Lin, Lilie L. MD*; Brown, Justin C. BS*; Segal, Saya MD†; Schmitz, Kathryn H. PhD*
Endometrial cancer is the most common gynecologic malignancy in the United States with an estimated 49,000 cases expected in 2013.1 The standard therapy is hysterectomy and bilateral salpingo-oophorectomy with adjuvant chemotherapy and/or radiation therapy depending on pathologic risk factors. Most women are with conditions diagnosed at an early stage when survival is over 90% at 5 years.2 However, treatment (including surgery, chemotherapy, and radiation therapy) can result in both acute and chronic adverse effects that can affect health-related quality of life (QoL).3,4 Concurrent medical comorbidities in this population including diabetes, hypertension, obesity, and cardiovascular conditions can also have a substantial impact on QoL. Furthermore, low QoL is associated with prolonged length of hospital stay among gynecologic cancer patients undergoing surgery and consequently potentially higher health care costs.5 As a result, focusing on methods to improve QoL in the survivorship period is a priority.
Prior research has observed that low physical activity (PA) negatively impacts QoL in patients with endometrial cancer.6 Patients meeting guidelines for PA had significantly better QoL than those not meeting guidelines.7 One of the potential comorbidities influencing the level of PA in this population is the high prevalence of obesity; up to 90% of women with type 1 endometrial cancer are overweight or obese.8 High rates of obesity and low levels of PA have been reported in uterine cancer patients, whereas higher rates of PA and lower body mass index (BMI) were both independently associated with improved QoL and less fatigue in this population.6
The purpose of our study was to estimate the levels of PA and BMI in a hospital-based cohort of endometrial cancer survivors and to describe the association of BMI with PA level and overall health-related QoL. We were particularly interested in the physical and functional well-being aspects of QoL. Furthermore, we were interested in determining whether the associations of BMI and QoL varied according to whether survivors are compliant with the PA at the levels recommended by the American Cancer Society, the American College of Sports Medicine, and the National Comprehensive Cancer Network.
Patients and Methods
We conducted a mailed survey of patients with uterine cancer who received care at the Abramson Cancer Center at the University of Pennsylvania (Philadelphia, PA). Patients were women aged 20 years or older with a diagnosis of uterine cancer. Patients were identified using surgical logs from 2008 to 2010 and the International Classification of Diseases, Ninth Revision codes 179.0 and 182.0 to 182.8 from 2006 to 2010. Patients who met the inclusion criteria were sent a letter signed by their oncologist explaining the purpose of the study. Potentially eligible patients were provided with the option to decline participation within 2 weeks of receiving the letter from their oncologist. Those who did not decline participation were sent a survey to complete. After 2 weeks, a second survey was sent to those who did not reply to the first mailed survey.9 Disease recurrence or persistence was not an exclusion criterion for the study. The National Coalition for Cancer Survivorship defines cancer survivor as anyone from the time of diagnosis and for the balance of life including patients with metastatic disease. This protocol was approved by the University of Pennsylvania institutional review board and the University of Pennsylvania cancer center. Patients who provided their informed consent were those who mailed back the completed survey. Women who were unable to complete a written survey because they were non–English-speaking, illiterate, or had cognitive impairments were excluded.
Quality of Life Questionnaire
Quality of life was measured using the Functional Assessment of Cancer Therapy–Gynecologic Oncology Group (FACT-G) questionnaire.10,11 The FACT-G questionnaire has 4 subscales that measure physical well-being (PWB), social and family well-being (SFWB), emotional well-being (EWB), and functional well-being (FWB). These subscales can be aggregated to create a composite QoL outcome score. Patients were asked to consider how they felt in the previous 7 days. Higher values denote better QoL.
Body Mass Index
Patients self-reported their height and current body weight. We then calculated BMI as weight divided by height squared (kg/m2). For descriptive purposes, we calculated categories of BMI, where less than 25.0, 25.0 to 29.9, 30.0 to 34.9, 35.0 to 39.9, and greater than or equal to 40.0 represent healthy weight, overweight, moderately obese, severely obese, and very severely obese, respectively.
Physical Activity Questionnaire
The Paffenbarger Physical Activity Questionnaire was used to assess participation in PA.12 The PA questionnaire is valid,13 correlates with objective measures of physical fitness,14 and has been used among other cancer sites for epidemiologic studies.15,16 Patients were asked to free list any PAs they participated in on a regular basis in the past 1 year. For each PA, patients listed the average number of sessions per week and the duration of the activity in minutes. Total PA was generated by summing the number of minutes of PA reported each week (min·wk−1). We then dichotomized this variable between women who met (versus did not meet) the recommended dose of PA of 150 min·wk−1, as recommended by the American College of Sports Medicine, American Cancer Society, and National Comprehensive Cancer Network.
Information on covariates came from self-report or the electronic medical record. Age, race, BMI, and PA were self-reported. Variables collected from the electronic medical record included pathology type, stage of cancer, cancer treatment history, number of lymph nodes removed, and time since diagnosis. The Charlson Comorbidity Index was used to quantify number of comorbidities.17
The response rate to our survey was calculated using methods described by the American Association for Public Opinion Research.9 Continuous variables are reported as mean (SD), and categorical variables are reported as counts with percentages (%). Normality of QoL outcomes were examined using the Shapiro-Wilk test and graphically with histogram plots. All QoL outcomes were negatively skewed. Quality of life outcomes were transformed using a square transformation (ie, QoL2) to achieve Gaussian distribution. We used least squares regression to estimate the magnitude of association for each kilogram per square meter increase in BMI or each min·wk−1 increase in PA on the QoL outcome of interest. We then conducted regression analysis of BMI on QoL, stratified among those who did (versus did not) meet recommended PA guidelines. All results presented herein are back transformed (ie, using the square root) to ease the interpretation of results. We examined unadjusted regression models and then built multivariable regressions model adjusting for sociodemographic and clinical characteristics. Results were consistent in both adjusted and unadjusted models; therefore multivariable adjusted models are presented. Statistical tests were 2-sided, and P < 0.05 was the threshold for statistical significance. All statistical analyses were conducted using Stata 12.0 (College Station, TX).
Mailed Survey Results
Five hundred thirty-one potentially eligible patients were identified using surgical case logs and the International Classification of Diseases, Ninth Revision codes. Among 531 mailed letters, 225 patients returned surveys. Twelve surveys were identified as not meeting the inclusion criteria (ie, 10 diagnosed with cancer before 2006 and 2 misclassified [diagnosed with other gynecologic cancers]); thus our response rate was 43% and included 213 patients.
Sociodemographic and Clinical Characteristics
Sociodemographic and clinical characteristics are depicted in Table 1. Age ranged from 29 to 94 years. Patients were most commonly diagnosed with early stage endometrial adenocarcinoma and treated surgically. Time since diagnosis ranged from 4 to 72 months.
BMI and PA Characteristics
Distribution of BMI among the study sample is depicted in Table 2. Body mass index ranged from 14 to 67 kg/m2, and the mean BMI was 31.1 (8.9) kg/m2. Categorically, 26%, 22%, 23%, 14%, and 15% of women were healthy weight, overweight, moderately obese, severely obese, and very severely obese, respectively. The median volume of PA was 90.0 min·wk−1 (interquartile range, 0–240). Categorically, approximately half (52%) reported less than 150 min·wk−1 of PA, with 80 (38%) reporting being completely sedentary (ie, 0 min·wk−1 of PA). The most common PAs reported were walking (42%), aerobic gym-based activities including the recumbent bicycle and elliptical machine (11%), and swimming (8%). The distribution of BMI categories were similar among those who did (versus did not) meet recommended PA guidelines (P = 0.847). When treated as continuous variables, there was no correlation between BMI and min·wk−1 of PA (r = 0.02, P = 0.822).
Quality of Life Scores
Quality of life scores are depicted in Table 3. We compared the QoL scores in our sample to those included in the validation study of the FACT-G questionnaire.11 The composite FACT-G QoL outcome were similar between our sample and the validation sample (P = 0.452). Quality of life subscales were comparable between groups, with exception of SFWB where our sample reported lower scores, but this comparison did not reach statistical significance (P = 0.088).
Independent Effect of BMI on QoL
In multivariable analyses controlling for demographic-, treatment-, and patient-related variables, higher levels of BMI were associated with significantly poorer overall QoL (P = 0.050; Table 4). Higher levels of BMI were associated with poorer PWB (P = 0.002) and FWB (P = 0.008). Higher levels of BMI were not associated with SFWB (P = 0.603) or EWB (P = 0.899).
Independent Effect of PA on QoL
In multivariable analyses controlling for demographic-, treatment-, and patient-related variables, higher min·wk−1 of PA was not associated with any QoL outcome (Table 4).
Joint Effects of BMI and PA on QoL
In stratified analysis, among patients who engaged in greater than or equal to 150 min·wk−1 of PA, the negative association between BMI and QoL was attenuated (P = 0.558), whereas among patients who engaged in less than 150 min·wk−1 of PA, the negative association between BMI and QoL persisted (P = 0.025). This pattern was similar for PWB and FWB. Among patients who engaged in greater than or equal to 150 min·wk−1 of PA, the negative association between BMI and PWB and FWB were attenuated (P = 0.765 and P = 0.284), whereas among patients who engaged in less than 150 min·wk−1 of PA, the negative association between BMI and PWB and FWB persisted (P < 0.001 and P = 0.010), respectively.
Our results demonstrate that higher BMI is associated with inferior overall QoL and decreased physical and functional well-being in patients treated for endometrial cancer after controlling for standard patient demographic, treatment, and pathologic variables. The decreased QoL, PWB, and FWB associated with a higher BMI, however, were attenuated with levels of PA that met American Cancer Society, American College of Sports Medicine, and National Comprehensive Cancer Network guidelines. Among those patients who did not reach the recommended PA level, the negative association between QoL, FWB, and PWB persisted with elevated BMI score. Sustained weight loss is challenging in this patient population; however, our data are encouraging in that even among women with higher BMI score, those who do regular PA may be protected from the lower QoL observed among sedentary overweight or obese survivors. The take home message for clinicians might be that overweight/obese endometrial cancer survivors who can tolerate exercise should be prescribed exercise, particularly if the patient reports poor QoL.
Other groups have examined the interaction of BMI and PA on QoL and have found that they contributed independently to QoL. Our analysis demonstrates that PA level in endometrial cancer patients who have a higher BMI may offer some protection from the negative effects of high BMI on QoL, PWB, and FWB. These findings are encouraging and suggest that programs aimed at improving levels of PA may have a significant impact on QoL and physical and functional well-being particularly on those who have higher BMI and are at greatest risk of lower QoL. Our observation that PA attenuated the negative effects of increased BMI on QoL, PWB, and FWB is contrary to what was observed by Courneya et al6 who found that exercise and BMI independently improved QoL and PA and did not observe any interactions between BMI and PA and their association with QoL.3 This may be due to the higher level of PA reported by our study population particularly in those who were obese compared with similar study populations. From a patient perspective, there is also an expectation regarding the benefits of exercise. In a survey study of stage I endometrial cancer survivors regarding their level of exercise in the prior 6 months, both self-reported exercisers and nonexercisers indicated that improved physical and emotional well-being is a likely consequence of exercise.17 Courneya et al6 also observed positive associations between patients meeting guidelines for exercise and QoL.3 Similarly, in a study of 200 endometrial cancer survivors, Basen-Engquist et al18 found that patients with higher levels of PA and lower BMI reported better physical function and less fatigue.12 They found significant differences between normal weight and obese women (P = 0.005) and between sedentary women and those who met PA guidelines (P = 0.000). The interaction between BMI and PA was not significant, however.
Approximately 74% of our population was overweight or obese with 22% overweight and 52% obese. Although these proportions are higher than rates of obesity in the general public,19 these percentages are in line with what has been reported in other series involving endometrial cancer patients.6,18 In our study, 48% of women indicated a level of PA that met guidelines, which is in line with the PA level of the general population.20 Approximately 55% of obese endometrial cancer survivors in our study were meeting guidelines for PA, which is slightly higher than rates of PA meeting guidelines in the general population (43%). The level of PA in our analyses is higher than what has been previously reported in endometrial cancer survivors and may be due to the period of the analyses because our study was conducted more recently.6 Differences may also be secondary to geographic region of the studies because our study was conducted in a large metropolitan area in the northeastern United States, as compared with the prior study that was conducted in a less populous, colder Canadian location. Conversely, the level of activity was based on self-reports that are prone to reporting bias. In addition, we found no association between BMI and SFWB and EWB. This is consistent with prior reports that have found no association between BMI and mental health function.
Obesity and lack of PA are known risk factors for development of endometrial cancer, and thus a high proportion of survivors are also likely to be overweight and obese with a sedentary lifestyle.21 One could hypothesize that apart from improvements in QoL, PA may also reduce rates of recurrence through the insulin pathway by decreasing levels of insulin and insulinlike growth factor.22 Elevated levels of IGF-I activity has been associated with enhanced proliferation in endometrial tissue.23 Hyperinsulinemia has been positively associated with endometrial adenocarcinoma incidence in the Women’s Health Initiative Observational Study although conclusive evidence of an association between PA and endometrial-cancer specific mortality has not been demonstrated.24 A recent prospective analysis of BMI and PA in women who participated in the NIH-AARP Diet and Health Study also demonstrated that higher BMI prediagnosis increased the overall and disease-specific mortality in endometrial cancer patients, whereas higher levels of moderate to vigorous PA were associated with lower 5-year all-cause mortality although no association was observed between PA and disease-specific mortality.25
Our study was a cross-sectional study conducted in a large urban medical center that draws patients from both the urban and suburban region, which improves the generalizability of our findings and is a strength of our study. There are several potential important limitations. Our study had a response rate of 43%, which is lower than what has been previously reported in similar series,18 but the response rate is similar to a 16-page survey sent to colon cancer survivors in the region.9 We relied on patients’ self-report of both body weight and height, which may be underestimated. Similarly, we relied on patient self-report regarding their level of PA, which may also be subject to recall bias and is high for this population. Misclassification regarding activity level on self-administered questionnaires is well known. In a recent prospective study of PA in cancer survivors by Loprinzi et al,26 only 13% engaged in PA that met PA guidelines, and obese cancer survivors engaged in 47% less PA than normal weight cancer survivors. In addition, this study cannot establish a causal relationship between BMI, PA, and QoL given it is cross-sectional analysis. We should emphasize as well that our findings represent the experience at 1 large academic urban medical institution during the period studied and should be taken as hypothesis generating. Further studies are needed to verify our findings and support the need for prospective clinical studies evaluating exercise interventions in this population to improve QoL particularly in obese endometrial cancer survivors.
Overall, the results of our study support prior studies demonstrating an association between QoL, BMI, and PA. They also demonstrate that among endometrial survivors with elevated BMI scores, PA programs may offer protection from the lower QoL sometimes observed in this population. We have known for decades that exercise and body weight are associated with reduced incidence, morbidity, and mortality for cardiovascular diseases27,28; however, no substantial concomitant changes in population level of regular PA has been observed29 and levels of obesity have concurrently increased in the United States.19 Clearly, attempts to increase PA level by focusing on long-term outcomes relating to incidence, morbidity, and mortality from major chronic diseases does not result in behavior changes. Perhaps a focus on shorter term outcomes such as improved QoL would be more motivating to patients.
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin
. 2013; 63: 11–30.
3. van de Poll-Franse LV, Pijnenborg JM, Boll D, et al. Health-related quality of life and symptoms after pelvic lymphadenectomy or radiotherapy vs. no adjuvant regional treatment in early-stage endometrial carcinoma: a large population-based study. Gynecol Oncol
. 2012; 127: 153–160.
4. Bruner DW, Barsevick A, Tian C, et al. Randomized trial results of quality of life comparing whole abdominal irradiation and combination chemotherapy in advanced endometrial carcinoma: a gynecologic oncology group study. Qual Life Res
. 2007; 16: 89–100.
5. Laky B, Janda M, Kondalsamy-Chennakesavan S, et al. Pretreatment malnutrition and quality of life—association with prolonged length of hospital stay among patients with gynecological cancer: a cohort study. BMC Cancer
. 2010; 10: 232.
6. Courneya KS, Karvinen KH, Campbell KL, et al. Associations among exercise, body weight, and quality of life in a population-based sample of endometrial cancer survivors. Gynecol Oncol
. 2005; 97: 422–430.
7. Blanchard CM, Courneya KS, Stein K, American Cancer Society’s SCS, II. Cancer survivors’ adherence to lifestyle behavior recommendations and associations with health-related quality of life: results from the American Cancer Society’s SCS-II. J Clin Oncol
. 2008; 26: 2198–2204.
8. McTiernan A, Irwin M, Vongruenigen V. Weight, physical activity, diet, and prognosis in breast and gynecologic cancers. J Clin Oncol
. 2010; 28: 4074–4080.
9. Kelly BJ, Fraze TK, Hornik RC. Response rates to a mailed survey of a representative sample of cancer patients randomly drawn from the Pennsylvania Cancer Registry: a randomized trial of incentive and length effects. BMC Med Res Methodol
. 2010; 10: 65.
10. Cella DF, Tulsky DS, Gray G, et al. The Functional Assessment of Cancer Therapy scale: development and validation of the general measure. J Clin Oncol
. 1993; 11: 570–579.
11. Calhoun EA, Welshman EE, Chang CH, et al. Psychometric evaluation of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol Cancer
. 2003; 13: 741–748.
12. Paffenbarger RS Jr, Hyde RT, Wing AL. Physical activity and incidence of cancer in diverse populations: a preliminary report. Am J Clin Nutr
. 1987; 45: 312–317.
13. Ainsworth BE, Leon AS, Richardson MT, et al. Accuracy of the College Alumnus Physical Activity Questionnaire. J Clin Epidemiol
. 1993; 46: 1403–1411.
14. Kohl HW, Blair SN, Paffenbarger RS Jr, et al. A mail survey of physical activity habits as related to measured physical fitness. Am J Epidemiol
. 1988; 127: 1228–1239.
15. Meyerhardt JA, Giovannucci EL, Holmes MD, et al. Physical activity and survival after colorectal cancer diagnosis. J Clin Oncol
. 2006; 24: 3527–3534.
16. Meyerhardt JA, Heseltine D, Niedzwiecki D, et al. Impact of physical activity on cancer recurrence and survival in patients with stage III colon cancer: findings from CALGB 89803. J Clin Oncol
. 2006; 24: 3535–3541.
17. Charlson M, Szatrowski TP, Peterson J, et al. Validation of a combined comorbidity index. J Clin Epidemiol
. 1994; 47: 1245–1251.
18. Basen-Engquist K, Scruggs S, Jhingran A, et al. Physical activity and obesity in endometrial cancer survivors: associations with pain, fatigue, and physical functioning. Am J Obstet Gynecol
. 2009; 200: 288.e1–288.e8.
19. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults, 1999–2008. JAMA
. 2010; 303: 235–241.
20. Carlson SA, Fulton JE, Schoenborn CA, et al. Trend and prevalence estimates based on the 2008 Physical Activity Guidelines for Americans. Am J Prev Med
. 2010; 39: 305–313.
21. Dieli-Conwright CM, Ma H, Lacey JV Jr, et al. Long-term and baseline recreational physical activity and risk of endometrial cancer: the California Teachers Study. Br J Cancer
. 2013; 109: 761–768.
22. Ballard-Barbash R, Friedenreich CM, Courneya KS, et al. Physical activity, biomarkers, and disease outcomes in cancer survivors: a systematic review. J Natl Cancer Inst
. 2012; 104: 815–840.
23. Kaaks R, Lukanova A, Kurzer MS. Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev
. 2002; 11: 1531–1543.
24. Gunter MJ, Hoover DR, Yu H, et al. A prospective evaluation of insulin and insulin-like growth factor-I as risk factors for endometrial cancer. Cancer Epidemiol Biomarkers Prev
. 2008; 17: 921–929.
25. Arem H, Park Y, Pelser C, et al. Prediagnosis body mass index, physical activity, and mortality in endometrial cancer patients. J Natl Cancer Inst
. 2013; 105: 342–349.
26. Loprinzi PD, Lee H, Cardinal BJ. Objectively measured physical activity among US cancer survivors: considerations by weight status. J Cancer Surviv
. 2013; 7: 493–499.
27. Morris JN, Crawford MD. Coronary heart disease and physical activity of work: evidence of a national necropsy survey. Br Med J
. 1958; 2: 1485–1496.
28. Morris JN, Chave SP, Adam C, et al. Vigorous exercise in leisure-time and the incidence of coronary heart-disease. Lancet
. 1973; 1: 333–339.
29. Brownson RC, Boehmer TK, Luke DA. Declining rates of physical activity in the United States: what are the contributors? Annu Rev Public Health
. 2005; 26: 421–443.
© 2014 by the International Gynecologic Cancer Society and the European Society of Gynaecological Oncology.