title: Phase I study of alternating doublets of topotecan/carboplatin and paclitaxel/carboplatin in patients with newly diagnosed, advanced ovarian cancer.
abstract: OBJECTIVE
  The aim of this study was to evaluate topotecan with carboplatin in an alternating doublet with carboplatin and paclitaxel in first-line ovarian cancer.
  
  
  METHODS
  Patients with newly diagnosed stage III/IV ovarian cancer were studied. The maximum tolerated dose (MTD) of topotecan (cycles 1, 3, 5, 7) in an alternating doublet regimen was determined through standard dose escalation in cohorts of three; doses of carboplatin (area under the curve [AUC] 4 to 5) and paclitaxel (175 mg/m(2), cycles 2, 4, 6, 8) were fixed. Dose-limiting toxicity (DLT) was defined only for cycle 1 as febrile neutropenia, prolonged grade 4 granulocytopenia, grade 4 thrombocytopenia, > or =grade 3 nonhematologic toxicity, or failure to recover in < or =7 days. The use of granulocyte colony-stimulating factor (G-CSF) to permit further dose escalation was also studied.
  
  
  RESULTS
  Thirty-seven patients received 142 cycles of topotecan/carboplatin. Hematologic DLTs included grade 4 neutropenia (59 events, 42% of cycles) and thrombocytopenia (32 events, 23% of cycles). Granulocytopenia was generally short-lived, and only 2 cases of febrile neutropenia occurred. The MTD was 1.0 mg/m(2)/day topotecan and carboplatin AUC 4, alternating with 175 mg/m(2) paclitaxel and carboplatin AUC 4. Although G-CSF effectively managed myelosuppression, thrombocytopenia developed in later cycles, limiting further topotecan dose escalation. The median progression-free survival was 20.5 months, and elevated pretreatment CA-125 levels normalized in 29 of 34 (85%) patients.
  
  
  CONCLUSIONS
  The establishment of a reasonably well-tolerated alternating doublet regimen, coupled with evidence of antitumor activity, provides the basis for further investigation of topotecan in first-line therapy of ovarian cancer. Topotecan (1.0 mg/m(2) daily for 3 days) was chosen for further evaluation in a phase II study.
authors.affiliation: Texas Oncology, P.A., Charles A. Sammons Cancer Center, Dallas, Texas 75246-2044, USA. alan.gordon@usoncology.com
authors.forename: Alan N
authors.initials: AN
authors.lastname: Gordon
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Hancock
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Matthews
authors.forename: Mark
authors.initials: M
authors.lastname: Messing
authors.forename: C A
authors.initials: CA
authors.lastname: Stringer
authors.forename: Mark G
authors.initials: MG
authors.lastname: Doherty
authors.forename: Michael
authors.initials: M
authors.lastname: Teneriello
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D018394:CA-125 Antigen / Q000097:blood; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D019772:Topotecan / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D018394:CA-125 Antigen; D019772:Topotecan; D016190:Carboplatin; D017239:Paclitaxel