In patients with five to 20 brain metastases, stereotactic radiation targeting individual lesions led to significantly better symptom control and preservation of daily functioning compared with hippocampal-avoidance whole-brain radiation (HA-WBRT), according to a Phase III randomized trial published in JAMA Oncology.
The findings challenge longstanding practice patterns that favor whole-brain approaches when tumor burden is high and reinforce a broader shift toward precision radiation techniques.
A clinically meaningful quality-of-life advantage
The trial randomized 196 patients across four U.S. centers to stereotactic radiation or HA-WBRT. Eligible patients had between five and 20 brain metastases and no prior brain-directed radiation.
The primary endpoint was change in patient-reported symptom severity and interference with daily functioning using the MD Anderson Symptom Inventory–Brain Tumor (MDASI-BT) instrument. Over six months, stereotactic radiation improved scores, while HA-WBRT worsened them.
Between baseline and postbaseline assessments, the weighted composite MDASI-BT 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 HA-WBRT group, for a mean difference of −1.06.
In the Discussion, the authors note that “the magnitude of benefit (difference in score change, −1.06) approximated half the difference between patients with good versus poor Karnofsky Performance Status.” For clinicians, that comparison provides context: This was not a trivial statistical difference, but one patients would likely feel in their daily lives.
According to the researchers, overall survival did not differ significantly between groups (median 8.3 vs 8.5 months; P = .30), underscoring that quality-of-life improvements were not achieved at the expense of survival.
Functional independence and cognitive preservation
Secondary outcomes further favored stereotactic radiation.
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.
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. Notably, “no neurocognitive test favored hippocampal-avoidance whole brain radiation.”
The authors conclude that “these findings support stereotactic radiation over hippocampal-avoidance whole brain radiation to improve symptom burden and interference with daily functioning, key components of quality of life.”
Tradeoffs: New lesions versus local control
As expected, stereotactic radiation was associated with a higher rate of new brain metastases at one year (45.4% vs 24.2%). However, local recurrence of treated lesions was dramatically lower (3.2% vs 39.5%).
Only 9.2% of patients in the stereotactic group ultimately required salvage whole-brain radiation. In the Discussion, the authors suggest that stereotactic radiation “often avoids, rather than merely delays, whole brain radiation when paired with frequent magnetic resonance imaging–based surveillance.”
Radiographic radiation necrosis was more common after stereotactic radiation (14.8% vs. 1.1% at one year), a known tradeoff of high-dose focal therapy. However, rates of grade 3 or greater adverse events were similar between groups.
A paradigm shift in radiation oncology
Historically, whole-brain radiation was favored for patients with more than four metastases, in part because of concerns about missing microscopic disease. Yet stereotactic radiation is already standard for patients with up to four lesions based on cognitive preservation data.
This trial extends that paradigm. As the authors write, “This study extends prior work by demonstrating that the advantages of stereotactic radiation apply to patients with more than four brain metastases.” They add that the results “underscore a paradigm shift toward precision techniques that prioritize patient well-being.”
In the era of targeted therapies and immune checkpoint inhibitors—many with central nervous system activity—the durability of intracranial control is improving. As survival lengthens, neurocognitive preservation becomes increasingly critical. The authors note that “as systemic therapy improves and survival lengthens, the value of stereotactic radiation… may increase.”
Implications for practice
The researchers believe that for radiation oncologists and multidisciplinary neuro-oncology teams, the message is clear: tumor count alone should not default patients to whole-brain therapy.
In patients with five to 20 brain metastases who can undergo close MRI surveillance, stereotactic radiation appears to offer better symptom control, improved functional independence, and superior cognitive outcomes—without compromising survival.
In a disease setting where median survival remains under a year for many patients, preserving autonomy, memory, and day-to-day functioning may be the most meaningful endpoint of all.
