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.

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.