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.
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.
Pfisterer
Jacobus
J
Klinik für Gynäkologie und Geburtshilfe, Campus Kiel, Universitätsklinikum Schleswig-Holstein, Michaelisstr. 16, D-24105 Kiel, Germany. jpfisterer@email.uni-kiel.de
Weber
Béatrice
B
Reuss
Alexander
A
Kimmig
Rainer
R
du Bois
Andreas
A
Wagner
Uwe
U
Bourgeois
Hugues
H
Meier
Werner
W
Costa
Serban
S
Blohmer
Jens-Uwe
JU
Lortholary
Alain
A
Olbricht
Sigrid
S
Stähle
Anne
A
Jackisch
Christian
C
Hardy-Bessard
Anne-Claire
AC
Möbus
Volker
V
Quaas
Jens
J
Richter
Barbara
B
Schröder
Willibald
W
Geay
Jean-François
JF
Lück
Hans-Joachim
HJ
Kuhn
Walther
W
Meden
Harald
H
Nitz
Ulrike
U
Pujade-Lauraine
Eric
E
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
D019772:Topotecan; D016190:Carboplatin; D017239:Paclitaxel