Stereotactic Radiosurgery May Delay Cognitive Deterioration vs WBRT in Patients With Numerous Brain Metastases

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Stereotactic radiosurgery (SRS) may represent a new standard of care for patients with four or more brain metastases, replacing whole-brain radiation therapy (WBRT) in this setting, according to a phase III study presented at the virtual 2020 American Society for Radiation Oncology (ASTRO) Annual Meeting (Abstract 41).

Highly focused radiation therapy with SRS led to less cognitive decline compared with WBRT, with similar overall survival in patients with 4 to 15 brain metastases. SRS allowed patients to continue systemic anticancer therapy without interruption, whereas WBRT required time off of systemic therapy.

“Up to 30% of all [patients with] cancer develop brain metastasis, and they typically don’t have a good prognosis. Radiation and surgery are the main treatment approaches, and historically, these patients have poor survival. WBRT has been the standard radiation approach, and it is associated with significant cognitive side effects. Our study provides strong evidence to support replacing WBRT with more focal radiation [with SRS] for patients with multiple brain metastases,” stated lead author Jing Li, MD, PhD, Associate Professor of Radiation Oncology at The University of Texas MD Anderson Cancer Center. “SRS preserves cognitive function  and minimizes interruption of systemic therapy without compromising overall survival.”

Jing Li, MD, PhD

Jing Li, MD, PhD

The study presented at ASTRO builds on previous research aimed at preserving cognitive function in patients with brain metastasis. “Two phase III randomized trials have established SRS as standard of care for patients with one to three or four brain metastases. We wanted to extend this to patients with four or more brain metastases. The concern in using SRS in patients with higher disease burden is that SRS cannot address microscopic disease,” explained Dr. Li.

SRS is more convenient than WBRT for patients and minimizes interruption of systemic therapy. WBRT is typically delivered in 10 treatment sessions over 2 weeks, whereas SRS is generally completed in a single session, requiring only 1 day of treatment. 

Study Details

The study enrolled 50 patients with 4 to 15 untreated nonmelanoma brain metastases confirmed by neuroradiology. All lesions were amenable to treatment with SRS. Systemic therapy was allowed at the discretion of the treating radiologist.

Patients were randomly assigned 1:1 to receive SRS (15 to 24 Gy) vs WBRT (30 Gy in 10 fractions). Patients were stratified for histology, age, number of lesions (4–7 vs 8–15), performance status, extracranial disease status, and prior SRS vs no prior SRS.

After about one-third of the 50 patients were enrolled, a phase III trial (RTOG 0614) showed that memantine (approved for dementia) slowed cognitive decline in patients treated with WBRT. After that, memantine was given to all patients assigned to the WBRT arm.

The primary endpoints were memory function at 4 months (as measured by the Hopkins Verbal Learning Test [HVLT]) and local control at 4 months.


At 4 months, memory function increased by 0.21 points in the SRS arm vs a decrease of 0.74 points in the WBRT arm (P = .041). At 4 months following treatment, clinically meaningful cognitive decline was observed in 6% of patients in the SRS arm vs 50% in the WBRT arm (P = .018)

“At 1 month and at 6 months, a statistically significant and clinically meaningful benefit with SRS was also observed,” said Dr. Li. Statistical significance favoring SRS over WBRT was P = .033 at 1 month and P = .012 at 6 months.

According to a global composite score reflecting cognitive function based on a battery of nine cognitive tests, cognitive scores were significantly better in the SRS arm at 1 month, 4 months, and 6 months (P = .024, P = .004, and P = .027, respectively). The battery of cognitive tests assessed learning and memory, attention span, executive function, verbal fluency, processing speed, and motor dexterity.

In both groups, overall survival was similar in an intent-to-treat analysis: a median of 7.8 months in the SRS arm and 8.9 months in the WBRT arm.

Other Endpoints

Local control at 4 months was 95% in the SRS arm vs 87% in the WBRT arm. Distant brain control was 60% for SRS vs 80% for WBRT. Median time to distant brain failure was 6.3 months for SRS and 10.5 months for WBRT.

Time to systemic therapy was shorter for patients who got SRS compared with WBRT: 1.7 weeks vs 4.1 weeks (P = .001). “This is important for patients, because they benefit from systemic therapy to control cancer outside the brain,” said Dr. Li. Patients treated with SRS also had fewer grade 3 or higher toxicities: 8% vs 15% for WBRT.

“Our trial was conducted over a span of 7 years, with two practice changes occurring during that time: memantine was given to patients who got WBRT, and SRS was adopted as a standard for patients with one to three brain metastases. Despite early termination of our study, where two-thirds of the WBRT patients got memantine, we were able to show that SRS reduced the risk of neurocognitive deterioration compared to WBRT, as demonstrated by a constellation of neurocognitive tests, individually or by composite score,” she noted.

Looking Ahead

Next steps for the research team include comparing SRS with a newer form of WBRT designed specifically to avoid the hippocampus. Although a recently published trial found an advantage of hippocampal avoidance over standard whole-brain treatment, no trial has compared it with SRS.

"Both options are currently considered standard treatment, and both options have pros and cons. We need randomized data to understand which patients will benefit most from each of these treatments," said Dr. Li.

Disclosure: For full disclosures of the study authors, visit

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