Evaluation of New Platinum-Based Treatment Regimens in Advanced-Stage Ovarian Cancer: A Phase III Trial of the Gynecologic Cancer InterGroup. J Clin Oncol 27(9): 1419-1425

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


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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    ABSTRACT: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) based strategy is a promising targeted therapeutic approach for the treatment of a variety of cancers including ovarian cancer. However, the inherent or acquired resistance of tumor cells to TRAIL limits the potential application of TRAIL-mediated therapy. In this study, we identified that mitochondrial division inhibitor-1 (mdivi-1) is able to enhance the sensitivity of human ovarian cancer cells to death receptor ligands including TRAIL, FAS ligands, and TNF-α. Importantly, the combination of TRAIL and mdivi-1 has no apparent cytotoxic effect on non-transformed human cells, indicating a significant therapeutic window. We identified that caspase-8 and not the modulation of TRAIL receptors is required for the combination effect of TRAIL and mdivi-1. We further demonstrated that the enhanced efficacy of combination of mdivi-1 and death ligands is not dependent on the originally reported target of mdivi-1, Drp1, and is also not dependent on the two important pro-apoptotic Bcl-2 family proteins Bax and Bak. Thus, our study presents a novel strategy in enhancing the apoptotic effect of death receptor ligands and provides a new effective TRAIL-based combination approach for treating human ovarian cancer.
    Biochemical and Biophysical Research Communications 11/2014; 456(1). DOI:10.1016/j.bbrc.2014.11.010 · 2.30 Impact Factor
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    • "Annual OS rates in the four cohorts comprising the control arm are based on extrapolation of the published Kaplan–Meier survival curves [2–5, 45] "
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    ABSTRACT: The objective of this review is to summarize recent scientific and medical literature regarding chemoresponse assays or chemotherapy sensitivity and resistance assays (CSRAs), specifically as applied to epithelial ovarian cancer. A total of sixty-seven articles, identified through PubMed using the key words "in vitro chemoresponse assay," "chemo sensitivity resistance assay," "ATP," "HDRA," "EDR," "MiCK," and "ChemoFx," were reviewed. Recent publications on marker validation, including relevant clinical trial designs, were also included. Recent CSRA research and clinical studies are outlined in this review. Published findings demonstrate benefits regarding patient outcome with respect to recent CSRAs. Specifically, analytical and clinical validations, as well as clinical utility and economic benefit, of the most common clinically used CSRA in the United States support its use to aid in making effective, individualized clinical treatment selections for patients with ovarian cancer.
    Clinical and Translational Oncology 07/2014; 16(9). DOI:10.1007/s12094-014-1192-8 · 2.08 Impact Factor
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    • "The initial treatment of advanced ovarian cancer consists of maximal cytoreductive surgery and platinum-based chemotherapy.5 Over the years, there have been studies addressing other chemotherapy combinations, duration of treatment, and the addition of a third agent;6,7 however, up until recently, there was little doubt that carboplatin in combination with paclitaxel (3-weekly) remained the standard of care for first-line therapy in advanced ovarian cancer. The addition of the antiangiogenic agent bevacizumab (Avastin®; Genentech, South San Francisco, CA, USA) to standard therapy was shown to significantly improve survival in two Phase III trials and is arguably the standard of care for selected patients.8,9 "
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    ABSTRACT: Targeting angiogenesis is proving to be a successful approach in the management of ovarian cancer. The vascular endothelial growth factor inhibitor, bevacizumab, is the first angiogenesis inhibitor to have shown a significant progression-free survival advantage in the Phase III setting. There is now evidence supporting the use of bevacizumab in combination with chemotherapy for first-line and relapsed (platinum-sensitive and resistant) ovarian cancer. In this review, we summarize the positive Phase III trial (OCEANS [Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in Platinum-Sensitive Recurrent Disease]) that led to European Medicines Agency approval of bevacizumab in platinum-sensitive first relapse and discuss the best use of the drug in this disease.
    OncoTargets and Therapy 06/2014; 7:1025-32. DOI:10.2147/OTT.S40527 · 2.31 Impact Factor
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