RDTA-14 COGNITIVE DECLINE FROM WHOLE BRAIN RADIATION THERAPY: A SYSTEMATIC REVIEW OF PHASE II AND III TRIALS ON THERAPEUTIC ADVANCES

Abstract Brain radiation can cause cognitive impairment in up to 90% of patients, significantly reducing quality of life (QOL). Various management strategies have been explored, though none are FDA-approved. This systematic review evaluates interventions aimed at mitigating radiation-induced cognitive decline. Using MeSH terms for brain radiation, cognitive decline, and therapeutics, we screened PubMed, Google Scholar, Cochrane, and Embase. Of 245 initial articles, we included nine phase II and III studies. Shaw et al. (2006) reported that donepezil (n=34) in a phase II trial improved QOL and various cognitive domains at 24 weeks (p<0.05), including attention, memory, and verbal fluency, with minimal toxicity. Rapp et al. (2015) compared donepezil (n=99) with placebo (n=99), demonstrating similar composite cognitive scores but improved memory scores (HVLT-R; recognition: 10.91 vs. 10.34, p=0.027; discrimination: 1.10 vs. 9.16, p=0.007), and motor dexterity (GP-D 105.06 vs. 116.99, p=0.016) at 24 weeks. Attia et al. (2012) reported that ginkgo biloba improved executive function, attention, and QOL in a phase II trial (n=34) at 24 weeks (p<0.05) but had a higher dropout rate. Brown et al. (2013) reported that memantine (n=235) vs. placebo (n=238) at 24 weeks led to reduced decline in delayed-recall (p=0.058), delayed-recognition (p=0.015), MMSE (p=0.009), and time to cognitive decline (HR 0.78, p=0.01). Other parameters were favorable, albeit statistically nonsignificant. Toxicity profiles were similar. Brown et al. (2020) demonstrated that hippocampal-avoidant whole-brain radiation therapy (HA-WBRT) plus memantine (n=261) reduced cognitive, executive function, learning, and memory decline at 6 months (p</=0.016) compared to traditional WBRT plus memantine (n=257), without affecting survival. Gondi et al. (2023) confirmed these findings at 1-year follow-up, reporting reduced symptom-burden (p<0.001) and cognitive (HR 0.74, p=0.016), executive function (p<0.001), and memory (p<0.001) decline. This review underscores the efficacy of these interventions in mitigating radiation-induced cognitive decline, providing a foundation for research and potential regulatory approval.