The impact of changes in therapy for childhood acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL) on the prevalence of physical performance limitations and participation restrictions among survivors is unknown. We aimed to describe the prevalence of reduced function among ALL and NHL survivors by treatment era. Participants included survivors of childhood ALL and NHL, and a cohort of their siblings, participating in the Childhood Cancer Survivor Study (CCSS). Physical function was measured using questionnaire. The prevalence of reduced function was compared to siblings using generalized estimating equations, overall and stratified by treatment decade. Associations between organ system–specific chronic conditions (CTCAE v4.03) and function were also evaluated. Among 6511 survivors (mean age 25.9 years (standard deviation 6.5)) and 4127 siblings, risk of performance limitations (15.2

Background: Exercise intolerance among childhood cancer survivors substantially increases risk for early mortality, reduced cognitive function, poor quality of life, emotional distress, and sub-optimal participation in social roles. Fortunately, exercise intolerance is modifiable, even among individuals with impaired cardiopulmonary and neuromuscular health. This study aims to evaluate the impact of tailored exercise intervention remotely supervised by fitness professionals in survivors with exercise intolerance. Telehealth-based delivery of the intervention aims to enhance uptake by removing the burden of travel and allowing participants to gain confidence with exercise and physical activity at home.Methods: This is an ongoing single-blind, two-arm, prospective, clinical trial that will randomize 160 participants 1:1 to intervention (n = 80) and attention control (n = 80) groups. The intervention group receives an individually tailored exercise prescription based on results from baseline assessments performed remotely via a Health Insurance Portability and Accountability Act-compliant virtual platform and personal preferences for aerobic exercise. Each prescription includes aerobic and strengthening components designed to progress grad-ually to 150-300-min of moderate aerobic activity and twice weekly strengthening exercises over 20-weeks. The first two weeks are supervised for 6 sessions, tapering to twice/week for weeks 3-4, once/week for weeks 5-8, every other week for weeks 9-16 and once midway between weeks 17-20. The schedule is modifiable depending on participant need, adherence, and response to exercise. Each session is approximately one hour.Conclusion: This study tests the efficacy of an individually prescribed, virtually supervised exercise intervention on exercise intolerant childhood cancer survivors.Clinicaltrials.gov registration: NCT04714840.

PURPOSE:Cancer survivors develop cancer and treatment-related morbidities at younger than normal ages and are at risk for early mortality, suggestive of an aging phenotype. The Cumulative Illness Rating Scale for Geriatrics (CIRS-G) is specifically designed to describe the accumulation of comorbidities over time with estimates of severity such as total score (TS) which is a sum of possible conditions weighted by severity. These severity scores can then be used to predict future mortality. METHODS:CIRS-G scores were calculated in cancer survivors and their siblings from Childhood Cancer Survivor Study cohort members from two time points 19 years apart and members of the National Health and Nutrition Examination Survey (NHANES) from 1999 to 2004. CIRS-G metrics were analyzed using Cox proportional hazards regression to determine subsequent mortality risk. RESULTS:In total, 14,355 survivors with a median age of 24 (IQR, 18-30) years and 4,022 siblings with a median age of 26 (IQR, 19-33) years provided baseline data; 6,138 survivors and 1,801 siblings provided follow-up data. Cancer survivors had higher median baseline TS than siblings at baseline (5.75 v 3.44) and follow-up (7.76 v 4.79), all P < .01. The mean increase in TS from baseline to follow-up was significantly steeper in cancer survivors (2.89 males and 3.18 females) vs. siblings (1.79 males and 1.69 females) and NHANES population (2.0 males and 1.94 females), all P < .01. Every point increase in baseline TS increased hazard for death by 9% (95% CI, 8 to 10) among survivors. CONCLUSION:Application of a geriatric rating scale to characterize disease supports the hypothesis that morbidity accumulation is accelerated in young adult survivors of childhood cancer when compared with siblings and the general population.

PURPOSE: Perceived cancer impact (PCI) is the degree to which one feels cancer has impacted domains of life. In childhood cancer survivors, females are more likely to endorse positive PCI on diet and exercise. It is unknown if PCI is associated with health behavior, such as physical activity (PA). The aims of this study were to determine overall and sex-stratified associations between PCI and objectively measured PA in survivors. METHODS: Participants were 5+ year survivors recruited from a St. Jude Lifetime (SJLIFE) ancillary study. PCI was measured using the Brief Cancer Impact Assessment (BCIA) PA item. Likert responses were categorized as negative, neutral, or positive impact. Moderate and vigorous physical activity (MVPA) minutes were captured via accelerometry and categorized into meeting or not meeting American College of Sports Medicine (ACSM) PA guidelines (150 moderate and/or 75 vigorous minutes/week). Associations between PCI and MVPA were evaluated via multivariable logistic regression adjusting for sex, race, diagnosis, current age, age at diagnosis, grade 3-4 chronic conditions (National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 (modified)), perceived stress (Perceived Stress Scale), and psychological distress (Global Symptoms Index of Brief Symptom Inventory-18). RESULTS: Among 992 survivors (mean age 36 ± 7 years, 47% female, 84% white), 24% met MVPA guidelines. Among survivors, 30% reported negative impact, 17% reported positive impact, and 52% reported neutral impact of cancer on PA. Female survivors (OR: 3.55, CI 2.53-4.99), CNS tumor survivors (OR: 1.91, CI 1.02-3.56), and survivors endorsing negative (OR: 2.08, CI 1.29-3.35) or neutral PCI (OR 1.78, CI 1.18-2.69) were less likely to meet PA guidelines. In sex-stratified models, odds for not meeting PA guidelines were higher in females with endocrine conditions (OR: 1.78 CI 1.00-3.17) and negative PCI (OR: 2.54 CI 1.09-5.90). Odds for not meeting PA guidelines were higher in males with negative (OR: 1.97, CI 1.08-3.58) and neutral PCI (OR: 2.02, CI 1.20-3.40). CONCLUSION: PCI on PA adversely impacts PA behavior in childhood cancer survivors. Future studies should consider factors contributing to PCI on PA in survivors. Assessing and addressing these factors could lead to improvements in PA behavior.

ABSTRACT Purpose Cancer-related worry (CRW; concerns related to cancer and its late effects) is prevalent among childhood cancer survivors. Elevated CRW has been associated with self-reported suboptimal physical activity. The aim of this investigation was to describe associations between CRW and objectively assessed physical activity in childhood cancer survivors. Methods CRW was assessed at a baseline evaluation using six survey items. Weekly minutes of moderate and vigorous physical activity were captured by actigraphy 5.25 (3.8–8.0) yr later. Factor analysis was used to identify types of worry; multiple regression determined independent associations between CRW and moderate and vigorous physical activity adjusting for sex, race, diagnosis, age at baseline, anxiety level at baseline, self-reported physical activity at baseline, and pain interference at baseline. Results Participants (n = 1223) were an average of 30.9 (SD, 6.9) yr at baseline and 36.1 (SD, 7.1) yr at follow-up. Thirty-seven percent were survivors of leukemia, 26% of non-CNS solid tumors, 19% of lymphoma, 11% of CNS tumors, and 6% of other malignancies. Two types of CRW were identified: “body-focused” and “general fear.” Body-focused CRW (β = −19.6, P = 0.012), endorsing pain interference (β = −27.7, P = 0.002) at baseline, and having a diagnosis of CNS tumor (β = −41.3, P = 0.0003) or non-CNS solid tumor (β = −19.4, P = 0.02) were negatively associated with physical activity at follow-up. Conclusions CRW related to bodily function and appearance is associated with decreased physical activity. Clinicians should consider the potential negative impact of CRW on physical activity levels and provide behavioral counseling.

There is limited understanding of associations between a combination of health behaviors (physical activity, sedentary/screen‐time, diet) and cardiometabolic health risk factors, physical performance, and emotional health among young (<18) childhood cancer survivors (CCS). The aims of this research were to address this gap by 1) deriving health behavior adherence profiles among CCS, and 2) examining associations among demographic, diagnosis and/or treatment exposures, cardiometabolic, physical performance, and emotional functioning with health behavior profile membership.

BACKGROUND:Promoting physical activity soon after treatment for childhood cancer may benefit health because sedentary lifestyle during curative therapy may perpetuate physical and emotional complications. The primary goals of this study are to evaluate the effects of a 6-month web-based, rewards-based physical activity intervention on fitness, biomarkers of cardiometabolic health, inflammation, adipokine status, quality of life and school attendance, and determine if effect of intervention on markers of cardiometabolic health is mediated by changes in fitness. The primary outcome of interest is fitness (physiological cost index, six-minute walk test) measured at end of intervention. METHODS:This ongoing study is a two-arm, prospective, randomized design with accrual goals of 192 children for intervention and control groups. Children ≥8 years and < 16 years of age, not meeting recommended levels of physical activity, who completed therapy within the past 12 months are eligible. Both groups receive: 1) educational materials encouraging physical activity, 2) activity monitor, 3) access to web-based interface designed to motivate physical activity, 4) rewards based on physical activity levels, and 5) access to their activity data on the web-interface. Those randomized to intervention: 1) can view others' activity and interact with other participants, and 2) receive rewards based on physical activity levels throughout the intervention (vs. at the end of the intervention for control group). CONCLUSION:Unique, scalable, and portable physical activity interventions that motivate young survivors are needed. This study will inform future web-based physical activity interventions for children with cancer by demonstrating effects of rewards and social interaction. CLINICAL TRIALS:ClinicalTrials.gov Identifier: NCT03223753; COG Identifier: ALTE1631.

Background: Promoting physical activity soon after treatment for childhood cancer may benefit health because sedentary lifestyle during curative therapy may perpetuate physical and emotional complications. The primary goals of this study are to evaluate the effects of a 6-month web-based, rewards-based physical activity intervention on fitness, biomarkers of cardiometabolic health, inflammation, adipokine status, quality of life and school attendance, and determine if effect of intervention on markers of cardiometabolic health is mediated by changes in fitness. The primary outcome of interest is fitness (physiological cost index, six-minute walk test) measured at end of intervention. Methods: This ongoing study is a two-arm, prospective, randomized design with accrual goals of 192 children for intervention and control groups. Children >= 8 years and < 16 years of age, not meeting recommended levels of physical activity, who completed therapy within the past 12 months are eligible. Both groups receive: 1) educational materials encouraging physical activity, 2) activity monitor, 3) access to web-based interface designed to motivate physical activity, 4) rewards based on physical activity levels, and 5) access to their activity data on the web-interface. Those randomized to intervention: 1) can view others' activity and interact with other participants, and 2) receive rewards based on physical activity levels throughout the intervention (vs. at the end of the intervention for control group). Conclusion: Unique, scalable, and portable physical activity interventions that motivate young survivors are needed. This study will inform future web-based physical activity interventions for children with cancer by demonstrating effects of rewards and social interaction. Clinical trials: ClinicalTrials.gov Identifier: NCT03223753; COG Identifier: ALTE1631.

Children diagnosed with craniopharyngioma are vulnerable to adverse health outcomes. Characterization of body mass index (BMI), physical function, and cardiopulmonary fitness in those treated with proton radiotherapy (PRT) will serve to design interventions to improve outcomes. Ninety-four children with craniopharyngioma completed physical function testing prior to PRT and annually for 5 years. For each outcome, age- and sex-specific z-scores were calculated using normative values. Participants with z-scores > 1.5 or < − 1.5 were classified as impaired. Those with z-scores > 2.0 or < − 2.0 were classified as significantly impaired. Descriptive statistics were used to describe study outcomes and change in prevalence of impairments from 2 to 5 years after treatment. Nearly half of participants [45.2%, 95% confidence interval (CI) 39.4, 51.0] had mean BMI z-scores > 1.5 at baseline, with prevalence increasing to 66.7% (95% CI 61.5, 71.9) at 5 years. More than half of participants (54.2%, 95% CI 48.4, 60.0) had knee extension strength z-scores < − 1.5 at baseline, with prevalence increasing to 81.3% (95% CI 77.7, 84.9) at 5 years. BMI and knee extension strength had the largest proportion of participants impaired at both 2 and 5 years (53.2% and 62.3%, respectively). Resting heart rate had the highest proportion of participants not impaired at 2 years but became impaired at 5 years (26.6%). Children with craniopharyngioma have BMI and fitness abnormalities at diagnosis and continue 5 years after treatment. This cohort may benefit from interventions designed to improve BMI, strength, and resting indicators of cardiopulmonary fitness.

Skeletal muscle (muscle) is essential for physical health and for metabolic integrity, with sarcopenia (progressive muscle mass loss and weakness), a precursor of aging and chronic disease. Loss of lean mass and muscle quality (force generation per unit of muscle) in the general population are associated with fatigue, weakness, and slowed walking speed, eventually interfering with the ability to maintain physical independence, and impacting participation in social roles and quality of life. Muscle mass and strength impairments are also documented during childhood cancer treatment, which often persist into adult survivorship, and contribute to an aging phenotype in this vulnerable population. Although several treatment exposures appear to confer increased risk for loss of mass and strength that persists after therapy, the pathophysiology responsible for poor muscle quantity and quality is not well understood in the childhood cancer survivor population. This is partly due to limited access to both pediatric and adult survivor muscle tissue samples, and to difficulties surrounding noninvasive investigative approaches for muscle assessment. Because muscle accounts for just under half of the body's mass and is essential for movement, metabolism, and metabolic health, understanding mechanisms of injury responsible for both initial and persistent dysfunction is important and will provide a foundation for intervention. The purpose of this review is to provide an overview of the available evidence describing associations between childhood cancer, its treatment, and muscle outcomes, identifying gaps in current knowledge.

PURPOSE Eight percent of young-adult childhood cancer survivors meet criteria for frailty, an aging phenotype associated with poor health. In the elderly general population, frailty is associated with neurocognitive decline; this association has not been examined in adult survivors of childhood cancer. METHODS Childhood cancer survivors 18-45 years old (≥ 10 years from diagnosis) were clinically evaluated for prefrailty or frailty (respectively defined as ≥ 2 or ≥ 3 of: muscle wasting, muscle weakness, low energy expenditure, slow walking speed, and exhaustion [Fried criteria]) and completed neuropsychologic assessments at enrollment (January 2008-June 2013) and 5 years later. Weighted linear regression using inverse of sampling probability estimates as weights compared differences in neurocognitive decline in prefrail and frail survivors versus nonfrail survivors, adjusting for diagnosis age, sex, race, CNS–directed therapy (cranial radiation, intrathecal chemotherapy, and neurosurgery), and baseline neurocognitive performance. RESULTS Survivors were on average 30 years old and 22 years from diagnosis; 18% were prefrail and 6% frail at enrollment. Frail survivors declined an average of 0.54 standard deviation (95% CI, −0.93 to −0.15) in short-term verbal recall, whereas nonfrail survivors did not decline (β = .22; difference of βs = −.76; 95% CI, −1.19 to −0.33). Frail survivors declined more than nonfrail survivors on visual-motor processing speed (β = −.40; 95% CI, −0.67 to −0.12), cognitive flexibility (β = −.62; 95% CI, −1.02 to −0.22), and verbal fluency (β = −.23; 95% CI, −0.41 to −0.05). Prefrail and frail survivors experienced greater declines in focused attention (prefrail β = −.35; 95% CI, −0.53 to −0.17; frail β = −.48; 95% CI, −0.83 to −0.12) compared with nonfrail survivors. CONCLUSION Over approximately 5 years, prefrail and frail young-adult survivors had greater declines in cognitive domains associated with aging and dementia compared with nonfrail survivors. Interventions that have global impact, designed to target the mechanistic underpinnings of frailty, may also mitigate or prevent neurocognitive decline.

Abstract Background Estimates indicate that nearly 8% of the over 500,000 survivors of childhood cancer living in the United States are frail in their fourth and fifth decades of life, a phenotype typically seen in geriatric populations. Participation in regular physical activity to improve physical fitness in healthy and diseased populations reduces risk for frail health by increasing physiologic reserve. However, physical activity may not have the same effects on fitness in childhood cancer survivors as it does among their peers with no cancer history. Aims This scoping review seeks to describe associations between physical activity, physical fitness, chronic disease, and mortality in childhood cancer survivors. Methods Relevant literature was identified through a comprehensive search in the PubMed, Web of Science, CINAHL, and Cochrane databases. A narrative synthesis was performed on observational studies that had physical activity or physical fitness clearly defined and compared with chronic disease outcomes. Results A total of 595 studies were screened, and results from 11 studies are presented. Childhood cancer survivors who participate in regular physical activity have improved markers of cardiovascular health, decreased risk of overt cardiovascular disease, and decreased risk of all‐cause mortality compared to survivors who are not physically active. Childhood cancer survivors who are physically fit have increased neurocognition, and decreased risk of all‐cause mortality compared to survivor's who are not fit. The differential effects of physical activity on fitness and health among childhood cancer survivors when compared to peers is potentially related to treatment exposures that damage cardiovascular tissue and impact regenerative potential. Conclusion Research is needed to determine the optimal timing, frequency, intensity, and duration of physical activity necessary to optimize fitness in childhood cancer survivors.

BACKGROUND:Survivors of childhood cancer have an increased risk of therapy-related cardiovascular disease. It is not known whether family history of cardiovascular disease further increases risk of adverse cardiovascular outcomes among survivors. METHODS:Family history of cardiovascular disease was collected from 1,260 survivors [median age at diagnosis, 8 years (range, 0-23); age at last follow-up, 35 years (range, 18-66)] of childhood cancer in the St. Jude Lifetime Cohort Study. Multivariable risk models evaluated associations with cardiovascular disease (Common Terminology Criteria for Adverse Events grade 2-4 events) and cardiovascular risk factors. RESULTS:Among survivors exposed to chest-directed radiation and/or anthracycline chemotherapy (n = 824), 7% reported a first-degree family history of heart failure, 19% myocardial infarction, 11% stroke, 26% atherosclerotic disease (myocardial infarction and/or stroke), 62% hypertension, and 31% diabetes mellitus. Eighteen percent of exposed survivors developed heart failure, 9% myocardial infarction, 3% stroke, 11% atherosclerotic disease, 30% hypertension, and 9% diabetes mellitus. Having a first-degree family history of atherosclerotic disease was independently associated with development of treatment-related heart failure [RR, 1.38; 95% confidence interval (CI), 1.01-1.88; P = 0.04] among exposed survivors. Risk for hypertension was increased among exposed survivors with a first-degree family history of hypertension (RR, 1.55; 95% CI, 1.26-1.92; P < 0.0001) or of any cardiovascular disease [myocardial infarction, stroke, or heart failure (RR, 1.30; 95% CI, 1.06-1.59; P = 0.01)]. CONCLUSIONS:Family history of cardiovascular disease and cardiovascular risk factors independently increased risk of heart failure and hypertension among survivors of childhood cancer exposed to cardiotoxic therapies. IMPACT:These data show the importance of cardiovascular family history as a risk factor for cardiovascular disease in survivors of childhood cancer.

ABSTRACT Purpose Muscle weakness, low lean body mass, and poor physical performance are prevalent among adult survivors of childhood cancer (survivors). We evaluated the feasibility and effects of resistance training with and without protein supplementation on lean body mass and muscle strength among survivors. Methods This double-blind placebo-controlled trial enrolled survivors ≥18 to <45 yr old. Participants were randomized to resistance training with protein supplement (21 g whey protein per day, 90 kcal) (RT + S) or resistance training with placebo (sucrose, 90 kcal) (RT + P). Participants received educational materials, access to a local fitness center, and a tailored resistance training program with tapered supervision. Participant retention and adherence were used to evaluate feasibility. Lean body mass and muscle strength were assessed at baseline and 24 wk, using dual x-ray absorptiometry, and dynamometer testing or one-repetition maximum testing, respectively. Mean changes were compared with two-way ANOVA. Results Of 70 participants randomized, 57 completed the 24-wk intervention (24 in RT + S, 33 in RT + P). The RT + S group completed 74.8% and the RT + P group completed 67.0% of exercise sessions. Mean ± SD age for those who completed was 33.1 ± 7.0 yr, 67% were White and 47% female. There were no differences in change in lean mass (RT + S, 1.05 ± 2.34 kg; RT + P, 0.13 ± 2.19 kg; P = 0.10) or strength (grip RT + S, 1.65 ± 4.17 kg; RT + P, 1.63 ± 4.47 kg; P = 0.98; mean leg press RT + S, 58.4 ± 78.8 kg; RT + P, 51.0 ± 65.1 kg; P = 0.68) between groups. Both lean mass ( P = 0.03) and strength (grip P = 0.003, leg press P < 0.001) increased over time. Conclusions Supervised resistance training among survivors with protein supplementation is feasible but not more effective at increasing total lean body mass than resistance training alone.

PURPOSE:Exercise intolerance, associated with heart failure and death in general populations, is not well studied in survivors of childhood cancer. We examined prevalence of exercise intolerance in survivors exposed or not to cardiotoxic therapy, and associations among organ system function, exercise intolerance, and mortality.METHODS:Participants consisted of 1,041 people who had survived cancer ≥ 10 years (and had or did not have exposure to anthracyclines and/or chest-directed radiation) and 285 control subjects. Exercise intolerance was defined as peak oxygen uptake < 85% predicted from maximal cardiopulmonary exercise testing; organ functions were ascertained with imaging or clinical testing. Multivariable regression of the data was performed to compare exercise capacity between survivors exposed or unexposed to cardiotoxic therapy and control subjects, and to evaluate associations between treatment and organ function, and organ function and exercise intolerance. Propensity score methods in time-to-event analyses evaluated associations between exercise intolerance and mortality.RESULTS:Survivors (mean age ± standard deviation [SD], 35.6 ± 8.8 years) had lower mean (± SD) peak oxygen uptake (exposed: 25.74 ± 8.36 mL/kg/min; unexposed: 26.82 ± 8.36 mL/kg/min) than did control subjects (32.69 ± 7.75 mL/kg/min; P for all < .001). Exercise intolerance was present in 63.8% (95% CI, 62.0% to 65.8%) of exposed survivors, 55.7% (95% CI, 53.2% to 58.2%) of unexposed survivors, and 26.3% (95% CI, 24.0% to 28.3%) of control subjects, and was associated with mortality (hazard ratio, 3.9; 95% CI, 1.09 to 14.14). Global longitudinal strain (odds ratio [OR], 1.71; 95% CI, 1.11 to 2.63), chronotropic incompetence (OR, 3.58; 95% CI, 1.75 to 7.31); forced expiratory volume in 1 second < 80% (OR, 2.59; 95% CI, 1.65 to 4.09), and 1 SD decrease in quadriceps strength (OR, 1.49; 95% CI, 1.23 to 1.82) were associated with exercise intolerance. Ejection fraction < 53% was not associated with exercise intolerance.CONCLUSION:Exercise intolerance is prevalent among childhood cancer survivors and associated with all-cause mortality. Treatment-related cardiac (detected by global longitudinal strain), autonomic, pulmonary, and muscular impairments increased risk. Survivors with impairments may require referral to trained specialists to learn to accommodate specific deficits when engaging in exercise.

The study aims were to determine the prevalence of balance impairments in adult survivors of pediatric central nervous system (CNS) tumors, and to identify predictors of and limitations associated with balance impairments. Participants were adult survivors (N = 329) of pediatric CNS tumors. Balance was considered impaired among those with composite scores < 70 on the sensory organization test. Potential predictors of impaired balance were evaluated with generalized linear regression. Multivariable logistic regression was used to evaluate associations between balance impairment and function. Balance impairment was observed in 48% of survivors, and associated with infratentorial tumor location (OR = 4.0, 95% CI, 2.0–7.6), shunt placement (OR = 3.5, 95% CI, 1.8–6.7), increased body fat percentage (OR = 1.1, 95% CI, 1.0–1.1), hearing loss (OR = 11.1, 95% CI, 5.6–22.2), flexibility limitations (OR = 2.0, 95% CI, 1.0–3.9), peripheral neuropathy (OR = 2.4, 95% CI, 1.2–4.5), and cognitive deficits (OR = 2.2, 95% CI, 1.1–4.7). In adjusted models, impaired balance was associated with limitations in overall physical performance (OR = 3.6, 95% CI, 2.0–6.3), mobility (OR = 2.6, 95% CI, 1.5–4.4), diminished walking endurance (OR = 2.9, 95% CI, 1.7–5.0), and non-independent living (OR = 2.0, 95% CI, 1.0–4.3). Nearly half of adult survivors of pediatric CNS tumors have impaired balance, which is associated with mobility and physical performance limitations. Interventions to address the complex needs of this population should be prioritized. Survivors with identified risk factors should be closely evaluated for presence of balance impairment. Interventions tailored to improve balance also can positively affect function and mobility in survivors.