Immune Checkpoint Inhibition and the Risk of Radionecrosis in Patients Treated with SRS for Brain Metastases

Abstract

Stereotactic radiosurgery (SRS) is the preferred non-surgical treatment for patients (pts) with brain metastases (BMs). Pts often take immune checkpoint simultaneously (SRS+ICI) to manage their systemic disease. SRS+ICI may act synergistically to intensify the immune response. In pts with BMs, the combination of SRS and ICI (SRS+ICI) may improve outcomes but potentially at the expense of increased radionecrosis (RN). The objective of this study was to compare outcomes for pts undergoing SRS with and without ICI. We retrospectively reviewed pts treated for BMs with single or multi-fraction SRS at our primary academic institution and affiliated community practices. ICI included anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4, ipilimumab), anti-programmed cell death protein receptor (PD-1, pembrolizumab, nivolumab) and anti-programmed cell death ligand (PD-L1, durvalumab). Local control (LC), symptomatic radiation necrosis (RN) and overall survival (OS), stratified by receipt of ICI, were estimated using Kaplan-Meier survival curves. Symptomatic RN was defined by a pt’s need for medication intervention to manage their symptoms. Univariate and step-wise multivariate analyses (MVA) with propensity adjustments were performed. One-hundred and sixty-nine pts were treated with SRS to 314 BMs and followed for 7.1 months (median). Sixty-two BMs were treated with SRS + ICI, received in the 3 months prior (n=20, 32.3%), 3 months after (n=31, 50%) or concurrently (n= 11, 18%) with SRS. Three pts received concurrent or sequential dual anti CTLA-4 and PD-1 therapy. The one-year LC rate for BMs treated with SRS + ICI was 95.2% compared to 85.2% for BMs treated with SRS alone (p=0.18). OS was similar between the groups (SRS: 40% vs. SRS+ICI: 38%, p=0.80). At one-year, 9.3% of BMs treated with SRS + ICI developed symptomatic RN vs. 8.5% of BMs treated with SRS alone (p=0.85). After MVA with propensity adjustments, non-squamous histology was associated with improved LC (HR 0.33, 95% CI 0.11-0.98, p=0.045) and resected BMs were associated with inferior LC (gross total resection: HR 2.57, 95% CI 0.71-9.29, p=0.15, sub-total resection: HR 10.79, 95% CI 3.43-33.97, p<0.0001). BMs ≥2 cm predicted for symptomatic RN (HR 10.72, 95% CI 4.16-27.60, p<0.0001). This experience suggests that SRS + ICI is safe and not associated with increased risk of symptomatic, grade 2+ RN. Apprehension regarding increased toxicity with SRS + ICI may prompt clinicians to change their standard treatment practices for SRS, for example by lowering the dose prescribed to a BM. This experience suggests this may not be necessary and SRS + ICI may not increase the risk of symptomatic RN. Although there was a trend towards improved LC for BMs treated with SRS + ICI, this difference was not statistically significant. Further follow-up is needed to fully analyze these findings.