Whole brain radiation therapy (WRBT) is used for the treatment of multiple 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). It 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 with 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) of 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 which 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-occuring and progressive side effect, that can occur anytime from 6 months to years afterwards.
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 to women who have a good prognosis, because there are fewer long-term side effects. Factors associated with a longer life expectancy include either well-controlled or no metastases outside the brain, and being able to carry out daily routines without help. Since most chemotherapy treatment is halted during WBRT because of increased toxicity, the trade-off of extending WBRT with smaller daily doses is not always beneficial. There is some evidence (but not definitive) that a 5 day course of radiation is as good as a 10 day course.
It has been estimated that about fifty percent of those who receive WBRT have recurrences in the brain within a year. Treatments for brain recurrence include radiosurgery (see explanation below) or chemotherapy. A recent study shows that re-irradiation (doing WBRT a second time) can prolong life on the average of a few months safely in 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.
Use of radiosensitizers (agents that supposedly make brain metastases more responsive to whole brain radiation) is experimental. None have yet been shown to be beneficial.
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 brain metastasis. Because the beams of radiation converge from many different directions on the metastasis itself, the rest of the brain is spared these high doses. The name “radiosurgery” is misleading because it is not surgery. Radiation is given from the outside the head without having to cut into the skull. Unlike WBRT, it targets just the metastases, not the entire brain, which minimizes toxicities. It 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 the name given to 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. Some doctors do go outside the guidelines treating more than three metastases as well as up to four centimeters in size. Severe side effects occur in only 1-2% of those treated. They include seizures, edema, hemorrhage, and radionecrosis (dead tumor tissue). Treatments such as chemotherapy or Herceptin are usually not discontinued. As brain metastases are being picked up earlier and are smaller, radiosurgery is being used much more often than surgery.
Because radiation takes several weeks to shrink tumors, symptoms caused by brain metastases are not alleviated immediately. Regular surgery is therefore sometimes necessary to prevent serious brain damage from the pressure of 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, so sometimes surgery is necessary to biopsy the lesion to determine if it is, in fact, radionecrosis. 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 up to three centimeters. Radiosurgery can also be used after regular surgery or WBRT as a “boost” to prevent brain metastases from recurring.
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. Recently, 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 70% for those not receiving WBRT to 18% 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 and that frequent scanning (every three months) will allow recurrences to be picked up earlier 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, holding off 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 to do 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. Recurrences in the brain without WBRT are believed to be very common and have been estimated in various studies to occur in 70-90% of patients. We await the results of a randomized clinical trial which is ongoing on this question. Until then, all studies are biased by the fact that women with the best prognosis are more likely to receive radiosurgery without WBRT.
For different opinions on this controversy, click on the interviews with Dr. Andrew Seidman and Dr. Kevin Camphausen in the Doctor's Corner and the debate on this issue at the American Sciety of Clinical Oncology Annual Meeting, 2006.
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 really is. Surgery has a very low complication rate, mainly infection, although a hospital stay of several days to a week is required. A longer time may be necessary if there are 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 do surgery.
Some, though not all, systemic therapy is stopped in advance of surgery and while the incision is healing. 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 “boost” to prevent recurrence at the site of surgery.
CHEMOTHERAPY AND SYSTEMIC THERAPY
Chemotherapy has not been extensively studied 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 as brain metastases grow they can disrupt the blood-brain barrier, making it possible for chemotherapeutic drugs to get into the brain. Another problem has been that brain metastases usually occur late in the course of breast cancer when resistance to different chemotherapies is more likely. It has thus been unclear if and when drug resistance plays a role, or if inability of drugs to reach the tumor is more important.
Studies have shown that in some cases brain metastases do shrink in response to chemotherapy, but it is not known if this response actually extends life. Some studies have suggested that Xeloda (capecitabine), high-dose mexthotrexate, the platinum drugs carboplatin and cisplatin, and Adriamycin (doxorubicin) can be effective in shrinking brain metastases.
Hormonal therapies such as tamoxifen, letrozole (Femara) and megestrol acetate (Megace) 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. 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 the estrogen receptor and progesterone receptor, as well as for HER2 overexpression, are more likely to change from positive to negative than vice-versa.
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 mg per day on a variety of schedules. It is usually best to give the whole dose with breakfast or divided between breakfast and lunch.
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 get off steroids suddenly unless it is an emergency. Doses should be tapered gradually.
Anti-convulsants 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 anti-convulsants 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
