title: Phase II trial of two different irinotecan schedules with pharmacokinetic analysis in patients with recurrent glioma: North Central Cancer Treatment Group results.
abstract: OBJECTIVE
  The aims of this trial were to assess the safety and efficacy of two different dosing schedules of irinotecan (CPT-11) in recurrent glioma patients, to assess irinotecan pharmacokinetics in patients on enzyme-inducing antiepileptic drugs (EIAEDs) and steroids, and to correlate with toxicity and response to treatment.
  
  
  METHODS
  Sixty-four recurrent glioma patients were included in this study. Schedule A patients received irinotecan weekly (125 mg/m(2)/w) for four out of six weeks. Schedule B patients received irinotecan every three weeks at a dose of 300 mg/m(2). A 20% dose reduction was implemented for patients who had received prior nitrosureas. Treatment was continued until unacceptable toxicity, tumor progression or patient withdrawal.
  
  
  RESULTS
  There was no difference in confirmed responses between the two groups (6.3%). PFS at 6 months was 6.25% (2/32 patients) on schedule A and 18.75% (6/32 patients) on schedule B but median OS (5.1 versus 5.5 months), and survival at one year (19%) was similar for both arms. The most common grade 3-4 toxicities on schedules A/B were: thrombocytopenia (15.6%/21.9%), diarrhea (6.3%/12.5%) and nausea and vomiting (0%/15.7%). One toxic death due to infection in the absence of neutropenia occurred in schedule B. EIAEDs reduced SN-38 and CPT-11 area under the curve and increased CPT-11 clearance. This effect was more prominent in schedule A patients. Steroids did not alter CPT-11 pharmacokinetics in either schedule.
  
  
  CONCLUSIONS
  Single agent irinotecan has modest activity in patients with recurrent gliomas, independently of the administration schedule. Irinotecan administration on an every 3 week schedule resulted in longer PFS-6, at the expense of more toxicity. EIAEDs alter CPT-11 pharmacokinetics in this group of patients, and should be taken into consideration when determining optimal dosing.
authors.affiliation: Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Santisteban
authors.forename: Jan C
authors.initials: JC
authors.lastname: Buckner
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Wenting
authors.initials: W
authors.lastname: Wu
authors.forename: Bernd W
authors.initials: BW
authors.lastname: Scheithauer
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Felten
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Nikcevich
authors.forename: Martin
authors.initials: M
authors.lastname: Wiesenfeld
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Jaeckle
authors.forename: Evanthia
authors.initials: E
authors.lastname: Galanis
mesh_terms: D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001932:Brain Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D004347:Drug Interactions; D005260:Female; D005910:Glioma / Q000188:drug therapy*; D020719:Glucuronides / Q000097:blood; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*
chemical_list: C441475:7-ethyl-10-hydroxycamptothecin glucuronide; D000927:Anticonvulsants; D000972:Antineoplastic Agents, Phytogenic; D020719:Glucuronides; D000077146:Irinotecan; D002166:Camptothecin