Phase 1/2 Dose Escalation Trial of 3-Fraction Stereotactic Radiosurgery for Resection Cavities from Large Brain Metastases.

Abstract

We performed a dose escalation trial of hypofractionated stereotactic radiosurgery (SRS) to determine the maximum tolerated dose (MTD) of 3-fraction SRS for brain metastases resection cavities. Following surgical resection of a brain metastasis, patients were enrolled by SRS treatment volume onto 2 arms: arm 1 = 4.2-14.1 cm³, approximating a 2 to 3 cm diameter sphere, and arm 2 = 14.2-33.5 cm³ or a 3 to 4 cm sphere equivalent. Dose escalation levels were 24, 27, 30, and 33 Gy in 3 consecutive-day fractions, with 6 patients at each dose level in a 6 + 6 trial design. Dose-limiting toxicity was defined as either acute (within 30 days of SRS) grade 3 to 5 central nervous system toxicity and/or late grade 3 to 5 radiation necrosis occurring at any subsequent timepoint. The MTD was defined as the highest dose where 0 to 1 out of 6 or 0 to 3 out of 12 had a dose-limiting toxicity. From 2009 to 2014, 48 evaluable patients were enrolled. One (2%) patient had acute G3 toxicity; dose escalation proceeded to 33 Gy. No MTD was reached. Overall, 14 (29%) of 48 patients had G1-4 late radiation necrosis; G1 in 4 (8%), G2 in 6 (13%), G3 in 2 (4%), and G4 in 2 (4%). At the 33 Gy dose level, any grade necrosis was 58% in all 12 patients, 83% in the 6 patients on the larger volume arm 2; no G3-4 necrosis occurred in smaller arm 1 targets. With a median overall survival of 24 months (95% CI, 18-35), the 1-year cumulative incidence rates were: 10% (95% CI, 3.8-21) for local progression, 48% (95% CI, 33-61) for distant intracranial progression, and 13% (95% CI, 5-24) for radiation necrosis. Nodular meningeal disease occurred in 15% (7 of 48) of patients. Grade 3 to 4 toxicity was 8% and no MTD was reached with dose escalation to 33 Gy in 3 fractions. However, with a 58% incidence of G1-4 radiation necrosis at the 33 Gy level and 33% G3-4 necrosis at 30 Gy on arm 2, a 3-fraction dose of 27-30 Gy for targets 2 to 3 cm and 27 Gy for targets 3 to 4 cm may provide the optimal balance between toxicity and tumor control. A dose of 33 Gy is reserved for cavities <3 cm where tumor control may benefit from higher doses.