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
Rapid ReviewNovel anti-angiogenic therapies for malignant gliomas
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 (84)
- et al.
Highly anaplastic astrocytoma: a review of 357 patients treated between 1977 and 1989
Int J Radiat Oncol BiolPhys
(1992) - et al.
Phase III randomized study of radiotherapy plus procarbazine, lomustine, and vincristine with or without BUdR for treatment of anaplastic astrocytoma: final report of RTOG 9404
Int J Radiat Oncol BiolPhys
(2004) - et al.
Characterization of novel vascular endothelial growth factor (VEGF) receptors on tumor cells that bind VEGF165 via its exon 7-encoded domain
J Biol Chem
(1996) - et al.
Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2
Cancer Cell
(2004) - et al.
Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme
Int J Radiat Oncol BiolPhys
(2004) - et al.
Bevacizumab/irinotecan. An active treatment for recurrent high grade gliomas: preliminary results of an ANOCEF Multicenter Study
Rev Neurol
(2008) - et al.
VEGF trap in combination with radiotherapy improves tumor control in u87 glioblastoma
Int J Radiat Oncol BiolPhys
(2007) - et al.
AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients
Cancer Cell
(2007) - et al.
Platelet-derived growth factor (PDGF) and glial tumorigenesis
Cancer Lett
(2006) - et al.
Medical management of brain tumor patients
Neurol Clin
(2007)