Neurocognitive outcomes in patients with brain metastases: a systematic review.

Tarek Bou Dargham, Sebastian F Winter, Kristen Batich, Karin Gehring, Michael W Parsons, Jorg Dietrich, Trey Mullikin, Zachary J Reitman, Scott R Floyd, John P Kirkpatrick, Paul W Sperduto, Jona Hattangadi-Gluth, Helen A Shih, Paul D Brown, Minesh Mehta, Erik P Sulman, Katherine B Peters, Eugene J Vaios

Journal: The Lancet. Oncology 2025;26(12):e671-e682

PMID: 41308688

View on PubMed

Abstract

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.

Address: Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA.; Department of Neurology, Division of Neuro-Oncology, Massachusetts General Hospital, Boston, MA, USA.; Department of Cognitive Neuropsychology, Tilburg University, Tilburg, Netherlands; Department of Neurosurgery, Elisabeth-TweeSteden Hospital, Tilburg, Netherlands.; Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA.; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA.; Department of Radiation Oncology, University of California, San Diego, CA, USA.; Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.; Department of Radiation Oncology, Miami Cancer Institute, Baptist Health South Florida, Miami, FL, USA.; Department of Radiation Oncology, Laura and Isaac Perlmutter Cancer Center at NYU Langone, New York, NY, USA.; Department of Radiation Oncology, Duke University Medical Center, Durham, NC, USA. Electronic address: [email protected].

DOI: 10.1016/S1470-2045(25)00525-X

MeSH Terms: Humans, Brain Neoplasms, Quality of Life, Radiosurgery, Cranial Irradiation, Cognition, Combined Modality Therapy, Treatment Outcome