Michaud DS, Giovannucci E, Willett WC, Colditz GA, Stampfer MJ, Fuchs CS. Physical Activity, Obesity, Height, and the Risk of Pancreatic Cancer. JAMA. 2001;286(8):921-929. doi:10.1001/jama.286.8.921
Author Affiliations: Departments of Nutrition (Drs Michaud, Giovannucci, Willett, and Stampfer) and Epidemiology (Drs Giovannucci, Willett, Colditz, and Stampfer), Harvard School of Public Health; Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School (Drs Giovannucci, Willett, Colditz, Stampfer, and Fuchs); and Department of Adult Oncology, Dana-Farber Cancer Institute (Dr Fuchs), Boston, Mass.
Context Diabetes mellitus and elevated postload plasma glucose levels have been
associated with an increased risk of pancreatic cancer in previous studies.
By virtue of their influence on insulin resistance, obesity and physical inactivity
may increase risk of pancreatic cancer.
Objective To examine obesity, height, and physical activity in relation to pancreatic
Design and Setting Two US cohort studies conducted by mailed questionnaire, the Health
Professionals Follow-up Study (initiated in 1986) and the Nurses' Health Study
(initiated in 1976), with 10 to 20 years of follow-up.
Participants A total of 46 648 men aged 40 to 75 years and 117 041 women
aged 30 to 55 years who were free of prior cancer at baseline and had complete
data on height and weight.
Main Outcome Measures Relative risk of pancreatic cancer, analyzed by self-reported body mass
index (BMI), height, and level of physical activity.
Results During follow-up, we documented 350 incident pancreatic cancer cases.
Individuals with a BMI of at least 30 kg/m2 had an elevated risk
of pancreatic cancer compared with those with a BMI of less than 23 kg/m2 (multivariable relative risk [RR], 1.72; 95% confidence interval [CI],
1.19-2.48). Height was associated with an increased pancreatic cancer risk
(multivariable RR, 1.81; 95% CI, 1.31-2.52 for the highest vs lowest categories).
An inverse relation was observed for moderate activity (multivariable RR,
0.45; 95% CI, 0.29-0.70 for the highest vs lowest categories; P for trend <.001). Total physical activity was not associated with
risk among individuals with a BMI of less than 25 kg/m2 but was
inversely associated with risk among individuals with a BMI of at least 25
kg/m2 (pooled multivariable RR, 0.59; 95% CI, 0.37-0.94 for the
top vs bottom tertiles of total physical activity; P
for trend = .04).
Conclusion In 2 prospective cohort studies, obesity significantly increased the
risk of pancreatic cancer. Physical activity appears to decrease the risk
of pancreatic cancer, especially among those who are overweight.
Cancer of the pancreas represents the fifth leading cause of cancer-related
mortality in the United States.1 Nonetheless,
other than cigarette smoke, few environmental factors have been linked to
the risk of pancreatic cancer.2,3
An association between diabetes and pancreatic cancer has been shown in many
studies. In a meta-analysis including more than 20 epidemiologic studies,
the pooled relative risk (RR) of pancreatic cancer among those diagnosed with
diabetes for at least 5 years was 2.0 (95% confidence interval [CI], 1.3-2.2).4 Recently, a positive association between postload
plasma glucose concentration and pancreatic cancer risk was found in 2 studies,
supporting the hypothesis that impaired glucose tolerance, insulin resistance,
and hyperinsulinemia play a role in pancreatic cancer etiology.5,6
Obesity has been linked to significant metabolic abnormalities including
insulin resistance, glucose intolerance, and diabetes mellitus.7- 10
Epidemiologic findings on obesity and the risk of pancreatic cancer have been
To date, suggestive associations have been observed for height and pancreatic
cancer risk in 3 studies.15- 17
Height has been associated with elevated risks of other cancers19- 21
and may be a marker for exposure levels to growth factors or a proxy for net
energy intake during childhood and early adolescence.
Because physical activity improves glucose tolerance, even in the absence
of weight loss,22,23 we hypothesized
that physical activity would reduce the risk of pancreatic cancer. However,
to our knowledge no study has examined the association between physical activity
and pancreatic cancer risk.
We therefore examined the relationship between body mass index (BMI),
height, and physical activity and the risk of pancreatic cancer in 2 large
prospective cohort studies of men and women. In both studies, weight and physical
activity data were measured prior to pancreatic cancer detection, thus avoiding
potential biases that may occur when obtaining such information from pancreatic
cancer patients and next-of-kin.
Two ongoing cohort studies provided data for our analyses, the Health
Professionals Follow-up Study (HPFS) and the Nurses' Health Study (NHS). The
HPFS was initiated in 1986 when 51 529 US men aged 40 to 75 years responded
to a mailed questionnaire. The NHS began in 1976 when 121 700 female
registered nurses aged 30 to 55 years responded to a mailed questionnaire.
Detailed information on individual characteristics and habits was obtained
from the mailed questionnaires at baseline and subsequently every 2 years.
Most of the deaths in this cohort were reported by family members or by the
postal service in response to the follow-up questionnaires. In addition, the
National Death Index was searched for nonrespondents; this method has been
shown to have a sensitivity of 98%.24
For those analyses using anthropometric measurements, a total of 46 648
HPFS men and 117 041 NHS women were eligible after excluding participants
diagnosed with cancer (other than nonmelanoma skin cancer) prior to baseline
or with missing weight data at baseline. In the NHS, detailed data on physical
activity were not obtained until 1986. A total of 77 559 women completed
the physical activity questions on the 1986 questionnaire and were free of
Baseline height, current weight, weight at 21 years old, and weight
change in past 5 years were reported by men participating in the HPFS in 1986.
Similarly, women in the NHS reported their baseline height and current weight
in 1976. Weight at 18 years old was collected in 1980. In addition, participants
of the 2 cohorts reported their current weight on the biennial mailed questionnaires.
We estimated BMI from weight and height (weight in kilograms divided by square
of height in meters) as a measure of total adiposity. We evaluated the precision
of self-reported anthropometric measures among 123 HPFS participants by having
trained technicians visit those participants twice (6 months apart) to measure
current weight.25 After adjustment for age
and within-person variability, the Pearson correlation between self-report
and the average of the 2 technician measurements was 0.97 for weight. Among
women in the NHS, the correlation between self-reported and measured weight
was 0.96, although self-reported weight averaged 1.5 kg less than directly
In 1986, the questionnaires mailed to the 2 cohorts included a section
assessing physical activity. Participants were asked to average the time spent
per week in each of the following 8 activities over the previous year: walking
or hiking outdoors; jogging (<10 minutes per mile); running (≥10 minutes
per mile); bicycling (including on stationary machines); lap swimming; tennis;
squash or racquetball; and calisthenics (use of a rowing machine [HPFS] or
aerobics, aerobic dance [NHS]). A total of 10 possible answers were available
for each of the exercises, ranging from 0 to 11 or more hours per week. In
addition, individuals reported their usual walking pace (<2.0, 2.0-2.9,
3.0-3.9, or ≥4.0 mph [<3.2, 3.2-4.6, 4.8-6.2, or ≥6.4 km/h]) and
the number of flights of stairs climbed daily. Our calculations did not include
household activities or occupational physical activity. The reliability and
validity of the assessment of physical activity as used in these 2 cohorts
were tested among 147 participants of the Nurses' Health Study II, a similar
cohort to the NHS but participants were younger nurses. The correlation between
physical activity reported on the questionnaire and that recorded in the 4
1-week diaries was 0.62.26 The validity of
the physical activity questionnaire used in the HPFS in 1986 was assessed
among 238 randomly selected participants by comparisons with 4 1-week activity
diaries, 4 1-week activity recalls, and resting and postexercise pulse rates.27 The correlation for vigorous physical activity with
the activity diaries was 0.58. Vigorous activity assessed by the questionnaire
was correlated with resting pulse (r = –0.45)
and postexercise pulse (r = –0.41).
A weekly physical activity score expressed in metabolic equivalent tasks
(METs) was derived by multiplying the time spent in each activity per week
by its typical energy-expenditure requirements.28
The MET is the caloric expenditure per kilogram of body weight per hour of
activity divided by the equivalent per hour at rest. One MET, which is the
energy expended by sitting quietly, is equivalent to 3.5 mL of oxygen uptake
per kilogram of body weight per minute for a 70-kg adult. Body weight was
excluded from the derivation of energy expenditure from physical activity
to avoid confounding the expenditure variable by body weight. We further classified
activities into vigorous (≥6 METs) and moderate (<6 METs). Accordingly,
moderate activities included walking or hiking outdoors and stair climbing,
and all other activities were classified as vigorous (eg, MET values of 7
were assigned to swimming and bicycling).
Smoking status and history of smoking were obtained at baseline and
in all subsequent questionnaires in both cohorts. Current smokers also reported
intensity of smoking (average number of cigarettes smoked per day) on each
questionnaire. Past smokers reported when they last smoked and time since
quitting was also calculated for those who quit during follow-up. In a previous
publication,29 we examined the relationship
between smoking and pancreatic cancer risk in detail; the strongest associations
were observed in analyses of pack-years smoked within the previous 15 years.
Participants were asked about history of diabetes at baseline and in
all subsequent questionnaires. In 1986 (HPFS) and in 1982 (NHS), and biennially
thereafter, participants were asked about their history of cholecystectomy.
In both cohorts, 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 telephone call to the participant. If the primary cause of death
as reported on 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.
In the HPFS cohort, we were able to obtain pathology reports confirming the
diagnosis of pancreatic cancer for 95% of cases. For the other 5% of cases,
we obtained confirmation of the self-reported cancer from a secondary source
(eg, death certificate, physician, or telephone interview of a family member).
In the NHS cohort, we were able to obtain pathology reports confirming the
diagnosis of pancreatic cancer for 85% of cases. For the other 15% of cases,
we obtained confirmation of the self-reported cancer from a secondary source
(eg, death certificate, physician, or telephone interview of a family member).
In both cohorts, all medical records had complete information on histology
(hospitals were recontacted if the original information sent was incomplete).
In our analyses, associations were examined including and excluding cases
with missing medical records; because no differences were observed between
these 2 types of analyses, we included cases without medical records.
In the HPFS cohort, 140 confirmed incident cases of pancreatic cancer
were diagnosed between 1986 and 1998 (after exclusions); 139 cases were available
with data on physical activity at baseline. In the NHS, 210 confirmed incident
pancreatic cancer cases, diagnosed between 1976 and 1996, were available for
the anthropometric analyses (after exclusions); 110 confirmed cases were available
for analyses on physical activity (1986-1996).
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 (January 31, 1998, for men and
June 30, 1996, for women), 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 exposure. We computed the RR for each
of the upper categories by dividing the rates in these categories by the rate
in the lowest category.
We estimated the power to detect trends across quintiles for specified
RRs comparing highest vs the lowest quintile, assuming a linear relationship
and fixing the 2-tailed α = .05.30 We
found an 80% power to detect an RR of 1.5 between the highest and lowest quintiles;
a 95% power to detect an RR of 1.75 between the highest and lowest quintiles;
and a greater than 99% power to detect an RR of 2.0 between the highest and
For each cohort, RRs adjusted for potential confounders were estimated
using pooled logistic regression analyses with 2-year time increments. With
short intervals between questionnaires and the low rates of events, this approach
yields results similar to those of a Cox regression analysis with time-varying
covariates.31 In these models, age was categorized
into 5-year age groups and cigarette smoking was categorized as follows (based
on a previous analysis of these cohorts29):
never smoker, quit more than 15 years ago, quit less than 15 years ago and
smoked less than 25 pack-years in past 15 years, quit less than 15 years ago
and smoked more than 25 pack-years in past 15 years, current smoker with less
than 25 pack-years in past 15 years, and current smoker with more than 25
pack-years in past 15 years (age and smoking variables were updated biennially).
In addition, we controlled for history of diabetes and cholecystectomy updating
these variables biennially in the analyses.4,32,33
We categorized men and women into 5 groups of BMI using whole number cutpoints
that included widely used definitions of overweight and obesity.34,35
BMI was not updated in the main analyses because pancreatic cancer is frequently
associated with profound weight loss. In addition, we performed analyses with
a 2-year lag to exclude preclinical cases at baseline. We used quintiles of
total, vigorous, and moderate physical activity in both cohorts and did not
update these variables over time since preclinical symptoms could affect activity
levels. For height, whole cutpoints were made to approximate increments of
2.54 to 5.08 cm and keeping person-years fairly evenly distributed across
the categories. All P values are based on 2-sided
We pooled the data from the 2 cohorts using a random-effects model for
the log of the RRs.36 Tests of heterogeneity
using the Q statistic36 were obtained for continuous
variables to evaluate the overall trend before pooling. All statistical procedures
were performed using SAS version 6.12 (SAS Institute Inc, Cary, NC). The Human
Research Committee at the Brigham and Women's Hospital approved the NHS and
the Harvard School of Public Health Human Subjects Committee approved the
We examined BMI and physical activity in relation to potential confounders
for both men and women (Table 1).
History of diabetes or cholecystectomy was higher among individuals with elevated
BMI or with low physical activity. Men and women with low BMI or low physical
activity were more likely to be current smokers, although men with high BMI
had smoked more cigarettes in the past. Height and age were not substantially
different by BMI or physical activity level. Caloric intake was slightly higher
and percentage of total calories from fat was slightly lower among those in
the top quintile of physical activity. As expected, physically active individuals
tended to be leaner whereas heavier individuals tended to be more sedentary.
During 2 800 837 person-years of follow-up from the 2 cohorts,
we identified 140 men and 210 women who were diagnosed as having pancreatic
cancer. A statistically significant association between BMI and the risk of
pancreatic cancer was observed in both cohorts (Table 2). After adjusting for known risk factors, men and women
with a BMI of 30 or higher had a 72% increase in the risk of pancreatic cancer
compared with men and women with a BMI of less than 23. In multivariable analyses,
an increment of 1 BMI unit (1 kg/m2) was associated with a 5% increased
risk of pancreatic cancer in the HPFS (RR, 1.05; 95% CI, 1.00-1.11) and a
3% increased risk in the NHS (RR, 1.03; 95% CI, 1.00-1.07). Of all the pancreatic
cancer cases, only 24 women and 14 men were diabetic prior to diagnosis. Controlling
for smoking history using cumulative (lifetime) pack-years did not change
the results for BMI and pancreatic cancer risk.
To eliminate preclinical cases that might have experienced weight loss
before completing the baseline questionnaires, we performed analyses that
excluded the first 4 years of follow-up. In both cohorts, associations with
BMI were strengthened in lag analyses in top vs bottom category comparison
(multivariable RR, 1.94; 95% CI, 1.26-2.98 in women and multivariable RR,
2.03; 95% CI, 0.90-4.57 in men).
In each cohort, we examined the effect of body size at a younger age
using BMI at ages 18 years (NHS) and 21 years (HPFS). Women with a BMI of
24 or greater at age 18 years had a nonsignificant elevation in the risk of
pancreatic cancer when compared with a BMI of less than 20 among women at
age 18 years (RR, 1.45; 95% CI, 0.92-2.31). After adjusting for current BMI
and other risk factors, the risk of pancreatic cancer associated with BMI
at age 18 years was attenuated (multivariable RR, 1.09; 95% CI, 0.66-1.80).
Men with a BMI of 27 or higher at age 21 years had an RR of 1.80 (95% CI,
0.97-3.34) compared with men who had a BMI of less than 21 at age 21 years,
but controlling for current BMI also attenuated the association (multivariable
RR, 1.50; 95% CI, 0.75-3.00).
We also examined the relation of weight loss to risk of pancreatic cancer.
Compared with individuals whose weight had not changed by more than 2.25 kg
between 2 consecutive biennial questionnaires, individuals who reported losing
6.75 or more kg between 2 consecutive biennial questionnaires had an RR of
4.56 (95% CI, 2.35-8.84) among men and 2.44 (95% CI, 1.46-4.06) among women.
In both cohorts, only recent weight loss was associated with risk suggesting
an influence of preclinical disease. Compared with those who had not lost
6.75 kg, the RR of pancreatic cancer was 3.66 (95% CI, 2.00-6.70) and 2.60
(95% CI, 1.53-4.40) in men and women, respectively, for a 6.75-kg weight loss
within the past 2 years.
We observed an association between height and risk of pancreatic cancer
in both cohorts (Table 2). Although
cutpoints for the categories of height were different for men and women, both
cohorts had similar increases in RR when comparing the highest and lowest
categories. When men and women were combined, individuals in the highest vs
lowest category of height had an RR of 1.81 (95% CI, 1.31-2.52) adjusting
for potential confounders and BMI. The age-adjusted RRs were very similar,
however, and including BMI in the multivariable model did not change the association.
In multivariable analyses, an additional 2.54 cm of height increased the risk
of pancreatic cancer by 6% in the HPFS (RR, 1.06; 95% CI, 0.99-1.12) and by
10% in the NHS (RR, 1.10; 95% CI, 1.04-1.16).
A total of 1 277 183 person-years and 249 pancreatic cancer
cases (139 men, 110 women) were available for the physical activity analyses.
We detected a slight inverse association between total physical activity and
pancreatic cancer risk, but associations were not statistically significant
in either cohort (Table 3). Vigorous
activity was not related to the risk of pancreatic cancer in men or women
in the multivariable models. In contrast, we observed inverse associations
for moderate activity and pancreatic cancer risk in both cohorts. In the multivariable
pooled analysis, men and women in the highest quintile of moderate activity
had a significant reduction in the risk of pancreatic cancer (RR, 0.45; 95%
CI, 0.29-0.70; P<.001 for trend) compared with
those in the lowest quintile (Table 3).
Additional control for total fat, protein, fruit and vegetables, and coffee
or alcohol intakes did not alter the associations reported in Table 2 or Table 3.
Walking or hiking outdoors accounted for an average of 70% of the METs
associated with moderate activity in each cohort. In both cohorts, we observed
inverse associations between hours per week of walking or hiking and pancreatic
cancer risk. Among men and women, walking or hiking 4 or more hours per week
was associated with a 54% lower risk of pancreatic cancer when compared with
less than 20 minutes per week.
The potential inverse association between moderate activity and pancreatic
cancer risk could be the result of early symptoms associated with the disease.
To address this question, we performed 2-year lag analyses in each cohort
(starting follow-up time in 1988) to avoid including individuals who were
diagnosed as having pancreatic cancer within 2 years of having responded to
the physical activity questions. Associations in these analyses were not substantially
different for total physical activity, vigorous activity, or moderate activity
(pooled multivariable RR, 0.48; 95% CI, 0.25-0.92 top vs bottom quintile comparison).
To explore the possibility of an interaction between physical activity
and BMI, we examined the risk of pancreatic cancer according to both total
physical activity (in tertiles) and BMI (<25.0, 25.0-29.9, and ≥30.0
kg/m2) among men and women combined. After adjusting for potential
confounders, the association between total physical activity level and the
pancreatic cancer risk was modified by BMI (Figure 1). Among nonoverweight participants (BMI <25 kg/m2), total physical activity was not related to the risk of pancreatic
cancer, but total physical activity was inversely associated with risk among
overweight individuals (pooled multivariable RR, 0.59; 95% CI, 0.37-0.94 for
top vs bottom tertile of total physical activity among individuals with BMI ≥25
kg/m2; P = .04 for trend). Individuals
with a BMI of 30 kg/m2 or higher in the lowest tertile of exercise
had twice the risk of pancreatic cancer compared with individuals who had
a BMI of lower than 25 kg/m2 in the highest tertile of total physical
While Figure 1 presents data
for the pooled analysis, findings were homogeneous across the 2 cohorts with
the exception of a greater increase in risk in the high BMI and low physical
activity category in men than women, compared with the reference (HPFS: multivariable
RR, 2.43; 95% CI, 1.13-5.23; NHS: multivariable RR, 1.57; 95% CI, 0.65-3.82).
The nature of the association between physical activity and BMI appears to
be an example of a "joint exposure" in which elevated risk of pancreatic cancer
is only apparent in individuals who have combined exposures (high BMI and
low physical activity). However, the multiplicative interaction reported in Figure 1 was not statistically significant.
Removing current smokers from these analyses resulted in similar findings.
In 2 prospective cohort studies, we found a consistent and significant
excess risk of pancreatic cancer among obese men and women (BMI ≥30 kg/m2 compared with <23 kg/m2). A direct association between
height and the risk of pancreatic cancer was also observed in these 2 cohorts.
Both cohorts demonstrated strong inverse associations for moderate physical
activity, specifically for walking or hiking outdoors. Although total physical
activity was not significantly related to the risk of pancreatic cancer overall,
it was inversely associated with risk among overweight individuals (BMI ≥25
kg/m2). Physical activity appeared to have no effect on risk among
nonoverweight participants (<25 kg/m2). Moreover, BMI had no
apparent influence on risk among men and women who were exercising (top 2
tertiles of physical activity).
Several case-control studies have examined BMI or weight and pancreatic
cancer risk, but findings have been inconsistent. A total of 416- 18,37
of 714- 18,37- 39
case-control studies reported no association for BMI or weight and the risk
of pancreatic cancer. The largest study to date,38,39
based only on direct interviews with cases, showed a 50% to 60% increase in
the risk of pancreatic cancer in obese individuals that was consistent by
sex and race. Obesity was associated with increased risk of pancreatic cancer
in 3 studies in which weight was determined prior to the detection of pancreatic
cancer11- 13 in
men, but not women, in a recent mortality cohort study.5
A prospective cohort study of pancreatic cancer in elderly persons did not
detect any association for BMI.40
There are several possible explanations for the discrepancies across
studies on obesity and pancreatic cancer risk. Because pancreatic cancer is
highly fatal, numerous case-control studies had to obtain information on cases
through indirect interviews15- 18
or did not obtain weight on deceased cases.14,38,39
These methods may have led to biased findings, if, for example, leaner individuals
had higher survival rates. In retrospective studies, prediagnostic weight
loss associated with pancreatic cancer may have biased weight recall. Among
previous studies, cutpoints for the top categories of BMI may not have been
set high enough to detect an association with BMI, as risk appears to be most
elevated among men and women with a BMI of 30 or higher. In 2 studies in which
no influence of BMI was observed, the cutpoints of the top categories were
relatively low: 23.2 in women, 23.9 in men,40
and 26.5 in both sexes.16
Previous studies have also examined the association of height and pancreatic
cancer risk. Although findings have not been entirely consistent,14- 17,37
at least 2 studies reported nonsignificant positive associations for height.16,17 In a third study conducted in the
Netherlands, a significant positive association was reported among women.15 An association between height and cancer risk at
other sites has been reported in the HPFS cohort and in other studies.19- 21 Height may serve
as a proxy for net energy intake or exposure levels to growth factors such
as insulin and insulin-like growth factor 1 during childhood.
To our knowledge, this was the first epidemiologic study to examine
the relation between physical activity and the risk of pancreatic cancer.
Thus, further studies are needed. Nonetheless, the consistency in the associations
for moderate physical activity observed in 2 entirely separate cohorts argues
strongly against the role of chance as an explanation for our findings.
Our findings related to BMI and physical activity may be explained,
biologically, within the axis of abnormal glucose intolerance and hyperinsulinemia.
In a recent prospective study, a 2-fold elevation in fatal pancreatic cancer
was detected among individuals with high prediagnostic postload plasma glucose
levels (>200 mg/dL [>11.1 mmol/L]) compared with low levels (<119 mg/dL
[<6.6 mmol/L]).5 Abnormal glucose metabolism
and hyperinsulinemia have been proposed as underlying mechanisms that might
explain the positive association between diabetes mellitus and the risk of
pancreatic cancer.4 Hyperinsulinemia has been
shown to increase local blood flow and cell division within the pancreas.41,42 By causing the down-regulation of
insulin-like growth factor binding protein 1, excess insulin may also result
in an increase in exposure to free insulin-like growth factor 1, which has
been shown to promote growth in human pancreatic cell lines.43- 45
Physical activity has long been known to reduce glucose intolerance
and an elevated BMI is associated with an increase in risk of hyperinsulinemia
and diabetes. In addition, studies have demonstrated that weight loss is not
necessary to benefit from the effects of physical activity on glucose tolerance
and insulin clearance rates.23,46
Our findings are consistent because we observed an inverse association between
physical activity and pancreatic cancer risk, especially among those who were
obese. Moreover, since the obese group is more likely to include persons with
glucose abnormalities than the overweight group, evidence for a stronger inverse
association with activity in the obese is consistent with a mechanism involving
An alternative mechanism for the association between BMI and pancreatic
cancer may be related to DNA adduct formation.47
Comparing pancreatic tissue from healthy individuals (organ donors) and cancer
patients, DNA adduct levels were reported to be significantly higher in cancer
patients. Positive correlations were found between BMI and the levels of lipid
peroxidation–related DNA adducts and total adduct levels in cancer patients,
which persisted after controlling for age, sex, and smoking. Thus, an increase
in DNA damage to the pancreas caused by increased lipid peroxidation in individuals
with elevated BMIs may be an alternative explanation for the observed association
Our findings observed a strong association for moderate activity in
both cohorts, but not for vigorous activity. One possible explanation is related
to the modifying effect of obesity. Because men and women who are overweight
or obese appear to benefit the most from physical activity but are less likely
to participate in vigorous exercise, the effect of physical activity may be
most apparent for moderate activity.
An alternative explanation for our findings is related to energy expenditure
vs cardiorespiratory fitness. A recent study demonstrated that regular exercise
at low intensity may be more important than cardiorespiratory fitness obtained
with vigorous exercise in reducing glucose intolerance.48
In both our cohorts, the level of vigorous activity was much lower among those
with BMI of 30 kg/m2 or higher compared with a BMI of lower than
30 (for vigorous activities: 13.0 vs 6.3 METs for BMI <30 vs BMI ≥30
in HPFS; 7.1 vs 4.5 METs for BMI <30 vs BMI ≥30 in NHS). In contrast,
the difference in METs for moderate activity was substantially lower (7.8
vs 6.3 METs for BMI <30 vs BMI ≥30 in HPFS; 7.3 vs 5.5 METs for BMI
<30 vs BMI ≥30 in NHS). Although the average level of METs expended
in vigorous and moderate activities is similar for individuals with elevated
BMIs, less time is spent exercising for those performing vigorous exercise,
given that METs reflect time exercising and intensity level (intensity is
higher). It is therefore possible that low activity exercising (moderate activity)
is more successful at reducing risk in overweight individuals because, on
average for those individuals, more time is spent exercising.
Alternatively, we cannot exclude the possibility that vigorous and moderate
exercisers may have differed on other characteristics that were not considered
in this article, possibly explaining the relationship reported for physical
activity. However, certain dietary factors are unlikely to account for the
relationships given that we observed no association for either coffee or alcohol
intakes and pancreatic cancer risk,49 and that
adjusting for total fat intake did not change the associations.
The strengths of this study include a prospective design, large sample
size, data from 2 completely separate cohorts, and detailed information on
potential risk factors of pancreatic cancer. The prospective design precluded
recall bias and the need to use next-of-kin respondents. Moreover, because
exposure data were collected before the diagnosis of any cases of pancreatic
cancer, any error in recall (nondifferential misclassification) would have
attenuated rather than exaggerated a true association. Differential follow-up
is unlikely to have made a material contribution to these findings, since
follow-up was high.50
In summary, we observed an increased risk of pancreatic cancer among
obese men and women in 2 prospective cohorts. Walking or hiking 1.5 hours
or more per week was associated with a 50% reduction in pancreatic cancer
risk in men and women. The inverse association of physical activity with the
risk of pancreatic cancer was most apparent among obese individuals who were
more likely to have glucose abnormalities and who may thus benefit from an
improved glucose response associated with exercising. While our findings require
confirmation, they provide support for a role of insulin resistance and hyperinsulinemia
in the pathogenesis of pancreatic cancer.