Despite advances in treatment therapeutics, patients with malignant gliomas still have poor prognosis. A better understanding of tumor angiogenesis has allowed us to target VEGF in antiangiogenic therapy. Bevacizumab is considered as a well-established antiangiogenic therapy in several solid tumors. A phase II trials of recurrent glioblastoma showed favorable response rates (28% to 57%) and 6-month PFS (29% to 50.3%) [11
]. Based on these promising results, bevacizumab was approved by the FDA for the recurrent glioblastoma. Regarding recurrent anaplastic gliomas, bevacizumab has been reported to be effective as well [28
]. Additional therapies (e.g., chemotherapy, targeting therapy, and radiotherapy) to bevacizumab have been reported for recurrent malignant gliomas, and these results were encouraging. However, the timing, dosing, and the ideal treatment partners of bevacizumab have remained controversial. Further investigations are warranted to establish an antiangiogenic treatment for recurrent malignant gliomas.
Bevacizumab is expected to be on the frontline treatment of patients with glioblastoma. Phase II trials have reported the addition of bevacizumab to standard temozolomide and radiotherapy regimen for newly diagnosed glioblastoma [14
]. However, the authors concluded that this regimen improved PFS but not overall survival when compared with control group [14
]. Currently two randomized phase III trials, RTOG 0825 and AVAGLIO, are ongoing to demonstrate the efficacy and safety of combined therapy of bevacizumab, temozolomide, and radiotherapy for newly diagnosed glioblastoma [56
]. These studies will show the role of bevacizumab in the first-line treatment of newly diagnosed glioblastoma.
Many other antiangiogenic therapies (e.g., cilengitide and cediranib) have also been performed in clinical trials. These studies showed encouraging results and are expected to improve the prognosis of malignant gliomas. However, some phase II trials have several limitations such as small sample size, possible enrollment bias, patient selection, and reliance on historical control data. These limitations are associated with a high false-positive rate, and the results from phase II studies are often not validated in phase III studies [109
]. Phase II studies must be appropriately planned to have the greatest potential for informing the design of phase III trials [109
Antiangiogenic therapies provide favorable results and seem to be attractive strategy in malignant gliomas. However, several problems such as including severe toxicities, resistance, evaluation of response, and lack of predictive biomarkers still remain. The unique severe adverse effects related to bevacizumab have been reported, such as CNS hemorrhage, deep venous thrombosis, and pulmonary emboli [11
]. BRAIN study reported that Grade ≥3 adverse events were observed 65.8% and 46.4% in bevacizumab plus irinotecan and bevacizumab alone groups, respectively [13
]. To reduce the serious adverse events associated with bevacizumab, selecting appropriate patients, early assessment of toxicity, and adequate management should be required.
Malignant glioma patients maintained on bevacizumab inevitably experience the treatment failure. Recurrent tumors following bevacizumab failure appear to be more aggressive with rebound edema [38
]. Preclinical study showed that other angiogenic factors, such as fibroblast growth factors and PDGF, can compensate for the loss of VEGF activity under bevacizumab treatment [42
]. A novel therapeutic strategy is required to overcome the resistance to bevacizumab of malignant gliomas.
An accurate assessment of tumor response by conventional modality is limited in antiangiogenic therapy due to alterations in tumor blood vessels [44
]. The Response Assessment in Neuro-Oncology Working Group proposed that T2 and FLAIR changes on MRI should include the response criteria [47
]. FDG-FLT is also expected to accurately evaluate the treatment response in bevacizumab due to its ability to detect cell proliferation [48
Tumor VEGF expressions or circulating markers potentially predict the prognosis in malignant glioma treated by bevacizumab, although the rational biomarker has not been established. Novel biological markers are required to investigate, providing a personalized treatment that selects the patients who can benefit from bevacizumab.
Although several limitations on antiangiogenic therapy have been reported, this treatment is expected to improve the prognosis of malignant gliomas. Further investigation is warranted to establish the safe and effective antiangiogenic therapy for malignant gliomas.