Clinical Investigation
Randomized Double-Blind Placebo-Controlled Trial of Bevacizumab Therapy for Radiation Necrosis of the Central Nervous System

https://doi.org/10.1016/j.ijrobp.2009.12.061Get rights and content

Purpose

To conduct a controlled trial of bevacizumab for the treatment of symptomatic radiation necrosis of the brain.

Methods and Materials

A total of 14 patients were entered into a placebo-controlled randomized double-blind study of bevacizumab for the treatment of central nervous system radiation necrosis. All patients were required to have radiographic or biopsy proof of central nervous system radiation necrosis and progressive neurologic symptoms or signs. Eligible patients had undergone irradiation for head-and-neck carcinoma, meningioma, or low- to mid-grade glioma. Patients were randomized to receive intravenous saline or bevacizumab at 3-week intervals. The magnetic resonance imaging findings 3 weeks after the second treatment and clinical signs and symptoms defined the response or progression.

Results

The volumes of necrosis estimated on T2-weighted fluid-attenuated inversion recovery and T1-weighted gadolinium-enhanced magnetic resonance imaging scans demonstrated that although no patient receiving placebo responded (0 of 7), all bevacizumab-treated patients did so (5 of 5 randomized and 7 of 7 crossover) with decreases in T2-weighted fluid-attenuated inversion recovery and T1-weighted gadolinium-enhanced volumes and a decrease in endothelial transfer constant. All bevacizumab-treated patients—and none of the placebo-treated patients—showed improvement in neurologic symptoms or signs. At a median of 10 months after the last dose of bevacizumab in patients receiving all four study doses, only 2 patients had experienced a recurrence of magnetic resonance imaging changes consistent with progressive radiation necrosis; one patient received a single additional dose of bevacizumab and the other patient received two doses.

Conclusion

The Class I evidence of bevacizumab efficacy from the present study in the treatment of central nervous system radiation necrosis justifies consideration of this treatment option for people with radiation necrosis secondary to the treatment of head-and-neck cancer and brain cancer.

Introduction

Radiotherapy, although helpful in the management of central nervous system (CNS) and head-and-neck tumors, can cause devastating radiation necrosis of normal CNS tissues. At present, we believe this damage results from local cytokine release, an increase in capillary permeability and extracellular edema, and the loss of the myelin covering of neurons. If allowed to progress, radiation necrosis can lead to small vessel occlusive disease and bleeding from friable small vessels 4, 5. These changes combine to cause a definable worsening in patients' neurologic signs and symptoms 1, 2, 3, 4.

Traditionally, physicians have tried to combat CNS radiation necrosis with corticosteroids, antiplatelet agents, anticoagulants, hyperbaric oxygen, high-dose vitamins, and surgery 2, 6. However, none of these approaches has proved effective in controlled clinical trials.

The development of effective therapy for CNS radiation necrosis is complicated because the mechanisms of radiation-induced injury are not completely understood. The current dogma views radiation necrosis as a continuous process from endothelial cell dysfunction to tissue hypoxia and necrosis, with the concomitant liberation of a vasoactive compound such as the vascular endothelial growth factor (VEGF) that can lead to progressive blood–brain barrier dysfunction and brain edema 7, 8, 9, 10, 11. We hypothesized that blocking VEGF from reaching its capillary targets was a logical treatment strategy for radiation necrosis to reduce the movement of plasma and plasma water through leaky brain capillary endothelium to the extracellular space. Early descriptions of VEGF by Dvorak et al. (12) and Senger et al. 13, 14, 15 used the term “vascular permeability factor” to recognize VEGF's ability to dramatically increase vascular permeability.

Recently, we observed that in 8 patients with CNS radiation necrosis, bevacizumab (16), alone or with anticancer agents, markedly reduced the apparent lesion extent on T2-weighted fluid attenuated inversion recovery (FLAIR) and T1-weighted gadolinium-enhanced magnetic resonance imaging (MRI), and reduced the patients' dexamethasone dependence (17). Others have reported similar observations (18). Thus, to better determine whether bevacizumab can effectively treat symptomatic and progressive CNS radiation necrosis, we conducted a placebo-controlled double-blind study to determine the extent that intravenous bevacizumab, administered every 3 weeks, could reduce active radiation necrosis in the CNS.

Section snippets

Study design

Eligible patients were randomized to Group A to receive intravenous bevacizumab at a dose of 7.5 mg/kg at 3-week intervals for two treatments or to Group B to receive intravenous placebo at 3-week intervals for two treatments. It was planned that all patients would undergo MRI before beginning treatment and 3 weeks after the second dose of placebo/bevacizumab (i.e., 6 weeks after study entry). At that point, the patients responding to the treatment or placebo and showing no adverse effects that

Patient demographics

Table 1 summarizes the demographic data for the patients included in the present study. Most patients had not had primary CNS tumors. The symptoms varied from headaches to hemiparesis and decreasing macular vision. In the process of screening the patients for eligibility for the present study, we found that not all patients with obvious MRI evidence of radiation necrosis had neurologic symptoms or signs. Thus, 2 patients were followed by serial clinical visits with MRI until they developed

Discussion

The results of the present study have demonstrated Class I evidence (27) of the efficacy of bevacizumab therapy for CNS radiation necrosis. Only bevacizumab-treated patients showed improvement in clinical symptoms and signs and a reduction in the volume of necrosis on T2-weighted FLAIR and T1-weighted gadolinium-contrast MRI and a 90–100% reduction in the Ktransnormalized. Formal neurocognitive testing revealed a mixed pattern of findings from the objective tests of neurocognitive function and

Acknowledgments

The magnetic resonance imaging data acquisition contributions by David T. Evans, R.T., are gratefully acknowledged; the authors also acknowledge the support of Sandeep N. Gupta, Ph.D. (GE Global Research) for his support of the CineTool software package used for the dynamic contrast-enhanced magnetic resonance imaging analyses.

References (28)

  • J. Gonzalez et al.

    Effect of bevacizumab on radiation necrosis of the brain

    Int J Radiat Oncol Biol Phys

    (2007)
  • C.R. Meyer et al.

    Evaluation of lung MDCT nodule annotation across radiologists and methods

    Acad Radiol

    (2006)
  • D. Sackett

    Evidence-based medicine

    Lancet

    (1995)
  • M.-C. Cheung et al.

    Impact of radionecrosis on cognitive dysfunction in patients after radiotherapy for nasopharyngeal carcinoma

    Cancer

    (2003)
  • P. Giglio et al.

    Cerebral radiation necrosis

    Neurology

    (2003)
  • J.R. Crossen et al.

    Neurobehavioral sequelae of cranial irradiation in adults: A review of radiation-induced encephalopathy

    J Clin Oncol

    (1994)
  • S.A. Leibel et al.

    Tolerance of the brain and spinal cord to conventional irradiation

  • V.A. Levin et al.

    Neoplasms of the central nervous system

  • M.J. Glantz et al.

    Treatment of radiation-induced nervous system injury with heparin and warfarin

    Neurology

    (1994)
  • J.H. Kim et al.

    Upregulation of VEGF and FGF2 in normal rat brain after experimental intraoperative radiation therapy

    J Korean Med Sci

    (2004)
  • Y.-Q. Li et al.

    Hypoxia in radiation-induced blood-spinal cord barrier breakdown

    Cancer Res

    (2001)
  • M.N. Tsao et al.

    Upregulation of vascular endothelial growth factor is associated with radiation-induced blood-spinal cord barrier breakdown

    J Neuropathol Exp Neurol

    (1999)
  • J.H. Kim et al.

    Upregulation of VEGF and FGF2 in normal rat brain after experimental intraoperative radiation therapy

    J Korean Med Sci

    (2004)
  • D.S. Gridley et al.

    Pilot evaluation of cytokine levels in patients undergoing radiotherapy for brain tumor

    Cancer Detect Prev

    (1998)
  • Cited by (0)

    Supported in part by National Institutes of Health N01 Phase II contract N01-CM-62202 and from the University of Texas M. D. Anderson Cancer Center institutional funds and Core Grant CA 16672 to support clinical trials.

    Conflict of interest: J. Wefel is a neuropsychology consultant and M. Gilbert is a consultant to Genentech, Hoboken, NJ.

    View full text