Purpose: 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/m2/w) for four out of six weeks. Schedule B patients received irinotecan every three weeks at a dose of 300 mg/m2. 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 cleareance. 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.
Bibliographical noteFunding Information:
Acknowledgements This study was supported by NCI grant CA25224 and Pharmacia & Upjohn. The authors would like to thank Paul Novotny and Stephen Cha from the Mayo Clinic Department of Biostatistics for their help with data analysis and Dr. Larry Schaaf from Ohio State for his help with sample analysis. They would also like to thank Mrs. Raquel Ostby for her help with manuscript preparation. This study was conducted as a collaborative trial of the North Central Cancer Treatment Group and Mayo Clinic and was supported in part by Public Health Service grants CA-25224, CA-35269, CA-52352, CA-35195, CA-35101, CA-37417, CA-35415, CA-35448, CA-35103, CA-63849, CA-63848.
- Enzyme-inducing antiepileptic drugs
- Recurrent gliomas