The goal of this study was to investigate the impact of stereotactic radiosurgery (SRS), BRAF status, and targeted and immune-based therapies on the recurrence patterns and factors associated with overall survival (OS) among patients with melanoma brain metastasis (MBM).
A total of 366 patients were treated for 1336 MBMs; a lesion-based analysis was performed on 793 SRS lesions. The BRAF status was available for 78 patients: 35 had BRAFmut and 43 had BRAF wild-type (BRAF-WT) lesions. The Kaplan-Meier method evaluated unadjusted OS; cumulative incidence analysis determined the incidences of local failure (LF), distant failure, and radiation necrosis (RN), with death as a competing risk.
The 12-month OS was 24% (95% CI 20%–29%). On multivariate analysis, younger age, lack of extracranial metastases, better Karnofsky Performance Status score, and fewer MBMs, as well as treatment with BRAF inhibitors (BRAFi), anti–PD-1/CTLA-4 therapy, or cytokine therapy were significantly associated with OS. For patients who underwent SRS, the 12-month LF rate was lower among those with BRAFmut lesions (6%, 95% CI 2%–11%) compared with those with BRAF-WT lesions (22%, 95% CI 13%–32%; p < 0.01). The 12-month LF rates among lesions treated with BRAFi and PD-1/CTLA-4 agents were 1% (95% CI 1%–4%) and 7% (95% CI 1%–13%), respectively. On multivariate analysis, BRAF inhibition within 30 days of SRS was protective against LF (HR 0.08, 95% CI 0.01–0.55; p = 0.01). The 12-month rates of RN were low among lesions treated with BRAFi (0%, 95% CI 0%–0%), PD-1/CTLA-4 inhibitors (2%, 95% CI 1%–5%), and cytokine therapies (6%, 95% CI 1%–13%).
Prognostic schema should incorporate BRAFi or immunotherapy status and use of targeted therapies. Treatment with a BRAF inhibitor within 4 weeks of SRS improves local control without an increased risk of RN.
Correspondence Manmeet S. Ahluwalia, Department of Hematology/Oncology, Taussig Cancer Institute, Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic Main Campus, Mail Code S73, 9500 Euclid Ave., Cleveland, OH 44195. email: email@example.com.
INCLUDE WHEN CITING Published online August 11, 2017; DOI: 10.3171/2017.1.JNS162797.
Disclosures Dr. Suh received consulting payment from Varian Medical Systems; had travel and lodging paid for by Elekta; and received speaking fees from Philips. Dr. Ahluwalia received a consulting payment and grant from Elekta; grant support from Boehringer Ingelheim, Bristol-Myers Squibb, Novartis, Spectrum Pharmaceuticals, Tracon Pharmaceuticals, and Novocure; and is a consultant for Merck, Genentech/Roche, Incyte, Caris Lifesciences, Monteris Medical, MRI Interventions Inc., Bristol-Myers Squibb, Astrazeneca, and Abbvie. He received support of non–study-related clinical or research efforts that he oversaw from Novartis, Novocure, and Bristol-Myers Squibb. Dr. Kotecha is on the medical advisory board of Varian Medical Systems.
AnkerCJGrossmannKFAtkinsMBSunejaGTarhiniAAKirkwoodJM: Avoiding severe toxicity from combined BRAF inhibitor and radiation treatment: consensus guidelines from the Eastern Cooperative Oncology Group (ECOG). Int J Radiat Oncol Biol Phys95:632–6462016
BrownPDAsherALBallmanKVFaraceECerhanJHAndersonSK: NCCTG N0574 (Alliance): A phase III randomized trial of whole brain radiation therapy (WBRT) in addition to radiosurgery (SRS) in patients with 1 to 3 brain metastases. J Clin Oncol33Suppl:LBA42015 (Abstract)
DummerRGoldingerSMTurtschiCPEggmannNBMichielinOMitchellL: Vemurafenib in patients with BRAFV600 mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer50:611–6212014
Gaudy-MarquesteCCarronRDelsantiCLoundouAMonestierSArchierE: On demand Gamma-Knife strategy can be safely combined with BRAF inhibitors for the treatment of melanoma brain metastases. Ann Oncol25:2086–20912014
LongGVTrefzerUDaviesMAKeffordRFAsciertoPAChapmanPB: Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol13:1087–10952012
LyDBagshawHPAnkerCJTwardJDGrossmannKFJensenRL: Local control after stereotactic radiosurgery for brain metastases in patients with melanoma with and without BRAF mutation and treatment. J Neurosurg123:395–4012015
MillerJABennettEEXiaoRKotechaRChaoSTVogelbaumMA: Association between radiation necrosis and tumor biology after stereotactic radiosurgery for brain metastasis. Int J Radiat Oncol Biol Phys96:1060–10692016
SahgalAAoyamaHKocherMNeupaneBColletteSTagoM: Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis. Int J Radiat Oncol Biol Phys91:710–7172015
SambadeMJPetersECThomasNEKaufmannWKKimpleRJShieldsJM: Melanoma cells show a heterogeneous range of sensitivity to ionizing radiation and are radiosensitized by inhibition of B-RAF with PLX-4032. Radiother Oncol98:394–3992011
SawrieSMGuthrieBLSpencerSANordalRAMeredithRFMarkertJM: Predictors of distant brain recurrence for patients with newly diagnosed brain metastases treated with stereotactic radiosurgery alone. Int J Radiat Oncol Biol Phys70:181–1862008
SchulzeBMeissnerMWolterMRodelCWeissC: Unusual acute and delayed skin reactions during and after whole-brain radiotherapy in combination with the BRAF inhibitor vemurafenib. Two case reports. Strahlenther Onkol190:229–2322014
ShawEScottCSouhamiLDinapoliRKlineRLoefflerJ: Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys47:291–2982000
SperdutoPWKasedNRobergeDXuZShanleyRLuoX: Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases. J Clin Oncol30:419–4252012
VillanuevaJVulturALeeJTSomasundaramRFukunaga-KalabisMCipollaAK: Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell18:683–6952010
WolfAZiaSVermaRPavlickAWilsonMGolfinosJG: Impact on overall survival of the combination of BRAF inhibitors and stereotactic radiosurgery in patients with melanoma brain metastases. J Neurooncol127:607–6152016