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Body Composition in Pediatric Solid Tumors: State of the Science and Future Directions

Body Composition in Pediatric Solid Tumors: State of the Science and Future Directions Abstract Sarcopenia (severe skeletal muscle wasting) and sarcopenic obesity (skeletal muscle wasting in the setting of excess fat) have been increasingly recognized as important prognostic indicators in adult oncology. Unfavorable changes in lean and adipose tissue masses manifest early in therapy and are associated with altered chemotherapy metabolism as well as increased treatment-related morbidity and mortality. Existing literature addresses the role of body composition in children with hematologic malignancies; however, data is lacking among solid tumor patients. Advances in imaging techniques for quantification of tissue compartments potentiate further investigation in this highly understudied area of pediatric oncology. The following review presents an in-depth discussion of body composition analysis and its potential role in the care of pediatric solid tumor patients. Integration of body tissue measurement into standard practice has broad clinical implications and may improve quality of life and treatment outcomes in this at-risk population. Over the last decade, body composition has been increasingly recognized as an important factor in cancer outcomes (1,2). Sarcopenia, defined as severe depletion of skeletal muscle, and sarcopenic obesity, which is muscle depletion in the setting of excess fat, have been shown to adversely affect treatment-related complications and survival in the adult population (1–9). Nutritional status has been long suggested to impact treatment outcomes in pediatric oncology (10). Because of their ease of collection, anthropometric measures such as body mass index (BMI), skin-fold thickness, mid-upper arm circumference, and waist circumference are often relied on for assessment of body store depletion in the clinical setting. However, these nonimaging modalities are limited by their variability (11). Moreover, BMI does not distinguish between lean mass and adiposity, thus its use as a prognostic variable may result in misclassification of patients (3,11,12). The advent of advanced imaging techniques in body composition analysis has enabled practitioners to accurately discern and quantify lean and adipose tissue compartments and to further investigate their role in cancer care (4). At present, body composition in pediatric patients with solid tumors is a highly understudied area. Patients with solid tumors are treated with multimodal therapy, including dose-intense antineoplastic agents, surgery, and radiotherapy. This multimodality renders them highly susceptible to clinically significant morbidity and mortality (10). Herein, we summarize the current state of body composition analysis research in the field of oncology, specifically focusing on its relevance to pediatric solid tumors and potential role in improving health outcomes for this at-risk population. Body Composition Analysis: Practical Approach in Clinical Practice A wide variety of modalities enable body tissue delineation and quantification in the pediatric population. Among available techniques, the most commonly used are bioimpedance analysis, air-displacement plethysmography (ADP), three-dimensional body scanning, dual-energy x-ray absorptiometry (DXA), computed tomography (CT), and magnetic resonance imaging (MRI). Bioimpedance analysis and ADP are nonimaging techniques that estimate fat and lean tissue masses, and practical application of these methods among critically ill pediatric patients is limited (4,12). Imaging with DXA is advantageous in that it differentiates lean and fat tissues, and pediatric-specific equations can be used to extrapolate muscle mass from appendicular lean soft tissue measures (13). However, DXA does not discern visceral from subcutaneous fat. Conversely, because of their ability to create three-dimensional images, CT and MRI have the unique capability of distinguishing visceral and subcutaneous adipose tissues, as well as skeletal muscle mass, from other lean tissues (4). In recent years, CT and MRI have emerged as superior techniques for body composition analysis, particularly in the adult cancer population. MRI ascertains whole body composition, whereas CT is typically limited to the abdomen or thigh to reduce radiation exposure (14). Trained technicians utilize commercial or in-house developed software to conduct the analysis in a semi-automated process. Multi-slice assessment of images provides a full-volume measure of the varying tissue compartments and is therefore considered the most precise method for measuring body composition (14). However, successful use of a single-slice CT image (eg, L3 vertebral level) to evaluate body composition has been consistently demonstrated in adult oncology literature (4,6). Single-slice analysis provides a more readily available, practical, and cost-effective means of assessment in cross-sectional studies (14). A validated skeletal muscle index cutoff point at L3 defining sarcopenia has been described and well studied in the adult cancer population (6). However, such a point has not been delineated in pediatrics. Longitudinal studies validating the use of single-slice imaging in pediatrics are needed to determine the feasibility and utility of implementing these techniques in pediatric cancer and, ultimately, to facilitate incorporation of this methodology into clinical practice (15). The feasibility of conducting such investigations is restricted by the associated radiation exposure. One single-slice CT image confers an average effective radiation dose of 7.4 millisievert, although adherence to optimized protocols and use of advanced CT technology may reduce this dosage (16). Clinical Applications of Body Composition Adult Oncology Whereas sarcopenia was first described in the elderly, in recent years this term has been adapted in the field of oncology to denote severe skeletal muscle loss in cancer patients regardless of age (1,2,8,17). Sarcopenia can occur in the setting of depleted, normal, or excess fat mass (sarcopenic obesity) (4,6,9). Both sarcopenia and sarcopenic obesity have emerged as important prognostic indicators in a wide variety of adult malignancies (2–4,6–9). A recent meta-analysis evaluating the significance of sarcopenia in a diverse group of solid tumor patients showed that a low pretreatment skeletal muscle index is predictive of worse overall survival (OS), regardless of disease type or stage (hazard ratio [HR] = 1.44, 95% confidence interval [CI] = 1.32 to 1.56; P < .001) (2). Similarly, in patients with gastrointestinal and respiratory tract cancers, sarcopenic obesity was associated with poorer functional status (P = .009) and OS (HR = 4.2, 95 % CI = 2.4 to 7.2; P < .0001) (6). It was also identified as a statistically significant predictor of diminished OS in pancreatic cancer (HR = 2.07, 95 % CI = 1.23 to 3.50; P = .006) (7). The impact of body composition extends beyond long-term survival outcomes. Diminished skeletal muscle mass has been associated with increased morbidities, such as postoperative complication rates, risk of infection, and longer hospital length of stay (4,9). Moreover, sarcopenia has repeatedly demonstrated an adverse relationship with tolerance to treatment and prevalence of dose-limiting toxicities (4,18). Sarcopenic vs nonsarcopenic patients exhibited increased toxicity with use of 5-fluorouracil to treat colorectal cancer (19), as well as capecitabine (50% vs 20%; P = .03) (1) and taxane-based chemotherapy (57% vs 18%; P = .02) (20) to treat breast cancer. Indeed, among those treated with taxane chemotherapy, sarcopenic patients had increased adverse events overall, including toxicity-related hospitalizations, chemotherapy dose reductions, and dose delays (74% vs 35%; P = .02) (20). In a large proportion of patients, sarcopenia is detectable by imaging at the time of diagnosis and affects patient outcomes regardless of cancer stage or progression (1–3,21). By relying on BMI alone to assess nutritional status and body-store depletion, many at-risk patients are left underrecognized (3,6,9,11). In a recent breast cancer study, sarcopenic patients with concurrent high total adipose tissue had the greatest risk of mortality (HR = 1.89; 95% CI = 1.30 to 2.73). Yet, in that same group, BMI alone did not show a statistically significant association with overall mortality and did not properly distinguish patients at increased risk owing to their body composition (3). These findings reinforce the limited utility of BMI in establishing the prognostic significance of malnutrition. The acquisition of CT imaging as part of routine care in patients with solid tumors renders it the ideal modality for lean and fat tissue assessment in this population, and therefore, most published methodology evaluating adult patients centers on its use (4). Early identification of high-risk patients via diagnostic and follow-up imaging potentiates the implementation of guided interventions to enhance clinical practice and improve patient outcomes. Pediatric Oncology The detrimental effects of sarcopenia have been established in young patients suffering from muscle disuse, malnutrition, and various inflammatory conditions (8). Yet, body composition studies in pediatric cancer are limited. Existing literature in this area has largely focused on hematologic malignancies, and in recent years, DXA has been at the forefront of body composition analysis among acute lymphoblastic leukemia (ALL) patients. One clinical investigation (n = 91) showed that children with ALL experience a statistically significant decrease in skeletal muscle mass within the first 6 months of treatment initiation (22). These findings were reinforced by a recent prospective study (n = 50) which demonstrated that ALL patients commonly develop sarcopenic obesity while undergoing therapy, resulting in a discordant relationship between BMI and body fat percentage (11). The application of imaging has also been explored in pediatric ALL. The use of CT imaging at the L3 level was evaluated to assess skeletal muscle mass changes among ALL patients (n = 47) (17). Loss of muscle mass following initiation of therapy occurred in all included study patients, and nearly one-third developed sarcopenia; however, sarcopenia was not correlated with survival in this group. Importantly, sarcopenia did show a statistically significant association with other clinically significant parameters including severe adverse events (P = .009) and invasive fungal infection (P = .018). Despite robust evidence linking body composition to unfavorable outcomes in the adult solid tumor population, and the demonstration of similar adverse changes in children and adolescents undergoing treatment for ALL, to date, there have been merely two noteworty publications examining body composition in solid tumor patients. Both studies were comprised of a diverse group of pediatric malignancies and included a small [n = 14 (12), n = 18 (23)], heterogeneous group of solid tumor patients at various stages of therapy. Investigators used ADP to measure fat and fat-free mass. Findings from these studies suggest that patients undergoing treatment for solid tumors experience a statistically significant decrease in fat-free mass and increase in fat mass as compared to age and sex-matched control subjects (12,23). Although each of these studies are limited by their sample sizes, their findings are compelling and warrant further research. Notably, neither study employed an imaging modality for body composition evaluation. To the authors’ knowledge, there have been no publications reporting on the efficacy of imaging techniques for body composition assessment in the pediatric solid tumor patient population. Pathogenesis and Treatment Implications The pathogenesis of muscle wasting in cancer patients is a multifactorial process wherein an imbalance between synthetic and degradative protein pathways, increased myocyte apoptosis, and decreased muscle regeneration are the drivers (24). A heightened state of inflammation is widely believed to be a key contributor to the activation of many of the altered metabolic pathways present in skeletal muscle wasting (24–26). Various inflammatory cytokines have been implicated in cancer-related muscle breakdown (25,26). These markers of immune activation are likely manufactured by the tumor itself or by surrounding cells and promote activation of catabolic pathways (21,24–26). Additionally, proinflammatory cytokines have an anorectic effect that may negatively influence skeletal muscle via indirect pathways (25). In adults with colorectal cancer, increased prediagnostic systemic inflammation, measured via surrogate markers like neutrophil-to-lymphocyte ratio, had increased odds of having sarcopenia, regardless of other confounding factors such as age, disease stage, and BMI (21). Moreover, the concurrence of sarcopenia and high neutrophil-to-lymphocyte ratio was identified as an independent prognostic indicator for poorer survival outcomes (21,25). The interplay between host inflammatory and/or immune response, tumor microenvironment, and skeletal muscle changes has not been elucidated in pediatric oncology. Further study in this area potentiates the identification of similar prognostic biomarkers in pediatric solid tumors, as well as new opportunities for therapeutic intervention development. The mechanism underlying the relationship of body composition and outcomes in patients with cancer remains uncertain (2). However, it is widely hypothesized that variations in fat and lean tissue masses alter chemotherapy volume of distribution, metabolism, and clearance of hydrophilic and/or lipophilic drugs from systemic circulation (1,4,19,27–29). It is well recognized that traditional methods of dosing by body surface area (BSA) do not accurately predict chemotherapy pharmacokinetics (5,19). Prado et al. demonstrated that there is a poor correlation between BSA and fat-free mass (r2 = 0.37), potentially accounting for up to three-times difference in effective volume of distribution of chemotherapy administered per BSA unit (6). Thus, in a patient with diminished lean tissue mass and excess fat mass, dosing of chemotherapy by anthropometric measures may result in overexposure and early acute toxicity (29), providing a potential mechanism for increased morbidities observed among sarcopenic patients. In a diverse group of pediatric cancer patients (n = 22) being treated with doxorubicin, those with more than 30% body fat (measured via DXA) exhibited disturbed clearance of the doxorubicin metabolite, doxorubicinol. The authors surmised that this extended exposure could considerably contribute to the development of future treatment-related cardiac toxicity in this population (28). Similarly, vincristine pharmacokinetics were altered in obese vs nonobese leukemia mouse models, leading to decreased overall exposure to the drug in the circulation and bone marrow of the obese mice, and thereby potentially reducing its efficacy in this group (27). The implications of these findings extend not only to dose-limiting toxicities of traditional cytotoxic agents but also to those of novel targeted therapies. In adult malignancies, the association of body composition with toxicities has been described with use of tyrosine kinase inhibitors (30) as well as various immunotherapy agents [pembrolizumab (29), nivolumab (29), and ipilimumab (18)]. With the burgeoning shift of cancer treatment research to individualized therapies, body composition has the potential to play a key role in the manner by which we dose chemotherapy and personalize care. Potential Targets for Intervention Currently, there is no universally accepted treatment for reversing or preventing sarcopenia in cancer patients. Diet and muscle building exercise (aerobic and/or resistance training) have long been suggested to be key factors in ameliorating the negative trajectory and effects of muscle loss. Early recognition of malnutrition and initiation of a high-calorie, high-protein diet is critical to tempering the wasting process and improving patient quality of life; however, the feasibility and effectiveness of nutritional interventions among children with cancer is unknown and is an opportunity for further inquiry (31,32). Clinical studies examining exercise in pediatric oncology have shown that its implementation during therapy is feasible and well tolerated and confers an overwhelmingly positive benefit in this population (33,34). In adults with head and/or neck squamous cell carcinoma, a 12-week progressive resistance exercise intervention resulted in a greater than 4% average increase in lean body mass (measured via DXA) (35). Although such quantitative studies are lacking in pediatrics, muscle strength has been used as a proxy for change in muscle mass. In a study comparing regimented thrice weekly exercise sessions to a control (no structured exercise) arm during neoadjuvant therapy among pediatric solid tumor patients, there was a statistically significant increase in muscle strength in the intervention arm and decrease among control subjects (36). Similar results of improved muscle strength were seen after exercise interventions in children with leukemia (37). Preclinical data suggests that in addition to maintaining muscle mass, another benefit to exercise during therapy is its potential to augment chemotherapeutic efficacy against solid tumors. Animal models of melanoma, breast, prostate, and pancreatic cancers consistently demonstrate remodeling of tumor vasculature in response to moderate exercise (38–40). Remodeled tumor vasculature is more efficient and thereby improves delivery of chemotherapy to the tumor. Indeed, chemotherapy combined with exercise was statistically significantly more effective than chemotherapy alone among several solid tumor mouse models (38,40). To date, published literature in this area has predominantly addressed adult cancer models. However, unpublished data utilizing aerobic exercise in combination with doxorubicin in mice-bearing Ewing sarcoma suggests that exercise enhances doxorubicin efficacy against Ewing sarcoma (K. Schadler, unpublished data). Taken together, emerging evidence indicates that incorporating physical activity as part of a multifaceted approach in the treatment of cancer-related sarcopenia holds substantial promise for improving body composition and long-term patient outcomes. Future Directions There is a growing body of data supporting the prognostic significance of body composition in cancer outcomes. Although it is limited, existing literature reinforces the notion that cancer and its therapy can also have a meaningful impact on body composition in the pediatric population and underscores the need to further promote this area of investigation in patients with solid tumors. Survival rates among many of the most common pediatric solid tumors have remained stagnant over the past several decades, and marked treatment-related morbidity occurs both during therapy and well into survivorship (41). The frequent and standard use of CT imaging for disease diagnosis and monitoring throughout therapy in this group provides an accurate and readily available modality for body composition assessment (2,4). Identifying the prevalence and clinical significance of sarcopenia and sarcopenic obesity in this population will enhance and complement current understanding in patient nutritional status, aid in early identification of those at greatest risk for adverse outcomes, and enable clinicians to optimize treatment plans and ameliorate the effects of these potentially modifiable risk factors (4,9). Clinical and translational trials aimed at elucidating the mechanisms by which cancer and its therapy potentiate adverse changes and clinical outcomes in pediatric solid tumors are critical to closing the current knowledge gap in this field. Further research in this area may lead to refinement and personalization of chemotherapy dosing, optimize timing of nutritional and physiotherapy supportive care interventions, and improve tolerance to both traditional and novel therapies. Thus, advancement in this area may have a long-lasting impact on patient quality of life and successful transition into survivorship. Funding This work was supported by the Tamarind Foundation to EJL; American Cancer Society (grant number 127000-MRSG-14–157-01-CCE to EJL); National Institutes of Health (grant number T32 CA094061-17 to LJ); National Institute of Aging (grant number R01 AG045761 to WS); National Institute of Diabetes and Digestive and Kidney Diseases (grant number P30 DK26687 to WS); National Center for Advancing Translational Sciences (grant number UL1 TR000040, with Pilot Integrating Special Population Award on Body Composition after Bariatric Surgery to WS); and Zuckerman Mind Brain Behavior Institute (Seed Grant 2018 to WS) Notes Affiliations of authors: Department of Pediatric Hematology, Oncology and Stem Cell Transplant, Morgan Stanley Children’s Hospital, Columbia University Medical Center, New York, NY (LJ, EJL); Department of Pediatrics Research, MD Anderson Cancer Center, Houston, TX (KLS); Department of Pediatric Gastroenterology, Hepatology and Nutrition, Institute of Human Nutrition, and MR Research Center, Columbia University Medical Center, New York, NY (WS). 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CA Cancer J Clin . 2014 ; 64 2 : 83 – 103 . Google Scholar Crossref Search ADS PubMed WorldCat © 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) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JNCI Monographs Oxford University Press

Body Composition in Pediatric Solid Tumors: State of the Science and Future Directions

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Abstract

Abstract Sarcopenia (severe skeletal muscle wasting) and sarcopenic obesity (skeletal muscle wasting in the setting of excess fat) have been increasingly recognized as important prognostic indicators in adult oncology. Unfavorable changes in lean and adipose tissue masses manifest early in therapy and are associated with altered chemotherapy metabolism as well as increased treatment-related morbidity and mortality. Existing literature addresses the role of body composition in children with hematologic malignancies; however, data is lacking among solid tumor patients. Advances in imaging techniques for quantification of tissue compartments potentiate further investigation in this highly understudied area of pediatric oncology. The following review presents an in-depth discussion of body composition analysis and its potential role in the care of pediatric solid tumor patients. Integration of body tissue measurement into standard practice has broad clinical implications and may improve quality of life and treatment outcomes in this at-risk population. Over the last decade, body composition has been increasingly recognized as an important factor in cancer outcomes (1,2). Sarcopenia, defined as severe depletion of skeletal muscle, and sarcopenic obesity, which is muscle depletion in the setting of excess fat, have been shown to adversely affect treatment-related complications and survival in the adult population (1–9). Nutritional status has been long suggested to impact treatment outcomes in pediatric oncology (10). Because of their ease of collection, anthropometric measures such as body mass index (BMI), skin-fold thickness, mid-upper arm circumference, and waist circumference are often relied on for assessment of body store depletion in the clinical setting. However, these nonimaging modalities are limited by their variability (11). Moreover, BMI does not distinguish between lean mass and adiposity, thus its use as a prognostic variable may result in misclassification of patients (3,11,12). The advent of advanced imaging techniques in body composition analysis has enabled practitioners to accurately discern and quantify lean and adipose tissue compartments and to further investigate their role in cancer care (4). At present, body composition in pediatric patients with solid tumors is a highly understudied area. Patients with solid tumors are treated with multimodal therapy, including dose-intense antineoplastic agents, surgery, and radiotherapy. This multimodality renders them highly susceptible to clinically significant morbidity and mortality (10). Herein, we summarize the current state of body composition analysis research in the field of oncology, specifically focusing on its relevance to pediatric solid tumors and potential role in improving health outcomes for this at-risk population. Body Composition Analysis: Practical Approach in Clinical Practice A wide variety of modalities enable body tissue delineation and quantification in the pediatric population. Among available techniques, the most commonly used are bioimpedance analysis, air-displacement plethysmography (ADP), three-dimensional body scanning, dual-energy x-ray absorptiometry (DXA), computed tomography (CT), and magnetic resonance imaging (MRI). Bioimpedance analysis and ADP are nonimaging techniques that estimate fat and lean tissue masses, and practical application of these methods among critically ill pediatric patients is limited (4,12). Imaging with DXA is advantageous in that it differentiates lean and fat tissues, and pediatric-specific equations can be used to extrapolate muscle mass from appendicular lean soft tissue measures (13). However, DXA does not discern visceral from subcutaneous fat. Conversely, because of their ability to create three-dimensional images, CT and MRI have the unique capability of distinguishing visceral and subcutaneous adipose tissues, as well as skeletal muscle mass, from other lean tissues (4). In recent years, CT and MRI have emerged as superior techniques for body composition analysis, particularly in the adult cancer population. MRI ascertains whole body composition, whereas CT is typically limited to the abdomen or thigh to reduce radiation exposure (14). Trained technicians utilize commercial or in-house developed software to conduct the analysis in a semi-automated process. Multi-slice assessment of images provides a full-volume measure of the varying tissue compartments and is therefore considered the most precise method for measuring body composition (14). However, successful use of a single-slice CT image (eg, L3 vertebral level) to evaluate body composition has been consistently demonstrated in adult oncology literature (4,6). Single-slice analysis provides a more readily available, practical, and cost-effective means of assessment in cross-sectional studies (14). A validated skeletal muscle index cutoff point at L3 defining sarcopenia has been described and well studied in the adult cancer population (6). However, such a point has not been delineated in pediatrics. Longitudinal studies validating the use of single-slice imaging in pediatrics are needed to determine the feasibility and utility of implementing these techniques in pediatric cancer and, ultimately, to facilitate incorporation of this methodology into clinical practice (15). The feasibility of conducting such investigations is restricted by the associated radiation exposure. One single-slice CT image confers an average effective radiation dose of 7.4 millisievert, although adherence to optimized protocols and use of advanced CT technology may reduce this dosage (16). Clinical Applications of Body Composition Adult Oncology Whereas sarcopenia was first described in the elderly, in recent years this term has been adapted in the field of oncology to denote severe skeletal muscle loss in cancer patients regardless of age (1,2,8,17). Sarcopenia can occur in the setting of depleted, normal, or excess fat mass (sarcopenic obesity) (4,6,9). Both sarcopenia and sarcopenic obesity have emerged as important prognostic indicators in a wide variety of adult malignancies (2–4,6–9). A recent meta-analysis evaluating the significance of sarcopenia in a diverse group of solid tumor patients showed that a low pretreatment skeletal muscle index is predictive of worse overall survival (OS), regardless of disease type or stage (hazard ratio [HR] = 1.44, 95% confidence interval [CI] = 1.32 to 1.56; P < .001) (2). Similarly, in patients with gastrointestinal and respiratory tract cancers, sarcopenic obesity was associated with poorer functional status (P = .009) and OS (HR = 4.2, 95 % CI = 2.4 to 7.2; P < .0001) (6). It was also identified as a statistically significant predictor of diminished OS in pancreatic cancer (HR = 2.07, 95 % CI = 1.23 to 3.50; P = .006) (7). The impact of body composition extends beyond long-term survival outcomes. Diminished skeletal muscle mass has been associated with increased morbidities, such as postoperative complication rates, risk of infection, and longer hospital length of stay (4,9). Moreover, sarcopenia has repeatedly demonstrated an adverse relationship with tolerance to treatment and prevalence of dose-limiting toxicities (4,18). Sarcopenic vs nonsarcopenic patients exhibited increased toxicity with use of 5-fluorouracil to treat colorectal cancer (19), as well as capecitabine (50% vs 20%; P = .03) (1) and taxane-based chemotherapy (57% vs 18%; P = .02) (20) to treat breast cancer. Indeed, among those treated with taxane chemotherapy, sarcopenic patients had increased adverse events overall, including toxicity-related hospitalizations, chemotherapy dose reductions, and dose delays (74% vs 35%; P = .02) (20). In a large proportion of patients, sarcopenia is detectable by imaging at the time of diagnosis and affects patient outcomes regardless of cancer stage or progression (1–3,21). By relying on BMI alone to assess nutritional status and body-store depletion, many at-risk patients are left underrecognized (3,6,9,11). In a recent breast cancer study, sarcopenic patients with concurrent high total adipose tissue had the greatest risk of mortality (HR = 1.89; 95% CI = 1.30 to 2.73). Yet, in that same group, BMI alone did not show a statistically significant association with overall mortality and did not properly distinguish patients at increased risk owing to their body composition (3). These findings reinforce the limited utility of BMI in establishing the prognostic significance of malnutrition. The acquisition of CT imaging as part of routine care in patients with solid tumors renders it the ideal modality for lean and fat tissue assessment in this population, and therefore, most published methodology evaluating adult patients centers on its use (4). Early identification of high-risk patients via diagnostic and follow-up imaging potentiates the implementation of guided interventions to enhance clinical practice and improve patient outcomes. Pediatric Oncology The detrimental effects of sarcopenia have been established in young patients suffering from muscle disuse, malnutrition, and various inflammatory conditions (8). Yet, body composition studies in pediatric cancer are limited. Existing literature in this area has largely focused on hematologic malignancies, and in recent years, DXA has been at the forefront of body composition analysis among acute lymphoblastic leukemia (ALL) patients. One clinical investigation (n = 91) showed that children with ALL experience a statistically significant decrease in skeletal muscle mass within the first 6 months of treatment initiation (22). These findings were reinforced by a recent prospective study (n = 50) which demonstrated that ALL patients commonly develop sarcopenic obesity while undergoing therapy, resulting in a discordant relationship between BMI and body fat percentage (11). The application of imaging has also been explored in pediatric ALL. The use of CT imaging at the L3 level was evaluated to assess skeletal muscle mass changes among ALL patients (n = 47) (17). Loss of muscle mass following initiation of therapy occurred in all included study patients, and nearly one-third developed sarcopenia; however, sarcopenia was not correlated with survival in this group. Importantly, sarcopenia did show a statistically significant association with other clinically significant parameters including severe adverse events (P = .009) and invasive fungal infection (P = .018). Despite robust evidence linking body composition to unfavorable outcomes in the adult solid tumor population, and the demonstration of similar adverse changes in children and adolescents undergoing treatment for ALL, to date, there have been merely two noteworty publications examining body composition in solid tumor patients. Both studies were comprised of a diverse group of pediatric malignancies and included a small [n = 14 (12), n = 18 (23)], heterogeneous group of solid tumor patients at various stages of therapy. Investigators used ADP to measure fat and fat-free mass. Findings from these studies suggest that patients undergoing treatment for solid tumors experience a statistically significant decrease in fat-free mass and increase in fat mass as compared to age and sex-matched control subjects (12,23). Although each of these studies are limited by their sample sizes, their findings are compelling and warrant further research. Notably, neither study employed an imaging modality for body composition evaluation. To the authors’ knowledge, there have been no publications reporting on the efficacy of imaging techniques for body composition assessment in the pediatric solid tumor patient population. Pathogenesis and Treatment Implications The pathogenesis of muscle wasting in cancer patients is a multifactorial process wherein an imbalance between synthetic and degradative protein pathways, increased myocyte apoptosis, and decreased muscle regeneration are the drivers (24). A heightened state of inflammation is widely believed to be a key contributor to the activation of many of the altered metabolic pathways present in skeletal muscle wasting (24–26). Various inflammatory cytokines have been implicated in cancer-related muscle breakdown (25,26). These markers of immune activation are likely manufactured by the tumor itself or by surrounding cells and promote activation of catabolic pathways (21,24–26). Additionally, proinflammatory cytokines have an anorectic effect that may negatively influence skeletal muscle via indirect pathways (25). In adults with colorectal cancer, increased prediagnostic systemic inflammation, measured via surrogate markers like neutrophil-to-lymphocyte ratio, had increased odds of having sarcopenia, regardless of other confounding factors such as age, disease stage, and BMI (21). Moreover, the concurrence of sarcopenia and high neutrophil-to-lymphocyte ratio was identified as an independent prognostic indicator for poorer survival outcomes (21,25). The interplay between host inflammatory and/or immune response, tumor microenvironment, and skeletal muscle changes has not been elucidated in pediatric oncology. Further study in this area potentiates the identification of similar prognostic biomarkers in pediatric solid tumors, as well as new opportunities for therapeutic intervention development. The mechanism underlying the relationship of body composition and outcomes in patients with cancer remains uncertain (2). However, it is widely hypothesized that variations in fat and lean tissue masses alter chemotherapy volume of distribution, metabolism, and clearance of hydrophilic and/or lipophilic drugs from systemic circulation (1,4,19,27–29). It is well recognized that traditional methods of dosing by body surface area (BSA) do not accurately predict chemotherapy pharmacokinetics (5,19). Prado et al. demonstrated that there is a poor correlation between BSA and fat-free mass (r2 = 0.37), potentially accounting for up to three-times difference in effective volume of distribution of chemotherapy administered per BSA unit (6). Thus, in a patient with diminished lean tissue mass and excess fat mass, dosing of chemotherapy by anthropometric measures may result in overexposure and early acute toxicity (29), providing a potential mechanism for increased morbidities observed among sarcopenic patients. In a diverse group of pediatric cancer patients (n = 22) being treated with doxorubicin, those with more than 30% body fat (measured via DXA) exhibited disturbed clearance of the doxorubicin metabolite, doxorubicinol. The authors surmised that this extended exposure could considerably contribute to the development of future treatment-related cardiac toxicity in this population (28). Similarly, vincristine pharmacokinetics were altered in obese vs nonobese leukemia mouse models, leading to decreased overall exposure to the drug in the circulation and bone marrow of the obese mice, and thereby potentially reducing its efficacy in this group (27). The implications of these findings extend not only to dose-limiting toxicities of traditional cytotoxic agents but also to those of novel targeted therapies. In adult malignancies, the association of body composition with toxicities has been described with use of tyrosine kinase inhibitors (30) as well as various immunotherapy agents [pembrolizumab (29), nivolumab (29), and ipilimumab (18)]. With the burgeoning shift of cancer treatment research to individualized therapies, body composition has the potential to play a key role in the manner by which we dose chemotherapy and personalize care. Potential Targets for Intervention Currently, there is no universally accepted treatment for reversing or preventing sarcopenia in cancer patients. Diet and muscle building exercise (aerobic and/or resistance training) have long been suggested to be key factors in ameliorating the negative trajectory and effects of muscle loss. Early recognition of malnutrition and initiation of a high-calorie, high-protein diet is critical to tempering the wasting process and improving patient quality of life; however, the feasibility and effectiveness of nutritional interventions among children with cancer is unknown and is an opportunity for further inquiry (31,32). Clinical studies examining exercise in pediatric oncology have shown that its implementation during therapy is feasible and well tolerated and confers an overwhelmingly positive benefit in this population (33,34). In adults with head and/or neck squamous cell carcinoma, a 12-week progressive resistance exercise intervention resulted in a greater than 4% average increase in lean body mass (measured via DXA) (35). Although such quantitative studies are lacking in pediatrics, muscle strength has been used as a proxy for change in muscle mass. In a study comparing regimented thrice weekly exercise sessions to a control (no structured exercise) arm during neoadjuvant therapy among pediatric solid tumor patients, there was a statistically significant increase in muscle strength in the intervention arm and decrease among control subjects (36). Similar results of improved muscle strength were seen after exercise interventions in children with leukemia (37). Preclinical data suggests that in addition to maintaining muscle mass, another benefit to exercise during therapy is its potential to augment chemotherapeutic efficacy against solid tumors. Animal models of melanoma, breast, prostate, and pancreatic cancers consistently demonstrate remodeling of tumor vasculature in response to moderate exercise (38–40). Remodeled tumor vasculature is more efficient and thereby improves delivery of chemotherapy to the tumor. Indeed, chemotherapy combined with exercise was statistically significantly more effective than chemotherapy alone among several solid tumor mouse models (38,40). To date, published literature in this area has predominantly addressed adult cancer models. However, unpublished data utilizing aerobic exercise in combination with doxorubicin in mice-bearing Ewing sarcoma suggests that exercise enhances doxorubicin efficacy against Ewing sarcoma (K. Schadler, unpublished data). Taken together, emerging evidence indicates that incorporating physical activity as part of a multifaceted approach in the treatment of cancer-related sarcopenia holds substantial promise for improving body composition and long-term patient outcomes. Future Directions There is a growing body of data supporting the prognostic significance of body composition in cancer outcomes. Although it is limited, existing literature reinforces the notion that cancer and its therapy can also have a meaningful impact on body composition in the pediatric population and underscores the need to further promote this area of investigation in patients with solid tumors. Survival rates among many of the most common pediatric solid tumors have remained stagnant over the past several decades, and marked treatment-related morbidity occurs both during therapy and well into survivorship (41). The frequent and standard use of CT imaging for disease diagnosis and monitoring throughout therapy in this group provides an accurate and readily available modality for body composition assessment (2,4). Identifying the prevalence and clinical significance of sarcopenia and sarcopenic obesity in this population will enhance and complement current understanding in patient nutritional status, aid in early identification of those at greatest risk for adverse outcomes, and enable clinicians to optimize treatment plans and ameliorate the effects of these potentially modifiable risk factors (4,9). Clinical and translational trials aimed at elucidating the mechanisms by which cancer and its therapy potentiate adverse changes and clinical outcomes in pediatric solid tumors are critical to closing the current knowledge gap in this field. Further research in this area may lead to refinement and personalization of chemotherapy dosing, optimize timing of nutritional and physiotherapy supportive care interventions, and improve tolerance to both traditional and novel therapies. Thus, advancement in this area may have a long-lasting impact on patient quality of life and successful transition into survivorship. Funding This work was supported by the Tamarind Foundation to EJL; American Cancer Society (grant number 127000-MRSG-14–157-01-CCE to EJL); National Institutes of Health (grant number T32 CA094061-17 to LJ); National Institute of Aging (grant number R01 AG045761 to WS); National Institute of Diabetes and Digestive and Kidney Diseases (grant number P30 DK26687 to WS); National Center for Advancing Translational Sciences (grant number UL1 TR000040, with Pilot Integrating Special Population Award on Body Composition after Bariatric Surgery to WS); and Zuckerman Mind Brain Behavior Institute (Seed Grant 2018 to WS) Notes Affiliations of authors: Department of Pediatric Hematology, Oncology and Stem Cell Transplant, Morgan Stanley Children’s Hospital, Columbia University Medical Center, New York, NY (LJ, EJL); Department of Pediatrics Research, MD Anderson Cancer Center, Houston, TX (KLS); Department of Pediatric Gastroenterology, Hepatology and Nutrition, Institute of Human Nutrition, and MR Research Center, Columbia University Medical Center, New York, NY (WS). 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CA Cancer J Clin . 2014 ; 64 2 : 83 – 103 . Google Scholar Crossref Search ADS PubMed WorldCat © 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