title: The impact of tumor biology on survival and response to radiation therapy among patients with non-small cell lung cancer brain metastases.
abstract: OBJECTIVE
  To investigate the natural history and response to radiation therapy among ALK-rearranged, EGFR-mutated, wild-type adenocarcinoma, and squamous cell non-small cell lung cancer (NSCLC) brain metastases.
  
  
  METHODS
  Patients with NSCLC brain metastasis diagnosed from 1989 through 2014 at a single tertiary-care institution were included. The primary outcome was overall survival, whereas secondary outcomes included local failure, distant intracranial failure, and radiation necrosis. Cox proportional hazards regression was used to model overall survival; multivariate competing risks regression was used to model secondary outcomes.
  
  
  RESULTS
  Within the study period, 1920 patients presented with 6312 brain metastases. Squamous histology was associated with poorer median survival compared with adenocarcinomas (5.4 vs 8.8 months, P < .01). Median survival was greatest among ALK+ patients (49.2 months), followed by EGFR+ (20.3 months), and wild-type adenocarcinomas (10.0 months, P < .01). Treatment with estimated glomerular filtration rate inhibitors (hazard ratio [HR], 0.66; P < .01) and vascular endothelial growth factor antibodies (HR, 0.65; P < .01) increased survival independent of mutational status. Among 2056 lesions treated with stereotactic radiosurgery, the 12-month cumulative incidence of local failure was significantly greater among squamous cell carcinomas relative to adenocarcinomas (15% vs 10%, HR, 1.26; P = .04). Patients with ALK+ metastases experienced higher rates of local failure (10%; HR, 2.00; P = .05), distant failure (39%; HR, 2.94; P < .01), and radiation necrosis (18%; HR, 5.77; P < .01), whereas EGFR+ patients experienced the lowest rates of local failure (5%; HR, 0.46; P = .04) and distant failure (3%; HR, 0.13; P = .04).
  
  
  CONCLUSIONS
  Advances in precision medicine have increased survival among select patients with NSCLC. In the present investigation, ALK+ and EGFR+ status were associated with improved survival. However, patients with ALK+ metastases have poor intracranial control relative to EGFR+ metastases, possibly because of limited intracranial penetration of crizotinib compared with estimated glomerular filtration rate inhibitors. Future investigations are warranted to determine the optimal management of ALK+ brain metastases with the introduction of second-generation ALK inhibitors.
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Jacob A
authors.initials: JA
authors.lastname: Miller
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 of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio; Department of Hematology/Oncology, 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 of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio; Department of Hematology/Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Alireza M
authors.initials: AM
authors.lastname: Mohammadi
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio; Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
authors.forename: John H
authors.initials: JH
authors.lastname: Suh
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio; Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Gene H
authors.initials: GH
authors.lastname: Barnett
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio; Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Erin S
authors.initials: ES
authors.lastname: Murphy
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio; Department of Neurosurgery, Neurological Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Vogelbaum
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio; Department of Hematology/Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Lilyana
authors.initials: L
authors.lastname: Angelov
authors.affiliation: Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland Clinic, Cleveland, Ohio; Department of Radiation Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio; Rose Ella Burkhardt Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio. Electronic address: chaos@ccf.org.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Chao
mesh_terms: D001932:Brain Neoplasms / Q000556:secondary*; D002289:Carcinoma, Non-Small-Cell Lung / Q000150:complications* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000150:complications* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016019:Survival Analysis; D016896:Treatment Outcome