Current treatments for brain metastases

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Whole-brain radiation has until recently been the standard treatment for breast cancer brain metastases. But as better treatments for extra-cranial disease (metastases outside the brain) have emerged, concern about the short- and long-term toxicities of whole-brain radiation has sharply reduced its use. For many people with brain metastases, stereotactic (focused) radiation (SRS) has been equally effective and much less toxic and time consuming (see RADIOSURGERY). However, when brain metastases are too numerous or too large to be treated by radiosurgery whole-brain radiation is required.

As its name indicates, whole-brain radiation (WBRT) delivers a moderate dose of radiation to the entire brain. Because it treats the whole brain, regrowth or new brain metastases are less likely to recur than with radiosurgery or surgery. WBRT also can improve the quality of life for those whose brain metastases are causing symptoms. With WBRT, 30% to 40% of patients will achieve complete reversal of symptoms, with 70% experiencing some improvement or stabilization of their symptoms, especially headaches or seizures. Motor loss (walking, coordination and balance) are less successfully treated with WBRT. The short-term side effects of WBRT, which last about a month or two, include memory loss, 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 include memory loss, confusion, loss of urinary control and lack of coordination. Dementia is a late occurring and progressive process that usually takes five years or so to appear. A recent study has shown that taking the drug memantine (Namenda), approved for Alzheimer's disease, during WBRT offers some protection against cognitive loss, although it is unknown for how long and by how much.

Although practice varies, WBRT is generally used for those with more than three or four brain metastases or brain metastases that are larger than 3 to 3.5 centimeters, although there are radiation oncologists wholl will treat more numerous and larger brain metastases with SRS. There are clinical trials treating from 5 to 20 brain metastases with SRS instead of WBRT. WBRT can be reserved for use after several recurrences of brain metastases after SRS. Recurrences after WBRT can be treated with SRS and other systemic treatments such as chemotherapy. Repeating WBRT a second time can extend life for a few months for a select group of patients, particularly those who have had good response to WBRT the first time and a longer time to recurrence.

For a person with very small but numerous brain metastases, drugs may be used to delay WBRT as long as possible

 RADIOSURGERY (Gammaknife, Cyberknife, X-Knife or Stereotactic Radiosurgery)

Stererotactic radiosurgery, sometimes called radiosurgery, or SRS, is a procedure that aims very high doses of radiation directly at brain metastases. The biggest advantage of SRS is that the rest of the brain is spared radiation exposure. This greatly minimizes both short-term and long-term toxicities that may occur with whole-brain radiation, such as confusion, memory loss, dementia, fatigue, etc. SRS can be delivered in one or several doses, whereas whole-brain radiation is usually given over a period of 10 days.

The term radiosurgery is misleading because the procedure does not actually involve what most people think of as surgery. Radiation is delivered from outside of the head without cutting into the brain. SRS can be used in areas like the brainstem that are unsafe for surgery. Another advantage is that SRS can be repeated many times on either local or distant recurrences in the brain.

Clinical trials have proven that SRS is safe and effective for those with up to four metastases that are no bigger than 3 to 3.5 cm. However, in practice, some radiation oncologists treat more than four metastases and metastases that are larger in size (see clinical trials).

Severe side effects occur in only 1% to 2% of those treated with SRS. They include seizures, edema, hemorrhage and radionecrosis (dead tumor tissue left behind by SRS, which may need to be biopsied to distinguish it from metastasis.) During stereotactic radiosurgery, other systemic treatments do not have to be discontinued. One disadvantage of SRS, compared with regular surgery, is that it is not as fast-acting, taking several weeks for the radiation to start working—i.e., for the tumors to shrink. For that reason, surgery is sometimes necessary to prevent serious brain damage from the pressure of large tumors or swelling within the limited space of the skull. 

After radiosurgery, there are different options: watchful waiting with careful follow-up (imaging every three months to see if the brain metastases have recurred), chemotherapy or immunotherapy, which may prevent new or recurrent brain metastases, or whole-brain radiation. This last option, whole-brain radiation, is used much less than in the past because of its short-term and long-term side effects.


Brain surgery, also called neurosurgery or craniotomy, entails having a neurosurgeon cut into the brain in order to physically remove a brain metastasis and a small margin of surrounding tissue. Despite what people may think, surgical removal has a very low complication rate, with the possibility of infection being the primary problem. A hospital stay of several days to a week is required. In recent years, imaging technology has been developed that makes it possible to view the precise location of the metastasis and surrounding tissue, which allows the neurosurgeon to avoid damaging areas of the brain important for speech, coordination, or memory. Ninety-one percent of patients get almost immediate relief after brain metastases have been surgically removed, in contrast with radiation, which may take several weeks to take effect. However, for the sake of healing, systematic treatments such as chemotherapy must be stopped for a period before, during, and after the surgery, which is often not optimal. There is evidence from randomized controlled trials that surgical removal of a single metastasis extends life more than radiation.

Brain surgery is used for one or two large metastases that need to removed immediately because of potential brain damage or when metastases are two big or too numerous for either of the two types of radiation. Some doctors will remove more than two brain metastases depending on their location. If possible, it is advantageous to remove more than one metastasis en bloc (in one piece) because doing so reduces recurrence rates.

Because of the high rates of recurrence after brain surgery, radiosurgery is now frequently given to the tumor bed either before or after a tumor has been surgically removed, although which strategy is superior has not yet been proven in clinical trials. Only one small study has compared pre- or post-radiosurgery added to surgery for removal of the tumor. This study (Preoperative vs Postoperative Radiosurgery for Resected Brain Metastases: A Review, Neurosurgery, Volume 84, Issue 1 Jan. 2019) showed no difference between the groups at one year for overall survival, cavity recurrence, or distant brain metastasis (other parts of the brain). However, radiosurgery following surgery did significantly lower cumulative incidence of leptomeningeal disease (when breast cancer cells have spread to the fluid around the brain or in the spinal column called the meninges.) More clinical trials are needed in this important area. 

Since radiation destroys brain tissue making biopsy impossible, brain surgery may also be necessary if the diagnosis of brain metastases is uncertain. About 10% of the time, a suspected brain metastasis can turn out to be something else, like a non-cancerous mass, an infection, or a primary brain tumor. Surgery also has the advantage of being able to provide tissue for a biopsy to see if the biology of the brain metastases is different from the primary tumor or other metastases. A tumor in the breast may be ER+ but become HER2+ in the brain. This has been shown to happen about 10%--and possibly more—of the time.


Treatment for HER2-positive brain metastases is in constant flux. This is because newer drugs are being developed at a rapid pace. The newest approved treatments on the market for breast cancer brain metastases are the following combinations: neratinib (Nerlynx) and capecitibine (Xeloda); lapatinib (Tykerb); and capecitabine (Xeloda) and a yet-to-be-approved drug, tucatinib. That being said, older HER2-positive drugs have also shown some efficacy, especially ado-trastuzumab emtansine (Kadcyla, or T-DM1). 

Treatments such as tucatinib and lapatinib (Tykerb) plus capecitibine (Xeloda) are also being used to postpone radiation as long as possible, especially WBRT. Chemotherapy and HER2-positive therapies are also being tried after recurrences of brain metastases following WBRT or stereotactic radiosurgery. Two drugs that have shown efficacy in HER2-positive breast brain metastases are everolimus (Afinitor) and abemaciclib (Verzenio).


 For many years it was thought that the blood brain barrier, which protects the brain from toxic substances, also prevented chemotherapy from getting into the brain. Recently, however, it has been shown that some chemotherapy drugs like capecitibine (Xeloda), carboplatin, cisplatin, the taxanes, anthracyclines, and irinotecan do penetrate the blood-brain barrier to varying degrees. Also, some of these drugs are being reformulated for better penetration of the blood-brain barrier. Two such examples are etirinotecan pegol (Nektar) and ang1005 (paclitaxel trevatide), both of which are in clinical trials. Chemotherapy drugs are also being used prior to and after radiation to prevent recurrences.


Hormonal therapies such as tamoxifen, aromatase inhibitors, Fulvestrant, and Megace have shown to penetrate the blood-brain barrier and shrink estrogen receptor positive brain metastases. The problem with hormonal treatments, however, is that since many brain metastases develop late in the course of metastatic disease, the metastases have already developed resistance to hormonal treatments in the brain as well as in other parts of the body. Therefore, they are generally only effective for those with brain metastases that occur early in metastatic disease.  


Treatments for triple negative brain metastases are primarily the drugs listed in this section under chemotherapy. Etirinotecan pegol which is still in clinical trials appears to be very promising as does enzalutamide (Xtandi), which looks promising for triple negative brain metastases expressing the androgen receptor.


Corticosteroids or steroids are usually the first therapy administered to women with symptomatic brain metastases. However, those whose brain metastases are found by imaging, and who do not yet have any symptoms, may be able to avoid steroid use altogether. Decadon (dexamethasone) is the steroid of choice. It is given in pill form or as an injection to reduce edema or swelling in the brain. The drug 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 divide the doses 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, insomnia, moodiness, acne, osteoporosis, hypertension, swelling of the face, cataracts, osteonecrosis (death of bone cells), impaired wound healing, pneumonia, and diabetes. Physicians can check blood glucose for diabetes and prescribe medicine to prevent pneumonia or gastritis when 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 muscle weakness that can be mistaken for progression of brain metastases triggering more steroid use which only increases the muscle weakness. 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 off gradually.


Anticonvulsants are used for patients who have had or are having seizures. Studies show that taking an anticonvulsant before having seizures does not prevent them. Newer anticonvulsants have fewer side effects than the older ones. They do not make patients as sleepy and have less effect on cognition (understanding). 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. To avoid interaction with systemic treatment like chemotherapy the newer drug, levetiracetam (Keppra), is recommended.