title: Direct intracerebral delivery of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma: a report by the Cintredekin Besudotox Intraparenchymal Study Group.
abstract: OBJECTIVE
  Glioblastoma multiforme (GBM) is a devastating brain tumor with a median survival of 6 months after recurrence. Cintredekin besudotox (CB) is a recombinant protein consisting of interleukin-13 (IL-13) and a truncated form of Pseudomonas exotoxin (PE38QQR). Convection-enhanced delivery (CED) is a locoregional-administration method leading to high-tissue concentrations with large volume of distributions. We assessed the use of intracerebral CED to deliver CB in patients with recurrent malignant glioma (MG).
  
  
  METHODS
  Three phase I clinical studies evaluated intracerebral CED of CB along with tumor resection. The main objectives were to assess the tolerability of various concentrations and infusion durations; tissue distribution; and methods for optimizing delivery. All patients underwent tumor resection followed by a single intraparenchymal infusion (in addition to the intraparenchymal one following resection), with a portion of patients who had a preresection intratumoral infusion.
  
  
  RESULTS
  A total of 51 patients with MG were treated including 46 patients with GBM. The maximum tolerated intraparenchymal concentration was 0.5 microg/mL and tumor necrosis was observed at this concentration. Infusion durations of up to 6 days were well tolerated. Postoperative catheter placement appears to be important for optimal drug distribution. CB- and procedure-related adverse events were primarily limited to the CNS. Overall median survival for GBM patients is 42.7 weeks and 55.6 weeks for patients with optimally positioned catheters with patient follow-up extending beyond 5 years.
  
  
  CONCLUSIONS
  CB appears to have a favorable risk-benefit profile. CED is a complex delivery method requiring catheter placement via a second procedure to achieve accurate catheter positioning, better drug distribution, and better outcome.
authors.affiliation: Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, 94143-0350, USA. KunwarS@neurosurg.ucsf.edu
authors.forename: Sandeep
authors.initials: S
authors.lastname: Kunwar
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: Susan M
authors.initials: SM
authors.lastname: Chang
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.forename: Frederick F
authors.initials: FF
authors.lastname: Lang
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Piepmeier
authors.forename: John H
authors.initials: JH
authors.lastname: Sampson
authors.forename: Zvi
authors.initials: Z
authors.lastname: Ram
authors.forename: Philip H
authors.initials: PH
authors.lastname: Gutin
authors.forename: Robert D
authors.initials: RD
authors.lastname: Gibbons
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.forename: David J
authors.initials: DJ
authors.lastname: Croteau
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Sherman
authors.forename: Raj K
authors.initials: RK
authors.lastname: Puri
mesh_terms: D000328:Adult; D000368:Aged; D002404:Catheterization; D018481:Convection; D016503:Drug Delivery Systems / Q000379:methods*; D005098:Exotoxins / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage*; D018793:Interleukin-13 / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011993:Recombinant Fusion Proteins; D015173:Supratentorial Neoplasms / Q000188:drug therapy* / Q000401:mortality; D014018:Tissue Distribution
chemical_list: D005098:Exotoxins; C521502:IL13-PE38; D000922:Immunotoxins; D018793:Interleukin-13; D011993:Recombinant Fusion Proteins