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Published on in Vol 11, No 4 (2022): April

Preprints (earlier versions) of this paper are available at https://preprints.jmir.org/preprint/33517, first published .
Dexamethasone-Induced Sarcopenia and Physical Frailty in Children With Acute Lymphoblastic Leukemia: Protocol for a Prospective Cohort Study

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

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

Authors of this article:

Emma Jacobine Verwaaijen1 Author Orcid Image ;   Annelienke van Hulst1 Author Orcid Image ;   Marta Fiocco1 Author Orcid Image ;   Annelies Hartman2 Author Orcid Image ;   Martha Grootenhuis1 Author Orcid Image ;   Saskia Pluijm1 Author Orcid Image ;   Rob Pieters1 Author Orcid Image ;   Erica van den Akker3 Author Orcid Image ;   Marry M van den Heuvel-Eibrink1 Author Orcid Image
Article Authors Cited by (5) Tweetations (5) Metrics

    Protocol

    1Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands

    2Department of Pediatric Physiotherapy, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, Netherlands

    3Department of Endocrinology, Erasmus Medical Center-Sophia Children’s Hospital, Rotterdam, Netherlands

    Corresponding Author:

    Emma Jacobine Verwaaijen, MSc

    Princess Máxima Center for Pediatric Oncology

    Heidelberglaan 25

    Utrecht, 3584 CS

    Netherlands

    Phone: 31 650006739

    Email: e.j.verwaaijen@prinsesmaximacentrum.nl


    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

    JMIR Res Protoc 2022;11(4):e33517

    doi:10.2196/33517

    Keywords

    acute lymphoblastic leukemia; sarcopenia; physical frailty; muscle atrophy; dexamethasone; fatigue; physical activity; glucocorticoid-induced atrophy 


    Acute lymphoblastic leukemia (ALL) is the most prevalent pediatric cancer worldwide. Advances in treatment strategies and supportive care have resulted in a 5-year survival rate of about 90% in high-income countries [1-3]. Consequently, there is growing attention for adverse health effects, including impairments in physical performance during and after therapy [4-6]. Impairments in physical performance, either transient or permanent, in children with ALL are usually explained by a neurological disorder, fractures, osteonecrosis, general malaise, pain, or severe muscle atrophy [7-11]. Muscle atrophy, in turn, can be caused by malnutrition, inflammation, low physical activity, and can be aggravated by treatment with glucocorticoids [12,13]. Glucocorticoids, which are essential in the treatment of ALL, are known to regulate protein metabolism in skeletal muscle, thereby inducing a catabolic effect and consequent muscle atrophy [14,15].

    Dexamethasone is the most potent glucocorticoid and a cornerstone for the treatment of pediatric ALL, because it reduces the frequency of central nervous system relapse [15]. As it is administered in high doses for considerable periods in various ALL protocols worldwide (6 mg/m2 per day) [16-18], children with ALL carry an increased risk of glucocorticoid-induced muscle atrophy [15].

    Muscle atrophy (loss of muscle mass) when accompanied by decreased muscle strength may indicate a generalized skeletal muscle disorder called sarcopenia [19]. Sarcopenia, defined as the combination of low muscle mass and strength or function, is associated with increased adverse health outcomes in various adult populations [20]. The presence of sarcopenia has been investigated to a limited extent in 3 previous studies including children with ALL [4,21,22], which indicated that muscle mass loss in children during ALL therapy was associated with the number and duration of hospital admissions [4], occurrence of invasive fungal infections, other adverse events of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥III [21], and even—when fat mass and body mass index were increased—with impaired survival [22]. However, due to small sample sizes and methodological limitations, which make it difficult to correct for relevant confounders, it is unclear if these results indicate a true causal relationship or coassociation.

    Physical frailty is another undesired consequential state, and is characterized by 5 components: unintentional weight loss (due to muscle mass loss), muscle weakness, self-reported exhaustion, slow walking speed, and low physical activity [23]. Physical frailty has been reported as a state of reduced physiologic reserve with increased vulnerability to stressors. It was first defined in the elderly by Fried et al [23], and was shown to be associated with disabilities and early mortality in young adult survivors of childhood cancer [24-27]. The 5 components of physical frailty have all been individually described to occur in children with ALL. For example, higher levels of fatigue were reported in children with ALL compared with children from the general population, and more often during dexamethasone treatment [28,29]. Besides, several studies showed that children with ALL had muscle mass loss [22], muscle weakness [5,6,30], slow walking speed [5,31], and reduced physical activity levels [32-34]. It is therefore relevant to study whether co-occurrence of these 5 physical frailty components may be prevalent in children with ALL, putting them at risk for serious complications.

    There is some known overlap between physical frailty and sarcopenia; in fact, sarcopenia has been reported as a precursor of frailty in older adults [23,35-37]. The biological and clinical relationships between these 2 states in pediatric cancer populations are not clear yet.

    The development of sarcopenia or physical frailty or both in children during ALL therapy is undesirable because of the consequences it may have for therapy (discontinuation or dose reduction due to clinical state), physical abilities, motor development, and child participation levels in daily life activities, as well as the potential negative effects on the longer term. To our knowledge, physical frailty in children has been assessed in only 2 previous studies, but not yet in pediatric patients with cancer. In both studies the frailty phenotype was associated with severe infections and increased hospitalizations [38,39].

    So far, frailty has not been examined in children during ALL treatment nor has the relationship between dexamethasone and sarcopenia/frailty been investigated. Hence, the aims of this study are to estimate the occurrence of sarcopenia and physical frailty in children with ALL during maintenance therapy, to evaluate the effect of administering dexamethasone on sarcopenia and frailty (and their individual components) and to explore potential determinants associated with these outcomes. This paper describes the statistical design and methodology for this study.


    Study Design and Patient Recruitment

    This prospective national observational cohort study is taking place at the Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands. The children included in this study are participating in the DexaDays-2 study: a randomized controlled trial on neurobehavioral side effects in pediatric patients with ALL [40]. In that study, Dutch patients with ALL are eligible when they fulfill the following criteria: age 3-18, confirmed diagnosis of ALL, and inclusion in the Dutch Childhood Oncology Group (DCOG) medium-risk group of the ALL-11 protocol. Only patients between 3 and 18 years can participate as this was an inclusion criterion for the DexaDays-2 study, because the questionnaires used in that study are validated only for those ages. Children who reach the age of 3 years during maintenance therapy and are still due to receive 5 dexamethasone courses after their birthday (at least 15 weeks before the end of therapy) are also eligible. Exclusion criteria of that study are anticipated compliance problems, underlying conditions that affect the absorption of oral medication, uncontrolled infections, or any other complications that may interfere with administering dexamethasone treatment, insufficient command of the Dutch language, preexisting mental retardation, and hydrocortisone or risperidone use during the invitation to participate.

    Our study on sarcopenia and frailty is being pursued within the framework of the aforementioned DexaDays-2 study. The latter consists of 2 parts: an identification study (including 2 timepoints: T1-T2) and a randomized controlled trial (T3-T11). The prospective observations of the current study are performed at a subset of these time points (Figure 1) during 15 weeks of the maintenance phase of ALL therapy.

    A total of 105 patients will undergo a physical frailty assessment before (T1) and after 5 days (T2) of dexamethasone administration (6 mg/m2 per day in 3 dosages). A subset of 50 children will be assessed at 3 additional timepoints (T3, T7, and T11), to observe the process of sarcopenia and physical frailty longitudinally. This subset comprised children participating in the DexaDays-2 randomized controlled trial based on the severity of their neurobehavioral problems. These 50 patients will receive physiological dosages of hydrocortisone or placebo during a 5-day dexamethasone treatment, and the cross-over will take place after 2 courses of dexamethasone treatment. The sample size is based on the DexaDays-2 study power calculation [40].

    ‎
    Figure 1. Timeline for sarcopenia and physical frailty assessment during the study. aPatients continue with this part of the study when they have significant dexamethasone-induced behavioral problems, based on the study design of the DexaDays-2 study. ALL: acute lymphoblastic leukemia; MR: medium risk; Dexa: dexamethasone.
    View this figure

    Ethics Approval

    The study was approved by the Medical Ethics Committees of the Erasmus Medical Center Rotterdam (reference number: NL62388.078.174).

    Outcome Definitions: Sarcopenia and Physical Frailty

    Sarcopenia

    We will use the most widely cited definition of sarcopenia as proposed by the European Working Group on Sarcopenia [19,39], that is, the combination of low muscle strength or function, and impaired muscle mass [19]. For decades, the term sarcopenia had been used to describe muscle loss alone without reference to function. However, recent updates and consensus definitions state the importance of including muscle function in the concept of sarcopenia [39]. Therefore, in this study, sarcopenia is defined as a combination of impaired muscle mass and low muscle strength.

    These components are also separately included in the frailty definition (Table 1, Figure 2).

    Table 1. Short overview of definition and measurements used to assess sarcopenia in children with ALLa.
    EWGSOPb sarcopenia definitionConcept used in previous pediatric ALL studiesMethod used in our study
    Loss of muscle massPsoas muscle area loss evaluated using computed tomography [20].
    Skeletal muscle mass or lean body mass evaluated using dual-energy X-ray absorptiometry [4,21].    		Skeletal muscle mass evaluation by bioimpedance analysis.
    Muscle weaknessN/AcHandgrip strength evaluation using handheld dynamometry.

    aALL: acute lymphoblastic leukemia.

    bEWGSOP: European Working Group on Sarcopenia in Older People.

    cNA: not applicable.

    ‎
    Figure 2. Physical frailty and sarcopenia definitions and the individual components.
    View this figure
    Physical Frailty

    In accordance with the original definition of Fried et al [23] and previous clinical frailty studies in childhood cancer survivors, we will define frailty using the following components: low muscle mass, muscle weakness, self-reported fatigue, slow walking speed, and low physical activity [24,25]. Prefrailty and frailty will be defined, respectively, by the presence of 2, or 3 or more of the 5 components [22]. Assessments are excluded if 3 or more components are missing.

    The outcome measures to examine sarcopenia and physical frailty components are selected based on suitability for children with an age range of 3-18 years (Table 2).

    Table 2. Short overview of measurements used to assess frailty in childhood cancer survivors and in this study.
    Frailty componentsConcept used in CCSaMethod used in the current study in children with ALLb
    Shrinking/weight lossLean muscle mass evaluated using DXAc [24,25].Skeletal muscle mass evaluation by bioimpedance analysis.
    WeaknessHandgrip strength evaluated using handheld dynamometry [24,25].Handgrip strength evaluation using handheld dynamometry.
    ExhaustionSelf-reported exhaustion assessed using the SF-36d [25] or during a semistructured interview [24]. Self-reported fatigue assessment using PedsQL-MFSe.
    SlownessSlow walking speed evaluated based on cut-off points for 15 ft [25], or by using the 6-Minute Walk Test [24].Slow walking speed evaluation using the Timed Up and Go Test.
    Low physical activity Energy expenditure during leisure time physical activity based on the NHANESf Physical Activity [25] and based on frequency and duration per week derived from a semistructured interview [24].Energy expenditure evaluation based on physical activity questionnaires.

    aCCS: childhood cancer survivors.

    bALL: acute lymphoblastic leukemia.

    cDXA: dual x-ray absorptiometry.

    dSF-36: 36-item Short Form Survey.

    ePedsQL-MFS: Pediatric Quality of Life-Multidimensional Fatigue Scale.

    fNHANES: National Health and Nutrition Examination Survey.

    Skeletal Muscle Mass

    Total body SMM will be measured using multifrequency segmental bioimpedance analysis (Tanita MC-780; Tanita Corporation) [41]. The measurement procedure requires the child to stand in bare feet on the analyzer and to hold a pair of handgrips, 1 in each hand for approximately 15 seconds. Subsequently, the Skeletal Muscle Index (SMI) will be calculated by dividing the individual SMM (kilogram) by height (m2; ie, SMI=SMM/height). The Tanita device has shown excellent test-retest reliability [42]. High significant correlations (correlation coefficients ≥0.85) were shown for body composition values in children and adolescents, between bioimpedance analysis and dual-energy X-ray absorptiometry (which is the golden standard for the measurement of muscle mass) [43].

    Muscle Strength

    Handgrip strength (kilogram) will be measured in sitting position with the elbow flexed at 90° using a hydraulic Jamar handheld dynamometer (Sammons Preston). During the measurement the child will be verbally encouraged to achieve a maximum performance. For both the dominant and nondominant hand the mean score of 3 repeats will be calculated. Raw results will be compared with population-based age- and sex-specific reference values [44]. Handgrip dynamometry showed good validity (intraclass correlation coefficients [ICCs] 0.73-0.91) with high reproducibility in children from the age of 4 years and has excellent test-retest reliability (ICC 0.91-0.93) [45,46], and the measurement was feasible in children with leukemia [47].

    Fatigue

    Fatigue-related complaints will be assessed using the validated Dutch version of the Pediatric Quality of Life Inventory (PedsQL)-Multidimensional Fatigue Scale (MFS) [48,49]. This questionnaire consists of 3 scales: General Fatigue, Sleep/Rest Fatigue, and Cognitive Fatigue, resulting in subscores and in a total fatigue score. We will use parent proxy reports for children aged 2-4, 5-7, 8-12, and 13-18 years, as well as self-report versions for children aged 8-12 and 13-18 years. The results of PedsQL-MFS will be compared with Dutch normative values from the general population [48]. The internal consistency of the Dutch version of the PedsQL-MFS has been reported as satisfactory (Cronbach coefficient α >.70), test-retest reliability was good (ICC 0.68-0.84), and the interobserver reliability varied from moderate to excellent (ICC 0.56-0.93) [48]. The original version of PedsQL-MFS has been validated in patients with pediatric cancer, 50% of whom had ALL [49], and the Dutch version has been used previously in studies in children with ALL [28,50].

    Walking Speed

    The TUG will be used to asses walking speed. A chair, without arm rests, allowing the child to sit with his feet flat on the floor and his hip and knees flexed at 90° will be used. The chair will be positioned at a 3-m distance from a wall. The child will be asked to get up from the sitting position and walk “as fast as he can, without running” to the wall and touch a self-chosen picture on the wall, turn around without using the wall for support, walk back to the chair, and sit down. During the test verbal instructions will be repeated and encouragements are made. Time is recorded from the “go” cue to when the child is sitting down in the chair. The mean time of 3 trials will be considered as the test result [51]. The results of the test will be compared with age-specific reference values [52]. The TUG has shown excellent test-retest reliability (ICC 0.80-0.98) and interobserver reliability (ICCs 0.86 to 0.99) in the pediatric population [53], and the measurement was feasible in children with leukemia [47].

    Physical Activity

    Physical activity will be estimated using parent and self-reported questionnaires. We will use questionnaires generated in a Dutch population–based prospective cohort study investigating the development of a cohort of newborn children until young adulthood [54]. We will use parent proxy-reported versions for children aged 3-11 years, and child-reported versions for children aged 9-11 years [55,56]. These questionnaires comprise questions regarding frequency and duration of outdoor playing, sports participation, and active transport to/from school, as well as sedentary behavior such as watching television and computer use. Children aged 12-18 years will be asked to fill in the modified Baecke questionnaire, which consists of 3 components: school activity, sports activity, and leisure activity [57]. The results of the physical activity questionnaires (type of activity, frequency, and duration) will be compared with the Youth Compendium of Physical Activities [58]. The age-specific metabolic equivalent of the specific activity (either leisure or sports) will be used to estimate the energy expenditure in calories of an individual participant.

    In addition, we hypothesized that generalized muscle weakness might be better expressed in a functional performance test, which is currently not a part of the frailty assessments. To explore the potential value of a functional muscle strength measurement in the concept of sarcopenia and frailty, we will use the “Time to Rise From the Floor Test” (TRF) [59]. The child will be asked to sit in the cross-legged position on the floor and to get up as fast as possible. The TRF will be performed 2 times, and for both performances, the quantitative performance (time in seconds) and a quality grade will be scored. We will use the “Gowers maneuver” as a quality performance by grading the amount of support needed to rise [60]. This is a standardized method to quantify on a 1-7 scale, where 1 means normal rising and 7 means unable to rise (Table 3).

    All assessments will be performed by a pediatric physiotherapist (EV) or a trained medical doctor (AvH).

    Table 3. Gowers maneuver grade: to quantify the ability to rise from the floora.
    PerformanceGrade
    Normal rising1
    Butt-first maneuver, 1 hand on floor2
    Butt-first maneuver, 2 hands on floor3
    Unilateral hand support on thigh4
    Bilateral hand support on thighs5
    Arises only with aid of an object (table, chair)6
    Unable to arise7

    aStandardized method to quantify the quality of rising by grading the amount of support needed to rise.

    Potential Determinants

    We will explore the following potential determinants for the components of sarcopenia and physical frailty: sex, age, weight Z-scores at diagnosis, time since the start of treatment, registered toxicity and serious adverse events in induction therapy, cumulative vincristine dosage, dexamethasone pharmacokinetics, and carrier of relevant genetic variants (candidate single-nucleotide polymorphisms). Information regarding these factors will be extracted from the electronic patient files or is collected in the DexaDays-2 study. Dexamethasone kinetics are measured through peak levels (2-3 hours after the first dexamethasone administration on day 1 of the dexamethasone course) and trough levels (measured on day 6, at least 12 hours after the last dexamethasone dose administered on the previous evening). A peripheral blood sample to extract germline DNA, for evaluation of carrier status of relevant candidate single-nucleotide polymorphisms related to sarcopenia and physical frailty, is taken on T1 as part of the DexaDays-2 study. As a complete array (Illumina GSA) will be run, we will be able to select the most relevant specific additional single-nucleotide polymorphisms of interest, based on evidence from the most recent literature (Figure 1).

    Statistical Analysis

    The results of the physical frailty assessments, that is, SMI, handgrip strength, self-reported fatigue, walking speed, and physical activity (component scores), will be reported as means and SDs, or as median and interquartile ranges if data are non-normally distributed. The frequency of sarcopenia and physical frailty, as well as the individual components at all timepoints will be reported in percentages and schematically visualized. A correlation matrix will be built to explore coherence between the additional measure TRF and the other frailty components.

    To evaluate the potential change in frailty components after 5 days of dexamethasone administration, a paired Student t test or Mann-Whitney U test will be used depending on the distribution of the data.

    To evaluate whether the mean scores from the frailty components change between T1, T3, T7, and T11, 1-way ANOVA will be employed.

    To study the effect of dexamethasone administration at T1, T3, T7, and prior to T11 on sarcopenia, physical frailty, and each individual components, generalized mixed models will be estimated. These models incorporate correlations between repeated responses on the same individual. Patient-specific random intercept, age, weight, time since the start of therapy, and cumulative vincristine dosage will be included in the model.

    Multivariable linear regression model will be estimated to investigate associations between the potential determinants (patient- and treatment-related factors, pharmacokinetics, and genetics) and the assessment scores at T1 and T2 (SMI, handgrip strength, self-reported fatigue, walking speed, TRF, and physical activity). Results will be presented as regression coefficients along with 95% CI.

    Multivariable logistic regression models will be estimated to explore associations between the aforementioned potential determinants and the occurrence of sarcopenia and physical frailty at T1 and T2. Odds ratios along with 95% CIs will be estimated.

    Statistical analyses will be performed using software packages R Statistics (version 1.0.143; R Foundation) and SPSS (version 26.0.0.1) for Windows (IBM).


    Patient accrual started in 2018 and was finalized in spring 2021. A total of 105 children undergoing ALL therapy will participate in this study. From autumn 2021 statistical analyses will be performed.


    This paper describes the design of the first study on sarcopenia and physical frailty in children during maintenance therapy for ALL. The results of this study will provide information and create awareness on the magnitude and severity of sarcopenia and physical frailty in this specific group of children, which may help us understand which factors are associated with the large variations in physical ability between children receiving similar treatments. With this knowledge we may be able to identify physically vulnerable children at an earlier stage. This is important because being vulnerable to sarcopenia or frailty can complicate continuation of ALL therapy, independence in physical functioning, reaching motor milestones, and participation in daily life activities.

    In this study we will assess sarcopenia involving a combination of low muscle mass and low muscle strength for the first time in patients with ALL. The SMM will be estimated using the Tanita MC-780 multifrequency segmental body composition analyzer, which is a validated, reliable, low-cost, fast, and non-invasive device to estimate body composition in the pediatric population [43].

    None of the previous studies in children with ALL concerning muscle mass loss incorporated functional muscle strength assessments. We expect this to be of additional value because recent updates and consensus definitions state the importance of including muscle function in the concept of sarcopenia [61], as reduced muscle mass in combination with normal muscle strength may suggest malnutrition rather than sarcopenia [62]. Besides, in children, impaired muscle function directly influences motor development and is therefore relevant [63].

    To explore this aspect further, we added a functional strength measurement to the assessment: the TRF. Although the handgrip dynamometer is a reliable instrument to measure handgrip strength in children [46], this may not be the first sign of reduction of muscle strength. We suspect that a generalized reduction in muscle strength (such as in sarcopenia and physical frailty) might be better shown by a functional performance test. The time and degree of support needed to rise from the floor are standardized measures to quantify deterioration and are associated with walking ability in children with muscular dystrophy [64].

    The results of this study will provide knowledge about the effect of treatment with high doses of dexamethasone on muscle loss and other components of physical frailty, and therefore insights into the severity and risks of these side effects. Furthermore, through exploring potential determinants that could influence the occurrence of the sarcopenia or frailty, we might be able to identify children at risk for substantial problems at an earlier stage. As a result, we might be able to start targeted interventions and clinical studies on reducing the dexamethasone-induced components of physical frailty with, for example, nutrition and exercise.

    This study has a number of strong points. First, because care for children with ALL in the Netherlands is centralized, a national cohort of Dutch children can be screened on eligibility for this study, rendering a large and hopefully unbiased population. Second, all children will have a physical frailty assessment by a skilled pediatric physiotherapist or a trained medical doctor, which benefits the validity and reliability of the performed physical assessment. Third, the burden of the study will be minimal because the assessments are performed during maintenance therapy of ALL, in which children experience less toxicities, fewer hospital admissions, and therapy is mainly administered at home and in the outpatient clinic. Fourth, we selected sarcopenia and frailty endpoints in accordance with previous research and the official definitions. Furthermore, we added 1 functional strength measurement, the TRF, based on expert opinion and on particular feasibility in children with ALL.

    Some possible study limitations have to be taken into account as well. We will only include children participating in the DexaDays-2 study, which could potentially lead to selection bias, as patients who experience dexamethasone-induced neurobehavioral problems could be more motivated to participate because in that trial they will receive a drug to potentially reduce these problems. Furthermore, the subset of 50 children that will be measured longitudinally comprises children participating in the DexaDays-2 randomized controlled trial based on the severity of their neurobehavioral problems. These patients will receive physiological dosages of hydrocortisone or placebo during a 5-day dexamethasone treatment, and the cross-over will take place after 2 courses of dexamethasone treatment. We do not know if this affects the occurrence of sarcopenia and physical frailty in this cohort, for example, whether children with dexamethasone-induced clinically relevant neurobehavioral problems also show more physical side effects. Besides, within the DexaDays-2 study patients aged 3-18 years were selected, which complicated selecting outcome measures suitable for all participants. We succeeded in selecting measurements that have previously been used and validated in pediatric populations indicating their usefulness; however, with the exception of the PedsQL-MFS, none of the measurements has been validated in pediatric oncology patients.

    In conclusion, this study is designed to determine the occurrence and severity of sarcopenia and frailty components in children during the maintenance phase of ALL therapy, and to determine the effects of administration of high doses of dexamethasone on physical vulnerability. With this study we aim to create awareness about these potential risks in children with ALL, as well as expanding our knowledge for reducing further side effects.

    Acknowledgments

    MH-E, MG, and EA are the principal investigators of this study. SP contributed to the concept and design of the study. MF is the trial statistician. RP and AH are involved as content experts. EV and AvH collected data and wrote this protocol. All authors read and approved the manuscript. EV and AvH are funded by Kinderen Kankervrij (KiKa number 268), the Netherlands. The authors thank all participating patients and parents, Dr P. van der Torre for his contribution to the frailty definition and selection of the assessments, and the trial and data center of the Princess Máxima Center for their support.

    Conflicts of Interest

    None declared.

    1. Gatta G, Botta L, Rossi S, Aareleid T, Bielska-Lasota M, Clavel J, et al. Childhood cancer survival in Europe 1999–2007: results of EUROCARE-5—a population-based study. The Lancet Oncology 2014 Jan;15(1):35-47. [CrossRef] [Medline]
    2. Pieters R, de Groot-Kruseman H, Van der Velden V, Fiocco M, van den Berg H, de Bont E, et al. Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: Study ALL10 From the Dutch Childhood Oncology Group. J Clin Oncol 2016 Aug 01;34(22):2591-2601. [CrossRef] [Medline]
    3. Pui C, Evans WE. A 50-year journey to cure childhood acute lymphoblastic leukemia. Semin Hematol 2013 Jul;50(3):185-196 [FREE Full text] [CrossRef] [Medline]
    4. Rayar M, Webber C, Nayiager T, Sala A, Barr R. Sarcopenia in children with acute lymphoblastic leukemia. J Pediatr Hematol Oncol 2013;35(2):98-102. [CrossRef] [Medline]
    5. Ness KK, Kaste SC, Zhu L, Pui C, Jeha S, Nathan PC, et al. Skeletal, neuromuscular and fitness impairments among children with newly diagnosed acute lymphoblastic leukemia. Leukemia & Lymphoma 2014 Aug 20;56(4):1004-1011. [CrossRef] [Medline]
    6. Gocha Marchese V, Chiarello LA, Lange BJ. Strength and functional mobility in children with acute lymphoblastic leukemia. Med Pediatr Oncol 2003 Apr;40(4):230-232. [CrossRef] [Medline]
    7. te Winkel ML, Pieters R, Hop WC, de Groot-Kruseman HA, Lequin MH, van der Sluis IM, et al. Prospective Study on Incidence, Risk Factors, and Long-Term Outcome of Osteonecrosis in Pediatric Acute Lymphoblastic Leukemia. JCO 2011 Nov 01;29(31):4143-4150. [CrossRef] [Medline]
    8. Cummings EA, Ma J, Fernandez CV, Halton J, Alos N, Miettunen PM, et al. Incident Vertebral Fractures in Children With Leukemia During the Four Years Following Diagnosis. The Journal of Clinical Endocrinology & Metabolism 2015 Sep;100(9):3408-3417. [CrossRef] [Medline]
    9. Ward L, Ma J, Lang B. Bone Morbidity and Recovery in Children With Acute Lymphoblastic Leukemia: Results of a Six-Year Prospective Cohort Study. J Bone Miner Res 2018;33(8):1435-1443. [CrossRef] [Medline]
    10. te Winkel ML, Pieters R, Wind ED, Bessems JHJM, van den Heuvel-Eibrink MM. Management and treatment of osteonecrosis in children and adolescents with acute lymphoblastic leukemia. Haematologica 2014 Mar 05;99(3):430-436 [FREE Full text] [CrossRef] [Medline]
    11. Cox CL, Zhu L, Kaste SC, Srivastava K, Barnes L, Nathan PC, et al. Modifying bone mineral density, physical function, and quality of life in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 2018 Apr 29;65(4):e26929 [FREE Full text] [CrossRef] [Medline]
    12. Barr RD, Gomez-Almaguer D, Jaime-Perez JC, Ruiz-Argüelles GJ. Importance of Nutrition in the Treatment of Leukemia in Children and Adolescents. Arch Med Res 2016 Nov;47(8):585-592. [CrossRef] [Medline]
    13. Brinksma A, Roodbol PF, Sulkers E, Kamps WA, de Bont ES, Boot AM, et al. Changes in nutritional status in childhood cancer patients: a prospective cohort study. Clin Nutr 2015 Feb;34(1):66-73. [CrossRef] [Medline]
    14. Bodine S, Furlow J. Glucocorticoids and Skeletal Muscle. Adv Exp Med Biol 2015;872:145-176. [CrossRef] [Medline]
    15. Inaba H, Pui C. Glucocorticoid use in acute lymphoblastic leukaemia. The Lancet Oncology 2010 Nov;11(11):1096-1106. [CrossRef] [Medline]
    16. Bostrom BC, Sensel MR, Sather HN, Gaynon PS, La MK, Johnston K, Children's Cancer Group. Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group. Blood 2003 May 15;101(10):3809-3817 [FREE Full text] [CrossRef] [Medline]
    17. Kaspers GJL, Veerman AJP, Popp-Snijders C, Lomecky M, Van Zantwijk CH, Swinkels L, et al. Comparison of the antileukemic activity in vitro of dexamethasone and prednisolone in childhood acute lymphoblastic leukemia. Med. Pediatr. Oncol 1996 Aug;27(2):114-121. [CrossRef] [Medline]
    18. Veerman AJ, Kamps WA, van den Berg H, van den Berg E, Bökkerink JP, Bruin MC, et al. Dexamethasone-based therapy for childhood acute lymphoblastic leukaemia: results of the prospective Dutch Childhood Oncology Group (DCOG) protocol ALL-9 (1997–2004). The Lancet Oncology 2009 Oct;10(10):957-966. [CrossRef] [Medline]
    19. Cruz-Jentoft A. Sarcopenia, the last organ insufficiency. European Geriatric Medicine 2016 Jun;7(3):195-196. [CrossRef]
    20. Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, Writing Group for the European Working Group on Sarcopenia in Older People 2 (EWGSOP2)‚the Extended Group for EWGSOP2. Sarcopenia: revised European consensus on definition and diagnosis. Age Ageing 2019 Jan 01;48(1):16-31 [FREE Full text] [CrossRef] [Medline]
    21. Suzuki D, Kobayashi R, Sano H, Hori D, Kobayashi K. Sarcopenia after induction therapy in childhood acute lymphoblastic leukemia: its clinical significance. Int J Hematol 2018 May 12;107(4):486-489. [CrossRef] [Medline]
    22. den Hoed MAH, Pluijm SMF, de Groot-Kruseman HA, te Winkel ML, Fiocco M, van den Akker ELT, et al. The negative impact of being underweight and weight loss on survival of children with acute lymphoblastic leukemia. Haematologica 2015 Jan 10;100(1):62-69 [FREE Full text] [CrossRef] [Medline]
    23. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in Older Adults: Evidence for a Phenotype. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2001 Mar 01;56(3):M146-M157. [CrossRef]
    24. Vatanen A, Hou M, Huang T, Söder O, Jahnukainen T, Kurimo M, et al. Clinical and biological markers of premature aging after autologous SCT in childhood cancer. Bone Marrow Transplant 2017 May 09;52(4):600-605. [CrossRef] [Medline]
    25. Ness KK, Krull KR, Jones KE, Mulrooney DA, Armstrong GT, Green DM, et al. Physiologic Frailty As a Sign of Accelerated Aging Among Adult Survivors of Childhood Cancer: A Report From the St Jude Lifetime Cohort Study. JCO 2013 Dec 20;31(36):4496-4503. [CrossRef]
    26. Hayek S, Gibson TM, Leisenring WM, Guida JL, Gramatges MM, Lupo PJ, et al. Prevalence and Predictors of Frailty in Childhood Cancer Survivors and Siblings: A Report From the Childhood Cancer Survivor Study. JCO 2020 Jan 20;38(3):232-247. [CrossRef]
    27. Verwaaijen EJ, Corbijn DM, Hulst AM, Neggers SJ, Boot AM, Heuvel‐Eibrink MM, et al. Frailty in long‐term Dutch adult survivors of childhood acute myeloid leukaemia, neuroblastoma, and Wilms' tumour. JCSM Clinical Reports 2020 Oct 07;6(1):3-10. [CrossRef]
    28. Steur LMH, Kaspers GJL, van Someren EJW, van Eijkelenburg NKA, van der Sluis IM, Dors N, et al. The impact of maintenance therapy on sleep-wake rhythms and cancer-related fatigue in pediatric acute lymphoblastic leukemia. Support Care Cancer 2020 Dec 13;28(12):5983-5993 [FREE Full text] [CrossRef] [Medline]
    29. Zupanec S, Jones H, Stremler R. Sleep habits and fatigue of children receiving maintenance chemotherapy for ALL and their parents. J Pediatr Oncol Nurs 2010 Jun 18;27(4):217-228. [CrossRef] [Medline]
    30. Hartman A, van den Bos C, Stijnen T, Pieters R. Decrease in peripheral muscle strength and ankle dorsiflexion as long-term side effects of treatment for childhood cancer. Pediatr Blood Cancer 2008 May 30;50(4):833-837. [CrossRef] [Medline]
    31. Manchola-González JD, Bagur-Calafat C, Girabent-Farrés M, Serra-Grima JR, Pérez RÁ, Garnacho-Castaño MV, et al. Effects of a home-exercise programme in childhood survivors of acute lymphoblastic leukaemia on physical fitness and physical functioning: results of a randomised clinical trial. Support Care Cancer 2020 Jul;28(7):3171-3178. [CrossRef] [Medline]
    32. Fuemmeler B, Pendzich M, Clark K, Lovelady C, Rosoff P, Blatt J, et al. Diet, physical activity, and body composition changes during the first year of treatment for childhood acute leukemia and lymphoma. J Pediatr Hematol Oncol 2013 Aug;35(6):437-443 [FREE Full text] [CrossRef] [Medline]
    33. Tan SY, Poh BK, Chong HX, Ismail MN, Rahman J, Zarina AL, et al. Physical activity of pediatric patients with acute leukemia undergoing induction or consolidation chemotherapy. Leuk Res 2013 Jan;37(1):14-20. [CrossRef] [Medline]
    34. Winter C, Müller C, Brandes M, Brinkmann A, Hoffmann C, Hardes J, et al. Level of activity in children undergoing cancer treatment. Pediatr Blood Cancer 2009 Oct 04;53(3):438-443. [CrossRef] [Medline]
    35. Dodds R, Sayer AA. Sarcopenia and frailty: new challenges for clinical practice. Clin Med (Lond) 2016 Oct 03;16(5):455-458 [FREE Full text] [CrossRef] [Medline]
    36. Cesari M, Landi F, Vellas B, Bernabei R, Marzetti E. Sarcopenia and physical frailty: two sides of the same coin. Front Aging Neurosci 2014;6:192 [FREE Full text] [CrossRef] [Medline]
    37. Landi F, Calvani R, Cesari M, Tosato M, Martone AM, Bernabei R, et al. Sarcopenia as the Biological Substrate of Physical Frailty. Clin Geriatr Med 2015 Aug;31(3):367-374. [CrossRef] [Medline]
    38. Sgambat K, Matheson MB, Hooper SR, Warady B, Furth S, Moudgil A. Prevalence and outcomes of fragility: a frailty-inflammation phenotype in children with chronic kidney disease. Pediatr Nephrol 2019 Dec 2;34(12):2563-2569 [FREE Full text] [CrossRef] [Medline]
    39. Lurz E, Quammie C, Englesbe M, Alonso EM, Lin HC, Hsu EK, et al. Frailty in Children with Liver Disease: A Prospective Multicenter Study. J Pediatr 2018 Mar;194:109-115.e4. [CrossRef] [Medline]
    40. van Hulst AM, Verwaaijen EJ, Fiocco MF, Pluijm SMF, Grootenhuis MA, Pieters R, et al. Study protocol: DexaDays-2, hydrocortisone for treatment of dexamethasone-induced neurobehavioral side effects in pediatric leukemia patients: a double-blind placebo controlled randomized intervention study with cross-over design. BMC Pediatr 2021 Sep 27;21(1):427 [FREE Full text] [CrossRef] [Medline]
    41. McCarthy HD, Samani-Radia D, Jebb SA, Prentice AM. Skeletal muscle mass reference curves for children and adolescents. Pediatr Obes 2014 Aug 18;9(4):249-259. [CrossRef] [Medline]
    42. Kabiri LS, Hernandez DC, Mitchell K. Reliability, Validity, and Diagnostic Value of a Pediatric Bioelectrical Impedance Analysis Scale. Child Obes 2015 Oct;11(5):650-655. [CrossRef] [Medline]
    43. Chula de Castro JA, Lima TRD, Silva DAS. Body composition estimation in children and adolescents by bioelectrical impedance analysis: A systematic review. J Bodyw Mov Ther 2018 Jan;22(1):134-146. [CrossRef] [Medline]
    44. Bohannon R, Wang Y, Bubela D, Gershon R. Handgrip Strength: A Population-Based Study of Norms and Age Trajectories for 3- to 17-Year-Olds. Pediatr Phys Ther 2017 Apr;29(2):118-123. [CrossRef] [Medline]
    45. van den Beld WA, van der Sanden GAC, Sengers RCA, Verbeek ALM, Gabreëls FJM. Validity and reproducibility of the Jamar dynamometer in children aged 4-11 years. Disabil Rehabil 2006 Dec 15;28(21):1303-1309. [CrossRef] [Medline]
    46. Gąsior J, Pawłowski M, Jeleń P, Rameckers E, Williams C, Makuch R, et al. Test-Retest Reliability of Handgrip Strength Measurement in Children and Preadolescents. Int J Environ Res Public Health 2020 Oct 31;17(21):8026 [FREE Full text] [CrossRef] [Medline]
    47. Nielsen MKF, Christensen JF, Frandsen TL, Thorsteinsson T, Andersen LB, Christensen KB, et al. Testing physical function in children undergoing intense cancer treatment-a RESPECT feasibility study. Pediatr Blood Cancer 2018 Aug 09;65(8):e27100. [CrossRef] [Medline]
    48. Gordijn MS, Suzanne Gordijn M, Cremers EMP, Kaspers GJL, Gemke RJBJ. Fatigue in children: reliability and validity of the Dutch PedsQL™ Multidimensional Fatigue Scale. Qual Life Res 2011 Oct 19;20(7):1103-1108 [FREE Full text] [CrossRef] [Medline]
    49. Varni JW, Burwinkle TM, Katz ER, Meeske K, Dickinson P. The PedsQL in pediatric cancer: reliability and validity of the Pediatric Quality of Life Inventory Generic Core Scales, Multidimensional Fatigue Scale, and Cancer Module. Cancer 2002 May 01;94(7):2090-2106 [FREE Full text] [CrossRef] [Medline]
    50. Gordijn MS, van Litsenburg RR, Gemke RJ, Huisman J, Bierings MB, Hoogerbrugge PM, et al. Sleep, fatigue, depression, and quality of life in survivors of childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2013 Mar 08;60(3):479-485. [CrossRef] [Medline]
    51. Williams EN, Carroll SG, Reddihough DS, Phillips BA, Galea MP. Dev Med Child Neurol 2005 Aug 14;47(8):518-524 [FREE Full text] [CrossRef] [Medline]
    52. Nicolini-Panisson RD, Donadio MVF. Normative values for the Timed 'Up and Go' test in children and adolescents and validation for individuals with Down syndrome. Dev Med Child Neurol 2014 May 08;56(5):490-497 [FREE Full text] [CrossRef] [Medline]
    53. Nicolini-Panisson RD, Donadio MVF. Timed "Up & Go" test in children and adolescents. Rev. paul. pediatr 2013 Sep;31(3):377-383. [CrossRef]
    54. Hofman A, Jaddoe VWV, Mackenbach JP, Moll HA, Snijders RFM, Steegers EAP, et al. Growth, development and health from early fetal life until young adulthood: the Generation R Study. Paediatr Perinat Epidemiol 2004 Jan;18(1):61-72. [CrossRef] [Medline]
    55. Jaddoe VWV, van Duijn CM, Franco OH, van der Heijden AJ, van Iizendoorn MH, de Jongste JC, et al. The Generation R Study: design and cohort update 2012. Eur J Epidemiol 2012 Oct 20;27(9):739-756. [CrossRef] [Medline]
    56. Wijtzes AI, Bouthoorn SH, Jansen W, Franco OH, Hofman A, Jaddoe VW, et al. Sedentary behaviors, physical activity behaviors, and body fat in 6-year-old children: the Generation R Study. Int J Behav Nutr Phys Act 2014 Aug 15;11(1):96. [CrossRef]
    57. Vogels N, Westerterp K, Posthumus D, Rutters F, Westerterp-Plantenga M. Daily physical activity counts vs structured activity counts in lean and overweight Dutch children. Physiol Behav 2007 Dec 23;92(4):611-616. [CrossRef] [Medline]
    58. Butte N, Watson K, Ridley K, Zakeri IF, McMurray RG, Pfeiffer KA, et al. A Youth Compendium of Physical Activities: Activity Codes and Metabolic Intensities. Med Sci Sports Exerc 2018 Feb;50(2):246-256 [FREE Full text] [CrossRef] [Medline]
    59. Pereira AC, Ribeiro MG, Araújo APDQC. Timed motor function tests capacity in healthy children. Arch Dis Child 2016 Mar 13;101(2):147-151 [FREE Full text] [CrossRef] [Medline]
    60. Angelini C, Peterle E. Old and new therapeutic developments in steroid treatment in Duchenne muscular dystrophy. Acta Myol 2012 May;31(1):9-15 [FREE Full text] [Medline]
    61. Cruz-Jentoft AJ, Sayer AA. Sarcopenia. The Lancet 2019 Jun;393(10191):2636-2646. [CrossRef]
    62. ter Beek L, Vanhauwaert E, Slinde F, Orrevall Y, Henriksen C, Johansson M, et al. Unsatisfactory knowledge and use of terminology regarding malnutrition, starvation, cachexia and sarcopenia among dietitians. Clin Nutr 2016 Dec;35(6):1450-1456. [CrossRef] [Medline]
    63. Ooi PH, Thompson-Hodgetts S, Pritchard-Wiart L, Gilmour SM, Mager DR. Pediatric Sarcopenia: A Paradigm in the Overall Definition of Malnutrition in Children? JPEN J Parenter Enteral Nutr 2020 Mar 22;44(3):407-418. [CrossRef] [Medline]
    64. Mazzone ES, Coratti G, Sormani MP, Messina S, Pane M, D'Amico A, et al. Timed Rise from Floor as a Predictor of Disease Progression in Duchenne Muscular Dystrophy: An Observational Study. PLoS One 2016;11(3):e0151445 [FREE Full text] [CrossRef] [Medline]

    ‎
    ALL: acute lymphoblastic leukemia
    CTCAE: Common Terminology Criteria for Adverse Events
    DCOG: Dutch Childhood Oncology Group
    ICC: intraclass correlation coefficient
    PedsQL-MFS: Pediatric Quality of Life Inventory-Multidimensional Fatigue Scale
    SMI: Skeletal Muscle Index
    SMM: skeletal muscle mass
    TRF: time to rise from the floor
    TUG: Timed Up and Go Test

    Edited by T Leung; submitted 10.09.21; peer-reviewed by R Skinner; comments to author 22.12.21; revised version received 24.01.22; accepted 07.02.22; published 11.04.22

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    ©Emma Jacobine Verwaaijen, Annelienke van Hulst, Marta Fiocco, Annelies Hartman, Martha Grootenhuis, Saskia Pluijm, Rob Pieters, Erica van den Akker, Marry M van den Heuvel-Eibrink. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 11.04.2022.

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