Tips-15 neurocognitive function and neurocognitive concerns in an ongoing phase iii trial of pre-operative srs versus post-operative srs for brain metastases

Abstract In our ongoing phase III randomized trial (NCT03741673) evaluating risk of leptomeningeal disease (LMD) in patients with brain metastasis, patients are stratified by tumor size, location, and histology, and randomized to pre-operative SRS versus post-operative SRS. The primary endpoint is 1-year LMD-free rate, and exploratory endpoints include neurocognitive function (NCF). NCF is assessed prior to treatment and longitudinally (1.5, 6, and 12 months from the start of treatment) with the HVLT-R, TMT, and COWA yielding the Clinical Trial Battery Composite score (CTB COMP). Patients also complete the MDASI-BT, which includes a Cognitive Factor measuring patient reported cognitive concerns. Currently, 41 patients completed pre-treatment NCF baseline. Characteristics of patients with pre-treatment NCF baseline include mean (SD): age 60.0+/-11.7 years, 2.6+/-2.2 metastases, 15.2+/-10.1 cc brain metastases volume, median KPS 90 (range: 70-100), 83% white, 52% male, and 50% received AEDs at time of surgery. The most common primary cancers among this cohort were: 31% NSCLC, 19% RCC, 14% melanoma, 7% breast, 2% thyroid, and 26% other. Mean (SD) NCF z-scores ranged from z= -0.09 (1.08) to -3.09 (6.13), CTB COMP z=-1.13 (1.65), and the mean (SD) MDASI-BT Cognitive Factor score was 1.1 (1.3). Using multivariable linear regression including CTB COMP, MDASI-BT Cognitive and Affective Factor, KPS, number of and intracranial volume of metastases, only intracranial volume of metastases was statistically significantly associated with CTB COMP (B=-.058, p=.034) and only the MDASI-BT Affective Factor was statistically significantly associated with the MDASI-BT Cognitive Factor (B=.305, p=<.001). At baseline, disease factors such as tumor burden appear to be the primary driver of objectively measured neurocognitive dysfunction and mood factors appear to be the primary driver of subjective patient reported neurocognitive concerns. This has important implications for interpretation of these different clinical outcome assessments in clinical trials measuring objective neurocognitive function and subjective neurocognitive concerns.