Reduced Risk of Brain Cancer Mortality from

Walking and Running

PAUL T. WILLIAMS
Ernest Orlando Lawrence Berkeley National Laboratory, Berkeley, CA
ABSTRACT
WILLIAMS, P. T. Reduced Risk of Brain Cancer Mortality from Walking and Running. Med. Sci. Sports Exerc., Vol. 46, No. 5,
pp. 927932, 2014. Purpose: This study aimed to test prospectively whether exercise is associated with lower brain cancer mortality
in 111,266 runners and 42,136 walkers from the National Runners and Walkers Health Studies. Methods: Hazard ratios and 95%
confidence intervals (95% CI) from Cox proportional hazards analyses of mortality versus metabolic equivalent hours per day of exercise
(MET-hours per day, where 1 MET = 3.5 mL O
2
Ikg
j1
Imin
j1
, or approximately 1-km run). Results: The National Death Index
identified 110 brain cancer deaths during an 11.7-yr average follow-up. Runners and walkers were combined because the brain cancer
risk reduction did not differ significantly between MET-hours per day run and MET-hours per day walked (P = 0.66). When adjusted
for sex, age, race, education, and cohort effects, the risk for brain cancer mortality was 43.2% lower for those who exercised 1.8 to
3.5 METIhId
j1
(95% CI = 2.6%66.8% lower, P = 0.04) and 39.8% lower for those who exercised Q3.6 METIhId
j1
(95%
CI = 0.0%64.0% lower, P = 0.05) compared with G1.8 METIhId
j1
at baseline. Pooling the runners and walkers who expended
Q1.8 METIhId
j1
showed a 42.5% lower risk of brain cancer mortality for the entire sample (95% CI: 8.0 to 64.1, P = 0.02) and 40.0%
lower risk when three deaths that occurred within 1 yr of the baseline survey were excluded (95% CI = 1.3%62.4%, P = 0.04).
Conclusions: The risk for fatal brain cancer decreased in association with running and walking energy expenditure. Our ability to
detect an exercisebrain cancer relationship may relate to the use of cohorts specifically designed to detect exercisehealth associa-
tions, and the calculation of exercise energy expenditure from kilometers per day walked and run rather than time spent exercising.
Key Words: PREVENTION, VIGOROUS EXERCISE, MODERATE EXERCISE, PHYSICAL ACTIVITY, RACE
A
n estimated 24,560 malignant tumors of the brain and
central nervous system are projected to occur in 2013
(7). Seventy percent of all adult malignant primary
brain tumors are gliomas, that is, tumors arising from glial
cells (27). The risk for glioma increases with age is approxi-
mately 40% greater for males than females and is greater in
whites than blacks (39). Taller individuals may be at greater
risk than those who are short (2,12). The only established
modifiable risk factor for glioma is exposure to ionizing radi-
ation (15), which accounts for only a small proportion of cases.
Prognosis depends on age, tumor grade, histology, prior pro-
gressions, and performance status (28,40).
Studies to date reported only a weak, mostly nonsignificant
effect of physical activity on glioma, including the Million
Woman Study cohort (2) and the European Prospective In-
vestigation into Cancer and Nutrition study (23). The Na-
tional Institutes of HealthAmerican Association of Retired
Persons study of slightly more than 300,000 subjects found
35% lower glioma risk for subjects who recalled being
physically active when they were between 15 and 18 yr old,
but no significant risk reduction for activity later in life (24).
Prognosis may be improved with exercise, that is, Ruden
et al. (28) reported that median survival time was 68% greater
in patients with recurrent malignant glioma who exercised
Q1.3 METIhId
j1
versus less active patients. Performance
status has also been associated with prognosis (40), and
although physical activity is a strong determinant of per-
formance status, their effects on prognosis are apparently
independent (28).
This report tests whether exercise deceases the risk of
brain cancer mortality prospectively in the National Walkers
and Runners Health Study cohorts (3238). These cohorts
were specifically designed to maximize the statistical power
to detect exercisehealth associations. In addition to their
EPIDEMIOLOGY
Address for correspondence: Paul T. Williams, Ph.D., Donner Laboratory,
Life Sciences Division, Ernest Orlando Lawrence Berkeley National Lab-
oratory, Berkeley, CA 94720; E-mail: ptwilliams@lbl.gov.
Submitted for publication June 2013.
Accepted for publication September 2013.
0195-9131/14/4605-0927/0
MEDICINE & SCIENCE IN SPORTS & EXERCISE

Copyright 2014 by the American College of Sports Medicine

DOI: 10.1249/MSS.0000000000000176
927
Copyright 2014 by the American College of Sports Medicine. Unauthorized reproduction of this article is prohibited.
large sample size, the broad range of energy expenditures,
and the use of subjects knowledgeable of their exercise rou-
tines, their exercise energy expenditures were calculated from
kilometers walked and run, which has been shown to be a
superior metric to traditional time-based calculations (3436).
This is important because nondifferential errors in recall of
physical activity are likely to bias results toward the null in
most existing studies (21).
For these reasons, significant associations between exercise
and brain cancer might be detected in the specialized cohorts
of the current report, but not in general-purpose cohorts of
primarily sedentary individuals reported by others.
MATERIALS AND METHODS
Mortality surveillance through December 31, 2008, was
carried out by the National Death Index for three cohorts: the
first and the second National Runners Health Study cohorts
(NRHS-I and NRHS-II) and the National Walkers Health
Study (NWHS). NRHS-I was recruited between 1991 and
1994 (primarily 1993), whereas NRHS-II and NWHS were
recruited primarily between 1998 and 2001 (3038). The three
cohorts may be more accurately characterized as a single
cohort that targeted the runners and walkers because all three
used the same questionnaire (modified slightly for the different
activities), the same sampling domain (subscription lists to
running and walking publications and running and walking
events), and the same survey staff and were funded by the
same grants.
Participants completed baseline questionnaires on exercise,
height, current and past body weight, diet, current and past
cigarette use, and history of disease. The runners reported the
usual miles run per week, and the walkers reported the usual
miles walked per week and the usual pace (minImile
j1
).
These were used to estimate energy expenditure in terms
of METs, where 1 MET is the energy expended sitting at
rest (3.5 mL O
2
Ikg
j1
Imin
j1
) (13). In walkers, MET-hours
per day walked was calculated by converting reported dis-
tance into duration (i.e., distance divided by miles per hour),
which was then multiplied by the MET value for the re-
ported pace (34,36). In runners, MET-hours per day run
was calculated as kilometers run 1.02 METIhIkm
j1
(34,35). Previously, we have reported strong correlations
between repeated questionnaires for self-reported running
distance (r = 0.89) (32).
Education was solicited by requesting the participant to
provide years of education (e.g., HS = 12, BS or BA = 16,
MS or MA = 18, PhD or MD = 20). Height and weight were
determined by asking the participant, What is your current
height (in inches, without shoes)? and What is your current
weight (prepregnancy weight if pregnant)? Body mass index
(BMI) was calculated as weight in kilograms divided by the
square of height in meters. Intakes of meat and fruit were
based on the questions During an average week, how many
servings of beef, lamb, or pork do you eat? and During an
average week, how many pieces of fruit do you eat? Corre-
lations between these responses and values obtained from 4-d
diet records in 110 men were r = 0.46 and r = 0.38 for con-
sumptions of meat and fruit, respectively. Alcohol intake was
estimated from the corresponding questions for 4-oz (112 mL)
glasses of wine, 12-oz (336 mL) bottles of beer, and mixed
drinks and liqueurs. Alcohol was computed as 10.8 g per 4-oz
glass of wine, 13.2 g per 12 oz bottle of beer, and 15.1 g per
mixed drink. The study protocol was approved by the Uni-
versity of California Berkeley committee for the protection of
human subjects, and all subjects provided a signed statement
of informed consent.
The underlying and contributing (entity axis) causes of
death were obtained from the National Death Index mortality
surveillance through December 31, 2008. Possible matches
between cohort members and the National Death Index data-
base needed to agree on at least one of the following condi-
tions: 1) social security number; 2) exact month and T1 yr
of birth and first and last names; 3) exact month and T1 yr of
birth and first name, middle initial(s), and last name; 4) exact
month and day of birth and first and last names; 5) exact
month and day of birth and first name, middle initial(s), and
last name; or 6) exact month and year of birth and first and
last names with the fathers surname on the National Death
Index record. Agreement on last names was based on exact
spelling or common misspellings. Multiple records were
submitted for each participant to cover potential name varia-
tions (e.g., nicknames and previous married names). The
National Death Index assigned probability scores to poten-
tial matches, and high probability score matches were fur-
ther reviewed by survey staff for acceptance while blinded
to exercise level and other variables that could influence
mortality.
Cox proportional hazard analyses (STATA version 11.1;
StataCorp, College Station, TX) were used to test whether
brain cancer deaths (International Classification of Disease
version 9 code 191 and version 10 code C71) were signifi-
cantly related to MET-hours per day run or walked and other
risk factors when adjusted for sex, baseline age (age and age
2
),
education, winter birth, being white, and cohort effects. Results
are presented as hazard ratios (HR) and their percent reduc-
tions in the risk (calculated as 100 [HR j 1]) for three cate-
gories of running or walking energy expenditure: 1) falling
short or achieving the current physical activity recommen-
dations for health (G750 METIminIwk
j1
=1.8 METIhId
j1
),
2) exceeding the recommendations by 1- to 2-fold (1.8
3.5 METIhId
j1
), and 3) exceeding the recommendations by
Q2-fold (Q3.6 METIhId
j1
) (13). The trend for increased brain
cancer risk for winter versus summer births was tested by
recoding the birth month as follows: February = 1, March =
5/6, April = 2/3, May = 1/2, June = 1/3, July = 1/6, August = 0,
September = 1/6, October = 1/3, November = 1/2, December =
2/3, and January = 5/6. This coding of the birth month repre-
sents a linear change in risk between the highest (February)
and lowest (August) risk months as identified in the article
by Brenner et al. (4). All analyses were verified using logistic
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regression analyses (also STATA version 11.1), which are
not dependent on the proportional hazard assumption.
RESULTS
Of the 153,420 subjects with complete data and eligible
for analyses, 18 were excluded for reporting a previous di-
agnosis of brain cancer on their baseline questionnaires. The
remaining sample included 110 deaths that had brain cancer
listed as the underlying cause during the 11.7 T 3.1 yr
follow-up (mean T SD). Table 1 presents their sample char-
acteristics. Social security number was provided by 79.8% of
those who ran or walked G1.8 METIhId
j1
, 84.8% of those
who ran or walked 1.83.5 METIhId
j1
, and 88.7% of those
who ran or walked Q3.6 METIhId
j1
.
Cox proportional hazard analyses. Runners and
walkers were combined because the brain cancer risk reduc-
tion did not differ significantly between MET-hours per day
run and MET-hours per day walked (P = 0.66). When ad-
justed for sex, age, race, education, and cohort effects, the risk
for brain cancer mortality was 43.2% lower for those who
walked or ran 1.83.6 METIhId
j1
(95% confidence interval
[CI] = 2.6%66.8% lower, P = 0.04) and 39.8% lower for
those who walked or ran Q3.6 METIhId
j1
(95% CI = 0.0%
64.0% lower, P = 0.05) when compared with G1.8 METIhId
j1
.
These results provide little evidence for additional risk re-
duction higher than 1.8 METIhId
j1
, although there may be
limited statistical power to detect any additional improve-
ment. Table 2 shows that when pooled, the runners and
walkers who expended Q1.8 METIhId
j1
had a 42.5% lower
risk of brain cancer mortality for the entire sample and 40.0%
lower risk when three deaths that occurred within 1 yr of
the baseline survey were excluded (95% CI = 1.3%62.4%,
P = 0.04). The risk reduction was weakened slightly when
race, education, type of activity, and cohort effects were
disregarded (P = 0.07) and was somewhat stronger for sub-
jects Q50 yr of age versus younger subjects at baseline.
The risk for brain cancer mortality was also 4.13-fold greater
for whites than nonwhites (95% CI = 1.02- to 16.80-fold, P =
0.05) and 1.91-fold greater for winter births (February vs
August, 95% CI = 1.01- to 3.59-fold, P = 0.05) but was
unrelated to height (HR = 0.36 per meter, 95% CI = 0.035.09,
P = 0.45), BMI (HR = 1.00 per kilogram per square meter,
95% CI = 0.951.06, P = 0.87), medications for hypertension
(HR = 1.04, 95% CI = 0.561.92, P = 0.11) or diabetes
(HR = 0.51, 95% CI = 0.073.68, P = 0.80), or intakes of
red meat (HR = 0.86 per serving per day, 95% CI = 0.491.50,
P = 0.59), fruit (HR = 0.90 per piece per day, 95% CI = 0.76
1.07, P = 0.23), or alcohol (HR = 1.00 per gram per day,
95% CI = 0.991.00, P = 0.95). The adjustment for these
additional variables did not eliminate the significantly lower
risk for brain cancer mortality for Q1.8 METIhId
j1
versus G1.8
METIhId
j1
run or walked, including adjustment for BMI
(Table 2). The reduction in brain cancer mortality for Q1.8
versus G1.8 METIhId
j1
also remained significant when the
data were restricted to subjects who provided their social
security numbers (41.4% risk reduction, 95% CI = 1.9%
65.0%, P = 0.04).
Verification using logistic regression analyses. The
results cited previously are entirely consistent with those from
the less-restrictive logistic regression analyses that adjusted
for follow-up duration, that is, the adjusted odds for brain
cancer mortality were as follows: 1) 43.2% lower for those who
walked or ran 1.83.5 METIhId
j1
(95% CI = 2.4%66.9%,
P = 0.04), 2) 40.3% lower for those who walked or ran
Q3.6 METIhId
j1
(95% CI = 0.0%64.5%, P = 0.05), 3)
4.1-fold greater for whites than nonwhites (95% CI = 1.0- to
16.7-fold, P = 0.05), and 3) 1.9-fold greater for winter than
summer births (February vs August, 95%CI = 1.0- to 3.6-fold,
P = 0.05). Brain cancer mortality was unrelated to height
(P = 0.44), BMI (P = 0.85), hypertension medication
TABLE 1. Sample baseline characteristics by MET-hours per day run or walked.
MET-Hours per Day
G1.8 1.83.5 Q3.6
Sample (n) 31,422 45,736 76,244
Brain cancer deaths (n) 29 28 53
Females (%) 67.72 56.68 43.36
Walkers (%) 60.38 34.13 9.91
Follow-up (yr) 10.36 T 2.51 11.34 T 2.92 12.40 T 3.18
Age (yr) 48.72 T 14.88 45.92 T 12.75 42.56 T 11.41
White (%) 86.86 91.08 91.89
Education (yr) 15.53 T 2.80 15.97 T 2.56 16.09 T 2.51
Height (m) 1.68 T 0.10 1.71 T 0.10 1.72 T 0.10
BMI (kgIm
j2
) 26.08 T 5.51 24.18 T 3.82 22.88 T 3.02
Hypertensive
medications (%)
14.11 8.21 4.02
Diabetes medications (%) 3.44 1.36 0.59
Red meat (servings per day) 0.42 T 0.39 0.38 T 0.37 0.33 T 0.43
Fruit (pieces per day) 1.37 T 1.12 1.48 T 1.24 1.61 T 1.23
Alcohol (gId
j1
) 6.39 T 11.45 8.54 T 13.03 9.43 T 14.46
Data are presented as mean T SD or %.
TABLE 2. Cox proportional hazard analyses of brain cancer mortality versus MET-hours
per day run or walked, race, and winter birth.
All G50 yr Old Q50 yr Old
Deaths and sample size
G1.8 METIhId
j1
, reference group
Brain cancer deaths 30 7 23
Person-years of follow-up 328,875 195,267 133,608
Q1.8 METIhId
j1
, exercise group
Brain cancer deaths 80 38 42
Person-years of follow-up 1,436,871 1,055,083 381,787
Cox proportional hazard analyses of Q1.8 vs G1.8 METIhId
j1
Age and sex adjusted only
HR 0.661 0.872 0.580
95% CI 0.4231.034 0.3831.984 0.3371.000
Significance 0.07 0.74 0.05
Multivariate adjustment without BMI
a
HR 0.575 0.777 0.497
95% CI 0.3590.920 0.3311.827 0.2790.885
Significance 0.02 0.56 0.02
Multivariate adjustment, including BMI
a
HR 0.579 0.842 0.473
95% CI 0.3540.947 0.3512.023 0.2570.871
Significance 0.03 0.70 0.02
a
Adjusted for age (age, age
2
), sex, race, education, activity (running vs walking),
and cohort.
REDUCED RISK OF BRAIN CANCER WITH EXERCISE Medicine & Science in Sports & Exercise
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(P = 0.94), diabetes medications (P = 0.46), and intakes of
red meat (P = 0.59), fruit (P = 0.24), or alcohol (P = 0.96).
DISCUSSION
Our analyses demonstrate a significant, inverse associa-
tion between baseline exercise and brain cancer mortality.
Specifically, the risk for brain cancer mortality was 43.2%
lower for those who ran or walked 1.83.6 METIhId
j1
(equivalent to 12- to 25-km running or 19- to 37-km brisk
walking per week) and was 39.8% lower for those who ran
or walked 93.6 METIhId
j1
compared with those less active
(G1.8 METIhId
j1
). We combined not meeting the exercise
recommendations (i.e., G1.07 METIhId
j1
) with achieving
the recommendations (i.e., 1.071.8 METIhId
j1
) because
their HRs were similar and because of the need to increase
statistical power. A greater proportion of more-active sub-
jects provided their social security numbers to assist with
follow-up, suggesting a possible bias favoring more com-
plete mortality surveillance in the most active subjects. The
lower risk for brain cancer mortality with greater exercise
was observed despite this bias and was also shown to be sig-
nificant when the analyses were restricted to subjects who
provided social security numbers.
Our analyses also provide additional evidence that glioma
or brain tumor mortality risk is greater for whites versus
nonwhites (39) and for winter versus summer births (9), even
when adjusted for education.
Gliomas are heterogeneous, and their etiologies presumably
diverse. In vitro studies suggest a role of the insulin-like growth
factor 1 (IGF-1) signaling pathway in glioma proliferation
and progression (1,30,31), where overexpression of IGF-1
receptors in glioma cells correlates with histopathologic grade
and proliferation index (14), and the disruption of the IGF-1
pathway causes tumor regression (10). Different physical
activities appear to affect IGF-1 differently, which may also
explain the significant reduction in brain cancer mortality
risk with running and walking (reported here), but not total
activity (used by other studies). Running and walking are
endurance-type exercises. Resting IGF-I concentrations de-
crease after short-term endurance training (25) and increase
after short-term resistance training (3). Running and walking
might also reduce glioma risk by reducing the amount of
bioavailable IGF-1. Endurance exercise training is reported to
increase basal IGFBP-1 concentrations, an important inhibitor
of IGF-I bioactivity, while decreasing free and total IGF-I
concentrations (25). Immediately after running a marathon,
circulating IGFBP-I levels are reported to increase 12-fold
while insulin remains unchanged (18). Coincidentally perhaps,
the risks for breast, colorectal, prostate, and lung cancers are
increased 1.2- to 5-fold in association with elevated IGF-I
(29), and the risks for each have been purported to decreased
with exercise (19).
The significant reduction in brain cancer mortality could
also be related metabolic processes affecting blood pressure,
plasma triglyceride concentrations, type 2 diabetes, or insulin
resistance. High-grade gliomas have been associated with
elevated diastolic blood pressure and plasma triglyceride
concentrations (8). In addition, glioma prognosis is made
worst by hyperglycemia (6,22), type 2 diabetes, and obesity
(5). Elevated insulin concentrations may increase glioma risk
because of insulins promitotic properties and by increasing
free (unbound) IGF-1 by binding competitively to IGF-1
binding proteins (11,16). Running lowers blood pressure,
plasma triglyceride concentrations, body weight, and fasting
plasma glucose concentrations (32,33).
Low-grade gliomas (WHO grade 2 astrocytomas, oligoden-
drogliomas, and oligoastrocytomas) occur in young adults
between the ages of 30 and 45 yr and are characterized by
continuous slow growth and death 515 yr after onset (27).
Histological classification was not available for our sam-
ple; however, low-grade gliomas are expected to represent
a greater proportion of younger than older brain cancer
deaths. Although running or walking Q1.8 METIhId
j1
was
associated with significantly lower brain cancer mortality
in subjects 950 yr but not younger subjects, there was no
significant interaction between exercise and baseline age
and, thus, no evidence to suggest that exercise affects
brain cancer mortality differently for high versus low grade
glioma. The longer survival for low-grade glioma also
provides the opportunity for death due to other causes;
however, only three deaths listed brain cancers as a con-
tributing cause of death, and their inclusion did not affect
the analyses (results not displayed).
Caveats. Several important caveats warrant consider-
ation. There were only 110 brain cancer deaths, and additional
follow-up is required to more firmly establish this potentially
important benefit of exercise. The small number of brain
cancer deaths meant that even a 40% risk reduction achieved
only a P = 0.05 level of significance. As only fatal brain
cancers were studied, these analyses cannot distinguish an
etiologic from a prognostic effect of exercise. Some diagno-
ses of brain cancer as the underlying cause may actually be
metastatic rather than primary brain tumors, given that the
former are 10-fold more common (20). Running, walking,
and other baseline variables were self-reported from the par-
ticipants baseline questionnaires. Exercise levels and other
subject characteristics could have changed before the onset of
brain cancer. In addition, the effects of other (nonrunning
and nonwalking) exercises on brain cancer mortality could
not be assessed because walking and other exercise were not
collected in the original runners cohort, which represented
55% of the brain cancer death. Thus, these results pertain
exclusively to the subjects primary exercise: walking in the
walkers and running in the runners. Because the exercise
performed was self-selected, it is not known whether exer-
cise caused the reduction in brain cancer mortality, or if
persons with less susceptibility to brain cancer chose to
exercise. Although self-reported running and walking dis-
tances have been shown 1) to be highly reproducible in re-
peated questionnaires (32); 2) to show stronger relationships
to body weight and the prevalence of hypertension, high
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cholesterol, diabetes than time-based running and walking
measurements (3436); and 3) to be predictive of multiple
diseases prospectively (32,33,37,38), they have not been
validated using objectively measured distance. Vital status
was known only from the National Death Index, and there-
fore, some subjects who have died are likely to be mis-
classified as alive.
In conclusion, these analyses may provide the best evidence
to date that regular exercise reduces brain cancer risk pro-
spectively. They suggest a benefit to exercising at a greater
dose (e.g., running 1225 kmIwk
j1
) than currently recom-
mended (e.g., running 7.312 kmIwk
j1
). Although we did not
find a greater benefit for running over walking, a substantially
greater proportion of by runners (88.8%) than walkers (52.1%)
managed to exercise Q1.8 METIhId
j1
, which might simply
reflect the practical advantage of achieving the same amount of
exercise in half the time. It has been suggested that 40% brain
cancer patients already meet national guidelines for physical
activity (17); however, this is probably an overestimate
because: 1) physical activity questionnaires that record
frequency, intensity, and time spent being physically active
substantially overestimate the proportion who meet the guide-
lines (26), and 2) the surveys 28% response rate was probably
somewhat enriched with exercisers. Although our analyses
cannot test whether exercise specifically improves survival
in brain cancer patients, it is not unreasonable to expect that
if physical activity decreases the risk of incident glioma, it
might also extend survival, as has been reported (28).
This research was supported by grant HL094717 from the Na-
tional Heart, Lung, and Blood Institute and was conducted at the
Ernest Orlando Lawrence Berkeley National Laboratory (Department
of Energy DE-AC03-76SF00098 to the University of California). The
funders had no role in the study design, data collection and analysis,
decision to publish, or preparation of the manuscript. The author has
declared that no competing interests exist.
Results of the present study do not constitute endorsement by
the American College of Sports Medicine.
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