Stereotactic radiosurgery (SRS) may offer an alternative to hippocampal-avoidant whole-brain radiotherapy (WBRT) for brain metastases from small cell lung cancer (SCLC), according to the first randomized phase 3 trial to compare the approaches.

The NRG-CC009 trial yielded two unexpected findings: SRS did not improve patients’ cognitive outcomes compared with WBRT plus memantine, the trial’s primary endpoint. However, it was associated with a nearly 9-month gain in overall survival, according to results presented at the American Society for Radiation Oncology (ASTRO) 2026 Annual Meeting in Boston.

Historically, there has been concern that omitting WBRT from the management of SCLC brain metastases would worsen patients’ survival. So the new data help address a “fundamental historical objection” to upfront SRS in these patients, said lead investigator Chad G. Rusthoven, MD, from the University of Colorado Anschutz School of Medicine in Aurora, Colorado.

However, Rusthoven cautioned against drawing firm conclusions just yet. Overall survival was a prespecified secondary endpoint, and the trial was not powered to show a survival advantage.

“At this point, we need to be cautious about assigning a specific cause to the observed differences in survival,” Rusthoven said in an ASTRO news release. Although measured prognostic factors were well balanced between the treatment groups, he noted, unmeasured differences could still be at work.

SRS Moves Into SCLC

In many solid tumors, SRS has become a standard treatment for patients with a limited number of brain metastases based on randomized trials showing better preservation of cognitive function and quality of life than with WBRT.

Patients with SCLC, however, were largely excluded from those pivotal trials due to concern that omitting WBRT could allow rapid intracranial progression from untreated microscopic disease. WBRT has also evolved to better protect patients’ cognition through hippocampal avoidance and the use of memantine, and it remains a standard treatment for SCLC brain metastases.

NRG-CC009 set out to compare SRS with modern, cognition-sparing WBRT. It randomly assigned 151 patients with SCLC brain metastases to SRS or hippocampal-avoidant WBRT (30 Gy in 10 fractions) plus memantine. All patients had brain metastases at least 5 mm outside the hippocampi, no larger than 4 cm, and no more than 30 cm³ in total volume.

The protocol initially limited enrollment to patients with up to 10 metastases and then later removed the numerical ceiling. Patients had a median of two metastases, but some had more than 20.

The trial’s primary endpoint was negative, with no significant difference between treatment groups in time to neurocognitive failure on a standardized test battery assessing memory, verbal fluency, and processing speed or executive function.

At 6 months, neurocognitive failure occurred in 62% vs 59% of patients receiving SRS vs WBRT (adjusted hazard ratio [HR] for SRS, 0.83; P = .39). There were no significant differences in neurologic mortality, local central nervous system control, or leptomeningeal disease progression.

However, SRS was associated with superior overall survival, with a median of 17.4 months vs 8.6 months with WBRT (adjusted HR, 0.60; P = .016). Overall survival rates were 58.9% vs 40.8% at 1 year and 31.1% vs 18.5% at 2 years. Better performance status was also associated with longer survival.

Treatment-related adverse events were more common with WBRT plus memantine, but grade ≥ 3 events were not significantly different between the treatment groups. Patient-reported quality-of-life outcomes and analyses of salvage therapy will be reported separately.

SRS for All Comers?

“These findings support SRS as a treatment option for patients with brain metastases from SCLC,” Rusthoven told conference attendees.

Study discussant Henning Willers, MD, of Massachusetts General Hospital in Boston, agreed but also cautioned against a one-size-fits-all approach.

SRS has the clearest role, Willers said, when the intracranial disease burden is relatively low — where the number of metastases is “no more than a handful.”

With increasing numbers of lesions, the risk for high micrometastatic burden rises, and “the data become less clear,” Willers said. Although treating many visible lesions with SRS is feasible, he added, doing so does not guarantee disease control, making early intracranial progression a concern.

Willers also highlighted the fact that neurocognitive risk from radiotherapy is variable, and that should inform treatment decisions.

“We should remember that the neurocognitive risk from whole-brain radiation therapy goes up sharply once patients reach 60-70 years of age,” he said. “In the elderly, whole-brain radiation therapy, even if it’s hippocampus-sparing, may do more harm than good and maybe shouldn’t be given at any point in time.”

In sum, Willers said, “We need to individualize treatments.”

Those decisions, he noted, could become even more complex going forward due to emerging systemic therapies with intracranial activity — particularly for patients with small, asymptomatic metastases.

The study was funded by NRG Oncology. Rusthoven reported being a partner at East Radiation Oncology and receiving honoraria from Suzhou Liangyihui Network Technology Co., Ltd. Willers had no relevant disclosures.