Ovarian cancer and antiangiogenic therapy: caveat emptor.

Abstract

Platinum and taxane-based chemotherapy after surgical cytoreduction remains the mainstay of treatment for advanced ovarian malignancies, with median progression-free survival (PFS) ranging from 17 to 30 months and median overall survival (OS) ranging from 36 to 65 months depending on the volume of postcytoreductive disease. Furthermore, adding additional cytotoxic agents to first-line therapy has not had an impact on outcome. Given the therapeutic limitations of conventional chemotherapy, recent investigations have explored molecularly guided therapies to target pathways of oncogenesis. Angiogenesis is recognized as a hallmark of several types of tumors, including ovarian cancer. One of the most important cytokines responsible for tumor-mediated angiogenesis is vascular endothelial growth factor (VEGF), which is secreted by tumor cells and binds to the VEGF receptor (VEGFR) that is present on normal endothelial cells, stimulating new blood vessel formation. Thus, efforts to block this pathway, either by inhibiting VEGF or its receptor, have emerged as attractive strategies for cancer treatment. Approaches to manipulation of the VEGF pathway include extracellular interference with VEGF itself, as well as intracytoplasmic inhibition of the tyrosine kinase domain of the VEGFR. The most investigated antiangiogenic agent to date is the humanized monoclonal antibody to VEGF, bevacizumab, which prevents binding of VEGF to its receptor and thereby inhibits angiogenesis. More recently, small-molecule tyrosine kinase inhibitors, which interact with the cytoplasmic domains of VEGFR, have been investigated clinically. Pazopanib is a multitargeted tyrosine kinase inhibitor that inhibits several tyrosine kinase receptors including VEGFR, platelet-derived growth factor receptor, and fibroblast growth factor receptor, all of which modulate signaling through angiogenic, proliferative, or cell survival pathways. Early clinical trials have demonstrated promising single-agent activity of pazopanib in recurrent ovarian cancer. To date, four phase III randomized clinical trials testing bevacizumab in ovarian cancer have been published. The first, Gynecologic Oncology Group (GOG) protocol 218, was a three-arm placebo-controlled study investigating the addition of bevacizumab 15 mg/kg to standard carboplatin and paclitaxel chemotherapy in first-line, adjuvant treatment of advanced-stage epithelial ovarian carcinoma (EOC). The 1,873 enrolled patients were treated either with standard chemotherapy alone, standard chemotherapy with concurrent bevacizumab followed by placebo maintenance, or standard chemotherapy with concurrent and maintenance bevacizumab every 21 days for up to 16 doses. Patients who were treated with concurrent and maintenance bevacizumab experienced a significantly prolonged PFS when compared with chemotherapy alone (14.1 v 10.3 months; hazard ratio [HR], 0.717; 95% CI, 0.625 to 0.824; P .001). Although the PFS advantage was encouraging, this benefit did not translate into an OS or quality of life (QOL) advantage. A substantial crossover to bevacizumab ( 40%) occurred during this trial, thereby confounding OS analysis. The second trial of first-line bevacizumab, International Cooperative Group for Ovarian Neoplasia study 7 (ICON-7), compared standard carboplatin and paclitaxel chemotherapy alone or the same chemotherapy with concurrent bevacizumab followed by 12 cycles of maintenance bevacizumab at 7.5 mg/kg in 1,528 patients with early-stage, high-risk (clear cell histology or grade 3) and stages IIB to IV EOC. As was observed with GOG 218, a statistically significant improvement in PFS was reported in the bevacizumab arm compared with standard chemotherapy (19 v 17.3 months; HR, 0.81; 95% CI, 0.70 to 0.94; P .0041). Unfortunately, this PFS advantage again did not translate into an OS benefit. Post hoc subgroup analysis in patients at high risk for recurrence (patients with suboptimally cytoreduced stage III and stage IV disease) demonstrated an even larger 5.4-month improvement in PFS and a 9.4-month median OS advantage (30.3 v 39.7 months; P .0072), which seems somewhat counterintuitive. Final analysis of the ICON-7 data was presented at the 2013 European Cancer Congress. In the poor-prognosis group, 332 of 502 patients died (174 in the control arm; 158 in the bevacizumab arm), with an improvement of 4.8 months in restricted mean survival time from 34.5 to 39.3 months (log-rank P .03; proportional hazards test 0.007). Two additional phase III trials were undertaken to assess the effects of bevacizumab in platinum-sensitive and platinumresistant recurrent EOC, respectively. The Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and AntiAngiogenic Therapy in Platinum-Sensitive Recurrent Disease (OCEANS), a phase III, randomized, placebo-controlled trial, evaluated bevacizumab in the treatment of 484 patients with platinum-sensitive recurrent disease, comparing gemcitabine and JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 30 OCTOBER 2