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May 31, 2017 11:43PM
Please forgive me for intruding on this thread. When Kaption mentioned that she would like to see additional information regarding LM, I wanted to take this opportunity to provide the chapter about LM from my complimentary MBC Guide. The 130+ page booklet can be requested by visiting: https://community.breastcancer.org/forum/8/topics/831507?page=3#idx_73
Breast Cancer Brain Metastasis (BCBM) and Leptomeningeal Metastasis (LM), which is also known as Carcinomatous Meningitis, are the two types of Central Nervous System (CNS) metastasis.Symptoms of LM may include headache, backache, loss of sensation in the face (especially the chin), loss of bladder or bowel control, constipation, dizziness, extreme fatigue, confusion, weakness or loss of sensation in the legs and inner thighs, vision problems and/or hearing difficulties.Elevated CerebroSpinal Fluid (CSF) pressure, white blood count, and protein levels, and lowered glucose levels can also be signs of LM.Some patients with LM have no symptoms at all.
CNS metastasis is more common in the following MBC patient populations than in other MBC patients, so these patients should be especially vigilant about reporting any symptoms described above to their doctor:
- Patients who have taken a Taxane-based chemotherapy (Taxane drugs are Taxol, Paclitaxel, or Abraxane)
- Patients with CK-19 mRNA-positive Circulating Tumor Cells (CTCs)
From: http://www.ascopost.com/issues/march-15,-2014/how-to-approach-the-problem-of-cns-metastasis-in-her2-positive-patients.aspx and http://www.cancernetwork.com/oncology-journal/management-breast-cancer-brain-metastases-moving-forward-new-options-are-still-needed and http://breast-cancer-research.com/content/8/4/r36
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 via the cerebrospinal fluid that flows through the meninges.About 2% to 5% of patients with metastatic breast cancer experience LM.
Although LM usually occurs at a later stage in the course of metastatic breast cancer, in very rare instances, it can occur as a first metastasis.LM is difficult to treat because many drugs are not able to penetrate from the bloodstream through the meninges into the cerebrospinal fluid. Often brain metastasis and LM occur at the same time. For that reason, women diagnosed with LM should also have an MRI of the brain.From: http://brainmetsbc.org/en/content/leptomeningeal-metastases-1
LM 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 metastasis.An MRI with gadolinium (a contrast agent) of the entire brain and spine can also be used to diagnosis LM and may be better than a CT scan.An MRI with a radioactive tracer can also be used to locate obstructions in the spinal fluid or blood flow caused by LM.However, on an MRI, inflammatory disease or local infection can sometimes be mistaken for LM.From: http://brainmetsbc.org/en/content/leptomeningeal-metastases-1
Once LM is diagnosed, it is important to check:
- The patient's ER, PR and HER2 status, as this will help to determine potential therapies.
- Whether the disease is bulky or diffuse:
- Bulky Disease: 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. From: http://brainmetsbc.org/en/content/leptomeningeal-metastases-1
- Diffuse Disease: Chemotherapy is given for diffuse disease and may extend life for several months, or sometimes for a longer time. From: http://brainmetsbc.org/en/content/leptomeningeal-metastases-1
- Whether IntraCranial Pressure (ICP) is elevated. If intracranial pressure is elevated, radiation may be a way to relieve CerebroSpinal Fluid (CSF) obstruction if needed. Relief of CSF outflow obstruction has been shown to improve functional status and is likely to prolong survival in these cases.A VentriculoPeritoneal Shunt (VPS) placement procedure can be used, which carries a small risk of hemorrhage, infection, or shunt malfunction.However, placement of a VPS is a definitive treatment for elevated ICP, and may be combined with a reversible on/off valve to facilitate administration of IntraThecal (IT) chemotherapy.For those in whom a surgical procedure is not desired or tolerable, palliative Radiation Therapy is also effective in relieving CSF outflow obstruction, although the duration of benefit is variable.From: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623833/
The information below focuses on medications to treat LM.In addition to drugs, palliative radiotherapy can be used with Intrathecal or intravenous chemotherapy.From:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623833/
Unfortunately, there currently is no agreed-upon standard treatment LM. Sometimes 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.
Drug Delivery options for leptomeningeal metastasis
Depending on the therapy, drug delivery may be provided as follows:
- IntraThecally (IT) directly into the cerebrospinal fluid, usually via an Ommaya reservoir
- Through an IV port
- Intrathecal drugs are 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 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.Intrathecal therapy is generally reserved for patients whose systemic disease is under reasonable control and who are in good physical condition. 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.From: http://brainmetsbc.org/en/content/leptomeningeal-metastases-1
Interestingly, one mbc patient indicated that because her doctor had worked at a Children's Hospital, he was versed in using childrens' ports and provided her with a pediatric Ommaya port, which she said is more comfortable than the adult version.
There is no direct evidence that IntraThecal (IT) chemotherapy, which is introduced directly into the cerebrospinal fluid, is better than intravenous chemotherapy, which is given through the veins. From: http://brainmetsbc.org/en/content/leptomeningeal-metastases-1
- Orally administered medications are usually taken in pill, capsule, or liquid form.
- IV (Intravenous) Ports: The types of chemotherapy "port" devices are listed in the section entitled "Chemotherapy."
treatments for leptomeningeal metastasis
LM drug options are varied, and may include the following drugs. Typically, Cytarabine, Herceptin, Methotrexate and Thiotepa are the most commonly used.
- ANG1005 (Not Yet FDA approved)
- CranioSpinal Irradiation (CSI)
- Cytarabine (DepoCyt)
- Gemzar (Gemcitabine)
- Herceptin, with or without Tykerb
- Hormonal Therapies
- Thiotepa (Thioplex)
- Whole Brain Radiation (WBR)
- Xeloda (Capecitabine)
- ANG1005: This is a Taxol-like drug being studied to treat brain metastases and Leptomeningeal Metastases (LM). Interim Phase 2 study results demonstrate that breast cancer patients with brain metastases treated with ANG1005, including a subset of patients with LM, achieved encouraging responses. Of the 21 heavily pre-treated patients with LM, 5 patients (24%) achieved a partial response and 11 patients (52%) had stable disease. Estimates of survival in patients with LM treated with ANG1005 predict a median survival of 38.4 weeks as compared to 4-6 weeks if left untreated, or 12-24 weeks with conventional chemotherapy. In addition, ANG1005 demonstrated intracranial and extracranial antitumor activity in patients with various other subtypes of breast cancer including patients previously treated with paclitaxel. ANG1005 was shown to be generally safe and well-tolerated, and demonstrated an adverse event profile consistent with conventional taxane therapy.From: http://www.businesswire.com/news/home/20151120005128/en/Angiochem-Reports-Positive-Clinical-Data-ANG1005-Breast
- CranioSpinal Irradiation (CSI): Full CranioSpinal Irradiation to the skull and/or spine may lead to complete or partial response in approximately half of breast cancer patients with leptomeningeal disease, though it is not curative and reports are limited.This therapy can cause significant side effects, so other treatments may be preferable. From: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625760/
- Cytarabine also known as DepoCyt, Cytosar-U, Ara-C, or Cytosine Arabinoside belongs to a group of drugs called anti-metabolites which interfere with cells' ability to make DNA and RNA, which stops the growth of cancer cells.
- Gemzar (Gemcitabine): This is a commonly used chemotherapy drug for MBC which may be helpful in cases of LM. From: http://emedicine.medscape.com/article/1156338-treatment
- Herceptin: For women with HER2 positive LM there is increasing and seemingly successful use of intrathecal Herceptin both with chemotherapy and alone.Many of these successes have been reported as case studies, although one small trial was done in Spain with promising results.Several trials are now underway to verify these results in larger numbers of patients.In these case studies, low dose (15mg-40mg weekly) and high dose (100mg-150mg weekly) Herceptin have been used.High doses appear 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.One woman survived 27 months after LM diagnosis.A complete leptomeningeal response, with no evidence LM at necropsy, was achieved after receiving 67 weekly administrations of intrathecal Herceptin with marked clinical improvement and no adverse events. In some cases, Herceptin may be combined with Tykerb.. From: http://www.ncbi.nlm.nih.gov/pubmed/21369716
- Methotrexate is one of the most commonly used chemotherapy agents for LM. It appears as though IV chemotherapy with high-dose Methotrexate may confer increased survival over radiation therapy alone.From:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3623833/
- Whole Brain Radiation (WBR): As its name indicates, in this therapy, radiation is delivered to the entire brain.One study reported a series of patients with leptomeningeal spread of cancer, of which 46 patients had breast cancer, and 43 underwent WBR. Among the breast cancer patients, there was a 61% "crude" rate of stabilization or improvement of symptoms with WBR.From:http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3625760/
Preservation of Memory with WBR:There is a type of WBR that is a "hippocampus sparing procedure" which may help to preserve a degree of memory that might otherwise be lost as a result of the procedure.In a study of 113 patients, at four months after undergoing the hippocampus sparing procedure, the decline in recall (as compared to baseline) was 7%, significantly better than the 30% cognitive decline in the historical control group that received WBR without thehippocampus sparing procedure.From:http://jco.ascopubs.org/content/early/2014/10/21/JCO.2014.57.2909
- Xeloda (Capecitabine): There have been some reports of remission with this drug.From: http://www.brainmetsbc.org/en/content/leptomeningeal-metastases-1
10/6/2011, IDC, Left, Stage IV, ER+/PR+, HER2-