Association Between Neurocognitive Outcomes and Radiation Dose to the Corpus Callosum and Hippocampus in Children With Medulloblastoma Treated on a Phase III Study.

PURPOSE/OBJECTIVE(S) To characterize the association between neurocognitive outcomes and radiation dose to the corpus callosum and the hippocampus in children with medulloblastoma treated on a phase III study. MATERIALS/METHODS Patients aged 3 to 21 years with medulloblastoma were treated at a single institution on a phase III risk-adapted study. Craniospinal radiation dose was 23.4 Gy for average-risk patients (M0 and GTR/NTR) and 36-39.6 Gy for high-risk patients (M+ or STR). All patients were treated with photons and received 55.8 Gy to the tumor bed using a 1cm clinical target volume margin. Metastasis > 0.5 cm received 50.4-54 Gy. Patients underwent age-appropriate cognitive testing at baseline (prior to completion of radiation) and yearly for 5 years. Neurocognitive scores were reported as standard deviations (SD) derived from age-standardized normative samples. Mixed effects models were used to estimate the longitudinal trends in neurocognitive scores. Reliable change index was used to identify patients whose scores declined significantly from baseline to last follow-up. Logistic regression was used to identify variables associated with a significant decline in neurocognitive outcomes. RESULTS One hundred and twenty-four patients were eligible for analysis. The median neurocognitive follow-up was 59.4 months. Decline in processing speed was associated with mean dose to the corpus callosum genu (slope: -.166 points/year/Gy, P < .001), body (slope: -.176 points/year/Gy, P < .001) and splenium (slope: -.115 points/year/Gy, P < .001), after adjusting for age and sex. Of the 90 patients with baseline processing speed scores, 21 (19%) demonstrated significant decline at last follow up. Patients with a mean corpus callosum genu and body dose of ≥40 Gy were at a four to seven-fold increased odds of experiencing significant decline compared to those with a mean dose of < 40 Gy (genu: OR: 7.47, 95% CI: 2.64 - 21.12, P < .001; body: OR: 4.47, 95% CI: 1.65 - 12.11, P = .003). Decline in associative memory was associated with mean right hippocampal dose (slope: -.11 points/year/Gy, P = .013) and left hippocampal dose (slope: -.109 points/year/Gy, P = .019), after adjusting for age and sex. Of 98 patients with baseline memory scores, 11 (11%) demonstrated significant decline at last follow up. Patients with a mean hippocampal dose of ≥50 Gy were at a five to seven-fold increased odds of experiencing significant decline compared to those with mean dose < 50 Gy (right hippocampus: Odds Ratio [OR]: 7.21, 95% Confidence Interval [CI]: 1.98 - 27.46, P = .004; left hippocampus: OR: 5.17, 95% CI: 1.38 - 19.36, P = .015). CONCLUSION For children with medulloblastoma, increasing radiation dose to the corpus callosum and hippocampus is associated with decreased performance on tests of processing speed and memory, respectively. During radiation plan optimization, careful consideration should be given to minimizing dose to these structures while achieving appropriate tumor bed coverage.