Journal of Clinical Oncology, Vol 12, 1427-1435, Copyright © 1994 by American Society of Clinical Oncology
A randomized trial of two etoposide schedules in small-cell lung cancer: the influence of pharmacokinetics on efficacy and toxicity
PI Clark, ML Slevin, SP Joel, RJ Osborne, DI Talbot, PW Johnson, R Reznek, T Masud, W Gregory and PF Wrigley
Medical Oncology Department, St Bartholomew's Hospital, London, United Kingdom.
PURPOSE: Etoposide is a schedule-dependent drug, as demonstrated by the
superiority of 5 consecutive daily infusions over a continuous 24-hour
infusion in patients with small-cell lung cancer. A randomized trial has
therefore been conducted to compare an extended 8-day regimen with the
5-day schedule. PATIENTS AND METHODS: Ninety-four patients with small-cell
lung cancer (35 limited disease, 59 extensive disease) were randomized to
receive single-agent etoposide 500 mg/m2, either as 5 daily 2-hour
infusions of 100 mg/m2 or as 8 daily 75-minute infusions of 62.5 mg/m2,
both repeated every 3 weeks for six cycles. Single-agent carboplatin was
administered at relapse in both arms of the study. Patients were stratified
at randomization according to extent of disease and Karnofsky performance
status (KPS). RESULTS: The overall response rate was 81% in the 5-day arm
and 87% in the 8-day arm, with median survival durations of 7.1 and 9.4
months, respectively (no significant differences). The time over which
plasma etoposide exceeded low plasma concentrations was significantly
longer in patients who responded compared with patients who did not
respond. This was most significant for time at concentrations greater than
1, 1.5, and 2 micrograms/mL. Hematologic toxicity was significantly worse
in the 5- day arm of the study (cycle no. 1 nadir neutrophil count, 0.8 x
10(9)/L v 1.7 x 10(9)/L). Stepwise regression analysis found duration of
exposure to plasma etoposide greater than 3 micrograms/mL to be predictive
of nadir neutrophil count and duration of exposure to plasma etoposide
greater than 2 micrograms/mL to be predictive of nadir WBC count.
CONCLUSION: The 5-day and 8-day regimens had equivalent activity in
small-cell lung cancer. A pharmacokinetic association between
concentrations of etoposide and response and toxicity was found. Antitumor
activity was associated with the maintenance of lower levels of etoposide
than found to be associated with hematologic toxicity. This supports the
hypothesis that the schedule of etoposide administration may affect
efficacy and toxicity, and that prolonged exposure to low concentrations of
etoposide may improve the therapeutic ratio for this drug.
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