Leptomeningeal Disease: When Breast Cancer Metastasize to the Brain
Introduction
When breast cancer cells spread to the brain, it is called as brain metastases or secondary breast cancer. It is also known as metastatic breast cancer, advanced breast cancer, secondary or stage four breast cancer, or secondary tumor. When cancer cells reach the brain, it cannot be cured but can only be treated. The main goal of the treatment is to slow down and control the spread of the cancer cells. Treatment helps in providing the best quality of life to the patient by relieving the symptoms. Thus, breast cancer cells that spread to the brain is not the same as cancer that starts in the brain.
Leptomeningeal Metastases
Almost 2-5 percent of women with breast cancer experience this disease, which is also referred to as carcinomatous meningitis. Leptomeningeal metastases occur when cancer cells from the breast, lung, or any part of the body spread to the tissue layer surrounding the brain and spinal cord. These tumor cells can reach the meninges through the bloodstream or become a part of the CSF that flows through the meninges.
Usually, leptomeningeal metastasis occurs as a late complication of metastatic breast cancer. It is difficult to treat leptomeningeal metastases since many drugs cannot penetrate from the blood into the CSF through the meninges. If a person is diagnosed with leptomeningeal metastases, that person should also get an MRI of the brain since brain metastases and leptomeningeal metastases often occur at the same time
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Symptoms
Leptomeningeal metastases are caused by the pressure exerted by the metastases on the nerves running through the brain and the spinal cord and the nerves that exit the spinal cord. Symptoms also depend on where the metastasis is located. Hydrocephalus is a condition in which water accumulates in the brain. It is also a symptom indicative of leptomeningeal metastases. Other symptoms that suggest leptomeningeal metastases are:
- Headache
- Loss of facial sensations
- Backache
- Dizziness
- Mental confusion
- Loss of sensation in the legs and inner thighs
- Weakness
- Loss of bowel or bladder control
- Constipation
- Lethargy
- Vision problems
- Hearing problems
- Extreme sleepiness
- Loss of consciousness
Clinical Features
Headache is the most common symptom of the disease because tumor cells get infiltrated in the meninges. It can also be due to an elevation of intracranial pressure. The signs that suspect leptomeningeal metastases are new headache syndrome in a cancer patient, a headache that becomes worse upon waking up, or heightened headache that awakens a person from sleep. These are also signs of increased intracranial pressure.
Other symptoms are papilledema and depressed level of consciousness. There is confirmed intracranial pressure in almost 46 percent of people diagnosed with breast cancer and leptomeningeal metastases. Due to the involvement of spinal roots, there is neuropathy or back pain. The period between the diagnosis of initial cancer and for leptomeningeal metastases to occur is longer in case of breast cancer than in other solid tumors.
Diagnosis
The diagnosis is based on the combination of clinical symptoms and presence of malignant cells in the CSF. However, the cytology of CSF is influenced by sample size or delay in processing. Hence, its sensitivity is limited. Repeating it will increase the sensitivity up to 90 percent from 75 percent. It is not easy to diagnose leptomeningeal metastases. The most commonly used methods for examining breast cancer cells are:
- Lumbar Puncture - It is also called as a spinal tap. It is done by withdrawing the CSF with a needle. This procedure should be repeated 2-3 times if it comes out negative in the first instance. It gives a 90 percent accuracy only after three attempts. If it is done only once, it gives an accuracy of 45 percent. The lumbar puncture should be done close to the site of suspected areas of leptomeningeal metastases. Signs of leptomeningeal metastases are increased CSF pressure, raised protein level and white blood cell count, and low glucose levels.
- Magnetic Resonance Imaging (MRI) - It is a type of scan that uses a contrast agent such as gadolinium. An MRI of the entire brain and spine can be done. This is another method for the diagnosis of leptomeningeal metastases. This method is preferred over a CT scan due to its sensitivity. However, the only problem is that if there is an inflammatory disease or local infection, it can be mistaken as leptomeningeal metastases. The obstruction in the CSF flow or blood flow can be located by using a radioactive tracer.
Surgery
There is no standard treatment for leptomeningeal metastases. The benefits also have side effects. It is better to treat the symptoms rather than the disease itself, especially if there is an uncontrolled disease in other organs. One treatment option is radiation. Treatment options also depend on whether the leptomeningeal metastasis is diffuse or bulky with large tumors. If both conditions are present, then it is necessary to treat both.
An entire central nervous system scan should be done. Since chemotherapeutic agents cannot reach the tumors or nodules present in the meninges, radiation therapy is given. If the disease is of diffuse type, then chemotherapy can prolong life by several months or sometimes even longer.
Intrathecal chemotherapy is administered through injections directly into the CSF. However, there has been no evidence that intrathecal chemotherapy is better than intravenous chemotherapy. In women who are in good physical condition and in whose systemic disease is under control, intrathecal chemotherapy can be used. One chemotherapy agent used is methotrexate. Along with treating leptomeningeal metastases, it is also important to treat other organs affected by the metastatic disease.
Intrathecal Chemotherapy
It is usually delivered directly into the CSF through the Ommaya reservoir. An Ommaya reservoir consists of a device, which is inserted under the scalp in the head. That region of the head where the device is inserted is shaved and the patient is made to sleep while putting the device. The area where the Ommaya reservoir is located will be slightly raised.
During the entire course of treatment, the device remains like a port in its place. Before starting intrathecal chemotherapy, it is better to study the CSF to check that there are no blockages. To relieve flow blockages, doctors use radiation. There are frequent complications that arise from intrathecal chemotherapy. These complications can be serious and life-threatening. It is estimated that only 20 percent of the patients actually respond to intrathecal chemotherapy.
There is an increasingly successful use of intrathecal Herceptin both with chemo and alone in women with HER2 + leptomeningeal disease. Promising results were obtained from case studies. Moreover, to verify such results in many women, several case trials are being carried out.
In these studies, low and high doses of Herceptin have been used. It has been found that high doses of Herceptin are not toxic. Brain swelling can also be controlled by gradually increasing the dose along with using steroids. Through lumbar puncture, Herceptin can be intrathecally delivered.
Cases of remission have been reported with the use of Xeloda, tamoxifen, Arimidex, Femara, Megace, and Aromasin. Xeloda is an oral chemotherapy drug and the other five hormonal therapies are for ER+ leptomeningeal disease.
Patients who survive for a long time are at risk of developing leukoencephalopathy, which can cause further changes in personality, lethargy, and dementia. However, there is no evidence whether the order of treatment (chemotherapy and radiation) can lower the risk of leukoencephalopathy. It has been suggested that it is better to give radiation after chemotherapy. It is hoped that drug advancement will not only work for brain metastases, but also for leptomeningeal metastases.
Therapies
The following options can be considered for breast cancer therapy:
- Surgery
- Radiation Therapy
- Chemotherapy
Treatment options depend on the functional status of the individual, response to the treatment, and the extent of active systemic disease. If leptomeningeal metastases are accompanied by a dramatic clinical decline, then the diagnosis of leptomeningeal metastases compels the patients and providers to pursue palliative care.
When doing assessments of the functional status of patients with leptomeningeal metastases, intracranial pressure must be considered. When the arachnoid villi cannot effectively reabsorb CSF, an outflow obstruction of CSF occurs. This case is generally accompanied by headache syndrome and depressed level of consciousness. It has been observed that the functional status of an individual can be improved by relieving the flow of CSF. It can also prolong the survival of the patient.
Ventriculoperitoneal (VP) Shunt
A VP shunt is a medical device used for the treatment of elevated intracranial pressure. However, a VP shunt procedure carries a small risk of infection, hemorrhage, or shunt malfunction. This treatment can be combined with on/off valve, which can facilitate intrathecal chemotherapy administration.
Palliative radiotherapy is also an alternative to relieve CSF for those who do not desire or cannot tolerate a surgical procedure. This palliative treatment is an adjunctive therapy with IT or IV chemotherapy. A short course of palliative RT is used to relieve pain in places where there is nerve root compression. Also, it is generally tolerable by the patient.
In patients with bulky leptomeningeal disease, RT is considered since intrathecal chemotherapy poorly penetrates. The survival of the patient can be improved with high-dose methotrexate IV chemotherapy than radiation alone. Moreover, compared to intrathecal chemotherapy, IV chemo has shown overall survival and improved tolerability. The risk of leukoencephalopathy is lowered by IV chemotherapy and does not cause chemical meningitis. However, methotrexate can cause side effects such as bone marrow suppression, mucositis, and nephrotoxicity.
Such patients need monitoring. This method is an alternative to intrathecal chemotherapy. However, intrathecal chemotherapies have an advantage over IV administration, since it can be given every two weeks in an ambulatory setting. The most commonly administered intrathecal chemotherapeutic agents are liposomal cytarabine, thiotepa, and methotrexate. Since intrathecal chemotherapy is less myelotoxic and can circumvent the challenge of going beyond the blood-brain barrier, it is mechanistically more attractive.
Hence, for those receiving IV chemotherapy for systemic disease and for pretreated individuals, this comes as an attractive option. However, it has its own limitations when it comes to distribution and toxicity. Intrathecal chemotherapy distribution depends on the CSF flow. Before starting intrathecal chemotherapy, it is important to check the CSF flow and the intracranial pressure or else it can lead to toxicity such as ventriculitis/arachnoiditis. Almost in 10-23 percent of cases, this occurs in response to intrathecal chemotherapy. It is also called as non-infectious chemical meningitis. It may cause severe headaches, vomiting, and nausea.
These incidences can be reduced by pretreatment with dexamethasone. Other toxicities include bacterial meningitis with the presence of an intraventricular reservoir and leukoencephalopathy.
Epidemiology
Advanced cancer patients have a long-term survival due to the improvement of systemic therapies. There has been an increased incidence of central nervous system metastases. Aggressive chemotherapy has shown an improvement in patients with breast cancer and advanced diseases. Patients with breast cancer at early stages have a 5 percent risk of developing CNS metastasis. People with breast cancer and CNS metastasis have a median survival period of 9 months. The survival rate is around 20 percent.
Outlook
People with secondary breast cancer usually ask how much time they still have to live their life. Due to advanced treatment after the diagnosis of secondary breast cancer, life can be extended. However, it is difficult to predict how long a person will live as the disease and treatment response in each individual is not the same. Brain metastases have been extensively studied and found to be more common than leptomeningeal metastases.
