BJ Rimel, MD
Antiangiogenesis agents target tumor vascular biology which is a known driving force in ovarian cancer. Many of these agents have been studied in ovarian cancer with some important successes. Specifically, bevacizumab, cediranib, pazopanib, and trebananib have shown positive effects either alone or in combination with other drugs.
The timing and length of use of these agents is still being studied as there have been some benefits seen in upfront, maintenance and recurrent settings. Toxicity remains an issue with this class of agents and physicians should carefully select patients for these drugs. This article will discuss the current literature surrounding antiangiogenesis agents in ovarian cancer.Background
Ovarian cancer remains the most lethal gynecologic malignancy in the United States.1
Despite advances in the delivery of platinum- and taxane-based chemotherapy such as intraperitoneal cisplatin and dose-dense paclitaxel, overall survival (OS) has remained largely constant for the last 10 years. Even the addition of other cytotoxic agents in combination or in sequence has not improved outcomes.2
Basic science accomplishments have led to the elucidation of some of the mechanisms of cancer promotion in ovarian cancer. Angiogenesis is now known to be a major biologic pathway in ovarian cancer progression and metastasis but remains complex with multiple actors, including vascular endothelial growth factor and its three receptors (VEGFR 1, 2, and 3), platelet-derived growth factor receptor, the angiopoietin pathway, and integrins that stabilize tumor blood vessels.3-5
Specifically, high levels of vascular endothelial growth factor are noted in ovarian cancer.6
In addition, the angiopoietin pathway is also involved in angiogenesis in ovarian cancer.7
Drugs developed to interfere with these pathways have also been studied in ovarian cancer. Recently, the first biologic therapy in ovarian cancer, bevacizumab (Avastin), was approved for use by the FDA.8
Several other antiangiogenesis agents have been studied in ovarian cancer, with varying success. This review will focus on the study of antiangiogenesis agents in ovarian cancer with special emphasis on those drugs that have shown benefit.Aflibercept, Ramucirumab, Volociximab—Not Ready for Primetime
Aflibercept works as a VEGF-trap, removing circulating VEGF. This drug was an obvious choice for study in recurrent ovarian cancer with ascites. Colombo et al demonstrated a repeat paracentesis response rate of 62%.9
However, a randomized phase 2 study in platinum-resistant ovarian cancer did not meet its primary endpoint for response with only 4.6% of patients responding.10
Similarly, a phase 2 study of ramucirumab, an anti-VEGFR2 antibody, had a best response rate of only 5%.11
Attempts to use anti-integrin antibodies to disrupt ovarian cancer angiogenesis have also been lackluster.
A phase 2 study of the anti-integrin α5β1 antibody, volociximab, in platinum-resistant ovarian cancer involved 16 patients who demonstrated no responses.12
Unfortunately, none of these 3 agents indicated significant activity in ovarian cancer.Bevacizumab—Up Front, Maintenance, or Recurrence?
The most studied antiangiogenesis agent in ovarian cancer is bevacizumab. Bevacizumab is a monoclonal antibody to VEGF and acts to bind and sequester the ligand. This therapy has been studied in the upfront and recurrent settings, both alone and in combination with cytotoxic therapy. It has recently received approval from the Food and Drug Administration (FDA) for use in recurrent ovarian cancer.
There are 2 large phase 3 studies of bevacizumab in combination with platinum-taxane therapy in the upfront setting, GOG 218 and ICON 7.13,14
Both included women at high risk for recurrence and both included a maintenance arm that extended the bevacizumab treatments past the completion of the chemotherapy.
However, there were some significant differences in these studies. ICON 7 included women with stage IC ovarian cancer as well as advanced stage. The bevacizumab dose was 7.5mg/kg every 21 days. GOG 218 included patients in stage 3 or 4, included a placebo arm, and perhaps most strikingly, twice the amount of bevacizumab at 15mg/kg. Both studies demonstrated improved progression-free survival (PFS) but not improved OS, with an increase of 2.3 months seen in ICON 7 with bevacizumab and 3.8 months in GOG 218.