Objective: Patients with renal cell carcinoma brain metastases are frequently treated with a bimodality regimen consisting of immune checkpoint inhibitors (ICI) and stereotactic radiosurgery (SRS). Multiple single institution retrospective studies have suggested this therapy to be both safe and effective with improved overall survival (OS) with concurrent therapy (SRS and ICI administered within 4 weeks of one another). However, those studies were largely limited to other tumor histologies, and data regarding the risk of development of radiation necrosis are markedly limited. We hypothesized that SRS and ICI may be administered concurrently without an increased risk of developing radiation necrosis.  
     
Methods: This analysis was approved by the International Radiosurgery Research Foundation. Radiation necrosis was evaluated using the CTCAE 5.0 toxicity grading system. Rates of any grade radiation necrosis and symptomatic radiation necrosis (Grade 2+) were compared for concurrent and non-concurrent therapy using the chi-square test. Univariate logistic regression was used to identify factors associated with an increased risk of developing radiation necrosis of any grade. The Kaplan Meier method and log-rank test were used to compare 1-year OS and 1-year local control (LC) for the concurrent and non-concurrent groups, where the null-hypothesis was rejected for p<0.05.    
    
Results: There were 50 patients included in the analysis with 382 brain metastases across 7 international institutions. The median follow-up was 12.1 months; median age was 65 years (range: 49-85 years). Active extracranial disease was present in 86% of patients. The median Karnofsky Performance Status (KPS) was 80. The median margin dose was 20 Gy prescribed to the 50% isodose line. All patients were treated with single fraction SRS and 4% underwent prior whole brain radiation therapy (WBRT). The median treated tumor volume was 3.32 cm3 (range: 0.06-42.38 cm3). The median V12 was 8.42 cm3 (range: 0.27-111.22 cm3). Radiation necrosis of any grade occurred in 17.4% and 21.9% of patients in the concurrent and non-concurrent groups, respectively (p=0.17). Symptomatic radiation necrosis occurred in 4.3% and 12.5% of patients in the concurrent and non-concurrent groups, respectively (p=0.30). On univariate logistic regression, volume of irradiated brain during SRS (OR: 1.08; 95% CI: 1.01-1.19; p=0.04) was associated with an increased risk of developing radiation necrosis and a trend was observed for increasing V12 (OR: 1.03; 95% CI: 0.99-1.06; p=0.06). The use of concurrent therapy (OR: 0.74; 95% CI: 0.17-2.30; p=0.76), KPS (OR: 0.96; 95% CI: 0.90-1.02; p=0.19), prior WBRT (OR: 0.23; 95% CI: 0.01-6.20; p=0.32), and immune checkpoint inhibitor agent were not significant predictors of radiation necrosis. The 1-year OS was 71.9% and 84.9% for the concurrent and non-concurrent groups, respectively (p=0.09). The 1-year LC was 90.9% and 96.3% for the concurrent and non-concurrent groups, respectively (p=0.45).   
       
Conclusion: Concurrent administration of ICI and SRS in patients with renal cell carcinoma brain metastases does not increase the risk of development of radiation necrosis when compared to non-concurrent therapy. Attempts to minimize V12 and consideration of fractionated radiosurgery in patients with higher volume disease are acceptable strategies to mitigate this risk. Prospective data are needed to further validate these findings.