SRS Lessens Rate of Neurologic Death vs WBRT in SCLC and Brain Metastases

Results from a phase 2 study showed a median OS of 10.2 months in all patients with small cell lung cancer who received stereotactic radiation therapy.

Stereotactic radiation led to lower rates of neurologic death compared with whole-brain radiation (WBRT) in patients with small cell lung cancer (SCLC) and 1 to 10 brain metastases who were surveilled closely following treatment, according to results from a phase 2 trial (NCT03391362) published in the Journal of Clinical Oncology.1

In all patients, the median overall survival (OS) was 10.2 months (95% CI, 8.5-12.2); there was a total of 20 neurologic deaths compared with 64 non-neurologic deaths. Between the 2 reviewers, agreement was 98% regarding neurologic death and non-neurologic death, with disagreement requiring a tie occurring in 2%.

The 1-year and 2-year neurologic death incidence was 11.0% (95% CI, 5.8%-18.1%) and 20.3% (95% CI, 12.7%-29.1%), respectively. The trial investigators noted that the historical incidence of neurologic death with WBRT was 17.5% at 1 year and 35.2% at 2 years. The 1-year and 2-year incidence of non-neurologic death was 48.0% (95% CI, 37.9%-57.4%) and 61.7% (95% CI, 50.8%-70.8%).

Via the Fine and Gray regression analysis, age, number of brain metastases, size of largest brain metastases, presence of neurologic symptoms, presence of distant extracranial metastases, and employment of neurological resection before enrollment were not associated with neurological death (P >.05 in all cases).

New brain metastases were developed by 61.0% of patients, with a 1-year estimate of 59.0% (95% CI, 48.6%-68.0%); at least 1 course of salvage stereotactic radiation was received by 39.0% of patients, with a 1-year estimate of 37.0% (95% CI, 27.5%-46.5%); WBRT was received by 22.0%, with a 1-year estimate of 21.0% (95% CI, 13.6%-29.5%); and leptomeningeal disease was observed in 9.0%, with a 1-year estimate of 7.0% (95% CI, 3.1%-13.1%).

Overall, systemic disease progression occurred in 65.0% of patients, with a 1-year estimate of 58% (95% CI, 47.6%-67.0%).

Additionally, in aggregate, at least 1 local recurrence in a metastasis treated in the study was experienced by 13.0%, with a 1-year estimate of 15.0% (95% CI, 8.8%-22.7%); the respective per-patient rates of radiographic and symptomatic necrosis were 9.0% and 5.0% in total, with 1-year estimates of 6.0% (95% CI, 2.4%-11.9%) and 3.0% (95% CI, 0.8%-7.9%), respectively.

“Despite being the historical standard, whole brain radiation might not be necessary for all patients,” stated first study author Ayal Aizer, MD, MHS, director of Central Nervous System Radiation Oncology at Brigham and Women’s Hospital, and a founding member of the Mass General Brigham healthcare system, in a press release on the study.2 “Our findings demonstrate that targeted, brain-directed radiation may be a viable treatment for patients with limited brain metastases from SCLC and potentially spare them from the [adverse] effects of whole brain radiation.”

The trial enrolled a total of 100 patients who were 18 years or older with SCLC or an extrathoracic small cell primary and 1 to 6 intracranial lesions consistent with brain metastases. All patients received brain-directed stereotactic radiation within 21 days of radiation, and it was delivered with volumetric-modulated arc therapy on a linear accelerator in all cases but one. Those with tumors smaller than 2 cm in maximal unidimensional size were treated with 20 Gy in 1 fraction, and those with larger tumors were treated with lower doses to maintain a volume of surrounding brain receiving 12 Gy (V12) of less than 10cc.

If the brain V12 metric was not met at 16 Gy, tumors were treated with 30 Gy in 5 fractions. Furthermore, gross totally resected metastases received 25 Gy in 5 fractions, and residual or recurrent lesions received 30 Gy in 5 fractions via simultaneous integrated boost, postoperatively.

Trial exclusion criteria included patients who had leptomeningeal disease, stage IV to V chronic kidney disease, end-stage renal disease, or an inability to undergo a contrast-enhanced MRI study of the brain.

The primary end point of the trial was neurologic death defined as marked, progressive radiographic progression in the brain accompanied by corresponding neurologic symptomatology in the absence of systemic disease progression or systemic symptoms of a life-threatening nature. Secondary end points included OS, systemic disease progression, seizures, and the incidence and time to detection of new brain metastases, among others.

Regarding safety, observed toxicities of grades 3 were esophagitis (n = 1), anorexia (n = 1), muscle weakness (n = 1), edema cerebral (n = 1), intracranial hemorrhage (n = 1), seizure (n = 4), syncope (n = 1), and atelectasis (n = 1); the only grade 4 toxicity was a nervous system disorder (n = 1). Death was observed in 82 patients.

“These results support a shift toward more personalized, targeted treatment approaches that can help maintain quality of life while effectively managing brain metastases. By avoiding whole brain radiation in select patients, we may be able to improve quality of life and reduce cognitive [adverse] effects without compromising outcomes,” concluded Aizer.2

References

1. Aizer AA, Tanguturi SK, Shi DD, et al. Stereotactic radiosurgery in patients with small cell lung cancer and 1-10 brain metastases: a multi-institutional, phase II, prospective clinical trial. J Clin Oncol. Published online July 11, 2025. doi:10.1200/JCO-25-00056
2. Targeted radiation offers promise in patients with metastasized small cell lung cancer to the brain. News release. Mass General Brigham. July 11, 2025. Accessed July 14, 2025. https://tinyurl.com/yhbzrccs