Review

Continuing Medical EducationNature Clinical Practice Oncology (2008) 5, 194-204
doi:10.1038/ncponc1051  
Received 2 May 2007 | Accepted 22 October 2007 | Published online: 12 February 2008

Angiogenesis as a strategic target for ovarian cancer therapy

Whitney A Spannuth, Anil K Sood and Robert L Coleman*  About the authors

Correspondence *Department of Gynecologic Oncology, University of Texas MD Anderson Cancer Center, Unit 1362, 1155 Herman Pressler Drive, PO Box 301439, Houston, TX 77230-1439, USA

Email rcoleman@mdanderson.org

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Learning objectives

Upon completion of this activity, participants should be able to:

  1. Specify the most promising receptor targeted by antivascular treatment.
  2. Describe the efficacy and safety of treatments that target vascular endothelial growth factor
  3. Describe possible future antivascular treatments for ovarian cancer.
  4. Identify biomarkers that may be helpful to follow the efficacy of antivascular treatment for ovarian cancer.

Competing interests

The authors declared no competing interests. Charles P Vega, the CME questions author, declared that he has served as an advisor or consultant to Novartis, Inc.

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Summary

Angiogenesis is a complex and highly regulated process that is crucial for tumor growth and metastasis. Insights into the molecular mechanisms of tumor angiogenesis have led to the identification of potential angiogenic targets and the development of novel antivascular agents. Many of these agents are being evaluated in clinical trials and have shown promising antitumor activity. This Review highlights the results of the latest clinical studies of antivascular agents in ovarian cancer and discusses the challenges and opportunities for future clinical trials.

Review criteria

The information for this review was compiled using the PubMed and MEDLINE databases for articles published until 1 September 2007. The search terms used included "ovarian cancer", "angiogenesis", "antivascular", "molecular targeted therapy", "chemotherapy", "tyrosine kinase inhibitor", "bevacizumab", "metronomic", "pericytes", "tumor vasculature", and "tumor biomarker". Information regarding ongoing and completed phase I–III trials for antiangiogenic agents and publications related to these trials was obtained from the following websites: http://www.clinicaltrials.gov and http://www.nci.nih.gov/clinicaltrials. Electronic early-release publications were also included. Relevant published abstracts in scientific oncologic meetings were also considered. If possible, primary sources have been quoted. Full articles were obtained and references were checked for additional material, as appropriate. Additional references were added after manuscript submission.

Keywords:

angiogenesis, antivascular agents, biomarkers, clinical trials, ovarian cancer

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Introduction

According to the 2007 American Cancer Society statistics, ovarian cancer will be distinguished as the most lethal gynecologic cancer; of the 28,020 expected deaths from gynecologic malignancies, nearly 55%, or 15,280, will be attributed to ovarian cancer.1 Despite aggressive primary therapy and high initial response rates (RRs), most women with advanced ovarian carcinoma will relapse and develop drug-resistant disease.2 In the recurrent setting, RRs to subsequent chemotherapy are substantially diminished,3 highlighting the crucial need to develop better therapeutic agents and strategies.

An attractive target in this regard is the tumor microenvironment, which is genetically more stable than tumor cells. Angiogenesis is a complex and highly regulated process by which tumors develop new vasculature—a feature essential for growth of the tumor beyond 1 mm in size.4, 5, 6 The dynamic evolution of angiogenesis is regulated by a number of proangiogenic and antiangiogenic molecules that are necessary for physiologic homeostasis. In response to several stimuli, such as oxidative and mechanical stresses, and acidosis, cytokines and proangiogenic growth factors (for example, VEGF, fibroblast growth factor, and platelet-derived growth factor [PDGF]), are released from endothelial cells (ECs) and associated stromal cells into the microenvironment.7 These factors activate ECs and endothelial progenitor cells (EPCs) from the bone marrow to form new blood vessels. Naturally occurring inhibitors of EC proliferation include thrombospondin 1, endostatin, and angiostatin.8, 9

There are several other mechanisms that have a role in tumor neovascularization, including sprouting, co-option of pre-existing vessels, vasculogenic mimicry and mosaic vessels, and mobilization of latent vessels (Figure 1).10, 11, 12 Compared with normal vessels, tumor vasculature is highly tortuous and leaky, and even the perivascular coverage of tumor blood vessels, is altered.13 In this article, we review existing and emerging antivascular strategies in ovarian cancer therapy on the basis of the growing knowledge regarding the biological processes underlying tumor angiogenesis. We also consider relevant surrogate biomarkers for assessing the efficacy of these strategies.

Figure 1 Mechanisms of tumor neovascularization.
Figure 1 : Mechanisms of tumor neovascularization. Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

(A) Endothelial sprouting is the dominant process of vessel growth. Luminal endothelial cells migrate through the vessel basement membrane into the underlying extracellular matrix, developing an elongated 'sprouting' morphology. (B) Vasculogenic mimicry is the development of microvascular channels by aggressive tumor cells. (C) Vessel co-option involves the use of the pre-existing vasculature in the host tissue. (D) The process of tumor neovascularization, involving the release of proangiogenic factors (e.g. VEGF) by tumor cells to cause endothelial activation, blood vessel growth, and subsequent tumor expansion.

Full figure and legend (71K)Figures & Tables indexDownload PowerPoint slide (276K)

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Antivascular strategies

Antivascular strategies can be broadly classified into two groups: antiangiogenic and vascular-disrupting therapies (Table 1).14

Table 1 Antivascular agents in clinical development for ovarian cancer.
Table 1 - Antivascular agents in clinical development for ovarian cancer.
Full tableFigures & Tables indexDownload PowerPoint slide (266K)

Antiangiogenic therapies

The VEGF–VEGF receptor (VEGFR) signaling axis has emerged as the most promising angiogenic target because of its central role in tumor angiogenesis and growth. The VEGF family consists of the following seven ligands: VEGFA, VEGFB, VEGFC, VEGFD, VEGFE, placenta growth factor (PlGF) 1, and PlGF2. The VEGF ligands have specific binding affinities for VEGFR type 1 (VEGFR1), VEGFR2 and VEGFR3 tyrosine kinase receptors. VEGFA (commonly referred to as 'VEGF') has been identified as the predominant proangiogenic growth factor expressed by tumor cells and binds both VEGFR1 and VEGFR2.15 VEGFA expression is regulated by several mechanisms, including hypoxia, acidosis, mechanical stress, and alterations in the expression of oncogenes and tumor-suppressor genes.7 VEGF stimulates EPC mobilization from the bone marrow and promotes EC proliferation, migration, survival, and differentiation, and vascular permeability.

Overexpression of VEGF occurs in most solid tumors, including those of the breast, lung, colon, uterus, and ovary, and has been associated with tumor progression and poor prognosis.16, 17, 18, 19 On the basis of encouraging preclinical data,6 bevacizumab (Avastin® [Genentech, San Francisco, CA]), a humanized antibody that targets VEGF, has been evaluated in phase II–III studies in combination with standard chemotherapy in patients with advanced colorectal cancer,20, 21 breast cancer,22 and non-small-cell lung cancer (NSCLC),23 and has demonstrated improved overall survival or progression-free survival (PFS) times. Randomized phase III clinical trials of bevacizumab in patients with colorectal cancer21 and NSCLC24 led to this drug becoming the first US FDA-approved antiangiogenic therapy. A summary of phase III clinical trials of bevacizumab is presented in Table 2.

Table 2 Phase III clinical trials of bevacizumab with and without standard chemotherapy.
Table 2 - Phase III clinical trials of bevacizumab with and without standard chemotherapy.
Full tableFigures & Tables indexDownload PowerPoint slide (269K)

Anti-VEGF therapy also seems to be a relevant, although less well studied, strategy in ovarian cancer. Several retrospective reviews of patients treated with bevacizumab, alone or in combination with other agents (including docetaxel, cyclophosphamide, and gemcitabine), have demonstrated responses in up to 35% of patients and disease stabilization in up to 100%.25, 26, 27, 28, 29 The first prospective phase II trial of single-agent bevacizumab therapy in patients with persistent or recurrent ovarian carcinoma (Gynecologic Oncology Group [GOG] 170-D) showed an unprecedented 21% RR, with 40% of patients showing no signs of progression at 6 months. The median response duration was 10.3 months.30 Cannistra and colleagues reported a similar RR (16%) in a phase II study in 44 patients with platinum-resistant disease.31 Consistent with the experiences reported in retrospective studies, RRs with the combination of bevacizumab and other agents seem to be even higher than those with bevacizumab alone. An interim phase II study report of bevacizumab combined with metronomic oral cyclophosphamide in 70 patients with recurrent ovarian cancer showed a partial response in 24% of individuals, stable disease in 63%, and a median PFS of 7.2 months.32 Preliminary results of a multicenter phase II trial of bevacizumab plus erlotinib (Tarceva® [Genentech]) in 13 patients with recurrent ovarian cancer showed an RR of 8% and stable disease in 67%.33 A summary of trials of bevacizumab in patients with recurrent ovarian cancer is shown in Table 3.

Table 3 Clinical trials of bevacizumab use in patients with recurrent ovarian cancer.
Table 3 - Clinical trials of bevacizumab use in patients with recurrent ovarian cancer.
Full tableFigures & Tables indexDownload PowerPoint slide (256K)

On the basis of promising results from phase II trials, phase III trials are currently underway in the adjuvant setting; for example, GOG 218, a three-arm, placebo-controlled, randomized clinical study comparing paclitaxel and carboplatin with or without bevacizumab followed by placebo or bevacizumab maintenance therapy, and ICON-7, an open-label, randomized Gynecologic Cancer InterGroup trial comparing paclitaxel, carboplatin, and bevacizumab versus paclitaxel, carboplatin, and bevacizumab followed by bevacizumab maintenance therapy. In addition, the GOG has opened a bifactorial randomized study (GOG 213) of paclitaxel and carboplatin with and without bevacizumab in the presence or absence of secondary surgical cytoreduction in women with platinum-sensitive recurrent disease. The major toxic effects caused by bevacizumab in these phase II studies are similar to those observed in other solid tumor sites, that is hypertension, thrombosis, hemoptysis, proteinuria, and headache. Potentially unique to the use of bevacizumab therapy in ovarian cancer is an alarming rate of gastrointestinal perforation. In the study by Cannistra and co-authors of single-agent bevacizumab therapy, accrual was halted short of the intended 53 patients with recurrent ovarian cancer after 5 patients in the initial cohort of 44 had bowel perforations (11%).31 Although a common etiology was not discovered, patients with impending or symptomatic bowel obstruction were at highest risk. By contrast, bowel perforation in colon cancer patients undergoing combination chemotherapy with bevacizumab is about 2%. Data from the literature of nearly 300 treated ovarian cancer patients show that approximately 5% have suffered this complication.34 Greater experience in less heavily pretreated patients, and better case selection, will probably lower the rate of this complication.

Another VEGF-ligand-binding antiangiogenic agent in clinical development is VEGF Trap (Aflibercept® [Sanofi-Aventis, Paris, France]).35 This fusion protein binds and inactivates the A and B isoforms of VEGF, in addition to PlGF. A phase I trial of this agent in patients with solid tumors included one patient with ovarian cancer who had a partial response and improved performance status. The drug was well tolerated, with the most common adverse events being fatigue, pain, and constipation.36 Ongoing clinical development of VEGF Trap in ovarian cancer includes phase I–II studies of single-agent and combination regimens in women with recurrent ovarian cancer and symptomatic ascites.

VEGF receptor and tyrosine kinase inhibitors

AZD2171 (Recentin™ [AstraZeneca, London, UK]) is a small-molecule inhibitor of VEGFR2 that has shown efficacy in preclinical studies37 and is currently being evaluated in single-agent phase II and multicenter, randomized phase III trials (e.g. ICON-6, a three-arm trial for patients with recurrent, platinum-sensitive ovarian cancer comparing platinum-based chemotherapy in various combinations with AZD2171). IMC-1121B (Imclone, New York, NY) is a fully humanized anti-VEGFR2 IgG1 monoclonal antibody. A phase I dose-escalation study of IMC-1121B in 12 patients with advanced cancer has shown promising results, with two patients achieving a partial response and evidence of stable disease in seven patients.38 On the basis of these observations, a phase II study is planned in patients with recurrent, reviously treated ovarian cancer.

Several other antivascular strategies are showing promise in preclinical and clinical studies. Whereas broadly targeting the PDGF receptor (PDGFR) with imatinib (Glivec® [Novartis, Basel, Switzerland]) or monoclonal antibodies alone might actually promote tumor growth by making the vasculature leakier and immature;39 multitargeted kinase inhibitors that target the ECs (VEGFR blockade) and pericytes (PDGFR inhibition) have demonstrated efficacy in both preclinical studies and phase I–II clinical trials.40, 41 Sunitinib, also known as SU11248 (Sutent® [Pfizer, New York, NY]), targets VEGFRs, PDGFRbeta, the KIT receptor, and fms-related tyrosine kinase 3, and has been approved by the FDA for the treatment of patients with imatinib-resistant gastrointestinal stromal tumors.42, 43 In a phase I trial of sunitinib in 13 evaluable patients with advanced solid tumors, including two patients with ovarian cancer, one patient remained on treatment for over 20 weeks.40 A National Cancer Institute phase II trial of sunitinib is underway in patients with recurrent ovarian epithelial cancer. Sorafenib (Nexavar® [Bayer Pharmaceuticals, Leverkusen, Germany]) is a multitargeted kinase inhibitor that targets VEGFR2, VEGFR3, PDGFR, KIT, RAF, fms-related tyrosine kinase 3, and RET, and has recently been approved by the FDA for the treatment of renal cell carcinoma.35 In the phase I setting, 50% of patients with ovarian cancer had evidence of stable disease.44 A phase II consortium conducted at the Princess Margaret Hospital, Windsor, Berkshire, UK, evaluating the efficacy of sorafenib in combination with gemcitabine in patients with recurrent or refractory ovarian carcinoma, is continuing to accrue patients into a second stage. Preliminary results showed encouraging activity, with an overall RR of 33% in 18 evaluable patients, and the treatment was reasonably well tolerated.41 PTK787 (vatalanib [Novartis]), a multitargeted inhibitor of PDGFR, all VEGFRs, and KIT,45 has had mixed results in clinical trials in colorectal cancer patients (a subset of patients with high lactate dehydrogenase levels had a 32% reduction in relative risk of progression).46 A phase I study in ovarian cancer patients demonstrated that vatalanib combined with carboplatin and paclitaxel is feasible and well tolerated as first-line therapy in patients with advanced disease.47 In addition, interest is being gained in specific targeting of PDGFR-alpha as this receptor appears to be expressed on ovarian cancer cells.

Recent studies have demonstrated the presence of activated EGFRs in the tumor vasculature.48, 49 EGFR inhibitors, such as erlotinib and gefitinib (Iressa® [AstraZeneca]), have shown limited antitumor activity as single-agent therapies in ovarian carcinoma,50, 51 and additional studies are needed to fully understand the role of EGFR ligands in addition to their nonkinase-dependent functions in tumor pathogenesis, which might be relevant for determining the response to EGFR inhibitors in clinical settings. Agents with dual EGFR and VEGFR inhibitory activity (e.g. ZD6474, also known as vandetanib; Zactima® [AstraZeneca]) have shown encouraging preclinical activity, especially in combination with chemotherapy in ovarian and other cancers.49 In patients with NSCLC, ZD6474 demonstrated superior PFS alone (vs gefitinib) and in combination with docetaxel (vs docetaxel alone) and will be evaluated in a randomized phase II study at MD Anderson Cancer Center, Houston, TX, in combination with docetaxel in women with recurrent ovarian cancer.

Another strategy pertains to chronic, low-dose administration of chemotherapeutic agents without extended drug-free breaks (i.e. metronomic chemotherapy [MCT]).52 The primary targets of MCT seem to be tumor-associated ECs, but MCT also induces the production of angiogenesis inhibitors, such as thrombospondin 1, and decreases EPC migration.52 In preclinical models of ovarian cancer, MCT inhibited tumor growth and prolonged survival.53 In phase II trials, MCT has shown promising results in patients with advanced cancer.32, 54

Vascular-disrupting agents and other approaches

Vascular-disrupting agents (VDAs) are a relatively new class of drugs that occlude pre-existing tumor vessels to cause tumor cell death from ischemia and necrosis.55 The ECs of tumor vessels are phenotypically different from normal ECs, and VDAs can distinguish between the two different forms of ECs. VDAs are classified into two groups: small-molecule and ligand-based VDAs.55 These agents might have particular efficacy against advanced disease, and ongoing clinical trials will be instructive with regard to their role in ovarian cancer therapy.56 Early clinical trials of 5,6-dimethylxantenone-4-acetic acid (DMXAA; AS1404 [Antisoma, London, UK]), a flavonoid that induces vascular disruption through the release of cytokines, such as tumor necrosis factor, demonstrate this drug is well tolerated, with the main toxic effects being urinary incontinence, visual disturbance, and anxiety.57, 58 Combretastatin prodrug A4 (Oxigene Waltham, MA) is a tubulin-binding agent that can induce a rapid change in the shape of ECs, causing vascular congestion and decreased blood flow. Dose-limiting toxic effects in a phase I trial included acute coronary syndrome, tumor pain, and ataxia.8

Thalidomide (Celgene, Summit, NJ) downregulates the expression of tumor necrosis factor and VEGF, and modulates the activity of other cytokines; the drug has shown antiangiogenic and antitumor effects in preclinical studies.7 The most encouraging results from clinical trials of thalidomide were observed in patients with multiple myeloma, but some responses have also been noted in patients with solid tumors.59 A phase II trial of continuous low-dose thalidomide in patients with advanced melanoma and renal cell, breast, and ovarian cancers resulted in a 17% RR and evidence of disease stabilization in 17% of patients.60 Remarkably, a prospective randomized trial that used topotecan with or without thalidomide in patients with recurrent epithelial ovarian cancer reported a 50% RR with combination therapy (32% had a complete response and 18% had a partial response) compared with a 22% RR in the control arm.61 The overall survival time, however, was not extended.

Small interfering RNA (siRNA)-targeted therapy is another novel antivascular strategy that has been developed to target the genes responsible for angiogenesis and has shown therapeutic efficacy in preclinical models. Therapeutic delivery of siRNA directed against EphA2, a receptor tyrosine kinase associated with tumor growth and angiogenesis, resulted in decreased tumor growth in combination with chemotherapy in an orthotopic mouse model of ovarian cancer. These approaches are currently being developed clinically and will soon be in phase I testing.62, 63

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Antivascular therapy challenges

Biomarkers

Traditional biomarkers, such as tumor size and CA125 level, might not be optimal for following patients on antiangiogenic therapies. With the growing portfolio of antivascular agents, identification of biomarkers to guide drug choice, dosing, the pharmacologic response, and drug resistance is of paramount importance.64 Repeat biopsies are neither practical nor desirable in ovarian cancer patients; therefore, additional noninvasive biomarkers are needed. A list of surrogate biomarkers for evaluation of the efficacy of antivascular agents is presented in Table 4. For VEGF-targeted therapies, the level of expression of VEGF and microvessel density in the tumor do not seem to be reliable predictors of treatment response.65, 66 Circulating VEGF levels during treatment, however, might serve as a biomarker of response. VEGF levels actually increase in response to treatment with bevacizumab,65 sunitinib,67 vatalanib,68 IMC-1121B,36 and BAY 57-9352.69

Table 4 Surrogate markers for evaluation efficacy of antivascular agents.
Table 4 - Surrogate markers for evaluation efficacy of antivascular agents.
Full tableFigures & Tables indexDownload PowerPoint slide (290K)

In a phase I trial of vatalanib in patients with advanced colorectal cancer, plasma VEGF levels increased in a dose-dependent fashion and correlated with nonprogressive disease.68 In addition to VEGF, other circulating proteins that might act as potential biomarkers have been identified. Plasma basic fibroblast growth factor levels are reported to increase after treatment with vatalanib, but are not associated with an objective response.68 Soluble VEGFR or monocyte levels show modulation by VEGF-targeted therapies and could be useful for predicting and monitoring the treatment response.67, 70 Gene-expression profiling might be a viable option in the future to predict benefit from antivascular agents, but at present there are no clinical data. The Biomarker-integrated Approaches of Targeted Therapy of Lung cancer Elimination (BATTLE) program is an 'umbrella trial' plus four phase II clinical trials for patients with stage IIIB, stage IV, or advanced, incurable NSCLC. Eligible patients will have biopsy samples taken for the assessment of the biomarker profile before randomized allocation. The expression of four types of biomarkers will be assessed: EGFR; K-ras and/or B-raf; VEGF and/or VEGFR; and RXR and/or cyclin D1. This trial might provide new approaches for tailored therapy in cancer patients.

Tumor-derived cell-free DNA (CFDNA) is another potential biomarker; several studies have reported the presence of altered CFDNA in over 50% of cancer patients.71, 72 It was recently demonstrated that CFDNA levels might be a useful biomarker of the response to antivascular therapies in orthotopic ovarian cancer models.53, 73 CFDNA levels were also found to be higher among patients with advanced-stage ovarian cancer compared with control subjects and could prove to be a surrogate measure of the tumor burden in clinical trials.74

Biomarkers are also needed to guide dosing and assess ongoing benefit. The maximum tolerated dose of a cytotoxic drug is usually correlated with the maximum clinical benefit, which might not be the case with biologic therapies.64 For example, in a phase II trial of bevacizumab in patients with colorectal cancer, a dose of 5 mg/kg body weight was more effective than a dose of 10 mg/kg body weight.20 A lower optimal biologic dose could spare patients from unnecessary toxicity and cost. Levels of circulating endothelial cells (CECs) are increased in cancer patients, probably because of mobilization from the bone marrow or displacement from the vessel wall.75 CECs and circulating endothelial progentitor cells (CEPCs) can be identified according to their expression of endothelial markers, such as VEGFR2, AC133, and CD34. In a preclinical model of ovarian cancer, a decrease in CEPCs was found following treatment with antivascular therapy combined with MCT,53 and these markers are being evaluated in clinical trials in ovarian cancer patients. In clinical trials of antiangiogenic therapies in patients with breast or colon cancer, modulation of CEC and CEPC levels was associated with a treatment response.76, 77

Imaging

Vascular imaging is a noninvasive technique that relies on the ability to measure functional changes in tumor hemodynamics associated with antivascular therapy. These techniques include dynamic contrast-enhanced MRI (DCE-MRI), dynamic CT, and PET.64 DCE-MRI has been used in several phase I–II clinical trials to evaluate the effects of antivascular agents, including bevacizumab70 and vatalanib.78 DCE-MRI measures of tumor vascularity have demonstrated an early dose-response effect in these trials. Both preclinical and clinical studies of antivascular therapies using [18F]fluorodeoxyglucose-PET imaging suggest that early effects on the metabolic activity of the tumor might be early indicators of a therapeutic response.79, 80, 81

Resistance

Biomarkers of tumor escape are needed to identify the emergence of resistance to antivascular agents and to better inform the choice of subsequent therapy. Antivascular therapy is thought to target genetically stable ECs, but there is emerging evidence that tumor resistance to these agents occurs.21 Several hypotheses for the acquisition of resistance to antivascular therapy have been proposed, including increased redundancy of angiogenic factors,82 epigenetic mechanisms of resistance,83 and maturation of the tumor vasculature rendering vessels unresponsive to antivascular agents.84 Identification of additional targets on the tumor endothelium could provide opportunities for development of new therapeutic strategies to combat resistance. Specific gene alterations have been identified by gene-expression profiling in tumor-associated ECs from invasive ovarian carcinomas, which might serve as potential therapeutic targets.85 Additional antiangiogenic strategies include targeting nonreceptor kinases, such as the Src family, which have key roles in EC signaling pathways. Selective targeting of transcription factors that contribute to the angiogenic phenotype, such as hypoxia-inducible factor-1 alpha and members of the signal transducer and activator of transcription family, has also been the focus of current research efforts.14

Clinical trial design

Arguably, one of the greatest challenges for the effective implementation of the antivascular paradigm is the development of reliable benchmarks through which to document clinical relevance. Antivascular agents largely produce cytostatic effects, and traditional measures of efficacy, such as RR or time to progression, might overlook a potentially important clinical effect of these agents. By contrast, if primary end points, such as PFS and overall survival, are not improved, despite target modulation, can this approach be considered meritorious? Determination and documentation of these clinical issues are related to not only the agent and its mechanism of action, but also the specific disease and clinical setting. In this regard, careful consideration of statistical methodology and trial design are crucial to drug discovery and development.

Although overall survival is considered by most to be the most valid and least ambiguous end point for clinical efficacy, it is one that requires significant time and expense to reach and is potentially influenced by factors following drug exposure, such as additional therapy. Surrogate end points are being developed and validated to provide an accurate indication of the effects of these factors. For instance, the Adjuvant Colon Cancer Endpoints Group (ACCENT) recently provided convincing evidence (correlative hazard ratios) that 3-year PFS was a good surrogate for 5-year overall survival.86 In ovarian cancer, GOG phase II trials of biologic agents (GOG170 series) such as bevacizumab, sorafenib, and sunitinib are measuring response by a combination of traditional response and lack of progression at 6 months. The bifactorial decision rule allows, for instance, a low objective response if the criteria for nonprogression are met. Nonetheless, such robust end points might not prove that the target is being modulated or that these results will translate to success in the phase III setting, particularly if biologic agents are used in combination with cytotoxic agents. Another design under consideration is whether to treat all patients with the experimental agent and then randomly allocate those with stable disease over a specified period of time to a placebo or drug. A modification to this approach would be continued enrollment of patients documenting a signal in a relevant circulating (e.g. CEPCs) or imaging (e.g. DCE-MR) biomarker. This 'randomized discontinuation' design provides population enrichment by eliminating patients unlikely to respond to the agent of interest.87 Alternatively, tumor profiling might identify patients most likely to respond to an agent or class of agents who would then enter randomized trials with and without the agent of interest.

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Conclusions

Increasing knowledge surrounding cancer biology and the molecular pathways driving tumor angiogenesis has led to the identification of several novel antivascular agents to treat ovarian cancer and other cancers. Although there have been several successes with antivascular agents in patients with solid tumors, challenges facing future clinical trials of such agents include careful study design with appropriate translational research, multiple end points, and testing of surrogate biomarkers for patient identification and efficacy assessment. Improvement in clinical trial design is crucial so that potentially useful agents are not prematurely rejected owing to an apparent lack of efficacy. Although antivascular agents have yielded promising results in ovarian cancer, a better understanding of their mechanisms of action and of optimal combinations is needed. Clinically relevant biomarkers will help to guide patient selection, inform drug dosing, and monitor treatment response. Choosing appropriate strategies for individual patients will improve ovarian cancer treatment and hopefully extend patient survival in the near future.

Key points

  • Angiogenesis is a complex and highly regulated process by which tumors develop new vasculature, which is essential for growth of the tumor beyond 1 mm in size
  • Anti-VEGF therapy with bevacizumab seems to be a relevant strategy for the treatment of ovarian cancer, with promising results from phase II trials
  • Potentially unique to ovarian cancer is an alarming rate of gastrointestinal perforation, and patients with impending or symptomatic bowel obstruction are at highest risk
  • Additional antivascular strategies, including multitargeted tyrosine kinase inhibitors, have proven efficacious in both preclinical and clinical phase I–II trials
  • With the growing portfolio of antivascular agents, identification of biomarkers to guide drug choice, dosing, the pharmacologic response, and drug resistance is of paramount importance
  • Careful consideration of statistical methodology and trial design are crucial to drug discovery and development

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Acknowledgments

This research was funded, in part, by the National Cancer Institute grants CA109298 and CA110793, the UTMD Anderson Cancer Center SPORE in Ovarian Cancer (P50 CA083639), the Department of Defense (#W81XWH-04-1-0227), the Gynecologic Cancer Foundation, the Marcus Foundation, a Program Project Development Grant from the Ovarian Cancer Research Fund, Inc, and the NCI T32 Academic Gynecologic Oncologist Training Grant. Charles P Vega, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscapeaccredited continuing medical education activity associated with this article.

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Competing interests

The authors declared no competing interests.

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Subject areas under which this article appears: Experimental Therapies | Medical Oncology