Over the past few years we have conducted several clinical studies with etoposide phosphate (Etopophos; Bristol-Myers Squibb Company, Princeton, NJ). A phase I trial initially was performed to determine the maximum tolerated dose and pharmacokinetics. A brief intravenous infusion for 5 consecutive days was given every 3 weeks. Myelosuppression was the dose-limiting toxicity and other toxicities were quite similar to those associated with etoposide. The maximum tolerated dose was 100 mg/m2/d for 5 consecutive days. No cytokine support was used in this phase I trial. Pharmacokinetic studies showed very rapid conversion of etoposide phosphate to etoposide. The kinetics of etoposide phosphate were similar to those expected after a comparable etoposide dose. We subsequently began three additional studies, including a phase II randomized comparison of etoposide phosphate plus cisplatin versus etoposide plus cisplatin in patients with small cell lung cancer, a study of low-dose continuous infusion daily etoposide phosphate, and a high-dose etoposide phosphate trial to determine the maximum tolerated dose given in concert with granulocyte colony-stimulating factor. The latter two studies are complete; these data are currently being evaluated. The phase II comparative trial was important and showed unequivocally that the response rate and toxicity with etoposide phosphate plus cisplatin is equivalent to those with etoposide plus cisplatin in patients with small cell lung cancer. In addition, it appears that there was no survival difference between these two treatment arms in this phase II trial of 120 patients. Etoposide phosphate is easier to administer than etoposide and, considering all other factors, including total cost of administration, it is preferable to etoposide for routine clinical use.