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

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Title: Phase 1/2 Dose Escalation Trial of 3-Fraction Stereotactic Radiosurgery for Resection Cavities from Large Brain Metastases.
Authors: Klebaner, Daniella1 (AUTHOR), Pollom, Erqi L.1 (AUTHOR), Rahimy, Elham1 (AUTHOR), Gibbs, Iris C.1 (AUTHOR), Adler, John R.2 (AUTHOR), Chang, Steven D.2 (AUTHOR), Li, Gordon2 (AUTHOR), Choi, Clara Y.H.3 (AUTHOR), Soltys, Scott G.1 (AUTHOR) sgsoltys@stanford.edu
Source: International Journal of Radiation Oncology, Biology, Physics. Aug2025, Vol. 122 Issue 5, p1292-1300. 9p.
Subjects: Nodular disease, Stereotactic radiosurgery, Central nervous system, Brain metastasis, Overall survival
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. [ABSTRACT FROM AUTHOR]
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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. [ABSTRACT FROM AUTHOR]
ISSN:03603016
DOI:10.1016/j.ijrobp.2025.03.015