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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. Updated version Access the most recent version of this article at: http://cebp.aacrjournals.org/content/16/11/2321 Cited Articles This article cites by 55 articles, 13 of which you can access for free at: http://cebp.aacrjournals.org/content/16/11/2321.full.html#ref-list-1 Citing articles This article has been cited by 14 HighWire-hosted articles. Access the articles at: http://cebp.aacrjournals.org/content/16/11/2321.full.html#related-urls E-mail alerts Reprints and Subscriptions Permissions Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected]. Downloaded from cebp.aacrjournals.org on March 25, 2014. © 2007 American Association for Cancer Research. 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 Cancer Epidemiol Biomarkers Prev 2007;16(11). November 2007 Downloaded from cebp.aacrjournals.org on March 25, 2014. © 2007 American Association for Cancer Research. 2322 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 Cancer Epidemiol Biomarkers Prev 2007;16(11). November 2007 Downloaded from cebp.aacrjournals.org on March 25, 2014. © 2007 American Association for Cancer Research. Cancer Epidemiology, Biomarkers & Prevention 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. Cancer Epidemiol Biomarkers Prev 2007;16(11). November 2007 Downloaded from cebp.aacrjournals.org on March 25, 2014. © 2007 American Association for Cancer Research. 2323 2324 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. Cancer Epidemiol Biomarkers Prev 2007;16(11). November 2007 Downloaded from cebp.aacrjournals.org on March 25, 2014. © 2007 American Association for Cancer Research. 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. Cancer Epidemiol Biomarkers Prev 2007;16(11). November 2007 Downloaded from cebp.aacrjournals.org on March 25, 2014. © 2007 American Association for Cancer Research. 2325 2326 Recreational Physical Activity and Ovarian Cancer 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) Cancer Epidemiol Biomarkers Prev 2007;16(11). November 2007 Downloaded from cebp.aacrjournals.org on March 25, 2014. © 2007 American Association for Cancer Research. 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 Cancer Epidemiol Biomarkers Prev 2007;16(11). November 2007 Downloaded from cebp.aacrjournals.org on March 25, 2014. © 2007 American Association for Cancer Research. 2327 2328 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. Cancer Epidemiol Biomarkers Prev 2007;16(11). November 2007 Downloaded from cebp.aacrjournals.org on March 25, 2014. © 2007 American Association for Cancer Research. 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). References 1. 2. 3. 4. 5. 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 Centre); Western Australia—T. Schmidt, H. Shirley, S. Viduka, H. Tran, S. Bilic, L. Glavinas [Western Australia Research Tissue Network (WARTN)]. Clinical Collaborators: New South Wales— 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, D. Marsden, G. Robertson (Royal Hospital for Women); P. Beale, J. Beith, J. Carter, C. Dalrymple, A. Hamilton, R. Houghton, P. Russell (Royal Prince Alfred Hospital); A. Brand, R. Jaworski, P. Harnett, G. Wain (Westmead Hospital); Queensland— A. Crandon, M. Cummings, K. Horwood. A. Obermair, D. Wyld [Royal Brisbane and Women’s Hospital (RBWH)]; J. Nicklin (RBWH and Wesley Hospital), L. Perrin (RBWH and Mater Misericordiae Hospitals), B. Ward (Mater Misericordiae Hospitals); South Australia—M. Davy, C. Hall, T. Dodd, T. Healy, K. Pittman (Royal Adelaide Hospital, Burnside Memorial Hospital); D. Henderson, S. Hyde (Flinders Medical Centre); J. Miller, J. Pierdes (Queen Elizabeth Hospital); Tasmania—P. Blomfield, D. Challis, R. McIntosh, A. Parker (Royal Hobart Hospital); Victoria—B. Brown, R. Rome (Freemasons Hospital); D. Allen, P. Grant, S. Hyde, R. Laurie, M. Robbie (Mercy 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. Weight control and physical activity. In: Vainio H, Bianchini F, editors. IARC handbooks of cancer prevention. Vol. 6. Lyon: IARC Press; 2002. p. 83 – 199. Lipworth L. Epidemiology of breast cancer. Eur J Cancer Prev 1995;4: 7 – 30. Grady D, Gebretsadik T, Kerlikowske K, Ernster V, Petitti D. Hormone replacement therapy and endometrial cancer risk: a meta-analysis. Obstet Gynecol 1995;85:304 – 13. McTiernan A, Ulrich C, Slate S, Potter J. Physical activity and cancer etiology: associations and mechanisms. Cancer Causes Control 1998; 9:487 – 509. Riman T, Nilsson S, Persson IR. Review of epidemiological evidence for reproductive and hormonal factors in relation to the risk of epithelial ovarian malignancies. Acta Obstet Gynecol Scand 2004;83: 783 – 95. Risch HA. Hormonal etiology of epithelial ovarian cancer, with a hypothesis concerning the role of androgens and progesterone. J Natl Cancer Inst 1998;90:1774 – 86. Campbell KL, McTiernan A. Exercise and biomarkers for cancer prevention studies. J Nutr 2007;137:161 – 9S. Ness RB, Cottreau C. Possible role of ovarian epithelial inflammation in ovarian cancer. J Natl Cancer Inst 1999;91:1459 – 67. De Souza MJ. Menstrual disturbances in athletes: a focus on luteal phase defects. Med Sci Sports Exerc 2003;35:1553 – 63. Cannavo S, Curto L, Trimarchi F. Exercise-related female reproductive dysfunction. J Endocrinol Invest 2001;24:823 – 32. Fathalla MF. Incessant ovulation-a factor in ovarian neoplasia? Lancet 1971;2:163. Shephard RJ, Shek PN. Cancer, immune function, and physical activity. Can J Appl Physiol 1995;20:1 – 25. Purdie DM, Webb PM, Siskind V, Bain CJ, Green AC. The different etiologies of mucinous and nonmucinous epithelial ovarian cancers. Gynecol Oncol 2003;88:S145 – 8. Kurian AW, Balise RR, McGuire V, Whittemore AS. Histologic types of epithelial ovarian cancer: have they different risk factors? Gynecol Oncol 2005;96:520 – 30. Pan SY, Ugnat AM, Mao Y. Physical activity and the risk of ovarian cancer: a case-control study in Canada. Int J Cancer 2005;117:300 – 7. Riman T, Dickman PW, Nilsson S, et al. Some life-style factors and the risk of invasive epithelial ovarian cancer in Swedish women. Eur J Epidemiol 2004;19:1011 – 9. Tavani A, Gallus S, La Vecchia C, et al. Physical activity and risk of ovarian cancer: an Italian case-control study. Int J Cancer 2001;91:407 – 11. Bertone ER, Willett WC, Rosner BA, et al. Prospective study of recreational physical activity and ovarian cancer. J Natl Cancer Inst 2001;93:942 – 8. Patel AV, Rodriguez C, Jacobs EJ, et al. Recreational physical activity and risk of prostate cancer in a large cohort of U.S. men. Cancer Epidemiol Biomarkers Prev 2005;14:275 – 9. Merritt MA, Green AC, Nagle CM, Webb PM, Group A, a. A. S. Talcum powder, chronic pelvic inflammation and NSAIDs in relation to risk of epithelial ovarian cancer. Int J Cancer. 2007 Aug 23 [Epub ahead of print]. Kriska AM. Historical leisure activity questionnaire. Med Sci Sports Exerc 1997;29:43 – 5. Anderson JP, Ross JA, Folsom AR. Anthropometric variables, physical activity, and incidence of ovarian cancer: The Iowa Women’s Health Study. Cancer 2004;100:1515 – 21. Mink PJ, Folsom AR, Sellers TA, Kushi LH. Physical activity, waistto-hip ratio, and other risk factors for ovarian cancer: a follow-up study of older women. Epidemiology 1996;7:38 – 45. Physical status: the use and interpretation of anthropometry. Report of a WHO Expert Committee. World Health Organ Tech Rep Ser 1995;854:1 – 452. Cancer Epidemiol Biomarkers Prev 2007;16(11). November 2007 Downloaded from cebp.aacrjournals.org on March 25, 2014. © 2007 American Association for Cancer Research. 2329 2330 Recreational Physical Activity and Ovarian Cancer 25. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177 – 88. 26. Macaskill P, Walter SD, Irwig L. A comparison of methods to detect publication bias in meta-analysis. Stat Med 2001;20:641 – 54. 27. Patel AV, Rodriguez C, Pavluck AL, Thun MJ, Calle EE. Recreational physical activity and sedentary behavior in relation to ovarian cancer risk in a large cohort of US women. Am J Epidemiol 2006;163:709 – 16. 28. Riman T, Dickman PW, Nilsson S, et al. Risk factors for epithelial borderline ovarian tumors: results of a Swedish case-control study. Gynecol Oncol 2001;83:575 – 85. 29. Biesma RG, Schouten LJ, Dirx MJ, Goldbohm RA, van den Brandt PA. Physical activity and risk of ovarian cancer: results from the Netherlands cohort study (the Netherlands). Cancer Causes Control 2006;17:109 – 15. 30. Schnohr P, Gronbaek M, Petersen L, Hein HO, Sorensen TI. Physical activity in leisure-time and risk of cancer: 14-year follow-up of 28,000 Danish men and women. Scand J Public Health 2005;33:244 – 9. 31. Hannan LM, Leitzmann MF, Lacey JV, Jr., et al. Physical activity and risk of ovarian cancer: a prospective cohort study in the United States. Cancer Epidemiol Biomarkers Prev 2004;13:765 – 70. 32. Weiderpass E, Margolis KL, Sandin S, et al. Prospective study of physical activity in different periods of life and the risk of ovarian cancer. Int J Cancer 2006;118:3153 – 60. 33. Zhang M, Xie X, Lee AH, Binns CW. Sedentary behaviours and epithelial ovarian cancer risk. Cancer Causes Control 2004;15:83 – 9. 34. Bertone ER, Newcomb PA, Willett WC, Stampfer MJ, Egan KM. Recreational physical activity and ovarian cancer in a populationbased case-control study. Int J Cancer 2002;99:431 – 6. 35. Cottreau CM, Ness RB, Kriska AM. Physical activity and reduced risk of ovarian cancer. Obstet Gynecol 2000;96:609 – 14. 36. Bain C, Purdie D, Green A, et al. Exercise may protect against ovarian cancer. Am J Epidemiol 1996;143:72. 37. Zhang M, Lee AH, Binns CW. Physical activity and epithelial ovarian cancer risk: a case-control study in China. Int J Cancer 2003;105:838 – 43. 38. Dosemeci M, Hayes RB, Vetter R, et al. Occupational physical activity, socioeconomic status, and risks of 15 cancer sites in Turkey. Cancer Causes Control 1993;4:313 – 21. 39. Freedman DM, Dosemeci M, McGlynn K. Sunlight and mortality from breast, ovarian, colon, prostate, and non-melanoma skin cancer: a composite death certificate based case-control study. Occup Environ Med 2002;59:257 – 62. 40. Lichtman SW, Pisarska K, Berman ER, et al. Discrepancy between self-reported and actual caloric intake and exercise in obese subjects. N Engl J Med 1992;327:1893 – 8. 41. Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet 1991;337:867 – 72. 42. Verkasalo PK, Thomas HV, Appleby PN, Davey GK, Key TJ. Circulating levels of sex hormones and their relation to risk factors 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. for breast cancer: a cross-sectional study in 1092 pre- and postmenopausal women (United Kingdom). Cancer Causes Control 2001;12:47 – 59. De Souza MJ, Miller BE, Loucks AB, et al. High frequency of luteal phase deficiency and anovulation in recreational women runners: blunted elevation in follicle-stimulating hormone observed during luteal-follicular transition. J Clin Endocrinol Metab 1998;83:4220 – 32. McTiernan A, Tworoger SS, Rajan KB, et al. Effect of exercise on serum androgens in postmenopausal women: a 12-month randomized clinical trial. Cancer Epidemiol Biomarkers Prev 2004;13: 1099 – 105. Mitsuzono R, Ube M. Effects of endurance training on blood lipid profiles in adolescent female distance runners. Kurume Med J 2006; 53:29 – 35. Kramer MM, Wells CL. Does physical activity reduce risk of estrogen-dependent cancer in women? Med Sci Sports Exerc 1996; 28:322 – 34. Wu F, Ames R, Evans MC, France JT, Reid IR. Determinants of sex hormone-binding globulin in normal postmenopausal women. Clin Endocrinol (Oxf) 2001;54:81 – 7. Feskens EJ, Loeber JG, Kromhout D. Diet and physical activity as determinants of hyperinsulinemia: the Zutphen Elderly Study. Am J Epidemiol 1994;140:350 – 60. Raastad T, Bjoro T, Hallen J. Hormonal responses to high- and moderate-intensity strength exercise. Eur J Appl Physiol 2000;82:121 – 8. Giovannucci E. Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutr 2001;131:3109 – 20S. Kaaks R. Nutrition, insulin, IGF-1 metabolism and cancer risk: a summary of epidemiological evidence. Novartis Found Symp 2004; 262:247 – 60; discussion 260 – 68. Ahmed RL, Thomas W, Schmitz KH. Interactions between insulin, body fat, and insulin-like growth factor axis proteins. Cancer Epidemiol Biomarkers Prev 2007;16:593 – 7. Lukanova A, Lundin E, Toniolo P, et al. Circulating levels of insulinlike growth factor-I and risk of ovarian cancer. Int J Cancer 2002;101: 549 – 54. Hankinson SE, Willett WC, Manson JE, et al. Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 1998;90:1292 – 9. Chan JM, Stampfer MJ, Giovannucci E, et al. Plasma insulin-like growth factor-I and prostate cancer risk: a prospective study. Science 1998;279:563 – 6. Olsen CM, Green AC, Whiteman DC, et al. Obesity and the risk of epithelial ovarian cancer: a systematic review and meta-analysis. Eur J Cancer 2007;43:690 – 709. Friedenreich CM. Physical activity and cancer prevention: from observational to intervention research. Cancer Epidemiol Biomarkers Prev 2001;10:287 – 301. Cancer Epidemiol Biomarkers Prev 2007;16(11). November 2007 Downloaded from cebp.aacrjournals.org on March 25, 2014. © 2007 American Association for Cancer Research.