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Background  Hypofractionated-SRS (HF-SRS) may allow for improved local control and a reduced risk of radiation necrosis compared to single-fraction-SRS (SF-SRS). However, data comparing these two treatment approaches are limited. The purpose of this study was to compare clinical outcomes between SF-SRS versus HF-SRS across our multi-center academic network.    Methods  Patients treated with SF-SRS or HF-SRS for brain metastasis from 2013 to 2018 across 5 radiation oncology centers were retrospectively reviewed. SF-SRS dosing was standardized, whereas HF-SRS dosing regimens were variable. The co-primary endpoints of local control and radiation necrosis were estimated using the Kaplan Meier method. Multivariate analysis using Cox proportional hazards modeling was performed to evaluate the impact of select independent variables on the outcomes of interest. Propensity score adjustments were used to reduce the effects confounding variables. To assess dose response for HF-SRS, Biologic Effective Dose (BED) assuming an α/β of 10 (BED 10 ) was used as a surrogate for total dose.    Results  One-hundred and fifty six patients with 335 brain metastasis treated with SF-SRS ( n  = 222 lesions) or HF-SRS ( n  = 113 lesions) were included. Prior whole brain radiation was given in 33% ( n  = 74) and 34% ( n  = 38) of lesions treated with SF-SRS and HF-SRS, respectively ( p  = 0.30). After a median follow up time of 12 months in each cohort, the adjusted 1-year rate of local control and incidence of radiation necrosis was 91% (95% CI 86–96%) and 85% (95% CI 75–95%) ( p  = 0.26) and 10% (95% CI 5–15%) and 7% (95% CI 0.1–14%) ( p  = 0.73) for SF-SRS and HF-SRS, respectively. For lesions > 2 cm, the adjusted 1 year local control was 97% (95% CI 84–100%) for SF-SRS and 64% (95% CI 43–85%) for HF-SRS ( p  = 0.06). On multivariate analysis, SRS fractionation was not associated with local control and only size ≤2 cm was associated with a decreased risk of developing radiation necrosis (HR 0.21; 95% CI 0.07–0.58,  p  < 0.01). For HF-SRS, 1 year local control was 100% for lesions treated with a BED 10  ≥ 50 compared to 77% (95% CI 65–88%) for lesions that received a BED 10  < 50 ( p  = 0.09).    Conclusions  In this comparison study of dose fractionation for the treatment of brain metastases, there was no difference in local control or radiation necrosis between HF-SRS and SF-SRS. For HF-SRS, a BED 10  ≥ 50 may improve local control.

A multi-center analysis of single-fraction versus hypofractionated stereotactic radiosurgery for the treatment of brain metastasis