Clinical Investigation
Feasibility of Using Bevacizumab With Radiation Therapy and Temozolomide in Newly Diagnosed High-Grade Glioma

https://doi.org/10.1016/j.ijrobp.2008.05.062Get rights and content

Introduction

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), has shown promise in the treatment of patients with recurrent high-grade glioma. The purpose of this study is to test the feasibility of using bevacizumab with chemoradiation in the primary management of high-grade glioma.

Methods and Materials

Fifteen patients with high-grade glioma were treated with involved field radiation therapy to a dose of 59.4 Gy at 1.8 Gy/fraction with bevacizumab 10 mg/kg on Days 14 and 28 and temozolomide 75 mg/m2. Subsequently, bevacizumab 10 mg/kg was continued every 2 weeks with temozolomide 150 mg/m2 for 12 months. Changes in relative cerebral blood volume, perfusion-permeability index, and tumor volume measurement were measured to assess the therapeutic response. Immunohistochemistry for phosphorylated VEGF receptor 2 (pVEGFR2) was performed.

Results

Thirteen patients (86.6%) completed the planned bevacizumab and chemoradiation therapy. Four Grade III/IV nonhematologic toxicities were seen. Radiographic responses were noted in 13 of 14 assessable patients (92.8%). The pVEGFR2 staining was seen in 7 of 8 patients (87.5%) at the time of initial diagnosis. Six patients have experienced relapse, 3 at the primary site and 3 as diffuse disease. One patient showed loss of pVEGFR2 expression at relapse. One-year progression-free survival and overall survival rates were 59.3% and 86.7%, respectively.

Conclusion

Use of antiangiogenic therapy with radiation and temozolomide in the primary management of high-grade glioma is feasible. Perfusion imaging with relative cerebral blood volume, perfusion-permeability index, and pVEGFR2 expression may be used as a potential predictor of therapeutic response. Toxicities and patterns of relapse need to be monitored closely.

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)

  • H. Hurwitz et al.

    Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer

    N Engl J Med

    (2004)
  • D.H. Johnson et al.

    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

    (2004)
  • W. Chen et al.

    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

    (2007)
  • W.B. Pope et al.

    MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy

    Neurology

    (2006)
  • J.J. Vredenburgh et al.

    Bevacizumab plus irinotecan in recurrent glioblastoma multiforme

    J Clin Oncol

    (2007)
  • A. Narayana et al.

    Anti-angiogenic therapy using bevacizumab in recurrent high grade glioma: Impact on local control and survival

    J Neurosurg

    (2008)
  • Cited by (0)

    Presented at the American Society for Therapeutic Radiology and Oncology 49th Annual Meeting, Los Angeles, CA, on October 31, 2007.

    Conflict of interest: none.

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