Transatlantic progress in measurement of cognitive outcomes in paediatric oncology trials.

The importance of measuring quality of survival within paediatric oncology trials is increasingly recognised. However, capturing neuropsychological outcomes and other aspects of quality of survival in the context of large or multinational trials can be challenging. We provide examples of protocols designed to address this challenge recently employed in clinical trials in the USA and Europe. We discuss their respective strengths and challenges, obstacles encountered and future opportunities for transatlantic collaboration.

Does a Bevacizumab-based regime have a role in the treatment of children with diffuse intrinsic pontine glioma? A systematic review.

Background: There are no effective treatments for diffuse intrinsic pontine glioma (DIPG); median survival is 11.2 months. Bevacizumab has the potential to improve quality of life (QOL) and survival in DIPG but has never been evaluated systematically. The aim of this review was to assess Bevacizumab's role in the treatment of DIPG. Methods: MEDLINE, EMBASE, Scopus, and Web of Science were searched for relevant studies using terms developed from alternatives for Bevacizumab and DIPG. One reviewer screened titles and abstracts, then two reviewers screened full texts. Data were extracted into tables and quality assessed using methodological index for non-randomized studies and JBI tools. Results: Searching revealed 1001 papers; after deduplication 851 remained. After screening of titles and abstracts, then 28 full texts, 11 studies were included. Four studies reported a median overall survival longer than historical data, however, two found no significant impact of Bevacizumab. Five studies reported a radiological response in a proportion of participants and two reported no response. Three studies, evaluating clinical response, reported improvement in a proportion of patients. Three studies, evaluating QOL, reported stability or improvement. Four studies, evaluating steroid use, reported reductions in the proportion of patients receiving steroids. In radiation necrosis treatment, Bevacizumab led to clinical improvement in 6/12 patients in 2 studies and permitted a reduction in steroid use in most patients. Conclusions: Insufficient evidence means the role of Bevacizumab in the treatment of DIPG is unclear. However, Bevacizumab may be beneficial to some patients. The review highlights the need for further research in this area.

Paediatric health-related quality of life in congenital cytomegalovirus.

OBJECTIVE: Congenital cytomegalovirus (cCMV) is the most common congenital infection globally. This cross-sectional study aimed to describe the health-related quality of life (HRQoL) of children with cCMV and that of their parents. METHODS: Families of children with cCMV in the UK were approached through the charity CMV Action. Parents completed questionnaires about their own HRQoL and that of their child. Children who were able to self-report completed questionnaires about their own HRQoL. Demographic characteristics of the sample were described using descriptive statistics. Questionnaire responses were scored, and domain and summary scores were calculated and compared with UK population norms, where available. RESULTS: Seventy families participated, with children aged between 5 months and 18 years. Children with cCMV had poorer HRQoL compared with children from UK population data. HRQoL of children whose health was more severely affected by cCMV was poorer than that of children whose health was less severely affected. Parents of children whose health was moderately or severely affected had greater psychological morbidity and poorer HRQoL in physical, emotional, social, and cognitive functioning domains than parents of less severely affected children. CONCLUSIONS: cCMV has a significant effect on the HRQoL of children with cCMV and their parents, with the children with the most significant health needs having the lowest HRQoL compared with those children with little or no effects on their health. This data could contribute to health economic analyses, informing resource allocation to potential interventions for the prevention and treatment of cCMV.

Additional validation study and French cross-cultural adaptation of the Pediatric Stroke Outcome Measure-Summary of Impressions (PSOM-SOI).

BACKGROUND: The Pediatric Stroke Outcome Measure-Summary of Impressions (PSOM-SOI) measures neurological function across right and left sensorimotor domains (Item A), language production (Item B), language comprehension (Item C), and cognition/behaviour (Item D). OBJECTIVE: This study was a cross-cultural adaptation into French of the PSOM-SOI and an assessment of its reliability and limitations of use. MATERIAL AND METHODS: The translation and adaptation of the PSOM-SOI was followed by the assessment of its reliability in a cohort of 69 children with diagnosed acute neonatal arterial ischemic stroke. Three independent raters retrospectively scored the PSOM-SOI based on data from in-person neurological examination and results of standardized tests performed at age 7 in the cohort database. Comparison 1 (C1) involved a less experienced rater and an experienced rater and comparison 2 (C2) involved 2 experienced raters. Inter-rater reliability (IRR) was measured with Kappa coefficients. RESULTS: The cross-cultural adaptation was easily performed, and no rater had difficulties using the French PSOM-SOI. The IRR was better in C1 than C2. For Item A, the agreement in C1 (κ=0.47) and C2 (κ=0.44) was moderate. The C1 agreement was substantial for Items B (κ=0.71) and C (κ=0.70); the C2 agreement was fair for Item B (κ=0.23) and slight for Item C (κ=0.16). For Item D, the agreement was moderate in C1 (κ=0.52) and fair in C2 (κ=0.35). In all but one comparison, agreement or minor disagreement (≤0.5 points) was obtained for more than 90% of the item scores. Regarding the total score, agreement for normal function (≤0.5) versus abnormal function (>0.5) was achieved for 90% in C1 and 67% in C2. CONCLUSION: The IRR of the French PSOM-SOI gave variable results depending on the item and rater's experience, but the extent of disagreements was minor for individual items and total score. Additional prospective validation studies using the French PSOM-Short Neurological Exam to score the PSOM-SOI are needed. A dichotomised total score (cut-off≤0.5) could be used to define normal function versus poor outcome.

Systematic review: measurement properties of patient-reported outcome measures evaluated with childhood brain tumor survivors or other acquired brain injury.

BACKGROUND: Survivors of childhood brain tumors or other acquired brain injury (ABI) are at risk of poor health-related quality of life (HRQoL); its valid and reliable assessment is essential to evaluate the effect of their illness on their lives. The aim of this review was to critically appraise psychometric properties of patient-reported outcome measures (PROMs) of HRQoL for these children, to be able to make informed decisions about the most suitable PROM for use in clinical practice. METHODS: We searched MEDLINE, EMBASE, and PsycINFO for studies evaluating measurement properties of HRQoL PROMs in children treated for brain tumors or other ABI. Methodological quality of relevant studies was evaluated using the consensus-based standards for the selection of health status measurement instruments checklist. RESULTS: Eight papers reported measurement properties of 4 questionnaires: Health Utilities Index (HUI), PedsQL Core and Brain Tumor Modules, and Child and Family Follow-up Survey (CFFS). Only the CFFS had evidence of content and structural validity. It also demonstrated good internal consistency, whereas both PedsQL modules had conflicting evidence regarding this. Conflicting evidence regarding test-retest reliability was reported for the HUI and PedsQL Core Module only. Evidence of measurement error/precision was favorable for HUI and CFFS and absent for both PedsQL modules. All 4 PROMs had some evidence of construct validity/hypothesis testing but no evidence of responsiveness to change. CONCLUSIONS: Valid and reliable assessment is essential to evaluate impact of ABI on young lives. However, measurement properties of PROMs evaluating HRQoL appropriate for this population require further evaluation, specifically construct validity, internal consistency, and responsiveness to change.

Video Analysis of Parent-Child Interactions in Behavioral Sleep Disorders: Development of a Scoring Algorithm.

Introduction: Behavioral sleep disorders, including chronic insomnia (CI), are generally assessed by subjective parent interview. However, evidence suggests that parental report of children's overnight behaviors is unreliable, perhaps due to recall bias or confusion due to sleep deprivation. Video technology has been used clinically to capture complex behavioral disorders in children during the day. However, there is no standardized means of analyzing child and parent behavior at bedtime or during the night. We aimed to create an algorithm for this purpose. Methods: Child brain tumor survivors (a population previously shown to have a high prevalence of CI) were screened for difficulties initiating and maintaining sleep using sub-scales from the Sleep Disturbance Scale for Children. Those who screened positive (n = 3) then completed a detailed parent interview to confirm a clinical diagnosis of CI. One night of home video footage was obtained from initial settling period to morning waking (SOMNOmedics camera). Footage was imported into BORIS© software and a coding system for parent and child behavior was developed over multiple iterations until agreeable inter-rater reliability (>70%) was achieved between two independent coders. Results: The final coding categories were: 1) time domains, 2) physical environment, 3) child global status, 4) location, 5) activity, and 6) physical interaction. This achieved 74% inter-reliability in its last iteration. Discussion: A statistically acceptable behavior scoring algorithm was achieved. With further development, this tool could be applied clinically to investigate behavioral insomnia and in research to provide more objective outcome measurement.

Paediatric neuro-oncology rehabilitation in the UK: carer and provider perspectives.

OBJECTIVE: The provision of rehabilitation services after childhood brain tumour has not been established, despite a recent parliamentary call for urgent action. This service evaluation aimed to determine what specialist paediatric neuro-oncology rehabilitation services were available across the UK at the time of the surveys and whether the needs of patients and their families were being met. DESIGN: Cross-sectional on-line surveys. PARTICIPANTS: Survey 1: neuro-oncologist and nurse specialist members of the Children's Cancer and Leukaemia Group (CCLG) at Children's Principle Treatment Centres (PTCs) in the UK; Survey 2: parents of paediatric neuro-oncology patients belonging to The Brain Tumour Charity (TBTC) Research Involvement Network (RIN). RESULTS: 17 of the 20 (85%) PTCs in the UK and two teenagers and young adult cancer units responded to Survey 1, and 17 members of TBTC's RIN responded to Survey 2. Access to inpatient and outpatient neuro-oncology rehabilitation services after treatment for a central nervous system (CNS) tumour varied across regions in the UK. Service users in the RIN identified a need for an established neuro-oncology rehabilitation service for young people, a need for better communication across services and with families, and a need to fill gaps in multidisciplinary teams. CONCLUSION: The urgent need for specialist paediatric, teenage and young adult neuro-oncology rehabilitation services in the UK is often unmet, particularly for outpatients. Where services are not provided for those children and young people disadvantaged by the diagnosis of a CNS tumour, in clear breach of current guidelines, remedial action needs to be taken to ensure appropriate and equal access.

Quality of survival and cognitive performance in children treated for medulloblastoma in the PNET 4 randomized controlled trial.

BACKGROUND: The relationship between direct assessments of cognitive performance and questionnaires assessing quality of survival (QoS) is reported to be weak-to-nonexistent. Conversely, the associations between questionnaires evaluating distinct domains of QoS tend to be strong. This pattern remains understudied. METHODS: In the HIT-SIOP PNET4 randomized controlled trial, cognitive assessments, including Full Scale, Verbal and Performance IQ, Working Memory, and Processing Speed, were undertaken in 137 survivors of standard-risk medulloblastoma from 4 European countries. QoS questionnaires, including self-reports and/or parent reports of the Behavior Rating Inventory of Executive Function (BRIEF), the Health Utilities Index, the Strengths and Difficulties Questionnaire, and the Pediatric Quality of Life Inventory, were completed for 151 survivors. Correlations among direct cognitive assessments, QoS questionnaires, and clinical data were examined in participants with both assessments available (n = 86). RESULTS: Correlations between direct measures of cognitive performance and QoS questionnaires were weak, except for moderate correlations between the BRIEF Metacognition Index (parent report) and working memory (r = .32) and between health status (self-report) and cognitive outcomes (r = .35-.44). Correlations among QoS questionnaires were moderate to strong both for parent and self-report (r = .39-.76). Principal Component Analysis demonstrated that questionnaires and cognitive assessments loaded on 2 separate factors. CONCLUSIONS: We hypothesize that the strong correlations among QoS questionnaires is partially attributable to the positive/negative polarity of all questions on the questionnaires, coupled with the relative absence of disease-specific questions. These factors may be influenced by respondents' personality and emotional characteristics, unlike direct assessments of cognitive functioning, and should be taken into account in clinical trials.

Screening for cognitive deficits in 8 to 14-year old children with cerebellar tumors using self-report measures of executive and behavioral functioning and health-related quality of life.

BACKGROUND: We aimed to identify a brief screening measure for detection of cognitive deficit in children treated for cerebellar tumors that would be useful in clinical practice. METHODS: A sample of 72 children, aged 8-14 years, and within 3 years post diagnosis for standard-risk medulloblastoma (n = 37) or low-grade cerebellar astrocytoma (n = 35) and 38 children in a nontumor group were assessed using teacher-, parent-, and child-report of the Behavior Rating Inventory of Executive Function (BRIEF), Strengths and Difficulties Questionnaire (SDQ), and Pediatric Quality of Life Inventory (PedsQL). The accuracy of these scores as a screen for a full-scale Intelligence Quotient (FSIQ) < 80 on the Wechsler Intelligence Scale for Children (WISC-IV UK) was assessed using their receiver operating characteristic (ROC) curves. RESULTS: The questionnaires with the highest areas under the ROC curves were the child- and parent-report PedsQL, the teacher-report BRIEF, and the SDQ. At optimal cutoff scores, their sensitivities (95% CIs) to cases of FSIQ < 80 were 84 (60-96)%, 65 (41-84)%, 79 (54-93)%, and 84 (60-96)%, and their specificities (95% CIs) were 79 (68-86)%, 87 (77-93)%, 77 (66-86)%, and 71 (64-84)% respectively. All cases of FSIQ < 80 screened positive on either teacher-report SDQ or self-report PedsQL. CONCLUSIONS: The PedsQL child- and parent-report and the teacher-report BRIEF and SDQ have moderately good accuracy for discriminating between children with and without a FSIQ < 80. The PedsQL could be used in a clinical setting, and the BRIEF and SDQ in an educational setting, to screen for cases with FSIQ < 80 in children treated for brain tumors.

Quality of survival assessment in European childhood brain tumour trials, for children aged 5 years and over.

INTRODUCTION: There is increasing recognition of the long-term sequelae of brain tumours treated in childhood. Five year survival rates now exceed 75% and assessing the quality of survival (QoS) in multiple domains is essential to any comparison of the benefits and harms of treatment regimens. AIM: The aim of this position statement is to rationalise assessments and facilitate collection of a common data set across Europe. Sufficient numbers of observations can then be made to enable reliable comparisons between outcomes following different tumour types and treatments. METHODS: This paper represents the consensus view of the QoS working group of the Brain Tumour group of the European Society of Paediatric Oncology regarding domains of QoS to prioritise for assessment in clinical trials. This consensus between clinicians and researchers across Europe has been arrived at by discussion and collaboration over the last eight years. RESULTS: Areas of assessment discussed include core medical domains (e.g. vision, hearing, mobility, endocrine), emotion, behaviour, adaptive behaviour and cognitive functioning. CONCLUSIONS: A 'core plus' approach is suggested in which core assessments (both direct and indirect tests) are recommended for all clinical trials. The core component is a relatively brief screening assessment that, in most countries, is a sub-component of routine clinical provision. The 'plus' components enable the addition of assessments which can be selected by individual countries and/or tumour-, age-, and location-specific groups. The implementation of a QoS protocol common to all European clinical studies of childhood brain tumours is also discussed.

Neuropsychological Outcome of Children Treated for Standard Risk Medulloblastoma in the PNET4 European Randomized Controlled Trial of Hyperfractionated Versus Standard Radiation Therapy and Maintenance Chemotherapy.

PURPOSE: In the European HIT-SIOP PNET4 randomized controlled trial, children with standard risk medulloblastoma were allocated to hyperfractionated radiation therapy (HFRT arm, including a partially focused boost) or standard radiation therapy (STRT arm), followed, in both arms, by maintenance chemotherapy. Event-free survival was similar in both arms. Previous work showed that the HFRT arm was associated with worse growth and better questionnaire-based executive function, especially in children <8 years of age at diagnosis. Therefore, the aim of this study was to compare performance-based cognitive outcomes between treatment arms. METHODS AND MATERIALS: Neuropsychological data were collected prospectively in 137 patients. Using the Wechsler Intelligence Scales, Kaufman Assessment Battery for Children, and Raven's Progressive Matrices, we estimated full-scale intelligence quotient (FSIQ) and, when available, verbal IQ (VIQ), performance IQ (PIQ), working memory index (WMI), and processing speed index (PSI). RESULTS: Among the 137 participants (HFRT arm n=71, STRT arm n=66, 63.5% males), mean (±SD) ages at diagnosis and assessment respectively were 9.3 (±3.2) years of age (40.8% < 8 years of age at diagnosis) and 14.6 (±4.3) years of age. Mean (±SD) FSIQ was 88 (±19), and mean intergroup difference was 3.88 (95% confidence interval: -2.66 to 10.42, P=.24). No significant differences were found in children >8 years of age at diagnosis. In children <8 years of age at diagnosis, a marginally significant trend toward higher VIQ was found in those treated in the HFRT arm; a similar trend was found for PSI but not for PIQ, WMI, or FSIQ (mean intergroup differences were: 12.02 for VIQ [95% CI: 2.37-21.67; P=.02]; 3.77 for PIQ [95% CI: -5.19 to 12.74; P>.10]; 5.20 for WMI [95% CI: -2.07 to 12.47; P>.10]; 10.90 for PSI [95% CI: -1.54 to 23.36; P=.08]; and 5.28 for FSIQ [95% CI: -4.23 to 14.79; P>.10]). CONCLUSIONS: HFRT was associated with marginally higher VIQ in children <8 years of age at diagnosis, consistent with a previous report using questionnaire-based data. However, overall cognitive ability was not significantly different.

Child-related characteristics predicting subsequent health-related quality of life in 8- to 14-year-old children with and without cerebellar tumors: a prospective longitudinal study.

BACKGROUND: We identified child-related determinants of health-related quality of life (HRQoL) in children aged 8-14 years who were treated for 2 common types of pediatric brain tumors. METHODS: Questionnaire measures of HRQoL and psychometric assessments were completed by 110 children on 3 occasions over 24 months. Of these 110, 72 were within 3 years of diagnosis of a cerebellar tumor (37 standard-risk medulloblastoma, 35 low-grade cerebellar astrocytoma), and 38 were in a nontumor group. HRQoL, executive function, health status, and behavioral difficulties were also assessed by parents and teachers as appropriate. Regression modeling was used to relate HRQoL z scores to age, sex, socioeconomic status, and 5 domains of functioning: Cognition, Emotion, Social, Motor and Sensory, and Behavior. RESULTS: HRQoL z scores were significantly lower after astrocytoma than those in the nontumor group and significantly lower again in the medulloblastoma group, both by self-report and by parent-report. In regression modeling, significant child-related predictors of poorer HRQoL z scores by self-report were poorer cognitive and emotional function (both z scores) and greater age (years) at enrollment (B = 0.038, 0.098, 0.136, respectively). By parent-report, poorer cognitive, emotional and motor or sensory function (z score) were predictive of lower subsequent HRQoL of the child (B = 0.043, 0.112, 0.019, respectively), while age at enrollment was not. CONCLUSIONS: Early screening of cognitive and emotional function in this age group, which are potentially amenable to change, could identify those at risk of poor HRQoL and provide a rational basis for interventions to improve HRQoL.

Quality of survival and growth in children and young adults in the PNET4 European controlled trial of hyperfractionated versus conventional radiation therapy for standard-risk medulloblastoma.

PURPOSE: To compare quality of survival in "standard-risk" medulloblastoma after hyperfractionated radiation therapy of the central nervous system with that after standard radiation therapy, combined with a chemotherapy regimen common to both treatment arms, in the PNET4 randomised controlled trial. METHODS AND MATERIALS: Participants in the PNET4 trial and their parents/caregivers in 7 participating anonymized countries completed standardized questionnaires in their own language on executive function, health status, behavior, health-related quality of life, and medical, educational, employment, and social information. Pre- and postoperative neurologic status and serial heights and weights were also recorded. RESULTS: Data were provided by 151 of 244 eligible survivors (62%) at a median age at assessment of 15.2 years and median interval from diagnosis of 5.8 years. Compared with standard radiation therapy, hyperfractionated radiation therapy was associated with lower (ie, better) z-scores for executive function in all participants (mean intergroup difference 0.48 SDs, 95% confidence interval 0.16-0.81, P=.004), but health status, behavioral difficulties, and health-related quality of life z-scores were similar in the 2 treatment arms. Data on hearing impairment were equivocal. Hyperfractionated radiation therapy was also associated with greater decrement in height z-scores (mean intergroup difference 0.43 SDs, 95% confidence interval 0.10-0.76, P=.011). CONCLUSIONS: Hyperfractionated radiation therapy was associated with better executive function and worse growth but without accompanying change in health status, behavior, or quality of life.

Reduction of health status 7 years after addition of chemotherapy to craniospinal irradiation for medulloblastoma: a follow-up study in PNET 3 trial survivors on behalf of the CCLG (formerly UKCCSG).

PURPOSE: To compare quality of survival after craniospinal irradiation (CSI) alone with survival after CSI plus chemotherapy (CT) for medulloblastoma. PATIENTS AND METHODS: Follow-up study of surviving UK patients with medulloblastoma diagnosed between 1992 and 2000 treated according to one or other treatment arm of the PNET 3 controlled trial. RESULTS: Seventy three percent of all 147 eligible patients ages 6.6 to 24.3 years were assessed at a mean of 7.2 years after diagnosis. Health status was significantly poorer in the group treated in the CSI plus CT arm of the trial than in the CSI alone arm, and there were also trends to poorer outcomes for behavior and quality of life scores. The CSI plus CT group were also significantly more restricted physically and needed more therapeutic and educational support. Body mass index, stature, and other endocrine outcomes were similar in the two treatment arms, except for the trend in increased frequency of medical induction of puberty in the CSI plus CT group. CONCLUSION: The addition of CT to CSI for medulloblastoma was associated with a significant decrease in health status. The effect of the addition of other CT regimens to CSI on quality of survival should be evaluated.