Redefining Neurocognitive Outcomes After Radiation for Brain Metastases: A Patient-Level Meta-Analysis of Recovery Following Initial Decline

BACKGROUND: Although there are data describing the onset of neurocognitive toxicity following radiation for patients with brain metastases, less is known about the potential for functional cognitive recovery (CR). This study sought to evaluate CR following neurocognitive function failure (NCF) in patients treated with stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and hippocampal avoidance (HA)-WBRT.

METHODS: A pooled analysis of three (NCCTG N107C/CEC.3, NCCTG N0574, and NRG CC001) clinical trials was performed. Patients with trial-defined NCF and longitudinal cognitive testing were included. The primary endpoint was time to CR, defined as patients no longer exhibiting a one or more standard deviation decline from baseline on any cognitive test.

FINDINGS: 288 patients were included, with a median follow-up of 12.2 months. The cumulative incidence of CR was 38% (95% CI 32.5-43.9%) at 6 months after NCF. Incidence of CR was significantly improved with post-op SRS vs WBRT (HR: 2.68, 95% CI: 1.43-5.03, p = .002) and with SRS vs SRS+WBRT (HR: 2.35, 95% CI: 1.16-4.79, p = .008). On multivariable analysis, SRS was highly prognostic of CR compared to WBRT (HR: 2.42, 95% CI: 1.70-3.45, p < .0001). Meta-analysis demonstrated that conformal RT techniques (SRS or HA-WBRT) conferred a significantly higher rate of CR compared to WBRT (pooled HR 2.12, 95% CI: 1.49-3.02, p < .001). 68% of patients had long-term sustained CR.

INTERPRETATION: A sizeable proportion of patients who experience NCF following brain radiation eventually attain full and sustained CR, thereby highlighting that neurocognitive decline may not be permanent. The use of conformal radiation techniques results in greater rates of neurocognitive recovery.