Phase I clinical and pharmacokinetic study of a 14-day infusion of etoposide in patients with lung cancer

Purpose: A phase I study was conducted to determine the maximum-tolerated dose (MTD) of a 14-day continuous infusion of etoposide, and to evaluate the pharmacokinetics in patients with lung cancer. Patients and Methods: Etoposide was administered continuously through a central venous catheter using a pump. The starting dose level was 300 mg/m² over 14 days, with dose escalations of 100 mg/m² over 14 days until unacceptable toxicities occurred. Pharmacokinetic studies were performed in all patients. Results: Twenty-one patients, 20 with non-small-cell lung cancer and one with refractory small-cell lung cancer, received 37 courses. No World Health Organization (WHO) grade III or greater toxicity occurred at doses up to 400 mg/m² over 14 days. At 700 mg/m² over 14 days, all four patients experienced grade III or IV leukocytopenia, and two developed grade III stomatitis. No cu-mulative toxicity was observed. A steady concentration of etoposide was achieved 24 hours after the start of chemotherapy, and it was significantly correlated with surviving fractions of leukocytes (r = -.64, P = .001) and platelets (r = -.68, P < .001). The leukocyte count at the termination of chemotherapy predicted the nadir count (r = .93, P < .001). Conclusion: Steady blood levels of etoposide were maintained for prolonged periods, during 14-day continuous infusions. Leukocytopenia and stomatitis were dose-limiting. Nadir counts and surviving fractions of leukocytes were predicted by the leukocyte count at the end of chemotherapy and the concentration of etoposide, respectively. The recommended dose for phase II trials is 600 mg/m² over 14 days.