Adverse Radiation Effect and Disease Control in Patients Undergoing Concurrent Stereotactic Radiosurgery and Immunotherapy for Brain Metastases

Abstract

Immune checkpoint inhibitors (ICIs) and stereotactic radiosurgery (SRS) are increasingly used in the management of patients with brain metastases (BMs). We evaluated the impact of concurrent ICIs and SRS on rates of adverse radiation effect (ARE), patterns of failure, and overall survival (OS). In this institutional review board-approved retrospective study, we reviewed the records of patients treated for BMs with SRS and ICIs at our institution from 2011 to 2017. We included patients who received ipilimumab, nivolumab, pembrolizumab, atezolizumab, or a combination one month before or after SRS. ARE was defined by pathologic confirmation of necrosis or radiologic evidence on serial MRIs as determined by the treating radiation oncologist and neurosurgeon. We analyzed data per lesion (local failure [LF], ARE), per SRS course (distant intracranial failure, extracranial failure), and per patient (OS). Failure time was defined from the end of SRS and survival was defined from diagnosis with BMs. Cumulative incidence rates and competing risk regressions were used to evaluate ARE and patterns of failure with death as a competing risk. We identified 62 patients with 265 BMs and follow-up imaging who met our inclusion criteria. Median age was 63 years (interquartile range [IQR] 43-71 years). Primary tumor histologies included melanoma (45%), non-small cell lung cancer (40%), and renal cell carcinoma (5%), and 81% had extracranial metastases at the time of SRS. Median SRS dose was 22 Gy (IQR 20-24 Gy), with 88% of lesions treated in one fraction. 55% (n=146) of lesions were treated with SRS between doses of ICI. 42 (16%) lesions were treated with ipilimumab, 174 (66%) with anti-PD1/PDL1 ICIs, and 49 (18%) with a combination. Median follow-up time from the end of SRS was 9.0 months (range 0.8 to 46.2 months). Median OS for patients treated with SRS before, between ICI doses, and after ICI therapy was 12.3, 15.9, and 8.5 months, respectively (p=0.04). 1-year cumulative incidence of ARE was 8.2% (95% confidence interval [CI] 5.2-12.1%). 1-year cumulative incidence of LF, distant intracranial failure, and extracranial failure was 4.4% (95% CI 2.3-7.4%), 60.1% (95% CI 47.9-70.3%), and 55.3% (95% CI 43.3-65.7%), respectively. Greater maximum lesion diameter in mm at the time of SRS was associated with ARE (HR 1.02; p=0.004) and LF (HR 1.03; p=0.03). The number of BMs treated per course of SRS was associated with distant intracranial failure (HR 1.12; p<0.001). Lesions treated with pembrolizumab (vs ipilimumab) were less likely to develop ARE (HR 0.12; p=0.05). SRS within 1 month of ICIs is associated with low rates of ARE and LF. Lesion size may be used to predict risk of ARE or LF while the number of BMs may be used to predict risk of distant intracranial failure. Future study of the optimal timing of SRS and ICIs is warranted.