Initial report of NRG Oncology CC001, a phase III trial of whole-brain radiotherapy plus memantine (WBRT+memantine) with or without hippocampal avoidance (HA), demonstrated neuroprotective effects of HA with median follow-up less than 8 months. Herein, we report the final results with complete cognition and patient-reported outcomes and longer-term follow-up exceeding one year.
Adult patients with brain metastases were randomized to HA-WBRT+memantine or WBRT+memantine. The primary endpoint was time to cognitive function failure, defined as decline using the reliable change index on the Hopkins Verbal Learning Test-Revised (HVLT-R), Controlled Oral Word Association (COWA), and/or the Trail Making Tests (TMT) A and B. Patient-reported symptom burden was assessed using the M.D. Anderson Symptom Inventory with Brain Tumor Module and EQ-5D-5L.
Between July 2015 and March 2018, 518 patients were randomized. Median follow-up for alive patients was 12.1 months. The addition of HA to WBRT+memantine prevented cognitive failure (adjusted hazard ratio, 0.74, p=0.016), and was associated with less deterioration in TMT-B at 4 months (p=0.012) and HVLT-R Recognition at 4 (p=0.055) and 6 months (p=0.011). Longitudinal modeling of imputed data showed better preservation of all HVLT-R domains (p<0.005). Patients who received HA-WBRT+Memantine reported less symptom burden at 6 (p<0.001 using imputed data) and 12 months (p=0.026 using complete-case data; p<0.001 using imputed data), less symptom interference at 6 (p=0.003 using complete-case data; p=0.0016 using imputed data) and 12 months (p=0.0027 using complete-case data; p=0.0014 using imputed data), and fewer cognitive symptoms over time (p=0.043 using imputed data). Treatment arms did not differ significantly in overall survival, intracranial progression-free survival or toxicity.
With median follow-up exceeding one-year, HA during WBRT+memantine for brain metastases leads to sustained preservation of cognitive function and continued prevention of patient-reported neurologic symptoms, symptom interference and cognitive symptoms with no difference in survival or toxicity.

Copyright © 2023. Published by Elsevier Inc.