Irinotecan in the treatment of glioma patients: current and future studies of the North Central Cancer Treatment Group.
Other than nitrosoureas (carmustine and lomustine) and temozolomide, no agents have consistently demonstrated clinically meaningful benefits for patients with gliomas. The active metabolite of irinotecan, 7-ethyl-10-hydroxy camptothecin (SN-38), exhibited promising antitumor effects in preclinical glioma models. Clinical trials using weekly or every 3 weeks dosing of irinotecan have been completed. Toxicity consisted primarily of mild to moderate neutropenia and diarrhea with both schedules, with occasional severe toxicity including one death from neutropenia and infection. Preliminary analyses have suggested imaging responses in 10-15% of patients. Preclinical models and our understanding of the mechanism of action suggest that irinotecan may sensitize glioma cells to the cytotoxic actions of radiation therapy and alkylating agents; clinical trials designed to assess the therapeutic benefit of combination therapy currently are in progress. There is substantial clinical evidence that the concurrent administration of irinotecan with certain anticonvulsants produces reduced exposure to SN-38. In the absence of anticonvulsants, there is also substantial interpatient variability in drug exposure, perhaps reflecting inherited differences in drug metabolism. Finally several mechanisms of tumor cell resistance to irinotecan have been hypothesized, but the clinical significance of these observations has not been confirmed. Correlative studies to address these pharmacokinetic, pharmacogenetic, and drug resistance questions are ongoing.
Buckner
Jan C
JC
Division of Medical Oncology and Developmental Oncology Research, Cancer Center Statistics Unit, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. buckner.jan@mayo.edu
Reid
Joel M
JM
Wright
Keith
K
Kaufmann
Scott H
SH
Erlichman
Charles
C
Ames
Matthew
M
Cha
Steve
S
O'Fallon
Judith R
JR
Schaaf
Lawrence J
LJ
Miller
Langdon L
LL
D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D001932:Brain Neoplasms / Q000188:drug therapy*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use* / Q000633:toxicity; D002986:Clinical Trials as Topic; D005909:Glioblastoma / Q000188:drug therapy; D005910:Glioma / Q000188:drug therapy*; D006801:Humans; D000077146:Irinotecan
D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin