Risk Factors Associated With Radiation Necrosis Among Brain Metastasis Patients Undergoing Fractionated Stereotactic Radiosurgery For Cns Brain Metastases

To examine the risk factors associated with the development of symptomatic radiation necrosis (sRN) among patients with brain metastases undergoing fractionated stereotactic radiosurgery (fSRS). Patients with brain metastases treated with 5-fraction fSRS at our institution with clinical and radiographic follow-up were retrospectively reviewed. fSRS was delivered using either a Cobalt-based or LINAC-based system. sRN was defined as grade 2 or higher per CTCAE v4.0. Biologically equivalent dose in 2 Gy fractions (EQD2) was calculated using the linear-quadratic model assuming α/β ratio of 3 for brain tissue. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression analysis. Rates of sRN were estimated using Kaplan-Meier method and compared using log-rank tests. From 2011-2018, 75 patients were treated at the following prescription dose levels: 25 (n = 12), 30 (n = 46), 35 (n = 14), and > 35 Gy (n = 3) in five fractions. Fifty-three patients had not received intracranial radiation, while 22 patients (29%) had received prior brain radiation to the site of interest. The most common metastasis histology was non-small cell lung cancer (n = 36), followed by breast (n = 11), melanoma (n = 6), and colorectal (n = 5). At a median follow-up of 8 months (range 1.2 – 48), 14 patients (18.4%) developed sRN, with an equal number of sRN events in patients with and without prior intracranial RT. Among patients without prior radiation, 0% had sRN after 25 Gy (n = 5), 11.1% had sRN after 30 Gy (n = 34), 15.1% had sRN after 35 Gy (n = 14), and 100% had sRN after 40 Gy (n = 1). For patients without prior RT, radiation doses above 30 Gy were associated with increased risk of radiation necrosis (HR: 9.4, CI: 1.5 - 58.4, p = 0.016). After accounting for prior radiation exposure, a cumulative EQD2 > 60 Gy was associated with significantly higher rates of radiation necrosis (HR: 5.7, CI: 1.7 - 18.9, p = 0.004). At 1 year, 10.8% of patients with a cumulative EQD2 < 60 Gy and 59.5% of patients with an EQD2 > 60 Gy developed sRN (p = 0.002). In the absence of prior intra-cranial radiation, fSRS of up to 30 Gy in 5 fractions for brain metastasis appear to have relatively low incidence of sRN, but the tolerability of doses ≥ 35 Gy may require further investigation. Cumulative EQD2 > 60 Gy appears to be associated with higher risk of sRN. Further detailed dosimetric data with longer follow-up data is underway to better ascertain the significance of these findings.