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Nutrition & Exercise Interventions in Pediatric Patients with Brain Tumors: A Narrative Review

Nutrition & Exercise Interventions in Pediatric Patients with Brain Tumors: A Narrative Review Abstract Brain tumors have been the most common pediatric solid tumor and leading cause of morbidity and mortality. Improved survival emphasizes the importance of adverse treatment effects especially related to nutrition and exercise. Although studies have examined nutrition and exercise outcomes, few randomized trials exist. This narrative review included a systematic literature search with analysis of controlled or single group studies examining clinical and quality-of-life impact of nutrition or exercise interventions. Seven articles were included. Three nutrition studies demonstrated improvement with proactive feeding tubes, nutritional supplementation, and nutritional status. Two exercise studies showed improvement in measures of fitness and neuroanatomy with exercise in pediatric brain tumor survivors; two cohort studies demonstrated a link between quality of life and physical activity. Preliminary studies show nutrition and exercise may improve physical well-being and quality of life, suggesting future controlled studies are warranted to inform clinical care of children with brain tumors. The most common pediatric solid tumor, brain tumors cause most childhood cancer deaths, but survival continues to improve (1). Recent pediatric oncology research has focused on secondary effects especially in pediatric brain tumor survivors who average 24 chronic health conditions including unhealthy weight, dyslipidemia, hypertension, and disordered glucose metabolism (2). However, few randomized trials of nutrition and exercise interventions exist. Proper nutrition is necessary for brain myelination and is required for motor, cognitive, and social development (3). During childhood cancer treatment, nutrition affects physical activity (4). Undernutrition decreases muscle mass, affecting exercise capabilities, and nearly 40% of children with brain tumors experience swallowing difficulty, exacerbating anorexia and fatigue (5,6). Although nutritional support is often used, malnutrition rates vary between 5 and 90% (7–10). Malnutrition is associated with higher rates of infection and mortality and lower quality of life (QOL) (4,11,12). Additionally, multidisciplinary treatment teams including physical and occupational therapists, dietitians, and medical providers can improve nutrition-related anxiety in patients and providers (13–16). Pediatric brain tumor treatment impairs cognitive and physical function in survivors (2). Radiation negatively affects intelligence, academic achievement, and independence in adulthood (17,18). Children treated with radiation experienced a 74% decline in physical activity, strongly correlating with inability to meet recommended activity guidelines (19,20). Patients with brain tumors demonstrated more sedentary behaviors and lower cardiorespiratory fitness (17,21). Compared with age- and sex-matched peers, survivors had lower physical fitness levels and clinical measures of V02max (17). Deficits in executive functioning and problem-solving interfere with maintaining proper nutrition and engaging in physical activity (7,18,22). Although patients and survivors of pediatric brain tumors have impaired QOL, evidence for specific nutrition and exercise interventions is based largely on observational studies and expert opinion. Randomized controlled trials are challenging to ethically implement for malnourished or deconditioned patients, but well-designed trials could lend valuable insight for nutritional supplementation or specialized swallow training (9,23). Similarly, controlled exercise studies could define benefits of physical activity during and after treatment (16,24). This narrative review describes available evidence for nutrition and exercise interventions in children with brain tumors with clinical analysis and identification of future direction for study. Methods This narrative review included a systematic electronic search of MEDLINE, CINAHL, AMED, EMBASE, and Cochrane databases. The search was limited to English language publications, human patients, and 10 years through May 2019 to reflect contemporary treatment and supportive care practices. MeSH terms included brain tumor, nutrition, exercise, pediatric, childhood, feeding, and QOL; keywords included physical activity, diet, and nutrition supplement. Brain tumor was combined with terms using “and,” whereas other keywords were combined with “or.” The search was augmented by screening reference lists of identified studies and Web of Science search for subsequent citation of the included articles. Article Selection Two readers reviewed each exercise article for inclusion (LY, CKW), with a third reviewer available for disagreements (DVR). Nutrition articles were reviewed similarly (DVR, SAG, and LY for disagreements). Randomized control trials, prospective, single group, or case-controlled studies were included. Participants were 0–18 years old, at least 20% of whom had primary brain tumors. Interventions included diet or nutritional supplement or exercise or physical activity. Outcomes included measures of QOL (self-report, cognitive, medical, behavioral, functional) in combination with quantifiable measures of nutrition or exercise. The nutrition article search yielded no QOL measures so surrogate markers were included (ie, febrile neutropenia, hospital length of stay [LOS], and nutritional status). Case studies, reviews, practice guidelines, and expert opinions were excluded. Finally, education only and unsupervised exercise interventions were excluded. Data Extraction, Synthesis, and Analysis Study design, sample, intervention, and outcome were compiled (Table 1). Patient characteristics, measures of nutrition and exercise, and QOL were included. Study quality was assessed with discussion of potential biases. Table 1. Nutrition and exercise intervention studies Publication Design or sample Measures Results Mousa et.al. (2017) (25) Randomized, pre- and post-test control study N = 80 (BTn = 80, 100% of patients) Nigella seed supplementation Episodes of FN Length of hospital stay Loss of body weight Less severe weight loss (15.7%) intervention vs control group (30.4%) (P = .048) Fewer patients in intervention group had FN (2.2 vs 19.3%) Shorter median hospital stay for intervention group (2.5 vs 5 days) Brinksma et al. (2015) (26) Prospective, repeated-measures cohort N = 133 (BTn = 36, 27.1% of patients) Nutritional status with symptom and physical at initiation and 3, 6, and 12 mo Nutritional status Memorial Symptom Assessment Scale Lansky Play Performance Scale Weight changes in 63.7% of patients Nasogastric feeding in 45.1% of patients Decreased weight-for-age in first 3 months for heme and solid malignancies but increased for brain tumors No association with body composition, symptom report, physical function, or demographic factors Sacks et.al. (2014) (8) Case control, nonrandomized, pilot study N = 69 (PP n = 16; CC n = 49; BTn = 15, 22% of patients) Enteral feeding tube placement at enrollment; weekly dietitian calls Nutritional status Weight-for-age percentiles Use of enteral tube feeding Infection rates 33% of underweight patients had brain tumors Patients >2 y old more likely to lose weight PP group lost less absolute body weight (6.0%) vs CC (10.6%) More CC patients lost >5% of body weight compared with PP (48% vs 25%) PP group improved nutritional status No difference in bacteremia or enterostomy site infection Riggs et al. (2017) (27)* Crossover, quasi randomized N = 28 (n = 16 GEX; n = 12 CEX; BTn = 28, 100% of patients) 12-wk group vs no group training, then cross-over aerobic training 6MWT BOT-2 Improvement in 6MWT (P < .01) Training increased white matter FA (Δ =0.05, P < .001), hippocampal volume in GEX (Δ= 130.98 mm3, P = .001), mean reaction time Δ = 457.04 ms, P = .36) Related carryover effects predicted by increased FA (R = −0.62, P = .01) Carryover effect 12 wk post (Δ= 0.05, P < .001) Piscione et al. (2017) (28)* BOT-2 Pro-rated work rate Training improved BOT-2 bilateral coordination scores P = .02, exceeding MID (2.52 vs 1.11) Carryover effect after 12 wk ( P= .005) Other BOT-2 subtests did not attain MID levels (balance, strength, running speed or agility) Improved pro-rated work rate in GEX only (P = .04); carryover effect 12 wk post ( P= .01) Ovans et al. (2018) (29) Quasi experimental, repeated-measures, single-group design N = 15 (100% BTn) N = 15 (baseline and 12 wk) N = 11 (baseline, 12 wk, and 24 wk) 12-week PA intervention using fitness tracker with 5 PT sessions Fitbit Flex steps per day at baseline, 12 wk, 24 wk Godin Leisure-Time Exercise Questionnaire 6MWT PedsQL Generic Core and Multidimensional Fatigue Scale No significant increase in steps per day Higher steps per day associated with lower fatigue Total fatigue, general, and sleep or rest subscales improved; cognitive fatigue and QOL unchanged Strong association between activity and higher QOL and lower fatigue in last 4 weeks of study Muller et.al. (2016) (30) Prospective, longitudinal, cohort N = 150 (BTn = 38 of 150; 25.3% of patients) 4-wk rehabilitation program (hippotherapy, land, aquatic therapy, exercise, and sports training) Pre- and postintervention, 6-mo, 12 mo StepWatch Activity Monitor Health-related QOL (KINDL) HRQOL global and well-being increased at 4 wk; nonsignificant at 12 mo for global and 6 and 12 mo for well-being Change in physical activity and well-being correlated (P = .15 to .32) in BTn Significant effects on physical activity at 12-mo follow-up for amount and cadence variables Publication Design or sample Measures Results Mousa et.al. (2017) (25) Randomized, pre- and post-test control study N = 80 (BTn = 80, 100% of patients) Nigella seed supplementation Episodes of FN Length of hospital stay Loss of body weight Less severe weight loss (15.7%) intervention vs control group (30.4%) (P = .048) Fewer patients in intervention group had FN (2.2 vs 19.3%) Shorter median hospital stay for intervention group (2.5 vs 5 days) Brinksma et al. (2015) (26) Prospective, repeated-measures cohort N = 133 (BTn = 36, 27.1% of patients) Nutritional status with symptom and physical at initiation and 3, 6, and 12 mo Nutritional status Memorial Symptom Assessment Scale Lansky Play Performance Scale Weight changes in 63.7% of patients Nasogastric feeding in 45.1% of patients Decreased weight-for-age in first 3 months for heme and solid malignancies but increased for brain tumors No association with body composition, symptom report, physical function, or demographic factors Sacks et.al. (2014) (8) Case control, nonrandomized, pilot study N = 69 (PP n = 16; CC n = 49; BTn = 15, 22% of patients) Enteral feeding tube placement at enrollment; weekly dietitian calls Nutritional status Weight-for-age percentiles Use of enteral tube feeding Infection rates 33% of underweight patients had brain tumors Patients >2 y old more likely to lose weight PP group lost less absolute body weight (6.0%) vs CC (10.6%) More CC patients lost >5% of body weight compared with PP (48% vs 25%) PP group improved nutritional status No difference in bacteremia or enterostomy site infection Riggs et al. (2017) (27)* Crossover, quasi randomized N = 28 (n = 16 GEX; n = 12 CEX; BTn = 28, 100% of patients) 12-wk group vs no group training, then cross-over aerobic training 6MWT BOT-2 Improvement in 6MWT (P < .01) Training increased white matter FA (Δ =0.05, P < .001), hippocampal volume in GEX (Δ= 130.98 mm3, P = .001), mean reaction time Δ = 457.04 ms, P = .36) Related carryover effects predicted by increased FA (R = −0.62, P = .01) Carryover effect 12 wk post (Δ= 0.05, P < .001) Piscione et al. (2017) (28)* BOT-2 Pro-rated work rate Training improved BOT-2 bilateral coordination scores P = .02, exceeding MID (2.52 vs 1.11) Carryover effect after 12 wk ( P= .005) Other BOT-2 subtests did not attain MID levels (balance, strength, running speed or agility) Improved pro-rated work rate in GEX only (P = .04); carryover effect 12 wk post ( P= .01) Ovans et al. (2018) (29) Quasi experimental, repeated-measures, single-group design N = 15 (100% BTn) N = 15 (baseline and 12 wk) N = 11 (baseline, 12 wk, and 24 wk) 12-week PA intervention using fitness tracker with 5 PT sessions Fitbit Flex steps per day at baseline, 12 wk, 24 wk Godin Leisure-Time Exercise Questionnaire 6MWT PedsQL Generic Core and Multidimensional Fatigue Scale No significant increase in steps per day Higher steps per day associated with lower fatigue Total fatigue, general, and sleep or rest subscales improved; cognitive fatigue and QOL unchanged Strong association between activity and higher QOL and lower fatigue in last 4 weeks of study Muller et.al. (2016) (30) Prospective, longitudinal, cohort N = 150 (BTn = 38 of 150; 25.3% of patients) 4-wk rehabilitation program (hippotherapy, land, aquatic therapy, exercise, and sports training) Pre- and postintervention, 6-mo, 12 mo StepWatch Activity Monitor Health-related QOL (KINDL) HRQOL global and well-being increased at 4 wk; nonsignificant at 12 mo for global and 6 and 12 mo for well-being Change in physical activity and well-being correlated (P = .15 to .32) in BTn Significant effects on physical activity at 12-mo follow-up for amount and cadence variables * Two manuscripts published from the same study population. N = total study subjects; n = subgroup of subjects; BOT-2 = Bruininks-Oseretsky Test of Motor Proficiency; BTn = patients with brain tumors; CC = control group; CEX = combined group/home exercise; FA = fractional ansiotropy; FN = febrile neutropenia; GEX = group exercise; MID = minimally important difference; 6MWT = 6-minute walk test; PP = proactive group; HRQOL = health related quality of life; QOL = quality of life. Open in new tab Table 1. Nutrition and exercise intervention studies Publication Design or sample Measures Results Mousa et.al. (2017) (25) Randomized, pre- and post-test control study N = 80 (BTn = 80, 100% of patients) Nigella seed supplementation Episodes of FN Length of hospital stay Loss of body weight Less severe weight loss (15.7%) intervention vs control group (30.4%) (P = .048) Fewer patients in intervention group had FN (2.2 vs 19.3%) Shorter median hospital stay for intervention group (2.5 vs 5 days) Brinksma et al. (2015) (26) Prospective, repeated-measures cohort N = 133 (BTn = 36, 27.1% of patients) Nutritional status with symptom and physical at initiation and 3, 6, and 12 mo Nutritional status Memorial Symptom Assessment Scale Lansky Play Performance Scale Weight changes in 63.7% of patients Nasogastric feeding in 45.1% of patients Decreased weight-for-age in first 3 months for heme and solid malignancies but increased for brain tumors No association with body composition, symptom report, physical function, or demographic factors Sacks et.al. (2014) (8) Case control, nonrandomized, pilot study N = 69 (PP n = 16; CC n = 49; BTn = 15, 22% of patients) Enteral feeding tube placement at enrollment; weekly dietitian calls Nutritional status Weight-for-age percentiles Use of enteral tube feeding Infection rates 33% of underweight patients had brain tumors Patients >2 y old more likely to lose weight PP group lost less absolute body weight (6.0%) vs CC (10.6%) More CC patients lost >5% of body weight compared with PP (48% vs 25%) PP group improved nutritional status No difference in bacteremia or enterostomy site infection Riggs et al. (2017) (27)* Crossover, quasi randomized N = 28 (n = 16 GEX; n = 12 CEX; BTn = 28, 100% of patients) 12-wk group vs no group training, then cross-over aerobic training 6MWT BOT-2 Improvement in 6MWT (P < .01) Training increased white matter FA (Δ =0.05, P < .001), hippocampal volume in GEX (Δ= 130.98 mm3, P = .001), mean reaction time Δ = 457.04 ms, P = .36) Related carryover effects predicted by increased FA (R = −0.62, P = .01) Carryover effect 12 wk post (Δ= 0.05, P < .001) Piscione et al. (2017) (28)* BOT-2 Pro-rated work rate Training improved BOT-2 bilateral coordination scores P = .02, exceeding MID (2.52 vs 1.11) Carryover effect after 12 wk ( P= .005) Other BOT-2 subtests did not attain MID levels (balance, strength, running speed or agility) Improved pro-rated work rate in GEX only (P = .04); carryover effect 12 wk post ( P= .01) Ovans et al. (2018) (29) Quasi experimental, repeated-measures, single-group design N = 15 (100% BTn) N = 15 (baseline and 12 wk) N = 11 (baseline, 12 wk, and 24 wk) 12-week PA intervention using fitness tracker with 5 PT sessions Fitbit Flex steps per day at baseline, 12 wk, 24 wk Godin Leisure-Time Exercise Questionnaire 6MWT PedsQL Generic Core and Multidimensional Fatigue Scale No significant increase in steps per day Higher steps per day associated with lower fatigue Total fatigue, general, and sleep or rest subscales improved; cognitive fatigue and QOL unchanged Strong association between activity and higher QOL and lower fatigue in last 4 weeks of study Muller et.al. (2016) (30) Prospective, longitudinal, cohort N = 150 (BTn = 38 of 150; 25.3% of patients) 4-wk rehabilitation program (hippotherapy, land, aquatic therapy, exercise, and sports training) Pre- and postintervention, 6-mo, 12 mo StepWatch Activity Monitor Health-related QOL (KINDL) HRQOL global and well-being increased at 4 wk; nonsignificant at 12 mo for global and 6 and 12 mo for well-being Change in physical activity and well-being correlated (P = .15 to .32) in BTn Significant effects on physical activity at 12-mo follow-up for amount and cadence variables Publication Design or sample Measures Results Mousa et.al. (2017) (25) Randomized, pre- and post-test control study N = 80 (BTn = 80, 100% of patients) Nigella seed supplementation Episodes of FN Length of hospital stay Loss of body weight Less severe weight loss (15.7%) intervention vs control group (30.4%) (P = .048) Fewer patients in intervention group had FN (2.2 vs 19.3%) Shorter median hospital stay for intervention group (2.5 vs 5 days) Brinksma et al. (2015) (26) Prospective, repeated-measures cohort N = 133 (BTn = 36, 27.1% of patients) Nutritional status with symptom and physical at initiation and 3, 6, and 12 mo Nutritional status Memorial Symptom Assessment Scale Lansky Play Performance Scale Weight changes in 63.7% of patients Nasogastric feeding in 45.1% of patients Decreased weight-for-age in first 3 months for heme and solid malignancies but increased for brain tumors No association with body composition, symptom report, physical function, or demographic factors Sacks et.al. (2014) (8) Case control, nonrandomized, pilot study N = 69 (PP n = 16; CC n = 49; BTn = 15, 22% of patients) Enteral feeding tube placement at enrollment; weekly dietitian calls Nutritional status Weight-for-age percentiles Use of enteral tube feeding Infection rates 33% of underweight patients had brain tumors Patients >2 y old more likely to lose weight PP group lost less absolute body weight (6.0%) vs CC (10.6%) More CC patients lost >5% of body weight compared with PP (48% vs 25%) PP group improved nutritional status No difference in bacteremia or enterostomy site infection Riggs et al. (2017) (27)* Crossover, quasi randomized N = 28 (n = 16 GEX; n = 12 CEX; BTn = 28, 100% of patients) 12-wk group vs no group training, then cross-over aerobic training 6MWT BOT-2 Improvement in 6MWT (P < .01) Training increased white matter FA (Δ =0.05, P < .001), hippocampal volume in GEX (Δ= 130.98 mm3, P = .001), mean reaction time Δ = 457.04 ms, P = .36) Related carryover effects predicted by increased FA (R = −0.62, P = .01) Carryover effect 12 wk post (Δ= 0.05, P < .001) Piscione et al. (2017) (28)* BOT-2 Pro-rated work rate Training improved BOT-2 bilateral coordination scores P = .02, exceeding MID (2.52 vs 1.11) Carryover effect after 12 wk ( P= .005) Other BOT-2 subtests did not attain MID levels (balance, strength, running speed or agility) Improved pro-rated work rate in GEX only (P = .04); carryover effect 12 wk post ( P= .01) Ovans et al. (2018) (29) Quasi experimental, repeated-measures, single-group design N = 15 (100% BTn) N = 15 (baseline and 12 wk) N = 11 (baseline, 12 wk, and 24 wk) 12-week PA intervention using fitness tracker with 5 PT sessions Fitbit Flex steps per day at baseline, 12 wk, 24 wk Godin Leisure-Time Exercise Questionnaire 6MWT PedsQL Generic Core and Multidimensional Fatigue Scale No significant increase in steps per day Higher steps per day associated with lower fatigue Total fatigue, general, and sleep or rest subscales improved; cognitive fatigue and QOL unchanged Strong association between activity and higher QOL and lower fatigue in last 4 weeks of study Muller et.al. (2016) (30) Prospective, longitudinal, cohort N = 150 (BTn = 38 of 150; 25.3% of patients) 4-wk rehabilitation program (hippotherapy, land, aquatic therapy, exercise, and sports training) Pre- and postintervention, 6-mo, 12 mo StepWatch Activity Monitor Health-related QOL (KINDL) HRQOL global and well-being increased at 4 wk; nonsignificant at 12 mo for global and 6 and 12 mo for well-being Change in physical activity and well-being correlated (P = .15 to .32) in BTn Significant effects on physical activity at 12-mo follow-up for amount and cadence variables * Two manuscripts published from the same study population. N = total study subjects; n = subgroup of subjects; BOT-2 = Bruininks-Oseretsky Test of Motor Proficiency; BTn = patients with brain tumors; CC = control group; CEX = combined group/home exercise; FA = fractional ansiotropy; FN = febrile neutropenia; GEX = group exercise; MID = minimally important difference; 6MWT = 6-minute walk test; PP = proactive group; HRQOL = health related quality of life; QOL = quality of life. Open in new tab Results Overall, 375 papers were identified, 14 papers reviewed, and seven included (Figure 1). Included patients had varied treatment (chemotherapy, surgery, and radiation), time since diagnosis, and comorbidities. Most diagnoses were medulloblastoma, ependymoma, or low-grade gliomas. There were smaller numbers of other less common brain tumors. Broader classifications without specifics (such as “other” or “astrocytoma”) were also seen. Figure 1. Open in new tabDownload slide PRISMA diagram (31). Outline of included publications. Figure 1. Open in new tabDownload slide PRISMA diagram (31). Outline of included publications. Nutrition Mousa et al. studied Nigella sativa seeds’ effect on incidence and hospital LOS associated with febrile neutropenia (25). The seed is thought to have antimicrobial properties, and patients taking the supplement had fewer and shorter hospital admissions for febrile neutropenia. In addition to shorter hospital LOS, patients taking Nigella seeds had less weight loss (Table 1). Importantly, patients were stratified by diagnosis to control for side effects of particular treatment regimens. Limitations included no placebo control and intervention based on self-report. Nigella seeds’ direct improvement of nutritional status remains unclear, especially without blinding or placebo. Brinksma et al. also examined nutritional status in a larger volume of pediatric cancer patients and included subanalysis of brain tumor diagnoses (26). Although nutritional status changed in 63% of patients, those with brain tumors gained weight while those with solid and hematologic malignancies lost weight, especially within the first 3 months. Although physical function, symptom report, and QOL metrics were collected, none were statistically significant so were not included in the article. The nonblinded, observation design also limits this study. Sacks et al. studied newly diagnosed children with cancer and found weight and nutritional status improvement with proactive, enteral tube feeding (ETF) and dietitian support (8). This study demonstrated the feasibility, effectiveness, and improvement of nutritional status with proactive, enteral feeding supplement without increased adverse outcomes. Limitations of this pilot included nonrandom patient assignment, no assessor blinding, few children with brain tumors, and lack of power to determine differences between diagnoses. The small sample prohibited subgroup analyses. Exercise In a single crossover study, Riggs et al. and Piscione et al. studied exercise and physical functioning and brain structures in pediatric brain tumor survivors treated with cranial radiation (27,28). For both studies, 32 patients were enrolled and quasi-randomly assigned into group exercise (GEX) or combined group and home exercise (CEX) for 12 weeks. The GEX group participated in 90 minutes of activity three times weekly; CEX patients received 90 minutes of group activity two times weekly and two 30-minute home sessions monitored by a parent. Each session aimed for at least 30 minutes of aerobic exercise by maintaining heart rate at 80% or higher peak heart rate. After 12 weeks, participants switched conditions for the subsequent 12 weeks. Riggs et al. reported on the impact of aerobic exercise on brain imaging, cognition, and fitness (27). Group exercise improved white matter architecture, hippocampal volume, and reaction time. Participants in both GEX and CEX groups exhibited improvement in fitness with carryover effects in white matter organization 12 weeks after training, but only hippocampal volume and mean reaction time improved in the GEX group. Piscione et al. analyzed the Bruininks-Oseretsky Test of Motor Performance and pro-rated work rate from a cycle ergometer as measures after GEX and CEX (28). Both groups demonstrated improved Bruininks-Oseretsky Test of Motor Performance in body coordination and carryover effects 12 weeks postintervention. Differences between groups were not evident at any time points. Pro-rated training work rate increased following training for those in the GEX only. Riggs et al. and Piscione et al. used clinical measures and neuroimaging to demonstrate improved physical function and neuroanatomy. The GEX group demonstrated evidence of carryover, change in hippocampal volume, mean reaction time, and pro-rated work. The potential impact of the first treatment condition on the second in the crossover design makes clear group comparison difficult. In addition, both studies were limited by quasi-randomization and large dropout rate. Muller et al. prospectively studied 38 children with brain tumors following a 4-week hospital-based individualized program of land, aquatic, and hippotherapy and exercise training and sports games (30). Change in physical activity and cadence were measured using the StepWatch 3 activity monitor as well as QOL at four time points. In the brain tumor group, cadence and QOL improved after intervention and at 6 and 12 month follow-up. Ovans et al. prospectively studied 15 children with brain tumors (29). Changes were noted in QOL measures of total fatigue, general, and sleep subscales after an intervention using a fitness tracker and five physical therapy coaching sessions. Higher steps per day were associated with lower fatigue, though the increase in overall steps per day was not statistically significant. The strength of the study by Muller et al. was the large number of brain tumor participants in the study. However, the actual intervention lacked description, preventing replication. The strength of the Ovans et al. study was using a functional and accessible activity that can be carried over postintervention and the minimal use of facility, therapist, and participant time and resources. Both studies used activity trackers, providing objective measures of activity, although both were limited by nonrandomization, selection bias, and lack of concealed intervention. Discussion Few controlled nutrition or exercise studies exist in pediatric patients with brain tumors and none utilizing nutrition and exercise together. Patients with brain tumors can experience feeding problems and nutritional deficits and decreased physical activity and physical capacity. Nutritional status improved with proactive ETF and nutritional supplements (as in decreased episodes of febrile neutropenia with shorter hospital stays using Nigella seeds). However, no studies identified improvement in physical function or symptom report with nutrition interventions or supplementation. Measures of physical capacity and fitness and brain neuroanatomy improved with exercise in survivors of pediatric brain tumors, with preliminary associations between physical activity and QOL. Although 12 weeks is frequently chosen as the intervention length in exercise studies, deconditioned and chronically ill participants may require more time to demonstrate changes in physical function or capacity. Therefore, the potential of nutritional and exercise interventions over longer periods remains unknown. Evidence for the benefit of particular interventions in achieving and maintaining proper nutrition has slowly emerged. Proactive ETF has benefitted other at-risk populations including head and neck cancers (32). However, proactive ETF in pediatric patients with brain tumors has little randomized data (33,34). Additionally, no standardized risk assessment has been used and very few studies have examined nutritional supplements. The review found only one study examining a supplement in relation to febrile neutropenia admissions, but Nigella seeds are not commonly used or well known. Brinksma et al. also did not find differences in physical function or symptom report for undernourished patients receiving feeding supplements, but other studies have demonstrated the significant impact this has on the family and medical team (26,35). Although strong evidence is lacking, our findings suggest the method and type of proactive nutritional interventions may improve QOL outcomes in pediatric brain tumor survivors. Nutrition and exercise may improve body composition in patients with brain tumors (12,14). At diagnosis, children with brain tumors have worse physical limitations and motor disabilities (17,20). Increasing physical activity and improved nutritional status may ameliorate loss of muscle strength, altered drug metabolism, and increased morbidity and mortality (14). Aerobic exercise also improved physical function and fitness specifically for children with brain tumors beyond the time when improvements are typically seen (27,28). In neurocognitively impaired rats, exercise increased brain fiber and mitigated brain stunting while improving behavioral control and processing speed (36). Other exercise studies improved white cortical development and vascular function, all changes not thought possible after cranial radiation (37,38). Although regular exercise has been recommended for healthy and obese children and physical activity as safe during cancer treatment, physical function of children treated for brain tumors and best methods to incorporate physical activity remain unknown (24,39–42). Additional late effects including obesity, hyperlipidemia, osteoporosis, and cardiovascular disease progressively worsen years after completing cancer therapy and can negatively affect survivors’ exercise tolerance (2,22,43). Traditional methods to improve physical activity require adaptations to accommodate physical and neurocognitive deficits (21,24,29). Specific interventions like strengthening, balance, and coordination exercises have not been fully investigated, but frequency, intensity, time, and type of exercise should be included in future study (24,44). A group-based environment may also provide greater incentive to exercise at a higher intensity (27,28). Other methods incorporating physical activity, including technology, accessing home or community-based resources, and coaching should be explored as feasible adjuncts (24,27,28,44,45). Despite a structured search strategy, this narrative review lacks sensitivity analysis of the search, oversight of reviewers, and statistical analysis of heterogeneity. Evidence was drawn from a small number of studies with heterogeneous samples of children with brain tumors. No randomized controlled trials were found. Study biases were identified, but standardized quality measures are not applicable with varied study designs. This review highlights the need for evidence-based guidelines to improve treatment-related morbidity and mortality in pediatric brain tumors. Although evidence favors the clinical and QOL benefit of nutrition and exercise interventions, the lack of prospective, controlled trials limits generalizability and warrants further research. The interrelation of nutrition and exercise necessitates early, multidisciplinary care to improve treatment outcomes for patients and families. Specifically utilizing patient and family reported outcomes in evaluating nutrition supplementation and exercise interventions can potentially improve the patient experience as well as morbidity and mortality. Funding This manuscript was completed without funding and the authors have no conflicts of interest disclosures. Notes Affiliations of authors: Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA (DVR); Emory University School of Medicine, Department of Pediatrics, Division of Pediatric Hematology/Oncology/BMT, Atlanta, GA (DVR); Department of Rehabilitative and Regenerative Medicine, Program in Physical Therapy, Columbia University Irving Medical Center, New York, NY (LY, CKW); Center for Cancer and Blood Disorders, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL (SAG). 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Nutrition & Exercise Interventions in Pediatric Patients with Brain Tumors: A Narrative Review

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Oxford University Press
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© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com
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1052-6773
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1745-6614
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Abstract

Abstract Brain tumors have been the most common pediatric solid tumor and leading cause of morbidity and mortality. Improved survival emphasizes the importance of adverse treatment effects especially related to nutrition and exercise. Although studies have examined nutrition and exercise outcomes, few randomized trials exist. This narrative review included a systematic literature search with analysis of controlled or single group studies examining clinical and quality-of-life impact of nutrition or exercise interventions. Seven articles were included. Three nutrition studies demonstrated improvement with proactive feeding tubes, nutritional supplementation, and nutritional status. Two exercise studies showed improvement in measures of fitness and neuroanatomy with exercise in pediatric brain tumor survivors; two cohort studies demonstrated a link between quality of life and physical activity. Preliminary studies show nutrition and exercise may improve physical well-being and quality of life, suggesting future controlled studies are warranted to inform clinical care of children with brain tumors. The most common pediatric solid tumor, brain tumors cause most childhood cancer deaths, but survival continues to improve (1). Recent pediatric oncology research has focused on secondary effects especially in pediatric brain tumor survivors who average 24 chronic health conditions including unhealthy weight, dyslipidemia, hypertension, and disordered glucose metabolism (2). However, few randomized trials of nutrition and exercise interventions exist. Proper nutrition is necessary for brain myelination and is required for motor, cognitive, and social development (3). During childhood cancer treatment, nutrition affects physical activity (4). Undernutrition decreases muscle mass, affecting exercise capabilities, and nearly 40% of children with brain tumors experience swallowing difficulty, exacerbating anorexia and fatigue (5,6). Although nutritional support is often used, malnutrition rates vary between 5 and 90% (7–10). Malnutrition is associated with higher rates of infection and mortality and lower quality of life (QOL) (4,11,12). Additionally, multidisciplinary treatment teams including physical and occupational therapists, dietitians, and medical providers can improve nutrition-related anxiety in patients and providers (13–16). Pediatric brain tumor treatment impairs cognitive and physical function in survivors (2). Radiation negatively affects intelligence, academic achievement, and independence in adulthood (17,18). Children treated with radiation experienced a 74% decline in physical activity, strongly correlating with inability to meet recommended activity guidelines (19,20). Patients with brain tumors demonstrated more sedentary behaviors and lower cardiorespiratory fitness (17,21). Compared with age- and sex-matched peers, survivors had lower physical fitness levels and clinical measures of V02max (17). Deficits in executive functioning and problem-solving interfere with maintaining proper nutrition and engaging in physical activity (7,18,22). Although patients and survivors of pediatric brain tumors have impaired QOL, evidence for specific nutrition and exercise interventions is based largely on observational studies and expert opinion. Randomized controlled trials are challenging to ethically implement for malnourished or deconditioned patients, but well-designed trials could lend valuable insight for nutritional supplementation or specialized swallow training (9,23). Similarly, controlled exercise studies could define benefits of physical activity during and after treatment (16,24). This narrative review describes available evidence for nutrition and exercise interventions in children with brain tumors with clinical analysis and identification of future direction for study. Methods This narrative review included a systematic electronic search of MEDLINE, CINAHL, AMED, EMBASE, and Cochrane databases. The search was limited to English language publications, human patients, and 10 years through May 2019 to reflect contemporary treatment and supportive care practices. MeSH terms included brain tumor, nutrition, exercise, pediatric, childhood, feeding, and QOL; keywords included physical activity, diet, and nutrition supplement. Brain tumor was combined with terms using “and,” whereas other keywords were combined with “or.” The search was augmented by screening reference lists of identified studies and Web of Science search for subsequent citation of the included articles. Article Selection Two readers reviewed each exercise article for inclusion (LY, CKW), with a third reviewer available for disagreements (DVR). Nutrition articles were reviewed similarly (DVR, SAG, and LY for disagreements). Randomized control trials, prospective, single group, or case-controlled studies were included. Participants were 0–18 years old, at least 20% of whom had primary brain tumors. Interventions included diet or nutritional supplement or exercise or physical activity. Outcomes included measures of QOL (self-report, cognitive, medical, behavioral, functional) in combination with quantifiable measures of nutrition or exercise. The nutrition article search yielded no QOL measures so surrogate markers were included (ie, febrile neutropenia, hospital length of stay [LOS], and nutritional status). Case studies, reviews, practice guidelines, and expert opinions were excluded. Finally, education only and unsupervised exercise interventions were excluded. Data Extraction, Synthesis, and Analysis Study design, sample, intervention, and outcome were compiled (Table 1). Patient characteristics, measures of nutrition and exercise, and QOL were included. Study quality was assessed with discussion of potential biases. Table 1. Nutrition and exercise intervention studies Publication Design or sample Measures Results Mousa et.al. (2017) (25) Randomized, pre- and post-test control study N = 80 (BTn = 80, 100% of patients) Nigella seed supplementation Episodes of FN Length of hospital stay Loss of body weight Less severe weight loss (15.7%) intervention vs control group (30.4%) (P = .048) Fewer patients in intervention group had FN (2.2 vs 19.3%) Shorter median hospital stay for intervention group (2.5 vs 5 days) Brinksma et al. (2015) (26) Prospective, repeated-measures cohort N = 133 (BTn = 36, 27.1% of patients) Nutritional status with symptom and physical at initiation and 3, 6, and 12 mo Nutritional status Memorial Symptom Assessment Scale Lansky Play Performance Scale Weight changes in 63.7% of patients Nasogastric feeding in 45.1% of patients Decreased weight-for-age in first 3 months for heme and solid malignancies but increased for brain tumors No association with body composition, symptom report, physical function, or demographic factors Sacks et.al. (2014) (8) Case control, nonrandomized, pilot study N = 69 (PP n = 16; CC n = 49; BTn = 15, 22% of patients) Enteral feeding tube placement at enrollment; weekly dietitian calls Nutritional status Weight-for-age percentiles Use of enteral tube feeding Infection rates 33% of underweight patients had brain tumors Patients >2 y old more likely to lose weight PP group lost less absolute body weight (6.0%) vs CC (10.6%) More CC patients lost >5% of body weight compared with PP (48% vs 25%) PP group improved nutritional status No difference in bacteremia or enterostomy site infection Riggs et al. (2017) (27)* Crossover, quasi randomized N = 28 (n = 16 GEX; n = 12 CEX; BTn = 28, 100% of patients) 12-wk group vs no group training, then cross-over aerobic training 6MWT BOT-2 Improvement in 6MWT (P < .01) Training increased white matter FA (Δ =0.05, P < .001), hippocampal volume in GEX (Δ= 130.98 mm3, P = .001), mean reaction time Δ = 457.04 ms, P = .36) Related carryover effects predicted by increased FA (R = −0.62, P = .01) Carryover effect 12 wk post (Δ= 0.05, P < .001) Piscione et al. (2017) (28)* BOT-2 Pro-rated work rate Training improved BOT-2 bilateral coordination scores P = .02, exceeding MID (2.52 vs 1.11) Carryover effect after 12 wk ( P= .005) Other BOT-2 subtests did not attain MID levels (balance, strength, running speed or agility) Improved pro-rated work rate in GEX only (P = .04); carryover effect 12 wk post ( P= .01) Ovans et al. (2018) (29) Quasi experimental, repeated-measures, single-group design N = 15 (100% BTn) N = 15 (baseline and 12 wk) N = 11 (baseline, 12 wk, and 24 wk) 12-week PA intervention using fitness tracker with 5 PT sessions Fitbit Flex steps per day at baseline, 12 wk, 24 wk Godin Leisure-Time Exercise Questionnaire 6MWT PedsQL Generic Core and Multidimensional Fatigue Scale No significant increase in steps per day Higher steps per day associated with lower fatigue Total fatigue, general, and sleep or rest subscales improved; cognitive fatigue and QOL unchanged Strong association between activity and higher QOL and lower fatigue in last 4 weeks of study Muller et.al. (2016) (30) Prospective, longitudinal, cohort N = 150 (BTn = 38 of 150; 25.3% of patients) 4-wk rehabilitation program (hippotherapy, land, aquatic therapy, exercise, and sports training) Pre- and postintervention, 6-mo, 12 mo StepWatch Activity Monitor Health-related QOL (KINDL) HRQOL global and well-being increased at 4 wk; nonsignificant at 12 mo for global and 6 and 12 mo for well-being Change in physical activity and well-being correlated (P = .15 to .32) in BTn Significant effects on physical activity at 12-mo follow-up for amount and cadence variables Publication Design or sample Measures Results Mousa et.al. (2017) (25) Randomized, pre- and post-test control study N = 80 (BTn = 80, 100% of patients) Nigella seed supplementation Episodes of FN Length of hospital stay Loss of body weight Less severe weight loss (15.7%) intervention vs control group (30.4%) (P = .048) Fewer patients in intervention group had FN (2.2 vs 19.3%) Shorter median hospital stay for intervention group (2.5 vs 5 days) Brinksma et al. (2015) (26) Prospective, repeated-measures cohort N = 133 (BTn = 36, 27.1% of patients) Nutritional status with symptom and physical at initiation and 3, 6, and 12 mo Nutritional status Memorial Symptom Assessment Scale Lansky Play Performance Scale Weight changes in 63.7% of patients Nasogastric feeding in 45.1% of patients Decreased weight-for-age in first 3 months for heme and solid malignancies but increased for brain tumors No association with body composition, symptom report, physical function, or demographic factors Sacks et.al. (2014) (8) Case control, nonrandomized, pilot study N = 69 (PP n = 16; CC n = 49; BTn = 15, 22% of patients) Enteral feeding tube placement at enrollment; weekly dietitian calls Nutritional status Weight-for-age percentiles Use of enteral tube feeding Infection rates 33% of underweight patients had brain tumors Patients >2 y old more likely to lose weight PP group lost less absolute body weight (6.0%) vs CC (10.6%) More CC patients lost >5% of body weight compared with PP (48% vs 25%) PP group improved nutritional status No difference in bacteremia or enterostomy site infection Riggs et al. (2017) (27)* Crossover, quasi randomized N = 28 (n = 16 GEX; n = 12 CEX; BTn = 28, 100% of patients) 12-wk group vs no group training, then cross-over aerobic training 6MWT BOT-2 Improvement in 6MWT (P < .01) Training increased white matter FA (Δ =0.05, P < .001), hippocampal volume in GEX (Δ= 130.98 mm3, P = .001), mean reaction time Δ = 457.04 ms, P = .36) Related carryover effects predicted by increased FA (R = −0.62, P = .01) Carryover effect 12 wk post (Δ= 0.05, P < .001) Piscione et al. (2017) (28)* BOT-2 Pro-rated work rate Training improved BOT-2 bilateral coordination scores P = .02, exceeding MID (2.52 vs 1.11) Carryover effect after 12 wk ( P= .005) Other BOT-2 subtests did not attain MID levels (balance, strength, running speed or agility) Improved pro-rated work rate in GEX only (P = .04); carryover effect 12 wk post ( P= .01) Ovans et al. (2018) (29) Quasi experimental, repeated-measures, single-group design N = 15 (100% BTn) N = 15 (baseline and 12 wk) N = 11 (baseline, 12 wk, and 24 wk) 12-week PA intervention using fitness tracker with 5 PT sessions Fitbit Flex steps per day at baseline, 12 wk, 24 wk Godin Leisure-Time Exercise Questionnaire 6MWT PedsQL Generic Core and Multidimensional Fatigue Scale No significant increase in steps per day Higher steps per day associated with lower fatigue Total fatigue, general, and sleep or rest subscales improved; cognitive fatigue and QOL unchanged Strong association between activity and higher QOL and lower fatigue in last 4 weeks of study Muller et.al. (2016) (30) Prospective, longitudinal, cohort N = 150 (BTn = 38 of 150; 25.3% of patients) 4-wk rehabilitation program (hippotherapy, land, aquatic therapy, exercise, and sports training) Pre- and postintervention, 6-mo, 12 mo StepWatch Activity Monitor Health-related QOL (KINDL) HRQOL global and well-being increased at 4 wk; nonsignificant at 12 mo for global and 6 and 12 mo for well-being Change in physical activity and well-being correlated (P = .15 to .32) in BTn Significant effects on physical activity at 12-mo follow-up for amount and cadence variables * Two manuscripts published from the same study population. N = total study subjects; n = subgroup of subjects; BOT-2 = Bruininks-Oseretsky Test of Motor Proficiency; BTn = patients with brain tumors; CC = control group; CEX = combined group/home exercise; FA = fractional ansiotropy; FN = febrile neutropenia; GEX = group exercise; MID = minimally important difference; 6MWT = 6-minute walk test; PP = proactive group; HRQOL = health related quality of life; QOL = quality of life. Open in new tab Table 1. Nutrition and exercise intervention studies Publication Design or sample Measures Results Mousa et.al. (2017) (25) Randomized, pre- and post-test control study N = 80 (BTn = 80, 100% of patients) Nigella seed supplementation Episodes of FN Length of hospital stay Loss of body weight Less severe weight loss (15.7%) intervention vs control group (30.4%) (P = .048) Fewer patients in intervention group had FN (2.2 vs 19.3%) Shorter median hospital stay for intervention group (2.5 vs 5 days) Brinksma et al. (2015) (26) Prospective, repeated-measures cohort N = 133 (BTn = 36, 27.1% of patients) Nutritional status with symptom and physical at initiation and 3, 6, and 12 mo Nutritional status Memorial Symptom Assessment Scale Lansky Play Performance Scale Weight changes in 63.7% of patients Nasogastric feeding in 45.1% of patients Decreased weight-for-age in first 3 months for heme and solid malignancies but increased for brain tumors No association with body composition, symptom report, physical function, or demographic factors Sacks et.al. (2014) (8) Case control, nonrandomized, pilot study N = 69 (PP n = 16; CC n = 49; BTn = 15, 22% of patients) Enteral feeding tube placement at enrollment; weekly dietitian calls Nutritional status Weight-for-age percentiles Use of enteral tube feeding Infection rates 33% of underweight patients had brain tumors Patients >2 y old more likely to lose weight PP group lost less absolute body weight (6.0%) vs CC (10.6%) More CC patients lost >5% of body weight compared with PP (48% vs 25%) PP group improved nutritional status No difference in bacteremia or enterostomy site infection Riggs et al. (2017) (27)* Crossover, quasi randomized N = 28 (n = 16 GEX; n = 12 CEX; BTn = 28, 100% of patients) 12-wk group vs no group training, then cross-over aerobic training 6MWT BOT-2 Improvement in 6MWT (P < .01) Training increased white matter FA (Δ =0.05, P < .001), hippocampal volume in GEX (Δ= 130.98 mm3, P = .001), mean reaction time Δ = 457.04 ms, P = .36) Related carryover effects predicted by increased FA (R = −0.62, P = .01) Carryover effect 12 wk post (Δ= 0.05, P < .001) Piscione et al. (2017) (28)* BOT-2 Pro-rated work rate Training improved BOT-2 bilateral coordination scores P = .02, exceeding MID (2.52 vs 1.11) Carryover effect after 12 wk ( P= .005) Other BOT-2 subtests did not attain MID levels (balance, strength, running speed or agility) Improved pro-rated work rate in GEX only (P = .04); carryover effect 12 wk post ( P= .01) Ovans et al. (2018) (29) Quasi experimental, repeated-measures, single-group design N = 15 (100% BTn) N = 15 (baseline and 12 wk) N = 11 (baseline, 12 wk, and 24 wk) 12-week PA intervention using fitness tracker with 5 PT sessions Fitbit Flex steps per day at baseline, 12 wk, 24 wk Godin Leisure-Time Exercise Questionnaire 6MWT PedsQL Generic Core and Multidimensional Fatigue Scale No significant increase in steps per day Higher steps per day associated with lower fatigue Total fatigue, general, and sleep or rest subscales improved; cognitive fatigue and QOL unchanged Strong association between activity and higher QOL and lower fatigue in last 4 weeks of study Muller et.al. (2016) (30) Prospective, longitudinal, cohort N = 150 (BTn = 38 of 150; 25.3% of patients) 4-wk rehabilitation program (hippotherapy, land, aquatic therapy, exercise, and sports training) Pre- and postintervention, 6-mo, 12 mo StepWatch Activity Monitor Health-related QOL (KINDL) HRQOL global and well-being increased at 4 wk; nonsignificant at 12 mo for global and 6 and 12 mo for well-being Change in physical activity and well-being correlated (P = .15 to .32) in BTn Significant effects on physical activity at 12-mo follow-up for amount and cadence variables Publication Design or sample Measures Results Mousa et.al. (2017) (25) Randomized, pre- and post-test control study N = 80 (BTn = 80, 100% of patients) Nigella seed supplementation Episodes of FN Length of hospital stay Loss of body weight Less severe weight loss (15.7%) intervention vs control group (30.4%) (P = .048) Fewer patients in intervention group had FN (2.2 vs 19.3%) Shorter median hospital stay for intervention group (2.5 vs 5 days) Brinksma et al. (2015) (26) Prospective, repeated-measures cohort N = 133 (BTn = 36, 27.1% of patients) Nutritional status with symptom and physical at initiation and 3, 6, and 12 mo Nutritional status Memorial Symptom Assessment Scale Lansky Play Performance Scale Weight changes in 63.7% of patients Nasogastric feeding in 45.1% of patients Decreased weight-for-age in first 3 months for heme and solid malignancies but increased for brain tumors No association with body composition, symptom report, physical function, or demographic factors Sacks et.al. (2014) (8) Case control, nonrandomized, pilot study N = 69 (PP n = 16; CC n = 49; BTn = 15, 22% of patients) Enteral feeding tube placement at enrollment; weekly dietitian calls Nutritional status Weight-for-age percentiles Use of enteral tube feeding Infection rates 33% of underweight patients had brain tumors Patients >2 y old more likely to lose weight PP group lost less absolute body weight (6.0%) vs CC (10.6%) More CC patients lost >5% of body weight compared with PP (48% vs 25%) PP group improved nutritional status No difference in bacteremia or enterostomy site infection Riggs et al. (2017) (27)* Crossover, quasi randomized N = 28 (n = 16 GEX; n = 12 CEX; BTn = 28, 100% of patients) 12-wk group vs no group training, then cross-over aerobic training 6MWT BOT-2 Improvement in 6MWT (P < .01) Training increased white matter FA (Δ =0.05, P < .001), hippocampal volume in GEX (Δ= 130.98 mm3, P = .001), mean reaction time Δ = 457.04 ms, P = .36) Related carryover effects predicted by increased FA (R = −0.62, P = .01) Carryover effect 12 wk post (Δ= 0.05, P < .001) Piscione et al. (2017) (28)* BOT-2 Pro-rated work rate Training improved BOT-2 bilateral coordination scores P = .02, exceeding MID (2.52 vs 1.11) Carryover effect after 12 wk ( P= .005) Other BOT-2 subtests did not attain MID levels (balance, strength, running speed or agility) Improved pro-rated work rate in GEX only (P = .04); carryover effect 12 wk post ( P= .01) Ovans et al. (2018) (29) Quasi experimental, repeated-measures, single-group design N = 15 (100% BTn) N = 15 (baseline and 12 wk) N = 11 (baseline, 12 wk, and 24 wk) 12-week PA intervention using fitness tracker with 5 PT sessions Fitbit Flex steps per day at baseline, 12 wk, 24 wk Godin Leisure-Time Exercise Questionnaire 6MWT PedsQL Generic Core and Multidimensional Fatigue Scale No significant increase in steps per day Higher steps per day associated with lower fatigue Total fatigue, general, and sleep or rest subscales improved; cognitive fatigue and QOL unchanged Strong association between activity and higher QOL and lower fatigue in last 4 weeks of study Muller et.al. (2016) (30) Prospective, longitudinal, cohort N = 150 (BTn = 38 of 150; 25.3% of patients) 4-wk rehabilitation program (hippotherapy, land, aquatic therapy, exercise, and sports training) Pre- and postintervention, 6-mo, 12 mo StepWatch Activity Monitor Health-related QOL (KINDL) HRQOL global and well-being increased at 4 wk; nonsignificant at 12 mo for global and 6 and 12 mo for well-being Change in physical activity and well-being correlated (P = .15 to .32) in BTn Significant effects on physical activity at 12-mo follow-up for amount and cadence variables * Two manuscripts published from the same study population. N = total study subjects; n = subgroup of subjects; BOT-2 = Bruininks-Oseretsky Test of Motor Proficiency; BTn = patients with brain tumors; CC = control group; CEX = combined group/home exercise; FA = fractional ansiotropy; FN = febrile neutropenia; GEX = group exercise; MID = minimally important difference; 6MWT = 6-minute walk test; PP = proactive group; HRQOL = health related quality of life; QOL = quality of life. Open in new tab Results Overall, 375 papers were identified, 14 papers reviewed, and seven included (Figure 1). Included patients had varied treatment (chemotherapy, surgery, and radiation), time since diagnosis, and comorbidities. Most diagnoses were medulloblastoma, ependymoma, or low-grade gliomas. There were smaller numbers of other less common brain tumors. Broader classifications without specifics (such as “other” or “astrocytoma”) were also seen. Figure 1. Open in new tabDownload slide PRISMA diagram (31). Outline of included publications. Figure 1. Open in new tabDownload slide PRISMA diagram (31). Outline of included publications. Nutrition Mousa et al. studied Nigella sativa seeds’ effect on incidence and hospital LOS associated with febrile neutropenia (25). The seed is thought to have antimicrobial properties, and patients taking the supplement had fewer and shorter hospital admissions for febrile neutropenia. In addition to shorter hospital LOS, patients taking Nigella seeds had less weight loss (Table 1). Importantly, patients were stratified by diagnosis to control for side effects of particular treatment regimens. Limitations included no placebo control and intervention based on self-report. Nigella seeds’ direct improvement of nutritional status remains unclear, especially without blinding or placebo. Brinksma et al. also examined nutritional status in a larger volume of pediatric cancer patients and included subanalysis of brain tumor diagnoses (26). Although nutritional status changed in 63% of patients, those with brain tumors gained weight while those with solid and hematologic malignancies lost weight, especially within the first 3 months. Although physical function, symptom report, and QOL metrics were collected, none were statistically significant so were not included in the article. The nonblinded, observation design also limits this study. Sacks et al. studied newly diagnosed children with cancer and found weight and nutritional status improvement with proactive, enteral tube feeding (ETF) and dietitian support (8). This study demonstrated the feasibility, effectiveness, and improvement of nutritional status with proactive, enteral feeding supplement without increased adverse outcomes. Limitations of this pilot included nonrandom patient assignment, no assessor blinding, few children with brain tumors, and lack of power to determine differences between diagnoses. The small sample prohibited subgroup analyses. Exercise In a single crossover study, Riggs et al. and Piscione et al. studied exercise and physical functioning and brain structures in pediatric brain tumor survivors treated with cranial radiation (27,28). For both studies, 32 patients were enrolled and quasi-randomly assigned into group exercise (GEX) or combined group and home exercise (CEX) for 12 weeks. The GEX group participated in 90 minutes of activity three times weekly; CEX patients received 90 minutes of group activity two times weekly and two 30-minute home sessions monitored by a parent. Each session aimed for at least 30 minutes of aerobic exercise by maintaining heart rate at 80% or higher peak heart rate. After 12 weeks, participants switched conditions for the subsequent 12 weeks. Riggs et al. reported on the impact of aerobic exercise on brain imaging, cognition, and fitness (27). Group exercise improved white matter architecture, hippocampal volume, and reaction time. Participants in both GEX and CEX groups exhibited improvement in fitness with carryover effects in white matter organization 12 weeks after training, but only hippocampal volume and mean reaction time improved in the GEX group. Piscione et al. analyzed the Bruininks-Oseretsky Test of Motor Performance and pro-rated work rate from a cycle ergometer as measures after GEX and CEX (28). Both groups demonstrated improved Bruininks-Oseretsky Test of Motor Performance in body coordination and carryover effects 12 weeks postintervention. Differences between groups were not evident at any time points. Pro-rated training work rate increased following training for those in the GEX only. Riggs et al. and Piscione et al. used clinical measures and neuroimaging to demonstrate improved physical function and neuroanatomy. The GEX group demonstrated evidence of carryover, change in hippocampal volume, mean reaction time, and pro-rated work. The potential impact of the first treatment condition on the second in the crossover design makes clear group comparison difficult. In addition, both studies were limited by quasi-randomization and large dropout rate. Muller et al. prospectively studied 38 children with brain tumors following a 4-week hospital-based individualized program of land, aquatic, and hippotherapy and exercise training and sports games (30). Change in physical activity and cadence were measured using the StepWatch 3 activity monitor as well as QOL at four time points. In the brain tumor group, cadence and QOL improved after intervention and at 6 and 12 month follow-up. Ovans et al. prospectively studied 15 children with brain tumors (29). Changes were noted in QOL measures of total fatigue, general, and sleep subscales after an intervention using a fitness tracker and five physical therapy coaching sessions. Higher steps per day were associated with lower fatigue, though the increase in overall steps per day was not statistically significant. The strength of the study by Muller et al. was the large number of brain tumor participants in the study. However, the actual intervention lacked description, preventing replication. The strength of the Ovans et al. study was using a functional and accessible activity that can be carried over postintervention and the minimal use of facility, therapist, and participant time and resources. Both studies used activity trackers, providing objective measures of activity, although both were limited by nonrandomization, selection bias, and lack of concealed intervention. Discussion Few controlled nutrition or exercise studies exist in pediatric patients with brain tumors and none utilizing nutrition and exercise together. Patients with brain tumors can experience feeding problems and nutritional deficits and decreased physical activity and physical capacity. Nutritional status improved with proactive ETF and nutritional supplements (as in decreased episodes of febrile neutropenia with shorter hospital stays using Nigella seeds). However, no studies identified improvement in physical function or symptom report with nutrition interventions or supplementation. Measures of physical capacity and fitness and brain neuroanatomy improved with exercise in survivors of pediatric brain tumors, with preliminary associations between physical activity and QOL. Although 12 weeks is frequently chosen as the intervention length in exercise studies, deconditioned and chronically ill participants may require more time to demonstrate changes in physical function or capacity. Therefore, the potential of nutritional and exercise interventions over longer periods remains unknown. Evidence for the benefit of particular interventions in achieving and maintaining proper nutrition has slowly emerged. Proactive ETF has benefitted other at-risk populations including head and neck cancers (32). However, proactive ETF in pediatric patients with brain tumors has little randomized data (33,34). Additionally, no standardized risk assessment has been used and very few studies have examined nutritional supplements. The review found only one study examining a supplement in relation to febrile neutropenia admissions, but Nigella seeds are not commonly used or well known. Brinksma et al. also did not find differences in physical function or symptom report for undernourished patients receiving feeding supplements, but other studies have demonstrated the significant impact this has on the family and medical team (26,35). Although strong evidence is lacking, our findings suggest the method and type of proactive nutritional interventions may improve QOL outcomes in pediatric brain tumor survivors. Nutrition and exercise may improve body composition in patients with brain tumors (12,14). At diagnosis, children with brain tumors have worse physical limitations and motor disabilities (17,20). Increasing physical activity and improved nutritional status may ameliorate loss of muscle strength, altered drug metabolism, and increased morbidity and mortality (14). Aerobic exercise also improved physical function and fitness specifically for children with brain tumors beyond the time when improvements are typically seen (27,28). In neurocognitively impaired rats, exercise increased brain fiber and mitigated brain stunting while improving behavioral control and processing speed (36). Other exercise studies improved white cortical development and vascular function, all changes not thought possible after cranial radiation (37,38). Although regular exercise has been recommended for healthy and obese children and physical activity as safe during cancer treatment, physical function of children treated for brain tumors and best methods to incorporate physical activity remain unknown (24,39–42). Additional late effects including obesity, hyperlipidemia, osteoporosis, and cardiovascular disease progressively worsen years after completing cancer therapy and can negatively affect survivors’ exercise tolerance (2,22,43). Traditional methods to improve physical activity require adaptations to accommodate physical and neurocognitive deficits (21,24,29). Specific interventions like strengthening, balance, and coordination exercises have not been fully investigated, but frequency, intensity, time, and type of exercise should be included in future study (24,44). A group-based environment may also provide greater incentive to exercise at a higher intensity (27,28). Other methods incorporating physical activity, including technology, accessing home or community-based resources, and coaching should be explored as feasible adjuncts (24,27,28,44,45). Despite a structured search strategy, this narrative review lacks sensitivity analysis of the search, oversight of reviewers, and statistical analysis of heterogeneity. Evidence was drawn from a small number of studies with heterogeneous samples of children with brain tumors. No randomized controlled trials were found. Study biases were identified, but standardized quality measures are not applicable with varied study designs. This review highlights the need for evidence-based guidelines to improve treatment-related morbidity and mortality in pediatric brain tumors. Although evidence favors the clinical and QOL benefit of nutrition and exercise interventions, the lack of prospective, controlled trials limits generalizability and warrants further research. The interrelation of nutrition and exercise necessitates early, multidisciplinary care to improve treatment outcomes for patients and families. Specifically utilizing patient and family reported outcomes in evaluating nutrition supplementation and exercise interventions can potentially improve the patient experience as well as morbidity and mortality. Funding This manuscript was completed without funding and the authors have no conflicts of interest disclosures. Notes Affiliations of authors: Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA (DVR); Emory University School of Medicine, Department of Pediatrics, Division of Pediatric Hematology/Oncology/BMT, Atlanta, GA (DVR); Department of Rehabilitative and Regenerative Medicine, Program in Physical Therapy, Columbia University Irving Medical Center, New York, NY (LY, CKW); Center for Cancer and Blood Disorders, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL (SAG). 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Published: Sep 1, 2019

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