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, Neoplasms - drug therapy, Time Factors