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.

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.

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.

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.

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.