© Springer International Publishing Switzerland 2016
David Alberts, Maria Lluria-Prevatt, Stephanie Kha and Karen Weihs (eds.)Supportive Cancer Care10.1007/978-3-319-24814-1_1414. Symptom Management: Weight Gain
(1)
Department of Medicine and Nutritional Sciences, University of Arizona Cancer Center, 1515 N. Campbell Ave., 245024, Tucson, AZ 85724-0524, USA
(2)
Department of Physical Therapy and Athletic Training, Northern Arizona University, 208 E Pine Knoll Dr., Flagstaff, AZ 86011, USA
(3)
School of Nursing, Northern Arizona University, 202 E Pine Knoll Dr., Flagstaff, AZ 86011, USA
(4)
Biobehavioral Nursing and Health Sciences, University of Washington, 202 E Pine Knoll Dr., Flagstaff, AZ 86011, USA
(5)
Nurse Practitioner, Northern Arizona Oncology, 202 E Pine Knoll Dr., Flagstaff, AZ 86011, USA
14.1 The Problem
Being overweight or obese, classified by body mass index (BMI) of 25–29.9 kg/m2 and ≥30 kg/m2, respectively, is considered a risk factor for several cancers. Approximately one-third of all cancers in the United States are related to patients being overweight or obese and physically inactive and consuming a diet poor in nutritional value [1, 2]. The cancers most often associated with obesity are postmenopausal breast cancer; colorectal, endometrial, kidney,pancreatic cancer, and the adenocarcinoma subtype of esophageal cancer. The risk of other cancer types has been inconsistently associated with obesity, such as prostate cancer [3–5].
Many physicians, scientists, and the public are aware of the cancer risks associated with excess weight. It is less well known that post-diagnosis weight gain is associated with some cancers and cancer treatments. Although weight gain is common in some cancers, the risks associated with the weight gain are unclear. Some studies indicate that overweight, obesity, and weight gain are associated with poorer outcomes, including increased risk for recurrence, metastasis, poorer quality of life (QOL), and reduced survival for several types of cancers [2, 6–10], while others show no association between weight gain and recurrence or survival [11–13]. In addition, weight loss can also occur in cancer survivorship within the cancer types commonly associated with weight gain, although it may be less common. Weight loss can also be associated with poorer outcomes [13].
It appears that monitoring weight change and considering overall medical history and treatment are critical to providing advice regarding weight management in cancer survivorship. For example, poorer outcomes with weight gain may be due, in part, to decreased effectiveness of extended adjuvant endocrine-modulating therapies in obese survivors compared to normal weight survivors [14–17]. So, whether an individual is overweight or obese when diagnosed or experiences weight changes over the course of treatment, weight management can be an important component of supportive care.
This chapter will focus primarily on issues related to weight gain. First, we will review the evidence describing which cancers and cancer treatments are associated with weight gain. Research will be summarized detailing what cancer patients and survivors can do to prevent and treat weight gain, both during and after cancer treatment. In this section, behavioral strategies (such as modification of physical activity and dietary intake) and therapeutic and pharmacological approaches will be highlighted. In addition, surgical approaches and integrative approaches that combine several strategies will be discussed. It should be noted that the current body of literature related to cancer and weight gain is heavily weighted toward breast cancer research, and thus, this chapter is similarly skewed. The chapter will conclude with directions for future research in the area of weight gain and cancer prevention and treatment.
14.2 Evidence
Adverse changes in body composition, along with weight gain and weight loss, have been described among cancer survivors, both during and after treatment. Several of the most common cancers and cancer treatments have been associated with weight gain – the most commonly studied are breast cancer (including ductal carcinoma in situ) and colorectal cancers. Some evidence is available for prostate cancer, ovarian cancer, and some other less common cancers.
14.2.1 Breast Cancer
The majority of the research regarding risks associated with weight gain and cancer has been conducted among breast cancer survivors. These studies have found that weight gain following breast cancer diagnosis remains a significant concern, in spite of changes in cancer therapy. Evidence has suggested that post-diagnosis weight gain among breast cancer survivors is associated with functional limitations, pain, decreased QOL, and poorer survival particularly among racial/ethnic minorities. However, not all study findings have been consistent, as described below [12].
14.2.1.1 Prevalence of Weight Gain
A 2011 review by Vance and colleagues [18] including 32 studies reported that between 50 and 96 % of women experience weight gain during treatment for breast cancer, and many (including some who did not gain weight during treatment) have reported weight gain during the months after diagnosis.
The earliest studies reported a high proportion of patients gaining weight. For example, the oldest study in the review by Haesman and colleagues reported that 96 % of a sample of 237 women treated with adjuvant chemotherapy gained weight during treatment [19]. In 1986, Chlebowski and colleagues reported that among 62 women receiving adjuvant chemotherapy, 91 % of CMF-treated women reported weight gain and 74 % of 5-FU-treated patients [20].
Although lower than the initial studies, more recent, larger studies report that substantial proportions of patients gained weight during and after treatment. The study with the largest number of participants was the Nurses’ Health Study, which included 5204 participants diagnosed with incident, invasive, nonmetastatic breast cancer [21]. In this study, it was found that about half experienced post-diagnosis weight gain, whereas 21.5 % reported weight loss. The weight gain or loss was defined as the weight change from pre-diagnosis to first measured BMI at least 12-month post-diagnosis. The second largest study (N = 3993) of women diagnosed with invasive nonmetastatic breast cancer found that 70 % of participants gained at least 2 kg. The average follow-up from diagnosis was 5.8 years [22].
14.2.1.2 Amount of Weight Gain
The mean amount of weight gain for the entire study population ranges from 0.30 kg among a study of 260 Korean women [23] to 5.0 kg among 17 patients in early-stage breast cancer receiving adjuvant chemotherapy [24]. Most studies reported a weight gain of about 2–3 kg on average, with a follow-up period of about 3 years. For example, Rock and colleagues found that among 1116 stage I–IIIA breast cancer patients who had completed adjuvant chemotherapy and/or antiestrogen treatment, average weight gain was 2.7 kg over a 26-month period [25]. A large study (N = 3250) by Cann et al. reported that mean weight gain over the study period (median follow-up of 5 years) was 2.4 kg [11].
14.2.1.3 Factors Associated with Weight Gain
Several factors have been identified to be associated with weight gain. First, several studies tracked weight at different time points and found that weight gain increased in the years after follow-up. For example, in a study of 185 stage I–III breast cancer patients receiving adjuvant chemotherapy and/or hormonal therapy, Makari-Judson and colleagues reported that average weight gain in the first year was 1.5 kg, at 2 years 2.7 kg, and at 3 years 2.8 kg [26]. Levine and colleagues reported that for 69 % of breast cancer patients receiving adjuvant therapy (N = 32), weight gain during treatment averaged 1.8 kg, whereas at 2-year follow-up, 84 % had gained weight with an average of 4.18 kg [27]. Caan and colleagues further reported that in their study of 3250 patients in stage I–IIIA breast cancer, weight gain was progressive after diagnosis in all treatment groups, but stabilized at about the 3-year follow-up time point [11].
Another factor that may impact weight gain and its consequences is whether patients treated were premenopausal or postmenopausal. Several studies have reported that weight gain during and after treatment was greater among premenopausal women compared to women who were postmenopause. In a study of 646 patients with node-positive disease treated with or without adjuvant chemotherapy, Camoriano and colleagues found that premenopausal women gained an average of 5.9 kg at a median follow-up of 6.6 years, compared to 3.6 kg for postmenopausal women who were treated with adjuvant chemotherapy [28]. Women who were postmenopause and did not receive adjuvant chemotherapy only gained an average of 1.8 kg. Consistent with these findings was a recent study by Heideman and colleagues among 271 Dutch women with stage I–III breast cancer who received chemotherapy and/or hormonal therapy (71 %) or no systemic treatment (29 %). At the follow-up (mean 3.1 years), it was found that on average, premenopausal women gained 3.9 kg, compared to 1.1 kg of postmenopausal women [29]. However, findings are not all consistent, as a small study by McInnes and Knobf (N = 44) reported little difference in weight gain between premenopausal and postmenopausal breast cancer patients at 1- and 2-year follow-up (although from 2–3-year follow-up, postmenopausal women gained 1.5 kg on average, compared to 0.4 kg among premenopausal women) [30]. These effects may further be impacted by age. For example, in a large study (N = 1116), Rock and colleagues reported that postmenopausal breast cancer patients over the age of 50 gained on average 2.0 kg, compared to 2.4 kg for premenopausal women. However, women who were postmenopause and under 50 gained an average of 4.5 kg [25].
The most recent study of weight changes in breast cancer survivors (N = 665) confirmed the factors associated with weight gain in breast cancer survivorship above as well as adding some additional insight. The study evaluated up to 5-year post-diagnosis weight changes to determine patterns and influencing factors. The mean weight gain was 4.5 % ± 10.6 % body weight; a total of 44 % of women gained at least 5 % body weight. Older age again conferred slightly lower risk of weight gain (ORadj = 0.97, 95 % CI 0.95–0.99), as did Hispanic ethnicity (ORadj = 0.30, 95 % CI 0.13–0.68). Being overweight (ORadj = 0.11, 95 % CI 0.05–0.23) or obese (ORadj = 0.03, 95 % CI 0.02–0.07) at diagnosis was also inversely associated with weight gain. Time elapsed since diagnosis (ORadj = 1.19/year, 95 % CI 1.04–1.36) and smoking at diagnosis (ORadj = 2.69, 95 % CI 1.12–6.49) were positively associated with weight gain [31].
14.2.1.4 Weight Gain and Disease-Free Survival
Most studies evaluating the impact of weight gain on breast cancer treatment outcomes have included disease-free survival, generally defined as cancer recurrence and mortality. Additionally, several studies have evaluated the impact of weight change on functional abilities, quality of life, and pain.
In several large studies, weight gain during and after treatment has been associated with poorer disease-free survival. In the Nurses’ Health study (N = 5204), the authors contrasted those who maintained their weight (median weight change 0.0 lbs) to participants who lost weight (median 9.0 lbs) and those who gained weight (median 6.0 lbs) and participants who gained a substantial amount of weight (median 18.0 lbs). They found that among participants who never smoked, at follow-up (median 9 years), weight gain (but not weight loss) was significantly associated with higher all-cause mortality, breast cancer deaths, and cancer recurrence. Greater weight gain was associated with greater risk of recurrence and mortality [21].
These findings are consistent with another large recent study (Nichols et al. 2009) of 3993 women with invasive nonmetastatic breast cancer. The authors found that each 5 kg weight gain was associated with an increased risk of all-cause (RR = 1.12) and breast cancer mortality (RR = 1.13). Weight gain of greater than 10 kg was associated with a 70 % and 78 % increased risk, respectively [22]. Not all findings are consistent, however, as other large studies did not find an association between weight gain and recurrence or mortality. A study of 1692 breast cancer survivors followed for up to 4 years demonstrated that weight gain after a breast cancer diagnosis was not associated with an increased risk of recurrence or death from any cause; additionally moderate weight loss (5–10 %) did not decrease risk of these outcomes [12]. Similarly, risk of recurrence was not associated with weight gain in breast cancer survivors followed for 5–7 years [11]. Yet, other factors may influence the results, for example, Camoriano et al. only found an association of premenopausal women between weight gain and recurrence and mortality [28].
14.2.1.5 Weight Gain and Functional Outcomes
Weight gain during and after treatment has further been associated with other treatment outcomes such as functional limitations and pain. In a large, recent, cohort of early-stage breast cancer survivors (N = 1841), post-diagnosis weight gain ≥10 % was associated with an increase in any limitation (OR = 1.79; 95 % CI = 1.23–2.61), moderate to severe limitations (OR = 2.30; 95 % CI = 1.75–3.02), and lower body limitations (OR = 2.05; 95 % CI = 1.53–2.76) compared to women who maintained weight within 5 % of pre-diagnosis weight [32]. In another recent study, even less weight gain (≥5 %) was associated with lower scores in physical functioning (−7.2 %) and vitality (−11.2 %) among breast cancer survivors (N = 483; all P trend <0.05) [33]. The association between functional limitations and weight loss is less clear. Significant weight loss (≥10 % pre-diagnosis weight) among normal weight women without comorbidity and overweight/obese women with a comorbidity may increase the risk of functional limitations, but significant weight loss in overweight/obese women without comorbidities was associated with a lower risk of limitations [32]. Preventing functional limitations may be best achieved by supporting weight maintenance during and after breast cancer therapy.
Post-diagnosis weight gain (>5 %) has also been positively associated with above-average pain determined by SF-36 bodily pain scores (OR, 95 % CI = 1.76, 1.03–3.01, above average = bodily pain scores ≥1/2 standard deviation worse than age-specific population norms). Physical activity may mitigate the pain, but a large randomized controlled trial specifically designed to test the effects of physical activity on pain and other symptoms in breast cancer survivors who have experienced significant post-diagnosis weight gain has not yet been conducted [34]. There is some indication that the negative impact of endocrine-modulating therapies on body habitus, pain, and QOL may be ameliorated by physical activity in premenopausal breast cancer survivors based on a small feasibility study (N = 41) [35].
14.2.2 Colorectal Cancer
Given the prevalence of colon cancer and the established increased risk for colon cancer among the overweight and obese [3], there is a surprising gap in the state of knowledge related to weight status and weight gain during survivorship. Among resected colon cancer patients, some recent evidence suggests that being overweight or obese may be associated with poorer prognosis compared to being of normal weight [36]; however, the relationship may not be linear and may be geographically specific. For example, one large prospective study by Meyerhardt reported that weight change during the time period between ongoing adjuvant therapy and 6 months after completion of therapy did not significantly impact recurrence and survival among 1053 patients with stage III colon cancer, although 64.3 % of participants reported a weight gain of 5 kg or more and 76.8 % of participants reported a weight gain of at least 2 kg. Less than 10 % of participants reported a weight loss greater than 2 kg. However, the data revealed that the pattern of the chances of cancer recurrence was quadratic, with people losing or gaining a lot of weight having the highest hazard ratios and the people maintaining their weight having the lowest hazard ratios [37]. Meanwhile, another recent study in Taiwan demonstrated no effect of overweight or obese status on survival outcomes [38]. The differences between studies may be partially explained by tumor characteristics. For example, tumor expression of p27 [39] and p21 [39] has been shown to interact with body mass index to influence prognosis and survival. Further, exercise post-diagnosis has been associated with improved survival among colon cancer survivors [40], which may be partially influenced by the positive changes in body composition induced by exercise.
14.2.3 Prostate Cancer
The effects of obesity on prostate cancer are varied. The differences between earlier studies may have been due to obesity increasing the risk of aggressive prostate cancer, but reducing the risk of low-grade, nonaggressive, and more treatable cancer, which has been made evident more recently [41, 42]. Recent reviews suggest that overweight or obesity status may also increase the risk of recurrence in prostate cancer patients [36, 41], and the larger individual studies support the notion that obesity prior to diagnosis leads to poorer outcomes post-diagnosis. For example, the prospective National Institutes of Health-AARP Diet and Health Study demonstrated an increased risk of prostate cancer mortality, but not incidence with higher BMI and adult weight gain among the 287,760 men ages 50–71 years followed for 5–6 years [5]. Similarly, the recent Physicians’ Health Study analysis of men diagnosed with prostate cancer (N = 2546) followed for approximately four times as long (24 years) showed that overweight and obese men had a significantly higher risk of prostate cancer mortality (proportional hazard ratio [HR] 1.47 [95 % CI 1.16–1.88] and 2.66 [1.62–4.39], respectively; P(trend) < 0.0001), which remained even after controlling for clinical stage and Gleason grade. In a subgroup analysis, overweight/obese status with high C peptide concentrations conferred four times higher risk of mortality (4.12 [1.97–8.61]; P(interaction) = 0.001) [43].
Joshu et al. demonstrated nearly double the risk of prostate cancer recurrence with weight gain >2.2 kg from the years prior to prostatectomy to the years postsurgery [44]. Another very recent analysis by Bonn et al. of weight status at diagnosis as well as weight change and prostate cancer progression and survival was conducted in N = 4376 men diagnosed with localized prostate cancer, confirming increased risk of all-cause mortality among men who were obese at diagnosis (HR 1.47, 95 % CI 1.03–2.10). Further, the post-diagnosis weight change analysis demonstrated a U-shaped relationship, such that weight loss >5 % after diagnosis almost doubled the rate of all-cause mortality (HR 1.94, 95 % CI 1.41–2.66), and weight gain >5 % nearly doubled the rate of prostate cancer-specific mortality (HR 1.93, 95 % CI 1.18–3.16), compared to maintaining a stable weight [45]. However, the influence of adult weight gain prior to diagnosis remains unclear [42, 46, 47].
Several studies have documented that men diagnosed with prostate cancer experience adverse changes in body composition during and after treatment. These changes appear to be strongly related to androgen deprivation therapy and other treatments that will be discussedmore in depth within Sect.14.2.9.
14.2.4 Gynecologic Cancers
14.2.4.1 Ovarian Cancer
One of the largest prospective studies, the European Prospective Investigation into Cancer and Nutrition (EPIC, N = 226,798 women) confirms the suspected relationship between obesity and risk epithelial ovarian cancer [48], although the relationship may vary by early adulthood weight status and pre- versus postmenopausal diagnosis, even after accounting for age of menarche [49]. Further, obesity may delay diagnosis, interfere with surgical and cytotoxic treatment, and increase complications [50], yet there is little information on the impact of weight status at diagnosis and weight gain following diagnosis. In general, it appears that weight change (increase or decrease) during and after treatment for ovarian cancer may be stage specific [51], but overall, post-diagnosis weight gain has been identified as a concern among ovarian cancer survivors themselves [52]. As such, a panel of experts from the National Cancer Institute recommends evaluating weight gain in ovarian cancer clinical trials [53]. Given the limited evidence, the association between mortality and high BMI and weight gain is unclear, for example, Backes et al. found no effect of BMI on overall survival in a study of 198 patients, but a nonsignificant trend toward increased risk of death with weight gain over the 6-month posttreatment period [54], while Zhou et al. found that post-diagnosis BMI was significantly associated with ovarian cancer mortality, as was adult weight gain, in a study roughly twice the size [55]. One reason for disparate outcomes may be weight gain and resolution due to water retention with treatment, which should be distinguished from changes in body composition related to fat mass, lean mass, and bone [56].
Of note, there is some evidence that diet may influence overall survival among ovarian cancer patients [57]; however, trials to prevent weight gain or promote weight loss among ovarian cancer survivors are lacking. Two ongoing trials to determine if healthy lifestyle may influence survival in ovarian cancer will likely shed light on outcomes related to weight change, as well. The trials are described in Sect. 14.3.
14.2.4.2 Endometrial/Uterine Cancer
Endometrial cancer of the uterus is the most common gynecologic cancer. Body mass and degree of fat mass have been associated with risk of endometrial/uterine cancer [3, 58], with early life exposure to high BMI and weight gain contributing to higher risk and earlier onset [59]. Although the majority of women are diagnosed with early stage-disease, obesity-related comorbidities, such as cardiovascular disease, may be contributing to overall mortality, as up to 70 % of these patients may be obese today [7, 60]. However, there is a paucity of research related to body habitus and disease outcomes following endometrial cancer diagnosis [7, 60], the studies that are available are not aligned in design or outcome. The first reviewed study demonstrated that BMI was associated with all-cause mortality and complications, but not disease-specific mortality or cancer recurrence among early-stage uterine cancer patients (N = 2596 women) [61]. In contrast, another study found no association between obesity and overall survival [62], and yet another found moderate weight gain 6 months after diagnosis to be associated with the best prognosis. The worst prognosis was among those with weight loss which persisted when the analysis was restricted to recurrences at follow-up >18 months. In a relatively large trial limited to obese patients (N = 659; BMI obese 30–39 kg/m2, morbidly obese 40–49 kg/m2, and super obese ≥50 kg/m2, respectively) with endometrial hyperplasia/uterine cancer, the degree of obesity did not influence progression-free or disease-specific survival, but did influence surgical outcomes in those with a BMI ≥40 kg/m2 [63]. Based on the small amount of evidence, targeting lifestyle changes and weight maintenance may be the best course of action in endometrial cancer patients who are not morbidly obese. Recent lifestyle interventions among obese endometrial cancer survivors have shown that significant intentional weight loss and improved lifestyle behaviors are feasible in this population [64, 65], but clinical outcomes are not yet known and will require larger randomized controlled trials.
14.2.5 Other Cancers
There is very little literature on the topic of post-diagnostic weight gain and cancer outcomes for thyroid cancer and lymphoma. The limited amount of evidence is summarized here.
Risk of thyroid cancer has been associated with high adult BMI, weight gain, and fat distribution [66, 67]. Post-diagnosis, one study found no differences in weight gain over time between patients with thyroid cancer receiving thyroidectomy and a control group of euthyroid patients with thyroid nodules or goiter [68]. Another study that included thyroidectomy due to multiple causes found that thyroidectomy may be associated with increased body weight [69]. Despite the lack of clear evidence for thyroid cancer outcomes of QOL, prognosis, and survival related to body weight, thyroid-stimulating hormone levels are dependent on body weight, and medications should be titrated accordingly [70].
Higher weight and BMI in early adulthood have been associated with non-Hodgkin lymphoma risk [71]. Although non-Hodgkin lymphoma patients may be prone to weight gain and adverse body composition changes with treatment [72], the effects of weight change on QOL, prognosis, and survival are unclear for this cancer, as well. Among non-Hodgkin lymphoma patients, being underweight at diagnosis or any pre- or post-diagnosis or treatment weight changes were associated with poorer survival in one study (underweight HR = 2.84; 95 % CI = 1.12–7.15; pre-diagnosis weight loss HR = 1.42; 95 % CI = 1.02–1.97; posttreatment weight loss HR = 1.98; 95 % CI = 1.14–3.45; post-diagnosis weight gain HR = 1.85; 95 % CI = 1.04–3.32) [73], while posttreatment weight gain was associated with a positive prognosis in another study [74].
14.2.6 Cancer Treatments Associated with Weight Gain
Some chemotherapies and endocrine modulating therapies have been associated with weight and body composition changes. Sex steroids play a significant role in body weight and body composition regulation. Cancer treatments that limit or eliminate circulating sex steroids such as estrogen, testosterone, and dihydroepitestosterone (DHT) have been associated with weight gain; these include pharmaceutical blockade, ovarian and testicular failure, and/or gonad removal.
14.2.7 Chemotherapy
Adjuvant chemotherapy has been implicated in weight gain among breast cancer survivors in the United States and Europe as well as the promotion of sarcopenic obesity (preferential gain of fat and loss of lean body mass) in both chemotherapy-induced ovarian failure patients and naturally postmenopausal breast cancer survivors, although pretreatment weight and menopausal status may modify the relationship between chemotherapy and body composition and weight changes [10, 75–77]. Other regions do not experience weight gain with chemotherapy, which may be attributable to differences in age of diagnosis, initial body weight, therapeutic regimens, environment, and behavior [78, 79]. Whether or not the weight gain resulting from chemotherapy in breast cancer directly results in poorer outcomes is not clear. Results from the large Nurses’ Health Study (N = 5204) suggest that weight gain may significantly increase the risk of breast cancer recurrence [21], while results from other observational studies have been mixed [11, 80]. However, other prognostic outcomes in breast cancer patients, including overall survival and new cancers, that may be related to post-chemotherapy weight gain have not been sufficiently evaluated. The effects of chemotherapy on weight in other cancer survivor populations await further study.
14.2.8 Estrogen Modulation in Women
In addition to loss of ovarian function either from chemotherapy or simply natural menopause, extended endocrine-modulating therapies, such as selective estrogen receptor modulators (SERM), aromatase inhibitors (AI), or estrogen receptor blockers, are administered to reduce recurrence and improve overall survival in breast cancer survivors, with choice of medication depending on menopausal status [81]. Tamoxifen, an SERM, often given to breast cancer survivors, has long been associated with increased body weight [82] and more recently associated with increased body fat, fatty liver, and intra-abdominal fat [83, 84]. Aromatase inhibitors, which act to reduce the availability of estrogen, were less likely to be associated with weight gain than SERMs (ORadj = 0.54, 95 % CI 0.31–0.93) [31], and women who switched from SERMs to AIs experienced a favorable shift in body composition up to 24 months due to decreases in body fat (P < 0.05) and increased lean body mass [85, 86]. Fulvestrant, an agent that competitively binds estrogen receptors, may be employed for tamoxifen-resistant, estrogen-sensitive, human breast cancers; however, there is insufficient evidence in the literature to determine if luteinizing hormone-releasing hormone (LH-RH) agonist or estrogen receptor blocker (fulvestrant) therapies contribute to weight gain, although the common biological mechanism of limiting circulating estrogen implies that they may.
14.2.9 Antiandrogen Therapy in Men
Androgen deprivation therapy (ADT) is associated with weight gain and adverse changes in body composition in men being treated for nonmetastatic prostate cancer [87–91]. Similar to weight gain in breast cancer survivors, the weight gain in prostate cancer survivors varies by baseline age and BMI. Those <65 years of age or a BMI <30 kg/m2 treated with leuprolide were more likely to gain weight in a recent study of nonmetastatic prostate cancer survivors treated with ADT for at least 6 months (N = 118) [89]. Additionally, smaller studies of men with nonmetastatic prostate cancer treated with the GnRH agonist leuprolide (N = 32) or either GnRH agonist or bilateral orchiectomy (N = 79) had significant increases in body weight and percentage fat body mass and decreases in percentage lean body mass and muscle size [88, 92]. Of note, the increased body fat was primarily a result of subcutaneous rather than intra-abdominal fat [88]. A prospective study of age- and education-matched prostate cancer survivors on ADT, prostate cancer survivors not on ADT, and healthy controls followed for 3 years (N = 257) confirmed that prostate cancer survivors on ADT gained significantly more weight than those not using ADT and healthy controls. It also demonstrated greater weight gain in those <65 years of age (P = 0.005) [93]. Although counterintuitive, it may be that the younger, healthier prostate cancer survivors are in greater need of weight management counseling than older survivors.
Further, Hakimian et al. reported that ADT has been prospectively linked to increased high cholesterol and triglycerides, insulin resistance, and metabolic syndrome [94], which are biomarkers commonly associated with obesity and weight gain. As a result, Saylor and Smith report that ADT has been associated with an increased risk of diabetes and cardiovascular disease [94–97]. Again, exercise has been associated with decreased cancer-specific mortality among prostate cancer survivors, and known positive effects of exercise on body composition may account for a portion of the association [40].
14.2.10 Changes in Body Composition
Even without weight gain, unfavorable changes in body composition (i.e., decrease in lean muscle mass, fat gain, bone density changes) have been found to be prevalent. Several studies have documented that fat mass has increased and represents most of the weight gain during and after breast cancer. A recent review by Vance et al. indicated that breast cancer patients stages 0–III may gain about 2 kg in fat mass at 6 and 12 months follow-up, representing an approximate increase in body fat of 2 %; a similar 2 % increase in body fat was also found between the first- to third-year post-diagnosis in another study. Other unfavorable changes have included a decrease up to 4 % of fat-free mass, especially pronounced in the leg region, and a decrease in bone mineral density [18].
Sarcopenia, the degenerative loss of skeletal muscle, is commonly found among cancer patients. For example, the Health, Eating, Activity and Lifestyle (HEAL) study enrolled 1183 women with breast cancer who were within 12 months of diagnosis. In a sub-analysis, 471 women with invasive ductal carcinoma had a dual-energy X-ray absorptiometry (DXA) scan12 months post-diagnosis and were followed for 9 years; of these women, 75 (16 %) were sarcopenic and 38 % were obese. Women with sarcopenia were older at diagnosis and had lower body fat, smaller waist circumference, and lower BMI compared to nonsarcopenic women. Sarcopenic women were postmenopausal and diagnosed with earlier stage of disease. Sarcopenia was associated with an increase risk of all-cause mortality and a higher cancer-specific mortality and shorter survival compared to nonsarcopenic survivors [98].
Sarcopenia is strongly associated with adverse outcomes (treatment toxicity and poorer survival) in other cancers too [99]. Low skeletal muscle mass is associated with greater chemotherapy toxicity in colon cancer patients (N = 62) receiving 5-FU and leucovorin, with women having a higher odds ratio for toxicity (OR, 16.73; P = 0.021) [100]. Obese sarcopenic patients with gastrointestinal or lung cancer (N = 250) also have a higher risk of mortality (HR = 4.2; 95 % CI, 2.4–7.2) compared to nonsarcopenic patients [101]. In the pancreatic setting, sarcopenia predicts mortality among overweight and obese patients (N = 111) (HR = 2.07; 95 % CI, 1.23–3.50) [102].
Taken together, these findings indicate that unfavorable changes in body composition including lean mass, fat percentage, and bone density are prevalent among most cancer patients/survivors. The absence of weight gain does not preclude cancer survivors from experiencing adverse consequences based on changes in body composition.
14.2.11 Weight Loss
Although the focus of this chapter is on weight gain, it should be noted that weight loss can be a significant problem in breast cancer survivorship, as well. A recent pooling project by Caan et al. with more than 12,000 participants supported the prior literature on increased risk of death with weight gain, although it did not reach significance. However, while fewer women lost weight than gained it, 14.7 % versus 34.7 %, the study participants who lost ≥10 % were at a 40 % increased risk of death in the United States and greater than 3 times the risk in Shanghai (P < 0.05) [13]. These results imply unintentional weight loss due to recurrence. Additionally, pre-diagnosis weight status was a mediating factor, as were comorbidities [13]. Unintentional weight loss is also associated with poorer outcomes and survival in various advanced cancers, such as colon, head and neck, ovarian, and others [103–106]. Taken together, weight stability throughout treatment and survival is optimal and individual medical history should inform on the type of weight management advice given to cancer patients and survivors.
14.3 Ongoing Research
Several studies funded by the National Cancer Institute (NCI) are underway to examine lifestyle interventions for weight management in cancer survivorship. Additionally, there are both core centers (P30) and research consortia (U54) funded by the NCI that include weight management pilot and full projects. The following paragraphs describe a few NCI trials funded at the R21 and R01 level that are underway; it is in no way an exhaustive list of clinical trials. Nevertheless, great strides are expected to be made in the field in the coming decade.
14.3.1 Individual Cancer Types
As noted earlier in the chapter, current interventions are more heavily weighted toward breast cancer survivors. However, trials incorporating other cancer types and underserved populations within breast cancer are underway and will lead to advances in the literature and perhaps the standard of care for survivors. Dr. Cheryl Rock is leading a multidisciplinary trial named “Reducing Breast Cancer Recurrence with Weight Loss: A Vanguard Trial” from the University of California, San Diego, but the trial joins experienced investigators from five of the leading cancer centers. Along with primary and secondary aims related to weight loss maintenance, cost-effectiveness, QOL, and mechanisms, the ultimate goal of the trial is to initiate the effort to establish weight control support for breast cancer survivors as a new standard of clinical care. The project is expected to be completed by February 2015. Another study to explore the efficacy of a weight loss intervention on BMI, biological markers of breast cancer progression, comorbidities, and psychosocial factors among breast cancer survivors will incorporate the underserved African American population. The trial is led by Dr. Melinda Stolley at the University of Illinois in Chicago. The project is expected to come to a close in July of 2016. To better understand and serve rural breast cancer survivors, Dr. Befort at the University of Kansas Medical Center is leading a group phone-based intervention for weight control among rural breast cancer survivors. The purpose of the study is to develop a clinically effective and cost-efficient strategy for producing long-term weight loss maintenance, associated biomarker modulation, and improved quality of life among rural breast cancer survivors who are at greater risk for recurrence than their urban counterparts. The project is expected to end in May of 2016. Additionally, ductal carcinoma in situ (DCIS) will be used as a model to explore mechanisms by which obesity and weight loss may affect neoplasia by Dr. Wendy Demark-Wahnefried at the University of Alabama in Birmingham. The trial is exploring the feasibility and potential impact of presurgical weight loss on serum biomarkers, tumor characteristics, and clinical outcomes of overweight and obese patients with DCIS. The planned completion date is March 2016.
The less studied ovarian cancer survivor population will contribute to two large trials that have been recently initiated to examine the effects of diet and physical activity in ovarian cancer. Although weight loss is not the primary aim of either trial, useful information about weight management in the context of ovarian cancer is likely to emerge. The “Impact of Exercise on Ovarian Cancer Prognosis” study (PI: Dr. Melinda Irwin) will enroll women diagnosed with stage I–III ovarian cancer (N = 230). Women will be randomly assigned to 6 months of moderate intensity aerobic physical activity, at 150 min per week, or attention control. The primary outcomes are QOL and surrogate markers of prognosis. The LIvES (Lifestyle Intervention for Ovarian Cancer Enhanced Survival; PI: Dr. David Alberts) study is a randomized trial of recent stage II–IV ovarian, primary peritoneal, and fallopian tube cancer survivors from among the Gynecologic Oncology Group (GOG) clinics across the United States (N = 1070). It will evaluate whether diet and physical activity combined can improve QOL and prevent recurrence for women who are in clinical complete remission from advanced ovarian peritoneal or tubal cancer.
A trial by Dr. Nora Nock at Case Western Reserve University will expand the research base for obese endometrial cancer (EC) survivors by evaluating a novel transdisciplinary approach to improve self-reported eating behavior, exercise motivation, and quality of life as well as decreased neural activation in response to high-calorie food images in brain regions associated with food reward and motivation among obese EC patients. The ultimate goal is improved survival of obese EC patients. This recently initiated project is not expected to be completed until 2018.
The National Cancer Institute of Canada Clinical Trials Group funds an ongoing exercise and colon cancer survivorship trial. This Colon Health and Life-Long Exercise Change trial will utilize a multi-site, structured physical activity intervention compared to general health education materials. The intervention will include supervised physical activity sessions and behavioral support over 3 years with the primary end point of disease-free survival. The team will also evaluate multiple patient-reported outcomes, objective physical functioning, biological correlative markers, and an economic analysis [107].
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