title: Association Between Radiation Necrosis and Tumor Biology After Stereotactic Radiosurgery for Brain Metastasis.
abstract: The primary dose-limiting toxicity of stereotactic radiosurgery (SRS) is radiation necrosis (RN), which occurs after approximately 5% to 10% of treatments. This adverse event may worsen neurologic deficits, increase the frequency and cost of imaging, and necessitate prolonged treatment with steroids or antiangiogenic agents. Previous investigations have primarily identified lesion size and dosimetric constraints as risk factors for RN in small populations. We hypothesized that disease histology, receptor status, and mutational status are associated with RN.
  
  
  
  All patients presenting with brain metastasis between 1997 and 2015 who underwent SRS and subsequent radiographic follow-up at a single tertiary-care institution were eligible for inclusion. The primary outcome was the cumulative incidence of radiographic RN. Multivariate competing risks regression was used to identify biological risk factors for RN.
  
  
  
  1939 patients (5747 lesions) were eligible for inclusion; 285 patients (15%) experienced radiographic RN after the treatment of 427 (7%) lesions. After SRS, the median time to RN was 7.6 months. After multivariate analysis, graded prognostic assessment, renal pathology, lesion diameter, and the heterogeneity index remained independently predictive of RN in the pooled cohort. In subset analyses of individual pathologies, HER2-amplified status (hazard ratio [HR] 2.05, P=.02), BRAF V600+ mutational status (HR 0.33, P=.04), lung adenocarcinoma histology (HR 1.89, P=.04), and ALK rearrangement (HR 6.36, P<.01) were also associated with RN.
  
  
  
  In the present investigation constituting the largest series of RN, several novel risk factors were identified, including renal histology, lung adenocarcinoma histology, HER2 amplification, and ALK/BRAF mutational status. These risk factors may be used to guide clinical trial design incorporating biological risk stratification or dose escalation. Future studies determining the optimal timing of targeted therapies are warranted to further define the risk of RN.
authors.affiliation: Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Miller
authors.affiliation: Department of Neurological Surgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Bennett
authors.affiliation: Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Roy
authors.initials: R
authors.lastname: Xiao
authors.affiliation: Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Rupesh
authors.initials: R
authors.lastname: Kotecha
authors.affiliation: Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio; Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Chao
authors.affiliation: Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio; Department of Neurological Surgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Vogelbaum
authors.affiliation: Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio; Department of Neurological Surgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Gene H
authors.initials: GH
authors.lastname: Barnett
authors.affiliation: Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio; Department of Neurological Surgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Lilyana
authors.initials: L
authors.lastname: Angelov
authors.affiliation: Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio; Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Erin S
authors.initials: ES
authors.lastname: Murphy
authors.affiliation: Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio; Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Yu
authors.affiliation: Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Manmeet S
authors.initials: MS
authors.lastname: Ahluwalia
authors.affiliation: Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio; Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: John H
authors.initials: JH
authors.lastname: Suh
authors.affiliation: Cleveland Clinic Lerner College of Medicine, Cleveland Clinic, Cleveland, Ohio; Department of Neurological Surgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio. Electronic address: mohamma3@ccf.org.
authors.forename: Alireza M
authors.initials: AM
authors.lastname: Mohammadi
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000556:secondary; D001921:Brain / Q000473:pathology* / Q000528:radiation effects*; D001932:Brain Neoplasms / Q000737:chemistry / Q000235:genetics / Q000532:radiotherapy* / Q000556:secondary*; D001943:Breast Neoplasms / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D018734:Genes, erbB-2; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000235:genetics; D008875:Middle Aged; D015999:Multivariate Analysis; D009336:Necrosis / Q000000981:diagnostic imaging / Q000209:etiology / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf; D011832:Radiation Injuries / Q000150:complications* / Q000000981:diagnostic imaging / Q000473:pathology; D016634:Radiosurgery / Q000009:adverse effects*; D012044:Regression Analysis; D012189:Retrospective Studies
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf