title: Efficacy and safety of topotecan in the treatment of advanced ovarian carcinoma.
abstract: Topotecan (Hycamtin; SmithKline Beecham Pharmaceuticals, Philadelphia, PA) has emerged as a promising new chemotherapy drug for patients with refractory and progressive stage III and IV epithelial ovarian carcinoma. A semisynthetic analog of camptothecin, topotecan exerts its antitumor effects through inhibition of the nuclear enzyme topoisomerase I. Phase I trials found antitumor activity in many topotecan dosing schedules, one of which involved the administration of topotecan daily as a 30-minute infusion for 5 consecutive days, with the cycle repeated every 21 days. With this schedule, the maximum tolerated dose was found to be 1.5 mg/m2/d. In a series of phase II investigations in platinum-resistant ovarian cancer patients, response rates have ranged from 13% to 25%. In addition, a number of patients exhibit prolonged disease stabilization, with overall rates of nonprogression ranging from 37% to 81%. Activity in paclitaxel-resistant patients is also seen, with a multicenter phase II trial showing a response rate of 13% among first-line paclitaxel failures and 14.3% among second-line failures. A phase III trial compared topotecan and paclitaxel as second-line therapies in 226 advanced ovarian cancer patients who had been previously treated with platinum-containing regimens. Preliminary data show that patients treated with topotecan evidenced a higher response rate (23% v 14%), longer response duration (32 weeks v 20 weeks), and significantly longer time to progression (23 weeks v 14 weeks; P = .002). Additional schedules are still being evaluated, with a phase II trial of prolonged infusion of relatively low-dose topotecan over 21 days demonstrating a 37% response rate in 16 patients. All phase II and III trials analyzed thus far indicate that topotecan is well tolerated with an acceptable toxicity profile, with myelosuppression as the dose-limiting toxicity. Hematologic toxicities are predictable, of short duration, and noncumulative. Mild to moderate nonhematologic toxicities are manageable. These findings demonstrate that topotecan is a viable new second-line or salvage treatment for patients with advanced ovarian cancer who are refractory or resistant to prior chemotherapy, including platinum-based agents and/or paclitaxel.
authors.affiliation: Department of Internal Medicine, The Netherlands Cancer Institute, Amsterdam.
authors.forename: W
authors.initials: W
authors.lastname: ten Bokkel Huinink
authors.forename: J
authors.initials: J
authors.lastname: Carmichael
authors.forename: D
authors.initials: D
authors.lastname: Armstrong
authors.forename: A
authors.initials: A
authors.lastname: Gordon
authors.forename: J
authors.initials: J
authors.lastname: Malfetano
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D002277:Carcinoma / Q000188:drug therapy; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D015337:Multicenter Studies as Topic; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000627:therapeutic use; D010984:Platinum / Q000627:therapeutic use; D012074:Remission Induction; D012449:Safety; D015996:Survival Rate; D059004:Topoisomerase I Inhibitors; D019772:Topotecan
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D010984:Platinum; D019772:Topotecan; D017239:Paclitaxel; D002166:Camptothecin