Communicating neurocognitive impacts of childhood cancer: Engaging stakeholders to identify research priorities.

OBJECTIVE: Supporting childhood cancer survivors with neurocognitive late effects is critical and requires additional attention in the research arena. This convening project's aim was to engage parents, healthcare providers, and education stakeholders in order to identify research priorities regarding patient/family-provider communication about neurocognitive impacts associated with childhood cancer. METHODS: Specific components of the Stakeholder Engagement in quEstion Development (SEED) method were combined with an online e-Delphi consensus building approach. Multiple modalities were utilized for engagement including in-person/hybrid meetings, email/Zoom/call communications, targeted-asynchronous learning activities by stakeholders, iterative surveys, and hands-on conceptual modeling. RESULTS: Twenty-four (parents n = 10, educators n = 5, healthcare providers n = 9) participated in the year-long project, generating 8 research questions in the stakeholder priority domains of training families/caregiver, access of neuropsychological assessment, tools to facilitate communication and training medical providers. CONCLUSIONS: This paper illustrates a successful stakeholder convening process using multi-modal engagement to establish research priorities. The resulting questions can be utilized to guide research projects that will fill gaps to providing optimal care to children with neurocognitive late effects. PRACTICE IMPLICATIONS: This process can be used as a template for tackling other healthcare issues that span across disciplines and domains, where stakeholders have rare opportunities to collaborate.

Children's Oncology Group's 2023 blueprint for research: Behavioral science.

As survival rates for childhood cancer have improved, there has been increasing focus on identifying and addressing adverse impacts of cancer and its treatment on children and their families during treatment and into survivorship. The Behavioral Science Committee (BSC) of the Children's Oncology Group (COG), comprised of psychologists, neuropsychologists, social workers, nurses, physicians, and clinical research associates, aims to improve the lives of children with cancer and their families through research and dissemination of empirically supported knowledge. Key achievements of the BSC include enhanced interprofessional collaboration through integration of liaisons into other key committees within COG, successful measurement of critical neurocognitive outcomes through standardized neurocognitive assessment strategies, contributions to evidence-based guidelines, and optimization of patient-reported outcome measurement. The collection of neurocognitive and behavioral data continues to be an essential function of the BSC, in the context of therapeutic trials that are modifying treatments to maximize event-free survival, minimize adverse outcomes, and optimize quality of life. In addition, through hypothesis-driven research and multidisciplinary collaborations, the BSC will also begin to prioritize initiatives to expand the systematic collection of predictive factors (e.g., social determinants of health) and psychosocial outcomes, with overarching goals of addressing health inequities in cancer care and outcomes, and promoting evidence-based interventions to improve outcomes for all children, adolescents, and young adults with cancer.

Impact of MEK Inhibitor Therapy on Neurocognitive Functioning in NF1.

BACKGROUND AND OBJECTIVES: Neurofibromatosis type 1 (NF1)-associated cognitive impairments carry significant lifelong morbidity. The lack of targeted biologic treatments remains a significant unmet need. We examine changes in cognition in patients with NF1 in the first 48 weeks of mitogen-activated protein kinase inhibitor (MEKi) treatment. METHODS: Fifty-nine patients with NF1 aged 5-27 years on an MEKi clinical trial treating plexiform neurofibroma underwent pretreatment and follow-up cognitive assessments over 48 weeks of treatment. Performance tasks (Cogstate) and observer-reported functioning (BRIEF) were the primary outcomes. Group-level (paired t tests) and individual-level analyses (Reliable Change Index, RCI) were used. RESULTS: Analysis showed statistically significant improvements on BRIEF compared with baseline (24-week Behavioral Regulation Index: t (58) = 3.03, p = 0.004, d = 0.24; 48-week Metacognition Index: t (39) = 2.70, p = 0.01, d = 0.27). RCI indicated that more patients had clinically significant improvement at 48 weeks than expected by chance (χ2 = 11.95, p = 0.001, odds ratio [OR] = 6.3). Group-level analyses indicated stable performance on Cogstate (p > 0.05). RCI statistics showed high proportions of improved working memory (24-week χ2 = 8.36, p = 0.004, OR = 4.6, and 48-week χ2 = 9.34, p = 0.004, OR = 5.3) but not visual learning/memory. Patients with baseline impairments on BRIEF were more likely to show significant improvement than nonimpaired patients (24 weeks 46% vs 8%; χ2 = 9.54, p = 0.008, OR = 9.22; 48 weeks 63% vs 16%; χ2 = 7.50, p = 0.02, OR = 9.0). DISCUSSION: Our data show no evidence of neurotoxicity in 48 weeks of treatment with an MEKi and a potential clinical signal supporting future research of MEKi as a cognitive intervention.

Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1.

OBJECTIVE: Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism-based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test-retest reliability of the measures and the application of data reduction techniques to improve reproducibility. METHODS: Data were analyzed from the STARS clinical trial (n = 146), a multi-center double-blind placebo-controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra-class correlation coefficients were generated between pre- and post-performances (16-week interval) on neuropsychological endpoints in the placebo group to determine test-retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error. RESULTS: Test-retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test-retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data. INTERPRETATION: These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test-retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.

Tumor bed proton irradiation in young children with localized medulloblastoma.

BACKGROUND: Radiotherapy is often deferred in very young children with medulloblastoma, in favor of more intense chemotherapy and stem cell rescue; however, posterior fossa radiation has been shown to improve overall survival (OS) and event-free survival compared with adjuvant chemotherapy alone. This study was performed to assess the OS, recurrence-free survival (RFS), patterns of failure, and clinical toxicity for children aged five and under who received focal proton radiation to the tumor bed alone. PROCEDURE: From 2010 to 2017, 14 patients with newly diagnosed medulloblastoma at one institution received tumor bed irradiation following surgery and chemotherapy. The median age of the patients was 40 months (range, 10.9-62.9 months). RESULTS: With a median follow-up of 54 months, four patients relapsed: three within the central nervous system (CNS) outside of the posterior fossa, and one within the tumor bed after subtotal resection. All relapses occurred within 28 months after the completion of radiation therapy. Five-year OS and RFS for this cohort of patients were 84% (95% CI, 48%-96%) and 70% (95% CI, 38%-88%), respectively. One patient experienced significant tumor regrowth soon after completion of radiation, autopsy showed viable tumor and necrosis near and within the brainstem, with relation to radiation unknown; however, no other acute clinical toxicities greater than grade 2 were observed in this group of patients. In the nine patients with available performance status follow-up, no significant changes in Lansky performance status were observed. CONCLUSIONS: Five-year OS and RFS following tumor bed irradiation in young children with medulloblastoma appear to be improved compared with other studies that forego the use of radiation therapy in this patient population. This approach should be further investigated in young children with medulloblastoma.

Acceptability and Feasibility in a Pilot Randomized Clinical Trial of Computerized Working Memory Training and Parental Problem-Solving Training With Pediatric Brain Tumor Survivors.

OBJECTIVE: To evaluate the feasibility and acceptability of computerized working memory training in pediatric brain tumor survivors (PBTS) with cognitive deficits, as well as computerized working memory training that is enhanced with parental problem-solving skills training (PSST). METHODS: Twenty-seven PBTS (ages 7-16) recruited from a large, tertiary academic medical center were randomly assigned to computerized working memory training (Standard; n = 14) or computerized working memory training plus PSST (Combined; n = 13). PBTS completed a baseline assessment and parents completed acceptability surveys. Primary outcomes included number of intervention sessions completed and acceptability ratings. RESULTS: Fourteen of the 27 participants completed at least 20 sessions of the computerized training with average sessions lasting over an hour (M = 68.42 min, SD = 14.63). Completers had significantly better baseline auditory attention abilities than noncompleters. Parents reported both frustration and satisfaction related to the interventions and identified barriers to completing intervention sessions. CONCLUSIONS: This pilot randomized clinical trial raises significant questions related to the feasibility of computerized working memory training in PBTS with cognitive deficits. Findings also offer considerations for integrating family-based treatment approaches into cognitive remediation interventions for PBTS.

Parent perspectives on the educational barriers and unmet needs of children with cancer.

Childhood cancer challenges academic success and school engagement, yet little research has described these hardships. This study documented parental perspectives of the educational barriers and unmet needs of youth treated for cancer (n = 102). Treatment-related physical sequelae were noted as common problems interfering with school attendance and engagement. One-fourth of parents reported worse academic performance since diagnosis; however, many never had their child evaluated (63.3%) or enacted formalized educational accommodations (55%). Findings reflect educational challenges across the continuum of cancer care and survivorship, and highlight the importance of education of school staff on both acute and long-term effects of cancer treatment.

Implementing guidelines: Proposed definitions of neuropsychology services in pediatric oncology.

Several organizations have published guidelines for the neuropsychological care of survivors of childhood cancer. However, there is limited consensus in how these guidelines are applied. The model of neuropsychology service delivery is further complicated by the variable terminology used to describe recommended services. In an important first step to translate published guidelines into clinical practice, this paper proposes definitions for specific neuropsychological processes and services, with the goal of facilitating consistency across sites to foster future clinical program development and to clarify clinical practice guidelines.

Discrepancies among Measures of Executive Functioning in a Subsample of Young Adult Survivors of Childhood Brain Tumor: Associations with Treatment Intensity.

OBJECTIVES: Treatments for childhood brain tumors (BT) confer substantial risks to neurological development and contribute to neuropsychological deficits in young adulthood. Evidence suggests that individuals who experience more significant neurological insult may lack insight into their neurocognitive limitations. The present study compared survivor, mother, and performance-based estimates of executive functioning (EF), and their associations with treatment intensity history in a subsample of young adult survivors of childhood BTs. METHODS: Thirty-four survivors (52.9% female), aged 18 to 30 years (M=23.5; SD=3.4), 16.1 years post-diagnosis (SD=5.9), were administered self-report and performance-based EF measures. Mothers also rated survivor EF skills. Survivors were classified by treatment intensity history into Minimal, Average/Moderate, or Intensive/Most-Intensive groups. Discrepancies among survivor, mother, and performance-based EF estimates were compared. RESULTS: Survivor-reported and performance-based measures were not correlated, although significant associations were found between mother-reported and performance measures. Survivors in the Intensive/Most-Intensive treatment group evidenced the greatest score discrepancies, reporting less executive dysfunction relative to mother-reported F(2,31)=7.81, p.05). CONCLUSIONS: There may be a lack of agreement among survivor, mother, and performance-based estimates of EF skills in young adult survivors of childhood BT, and these discrepancies may be associated with treatment intensity history. Neuropsychologists should use a multi-method, multi-reporter approach to assessment of EF in this population. Providers also should be aware of these discrepancies as they may be a barrier to intervention efforts. (JINS, 2016, 22, 900-910).

Everyday executive function in standard-risk acute lymphoblastic leukemia survivors.

We aimed to evaluate parent-rated executive function (EF) in pediatric standard risk acute lymphoblastic leukemia (SR-ALL) survivors compared to a healthy comparison (HC) group. We hypothesized that SR-ALL survivors would have greater reported executive dysfunction compared to HC, and that those younger at the time of treatment would demonstrate greater EF difficulties. A sample of 256 SR-ALL survivors evaluated an average nine years after treatment were compared to HC matched for gender, assessment age, and maternal education. Profile analysis was used to compare the groups across EF scales on the BRIEF. The prevalence of clinical elevations in the groups was compared via chi square, and odds ratios were calculated. Regression models were applied to examine the role of age at diagnosis and age at assessment in reported EF. Results indicated that SR-ALL survivors' mean scores of EF are similar to HC, except for flexibility and initiation. Survivors were rated as having clinical impairments with flexibility, initiation, working memory, and emotional control at rates two to three times that of HC. The risk of working memory and self-monitoring deficits was greater in survivors who were older when assessed. There was no relationship between age at diagnosis or treatment regimen on EF. These findings suggest sparing of extensive and severe EF deficits in SR-ALL survivors overall. However, a subset of survivors displays clinically significant executive dysfunction. There appears to be a heightened susceptibility to disrupted metacognitive functions as survivors age. This has implications for how we monitor neurocognitive development and functioning of SR-ALL survivors, and highlights opportunities for cognitive interventions.

Executive functions and social skills in survivors of pediatric brain tumor.

Medical advances have resulted in increased survival rates for children with brain tumors. Consequently, issues related to survivorship have become more critical. The use of multimodal treatment, in particular cranial radiation therapy, has been associated with subsequent cognitive decline. Specifically, deficits in executive functions have been reported in survivors of various types of pediatric brain tumor. Survivors are left with difficulties, particularly in self-monitoring, initiation, inhibition, and planning, to name a few. Another domain in which survivors of pediatric brain tumor have been reported to show difficulty is that of social skills. Parents, teachers, and survivors themselves have reported decreased social functioning following treatment. Deficits in executive functions and social skills are likely interrelated in this population, as executive skills are needed to navigate various aspects of social interaction; however, this has yet to be studied empirically. Twenty-four survivors of pediatric brain tumor were assessed using a computerized task of executive functions, as well as paper-and-pencil measures of social skills and real-world executive skills. Social functioning was related to a specific aspect of executive functions, that is, the survivors' variability in response time, such that inconsistent responding was associated with better parent-reported and survivor-reported social skills, independent of intellectual abilities. Additionally, parent-reported real-world global executive abilities predicted parent-reported social skills. The implications of these findings for social skills interventions and future research are discussed.