Different subtypes of chronic fatigue in childhood cancer survivors: A DCCSS LATER study.

INTRODUCTION: The aim of the current study was to investigate whether subtypes of chronic fatigue (CF) can be identified in childhood cancer survivors (CCS), and if so, to determine the characteristics of participants with a specific subtype. METHODS: Participants were included from the nationwide DCCSS LATER cohort. The Checklist Individual Strength (CIS) was completed to assess fatigue. Participants with CF (scored ≥35 on the fatigue severity subscale and indicated to suffer from fatigue for ≥6 months) were divided into subgroups using two-step cluster analysis based on the CIS concentration, motivation, and physical activity subscales. Differences between groups on demographics, psychosocial, lifestyle, and treatment-related variables were determined using ANOVA and chi-square analyses (univariable) and multinomial regression analysis (multivariable). RESULTS: A total of 1910 participants participated in the current study (n = 450 with CF; n = 1460 without CF). Three CF subgroups were identified: Subgroup 1 (n = 133, 29% of participants) had CF with problems in physical activity; Subgroup 2 (n = 111, 25% of participants) had CF with difficulty concentrating; and Subgroup 3 (n = 206, 46% of participants) had multi-dimensional CF. Compared to Subgroup 1, Subgroup 2 more often reported sleep problems, limitations in social functioning, and less often have more than two comorbidities. Subgroup 3 more often reported depression, sleep problems, a lower self-esteem, and limitations in social functioning and a lower educational level compared to Subgroup 1. CONCLUSION: Different subgroups of CCS with CF can be identified based on fatigue dimensions physical activity, motivation and concentration. Results suggest that different intervention strategies, tailored for each subgroup, might be beneficial.

Unraveling the relations between post-traumatic stress symptoms, neurocognitive functioning, and limbic white matter in pediatric brain tumor patients.

Background: Pediatric brain tumor patients are at risk of developing neurocognitive impairments and associated white matter alterations. In other populations, post-traumatic stress symptoms (PTSS) impact cognition and white matter. This study aims to investigate the effect of PTSS on neurocognitive functioning and limbic white matter in pediatric brain tumor patients. Methods: Sixty-six patients (6-16 years) completed neuropsychological assessment and brain MRI (1-year post-diagnosis) and parents completed PTSS proxy questionnaires (CRIES-13; 1-3 months and 1-year post-diagnosis). Mean Z-scores and percentage impaired (>1SD) for attention, processing speed, executive functioning, and memory were compared to normscores (t-tests, chi-square tests). Multi-shell diffusion MRI data were analyzed for white matter tractography (fractional anisotropy/axial diffusivity). Effects of PTSS on neurocognition and white matter were explored with linear regression models (FDR correction for multiple testing), including age at diagnosis, treatment intensity, and tumor location as covariates. Neurocognition and limbic white matter associations were explored with correlations. Results: Attention (M = -0.49, 33% impaired; P < .05) and processing speed (M = -0.57, 34% impaired; P < .05) were significantly lower than healthy peers. PTSS was associated with poorer processing speed (ß = -0.64, P < .01). Treatment intensity, age at diagnosis, and tumor location, but not PTSS, were associated with limbic white matter metrics. Neurocognition and white matter metrics were not associated. Conclusions: Higher PTSS was associated with poorer processing speed, highlighting the need for monitoring, and timely referrals to optimize psychological well-being and neurocognitive functioning. Future research should focus on longitudinal follow-up and explore the impact of PTSS interventions on neurocognitive performance.

Experiences of pediatric cancer patients (age 12-18 years) with extensive germline sequencing for cancer predisposition: a qualitative study.

This study explored the experiences and needs of adolescents, ranging from 12 to 18 years old, who have recently been diagnosed with cancer and participated in a nationwide germline genetic sequencing study within the context of pediatric oncology. The 21 adolescents in this qualitative interview study viewed genetic sequencing as an integral part of their cancer journey. They often characterized germline sequencing as "good-to-know" without specifying immediate utility. While the adolescents comprehended the significance of germline genetic sequencing, they were less focused on its potential long-term implications. Adolescents expressed a strong desire to be actively engaged in decisions related to genetics. They advocated for a participatory role in genetic decision-making from a young age onwards. They recommended that re-consent should be sought before re-analysis of their genetic data is performed and believe that patients should have the opportunity to provide (re-)consent once they reach adulthood. Moreover, the adolescents emphasized the importance of developing counseling materials that are not only concise but also visually attractive. In conclusion, this study underscores the positive perception that adolescents diagnosed with cancer hold regarding germline genetic sequencing. They articulate a strong interest in being actively involved in genetic decision-making. To address these articulated needs and preferences, we recommend the development of visually engaging counseling materials. These materials should effectively convey both the immediate and long-term implications of genetic sequencing, enabling adolescents with cancer to make informed decisions about genetic sequencing.

Leptin Increase During Dexamethasone and Its Association With Hunger and Fat in Pediatric Acute Lymphoblastic Leukemia.

CONTEXT: During treatment, children with acute lymphoblastic leukemia (ALL) receive high doses dexamethasone, which induce acute side effects. OBJECTIVE: To determine the influence of a 5-day dexamethasone course on changes in leptin, fat mass, BMI, hunger, sleep, and fatigue and to explore associations between these changes. METHODS: Pediatric ALL patients were included during maintenance treatment. Data were collected before (T1) and after (T2) a 5-day dexamethasone course (6 mg/m2/day). At both time points, BMI, fat mass (bioelectrical impedance analysis), and leptin were assessed, as well as parent-reported questionnaires regarding hunger, fatigue, and sleep problems. Changes between T1 and T2 were assessed using paired tests. Correlation coefficients were calculated to assess associations between these changes (Delta scores: T2-T1). Univariable regression models were estimated to study associations between covariates and elevated leptin. RESULTS: We included 105 children, with median age 5.4 years (range, 3.0-18.8). Leptin and fat mass, as well as hunger scores, fatigue, and sleep deteriorated after 5 days of dexamethasone (P < .001), in contrast to BMI (P = .12). No correlations between delta leptin and delta fat mass, BMI, hunger, fatigue, or sleep were found. Elevated leptin on T1 was associated with older age (odds ratio [OR] 1.51; 95% CI, 1.28-1.77), higher fat mass (OR 1.19; 95% CI, 1.07-1.33), and earlier maintenance week (OR 0.96; 95% CI, 0.92-0.99). CONCLUSION: Five days of high-dose dexamethasone treatment led to direct and significant changes in leptin, hunger scores, and fat mass. Since children with ALL are at increased risk for metabolic adverse events, understanding underlying mechanisms is important, and a dexamethasone-induced state of acute leptin resistance might play a role.

The cumulative burden of self-reported, clinically relevant outcomes in long-term childhood cancer survivors and implications for survivorship care: A DCCSS LATER study.

BACKGROUND: The aim of this study is to evaluate how cumulative burden of clinically relevant, self-reported outcomes in childhood cancer survivors (CCSs) compares to a sibling control group and to explore how the burden corresponds to levels of care proposed by existing risk stratifications. METHODS: The authors invited 5925 5-year survivors from the Dutch Childhood Cancer Survivor Study (DCCSS LATER) cohort and their 1066 siblings to complete a questionnaire on health outcomes. Health outcomes were validated by self-reported medication use or medical record review. Missing data on clinically relevant outcomes in CCSs for whom no questionnaire data were available were imputed with predictive mean matching. We calculated the mean cumulative count (MCC) for clinically relevant outcomes. Furthermore, we calculated 30-year MCC for groups of CCSs based on primary cancer diagnosis and treatment, ranked 30-year MCC, and compared the ranking to levels of care according to existing risk stratifications. RESULTS: At median 18.5 years after 5-year survival, 46% of CCSs had at least one clinically relevant outcome. CCSs experienced 2.8 times more health conditions than siblings (30-year MCC = 0.79; 95% confidence interval [CI], 0.74-0.85 vs. 30-year MCC = 0.29; 95% CI, 0.25-0.34). CCSs' burden of clinically relevant outcomes consisted mainly of endocrine and vascular conditions and varied by primary cancer type. The ranking of the 30-year MCC often did not correspond with levels of care in existing risk stratifications. CONCLUSIONS: CCSs experience a high cumulative burden of clinically relevant outcomes that was not completely reflected by current risk stratifications. Choices for survivorship care should extend beyond primary tumor and treatment parameters, and should consider also including CCSs' current morbidity.

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.

Pain monitoring app leads to less pain in children with cancer at home: Results of a randomized controlled trial.

BACKGROUND: The authors developed a pain monitoring app offering educational information, and real-time health care professional feedback on clinically significant pain (>4 numeric rating scale [NRS]-11) for children with cancer to reduce pain at home. METHODS: This monocenter, nonblinded randomized controlled trial enrolled Dutch children (0-18 years old) receiving cancer treatment (≥3 months after diagnosis, ≥2 months treatment remaining). Children were randomly assigned to use the app or receive usual care (two parallel groups). We assessed whether use of the app yielded less clinically significant pain (aim 1) and whether it affected pain severity, duration, interference, pain management strategies, and parental emotional well-being (aim 2). The app was also evaluated by families (aim 3). RESULTS: A total of 94 children were randomized to use the app (15 drop-outs), and 90 were to receive care as usual (11 drop-outs). The app group (n = 79, mean age: 7.5 [5.1] years, 48% girls, 63% hemato-oncology diagnosis) reported significantly less clinically significant pain compared to usual care (n = 79, mean age: 7.5 [5.4] years, 52% girls, 65% hemato-oncology diagnosis) (odds ratio [OR], 0.38; 95% confidence interval [CI], 0.198-0.734]) (aim 1), as well as significantly lower pain severity (ß = -0.27; 95% CI, -0.407 to -0.142). No differences were found for duration, interference, or management strategies. Parents in the app group reported significantly less distress compared to usual care (ß = -0.84; 95% CI, -1.61 to -0.03]) (aim 2). Families generally evaluated the app positively (aim 3). CONCLUSIONS: Use of the app resulted in less clinically significant pain at home. The exact working mechanisms of the app should be further elucidated.

Health-related quality of life and its determinants during and after treatment for paediatric acute lymphoblastic leukaemia: a national, prospective, longitudinal study in the Netherlands.

OBJECTIVES: Health-related quality of life (HRQoL) is impaired in paediatric patients with acute lymphoblastic leukaemia (ALL). Over the past decades, ALL treatment has successfully been adjusted to the risk of relapse, which is now reflected by the stratification of patients into three risk groups who receive treatment of differing intensities. This study is the first to evaluate the longitudinal course of HRQoL in light of these adjustments and identify determinants of HRQoL. DESIGN: Two prospective, national cohort studies (add-on studies within the two most recent treatment protocols for children with ALL (ALL-10 and ALL-11)). SETTING: Dutch paediatric oncology hospitals between October 2006 and October 2009 (ALL-10) and between August 2013 and July 2017 (ALL-11). PARTICIPANTS: Patients with ALL (2-18 years) are treated according to the ALL-10 or ALL-11 treatment protocol. Patients treated according to the ALL-10 protocol only completed a cancer-specific QoL measure and patients treated according to the ALL-11 protocol completed both a cancer-specific and generic QoL measure (see below). OUTCOME MEASURES: HRQoL, assessed with parent-proxy questionnaires (PedsQL Generic and Cancer module) within the first 5 months (T0), at 1 year (T1), 2 years (T2) and 3 years (T3) after diagnosis. The proportion of patients with clinically relevant generic HRQoL impairment was compared with healthy norm values. Multivariable mixed model analyses were used to evaluate the development of HRQoL over time and its medical and sociodemographic determinants (collected on enrolment). RESULTS: Of the ALL-10 cohort, 132 families participated and of the ALL-11 cohort, 136 families participated (268 total). Thus, cancer-specific HRQoL assessments were available for 268 patients (median age 5.3 years (IQR 6.15), 56.0% boys, 69.0% medium-risk ALL), and generic HRQoL assessments for 136 patients (median age 4.8 years (IQR 6.13), 60.3% boys, 75.0% medium-risk ALL). Generic HRQoL improved between timepoints T0 and T3 (total score B 16.1, 95% CI 12.2 to 20.1, p<0.001), but did not restore to normal 1 year after the end of treatment: 28.0% of children remained impaired compared with 16% in the general population (p=0.003). Cancer-specific HRQoL generally improved from T0 to T2 (Pain B 11.3, 95% CI 7.1 to 15.5; Nausea B 11.7, 8.4 to 15.1; Procedural Anxiety B 19.1, 14.8 to 23.4; Treatment Anxiety B 12.8, 9.5 to 16.0; Worry B 3.5, 0.6 to 6.3; Communication B 8.5, 5.0 to 11.9; all p<0.001 except for Worry (p=0.02)), while Physical Appearance and Cognitive Functioning remained stable. Higher treatment intensity and experiencing pain or simultaneous chronic illness were associated with lower HRQoL over time for multiple subscales. CONCLUSIONS: HRQoL impairment is prevalent during and after ALL treatment. Patients with standard-risk ALL and reduced treatment intensity have better HRQoL than patients in higher risk groups. Systematic monitoring of HRQoL is of utmost importance in order to provide timely psychosocial interventions and supportive care.

The course of health-related quality of life after the diagnosis of childhood cancer: a national cohort study.

BACKGROUND: Comprehensive insight in the longitudinal development of health-related quality of life (HRQOL) after childhood cancer diagnosis could improve quality of care. Thus, we aimed to study the course and biopsychosocial determinants of HRQOL in a unique national cohort of children with cancer. METHODS: HRQOL of 2154 children with cancer was longitudinally reported (median: 3 reports) between diagnosis and 5 years after, using the pediatric quality of life inventory generic core scales (PedsQL). HRQOL was modelled over time since diagnosis using mixed model analysis for children 2-7 years (caregiver-reports) and ≥ 8 years (self-reports). Differences in the course between hematological, solid and central nervous system malignancies were studied. Additional associations of demographics, disease characteristics (age at diagnosis, relapse, diagnosis after the national centralization of childhood cancer care and treatment components) and caregiver distress (Distress thermometer) were studied. RESULTS: Overall, HRQOL improved with time since diagnosis, mostly in the first years. The course of HRQOL differed between diagnostic groups. In children aged 2-7 years, children with a solid tumor had most favorable HRQOL. In children aged ≥ 8 years, those with a hematological malignancy had lower HRQOL around diagnosis, but stronger improvement over time than the other diagnostic groups. In both age-groups, the course of HRQOL of children with a CNS tumor showed little or no improvement. Small to moderate associations (ß: 0.18 to 0.67, p < 0.05) with disease characteristics were found. Centralized care related to better HRQOL (ß: 0.25 to 0.44, p < 0.05). Caregiver distress was most consistently associated with worse HRQOL (ß: - 0.13 to - 0.48, p < 0.01). CONCLUSIONS: The HRQOL course presented can aid in identifying children who have not fully recovered their HRQOL following cancer diagnosis, enabling early recognition of the issue. Future research should focus on ways to support children, especially those with a CNS tumor, for example by decreasing distress in their caregivers.

Fatigue mediates the relationship between emotional and cognitive functioning in children post-cancer treatment.

BACKGROUND/OBJECTIVES: Children treated for cancer are at risk to develop cognitive problems. Insight in underlying associations with emotional functioning and fatigue can be used to optimize interventions. We therefore aim to study emotional functioning, fatigue, and cognitive functioning in children postcancer treatment and investigate whether fatigue mediates the relationship between emotional and cognitive functioning. DESIGN/METHODS: Emotional functioning, fatigue, and cognitive functioning were assessed in children post-cancer treatment using subscales of the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales, Multidimensional Fatigue Scale and Cognitive Functioning Scale. A one sample t-test was used to compare outcomes with general population peers and mediation analysis was used to address the effect of fatigue on the relationship between emotional and cognitive functioning. RESULTS: A total of 137 children (mean age: 13.6, SD ± 3.3 years; mean time since end of treatment: 7.1 months, SD ± 5.9) participated. Lower scores on emotional functioning (Cohen's d [D]: 0.4), fatigue (D: 0.8) and cognitive functioning (D: 0.6) were found (p < .001) in children post-cancer treatment than in peers. A medium association was found between emotional and cognitive functioning (standardized regression coefficient [ß]: 0.27, p < .001), which was mediated by fatigue (ß = 0.16). CONCLUSIONS: Outcomes on emotional and cognitive functioning are decreased and fatigue is increased in children postcancer treatment. Fatigue mediates the relationship between emotional and cognitive functioning. Our results show the importance to focus on fatigue amongst stress as a target for intervention to improve cognitive functioning.

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.

Psychosocial functioning of adult siblings of Dutch very long-term survivors of childhood cancer: DCCSS-LATER 2 psycho-oncology study.

OBJECTIVE: To describe psychosocial outcomes among adult siblings of very long-term childhood cancer survivors (CCS), to compare these outcomes to reference populations and to identify factors associated with siblings' psychosocial outcomes. METHODS: Siblings of survivors (diagnosed <18 years old, between 1963 and 2001, >5 years since diagnosis) of the Dutch Childhood Cancer Survivor Study DCCSS-LATER cohort were invited to complete questionnaires on HRQoL (TNO-AZL Questionnaire for Adult's HRQoL), anxiety/depression (Hospital Anxiety and Depression Scale), post-traumatic stress (Self-Rating Scale for Post-traumatic Stress Disorder), self-esteem (Rosenberg Self-Esteem Scale) and benefit and burden (Benefit and Burden Scale for Children). Outcomes were compared to a reference group if available, using Mann-Whitney U and chi-Square tests. Associations of siblings' sociodemographic and CCS' cancer-related characteristics with the outcomes were assessed with mixed model analysis. RESULTS: Five hundred five siblings (response rate 34%, 64% female, mean age 37.5, mean time since diagnosis 29.5) of 412 CCS participated. Siblings had comparable HRQoL, anxiety and self-esteem to references with no or small differences (r = 0.08-0.15, p < 0.05) and less depression. Proportions of symptomatic PTSD were very small (0.4%-0.6%). Effect sizes of associations of siblings' sociodemographic and CCS cancer-related characteristics were mostly small to medium (ß = 0.19-0.67, p < 0.05) and no clear trend was found in the studied associated factors for worse outcomes. CONCLUSIONS: On the very long-term, siblings do not have impaired psychosocial functioning compared to references. Cancer-related factors seem not to impact siblings' psychosocial functioning. Early support and education remain essential to prevent long-term consequences.

A joint international consensus statement for measuring quality of survival for patients with childhood cancer.

The aim of treating childhood cancer remains to cure all. As survival rates improve, long-term health outcomes increasingly define quality of care. The International Childhood Cancer Outcome Project developed a set of core outcomes for most types of childhood cancers involving relevant international stakeholders (survivors; pediatric oncologists; other medical, nursing or paramedical care providers; and psychosocial or neurocognitive care providers) to allow outcome-based evaluation of childhood cancer care. A survey among healthcare providers (n = 87) and online focus groups of survivors (n = 22) resulted in unique candidate outcome lists for 17 types of childhood cancer (five hematological malignancies, four central nervous system tumors and eight solid tumors). In a two-round Delphi survey, 435 healthcare providers from 68 institutions internationally (response rates for round 1, 70-97%; round 2, 65-92%) contributed to the selection of four to eight physical core outcomes (for example, heart failure, subfertility and subsequent neoplasms) and three aspects of quality of life (physical, psychosocial and neurocognitive) per pediatric cancer subtype. Measurement instruments for the core outcomes consist of medical record abstraction, questionnaires and linkage with existing registries. This International Childhood Cancer Core Outcome Set represents outcomes of value to patients, survivors and healthcare providers and can be used to measure institutional progress and benchmark against peers.

Unraveling Dexamethasone-Induced Neurobehavioral and Sleep Problems in Children With ALL: Which Determinants Are Important?

PURPOSE: Dexamethasone, the preferred corticosteroid in most treatment protocols for pediatric acute lymphoblastic leukemia (ALL), can induce undesirable side effects. Neurobehavioral and sleep problems are frequently reported, but the interpatient variability is high. We therefore aimed to identify determinants for parent-reported dexamethasone-induced neurobehavioral and sleep problems in pediatric ALL. METHODS: Our prospective study included patients with medium-risk ALL and their parents during maintenance treatment. Patients were assessed before and after one 5-day dexamethasone course. Primary end points were parent-reported dexamethasone-induced neurobehavioral and sleep problems, measured with the Strengths and Difficulties Questionnaire and Sleep Disturbance Scale for Children, respectively. Analyzed determinants included patient and parent demographics, disease and treatment characteristics, parenting stress (Parenting Stress Index and Distress Thermometer for Parents), dexamethasone pharmacokinetics, and genetic variation (candidate single-nucleotide polymorphisms rs41423247 and rs4918). Statistically significant determinants identified in univariable logistic regression analyses were incorporated in a multivariable model. RESULTS: We included 105 patients: median age was 5.4 years (range, 3.0-18.8) and 61% were boys. Clinically relevant dexamethasone-induced neurobehavioral and sleep problems were reported by parents in 70 (67%) and 61 (59%) patients, respectively. In our multivariable regression models, we identified parenting stress as a significant determinant for parent-reported neurobehavioral (odds ratio [OR], 1.16; 95% CI, 1.07 to 1.26) and sleep problems (OR, 1.06; 95% CI, 1.02 to 1.10). Furthermore, parents who experienced more stress before start of a dexamethasone course reported more sleep problems in their child (OR, 1.16; 95% CI, 1.02 to 1.32). CONCLUSION: We identified parenting stress, and not dexamethasone pharmacokinetics, genetic variation, patient/parent demographics, or disease/treatment characteristics, as a significant determinant for parent-reported dexamethasone-induced neurobehavioral and sleep problems. Parenting stress may be a modifiable target to reduce these problems.

Hydrocortisone to reduce dexamethasone-induced neurobehavioral side-effects in children with acute lymphoblastic leukaemia-results of a double-blind, randomised controlled trial with cross-over design.

BACKGROUND: Dexamethasone is a cornerstone of paediatric acute lymphoblastic leukaemia (ALL) treatment, although it can induce serious side-effects. Our previous study suggests that children who suffer most from neurobehavioural side-effects might benefit from physiological hydrocortisone in addition to dexamethasone treatment. This study aimed to validate this finding. METHODS: Our phase three, double-blind, randomised controlled trial with cross-over design included ALL patients (3-18 years) during medium-risk maintenance therapy in a national tertiary hospital between 17th May 2018 and 5th August 2020. A baseline measurement before and after a 5-day dexamethasone course was performed, whereafter 52 patients with clinically relevant neurobehavioural problems were randomised to receive an intervention during four subsequent dexamethasone courses. The intervention consisted of two courses hydrocortisone (physiological dose 10 mg/m2/d in circadian rhythm), followed by two courses placebo, or vice versa. Neurobehavioural problems were assessed before and after each course using the parent-reported Strengths and Difficulties Questionnaire (SDQ) as primary end-point. Secondary end-points were sleep problems, health-related quality of life (HRQoL), hunger feeling, and parental stress, measured with questionnaires and actigraphy. A generalised mixed model was estimated to study the intervention effect. RESULTS: The median age was 5.5 years (range 3.0-18.8) and 61.5% were boys. The SDQ filled in by 51 primary caregivers showed no difference between hydrocortisone and placebo in reducing dexamethasone-induced neurobehavioral problems (estimated effect -2.05 (95% confidence interval (CI) -6.00-1.90). Also, no benefit from hydrocortisone compared to placebo was found for reducing sleep problems, hunger, parental stress or improving HRQoL. CONCLUSIONS: Hydrocortisone, when compared to placebo, had no additional effect in reducing clinically relevant dexamethasone-induced neurobehavioural problems. Therefore, hydrocortisone is not advised as standard of care for children with ALL who experience dexamethasone-induced neurobehavioural problems. TRIAL REGISTRATION: Netherlands Trial Register NTR6695/NL6507 (https://trialsearch.who.int/) and EudraCT 2017-002738-22 (https://eudract.ema.europa.eu/).

Positive and negative survivor-specific psychosocial consequences of childhood cancer: the DCCSS-LATER 2 psycho-oncology study.

PURPOSE: Numerous studies investigated generic psychosocial outcomes in survivors of childhood cancer (CCS). The present study aimed to describe survivor-specific psychosocial consequences in CCS, and to identify socio-demographic and medical associated factors. METHODS: CCS from the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER cohort (diagnosed 1963-2001) part 2 (age ≥ 18 years, diagnosed < 18 years, ≥ 5 years since diagnosis) completed the Benefit & Burden Scale (BBSC) and the Impact of Cancer-Childhood Cancer (IOC-CS). Items were scored on a 5-point Likert scale (range 1-5). We examined outcomes with descriptive statistics, and socio-demographic and medical associated factors with regression analyses, corrected for multiple testing (p < 0.004). RESULTS: CCS, N = 1713, age mean (M) 36 years, 49% female, ≥ 15 years since diagnosis, participated. On average, CCS reported 'somewhat' Benefit (M = 2.9), and 'not at all' to 'a little' Burden (M = 1.5) of childhood cancer. Average scores on IOC-CS' positive impact scales ranged from 2.5 (Personal Growth) to 4.1 (Socializing), and on the negative impact scales from 1.4 (Financial Problems) to 2.4 (Thinking/Memory). Apart from cognitive problems, CCS reported challenges as worries about relationship status, fertility, and how cancer had affected siblings. Female sex was associated with more Personal Growth, and more negative impact. CCS more highly educated, partnered, and employed had higher positive and lower negative impact. CCS older at diagnosis reported more positive impact. CNS tumor survivors and those who had head/cranium radiotherapy had higher negative impact. CNS tumor survivors reported less positive impact. CONCLUSION AND IMPLICATIONS: The majority of CCS reported positive impact of cancer while most CCS reported little negative impact. While this may indicate resiliency in most CCS, health care providers should be aware that they can also experience survivor-specific challenges that warrant monitoring/screening, information provision and psychosocial support.

Frailty and sarcopenia within the earliest national Dutch childhood cancer survivor cohort (DCCSS-LATER): a cross-sectional study.

BACKGROUND: Childhood cancer survivors appear to be at increased risk of frailty and sarcopenia, but evidence on the occurrence of and high-risk groups for these aging phenotypes is scarce, especially in European survivors. The aim of this cross-sectional study was to assess the prevalence of and explore risk factors for pre-frailty, frailty, and sarcopenia in a national cohort of Dutch childhood cancer survivors diagnosed between 1963 and 2001. METHODS: Eligible individuals (alive at the time of study, living in the Netherlands, age 18-45 years, and had not previously declined to participate in a late-effects study) from the Dutch Childhood Cancer Survivor Study (DCCSS-LATER) cohort were invited to take part in this cross-sectional study. We defined pre-frailty and frailty according to modified Fried criteria, and sarcopenia according to the European Working Group on Sarcopenia in Older People 2 definition. Associations between these conditions and demographic and treatment-related as well as endocrine and lifestyle-related factors were estimated with two separate multivariable logistic regression models in survivors with any frailty measurement or complete sarcopenia measurements. FINDINGS: 3996 adult survivors of the DCCSS-LATER cohort were invited to participate in this cross-sectional study. 1993 non-participants were excluded due to lack of response or a decline to participate and 2003 (50·1%) childhood cancer survivors aged 18-45 years were included. 1114 (55·6%) participants had complete frailty measurements and 1472 (73·5%) participants had complete sarcopenia measurements. Mean age at participation was 33·1 years (SD  7·2). 1037 (51·8%) participants were male, 966 (48·2%) were female, and none were transgender. In survivors with complete frailty measurements or complete sarcopenia measurements, the percentage of pre-frailty was 20·3% (95% CI 18·0-22·7), frailty was 7·4% (6·0-9·0), and sarcopenia was 4·4% (3·5-5·6). In the models for pre-frailty, underweight (odds ratio [OR] 3·38 [95% CI 1·92-5·95]) and obesity (OR 1·67 [1·14-2·43]), cranial irradiation (OR 2·07 [1·47-2·93]), total body irradiation (OR 3·17 [1·77-5·70]), cisplatin dose of at least 600 mg/m2 (OR 3·75 [1·82-7·74]), growth hormone deficiency (OR 2·25 [1·23-4·09]), hyperthyroidism (OR 3·72 [1·63-8·47]), bone mineral density (Z score ≤-1 and >-2, OR 1·80 [95% CI 1·31-2·47]; Z score ≤-2, OR 3·37 [2·20-5·15]), and folic acid deficiency (OR 1·87 [1·31-2·68]) were considered significant. For frailty, associated factors included age at diagnosis between 10-18 years (OR 1·94 [95% CI 1·19-3·16]), underweight (OR 3·09 [1·42-6·69]), cranial irradiation (OR 2·65 [1·59-4·34]), total body irradiation (OR 3·28 [1·48-7·28]), cisplatin dose of at least 600 mg/m2 (OR 3·93 [1·45-10·67]), higher carboplatin doses (per g/m2; OR 1·15 [1·02-1·31]), cyclophosphamide equivalent dose of at least 20 g/m2 (OR 3·90 [1·65-9·24]), hyperthyroidism (OR 2·87 [1·06-7·76]), bone mineral density Z score ≤-2 (OR 2·85 [1·54-5·29]), and folic acid deficiency (OR 2·04 [1·20-3·46]). Male sex (OR 4·56 [95%CI 2·26-9·17]), lower BMI (continuous, OR 0·52 [0·45-0·60]), cranial irradiation (OR 3·87 [1·80-8·31]), total body irradiation (OR 4·52 [1·67-12·20]), hypogonadism (OR 3·96 [1·40-11·18]), growth hormone deficiency (OR 4·66 [1·44-15·15]), and vitamin B12 deficiency (OR 6·26 [2·17-1·81]) were significantly associated with sarcopenia. INTERPRETATION: Our findings show that frailty and sarcopenia occur already at a mean age of 33 years in childhood cancer survivors. Early recognition and interventions for endocrine disorders and dietary deficiencies could be important in minimising the risk of pre-frailty, frailty, and sarcopenia in this population. FUNDING: Children Cancer-free Foundation, KiKaRoW, Dutch Cancer Society, ODAS Foundation.