Simple SummaryBased on Radiation Therapy Oncology Group (RTOG) 90-05, a maximum biologically effective dose (BED) of 45 Gy12is recommended for the stereotactic radiosurgery (SRS) of brain metastases measuring 21–30 mm. Given that patients on RTOG 90-05 received prior brain irradiation, the tolerable BED for de novo lesions may be >45 Gy12. We investigated radiation necrosis (RN) after single-fraction SRS or fractionated stereotactic radiotherapy (FSRT) with BED > 49 Gy12for 1–4 radiotherapy-naïve brain metastases. In the entire cohort (169 patients with 218 lesions) and in patients with all brain metastases ≤ 20 mm (137 patients with 185 lesions), 1-year and 2-year RN rates were not significantly different after SRS or FSRT. In patients with metastases > 20 mm (32 patients with 33 lesions), the RN rates were significantly higher after SRS in both per-patient and per-lesion analyses. Moreover, in the SRS group, lesion size > 20 mm was significantly associated with RN. FSRT with BED > 49 Gy12was associated with low RN risk for metastases > 20 mm and appeared to be safer than SRS for such lesions.AbstractIn Radiation Therapy Oncology Group 90-05, the maximum tolerated dose of single-fraction radiosurgery (SRS) for brain metastases of 21–30 mm was 18 Gy (biologically effective dose (BED) 45 Gy12). Since the patients in this study received prior brain irradiation, tolerable BED may be >45 Gy12for de novo lesions. We investigated SRS and fractionated stereotactic radiotherapy (FSRT) with a higher BED for radiotherapy-naive lesions. Patients receiving SRS (19–20 Gy) and patients treated with FSRT (30–48 Gy in 3–12 fractions) with BED > 49 Gy12for up to 4 brain metastases were compared for grade ≥ 2 radiation necrosis (RN). In the entire cohort (169 patients with 218 lesions), 1-year and 2-year RN rates were 8% after SRS vs. 2% and 13% after FSRT (p= 0.73) in per-patient analyses, and 7% after SRS vs. 7% and 10% after FSRT (p= 0.59) in per-lesion analyses. For lesions ≤ 20 mm (137 patients with 185 lesions), the RN rates were 4% (SRS) vs. 0% and 15%, respectively, (FSRT) (p= 0.60) in per-patient analyses, and 3% (SRS) vs. 0% and 11%, respectively, (FSRT) (p= 0.80) in per-lesion analyses. For lesions > 20 mm (32 patients with 33 lesions), the RN rates were 50% (SRS) vs. 9% (FSRT) (p= 0.012) in both per-patient and per-lesion analyses. In the SRS group, a lesion size > 20 mm was significantly associated with RN; in the FSRT group, lesion size had no impact on RN. Given the limitations of this study, FSRT with BED > 49 Gy12was associated with low RN risk and may be safer than SRS for brain metastases > 20 mm.