Stereotactic radiosurgery recommended for patients with more than three brain metastases

MD Anderson study provides first evidence for stereotactic radiosurgery over whole brain radiation in patients with four to 15 brain metastases 

Researchers from The University of Texas MD Anderson Cancer Center have conducted the first randomized clinical trial comparing stereotactic radiosurgery (SRS) to whole brain radiation therapy (WBRT) in patients with four to 15 brain metastases, providing evidence to support the use of SRS in this patient population.

Results from the Phase III trial, led by Jing Li, M.D., Ph.D., associate professor of Radiation Oncology and co-director of MD Anderson’s Brain Metastasis Clinic, were presented today (Abstract 41) at the American Society for Radiation Oncology (ASTRO) Annual Meeting.

Brain metastases are tumors that form when cancer from another part of the body spreads to the brain. SRS is a highly precise form of radiation therapy that treats each brain tumor with a single, targeted high-dose of radiation, delivered in an outpatient setting. WBRT delivers radiation to the entire brain over weeks, and is associated with significant cognitive side effects that negatively impact patients’ quality of life.

Within the last five years, SRS became the standard of care for patients with one to three brain metastases, based on results from randomized clinical trials that demonstrated better cognitive function with no impact to overall survival. Patients with four or more metastatic brain tumors were not included in the earlier trials, and WBRT remained the standard of care for this group, due to concerns about disease control in the brain.

“The number of lesions in the brain is an indicator of the metastatic disease burden in the brain,” Li said. “For example, if a patient has a single brain metastasis, it's likely that's the only site of metastasis in the brain. However, a patient with 10 metastases has a higher risk of also having microscopic tumors that we don't see on MRI scan. Our trial was designed to determine if it’s still appropriate to omit or delay whole brain radiation for these patients. Based on our data, stereotactic radiosurgery helps patients preserve their cognitive functions, as compared to whole brain radiation therapy, without causing any difference in the overall survival.”  

Stereotactic radiosurgery preserves cognition without compromising overall survival

The study opened in 2012 and enrolled 72 patients. Trial participants were 83% Caucasian, 8% Black, 6% Hispanic and 3% Asian. Nearly half of the participants (35) were age 60 or older, and 58% were female.  Based on the results of a different phase III trial (RTOG 0614) that published in 2013, 62% of patients in the WBRT arm also received memantine, a dementia drug that helps preserve cognitive function.

Participants had a median of eight brain metastases and were randomized to receive WBRT or SRS. They completed neurocognitive testing, including learning, memory, attention span, executive function, verbal fluency, processing speed and motor dexterity, at enrollment and longitudinally.

Four months after radiation therapy, patients in the SRS group scored higher on a memory function test than those who received WBRT (average z-score change from patient’s own baseline, +0.21 for SRS and -0.74 for WBRT; p=0.04). Far more patients in the WBRT arm (50%) experienced a clinically meaningful decline in cognitive function, than the SRS arm (6%).

Overall survival did not differ between the groups (SRS median 7.8 months, WBRT median 8.9 months, p=0.59). SRS resulted in better local control rates (95% at four months with SRS and 86.7% with WBRT, p=0.09), but shorter median time to distant brain failure (10.5 months for WBRT and 6.3 months for SRS, p=0.37). Patients in the SRS arm also experienced shorter interruptions of systemic therapy (SRS median time to systemic therapy 1.7 weeks, WBRT 4.1 weeks, p=0.001). Grade 3 or higher toxicities were observed in four patients in the WBRT arm and two in the SRS arm.

“Patients receiving stereotactic radiosurgery need to be closely monitored with brain re-imaging every three months so any new tumors can be caught and treated when they are small,” Li said. “In the end, patients do not have increased risk of dying from managing the recurrent disease with salvage treatment, and they get to enjoy having better cognitive function.”

Despite enrollment challenges, data supports the use of SRS for this patient population

The trial was terminated early after enrolling 72 patients, due to the publication of another phase III trial (NRG Oncology CC 001) that provided level 1 evidence for replacing standard WBRT with hippocampal avoidance WBRT.

“Despite early closure of the study, we were pleased to see such strong signals in our data with neurocognitive benefit associated with SRS,” Li said. “We are extremely grateful to the patients and families who participated in our trial and made this progress possible. Our next steps are to compare stereotactic radiosurgery with hippocampal avoidance WBRT to determine which treatment option provides the most benefit, and also to investigate how SRS can be combined with systemic therapy to further improve treatment outcomes of patients with brain metastases.”

A full list of co-authors and their disclosures can be found here.