Multimodality therapy, including surgery, radiotherapy, and systemic therapy, has significantly improved overall survival for patients with brain metastases. However, treatment-related neurocognitive sequelae remain a major challenge in survivorship. Although advances in radiotherapy delivery techniques have reduced toxicity, the potential interaction with chemotherapy, targeted therapy, and immunotherapy, and the consequent effect on neurocognitive outcomes is poorly characterised. We conducted a systematic review of clinical trials reporting neurocognitive endpoints in patients with brain metastases receiving radiotherapy with or without other concurrent systemic therapies. Neurocognitive outcomes were manually extracted from published reports. 39 studies from 1997 to 2024 involving 6617 patients met inclusion criteria (n=27 whole-brain radiotherapy; n=12 radiosurgery), including six studies evaluating combined-modality therapy. Baseline neurocognitive disability was frequently observed, and the majority of randomised trials evaluating advanced radiotherapy delivery techniques (hippocampal avoidance and radiosurgery) compared with whole-brain radiotherapy reported reduced cognitive decline and improved quality of life. There was no signal for increased toxicity with combined-modality therapy, including radiotherapy with concurrent systemic therapy, although evaluable trials were few in number. Given improvements in survival for patients with brain metastases, characterisation of long-term neurocognitive outcomes is growing in importance. There is an urgent need for targeted research to resolve evidence gaps around modality-specific neurocognitive toxicity and optimal sequencing of therapies. Systemic issues, such as integration of routine neuropsychological screening or assessment and incorporation of rehabilitation strategies into neuro-oncology care pathways, warrant evaluation. Exploration of emerging strategies, ranging from neuroprotectants to dose-sparing radiotherapy techniques, could further mitigate long-term adverse effects.
