Hippocampal avoidance whole-brain radiotherapy with memantine preserves cognition in brain metastases

Brain metastases are a common complication of non-small cell lung cancer (NSCLC), and whole-brain radiotherapy (WBRT) often leads to cognitive decline. Hippocampal avoidance during WBRT (HA-WBRT) structurally protects the neurogenic niche, while memantine (MEM) pharmacologically mitigates radiation-induced excitotoxicity. This study aimed to evaluate whether their combination could better preserve cognitive function and reduce brain imaging changes. This retrospective cohort study included 221 NSCLC patients with brain metastases treated between April 2021 and August 2023. Patients were divided into two groups based on treatment: HA-WBRT + MEM (n = 107) and WBRT + MEM (n = 114). Cognitive function was assessed at baseline, 3, 6, and 12 months. Performance status, quality of life, tumor response, hippocampal volume, and white matter integrity (assessed by fractional anisotropy, FA) were assessed at baseline and 6 months. Adverse events and survival data were also collected. The HA-WBRT + MEM group showed significantly higher Montreal Cognitive Assessment (MoCA) scores at 3 months (P = 0.006), 6 months (P = 0.002), and 12 months (P < 0.001). At 6 months, this group also had better Eastern Cooperative Oncology Group (ECOG) scores (P < 0.001), higher European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30) scores (P < 0.001), larger hippocampal volumes (P = 0.016), and higher fractional anisotropy (FA) values in hippocampal white matter and splenium (all P < 0.001). There were no notable differences detected in tumor response, severe adverse events, or survival outcomes. The combination of HA-WBRT and memantine significantly enhances the preservation of cognitive function, reduces hippocampal atrophy, and maintains white matter integrity without compromising treatment efficacy or safety. These findings support the integration of HA-WBRT and memantine into clinical practice to improve cognitive outcomes for NSCLC patients with brain metastases.