Clinical and pharmacokinetic study of fractionated doses of oral etoposide in pediatric patients with advanced malignancies
Lauro J. Gregianin, Algemir L. Brunetto, Luciane Di Leone, Teresa Dalla Costa, Pedro P. Santos, Gilberto Schwartsmann
Med Sci Monit 2002; 8(9): PI70-77
Background: The purpose of this phase I study was to evaluate the toxicity profile, dose-limiting toxicities (DLT), maximum tolerated dose (MTD), and plasma pharmacokinetics of oral etoposide, and
to recommend a safe fractionated dose for phase II trials in pediatric patients with refractory solid tumors.
Material/Methods: All patients had tumors no longer amenable to established forms of treatment. The initial dose of etoposide was 20 mg/m2 TID for 14 days every 21 days (dose-level I). Etoposide plasma pharmacokinetics were studied on day 1 of treatment and determined by HPLC.
Results: Seventeen children were enrolled, 13 of whom were included in the pharmacokinetic study, for a total of 64 courses. Nine patients were included at dose-level I; grade 2–3 leucopenia was observed in 5. The dose was then raised to 25 mg/m2 (dose-level II) in another 8 patients; grade 3–4 leucopenia was observed in 4. This dose-level was therefore considered the MTD. The DLT was neutropenia. In patients at dose-level I and II the maximum plasma etoposide concentration was 2.97 and 8.59 µg/ml, respectively. Drug levels > 1 µg/ml were maintained for about 6.3 hours following drug administration at both dose-levels. Partial response was observed in 1 patient and 4 patients showed stable disease.
Conclusions: Prolonged oral etoposide was well tolerated by our patients. Considering the MTD, and the fact that the patients included at dose-level I achieved an adequate (>1 µg/ml) plasma concentration
of etoposide for a sufficient time, this dose level was recommended for phase II studies in pediatric malignancies.
This work was performed at the Pediatric Oncology Service, Hospital de Clínicas de Porto Alegre; the Pediatric Hematology-Oncology Service, Hospital da Crianca Conceicao; and at the South American Office for Anticancer Drug Development (SOAD), Porto Alegre, Brazil.
Keywords: Administration, Oral, Adolescent, Antineoplastic Agents, Phytogenic - administration & dosage, Antineoplastic Agents, Phytogenic - pharmacokinetics, Area Under Curve, Child, Child, Preschool, Etoposide - administration & dosage, Etoposide - pharmacokinetics, Female, Humans, Male, Neoplasms - drug therapy, Time Factors, Treatment Outcome