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Background: Parents of children with cancer are at risk for impaired health-related quality of life (HRQoL). Most prior research has focused on the HRQoL of mothers. The aim of this study is to describe HRQoL in mothers and fathers, and determine the influence of sociodemographic, medical, and psychosocial factors., Procedure: In a cross-sectional study, both parents completed questionnaires on sociodemographics, distress, and HRQoL. Parental HRQoL was compared to healthy population values. Differences between mothers and fathers were evaluated with multilevel analysis. Gender-specific HRQoL determinants were assessed via multiple linear regression analysis., Results: Parents (202 mothers, 150 fathers; comprising 121 couples) of 231 children with different cancer diagnoses (mean time since diagnosis 3.3 ± 1.4 years, 90% posttreatment) participated. Compared to healthy women and men, mothers and fathers reported significantly impaired HRQoL on the following domains: cognitive functioning, sleep, daily activities, and vitality (Cohen's d = 0.3-0.9). Additionally, maternal HRQoL was reduced on the domains gross motor functioning, pain, social functioning, sexuality, and depressive emotions. Mothers scored worse than fathers on six of 12 domains. Risk factors for adverse outcomes in both parents were higher distress, emotional and parenting problems, little social support, medication use, and active treatment of the child. Other determinants in mothers were non-Dutch background and unemployment, while lower HRQoL in fathers was predicted by their child's diagnosis type, shorter time since diagnosis, and treatment intensity., Conclusion: These outcomes illustrate the need for family-centered care. Future interventions aimed at improving parental functioning should take into account gender-specific differences in HRQoL to reach optimal efficacy., (© 2019 The Authors. Pediatric Blood & Cancer Published by Wiley Periodicals, Inc.)

Background: Sleep problems are common in adolescents and can have a negative impact on daily functioning and quality of life; therefore recognition of sleep problems is important. The PROMIS (Patient-Reported Outcomes Information System) Sleep Disturbance (SD) and Sleep Related Impairment (SRI) items banks are internationally used, well-validated instruments developed for and tested in adults. This study evaluates the content validity of the self- and proxy versions of the PROMIS-SD and the PROMIS-SRI in adolescents., Methods: Experts (n = 6), adolescents (n = 24, 12-18 years) and their parents (n = 7) commented on the relevance and comprehensibility of the item banks., Results: Experts considered all items relevant, only a few items were found irrelevant by adolescents and parents. The majority of items were comprehensible. The ability of parents to report on their adolescent's sleep was limited., Conclusion: The PROMIS-SD and PROMIS-SRI have adequate content validity in adolescents. Considering their psychometric robustness and the possibility of Computerized Adaptive Testing, which is efficient as well as patient-friendly, these item banks could prove very useful in the evaluation of adolescent sleep. The validity of the proxy scales, however, is limited considering the difficulties reported by the parents. Further psychometric evaluation of these scales in adolescents is required.

Purpose: Improvement in survival of pediatric acute lymphoblastic leukemia (ALL) has increased the attention to quality of life (QoL) . QoL is impaired during maintenance treatment, but little is known about QoL during induction therapy. Identification of patients with poor QoL during induction will provide opportunities for early interventions, and may subsequently improve future QoL. This national multi-center study aimed to assess QoL and its determinants during ALL induction treatment., Methods: Proxy reports of the Child Health Questionnaire (CHQ) and the PedsQL cancer version were collected. Child, treatment, and parental characteristics were analyzed as potential determinants in a multiple regression model., Results: One hundred thirty parents of children participated (response rate 82 %), median child age was 5.7 years and 48 % were female. QoL, as measured with the CHQ, was significantly lower than the norm, the effect sizes were large, and the differences were clinically relevant. Physical QoL was more often affected than psychosocial QoL. Regression models could be constructed for 4/ 10 CHQ scales and 6/ 8 PedsQL cancer scales, accounting for 7 to 36 % of the variance in scores. Impaired QoL was most often associated with older children, girls, and time since diagnosis. Also, father respondents seem to have a lower QoL perception compared to mother respondents although this needs to be confirmed in future research., Conclusions: Specific counseling for subsets of patients with a higher risk of low QoL during the early phases of therapy is warranted.

Background: Measuring utilities and health-related quality of life (HRQL) in children is challenging due to their cognitive abilities and changing developmental stages., Purpose: . To identify methodological issues on utility measurements in children, we performed a systematic review on utilities measured with a single instrument, the Health Utilities Index (HUI), in pediatric acute lymphoblastic leukemia (ALL). The secondary goal was to facilitate future cost-utility analyses without the need for time-consuming assessments. Data Sources. PubMed, Embase, Cochrane Library, CINAHL, and PsycINFO were searched from inception to June 2012. Studies had to report on utility scores in pediatric ALL, either on or after treatment, to be included., Results: . Fifteen studies were included. Most studies had methodological shortcomings, which mainly concerned, Study Design: and definition and representativeness of the study group. Utility scores were dependent on treatment variables, and there generally was an improvement in HRQL as treatment or survivorship advanced. In general, proxy-respondents were less reliable for subjective phenomena than for observable conditions. HUI2 and HUI3 scores were not interchangeable. Limitations. Studies may have been missed because no validated search method for utility studies exists, due to language bias or the exclusion of non-peer-reviewed papers., Conclusions: . Most studies in this review were methodologically suboptimal. Future developments should focus on including developmentally appropriate items for the whole pediatric age group. Adding disease-specific domains may enhance the sensitivity and responsiveness of instruments. Efforts should be undertaken to elicit valuation of health states from older children and teenagers as much as possible. For now, it remains difficult to make valid and informed decisions on the financing of interventions until health state valuation in children has become more methodologically robust.

Asparaginase is an expensive drug, but important in childhood acute lymphoblastic leukemia. In order to compare costs of PEGasparaginase, Erwinia asparaginase and native E. coli asparaginase, we performed a cost-analysis in the Dutch Childhood Oncology Group ALL-10 medium-risk group intensification protocol. Treatment costs were calculated based on patient level data of 84 subjects, and were related to the occurrence of allergy to PEGasparaginase. Simultaneously, decision tree and sensitivity analyses were conducted. The total costs of the intensification course of 30 weeks were $57,893 in patients without PEGasparaginase allergy (n=64). The costs were significantly higher ($113,558) in case of allergy (n=20) necessitating a switch to Erwinia asparaginase. Simulated scenarios (decision tree analysis) using native E. coli asparaginase in intensification showed that the costs of PEGasparaginase were equal to those of native E. coli asparaginase. Also after sensitivity analyses, the costs for PEGasparaginase were equal to those of native E. coli asparaginase. Intensification treatment with native E. coli asparaginase, followed by a switch to PEGasparaginase, and subsequently to Erwinia asparaginase in case of allergy had similar overall costs compared to the treatment with PEGasparaginase as the first-line drug (followed by Erwinia asparaginase in the case of allergy). PEGasparaginase is preferred over native E. coli asparaginase, because it is administered less frequently, with less day care visits. PEGasparaginase is less immunogenic than native E. coli asparaginase and is not more expensive. Asparaginase costs are mainly determined by the percentage of patients who are allergic and require a switch to Erwinia asparaginase.

Purpose: Increase of survival in pediatric acute lymphoblastic leukemia (ALL) has made outcomes such as health-related quality of life (HRQL) and economic burden more important. To make informed decisions on the use of healthcare resources, costs as well as utilities need to be taken into account. Among the preference-based HRQL instruments, the Health Utilities Index (HUI) is the most employed in pediatric cancer. Information on utility scores during ALL treatment and in long-term survivors is available, but utility scores in short-term survivors are lacking. This study assesses utility scores, health state, and HRQL in short-term (6 months to 4 years) ALL survivors., Methods: Cross-sectional single-center cohort study of short-term ALL survivors using HUI3 proxy assessments., Results: Thirty-three survivors (median 1.5 years off treatment) reported 14 unique health states. The majority of survivors (61 %) enjoyed a perfect health, but 21 % had three affected attributes. Overall, HRQL was nonsignificantly lower compared to the norm, although the difference was large and may be clinically relevant. Cognition was significantly impaired (p = 0.03)., Conclusion: Although 61 % of short-term survivors of ALL report no impairment, the health status of the other patients lead to a clinically important impaired HRQL compared to norms. Prospective studies assessing utility scores associated with pediatric ALL should be performed, enabling valid and reliable cost-utility analyses for policy makers to make informed decisions.

Background: With the improved survival of childhood acute lymphoblastic leukemia (ALL), the effect of treatment on psychosocial well-being becomes increasingly relevant. Literature on sleep and fatigue during treatment is emerging. However, information on these subjects after treatment is sparse. This cross-sectional study examined sleep and fatigue in relation to depression and quality of life (QoL) after treatment for childhood ALL., Procedure: Sleep, fatigue, depression, and QoL were evaluated by parent proxy and/or child self-reports of the Children's Sleep Habits Questionnaire, the PedsQL™ multidimensional fatigue scale, the Children's Depression Inventory and the Child Health Questionnaire. All total scores were compared to Dutch norm references., Results: Sixty-two children were included, being 36 (interquartile range 22-62) months after finishing treatment. Parents rated the ALL survivors as having more disturbed sleep, more fatigue and poorer physical QoL compared to the Dutch norm. ALL survivors themselves reported less sleep problems, less depressive symptoms, and better psychosocial QoL than the Dutch norm. More sleep disturbances and fatigue correlated with more symptoms of depression and a worse QoL., Conclusions: Differences in parental and self-reports, including worse parental ratings, might be explained by worried parents and/or the adaptive style of the children. Impaired sleep and fatigue correlated with more depressive symptoms and a worse QoL., (Copyright © 2012 Wiley Periodicals, Inc.)

Of all malignancies in children, acute lymphoblastic leukemia (ALL) is the most common type. Since survival significantly improves over time, treatment-related side effects become increasingly important. Glucocorticoids play an important role in the treatment of ALL, but they may suppress the hypothalamic-pituitary-adrenal (HPA) axis. The duration of HPA axis suppression is not yet well defined. The present study aimed at assessing the function of the HPA axis by determining the cortisol awakening response (CAR) and the dexamethasone (DEX) suppression test in children that were treated for childhood ALL, compared to a healthy age and sex matched reference group. In addition, questionnaires regarding sleep, fatigue, depression and quality of life were completed by the children and their parents. Fourty-three survivors who finished their treatment for childhood ALL 37 (interquartile range 22-75) months before and 57 healthy controls were included. No differences in CAR were observed between ALL survivors and the reference group, but survivors of ALL had higher morning cortisol levels and an increased cortisol suppression in response to oral dexamethasone. Higher cortisol levels in childhood ALL survivors were associated with more fatigue and poorer quality of life. We conclude that the experience of a stressful life event in the past may have caused a long-term dysregulation of the HPA axis in childhood ALL survivors, as reflected in an increased cortisol production and an enhanced negative feedback mechanism., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Survival for childhood acute lymphoblastic leukemia (ALL) has reached 80-90%. Future improvement in treatment success will involve new technologies and medication, adding to the pressure on limited financial resources. Therefore a retrospective cost-effectiveness analysis of ALL treatment with chemotherapy only according to the two most recent Dutch Childhood Oncology Group treatment protocols was performed. The most recent protocol ALL10 included more expensive medication (pegasparaginase) and implemented a new diagnostic technique (minimal residual disease levels) compared to the previous ALL9 protocol., Procedure: Fifty children from a single center cohort were included. All direct medical costs made during treatment, including those in satellite hospitals, were determined. Costs per life year saved (LYS) were calculated. The cost-effectiveness ratio of the most recent treatment protocol was determined. LYS were calculated based on national 5-year event-free survival., Results: Mean total costs were between $115,858 (ALL9) and $163,350 (ALL10) per patient. Hospital admissions (57%) and medication (11-17%) were important drivers of overall costs, and were higher in the most recent protocol ALL10. Costs per LYS were $1,962 (ALL9) and $2,655 (ALL10) and the cost-effectiveness ratio was $8,215., Conclusion: Treatment of childhood ALL with chemotherapy only is well within accepted ranges of cost-effectiveness. The use of new technology and more expensive medication in the most recent protocol ALL10 lead to higher costs but more LYS. In future (ALL) treatment protocols, costs in relation to effects should be taken into account in order to establish more cost-effective disease management without jeopardizing survival and quality of life., (Copyright © 2011 Wiley-Liss, Inc.)

Background: With the increase of pediatric cancer survival rates, late effects and quality of life (QoL) have received more attention. Disturbed sleep in pediatric cancer is a common clinical observation, but research on this subject is sparse. In general, sleep problems can lead to significant morbidity and are associated with impaired QoL. Information on sleep is essential to develop interventions to improve QoL., Methods: Children (2-18 years) with acute lymphoblastic leukemia (ALL) were eligible for this multi-center study. The Children's Sleep Habits Questionnaire (CSHQ), Child Health Questionnaire (CHQ) and Pediatric Quality of Life Inventory 3.0™ Acute Cancer Version (PedsQL) were used to assess sleep and QoL halfway through maintenance therapy. Sleep and QoL were measured during and after dexamethasone treatment (on-dex and off-dex)., Results: Seventeen children participated (age 6.7 ± 3.3 years, 44% boys). Children with ALL had more sleep problems and a lower QoL compared to the norm. There were no differences on-dex and off-dex. Pain (r = -0.6; p = 0.029) and worry (r = -0.5; p = 0.034) showed a moderate negative association with sleep. Reduced overall QoL was moderately associated with impaired overall sleep (r = -0.6; p = 0.014) and more problems with sleep anxiety (r = -0.8; p = 0.003), sleep onset delay (r = -0.5; p = 0.037), daytime sleepiness (r = -0.5; p = 0.044) and night wakenings (r = -0.6; p = 0.017)., Conclusion: QoL is impaired in children during cancer treatment. The results of this study suggest that impaired sleep may be a contributing determinant. Consequently, enhanced counseling and treatment of sleep problems might improve QoL. It is important to conduct more extensive studies to confirm these findings and provide more detailed information on the relationship between sleep and QoL, and on factors affecting sleep in pediatric ALL and in children with cancer in general.

Sleep disorders can lead to significant morbidity. Information on sleep in healthy children is necessary to evaluate sleep disorders in clinical practice, but data from different societies cannot be simply generalized. The aims of this study were to (1) assess the prevalence of sleep disturbances in Dutch healthy children, (2) describe sleep habits and problems in this population, (3) collect Dutch norm data for future reference, and (4) compare sleep in children from different cultural backgrounds. A population-based descriptive study was conducted using the Children's sleep habits questionnaire and the sleep self-report. One thousand five hundred seven proxy-reports and 262 self-reports were analyzed. Mean age was 8.5 years (95% confidence interval, 8.4-8.6), 52% were boys. Sleep problems in Dutch children were present in 25%, i.e., comparable to other populations. Sleep habits were age-related. Problem sleepers scored significantly higher on all scales. Correlations between parental and self-assessments were low to moderate. Dutch children had significantly more sleep disturbances than children from the USA and less than Chinese children. Cognitions and attitudes towards what is considered normal sleep seem to affect the appraisal of sleep, this probably accounts partly for cultural differences. For a better understanding of cultural influences on sleep, more information on these determinants and the establishment of cultural norms are mandatory.

Background: Glucocorticoids are important in the treatment of childhood acute lymphoblastic leukaemia (ALL). However, cyclic administration of high dose glucocorticoids may cause rapid and substantial changes in quality of life (QoL). The maintenance phase of the Dutch ALL-9 protocol consisted of alternating two weeks on and five weeks off dexamethasone (6 mg/m(2)/day). The present study was performed to assess the effect of dexamethasone on QoL during treatment for ALL according to this protocol., Methods: In a multicentre prospective cohort study, QoL was assessed halfway (T1) and at the end of the two-year treatment (T2). A generic (Child Health Questionnaire) and disease specific (PedsQL cancer version) QoL questionnaire were used to assess QoL in two periods: on and off dexamethasone, respectively., Results: 41 children (56% males) were evaluated, mean age at diagnosis was 5.6 years. The CHQ physical and psychosocial summary scores were significantly lower than population norms. At T1 and T2, overall QoL showed no significant change. However, regarding specific domains (pain, cognitive functioning, emotion/behaviour and physical functioning) QoL decreased over time. QoL was significantly more impaired during periods on dexamethasone., Conclusion: Dexamethasone was associated with decreased QoL. At the end of treatment, reported QoL during dexamethasone deteriorated even more on certain scales (pain, cognitive functioning, emotion/behaviour and physical functioning). Knowledge of the specific aspects of QoL is essential to improve counselling and coping in paediatric oncology. Adverse effects of specific drugs on QoL should be taken into account when designing treatment protocols.

Objective: To describe the incidence, survival, and neurologic outcome of in-intensive-care-unit (ICU) cardiac arrest and to identify factors predictive of survival to hospital discharge., Methods: We performed a retrospective cohort study. Eligible patients were <18 yrs of age and experienced a cardiac arrest during their admission to a multidisciplinary pediatric intensive care unit in the 5.5-yr period ending June 2002. Cardiac arrest was defined as the administration of chest compressions or defibrillation for a nonperfusing cardiac rhythm. Mortality and the Paediatric Cerebral Performance Score were measured and presented according to the Utstein style. Factors predictive of survival to hospital discharge were identified by univariate analysis and independent predictors were identified by multivariate analysis., Main Measurements and Results: Ninety-one children had cardiac arrest, yielding an incidence of 0.94 cardiac arrests per 100 admissions. Resuscitation was successful in 75 (82%) children, 61 (67%) survived 24 hrs, 25 (27%) children survived to ICU discharge and 23 (25%) to hospital discharge. At hospital discharge, the median Pediatric Cerebral Performance Category score was 2 (range, 1-3) and the median Pediatric Overall Performance Category score was 3 (range, 1-4). No child was assessed as normal on both scores. The independent positive predictors of hospital mortality were the presence of renal failure before cardiac arrest (odds ratio [OR], 6.1; 95% confidence interval [CI], 1.8-31), being on epinephrine infusion at time of cardiac arrest (OR, 9.5; 95% CI, 1.5-62), and the administration of one or more calcium boluses during resuscitation (OR, 5.4; 95% CI, 1.1-25). The use of extracorporeal membrane oxygenation (ECMO) within 24 hrs after cardiac arrest was associated with reduced hospital mortality (OR, 0.18; 95% CI, 0.04-0.76)., Conclusions: In-ICU cardiac arrest is associated with high in-hospital mortality and subsequent morbidity in survivors. Prearrest renal dysfunction and epinephrine infusion were associated with increased in-hospital mortality. The use of post-arrest ECMO within 24 hrs was associated with reduced mortality. Rigorous prospective evaluation of the role of ECMO following cardiac arrest is needed.