Comparison of Hippocampal Volume Change after Whole-Brain Radiotherapy with and without Hippocampal Avoidance: A Post-Hoc Analysis of a Phase II Randomized Trial

Abstract

Hippocampal avoidance whole-brain radiotherapy (HA-WBRT) preserves verbal memory compared to conformal WBRT in the previously reported randomized phase II clinical trial. In the present study, we analyzed the changes in hippocampus volume between groups at longitudinal follow-up time points. We hypothesize better preservation of hippocampus volumes with time in the HA-WBRT group. In this post-hoc analysis of a single institution, single-blind, randomized phase II trial, patients with brain metastases were randomized to receive either HA-WBRT or conformal WBRT with 30 Gy in 10 fractions. Patients received gadolinium contrast-enhanced MRI every three months or when clinically indicated after WBRT until progression. Only patients with at least one follow-up MRI were included. The MRI was used to assess baseline intracranial volume, hippocampal volume, the ratio of the total hippocampus to total intracranial volume (HT%), and the ratio of the left (HL%) or right (HR%) hippocampus to total intracranial volume. The volumes were automatically calculated by volBrain, an online MRI brain volumetry system. We used linear mixed models with fixed and random effects to compare the changes of repeated measures of the hippocampus volumes over time between the two groups. Among 70 randomized patients, 51 (25 in the HA-WBRT group and 26 in the WBRT group) were included in the present analysis. There were no significant differences between the two groups in the baseline demographics, HT%, HR%, and HL%. The median follow-up time was 13.9 months (range 2.1-31.8 months), and more than 60% of patients had at least one year of follow-up. Linear mixed model analyses showed a more significant decrease of HT% over time in the WBRT arm (regression coefficient β = -0.002, p = 0.001) compared to the HA-WBRT arm (regression coefficient, β = -0.001, p = 0.254), with a significant group by time interaction (F-value = 4.27, p = 0.050). The HL% was stable over time in the HA-WBRT arm (β = 0.0001, p = 0.769) while it decreased in the WBRT arm (β = -0.001, p = 0.003), with a significant group by time interaction (F-value = 6.51, p = 0.015). In contrast, the HR% decreased over time in both groups (HA-WBRT: regression coefficient β = -0.001, p = 0.006; WBRT: regression coefficient β = -0.001, p < 0.001) without significant group by time interaction (F-value = 0.20, p = 0.662). HA-WBRT better preserves total hippocampus volume with time compared to WBRT, with the main effect contributed by preserving the left hippocampus volume. Further research is warranted to establish the relationship between hippocampus volume perpetuation and cognitive function preservation. The future goal is to investigate whether left-side unilateral HA-WBRT provides similar neurocognitive function preservation compared to standard bilateral HA-WBRT.