The Incidence and Its Associated Factors Relevant to Brain Radionecrosis That Requires Intervention Following Single or Fractionated Stereotactic Radiosurgery Using Vero4DRT for Brain Metastases

Purpose: Several factors, including the surrounding brain volume receiving specific doses, have hitherto been reported to correlate with brain radionecrosis (BR) after single or fractionated stereotactic radiosurgery (sSRS or fSRS) for brain metastases (BMs); however, those, especially for fSRS, have not yet been fully elucidated. Furthermore, the clinical outcome data of patients with BM treated with SRS using Vero4DRT are extremely limited. Therefore, this study aimed to demonstrate the incidence of BR requiring intervention (BRRI) and its highly correlated factors. Materials and Methods: Patients with BMs treated with sSRS or fSRS using Vero4DRT at Toyohashi Municipal Hospital between July 2017 and June 2021 were retrospectively reviewed, of whom patients were available for at least 20 weeks of magnetic resonance imaging follow-up from SRS were included, and analyzed. The prescribed dose fractionation schemes to the planning target volume (PTV) boundary included 24 Gy (sSRS), 35 Gy (5 fractions [fr]), 42 Gy (10 fr), and 30 Gy (3 fr), according to the tumor volume and location. The volume of the surrounding normal brain receiving 84 Gy (V84 Gy, biologically effective dose [BED2] based on a linear-quadratic model with an alpha/beta ratio of 2, single-dose equivalent [SDE] to 12 Gy), V112 Gy (BED2, SDE to 14 Gy) for all lesions, and all irradiated volume, including gross tumor volume (GTV) receiving 81.6 Gy (81.6 Gy vol., BED2) for fSRS were calculated, for which cerebrospinal fluid and bone volumes were cautiously excluded. The diagnosis of tumor progression or BR dominance was based on serial T1/T2 matching. Results: Sixty patients with 120 lesions (65 treated with sSRS and 55 treated with fSRS) were included in the final analysis, with a median follow-up period of 65 weeks. The local control rate at one year was 87.5%. The cumulative incidence of BRRI within two years was 11.5%. The risk of symptomatic BR was significantly higher for V84 Gy >10 cc (p <0.001) and V112 Gy >5 cc (p = 0.021). In the fSRS group, the cumulative incidence of Grade 3 BR and those requiring resection was significantly higher for 81.6 Gy vol. >14 cc (p = 0.003 and p = 0.004, respectively). The coexistence of viable tumor tissue and BR could not be ruled out for enlarging lesions after the nadir response, especially for fSRS, due to a lower BED10 to GTV margin (<80 Gy, BED10). Conclusions: Stereotactic irradiation with Vero4DRT provided efficacy and safety comparable to previous linear accelerator series, and most of the dose-volume thresholds for BRRI presented in this study were notably lower than those reported in previous studies. This study suggests that the indication of single and up to 5 frSRS should be limited to far smaller tumors than previously acknowledged to ensure long-term safety and efficacy.