title: Multicentre phase II study and pharmacokinetic analysis of irinotecan in chemotherapy-naïve patients with glioblastoma.
abstract: BACKGROUND
  To assess the antitumour activity and safety profile of irinotecan and its pharmacokinetic interactions with anticonvulsants in patients with glioblastoma multiforme.
  
  
  METHODS
  This multicentre phase II and pharmacokinetic study investigated the effects of irinotecan 350 mg/m(2) given as a 90-min infusion every 3 weeks either prior to (group A) or after relapse following radiotherapy (group B) in chemotherapy-naïve patients with glioblastoma. Preferred concomitant medication for seizure prevention was valproic acid. Pharmacokinetic analysis of irinotecan and its main metabolites (SN-38, SN-38-G, APC and NPC) was performed during cycle 1. An independent panel of experts reviewed the activity data.
  
  
  RESULTS
  Fifty-two patients (25 patients in group A and 27 patients in group B) received a total of 191 cycles of irinotecan. Forty-six patients (22 patients in group A and 24 patients in group B) were evaluable and externally reviewed for activity. According to external review, one partial response (group B), seven minor responses (three in group A and four in group B), 12 disease stabilisations (seven in group A and five in group B) were observed. This resulted in an overall response rate of only 2.2% (95% confidence interval 0.2% to 6.5%). The median time to tumour progression was 9 weeks in group A and 14.4 weeks in group B. Six-month progression-free survival rates were 26% in group A and 43% in group B. Grade 3-4 toxicities (percentage of patients in groups A and B) consisted of neutropenia (12.5% and 25.9%), diarrhoea (8.3% and 7.4%), asthenia (12.5% and 7.4%) and vomiting (0% and 7.4%). The clearance of irinotecan was 12.4 and 14.4 l/h/m(2) in two patients who received no anticonvulsant. In patients receiving valproic acid, the clearance of irinotecan was 17.2 +/- 4.4 l/h/m(2).
  
  
  CONCLUSIONS
  Irinotecan given at the dose of 350 mg/m(2) every 3 weeks has limited clinical activity as a single agent in patients with newly diagnosed and recurrent glioblastoma after radiotherapy. The toxicity profile and plasma disposition of irinotecan and SN-38 were not strongly influenced by anticonvulsant valproic acid therapy. Although the response rate of irinotecan as a single agent was limited, it remains an attractive drug for combination studies in patients with glioblastoma.
authors.affiliation: Institut Gustave Roussy, Villejuif, France. raymond@igr.fr
authors.forename: E
authors.initials: E
authors.lastname: Raymond
authors.forename: M
authors.initials: M
authors.lastname: Fabbro
authors.forename: V
authors.initials: V
authors.lastname: Boige
authors.forename: O
authors.initials: O
authors.lastname: Rixe
authors.forename: M
authors.initials: M
authors.lastname: Frenay
authors.forename: G
authors.initials: G
authors.lastname: Vassal
authors.forename: S
authors.initials: S
authors.lastname: Faivre
authors.forename: E
authors.initials: E
authors.lastname: Sicard
authors.forename: C
authors.initials: C
authors.lastname: Germa
authors.forename: J M
authors.initials: JM
authors.lastname: Rodier
authors.forename: L
authors.initials: L
authors.lastname: Vernillet
authors.forename: J P
authors.initials: JP
authors.lastname: Armand
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics* / Q000494:pharmacology*; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009503:Neutropenia / Q000139:chemically induced; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin