Does Immunotherapy Influence the Risk of Developing Radiation Necrosis After Radiosurgery of Brain Metastases?

Abstract

The risk of radiation necrosis (RN) in patients with brain metastases (BM) treated with stereotactic radiosurgery (SRS) can be estimated on the volume of normal brain receiving 12 Gy (V12). Reference RN risks at 1 year for V12 <3.3 cm3 and 3.3-5.9 cm3 are 0% and 16%, respectively. It is unclear if immunotherapy (IT), now commonly used in the treatment of various malignancies, modifies the risk of RN with long term follow-up. We have correlated V12 with radiographic appearance of RN for BMs treated with SRS +/- IT. We reviewed 71 patients harboring 112 brain lesions from breast cancer (n = 9), non-small cell lung cancer (n = 28) and melanoma (n = 34) primaries. In 63 of the lesions (56%), immunotherapy was administered during the course of the patient’s treatment, while 49 lesions (44%) only received SRS. The median SRS dose was 21 Gy (range 15-24 Gy) delivered on a Linac-based platform with a 6D robotic table. The median dosimetric data (and range) for all lesions were as follows: V12 2.0 cc (0.45-18.64), GTV 0.25 cc (0.01-4.20 cc), PTV 0.51 cc (0.07-8.55 cc), conformity index CI 1.56 (1.0-2.16), prescription IDL 79.4% (69.4-99.2%) with 99.3% (88.4-100%) coverage of the PTV. Patients were followed for a median follow-up of 13.1 months with serial MRIs and RN assessments were rendered based on multiparametric MRIs with perfusion techniques; in 6/16 cases RN was pathologically proven with surgical biopsy. The radiographic incidence of RN was then correlated with dosimetric factors and the infusion (or lack thereof) of IT. Statistical analysis was performed using Kaplan Meier analysis and Fischer’s exact chi-square test. The overall incidence of radiographic RN was 14% (16/112), peaking at a median time of 14.9 month post SRS (range 8.1-71.7 months). However only 5/16 patients had symptomatic RN necessitating treatment with bevacizumab, surgery and/or pentoxifylline/vitamin E. The 1-, 2-, and 3-year rates of RN were 2.7%, 11.6%, and 13.4%, respectively, for all patients. The risk of RN correlated with V12; lesions with V12 <5.09 cc had a significantly lower risk of RN at 3 years compared to V12 ≥5.09 cc (10% vs 32%, respectively, P = 0.044). The percentage of patients that developed RN in the presence of IT was higher (12/63, 19%) than in the control group (4/49, 8%) but this did not reach statistical significance. Finally, the V12 threshold for patients receiving IT was 5.39 cc; a V12 <5.39 cc was associated with 12.5% risk of RN at 3 years vs 46% for V12 ≥ 5.39 cc. Based on this retrospective analysis, the overall incidence of RN appears to be higher in the IT group (19% vs 8%), but this could be due to longer survival secondary to systemic response to immunotherapy. As a results, the rate of RN based on Kaplan-Meier estimates continues to increase at 3-years post SRS. This information may be useful to clinicians when trying to distinguish late recurrence vs late radiation necrosis in long-term survivors receiving SRS and immunotherapy.