Etoposide in the management of non-small cell lung cancer. Etoposide is a phase-specific, schedule-dependent derivative of podophyllotoxin that appears to act by inhibiting DNA-topoisomerase II. Early preclinical work demonstrated sharp activity in mouse leukemias and possible synergy with cisplatin. As a single agent (either orally or intravenously), it demonstrated limited benefit in non-small cell lung cancer (NSCLC), with response rates around 10%. In combination with cisplatin, it has become a mainstay of chemotherapeutic efforts, either as primary therapy or in conjunction with radiation. Response rates in advanced disease average around 30%, climbing to more than 50% in patients with Stage IIIA or IIIB disease. More recent work suggests that the issue of the true synergy of etoposide with cisplatin in NSCLC needs reassessment. The relative roles of etoposide and cisplatin in the combination are unclear, as several studies conflict. Pharmacokinetic data suggest that multiple daily fractions of etoposide are superior to prolonged infusions, warranting several future trials. The current major role for etoposide plus cisplatin would appear to be in multimodality therapy where the combination can be readily combined with radiation and/or surgery. Several other agents have been studied with etoposide or etoposide plus cisplatin (mitomycin, vindesine, doxorubicin, cyclophosphamide, ifosfamide, and carboplatin), but it is unclear whether the addition of any of them offers any response or survival advantage. 