Prolonged administration of low dose infusional etoposide in patients with advanced malignancies. A phase I/II study

Etoposide displays remarkable schedule dependency. To better define the optimal dose and schedule, the authors administered etoposide as a prolonged low daily dose infusion in patients with a variety of advanced malignancies.

Between October 1989 and April 1992, 40 patients met inclusion criteria and were enrolled in this study; the initial dose of infusional etoposide was 25 mg/m2/day. Doses were not escalated further, because it became evident that 25 mg/m2/day was the maximum tolerated dose (MTD) in most patients using this prolonged schedule. Because the initial dose proved to be the MTD on this prolonged schedule, several patients received a starting dose of either 20 mg/m2/day or 18 mg/m2/day. This continuous infusion was administered for at least 21 days or until either the leukocyte count dropped to less than 2,000/mm3, platelets dropped to less than 75,000/mm3, or tumor progression occurred. Plasma etoposide levels were obtained at random times during infusions at 25 mg/m2/day.

Duration of therapy ranged from 15-561 days. Myelosuppression was the major toxic reaction, although it was mild in most patients and reduced compared with other schedules. Myelosuppression correlated with the extent of prior treatment: minimally pretreated patients tolerated prolonged infusions with only mild hematologic toxic effects, whereas heavily pretreated patients experienced moderate myelosuppression. Patients treated at an initial dose of 25 mg/m2/day had more myelosuppression than did those treated at 20 mg/m2/day. A leukocyte count of less than 1,000/mm3 developed in only 5 of 40 patients (12%) at any time during therapy. Twenty-one patients required packed erythrocyte transfusions, and one required platelet transfusion. The mean serum etoposide concentration in patients receiving 25 mg/m2/day was 0.7 plus or minus 0.42 microgram/ml. Objective responses were obtained in 5 of 10 patients with previously treated non-Hodgkin's lymphoma and 2 of 3 patients with previously untreated extensive stage small cell lung cancer.

Etoposide administered by continuous infusion can be given at 25 mg/m2/day for prolonged periods to most patients and is the MTD in previously treated patients. Tumoricidal activity in selected tumor types is demonstrated with this dose. Further study in neoplasms that considered "etoposide-sensitive" seems warranted.