Topotecan in combination chemotherapy

The safety and efficacy of combination chemotherapy regimens containing topotecan (Hycamtin; SmithKline Beecham Pharmaceuticals, Philedelphia, PA), a topoisomerase I-targeting drug that has demonstrated significant antitumor activity in a wide range of human tumors, and various classes of antineoplastic agents is currently being evaluated. To date, phase I and pharmacologic studies of topotecan combined with cisplatin, carboplatin, doxorubicin, and etoposide have been performed in adult and pediatric patients with solid tumors. Combination regimens consisting of topotecan combined with cytarabine, cyclophosphamide, and carboplatin also have been studied in patients with refractory leukemia. Myelosuppression, primarily neutropenia, has been the principal dose-limiting toxicity of these combination regimens. Major responses have been observed in many early studies. Both the toxicologic and antineoplastic effects have exhibited sequence dependence in preclinical and phase I studies, especially in evaluations of topotecan combined with alkylating agents and topoisomerase II-targeting drugs. At this juncture, additional phase I and II trials are required to evaluate the toxicity and efficacy of topotecan in combination with other agents and address critical issues related to optimal drug dosing and sequencing.