Abstract

Objective

To examine the association of smoking and lifestyle factors with pancreatic cancer death in the prospective design.

Methods

Mortality from pancreatic cancer in regard to smoking, body mass index, physical activity, and alcohol, coffee and green tea intake, was studied in a prospective cohort of 30 826 inhabitants in Takayama, Japan. In 1992, each subject completed a self-administered questionnaire on demographic information, smoking, drinking habits, diet, exercise and medical histories. The response rate was 85.3%.

Results

From 1992 to 1999, 33 men and 19 women died due to pancreatic cancer. Hazard ratios and 95% confidence intervals were determined using Cox proportional hazards models. Women who were defined as current smokers at baseline had significant and increased risk of pancreatic cancer death after adjustment for age, body mass index and history of diabetes mellitus (Hazard ratio:4.77, 95% confidence intervals:1.58–14.4). There were significant positive associations of pancreatic cancer death with the years of smoking and the number of cigarettes consumed daily in women in a dose-dependent manner. Current smokers indicated a non-significant risk increase in men (Hazard ratio: 3.81, 95% confidence intervals: 0.88–16.6). Body mass index, physical activity, and alcohol, coffee and green tea intake were not significantly associated with pancreatic cancer death.

Conclusions

These data suggested that smoking increases the risk of death from pancreatic cancer in Japanese women.

INTRODUCTION

Cigarette smoking has been well-known as a risk factor for pancreatic cancer, according to findings from the USA and European nations (1–3). Data from prospective studies in Japan are still insufficient. So far, four prospective cohort studies have addressed the association between smoking and pancreatic cancer in Japan (4–7). In these studies, there were somewhat increased risks of pancreatic cancer for smoking among men and women, indicating that relative risks (RRs) range from 1.1 to 3.3. An upward trend of the risk of pancreatic cancer in men was observed in proportion to the intensity of smoking increased. However, dose–response relationship between smoking and the risk of pancreatic cancer remains unclear among women.

Other than cigarette smoking, prospective studies have disclosed that some lifestyle-related factors, such as obesity, exercise or alcohol drinking, have contributed to the development of pancreatic cancer; however, most of these findings were the results of systematic reviews from western world (1,8–11). Evidence regarding the association of smoking and other factors with pancreatic cancer risk is scarce in Japan.

The aim of this present study was to assess the relationship of smoking and of other lifestyle-related factors with mortality from pancreatic cancer in a cohort of men and women in Japan.

PATIENTS AND METHODS

Study Population

Subjects were from a cohort of the Takayama Study, which was a population-based prospective study initiated in Takayama, Gifu Prefecture, Japan in September 1992. Detailed methods have been reported elsewhere (12). Every non-hospitalized inhabitant of Takayama aged 35 years and older was invited to participate in the study. At the baseline in July 1992, a self-administered questionnaire seeking information on demographic characteristics, smoking and drinking habits, diet, physical activity, and reproductive and medical histories including diabetes mellitus and gallbladder disease, was distributed to 36 990 residents. A total of 14 427 men and 17 125 women, 85.3% of the target population, responded to the questionnaire.

Data Collection

Participants who had reported smoking a total of 20 or more packs of cigarettes in their lifetime were defined as smokers. Those who had never smoked were categorized as never smokers; those who still smoked at the baseline, as current smokers; and those who stopped smoking before the baseline, as former smokers. Information on the number of years of smoking and the number of cigarettes smoked daily was obtained from current and former smokers. Values of individual height and body weight at the baseline and recalled weight at 20 years old were self-reported through the questionnaire. Body mass index (BMI), as a measure of adiposity, at the baseline and at age 20 years were calculated as weight at baseline and at age 20 years divided by height squared and presented as kg/m2. The validity and reproducibility of the self-administered individual height and weight have been reported elsewhere (13). The intra-class correlation coefficients between the self-reported and the measured data were 0.93 for height and 0.97 for weight in both sexes. Physical activity was assessed by asking subjects to state the average number of hours a week that they had spent performing various kinds of physical activities during the past year. The time per week spent at each activity was multiplied by its correspondent energy expenditure requirements, which was expressed as a metabolic equivalent (MET) and summed up to yield a MET score (h/week). The details are described elsewhere (14).

Diet and alcohol, coffee and tea use were evaluated using a semi-quantitative food frequency questionnaire that consisted of 169 food items, seeking to report average intake frequency and usual serving sizes for each food in the last year. Individual intake of food and nutrients was estimated from the frequency of intake and portion size using the Standard Tables of Food Composition in Japan (15). Details of the food frequency questionnaire, including validity, were demonstrated in a previous article (16). Questions about alcohol included six types of beverage, sake, beer, light beer, shochu (distilled from sweet potatoes, rice or buckwheat), wine and hard liquor. Each item had nine frequency categories (never/less than once a month; once a month; twice or three times a month; once a week; twice or three times a week; four to six times a week; once a day; twice or three times a day; more than three times a day) and included the number of cups, glasses or bottles consumed. Using the Standard Tables of Food Composition in Japan, the amount of ethanol consumed daily was calculated in grams. Concerning coffee and green tea, the frequency of consumption was asked: 1 cup and more/day, 1–24 cups/month and never, which were defined as high frequency, low and never consume.

Outcome Measurement

The Statistics and Information Department of the Japanese Ministry of Health and Welfare has nationwide mortality information and lists all causes of death, which are coded according to the International Classification of Diseases, Tenth Revision (ICD10). The primary endpoint was death from pancreatic cancer, which was classified as code C25. Deaths and their causes in the cohort between 1992 and 1999 were confirmed with the data from the Office of the National Vital Statistics after obtaining permission from the Ministry of Internal Affairs and Communications to inspect the data regarding death. Relocation from Takayama during the study period was informed from the residential registers of the city. During the follow-up, 640 men and 506 women moved out of Takayama. Detailed information of tumors from pathologic examination and autopsy was not available. This study was approved by the ethics board of the Gifu University Graduate School of Medicine.

Data Analysis

To assess the associations of smoking and other lifestyle factors with deaths from pancreatic cancer, a Cox proportional hazards model was applied to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs). We excluded the subjects who reported at the baseline that they had any past history of cancer (186 men and 540 women). Thus, the final analytic population was 30 826 (14 241 men and 16 585 women). Person-years of follow-up for each subject were accumulated from the beginning of the study (1 September 1992) to the date of death from pancreatic cancer or any other cause, the date of moving out of Takayama or the final date of the study (31 December 1999), whichever occurred first.

Years of smoking were categorized into ≤30 and ≥31 years in men and ≤20 and ≥21 in women. The number of cigarettes smoked daily was categorized into ≤20 and ≥21 cigarettes per day in men and ≤10 and ≥11 in women. BMI at the baseline, that at age 20 years, and MET score were divided into tertiles according to the distribution of the values. The lowest tertile was defined as a reference when calculating HRs. MET score and intake of alcohol were logarithmically transformed for a normal distribution. As the number of male participants who had never drunk was small, we categorized all male participants into tertiles based on the distribution of ethanol intake and adopted the lowest tertile as a reference. Among women, the category of never drinking was used as a reference. Women who consumed any alcohol were categorized into two groups by the median of distribution of ethanol intake. Testing for linear trend was conducted using continuous variables in MET score and alcohol intake. Age was used in the model for adjustment because of a potent risk factor for pancreatic cancer. The multivariate model was adopted with adjustment for age, BMI and history of diabetes, which were thought to be associated with pancreatic cancer (8,17). All statistical analyses were performed using SAS programs (version 9.1.3.; SAS Institute).

RESULTS

During the follow-up of 212 247 person-years, a total of 52 (33 men and 19 women) died due to pancreatic cancer. The baseline characteristics of participants in the Takayama Study are shown in Table 1. Table 2 is a presentation of the HRs of death from pancreatic cancer according to individual smoking status at the baseline. Current smokers had 3.8 times increased HR of pancreatic cancer death after adjustment for age, BMI and history of diabetes mellitus in men, although this association did not obtain a statistical significance. The increase in HR of death from pancreatic cancer was observed among current male smokers who consumed 1–20 cigarettes daily after adjustment for covariates (HR: 5.25 and 95% CI: 1.06–26.1). In women, when compared with never smokers, HR of pancreatic cancer death for current smokers significantly increased in the multivariate model. Women who had smoked for 21 or more years had around 9-fold increased HR of death from pancreatic cancer compared with never smoking women in the multivariate model, and the linear trend also indicated statistical significance (P for trend was <0.001). Women who reported to have smoked 11 or more cigarettes per day at baseline were at increased risk of pancreatic cancer (HR: 5.91) with a significant trend on daily cigarette consumption (P = 0.005).

Table 1.

Baseline characteristics of participants in Takayama cohort in 1992

Characteristics Men (n = 14 241) Women (n = 16 585) 
Age (years) 54.7 ± 12.4 55.8 ± 13.2 
Smoking status (%) 
 Never 16.6 82.4 
 Former 29.7 4.6 
 Current 53.7 13.0 
BMI (kg/m222.5 ± 2.8 22.0 ± 2.9 
BMI (%) 
 <25.0 83.9 87.2 
 25.0–30.0 15.2 11.9 
 ≥30.0 0.8 0.9 
History of diabetes mellitus (%) 6.3 2.9 
History of gallbladder disease (%) 3.3 3.4 
Never drinkers (%) 8.9 34.8 
Characteristics Men (n = 14 241) Women (n = 16 585) 
Age (years) 54.7 ± 12.4 55.8 ± 13.2 
Smoking status (%) 
 Never 16.6 82.4 
 Former 29.7 4.6 
 Current 53.7 13.0 
BMI (kg/m222.5 ± 2.8 22.0 ± 2.9 
BMI (%) 
 <25.0 83.9 87.2 
 25.0–30.0 15.2 11.9 
 ≥30.0 0.8 0.9 
History of diabetes mellitus (%) 6.3 2.9 
History of gallbladder disease (%) 3.3 3.4 
Never drinkers (%) 8.9 34.8 

Values are means or percent.

Table 2.

Hazard ratios and 95% confidence intervals of death from pancreatic cancer according to smoking status at baseline

 Person-years No. of death Age-adjusted HR 95% CI Multivariate-adjusted HRa 95% CI 
Men 
 Smoking status at baseline 
  Never 15 550 1.00  1.00  
  Former 27 576 0.83 0.24–2.83 1.43 0.29–7.07 
  Current 50 749 19 2.04 0.69–6.07 3.81 0.88–16.6 
 Years of smoking 
  ≤30 29 469 0.73 0.16–3.21 1.03 0.20–5.38 
  ≥31 20 719 16 1.68 0.69–4.09 2.61 0.87–7.84 
  P for trend   0.16  0.18  
 No. of cigarettes per day 
  ≤20 7702 2.64 0.74–9.35 5.25 1.06–26.1 
  ≥21 42 759 13 1.86 0.59–5.88 3.53 0.78–16.1 
  P for trend   0.42  0.40  
Women 
 Smoking status at baseline 
  Never 85 623 1.00  1.00  
  Former 4576 3.37 0.72–15.7 1.70 0.21–13.5 
  Current 13 335 4.55 1.51–13.7 4.77 1.58–14.4 
 Years of smoking 
  ≤20 11 300 2.38 0.50–11.3 2.47 0.52–11.7 
  ≥21 1865 9.77 2.65–36.0 9.49 2.56–35.2 
  P for trend   0.001  0.001  
 No. of cigarettes per day 
  ≤10 6298 3.46 0.75–16.1 3.78 0.81–17.7 
  ≥11 6887 5.82 1.54–22.1 5.91 1.56–22.4 
  P for trend   0.006  0.005  
 Person-years No. of death Age-adjusted HR 95% CI Multivariate-adjusted HRa 95% CI 
Men 
 Smoking status at baseline 
  Never 15 550 1.00  1.00  
  Former 27 576 0.83 0.24–2.83 1.43 0.29–7.07 
  Current 50 749 19 2.04 0.69–6.07 3.81 0.88–16.6 
 Years of smoking 
  ≤30 29 469 0.73 0.16–3.21 1.03 0.20–5.38 
  ≥31 20 719 16 1.68 0.69–4.09 2.61 0.87–7.84 
  P for trend   0.16  0.18  
 No. of cigarettes per day 
  ≤20 7702 2.64 0.74–9.35 5.25 1.06–26.1 
  ≥21 42 759 13 1.86 0.59–5.88 3.53 0.78–16.1 
  P for trend   0.42  0.40  
Women 
 Smoking status at baseline 
  Never 85 623 1.00  1.00  
  Former 4576 3.37 0.72–15.7 1.70 0.21–13.5 
  Current 13 335 4.55 1.51–13.7 4.77 1.58–14.4 
 Years of smoking 
  ≤20 11 300 2.38 0.50–11.3 2.47 0.52–11.7 
  ≥21 1865 9.77 2.65–36.0 9.49 2.56–35.2 
  P for trend   0.001  0.001  
 No. of cigarettes per day 
  ≤10 6298 3.46 0.75–16.1 3.78 0.81–17.7 
  ≥11 6887 5.82 1.54–22.1 5.91 1.56–22.4 
  P for trend   0.006  0.005  

aAdjusted by age, body mass index, history of diabetes mellitus.

Table 3 presents HRs for pancreatic cancer death with regard to BMI at the baseline, BMI at age 20 years and physical activity. There was no significant association between BMI at the baseline as well as at age 20 and the risk of death from pancreatic cancer among men. Men in the second or highest tertile of BMI at the baseline and at age 20 were somewhat at decreased HRs of pancreatic cancer. The trend for decreasing HR of pancreatic cancer death with increasing BMI at the baseline was of borderline significance (P for trend: 0.05 in the multivariate model). Women in the second tertile of BMI at the baseline and at age 20 had also reduced HRs of pancreatic cancer. However, these associations were not statistically significant. No association was found between physical activity and the risk of death from pancreatic cancer in men. High intensity of physical activity was positively associated with pancreatic cancer death (HR: 3.29) with borderline significance (P = 0.06) in women. There were no significant associations between intakes of alcohol, coffee and green tea and the risk of pancreatic cancer death (Table 4). Additional adjustments for history of gallbladder disease and reproductive factors including parity, age at menarche and age at menopause did not alter the results.

Table 3.

Hazard ratios and 95% confidence intervals of death from pancreatic cancer according to BMI, weight change and physical activity in Takayama study

 Person-years No. of death Age-adjusted HR 95% CI Multivariate-adjusted HR 95% CI 
Men 
 BMI at baselinea 
  ≤21.3 29 923 16 1.00  1.00  
  <21.3 to ≤23.6 30 764 0.51 0.22–1.22 0.55 0.23–1.32 
  >23.6 30 670 0.51 0.20–1.28 0.59 0.23–1.50 
  P for trend   0.02  0.05  
 BMI at 20 years olda 
  ≤20.3 30 297 11 1.00  1.00  
  <20.3 to ≤22.2 30 141 0.41 0.14–1.19 0.41 0.14–1.18 
  >22.2 29 528 13 0.76 0.33–1.72 0.71 0.31–1.62 
  P for trend   0.56  0.49  
 Physical activity, MET scoreb 
  Low (1.44c32 198 13 1.00  1.00  
  Middle (12.5c31 855 11 1.05 0.47–2.37 1.13 0.48–2.67 
  High (67.2c32 493 1.01 0.43–2.42 1.03 0.41–2.60 
  P for trend   0.36  0.40  
Women 
 BMI at baselinea 
  ≤20.7 35 713 1.00  1.00  
  <20.7 to ≤23.0 36 628 0.35 0.07–1.67 0.37 0.08–1.77 
  >23.0 36 824 1.35 0.50–3.64 1.42 0.52–3.85 
  P for trend   0.92  0.82  
 BMI at 20 years olda 
  ≤20.0 36 046 1.00  1.00  
  <20.0 to ≤22.0 35 840 0.71 0.19–2.65 0.70 0.19–2.64 
  >22.0 34 697 1.06 0.33–3.38 1.05 0.33–3.36 
  P for trend   0.20  0.20  
 Physical activity, MET scoreb 
  Low (0.88c40 934 1.00  1.00  
  Middle (9.34c40 741 1.30 0.39–4.41 1.56 0.44–5.56 
  High (51.6c34 027 2.64 0.83 8.39 3.29 0.96–11.2 
  P for trend   0.18  0.12  
 Person-years No. of death Age-adjusted HR 95% CI Multivariate-adjusted HR 95% CI 
Men 
 BMI at baselinea 
  ≤21.3 29 923 16 1.00  1.00  
  <21.3 to ≤23.6 30 764 0.51 0.22–1.22 0.55 0.23–1.32 
  >23.6 30 670 0.51 0.20–1.28 0.59 0.23–1.50 
  P for trend   0.02  0.05  
 BMI at 20 years olda 
  ≤20.3 30 297 11 1.00  1.00  
  <20.3 to ≤22.2 30 141 0.41 0.14–1.19 0.41 0.14–1.18 
  >22.2 29 528 13 0.76 0.33–1.72 0.71 0.31–1.62 
  P for trend   0.56  0.49  
 Physical activity, MET scoreb 
  Low (1.44c32 198 13 1.00  1.00  
  Middle (12.5c31 855 11 1.05 0.47–2.37 1.13 0.48–2.67 
  High (67.2c32 493 1.01 0.43–2.42 1.03 0.41–2.60 
  P for trend   0.36  0.40  
Women 
 BMI at baselinea 
  ≤20.7 35 713 1.00  1.00  
  <20.7 to ≤23.0 36 628 0.35 0.07–1.67 0.37 0.08–1.77 
  >23.0 36 824 1.35 0.50–3.64 1.42 0.52–3.85 
  P for trend   0.92  0.82  
 BMI at 20 years olda 
  ≤20.0 36 046 1.00  1.00  
  <20.0 to ≤22.0 35 840 0.71 0.19–2.65 0.70 0.19–2.64 
  >22.0 34 697 1.06 0.33–3.38 1.05 0.33–3.36 
  P for trend   0.20  0.20  
 Physical activity, MET scoreb 
  Low (0.88c40 934 1.00  1.00  
  Middle (9.34c40 741 1.30 0.39–4.41 1.56 0.44–5.56 
  High (51.6c34 027 2.64 0.83 8.39 3.29 0.96–11.2 
  P for trend   0.18  0.12  

BMI, Body mass index.

aAdjusted by age, smoking and history of diabetes mellitus.

bAdjusted by age, smoking status, BMI, history of diabetes mellitus.

cMeans of Metabolic equivalent (MET) score.

Table 4.

Hazard ratios and 95% confidence intervals of death from pancreatic cancer according to alcohol, coffee and green tea intake in Takayama study

 Person-years No. of death Age-adjusted HR 95% CI Multivariate-adjusted HRa 95% CI 
Men 
 Amount of alcohol intake 
  Low (<15.6b31 395 16 1.00  1.00  
  Middle (≤15.6 to <53.5b32 461 0.52 0.21–1.27 0.63 0.25–1.59 
  High (≥53.5b32 689 10 0.93 0.41–2.11 0.89 0.37–2.15 
  P for trend   0.09  0.17  
 Frequency of coffee intake 
  Never 19 257 14 1.00  1.00  
  Low (≤1/month to ≤4–6/week) 37 689 11 0.61 0.27–1.36 0.67 0.29–1.55 
  High (≥1/day) 39 600 0.70 0.27–1.79 0.44 0.15–1.29 
  P for trend   0.40  0.08  
 Frequency of green tea intake 
  Never 37 618 11 1.00  1.00  
  Low (≤1/month to ≤4–6/week) 13 280 1.94 0.67–5.63 2.02 0.61–6.63 
  High (≥1/day) 46 097 17 1.48 0.69–3.15 1.77 0.78–4.04 
  P for trend   0.25  0.09  
Women 
 Amount of alcohol intake 
  Never(0b39 249 1.00  1.00  
  Low (<3.8b38 357 1.05 0.36–3.11 0.87 0.28–2.70 
  High (≥3.8b38 097 0.80 0.23–2.76 0.68 0.19–2.40 
  P for trend   0.69  0.48  
 Frequency of coffee intake 
  Never 30 641 1.00  1.00  
  Low (≤1/month to ≤4–6/week) 45 625 0.59 0.19–1.84 0.62 0.20–2.00 
  High (≥1/day) 39 436 0.80 0.21–3.13 0.68 0.17–2.78 
  P for trend   0.97  0.71  
 Frequency of green tea intake 
  Never 25 359 1.00  1.00  
  Low (≤1/month to ≤4–6/week) 16 174 0.33 0.04–2.77 0.31 0.04–2.59 
  High (≥1/day) 74 169 11 0.66 0.25–1.79 0.59 0.21–1.61 
  P for trend   0.41  0.31  
 Person-years No. of death Age-adjusted HR 95% CI Multivariate-adjusted HRa 95% CI 
Men 
 Amount of alcohol intake 
  Low (<15.6b31 395 16 1.00  1.00  
  Middle (≤15.6 to <53.5b32 461 0.52 0.21–1.27 0.63 0.25–1.59 
  High (≥53.5b32 689 10 0.93 0.41–2.11 0.89 0.37–2.15 
  P for trend   0.09  0.17  
 Frequency of coffee intake 
  Never 19 257 14 1.00  1.00  
  Low (≤1/month to ≤4–6/week) 37 689 11 0.61 0.27–1.36 0.67 0.29–1.55 
  High (≥1/day) 39 600 0.70 0.27–1.79 0.44 0.15–1.29 
  P for trend   0.40  0.08  
 Frequency of green tea intake 
  Never 37 618 11 1.00  1.00  
  Low (≤1/month to ≤4–6/week) 13 280 1.94 0.67–5.63 2.02 0.61–6.63 
  High (≥1/day) 46 097 17 1.48 0.69–3.15 1.77 0.78–4.04 
  P for trend   0.25  0.09  
Women 
 Amount of alcohol intake 
  Never(0b39 249 1.00  1.00  
  Low (<3.8b38 357 1.05 0.36–3.11 0.87 0.28–2.70 
  High (≥3.8b38 097 0.80 0.23–2.76 0.68 0.19–2.40 
  P for trend   0.69  0.48  
 Frequency of coffee intake 
  Never 30 641 1.00  1.00  
  Low (≤1/month to ≤4–6/week) 45 625 0.59 0.19–1.84 0.62 0.20–2.00 
  High (≥1/day) 39 436 0.80 0.21–3.13 0.68 0.17–2.78 
  P for trend   0.97  0.71  
 Frequency of green tea intake 
  Never 25 359 1.00  1.00  
  Low (≤1/month to ≤4–6/week) 16 174 0.33 0.04–2.77 0.31 0.04–2.59 
  High (≥1/day) 74 169 11 0.66 0.25–1.79 0.59 0.21–1.61 
  P for trend   0.41  0.31  

aAdjusted by age, smoking, body mass index, history of diabetes mellitus.

bRange of the category for alcohol intake (g/day).

DISCUSSION

We observed a significantly increased risk of pancreatic cancer mortality among smoking women in the present prospective population-based study. The intensity of smoking was also significantly associated with the elevated risk of pancreatic cancer death in women in a dose–response manner. An increased risk of death from pancreatic cancer for current smokers was also observed among men, although this association was not significant. The upward trend in the risk of pancreatic cancer death was observed among current male smokers, as the duration of smoking increased but not the daily cigarette consumption.

A recent review using a meta-analysis based on 35 prospective studies indicated a relationship between smoking and the risk of pancreatic cancer (3). Compared with never smokers, the RRs (95% CIs) were 1.74 (1.61–1.87) and 1.2 (1.11–1.29) for current and former smokers, respectively. Three studies from Japan were included in this meta-analysis. The strength of association from these studies in Japan was relatively weak (HRs ranging from 1.1 to 3.0) in men and women. Our results showed a stronger association between smoking and pancreatic cancer in women. The studies in the aforementioned meta-analysis reported similar increases of HR among smokers between men and women; the summarized RRs were 1.69 in men and 1.72 women. A synergistic effect of gene polymorphism in X-ray repair cross-complementing group 1 (XRCC1) and smoking on the risk of pancreatic cancer in women was observed to be stronger; the odds ratios of pancreatic cancer for the combination of XRCC1 399Gln allele (Arg/Gln or Gln/Gln) and pack-years of over 41 were 2.4 (1.1–5.0) among men and 7.0 (2.4–20.7) among women (18). Dependent on the distributions of this genotype in men and women, the observed increased HR among women may be explained by the interaction between this genotype and smoking. However, we obtained no genetic information in the present study. We cannot deny the possibility that female smokers who had underlying illness due to pancreatic cancer were willing to report their smoking status correctly and that other female smokers falsely reported that they were never smokers. Although additional adjustment for reproductive factors did not alter the results, there may be unmeasured confounders specific to women. It is also possible that this significant result in women may be just an alpha error.

Excess body weight has been expected to be associated with risk of pancreatic cancer through the effects of abnormal glucose metabolism, hyperinsulinemia and insulin-like growth factor 1 on the pancreas (1). Renehan et al. (8) conducted a systematic review of 16 prospective studies of BMI and risk of pancreatic cancer. They observed a moderate positive association between BMI and pancreatic cancer, indicating that the estimated RR per 5 kg/m2 increase in BMI was 1.07 (95% CI: 0.93–1.23) in men and 1.12 (95% CI: 1.02–1.22) in women. Our result of somewhat decreasing risk associated with BMI may reflect the effect of the prognosis of pancreatic cancer. Two previous cohort studies in Japan on BMI and pancreatic cancer (5,19) failed to observe a significant positive association. The lack of an association between BMI and pancreatic cancer might be partially explained by the lower prevalence of obesity among Japanese than Western populations (20).

Some studies observed that increased physical activity was associated with a reduced risk of pancreatic cancer, explained by an improvement of insulin resistance, but others did not (9,10). Previous studies in Japan reported no relationship between exercise and pancreatic cancer (5,19). In the present study, we observed an increased risk of pancreatic cancer death among women with the highest intensity of exercise, although the association and trend were not significant. Strenuous exercise, which induces free radicals, might have increased the risk of pancreatic cancer (21). However, a high intensity of physical activity may be associated with the prognosis of pancreatic cancer rather than its incidence. We cannot also deny the possibility that this significant risk increase in women was caused by chance.

Our current study was a prospective design in a general community with a high participation rate. However, methodological problems must be considered in interpretation of the present study. The lack of statistical power, due to the small number of deaths from pancreatic cancer, small sample size and short duration of follow-up in this cohort, was a limitation to an adequate assessment of the relationship of lifestyle factors and pancreatic cancer. Another limitation is the use of mortality data instead of incidence data. Although mortality from pancreatic cancer is very close to incidence (1), our results would reflect an association of factors in interest with both the incidence and prognosis of this disease.

In conclusion, we observed a positive association between smoking and death from pancreatic cancer in Japanese women. The associations of the other measured lifestyle factors with pancreatic cancer death were equivocal in this small scale study. Larger studies are needed to clarify the risk factors for pancreatic cancer among the Japanese.

Funding

This study was supported in part by grant from the Ministry of Education, Culture, Sports, Science, and Technology, Japan. It was also funded by Grant-in-Aid for Cancer Research (21Shi-11-1) from the Ministry of Health, Labour and Welfare, Japan.

Conflict of interest statement

None declared.

References

1
Hart
AR
Kennedy
H
Harvey
I
Pancreatic cancer: a review of the evidence on causation
Clin Gastroenterol Hepatol
 , 
2008
, vol. 
6
 (pg. 
275
-
82
)
2
Gandini
S
Botteri
E
Iodice
S
Boniol
M
Lowenfels
AB
Maisonneuve
P
, et al.  . 
Tobacco smoking and cancer: a meta-analysis
Int J Cancer
 , 
2008
, vol. 
122
 (pg. 
155
-
64
)
3
Iodice
S
Gandini
S
Maisonneuve
P
Lowenfels
AB
Tobacco and the risk of pancreatic cancer: a review and meta-analysis
Langenbecks Arch Surg
 , 
2008
, vol. 
393
 (pg. 
535
-
45
)
4
Lin
Y
Tamakoshi
A
Kawamura
T
Inaba
Y
Kikuchi
S
Motohashi
Y
, et al.  . 
JACC Study Group
Japan Collaborative Cohort. A prospective cohort study of cigarette smoking and pancreatic cancer in Japan
Cancer Causes Control
 , 
2002
, vol. 
13
 (pg. 
249
-
54
)
5
Luo
J
Iwasaki
M
Inoue
M
Sasazuki
S
Otani
T
Ye
W
, et al.  . 
JPHC Study Group
Body mass index, physical activity and the risk of pancreatic cancer in relation to smoking status and history of diabetes: a large-scale population-based cohort study in Japan—the JPHC study
Cancer Causes Control
 , 
2007
, vol. 
18
 (pg. 
603
-
12
)
6
Hirayama
T
Epidemiology of pancreatic cancer in Japan
Jpn J Clin Oncol
 , 
1989
, vol. 
19
 (pg. 
208
-
15
)
7
Akiba
S
Hirayama
T
Cigarette smoking and cancer mortality risk in Japanese men and women—results from reanalysis of the six-prefecture cohort study data
Environ Health Perspect
 , 
1990
, vol. 
87
 (pg. 
19
-
26
)
8
Renehan
AG
Tyson
M
Egger
M
Heller
RF
Zwahlen
M
Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies
Lancet
 , 
2008
, vol. 
371
 (pg. 
569
-
78
)
9
Bao
Y
Michaud
DS
Physical activity and pancreatic cancer risk: a systematic review
Cancer Epidemiol Biomarkers Prev
 , 
2008
, vol. 
17
 (pg. 
2671
-
82
)
10
O'Rorke
MA
Cantwell
MM
Cardwell
CR
Mulholland
HG
Murray
LJ
Can physical activity modulate pancreatic cancer risk? A systematic review and meta-analysis
Int J Cancer
 , 
2010
, vol. 
126
 (pg. 
2957
-
68
)
11
Genkinger
JM
Spiegelman
D
Anderson
KE
Bergkvist
L
Bernstein
L
van den Brandt
PA
, et al.  . 
Alcohol intake and pancreatic cancer risk: a pooled analysis of fourteen cohort studies
Cancer Epidemiol Biomarkers Prev
 , 
2009
, vol. 
18
 (pg. 
765
-
76
)
12
Shimizu
H.
A Basic Report on Takayama Study
1996
Gifu (Japan)
Department of Public Health, Gifu University School of Medicine
13
Shimizu
N
Nagata
C
Shimizu
H
Kametani
M
Takeyama
N
Ohnuma
T
, et al.  . 
Height, weight, and alcohol consumption in relation to the risk of colorectal cancer in Japan: a prospective study
Br J Cancer
 , 
2003
, vol. 
88
 (pg. 
1038
-
43
)
14
Suzuki
I
Kawakami
N
Shimizu
H
Reliability and validity of a questionnaire for assessment of energy expenditure and physical activity in epidemiological studies
J Epidemiol
 , 
1998
, vol. 
8
 (pg. 
152
-
9
)
15
Ministry of Education, Culture, Sports, Science and Technology, Japan
 
Standard Tables of Food Composition in Japan, Fifth Revised and Enlarged Edition. 2005.
16
Shimizu
H
Ohwaki
A
Kurisu
Y
Takatsuka
N
Ido
M
Kawakami
N
, et al.  . 
Validity and reproducibility of a quantitative food frequency questionnaire for a cohort study in Japan
Jpn J Clin Oncol
 , 
1999
, vol. 
29
 (pg. 
38
-
44
)
17
Huxley
R
Ansary-Moghaddam
A
Berrington de González
A
Barzi
F
Woodward
M
Type-II diabetes and pancreatic cancer: a meta-analysis of 36 studies
Br J Cancer
 , 
2005
, vol. 
92
 (pg. 
2076
-
83
)
18
Duell
EJ
Holly
EA
Bracci
PM
Wiencke
JK
Kelsey
KT
A population-based study of the Arg399Gln polymorphism in X-ray repair cross- complementing group 1 (XRCC1) and risk of pancreatic adenocarcinoma
Cancer Res
 , 
2002
, vol. 
62
 (pg. 
4630
-
6
)
19
Lin
Y
Kikuchi
S
Tamakoshi
A
Yagyu
K
Obata
Y
Inaba
Y
, et al.  . 
JACC Study Group
Obesity, physical activity and the risk of pancreatic cancer in a large Japanese cohort
Int J Cancer
 , 
2007
, vol. 
120
 (pg. 
2665
-
71
)
20
Kanazawa
M
Yoshiike
N
Osaka
T
Numba
Y
Zimmer
P
Inoue
S
Criteria and classification of obesity in Japan and Asia-Oceania
Asia Pac J Clin Nutr
 , 
2002
, vol. 
11
 
Suppl 8)
(pg. 
S732
-
S737
)
21
Banerjee
AK
Mandal
A
Chanda
D
Chakraborti
S
Oxidant, antioxidant and physical exercise
Mol Cell Biochem
 , 
2003
, vol. 
253
 (pg. 
307
-
12
)