Our results provide weak evidence in support of a reduced risk of ovarian cancer among women who engaged in aerobic physical activity as compared to those who reported less than one hour of activity per week. Although most of the ORs associated with higher levels of physical activity were less than one, statistically significant associations were identified only for women reporting one to two hours of weekly activity in either the year before or the ten years before diagnosis. There was no clear dose response relation between the amount of physical activity and risk for ovarian cancer. The magnitude of the ORs for ovarian cancer risk in the present study, while not statistically significant, are consistent with a meta-analysis conducted by Olsen et al. (19
) in which they reported a pooled relative risk of 0.81 (95% CI , 0.72 – 0.92) when comparing the highest to lowest categories of recreational physical activity. It is noteworthy that among the individual studies included in the meta-analysis, the majority showed modest inverse associations with physical activity that were not statistically significant. In additional studies published after the meta-analysis, a case-control study (4
) reported a significant inverse relationship among women with the highest frequency and intensity of physical activity whereas a cohort study (32
) reported no association with either vigorous or moderate physical activity.
The lack of statistically significant associations between physical activity and ovarian cancer risk in most studies may reflect that the risk reduction associated with higher levels of physical activity is modest and some of the studies may have had inadequate power to detect an association. It also may be a reflection of the difficulty in measuring physical activity in relation to cancer risk, where the most relevant exposure period may be many years before the actual diagnosis of cancer. An individual's physical activity is likely to vary across seasons of the year and over one's lifespan. Many epidemiologic studies, including the North Carolina Ovarian Cancer Study, asked study participants to give an estimate of average physical activity in various periods of life, a task that is challenging and fraught with error. In addition, the questions used to assess physical activity vary in detail across studies, with various surveys obtaining more or less detail about the type of activity, intensity and frequency.
The effect of the misclassification of physical activity would depend in part on whether it differed by case-control status. It is impossible to determine with certainty whether there is differential misclassification between cases and controls, however one approach is to compare findings from case-control studies to those from cohort studies, where report of physical activity precedes the diagnosis and would not be subject to recall bias related to case status. In the meta-analysis by Olsen, et al.(19
), the pooled estimate from the case-control studies (OR= 0.79, 95% CI 0.70 – 0.85) was very similar to the pooled estimate from the cohort studies (OR=0.81, 95% CI 0.72 – 0.92). The similarity of these estimates argues against the ORs in case-control studies being biased due to differential misclassification of physical activity. Instead, it suggests that the inevitable misclassification of physical activity is likely to be non-differential by case-control status. In the situation of a dichotomous variable, non-differential misclassification usually results in an underestimate of the true association however misclassification of a multilevel variable like physical activity would not necessarily result in a bias towards the null. Therefore it cannot be concluded with certainty that misclassification of physical activity will result in an attenuation of its true association with ovarian cancer.
A limitation of our study is its low response rates, particularly among control women. The lack of information from non-participants precludes us from determining how non-response may have affected our findings, however our study population does show the expected associations with well-established risk factors for ovarian cancer. In addition, when we compared selected characteristics of the controls to comparable statistics reported by the North Carolina Behavioral Risk Factor Surveillance Study, we found similar prevalences of factors such as smoking, hysterectomy status and overweight, suggesting that the controls were a fairly representative sample of the North Carolina population despite the sub-optimal response rates.
Our North Carolina study population differs from other studies of ovarian cancer in its racial composition, with African American women comprising approximately 10% of the population. We did find that African American women reported levels of physical activity that were somewhat lower, although not statistically significant different from white women. Our analyses controlled for race as a potential confounding variable.
Our analyses of physical activity among ovarian cancer cases found evidence of improved survival for women who engaged in greater than two hours of activity per week as compared to those who reported less than one hour per week, but only among women who were not obese (BMI<30kg/m2
). In the only other published study of physical activity and ovarian cancer survival, a population-based, prospective study conducted in Sweden, there was no overall association between physical activity during childhood, young adulthood or recent years and survival after ovarian cancer, but there was a statistically significant survival advantage among women with Stage I or II disease who were in the highest category of activity at ages 18 to 30.(28
Although the literature on physical activity and ovarian cancer survival is very limited, studies of other cancer types that have evaluated physical activity both before and after diagnosis suggest that higher levels of physical activity may improve outcomes in people diagnosed with cancer. (23
) Higher levels of self-reported physical activity and measures of cardiorespiratory fitness have been associated with improved survival from breast, colorectal and lung cancer.(23
) Further studies among women with ovarian cancer, including intervention studies designed to improve fitness after diagnosis, are warranted.
An obvious limitation of both our analysis and the Swedish survival study is that the physical activity data were collected shortly after the time of the ovarian cancer diagnosis and no information was obtained about changes in physical activity that occurred after diagnosis. One might presume that the women who were most physically active before being diagnosed with cancer would be more likely to continue to exercise, but individual variation is expected. Some women who were physically active before their cancer diagnosis may have been unable to continue to exercise at the same level afterwards, whereas the cancer diagnosis could have served as an impetus to improve lifestyle habits among some women who were inactive before their diagnosis. It is also likely that the ability to exercise after diagnosis may be related to stage of disease, and women with more advanced disease and a poorer prognosis may be less likely to engage in physical activity. The uncertainty about how pre-diagnostic exercise patterns relate to post-diagnosis physical activity underscores the limitation of having reports of physical activity only around the time of diagnosis.
Our survival analyses also are limited by the incomplete information on co-morbid conditions, which could be associated with both physical activity and risk for death. Our analyses were based on deaths from all causes, of which the vast majority would be expected to be ovarian cancer-related, however there is the possibility of confounding by co-morbid conditions. A prospective study that ascertains changes in physical activity in the months and years following an ovarian cancer diagnosis and has more specific information on other conditions that contribute to risk for mortality could provide more definitive evidence on the effect of physical activity on ovarian cancer survival.
Overall, our findings are suggestive of modest benefits of physical activity in relation to both ovarian cancer risk and survival. While the interpretation of our results must be tempered by considering the inevitable misclassification of physical activity in retrospective epidemiologic studies, there are biological reasons that support the plausibility of exercise reducing cancer risk and improving survival.(20
The factors most consistently associated with ovarian cancer risk, oral contraceptive use and greater number of pregnancies, are hypothesized to reduce risk by reducing the number of ovulatory cycles.(34
) It is well-established that physical activity affects menstrual patterns. Oligomenorrhea or amenorrhea is commonly reported in competitive athletes, and increases in cycle length have been reported among women engaging in less vigorous activity who continue to cycle regularly.(35
) Although relatively few women in our study reported activity levels that would likely result in amenorrhea, more subtle effects of moderate physical activity on menstrual cycle length could result in fewer lifetime ovulatory cycles and reduce ovarian cancer risk.
Effects on inflammatory processes and immune response also could account for reduced risk of or better prognosis after ovarian cancer in more physically active women. Epithelial inflammation has been proposed as a common pathway linking several established risk factors for ovarian cancer including ovulation, endometriosis and talc exposure.(37
) In some studies, physical activity has been associated with reduced levels of inflammatory markers such as C-reactive protein and tumor necrosis factor (TNF)-α.(20
) Similarly, markers of immune function have been reported to be enhanced among those engaging in moderate levels of physical activity. (20
The data from the present study add to the body of literature on physical activity ovarian cancer risk and survival. While some of the findings are weakly supportive of inverse associations with both risk and survival, our study was limited by the many challenges of assessing physical activity in epidemiologic studies, including retrospective assessment of activity over a lifetime, inaccurate recall and lack of objective measures of physical fitness. The literature on the effects of physical activity on ovarian cancer risk and survival is suggestive, but not conclusive, that there are beneficial effects. Although it is not clear what it is about exercise that will specifically benefit ovarian cancer patients, the general health benefits that accompany physical activity suggest that recommendations to engage in exercise training to the extent possible would be reasonable and prudent for ovarian cancer patients.