Stereotactic Radiation Improves Quality of Life in Patients With 5-20 Brain Metastases

A phase III randomized clinical trial has found that stereotactic radiation targeting individual tumors significantly improved symptom burden and interference with daily functioning compared with hippocampal-avoidance whole-brain radiation in patients with 5 to 20 brain metastases. The findings, published in JAMA, challenge longstanding practice patterns that favor whole-brain approaches when tumor burden is high.

The trial randomized 196 patients across four U.S. centers to receive either stereotactic radiation or hippocampal-avoidance whole-brain radiation. Eligible patients had between 5 and 20 brain metastases and no prior brain-directed radiation. Enrollment occurred between April 11, 2017, and May 17, 2024, with final follow-up on March 18, 2025. The median number of brain metastases was 14. Of the randomized patients, the mean age was 61 years, 129 (66%) were female, 176 (90%) were White, and 49 (25%) had prior neurosurgical resection.

The primary endpoint was 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. Between baseline and postbaseline assessments, the weighted composite score changed from 2.69 to 2.37 (mean change −0.32) in the stereotactic group and from 2.29 to 3.03 (mean change +0.74) in the hippocampal-avoidance whole-brain radiation group, for a mean difference of −1.06 (95% CI, −1.54 to −0.58; P < .001). The magnitude of benefit approximated half the difference between patients with good versus poor Karnofsky Performance Status.

Functional independence measured by the Barthel Index was significantly better in the stereotactic group at four and 12 months. Karnofsky Performance Status scores were also consistently higher between two and 12 months, with between-group differences reaching nearly 12 points at eight months. Patients managed with stereotactic radiation displayed better performance status and could remain more independent with everyday activities than those who received hippocampal-avoidance whole-brain radiation.

Objective neurocognitive testing showed advantages for stereotactic radiation across multiple domains, including verbal learning and memory (Hopkins Verbal Learning Test–Revised), executive function (Trail Making Test), and verbal fluency. No neurocognitive test favored hippocampal-avoidance whole-brain radiation.

Median survival did not significantly differ between the two groups (8.3 vs 8.5 months; P = .30). New metastases were more common among those who received stereotactic radiation vs whole-brain radiation (45.4% vs 24.2% at 1 year); however, most new metastases were treated with repeated stereotactic radiation or did not require treatment. Only 3.2% of patients had a recurrence in a tumor treated with stereotactic radiation therapy, compared with 39.5% in patients who received hippocampal-avoidance whole-brain radiation therapy.

Approximately 9.2% of patients in the stereotactic radiation group required subsequent whole-brain radiation to treat new brain tumors that later emerged. Stereotactic radiation often allowed patients to avoid whole-brain radiation, rather than merely delaying it.

Radiographic radiation necrosis was more common after stereotactic radiation (14.8% vs. 1.1% at one year). 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).

Of 196 randomized patients, 83 (42%) completed the 6-month assessment. Limitations of the study include that it was not feasible to blind investigators regarding treatment assignment. In addition, high mortality rates among patients with multiple brain tumors could have impacted data analysis.

The trial was supported by Varian, a Siemens Healthineers Company.