title: Phase II study of irinotecan (CPT-11) in children with high-risk malignant brain tumors: the Duke experience.
abstract: A phase II study of irinotecan (CPT-11) was conducted at Duke University Medical Center, Durham, NC, to evaluate the activity of this agent in children with high-risk malignant brain tumors. A total of 22 children were enrolled in this study, including 13 with histologically verified recurrent malignant brain tumors (glioblastoma multiforme [GBM] 4, anaplastic astrocytoma 1, ependymoma 5, and medulloblastoma/primitive neuroectodermal tumor 3), 5 with recurrent diffuse pontine glioma, and 4 with newly diagnosed GBM. All patients with recurrent tumor had prior chemotherapy and/or irradiation. Each course of CPT-11 consisted of 125 mg/m ( 2 ) per week given i.v. for 4 weeks followed by a 2-week rest period. Patients with recurrent tumors received therapy until disease progression or unacceptable toxicity. Patients with newly diagnosed tumors initially received 3 cycles of treatment to assess tumor response and then were allowed radiotherapy at physician's choice; patients who demonstrated a response to CPT-11 prior to radiotherapy were allowed to continue the drug after radiation until disease progression or unacceptable toxicity. A 25% to 50% dose reduction was made for grade III-IV toxicity. Responses were assessed after every course by gadolinium-enhanced MRI of the brain and spine. Twenty-two patients received a median of 2 courses of CPT-11 (range, 1-16). Responses were seen in 4 of 9 patients with GBM or anaplastic astrocytoma (44%; 95% confidence interval, 11%-82%) (complete response in 2 patients with recurrent GBM lasting 9 months and 48+ months; partial response in one patient with a newly diagnosed midbrain GBM lasting 18 months prior to radiotherapy; and partial response lasting 11 months in 1 patient with recurrent anaplastic astrocytoma), 1 of 5 patients with recurrent ependymoma (partial response initially followed by stable disease lasting 11 months), and none of 5 patients with recurrent diffuse pontine glioma. Two of 3 patients with medulloblastoma/primitive neuroectodermal tumor had stable disease for 9 and 13 months. Toxicity was mainly myelosuppression, with 12 of 22 patients (50%) suffering grade II-IV neutropenia. Seven patients required dose reduction secondary to neutropenia. CPT-11, given in this schedule, appears to be active in children with malignant glioma, medulloblastoma, and ependymoma with acceptable toxicity. Ongoing studies will demonstrate if activity of CPT-11 can be enhanced when combined with alkylating agents, including carmustine and temozolomide.
authors.affiliation: The Brain Tumor Center at Duke, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Turner
authors.forename: Sridharan
authors.initials: S
authors.lastname: Gururangan
authors.forename: James
authors.initials: J
authors.lastname: Eastwood
authors.forename: Krystal
authors.initials: K
authors.lastname: Bottom
authors.forename: Melody
authors.initials: M
authors.lastname: Watral
authors.forename: Rodney
authors.initials: R
authors.lastname: Beason
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.forename: Sandra
authors.initials: S
authors.lastname: Tourt-Uhlig
authors.forename: Langdon L
authors.initials: LL
authors.lastname: Miller
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
mesh_terms: D000293:Adolescent; D000328:Adult; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001254:Astrocytoma / Q000188:drug therapy; D001932:Brain Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004334:Drug Administration Schedule; D004806:Ependymoma / Q000188:drug therapy; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy; D005910:Glioma; D006801:Humans; D000077146:Irinotecan; D008279:Magnetic Resonance Imaging; D008297:Male; D008527:Medulloblastoma / Q000188:drug therapy; D059003:Topoisomerase Inhibitors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D059003:Topoisomerase Inhibitors; D000077146:Irinotecan; D002166:Camptothecin