[Topotecan: prospects for using it in combination therapy for ovarian carcinoma]

Topotecan is a semi-synthetic, water soluble topoisomerase I inhibitor which has recently been approved for the treatment of ovarian cancers after failure of first-line therapy. A number of different dosing schedules are being investigated in clinical trials including oral administration, a daily infusion on 5- or 3-consecutive days and a continuous infusion for 21 days. A 30-minute infusion of topotecan 1.5 mg/m2 on 5 consecutive days every 3 weeks, as standard schedule, produced response rates of 13.8 to 20.5% in the 3 largest phase II/III studies in women with advanced ovarian cancers who had either failed to respond or had relapsed after an initial response to platinum-based chemotherapy (N = 92 to 139), continuous 21-day infusion of topotecan 0.3 to 0.5 mg/m2 has shown efficacy in 2 small phase II studies. There were no statistically significant difference in efficacy between topotecan (1.5 mg/m2/day for 5 consecutive days every 21 days) and paclitaxel (175 mg/m2/day given over 3-h every 21 days) in the randomized phase III study. In 3 large clinical trials, response to topotecan was higher in patients who were platinum sensitive (19.2 to 29%) than in those whose disease was platinum resistant or refractory (11.3 to 13.3%) not statistically significant in 1 study, statistical analysis not reported in the other 2 trials. Myelosuppression, particularly neutropenia, is the dose-limiting toxicity of topotecan. It is reversible, dose-related and non-cumulative. In 2 large studies, topotecan produced grade 4 neutropenia in 78 and 79% of patients and in 40 and 37% of all treatment courses (febrile neutropenia occurred during 3% of 552 courses in 1 study). Grade 4 thrombocytopenia was seen in 18 and 25% of patients and in 6 and 10% of all courses, respectively. Grade 4 neutropenia was significantly more common in patients receiving topotecan than in those receiving paclitaxel (79 vs 23%), as was grade 4 thrombocytopenia (25 vs 2%), in a single randomized clinical trial. Non-hematological adverse events during topotecan therapy were mostly mild. A step beyond is the combination treatment including topotecan as a 3- or 5 days schedule plus a platinum compounds or topoisomerase II inhibitor. These associations of drugs are based on the preclinical data of the in vitro studies showing a synergy of the anti-tumor activity. A novel schedule of topotecan is also the "alternating" chemotherapy consisting of different doublet of drugs given as a sequential way or as a really sequential topotecan therapy. Both methods of combining topotecan as second/salvage treatment or front line therapy are being investigated by numerous authors. Preliminary data suggest interesting results in terms of efficacy, manageable toxicity and new schedules of treatment for topotecan. Low dosages of drug in combination with other agent do not seem to influence the well-known data of efficacy or safety of topotecan literature. Probably the 3-day schedule allows a combination treatment, otherwise not feasible with the standard 5-day administration.