Elsevier

The Lancet Neurology

Volume 7, Issue 12, December 2008, Pages 1152-1160
The Lancet Neurology

Rapid Review
Novel anti-angiogenic therapies for malignant gliomas

https://doi.org/10.1016/S1474-4422(08)70260-6Get rights and content

Summary

Background

Despite optimum treatment with surgery, radiation therapy, and chemotherapy, most patients with malignant glioma have a poor prognosis. Malignant gliomas are vascular tumours that produce vascular endothelial growth factor (VEGF), which is an important mediator of angiogenesis. Preclinical data indicate that angiogenesis is essential for the proliferation and survival of malignant glioma cells, which suggests that inhibition of angiogenesis might be an effective therapeutic strategy. Anti-angiogenic therapies that target VEGF and the VEGF receptor (VEGFR) are effective adjuncts to the treatment of solid tumours. Normalisation of dilated and leaky tumour vasculature might also enable anti-angiogenic therapy to increase the efficacy of radiation therapy and cytotoxic chemotherapy.

Recent developments

Several studies have investigated the use of bevacizumab—a humanised monoclonal antibody against VEGF—for patients with recurrent malignant glioma. Treatment with bevacizumab is commonly combined with cytotoxic chemotherapy and results in dramatic responses seen on radiographs, prolongation of progression-free survival, and less need for corticosteroids. Similar results have been shown with small-molecule inhibitors of VEGFR, such as cediranib. Anti-angiogenic treatment is generally well tolerated but common adverse effects include hypertension and proteinuria, whereas the potentially more serious adverse effects, such as thromboembolic disease and haemorrhage, occur infrequently. At least half of patients fail to respond to anti-angiogenic treatment and the response duration is variable. Resistance to anti-angiogenic therapy might implicate alternative pro-angiogenic factors, such as basic fibroblast growth factor, stromal-derived factor-1α, the angiopoietin receptor Tie2, and placental growth factor. Anti-angiogenic therapy might also lead to mobilisation of circulating endothelial cells towards the tumour, which supports angiogenesis. Another possible mechanism of resistance of malignant glioma cells might be upregulation of pro-invasive molecules, which would result in increased infiltrative tumour growth along the blood vessels.

Where next?

Although anti-angiogenic therapies are promising, the duration of response with available regimens is modest. Continuing investigations will determine whether these drugs are best used for newly diagnosed or recurrent tumours and will establish the optimum combinations with radiation, cytotoxic chemotherapy, and other targeted molecular compounds. As yet, there are no effective treatments for patients on anti-angiogenic therapies whose tumours progress. Further understanding of the mechanisms of resistance to anti-angiogenic therapies and better selection of patients will be crucial to improve outcomes for patients with malignant glioma.

Introduction

Despite therapeutic advances, most patients with malignant glioma have a poor prognosis. Glioblastoma is the most common and aggressive subtype of malignant glioma. In 2005, results from a randomised phase III trial indicated that the addition of temozolomide chemotherapy to radiation therapy for the treatment of newly diagnosed glioblastoma prolonged median survival from 12·1 to 14·6 months.1 This treatment regimen is now the standard therapy for glioblastoma. Patients with anaplastic gliomas have a modestly better prognosis, with a median survival of 2–5 years.2, 3, 4 Almost all cases of malignant glioma recur after initial therapy. In patients with recurrent glioblastoma, the 6-month progression-free survival is only 21% after treatment with temozolomide,5 whereas the 6-month progression-free survival for anaplastic glioma is 46% after treatment with temozolomide.6 Most patients with recurrent malignant glioma do not survive for 1 year after diagnosis of recurrent disease.7

Anti-angiogenic compounds have recently become important components of the therapy for solid tumours.8, 9 The prototypical anti-angiogenic drug is bevacizumab, which is a humanised monoclonal antibody that is directed against vascular endothelial growth factor-A (VEGF-A; figure 1). Other members of the VEGF family include VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF); however, only VEGF-A has an established part in pathological angiogenesis. Bevacizumab is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for use with chemotherapy in patients with metastatic colorectal cancer, advanced or metastatic non-small cell lung cancer, and metastatic breast cancer. In addition, the EMEA has approved bevacizumab for use in advanced or metastatic kidney cancer, in combination with interferon alfa-2a. Angiogenic signalling can also be inhibited by small-molecule tyrosine kinase inhibitors of the VEGF receptor 2 (VEGFR2; also known as KDR or Flk-1); for example, sorafenib targets VEGFR, platelet-derived growth factor receptor (PDGFR), and Raf kinase. Sorafenib is approved by the FDA and the EMEA for renal cell carcinoma and unresectable hepatocellular carcinoma. Sunitinib, which inhibits VEGFR, PDGFR, and c-Kit, is a similar drug and is approved by the FDA and the EMEA for advanced renal cell carcinoma and gastrointestinal stromal tumours. Phase II trial data indicate that anti-angiogenic therapy produces remarkable radiographic responses and prolongs progression-free survival in patients with malignant glioma. On the basis of these data, many neuro-oncology centres now use anti-angiogenic therapies for patients with recurrent malignant glioma.

Section snippets

Rationale for targeting angiogenesis in malignant gliomas

Solid tumour growth cannot proceed without angiogenesis.10, 11 Malignant gliomas also need angiogenesis to establish a source of nutrients and oxygen and to eliminate cellular waste products; malignant gliomas are among the most vascularised of tumours in human beings, and endothelial proliferation is a diagnostic hallmark of glioblastoma. Data from studies in animals have also shown that malignant glioma cell growth and survival are dependent on angiogenesis.12 Examples of the

First-generation angiogenesis inhibitors

Anti-angiogenic therapy for malignant gliomas is one of the most active areas of research in neuro-oncology (table 1). Thalidomide29 was among the first oral inhibitors of angiogenesis to be assessed in therapy for malignant glioma; modest activity was observed in trials of thalidomide alone,30, 31 and in combination with carmustine32 for recurrent malignant gliomas. No benefit was seen when thalidomide was added to temozolomide and radiation therapy for the treatment of newly diagnosed tumours.

Inhibitors of VEGF in malignant glioma therapy

The modest results from studies on first-generation angiogenesis inhibitors have directed attention towards more potent compounds. Several investigators have given bevacizumab and chemotherapy to patients with recurrent malignant glioma. In the first study, 29 patients were treated with bevacizumab and the topoisomerase inhibitor irinotecan; three patients had complete responses (complete resolution of abnormal MRI contrast enhancement) and 16 patients had partial responses (50% or larger

Inhibitors of VEGFR in malignant glioma therapy

Small-molecule inhibitors of VEGFR are an alternative approach to anti-angiogenic therapy. Cediranib is an oral tyrosine kinase inhibitor that targets PDGFR, c-Kit, and all subtypes of VEGFR. In a phase II trial of 31 patients with recurrent glioblastoma there was a response rate of 56% and a 6-month progression-free survival of 26%.55, 56 Of 11 patients who needed steroids at study enrolment, all had reduced steroid doses or had stopped steroids entirely. Common adverse effects included

Other anti-angiogenic approaches

The VEGF pathway is the cornerstone of the angiogenic signalling axis; therefore, most anti-angiogenic therapies that have been tested so far target VEGF or VEGFR. However, several other promising approaches are also under investigation (table 2).

Toxicity of anti-angiogenic therapy

Anti-angiogenic drugs are well tolerated by most patients. The common adverse effects of bevacizumab and other VEGFR inhibitors include hypertension and proteinuria. Patients are also at increased risk for more serious complications, such as thromboembolic disease, haemorrhage, gastrointestinal perforation, and impaired wound healing.72 These adverse effects occur because of the many complex biological functions that VEGF signalling plays a part in. In clinical trials for malignant glioma,

Angiogenesis blockade and tumour invasion

Although anti-angiogenic drugs are an important advance in therapy for malignant glioma, tumours invariably progress and patients have poor prognoses. Results from animal studies have shown that anti-angiogenic therapy might lead to the use of pre-existent cerebral blood vessels by tumour cells, which results in an increase in infiltrative growth.19, 40, 75, 76, 77, 78 The molecular mechanisms by which this process occurs are not fully understood, but angiopoietins might play an important part.

Looking towards the future

In addition to bevacizumab, there is an array of inhibitors of VEGF, VEGFR, and other relevant targets that could be effective in selected patients with malignant gliomas or in patients whose tumours progress while being treated with bevacizumab. Studies of anti-angiogenic therapies in patients with newly diagnosed malignant glioma are in progress and will help to determine whether these drugs are best used in the upfront setting or in patients with refractory disease. The problem of how to

Conclusions

There is increasing evidence that bevacizumab is an active therapy for patients with recurrent malignant glioma. A 6-month progression-free survival of 40–50% far exceeds that of any previously assessed treatment for this highly resistant neoplasm. Despite small risks of life-threatening complications, including thromboembolic disease and haemorrhage, bevacizumab and most other anti-angiogenic compounds are well tolerated. Studies that are in progress will help to optimise how bevacizumab and

Search strategy and selection criteria

References for this Review were identified through searches of PubMed by use of the search terms up to July, 2008. Search terms included “angiogenesis”, “brain tumor”, “glioma”, “treatment”, “therapy”, and “vascular endothelial growth factor”. Papers were also selected from the authors' personal files and from references cited in relevant articles. Abstracts were reviewed from recent scientific meetings, including the American Society of Clinical Oncology and the Society for

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