Phase II Evaluation of Carboplatin, Paclitaxel and Bevacizumab as First Line Chemotherapy and Consolidation for Advanced Ovarian Cancer

Ovarian cancer is diagnosed in approximately 26,000 American women each year, and is the leading cause of death from gynecologic cancers. Difficult to detect, the disease typically presents only when advanced. Ovarian cancer is among the most sensitive of solid tumors to chemotherapy. However, the majority of patients with ovarian cancer who achieve a complete remission with first line platinum-based chemotherapy will ultimately develop recurrent disease. The combination of carboplatin and paclitaxel is the standard first line combination in the US.

In patients with advanced ovarian cancer, carboplatin plus paclitaxel results in less toxicity, is easier to administer, and is not inferior, when compared with cisplatin plus paclitaxel. The randomized trial, GOG-158 finally confirmed the adoption of this standard with an improved toxicity profile of the combination of cisplatin and paclitaxel, a doublet that had been previously demonstrated to have a substantially better progression free and overall survival advantage compared with cisplatin and cyclophosphamide in advanced-stage epithelial ovarian cancer. Although in nonrandomized trials, carboplatin and paclitaxel was a less toxic and highly active combination regimen, there remained concern regarding its efficacy in patients with good prognosis completely resected advanced disease.

In parallel European, multicentre, randomised trials, between January, 1996, and March, 2002, 802 patients with platinum-sensitive ovarian cancer relapsing after 6 months of being treatment-free were enrolled from 119 hospitals in five countries (ICON III). Patients were randomly assigned paclitaxel plus platinum chemotherapy or conventional platinum-based chemotherapy. Survival curves demonstrated a difference in favor of paclitaxel plus platinum (hazard ratio 0.82 [95% CI 0.69-0.97], p=0.02), corresponding to an absolute difference in 2-year survival of 7% between the paclitaxel and conventional treatment groups (57 vs 50% [95% CI for difference 1-12]), and median survival of 5 months (29 vs 24 months [1-11]).

Since the hypothesis of targeting angiogenesis to treat cancer was first described in 1971 by Judah Folkman, there has been intense research into the development of antiangiogenic cancer therapies. Tumors are dependent on their development of a vascular supply. Recent work has shown that, if cells are already transformed, angiogenesis can be initiated with a tumor mass comprising as few as 100-300 cells.

VEGF actions are mediated through binding to two receptor tyrosine kinases, VEGF-R-1 (Flt-1) and VEGF-R- 2 (KDR; whose murine form is known as Flk-1). Activation of these receptors by VEGF triggers the phosphorylation of a multitude of proteins that are active in signal transduction cascades. VEGF gene expression is upregulated by a wide range of stimuli including hypoxia, nitric oxide, estrogen, a variety of growth factors (e.g., FGF-4, PDGF, TNF, TGF-b, EGF, IL-6, IL-1b, #76) and common genetic events associated with the malignant phenotype (loss of tumor suppressor genes such as p53 and activation of oncogenes such as ras, v-src and HER2/neu). Beside major angiogenic properties, VEGF is a potent mitogen for vascular endothelium, inhibits endothelial apoptosis and mobilizes bone marrow-derived endothelial cell precursors. VEGF also mediates the secretion of enzymes involved in the degradation of extracellular matrix, modulates migration, increases vascular permeability, upregulates hexose transport and induces monocyte migration.