Review

Nature Clinical Practice Gastroenterology & Hepatology (2008) 5, 250-267
doi:10.1038/ncpgasthep1097  
Received 16 November 2007 | Accepted 30 January 2008 | Published online: 1 April 2008

Drug Insight: antiangiogenic therapies for gastrointestinal cancers—focus on monoclonal antibodies

Anke Reinacher-Schick, Michael Pohl and Wolff Schmiegel*  About the authors

Correspondence *Department of Medicine, Knappschaftskrankenhaus, Ruhr-University, In der Schornau 23–25, 44892 Bochum, Germany

Email meduni-kkh@ruhr-uni-bochum.de

Summary

Tumor angiogenesis is strongly induced by vascular endothelial growth factor (VEGF), which is overexpressed in most human gastrointestinal cancers. VEGF overexpression is known to be associated with poor prognosis and survival in patients with various solid tumors. The humanized monoclonal anti-VEGF antibody bevacizumab (Avastin®, Genentech Inc., South San Francisco, CA) is a prototypic antiangiogenic compound, and has proven therapeutic benefit combined with conventional chemotherapy—namely, significantly improved progression-free survival in patients with metastatic colorectal cancer. Bevacizumab is the only anti-VEGF antibody that has been approved by the FDA and the European Medicines Agency for the treatment of metastatic colorectal cancer. Several ongoing clinical studies are evaluating the potential of bevacizumab therapy for other gastrointestinal cancers, in combination with chemotherapy, other targeted therapies and/or radiation. Soluble chimeric receptors, tyrosine kinase inhibitors, and monoclonal antibodies against VEGF and molecular targets in the integrin and Delta-like protein 4–Notch pathways are being developed. As tumors acquire resistance to anti-VEGF therapy, further development of antiangiogenic and vascular targets and therapy is warranted.

Review criteria

PubMed and the ASCO website were searched in October 2007 for full papers, reviews and abstracts published in English-language journals using the following keywords alone and in combination: "antiangiogenic therapy", "monoclonal antibody", "vascular endothelial growth factor", "bevacizumab", "gastrointestinal cancer", "colorectal cancer", "pancreatic cancer", "hepatocellular cancer" and "gastric cancer". Papers identified by the search were reviewed and prioritized by relevance. When possible, primary sources have been quoted. Full articles, company homepages and references were also checked for additional material when appropriate. References were chosen on the basis of the best clinical or laboratory evidence available. The reference list was updated in January 2008.

Keywords:

antiangiogenic therapy, bevacizumab, gastrointestinal cancer, monoclonal antibody, vascular endothelial growth factor

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Introduction

As first proposed by Judah Folkman in 1971, new blood-vessel formation via angiogenesis is one of the most important steps in progression of cancer from localized to metastatic disease.1 The target of antiangiogenic therapy for cancer is, therefore, the tumor vasculature. Vascular endothelial growth factor (VEGF) was originally characterized as a tumor-secreted protein that increased microvascular permeability to plasma proteins: VEGF has since been recognized as one of the most important factors involved in tumor angiogenesis.2

During the past decade it has been shown that increased circulating levels of VEGF correlate with advanced disease in patients with colorectal cancer or one of the four most prevalent gastrointestinal cancers—esophageal, gastric, hepatocellular and pancreatic cancer—indeed, VEGF is overexpressed by these tumors.3, 4, 5, 6, 7 For some types of cancer, increased VEGF expression levels in tumors are more sensitive than traditional staging methods for predicting prognosis and risk of relapse.4, 6, 8 Increased expression of VEGF in patients with colorectal cancer has been associated with tumor neovascularization, metastasis and proliferation of cancer cells.4, 9

VEGF and its receptors (VEGFRs) are overexpressed in pancreatic tumors, and this overexpression seems to be an important predictor of liver metastases and poor prognosis in patients with ductal pancreatic adenocarcinoma.10 VEGF can also promote the dissemination of metastases, which leads to early cancer recurrence and poor outcome.6 VEGF is also overexpressed in gastric and esophageal tumors, and this overexpression correlates with recurrence and worse prognosis.5, 11 Hepatocellular carcinomas (HCCs) are highly vascular tumors in which VEGF is overexpressed.7 Tumor expression of VEGF significantly correlates with the serum VEGF level in patients with HCC, and the concentration of circulating VEGF increases with advancing HCC stage.12 VEGF is, therefore, a potential therapeutic target for a number of gastrointestinal cancers. In this Review, data on the activity of bevacizumab in colorectal and other gastrointestinal cancers are presented. Where applicable, current and future studies are also considered. Furthermore, some promising new targets for monoclonal antibodies and further targeted therapies that have been tested in preclinical as well as early clinical trials are discussed.

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Vascular endothelial growth factor

VEGF, also known as VEGF-A, is a multifunctional cytokine with several important effects on endothelial cells that promote the formation of new blood vessels. During sprouting angiogenesis, vessels dilate and become leaky as an initial response to VEGF secreted by cancer or stromal cells.2, 13 VEGF is one of the most potent vascular permeability factors known and is a member of a large family of dimeric glycoprotein growth factors, which includes VEGF-B and platelet-derived growth factor, among others.14 In vitro, VEGF promotes the growth of endothelial cells, and induces a potent angiogenic response in various in vivo models.15 VEGF activates endothelial cells to express various proteins and growth factors, including tissue factor and plasminogen activator inhibitor 1.2 The VEGF pathway is upregulated by hypoxia and growth factors such as epidermal growth factor and platelet-derived growth factor.16, 17, 18

VEGF binds with high affinity to the transmembrane tyrosine kinase receptors VEGFR1 (also known as FLT-1) and VEGFR2 (also known as KDR or FLK-1), which are predominantly expressed on the surface of endothelial cells.19 VEGFR2 is the main mediator of several physiological and pathological effects of VEGF on endothelial cells, including survival, proliferation, migration and permeability.3, 20 Neovascularization of tumors is mainly driven by VEGF signaling through VEGFR2.21 Binding of VEGF to VEGFR2 results in dimerization of the receptor and tyrosine kinase autophosphorylation, followed by induction of signaling cascades via proteins such as phospholipase C, phosphoinositide 3 kinase, Ras small GTPases and mitogen-activated protein kinases in endothelial cells.22 The functions of VEGFR1 are complex, and this receptor is not directly implicated in mitogenesis or angiogenesis. It is possible that VEGFR1 functions as a 'decoy' receptor that sequesters VEGF and prevents its interaction with VEGFR2.23

VEGF also interacts with a family of co-receptors, the neuropilins (e.g. NRP1 and NRP2).24 Neuropilins differ from VEGFR in that they do not have an intracellular signaling domain—they function as co-receptors for VEGFR1 and VEGFR2 by enhancing the affinity of VEGF for VEGFR1 and VEGFR2, which affects subsequent signaling.24 VEGF binding to NRP1 and NRP2 leads to increased endothelial mitogenesis and chemotaxis.24, 25

Human placenta growth factor (PlGF) is a pleiotropic cytokine that stimulates endothelial cell growth, migration and survival, and has chemoattractant properties for angiocompetent macrophages and bone-marrow progenitors. In contrast to VEGF, PlGF selectively binds VEGFR1 and its co-receptors NRP1 and NRP2.23 As PlGF signals directly via VEGFR1, this cytokine acts independently of VEGF in endothelial cells, macrophages, bone-marrow progenitors, and tumor cells, which primarily express VEGFR1.26, 27

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Adhesion molecules and integrins

The VEGF receptors themselves form complexes with a broad spectrum of molecules that function as co-receptors in VEGF signaling. Blood flow and shear stress influence vascular development and remodeling through the creation of a mechanosensory complex. This complex involves VEGFR2, platelet and endothelial cell adhesion molecule 1 and vascular endothelial cadherin.28 Vascular endothelial cadherin functions upstream of integrin activation, and is located in endothelial cell–cell adherens junctions.

Integrins are heterodimeric transmembrane receptors composed of two transmembrane glyco-proteins—the alpha and beta subunits—that are noncovalently associated.29 They are receptors for extracellular matrix proteins, and their ligands include not only laminin, collagen, fibronectin, and vitronectin, but also fibrinogen and fibrin, thrombospondin, matrix metalloproteinase 2, and fibroblast growth factor 2. Integrins bind these ligands by recognizing short amino-acid stretches, particularly the arginine–glycine–aspartic acid (RGD) sequence.30 There are more than 20 different integrins, and the alphaVbeta3 and alphaVbeta5 integrins seem to be closely associated with tumor angiogenesis.29 Cell–matrix interaction via alphaVbeta3 and alphaVbeta5 integrins has an important role in the maintenance of tumor vasculature.28 Only minimally expressed in quiescent blood vessels, expression of alphaVbeta3 integrin is significantly upregulated during angiogenesis in vivo.31 During angiogenesis, the integrins are essential for endothelial-cell migration, proliferation, and survival. Many integrins are involved, directly or indirectly, in regulating endothelial-cell function.32 The interplay between angiogenic growth factors and integrin-mediated signal transduction is of special interest in the discovery of future drug targets.

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Modulation of angiogenesis

Bevacizumab

One of the most promising antiangiogenic treatments is the anti-VEGF monoclonal antibody (mAb) bevacizumab (also known as rhuMAb-VEGF and marketed as Avastin® by Genentech Inc., South San Francisco, CA).33 This humanized mAb binds VEGF with high affinity (dissociation constant, Kd approx0.5 nM) and neutralizes all human VEGFA isoforms and bioactive proteolytic fragments. Bevacizumab does not neutralize other products of the VEGF gene family.34 The half-life of bevacizumab in humans is 17–21 days when it is administered every 2 or 3 weeks.35 So far, there has been no evidence of an antibody response to bevacizumab in any clinical trials, which verifies the success of the humanization of bevacizumab.36 Bevacizumab induces several effects on tumor vasculature and on the cancer cells themselves.

Bevacizumab therapy: mechanisms of action

Tumor blood vessels have become an attractive target of anticancer treatment, and anti-VEGF therapy is considered the most potent antiangiogenic strategy. However, normalization of the tumor vasculature reduces drug and oxygen delivery to parts of the tumor, which reduces the efficacy of chemotherapy and radiation therapy. There is, therefore, a need to find the balance between inhibiting angiogenesis and causing unnecessary vascular regression.37

Bevacizumab monotherapy is not antiproliferative, and does not kill cancer cells directly: in the long term, regrowth of the tumor will occur via alternative neovascularization pathways.13 By contrast, cytotoxic drugs target proliferating endothelial cells. In patients with metastatic colorectal cancer, bevacizumab combined with chemotherapeutic agents conferred a survival benefit through increased tumor cytotoxicity after vascular normalization.13

Jain et al. were the first to propose the theory that antiangiogenic treatment 'normalizes' the tumor vasculature by pruning away excessive endothelial cells and perivascular cells, which leads to a drop in interstitial pressure and, consequently, to improved oxygenation and delivery of chemotherapy to tumor cells (Figure 1).13 The abnormal tumor microenvironment is characterized not only by heterogeneity in tumor blood flow, but also by interstitial hypertension with elevated hydrostatic pressure outside the blood vessels, hypoxia, and tissue acidosis.13, 38 The impaired blood supply and high interstitial fluid pressure interfere with the delivery of therapeutic agents to solid tumors.39 A normalized tumor vasculature would be characterized by less leaky, less dilated and less tortuous vessels, with a normal basement membrane and coverage by pericytes.13 These morphologic changes can be accompanied by decreased interstitial fluid pressure, increased tumor oxygenation and improved tumor penetration of drugs.13 Improved drug penetration has significant implications for the clinical use of antiangiogenic therapy. Willett et al. have shown that VEGF blockade with bevacizumab decreases tumor perfusion, vascular volume, microvascular density, tumor interstitial fluid pressure and the number of viable circulating endothelial and progenitor cells in patients with colorectal cancer.38 This result is consistent with other preclinical and clinical data, and supports the concept that normalization of the tumor vasculature occurs during anti-VEGF therapy.40, 41

Figure 1 Mechanistic view of antiangiogenic therapy.
Figure 1 : Mechanistic view of antiangiogenic therapy. 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) A balance of proangiogenic and antiangiogenic molecules maintains an organized and efficient normal vascular and blood supply in tissues. (B) Tumors produce proangiogenic factors, which result in growth of an abnormal and inefficient vascular network. (C) Antiangiogenic therapy can normalize the balance and restore the vascular network to a normal state, which improves drug delivery and efficacy. Antiangiogenic agents are intended to destroy angiogenic vessels and starve tumors, but tumors could recur. (D) If antiangiogenesis is potent and persistent it can completely destroy the vascular network, which impedes delivery of oxygen and nutrients and ultimately starves the tumor. Abbreviations: Anti, antiangiogenic; IFP, interstitial fluid pressure; pO2, tissue oxygen level; Pro, proangiogenic. Permission obtained from Macmillan Publishing © Jain RK et al. (2007) Nature Rev Neurosci 8: 610–622.

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Beyond bevacizumab: new target (DLL4–Notch) signaling pathway

Current antiangiogenic therapies are unable to maintain vascular regression. Furthermore, not all tumors are sensitive to VEGF blockade, and those that are initially sensitive can develop resistance, as shown by clinical observations of tumor regrowth and a return to abnormal new vessel formation.42, 43 Additional targets and pathways, therefore, need to be found to take full advantage of the antiangiogenic approach to cancer treatment.

The Delta-like protein 4 (DLL4)–Notch signaling pathway is required for normal vascular development and is a potential target for antiangiogenic therapy. Notch receptor family members regulate cellular proliferation and differentiation during normal organogenesis.44 The Notch receptors are transmembrane proteins that are proteolytically cleaved upon ligand binding. The cytoplasmic portion of the receptor then directly transduces a signal from the cell surface to the nucleus, and thereby regulates the expression of target genes. Activation of the Notch pathway has also been implicated in colorectal cancer.45 In addition, DLL4 was found to be expressed in normal vasculature and strongly expressed in tumor vessels.46

In mouse tumor-xenograft models, treatment with the DLL4-neutralizing mAb YW152F dramatically increased vascular density, but also decreased the tumor growth rate.47 Anti-VEGF mAb treatment of these mice resulted in the expected decrease in tumor-vessel density and suppression of tumor growth; however, a combination of YW152F and anti-VEGF mAb yielded a much more potent antitumor response.47 In the same study, in vitro treatment of human umbilical vein endothelial cells with YW152F resulted in upregulation of VEGFR2, hyperproliferation and cell sprouting. Inhibition of YW152F-dependent proliferation of human umbilical vein endothelial cells by anti-VEGF mAb treatment demonstrated that the effects of DLL4 blockade were VEGF-dependent.47 This study clearly establishes an important role for DLL4–Notch signaling in tumor angiogenesis and demonstrates that promoting the growth of nonfunctional vasculature can be an efficient means of inhibiting tumor growth. The DLL4–Notch pathway is a possible new therapeutic target for antiangiogenic therapy that could benefit patients with tumors that are resistant to anti-VEGF therapies (Figure 2).

Figure 2 Roles of VEGF and DLL4 in the regulation of tumor angiogenesis.
Figure 2 : Roles of VEGF and DLL4 in the regulation of tumor angiogenesis. 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

Whereas VEGF activates the VEGFR2 signaling pathway to stimulate tumor angiogenesis, DLL4 binding to Notch negatively regulates endothelial-cell sprouting and branching during tumor angiogenesis, which results in a functionally improved vascular network. Antiangiogenic, anti-VEGF treatment inhibits neovascularization and suppresses tumor growth. In contrast to the current antiangiogenic treatment concept, blockade of the Notch pathway with DLL4 inhibitors leads to increased but nonproductive tumor vascularization. These vessels are poorly functional, which results in decreased tumor perfusion and tumor growth. Abbreviations: DLL4, Delta-like ligand 4; VEGF, vascular endothelial growth factor; VEGFR; vascular endothelial growth factor receptor. Permission obtained from Macmillan Publishing © Hicklin DJ (2007) Nature Biotechnol 25: 300–302.

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Indirect VEGF targeting with anti-erbB antibodies

A potentially interesting combination of targeted therapies involves the addition of VEGF-targeted agents to erbB-targeted drugs. The erbB family of growth factor receptors includes erbB1 (also known as epidermal growth factor receptor, EGFR) and erbB2 (also termed HER2), which are known to have a role in the angiogenesis pathway as upstream regulators of VEGF expression.

The FDA and European Medicines Agency have approved cetuximab (Erbitux®, Imclone Inc., Branchburg, NJ) and panitumumab (Vectibix®, Amgen Inc., Thousand Oaks, CA) for use as anticancer agents. Both are mAbs that bind EGFR and have shown some antitumor activity in various cancer cell lines and tumor-xenograft models.48, 49, 50, 51, 52, 53, 54, 55 They have indirect antiangiogenic properties through the inhibition of VEGF secretion. Some studies have demonstrated that inhibition of EGFR with cetuximab has an antiangiogenic effect.18, 56 The increased production of VEGF is one mechanism by which tumor cells overcome the effects of anti-EGFR mAb therapy.57 In patients with irinotecan-refractory colorectal cancer, cetuximab has shown significant antitumor activity when given alone or in combination with irinotecan.58

Targeting VEGF signaling with small molecule inhibitors

Another group of agents that target VEGFR have been approved as antitumor treatments—the multitargeted tyrosine-kinase inhibitors sorafenib (Nexavar®, Bayer HealthCare Pharmaceuticals) and sunitinib (Sutent®, Pfizer, New York). These tyrosine-kinase inhibitors are thought to target both cancer and stromal cells, and might act by transiently normalizing the tumor vessels and enhancing the delivery and efficacy of concurrently administered cytotoxic agents. This Review, however, focuses on antiangiogenic antibody therapy; a discussion of multitargeted tyrosine-kinase inhibitors is beyond its scope. Reports on multitargeted tyrosine-kinase inhibitors that target VEGF and other receptors can be found elsewhere.13

Drugs in development

Modulation of angiogenesis by targeting the VEGF pathway

The success of bevacizumab suggests that inhibiting the VEGF pathway is a promising antiangiogenic approach for the treatment of multiple types of solid gastrointestinal tumor. Inhibition of VEGF can be achieved by direct or indirect targeting of VEGF itself (at the mRNA or protein level), direct targeting of VEGFR1, VEGFR2 and NRP1, and/or by blocking other elements of downstream signaling pathways. Several mAbs that block VEGFR1 (e.g. the humanized mAb IMC-18F1 from ImClone Systems Inc., New York, NY) or its specific ligand PlGF (e.g. the humanized mAb TB-403 from BioInvent International, Lund, Sweden and ThromboGenics NV, Leuven, Belgium) are under development (Table 1).

Table 1 Examples of antiangiogenic agents currently under investigation.
Table 1 - Examples of antiangiogenic agents currently under investigation.
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The monoclonal antibody 2C3 (Peregrine Pharmaceuticals Inc., Tustin, CA) has been designed to inhibit VEGFR2 activation by human VEGF.54, 59 Antiangiogenic agents that selectively block the blood-vessel growth function of VEGF without blocking other VEGF-mediated functions might have advantages over inhibition strategies that block all VEGF functions.59 The therapeutic effects of 2C3 on tumor growth were first examined in a mouse orthotopic tumor-xenograft model that used MDA-MB-231 human breast adenocarcinoma cells. Administration of 2C3 to these mice inhibited tumor growth by 75% when compared with administration of the control IgG mAb, C44. Treatment with 2C3 also inhibited the establishment of tumor colonies and reduced tumor burden in the lungs.55 Another study also examined the effect of 2C3 in an orthotopic tumor-xenograft model that used MDA-MB-231 cells. 2C3 therapy reduced blood and lymphatic vessel densities by 70% and 80% compared with the control antibody and also decreased the incidence of lymphatic and pulmonary metastases by 3.2-fold and 4.5-fold, respectively.60

Furthermore, 2C3 also controlled the growth of human pancreatic xenograft tumors in mice.61 Human pancreatic cancer cell lines (MiaPaCa-2, Panc-1, and Capan-1) were used to establish xenografts in nude (athymic) mice. Therapy with 2C3 decreased the tumor burden in recipient mice—it also reduced vascular function, as measured by a decrease in vessel density and in the percentage of vessels associated with pericytes.61

Aflibercept or VEGF Trap (developed by Regeneron Pharmaceuticals Inc., Tarrytown, NY, in collaboration with Sanofi-Aventis, Bridgewater, NJ) is a fully human, soluble, VEGRF fusion protein with potent antiangiogenic properties.21, 62 The fusion-protein construct consists of parts of the extracellular domains of human VEGFR1 and VEGFR2 fused to the Fc portion of human IgG1. Aflibercept is the most potent VEGF-blocker available and binds VEGF with a 100–1,000-fold higher affinity than other reported VEGF antagonists.62 In mouse tumor-xenograft models, aflibercept almost completely abolished tumor vasculature and caused a rapid disappearance of endothelial cells.63 Aflibercept binds and neutralizes all isoforms of VEGFA and PlGF, which is of interest because this broad mode of action could overcome the problem of acquired drug resistance seen with treatments that target individual angiogenic factors. For example, in a clinical trial in patients with rectal cancer, plasma levels of VEGF and PlGF increased after treatment with bevacizumab alone.38 Aflibercept has a relatively long half-life of approximately 2 weeks.64 Two early-phase trials evaluated various routes of administration (subcutaneous and intravenous) for aflibercept and demonstrated acceptable toxicity profiles.64, 65 Phase III trials of aflibercept for second-line treatment of metastatic colorectal cancer and as first-line therapy for metastatic pancreatic cancer are planned.66

RNA-interference-based antiangiogenic approaches that target VEGF, such as the nanoparticle-based small interfering RNA product ICS-283 (Intradigm Corporation, Paolo Alto, CA), are currently in preclinical development.67, 68, 69, 70 ICS-283 is composed of multiple small interfering RNAs that target both VEGF and its receptor. Data from in vivo models, including tumor-xenograft models of several cancers, have confirmed that systemic administration of ICS-283 has an RNA-interference-mediated antiangiogenic effect similar to that of anti-VEGF mAbs.71

The aptamer pegaptanib (Macugen®, OSI Pharmaceuticals Inc., Long Island, NY), as well as the antibody fragment ranibizumab (Lucentis®, Genentech, San Francisco, CA) also target VEGF and have been approved by the FDA to treat patients with age-related macular degeneration but have not yet been tested as a potential treatment for cancer.72

Targeting the integrin pathway

Since integrins were identified as a prognostic indicator of survival, anti-integrin therapies have been developed as antiangiogenic strategies. Neovascular endothelial cells express alphaVbeta3 and alphaVbeta1 integrins, and specific targeting of these proteins is of special interest in the suppression of tumor angiogenesis.73 Integrin inhibitors are, therefore, currently under development: alphaVbeta3 mAbs that target the extracellular domain of the heterodimeric receptor or synthetic peptides that contain an RGD sequence (Table 1).30

The alphaVbeta3 integrin is overexpressed in new blood vessels. The mAb LM609 is specific for alphaVbeta3 integrin, and was shown to immunoprecipitate it from M21 human melanoma cells.74 The humanized mAb etaracizumab (Vitaxin®, also known as Abegrin® or MEDI-522, MedImmune Inc., Gaithersburg, MD) has specificity for the alphaVbeta3 integrin, also known as the vitronectin receptor.75 Etaracizumab interferes with blood-vessel formation and has been tested in the treatment of advanced leiomyosarcomas,29 as well as in other advanced carcinomas such as colon, breast and kidney cancer.75, 76 In a phase I trial, MEDI-522 seemed to be without significant toxicity and to have effects on tumor perfusion. No objective response was observed, but several patients with colorectal cancer experienced prolonged tumor stabilization.77

Volociximab (also known as M200 and developed by PDL BioPharma Inc., Fremont, CA, in collaboration with Biogen Idec Inc., Cambridge, MA) is a high-affinity, function-blocking, chimeric mAb against integrin alphaVbeta1.78 Phase II clinical trials evaluating volociximab in solid tumors are underway.79 The Fab fragment of volociximab, which binds integrin alphaVbeta1 and is known as F200, is also under investigation for the treatment of age-related macular degeneration.29

EMD 121974 or cilengitide (Merck & Co. Inc., Whitehouse Station, NJ) is a low-molecular-weight antiangiogenic agent. This cyclic peptide contains multiple RGD motifs, which allow it to bind with high specificity and to inhibit the endothelial cell-surface receptors integrins alphaVbeta3 and alphaVbeta5.80 Tumor stabilization was observed in patients with colorectal cancer who were treated with EMD 121974.81 A phase II trial of EMD 121974 in patients with pancreatic cancer (in combination with gemcitabine) showed no adverse effects in relation to safety, tolerability and pharmacokinetics, but there was also no difference in efficacy between groups who did and did not receive EMD 121974.82

VEGF and integrins are involved in normal processes of angiogenesis that occur in both normal and cancerous tissues and are not specific to tumor vasculature. Agents that target VEGF and integrins, therefore, inhibit neovascularization in all tissues. A different antiangiogenic approach seeks to destroy established tumor vasculature by use of vascular-targeted agents. Further mAbs that target phosphatidylserine (i.e. bavituximab, also known as 3G4; Peregrine Pharmaceuticals Inc., Tustin, CA)83 or the extracellular domain of prostate-specific membrane antigen (i.e. J591 MAb; BZL Biologics Inc., Framingham, MA)84 are undergoing investigation to determine whether they can destroy established vasculature in solid tumors.

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Clinical applications

Bevacizumab in colorectal cancer

Colorectal cancer is the second most common cause of cancer deaths in the Western world.85 Approximately 50% of patients who undergo potentially curative surgery later present with metastases during the course of their disease.86 Modern chemotherapeutic compounds have improved response rates to treatment and overall survival in patients with advanced colorectal cancer, and the introduction of bevacizumab as a treatment for colorectal cancer has further improved the management of this disease (Table 2).

Table 2 Examples of recent trials with the VEGF-specific antibody bevacizumab.
Table 2 - Examples of recent trials with the VEGF-specific antibody bevacizumab.
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Early phase I and II trials

In 1997 bevacizumab was used in a phase I trial of patients with colorectal cancer and had low toxicity as a single agent or in combination with chemotherapy.87 Subsequently, phase II studies were conducted of bevacizumab in combination with standard chemotherapy as a first-line treatment for metastatic colorectal cancer.88, 89 In one trial, 104 patients with metastatic colorectal cancer were randomly allocated to receive 5-fluorouracil plus leucovorin alone, or 5-fluorouracil and leucovorin plus either 5 mg/kg bevacizumab for 2 weeks or 10 mg/kg bevacizumab for 2 weeks. The addition of bevacizumab at either dose to chemotherapy led to an increase in the response rate (40% versus 17%), an increase in time to progression (from 5.2 months to 9.0 months) and an increase in the median survival time (21.5 months versus 13.8 months).88 Surprisingly, patients given the lower bevacizumab dose benefited slightly more than patients given the higher dose. The reason for this difference remains unclear, but a randomization bias might be responsible, because there were more patients with worse prognostic factors in the high-dose group than in the low-dose group. Another randomized, phase II trial in 209 patients confirmed these results; the addition of bevacizumab to chemotherapy increased the median progression-free survival from 5.5 months to 9.2 months (P <0.0002, hazard ratio [HR] 0.5).89

Phase III trials with bevacizumab: first-line treatment

The promising activity of bevacizumab in phase II trials led to the initiation of a phase III trial that recruited 813 patients.90 In this trial, a bolus irinotecan plus 5-fluorouracil and leucovorin (IFL) protocol was compared with IFL plus bevacizumab in a randomized, double-blind, placebo-controlled fashion. In the third arm of the trial, treatment consisted of 5-fluorouracil and leucovorin only plus bevacizumab, but this arm was terminated early when safety did not seem to be an issue in patients treated with IFL plus bevacizumab. The mean duration of therapy was 27.6 weeks in the IFL group and 40.4 weeks in the IFL plus bevacizumab group.90

In this pivotal, placebo-controlled trial, bevacizumab increased overall response rates from 35% to 45% (P <0.001) and progression-free survival from 6.2 months to 10.6 months (HR 0.54, P <0.001). Overall survival also increased, from 15.6 to 20.3 months (HR 0.66, P <0.001).90 In relation to adverse events, only grade 3 hypertension was seen more often in patients who received bevacizumab than in patients who did not (11% versus 2.3%, P <0.01). In contrast to the phase II data, bleeding or thrombosis was no more common in bevacizumab-treated patients than in those who received the other treatments.

This phase III trial suggested, for the first time, that the addition of an antiangiogenic compound to chemotherapy could be beneficial for patients with metastatic colorectal cancer. Subsequently, bolus 5-fluorouracil protocols were abandoned, because of their high toxicity and limited efficacy,91, 92 in favor of infusional regimens such as FOLFOX (oxaliplatin, 5-fluorouracil and leucovorin) or FOLFIRI (irinotecan, 5-fluorouracil and leucovorin). The BIC-C trial tested, in a randomized, phase III design, the efficacy and safety of FOLFIRI with bevacizumab versus IFL with bevacizumab and found a significantly longer median progression-free survival of 11.3 months for FOLFIRI with bevacizumab versus 8.2 months for IFL with bevacizumab.93 FOLFIRI is now, therefore, the recommended combination protocol if irinotecan is chosen as the first-line treatment for metastatic colorectal cancer.

Bevacizumab has been assessed in combination with oxaliplatin in the TREE trials, which compared oxaliplatin-based regimens with and without bevacizumab in a nonrandomized fashion. The data from these trials were promising, in particular when response rates were evaluated, and they also gave an insight into the activity of bevacizumab and/or oxaliplatin combinations with oral 5-fluorouracil (in the form of capecitabine).94

Most recently, bevacizumab and oxaliplatin combination regimens have been evaluated in a controlled design in the NO16966 trial.95 This trial tested, in a two-by-two design, FOLFOX or capecitabine plus oxaliplatin (CapOx), with or without bevacizumab, as a first-line treatment for metastatic colorectal cancer. In this trial, 1,400 patients were randomly allocated to receive either FOLFOX or CapOx alone, or a combination of either chemotherapy plus bevacizumab. While on the one hand the trial showed equal efficacy for infusional and oral formulations of 5-fluorouracil, it also demonstrated the superiority of bevacizumab-containing combinations over chemotherapy without bevacizumab (progression-free survival was 9.4 months with bevacizumab versus 8.0 months without it, P = 0.0023).95 The difference in overall survival was not statistically significant, although the data might be too preliminary to be certain. The improvement in progression-free survival was, however, less than expected from the Hurwitz trial and was somewhat disappointing.90 When the data were analyzed further, it became evident that treatment had been stopped in a substantial proportion of patients as a result of oxaliplatin-related toxicity, mainly neuropathy. However, this finding was derived from a retrospective subgroup analysis that was not predefined in the study protocol. As a secondary end point, progression-free survival of those patients who stayed on treatment was 10.4 months for bevacizumab-containing combinations versus 7.9 months for regimens without bevacizumab. Seemingly, this benefit was detectable even in patients in whom oxaliplatin was discontinued because of neuropathy but who remained on 5-fluorouracil plus bevacizumab. This finding could potentially mean that bevacizumab should be administered until disease progression in all patients, even if side effects force discontinuation of one of the other chemotherapeutic agents. This observation is in line with early preclinical data that show rapid blood-vessel regrowth immediately after discontinuation of bevacizumab.96 Although these data might be strong evidence for continued bevacizumab maintenance therapy until progression, a role for bevacizumab in maintenance therapy has not been formally established in randomized controlled trials (see below).

Phase III data from the FOCUS trial and the CAIRO trial suggest that in selected patients who have either clinically significant comorbidities or—on the contrary—only a few tumor-related symptoms, 5-fluorouracil monotherapy can be administered and combination chemotherapy postponed until disease progression occurs.97, 98 Combination therapy with a fluoropyrimidine and bevacizumab could be a good alternative to 5-fluorouracil monotherapy, although such combinations have not been formally tested in the above-mentioned trials. In a report by Kabbinavar that compared bevacizumab plus 5-fluorouracil with 5-fluorouracil alone in patients with metastatic colorectal cancer, combination therapy increased the median progression-free survival from 5.5 months to 9.2 months (P <0.0002), although the response rate was not significantly increased (26.0% versus 15.5%, P = 0.055).89

Phase III trials: second-line treatment

The activity of bevacizumab has also been tested as a second-line treatment for metastatic colorectal cancer. The E3200 phase III trial compared FOLFOX alone, bevacizumab alone, and FOLFOX plus bevacizumab in 829 patients with irinotecan-refractory metastatic colorectal cancer who had not received bevacizumab as a first-line treatment.99 These patients had experienced tumor recurrence within 6 months of their first-line treatment. Of note, bevacizumab was administered at a high dose of 10 mg/kg body weight every 2 weeks. The bevacizumab-monotherapy arm was terminated early because this treatment was observed to be inferior to the chemotherapy-containing arms, which suggested that antiangiogenic monotherapy had poor efficacy. Compared with the FOLFOX arm, the FOLFOX plus bevacizumab arm showed significant improvements in the response rate (22.7% versus 8.6%, P <0.0001), progression-free survival (7.3 months versus 4.7 months, HR 0.061, P <0.0001) and overall survival (13.0 months versus 10.8 months, HR 0.75, P = 0.0011).99 On the basis of these data, in June 2006, bevacizumab was approved in the US as a second-line treatment for colorectal cancer. In contrast to the study of Hurwitz et al., which used bevacizumab as a first-line treatment, there was a wide variety of adverse events in Giantonio and colleagues' study,99 in particular gastrointestinal side effects, bleeding and hypertension, which were more often seen with bevacizumab than with FOLFOX alone (see also the section on toxicities below).

Combinations with other molecular agents: double targeting

One important question is to determine whether patients could benefit from combinations of targeted agents, such as the anti-EGFR antibody cetuximab with bevacizumab. While the BOND-1 trial evaluated the efficacy of cetuximab in patients with irinotecan-refractory colorectal cancer, the BOND-2 trial compared a combination of irinotecan, cetuximab and bevacizumab with cetuximab plus bevacizumab.58, 100 Response rates were 37% for the chemotherapy plus antibody combination and 20% for the targeted-therapies combination in this (heavily pretreated) patient group. The median progression-free survival in patients who received the triple combination therapy amounted to 7.9 months.100 However, this phase II trial could not determine whether this combination of targeted agents was superior to either targeted agent in combination with chemotherapy. Of note, the PACCE phase III randomized trial,101 which compared the efficacy of double targeting with bevacizumab and the anti-EGFR receptor antibody panitumumab plus FOLFOX or FOLFIRI with that of the chemotherapy and bevacizumab alone, had to be terminated early because of a lack of benefit in the experimental arm.

The Gastrointestinal Intergroup Study C80405, led by the Cancer and Leukemia Group B (CALBG) and the Southwest Oncology Group (SWOG), is carrying out a phase III, randomized trial to investigate the combination of cetuximab and bevacizumab versus each agent alone in combination with first-line FOLFOX or FOLFIRI chemotherapy in patients with metastatic colorectal cancer.102

Open questions

Bevacizumab beyond progression

There are currently no data from randomized trials to indicate that bevacizumab should be continued as a second-line treatment when patients have failed to respond to an initial combination of chemotherapy with bevacizumab. Although the E3200 trial clearly established bevacizumab as a valid second-line therapy for patients who are bevacizumab-naive, there are no data to support such second-line treatment in bevacizumab-pretreated patients.99 The available experimental data seem to suggest that it is sensible to continue with antiangiogenic treatment strategies while switching the chemotherapy regimen. As mentioned, tumor vasculature is normalized during treatment with bevacizumab and rapidly becomes disorganized again when bevacizumab is stopped, as shown in preclinical studies.13, 96 Furthermore, normal endothelial cells might not acquire resistance to chemotherapy or targeted therapy as quickly as malignant cells. By contrast, it could be argued that bevacizumab targets tumor cells through induction of hypoxia or glucose deprivation, so this agent might very well be expected to induce resistance in the tumor cell itself.

So, what are the clinical data on the use of bevacizumab therapy after cancer progression? The BRiTE registry103 was established in the US and included data on 1,953 patients with metastatic colorectal cancer. With a median follow-up time of 19.6 months, 74% of these patients were treated with bevacizumab after first-line therapy failed to halt progression of their cancers, while 37% of patients received chemotherapy without bevacizumab and 18% of patients received no therapy. The patients who received bevacizumab after first-line therapy failed showed a median overall survival of 31.8 months, while those treated with chemotherapy had a median overall survival of 19.9 months. This difference could be caused by selection bias, because significantly more patients who received bevacizumab after progression had an 'excellent' performance status compared with those who did not receive bevacizumab (50% versus 40%).103 This study, however, is observational and noninterventional, so it cannot formally prove the effectiveness of bevacizumab treatment after cancer progession.

The gastrointestinal cancer group of the AIO (the German Working Group for Medical Oncology) has initiated a randomized, clinical, second-line trial (AIO trial KRK-0504) to address whether a strategy of bevacizumab treatment after progession is effective.104 Patients initially treated with bevacizumab plus chemotherapy (irinotecan plus fluoropyrimidine, or oxaliplatin plus fluoropyrimidine) will subsequently be randomly allocated to second-line chemotherapy (FOLFOX or FOLFIRI) with or without bevacizumab. Progression-free survival is the primary end point. In total, 576 patients from Germany and Austria are planned to be recruited to the trial. The first safety data are expected to be reported in 2008 with final results in 2009 or 2010. This phase III study should help to clarify whether bevacizumab therapy should be continued even after progression in bevacizumab-pretreated patients.

Bevacizumab as maintenance therapy after intensified induction

The initial data from the NO16966 trial suggested that continued therapy with bevacizumab might improve patients' outcomes, even when one of the chemotherapeutic agents (mainly oxaliplatin) has to be stopped due to toxicity.95 Such a strategy of continued bevacizumab, alone or in combination with a fluoropyrimidine, could be regarded as bevacizumab maintenance therapy. If vasculature normalization is considered to be the main mechanism of action of bevacizumab, then bevacizumab maintenance—only in combination with other chemotherapeutic or targeted compounds, not as monotherapy—seems sensible.13 In Europe several current trials are investigating the use of bevacizumab in maintenance therapy, and their results could further clarify this issue. For example, the Dutch trial, CAIRO3, is comparing maintenance treatment with low-dose capecitabine plus bevacizumab versus no maintenance treatment in patients with metastatic colorectal cancer after 18 weeks of induction chemotherapy with oxaliplatin, capecitabine and bevacizumab.105 By contrast, the Spanish cooperative group is evaluating treatment until progression (or toxicity) with capecitabine, oxaliplatin and bevacizumab as the standard arm, versus maintenance treatment with bevacizumab monotherapy after 18 weeks of induction chemotherapy. Furthermore, the Optimox-3–DREAM trial is evaluating maintenance therapy with bevaci-zumab and erlotinib after induction with bevacizumab plus either CapOx or FOLFOX.106 These trials might help determine the role of antiangiogenic therapy as a maintenance treatment for metastatic colorectal cancer.

Bevacizumab in neoadjuvant treatment of marginally resectable liver metastases

The introduction of modern chemotherapeutic compounds and biological agents has enabled the secondary resection of liver and (less often) pulmonary metastases; consequently, metastatic disease that previously would have been fatal can now potentially be cured. The role of bevacizumab in neoadjuvant treatment of marginally resectable liver metastases has not been conclusively determined. Folprecht et al. showed that hepatic resection rates are significantly associated with response rates in patients with advanced colorectal cancer.107

Although the response rates in the original Hurwitz trial90 were significantly increased by the addition of bevacizumab, response rates remained unchanged in the NO16966 trial despite the addition of bevacizumab.95 This surprising result contrasted with a significant increase in progression-free survival in the bevacizumab arms. Preliminary data from the patients in the NO16966 trial suggest that resection rates in bevacizumab-treated patients were still higher than in patients who received chemotherapy alone, but this observation needs further investigation (the overall R0 resection rates with and without bevacizumab were 8.6% and 6.1%, respectively; the resection rates for liver metastases only with and without bevacizumab were 19.2% and 12.9%, respectively).95

One major issue with bevacizumab therapy before liver resection is a potentially increased risk of perioperative morbidity caused by bevacizumab's anti-VEGF effects. The close relationship between hepatocyte growth factor and VEGF could be problematic, in particular when large parts of the liver have to be resected. We still do not know whether liver regeneration after surgery is impaired in patients who receive treatment with bevacizumab before surgery, as preclinical data suggest.108 In a pooled analysis, Scappaticci et al. analyzed the side effects of bevacizumab when given perioperatively.109 Although there were very low complication rates of approximately 1% when bevacizumab was given postoperatively, complication rates were increased (from 3.4% to 13%) when bevacizumab was administered preoperatively. However, no such complications have been seen in another study.110

There are also interesting preliminary data from the first BEAT study, which aims to evaluate the safety profile of bevacizumab in combination with various chemotherapy regimens in a broad patient population, all of whom have metastatic colorectal cancer.111 Of the 81 patients who have undergone liver resection so far, only 28% had postoperative complications such as wound infection or thrombosis. This complication rate is not significantly increased in these patients compared with that in historical controls. The median time from last bevacizumab application to surgery was 67 days. The authors of this study concluded that surgery after bevacizumab treatment was feasible.111 As bevacizumab has a half-life of 3 weeks, it is recommended that a 6–8 week interval should be left after the last infusion of bevacizumab for liver surgery to be safe.112

In a nonrandomized, single-center, phase II study, 56 patients with potentially resectable liver metastases were treated with CapOx in combination with bevacizumab, and underwent surgical resection after responding to this treatment.113 Overall, 11 patients underwent simultaneous resection of liver metastases and the primary tumor. The interval between the last bevacizumab application and surgery was 5 weeks. There were no bleeding complications or wound-healing impairment observed in this patient population. In addition, bevacizumab did not seem to impair liver regeneration after resection.113

Bevacizumab in adjuvant treatment

With bevacizumab's activity shown in metastatic colorectal cancer, it is reasonable to ask whether this mAb is effective in the adjuvant treatment of patients with localized cancer. At present, it is unclear whether putative micrometastases that have only a limited blood supply are sensible targets for antiangiogenic therapy. Antiangiogenic therapy could be argued to keep micrometastases in a dormant state or possibly to decrease tumor cell dissemination by normalizing the tumor vasculature in the neoadjuvant setting. Several phase III trials have been initiated to test the activity of bevacizumab in the adjuvant setting in patients with colon cancer.

The National Surgical Adjuvant Breast and Bowel Project C-08 phase III trial recruited patients with curatively resected stage II or III colorectal cancer and will compare mFOLFOX6 for 12 cycles with or without bevacizumab. Patients allocated to receive bevacizumab plus chemotherapy will receive an additional 6 months of bevacizumab.114 Similarly, the AVANT phase III study included patients with either high-risk stage II or stage III colorectal cancer. They were randomly allocated to receive one of three chemotherapy combinations (FOLFOX4 alone, FOLFOX4 plus bevacizumab, or CapOx plus bevacizumab). Again, patients who receive the bevacizumab combination regimens will also receive 6 months of maintenance treatment with bevacizumab monotherapy. Results of these trials, which have partly finished accrual, are expected in 2010.115 In the phase II clinical trial of the Eastern Cooperative Oncology Group (ECOG) E5202, stage II patients whose tumors have putative high-risk DNA characteristics, such as microsatellite instability or loss of chromosome 18, have been randomly allocated to receive FOLFOX alone or FOLFOX plus bevacizumab.116, 117 Results from this trial are also not expected soon. Currently, no trial supports the use of bevacizumab in the adjuvant setting to improve survival.

Adverse events associated with bevacizumab

In the initial phase II trial of bevacizumab the major safety concerns were hypertension and thrombosis.88 An additional phase II trial had also identified minimal safety concerns with manageable side effects.89 Although in the Hurwitz trial there was little increase in toxicity observed with the addition of bevacizumab to chemotherapy,90 the E5200 trial of bevacizumab as a second-line treatment detected more bleeding, hypertension and wound healing when bevacizumab was added to FOLFOX chemotherapy.99 When all studies were analyzed, wound-healing complications, arterial thromboembolic events (including acute myocardial infarction) and gastrointestinal perforations (including intra-abdominal abcesses and fistulas) were among the most serious side effects, which all occurred in around 1% of patients.88, 89, 90, 99 Hypertension (including hypertensive crisis) and reversible posterior leukoencephalopathy syndrome were also observed.88, 89, 90, 99 An interval of 6–8 weeks between bevacizumab administration and major surgery, and an interval of approximately 1–2 weeks between bevacizumab treatment and minor surgery, is recommended.109, 118

In the first BEAT study, bevacizumab-specific adverse effects, such as hypertension, bleeding or proteinuria, were common; however, severe toxicity was rare.119 The BRiTE registry reports a rate of 1.8% for serious arterial thromboembolic events, mainly cerebrovascular accidents and myocardial infarction.111 Only a history of arterial disease and reduced performance status, not age, seemed to be a risk factor for serious arterial thromboembolism.111

Bevacizumab in hepatocellular carcinoma

HCC is a highly vascular tumor and is the fifth most common solid tumor worldwide.7, 120 The incidence of HCC is rising in Western countries.120 VEGF is known to have a central role in HCC tumor development.8, 12 Most cases of HCC are diagnosed at an advanced stage, when interventions such as liver transplantation or resection are not beneficial.121 Patients with metastatic HCC have an especially poor prognosis, with an estimated median survival of 2–5 months. Existing cytotoxic chemotherapies have not been shown to prolong survival and can have significant toxicity, particularly in patients with underlying hepatic dysfunction.122, 123

The SHARP trial of the oral, multitargeted, tyrosine-kinase inhibitor sorafenib showed, for the first time, significantly improved overall survival in patients with advanced HCC. Sorafenib is the first therapy for advanced HCC to be approved by the FDA and European Medicines Agency.124

One of the first studies of bevacizumab in patients with unresectable HCC was conducted in 30 patients (bevacizumab monotherapy at 5 mg/kg or 10 mg/kg every 14 days, with assessment every 8 weeks).125 Of the first 28 patients treated at either dose, 4 had to stop treatment because of serious adverse events, mainly esophageal bleeding. Esophageal varices should, therefore, be treated before giving bevacizumab to patients with HCC. Of the initial 25 patients who were evaluable for efficacy, 2 patients had a partial response and 18 had stable disease. Preliminary results suggested that bevacizumab has a significant disease-modifying effect; the median time to progression was 6.5 months (range 3.9–24.2 months).125

A further phase II study was undertaken to examine the efficacy and safety profiles of combining bevacizumab with gemcitabine and oxaliplatin (GEMOX) in patients with HCC.126 Efficacy was assessed in 30 patients; the objective response rate was 20%, and 27% of patients had stable disease. The median overall survival was 9.6 months and the median progression-free survival was 5.3 months (95% CI 3.7–8.7 months). The progression-free survival rate at 6 months was as high as 48%.126

Another phase II study was conducted by Sun et al. to evaluate the efficacy and tolerability of the combination of bevacizumab, oxaliplatin, and capecitabine in patients with advanced or metastatic HCC.127 This study enrolled 32 patients: 13.3% achieved a partial response and 76.7% had stable disease. Two patients had bleeding from esophageal varices, which was probably disease-related; however, the possible role of bevacizumab could not be excluded.127

On the basis of the overexpression of VEGF and EGFRs in HCC, Thomas et al. conducted a phase II, single-arm, open-label trial of bevacizumab plus erlotinib in patients with HCC.128 There were 29 patients who could be evaluated for response to treatment. The response rate was 21% in the intent-to-treat population. The median progression-free survival was 9 months and the overall survival was 19 months. Bevacizumab plus erlotinib was generally well tolerated. These early encouraging results, suggest that the combination of bevacizumab plus erlotinib has clinically meaningful biologic activity in patients with HCC, and its phase III evaluation in patients with advanced HCC is planned.128

Bevacizumab in gastric cancer

Treatment of advanced gastric cancer has been improved by combination chemotherapy with docetaxel, cisplatin and 5-fluorouracil versus cisplatin and 5-fluorouracil alone.129 Treatment was also improved by substitution of oral 5-fluorouracil for infusional 5-fluorouracil and oxaliplatin for cisplatin, which demonstrated response rates of around 40% and overall survival times of approximately 9–10 months.130 Nonetheless, a true standard treatment has not been defined. In particular, combination therapy with docetaxel, cisplatin and 5-fluorouracil is associated with significant toxicities, mainly febrile neutropenia. Protocols modified to be less toxic were, therefore, developed such as the German FLOT regimen (mFOLFOX with docetaxel).131 In addition, some investigators have evaluated the role of antiangiogenic therapies in gastric cancer. So far, only phase II studies have been reported in gastric cancer. For example, a combination of irinotecan and cisplatin plus bevacizumab as a first-line treatment for metastatic gastric cancer showed an impressive response rate of 65%, with a median overall survival time of 12.3 months.132 As a second-line treatment, Enzinger et al. have reported a 27% response rate in bevacizumab-pretreated patients with advanced gastric cancer.133 Phase III studies are ongoing.

Bevacizumab in pancreatic cancer

Pancreatic cancer is the gastrointestinal cancer with the worst prognosis. In 1997, gemcitabine was established as the standard treatment for patients with metastatic pancreatic cancer, and provided a median survival time of 6 months.22 Although several combination treatments have been compared with gemcitabine alone, and have shown promise in phase II studies, not one combination treatment has been established as a new standard owing to a lack of benefit in phase III trials.134, 135, 136, 137, 138, 139 The combination of gemcitabine with erlotinib also failed to increase survival significantly in patients with stage IV pancreatic cancer.140 A phase II study showed significant activity of bevacizumab in combination with gemcitabine, with a response rate of 21%, a median overall survival time of 8.8 months, and a 1-year survival rate of 29%.141 Unfortunately, the phase III trial of gemcitabine plus bevacizumab versus gemcitabine alone (the CALGB study 80303), had to be terminated owing to low efficacy in the experimental arm: in the preplanned interim analysis, the combination of gemcitabine plus bevacizumab showed disappointing median survival times of 5.8 months, versus 6.1 months in the gemcitabine monotherapy arm.142 The results of the AVITA phase III trial, which will compare gemcita-bine, erlotinib and bevacizumab with gemcitabine and erlotinib alone, are awaited: recruitment finished in the second quarter of 2007.143

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Conclusions

Increased VEGF expression has been detected in most gastrointestinal tumors and is associated with increased risks of recurrence, metastasis and death. Other factors are also involved in angiogenesis promotion, such as integrins and the Notch pathway and, indirectly, the erbB family of growth factor receptors.

Bevacizumab, which is a humanized, monoclonal, anti-VEGF antibody, is a prototypic antiangiogenic treatment that has proven benefits in combination with conventional chemotherapy for patients with colorectal cancer. Pivotal phase III trials in patients with colorectal cancer have demonstrated improved progression-free survival and overall survival with acceptable toxicity, which led to approval of bevacizumab by the FDA and European Medicines Agency for the treatment of colorectal cancer. Bevacizumab has since been evaluated in various gastrointestinal tumors; however, although data in patients with HCC seem promising, bevacizumab seems to have no effect on pancreatic cancer.

The success of bevacizumab supports research and development of further approaches to block tumor angiogenesis. Soluble chimeric receptors, tyrosine kinase inhibitors and mAbs against VEGF and other angiogenic pathway components have shown considerable promise in preclinical and early clinical studies, and could be useful for the treatment of gastrointestinal malignancies.

Key points

  • Vascular endothelial growth factor (VEGF) and VEGF receptors are overexpressed in most human gastrointestinal cancers and this overexpression is associated with poor prognosis
  • Monoclonal antibodies, tyrosine kinase inhibitors and soluble chimeric receptors that bind various targets in the VEGF pathway (including VEGF, the external domain of the VEGF receptor, and the intracellular tyrosine-kinase domains of VEGF receptors) are currently being studied as potential antiangiogenic treatments
  • Monoclonal antibodies and multitargeted tyrosine-kinase inhibitors that are specific for other pathways and critical for targeting angiogenesis and tumor vascularization are currently under investigation in preclinical and clinical trials
  • When combined with cytotoxic agents, anti-VEGF therapy with bevacizumab can increase overall survival and/or progression-free survival in patients with colorectal cancer
  • Anti-VEGF therapy with bevacizumab is being studied in various other gastrointestinal cancers such as hepatocellular carcinoma, gastric cancer and pancreatic cancer

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Competing interests

Anke Reinacher-Schick has received grant and/or research support from Amgen, Roche and Sanofi-Aventis. Michael Pohl has received grant and/or research support from Merck, Merck Sharp and Dohme, and Roche, and is a stockholder and/or director of Bayer and Novartis. Wolff Schmiegel has received travel grants from Astra-Zeneca, Roche, and Sanofi-Aventis.

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Subject areas under which this article appears: Cancer | Therapy