A randomised, concentration-controlled, comparison of standard (5-day) vs.prolonged (15-day) infusions of etoposide phosphate in small-cell lung cancer

Purpose: This randomised trial was designed to investigate the activity and toxicity of continuous infusion etoposide phosphate (EP), targeting a plas ma etoposide concentration of either 3 mu g/ml for five days (5d) or 1 mu g /ml for 15 days (15d), in previously untreated SCLC patients with extensive disease. Patients and methods: EP was used as a single agent. Plasma etoposide conce ntration was monitored on days 2 and 4 in patients receiving 5d EP and on d ays 2, 5, 8 and 11 in patients receiving 15d EP, with infusion modification to ensure target concentrations were achieved. Treatment was repeated ever y 21 days for up to six cycles, with a 25% reduction in target concentratio n in patients with toxicity. Results. The study has closed early after entry of 29 patients (14 with 5d EP, 15 with 15d EP). Objective responses were seen in seven of 12 (58%, con fidence interval (CI): 27%-85%) evaluable patients after 5d EP, and two of 14 (14%, CI: 4%-42%) evaluable patients after 15d EP (P = 0.038). Grade 3 o r 4 neutropenia or leucopenia during the first cycle of treatment was obser ved in six of 12 patients after id EP and 0/14 patients after 15d EP (P = 0 .004), with median nadir WBC count of 2.6 x 10(9)/l after 5d and 5.0 x 10(9 )/l after 15d EP (P = 0.017). Only one of 49 cycles of 15d EP was associate d with grade 3 or worse haematological toxicity, compared to 14 of 61 cycle s of 5d EP. Conclusions. Although the number of patients entered into this trial was sm all, the low activity seen at 1 mu g/ml in the 15d arm suggests that this c oncentration is below the therapeutic window in this setting. Further conce ntration-controlled studies with prolonged EP infusions are required.