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Female Cancer Survivorship and Obesity
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Female Cancer Survivorship and Obesity Michele L. McCarroll, G. Dante Roulette, and Vivian E. von Gruenigen Department of Obstetrics and Gynecology, Summa Health System, Akron, Ohio, USA
OBESITY AND FEMALE CANCER Obesity is an epidemic in the developed world. As of 2012, in the United States the prevalence of overweight and obese individuals in the population approaches 60%, as measured by a body mass index (BMI) greater than 25 kg/m2 [1]. Obesity has long been recognized as a risk factor for many chronic diseases, chief among these being diabetes and disorders of the cardiovascular system. The link between obesity and the risk of cancer has been known since as early as 2002, when the International Agency for Research on Cancer (IARC) concluded there was adequate evidence for an association between obesity and several types of cancer [2]. Obesity contributes to 11% of colon cancers, 9% of breast cancer in postmenopausal women, 39% of gynecological cancers, 37% of esophageal cancers, and 25% of renal cancers, as published by the IARC in 2011 [3]. It is estimated that <90,000 deaths could be avoided each year in the United States if the adult population maintained a normal BMI [4]. The exact mechanisms leading to the elevation in cancer risk are incompletely understood, although several plausible mechanisms have been proposed. These mechanisms center on derangements of metabolism and endocrine signaling. Obesity is marked by an increase in the amount of subcutaneous and visceral adipose tissue, with visceral adipose tissue being more metabolically active [5]. This adipose tissue, through several mechanisms, alters the synthesis and bioavailability of endogenous sex steroids (estrogens, androgens, and progesterone). Adipose tissue itself is an active endocrine gland and can have wide-ranging effects on metabolism. In 2004, Calle et al. summarized these effects succinctly by demonstrating that adipose tissue responds to signaling by increasing or decreasing the levels of circulating free fatty acids [6,7]. In addition, peptide
Nutrition in the Prevention and Treatment of Abdominal Obesity http://dx.doi.org/10.1016/B978-0-12-407869-7.00005-2
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hormones including leptin, adiponectin, resistin, and tumor necrosis factor (TNF-α) are released. Insulin resistance is mediated by the release of these hormones. A relative increase in insulin resistance by peripheral tissue leads to compensatory hyperinsulinemia. Insulin acts as a growth factor, and chronically elevated levels of insulin have been associated with tumor growth both directly and indirectly via effects on insulin-like growth factor I (IGF-I) in animal models. Tumor tissues generally have increased levels of IGF-I and insulin receptors. Adipose tissue also expresses various sex steroid-metabolizing enzymes, which ultimately increase the levels of endogenous estrogens through the conversion of androstenedione to estrone and the aromatization of androgens to estradiol. The levels of circulating estrogens are therefore directly related to the amount of adipose tissue. A secondary effect is a decrease in the level of sex hormone-binding globulin (SHBG) by the liver due to increases in insulin and IGF-I. As estrogens normally circulate in the bloodstream in a bound (and biologically inactive) form, this leads to a relative increase in the amount of estrogens in the bloodstream. Together, these two increases are thought to account for most of the increased amount and bioavailability of estrogen seen by target tissues [6–8]. Increased androgen synthesis and hyperestrogenism is also seen in polycystic ovary syndrome (PCOS), a disorder specific to women. The condition is seen in 4–6% of women and is characterized by obesity, hyperinsulinemia, and the subsequent relative increase in estrogen via previously discussed mechanisms. Obesity is one of the only risk factors that is modifiable throughout life. Cancers specific to women present an interesting opportunity to discuss mechanisms and treatment. Herein, we discuss these hormonally driven cancers, specifically breast, endometrial, and ovarian
© 2014 Elsevier Inc. All rights reserved.
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cancer, as well the impact of obesity on treatment and quality of life outcomes.
Gynecological Cancers Endometrial cancer was among the first to be recognized as related to obesity. Cancer of the uterine lining, or endometrial cancer, is the fourth most common cancer among women, with an estimated 47,130 new diagnoses in 2012 [9]. It is the second most common cause of death from gynecological cancer, with an estimated 8120 deaths in 2011. Women have a 2.6% lifetime risk of this malignancy. The incidence of endometrial cancer has been increasing, more than doubling from 1987 to 1998, in the face of plateauing incidence and mortality for several other cancers over the same time period. Among the recognized risk factors for the development of endometrial cancer include unopposed estrogen therapy, increasing age, diabetes, nulliparity, and obesity (Table 5.1). It is estimated that approximately 90% of type 1 (hormone-mediated) endometrial cancer patients are obese [10]. There is a significant increased risk of endometrial cancer with higher BMI categories and higher body fat measurements using skinfold calipers [11]. Of all women diagnosed with endometrial cancer, 25% will be premenopausal, with obesity and nulliparity shown to be the strongest risk factors in a retrospective series [12]. Women diagnosed with endometrial cancer are typically treated with surgical staging, and in some cases with adjuvant radiotherapy and/or chemotherapy. Surgical treatment can be technically challenging in this
TABLE 5.1 Risk Factors for Endometrial Cancer Obesity (relative risk of 2–11) • Relative risk of 3.0 in women 21–50 lb overweight and 10 in women more than 50 lb overweight Nulliparity (relative risk of 2–3) Late menopause, i.e., occurring in women older than 52 years (relative risk of 2.4)
cohort of patients, given the frequency of obesity. These patients may also present with medical comorbidities that make desirous a shortened surgical time and duration of anesthesia. Numerous studies have made it clear that minimally invasive procedures can be performed in this population without compromise in oncologic outcomes [13–15]. Giugale et al. recently reported a decrease in the percentage of minimally invasive procedures from obese to morbidly obese to super obese women. There was also a concomitant increase in blood loss, rising with the degree of obesity, and a decrease in the number of nodes retrieved during lymph node dissection [16]. Fortunately, with treatment, the expectation is that the majority of women with endometrial cancer will live longer than 5 years after diagnosis; however, many studies do reveal in increase in mortality from causes unrelated to cancer in obese endometrial cancer patients [17,18]. While weight has been shown to impact cancer recurrence in breast, colorectal, and prostate cancers, it has not been shown to impact endometrial cancer recurrence [19–21]. A 2013 study shows a 5-year, all-cause mortality hazard ratio (HR) of 1.84 [95% confidence interval (CI) = 1.17–2.88] for BMI of 30–35 kg/m2, and 2.35 (95% CI = 1.48 to 3.73) for BMI ≥35 kg/m2 [22]. Furthermore, while HR estimates for 10-year all-cause and endometrial cancer-specific mortality, as related to BMI, were similar to 5-year HR estimates, 10-year cardiovascular disease mortality was significantly higher for BMI > 35 kg/m2 (HR = 4.08, 95% CI = 1.56–10.71). Comparable studies have demonstrated parallel correlations with ovarian cancer and obesity. In a metaanalysis by the Collaborative Group on Epidemiological Studies of Ovarian Cancer, ovarian cancer risk significantly increased with increasing height and increasing BMI (P = 0.001 for each) [23]. In short, the heavier/more obese women were, the greater the risk of ovarian cancer. Conversely, in a large population-based study of n = 1423 invasive epithelial ovarian cancer survivors, there were no significant associations between height, weight, or BMI and ovarian cancer-specific mortality [24]. Thus, for ovarian cancer risk related to obesity more research is needed to identify continued associations of risk and mortality.
Exogenous unopposed estrogen (relative risk of 1.6–12) Tamoxifen (relative risk of 1.7–2.5)
Breast Cancer
Diabetes (relative risk of 1.3–2.7)
Breast cancer is the most common female cancer iagnosed among all demographic groups, and the d second most common cause of death from cancer among women in the United States [25]. Since as early as 1992, obesity has been known to be significantly associated with breast cancer. A meta-analysis at the time estimated that being overweight (BMI of 25–29.9 kg/m2) or obese (BMI > 30 kg/m2) was significantly associated with a 78% and 91% risk of recurrence, respectively, and
Hypertension (relative risk of 1.2–2.1) High dietary fat consumption (relative risk of 1.1–2.0) Radiation therapy (relative risk of 8) Hereditary Non-polyposis Colorectal Cancer (HNPCC; 39–60% lifetime risk of EC) Source: Ref. [10]. Modified from: Smith RA et al. American Cancer Society Guidelines for Early Endometrial Cancer Detection: Update 2001.
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Physical Activity
an increased risk of mortality [26]. Subsequently, this was confirmed in numerous studies in both pre- and postmenopausal women. In 2004, using data from the Nurses’ Health Study in which 5204 participants were diagnosed with breast cancer, Kroenke et al. were able to conclude that weight before diagnosis was associated with recurrence of breast cancer and with death [27]. Furthermore, in women whose BMI increased by 0.5–2.0 kg/m2, the relative risk of breast cancer death was 1.35 (95% CI = 0.93–1.95). For women with a BMI increase of >2.0 kg/m2, the relative risk of breast c ancer death further increased to 1.64 [28]. Several other large cohort studies have corroborated this association between obesity and breast cancer prognosis [29,30].
FEMALE CANCER SURVIVORSHIP Cardiovascular disease (CVD) is the leading cause of death in female cancer survivors, and CVD comorbidities are the leading cause of death among gynecological and breast cancer survivors secondary to obesity. Specifically, the risk of death from CVD-related causes in gynecological cancer begins to exceed the risk from cancer-related causes 3.5 years after diagnosis (Figure 5.1) [31]. In a prospective study by Ward et al., researchers examined the relationship between cancer, BMI, and risk of death, demonstrating a significantly increased risk of death in obese women with endometrial cancer. From the current data, we know the majority of obese cancer survivors are not meeting public health exercise and/or nutrition recommendations. Unfortunately, gynecological cancer survivors are not likely to engage in exercise without supervision or direct intervention [32]. According to the Institute of Medicine, survivorship care plans should be crafted to focus on four goals: prevention of recurrent cancer, surveillance,
intervention to treat the consequences of cancer, and coordination of survivorship care [33,34]. Today, the increasing population of women diagnosed with obesity-driven female cancers underscores the need for health-care providers to provide health promotion interventions in this population [35]. The majority of research on exercise programs for gynecological and breast cancer patients support mixed interventions to improve aerobic fitness, strength, dietary compliance, weight loss, and quality of life. The National Cancer Institute (NCI) recognizes the need to specifically define patterns of weight, physical activity, and nutrition that contribute to cancer survivorship [36]. Since cardiovascular comorbidities are the leading cause of death for most gynecological and breast cancer survivors, interventions addressing cardiac risk factors (physical activity, nutrition quality, and weight loss) are essential for improving both short-term and long-term cancer survivorship.
PHYSICAL ACTIVITY One historical approach to improving cardiovascular comorbidities is the implementation of physical activity or rehabilitation programs using a multidisciplinary, medically supervised, and risk factor reduction strategy to assist adherence to lifestyle changes, including exercise, in cancer survivorship. Exercise is therapeutic but has the literature defined the dosage for a specific diagnosis, symptom, and sign?
Definitions Exercise and physical activity are important for the prevention and control of several chronic diseases. Exercise and physical activity are encouraged in overweight and obese cancer survivors to encourage energy
FIGURE 5.1 Endometrial cancer cardiovascular death rates after diagnosis. Source: Ref. [31]. 1. EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF ABDOMINAL OBESITY
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balance for weight loss. According to the World Health Organization (WHO), physical activity is defined as any bodily movement produced by skeletal muscles that requires energy (caloric) expenditure, whereas exercise is a subcategory of physical activity that is planned, structured, repetitive, and purposeful [37]. Energy balance for weight control is defined as a balance of caloric intake and expenditure (Figure 5.2) [38]. Exercise and physical activity are promoted to maintain energy balance or to create an energy deficit for weight loss. Interestingly, total caloric energy intake ≥1972.1 kcal/ day among endometrial cancer patients was significantly higher compared to women without endometrial cancer [39]. Consequently, it appears that an energy imbalance among endometrial cancer survivors is the leading cause of obesity. Overall, exercise can be beneficial to gynecological oncology patients at any place on the spectrum of survivorship in various settings of outpatient or inpatient venues [40]. The Society of Gynecologic Oncology (SGO) recently developed recommendations for physical activity for cancer survivors to help guide survivorship treatment [41]. The SGO recommends exercise and lifestyle programming to improve survivorship. Specifically, they encourage a healthy lifestyle that engages a healthy diet, stress management, tobacco cessation, and wholesystem approaches to wellness. In particular, supervised exercise programs have produced promising outcomes in reducing symptoms and improving physical and psychosocial functioning [42,43]. A recent Cochrane review on the effects of exercise and cancer-related fatigue [44] reviewed a total of 56 studies that demonstrated a significant impact on the aerobic system and in reducing fatigue for cancer patients compared to controls. In addition, a systematic review by Ballard-Barbash et al.
FIGURE 5.2 Energy balance for weight loss.
[45], identified cancer survivors with higher levels of activity as being more likely to reduce risk of death from any cause, and there may even be a dose-related response to physical activity. However, the question still remains as to whether the exercise programming actually reduces cardiovascular risk factors such as obesity.
Interventions Several studies cite the benefits of physical activity in survivorship, yet the optimal frequency, intensity, type, and timing of exercise for patients undergoing treatment or in survivorship remain unclear. The American College of Sports Medicine (ACSM) and the American Cancer Society (ACS) have joint guidelines that establish detailed exercise prescriptions for cancer survivorship during and after treatment [46]. The ACSM follows the 2008 Federal Physical Activity Guidelines for Americans, which encourage at least 150 min/week of moderate intensity aerobic activity [47]. Generally, studies have determined that moderate intensity aerobic exercise, resistance exercise, neurocognitive training, and/or combined programs lead to improved functional capacity, quality of life, and reduced chronic fatigue; however, the effects of regular physical activity alone on weight regulation and weight loss in survivorship are complex. Consequently, obese women appear to have more barriers to exercise adherence than do women of normal weight. Similarly, correlations of physical activity and obesity in gynecological cancer survivors have been further verified by Blanchard et al., who found that only 30% of endometrial cancer patients met physical activity recommendations and most exhibited a BMI > 30 kg/m2 [48]. Even with these startling correlations of obesity, weight gain, and physical inactivity commonly found in gynecological cancer patients before and after a cancer diagnosis, there is still a lack of participation in exercise programming [49]. Courneya et al. found significant negative correlations between BMI and the number of minutes per week of moderate-to-strenuous exercise in 386 endometrial and ovarian cancer survivors [50]. Moreover, Courneya and colleagues demonstrated that cancer survivors who met exercise guidelines were more likely to be of normal weight. Continued work by von Gruenigen et al. [51] provides further support by showing that 90% of obese endometrial cancer survivors had dangerous amounts of abdominal obesity as well as poor physical activity patterns––80% reported no strenuous exercise and 54% did not even participate in moderate exercise. Likewise, a 6-month physical activity intervention in cancer survivors demonstrated that women with higher BMI and larger waist circumference adhered to fewer minutes of physical activity and did not meet the prescribed 150 min/week of moderate intensity exercise [52].
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Hazard Rations and 95% Confidence Intervals
4.5 4 3.5 3 2.5 2 1.5 1 0.5 0
Nonobese & Active, Deaths/Total = 50/440
Nonobese & Inactive, Deaths/Total = 17/68
Obese & Active, Deaths/Total = 17/81
Obese & Inactive, Deaths/Total = 53/286
FIGURE 5.3 Joint effects of prediagnosis physical activity and obesity (n = 875) on 5-year all-cause mortality rate in the National Institutes of Health AARP Diet and Health Study. Cox proportional hazards models were used with age as the underlying time metric (age at diagnosis and age at death or censoring). Nonobese was defined as a body mass index of < 30kg/m2 and active was defined as >1 h/week of moderate-to-vigorous physical activity. Pinteraction = 0.14 for obesity and physical activity. Source: Ref. [56].
Other publications have reported associations between physical activity after diagnosis and prognosis among breast cancer survivors. In 2987 women from the Nurses’ Health Study diagnosed with stage I-III breast cancer between 1984 and 1998 and followed until death or 2002, the relative risk of death from breast cancer for activity equivalents of walking was 0.80 for 1–3 h/week, 0.50 for 3–5 h/week, 0.56 for 5-8 h/week, and 0.60 for 8 h/week, compared with inactive women [53]. Similar outcomes have also been reported in other studies [54]. A new study, the ENERGY (Exercise and Nutrition to Enhance Recovery and Good Health for You) trial, aims to be part of a fully powered trial of women who will be evaluated for breast cancer recurrence and disease-free survival [55]. The trial is underway and results are forthcoming. In a cohort of 1400 women diagnosed with invasive epithelial endometrial cancer, combined BMI and physical activity had an effect on endometrial cancer survival [56]. Specifically, Arem and colleagues found beneficial effects of physical activity to be more pronounced in overweight or obese patients compared to those of normal weight (Figure 5.3). Nevertheless, evidence on physical activity and weight loss in endometrial cancer survival is sparse. Indeed, a number of gynecological cancer patients gain weight after diagnosis. An example of the conundrum of physical activity and weight loss effect on survivorship stems from a randomized clinical trial incorporating a 12-week, homebased, moderate intensity exercise program, where some cancer survivors believed that physical activity was helping to improve body image and functional capacity but weight loss was less impressive (Figure 5.4) [57]. Von
Gruenigen et al. [58] validated a lifestyle intervention program with exercise and diet modifications for obese endometrial cancer patients in which the intervention group lost 3.5 kg compared to a 1.4 kg gain in controls, with no significant decrease in intake of calories.
Increased Activity Levels
Increased Physical Fitness/Functioning
Physical Activity Associated Benefits
Psychological Benefits
Fatigue Benefits Range of Programme Benefits
Body Shape Changes
Normalising of Symptoms Additional Benefits
Opportunity for Emotional Expression
FIGURE 5.4 A focus group study exploring gynecological cancer survivors’ experiences and perceptions of participating in a randomized controlled trial (RCT) testing the efficacy of a home-based physical activity intervention. Source: Ref. [57].
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Encouraging patients to be physically active can improve glucose metabolism, digestive function, immune function, and cardiovascular risk factors [59,60]. However, according to Gary Taubes, the energy balance concept of calories in versus calories out for weight loss and/or weight management falls short of supporting evidence via clinical trials [61]. Furthermore, Taubes demonstrates in his book that exercise may actually increase appetite and cause people to be carbohydrate (i.e. the fuel for making people fat) hungry. From these studies, we can determine that obesity appears to be related to physical inactivity; however, the question remains as to whether exercise helps with weight loss regardless of diet. This is not to diminish the documented benefits of exercise also found in a selfreported cohort study of 126 gynecological cancer survivors, where 43 women reported that exercising for more than 6-months led to significant improvements in weight, sleep, feeling better, and a perceived reduction of other chronic diseases compared to nonexercisers [62]. Thus, the debate continues. There are few studies showing an association between cancer survivors meeting physical activity guidelines and eating a healthy diet (including five-a-day fruit or vegetable servings) and successful weight loss. Moreover, there are fewer studies related to long-term survivorship of endometrial cancer, particularly in the areas of lifestyle modifications to reduce cardiovascular risk factors such as obesity [63]. Most studies published on any lifestyle programming in gynecological cancer patients including endometrial, uterine, and ovarian are limited to 1-year follow-up and still require further study.
DIET CONSIDERATIONS As described above, many studies have explored the relationship between obesity and physical inactivity in gynecological malignancies, yet evidence for the effects of nutrition and diet remain inconclusive. For example, a cohort study of gynecological cancer cases and controls reported no significant differences in physical activity status; however, cases with higher recent weight and BMI were associated with significantly increased risks [64]. Remarkably, Nagle et al. discovered that women who intentionally lost weight (approximately 9 kg) and maintained this weight loss were not at increased risk. This provides further evidence that weight loss reduces risk, yet how does a patient accomplish this task in cancer survivorship?
Definitions Diets are synonymous with weight loss. There are various types of diets, paradigms, and hypotheses to answer the conundrum of the obesity epidemic. To date,
there is no overwhelming evidence that one specific plan works for any single overweight/obese individual. We previously mentioned that the caloric theory is the mainstay of maintaining energy balance and is endorsed by the United States Department of Agriculture (USDA), which recommends a daily intake of approximately 1600–2000 calories for those women who are not physically active. Also, the USDA states that a “healthy diet” for women is one containing daily portions of 1.5–2 cups of fruit, 2–2.5 cups of vegetables, 3 ounce equivalents of whole grains, 5–5.5 ounce equivalents of protein, 3 cups of dairy, and 5–6 teaspoons of oils [65].
Interventions Diet plays an important role in survivorship, especially during chemotherapy treatments. A cross-sectional mail survey from 802 gynecological cancer survivors evaluated health behaviors revealed no association between quality of life and fruit consumption, vegetable consumption, or BMI class [66]. In parallel to the selfreported survey study, an interventional lifestyle study of 27 ovarian cancer patients receiving chemotherapy treatment revealed minimal changes in fruit, vegetable, and low-fat dairy consumption––although this did not meet the recommended guidelines by the ACS [67]. Ovarian cancer patients with high-nutrient diets showed significantly longer survival rates with increased fruits and vegetables, in particular, yellow and cruciferous vegetables significantly favored survival [68,69]. With respect to protein intake, few prospective studies have investigated meat intake as a potential determinant of gynecological cancer risks in survivorship. In a case-cohort analysis of 39,614 women, a nonsignificant increase in survival was associated with an increased consumption of red meat, processed meat, and all meat combined, but with no clear patterns for poultry or fish only [70]. In 1994, the Canadian National Breast Screening Study reported on a subsample of 678 patients who completed a diet history prior to diagnosis. In the study, the risk of dying from breast cancer increased by 50% (HR = 1.50, 95% CI = 1.08–2.08) for every 5% increase in energy from saturated fat. Thus, lower saturated fat intake was associated with survival [71]. Unfortunately, these studies do not relate improved nutritional content to weight loss, even after diagnosis and during treatment. In a recent study using the Health Eating Index, ovarian cancer patients scored very similar to controls: no differences in the consumption of whole fruit, dark green and orange vegetables, and whole grains were identified [72]. The only significant difference between groups was related to meat and bean intake, which were slightly higher in controls. Given the linkage between obesity, breast cancer, risk of recurrence, and mortality, observational studies
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References
evaluating dietary interventions were undertaken. Two subsequent randomized controlled trials, the Women’s Intervention Nutrition Study (WINS) and the Women’s Healthy Eating and Living (WHEL) study reduced the amount of energy from dietary fat, with WHEL primarily focused on increasing vegetable, fruit, and fiber in the diet. Among early stage breast cancer patients, the WHEL study revealed no difference in breast cancer recurrence (HR = 0.96, 95% CI = 0.80–1.14) or mortality (HR = 0.91, 95% CI = 0.72–1.15) [73]. Among the 2437 women in the WINS trial, there were a total of 277 relapse events (local, regional, distant, or ipsilateral breast cancer recurrence or new contralateral breast cancer) reported: 96 (9.8%) out of 975 women in the dietary group and 181 (12.4%) out of 1462 women in the control group [74]. The discrepancy in results between the trials was initially explained by a lack of change in body weight in the WHEL trial; however, there were differences in the eligibility criteria for each study. The WHEL study enrolled both pre- and postmenopausal patients, and those patients were enrolled within 4 years of diagnosis, as opposed to 1 year in the WINS study. Furthermore, patients with relatively worse prognoses may have been excluded from the WINS trial, compared to WHEL [75]. Taken as a whole, the evidence tends toward a negative effect of dietary fat consumption, and the potential for other dietary interventions.
FUTURE DIRECTIONS In summary, a multidisciplinary approach highlighting nutrition and physical activity appears to be the combination required for successful survivorship. Von Gruenigen et al. [76] used a whole systems approach in a 6-month lifestyle intervention program supporting physical activity, dietary compliance of fruits and vegetables, and counseling to improve self-efficacy and quality of life. As a result, significant increases in physical activity, daily intake of fruits and vegetables, and significant weight loss were achieved, thus providing evidence that a combination of lifestyle changes leads to improved weight loss [77,78]. Nevertheless, dietary and exercise recommendations for cancer survivorship and weight loss remain controversial. We hope that results from the NCI evaluating nutrition, energetics, and physical activity, and the Transdisciplinary Research on Energetics and Cancer (TREC) initiative will be able to identify more specifically the time, dose, and type of substrate required by gynecological and breast cancer patients to improve long-term survivorship [79]. Ultimately, studies may show that physical activity and obesity predict overall cancer survivorship. It is important to engage survivors in supervised exercise and lifestyle programs because most female cancer
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survivors do not make spontaneous lifestyle changes. Accordingly, physicians have a responsibility to ensure that patients receive referrals to rehabilitation programs to improve their well-being and provide support on the journey of survivorship. We conclude that obesity is linked to prognosis and overall survival in gynecological cancer survivors and that medically supervised programs to encourage weight loss are essential.
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1. EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF ABDOMINAL OBESITY