title: Antiangiogenic therapy for high-grade glioma.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  Searches were conducted to identify published and unpublished Randomised Controlled Trials (RCTs) starting in 2000; the following databases were searched: the Cochrane Central Register of Controlled Trials (CENTRAL),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.
  
  
  METHODS
  RCTs evaluating the use of antiangiogenic therapy versus control treatment without antiangiogenic therapy in the treatment of HGG.
  
  
  METHODS
  Review authors screened the search results and reviewed the abstracts of potentially relevant articles before retrieving the full text of eligible articles.
  
  
  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.
  
  
  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.
authors.affiliation: NHMRC Clinical Trials Centre, University of Sydney, University of Sydney, Sydney, Australia.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Khasraw
authors.forename: Malaka S
authors.initials: MS
authors.lastname: Ameratunga
authors.forename: Robin
authors.initials: R
authors.lastname: Grant
authors.forename: Helen
authors.initials: H
authors.lastname: Wheeler
authors.forename: Nick
authors.initials: N
authors.lastname: Pavlakis
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000401:mortality; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D005909:Glioblastoma / Q000098:blood supply* / Q000188:drug therapy / Q000401:mortality; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D000077146:Irinotecan; D008130:Lomustine / Q000627:therapeutic use; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011507:Proteinuria / Q000139:chemically induced; D016032:Randomized Controlled Trials as Topic; D012910:Snake Venoms / Q000627:therapeutic use; D000077204:Temozolomide
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D012910:Snake Venoms; D000068258:Bevacizumab; C422910:Cilengitide; D000077146:Irinotecan; D008130:Lomustine; D003606:Dacarbazine; D002166:Camptothecin; D000077204:Temozolomide