BRAF inhibitor and stereotactic radiosurgery is associated with an increased risk of radiation necrosis

Abstract

We retrospectively compared the outcomes and toxicities of melanoma brain metastases (MBM) patients treated with BRAF inhibitors (BRAFi) and stereotactic radiosurgery (SRS) with SRS alone. We identified 87 patients with 157 MBM treated with SRS alone from 2005 to 2013. Of these, 15 (17.2%) patients with 32 MBM (21.4%) received BRAFi therapy: three (20.0%) before SRS, two (13.3%) concurrent, and 10 (66.7%) after SRS. Overall survival (OS) was compared between cohorts using the product limit method. Intracranial outcomes were compared using cumulative incidence with competing risk for death. Baseline patient characteristics were similar between groups, except for the SRS cohort, which had higher rates of chemotherapy and more recent year of diagnosis. Radiation characteristics, including dose per fraction, total dose, gross tumor volume size, and prescription isodose, were also similar between cohorts. One-year outcomes - OS (64.3 vs. 40.4%, P=0.205), local failure (3.3 vs. 9.6%, P=0.423), and distant intracranial failure (63.9 vs. 65.1%, P=0.450) were not statistically different between the SRS+BRAFi and SRS-alone groups, respectively. The SRS+BRAFi group showed higher rates of radiographic radiation necrosis (RN) (22.2 vs. 11.0% at 1 year, P<0.001) and symptomatic radiation necrosis (SRN) (28.2 vs. 11.1% at 1 year, P<0.001). Multivariable analysis showed that BRAFi predicted an increased risk of both radiographic and SRN. SRS and BRAFi predicted for an increased risk of radiographic and SRN compared with SRS alone. Approaches to mitigate RN for patients receiving SRS and BRAFi should be considered until the clinical trial (http//:www.clinicaltrials.gov: NCT01721603) evaluating this treatment regimen is completed.

Conflict of interest statement

David Lawson has previously served as a consultant for Bristol Myer Squibb (BMS). BMS has sponsored clinical trials at our institution. For the remaining authors there are no conflicts of interest.

Figures

Figure 1

Kaplan–Meier curve showing the comparison of stereotactic radiosurgery (SRS) with BRAF inhibitor (solid line) to SRS alone (dashed line) with respect to overall survival. BRAFi, BRAF inhibitor.

Figure 2

Competing risk model showing the comparison of stereotactic radiosurgery (SRS) with BRAF inhibitor (square) to SRS alone (triangle) with respect to local control (white) and death (black). BRAFi, BRAF inhibitor.

Figure 3

Change in the size of lesion 3 months after stereotactic radiosurgery. MRI, T1 before (top panels) and after (bottom panels) contrast. Images on the left are 3 months after treatment; images on the right are at the time of initial stereotactic radiosurgery. The lesion in the right temporal lobe is stable in size; the lesion in the left medial occipital lobe develops hemorrhage, as can be seen by increased intensity on T1 precontrast MRI scans. This patient was in the non-BRAF inhibitor cohort.

Figure 4

Competing risk model showing the comparison of stereotactic radiosurgery (SRS) with BRAF inhibitor (square) to SRS alone (triangle) with respect to symptomatic radiation necrosis (white) and death (black). BRAFi, BRAF inhibitor.