title: Methotrexate administration directly into the fourth ventricle in children with malignant fourth ventricular brain tumors: a pilot clinical trial.
abstract: We hypothesize that chemotherapy can be safely administered directly into the fourth ventricle to treat recurrent malignant brain tumors in children. For the first time in humans, methotrexate was infused into the fourth ventricle in children with recurrent, malignant brain tumors. A catheter was surgically placed into the fourth ventricle and attached to a ventricular access device. Cerebrospinal fluid (CSF) flow was confirmed by CINE MRI postoperatively. Each cycle consisted of 4 consecutive daily methotrexate infusions (2 milligrams). Disease response was monitored with serial MRI scans and CSF cytologic analysis. Trough CSF methotrexate levels were sampled. Five patients (3 with medulloblastoma and 2 with ependymoma) received 18, 18, 12, 9, and 3 cycles, respectively. There were no serious adverse events or new neurological deficits attributed to methotrexate. Two additional enrolled patients were withdrawn prior to planned infusions due to rapid disease progression. Median serum methotrexate level 4 h after infusion was 0.04 µmol/L. Range was 0.02-0.13 µmol/L. Median trough CSF methotrexate level 24 h after infusion was 3.18 µmol/L (range 0.53-212.36 µmol/L). All three patients with medulloblastoma had partial response or stable disease until one patient had progressive disease after cycle 18. Both patients with ependymoma had progressive disease after 9 and 3 cycles, respectively. Low-dose methotrexate can be infused into the fourth ventricle without causing neurological toxicity. Some patients with recurrent medulloblastoma experience a beneficial anti-tumor effect both within the fourth ventricle and at distant sites.
authors.affiliation: Division of Pediatric Neurosurgery, Departments of Pediatric Surgery and Neurosurgery, University of Texas Health Science Center at Houston and Mischer Neuroscience Center, 6431 Fannin Street, MSB 5.144, Houston, TX, 77030, USA. david.i.sandberg@uth.tmc.edu.|Divisions of Neurosurgery and Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX, USA. david.i.sandberg@uth.tmc.edu.
authors.forename: David I
authors.initials: DI
authors.lastname: Sandberg
authors.affiliation: Division of Pediatrics, Unit 87, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Rytting
authors.affiliation: Division of Pediatrics, Unit 87, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Wafik
authors.initials: W
authors.lastname: Zaky
authors.affiliation: Division of Neurosurgery, Department of Pediatric Surgery, University of Texas Health Science Center at Houston, 6431 Fannin St., MSB 5.146, Houston, TX, 77030, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Kerr
authors.affiliation: Unit 1482, Department of Diagnostic Imaging, Section of Neuroradiology, FCT 16.5020, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX, 77030, USA.
authors.forename: Leena
authors.initials: L
authors.lastname: Ketonen
authors.affiliation: Unit 85, Department of Pathology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Uma
authors.initials: U
authors.lastname: Kundu
authors.affiliation: Division of Pediatrics, Unit 87, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Bartlett D
authors.initials: BD
authors.lastname: Moore
authors.affiliation: Division of Pediatrics, Unit 87, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Yang
authors.affiliation: Unit 1472, Department of Imaging Physics, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Hou
authors.affiliation: Department of Diagnostic & Interventional Imaging, University of Texas Health Science Center at Houston, 6431 Fannin Street, MSB 2.130B, Houston, TX, 77030, USA.
authors.forename: Clark
authors.initials: C
authors.lastname: Sitton
authors.affiliation: Division of Pediatrics, Unit 87, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.|Ziopharm Oncology Inc., 1 First Avenue; Parris Building, #34, Navy Yard Plaza, Boston, MA, 02129, USA.
authors.forename: Laurence J
authors.initials: LJ
authors.lastname: Cooper
authors.affiliation: Division of Pediatrics, Unit 87, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Vidya
authors.initials: V
authors.lastname: Gopalakrishnan
authors.affiliation: Division of Pediatrics, Unit 87, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Lee
authors.affiliation: Department of Biostatistics, Office FCT 4.614, MD Anderson Cancer Center, Houston, TX, 77230-1402, USA.
authors.forename: Peter F
authors.initials: PF
authors.lastname: Thall
authors.affiliation: Division of Pediatrics, Unit 87, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Soumen
authors.initials: S
authors.lastname: Khatua
mesh_terms: D000293:Adolescent; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002551:Cerebral Ventricle Neoplasms / Q000188:drug therapy*; D002648:Child; D002675:Child, Preschool; D004806:Ependymoma / Q000188:drug therapy*; D005260:Female; D020546:Fourth Ventricle / Q000187:drug effects; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy*; D008727:Methotrexate / Q000008:administration & dosage*; D009364:Neoplasm Recurrence, Local; D010865:Pilot Projects; D018335:Rhabdoid Tumor / Q000188:drug therapy*; D013116:Spinal Cord / Q000473:pathology; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D008727:Methotrexate
keywords: Ependymoma; Fourth ventricle; Intraventricular chemotherapy; Medulloblastoma; Methotrexate