Dose Reductions to Critical Brain Organs-at-Risk and Better Cognition in Children with Medulloblastoma Receiving Proton Therapy

Abstract

Our group previously demonstrated an improvement in cognition among children with medulloblastoma treated with proton therapy, as compared to photon therapy. However, the reason for this cognitive improvement was unclear. In this study, our aim was to determine whether dose to critical brain structures acted as a mediator of improved cognition in patients treated with proton therapy. In this retrospective study, a cohort of 75 children with medulloblastoma from two institutions was assembled (39 photon, 36 proton). Included patients were treated with similar radiation and cognitive follow-up protocols. Study endpoints were verbal comprehension (VCI), perceptual reasoning (PRI), working memory (WMI), processing speed (PSI) indices and full-scale IQ (FSIQ). Brain structures were segmented and dose comparisons by RT modality were compared using independent t-tests. Linear mixed effects models with random intercepts were created to evaluate cognitive endpoints using R version 4.2.2. Median follow-up from RT to last cognitive assessment was 4.8 years. Total dose, including RT boost, was slightly lower in the proton cohort than the photon cohort (mean, 54.6 Gy vs. 56.1 Gy, respectively, p < 0.001). Eleven children (31%) treated with proton therapy received 36 Gy CSI, while 6 children (15%) treated with photon therapy received 36 Gy CSI (p = 0.07). Children treated with proton therapy had reduced total doses to the brain (mean, D40), left and right temporal lobes (mean, D40, D50), and left and right hippocampi (mean, D40, D50 - see Table). After adjustment for age at RT and posterior fossa syndrome, higher whole brain mean dose and time since RT were associated with greater decrease in VCI (p = 0.033), higher left temporal D50 and time since RT with greater decrease in PRI (p = 0.031), higher whole brain D40 and time since RT with greater decrease in PSI (p < 0.001) and FSIQ (p = 0.030). Our study demonstrates that proton therapy for patients with medulloblastoma reduces dose to normal brain tissues, which is associated with better intellectual outcomes. Children with medulloblastoma who undergo RT should be treated with proton therapy, if available.