Evaluation of new platinum-based treatment regimens in advanced-stage ovarian cancer: a Phase III Trial of the Gynecologic Cancer Intergroup.
OBJECTIVE
To determine if incorporation of an additional cytotoxic agent improves overall survival (OS) and progression-free survival (PFS) for women with advanced-stage epithelial ovarian carcinoma (EOC) and primary peritoneal carcinoma who receive carboplatin and paclitaxel.


METHODS
Women with stages III to IV disease were stratified by coordinating center, maximal diameter of residual tumor, and intent for interval cytoreduction and were then randomly assigned among five arms that incorporated gemcitabine, methoxypolyethylene glycosylated liposomal doxorubicin, or topotecan compared with carboplatin and paclitaxel. The primary end point was OS and was determined by pairwise comparison to the reference arm, with a 90% chance of detecting a true hazard ratio of 1.33 that limited type I error to 5% (two-tail) for the four comparisons.


RESULTS
Accrual exceeded 1,200 patients per year. An event-triggered interim analysis occurred after 272 events on the reference arm, and the study closed with 4,312 women enrolled. Arms were well balanced for demographic and prognostic factors, and 79% of patients completed eight cycles of therapy. There were no improvements in either PFS or OS associated with any experimental regimen. Survival analyses of groups defined by size of residual disease also failed to show experimental benefit in any subgroup.


CONCLUSIONS
Compared with standard paclitaxel and carboplatin, addition of a third cytotoxic agent provided no benefit in PFS or OS after optimal or suboptimal cytoreduction. Dual-stage, multiarm, phase III trials can efficiently evaluate multiple experimental regimens against a single reference arm. The development of new interventions beyond surgery and conventional platinum-based chemotherapy is required to additionally improve outcomes for women with advanced EOC.
Bookman
Michael A
MA
Fox Chase Cancer Center, Philadelphia, PA 19111, USA. michael.bookman@fccc.edu
Brady
Mark F
MF
McGuire
William P
WP
Harper
Peter G
PG
Alberts
David S
DS
Friedlander
Michael
M
Colombo
Nicoletta
N
Fowler
Jeffrey M
JM
Argenta
Peter A
PA
De Geest
Koen
K
Mutch
David G
DG
Burger
Robert A
RA
Swart
Ann Marie
AM
Trimble
Edward L
EL
Accario-Winslow
Chrisann
C
Roth
Lawrence M
LM
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000473:pathology; D011092:Polyethylene Glycols / Q000008:administration & dosage; D019772:Topotecan / Q000008:administration & dosage; D000093542:Gemcitabine
C506643:liposomal doxorubicin; D003841:Deoxycytidine; D011092:Polyethylene Glycols; D019772:Topotecan; D004317:Doxorubicin; D016190:Carboplatin; D017239:Paclitaxel; D000093542:Gemcitabine