Treatment for Brain Metastases With Stereotactic Radiation vs Hippocampal-Avoidance Whole Brain Radiation: A Randomized Clinical Trial

Clinical Snapshot

Key Findings

• P Value: P < 0.001

• Effect Size: Mean difference -1.06 favouring stereotactic radiation

• Primary Outcome: MD Anderson Symptom Inventory-Brain Tumor weighted composite score change over 6 months

• Nnt Or Sensitivity: Effect exceeds clinically meaningful difference of 0.98 points

• Confidence Interval: 95% CI: -1.54 to -0.58

Clinical Application

Requires access to stereotactic radiosurgery facilities and expertise, which may be limited in regional Australian centres Aligns with current RANZCR guidelines favouring stereotactic approaches for limited brain metastases. PBS funding considerations may apply for multiple fraction stereotactic treatments versus single whole brain radiation course Patients with 5-20 brain metastases without prior brain radiation, particularly those prioritising quality of life and symptom control

Abstract

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.

References

1. 1.Aizer, A. A., Shin, K. Y., Catalano, P. J., Ricca, I., Johnson, M., Benham, G., Roper, K., Spicer, B., Mann, E., Nosker, J., Parsons, M. W., Mendu, M. L., Hepel, J., Chipidza, F., Krishnan, M., Shi, D. D., Lamba, N., Pashtan, I., Peng, L., Alexander, B., Brown, P. D., Wen, P. Y., Haas-Kogan, D. A., Rahman, R., & Tanguturi, S. (2026). Treatment for Brain Metastases With Stereotactic Radiation vs Hippocampal-Avoidance Whole Brain Radiation: A Randomized Clinical Trial. *JAMA*. https://doi.org/10.1200/JCO.20.00775