Radiation Necrosis with Stereotactic Radiosurgery Combined with CTLA-4 Blockade and PD-1 Inhibition for Treatment of Intracranial Disease in Metastatic Melanoma

Immune checkpoint inhibitors have demonstrated remarkable benefits in cancer patients. However, concern regarding toxicity in the setting of stereotactic radiosurgery (SRS) is often raised. In this study, we characterize radiation necrosis (RN) following immunotherapy and SRS. Melanoma patients treated with SRS and anti-CTLA-4 and/or anti-PD-1 at our institution from January 2006 to December 2015 were retrospectively reviewed. Overall survival (OS) and time to RN were assessed using Kaplan-Meier analysis. Logistic regression and Cox proportional hazards analyses were performed to identify predictors of radiation necrosis-free survival (RNFS) and RN risk. One-hundred thirty-seven patients with 1094 treated lesions over 296 SRS sessions were analyzed. Median follow-up was 9.8 months from SRS. Rate of RN was 27% of patients with median time to RN of 6 months. Median OS from SRS treatment was 16.9 months. RNFS at 6 months, 1 and 2 years was 92.7, 83.0, and 81.2%. Treatment with chemotherapy within 6 months of SRS was associated with worse RNFS at 1 year (78.4 vs. 87.5%, p = 0.017). On multivariate analysis, chemotherapy within 6 months and increased number of lesions treated were predictive of increased RN risk (HR 2.20, 95% CI 1.22-3.97, p = 0.009; HR 1.09, 95% CI 1.03-1.15, p = 0.002), whereas immunotherapy type and targeted therapy were not predictive. Median target volume of lesions that developed RN was greater than that of lesions that did not (p < 0.001). Concurrent treatment with chemotherapy, larger size and number of lesions treated were predictive of RN. Immunotherapy type and timing proximity to SRS were not associated with RN risk.