LAUSR

Compared to whole brain radiation (WBRT), stereotactic radiation (SRS/SRT) and Hippocampal Avoidant (HA)-WBRT produce superior neurocognitive function (NCF) outcomes for brain metastasis survivors. In a multi-center, phase 3 randomized clinical trial comparing SRS/SRT to HA-WBRT in patients with 5-20 brain metastases (NCT03075072), we found reduced symptom burden and NCF decline in the SRS/SRT arm. The current study examines the secondary endpoint, NCF outcome, in 12-month survivors. Patients were age 18-80 with 5-20 brain metastases and had no prior brain-directed radiation or leptomeningeal disease. Neuropsychological tests of memory (Hopkins verbal learning test; HVLT), processing speed (TrailsA; TMTA), executive function (TrailsB; TMTB), and verbal fluency (Controlled oral word association; COWA) and self-reported cognition (MOS) were administered at baseline, 4-months, and 12-months post-treatment. A composite score (COG) was created by averaging the Z-scores. Cognitive decline at 12-months was defined as ≥1.5 Z-score decline from baseline or 4-months and group differences were examined with repeated measures ANOVA. Between 4/2017-5/2024, 196 patients enrolled, 98 in each arm, with no group differences in clinical/demographic variables. There were 35 12-month survivors who completed neuropsychological testing at both baseline and 12-months, 33 of whom completed the 4-month testing. At baseline, COG Z-scores were not different (SRS=-0.56; HA-WBRT=-0.65). There was lower risk of decline with SRS/SRT vs HA-WBRT (2/19=11% vs 7/16=44%; chi-square=5.02;p=0.025). Repeated measures ANOVA, conducted with subjects who had data at all 3 timepoints (SRS n=19; WBRT n=14) showed less decline with SRS/SRT than HA-WBRT (COG Z-score12 mos =-0.21 vs -2.09, respectively; F [timeXtreatment]=5.97;p=0.02). Individual test score declines were greater for HA-WBRT on HVLT (delayed recall and recognition) and TMTA (p’s <0.05). Self-reported cognitive symptoms did not differ by group or over time. This analysis demonstrates significantly reduced risk of cognitive decline for 1-year survivors of 5-20 brain metastases treated with SRS/SRT vs HS-WBRT. Implications and predictors of long-term outcomes are discussed.