Sustained Preservation of Cognition and Prevention of Patient-Reported Symptoms With Hippocampal Avoidance During Whole-Brain Radiation Therapy for Brain Metastases: Final Results of NRG Oncology CC001

Abstract

Initial report of NRG Oncology CC001, a phase 3 trial of whole-brain radiation therapy plus memantine (WBRT+memantine) with or without hippocampal avoidance (HA), demonstrated neuroprotective effects of HA with a median follow-up of fewer than 8 months. Herein, we report the final results with complete cognition, patient-reported outcomes, and longer-term follow-up exceeding 1 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, or the Trail Making Tests (TMT) A and B. Patient-reported symptom burden was assessed using the MD Anderson Symptom Inventory with Brain Tumor Module and EQ-5D-5L. Between July 2015 and March 2018, 518 patients were randomized. The median follow-up for living patients was 12.1 months. The addition of HA to WBRT+memantine prevented cognitive failure (adjusted hazard ratio, 0.74, P=.016) and was associated with less deterioration in TMT-B at 4 months (P=.012) and HVLT-R recognition at 4 (P=.055) and 6 months (P=.011). Longitudinal modeling of imputed data showed better preservation of all HVLT-R domains (P < .005). Patients who received HA-WBRT+Memantine reported less symptom burden at 6 (P < .001 using imputed data) and 12 months (P=.026 using complete-case data; P < .001 using imputed data), less symptom interference at 6 (P=.003 using complete-case data; P=.0016 using imputed data) and 12 months (P=.0027 using complete-case data; P=.0014 using imputed data), and fewer cognitive symptoms over time (P=.043 using imputed data). Treatment arms did not differ significantly in overall survival, intracranial progression-free survival, or toxicity. With median follow-up exceeding 1 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.