Salvage Stereotactic Radiosurgery is Associated with Improved Overall Survival Compared to Whole Brain Radiation in the Setting of Progressive Brain Metastases

Abstract

Brain metastasis velocity (BMV) is a recently defined metric that is highly prognostic for overall survival (OS) after distant brain failure (DBF) following stereotactic radiosurgery (SRS). At time of first DBF, BMV can be calculated by dividing the number of brain metastases (BrM) by the amount of time (unit of years) since initial SRS. A proposed utility for BMV has been to help triage patients to proper salvage therapy after SRS failure based on low (BMV of <4), intermediate (BMV 4-13), and high (BMV>13) risk groups. The purpose of this study was to determine the effect of salvage modality (SRS or whole brain radiation therapy [WBRT]) on OS at the time of first salvage therapy for each BMV risk group. Patients from nine academic centers were treated with upfront SRS alone for BrM. BMV was defined as the number of new BrM at first DBF divided by the time (years) since first SRS for to create a unit of BrM/year. Patients were classified by BMV into low-, intermediate-, and high-risk groups, consisting of <4, 4 to 13, and >13 new BrM/year, respectively. Time-to-event outcomes were estimated using Kaplan-Meier method. For patients in the low, intermediate, and high-risk groups, OS was calculated by stratifying by salvage SRS or WBRT. A univariate and multivariate model (MVA) was created to evaluate OS after first DBF based on patient characteristics and salvage treatment with SRS vs WBRT. Two thousand and eighty patients were included in the study. Median OS from initial SRS was 10.2 mo (95% Confidence Interval [CI] 9.7-11.0 mo). Nine hundred and thirteen (32%) had a DBF treated with salvage SRS or WBRT. The median OS after first DBF for patients who received salvage SRS was 13.1 mo (CI 11.2-16.5 mo), 9.6 mo (CI: 7.8-11.9 mo) and 6.0 mo (CI: 4.9-9.2 mo) for patients with BMV < 4, BMV 4-13, and BMV > 13, respectively. In contrast, for patients who received salvage WBRT for DBF, median OS after initial DBF was 6.6 mo (CI: 5.0-12.7), 4.7 mo (CI: 3.9-8.6) and 3.9 mo (CI: 2.8-5.2) for patients with BMV < 4, BMV 4-13, and BMV > 13, respectively. Compared to patients who received WBRT as salvage therapy, SRS was associated with improved OS after first DBF for BMV < 4 (log-rank p=0.005), BMV 4-13 (p=0.005) and BMV >13 (p=0.0006). Salvage with SRS (vs. WBRT) remained a significant predictor of survival after DBF in multivariate models that included the covariates of age, recursive partitioning analysis class, number of BrM at time of first DBF, and histology for BMV <4 (Hazard Ratio [HR] 0.56, p=0.002), BMV 4-13 (HR 0.60, p=0.005), and BMV >13 (HR 0.48 p<0.001). Salvage SRS after progressive BrM was associated with a higher OS compared to patients treated with WBRT. This was observed across all BMV risk groups and remained significant on MVA. Initial steps have been taken to validate these findings in a multi-institutional prospective randomized trial.