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Obesity in Pediatric Oncology: Assessment, Treatment Strategies, and Knowledge Gaps

Obesity in Pediatric Oncology: Assessment, Treatment Strategies, and Knowledge Gaps The development of obesity is a frequent consequence of the treatment of childhood cancer. Moreover, because of the overall prevalence of obesity in the United States, many children are already obese at diagnosis. In this article, the authors review key considerations in the prevention and treatment of obesity in children with cancer, such as nutritional assessment, the pathophysiology of obesity in children with cancer, implications of obesity in therapeutic dosing for cancer, management strategies, and knowledge gaps and research priorities. A discussion of the pathophysiology of obesity in children with cancer, along with its management, is relevant to the field of pediatric oncology, not just because of its well-described long-term health and social consequences, but because obesity is associated with a worse event-free survival and increased treatment-related mortality in children with the most frequent type of childhood cancer: acute lymphocytic leukemia (ALL) (1,2). In a meta-analysis of the six studies published to date on this topic that include together 8680 children and adolescents with ALL, higher body mass index (BMI) was associated with reduced event-free survival (fixed-effects relative risk (RR) = 1.35, 95% confidence interval = 1.20 to 1.51) (2). (The relationship between obesity and outcomes of other types of childhood cancers has not been as well-studied, but the state of the science is discussed in other manuscripts in this series.) Therefore, in this manuscript, we will describe the assessment of obesity in pediatric patients with cancer in the United States and other high-income countries, the potential factors that contribute to the development of obesity during treatment, and the challenges and strategies associated with the prevention of and treatment of obesity. In addition, we will also highlight the gaps of knowledge in the field of pediatric oncology on how nutrition, body composition, and energy balance affect pediatric cancer outcomes and an agenda for future research. Nutritional Assessment The 2000 Centers for Disease Control and Prevention (CDC) growth charts constitute the standards used for the assessment of nutritional status of 2- to 19-year-old children and adolescents. The CDC growth charts were developed by combining growth data from multiple national surveys including the National Health and Nutrition Examination Surveys conducted before 1988–1994 to construct a new series of growth curves representative of the US population of children and adolescents (3). Growth data from the 1988–1994 National Health and Nutrition Examination Surveys were excluded because of the recognition that the increasing prevalence of obesity within the population would increase the baseline for comparison. The 2000 CDC growth charts also provided the first BMI [weight (kg)/height (2)] growth charts. In children, nutritional status is assessed by measuring height, weight, and BMI and comparing these values to a z-score (SD score). Obesity, or “overnutrition,” represents one end of the spectrum of malnutrition; undernutrition is also equally important to recognize and is often overlooked by pediatric oncologists; hence, here we offer the definition of both diagnoses. Undernutrition is categorized either as “wasting,” measured by a z-score of weight for height of 2 or less, or “stunting,” measured by a z-score of height for age of 2 or less (4). In the United States, where severe undernutrition is rare, undernutrition is commonly defined as a BMI in at least the 5th percentile. Equally important, from a therapeutic perspective, is the trajectory of weight, height, and BMI. Acute undernutrition is characterized by weight loss. Acute undernutrition therefore will be characterized by a decrease in BMI, reflecting a decrease in weight for height (“wasting”), whereas chronic undernutrition is characterized by a decrease in height for age (“stunting”). The weight for height and BMI may, however, be within the normal range in a child with stunting. Because weight changes more rapidly than height over time, weight changes can be used to assess more acute changes in nutritional status, whereas decreases in height velocity will reflect longer term changes in nutritional status. It should be apparent that longitudinal height and weight data from the same child that allow an assessment of changes in height, weight, and BMI over time are much more meaningful than measurements at a single time point. The diagnosis of overweight is based on a BMI between the 85th and 95th percentiles, whereas obesity is characterized by a BMI at the 95th percentile or higher. However, it is important for the clinician to recognize that BMI and body composition (or percent body fat) are two separate measures. Body composition is increasingly recognized as an independent predictor of health other articles in this series, as discussed in this series. BMI is an unreliable measure of fat and body composition between the 5th and 85th percentiles. Although fatness is more reliably associated with a BMI of at least the 85th percentile, clinical inspection, particularly in overweight children and adolescents, is necessary to determine whether overweight is attributable to excess fat, increased frame size, or increased muscle mass. Body fat is significantly increased in most youth with a BMI of at least the 95th percentile. In some adolescents, however, the 95th BMI percentile exceeds a BMI of 30, which is the standard measure used for the identification of obesity in adults. In such cases, a BMI of 30 constitutes obesity. Excessive weight gain is also associated with an increased height velocity, so that children with overweight or obesity are often taller than their healthy weight peers (5). Use of z-scores in the United States to assess the severity of obesity is of limited value. The z-scores in use in the United States were based on the distribution of BMI in the CDC growth charts between the 3rd and 97th percentiles and can be used reliably for measurements between the 3rd and 97th percentiles. However, z-scores or percentiles higher than the 97th percentile to assess severe obesity are not useful insofar as small changes in BMI z-scores or BMI percentiles above the 97th percentile can be associated with large changes in body weight (6). Furthermore, recent analyses have shown that longitudinal correlations of BMI z-scores were poorer than those for BMI as a percent of the 95th percentile (7). Severe obesity is generally classified as a BMI of at least 120% of the 95th percentile for children or adolescents of the same age and sex (8). However, an alternative measure to assess the distribution of obesity above the 95th percentile is to express BMI as a percent of the 95th percentile for children of the same age and sex (8). A third measure that can be applied across the entire range of BMI is the expression of BMI as a percentage of the median for children or adolescents of the same age and sex (9). For example, the median BMI for a 10-year-old boy is 16.6 and the 95th percentile is a BMI of 21.8. Severe obesity, calculated as 120% of the 95th percentile, is a BMI of 26.2, which is also 158% of the median BMI for a 10-year-old boy. BMI as a percentage of the median may have more utility in pediatric oncology patients, because it can be used to assess changes in BMI both above and below the median. This measure is not yet in common use but is worth consideration in the evaluation of children treated on future protocols. Another anthropometric measure used in adults, waist circumference, is a risk factor for cardiovascular disease (10) and mortality (11), independent of BMI. However, in children and adolescents, waist circumference appears to have no advantage over BMI as a predictor of risk factors for cardiovascular disease (12). Pathophysiology of Obesity in Pediatric Patients With Cancer Corticosteroid therapy appears to play a central role in the pathophysiology of obesity in ALL. In a careful investigation of 26 patients studied with multiple-pass 24-hour recall over 4 days when patients were either on or off corticosteroids, reported caloric intake increased significantly during corticosteroid therapy (13). The authors compared two different types of corticosteroids: dexamethasone and prednisone. The effect of dexamethasone on caloric intake did not differ significantly from the effects of prednisone. Using data from parental dietary diaries, similar findings on the impact of dexamethasone on caloric input have been reported (14). To further understand the impact of corticosteroids on caloric intake, it would be helpful to examine which macro- and micronutrients underlie the increased energy intake. A recent study found that dexamethasone therapy in a 4-day pulse resulted in significant increases in sodium and saturated fat intake, beyond the recommended intakes, as well as decreases in restrained eating and paradoxical increases in both leptin and adiponectin (15). However, changes in adiponectin have also been ascribed to treatment with methotrexate (16). This observation underlines one of the challenges of attributing observed changes in weight of a child to the effect of a single drug such as dexamethasone because most pediatric cancers are treated with multiple therapeutic agents administered concurrently. Shorter sleep duration has been associated with obesity (17,18), and corticosteroids appear to affect sleep patterns. Although dexamethasone has been associated with increased sleep duration among children and adolescents (19,20), sleep disturbances, such as frequent awakening, appear increased (19,21). Dexamethasone therapy has also been associated with fatigue (19,21) and fatigue may explain why energy expenditure decreases. Doubly labeled water (DLW) can be used to assess total energy expenditure (TEE), and TEE minus resting metabolic rate (RMR) provides a combined estimate of physical activity and the rise in metabolic rate that follows a meal, known as the thermic effects of food. Because thermic effects of food are constant within the same individual and account for approximately 10% of TEE, the greatest contribution to TEE minus RMR is physical activity. A study comparing nonobese children with ALL with control children at a mean of 2.9 years following diagnosis of ALL using DLW showed a reduction in of approximately 120 kcal/d among the children with ALL (22). Less accurate measures of physical activity, such as heart rate monitoring in ALL survivors (23) or pedometers in ALL patients during maintenance (14), were consistent with the findings of low levels of physical activity found in the DLW study. Implications of High BMI in Determinations of Therapeutic Dosing for Pediatric Cancer Patients Elevated BMI during cancer treatment also has challenging implications for calculation of chemotherapeutic doses. Current recommendations for the administration of conventional chemotherapeutic drugs use adjusted ideal body weight. However few studies have examined whether this approach results in optimal drug distribution and levels in pediatric patients. One study examining busulfan pharmacokinetics (PK) in pediatric bone marrow transplant patients undergoing conditioning therapy found that in overweight patients (BMI > 85th percentile), use of PK dosing led to improved achievement of the targeted AUC dose (in an additional 40% of patients) compared with use of the adjusted ideal body weight (24). In adults, a recent review highlighted the relevance of body composition, that is, fat distribution, rather than obesity alone when considering the impact of elevated BMI on efficacy of chemotherapy and cytotoxic clearance (25). For example, newer targeted agents (eg, Herceptin) administered subcutaneously may result in lower concentrations in patients with obesity. Similar PK studies are needed in pediatrics where many drugs including ones used commonly in both chemotherapy and supportive care are given subcutaneously. It will be important in pediatric oncology to understand how body composition, for instance subcutaneous and visceral fat distributions, affect the PK of both conventional and newer targeted therapies. Management of Obesity Awareness of Physician Bias in Discussions About Obesity Management Obesity is among the most stigmatized conditions in the United States (26). Among adults, the most frequent sources of weight bias were family members and physicians (27). Physician bias has been associated with obesity (28,29) and impaired care (30). Children with cancer may also experience bias for other reasons such as hair loss or other consequences of therapy. Thus, pediatric patients with cancer who also have obesity may suffer a double burden of stigmatization. When middle-school children were shown images of children with obesity, disabilities, or neither disability nor obesity, the child with obesity was ranked as least liked (31). This bias may lead to teasing and bullying. Providers should therefore recognize that teasing and bullying of youth with obesity and the other stigmata of cancer treatment have significant emotional and psychological effects, including depression, poor body image, and low self-esteem (32). One of the most important strategies to reduce the impact of bias is to use appropriate language when discussing obesity with families. “Obese” and “obesity” are pejorative terms. “Weight” and “body mass index” are preferable terms to use with adolescents who are overweight or have obesity, whereas terms like “obese,” “weight problem,” or “fat” are poorly received (32). Use of terms like “obese” may add to bias directed against people with obesity. Use of the term “obese people” denotes an identity and suggests that they are to be blamed for their obesity, whereas use of “people with obesity” or “people-first” language describes people with a disease (33). Although youth are less likely to blamed for their obesity, use of people-first language among health professionals in discussions with parents and staff may help reduce the stigmatization of obesity. Management Strategies and Interventions The diagnosis of cancer prompts extraordinary parental fear and anxiety and can be expected to alter usual parenting practices. A child who was previously perceived as healthy becomes a vulnerable child. Prevention of both undernutrition and obesity become important concerns, although weight loss on active treatment is generally a more salient concern than obesity for both providers and parents. In both situations, however, continuation or implementation of standard feeding practices may help prevent the deterioration of healthy feeding practices and development of disordered eating. Counseling with a registered dietitian may be particularly helpful in children with either obesity or undernutrition. Because interactional issues may be as important as the nutritional issues, a dietitian trained in motivational interviewing or cognitive behavioral therapy may be particularly appropriate. Many of the recommendations below come from experience in dealing with vulnerable children with failure to thrive or management of pediatric patients with obesity. One of the most important strategies for parents is to maintain consistent practices around food intake. Parents are in charge of what children are offered, and children can decide whether to eat what is offered and how much (34). If a child decides not to eat what is offered, it is not up to the parent to find a food that the child will eat. Under such circumstances, the parent should tell the child that they do not have to eat the food now and should put the food aside in the event that the child becomes hungry later. These strategies are less likely to succeed in adolescents where autonomy is an important issue. During hospitalizations, consultation with a nutritionist may be helpful to design a diet consistent with the patient’s nutritional status. For adolescents, nutrition plans can be part of therapeutic contracts or other strategies designed in concert with psychologists or child life specialists. Efforts to control a child’s intake make children less likely to regulate their caloric intake (35). A common dilemma is that the child who has obesity or is gaining excess weight wants more of a high caloric density food. Parents can forestall this problem by preparing a limited amount of the high caloric density food and offering additional helpings of the low caloric density foods. In the event that the child wants more, they should be offered foods of low caloric density. Anxiety about a child who is not hungry or keeping a child well-nourished may lead parents to put no time parameters around when food is available. This practice often leads to “grazing,” and the absence of hunger at mealtimes when more healthful food can be consumed. Scheduling snacks at regular intervals, or avoiding snacks completely, will increase the likelihood that the child will eat at a regularly scheduled mealtime. Parental stress about the care of a child with cancer may also lead parents to accede to the child’s requests for foods that under other circumstances would be restricted. Parents may have difficulty denying repeated requests for that food. Consistency is critical. If “no” sometimes becomes “yes” after frequent requests, children may become even more persistent in making future requests and overwhelm parental patience. Consistency may be particularly challenging when children are being treated with corticosteroids and constantly crave foods high in salt and fat (15) or conversely are nauseous, have mouth sores, or have lost the ability to taste certain foods. The dilemma for parents is how to respond to these demands when their child is beset with so many other painful experiences. Satiety is regulated by volume. In children with undernutrition, the caloric density of foods should be increased so that more calories are provided in the same volume of food. Milk products may be one of the most acceptable products, though seeds and nut butters are palatable alternatives, especially in lactose intolerant settings (36). In children with obesity or excessive weight gain, caloric density of foods should be decreased so that fewer calories are provided in the same volume of food. Caloric density can be decreased by starting meals with a salad or soup and increasing the intake of fruits, vegetables, and whole grain products. Protein is also a highly satiating food, so inclusion of a lean source of protein at each meal may also increase satiety. An increased variety of foods offered to children will likely increase food intake, so that choices should be limited. Sensory specific satiety occurs when the diet is repetitious. Repetition does not necessarily mean that the same food is served repeatedly, but rather that the same meal pattern is provided. For example, cereal with fruit every day for breakfast is more likely to provide a constant caloric intake than a diet in which breakfast foods change daily (37,38). Television time is associated with obesity, and its effects do not appear to be mediated by the displacement of physical activity (39,40). Televisions in children’s rooms increase television time and have been associated with obesity (41). A randomized clinical trial demonstrated that reduced television time was an effective obesity treatment (42,43). The effects of television on obesity are most likely mediated by the exposure of children to ads promoting foods, such as sugar breakfast cereals, which prompt requests for those foods. For children who are bedridden or fatigued, television may be an important source of comfort. However, videos without ads are preferable to commercial television. Dietary aspects of obesity prevention may be particularly helpful at the time of transition off therapy, when patients or caretakers are interested in strategies to maintain health. Consideration of healthy eating recommendations such as the USDA guidelines (44) may be helpful, particularly with reminders of moderation in added sugars (especially sugary sweetened beverages) and saturated fats. These same guidelines can be considered in outpatient clinic settings where foods may be offered to patients and families during visits or therapy. Knowledge Gaps and Research Priorities Understanding the inter-relationship between a child’s nutrition, body composition, and cancer outcomes remains an understudied field but one in which much of the relevant data are already being collected in the context of clinical trials. For instance, every time a child receives chemotherapy, the height, weight, and BMI are measured and recorded so that the chemotherapy can be accurately dosed. Therefore, it would be possible to analyze the impact of diagnostic BMI, as well as the longitudinal trajectory of BMI, on event-free and overall survival across the wide range of pediatric cancers treated on a Children’s Oncology Group protocol. On a more nuanced level, it would also be relatively easy to examine the effect of changes in body composition. Children often gain fat but lose muscle mass on treatment. Is there an adverse effect on outcome when a child develops sarcopenia or sarcopenic obesity? Because children undergoing treatment for cancer undergo frequent imaging studies to monitor for treatment response, these same films could be repurposed to study body composition. Using data already routinely being collected will be an efficient way to start to understand the relationship between nutrition and pediatric cancer outcomes. Understanding how diet composition and quality affect weight is another understudied area in the field of pediatric cancer. The most straightforward question would be how diet quality affects the development of obesity while on treatment. Another question would be how diet quality during treatment influences diet composition posttreatment. But one could also look at the impact of diet quality on cancer outcomes, such as whether a high glycemic diet promotes the development of insulin resistance and increases risk of relapse. Finally, attention should be paid to the other half of the energy balance equation: physical activity. In addition to the importance of physical activity in weight management, the relationship between exercise and reduced risk of cancer recurrence is resoundingly well-documented for breast and colorectal cancer and appears to also have a beneficial effect in several other adult cancers (45) studied. In a recent report, colorectal cancer patients who maintained moderate levels of exercise posttreatment had fewer circulating tumor cells (46). The precise mechanism for the relationship between exercise and decreased risk of cancer recurrence has not been definitively elucidated, but hypothesized mechanisms include decreased inflammation, increased immune surveillance, reduced oxidative stress, and sex hormone levels as well as epigenetic modifications (45). The beneficial effect of physical activity on cancer outcomes in children with cancer ought to be studied in more detail. In summary, in an age where cure is a reasonable expectation for 80% of children with cancer in the United States, the goal of treatment must be expanded from “cure” to ensuring the healthiest life possible over the rest of the child’s lifespan. Maintaining optimal body weight and healthy eating during pediatric cancer treatment, although daunting, ought therefore to become a salient objective of cancer treatment. Pediatric oncology can draw on lessons learned from the last several decades of research combating the pediatric obesity epidemic in the United States, and the key insights from that research on how to implement behavioral changes that optimize energy balance and healthy eating. Beyond trying to reduce the number of children who become obese as a consequence of their cancer treatment, however, there is much that still needs to be learned about the impact of body composition, diet composition, and energy balance on pediatric and adolescent cancer outcomes. Including research on these issues as core components of future pediatric oncology clinical trials would be a fruitful investment, at low cost because most of the data needed is already being measured or collected as part of standard treatment and disease evaluation. Notes Affiliations of authors: Departments of Pediatrics (Oncology) and Epidemiology, Columbia University Medical Center, New York, NY (MAOG); Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA (ALF); Department of Pediatrics, Harvard Medical School, Harvard University, Boston, MA (ALF); Milken Institute School of Public Health, George Washington University, Washington, DC (WD). References 1 Orgel E , Sposto R , Malvar J , et al. . Impact on survival and toxicity by duration of weight extremes during treatment for pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group . J Clin Oncol . 2014 ; 32 13 : 1331 – 1337 . 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Obesity in Pediatric Oncology: Assessment, Treatment Strategies, and Knowledge Gaps

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Abstract

The development of obesity is a frequent consequence of the treatment of childhood cancer. Moreover, because of the overall prevalence of obesity in the United States, many children are already obese at diagnosis. In this article, the authors review key considerations in the prevention and treatment of obesity in children with cancer, such as nutritional assessment, the pathophysiology of obesity in children with cancer, implications of obesity in therapeutic dosing for cancer, management strategies, and knowledge gaps and research priorities. A discussion of the pathophysiology of obesity in children with cancer, along with its management, is relevant to the field of pediatric oncology, not just because of its well-described long-term health and social consequences, but because obesity is associated with a worse event-free survival and increased treatment-related mortality in children with the most frequent type of childhood cancer: acute lymphocytic leukemia (ALL) (1,2). In a meta-analysis of the six studies published to date on this topic that include together 8680 children and adolescents with ALL, higher body mass index (BMI) was associated with reduced event-free survival (fixed-effects relative risk (RR) = 1.35, 95% confidence interval = 1.20 to 1.51) (2). (The relationship between obesity and outcomes of other types of childhood cancers has not been as well-studied, but the state of the science is discussed in other manuscripts in this series.) Therefore, in this manuscript, we will describe the assessment of obesity in pediatric patients with cancer in the United States and other high-income countries, the potential factors that contribute to the development of obesity during treatment, and the challenges and strategies associated with the prevention of and treatment of obesity. In addition, we will also highlight the gaps of knowledge in the field of pediatric oncology on how nutrition, body composition, and energy balance affect pediatric cancer outcomes and an agenda for future research. Nutritional Assessment The 2000 Centers for Disease Control and Prevention (CDC) growth charts constitute the standards used for the assessment of nutritional status of 2- to 19-year-old children and adolescents. The CDC growth charts were developed by combining growth data from multiple national surveys including the National Health and Nutrition Examination Surveys conducted before 1988–1994 to construct a new series of growth curves representative of the US population of children and adolescents (3). Growth data from the 1988–1994 National Health and Nutrition Examination Surveys were excluded because of the recognition that the increasing prevalence of obesity within the population would increase the baseline for comparison. The 2000 CDC growth charts also provided the first BMI [weight (kg)/height (2)] growth charts. In children, nutritional status is assessed by measuring height, weight, and BMI and comparing these values to a z-score (SD score). Obesity, or “overnutrition,” represents one end of the spectrum of malnutrition; undernutrition is also equally important to recognize and is often overlooked by pediatric oncologists; hence, here we offer the definition of both diagnoses. Undernutrition is categorized either as “wasting,” measured by a z-score of weight for height of 2 or less, or “stunting,” measured by a z-score of height for age of 2 or less (4). In the United States, where severe undernutrition is rare, undernutrition is commonly defined as a BMI in at least the 5th percentile. Equally important, from a therapeutic perspective, is the trajectory of weight, height, and BMI. Acute undernutrition is characterized by weight loss. Acute undernutrition therefore will be characterized by a decrease in BMI, reflecting a decrease in weight for height (“wasting”), whereas chronic undernutrition is characterized by a decrease in height for age (“stunting”). The weight for height and BMI may, however, be within the normal range in a child with stunting. Because weight changes more rapidly than height over time, weight changes can be used to assess more acute changes in nutritional status, whereas decreases in height velocity will reflect longer term changes in nutritional status. It should be apparent that longitudinal height and weight data from the same child that allow an assessment of changes in height, weight, and BMI over time are much more meaningful than measurements at a single time point. The diagnosis of overweight is based on a BMI between the 85th and 95th percentiles, whereas obesity is characterized by a BMI at the 95th percentile or higher. However, it is important for the clinician to recognize that BMI and body composition (or percent body fat) are two separate measures. Body composition is increasingly recognized as an independent predictor of health other articles in this series, as discussed in this series. BMI is an unreliable measure of fat and body composition between the 5th and 85th percentiles. Although fatness is more reliably associated with a BMI of at least the 85th percentile, clinical inspection, particularly in overweight children and adolescents, is necessary to determine whether overweight is attributable to excess fat, increased frame size, or increased muscle mass. Body fat is significantly increased in most youth with a BMI of at least the 95th percentile. In some adolescents, however, the 95th BMI percentile exceeds a BMI of 30, which is the standard measure used for the identification of obesity in adults. In such cases, a BMI of 30 constitutes obesity. Excessive weight gain is also associated with an increased height velocity, so that children with overweight or obesity are often taller than their healthy weight peers (5). Use of z-scores in the United States to assess the severity of obesity is of limited value. The z-scores in use in the United States were based on the distribution of BMI in the CDC growth charts between the 3rd and 97th percentiles and can be used reliably for measurements between the 3rd and 97th percentiles. However, z-scores or percentiles higher than the 97th percentile to assess severe obesity are not useful insofar as small changes in BMI z-scores or BMI percentiles above the 97th percentile can be associated with large changes in body weight (6). Furthermore, recent analyses have shown that longitudinal correlations of BMI z-scores were poorer than those for BMI as a percent of the 95th percentile (7). Severe obesity is generally classified as a BMI of at least 120% of the 95th percentile for children or adolescents of the same age and sex (8). However, an alternative measure to assess the distribution of obesity above the 95th percentile is to express BMI as a percent of the 95th percentile for children of the same age and sex (8). A third measure that can be applied across the entire range of BMI is the expression of BMI as a percentage of the median for children or adolescents of the same age and sex (9). For example, the median BMI for a 10-year-old boy is 16.6 and the 95th percentile is a BMI of 21.8. Severe obesity, calculated as 120% of the 95th percentile, is a BMI of 26.2, which is also 158% of the median BMI for a 10-year-old boy. BMI as a percentage of the median may have more utility in pediatric oncology patients, because it can be used to assess changes in BMI both above and below the median. This measure is not yet in common use but is worth consideration in the evaluation of children treated on future protocols. Another anthropometric measure used in adults, waist circumference, is a risk factor for cardiovascular disease (10) and mortality (11), independent of BMI. However, in children and adolescents, waist circumference appears to have no advantage over BMI as a predictor of risk factors for cardiovascular disease (12). Pathophysiology of Obesity in Pediatric Patients With Cancer Corticosteroid therapy appears to play a central role in the pathophysiology of obesity in ALL. In a careful investigation of 26 patients studied with multiple-pass 24-hour recall over 4 days when patients were either on or off corticosteroids, reported caloric intake increased significantly during corticosteroid therapy (13). The authors compared two different types of corticosteroids: dexamethasone and prednisone. The effect of dexamethasone on caloric intake did not differ significantly from the effects of prednisone. Using data from parental dietary diaries, similar findings on the impact of dexamethasone on caloric input have been reported (14). To further understand the impact of corticosteroids on caloric intake, it would be helpful to examine which macro- and micronutrients underlie the increased energy intake. A recent study found that dexamethasone therapy in a 4-day pulse resulted in significant increases in sodium and saturated fat intake, beyond the recommended intakes, as well as decreases in restrained eating and paradoxical increases in both leptin and adiponectin (15). However, changes in adiponectin have also been ascribed to treatment with methotrexate (16). This observation underlines one of the challenges of attributing observed changes in weight of a child to the effect of a single drug such as dexamethasone because most pediatric cancers are treated with multiple therapeutic agents administered concurrently. Shorter sleep duration has been associated with obesity (17,18), and corticosteroids appear to affect sleep patterns. Although dexamethasone has been associated with increased sleep duration among children and adolescents (19,20), sleep disturbances, such as frequent awakening, appear increased (19,21). Dexamethasone therapy has also been associated with fatigue (19,21) and fatigue may explain why energy expenditure decreases. Doubly labeled water (DLW) can be used to assess total energy expenditure (TEE), and TEE minus resting metabolic rate (RMR) provides a combined estimate of physical activity and the rise in metabolic rate that follows a meal, known as the thermic effects of food. Because thermic effects of food are constant within the same individual and account for approximately 10% of TEE, the greatest contribution to TEE minus RMR is physical activity. A study comparing nonobese children with ALL with control children at a mean of 2.9 years following diagnosis of ALL using DLW showed a reduction in of approximately 120 kcal/d among the children with ALL (22). Less accurate measures of physical activity, such as heart rate monitoring in ALL survivors (23) or pedometers in ALL patients during maintenance (14), were consistent with the findings of low levels of physical activity found in the DLW study. Implications of High BMI in Determinations of Therapeutic Dosing for Pediatric Cancer Patients Elevated BMI during cancer treatment also has challenging implications for calculation of chemotherapeutic doses. Current recommendations for the administration of conventional chemotherapeutic drugs use adjusted ideal body weight. However few studies have examined whether this approach results in optimal drug distribution and levels in pediatric patients. One study examining busulfan pharmacokinetics (PK) in pediatric bone marrow transplant patients undergoing conditioning therapy found that in overweight patients (BMI > 85th percentile), use of PK dosing led to improved achievement of the targeted AUC dose (in an additional 40% of patients) compared with use of the adjusted ideal body weight (24). In adults, a recent review highlighted the relevance of body composition, that is, fat distribution, rather than obesity alone when considering the impact of elevated BMI on efficacy of chemotherapy and cytotoxic clearance (25). For example, newer targeted agents (eg, Herceptin) administered subcutaneously may result in lower concentrations in patients with obesity. Similar PK studies are needed in pediatrics where many drugs including ones used commonly in both chemotherapy and supportive care are given subcutaneously. It will be important in pediatric oncology to understand how body composition, for instance subcutaneous and visceral fat distributions, affect the PK of both conventional and newer targeted therapies. Management of Obesity Awareness of Physician Bias in Discussions About Obesity Management Obesity is among the most stigmatized conditions in the United States (26). Among adults, the most frequent sources of weight bias were family members and physicians (27). Physician bias has been associated with obesity (28,29) and impaired care (30). Children with cancer may also experience bias for other reasons such as hair loss or other consequences of therapy. Thus, pediatric patients with cancer who also have obesity may suffer a double burden of stigmatization. When middle-school children were shown images of children with obesity, disabilities, or neither disability nor obesity, the child with obesity was ranked as least liked (31). This bias may lead to teasing and bullying. Providers should therefore recognize that teasing and bullying of youth with obesity and the other stigmata of cancer treatment have significant emotional and psychological effects, including depression, poor body image, and low self-esteem (32). One of the most important strategies to reduce the impact of bias is to use appropriate language when discussing obesity with families. “Obese” and “obesity” are pejorative terms. “Weight” and “body mass index” are preferable terms to use with adolescents who are overweight or have obesity, whereas terms like “obese,” “weight problem,” or “fat” are poorly received (32). Use of terms like “obese” may add to bias directed against people with obesity. Use of the term “obese people” denotes an identity and suggests that they are to be blamed for their obesity, whereas use of “people with obesity” or “people-first” language describes people with a disease (33). Although youth are less likely to blamed for their obesity, use of people-first language among health professionals in discussions with parents and staff may help reduce the stigmatization of obesity. Management Strategies and Interventions The diagnosis of cancer prompts extraordinary parental fear and anxiety and can be expected to alter usual parenting practices. A child who was previously perceived as healthy becomes a vulnerable child. Prevention of both undernutrition and obesity become important concerns, although weight loss on active treatment is generally a more salient concern than obesity for both providers and parents. In both situations, however, continuation or implementation of standard feeding practices may help prevent the deterioration of healthy feeding practices and development of disordered eating. Counseling with a registered dietitian may be particularly helpful in children with either obesity or undernutrition. Because interactional issues may be as important as the nutritional issues, a dietitian trained in motivational interviewing or cognitive behavioral therapy may be particularly appropriate. Many of the recommendations below come from experience in dealing with vulnerable children with failure to thrive or management of pediatric patients with obesity. One of the most important strategies for parents is to maintain consistent practices around food intake. Parents are in charge of what children are offered, and children can decide whether to eat what is offered and how much (34). If a child decides not to eat what is offered, it is not up to the parent to find a food that the child will eat. Under such circumstances, the parent should tell the child that they do not have to eat the food now and should put the food aside in the event that the child becomes hungry later. These strategies are less likely to succeed in adolescents where autonomy is an important issue. During hospitalizations, consultation with a nutritionist may be helpful to design a diet consistent with the patient’s nutritional status. For adolescents, nutrition plans can be part of therapeutic contracts or other strategies designed in concert with psychologists or child life specialists. Efforts to control a child’s intake make children less likely to regulate their caloric intake (35). A common dilemma is that the child who has obesity or is gaining excess weight wants more of a high caloric density food. Parents can forestall this problem by preparing a limited amount of the high caloric density food and offering additional helpings of the low caloric density foods. In the event that the child wants more, they should be offered foods of low caloric density. Anxiety about a child who is not hungry or keeping a child well-nourished may lead parents to put no time parameters around when food is available. This practice often leads to “grazing,” and the absence of hunger at mealtimes when more healthful food can be consumed. Scheduling snacks at regular intervals, or avoiding snacks completely, will increase the likelihood that the child will eat at a regularly scheduled mealtime. Parental stress about the care of a child with cancer may also lead parents to accede to the child’s requests for foods that under other circumstances would be restricted. Parents may have difficulty denying repeated requests for that food. Consistency is critical. If “no” sometimes becomes “yes” after frequent requests, children may become even more persistent in making future requests and overwhelm parental patience. Consistency may be particularly challenging when children are being treated with corticosteroids and constantly crave foods high in salt and fat (15) or conversely are nauseous, have mouth sores, or have lost the ability to taste certain foods. The dilemma for parents is how to respond to these demands when their child is beset with so many other painful experiences. Satiety is regulated by volume. In children with undernutrition, the caloric density of foods should be increased so that more calories are provided in the same volume of food. Milk products may be one of the most acceptable products, though seeds and nut butters are palatable alternatives, especially in lactose intolerant settings (36). In children with obesity or excessive weight gain, caloric density of foods should be decreased so that fewer calories are provided in the same volume of food. Caloric density can be decreased by starting meals with a salad or soup and increasing the intake of fruits, vegetables, and whole grain products. Protein is also a highly satiating food, so inclusion of a lean source of protein at each meal may also increase satiety. An increased variety of foods offered to children will likely increase food intake, so that choices should be limited. Sensory specific satiety occurs when the diet is repetitious. Repetition does not necessarily mean that the same food is served repeatedly, but rather that the same meal pattern is provided. For example, cereal with fruit every day for breakfast is more likely to provide a constant caloric intake than a diet in which breakfast foods change daily (37,38). Television time is associated with obesity, and its effects do not appear to be mediated by the displacement of physical activity (39,40). Televisions in children’s rooms increase television time and have been associated with obesity (41). A randomized clinical trial demonstrated that reduced television time was an effective obesity treatment (42,43). The effects of television on obesity are most likely mediated by the exposure of children to ads promoting foods, such as sugar breakfast cereals, which prompt requests for those foods. For children who are bedridden or fatigued, television may be an important source of comfort. However, videos without ads are preferable to commercial television. Dietary aspects of obesity prevention may be particularly helpful at the time of transition off therapy, when patients or caretakers are interested in strategies to maintain health. Consideration of healthy eating recommendations such as the USDA guidelines (44) may be helpful, particularly with reminders of moderation in added sugars (especially sugary sweetened beverages) and saturated fats. These same guidelines can be considered in outpatient clinic settings where foods may be offered to patients and families during visits or therapy. Knowledge Gaps and Research Priorities Understanding the inter-relationship between a child’s nutrition, body composition, and cancer outcomes remains an understudied field but one in which much of the relevant data are already being collected in the context of clinical trials. For instance, every time a child receives chemotherapy, the height, weight, and BMI are measured and recorded so that the chemotherapy can be accurately dosed. Therefore, it would be possible to analyze the impact of diagnostic BMI, as well as the longitudinal trajectory of BMI, on event-free and overall survival across the wide range of pediatric cancers treated on a Children’s Oncology Group protocol. On a more nuanced level, it would also be relatively easy to examine the effect of changes in body composition. Children often gain fat but lose muscle mass on treatment. Is there an adverse effect on outcome when a child develops sarcopenia or sarcopenic obesity? Because children undergoing treatment for cancer undergo frequent imaging studies to monitor for treatment response, these same films could be repurposed to study body composition. Using data already routinely being collected will be an efficient way to start to understand the relationship between nutrition and pediatric cancer outcomes. Understanding how diet composition and quality affect weight is another understudied area in the field of pediatric cancer. The most straightforward question would be how diet quality affects the development of obesity while on treatment. Another question would be how diet quality during treatment influences diet composition posttreatment. But one could also look at the impact of diet quality on cancer outcomes, such as whether a high glycemic diet promotes the development of insulin resistance and increases risk of relapse. Finally, attention should be paid to the other half of the energy balance equation: physical activity. In addition to the importance of physical activity in weight management, the relationship between exercise and reduced risk of cancer recurrence is resoundingly well-documented for breast and colorectal cancer and appears to also have a beneficial effect in several other adult cancers (45) studied. In a recent report, colorectal cancer patients who maintained moderate levels of exercise posttreatment had fewer circulating tumor cells (46). The precise mechanism for the relationship between exercise and decreased risk of cancer recurrence has not been definitively elucidated, but hypothesized mechanisms include decreased inflammation, increased immune surveillance, reduced oxidative stress, and sex hormone levels as well as epigenetic modifications (45). The beneficial effect of physical activity on cancer outcomes in children with cancer ought to be studied in more detail. In summary, in an age where cure is a reasonable expectation for 80% of children with cancer in the United States, the goal of treatment must be expanded from “cure” to ensuring the healthiest life possible over the rest of the child’s lifespan. Maintaining optimal body weight and healthy eating during pediatric cancer treatment, although daunting, ought therefore to become a salient objective of cancer treatment. Pediatric oncology can draw on lessons learned from the last several decades of research combating the pediatric obesity epidemic in the United States, and the key insights from that research on how to implement behavioral changes that optimize energy balance and healthy eating. Beyond trying to reduce the number of children who become obese as a consequence of their cancer treatment, however, there is much that still needs to be learned about the impact of body composition, diet composition, and energy balance on pediatric and adolescent cancer outcomes. Including research on these issues as core components of future pediatric oncology clinical trials would be a fruitful investment, at low cost because most of the data needed is already being measured or collected as part of standard treatment and disease evaluation. Notes Affiliations of authors: Departments of Pediatrics (Oncology) and Epidemiology, Columbia University Medical Center, New York, NY (MAOG); Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA (ALF); Department of Pediatrics, Harvard Medical School, Harvard University, Boston, MA (ALF); Milken Institute School of Public Health, George Washington University, Washington, DC (WD). References 1 Orgel E , Sposto R , Malvar J , et al. . Impact on survival and toxicity by duration of weight extremes during treatment for pediatric acute lymphoblastic leukemia: a report from the Children's Oncology Group . J Clin Oncol . 2014 ; 32 13 : 1331 – 1337 . Google Scholar Crossref Search ADS PubMed WorldCat 2 Orgel E , Genkinger JM , Aggarwal D , Sung L , Nieder M , Ladas EJ. Association of body mass index and survival in pediatric leukemia: a meta-analysis . Am J Clin Nutr . 2016 ; 103 3 : 808 – 817 . 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Epidemiol Rev . 2017 ; 39 1 : 71 – 92 . Google Scholar Crossref Search ADS PubMed WorldCat 46 Brown JC , Rhim AD , Manning SL , et al. . Effects of exercise on circulating tumor cells among patients with resected stage I-III colon cancer . PLoS One . 2018 ; 13 10 : e0204875. Google Scholar Crossref Search ADS PubMed WorldCat Author notes Authors contributed equally to this work. © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

JNCI MonographsOxford University Press

Published: Sep 1, 2019

References