Phase I trial of dose escalation for preoperative stereotactic radiosurgery for patients with large brain metastases

Abstract Background Single-session stereotactic radiosurgery (SRS) or surgical resection alone for brain metastases larger than 2 cm results in unsatisfactory local control. We conducted a phase I trial for brain metastases(>2 cm) to determine the safety of preoperative SRS at escalating doses. Methods Radiosurgery dose was escalated at 3 Gy increments for 3 cohorts based on maximum tumor dimension starting at: 18 Gy for >2–3 cm, 15 Gy for >3–4 cm, and 12 Gy for >4–6 cm. Dose-limiting toxicity was defined as grade III or greater acute toxicity. Results A total of 35 patients/36 lesions were enrolled. For tumor size >2–3 cm, patients were enrolled up to the second dose level (21 Gy); for >3–4 cm and >4–6 cm cohorts the third dose level (21 and 18 Gy, respectively) was reached. There were 2 DLTs in the >3–4 cm arm at 21 Gy. The maximum tolerated dose of SRS for >2–3 cm was not reached; and was 18 Gy for both >3–4 cm arm and >4–6 cm arm. With a median follow-up of 64.0 months, the 6- and 12-month local control rates were 85.9% and 76.6%, respectively. One patient developed grade 3 radiation necrosis at 5 months. The 2-year rate of leptomeningeal disease (LMD) was 0%. Conclusions Preoperative SRS with dose escalation followed by surgical resection for brain metastases greater than 2 cm in size demonstrates acceptable acute toxicity. The phase II portion of the trial will be conducted at the maximum tolerated SRS doses.