OncoLog

 

From OncoLog, October 2012, Vol. 57, No. 10

Treatments May Alleviate and Reverse Central Nervous System Radiation Necrosis

By Jill Delsigne

Although radiation therapy is effective against many tumors of the brain and spine, it also damages normal tissue.

One of the most debilitating types of damage is radiation necrosis of the central nervous system (CNS). But in recent years, treatments have been found that can slow—and in some cases reverse—this damage.

CNS radiation necrosis may cause any of the following symptoms: abnormal headaches, seizures, personality changes, difficulty concentrating or reading, a sense of slowing down, focal weakness, or problems with speech. These symptoms can appear during or just after radiation therapy (acute injury), within a few weeks or months after treatment (early delayed injury), or 6 months to many years after treatment (late radiation injury). Acute and early delayed injuries can usually be reversed with steroid therapy, and sometimes they appear to spontaneously resolve. Late radiation injury is the most serious kind of damage and usually is irreversible.

Prevalence and causes

A retrospective study from The University of Texas MD Anderson Cancer Center found that CNS radiation necrosis developed in 36 (24%) of 148 patients treated with radiation and chemotherapy after surgical resection of glial tumors; of those patients, 16 (44%) had both necrotic lesions and recurrent or residual tumors. Several studies have shown that combining radiation therapy and chemotherapy increases the incidence of brain necrosis to three times that seen with radiation therapy alone. This combination disrupts the blood-brain barrier, which allows chemotherapy to more effectively target tumor cells; unfortunately, this disruption of the blood-brain barrier also makes normal brain tissue vulnerable to damage.

“[T]he fact that even short treatment with bevacizumab seems to turn off the cycle of radiation damage further confirms the central role of VEGF in the process.”
– Dr. Victor Levin
Even though radiation necrosis was first reported more than 60 years ago, potential mechanisms for this condition have only recently been discovered. It has been shown that CNS radiation necrosis is associated with increased cytokine production. According to this model, radiation therapy causes vascular abnormalities in the brain that reduce blood vessel density, ultimately restricting the blood supply to brain tissue (chronic ischemia). Ischemia, in turn, causes infiltrative tumor cells and adjacent astrocytes to respond by producing cytokines, such as vascular endothelial growth factor (VEGF), to help the tumor cells or astrocytes survive. In addition to irradiation, some chemotherapy drugs also cause ischemia and may exacerbate necrosis.

Irradiation of the CNS can also produce damage to the myelin sheath of neurons (demyelination). This appears to be caused by the effect of radiation on the oligodendrocytes that make and repair the myelin covering neuronal axons. This effect is seen early on magnetic resonance images of most patients treated with radiation therapy, with or without chemotherapy.

Diagnosis

CNS radiation necrosis is difficult to diagnose accurately because it often appears the same as a progressive tumor on diagnostic imaging. Radiation necrosis usually occurs at the treatment site but can also be distant, usually near a cerebral ventricle; necrosis can also be diffuse or multifocal and resemble tumor metastasis.

Ashok J. Kumar, M.D., a professor in the Department of Diagnostic Radiology at MD Anderson, was the first author of a seminal study published in 2000 of imaging patterns that differentiate radiation necrosis from brain tumors. According to Dr. Kumar, diagnosing radiation necrosis remains difficult, but experienced physicians can recognize the patterns of necrosis and treat it early. Dr. Kumar said radiation necrosis lesions have a “Swiss cheese” or “soap bubble” enhancement pattern on magnetic resonance imaging (MRI). However, this pattern does not provide a definitive diagnosis.

On diffusion-weighted MRI, which measures the magnitude and direction of free water movement, tumors tend to restrict water movement, whereas necrosis tends to increase water mobility. On magnetic resonance spectroscopy, necrotic lesions tend to exhibit reduced levels of N-acetyl aspartate and creatine, whereas tumors tend to exhibit high levels of choline. Magnetic resonance perfusion, which measures the relative cerebral blood volume, can indicate necrotic lesions, but this modality also detects fast-growing tumors that exceed their blood supply.

None of these imaging modalities can differentiate necrosis from tumor progression (or necrotic lesions mixed with a recurrent tumor) definitively. Even invasive tests such as biopsy cannot definitively distinguish between necrosis and recurrent cancer owing to sampling error. Experienced physicians and radiologists can learn to recognize signs that indicate a high probability of necrosis versus tumor progression. A diagnosis of CNS radiation necrosis instead of cancer is not cause for relief, however. Necrosis can have the same debilitating effects as a tumor and can even be fatal if unchecked.

Treatment

Until just a few years ago, treatment for CNS radiation necrosis was restricted to alleviating its symptoms. Physicians have long prescribed corticosteroids to control swelling and psychostimulants to address psychomotor slowing and fatigue in patients with CNS necrosis. Corticosteroids also help counteract the radiation-induced vascular damage that can disrupt the blood-brain barrier. Sometimes symptoms return if patients stop using the steroids, so problems arising from chronic steroid use must also be treated. Anticoagulants, such as warfarin or heparin, can slow the progression of necrosis in some patients. Hyperbaric oxygen treatment can help restore oxygen concentrations to a normal level in order to encourage angiogenesis. Patients can also undergo brain surgery to remove necrotic tissue.

In 2009, a group at MD Anderson revolutionized treatment options for radiation necrosis. They found that bevacizumab, a monoclonal antibody that prevents blood vessel growth in tumors by blocking VEGF, also causes necrotic lesions in the brain to regress, reversing radiation damage. This observation spurred the design of a double-blind, placebo-controlled phase II trial of bevacizumab as a therapy for CNS radiation necrosis. Treatment involved four cycles of bevacizumab (7.5 mg/kg intravenously every 3 weeks). At a median 10 months’ follow-up, 9 of the 12 patients treated with the drug had necrotic lesion shrinkage on MRI. This trial provided class I evidence of the efficacy of bevacizumab as a treatment for CNS radiation necrosis.

“Just the fact that bevacizumab works has helped us understand much more about what happens in radiation necrosis,” said Victor A. Levin, M.D., a professor emeritus in the Department of Neuro-Oncology at MD Anderson and the senior researcher on these studies. “We presume necrosis is related to the release of cytokines like VEGF, since bevacizumab is very specific and only reduces VEGF levels. We think aberrant production of VEGF is involved with radiation necrosis of the brain, and the fact that even short treatment with bevacizumab seems to turn off the cycle of radiation damage further confirms the central role of VEGF in the process.” Astrocytes try to protect neurons by expressing VEGF, but this strategy threatens the brain by causing a leak in the blood-brain barrier. Bevacizumab turns off this cytokine loop and reduces plasma leakage across brain capillaries, thus reducing brain edema.

MD Anderson researchers presented at the Society for Neuro-Oncology conference in November 2011 on the ability of diffusion-weighted MRI to predict which patients are most likely to benefit from bevacizumab treatment.

Although some researchers have claimed that a larger study is needed to validate bevacizumab as a standard treatment for CNS necrosis, Dr. Levin asserts that the success of each treatment outside of a research study adds to the growing evidence of its efficacy. He currently treats primary brain tumor patients as part of the Kaiser Medical Group in California and continues to prescribe bevacizumab, both pre-emptively to minimize radiation damage and after treatment to reverse radiation necrosis.

While research for treatments continues, advances in radiation therapy may reduce the incidence and severity of CNS necrosis and other side effects by minimizing radiation damage to healthy tissue. Dr. Levin said that proton therapy may prove to be such an advance because radiologists can calculate the trajectory of the proton to pinpoint the release of energy to occur precisely when the proton reaches the tumor cell, minimizing damage to the surrounding healthy tissue. Although this new technique also has caused instances of radiation necrosis, Dr. Levin is hopeful that it will lead to fewer cases of radiation necrosis compared with other treatment modalities.

These exciting developments in radiation therapy and treatment options for CNS radiation necrosis offer hope for CNS cancer patients and survivors.

For more information, call Dr. Ashok Kumar at 713-792-3817.

FURTHER READING

Giglio P, Gilbert MR. Cerebral radiation necrosis. Neurologist 2003;9:180–188.

Kumar AJ, Leeds NE, Fuller GN, et al. Malignant gliomas: MR imaging spectrum of radiation therapy- and chemotherapy-induced necrosis of the brain after treatment. Radiology 2000;217:377–384.

Levin VA, Bidaut L, Hou P, et al. Randomized double-blind placebo-controlled trial of bevacizumab therapy for radiation necrosis of the central nervous system. Int J Radiat Oncol Biol Phys 2011;79:1487–1495.

Wu J, Levin VA. Role of Avastin for treatment of central nervous system radiation necrosis. In: Chen TC, ed. Controversies in Neuro-Oncology. Vol 1. Sharjah, United Arab Emirates: Bentham; 2010:117–126.

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