1 Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD.
2 Channing Laboratory, Department of Medicine, Brigham and Womens Hospital and Harvard Medical School, Boston, MA.
3 Department of Nutrition, Harvard School of Public Health, Boston, MA.
4 Department of Epidemiology, Harvard School of Public Health, Boston, MA.
5 Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, MA.
Received for publication August 1, 2002; accepted for publication January 8, 2003.
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
cholesterol; dairy products; fats; meat; pancreatic neoplasms
Abbreviations: Abbreviation: ATBC, Alpha-Tocopherol, Beta-Carotene.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Ecologic studies examining international variations in rates suggested that per capita intakes of egg, animal protein, and sugar were related to pancreatic cancer rates (4, 5). Many case-control studies have since examined how intakes of meat, egg, and dairy products and different types of fat are related to the risk of pancreatic cancer. At least six case-control studies have reported positive associations for meat intake and pancreatic cancer risk (6, 7). Consistent positive findings have also been observed for cholesterol intake (6, 7). However, case-control studies of pancreatic cancer are especially prone to biases due to the high and rapid fatality rates. As a result, these studies have frequently relied on next-of-kin interviews to determine exposures, and they tend to have poor response rates among cases. Dietary data from these types of studies should therefore be interpreted with caution (6).
Prospective studies offer unique advantages in the study of dietary factors and pancreatic cancer risk. In these studies, diet is measured prior to cancer and, consequently, they are not prone to recall bias and do not include any proxy interviews. To date, six cohort studies have reported associations between diet and pancreatic cancer risk (813); however, many of these studies included fewer than 100 cases (911), and only one examined total or different types of fat intakes (13). A significant, positive association between total meat intake and pancreatic cancer risk was reported in one prospective analysis (10), and saturated fat was associated with a significant increase in risk in another cohort (13).
Rodent models of pancreatic cancer indicate that dietary fat can enhance or promote tumor development (14). Certain compounds found in meats with known carcinogenic properties, such as N-nitroso compounds, may increase the risk of pancreatic cancer.
We examined consumption of meat, dairy products, types of fat, and cholesterol in relation to pancreatic cancer risk in a large cohort of women with detailed and updated dietary information with 18 years of follow-up.
![]() |
MATERIALS AND METHODS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
After exclusion of participants with 10 or more blank items on the dietary questionnaire, implausibly high or low caloric intake (<500 or >3,500 kcal per day) (6.1 percent), or a cancer diagnosis (other than nonmelanoma skin cancer) prior to baseline (3.7 percent), 88,802 women were eligible for analysis.
Dietary assessment
Dietary intake was assessed in 1980, 1984, 1986, and 1990 by using a standard semiquantitative food frequency questionnaire. A 61-item food frequency questionnaire was mailed to all participants of the study in 1980, whereas the food frequency questionnaire used in 1984, 1986, and 1990 was expanded to include 131 foods. About 80 percent of the women completed the food frequency questionnaires during follow-up. Participants were asked to report their average frequency of intake over the previous year for a specified serving size of each food. Individual nutrient intakes were calculated by multiplying the frequency of each food consumed by the nutrient content of the specified portion size (obtained from the US Department of Agriculture and supplemented by other publications) and then summing the contributions from all foods.
Intakes of red meat, total meat, and dairy products were calculated by multiplying the intake frequency of individual items in those food categories by their weights, estimated from the specified portion size, and summing over those items. Total meat consisted of the following items: chicken with skin; chicken without skin; processed meats; bacon; hot dogs; hamburger; beef, pork, or lamb as a sandwich or mixed dish; and beef, pork, or lamb as a main dish. Red meat consisted of the total meat items minus the chicken items. Dairy products consisted of skim or low fat milk, whole milk, ice cream, yogurt, cottage cheese, hard cheese, and butter. For dairy products, dry weights were used for the calculations instead of total weight.
We used the food intake information on the food frequency questionnaire to calculate each participants total fat intake as well as her intake of specific types of fat. These included animal, vegetable, saturated, monounsaturated, polyunsaturated, and trans-fatty acids and cholesterol. In addition, we measured intakes of stearic, oleic, linoleic, and -linolenic acids.
In a validity study of 173 women, the 61-item food frequency questionnaire was compared with four 1-week diet records. Correlation coefficients between the average intake assessed by two 1-week diet records completed 6 months apart and our food frequency questionnaire (corrected for within-person variation in the diet records) were as follows: 0.41 for processed meats, 0.43 for meat (from a main dish or mixed dish), 0.69 for skim milk, 0.56 for whole milk, 0.72 for butter, and 0.72 for eggs (16). Correlation coefficients for total fat, saturated fat, and cholesterol were 0.48, 0.49, and 0.61, respectively, comparing two 1-week diet records and one food frequency questionnaire in the same validation study of women (17). In addition, in a study of 185 women, the percentage of calories from fat as measured by the 1984 food frequency questionnaire predicted serum triglyceride levels (18).
Assessment of nondietary factors
Height, current weight, and smoking history (including time since quitting for past smokers) were initially reported at baseline. During follow-up, data on current weight and smoking status were obtained from the biennial mailed questionnaires. We estimated body mass index from weight and height (weight (kg)/height (m)2) as a measure of total adiposity. Participants were asked about history of diabetes at baseline and in all subsequent questionnaires. In 1982 and biennially thereafter, participants were asked about their history of cholecystectomy. For physical activity, we derived a score based on questions asked in the 1980 questionnaire ("At least once a week, do you engage in any regular activity similar to brisk walking, jogging, bicycling, etc., long enough to break a sweat?" "If yes, how many times per week?" "What activity is this?").
Identification of pancreatic cancer cases
Participants were asked to report specified medical conditions including cancers that were diagnosed in the 2-year period between each follow-up questionnaire. Whenever a participant (or next-of-kin for decedents) reported a diagnosis of pancreatic cancer, we asked for permission to obtain related medical records or pathology reports. If permission to obtain records was denied, we attempted to confirm the self-reported cancer with an additional letter or phone call to the participant. If the primary cause (or secondary cause) of death as reported by a death certificate was a previously unreported pancreatic cancer case, we contacted a family member to obtain permission to retrieve medical records or at least to confirm the diagnosis of pancreatic cancer. Less than 4 percent of the total cases of pancreatic cancer initially identified were subsequently rejected as not being pancreatic cancer. We confirmed 178 incident pancreatic cancer cases, diagnosed between 1980 and 1998. We had medical records for 161 (90 percent) of the cases and confirmed 12 cases using death certificates, and the remaining five cases were confirmed by telephone contact.
Statistical analysis
We computed person-time of follow-up for each participant from the return date of the baseline questionnaire to the date of pancreatic cancer diagnosis, death from any cause, or the end of follow-up (May 31, 1998), whichever came first. Incidence rates of pancreatic cancer were calculated by dividing the number of incident cases by the number of person-years in each category of dietary exposure. We computed the relative risk for each of the upper categories by dividing the rates in these categories by the rate in the lowest category.
We examined the relative risk of pancreatic cancer according to intake on the baseline 1980 food frequency questionnaire. In addition, we repeated our analyses using cumulative updating of the dietary exposures with follow-up data in 1984, 1986, and 1990 (19).
Relative risks adjusted for potential confounders were estimated using Cox proportional hazards models stratified on age in years. In these models, cigarette smoking was categorized as follows (based on a previous analysis of these cohorts (2)): never smoker, quit ≥15 years ago, quit <15 years ago and smoked ≤25 pack-years in the past 15 years, quit <15 years ago and smoked >25 pack-years in the past 15 years, current smoker with ≤25 pack-years in the past 15 years, and current smoker with >25 pack-years in the past 15 years. Women with missing smoking data were excluded (there were no cases with missing data on smoking). In addition, we controlled for body mass index (<23, 2324.9, 2526.9, 2729.9, ≥30, missing), height (≤62.0, 62.163.0, 63.164.5, 64.666.0, >66.0 inches; 1 inch = 2.54 cm) (20), total energy intake (quintiles: <1,139, 1,1391,392, 1,3931,634, 1,6351,954, >1,954 kcal), physical activity (hours of activity, continuous variable), menopausal status (pre-, post-, and dubious), and history of diabetes (21, 22) (less than 4 percent of the women in this cohort were type I diabetics). Women who did not indicate that they had diabetes were categorized as nondiabetics. History of diabetes was updated every other year with data from the follow-up questionnaires; for women who did not complete follow-up questionnaires, we used the data from the previous questionnaire. Body mass index was not updated in the main analyses because pancreatic cancer is frequently associated with profound weight loss, and our previous findings showed the strongest associations for body mass index in 1976 (Nurses Health Study cohort baseline) (20). In addition, we adjusted for glycemic load, shown in separate analyses, as we previously reported an association between this variable and pancreatic cancer risk in this population (23). All p values are based on two-sided tests. We performed tests for trend by assigning the median value to each category and modeling this variable as a continuous variable.
![]() |
RESULTS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
|
Individual dietary items contributing to meat intake were examined separately using the items and frequencies offered on the food frequency questionnaire (table 4). After controlling for potential confounders, we found that none of the meat items appeared to be related to the risk of pancreatic cancer (table 4). Similarly, individual items contributing to dairy product intake, as well as intakes of egg and fish (one item on the food frequency questionnaire), were not associated with the risk of pancreatic cancer (table 5).
|
|
![]() |
DISCUSSION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Rodents fed high-fat diets experienced a greater incidence of pancreatic tumors than did rodents fed low-fat diets with a similar caloric content (25, 26). In one study, rodents fed diets rich in saturated fat and also linoleic acid had the greatest increase in pancreatic tumorigenesis (26). Fats and fatty acids in the duodenum stimulate the release of cholecystokinin, and chronic cholecystokininemia in rodents stimulates pancreatic hyperplasia and increases susceptibility of the pancreas to carcinogens (27, 28). Among humans, a large, collaborative, population-based, case-control report on pancreatic cancer comprising five studies (SEARCH programme; International Agency for Research on Cancer, Lyon, France) observed elevated risks of pancreatic cancer for higher cholesterol intake but not for total or saturated fat (29). However, only two of the SEARCH studies had dose-dependent associations for cholesterol intake (30, 31), and two separate case-control studies reported no statistically significant associations (32, 33). In addition, four other case-control studies found no association with total or saturated fat intake (3235). Altogether, only two studies have reported elevated risks of pancreatic cancer with higher total fat intake (36, 37). In addition, the majority of case-control studies have reported no association with dairy products and pancreatic cancer risk (7, 33, 38)
Only one prospective cohort study has previously examined the relation between fat intake and pancreatic cancer (13). Analyzing a cohort of male smokers (the Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study cohort) in Finland, investigators reported elevated pancreatic cancer risks with higher intakes of butter and saturated fat. In contrast to the ATBC cohort, the current study consisted of women who were predominantly former or never smokers. Notably, levels of saturated fat and butter consumption were substantially higher in the ATBC cohort; for example, the median saturated fat intake in the ATBC cohort was 58.5 g/day compared with 28 g/day in our study.
Meat intake has been associated with elevated risk of pancreatic cancer in seven case-control studies (35, 3843). However, associations from these studies were rarely observed for total meat intake. Results were often based on specific food items, including the following: beef (39); beef and pork (42); pork products (41); fried, grilled, and smoked meats (40); and fat from meat (43). No positive associations for meat items were found in six other case-control studies (33, 34, 4447). To date, only four cohort studies have reported associations between meat intake and pancreatic cancer risk. For three of these studies, dietary information was based on 35 or fewer food items (8, 10, 12). In a fourth study (9), which included more detailed dietary data, associations with diet were based on 40 or fewer cases of pancreatic cancer deaths. Zheng et al. (10) did report a strong association between total meat intake and pancreatic cancer risk (relative risk = 3.0, 95 percent confidence interval: 1.2, 7.5; top to bottom quartile comparison); however, their study was based on only 60 cases and utilized a limited dietary assessment.
It has been suggested that the different practices of cooking or processing meat may be related to the risk of pancreatic cancer. Cooking meat at high temperatures can result in the formation of heterocyclic amines, and processing meats (e.g., curing or smoking) increases N-nitroso compounds. In a case-control study in China, intake of deep-fried foods was not associated with pancreatic cancer risk, but smoked and cured foods increased the risk of pancreatic cancer (34). Other findings on cooking and processing practices have been mixed (7). In our cohort, information on cooking practices was not collected until 1990, and thus, we had insufficient statistical power to examine cooking practices in the current study. Future studies with data on cooking methods will have to examine this issue in detail.
The strengths of our study include its large size, the prospective design with 18 years of follow-up, and multiple assessments of diet. This is the largest prospective study to examine diet and pancreatic cancer, and it thus provided greater power for the detection of differences in risk factors. It is also one of the few prospective studies of diet and pancreatic cancer to use a complete food frequency questionnaire to assess nutrient intake, allowing us to adjust for the effects of total energy intake. Control for calorie intake can limit misclassification in nutrient intake caused by differences in body size and physical activity level (48). In addition, repeated dietary assessment over the follow-up period minimized random within-person variation in the measurement of food and nutrient intake (49).
We cannot exclude measurement error as an explanation for the lack of any significant associations in the current study. Misclassification of dietary intake as measured by the food frequency questionnaire may have attenuated the results to some degree; however, this is an unlikely explanation for the lack of any association over extreme levels of intake, because it is improbable that many participants were misclassified from one extreme category to the other. Moreover, previous studies in this cohort have observed a significant positive association between red meat intake and the risk of colon cancer (50). In addition, utilizing the same food frequency questionnaire, we observed significant positive associations for dairy product and meat consumption and the risks of prostate and colon cancers in a large cohort of male health professionals (5153). Thus, the food frequency questionnaire does appear to capture etiologically relevant variation in these factors for a number of conditions.
In conclusion, we observed no association between meat, dairy product, cholesterol, or fat intakes and the risk of pancreatic cancer in this large prospective cohort of women. We cannot exclude the possibility that different methods of cooking or processing meats may be related to the risk of pancreatic cancer. Moreover, we cannot exclude the possibility that these dietary factors may influence risk among men. Future prospective studies should examine the influence of cooking practices as well as other potential dietary habits on the risk of pancreatic cancer.
![]() |
ACKNOWLEDGMENTS |
---|
![]() |
NOTES |
---|
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|