Volume Of Disease As A Predictor For Clinical Outcomes In Patients With Melanoma Brain Metastases Treated With Stereotactic Radiosurgery And Immunotherapy

Several clinical trials of anti-PD-1 and CTLA-4 therapies have demonstrated a clinical benefit with a low incidence of neurologic adverse events in patients with melanoma brain metastases (MBMs). While the combined effect of these immunotherapies (IT) and stereotactic radiosurgery (SRS) has yielded impressive results with regards to local control and overall survival, it has also been associated with increased rates of radiation necrosis compared to historical series of SRS alone. We retrospectively reviewed patients treated with anti-PD-1, anti-CTLA-4 therapy or the combination and SRS to report on predictors of clinical outcomes. Patients were included if they had MBMs treated with SRS within one year of receiving systemic therapy with anti-PD-1 and/or CTLA-4 therapy. Clinical outcomes such as overall survival (OS), intracranial death (ID), local control of treated lesions (LC) and symptomatic radiation necrosis (RN) were correlated with type and timing of IT with SRS, size of lesions treated, number of lesions treated, total volume of lesions and radiation dose. 29 patients with 171 MBMs were treated over 60 sessions between May 2012 and May 2018. Patients had a median of 5 lesions (range 1-23) treated over a median of 2 courses of SRS. The median volume treated was 6.5 cm3 and the median dose was 21 Gy. Patients were treated with ipilimumab (n = 13), nivolumab-ipilimumab (n = 10), pembrolizumab (n = 5) and pembrolizumab-ipilimumab (n = 1). The majority of patients received at least one fraction of SRS concurrently or within 3 months of receiving immunotherapy (n = 21). 2-year OS and LC were 54.4% and 85.5%, respectively. Overall 14% of patients developed RN; however, only 4.7% of the total number of treated lesions developed RN. The median time to development of RN was 9.5 months. Patients with an aggregate tumor volume >5 cm3 were found to be at increased risk of intracranial death (p = 0.05) and RN (p = 0.03). The median time to intracranial death was 29 months in patients with tumor volume >5 cm3 and not-yet reached at 60 months in those with tumor volume < 5 cm3. There was no difference in OS, LC, IC or RN with regards to type of IT, timing of SRS and IT, number of SRS courses, SRS dose, or number of lesions treated. In our institutional analysis of patients treated with SRS and IT for MBMs we found overall excellent rates of OS and LC, however, patients with an aggregate tumor volume > 5 cm3 were found to be at increased risk of intracranial death and symptomatic radionecrosis. Given the efficacy of combined anti-PD-1/CTLA-4 therapy for MBM management, further study of optimal selection criteria for the addition of SRS is warranted.