International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationSafety and Efficacy of Bevacizumab With Hypofractionated Stereotactic Irradiation for Recurrent Malignant Gliomas
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.
References (48)
- et al.
Therapeutic irradiation and brain injury
Int J Radiat Oncol Biol Phys
(1980) - et al.
An analysis of dose–effect relationship in the radiotherapy of malignant gliomas
Int J Radiat Oncol Biol Phys
(1979) - et al.
A comparison of treatment results for recurrent malignant gliomas
Cancer Treat Rev
(2000) - et al.
Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: Role of reoxygenation, free radicals, and stress granules
Cancer Cell
(2004) - et al.
Bevacizumab, oxaliplatin, and capecitabine with radiation therapy in rectal cancer: Phase I trial results
Int J Radiat Oncol Biol Phys
(2007) - et al.
Phase II pilot study of Bevacizumab in combination with temozolomide and regional radiation therapy for up-front treatment of patients with newly diagnosed glioblastoma multiforme: Interim analysis of safety and tolerability
Int J Radiat Oncol Biol Phys
(2008) - et al.
Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: Role of bone marrow-derived myelomonocytic cells
Cancer Cell
(2008) - et al.
A perivascular niche for brain tumor stem cells
Cancer Cell
(2007) - et al.
Image-guided robotic radiosurgery for spinal metastases
Radiother Oncol
(2007) - et al.
Phase I study of stereotactic radiosurgery in patients with locally advanced pancreatic cancer
Int J Radiat Oncol Biol Phys
(2004)
Stereotactic hypofractionated radiotherapy for Stage I non-small cell lung cancer—mature results for medically inoperable patients
Lung Cancer
Radiosurgery for brain metastases: Relationship of dose and pattern of enhancement to local control
Int J Radiat Oncol Biol Phys
High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions
Int J Radiat Oncol Biol Phys
High-dose single-fraction radiotherapy: Exploiting a new biology?
Int J Radiat Oncol Biol Phys
AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients
Cancer Cell
Endostatin improves radioresponse and blocks tumor revascularization after radiation therapy for A431 xenografts in mice
Int J Radiat Oncol Biol Phys
VEGF-targeted cancer therapy strategies: Current progress, hurdles and future prospects
Trends Mol Med
Angiogenesis in brain tumours
Nat Rev Neurosci
Levels of soluble vascular endothelial growth factor (VEGF) receptor 1 in astrocytic tumors and its relation to malignancy, vascularity, and VEGF-A
Clin Cancer Res
Tumor angiogenic and hypoxic profiles predict radiographic response and survival in malignant astrocytoma patients treated with bevacizumab and irinotecan
J Clin Oncol
Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo
Nature
Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation
Cancer Res
Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer
N Engl J Med
Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer
N Engl J Med
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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.