title: A phase I study of periocular topotecan in children with intraocular retinoblastoma.
abstract: OBJECTIVE
  To identify the maximum tolerated dose and dose-limiting toxicity of periocular topotecan in patients with relapsed or resistant intraocular retinoblastoma who are facing imminent enucleation.
  
  
  METHODS
  For this phase I study, a starting dose of 0.5 mg of periocular topotecan administered through a 25-gauge needle was given with intrapatient escalation at a rate of 0.5 mg/cycle according to toxicity, up to a maximum dose of 2 mg. Two courses separated by 2 weeks were scheduled. Plasma levels of topotecan were measured by high-performance liquid chromatography in patients with available intravenous catheters.
  
  
  RESULTS
  Seven eyes of five patients were treated with a total of 14 courses of periocular topotecan. Only mild orbital edema occurred, and grade 1 vomiting developed in the first patient that was controlled with ondansetron for the following courses. Dose-limiting toxicity was not reached and the maximum tolerated dose was set at the target dose of 2 mg (n=5 eyes). Lactone topotecan systemic exposure was lower than 55 ng/mL x h and it correlated linearly with dose in this small cohort. Even though the study was not designed to assess response, one eye was preserved after a partial response, but the remaining six were enucleated, either after a short period of disease stabilization followed by further therapy with other agents in five patients or by rapidly progressive disease in one.
  
  
  CONCLUSIONS
  The dose limiting toxicity was not reached. Up to 2 mg of periocular topotecan could be given safely, but further studies are necessary to determine its effect on retinoblastoma (ClinicalTrials.gov number, NCT00460876).
authors.affiliation: Hematology/Oncology, Hospital J. P. Garrahan, Buenos Aires, Argentina. gchantada@yahoo.com
authors.forename: Guillermo L
authors.initials: GL
authors.lastname: Chantada
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Fandino
authors.forename: Angel M
authors.initials: AM
authors.lastname: Carcaboso
authors.forename: Eduardo
authors.initials: E
authors.lastname: Lagomarsino
authors.forename: Maria T G
authors.initials: MT
authors.lastname: de Davila
authors.forename: Myriam R
authors.initials: MR
authors.lastname: Guitter
authors.forename: Adriana B
authors.initials: AB
authors.lastname: Rose
authors.forename: Julio
authors.initials: J
authors.lastname: Manzitti
authors.forename: Guillermo F
authors.initials: GF
authors.lastname: Bramuglia
authors.forename: David H
authors.initials: DH
authors.lastname: Abramson
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019540:Area Under Curve; D002675:Child, Preschool; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D015353:Eye Enucleation; D006801:Humans; D008279:Magnetic Resonance Imaging; D020714:Maximum Tolerated Dose; D019572:Retinal Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D012175:Retinoblastoma / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D014057:Tomography, X-Ray Computed; D019772:Topotecan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics
chemical_list: D000970:Antineoplastic Agents; D019772:Topotecan