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Current treatments for brain metastases

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UPDATED MAY 2017

WHOLE BRAIN RADIATION THERAPY (WBRT)

As its name indicates, whole brain radiation therapy (WBRT), delivers a moderate dose of radiation to the entire brain. WBRT has been shown in research studies to extend life. It also improves 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, while about 70% of patients will experience some improvement or stabilization of their symptoms, especially headaches and seizures. However, motor loss (problems with walking, coordination, balance etc.) is less successfully treated with WBRT.

Whole brain radiation is most often used for those who have too many brain metastases to undergo brain surgery or metastases that are too big to be treated with stereotactic radiosurgery (targeted radiation therapy). Although practice varies, generally WBRT is used for those with more than three or four brain metastases that are larger that 3 to 3.5 cms (centimeters). It is also used for women with rapidly advancing metastases elsewhere in their bodies who have a bad prognosis, because it can easily be delivered and long-term loss of cognition is not a concern. Compared to supportive or hospice care alone, WBRT extends survival about 50 days, from to three to six months. It is given daily Monday thru Friday for ten days to two weeks.

The side effects of WBRT fall into three categories: sub-acute, acute, and long term. Sub-acute or short term side effects include memory loss, extreme fatigue, temporary baldness, skin rash, inflammation of the outer ear and hearing loss. These side effects usually last a month or two. Longer-term toxicities that can occur within six months to two years include memory loss, confusion, lack of urinary control and lack of coordination. Dementia is a late-occurring and progressive disease process that usually takes five years to appear though it can occur sooner. A recent study has shown that taking memantine (Namenda), a drug approved for Alzheimer’s disease, during WBRT may protect against cognitive loss. It has been estimated that about 30% to 50% of those who receive WBRT alone will recur within a year.

WBRT is used also as an adjuvant (additional) treatment after surgery or stereotactic radiosurgery. It has been shown to extend life after surgical removal of one brain metastasis from 15 to 40 weeks. For more than one brain metastasis removed by surgery, or after stereotactic radiosurgery, WBRT reduces recurrences of brain metastases but does not extend overall survival. In the first year after surgery WBRT reduces the incidence of brain recurrences from 70% to 18%. Recurrences in the brain after WBRT can be treated with stereotactic radiosurgery, other systemic (whole body) treatments such as chemotherapy or anti-HER2 therapy, or another course of WBRT. Repeating WBRT a second time can extend life for a few months for a select group of patients, particularly those who have had a good response to WBRT the first time and a longer time to recurrence.

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

Stereotactic radiosurgery, sometimes called radiosurgery, is a procedure that aims very high does of radiation (much higher than WBRT) directly at the brain metastases. The rest of the brain is spared radiation exposure which greatly minimizes the short term and long term toxicities that occur with WBRT. It can be delivered in one or several doses. The term radiosurgery is misleading because the procedure does not involve any surgery. Radiation is delivered from outside of the head without cutting into the brain. Stereotactic radiosurgery can be used in areas like the brainstem that are unsafe to cut into. Although there has not been a direct comparison, radiosurgery is thought to be safer and as effective as surgery.

Guidelines restrict radiosurgery to those with no more than three metastases that are no bigger than 3cm. However in practice these guidelines are not strictly adhered to with some doctor allowing a larger number of metastases. Stereotactic radiosurgery is not a substitute for WBRT since the size and number of brain metastases are often too numerous and too big for it to be used.

Severe side effects occur in only 1 to 2% of those treated. These include seizures, edema, hemorrhage, and radionecrosis (dead tumor tissue). During stereotactic radiosurgery (unlike surgery) other systemic treatments do not have to be discontinued. A disadvantage of SRS, compared to regular surgery, is that it is not as fast acting as surgery taking, several weeks for the treatment to start working. For that reason, surgery is sometimes necessary to prevent serious brain damage from the pressure of large tumors or swelling. Unfortunately, stereotactic radiosurgery can cause radionecrosis (dead tumor tissue. While it does not usually cause symptoms it can be hard to distinguish from recurring metastases. Usually radionecrosis is treated with a corticosteroid although sometimes surgery is necessary in order to biopsy the lesion to see if it is radionecrosis or a metastasis.

After radiosurgery there are two possibilities: either watchful waiting with very careful follow up (imaging every 3 months to see if brain metastases have recurred) or WBRT. While WBRT will reduce the chance of recurrence there is evidence that careful follow up and what is called “salvage” WBRT at time of recurrence does not diminish overall survival. Some doctors repeat stereotactic radiosurgery several times for recurrences before going to WBRT. It is not known how many times stereotactic radiosurgery can done safely or what the long term side effects of multiple treatments of stereotactic radiosurgery are.

Whole Brain Radiation Therapy Following Brain Surgery or Radiosurgery (Gamma Knife, CyberKnife, etc.)

Until recently whole brain radiation therapy was routinely given after surgery or stereotactic radiosurgery.  However, in the last several years there has been a shift away from using WBRT after surgery or stereotactic radiosurgery. There are three studies showing that for people with three or four brain metastases which are no larger in size than 3 cm, stereotactic radiosurgery provides a better quality of life, less cognitive loss, and equal overall survival compared to stereotactic radiosurgery followed by WBRT. A recent study has shown that in fact overall survival might be better in those receiving stereotactic radiosurgery without immediate WBRT. But this remains to be confirmed. The downside to leaving out WBRT is that there more recurrences in the brain, about 28% recurrences in the first year and 52% recurrences in the second year.

A recurrence after stereotactic radiosurgery can be treated with WBRT with no difference in overall survival. Some doctors will follow up with stereotactic radiosurgery several times before opting for WBRT. The point of this approach is to avoid as long as possible the reduced quality of life and cognitive loss that can be caused by WBRT.

However, to say overall survival is the same for both stereotactic radiosurgery alone or with WBRT is problematic. Most people with brain metastases die from the damage caused by metastases outside the brain, so that measuring the survival effects of the different radiation treatments tends to be diluted by deaths due to metastases outside the brain. Another problem with these studies is that they include patients with brain metastases caused by other cancers. Most of those enrolled in the three studies mentioned above have lung cancer. Only about 12% of those enrolled have breast cancer. It is assumed that these finding hold for breast cancer patients.

When deciding treatment options, it is very important to consider overall prognosis. Patients with a good prognosis i.e., who have well-controlled metastases outside the brain, are younger than 50, and have a good “performance status” (are not bed-ridden) might make different decisions than someone with uncontrolled metastatic disease outside the brain. Women with HER2+ or ER+ breast cancer tend to live long because their extracranial metastases can be getter controlled. They may want to avoid WBRT as long as possible so as to avoid any long-range effects on cognition and quality of life. On the other hand, repeated recurrences and repeated treatments can also affect quality of life and increase cognitive loss.  

BRAIN SURGERY (CRANIOTOMY)

Brain surgery, also called neurosurgery or craniotomy, entails having a neurosurgeon cut into the brain 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, with infection being the primary issue. 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 to avoid damage to areas of the brain important for speech, coordination, memory, and other functions. Ninety-one percent of patients get relief after brain metastases are removed surgically. The relief is almost immediate, in contrast to radiation which may take several weeks to get results.

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. However, some doctors will surgically remove up to 4 brain metastases depending on location. If possible it is advantageous to remove more than one metastasis en bloc (in one piece) because doing so reduces recurrence rates.

Compared to WBRT alone, surgical resection added to WBRT extended life from 15 weeks to 40 weeks for those with a single metastasis. While there was no survival advantage for those with more than one brain metastasis, there was a reduction of recurrences in the brain. With WBRT added to surgery, local recurrences were reduced in the brain from 70% to18%. Because of the high rate of recurrence, stereotactic radiosurgery is now frequently given to the tumor bed after the tumor has been surgically removed. This strategy has not yet been proven to be effective in clinical trials and concerns about it causing leptomeningeal metastases have been raised. Leptomeningeal metastases occur in the spinal fluid surrounding the brain and the spinal cord. In addition, stereotactic radiosurgery to the tumor bed reduces the risk of local recurrence only at the site of metastasis, not at distant locations in the brain (called distant recurrences).

Brain surgery may be needed if the diagnosis of a brain metastasis is not certain, so that a biopsy can be performed on the tissue. Any kind of prior radiation can burn the tissue, making it impossible to biopsy. About 10% of the time, a suspected brain metastasis can turn out to be something else like a primary brain tumor, a non-cancerous mass, or an infection. Surgery also has the advantage of being able to provide tissue for a biopsy to see if the biology of brain metastases is different from the primary tumor or other metastases in regards to estrogen or HER2 positivity or negativity which occurs in about 10% of the time.

The downside of neurosurgery is that many systemic treatments must be stopped for two weeks during the period of the surgery. In addition there are some locations in the brain that are too dangerous to cut into (such as the part of the brain that controls talking) making radiation a better alternative. 

ANTI-HER2 THERAPY

 Treatment of HER2 positive brain metastases is in constant flux. This is because newer drugs like pertuzumab (Perjeta) and TDM-1 (Kadcyla), which have not been tested directly for Her2+ brain metastases, have shown benefit in trials that have included patients with Her2+ brain metastases. These findings, referred to as subset analyses, are less likely to be accurate. However, many doctors will treat with drugs that show a strong benefit in a subset analysis, especially if no other drugs have a proven benefit.

The combination of two drugs, capecitabine (Xeloda) and lapatinib (Tykerb), have been proven to be effective treatments for Her2+ brain metastases. It is extremely important not to stop treatment with trastuzumab (Herceptin) if it is effectively keeping metastases outside the brain in check because Xeloda and Tykerb are not as effective as Herceptin in controlling metastases outside the brain.

Some doctors are experimenting with treating women whose extracranial disease is well- controlled (usually women with HER2+ disease) with watchful waiting or systemic treatment, putting off radiation for as long as possible. Systemic treatments such as chemotherapy or anti-HER2 therapies are also being tried after recurrence of brain metastases, following WBRT or stereotactic radiosurgery.

CHEMOTHERAPY 

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 Xeloda are able to penetrate into the brain and affect brain metastases. Common breast cancer drugs, such as paclitaxel (Taxol), irinotecan (Camptosar), and Herceptin are being reformulated to see if they too can gain access to the brain. These drugs are now in clinical trials. Other chemotherapy drugs that are showing promise for penetrating the blood brain barrier are eribulin (Halaven), everolimus (Afinitor), and the platinum drugs carboplatin and cisplatin, various brand names. They are being studied for effectiveness especially in triple negative breast cancer. PARP inhibitors are also in trials for triple negative and/or BRCA positive brain metastases.

HORMONAL THERAPY

Hormonal therapies such as tamoxifen and aromatase inhibitors, (Femara, Arimidex, and Aromasin), as well as Fulvestrant and Megace. have shown to be effective in treating breast cancer brain metastases for those with hormonal positive breast cancer. Hormonal drugs are able to penetrate through the blood brain barrier. However, since brain metastases are usually a late development in hormone sensitive disease, resistance to these treatments might have already developed. Drugs in trials such as palbociclib (Ibrance) and abemaciclib for hormone sensitive resistant metastatic breast cancer are now in clinical trials for recurrent brain metastases. Also in trials are chemotherapy drugs such as paclitaxel (Taxol) and irinotecan reformulated into conjugates and liposomes that would be active for ER+ brain metastases.  

CORTICOSTEROIDS

Corticosteroids or steroids are usually the first therapy administered to women with brain metastases who are symptomatic. 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.  Decadron (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 the use of more steroids 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.

ANTI-CONVULSANTS

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.

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