title: Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a gynecologic cancer intergroup trial of the AGO-OVAR and GINECO.
abstract: BACKGROUND
  The combination of carboplatin and paclitaxel is the standard of care for the treatment of ovarian cancer, yet rates of recurrence and death remain high. We performed a prospective randomized phase III study to examine whether sequential administration of topotecan can improve the efficacy of carboplatin and paclitaxel in first-line treatment of advanced epithelial ovarian cancer.
  
  
  METHODS
  A total of 1308 patients with previously untreated ovarian cancer (International Federation of Gynecology and Obstetrics stages IIB-IV) were randomly assigned to receive six cycles of paclitaxel and carboplatin followed by either four cycles of topotecan (TC-Top; 658 patients) or surveillance (TC; 650 patients) on a 3-week per cycle schedule. The primary endpoint was overall survival, and secondary endpoints were progression-free survival, response rate, toxicity, and quality of life. Time-to-event data were analyzed using the Kaplan-Meier method, and a stratified log-rank test was used to compare distributions between treatment groups. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using a Cox proportional hazards model. Categorical data were compared using a stratified Cochran-Mantel-Haenszel test. All statistical tests were two-sided.
  
  
  RESULTS
  Median progression-free survival was 18.2 months in the TC-Top arm versus 18.5 months in the TC arm (stratum-adjusted HR = 0.97 [95% CI = 0.85 to 1.10]; P = .688). Median overall survival was 43.1 months for the TC-Top arm versus 44.5 months for the TC arm (stratum-adjusted HR = 1.01 [95% CI = 0.86 to 1.18]; P = .885). At 3 years, overall survival in both arms was 57% (58.5% in the TC arm and 55.7% in the TC-Top arm). Compared with patients in the TC arm, patients in the TC-Top arm had more grade 3-4 hematologic toxic effects (requiring more supportive care) and more grade 3-4 infections (5.1% versus 2.7%; P = .034) but did not have a statistically significant increase in febrile neutropenia (3.3% versus 3.1%; P = .80). Among patients who had measurable disease (TC, n = 147; TC-Top, n = 145), overall (i.e., complete or partial) response was 69.0% (95% CI = 61.4% to 76.5%) in the TC-Top arm and 76.2% (95% CI = 69.3% to 83.1%) in the TC arm (P = .166).
  
  
  CONCLUSIONS
  The sequential addition of topotecan to carboplatin-paclitaxel did not result in superior overall response or progression-free or overall survival. Therefore, this regimen is not recommended as standard of care treatment for ovarian cancer.
authors.affiliation: Klinik für Gynäkologie und Geburtshilfe, Campus Kiel, Universitätsklinikum Schleswig-Holstein, Michaelisstr. 16, D-24105 Kiel, Germany. jpfisterer@email.uni-kiel.de
authors.forename: Jacobus
authors.initials: J
authors.lastname: Pfisterer
authors.forename: Béatrice
authors.initials: B
authors.lastname: Weber
authors.forename: Alexander
authors.initials: A
authors.lastname: Reuss
authors.forename: Rainer
authors.initials: R
authors.lastname: Kimmig
authors.forename: Andreas
authors.initials: A
authors.lastname: du Bois
authors.forename: Uwe
authors.initials: U
authors.lastname: Wagner
authors.forename: Hugues
authors.initials: H
authors.lastname: Bourgeois
authors.forename: Werner
authors.initials: W
authors.lastname: Meier
authors.forename: Serban
authors.initials: S
authors.lastname: Costa
authors.forename: Jens-Uwe
authors.initials: JU
authors.lastname: Blohmer
authors.forename: Alain
authors.initials: A
authors.lastname: Lortholary
authors.forename: Sigrid
authors.initials: S
authors.lastname: Olbricht
authors.forename: Anne
authors.initials: A
authors.lastname: Stähle
authors.forename: Christian
authors.initials: C
authors.lastname: Jackisch
authors.forename: Anne-Claire
authors.initials: AC
authors.lastname: Hardy-Bessard
authors.forename: Volker
authors.initials: V
authors.lastname: Möbus
authors.forename: Jens
authors.initials: J
authors.lastname: Quaas
authors.forename: Barbara
authors.initials: B
authors.lastname: Richter
authors.forename: Willibald
authors.initials: W
authors.lastname: Schröder
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Geay
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lück
authors.forename: Walther
authors.initials: W
authors.lastname: Kuhn
authors.forename: Harald
authors.initials: H
authors.lastname: Meden
authors.forename: Ulrike
authors.initials: U
authors.lastname: Nitz
authors.forename: Eric
authors.initials: E
authors.lastname: Pujade-Lauraine
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005602:France; D005858:Germany; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011788:Quality of Life; D016019:Survival Analysis; D019772:Topotecan / Q000008:administration & dosage; D017211:Treatment Failure
chemical_list: D019772:Topotecan; D016190:Carboplatin; D017239:Paclitaxel