OBJECTIVE The primary objective of this study was to determine the pharmacodynamics of prolonged administration of low-dose etoposide by continuous infusion (CI). We investigated the hypothesis that maintenance of an etoposide concentration of 1 microgram/mL would be cytotoxic in non-small-cell lung cancer (NSCLC). METHODS Thirty patients with advanced NSCLC without prior chemotherapy or radiotherapy were treated with etoposide at 20, 25, or 30 mg/m2/d infused continuously for 14 days (336 hours), following a 10-mg/m2 bolus. They also received cisplatin 30 mg/m2 on chemotherapy days 1, 2, and 3. Plasma concentrations of etoposide were measured by high-performance liquid chromatography at 0, 2, 4, 24, 48, 120, 336, and 342 hours after initiation of CI etoposide. RESULTS The maximum-tolerated dose (MTD) of etoposide was 25 mg/m2/d with leukocytopenia as the dose-limiting toxicity. Plasma concentrations of etoposide at steady-state (Css) showed approximately twofold interpatient variability at each dose level, and were greater than 1 microgram/mL in most patients at higher dose levels. The severity of neutropenia was dependent on performance status (PS), age, and the Css of etoposide. The overall response rate for the 29 assessable cases was 28%. Five of 11 patients with a Css greater than 1.2 micrograms/mL responded to the therapy, whereas only one of 10 patients with a Css less than 1 microgram/mL responded. CONCLUSIONS With long-term CI of etoposide, a Css greater than 1 or 1.2 micrograms/mL appeared necessary, but not sufficient, to achieve a major response against NSCLC.