Hypofractionated Gamma Knife Radiosurgery for Large Brain Metastases in Surgery-Ineligible Patients: Outcomes of a Uniform 5-Fraction Regimen

Background: Surgical resection remains the standard treatment for large brain metastases (LBMs), but many patients are not surgical candidates due to poor performance status or uncontrolled systemic disease. Gamma Knife-based hypofractionated stereotactic radiotherapy (GKRS) has emerged as a potential alternative; however, its clinical role in this population remains insufficiently defined. We evaluated whether a uniform daily 5-fraction GKRS provides effective and safe local treatment for surgery-ineligible LBMs. Methods: We retrospectively analyzed 100 patients with LBMs (>14 cm3) who underwent primary hypofractionated GKRS using a uniform daily 5-fraction schedule. Forty-six patients were male; the median age was 60 years. The median Karnofsky Performance Status (KPS) was 70 (60–100); a total of 47 patients (47%) had pre-GKRS neurological deficits. The most common primary sites were lung (41), breast (24), and kidney (14). The median tumor volume was 22.0 cm3 (14–70 cm3), and the marginal dose was 35.2 Gy (50% isodose line) in 5 fractions. The primary endpoints included local tumor control (LTC), intracranial progression-free survival (PFS), and overall survival (OS). Radiation necrosis (RN) was assessed as a key safety outcome. Results: At a median follow-up of 18 months, the overall LTC rate was 74%, with 1-, 2-, and 3-year rates of 73%, 65%, and 60%, respectively. Median PFS and OS were 7.5 and 16.3 months. Higher pre-treatment KPS and absence of neurological deficits were independently associated with improved OS (p = 0.003 and 0.025, respectively). RN occurred in 16% of patients, with 9% developing symptoms; all symptomatic cases were effectively managed with corticosteroids or bevacizumab. Most tumors demonstrated substantial volumetric reduction, with a median decrease of 80% and 30% achieving near-complete response (>95%). Conclusions: A uniform daily 5-fraction hypofractionated GKRS provides effective local control with acceptable toxicity in patients with LBMs. These findings support its role as a feasible local treatment option in selected patients who are not candidates for surgery. Integration with systemic therapies and prospective validation are warranted to refine patient selection and optimize outcomes.