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WHOLE BRAIN RADIATION THERAPY
Whole brain radiation therapy (WRBT) is used for the treatment of multiple and larger brain metastases. It is also used for those patients with rapidly progressing metastatic disease outside of the brain and for what is known as "poor performance status" (ability to take care of oneself). WBRT is the most frequently used therapy for breast cancer brain metastases. As its name indicates, radiation is delivered to the entire brain. WBRT has been shown in research studies to extend life and improve the quality of life for those whose brain metastases are causing symptoms. Thirty to forty percent of patients will achieve a complete reversal of symptoms, while seventy-five to eighty-five percent of patients will experience some improvement or stabilization of their symptoms, especially headache and seizure. Motor loss (problems with walking, coordination, balance, etc.) is less successfully treated.
Short term side effects (lasting 1-2 months) after WBRT can include memory loss, particularly verbal memory (remembering what someone said to you), extreme fatigue, temporary baldness, skin rash, inflammation of the outer ear, and hearing loss. Longer term toxicities that can occur within six months to two years after WBRT include memory loss, confusion, lack of urinary control, and lack of coordination. The most feared long term side effect, dementia, occurs in one to five percent of those treated. However, as women live longer after being treated for brain metastases, incidence of dementia is likely to increase, since dementia is a late-occurring and progressive side effect that can occur anytime from 6 months to years after WBRT. A recent study has shown that taking memantine (Namenda), a drug already approved for Alzheimerâ€™s Disease, may lead to less cognitive loss as a result of WBRT.
With WBRT, radiation is given daily, Monday thru Friday, for ten days to two weeks. Some doctors will spread out the same dose of radiation over a longer period of time for women who have a very good prognosis, because there are fewer long-term side effects. Factors associated with a longer life expectancy (a good prognosis) include either well-controlled metastatic disease or no metastases outside the brain, and being able to carry out daily routines without help. Women with HER2+ disease tend to live longer because metastases in other organs are usually better controlled by HER2-targeted treatments. Since most chemotherapy treatment is halted during WBRT due to increased toxicity, the trade-off of extending WBRT with smaller daily doses is not always beneficial. In the case of Herceptin (trastuzumab) and Tykerb (lapatinib), treatment does not have to be discontinued.
It has been estimated that about fifty percent of those who receive WBRT have recurrences in the brain within a year. Treatments for such brain recurrence include radiosurgery (see explanation below) or chemotherapy. A recent study shows that re-irradiation (doing WBRT a second time) can prolong life an average of a few months safely in a very select group of patients. Important factors to consider for re-irradiation include a good response to WBRT the first time and a longer time to recurrence. Although WBRT has been the mainstay for treatment of brain metastases, there is a recent effort by some oncologists to try to control brain metastases with chemotherapy and/or targeted agents. This approach may be useful for patients who have well-controlled metastatic disease outside the brain and who want to avoid the long term effects of WBRT.
RADIOSURGERY (Gammaknife, Cyberknife, X-Knife or Stereotactic Radiosurgery)
Radiosurgery, also called stereotactic radiosurgery or SRS, is a procedure that aims very high doses of radiation (higher than WBRT) directly at a brain metastasis. Because the beams of radiation converge from many different directions on the metastasis, the rest of the brain is spared these high doses. The term â€śradiosurgeryâ€ť is misleading because the procedure does not involve surgery. Radiation is given from the outside the head without having to cut into the skull. Unlike WBRT, only the metastasis is targeted, not the entire brain, which minimizes toxicities, including dementia. SRS can be used to treat metastases deep within the brain, for example in the brainstem, where regular surgery cannot be done safely. It is considered to be at least as effective as surgical resection, although that has not been proven.
Radiosurgery is delivered by several different technologies, including Gamma Knife, CyberKnife, or XKnife. They are considered to be equally effective. Since radiosurgery is generally not used for more than three metastases at a time or metastases that are larger than approximately 3 centimeters, it is not a substitute for whole brain radiation or surgery. However, more and more patients and their doctors are going outside these guidelines, treating more than three metastases as well as metastases larger than 3 centimeters. Severe side effects occur in only 1-2% of those treated with radiosurgery. These include seizures, edema, hemorrhage, and radionecrosis (dead tumor tissue). During radiosurgery, other treatments do not have to be discontinued. As brain metastases are being found earlier when they are smaller, radiosurgery is being used much more often than surgery. However, because radiosurgery takes several weeks to shrink tumors, symptoms caused by brain metastases are not alleviated immediately. Therefore, regular surgery is sometimes necessary to prevent serious brain damage from the pressure of larger tumor(s) in the confined space of the skull.
Unfortunately, radionecrosis (dead tissue) from radiosurgery can be hard to distinguish from recurring brain metastases. Usually radionecrosis is treated with a corticosteroid, although sometimes surgery is necessary to biopsy the lesion to determine if it is, in fact, radionecrosis, or a recurring metastasis. Radiosurgery can be repeated if new brain metastases appear. Although no direct evidence exists, radiosurgery is thought to be as effective, and safer, than regular surgery for metastases of up to three centimeters. Radiosurgery can also be used after regular surgery or WBRT as a â€śboostâ€ť to prevent brain metastases from recurring in the same location.
One of the most controversial issues in the treatment of brain metastases is whether or not WBRT is necessary after radiosurgery. For more on this, read the next section on whole brain radiation therapy following radiosurgery or surgery.
Whole Brain Radiation Therapy Following Brain Surgery or Radiosurgery (Gamma Knife, CyberKnife, etc.)
Until recently WBRT has been recommended after either surgical removal of a brain metastasis or radiosurgery, in order to reduce the risk of recurrence in the brain in either the same area or different areas of the brain. Recently, however, WBRT following surgery or radiotherapy has become a hotly debated question. Unfortunately, there is no high-quality evidence on this question to help patients decide, except in the case of a single brain metastasis where WBRT following surgery does extend survival. In one study, recurrence rates in the brain were reduced from seventy percent for those not receiving WBRT, to eighteen percent for those who did receive WBRT. However, some radiation oncologists think a better quality of life is maintained if WBRT is withheld if and until there is a recurrence after radiosurgery and that frequent scanning (every three months) will allow recurrences to be picked up early enough to prevent compromising quality of life or length of life. Brain recurrences can be treated repeatedly with radiosurgery as long as the metastases are small, potentially delaying WBRT and its side effects indefinitely.
However, there is no guarantee that brain metastases, if they recur, will be small, even with scanning at three month intervals, and large brain metastases can severely compromise quality of life and length of life. Some doctors advise women with a longer life expectancy to wait until a recurrence of brain metastases to undergo WBRT, putting it off for as long as possible. Other doctors advise just the opposite. They believe women with a longer life expectancy should be treated more aggressively to lower their chances of getting brain recurrences. It is true that WBRT does â€śsterilizeâ€ť the entire brain, making a recurrence much less likely. Recurrences in the brain after initial treatment for brain metastasis, when WBRT is not given, are believed to be very common and have been estimated in various studies to occur in seventy to ninety percent of patients. We await the results of a randomized clinical trial which is ongoing to answer this question. Until then, all non-randomized studies are biased by the fact that women with the best prognosis are more likely to receive radiosurgery without WBRT, while those with the worst prognosis are given WBRT. For different opinions on this controversy, click on the interviews with Dr. Andrew Seidman and Dr. Kevin Camphausen in the Doctor's Corner.
BRAIN SURGERY (CRANIOTOMY)
Brain surgery (a form of neurosurgery known as a craniotomy) entails having a neurosurgeon cut into the brain in order to physically remove the metastasis and a small margin of surrounding tissue. It sounds much scarier than it is. Surgery has a very low complication rate, mainly infection, although a hospital stay of several days to a week is required, even without complications. In recent years, imaging technology has been developed that makes it possible to view the precise location of the metastasis and surrounding tissue which helps avoid damage to areas of the brain that are important for speech, coordination, memory, and other functions.
Brain surgery is used for one or two large metastases that need to be removed immediately because of potential brain damage or when metastases are too big for radiosurgery. Some doctors will surgically remove up to four metastases, depending on their location. Surgery is also needed if the diagnosis of a brain metastasis is not certain, so that a biopsy can be performed on the tissue. About 10% of the time the suspected brain metastasis can be something else like a primary brain tumor, a non-cancerous mass, or an infection. However, in some areas of the brain, such as the brainstem, it is too dangerous to perform surgery.
Some, though not all, systemic therapy is stopped in advance of surgery and while the incision is healing. Targeted therapies such as Herceptin or Tykerb do not have to be discontinued. Whole brain radiation is often given after surgery to prevent brain metastases from recurring in the same location or in new areas. There is definitive evidence that WBRT extends life when there is a single brain metastasis. (See whole brain radiation therapy and stereotactic radiosurgery for discussion of this question). Radiosurgery after surgery can be used as a â€śboostâ€ť to prevent recurrence at the site of surgery.
CHEMOTHERAPY AND SYSTEMIC THERAPY
Chemotherapy has not been extensively studied as treatment for brain metastases in breast cancer. The conventional wisdom has been that chemotherapy drugs are not able to cross the blood brain barrier into the brain. Recently, there has been renewed interest in chemotherapy because evidence is emerging that some breast cancer drugs do cross the blood-brain barrier, and as some brain metastases grow they can disrupt the blood-brain barrier, making it possible for chemotherapeutic drugs to get into the brain. Recently, two breast cancer drugs used in combination, Tykerb (lapatinib) and Xeloda (capecitabine), have been shown to cross the blood-brain barrier, making them good treatments for women with HER2-positive brain metastases following radiation. Some doctors are treating with these drugs before using radiation in an attempt to control brain metastases for as long as possible without radiation. Other doctors are using these drugs after radiation to prevent recurrences in the brain.
However, it is extremely important not to substitute these two drugs for other HER2-targeted treatments such as Herceptin (trastuzumab), Kadcyla (T-DM1), or Perjeta (pertuzumab), if these treatments are keeping metastatic disease outside the brain in check. Studies have found these drugs to be more effective than the Tykerb-Xeloda combination in treating disease outside the brain.
Some studies show brain metastases shrinking in response to some of the older chemotherapeutic drugs, such as carboplatin and cisplatin, Taxol (paclitaxel) and Adriamycin (doxorubicin). Some of these older drugs are being reformulated to penetrate the blood-brain barrier (see clinical trials). The development of more brain permeable drugs may result in a shift away from whole brain radiation therapy as first-line treatment for brain metastases to up front drug therapy, especially for patients whose extra-cranial disease is well controlled.
Hormonal therapies such as tamoxifen, the aromatase inhibitors Femara (letrozole), Arimidex (anastrazole) and Aromasin (exemestane), and Megace (megestrol acetate) have been shown to be effective in treating breast cancer brain metastases in some women with ER-positive tumors. However, the majority of women with brain metastases have tumors that are estrogen receptor-negative. Those women whose tumors have been tested as estrogen receptor-positive may have already built up resistance to the existing hormonal therapies before developing brain metastases. It is assumed that hormonal treatments will not work in these women. An important area of research is how often the hormone status of a brain metastasis can be different from the hormonal status of the primary tumor. There is preliminary evidence that in metastases, including brain metastases, markers for estrogen receptor and progesterone receptor disease, as well as HER2-negative disease change in about ten percent of cases.
Corticosteroids or steroids are usually the first therapy administered to many women with brain metastases. However, those whose brain metastases are found by imaging and who do not yet have any symptoms, can often avoid steroid use completely. Dexamethasone (Decadron) is the steroid of choice. It is given in pill form or as an injection to reduce edema (swelling in the brain). It can start working within several hours. The usual starting dose is 4 to 16 milligrams per day on a variety of schedules. It is usually best to give the whole dose with breakfast or divided between breakfast and lunch so as to disrupt sleep as little as possible. Steroids may be continued for weeks or even longer. However, the longer they are used, the worse the side effects become. Side effects from steroids can be very serious, but the brain swelling they counteract can be even more serious and possibly life-threatening. Common side effects from long-term use include weight gain, muscle weakness (myopathy), insomnia, moodiness, acne, osteoporosis, hypertension, swelling of the face, cataracts, osteonecrosis (death of bone cells), impaired wound healing, muscle weakness, pneumonia, and diabetes. Physicians can check blood glucose (for diabetes) and prescribe medicine to prevent pneumonia or gastritis if long-term administration of steroids is needed.
The steroid dose can often be tapered as other therapy kicks in. The dose should be as low as possible. A common short-term complication is steroid myopathy (muscle weakness) which can be mistaken for progression of brain metastases, triggering the use of more steroids which only worsens the myopathy. Physical therapy can be helpful for patients with myopathy. Under study is the use of a lower dose of steroids. Do not stop taking steroids suddenly unless it is an emergency. Doses should be tapered gradually.
Anticonvulsants are used for patients who have had seizures. Studies show that taking them before having had seizures does not prevent seizures in the future. Newer anticonvulsants have fewer side effects than the older ones. They make patients less sleepy and have less effect on cognition. However, because they come in pill form, very sick patients may not be able to take them and will require the older medication which is given intravenously.
Read more on chemotherapy and hormonal therapy in Selected Bibliography.
Read more on conventional brain surgery, whole brain radiation, and stereotactic radiosurgery in Selected Bibliography