From Bias to Evidence-The Rise of Stereotactic Radiosurgery in Brain Metastasis Treatment

# From Bias to Evidence-The Rise of Stereotactic Radiosurgery in Brain Metastasis Treatment *Published: 2026 Apr 7* Treatment for Brain Metastases With Stereotactic Radiation vs Hippocampal-Avoidance Whole Brain Radiation: A Randomized Clinical Trial. Aizer AA(1), Shin KY(2), Catalano PJ(2)(3), Ricca I(1), Johnson M(1), Benham G(1), Roper K(4)(5), Spicer B(1), Mann E(1), Nosker J(6), Parsons MW(7), Mendu ML(8), Hepel J(9), Chipidza F(4)(5), Krishnan M(4)(5), Shi DD(1), Lamba N(1), Pashtan I(4)(5), Peng L(4)(5), Alexander B(10), Brown PD(11), Wen PY(12), Haas-Kogan DA(1), Rahman R(1), Tanguturi S(1). Author information: (1)Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Boston, Massachusetts. (2)Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts. (3)Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts. (4)Department of Radiation Oncology, Milford Regional Medical Center, Milford, Massachusetts. (5)Department of Radiation Oncology, South Shore Health, Weymouth, Massachusetts. (6)Department of Neurology, Brigham and Women's Hospital, Boston, Massachusetts. (7)Department of Psychiatry, Massachusetts General Hospital, Boston. (8)Population Health Services Organization, Mass General Brigham, Boston, Massachusetts. (9)Department of Radiation Oncology, Rhode Island Hospital/Brown University, Providence. (10)Valo Health, Lexington, Massachusetts. (11)Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota. (12)Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Comment in JAMA. 2026 Apr 7;335(13):1123-1124. doi: 10.1001/jama.2025.18180. ## IMPORTANCE Brain metastases are common in patients with cancer, and radiation is often used for management. Among patients with more than 4 brain metastases, the effects of stereotactic radiation targeting only individual tumors, compared with whole brain radiation with hippocampal avoidance, which radiates both tumors and normal brain, remain unknown. ## OBJECTIVE To determine whether stereotactic radiation improves symptom severity and interference with daily functioning, compared with whole brain radiation with hippocampal avoidance. DESIGN, SETTING, AND PARTICIPANTS Phase 3, open-label, randomized clinical trial conducted at 4 United States-based centers. Eligible patients had 5 to 20 brain metastases and no prior brain-directed radiation. Enrollment occurred between April 11, 2017, and May 17, 2024 (final follow-up, March 18, 2025). INTERVENTION: Stereotactic radiation, compared with whole brain radiation with hippocampal avoidance. MAIN OUTCOMES AND MEASURES Mean weighted patient-reported symptom severity and interference score change over 6 months postbaseline relative to baseline using the MD Anderson Symptom Inventory-Brain Tumor instrument (scale, 0-10; score change range, -10 to 10; -10 = best). A clinically meaningful Δ was defined as 0.98. ## RESULTS Of 196 randomized patients (mean age, 61 years; 129 [66%] female; 176 [90%] White; median number of brain metastases, 14 [IQR, 11-18]; 49 [25%] with prior neurosurgical resection), 83 (42%) completed the 6-month assessment. For the primary outcome, between baseline and postbaseline assessments through the 6-month follow-up, stereotactic radiation changed the weighted composite MD Anderson Symptom Inventory-Brain Tumor score from 2.69 to 2.37 (mean change, -0.32) and hippocampal-avoidance whole brain radiation changed the score from 2.29 to 3.03 (mean change, 0.74) (mean difference, -1.06 [95% CI, -1.54 to -0.58]; P < .001). Related grade 3-5 adverse events occurred in 12 patients (12%) in the stereotactic radiation group and 13 patients (13%) in the hippocampal-avoidance whole brain radiation group; grade 1-3 fatigue was most frequent (27 [28%] vs 43 [44%], respectively). CONCLUSIONS AND RELEVANCE In patients with 5 to 20 brain metastases, these findings support stereotactic radiation over hippocampal-avoidance whole brain radiation to improve symptoms and interference with daily functioning, key components of quality of life. ## TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03075072. DOI: 10.1001/jama.2026.0076 PMCID: PMC12921566 DOI: 10.1001/jama.2025.18180