Treating Brain Mets

[Jackie07]

Thought I would attach the ABTA (American brain Tumor Association) brochure on metastatic brain tumor here. That particular brochure was dated 2004, a bit old, but gives a good overview on the topic. And the link has a date of 1/2009.

http://www.abta.org/siteFiles/SitePa...42670EC586.pdf

[gdpawel]

Reprinted from MDA OncoLog

Today, brain metastasis, even multiple metastases, is not an automatic death sentence, and its treatment, while still not to be taken lightly, has become safer, minimally invasive, and more effective than it was not many years ago.

"Multiple tumors in the brain do not have as bad a prognosis as one would think," said Jeffry Weinberg, M.D., assistant professor in the Department of Neurosurgery at The University of Texas M.D. Anderson Cancer Center. A study showed that a patient who has two or three lesions that can be removed actually has the same prognosis as someone who has only one brain tumor.

In the past, the only treatment for multiple metastases was whole brain radiation (WBR), which on its own had little effect on survival. While that is still the standard treatment for four or more brain tumors, there are now a variety of effective treatment modalities for people who have fewer than four tumors.

"With a small, finite number of tumors, it may be better to treat the individual brain tumors themselves rather than the whole brain when possible," Dr. Weinberg stated.

He explained that while whole brain radiation (WBR) has benefits such as treating micrometastases (individual cells that can eventually grow into brain tumors), today it is most often used in conjunction with other treatment modalities, such as surgery and radiosurgery.

"Surgery and radiosurgery allow treatment to be directed at the tumor itself," said Dr. Weinberg. "Because of technological advancements, both are now minimally invasive and have lower risks." At M.D. Anderson, multidisciplinary teams that include radiation oncologists and neurosurgeons design treatment plans tailored to the patient's individual situation.

Imaging Techniques Improve Precision

Computer-assisted surgery has made brain surgery faster, safer and more precise. Magnetic resonance imaging allows neurosurgeons to see beneath the skull before the incision is made and locate the tumor exactly. Ultrasound provides real-time imaging of the brain as the surgery is being performed. Because of the precision, surgeons can make smaller bone openings, approach the tumor more precisely, and more completely resect it.

Advanced operative and imaging technology also allows doctors to map and speech, motor and sensory areas of the brain before surgery and thereby preserve or avoid them during surgery. Furthermore, they can perform the surgery on patients who are awake if need be in order to better identify speech control areas of the brain.

"We've really perfected brain surgery to be relatively safe, even for many lesions that previously were considered unresectable," said Frederick Lang, M.D., associate professor in the Department of Neurosurgery.

While surgery now involves fewer risks and is less invasive, radiosurgery avoids the risks of a craniotomy altogether and requires only local anesthesia. This highly localized treatment is a same-day procedure.

At M.D. Anderson, radiosurgery is delivered by a team of neurosurgeons and radiation oncologists. Linear accelarators (Linac) are used in conjunction with stereotaxis that allows doctors to align exactly the correct angle and distance for directing radiation beams. The multiple low-dose beams converge from various angles, delivering to the tumor a very high dose of radiation. While radiosurgery does not actually remove the tumor, it damages the DNA so badly that the tumor is eradicated.

Weighing the Options

There is an ongoing debate about whether surgery or radiosurgery is the better option for treating brain metastasis and under what circumstances. In actuality, each has its own advantages and disadvantages.

Dr. Lang summarized the pros and cons: "The advantage of removing a tumor surgically is that it is taken out in one swoop and people tend to recover faster from swelling and neurocompromise. The disadvantage is that it requires invasive surgery."

"Radiosurgery is lot easier and avoids many of the problems of invasive surgery, but it does not eliminate the tumor immediately. It sometimes takes three or four months to shrink, causing the patient to deal with the tumor's symptoms longer and to possibly need steroids for a longer period. The follow-up can be more complicated with radiosurgery than with surgery because of the risk of destroying surrounding tissue."

Thanks to treatment advances, both surgery and radiosurgery are now minimally invasive and relatively safe

Radiosurgery is optimal for very small lesions, particularly those located deep in the brain, which are hard to find, much less excise surgically. It can't, however, be used on tumors larger than three centimeters because too large an area of brain tissue surrounding the tumor may be exposed to radiation.

Tumors that are between one and three centimeters can be treated with either approach. it's not yet clear which approach is optimal, but M.D. Anderson is working on finding out.

For people with more than one metastasis, M.D. Anderson physicians tend to take a more aggressive approach than many other treatment centers. Most patients with two or three tumors receive a combined surgery/radiosurgery treatment tailored to their particular situation.

"For example, we might take out one large lesion and give radiosurgery to two small ones," said Dr. Lang. "Tumors that can be removed are, and those that cannot are treated with radiosurgery. The critical idea is to focally treat all of the tumors, because if you lease one or two behind untreated, the patient is not going to do as well.

Today, brain metastasis can be regarded as another round in a person's fight against cancer, rather than the end of the battle. "There's a completely different perspective about it now," Dr. Lang said. "The chance of living through treatment fro brain metastasis today is very high. With these newer aggressive treatments and better outcomes, the focus can remain on trying to cure the underlying cause of metastatic disease."

You could also look into information from noted brain surgeon Dr. Christopher Duma

http://www.cduma.com/

[gdpawel]

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

http://www2.mdanderson.org/depts/onc...ay/5-09-2.html

Visualizing the effects of Avastin (bevacizumab)

http://www2.mdanderson.org/depts/onc...5-may/pop.html

[gdpawel]

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.

Scientists from MD Anderson (and other institutions) have found out that they could treat radiation-induced necrosis of the brain with Avastin. Recent studies have shown that Avastin may be able to stop radiation necrosis of the brain and allow some of the damage to be reversed.

I can see where radiation can allow the lining of the brain to become permeable to VEGF, and VEGF can induce the brain cells to make more VEGF, and self-propagating brain damage ensues. And Avastin can disable VEGF.

The MD Anderson research team postulates 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. And the ultimate question is "is that all that's going on?"

With Hyperbaric Oxygen Therapy (HBOT), wound healing requires oxygen delivery to the injured tissues. Radiation damaged tissue has lost blood supply and is oxygen deprived. HBOT provides a better healing environment and leads to the growth of new blood vessels in a process called re-vascularization. HBOT acts as a drug when 100 percent oxygen is delivered at pressures greater than atmospheric (sea level) pressure to a patient in an enclosed chamber.

If this is the case, the judicious application of Avastin can normalize the vasculature by pruning the immature vessels and fortifying the remaining ones. Normalized vasculature is less tortuous and the vessels are more uniformally covered by pericytes (in capillaries which regulate the blood-brain barrier) and basement membrane (thin sheet of fibers which lines the interior surface of blood vessels).

Source: Cell Function Analysis