Neurocognitive Outcomes in Multiethnic Pediatric Brain Tumor Patients Treated With Proton Versus Photon Radiation.

BACKGROUND: We analyzed post-radiation (RT) neurocognitive outcomes in an ethnically diverse pediatric brain tumor population undergoing photon radiotherapy (XRT) and proton radiotherapy (PRT). PROCEDURE: Post-RT neurocognitive outcomes from 49 pediatric patients (37% Hispanic/Latino) with primary brain tumors were analyzed. Tests included cognitive outcomes, behavioral outcomes, and overall intelligence. For each outcome, proportion of patients with cognitive impairment (scores <1.5 SD) was calculated. The Fisher exact tests compared proportion of patients with impairment and t tests compared T-scores between XRT (n=32) and PRT (n=17) groups. Linear regression assessed associations between radiation modality and outcomes. RESULTS: Median follow-up was 3.2 and 1.8 years in the XRT and PRT groups, respectively. The median RT dose was 54.0 Gy. We found impairment in 16% to 42% of patients across most neurocognitive domains except executive function. There was no difference in scores between XRT and PRT groups. Regression analyses revealed no association of neurocognitive outcomes with radiation modality. Non-Hispanic patients had better Verbal Comprehension Index and General Ability Index scores than Hispanic patients ( P <0.05). CONCLUSIONS: Among pediatric patients with brain tumors receiving RT, all cognitive domains were affected except executive function. Radiation modality was not associated with neurocognitive outcomes. Hispanic patients may be more vulnerable to posttreatment cognitive effects that warrant further study.

Neurocognitive outcomes in pediatric brain tumors after treatment with proton versus photon radiation: a systematic review and meta-analysis.

BACKGROUND: Advances in cancer treatments, particularly the development of radiation therapy, have led to improvements in survival outcomes in children with brain tumors. However, radiation therapy is associated with significant long-term neurocognitive morbidity. The present systematic review and meta-analysis aimed to compare the neurocognitive outcomes of children and adolescents with brain tumors treated with photon radiation (XRT) or proton therapy (PBRT). METHODS: A systematic search was conducted (PubMed, Embase, Cochrane, and Web of Science from inception until 02/01/2022) for studies comparing the neurocognitive outcomes of children and adolescents with brain tumors treated with XRT vs. PBRT. The pooled mean differences (expressed as Z scores) were calculated using a random effects method for those endpoints analyzed by a minimum of three studies. RESULTS: Totally 10 studies (n = 630 patients, average age range: 1-20 years) met the inclusion criteria. Patients who had received PBRT achieved significantly higher scores (difference in Z scores ranging from 0.29-0.75, all P < 0.05 and significant in sensitivity analyses) after treatment than those who had received XRT for most analyzed neurocognitive outcomes (i.e., intelligence quotient, verbal comprehension and perceptual reasoning indices, visual motor integration, and verbal memory). No robust significant differences (P > 0.05 in main analyses or sensitivity analyses) were found for nonverbal memory, verbal working memory and working memory index, processing speed index, or focused attention. CONCLUSIONS: Pediatric brain tumor patients who receive PBRT achieve significantly higher scores on most neurocognitive outcomes than those who receive XRT. Larger studies with long-term follow-ups are needed to confirm these results.

Microstructural Cerebellar Injury Independently Associated With Processing Speed in Adult Patients With Primary Brain Tumors: Implications for Cognitive Preservation.

PURPOSE: The cerebellum's role in posttreatment neurocognitive decline is unexplored. This study investigated associations between cerebellar microstructural integrity using quantitative neuroimaging biomarkers and neurocognition among patients with primary brain tumors receiving partial-brain radiation therapy (RT). METHODS AND MATERIALS: In a prospective trial, 65 patients underwent volumetric brain magnetic resonance imaging, diffusion tensor imaging, and memory, executive function, language, attention, and processing speed (PS) assessment before RT and at 3, 6, and 12 months after RT. Delis-Kaplan Executive Function System-Trail Making (D-KEFS-TM) visual scanning and number and letter sequencing and Wechsler Adult Intelligence Scale, Fourth Edition, coding were used to evaluate PS. The cerebellar cortex and white matter (WM) and supratentorial structures subserving the previously mentioned cognitive domains were autosegmented. Volume was measured within each structure at each time point along with diffusion biomarkers (fractional anisotropy and mean diffusivity) in WM structures. Linear mixed-effects models assessed cerebellar biomarkers as predictors of neurocognitive scores. If associated, cerebellar biomarkers were evaluated as independent predictors of cognitive scores controlling for domain-specific supratentorial biomarkers. RESULTS: Left (P = .04) and right (P < .001) cerebellar WM volume declined significantly over time. Cerebellar biomarkers were not associated with memory, executive function, or language. Smaller left cerebellar cortex volume was associated with worse D-KEFS-TM number (P = .01) and letter (P = .01) sequencing scores. A smaller right cerebellar cortex volume correlated with worse D-KEFS-TM visual scanning (P = .02) and number (P = .03) and letter (P = .02) sequencing scores. Greater right cerebellar WM mean diffusivity, indicating WM injury, was associated with worse D-KEFS-TM visual scanning performance (P = .03). Associations remained significant after controlling for corpus callosum and intrahemispheric WM injury biomarkers. CONCLUSIONS: Injury to the cerebellum as measured with quantitative biomarkers correlates with worse post-RT PS, independent of corpus callosum and intrahemispheric WM damage. Efforts to preserve cerebellar integrity may preserve PS.

Fine Motor Skill Decline After Brain Radiation Therapy-A Multivariate Normal Tissue Complication Probability Study of a Prospective Trial.

PURPOSE: Brain radiation therapy can impair fine motor skills (FMS). Fine motor skills are essential for activities of daily living, enabling hand-eye coordination for manipulative movements. We developed normal tissue complication probability (NTCP) models for the decline in FMS after fractionated brain radiation therapy (RT). METHODS AND MATERIALS: On a prospective trial, 44 patients with primary brain tumors received fractioned RT; underwent high-resolution volumetric magnetic resonance imaging, diffusion tensor imaging, and comprehensive FMS assessments (Delis-Kaplan Executive Function System Trail Making Test Motor Speed [DKEFS-MS]; and Grooved Pegboard dominant/nondominant hands) at baseline and 6 months postRT. Regions of interest subserving motor function (including cortex, superficial white matter, thalamus, basal ganglia, cerebellum, and white matter tracts) were autosegmented using validated methods and manually verified. Dosimetric and clinical variables were included in multivariate NTCP models using automated bootstrapped logistic regression, least absolute shrinkage and selection operator logistic regression, and random forests with nested cross-validation. RESULTS: Half of the patients showed a decline on grooved pegboard test of nondominant hands, 17 of 42 (40.4%) on grooved pegboard test of -dominant hands, and 11 of 44 (25%) on DKEFS-MS. Automated bootstrapped logistic regression selected a 1-term model including maximum dose to dominant postcentral white matter. The least absolute shrinkage and selection operator logistic regression selected this term and steroid use. The top 5 variables in the random forest were all dosimetric: maximum dose to dominant thalamus, mean dose to dominant caudate, mean and maximum dose to the dominant corticospinal tract, and maximum dose to dominant postcentral white matter. This technique performed best with an area under the curve of 0.69 (95% CI, 0.68-0.70) on nested cross-validation. CONCLUSIONS: We present the first NTCP models for FMS impairment after brain RT. Dose to several supratentorial motor-associated regions of interest correlated with a decline in dominant-hand fine motor dexterity in patients with primary brain tumors in multivariate models, outperforming clinical variables. These data can guide prospective fine motor-sparing strategies for brain RT.

Dose-Dependent Atrophy in Bilateral Amygdalae and Nuclei After Brain Radiation Therapy and Its Association With Mood and Memory Outcomes on a Longitudinal Clinical Trial.

PURPOSE: Amygdalae are bilateral, almond-shaped structures located anterior to the hippocampi, critical to limbic system functions of emotional processing and memory consolidation. The amygdalae are heterogeneous, composed of multiple nuclei with distinct structural and functional properties. We prospectively assessed associations between longitudinal changes in amygdala morphometry, including component nuclei, and functional outcomes in patients with primary brain tumors receiving radiation therapy (RT). METHODS AND MATERIALS: On a prospective longitudinal trial, 63 patients underwent high-resolution volumetric brain magnetic resonance imaging and testing for mood (Beck Depression Inventory and Beck Anxiety Inventory), memory (Brief Visuospatial Memory Test-Revised [BVMT] Total Recall and Delayed Recall; Hopkins Verbal Learning Test-Revised [HVLT] Total Recall and Delayed Recall), and health-related quality-of-life outcomes (Functional Assessment of Cancer Therapy-Brain Social/Family Well-Being and Emotional Well-Being) at baseline and 3, 6, and 12 months after RT. Amygdalae, including 8 nuclei, were autosegmented bilaterally using validated techniques. Linear mixed-effects models assessed longitudinal change in amygdalae and nuclei volumes and associations with dose and outcomes. Wilcoxon rank sum tests compared amygdala volume change between patient groups with worse and more stable outcomes at each time point. RESULTS: Atrophy was found in the right amygdala at 6 months (P = .001) and the left amygdala at 12 months (P = .046). A higher dose was associated with atrophy of the left amygdala (P = .013) at 12 months. The right amygdala showed dose-dependent atrophy at 6 months (P = .016) and 12 months (P = .001). Worse BVMT-Total, HVLT-Total, and HVLT-Delayed performance was associated with smaller left lateral (P = .014, P = .004, and P = .007, respectively) and left basal (P = .034, P = .016, and P = .026, respectively) nuclei volumes. Increased anxiety at 6 months was associated with greater combined (P = .031) and right (P = .007) amygdala atrophy. Greater left amygdala atrophy (P = .038) was noted in patients with decreased emotional well-being at 12 months. CONCLUSIONS: Bilateral amygdalae and nuclei undergo time- and dose-dependent atrophy after brain RT. Atrophy in amygdalae and specific nuclei was associated with poorer memory, mood, and emotional well-being. Amygdalae-sparing treatment planning may preserve neurocognitive and neuropsychiatric outcomes in this population.

Post-treatment neuroendocrine outcomes among pediatric brain tumor patients: Is there a difference between proton and photon therapy?

Purpose: Pediatric brain tumor patients are vulnerable to radiotherapy (RT) sequelae including endocrinopathies. We compared post-RT neuroendocrine outcomes between pediatric brain tumor patients receiving photons (XRT) versus protons (PRT). Methods: Using a prospectively maintained single-institution database, we analyzed 112 pediatric primary brain tumor patients (80 XRT, 32 PRT) from 1996 to 2019. Patient/treatment characteristics and endocrinopathy diagnoses (growth hormone deficiency [GHD], sex hormone deficiency [SHD], hypothyroidism, and requirement of hormone replacement [HRT]) were obtained via chart review. Univariable/multivariable logistic regression identified neuroendocrine outcome predictors. Time-adjusted propensity score models accounted for treatment type. Craniospinal irradiation (CSI) patients were evaluated as a sub-cohort. Results: Median follow-up was 6.3 and 4.4 years for XRT and PRT patients respectively. Medulloblastoma was the most common histology (38%). Half of patients (44% in XRT, 60% in PRT) received CSI. Common endocrinopathies were GHD (26% XRT, 38% PRT) and hypothyroidism (29% XRT, 19% PRT). CSI cohort PRT patients had lower odds of hypothyroidism (OR 0.16, 95% CI[0.02-0.87], p = 0.045) on multivariable regression and propensity score analyses. There were no significant differences in endocrinopathies in the overall cohort and in the odds of GHD or HRT within the CSI cohort. SHD developed in 17.1% of the XRT CSI group but did not occur in the PRT CSI group. Conclusion: Endocrinopathies were common among pediatric brain tumor survivors. Among CSI patients, PRT was associated with lower risk of hypothyroidism, and potentially associated with lower incidence of SHD. Future studies should involve collaborative registries to explore the survivorship benefits of PRT.