Association Between Brain Substructure Dose and Cognitive Outcomes in Children With Medulloblastoma Treated on SJMB03: A Step Toward Substructure-Informed Planning

Sahaja Acharya, Yian Guo, Tushar Patni, Yimei Li, Chuang Wang, Melissa Gargone, Jason M Ashford, Lydia Wilson, Austin Faught, Wilburn E Reddick, Zoltan Patay, Amar Gajjar, Heather M Conklin, Thomas E Merchant, Sahaja Acharya, Yian Guo, Tushar Patni, Yimei Li, Chuang Wang, Melissa Gargone, Jason M Ashford, Lydia Wilson, Austin Faught, Wilburn E Reddick, Zoltan Patay, Amar Gajjar, Heather M Conklin, Thomas E Merchant

Abstract

Purpose: To characterize the association between neurocognitive outcomes (memory and processing speed) and radiation (RT) dose to the hippocampus, corpus callosum (CC), and frontal white matter (WM) in children with medulloblastoma treated on a prospective study, SJMB03.

Patients and methods: Patients age 3-21 years with medulloblastoma were treated at a single institution on a phase III study. The craniospinal RT dose was 23.4 Gy for average-risk patients and 36-39.6 Gy for high-risk patients. The boost dose was 55.8 Gy to the tumor bed. Patients underwent cognitive testing at baseline and once yearly for 5 years. Performance on tests of memory (associative memory and working memory) and processing speed (composite processing speed and perceptual speed) was analyzed. Mixed-effects models were used to estimate longitudinal trends in neurocognitive outcomes. Reliable change index and logistic regression were used to define clinically meaningful neurocognitive decline and identify variables associated with decline.

Results: One hundred and twenty-four patients were eligible for inclusion, with a median neurocognitive follow-up of 5 years. Mean right and left hippocampal doses were significantly associated with decline in associative memory in patients without posterior fossa syndrome (all P < .05). Mean CC and frontal WM doses were significantly associated with decline in both measures of processing speed (all P < .05). Median brain substructure dose-volume histograms were shifted to the right for patients with a decline in associative memory or processing speed. The odds of decline in associative memory and composite processing speed increased by 23%-26% and by 10%-15% for every 1-Gy increase in mean hippocampal dose and mean CC or frontal WM dose, respectively.

Conclusion: Increasing RT dose to the CC or frontal WM and hippocampus is associated with worse performance on tests of processing speed and associative memory, respectively. Brain substructure-informed RT planning may mitigate neurocognitive impairment.

Trial registration: ClinicalTrials.gov NCT00085202.

Conflict of interest statement

Lydia WilsonHonoraria: Elekta Amar GajjarConsulting or Advisory Role: Roche/Genentech, QED Therapeutics, Day One TherapeuticsResearch Funding: Genentech (Inst), Kazia Therapeutics (Inst) Thomas E. MerchantHonoraria: Varian Medical SystemsTravel, Accommodations, Expenses: Philips HealthcareNo other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
Violin plots of Dmean to (A) the hippocampus, (B) the CC, and (C) the frontal WM, stratified by craniospinal dose. CC, corpus callosum; CSI, craniospinal irradiation; Dmean, mean dose; WM, white matter.
FIG 2.
FIG 2.
Association between age, brain substructure, and neurocognitive outcomes for (A) the right hippocampus and associative memory, (B) the CC genu and composite processing speed, (C) the CC body and composite processing speed, (D) the CC splenium and composite processing speed, and (E) the right frontal WM and composite processing speed. Data from the left hippocampus and left frontal WM are not shown because the results are similar to those for the contralateral side. The doses displayed represent the fifth and 95th percentiles of the substructure Dmean distribution in average-risk patients. CC, corpus callosum; Dmean, mean dose; WM, white matter.
FIG 3.
FIG 3.
Median population DVHs for patients exhibiting no decline (solid line, blue) compared with patients exhibiting decline (dotted line, red) for the following brain substructures and neurocognitive outcomes: (A) the left hippocampus and associative memory, (B) the right hippocampus and associative memory, (C) the CC genu and composite processing speed, (D) the left hippocampus and working memory, (E) the right hippocampus and working memory, (F) the CC body and composite processing speed, (G) the CC splenium and composite processing speed, (H) the right frontal WM and composite processing speed, and (I) the left frontal WM and composite processing speed. The shaded region represents the 25th-75th percentile. CC, corpus callosum; DVH, dose–volume histogram; WM, white matter.
FIG 4.
FIG 4.
The odds of experiencing neurocognitive decline on the basis of age and Dmean with respect to (A) associative memory, (B) working memory, (C) composite processing speed, and (D) perceptual speed. All variables are continuous, and mean doses are represented in Gy. CC, corpus callosum; Dmean, mean dose; Hipp, hippocampus; L, left; OR, odds ratio; R, right; WM, white matter.
FIG A1.
FIG A1.
Flow diagram. aThere were no statistically significant differences in age, sex, and risk group when comparing SJMB03 patients excluded from this study with those included in this study (age, P = .107; sex, P = .942; risk group, P = .872). CSI, craniospinal irradiation; MRI, magnetic resonance imaging; RT, radiation.
FIG A2.
FIG A2.
Raw individual patient data for (A) associative memory, (B) associative memory for patients without PFS, (C) associative memory for patients with PFS, (D) working memory, (E) composite processing speed, and (F) perceptual speed. PFS, posterior fossa syndrome.
FIG A3.
FIG A3.
Median population DVHs for patients exhibiting no decline (solid line, blue) compared with patients exhibiting decline (dotted line, red) in perceptual speed for the following brain substructures: (A) the CC genu, (B) the CC body, (C) the CC splenium, (D) the left frontal WM, and (E) the right frontal WM. The shaded region represents the 25th-75th percentile. CC, corpus callosum; DVH, dose–volume histogram; WM, white matter.
FIG A4.
FIG A4.
Violin plots comparing patient (SJMB03) and healthy participant (healthy) substructure volumes for (A) the hippocampus, (B) the CC, and (C) the frontal WM. The follow-up time was 1-2 years after the baseline time point. CC, corpus callosum; L, left; R, right; WM, white matter.

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