can you really die from WBR?

[gdpawel]

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 (which measures cellular metabolism) and T1-SPECT studies are useful in differentiating radiation-induced necrosis from recurrent tumor.

Hyperbaric Oxygen Therapy (HBOT) is 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. Both Duke University for Hyperbaric Oxygen Therapy and the University of Cincinnati previously had clinical trials on this science.

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.

Sources:
http://www.hbot4u.com/radiation.html
http://www.hbot.com/frontpage.htm
http://health.ucsd.edu/specialties/hyperbaric
http://www.baromedical.com/about_hyp...c_medicine.asp
http://www.spinalrehab.com.au/Updates/Hyperbaric%20Oxygen%20treatments%20ca n%20help%20patients%20with%20radiation-induced%20brain%20injuries.htm

[nvsavin]

Hi everyone,
I just posted this, but it got lost so I'm writing it again.
I wrote a couple days ago about my mother who started experiencing confusion, incontinence, and who has difficulty walking. She is NED throughout her body since 2002. She had six brain lesions treated in early 2005 with WBR and gamma knife. They are all considered gone. Now at the hospital because of these new symptoms, no doctor could figure out what was going on. Finally, her neurosurgeon, who performed the gamma knife and who has been following her MRIs, took a "closer look" at the most recent MRI and said that he sees some "signals" which indicate permanent radiation damage. He said this is irreversible and that unfortunately the condition generally worsens and the patient dies within 6-9 months. My father is the one who spoke with him and I think he was probably too stunned to even think of any follow up questions. I can't believe this. Is this really true? Will she really die from WBR or is there hope? Could she continue as is for quite some time? Haven't so many of you had WBR and are doing fine? Any input or experience or knowledge is appreciated.

[al from Canada]

I have often wondered if Linda's untimely demise was from the rads or the cancer........jury's out on that one.

Al

[Barbara H.]

Find out if this radiation effect is necrosis. Some patients with necrosis have tried pressurized oxygen therapy with very limited success. I would further question her radiologist and maybe get a second opinion. Sometimes necrosis can continue to worsen and other times it can resolve. The brain is plastic even at an older age, and other parts of the brain can take over some of the functions she has lost. She would probably need physical therapy. This is an unfortunate side effect for WBR. Most patients who had WBR in the past did not survive this long.
I would not comepletely give up up until you have checked out all the possibilities.
Good luck!!
Barbara H.

[pattyz]

Dear "nvsavin",

This has always been the worst outcome after WBR. If the brain becomes permantly damaged, the outlook is not good.

This happened to Mr. gdpawel's wife. He has made it his mission over the past years to make people aware of what can happen... and the possible alternatives to treat the brain.

Your mom's neurosurgeon should speak to you and your mom and family frankly about what may lie ahead.

I continue to refuse WBR these past four yrs for my brain mets, yet even with the focalized rads I have had, there can be permanent damage done.

I am so very sorry if this is indeed the case for your mom.
You are good to be so supportive in these difficult times.

Has anyone talked to you or your family about hospice yet? They can be very helpful where available, from all I've heard.

Keeping you in thought and prayer,
pattyz

[gdpawel]

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.

http://neurosurgery.ucla.edu/Program...tic_Intro.html

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://www2.mdanderson.org/depts/onc...an/1-05-1.html

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.

http://newsbureau.upmc.com/UPCI/GammaKnifeStudy2005.htm

An editorial to Patchell's studies in the '90's 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.

Of course, surgical excision is the gold standard of treatment for surgically accessible lesions. Many studies in the medical literature clearly demonstrate the efficacy and superiority of surgical resection followed by focal radiation over radiation therapy as a first-line treatment for metastatic brain tumors. Doctors at UCLA and MD Anderson say that even for patients with up to four metastases, surgical excision of all intracranial disease has been shown to provide the long survival with good quality of life, and has the same prognosis as someone who has only one brain tumor.

[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

Visualizing the effects of Avastin (bevacizumab)

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

[Jackie07]

My three brain tumors inside of the right lateral ventricle had increased in their sizes last fall according to the MRI. I think the three doses of Gamma-knife radiosurgery did not harm my brain too much because the foci were on the ventricle which is filled with cerebral-spinal fluid and the radiation side effect probably was diffused somewhat by the fluid.

However, I continue to lose jobs after jobs and finally applied for disability. [I think anyone who's seen the MRI of my brain would automatically consider me very disabled. The problem is that I was the only one that wasn't aware of it! ]

[gdpawel]

Jackie

I've just discovered this recently and I'm going to look into it further, since treatment for radiation-induced necrosis was a subject dear to me. I think Avastin and radionecrosis may dovetail with some current work in cell function analysis.

Your comment about not being aware of it. I wonder if my wife thought the same also? She had this way about her that made it seem that way.

[Mary Anne in TX]

Jackie, I'm not sure what is disabled about you????
Surely not your sense of humor. You are amazing to me.
You sure do bless me! ma

[loveher]

i wonder the same thing about my mom. i wonder if it was the actual tumors or the wbr. all i know is right after the second wbr her condition declined very rapidly

[flynny]

Thanks for all this great information.

My mother also had WBR in August 2007. She had two prior SRS tx (May '07 and July '07) and then it changed to leptomeningeal cancer. Due to the fact that she had Multiple Sclerosis they did a 14 day tx of WBR. We knew the risks and seeing my father died at 31 (almost 32) of mets from Melanoma he too had WBR and didn't live much longer after that. My mother's memory and the way she articulated herself wasn't perfect, but her sense of humor was till there and how much she wanted to live was very apparent. Most patients that have leptomeningeal only live up to 6 months at best, but mother lived over 10 months. They tried a few "experimental" drugs - era C (I think) and Alimta. It helped some and then it stopped working.

I think about myself and I hate that I know so much about what she went through and then with my own diagnosis I just pray that I don't follow suite.

[gdpawel]

flynny

My wife went another 15 months with leptomeningeal carcinomatous (cancer cells getting into the thin sheets [meningies] of body tissue that surround and protect the brain and spine) after chemotherapy (methotrexate) injected into the spinal fluid (via Ommya Reservoir). Without treatment, the median survival of patients is 4-6 weeks and intrathecal chemotherapy increases the median survival to 3-6 months.

Another alternative to Methotrexate is Cytarabine (cytosine arabinoside) or Ara-C. There had been some clinical trials using Temodar (temozolomide) instead of Methotrexate, Ara-C or combination gemcitabine (Gemzar) plus Thiotepa in treating patients with LC from a solid tumor. There have been clinical trials with small molecule-targeted Iressa.

What may be another alternative is high doses of two small molecule drugs, Tarceva (erlotnib) and Iressa (gefitinib), given together. It might cross the blood-brain barrier and some patients may get a long-lived remission with these drugs. High-dose tamoxifen could then be given continuously as a potentiator and an anti-angiogenic effect. This suggestion comes from cell function analysis.

[flynny]

gdpawel,

My mother also had the intrathecal chemo. I believe she also used the Temodar. My memory is a little foggy at the moment. There was a definite benefit with the intrathecal chemo using the Ara-C and Alimta (the experimental drug used primarily used for lung cancers).

If we could just find a drug that would work through the BBB!!

Thanks again for all your information

[joyce lutz]

gdpawl - So at this point in time would you think a treatment of Temodar and Avastin for brain mets and liver mets (after wbr) would be a good route to follow? I wish none of us had to be here, but alas we are! My best to you.
Joyce

[gdpawel]

Joyce

The Patchell studies have never shown any value (improving overall survial) of whole brain radiation. The morbidity associated with whole brain radiation does not justify its use. Particularly with today's small molecule intervention.

The idea that systemic therapies can be as effective as PCI, WBR or even stereotactic radiosurgy has been looked upon for a number of years now, with agents like Temodar and EGFR inhibitors against brain metastases.

Accumulating evidence suggests that systemic chemotherapy may play an important role. There have been clinical observations of frequent brain metastasis responses with systemic chemotherapy.

With a brain metastasis indicated or not, small molecule intervention can be beneficial by dissolving through the capillary cell membranes and absorbed into the brain. Systemic brain chemotherapy can also treat coexistent systemic disease.

A drug like Temodar is small molecule. Empirically, it has been shown to cross the BBB to affect cell death in circulating tumor cells. Exciting results have come from studies of multitargeted tyrosine kinase inhibitors, small molecules that act on multiple receptors in the cancerous cells, like Tykerb and Sutent.

Iressa and Tarceva have been shown to cross the blood-brain barrier and some patients may get a long-lived remission with these drugs. High-dose tamoxifen can be given as a potentiator and an anti-angiogenic effect.

But if one is already getting whole brain radiation, perhaps Avastin can be given in low doses before radiation or intermittently afterword to reduce VEGF levels and protect the brain from abnormally high levels of the protein.

I never thought whole brain radiation was necessary or even effective when my wife received it and after many years of researching it, I still don't. There are a lot of better alternatives.

[joyce lutz]

Unfortunately, my daughter was given wbr w/o any time to consider other alternatives! So now we are looking to further decrease the tumor size and give her good quality of life at the same time by giving her the best drug to accomplish that. And as I previously stated that is Temador and Avastin. She is also trying to get off decadron.

I'm not always convinced that the dr's. KNOW what is the best drug. They use trial and error. I know one thing, if I have any say in the matter that she will not have wbr in the future. (her radiologist said she might have that if tumors began to grow after 6 months) They told her that she had too many tumors (7) to do gamma knife and now after reading on this and other message boards I don't believe that was the case and will encourage her to go for a 2nd opinion. My best to you
Joyce