Quantitative Volumetric Tumor Response And Toxicity Outcomes In Patients Treated With Combination Stereotactic Radiosurgery (SRS) And Immunotherapy For Melanoma Brain Metastases

Abstract

Stereotactic radiosurgery (SRS) confers excellent local control for melanoma brain metastases (MBM). Factors impacting the rate of volumetric regression in the follow-up period, including the nature and timing of systemic therapy, are poorly understood. This study examines the impact of systemic therapy on MRI volumetric tumor response over time of melanoma brain metastases following SRS. A retrospective analysis was performed of patients who received single-fraction Cobalt-based SRS for MBM from January 2016 to June 2019. Predictive factors relating to SRS dose, volume and systemic therapy treatment factors such type (CTLA-4, PD-1 and/or BRAF/MEK inhibitors) and timing were collected. Treatment volume of each lesion was delineated on a T1-weighted Gadolinium contrast enhanced MRI at baseline and follow-up. Cubic spline interpolation was used to impute missing data across time intervals. The primary outcome was relative volumetric change in T1-contrast enhancement at 3, 6, 9, 12- and 15-months relative to baseline. A repeated measures ANOVA was used to assess for differences in mean volumetric change between intervals. A linear mixed multivariate regression analysis was performed to assess the relationship between explanatory variables and volumetric change with a two-tailed significance of α = 0.05. 101 patients with 425 MBM were treated with SRS. Median follow-up was 29.2 months (IQR 19.7-39.8). Median dose, baseline volume and lesion diameter were 20Gy (IQR 18-20), 0.24cc (IQR 0.06-1.02) and 7.7mm (IQR 4.8-12.4). 53% of patients were BRAF mutant. 65% had failed BRAF inhibitors at time of SRS. 34% of patients received BRAF inhibitors concurrently (± 48 hours). 77% of patients received concurrent CTLA-4/PD-1 immunotherapy (2 weeks prior-4 weeks post-SRS). Median interpolated lesion size at 3, 6, 9, 12 and 15-month was 73.6%, 55.4%, 49.7%, 54.2% and 42.5% of baseline respectively. There was a statistically significant decrease in lesion size in the 0-3 and 3-6 month interval (p<0.001). Lesion regression stabilized after 6-months. 89.7% of treated lesions had durable local control on MRI at last follow-up. Patients receiving concurrent immunotherapy had a significantly greater regression in tumor volume at 3-months (37% superior [95% CI 6-68.1%, p = 0.02] and 6-months (48% superior [95% CI 7.4-89.5%, p = 0.02] compared to those commencing >4 weeks post SRS however lesion regression velocity was comparable by 9- and 12-months. A 1mm increase in maximal lesion diameter was associated with a 1.5% (95% CI 0.04-2.9, p = 0.04) and 2% (95% CI 0.4-3.7%, p = 0.016) greater reduction in volume at 3- and 6-months. 5% of patients experienced symptomatic radionecrosis (RN). 19% had non-RT grade 3 or higher toxicity. This study demonstrates a significantly greater volumetric regression with concurrent immunotherapy and SRS in MBM in the initial 6 months post SRS. Combined modality treatment offers excellent local control with low RN specific toxicity.