Patients with small cell lung cancer (SCLC) that had spread to the brain lived a median of 17 months after focused stereotactic radiosurgery, compared with nine months after an advanced form of whole brain radiation therapy, an unexpected secondary finding from the first randomized phase 3 trial to compare the treatment approaches in this population.
SCLC has remained an exception to the broader shift toward focused treatment for brain metastases because of concern that treating only visible tumors could leave microscopic disease elsewhere in the brain unchecked. In the trial, radiosurgery did not improve the primary endpoint of time to neurocognitive decline, but researchers found no significant difference in neurologic death or serious treatment-related side effects. Results will be presented today at the American Society for Radiation Oncology (ASTRO) Annual Meeting.
Although stereotactic radiosurgery is the preferred treatment for brain metastases caused by most other tumors, small cell lung cancer has been an exception where whole brain radiotherapy has remained standard of care. Our findings suggest that patients can now have a more individualized discussion about whether focused radiosurgery or whole brain treatment is right for them."
Chad Rusthoven, MD, co-principal investigator of the trial and radiation oncologist, University of Colorado Anschutz School of Medicine, Aurora, Colo.
Brain metastases develop when cancer spreads from elsewhere in the body to the brain and are typically removed surgically or treated with one of two non-invasive radiation therapy approaches. Stereotactic radiosurgery (SRS) directs high-dose radiation therapy precisely to individual lesions while limiting exposure to surrounding brain tissue. Whole brain radiation therapy (WBRT) treats the entire brain, including both visible tumors and microscopic cancer that may not yet appear on scans.
For many other solid tumors, radiosurgery has become a standard treatment for patients with a limited number of brain metastases after randomized trials showed better preservation of cognitive function and quality of life compared with WBRT. Patients with small cell lung cancer were largely excluded from those prior studies, however, leaving whole brain treatment as the traditional standard.
Whole brain radiation therapy has also evolved to better protect cognitive function. The approach used in this study, hippocampal-avoidant (HA)-WBRT, spares the structures involved in memory and was combined with memantine, a drug that helps protect cognitive function. The trial, therefore, tested SRS against a modern, cognitive-sparing form of whole brain treatment rather than against older techniques.
"Advances in radiation therapy have fundamentally changed the options for patients with brain metastases," said Vinai Gondi, MD, lead principal investigator of the trial and director of radiation oncology at the Northwestern Medicine West Region and Proton Center in Warrenville, Ill. "NRG-CC009 reflects how far both approaches have come. For patients with small cell lung cancer, we now have two modern radiation therapy strategies to consider and randomized evidence to help us understand how best to use them."
NRG-CC009 randomly assigned 151 patients with SCLC and brain metastases between 2021 and 2026 to receive focused SRS to visible metastases or HA-WBRT plus memantine. Eligible patients had brain metastases no larger than 4 centimeters and a total tumor volume no greater than 30 cubic centimeters. The protocol initially limited enrollment to patients with up to 10 metastases but later removed the numerical limit. The median number of metastases was two, although some patients had more than 20.
The primary endpoint was the length of time before a patient experienced cognitive decline on standardized tests of memory and thinking. Researchers found no significant difference between the treatment groups.
Dr. Rusthoven said the modern whole brain treatment with hippocampal avoidance and memantine used in the control group may have narrowed the expected cognitive difference between the approaches. The survival difference between treatment arms also may have complicated interpretation of longer-term cognitive outcomes, because fewer patients in the HA-WBRT group were available for cognitive testing at later follow-up visits.
Median overall survival was 17.4 months with SRS and 8.6 months with HA-WBRT plus memantine. After adjustment for patient and disease characteristics, radiosurgery was associated with a 40% lower risk of death. Dr. Rusthoven noted that survival was a prespecified secondary endpoint, but that the trial was not designed or specifically powered to prove a survival benefit.
"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 SRS and HA-WBRT may have differential downstream effects on the disease course that affect survival. Further investigation into these areas is needed."
There were no significant differences between treatment groups in analyses of death from neurologic causes. The incidence of CNS disease progression was lower with HA-WBRT overall, but the difference was not statistically significant in analyses that adjusted for baseline patient characteristics. Rates of serious treatment-related side effects also did not differ significantly between cohorts.
"Although no differences were observed in neurocognitive function between the treatment arms, the improved survival with SRS addresses a fundamental historical concern with SCLC – that omission of WBRT might lead to worse survival" Dr. Gondi said. "Overall, these results support SRS as a reasonable option for patients with brain metastases from SCLC."
ASTRO expert perspective
"Patients with small cell lung cancer 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," said 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.
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