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Leptomeningeal Metastases

Two to five percent of women with metastatic breast cancer experience leptomeningeal metastases (LM). This is also referred to as carcinomatous meningitis. LM occurs when breast cancer spreads to the meninges, which are layers of tissue that cover the brain and the spinal cord. Metastases can spread to the meninges through the blood or they can travel from brain metastases, carried by the cerebrospinal fluid that flows through the meninges.

LM usually occurs at a very late stage in the course of metastatic breast cancer. In very rare instances, it can occur as a first metastasis. Leptomeningeal metastases are difficult to treat, since many drugs are not able to penetrate from the bloodstream through the meninges into the cerebrospinal fluid (CSF, or simply spinal fluid). Often brain metastases and leptomeningeal metastases occur at the same time. For that reason, women diagnosed with leptomeningeal metastases should also have an MRI of the brain.

Symptoms

 Symptoms of leptomeningeal metastases are caused by the pressure that metastases put on the nerves that run across the meninges in both the head and the spine, including those that run from the spinal cord out to the body, and depend on where metastases are located. Symptoms that occur simultaneously in both the head and the spine suggest a diagnosis of LM. Leptomeningeal metastases can also cause hydrocephalus (water on the brain), a condition that occurs when a metastasis interferes with the flow of blood or cerebrospinal fluid. The spinal fluid, which is produced inside the brain, is unable to exit the brain through its normal paths, causing increased pressure in the brain.

Symptoms of leptomeningeal metastases may include:

  • Headache
  • Backache
  • Loss of sensation in the face
  • Mental confusion
  • Dizziness
  • Weakness or loss of sensation in the legs and inner thighs
  • Loss of control of the bladder or bowel
  • Constipation
  • Vision and hearing problems
  • Lethargy
  • Extreme Sleepiness and even loss of consciousness

Diagnosis

Leptomeningeal metastases can be difficult to diagnose. The most common method is by withdrawing spinal fluid with a needle and examining it for breast cancer cells. This procedure is called a spinal tap or lumbar puncture. If the first lumbar puncture comes out negative it must be repeated two more times to assure a 90% chance of an accurate diagnosis. Doing one puncture only assures a 45% accuracy. It is important that the lumbar puncture be close to the site of the suspected area of leptomeningeal metastases. Elevated CSF pressure, white count, and protein levels, and lowered glucose levels can also be signs of LM. An MRI with gadolinium (a contrast agent) of the entire brain and spine can also be used to diagnosis LM and is better than a CT scan.  However, on an MRI, inflammatory disease or local infection can be mistaken for leptomeningeal metastases. An MRI with a radioactive tracer can also be used to locate obstructions in the spinal fluid or blood flow caused by LM. 

Treatment

There is no agreed-upon standard treatment for leptomeningeal metastases. Much of the time, the benefits of treatment are offset by treatment side effects. Especially if there is uncontrollable disease in other organs, treating symptoms of the disease but not the disease itself may be the best option. This may include radiation.

Actual treatment depends on whether leptomeningeal metastases are bulky, with large tumors, or diffuse (small clusters of cancer cells in the spinal fluid). Scans of the entire central nervous system are necessary and if both are present it is important to treat both. Radiation therapy is only given to relieve symptoms in areas of bulky disease because chemotherapeutic agents do not appear to penetrate tumors or nodules (smaller tumors) in the meninges. Chemotherapy is given for diffuse disease and may extend life for several months, or sometimes for a longer time. 

There is no direct evidence that intrathecal chemotherapy, which is introduced directly into the cerebrospinal fluid, is better than intravenous chemotherapy, which is given through the veins. Intrathecal therapy is generally reserved for women whose systemic disease is under reasonable control and who are in good physical condition. Methotrexate is one of the most commonly used chemotherapy agents. It is important to continue to treat metastatic disease in other organs while treating LM.

Intrathecal chemotherapy is usually delivered directly into the cerebrospinal fluid through an Ommaya reservoir, which is a device inserted in the head, under the scalp. The hair where the reservoir will be inserted is shaved and the patient is put to sleep or made very drowsy while the device is being put in place. There may be a small raised area where the Ommaya reservoir is located.  Like a port, the device remains in place during the course of treatment.  It is important to have cerebrospinal flow studies done before intrathecal chemotherapy is undertaken to make sure there are no blockages. Occasionally, doctors will use radiation to relieve flow blockages.

Complications resulting from intrathecal chemotherapy are frequent (infections) and can be serious and even life-threatening. Studies show that response to intrathecal chemotherapy occurs in a small minority of patients, perhaps up to 20%.

However, for women with HER2 + leptomeningeal disease there is increasing and seemingly successful use of intrathecal Herceptin both with chemo and alone. Many of these successes have been reported as case studies, although there is one small trial that was done in Spain with promising results. Several trials are now underway to verify these results in larger numbers of women. (see Clinical Trials Leptomeningeal Disease) In these case studies, low dose (15mg-40mg weekly) and high dose (100mg-150mg weekly) Herceptin have been used. High dose appears not to be toxic and the brain swelling that it causes can be controlled by gradually increasing the dose of Herceptin and using steroids. Intrathecal Herceptin can also be delivered by lumbar puncture to the spine.

In addition,there have also been reports of remissions with capecitabine (Xeloda), tamoxifen, Arimidex, Femara, Aromasin and Megace. While Xeloda is an oral chemotherapy, the other five are hormonal therapies for ER+ leptomeningeal disease. (see Clinical Trials Leptomeningeal Disease).

Long term survivors are at risk for leukoencephalopathy (damage to the white matter of the brain), which can cause lethargy, personality changes, and dementia. It is not known whether the order in which chemotherapy and radiation are given can lower the risk of leukoencephalopathy, although there is some suggestion that giving radiation after chemotherapy may be better than giving it before. It is hoped that the new drugs being developed for brain metastases will also work for leptomeningeal metastases.

For more on leptomeningeal metastases, check out our Selected Bibliography.