Stereotactic radiosurgery demonstrated a prolonged overall survival compared with hippocampal-avoidant whole-brain radiotherapy with memantine in patients with small cell lung cancer (SCLC) and brain metastases, according to phase III study findings presented at the 2026 American Society for Radiation Oncology (ASTRO) Annual Meeting (Abstract LBA 02). However, no significant difference was noted between study arms for the primary study endpoint, time to neurocognitive failure.
“Although stereotactic radiosurgery is the preferred treatment for brain metastases caused by most other tumors, [SCLC] has been an exception where whole-brain radiotherapy has remained standard of care,” said co-principal investigator Chad Rusthoven, MD, a radiation oncologist at the University of Colorado Anschutz School of Medicine in Aurora, Colorado. “Our findings suggest that patients can now have a more individualized discussion about whether focused radiosurgery or whole-brain treatment is right for them.”
Study Methods
The phase III NRG-CC009 trial enrolled 151 patients with SCLC and brain metastases who were randomly assigned 1:1 to receive either stereotactic radiosurgery or hippocampal-avoidant whole-brain radiotherapy with memantine. All patients had brain metastases at least 5 mm outside the hippocampi, at least 4 cm at their largest diameter, and no more than 30 cm3 in total volume. Patient stratification was conducted by disease-specific graded prognostic assessment score as well as by the number of brain metastases.
“Advances in radiation therapy have fundamentally changed the options for patients with brain metastases,” said lead principal investigator Vinai Gondi, MD, Director of Radiation Oncology at the Northwestern Medicine West Region and Proton Center in Warrenville, Illinois. “NRG-CC009 reflects how far both approaches have come. For patients with [SCLC], we now have two modern radiation therapy strategies to consider and randomized evidence to help us understand how best to use them.”
The primary endpoint was time to neurocognitive failure, which was assessed with the Hopkins Verbal Learning Test-Revised, Controlled Oral Word Association, and Trail Making Test, with a competing risk of death without failure. Secondary endpoints included overall survival, intracranial disease progression, neurologic death, salvage therapy use, and toxicity.
The study was powered 85% to detect a 17% absolute reduction in neurocognitive failure between the study arms with a two-sided type I error of 0.05, with the assumption of a death without neurocognitive failure rate of 29.8% in each arm.
Key Findings
No significant difference was observed in neurocognitive failure between the two treatment arms (Gray's test, P = .66; adjusted hazard ratio [HR] for stereotactic radiosurgery arm = 0.83; P = .39).
Overall survival measurements showed superiority for the stereotactic radiosurgery arm with a median overall survival of 17.4 months vs 8.6 months with standard whole-brain radiotherapy, resulting in an adjusted reduction in the risk of death of 40% (95% confidence interval [CI] = 0.39–0.91; P = .016).
“At this point, we need to be cautious about assigning a specific cause to the observed differences in survival,” Dr. Rusthoven said. “The baseline prognostic factors were well-balanced between the treatment arms, but there is always a possibility of imbalances in unmeasured variables. It is also possible that stereotactic radiosurgery and hippocampal-avoidant whole-brain radiotherapy may have differential downstream effects on the disease course that affect survival. Further investigation into these areas is needed.”
Comparable outcomes were found between the two arms in terms of central nervous system control. Additionally, no significant differences were reported between the treatment arms in adjusted analyses for intracranial failure, neurologic mortality, salvage therapy, or rates of treatment-related adverse events of grade 3 or higher.
“Although no differences were observed in neurocognitive function between the treatment arms, the improved survival with stereotactic radiosurgery addresses a fundamental historical concern with [SCLC]—that omission of whole-brain radiotherapy might lead to worse survival” Dr. Gondi commented. “Overall, these results support stereotactic radiosurgery as a reasonable option for patients with brain metastases from [SCLC].”
“Patients with [SCLC] have largely been left out of the randomized trials that established radiosurgery as a standard treatment for patients with brain metastases. This study begins to close that evidence gap and gives clinicians much greater confidence that focused treatment can be a reasonable option for appropriately selected patients. The long-term goal is to give each patient the treatment that best fits their disease and priorities rather than defaulting to one approach based on diagnosis alone,” stated ASTRO expert Charles B. Simone II, MD, FASTRO, Chair of ASTRO’s Lung Cancer Resource Panel and a radiation oncologist at New York Proton Center and Memorial Sloan Kettering Cancer Center.
DISCLOSURES: For full disclosures of the study authors, visit elsevierdigitaledition.com.
