Dose-escalating study of weekly bolus topotecan in previously treated ovarian cancer patients

Objective. Topotecan is an established topoisomerase I inhibitor for the treatment of relapsed ovarian cancer. Myelotoxicity and suboptimal patient convenience associated with daily topotecan, however, have prompted investigators to explore alternate regimens, including a weekly regimen of topotecan. The objective of this study was to determine the maximum tolerated dose (MTD) of topotecan given as a weekly bolus in previously treated ovarian cancer patients. Methods. Second- and third-line ovarian cancer patients with measurable disease or elevated cancer antigen 125 received weekly bolus topotecan intravenously starting at 1.5 mg/m(2). Topotecan was escalated in dose increments of 0.5 mg/m(2) every 21 days as tolerability allowed. Dose-limiting toxicity was defined as grade 3/4 neutropenia or thrombocytopenia. Results. Thirty-two of 35 patients were evaluable for safety, and tolerability. No notable toxicity was observed with weekly topotecan doses <4 mg/m(2). Additionally, there was an absence of dose-limiting myelotoxicity and thrombocytopenia with weekly topotecan. The MTD of weekly topotecan without the use of granulocyte colony-stimulating factor support was 4 mg/m(2), with grade 2 anemia, chronic fatigue, and grade 2 gastrointestinal toxicity limiting further dose escalation. Weekly topotecan also demonstrated antitumor activity at doses >2 mg/m(2). Conclusions. The establishment of a well-tolerated, weekly regimen of topotecan (4 mg/m(2), with a maximum recommended dose of 6 mg/m(2)) provides the basis for further investigation in phase II studies of single-agent and combination regimens in previously treated ovarian cancer patients. (C) 2001 Academic Press.