New Perspectives on Brain Metastasis

[gpawelski]

The initial approach to using radiation postoperatively to treat brain metastases, used to be whole brain radiation, but this was abandoned because of the substantial neurological deficits that resulted, sometimes appearing a considerable time after treatment. Whole brain radiation was routinely administered to patients after craniotomy for excision of a cerebral metastasis in an attempt to destroy any residual cancer cells at the surgical site. However, the deleterious effects of whole brain radiation, such as dementia and other irreversible neurotoxicities, became evident.

This raised the question as to whether elective postoperative whole brain radiation should be administered to patients after excision of a solitary brain metastasis. Current clinical practice, at a number of leading cancer centers, use a more focused radiation field (Radiotherapy) that includes only 2-3cm beyond the periphery of the tumor site. This begins as soon as the surgical incision has healed.

Many metastatic brain lesions are now being treated with stereotactic radiosurgery. In fact, some feel radiosurgery is the treatment of choice for most brain metastases. There are a number of radiation treatments for therapy (Stereotatic, Gamma-Knife, Cyber-Knife, Brachyradiation and IMRT to name a few). These treatments are focal and not diffuse. Unlike surgery, few lesions are inaccessible to radiosurgical treatment because of their location in the brain. Also, their generally small size and relative lack of invasion into adjacent brain tissue make brain metastases ideal candidates for radiosurgery. Multiple lesions may be treated as long as they are small.

The risk of neurotoxicity from whole brain radiation is not insignificant and this approach is not indicated in patients with a solitary brain metastasis. Observation or focal radiation is a better choice in solitary metastasis patients. Whole brain radiation can induce neurological deterioration, dementia or both. Those at increased risk for long-term radiation effects are adults over 50 years of age. However, whole brain radiation therapy has been recognized to cause considerable permanent side effects mainly in patients over 60 years of age. The side effects from whole brain radiation therapy affect up to 90% of patients in this age group. Focal radiation to the local tumor bed has been applied to patients to avoid these complications.

Aggressive treatment like surgical resection and focal radiation to the local tumor bed in patients with limited or no systemic disease can yield long-term survival. In such patients, delayed deleterious side effects of whole brain radiation therapy are particularly tragic. Within 6 months to 2 years patients can develop progressive dementia, ataxia and urinary incontinence, causing severe disability and in some, death. Delayed radiation injuries result in increased tissue pressure from edema, vascular injury leading to infarction, damage to endothelial cells and fibrinoid necrosis of small arteries and arterioles.

Even the studies performed by Dr. Roy Patchell, et al, in the early and late 90's have been recognized incorrectly, sometimes, in the radiation oncology profession. The studies were thought to have been the difference between surgical excision of brain tumor alone vs. surgical excision & whole brain radiation. It was a study of whole brain radiation of a brain tumor alone vs. whole brain radiation & surgical excision. The increased success had been the surgery. And they measured "tumor recurrence", not "long-term survival". Patients experiencing any survival could have been dying from radiation necrosis, starting within two years of whole brain radiation treatment and documented as "complications of cancer" not "complications of treatment". There may have been less "tumor recurrence" but not more "long-term survival".

Patchell's studies convincingly showed there was no survival benefit or prolonged independence in patients who received postoperative whole brain radiation therapy. The efficacy of postoperative radiotherapy after complete surgical resection had not been established. It never mentioned the incidence of dementia, alopecia, nausea, fatigue or any other numerous side effects associated with whole brain radiation. The most interesting part of this study were the patients who lived the longest. Patients in the observation group who avoided neurologic deaths had an improvement in survival, justifying the recommendation that whole brain radiation therapy is not indicated following surgical resection of a solitary brain metastasis.

An editorial to Patchell's studies by Drs. Arlan Pinzer Mintz and J. Gregory Cairncross (JAMA 1998;280:1527-1529) described the morbidity associated with whole brain radiation and emphasized the importance of individualized treatment decisions and quality-of-life outcomes. The morbidity associated with whole brain radiation does not indicate whole brain radiation therapy following surgical resection of a solitary brain metastasis. Patients who avoided the neurologic side effects of whole brain radiation had an improvement in survival. His studies convincingly showed there was no survival benefit or prolonged independence in patients who received postoperative whole brain radiation therapy. There may have been some less tumor recurrence but not more long-term survival.

Had fatigue, memory loss and other adverse effects of whole brain radiation been considered, and had quality of life been measured, it might be less clear that whole brain radiation is the right choice for all patients. These patients do not remain functionally independent longer, nor do they live longer than those that have surgery alone, said researchers in a report in an issue of The Journal of the American Medical Association. Patchell's standard for proving the value (improving overall survival) of whole brain radiation fell short of this criteria.

The UCLA Metastatic Brain Tumor Program treats metastatic disease focally so as to spare normal brain tissue and function. Focal treatment allows retreatment of local and new recurrences (whole brain radiation is once and done, cannot be used again). UCLA is equipped with X-knife and Novalis to treat tumors of all sizes and shapes. For patients with a large number of small brain metastases (more than 5), they offer whole brain radiotherapy.

The results of a study at the University of Pittsburgh School of Medicine reported that treating four or more brain tumors in a single radiosurgery session resulted in improved survival compared to whole brain radiation therapy alone. Patients underwent Gamma-Knife radiosurgery and the results indicate that treating four or more brain tumors with radiosurgery is safe and effective and translates into a survival benefit for patients.

Sometimes, symptoms of brain damage appear many months or years after radiation therapy, a condition called late-delayed radiation damage (radiation necrosis or radiation encephalopathy). Radiation necrosis may result from the death of tumor cells and associated reaction in surrounding normal brain or may result from the necrosis of normal brain tissue surrounding the previously treated metastatic brain tumor. Such reactions tend to occur more frequently in larger lesions (either primary brain tumors or metastatic tumors). Radiation necrosis has been estimated to occur in 20% to 25% of patients treated for these tumors. Some studies say it can develop in at least 40% of patients irradiated for neoplasms following large volume or whole brain radiation and possibly 3% to 9% of patients irradiated focally for brain tumors that developed clinically detectable focal radiation necrosis. In the production of radiation necrosis, the dose and time over which it is given is important, however, the exact amounts that produce such damage cannot be stated.

Late effects of whole brain radiation can include abnormalities of cognition (thinking ability) as well as abnormalities of hormone production. The hypothalamus is the part of the brain that controls pituitary function. The pituitary makes hormones that control production of sex hormones, thyroid hormone, cortisol. Both the pituitary and the hypothalamus will be irradiated if whole brain radiation occurs. Damage to these structures can cause disturbances of personality, libido, thirst, appetite, sleep and other symptoms as well. Psychiatric symptoms can be a prominent part of the clinical picture presented when radiation necrosis occurs.

Again, whole brain radiation is the most damaging of all types of radiation treatments and causes the most severe side effects in the long run to patients. In the past, patients who were candidates for whole brain radiation were selected because they were thought to have limited survival times of less than 1-2 years and other technology did not exist. Today, many physicians question the use of whole brain radiation in most cases as one-session radiosurgery treatment can be repeated for original tumors or used for additional tumors with little or no side effects from radiation to healthy tissues. Increasingly, major studies and research have shown that the benefits of radiosurgery can be as effective as whole brain radiation without the side effects.

And, as reported in MD Anderson's OncoLog, in the past the only treatment for multiple metastases was whole brain radiation, which on its own had little effect on survival. There are now a variety of effective treatment modalities for people who have fewer than four tumors. Dr. Jeffrey Weinberg at the Department of Neurosurgery at MD Anderson has said "with a small, finite number of tumors, it may be better to treat the individual brain tumors themselves rather than the whole brain." Anderson is equipped with Linac Linear Accelerator. The critical idea is to focally treat all tumors.

http://cancerfocus.org/forum/showthread.php?t=526

[karen335]

Very interesting gd. Thank you for sharing...

[ILUMOM]

I am so glad you posted this information. Perfect timing. My mom had chemo and radiation. The primary tumor in her lung shrunk significantly. We were so hopeful. But then, a couple months post end of treatment, she had a MRI and they found 6 mets to her brain. She immediately began WBR. I have been researching WBR and do not like anything I read. She has already had 4 treatments with 10 to go.

This is great information. I am having my mom print it out and take it to her next onc. appt. to discuss.

Thanks.

Liz

[gpawelski]

Radiation-induced necrosis is a serious reaction to radiation treatment. It may result from the death of tumor cells and associated reaction in surrounding normal brain or it may result from the necrosis of normal brain tissue surrounding the previously treated metastatic brain tumor. Such reactions tend to occur more frequently in larger lesions, either primary brain tumors or metastatic tumors.

The diagnosis of radiation-induced necrosis is difficult to confirm. Many patients have a mixture of tumor and radiation necrosis and a biopsy may be necessary to distinguish it. Neither symptoms nor radiographic findings clearly distinguish radiation-induced necrosis from tumor. However, the FDG-PET Scan and T1-SPECT studies are useful in differentiating radiation-induced necrosis from recurrent tumor.

Hyperbaric Oxygen Therapy (HBO) is now a useful therapeutic option for patients with confirmed symptomatic radiation necrosis. Until the new millenium, the only treatment for patients was pentoxifyline or heparin therapy, and it was almost always unsuccessful. I had an appointment to take my wife to Duke University for Hyperbaric Oxygen Therapy for radiaton-induced necrosis, to reverse the effects, but it was too late, she expired before we could even try. I've received a number of emails from radiation necrosis patients who had HBO Therapy, and (the good news is) it works!

The most common condition treated at some Hyperbaric Oxygen Therapy Centers is tissue injury caused by brain radiation therapy for cancer. Wound healing requires oxygen delivery to the injured tissues. Radiation damaged tissue has lost blood supply and is oxygen deprived. Chronic radiation complications result from scarring and narrowing of the blood vessels within the area which has received the treatment. Hyperbaric Oxygen Therapy provides a better healing environment and leads to the growth of new blood vessels in a process called re-vascularization. It also fights infection by direct bacteriocidal effects. Using hyperbaric treatment protocols, "most" patients with chronic radiation injuries can be cured.

Hyperbaric oxygen therapy is administered by delivering 100 percent oxygen at pressures greater than atmospheric (sea level) pressure to a patient in an enclosed chamber. Hyperbaric oxygen acts as a drug, eliciting varying levels of response at different treatment depths, durations and dosages, and has been proven effective as adjunctive therapy for specifically indicated conditions.

Oxygen is a natural gas that is absolutely necessary for life and healing. Purified oxygen is defined as a drug but is the most natural of all drugs. Oxygen under pressure is still the same gas but is more able to penetrate into parts of the body where the arterial flow is hindered, producing ischemia (loss of blood flow) and hypoxia (lack of oxygen). When oxygen under pressure is breathed by a patient in a sealed chamber, it is termed a hyperbaric oxygen treatment (HBOT).

In addition to raising the arterial levels of oxygen 10 to 15 times higher than that produced by normal atmospheric pressure, the pressure exerted within the body can and does exert therapeutic benefits on acute and chronically traumatized and swollen tissus.

If on medicare, the approved course is 2.0 atm (two times above atmospheric pressure) for 90 minutes 20-30 sessions. For hyperbaric oxygen therapy to be covered under the Medicare program in the United States, the physician must be in constant attendance during the entire treatment. This is a professional activity that cannot be delegated in that it requires independent medical judgment by the physician. The physician must be present, carefully monitoring the patient during the hyperbaric oxygen therapy session and be immediately available should a complication occur. This requirement applies in all settings and no payment will be made by Medicare unless the physician is in constant attendance during the procedure.

Who Should Avoid This Therapy?

Avoid these treatments if you have a seizure disorder, emphysema, a high fever, or an upper respiratory infection. Do not undergo them if you have a severe fluid build-up in the sinuses, ears, or other body cavities. Forego them if you've had surgery for optic neuritis, or have ever had a collapsed lung. Avoid them, too, if you are taking doxorubicin (Adriamycin), cisplatin (Platinol), disulfiram (Antabuse), or mafenide acetate (Sulfamylon).

Pregnancy was once considered a contraindication for hyperbaric therapy. However, it's now deemed acceptable if a condition will cause long-term damage to the mother or fetus. For example, the treatments are given to pregnant women with carbon monoxide poisoning, which is toxic to both mother and child.

What Side Effects May Occur?

Seizures, a result of the direct effect of oxygen on the brain, are the most serious side effect associated with hyperbaric therapy. The risk is estimated at one in 5,000. Every chamber is equipped with a quick-release mechanism. If a seizure occurs, the oxygen will be immediately released and the seizure will subside.

Minor side effects include popping of the ears similar to that experienced in a descending aircraft. Sinus pain, earache, and headache are other possible side effects. In fact, pain may occur in any body cavity where air can get in but can't get out. For example, dental pain may occur if a filling has trapped air beneath it. In rare cases, pressurized oxygen may rupture an eardrum.

[jcawork]

Hello where did you get this article, you did not site the source.

Thanks Jen

[gpawelski]

Sources:

http://www.hbot4u.com/radiation.html

http://www.hbot.com/frontpage.htm

http://health.ucsd.edu/specialties/hyperbaric

http://www.baromedical.com/about_hyperb ... dicine.asp

http://www.spinalrehab.com.au/Updates/H ... ments%20ca n%20help%20patients%20with%20radiation-induced%20brain%20injuries.htm

[jcawork]

Thanks for the reply. So, you wrote this. Did you publish it?

Jen

[gpawelski]

Yes.

Patients with small-cell lung cancer, it is one of the very few forms of carcinoma for which chemotherapy has some positive effect on survival. Small-cell lung cancer tends to metastasize readily and grow rapidly.

Although patients suffering from advanced cancer are unlikely to be cured, several active agents are available that can prolong their lives. The use of these agents is based on demonstrated benefit in large randomized clinical trials, and the clinical activity of these chemotherapy regimens is initially high, with 60% - 70% of patients responding. However, statistical results of these population-based studies might not apply to an individual.

One of the main problems in providing effective chemotherapy is the situation that every patient is unique. Tumors grow and spread in different ways and their response to treatment depends on these characteristics. The amount of chemotherapy that each patient can tolerate varies considerably from patient to patient. Therapeutic protocols currently in use are limited in their effectiveness because they are based on the results of clinical trials conducted on a general patient population, yet no two patients are alike. Chemosensitivity testing can help to improve the efficacy of cancer therapies on an individual patient basis.

The clinical utility and clinical accuracy of cell culture drug resistance testing (chemosensitivity testing) with "cell-death" endpoints has now been proven beyond doubt. The cost of drugs is enormous. Patients are followed with serial CT scans, MRIs and even Pet Scans, just to see if a tumor is growing or shrinking. Not to mention the hospitalizations for toxicity, bone marrow transfusions, etc. The point is, the cost of ineffective therapy is truly enormous and assay-testing is particularly good at identifying ineffective therapy.

It is true that what happens in the lab is not necessarily what happens in the patient. Individual testing of patients are not scale models of chemothrapy in the patient, anymore than the barometric pressure is a scale model of the weather. But it's always more likely to rain when the barometer is falling than when it is rising, and chemotherapy is more likely to work in the patient when it kills the patient's cancer cells in the laboratory. It's no different than any other medical test in this regard.

You may want to look at virtualtrials.com about a Chemosensitivity assay for malignant brain tumors (brain mets). Chemosensitivity testing might help you find the best option. It's an idea worth looking into.

http://virtualtrials.com/trialdetails.cfm?id=96100226

[karen335]

Thank you for sharing.

[gpawelski]

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/

[gpawelski]

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/oncolo ... -09-2.html

[gpawelski]

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

[gpawelski]

http://cancerfocus.org/forum/showthread.php?t=3781