Ovarian cancer (Figure 1) is particularly sensitive to chemotherapy and about 70% to 80% of newly diagnosed patients respond to a combination of platinum and taxane chemotherapy.1,2
The growth and metastatic spread of tumours is dependent on the development of a vascular supply.3,4 A number of factors have been identified that contribute towards the homeostasis of angiogenesis. Angiogenesis stimulated by hypoxia, mechanical stress and acidosis results in proangiogenic cytokine production in endothelial cells, associated stromal cells and bone marrow. Vascular endothelial growth factor (VEGF) is the dominant proangiogenic vascular growth factor controlling blood vessel formation. Tumour growth beyond 1-2mm and the ability to metastasise require the establishment of a vascular supply through a process of angiogenesis.4
The induction of angiogenesis is a discrete component of the tumour phenotype and a potentially rate-limiting step that is an essential part of the phenotypic repertoire characterising tumour development.5 The angiogenic switch is governed by regulatory mechanisms that manage the balance between inhibitors and inducers of angiogenesis produced by tumours.
The VEGF cytokine family consists of six glycoproteins and VEGF-A (commonly referred to as VEGF) is the most potent direct-acting angiogenic protein. VEGFs mediate angiogenic signals through high-affinity tyrosine kinase receptors. Binding of VEGF initiates a cascade of signalling events leading to endothelial mitogenesis, proliferation and survival, as well as increased vascular permeability. These receptors are present on vascular endothelium and some ovarian cancer cells, indicating a possible direct antitumour effect of anti-VEGF therapy.
Achieving VEGF inhibition
The antitumour effects of VEGF inhibition are due to a reduction in tumour microvessel density and blood flow. A temporary and paradoxical ‘normalisation’ of tumour vasculature has also been demonstrated. This results in improvement of blood flow and oxygen delivery to the tumour, with consequent enhanced delivery of chemotherapy.6
In humans, VEGF expression is upregulated in most solid tumours, including ovarian cancer.7 In epithelial ovarian cancer, angiogenesis is central to disease progression and prognosis, and the overexpression of VEGF in ovarian tumours is associated with poorer prognosis and survival.8
Experimental data have repeatedly confirmed the hypothesis that cancer growth is angiogenesis-dependent, using angiogenesis inhibitors such as anti-VEGF monoclonal antibodies or VEGF receptor small molecule kinase inhibitors.9 In murine models of epithelial cancer, blocking VEGF slows tumour progression, inhibits ascites formation10 and significantly prolongs the lifespan of the mice.11 Mice that have been inoculated with ovarian carcinoma cells that overexpress VEGF have a significantly reduced time to the formation of ascites. Blocking the effects of VEGF results in resolution of the ascites and prevents further accumulation.10 Agents that inhibit angiogenesis may have the ability to inhibit ascites formation, stop tumour progression and possibly even cause tumour regression in patients with epithelial ovarian cancer.
Many agents that inhibit VEGF receptors have the advantage of oral bioavailability. Some–known as multitarget tyrosine kinase inhibitors (TKIs)–have an affinity for tyrosine kinase on several receptors, such as the VEGF receptor family, the platelet derived growth factor (PDGF) receptor, the epithelial growth factor (EGF) receptor and the fibroblast growth factor (FGF) receptors. This may broaden their spectrum of activity, because PDGF has been implicated in regulation of endothelial/smooth muscle interactions and FGF is a potent endothelial mitogen. Beneficial clinical effects or toxicity may therefore be due to several mechanisms of action. Many multitargeted TKIs are undergoing evaluation in ovarian cancer (see box 1).
Bevacizumab is a recombinant humanised anti-VEGF monoclonal antibody that binds to all the isoforms of VEGF-A, and has a long circulating half-life of 17-21 days. In three phase II trials to evaluate bevacizumab, the objective response rates were 16% to 24% in patients with recurrent ovarian cancer who had extensive disease.12-14 Recruitment to the trial was halted early after five patients (11%) experienced bowel perforations. In a review of the literature of almost 300 ovarian cancer patients treated with bevacizumab, the rate of bowel perforation was 5.4%,15 higher than that reported in similar trials with patients who have colon cancer.
VEGF-Trap is a soluble receptor that is a fully humanised fusion of the VEGF-binding domains of both VEGF receptors and an antibody to the Fc fragment (a constant region on immunoglobulin molecules). It binds to VEGF-A and neutralises all VEGF-A isoforms plus placental growth factor. VEGF-Trap is in the early stages of investigation, but may offer comparable or higher affinity for VEGF when compared to monoclonal antibody approaches.16 It has been reported that the time to repeat paracentesis for ascites was delayed in 80% of patients on IV VEGF-Trap therapy.17
Clinical experience of TKIs
The experience of using VEGF inhibitors is evolving, with investigators learning about the most appropriate dosages, common toxicities and those unique to the individual drug.Cediranib (also known as AZD2171) is a multitargeted TKI with activity against all VEGF receptors and c-kit, a transmembrane tyrosine kinase protein. It has demonstrated significant activity in a range of histologically diverse tumour xenograft models.18
The activity of cediranib has been demonstrated in monotherapy and combination studies with both chemotherapy and gefitinib in several tumour types. As experience increases with the use of cediranib alone or in combination, the dose has been lowered to improve the side-effect profile without affecting its activity. Although 30mg is tolerable as a single agent, 20mg appears more manageable for patients receiving it in combination with chemotherapy.
Trials of antiangiogenics
ICON6 is a randomised trial of concurrent and maintenance cediranib in combination with platinum-based chemotherapy in women with platinum-sensitive relapsed ovarian cancer in first relapse.19 The first stage is under way, with the aim of recruiting 2,000 patients. ICON6 is an academically led trial, developed through the Gynecologic Cancer InterGroup (GCIG).
Two other continuing randomised phase III trials, both involving first-line therapy following surgery and using bevacizumab,20,21 are due to complete recruitment in 2009.
GOG-218 is a three-arm placebo-controlled randomised trial that will address the question of concurrent and maintenance therapy with bevacizumab. It is open to patients who have undergone surgery with optimal or suboptimal debulking. The primary outcome objective is progression-free survival.
ICON7 is an open-label, randomised GCIG trial comparing carboplatin and paclitaxel with this combination given concurrently with bevacizumab, then followed by maintenance bevacizumab in the experimental arm. The dose of bevacizumab is 7.5mg/kg, half the dose used in the GOG-218 trial, and the primary outcome objective is progression-free survival.
The rapid increase in knowledge of the molecular pathways responsible for tumour angiogenesis has led to a growing portfolio of novel agents to treat cancers, including ovarian cancer. These agents have demonstrated promise in the treatment of ovarian cancer, although work continues to understand the mechanisms of action, optimal dosages, combinations and side-effect profile.
The clinical trial design for assessing novel antiangiogenics demands careful consideration to ensure these drugs are rapidly assessed and not prematurely discarded because of apparent lack of efficacy. Whether they will increase cure rates is unclear but ovarian cancer has the potential to become a chronic disease as the list of effective vascular targeting agents grows. The outcome of trials with vascular-targeted agents is keenly awaited.
|Dr Mohini A. Varughese is consultant in clinical oncology, Beacon Centre, Taunton and Somerset Foundation Trust, Musgrove Park Hospital, Taunton, and Professor Jonathan A. Ledermann is professor of medical oncology, UCL Cancer Institute, University College, London. Competing interests: None declared|
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Originally published in the September 2009 edition of MIMS Oncology & Palliative Care.