Left Hippocampal Dosimetry Correlates With Visual and Verbal Memory Outcomes in Pediatric Brain Tumor Survivors

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The late neurocognitive effects of radiation therapy in the pediatric brain tumor population are well known. Here, we specifically investigate outcomes of verbal and visual memory in a cohort treated with proton radiotherapy (RT), as well as potential clinical and regional dosimetric predictors of these outcomes. We hypothesize that increased RT dose to the hippocampi will amount to decline in memory scores. Seventy pediatric brain tumor patients (median age at RT = 12.1, range = 5.0–22.5) treated with proton RT between 2002 and 2013 were identified as having baseline and follow-up evaluations of visual and verbal memory (Children’s Memory Scale [CMS] and/or Wechsler Memory Scale-third edition [WMS-III]) conducted at our institution, as well as available dosimetry plans. Hippocampi, temporal lobes, and whole brain contours were manually delineated for calculation of multiple dosimetric indices using MimVista 6.6.5. Univariate analysis was performed to determine clinical predictors of score decline or improvement, and multivariate linear regression using dosimetric indices and other clinical covariates (age, gender, baseline score, presence or absence of baseline neurologic symptoms, and time elapsed since RT) allowed calculation of models to predict follow-up memory scores. The median neurocognitive follow-up time was 3.0 years (range = 1.1 – 11.4 years), and 140 cognitive assessments—70 baseline and 70 latest follow-up—were included in the analysis. On histogram analysis, Delayed Verbal memory scores showed a statistically significant decline in the overall cohort (P = 0.01), but Immediate Verbal memory and both measures of visual memory did not. On univariate analysis, higher baseline scores (P < 0.001) and female gender (P = 0.034) were significant predictors of Delayed Verbal memory score decline at follow-up. On multivariate analysis, increased left hippocampal dosimetry was correlated with decline in all four measures, with the individual dosimetric components (left hippocampal V20GyE) of the Immediate Verbal and Delayed Visual memory models being statistically significant (P = 0.027 and P = 0.016, respectively). Additionally, male gender predicted higher Delayed Verbal memory scores (P = 0.035). Of the four memory subtests evaluated here, only Delayed Verbal memory declined, while others were relatively stable between baseline and patients’ most recent follow-up assessments. Given a correlation of hippocampal dosimetry and memory outcomes after RT and a modest effect size of RT dose in these multivariate models, hippocampal-sparing RT plans may assist pediatric brain tumor patients in preserving memory functions.