title: Treatment and survival of patients with EGFR-mutated non-small cell lung cancer and leptomeningeal metastasis: A retrospective cohort analysis.
abstract: OBJECTIVE
  Development of leptomeningeal metastasis (LM) in non-small cell lung cancer (NSCLC)-patients is associated with a poor prognosis. It has been suggested that LM-patients with epidermal growth factor receptor mutated (EGFR+) NSCLC have a superior prognosis compared to EGFR-wild type NSCLC. Studies in EGFR+ NSCLC-patients with LM are scarce. We retrospectively evaluated a multi-institutional cohort of EGFR+ NSCLC-patients for LM to assess clinical outcome in relation to patient characteristics and treatment modalities.
  
  
  METHODS
  Medical records of advanced-stage EGFR+ NSCLC-patients (diagnosed between August 2000 and June 2014) from 11 Dutch hospitals were evaluated for LM as diagnosed by MRI and/or cytopathological liquor analysis. Data on patient characteristics, treatment and outcome were collected.
  
  
  RESULTS
  Thirty-two of 356 (9.0%) advanced-stage EGFR+ NSCLC-patients (median follow-up 21.0 months), were diagnosed with LM between 2006 and 2014. LM was diagnosed by MRI (59.4%), liquor analysis (9.4%) or by both MRI and liquor analysis (31.3%). Median survival after LM-diagnosis was 3.1 months (95% CI: 0.0-7.3). Six- and 12-month survival rates were 43.8% and 18.8%, respectively. Patients with performance status (PS) 0-1 at time of diagnosis of LM had a significantly higher chance to be alive after 6 months and had a significantly longer survival after diagnosis of LM compared to patients with PS≥2. Age, treatment with high-dose EGFR-TKI, radiotherapy and whether LM was the only site of progressive disease did not influence survival after LM-diagnosis.
  
  
  CONCLUSIONS
  Although median survival after LM-diagnosis in EGFR-mutated NSCLC-patients was poor, a substantial part of the patients had a prolonged survival of more than 6 months. PS of 0-1 at time of diagnosis of LM was associated with prolonged survival. No other patient- or treatment-related characteristics were identified. Further research is warranted to identify treatment strategies that improve survival in EGFR+ NSCLC-patients with LM.
authors.affiliation: Department of Pulmonary Diseases, VU University Medical Center, Boelelaan 1117, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands. Electronic address: jl.kuiper@vumc.nl.
authors.forename: Justine L
authors.initials: JL
authors.lastname: Kuiper
authors.affiliation: Department of Pulmonary Diseases, GROW-School for Developmental Biology & Oncology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
authors.forename: Lizza E
authors.initials: LE
authors.lastname: Hendriks
authors.affiliation: Department of Pulmonary Diseases, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: Anthonie J
authors.initials: AJ
authors.lastname: van der Wekken
authors.affiliation: Department of Pulmonary Diseases, VU University Medical Center, Boelelaan 1117, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands; Department of Pulmonary Diseases, Academic Medical Center, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands.
authors.forename: Adrianus J
authors.initials: AJ
authors.lastname: de Langen
authors.affiliation: Department of Pulmonary Diseases, VU University Medical Center, Boelelaan 1117, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands; Department of Pulmonary Diseases, Academic Medical Center, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands.
authors.forename: Idris
authors.initials: I
authors.lastname: Bahce
authors.affiliation: Department of Pathology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Erik
authors.initials: E
authors.lastname: Thunnissen
authors.affiliation: Department of Pathology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
authors.affiliation: Department of Pulmonary Diseases, Canisius Wilhelmina hospital, P.O. Box 9015, 6500 GS Nijmegen, The Netherlands.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Berk
authors.affiliation: Department of Pulmonary Diseases, VU University Medical Center, Boelelaan 1117, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Ed J M
authors.initials: EJ
authors.lastname: Buijs
authors.affiliation: Department of Pathology, GROW-School for Developmental Biology & Oncology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
authors.forename: Ernst-Jan M
authors.initials: EJ
authors.lastname: Speel
authors.affiliation: Department of Pulmonary Diseases, Spaarne Hospital, P.O. Box 770, 2130 AT Hoofddorp, The Netherlands.
authors.forename: Frans H
authors.initials: FH
authors.lastname: Krouwels
authors.affiliation: Department of Pulmonary Diseases, Rijnstate Hospital, P.O. Box 9555, 6800 TA Arnhem, The Netherlands.
authors.forename: Hans J M
authors.initials: HJ
authors.lastname: Smit
authors.affiliation: Department of Pulmonary Diseases, University of Groningen and University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: Harry J M
authors.initials: HJ
authors.lastname: Groen
authors.affiliation: Department of Pulmonary Diseases, GROW-School for Developmental Biology & Oncology, Maastricht University Medical Center, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands.
authors.forename: Anne-Marie C
authors.initials: AM
authors.lastname: Dingemans
authors.affiliation: Department of Pulmonary Diseases, VU University Medical Center, Boelelaan 1117, P.O. Box 7057, 1007 MB Amsterdam, The Netherlands; Department of Pulmonary Diseases, The Netherlands Cancer Institute, P.O. Box 90203, 1006 BE Amsterdam, The Netherlands.
authors.forename: Egbert F
authors.initials: EF
authors.lastname: Smit
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D015331:Cohort Studies; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D008297:Male; D008577:Meningeal Neoplasms / Q000175:diagnosis / Q000556:secondary* / Q000628:therapy*; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors
keywords: EGFR; Leptomeningeal metastasis; NSCLC; TKI