Guidelines for the Management of Brain Mets

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Joe

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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.

The studies performed by Dr. Roy Patchell, et al, 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.

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Whole Brain Radiation Increases Risk Of Learning And Memory Problems In Cancer Patients With Brain Metastases

Cancer patients who receive stereotactic radiosurgery (SRS) and whole brain radiation therapy (WBRT) for the treatment of metastatic brain tumors have more than twice the risk of developing learning and memory problems than those treated with SRS alone, according to new research from The University of Texas M. D. Anderson Cancer Center.

The findings of the phase III randomized trial were presented at today's 50th annual meeting of the American Society for Therapeutic Radiology and Oncology.

Led by Eric L. Chang, M.D., associate professor in the Department of Radiation Oncology at M. D. Anderson, the study offers greater context to the ongoing debate among oncologists about how best to manage the treatment of cancer patients with one to three brain metastases.

The American Cancer Society estimates approximately 170,000 cancer patients will experience metastases to the brain from common primary cancers such as breast, colorectal, kidney and lung in 2008. More than 80,000 of those patients will have between one and three brain metastases.

Over the last decade, SRS, which uses high-doses of targeted x-rays, has gained acceptance as an initial treatment for tumors that have spread to the brain. SRS is also commonly used in combination with WBRT, radiation of the entire brain, to treat tumors that are visible and those that may not be detected by diagnostic imaging.

"Determining how to optimize outcomes with the smallest cost to the quality of life is a treatment decision every radiation oncologist faces," said Chang. "While both approaches are in practice and both are equally acceptable, data from this trial suggest that oncologists should offer SRS alone as the upfront, initial therapy for patients with up to three brain metastases."

The seven year study observed 58 patients presenting with one to three newly diagnosed brain metastases who were randomized to receive SRS followed by WBRT or SRS alone. Approximately four months after treatment, 49 percent of patients who received WBRT experienced a decline in learning and memory function compared to 23 percent in those patients who received SRS alone.

An independent data monitoring committee halted the trial after interim results showed the high statistical probability (96.4 percent) that patients randomized to SRS alone would continue to perform better.

M. D. Anderson researchers measured participants' neurocognitive function using a short battery of neuropsychological tests, with the primary endpoint being memory function as tested by the Hopkins Verbal Learning Test Revised. Patient performance that decreased more than a predefined criteria relative to their baseline were considered to exhibit a marked decline.

"This is a case where the risks of learning dysfunction outweigh the benefits of freedom from progression and tip the scales in favor of using SRS alone. Patients are spared from the side effects of whole brain radiation and we are able to preserve their memory and learning function to a higher degree" said Chang. "Here the research suggests patients who receive SRS as their initial treatment and then are monitored closely for any recurrence will fare better."

The study builds on previous research by senior author Christina A. Meyers, Ph.D., M. D. Anderson's chief of the Section Neuropsychology in the Department of Neuro-Oncology, examining neurocognitive function in patients with brain metastases treated with whole-brain radiation. "Unlike past studies comparing the two treatment strategies which did not use sensitive cognitive tests or closely follow patients after being treated with SRS, radiation oncologists in this trial were able to identify new lesions early and treat them with either radiosurgery, surgery, whole brain radiation or less commonly, chemotherapy," Meyers said. "We believe doctors and patients alike will favor this method over upfront whole brain radiation."

M. D. Anderson is a leader in the application of SRS to cancers of the spine and head and neck, as well as research determining the effects toxic cancer treatment, like radiation therapy, has on brain function. Based on these results, future research studies are planned to determine if there are expanded indications of using SRS alone for patients with more than three brain metastases.

In addition to Chang and Meyers, M. D. Anderson researchers contributing to the study include Jeffrey S. Wefel, Ph.D., Department of Neuro-Oncology; Kenneth R. Hess, Ph.D., Division of Quantitative Sciences; Fredrick F. Lang, M.D., Department of Neurosurgery and Pamela K. Allen, Ph.D., David Kornguth, M.D., Anita Mahajan, M.D., Moshe Maor, M.D., Christopher Pelloski, M.D. and Shiao Y. Woo, M.D., all of the Department of Radiation Oncology.

About M. D. Anderson

The University of Texas M. D. Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. M. D. Anderson is one of only 41 Comprehensive Cancer Centers designated by the National Cancer Institute. For four of the past six years, M. D. Anderson has ranked No. 1 in cancer care in "America's Best Hospitals," a survey published annually in U.S. News and World Report.

http://www.mdanderson.org (http://www.mdanderson.org/)

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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/