International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationFeasibility of Using Bevacizumab With Radiation Therapy and Temozolomide in Newly Diagnosed High-Grade Glioma
Introduction
The combination of surgery, radiation therapy, and temozolomide chemotherapy represents the standard approach to the treatment of patients with high-grade gliomas (1). However, both local control and survival remain poor. The prognosis for patients with newly diagnosed malignant glioma is poor, with a median survival of 9–36 months based on tumor grade (2). The pattern of recurrence in gliomas is almost always local (3). As a result, there is a lot of interest in developing novel therapeutic agents that can target glial tumor progression, growth, and invasion.
Because malignant gliomas are highly vascular and express vascular endothelial growth factor (VEGF), targeting the vascular endothelium offers an interesting option for these patients (4).
Bevacizumab (Avastin; Genentech, San Francisco, CA), a humanized immunoglobulin G1 monoclonal antibody that inhibits VEGF, is the first Food and Drug Administration–approved antiangiogenic agent that has shown its effectiveness in metastatic colorectal, breast, and lung cancers 5, 6, 7. Preclinical data showed that it regressed microvascular density, normalized existing mature vasculature, and inhibited vessel regrowth in a glioma model (8). Marked improvement in radiologic response after bevacizumab therapy in patients with recurrent high-grade gliomas has been reported 9, 10. In a recently reported Phase II trial in recurrent glioblastoma, the combination of bevacizumab and irinotecan resulted in a 6-month survival rate of 72%, with acceptable morbidity (11). At our institution, we have shown the feasibility of using vascular perfusion imaging in monitoring the response to therapy in patients with recurrent gliomas (12).
In view of the previously reported encouraging results, we performed a pilot study to test the feasibility of using bevacizumab with radiation therapy and temozolomide in the primary management of newly diagnosed high-grade gliomas. Secondary aims are to correlate changes in perfusion imaging with contrast enhancement and evaluate immunostaining for phosphorylated (activated) VEGF receptor 2 (pVEGFR2) a potential biomarker of treatment response.
Section snippets
Methods and Materials
Fifteen consecutive patients with newly diagnosed high-grade gliomas were treated with involved field radiation therapy, temozolomide, and bevacizumab between July 2006 and January 2008 and were prospectively analyzed. Patient characteristics are listed in Table 1. Glioblastoma accounted for 80% of the cases at the time of initial diagnosis. Anaplastic astrocytoma (n = 2) and anaplastic oligodendroglioma (n = 1) histologic types accounted for the remaining cases. Median age at therapy was 53
Treatment compliance
Median follow-up was 12 months (range, 5–21 months). Median number of bevacizumab infusions administered was 16 (range, four to 20 infusions). Eight patients received 16 or more infusions of bevacizumab along with temozolomide (Fig. 1). Thirteen patients (86.6%) tolerated the planned radiation therapy with concomitant temozolomide and bevacizumab. Two patients (13.3%) experienced progression of disease with toxicity while on therapy, and treatment was discontinued. Planned adjuvant therapy with
Discussion
Use of angiogenic blockade as a possible treatment strategy in patients with malignant tumors was proposed by Judah Folkman (17) more than three decades ago. Identification of VEGF in tumors and receptors in the vasculature since then has resulted in the development of antiangiogenic agents, especially during the last decade 18, 19. Glioblastoma, for which the hallmark is angiogenesis, particularly offers an attractive target for these agents. Jain (20) showed that VEGF blockade resulted in a
References (32)
- et al.
Bevacizumab for advanced breast cancer
Hematol Oncol Clin North Am
(2007) - et al.
Targeting the tumor blood vessel network to enhance the efficacy of radiation therapy
Semin Radiat Oncol
(2003) - et al.
Intensity-modulated radiotherapy in high-grade gliomas: Clinical and dosimetric results
Int J Radiat Oncol Biol Phys
(2006) - et al.
A novel antiangiogenesis therapy using an integrin antagonist or anti-Flk-1 antibody coated 90Y-labeled nanoparticles
Int J Radiat Oncol Biol Phys
(2004) - et al.
Phase II study of temozolomide and thalidomide with radiation therapy for newly diagnosed glioblastoma multiforme
Int J Radiat Oncol Biol Phys
(2004) - et al.
Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors
Cancer Cell
(2005) - et al.
Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma
N Engl J Med
(2005) - et al.
Primary and metastatic brain tumors in adults
- et al.
Drug insight: Temozolomide as a treatment for malignant glioma—Impact of a recent trial
Nat Clin Pract Neurol
(2005) - et al.
Monoclonal antibodies to vascular endothelial growth factor (VEGF) and the VEGF receptor, FLT-1, inhibit the growth of C6 glioma in a mouse xenograft
J Neurooncol
(2001)
Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer
N Engl J Med
Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer
J Clin Oncol
Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F] fluorothymidine positron emission tomography: A pilot study
J Clin Oncol
MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy
Neurology
Bevacizumab plus irinotecan in recurrent glioblastoma multiforme
J Clin Oncol
Anti-angiogenic therapy using bevacizumab in recurrent high grade glioma: Impact on local control and survival
J Neurosurg
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Presented at the American Society for Therapeutic Radiology and Oncology 49th Annual Meeting, Los Angeles, CA, on October 31, 2007.
Conflict of interest: none.