Predictors of Radiation Necrosis and Dose/Volume Tolerance of the Brain after Three-Fraction Radiosurgery for Brain Metastases: A Large Single-Institutional Analysis

Abstract

<h3>Purpose/Objective(s)</h3> Stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) is the current standard of care in patients with brain metastases and controlled extracranial disease. Radiation necrosis (RN) is the dose-limiting side-effect of SRS but the dose constraints are poorly defined. FSRT can decrease risk of RN over SRS while maintaining or improving high rates of overall survival (OS). We assessed the survival and risk of RN after FSRT with a goal to identify specific dose/volume constraints associated with grade 3 or higher RN using NTCP modeling. <h3>Materials/Methods</h3> A single-institutional retrospective review of patients treated with 3-fraction FSRT from 2015 to 2020 was performed. Tissue volume (brain + target) around each target lesion was contoured in a consistent manner and volumetric doses per lesion were recorded. RN was defined using biopsy or MRI with perfusion as available and graded using CTCAE version 5.0. Our primary endpoint was grade 3 or higher RN. All statistical analyses were performed using statistical software. <h3>Results</h3> From 2015 to 2020, a total of 439 patients underwent 509 courses of 3-fraction Linac-based FSRT, treating a total of 2394 metastatic lesions (range 1-71, mean = 4.7 and median = 3 lesions per course). 61 patients had ≥10 and 31 patients had ≥15 lesions treated per course. Median RT dose per fraction was 8 Gy (range 5-9 Gy). 11.8% patients received prior whole brain radiation (WBRT). Median follow-up after RT was 8 months (IQR 3-18m). A total of 64 patients (78 lesions) developed RN with 17, 17, 29 and 1 patients developing grade 1, 2, 3 and 4 RN respectively. Grade 3 or higher RN was observed in 5.9% patients. On per lesion analysis, rate of any RN and grade 3 RN was 3.2% and 1.5% respectively. Median time to RN was 11.3m (range 0.7 – 38.4). Of 30 patients with grade 3 or higher RN, 7 (23%) received prior WBRT, 19 (63%) received post-op FSRT to the cavity and 1 (3%) received pre-op FSRT. Most of these patients were managed by steroids, while 25 underwent resection and 6 received bevacizumab. Tissue volume receiving 20 Gy (V20) of <20cc or >20 cc was associated with 2.5% and 10.2% risk of RN respectively, while a V23 of <20 cc or >20 cc was associated with 2.3% vs 12.1% risk of grade 3 or higher RN. Mean V20 in patients who developed Grade 3 or higher RN was statistically higher than the entire cohort (36.9cc vs 14.1cc, p=0.002). Median OS after RT was 10m (1yr and 2yr OS of 45.8% and 30.4%, respectively) while patients who developed RN survived longer compared to rest of the cohort (32m vs 8m, p <0.001). Patients with 15 or more lesions treated per course had similar survival compared to rest of the cohort (8m vs 10m, p = 0.136), after excluding those who received prior WBRT. <h3>Conclusion</h3> In patients receiving 3 fraction FSRT, grade 3 or higher RN was seen in 5.9% patients and 1.5% lesions treated. Risk of RN was significantly lower in patients with V23 of <20 cc. Further studies evaluating the outcomes and RN in patients treated with FSRT compared to SRS or hippocampal avoidance WBRT are warranted.