Stereotactic radiotherapy (SRT) is an effective treatment for patients with a limited number of brain metastases (BM). However, radionecrosis (RN) remains a concern, particularly in long-term survivors, as its distinction from tumor progression is challenging and may lead to inappropriate salvage strategies. Fractionated stereotactic radiotherapy (FSRT) has been proposed to improve the therapeutic ratio for larger lesions or postoperative cavities, but the optimal dose and fractionation remain uncertain.

We conducted a retrospective single-center study involving all consecutive patients who received SRT with CyberKnife^® for BM between January 1, 2016, and December 31, 2023. Local control (LC) and RN were assessed on MRI according to RANO-BM criteria; RN was graded using CTCAE v5.0.

A total of 131 patients with 197 BM were analyzed with a median follow-up of 41.7 months (range, 1.7–207.8). Median age was 63.4 years; lung cancer was the most common primary (70.2%). Most patients had a single BM (68.8%) and received treatment in the first-line metastatic setting (70.2%). At the lesion level (n = 197), most targets received 27 Gy in 3 fractions (52.3%) or 30 Gy in 5 fractions (45.7%). Crude LC was 85.3%, with 29 local failures. Larger BM was significantly associated with local failure (HR 1.03; 95% CI 1.01–1.05; p = 0.017). Median brain progression-free survival (bPFS) was 9.8 months (95% CI 7.4–13.6). Brain progression correlated with the initial number of BM (HR 1.41; 95% CI 1.10–1.8; p = 0.006). RN occurred in 42 patients (32.1%), symptomatic in 14.5% cases (11.4% grade 2, and 3.1% grade 3). Larger size of BM (HR 1.58; 95% CI 1.04–2.49; p = 0.048) and prior surgery (HR 2.12; 95% CI 1.05–4.33; p = 0.037) were independent predictors of RN.

FSRT achieved durable LC with acceptable rates of symptomatic RN in this cohort. Tumor volume and prior surgery were associated with both LC and RN, supporting individualized dose–fractionation strategies based on lesion size and clinical context. Further prospective data are needed to refine dose constraints and integrate evolving therapies.