Treating Radiation Necrosis of the Brain with Avastin

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Treating Radiation Necrosis of the Brain with Avastin

by Gdpawel on Mon Dec 06, 2010 02:01 AM

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When brain tumors are treated with radiation therapy, there is always a risk of radiation-induced necrosis of healthy brain tissue. Insidious and potentially fatal, radiation necrosis of the brain may develop months or even years after irradiation.

This poorly understood side effect can occur even when the most stringent measures are taken to avoid exposing healthy tissue to harmful levels of radiation. In most cases, radiation necrosis of the brain occurs at random, without known genetic or other predisposing risk factors. The only treatment options typically available for radiation necrosis of the brain are surgery to remove dead tissue and use of the steroid dexamethasone to provide limited symptom control. But clinicians have not found a way to stop the progression of necrosis, despite having tested a range of therapies including anticoagulants, hyperbaric oxygen, and high-dose anti-inflammatory regimens.

However, recent studies at M. D. Anderson have shown that the monoclonal antibody bevacizumab (Avastin) may be able to stop radiation necrosis of the brain and allow some of the damage to be reversed. Victor A. Levin, M.D., a professor in the Department of Neuro-Oncology and the senior researcher on the studies, said the findings suggest that radiation necrosis of the brain can be successfully managed—and perhaps even prevented—with bevacizumab or similar drugs.

The need for such a breakthrough is as old as radiation therapy for cancers in the brain. “No matter what we do or how good we do it, we know a small percentage of patients who receive radiation therapy to the central nervous system will suffer late-occurring radiation necrosis,” Dr. Levin said. “We used to think it was the dose that was causing problems. Then we did a study and found that there was little to no relation to radiation dose or radiation volume—the necrosis occurred simply by chance. So it is impossible to say which patients will develop this problem; we just have to monitor them and hope for the best.”

Like necrosis, the discovery that bevacizumab has an effect on necrosis can also be attributed to chance. Bevacizumab, a newer drug that prevents blood vessel growth in tumors by blocking vascular endothelial growth factor (VEGF), was originally approved in the United States for the treatment of metastatic colon cancer and non–small cell lung cancer. An M. D. Anderson group that included Dr. Levin decided to test the drug in patients who had VEGF-expressing brain tumors. “Some of these patients also had necrosis from prior radiation therapy, and we were struck by the positive response of those patients to bevacizumab,” Dr. Levin said. “We had never seen such a regression of necrotic lesions with any other drug like we did in those patients.” The observation prompted the researchers to design a placebo-controlled, double-blind, phase II trial sponsored by the U.S. Cancer Therapy Evaluation Program in which bevacizumab would be tested specifically for the treatment of radiation necrosis of the brain.

The trial is small, having accrued 13 of a planned 16 patients, and is limited to those with progressive symptoms, lower-grade primary brain tumors, and head and neck cancers. But the results have been unlike anything the researchers have seen before in radiation necrosis therapy. All of the patients receiving bevacizumab responded almost immediately to treatment, with regression of necrotic lesions evident on magnetic resonance images, while none of the patients receiving the placebo showed a response. The results were striking, and all of the patients who switched from placebo showed a response to bevacizumab as well. So far, responses have persisted over 6 months even after the end of bevacizumab treatment.

Side effects seen in the trial so far included venous thromboembolism in one patient, small vessel thrombosis in two patients, and a large venous sinus thrombosis in one patient. Dr. Levin is unsure whether the side effects were caused by therapy or the radiation necrosis itself. “We’re also not absolutely sure what is causing the positive effects against the radiation necrosis,” he said. “We presume it’s 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.”

The multidisciplinary research team has also postulated that radiation therapy damages astrocytes, a cell type involved in various brain functions, and causes them to leak VEGF. This leaked VEGF might then cause further damage to brain cells and further leakage of VEGF. “It gets to be a very vicious cycle,” Dr. Levin said. “The question is, is that all that’s going on?”

Dr. Levin hopes that the answers to that question and others may lead to preventive measures against radiation necrosis, beyond what is already done to control the development of radiation itself. Perhaps bevacizumab can be given in low doses before radiation or intermittently afterward to reduce VEGF levels and protect the brain from abnormally high levels of the protein. He hopes such approaches can be tested in future studies. “Just the fact that bevacizumab works has helped us understand so much more about what happens in radiation necrosis,” he said. “Everything we’ve tried up until now has been a brick wall.”

Source: OncoLog, May 2009, Vol. 54, No. 5

What is Radiation Necrosis?

by Gdpawel on Mon Feb 28, 2011 08:56 PM

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Author: Michael J Schneck, MD, Associate Professor, Departments of Neurology and Neurosurgery, Stritch School of Medicine, Loyola University; Associate Director, Stroke Program, Director, Neurology Intensive Care Program, Medical Director, Neurosciences ICU, Loyola University Medical Center

Coauthor(s): Anna Janss, MD, PhD, Associate Professor of Pediatric Neuro-oncology, Emory University School of Medicine; Consulting Neuro-oncologist, Children's Healthcare of Atlanta

INTRODUCTION

Background

Radiation necrosis, a focal structural lesion that usually occurs at the original tumor site, is a potential long-term central nervous system (CNS) complication of radiotherapy or radiosurgery. Edema and the presence of tumor render the CNS parenchyma in the tumor bed more susceptible to radiation necrosis. Radiation necrosis can occur when radiotherapy is used to treat primary CNS tumors, metastatic disease, or head and neck malignancies. It can occur secondary to any form of radiotherapy modality or regimen.

In the clinical situation of a recurrent astrocytoma (postradiation therapy), radiation necrosis presents a diagnostic dilemma. Astrocytic tumors can mutate to the more malignant glioblastoma multiforme. Glioblastoma multiforme's hallmark histology of pseudopalisading necrosis makes it difficult to differentiate radiation necrosis from recurrent astrocytoma using MRI. See eMedicine articles Glioblastoma Multiforme and Low-Grade Astrocytoma.

Therapeutic effects of radiotherapy

Radiation creates ionized oxygen species that react with cellular DNA. Tumor cells have less ability than healthy cells for DNA repair. Thus, between fractionation doses, healthy cells have a greater probability than tumor cells of repairing themselves. With each subsequent mitosis, the cumulative effects of unrepaired DNA result in apoptosis (cell death) of these tumor cells.

Central nervous system syndromes secondary to radiotherapy

Radiation necrosis is part of a series of clinical syndromes related to CNS complications of radiotherapy. These syndromes occur in a distinct chronologic order and have characteristic pathophysiology. While the term radiation necrosis is used to refer to radiation injury, pathology is not limited to necrosis and a spectrum of injury patterns may occur.

Acute encephalopathy occurs during and up to 1 month after radiotherapy. This acute encephalopathy is due to disruption of the blood-brain barrier.

Early delayed complications occur 1-4 months after radiotherapy. Early delayed complications are caused by white matter injury characterized by demyelination and vasogenic edema. Early delayed changes may produce a somnolence syndrome in children, reappearance of the initial tumor's symptomatology, temporary decline in long-term memory, and encephalopathy. In early delayed complications, patients may have increased edema and contrast enhancement on MRI (both symptomatic and asymptomatic) that may resolve spontaneously over a few months. Both the acute and early delayed complications are steroid responsive.

Treatment-induced leukoencephalopathy is the leading toxicity after primary CNS lymphoma and may be seen both early1 and as a delayed consequence of treatment. It may be seen in greater than 90% of patients older than 60 years who have been successfully treated with combination chemotherapy and whole-brain radiation. A relationship between increased blood-brain barrier permeability and radiation therapy has been posited to contribute to this leukoencephalopathy and to methotrexate-induced vasculopathy. This also may be an etiology for the changes seen with radiation necrosis.

Radiation necrosis and diffuse cerebral atrophy are considered long-term complications of radiotherapy that occur from months to decades after radiation treatment. As opposed to the focal nature of radiation necrosis, diffuse cerebral atrophy is characterized by bihemispheric sulci enlargement, brain atrophy, and ventriculomegaly. Diffuse cerebral atrophy clinically is associated with cognitive decline, personality changes, and gait disturbances.

Recent studies

Liu et al reported that in children with pontine gliomas, a nearly always fatal brain tumor, bevacizumab may provide both therapeutic benefit and diagnostic information. They note that although radiation therapy can provide some palliation in such patients, it can also result in radiation necrosis and neurologic decline. In a study of 4 children, 3 children showed significant clinical improvement with bevacizumab and were able to discontinue steroid use, which, according to the authors, can have numerous side effects that significantly compromise a patient's quality of life. In 1 child who continued to decline on bevacizumab, it was later determined that the patient had disease progression, not radiation necrosis. In all cases, according to the investigators, bevacizumab was well tolerated.2

Barajas et al attempted, in a study of 57 patients, to determine whether T2-weighted dynamic susceptibility-weighted contrast material-enhanced (DSC) MRI can differentiate radiation-therapy-induced necrosis from glioblastoma multiforme. They found that mean, maximum, and minimum relative peak height and relative cerebral blood volume were significantly higher in patients with recurrent glioblastoma multiforme than in patients with radiation necrosis. In addition, they determined that mean, maximum, and minimum relative percentage of signal intensity recovery values were significantly lower in patients with recurrent glioblastoma multiforme than in patients with radiation necrosis.3

Pathophysiology

Radiation necrosis is coagulative and predominantly affects white matter. This coagulative necrosis is due to small artery injury and thrombotic occlusion. These small arteries demonstrate endothelial thickening, lymphocytic and macrophagic infiltrates, presence of cytokines, hyalinization, fibrinoid deposition, thrombosis, and finally occlusion.

The primary mechanism of the delayed injury in radiation associated with necrosis is secondary to vascular endothelial injury or direct damage to oligodendroglia. As a result, white matter tissue is often more affected than gray matter tissue. Radiation may have effects on fibrinolytic enzyme systems, with an absence of tissue plasminogen activator and an excess in urokinase plasminogen activator impacting tissue fibrinogen and extracellular proteolysis with subsequent cytotoxic edema and tissue necrosis. Whether immune-mediated mechanisms may also contribute to radiation-induced neurotoxicity is unclear, but an autoimmune vasculitis has been postulated as a secondary host response to tissue damage.

Animals exposed to radiation and given antibodies to cytokines (tumor necrosis factor, interleukin-1, tissue growth factor) have decreased survival compared to animals that do not receive these antibodies. These cytokines may be involved in initially protecting healthy tissue from the effects of radiation. With prolonged radiation exposure, these particular cytokines are overexpressed and result in a cascade of inflammatory events and vascular injury.4

In addition to vessel occlusion with resultant tissue necrosis, telangiectatic vessels, which may hemorrhage, occasionally form. Demyelination, oligodendrocyte dropout, axonal swelling, reactive gliosis, and disruption of the blood-brain barrier also can be observed.

Frequency

Natural history of the tumor in terms of prognosis and survival may affect the occurrence of radiation necrosis in a particular tumor population. In glioblastoma multiforme or metastatic disease with a poor long-term prognosis, the patient may not live long enough to develop radiation necrosis. Radiation necrosis can occur as soon as a few months or as long as decades after treatment. It generally occurs 6 months to 2 years after radiation therapy. Radiation injury may occur in 5-37% of patients treated for intracranial neoplasms.5

Mortality/Morbidity

Radiation necrosis can be fatal. It also can cause problems associated with a mass lesion, such as seizures, focal deficits, increased intracranial pressure, and herniation syndromes.

Continue: http://emedicine.medscape.com/article/1157533-overview

 

RE: Treating Radiation Necrosis of the Brain with Avastin

by bayportblue on Thu Apr 07, 2011 03:44 PM

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Does anyone know how the 13 original patients receiving Avastin treatment for necrosis in 2008 are doing now? I've searched for update info on them, but couldn't find anything.

Thanks.

RE: Treating Radiation Necrosis of the Brain with Avastin

by navion2367t on Mon Jan 23, 2012 11:02 PM

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  I was one of 13 patients in Levins study.  I developed  venous thrombi in my brain.  Levin claims 100%sucess but only 13 patients in the study and nearly 1/3 developed vnous thrombi.  Levin claims 100% sucess ...but is only measuring the FLAIR. This may look impressive to the patients and their concerned family  BUT Avastin further depletes blood to the nearly avasculr white matter.  The radiation damages the blood vessels of the white matter.  I believe Avastin could promote future necrosis.  WHEN RESEARCHERS CLAIM SUCCESS WITH AVASTIN..  ASK IF THEY ARE CLAIMING SUCCESS BASED ON AN IMPROVEMENT OF THE mri.  If they say yes, question if the avastin is merely stopping the image of opaque dye leakingThe FLAIR may be arrested while further damage is being done

RE: Treating Radiation Necrosis of the Brain with Avastin

by Gdpawel on Wed Jan 25, 2012 01:15 AM

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The mechanism for cerebral radiation necrosis appears to be a result of radiation damage to vascular endothelial cells, causing endothelial cell proliferation, telangiectatic vessels and fibrinoid necrosis with accompanying perivascular exudation and edema.

Previous research findings suggest that hypoxia and its subsequent induction of vascular endothelial growth factor (VEGF), may be the primary events causing neovascularization in cerebral radiation necrosis.

Avastin blocks VEGF and causes existing microcapillaries to die. This is what is measured with the AngioRx assay, death of existing endothelial cells of microcapillaries, and associated cells. Microcapillary blood vessels run throughout the brain in close proximity to brain cells.

Some clinical work on Avastin suggests that there could be several possible mechanisms for Avastin, including potentially decreasing the oncotic pressure within the center of a necrotic tumor, which can limit the ability of the drug it is given with to be delivered into the tumor.

The oncotic pressure (or colloid osmotic pressure) is a form of osmotic pressure exerted by proteins in blood plasma that usually tends to pull water into the circulatory system. Because "large" plasma proteins cannot easily cross through the capillary walls, their effect on the osmotic pressure of the capillary interiors will, to some extent, balance out the tendency for fluid to leak out of the capillaries (oncotic pressure tends to pull fluid into the capillaries).

A drop in vascular permeability induces trans-vascular gradients in oncotic and hydrostatic pressure iin blood vessels. The induced hydrostatic pressure gradient improves the penetration of large molecules (Avastin is a large molecule drug) into vessels.

It remains unclear whether Avastin is effecting a benefit on the vasculature or reactive vascularization in response to the hypoxic environment. The resolution of enhancement is primarily from removal of vascular endothelial growth factor-induced reactive vascularization, resulting in improvement of cerebral edema and neurocognitive functions.

RE: Treating Radiation Necrosis of the Brain with Avastin

by navion2367t on Mon Feb 20, 2012 07:11 PM

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On Jan 23, 2012 11:02 PM navion2367t wrote:

  I was one of 13 patients in Levins study.  I developed  venous thrombi in my brain.  Levin claims 100%sucess but only 13 patients in the study and nearly 1/3 developed vnous thrombi.  Levin claims 100% sucess ...but is only measuring the FLAIR. This may look impressive to the patients and their concerned family  BUT Avastin further depletes blood to the nearly avasculr white matter.  The radiation damages the blood vessels of the white matter.  I believe Avastin could promote future necrosis.  WHEN RESEARCHERS CLAIM SUCCESS WITH AVASTIN..  ASK IF THEY ARE CLAIMING SUCCESS BASED ON AN IMPROVEMENT OF THE mri.  If they say yes, question if the avastin is merely stopping the image of opaque dye leakingThe FLAIR may be arrested while further damage is being done

I appreciated your explanation of the FLAIR. My concern is the further depletion of oxygenated blood getting to the white matter. many of The neurons especially are on the threshold of living or dying. Tha Avastin could put them over the threshold and die. I feel my flares worsened as a result of the decrease in oxygenated blood. I reggret taking the drug. I am also concerned that the avastin could cause a diffuse larger area of necrosis. especially in 1/2 brain or whole brain therapy. Seems like the success with avastin is based on a short term decrease in the FLAIR My flares seem to have reduced slightly. Less frequency and shorter and milder. In my case sucess is in the quality of life. Could the avastin be administered with anticoagulation? What food or drugs should i avoid to decrease flairs? I was told by a neurologist at MD Anderson that flares from radionecrosis often decrease or burn out with time. My damage is the occiptal lobe and my blind spots are stable. Thank you

RE: Treating Radiation Necrosis of the Brain with Avastin

by Gdpawel on Sat Jun 09, 2012 02:33 PM

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VEGF was originally known as VPF (vascular permeability factor), by the scientist who developed Avastin (Napoleon Ferrara, PhD). He showed that anti-angiogenic factors actually "pruned" the blood supply and returned normal flow. The short-term control of vasculature is followed by revascularizaton.

Revascularization is what's needed with radiation-induced necrosis. Revascularization is what HBOT does to radiation-induced necrosis. It is revascularization that Avastin helps with in radiation-induced necrosis. The radiation damages the blood vessels of the white matter. Avastin is helping to revascularize them.

RE: Treating Radiation Necrosis of the Brain with Avastin

by navion2367t on Tue Jun 12, 2012 02:36 PM

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How does avastin aid in revascularization? I understand the blockage of permeability as explained by the mechanism of avastin in the previous thread. I [as well as many other trial patients] experienced decreased vascularization with venous thrombi. It was not until the avastin was discontinued and anticoagulation with warfarin that revascularization occured. Now scans have shown that my clots have disappeared. Many others have experienced the exacerbation of side effects. Maybe Avastin should be administered in conjunction with an anticoagulant. My experience with avastin was negative. There is a scholarly article in one of the oncology journals titled "Exacerbation of effects..." sorry I don"t have the link. I am afraid of the damage Avastin could cause.I do believe It stops the FLARE but for how long? and at what cost? Any recommendation for diet or meds to promote healing and minimize the Flare? I feel my FLARES are decreasing and I have a positive hope. Any help or comments appreciated.. Thank you

RE: Treating Radiation Necrosis of the Brain with Avastin

by Gdpawel on Tue Jun 12, 2012 07:33 PM

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Navion

Your postings have kept me active about the research on this. A couple of neurosurgeons I know are also looking into this. I relayed your information to them. I remember Dr. Levin previously saying that they are not absolutely sure what is causing the positive effects against the radiation necrosis. He presumed it was related to the release of cytokines like VEGF, since Avastin is very specific and only reduces VEGF levels. He thought aberrant production of VEGF was involved with radiation necrosis of the brain, and the fact that even short treatment with Avastin seemed to turn off the cycle or radiation damage further confirming the central role of VEGF in the process.

However, Dr. Robert Nagourney blogged last week about VEGF being originally known as VPF (vascular permeability factor) before they settled on VEGF (vascular endothelial growth factor). It would explain the minimal single-agent activity of Avastin, yet profound combinatorial effects of Avastin with other cytotoxic drugs. The short-term control of vasculature followed by revascularization. Cells deprived of oxygen and nutrients devolved into more stem cell-like phenotypes. Therapies based on an incomplete understanding of angiogenesis might, in the opinion of the Avastin developer, be adding to the problem.

Dr. Larry Weisenthal actually had developed a biomarker for Avastin (and other anti-angiogenesis drugs). When you culture endothelial cells (either pure cultures of endothelial cells or endothelial cells associated with fresh human tumor microclusters) with Avastin, all of the VEGF gets pulled out of the culture medium and the endothelial cells undergo what is called: massive calcium accumulation death. Cytotoxic anti-cancer drugs antagonize the ability of Avastin to kill endothelia cells through this specific cell death mechanism.

Single-agent Avastin has shown to revascularize cancer cells (regrowth or rebound). Single agent Avastin actually supports endothelial cell growth in cell culture. When you get rid of VEGF with Avastin, the body cranks out other types of blood vessel growth (survival) factors (revascularization). Or more scientifically: removal of antiangiogenic effect leads to rebound increase in proangiogenic signaling.

There is so much to learn about this phenomenon but at least there is a tool to measure this in cell function analysis.

Greg

RE: Treating Radiation Necrosis of the Brain with Avastin

by navion2367t on Thu Jun 14, 2012 01:40 PM

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On Jun 12, 2012 7:33 PM Gdpawel wrote:

Navion

Your postings have kept me active about the research on this. A couple of neurosurgeons I know are also looking into this. I relayed your information to them. I remember Dr. Levin previously saying that they are not absolutely sure what is causing the positive effects against the radiation necrosis. He presumed it was related to the release of cytokines like VEGF, since Avastin is very specific and only reduces VEGF levels. He thought aberrant production of VEGF was involved with radiation necrosis of the brain, and the fact that even short treatment with Avastin seemed to turn off the cycle or radiation damage further confirming the central role of VEGF in the process.

However, Dr. Robert Nagourney blogged last week about VEGF being originally known as VPF (vascular permeability factor) before they settled on VEGF (vascular endothelial growth factor). It would explain the minimal single-agent activity of Avastin, yet profound combinatorial effects of Avastin with other cytotoxic drugs. The short-term control of vasculature followed by revascularization. Cells deprived of oxygen and nutrients devolved into more stem cell-like phenotypes. Therapies based on an incomplete understanding of angiogenesis might, in the opinion of the Avastin developer, be adding to the problem.

Dr. Larry Weisenthal actually had developed a biomarker for Avastin (and other anti-angiogenesis drugs). When you culture endothelial cells (either pure cultures of endothelial cells or endothelial cells associated with fresh human tumor microclusters) with Avastin, all of the VEGF gets pulled out of the culture medium and the endothelial cells undergo what is called: massive calcium accumulation death. Cytotoxic anti-cancer drugs antagonize the ability of Avastin to kill endothelia cells through this specific cell death mechanism.

Single-agent Avastin has shown to revascularize cancer cells (regrowth or rebound). Single agent Avastin actually supports endothelial cell growth in cell culture. When you get rid of VEGF with Avastin, the body cranks out other types of blood vessel growth (survival) factors (revascularization). Or more scientifically: removal of antiangiogenic effect leads to rebound increase in proangiogenic signaling.

There is so much to learn about this phenomenon but at least there is a tool to measure this in cell function analysis.

Greg

  amazing. A complex picture needing alot more research.  What is your opinion on HBOT? I always questioned it .  Seems those that promote it sell the chambers or services.  Any suggestions on nutrition or pharmacology.  Thanks for your time   navion

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