Epidemiology of pancreatic cancer in Japan: a nested case-control study from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC)

Manami Inoue1, Kazuo Tajima1, Toshiro Takezaki1, Nobuyuki Hamajima1, Kaoru Hirose1, Hidemi Ito1 and Suketami Tominaga2

1 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya 464-8681, Japan.
2 Aichi Cancer Center, Nagoya 464-8681, Japan.

Correspondence: Manami Inoue, Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1–1 Kanokoden Chikusa-ku Nagoya 464-8681, Japan. E-mail: minoue{at}aichi-cc.jp


    Abstract
 Top
 Abstract
 Subjects and Methods
 Results
 Discussion
 References
 
Background To clarify lifestyle factors that affect the risk of pancreatic cancer among the Japanese population, a nested case-control study was conducted using data from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan.

Methods The study subjects included 200 incident cases of pancreatic cancer and 2000 age-class frequency-matched cancer-free outpatients attending the baseline questionnaire of HERPACC in the period 1988–1999. Associations between lifestyles and the risk of pancreatic cancer were evaluated using odds ratios estimated by the unconditional logistic regression model, adjusting for potential confounding factors.

Results A positive family history of pancreatic cancer and a past or present history of diabetes significantly increased the risk of pancreatic cancer. In contrast, regular physical exercise, a regular bowel habit, and frequent consumption of raw vegetables appeared to be protective. Current alcohol drinkers showed decreased risk, but the opposite was the case for former drinkers. Current smoking did not affect the risk of pancreatic cancer, while former smokers showed a tendency for decreased risk. Compared with light smokers, heavy smokers showed a modest tendency for increase in risk, especially those who starting smoking at a younger age, but there were no clear tendencies for duration and pack-years of smoking.

Conclusions From these results it appears that smoking habit, which has long been considered a sole important determinant, has only a modest role, if any, in pancreatic cancer in Japanese.


Keywords Pancreatic cancer, risk factor, Japanese, nested case-control study

Accepted 14 November 2002

Pancreatic cancer is relatively uncommon in the world, accounting for only 2% of all incident cancer cases in 2000.1 In Japan, age-standardized incidence and mortality rates increased for a few decades before levelling-off after 1985, although the numbers of incident cases and deaths continue to show consistent absolute increase due to the ageing of the population.2 In the latest vital statistics, this cancer ranked as the fifth leading cause of cancer death.3

Previous studies have highlighted the difficulties in conducting case-control studies of pancreatic neoplasia because the cancers are generally rapidly fatal so that it is not easy to collect lifestyle information directly from cases when they are alive. Furthermore, evidence based on cohort studies has been limited due to relatively low incidence. Nevertheless, possible risk factors for pancreatic cancer have been identified, such as smoking, alcohol, coffee, and low vegetable and fruit intake.4–23 Host-related factors such as diabetes, familial pancreatic cancer, and hormonal aspects have also been suggested24–26 but only cigarette smoking was generally recognized as important, and other modifiable factors have yet to be unequivocally identified. The previous studies were mainly conducted in Western populations where the rates of this cancer are high compared with in Asians. In spite of male predominance, the male to female ratio, which is generally correlated with the relative risk (RR) of smoking habit, is less than 2, decreasing with age. This casts doubt on the smoking habit being a strong determinant. Epidemiological studies of pancreatic cancer targeted on the Japanese population27–30 and other Orientals20 have been relatively few. Because of the high fatality of this cancer and the rapid ageing of the Japanese population, in particular, there is an urgent need to clarify risk and protective factors.

The present study was therefore conducted to obtain further epidemiological evidence on the association between lifestyle factors and pancreatic cancer in a Japanese population by means of a nested case-control study with data from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center, Japan (HERPACC).31


    Subjects and Methods
 Top
 Abstract
 Subjects and Methods
 Results
 Discussion
 References
 
The HERPACC was started in Nagoya, Japan in 1988, with information on lifestyle factors routinely collected from all first-visit outpatients, using a self-administered questionnaire checked by a trained interviewer. Each patient is asked about his or her lifestyle when healthy or before the current symptoms developed. The questionnaire includes items on demographic characteristics, medical history, family history, smoking and drinking habits, regular physical exercise, dietary habits, and menstrual and reproductive history.

The Aichi Cancer Center Hospital (ACCH) is a typical domestic hospital, located in the central part of Japan, and over 95% of outpatients reside in the Tokai area, which has a population of 15 million. The ACCH accepts new outpatients who visit of their own volition with or without doctor’s referral, as with most general hospitals in Japan. Therefore, even though the ACCH is called a cancer hospital, only 19% of all new outpatients have cancer. Among these non-cancer outpatients, 45% present with no abnormal findings by clinical examination and 35% present with benign non-specific diseases.32 Our earlier evaluation of discrepancies in lifestyle between these outpatients and the general population selected by electoral roll suggested that some differences do generally exist between males and females, across age groups, and between seasons in specific food items where supply was seasonal. However, these were small between outpatients and the general population after adjustment for gender, age, and season.33 Thus, non-cancer outpatients at ACCH can be regarded as appropriate controls for epidemiological studies.

The data are loaded into an HERPACC database and routinely linked with the hospital cancer registry system for updating. This project has been approved by the ethical review board of the prefectural government. Details of the questionnaire and data collection procedures have been described elsewhere.31

The present study is based on data collected between January 1988 and December 1999. Among all first-visit outpatients during this period (n = 86 440), the questionnaire was given to 78 755 subjects (91.1%). The remaining 7685 (8.9%) were excluded as too young (<18 years), because an interviewer was absent, or because the consultation visit was by someone other than the patients themselves. Out of 78 755 outpatients, 77 803 (98.8%) provided adequate responses to the questionnaire. In the present study, 6% of the questionnaires were filled out by proxies although the study subjects were present in all these cases.

Among these subjects, 14 958 incident cases of cancer (19.2%) were identified as diagnosed by the end of the year 2000 by means of a hospital-based and population-based cancer registry system. In the present study, all cases of pancreatic cancer newly diagnosed from the commencement of the questionnaire study to the end of the year 2000 were deemed eligible as case subjects, a total of 200 (122 males and 78 females). Controls were selected by random sampling from all cancer-free individuals without a past history of cancer, with comparable gender and age strata (1 case versus 10 referents). Consequently, 200 cases and 2000 controls were selected and used as study subjects.

For the analysis of smoking habit, status was categorized as never, former, and current smoker, the last being further divided by the number of cigarettes per day (<=19 and >=20), age started (>=20, 18–19, <=17 years), duration (<=19, 20–39, >=40 years), and pack-years of smoking (<=19, 20–39, >=40). Former smokers were defined as people who had quit smoking for at least 1 year. These subjects were further divided by duration after quitting smoking (1–10, 11–20, >=21 years).

Plausible risk or protective factors for pancreatic cancer, other than the smoking habit, were selected from the questionnaire items based on the previous studies. According to the strength of the age-adjusted association with these selected items, variables on family history of pancreatic cancer, history of diabetes, regular physical exercise, bowel habit, raw vegetable intake, and alcohol drinking were further selected for the multivariate analysis.

Odds ratios (OR) were used to describe associations. Multivariate-adjusted OR with the corresponding 95% CI associated with selected lifestyles were estimated by unconditional logistic regression model. Accordingly, variables like age and year of interview (continuous), season of interview (spring, summer, autumn, winter), family history of pancreatic cancer (yes, no), history of diabetes (yes, no), regular physical exercise (>=2 times/week, less), bowel habit (every day, less), raw vegetable intake (every day, less), and alcohol drinking (current, former, never) were included in the model when the risk of each variable was estimated, together with variables for the smoking habit when the risk of the latter was estimated. Stata version 734 was used to perform the statistical analysis.


    Results
 Top
 Abstract
 Subjects and Methods
 Results
 Discussion
 References
 
The mean age of cases was 60.5 years (range 32–85 years). The males were a little younger than female cases (mean age: 60.2 and 61.1 years, respectively) (Table 1Go).


View this table:
[in this window]
[in a new window]
 
Table 1 Age and gender distribution of pancreatic cancer cases and referent subjects
 
Table 2Go shows adjusted OR and their 95% CI of pancreatic cancer according to selected lifestyle factors other than smoking habit. A positive family history of pancreatic cancer significantly elevated the risk (OR = 2.09, 95% CI: 1.01–4.33), along with a past or present history of diabetes (OR = 1.79, 95% CI: 1.08–2.97), especially in males (OR = 2.07, 95% CI: 1.14–3.74). Frequent regular physical exercise (>=2 times per week) decreased the pancreatic cancer risk (OR = 0.66, 95% CI: 0.43–1.01), as did a regular bowel habit (OR = 0.70, 95% CI: 0.49–0.99) and raw vegetable consumption (OR = 0.71, 95% CI: 0.51–0.99). Other vegetable and fruit variables also showed tendencies to reduce the risk, but without statistical significance. Current alcohol drinkers showed a significantly decreased risk of pancreatic cancer (OR = 0.50, 95% CI: 0.34–0.73), this being apparent in both males and in females. On the other hand, former drinkers showed a significantly increased risk of pancreatic cancer (OR = 3.70, 95% CI: 2.28–6.00). Together with potential confounding factors such as age, year, and season of interview, the variables in Table 2Go were included into the model for risk estimates on smoking habit.


View this table:
[in this window]
[in a new window]
 
Table 2 Adjusted odds ratios (OR) and their 95% CI of pancreatic cancer with reference to selected lifestyles factorsa
 
Table 3Go lists multivariate OR and 95% CI according to smoking habit. Current smoking did not affect the risk of pancreatic cancer, while former smokers showed a tendency for decreased risk (OR = 0.60, 95% CI: 0.35–1.00), especially those who had quit smoking after a short duration (1–10 years) (OR = 0.42, 95% CI: 0.20–0.91). However, the data indicated that heavy smokers who smoke >=20 cigarettes per day are at greater risk, compared with light smokers consuming less. It also appeared that a younger age at starting smoking might result in higher risk, but there were no clear tendencies for age started, duration, and pack-years of smoking. Additional analysis demonstrated no clear association for passive smoking.


View this table:
[in this window]
[in a new window]
 
Table 3 Adjusteda odds ratios (OR) and their 95% CI for pancreatic cancer with reference to tobacco smoking
 

    Discussion
 Top
 Abstract
 Subjects and Methods
 Results
 Discussion
 References
 
The main purpose of the present study was to determine lifestyle factors which affect the risk of pancreatic cancer, including a smoking habit, long considered as an important determinant, among a typical Japanese population. From our results, we conclude that a positive family history of pancreatic cancer and past or present history of diabetes significantly increased the risk of pancreatic cancer, whereas frequent regular physical exercise (>=2 times per week), a regular bowel habit, and raw vegetable consumption are associated with decreased risk.

Smoking has demonstrated only a modest impact on pancreatic cancer risk, and a number of previous epidemiological studies pointed to the same conclusion,4–8,10–16,20,27,28 despite the fact that tobacco smoking is regarded as the most important contributing risk factor for many cancers.

Regarding possible bias, because the method employed for data collection was prospective with data linkage to hospital- and population-based cancer registries, independent of our study base, the possibility that the overall null result for smoking may have resulted from selection of a subset of cases with a lower smoking prevalence than all pancreatic cancer patients is low, and if any, it would be non-differential. Likewise, another possible bias, a higher prevalence of smoking among controls than the general population, is unlikely according to our previous validity study.33 It is also the case that strength of effects of smoking on cancer may vary between populations, and even for lung cancer for instance, the smoking RR is low in Japanese as compared with Western populations. Thus, some ethnic difference may exist regarding susceptibility to effects of smoking.

In experimental studies, although available data are limited, evidence for possible pancreatic carcinogens in tobacco smoke has been provided by induction of tumours by NNK (4-(N-Nitrosomethylamino)-1-(3-pyridyl)-1-butanone) and its major metabolite35,36 through blood or reflux bile.37 One study on patients with hereditary pancreatitis, demonstrating a dramatically earlier age of diagnosis of pancreatic cancer with the smoking habit, suggests that smoking–genetic interactions may be important.38

Regarding alcohol drinking, the great majority of previous epidemiological studies with a focus on this parameter demonstrated no association with pancreatic cancer,7,8,13,16,18,20 and there is no clear biological mechanism, although alcohol drinking is an important determinant of chronic pancreatitis, a suspected risk factor for pancreatic cancer.21,22 If the reason for quitting were because of symptoms of chronic disease, this might explain our finding of increased risk in ex-drinkers.

Previous studies demonstrated decreased risks with high vegetable and fruit intake,17,20,23,29 consistent with our results, and vitamin C is considered to be a major contributor. Regular physical exercise also appears to decrease the risk of pancreatic cancer in our population. The previous reports revealed an inconsistent association,15,19 and it appears that the risk modification may vary with the type of physical activity, i.e. leisure time and occupational. The influence of physical activity should be considered in relation to obesity and insulin resistance, since it is known to reduce glucose intolerance and high body mass index (BMI) is associated with an increase in risk of hyperinsulinaemia and diabetes. Here we did not observe a significantly increased risk with BMI (data not shown), but in our Japanese population, BMI is distributed in a lower range than in Western countries and this may have been a confounding influence. Studies focusing on familial pancreatic cancer and a history of diabetes, report-ing a positive association with this tumour, have suggested an important role of abnormal glucose metabolism in the aetiology,24–26,39–41 although it is still under discussion whether diabetes is a determinant or a consequence of this cancer.42 Possible mechanisms are explained by obesity through diabetes17,43 and hyperinsulinaemia,39 but the studies also pointed to potential interactions between host-related and environmental factors such as smoking. Further investigations targeting this issue are needed to determine the preventable fraction of this cancer, but since the effects of smoking regarding pancreatic cancer appear to be moderate, the major focus should perhaps be on gene– environment interactions.

A number of methodological issues relevant to the present nested case-control study need consideration. The prospective design of the present study precludes the possibility of recall bias, since the information on lifestyle exposure was collected before the diagnosis. Potential for selection bias is also unlikely, and follow-up of the outcome status was conducted by data linkage, using population- and hospital-based cancer registries. We cannot preclude the possibility of loss to follow-up when the study subjects were diagnosed outside the defined area, but the misclassification, if any, is probably non-differential and underestimates the results. Since our study was based on an outpatient population, generalizability of the results is a concern. However, evaluation of discrepancies in lifestyle between these outpatients and the general population in the same geographical area selected by electoral roll confirmed that differences after adjustment for gender, age, and season were small.33 Lack of compliance with the questionnaire request was negligible, since the response rate was 98.8%. Because the study subjects were outpatients, it is nevertheless possible that information was dependent on some symptom or illness, as for example with ex-drinkers or ex-smokers, even though each outpatient was asked about lifestyle factors when healthy or before the current symptoms developed.

Allowing for these methodological issues, our study failed to detect any consistent association between the smoking habit and occurrence of pancreatic cancer, and other factors such as family history of pancreatic cancer, history of diabetes, and infrequent physical exercise appear to have more risk influence in Japan. Further studies are now needed to give clues to interactions between smoking and other environmental or host-related factors, including the genetic background.


KEY MESSAGES

  • Lifestyle factors that affect the risk of pancreatic cancer including a smoking habit, long considered as an important determinant, were investigated among a Japanese population by nested case-control study design.
  • A positive family history of pancreatic cancer and past or present history of diabetes significantly increased the risk of pancreatic cancer, and frequent physical exercise, a regular bowel habit, and raw vegetable consumption were associated with decreased risk.
  • Smoking has only a modest impact on pancreatic cancer risk in this population.

 


    Acknowledgments
 
Second Term Comprehensive 10-Year Strategy for Cancer Control, the Ministry of Health, Labor and Welfare, Japan.


    References
 Top
 Abstract
 Subjects and Methods
 Results
 Discussion
 References
 
1 Ferlay J, Bray F, Pisani P, Parkin DM. GLOBOCAN 2000: Cancer Incidence, Mortality and Prevalence Worldwide, Version 1.0. International Agency for Research on Cancer CancerBase No. 5. Lyon: IARC Press, 2001.

2 Lin Y, Tamakoshi A, Wakai K et al. Descriptive epidemiology of pancreatic cancer in Japan. J Epidemiol 1998;8:52–59.[Medline]

3 Foundation for Promotion of Cancer Research. Cancer Statistics in Japan 2001. Tokyo, 2001.

4 Heuch I, Kvåle G, Jacobsen BK, Bjelke E. Use of alcohol, tobacco and coffee, and risk of pancreatic cancer. Brit J Cancer 1983;48:637–43.[ISI][Medline]

5 Howe GR, Jain M, Burch JD, Miller AB. Cigarette smoking and cancer of the pancreas: evidence from a population-based case-control study in Toronto, Canada. Int J Cancer 1991;47:323–28.[ISI][Medline]

6 Bueno de Mesquita HB, Maisonneuve P, Moerman CJ, Runia S, Boyle P. Life-time history of smoking and exocrine carcinoma of the pancreas: a population-based case-control study in the Netherlands. Int J Cancer 1991;49:816–22.[ISI][Medline]

7 Zatonski WA, Boyle P, Przewzniak K, Maisonnueve P, Drosik K, Walker AM. Cigarette smoking, alcohol, tea and coffee consumption and pancreas cancer risk: a case-control study from Opole, Poland. Int J Cancer 1993;53:601–07.[ISI][Medline]

8 Kalapothaki V, Tzonou A, Hsieh C, Toupadaki N, Karakatsani A, Trichopoulos D. Tobacco, ethanol, coffee, pancreatitis, diabetes mellitus, and cholelithiasis as risk factors for pancreatic carcinoma. Cancer Causes Control 1993;4:375–82.[ISI][Medline]

9 Kalapothaki V, Tzonou A, Hsieh C et al. Nutrient intake and cancer of the pancreas: a case-control study in Athens, Greece. Cancer Causes Control 1993;4:383–89.[CrossRef][ISI][Medline]

10 Engeland A, Andersen A, Haldorsen T, Tretli S. Smoking habits and risk of cancers other than lung cancer: 28 years’ follow-up of 26,000 Norwegian men and women. Cancer Causes Control 1996;7:497–506.[ISI][Medline]

11 Boyle P, Maisonnueve P, Bueno de Mesquita B, Ghadirian P et al. Cigarette smoking and pancreatic cancer: a case-control study of the search programme of the IARC. Int J Cancer 1996;67:71.

12 Muscat JE, Stellman SD, Hoffmann D, Wynder EL. Smoking and pancreatic cancer in men and women. Cancer Epidemiol Biomarkers Prev 1997;6:15–19.[Abstract]

13 Harnack LJ, Anderson KE, Zheng W, Folsom RA, Sellers TA, Kushi LH. Smoking, alcohol, coffee, and tea intake and incidence of cancer of the exocrine pancreas: The Iowa Women’s Health Study. Cancer Epidemiol Biomarkers Prev 1997;6:1081–86.[Abstract]

14 Shapiro JA, Jacobs EJ, Thun MJ. Cigar smoking in men and risk of death from tobacco-related cancers. J Natl Cancer Inst 2000;92:333–37.[Abstract/Free Full Text]

15 Nilsen TI, Vatten LJ. A prospective study of lifestyle factors and the risk of pancreatic cancer in Nord-Trøndelag, Norway. Cancer Causes Control 2000;11:645–52.[CrossRef][ISI][Medline]

16 Coughlin SS, Calle EE, Patel AV, Thun MJ. Predictors of pancreatic cancer mortality among a large cohort of United States adults. Cancer Causes Control 2000;11:915–23.[CrossRef][ISI][Medline]

17 Silverman DT, Swanson CA, Gridley G et al. Dietary and nutritional factors and pancreatic cancer: a case-control study based on direct interviews. J Natl Cancer Inst 1998;90:1710–19.[Abstract/Free Full Text]

18 Michaud DS, Giovannucci E, Willett WC, Colditz GA, Fuchs CS. Coffee and alcohol consumption and the risk of pancreratic cancer in two prospective United States cohorts. Cancer Epidemiol Biomarkers Prev 2001;10:429–37.[Abstract/Free Full Text]

19 Michaud DS, Giovannucci E, Willett WC, Colditz GA, Stampfer MJ, Fuchs CS. Physical activity, obesity, height, and the risk of pancreatic cancer. J Am Med Assoc 2001;286:921–29.[Abstract/Free Full Text]

20 Ji B, Chow W, Dai Q et al. Cigarette smoking and alcohol consumption and the risk of pancreatic cancer: a case-control study in Shanghai, China. Cancer Causes Control 1995;6:369–76.[ISI][Medline]

21 Farrow D, Davis S. Risk of pancreatic cancer in relation to medical history and the use of tobacco, alcohol, and coffee. Int J Cancer 1990;45:816–20.[ISI][Medline]

22 Jain M, Howe G, St Luis P, Miller A. Coffee and alcohol as determinants of risk of pancreas cancer: a case-control study from Toronto. Int J Cancer 1991;47:384–89.[ISI][Medline]

23 Falk RT, Pickle LW, Fontham et al. Life-style risk factors for pancreatic cancer in Louisiana: a case-control study. Am J Epidemiol 1988; 128:324–36.[Abstract]

24 Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A. Abnormal glucose metabolism and pancreatic cancer mortality. J Am Med Assoc. 2000;283:2552–58.[Abstract/Free Full Text]

25 Silverman DT, Schiffman M, Everhart J et al. Diabetes mellitus, other medical conditions and familial history of cancer as risk factors for pancreatic cancer. Brit J Cancer 1999;80:1830–37.[CrossRef][ISI][Medline]

26 Schenk M, Schwartz AG, O’Neal E et al. Familial risk of pancreatic cancer. J Natl Cancer Inst 2001;93:640–44.[Abstract/Free Full Text]

27 Hirayama T. Life-style and Mortality: A Large-Scale Census-Cohort Study in Japan. New York: Karger, 1990.

28 Mizuno S, Watababe S, Nakamura K et al. A multi-institute case-control study on the risk factors of developing pancreatic cancer. Jpn J Clin Oncol 1992;22:286–91.[ISI][Medline]

29 Ohba S, Nishi M, Miyake H. Eating habits and pancreatic cancer. Int J Pancreatol 1996;20:37–42.[ISI][Medline]

30 Nishino Y, Tsubono Y, Tsuji I et al. Passive smoking at home and cancer risk: a population-based prospective study in Japanese nonsmoking women. Cancer Causes Control 2001;12:797–802.[ISI][Medline]

31 Tajima K, Hirose K, Inoue M, Takezaki T, Hamajima N, Kuroishi T. A model of practical cancer prevention for out-patients visiting a hospital: the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC). Asian Pacific J Cancer Prev 2000;1:35–47.

32 Inoue M, Tajima K, Hirose K et al. Subsite-specific risk factors for colorectal cancer: a hospital-based case-control study in Japan. Cancer Causes Control 1995;6:14–22.[ISI][Medline]

33 Inoue M, Tajima K, Hirose K et al. Epidemiological features of first-visit outpatients in Japan: comparison with general population and variation by sex, age, and season. J Clin Epidemiol 1997;50:69–77.[CrossRef][ISI][Medline]

34 Stata Corporation. Stata Statistical Software, 7.0. Texas: Stata Corporation, 2001.

35 Hecht SS, Hoffmann D. N-nitroso compounds and tobacco-induced cancers in man. IARC Scientific Publication 1991;105:54–61.

36 Revinson A, Hoffmann D, Prokopczyk B, Amin S, Hecht SS. Induction of lung and exocrine pancreas tumors in F344 rats by tobacco-specific and Areca-derived N-nitrosamines. Cancer Res 1988;48:6912–17.[Abstract]

37 Schulze J, Richter E, Binder U, Zwickenpflung W. Biliary excretion of 4-(methylnitrosoamino)-1-(3-pyridy)-1-butanone in the rat. Carcinogenesis 1992;13:1961–65.[Abstract]

38 Lowenfels AB, Maisonneuve P, Whitecomb DC, Lerch MM, DiMangno EP. Cigarette smoking as a risk factor for pancreatic cancer in patients with hereditary pancreatitis. J Am Med Assoc 2001; 286:169–70.[Free Full Text]

39 Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer. A meta-analysis. J Am Med Assoc 1995;273:1605–09.[Abstract]

40 Calle EE, Murphy TK, Rodriguez C, Thun MJ, Heath CW Jr. Diabetes mellitus and pancreatic cancer mortality in a prospective cohort of United States adults. Cancer Causes Control 1998;9:403–10.[CrossRef][ISI][Medline]

41 Wideroff L, Gridley G, Mellemkjaer L et al. Cancer incidence in a population-based cohort of patients hospitalized with diabetes mellitus in Denmark. J Natl Cancer Inst 1997;89:1360–65.[Abstract/Free Full Text]

42 Gullo L. Diabetes and the risk of pancreatic cancer. Ann Oncol 1999;10:S79–S81.

43 Colditz GA, Willett WC, Rotnitzky A, Manson JE. Weight gain as a risk factor for clinical diabetes mellitus in women. Ann Int Med 1995;122:481–86.[Abstract/Free Full Text]

44 World Cancer Research Fund/American Institute for Cancer Research. Food, Nutrition and the Prevention of Cancer: A Global Perspective. 4.7 Pancreas. Washington DC: American Institute for Cancer Research, 1997, pp. 176–97.