title: Chemotherapy administration directly into the fourth ventricle in a new piglet model. Laboratory Investigation.
abstract: OBJECTIVE
  The authors hypothesized that chemotherapy infusions directly into the fourth ventricle may potentially play a role in treating malignant posterior fossa tumors. In this study the safety and pharmacokinetics of etoposide administration into the fourth ventricle was tested using an indwelling catheter in piglets.
  
  
  METHODS
  A closed-tip silicone lumbar drain catheter was inserted into the fourth ventricle via a posterior fossa craniectomy and 5 daily infusions of etoposide (0.5 mg in 5 animals) or normal saline (in 2 animals) were instilled. Piglets (10-18 kg, 2-3 months of age) underwent daily neurological examinations and 4.7-T magnetic resonance (MR) imaging after the final infusion and were then killed for postmortem examination. Pharmacokinetics were studied using reversed-phase high-performance liquid chromatography on cerebrospinal fluid (CSF) samples at 0.25, 1, 2, 4, 8, 12, and 24 hours after etoposide infusion. Peak and trough CSF etoposide levels were measured for each subsequent infusion. Serum etoposide levels were obtained at 2 and 4 hours after infusion.
  
  
  RESULTS
  All piglets remained neurologically intact, and MR images demonstrated catheter placement within the fourth ventricle without signal changes in the brainstem or cerebellum. Serum etoposide was absent at 2 and 4 hours after intraventricular infusions. When adequate samples could be obtained for analysis, CSF etoposide levels peaked 15 minutes after infusion and progressively decreased. Cytotoxic levels (> 0.1 microg/ml) were maintained for 5 consecutive peak and trough measurements with 1 exception. Etoposide-related neuropathology included moderate-to-severe T-lymphocytic meningitis and fourth and lateral ventricular choroid plexitis with associated subependymal inflammation.
  
  
  CONCLUSIONS
  Etoposide can be infused directly into the fourth ventricle without clinical or imaging evidence of damage. Cytotoxic CSF etoposide levels can be maintained for 24 hours with a single daily infusion into the fourth ventricle using an indwelling catheter. Intraventricular etoposide elicits an inflammatory response, the long-term effects of which are as yet undetermined.
authors.affiliation: Department of Neurological Surgery, University of Miami Miller School of Medicine and Miami Children's Hospital, Miami, Florida 33155, USA. dsandberg@med.miami.edu
authors.forename: David I
authors.initials: DI
authors.lastname: Sandberg
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Crandall
authors.forename: Carol K
authors.initials: CK
authors.lastname: Petito
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Padgett
authors.forename: John
authors.initials: J
authors.lastname: Landrum
authors.forename: Darwin
authors.initials: D
authors.lastname: Babino
authors.forename: Danshe
authors.initials: D
authors.lastname: He
authors.forename: Juan
authors.initials: J
authors.lastname: Solano
authors.forename: Manuel
authors.initials: M
authors.lastname: Gonzalez-Brito
authors.forename: John W
authors.initials: JW
authors.lastname: Kuluz
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002404:Catheterization; D002408:Catheters, Indwelling; D005047:Etoposide / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D020546:Fourth Ventricle / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D007263:Infusions, Parenteral; D023421:Models, Animal; D013552:Swine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005047:Etoposide