Download Meta-analysis Cancer: A Case-Control Study, Systematic Review

Recreational Physical Activity and Epithelial Ovarian
Cancer: A Case-Control Study, Systematic Review, and
Meta-analysis
Catherine M. Olsen, Christopher J. Bain, Susan J. Jordan, et al.
Cancer Epidemiol Biomarkers Prev 2007;16:2321-2330.
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2321
Recreational Physical Activity and Epithelial Ovarian
Cancer: A Case-Control Study, Systematic Review,
and Meta-analysis
Catherine M. Olsen,1,2 Christopher J. Bain,2 Susan J. Jordan,1,2 Christina M. Nagle,1
Adèle C. Green,1 David C. Whiteman,1 Penelope M. Webb,1 and Australian Cancer
Study (Ovarian Cancer) and Australian Ovarian Cancer Study Group
1
Cancer and Population Studies Group, Queensland Institute of Medical Research and 2School of Population Health,
University of Queensland, Brisbane, Australia
Abstract
It remains unclear whether physical activity is associated with epithelial ovarian cancer risk. We therefore
examined the association between recreational physical activity and risk of ovarian cancer in a national
population-based case-control study in Australia. We
also systematically reviewed all the available evidence
linking physical activity with ovarian cancer to
provide the best summary estimate of the association.
The case-control study included women ages 18 to 79
years with a new diagnosis of invasive (n = 1,269) or
borderline (n = 311) epithelial ovarian cancer identified through a network of clinics, physicians, and state
cancer registries throughout Australia. Controls (n =
1,509) were randomly selected from the national
electoral roll and were frequency matched to cases
by age and state. For the systematic review, we
identified eligible studies using Medline, the ISI
Science Citation Index, and manual review of retrieved references, and included all case-control or
cohort studies that permitted assessment of an
association between physical activity (recreational/
occupational/sedentary behavior) and histologically
confirmed ovarian cancer. Meta-analysis was restricted
to the subset of these studies that reported on
recreational physical activity. In our case-control study,
we observed weakly inverse or null associations
between recreational physical activity and risk of
epithelial ovarian cancer overall. There was no evidence
that the effects varied by tumor behavior or histologic
subtype. Twelve studies were included in the metaanalysis, which gave summary estimates of 0.79 (95%
confidence interval, 0.70-0.85) for case-control studies
and 0.81 (95% confidence interval, 0.57-1.17) for cohort
studies for the risk of ovarian cancer associated with
highest versus lowest levels of recreational physical
activity. Thus, pooled results from observational studies suggest that a modest inverse association exists
between level of recreational physical activity and the
risk of ovarian cancer. (Cancer Epidemiol Biomarkers
Prev 2007;16(11):2321 – 30)
Introduction
There is evidence that physical activity has a protective
effect against cancers of the colon and breast and
possibly of the endometrium and prostate as well (1). It
remains unclear, however, whether physical activity is
associated with epithelial ovarian cancer risk. Hormonal
factors are well known to be involved in the etiology of
both breast (2) and endometrial cancer (3), and the
protective effect of physical activity for these cancers is
thought to be mediated through alterations in the levels
of endogenous sex hormones (4). Although the causal
Received 6/20/07; revised 8/21/07; accepted 9/7/07.
Grant support: National Health and Medical Research Council of Australia (Program
no. 199600) and U.S. Army Medical Research and Materiel Command under
DAMD17-01-1-0729, the Cancer Council Tasmania, and Cancer Foundation of
Western Australia; Senior Research Fellowships from the National Health and
Medical Research Council of Australia (D. Whiteman) and Queensland Cancer Fund
(P. Webb); and University of Queensland Postdoctoral Fellowship (C. Olsen).
The costs of publication of this article were defrayed in part by the payment of page
charges. This article must therefore be hereby marked advertisement in accordance
with 18 U.S.C. Section 1734 solely to indicate this fact.
Requests for reprints: Catherine M. Olsen, Cancer and Population Studies Group,
Queensland Institute of Medical Research, P.O. Royal Brisbane Hospital, Herston
4029, Queensland, Australia. Phone: 61-7-3375-4083; Fax: 61-7-3845-3502.
E-mail: [email protected]
Copyright D 2007 American Association for Cancer Research.
doi:10.1158/1055-9965.EPI-07-0566
pathway to ovarian cancer is unclear, hormonal factors
have been implicated (5, 6) because high parity and oral
contraceptive use are highly protective. We might
therefore expect an analogous protective effect of higher
levels of physical activity against the risk of ovarian
cancer.
Physical activity may also influence ovarian cancer
risk through a reduction in chronic inflammation (7),
which has been hypothesized to play a role in ovarian
carcinogenesis (8). In addition, regular high levels of
exercise can cause anovulation (9, 10) and thereby
potentially reduce ovarian cancer risk, which, according
to the ‘‘incessant ovulation’’ hypothesis (11), is increased
by the repeated injury to the ovarian epithelium from
regular ovulation. Physical activity might also influence
ovarian cancer risk through alterations in immune
system functioning (12).
Although a number of studies have examined the
relationship between physical activity and ovarian
cancer, their findings are inconsistent. This may be due,
in part, to the use of different definitions of physical
activity, different parameters of activity (type, frequency,
duration, intensity), and different methods of measurement. In addition, although evidence is emerging that the
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Recreational Physical Activity and Ovarian Cancer
different histologic subtypes of ovarian cancer have
different risk factor profiles (13, 14), only a small number
of studies have examined the effects of physical activity
separately for the subtypes (15-19), and only one of these
studies examined the effects for all four major subtypes
(16). In addition, there is no consensus on the critical
exposure period during which physical activity may
have the greatest effect on ovarian cancer risk.
We have endeavored to resolve some of these
uncertainties by examining the influence of recreational
physical activity on the risk of the different subtypes of
epithelial ovarian cancer in a large national case-control
study conducted in Australia. We have also included our
data in a systematic review and meta-analysis of all
available evidence linking recreational physical activity
with epithelial ovarian cancer to obtain the best summary
estimate of the association.
Materials and Methods
Case-Control Study
Study Participants. The Australian Ovarian Cancer
Study was an Australia-wide population-based casecontrol study of epithelial ovarian cancer. The study
methods have been described elsewhere (20). Cases were
women ages 18 to 79 years, living in Australia with
newly diagnosed histologically confirmed epithelial
ovarian, fallopian tube, or primary peritoneal cancer in
the period between January 2002 and June 2005. Cases
were recruited by trained nurses who liaised with the
treatment clinics, physicians, and state cancer registries
throughout Australia.
Of 3,553 women identified with suspected ovarian
cancer (most women were approached before surgery
and thus before histologic diagnosis), 304 died before
contact could be made, physicians refused to give
consent to contact 133 usually because they were too
sick or unable to give informed consent, and 194 women
could not be contacted. A further 167 (5%) were excluded
on the basis of language difficulties (n = 70), mental
incapacity (n = 33), and illness (n = 64). The remaining
2,755 women were invited to participate, and of these,
2,319 (84%) agreed to take part. Two researchers
independently abstracted information on tumor site,
histologic subtype, and tumor behavior (invasive versus
borderline) from the diagnostic histopathology reports,
and discrepancies were resolved by consensus. For a
sample of 87 women, the pathology reports and full set of
diagnostic slides were reviewed by a gynecologic
pathologist and the agreement with the original abstracted data was >97% for tumor site, behavior, and subtype.
Following the histopathology review, 624 women were
excluded because their final diagnosis was not confirmed
as epithelial ovarian cancer, and 10 because their cancer
was diagnosed before the start of the study period. Of the
final 1,685 eligible participants, 1,580 (94%) returned a
questionnaire.
Controls were randomly selected from the national
electoral roll and were frequency matched by age (in
5-year age bands) and state of residence to the case
group. Selected women were mailed an invitation letter
and information brochure explaining the study and then,
where possible, followed up by telephone. At least five
attempts were made to reach each woman; those who did
not have a listed telephone number were mailed a second
invitation letter. Of the 3,600 women contacted and
invited to participate, 158 were unable to complete the
questionnaire due to illness (n = 61) or language
difficulties (n = 97). Of the 3,442 remaining women,
1,612 (47%) agreed to participate and returned a
completed questionnaire. Six of them reported a history
of ovarian cancer and 97 reported a previous bilateral
oophorectomy and thus were excluded from the present
study, leaving 1,509 population controls.
The study was approved by the ethics committees of
the Queensland Institute of Medical Research, Peter
MacCallum Cancer Centre, and all participating hospitals and cancer registries.
Exposure Measurement. Information was collected
using a self-administered questionnaire, which included
questions about demographic, medical, hormonal, reproductive, diet, family history, and other potential risk
factors. Exposures were assessed before a reference date,
defined as 1 year before the date of diagnosis (or date of
first approach for controls), because it was felt that more
recent exposures in cases could be influenced by the
presence of subclinical disease. Recreational physical
activity was assessed using two questions. First, women
were asked, for different age periods (ages 10-19, 20-29,
30-49, and 50-79 years), how often they engaged in
strenuous physical activity (i.e., ‘‘activity that made you
puff heavily, e.g., running, aerobics, and sports at a
competitive level such as tennis, swimming laps,
squash’’) for at least 20 min in their leisure time (never,
less than once a month, less than once a week, once a
week, 2-3 times per week, 4+ times per week). They were
asked the same question about moderate physical
activity (e.g., brisk walking, heavy gardening, sports at
a social level such as tennis, golf, and cricket). These
questions incorporate the ‘‘frequency’’ and ‘‘intensity’’
components of physical activity measured by the
‘‘Historical Leisure Activity Questionnaire’’ developed
and validated by Kriska (21) and were validated in
the Iowa Women’s Health Study Cohort (22, 23). We
examined responses to these two questions individually,
and for comparability with other studies, we also
combined them to form a three-level physical activity
index (PAI; low, moderate, and high) based on frequency
and intensity of activity (23). The ‘‘high’’ category included women who participated in strenuous activity 2+
times per week or moderate activity 4+ times per week.
The ‘‘medium’’ category included women who participated in strenuous activity once per week or moderate
activity one to three times per week. The ‘‘low’’ category
comprised the remaining women (participating in
strenuous or moderate activity less than once per week).
Physical activity data were incomplete for 99 cases and
35 controls who self-completed an abbreviated form of
the questionnaire, which did not include questions about
lifetime physical activity. These women were excluded
from the analyses.
Statistical Analysis. Unconditional logistic regression
was used to estimate the odds ratios (OR) and 95%
confidence intervals (95% CI) for the association between
physical activity and ovarian cancer risk. Multivariable
logistic models were used to adjust for potential
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confounders, including age at diagnosis/first approach
(in 10 year age-groups as this gave the most efficient
control for confounding by age), education (secondary
school, technical college/apprenticeship, university),
parity (0, 1-2, z3 full-term births), hormonal contraceptive use (none, <60 months, z60 months), and body mass
index (BMI). BMI was classified using the WHO
definitions of obesity: <18.5 kg/m2, ‘‘underweight’’;
18.5 to 24.9 kg/m2, ‘‘normal weight’’; 25 to 29.9 kg/m2,
‘‘overweight’’; and z30 kg/m2, ‘‘obese’’ (24). Other
potential confounders that were considered for all
analyses but not included in the final models because
they did not substantially alter risk estimates were
smoking (current, former, never), total energy intake
(quartiles), perineal talc use, history of hysterectomy or
tubal sterilization, menopausal status, use of hormone
replacement therapy, family history of breast or ovarian
cancer in a first-degree relative, breast-feeding, and state
of residence. Tests for linear trend were done using the
maximum likelihood test with the categorical variable of
interest entered as a continuous term.
We conducted analyses for invasive and borderline
tumors first for all histologic subtypes combined, and
then separately by subtype. We also examined the
association with recent physical activity stratified by
recent BMI and that with activity at age 20 to 29 years
stratified by BMI at age 20 years (using WHO-defined
categories of BMI). We conducted subgroup analysis to
assess the interaction between menopausal status and all
measures of recent physical activity (moderate, strenuous PAI). We defined ‘‘recent’’ physical activity as that
occurring in the time period that included the woman’s
age at the reference date. The statistical significance of
any observed stratum-specific differences was assessed
by including a cross-product term in regression models.
We classified women as postmenopausal if they reported
natural or medical menopause before the reference date.
Women for whom menopausal status could not be
determined were excluded from this stratified analysis.
All statistical analyses were done using SAS version 9.1
(SAS Institute, Inc.).
Systematic Review and Meta-analysis
Selection of Studies. Eligible studies were identified
using PubMed software to search Medline (U.S. National
Library of Medicine, Bethesda, MD) for relevant articles
from 1950 to February 2007 and by hand-searching the
reference lists of the retrieved articles. For computer
searches, we used the following MeSH terms or text
words: ‘‘physical activity’’, ‘‘exercise’’, ‘‘activity’’, or
‘‘recreational physical activity’’, combined with ‘‘ovarian
cancer’’, ‘‘ovarian malignancy’’, or ‘‘ovarian neoplasm’’.
Studies that had been commonly cited in the literature
were also included as citation search terms in the ISI
Science Citation Index (1990-present) to identify other
studies that had referenced them. The search was not
limited to studies published in English.
We read the abstracts of all identified studies to exclude
those that were clearly not relevant. The full texts of the
remaining articles were read to determine if they met
the study inclusion criteria. Where multiple reports from
one study were found, the most recent or most complete
publication was used. Studies were included in the systematic review if they were a case-control or cohort study
that permitted assessment of the association between
physical activity (recreational/occupational/sedentary
behavior) and histologically confirmed ovarian cancer.
Studies that permitted quantitative assessment of an
association between recreational physical activity and
ovarian cancer were included in the meta-analysis.
The following information was recorded for each
study: study type, years of data collection (case-control
studies), duration of follow-up (cohort studies), age
range of participants, country, variables for which
statistical adjustment was done, number of cases and
controls or person years, definitions and categories of
physical activity exposures, point estimates [relative risk
(RR), OR, or standardized incidence ratio], and 95% CIs.
We included studies reporting the different measures of
RR because ovarian cancer is a rare disease, and in such
instances ORs and standardized incidence ratios provide
a valid estimate of the RR. Where several risk estimates
were presented, we used those adjusted for the greatest
number of potential confounders. Where risk estimates
for physical activity at different time periods were
presented, we used the most recent period for casecontrol studies and either baseline measurements or
cumulative averages, if available, for the cohort studies.
Table 1. Descriptive characteristics of 1,580 women
with epithelial ovarian cancer and 1,509 randomly
selected population-based controls
Variable
Controls*
(n = 1,509),
n (%)
Cases*
(n = 1,580),
n (%)
P
c
Age (y)
<30
42 (3)
35 (2)
30-39
112 (7)
86 (5)
40-49
278 (18)
260 (16)
50-59
452 (30)
484 (31)
60-69
399 (26)
461 (29)
70+
226 (15)
254 (16)
0.07
Highest level of education
High school
741 (49)
864 (55)
Technical college/
550 (36)
502 (32)
trade certificate
University
218 (14)
214 (14)
0.007
No. pregnancies (z6 mo)
Nulliparous
181 (12)
298 (19)
1-2
644 (43)
649 (41)
z3
684 (45)
630 (40)
<0.0001
Ever use of oral contraceptives
No
330 (22)
506 (32)
V5 y
361 (24)
434 (28)
>5 y
811 (54)
620 (40)
<0.0001
History of hysterectomy
Yes
289 (19)
364 (23)
No
1,204 (81)
1,207 (77)
0.02
History of tubal sterilization
Yes
406 (27)
357 (23)
No
1,084 (72)
1,215 (77)
0.001
Ever use of talc in the perineal area
Yes
668 (45)
761 (49)
No
824 (55)
805 (51)
0.03
History of breast or ovarian cancer in a first-degree relative
Yes
195 (13)
272 (17)
No
1,314 (87)
1,308 (83)
0.0009
BMI 1 y ago
<25
664 (46)
608 (43)
25-29.9
435 (30)
470 (33)
z30
334 (23)
346 (24)
0.26
*Numbers may not sum to total because of missing data.
cm2 test for heterogeneity.
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Recreational Physical Activity and Ovarian Cancer
Statistical Methods. To pool RR estimates for the
highest category of recreational physical activity compared with the lowest, a weighted average of the log RR
was estimated, taking into account the random effects
using the method of DerSimonian and Laird (25). We
assessed heterogeneity for each pooled estimate with a
Cochran’s Q test for heterogeneity. We also conducted
separate analyses by study type. Finally, we conducted
sensitivity analyses, omitting each study in turn to
determine whether the results could have been influenced excessively by a single study. We evaluated
publication bias by qualitatively assessing a funnel plot
of the natural logarithms of the effect estimates for the
risk of ovarian cancer related to recreational physical
activity against their variance (26).
Results
Case-Control Study. Based on the histopathology
review, 1,269 women had invasive cancer classified as
follows: serous, 846 (67%); endometrioid, 138 (11%); clear
cell, 88 (7%); mucinous, 44 (3%); and mixed histopathology, 153 (12%). A further 311 women had borderline
(low malignant potential) tumors classified as follows:
serous, 152 (49%); mucinous, 147 (47%); endometrioid,
3 (1%); and mixed, 9 (3%). This distribution is consistent
with previous studies (14, 27, 28). Cases were significantly older than controls (mean age: cases, 57.9 years;
controls, 56.4 years; P = 0.001) and were less likely to
have continued their education beyond high school. As
expected, cases were more likely to be nulliparous and to
report a history of breast or ovarian cancer in a firstdegree relative, but were less likely to have ever used
oral contraceptives (Table 1).
Table 2 presents the ORs for invasive and borderline
ovarian cancer associated with recent recreational activity, both moderate and strenuous, together with recent
PAI and PAI at different ages. Compared with women in
the lowest categories of recent moderate or strenuous
physical activity and PAI, the multivariable-adjusted
ORs (and 95% CIs) for the highest category of activity
were 0.8 (0.6-1.1) for moderate activity, 1.0 (0.8-1.4) for
Table 2. Multivariable-adjusted ORs and 95% CIs of epithelial ovarian cancer with different levels of recreational
physical activity, by tumor invasiveness
Physical activity measure
Controls* (n = 1,509)
Invasive
Cases* (n = 1,269)
Recent moderate physical activity
0-<1/mo
<1-1/wk
2-3/wk
4+/wk
Borderline
c
OR
(95% CI)
Cases* (n = 311)
c
OR
(95% CI)
b
177
426
459
398
176
326
366
317
1.0
0.8 (0.6-1.1)
0.8 (0.6-1.1)
0.8 (0.6-1.1)
P trend = 0.30
36
88
93
70
1.0
0.9 (0.5-1.3)
0.9 (0.6-1.3)
0.8 (0.5-1.4)
P trend = 0.64
613
474
256
130
557
323
203
106
1.0
0.9 (0.7-1.0)
1.0 (0.8-1.2)
1.0 (0.8-1.4)
P trend = 0.93
113
105
47
23
1.0
1.0 (0.7-1.4)
0.8 (0.6-1.2)
0.9 (0.5-1.5)
P trend = 0.37
308
554
611
274
439
478
60
118
110
PAI ages 10-19 yk
Low
Medium
High
1.0
0.9 (0.7-1.1)
0.9 (0.7-1.1)
P trend = 0.41
1.0
1.0 (0.7-1.4)
0.9 (0.6-1.2)
P trend = 0.34
258
400
802
214
331
645
42
97
149
PAI ages 20-29 yk
Low
Medium
High
1.0
1.0 (0.8-1.3)
1.0 (0.8-1.3)
P trend = 0.83
1.0
1.6 (1.0-2.4)
1.1 (0.7-1.6)
P trend = 0.69
242
576
641
242
453
494
1.0
0.9 (0.7-1.1)
0.9 (0.7-1.1)
P trend = 0.23
55
116
115
1.0
0.8 (0.6-1.2)
0.7 (0.5-1.0)
P trend = 0.04
232
598
593
240
447
495
1.0
0.7 (0.6-0.9)
0.8 (0.6-1.0)
P trend = 0.19
52
108
106
1.0
0.8 (0.5-1.1)
0.7 (0.5-1.1)
P trend = 0.13
241
381
432
227
364
388
1.0
1.0 (0.8-1.2)
0.9 (0.7-1.2)
P trend = 0.50
38
54
58
1.0
0.8 (0.5-1.3)
0.8 (0.5-1.2)
P trend = 0.24
b
Recent strenuous physical activity
0-<1/mo
<1-1/wk
2-3/wk
4+/wk
Recent PAIx,
Low
Medium
High
b
b
PAI ages 30-49 y
Low
Medium
High
b
PAI ages 50-79 y
Low
Medium
High
*Numbers may not sum to total because of missing data; age-specific PAIs are restricted to those participants who attained the relevant ages.
cAdjusted for age, education, parity, and hormonal contraceptive use.
bAdditionally adjusted for BMI 1 y ago.
xPAI based on frequency and intensity.
kAdditionally adjusted for BMI at age 20 y.
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Cancer Epidemiology, Biomarkers & Prevention
Table 3. Multivariable-adjusted ORs and 95% CIs of epithelial ovarian cancer with different levels of recent
recreational physical activity, by histologic subtype and tumor invasiveness
Recent PAI*
c
Controls
(n = 1,509)
Invasive histologies
Borderline histologies
Serous
(n = 846)
Endometrioid
(n = 138)
Clear Cell
(n = 88)
1.0 (reference)
0.9 (0.7-1.2)
0.9 (0.7-1.1)
P trend = 0.24
1.0 (reference)
0.6 (0.4-1.1)
0.8 (0.5-1.3)
P trend = 0.66
1.0 (reference)
1.1 (0.6-2.2)
1.0 (0.5-2.0)
P trend = 0.96
Mucinous
(n = 44)
Serous
(n = 152)
Mucinous
(n = 147)
1.0 (reference)
0.7 (0.5-1.2)
0.7 (0.5-1.2)
P trend = 0.28
1.0 (reference)
1.4 (0.8-2.3)
1.0 (0.6-1.8)
P trend = 0.80
OR (95% CI)
Low
Medium
High
308
554
611
1.0 (reference)
0.8 (0.3-2.0)
1.1 (0.4-2.5)
P trend = 0.17
NOTE: Data adjusted for age, education, parity, hormonal contraceptive use, and BMI 1 y ago.
*PAI based on frequency and intensity.
cNumbers may not sum to total because of missing data.
strenuous activity, and 0.9 (0.7-1.1) for PAI for invasive
tumors. Inclusion of both strenuous and moderate
activity in the same model made no material difference
to the results. Results were similar for borderline tumors.
Similarly, associations with PAI at different ages were
mostly weakly inverse or null.
Overall, the relationship between recreational physical
activity and risk of ovarian cancer did not differ
substantially for the different histologic subtypes, although moderate levels of recent PAI were associated
with a nonsignificant increased risk of mucinous borderline tumors (OR, 1.4; 95% CI, 0.8-2.3) and a reduced risk
of invasive endometrioid tumors (OR, 0.6; 95% CI,
0.4-1.1; Table 3). The relationship of recent physical
activity (moderate, strenuous, PAI) and physical activity
at age 20 to 29 years (PAI) with ovarian cancer risk
did not differ materially for women in different WHO
categories of BMI (data not presented). We found no
effect modification by menopausal status.
Systematic Review and Meta-analysis. The primary
computerized literature search identified 129 potentially
relevant studies. After review of the study abstracts, we
retrieved 20 articles for further assessment, of which 7
reports of cohort studies (18, 22, 27, 29-32) and 9 from
case-control studies (15-17, 33-39) met the criteria for
inclusion in the systematic review. Of these, 12 studies
were restricted to epithelial ovarian cancer and the
other 4 included predominantly epithelial ovarian
cancers.
Recreational Activity. Twelve of the 16 studies
assessed recreational physical activity [six case-control
studies (15-17, 34-36) and six cohort studies (18, 22, 27,
29, 30, 32)] and all presented risk estimates permitting
meta-analysis together with the results of the current
study. These studies are summarized in Table 4. One of
the cohort studies (32) used ‘‘moderate’’ rather than
‘‘low’’ as the reference category; however, there was very
little difference in risk between the low and moderate
categories in this study, and thus the OR for high versus
moderate was included in the meta-analysis.
For all studies, the pooled RR of ovarian cancer in
women in the highest category of recreational physical
activity compared with those in the lowest category
was 0.81 (95% CI, 0.72-0.92) with significant heterogeneity (P = 0.03; Fig. 1). After stratifying by study design, the
pooled RRs were 0.79 (95% CI, 0.70-0.85) for case-control
studies and 0.81 (95% CI, 0.57-1.17) for cohort studies.
Heterogeneity was evident among the cohort studies
(P = 0.004) due almost entirely to the outlying result of
Anderson et al. (22). Excluding this study gave a pooled
RR of 0.72 (95% CI, 0.53-0.98) with no significant
heterogeneity (P = 0.14). We observed no heterogeneity
among the case-control studies (P = 0.70), with pooled
RRs ranging from 0.71 to 0.84 after omitting individual
studies. All studies adjusted for age and parity and most
also adjusted for oral contraceptive use and BMI.
Excluding studies that did not adjust for oral contraceptive use (15, 22, 30, 34) and BMI (18, 22, 30, 32) resulted in
pooled estimates of 0.83 (95% CI, 0.80-0.86) and 0.81 (95%
CI, 0.76-0.86), respectively, with no significant heterogeneity. The funnel plot of the effect estimates for the risk of
ovarian cancer related to recreational physical activity
was close to symmetrical, suggesting that there was no
appreciable publication bias.
Several case-control (15, 17, 34, 36) and cohort studies
(18, 27, 29, 31, 32), as well as the current study, assessed
the effect of recreational physical activity stratified by
BMI. Two case-control studies (15, 36) observed larger
risk reductions with higher levels of activity for obese
women. In contrast, all other studies including our own
found no significant effect modification of the relationship between physical activity and ovarian cancer risk
by BMI.
Vigorous Activity. Four cohort studies (18, 22, 30, 32)
and three additional case-control studies (15, 34, 37)
reported on ‘‘vigorous’’ recreational activity and risk of
ovarian cancer. Two of these, one case-control (37) and
one cohort (30), reported significant inverse associations
with vigorous physical activity. One cohort study (22)
reported a significant positive association, whereas the
other four studies, like ours, found no significant
association (15, 18, 32, 34). One of the case-control
studies and one additional study also found no significant relationship with vigorous occupational activity
(37) or total (recreational and occupational) vigorous
activity (31).
Sedentary Behavior. Two case-control studies (33, 38)
and one cohort study (27) reported the results of analyses
of sedentary behavior, based on duration of sitting,
and risk of ovarian cancer. Patel et al. (27) reported a
significantly increased risk for the highest category of
hours of sitting per day and Zhang et al. (33) reported a
nonsignificant increased risk, whereas Dosemeci et al.
(38) reported a nonsignificant inverse association.
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Table 4. Summary of published results on recreational physical activity and risk of epithelial ovarian cancer
Study
Age range,
(reference
years)
Cohort studies
Weiderpass
30-49
et al. (32)
(1990-2002)
Biesma
et al. (29)
Geographic
location
No. cases/
noncases
Type of
measurement
Exposure
level
OR/RR
(95% CI)
Adjustment
Norway,
Sweden
Cases: 264
(183 INV,
81 BL)
Cohort:
96,541
At enrollment
None
Low
Moderate
High
Vigorous
1.0
0.9
1.0
1.0
(0.5-1.7)
(0.6-1.3)
(reference)
(0.6-1.7)
Age at baseline,
height, years of
education,
smoking status,
years of smoking,
parity, alcohol
intake, age at first
birth, HRT use,
breast-feeding
(duration),
menopausal
status, OC use
(and duration),
age at menopause
55-69
(1986-1997)
The
Netherlands
Cases:
252 INV
Cohort:
62,573
Baseline
(min/d)
<30
30-<60
60-90
>90
1.0
0.8
0.9
0.7
(reference)
(0.6-1.1)
(0.6-1.2)
(0.5-1.1)
Age at baseline,
height, parity,
OC use, age at
first birth, BMI
Patel
Mean 62.7
et al. (27) (1992-2001)
United States
Cases:
314 INV
Cohort:
59,695
post-M
Baseline
(MET-h/wk)
None
>0-<8
8-<17.5
17.5-<31.5
z31.5
1.0
0.9
1.0
1.0
0.7
(reference)
(0.6-1.3)
(0.7-1.5)
(0.7-1.6)
(0.4-1.3)
Age, race, BMI, family
history of breast or
ovarian cancer, age
at menopause,
age at menarche,
OC use, parity,
hysterectomy,
HRT use
Schnohr
et al. (30)
20-91
(1984-1998)
Denmark
Cases:
107 INV
Cohort:
13,216
post-M
Baseline
Low
1.0 (reference)
Moderate 0.7 (0.5-1.1)
Vigorous 0.3 (0.2-0.7)
Age, birth
cohort, smoking,
education, alcohol
consumption, parity
Anderson
et al. (22)
55-69
(1986-2000)
United States
(Iowa)
Cases:
223 INV
Cohort:
41,836
PAI*
Low
1.0 (reference)
Moderate 1.1 (0.8-1.6)
High
1.4 (1.0-2.0)
Age, family history
of ovarian cancer,
parity, hysterectomy
status, oophorectomy
status, estrogen
replacement
therapy, smoking
(pack-years)
Bertone
et al. (18)
30-55
(1980-1996)
United States
Cases: 377
(338 INV,
39 BL)
Cohort:
92,825
Cumulative
average
(1980-1996),
h/wk
1
1-<2
2-<4
4-<7
1.0
0.8
0.9
1.1
Age, parity, OC use,
tubal ligation, age
at menarche,
menopausal status,
postmenopausal
hormone use,
smoking status
Canada
Cases:
442 INV
Controls:
2,135
MET
units/wk,
total
<11.6
11.6-34.6
z34.6
1.0 (reference)
0.9 (0.7-1.2)
0.7 (0.6-1.0)
Age, province of
residence, education,
alcohol consumption,
cigarette pack-years,
BMI, total calorie
intake, no. of live
births, vegetable
consumption,
menopause
Sweden
Cases:
655 INV
Controls:
3,899
1 y ago
Never
<1 hr/wk
1-2 h/wk
>2 h/wk
1.0
0.8
0.8
0.7
Age, parity, BMI,
age at menopause,
duration of OC use,
ever use of HRT
Case-control studies
Population based
Pan
20-76
et al. (15) (1994-1997)
Riman
et al.
(16)
50-74
(1993-1995)
(reference)
(0.6-1.1)
(0.7-1.2)
(0.8-1.5)
(reference)
(0.6-1.2)
(0.5-1.2)
(0.5-1.1)
(Continued on the following page)
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Cancer Epidemiology, Biomarkers & Prevention
Table 4. Summary of published results on recreational physical activity and risk of epithelial ovarian cancer (Cont’d)
Study
Age range,
(reference
years)
Geographic
location
No. cases/
Type of
noncases measurement
Exposure
level
OR/RR
(95% CI)
Adjustment
Bertone
et al.
(34)
40-79
(1991-1994)
United States
Cases:
(Wisconsin,
327 INV
Massachusetts) Controls:
3,129
MET-hr/wk,
5 y before
diagnosis
0
0-7
7-14
14-28
28-42
>42
Cottreau
et al.
(35)
20-69
(1994-1998)
United States
(Pennsylvania,
New Jersey,
Delaware)
Cases: 767
(616 INV,
151 BL)
Controls:
1,367
Lifetime
Low
1.0 (reference) Age, parity, OC use, tubal
Moderate 0.9 (0.7-1.1)
ligation, BMI, family
High
0.7 (0.6-0.9)
history of ovarian
cancer, education, race
Bain
et al.
(36)
18-79
(1990-1993)
Australia
Cases: 203
(166 INV,
37 BL)
Controls:
265
Regular
exercise that
raised a
sweat
No
Yes
18-79
(1992-1999)
Italy
Cases:
1,031 INV
Age 30-39 y,
3 levels
(lowest is
reference)
Hospital
based
Tavani
et al.
(17)
1
2
3
1.0
1.2
1.1
1.2
1.0
0.7
(reference) Age, state, parity, tubal
(0.8-1.8)
ligation, lutein/
(0.7-1.6)
zeaxanthin intake,
(0.8-1.6)
no. of pelvic exams
(0.5-1.7)
(last 5 y), family
(0.4-1.4)
history of ovarian cancer
1.0 (reference) Age, OC use, parity,
0.8 (0.5-1.1)
kilojoules, hysterectomy,
tubal ligation, smoking,
state, BMI
1.0 (reference) Age, year of interview,
0.8 (0.7-1.0)
education, BMI, study
0.9 (0.7-1.1)
center, parity, menopausal
status, family history of
breast or ovarian cancer,
OC use, calorie intake
Abbreviations: INV, invasive; BL, borderline; post-Me postmenopausal; OC, oral contraceptive; HRT, hormone replacement.therapy.
*PAI based on frequency and intensity.
Occupational Activity. Five case-control studies (15,
17, 37-39) and one cohort study (27) presented results
for nonrecreational or occupational physical activity.
Whereas the cohort study (27) and two case-control
studies (15, 37) found no relationship with risk of
ovarian cancer, the other three reported modest inverse
associations with higher levels of occupational physical
activity (17, 38, 39).
Timing of Activity. A further five case-control (15-17,
34, 35) and three cohort studies (18, 27, 32) have
examined whether there are critical exposure periods in
which physical activity may influence ovarian cancer
risk. Although caution must be taken in interpreting
these studies due to the use of different age-categories/
time periods of measurement, these studies did not find
differential effects of physical activity on ovarian cancer
risk across time, showing either protective (15-17, 32, 35)
or null effects (18, 27, 34) across all time/age periods.
Histologic Subtypes. The current study, three other
case-control studies (15-17) and two cohort studies
(18, 19) have reported on the effects of physical activity
separately for the different histologic subtypes of ovarian
cancer. Generally, there were no notable differences
between the subtypes, although there was a suggestion
in two previous case-control studies and the present
study that effects might differ for mucinous tumors
(15, 16). Pan et al. (15) observed inverse associations for
moderate activity for all subtypes except mucinous; they
also observed an increased risk of mucinous tumors associated with high levels of vigorous activity. Riman et al.
(16) found protective effects for recreational physical
activity for all subtypes during all ages except for activity
during the ages of 18 to 30 years and mucinous tumors.
The present study observed a nonsignificant increased
risk of mucinous borderline tumors associated with
medium levels of recreational physical activity (Table 3).
Discussion
Overall, the findings of our population-based casecontrol study point to a null or, at most, weakly inverse
association between recreational physical activity and
risk of epithelial ovarian cancer. Our meta-analysis,
however, shows a consistent and significant pattern of
weak to modest inverse associations between recreational physical activity and epithelial ovarian cancer risk
despite the variation in populations, study design, and
adjustment in analyses. Heterogeneity among studies
was due to a single cohort study (22); this was similar in
design and conduct to the other cohort studies, although
it lacked adjustment for oral contraceptive use or BMI. It
was also apparent graphically (Fig. 1) that a number of
studies suffered from a lack of power to detect modest
effects and were unable to exclude chance as an
explanation for their findings when considered in
isolation. These studies, however, revealed a consistent
pattern of decreased risk associated with higher levels of
recreational physical activity, leading to a summary
effect estimate of 0.81 (95% CI, 0.72-0.92). These
observations underline the importance of considering
new data carefully in the context of all previous findings
whenever possible. Overall, the evidence was less
consistent for occupational activity, vigorous activity,
and sedentary behavior, and fewer studies had examined these measures. Although it has been suggested
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Recreational Physical Activity and Ovarian Cancer
Figure 1. Forest plot of the association between recreational
physical activity and ovarian cancer using a random-effects
model. Each line represents an individual study result with the
width of the horizontal line indicating the 95% CI, the position
of the box representing the point estimate, and the size of the
box being proportional to the weight of the study. All casecontrol studies are population based with the exception of the
study by Tavani et al. (17).
that there may be critical time periods throughout a
woman’s life where physical activity may have the most
effect on ovarian cancer risk (18), our study and the
findings of others do not point to a differential effect
across time.
Possible limitations of the meta-analysis include
potential residual confounding of the associations due
to different degrees of control for confounding variables
in different studies. All studies, however, adjusted for
important confounding factors such as age and parity,
and most also adjusted for oral contraceptive use and
BMI. Given that there was no material difference in the
summary estimate when the studies that did not control
for these latter characteristics were excluded, we are
confident that the observed relationship between recreational physical activity and risk of ovarian cancer
was not influenced by these factors. Second, the studies
contributing to the summary estimates were vulnerable
to various types of bias. The majority relied on selfreports of physical activity, which are prone to
overestimation, particularly by overweight and obese
subjects (40). This could have resulted in nondifferential
misclassification, which may have led to underestimation of the true association between recreational
physical activity and ovarian cancer. Differential misclassification was also a possibility in the case-control
studies, but this is unlikely because cases would not
readily associate their levels of physical activity with
their cancer. Selection bias due to self-selection of more
health-conscious control women, who are more likely to
be physically active, also needs to be considered, but the
consistency of results from the case-control and cohort
studies suggests that such a bias is unlikely. Third,
publication bias is always possible, and we searched
only indexed journals. The funnel plot of the effect
estimates for the risk of ovarian cancer related to
recreational activity, however, was close to symmetrical,
suggesting that there was no appreciable publication
bias, and in general positive findings are more likely to
be reported than otherwise (41). Thus, on balance, we
believe that our systematic review provides a reasonably valid summary of the available evidence.
Strengths of the current study include the populationbased design, large number of cases, and detailed
information on multiple exposures. A limitation was
the relatively low participation rate among controls
(47%); however, the consistency of our findings with
previous research on physical activity and ovarian cancer
suggests that it is unlikely that nonresponse could have
biased the results appreciably. A comparison with
statistics from the Australian National Health Survey
conducted in 2004 (a representative survey of the
Australian adult population) revealed that the distributions of education level, parity, and BMI among our
control women were almost identical to those from the
National Health Survey;3 however, physical activity was
more difficult to compare due to differences in the
assessment of activity levels.
There are several biological mechanisms whereby
physical activity could reduce the risk of ovarian cancer,
and these include alterations in endogenous sex hormone
levels (estrogen, progesterone, and androgens), suppression of ovulation, insulin-mediated pathways, and
maintenance of energy balance (1). Regular physical activity has been shown to lower the levels of biologically
available estrogens, progesterone, and androgens (42-46)
and increase levels of circulating sex hormone binding
protein (47). There is a significant body of evidence
suggesting that androgens may increase ovarian cancer
risk whereas progesterone plays a protective role (6).
Regular strenuous physical activity can increase the
probability of anovulation and amenorrhea (9), which
may offer protection according to the ‘‘incessant ovulation’’ hypothesis (10). Regular physical activity also
significantly lowers insulin levels and enhances insulin
sensitivity, independently of BMI (48-50), and insulin
increases the bioactivity of insulin-like growth factor I
(51, 52). Lukanova et al. (53) found a strong direct
relationship between circulating insulin-like growth
factor I levels and risk of developing ovarian cancer
before age 55 years, and high levels of insulin-like
growth factor I have been associated with other
hormone-related cancers: prostate and breast cancers
(54, 55).
Regular physical activity also helps prevent or reduce
obesity with consequent improvement in the metabolic
profile (endogenous hormone and growth factor levels)
3
N. Pandeya, personal communication.
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Cancer Epidemiology, Biomarkers & Prevention
(1). A recent meta-analysis concluded that obesity is a
modest but significant risk factor for ovarian cancer (56).
Physical activity may also influence carcinogenesis
through alterations in immune system functioning (12),
a reduction in chronic inflammation (7, 8), or other
associated lifestyle factors (57).
In summary, our meta-analysis points to a consistent,
albeit weak, inverse relationship between recreational
physical activity and the occurrence of epithelial ovarian
cancer. The cohort data indicate that the relation does
indeed refer to activity that precedes the origins of the
cancers, and there are a number of biologically plausible
pathways that may underlie a protective effect of higher
levels of activity. There are also analogies with stronger
findings for other hormonal tumors. Hence, it is
reasonable to speculate that the observed effect could
be causal. In contrast to many known risk factors for
ovarian cancer, physical activity is potentially a more
modifiable behavior. This therefore potentially offers
women an opportunity to reduce their risk of ovarian
cancer in addition to the numerous other chronic
diseases associated with low physical activity.
Hospital for Women); D. Healy, T. Jobling, T. Maniolitas,
J. McNealage, P. Rogers, B. Susil, A. Veitch, J. Constable, S. Ping
Tong, I. Robinson, I. Simpson (Monash Medical Centre); K.
Phillips, D. Rischin, P. Waring, M. Loughrey, N. O’Callaghan,
Bill Murray (PMCC); V. Billson, S. Galloway, J. Pyman,
M. Quinn (Royal Women’s Hospital); Western Australia—I.
Hammond, A. McCartney, Y. Leung (King Edward Memorial
Hospital, St John of God). Scientific Collaborators: I. Haviv
(PMCC); D. Purdie, D. Whiteman (QIMR); N. Zeps (WARTN).
The Australian Cancer Study Group investigators are A.C.
Green, P.G. Parsons, N. Hayward, P. Webb, D. Purdie, and
D. Whiteman (QIMR).
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Acknowledgments
We thank the New South Wales, Queensland, South Australian,
Victorian and Western Australian Cancer Registries as well as all
the collaborating institutions represented within the Australian
Ovarian Cancer Study Group (below). We also thank all of the
women who participated in the study.
The Australian Ovarian Cancer Study Group. Management
Group: D. Bowtell [Peter MacCallum Cancer Centre (PMCC)], G.
Chenevix-Trench, A. Green, P. Webb [Queensland Institute of
Medical Research (QIMR)], A. deFazio (Westmead Hospital), D.
Gertig (University of Melbourne). Project Managers: N. Traficante
(PMCC), S. Moore (QIMR), J. Hung (Westmead Hospital).
Data Managers: S. Fereday (PMCC), K. Harrap, T. Sadkowsky
(QIMR). Research Nurses: New South Wales—A. Mellon, R.
Robertson (John Hunter Hospital), T. Vanden Bergh (Royal
Hospital for Women), J. Maidens (Royal North Shore Hospital),
K. Nattress (Royal Prince Alfred Hospital), Y.E. Chiew, A.
Stenlake, H. Sullivan (Westmead Hospital); Queensland—
B. Alexander, P. Ashover, S. Brown, T. Corrish, L. Green, L.
Jackman, K. Martin, B. Ranieri (QIMR); South Australia—J.
White (QIMR); Tasmania—V. Jayde (Royal Hobart Hospital);
Victoria—L. Bowes (PMCC), P. Mamers (Monash Medical
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H. Tran, S. Bilic, L. Glavinas [Western Australia Research Tissue
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A. Proietto, S. Braye, G. Otton (John Hunter Hospital);
T. Bonaventura, J. Stewart (Newcastle Mater Misericordiae); M.
Friedlander (Prince of Wales Hospital); D. Bell, S. Baron-Hay, A.
Ferrier, G. Gard, D. Nevell, B. Young (until mid-2003; Royal North
Shore Hospital); C. Camaris, R. Crouch, L. Edwards, N. Hacker,
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