title: Erlotinib efficacy and cerebrospinal fluid concentration in patients with lung adenocarcinoma developing leptomeningeal metastases during gefitinib therapy.
abstract: OBJECTIVE
  We have treated patients with non-small-cell lung cancer (NSCLC) who developed leptomeningeal metastases (LM) during gefitinib therapy, and then found symptomatic improvement following treatment change to erlotinib. Based on this experience, we wondered whether erlotinib could be detected in cerebrospinal fluid (CSF) when it was used for NSCLC patients with LM. This study was conducted to determine erlotinib concentrations in CSF and assess responses to erlotinib in patients with NSCLC developing LM during gefitinib therapy.
  
  
  METHODS
  Three advanced NSCLC patients with LM that developed during gefitinib therapy were treated with erlotinib. On day 28 after the initiation of erlotinib treatment, plasma and CSF were obtained and the concentrations of erlotinib in these samples were measured. Eastern Cooperative Oncology Group (ECOG) performance status (PS) and neurologic symptoms were determined.
  
  
  RESULTS
  Erlotinib CSF penetration was 6.3% ± 6.1% (mean ± SD). In cases 1 and 2, we observed improvements in ECOG PS and neurologic symptoms. In case 3, cytological improvement was seen in the CSF. In each patient, deletion of exon 19 or exon 21 L858R mutation of the epidermal growth factor receptor (EGFR) gene was detected in carcinoma cells from the CSF.
  
  
  CONCLUSIONS
  We report on 3 patients with NSCLC who had developed LM during gefitinib treatment and showed clinical improvements following change to erlotinib therapy. In all cases, small but measurable penetration of erlotinib into CSF was observed. Because EGFR mutations were detected in all cases, we suggest that erlotinib is a therapeutic option for LM carcinoma cells with EGFR mutations.
authors.affiliation: Department of Molecular and Internal Medicine, Graduate School of Biomedical Science, Hiroshima University, 1-2-3 Kasumi Minami-ku, Hiroshima 734-8551, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Masuda
authors.forename: Noboru
authors.initials: N
authors.lastname: Hattori
authors.forename: Akinobu
authors.initials: A
authors.lastname: Hamada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Iwamoto
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Ohshimo
authors.forename: Masashi
authors.initials: M
authors.lastname: Kanehara
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Ishikawa
authors.forename: Kazunori
authors.initials: K
authors.lastname: Fujitaka
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Haruta
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Murai
authors.forename: Nobuoki
authors.initials: N
authors.lastname: Kohno
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary; D000328:Adult; D000970:Antineoplastic Agents / Q000134:cerebrospinal fluid / Q000627:therapeutic use*; D057915:Drug Substitution; D066246:ErbB Receptors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D055756:Meningeal Carcinomatosis / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D009154:Mutation; D011799:Quinazolines / Q000134:cerebrospinal fluid / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib