Clinical Investigation
Safety and Efficacy of Bevacizumab With Hypofractionated Stereotactic Irradiation for Recurrent Malignant Gliomas

https://doi.org/10.1016/j.ijrobp.2008.10.043Get rights and content

Purpose

Preclinical studies suggest that inhibition of vascular endothelial growth factor (VEGF) improves glioma response to radiotherapy. Bevacizumab, a monoclonal antibody against VEGF, has shown promise in recurrent gliomas, but the safety and efficacy of concurrent bevacizumab with brain irradiation has not been extensively studied. The objectives of this study were to determine the safety and activity of this combination in malignant gliomas.

Methods and Materials

After prior treatment with standard radiation therapy patients with recurrent glioblastoma (GBM) and anaplastic gliomas (AG) received bevacizumab (10 mg/kg intravenous) every 2 weeks of 28-day cycles until tumor progression. Patients also received 30 Gy of hypofractionated stereotactic radiotherapy (HFSRT) in five fractions after the first cycle of bevacizumab.

Results

Twenty-five patients (20 GBM, 5 AG; median age 56 years; median Karnofsky Performance Status 90) received a median of seven cycles of bevacizumab. One patient did not undergo HFSRT because overlap with prior radiotherapy would exceed the safe dose allowed to the optic chiasm. Three patients discontinued treatment because of Grade 3 central nervous system intratumoral hemorrhage, wound dehiscence, and bowel perforation. Other nonhematologic and hematologic toxicities were transient. No radiation necrosis was seen in these previously irradiated patients. For the GBM cohort, overall response rate was 50%, 6-month progression-free survival was 65%; median overall survival was 12.5 months, and 1-year survival was 54%.

Discussion

Bevacizumab with HFSRT is safe and well tolerated. Radiographic responses, duration of disease control, and survival suggest that this regimen is active in recurrent malignant glioma.

Introduction

Radiotherapy (RT) has been shown to be the most effective adjuvant treatment for malignant gliomas but has only limited benefit in these tumors because of intrinsic radioresistance and the limited radiation tolerance of surrounding normal brain 1, 2. Attempts to improve the therapeutic index of brain tumor irradiation by localized dose escalation, altered fractionation, and radiosensitization have failed to affect survival of patients with malignant gliomas significantly (3).

Malignant gliomas are innately hypoxic tumors with strong endogenous expression of hypoxia-inducible factor-1 (HIF-1), vascular endothelial growth factor (VEGF), and VEGF receptors and consequently demonstrate vigorous angiogenesis 4, 5, 6, 7. Tumor xenografts, including U87 gliomas, induce VEGF expression in response to irradiation, which may serve to protect their endothelium 8, 9. Furthermore, adding VEGF to cultures of human umbilical endothelial cells enhances radioresistance (8).

Bevacizumab, a humanized monoclonal antibody to VEGF, has been used with safety and clinical success with concomitant chemotherapy in solid tumors 10, 11, 12. In recurrent malignant gliomas, it has been used alone and in combination with irinotecan 13, 14, 15. Bevacizumab has been successfully used in patients undergoing radiotherapy and chemotherapy for solid tumors, including glioblastomas 16, 17, 18, 19. Reasons to combine bevacizumab and RT include the ability of antiangiogenic agents to sensitize tumor endothelium to RT by depletion of VEGF and reduction of its pro-survival signaling 8, 20. It is known that blockade of the VEGF receptor-2 by the monoclonal antibody DC101 can lower the dose of radiation needed to control 50% of tumor xenografts, including the glioblastoma U87 (21). Recent evidence points to a population of radioresistant glioma stem cells residing within vascular niches. These stem cells may be a nidus for regrowth following RT, but, promisingly, this niche can be disrupted by bevacizumab in xenograft brain tumor models 22, 23. Garcia-Barros et al.(24) have found that at a single dose threshold of approximately 8–10 Gy, the endothelium in tumor xenografts undergoes apoptosis, legitimizing tumor endothelium as an additional target for radiotherapy. Early clinical trials have shown efficacy of stereotactic high-dose fraction irradiation for paraspinal and brain metastases, lung cancer, pancreatic cancer, and renal cancer 25, 26, 27, 28, 29, 30, 31, 32. The threshold for endothelial apoptosis in glioblastoma endothelium is not clear; therefore, we chose an aggressive fractionation scheme to optimize the antiendothelial impact, particularly because bevacizumab could maximize the effects of radiation on this target (8).

We hypothesized that a combined approach of hypofractionated stereotactic radiotherapy (HFSRT) with VEGF inhibition would be an effective strategy for malignant glioma. The study was performed in previously irradiated patients with recurrences as a pilot to assess the safety of bevacizumab used during RT for glioma treatment in general and also the potential of this regimen in particular for patients at all stages of disease. Correlative markers of response to anti-angiogenic therapy are being actively sought (33); perfusion MRI was performed in some patients to assess changes in tumor perfusion after bevacizumab administration.

Section snippets

Patient eligibility

Patients were recruited from March 2006 to February 2008. Adult patients (aged ≥ 18 years) with histopathologic confirmation of malignant glioma who had recurrent or progressive tumor and had failed prior RT were eligible. Brain MRI needed to show a circumscribed enhancing tumor ≤ 3.5 cm in its largest diameter; surgery for recurrent malignant glioma could be offered before enrollment in this protocol, but at least 4 weeks had to elapse between the surgery and first dose of bevacizumab.

Patients characteristics

Twenty-five patients (14 men, 11 women) with histologically confirmed malignant glioma (20 GBM, 5 anaplastic gliomas [AG]) were enrolled in this trial (Table 1). The median age was 56 years (range, 30–80), and median KPS was 80 (range, 70–100). The median elapsed time between prior RT and study enrollment was 15 months, and 23 patients (92%) had completed RT at least 6 months before enrollment. Two patients were enrolled 2 and 4 months after completing RT but after receiving adjuvant

Discussion

Concomitant administration of bevacizumab and HFSRT in previously irradiated malignant glioma recurrences was safe and effective in this pilot study. Overall toxicity in our study was in line with other reports of bevacizumab use in patients with malignant glioma 13, 14, 15, 18. No significant adverse reactions were attributable to the interaction of bevacizumab with radiation, except possibly the single wound dehiscence. In fact, the combination appears to have improved the therapeutic ratio

Acknowledgments

Genentech provided drug and research support. We thank Judy Lampron for her expert editorial support.

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    ClinicalTrials.gov Identifier: NCT00595322.

    This study has been presented in part at the 2007 Annual Meeting of the American Society of Clinical Oncology (Chicago, June 1–5, 2007) at the 49th Annual Meeting of the American Society for Therapeutic Radiology and Oncology (Los Angeles, October 28–November 1, 2007), at the 16th Annual Meeting of the International Society for Magnetic Resonance in Medicine (Toronto, May 3–9, 2008), and at the 46th Annual Meeting of the American Society of Neuroradiology (New Orleans, May 31–June 5, 2008).

    Conflict of interest: Drs. Abrey and Gutin received research support and consultation fees from Genentech.

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