Physical frailty deteriorates after a 5-day dexamethasone course in children with acute lymphoblastic leukemia, results of a national prospective study.

BACKGROUND: Dexamethasone is important in the treatment for pediatric acute lymphoblastic leukemia (ALL) but induces muscle atrophy with negative consequences for muscle mass, muscle strength, and functional abilities. The aim of this study was to establish the effect of a dexamethasone course on sarcopenia and physical frailty in children with ALL, and to explore prognostic factors. METHODS: Patients with ALL aged 3-18 years were included during maintenance therapy. Patients had a sarcopenia/frailty assessment on the first day of (T1) and on the day after (T2) a 5-day dexamethasone course. Sarcopenia was defined as low muscle strength in combination with low muscle mass. Prefrailty and frailty were defined as having two or ≥three of the following components, respectively: low muscle mass, low muscle strength, fatigue, slow walking speed, and low physical activity. Chi-squared and paired t-tests were used to assess differences between T1 and T2. Logistic regression models were estimated to explore patient- and therapy-related prognostic factors for frailty on T2. RESULTS: We included 105 patients, 61% were boys. Median age was 5.3 years (range: 3-18.8). At T1, sarcopenia, prefrailty, and frailty were observed in respectively 2.8%, 23.5%, and 4.2% of patients. At T2, the amount of patients with frailty had increased to 17.7% (p = 0.002), whereas the number of patients with sarcopenia and prefrailty remained similar. Higher ASMM (odds ratio [OR]: 0.49, 95% CI: 0.28-0.83), stronger handgrip strength (OR: 0.41, 95% CI: 0.22-0.77) and more physical activity minutes per day (OR: 0.98, 95% CI: 0.96-0.99) decreased the risk of frailty at T2. Slower walking performance (OR: 2, 95% CI: 1.2-3.39) increased the risk. Fatigue levels at T1 were not associated with frailty at T2. CONCLUSION: Physical frailty increased strikingly after a 5-days dexamethasone course in children with ALL. Children with poor physical state at start of the dexamethasone course were more likely to be frail after the course.

The utility of a portable muscle ultrasound in the assessment of muscle alterations in children with acute lymphoblastic leukaemia.

BACKGROUND: During treatment for acute lymphoblastic leukaemia (ALL), children are prone to musculoskeletal deterioration. However, non-invasive tools to measure muscle mass and intramuscular alterations are limited. In this study we explored the feasibility of muscle ultrasound in children with ALL. Additionally, we analysed whether automated ultrasound outcomes of muscle size and intramuscular fat infiltration (IMAT) were associated with appendicular skeletal muscle mass (ASMM), muscle strength and physical performance. METHODS: Children with ALL, aged 3-18 years were included during maintenance therapy. Bilateral images of the rectus femoris muscle were captured using a portable linear array transducer connected to a tablet. Subsequently, an automated image annotation software (MuscleSound) was used to estimate cross-sectional area, muscle thickness and IMAT. Feasibility was assessed using acceptance (percentage of children approached who were enrolled), practicality (percentage of children that completed the ultrasound measurement after enrolment) and implementation (percentage of children that had sufficient imaging to be processed and analysed by the software). Assessments of ASMM by bioimpedance analysis, muscle strength using handheld dynamometry and timed physical performance tests were administered at the same visit. Multivariable linear models were estimated to study the associations between muscle ultrasound outcomes and ASMM, strength and physical performance, adjusted for sex, age, body mass index and ALL treatment week. RESULTS: Muscle ultrasound was performed in 60 out of 73 invited patients (76.9%), of which 37 were boys (61.7%), and median age was 6.1 years (range: 3-18.8 years). The acceptance was 98.7%, practicality 77.9% and implementation was 100%. Patients who refused the examination (n = 13) were younger (median: 3.6, range: 3-11.2 years) compared with the 60 examined children (P = 0.0009). In multivariable models, cross-sectional area was associated with ASMM (ß = 0.49 Z-score, 95% confidence interval [CI]:0.3,2.4), knee-extension strength (ß = 16.9 Newton [N], 95% CI: 4.8, 28.9), walking performance (ß = -0.46 s, 95% CI: -0.75, -0.18) and rising from the floor (ß = -1.07 s, 95% CI: -1.71, -0.42). Muscle thickness was associated with ASMM (ß = 0.14 Z-score, 95% CI: 0.04, 0.24), knee-extension strength (ß = 4.73 N, 95% CI: 0.99, 8.47), walking performance (ß = -0.13 s, 95% CI: -0.22, -0.04) and rising from the floor (ß = -0.28 s, 95% CI: -0.48, -0.08). IMAT was associated with knee-extension strength (ß = -6.84 N, 95% CI: -12.26, -1.41), walking performance (ß = 0.2 s, 95% CI: 0.08, 0.32) and rising from the floor (ß = 0.54 s, 95% CI: 0.27, 0.8). None of the muscle ultrasound outcomes was associated with handgrip strength. CONCLUSIONS: Portable muscle ultrasound appears a feasible and useful tool to measure muscle size and intramuscular alterations in children with ALL. Validation studies using magnetic resonance imaging (gold standard) are necessary to confirm accuracy in paediatric populations.

Novel Adaption of the SARC-F Score to Classify Pediatric Hemato-Oncology Patients with Functional Sarcopenia.

Sarcopenia in pediatric hemato-oncology patients is undesirable because of the consequences it may have for treatment continuation and outcome, physical abilities and participation in daily life. An easy-to-use screening tool for sarcopenia will facilitate the identification of children at risk who need interventions to prevent serious physical deterioration. In the elderly, the use of the SARC-F score as a case-finding tool for sarcopenia is recommended. The aim of this cross-sectional study was to investigate the accuracy of the pediatric SARC-F (PED-SARC-F) for identifying sarcopenia in pediatric hemato-oncology patients, including the determination of a cut-off point for clinical use. Patients 3−20 years of age, under active treatment or within 12 months after treatment cessation were eligible. Patients had a physiotherapy assessment including a PED-SARC-F (0−10) and measurements of muscle strength (handheld dynamometry), physical performance (various tests) and/or muscle mass (bio-impedance analysis), as part of the standard of care. Spearman's correlation coefficient (rs) between the PED-SARC-F and physiotherapy outcomes were calculated. Structural sarcopenia was defined as low appendicular skeletal muscle mass (ASMM) in combination with low muscle strength and/or low physical performance. Functional sarcopenia indicated low muscle strength combined with low physical performance. Multiple logistic regression models were estimated to study the associations between the PED-SARC-F and structural/functional sarcopenia. To evaluate which cut-off point provides the most accurate classification, the area under the receiver operating characteristic curve (AUCs), sensitivity and specificity per point were calculated. In total, 215 assessments were included, 62% were performed in boys and the median age was 12.9 years (interquartile range: 8.5−15.8). The PED-SARC-F scores correlated moderately with the measurements of muscle strength (rs = −0.37 to −0.47, p < 0.001) and physical performance (rs = −0.45 to −0.66, p < 0.001), and weakly with ASMM (rs = −0.27, p < 0.001). The PED-SARC-F had an AUC of 0.90 (95% confidence interval (CI) = 0.84−0.95) for functional sarcopenia and 0.79 (95% CI = 0.68−0.90) for structural sarcopenia. A cut-off point of ≥5 had the highest specificity of 96% and a sensitivity of 74%. In conclusion, we adapted the SARC-F to a pediatric version, confirmed its excellent diagnostic accuracy for identifying functional sarcopenia and defined a clinically useful cut-off point in pediatric hemato-oncology patients.

Dexamethasone-Induced Sarcopenia and Physical Frailty in Children With Acute Lymphoblastic Leukemia: Protocol for a Prospective Cohort Study.

BACKGROUND: During treatment for pediatric acute lymphoblastic leukemia (ALL), children receive high doses of dexamethasone for its apoptotic effect on leukemia cells; however, muscle atrophy is a well-known serious side effect. Muscle atrophy (loss of muscle mass) accompanied by a decreased muscle strength may lead to a generalized impaired skeletal muscle state called sarcopenia. Loss of muscle mass is also an indicator of physical frailty, which is defined as a state of increased vulnerability that is characterized by co-occurrence of low muscle mass, muscle weakness, fatigue, slow walking speed, and low physical activity. Both sarcopenia and physical frailty are related to an increased risk of infections, hospitalizations, and decreased survival in children with chronic diseases. OBJECTIVE: This study aims to (1) estimate the occurrence of sarcopenia and physical frailty in children during ALL maintenance therapy, (2) evaluate the effect of administering dexamethasone, and (3) explore determinants associated with these outcomes. METHODS: This prospective study is being pursued within the framework of the DexaDays-2 study: a randomized controlled trial on neurobehavioral side effects in pediatric patients with ALL. A total of 105 children (3-18 years) undergoing ALL maintenance treatment at the Princess Máxima Center for Pediatric Oncology are included in this study. Sarcopenia/frailty assessments are performed before and just after a 5-day dexamethasone course. A subset of 50 children participating in the DexaDays-2 trial because of severe dexamethasone-induced neurobehavioral problems were assessed at 3 additional timepoints. The sarcopenia/frailty assessment consists of bioimpedance analysis (skeletal muscle mass [SMM]), handheld dynamometry (handgrip strength), Pediatric Quality of Life Inventory Multidimensional Fatigue Scale (fatigue), Timed Up and Go Test (TUG; walking speed), and physical activity questionnaires. To evaluate potential change in sarcopenia/frailty components after a 5-day dexamethasone administration, a paired Student t test or Mann-Whitney U test will be used. Because of the presence of repeated measurements, generalized linear mixed models will be used to estimate the effect of dexamethasone on sarcopenia and frailty outcomes. Multivariable regression models will be estimated to investigate associations between the assessment scores and patient and treatment-related factors. RESULTS: Patient accrual started in 2018 and was finalized in spring 2021. From autumn 2021 onward final data analyses will be performed. CONCLUSIONS: This first study combining parameters of sarcopenia and physical frailty is of importance because these conditions can seriously complicate continuation of ALL therapy, independence in physical functioning, reaching motor milestones, and participating in daily life activities. The results will provide knowledge about these complications, the association between dexamethasone treatment and muscle loss and other components of frailty, and therefore insights into the severity of this side effect. By exploring potential determinants that may be associated with sarcopenia and physical frailty, we may be able to identify children at risk at an earlier stage and provide timely interventions. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/33517.

A Validated Risk Prediction Model for Bone Fragility in Children With Acute Lymphoblastic Leukemia.

Although bone fragility may already be present at diagnosis of pediatric acute lymphoblastic leukemia (ALL), routine performance of dual-energy X-ray absorptiometry (DXA) in every child is not universally feasible. The aim of this study was to develop and validate a risk prediction model for low lumbar spine bone mineral density (LS BMD Z-score ≤ -2.0) at diagnosis, as an important indicator for fracture risk and further treatment-related BMD aggravation. Children with ALL (4-18 years), treated according to the Dutch Childhood Oncology Group protocol (DCOG-ALL9; model development; n = 249) and children from the Canadian Steroid-Associated Osteoporosis in the Pediatric Population cohort (STOPP; validation; n = 99) were included in this study. Multivariable logistic regression analyses were used to develop the prediction model and to confirm the association of low LS BMD at diagnosis with symptomatic fractures during and shortly after cessation of ALL treatment. The area under the receiver operating characteristic curve (AUC) was used to assess model performance. The prediction model for low LS BMD at diagnosis using weight (ß = -0.70) and age (ß = -0.10) at diagnosis revealed an AUC of 0.71 (95% CI, 0.63-0.78) in DCOG-ALL9 and 0.74 (95% CI, 0.63-0.84) in STOPP, and resulted in correct identification of 71% of the patients with low LS BMD. We confirmed that low LS BMD at diagnosis is associated with LS BMD at treatment cessation (OR 5.9; 95% CI, 3.2-10.9) and with symptomatic fractures (OR 1.7; 95% CI, 1.3-2.4) that occurred between diagnosis and 12 months following treatment cessation. In meta-analysis, LS BMD at diagnosis (OR 1.6; 95% CI, 1.1-2.4) and the 6-month cumulative glucocorticoid dose (OR 1.9; 95% CI, 1.1-3.2) were associated with fractures that occurred in the first year of treatment. In summary, a prediction model for identifying pediatric ALL patients with low LS BMD at diagnosis, as an important indicator for bone fragility, was successfully developed and validated. This can facilitate identification of future bone fragility in individual pediatric ALL patients. © 2021 American Society for Bone and Mineral Research (ASBMR).

Determinants of impairments in functioning, fatigue, and participation ability in pediatric brain tumor survivors.

BACKGROUND: Pediatric brain tumor survivors (PBTS) experience disease- and treatment-related sequelae. We aimed to investigate the occurrence of participation limitations, impairments in functioning, fatigue, and the association between patient, tumor- and treatment-related factors and these outcomes. METHODS: Children (4-18 years) after treatment for a brain tumor between 2005 and 2014 at the Erasmus Medical Center, Rotterdam, the Netherlands, were eligible. The parent-reported Child and Family Follow-up Survey developed to measure participation and impairments in functioning in youth with acquired brain injury, was used. Fatigue was assessed using the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale. Associations with patient, tumor- and treatment-related factors were explored using univariable analyses. RESULTS: Ninety-one PBTS (median age: 11.3 years [range: 9.5-14.1], time since treatment: 3.9 years [range: 4-6.2]) were included (response rate: 55%). Participation limitations were reported in 53% and were associated with impairments in functioning (15-67%) (P ≤ .01) and fatigue (P ≤ .03).Parent- and child-reported fatigue was increased compared to normative values (P ≤ .02). History of hydrocephalus was associated with increased fatigue (P ≤ .04). Younger age at diagnosis and longer time since diagnosis were associated with impairments in functioning and cognitive fatigue (P < .05).Participation limitations, impairments in functioning and fatigue were similar in PBTS who were <3 or ≥3 years since completion of treatment. CONCLUSION: More than half of PBTS reported limited participation ability, which is associated with impairments in functioning and fatigue. The complication hydrocephalus seems to lead to more fatigue. Participation limitations, impairments in functioning and fatigue appear not to diminish in the longer term.

Health-related fitness in very long-term survivors of childhood cancer: A cross-sectional study.

BACKGROUND: Impairment of health-related physical fitness (HRPF) in survivors of acute lymphoblastic leukemia has been shown. However, evidence of impairment in survivors of other pediatric malignancies and possible risk factors is limited. PARTICIPANTS AND METHODS: HRPF of 17 survivors of pediatric acute myeloid leukemia (AML), 26 survivors of neuroblastoma (NBL), 28 survivors of Wilms tumor (WT) (median age 28.8 [18.8-62.6] years) after a median follow-up time of 24.5 (6.5-43.6) years, and 74 healthy controls (median age 26.9 [17.9-61.7] years). Risk factors were investigated. Testing included submaximal cardiovascular endurance (6-Minute Walk Test (6 MWT), flexibility, and muscle strength. RESULTS: Results are expressed as mean (standard error). Survivors scored significantly lower than controls on the 6 MWT (588 ± 6.1 m vs. controls 611 ± 6.0 m; P = 0.008), on side flexion of the trunk (20.1 ± 0.4 cm vs. controls 22.4 ±0.4 cm; P < 0.001), and on vertical jump (39.7 ± 0.8 cm vs. controls 43.8 ± 0.8 cm; P < 0.001). Survivors of AML had lower scores on the 6 MWT (563 ± 12.4 m) than survivors of NBL (585 ± 9.9 m) and survivors of WT (606 ± 9.6 m), P = 0.046. Being a survivor, higher body mass index (BMI) and no participation in sports were independently associated with lower scores on the 6 MWT. CONCLUSION: Survivors of NBL, WT, and especially AML have impaired HRPF. Higher BMI and physical inactivity at adult age appeared prominent risk factors for impaired HRPF in these survivors.

Daily life physical activity in long-term survivors of nephroblastoma and neuroblastoma.

The risk of metabolic late effects after childhood cancer, such as obesity, hypertension, and diabetes, can be positively influenced by a healthy lifestyle with sufficient physical activity. Nevertheless, studies on physical activity in adult survivors of childhood cancer are scarce and involve different and often nonvalidated questionnaires. We used the Short QUestionnaire to ASsess Health-enhancing physical activity (SQUASH), which was developed and validated to assess daily life physical activity in the Dutch adult population. The aim of the study was to assess daily life physical activity in Dutch adult long-term nephroblastoma and neuroblastoma survivors. Sixty-seven nephroblastoma and 36 neuroblastoma survivors (median age, 30 y; range, 18 to 51 y) and 60 sociodemographically similar healthy control subjects (median age, 32 y; range, 18 to 62 y) were asked to complete the SQUASH during their regular follow-up visit. The adjusted mean physical activity score in male neuroblastoma survivors (mean, 7155; P=0.004) was significantly lower than in male controls (mean, 10,574), whereas it was not significantly lower in male nephroblastoma survivors (mean, 9122; P=0.108). Adjusted means for physical activity scores in females were not different from their controls. In conclusions, male neuroblastoma survivors were identified as performing less daily physical activity.

Motor performance and functional exercise capacity in survivors of pediatric acute lymphoblastic leukemia.

BACKGROUND: Impaired motor performance and reduced maximum exercise capacity during and after treatment of acute lymphoblastic leukemia (ALL) has been shown. However, no longitudinal study monitoring motor performance after cessation of treatment has been published. Whether sub-maximal exercise capacity is reduced is unknown. PROCEDURE: Motor performance of pediatric ALL survivors, treated with Dutch Childhood Oncology Group ALL-9 protocol was measured with the movement-ABC at stop treatment and ≥5 years later. At follow-up functional exercise capacity was also investigated using the 6-minute walk test (6MWT). Heart rate and oxygen saturation were measured with a portable pulse oximeter before and after the 6MWT. RESULTS: Nineteen boys and 15 girls, median age 12.3 years (range: 9.0-18.7), median time since completion of chemotherapy 5.2 years (5.0-7.1), participated. Mean height/age and weight/age were within the norm, whereas mean BMI/age was significantly increased (mean SDS 0.38, SEM 0.17, P = 0.04). Motor performance had improved significantly (P = 0.001). In contrast, functional exercise capacity at follow-up was significantly impaired (mean SDS -2.05, SEM 0.13, P < 0.001). CONCLUSIONS: At ≥5 years after completion of ALL treatment motor performance had improved significantly, but functional exercise capacity was significantly impaired. The exact underlying cause of this late effect needs further study.

Physical fitness in children with haemophilia and the effect of overweight.

Although children with haemophilia are advised to participate in physical activities, their physical fitness has not been studied in a large group. In addition, children with haemophilia may be at increased risk for becoming overweight as a result of inactivity because of joint bleedings or because of overprotection. This study aimed to assess physical fitness (aerobic capacity), joint status, muscle strength, quality of life (QoL), self-reported motor competence and also prevalence of overweight and its association with physical parameters. Weight and height were measured. Skin folds were measured unilaterally at biceps, triceps, subscapular and supra-iliac sites. Aerobic capacity was determined on a cycle ergometer or with a 6-min walk test (6MWT). Muscle strength and active range of motion of elbows, knees and ankle joints were measured. Self-reported motor competence was measured with the 'Competentie BelevingsSchaal voor Kinderen'. Joint pain was scored on a Visual Analogue Scale. The Haemo-QoL Index was used to measure QoL. In 158 Dutch boys with haemophilia, with a mean age of 12.7 years (SD 2.9), normal aerobic capacity and muscle strength were found. Joint pain was reported by 16% of the participants. The prevalence of overweight (16%) was slightly increased when compared with healthy Dutch boys (13.5%). Being overweight had a negative association with the6MWT and QoL. Dutch children with haemophilia have normal aerobic exercise capacity and muscle strength. The majority also has normal joint mobility. Prevalence of overweight is slightly increased.

Decrease in peripheral muscle strength and ankle dorsiflexion as long-term side effects of treatment for childhood cancer.

BACKGROUND: This study investigated muscle strength, passive ankle dorsiflexion, and their association with motor performance in children after treatment for acute lymphoblastic leukemia, Wilms tumor, B-non-Hodgkin lymphoma, and malignant mesenchymal tumors. PROCEDURE: Muscle strength was assessed with a hand-held dynamometer and ankle dorsiflexion with a goniometer in 92 and 64 survivors, respectively. Motor performance was measured with the Movement Assessment Battery for Children (movement-ABC). Age at testing: 6.1-12.9 years. Mean time since completing treatment: 3.3 years. Results were compared to 155 healthy controls. RESULTS: Muscle strength of the survivors was reduced in ankle dorsiflexors on both sides (P < 0.001), wrist dorsiflexors on the non-dominant side (P < 0.001), and pinch grip on the non-dominant (P = 0.001) and dominant side (P = 0.01). Passive ankle dorsiflexion of the survivors was significantly less on both sides (P < 0.01). Movement-ABC percentile score was affected by pinch grip strength on the non-dominant (P < 0.004), and dominant side (P = 0.024) but not by strength of other muscle groups or by passive ankle dorsiflexion. CONCLUSION: Peripheral muscle strength and ankle dorsiflexion are reduced in the long-term in children treated for cancer with chemotherapy. However, neither decreased muscle strength nor reduced ankle dorsiflexion could completely explain reduced scores on the movement-ABC.

Decrease in motor performance in children with cancer is independent of the cumulative dose of vincristine.

BACKGROUND: Impaired performance on motor tasks in children treated for acute lymphoblastic leukemia (ALL) after completion of treatment is often attributed to vincristine (VCR). Whether motor problems persist in other children who receive different cumulative doses of VCR is to the authors' knowledge not known. The objective of the current study was to determine the extent of motor problems in children with ALL, Wilms tumor (WT), B-cell non-Hodgkin lymphoma (B-NHL), and malignant mesenchymal tumors (MMT) and whether these motor problems were related to VCR dose. METHODS: In 128 children ages 4-12 years who completed treatment after at least 1 year, motor performance was measured using the Movement Assessment Battery for Children (m-ABC). RESULTS: The m-ABC scores of the total study group were significantly lower than those of the normal population (P < 0.001). There were no differences in scores noted between children with ALL, WT, B-NHL, or MMT. There also were no differences noted between those children with ALL who had received pulses of VCR and steroids during maintenance therapy and those who had not. All groups demonstrated large variability in scores. Scores were not found to be significantly different between those children who had received low (< 20 mg/m(2)), intermediate (20-40 mg/m(2)), or high (> 40 mg/m(2)) cumulative doses of VCR. Cumulative doses of corticosteroids and methotrexate did not affect scores, nor did age at diagnosis and time since the completion of therapy. CONCLUSIONS: Although motor performance was impaired in all patient groups, no correlation was found between motor performance and the cumulative dose of VCR or other drugs, age, and follow-up time. Future studies have to address several issues, including whether polymorphisms in drug metabolizing genes or drug target genes explain the significant variability noted in the long-term motor outcome of children with cancer.