Interventions to Promote Energy Balance and Cancer Survivorship: European and North American Priorities for Research and Care

Abstract

The growing population of cancer survivors worldwide and the growing epidemics of obesity and physical inactivity have brought increased attention to the role that interventions to promote exercise and a healthy body weight might play in mitigating the chronic and late effects of cancer. In this light, we describe the similarities and differences in research and clinical priorities related to energy balance interventions among post-treatment cancer survivors in Europe vs. North America. We review the randomized, controlled trials targeting nutrition, exercise, and weight to affect survivorship outcomes. We discuss the interventions focused on improving prognosis or survival, as well as the emerging literature on interventions targeting pathways and mechanisms of prognosis or survival. We describe current North American and European guidelines for diet, exercise, and weight control among cancer survivors and discuss implications of the current state of this science for clinical care. Finally, we delineate future European and American priorities for research and care involving energy balance among survivors. We hope that this dialogue launches an international conversation that will lead to better research and care for all post-treatment cancer survivors.

Introduction

Thanks to earlier detection and better, targeted and multi-modal cancer treatment, many individuals diagnosed with cancer can now expect to live for years beyond their treatment. Recent data showed that an estimated 28 million people worldwide had a history of cancer as of 2008¹, the most recent year for which worldwide data are available. That number represents 5-year prevalence, so it is a dramatic underestimate of the total number of cancer survivors. Further, the number of cancer survivors will increase significantly in the coming years with the aging of the Baby Boomer generation (those born 1946-1964).For example, in the US alone, it is estimated that there will be over 18 million survivors by 2022, 11 million of whom will be older adults².

While the increase in the number of cancer survivors is good news, it also means that more people than ever before are living with the chronic and late effects of cancer treatment. Chronic effects are problems present during treatment that may persist for months or years after treatment and include fatigue; neuropathy and pain syndromes; depression, anxiety, and distress; lymphedema; problems with cognition; incontinence; altered body image; and sexual dysfunction³. Late effects are not present during treatment but emerge during the post-treatment period and include cardiovascular disease; endocrine dysfunction; diabetes; osteoporosis; upper or lower quadrant mobility issues and functional limitations; and increased risk of recurrence, second cancers, and disability³. Research attention in the last 15 years on both sides of the Atlantic has focused on identifying risk factors for physical and psychosocial chronic and late effects of cancer treatment and on developing and testing interventions to prevent or reduce risk of these negative sequalae. One important line of this research has focused on the role of obesity and energy balance as determined by dietary intake and energy expenditure, in determining risk of chronic and late effects and the role that interventions to promote exercise and a healthy body weight might play in mitigating these problems.

Worldwide, physical inactivity and obesity are common. In the United States (US), over one-third of adults are obese with another one-third considered overweight⁴.Fifty-three percent of US men and 60% of women do not engage in recommended levels of physical activity⁵ while over one-third of adults are considered inactive. Rates of obesity^{6, 7} and inactivity⁷ are slightly better in Canada than the US. In Europe, the prevalence of obesity varies by country from 4-37%, lower in the western and northern regions and more akin to US estimates in the eastern, central, and southern areas⁸.The prevalence of inactivity in Europe also differs by country with Sweden, Finland, Austria, Ireland, and The Netherlands reporting lower levels of inactivity than the US and Belgium and Mediterranean countries reporting equivalent levels of inactivity to the US⁹.

Cancer, inactivity, and obesity are also related. Physical inactivity and obesity are associated with increased risk of many cancers¹⁰and with increased risk of cancer progression and poor prognosis¹¹.Preclinical studies have suggested that excess body weight and inactivity may affect cell growth, differentiation, and apoptosis to promote primary tumor growth and also affect tissue invasion and angiogenesis leading to tumor progression¹².Compounding the problem of cancer survivors being likely to be obese and inactive, people diagnosed with cancer often decrease their physical activity levels, eat poor quality diets, and gain weight over the course of treatment, noted especially among breast cancer survivors ^{13, 14}.The result of these factors is that the weight gain tends to be gains in fat mass with a corresponding loss of lean (muscle) mass. This problem, called sarcopenic obesity, may adversely affect risk of chronic and late effects, and poor prognosis.

In this commentary, we aim to describe the similarities and differences in research and clinical priorities related to energy balance interventions among post-treatment cancer survivors in Europe vs. North America. We do not mean this to be an exhaustive review of these topics; but rather a tool to initiate an international dialogue about these issues, which we hope will lead to better science and care for cancer survivors worldwide. We focus here on physical activity, weight, and diet as it contributes to obesity and sarcopenic obesity but do not cover the immense research on dietary components, isolates, or supplements and cancer. We present the problem of body composition changes among survivors as two sides of the same coin: greater overall body weight and/or elevated BMI values which can obscure, the presence of muscle wasting/cachexia.

Randomized, controlled trials targeting nutrition, exercise, and weight to affect survivorship outcomes

The last five years have brought a considerable increase in the number of studies that develop and test interventions that aim to help survivors improve their exercise or diet or lose weight. Most of these studies have been conducted in the US or Canada, perhaps due to the increased prevalence of obesity and inactivity there, but the reasons for the greater interest here are unknown. Some of these studies have been “proof of concept” studies, i.e., testing whether the intervention in fact does improve physical activity or reduce weight. But a growing body of studies have targeted survivorship outcomes; aiming to improve quality of life, reduce chronic effects of treatment, improve specific aspects of physical functioning, or reduce risk of late effects of cancer.

Systematic reviews and meta-analyses of the literature on physical activity interventions for cancer survivors have found that these interventions significantly reduce depression^15-17 and fatigue^16-25 and improve cardiorespiratory fitness, muscle strength, body composition, and physical functioning^{17, 22-26}, body image¹⁶and quality of life^{16, 17, 24-27}. Resistance training can improve cardiopulmonary and muscle function, peak oxygen update, strength²⁸and quality of life²⁹. Importantly, weight training has been shown to increase muscle mass and decrease body fat, thereby improving sarcopenic obesity³⁰. Exercise interventions that include strength training also may preserve bone health in cancer survivors³¹. Indeed, the available evidence shows that exercise is one of the most important therapies to improve functioning and quality of life of cancer survivors. In contrast to the recent burgeoning number of exercise trials, trials are just beginning to evaluate weight loss among cancer survivors. These interventions have been conducted almost exclusively among women with breast cancer. A recent review of this literature suggests that weight loss interventions may improve body composition (especially when combined with exercise), physical functioning, and quality of life³².

Lymphedema

Another major focus of research in the last 10 years has been investigating the role of energy balance in risk for lymphedema (LE) and the role of exercise and weight loss interventions in reducing risk for or exacerbations of LE. LE, which can occur after surgery for breast cancer and for other malignancies, has major physical (discomfort, swelling, increased risk for infections and secondary malignancies) and psychological (depression, body image disorders) consequences that can decrease quality of life and may affect survival. In most patients (approximately 75%) LE develops within 1 year of breast surgery, but because of its insidious onset, LE carries a lifetime risk for breast cancer survivors³³. Pre-operative body mass index has been largely recognized to increase the risk for LE^34-37 with BMI values >30 doubling the risk³⁸. In spite of the well-established relationship between preoperative overweight and postoperative risk of LE, few studies have evaluated the role of body weight reduction with either reduced-energy diets or exercise on the risk of developing or exacerbating LE in breast cancer survivors. Two British studies of breast cancer survivors showed thatweight loss through hypocaloric or a low-fat diet can significantly reduce breast cancer-related LE^{39, 40}. A review of strength training studies conducted with survivors who haveLE shows that slowly progressive strength training is safe and does not exacerbate LE symptoms⁴¹. Strength training interventions in the US have been found to decrease the severity and exacerbations of LE symptoms among breast cancer survivors⁴² and to decrease the likelihood of increased arm swelling among women at high-risk for lymphedema⁴³. In summary, the role of weight loss, physical exercise, dietary restrictions and nutritional counseling in the prevention or control of LE in long-term breast cancer survivors remains largely unexplored both in the US and in Europe, underscoring the urgent need for large multicenter trials addressing this relevant clinical issue.

Interventions Focused on Improving Prognosis/survival

Whether exercise and/or weight loss might favorably influence prognosis or overall survival is a matter of great interest in North America. Such trials must include large sample sizes and lengthy follow-up periods and thus have not been completed to date. However, a study funded by The National Cancer Institute of Canada is currently conducting a survival trial testing whether exercise can favorably influence disease-free survival among individuals diagnosed with higher risk colorectal cancer (CHALLENGE trial)⁴⁴.A study testing the effects of weight loss on survival from ER+ breast cancer (LISA trial; PI P Goodwin; clinicaltrials.gov identifier # NCT00463489) was also being conducted in Canada; however, the study was terminated early due to loss of funding.

Two diet intervention studies in breast cancer survivors in the US have been carried out. The Women’s Intervention Nutrition Study (WINS) tested the effects of a low-fat diet among 2437 women with early stage breast cancer on relapse. An interim analysis conducted with 5 years of follow-up data revealed marginally significantly lower relapse-free survival in the low-fat diet arm, with subgroup analyses showing significantly lower relapse among women with ER- breast cancers⁴⁵. However, it is not known whether these effects are due to the low-fat diet or to the average 6-pound weight loss experienced by women in the intervention group. The Women’s Healthy Eating and Living (WHEL) study tested the effects of a low-fat, high fruit &vegetable/fiber diet on cancer outcomes in 3088 women with breast cancer. Women in the intervention arm reduced their fat intake but did not lose weight, and there was no difference between the intervention and control arms in recurrence-free survival⁴⁶. However, subgroup analyses revealed that prognosis was improved among women in the intervention group who did not report hot flashes (who likely had higher circulating estrogen levels)⁴⁷.

Interventions Focused on Improving Biomarkers of Prognosis or Survival

In the absence of trials targeting survival, some investigators in the US and Canada have begun to investigate whether physical activity, diet, or weight change can favorably influence intermediate biomarkers of prognosis/survival including sex hormones, insulin or insulin-like growth factors or their binding proteins, insulin resistance, glucose metabolism, leptin and other adipokines, immunologic or inflammatory factors, oxidative stress and DNA damage or repair capacity, angiogenesis, or prostaglandins. For example, Pakiz et al. investigated the effect of weight loss intervention (regular physical activity and reduced energy intake) on inflammation and vascular endothelial growth factor in overweight or obese breast cancer survivors. Weight loss was associated with reduced cytokines levels and, increased energy expenditure was associated with a significant reduction of circulating interleukin-6⁴⁸. Befort et al. showed that a low calorie diet and physical activity reduced body weight and improved fasting insulin and leptin levels in rural American breast cancer survivors⁴⁹. Allgayer and colleagues in Germany documented the effects of exercise on DNA damage⁵⁰ and inflammation⁵¹ in colorectal cancer survivors. For a complete summary, please see recent reviews of this emerging literature^{52, 53}, and the recent US Institute of Medicine report on this topic¹¹. Of note, although this has been a topic of emphasis in North America, aside from the work of Allgayer cited above and a recently closed clinical trial in the UK⁵⁴, this has not been a priority among European investigators. Future studies are needed to clarify the role of weight loss and physical activity on biomarkers of prognosis or survival among cancer survivors, including the dose and type of these interventions that are needed to garner protective effects.

Guidelines & Care Implications

United States

The American Cancer Society (ACS) provides guidelines on nutrition and physical activity for cancer survivors⁵⁵. These guidelines state that during the post-treatment phase, setting and achieving lifelong goals for weight management, a physically active lifestyle, and a healthy diet are important tools to promote overall health and quality and quantity of life. These guidelines are based on the consideration that individuals who have been diagnosed with cancer are at a significantly higher risk of developing second primary cancers and chronic diseases such as cardiovascular disease, diabetes, and osteoporosis, and thus the guidelines established to prevent those diseases are relevant. In brief, the ACS guidelines advise survivors to achieve and maintain a healthy weight. Overweight or obese survivors should limit consumption of high-calorie foods and beverages and increase physical activity to promote weight loss. All survivors should engage in regular physical activity and avoid inactivity, aiming to exercise at least 150 minutes per week, including strength training exercises at least 2 days per week, and eat a diet high in vegetables, fruits, and whole grains. These guidelines are consistent with the ACS Guidelines on Nutrition and Physical Activity for Cancer Prevention for the general population. The American College of Sports Medicine Roundtable on Exercise Guidelines for Cancer Survivors echoes the ACS guidelines, stating the current national exercise guidelines for the US population are appropriate for cancer survivors⁵⁶.

Europe

The National Cancer Survivorship Initiative Supported Self-Management Workstream developed in 2010 in the UK (Department of Health, Macmillan Cancer Support, NHS Improvement, 2010) aimed at updating the World Cancer Research Fund (WCRF) report’s guidelines⁵⁷. Although the authors recognize the gaps in the evidence for lifestyle benefits in cancer survivors, some key lifestyle general recommendations are provided regarding diet (reduce saturated fats, increase fish intake and consume a varied diet in order to ensure adequate intakes of vitamins and essential minerals; increase consumption of green and cruciferous vegetables, etc) and physical activity (at least 30 minutes a day of moderate-intensity physical activity on five or more days of the week, but even a modest amount of exercise is considered beneficial and thus encouraged). The role of body composition changes occurring in many cancer patients depending on tumor localization and treatments is also emphasized. In particular, the loss of lean body mass (sarcopenia) for patients with head and neck and gastrointestinal cancers is highlighted, and physical exercise is suggested to build lean muscle to prevent post-treatment disability, loss of autonomy and impaired quality of life. In breast cancer patients exercise/activity is suggested for controlling body weight and losing fat to combat treatment-related weight gain (exacerbated if pre- diagnosis BMI is not in the healthy range). Excess weight should be avoided. The recommendation is also given to maintain a stable healthy weight as opposed to fluctuating between a healthy and unhealthy BMI. As with the US exercise guidelines, the British Association of Sport and Exercise Sciences provided guidance on exercise for cancer survivors citing that survivors should follow health-related physical activity guidelines for the general UK population⁵⁸. Besides its role in the achievement of energy balance and maintenance of healthy body weight, regular physical exercise should be encouraged to prevent or counteract the loss of muscle mass and function (i.e.sarcopenia) that frequently complicates cancer and its therapies. Although most frequently occurring during the phase of active disease and treatments and in advanced cancer,⁵⁹sarcopenia and the consequent functional impairment may represent a life-long disability for cancer survivors and thus survivorship care needs to prevent, assess and treat this debilitating condition. Permanent impairment in nutritional status secondary to medical or surgical cancer therapy may ultimately lead to skeletal muscle loss that interferes with everyday activities. Overall, little attention has been paid both in the US and European guidelines to sarcopenia-related impairment in quality of life in long-term cancer survivors. In this view, attention to body composition should be improved, since normal/elevated body weight or BMI might well mask an underlying life-threatening sarcopenia.

Future priorities for research and care involving energy balance among survivors: European and American perspectives

Meeting the needs of the growing population of cancer survivors requires the development of innovative models of care, which may be used to inform and enhance cancer survivorship care in different health care settings⁶⁰. The relevance of researching and optimizing the delivery of care to cancer survivors is being widely recognized in North America, and is being progressively recognized in Europe. However, critically looking at the available literature, it is apparent that both the American and European approaches to cancer survivorship have pitfalls, particularly where non-cancer-related health problems, such as promotion of healthy behaviors, are concerned. A number of specific issues have to be addressed and solved by future research in this field to build support for a model of comprehensive survivorship care that meets the needs of all survivors:

1. Although current evidence from cohort and cross-sectional studies suggests that excess body weight and sarcopenic obesity are associated with increased risk of chronic and late effects of cancer, trials should test whether intentional weight loss among cancer survivors results in decreased risk of lymphedema or late effects such as cardiovascular disease. Both North American and European investigators have acknowledged this as a priority area.

2. Current guidelines on prescribing exercise, nutrition, and weight control interventions for cancer survivors are based on general public-health advice given to the general population. However, achieving the level of healthy behaviors set forth in these recommendations may not be effective for reducing morbidity and mortality among cancer survivors. Randomized clinical trials are needed to generate evidence-based guidelines for cancer survivors.

3. A related direction concerns being able to prescribe appropriately targeted, individualized lifestyle recommendations for cancer survivors. On both sides of the Atlantic there is interest in conducting trials that establish what intensity and type of intervention is needed given an individual survivor’s unique disease, psychosocial, behavioral, and genetic profile.

4. The extent to which psychosocial issues like depression or diminished social support play a role in eating behavior and exercise after cancer treatment has received little attention in the literature on both sides of the Atlantic. For example, research should test whether ongoing psychosocial issues or effects of cancer treatments change hormones that govern appetite (e.g., leptin, ghrelin).

5. Given the demands of the cancer survivor population on the healthcare system, and the projected dramatic increase in the number of cancer survivors in the future, trials are needed to establish a risk-stratification system for triaging survivors into appropriate levels of lifestyle interventions. For example, many survivors may be able to exercise safely without medical supervision. However, others may need intense oversight and targeted exercise prescription based on cardiovascular functioning parameters along the lines of current supervised cardiac rehabilitation programs in the US. Investigators in the US⁶¹ and the United Kingdom⁶² have begun work on this kind of risk-stratification. More research is needed to identify those individuals who need different levels of lifestyle intervention and to guide the development and delivery of the intervention.

6. We need to focus on promotion of long-term maintenance of healthy behavior changes. The few studies available on this topic suggest that survivors do not maintain their healthy behavior changes over time¹¹. Current interest in Europe and North America is focusing on how to keep people exercising, eating well, and avoiding weight re-gain once the intervention ends. For example, studies are investigating the predictors of maintenance of behavior changes using behavioral theory^{63, 64} .

7. Another future direction concerns dissemination of these lifestyle interventions to all survivors who need them. Given the large geographic area of the US, there is great interest in using technology and tele-medicine approaches to increase the reach of behavioral change interventions to allow minorities and underserved populations to benefit from these interventions. For example, Demark-Wahnefried and colleagues have found that a home-based diet and exercise program utilizing telephone counseling can reduce the rate of physical decline in at-risk cancer survivors⁶⁵. Befort and colleagues have used conference call technology to significantly decrease weight among overweight, rural breast cancer survivors⁴⁹. Similar initiatives are still lacking in Europe.

8. A final area of emerging interest and debate in the US concerns bariatric surgery for cancer survivors. Bariatric surgery can result in much greater weight loss than behavioral interventions and is associated with better maintenance of weight loss¹¹. Further, bariatric surgery studies with the general population show that weight loss is associated with reductions in biomarkers of cancer prognosis¹¹. However, to date, studies have not addressed the safety and efficacy of bariatric surgery in cancer survivors specifically. In Europe, to our knowledge, there is not yet any discussion about whether bariatric surgery should be used for cancer survivors.

Conclusions

Research interests and priorities related to exercising, maintaining healthy weight and to losing weight in overweight and obese cancer survivors in Europe vs. North America are more alike than different. Much of the research in this area has been conducted in North America, but a growing body of research is being conducted in Europe as well. Where differences exist between the two continents, these are likely due to geographic-specific factors. For example, that bariatric surgery for weight loss among very obese survivors and tele-medicine approaches to delivering energy balance interventions in underserved communities are areas of interest in the US but not Europe likely reflects the larger obesity epidemic and greater geographic area of the US. However, given obesity trends in Europe suggesting an imminent surge in the epidemic⁸ and given the geographic variation between EU countries (e.g., Northern and Southern Europe), it is likely these largely US-focused debates will be relevant to Europe in the near future.

Cancer survivors on both sides of the Atlantic face some of the same barriers to receiving adequate intervention programs to promote a healthy energy balance. Although this is changing now in the UK, for the most part, energy balance interventions are not delivered routinely on either continent as part of post-treatment survivorship care. The lack of a risk-stratification system makes it impossible for health-care providers to know which survivors to refer to what types of lifestyle interventions. Weight, diet, and exercise guidelines on both continents are based on guidelines for the general population and may not be sufficient to achieve optimal health and well-being in certain subgroups of survivors. Finally, focus on assessment of BMI but not body composition may be leading to missed diagnoses of sarcopenia and missed opportunities to prevent or ameliorate this debilitating condition. That these problems are universal underscores the need for international efforts to identify and implement their solutions. We hope that this dialogue launches an international conversation that will lead to better research and care for all post-treatment cancer survivors.