Irinotecan (CPT-11, Camptosar) has significant activity in small-cell lung cancer. In addition, preclinical models have demonstrated synergy between irinotecan and two standard front-line drugs for small-cell lung cancer: cisplatin and etoposide; phase III data also show significant survival benefit for irinotecan/cisplatin compared to standard treatment. These data suggest a potential clinical advantage to combining etoposide, cisplatin, and irinotecan as first-line therapy for small-cell lung cancer. The purpose of this phase I study was to establish if alternating weekly therapy with irinotecan/cisplatin and etoposide/cisplatin was tolerated and to determine the maximum tolerated dose of these agents in patients with small-cell lung cancer. Patients generally tolerated the weekly alternating chemotherapy with irinotecan/cisplatin and etoposide/cisplatin well, and this combination possessed significant antitumor activity in small-cell lung cancer.