Drugs that target blood vessels in malignant brain tumours

Background

The most common primary brain tumours of adults are gliomas, which account for about two-fifths of all primary brain tumours. Gliomas span a spectrum from low to high grade and are graded pathologically on a scale of one to four according to a classification by the World Health Organization (WHO). High-grade glioma (HGG), including glioblastoma, or GBM, is difficult to treat and carries a poor prognosis.

These brain tumours form new blood vessels to help them grow. Drugs have been developed to reduce the formation of new blood vessels (angiogenesis) and to slow tumour growth. Bevacizumab, cediranib given directly and cilengitide given indirectly target blood vessel formation and have been studied in randomised clinical trials for the treatment of GBM. 

Study characteristics

After a comprehensive search of the literature, seven eligible randomised clinical trials were identified (totaling 2987 participants). All eligible studies were restricted to GBMs, and no eligible studies included other brain tumour types. The largest trials were conducted in patients with newly diagnosed GBM who were treated with antiangiogenic therapy. Overall, the trials included in this systematic review did not show improvement in overall survival with the use of antiangiogenic therapy. However, clinical trials in bevacizumab-treated GBM did prolong the time until tumour growth (progression-free survival).

Key results

The adverse events observed were infrequent and were similar to those seen in trials of antiangiogenic therapies in other tumours. Adverse events included high blood pressure, loss of protein in the urine, poor wound healing and increased risk of blood clots.  

In summary, we found insufficient evidence to show whether the antiangiogenic therapies evaluated so far prolong life in patients with high-grade malignant brain tumours.

Authors' conclusions: 

In patients with newly diagnosed GBM, the use of antiangiogenic therapy does not improve survival, despite evidence of improved progression-free survival. Thus at this time, evidence is insufficient to support the use of antiangiogenic therapy in patients with newly diagnosed GBM on the basis of effects on survival.

Bevacizumab may confer a progression-free survival benefit in GBM; however evidence in favour of using other antiangiogenic therapies in recurrent GBM is insufficient.

Although bevacizumab appears to prolong progression-free survival in newly diagnosed and recurrent GBM, the impact of this on quality of life remains unclear.

Adequately powered, randomised, placebo-controlled studies of bevacizumab in recurrent GBM (or HGG) are needed.

Not addressed here is whether subsets of patients with newly diagnosed GBM may benefit from antiangiogenic therapies and whether these therapies are useful in other high-grade glioma histologies.

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Background: 

The most common primary brain tumours in adults are gliomas. Gliomas span a spectrum from low to high-grade and are graded pathologically on a scale of one to four according to the World Health Organization (WHO) classification. High-grade glioma (HGG) carries a poor prognosis. Grade IV glioma is known as glioblastoma (GBM) and carries a median survival in treated patients of about 15 months. GBMs are rich in blood vessels (i.e. highly vascular) and in a protein known as vascular endothelial growth factor (VEGF), which promotes new blood vessel formation (the process of angiogenesis). Antiangiogenic agents inhibit the process of new blood vessel formation and promote regression of existing vessels. Several antiangiogenic agents have been investigated in clinical trials in newly diagnosed and recurrent HGG, showing promising preliminary results. This review was undertaken to report on the benefits and harms associated with the use of antiangiogenic agents in the treatment of HGGs.

Objectives: 

To evaluate the efficacy and toxicity of antiangiogenic therapy in patients with high-grade glioma. This intervention can be used in two broad groups of patients: those with first diagnosis as part of 'adjuvant' therapy, and those with recurrent or progressive disease. Comparisons will include the following.

• Treatment with antiangiogenic therapy versus placebo.

• Treatment (such as chemotherapy or chemoradiotherapy) with antiangiogenic therapy added versus the same treatment without the addition of antiangiogenic therapy.

Search strategy: 

Searches were conducted to identify published and unpublished Randomised Controlled Trials (RCTs) starting in 2000; the following databases were searched: the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 3, 2014; MEDLINE to April 2014 and EMBASE to April 2014. Proceedings of relevant oncology conferences since 2000 were handsearched.

Selection criteria: 

RCTs evaluating the use of antiangiogenic therapy versus control treatment without antiangiogenic therapy in the treatment of HGG.

Data collection and analysis: 

Review authors screened the search results and reviewed the abstracts of potentially relevant articles before retrieving the full text of eligible articles.

Main results: 

After a comprehensive literature search, seven eligible RCTs were identified (total of 2987 participants). Significant design heterogeneity was noted in the included studies, especially in the response assessment criteria used. All eligible studies were restricted to GBMs, and no eligible studies evaluated other HGGs. Four studies were available only in abstract form. We have reserved an overall assessment of the quality of the evidence until the final study publications are received. The three studies that have been published in full were judged to have low risk of bias. The seven trials of 2987 participants included in this systematic review did not show improvement in OS with the addition of antiangiogenic therapy (pooled hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.86 to 1.02; P value 0.16). However, pooled analysis of PFS from six studies (2847 participants) showed improvement in PFS with the addition of antiangiogenic therapy (HR 0.74, 95% CI 0.68 to 0.81; P value < 0.00001). Bevacizumab was the antiangiogenic therapy more likely to yield favourable results. Pooled HR for PFS for bevacizumab studies (three studies with 1712 participants) was significant at 0.66 (95% CI 0.59 to 0.74; P value < 0.00001), and this was reflected in the lower hazard ratio reported in the pooled analysis of bevacizumab studies compared with the overall analysis. Nevertheless, this finding was not significant for OS (HR 0.92, 95% CI 0.83 to 1.02; P value 0.12). Similar to trials of antiangiogenic therapies in other solid tumours, adverse events related to this class of therapy included hypertension and proteinuria, poor wound healing and the potential for thromboembolic events, although generally, the occurrence of grade 3 events of this kind was low (< 14.1%), consistent with reported findings of studies of bevacizumab in other tumours.

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