Papers and Websites

For an introductory overview of tumor angiogenesis, see NCI's Understanding Angiogenesis.

In addition, the following are several useful papers on the topic of tumor angiogenesis and anti-angiogenic treatment (eg, Avastin):

• Jain 2008 reviews tumor angiogenesis at an introductory level.
• Gasparini et al 2005 provides a general discussion related to combining anti-angiogenic agents with other anti-cancer agents.
• Wong and Brem 2007 provides a short commentary on treating GBM via targeting angiogenesis.
• Jain et al 2007 reviews angiogenesis of brain tumors.
• Verheul and Pinedo 2007 reviews toxicities associated with angiogenesis inhibitors.
• Kerbel and Kamen 2004 and Emmenegger and Kerbel 2007 review anti-angiogenic effects of metronomic chemotherapy.
• Buie and Valgus 2008 review the effect of Avastin + CPT-11 on PFS for recurrent GBM.
• Reardon et al 2008 reviews anti-angiogenic therapy specifically for malignant gliomas.
• Claes et al 2008 discusses the potential for anti-angiogenic therapy to interfere with chemotherapy.
• Ellis and Hicklin 2008 reviews the anti-tumor mechanisms of VEGF-targeted therapy.
• Bergers and Hanahan 2008 reviews modes of resistance to anti-angiogenic therapy.
• Narayana et al 2008  "report the mature results of a clinical study of bevacizumab-based treatment of recurrent high-grade gliomas" and note that "a possible change in the invasiveness of the tumor following therapy is worrisome and must be closely monitored."
• Paez-Ribes et al 2009 reviews the (worrisome) potential for anti-angiogenic therapy to increase local invasion and distant metastases.  See Science Daily 2009 for a summary of the paper.
• Gerstner et al 2009 reviews the effects of anti-VEGF treatment on tumor vasculature, cerebral edema, and survival, independently of any anti-angiogenic effects (or lack thereof) of such treatment.
• Lucio-Eterovic et al 2009 reviews the molecular mechanisms by which GBM tumors develop resistance and increase invasion in response to anti-angiogenic treatment.
• Iwamoto et al 2009 reviews patterns of relapse and prognosis after Avastin (bevacizumab) failure in recurrent GBM.
• Norden et al 2009 provides a general review of use of anti-angiogenic therapies for high-grade gliomas.
• Joost et al 2009 provides a general review of use of anti-angiogenic therapies for high-grade gliomas, emphasizing concerns related to Avastin.

For a rather elaborate website on VEGF and angiogenesis from a drug company (Genentech), see Research VEGF.  Keep in the mind the inevitable bias associated with this website.

Additional Abstracts

For a discussion of brain bleeding and stroke risks associated with Avastin, see Pharmawire 2008.  Also see Chi et al 2007, Goli et al 2007, Kang et al 2007, Raval et al 2007, Friedland et al 2007, Lassen et al 2007, Andre et al 2007, Quant et al 2008, di Tomaso et al 2008, Wagner et al 2008, Nghiemphu et al 2008, Lassman et al 2008, Narayana et al 2008, Mayer et al 2008, Gil Gil et al 2008, and Zuniga et al 2008.

Also see Tumor Invasion for related information.

Key Points

The following are some key points from the above Iwamoto et al 2009 and Norden et al 2009 papers:

• High-grade gliomas (HGGs) are among the most vascular (supplied with blood vessels) of all human tumors, with microvascular proliferation being a hallmark of GBM.
• In addition to inhibiting development of new tumor vasculature, anti-angiogenic treatments are hypothesized to also "normalize" established tumor vasculature, resulting in reduced vessel size, reduced vessel permeability (leakiness), and reduced vessel tortuosity.  It is unclear whether the net effect of this normalization is improved or worsened delivery of chemotherapy, and this may vary across chemotherapy drugs and patients.  The net effect on tumor hypoxia is similarly unclear, since there could theoretically be a reduction in hypoxia, whereas an experimental GBM model indicates increased hypoxia.
• Vascular endothelial growth factor (VEGF)-A is a primary effector of angiogenesis.  It is secreted by tumor cells and binds mainly to the receptor VEFGR-2 found on endothelial cells lining blood vessels.  This binding activates multiple pathways in endothelial cells which result in increased vascular permability, endothelial cell migration, and mobilization of endothelial precursor cells, thus resulting in development of new tumor vasculature.  Various other signaling molecules (eg, ANG-2, PDGF, bFGF, and HIF1α) also bind to receptors on endothelial cells and thereby contribute to angiogenesis.
• The level of VEGF production by a glioma correlates directly with malignancy, with high-grade tumors producing about 10 times as much VEGF as low-grade tumors.
• Glioma stem-like cells are an important source of VEGF and thus a potentially important target for treatment.  However, treatments targeting glioma stem-like cells may also target normal neuronal stem cells, since both reside in the same vascular microenvironmental niche, so there is a theoretical risk of cognitive impairment.
• Avastin (bevacizumab) is a humanized monoclonal antibody which targets VEGF-A by binding to it and thus inhibiting its binding to VEGFR-2.
• In various clinical studies for recurrent HGG, Avastin has provided at least a partial response (defined as at least 50% reduction in maximum cross-sectional tumor area enhancing on MRI) for about 20% to 60% of patients, with the response typically lasting a few to several months, although a small minority of patients have experienced a much longer response.  However, it appears that Avastin will eventually lose efficacy for all or nearly all patients, and will therefore rarely, if ever, be curative in this setting (see below for mechanisms of resistance).
• The majority of patients on Avastin have experienced significant reduction in peritumoral edema (and associated tumor mass), and have thereby been able to substantially reduce their corticosteroid (eg, Decadron) dosages.  This reduction in edema may provide a moderate survival benefit independent of any direct anti-tumor effect (or lack thereof).
• Common toxicities resulting from use of Avastin have included hypertension, proteinuria (reflecting kidney damage), and wound-healing complications.  These toxicities have often, but not always, been reversible upon discontinuing Avastin or reducing its dosage.  More serious but less common toxicities have included thromboembolic events (eg, blood clots), intracranial hemorrhage, gastrointestinal perforation, and leukoencephalopathy.  Progressive neurological disability has also been reported.
• Other anti-angiogenic agents, including agents targeting VEGFR (eg, aflibercept and cedaranib), have provided response rates similar to Avastin, and several are in clinical trials.
• Metronomic chemotherapy targets tumor vasculature through continuous low-dose exposure to a cytotoxic chemotherapy drug.  There is some evidence of efficacy with this approach.
• Preclinical data indicate that copper may be a critical cofactor in angiogenesis.  However, the copper chelating agent penicillamine did not provide survival benefit in a Phase II trial for newly diagnosed GBM.
• COX-2 inhibitors have shown in vitro anti-angiogenic effect, but clinical trials to date have not shown a survival benefit.
• At least three mechanisms are known to potentially contribute to development of resistance to anti-angiogenic treatment: (a) development of an invasive phenotype in which existing cerebral vasculature is co-opted, (b) upregulation of alternative angiogenic pathways, thus "bypassing" anti-VEGF and anti-VEGFR treatments, and (c) stabilization of new tumor vasculature through recruitment of pericytes  and facilitation of interaction between pericytes and endothelial cells.  These mechanisms of resistance suggest that targeting multiple angiogenic pathways and adding anti-invasive agents could be beneficial.
• Evaluation of response to anti-angiogenic treatment via conventional imaging is problematic for several reasons: (a) some tumors or portions of tumors are partially or completely non-enhancing in conventional MRI and PET images, (b) in about one-third of patients, anti-angiogenic treatment may control enhancing tumor more effectively than non-enhancing tumor, thus allowing undetected tumor progression in some areas, combined with detectable tumor shrinkage in other areas, (c) anti-angiogenic treatments may reduce vascular permeability and resulting leakage of contrast agents into tumors, thus reducing tumor enhancement without any actual anti-tumor effect, and thereby giving a false impression of treatment efficacy (pseudoresponse).  Close examination of fluid-attenuated inversion recovery (FLAIR) MRI images may enable improved detection of tumor behavior, at least for some patients.
• When used for treatment of recurrent HGG, continuation of Avastin after tumor progression is generally ineffective and may even be detrimental for some patients.  However, discontinuation of Avastin in this setting also often leads to increased peritumoral edema and neurological symptoms, possibly due to rapid tumor revascularization, and this can result in rapid clinical deterioration for some patients.
• When Avastin has been combined with a cytotoxic chemotherapy for treatment of recurrent HGG and the treatment has failed, switching to a different cytotoxic chemotherapy has generally been ineffective.  More broadly, no generally effective treatments have been identified for use after Avastin failure in this setting, and the subsequent median survival has been a few months.