title: Clinical outcomes of melanoma brain metastases treated with stereotactic radiosurgery and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors, BRAF inhibitor, or conventional chemotherapy.
abstract: The effect of immunologic and targeted agents on intracranial response rates in patients with melanoma brain metastases (MBMs) is not yet clearly understood. This report analyzes outcomes of intact MBMs treated with single-session stereotactic radiosurgery (SRS) and anti-PD-1 therapy, anti-CTLA-4 therapy, BRAF/MEK inhibitors(i), BRAFi, or conventional chemotherapy.
  
  
  
  Patients were included if MBMs were treated with single-session SRS within 3 months of receiving systemic therapy. The primary end point of this study was distant MBM control. Secondary end points were local MBM control defined as a >20% volume increase on follow-up MRI, systemic progression-free survival, overall survival (OS) from both SRS and cranial metastases diagnosis, and neurotoxicity. Images were reviewed alongside two neuro-radiologists at our institution.
  
  
  
  Ninety-six patients were treated to 314 MBMs over 119 SRS treatment sessions between January 2007 and August 2015. No significant differences were noted in age (P = 0.27), gender (P = 0.85), treated gross tumor volume (P = 0.26), or the diagnosis-specific graded prognostic assessment (P = 0.51) between the treatment cohorts. Twelve-month Kaplan-Meier (KM) distant MBM control rates were 38%, 21%, 20%, 8%, and 5% (P = 0.008) for SRS with anti-PD-1 therapies, anti-CTLA-4 therapy, BRAF/MEKi, BRAFi, and conventional chemotherapy, respectively. No significant differences were noted in the KM local MBM control rates among treatment groups (P = 0.25). Treatment with anti-PD-1 therapy, anti-CTLA-4 therapy, or BRAF/MEKi significantly improved OS on both univariate and multivariate analyses when compared with conventional chemotherapy.
  
  
  
  In our institutional analysis of patients treated with SRS and various systemic immunologic and targeted melanoma agents, significant differences in distant MBM control and OS are noted. Prospective evaluation of the potential synergistic effect between these agents and SRS is warranted.
authors.affiliation: Department of Radiation Oncology.
authors.forename: K A
authors.initials: KA
authors.lastname: Ahmed
authors.affiliation: Department of Radiation Oncology.
authors.forename: Y A
authors.initials: YA
authors.lastname: Abuodeh
authors.affiliation: Department of Radiation Oncology.
authors.forename: M I
authors.initials: MI
authors.lastname: Echevarria
authors.affiliation: Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa.
authors.forename: J A
authors.initials: JA
authors.lastname: Arrington
authors.affiliation: Department of Radiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa.
authors.forename: D G
authors.initials: DG
authors.lastname: Stallworth
authors.affiliation: Department of School of Medicine, University of Louisville, Louisville.
authors.forename: C
authors.initials: C
authors.lastname: Hogue
authors.affiliation: Department of Radiation Oncology.
authors.forename: A O
authors.initials: AO
authors.lastname: Naghavi
authors.affiliation: Department of Radiation Oncology.
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Biostatistics, H. Lee Moffitt Cancer Center and Research Institute, Tampa.
authors.forename: Y
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Morsani College of Medicine, University of South Florida, Tampa.
authors.forename: B G
authors.initials: BG
authors.lastname: Patel
authors.affiliation: Department of Radiation Oncology.
authors.forename: S
authors.initials: S
authors.lastname: Sarangkasiri
authors.affiliation: Department of Radiation Oncology.
authors.forename: P A S
authors.initials: PA
authors.lastname: Johnstone
authors.affiliation: Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa.
authors.forename: S
authors.initials: S
authors.lastname: Sahebjam
authors.affiliation: Department of Cutaneous-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA.
authors.forename: N I
authors.initials: NI
authors.lastname: Khushalani
authors.affiliation: Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa.
authors.forename: P A
authors.initials: PA
authors.lastname: Forsyth
authors.affiliation: Department of Radiation Oncology.
authors.forename: L B
authors.initials: LB
authors.lastname: Harrison
authors.affiliation: Department of Radiation Oncology.
authors.forename: M
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Neuro-Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa.
authors.forename: A B
authors.initials: AB
authors.lastname: Etame
authors.affiliation: Department of Radiation Oncology jimmy.caudell@moffitt.org.
authors.forename: J J
authors.initials: JJ
authors.lastname: Caudell
mesh_terms: D000181:Acrylonitrile / Q000008:administration & dosage / Q000031:analogs & derivatives; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000814:Aniline Compounds / Q000008:administration & dosage; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary / Q000601:surgery*; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000601:surgery*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics; D016634:Radiosurgery
chemical_list: D000814:Aniline Compounds; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C000610759:MEK inhibitor I; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000181:Acrylonitrile
keywords: anti-PD-1 therapy; brain metastases; melanoma; stereotactic radiation