Phase I Trial of Dose Escalation for Preoperative Stereotactic Radiosurgery for Patients with Large Brain Metastases

This is a phase I clinical trial that explored the safety of preoperative single-fraction stereotactic radiosurgery (SRS) with dose escalation for patients with brain metastases. The background of this study is that for brain metastases larger than 2cm in diameter, surgery alone or single-fraction SRS alone is difficult to achieve ideal local control. Therefore, the researchers hoped to improve local control rates and reduce the risk of complications by preoperative single-fraction SRS followed by surgical resection.

This study was conducted by Erin S. Murphy and colleagues from the Cleveland Clinic from September 2013 to June 2022. Patients were divided into three groups with tumor diameters of >2-3cm, >3-4cm, and >4-6cm, respectively. Different starting radiation doses (18, 15, and 12 Gy) were used for each group, and the dose was escalated by 3 Gy in each level until dose-limiting toxicity (DLT) was observed.

A total of 35 patients/36 lesions were enrolled. In the >2-3cm group, patients had escalated to the second dose level of 21 Gy; in the >3-4cm and >4-6cm groups, they escalated to the third dose level of 21 and 18 Gy, respectively. Two DLTs (grade 3 wound dehiscence and infection) were observed in the 21 Gy >3-4cm group, and thus the maximum tolerated dose (MTD) for this group was determined as 18 Gy; the MTD for the >4-6cm group was also 18 Gy.

The median follow-up after surgery was 64 months. The local control rates at 6 and 12 months were 85.9% and 76.6%, respectively. Only one case of grade 3 radiation necrosis and one case of leptomeningeal metastasis were observed. The researchers concluded that preoperative dose-escalated SRS followed by surgical resection for brain metastases had acceptable acute toxicity, and a phase II trial would be initiated to evaluate the efficacy at the MTD.

The innovation of this study lies in the first systematic exploration of the safety of preoperative single-fraction SRS with dose escalation for brain metastases, providing new insights for improving local control rates for brain metastases in the future. The results showed that the acute complications of this treatment were manageable, with a relatively low local recurrence rate, and no increased risk of leptomeningeal dissemination was observed. Notably, this strategy may potentially improve the currently suboptimal prognosis of brain metastases.