Keywords

Introduction

In the last two decades, considerable progress has been made in combating cancer. Significant advances in cancer detection and treatment, and changes in modifiable behaviors (primarily smoking cessation) have led to a 27% decline in cancer mortality rates from a peak in the mid-1990s [1, 2]. Because of this improved survival rate, as well as a growing older population, the number of cancer survivors in the United States and worldwide has increased substantially. Estimates from 2019 indicate nearly 16.9 million people (approximately 5% of the US population) are cancer survivors, an increase from 1.8% of the US population in 1978 [3]. This number is projected to grow to 21.7 million by 2029 [3].

As the number of cancer survivors has increased, the importance of understanding the needs of this population has also grown. Evidence continues to accumulate suggesting obesity plays a key role in both the risk of developing and dying of cancer. Obesity is the excessive accumulation of body fat. Body mass index (BMI, weight in kilograms divided by the square of height in meters) is a common proxy for assessing overall body fatness. Among adults, overweight is defined as a BMI of 25.0–29.9 and obesity as a BMI of 30 or more. Obesity can further be divided into class 1 (BMI, 30.0–34.9), class 2 (BMI, 35.0–39.9), and class 3 (BMI, ≥40.0). Interestingly, as cancer mortality rates have declined over the last two decades, the prevalence of obesity in the United States and globally has increased significantly over the last two decades. At present, more than one-third of the US adults are categorized as obese and two-thirds are categorized as overweight [4]. Data from the National Health Interview Survey indicate the prevalence of obesity in adults with a history of cancer increased from 22.4% to 31.7% between 1997 and 2014 and the rate of increase in cancer survivors was greater than in the general population [5].

Based on a recent review of the epidemiologic literature, obesity was identified as a risk factor for 13 cancer types [6]. Incidence rates of several obesity-related cancer types have increased in the United States, in part, due to the increase in obesity prevalence [1]. Approximately 8% of all cancers (excluding nonmelanoma skin cancers) among adults are attributable to obesity [7, 8]. Obesity is primarily caused by poor diet and physical inactivity, which are also independent risk factors for cancer development and mortality. Taken together, obesity, diet, and physical activity are known as “energy balance” or “energetics.” At present, research is still being conducted to understand the relationships between energy balance and carcinogenesis and survival.

This chapter discusses the observational findings related to energetics, with a focus on obesity and cancer risk and mortality; the mechanisms mediating this relationship; and effects of weight loss interventions utilizing exercise and/or diet interventions on numerous cancer outcomes. Outcomes addressed include cancer risk and mortality as well as biological, psychosocial, and behavioral outcomes associated with cancer. Our discussion of the intervention research is primarily of studies among adults diagnosed with cancer.

Observational Studies of Obesity and Cancer Risk and Mortality

Obesity and Cancer Risk

Recently, the International Agency for Research on Cancer (IARC) reported that there is sufficient evidence to conclude that avoidance of excess body fat is associated with a lower risk for cancers of the endometrium, esophagus (adenocarcinoma), gastric cardia, kidney (renal cell), multiple myeloma, meningioma, liver, pancreas, colorectum, gallbladder, breast (postmenopausal), ovary, and thyroid [6]. Associations from meta-analyses or pooled analyses ranged from 1.2 to 1.5 for overweight and 1.5 to 1.8 for obesity for cancers of the colon, gastric cardia, liver, gallbladder, pancreas, and kidney. The association for esophageal adenocarcinoma was quite strong, with a relative risk of 4.8 for a BMI of 40 or more. For each of these cancers, there was evidence for a dose–response relationship. IARC also concluded that there was limited evidence for an association between excess body fatness and fatal prostate cancer, diffuse large B-cell lymphoma, and male breast cancer.

Obesity and Cancer Mortality

A growing body of evidence from observational studies has found that obesity is associated with poorer cancer outcomes among individuals with cancer. IARC also reviewed the relationship between body fatness and cancer recurrence and survival after diagnosis [6] and found some limitations to the existing data, including variation in study design, setting, and when body fatness was measured in relation to the cancer diagnosis. Currently, the largest body of evidence addresses breast cancer survivors, whereas studies of survivors of other cancers was more limited and findings varied [6].

A recent systematic review and meta-analysis of 79 cohort studies including over 210,000 women with 41,477 deaths estimated that compared with normal-weight women (BMI 18.5–24.9 kg/m2), those who were overweight (BMI 25.0–29.9 kg/m2) or obese (≥30.0 kg/m2) before diagnosis had statistically significant 11% and 35% increased risks for breast-cancer-specific mortality, respectively [9]. The risk of mortality associated with overweight and obesity was similar for patients with estrogen receptor (ER)-positive and ER-negative breast cancer [10].

Evidence for a role of obesity in survival from other cancers supports adverse outcomes with higher levels of obesity for endometrial, prostate, pancreatic, colorectal, hepatocellular, and ovarian cancer (limited to early-stage disease), as well as some hematologic malignancies [11, 12]. Though, as we will discuss later, overweight and obesity are at times associated better outcomes for certain cancer types. This has been seen for lung, esophageal, and kidney cancer and maybe, at least in part, due to the fact that these cancers are often associated with cachexia. It has been observed that these tumor types are more likely to be diagnosed at an advanced stage [11,12,13].

A growing number of observational studies have also observed an association between post-diagnosis weight gain and a higher risk of recurrence and mortality, independent of body mass index at diagnosis [14]. While IARC was not able to formally evaluate the association due to limited lower quality data, intentional weight loss in observational studies or from follow-up of patients undergoing bariatric surgery has been associated with reduced cancer risk, especially for breast and endometrial cancer [6]. However, not all results of observational studies of weight change have been consistent and the associations in these studies may be due to reverse causation. Therefore, randomized trials are needed to better address whether post-diagnosis weight loss in overweight or obese cancer survivors negates this adverse association between obesity and poor prognosis.

Body Composition

As mentioned earlier, most observational studies of obesity and cancer risk and mortality rely on BMI as a measure of obesity. Although BMI is correlated with obesity, it is an imperfect measure because it does not distinguish between the components of body composition, namely adiposity and muscle mass. Additionally, BMI does not fully reflect metabolic responses to excess weight and/or adiposity. Thus, some people with normal BMI have excess adipose tissue and metabolic abnormalities that are associated with poor health outcomes. These individuals have been considered to have metabolic obesity. Therefore, the use of BMI alone is a suboptimal predictor of health outcomes and of metabolic factors that may be related to cancer risk and mortality.

As discussed earlier, higher BMI is positively associated with incidence and mortality of many cancers. Although it is important to note that BMI can also exhibit a null or U-shaped relationship with cancer risk and survival, with the lowest risk of cancer associated with the overweight BMI category (i.e., BMI: 25–29). This observation of overweight associated with improved survival is termed the “obesity paradox,” [15] yet some argue the term “overweight paradox” or “BMI paradox” may be more appropriate. It is hypothesized that the shape of the association between BMI and cancer risk and survival may be determined by relationships with lean body mass and fat mass. Therefore, the “obesity paradox” controversy may be largely explained by low muscle mass, rather than low-fat mass, in the lower range of BMI (i.e., BMI <25) [16]. Low muscle mass may be important to understand in this relationship, as it is associated with higher risk of recurrence, overall and cancer-specific mortality, as well as surgical complications, and treatment-related toxicities [16]. When comparing individuals who are overweight or obese to those who are normal weight, those who are overweight/obese have higher levels of muscle on average [16].

A recent example of alternative measures of obesity was a study of dual energy x-ray absorptiometry (DXA) measures of obesity and the risk of breast cancer in a secondary analysis of 3460 postmenopausal women with normal BMI(18.5 to <25) enrolled in the Women’s Health Initiative (WHI) [17]. Percentage of whole-body fat was associated with increased breast cancer risk; hazard ratio (HR) = 1.79 (95% CI, 1.14–2.83; P = 0.03) for the upper versus lower quartile of this measure [17].

More attention is being paid to body composition and cancer. Focus is being directed here, as sarcopenia (low muscle mass) has been associated with mortality across multiple disease stages and cancer types, as well as toxicity and surgery complications [18]. A limited number of studies have evaluated body composition measures from computed tomography (CT) in relation to mortality in breast cancer patients and have found sarcopenia associated with an increased risk of death [19,20,21,22,23]. Recently, Caan et al. reported that sarcopenia defined as skeletal muscle index <40cm2/m2 (measured by a single-slice abdominal cross-sectional area at the L3 vertebra) was associated with an increased risk of death (HR = 1.41; 95 % CI, 1.18–1.69) in patients with non-metastatic breast cancer [24]. This observation raises the possibility that muscle mass, in addition to fat mass, may provide important and novel information regarding the risk of cancer and cancer outcomes. In a meta-analysis of 38 studies, low muscle area assessed from clinically acquired CT was observed in 27.7% of patients with cancer and associated with poorer overall survival (HR = 1.44, 95% CI: 1.32–1.56) [25].

Future research should use new approaches to assess body composition, such as computed tomography, which provides more detailed information on the extent and location of adipose tissue (e.g., visceral, subcutaneous, and intramuscular), as well as muscle mass.

Guidelines for Lowering the Risk of Cancer Mortality Associated with Obesity

For achieving and maintaining a healthy weight, the American Cancer Society recommends following a dietary pattern that is high in vegetables, fruits, and whole grains, avoiding sugar-sweetened beverages and limiting the consumption of processed and red meats, as well as alcohol (Table 15.1) [26]. They also advise an exercise regimen that includes 150 min per week of aerobic exercise and at least two sessions of strength training exercise per week for cancer survivors and decreasing sedentary time. The physical activity recommendations are similar to the US Department of Health and Human Resources Physical Activity Guidelines and the American College of Sports Medicine recommendation for physical activity [27].

Table 15.1 Lifestyle guidelines
Full size table

Adherence to the lifestyle recommendations on weight, nutrition, and physical activity has been associated with a reduced risk of total cancer incidence and mortality in prospective observational studies. For example, the VITAL study showed that breast cancer risk was reduced by 60% in women who met the WCRF/AICR recommendations, which are similar to the ACS recommendations, compared with those who did not meet the recommendations [28]. In another analysis of both men and women in VITAL, cancer-specific mortality was 61% lower among those who met at least five of the recommendations compared to those who did not meet any of the recommendations [29]. The Cancer Prevention Study-II (CPS-II) found a 24% and 30% lower risk of cancer mortality in 6613 women and 10,369 men, respectively, who adhered to the ACS lifestyle guidelines [30].

Despite these lifestyle recommendations being in place, a majority of cancer survivors are overweight or obese, and fewer follow the diet and physical activity recommendations. In the CPS-II, only 4% of women met all the lifestyle recommendations [30]. Similarly, in the DIANA trial, at baseline, only 7% of breast cancer patients with metabolic syndrome (and 13% of breast cancer patients without the metabolic syndrome) met the lifestyle recommendations [31]. The Iowa Women’s Health Study observed that 34% of the 2193 female cancer survivors met the lifestyle recommendations [32] and while higher than some other studies, still less than ideal.

The reason for low adherence to lifestyle guidelines is likely multifactorial. It is very difficult to make lifestyle changes and this may be further complicated by lack of access and reimbursement to structured weight management and exercise programs. Data from large-scale randomized trials of weight loss are also currently lacking regarding the amount of weight which needs to be lost and/or specific lifestyle changes that need to be made to maximize reduction in cancer risk and mortality.

In 2014, the American Society of Clinical Oncology (ASCO) published a position statement on obesity and cancer, citing their commitment to reducing the impact of obesity on cancer through a multipronged initiative to increase education and awareness of the evidence linking obesity and cancer [11].

Mechanisms Potentially Mediating the Association Between Obesity and Cancer Outcomes

The link between obesity and cancer outcomes has strong biologic plausibility. The mechanisms, through which obesity could increase cancer risk and mortality, include changes in hormones involved in glucose and energy metabolism (e.g., insulin, leptin, and adiponectin), cellular growth factors (insulin-like growth factors and their binding proteins), steroid hormone metabolism, inflammatory mediators, DNA oxidative damage, and immune function [33,34,35]. To date, many studies among cancer survivors have relied on measures related to these potential mechanisms as surrogate markers of cancer risk, recurrence, and mortality when those definitive endpoints cannot be assessed.

Goodwin and colleagues demonstrated a three-fold increase in the risk of breast cancer mortality in patients within the highest quartile of fasting insulin levels compared to the lowest [36]. In addition to insulin, other growth factors and metabolic hormones, such as insulin-like growth factor-1, leptin, and adiponectin, have been associated with poor outcomes in patients with cancer. Chronic inflammation, also associated with obesity, has also been linked to cancer prognosis.

Other newer potential mechanisms of action and biomarkers under investigation include changes in proliferation (i.e., Ki-67) in benign or tumor tissue. Assessment of gene changes at the mRNA level including microRNA, tissue cytokine changes, or changes in key proteins in pathways, such as MAP kinase and mTOR, are also being explored [37, 38]. Other novel, understudied biomarkers include DNA methylation of cancer genes and small molecule metabolite levels.

Most recently, a weight control intervention in an obese mouse model in melanoma found that obesity restricted the accessibility of chemotherapy to tumor tissues [39]. Upon weight loss, the accumulation and efficacy of chemotherapy was improved. In vitro approaches suggest drug-resistance in obese mice. Thus, preclinical models suggest that obesity not only supports cancer progression, but also impairs chemotherapy outcomes, which can be improved with weight loss.

Energy balance interventions are also being conducted to examine the impact of healthy lifestyle behavior changes in diet and physical activity on adjuvant and endocrine therapy adherence among cancer patients. It is hypothesized that favorable changes in diet and exercise may improve side effects and toxicity associated with treatment, in turn, improving adherence to treatment [40, 41].

There is growing interest in the interplay between adiposity, diet, and physical activity and the microbiome. Much of the microbiome research on body composition, to date, has focused predominantly on adiposity, with changes in adiposity impacting the gut microbiota of mice [42], and evidence that BMI is strongly related to the human gut microbiome [43, 44]. Furthermore, studies have demonstrated that the relative abundance of Bacteroidetes, a dominant bacterial phylum, in the human gut, is lower in those who are obese as compared to those who are lean, and relative abundance of Bacteroidetes tends to increase as individuals lose weight [45, 46]. There are a few human studies that have examined the relationship between weight-loss interventions and the gut microbiota, but these are largely restricted to studies of surgery-mediated weight loss. One study of 30 obese women who underwent bariatric surgery detected 58 bacterial genera, which were undetectable before bariatric surgery, in 6-month postsurgical fecal samples from all patients [47]. The results of this study and two smaller studies [48, 49] provide compelling evidence that microbial diversity increases after weight loss. However, it remains unclear if these changes are restricted to surgery-mediated or extreme weight loss.

Tying research on the microbiome together with carcinogenesis has also revealed that altered composition of the gut microbiota, including lower alpha-diversity (i.e., the number of taxa detected in the gut) was associated with postmenopausal breast cancer [50], as well as high non-ovarian systemic estrogen levels that contribute to postmenopausal breast cancer risk [51]. Kwa et al. also recently described the “estrobolome” as important in breast cancer, whereby intestinal bacterial genes capable of metabolizing estrogens might be associated with ER+ postmenopausal breast cancer [52]. Metabolites and numerous microbial metabolites, such as enterolactone, have been inversely associated with lower all-cause mortality, breast cancer-specific mortality, and disease-free survival among breast cancer patients [53].

Given the hypothesized and known mechanisms mediating the association between obesity and cancer, there is a need to identify energy balance interventions that can favorably change these mediators or surrogate markers. While this will not prove cause-and-effect, it can point to types of interventions that could have biological effects, and which would be most advantageous to test in a randomized clinical trial with disease-free survival endpoints.

Randomized Trials of Weight Loss on Cancer Outcomes

Trials on Surrogate Markers

A growing number of interventions have been conducted evaluating weight loss as a surrogate marker of cancer outcomes in cancer survivors, given the associations between BMI and cancer risk and mortality. Research has focused largely on breast cancer survivors. The majority of weight loss interventions have achieved over 5% weight loss from baseline. A 10% weight loss goal had previously been adopted for many weight loss trials. However, a weight loss of 5% or more is considered clinically significant by the United States Preventive Services Taskforce (USPSTF) [54].

The Lifestyle Intervention Study in Adjuvant Treatment of Early Breast Cancer (LISA) by Goodwin et al. was a 2-year multicenter, telephone-based weight loss intervention in women with breast cancer [55]. The intervention entailed decreasing total energy intake (500–1000 kcal per day deficit) and attaining 150–200 minutes of moderate intensity physical activity per week to achieve up to a 10% weight loss (up to 10%). They observed a statistically significant 5.3% weight loss at 6 months in the weight loss group compared with a 0.7% weight loss in the control group. A statistically significant weight loss was sustained over 2 years (3.6% loss versus 0.4% loss), The original aim of LISA was to examine the impact of weight loss on disease-free survival; however, accrual was terminated after the enrollment of 338 of the 2150 planned participants because a loss of funding, leaving the clinically important questions of weight loss effect on breast cancer recurrence and mortality unanswered.

Irwin and colleagues conducted an in-person and telephone-based weight loss trial in 100 women treated for breast cancer [56]. This intervention also recommended dietary changes and increasing physical activity to achieve weight loss. Women who were randomized to intervention lost 6% body weight on average versus 2% in control subjects. This weight loss led to a 30% statistically significant reduction in C-reactive protein and nonsignificant 10% and 15% reductions in insulin and leptin, respectively.

Recently, Dieli-Conwright and colleagues examined the impact of a 16-week exercise trial on adipose tissue changes related to inflammation, specifically in white adipose tissues, in breast cancer survivors [57]. Exercise participants experienced significant improvements in body composition, cardiometabolic biomarkers, and systemic inflammation (all p < 0.03 versus control). Adipose tissues from exercise participants showed a significant decrease in pro-inflammatory M1 adipose tissue macrophages (ATM) (p < 0.001), an increase in anti-inflammatory M2 ATM (p < 0.001), increased adipose tissue secretion of anti-inflammatory cytokines such as adiponectin and decreased secretion of the pro-inflammatory cytokines IL-6 and TNF- α (all p < 0.055). Thus, suggesting that exercise attenuates adipose tissue inflammation in obese postmenopausal breast cancer survivors, though the small sample size limits conclusions from this trial.

Building off of clinically important research showing a benefit of supervised resistance training on breast cancer-related lymphedema [58], Schmitz and colleagues recently conducted a 4-arm trial of diet-induced weight loss, home-based exercise, the combination of weight loss and exercise versus control on breast cancer-related lymphedema in 351 breast cancer survivors experiencing lymphedema [59]. Despite clinically meaningful weight loss and high adherence to the home-based exercise, these lifestyle interventions did not improve lymphedema outcomes. Thus, supervised, facility-based exercise programs may be necessary for improving lymphedema. Some research has been conducted in relation to other cancer types. For example, a recent study examined weight loss in 44 men with prostate cancer prior to radical prostatectomy to determine if weight loss affects tumor apoptosis and proliferation [60]. Overweight and obese men scheduled for radical prostatectomy were randomized to a 5–8-week weight loss program consisting of standard structured energy-restricted meal plans (1200–1500 Kcal/day) and physical activity or to a control group. The primary endpoint was apoptotic index in the radical prostatectomy malignant epithelium. Men randomized to the intervention group had significantly more weight loss (Intervention: −3.7 ± 0.5 kg; Control: −1.6 ± 0.5 kg; p = 0.007) than the control group; however, there was no significant difference in apoptotic or proliferation index between the groups. In addition, triglyceride and insulin levels were significantly decreased in the weight loss group compared with the control group.

Trials on Cancer Risk and Mortality

A large body of observational data supports a relationship between weight and cancer risk and mortality and preclinical trials and smaller biomarker trials, providing a biologic rationale for this relationship. However, there are little data regarding the impact of weight loss upon the risk of recurrence and mortality in those diagnosed with cancer from randomized controls trials. Given that weight is a modifiable factor, further research is needed to determine if weight loss could be an effective strategy to improve prognosis in overweight and obese men and women with cancer.

Diet trials on breast cancer risk and mortality have been conducted and weight loss trials in cancer survivors are underway and will provide definitive evidence as to whether lifestyle change will improve cancer outcomes.

Diet Trials

Two diet trials have been conducted among early-state breast cancer survivors addressing breast cancer recurrence and survival [61, 62]. Though the studies did not focus specifically on caloric restriction, they warrant review here. The Women’s Healthy Eating and Living (WHEL) study was a multicenter trial conducted among 3088 women who had been previously treated for early-stage breast cancer [62]. The intervention involved a telephone counseling program, cooking classes, and newsletters to promote diet that included a daily diet of 5 vegetable servings plus 16 oz. of vegetable juice, 3 fruit servings, 30 g of fiber, and 15–20% of energy intake from fat. The primary study outcomes were recurrent and new primary breast cancer and all-cause mortality. The study followed women for 7.3 years and there was no reduction in breast cancer events or mortality. Over the course of the study, it was found that the groups differed by less than 80 kcal/d in energy intake and by less than 1 kg in body weight. Thus, if the effect of a dietary change on these outcomes would function through a weight change causal pathway, it is possible that the lack of weight loss in the intervention group may partially explain the null finding. It was also noted that WHEL participants in both groups had a high fruit and vegetable intake at baseline, such that it may have been difficult to detect differences across the groups due to diet composition changes.

The Women’s Intervention Nutrition Study (WINS) did observe a statistically significant modest difference in weight loss and observed a reduction in breast cancer recurrent among those in the intervention groups compared to the usual diet group after a median follow-up of 5 years [61]. These effects were stronger in the subgroup of estrogen receptor negative tumors. The intervention group targeted a low-fat diet (15% of total energy intake) and provided individual counseling to participants from registered dietitians.

A third trial focused on diet and breast cancer was the Women’s Health Initiative (WHI) Dietary Modification trial, though the primary outcome was breast cancer risk among 48,835 women without a history of the disease [63]. The intervention sought to reduce fat to 20% of total energy intake as well as increase fruit, vegetable, and grain intake. The intervention group had a modest statistically significant 3% weight loss after 1 year. Though the main intervention findings for a low-fat diet on the risk of breast cancer after a median of 8.5 years of follow-up were suggestive of an inverse association, the results were not statistically significant. With continued follow-up (16.1 years), a recent analysis found deaths after breast cancer were significantly reduced in the intervention group [64]. There was also a reduction in deaths from breast cancer, but this was not statistically significant. These effects were not altered with adjustment for weight change.

As research studies on energetics and cancer outcomes continue, diet may be an important component to attaining weight loss in lifestyle interventions. While the existing studies were not designed for weight loss, data from these point to the importance of weight change for cancer survivors. Additionally, diet quality, independent of physical activity and BMI, may also be relevant to cancer outcomes, as a recent meta-analysis found higher diet quality associated with lower overall mortality in cancer survivors [65].

Ongoing Weight Loss and Lifestyle Trials

The Breast Cancer Weight Loss (BWEL) study is an ongoing study designed to test the impact of a 2-year telephone-based weight loss intervention on invasive disease-free survival in 3136 women with stage II-III, HER-2 negative breast cancer who have a body mass index (BMI) of at least 27 kg/m2 [66]. Secondary outcomes of the trial include the impact of the weight loss intervention on overall survival, body weight, physical activity, dietary intakes, incidence of comorbidities, serum biomarkers, and patient-reported outcomes. The intervention content is based on the Diabetes Prevention Program, Look Ahead, and LISA and has a weight loss goal of 10% based on caloric restriction and increased physical activity. The intervention entails 42 telephone calls, delivered by health coaches based at the Dana-Farber Cancer Institute. Calls are supplemented by an intervention workbook, as well as a number of tools to help facilitate weight loss.

The SUCCESS C trial is another lifestyle intervention on women with breast cancer with an evaluation of disease-free survival [67]. This study has enrolled 2292 women with a BMI of 24 or higher who were diagnosed with HER2-negative early-stage breast cancer and were treated with one of two chemotherapy regimens. Results should be forthcoming in the next couple of years.

Another ongoing study called LIVES [68] involves a 24-month lifestyle intervention in relation to progression-free survival after oncologic therapy for stage II-IV ovarian cancer. Women are randomized 1:1 to a high vegetable and fiber, low-fat diet with daily physical activity goals or an attention control group. Secondary outcomes to be evaluated include QoL and gastrointestinal health.

In summary, a favorable finding from these and other future energy balance interventions in relation to survival would likely influence the number of clinicians recommending weight management through diet and/or exercise. Additional data relevant to cancer outcomes would also improve the landscape of reimbursement of lifestyle programs, especially given that lifestyle behaviors are associated with improved quality of life and reduced comorbidities.

Other Cancer Outcomes Examined in Weight Loss Trials in Cancer Survivors

In the absence of convincing information regarding the beneficial effects of weight management, healthy eating, and exercise on recurrence or death, we can look to the impact of these factors on general health, reduced toxicity and fatigue, enhanced physical functioning, better quality of life, and lower risk of diabetes and cardiovascular disease among cancer survivors. All of these additional outcomes can provide important potential benefits to survivors.

A growing number of studies have examined the effects of exercise on cardiovascular disease in cancer survivors, with a review indicating that exercise improves cardiorespiratory fitness—a powerful predictor of mortality [69]. Growing evidence and numerous systematic reviews and meta-analyses also suggest that exercise may improve quality of life in patients treated for cancer [70,71,72,73].

In a randomized controlled trial entitled RENEW (Reach-out to Enhance Wellness), which promoted increased physical activity, a healthy diet, and as low rate of weight loss among 641 older, overweight, and obese long-term cancer survivors, of which 45% (n = 289) had been diagnosed with breast cancer, Morey and colleagues found that at 12-month follow-up, mean physical function scores declined less rapidly in the intervention arm (−2.15; 95% confidence interval [CI], −0.36 to −3.93) than in the control arm (−4.84; 95% CI, −3.04 to −6.63) (p = 0.03) [74]. Moreover, changes in the intervention arm were significantly more favorable in terms of lessened pain and enhanced vitality, overall health, social functioning, mental health, and physical and emotional roles.

Results from the ENERGY weight loss trial conducted in 692 breast cancer survivors found improvements in physical function [75]. However, differences in vitality were not as strong and only reached borderline significance; moreover, between-arm differences in quality-of-life components diminished more rapidly over time, rather than being largely sustained over the 2-year study period.

Research Gaps in Regard to Socioeconomic Status, Race/Ethnicity, Age, and Geography

A workshop convened by the National Cancer Policy Forum of the National Academies of Sciences, Engineering, and Medicine in 2017 discussed multiple issues related to obesity and cancer and identified some key gaps in the current research [72]. Below, we highlight the areas identified by this recent workshop that brought together experts in energetics and cancer. The opportunities, for additional work they discussed, included expanding research into certain populations of cancer survivors with a focus on several key groups that have a higher burden of cancer, namely cancer survivors who are low-income, minority, older, or living in rural settings [72]. Compounding this issue is the fact that these individuals are also more likely to be inactive, overweight or obese, and suffer some other comorbid chronic conditions.

As mentioned early, much of the energy balance research, particularly interventions in cancer survivors, to date, has focused on breast cancer and even when addressing other cancers, studies have largely enrolled non-Hispanic whites. Therefore, research is needed to develop culturally appropriate weight loss interventions in a diverse range of populations to assess how these can potentially benefit a wider swath of cancer survivors [72]. This includes not only survivors of racial and ethnic minorities, but also those from different socioeconomic backgrounds. This work is critical to not only address the needs of these survivors but also reduce disparities in cancer outcomes.

Existing research, among racial and ethnic minority cancer survivors, had been limited by small sample sizes as well as quasi-experimental designs, and most have been conducted among only breast cancer survivors [72]. While these studies have helped to establish important issues related to feasibility, much can be done to expand upon this area, including assessing biomarkers and address other cancer types. Encouragingly, many of the studies have found favorable changes on outcomes, such as weight loss, behavior changes, and quality of life indicating the great potential for future work in these populations.

One study of a lifestyle intervention in an understudied population was conducted by Stolley and colleagues. They examined the effects of Moving Forward, a weight loss intervention for African American breast cancer survivors on weight, body composition, and behavior [76]. Women were randomly assigned to a 6-month interventionist-guided (n = 125) or self-guided (n = 121) weight loss program supporting behavioral changes to promote a 5% weight loss. Both groups lost weight. Mean and percentage of weight loss were greater in the guided versus self-guided group; 44% in the guided group and 19% in the self-guided group met the 5% goal. This study supports the efficacy of a community-based interventionist-guided weight loss program in African-American breast cancer survivors.

In addition to addressing the minority cancer survivors, there is a need for energy balance research among both older and younger cancer survivors [72]. Approximately 64% of cancer survivors are 65 years and older, and by 2040 older survivors are projected to make up 74% of survivors [3]. Recent estimates indicate there are 429,000 childhood cancer survivors and more than 80% of children with cancer survive 5 years or more [3, 77]. There are also an estimated 70,000 adolescent and young adult cancer survivors [3, 77]. In both of these groups of cancer survivors, there is a strong need to research the side effects of cancer and their treatment [72]. Given the increased risk of cardiovascular disease, second cancers, osteoporosis, metabolic syndrome, fatigue, cognitive changes, and sarcopenia in these survivors, these two groups could potentially benefit from lifestyle energy balance interventions.

Rural cancer survivors are also understudied in the existing energy balance research. They have higher cancer mortality rates, comorbidities, obesity, and physical inactivity than their urban counterparts [72], suggesting an opportunity for interventions that improve outcomes.

As the field moves forward, expanding research in the groups identified above will help to ensure that energy balance intervention associated with better outcomes can benefit a larger group of cancer survivors. In addition, since these populations may have a lower prevalence of many of the lifestyle recommendations related to diet and physical activity, there may be an even greater chance for interventions to have measurable effects. Tailored interventions developed with input from these populations and key stakeholders are key to ensure short- and long-term success.

Implementation of Energy Balance Interventions in Clinical Care

Physical activity and weight management have not traditionally been a part of cancer treatment or cancer survivorship programs. Given that programs targeting these factors carry a tremendous potential to affect the length and quality of survival in a positive manner and prevent or control morbidity associated with cancer or its treatment, oncologists and primary care physicians should be encouraged to counsel cancer survivors proactively about exercise and weight management.

As a result of the strong effect of lifestyle changes on diabetes prevention in the Diabetes Prevention Program (DPP) trial, certain YMCA facilities across the country offer a modified version of the DPP program. Additionally, certain YMCAs across the country offer the LIVESTRONG at the YMCA program, which is a free 3-month exercise program for cancer survivors [78].

In general though, for adults with obesity, the USPSTF recommends obesity behavioral interventions that entail 12–26 visits over the course of a year [54]. However, few providers have been trained in the delivery of behavior change therapies; and, currently, few major insurance plans provide reimbursement for the duration of care recommended by the USPSTF. Counseling for obesity is also typically underutilized. Lack of utilization may involve limited access to care, time constraints of primary care physicians, as well as a lack of training available for learning to deliver effective behavioral counseling.

Future Directions of Energy Balance and Cancer Research and Clinical Care

The immediate priorities for research related to obesity, energetics, and cancer outcomes include the need for information on the amount of weight loss and exercise likely to result in reduced cancer risk and mortality; more research in minorities, rural populations, and varied age groups; cost-effective methods for delivering energy balance interventions; and surrogate markers strongly associated with cancer risk and mortality. There is also a need to expand research to include different cancer sites and address the effects of energetics on newer cancer therapies.

Further, a more detailed elucidation of the contributions of body composition to cancer risk and mortality will be important to help identify those most at risk for poorer outcomes and to inform preventive strategies. Data also support the inclusion of sarcopenia, along with adiposity and BMI, as standard oncological markers.

Lastly, future studies should explore what factors influence weight loss success in various cancer types. Overall, the limited number of well-powered randomized trials in cancer survivors highlights the need for future studies to determine whether weight loss, and which components of weight loss interventions, in cancer survivors (or those at high risk) improves cancer outcomes.