Treatments for Brain Metastases

Whole Brain Radiation Therapy

Whole brain radiation therapy (WRBT) is used for the treatment of multiple brain

metastases. This is the most frequently used therapy for breast cancer brain

metastases. In this treatment, 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. 30% to 40% of patients will achieve a complete

reversal of symptoms while 75% to 85% 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.

Immediate side effects 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.

Radiation is given daily Monday thru Friday for ten days to two weeks. Some

doctors will give a lower dose of radiation over a longer period of time to women

who have a good prognosis. 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.

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.

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, this has become a hotly debated question. Unfortunately, there

is no high-quality evidence on this question to help patients decide. 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.

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.

Radiosurgery is the name given to several different technologies including

Gamma Knife, CyberKnife, or XKnife. They are cconsidered to be equally

effective. Since radiosurgery is generally not used for more than three

metastases at a time orcmetastases 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 and 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.

Because radiation takes several weeks to shrink tumors, symptoms caused by

brain metastases are not alleviated immediately. Regular surgery is sometimes

necessary to prevent serious brain damage from the pressure of tumor(s) in

the confined space of the skull. Radionecrosis from radiosurgery can be hard to

distinguish from recurrence. Though it is usually treated with a corticosteroid,

sometimes surgery is necessary. Radiosurgery can be repeated if new brain

metastases appear, and is thought to be as effective, and safer, than regular

surgery for metastases up to three centimeters though no direct evidence exists.

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 preceding section on whole brain

radiation therapy following radiosurgery or surgery.

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 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 if 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-malignant mass, or an infection. 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.

(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.

Chemotheray 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 Therapy

Hormonal therapies such as tamoxifen, letrozole (Femara) and megestrol acetate

(Megace) have been shown to be effective in treating breast cancer brain

metastases. However, the majority of women with brain metastases have

tumors that are estrogen receptor-negative. Those women whose tumors have

been tested as estrogen receptorpositive 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 has changed from the primary tumor.

Corticosteriods

Corticosteroids or steroids are usually the first therapy administered to women

with brain metastases. 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 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. Those

whose brain metastases are found by imaging and who do not yet have any

symptoms can often avoid steroid use completely. 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.