Article

Evaluation of New Platinum-Based Treatment Regimens in Advanced-Stage Ovarian Cancer: A Phase III Trial of the Gynecologic Cancer InterGroup

Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 03/2009; 27(9):1419-25. DOI: 10.1200/JCO.2008.19.1684
Source: PubMed

ABSTRACT 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.
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.
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.
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.

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    • "Despite the high initial response rate, up to 80% of patients will recur and eventually develop resistance to therapy, which leads to incurable disease [3]. Addition of doxorubicin, topotecan, gemcitabine [4], or bevacizumab (anti-VEGF anti-angiogenic antibody) [5] to standard chemotherapy unfortunately has no advantages in improving patient overall survival, further indicating the significant therapeutic challenges in the treatment of ovarian cancer. "
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    • "The responses of refractory or platinumresistant EOC to salvage chemotherapy are generally low and range from 10-20% (Lund et al., 1994; Rose et al., 1998; Gordon et al., 2001; Markman et al., 2002). Although the combined chemotherapy can yield higher responses, a survival improvement cannot be demonstrated (Bookman et al., 2009). Rarely and experimentally are that combined drugs will be used (Havrilesky et al., 2003). "
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    • "Ovarian cancer is the sixth most common cancer in women in the United States and Europe (Jemal et al, 2011). Most patients present with advanced stage disease and though the majority of them experience remission after surgery and a frontline platinum/ taxane-based regimen, the relapse rate is 80% (Bookman et al, 2009). Historically, the efficacy of chemotherapy retreatment in relapsed ovarian cancer has been correlated with prior platinum sensitivity, namely with the platinum-free interval (PFI; Cannistra, 2004). "
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