Study Suggests Stereotactic Radiosurgery Become Standard of Care for Patients with 4+ Brain Metastases

When compared with whole brain radiation therapy, researchers discovered highly focused radiation therapy led to less cognitive decline while simultaneously delivering equivalent overall survival rates.

Results from a randomized, controlled, phase 3 trial presented at the American Society for Radiation Oncology (ASTRO) Annual Meeting suggested that stereotactic radiosurgery (SRS) should replace whole brain radiation therapy (WBRT) as the standard of care for patients with 4 or more brain metastases.1

When compared with WBRT, researchers discovered highly focused radiation therapy led to less cognitive decline while simultaneously delivering equivalent overall survival (OS) rates.

“This study provides strong evidence to support replacing whole brain radiation with more focal radiation for patients with multiple brain metastases,” lead author Jing Li, MD, PhD, an associate professor of radiation oncology and co-director of the Brain Metastasis Clinic at The University of Texas MD Anderson Cancer Center in Houston, said in a press release.2

"Whole brain radiation was the backbone of treatment for brain metastases for a very long time,” added Li. “When stereotactic radiosurgery became available, however, we saw its potential to reduce the cognitive deterioration associated with whole-brain treatment and improve patients' quality of life.”

Investigators stratified adult patients with 4 to 15 untreated non-melanoma brain metastases by histology, number of lesions, baseline Hopkins Verbal Learning Test - Revised Total Recall (HVLT-R TR) score, extracranial disease, Karnofsky Performance Scale (KPS), and age, then randomly assigned them to receive either SRS or WBRT. Between September 2012 and September 2019, a total of 72 patients were randomized to either SRS (n = 36) or WBRT (n = 36) with an estimated median follow-up time of 6.6 months (range 0.2-69.8).

The study’s dual primary end points were HVLT-R TR and local control (LC) at 4 months. Key secondary end points included additional neurocognitive function tests, OS, distant brain failure, toxicity, and time to systemic therapy.

Of note, the trial was terminated early due to slow accrual.

The median number of brain metastases at enrollment was 8 and 31 patients were evaluable for HVLT-R TR at 4 months.

Following the publication of RTOG 0614, the researchers encouraged memantine in the WBRT arm; 62% of patients in the WBRT arm received memantine.

Relative to baseline, in the primary end point analysis the 4-month HVLT-R TR standardized z-score increased by 0.21 (standard error [SE], 0.27) for patients treated with SRS and declined by 0.74 (SE, 0.36) for those treated with WBRT (P = .041). Based on the Clinical Trial Battery Composite (the mean z-score for the HVLT-R, COWA, TMT), at 4 months the neurocognitive function of patients in the SRS arm also improved on average 0.23 (SE, 0.14) and the neurocognitive function of patients in the WBRT arm declined on average 0.73 (SE, 0.35; P = .008). Median OS time was 10.4 months in the SRS arm and 8.4 months in the WBRT arm (P = .45).

“Cognitive decline is one of the most debilitating effects of brain metastases and treatment, and a key goal of treatment is to improve functioning in the brain for patients with these tumors,” Li explained.

Moreover, preliminary analyses of local control at 4 months demonstrated a 100% local control rate for SRS and 95.5% for WBRT (P = .53) and median time to distant brain failure was 4.3 months for SRS versus 18.1 months for WBRT (P = .09). However, the local control and distant brain failure results are currently being independently confirmed by the trial radiologist.

Importantly, when compared to WBRT, radiosurgery was associated with shorter interruptions of systemic therapy (time to systemic therapy: SRS 1.7 weeks, WBRT 4.1 weeks, P = .001). According to Li, this finding is especially important for patients with metastatic disease, as they benefit from systemic therapy to control cancer outside of the brain.

Regarding safety, 4 patients who received WBRT (15%) and 2 who received SRS developed (8%) grade 3 or higher toxicities. Radiographic evidence of radiation necrosis, a side effect associated with SRS, was also observed in 17% of patients on the SRS arm of the trial (4% of all treated lesions).

Moving forward, the investigators intend to compare SRS with a newer form of WBRT designed specifically to avoid the hippocampus. While the recently published NRG Oncology CC 001 trial found an advantage of hippocampal-avoidance over standard whole-brain treatment, no trial to date has compared it with SRS.

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


1. Li J, Ludmire EB, Wang Y, et al. Stereotactic radiosurgery versus whole-brain radiation therapy for patients with 4-15 brain metastases: A phase III randomized controlled trial. Presented at the American Society for Radiation Oncology (ASTRO) Annual Meeting. Abstract #: 41.

2. Radiosurgery reduces cognitive decline without compromising survival for patients with 4+ brain metastases [news release]. Arlington, Virginia. Published October 26, 2020. Accessed October 29, 2020.