharides. Female cases reported a significantly higher mean intake of total energy, total and saturated fats and total and complex carbohydrates. Taking the quintile of lowest intake as reference and after adjustment for age, total smoking and response status, findings of the categorical analysis for males and females diverged considerably and further analyses were done for both sexes as well (Table IV). In men, compared to the lowest quintile of energy intake, none of the odds ratios for the upper 4 quintiles of usual intake of energy was significantly different from unity and no significant trend was observed. In females, the upper 4 quintiles of usual intake of total energy showed elevated risks with a significant test for trend; however, the trend did not appear to be linear. After adjustment for gender the upper 4 levels of energy intake showed raised risks (OR 1.OO, 1.71, 1.54,1.65, 3.44) and the test for trend for energy intake became highly significant (p < 0.005). Subjects in the highest quintile of intake experienced a 3- to 4-fold, significantly elevated risk (OR 3.44; 95% CI 1.73-6.86). Among males the tests for trend for past habitual intake of total carbohydrates and mono- and disaccharides were significant, but not clearly linear, while none of the other energyproviding nutrients showed a relationship with risk (Table IV). In women, significantly raised odds ratios for higher levels of daily intake of several nutrients, i.e. animal protein, total fat,
saturated and mono-unsaturated fatty acids, total carbohydrates and polysaccharides, were observed. Significant, positive tests for trend were seen for animal protein, mono-unsaturated fatty acids and polysaccharides; however, none of the risks showed a linear trend. After adjustment for gender (data not shown) elevated risk estimates and significant tests for trend emerged for past habitual intake of total protein, animal protein, polyunsaturated fatty acids, total carbohydrates, mono- and disaccharides and polysaccharides. Linear analysis and the eflect of long-term stability of the dietary pattern Next, a linear analysis of usual intake of total energy and energy-providing nutrients was performed, taking into account the confounding effect of total energy intake (Tables V and VI). After adjustment for age, total smoking and response status, both males and females showed a positive relationship with total energy (Table V). After adjustment for gender, an increase in usual energy intake of 1,457 kcal/day (i.e. from the median of the lowest quintile of 1,506 kcaYday to the median of the highest quintile of 2,963 kcallday) was associated with a significant, approximately 2.5-fold increase in risk of pancreatic cancer (OR 2.69; 95% CI 1.50-4.75). The exclusion of those who reported long-term instability of dietary pattern yielded a similar risk estimate (OR 2.50; 95% CI 1.34-4.68). Total carbohydrates and mono- and di-saccharides in males were the only energy-providing nutrients, which showed differences with energy from other sources approaching significance (models A, Tables V and VI), as well as significant effects independent of other sources of energy (models B in Tables V and VI), without significant effects of other sources of energy (data not shown). Consequently, the best risk estimates were obtained by using model C with the nutrient alone. Compared to the median of the lowest quintile, i . e . 169 glday, an increase in daily intake of total carbohydrates up to the median of the highest quintile, i.e. 350 glday, was associated with a significant, more than 2-fold increase in risk of male pancreatic cancer (OR 2.22; 95% CI 1.09-4.53). An increase in past usual intake of mono- and disaccharides from 75 up to 176 g/day was associated with a significant increase in male risk of about equal strength (OR 2.15; 95% CI 1.18-3.93). A similar, though somewhat weaker, risk pattern was observed when excluding males who reported instability in long-term dietary intake (data not shown). After adjustment for gender, carbohydrates and mono- and disaccharides were the only energy-providing nutrients which showed elevated risks for the difference with energy from other
TABLE 111 - MEAN AND STAKDARI) DEVIATIOY OF PAXI’ DAILY INTAKE OF ENERGY-PROVIDING YUTRIEKIS FOR CASES ASD COS1‘ROI.S BY GENDER TIIII SEARCH PAKCRCATIC CANCER STUDY, CTRECIIT ~1983-88)
Males
Total energy, kcall Total protein, g Vegetable, g Animal, g Total fats, g Saturated, g Mono-unsatur., g Poly-unsatur., g Total carbohydr., g Mono- anddissach., g Polysacch., g
Females
cases
controls
cases
controls
n = 90
n = 232
n = 74
n = 248
Mean
SD
Mean
SD
Mean
SD
Mean
SD
2518 82 28 54 110 47 42 18 264
570 19 8 15 31 16
2430 79 28 52 110 47 42 19 252 120 131
504 17 7 14 28 12 12 8 64 40 36
19792 70 23 46 89’ 392 34 15 215‘ 106, 108
494 16 7 12 25 12 10 7 68 47 34
1827 66 22 44 82 36 32 13 197 98 98
435 14 6
131’
131
13
7 72 47 38
11
22 10 9 6 60
44 26
’Includes calories obtained from alcohol.-*Mean daily intake of cases is significantly different from that of controls (95% confidence limits of mean difference do not include zero).
439
ENERGY-PROVIDING NUTRIENTS A N D PANCREATIC CANCER TABLE IV - ODDS RATIOS’ FOR PANCREATIC CANCER FOR QUINTILES OF INTAKE OF ENERGY-PROVIDWG NUTRIENTS ADJUSTED FOR AGE, TOTAL SMOKING AND RESPONSE STATUS BY GENDER. THE SEARCH PANCREATIC CANCER STUDY, UTRECHT (1984-88)
Nutrients
1
2
1.00 1 .oo 1.00 1 .oo 1.00 1.00
1 .oo 1 .oo 1.00 1.00 1 .oo
0.87 1.25 0.99 1.30 0.97 0.56 1.15 1.54 0.69 1.04 1.06
1.00 1.00 1.00 1 .oo 1 .oo 1 .oo 1 .oo 1.00 1 .oo 1.00 1.00
2.72’ 0.84 0.55 1.15 2.00 1.99 1.73 0.45 1.72 0.98 0.69
Quintiles* 3
x2 for 4
5
trend3
0.54 0.88 0.89 1.60 0.43 0.47 0.38’ 1.06 1.93 2.13 0.82
1.59 1.49 1.76 1.42 0.94 0.75 0.72 1.42 1.11 1.84 1.18
1.37 1.67 0.92 2.00 1.10 0.86 1.41 1.13 2.02 2.28 1.01
1.66 1.61 0.25 2.34 0.04 0.01 0.16 0.04 4.0S 5.445 0.03
2.16 1.08 0.71 1.00 2.87’ 2.05 1.78 0.79 2.28 1.48 0.80
2.02 1.14 0.52 1.54 2.35 1.16 3.585 1.15 1.56 1.55 1.37
4.51’ 1.98 1.67 2.65’ 2.49 3.21’ 2.22 1.39 2.805 1.46 2.64’
5.95’ 2.83 1.17 5.035 2.84 2.95 4. 185 2.85 3.62 1.36 6.69’
Males
Total energy, kca14 Total protein, g Vegetable, g Animal, g
Total fat, g Saturated, g Mono-unsaturated, g Poly-unsaturated, g Total carbohydrates, g Mono- and disacch., g Polysaccharides, g Females
Total energy, kca14 Total protein, g Vegetable, g Animal, g
Total fat, g Saturated, g Mono-unsaturated, g Poly-unsaturated, g Total carbohydrates, g Mono- and disacch. Polysaccharides
’Odds ratios are obtained by logistic regression analysis.-’Quintile boundaries in men for energy 1987, 2288, 2517, 2918; total protein 66.5, 74.2, 82.7, 93.8; vegetable protein 21.1, 25.1, 29.0, 33.7; animal protein 42.6, 48.0, 54.0, 62.4; total fat 85.5,99.7, 113.7, 132.0; saturatedfat 35.7,42.0,48.1,56.3;mono-unsatur. fattyacids 33,38,44,52; ply-unsatur. fattyacids 12, 16, 19, 25; total carbohydrates 198.2, 231.2, 260.8, 315.9; mono- and disaccharides 85.5, 105.6, 128.0, 157.9; polysaccharides 98.5, 118.4, 135.5, 158.1; in women 1514, 1713, 1903, 2178; total protein 54.7, 61.6, 69.1, 77.2; vegetable protein 17.6, 20.3.22.7, 25.9; animal protein 35.1,40.7, 45.8.53.3; total fat 64.8.76.0.86.5, 100.5; saturated fat 27.4, 33.0, 36.8, 44.5; mono-unsatur. fatty acids 24,28,34, 39; ply-UnSaNI. fatty acids 8, 1 1 , 14, 18; total carbohydrates 155.4, 177.2,205.7. 240.9; mono- and disaccharides 66.0, 82.7, 105.2, 124.7; plysaccharides 77.6, 89.5, 103.8, 120.3.-3Test for trend excludes unknown c~nsumption.-~Includescalories obtained from al~ohol.-~p < 0.05.
sources (model A), as well as significant effects independent of other sources of energy without an effect of other sources of energy (model B) (Table VII). Best risk estimates were obtained by including variables for the nutrients alone (model C). An increase in daily intake of total carbohydrates of 173 glday, i.e. the difference in medians of the extreme quintiles, was associated with a significant, 2- to 3-fold increase in risk for pancreatic cancer (OR 2.40; 95% CI 1.44-3.99). An increase of 107 glday in mono- and disaccharides was associated with a 2-fold increase in risk (OR 1.95; 95% CI 1.24-3.07). After restricting the analysis to those who reported long-term stable dietary intake, and after adjustment for other sources of energy (model B), the effect estimates for carbohydrates and monoand disaccharides were reduced in strength and no sevarate effects, independent of other sources of energy, were observed (Table VII). Effect of response status A stratified categorical analysis of quintiles of Quetelet index and maximum Quetelet index by response status and gender did not indicate an association with risk in any of the strata examined (data not shown). Interaction between response status and total energy consumption among males was not significant but was substantial. In directly interviewed men, dietary intake of total energy was significantly associated with disease (OR 2.65; 95% CI 1.04-6.71), a finding which was not affected by excluding those who reported that their diet 1 year earlier was “very different” from 10 years previously (OR 2.63; 95%CI 0.93-7.46). Indirectly interviewed male subjects showed no relationship between disease and total energy (OR
1.18; 95% CI 0.41-3.41). The response status-exposure interaction term among females was neither significant nor substantial in relation to the main effect of energy intake. After adjustment for gender, a significant interaction with response status was observed. A stratified analysis by response status showed that an increase in reported intake of 1,389 kcallday in directly interviewed subjects was associated with a more than 3-fold increase in risk (OR 3.35; 95% CI 1.56-7.18). ‘This excess in risk was still present after excluding those who reported long-term instability of dietary intake (OR 2.96; 9 5 8 CI 1.23-7.11). Indirectly interviewed subjects did not show a relationship with energy intake. In both sexes and in the sex-adjusted analysis, none of the differences in deviance between models with and without interaction terms for response status and intake of total carbohydrates and other energy were significant. Results on mono- and disaccharides also did not show a significant effect of interaction with response status. DISCUSSION
The results of logistic regression analysis adjusted for age, gender and response status pointed to a dose-response effect for life-time consumption of cigarettes. After adjustment for age, gender, total cigarette consumption and response status, our findings suggested that, compared to population-based controls, past habitual intake of total energy was significantly higher in patients with exocrine pancreatic carcinoma. However, a statistically significant interaction with response status was present. The analysis stratified by response status showed
440
BUENO DE MESQUITA ET AL.
Males Odds
rati"2
Total energy, kcallday' Total protein, g/day A
B C
1.88
(95%
Females
a
Odds
rafio2
(95%CI)
(0.97-3.66)
2.473 (1.32-4.56)
1.43 (0.54-3.79) 1.47 (0.61-3.55) 1.71 (0.91-3.19)
0.88 (0.32-2.47) 1.01 (0.4G2.55) 1.943 (1.01-3.75)
Total fat, q Y
0.153 (0.03-0.75) 1.36 (0.31-6.02) B 0.46 (0.18-1.13) 1.90 (0.72-5.00) C 1 . 1 1 (0.58-2.12) 2.623 (1.26-5.45) Total carbohydrates,
Y:lg B C
4.21 (0.93-19.13) 0.80 (0.17-3.73) 2.923 (1.17-7.26) 1.50 (0.65-3.45) 2.223 (1.09-4.53) 2.213 (1.17-4.19)
'Including calories from alcoholic beverages.-'Odds ratios represent estimates of relative risks associated with an increase in the variable examined equal to the difference in the medians of the extreme quintiles, i.e. in men for total energy 1310 kcallday, total protein 43 @day, total fat 72 g/day, total carbohydrates 181 g/day; in women for total energy 961 kcaYday, total protein 33 g/day, total fat 56 g/day, total carbohydrates 142 g / d a ~ . - ~
