title: A new therapeutical approach: topotecan plus gemcitabine in the treatment of patients with relapsed ovarian cancer after failure of first-line chemotherapy with paclitaxel and platinum.
abstract: OBJECTIVE
  Topotecan and gemcitabine have demonstrated mono-activity against recurrent ovarian cancer. Both drugs affect DNA replication; in addition, topotecan inhibits DNA repair. Based on the efficacy profiles and different mechanisms of action, a phase-I study was conducted to determine the maximum tolerated dose (MTD) of topotecan (day 1-5) and the dose-limiting toxicities (DLT) in combination with gemcitabine (day 1 + 8) every 21 days.
  
  
  METHODS
  Three to six patients were treated per dose-level. Patients with ovarian cancer who had failed a platinum and paclitaxel-containing therapy were enrolled. No individual dose escalation or use of cytokines were allowed.
  
  
  RESULTS
  Twenty-three patients were recruited. Fifty percent of all patients were pretreated with at least two platinum-containing therapies. Eighty courses were assessable for toxicity. The MTD was reached at a dosage of 0.75 mg/m2 topotecan in combination with 800/600 mg/m2 gemcitabine. Thrombocytopenia and leucopenia were the major DLTs. The dose for phase-II trials is 0.50 mg/m2 topotecan given with 800/600 mg/m2 gemcitabine. In this dose-level only one related non-haematological adverse event > grade 2 was observed (grade 3 mycotic stomatitis) and one grade 4 thrombocytopenia occurred. Responses were observed in six patients and stable disease in four out of 12 assessable patients. Median survival time was 15.3 (95% CI: 13.21-28.64) months.
  
  
  CONCLUSIONS
  The results demonstrate feasibility and the tolerability of topotecan in combination with gemcitabine in recurrent ovarian cancer patients. Based on these results a phase-II study was conducted to evaluate the efficacy of this new combination.
authors.affiliation: Department of Gynecology and Obstetrics, Charite/Campus Virchow-Klinikum, Humboldt-University, Berlin, Germany. sehouli@aol.com
authors.forename: Jalid
authors.initials: J
authors.lastname: Sehouli
authors.forename: Dirk
authors.initials: D
authors.lastname: Stengel
authors.forename: Gülten
authors.initials: G
authors.lastname: Oskay
authors.forename: Jens
authors.initials: J
authors.lastname: Blohmer
authors.forename: Sabine
authors.initials: S
authors.lastname: Kaubitzsch
authors.forename: Werner
authors.initials: W
authors.lastname: Lichtenegger
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D003841:Deoxycytidine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives*; D005260:Female; D006801:Humans; D007970:Leukopenia / Q000139:chemically induced; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D017239:Paclitaxel / Q000627:therapeutic use; D017671:Platinum Compounds / Q000627:therapeutic use; D015996:Survival Rate; D013921:Thrombocytopenia / Q000139:chemically induced; D019772:Topotecan / Q000008:administration & dosage* / Q000009:adverse effects; D017211:Treatment Failure; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D017671:Platinum Compounds; D003841:Deoxycytidine; D019772:Topotecan; D017239:Paclitaxel; D000093542:Gemcitabine