title: Pulsatile Erlotinib in EGFR-Positive Non-Small-Cell Lung Cancer Patients With Leptomeningeal and Brain Metastases: Review of the Literature.
abstract: Patients with epidermal growth factor receptor (EGFR)-positive (EGFR+) non-small-cell lung cancer (NSCLC) show improved response rates when treated with tyrosine kinase inhibitors (TKIs) such as erlotinib. However, standard daily dosing of erlotinib often does not reach therapeutic concentrations within the cerebrospinal fluid (CSF), resulting in progression of central nervous system (CNS) disease. Intermittent, high-dose administration of erlotinib reaches therapeutic concentrations within the CSF and is well tolerated in patients. Experience with "pulsatile" dosing, however, is limited. We review the literature on the pharmacology and clinical outcomes of pulsatile erlotinib in the treatment of EGFR+NSCLC with brain and leptomeningeal metastases, and include available data on the use of next-generation TKIs in CNS progression. We also provide our institution's experience with patients treated with pulsatile erlotinib for CNS metastasis, and propose clinical criteria for its use. Pulsatile erlotinib is a reasonable alternative in EGFR+patients with new or worsening CNS disease, without evidence of systemic progression, and without confirmed T790M resistance mutations within the CNS.
authors.affiliation: Barnes-Jewish Hospital, St Louis, MO.
authors.forename: Joan
authors.initials: J
authors.lastname: How
authors.affiliation: Mallinckrodt Institute of Radiology at Washington University, St Louis, MO.
authors.forename: Janelle
authors.initials: J
authors.lastname: Mann
authors.affiliation: Division of Pharmacology, Washington University School of Medicine, St Louis, MO.
authors.forename: Andrew N
authors.initials: AN
authors.lastname: Laczniak
authors.affiliation: Division of Oncology, Washington University School of Medicine, St Louis, MO. Electronic address: mbaggstr@wustl.edu.
authors.forename: Maria Q
authors.initials: MQ
authors.lastname: Baggstrom
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000556:secondary; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000556:secondary; D054796:Drug Dosage Calculations; D004351:Drug Resistance; D066246:ErbB Receptors / Q000378:metabolism; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D055756:Meningeal Carcinomatosis / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Blood brain barrier; Central nervous system metastasis; High-dose; Leptomeningeal disease; Tyrosine kinase inhibitor